Drug Class Review
Controller Medications for Asthma
Final Update 1 Report
April 2011
The Agency for Healthcare Research and
Quality has not yet seen or approved this report.
The purpose of this report is to make available information regarding the comparative
effectiveness and safety profiles of different drugs within pharmaceutical classes. Reports are
not usage guidelines, nor should they be read as an endorsement of, or recommendation for,
any particular drug, use or approach. Oregon Health & Science University does not recommend
or endorse any guideline or recommendation developed by users of these reports.
Original Report: November 2008
Daniel E. Jonas, MD, MPH
Roberta C. M. Wines, MPH
Marcy DelMonte, PharmD, BCPS
Halle R. Amick, MSPH
Tania M. Wilkins, MS
Brett D. Einerson, MPH
Christine L. Schuler, MD
Blake A. Wynia, MPH
Betsy Bryant Shilliday, Pharm.D., CDE, CPP
Produced by
RTI-UNC Evidence-based Practice Center
Cecil G. Sheps Center for Health Services Research
University of North Carolina at Chapel Hill
725 Martin Luther King Jr. Blvd, CB# 7590
Chapel Hill, NC 27599-7590
Tim Carey, M.D., M.P.H., Director
Oregon Evidence-based Practice Center
Oregon Health & Science University
Mark Helfand, MD, MPH, Director
Copyright © 2011 by Oregon Health & Science University
Portland, Oregon 97239. All rights reserved.
Final Update 1 Report
Drug Effectiveness Review Project
The medical literature relating to this topic is scanned periodically. (See
http://www.ohsu.edu/xd/research/centers-institutes/evidence-based-policycenter/derp/documents/methods.cfm for description of scanning process). Prior versions of
this report can be accessed at the DERP website.
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STRUCTURED ABSTRACT
Purpose
To compare the efficacy and safety of inhaled corticosteroids (ICSs), long-acting beta-2 agonists
(LABAs), leukotriene modifiers (LMs), anti-IgE therapy, combination products, and tiotropium
for people with persistent asthma.
Data Sources
To identify published studies, we searched MEDLINE, The Cochrane Library, Embase,
International Pharmaceutical Abstracts, and reference lists of included studies through
September 2010. We also requested dossiers of information from pharmaceutical manufacturers.
Review Methods
Study selection, data abstraction, validity assessment, grading the strength of the evidence, and
data synthesis were all carried out according to standard Drug Effectiveness Review Project
methods.
Results
Efficacy studies provide moderate strength of evidence (SOE) that equipotent doses of ICSs
administered through comparable delivery devices do not differ in their ability to control asthma
symptoms, prevent exacerbations, reduce the need for additional rescue medication, or in their
overall incidence of adverse events or withdrawals due to adverse events. Evidence does not
support a difference between montelukast and zafirlukast in their ability to decrease rescue
medicine use or improve quality of life (low SOE for ≥12 years of age, insufficient <12),
between formoterol and salmeterol in their ability to control symptoms, prevent exacerbations,
improve quality of life, or cause harms among patients not controlled on ICSs alone (moderate
SOE), or between budesonide/formoterol and fluticasone/salmeterol for efficacy or harms when
each combination is administered via a single inhaler (moderate SOE for ≥12, insufficient <12).
Meta-analyses and efficacy studies provide consistent evidence favoring omalizumab over
placebo for most included outcomes. Omalizumab-treated patients have an increased incidence
of injection site reactions and anaphylaxis compared to placebo-treated patients.
We found consistent evidence of greater benefit for subjects treated with ICS
monotherapy compared with those treated with LM monotherapy (high SOE). Direct evidence
suggests no difference in tolerability or overall adverse events between ICSs and LMs (moderate
SOE). Specific adverse events reported with ICSs, such as cataracts and decreased growth
velocity, were not found among patients taking LMs. The best longer-term evidence on growth
(avg 4.3 years) for ICSs compared with placebo found that very small differences (1.1 cm)
occurred primarily during the first year of treatment, suggesting that the effect on growth
velocity occurs early in treatment and is not progressive. Evidence is insufficient to determine if
long-term treatment with ICSs leads to a reduction in final adult height. Overall evidence
indicates that ICSs and leukotriene receptor antagonists (LTRAs) are safer than LABAs for use
as monotherapy (high SOE). Indirect evidence suggests that the potential increased risk of
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asthma-related death for those taking LABAs may be confined to patients not taking ICSs at
baseline.
We did not find sufficient evidence to support the routine use of combination therapy
rather than an ICS alone as first line therapy (moderate SOE for ≥12, insufficient <12). Results
from large trials support greater efficacy with the addition of a LABA to an ICS than with a
higher dose ICS (high SOE for ≥12, low <12) and greater efficacy with the addition of a LABA
to an ICS over continuing the current dose of ICS alone for poorly controlled persistent asthma
(high SOE). The addition of LMs to ICSs compared to continuing the same dose of ICSs resulted
in improvement in rescue medicine use and no statistically significant differences in other health
outcomes (low SOE for ≥12, insufficient <12). There is no apparent difference in symptoms,
exacerbations, rescue medicine use, overall adverse events, or withdrawals due to adverse events
between those treated with ICSs plus LTRAs compared to those treated with increasing the dose
of ICSs (moderate SOE for ≥12, low <12). Results provide strong evidence that the addition of a
LABA to ICS therapy (ICS+LABA) is more efficacious than the addition of an LTRA to ICS
therapy (ICS+LTRA) (high SOE for ≥12, low <12). We found no difference in overall adverse
events or withdrawals due to adverse events between ICS+LABA and ICS+LTRA (moderate
SOE for ≥12, insufficient <12).
Conclusion
Overall findings do not suggest that one medication within any of the classes evaluated is
significantly more effective or harmful than the other medications within the same class, with the
exception of zileuton being more harmful than the other LMs. Our results support the general
clinical practice of starting initial treatment for persistent asthma with an ICS. For people with
poorly controlled persistent asthma taking an ICS, our findings suggest that the addition of a
LABA is most likely to provide the greatest benefit as the next step in treatment.
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TABLE OF CONTENTS
INTRODUCTION .......................................................................................................................... 9
Purpose and Limitations of Evidence Reports........................................................................................ 18
Scope and Key Questions ...................................................................................................................... 20
Inclusion Criteria ..................................................................................................................................... 20
METHODS .................................................................................................................................. 21
Literature Search .................................................................................................................................... 21
Study Selection ....................................................................................................................................... 22
Data Abstraction ..................................................................................................................................... 23
Validity Assessment (Quality Assessment) ............................................................................................ 24
Data Synthesis ........................................................................................................................................ 24
Grading the Strength of Evidence........................................................................................................... 25
RESULTS ................................................................................................................................... 26
Overview ................................................................................................................................................. 26
Key Question 1. Efficacy and Effectiveness ........................................................................................... 28
I. Intra-class comparisons (within one class)...................................................................................... 28
A. Inhaled Corticosteroids .............................................................................................................. 28
B. Leukotriene Modifiers ................................................................................................................ 52
C. Long-Acting Beta-2 Agonists (LABAs) ...................................................................................... 53
D. Anti-IgE Therapy........................................................................................................................ 56
E. Combination Products ............................................................................................................... 62
F. Long-Acting Anticholinergics ..................................................................................................... 74
II. Inter-class comparisons (between classes) ................................................................................... 74
A. Monotherapy .............................................................................................................................. 74
B. Combination therapy.................................................................................................................. 96
Key Question 2. Adverse Events .......................................................................................................... 145
I. Intra-class Evidence (within one class) ......................................................................................... 145
A. Inhaled Corticosteroids ............................................................................................................ 145
B. Leukotriene Modifiers .............................................................................................................. 153
C. Long-Acting Beta-2 Agonists (LABAs) .................................................................................... 154
D. Anti-IgE Therapy...................................................................................................................... 158
E. Combination Products ICS+LABA compared with ICS+LABA ................................................ 159
II. Inter-class comparisons (between classes) ................................................................................. 163
A. Monotherapy ............................................................................................................................ 163
B. Combination therapy................................................................................................................ 165
Key Question 3. .................................................................................................................................... 171
Summary of findings ......................................................................................................................... 171
Detailed assessment ........................................................................................................................ 171
I. Demographics ........................................................................................................................... 171
II. Comorbidities ........................................................................................................................... 173
III. Other medications ................................................................................................................... 173
IV. Smoking status ....................................................................................................................... 174
V. Pregnancy................................................................................................................................ 174
VI. Genetics .................................................................................................................................. 175
SUMMARY ............................................................................................................................... 177
Strength of Evidence (SOE) ................................................................................................................. 177
Limitations of this Report ...................................................................................................................... 179
Applicability ........................................................................................................................................... 179
Studies Currently Being Conducted ..................................................................................................... 180
CONCLUSIONS ....................................................................................................................... 188
REFERENCES ......................................................................................................................... 189
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TABLES
Table 1. Classification of asthma ............................................................................................................... 9
Table 2. Long-term controller medication class, trade names, manufacturers, formulations, and
indications ................................................................................................................................................. 11
Table 3. Estimated comparative daily dosages for inhaled corticosteroids ............................................. 16
Table 4. Outcome measures and study eligibility criteria ......................................................................... 21
Table 5. Study inclusion criteria ............................................................................................................... 22
Table 6. Definitions of the grades of overall strength of evidence ........................................................... 25
Table 7. Characteristics of head-to-head studies comparing inhaled corticosteroids in children and
adults ........................................................................................................................................................ 37
Table 8. Characteristics of head-to-head studies comparing inhaled corticosteroids that included
children ..................................................................................................................................................... 49
Table 9. Characteristics of head-to-head studies comparing leukotriene modifiers in children and
adults ........................................................................................................................................................ 53
Table 10. Characteristics of head-to-head studies comparing LABAs in children and adults ................. 55
Table 11. Characteristics of head-to-head studies comparing omalizumab with placebo in children and
adults ........................................................................................................................................................ 59
Table 12. Characteristics of head-to-head studies comparing ICS+LABA with ICS+LABA .................... 66
Table 13. Characteristics of head-to-head studies comparing BUD/FM for maintenance and relief
(MART) with ICS/LABA for maintenance and Short-Acting Beta-Agonist (SABA) for relief .................... 72
Table 14. Characteristics of head-to-head studies comparing ICSs with LTRAs in children and adults . 79
Table 15. Characteristics of head to head studies comparing ICSs with LTRAs in children < 12 ........... 84
Table 16. Characteristics of head-to-head studies comparing ICSs with LABAs .................................... 90
Table 17. Characteristics of head-to-head studies comparing leukotriene modifiers with LABAs for
monotherapy ............................................................................................................................................. 95
Table 18. Characteristics of head-to-head studies comparing ICS+LABA with ICS alone as first line
therapy in children and adults .................................................................................................................. 99
Table 19. Characteristics of head-to-head studies comparing ICS+LABA (in one or separate inhalers)
with higher dose ICS .............................................................................................................................. 107
Table 20. Characteristics of head-to-head studies comparing ICS+LABA compared with same dose
ICS .......................................................................................................................................................... 119
Table 21. Characteristics of head-to-head studies comparing ICS + LTRA with ICS ............................ 131
Table 22. Characteristics of head-to-head studies comparing ICS+LABA with leukotriene modifiers .. 136
Table 23. Characteristics of head-to-head studies comparing ICS+LABA with ICS+leukotriene
modifiers ................................................................................................................................................. 141
Table 24. Characteristics of head-to-head studies comparing ICS+LABA with LTRA+LABA ............... 144
Table 25. Summary of studies on bone density or fractures .................................................................. 147
Table 26. Summary of studies on growth retardation ............................................................................ 149
Table 27. Summary of studies on posterior subcapsular cataracts ....................................................... 151
Table 28. Summary of studies on ocular hypertension or open-angle glaucoma .................................. 152
Table 29. Tolerability and frequency of adverse events results from systematic reviews comparing
ICS+LABA with ICS+LABA..................................................................................................................... 161
Table 30. Summary of studies evaluating subgroups of patients for whom asthma controller medications
may differ in efficacy or frequency of adverse events ............................................................................ 176
Table 31. Summary of the evidence by key question for controller medications for the treatment of
persistent asthma in adolescents/adults ≥ 12 years of age and children < 12 years of age.................. 180
FIGURES
Figure 1. Results of Literature Search...................................................................................................... 27
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APPENDIXES
Appendix A. Glossary ............................................................................................................................. 210
Appendix B. Abbreviations ..................................................................................................................... 216
Appendix C. Boxed warnings ................................................................................................................. 218
Appendix D. Labeled and delivered doses ............................................................................................. 224
Appendix E. Search strategies ............................................................................................................... 225
Appendix F. Studies of poor quality........................................................................................................ 232
Appendix G. Excluded studies at full-text level ...................................................................................... 236
Appendix H. Strength of evidence ......................................................................................................... 244
Appendix I. Meta-analyses ..................................................................................................................... 260
Appendix J. Tolerability and overall adverse events of ICSs ................................................................. 342
Appendix K. Tolerability and overall adverse events of LABAs ............................................................. 363
EVIDENCE TABLES
Published in two separate documents: Original Report Evidence Tables and Update Report Evidence
Tables. References throughout this report identify the respective documents as Evidence Tables A or B.
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Suggested citation
Jonas DE, Wines R, DelMonte M, Amick H, Wilkins T, Einerson B, Schuler CL, Wynia BA,
Bryant Shilliday B. Drug class review: Controller medications for asthma. Final update 1 report.
http://derp.ohsu.edu/about/final-document-display.cfm
Acknowledgements
We extend our greatest appreciation to Katie Kiser, Pharm D., BCPS, Laura C. Morgan, MA,
Patricia Thieda Keener, MA, and Daniel Reuland, MD, MPH for their expertise and contributions
toward creating the original controller medications for asthma report. We also thank Irvin Mayers,
MD, FRCPC, University of Alberta and Allan Luskin, MD, University of Wisconsin who served
as clinical advisors and provided their thoughtful advice and input during the research process for the
original report. Finally, we thank Claire Baker, Shannon Brode, Elizabeth Harden, and Megan Van
Noord for their invaluable assistance with data abstraction, literature searches, and data entry.
Funding
The Drug Effectiveness Review Project, composed of 12 organizations including 11 state
Medicaid agencies, and the Canadian Agency for Drugs and Technology in Health
commissioned and funded for this report. These organizations selected the topic of the report and
had input into its Key Questions. The content and conclusions of the report were entirely
determined by the Evidence-based Practice Center researchers. The authors of this report have no
financial interest in any company that makes or distributes the products reviewed in this report.
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INTRODUCTION
Asthma is a chronic lung disease characterized by reversible airway obstruction, inflammation,
and increased airway responsiveness. As a result of inflammation, individuals with asthma may
experience symptoms such as wheezing, difficulty breathing, or coughing. The airway
obstruction which occurs with asthma is generally reversible spontaneously or with treatment.
Asthma is thought to have a genetic, inheritable component, often begins early in life, and
consists of variable symptoms regardless of asthma classification.1 The Expert Panel of the
National Asthma Education and Prevention Program (NAEPP) recently reclassified asthma
categories; the mild intermittent category was eliminated (now called intermittent) and the
persistent category was subdivided into mild, moderate, or severe.1 The change was partly done
to acknowledge that exacerbations can be severe in any asthma category. Table 1 lists the criteria
used to classify asthma severity.
Table 1. Classification of asthma1
Intermittent
Daytime
symptoms
Nighttime
symptoms
Short-Acting
Beta-2 Ag o n is t
use
Interference
with daily
activity
FEV1
%
predicted
FEV1/FVC
≤2
days/week
≤2
nights/month
≤ 2 days/week
None
> 80%
Normal
> 2/week but
< 1/day
3-4
nights/month
> 2 days/week
Minor
≥ 80%
Normal
Daily
> 1 night/week
but < 1/night
Daily
Some
> 60% - <
80%
Reduced
5%
Continual
Frequent
Several times
daily
Extreme
≤ 60%
Reduced >
5%
Persistent
Mild
Moderate
Severe
Asthma outcomes have improved over the past several years but the burden remains
substantial. Asthma is estimated to affect 300 million individuals worldwide with 22 million of
those individuals being in the US.2-4 It is the cause of 250,000 worldwide deaths annually with
4,000 of them in the US.2-4 The World Health Organization estimates 15 million disabilityadjusted life years (DALYs) lost annually due to asthma.2 Based on 2007 data, asthma accounts
for 19.7 billion dollars annually in the US with 14.7 billion in direct, 5 billion in indirect, and 6.2
billion in prescription cost. In 2005, there were 488,594 hospital discharges in the US, 12.8
physician office visits, 1.3 million hospital outpatient department visits, and 1.8 million
emergency department visits due to asthma in the United States.4
Many current medications available to treat persistent asthma target the inflammatory
process caused by multiple inflammatory cells and mediators including lymphocytes, mast cells,
eosinophils, among others.1 There are currently two categories of medications used in asthma
treatment: controller medications and quick relief (or rescue) medications. Although all patients
with persistent asthma should have a short-acting relief medication on hand for treatment of
exacerbations and a controller medication for long-term control, this report will focus on the
following currently available controller medications: inhaled corticosteroids (ICSs), Long-Acting
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Beta-2 Agonists (LABAs), leukotriene modifiers, anti-IgE medications, and combination
products.
Inhaled corticosteroids are the preferred agents for long-term control of persistent asthma
according to expert panel recommendations.1 The inhaled route of administration serves to
directly target the inflammation while minimizing systemic effects which can result from oral
administration. These agents act via anti-inflammatory mechanisms and have been approved as
first line therapy for asthma control in all stages of persistent asthma.1 The 7 ICSs currently
available include: beclomethasone dipropionate, budesonide, ciclesonide, flunisolide, fluticasone
propionate, mometasone furoate, and triamcinolone acetonide. Table 2 lists the trade names,
manufacturers, available formulations, and age indications for controller medications for
persistent asthma. Although it is not approved for the treatment of asthma and thus is not
included in Table 2, tiotropium (Spiriva®) was included in this report to determine if there is any
published evidence for its use in people with asthma. Dulera (mometasone/formoterol), now
approved for treatment of asthma in people >12 years, is not included in this report because it
was approved after our cutoff date for the inclusion of new medications.
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Table 2. Long-term controller medication class, trade names, manufacturers, formulations, and indications1, 5-10
Medication class
Generic name
Trade name
Budesonide
Inhaled
corticosteroids
Ciclesonide
Ivax
HFA
Vanceril®b
Schering
MDI
42 mcg/puff
84 mcg/puff
Pulmicort
Flexhaler®c
AstraZeneca
DPI
90 mcg/dose
180 mcg/dose
Approved indication
in US and Canada
Asthma (age ≥ 5)
Asthma (age ≥ 5)
Asthma (age ≥ 6)
Pulmicort
®a
Turbuhaler
AstraZeneca
DPI
100 mcg/dose
200 mcg/dose
400 mcg/dose
Pulmicort
®c
Respules
AstraZeneca
Inhalation
suspension
0.25 mg/2ml
0.5 mg/2ml
1 mg/2ml
Pulmicort
®a
Nebuamp
AstraZeneca
(Canada)
Inhalation
suspension
0.125 mg/ml
0.25 mg/ml
0.5 mg/ml
Asthma (age ≥ 3
months)
Sunovion (US)
Nycomed Canada Inc
(Canada)
HFA-MDI
80 mcg/puff
160 mcg/puff
100 mcg/dosea
200 mcg/dosea
Asthma (age ≥ 12)
Forest
MDI
MDI-menthol
250 mcg/puff
Asthma (age ≥ 6)
AeroSpan
Acton
HFA
80 mcg/puff
Bronalide®b
Boehringer
Ingleheim (Canada)
MDI
250 mcg/puff
®d
Alvesco
®c
®e
Asthma (age 1-8)
Asthma (age ≥ 4)
Flovent® HFA
GlaxoSmithKline
HFA
44 mcg/puff
a
50 mcg/puff
110 mcg/puff
125 mcg/puffa
220 mcg/puff
250 mcg/puffa
Flovent
®b
Rotadisk
GlaxoSmithKline
DPI
50 mcg/dose
100 mcg/dose
250 mcg/dose
Asthma (age ≥ 12)
Flovent Diskus®
GlaxoSmithKline
DPI
50 mcg/dose
Asthma (age ≥ 4 yrs)
Fluticasone
propionate
Controller medications for asthma
Strength
QVAR
AeroBid
®c
AeroBid-M
Flunisolide
Dosage
form/device
40 mcg/puff
50 mcg/puffa
80 mcg/puff
100 mcg/puffa
®
Beclomethasone
dipropionate
Manufacturer
Asthma (age ≥ 4)
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Table 2. Long-term controller medication class, trade names, manufacturers, formulations, and indications1, 5-10
Medication class
Generic name
Trade name
Manufacturer
Dosage
form/device
Strength
Approved indication
in US and Canada
100 mcg/dose
250 mcg/dose
500 mcg/dosea
Leukotriene
modifiers
Leukotriene
receptor
antagonists
Asmanex
Twisthaler®c
Schering
DPI
110 mcg/dose
220 mcg/dose
Triamcinolone
acetonide
Azmacort®b
Abbot
MDI – with spacer
mouthpiece
75 mcg/dose
Montelukast
Singulair®
Merck
Tablets
Chewable tablets
Granules
10 mg
4 mg, 5 mg
4 mg/packet
Zafirlukast
Accolate®
AstraZeneca
Tablets
10 mg
20 mg
Zileuton
Zyflo
®c
Zyflo CR
Critical Therapeutics
Tablets
Extended release
tablets
600 mg
600 mg
Arformoterol
Brovana®c
Sunovion
Inhalation solution
15 mcg/2ml
Foradil Aerolizer®c
Schering
DPI
12 mcg/capsule
Asthma (age ≥ 5 yrs)
Foradil®a
Novartis
Pharmaceuticals
Canada Inc.
DPI
12 mcg/capsule
Asthma (age > 6 yrs)
Oxeze
Turbuhaler®a
AstraZeneca (Canada)
DPI
6 mcg/capsule
12 mcg/capsule
Asthma (age ≥ 6 yrs)
Oxis Turbohaler®f
Astra Pharmaceuticals
DPI
6 mcg/puff
12 mcg/puff
Asthma (age ≥ 6 yrs)
Serevent Diskus®
GlaxoSmithKline
DPI
50 mcg/blister
Asthma (age ≥ 4 yrs)
Salmeterol xinafoate
Serevent
Diskhaler®a
GlaxoSmithKline
DPI
50 mcg/blister
Asthma (age ≥ 4 yrs)
Omalizumab
Xolair®
Genentech (US)
Novartis
Pharmaceuticals Inc
(Canada)
Powder for
subcutaneous
injection
202.5 mg
(delivers 150
mg/1.2ml)
c
®c
5-lipoxygenase
Inhibitor
Long-Acting Beta2 Agonists
Anti-IgE
medications
Asthma (age ≥ 4)
Mometasone furoate
Formoterol fumarate/
Eformoterol
Controller medications for asthma
Asthma (age ≥ 6)
Asthma (age ≥ 1)
Asthma (age ≥ 5 yrs in
US); (age ≥ 12 yrs in
Canada)
Asthma (age ≥ 12 yrs)
Not approved for
asthma (COPD only)
Asthma (age ≥ 12 yrs)
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Table 2. Long-term controller medication class, trade names, manufacturers, formulations, and indications1, 5-10
Medication class
Generic name
Fluticasone
propionate/
Salmeterol xinafoate
Combination
productsg
Budesonide/
Formoterol
Dosage
form/device
Strength
Approved indication
in US and Canada
Trade name
Manufacturer
Advair Diskus®
GlaxoSmith
Kline
DPI
100mcg/50mcg
250mcg/50mcg
500mcg/50mcg
Asthma (age ≥ 4 yrs)
Advair HFA®c
GlaxoSmith
Kline
HFA
45mcg/21mcg
115mcg/21mcg
230mcg/21mcg
Asthma (age ≥ 12 yrs)
Advair®a
GlaxoSmith
Kline
HFA
50 mcg/25 mcg
125mcg/25mcg
250mcg/25mcg
Asthma (age ≥ 12 yrs)
Symbicort®c
AstraZeneca
HFA
80mcg/4.5mcg
160mcg/4.5mcg
Asthma (age ≥ 12 yrs)
Symbicort
Turbuhaler®a
AstraZeneca (Canada)
DPI
100mcg/6mcg
200mcg/6mcg
Asthma (age ≥ 12 yrs)
Symbicort Forte
®a
Turbuhaler
AstraZeneca (Canada)
DPI
400mcg/12/cg
Asthma (age > 12 yrs)
Abbreviations: DPI = dry powder inhaler; HFA = hydrofluoroalkane propellant; MDI = metered dose inhaler.
Note: Unless otherwise noted, the products are available in both the US and Canada
a
This product is available in Canada only.
b
This product has been discontinued by the manufacturer.
c
This product is available in the US only.
d
The FDA approved dosing regimen for ciclesonide is twice daily.
e
This product is not yet available.
f
This product is not available in the US or Canada.
®
®
g
Dulera (Zenhale in Canada) (mometasone furoate/formoterol fumarate), now approved for treatment of asthma in people >12 years, is not included in this report because it was
approved after our cutoff date for the inclusion of new medication.
.
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Inhaled corticosteroids are delivered through a variety of devices including metered dose
inhalers (MDIs), dry powder inhalers (DPIs), or nebulizers. In the past, MDI products contained
chlorofluorocarbons (CFCs) which were found to be detrimental to the ozone and have now been
banned from use. They were replaced with alternative administration devices including
hydrofluoroalkane propellant (HFA) MDIs and dry powder inhalers. The ICSs often have
different kinetic and side effect profiles with similar numerical doses depending on the delivery
device and the product.1 Since there are not enough head-to-head trials comparing all of the
various ICSs, determining equivalency among products is sometimes difficult. Table 3 lists
comparative dosing of the available products based on the recently updated NAEPP guidelines.1
Long-Acting Beta-2 Agonists (LABAs) are agents used in combination with ICSs to
obtain control in persistent asthma. The mechanism of action of these agents is through
relaxation of airway smooth muscles to reverse bronchoconstriction.1, 5 In contrast to short-acting
beta-2 agonists, which are used for quick relief of acute symptoms due to their quick onset and
short-duration of action, LABAs provide long-acting bronchodilation for 12 hours allowing for
twice daily administration.1 The NAEPP expert panel advocates the use of LABAs as the
preferred adjunct therapy with ICSs in individuals ≥ 12 years old for persistent asthma.1 In
addition, LABAs are useful in the prevention of exercise-induced bronchospasm (EIB).1, 5 These
agents are not recommended nor approved for relief of acute asthma symptoms or for use as
monotherapy for persistent asthma.1 Currently there are two available LABAs: formoterol
(formerly known as eformoterol in the UK) and salmeterol. Arformoterol is available in the US
but is currently approved only for COPD (Table 2). The main clinical difference in the two
available agents is that formoterol has a quicker onset of action than salmeterol.1
The leukotriene modifiers are another class of controller medications used in the
treatment of asthma and are comprised of two classes of medications: leukotriene receptor
antagonists (montelukast and zafirlukast) and 5-lipoxygenase inhibitors (zileuton) (Table 2).
Leukotrienes cause contraction of smooth muscles, mucous secretion, and inflammation
contributing to asthma symptoms.1, 5 The leukotriene receptor antagonists (LTRAs) bind to cell
receptors to prevent these actions from occurring.1 Montelukast is approved for children ≥ 1 year
old and zafirlukast for children ≥ 5 years old in the United States and ≥ 12 years old in Canada.
They are approved for mild persistent asthma and as adjunct therapy with ICSs.1, 5 Montelukast
is also approved for EIB.5 The leukotriene modifiers are the only medications delivered orally in
pill-form, rather than as inhalers, for the treatment of persistent asthma.
Zileuton’s mechanism of action is through the inhibition of 5-lipoxygenase which is
involved in the production of leukotrienes.1 This medication is indicated for use in children ≥ 12
years old.1, 5 Metabolism of this drug is through the CYP 450 1A2, 2C9, and 3A4 isoenzymes
which are responsible for a variety of drug-drug interactions.5 In addition, liver function
monitoring is required with zileuton therapy,1, 5 due to the involvement of the CYP 450 system
and potential adverse events, which has limited the use of this product.
The newest class of asthma control medications is the anti-IgE medication class, which
currently consist of one agent, omalizumab (Table 2). This agent binds to IgE receptors on mast
cells and basophils to decrease sputum production and asthma symptoms.1 Omalizumab is
approved for use in patients ≥ 12 years old who have uncontrolled asthma on inhaled
corticosteroids.1, 5 This agent is an injectable medication (given every two to four weeks)
approved for adjunct therapy with ICSs in moderate to severe persistent asthma as well as for
adjunct therapy with high dose ICSs plus LABA in severe persistent asthma.1
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Lastly, the combination controller medications available for the treatment of asthma include
fluticasone/salmeterol (FP/SM) and budesonide/formoterol (BUD/FM) (Table 2). These
medications are both combinations of an ICS and a LABA and are indicated for use in those
patients requiring two agents for control.1, 5 These combination products can be used when
monotherapy with ICS is not adequate or when disease severity warrants treatment with two
controller medications. These agents are available as DPI or HFA products (Table 2).
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Table 3. Estimated comparative daily dosages for inhaled corticosteroids1, 11
Low daily dose
Drug
Child
0-4 yrs
Beclomethasone CFC
Child
5-11 yrs
Medium daily dose
≥12yrs
& adults
Child
0-4 yrs
Child
5-11 yrs
High Daily Dose
≥12yrs
& adults
Child
0-4 yrs
Child
5-11 yrs
≥12yrs
& Adults
84-336 mcg
168-504 mcg
336-672 mcg
504-840 mcg
> 672 mcg
> 840 mcg/d
42 mcg/puff
2-8 puffs/d
4-12 puffs/d
8-16 puffs/d
13-20 puffs/d
> 16 puffs/d
> 20 puffs/d
84 mcg/puff
1-4 puffs/d
2-6 puffs/d
4-8 puffs/d
7-10 puffs/d
> 8 puffs/d
> 10 puffs/d
80-160mcg
80-240mcg
> 320 mcg
> 480 mcg
40 mcg/puff
2-4 puffs/d
2-6 puffs/d
4-8 puffs/d
6-12 puffs/d
> 8 puffs/d
> 12 puffs/d
80 mcg/puff
1-2 puffs/d
1-3 puffs/d
2-4 puffs/d
3-6 puffs/d
> 4 puffs/d
> 6 puffs/d
400-800 mcg
400-1200 mcg
> 1600 mcg
> 2400mcg
2-4 puffs/d
2-6 puffs/d
> 8 puffs/d
> 12 puffs/d
180-400 mcg
180-600 mcg
> 800 mcg
> 1200 mcg
90 mcg/dose
2-4 puffs/d
2-6 puffs/d
4-8 puffs/d
6-13 puffs/d
> 8 puffs/d
> 13 puffs/d
180 mcg/dose
1-2 puffs/d
1-3 puffs/d
2-4 puffs/d
3-6 puffs/d
> 4 puffs/d
> 6 puffs/d
180-400 mcg
180-600 mcg
> 800 mcg
> 1200 mcg
1-2 puffs/d
1-3 puffs/d
> 4 puffs/d
> 6 puffs/d
Beclomethasone HFA
Budesonide CFC
†
200 mcg/dose
Budesonide DPI (Flexhaler)
Budesonide DPI
(Turbuhaler)
200 mcg/dose
Budesonide suspension
(Respules)
> 160-320 mcg > 240-480 mcg
800-1600 mcg 1200-2400 mcg
4-8 puffs/d
6-12 puffs/d
> 400-800 mcg > 600-1200 mcg
> 400-800 mcg > 600-1200 mcg
2-4 puffs/d
3-6 puffs/d
0.25-0.5mg
0.5mg
> 0.5-1mg
1mg
> 1mg
2mg
0.25 mg/2ml inhalation
2-4 ml/d
4 ml/d
4-8 ml/d
8 ml/d
> 8 ml/d
16 ml/d
0.5mg/2ml inhalation
1-2ml/d
2ml/d
2-4ml/d
4ml/d
> 4ml/d
1 mg/2ml inhalation
0.5-1ml/d
1ml/d
1-2ml/d
2 ml/d
Ciclesonide
a
> 2 ml/d
4 ml/d
80-160 mcg
>160-320 mcg
>320 mcg/d
80mcg/puff
2 puffs/d
2-4 puffs/d
4-16 puffs/d
160mcg/puff
NA
2 puffs/d
2-8 puffs/d
500-750 mcg
500-1000 mcg
1000-1250 mcg
>1000-2000
mcg
> 1250 mcg
> 2000 mcg
250 mcg/puff
2-3 puffs/d
2-4 puffs/d
4-5 puffs/d
4-8 puffs/d
> 5 puffs/d
> 8 puffs/d
Flunisolide HFA
160 mcg
320 mcg
320mcg
> 320-640 mcg
≥ 640 mcg
> 640 mcg
2 puffs/d
4 puffs/d
4 puffs/d
4-8 puffs/d
> 8 puffs/d
> 8 puffs/d
Flunisolide
80 mcg/puff
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Table 3. Estimated comparative daily dosages for inhaled corticosteroids1, 11
Low daily dose
Medium daily dose
≥12yrs
& adults
Child
0-4 yrs
Child
5-11 yrs
Fluticasone MDI
176 mcg
88-176 mcg
88-264 mcg
44 mcg/puff
4 puffs/d
2-4 puffs/d
2-6 puffs/d
6-15 puffs/d
4-10 puffs/d
110 mcg/puff
1 puff/d
1 puff/d
1-2 puffs/d
2-6 puffs/d
1-4 puffs/d
220 mcg/puff
NA
NA
1 puff/d
1-3 puffs/d
1-2 puffs/d
100-200 mcg
100-300 mcg
50 mcg/dose DPI
2-4 puffs/d
2-6 puffs/d
4-8 puffs/d
100 mcg/dose DPI
1-2 puffs/d
1-3 puffs/d
2-4 puffs/d
250 mcg/dose DPI
NA
1 puff/d
1 puff/d
Drug
Fluticasone DPI
(Rotadisk; Diskus)
Mometasone DPI
(Asmanex Twisthaler)
100 mcg
Child
0-4 yrs
Child
5-11 yrs
High Daily Dose
≥12yrs
& adults
≥12yrs
& Adults
Child
0-4 yrs
Child
5-11 yrs
> 352 mcg
> 352 mcg
> 440 mcg
6-10 puffs/d
> 8 puffs/d
> 8 puffs/d
> 10 puffs/d
2-4 puffs/d
> 4 puffs/d
> 4 puffs/d
> 4 puffs/d
1-2 puffs/d
> 1 puffs/d
> 1 puffs/d
> 2 puffs/d
> 400 mcg
> 500 mcg
6-10 puffs/d
> 8 puffs/d
> 10 puffs/d
3-5 puffs/d
> 4 puffs/d
> 5 puffs/d
1-2 puffs/d
> 1 puff/d
> 2 puffs/d
> 176-352 mcg > 176-352 mcg > 264-440 mcg
> 200-400 mcg > 300-500 mcg
200 mcg
400 mcg
> 400 mcg
110 mcg/dose
(delivers 100mcg/dose)
1 puff/d
2 puff/d
4 puff/d
> 4 puffs/d
220 mcg/dose
(delivers 200mcg/dose)
NA
1 puff/d
2 puffs/d
> 2 puffs/d
300-600 mcg
300-750 mcg
4-8 puffs/d
4-10 puffs/d
Triamcinolone MDI
75 mcg/puff
> 600-900 mcg > 750-1500 mcg
8-12 puffs/d
10-20 puffs/d
> 900 mcg
> 1500 mcg
> 12 puffs/d
> 20 puffs/d
12
Abbreviations: HFA = Hydrofluoroalkane propellant; MDI = Metered dose inhaler; DPI = Dry powder inhaler; estimated dosing equivalency from Thorsson et al. and Agertoft &
13
Pedersen; CFC = Contains chlorofluorocarbons; substances known to destroy ozone in the upper atmosphere.
a
FDA approved labeling for ciclesonide: Initial treatment for patients on prior therapy with bronchodilators alone: 80 mcg twice daily (for a total of 160mcg/day, considered low dose;
maximum dose 320 mcg/day). Initial treatment for patients with prior therapy with inhaled corticosteroids: 80 mcg twice daily (maximum dose: 640 mcg/day). For patients with prior
therapy with oral corticosteroids: 320 mcg twice daily (maximum dose: 640 mcg/day). Canadian labeling: Initial: 400 mcg once daily; maintenance: 100-800 mcg/day (1-2 puffs once or
twice daily)
.
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Purpose and Limitations of Evidence Reports
Systematic reviews, or evidence reports, are the building blocks underlying evidence-based
practice. An evidence report focuses attention on the strength and limits of evidence from
published studies about the effectiveness of a clinical intervention. The development of an
evidence report begins with a careful formulation of the problem. The goal is to select questions
that are important to patients and clinicians, then to examine how well the scientific literature
answers those questions. Terms commonly used, such as statistical terms, are provided in
Appendix A and are defined as they apply to reports produced by the Drug Effectiveness Review
Project. Topic-specific abbreviations used in this report are presented in Appendix B.
An evidence report emphasizes the patient’s perspective in the choice of outcome
measures. Studies that measure health outcomes (events or conditions that the patient can feel,
such as quality of life, functional status, and fractures) are emphasized over studies of
intermediate outcomes (such as changes in bone density). Such a report also emphasizes
measures that are easily interpreted in a clinical context. Specifically, measures of absolute risk
or the probability of disease are preferred to measures such as relative risk. The difference in
absolute risk between interventions is dependent on the numbers of events in both groups, such
that the difference (absolute risk reduction) is smaller when there are fewer events. In contrast,
the difference in relative risk is fairly constant across groups with different baseline risk for the
event, such that the difference (relative risk reduction) is similar across these groups. Relative
risk reduction is often more impressive than the absolute risk reduction. Another measure useful
in applying the results of a study is the number needed to treat (or harm), the NNT (or NNH).
The NNT represents the number of patients who would have to be treated with an intervention
for 1 additional patient to benefit (experience a positive outcome or avoid a negative outcome).
The absolute risk reduction is used to calculate the NNT.
An evidence report also emphasizes the quality of the evidence, giving more weight to
studies that meet high methodological standards that reduce the likelihood of biased results. In
general, for questions about the relative benefits of a drug, the results of well-done, randomized
controlled trials are regarded as better evidence than results of cohort, case-control, or crosssectional studies. In turn, these studies are considered better evidence than uncontrolled trials or
case series. For questions about tolerability and harms, controlled trials typically provide limited
information. For these questions, observational study designs may provide important information
that is not available from trials. Within this hierarchy, cohort designs are preferred when well
conducted and assessing a relatively common outcome. Case control studies are preferred only
when the outcome measure is rare, and the study is well conducted.
An evidence report pays particular attention to the generalizability of efficacy studies
performed in controlled or academic settings. Efficacy studies provide the best information about
how a drug performs in a controlled setting that allows for better control over potential
confounding factors and bias. However, the results of efficacy studies are not always applicable
to many, or to most patients seen in everyday practice. This is because most efficacy studies use
strict eligibility criteria that may exclude patients based on their age, sex, medication
compliance, or severity of illness. For many drug classes, including antipsychotics, unstable or
severely impaired patients are often excluded from trials. Often, efficacy studies also exclude
patients who have comorbid diseases, meaning diseases other than the one under study. Efficacy
studies may also use dosing regimens and follow-up protocols that may be impractical in other
practice settings. They often restrict options, such as combining therapies or switching drugs that
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are of value in actual practice. They often examine the short-term effects of drugs that in practice
are used for much longer periods of time. Finally, efficacy studies tend to use objective measures
of effects that do not capture all of the benefits and harms of a drug or do not reflect the
outcomes that are most important to patients and their families.
An evidence report also highlights studies that reflect actual clinical effectiveness in
unselected patients and community practice settings. Effectiveness studies conducted in primary
care or office-based settings use less stringent eligibility criteria, assess health outcomes, and
have longer follow-up periods than most efficacy studies. The results of effectiveness studies are
more applicable to the “average” patient than results from highly selected populations in efficacy
studies. Examples of effectiveness outcomes include quality of life, hospitalizations, and the
ability to work or function in social activities. These outcomes are more important to patients,
family, and care providers than surrogate or intermediate measures such as scores based on
psychometric scales.
Efficacy and effectiveness studies overlap. For example, a study might use very narrow
inclusion criteria like an efficacy study, but, like an effectiveness study, might examine flexible
dosing regimens, have a long follow-up period, and measure quality of life and functional
outcomes. For this report we sought evidence about outcomes that are important to patients and
would normally be considered appropriate for an effectiveness study. However, many of the
studies that reported these outcomes were short-term and used strict inclusion criteria to select
eligible patients. For these reasons, it is neither possible nor desirable to exclude evidence based
on these characteristics. Labeling each study as an efficacy or effectiveness study, while
convenient, is of limited value; it is more useful to consider whether the patient population,
interventions, time frame, and outcomes are relevant to one’s practice, or, in the clinical setting,
how relevant they are to a particular patient.
Studies across the continuum from efficacy to effectiveness can be useful in comparing
the clinical value of different drugs. Effectiveness studies are more applicable to practice, but
efficacy studies are a useful scientific standard to determine whether the characteristics of
different drugs are related to their effects on disease. An evidence report reviews the efficacy
data thoroughly to ensure that decision-makers can assess the scope, quality, and relevance of the
available data. This thoroughness is not intended to obscure the fact that efficacy data, no matter
how much there is of it, may have limited applicability to practice. Clinicians can judge the
relevance of the study results to their practice and should note where there are gaps in the
available scientific information.
Unfortunately, for many drugs, there are few or no effectiveness studies and many
efficacy studies. As a result, clinicians must make decisions about treatment for many patients
who would not have been included in controlled trials and for whom the effectiveness and
tolerability of the different drugs are uncertain. An evidence report indicates whether or not there
is evidence that drugs differ in their effects in various subgroups of patients, but it does not
attempt to set a standard for how results of controlled trials should be applied to patients who
would not have been eligible for them. With or without an evidence report, these are decisions
that must be informed by clinical judgment.
In the context of developing recommendations for practice, evidence reports are useful
because they define the strengths and limits of the evidence, clarifying whether assertions about
the value of the intervention are based on strong evidence from clinical studies. By themselves,
they do not tell you what to do. Judgment, reasoning, and applying one’s values under conditions
of uncertainty must also play a role in decision making. Users of an evidence report must also
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keep in mind that not proven does not mean proven not; that is, if the evidence supporting an
assertion is insufficient, it does not mean the assertion is not true. The quality of the evidence on
effectiveness is a key component, but not the only component, in making decisions about clinical
policies. Additional criteria include acceptability to physicians or patients, the potential for
unrecognized harms, the applicability of the evidence to practice, and consideration of equity and
justice.
Scope and Key Questions
The purpose of this review is to assist healthcare providers, researchers and policy makers in
making clinical decisions, creating formularies, and developing policies regarding long-term
asthma control medications based on the most current available literature. We compare the
efficacy, effectiveness, and tolerability of controller medications used in the treatment of
persistent asthma as well as look for subgroups that may differ in these areas. The Research
Triangle Institute International-University of North Carolina Evidence-based Practice Center
(RTI-UNC EPC) wrote preliminary key questions, identifying the populations, interventions, and
outcomes of interest, and based on these, the eligibility criteria for studies. These were reviewed
and revised by representatives of organizations participating in the Drug Effectiveness Review
Project (DERP) along with the RTI-UNC EPC, after considering comments received from the
public which derived from a draft version posted to the DERP web site. The participating
organizations of DERP are responsible for ensuring that the scope of the review reflects the
populations, drugs, and outcome measures of interest to both clinicians and patients. The
participating organizations approved the following key questions to guide this review:
1. What is the comparative efficacy and effectiveness of controller medications used to treat
outpatients with persistent asthma?
2. What is the comparative tolerability and frequency of adverse events for controller
medications used to treat outpatients with persistent asthma?
3. Are there subgroups of these patients based on demographics (age, racial groups, gender),
asthma severity, comorbidities (drug-disease interactions, including obesity), other
medications (drug-drug interactions), smoking status, genetics, or pregnancy for which
asthma controller medications differ in efficacy, effectiveness, or frequency of adverse
events?
Inclusion Criteria
This review includes pediatric or adult outpatients with persistent asthma being treated with any
of the following agents: inhaled corticosteroids (beclomethasone, budesonide, ciclesonide,
flunisolide, fluticasone propionate, triamcinolone, mometasone), Long-Acting Beta-2 Agonists
(formoterol, arformoterol, salmeterol), leukotriene modifiers (montelukast, zafirlukast, zileuton),
anti-IgE therapy (omalizumab), combination products (fluticasone propionate/salmeterol
xinafoate, budesonide/formoterol), or tiotropium. For efficacy and effectiveness outcomes of
interest we included randomized controlled trials of at least 6 weeks duration and a sample size
of at least 40 which evaluate control of symptoms, functional capacity and quality of life, urgent
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care services, adherence, hospitalization, or mortality. For adverse events outcomes, we also
included observational studies of at least 6 months duration and a sample size of at least 100
(Table 4). Further details related to inclusion criteria are provided below in the Methods section
under Study Selection. Boxed warnings associated with these products are provided in Appendix
C. Dosing equivalency of the agents was based on the 2007 NAEPP Expert Panel publication.1A
comparison of labeled and delivered doses for inhalers is provided in Appendix D.
Table 4. Outcome measures and study eligibility criteria
Outcome
Outcome measures
•
Efficacy /
Effectiveness
•
•
•
•
•
•
•
•
•
•
Adverse
Events/Safety
Asthma control
- Asthma exacerbations
- Days/nights frequency of symptoms
- Frequency of rescue medication use
- Courses of oral steroids
Quality of life
Ability to participate in work, school, sports, or
physical activity
Adherence
Emergency department / urgent medical care
visits
Hospitalization
Mortality
Overall adverse events reported
Withdrawals due to adverse events
Serious adverse events
Specific adverse events including:
- Growth
- Bone mineral density
- Osteoporosis/fractures
- Ocular toxicity
- Suppression of HPA axis
- Anaphylaxis
- Death
Study eligibility criteria
•
•
•
•
•
Randomized controlled clinical trials
of at least 6 weeks duration and n ≥
40 or quality systematic reviews
When sufficient evidence was not
available for head-to-head trials within
a specific diagnostic group we
evaluated placebo-controlled trials
Randomized controlled clinical trials
of at least 6 weeks duration and n ≥
40
Observational studies of at least 6
months duration and n ≥ 100
When sufficient evidence was not
available for head-to-head trials within
a specific diagnostic group, we
evaluated placebo-controlled trials
METHODS
Literature Search
To identify relevant citations, we searched MEDLINE®, the Cochrane Database of Systematic
Reviews®, the Cochrane Central Register of Controlled Trials®, and the International
Pharmaceutical Abstracts (through September 2010), using terms for included drugs, indications,
and study designs (see Appendix E for complete search strategies). We limited the electronic
searches to “human” and “English language.” We attempted to identify additional studies
through hand searches of reference lists of included studies and reviews. In addition, we searched
the FDA’s Center for Drug Evaluation and Research (CDER) and Center for Biologics
Evaluation and Research (CBER), the Canadian Agency for Drugs and Technology in Health,
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and the National Institute for Health and Clinical Excellence web sites for medical and statistical
reviews, and technology assessments. Finally, we searched dossiers submitted by pharmaceutical
companies for the current review. All citations were imported into an electronic database
(Endnote® v. X.02).
Study Selection
All citations were reviewed for inclusion using the criteria shown in Table 5. Two reviewers
independently assessed titles and abstracts, where available, of citations identified from literature
searches. If both reviewers agreed that the trial did not meet eligibility criteria, it was excluded.
Full-text articles of potentially relevant citations were retrieved and again were assessed for
inclusion by two reviewers. Disagreements were resolved by consensus. Results published only
in abstract form and unpublished data were not included unless adequate details were available
for quality assessment.
Table 5. Study inclusion criteria
Populations
• Adult or pediatric outpatients with persistent asthma
• Persistent asthma is defined using the NAEPP classification1 (see Table 1)
Interventions/Treatments
Inhaled corticosteroids:
• Beclomethasone
• Budesonide
• Ciclesonide
• Flunisolide
• Fluticasone propionate
• Triamcinolone
• Mometasone
Long-Acting Beta-2 Agonists (LABAs)
• Formoterol
• Arformoterol
• Salmeterol
Leukotriene modifiers
• Montelukast
• Zafirlukast
• Zileuton
Anti-IgE therapy
• Omalizumab
Combination products
• Fluticasone propionate/Salmeterol xinafoate
• Budesonide/formoterol
Long-Acting Anticholinergics
• Tiotropium
Efficacy and effectiveness outcomes
• Control of symptoms (e.g., days/nights/frequency of symptoms, rate of asthma exacerbations, frequency of rescue
medication use, courses of oral steroids)
• Functional capacity and quality of life (missed school and missed work days, ability to participate in
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Table 5. Study inclusion criteria
•
•
•
•
work/school/sports/physical activity, activity limitation, improved sleep/sleep disruption)
Urgent care services (Emergency department visits/urgent medical care visits)
Adherence
Hospitalization
Mortality
Adverse events/safety outcomes
•
•
•
•
Overall adverse events
Withdrawals due to adverse events
Serious adverse events (e.g., acute adrenal crisis, fractures, mortality)
Specific adverse events (e.g. growth suppression, bone mineral density/osteoporosis, ocular toxicity, suppression
of the HPA axis, tachycardia, anaphylaxis, death)
Study designs
• For efficacy and effectiveness, randomized controlled trials of at least 6 weeks duration (N ≥ 40) and good-quality
systematic reviews
• For adverse events/safety, randomized controlled trials of at least 6 weeks (N ≥ 40) and observational studies of at
least 6 months duration (N ≥ 100)
We reviewed the literature using a hierarchy of evidence approach, where the best
evidence is the focus of our synthesis for each question, population, intervention and outcome
addressed. Results from well-conducted, systematic reviews and head-to-head trials provide the
strongest evidence to compare drugs with respect to effectiveness, efficacy, and adverse events;
head-to-head trials were defined as those comparing one included treatment of interest (those
listed in Table 5) with another treatment of interest. If sufficient evidence was available from
head-to-head trials we did not examine placebo-controlled trials for general
efficacy/effectiveness. If no head-to-head evidence was published, as was the case for
omalizumab, we reviewed placebo-controlled trials. We did not include studies that compare
step-down therapy for people with stable asthma, different doses of the same medication, or
different delivery devices with the same medication unless there was another eligible comparator
arm. We did not include studies evaluating adjustable dosing strategies.
A review was considered to be systematic if it presented a systematic approach to
reviewing the literature through a comprehensive search strategy, provided adequate data from
included studies, and evaluated the methods of included studies (with quality review/critical
appraisal).
Data Abstraction
We designed and used a structured data abstraction form to ensure consistency in appraisal for
each study. Trained reviewers abstracted data from each study. A second reviewer read each
abstracted article and evaluated the accuracy and completeness of the data abstraction. We
abstracted the following data from included trials: study design, population characteristics
(including age, sex, asthma severity, smoking status), inclusion and exclusion criteria,
interventions (drugs, dose, delivery device, duration), comparisons, numbers enrolled, additional
medications allowed, outcome assessments, attrition, withdrawals attributed to adverse events,
results, and adverse events reported. We recorded intention-to-treat (ITT) results if available.
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Validity Assessment (Quality Assessment)
Two independent reviewers assigned quality ratings; they resolved any disagreements by
discussion or by consulting a third, senior reviewer. We assessed the internal validity (quality) of
trials based on the predefined criteria (see www.ohsu.edu/drugeffectiveness). These criteria are
based on the U.S. Preventive Services Task Force and the National Health Service Centre for
Reviews and Dissemination (U.K.) criteria.14, 15
Elements of internal validity assessment for trials included, among others, the methods
used for randomization, allocation concealment, and blinding; the similarity of compared groups
at baseline; maintenance of comparable groups; adequate reporting of dropouts, crossover,
adherence, and contamination; overall and differential loss to follow-up; and the use of intentionto-treat analysis.
We assessed observational study designs based on the potential for selection bias
(methods of selection of subjects and loss to follow-up), potential for measurement bias
(equality, validity, and reliability of ascertainment of outcomes), and control for potential
confounders.
Systematic reviews which fulfilled inclusion criteria were rated for quality using
predefined criteria (www.ohsu.edu/drugeffectiveness): a clear statement of the questions and
inclusion criteria; adequacy of the search strategy; quality assessment of individual trials; the
adequacy of information provided; and appropriateness of the methods of synthesis.
Studies that had a fatal flaw were rated “poor quality” and were not included in the
evidence report. Trials that met all criteria were rated “good quality”. The remainder received a
quality rating of “fair”. This includes studies that presumably fulfilled all quality criteria but did
not report their methodologies to an extent that answered all our questions. As the fair-quality
category is broad, studies with this rating vary in their strengths and weaknesses: the results of
some fair-quality studies are likely to be valid, while others are only probably valid. A poorquality trial is not valid—the results are at least as likely to reflect flaws in the study design as
the true difference between the compared drugs. A fatal flaw is reflected by failing to meet
combinations of items of the quality assessment checklist.
Attrition, or loss to follow-up, was defined as the number of persons randomized who did
not reach the endpoint of the study,16 independent of the reason and the use of intention-to-treat
analysis. We adopted no formal cut-off point for loss to follow-up because many studies defined
withdrawals due to acute worsening of the disease as an outcomes measure.
Data Synthesis
We constructed evidence tables showing the study characteristics, quality ratings, and results for
all included studies. Trials that evaluated one included medication against another provided
direct evidence of comparative effectiveness and adverse event rates. These data are the primary
focus. In theory, trials that make comparisons with other drug classes or placebos can also
provide evidence about effectiveness. This is known as an indirect comparison and can be
difficult to interpret for a number of reasons, primarily issues of heterogeneity between trial
populations, interventions, and assessment of outcomes. Data from indirect comparisons are used
to support direct comparisons, where they exist, and are also used as the primary comparison
where no direct comparisons exist. Such indirect comparisons should be interpreted with caution.
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In addition to discussion of the findings of the studies overall, quantitative analyses were
conducted using meta-analyses on outcomes for which a sufficient number of studies reported
and for studies which they were homogeneous enough such that combining their results can be
justified. Otherwise, the data are summarized qualitatively. Random effects models were used
for the estimation of pooled effects.17 Forest plots are presented to graphically summarize the
study results and the pooled results.18 The Q-statistic and the I2 statistic (the proportion of
variation in study estimates due to heterogeneity) were calculated to assess heterogeneity
between the effects from the studies.19, 20 Potential sources of heterogeneity were examined with
subgroup analysis by factors such as study design, study quality, variations in interventions, and
patient population characteristics. Meta-analyses were conducted using Comprehensive Meta
Analysis V2.exe.
Grading the Strength of Evidence
We graded strength of evidence using a modified GRADE approach that included assessment of
the following domains: design, quality, consistency, directness, and magnitude of effect of the
set of studies relevant to the question. We also considered other domains that may be relevant
for some scenarios, such as equipotency (for inhaled corticosteroids), a dose-response
association, strength of association (magnitude of effect), and publication bias.
Table 6 describes the grades of evidence that can be assigned. Grades reflect the strength
of the body of evidence to answer key questions on the comparative effectiveness, efficacy, and
harms of the drugs included in this review. Grades do not refer to the general efficacy or
effectiveness of pharmaceuticals. Two reviewers assessed each domain for each comparison and
differences were resolved by consensus.
We graded the strength of evidence for the outcomes deemed to be of greatest importance
to decision makers and those most commonly reported in the literature. These included
improvement in symptoms, exacerbations, rescue medication use, growth, overall adverse
events, and asthma-related death. Because of time and resource constraints we did not grade the
strength of evidence for every possible outcome reported everywhere in the included literature.
Table 6. Definitions of the grades of overall strength of evidence21
Grade
Definition
High
High confidence that the evidence reflects the true effect. Further research is very unlikely to
change our confidence in the estimate of effect.
Moderate
Moderate confidence that the evidence reflects the true effect. Further research may change our
confidence in the estimate of the effect and may change the estimate.
Low
Low confidence that the evidence reflects the true effect. Further research is likely to change our
confidence in the estimate of the effect and is likely to change the estimate.
Insufficient
Evidence either is unavailable or does not permit estimation of an effect.
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RESULTS
Overview
We identified 3,745 citations from database searches and reviewing reference lists, with 960 new
citations for Update 1. We identified 32 additional references (9 in the original report, 23 for
Update 1) from dossiers submitted by pharmaceutical companies and 5 from public comments.
The total number of citations in our database was 3,782. In total we included 289 articles: 36
systematic reviews with meta-analyses, 211 articles for randomized controlled trials 12 articles
for observational studies, and one study of other design. Thirty of the included studies were rated
poor quality.(Appendix F) We retrieved 108 articles for background information.
Reasons for exclusions were based on eligibility or quality criteria (Figure 1). Studies
excluded from the update report at the full text level are listed in Appendix G. A complete list of
the placebo-controlled trials that were not included in the report will be provided upon request.
Requests should be directed to the Center for Evidence-based Policy at Oregon Health & Science
University (www.ohsu.edu/drugeffectiveness).
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Figure 1. Results of Literature Search
Titles and abstracts
identified through
searches:
N = 3782 (997)a
Citations excluded:
N = 2415 (691)
Abstracts
only:
N=8
Full text articles excluded:
N = 769 (218)
•
•
•
•
Full-text articles
retrieved:
N = 1359 (306)
•
•
•
Background articles:
N = 108 (1)
6 (2) Not published in English
108 (24) Wrong outcomes
18 (2) Drug not included
60 (33) Population not
included
173 (43) Wrong publication
type
280 (95) Wrong study design
124 (19) Wrong comparison
Placebo articles
not included in
analysis:
N = 193 (20)
Articles included in drug class review:
N = 289 (67)
•
•
•
•
a
211 (45) randomized controlled trials
36 (16) on systematic reviews or metaanalyses
12 (2) on observational studies
1 on studies of other design
Poor quality:
N = 30 (4)
Numbers in parentheses are new for Update 1.
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Key Question 1. Efficacy and Effectiveness
What is the comparative efficacy and effectiveness of controller medications used to
treat outpatients with persistent asthma?
I. Intra-class comparisons (within one class)
A. Inhaled Corticosteroids
Summary of findings
We found 3 systematic reviews with meta-analyses22-24 and 48 head-to-head RCTs (47
publications)25-71 (Table 7). Seven of the head-to-head RCTs included children < 12 (Table 8).31,
34, 44, 46, 62, 68, 69
No study was characterized as an effectiveness trial; all included efficacy studies
were conducted in narrowly defined populations and/or were limited to less than one year of
follow-up.
Overall, efficacy studies provide moderate evidence that ICSs do not differ in
their ability to control asthma symptoms, prevent exacerbations, and reduce the need for
additional rescue medication at equipotent doses administered through comparable delivery
devices (Appendix H, Table H-1). Relatively few studies reported exacerbations, healthcare
utilization (hospitalizations, emergency visits), or quality of life outcomes. Long-term data
beyond 12 weeks is lacking for most of the comparisons. In children, head-to-head trials support
the conclusion that ICSs do not differ in their impact on health outcomes, but data was only
available for 5 comparisons (3 systematic reviews and 7 RCTs): beclomethasone compared with
budesonide, beclomethasone compared with fluticasone, budesonide compared with ciclesonide,
budesonide compared with fluticasone, and ciclesonide compared with fluticasone. We
conducted meta-analyses for comparisons within this section when sufficient data were available
and a recent meta-analysis was not already published. There were often too few trials comparing
equipotent ICS doses reporting similar outcomes measures to allow quantitative synthesis.
Detailed Assessment
Description of Studies
Of the included studies (Table 7), one systematic review with meta-analysis and two RCTs
compared beclomethasone with budesonide; two systematic reviews with meta-analyses and
eleven RCTs compared beclomethasone with fluticasone; two RCTs compared beclomethasone
with mometasone; two RCTs compared beclomethasone with triamcinolone; five RCTs
compared budesonide with ciclesonide; one RCT compared budesonide with flunisolide; one
meta-analysis and eight RCTs compared budesonide with fluticasone; two RCTs compared
budesonide with mometasone; one RCT compared budesonide with triamcinolone; eight RCTs
compared ciclesonide with fluticasone; one RCT compared flunisolide with fluticasone; three
RCTs compared fluticasone with mometasone; three RCTs compared fluticasone with
triamcinolone.
Based on National Asthma Education and Prevention Program equipotent dose estimates
(Table 3), 36 head-to-head RCTs (75%) included equipotent comparisons for some arms (seven
of these had multiple arms, with both equipotent and non-equipotent comparisons)36, 38, 39, 43, 48, 52,
59
and 12 RCTs (25%) compared only non-equipotent doses.43, 45, 46, 49, 51, 54, 55, 58, 60, 66 Of the 36
head-to-head trials that compared equivalent doses, 10 compared high dose to high dose, 16
compared medium dose to medium dose, 10 compared low dose to low dose. The most
commonly used delivery devices were MDIs and DPIs; 19 studies (40%) compared MDI to
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MDI; 12 studies (25%) compared DPI to DPI; 15 studies (31%) compared MDI to DPI; one
study (2%) compared both MDI to MDI and MDI to DPI;36 one study (2%) compared both DPI
to DPI and MDI to DPI.27
Study Populations
The 48 head-to-head RCTs included a total of 19,071 patients. Most studies were conducted in
adult populations. Seven studies31, 34, 44, 46, 62, 68, 69 were conducted primarily in pediatric
populations. Ten studies (21%) were conducted in the United States, 15 (31%) in Europe, one in
Canada, one in Japan, and 19 (40%) were other multinational combinations often including
Europe, Canada, or the US. Asthma severity ranged from mild persistent to severe persistent:
nine studies (19%) were conducted in patients with mild to moderate persistent asthma, nine
(19%) in patients with mild to severe persistent asthma, 11 (23%) in patients with moderate
persistent asthma, eight (17%) in patients with moderate to severe persistent asthma, and five
(10%) in patients with severe persistent asthma. Six studies did not report the severity or it was
unable to be determined.
Smoking status was not reported for 15 studies (31%), including six studies in pediatric
populations. Among the others, 16 studies (33%) excluded individuals with a recent or current
history of smoking and 17 (35%) allowed participants to smoke. Among the studies that allowed
and reported smoking status, 2% to 34% of participants were current smokers.
Other asthma medications were often allowed if maintained at a constant dose; all trials
allowed the use of a short-acting beta-agonist. Most trials enrolled patients who were currently
being treated with ICS.
Methodologic Quality
The overall quality of the head-to-head trials included in our review was rated fair to good. Most
trials received a quality rating of fair. The method of randomization and allocation concealment
was rarely reported.
Sponsorship
Of the 48 head-to-head trials, 40 (83%) were funded by pharmaceutical companies; 4 trials (8%)
did not report the source of funding but at least one author had a primary affiliation with a
pharmaceutical company, and 4 studies (8%) did not report funding sources.
Head-to-head comparisons
1. Beclomethasone compared with budesonide
One good systematic review22 and two fair head-to-head RCTs27, 28 comparing beclomethasone
(BDP) to budesonide (BUD) met our inclusion criteria.
The systematic review22 compared included 24 studies (1174 subjects); 18 of these were
in adults. Twelve studies (50%) had treatment periods of between two and four weeks, 10 studies
(42%) had treatment periods of between six and 12 weeks. The longest study had an effective
treatment period of two years. As an inclusion criterion for the review, all studies had to assess
equal nominal daily doses of BDP and BUD. Results were distinguished by whether patients
were not treated with regular oral corticosteroids (OCS) (20 studies) or were dependent on
regular OCS. They further divided studies by parallel and crossover designs. The majority of
crossover trials had significant design flaws, so the results should be viewed with caution.
For asthma patients not treated with OCS, crossover studies showed no significant
difference between treatments for symptom measures (variety of symptom scores reported) or
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rescue medication use. There was no significant difference between BDP and BUD for daytime
breathlessness, morning breathlessness, and daily symptom scores (6 studies, 256 subjects;
standardized mean difference (SMD 0.06, 95% CI: -0.18, 0.31). Nor was there a significant
difference in night-time breathlessness and evening breathlessness scores (3 studies, 134
subjects; SMD -0.09, 95% CI: -0.43, 0.25). Similarly, for asthma patients not treated with OCS,
parallel group studies showed no significant differences in rescue medication use or withdrawals
due to asthma exacerbations.
For asthma patients treated with OCS, one crossover study assessed OCS-sparing effects
and three evaluated other outcomes. The outcomes for those that did not assess OCS-sparing
effects were pooled (3 studies, 144 subjects) and found no significant difference between BDP
and BUD for daytime or night-time breathlessness scores, sleep disturbance scores, or rescue
medication use.
Two fair-rated open-label head-to-head RCTs27, 28 met the criteria for our review. The
first was a 12-week parallel group trial (N = 460) with stratification for LABA use (2:1 yes:no)
that compared treatment with three inhaled corticosteroids: BDP extrafine aerosol (Qvar
Autohaler 800 mcg/d, N = 149), BUD Turbuhaler (1600 mcg/d, N = 162), and fluticasone Diskus
(1000 mcg/d, N = 149).27 It enrolled patients with moderate to severe persistent asthma who
were not controlled with a regimen that included ICS, with or without LABAs. Overall asthma
control, assessed by the French version of the Juniper asthma control questionnaire, was
improved in all groups with no significant difference between groups (mean change from
baseline for BDP compared with BUD: -1.0 compared with -0.8; 95% CI of the difference: -0.29,
0.08). Among the individual components of control included in the questionnaire (nocturnal
awakenings, morning discomfort, limitation of activity, dyspnea, wheezing, and consumption of
short-acting beta-agonist) there were no significant differences except for improvement in
nocturnal awakenings favoring BDP (-1.0 compared with -0.7; 95% CI of difference: -0.43, 0.05; P = 0.045).
The other fair-rated RCT (N = 209) compared BDP Autohaler (800 mcg/d) with BUD
Turbuhaler (1600 mcg/d)28 over 8 weeks. Patients were 18-75 years old and had poorly
controlled asthma while taking ICS. Subjects treated with BDP had greater improvement in
symptoms than those treated with BUD (mean change from baseline in % of days without
symptoms: wheeze 26.48 compared with 8.29, P = 0.01; shortness of breath 22.68 compared
with 11.25, P = 0.02; chest tightness 20.71 compared with 6.25, P = 0.01; daily asthma
symptoms 25.36 compared with 12.22, P = 0.03; difference not significant for cough or sleep
disturbance). There was no significant difference in beta-agonist use (mean change from baseline
% of days used; -23.76 compared with -17.13; P not significant).
2. Beclomethasone compared with ciclesonide
We did not identify any good or fair quality systematic reviews or head-to-head trials that
compared beclomethasone with ciclesonide.
3. Beclomethasone compared with flunisolide
We did not identify any good or fair quality systematic reviews or head-to-head trials that
compared beclomethasone to flunisolide.
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4. Beclomethasone compared with fluticasone
Two systematic reviews and 11 head-to-head RCTs comparing fluticasone (FP) to BDP met our
inclusion criteria. One systematic review23 included studies comparing FP compared with BDP
or BUD. Of the 71 studies included in this review, 33 compared FP to BDP (nine of those 33
were included in our review). Comparisons were stratified by FP:BDP/BUD dose ratios of 1:2 or
1:1. The pooled treatment effect of FP was compared to the pooled treatment effect for BDP and
BUD. For the studies conducted at dose ratios of 1:2, pooled estimates indicate that FP-treated
patients had fewer symptoms, required less rescue medication, and had a higher likelihood of
pharyngitis (see Key Question 2) than those treated with BDP or BUD. There was no difference
in exacerbations. For the studies conducted at dose ratios of 1:1, individual studies and pooled
estimates suggest no difference in symptoms, rescue medicine use, or the number of asthma
exacerbations. Although we rated the quality of this review as good, the comparison of
fluticasone to the combined effect of beclomethasone and budesonide limits possible conclusions
regarding the specific comparison of beclomethasone to fluticasone.
The other systematic review24compared either CFC or HFA-propelled FP with HFApropelled extrafine BDP. The review included nine studies (1265 participants) and found no
statistically significant difference between treatments for symptom scores and quality of life.
Eleven trials, one good-rated33 and ten fair-rated27, 29-32, 34-37, 56 head-to-head RCTs,
comparing BDP to FP met the inclusion/exclusion criteria for our review. The single good-rated
trial compared BDP 400 mcg/day (MDI-HFA) to FP 400 mcg/day (MDI) in 172 adults with mild
to severe persistent asthma for 6 weeks; both were medium potency doses.33 The trial was
conducted in 30 general practice sites in the United Kingdom and Ireland. There were no
significant differences in the improvement of asthma symptoms, sleep disturbance, rescue
medicine use, or quality of life (AQLQ mean change from baseline) between the two groups.
Of the ten fair-rated RCTs that compared BDP to FP,27, 29-32, 34-37, 56 just two included
children and adolescents <12 years of age. One was conducted exclusively in a population of
children and adolescents aged 4-1131 and one included children, adolescents, and young adults
aged 4-19.34 Asthma severity ranged from mild- to severe-persistent. Doses ranged from low to
high; all studies included comparisons of equipotent doses of BDP and FP. Study duration
ranged from 6 to 52 weeks. All but two trials35, 56 assessed asthma symptoms and rescue
medicine use.
The majority of trials reported no difference between BPD- and FP-treated patients for
the outcomes of interest reported. Four studies found FP to be better than BDP for at least one
outcome: symptoms,37 nighttime symptoms,36 rescue medicine use—increase in percent of
rescue free days34 or mean change in rescue puffs per day,37 or exacerbations.32 One study found
BDP-treated patients to have lower daytime symptom scores.36
5. Beclomethasone compared with mometasone
Two fair-quality RCTs38, 39 compared treatment with BDP and mometasone for 12 weeks. Both
compared medium-dose BDP MDI (336 mcg/d), multiple doses of mometasone DPI (low-dose
200 mcg/d and medium-dose 400 mcg/d in both studies, and high-dose 800 mcg/d in only one),38
and placebo in patients at least 12 years old with persistent asthma. Both studies found no
statistically significant differences between BDP and mometasone for symptoms, nocturnal
awakenings, and rescue medicine use.
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6. Beclomethasone compared with triamcinolone
We found two fair-quality multicenter RCTs comparing BDP to triamcinolone (TAA).40, 41 Both
compared medium-dose BDP (336 mcg/d), medium-dose TAA (800 mcg/d), and placebo for
eight weeks in adult subjects. Both found no difference between the active treatment groups for
rescue medicine use and one found no difference in nighttime awakenings.41 They reported
conflicting results for improvement of symptoms: one reported greater improvement with BDP
than TAA41 and one reported no difference.40
7. Budesonide compared with ciclesonide
Five fair-quality multicenter RCTs meeting our inclusion criteria compared BUD with
ciclesonide.58-62 All five were 12 weeks in duration. One was conducted in children age 6-1162
and one in adolescents 12-17 years old.61 One was conducted using subjects with mild to
moderate persistent asthma, two with mild to severe, one with moderate to severe, and one with
severe persistent asthma. Two trials only compared nonequivalent doses with ciclesonide given
at a higher relative dose than BUD.58, 60 The three studies comparing equivalent doses were noninferiority trials. All studies used dry powder formulations of BUD and HFA-MDI for
ciclesonide. All five trials evaluated outcomes for asthma symptoms and rescue medicine use
and all but one59 reported exacerbations. All five trials were funded by pharmaceutical
companies.
Overall, the evidence from the three studies comparing equivalent doses (low versus low or
medium versus medium doses of ICSs) was consistent, finding ciclesonide to be non-inferior to
BUD. All three studies reported similar improvement in symptoms, 59, 61, 62 rescue medication
use,59, 61, 62 and quality of life 61, 62 for subjects treated with ciclesonide and those treated with
BUD.
8. Budesonide compared with flunisolide
We found one fair-quality multicenter RCT comparing BUD (1200 mcg/d) to flunisolide (1500
mcg/d) in adults (N = 154) with moderate persistent asthma for 6 weeks.42 They reported no
statistically significant differences between BUD and flunisolide in change from baseline in
asthma symptoms, nocturnal awakenings, or rescue medicine use.
9. Budesonide compared with fluticasone
One previously described systematic review and eight head-to-head RCTs comparing FP to BUD
met our inclusion criteria. The systematic review23 included studies comparing FP with BDP or
BUD. Of the 71 studies included in this review, 37 compared FP to BUD. Comparisons were
stratified by FP: BDP/BUD dose ratios of 1:2 or 1:1. The pooled treatment effect of FP was
compared to the pooled treatment effect for BDP and BUD. For the studies conducted at dose
ratios of 1:2, pooled estimates indicate that FP-treated patients had fewer symptoms, required
less rescue medication, and had a higher likelihood of pharyngitis (see Key Question 2) than
those treated with BDP or BUD. There was no difference in exacerbations. For the studies
conducted at dose ratios of 1:1, individual studies and pooled estimates suggest no difference in
symptoms, rescue medicine use, or the number of asthma exacerbations. Although we rated the
quality of this review as good, the comparison of the effectiveness of BUD and FP cannot be
clearly ascertained from this systematic review23 because the comparator group contains both
BUD and BDP.
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Eight fair-rated head-to-head RCTs meeting our inclusion criteria compared budesonide
to fluticasone.25-27, 43-47 Trial duration ranged from six to 24 weeks. Two were conducted in
children and adolescents;44, 46 five were conducted in patients with moderate and/or severe
persistent asthma, one was conducted in patients with mild persistent asthma,26 one in mild to
moderate persistent asthma,46 and the severity was not reported in one trial.25 Three trials
compared nonequivalent doses with FP given at a higher relative dose than BUD.43, 45, 46 All but
one study43 used dry powder formulations of both medications. All eight trials evaluated
outcomes for asthma symptoms and rescue medicine use.
Overall, the evidence from these studies supports the conclusion that there is no
difference between equipotent doses of BUD and FP. Three of the trials27, 44, 47 that compared
equipotent doses and one46 that compared medium- with low-doses of BUD and FP found no
difference for symptoms, exacerbations, or rescue medicine use. In addition, one trial43
comparing two high-doses of FP (1000 mcg/d and 2000 mcg/d) with medium-dose BUD (1600
mcg/d) found no difference between the lower of the two high doses and medium-dose BUD for
symptoms, exacerbations, and rescue medicine use. Two open-label trials from the 1990s
compared FP Diskhaler with BUD reservoir powder device and reported some differences in
certain secondary outcomes favoring FP, but no statistically significant differences for most
outcomes.25, 26 Specifically, one reported a higher percentage of subjects treated with FP rating
their asthma control “excellent”25 and one reported greater improvement in rescue-free days and
nights.26 The remaining trial45 compared non-equivalent doses (relative potency of fluticasone
was greater at the doses given) and found FP to be superior to BUD for symptoms, rescue
medicine use, and missed days of work, but found no difference in exacerbations.
10. Budesonide compared with mometasone
One fair-rated 12-week RCT48 and one fair-rated 8-week trial49 compared BUD and
mometasone. Overall, the trials reported no significant differences for equipotent doses for most
outcomes of interest, but there were some dose-related differences favoring mometasone over
BUD when comparing non-equipotent doses. The 12-week trial randomized 730 persons 12
years and older with moderate persistent asthma to medium dose (800 mcg/day) BUD or low-,
medium-, or high-dose (200, 400, 800 mcg/day, respectively) mometasone.48 They found no
statistically significant differences between medium-dose BUD and medium-dose mometasone
for symptoms or nocturnal awakenings, but patients treated with medium-dose mometasone had
a greater decrease in rescue medicine use than those treated with medium-dose BUD (-90.66
mcg/d compared with -33.90 mcg/d; P < 0.05). The 8-week trial compared once daily low-dose
(400 mcg/day) BUD with once daily medium-dose (440 mcg/day) mometasone in 262 persons
12 years and older with moderate persistent asthma.49 The trial reported statistically significant
differences in evening asthma symptoms (P < 0.05), symptom-free days (P < 0.01), and rescue
medication use (P < 0.05), favoring medium-dose mometasone over low-dose BUD.
11. Budesonide compared with triamcinolone
One fair-rated 52-week RCT50 met our inclusion/exclusion criteria for this comparison. The trial
randomized 945 adults ≥18 with mild, moderate, or severe persistent asthma to BUD DPI (mean
dose at start and end: 941.9 and 956.8 mcg/d) or TAA pMDI (1028.2 and 1042.9 mcg/d,
respectively). On average, patients were treated with medium doses, but starting doses and dose
adjustments were left to the discretion of the clinical investigator. Patients treated with BUD had
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greater improvements in symptom- and episode-free days (P < 0.001), daytime and nighttime
asthma symptom scores (P < 0.001), and quality of life (P < 0.001) than those treated with TAA.
12. Ciclesonide compared with flunisolide
We did not identify any good or fair quality systematic reviews or head-to-head trials that
compared ciclesonide to flunisolide.
13. Ciclesonide compared with fluticasone
Eight fair-quality RCTs meeting our inclusion criteria compared ciclesonide with fluticasone.63-70
Six were 12 weeks in duration, one was 24 weeks,70 and one was 6 months.63 Two enrolled
children.68, 69 Three were conducted in subjects with mild to severe persistent asthma; two in
subjects with moderate persistent asthma;64, 65 and one each in mild to moderate70 and moderate
to severe persistent asthma.63 One trial did not report sufficient information to determine the
severity of persistent asthma.66 All but one trial compared equipotent doses of ICSs.66 Five of
the trials comparing equipotent doses compared low dose ciclesonide with low dose fluticasone;
one compared medium doses64 and one compared high doses.63 All but one trial used HFA-MDI
for delivery of both medications.64 All eight RCTs were funded by pharmaceutical companies
producing ciclesonide.
Overall, the evidence from these studies supports the conclusion that there is no
difference in the outcomes of interest between equipotent doses of ciclesonide and FP. All seven
trials comparing equipotent doses reported non-inferiority of ciclesonide compared to FP or no
statistically significant difference for the outcomes of interest with one exception. All of the
trials used some measure to assess symptoms and rescue medication use; all but one assessed
exacerbations; and four assessed quality of life. The one exception was reported in a 12 week
trial of 474 subjects, finding greater improvement in quality of life with ciclesonide than with FP
(mean change from baseline in AQLQ: 0.29 vs. 0.11, P = 0.005 for one-sided superiority).64 The
same trial reported non-inferiority or no statistically significant difference between medications
for symptoms.
We conducted meta-analyses of these studies for exacerbations, symptoms, and rescue
medication use and found no statistically significant differences between ciclesonide and FP
(Appendix I). There was no statistically significant difference between ciclesonide and FP for
exacerbations requiring treatment with oral steroids (OR 0.97, 95% CI: 0.50 to 1.88),
improvement in symptom scores (SMD 0.016, 95% CI: -0.05 to 0.08), or change in rescue
medication use (SMD 0.03, 95% CI: -0.03 to 0.09). There was no significant statistical
heterogeneity for any of these analyses (I2 = 0 for all).
14. Ciclesonide compared with mometasone
We did not identify any good or fair quality systematic reviews or head-to-head trials that
compared ciclesonide with mometasone.
15. Ciclesonide compared with triamcinolone
We did not identify any good or fair quality systematic reviews or head-to-head trials that
compared ciclesonide with triamcinolone.
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16. Flunisolide compared with fluticasone
We found two RCTs reported in one publication51 that compared flunisolide and fluticasone
meeting our inclusion/exclusion criteria. Both were fair-quality trials comparing non-equipotent
doses that randomized patients to high-dose FP MDI (500 mcg/d) or medium-dose flunisolide
MDI (1000 mcg/d). One was an 8-week double-blind RCT (N = 321) and the other was a 6-week
open-label RCT (N = 332). There was a trend toward greater improvement in symptom-free days
for patients treated with high-dose FP (P NR for either).
17. Flunisolide compared with mometasone
We did not identify any good or fair quality systematic reviews or head-to-head trials that
compared beclomethasone to flunisolide.
18. Flunisolide compared with triamcinolone
We did not identify any good or fair quality systematic reviews or head-to-head trials that
compared beclomethasone to flunisolide.
19. Fluticasone compared with mometasone
Three fair-rated trials comparing FP with mometasone met our inclusion/exclusion criteria.52, 57,
71
One fair-rated dose-ranging study (N = 733) conducted in 60 study centers compared mediumdose fluticasone (500 mcg/day) to low-, medium-, and high-dose mometasone (200, 400, and
800 mcg/day, respectively) in 733 patients 12 years and older with moderate persistent asthma.52
The investigators found no statistically significant differences at endpoint between patients
treated with medium-dose fluticasone and those treated with medium- and high-dose
mometasone with respect to wheeze and cough scores, nighttime awakenings, or rescue
medication use (P > 0.05 for all). However, patients treated with medium-dose fluticasone had
significantly greater improvement in the number of nighttime awakenings (P < 0.05) than did
those treated with low-dose mometasone. In addition, patients on medium-dose fluticasone had
significantly better morning difficulty breathing scores than did patients on either low- or
medium-dose mometasone (P < 0.05).
Another study was a multinational trial (N=203) that compared high dose mometasone
(800 mcg/day) with high dose fluticasone (1000 mcg/day) for 12 weeks.57 The investigators
found no statistically significant differences at endpoint with respect to rescue medication use,
symptoms, and exacerbations. The third study did not compare equipotent doses; it compared
medium dose mometasone with high dose fluticasone.71
20. Fluticasone compared with triamcinolone
Three fair-rated trials comparing FP to TAA met our inclusion/exclusion criteria.53-55 The only
one of the three trials comparing equipotent doses53 found greater improvements in subjects
treated with FP. The other two trials comparing non-equipotent doses54, 55 reported greater
improvements for FP-treated subjects for some outcomes and no difference for the others.
The trial comparing equipotent doses53 was a 12-week, multicenter RCT (N = 680)
comparing medium-dose FP MDI (440 mcg/d), medium-dose TAA MDI (1200 mcg/d), and the
combination of FP (196 mcg/d) and Salmeterol. Subjects were at least 12 years of age and were
poorly controlled on ICS therapy. FP-treated subjects had better improvements in symptoms,
nighttime awakenings, and rescue medicine use.
Controller medications for asthma
35 of 369
Final Update 1 Report
Drug Effectiveness Review Project
The two comparing non-equipotent doses were similarly designed fair-rated RCTs54, 55
conducted in 24 outpatient centers. Subjects in both were randomized to medium-dose FP (500
mcg/day by DPI), low-dose TAA (800 mcg/day by MDI with spacer), or placebo for 24 weeks.
Both were conducted in subjects 12 years or older previously being treated with ICS. No
differences were found in symptom scores or in the percentage of symptom-free days. Subjects
treated with FP had greater improvements in rescue medicine requirements in both studies than
those treated with TAA. One of the trials reported greater improvement in nighttime
awakenings55 for those treated with FP, but the other reported no difference.54 One reported
significantly better improvements in quality of life for FP-treated patients compared to TAAtreated patients.55
Controller medications for asthma
36 of 369
Final Update 1 Report
Drug Effectiveness Review Project
Table 7. Characteristics of head-to-head studies comparing inhaled corticosteroids in children and adults
Study
Study Design
N
Duration
Country
Population
Setting
Comparison
(total daily dose in mcg)
Equivalent
dosing
Quality
Rating
Beclomethasone compared with budesonide
Adams et al. 200022
Systematic review with metaanalysis
Majority in Europe
24 trials (6 trials in children, 18 in adults)
24 studies (1174 subjects), 5
parallel, 19 cross-over (two had
a washout)
BDP
compared with
BUD
Yes
Good
all studies assessed equal
nominal daily doses of BDP and
BUD
Range 2 weeks to 2 years; 50%
were 2-4 weeks
Molimard et al.
200527
RCT, open-label
France
460
Age 18-60, moderate to severe persistent,
not controlled on ICS, smoking status NR
12 weeks
BDP MDI (800)
compared with
BUD DPI (1600)
compared with
FP DPI (1000)
Yes (all high)
Fair
BDP MDI (800)
compared with
BUD DPI (1600)
Yes (high)
Fair
Multicenter, subspecialty clinics (69
pulmonologists)
Worth et al. 200128
RCT, open-label
Germany, France, Netherlands
209
Age 18-75, moderate to severe, on ICS,
smoking status NR
8 weeks
Multicenter (39)
Beclomethasone compared with ciclesonide
No systematic reviews or head-to-head trials found
Beclomethasone compared with flunisolide
No systematic reviews or head-to-head trials found
Beclomethasone compared with Fluticasone
Adams et al. 200723
Systematic review with metaanalysis
Multinational (most in Europe)
Severity ranged from mild to severe
71 trials (14,602 participants), 59 persistent
parallel, 14 cross-over (four had
Controller medications for asthma
FP compared with BDP (33 trials) For some of the
included
FP compared with BUD (37)
studies
Good
FP compared with BDP/BUD (2)
37 of 369
Final Update 1 Report
Drug Effectiveness Review Project
Table 7. Characteristics of head-to-head studies comparing inhaled corticosteroids in children and adults
Study Design
N
Duration
Study
Country
Population
Setting
Comparison
(total daily dose in mcg)
Equivalent
dosing
Quality
Rating
a washout)
38 studies had FP:BDP/BUD
dose ratio of
1:2; 22 had dose ratio 1:1;
remainder had multiple dose ratio
comparisons or ratio was unclear
Majority of studies (47) were
between 6 weeks and 5 months;
14 were ≤4 weeks
Lasserson et al.
201024
Systematic review with metaanalysis
9 trials (1265 participants)
Multinational (most in Europe)
FP compared with extrafine HFA
BDP
Yes
Good
FP MDI (1000)
compared with
BDP MDI (2000)
Yes (high)
Fair
FP DPI (1600)
compared with
BDP DPI (2000)
Yes (high)
Fair
FP DPI (400)
compared with
BDP DPI (400)
Yes (medium)
Fair
FP MDI (1500)
compared with
BDP MDI (1500)
Yes (high)
Fair
Severity ranged from mild to severe
persistent
3 to 12 weeks
29
Barnes et al. 1993
Boe et al. 199430
de Benedictis et al.
200131
RCT, DB
Multinational (7 countries worldwide)
154
Age ≥ 18, severe, 20% smokers
6 weeks
Multicenter (18 outpatient clinics)
RCT, DB
Norway
134
Age ≥ 18, poorly controlled, 34% smokers
12 weeks
Multicenter
RCT, DB
Multinational (7 countries: Holland,
Hungary, Italy, Poland,
Argentina, Chile, South Africa)
434
52 weeks
Age 4-11, prepubertal, severity and
smoking status NR
Multicenter (32)
32
Fabbri et al. 1993
RCT, DB
Multinational (10 European)
274
Age 12-80, moderate to severe, not
controlled on ICS, 11% smokers
12 months (daily symptom
outcomes collected for initial 12
Controller medications for asthma
Multicenter (25)
38 of 369
Final Update 1 Report
Drug Effectiveness Review Project
Table 7. Characteristics of head-to-head studies comparing inhaled corticosteroids in children and adults
Study Design
N
Duration
Study
Country
Population
Setting
Comparison
(total daily dose in mcg)
Equivalent
dosing
Quality
Rating
BDP MDI (extrafine HFA, 400)
compared with
FP MDI (CFC, 400)
Yes (medium)
Good
FP MDI (200)
compared with
BDP MDI (400)
Yes (medium)
Fair
FP MDI (1000)
compared with
BDP MDI (2000)
Yes (high)
Fair
FP MDI (500)
compared with
FP DPI (500)
compared with
BDP MDI (1000)
No, only for FP
MDI compared
with BDP MDI
(high) ; FP DPI
500 is medium
Fair
BDP MDI (800)
compared with
BUD DPI (1600)
compared with
FP DPI (1000)
Yes (all high)
Fair
FP DPI (NR)
compared with
Yes
Fair
weeks)
Fairfax et al. 2001
33
RCT, DB, DD
UK and Ireland
172
Age 18-65, mild to severe, symptomatic on
ICS, 24% current smokers
6 weeks
Multicenter (30 general practice sites)
Gustafsson et al.
199334
RCT, DB
Multinational (11 worldwide)
398
Age 4-19, mild to moderate, not controlled
on current meds, smoking status NR
6 weeks
Multicenter (32)
Lorentzen et al.
199635
RCT, DB
Multinational (7, Europe)
213
Age 18-77, severe, well controlled on high
dose ICS, 19% smokers
12 months
Multicenter (20 outpatient clinics)
Lundback et al.
199336
RCT, DB
Multinational (10)
585
Age 15-90, moderate, not controlled on
ICS, smoking status NR
6 weeks
(N = 489 continued an additional Multicenter (47)
46 weeks)
Molimard et al.
200527
RCT, open-label
France
460
Age 18-60, moderate to severe persistent,
not controlled on ICS, smoking status NR
12 weeks
Multicenter, subspecialty clinics (69
pulmonologists)
Ohbayashi et al.
200856
RCT, double cross-over every 3
months
Controller medications for asthma
Japan
39 of 369
Final Update 1 Report
Drug Effectiveness Review Project
Table 7. Characteristics of head-to-head studies comparing inhaled corticosteroids in children and adults
Study
Study Design
N
Duration
Country
Population
Setting
50
Age, mild to moderate persistent, controlled BDP MDI (NR)
on FP
Comparison
(total daily dose in mcg)
Equivalent
dosing
Quality
Rating
10 months
37
Raphael et al. 1999
RCT, DB, DD
US
399
Age ≥ 12 years, mild to severe, not
controlled on ICS, smokers excluded
12 weeks
Multicenter, specialty asthma and primary
care centers (23)
FP MDI (164)
compared with
FP MDI (440)
compared with
BDP MDI (336)
compared with
BDP MDI (672)
Yes (low,
medium, low,
medium)
Fair
Mometasone DPI (200)
vs.
Mometasone DPI (400)
vs.
Mometasone DPI (800)
vs.
BDP MDI (336)
vs.
placebo
No; only for
MOM 400 vs.
BDP 336 (both
medium)
Fair
Placebo
vs.
Mometasone DPI (200)
vs.
Mometasone DPI (400)
vs.
BDP MDI (336)
No; only for MF
200 vs. BDP
(both low), MF
400 is medium
Fair
BDP MDI (336)
vs.
TAA MDI (800)
vs.
placebo
Yes (medium)
Fair
Beclomethasone compared with mometasone
Bernstein et al.
199938
RCT, DB, DD
US
365
Age ≥12, mild to moderate, on ICS,
smokers excluded
12 weeks
Multicenter (20)
Nathan et al. 200139
RCT, DB, DD
US
227
Age ≥ 12, moderate, on ICS, smokers
excluded
12 weeks
Multicenter (15)
Beclomethasone compared with triamcinolone
Berkowitz et al.
199840
RCT, DB, DD
US
339
Age 18-65, mild to moderate, on ICS,
smokers excluded
8weeks
Multicenter (17), asthma/allergy centers
Controller medications for asthma
40 of 369
Final Update 1 Report
Drug Effectiveness Review Project
Table 7. Characteristics of head-to-head studies comparing inhaled corticosteroids in children and adults
Study Design
N
Duration
Study
Bronsky et al. 199841 RCT, DB, DD
329
8 weeks
Country
Population
Setting
Comparison
(total daily dose in mcg)
Equivalent
dosing
Quality
Rating
US
BDP MDI (336)
vs.
Age 18-65, mild to severe, on ICS, smokers TAA MDI (800)
excluded
vs.
placebo
Multicenter
Yes (medium)
Fair
Multinational - Canada and Europe
No
(medium vs.
low)
Fair
Yes for CIC 80
vs. BUD 400
No for CIC 320
vs. BUD
Fair
Budesonide compared with ciclesonide
Boulet et al. 200658
RCT, DB, DD
359
12 weeks
CIC HFA-MDI (320)
vs.
Age 12-75, mild to moderate, on ICS, heavy BUD DPI (320)
smokers or ex-smokers excluded (>10
cigarettes/day)
Multicenter
59
Hansel et al. 2006
RCT
Multinational - Europe
554
Age 12-75, mild to severe, on ICS, 9%
smokers
12 weeks
CIC HFA-MDI (80)
vs.
CIC HFA-MDI (320)
vs.
BUD DPI (400)
Multicenter
Ukena et al. 200760
RCT, DB, DD
Germany
399
Age 12-75, mild to severe, smokers
excluded
(low vs.
medium vs.
low)
CIC HFA-MDI (320)
vs.
BUD DPI (400)
No (medium vs.
low)
Fair
CIC HFA-MDI (320)
vs.
BUD DPI (800)
Yes (medium)
Fair
CIC HFA-MDI (160)
Yes (low)
Fair
12 weeks
Multicenter
Vermeulen et al.
200761
RCT, DB, DD
Multinational - Hungary, Poland,
Serbia/Montenegro, South Africa, Spain
403
12 weeks
Age 12-17, severe, not controlled on ICS,
excluded smokers
Multicenter
von Berg et al.
RCT, DB, DD
Controller medications for asthma
Multinational - Australia, Germany,
41 of 369
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Drug Effectiveness Review Project
Table 7. Characteristics of head-to-head studies comparing inhaled corticosteroids in children and adults
Study
Study Design
N
Duration
Country
Population
Setting
Comparison
(total daily dose in mcg)
621
Hungary, Poland, Portugal, Serbia and
Montenegro, South Africa and Spain
vs.
BUD DPI (400)
200762
12 weeks
Equivalent
dosing
Quality
Rating
Age 6-11, moderate to severe, smoking
status NR
Multicenter
Budesonide compared with flunisolide
Newhouse et al.
200042
RCT
Canada
179
Age 18-75, moderate, on ICS, 5% current
smokers
Flunisolide MDI + AeroChamber
(1500)
vs.
BUD DPI (1200)
Yes (medium)
FP vs. BDP (33 trials)
For some of the
included
studies
Fair
6 weeks
Multicenter (17)
Budesonide compared with fluticasone
Adams et al. 200723
Systematic review with metaanalysis
Multinational (most in Europe)
Severity ranged from mild to severe
71 trials (14,602 participants), 59 persistent
parallel, 14 cross-over (four had
a washout)
FP vs. BDP/BUD (2)
38 studies had FP:BDP/BUD
dose ratio of
1:2; 22 had dose ratio 1:1;
remainder had multiple dose ratio
comparisons or ratio was unclear
Majority of studies (47) were
between 6 weeks and 5 months;
14 were ≤4 weeks
Ayres et al. 199543
FP vs. BUD (37)
Good
RCT, DB, DD
Multinational (13 countries worldwide)
671
Age 18-70, severe, on ICS, smokers
excluded
6 weeks
FP MDI (1000)
vs.
FP MDI (2000)
vs.
BUD MDI (1600)
No (high vs.
high vs.
medium)
Fair
Yes (low)
Fair
Multicenter (66)
26
Connolly et al 1995
RCT
UK
FP DPI (200)
189
Age 18-70, mild, mixed population of
BUD DPI (400)
Controller medications for asthma
42 of 369
Final Update 1 Report
Drug Effectiveness Review Project
Table 7. Characteristics of head-to-head studies comparing inhaled corticosteroids in children and adults
Study
Ferguson et al.
199944
Study Design
N
Duration
Country
Population
Setting
8 weeks
subjects previously on ICS and not on ICS,
smoking status NR
RCT, DB, DD
Multinational (6 countries worldwide)
333
Ages 4-12, moderate to severe, on ICS,
smoking status NR
Comparison
(total daily dose in mcg)
Equivalent
dosing
Quality
Rating
FP DPI (400)
vs.
BUD DPI (800)
Yes (medium)
Fair
FP DPI (2000)
vs.
BUD DPI (2000)
No (both are
high doses, but
relative potency
of fluticasone is
greater at the
given doses)
Fair
FP DPI (400)
vs.
BUD DPI (400)
No (medium vs.
low)
Fair
UK
FP DPI (400)
Yes (medium)
Fair
BUD DPI (800)
8 weeks
Age 18-70, severity NR, mixed population
of subjects previously on ICS and not on
ICS, smoking status NR
RCT, open-label
France
Yes (all high)
Fair
460
Age 18-60, moderate to severe persistent,
not controlled on ICS, smoking status NR
BDP MDI (800)
vs.
BUD DPI (1600)
vs.
FP DPI (1000)
20 weeks
Multicenter
45
Heinig et al. 1999
RCT, DB, DD
Multinational (Belgium, Canada, Denmark,
Netherlands)
395
24 weeks
Age 18-75, severe, not controlled on ICS,
15% current smokers
Multicenter (47)
46
Hoekx et al, 1996
RCT, DB, DD
Multinational (4: Netherlands, Sweden,
Denmark, Finland)
229
8 weeks
Children up to 13, mild to moderate, on ICS,
smoking status NR
Multicenter (22)
Langdon et al 199425 RCT
281
Molimard et al.
200527
12 weeks
Multicenter, subspecialty clinics (69
pulmonologists)
Controller medications for asthma
43 of 369
Final Update 1 Report
Drug Effectiveness Review Project
Table 7. Characteristics of head-to-head studies comparing inhaled corticosteroids in children and adults
Study
Study Design
N
Duration
Country
Population
Setting
Ringdal et al. 199647
RCT, DB, DD
Multinational
518
Age 18-75, moderate to severe, not
controlled on ICS, 19% smokers
Comparison
(total daily dose in mcg)
Equivalent
dosing
Quality
Rating
FP DPI (800)
vs.
BUD DPI (1600)
Yes (high)
Fair
Mometasone DPI (200)
vs.
Mometasone DPI (400)
vs.
Mometasone DPI (800)
vs.
Budesonide DPI (800)
No (only for M
400 vs. BUD,
both medium)
Fair
Mometasone DPI (400)
vs.
BUD DPI (320)
vs.
placebo
No (medium vs.
low)
Fair
BUD DPI (mean dose at start and
end: 941.9 and 956.8 mcg/d)
vs.
TAA pMDI (1028.2/1042.9 mcg/d)
Yes, on
average both
are medium,
but difficult to
assess clearly
because
starting doses
and dose
adjustments
were left to the
discretion of
the clinical
investigator
Fair
12 weeks
Multicenter
Budesonide compared with mometasone
Bousquet et al.
200048
RCT, single-blind
Multinational (17)
730
Age ≥ 12, moderate, on ICS, smokers
excluded
12 weeks
Multicenter (57)
Corren et al. 200349
RCT, DB, DD
US
262
Age ≥ 12, moderate, on ICS, smokers
excluded
8 weeks
Multicenter (17)
Budesonide compared with triamcinolone
Weiss et al. 200450
RCT
US
945
Age ≥ 18, mild to severe, smoking status
NR
52 weeks
Multicenter, patients from 25 managed care
plans
Controller medications for asthma
44 of 369
Final Update 1 Report
Drug Effectiveness Review Project
Table 7. Characteristics of head-to-head studies comparing inhaled corticosteroids in children and adults
Study Design
N
Duration
Study
Country
Population
Setting
Comparison
(total daily dose in mcg)
Equivalent
dosing
Quality
Rating
CIC HFA-MDI (640)
vs.
FP HFA-MDI (660)
Yes (high)
Fair
CIC HFA-MDI (320)
vs.
FP DPI (400)
Yes (medium)
Fair
CIC HFA-MDI (160)
vs.
FP HFA-MDI (176)
Yes (low)
Fair
CIC HFA-MDI (80)
vs.
FP HFA-MDI (200)
Yes (low)
Fair
CIC HFA-MDI (160)
No (low vs.
Fair
Ciclesonide compared with flunisolide
No systematic reviews or head-to-head trials found
Ciclesonide compared with fluticasone
Bateman 200863
RCT
Multinational - Europe, North America,
South Africa
528
6 months
Age 12-75, moderate to severe, on ICS,
33% ex-smokers or current smokders
Multicenter
64
Boulet 2007
RCT
Multinational - Austria, Canada, Germany,
Hungary, South Africa, Spain
474
12 weeks
Age 12-75, moderate, 30% ex-smokers or
current smokders
Multicenter
65
Buhl 2006
RCT
529
12 weeks
Multinational - Germany, Austria, The
Netherlands, Spainn, Hungary, Poland,
South Africa
Age 12-75, moderate, on ICS, smoking
status NR
Multicenter
70
Dahl 2010
RCT, DB, DD
Multinational – Austria, Canada, Germany,
Poland, and South Africa
480
24 weeks
Age 12-75, on ICS, mild to moderate,
excluded current and ex-smokers with ≥ 10
pack-year history, 22-31% current or exsmokers enrolled
Multicenter
66
Knox 2007
RCT
Controller medications for asthma
United Kingdom, Belgium
45 of 369
Final Update 1 Report
Drug Effectiveness Review Project
Table 7. Characteristics of head-to-head studies comparing inhaled corticosteroids in children and adults
Study
Study Design
N
Duration
Country
Population
Setting
111
Age 17-75, on ICS, severity NR, 2-3%
smokers
Comparison
(total daily dose in mcg)
Equivalent
dosing
Quality
Rating
vs.
FP HFA-MDI (500)
medium)
CIC HFA-MDI (80)
vs.
CIC HFA-MDI (160)
vs.
FP HFA-MDI (176)
Yes (low)
Fair
CIC HFA-MDI (80)
vs.
CIC HFA-MDI (160)
vs.
FP HFA-MDI (176)
Yes (low)
Fair
CIC HFA-MDI (160)
vs.
FP HFA-MDI (176)
Yes (low)
Fair
FP MDI (500)
vs.
Flunisolide MDI (1000)
No (high vs.
medium)
Fair
12 weeks
Multicenter
67
Magnussen 2007
RCT
808
12 weeks
Multinational - Germany, Poland, Czech
Republic, France, Italy, The Netherlands,
Slovakia, Spain
Age >12, mild to severe, 21-24% ex- and
current smokers
Multicenter
Pedersen 2009
68
RCT
Multinational - Brazil, Germany, Hungary,
Poland, Portugal, South Africa
744
12 weeks
Age 6-11, mild to severe, smoking status
NR
Multicenter
Pedersen 2006
69
RCT
Multinational - 8 countries
556
Age 6-15, mild to severe, excluded current
smokers
12 weeks
Multicenter
Ciclesonide compared with mometasone
No systematic reviews or head-to-head trials found
Ciclesonide compared with triamcinolone
No systematic reviews or head-to-head trials found
Flunisolide compared with fluticasone
Volmer et al. 199951
Two RCTs (one DB, one open),
results reported within a costeffectiveness analysis
Controller medications for asthma
Germany
Age 18-70, moderate, ICS naïve, 26% and
46 of 369
Final Update 1 Report
Drug Effectiveness Review Project
Table 7. Characteristics of head-to-head studies comparing inhaled corticosteroids in children and adults
Study
Study Design
N
Duration
Country
Population
Setting
publication
19% smokers
321 and 332
Multicenter
Comparison
(total daily dose in mcg)
Equivalent
dosing
Quality
Rating
MF DPI (800)
vs.
FP DPI (1000)
Yes (high)
Fair
MF DPI (200)
vs.
MF DPI (400)
vs.
MF DPI (800)
vs.
FP DPI (500)
No (only for
medium doses
of each: MF
400 vs. FP
500)
Fair
No
Fair
Yes (medium
for both ICSonly arms)
Fair
8 weeks and 6 weeks
Flunisolide compared with mometasone
No systematic reviews or head-to-head trials found
Flunisolide compared with triamcinolone
No systematic reviews or head-to-head trials found
Fluticasone compared with mometasone
Harnest et al. 200857 RCT
203
Multinational
Age ≥18, moderate to severe, on ICS,
smoking status NR
12 weeks
Multicenter
O’Connor et al.
200152
RCT, DB
Multinational (20)
733
Age ≥12, moderate, on ICS, excluded
smokers
12 weeks
Multicenter,
University hospitals
Wardlaw et al. 200471 RCT
167
Multinational
MF DPI (400)
vs.
Age ≥12, moderate, on ICS, smoking status FP MDI (500)
NR
8 weeks
Multicenter
Fluticasone compared with triamcinolone
Baraniuk et al.
53
1999
RCT, DB, triple- dummy
US
680
Age ≥12, not controlled on ICS, excluded
smokers
Controller medications for asthma
FP MDI (196) + Salmeterol (84)
vs.
FP MDI (440)
vs.
47 of 369
Final Update 1 Report
Drug Effectiveness Review Project
Table 7. Characteristics of head-to-head studies comparing inhaled corticosteroids in children and adults
Study Design
N
Duration
Study
Country
Population
Setting
12 weeks
Comparison
(total daily dose in mcg)
Equivalent
dosing
Quality
Rating
TAA MDI (1200)
Multicenter,
Pulmonary/allergy medicine clinics (50)
Condemi et al.
199754
RCT, DB, DD
US
291
Age ≥12, persistent asthma, on ICS,
excluded smokers
24 weeks
FP DPI (500)
vs.
TAA MDI (800)
vs.
placebo
No (medium vs.
low)
Fair
FP DPI (500)
vs.
TAA MDI (800)
vs.
placebo
No (medium vs.
low)
Fair
Multicenter (24 outpatient centers)
55
Gross et al. 1998
RCT, DB, DD
US
304
Age ≥12, mild to moderate, on ICS,
excluded smokers
24 weeks
Multicenter (24 respiratory care or allergy
University Clinics)
Abbreviations: AQLQ = Asthma Quality of Life Questionnaire; BDP = beclomethasone dipropionate; BUD = Budesonide; CI =confidence interval; CIC = ciclesonide; DB = double-blind;
DD = double dummy; DPI = dry powder inhaler; FLUN = Flunisolide; FP = Fluticasone Propionate; FrACQ = French version of the Juniper Asthma Control Questionnaire; ICS =
Inhaled Corticosteroids; MA=meta-analysis; MDI = metered dose inhaler; MOM = Mometasone; NR = not reported; NS = not statistically significant; OR= odds ratio; QOL = quality of
life; RCT= randomized controlled trial; SMD = standard mean difference; SR=systematic review; TAA = Triamcinolone Acetonide.
Note: “No difference” in the above results section indicates that there was no statistically significant difference between active treatments with ICSs; results are written in the same
order as the drugs are entered in the comparison column for each study.
Symbol use: Drug X > Drug Y = statistically significant difference in outcomes favoring Drug X; Drug X > Drug Y trend = point estimate favors Drug X, but the difference is not
statistically significant or tests of statistical significance were NR; No difference = no statistically significant difference or tests of statistical significance were not reported and outcomes
are similar.
Note: “No difference” in the above results section indicates that there was no statistically significant difference between active treatments with ICSs; results are written in the same
order as the drugs are entered in the comparison column for each study.
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Table 8. Characteristics of head-to-head studies comparing inhaled corticosteroids that included children
Study Design
N
Study
Duration
Beclomethasone compared with budesonide
Adams, N et al.
Systematic review with meta200222
analysis
24 studies (1174 subjects), 5
parallel, 19 cross-over (two had a
washout)
Range 2 weeks to 2 years; 50%
were 2-4 weeks
Beclomethasone compared with fluticasone
Adams, et al.
Systematic review with meta200723
analysis
71 trials (14,602 participants), 59
parallel, 14 cross-over (four had
a washout)
Study Population
Majority in Europe
24 trials (6 trials in children, 18 in
adults)
Systematic review with metaanalysis
9 trials (1265 participants)
De Benedicts et
al. 200131
3 to 12 weeks
RCT, DB
434
52 weeks
Gustafsson et al.
199334
Qu a lity
Ra tin g
BDP
vs.
BUD
Yes
Good
For some of
the included
studies
Good
Yes
Good
FP DPI (400)
vs.
BDP DPI (400)
Yes (medium)
Fair
FP MDI (200)
vs.
BDP MDI (400)
Yes (medium)
Fair
Multinational (most in Europe)
FP vs. BDP (33 trials)
Severity ranged from mild to severe
persistent
FP vs. BUD (37)
FP vs. BDP/BUD (2)
Multinational (most in Europe)
38 studies had FP: BDP/BUD
dose ratio of
1:2; 22 had dose ratio 1:1;
remainder had multiple dose
ratio comparisons or ratio was
unclear
FP compared with extrafine HFA
BDP
Severity ranged from mild to severe
persistent
2/9 trials in children
Multinational (7 countries: Holland,
Hungary, Italy, Poland,
Argentina, Chile, South Africa)
Age 4-11, prepubertal, severity and
smoking status NR
RCT, DB
Multicenter (32)
Multinational (11 worldwide)
398
Age 4-19, mild to moderate, not
Controller medications for asthma
Equivalent
dosing
all studies assessed equal
nominal daily doses of BDP and
BUD
Majority of studies (47) were
between 6 weeks and 5 months;
14 were ≤ 4 weeks
Lasserson et al.
24
2010
Comparison
(total daily dose)
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Table 8. Characteristics of head-to-head studies comparing inhaled corticosteroids that included children
Study
Study Design
N
Duration
6 weeks
Comparison
(total daily dose)
Equivalent
dosing
Qu a lity
Ra tin g
CIC HFA-MDI (160)
vs.
BUD DPI (400)
Yes (low)
Fair
Multinational (most in Europe)
FP vs. BDP (33 trials)
Good
Severity ranged from mild to severe
persistent
FP vs. BUD (37)
For some of
the included
studies
Yes (medium)
Fair
No (medium
vs. low)
Fair
Study Population
controlled on current meds, smoking
status NR
Multicenter (32)
Budesonide compared with Ciclesonide
von Berg et al.
RCT, DB, DD
200762
621
Multinational - Australia, Germany,
Hungary, Poland, Portugal, Serbia
and Montenegro, South Africa and
Spain
12 weeks
Age 6-11, moderate to severe,
smoking status NR
Multicenter
Budesonide compared with Fluticasone
Adams et al.
Systematic review with meta200723
analysis
71 trials (14,602 participants), 59
parallel, 14 cross-over (four had
a washout)
FP vs. BDP/BUD (2)
Majority of studies (47) were
between 6 weeks and 5 months;
14 were ≤ 4 weeks
Ferguson et al.
44
1999
RCT, DB, DD
Multinational (6 countries worldwide)
333
Ages 4-12, moderate to severe, on
ICS, smoking status NR
38 studies had FP:BDP/BUD
dose ratio of
1:2; 22 had dose ratio 1:1;
remainder had multiple dose
ratio comparisons or ratio was
unclear
FP DPI (400)
vs.
BUD DPI (800)
20 weeks
Hoekx et al.
199646
RCT, DB, DD
Multicenter
Multinational (4: Netherlands,
Sweden, Denmark, Finland)
229
8 weeks
FP DPI (400)
vs.
BUD DPI (400)
Children up to 13, mild to moderate,
on ICS, smoking status NR
Multicenter (22)
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Table 8. Characteristics of head-to-head studies comparing inhaled corticosteroids that included children
Study Design
N
Study
Duration
Ciclesonide compared with Fluticasone
Pedersen 200968
RCT
744
12 weeks
Pedersen 200669
RCT
556
Study Population
Multinational - Brazil, Germany,
Hungary, Poland, Portugal, South
Africa
Age 6-11, mild to severe, smoking
status NR
Multicenter
Multinational - 8 countries
Age 6-15, mild to severe, excluded
current smokers
Comparison
(total daily dose)
Equivalent
dosing
Qu a lity
Ra tin g
CIC HFA-MDI (80)
vs.
CIC HFA-MDI (160)
vs.
FP HFA-MDI (176)
Yes (low)
Fair
CIC HFA-MDI (160)
vs.
FP HFA-MDI (176)
Yes (low)
Fair
12 weeks
Multicenter
Abbreviations: AQLQ = Asthma Quality of Life Questionnaire; BDP = beclomethasone dipropionate; BUD = Budesonide; CI = confidence interval; CIC = ciclesonide; DB = double-blind;
DD = double dummy; DPI = dry powder inhaler; FP = Fluticasone Propionate; MA = meta-analysis; MDI = metered dose inhaler; NR = not reported; NS = not statistically significant;
OR= odds ratio; QOL = quality of life; RCT= randomized controlled trial; SMD = standard mean difference; SR=systematic review.
Symbol use: Drug X > Drug Y = statistically significant difference in outcomes favoring Drug X; Drug X > Drug Y trend = point estimate favors Drug X, but the difference is not
statistically significant or tests of statistical significance were NR; No difference = no statistically significant difference or tests of statistical significance were not reported and outcomes
are similar.
.
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B. Leukotriene Modifiers
Summary of findings
We found just one fair-rated 12-week head-to-head trial comparing one leukotriene modifier
with another that met inclusion/exclusion criteria for our review (Table 9).72 The trial compared
montelukast and zafirlukast at recommended doses in adults with mild persistent asthma and
reported no statistically significant differences between groups in rescue medicine use and
quality of life. We found no head-to-head trials for comparisons of other leukotriene modifiers.
In addition, we found no head-to-head trials in children.
Overall, limited head-to-head evidence from one short-term study (12 weeks) does not
support a difference between montelukast and zafirlukast in their ability to decrease rescue
medicine use or improve quality of life (Appendix H, Table H-2).
Detailed Assessment
Head-to-head comparisons
1. Montelukast compared with Zafirlukast
One fair-rated 12-week72 head-to-head trial comparing montelukast to zafirlukast met the
inclusion/exclusion criteria for our review. The trial aimed to compare the effect of montelukast
(10 mg/day) and zafirlukast (40 mg/day) on quality of life and rescue medication use. The trial
enrolled 40 adults with mild persistent asthma from a subspecialty respiratory pathophysiology
center in Italy. At endpoint, improvement in beta-agonist use and asthma-related quality of life
(AQLQ) were not significantly different between montelukast- and zafirlukast-treated patients.
2. Montelukast compared with Zileuton
We did not identify any good or fair quality systematic reviews or head-to-head trials that
compared montelukast to zileuton.
3. Zafirlukast compared with Zileuton
We did not identify any good or fair quality systematic reviews or head-to-head trials that
compared zafirlukast to zileuton.
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Table 9. Characteristics of head-to-head studies comparing leukotriene modifiers
in children and adults
Study
Study design
N
Duration
Country
Study population
Setting
Comparison
(total daily dose in mg/day)
Quality rating
Montelukast (ML) compared with zafirlukast
Riccioni et al.72
RCT
Italy
40
Age ≥12, mild, smoking status
NR
ML (10)
compared with
ZAF (40)
Fair
12 weeks
Respiratory Pathophysiology
Center
Montelukast compared with zileuton
No systematic reviews or head-to-head trials found
Zafirlukast compared with zileuton
No systematic reviews or head-to-head trials found
Abbreviations: AQLQ = Asthma Quality of Life Questionnaire; ML = Montelukast; NR = not reported; NS = not statistically significant;
RCT= randomized controlled trial; ZAF = Zafirlukast.
Symbol use: Drug X > Drug Y = statistically significant difference in outcomes favoring Drug X;
Drug X > Drug Y trend = point estimate favors Drug X, but the difference is not statistically significant or tests of statistical
significance were NR;
No difference = no statistically significant difference or tests of statistical significance were not reported and outcomes are similar.
C. Long-Acting Beta-2 Agonists (LABAs)
Summary of findings
We found three fair RCTs73-76 that included head-to-head comparisons of one LABA with
another LABA meeting our inclusion/exclusion criteria. Two compared eformoterol with
salmeterol73, 74 and one compared formoterol with salmeterol.75, 76 Of note, formoterol was
formerly known as eformoterol in the UK and these are generally considered to be the same
medicine. We also found one 6-month open-label trial comparing formoterol and salmeterol that
we rated poor quality.77 (Table 10)
Overall, results from three efficacy studies provide moderate evidence (Appendix H,
Table H-3) that LABAs do not differ in their ability to control asthma symptoms, prevent
exacerbations, improve quality of life, and prevent hospitalizations or emergency visits in
patients with persistent asthma not controlled on ICSs alone (Evidence Tables A).
Detailed Assessment
Description of Studies
Of the 3 trials, two compared eformoterol (eFM) with salmeterol (SM) and one compared
formoterol (FM) with SM (Table 10). Study duration ranged from 8 weeks to 6 months. The
most commonly used delivery devices were MDIs and DPIs: two studies (66%) compared DPI to
DPI; one study (33%) compared DPI to DPI and to MDI (eFM DPI compared with SM DPI
compared with SM MDI).74
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Study Populations
The three head-to-head RCTs included a total of 1107 subjects. Two were conducted primarily in
adult populations.73, 75, 76 One study74 was conducted in a pediatric and adolescent population
(age 6-17) (Table 10). Two trials (66%) were conducted in the UK and Republic of Ireland73, 74
and one was conducted in France, Italy, Spain, Sweden, Switzerland and the UK.75, 76 Asthma
severity ranged from mild to severe persistent: one study (33%) was conducted in patients with
mild to moderate persistent asthma,73 one (33%) in patients with moderate persistent,74 and one
(33%) in patients with moderate to severe persistent.75, 76 All three trials enrolled subjects that
were not adequately controlled on ICSs. Smoking status was not reported for the
pediatric/adolescent trial.74 The other two studies (66%) allowed smokers and reported that 14 to
24 percent in each group were smokers.
Sponsorship
Of the 3 head-to-head trials, 2 (66%) were funded by pharmaceutical companies; 1 trial (33%)
did not report the source of funding but at least one author had a primary affiliation with a
pharmaceutical company.
Head-to-head comparisons
1. Eformoterol (eFM) compared with Salmeterol (SM)
Two fair-quality RCTs meeting our inclusion/exclusion criteria compared eFM with SM.73, 74
Both enrolled patients not adequately controlled on ICSs and were conducted in the UK and
Republic of Ireland. The first was an 8-week trial that enrolled 469 adolescents and adults ≥12
years of age with mild to moderate persistent asthma.73 The other was a 12-week trial that
enrolled 156 children and adolescents between six and 17 years of age with moderate persistent
asthma.74
Both trials assessed asthma symptoms, nocturnal awakenings, and exacerbations. One
trial also reported hospital admission or visits to A&E73 while the other study also reported
rescue medication use, quality of life, missed work, missed school, and compliance as well.74
The trials found no difference between those treated with eFM and those treated with SM for all
outcomes except for rescue medicine use: one trial74 found a greater decrease in rescue medicine
use in those treated with eFM than in those treated with SM (Evidence Tables A).
2. Formoterol (FM) compared with Salmeterol (SM)
One fair-quality open-label 6-month RCT meeting our inclusion/exclusion criteria compared FM
with SM in 482 adults ≥ 18 years of age with moderate to severe persistent asthma.75, 76 This trial
reported symptoms, rescue medicine use, quality of life, missed days of work, ER visits, and
hospitalizations. There were no statistically significant differences in these outcomes between
those treated with FM than those treated with SM.
3. Formoterol (FM) compared with Arformoterol (ARF)
We did not identify any systematic reviews or head-to-head trials that compared FM to ARF.
4. Salmeterol (SM) compared with Arformoterol (ARF)
We did not identify any systematic reviews or head-to-head trials that compared SM to ARF.
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Table 10. Characteristics of head-to-head studies comparing LABAs in children and adults
Study
Study Design
N
Duration
Country
Study population
Setting
Comparison
(total daily dose in mcg)
Quality rating
Eformoterol compared with Salmeterol
Campbell et al.
199973
RCT, cross-over
469
8 weeks
UK & Republic of Ireland
eFM DPI (24)
vs.
SM DPI (100)
vs.
SM MDI (100)
Fair
eFM DPI (24)
vs.
SM DPI (100)
Fair
FM DPI (24)
vs.
Age ≥ 18, moderate-severe, not controlled on ICS, 14-16% current SM DPI (100)
smokers
Fair
Age≥ 12, mild to moderate, not controlled on ICS, 20-24% current
smokers in each group
General practice & hospital centres
Everden et al.
200474
RCT, open
156
12 weeks
UK & Republic of Ireland
Children and adolescents age 6-17, moderate persistent, not
controlled on ICS, smoking status=NR
General practice outpatient clinics
Formoterol compared with Salmeterol
Vervloet et al.
199875
AND
Rutten-van Molken
et al. 199876
RCT, open
482
6 months
France, Italy, Spain, Sweden, Switzerland & UK
Outpatient centres
Abbreviations: AQLQ = Asthma Quality of Life Questionnaire; CI = confidence interval; DPI = dry powder inhaler; eFM = Eformoterol; FM = Formoterol; MDI = metered dose inhaler;
NR = not reported; NS = not statistically significant; QOL = quality of life; RCT= randomized controlled trial; SM = Salmeterol; SMD = standard mean difference.
Symbol use: Drug X > Drug Y = statistically significant difference in outcomes favoring Drug X; Drug X > Drug Y trend = point estimate favors Drug X, but the difference is not
statistically significant or tests of statistical significance were NR; No difference = no statistically significant difference or tests of statistical significance were not reported and outcomes
are similar.
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D. Anti-IgE Therapy
Summary of findings
Omalizumab is the only available anti-IgE drug approved for the treatment of asthma; therefore,
there are no studies of intra-class comparisons. We did not find any head-to-head studies directly
comparing omalizumab to ICSs, LABAs, leukotriene modifiers, or combination products. All
included trials are placebo comparisons. We found eight RCTs (13 publications)78-91 and two
systematic reviews with meta-analyses92, 93 that met our eligibility criteria. Only two of the
RCTs83, 84, 90 enrolled children (6-12 years old). Five of the other RCTs included adolescents and
adults ≥ 12 years of age, and one included only adults 20-75 years old.91 (Table 11)
Overall, efficacy studies provide consistent evidence favoring omalizumab over placebo
for the ability to control asthma symptoms, prevent exacerbations, and reduce the need for
additional rescue medication in patients already on ICSs with or without other controller
medications (high strength of evidence, Appendix H, Table H-4). Data from good and fair
quality RCTs and systematic reviews consistently found that omalizumab-treated patients
showed significant improvement in asthma-related health outcomes compared to placebo-treated
patients. Most trials were 28-32 weeks in duration with the exception being one 52 week trial.90
In addition, two trials conducted optional double-blind extensions providing data for up to 52
weeks. Our meta-analyses (Appendix I) and previously published systematic reviews with metaanalyses showed omalizumab to be statistically significantly superior to placebo for several
outcome measures.
Detailed Assessment
Description of Studies
Six of the RCTs were 28 weeks in duration, with the others being 32 and 52 weeks in duration81,
90
(Table 11). Four trials had 16 weeks of stable ICS dose followed by a 12-16 week phase of
ICS tapering. One trial used only a 16 week stable ICS phase without subsequent tapering,91 and
another, longer trial included 24 weeks of stable ICS dose followed by 28 weeks of tapering.90 In
all included RCTs, subjects continued ICS treatment throughout the study duration. In three
trials, all patients were also taking either a LABA or other standard maintenance therapy at
constant doses throughout the study,82, 90, 91 In all eight RCTs and one systematic review,92
omalizumab was administered subcutaneously. One systematic review included studies where
omalizumab was administered intravenously or by inhalation (modes that are not approved for
use in the US or Canada) as well as by subcutaneous injection.93
Study Populations
The eight RCTs included a total of 3,480 patients. Five trials were conducted in adolescent and
adult populations (ranging from 12 to 75 years of age) and one was conducted only in adults age
20 to 75.91 Only two studies were conducted in pediatric populations (6-12 years of age).83, 90 In
addition, all patients had moderate to severe asthma with concurrent allergies and/or rhinitis. One
trial was conducted in the US, one in the US and UK, and one in Japan; the remaining five trials
were multinational.
Current smoking status was not reported in either of the two studies that enrolled children
(age 6-12).83, 90 One study explicitly excluded smokers82 and one included both current and exsmokers;91 the remaining four studies had no current smokers enrolled but included previous
smokers.
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Methodological Quality
The RCTs and systematic reviews were of fair to good quality. Two efficacy studies that met our
eligibility criteria were not included in our analysis because they were rated poor quality
(Appendix F).
Sponsorship
Of the 8 included RCTs, 7 (88%) were funded by pharmaceutical companies; one did not report
the source of funding but at least one author had a primary affiliation with a pharmaceutical
company.82
Head-to-head comparisons
We found no head-to-head studies directly comparing the efficacy of omalizumab with another
asthma treatment. Omalizumab is the only anti-IgE medication approved in the US or Canada for
the treatment of asthma.
Omalizumab compared with placebo
The majority of trials assessed overall asthma symptom scores, exacerbations, use of rescue
medication, quality of life, urgent care or ER visits, and hospitalization rates. All trials found
greater improvements in omalizumab-treated patients (Evidence Tables A and B). One RCT
conducted in children reported nocturnal awakenings.83 One study reported no deaths in either
the omalizumab or placebo groups,90 but no other studies reported mortality or adherence. We
conducted meta-analyes on these outcomes when sufficient data was reported by multiple studies
(Appendix I).
The five trials in adolescent and adult populations reported statistically significant
differences favoring omalizumab in overall symptom scores. The study including only adult
subjects also showed an improvement in asthma symptom score in the omalizumab group, but
the difference was not statistically significant.91 One of the pediatric studies reported “little
change” in scores and “minimal difference” between omalizumab and placebo (data NR).83 The
other also noted no statistically significant difference between groups with respect to mean
change from baseline in nocturnal symptom scores at 24 weeks (–0.63 [0.72] vs –0.50 [0.71], P
= 0.114.90 Two trials reported the proportion of “low symptom days.”78, 85, 89 Both studies used
the term “asthma-free days” but defined the concept to allow for some daily symptoms and daily
use of rescue-medication.
Seven studies assessed the number of exacerbations per patient. The results of our metaanalysis show fewer exacerbations per patient with omalizumab compared to placebo (WMD = 0.18, 95% CI: -0.24, -0.11, I2 7.5). In addition, six studies reported the percentage of patients
with one or more exacerbations. Our meta-analysis results show significantly fewer omalizumabtreated subjects with one or more exacerbations compared to placebo-treated subjects (OR =
0.51, 95% CI: 0.40, 0.67, I2 25.8). There was no significant heterogeneity between studies.
Finally, three studies reported the rate of clinically significant asthma exacerbations.82, 90, 91
All RCTs assessing rescue medication use (seven trials) reported a greater decrease in use
of rescue medication for omalizumab. Differences were statistically significant in five of the
seven studies. The difference was not significant in two studies,82, 91 and the P value was not
reported in one.88 We were not able to conduct meta-analyses for rescue medicine use outcomes
because too few studies reported sufficient data.
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Six of the 8 RCTs that met our eligibility criteria utilized the AQLQ and demonstrated
significantly higher scores in omalizumab-treated patients. Results of our meta-analyses show
greater improvement in quality of life for those treated with omalizumab than for those treated
with placebo. Subjects treated with omalizumab had a statistically significantly greater increase
in AQLQ scores than subjects treated with placebo (SMD = 0.26, 95% CI: 0.18, 0.35, I2 0).
Two systematic reviews with meta-analyses reported results consistent with our findings.
One good quality systematic review included 14 RCTs (3143 subjects) comparing omalizumab
and placebo in children and adults with chronic asthma.93 This review included six RCTs that
met our inclusion criteria and eight studies that did not meet our eligibility criteria (e.g. studies
with N < 40, drug routes of administration not approved in the US or Canada, such as inhaled or
intravenous). All patients had a diagnosis of allergic asthma (ranging from mild to severe).
Another fair quality systematic review conducted a meta-analysis of asthma-related quality of
life from five RCTs.92 We included these trials in our analysis; in addition, we included the
INNOVATE trial.82 Results from this meta-analysis are consistent with our findings.
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Table 11. Characteristics of head-to-head studies comparing omalizumab with placebo in children and adults
Study
Niebauer et al.
200692
Walker et al.
200693
Study design
N
Duration
Country
Population
Setting
Systematic review with
meta-analysis
5 trials (2,056 patients)
Multinational
Systematic review with
meta-analysis
Multinational
14 DB RCTs (15 group
comparisons; 3,143
patients)
Trials of any duration were
included
Busse, et al.
200178
Finn et al. 200379
Lanier et al.
80
2005
RCT DB
525
28 weeks (16 weeks
followed by 12 weeks
tapering ICS dose)
Fair
OM (SQ, IV or inhaled)
Good
Adults and children with chronic asthma
US and UK
0.016 mg/kg per IU/mL of IgE
Fair
every 4 weeks (150 mg or 300
Age 12-75, moderate to severe allergic asthma requiring daily
mg every 4 wks or 225 mg, 300
ICS, on stable BDP dose 4 wks prior to randomization and during mg, or 375 mg every 2 wks)
wks 1-16
Multicenter (5)
Optional 24 week DB
extension
(N = 460)
Holgate et al.
200481
RCT DB
Multinational
246
Age 12-75, severe asthmatics, optimally controlled, requiring high
dose FP (between 1000 and 2000 mcg/day) stabilized for 4 wks
prior to randomization; allergic response (> 1 positive SPT) to
aeroallergen(s)
32 weeks (16 week
treatment phase, 16 week
steroid reduction phase)
0.016 mg/kg per IU/mL of IgE
every 2 or 4 weeks
Quality
rating
Adults and children
with asthma; 3 with adult and adolescent patients with moderate
to severe asthma, 1 trial of children and adolescents with allergic
asthma, 1 with adults and adolescents with asthma and allergic
rhinitis; concurrent ICS use in all trials
+ Unpublished
data from FDA89
+
Unpublished data
89
from FDA
Dose
0.016 mg/kg per IU/mL of IgE
every 4 weeks
Good
0.016 mg/kg per IU/mL of IgE
Fair
Multicenter
Humbert et al.
200582
RCT DB
Multinational
482
Age 12-75, positive SPT to ≥ 1 perennial aeroallergen, severe
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Table 11. Characteristics of head-to-head studies comparing omalizumab with placebo in children and adults
Study
Study design
N
Duration
Country
Population
Setting
28 weeks
persistent asthma requiring regular treatment with >1000 mcg
BDP or equivalent LABA, continued high dose ICS + LABA
throughout study
INNOVATE
Dose
Quality
rating
Multicenter (hospital clinics)
90
Lanier et al 2009
Milgrom et al.
83
2001
Lemanske et al.
200284
RCT DB
(2:1)
627
Age 6-12 with uncontrolled moderate to severe IgE-mediated
asthma despite treatment with medium- or high-dose ICSs with or
without other controller medications
52 weeks (24 week fixed
steroid phase, 28 week
adjustable steroid phase)
Multicenter
RCT DB
United States
334
Age 6-12, moderate to severe allergic asthma of at least 1 year
duration that was well controlled with ICSs equivalent to 168-420
mcg/day BDP, positive SP
28 weeks (16 week stable
steroid phase,12 week
steroid reduction phase)
+ Unpublished
data from FDA89
Multinational
Ohta et al. 200991 RCT DB
315
28 weeks (16 week
treatment phase, 12 week
follow up phase)
75-375 mg SC every 2 or 4
weeks
Fair
0.016 mg/kg per IU/mL of IgE
every 2 or 4 weeks
Fair
Multicenter
Japan
≥ 0.016 mg/kg per IU/mL of IgE Fair
every 2 or 4 weeks
Age 20-75, uncontrolled moderate to severe asthma despite
high-dose ICSs (≥ 800 mcg/day BDP or equivalent) + ≥ 1 other
standard therapy (LABA, LRTA, theophylline, etc), positive SPT
or in vitro reactivity to ≥ 1 perennial aeroallergen, serum total IgE
30-700 IU/mL
Multicenter (73)
85
Solèr et al. 2001
RCT DB
Multinational
Buhl et al. 200286
546
Age 12-75, Moderate-severe allergic asthma
28 weeks (16 week stable
ICS phase, 8 week
reduction phase,4 week
Multicenter
87
Buhl et al. 2002
+ Unpublished
Controller medications for asthma
≥ 0.016 mg/kg per IU/mL of IgE Good
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Table 11. Characteristics of head-to-head studies comparing omalizumab with placebo in children and adults
Study
Study design
N
Duration
data from FDA89
stable phase)
Country
Population
Setting
Dose
Quality
rating
24 week DB extension (N =
483)
Vignola et al.
200488
RCT DB
Multinational
405
Age 12-74, stable on ≥400 mcg BUD, continued BUD treatment,
allergic asthma and PAR
SOLAR
≥ 0.016 mg/kg per IU/mL of IgE
every 4 weeks
Fair
28 weeks
Concomitant asthma and rhinitis
Multicenter
Abbreviations: AQLQ= Asthma Quality of Life Questionnaire; BDP = beclomethasone dipropionate; FP = fluticasone propionate; ICS= inhaled corticosteroid; LSM= least squares
mean; NNT= number needed to treat; OM= omalizumab; OR= odds ratio; PAQLQ= Pediatric Asthma Quality of Life Questionnaire; PAR= persistent allergic rhinitis; QOL= quality of
life; RCT= randomized controlled trial; RQLQ= Rhinitis Quality of Life Questionnaire; SDM= standard differences in mean; SPT= skin prick test; WMD= weighted mean difference.
Symbol use: Drug X > Drug Y = statistically significant difference in outcomes favoring Drug X; Drug X > Drug Y trend = point estimate favors Drug X, but the difference is not
statistically significant or tests of statistical significance were NR; No difference = no statistically significant difference or tests of statistical significance were not reported and outcomes
are similar.
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E. Combination Products
1. ICS+LABA compared with ICS+LABA
Summary of findings
We found 1 good quality systematic review94 and four randomized controlled trials95-101 that
compared the combination of an ICS plus a LABA with another ICS/LABA combination for
controller therapy. (Table 12) The review and all four trials compared fixed (non-adjustable)
doses of the combination of budesonide and formoterol (BUD/FM) to fixed (non-adjustable)
doses of the combination of fluticasone and salmeterol (FP/SM).
Overall, results from large trials up to six months in duration support no significant
difference in efficacy between combination treatment with BUD/FM and combination treatment
with FP/SM when each is administered via a single inhaler. (Appendix H, Table H-5) The results
of our meta-analysis show no statistically significant difference between those treated with
BUD/FM and those treated with FP/SM for exacerbations requiring oral steroids (OR =1.16,
95% CI:0.95, 1.4; P = 0.15, 3 studies) or exacerbations requiring emergency visits or hospital
admissions (SMD = 0.74, 95% CI: 0.53, 1.04; P = 0.083, 3 studies). (Appendix I)
Detailed Assessment
Description of Studies
Systematic review
We found 1 systematic review of good quality that compared the combination of an ICS plus a
LABA with another ICS/LABA combination for controller therapy.94 The review included only
randomized, controlled, parallel-design trials and required that only single inhaler devices were
used to administer study drugs. Studies lasting fewer than 12 weeks or administering “adjustable
maintenance dosing” or “single inhaler therapy” rather than fixed doses were excluded. The
review included five studies, all of which compared BUD/FM with FP/SM and included a total
of 5,537 adult and adolescent subjects. Three of the five are included in the RCT section of this
report;95, 97, 98 one was excluded from this report due to the study design, with a second
randomization at one month (only allowing a valid comparison of FP/SM with BUD/FM for one
month; our duration criteria was at least 6 weeks).102 The fifth was a study whose results were
not published. Doses of BUD and FM in the included trials ranged from 400-800mcg/day and
12-24mcg/day, respectively. All of the studies administered 500mcg and 100mcg of FP and SM
per day. Included studies ranged from 12 weeks to 30 weeks and took place in the United States
and Europe.
All included studies enrolled adolescents and adults, and neither restricted asthma
severity or current treatment, although participants had to have a history of chronic asthma,
treated with moderate to high maintenance doses of ICS prior to entry. All trials required patients
to be stable for one month before the run-in period and to continue to demonstrate the need for
frequent reliever use during the run-in. Demographics of the included studies indicated that
treatment and comparison groups were well-balanced. All included studies were funded by
pharmaceutical manufacturers.
Four of the trials measured symptom scores, rescue medication use and exacerbations.95,
97, 98, 102
Two trials used a double-blind, double-dummy design; 97, 98 the other two were open-
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label. There were no statistically significant differences between FP/SM and BUD/FM in mean
change in daytime symptom scores (three studies; treatment difference = -0.02; 95% CI -0.6 to
0.03; N = 3,464) or percent of symptom-free days (two studies; treatment difference = 1.25; 95%
CI -1.18 to 3.67; N = 3,027). Exacerbations were reported as participants experiencing an
exacerbation requiring oral steroid treatment and as participants experiencing exacerbations
resulting in hospital admission. For exacerbations requiring oral steroid treatment, there was no
statistically significant difference between FP/SM and BUD/FM (four studies; OR = 0.89; 95%
CI 0.74 to 1.07; N=4,515). Similarly, no statistically significant difference was found between
FP/SM and BUD/FM groups for exacerbations resulting in hospital admissions (four studies; OR
= 1.29; 95% CI 0.68 to 2.47; N = 4,053). In addition, a composite measure was created in order
to measure exacerbations resulting in a hospital admission or an emergency department visit.
This comparison also failed to yield a statistically significant difference between treatments (four
studies; OR 1.3; 95% CI 0.94, 1.8; N = 4,861). There was also no significant difference between
FP/SM and BUF/FM in rescue medication use (three studies; treatment difference = -0.06
puffs/day; 95% CI -0.13 to 0.02; N = 3,469).
Randomized controlled trials
Of the four RCTs we included (seven articles) (Table 12), all four compared the same
medications (BUD/FM compared with FP/SM). All but one study administered both of the
ICS+LABA combinations in a single inhaler; one trial administered BUD+FM in separate
inhalers.101 Study duration ranged from 12 weeks101 to seven months.95 All four trials
administered BUD and FM via DPI; three did so in a single DPI; one trial administered
BUD+FM in separate inhalers.101
Within-trial equipotency of daily ICS dose varied. All four trials administered the same
total daily dose of FP/SM (500/100), which is considered a medium daily dose of ICS when
delivered via DPI and a high daily dose when delivered via pMDI (Table 3). In two trials,
500mcg of FP was compared with an equipotent daily dose of BUD.95-97 In one of these, there
was a third arm that contained an adjustable-dose BUD/FM arm, although this is not a
comparison of interest for the current report. Of the non-equipotent dosage studies, one study
compared low (but adjustable) and medium (but fixed) daily doses of BUD with a high dose of
FP,98-100 and another compared a high daily dose of BUD with a medium dose of FP.101
Study Populations
The four head-to-head RCTs included a total of 5,818 subjects. All studies were conducted in
adolescent and/or adult populations. None included children < 12 years of age. All trials were
multinational. All enrolled subjects that were not adequately controlled on current therapy. Three
were conducted in subjects with moderate to severe persistent asthma; one did not report the
severity classification.98, 99 Three trials (75%) excluded smokers with at least a 10 pack-year
history; one (25%) allowed some smokers and reported that 5% to 7% of subjects in each group
were current smokers.
Sponsorship
Of the four head-to-head trials, 3 (75%) were funded by pharmaceutical companies; 1 trial (25%)
did not report the source of funding but at least one author had a primary affiliation with a
pharmaceutical company. No trials were funded primarily by a source other than a
pharmaceutical company.
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Head-to-head comparisons
1. Budesonide/formoterol (BUD/FM) compared with Fluticasone/salmeterol (FP/SM)
All four trials and the systematic review reported asthma symptoms and exacerbations (Evidence
Tables A and B). Symptoms reported by at least two of the trials were weeks with “wellcontrolled” asthma,95-97 symptom-free days,97-100, nocturnal awakenings / symptom-free nights,95101
, and asthma symptoms scores – as either total98-100 or daytime95-97 scores. In addition, one trial
reported nights with a symptom score <2, 101 and another reported ACQ and AQLQ(S) scores.98100
All four trials reported either number or rate of exacerbations; one measured the number
of exacerbations requiring hospitalization or emergency treatment,96and two measured the
number or rate of exacerbations classified as moderate and/or severe.97-100
All but one trial101 reported use of rescue medication. Number of missed days of work
and AQLQ(S) score were reported by one study,98-100 Finally, one study reported rates of nonemergency health care services utilization, including general practitioner (GP) home visits, GP
clinic visits and GP telephone contacts.101
For most of these outcomes, there were no statistically significant differences between
the BUD/FM and FP/SM groups. The systematic review and three of the four trials were
relatively consistent in finding no difference between groups. One trial reported fewer
symptoms, nocturnal awakenings, exacerbations, hospitalization days, and unscheduled
outpatient visits for those treated with FP/SM than for those treated with BUD+FM.101 This trial
was the smallest (N = 428) and shortest in duration (12 weeks) among the four making this
comparison. It was also the only one that administered BUD+FM in separate inhalers and used a
two-fold greater dose of BUD than the other trials.
The only other included outcomes that were statistically significantly different between
treatments were from a 6-month trial. (N = 3,335)98, 99 It reported no difference in symptoms,
nocturnal awakenings, exacerbations, asthma-related quality of life or missed work, but found
mixed results for rescue medicine use and hospitalizations or emergency visits. Specifically, the
authors reported greater improvement in the number of rescue puffs used per day for those
treated with FP/SM (mean difference, 95% CI: 0.10, 0.01-0.19) and a lower rate of
hospitalizations or emergency visits per 100 patients per six months for those treated with
BUD/FM (5 compared with 8, P = 0.013) . The total number of hospitalizations or emergency
visits was not analyzed for statistical significance, but there were fewer such events in the
BUD/FM arm compared with the FP/SM arm (72 and 106, respectively). A post-hoc analysis of
the original study that was limited to participants ages 16 and above yielded similar results. Of
note, the total daily dose of BUD delivered by DPI in this study is considered medium and the
total daily dose of FP delivered by pMDI is considered high.
There were additional numerical trends for some outcomes that favored one intervention
over the other but for which statistical tests were not performed. One study 95 reported
numerically fewer hospitalizations/ER visits in patients treated with BUD/FM; another 101
reported the same number of ER contacts in both arms but more inpatient days and outpatient
hospital visits in the BUD/FM arm than in the FP/SM arm. It is unclear in the latter study how
many hospital visits contributed to the total number of inpatient days. Median percentage of
patients with symptom-free days was slightly higher in the FP/SM arm than in the BUD/FM arm
(between-group difference = 3%) in another study.97 In the aforementioned 6-month trial, 98, 99
fewer severe exacerbations were reported in the BUD/FM arm, compared with the FP/SM arm
(173 and 208, respectively), but this difference was not reported to be statistically significant.
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We conducted meta-analyses for exacerbations requiring oral steroid treatment for ≥ 3
days and for exacerbations requiring emergency department visits and/or hospital admissions
(Appendix I). The results of our meta-analyses show no statistically significant difference
between those treated with BUD/FM and those treated with FP/SM in exacerbations requiring
oral steroids or exacerbations requiring emergency visits or hospital admissions.
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Table 12. Characteristics of head-to-head studies comparing ICS+LABA with ICS+LABA
Study design
N
Duration
Study
Country
Population
Setting
Comparison
(total daily ex-mouthpiece dose in
mcg)
Equipotent
steroid
component
Quality
rating
Variable
Good
Yes, for the nonadjustable arms
Fair
Yes
Good
No (low
compared with
medium
compared with
high)
Good
Budesonide/formoterol (BUD/FM) compared with fluticasone/salmeterol (FP/SM)
Lasserson et al.
200894
SR
5,537
> 12 weeks
Multinational
Any age; chronic asthma diagnosis,
unrestricted by severity, previous or current
treatment
BUD/FM (320-640/9-18) DPI, pMDI
vs.
FP/SM (500/100) DPI
Multicenter
95
Aalbers et al. 2004
RCT
658
AND
Aalbers et al. 201096a
Multinational (6:
Denmark, Finland, Germany, Norway,
Sweden and The
Netherlands)
7 months (1 month
double-blind, 6
Age > 12 years, asthma > 6 months, not
months open)
controlled on ICS alone, moderate to
severe, excluded smokers with ≥ 10 packyear history
BUD/FM (320-640/9-18) AD DPI
vs.
BUD/FM (640/18) DPI
vs.
FP/SM (500/100) DPI
Multicenter (93), outpatient clinics
97
Dahl et al. 2006
EXCEL trial
RCT
1397
24 weeks
Multinational
Age > 18 years with asthma for a minimum
of 6 months, not controlled on 1000-2000
BDP or equivalent, moderate to severe,
excluded smokers with ≥ 10 pack-year
history
BUD/FM (640/18) DPI
vs.
FP/SM (500/100) DPI
Multicenter
Kuna et al. 200798
RCT
AND
3335
Price et al. 200799
6 months
AND
Multinational
Age ≥12, not controlled, taking ICS at entry
(46-47% also taking LABA at entry), 5-7%
were current smokers
Multicenter, outpatients
BUD/FM (320/9 + as-needed use) DPI
(mean BUD/FM dose including rescue
use 483/13.6)
vs.
BUD/FM (640/18) DPI
vs.
FP/SM (500/100) pMDI
Kuna 2010100b
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Table 12. Characteristics of head-to-head studies comparing ICS+LABA with ICS+LABA
Study
Ringdal et al. 2002101
EDICT trial
Study design
N
Duration
Country
Population
Setting
Comparison
(total daily ex-mouthpiece dose in
mcg)
RCT
Multinational (11
European countries)
BUD (1280) DPI + FM (24) DPI
vs.
FP/SM (500/100) DPI
428
12 weeks
Equipotent
steroid
component
No (high BUD
compared with
medium FP)
Quality
rating
Good
Age 16-75 years, moderate to severe
persistent asthma, not controlled on ICS,
excluded smokers with ≥ 10 pack-year history
Primary care and hospital respiratory clinics
Abbreviations: AD= adjustable dosing; BUD+FM= budesonide and formoterol in seperate inhalers; BUD/FM= budesonide and formoterol in one inhaler; DPI= dry powder inhaler; FP =
fluticasone propionate; FP+SM= fluticasone and salmeterol in separate inhalers; FP/SM= fluticasone and salmeterol in one inhaler; ICS = inhaled corticosteroid; LABA = long-acting
beta-2 agonist; NS= not statistically significant; pMDI= pressurized metered dose inhaler; SR = systematic review; RCT= randomized controlled trial.
a
Post-hoc analysis of ages ≥ 16 (N = 644) from the full study population.
b
Post-hoc analysis of ages ≥ 16 (N = 2854) from the full study population.
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2. ICS/LABA for both maintenance and as-needed relief (ICS/LABA MART) vs.
ICS/LABA for maintenance with a Short-Acting Beta-Agonist (SABA) for relief
Summary of findings
We found four fair or good quality RCTs (making five relevant comparisons) meeting our
inclusion/exclusion criteria (Table 13).98-100, 103-106 All compared the combination of budesonide
(BUD) plus formoterol (FM) in a single inhaler for maintenance and as-needed relief with a
fixed dose ICS/LABA combination plus a Short-Acting Beta-Agonist (SABA) for as-needed
relief. BUD/FM is not approved for use as a relief medication in the United States, but it has
been approved for maintenance and reliever therapy in Canada when administered via a DPI.
Delivery of BUD/FM via pMDI is not indicated for MART. Two trials compared BUD/FM for
maintenance and relief to BUD/FM for maintenance with a SABA for relief;98-100, 103, 105 three
trials compared BUD/FM for maintenance and relief to the combination of fluticasone and
salmeterol (FP/SM) for maintenance with a SABA for relief.98, 100, 104, 106 Several of the trials
included in this section significantly reduced the total ICS doses for many of the subjects upon
randomization (some studies averaged a 75% dose reduction).
Overall, results from large trials up to twelve months in duration found statistically
significantly lower odds of exacerbations requiring medical intervention for those treated with
BUD/FM for maintenance and relief than for those treated with ICS/LABA for maintenance and
a SABA for relief (moderate strength of evidence, Appendix H, Table H-6). Our meta-analysis
showed an odds ratio of 0.746 (95% CI: 0.656, 0.848; 5 comparisons) favoring MART. A
separate meta-analysis of exacerbations resulting in emergency department visits or hospital
admissions revealed similar findings; the odds ratio for MART was 0.733 (95% CI: 0.597, 0.900;
4 comparisons). MART was also associated with fewer nocturnal awakenings, compared with
ICS/LABA + SABA (SMD = -0.076; 95% CI = -0.124, -0.027; 4 comparisons). I2 values for
each of those meta-analyses were < 25%, indicating low heterogeneity, and sensitivity analysis
results did not change our conclusions in either case. (Appendix I)
Results from individual trials for other outcomes were mixed, but generally favored
BUD/FM for maintenance and relief or were not different between groups. None of the
individual trials found a significant difference in symptoms. Our meta-analyses found no
statistically significant differences in symptom-free days (SMD = 0.023, 95% CI: -0.019, 0.065;
4 comparisons), symptom scores (SMD = -0.018, 95% CI: -0.066, 0.031; 5 comparisons),
rescue-free days (SMD = -0.040, 95% CI: -0.088, 0.009; 4 comparisons), or rescue medicine
puffs per day (SMD = -0.058, 95% CI: -0.137, 0.020; 5 comparisons). Sensitivity analyses for
each of these comparisons did not reveal anything that would change our conclusions. (Appendix
I) It is difficult to determine the applicability of the results of these trials given the heterogeneity
of study designs and dose comparisons.
Detailed Assessment
Description of Studies
Of the four RCTs we included (Table 13), two compared BUD/FM MART to BUD/FM for
maintenance and SABA for relief,98-100, 103, 105 and three compared BUD/FM MART to FP/SM
for maintenance and SABA for relief. All trials administered the ICS/LABA combinations in a
single inhaler. Study duration ranged from 6 months98, 100, 104 to 12 months.103, 105, 106
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Total daily maintenance ICS components of the BUD/FM MART groups varied. One
study compared low starting and mean ex-mouthpiece doses of BUD (in the MART arm) with
low fixed-dose BUD (fixed-dose BUD/FM arm),103, 105 one compared low mean daily dose of
BUD (MART arm) with medium and high doses of non-adjustable combinations,98-100 one
compared medium dose with medium dose,106 and one compared medium dose BUD (MART
arm) with high fixed-dose FP (FP/SM + SABA arm).104 In two studies, the mean total daily dose
of ICS administered ex-mouthpiece in the BUD/FM MART group was less than the total daily
dose in the ICS/LABA with a SABA for relief group.98-100, 104 Several of the trials significantly
reduced the total ICS doses for many of the subjects upon randomization. Some studies reduced
the starting ICS doses to levels that could be considered inadequate compared to the subjects’
previous dose requirements. In three studies all medications were delivered via DPIs; one study
compared BUD/FM DPI with FP/SM pMDI.98-100
Study Populations
The four head-to-head RCTs included a total of 10,547 subjects. Three studies were conducted in
adolescent and/or adult populations. One study included children and adults,105 and one
publication further described the subset of children four to 11 years of age from that study.103
Another publication examined only the subset of participants ages 16 and older.100
All trials were multinational. All enrolled subjects that were not adequately controlled on
current therapy. Two were conducted in subjects with mild to moderate persistent asthma103-105
and two did not report asthma severity classification.98-100, 106 Two trials did not report smoking
rates and two allowed some smokers.98-100, 104 Trials enrolling smokers reported that 4% to 7% of
subjects in each group were current smokers.
Sponsorship
Of the four head-to-head trials, all four (100%) were funded by pharmaceutical companies.
Head-to-head comparisons
1. BUD/FM MART compared with ICS/LABA for maintenance and SABA for relief
The results of the four RCTs contributing five comparisons (one study compared BUD/FM
MART with BUD/FM maintenance and SABA relief and with FP/SM maintenance and SABA
relief) are described below under the appropriate drug comparisons. Overall, all five comparisons
reported statistically significantly lower rates of exacerbations for those treated with BUD/FM
MART, but no differences in symptoms.
We conducted meta-analyses for seven outcomes that were reported with sufficient data
in multiple trials (Appendix I). These included symptom-free days, symptom scores, nocturnal
awakenings, exacerbations requiring medical intervention, exacerbations resulting in emergency
visit or hospital admission, rescue-free days, and rescue medicine use (puffs/day).
Our meta-analysis for exacerbations requiring medical intervention shows an odds ratio
of 0.75 (95% CI: 0.66, 0.85; 5 comparisons) favoring MART. A separate meta-analysis of
exacerbations resulting in emergency department visits or hospital admissions revealed similar
findings; the odds ratio for MART was 0.73 (95% CI: 0.60, 0.90; 4 comparisons). MART was
also associated with fewer nocturnal awakenings, compared with ICS/LABA + SABA (SMD = 0.08; 95% CI = -0.12, -0.03; 4 comparisons). I2 values for each of these analyses was < 25%.
We found no statistically significant differences in symptom-free days (SMD = 0.02,
95% CI:-0.02, 0.06, 3 studies contributing 4 comparisons), symptom scores (SMD = -0.02, 95%
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CI: -0.07, 0.03, P = 0.48; 4 studies contributing 5 comparisons), rescue-free days (SMD = -0.04,
95% CI: -0.09, 0.01, 3 studies contributing 4 comparisons), or rescue medicine puffs per day
(SMD = -0.06, 95% CI: -0.14, 0.02, P = 0.14; 4 studies contributing 5 comparisons). The I2 value
for rescue medication use was 76.6, indicating high statistical heterogeneity.
Of note, the comparisons that administered scheduled maintenance ICS doses that were
lower in the BUD/FM MART group all found statistically significantly lower exacerbation rates
for those treated with BUD/FM MART.98-100, 104 In addition, the BUD/FM MART group had a
lower mean daily steroid dose (maintenance plus relief) than the ICS/LABA for maintenance
with SABA relief in three of the five trials.98-100, 104, 106 Thus, it does not appear that delivering a
higher total ICS dose explains the better exacerbations outcomes in the BUD/FM MART group.
2. BUD/FM MART compared with BUD/FM for maintenance and SABA for relief
We found one good-98-100 and one fair-quality 103, 105 RCT for this comparison. Both trials
reported asthma symptoms, nocturnal awakenings, exacerbations, and rescue medicine use
(Table 13). One trial also reported missed work, hospitalizations, and emergency visits98-100
(Evidence Tables A and B). The results are mixed but show a trend favoring the BUD/FM
MART for several outcomes. Both reported statistically significant differences in exacerbations
favoring BUD/FM MART, but reported no difference in symptoms. One trial reported fewer
nocturnal awakenings in both children and adults treated with BUD/FM MART.103, 105 The single
study reporting hospitalizations and emergency visits found no difference between groups in the
full population analysis98, 99 but a small but significant decrease in hospitalizations / emergency
visits favoring BUD/FM MART among those age 16 and older.100 The trial reporting missed
work found a numerical difference favoring BUD/FM MART, but the statistical significance was
not reported.98-100
None of the trials reported any outcomes favoring the BUD/FM for maintenance and
SABA for relief.
3. BUD/FM MART compared with FP/SM for maintenance and SABA for relief
We found two good-98-100, 104 and one fair-quality RCTs106 comparing these treatments. All three
trials reported asthma symptoms, exacerbations, and rescue medicine use (Evidence Tables A
and B). Two trials reported nocturnal awakenings and hospitalizations or emergency visits.98-100,
104
One trial also reported missed work98-100 and two reported quality of life.98-100, 106
The results are mixed but show a trend favoring BUD/FM MART for some outcomes.
All three trials reported no difference in symptoms or nocturnal awakenings, but statistically
significantly lower exacerbation rates in those treated with BUD/FM MART. Outcomes related
to rescue medications use were mixed. One trial reported no difference in rescue medicine use or
rescue-free days;104 one reported no difference in rescue medicine use but a greater percentage of
rescue-free days for those treated with FP/SM plus SABA for relief (56% compared with 59.1%,
P < 0.05);98-100 one reported less rescue medicine use for those treated with BUD/FM MART
(0.58 puffs/day compared with 0.93, P < 0.001).106 The trials reporting quality of life, and
hospitalizations or emergency visits found no difference between treatment groups. The single
trial reporting missed work found the lowest mean number of sick days in the FP/SM arm (2.36
per 6 months), the highest in the BUD/FM fixed-dose arm (3.11 per 6 months), and 2.48 days per
6 months in the MART arm, but the statistical significance was not reported.98-100
Of note, the fair-quality trial106 reduced the starting doses to levels that could be
considered inadequate compared to the subjects’ previous doses. If randomized to FP/SM,
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subjects were stepping down in their level of control and did not have the possibility to adjust the
dose for 4 weeks. The BUD/FM MART group could increase their dose with as needed
BUD/FM. This initial possible under-treatment may have biased the study in favor of the
BUD/FM MART group.
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Table 13. Characteristics of head-to-head studies comparing BUD/FM for maintenance and relief (MART) with
ICS/LABA for maintenance and Short-Acting Beta-Agonist (SABA) for relief
Study design
N
Duration
Study
Country
Population
Setting
Comparison
(total daily ex-mouthpiece dose in mcg)
Equipotenta
Quality
rating
BUD/FM MART compared with BUD/FM for maintenance and SABA for relief or compared with FP/SM for maintenance and SABA for relief
Bisgaard et al.
2006103b
RCT, DB
Multinational (12)
341
Age 4-11, mild-moderate persistent
asthma > 6 months, not controlled
on ICS, smoking status NR
12 months
Multicenter (41)
Bousquet et al.
2007104
RCT
2309
6 months
BUD/FM MART (80/4.5 + as needed) DPI; overall
mean daily dose including rescue use 126/7.1
vs.
BUD/FM (80/4.5) DPI + terbutaline 0.4mg as
needed
vs.
BUD (80) DPI + terbutaline 0.4mg as needed
Multinational (17)
BUD/FM MART (640/18 + as-needed) DPI (overall
mean daily BUD dose including rescue use 792)
Age ≥ 12, uncontrolled on ICS or
vs.
ICS+LABA, moderate persistent
FP/SM (1000/100 + terbutaline 0.4mg as needed)
asthma, excluded smokers with ≥ 10 DPI
pack-year history, 4-5% were
current smokers
Yes
Fair
No (medium
BUD vs. high
FP)
Fair
Multicenter (184 centers)
105
O'Byrne et al. 2005
RCT
Multinational (22)
AND
2760
Bisgaard et al.
2006103
1 year
Age 4-80, uncontrolled on ICS,
moderate persistent asthma,
smoking status NR
Multicenter (246)
Adults:
BUD/FM MART (160/9 + as-needed) DPI; overall
mean daily dose approx. 250 – estimated from
graph)
vs.
BUD/FM (160/9) DPI + terbutaline 0.4mg as
needed)
vs.
BUD (640) DPI med + terbutaline 0.4mg as
needed;
Yes (for the 2
Fair
arms of interest
in this
comparison)
Children:
BUD/FM MART (80/4.5 + as needed) DPI; overall
mean daily dose including rescue use 126/7.1
vs.
BUD/FM (80/4.5) DPI + terbutaline 0.4mg as
needed
vs.
BUD (80) DPI + terbutaline 0.4mg as needed
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Table 13. Characteristics of head-to-head studies comparing BUD/FM for maintenance and relief (MART) with
ICS/LABA for maintenance and Short-Acting Beta-Agonist (SABA) for relief
Study
Kuna et al. 200798
AND
Price et al. 200799
Study design
N
Duration
RCT
3335
6 months
Country
Population
Setting
Multinational
Age ≥12, not controlled, taking ICS
at entry (46-47% also taking LABA
at entry), 5-7% were current
smokers
AND
Multicenter
Kuna 2010100
Vogelmeier, et al.106
RCT
Multinational (16)
2135
Age ≥12, not controlled, taking ICS
at entry,smoking status NR
12 months
Multicenter (246)
Comparison
(total daily ex-mouthpiece dose in mcg)
BUD/FM MART (320/9 + as-needed use) DPI
(mean BUD/FM dose including rescue use
483/13.6)
vs.
BUD/FM (640/18) med DPI + terbutaline 0.4mg as
needed
vs.
FP/SM (500/100) high pMDI + terbutaline 0.4mg as
needed
Equipotenta
No (low mean
AD dose BUD
compared with
medium fixed
dose BUD
compared with
high fixed dose
FP)
BUD/FM MART (640/18 + as-needed) DPI med
Yes
(overall mean daily BUD dose including rescue use
~ 650)
vs.
FP/SM (500/100 + as-needed SABA) DPI med +
salbutamol as needed DPI or pMDI
Quality
rating
Good
Good
Abbreviations: BUD = budesonide; BUD/FM budesonide and formoterol administered in a single inhaler; DB = double-blind; DPI = dry powder inhaler; FD= fixed dose; FM =
formoterol; FP = fluticasone propionate; FP/SM = fluticasone and salmeterol administered in a single inhaler; ICS = inhaled corticosteroids; LABAs = long-acting beta-2 agonists;
MART = maintenance and reliever therapy; OL = open-label; pMDI= pressurized metered dose inhaler; RCT= randomized controlled trial; SABA = short-acting beta agonist; SM =
salmeterol
a
Equipotency in BUD/FM + as-needed arms was determined by overall mean daily dose of ICS
b
This publication describes the pediatric subset of the population in the O’Byrne et al. 2005 trial below.
double counting subjects
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105
Thus it is not a separate trial and is not included in meta-analyses, to avoid
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F. Long-Acting Anticholinergics
1. Tiotropium
Summary of findings
Tiotropium is not approved for the treatment of asthma. It is approved for the treatment of
chronic obstructive pulmonary disease (COPD). We found no studies of tiotropium meeting our
inclusion criteria.
II. Inter-class comparisons (between classes)
A. Monotherapy
1. Inhaled Corticosteroids (ICSs) compared with Leukotriene modifiers (LMs)
Summary of findings
We found three systematic reviews with meta-analyses107-109 and 22 RCTs110-134 (Tables 14 and
15). Fourteen of the RCTs were in adolescents and adults ≥12 years of age and 8 (9 articles)
were in children < 12.124-130, 132, 133
Overall, efficacy studies up to 56 weeks in duration provide consistent evidence favoring
ICSs over LTRAs for the treatment of asthma as monotherapy for both children and adults for
rescue medicine use, symptoms, exacerbations, and quality of life (high strength of evidence,
Appendix H, Table H-7, meta-analysis results in Appendix I).
Detailed Assessment
Description of Studies
Of the 22 RCTs (Tables 14 and 15), 6 RCTs compared montelukast with beclomethasone; 9
RCTs compared montelukast with fluticasone; four compared zafirlukast with fluticasone; and
three RCTs compared montelukast with budesonide. Study duration ranged from six weeks to 56
weeks. Three trials included extension phases ranging 36-48 weeks in duration.112, 130, 134
Study Populations
The 22 RCTs included a total of 9,873 patients. Most studies were conducted in adult
populations. Eight studies (9 articles)124-130, 132, 133 were conducted primarily in pediatric
populations. Fourteen studies (45%) were conducted in the United States, two (9%) in Europe,
and six (27%) were other multinational combinations often including Europe, Canada, or the US.
Asthma severity ranged from mild persistent to severe persistent: six studies (27%) were
conducted in patients with mild persistent asthma, 11 (50%) in patients with mild to moderate
persistent asthma, 3 (14%) in patients with mild to severe persistent asthma, and two (9%) did
not report the severity or it was unable to be determined.
Methodologic Quality
The 22 RCTs included in our review were rated fair quality for internal validity. The method of
randomization and allocation concealment was rarely reported.
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Sponsorship
Of the 22 RCTs, 17 (77%) were funded by pharmaceutical companies; only three studies (14%)
were funded primarily by sources other than pharmaceutical companies; 2 studies (9%) did not
report any source of funding.
Head-to-head comparisons
1. Inhaled Corticosteroids (ICSs) compared with Leukotriene Receptor Antagonists (LTRAs)
We conducted meta-analyses for six outcomes that were reported with sufficient data in multiple
trials (Appendix I). Those treated with ICSs had a greater increase in the proportion of days free
from rescue medication (SMD -0.25, 95% CI: -0.31, -0.19, 12 studies), greater reduction in
rescue medicine use per day (SMD -0.23, 95% CI: -0.29, -0.17, 13 studies), greater increase in
percent of symptom free days (SMD -0.21, 95% CI: -0.28, -0.15, 13 studies), greater
improvement in symptom score (SMD -0.28, 95% CI: -0.34, -0.22, 10 studies), less frequent
exacerbations (SMD -0.17, 95% CI: -0.22, -0.12, 13 studies), and a greater increase in quality of
life (AQLQ scores; SMD -0.19, 95% CI: -0.27, -0.12, 7 studies) than those treated with
leukotriene modifiers. For all six meta-analyses, sensitivity analyses indicate no difference in
overall meta-analysis conclusions with any single study removed. In addition, there was no
significant heterogeneity between studies (Appendix I).
When looking at montelukast alone compared with ICSs, our meta-analysis again shows
that patients treated with ICSs had a greater increase in the proportion of days free from rescue
medication use, greater reduction in rescue medicine use per day, greater increase in the
proportion of symptom free days, greater improvement in symptom score, fewer exacerbations,
and greater improvement in quality of life than those treated with montelukast (Appendix I).
When looking at zafirlukast alone compared with ICSs, our meta-analysis again shows
that patients treated with ICSs had a greater increase of the proportion of days free from rescue
medication use, greater increase of the proportion of symptom free days, greater change in
symptom score, and fewer exacerbations than those treated with zafirlukast (Appendix I).
A previously published good quality systematic review included18 RCTs (N = 3,757), 13
of which compared ICS therapy to ML therapy in children and adolescents 18 years and younger
diagnosed with asthma at least 6 months prior to enrollment.109 Six of the included trials also met
our inclusion criteria125, 126, 129-132; seven did not. Duration of studies varied but ranged from 4-12
weeks, 24-28 weeks, and 48-56 weeks, with one study being 112 weeks long. While most of the
studies included patients age 6-18, one study included children younger than 6 (2-8 years) for
which a nebulizer was used for ICS administration. Intervention drugs included oral montelukast
(4 to 10 mg) compared to either inhaled BDP 200-400 mcg/day (0.5 mg nebulized), FP 200
mcg/day, BUD 200-800 mcg/day or TAA 400 mcg/day.
Seven trials (N = 2,429) contributed to the primary outcome, with ICS-treated patients
showing a significantly lower risk of developing an exacerbation requiring systemic
corticosteroids (RR 0.83, 95% CI: 0.72 – 0.96; NNT 24). However, no statistically significant
difference was noted between groups with respect to withdrawals due to exacerbations (N = 680,
RR 0.73, 95% CI: 0.36 – 1.48) and hospitalizations due to exacerbations (N = 533, RR 0.33,
95% CI: 0.03 – 3.15). Additional data were pooled based on secondary outcomes of interest and
found ICS significantly improved mean change from baseline of symptom score (N = 575, SMD
0.18, 95% CI 0.01 – 0.34]), rescue inhaler use (puffs/24 hours: N = 1823, SMD 0.34 puffs/day,
95% CI 0.16 – 0.53]), and rescue-free days (N = 1904, SMD 0.16, 95% CI 0.07 – 0.25).
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Another good quality systematic review with meta-analysis compared licensed doses of
LTRAs with ICSs.107 It included 3 trials testing a higher ICS dose; 3 trials testing a lower ICS
dose; and the 21 remaining trials using equal nominal daily doses of ICS. It included 27 studies
(9100 subjects); 3 of these in children and 24 in adults. Nine of these included trials also met our
inclusion criteria.110-115, 118, 120-123 Eighteen of the included studies in this systematic review did
not meet our inclusion/exclusion criteria. Duration of studies varied but ranged from 4-8 weeks,
12-16 weeks, and 24 to 37 weeks. The intervention drugs included montelukast (5 to 10 mg) and
zafirlukast (20 mg twice daily). The ICS dose was uniform across 21 trials; seven of those used
BDP 400 mcg/day, one used BDP 400-500 mcg/day, and 11 used FP 200 mcg/day. Three trials
tested a high dose of ICS (BUD 800 mcg/day), one trial failed to report the dose used, and three
trials used low dose BDP or equivalent. Eight trials enrolled patients who had mild asthma; 19
enrolled patients with moderate asthma; 3 trials did not report baseline FEV1.
Eighteen trials contributed to the primary outcome showing a 65% increased risk of
exacerbations requiring systemic steroids for any LTRA (10 trials in montelukast and 5 trials in
zafirlukast) compared to any ICS dosing regimen. The pediatric trials (3) could not be pooled
due to a lack of exacerbations. However, 5 trials were pooled for exacerbations requiring
hospitalization and there was no significant difference. Data at 12 weeks was pooled according
to outcome and found ICS significantly improved change in symptom score (6 trials, SMD 0.29,
95% CI: 0.21 to 0.37), nocturnal awakenings (6 trials, SMD 0.21, 95% CI: 0.13 to 0.30), daily
use of B2-agonists (6 trials, WMD 0.28 puffs/day, 95% CI: 0.20 to 0.36), symptom-free days (3
trials, WMD -12, 95% CI: -16 to -7), rescue-free days (3 trials, WMD -14%, 95% CI: -18, -10),
and quality of life (2 trials, WMD -0.3, 95% CI: -0.4, -0.2). Similarly, ICS significantly
improved asthma control days (3 trials, WMD -8 %, 95% CI: -15, -1]) and rescue-free days (2
trials, WMD -9%, 95% CI: -14, -03). LTRAs significantly increased the risk of withdrawal (19
trials, RR 1.3, 95% CI: 1.1, 1.6) which was attributable to poor asthma control (17 trials, RR 2.6,
95% CI: 2.0, 3.4).
A third and final fair-rated meta-analysis compared LTRAs to ICSs.108 It included 6
studies (5278 subjects); 5 retrospective cohort studies and 1 prospective trial. None of these 6
studies met our inclusion criteria. The analysis included trials of subjects with a diagnosis of
asthma, without restriction to severe asthma patients or children. Duration of trials was at least 6
months. The pooling of the 6 trials showed a significantly higher annual rate of emergency
department visits in the LTRA group (P < 0.005). The rate of hospitalizations was shown to
decrease significantly with the use of ICSs compared to LTRAs (2.23% compared with 4.3%; P
< 0.05).
2. Fluticasone (FP) compared with Montelukast (ML)
We found 9 fair quality RCTs (10 articles) that compared ML with FP114-117, 125-130, 133 that met
our inclusion criteria. Our meta-analyses of outcomes from these trials show that patients treated
with FP had a greater increase in the proportion of days free from rescue medication use (SMD 0.25, 95% CI: -0.34, -0.16, 7 studies), greater reduction in rescue medicine use per day (SMD 0.25, 95% CI: -0.33, -0.16, 5 studies), greater increase in the proportion of symptom-free days
(SMD -0.24, 95% CI: -0.32, -0.16, 6 studies), greater improvement in symptom score (SMD 0.24, 95% CI: -0.33, -0.14, 4 studies), fewer exacerbations (SMD -0.17, 95% CI: -0.26, -0.09, 6
studies), and greater improvement in quality of life (AQLQ scores: SMD -0.15, 95% CI: -0.25, 0.06, 4 studies) than those treated with ML (Appendix I).
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Details of the characteristics of the 9 individual RCTs114-117, 125-130, 133 are summarized in
Tables 14 and 15.
3. Beclomethasone (BDP) compared with Montelukast (ML)
Six fair quality RCTs110-113, 118, 124, 134 meeting our inclusion criteria compared montelukast with
beclomethasone (Tables 14 and 15). Most of the outcomes reported favored BDP over ML or
found no difference between groups. In general, the results comparing BDP with ML appear to
be consistent with the overall results comparing ICSs with LTRAs. Our meta-analyses of
outcomes using sufficient data from multiple trials shows that compared to ML-treated patients,
those treated with BDP had fewer exacerbations (SMD -0.15, 95% CI: -0.30, -0.002), and trends
toward a greater proportion of rescue free days (SMD -0.08, 95% CI: -0.19, -0.04) and a greater
proportion of symptom-free days (SMD -0.11, 95% CI: -0.25, 0.02), neither of which reached
statistical significance (Appendix I).
Details of the individual RCTs are summarized in Tables 14 and 15. The only trial
enrolling children < 12 years of age was a fair-rated multinational, multi-center RCT in children
(N = 360) comparing ML 5 mg/day (N = 120) compared with medium dose BDP 400 mcg/day
(N = 119) compared with placebo (N = 121) for 56 weeks.124 Subjects with mild persistent
asthma, age 6.4 – 9.4 for boys and 6.4 – 8.4 for girls were enrolled worldwide (from most
continents). The primary objective of the trial was to assess the effects of ML and BDP on linear
growth, however some of our primary outcomes of interest were also reported. Fewer subjects
treated with ML or BDP had asthma reported as an adverse experience compared to those treated
with placebo, but the difference between groups was not statistically significant (36.7%
compared with 42.9% compared with 50.4%, P = NS for ML compared with BDP). There were
no statistically significant differences in the percentage of patients requiring oral steroids (25%
compared with 23.5%), the percentage requiring more than one course of oral steroids (5.8%
compared with 5.9%), or the percentage of days of b-agonist use (10.55% compared with 6.65%)
between those treated with ML and those treated with BDP.
4. Budesonide (BUD) compared with Montelukast (ML)
We found three fair quality RCTs comparing BUD with ML119, 131, 132 that met our inclusion
criteria (Tables 14 and 15). Too few studies reported sufficient data for meta-analysis of our
included outcomes. Of the three RCTs, one enrolled adult populations, one131 enrolled children
and adolescents ages 6-18, and one132 enrolled children ages 2-8. Most subjects in these trials
had mild persistent asthma. Study duration ranged from 12 weeks to 52 weeks. The reported
outcomes of interest were either not statistically significantly different between the two groups or
favored BUD. For symptoms, two trials119, 131 reported no statistically significant difference
between groups. Two trials reporting exacerbations found more favorable results for those
treated with BUD than those treated with ML.119, 132 The single trial reporting quality of life
found no difference between the treatments for overall quality of life measures.132
5. Fluticasone (FP) compared with Zafirlukast
We found four fair quality RCTs comparing FP with zafirlukast120-123 that met our inclusion
criteria. All four trials show similar results favoring FP over zafirlukast for symptoms, rescue
medicine use, and quality of life. Our meta-analyses again show that subjects treated with FP had
a greater increase in days free from rescue medication use (SMD -0.30, 95% CI: -0.40, -0.20, 4
studies), greater increase of the proportion of symptom free days (SMD -0.29, 95% CI: -0.39, -
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0.19, 4 studies), greater improvement in symptom score (SMD -0.31, 95% CI: -0.41, -0.21, 4
studies), and fewer exacerbations (SMD 0.21, 95% CI: -0.31, -0.11, 4 studies) than those treated
with zafirlukast (Appendix I).
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Table 14. Characteristics of head-to-head studies comparing ICSs with LTRAs in children and adults
Study design
N
Duration
Study
Country
Study population
Setting
Comparison
(total daily dose)
Quality
rating
Inhaled corticosteroids (ICSs) compared with Leukotriene receptor antagonists (LTRAs)
Castro-Rodriguez et al.
2010109
ICS
Children < 18 yrs, diagnosed > 6 months before study entry vs.
ML
and/or vs.
18 RCTs (3,757 subjects
ICS + ML
total); 13 studies compared
ICSs with ML
Systematic review with
meta-analysis
Good
≥ 4 weeks treatment with
ICS or ML
Ducharme et al. 2004107
Systematic review with
meta-analysis
3 trials in children, 24 trials in adults
27 studies (91,00 subjects)
Halpern et al. 2003108
Meta-analysis
6 studies (5278 subjects)
United States
Licensed doses of LTRA vs. ICS
(3 trials tested a higher dose; 3
trials tested a lower dose;
remaining tested equal to
baseline daily doses of ICS)
Good
ICS vs. LTRA
Fair
FP (176 mcg)
vs.
ML (10 mg)
Fair
5 retrospective cohort, 1 prospective trial
Fluticasone (FP) compared with Montelukast (ML)
Busse et al. 2001114
RCT
533
24 weeks
United States
Age 15 and older, moderate to severe persistent asthma,
excluded current smokers within the past year and those
with ≥ 10 pack-year history
Low dose ICS
Multicenter (52)
125
Garcia et al. 2005
MOSAIC Study
RCT
Multinational (24 including Asia, Africa, North and South
America)
FP (200 mcg) via MDI vs.
ML (5 mg)
Fair
994
52 weeks
Children age 6 – 14, mild persistent asthma, smoking status Medium to Low (12-14 years of
NR
age) dose ICS
Multicenter (104)
Primary care
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Table 14. Characteristics of head-to-head studies comparing ICSs with LTRAs in children and adults
Study design
N
Duration
Study
Meltzer et al. 2002115
RCT
522
24 weeks
Country
Study population
Setting
United States
Age 15 and older, moderate to severe persistent asthma,
excluded current smokers within the past year and those
with ≥ 10 pack-year history
Comparison
(total daily dose)
FP (176 mcg)
vs.
ML (10 mg)
Quality
rating
Fair
Low dose ICS
Multicenter
Ostrom et al. 2005
126
RCT
342
12 weeks
United States
Children age 6-12, mild to moderate persistent asthma,
smoking status NR
FP (100 mcg)
vs.
ML (5 mg)
Fair
Low dose ICS
Multicenter (46)
Outpatient clinics
Peters et al. 2007127
RCT
500
16 weeks
United States
Age 6 and older, mild to moderate asthma, smoking status
NR
FP (200 mcg)
vs.
FP (200 mcg)/ SM (100 mcg)
vs.
ML (5 – 10mg)
Fair
Multicenter
Low dose ICS
128, 133
Sorkness et al. 2007
Pediatric Asthma
Controlled Trial (PACT)
RCT
285
48 weeks
United States
Children age 6-14, mild to moderate persistent asthma,
excluded current smokers within the past year
Childhood Asthma Research and Education Centers
FP (200 mcg)
vs.
FP (100 mcg)/ SM (50 mcg) plus
SM (50 mg)
vs.
ML (5 mg)
Fair
Low dose ICS
129
Szefler et al. 2005
RCT
144
16 weeks
United States
Children age 6-17, mild to moderate persistent asthma,
smoking status NR
FP (200 mcg)
vs.
ML (5 – 10mg)
Fair
Low dose ICS
University Clinics
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Table 14. Characteristics of head-to-head studies comparing ICSs with LTRAs in children and adults
Study design
N
Duration
Study
Zeiger et al. 2005116, 117
MIAMI Trial
Country
Study population
Setting
400
Age 15 – 85, mild persistent asthma, smoking status NR
ML (10mg)
vs.
FP (176 mcg)
12 weeks
Multicenter (39)
Low dose ICS
United States
FP (200 mcg)
vs.
ML (5 – 10mg)
RCT
United States
Comparison
(total daily dose)
Quality
rating
Fair
36 week open label
extension
Zeiger et al. 2006130
CARE Network Trial
RCT
144 (127 in analysis)
16 weeks (8 weeks,
crossover, 8 weeks);
additionally, only included
data from the last 4 weeks
of each treatment period
Children age 6-17, mild to moderate persistent asthma,
smoking status NR
Fair
Low dose ICS
Multicenter
Beclomethasone (BDP) compared with Montelukast (ML)
Baumgartner et al.
2003110
6 weeks
BDP (400 mcg)
vs.
Age 15 and older, mild to severe persistent asthma,
ML (10mg)
excluded current smokers within past year and those with > vs.
7 pack-year history
placebo
Multicenter (16)
Medium Dose ICS
RCT
Multinational (North and South America, Europe, Asia,
Africa)
Boys age 6.4-9.4 and girls age 6.4-8.4 years, mild to
moderate persistent asthma, smoking status NR
ML (5mg)
vs.
BDP (400 mcg)
vs.
placebo
Multicenter (30)
High dose ICS
United States
ML (10 mg)
vs.
BDP (400 mcg)
vs.
placebo
RCT
730
Becker et al. 2006124
Multinational (Canada and South America)
360
56 weeks
111
Israel et al. 2002
RCT
782
6 weeks
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Age 15 and older, mild to severe persistent asthma,
excluded current smokers within the past year and those
with > 7 pack-year history
Fair
Fair
Fair
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Table 14. Characteristics of head-to-head studies comparing ICSs with LTRAs in children and adults
Study design
N
Duration
Study
Laviolette et al. 1999
118
RCT
Country
Study population
Setting
Comparison
(total daily dose)
Multicenter (64)
Medium dose ICS
Multinational (18 including Europe, Asia, Africa, Australia,
North America)
BDP (400 mcg) plus ML (10 mg)
vs.
BDP (400 mcg)
vs.
ML (10mg)
vs.
placebo
642
16 weeks
Age 15 and older, mild to severe persistent asthma,
excluded current or former smoker
Multicenter (70)
Quality
rating
Fair
Low dose ICS
134
Lu et al. 2009
RCT, three-part 2x2
crossover study
United States
406 (126 in extension)
Adults age 15-65, ≥ 1 year clinical history of mild to severe
persistent asthma
12 weeks
Multicenter (42 total, 30 extension)
48 week open label
a
extension study
ML 10mg daily
vs.
Loratadine 10mg daily
vs.
ML 10mg + loratadine 10mg
daily
vs.
BDP 400 mcg
Fair
Medium dose ICS
Malmstrom et al. 1999112,
113
RCT
Multinational (19 in Europe, Africa, Australia, Central and
South America)
895 (436 in extension)
12 weeks plus a 3 week
placebo washout period
where patients were
switched from treatment to
placebo
Age 15 and older, mild to severe persistent asthma,
excluded current on former smokers
Multicenter (36), clinical centers
ML 10mg
vs.
BDP 400 mcg
vs.
placebo
Fair
(extension: ML vs. BDP in preassigned groups)
Medium dose ICS
37 week double-blind
extension phase
Budesonide (BUD) vs. Montelukast (ML)
Stelmach et al. 2005131
Controller medications for asthma
RCT
Poland
BUD (400 mcg)
vs.
Fair
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Table 14. Characteristics of head-to-head studies comparing ICSs with LTRAs in children and adults
Study design
N
Duration
Study
51
24 weeks
Szefler et al. 2007132
RCT, open label
Country
Study population
Setting
Comparison
(total daily dose)
Quality
rating
Children age 6-18, newly diagnosed asthma with sensitivity BUD (800 mcg)
to house dust mites, smoking status NR
vs.
ML (5 – 10 mg)
University clinics
Low to Medium Dose ICS
United States
395
Children 2-8, mild persistent asthma, smoking status NR
52 weeks
Multicenter
BUD inhalation suspension
(BIS) (0.5mg)
vs.
ML (4 or 5mg)
Fair
Low dose ICS
119
Yurdakul et al. 2003
RCT
74
12 weeks
Turkey
Adults age 23 – 45, mild persistent asthma, excluded
smokers
BUD (400 mcg)
vs.
ML (10mg)
Fair
Low dose ICS
Research hospital
Fluticasone (FP) compared with Zafirlukast (ZAF)
Bleecker et al. 2000120
RCT
451
12 weeks
Multinational
Age 12 and older, mild to severe persistent asthma,
excluded current smokers within the past year and those
with ≥ 10 pack-year history
FP (176 mcg)
vs.
ZAF (40mg)
Fair
Low dose ICS
Multicenter (41)
121
Brabson et al. 2002
RCT
440
6 weeks
United States
Age 12 and older, mild to moderate persistent asthma,
smoking status NR
FP (176 mcg)
vs.
ZAF (40mg)
Fair
Low dose ICS
Multicenter (44)
Busse et al. 2001122
RCT
338
12 weeks
Controller medications for asthma
United States
Age 15 and older, mild to severe persistent asthma,
excluded current smokers within the past year and those
FP (176 mcg)
vs.
ZAF (40mg)
vs.
Fair
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Table 14. Characteristics of head-to-head studies comparing ICSs with LTRAs in children and adults
Study design
N
Duration
Study
Kim et al. 2000123
RCT
437
6 weeks
Country
Study population
Setting
Comparison
(total daily dose)
with ≥ 10 pack-year history
placebo
Multicenter
50% primary care
Low dose ICS
United States
FP (176 mcg)
vs.
ZAF (40mg)
Age 12 and older, mild to severe persistent asthma,
excluded current smokers within the past year and those
with ≥ 10 pack-year history
Quality
rating
Fair
Low dose ICS
Multicenter
Allergy and Asthma centers
Abbreviations: AQLQ = Asthma Quality of Life Questionnaire; BDP = beclomethasone dipropionate; BUD = Budesonide; CI = confidence interval; FP = Fluticasone Propionate; ICS =
Inhaled Corticosteroids; LTRAs = Leukotriene receptor antagonists; ML = Montelukast; NR = not reported; NS = not statistically significant; QOL = quality of life; WMD = weighted
mean difference; ZAF = Zafirlukast.
Symbol use: Drug X > Drug Y = statistically significant difference in outcomes favoring Drug X; Drug X > Drug Y trend = point estimate favors Drug X, but the difference is not
statistically significant or tests of statistical significance were NR; No difference = no statistically significant difference or tests of statistical significance were not reported and outcomes
are similar.
a
Extension study: ML 10mg + loratadine 10mg daily vs. BDP 400 mcg
Table 15. Characteristics of head to head studies comparing ICSs with LTRAs in children < 12
Study
Study design
N
Duration
Country
Study population
Setting
Comparison
(total daily dose)
Quality
rating
Inhaled corticosteroids (ICSs) compared with Montelukast (ML)
CastroRodriguez et
109
al. 2010
Systematic review with
meta-analysis
18 RCTs (3,757 subjects
total); 13 studies compared
ICSs with ML
Children < 18 yrs, diagnosed > 6 months before study entry
ICS
vs.
ML
and/or vs.
ICS + ML
Good
≥ 4 weeks treatment with
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Table 15. Characteristics of head to head studies comparing ICSs with LTRAs in children < 12
Study
Study design
N
Duration
Country
Study population
Setting
Comparison
(total daily dose)
Quality
rating
ICS or ML
Fluticasone (FP) compared with Montelukast (ML)
Garcia et al.
125
2005
RCT
Multinational (24 including Asia, Africa, North and South
America)
FP (200 mcg) via MDI vs.
ML (5mg)
Children age 6-14, mild persistent asthma, smoking status NR
Medium to Low (12-14 years of age)
dose ICS
Fair
994
MOSAIC Study
52 weeks
Multicenter (104)
Primary care
Ostrom et al.
2005126
RCT
342
12 weeks
Peters et al.
2007127
RCT
United States
FP (100 mcg)
vs.
Children age 6-12, mild to moderate persistent asthma, smoking ML (5mg)
status NR
Low dose ICS
Multicenter (46)
Outpatient clinics
Fair
United States
Fair
500
Age ≥ 6, mild to moderate asthma, smoking status NR
16 weeks
Multicenter
FP (200 mcg)
vs.
FP (200mcg)/ SM (100 mcg)
vs.
ML (5 – 10mg)
Low dose ICS
Sorkness et al.
RCT
2007128, 133
285
Pediatric
48 weeks
Asthma
Controller Trial
(PACT)
United States
Children age 6-14, mild to moderate persistent asthma,
excluded current smokers within the past year
Childhood Asthma Research and Education Centers
FP (200 mcg)
vs.
FP (100 mcg)/SM (50 mcg) plus SM
(50mg)
vs.
ML (5 mg)
Fair
Low dose ICS
Szefler et al.
2005129
RCT
144
Controller medications for asthma
United States
FP (200 mcg)
vs.
Children age 6-17, mild to moderate persistent asthma, smoking ML (5 – 10 mg)
status NR
Fair
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Table 15. Characteristics of head to head studies comparing ICSs with LTRAs in children < 12
Study
Study design
N
Duration
Country
Study population
Setting
16 weeks
University Clinics
Zeiger et al.
RCT
2006130
CARE Network 144 (127 in analysis)
Trial
16 weeks (8 weeks,
crossover, 8 weeks);
additionally, only included
data from the last 4 weeks of
each treatment period
Comparison
(total daily dose)
Quality
rating
Low dose ICS
United States
FP (200 mcg)
vs.
Children age 6-17, mild to moderate persistent asthma, smoking ML (5 – 10mg)
status NR
Low dose ICS
Multicenter
Fair
Beclomethasone (BDP) compared with Montelukast (ML)
Becker et al.
2006124
RCT
360
56 weeks
Multinational (North and South America, Europe, Asia, Africa)
Boys age 6.4-9.4 and girls age 6.4-8.4 years, mild to moderate
persistent asthma, smoking status NR
ML (5mg)
vs.
BDP (400 mcg)
vs.
placebo
Fair
Multicenter (30)
High dose ICS
Budesonide (BUD) compared with Montelukast (ML)
Szefler et al.
2007132
RCT, open label
United States
395
Children 2-8, mild persistent asthma, smoking status NR
52 weeks
Multicenter
BUD inhalation suspension (BIS)
(0.5mg)
vs.
ML (4 or 5mg)
Fair
Low dose ICS
Abbreviations: AQLQ = Asthma Quality of Life Questionnaire; BIS = Budesonide inhalation suspension; BDP = beclomethasone dipropionate; BUD = Budesonide; CI = confidence
interval; FP = Fluticasone Propionate; MDI = metered dose inhaler; ML = Montelukast; NR = not reported; NS = not statistically significant; PAQLQ = Pediatric Asthma Quality of Life
Questionnaire; QOL = quality of life; RCT= randomized controlled trial; RR = relative risk.
Symbol use: Drug X > Drug Y = statistically significant difference in outcomes favoring Drug X; Drug X > Drug Y trend = point estimate favors Drug X, but the difference is not
statistically significant or tests of statistical significance were NR; No difference = no statistically significant difference or tests of statistical significance were not reported and outcomes
are similar.
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2. Inhaled Corticosteroids (ICSs) compared with Long-Acting Beta-2 Agonists (LABAs)
Summary of findings
We found 13 fair or good quality RCTs135-150 that included head-to-head comparisons of one ICS
with one LABA meeting our inclusion/exclusion criteria. Nine of these were multi-arm trials that
compared an ICS/LABA combination product with the individual ICS and LABA
components.135-144, 150 (Table 16)
Overall, efficacy studies provide consistent evidence favoring ICSs over LABAs for the
treatment of asthma as monotherapy for children and adults (high strength of evidence, Appendix
H, Table H-8). Those treated with LABAs had significantly higher odds of experiencing an
exacerbation (as defined by each study) than those treated with ICSs (OR = 2.845; 95% CI =
1.644, 4.863; 6 studies). Although our meta-analyses found no statistically significant differences
in measures of symptoms or rescue medicine use, the majority of individual RCTs included in
this review reported no differences or favorable results for those treated with ICSs compared to
those treated with LABAs for almost all outcomes. Of note, LABAs are not recommended nor
approved for use as monotherapy for persistent asthma.1
Detailed Assessment
Description of Studies
Of the 13 trials, 7 (54%) compared fluticasone with salmeterol, three (23%) compared
beclomethasone with salmeterol, one (8%) compared triamcinolone with salmeterol, and two
(15%) compared budesonide with formoterol (Table 16). Study duration ranged from 12 weeks
to 12 months. LABAs were compared with low-dose ICSs in seven trials (54%) and with
medium-dose ICSs in six (46%). The most commonly used delivery devices were MDIs and
DPIs; 6 studies (50%) compared DPI to DPI; 5 studies (42%) compared MDI to MDI, and two
studies (17%) compared pMDI to DPI.
Study Populations
The 13 head-to-head RCTs included a total of 4196 subjects. Most were conducted primarily in
adult populations. Two studies148, 149 were conducted in pediatric and adolescent populations.
Nine trials (69%) were conducted in the United States, one in Canada, one in Sweden, one in the
Netherlands, and one across North America. Asthma severity ranged from mild to severe
persistent but was most commonly not reported: three studies (23%) were conducted in patients
with mild to moderate persistent asthma, one (8%) in patients with moderate to severe
persistent, and the severity was not reported in nine (69%) trials.
Smoking status was not reported for the two pediatric/adolescent trials and one of the
adolescent/adult trials.136 Among the others, 9 (90%) excluded current smokers or those with a
recent history of smoking and 1 (10%) allowed smokers and reported that 12-17% in each group
were smokers.
Sponsorship
Of the 13 head-to-head trials, 12 (92%) were funded by pharmaceutical companies; only one
study (8%) was funded primarily by a source other than a pharmaceutical company.
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Head-to-head comparisons
1. ICS (any) compared with LABA (any) for monotherapy
We conducted meta-analyses for five outcomes that were reported with sufficient data in
multiple similar trials (Appendix I). These included percentage improvement in symptom-free
days, change in symptom scores, exacerbations, percentage improvement in rescue-free days,
and change in rescue medicine use. We found no statistically significant differences in the
percentage improvement in symptom-free days (SMD = 0.05; 95% CI = -0.10, 0.21; 7 studies),
change in symptom scores (SMD = 0.14; 95% CI = -0.05, 0.34; 6 studies), percentage
improvement in rescue-free days (SMD = -0.14; 95% CI = -0.35, 0.07; P = 0.186; 5 studies),
and change in rescue medicine use (as number of puffs per day) (SMD = 0.14; 95% CI = -0.11,
0.40; 7 studies). We found that those treated with LABAs had a significantly higher odds of
experiencing an exacerbation than those treated with ICSs (OR = 2.8; 95% CI = 1.7, 4.9; 6
studies). The measure of statistical heterogeneity was high in the analysis of rescue puffs per day
(I2 78.4). For all analyses except percentage of rescue free days, sensitivity analyses indicate no
difference in overall meta-analysis conclusions with single studies removed. For the percent
rescue free days analysis, removal of Lundback et al caused the difference between ICS and
LABA to reach statistical significance (favoring LABA) (point estimate = -0251; 95% CI: 0.390, -0.113; P < 0.001).
2. Fluticasone (FP) compared with Salmeterol (SM)
Seven fair-quality RCTs compared FP with SM for monotherapy.135, 137-141, 143, 144, 150 None
included children ≤ 12 years of age. All seven also included comparisons with an FP/SM
combination product. Study duration was 12-weeks for six trialsand 12 months for one.137 Four
compared SM with low-dose FP and three compared SM with medium-dose FP. Six of the seven
were conducted in the United States; one was conducted in Sweden.137
The majority of trials assessed asthma symptoms, nocturnal awakenings, exacerbations,
and rescue medicine use. Two trials140, 143 reported quality of life. The majority of trials found no
difference or a trend toward better outcomes in those treated with FP than those treated with SM
(Evidence Tables A and B).
3. Beclomethasone (BDP) compared with Salmeterol (SM)
Three fair-quality RCTs compared BDP with SM.147-149 One147 enrolled adolescents and adults ≥
12 years of age; the other two studies enrolled children and adolescents aged 6-14148 or 6-16.149
Study duration ranged from 26 weeks to 12 months. All three compared SM with medium-dose
BDP.
All three trials reported exacerbations and rescue medicine use; two reported
symptoms147, 149 and nocturnal awakenings;147, 148 one reported missed school.148 With the
exception of one trial that reported greater improvement in the percentage of rescue-free days for
those treated with SM (36% compared with 28%, P = 0.016),147 all three trials reported no
differences or better outcomes for those treated with BDP than for those treated with SM
(Evidence Tables A).
4. Triamcinolone (TAA) compared with Salmeterol (SM)
One good-rated 16-week multicenter RCT145, 146 (SOCS Trial) compared TAA with SM in 164
adolescents and adults aged 12-65. The trial reported fewer exacerbations and a lower treatment
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failure rate for those treated with TAA, but no statistically significant difference in symptoms,
rescue medicine use, or quality of life (Evidence Tables A).
5. Budesonide (BUD) compared with Formoterol (FM)
Two fair-rated 12-week multicenter RCTs136, 142 compared BUD with FM in adolescents and
adults aged ≥ 12. The results showed trends toward fewer exacerbations and greater
improvements in symptoms, nocturnal awakenings, and rescue medicine use for those treated
with BUD (Evidence Tables A). Whether these trends were statistically significantly different
was not reported (the studies focused on comparing BUD/FM with the other treatments).
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Table 16. Characteristics of head-to-head studies comparing ICSs with LABAs
Study
Study design
N
Duration
Country
Population
Setting
Fluticasone (FP) compared
with Salmeterol (SM)
Kavuru et al. 2000135
RCT, DB
US
AND
356
Age ≥12yr, asthma ≥ 6 months, patients well controlled
on current therapy (stratified into 2 eligible groups:
group 1 had to be on ICS for ≥3 months; group 2 was
taking SM for ≥1 week), severity NR, smokers
excluded
144
Nathan et al. 2003
Lundback et al. 2006137
12 weeks
RCT, DB
282
Murray et al. 2004138
Multicenter (42)
Sweden
12 months
Age 18 to 70, mild or moderate persistent,
uncontrolled on current medication,12-17% smokers in
each group
RCT, DB
Patients recruited from ~4000 individuals with asthma
who had participated in large epidemiologic studies
US
267
Age ≥12yr, asthma ≥6 months, not controlled severity
NR, smokers excluded
12 weeks
Multicenter (33 sites)
US
Nathan et al. 2006139
RCT, DB
AND
365
Edin et al. 2009140
12 weeks
Nelson et al. 2003141
RCT, DB
US
283
Age ≥12, persistent asthma not controlled, severity
NR, smokers excluded
Age ≥12yr, asthma ≥6 months, not controlled on ICS,
severity NR, smokers excluded
Multicenter (45)
12 weeks
Comparison
(total daily dose in mcg)
Quality Rating
Placebo
vs.
FP/SM DPI (200/100)
vs.
SM DPI (100)
vs.
FP DPI (200)
Fair
FP/SM DPI (500/100)
vs.
FP DPI (500)
vs.
SM DPI (100)
Fair
SM DPI (100)
vs.
FP DPI (200)
vs.
FP/SM DPI (200/100)
Fair
FP/SM MDI (440/84)
vs.
FP MDI (440)
vs.
SM MDI (84) vs.
Placebo
Fair
FP/SM MDI (176/84)
vs.
FP MDI (176)
vs.
SM MDI ( 84)
Fair
Multicenter (33)
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Table 16. Characteristics of head-to-head studies comparing ICSs with LABAs
Study
Shapiro et al. 2000143
Study design
N
Duration
RCT, DB
Country
Population
Setting
US
AND
349
Age ≥12, asthma ≥6 months, previously treated with
low to medium ICS, severity NR, smokers excluded
144
Nathan et al. 2003
12 weeks
Multicenter (42)
Pearlman et al. 2004150
RCT, DB
US
AND
360
Edin et al. 2009140
12 weeks
Age ≥12yr, asthma ≥ 6 months, patients well controlled
on current therapy (stratified into 2 eligible groups:
group 1 had to be on ICS for ≥3 months; group 2 was
taking SM for ≥1 week), severity NR, smokers
excluded
Comparison
(total daily dose in mcg)
Placebo
vs.
FP/SM DPI (500/100)
vs.
SM DPI (100)
vs.
FP DPI (500)
FP/SM MDI (176/84)
vs.
FP MDI (176)
vs.
SM MDI (84)
vs.
Placebo
Quality Rating
Fair
Fair
Multicenter (36)
Beclomethasone (BDP) compared with Salmeterol (SM)
Nathan et al. 1999147
RCT, DB
US
386
Age ≥12yr, on SABAs, not on inhaled or oral
corticosteroids, severity NR, smokers excluded
26 weeks
Simons et al. 1997148
RCT, DB
241
Multicenter (25)
Canada
Age 6-14, clinically stable asthma, not currently on
ICS, severity NR, smoking status NR
52 weeks
Verberne et al. 1997149
RCT, DB
67
Multicenter
Netherlands
Age 6-16, on ICS ≥3 months, mild to moderate
persistent asthma, smoking status NR
SM MDI (84)
vs.
BDP MDI (336)
vs.
placebo
Fair
BDP DPI (400)
vs.
SM DPI (100)
vs.
placebo
Fair
SM DPI (100)
vs.
BDP DPI (400)
Fair
TAA MDI (800)
vs.
SM MDI (84)
Good
54 weeks
Multicenter (18)
Triamcinolone (TAA) compared with Salmeterol (SM)
Lazarus et al. 2001145
RCT, triple-blind
North America
AND
Controller medications for asthma
164
Age 12-65, persistent asthma, well controlled on TAA,
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Table 16. Characteristics of head-to-head studies comparing ICSs with LABAs
Study
Study design
N
Duration
Deykin et al. 2005146
16 weeks
Country
Population
Setting
severity NR, smokers excluded
Comparison
(total daily dose in mcg)
vs.
placebo
Quality Rating
Multicenter (6)
SOCS Trial
Budesonide (BUD) compared with Formoterol (FM)
Noonan et al. 2006142
RCT; DB
US
596
12 weeks
Age ≥12, moderate to severe persistent asthma not
controlled, on moderate to high dose ICS for ≥4
weeks, smokers excluded
Multicenter (84)
Corren et al.
2007136
RCT, DB
US
480
Age ≥12, mild to moderate persistent asthma, treated
with low to medium dose ICS for ≥4 weeks, smoking
status NR
12 weeks
Multicenter (56)
BUD/FM pMDI (640/18)
vs.
BUD pMDI (640)
vs.
FM DPI (18)
vs.
BUD pMDI (640) + FM DPI
(18)
vs.
placebo
BUD/FM pMDI (320/18)
vs.
BUD pMDI (320)
vs.
FM DPI (18)
vs.
placebo
Fair
Fair
Abbreviations: BDP = beclomethasone dipropionate; BUD = Budesonide; DD= double dummy; DPI = dry powder inhaler; FM = Formoterol; FP = Fluticasone
Propionate; ICS = Inhaled Corticosteroids; LABAs = Long-Acting Beta-2 Agonists; MA=meta-analysis; MDI = metered dose inhaler; NR = not reported; NS = not
statistically significant; RCT= randomized controlled trial; SM = Salmeterol; SR=systematic review; TAA = Triamcinolone Acetonide
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3. Leukotriene modifiers compared with Long-Acting Beta-2 Agonists (LABAs)
Summary of findings
We found 2 fair quality RCTs151, 152 that included head-to-head comparisons of one leukotriene
modifier with one LABA meeting our inclusion/exclusion criteria. One trial compared
montelukast with salmeterol151 and one compared montelukast with eformoterol.152 (Table 17)
Overall, the 2 small trials do not provide sufficient evidence to draw any firm conclusions
about the comparative efficacy of leukotriene modifiers and LABAs for use as monotherapy for
persistent asthma (Appendix H, Table H-9). Of note, LABAs are neither recommended nor
approved for use as monotherapy for persistent asthma.1
Detailed Assessment
Description of Studies
We found two fair quality RCTs151, 152 that included head-to-head comparisons of one
leukotriene modifier with one LABA meeting our inclusion/exclusion criteria (Table 17). One 8week trial compared montelukast with salmeterol151 and one 18-week trial compared
montelukast with eformoterol.152
Study Populations
The two RCTs included a total of 249 subjects. All were conducted primarily in adult
populations. One was conducted in the United States151 and one was conducted in Australia.152
One trial included patients with moderate to severe asthma,152 and asthma severity was not
reported in the second trial.151 Both trials excluded current smokers or those with more than a 10
to 15 pack-year history.
Sponsorship
One trial was funded by a pharmaceutical company,151 and one trial was funded by a
combination of industry and federal government sources.152
Head-to-head comparisons
1. Montelukast compared with Salmeterol
One fair-rated RCT (N = 191) compared ML 10 mg/day (N = 97) compared with SM 100
mcg/day (N = 94) as monotherapy for 8 weeks.151 Subjects with chronic asthma and evidence of
exercise-induced bronchoconstriction age 15 to 45 were enrolled from multiple centers in the
United States. The trial was designed to evaluate exercise-induced bronchoconstriction and most
of the outcomes reported were intermediate outcomes that are not included in our report. The
trial also reported mortality as an outcome, with no deaths in the ML group and one in the SM
group (P = NR).
2. Montelukast compared with Eformoterol
One fair-rated cross-over RCT (N = 58) compared eformoterol 24 mcg/day with ML 10 mg/day
(six weeks of treatment, one-week washout, six weeks of treatment with the other medication,
one-week washout, then all subjects received fluticasone 500 mcg/day for six weeks).152 Subjects
age 16 to 75 with mild to moderate persistent asthma previously treated with or without ICS
were enrolled from multiple research centers in Australia. We only report results of the ML and
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eFM comparison because the fluticasone portion of the study does not have a comparison. Over
the 12 weeks of treatment, subjects treated with eFM had fewer symptoms (percentage of
symptom-free days: 23 compared with 0; P = 0.01; symptom scores: 1.2 compared with 1.6; P =
0.02), less rescue medicine use (percentage of rescue-free days: 40 compared with 30; P =
0.008), and better quality of life (QOL score: 0.4 compared with 0.6; P = 0.001) compared to
those treated with ML.
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Table 17. Characteristics of head-to-head studies comparing leukotriene modifiers with LABAs for monotherapy
Study
Study design
N
Duration
Country
Study population
Setting
Comparison
(total daily dose)
Quality rating
Montelukast compared with Salmeterol
Edelman et al.151
RCT
191
United States
ML (10mg)
vs.
Age 15-45, severity NR, excluded current smokers SM (100 mcg)
and those with ≥15 pack-year history
Fair
8 weeks
Multicenter (17), research centers
Montelukast compared with Eformoterol
Jenkins et al.
2005152
RCT, cross-over
Australia
58
Age 16-75, mild to moderate persistent asthma,
excluded current smokers and those with ≥10
pack-year history
20 weeks (eFM and ML were compared
for first 13 weeks, with 1 week washout
in between 6 week treatment periods)
Research centers
eFM DPI (24 mcg)
vs.
ML (10 mg)
Fair
After the first 14 weeks, all
subjects were treated with
FP 500 mcg/day + placebo
Abbreviations: eFM = eFormoterol; ML = Montelukast; NR = not reported; NS = not statistically significant; QOL = quality of life; SM = Salmeterol.
Symbol use: Drug X > Drug Y = statistically significant difference in outcomes favoring Drug X; Drug X > Drug Y trend = point estimate favors Drug X, but the difference is not
statistically significant or tests of statistical significance were NR; No difference = no statistically significant difference or tests of statistical significance were not reported and outcomes
are similar.
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B. Combination therapy
1. ICS+LABA compared with ICS (same dose) as first line therapy
Summary of findings
We found one good systematic review that was recently updated153 and 9 fair RCTs,138, 141, 154-160
that compared the combination of an ICS plus a LABA with an ICS alone (same dose) for first
line therapy in patients with persistent asthma meeting our inclusion/exclusion criteria (Table
18). Seven trials compared fluticasone plus salmeterol with fluticasone alone and two compared
budesonide plus formoterol with budesonide alone.
Overall, meta-analyses of results from large trials up to twelve months in duration found
mixed results and do not provide sufficient evidence to support the use of combination therapy
rather than ICS alone as first line therapy. Meta-analyses found statistically significantly greater
improvements in symptoms and rescue medicine use, but no difference in exacerbations for
adolescents and adults treated with ICS+LABA than for those treated with same dose ICS alone
for initial therapy (Appendix H, Table H-10). Results were consistent for estimates in differences
in symptoms between our meta-analysis and a previously published meta-analysis.153 However,
limited data were available for exacerbations and further research may change our confidence in
the estimate of effect for this outcome. The updated systematic review included studies with
children, but we found no studies for this comparison that met our inclusion criteria and enrolled
children < 12 years of age. Of note, according to FDA labeling, ICS+LABA combination
products are only indicated for patients not adequately controlled on other asthma-controller
medications (e.g., inhaled corticosteroids) or whose disease severity clearly warrants initiation of
treatment with both an inhaled corticosteroid and LABA.
Detailed Assessment
Description of Studies
The systematic review153 included 24 studies from 19 publications and 4 unpublished sources.
Eight of those trials met our inclusion criteria,138, 141, 154-157, 159, 160. Fourteen did not meet our
inclusion criteria and 1 study 161 was included but rated poor. We included 1 trial158 that was not
in the systematic review (it was published after the review).
We identified two other systematic reviews162, 163 that included studies of ICS+LABA
compared with same dose ICS. One review focused on FP+SM compared with FP163. This
review included 30 studies of adults and adolescents (N = 10,873) and 3 studies in children (N =
1,173). The other review focused on BUD+FM compared with BUD162. It included 21 studies of
adults (N = 8,028) and children (N = 2,788). These reviews combined studies of steroid naïve
patients with studies of patients who had previously used steroids and therefore are not included
in our assessment of ICS + LABA compared with same dose ICS alone as first line therapy.
Of the 9 RCTs we included (Table 18), 7 compared fluticasone + salmeterol with
fluticasone alone138, 141, 154, 155, 158-160 and two compared budesonide + formoterol with budesonide
alone.156, 157
Study duration was 12 weeks for 6 trials, 24 weeks for 2 trials,155, 158 and one year for one
157
trial. Eight trials used low doses of ICSs and 1 trial used medium doses.154 In 7 studies, all
medications were delivered via DPIs; 2 used MDIs.141, 160 Seven studies tested the combination
of a LABA and an ICS administered in a single inhaler and two used separate inhalers.156, 157
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Study Populations
The 9 head-to-head RCTs included a total of 3,932 subjects. All studies were conducted in
adolescent and/or adult populations. None included children < 12 years of age. Three trials were
multinational,154, 157, 160 4 were conducted in North America,138, 141, 158, 159 one in Denmark,155 and
one in Russia.156 The subjects generally had mild to moderate persistent asthma, were steroid
naïve, and were only taking short-acting beta-agonists prior to enrollment. Asthma severity
ranged from mild to moderate persistent: 3 studies were conducted in patients with mild
asthma,157, 158, 160 one in patients with mild to moderate asthma,156 and one in patients with
moderate asthma.154 Severity classification was not reported in 4 studies.138, 141, 155, 159
Three trials (33%) excluded current smokers or those with a recent history of smoking,138,
141, 159
5 (56%) allowed some smokers, and one (11%) did not report any information about
smoking status.157 Among those that allowed some smokers, 4154, 156, 158, 160 only allowed those
with less than a 10 pack-year smoking history and 2155, 158 reported that 9-46% of subjects in
each group were current smokers.
Sponsorship
Of the 9 head-to-head trials, all (100%) were funded by pharmaceutical companies.
Head-to-head comparisons
1. ICS+LABA compared with ICS
The results of the 9 individual trials are described below under the appropriate drug comparisons.
We conducted meta-analyses for outcomes that were reported with sufficient data in multiple
trials (Appendix I). These included symptom-free days, symptom scores, rescue medicine-free
days, and rescue medicine use (puffs/day). We found statistically significant differences favoring
those treated with ICS+LABA for all four outcomes. Those treated with ICS+LABA had greater
improvement in the percentage of symptom-free days (SMD = 0.24 , 95% CI: 0.14, 0.33; 6
studies), symptom scores (SMD = 0.28, 95% CI: 0.15, 0.41; 4 studies), percentage of rescue
medicine-free days (SMD 0.32, 95% CI 0.20, 0.43; 4 studies), and rescue medicine use (puffs
per day) (SMD 0.25, 95% CI 0.12, 0.38; 7 studies) (Appendix I)
2. Fluticasone (FP)+Salmeterol (SM) compared with Fluticasone (FP)
Seven fair-quality RCTs138, 141, 154, 155, 158-160 (2896 subjects) compared FP+SM with FP alone
(Table 18). All 7 compared the combination of FP and SM administered in a single inhaler with
FP alone. Six of the studies used low dose FP; one used medium dose FP.154 Five were 12-week
trials and 2 were 24-week trials.155, 158 All were conducted in populations of ≥ 12 or 18 years of
age.
All 7 trials reported outcome measures for symptoms and rescue medicine use, two trials
reported nocturnal awakenings,138, 141 and 3 reported exacerbations.155, 158, 160 Six trials reported
greater improvements in symptoms for those treated with FP/SM combination products than for
those treated with FP alone. Just one trial found no difference in symptoms.141 All 7 trials
reported statistically significantly better outcomes for most measures of rescue medicine use
(puffs/day, % of rescue-free days, % of rescue-free nights, episodes of use) for those treated with
FP/SM. Just one trial reported no statistically significant difference for one of its measures of
rescue medicine use, but there was a trend toward greater improvement for those treated with
FP/SM (mean improvement in puffs/24 hours: -2.4 compared with -1.8).141 The trials reporting
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nocturnal awakenings and exacerbations found no difference between groups (Evidence Tables
A and B).
3. Budesonide (BUD)+Formoterol (FM) compared with Budesonide (BUD)
Two fair-quality RCTs (1,036 subjects) compared BUD+FM with BUD alone.156, 157 Both
compared BUD+FM administered in separate inhalers with low-dose BUD alone. One was a 12week Russian trial that enrolled 338 adults.156 The other was a 1-year multinational trial that
enrolled 1970 adolescents and adults ≥ 12 years of age.157 The two trials reported some
conflicting results. The 12-week trial reported better improvement in symptoms and rescue
medicine use for subjects treated with BUD+FM, but no difference in quality of life. The 1-year
trial reported no statistically significant differences between the two groups for symptoms,
nocturnal awakenings, exacerbations, or rescue medicine use.
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Table 18. Characteristics of head-to-head studies comparing ICS+LABA with ICS
alone as first line therapy in children and adults
Study
Study Design
N
Duration
Country
Population
Setting
Comparison
(total daily dose in
mcg)
Quality
Rating
ICS + LABA compared with ICS alone (same dose) as first line therapy
Ni Chroinin et al. Systematic review with Multinational
2009153
meta-analysis
Age > 2 yr; persistent asthma and
steroid-naïve (no inhaled steroid
24 studies comparing
ICS + LABA with similar within one month of enrollment)
dose ICS, 4 studies
comparing ICS + LABA
with higher dose ICS
ICS + LABA vs. ICS
alone (same dose)
Good
ICS + LABA vs. ICS
alone (higher dose)
Range: 4 to 52 weeks
Fluticasone + salmeterol compared with fluticasone
Boonsawat,et al
2008160
RCT, DB
Multinational
464
Ages 12-79, >6 month history of
mild asthma receiving SABA only,
allowed smokers if <10 pack-year
history, smoking status NR
12 weeks
FP/SM MDI (100/50)
vs
FP MDI (100, low)
vs
Placebo
Fair
FP/SM (250/50)
vs
FP (250, low)
vs
FP/SM (200/100)
vs
Placebo
Fair
SM DPI (100)
vs.
FP DPI (200, low)
vs.
FP/SM DPI (200/100)
Fair
FP/SM MDI (176/84)
vs.
FP MDI (176, low)
vs.
SM MDI (84)
Fair
FP/SM DPI (200/100)
vs.
FP DPI (200, low)
Fair
Multicenter (69)
Kerwin et al.
2008159
RCT, DB
US and Canada
844
Age >12, uncontrolled on SABAs
alone, excluded smokers within the
past year or history of > 10 packyears
12 weeks
Multicenter (121)
Murray et al.
2004138
RCT, DB
US
267
Age ≥12yr, uncontrolled on SABAs
alone, severity NR, smokers
excluded
12 weeks
Multicenter (33 sites)
Nelson et al.
2003141
RCT, DB
US
283
Age ≥12, uncontrolled on SABAs
alone, severity NR, smokers
excluded
12 weeks
Multicenter (33)
Renzi et al.
2010158
RCT, DB
Canada
526
Age >12 with a history of mild
asthma treated with SABAs only,
allowed smokers if < 10 pack-year
history
24 weeks
Multicenter (60)
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N = 253
FP
N = 253
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Table 18. Characteristics of head-to-head studies comparing ICS+LABA with ICS
alone as first line therapy in children and adults
Study
Rojas et al.
2007154
Study Design
N
Duration
Country
Population
Setting
Comparison
(total daily dose in
mcg)
RCT, DB
Multinational (9)
362
Age 12-80, initiating therapy for
moderate persistent asthma,
symptomatic on SABAs only,
allowed smokers if < 10 pack-year
history
FP/SM DPI (500/100)
vs.
FP DPI (500, medium)
12 weeks
Multicenter (52)
Strand et al.
155
2004
RCT, DB
Denmark
150
Age ≥18, persistent asthma for ≥3
months, uncontrolled with SABA
only, severity NR, smokers allowed
(32% of SM/FP group and 46% of
FP group)
24 weeks
Quality
Rating
Fair
FP/SM
N = 182
FP
N = 180
FP/SM DPI (200/100)
vs.
FP DPI (200, low)
Fair
Steroid dose range: low
Multicenter (44 general practices
and 1 hospital)
Budesonide + formoterol compared with budesonide
Chuchalin et al.
2002156
RCT, DB, DD
338
And
12 weeks
Chuchalin et al.
2002164
O’Byrne et al.
2001157
RCT, DB
1970 (698 in group A)
OPTIMA trial
1 year
Russia
FM DPI (24) + BUD DPI
(400)
adults ≥18, mild to moderate
vs.
persistent asthma, allowed smokers BUD DPI (400, low)
if < 10 pack-year history
vs. “investigator’s choice
of non-corticosteroid
pulmonology center
treatment”
Fair
Multinational: Eastern Europe,
Canada, Spain
Fair
Age ≥ 12, mild, uncontrolled
persistent asthma, smoking status
NR
Group A (N = 698 ICSfree, had used no ICS
for ≥ 3 months): Placebo
vs.
BUD (200, low)
vs.
FM (9) + BUD (200)
Multicenter (198)
Group B (N = 1272 ICStreated, were taking ICS
for ≥ 3 months): 4
treatment arms
All delivery devices were
DPIs
Abbreviations: AQLQ = Asthma Quality of Life Questionnaire; BUD = Budesonide; CI = confidence interval; DB = double-blind DPI =
dry powder inhaler; FM = Formoterol; FP = Fluticasone Propionate; ICS = Inhaled Corticosteroids; LABAs = Long-Acting Beta-2
Agonists; MA=meta-analysis; MDI = metered dose inhaler; NR = not reported; NS = not statistically significant; QOL = quality of life;
RCT= randomized controlled trial; RR = relative risk; SM = Salmeterol; SR=systematic review; WMD = weighted mean difference.
Symbol use: Drug X > Drug Y = statistically significant difference in outcomes favoring Drug X; Drug X > Drug Y trend = point
estimate favors Drug X, but the difference is not statistically significant or tests of statistical significance were NR; No difference = no
statistically significant difference or tests of statistical significance were not reported and outcomes are similar.
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2. ICS+LABA compared with higher dose ICS
(addition of LABA to ICS compared with increasing the dose of ICS)
Summary of findings
We found 4 systematic reviews with meta-analysis165-168 and 33 RCTs (37 publications)53, 103, 105,
127, 157, 169-200
that included head-to-head comparisons between an ICS+LABA with a higher dose
ICS meeting our inclusion/exclusion criteria. These trials compared the addition of a LABA to
an ICS with increasing the dose of the ICS. Twenty-one of the 33 (64%) administered the ICS
and LABA in a single inhaler and twelve (36%) administered the ICS and LABA in separate
inhalers. Seven trials103, 105, 127, 185, 195, 197, 200 included children, and two enrolled an exclusively
pediatric population under 12 years of age.103, 195 (Table 19)
Overall, results from large trials up to twelve months in duration support greater efficacy
with the addition of a LABA to an ICS than with a higher dose ICS for adults and adolescents
with persistent asthma (high strength of evidence, Appendix H, Table H-11). Our meta-analysis
shows statistically significantly greater improvement in percent symptom-free days (SMD = 0.20, 95% CI: -0.25, -0.14; 15 studies), symptom scores (SMD = -0.22, 95% CI: -0.34, -0.11; 10
studies), percent rescue-free days (SMD = -0.24, 95% CI: -0.31, -0.16; 11 studies), and rescue
medicine use (SMD = -0.22, 95% CI: -0.28, -0.16; 16 studies) for subjects treated with
ICS+LABA. Despite a trend toward fewer subjects with exacerbations in the ICS+LABA group,
the difference was not statistically significant in our analysis (OR = 0.89, 95% CI: 0.78, 1.01; 22
studies). Just one trial exclusively enrolled children under 12 (four included some subjects < 12)
and results are not necessarily generalizable to pediatric populations.
Detailed Assessment
Description of Studies
Four large systematic reviews with meta-analyses165-168 compared the addition of any LABA to
any ICS (ICS+LABA) with increasing the ICS dose. The largest review by Ducharme et al.167
was an update to Greenstone, 2005.201 It included 48 trials (47 publications) (6 of them in
pediatric populations). Twenty-three of those trials met our inclusion/exclusion criteria. One of
the reviews included studies only in children aged 2 to 18 years.166
Of the 33 RCTs we included (Table 19), 14 (42%) compared fluticasone + salmeterol
with fluticasone; 7 (21%) compared budesonide + formoterol with budesonide, six (18%)
compared beclomethasone + salmeterol with beclomethasone, 3 (9%) compared beclomethasone
+ formoterol with beclomethasone, two (6%) compared fluticasone + salmeterol with
budesonide, one (3%) compared budesonide + formoterol with fluticasone, and one (3%)
compared fluticasone + salmeterol with triamcinolone (the total number of comparisons, 34, does
not equal the number of trials because one trial contributed comparisons to both FP+SM
compared with FP and to FP+SM compared with TAA).53
Study duration ranged from 8 weeks to 12 months. The most commonly used delivery
devices were DPIs: 22 studies (67%) delivered all medicines via DPIs, 8 studies (24%) delivered
all via MDIs, and 3 studies (9%) used MDIs for the ICSs in both groups and DPIs for the
LABAs.181, 189, 199 Twenty-one of the 33 (67%) administered the ICS and LABA in a single
inhaler and twelve (36%) administered the ICS and LABA in separate inhalers.
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Study Populations
The 33 head-to-head RCTs included a total of 18,153 subjects (Table 19). Most were conducted
primarily in adult populations. Eight studies (24%) included pediatric populations under 12 years
of age.103, 105, 127, 185, 195, 197, 200 Seventeen trials (52%) were multinational, 8 (24%) were
conducted in the United States, 3 in the Netherlands, 2 in Germany, and one each in Greece,
Australia, and the United Kingdom.
Asthma severity ranged from mild to severe persistent: 3 studies (9%) were conducted in
patients with mild persistent asthma, 8 (24%) in patients with mild to moderate persistent
asthma, 4 (12%) in patients with moderate persistent asthma, 6 (18%) in patients with moderate
to severe persistent, and the severity was not reported in 12 (36%) trials. Smoking status was not
reported for 14 trials (42%). Eleven (33%) excluded current smokers or those with greater than a
10 pack-year history. Eight (24%) allowed active smokers and reported that between five and
33% of subjects were active smokers
Almost all trials required use of ICS prior to randomization for all subjects. There were
two exceptions: one trial enrolled previously steroid naïve patients that achieved good control on
FP/SM169 and one trial enrolled patients that were uncontrolled on previous therapy (80% had
been on ICS).192 The vast majority enrolled subjects that were not controlled on ICS therapy. Just
four trials enrolled subjects that were described as controlled on ICS therapy.127, 171, 174, 185
Sponsorship
Of the 33 head-to-head trials, 30 (91%) were funded by pharmaceutical companies; one trial
(3%) did not report the source of funding but at least one author had a primary affiliation with a
pharmaceutical company. Two studies (6%) were funded primarily by a source other than a
pharmaceutical company.
Head-to-head comparisons
Using data from the head-to-head RCTs that met our inclusion criteria, we conducted metaanalyses for five outcomes that were reported with sufficient data in multiple trials (Appendix I).
These included percent symptom-free days, symptom scores, exacerbations, percent rescue-free
days, and rescue medicine use (puffs/day). Subjects treated with ICS+LABA had greater
improvement in the percentage of symptom-free days (SMD = -0.20. 95% CI: -0.25, -0.14, 14
studies contributing 15 comparisons), greater improvement in symptom scores (SMD = -0.22,
95% CI: -0.34, -0.11, 9 studies contributing 10 comparisons), greater improvement in the
percentage of rescue-free days (SMD = -0.24, 95% CI: -0.31, -0.16, 10 studies contributing 11
comparisons), and greater reduction in rescue medicine use (SMD = -0.22, 95% CI: -0.28, -0.16,
15 studies contributing 16 comparisons) than those treated with a higher dose ICS alone.
However, there was no statistically significant difference in the odds of experiencing an
exacerbation, but the pooled odds ratio favored those treated with ICS+LABA (OR = 0.89, 95%
CI: 0.78, 1.01, 22 studies). For all of the meta-analyses except the analysis for exacerbations,
sensitivity analyses indicate no significant difference in overall meta-analysis conclusions with
any single study removed. With the exception of the analysis for symptom score, there was no
significant heterogeneity between studies for these outcomes (Appendix I). The statistical
heterogeneity for the symptom score analysis was substantial (I2 = 70.5, P < 0.001) with the
inclusion of the FP arm of the Baraniuk et al, 1999 study, but was no longer significant (I2 =
40.8, P = 0.095) when this was removed from the analysis. Additional sensitivity analyses
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removing studies enrolling subjects that were well controlled on current therapy169, 171, 174, 185
found no difference in overall meta-analysis conclusions.
One good systematic review167 compared the addition of any LABA to any ICS
(ICS+LABA) with increasing the ICS dose (Table 19). The review included 48 trials (6 of them
in pediatric populations) that included a total of 15,155 subjects. Trial duration ranged from 4 to
54 weeks. The systematic review reported a significant difference between groups for the
primary outcome, the rate of patients with exacerbations requiring systemic corticosteroids (RR
0.88, 95% CI: 0.78, 0.98, N = 25). They reported no significant difference in exacerbations
requiring hospitalization. Results from meta-analyses for some measures of symptoms (change in
daytime symptom score, overall 24-hour symptom score, change in percent symptom free days,
and % nighttime awakenings) were statistically significant with a trend toward favoring ICS +
LABA therapy. Analyses of rescue medicine use (change in daytime rescue inhalations, change
in nighttime inhalations, change in rescue inhalations over 24 hours, and change in mean percent
of rescue free days) also showed a statistically significant trend toward improvement with ICS +
LABA therapy. However, there was no significant group difference in percent symptom-free
days at endpoint or percent overall rescue free days.
Another good systematic review with meta-analysis165 compared the impact of numerous
asthma therapies on exacerbations. They found that combination therapy with ICSs+LABAs was
associated with fewer exacerbations than was increasing the dose of ICSs (RR 0.86; 95% CI:
0.76, 0.96; P = 0.65 for heterogeneity; 10 studies) (full details available in Evidence Tables A
and B).
One recent good quality systematic review with meta-analyses compared the addition of
any LABA to any ICS (ICS+LABA) with increasing the ICS dose in children aged 2 to 18
years.166. The review included six studies for this comparison and the mean age of participants
across the studies was 10 years. A meta-analysis of the primary outcome (exacerbations
requiring oral steroids) included only 2 studies and found no statistically significant difference
between the ICS + LABA or higher dose ICS groups (RR = 1.5, 95% CI 0.65 to 3.48). The
review did not report results for outcomes such as daytime rescue inhalations, nighttime
awakenings, and daytime or nighttime symptoms because of insufficient data. (Evidence Tables
B)
A fair quality systematic review by Jaeschke et al.168 included 31 studies with 14,409
patients that compared ICS + LABA to higher dose ICS. The review analyzed studies of SM and
FM separately. The meta-analysis results for both medications for asthma related hospitalizations
were not statistically significant [(FM + ICS v ICS): OR = 0.68, 95% CI 0.38, 1.24 (N = 6); (SM
+ ICs v ICS): OR = 1.12, 95% CI 0.54 to 2.35 (N = 13)]. The results of analyses for total
mortality were also not statistically significant for either group [(FM + ICS v ICS): OR = 0.71,
95% CI 0.13 to 3.91 (N= 2); (SM + ICs v ICS): OR = 3.12, 95% CI 0.30 to 25.49 (N = 2)]. The
authors noted that asthma-related mortality could not be assessed because of low frequency of
events.
An additional systematic review by Rodrigo et al.202 analyzed 57 studies with 34,747
patients; 32 of these studies compared LABA + ICS to a higher dose of ICS. This review
combined studies of ICS + LABA compared with same dose ICS and ICS + LABA compared
with a higher dose ICS in the analyses, therefore it is not considered in our assessment of ICS +
LABA compared with higher dose ICS. The results of the combined analysis for exacerbations
requiring systemic steroids showed a statistically significant result in favor of LABA + ICS (RR
= 0.73, 95% CI 0.67 to 0.79, N = 30).
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2. Fluticasone (FP) + Salmeterol (SM) compared with Fluticasone (FP)
Fourteen fair-quality RCTs (7,091 subjects) compared FP+SM with a higher dose of FP53, 127, 169176, 195-197, 200
(Table 19). Eleven administered FP+SM in a single inhaler device127, 169-171, 173-175,
195-197, 200
and 3 tested the combination delivered by separate inhalers. Three studies127 included
children ≤ 12 years of age. Study duration was 8 weeks for 1 trial, 12 weeks for 6 trials, 16
weeks for 2 trials, 24 weeks for 4 trials, and 52 weeks for 1 trial.
The majority of trials assessed asthma symptoms and rescue medicine use. Eight trials
also reported exacerbations and two reported quality of life. For these outcomes, most of the
trials either reported no difference or outcomes favoring FP+SM combination therapy over the
increased dose of FP. One trial, comparing FP twice daily with FP/SM once daily, reported a
statistically significant difference in favor of FP alone for mean daily asthma symptom score.196
For subjects treated with FP+SM compared to those treated with FP alone, 7 trials reported fewer
symptoms or better improvement in symptoms,169, 170, 172, 173, 175, 176, 200 9 trials reported a greater
decrease or less frequent use of rescue medicine,53, 169-173, 176, 195, 200 one trial reported a trend
toward fewer exacerbations,170 and one trial reported greater improvement in nocturnal
awakenings.172 The two trials reporting quality of life found no statistically significant difference
in overall quality of life measures127, 175 (Evidence Tables A and B).
Meta-analyses of 8 trials show no statistically significant difference in exacerbations, but
the pooled odds ratio favors those treated with FP+SM (OR = 0.86, 95% CI: 0.67, 1.1; 8 studies).
Sensitivity analyses indicate that the removal of any one study does not change the overall
conclusion. There was no significant heterogeneity between studies (I2 = 0). Additional metaanalyses for symptom-free days, symptom scores, rescue-free days, and rescue medicine use
show a trend toward results similar to those in the overall meta-analysis for ICS+LABA
compared with higher dose ICS.
3. Budesonide (BUD) + Formoterol (FM) compared with Budesonide (BUD)
Seven fair quality RCTs (6,460 patients) compared BUD+FM with a higher dose of BUD103, 105,
157, 177-180, 198
(Table 19). Five administered BUD+FM in a single inhaler device103, 105, 177, 178 and
two tested the combination delivered by separate inhalers. Two of the trials103, 105 included
children ≤ 12 years of age. One enrolled children with mild to moderate persistent asthma
between the ages of four and 11.103 The other enrolled subjects with moderate persistent asthma
between the ages of 4 and 80.105 Study duration was 12 months for 6 trials and 12 weeks for one
trial.178
All trials assessed asthma symptoms, exacerbations, and rescue medicine use. Four trials
also reported nocturnal awakenings. For these outcomes, the majority of trials reported no
difference or outcomes favoring BUD+FM combination therapy. For subjects treated with
BUD+FM compared to those treated with BUD alone, 5 of 6 trials reported fewer symptoms or
better improvement in symptoms,103, 105, 178-180, 198 1 trial (of five reporting) found greater
reduction in nocturnal awakenings,178 and 4 trials reported a greater decrease or less frequent use
of rescue medicine.105, 178-180, 198 Four trials found no difference in exacerbations.103, 105, 177, 178
One study found that the number of asthma exacerbations per patient-treatment year was
significantly lower with BUD+FM (0.185) compared with a higher dose of BUD alone (0.315)
(P = 0.049).198The remainder of trials reported no difference for these outcomes except for one
trial reporting a trend toward fewer exacerbations in subjects treated with the increased dose of
BUD than those treated with BUD+FM179, 180.
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Meta-analyses of 7 trials found trends consistent with the overall ICS+LABA compared
with higher dose ICS meta-analyses. Subjects treated with BUD+FM had greater improvement in
the percentage of symptom-free days (SMD = -0.19, 95% CI: -0.27, -0.11, 6 studies), greater
improvement in symptom scores (SMD = -0.18, 95% CI: -0.28, -0.07; 2 studies), greater
improvement in the percentage of rescue-free days (SMD = -0.21, 95% CI: -0.36, -0.05, 3
studies), and greater reduction in rescue medicine use (SMD = -0.16, 95% CI: -0.26, -0.06 , 5
studies) than those treated with a higher dose BUD alone. There was no statistically significant
difference in exacerbations (OR = 0.98, 95% CI: 0.72, 1.34, 5 studies).
4. Beclomethasone (BDP) + Salmeterol (SM) compared with Beclomethasone (BDP)
Six fair quality RCTs (2,574 subjects) compared BDP+SM with a higher dose of BDP181-187
(Table 19). All six administered BDP+SM in separate inhalers. One trial185 enrolled children and
adolescents between the ages of four and 18. The remainder were conducted in populations ≥ 12
years of age. Study duration was 12 weeks for one trial,186 21-24 weeks for four,181-184, 187 and
one year for one.185
All trials assessed asthma symptoms, exacerbations, and rescue medicine use. Four trials
also reported nocturnal awakenings and two reported quality of life outcomes. For each of these
outcomes, the majority of trials reported no difference or outcomes favoring BDP+SM
combination therapy; none reported a statistically significantly greater improvment for those
treated with BDP alone. For symptoms, three trials reported no difference181, 182, 185, 186 and three
found results favoring BDP+SM.183, 184, 187 For nocturnal awakenings, one trial reported no
difference184 and three found results favoring BDP+SM.181-183, 187 For exacerbations, five trials
reported no difference181-184, 186, 187 and one reported a trend toward fewer exacerbations requiring
steroids for those treated with BDP alone.185 All but one trial181, 182 reported a greater decrease or
less frequent use of rescue medicine for those treated with BDP+SM than for those treated with
BDP alone. The two trials reporting quality of life found no significant difference between the
groups181, 182, 186.
Meta-analyses of these six trials showed trends consistent with the overall ICS+LABA
compared with higher dose ICS meta-analyses. Subjects treated with BDP+SM had statistically
significantly greater reduction in rescue medicine use (SMD = 0.18, 95% CI: 0.05, 0.31; 4
studies) and trended toward greater improvement in the percentage of symptom-free days (SMD
= 0.14, 95% CI: -0.01, 0.28; 2 studies) than those treated with a higher dose BDP alone. There
was no statistically significant difference in the percentage of subjects with exacerbations (SMD
= -0.019, 95% CI: -0.095, 0.058; 5 studies contributing 6 comparisons).
5. Beclomethasone (BDP) + Formoterol (FM) compared with Beclomethasone (BDP)
Three fair RCTs (982 subjects) meeting our inclusion/exclusion criteria compared BDP+FM
with a higher dose of BDP alone.188, 189, 199 All 3 enrolled adults ≥18 that were not controlled on
ICSs. Two compared BDP+FM in a single inhaler device188 and one tested the combination
delivered by separate inhalers.189 Two studies188, 189 reported statistically significantly better
symptom and rescue medicine use outcomes for subjects treated with BDP+FM than those
treated with FM alone (Evidence Tables A and B). Huchon et al.199 reported that a reduction in
rescue medication use was statistically significant from baseline for the BDP+FM group and did
not change for the BDP alone group, but did not report whether the difference between the
groups was significant. Two studies found a trend toward fewer exacerbations in those treated
with BDP+FM.189, 199
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6. Fluticasone (FP) + Salmeterol (SM) compared with Budesonide (BUD)
One good 12-week RCT (N = 349)192 and one fair 24-week RCT (N = 353)190, 191 meeting our
inclusion/exclusion criteria compared FP+SM with a higher relative dose of BUD alone. The 12week trial compared FP/SM (200/100) with BUD (800) and the 24-week trial compared FP/SM
(500/100) with BUD (1600). Both were multinational trials that enrolled subjects ≥ 12 years of
age. Both administered FP/SM in a single inhaler device. The two trials reported some
conflicting results. The 12-week trial found no statistically significant difference between
treatment groups in symptoms, exacerbations, or rescue medicine use. The 24-week trial reported
fewer symptoms, less rescue medicine use, and greater improvement in quality of life for those
treated with FP+SM than those treated with BUD alone, but no significant difference in
exacerbations.
7. Budesonide (BUD) + Formoterol (FM) compared with Fluticasone (FP)
One 12-week fair RCT meeting our inclusion/exclusion criteria compared BUD+FM in a single
inhaler with a higher relative dose of FP alone in 344 adults with moderate persistent asthma.193
The trial reported no statistically significant difference in symptoms or nocturnal awakenings.
But, those treated with BUD+FM had fewer exacerbations and required less rescue medicine
compared to those treated with FP alone.
8. Fluticasone (FP) + Salmeterol (SM) compared with Triamcinolone (TAA)
We found one fair RCT meeting our inclusion/exclusion criteria that compared FP+SM (in
separate inhalers) with a higher relative dose of TAA alone.53 This trial is also included above in
this section for the FP+SM compared with FP comparison because there was an FP-only arm as
well. It enrolled 680 adults and adolescents ≥ 12 years of age with persistent asthma not
adequately controlled on ICS. They reported greater improvement in symptoms, nocturnal
awakenings, and rescue medicine use for those treated with FP+SM than for those treated with
TAA alone.
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Table 19. Characteristics of head-to-head studies comparing ICS+LABA (in one or separate inhalers) with higher
dose ICS
Study Design
N
Duration
Study
Country
Population
Setting
Comparison
(total daily dose in mcg)
Quality
Rating
Fluticasone + salmeterol compared with fluticasone
Baraniuk et al. 199953
RCT, DB, triple-dummy US
680
Age ≥ 12, uncontrolled with low-dose ICS, severity NR,
smokers excluded
12 weeks
FP MDI (196) + SM (84)
compared with
FP MDI (440)
compared with
TAA MDI (1200)
Fair
FP/SM (200/100)
compared with
FP (500)
Fair
Pulmonary/allergy medicine clinics (50)
169
Bateman et al. 2006
RCT, DB
Multinational
484
Age 12 to 80, previously steroid naïve patients that achieved
good control on FP/SM (500/100), smokers excluded
12 weeks
All delivery devices=DPIs
Multicenter
Bergmann et al. 2004170
RCT, DB
Germany
FP/SM DPI (500/100)
compared with
FP DPI (1000)
Fair
365
Age 18-70, moderate persistent asthma, poorly controlled on
ICS, smokers excluded
FP/SM DPI (200/100)
compared with
FP DPI (500)
Fair
Ages 12-79, >6 month history of mild asthma receiving SABA
only, allowed smokers if <10 pack-year history,
FP/SM DPI (100/50)
vs
FP DPI (200)
vs
Placebo
Fair
RCT, DB, DD
US
Fair
437
age ≥12, uncontrolled on ICS, severity NR, smokers excluded
FP MDI (196) +SM MDI (84)
compared with
FP MDI (440)
12 weeks
Multicenter, private practice and outpatient clinics
171
Busse et al. 2003
RCT, DB
US
558
Age ≥ 12, mild to moderate persistent asthma, had to be
controlled on FP (500) during the third run-in, smoking status
NR
24 weeks
Multicenter
196
Chuchalin,et al 2008
RCT, DD
2258
1 year
172
Condemi et al. 1999
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Table 19. Characteristics of head-to-head studies comparing ICS+LABA (in one or separate inhalers) with higher
dose ICS
Study
de Blic et al.
195
2009
Study Design
N
Duration
Country
Population
Setting
24 weeks
Multicenter (36)
RCT, DB, DD
12 European Countries
321
Children, aged 4–11 yrs, with a clinical history of
asthma for at least 6 months and uncontrolled on ICS
12 weeks
Comparison
(total daily dose in mcg)
FP (100) + SM (200)
Vs.
FP (400)
Quality
Rating
Fair
All delivery devices - DPI
Multicenter
Gappa et al.
2009200
RCT, DB, DD
281
8 weeks
Ind et al. 2003173
RCT, DB, DD
502
24 weeks
Germany
FP/SM DPI (100/ 200)
Vs.
Age 4-16; symptomatic persistent mild to moderate seasonal or FP (400)
perennial asthma and currently using low-dose ICS
All delivery devices - DPI
Multicenter
Fair
Multinational (UK, Italy, Canada, Denmark, Iceland, Republic of FP/SM MDI (500/100)
Ireland)
vs.
FP MDI (500)
Age 16 to 75, moderate to severe persistent asthma,
vs.
uncontrolled on ICS, 13-24% smokers in each group
FP MDI (1000)
Fair
Multicenter (100) Hospitals and primary care centers
Jarjour et al. 2006174
RCT, DB
Multinational (US, Canada, UK)
88
Age≥18, well controlled during final run-in on FP (500),
excluded smokers with > 10 pack-year history
FP/SM DPI (200/100)
compared with
FP DPI (500)
Fair
24 weeks
Multicenter
Note: the subjects in
this study were a
subset of the subjects
in Busse et al. 2003171
and thus were not
included in metaanalyses to avoid
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Table 19. Characteristics of head-to-head studies comparing ICS+LABA (in one or separate inhalers) with higher
dose ICS
Study Design
N
Duration
Study
Country
Population
Setting
Comparison
(total daily dose in mcg)
USA
FP DPI (500)
Quality
Rating
double-counting.
Lemanske et al.
2010197
RCT
Fair
182
Age 6-17 years, mild-to-moderate asthma uncontrolled on low- FP/SM DPI (200/100)
dose ICS
48 wks (3 cross-over
FP (200) DPI + ML (5-10mg)
periods of 16 wks each) Childhood Asthma Research and Education Network Centers
Peters et al. 2007127
RCT, DB
US
500
Age ≥6, controlled on FP (200), severity NR, 10-18% were
former smokers
16 weeks
FP/SM (100/50) QID
vs.
FP (200)
vs.
ML (5-10mg)
Fair
Multicenter
All delivery devices=DPIs
Schermer et al. 2007
175
RCT, DB
Netherlands
177 (137 with asthma
and 40 with COPD,
results presented
separately)
Age ≥12, on ICS for at least 3 months, NR whether controlled
or not, severity NR, enrolled smokers (17% compared with
37%)
FP/SM (200 or 500/100)
compared with
FP (500 or 1000)
Fair
All delivery devices - DPI
Multi-site, patients recruited by 41 Family Practice physicians
12 weeks
van Noord et al. 1999176
RCT, DB
Netherlands
274
Age ≥18, mild or moderate persistent, uncontrolled on ICS,
smoking status NR
12 weeks
Multi-center (27)
Addition of SM compared with
doubling ICS dose
Fair
FP (200) + SM (100)
vs
FP (400)
FP (500) + SM (100)
vs
FP (1000)
All delivery devices - DPI
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Table 19. Characteristics of head-to-head studies comparing ICS+LABA (in one or separate inhalers) with higher
dose ICS
Study Design
N
Duration
Study
Country
Population
Setting
Comparison
(total daily dose in mcg)
Quality
Rating
SMART [BUD/FM (80/4.5)
+BUD/FM as needed]
vs
BUD/FM (80/4.5)
compared with
BUD (320)
Fair
Budesonide + formoterol compared with budesonide
Bisgaard et al.
2006103
RCT, DB
Multinational (12)
341
Age 4-11, mild-moderate persistent asthma, not controlled on
ICS, smoking status NR
12 months
Multicenter (41)
All given via DPI,
177
Kips et al. 2000
RCT, DB
Multinational (Canada, UK and Belgium)
60
Age 18-70, on ICS, controlled for at least 10 days out of the 1
month run-in, moderate, smoking status NR
BUD/FM DPI (200/24)a
compared with
BUD DPI (800)
Fair
BUD/FM DPI (160/9)
compared with
BUD DPI (400)
Fair
Group A (used no ICS for ≥ 3
months): Placebo
compared with BUD (200)
compared with BUD+FM
(200+9)
Fair
1 year
Multicenter (3 University clinics)
Lalloo et al. 2003178
RCT, DB
Multinational (Czech Republic, Hungary, Norway, Poland,
South Africa, United Kingdom)
467
12 weeks
Age > 18, mild to moderate, uncontrolled on ICS, smokers
excluded
Multicenter (51) University Hospitals
157
O’Byrne et al. 2001
RCT, DB
Multinational (Eastern Europe, Canada, Spain)
OPTIMA trial
1970
(698 in Group A, 1272
Group B)
Age ≥ 12, uncontrolled, mild persistent asthma (Group A ICS
naïve, Group B on ICS), smoking status NR
multicenter (198)
1 year
Controller medications for asthma
Group B (taking ICS for ≥ 3
months):
BUD (200)
vs.
BUD(200) +FM (9) vs.
BUD (400) vs.
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Table 19. Characteristics of head-to-head studies comparing ICS+LABA (in one or separate inhalers) with higher
dose ICS
Study Design
N
Duration
Study
Country
Population
Setting
Comparison
(total daily dose in mcg)
Quality
Rating
FM + BUD (9/400)
All delivery devices=DPIs
105
O'Byrne et al. 2005
RCT, DB
Multinational (22 countries)
2760
Age 4-80, uncontrolled on ICS, moderate persistent asthma,
smoking status NR
1 year
Multicenter (246 centers)
BUD/FM (160/9) (+ SABA for
relief)
compared with
BUD/FM (160/9) (maintenance
& relief)
compared with
BUD (640)
Fair
Drug 1: 909
Drug 2: 925
Drug 3: 926
All delivery devices=DPIs
Peters et al.
2008198
RCT
708
52 weeks
USA
BUD (640) + FM (18)
BID (160/4.5 x 4 inhalations)
> 12 years with a documented clinical diagnosis of moderate to vs.
BUD (320) + FM (9) BID
severe asthma
(160/4.5 x 2 inhalations)
vs.
Multicenter
BUD (640) BID
Fair
All delivery devices - pMDI
179
Pauwels, et al. 1997
RCT, DB, DD
AND
852 (470 in quality of
life evaluation)
Juniper, et al. 1999180
Multinational (9: Belgium, Canada, Netherlands, Israel, Italy,
Luxembourg, Norway, Spain, and UK)
Age 18-70, uncontrolled on ICS, severity NR, smoking status
NR
12 months
FACET (Formoteral And
Corticosteroids Establishing
Therapy) International study
group
Controller medications for asthma
Multicenter (71)
BUD (200)
compared with
BUD (200)+ FM (24)
compared with
BUD (800)
compared with
BUD (800)+ FM (24)
Fair
All delivery devices - DPI
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Table 19. Characteristics of head-to-head studies comparing ICS+LABA (in one or separate inhalers) with higher
dose ICS
Study Design
N
Duration
Study
Country
Population
Setting
Comparison
(total daily dose in mcg)
Quality
Rating
O'Byrne et al.
2008194
Beclomethasone + salmeterol compared with beclomethasone
Greening et al. 1994181
RCT, DB, DD
UK
AND
429
Hyland, 1995182
Age ≥ 18 with uncontrolled asthma on low-dose ICS, severity
NR, enrolled 26-27% smokers in each group
21 weeks
BDP MDI (400) + SM DPI (100)
compared with
BDP MDI (1000)
Fair
BDP MDI (336) + SM (84) MDI
compared with
BDP MDI (672)
Fair
Fair
514
BDP MDI (336) + SM MDI (84)
compared with
Age ≥18, uncontrolled on ICS, severity NR, smoking status NR BDP MDI (672)
24 weeks
Multicenter (35)
RCT, DB
Multinational (Netherlands, UK)
177
Children and adolescents age 4-18, mild to moderate asthma,
on ICS ≥3 months, stable asthma for ≥1 month prior to run-in,
smoking status NR
General practice Centers (99)
183
Kelsen et al. 1999
RCT, DB, DD
US
483
Age ≥18 with uncontrolled on ICS, severity NR, smokers
excluded
24 weeks
34 outpatient clinical sites
184
Murray et al. 1999
Verberne et al. 1998185
RCT, DB, DD
1 year
Vermetten et al. 1999186
US
BDP (400) + SM (100)
vs.
BDP (800)
vs.
BDP (400)
Multicenter (outpatient clinics of 9 hospitals, 6 university
hospitals, and 3 general hospitals)
All given by DPI
RCT, DB
Netherlands
233
Age 18-66, on ICS for ≥ 6 weeks, mild persistent asthma,
enrolled 33% smokers
BDP (400)+ SM (100)
compared with
BDP (800)
12 weeks
Fair
Fair
All given by DPI
Primary care
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Table 19. Characteristics of head-to-head studies comparing ICS+LABA (in one or separate inhalers) with higher
dose ICS
Study
Study Design
N
Duration
Country
Population
Setting
Woolcock et al. 1996187
RCT, DB
Multinational (14 countries)
738
Age ≥ 17, uncontrolled on ICS, severity NR, 13-19% smokers
in each group
24 weeks
Comparison
(total daily dose in mcg)
BDP (1000) + SM (100)
vs.
BDP (1000) + SM (200)
vs.
BDP (2000)
Quality
Rating
Fair
Multicenter (72)
All given by MDI
Beclomethasone + formoterol compared with beclomethasone
Bouros et al. 1999188
RCT, open
Greece
134
Age ≥ 18, poorly controlled on ICS, severity NR, smoking
status NR
BDP/FM pMDI (500/24)
compared with
BDP pMDI (1000)
Fair
3 months
Multicenter (11)
Huchon et al.
2009199
RCT
Russia, France, Poland, Romania, Hungary, Belgium
645
Men and non-pregnant women (18-70 years), moderate to
severe persistent asthma
24 weeks
BDP/FM pMDI (400/24
Vs.
BDP pMDI (1000) + FM DPI (24)
Vs.
BDP pMDI (1000)
Good
BDP MDI (1000) + FM DPI (24)
compared with
BDP MDI (2000)
Fair
FP/SM DPI (500/100)
compared with
BUD DPI (1600)
Fair
FP/SM DPI (200/100)
Good
Multicenter
189
Mitchell et al. 2003
RCT, DB, DD
Australia
203
Age ≥ 18, moderate to severe, uncontrolled on ICS, 8-10%
smokers in each group
12 weeks
Multicenter (16), outpatients
Fluticasone + salmeterol compared with budesonide
Jenkins et al. 2000190
RCT, DB, DD
Multinational (Australia, Finland, Sweden)
AND
353 (subanalysis 113
for AQLQ)
Age ≥12, moderate to severe persistent asthma, uncontrolled
on ICS, excluded smokers with > 10 pack-year smoking history
24 weeks
Multicenter (44)
RCT, DB, DD
Multinational (6: Canada, Greece, Israel, Italy, S Africa, and
191
Juniper et al. 2002
Johansson et al. 2001
192
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Table 19. Characteristics of head-to-head studies comparing ICS+LABA (in one or separate inhalers) with higher
dose ICS
Study
Study Design
N
Duration
Country
Population
Setting
Sweden)
349
12 weeks
Age ≥ 12, mild to moderate persistent asthma, uncontrolled on
previous therapy (~80% ICS), excluded smokers or those with
> 10 pack-year smoking history
Comparison
(total daily dose in mcg)
Quality
Rating
compared with
BUD DPI (800)
Multicenter
Budesonide + formoterol compared with fluticasone
Bateman et al. 2003193
RCT, DB, DD
344
12 weeks
Multinational (6: Germany, Greece, Israel, Netherlands,
Portugal, S. Africa)
Age ≥ 18; moderate persistent asthma, previous use of
constant dose of ICS > 30 days, 5-7% smokers in each group
BUD/FM DPI (320/9)
compared with
FP DPI (500)
Fair
FP MDI (196) + SM (84)
vs.
FP MDI (440)
vs.
TAA MDI (1200)
Fair
Multicenter (37)
Fluticasone + salmeterol compared with triamcinolone
Baraniuk et al. 199953
RCT, DB, triple-dummy US
This study is also listed
above under FP+SM
compared with FP section
680
Age ≥ 12, uncontrolled with low-dose ICS, severity NR,
smokers excluded
12 weeks
Pulmonary/allergy medicine clinics (50)
Abbreviations: AQLQ = Asthma Quality of Life Questionnaire; BDP = beclomethasone dipropionate; BID – twice per day; BUD = Budesonide; CI = confidence interval; FP =
Fluticasone Propionate; ICS = Inhaled Corticosteroids; LABAs = Long-Acting Beta-2 Agonists; MA=meta-analysis; OCS = oral corticosteroids; QID = once per day; QOL = quality of
life; RCT= randomized controlled trial; RR = relative risk; SM = Salmeterol; SMD = standard mean difference; SR=systematic review; TAA = Triamcinolone Acetonide; WMD =
weighted mean difference.
Symbol use: Drug X > Drug Y = statistically significant difference in outcomes favoring Drug X; Drug X > Drug Y trend = point estimate favors Drug X, but the difference is not
statistically significant or tests of statistical significance were NR; No difference = no statistically significant difference or tests of statistical significance were not reported and outcomes
are similar.
a
The dose of BUD/FM (200mcg BUD/6mcg FM ) used in this study is only available Canada.
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3. ICS+LABA compared with ICS (same dose)
(addition of LABA to ICS compared with continuing same dose ICS)
Summary of findings
We found 3 systematic reviews with meta-analyses166, 168, 203 and 32 RCTs (37 publications)135137, 139, 140, 142-144, 157, 173, 179, 180, 185, 198, 199, 204-225
that included head-to-head comparisons of an
ICS+LABA and the same dose ICS meeting our inclusion/exclusion criteria (Table 20). These
trials compared the addition of a LABA to an ICS with continuing the same dose of the ICS.
Eighteen of the 32 (56%) administered the ICS and LABA in a single inhaler, 10 (31%)
administered them in separate inhalers, and 4 studies (13%) administered them both as a single
inhaler and in separate inhalers to different study groups.
Overall, results from large trials up to one year in duration support greater efficacy with
the add ition of a LABA to an ICS over continuing the current dose of ICS alone for patients with
poorly controlled persistent asthma (high strength of evidence, Appendix H, Table H-12). Our
meta-analysis shows statistically significantly greater improvement in rescue medication-free
days (SMD 0.31 , 95% CI: 0.25, 0.37), rescue medicine use (SMD -0.29, 95% CI: -0.36, -0.23),
symptom free days (SMD 0.27, 95% CI: 0.22, 0.32), symptom scores (SMD -0.27, 95% CI: 0.33, -0.21), and quality of life (AQLQ scores; SMD 0.26, 95% CI: 0.14, 0.37). Results were
generally consistent with a previously published meta-analysis203 which also reported fewer
exacerbations in those treated with the addition of a LABA to ICS (RRR 23% with LABA) (N =
6808, RR = 0.77, 95% CI 0.68 to 0.87).
Detailed Assessment
Description of Studies
Of the included studies (Table 20), the 3 systematic reviews with meta-analyses166, 168, 203
compared the addition of any LABA to any ICS (ICS+LABA) with the addition of placebo and
continuing the same dose of the ICS. The largest review203 included 77 trials (16,623 adults and
4,625 children). Seventeen of these were unpublished.
Of the 32 RCTs that met our inclusion/exclusion criteria, 16 (50%) compared budesonide
+ formoterol with budesonide (one used eformoterol), 9 (28%) compared fluticasone +
salmeterol with fluticasone, 3 (9%) compared an ICS (not specified) + salmeterol with an ICS, 2
(6%) compared an ICS (not specified) + formoterol with an ICS, 1 (3%) compared
beclomethasone + salmeterol with beclomethasone, and 1 (3%) compared beclomethasone +
formoterol with beclomethasone. We also found one study of ICS+LABA compared with the
same dose of ICS, however the patient population included both steroid naïve and current ICS
users, therefore this study is not included in the analyses for this section.150
Study duration ranged from 12 weeks to 12 months. The most commonly used delivery
devices were DPIs: 18 studies (56%) delivered all study medicines via DPIs, 7 studies (22%)
delivered all via MDIs, and 7 studies (22%) used both MDIs and DPIs. Eighteen of the 32 (56%)
administered the ICS and LABA in a single inhaler, 10 (31%) administered them in separate
inhalers, and 4 studies (13%) administered them both as a single inhaler and in separate inhalers
to different study groups.
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Study Populations
The 32 head-to-head RCTs included a total of 14,737 subjects (Table 20). Most were conducted
primarily in adult populations. Nine studies (28%) included pediatric populations under 12 years
of age.185, 212, 214, 215, 218-222 The majority of trials were multinational (17 trials, 53%); 10 (31%)
were conducted in the United States, 2 (6%) were conducted in the UK, and one in each of the
following: Canada, Sweden, and the Netherlands.
All subjects were poorly controlled on ICS therapy prior to randomization in all but three
trials.135, 137, 213 One of the three enrolled subjects that were initially symptomatic on ICS (about
67%) or SABA alone, but re-randomized those that were well controlled during the initial 4
weeks (N = 505) and followed them for the remainder of the 32 week study.213 Another enrolled
subjects that were well controlled on current therapy (either ICS or ICS+SM).135 The last one
enrolled subjects uncontrolled on current medication, but only 68% were on ICSs.137
Sponsorship
Of the 32 head-to-head trials, 29 (91%) were funded by pharmaceutical companies; only two
studies (6%) were funded primarily by sources other than pharmaceutical companies; one study
(3%) did not report any source of funding.
Head-to-head comparisons
1. ICS+LABA compared with ICS (same dose)
We conducted meta-analyses for five outcomes that were reported with sufficient data using
similar measures in multiple trials (Appendix I). Those treated with ICS+LABA had a greater
increase in the proportion of days free from rescue medication (SMD 0.31 , 95% CI: 0.25, 0.37,
20 comparisons), greater reduction in rescue medicine use per day (SMD -0.29, 95% CI: -0.36, 0.23, 21 comparisons), greater increase in percentage of symptom free days (SMD 0.27, 95% CI:
0.22, 0.32, 25 comparisons), greater improvement in symptom score (SMD -0.27, 95% CI: -0.33,
-0.21, 17 comparisons), and a greater increase in quality of life (AQLQ scores; SMD 0.26, 95%
CI: 0.14, 0.37, 7 comparisons) than those treated with ICS alone.
One previously published good systematic review203 compared the addition of any LABA
to any ICS (ICS+LABA) with continuing the same dose of ICS. The review included 77 trials (N
= 21,248 with 16,623 adults and 4,625 children) that contributed information. Trial duration
ranged from 4 to 54 weeks. Most studies (N = 43) were 12 to 16 weeks. Twenty-seven trials
examined ICSs+LABAs delivered via a single device. The systematic review reported that the
addition of a LABA to an ICS reduced the risk of exacerbations requiring systemic steroids by
23% (RR 0.77, 95% CI: 0.68 to 0.87) compared to ICS alone. In addition, the addition of LABA
resulted in greater improvement in symptoms, rescue medicine use, and quality of life. They
found no difference in nocturnal awakenings.
2. Budesonide (BUD) + Formoterol (FM) compared with Budesonide (BUD)
Two good207, 217 and 14 fair RCTs136, 142, 157, 179, 198, 206, 210-213, 215, 219, 221, 222 (9,298 subjects total)
compared the addition of FM to BUD with continuing the same dose of BUD (Table 20). One of
these trials reported using eformoterol (eFM).213 Eight trials administered BUD+FM in a single
inhaler device,136, 198, 206, 211, 215, 219, 221, 222 three tested the combination delivered by separate
inhalers,157, 179, 213 and five administered them both as a single inhaler and in separate inhalers to
different study groups.142, 207, 210, 212, 217
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Five trials included children ≤ 12 years of age.212, 215, 219, 221, 222 Study duration was 12
weeks for 11 trials, 26 weeks for 1 trial,22232 weeks for one trial,213 and one year for three
trials.157, 179, 198
The majority of trials assessed asthma symptoms, nocturnal awakenings, exacerbations,
and rescue medicine use. Six trials also assessed quality of life and one assessed missed work or
school. For these outcomes, all trials either reported no difference or outcomes favoring
BUD+FM combination therapy over the same dose of BUD. No trial reported a statistically
significant difference in favor of BUD alone for any of these outcomes. For subjects treated with
BUD+FM compared to those treated with BUD alone, 10 trials (71%) reported fewer symptoms
or better improvement in symptoms,135, 137, 139, 142-144, 157, 173, 179, 180, 185, 198, 204-211, 213, 214, 216-218 six
trials (of seven reporting the outcome) reported fewer exacerbations or a lower risk
exacerbations,136, 157, 179, 206, 213, 215 and 10 trials (71%) reported a greater decrease or less frequent
use of rescue medicine.135, 137, 139, 143, 144, 157, 173, 179, 180, 185, 204-211, 213-218, 221 For three of the eleven
trials reporting nocturnal awakenings, results favored the BUD+FM group.206, 207, 211 The other
eight reported no difference.136, 142, 157, 210, 212, 215, 217, 219 Three212, 213, 219 of the four trials reporting
quality of life found no statistically significant difference in overall quality of life measures and
one211 reported greater improvement in those treated with BUD+FM. The single trial reporting
missed work or school found no significant difference between groups.213
3. Fluticasone (FP)+Salmeterol (SM) compared with Fluticasone (FP)
Nine fair quality RCTs (3,029 subjects) compared the addition of SM to FP with continuing the
same dose of FP135, 137, 139, 143, 173, 204, 209, 220, 223 (Table 20). All 9 administered FP+SM in a single
inhaler device.135, 137, 139, 143, 173, 204, 209, 220, 223 None tested the combination delivered by separate
inhalers. One trial included children ≤ 12 years of age.220 Study duration was 12 weeks for 5
trials,135, 139, 143, 204, 220 24 weeks for one trial,173 and 12 months for 3 trials.137, 209, 223
The majority of trials assessed asthma symptoms, exacerbations, and rescue medicine
use. Three trials also reported nocturnal awakenings and one reported quality of life. For these
outcomes, all trials either reported no difference or outcomes favoring FP+SM combination
therapy over the same dose of FP. No trial reported a statistically significant difference in favor
of FP alone for any of these outcomes. For subjects treated with FP+SM compared to those
treated with FP alone, five trials (71%) reported fewer symptoms or better improvement in
symptoms,135, 143, 173, 204, 209 three trials (of five reporting) reported fewer patients having
exacerbations or withdrawn due to exacerbations,135, 137, 143 and 6 trials (86%) reported a greater
decrease or less frequent use of rescue medicine.135, 139, 143, 173, 204, 209 Two of the three trials
reporting nocturnal awakenings found no difference between groups,135, 139 one reported a higher
percentage of awakening-free nights for the FP+SM group.143 The single trial reporting quality of
life measures reported a trend toward better scores on the activities limitation domain of the
AQLQ, but no difference in other domains (activities limitation: 1.0 compared with 0.62, P =
NR).143
4. ICS+Salmeterol (SM) compared with ICS
Three fair quality RCTs (835 subjects) compared the addition of SM to any ICS with continuing
the same dose of ICS (plus placebo)205, 208, 214 (Table 20). All three administered ICS+SM by
separate inhalers. One trial included children, enrolling 210 subjects between the ages of 4 and
16.214 Study duration was 12 weeks for two trials205, 214 and 14 weeks for one.208
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All three trials reported symptoms and rescue medicine use, one reported
exacerbations,205 and one reported quality of life measures.208 In all three trials, those treated
with ICS+SM had greater improvements in symptoms (in one trial the difference was only
statistically significant for nighttime symptoms)205 and rescue medicine use. The single trial
reporting exacerbations found no statistically significant difference in the number of patients
requiring a course of oral steroids (19 compared with 15, P = 0.19).205 The trial reporting quality
of life found no statistically significant difference in overall quality of life, but there was a trend
toward greater improvement in the ICS+SM group (AQLQ global score, mean change from
baseline: 1.08 compared with 0.61, P = 0.47).208
5. ICS+Formoterol (FM) compared with ICS
Two fair quality RCTs (541 subjects) compared the addition of FM to any ICS with continuing
the same dose of ICS (plus placebo)216, 218 (Table 20). Both administered ICS+FM by separate
inhalers. One was a 6 month trial that enrolled 239 adults with mild to moderate persistent
asthma that were not adequately controlled on ICSs.216 The other was a 12-week trial that
enrolled 302 children (ages 6-11) not adequately controlled on ICSs.218 The 6 month trial in
adults found greater improvement in symptoms and rescue medicine use in those treated with
ICS+FM, but no difference in exacerbations.216 The 12-week trial in children found no
statistically significant difference in symptoms, rescue medicine use, or quality of life.218
6. Beclomethasone (BDP) + Salmeterol (SM) compared with Beclomethasone (BDP)
One 12-month fair quality RCT meeting our inclusion/exclusion criteria compared BDP+SM in a
separate inhalers with the same dose of BDP alone in 177 children and adolescents (age 6-16)
with mild to moderate persistent asthma.185 The trial reported no statistically significant
difference in symptoms, exacerbations, or rescue medicine use.
7. Beclomethasone (BDP) + Formoterol(FM) compared with Beclomethasone (BDP)
One 24-week fair quality RCT meeting our inclusion criteria compared BDP+FM in separate
inhalers with same dose of BDP alone in 645 patients with moderate to severe asthma
uncontrolled by regular treatment. The results did not provide between group differences for this
comparison. Analyses were focused on the comparison of BDP+FM in a single inhaler with
BDP+FM in separate inhalers and with a higher dose of BDP alone.
Controller medications for asthma
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Table 20. Characteristics of head-to-head studies comparing ICS+LABA compared with same dose ICS
Study Design
N
Duration
Study
Country
Population
Setting
Comparison
(total daily dose in mcg)
Quality
Rating
Budesonide + formoterol compared with budesonide
Berger et al.
2010222
RCT
USA
Budesonide (640) + Formoterol (18)
vs.
Budesonide (800)
Fair
187
Ages 6-11 with a documented diagnosis of mild
to moderate asthma >=6 months
Fair
Age > 18, moderate persistent asthma, not
controlled on ICS
BUD/FM (320/9 given once daily)
vs.
BUD/FM (320/9 divided into two
doses)
vs.
a
BUD (400)
Multicenter (56)
All given by DPI
RCT, DB, DD
US
Fair
480
Age ≥ 12, uncontrolled on ICS, mild to moderate
persistent asthma
BUD/FM pMDI (320/18)
vs.
BUD pMDI (320)
vs.
FM DPI (18)
vs.
Placebo
Budesonide (160) + Fomoterol (9)
vs.
Budesonide (160) + Fomoterol (18)
vs.
Budesonide (160)
Fair
26 weeks
Setting
206
Buhl et al. 2003
RCT, DB, DD
523
12 weeks
Corren et al. 2007
136
Murphy et al., 2008
225
Multinational (9: Argentina, Belgium, Czech
Repub, Germany, Mexico, Russia, Spain,
Netherlands)
12 weeks
Multicenter (56)
Eid et al.
2010221
RCT, DB
USA
522
6 to 15 years; with a documented mild to
moderate asthma diagnosis for 6 months
12 weeks
Multicenter (95)
207
Jenkins et al. 2006
RCT, DB, DD
Multinational (6)
456
Age ≥ 12, uncontrolled on ICS, mild to moderate
persistent asthma
12 weeks
BUD/FM DPI (1280/36)
vs.
BUD MDI (1600) + FM (36)
vs.
a
BUD MDI (1600)
Good
Multicenter (54)
All given by MDI
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Table 20. Characteristics of head-to-head studies comparing ICS+LABA compared with same dose ICS
Study
Study Design
N
Duration
Country
Population
Setting
Kuna et al. 2006210
RCT, DB, DD
Multinational (8)
617
Age ≥18, mild or moderate persistent,
uncontrolled on ICS
12 weeks
Comparison
(total daily dose in mcg)
BUD/FM (160/9 give once daily)
vs.
BUD+FM (160/9 divided twice daily)
vs.
a
BUD (200)
Quality
Rating
Fair
Multicenter (61)
All given by DPI
Morice et al. 2007211
RCT, DB, DD
Multinational (8 countries)
680
Age ≥12, asthma for at least 6 months,
uncontrolled on ICS alone
12 weeks
BUD pMDI (800)
vs.
BUD/FM DPI (640/18)
vs.
BUD/FM pMDI (640/18)
Fair
BUD pMDI (400)
vs.
BUD/FM DPI (320/18)
vs.
BUD/FM pMDI (320/18)
Fair
BUD/FM pMDI (320/9)
vs.
BUD pMDI (320)
vs.
FM DPI (9)
vs.
BUD pMDI (320) + FM (9) DPI
vs.
placebo
Fair
Group A (used no ICS for ≥ 3
months): Placebo
vs. BUD (200 mcg/d)
vs. FM + BUD (9/200 mcg/d)
Fair
Multicenter (62 centers)
Morice et al. 2008
219
RCT, DB, DD
Multinational (8)
622
Age 6-11, not controlled, on ICS
12 weeks
Multicenter (53)
Noonan et al. 2006
RCT, DB, DD
US
Chervinsky et al, 2008 224
596
Age ≥12, moderate to severe persistent asthma
not controlled, on ICS for ≥4 weeks
142
12 weeks
Multicenter
O’Byrne et al. 2001157
RCT, DB
OPTIMA trial
1970
Age ≥ 12, Group B was not controlled with ICS
(698 in Group A, 1272 Group
B)
Multicenter (198)
1 year
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Multinational (Eastern Europe, Canada, Spain)
Group B (taking ICS for ≥ 3
months):
BUD (200)
vs.
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Table 20. Characteristics of head-to-head studies comparing ICS+LABA compared with same dose ICS
Study Design
N
Duration
Study
Country
Population
Setting
Comparison
(total daily dose in mcg)
Quality
Rating
BUD (200)+ FM (9)
vs.
BUD (400)
vs.
BUD (400)+ FM (9)
All delivery devices=DPIs
Morice et al. 2008219
Noonan et al. 2006
142
Chervinsky et al, 2008
224
RCT, DB, DD
Multinational (8)
622
Age 6-11, not controlled, on ICS
12 weeks
Multicenter (53)
RCT, DB, DD
US
596
Age ≥12, moderate to severe persistent asthma
not controlled, on ICS for ≥4 weeks
12 weeks
Multicenter
O’Byrne et al. 2001157
RCT, DB
OPTIMA trial
1970
Age ≥ 12, Group B was not controlled with ICS
(698 in Group A, 1272 Group
B)
Multicenter (198)
1 year
Multinational (Eastern Europe, Canada, Spain)
BUD pMDI (400)
vs.
BUD/FM DPI (320/18)
vs.
BUD/FM pMDI (320/18)
Fair
BUD/FM pMDI (320/9)
vs.
BUD pMDI (320)
vs.
FM DPI (9)
vs.
BUD pMDI (320) + FM (9) DPI
vs.
placebo
Fair
Group A (used no ICS for ≥ 3
months): Placebo
vs. BUD (200 mcg/d)
vs. FM + BUD (9/200 mcg/d)
Fair
Group B (taking ICS for ≥ 3
months):
BUD (200)
vs.
BUD (200)+ FM (9)
vs.
BUD (400)
vs.
BUD (400)+ FM (9)
All delivery devices=DPIs
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Table 20. Characteristics of head-to-head studies comparing ICS+LABA compared with same dose ICS
Study
Study Design
N
Duration
Country
Population
Setting
Price et al. 2002213
RCT, DB
UK and Ireland
FLOW research group
663 (505 for second
randomization)
Age > 12, asthma > 3 months, symptomatic on
ICS (about 67%) or SABA alone, subject that
were well controlled during initial 4 weeks (N =
505) were re-randomized to the same treatments
Comparison
(total daily dose in mcg)
Quality
Rating
BUD DPI (800) + eFM DPI (18)
vs.
BUD DPI (800) + placebo
Fair
BUD/FM DPI (320/9)
vs.
BUD DPI (400)
Fair
32 weeks
(Part I = 4 weeks, Part II =
well controlled subjects were Multicenter (152 general practices)
re-randomized for 28 more
weeks)
Tal et al. 2002215
RCT, DB, DD
Multi-national (Belgium, Czech Republic,
Hungary, Israel, South Africa, Spain, UK)
286
12 weeks
Age 4-17, suboptimal lung function despite
treatment with ICS, moderate persistent
BUD/FM N = 148
Multicenter (48),
University Hospitals
Zetterstrom et al. 2001217
RCT, DB, DD
362
12wk
BUD
N = 138
Multinational (Finland, Germany, Ireland, Norway, BUD/FM (640/18)
Spain, and Sweden)
vs.
BUD (800) + FM (18)
Age ≥ 18yr, mild to severe persistent asthma, not vs.
BUD (800)a
controlled with ICS alone
Good
Multicenter (59), University hospitals
All given by DPI
RCT, DB
USA
Fair
475
African Americans aged 12 – 65 years with
persistent asthma and symptomatic while being
treated with ICS at a low and consistent dose
FP/SM DPI (200/100)
vs.
FP DPI (200)
FP/SM MDI (200/100)
vs.
Fair
Fluticasone + salmeterol compared with fluticasone
Bailey et al., 2008223
52 weeks
Multicenter (59)
204
Bateman et al. 2001
Controller medications for asthma
RCT, DB, DD
Multinational (10)
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Table 20. Characteristics of head-to-head studies comparing ICS+LABA compared with same dose ICS
Study
Study Design
N
Duration
Country
Population
Setting
497
Age≥12, mild-moderate persistent asthma, not
controlled on ICS
12 weeks
Comparison
(total daily dose in mcg)
Quality
Rating
FP/SM DPI (200/100)
vs.
FP MDI (200)
Multicenter (69)
173
Ind et al. 2003
RCT, DB, DD
Multinational (UK, Italy, Canada, Denmark,
Iceland, Republic of Ireland)
502
24 weeks
Age 16 to 75, moderate to severe, not controlled
on ICS
FP/SM MDI (500/100)
vs.
FP MDI (500)
vs.
FP MDI (1000)
Fair
Placebo
vs.
FP/SM DPI (200/100)
vs.
SM DPI (100) vs.
FP DPI (200)
Fair
FP/SM (500/100)
vs.
FP (500)
Fair
Multicenter (100) Hospitals and primary care centers
Kavuru et al. 2000135
RCT, DB
US
356
Age ≥ 12yr, patients well controlled on current
therapy (stratified into 2 eligible groups: group 1
had to be on ICS for ≥3 months; group 2 was
taking SM for ≥1 week), severity NR
12 weeks
Multicenter
209
Koopmans et al. 2006
RCT, DB
The Netherlands
54
Age 18-60, mild-moderate persistent allergic
asthma, not controlled on ICS
1 year
All given by DPI
Outpatient, Academic Medical Center
Lundback et al. 2006137
RCT, DB
282
12 months
Sweden
FP/SM DPI (500/100)
vs.
Age ≥18, mild or moderate persistent,
FP DPI (500) vs.
uncontrolled on current medication (68% were on SM DPI (100)
ICS)
Fair
Patients recruited from ~4000 individuals with
asthma who had particpated in large
epidemiologic studies
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Table 20. Characteristics of head-to-head studies comparing ICS+LABA compared with same dose ICS
Study
Study Design
N
Duration
Country
Population
Setting
Malone et al, 2005220
RCT, DB, DD
US and Canada
203
Children aged 4 – 11 years with persistent
asthma who used ICS for at least 1 month prior to
visit 1
12 weeks
Comparison
(total daily dose in mcg)
Quality
Rating
FP/SM HFA (200/100)
vs.
FP HFA (200)
Fair
FP/SM MDI (440/84)
vs.
FP MDI (440)
vs.
SM MDI (84)
vs.
placebo
Fair
Placebo
vs.
FP/SM DPI (500/100)
vs.
SM DPI (100)
vs.
FP DPI (500)
Fair
ICS + SM DPI (200)
vs.
ICS + placebo
Fair
Multicenter
Nathan et al. 2006139
RCT, DB
US
Edin et al.
2009140b
365
Age ≥12yr, not controlled on ICS, severity NR
12 weeks
Multicenter (45)
Shapiro et al. 2000143
RCT, DB
US
AND
349
Age ≥12, previously treated with low to medium
ICS for at least 12 weeks
144
Nathan et al. 2003
12 weeks
Multicenter (42 Research Centers/ Allergy and
Asthma Centers)
ICS + salmeterol compared with ICS
Boyd et al. 1995205
RCT, DB
UK
119
Age ≥18, uncontrolled on ICS (≥ 1,500 mcg of
BDP or equivalent), under consideration for
maintenance oral corticosteroid
therapy
12 weeks
Subjects continued their current ICS
and were randomized to SM
compared with placebo
Multicenter (15 out-patient departments)
Kemp et al. 1998208
Controller medications for asthma
RCT, DB
US
506
Age ≥12yr, used a SABA on a daily
basis, symptomatic despite using fixed and
ICS + SM MDI (84)
vs.
ICS + placebo
Fair
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Table 20. Characteristics of head-to-head studies comparing ICS+LABA compared with same dose ICS
Study
Study Design
N
Duration
Country
Population
Setting
14 weeks
approved dose of ICS
Multicenter (44)
214
Russell et al. 1995
RCT, DB
UK
210
Age 4-16, uncontrolled on high-dose ICS (≥ 400
BDP daily or equivalent), moderate to severe
persistent asthma
12 weeks
Multicenter (78 hospitals)
Comparison
(total daily dose in mcg)
Quality
Rating
Subjects continued their current ICS
and were randomized to SM
compared with placebo
ICS + SM DPI (100)
vs.
ICS + placebo DPI
Fair
Subjects continued their current ICS
and were randomized to SM
compared with placebo
ICS + formoterol compared with ICS
van der Molen et al. 1997216
RCT, DB
Netherlands and Canada
239
Adults, uncontrolled on ICS, mild to moderate
persistent asthma
ICS + FM DPI (48)
vs.
ICS + placebo DPI
Fair
6 months
Multicenter (16), general practitioners and
outpatient hospitals
ICS + FM
N = 125
ICS + placebo
N = 114
Subjects continued their current ICS
and were randomized to FM
compared with placebo
Zimmerman et al. 2004218
RCT, DB
Canada
302
Age 6-11, not controlled on ICS alone
12 weeks
Multicenter (27)
ICS + FM DPI (18)
vs.
ICS + FM DPI (9)
vs.
ICS + placebo
Fair
Subjects continued their current ICS
and were randomized to FM (18)
vs. FM (9) vs. placebo
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Table 20. Characteristics of head-to-head studies comparing ICS+LABA compared with same dose ICS
Study
Study Design
N
Duration
Country
Population
Setting
Comparison
(total daily dose in mcg)
Quality
Rating
Beclomethasone + salmeterol compared with beclomethasone
Verberne et al. 1998185
RCT, DB
Multinational (Netherlands, UK)
177
Age 6-16, on ICS for at least 3 months, mild to
moderate asthma
1 year
Multicenter (outpatient clinics of 9 hospitals, 6
university hospitals, and 3 general hospitals)
BDP (400) + SM (100)
vs.
BDP (800)
vs.
BDP (400)
Fair
All given by DPI
Beclomethasone + formoterol compared with beclomethasone
Huchon, et al., 2009199
RCT, DB, DD
645
24 weeks
Multinational
BDP/FM pMDI (400/24)
vs.
Patients aged 18 – 70 years with moderate to
BDP pMDI (1000) + FM DPI(24)
severe persistent asthma uncontrolled by regular vs.
treatment with ICS.
BDP pMDI (1000)
Fair
Abbreviations: BDP = beclomethasone dipropionate; BUD = Budesonide; DB = double-blind; DD = double dummy; DPI = dry powder inhaler; eFM = Eformoterol; FM = Formoterol; FP
= Fluticasone Propionate; ; ICS = Inhaled Corticosteroids; LABAs = Long-Acting Beta-2 Agonists; MA=meta-analysis; MDI = metered dose inhaler; NR = not reported; OCS= oral
corticosteroids; pMDI= pressurized metered dose inhaler; RCT= randomized controlled trial; SM = Salmeterol; SR=systematic review;
a
Doses of ICS in this study are considered equivalent: differences in the number are explained by labeling changes for new inhaled drugs, which require the delivered dose rather than
metered dose to be reported.
b
Edin et al., 2009 is related to two other publications trials (Pearlman, 2004
Controller medications for asthma
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and Nathan, 2006
139
).
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4. ICS+LTRA compared with ICS
Summary of findings
We found two systematic reviews with meta-analyses226, 227 and five RCTs118, 197, 228-231 meeting
our inclusion/exclusion criteria (Table 21). Most studies were conducted in adolescent and adult
populations; one study enrolled a pediatric population ages six to 14231 and one enrolled children
and adolescents (6 to 17 years of age).197
Overall, the addition of LTRAs to ICSs compared to continuing the same dose of ICSs
resulted in improvement in rescue medicine use and a non-statistically significant trend toward
fewer exacerbations requiring systemic steroids. (Appendix H, Table H-13) There is no apparent
difference in symptoms, exacerbations, or rescue medicine use between those treated with ICSs
plus LTRAs compared to those treated with increasing the dose of ICSs. There were some
conflicting results and further research may alter the results (Evidence Tables A and B).
Detailed Assessment
Description of Studies
We found two systematic reviews with meta-analyses226, 227 and five RCTs118, 197, 228-231 meeting
our inclusion/exclusion criteria (Table 21). Three compared budesonide plus montelukast with
budesonide alone. Two studies118, 230 compared the combination of an ICS plus LTRA with the
same dose ICS and three studies197, 228, 229, 231 compared the combination with an increased dose
of ICS.
Study Populations
The five RCTs included a total of 2,423 patients. Most studies were conducted in adolescent and
adult populations; one study enrolled a pediatric population ages six to 14231 and one enrolled
children and adolescents (6 to 17 years of age).197 One was conducted in the United States, one
in Europe, one in India, and two were other multinational combinations. Asthma severity ranged
from mild persistent to severe persistent. Two enrolled patients with mild to moderate persistent
asthma; two enrolled patients with mild to severe persistent asthma; one enrolled patients with
moderate persistent asthma.
Methodologic Quality
The five included RCTs were fair quality studies. The method of randomization and allocation
concealment was rarely reported.
Head-to-head comparisons
1. ICS+LTRA compared with ICS
Of the two systematic reviews meeting our inclusion criteria, one227 identified just three studies
comparing ICS+LTRA with ICS that used constant doses of ICS. It did not find three others that
we identified.197, 228, 229, 231 Thus, we do not discuss this review further in this section and we do
not include it in our overall assessment of the evidence or our strength of evidence grades as it is
missing about half of trials relevant to this section.
One good systematic review with meta-analysis226 compared LTRA plus ICS with the
same dose of ICS, same dose of ICS with taper, or increased doses of ICS. The systematic
review included 27 studies (5871 subjects); two of the studies were in children and 25 were in
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adults. Sixteen of the 27 trials reported data in a way that allowed meta-analysis. Three of these
included trials met our inclusion criteria.118, 228-230 Many were excluded for wrong medication
(pranlukast) or short duration (less than six weeks). Thirteen of the studies (two in children)
compared an LTRA plus an ICS with the same doses of an ICS; seven studies compared an
LTRA plus an ICS with increased doses of an ICS; and seven studies compared an LTRA plus
an ICS with the same doses of ICS with tapering. The LTRAs included montelukast, zafirlukast,
and pranlukast. Many trials used higher than licensed doses of LTRAs. Most trials used BDP
with a dosing range from low (≤ 400 mcg/day BDP or equivalent) to high (> 800 mcg/day BDP
or equivalent) potency, with each trial ensuring same ICS dosing for both groups.
ICS+LTRA compared with same dose ICS. For ICS plus LTRA compared with the same
dose of ICS, the systematic review reported a non-significant reduction in the risk of
exacerbations requiring systemic steroids (RR 0.64, 95% CI: 0.38 to 1.07), the primary outcome.
Just four trials using licensed doses of LTRAs contributed data to the primary outcomes. The
systematic review found no significant difference in symptom score (WMD = -0.10, 95% CI: 0.24, 0.03) or nocturnal awakenings (WMD -6.25, 95% CI: -12.72, 0.23). Higher than licensed
doses of LTRA did show a significant difference in improvement from baseline in asthma
symptom scores (SMD= -0.46, 95% CI: -0.25, -0.66). Those treated with both licensed and
higher than licensed doses of LTRAs had a significant decrease in beta-agonists use compared to
those treated with same dose ICSs (SMD -0.15, 95% CI: -0.24, -0.05 and SMD-0.43, 95% CI:
-0.22, -0.63). There was no significant difference in quality of life (WMD 0.08, 95% CI: -0.03,
0.20).
ICS+LTRA compared with increased ICS. For ICS plus LTRA compared with increased
doses of ICS, only 3 of the trials included in the systematic review compared licensed doses of
LTRAs with increasing the dose of ICSs. The meta-analyses found no significant difference in
any outcomes including the following: change from baseline in symptoms score with licensed
(WMD 0.01, 95% CI: -0.09, 0.10) or higher than licensed doses of LTRA (WMD -0.06, 95% CI:
-0.16, 0.03); risk of experiencing an asthma exacerbation requiring systemic steroids with
licensed doses (RR 0.92, 95% CI: 0.56, 1.51) or higher than licensed doses of LTRA (RR 1.05
95% CI: 0.55, 2.00); withdrawals due to poor asthma control with licensed (RR 0.49, 95% CI:
0.15, 1.63) or higher than licensed doses of LTRA (RR 0.72 95% CI: 0.29, 1.76); and change
from baseline in use of rescue beta-agonists with licensed (WMD -0.03 95% CI: -0.24, 0.18) nor
higher than licensed doses of LTRA (WMD 0.00 95% CI: -0.37, 0.37).
ICS+LTRA compared with same ICS (tapering). For ICS plus LTRA compared with the
same ICS dose with tapering (seven studies), the systematic review found no significant
difference in final symptom scores (WMD -0.06, 95% CI: -0.17 to 0.05), number of patients with
exacerbations requiring systemic steroids (RR 0.47, 95% CI: 0.20, 1.09), difference in final betaagonist use (WMD -0.2 puffs/day, 95% CI: -0.7 to 0.3), or change from baseline in beta-agonist
use (WMD -0.15 puffs/week; 95% CI: -0.91, 0.61). There was a significant reduction in rate of
withdrawals due to poor asthma control for those treated with ICS plus LTRA (RR 0.63, 95% CI:
0.42 to 0.95), however this was not significant when only the trials using intention to treat
analysis were considered (RR 0.63, 95% CI: 0.42, 0.95).
2. Budesonide (BUD)+ Montelukast (ML) compared with Budesonide (BUD) same dose
We found one fair RCT230 comparing the combination of BUD+ML with the same dose of BUD
(Table 21). This fair-rated RCT (N = 639), the CASIOPEA study, compared low to high dose
BUD (400 to 1600 mcg/day) plus placebo (N = 313) with low to high dose BUD (400 to 1600
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mcg/day) + ML 10 mg/day (N = 326) for 16 weeks.230 Subjects age 18 to 70 with poorly
controlled mild to severe asthma currently being treated with a stable dose of ICS for at least 8
weeks were enrolled from hospital centers in Spain. At endpoint, there were no statistically
significant differences in asthma symptom scores or quality of life. However, those treated with
BUD+ML had fewer nocturnal awakenings, more asthma free days, fewer days with
exacerbations, and greater decrease in rescue medicine use. The differences were reportedly
independent of BUD dose.
3. Beclomethasone (BDP) + Montelukast (ML) compared to Beclomethasone (BDP) same dose
We found one trial (N = 642) which compared four treatments for 16 weeks:118 low dose BDP
(400 mcg/day) + ML (10 mg/day) (N = 193) compared with low dose BDP 400 mcg/day (N =
200) compared with ML 10mg/day (N = 201) compared with placebo (N = 48). Subjects with
uncontrolled mild to moderate asthma treated with ICS who were age 15 or greater were enrolled
from 18 countries and 70 different centers. At endpoint, those treated with BDP+ML had greater
improvement in daytime asthma symptom scores (-0.13 compared with -0.02; P = 0.041), nights
per week with awakenings (-1.04 compared with -0.45; P = 0.01), and percentage of days with
an exacerbation (13.37% compared with 17.92%; P = 0.041) compared to BDP. BDP+ML
showed no significant difference in % of patients with an asthma attack or difference in total
puffs/day compared to BDP. Compliance was high with both inhaled and oral groups
respectively.
4. Budesonide (BUD)+ Montelukast (ML) compared with Budesonide (BUD) increased dose
We found two fair RCTs228, 229, 231 comparing the combination of BUD+ML with an increased
dose of BUD (Table 21). One fair multinational trial (N = 889) compared medium dose BUD
(800 mcg/day) plus ML (10 mg/day) (N = 448) compared with high dose BUD (1600 mcg/day)
(N = 441) for 16 weeks.228, 229 The trial enrolled subjects age 15 to 75 with uncontrolled asthma
treated with medium dose ICS. At endpoint, there were no statistically significant differences
between those treated with BUD+ML and those treated with BUD for percentage of asthma free
days, daytime symptom score, percentage of nights with awakenings, percentage of days with an
exacerbation, percentage of patients requiring oral steroids or hospitalization, rescue medicine
use, or quality of life. Adherence was high for both the tablets and inhalers, with over 95% of
days fully compliant.
The other trial231 (N = 71) compared low dose BUD (400 mcg/day) (N = 33) compared
with low dose BUD (200 mcg/day) plus ML (5 mg/day) (N = 30) for 12 weeks. Subjects with
moderate persistent asthma age 6 to 14 were enrolled from a Pediatric Asthma Clinic in India. At
endpoint, those treated with increased dose of BUD had fewer exacerbations compared to
BUD+ML (9.1% compared with 33.3%; P < 0.01). Adherence was high in both groups with
only one patient declaring non-adherence.
5. Fluticasone (FP)+Montelukast (ML) compared with Fluticasone (FP) increased dose
We found one fair RCT197 (N = 182) comparing the combination of FP+ML with an increased
dose of FP in children and adolescents (6 to 17 years of age). The trial used a triple cross-over
design. Subjects with uncontrolled asthma while receiving FP (100 twice daily) were
randomized to FP (250 twice daily), FP (100 twice daily) plus salmeterol, or FP (100 twice daily)
plus montelukast. The primary outcome was a composite of exacerbations, number of asthma
control days, and FEV1. One hospitalization for asthma-related symptoms occurred in each of
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the three treatment groups. A total of 120 prednisone bursts were prescribed for exacerbations
(47 during treatment with FP compared with 43 during treatment with FP+ML, P = NR).
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Table 21. Characteristics of head-to-head studies comparing ICS + LTRA with ICS
Study
Study design
N
Duration
Country
Study population
Setting
Comparison
(total daily dose)
Quality
rating
ICS + LTRA compared with ICS same dose
Ducharm et al.
2004226
Systematic Review with meta-analysis 2 trials in children; 25 in adults
27 studies (5871 subjects)
LTRA plus ICS vs. ICS same dose, ICS same dose
tapering, or ICS increased dose.
Good
Budesonide + montelukast compared with budesonide same dose
Vaquerizo et al. RCT
2003230
639
CASIOPEA
Spain
Age 18 – 70
BUD (400 – 1600) + placebo
vs.
BUD (400 – 1600) + ML (10)
Hospital centers
Low to High dose ICS
Fair
16 weeks
Beclomethasone + montelukast compared with beclomethasone same dose
Laviolette et al.
118
1999
RCT
Multinational
642
Age ≥ 15
16 weeks
Multicenter
BDP (400) + ML (10)
vs.
BDP (400)
vs.
ML (10)
vs.
placebo
Fair
Low dose ICS
ICS + LTRA compared with ICS increased dose
Ducharm et al.
2004226
Systematic Review with meta-analysis 2 trials in children; 25 in adults
27 studies (5871 subjects)
LTRA plus ICS vs. ICS same dose, ICS same dose
tapering, or ICS increased dose.
Good
Budesonide (BUD)+Montelukast (ML) compared with Budesonide (BUD) increased dose
Jat et al. 2006231 RCT
71
India
Age 6-14
BUD (400)
vs.
BUD (200) + ML (5)
Pediatric Asthma Clinic
Low dose ICS
Multinational
ML (10) + BUD (800)
vs.
Fair
12 weeks
Price et al.
2003228, 229
RCT
889
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Table 21. Characteristics of head-to-head studies comparing ICS + LTRA with ICS
Study
Study design
N
Duration
COMPACT
16 weeks
Country
Study population
Setting
Comparison
(total daily dose)
Age 15 – 75
BUD (1600)
Multicenter
Medium to High dose ICS
Quality
rating
Fluticasone (FP)+Montelukast (ML) compared with Fluticasone (FP) increased dose
Lemanske et al. RCT
2010197
182
BADGER
United States
Age 6-17
48 wks (3 cross-over periods of 16 wks
Multicenter
each)
FP (500)
vs.
FP/SM (200/100)
vs.
FP (200) + ML (5-10)
Fair
High vs. low vs. low dose ICS
Abbreviations: AQLQ = Asthma Quality of Life Questionaire; BUD = Budesonide; CI = confidence interval;; FM = Formoterol; FP = Fluticasone Propionate; ICS = Inhaled
Corticosteroids; LABAs = Long-Acting Beta-2 Agonists; LTRAs = Leukotriene receptor antagonists; MA=meta-analysis; ML = Montelukast; NR = not reported; NS = not statistically
significant; OR = odds ratio; QOL = quality of life; RCT= randomized controlled trial; SM = Salmeterol; SMD = standard mean difference; SR = systematic review; WMD = weighted
mean difference.
Symbol use: Drug X > Drug Y = statistically significant difference in outcomes favoring Drug X; Drug X > Drug Y trend = point estimate favors Drug X, but the difference is not
statistically significant or tests of statistical significance were NR; No difference = no statistically significant difference or tests of statistical significance were not reported and outcomes
are similar.
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5. Combination products compared with Leukotriene Modifiers
Summary of findings
We found 5 RCTs 127, 128, 232-234 meeting our inclusion/exclusion criteria for this comparison
(Table 22). All 5 compared low dose fluticasone plus salmeterol with montelukast. Two of the
RCTs were in adolescents and adults, one enrolled subjects over the age of six127 (~15% of
subjects < 12 years of age), and 2 enrolled children ages 6-14.128, 234
Overall, our meta-analysis and results from 5 RCTs found the combination of fluticasone
plus salmeterol to be more efficacious than montelukast for the treatment of persistent asthma
(Appendix I and Appendix H, Table H-14).
Detailed Assessment
Description of Studies
We found 5 RCTs 127, 128, 232-234 meeting our inclusion/exclusion criteria (Table 22). Of the
included studies, all compared montelukast with low dose fluticasone plus salmeterol.
Study Populations
The 5 RCTs included a total of 2,188 patients. Two studies were conducted in adult populations;
three studies127, 128, 234 included children < 12 years of age. Four studies were conducted in the
United States and one study was conducted at sites in both Latin America and Turkey.234 Asthma
severity ranged from mild persistent to severe persistent: 2 studies enrolled subjects with mild to
moderate persistent asthma; three studies enrolled subjects with any severity of persistent
asthma.
Methodologic Quality
Four trials were rated fair quality; one was rated good quality.
Sponsorship
Of the 5 RCTs, 3 (60%) were funded by pharmaceutical companies; only one (20%) was funded
primarily by sources other than pharmaceutical companies, and one (20%) did not report the
source of funding but a significant portion of the study design was dictated by a pharmaceutical
company and several authors reported a primary affiliation with the company.234
Head-to-head comparisons
1. Fluticasone (FP)+Salmeterol (SM) compared with Montelukast (ML)
The 5 included studies are described below. We conducted meta-analyses for outcomes that were
reported with sufficient data in multiple trials (Appendix I). These included symptom-free days,
rescue medicine-free days, and exacerbations. We found statistically significant differences
favoring those treated with FP/SM for all three outcomes. Those treated with FP/SM had greater
improvement in the percentage of symptom-free days SMD -0.25, 95% CI: -0.35, -0.15), greater
improvement in the percentage of rescue medicine-free days (SMD -0.27, 95% CI: -0.37, -0.17),
and fewer exacerbations (SMD 0.26, 95% CI: 0.16, 0.35). (Appendix I)
The 5 studies included one good quality RCT232 and 4 fair quality RCTs (Table 22).127,
128, 233, 234
The good-rated RCT (N = 432) compared low dose FP/SM (200 mcg/100 mcg daily)
(N = 216) compared with ML (10 mg/day) (N = 216) as monotherapy for 12 weeks.232 Subjects
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with uncontrolled asthma treated with oral or inhaled short-acting beta-agonist age 15 and older
were enrolled from 51 different centers in the United States. At endpoint those treated with
FP/SM showed a greater improvement in all outcomes compared to ML including a decrease in
the combined asthma symptom score (-1 compared with -0.7; P ≤ 0.001), increase from baseline
in % symptom free days (+40.3% compared with +27%; P ≤ 0.001), increase from baseline in %
of awakening free nights (+29.8% compared with +19.6%; P = 0.011), decrease from baseline in
nights/ week with awakenings (-2.2 compared with -1.6; P ≤ 0.001), decrease in puffs/day (-3.6
compared with -2.2; P ≤ 0.001), increase in % of rescue free days (53.4% compared with 26.7%;
P ≤ 0.001), and increase in quality of life (AQLQ overall score, increase: 1.7 compared with 1.2;
P < 0.001). Exacerbations occurred less frequently in the FP/SM group (3% compared with 6%;
P = NR). Compliance was approximately 99% in both groups.
The first fair-rated RCT (N = 423) also compared low dose FP/SM (200 mcg/100mcg
daily) (N = 211) compared with ML (10mg/day) (N = 212) for 12 weeks.233 Subjects with
uncontrolled asthma treated with oral or inhaled short-acting beta-agonist age 15 or older were
enrolled from multiple centers in the United States. At endpoint, results were similar to those in
the good quality RCT described above232 with significant differences for all outcomes favoring
FP/SM over ML: including decrease in symptoms, rescue medicine use, and exacerbations (0%,
5%; P < 0.001) (Table 22).
A third fair-rated RCTs showed mixed results, with some outcomes favoring FP/SM and
others finding no difference. The first (N = 500) compared low dose FP (200 mcg/day) (N = 169)
compared with low dose FP (100 mcg/day) plus SM (50 mcg/day) (delivered once daily at night)
(N = 165) compared with ML (5-10 mg/day) (N = 166) for 16 weeks.127 Subjects were age six
and older, had mild to moderate asthma controlled on ICS, and were enrolled from multiple
American Lung Association Asthma Clinical Research Centers in the United States. At endpoint,
there were no significant differences between FP plus SM and ML in symptom-free days or
rescue medicine use. But, there were significant differences in the percentage of patients with
treatment failure (20.4% compared with 30.3%; P = 0.03) and asthma control (ACQ: 0.71
compared with 0.82; P = 0.004) favoring FP plus SM. Adherence was good for all groups
(FP/SM 93.3% compared with ML 90.5%). The last fair-rated RCT (N = 285), the Pediatric
Asthma Controller Trial (PACT), compared low dose FP 200 mcg/day via DPI (N = 96)
compared with ML 5 mg/day (N = 95) compared with low dose FP 100 mcg/day plus SM 100
mcg/day via DPI (FP 100 mcg plus SM 50 mcg in the morning plus SM 50 mcg in the evening)
(N = 94) for 48 weeks.128 Of note, the dose of FP/SM used was outside of the product label
recommendation. Subjects with mild to moderate asthma age 6 to 14 were enrolled from
Childhood Asthma Research and Education Centers in the United States. At endpoint, the trial
found no significant difference in the overall percentage of asthma control days (52.5%
compared with 59.6%; P = 0.08), but found favorable results for FP/SM in the change in the
percentage of asthma control days from baseline (33.3% compared with 22.3%; P = 0.011).
There was no significant difference in asthma control as measured by change in ACQ score from
baseline (-0.45 compared with 0.55; P = 0.42). Adherence was similar between groups (86%
compared with 90%; P = NR).
A final RCT showing mixed results, known as the Pediatric Asthma Control Evaluation
(PEACE) study, enrolled children age 6 to 14 with mild to moderate persistent asthma in
outpatient centers at 4 sites in Turkey and 23 in Latin America.234 Using a double-blind, doubledummy design, 281 children treated with FP/SM 100mcg/50mcg twice daily were compared to
267 patients treated with ML 5mg daily. While the results showed significant improvement in
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the percentage of symptom free days (OR 1.74, 95% CI 1.07 – 2.82), asthma controlled weeks
(16.7% more in FP/SM group, 95% CI 8.3 – 16.7), they found no difference between groups in
the percentage of nights without awakenings due to nocturnal symptoms (OR 2.33, 95% CI 0.73
– 7.47). The mean exacerbation rate and time was significantly reduced with FP/SM therapy
(0.12 vs. 0.3, OR 0.4, 95% CI 0.29 – 0.57) and the number of patients exacerbation free at 84
days was 89.6% in FP/SM patients compared with 74.8% in the ML group (95% CI 8 – 22). In
addition, the percentage of rescue free days increased significantly with FP/SM treatment (OR
3.24, 95% CI 2.09– 5.02). Quality of life measures, however, demonstrated mixed results. While
PACQLQ scores were higher in the FP/SM group (mean treatment difference 0.54, 95% CI 0.06
– 1.02), no difference was noted between groups with respect to PAQLQ score (mean treatment
difference 0.09, 95% CI -0.12 – 0.30). Finally, while 7.5% of FP/SM treated patients required
some form of unscheduled health care contact during the study period, substantially more
patients on ML therapy required medical attention (P = NR). Adherence was similar between
groups (87% compared with 84%; P = NR).
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Table 22. Characteristics of head-to-head studies comparing ICS+LABA with leukotriene modifiers
Study
Study design
N
Duration
Country
Study population
Setting
Comparison
(total daily dose)
Quality
rating
Montelukast (ML) compared with Fluticasone (FP) plus Salmeterol (SM)
Pearlman et al.
2002232
Calhoun et al. 2001233
Maspero et al. 2008234
Pediatric Asthma
Control Evaluation
(PEACE) study
432
Age 15 and older, mild to severe persistent asthma, smoking status NR
FP/SM (200 mcg/100 mcg)
vs.
ML (10 mg)
12 weeks
Multicenter (51)
Low dose ICS
United States
RCT
United States
423
Age 15 and older, mild to severe persistent asthma, smoking status NR
FP/SM (200 mcg/100 mcg)
vs.
ML (10 mg)
12 weeks
Multicenter
Low dose ICS
Latin America & Turkey
FP (200 mcg)/SM (100 mcg)
vs.
ML (5mg)
RCT
RCT DB, double
dummy
Children 6-14, mild to moderate persistent asthma
Good
Fair
Fair
548
Multicenter (23 Latin America, 4 Turkey)
14 weeks (2 week Outpatient setting
run-in period, 12
week treatment
period)
Peters et al. 2007127
United States
RCT
Age 6 and older, mild to moderate asthma, smoking status NR
500
Multicenter
Low dose ICS
FP (200 mcg)
vs.
FP/SM (100 mcg/50 mcg)
vs.
ML (5 – 10 mg)
Fair
16 weeks
Low dose ICS
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Table 22. Characteristics of head-to-head studies comparing ICS+LABA with leukotriene modifiers
Study
Study design
N
Duration
Country
Study population
Setting
Comparison
(total daily dose)
Quality
rating
Montelukast (ML) compared with Fluticasone (FP) plus Salmeterol (SM)
Sorkness et al.
2007128
Pediatric Asthma
Controller Trial
(PACT)
United States
RCT
285
Children age 6-14, mild to moderate persistent asthma, excluded current
smokers within the past year
48 weeks
Childhood Asthma Research and Education Centers
FP (200 mcg)
vs.
FP/SM (100 mcg/50 mcg)
once in the morning +
SM (50 mcg) in the evening
vs.
ML (5 mg)
Fair
Low dose ICS
Abbreviations: AQLQ = Asthma Quality of Life Questionaire; BUD = Budesonide; CI = confidence interval;; FM = Formoterol; FP = Fluticasone Propionate; ICS = Inhaled
Corticosteroids; LABAs = Long-Acting Beta-2 Agonists; LTRAs = Leukotriene receptor antagonists; MA=meta-analysis; ML = Montelukast; NR = not reported; NS = not statistically
significant; OR= odds ratio; QOL = quality of life; RCT= randomized controlled trial; SM = Salmeterol; SR=systematic review.
Symbol use: Drug X > Drug Y = statistically significant difference in outcomes favoring Drug X; Drug X > Drug Y trend = point estimate favors Drug X, but the difference is not
statistically significant or tests of statistical significance were NR; No difference = no statistically significant difference or tests of statistical significance were not reported and outcomes
are similar.
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6. ICS+LABA vs ICS+LTRA
(addition of LABAs compared with LTRAs as add-on therapy to ICSs)
Summary of findings
We found one systematic review with meta-analysis235 and eight RCTs197, 236-242 meeting our
inclusion/exclusion criteria that compared the addition of a LABA with the addition of an LTRA
for patients poorly controlled on ICS therapy (Table 23). Seven of the RCTs were in adolescents
and adults ≥ 12 years of age and one enrolled children and adolescents 6 to 17 years of age.197
Overall, results from a good quality systematic review with meta-analysis and eight
RCTs provide high strength of evidence (Appendix H, Table H-15) that the addition of a LABA
to ICS therapy is more efficacious than the addition of an LTRA to ICS therapy for adolescents
and adults with persistent asthma (Evidence Tables A and B). We found just one RCT that
included children < 12 years of age.197
Detailed Assessment
Description of Studies
We found one systematic review with meta-analysis235 and eight RCTs.197, 236-242 Of the included
studies (Table 23), seven RCTs compared montelukast plus fluticasone with salmeterol plus
fluticasone, one RCT242 compared montelukast plus budesonide with formoterol plus
budesonide. All but two of the included RCTs197, 240 were included in the systematic review and
meta-analysis.235
Study Populations
All but one of the included RCTs were conducted in adult populations.197 Four studies (50%)
were conducted in the United States, two (25%) in Europe, and two (25%) were other
multinational combinations often including Europe, Canada, or the US. Asthma severity ranged
from mild persistent to severe persistent: two studies (25%) were conducted in patients with mild
to moderate persistent asthma, two (25%) in patients with mild to severe persistent asthma, one
(12%) in patients with moderate persistent asthma, and two (25%) in patients with moderate to
severe persistent asthma. One study did not report the severity or it was unable to be determined.
Methodologic Quality
The overall quality of the eight RCTs included in our review was rated fair to good. Most trials
received a quality rating of fair. The method of randomization and allocation concealment was
rarely reported.
Sponsorship
Six of the included RCTs(75%) were funded by pharmaceutical companies; one trial197 was
funded by grants from the National Heart, Lung and Blood Institute, National Institute of Allergy
and Infectious Diseases, and National Center for Research Resources; and one trial did not report
the source of funding.
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Head-to-head comparisons
1. ICS+LABA compared with ICS+LTRA
One good quality systematic review with meta-analysis including 6,030 subjects (11 of 15
included trials contributed to the analyses) compared LABAs with LTRAs as add-on therapy to
ICSs.235 The included trials compared salmeterol (100 mcg/day) or formoterol (24 mcg/day) plus
ICS compared with montelukast (10 mg/day) or zafirlukast (40 mg/day) plus ICS. The ICS dose
average was 400 to 560 mcg/day of beclomethasone or equivalent.235 Of the fifteen trials the met
inclusion criteria, a total of 80 subjects were children. Of the 11 trials that contributed to the
analyses, 10 were in adults and one was in children. Six of the included trials met our inclusion
criteria.236-239, 241, 242 Five of the studies included in the analysis did not meet our inclusion
criteria.
The systematic review included randomized controlled trials conducted in adults or
children with persistent asthma where a LABA or LTRA was added to ICS for 4 to 48 weeks.
Inhaled Short-Acting Beta-2 Agonists and short courses of oral steroids were permitted as rescue
medications. Subjects had to be on a stable dose of ICSs throughout the trials.
The meta-analysis reported that LABA plus ICS was significantly better than LTRA plus
ICS for all observed outcomes.235 Six trials contributed to the primary outcome showing a
significant decrease in risk of exacerbation requiring systemic steroids for those treated with
LABAs (RR 0.83; 95% CI: 0.71, 0.97). The type of LTRA used did not impact the results. The
reported number of patients who must be treated with the combination of LABA and ICS instead
of LTRA and ICS to prevent one exacerbation over 48 weeks was 38 (95% CI: 23, 247).
Subjects treated with LABA+ICS had greater improvement in the percentage of
symptom-free days (WMD 6.75%; 95% CI: 3.11, 10.39, 5 studies), daytime symptom scores
(SMD -0.18; 95% CI: -0.25, -0.12, 5 studies), nighttime awakenings (WMD -0.12; 95% CI: 0.19, -0.06, 4 studies), percentage of rescue-free days (WMD 8.96%; 95% CI: 4.39, 13.53, 4
studies), rescue medication use per day (WMD -0.49 puffs/day; 95% CI: -0.75, -0.24, 7 studies),
overall asthma-related quality of life (WMD 0.11; 95% CI: 0.05, 0.17, 3 studies). There was
significant heterogeneity in one of the analyses (percentage of rescue-free days; I2 = 61%; P <
0.05).
The eight RCTs meeting the inclusion/exclusion criteria for our review are summarized
in Table 23. Six of the eight trials were included in the systematic review with meta-analysis235
described above. One of those not included was a fair-rated RCT,240 the SOLTA study. It
compared low dose FP (200 mcg/day) plus SM (100 mcg/day) (N = 33) with low dose FP (200
mcg/day) plus ML 10 mg/day (N = 33) for 12 weeks in 66 adults (age 18 to 50) with
uncontrolled mild to moderate asthma. The ICS/LABA combination was delivered via a single
inhaler. Patients being treated with medium dose ICSs were enrolled from multiple centers in the
United Kingdom. At endpoint, there were no statistically significant differences in asthma
symptoms, but the trends in direction of the effect sizes favored the ICS/LABA combination
(symptoms-free days: mean difference in change from baseline: 13.2%, 95% CI: -1.9%, - 32.9%;
P = 0.064; symptom-free nights: mean difference in change from baseline: 13.3%, 95% CI: 1.5%, -34.5%; P = 0.055). There was no significant difference in daytime rescue use (median %
rescue free days at endpoint 73% compared with 70%; P = NS), but there was a difference in
rescue use at night favoring FP/SM (median rescue free nights at endpoint: 93% compared with
82%; P = 0.01).
The other trial (BADGER) not included in the systematic review described above
enrolled 182 children and adolescents (6 to 17 years of age).197 The trial used a triple cross-over
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design. Subjects with uncontrolled asthma while receiving FP (100 twice daily) were
randomized to FP (250 twice daily), FP (100 twice daily) plus salmeterol, or FP (100 twice daily)
plus montelukast for 16 weeks of each treatment (total of 48 week treatment phase). The
primary outcome was a composite of exacerbations, number of asthma control days, and FEV1.
The response to LABA step-up therapy was most likely to be the best response compared with
LTRA step-up (relative probability, 1.6; 95% CI: 1.1 to 2.3). One hospitalization for asthmarelated symptoms occurred in each of the three treatment groups. A total of 120 prednisone
bursts were prescribed for exacerbations (30 during treatment with FP+SM compared with 43
during treatment with FP+ML, P = NR).
We do not describe all of the other included RCTs in detail because they generally found
results consistent with the overall conclusions of the meta-analysis. For all of our outcomes of
interest, most trials reported favorable results for subjects treated with ICS+LABA; the others
reported no statistically significant differences (Evidence Tables A and B).
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Table 23. Characteristics of head-to-head studies comparing ICS+LABA with ICS+leukotriene modifiers
Study
Study design
N
Duration
Study population
Comparison
(total daily dose)
Quality
rating
LTRA plus ICS compared with LABA plus ICS
Ducharme et al.
2006235
Systematic Review
with meta-analysis
1 trial in children; 10 in adults
11 studies (6,030
subjects) included in
meta-analysis
LABA (salmeterol 100 mcg or formoterol 24 mcg) plus
ICS
vs.
LTRA (montelukast 10 mg, zafirlukast 40 mg) plus ICS
Good
ICS was average 400 to 560 mcg/day of BDP or
equivalent (medium to high dose ICS)
Montelukast plus fluticasone compared with salmeterol plus fluticasone
Bjermer et al.236
IMPACT
RCT
1490
48 weeks
Multinational (37 countries - eastern Europe)
ML (10mg) plus FP (200 mcg)
vs.
SM (100 mcg) plus FP (200 mcg)
Good
Age 15 – 72, mild to severe persistent asthma
currently uncontrolled on low dose ICS, smoking
Same Low dose ICS
status NR
Multicenter (148)
Fish et al. 2001237
RCT
948
12 weeks
United States and Puerto Rico
SM (100 mcg) plus baseline ICS
vs.
Age 15 and older, moderate to severe persistent ML plus baseline ICS (10mg)
asthma despite low to high dose ICS, smoking
Same Low to High dose ICS
status NR
Fair
Multicenter (71)
Ilowite et al. 2004238
Lemanske et al.
2010197
RCT
1473
Age 14 – 73, mild to severe persistent asthma
uncontrolled on ICS, smoking status NR
48 weeks
Multicenter (132)
RCT
182
BADGER
United States
48 wks (3 cross-over
periods of 16 wks
each)
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Age 6-17
Multicenter
SM (84 mcg) plus FP (220 mcg)
vs.
ML (10 mg) plus FP (220 mcg)
Fair
Unspecified whether ICS dose changed from baseline
to study low dose ICS
FP (500 mcg)
vs.
FP/SM (200 mcg/100 mcg)
vs.
FP (200 mcg) + ML (5-10 mg)
Fair
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Table 23. Characteristics of head-to-head studies comparing ICS+LABA with ICS+leukotriene modifiers
Study
Nelson et al. 2000239
Study design
N
Duration
RCT
447
12 weeks
Study population
Comparison
(total daily dose)
United States
FP (200 mcg) / SM (100 mcg)
vs.
Age 15 and older, moderate to severe persistent FP (200 mcg) plus ML (10 mg)
asthma uncontrolled don low dose ICS, smoking
Same Low dose ICS
status NR
Quality
rating
Fair
Multicenter
Pavord et al. 2007240
SOLTA Study Group RCT
66
12 weeks
United Kingdom
Age 18 – 50, mild to moderate persistent
asthma uncontrolled on medium dose ICS,
excluded smokers
FP (200 mcg) / SM (100 mcg)
vs.
FP (200 mcg) plus ML (10 mg)
Fair
Decrease to Low dose ICS
Multicenter
Ringdal et al. 2003241
RCT
805
12 weeks
Multinational (19 – Europe, Middle East, Africa)
FP (200 mcg) / SM (100 mcg)
vs.
FP (200 mcg) plus ML (10 mg)
Fair
BUD (400 mcg) plus FM (18 mcg)
vs.
BUD (400 mcg) plus ML (10 mg)
Fair
Age 15 and older, mild to severe persistent
asthma on low to high dose ICS at baseline,
excluded patients with a 10 pack-year history of Decreased to Low dose ICS and had to remain
smoking
uncontrolled.
Multicenter (114)
Montelukast plus budesonide compared with formoterol plus budesonide
Ceylan et al. 2004242
RCT
48
8 weeks
Turkey
Age 15 – 60, moderate persistent asthma
uncontrolled on unspecified ICS dose, excluded
Unspecified change from baseline to Low dose ICS
smokers
University based clinics
Abbreviations: BUD = Budesonide; CI = confidence interval; DPI= Dry Powder Inhaler; FM = Formoterol; FP = Fluticasone Propionate; ICS = Inhaled Corticosteroids; LABAs = LongActing Beta-2 Agonists; LTRAs = Leukotriene receptor antagonists; MA=meta-analysis; ML = Montelukast; NR = not reported; NS = not statistically significant; OR= odds ratio; QOL =
quality of life; RCT= randomized controlled trial; SM = Salmeterol;; SR=systematic review.
Symbol use: Drug X > Drug Y = statistically significant difference in outcomes favoring Drug X; Drug X > Drug Y trend = point estimate favors Drug X, but the difference is not
statistically significant or tests of statistical significance were NR; No difference = no statistically significant difference or tests of statistical significance were not reported and outcomes
are similar.
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7. LTRA+LABA compared with ICS+LABA
Summary of findings
We found one fair quality RCT comparing LTRA plus LABA with ICS plus LABA (Appendix
H, Table H-16 and Table 24).243 The fair-rated, placebo-controlled, multi-center RCT (N = 192)
compared ML (10mg/day) plus SM (100 mcg/day) plus placebo ICS (N = 98) compared with
low dose BDP (160 mcg/day) plus SM (100 mcg/day) plus placebo LTRA (N = 92) for 14
weeks, washout for 4 weeks, then crossover for another 14 weeks.243 Subjects age 12 to 65 with
moderate asthma were enrolled from multiple sites in the United States. There was a 4-week runin period that involved a single-blind treatment with both BDP (160 mcg/day) and ML (10
mg/day). The primary objective of the study was to assess time until treatment failure. The trial
was terminated early because the Data and Safety Monitoring Board determined that the primary
research question had been answered. Those treated with LTRA+LABA had significantly shorter
time to treatment failure than those treated with ICS+LABA (P = 0.0008).
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Table 24. Characteristics of head-to-head studies comparing ICS+LABA with LTRA+LABA
Study
Study design
N
Duration
Country
Study population
Setting
Comparison
(total daily dose)
Quality rating
Montelukast plus salmeterol compared with beclomethasone plus salmeterol
Deykin et al.
2007243
RCT
United States
192
Age 12 to 65
14 weeks, washout for 4 weeks, then
crossover for 14 weeks
Multicenter
ML (10mg) + SM (100 mcg) plus placebo ICS vs.
BDP (160 mcg) + SM (100 mcg) plus placebo LTRA
Fair
Low dose ICS
Abbreviations: BDP = Beclomethasone dipropionate; ICS = Inhaled Corticosteroids; LABAs = Long-Acting Beta-2 Agonists; LTRAs = Leukotriene receptor antagonists; ML =
Montelukast; RCT= randomized controlled trial; SM = Salmeterol.
Symbol use: Drug X > Drug Y = statistically significant difference in outcomes favoring Drug X; Drug X > Drug Y trend = point estimate favors Drug X, but the difference is not
statistically significant or tests of statistical significance were NR; No difference = no statistically significant difference or tests of statistical significance were not reported and outcomes
are similar.
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Key Question 2. Adverse Events
What is the comparative tolerability and frequency of adverse events for controller
medications used to treat outpatients with persistent asthma?
I. Intra-class Evidence (within one class)
A. Inhaled Corticosteroids
Summary of Findings
We found seven systematic reviews,22, 23, 244-248 50 RCTs27-33, 35-50, 52-55, 58-70, 249-258 and 12
observational studies259-269 reporting the tolerability or frequency of adverse events for inhaled
corticosteroids meeting our inclusion/exclusion criteria (Table 7 and Evidence Tables A and B).
Few RCTs were designed to assess adverse events as primary outcomes; most published studies
designed to assess adverse events were observational studies.
The overall incidence of adverse events and withdrawals due to adverse events are
similar for equipotent doses of ICSs; results from head-to-head RCTs suggest no significant
differences between ICSs (moderate strength of evidence). Overall summaries for specific
adverse events are described below in the specific adverse events section. Most of the data for
specific adverse events comes from placebo-controlled trials or observational studies, rather than
from head-to-head comparisons.
Detailed Assessment
Description of Studies
Most studies that examined the efficacy of one ICS relative to another (described in Key
Question 1) also reported tolerability and adverse events. Six head-to-head RCTs that did not
report efficacy met our inclusion/exclusion criteria for tolerability or adverse events.249-252, 257, 258
Seven of the head-to-head RCTs included children < 12.31, 44, 46, 62, 68, 69, 249 Placebo-controlled
RCTs and observational studies are described below in their respective specific adverse event
sections.
Methods of adverse events assessment differed greatly. Few studies used objective scales
such as the adverse reaction terminology from the World Health Organization (WHO). Most
studies combined patient-reported adverse events with a regular clinical examination by an
investigator. Often it was hard to determine if assessment methods were unbiased and adequate;
many trials reported only those adverse events considered to be related to treatment. Rarely were
adverse events prespecified and defined. Short study durations and small sample sizes limited the
validity of adverse events assessment in many trials. Many studies excluded eligible participants
that did not tolerate treatment during the run-in period, limiting the generalizability of adverse
event assessment. Few RCTs were designed to assess adverse events as primary outcomes; some
studies were post hoc analyses or retrospective reviews of databases.
A. Overall adverse events, tolerability, and common adverse events
Of the 47 head-to-head studies reviewed for this section, most reported frequency of adverse
events without tests of statistical significance (Appendix I). The vast majority of studies reported
similar results for equipotent ICS doses. Only five studies reported a difference of greater than
5% in overall adverse events for equipotent doses.37, 40, 42, 61, 68 Only one study reported a
statistically significant difference in overall adverse events between two ICSs (overall AEs (%):
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20 compared with 5, P < 0.001 for FP compared with TAA, but the study did not compare
equipotent doses.55 Four studies reported a difference of greater than 5% in withdrawals due to
AEs for equipotent doses.30, 41, 68, 251
Most head-to-head trials reported specific adverse events (Appendix J). Oral candidiasis,
rhinitis, cough, sore throat, hoarseness, headache, and upper respiratory infection were among
the most commonly reported adverse events. In most head-to-head trials oral candidiasis, rhinitis,
cough, sore throat, hoarseness, and bronchitis were reported in fewer than 10 percent of ICStreated patients. Upper respiratory tract infections were reported by 3 to 32% of study
participants. For common specific adverse events, just three trials reported a statistically
significant difference between equipotent doses of different ICSs.35, 41, 64 One reported a greater
incidence of headache in those treated with BDP than those treated with FP (7% compared with
< 1%, P = 0.03);35 one reported a greater incidence of upper respiratory tract infection with TAA
than with BDP (10.4% compared with 2.7%, P = 0.027);41 one reported a greater incidence of
oral candidiasis with FP than with ciclesonide (3.8% vs. 0%, P = 0.002);64 and one reported that
a greater proportion of patients experienced local oropharyngeal adverse effects (candidiasis and
dysphonia) with FP than with ciclesonide (p = 0.0023).63 Meta-analysis of trials reporting “oral
candidiasis-thrush” that compared equipotent doses of ciclesonide with FP revealed lower odds
of oral candidiasis-thrush for those treated with ciclesonide (OR 0.33, 95% CI 0.17, 0.64,
Appendix I).
B. Specific adverse events
When we found direct evidence for patients with asthma, we did not include studies of mixed
populations (e.g., asthma + COPD) unless they reported results independently for subjects with
asthma. Only for the section on ocular hypertension and open-angle glaucoma were we unable to
find direct evidence for patients with asthma; thus we included two studies that included more
broad populations of subjects taking ICSs.
I. Bone density/osteoporosis
We found two fair quality systematic reviews with meta-analyses that studied the effect of ICSs
on markers of bone function and metabolism.244, 245 One included 14 studies (2,302 subjects) of
patients with asthma or COPD (both RCTs and prospective cohort studies) assessing BMD.244
The other included six studies of asthmatic subjects with median duration of ICS use of at least
three years.245 Pooled results from both meta-anlyses showed no statistically significant
difference in BMD between patients taking ICSs and controls. The one that included patients
with asthma and COPD reported that asthma patients treated with ICSs showed a slight increase
in BMD (0.13%) whereas COPD patients showed a slight decrease (-0.42%); however, neither
change was statistically significant.244
Our review includes nine studies: three of the trials251, 252, 259 in the systematic reviews, as
well as six additional studies.253, 255, 256, 260-262, 269 We excluded the remainder of studies from
these two reviews because of wrong population (COPD patients), insufficient sample size, and/or
poor quality. In total we include one good-rated RCT,255, 256 three fair-rated RCTs,251-253 and five
observational studies.259-262, 269
All nine studies assessed BMD, facture risk, or both (Table 25). In total, four studies
evaluated the risk of fracture252, 260, 261, 269 and seven measured BMD as an intermediate
outcome.251-253, 255, 256, 259, 262, 269 Two studies compared one ICS to another,251, 252 three compared
one ICS to placebo,253, 255, 256, 262 and four studies compared one ICS or any ICS to a population
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that did not use an ICS.259-261, 269 Most studies evaluated the risk of bone weakening over two to
six years.
Two of the trials were head-to-head RCTs comparing one ICS with another ICS in adult
subjects.251, 252 One 24-month open-label trial measuring BMD and vertebral fractures
randomized 374 adult patients with asthma to beclomethasone, budesonide, or placebo.252
Patients were titrated to the minimal effective dose following a pre-specified management plan;
subjects who required more than three courses of oral corticosteroids were withdrawn. At two
years, no significant differences in BMD were reported between the three treatment groups. A
smaller trial reporting BMD randomized 69 asthmatic patients to medium and high doses of
beclomethasone or fluticasone.251 At one year, no significant differences in bone mass or
metabolism were noted between the two treatment groups.
Seven studies (three of them in pediatric populations) comparing an ICS-treated
population to a population not treated with ICSs provided mixed evidence of an association
between ICS use and loss of BMD or osteoporosis;253, 255, 256, 259-262, 269 three of these studies
measured bone fractures.260, 261, 269 The studies conducted in pediatric populations reported no
difference in BMD between ICS- and placebo-treated subjects and no difference in risk of
osteoporosis or time to first fracture between ICS-treated subjects and those not treated with
ICS.255, 256, 262, 269 Of the remaining studies, one reported a dose-related decline in BMD with
ICS-treated subjects,259 one reported a dose-related increase in the risk of vertebral and
nonvertebral fractures with ICS,261 and two reported no difference in nonvertebral fracture260 or
BMD253 between ICS-treated subjects and controls (Table 25).
Table 25. Summary of studies on bone density or fractures
Author
Year
Adult populations
N
Design
Population
Results
Israel et al. 2001
109
Prospective
cohort
premenopausal
women with
asthma (age
18-45)
Johannes et al.
2005260
18,942
Nested casecontrol
Asthma &
COPD (adults)
Kemp et al. 2004253
160
RCT
Asthma (adult)
Medici et al.
2000251
69
RCT
Asthma (adult)
Tattersfield et al.
252
2001
374
RCT
(open label)
Asthma
(adult)
Van Staa et al.
2001261
450,422
Retrospective
cohort
Asthma &
COPD (adult)
TAA associated with dose-related
decline in BMD (total hip and
trochanter) of 0.00044 g/cm2 per
puff/year
No ICS-related increase in the risk of
nonvertebral fracture over 1 year for
the total group of subjects or for
either of the separate respiratory
disease categories (asthma or
COPD)
No difference in BMD between
placebo-treated patients and patients
treated with low to high doses of FP
No difference in BMD between BDPand FP-treated patients over 1 year
No difference in BMD/fractures
between BDP, BUD, and placebo
over 2 years
Statistically significant dose-related
increase in risk of vertebral and
nonvertebral fractures with ICS
RCT
Asthma
(pediatric)
259
Pediatric populations
Childhood Asthma
Management
1041
Program Research
255, 256
Group, 2000
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No difference in bone density
between BUD- and placebo-treated
patients
Quality
rating
Fair
Fair
Fair
Fair
Fair
Fair
Good
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Table 25. Summary of studies on bone density or fractures
Author
Year
Agertoft &
Pedersen, 1998262
Kelly, 2008269
N
157
877
Design
Crosssectional
Cohort study
(CAMP
subjects)
Population
Asthma
(pediatric)
Results
No difference between BUD and
placebo (3-6 years use) in BMD
Asthma
(pediatric)
ICS use was not related to time to
first fracture or to risk for osteopenia
Quality
rating
Fair
Fair
Abbreviations: BDP = beclomethasone dipropionate; BUD = Budesonide; COPD= chronic obstructive pulmonary disease; ICS =
Inhaled Corticosteroids; NA= not applicable; RCT= randomized controlled trial; TAA = Triamcinolone Acetonide.
Symbol use: Drug X > Drug Y = statistically significant difference in outcomes favoring Drug X; Drug X > Drug Y trend = point
estimate favors Drug X, but the difference is not statistically significant or tests of statistical significance were NR; No difference = no
statistically significant difference or tests of statistical significance were not reported and outcomes are similar.
II. Growth
Four head-to-head RCTs comparing fluticasone to beclomethasone, 31, fluticasone to
budesonide,44, 249, or ciclesonide to budesonide62 assessed differences in growth. A fair 1-year
multinational head-to-head trial determined differences in growth velocity comparing a medium
dose of fluticasone (400 mcg/day) to a medium dose of beclomethasone (400 mcg/day) in 343
pre-pubertal children with asthma.31 ITT analysis revealed that adjusted mean growth velocity
was significantly greater in fluticasone than in beclomethasone-treated patients (+0.70 cm/year;
95% CI: 0.13 to 1.26; P < 0.02). Another fair RCT compared growth velocity in 60 children
treated with either a low dose of fluticasone (200 mcg/day) or a low dose of budesonide (400
mcg/day) over one year.249 Fluticasone-treated children had less reduction in growth velocity
than the budesonide-treated group (height standard deviation score: 0.03 compared with 0.23; P
< 0.05); the authors did not provide absolute numbers in centimeters of differences in growth.
The third RCT compared differences in growth velocity in 333 children treated with a medium
dose of fluticasone (400 mcg/day) or a medium dose of budesonide (800 mcg/day) over 20
weeks.44 Linear growth velocity was greater for fluticasone-treated children compared to those
treated with budesonide (adjusted mean increase in height: 2.51 cm compared with 1.89;
difference 6.2 mm (95% CI: 2.9-9.6, P = 0.0003). The forth RCT compared growth in 621
children (age 6-11) treated with either a low dose of ciclesonide (160 mcg/day) or a low dose of
budesonide (400 mgc/day) over 12 weeks. Ciclesonide-treated subjects had a greater mean body
height increase (1.18cm vs. 0.70cm, P = 0.0025).
Four additional studies provide general evidence of growth retardation for ICSs (Table
26). These included two meta-analyses246, 247 and three RCTs.124, 254-256 A good quality metaanalysis assessed differences in short-term growth velocity in 273 children with mild to moderate
asthma treated with either beclomethasone (mean 400 mcg/day) or placebo for 7 to 12 months.246
The meta-analysis reported a statistically significant decrease in linear growth velocity of
children treated with beclomethasone (-1.54 cm per year; 95% CI: -1.15, -1.94) compared to the
placebo group. Another good-quality meta-analysis assessed short-term growth velocity in 855
children treated with beclomethasone or fluticasone compared to placebo. Growth velocity was
statistically significantly reduced in those treated with beclomethasone (1.51 cm/year; 95% CI:
1.15, 1.87; four studies) and in those treated with fluticasone (0.43cm/year; 95% CI: 0.1, 0.85; 1
study) compared to placebo.247
The best longer-term evidence of linear growth delay comes from the Childhood Asthma
Management Program (CAMP) study, a good quality RCT with median follow-up of 4.3 years
that randomized 1,041 asthmatic children to budesonide, nedocromil, or placebo.255, 256 The mean
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increase in height was significantly less in budesonide-treated patients than in placebo-treated
patients (-1.1 cm; 22.7 cm compared with 23.8 cm; P = 0.005). This analysis was performed on
an intent-to-treat basis, providing a more conservative result than an “as treated” analysis. The
differences in growth occurred, however, primarily during the first year of treatment. After two
years of treatment growth velocity was approximately the same between groups.
Another placebo controlled trial assessing growth velocity under low-dose
fluticasone treatment (100 mcg/day; 200 mcg/d) did not find any significant differences in linear
growth compared to placebo after one year of treatment.254, 270 One additional fair quality RCT
(N = 360) compared linear growth rates in prepubertal children treated with montelukast,
beclomethasone, or placebo over 56 weeks and found that the mean growth rate of subjects
treated with beclomethasone was 0.78 cm less than that of subjects treated with placebo and 0.81
cm less than that of subjects treated with montelukast (P < 0.001 for both).124
Table 26. Summary of studies on growth retardation
Author
Year
N
Design
Population
Duration
Results
Head-to-head comparisons of ICS compared with ICS
Prepubertal
Greater growth
De Benedictis et al. 200131
children
1 year
velocity in FP than in
343
RCT
with
BDP group
asthma
Children
Greater growth
with
velocity in FP than in
Ferguson et al, 199944
333
RCT
20 weeks
asthma
BUD group
Children
Greater growth
249
Kannisto et al. 2000
75
RCT
with
1 year
velocity in FP than in
asthma
BUD group
Children
Greater increase in
von Berg et al. 200762
621
RCT
with
12 weeks
growth in CIC than in
asthma
BUD group
General evidence from ICS-treated subjects compared with non-ICS treated controls
Children
Reduction in growth
More than
MetaSharek et al. 1999246
273
with
for BDP compared to
3 months
analysis
asthma
placebo
Reduction in growth
of 0.43 and 1.51
Children
7 months
Metacm/year for BDP and
Sharek et al. 2000247
855
with
to 54
analysis
FP, respectively, vs.
asthma
weeks
placebo
Childhood Asthma
Children
Reduction in growth
Management Program
1041
RCT
with
4.3 years
(1.1 cm) for BUD255,
Research Group, 2000
asthma
treated children
256
Allen et al. 1998
268
RCT
Children
with
asthma
Becker et al. 2006124
360
RCT
Children
with
asthma
254
1 year
56 weeks
No differences in
height and growth
velocity between FP
and placebo
Reduction in growth
for BDP-treated
children
Quality
rating
Fair
Fair
Fair
Fair
Good
Good
Good
Fair
Fair
Abbreviations: BDP = beclomethasone dipropionate; BUD = Budesonide; CIC = Ciclesonide; FP = Fluticasone Propionate; ICS =
Inhaled Corticosteroids; RCT= randomized controlled trial; SR=systematic review.
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III. Acute adrenal crisis
The use of ICSs includes the risk of altered hypothalamic-pituitary axis (HPA axis) functioning
and the rare possibility of resultant adrenal suppression. We did not find any studies meeting our
inclusion/exclusion criteria reporting on the comparative frequency of clinical adrenal
insufficiency in patients treated with ICSs. However, multiple studies report on adrenal
suppression during ICS therapy using urinary or serum cortisol levels and results of stimulation
tests as intermediate outcomes. It is unclear to what extent results from sensitive studies of HPA
axis suppression can be extrapolated to assess differences in risks for clinically significant
adrenal suppression.
Various case reports indicate that acute adrenal crisis is an extremely rare but potentially
fatal adverse event of ICS treatment.271-273 However, in most cases dosing was likely outside
approved labeling. These case reports did not meet eligibility criteria for this report.
IV. Cataracts
Systemic corticosteroid-induced cataracts typically are located on the posterior side of the lens
and are referred to as posterior subcapsular cataracts (PSC); we reviewed studies that compared
the risk of PSC in ICS-treated populations to non-ICS-treated populations (Table 27).
No study compared the risk of developing PSC between one ICS and another. One headto-head RCT evaluated the effect of ciclesonide and beclomethasone on eye lens opacity.257 One
placebo-controlled trial255, 256 and five observational studies263-267 evaluated the risk of
developing cataracts between ICS- and non-ICS-treated patients. One RCT255, 256 and one
observational study263 compared budesonide to placebo; the other studies all compared
nonspecific ICS use to no ICS use. Two studies were conducted in pediatric populations,255, 256,
263
one in a mixed population of children and adults,266 and four evaluated adult populations (≥
40 years).257, 264, 265, 267
The single head-to-head RCT257 evaluating eye lens opacity found ciclesonide to be noninferior to beclomethasone (both delivered at high doses). Both treatments were found to have
minimal impact on lenticular opacities development and/or progression. Both trials conducted in
children reported no significant differences in the development of PSC between budesonidetreated patients and placebo or matched controls.255, 256, 263 One of these was the CAMP study, a
good quality RCT with median follow-up of 4.3 years that allocated 1,041 asthmatic children to
budesonide, nedocromil, or placebo.255, 256 The single study that included a mixed population of
adults and children reported no increase in the risk of developing cataracts between ICS-treated
patients and controls in persons younger than 40 years; a dose-, duration-, and age-related
increase in risk was observed for persons older than 40 years of age.266
Consistent evidence from two case-control studies265, 267 and one cross-sectional study264
conducted in adult populations reported an increased risk of cataracts for ICS-treated patients
compared to controls. Both case-control studies found the risk of cataracts increased at higher
ICS doses and longer duration of treatment; one study reported a higher relative risk for ICS
doses greater than 1,600 mcg/day267 and one study reported a higher relative risk for budesonide
or beclomethasone doses greater than 1,000 mcg/day.265
Most studies did not control for or did not report previous exposure to systemic
corticosteroids, a known cause of cataracts. Only one observational study controlled for previous
exposure to systemic corticosteroids; controlling for systemic corticosteroid use and other
potential confounders had little effect on the magnitude of the associations in this study.264
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Table 27. Summary of studies on posterior subcapsular cataracts
Author
Year
N
Design
Population
Results
Mean changes in nuclear
opalescence and cortical and
posterior subcapsular opacification
were small and similar between
groups
Quality
rating
Chylack et al. 2008257
1,568
RCT
Adults
(age ≥ 18)
Childhood Asthma
Management Program
Research Group,
2000255, 256
1041
RCT
Children
No significant differences in PSC
between BUD-, nedocromil-, or
placebo-treated children
Agertoft et al., 1998263
268
Prospective
cohort
Children
(age 5-16)
No significant differences in PSC
between BUD-treated children and
matched controls
Fair
Cumming et al. 1997264
3654
Crosssectional
Increased risk of nuclear and PSC
among ICS users
NA
Adults
(age 4997)
RAMQ
age ≥ 70
years
Garbe et al. 1998265
25,545
Case-control
Jick et al. 2001266
201,816
(3,581)
Cohort +
case-control
GPRD
(age 3-90)
Smeeth et al. 2003267
30,958
Case-control
GPRD age
≥ 40 years
Increased risk of cataract extraction
for ICS users only at high dose and
duration
Dose-, duration-, and age-related
increased risk of cataracts among
ICS users; no increase in risk for age
< 40
Dose- and duration-related increased
risk of cataracts among ICS users
Fair
Good
Good
Good
Fair
Abbreviations: BUD = Budesonide; GPRD= general practice research database; ICS = Inhaled Corticosteroids; RCT=
randomized controlled trial; PSC= posterior subcapsular cataracts; RAMQ= regi de l’assurance maladie du Quebec
database
No difference = no statistically significant difference or tests of statistical significance were not reported and outcomes
are similar.
V. Ocular hypertension and open-angle glaucoma
No study compared one ICS to another for the risk of ocular hypertension or open-angle
glaucoma. One fair-rated case-control study of 48,118 Canadians age 66 years and older265 and
one cross-sectional population-based study of 3,654 Australians 49 to 97 years of age268
compared the risk of increased intraocular pressure or open-angle glaucoma between ICS- and
non-ICS-treated patients. The populations in these studies were not limited to asthmatics. Both
studies reported a dose-related increase in the risk of open-angle glaucoma for ICS-treated
patients compared to patients that had not used an ICS. In one study this relationship was
observed only among current users of high doses of ICSs prescribed regularly for three or more
months (OR 1.44; 95% C.I. 1.01 to 2.06).265 The other study found an association between ever
using ICSs and findings of elevated intraocular pressure or glaucoma only in subjects with a
glaucoma family history (OR 2.8; 95% CI: 1.2 to 6.8).268 Both studies adjusted for age, sex, oral
steroid use, history of diabetes, and history of hypertension (Table 28).
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Table 28. Summary of studies on ocular hypertension or open-angle glaucoma
Author
Year
Garbe et al. 1997265
Mitchell et al. 1999268
N
Design
Population
48,118
Casecontrol
RAMQ
age ≥ 66
years
Crosssectional
Adults
(age 4997)
3654
Results
≥ 3 months of high-dose ICS
associated with an increased risk of
open-angle glaucoma and ocular
hypertension
Dose-related increased risk of
elevated IOP and open-angle
glaucoma for ICS users with
glaucoma family history
Quality
rating
Fair
Fair
Abbreviations: ICS = Inhaled Corticosteroids; IOP – intraocular pressure; N/A= not applicable; RAMQ= regi de
l’assurance maladie du Quebec database.
Summary of the evidence
Osteoporosis/fractures/bone density
Overall, the evidence of an association between ICSs and significant changes in bone mineral
density is mixed. For adults, the strongest evidence comes from three studies that assessed
fractures.252, 260, 261 Two of these studies, one RCT (N = 374)252 and one case-control study (N =
18,942)260 reported no increased risk of fractures in those treated with ICSs. The other, a
retrospective cohort study (N = 450,422), reported a dose-related increase in fracture risk.261 Of
four studies reporting BMD in adult subjects, three RCTs reported no difference between ICStreated subjects and controls251-253 and one small prospective cohort study (N = 109) reported a
small dose-related decline in BMD in premenopausal women treated with ICSs.259 For children,
one good quality RCT and one cross-sectional study reported no difference in BMD between
those treated with BUD and those treated with placebo; and one cohort study reported no
relationship between ICS use and to time to first fracture or risk for osteopenia. We view BMD
as an intermediate outcome measure of osteoporosis; although a causal relationship exists
between loss of BMD and risk of fractures due to osteoporosis, the clinical significance of small
changes in BMD is uncertain.
Growth retardation
Three head-to-head trials provide moderate strength of evidence that short-term (20 weeks to 1
year) growth velocity is reduced less with fluticasone than with beclomethasone31 or
budesonide.44, 249 A forth head-to-head trial found that ciclesonide-treated subjects had a greater
mean body height increase than budesonide-treated subjects over 12 weeks.62 In addition, two
meta-analyses report a reduction in growth velocity for beclomethasone or fluticasone compared
to placebo.246, 247 Most studies of growth only address ICS treatment duration up to about one
year. The best longer-term evidence is from the CAMP study, which followed subjects for an
average of 4.3 years and found a 1.1 cm difference in mean increase in height (P = 0.005)
between budesonide-treated patients and placebo-treated patients.255, 256 The differences in
growth occurred primarily during the first year of treatment, suggesting that the small decrease in
growth velocity with ICSs occurs early in treatment and is not progressive. Insufficient evidence
exists to determine if long-term treatment with ICSs lead to a reduction in final adult height.
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Acute adrenal crisis
Evidence from randomized trials and observational studies is insufficient to draw conclusions
regarding the risk of rare but potentially fatal adverse events such as acute adrenal crisis.
Nonetheless, multiple case reports have indicated that high-dose ICS treatment is associated with
acute adrenal crisis, especially in children.271-273 Evidence from intermediate outcomes can not
be extrapolated reliably to form conclusions about the comparative frequency of acute adrenal
crisis for ICSs.
Cataracts
The single head-to-head RCT257 evaluating eye lens opacity found ciclesonide to be non-inferior
to beclomethasone (both delivered at high doses), with both treatments having minimal impact
on the development and/or progression of lenticular opacities. No study compared the risk of
developing PSC, per se, between one ICS and another. In adults, general evidence of an
association between ICS use and PSC is moderate. No significant differences have been reported
in the risk of PSC in children, adolescents, and adults less than 40 years of age between ICS
users and controls. In older adults, however, an increase in the risk of developing cataracts was
reported among individuals who took ICSs; increased risk was related to dose and duration of
treatment. No study evaluated the link between childhood ICS use and risk of cataracts in older
age.
Ocular hypertension and open-angle glaucoma
No study compared the risk of ocular hypertension or open-angle glaucoma between one ICS and
another. Two observational studies provide consistent evidence of a dose-related increase in risk
for ICS-treated patients. Overall, existing evidence of an association between ICS use and
increased intraocular pressure or open-angle glaucoma is low.
B. Leukotriene Modifiers
Summary of findings
There is insufficient head-to-head data (one trial) to determine differences in tolerability or
overall adverse events between any of the leukotriene modifiers using direct evidence. Indirect
evidence from placebo-controlled trials and large safety databases suggests that zileuton has an
increased risk of liver toxicity compared with either montelukast or zafirlukast.
Direct Evidence
We found just one fair-rated 12-week head-to-head trial comparing one leukotriene modifier
with another that met inclusion/exclusion criteria for our review.72 The trial compared quality of
life outcomes between montelukast and zafirlukast at recommended doses in adults with mild
persistent asthma and did not report any adverse events in either group. We found no head-tohead trials for comparisons of other leukotriene modifiers. In addition, we found no head-to-head
trials in children.
Indirect Evidence
Placebo-controlled trials and post-marketing surveillance provide further information on the
comparative safety of leukotriene modifiers.10
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Liver toxicity
Evidence from placebo-controlled trials of zileuton reported an increased risk of hepatic toxicity
with increased frequency of elevated liver transaminases (ALT elevations of ≥ 3 times the upper
limit of normal: 1.9% compared with 0.2% for zileuton compared with placebo).10 In patients
treated for up to 12 months with zileuton in addition to their usual asthma care, 4.6% developed
an ALT of at least three times the upper limit of normal, compared with 1.1% of patients
receiving their usual asthma care.10 Due to the increased risk, monitoring of liver function tests is
required with zileuton therapy.1
Rare cases of liver toxicity have been reported with montelukast (cholestatic hepatitis,
hepatocellular liver injury, and mixed-pattern liver injury) and zafirlukast (fulminant hepatitis,
hepatic failure, liver transplantation, and death have been reported).10 Data from safety databases
and placebo-controlled trials suggest numerically similar rates of increased transaminases
between montelukast (increased ALT: 2.1% compared with 2%; increased AST 1.6% compared
with 1.2%) or zafirlukast (increased ALT: 1.5% compared with 1.1%) and placebo.10
C. Long-Acting Beta-2 Agonists (LABAs)
Formoterol and salmeterol, the two LABAs currently available for the treatment of asthma, are
both selective beta2-adrenergic receptor agonists. At high doses, both can produce clinically
important sympathomimetic adverse effects including tremor and hyperglycemia.
Of greater concern are reports that regular use of LABAs increase the risk of asthmarelated death.274-278 Subgroup analysis from one study274 has suggested this risk may be
significantly higher in African Americans (see Key Question 3). These concerns have resulted in
an FDA boxed warning for products that contain formoterol or salmeterol. A boxed warning is a
type of warning that the FDA requires on the labels of prescription drugs that may cause serious
adverse effects, and it signifies that clinical studies have indicated that the drug carries a
significant risk of serious or even life-threatening side effects. Experts recommend strongly
against using LABAs as monotherapy for long-term control of persistent asthma.1 LABAs are
contraindicated for use as monotherapy in patients with persistent asthma.275-278
In February 2010, the FDA announced it was requiring manufacturers to revise their drug
279
labels.
The new recommendations in the updated labels state the following:279
• Use of a LABA alone without use of a long-term asthma control medication, such as an
inhaled corticosteroid, is contraindicated (absolutely advised against) in the treatment of
asthma.
• LABAs should not be used in patients whose asthma is adequately controlled on low or
medium dose inhaled corticosteroids.
• LABAs should only be used as additional therapy for patients with asthma who are
currently taking but are not adequately controlled on a long-term asthma control
medication, such as an inhaled corticosteroid.
• Once asthma control is achieved and maintained, patients should be assessed at regular
intervals and step down therapy should begin (e.g., discontinue LABA), if possible
without loss of asthma control, and the patient should continue to be treated with a longterm asthma control medication, such as an inhaled corticosteroid.
• Pediatric and adolescent patients who require the addition of a LABA to an inhaled
corticosteroid should use a combination product containing both an inhaled corticosteroid
and a LABA, to ensure adherence with both medications.
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The FDA believes that when LABAs are used according to the recommendations outlined
above and in the approved drug labels, the benefits of LABAs in improving asthma symptoms
outweigh their risks of increasing severe asthma exacerbations and deaths from asthma.279
Potential mechanisms by which LABAs could increase the risk of life-threatening asthma
exacerbations include: (1) a direct tachyphylactic effect on airway smooth muscle, leading to
more severe obstruction after a bronchoconstrictive stimulus, and/ or (2) transient maintenance
of bronchodilation (and symptom control) even in the face of worsening airways inflammation,
leading eventually to a sudden and severe increase in obstruction and/or to patients’ delaying in
seeking medical attention for a severe exacerbation.
For this review, we sought evidence of comparative safety of formoterol and salmeterol
with respect to these severe adverse events as well as for common side effects.
Summary of findings
We found four RCTs that met our inclusion criteria and provided direct evidence regarding the
relative safety of formoterol and salmeterol. (Appendix K) We rated three studies73, 75-77 as fair
quality for assessment of adverse events. The fourth74 was rated as poor quality for assessment of
adverse events. However, since it was the only head-to-head trial performed specifically in
children, we describe it in this section. In general, these trials were of relatively short duration,
with none lasting more than 24 weeks. All were designed primarily to assess efficacy. Adverse
events were typically collected via spontaneous reports from patients or “general questioning” by
the investigators, though study withdrawals and reasons for withdrawals were reported. In these
trials, all patients were taking ICS at the time of enrollment, and severe adverse events were rare.
We also identified two systematic reviews with meta-analyses that directly compared
subjects treated with formoterol and subjects treated with salmeterol280, 281 and five systematic
reviews with meta-analysis of placebo-controlled studies of LABAs that provided some indirect
evidence regarding the relative harms associated with LABAs as well as more robust evidence of
their harms (as a class) when compared with placebo.282-286
Overall, limited direct evidence from head-to-head trials and indirect evidence from
systematic reviews provides no evidence of a difference in tolerability or adverse events between
formoterol and salmeterol, regardless of whether or not corticosteroids are used concurrently.
Detailed Assessment
Direct Evidence
Of the four included head to head trials, two were conducted only in adults,76, 77 one enrolled
adults and adolescents73 and one enrolled only children and adolescents between 5-18 years
old.74 All four trials compared FM (12 mcg twice daily) with SM (50 mcg twice daily)
(Appendix K). Only one73 of the four trials was blinded. Detailed descriptions of these RCTs are
provided in the Key Question 1 section of this report with the exception of one study that was
included for this section but not for efficacy outcomes.77
One open-label RCT conducted in the United States77 compared formoterol (24 mcg/day)
to salmeterol (50 mcg/day) in 528 adult asthmatics who were already taking low dose ICSs. The
duration of the study was 24 weeks and the investigator found similar numbers of total
withdrawals (14.5% compared with 11.3%) and withdrawals due to adverse events (5.7%
compared with 3.4%).
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One trial73, 287 randomized 469 patients to blinded eFM via DPI, SM via DPI, or SM via
MDI. They found similar rates of hospital admission and ED visits and total study withdrawals.
Another trial75 compared FM administered via DPI with SM given via DPI in 482 adult
asthmatics. The trial found comparable rates of hospitalizations, study withdrawals, withdrawals
due to adverse events, and drug-related adverse events. The only trial enrolling children and
adolescents74 randomized subject (N = 156) to FM or SM and also found similar rates of study
withdrawals and withdrawals due to adverse events.
Two systematic reviews compared SM and FM directly. The first review281 compared
the risk of adverse events in patients with chronic asthma who received formoterol and
corticosteroid versus salmeterol and corticosteroid for chronic asthma. One trial compared
formoterol and beclomethasone to salmeterol and fluticasone, and the other 7 trials compared
formoterol and budesonide to salmeterol and fluticasone. They found no significant differences
in any serious adverse events, including all-cause mortality (OR 1.03, 95%: CI 0.06 to 16.44),
all-cause non-fatal serious adverse events (OR 1.14, 95% CI: 0.82 to 1.59), and asthma-related
serious adverse events (OR 0.69, 95% CI: 0.37 to 1.26). The study using beclomethasone
instead of budesonide was relatively small (N=228 participants) and showed no deaths or
hospital admissions.
The second systematic review280 compared the risk of adverse events in patients with
chronic asthma who received formoterol versus salmeterol, without the addition of inhaled
corticosteroids (ICS). They found no statistically significant differences in any serious adverse
events, including all-cause mortality (one total death in the salmeterol group, not attributable to
asthma), all-cause serious adverse events in adults (OR 0.77, 95% CI: 0.46 to 1.28) all-cause
serious events in children (OR 0.95, 95% CI: 0.06 to 15.33), and asthma-related serious adverse
events in adults (OR 0.86, 95% CI: 0.29 to 2.57) or children (no events in either group).
Indirect evidence
Among the 5 systematic reviews with meta-analysis of placebo-controlled studies of LABAs we
included for this section, the most recent was published in 2009 (Appendix K).286 This review286
aimed to assess the risk of serious adverse events in patients with chronic asthma who received
regular salmeterol versus placebo or short-acting beta2-agonists. They found 26 trials comparing
salmeterol to placebo, and eight trials comparing salmeterol to salbutamol (albuterol). For
salmeterol versus placebo, the meta-analysis found significant increases in non-fatal serious
adverse events in adults (OR 1.14; 95% CI: 1.01 to 1.28) but not children (OR 1.3; 95% CI: 0.82
to 2.05), and asthma-related mortality in adults (OR 3.49, 95% CI: 1.31 to 9.31). They found no
statistically significant difference in all-cause mortality in adults (OR 1.33, 95% CI: 0.85 to 2.08)
or in children (no deaths in either group), and no statistically significant difference in asthmarelated non-fatal serious events (OR 1.43; 95% CI: 0.75 to 2.71). They found a borderline
statistically significant increase in asthma-related non-fatal events in children (OR 1.72, 95% CI:
1.0 to 2.98) with salmeterol. Meta-analysis of trials comparing salmeterol to salbutamol (a
SABA) showed no statistically significant differences in all-cause mortality or non-fatal serious
adverse events.
Another systematic review published in 2007283 aimed to examine both efficacy and
safety outcomes of studies comparing LABAs to placebo in “real world” asthmatic populations
in which only some patients were using regular ICSs at baseline. They included 67 studies
randomizing a total of 42,333 participants. Salmeterol was used as a long-acting agent in 50
studies and formoterol in 17. The treatment and monitoring period was relatively short (4 -9
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weeks) in 29 studies, and somewhat longer (12 -52 weeks) in 38 studies. The systematic review
reported that LABAs were generally effective in reducing asthma symptoms in this population,
but they noted safety concerns for patients not using ICSs and for African Americans, based on
data from the Salmeterol Multicenter Asthma Research Trial (SMART), described below.274
From a post-hoc analysis of SMART, their estimate for the relative risk of asthma-related death
for those taking ICSs at baseline did not show an increased risk (RR 1.34, 95% CI: 0.30 to 5.97).
However, those not taking ICSs at baseline had an increased risk of asthma-related death (RR
18.98, 95% CI: 1.1 to 326). In addition, other asthma-related serious adverse events were
increased in LABA-treated patients (OR 7.46, 95% CI: 2.21 to 25.16). For respiratory-related
death, they found an increased risk in the total population (RR 2.18, 95% CI: 1.07 to 4.05), but
no difference between subgroups of subjects using ICS compared with those not using ICS at
baseline (test for interaction P = 0.84). Among their findings regarding less severe side effects,
they noted that tremor was more common in LABA treated patients (OR 3.86, 95% CI: 1.91 to
7.78).
Of the 5 systematic reviews included in this section (Appendix K), one282 was designed
specifically to examine risks for life-threatening or fatal asthma exacerbations associated with
LABA. The majority of subjects (about 80%) in the studies included in this review were treated
with salmeterol. The meta-analyses found that the risk of hospitalization was increased in
LABA treated patients (OR 2.6, CI: 1.6 to 4.3). The estimated risk difference for hospitalization
attributed to LABA was 0.7% (CI: 0.1% to 1.3%) over 6 months. Notably, the investigators
assessed separately the associations between SM and FM and risk for this outcome. They found
an increased risk for hospitalization associated with both salmeterol (OR, 1.7 [CI: 1.1 to 2.7])
and with formoterol (OR, 3.2 [CI: 1.7 to 6.0]). They also estimated the risk for life-threatening
asthma attacks and found it to be increased for LABA-treated patients (OR 1.8, CI: 1.1 to 2.9,
risk difference 0.12%, CI: 0.01% to 0.3% over 6 months). Lastly, they examined the risk for
asthma-related deaths in these studies and found it to be increased for LABA treated patients:
(OR 3.5, 95% CI: 1.3 to 9.3; risk difference 0.07%, CI: 0.01% to 0.1% over 6 months).
There was significant overlap between the two meta-analyses described above.282, 283
Twelve of 14 (86%) published studies included in the 2006 meta-analysis282 were also included
in the 2007 meta-analysis.283 The 2007 analysis included studies of shorter duration, which
partially accounted for the greater number of included studies.
An older systematic review284 evaluated RCTs in which the addition of LABAs to ICS
was compared with adding placebo to ICS. They found no differences in overall adverse effects,
serious adverse events, or in specific side effects. Comparative safety was examined secondarily,
and only one included study reported deaths, with three deaths reported overall. Further, the
Salmeterol Multicenter Asthma Research Trial (SMART),274 a large 28-week randomized study
of the safety of LABAs was categorized as “awaiting assessment” at the time this systematic
review was published.
SMART included 26,355 subjects and was terminated due to findings in African
Americans and difficulties in enrollment.274 The trial found no statistically significant difference
between those treated with salmeterol and those treated with placebo for the primary outcome,
respiratory-related deaths, or life-threatening experiences was low and not significantly different
for salmeterol compared with placebo (50 compared with 36; RR 1.40; 95% CI: 0.91 to 2.14).
However, the trial reported statistically significant increases in respiratory-related deaths (24
compared with 11; RR 2.16; 95% CI: 1.06 to 4.41) and asthma-related deaths (13 compared with
3; RR 4.37; 95% CI: 1.25 to 15.34), and in combined asthma-related deaths or life-threatening
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experiences (37 compared with 22; RR 1.71; 95% CI: 1.01 to 2.89) for subjects receiving
salmeterol compared to those receiving placebo. In addition, subgroup analyses suggest the risk
may be greater in African Americans compared with Caucasian subjects. The increased risk was
thought to be largely attributable to the African-American subpopulation: respiratory-related
deaths or life-threatening experiences (20 compared with 5; RR 4.10; 95% CI: 1.54 to 10.90) and
combined asthma-related deaths or life-threatening experiences (19 compared with 4; RR 4.92;
95% CI: 1.68 to 14.45) in subjects receiving salmeterol compared to those receiving placebo.274
Finally, another systematic review with meta-analysis285 examined the efficacy and safety
of initiating LABA with ICS compared with ICS alone in steroid naïve asthmatics. They found
no differences in rates of any adverse effects or in withdrawals dues to adverse effects. They did
find an increased risk for tremor associated with LABA (RR 5.05; 95% CI: 1.33 to 19.17).
D. Anti-IgE Therapy
Summary of findings
The prescription information for omalizumab has a boxed (or “black box”) warning for
anaphylaxis which includes bronchospasm, hypotension, syncope, urticaria, and/or angioedema
of the throat or tongue.10 A boxed warning is a type of warning that the FDA requires on the
labels of prescription drugs that may cause serious adverse effects, and it signifies that clinical
studies have indicated that the drug carries a significant risk of serious or even life-threatening
side effects. According to the boxed warning for omalizumab, there have been reports of
anaphylaxis as early as after the first dose of omalizumab, but anaphylaxis has also occurred
more than one year after the start of regular treatment with omilizumab. Some of these events
were life-threatening.
Omalizumab prescription information also contains a warning for a potential increased
risk of malignancy. In clinical studies, malignant neoplasms were seen in 0.5% of omalizumabtreated patients compared with 0.2% of control patients. The majority of patients in these studies
were observed for less than one year; consequently, longer-term studies are needed to better
determine the impact of longer exposure to omalizumab.
As previously noted, omalizumab is the only available anti-IgE drug approved for the
treatment of asthma; therefore, there are no studies of intra-class comparisons. We did not find
any head-to-head studies directly comparing omalizumab to ICSs, LABAs, leukotriene
modifiers. All included trials are placebo comparisons. We found seven fair to good quality
RCTs78, 80-83, 85, 86, 88, 91 and one systematic review with meta-analysis93 that met our eligibility
criteria.
Overall, tolerability and adverse events were similar in omalizumab- and placebo-treated
patients with the exception of injection site reactions which were greater in omalizumab-treated
patients. As noted above, omalizumab has a boxed warning for anaphylaxis.10 Further studies,
including those in pediatric populations, are needed to determine the impact of long-term
treatment.
Detailed Assessment
Of the seven included RCTs, only one83 focused on children (6-12 years old); one RCT focused
only on adults 20-75 years of age and all others included adolescents and adults ≥12 years. The
systematic review included six of the seven RCTs. These studies are described in detail in the
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Key Question 1 section of this report and the detailed results are provided in the Evidence
Tables.
A good quality systematic review with meta-analysis found no difference in headache,
urticaria, number of patients with any adverse events, and withdrawals due to adverse events
between subcutaneous omalizumab and placebo.93 However, injection site reactions were
significantly greater in omalizumab patients (OR 2, 95% CI: 1.37 to 2.92).
When looking at the individual studies, we found wide variation in incidence of injection
site reaction across studies. Most studies reported the occurrence of injection site reaction as less
than 10%. One study, however, reported that the frequency of occurrence was greater than 35%
in both the omalizumab and placebo groups.83 Wide variance in the occurrence of injection site
reactions across studies may be explained by the fact that one study interpreted this term more
broadly to encompass one or more of a number of symptoms (e.g., burning, itching, warmth,
bruising, redness, hive formation, rashes). Other studies limited the term to denote severe
reactions, and some studies do not describe how they applied the term. The package insert for
omalizumab used a broader definition (injection site reactions of any severity) and reported
occurrence rates of 45% and 43% for omalizumab and placebo, respectively.10
Withdrawals attributed explicitly to adverse events were similar in adult and pediatric
patients.In the pediatric study, 1.8% of omalizumab- and 1.8% of placebo-treated patients
withdrew because of pain or fear of injection.83
E. Combination Products ICS+LABA compared with ICS+LABA
1. ICS+LABA compared with ICS+LABA
Summary of findings
We found two good-quality systematic reviews 94, 281 (Table 29) and four head-to-head RCTs
comparing fixed-dose budesonide/formoterol (BUD/FM) with fixed-dose fluticasone/salmeterol
(FP/SM)95-101 for maintenance therapy.
Overall, data from the two systematic reviews and the four large head-to-head trials
(5,818 subjects) provide no evidence of a difference in tolerability or overall adverse events
between BUD/FM and FP/SM for maintenance therapy in adults and adolescents. There is
insufficient evidence to draw conclusions in children ≤ 12.(Appendix H, Table H-17)
Detailed Assessment
Description of Studies
Systematic review
We found 2 systematic reviews of good quality that compared the fixed-dose combination of an
ICS plus a LABA with another ICS/LABA combination for controller therapy.94, 281 One review
included only randomized, controlled, parallel-design trials and required that only single inhaler
devices were used to administer study drugs;94 the other allowed administration by either single
or multiple inhalers. Studies lasting fewer than 12 weeks or administering “adjustable
maintenance dosing” or “single inhaler therapy” rather than fixed doses were excluded from both
reviews.
One review has been described in detail in Key Question 1 (section IE) 94. The other
included eight studies, seven of which compared BUD/FM with FP/SM. The eighth compared
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FP/SM with beclomethasone/FM, a comparison not relevant to this section of the report. Among
the seven relevant studies in the 2010 review,281 four were also included in the earlier review and
in the RCT section of this report.95, 97, 98. An additional trial is also included in our RCT section
but not the earlier review due to its delivery of study medications via separate inhalers101, and
results of one unpublished trial and one trial we deemed poor quality102 were included in the
earlier review but not in our report. Results from a second unpublished trial were not reported in
either the earlier review, nor are they reported in our RCT section.
Doses of BUD and FM in the included trials ranged from 400-800 (320-640 exmouthpiece) mcg/day and 12-24 (9-18 ex-mouthpiece) mcg/day, respectively. All of the
published studies administered 500mcg and 100mcg of FP and SM per day; the two unpublished
studies administered 12mcg of FM daily and either 200 or 500mcg of FP daily. Included studies
ranged from 12 weeks to 30 weeks and took place in the United States and Europe. The total
number of participants in the seven relevant trials was 5,935. All included studies enrolled
adolescents and adults (no studies in children were identified), and neither restricted asthma
severity or current treatment. All included studies were funded by pharmaceutical manufacturers.
Randomized controlled trials
The studies that examined the efficacy of one fixed-dose combination treatment relative to
another (described in Key Question 1) also reported tolerability and adverse events. All trials
included adolescents and adults; Study duration ranged from 12 weeks to seven months. Methods
of adverse events assessment differed greatly. Few studies used objective scales such as the
adverse reaction terminology from the World Health Organization (WHO). Most studies
combined patient-reported adverse events with a regular clinical examination by an investigator.
Often it was hard to determine if assessment methods were unbiased and adequate; many trials
reported only those adverse events considered to be related to treatment. Rarely were adverse
events prespecified and defined.
A. Overall adverse events, tolerability, and common adverse events
Overall adverse events and withdrawals due to adverse events were commonly reported in trials
(Evidence Tables A and B). Most combination trials reported specific adverse events. Oral
candidiasis, rhinitis, cough, sore throat, hoarseness, headache, and upper respiratory infection
were among the most commonly reported adverse events (Evidence Tables A and B). Frequency
of adverse events was similar between those treated with BUD/FM and those treated with
FP/SM.
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Table 29. Tolerability and frequency of adverse events results from systematic
reviews comparing ICS+LABA with ICS+LABA
Study
Design
Comparison
Cates et al.
2010281
Overall AEs
All-cause non-fatal SAE
PETO OR = 1.14 (0.82,
1.59)
Withdrawals
due to AEs
NR
Specific AEs [odds ratio (CI)]
All-cause mortality: Peto OR = 1.03; 0.0616.44
SR
BUD/FM or
BUD+FM
compared with
FP/SM
Lasserson et al.
200894
Asthma-related non-fatal
SAEs:
Peto OR = 0.69 (0.37,
1.26)
Overall AEs:
OR = 0.92 (0.76, 1.12)
OR = 1.06
(0.68, 1.67)
Headache: 0.92 (0.70, 1.22)
Candidiasis: 0.36 (0.25, 1.47)
SR
BUD/FM
compared with
FP/SM
Asthma-related serious
adverse event:
OR = 0.53 (0.35, 1.33)
Dysphonia: 0.55 (0.41, 1.15)
Upper respiratory tract infection: 0.91 (0.68,
1.23)
Throat irritation: 0.61 (0.43, 1.22)
Cough: 0.85 (0.49, 1.56)
Tremor OR: 1.87 (0.96, 50)
2. ICS+LABA for both maintenance and as-needed relief vs. ICS+LABA for
maintenance with a Short-Acting Beta-Agonist (SABA) for relief
Summary of findings
We found four head-to-head RCTs98, 100, 103-106 comparing BUD/FM for maintenance and asneeded relief with BUD/FM or FP/SM for maintenance and a Short-Acting Beta-Agonist
(SABA) for relief reporting tolerability or frequency of adverse events. (Trial characteristics
summarized in KQ 1 IE).
No studies reported statistical significance of differences between BUD/FM for
maintenance and as-needed relief with BUD/FM or FP/SM for maintenance and a Short-Acting
Beta-Agonist (SABA) for relief. Most of the trials reported a numerical trend favoring BUD/FM
MART when considering withdrawals due to adverse events. The reported frequencies of
specific adverse events do not suggest a difference between treatments. Because of heterogeneity
of the reported safety data, we did not perform meta-analyses for tolerability or adverse events.
Detailed Assessment
Description of Studies
All four trials (five relevant comparisons) compared the combination of budesonide (BUD) plus
formoterol (FM) in a single DPI for maintenance and as-needed relief with a fixed dose
ICS/LABA combination plus a Short-Acting Beta-Agonist (SABA) for as-needed relief.
Summary data for these trials can be found in Key Question 1 IE.
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Head-to-head comparisons
1. Budesonide/formoterol for maintenance and relief (BUD/FM MART) compared with Inhaled
corticosteroid/Long-Acting Beta Agonist (ICS/LABA) for maintenance and Short-Acting BetaAgonist (SABA) for relief
The results of the four RCTs contributing five comparisons (one study compared BUD/FM
MART with BUD/FM for maintenance and SABA for relief and with FP/SM for maintenance
and SABA for relief) are described below under the appropriate drug comparisons. Overall, no
studies reported statistical significance of differences between treatments. However, the reported
frequencies of adverse events suggest either no difference or a trend toward favoring BUD/FM
MART.
Most of the trials reported a numerical trend favoring BUD/FM MART when considering
withdrawals due to adverse events. The few trials reporting occurrences of specific adverse
events found no difference between treatments.
2. Budesonide/formoterol for maintenance and relief (BUD/FM MART) compared with
budesonide/formoterol (BUD/FM) for maintenance and Short-Acting Beta-Agonist (SABA) for
relief
Neither trial comparing BUD/FM MART to BUD/FM for maintenance with a SABA for relief98,
found a difference in adverse events between treatments. The percentage of patients
experiencing at least one serious adverse event ranged from 3% to 7% among adults.
A subset analysis of the pediatric population of a larger study103 found a trend favoring BUD/FM
MART (2% of patients had a serious adverse event compared with 14%).
Rate of withdrawal due to adverse events was numerically higher in the BUD/FM+SABA
arms of both trials. The magnitude differed between them, possibly due to inconsistency in the
definition of an event. In one trial, 1.0% of patients in the BUD/FM MART arm and 1.2% in the
BUD/FM+SABA arm withdrew due to adverse events.98 In the other, 2.0% (BUD/FM MART)
and 4.4% (BUD/FM+SABA) of patients withdrew due to adverse events.
Specific adverse events were reported in only one of the two trials.103, 105 The most
frequently reported events (those occurring in at least 5% of patients) were respiratory infection,
pharyngitis, rhinitis, bronchitis, sinusitis and headache. There were no major qualitative
differences between treatments for occurrence of those events, nor were there major qualitative
differences in reports of tremor, palpitation, tachycardia, candidiasis or dysphonia, reports of
which were rare. In the subset of children within that trial, there was a trend favoring BUD/FM
MART for occurrences of serious adverse events, fractures, and pneumonia.
100, 103, 105
3. Budesonide/formoterol for maintenance and relief (BUD/FM MART) compared with
fluticasone/salmeterol (FP/SM) for maintenance and Short-Acting Beta-Agonist (SABA) for
relief
Three trials compared BUD/FM MART to FP/SM for maintenance with a SABA for relief.98, 100,
104, 106
The percentage of patients experiencing at least one serious adverse event ranged from 3%
to 8.2% among adults and adolescents. None of the three included children.
Rate of withdrawal due to adverse events was numerically higher in the FP/SM+SABA
arms of two of the three trials.104, 106 One percent and 1.2% of participants receiving BUD/FM
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for maintenance and relief withdrew due to adverse events, compared with 1.7% and 2.0% of
patients receiving FP/SM+SABA. One trial104 reported withdrawals due to “class effect,” a
composite measure that included dysphonia, oral candidiasis, oral fungal infection, tremor,
tachycardia, palpitations and headache. Fewer patients in the BUD/FM for maintenance and
relief arm withdrew due to class effects compared with those receiving FP/SM+SABA, although
the rate was <1% in each. In one trial,10627 (2.5%) and 28 (2.6%) patients in the BUD/FM
MART and FP/SM+SABA arms, respectively, discontinued the study drug but remained in the
trial.
In the third trial, the difference in withdrawals due to adverse event was 0.1% in favor of
FP/SM+SABA. Deaths were reported in all three trials, though occurrence was rare. A total of 2
patients treated with BUD/FM MART and three patients receiving FP/SM+SABA treatment
died during the trials. In the BUD/FM arms, one death was from severe typhoid fever and the
other was due to respiratory failure. One of the patients receiving FP/SM died from cardiac
failure; causes of the other two deaths were not specified.
II. Inter-class comparisons (between classes)
A. Monotherapy
1. Inhaled Corticosteroids (ICSs) compared with Leukotriene modifiers (LMs)
Summary of findings
We found two systematic reviews with meta-analyses107, 109 and 15 RCTs110, 112-117, 119-127, 132
(Evidence Tables A and B). These were described in the Key Question 1 section of this report.
Overall, data from two good quality systematic reviews and numerous fair-rated head-tohead RCTs provides no evidence of a difference in tolerability or overall adverse events between
ICSs and leukotriene modifiers. Of note, trials were generally not designed to compare
tolerability and adverse events. Indirect evidence suggests that ICSs may increase the risk of
cataracts and may decrease short term growth velocity and bone mineral density, none of which
have been identified with LMs.
Detailed Assessment
Most studies that examined the efficacy of ICSs compared to leukotriene modifiers (described in
Key Question 1) also reported tolerability and adverse events. Study duration ranged from six
weeks to 56 weeks. Methods of adverse events assessment differed greatly. Few studies used
objective scales such as the adverse reaction terminology from the World Health Organization
(WHO). Most studies combined patient-reported adverse events with a regular clinical
examination by an investigator. Often it was difficult to determine if assessment methods were
unbiased and adequate; many trials reported only those adverse events considered to be related to
treatment. Rarely were adverse events prespecified and defined.
Direct Evidence
One good quality systematic review with meta-analysis107 provides the best evidence for overall
adverse events and tolerability. The meta-analysis found no significant difference in the risk of
experiencing any adverse effects (N = 15 trials, RR 0.99, 95% CI: 0.93 to 1.04) or of specific
adverse events including elevation of liver enzymes, headaches, nausea, or oral candidiasis
(Evidence Table A). In addition, treatment with leukotriene modifiers was associated with a 30%
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increased risk of overall withdrawals (N = 19 trials, RR 1.3, 95% CI: 1.1 – 1.6), which appeared
to be due to poor asthma control (N = 17 trials, RR 2.6, 95% CI: 2.0 – 3.4) rather than due to
adverse effects (N = 14 trials, RR 1.2, 95% CI: 0.9 – 1.6).
A second systematic review with meta-analysis109 included 18 studies (N = 3,757)
enrolling children and adolescents less than 18 years of age, 13 of which compared ICS therapy
to that of ML. Six of the included trials also met our inclusion criteria125, 126, 129-132; seven did not.
Duration of studies varied but ranged from 4-12 weeks, 24-28 weeks, and 48-56 weeks, with one
study being 112 weeks long. While most of the studies included patients age 6-18, one study
included children younger than 6 (2-8 years) for which a nebulizer was used for ICS
administration. Intervention drugs included oral montelukast (4 to 10 mg) compared to either
inhaled BDP 200-400 mcg/day (0.5 mg nebulized), FP 200 mcg/day, BUD 200-800 mcg/day or
TAA 400 mcg/day.
Data related to adverse effects was available in five of the 18 trials. Overall, the metaanalysis reported no statistically significant difference between ICS- and ML-treated patients
with respect to incidence of adverse effects (N = 1,767, RR 0.98, 95% CI 0.86 – 1.11, P = 0.73).
Overall tolerability and adverse events from individual head-to-head trials are
summarized in Evidence Tables A and B. Most studies did not find a significant difference
between ICSs and leukotriene modifiers for overall tolerability and adverse events. Specific
adverse events reported with ICSs (see Key Question 2 section on ICSs above), such as cataracts
and decreased growth velocity, were not found among patients taking LTRAs. One fair quality
head-to-head RCT (N = 360) compared linear growth rates in prepubertal children treated with
montelukast, beclomethasone, or placebo.124 The mean growth rate of subjects treated with
beclomethasone was 0.81 cm less than that of subjects treated with montelukast.
Indirect Evidence
Indirect evidence from placebo-controlled trials is described in other sections of this report (see
Key Question 2, Inhaled Corticosteroids and Leukotriene Modifiers sections). Evidence from
placebo-controlled trials and observational studies suggest that ICSs may increase the risk of
cataracts and may decrease short term growth velocity and bone mineral density.
2. Inhaled Corticosteroids (ICSs) compared with Long-Acting Beta-2 Agonists (LABAs)
Summary of findings
LABAs are not recommended nor approved for use as monotherapy for persistent asthma
because they may increase the risk of asthma-related death.1 The indirect evidence comparing
LABAs (with or without ICSs) with placebo reporting this increased risk is described earlier in
this report (Key Question 2, Long-Acting Beta-Agonists) and contributes to the conclusion that
ICSs are safer than LABAs for use as monotherapy (high strength of evidence). Direct evidence
from 13 head-to-head trials (4,003 subjects) provides no evidence of a difference in overall
adverse events between ICSs and LABAs in adults and adolescents.
Direct Evidence
We found 13 fair or good quality RCTs135-139, 141-143, 145, 147-150 that included head-to-head
comparisons of one ICS with one LABA reporting tolerability or overall adverse events. These
trials are described in the Key Question 1 section of this report. Overall tolerability and adverse
events from individual head-to-head trials are summarized in (Evidence Tables A and B). Rates
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of overall adverse events and withdrawals due to adverse events were similar for those treated
with ICSs and those treated with LABAs.
Indirect Evidence
Indirect evidence from placebo-controlled trials is described in other sections of this report.
Evidence from several systematic reviews suggests that LABAs may increase the risk of asthmarelated death (see Key Question 2, Long-Acting Beta-Agonists section). Evidence from placebocontrolled trials and observational studies suggest that ICSs may increase the risk of cataracts
and may decrease short term growth velocity and bone mineral density (see Key Question 2,
Inhaled Corticosteroids section).
3. Leukotriene modifiers compared with Long-Acting Beta-2 Agonists (LABAs) for
monotherapy
Summary of findings
Overall, two small trials do not provide sufficient direct evidence to draw conclusions about the
comparative tolerability and adverse events of leukotriene modifiers and LABAs for use as
monotherapy for persistent asthma. Of note, LABAs are not recommended nor approved for use
as monotherapy for persistent asthma because they may increase the risk of asthma-related
death.1 The indirect evidence comparing LABAs (with or without ICSs) with placebo reporting
this increased risk is described earlier in this report (Key Question 2, Long-Acting BetaAgonists) and provides a high strength of evidence that leukotriene modifiers are safer than
LABAs for use as monotherapy.
Detailed Assessment
Direct Evidence
We found two fair quality RCTs151, 152 that included head-to-head comparisons of one
leukotriene modifier with one LABA. In both trials, overall adverse events and/or withdrawals
due to adverse events were similar between those treated with leukotriene modifiers and those
treated with LABAs (Evidence Tables A).
Indirect Evidence
Indirect evidence from placebo-controlled trials is described in other sections of this report.
Evidence from several systematic reviews suggests that LABAs may increase the risk of asthmarelated death (see Key Question 2, Long-Acting Beta-Agonists section).
B. Combination therapy
1. ICS+LABA compared with ICS (same dose) as first line therapy
Summary of findings
We found one good systematic review153 and 8 fair RCTs138, 141, 154-156, 158-160 that compared the
combination of an ICS plus a LABA with an ICS alone (same dose) for first line therapy in
patients with persistent asthma meeting our inclusion/exclusion criteria. Seven trials compared
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fluticasone plus salmeterol with fluticasone alone and one compared budesonide plus formoterol
with budesonide alone.
Overall, results from a good quality systematic review with meta-analysis and 8 RCTs
found no difference in overall adverse events or withdrawals due to adverse events between
subjects treated with ICSs plus LABAs and subjects treated with ICSs alone as first line therapy.
Trials were 12-52 weeks in duration and were generally not designed to compare tolerability and
adverse events. Indirect evidence from meta-analysis of placebo-controlled trials suggests that
the potential increased risk of asthma-related death for those taking LABAs may be confined to
patients not taking ICSs at baseline. We found no studies for this comparison that enrolled
children < 12 years of age. Thus, there is insufficient evidence to draw conclusions in children <
12 years of age. Of note, according to FDA labeling, ICS+LABA combination products are only
indicated for patients not adequately controlled on other asthma-controller medications (e.g.,
low- to medium-dose inhaled corticosteroids) or whose disease severity clearly warrants
initiation of treatment with both an inhaled corticosteroid and a LABA.
Detailed Assessment
Direct evidence
We found one good systematic review that was recently updated153 and 8 fair RCTs138, 141, 154-160.
Seven trials compared fluticasone plus salmeterol with fluticasone alone and two compared
budesonide plus formoterol with budesonide alone. The trials are described in the Key Question
1 section of the report.
The systematic review reported no significant differences between treatments in overall
adverse events (RR 1.02, 95% CI: 0.96, 1.09, 14 trials), withdrawals due to adverse events (RR
1.07, 95% CI: 0.67, 1.71, 11 trials), overall withdrawals (RR 0.95; 95% CI: 0.82, 1.11, 17 trials),
or in any of the specific adverse events (including headache, oral candidiasis, or tremor).153 The
authors note that the upper confidence interval was high for some adverse events, ruling out
complete reassurance that there is no increased risk. The overall adverse events, withdrawals due
to adverse events, and common adverse events reported in the head-to-head trials are
summarized in (Evidence Tables A and B). The results appear similar for those treated with
ICS+LABA and those treated with ICS alone.
Indirect evidence
Indirect evidence described previously in the Key Question 2 Long-Acting Beta-2 Agonists
(LABAs) section of this report describes the evidence suggesting the increased risk of asthmarelated death in patients treated with LABAs.274, 282, 283 Of note, the most current (2007)
systematic review included a post-hoc analysis of data from the the Salmeterol Multicenter
Asthma Research Trial (SMART) that did not show a statistically significantly increased risk of
asthma-related death for those taking ICSs at baseline (RR 1.34, 95% CI: 0.30 to 5.97). But,
those not taking ICSs at baseline had an increased risk of asthma-related death (RR 18.98, 95%
CI: 1.1 to 326).
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2. ICS+LABA compared with higher dose ICS
(addition of LABA to ICS compared with increasing the dose of ICS)
Summary of findings
We found 4 systematic reviews with meta-analysis165-168 and 33 RCTs (37 publications)53, 103, 105,
127, 157, 169-200
that included head-to-head comparisons between an ICS+LABA with a higher dose
ICS meeting our inclusion/exclusion criteria. Seven trials103, 105, 127, 185, 195, 197, 200 included
children, and 2 enrolled an exclusively pediatric population under 12 years of age.103, 195
Overall, results from a good quality systematic review with meta-analysis167 and
numerous RCTs found no difference in overall adverse events or withdrawals between subjects
treated with ICSs plus LABAs and subjects treated with an increased dose of ICSs. Those treated
with ICSs plus LABAs had an increased rate of tremor (N = 10, RR 2.96, 95% CI: 1.60, 5.45).
Indirect evidence from meta-analysis of placebo-controlled trials suggests that the potential
increased risk of asthma-related death for those taking LABAs may be confined to patients not
taking ICSs at baseline. Just one of the RCTs enrolled an exclusively pediatric population < 12
years of age (four included some subjects < 12) and results are not necessarily applicable to
pediatric populations.
Detailed Assessment
Direct Evidence
We found 4 systematic reviews with meta-analysis165-168 and 33 RCTs53, 103, 105, 127, 157, 169-200 that
included head-to-head comparisons between an ICS+LABA with a higher dose ICS meeting our
inclusion/exclusion criteria. These trials compared the addition of a LABA to an ICS with
increasing the dose of the ICS. Twenty-one of the 33 (64%) administered the ICS and LABA in a
single inhaler and twelve (36%) administered the ICS and LABA in separate inhalers. Although
6 trials103, 105, 127, 185, 197, 200 included children, just one enrolled an exclusively pediatric
population under 12 years of age.103 The trials are described in the Key Question 1 section of the
report.
The largest systematic review reported no difference in overall withdrawals (all reasons)
(N = 39, RR 0.92, 95% CI: 0.84 to 1.00), overall side events (N = 30, RR 0..99, 95% CI: 0.95 to
1.03), or specific side effects, with the exception of an increase rate of tremor in the LABA
group (N = 11, RR 1.84, 95% CI: 1.20 to 2.82), however this result became insignificant when a
single study using a higher dose of LABA was removed from the analysis. The rate of
withdrawals due to poor asthma control favored the combination of LABA and ICS (N = 29, RR
0.71, 95% CI: 0.56 to 0.91). The overall adverse events, withdrawals due to adverse events, and
specific adverse events for the included RCTs appear consistent with these findings (Evidence
Tables A and B).
Indirect evidence
Indirect evidence described previously in the Key Question 2 Long-Acting Beta-2 Agonists
(LABAs) section of this report describes the evidence suggesting the increased risk of asthmarelated death in patients treated with LABAs.274, 282, 283 Of note, the most current (2007)
systematic review included a post-hoc analysis of data from the the Salmeterol Multicenter
Asthma Research Trial (SMART) that did not show a statistically significantly increased risk of
asthma-related death for those taking ICSs at baseline (RR 1.34, 95% CI: 0.30 to 5.97). But,
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those not taking ICSs at baseline had an increased risk of asthma-related death (RR 18.98, 95%
CI: 1.1 to 326).
3. ICS+LABA compared with ICS (same dose)
(addition of LABA to ICS compared with continuing same dose ICS)
Summary of findings
We found 3 systematic reviews with meta-analyses166, 168, 203 and 32 RCTs (37 publications)135137, 139, 140, 142-144, 157, 173, 179, 180, 185, 198, 199, 204-219, 221-225, 288
that included head-to-head comparisons
between an ICS+LABA with the same dose ICS meeting our inclusion/exclusion criteria (Table
20). Nine studies (28%) included pediatric populations under 12 years of age.185, 212, 214, 215, 218, 219,
221, 222, 288
Overall, results from a large good quality systematic review with meta-analysis and
numerous RCTs203 found no difference in overall adverse events or withdrawals between
subjects treated with ICSs plus LABAs and subjects treated with the same dose of ICSs.
Although not statistically significantly different, the upper limits of the confidence intervals for
tachycardia or palpitations (N = 12, RR 2.11, 95% CI: 0.83, 5.37) and tremor (N = 16, RR 1.74,
95% CI: 0.72, 4.20) were relatively high, suggesting that these may be more frequent in patients
treated with ICSs plus LABAs. Indirect evidence from meta-analysis of placebo-controlled trials
suggests that the potential increased risk of asthma-related death for those taking LABAs may be
confined to patients not taking ICSs at baseline.
Detailed Assessment
Direct Evidence
We found 3 systematic reviews with meta-analyses166, 168, 203and and 33 RCTs (38
publications)135-137, 139, 140, 142-144, 157, 173, 179, 180, 185, 198, 199, 204-225, 288 that included head-to-head
comparisons between an ICS+LABA with the same dose ICS meeting our inclusion criteria
(Table 20 and Evidence Tables A and B).
Eighteen of the 33 (54%) administered the ICS and LABA in a single inhaler, 10
administered them in separate inhalers, and 4 studies administered them both as a single inhaler
and in separate inhalers to different study groups. Eight studies (24%) included pediatric
populations under 12 years of age.185, 212, 214, 215, 218-220, 288 With the exception of Li et al, these
trials are described in greater detail in the Key Question 1 section of the report. Li et al only
reports harms and did not report efficacy and effectiveness outcomes for Key Question 1.
The largest systematic review reported no difference between treatments in the risk of
overall adverse effects (N = 41, RR 1.00, 95% CI: 0.97 to 1.04), withdrawals due to adverse
effects (N = 52, RR 1.04, 95% CI: 0.86 to 1.26), or in any of the reported specific side effects
including headache (N = 37, RR .99, 95% CI: 0.87 to 1.13), hoarseness (N = 6 comparisons, RR
0.1.17, 95% CI: 0.44 to 3.1), oral thrush (N = 9, RR 1.65, 95% CI: 0.71 to 3.86), tachycardia or
palpitations (N = 12, RR 2.11, 95% CI: 0.83 to 5.37), cardiovascular adverse effects such as
chest pain (N = 4, RR 0.90, 95% CI: 0.32 to 2.54), or tremor (N = 16, RR 1.74, 95% CI: 0.72 to
4.20). However, the upper confidence interval for some adverse events was high (for example
tachycardia, palpitations and tremor). The overall adverse events, withdrawals due to adverse
events, and specific adverse events for the included RCTs appear consistent with these findings
(Evidence Tables A and B).
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Indirect evidence
Indirect evidence described previously in the Key Question 2 Long-Acting Beta-2 Agonists
(LABAs) section of this report describes the evidence suggesting the increased risk of asthmarelated death in patients treated with LABAs.274, 282, 283 Of note, the most current (2007)
systematic review included a post-hoc analysis of data from the the Salmeterol Multicenter
Asthma Research Trial (SMART) that did not show a statistically significantly increased risk of
asthma-related death for those taking ICSs at baseline (RR 1.34, 95% CI: 0.30 to 5.97). But,
those not taking ICSs at baseline had an increased risk of asthma-related death (RR 18.98, 95%
CI: 1.1 to 326).
4. ICS+LTRA compared with ICS
Summary of findings
We found one good systematic review with meta-analysis226 and two RCTs228-230 meeting our
inclusion/exclusion criteria. Both RCTs were in adolescents and adults ≥ 12 years of age.
Overall, the addition of LTRAs to ICSs compared to continuing the same dose of ICSs or
to increasing the dose of ICSs resulted in no significant differences in overall adverse events or
withdrawals due to adverse events. Trials were generally not designed to compare tolerability
and adverse events and many used higher than licensed doses of LTRAs. Evidence in children <
12 years of age is limited. Just two of the 27 trials in the systematic review enrolled children.
Detailed Assessment
Direct Evidence
We found one good systematic review with meta-analysis226 and two RCTs228-230 meeting our
inclusion/exclusion criteria (Evidence Tables A). These are described in the Key Question 1
section of the report. The systematic review included 27 studies (5871 subjects); two of the
studies were in children and 25 were in adults.
ICS+LTRA compared with same dose ICS
For ICS plus LTRA compared with the same dose of ICS, the systematic review reported
no significant differences in overall adverse events (2 trials, RR 1.01, 95% CI: 0.88 to 1.15),
specific adverse events (including elevated liver enzymes, headache, and nausea), or withdrawals
due to adverse effects (3 trials, RR 0.63, 95% CI: 0.29 to 1.37) among trials using licensed doses
of LTRAs (Evidence Tables A).
One fair 16 week trial230 (N = 639) reported similar rates of overall adverse events (41%
compared with 44%; P = NR) and withdrawals due to adverse events (2% compared with 3%; P
= NR) in those treated with BUD and those treated with BUD+ML.
ICS+LTRA compared with increased ICS
For ICS plus LTRA compared with increased doses of ICS, the systematic review reported
no significant differences in overall adverse events (2 trials, RR 0.95, 95% CI: 0.84 to 1.06), risk
of elevated liver enzymes (2 trials, RR 0.8 95% CI: 0.34 to 1.92), headache (2 trials, RR 1.07,
95% CI: 0.76 to 1.52), nausea (2 trials, RR 0.63 95% CI: 0.25 to 1.60), or withdrawals due to
adverse events (2 trials, RR 1.14, 95% CI: 0.55 to 2.37) among trials using licensed doses of
LTRAs. The trials that used two to four-fold higher than licensed doses of LTRA had a five-fold
increased risk of liver enzyme elevation (3 trials, RR 4.97 95% CI: 1.45 to 17).
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One fair 16 week trial228, 229 (N = 889) reported similar rates of overall adverse events
(37.1% compared with 41.3%; P = NR) between groups, but found a slightly increased rate of
respiratory infections (11.6% compared with 16.6%; P < 0.05) in those treated with BUD
compared to those treated with BUD+ML.
5. Combination products compared with Leukotriene Modifiers
Summary of findings
We found 4 RCTs127, 232-234 meeting our inclusion/exclusion criteria for this comparison. All
three compared low dose fluticasone plus salmeterol with montelukast. Two of the RCTs were in
adolescents and adults age 15 and older, one enrolled subjects over the age of six127 (~15% of
subjects were < 12 years of age), and one enrolled only children ages 6 to 14.234
Overall, ICS/LABA combinations and leukotriene modifiers have similar rates of overall
adverse events and withdrawals due to adverse events based on limited direct evidence from 4
short-term trials.
Detailed Assessment
Direct Evidence
We found 4 RCTs127, 232-234 comparing low dose fluticasone plus salmeterol with montelukast.
Two of the RCTs were in adolescents and adults, one enrolled subjects over the age of six127
(~15% of subjects were < 12 years of age) and one enrolled only children age 6-14 years.234
The trials are described in more detail in the Key Question 1 section of the report. The
four trials reporting withdrawals due to adverse events reported similar rates for those treated
with ML and those treated with FP/SM. The 3 trials reporting overall adverse events also
reported similar rates between groups (Evidence Tables A and B). One trial reported a greater
incidence of upper respiratory tract infections for those treated with FP/SM than those treated
with ML.127
6. ICS+LABA compared with ICS+LTRA
(addition of LABA compared with LTRA to ongoing ICS therapy)
Summary of findings
We found one systematic review with meta-analysis235 and six RCTs236-241 that compared the
addition of a LABA with the addition of an LTRA for patients poorly controlled on ICS therapy.
All six of the RCTs were in adolescents and adults ≥ 12 years of age.
Overall, results from a good quality systematic review with meta-analysis and six RCTs
provide moderate evidence that there is no difference in overall adverse events or withdrawals
due to adverse events between subjects treated with ICS plus LABA therapy and subjects treated
with ICS plus LTRA therapy. Trials were generally not designed to compare tolerability and
adverse events. We found no RCTs enrolling children < 12 years of age; the systematic review
included just one trial in children (that did not contribute data to the meta-analysis). Thus, there
is insufficient evidence to draw conclusions in children < 12 years of age.
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Detailed Assessment
Direct Evidence
We found one systematic review with meta-analysis235 and six RCTs.236-241 All six of the RCTs
were in adolescents and adults ≥ 12 years of age. Of the included studies (Evidence Tables A),
all six compared montelukast plus fluticasone with salmeterol plus fluticasone. The trials are
described in the Key Question 1 section of the report.
The systematic review reported no significant differences in overall adverse events (8
studies, RR 1.03, 95% CI: 0.99, 1.07), withdrawals due to adverse events (10 studies, RR 1.02,
95% CI: 0.80, 1.32), headache (10 studies, RR 1.07, 95% CI: 0.9, 1.26), cardiovascular events (5
studies, RR 1.09, 95% CI: 0.77, 1.52), and elevated liver enzymes (1 study, P = NS, NR). There
was a statistically significant difference in risk of oral moniliasis (6 studies, 1% for LABA
compared with 0.5% for LTRA; risk difference 0.01; 95% CI: 0, 0.01). All but one of the six
RCTs meeting our inclusion criteria were included in the systematic review and they reported
findings consistent with the conclusions of the meta-analysis (Evidence Tables A).
Key Question 3.
Are there subgroups of these patients based on demographics (age, racial groups,
gender), asthma severity, comorbidities (drug-disease interactions, including obesity),
other medications (drug-drug interactions), smoking status, genetics, or pregnancy for
which asthma controller medications differ in efficacy, effectiveness, or frequency of
adverse events?
Summary of findings
We did not find any studies that directly compared the efficacy or adverse events of our included
drugs between subgroups and the general population. In head-to-head comparisons, few
subgroups based on age, racial groups, sex, other medications, or comorbidities were evaluated.
We did not find any studies meeting our inclusion/exclusion criteria that directly compared our
included medications and found a difference in the comparative efficacy, tolerability, or adverse
events.
Detailed assessment
I. Demographics
A. Age
Differences in efficacy, tolerability, and adverse events between children < 12 years of age and
adolescents or adults ≥ 12 are described in the body of the report (Key Questions 1 and 2) in the
appropriate sections. These differences are also noted in the overall summary table. Therefore,
they are not discussed here.
Only a few trials have studied the efficacy and safety of asthma medications in very
young children (less than three years). Budesonide inhalation suspension is the only ICS that is
approved for use in children down to 12 months of age (see Introduction, Table 2). We found no
head-to-head studies comparing the efficacy or safety of our included drugs in very young
children with older children, adolescents, or adults. Long-term clinical trials have shown ICS
treatment to be effective in this population.1 Some evidence from placebo-controlled trials
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suggests that montelukast may be effective in children ages two to five; however, one trial
reported that montelukast did not reduce the need for oral systemic corticosteroids to control
exacerbations.1 Most recommendations for treatment are based on limited data and
extrapolations from studies in older children and adults.1 This data, as well as expert opinion,
supports the use of ICSs for the treatment for asthma in young children.1
A pooled analysis of 5 placebo-controlled trials of omalizumab aimed to evaluate the
effectiveness of omalizumab among adolescents (n=146) with moderate to severe allergic asthma
(a subset of the subjects enrolled in the 5 trials).289 In this population, omalizumab improved
asthma symptom scores and resulted in fewer exacerbations, school days missed, and
unscheduled office visits (Evidence Tables B).
B. Racial groups
We did not find any head-to-head studies that directly compared the efficacy and tolerability of
our included drugs between one ethnic population and another. Two studies performed subgroup
analyses; results may provide indirect evidence of differences between racial groups (Table 30).
A good systematic review examined both efficacy and safety outcomes of studies
comparing LABAs to placebo in “real world” asthmatic populations in which only some patients
were using regular ICSs at baseline.283 This study is described in detail in the Key Question 2
section of this report. A post-hoc subgroup analysis indicated that African Americans may be
more likely to experience respiratory-related death and life threatening adverse events than
Caucasians (Relative Risk Increase 3.9; 95% CI: 1.29, 11.84). There was, however, no
significant difference found in asthma-related deaths between African Americans and
Caucasians; results from life table analyses were not significantly different between African
Americans (7 compared with 1; RR 7.26; 95% CI: 0.89, 58.94), and Caucasians (6 compared
with 1; RR 5.82; 95% CI: 0.70, 48.37).
The Salmeterol Multicenter Asthma Reseach Trial (SMART),274 a large 28-week
randomized, double-blind study assessed the safety of salmeterol MDI (42 mcg twice/day)
compared with placebo. This study is described in detail in Key Question 2. The trial found no
statistically significant difference between those treated with salmeterol and those treated with
placebo for the primary outcome, respiratory-related deaths or life-threatening experiences (50
compared with 36; RR 1.40; 95% CI: 0.91, 2.14). However, the trial reported statistically
significant increases in respiratory-related deaths (24 compared with 11; RR 2.16; 95% CI: 1.06,
4.41), asthma-related deaths (13 compared with 3; RR 4.37; 95% CI: 1.25, 15.34), and in
combined asthma-related deaths or life-threatening experiences (37 compared with 22; RR, 1.71;
95% CI: 1.01, 2.89) for subjects receiving salmeterol compared to those receiving placebo.
Subgroup analyses suggest the risk may be greater in African Americans compared with
Caucasian subjects. The increased risk was thought to be largely attributable to the AfricanAmerican subpopulation: respiratory-related deaths or life-threatening experiences (20 compared
with 5; RR, 4.10; 95% CI: 1.54, 10.90) and combined asthma-related deaths or life-threatening
experiences (19 compared with 4; RR, 4.92; 95% CI: 1.68, 14.45) in subjects receiving
salmeterol compared to those receiving placebo.274
The FDA released a safety alert based on the results of the trial, reporting that there were no
significant differences in asthma-related events between salmeterol and placebo in Caucasian
patients; however, in African Americans, there was a statistically significantly greater number of
asthma-related events, including deaths, in salmeterol- compared with placebo-treated
patients.290
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One fair quality multicenter trial compared montelukast (10 mg/d plus salmeterol (100
mcg/d plus placebo ICS) with low dose BDP (160 mcg/d plus salmeterol 100 mcg/d plus placebo
LTRA) for 14 weeks, washout for 4 weeks, then crossover for another 14 weeks.243 This study is
described in detail in Key Question 1. The LTRA plus LABA combination led to significantly
more subjects having a shorter time to treatment failure compared to ICS plus LABA (29
compared with 8; P = 0.0008). Subgroup analysis found no difference between races. The
proportion of Caucasian subjects with preferential protection against treatment failure while
using an ICS + LABA (relative to an LTRA/LABA) was not significantly different from the
proportion of African-American subjects (P = 1.0).
C. Gender
We did not find any study that directly compared the efficacy and tolerability of our included
medications between males and females.
One prospective cohort study (described in detail in Key Question 2) evaluated the risk of
osteoporosis in premenopausal women using triamcinolone and found a dose-related decline in
BMD.259 Although several other studies conducted in mixed populations of men and women
found no relationship between ICS use and BMD, evidence is insufficient to support a
differential decline in BMD between male and female patients treated with ICSs.
II. Comorbidities
We did not find any study that directly compared the efficacy, effectiveness, or tolerability of our
included drugs in populations with specific comorbidities. Because mixed evidence supports an
increased risk of osteoporotic fractures, cataracts, and glaucoma in ICS-treated patients
(especially at high doses), ICSs should be used with care in populations at increased risk for
these conditions. No evidence reflects different risks between one ICS and another.
One study assessed differences in efficacy of montelukast, beclomethasone and placebo
in patients with differing BMI (normal, overweight and obese).291 This study did not meet our
eligibility criteria; it was a pooled data analysis that was not based on a systematic literature
search. Data were pooled from four trials (3 that are described in detail in Key Question 1 and 1
that was reported as an abstract only) to compare the efficacy of montelukast and
beclomethasone in patients with differing BMI. Pooled data included 3,073 patients. Patients
with normal BMI treated with placebo had a higher percentage of asthma control days than
patients who were overweight or obese (33.91% compared with 25.04% for overweight, P =
0.002; 25.80% for obese, P = 0.026). The effect of montelukast on asthma control days was
similar across all three BMI categories; however, the effect of beclomethasone decreased with
increasing BMI.
III. Other medications
We did not find any studies meeting our inclusion/exclusion criteria that examined the impact of
other medications on the comparative efficacy, tolerability, or adverse events of our included
medications.
Although little documentation supports the clinical relevance of this interaction, the
product labeling for budesonide, fluticasone, and mometasone does mention the potential for
interaction between ICSs and inhibitors of the cytochrome P450 isoenzyme 3A4 (CYP3A4).
Because beclomethasone, flunisolide, and triamcinolone also are metabolized by CYP3A4, the
potential for interaction with drugs that inhibit this isoenzyme likely applies to all ICSs. Drugs
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known to inhibit CYP3A4 include amiodarone, cimetidine, clarithromycin, delavirdine,
diltiazem, dirithromycin, disulfiram, erythromycin, fluoxetine, fluvoxamine, indinavir,
itraconazole, ketoconazole, nefazodone, nevirapine, propoxyphene, quinupristin-dalfopristin,
ritonavir, saquinavir, telithromycin, verapamil, zafirlukast, and zileuton. However, the clinical
significance of these “potential” interactions is questionable.
IV. Smoking status
We found one cross-over study comparing asthmatic smokers and nonsmokers.292 In this study,
44 nonsmokers (total lifetime smoking history of less than 2 pack-years and no smoking for at
least one year) and 39 “light” smokers (currently smoking 10-40 cigarettes/day and a 2-15 packyear history) were randomized to BDP (320 mcg/d) or montelukast (10 mg/d) for eight weeks of
active treatment, an eight week washout, and then eight weeks of active treatment with the other
medication. Both smokers and non-smokers showed some improvement in change in average
quality of life scores (AQOL). However, the change from baseline was only statistically
significant in montelukast-treated non-smokers. Average change was greater in montelukasttreated non-smokers compared with smokers than it was in BDP-treated non-smokers compared
with smokers. The difference was not based on a direct statistical comparison between the ML
and BDP groups and further studies are needed to determine if there are differences in the
response to ML and/or BDP based on smoking status.
V. Pregnancy
Maintaining adequate control of asthma during pregnancy is important for the health and wellbeing of both the mother and her baby. Inadequate control of asthma during pregnancy has been
associated with higher rates of premature birth, intrauterine growth retardation, lower birth
weight, perinatal death, and preeclampsia.1, 293, 294 Expert opinion recommends ICSs as the
preferred treatment for long-term control of asthma symptoms in pregnancy.1 This preference is
based on favorable efficacy data in both non-pregnant and pregnant women and also on safety
data in pregnant women; results do not show an increased risk of adverse perinatal outcomes.1
FDA approved labeling classifies medications by the potential for risk during pregnancy.
Budesonide is the only ICS labeled as a pregnancy category B – i.e., no well-controlled studies
have been conducted in women but animal studies have found little to no risk. Other ICS
products are pregnancy category C – i.e., no well-controlled studies have been conducted in
women but animal studies have shown harmful effects on the fetus. Currently, ICS product
labeling recommends the use of an ICS in pregnancy only when anticipated benefits outweigh
potential risk.10
In general, budesonide is the preferred ICS because more data are available on its use
during pregnancy than other ICSs. Minimal published data are available on the efficacy and
safety of LTRAs or LABAs during pregnancy, but there is theoretical justification for expecting
the safety profile of LABAs to resemble that of albuterol, for which there are data related to
safety during pregnancy.1
We found one systematic review and two observational studies focusing on ICS use in
pregnant asthmatics. We did not identify any studies assessing the efficacy or safety of LABAs,
LTSIs, or anti-IgE therapy during pregnancy. We found one observational study that reported
perinatal outcomes for a small sample (N = 96) of pregnant women who took LTRAs compared
with women who took only short-acting beta2-agonists.295 The latter study was rated poor for
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internal validity primarily due to the small sample size (inadequate to detect differences in the
adverse events of interest).
One systematic review with meta-analysis showed that ICSs did not increase the rates of
any adverse obstetrical outcomes.296 Studies were eligible for inclusion in this analysis if the
included women were exposed to any therapeutic doseage of any fluticasone, beclomethasone,
budesonide, triamcinolone or flunisolide during pregnancy. Studies were excluded if either did
not have a control group or had a control group comprised of non-asthmatic women. Four studies
met inclusion criteria. The summary OR for major malformations in two studies was 0.96 (95%
CI: 0.51, 1.83; P = 0.9582). The summary OR for preterm delivery in three studies was 0.99
(95% CI: 0.8, 1.22; P = 0.9687). The summary OR for low birth weight delivery in two studies
was 0.89 (95% CI: 0.7, 1.14; P = 0.4013). The summary OR for pregnancy-induced
hypertension in three studies was 0.97 (95% CI: 0.84, 1.2; P = 0.9932). Tests for heterogeneity
(P = 0.9249, P = 0.2521, P = 0 .6146 and P = 0.0013, respectively) indicated that the studies for
major malformation, preterm delivery and low birth weight were not significantly heterogeneous
and could be combined. ICSs do not increase the risk of major malformations, preterm delivery,
low birth weight and pregnancy-induced hypertension.
One observational study reported no significant differences between ICS- and non-ICStreated mothers.297 Compared with infants whose mothers did not use an ICS, infants born to
mothers treated with an ICS had no significant differences in gestational age, birth weight, and
length. Additionally, the rates of preterm delivery, congenital malformation, and stillbirth were
similar for ICS- and non-ICS-treated patients. A second observational study 298 aimed to
investigate the association between doses of ICSs during the first trimester of pregnancy and the
risk of congenital malformations among women with asthma. The study found that women
using low to moderate doses of ICSs (>0 to 1000 µg/d equivalent BDP) were not at increased
risk of having a baby with a malformation than women who did not use ICSs during the first
trimester. Women using high doses of ICSs (>1000 µg/d) were more likely to have a baby with
a malformation than women who used low to moderate doses (adjusted RR, 1.63; 95% CI, 1.02
to 2.60). However, these results should be interpreted with caution as confounding by severity of
asthma cannot be ruled out as the cause of these findings.
Insufficient data exists to determine if risks associated with ICSs differ among ICSs or
among other medications included in this review.
VI. Genetics
Several genes (coding for LTRA, ICS, or beta-agonist receptors), have been associated with
response to medications used in the treatment of asthma.1, 129, 299-303 To date, there is not
sufficient evidence to draw conclusions about whether testing for variants in these genes has any
clinical utility (insufficient strength of evidence). Multiple studies have investigated the impact
of polymorphisms of the Beta-2 adrenorecptor gene (ADRB2) on response to beta-agonist
therapy, but none have demonstrated clinical validity or clinical utility of testing for ADRB2
polymorphisms.1, 299, 300, 303, 304 The only prospective RCT (N=544) to evaluate therapy with a
LABA alone and in combination with an ICS found no evidence of a pharmacogenetic effect of
β-receptor variation on salmeterol response.304 It reported no difference over 16 weeks in
response to salmeterol for various ADRB2 genotype (Arg/Arg vs. Gly/Gly vs. Arg/Gly).
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Table 30. Summary of studies evaluating subgroups of patients for whom asthma
controller medications may differ in efficacy or frequency of adverse events
Study
Study design
N
Duration
Country
Population
Setting
Comparison
(total daily
dose)
Results
Quality
rating
Racial groups
Walters et
al. 2007283
Systematic
review with
meta-analysis
67 RCTs (N =
42,333
Duration: ≥ 4
weeks
Deykin et al. RCT
2007243
192
14 weeks,
washout for 4
weeks, then
crossover for
14 weeks
Multinational
Regular
inhaled LABA
Adults and children (either SM or
with asthma who
FM)
were not uniformly administered
on ICS. (Studies in twice daily vs.
which all subjects
placebo.
were uniformly
taking ICS
excluded from this
review.)
Composite endpoint of respiratoryrelated death and life threatening
adverse events (intubation and
mechanical ventilation):
Greater in African-Americans than
Caucasians (Relative Risk Increase
3.9; 95% CI: 1.29, 11.84).
Good
US
No difference in proportion of
Caucasian subjects with
preferentiala protection against
treatment failure while using ICS +
LABA (relative to an LTRA/LABA) as
vs. that in the African-American
subjects (P = 1.0)
Fair
Subgroup analysis, African
American participants:
Fair
ML (10 mg/d)
+ SM (100
Ages 12-65
mcg/d) +
No current smokers placebo ICS
vs. BDP (160
Multicenter
mcg/d) + SM
(100 mcg/d) +
placebo LTRA
Low dose ICS
Nelson et al. DB
2006274
Randomized
Observational
study
SMART
US
Age ≥ 12, asthma
severity=NR;
smoking status=NR
SM (84
mcg/d) vs.
placebo
Respiratory-related deaths or life
threatening experiences: significant
increase in SM vs. placebo (20 vs.
5; RR 4.10; 95% CI: 1.54 to 10.90)
26,355
Multicenter
28 weeks
Combined asthma-related deaths or
life-threatening experiences:
significant increase in SM vs.
placebo (19 vs. 4; RR 4.92; 95% CI:
1.68, 14.45)
Smoking status
Lazarus et
al. 2007292
RCT, DB, DD
crossover
83
SMOG study 24 weeks (16
weeks with 8
week washout
between)
US
Smokers vs.
non-smokers
Change in AQOL average score:
ML /Non-smoker 0.23 (0.04, 0.42 ; P
= 0.02)
ML smoker 0.07 (-0.19, 0.32; P =
NS)
BDP Non-smoker 0.13 (-0.06, 0.32;
P = NS)
BDP Smoker 0.12 (-0.13, 0.37; P =
NS)
Fair
no ICS use
(8, 734
pregnancies)
Adjusted RRs, all malformations:
G1: 1.08 (0.94-1.24)
G2: Reference
Fair
Age 18-50
Multicenter
Pregnancy
Blais et al.
2009298
Cohort
13,280
pregnancies
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Table 30. Summary of studies evaluating subgroups of patients for whom asthma
controller medications may differ in efficacy or frequency of adverse events
Study
Study design
N
Duration
Country
Population
Setting
Comparison
(total daily
dose)
vs. >0-1000
µg/d (4,392
pregnancies)
vs. >1,000
µg/d (154
pregnancies)
Results
Quality
rating
G3: 1.66 (1.02-2.68)
Adjusted RRs, major malformations:
G1: 1.06 (0.89-1.26)
G2: Reference
G3: 1.67 (0.91-3.06)
Norjavaara Database
&
review
Gerhardsson 293,948
de Verdier,
2003297
Pregnant asthmatic BUD vs.
women
control (no
(Swedish)
BUD
exposure
during
pregnancy)
No difference in gestational age,
birth weight, length, rate of stillbirths,
or multiple births for children born to
BUD-treated mothers. Rate of
caesarean birth was higher in
women taking BUD early in
pregnancy (P < 0.05)
Fair
Rahimi et al. Systematic
2006296
review with
meta-analysis
(SR)
Pregnant asthmatic Any
women
therapeutic
dosage of any
ICS (FP,
BDP, BUD,
TAA,
flunisolide) vs.
no ICS
exposure
ICSs did not increase the rates of
any obstetrical outcomes.
Fair
Major malformations:
Summary (2 studies) OR=0.96 (95%
CI: 0.51, 1.83); P = 0.9582
Preterm delivery:
Summary (3 studies) OR = 0.99
(95% CI: 0.8, 1.22); P = 0.9687
Low birth weight delivery:
Summary (2 studies) OR = 0.89
(95% CI: 0.7, 1.14); P = 0.4013
Pregnancy-induced hypertension:
Summary (3 studies) OR = 0.97
(95% CI: 0.84, 1.2); P = 0.9932
Abbreviations: BUD = Budesonide; CI = confidence interval; DPI= Dry Powder Inhaler; FM = Formoterol; FP = Fluticasone
Propionate; ICS = Inhaled Corticosteroids; LABAs = Long-Acting Beta-2 Agonists; LTRAs = Leukotriene receptor antagonists;
MA=meta-analysis; ML = Montelukast; NR = not reported; NS = not statistically significant; OR= odds ratio; QOL = quality of life;
RCT= randomized controlled trial; RR = relative risk; SM = Salmeterol;; SR=systematic review.
a
Treatment failure defined as increased as-needed albuterol, persistent asthma symptoms or drop in PEF despite rescue use, use
of oral, parenteral, or non-study related ICS, emergency department therapy with steroids, drop in FEV1 or PEF, or physician clinical
judgment for safety.
SUMMARY
Strength of Evidence (SOE)
The main results of this review are summarized in Table 31. Summaries of the strength of
evidence (SOE) for each comparison are presented in Appendix H. Efficacy studies provide
moderate strength of evidence (SOE) that equipotent doses of ICSs administered through
comparable delivery devices do not differ in their ability to control asthma symptoms, prevent
exacerbations, reduce the need for additional rescue medication, or in the overall incidence of
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adverse events or withdrawals due to adverse events. Evidence does not support a difference
between montelukast and zafirlukast in their ability to decrease rescue medicine use or improve
quality of life (low SOE for ≥12 years of age, insufficient <12), or between formoterol and
salmeterol in their ability to control symptoms, prevent exacerbations, improve quality of life, or
cause harms among patients not controlled on ICSs alone (moderate SOE). Evidence does not
support a difference between budesonide/formoterol and fluticasone/salmeterol for efficacy or
harms when each combination is administered via a single inhaler (moderate SOE for ≥12,
insufficient <12).
Meta-analyses and efficacy studies provide consistent evidence favoring omalizumab
over placebo for the ability to control asthma symptoms, prevent exacerbations, and reduce the
need for additional rescue medication. Omalizumab-treated patients have an increased incidence
of injection site reactions and anaphylaxis compared to placebo-treated patients.
Efficacy studies up to 56 weeks in duration provide consistent evidence of greater benefit for
subjects treated with ICS monotherapy compared with those treated with LM monotherapy (high
SOE). Direct evidence suggests no difference in tolerability or overall adverse events between
ICSs and LMs (moderate SOE). Specific adverse events reported with ICSs, such as cataracts
and decreased growth velocity, were not found among patients taking LMs. The best longer-term
evidence on growth (avg 4.3 years) is from the CAMP study, which found a 1.1cm difference in
mean increase in height (P = 0.005) between BUD and placebo-treated patients. The differences
in growth occurred primarily during the first year of treatment, suggesting that the small decrease
in growth velocity with ICSs occurs early in treatment and is not progressive. Evidence is
insufficient to determine if long-term treatment with ICSs leads to a reduction in final adult
height. Overall evidence indicates that ICSs and leukotriene receptor antagonists (LTRAs) are
safer than LABAs for use as monotherapy (high SOE). LABAs are not recommended nor
approved for use as monotherapy for persistent asthma because they may increase the risk of
asthma-related deaths. Indirect evidence suggests that the potential increased risk of asthmarelated death for those taking LABAs may be confined to patients not taking ICSs at baseline.
Meta-analyses of results from large trials up to twelve months in duration found mixed
results and do not provide sufficient evidence to support the routine use of combination therapy
rather than an ICS alone as first line therapy (moderate SOE for ≥12, insufficient <12). Of note,
FDA approved prescribing information and guidelines from the NAEPP suggest that
combination therapy should only be used for patients not adequately controlled on a long-term
asthma controller medication, such as an ICS, or whose disease severity clearly warrants
initiation of treatment with both an inhaled corticosteroid and a LABA. Results from large trials
up to twelve months in duration support greater efficacy with the addition of a LABA to an ICS
than with a higher dose ICS (high SOE for ≥12, low <12). Results from large trials up to one
year in duration support greater efficacy with the addition of a LABA to an ICS over continuing
the current dose of ICS alone for poorly controlled persistent asthma (high SOE). The addition of
LMs to ICSs compared to continuing the same dose of ICSs resulted in improvement in rescue
medicine use and no statistically significant differences in other health outcomes (low SOE for
≥12, insufficient <12). There is no apparent difference in symptoms, exacerbations, rescue
medicine use, overall adverse events, or withdrawals due to adverse events between those treated
with ICSs plus LTRAs compared to those treated with increasing the dose of ICSs (moderate
SOE for ≥12, low <12). Results provide strong evidence that the addition of a LABA to ICS
therapy (ICS+LABA) is more efficacious than the addition of an LTRAs to ICS therapy
(ICS+LTRA) (high SOE for ≥12, low <12). We found no difference in overall adverse events or
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withdrawals due to adverse events between ICS+LABA and ICS+ LTRAs (moderate SOE for
≥12, insufficient <12).
Limitations of this Report
As with other types of research, the limitations of this systematic review are important to
recognize. These can be divided into 2 groups, those relating to applicability of the results
(addressed below) and those relating to methodology within the scope of this review.
Methodological limitations of the review within the defined scope included the exclusion
of studies published in languages other than English and lack of a specific search for unpublished
studies. In addition, the data from RCTs included in this report have limited utility for assessing
real-world adherence to medications. This is largely because they enrolled selected populations,
often requiring a high degree of adherence to be included in the trial. For example, many of the
trials had a run-in period during which adherence was assessed and then only included subjects
that met a threshold for good adherence (e.g., adherence to 80% of recommended doses).
Unfortunately, for many drugs, there are few or no effectiveness studies and many
efficacy studies. As a result, clinicians must make decisions about treatment for many patients
who would not have been included in controlled trials and for whom the effectiveness and
tolerability of the different drugs are uncertain. An evidence report indicates whether or not there
is evidence that drugs differ in their effects in various subgroups of patients, but it does not
attempt to set a standard for how results of controlled trials should be applied to patients who
would not have been eligible for them. With or without an evidence report, these are decisions
that must be informed by clinical judgment.
In the context of developing recommendations for practice, evidence reports are useful
because they define the strengths and limits of the evidence, clarifying whether assertions about
the value of the intervention are based on strong evidence from clinical studies. By themselves,
they do not tell you what to do: Judgment, reasoning, and applying one's values under conditions
of uncertainty must also play a role in decision making. Users of an evidence report must also
keep in mind that not proven does not mean proven not; that is, if the evidence supporting an
assertion is insufficient, it does not mean the assertion is not true. The quality of the evidence on
effectiveness is a key component, but not the only component, in making decisions about clinical
policies. Additional criteria include acceptability to physicians or patients, the potential for
unrecognized harms, the applicability of the evidence to practice, and consideration of equity and
justice.
Applicability
The applicability of the results are limited by the scope of the Key Questions and inclusion
criteria and by the applicability of the studies included. Most studies included narrowly defined
populations of patients who met strict criteria for case definition, had few comorbidities, and
used few or no concomitant medications. Minorities, older patients, and the most seriously ill
patients were often underrepresented.
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Studies Currently Being Conducted
We identified no trials in progress that would meet inclusion criteria for this review that would
potentially change conclusions.
Table 31. Summary of the evidence by key question for controller medications for
the treatment of persistent asthma in adolescents/adults ≥ 12 years of age and
children < 12 years of age
Key Question 1. What is the comparative efficacy and effectiveness of controller medications used to treat
outpatients with persistent asthma?
Strength of evidence
Conclusions
Inhaled Corticosteroids (ICSs) compared with ICSs:
Moderate
(≥ 12 years)
Efficacy studies provide moderate evidence that ICSs do not differ in their ability to control
asthma symptoms, prevent exacerbations, and reduce the need for additional rescue
medication at equipotent doses administered through comparable delivery devices.
Relatively few studies reported exacerbations, healthcare utilization (hospitalizations,
emergency visits), or quality of life outcomes. Long-term data beyond 12 weeks is lacking
for most of the comparisons.
Moderate
(< 12 years)
In children, the body of evidence supports the above conclusion, but data was only
available for five comparisons (three systematic reviews and seven RCTs): beclomethasone
compared with budesonide, beclomethasone compared with fluticasone, budesonide
compared with ciclesonide, budesonide compared with fluticasone, and ciclesonide
compared with fluticasone.
Leukotriene Modifiers (LMs) compared with LMs:
Low
(≥ 12 years)
Limited head-to-head evidence from one short-term study (12 weeks) in adults and
adolescents ≥ 12 years of age does not support a difference between montelukast and
zafirlukast in their ability to decrease rescue medicine use or improve quality of life.
Insufficient
(< 12 years)
We found no head to head trials in children < 12 years of age.
Long-Acting Beta-2 Agonists (LABAs) compared with LABAs:
Moderate
(≥ 12 years)
Results from three efficacy studies provide moderate evidence that LABAs do not differ in
their ability to control asthma symptoms, prevent exacerbations, improve quality of life, and
prevent hospitalizations or emergency visits in patients with persistent asthma not controlled
on ICSs alone. Large systematic reviews comparing LABAs with other treatments provide
some indirect evidence supporting this conclusion.
Moderate
(< 12 years)
In children, direct evidence is limited to one fair trial enrolling children and adolescents age
6-17. The trial reported no difference in symptoms, exacerbations, quality of life, missed
work, or missed school, but found a greater decrease in rescue medicine use in subjects
treated with eformoterol compared to those treated with salmeterol.
Anti-IgE Therapy (Omalizumab):
High
(≥ 12 years)
Meta-analyses and efficacy studies provide consistent evidence favoring omalizumab over
placebo for the ability to control asthma symptoms, prevent exacerbations, and reduce the
need for additional rescue medication in adults and adolescents ≥ 12 years of age.
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Key Question 1. What is the comparative efficacy and effectiveness of controller medications used to treat
outpatients with persistent asthma?
Strength of evidence
Conclusions
Moderate
(< 12 years)
Limited evidence from two fair trials are available for children < 12 years of age. Both trials
reported fewer exacerbations. Both reported no statistically significant difference in
measures of symptoms. There were mixed results for other outcomes with one reporting
less rescue medicine use, greater quality of life, and fewer emergency visits and
hospitalizations for subjects treated with omalizumab and the other reporting no statistically
significant difference for rescue medicine use or quality of life.
Combination Products: Budesonide/Formoterol (BUD/FM) compared with
Fluticasone/Salmeterol (FP/SM):
Moderate
(≥ 12 years)
Insufficient
(< 12 years)
Results from large trials up to seven months in duration comparing equipotent steroid
components support no significant difference in efficacy between combination treatment
with BUD/FM and combination treatment with FP/SM when each is administered via a
single inhaler. The results of our meta-analyses show no difference between those treated
with BUD/FM and those treated with FP/SM in either exacerbations requiring oral steroids
or exacerbations requiring emergency visit or hospital admission.
None of the trials included children < 12 years of age.
Combination Products: BUD/FM for maintenance and relief compared with ICS/LABA
combination (BUD/FM or FP/SM) for maintenance with Short-Acting Beta-Agonist
(SABA) for relief:
Moderate
(≥ 12 years)
Of note, BUD/FM is not approved for use as a relief medication in the US, but has been
approved for maintenance and reliever therapy in Canada when administered via a DPI.
Meta-analyses of results from large trials (10,547 subjects) up to twelve months in duration
including children and adults revealed that MART was associated with significantly lower
odds of exacerbations requiring medical interventions (OR = 0.75; 95% CI: 0.66, 0.85) and
of exacerbations resulting in emergency department visits or hospital admissions (OR =
0.73; 95% CI: 0.60, 0.90). MART was also associated with fewer nocturnal awakenings,
compared with ICS/LABA + SABA, but no statistically significant difference in symptoms or
rescue medicine use.
Moderate
(< 12 years)
The one trial that included children found similar results. It enrolled children down to 4 years
of age.
It is difficult to determine the applicability of the results of these trials given the
heterogeneity of study designs and dose comparisons. In addition, several of the trials
significantly reduced the total ICS doses for many subjects upon randomization; some
studies reduced the starting doses to levels that could be considered inadequate compared
to the subjects’ previous dose requirements for control.
ICSs compared with Leukotriene Modifiers:
High
(≥ 12 years)
High
(< 12 years)
Efficacy studies up to 56 weeks in duration provide consistent evidence favoring ICSs over
LTRAs for the treatment of asthma as monotherapy for both children and adults. Those
treated with LTRAs had a significantly higher occurrence of exacerbations than those
treated with ICSs (SMD = -0.17, 95% CI: -0.22, -0.12). In addition, our meta-analyses found
statistically significant differences in favor of ICSs over LTRAs for measures of symptoms,
rescue medicine use, and quality of life.
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Key Question 1. What is the comparative efficacy and effectiveness of controller medications used to treat
outpatients with persistent asthma?
Strength of evidence
Conclusions
ICSs compared with LABAs for monotherapy:
High
(≥ 12 years)
High
(< 12 years)
LABAs are not recommended nor approved for use as monotherapy for persistent asthma
because they may increase the risk of asthma-related deaths. Efficacy studies up to 12
months in duration provide consistent evidence favoring ICSs over LABAs for the treatment
of asthma as monotherapy for children and adults. Those treated with LABAs had a
significantly higher occurrence of exacerbations than those treated with ICSs (SMD = 0.456;
95% CI = 0.225, 0.688; P < 0.001; 2 studies).
Leukotriene Modifiers compared with LABAs for monotherapy:
Insufficient
(≥ 12 years)
Insufficient
(< 12 years)
LABAs are not recommended nor approved for use as monotherapy for persistent asthma
because they may increase the risk of asthma-related deaths. Two small trials provide
insufficient evidence to draw firm conclusions about the comparative efficacy of leukotriene
modifiers and LABAs for use as monotherapy for persistent asthma.
ICS+LABA compared with ICS (same dose) as first line therapy:
Moderate
(≥ 12 years)
Meta-analyses of results from large trials up to twelve months in duration found mixed
results and do not provide sufficient evidence to support the use of combination therapy
rather than ICS alone as first line therapy. Meta-analyses found statistically significantly
greater improvements in symptoms and rescue medicine use, but no difference in
exacerbations for adolescents and adults treated with ICS+LABA than for those treated with
same-dose ICS alone for initial therapy. However, limited data were available for
exacerbations and further research may change our confidence in the estimate of effect for
this outcome. Of note, ICS+LABA combination products are only indicated for patients not
adequately controlled on other asthma-controller medications (e.g., inhaled corticosteroids)
or whose disease severity clearly warrants initiation of treatment with two maintenance
therapies.
Insufficient
(< 12 years)
We found no studies for this comparison that enrolled children < 12 years of age.
ICS+LABA compared with ICS (increased dose) (addition of LABA to ICS compared
with increasing the ICS dose):
High
(≥ 12 years)
Results from large trials up to twelve months in duration support greater efficacy with the
addition of a LABA to an ICS than with a higher dose ICS for adults and adolescents with
persistent asthma. Our meta-analysis shows statistically significantly greater improvement
in symptom-free days, symptom scores, rescue-free days, and rescue medicine use for
subjects treated with ICS+LABA. Despite a trend toward fewer subjects with exacerbations
in the ICS+LABA group, the difference was not statistically significant in our analysis
Low
(< 12 years)
Just one trial exclusively enrolled children < 12 (four included some subjects < 12) and
results are not necessarily generalizable to pediatric populations.
ICS+LABA compared with ICS (same dose)
(addition of LABA to ICS compared with continuing same dose ICS):
High
(≥ 12 years)
Results from large trials up to one year in duration support greater efficacy with the addition
of a LABA to an ICS over continuing the current dose of ICS alone for patients with poorly
controlled persistent asthma.
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Key Question 1. What is the comparative efficacy and effectiveness of controller medications used to treat
outpatients with persistent asthma?
Strength of evidence
Conclusions
High
(< 12 years)
Nine trials included pediatric populations < 12 years of age.
ICS+LTRA compared with ICS (same dose):
Low
(≥ 12 years)
The addition of LTRAs to ICSs compared to continuing the same dose of ICSs resulted in
improvement in rescue medicine use and a non-statistically significant trend toward fewer
exacerbations requiring systemic steroids. There were no statistically significant differences
in other health outcomes.
Insufficient
(< 12 years)
None of the included trials enrolled children < 12 years of age.
ICS+LTRA compared with ICS (increased dose):
Moderate
(≥ 12 years)
There is no apparent difference in symptoms, exacerbations, or rescue medicine use
between those treated with ICSs plus LTRAs compared to those treated with increasing the
dose of ICSs. There were some conflicting results and further research may alter the
results.
Low
(< 12 years)
Two trials enrolled children < 12 years of age. One 12-week trial conduced in India reported
fewer exacerbations in those treated with ICS+LTRA compared to increasing the dose of
BUD. The other reported no difference between groups for hospitalizations due to asthma
and similar numbers of oral steroid courses (43 vs. 47, P = NR)
Combination products (ICS/LABA) compared with LTRAs:
High
(≥ 12 years)
Overall, our meta-analysis and results from 5 RCTs find the combination of fluticasone plus
salmeterol to be more efficacious than montelukast for the treatment of persistent asthma.
Moderate
(< 12 years)
Two of the trials enrolled children ages 6-14 and another included about 15% of subjects <
12 years of age.
ICS+LABA compared with ICS+LTRA
(addition of LABA compared with LTRA to ongoing ICS therapy):
High
(≥ 12 years)
Overall, results from a good quality systematic review with meta-analysis and eight RCTs
provide strong evidence that the addition of a LABA to ICS therapy is more efficacious than
the addition of an LTRA to ICS therapy for adolescents and adults with persistent asthma.
Low
(< 12 years)
We found one trial including children < 12 years of age. It enrolled 182 subjects 6 to 17
years of age and reported results consistent with those from trials in adolescents and adults
(i.e., the addition of a LABA to ICS therapy was more efficacious).
LTRA+LABA compared with ICS+LABA:
Moderate
(≥ 12 years)
Results from one 32 week cross-over trial, which was terminated early, reported that
subjects treated with LTRA+LABA had significantly shorter time to treatment failure than
those treated with ICS+LABA (P = 0.0008). Indirect evidence from other comparisons
supports our confidence that the ICS+LABA combination is more efficacious than the
LTRA+LABA combination.
Insufficient
(< 12 years)
We found no studies for this comparison that enrolled children < 12 years of age.
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Key Question 1. What is the comparative efficacy and effectiveness of controller medications used to treat
outpatients with persistent asthma?
Strength of evidence
Conclusions
Long-acting anticholinergics:
Insufficient
(all ages)
Tiotropium is not approved for the treatment of asthma. It is approved for the treatment of
chronic obstructive pulmonary disease (COPD). We found no studies of tiotropium meeting
our inclusion criteria for any key question.
Key Question 2. What is the comparative tolerability and frequency of adverse events for controller
medications used to treat outpatients with persistent asthma?
Strength of evidence
Conclusions
Inhaled Corticosteroids (ICSs):
Moderate
(≥ 12 years)
The overall incidence of adverse events, withdrawals due to adverse events, and specific
adverse events (other than reduction in growth velocity and oral candidiasis) are similar for
equipotent doses of ICSs.
Moderate
(< 12 years)
Three fair head-to-head trials provide evidence that short-term (20 weeks to 1 year) growth
velocity is reduced less with fluticasone than with beclomethasone or budesonide. A forth
head-to-head trial found that ciclesonide-treated subjects had a greater mean body height
increase than budesonide-treated subjects over 12 weeks. In addition, two meta-analyses
report a reduction in growth velocity for beclomethasone or fluticasone compared to
placebo. The best longer-term evidence (avg 4.3 years) is from the CAMP study, which
found a 1.1cm difference in mean increase in height (P = 0.005) between BUD- and
placebo-treated patients. The differences in growth occurred primarily during the first year of
treatment, suggesting that the small decrease in growth velocity with ICSs occurs early in
treatment and is not progressive.
Moderate
Meta-analysis of trials reporting “oral candidiasis-thrush” that compared equipotent doses of
ciclesonide with FP revealed lower odds of oral candidiasis-thrush for those treated with
ciclesonide (OR 0.33, 95% CI 0.17, 0.64).
Insufficient
Evidence is insufficient to determine if long-term treatment with ICSs leads to a reduction in
final adult height.
Leukotriene Modifiers:
Moderate
(≥ 12 years)
Moderate
(< 12 years)
There is insufficient head-to-head data (one trial) to determine differences in tolerability or
overall adverse events between any of the leukotriene modifiers using direct evidence.
Indirect evidence from placebo-controlled trials and large safety databases suggests that
zileuton has an increased risk of liver toxicity compared with either montelukast or
zafirlukast.
Long-Acting Beta-2 Agonists (LABAs):
Moderate
(≥ 12 years)
Limited direct evidence from head-to-head trials and indirect evidence from systematic
reviews provides no evidence of a difference in tolerability or adverse events between
formoterol and salmeterol.
Moderate
(< 12 years)
Anti-IgE Therapy (Omalizumab):
High
(all ages)
Omalizumab is the only available anti-IgE drug approved for the treatment of asthma;
therefore, there are no studies of intra-class comparisons. Omalizumab-treated patients
have an increased incidence of injection site reactions and anaphylaxis compared to
placebo-treated patients. Omalizumab has a boxed warning for anaphylaxis.
Low (all ages)
Omalizumab also has a warning for a potential increased risk of malignancy, based on short
term data from studies less than one year in duration.
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Key Question 2. What is the comparative tolerability and frequency of adverse events for controller
medications used to treat outpatients with persistent asthma?
Strength of evidence
Conclusions
Combination Products: Budesonide/Formoterol (BUD/FM) compared with
Fluticasone/Salmeterol (FP/SM):
Moderate
(≥ 12 years)
Data from four large head-to-head trials (5,818 subjects) provide no evidence of a difference
in tolerability or overall adverse events between BUD/FM and FP/SM in adults and
adolescents.
Insufficient
(< 12 years)
There is insufficient evidence to draw conclusions in children ≤ 12.
Combination Products: BUD/FM for maintenance and relief compared with ICS/LABA
combination for maintenance with Short-Acting Beta-Agonist (SABA) for relief:
Of note, BUD/FM is not approved for use as a relief medication in the US but has been
approved for maintenance and reliever therapy in Canada when administered via a DPI.
Low (all ages)
No studies reported statistical significance of differences between BUD/FM for maintenance
and as-needed relief with BUD/FM or FP/SM for maintenance and a Short-Acting BetaAgonist (SABA) for relief. The reported frequencies of adverse events do not suggest a
difference between treatments.
ICSs compared with Leukotriene Modifiers:
Moderate
(≥ 12 years)
Moderate
(< 12 years)
Data from two good quality systematic reviews and numerous head-to-head RCTs provides
no evidence of a difference in tolerability or overall adverse events (risk of experiencing any
adverse effects: RR 0.99, 95% CI: 0.93, 1.04, 15 trials) between ICSs and leukotriene
modifiers. Trials were generally not designed to compare tolerability and adverse events.
Specific adverse events reported with ICSs, such as cataracts and decreased growth
velocity, were not found among patients taking leukotriene modifiers. One 56-week RCT
found that the mean growth rate of subjects treated with beclomethasone was 0.81 cm less
than that of subjects treated with montelukast.
ICSs compared with LABAs for monotherapy:
High
(all ages)
LABAs are not recommended nor approved for use as monotherapy for persistent asthma
because they may increase the risk of asthma-related deaths. Overall evidence indicates
that ICSs are safer than LABAs for use as monotherapy.
Leukotriene Modifiers compared with LABAs for monotherapy:
High
(all ages)
LABAs are not recommended nor approved for use as monotherapy for persistent asthma
because they may increase the risk of asthma-related deaths. Indirect evidence indicates
that leukotriene modifiers are safer than LABAs for use as monotherapy.
ICS+LABA compared with ICS (same dose) as first line therapy:
Moderate
(≥ 12 years)
Results from a good quality systematic review with meta-analysis and 8 RCTs found no
difference in overall adverse events or withdrawals due to adverse events between subjects
treated with ICSs plus LABAs and subjects treated with ICSs alone as first line therapy.
Trials were 12-52 weeks in duration and were generally not designed to compare tolerability
and adverse events. Indirect evidence from a recent systematic review that included a posthoc analysis of data from SMART suggests that the potential increased risk of asthmarelated death for those taking LABAs may be confined to patients not taking ICSs at
baseline. Of note, ICS+LABA combination products are only indicated for patients not
adequately controlled on other asthma-controller medications (e.g., low- to medium-dose
inhaled corticosteroids) or whose disease severity clearly warrants initiation of treatment
with two maintenance therapies.
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Key Question 2. What is the comparative tolerability and frequency of adverse events for controller
medications used to treat outpatients with persistent asthma?
Strength of evidence
Conclusions
Insufficient
(< 12 years)
We found no studies for this comparison that enrolled children < 12 years of age. Thus,
there is insufficient evidence to draw conclusions in children < 12 years of age.
ICS+LABA compared with ICS (increased dose)
(addition of LABA to ICS compared with increasing the ICS dose):
Moderate
(≥ 12 years)
Results from a good quality systematic review with meta-analysis and numerous RCTs
found no difference in overall adverse events or withdrawals between subjects treated with
ICSs plus LABAs and subjects treated with an increased dose of ICSs. Those treated with
ICSs plus LABAs had an increased rate of tremor (N = 11, RR 1.84, 95% CI: 1.20 to 2.82).
Indirect evidence from a recent systematic review that included a post-hoc analysis of data
from SMART suggests that the potential increased risk of asthma-related death for those
taking LABAs may be confined to patients not taking ICSs at baseline.
Low
(< 12 years)
Two of the RCTs enrolled an exclusively pediatric population < 12 years of age (7 included
some subjects < 12) and results are not necessarily applicable to pediatric populations.
ICS+LABA compared with ICS (same dose)
(addition of LABA to ICS compared with continuing same dose ICS):
Moderate
(≥ 12 years)
Results from a good quality systematic review with meta-analysis and numerous RCTs
found no difference in overall adverse events or withdrawals between subjects treated with
ICSs plus LABAs and subjects treated with the same dose of ICSs. Although not statistically
significantly different, the upper limits of the confidence intervals for tachycardia or
palpitations (N = 12, RR 2.11, 95% CI: 0.83 to 5.37) and tremor (N = 16, RR 1.74, 95% CI:
0.72 to 4.20) were relatively high, suggesting that these may be more frequent in patients
treated with ICSs plus LABAs. Indirect evidence from a recent systematic review that
included a post-hoc analysis of data from SMART suggests that the potential increased risk
of asthma-related death for those taking LABAs may be confined to patients not taking ICSs
at baseline.
Low
(< 12 years)
Nine studies (27%) included pediatric populations under 12 years of age
ICS+LTRA compared with ICS (same dose):
Moderate
(≥ 12 years)
Evidence from one good quality systematic review with meta-analysis (including 27 trials)
found that the addition of LTRAs to ICSs compared to continuing the same dose of ICSs
resulted in no significant differences in overall adverse events or withdrawals due to adverse
events. Trials were generally not designed to compare tolerability and adverse events and
many used higher than licensed doses of LTRAs.
Low
(< 12 years)
Evidence in children < 12 years of age is limited. Just two of the 27 trials in the systematic
review enrolled children.
ICS+LTRA compared with ICS (increased dose):
Moderate
(≥ 12 years)
Evidence from one good quality systematic review with meta-analysis (including 27 trials)
found that the addition of LTRAs to ICSs compared to increasing the dose of ICSs resulted
in no significant differences in overall adverse events or withdrawals due to adverse events.
Trials were generally not designed to compare tolerability and adverse events and many
used higher than licensed doses of LTRAs.
Low
(< 12 years)
Evidence in children < 12 years of age is limited. Just two of the 27 trials in the systematic
review enrolled children.
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Key Question 2. What is the comparative tolerability and frequency of adverse events for controller
medications used to treat outpatients with persistent asthma?
Strength of evidence
Conclusions
Combination products (ICS/LABA) compared with LTRAs:
Low
(≥ 12 years)
ICS/LABA combinations and leukotriene modifiers have similar rates of overall adverse
events and withdrawals due to adverse events based on direct evidence from 4 short-term
trials.
Low
(< 12 years)
One of the 4 trials enrolled subjects at least six years of age (about 15% were <12 years
old) and one enrolled only children ages 6 to 14
ICS+LABA compared with ICS+LTRA
(addition of LABA compared with LTRA to ongoing ICS therapy):
Moderate
(≥12 years)
Results from a good quality systematic review with meta-analysis and six RCTs provide
moderate evidence that there is no difference in overall adverse events or withdrawals due
to adverse events between ICS+LABA and ICS+LTRA. Trials were generally not designed
to compare tolerability and adverse events.
Insufficient
(<12 years)
We found no RCTs enrolling children <12 years of age; the systematic review included just
one trial in children (that did not contribute data to the meta-analysis). Thus, there is
insufficient evidence to draw conclusions in children < 12 years of age.
Key Question 3. Are there subgroups of these patients based on demographics (age, racial groups, gender),
asthma severity, comorbidities (drug-disease interactions, including obesity), other medications (drug-drug
interactions), smoking status, genetics, or pregnancy for which asthma controller medications differ in
efficacy, effectiveness, or frequency of adverse events?
Strength of evidence
Conclusions
Age:
Differences in the efficacy, tolerability, or adverse events between children <12 years of age
and adolescents or adults ≥12 are described in the body of the report (Key Questions 1 and
2) and summaries above.
Children ≤ 4 years of age
Insufficient
We found no head-to-head studies comparing the efficacy or safety of our included drugs in
this age group with older children, adolescents, or adults.
Racial groups:
Low
A large randomized trial (26,355 subjects) comparing salmeterol with placebo (SMART) was
discontinued early due to findings in African Americans, safety concerns, and difficulties in
enrollment. The trial reported an increased risk of asthma-related deaths (13 compared with
3; RR 4.37; 95% CI: 1.25 to 15.34). The increased risk was thought to be largely attributable
to the African-American subpopulation. Although the study was not designed to assess
subgroups, there were approximately four-fold relative increases in respiratory-related
deaths or life-threatening experiences (20 compared with 5; RR 4.10; 95% CI: 1.54 to
10.90) and combined asthma-related deaths or life-threatening experiences (19 compared
with 4; RR 4.92; 95% CI: 1.68 to 14.45) in African-Americans treated with salmeterol
compared to those treated with placebo.
Gender:
Insufficient
We did not find any study reporting a difference between the included medications.
Comorbidities:
Insufficient
We did not find any studies meeting our inclusion/exclusion criteria that directly compared
the efficacy, effectiveness, or tolerability of our included drugs in populations with specific
comorbidities.
Other medications (drug-drug interactions):
Insufficient
We did not find any studies meeting our inclusion/exclusion criteria that examined the
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Key Question 3. Are there subgroups of these patients based on demographics (age, racial groups, gender),
asthma severity, comorbidities (drug-disease interactions, including obesity), other medications (drug-drug
interactions), smoking status, genetics, or pregnancy for which asthma controller medications differ in
efficacy, effectiveness, or frequency of adverse events?
Strength of evidence
Conclusions
impact of other medications on the comparative efficacy, tolerability, or adverse events of
our included medications.
Smoking status:
Low
One study comparing ML and BDP in smokers and non-smokers provides some information
that there may be differential responses to treatment between smokers and non-smokers.
Pregnancy:
Insufficient
We did not find any studies that directly examined the comparative efficacy, tolerability, or
adverse events of our included medications. Budesonide is the only ICS labeled pregnancy
category B; the other ICSs are category C.
Genetics:
Insufficient
To date, there is not sufficient evidence to determine whether genetic polymorphisms in
general result in clinically important differences in responses to asthma medications.
Multiple studies have investigated the impact of polymorphisms on response to various
asthma treatments, but none have demonstrated clinical validity or clinical utility of testing
for polymorphisms.
Low
One RCT provides low strength of evidence of no difference in response to salmeterol (with
or without ICSs) for people with various ADRB2 (Beta-2 adrenorecptor gene) genotypes
(Arg/Arg vs. Gly/Gly vs. Arg/Gly)
CONCLUSIONS
Overall findings do not suggest that one medication within any of the classes evaluated is
significantly more effective or harmful than the other medications within the same class, with the
exception of zileuton being more harmful than the other LMs. Our results support the general
clinical practice of starting initial treatment for persistent asthma with an ICS. For people with
poorly controlled persistent asthma taking an ICS, our findings suggest that the addition of a
LABA is most likely to provide the greatest benefit as the next step in treatment.
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secondary to high-dose nebulized corticosteroid. Pediatr Pulmonol. 2002;34(1):85-86.
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adrenal crisis associated with inhaled corticosteroids in the United Kingdom. Archives of
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Polymorphisms in Patients Receiving Salmeterol with or without Fluticasone Propionate.
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Appendix A. Glossary
Following is a listing of terms commonly used in reports produced by the Drug Effectiveness
Review Project as they apply to these reports. For that reason, some definitions may vary
slightly from other published definitions.
Adherence: Following the course of treatment proscribed by a study protocol.
Adverse effect: An adverse event for which the causal relation between the drug/intervention and
the event is at least a reasonable possibility.
Adverse event: An adverse outcome that occurs during or after the use of a drug or other
intervention but is not necessarily caused by it.
Active-control trial: A trial comparing a drug in a particular class or group to another drug
outside of that class or group.
Allocation concealment: The process by which the person determining randomization is blinded
to a study participant’s group allocation.
Before-after study: A type non-randomized study where data are collected before and after
patients receive an intervention. Before-after studies can have a single arm or can include a
control group.
Bias: A systematic error or deviation in results or inferences from the truth. Several types of bias
can appear in published trials, including selection bias, performance bias, detection bias and
reporting bias.
Blinding: The process of preventing those involved in a trial from knowing to which comparison
group a particular participant belongs. Trials are frequently referred to as “double-blind” without
further describing if this refers to patients, caregivers, investigators or other study staff.
Case series: A study reporting observations on a series of patients, all receiving the same
intervention with no control group.
Case study: A study reporting observations on a single patient.
Case-control study: A study that compares people with a specific disease or outcome of interest
(cases) to people from the same population without that disease or outcome (controls).
Clinically significant: A result that is large enough to affect a patient’s disease state in a manner
that is noticeable to a patient and/or caregiver.
Cohort study: An observational study in which a defined group of people (the cohort) is followed
over time and compared to a group of people who were exposed or not exposed to a
particular intervention or other factor of interest. A prospective cohort study assembles
participants and follows them into the future. A retrospective cohort study identifies subjects
from past records and follows them from the time of those records to the present.
Confidence interval: The range of values calculated from the data such that there is a level of
confidence, or certainty, that it contains the true value. The 95% confidence interval is generally
used in DERP reports.
Confounder: A factor that is associated with both an intervention and an outcome of interest.
Controlled clinical trial: A clinical trial that includes a control group but no or inadequate
methods of randomization.
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Convenience sample: A group of individuals being studied because they are conveniently
accessible in some way. Convenience samples may or may not be representative of a population
that would normally be receiving an intervention.
Cross-over trial: A type of clinical trial comparing two or more interventions in which the
participants, upon completion of the course of one treatment, are switched to another.
Direct analysis: The practice of using data from head-to-head trials to draw conclusions about
the comparative effectiveness of drugs within a class or group. Results of direct analysis are the
preferred source of data in DERP reports.
Dose-response relationship: The relationship between the quantity of treatment given and its
effect on outcome. In meta-analysis, dose-response relationships can be investigated using metaregression.
Double-blind: The process of preventing those involved in a trial from knowing to which
comparison group a particular participant belongs. While double-blind is a frequently used term
in trials, its meaning can vary to include blinding of patients, caregivers, investigators and/or
other study staff.
Double-dummy: The use of two placebos in a trial that match the active interventions when they
vary in appearance or method of administrations (for example, an oral agent compared to an
injectable agent).
Effectiveness: The extent to which a specific intervention, when used under ordinary
circumstances, does what it is intended to do.
Effectiveness outcomes: Those outcomes that are generally important to patients and caregivers,
such as quality of life, hospitalizations and ability to work. Data on effectiveness outcomes
usually comes from longer-term studies of a “real-world” population.
Efficacy: The extent to which an intervention produces a beneficial result under ideal conditions
in a selected and controlled population.
Estimate of effect: The observed relationship between an intervention and an outcome. Estimate
of effect can be expressed in a number of ways, including number needed to treat, odds ratio, risk
difference and risk ratio.
Equivalence trial: A trial designed to determine whether the response to two or more treatments
differs by an amount that is clinically unimportant. This is usually demonstrated by showing that
the true treatment difference is likely to lie between a lower and an upper equivalence level of
clinically acceptable differences.
External validity: The extent to which reported results are generalizable to a relevant population.
Fixed-effect model: A model that calculates a pooled effect estimate using the assumption that all
observed variation between studies is caused by the play of chance. Studies are assumed to be
measuring the same overall effect. An alternative model is the random-effects model.
Forest plot: A graphical representation of the individual results of each study included in a metaanalysis together with the combined meta-analysis result. The plot also allows readers to see the
heterogeneity among the results of the studies. The results of individual studies are shown as
squares centered on each study’s point estimate. A horizontal line runs through each square to
show each study’s confidence interval - usually, but not always, a 95% confidence interval. The
overall estimate from the meta-analysis and its confidence interval are shown at the bottom,
represented as a diamond. The centre of the diamond represents the pooled point estimate, and its
horizontal tips represent the confidence interval.
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Funnel plot: A graphical display of some measure of study precision plotted against effect size
that can be used to investigate whether there is a link between study size and treatment effect.
Generalizability: see External Validity
Hazard ratio: The increased risk with which one group is likely to experience an outcome of
interest. It is similar to a risk ratio. For example, if the hazard ratio for death for a treatment is
0.5, then we can say that treated patients are likely to die at half the rate of untreated patients.
Head-to-head trial: A trial that directly compares one drug in a particular class or group to
another in the same class or group.
Heterogeneity: The variation in, or diversity of, participants, interventions, and measurement of
outcomes across a set of studies.
Indirect analysis: The practice of using data from trials comparing one drug in a particular class
or group to another drug outside of that class or group or to placebo and attempting to draw
conclusions about the comparative effectiveness of drugs within a class or group based on that
data. For example, using direct comparisons between drugs A and B and between drugs B and C
to make indirect comparisons between drugs A and C.
Intention to treat (ITT): The use of data from a randomized controlled trial in which data from all
randomized patients are accounted for in the final results. Trials often report results as being
based on ITT despite the fact that some patients are excluded from the analysis.
Internal validity: The extent to which the design and conduct of a study are likely to have
prevented bias. Generally, the higher the interval validity, the better the quality of the study
publication.
Inter-rater reliability: The degree of stability exhibited when a measurement is repeated under
identical conditions by different raters.
Intermediate outcome: An outcome not of direct practical importance but believed to reflect
outcomes that are important. For example, blood pressure is not directly important to patients but
it is often used as an outcome in clinical trials because it is a risk factor for stroke and heart
attacks.
Logistic regression: A form of regression analysis that models an individual's odds of disease or
some other outcome as a function of a risk factor or intervention.
Mean difference: A method used to combine measures on continuous scales (such as weight),
where the mean, standard deviation and sample size in each group are known.
Meta-analysis: The use of statistical techniques in a systematic review to integrate the results of
included studies. Although they are sometimes used interchangeably, meta-analyses are not
synonymous with systematic reviews. However, systematic reviews often include meta-analyses.
Meta-regression: A technique used to explore the relationship between study characteristics (e.g.
concealment of allocation, baseline risk, timing of the intervention) and study results (the
magnitude of effect observed in each study) in a systematic review.
Multivariate analysis: Measuring the impact of more than one variable at a time while analyzing
a set of data.
N of 1 trial: A randomized trial in an individual to determine the optimum treatment for that
individual.
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Non-inferiority trial: A trial designed to determine whether the effect of a new treatment is not
worse than a standard treatment by more than a pre-specified amount. A one-sided version of an
equivalence trial.
Non-randomized study: Any study estimating the effectiveness of an intervention (harm or
benefit) that does not use randomization to allocate patients to comparison groups. There are
many possible types of non-randomized studies, including cohort studies, case-control studies,
and before -after studies.
Null hypothesis: The statistical hypothesis that one variable (e.g. which treatment a study
participant was allocated to receive) has no association with another variable or set of variables.
Number needed to treat (NNT): An estimate of how many people need to receive a treatment
before one person would experience a beneficial outcome.
Observational study: A type of non-randomized study in which the investigators do not seek to
intervene, and simply observe the course of events.
Odds ratio (OR): The ratio of the odds of an event in one group to the odds of an event in
another group. An odds ratio of 1.0 indicates no difference between comparison groups. For
undesirable outcomes an OR that is < 1.0 indicates that the intervention was effective in reducing
the risk of that outcome.
One-tailed test : A hypothesis test in which the values for which we can reject the null
hypothesis are located entirely in one tail of the probability distribution. For example, testing
whether one treatment is better than another (rather than testing whether one treatment is either
better or worse than another).
Open-label trial: A clinical trial in which the investigator and participant are aware which
intervention is being used for which participant (i.e. not blinded). Random allocation may or may
not be used in open-label trials.
Per protocol: The subset of participants from a randomized controlled trial who complied with
the protocol sufficiently to ensure that their data would be likely to exhibit the effect of
treatment. Per protocol analyses are sometimes misidentified in published trials as ITT.
Point estimate: The results (e.g. mean, weighted mean difference, odds ratio, risk ratio or risk
difference) obtained in a sample (a study or a meta-analysis) which are used as the best estimate
of what is true for the relevant population from which the sample is taken.
Pooling: The practice of combing data from several studies to draw conclusions regarding
treatment effects.
Power: The probability that a trial will detect statistically significant differences among
intervention effects. Studies with small sample sizes can frequently be underpowered to detect
difference.
Precision: The likelihood of random errors in the results of a study, meta-analysis or
measurement. The greater the precision, the less random error. Confidence intervals around the
estimate of effect from each study are one way of expressing precision, with a narrower
confidence interval meaning more precision.
Prospective study: A study in which people are identified according to current risk status or
exposure, and followed forwards through time to observe outcome.
Publication bias: A bias caused by only a subset of all the relevant data being available. The
publication of research can depend on the nature and direction of the study results. Studies in
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which an intervention is not found to be effective are sometimes not published. Because of this,
systematic reviews that fail to include unpublished studies may overestimate the true effect of an
intervention. In addition, a published report might present a biased set of results (e.g. only
outcomes or sub-groups where a statistically significant difference was found.
P-value: The probability (ranging from zero to one) that the results observed in a study could
have occurred by chance if in reality the null hypothesis was true. A P value of ≤ 0.05 is often
used as a threshold to indicate statistical significance.
Random-effects model: A statistical model in which both within-study sampling error (variance)
and between-studies variation are included in the assessment of the uncertainty (confidence
interval) of the results of a meta-analysis. When there is heterogeneity among the results of the
included studies beyond chance, random-effects models will give wider confidence intervals than
fixed-effect models.
Randomization: The process by which study participants are allocated to treatment groups in a
trial. Adequate (i.e. unbiased) methods of randomization include computer generated schedules
and random numbers tables.
Randomized controlled trial (RCT): A trial in which two or more interventions are compared
through random allocation of participants.
Regression analysis: A statistical modelling technique used to estimate or predict the influence
of one or more independent variables on a dependent variable, e.g. the effect of age, sex, and
confounding disease on the effectiveness of an intervention.
Relative risk (RR): The ratio of risks in two groups; same as a risk ratio.
Retrospective study: A study in which the outcomes have occurred prior to study entry.
Risk difference: The difference in size of risk between two groups.
Risk ratio (RR): The ratio of risks in two groups. In intervention studies, it is the ratio of the risk
in the intervention group to the risk in the control group. A risk ratio of one indicates no
difference between comparison groups. For undesirable outcomes, a risk ratio that is <1 indicates
that the intervention was effective in reducing the risk of that outcome.
Sensitivity analysis: An analysis used to determine how sensitive the results of a study or
systematic review are to changes in how it was done. Sensitivity analyses are used to assess how
robust the results are to uncertain decisions or assumptions about the data and the methods that
were used.
Standard deviation (SD): A measure of the spread or dispersion of a set of observations,
calculated as the average difference from the mean value in the sample.
Standard error (SE): A measure of the variation in the sample statistic over all possible samples
of the same size. The standard error decreases as the sample size increases.
Statistically significant (SS): A result that is unlikely to have happened by chance.
Subgroup analysis: An analysis in which an intervention is evaluated in a defined subset of the
participants in a trial, such as by sex or in age categories.
Superiority trial: A trial designed to test if one intervention is superior to another.
Systematic review: A review of a clearly formulated question that uses systematic and explicit
methods to identify, select, and critically appraise relevant research, and to collect and analyze
data from the studies that are included in the review.
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Tolerability: Unpleasant adverse effects of drugs that are usually transient and not clinically
significant, although they can affect a person’s quality of life and willingness to continue a
treatment.
Type I error: A conclusion that there is evidence that a treatment works, when it actually does
not work (false-positive).
Type II error: A conclusion that there is no evidence that a treatment works, when it actually
does work (false-negative).
Validity: The degree to which a result (of a measurement or study) is likely to be true and free of
bias (systematic errors).
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Appendix B. Abbreviations
Abbreviaton
ACTH
AD
AQLQ
ARF
BDP
BMD
BUD
CFC
CI
CIC
COPD
DPI
ED
FD
FEV1
FLUN
FP
FM
FVC
GINA
HFA
HPA
HR
ICS
IS
ITT
LABA
LM
LOCF
LTRA
LTSI
MART
MDI
MOM
ML
NAEPP
NHLBI
NA
NR
NS
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Term
adrenocorticotropin hormone
adjustable dosing
Asthma Quality of Life Questionnaire
Arformoterol
beclomethasone dipropionate
bone mineral density
budesonide
chlorofluorocarbon
confidence interval
ciclesonide
chronic obstructive pulmonary disease
dry powder inhaler
emergency department
fixed dosing
forced expired volume in one second
flunisolide
fluticasone propionate
formoterol
forced vital capacity
Global Initiative for Asthma
hydrofluoroalkane
hypothalamo-pituitary-adrenal
hazard ratio
inhaled corticosteroid
inhalation suspension
intent to treat
long-acting beta-agonist
leukotriene modifiers
last observation carried forward
leukotriene receptor antagonist
leukotriene synthesis inhibitor
maintenance and reliever therapy
metered dose inhaler
mometasone
montelukast
National Asthma Education and Prevention Program
National Heart, Lung and Blood Institute
not applicable
not reported
not statistically significant
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Abbreviaton
OCS
OM
OR
PEF
pMDI
QOL
RR
SF-36
SGRQ
SM
SMART
SMD
TAA
WMD
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Term
oral corticosteroids
omalizumab
odds ratio
peak expiratory flow
pressurized metered dose inhaler
quality of life
relative risk
Medical Outcomes Study Short Form-36
St. George Respiratory Questionnaire
salmeterol
Symbicort® maintenance and reliever therapy
standard mean difference (standard difference in means)
triamcinolone acetonide
weighted mean difference
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Appendix C. Boxed warnings
Trade name
Qvar®
Vanceril®
Pulmicort
®
Turbuhaler
Pulmicort
Flexhaler®
Pulmicort
Respules®
Pulmicort
®
Nebuamp
®
AeroBid
AeroBid-M®
AeroSpan®
Bronalide®
Flovent®
Flovent
Rotadisk®
Flovent Diskus®
Flovent HFA®
Azmacort®
Asmanex
Twisthaler®
Alvesco®
Active ingredient(s)
Beclomethasone
Beclomethasone
Boxed warnings
No Box
No Box
Budesonide
No Box
Budesonide
No Box
Budesonide
No Box
Budesonide
No Box
Flunisolide
Flunisolide
Flunisolide
Flunisolide
Fluticasone
No Box
No Box
No Box
No Box
No Box
Fluticasone
No Box
Fluticasone
Fluticasone
Triamcinolone
No Box
No Box
No Box
Mometasone
No Box
Ciclesonide
Foradil®
Formoterol
No Box
Long-acting beta2-adrenergic agonists (LABA), such as formoterol the active ingredient in FORADIL, increase the
risk of asthma-related death. Data from a large placebo-controlled US study that compared the safety of another
LABA (salmeterol) or placebo added to usual asthma therapy showed an increase in asthma-related deaths in
patients receiving salmeterol. This finding with salmeterol is considered a class effect of LABA, including
formoterol. Currently available data are inadequate to determine whether concurrent use of inhaled corticosteroids
or other long-term asthma control drugs mitigates the increased risk of asthma-related death from LABA. Because
of this risk, use of FORADIL for the treatment of asthma without a concomitant long-term asthma control
medication, such as an inhaled corticosteroid, is contraindicated. Use FORADIL only as additional therapy for
patients with asthma who are currently taking but are inadequately controlled on a long-term asthma control
medication, such as an inhaled corticosteroid. Once asthma control is achieved and maintained, assess the patient
at regular intervals and step down therapy (e.g. discontinue FORADIL) if possible without loss of asthma control,
and maintain the patient on a long-term asthma control medication, such as an inhaled corticosteroid. Do not use
FORADIL for patients whose asthma is adequately controlled on low or medium dose inhaled corticosteroids.
Controller medications for asthma
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Trade name
Active ingredient(s)
Certihaler®
Formoterol
Foradil Aerolizer®
Formoterol
Oxis®
Eformoterol
Perforomist®
Formoterol
Controller medications for asthma
Boxed warnings
Long-acting beta2-adrenergic agonists (LABA), such as formoterol the active ingredient in CERTIHALER, increase
the risk of asthma-related death. Data from a large placebo-controlled US study that compared the safety of
another LABA (salmeterol) or placebo added to usual asthma therapy showed an increase in asthma-related
deaths in patients receiving salmeterol. This finding with salmeterol is considered a class effect of LABA, including
formoterol. Currently available data are inadequate to determine whether concurrent use of inhaled corticosteroids
or other long-term asthma control drugs mitigates the increased risk of asthma-related death from LABA. Because
of this risk, use of CERTIHALER for the treatment of asthma without a concomitant long-term asthma control
medication, such as an inhaled corticosteroid, is contraindicated. Use CERTIHALER only as additional therapy for
patients with asthma who are currently taking but are inadequately controlled on a long-term asthma control
medication, such as an inhaled corticosteroid. Once asthma control is achieved and maintained, assess the patient
at regular intervals and step down therapy (e.g. discontinue CERTIHALER) if possible without loss of asthma
control, and maintain the patient on a long-term asthma control medication, such as an inhaled corticosteroid. Do
not use CERTIHALER for patients whose asthma is adequately controlled on low or medium dose inhaled
corticosteroids.
Long-acting beta2-adrenergic agonists (LABA), such as formoterol the active ingredient in FORADIL AEROLIZER,
increase the risk of asthma-related death. Data from a large placebo-controlled US study that compared the safety
of another LABA (salmeterol) or placebo added to usual asthma therapy showed an increase in asthma-related
deaths in patients receiving salmeterol. This finding with salmeterol is considered a class effect of LABA, including
formoterol. Currently available data are inadequate to determine whether concurrent use of inhaled corticosteroids
or other long-term asthma control drugs mitigates the increased risk of asthma-related death from LABA. Because
of this risk, use of FORADIL AEROLIZER for the treatment of asthma without a concomitant long-term asthma
control medication, such as an inhaled corticosteroid, is contraindicated. Use FORADIL AEROLIZER only as
additional therapy for patients with asthma who are currently taking but are inadequately controlled on a long-term
asthma control medication, such as an inhaled corticosteroid. Once asthma control is achieved and maintained,
assess the patient at regular intervals and step down therapy (e.g. discontinue FORADIL AEROLIZER) if possible
without loss of asthma control, and maintain the patient on a long-term asthma control medication, such as an
inhaled corticosteroid. Do not use FORADIL AEROLIZER for patients whose asthma is adequately controlled on
low or medium dose inhaled corticosteroids.
No Box (not available in the US or Canada)
Long-acting beta2-adrenergic agonists (LABA) increase the risk of asthma-related death. Data from a large
placebo-controlled US study that compared the safety of another long-acting beta2-adrenergic agonist (salmeterol)
or placebo added to usual asthma therapy showed an increase in asthma-related deaths in patients receiving
salmeterol. This finding with salmeterol is considered a class effect of LABA, including formoterol, the active
ingredient in PERFOROMIST Inhalation Solution. The safety and efficacy of PERFOROMIST in patients with
asthma have not been established. All LABA, including PERFOROMIST, are contraindicated in patients with
asthma without use of a long-term asthma control medication.
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Trade name
Active ingredient(s)
Oxeze
Turbuhaler®
Formoterol
Brovana®
Arformoterol
Serevent®
Salmeterol
Serevent
Diskhaler®
Salmeterol
Controller medications for asthma
Boxed warnings
Data from a large placebo-controlled US study (Salmeterol Multi-center Asthma Research Trial) comparing the
safety of the long-acting beta2-adrenergic agonist salmeterol to that of a placebo added to the original asthma
therapy showed an increase in asthma-related deaths in patients receiving salmeterol. Although the trial results
were specific to salmeterol, one of the conclusions derived from this study is that long-acting beta2-adrenergic
agonists may increase the risk of asthma exacerbation and possibly asthma-related death. Although available data
for formoterol fumarate dihydrate do not suggest increased risk, it cannot be excluded that the findings with
salmeterol may apply to all longacting beta2-adrenergic agonists including formoterol fumarate dihydrate, the
active ingredient in OXEZE TURBUHALER. When treating asthma patients, OXEZE TURBUHALER should be
used only as additional therapy for patients whose conditions are not adequately controlled using low-to-medium
dose inhaled corticosteroids or whose disease severity clearly warrants the initiation of treatment with two
maintenance therapies, i.e. OXEZE TURBUHALER in addition to an inhaled corticosteroid. (Canadian labeling)
Long-acting beta2 –adrenergic agonists (LABA) increase the risk of asthma-related death. Data from a large
placebo-controlled US study that compared the safety of another long-acting beta2 –adrenergic agonist
(salmeterol) or placebo added to usual asthma therapy showed an increase in asthma-related deaths in patients
receiving salmeterol. This finding with salmeterol is considered a class effect of LABA, including arformoterol, the
active ingredient in BROVANA . The safety and efficacy of BROVANA in patients with asthma have not been
established. All LABA, including BROVANA, are contraindicated in patients with asthma without the use of a longterm asthma control medications
Long-acting beta2-agonists (LABAs), such as salmeterol, the active ingredient in SEREVENT, increase the risk of
asthma-related death. Currently available data are inadequate to determine whether concurrent use of inhaled
corticosteroids or other long-term asthma control drugs mitigates the increased risk of asthma-related death from
LABA. Because of this risk, use of SEREVENT for the treatment of asthma without concomitant use of a long-term
asthma control medication, such as an inhaled corticosteroid, is contraindicated. Use SEREVENT only as
additional therapy for patients with asthma who are currently taking but are inadequately controlled on a long-term
asthma control medication, such as an inhaled corticosteroid. Once asthma control is achieved and maintained,
assess the patient at regular intervals and step down therapy (e.g., discontinue SEREVENT) if possible without
loss of asthma control and maintain the patient on a long-term asthma control medication, such as an inhaled
corticosteroid. Do not use SEREVENT for patients whose asthma is adequately controlled on low- or medium-dose
inhaled corticosteroids.
Long-acting beta2-agonists (LABAs), such as salmeterol, the active ingredient in SEREVENT DISKHALER,
increase the risk of asthma-related death. Currently available data are inadequate to determine whether
concurrent use of inhaled corticosteroids or other long-term asthma control drugs mitigates the increased risk of
asthma-related death from LABA. Because of this risk, use of SEREVENT DISKHALER for the treatment of
asthma without concomitant use of a long-term asthma control medication, such as an inhaled corticosteroid, is
contraindicated. Use SEREVENT DISKHALER only as additional therapy for patients with asthma who are
currently taking but are inadequately controlled on a long-term asthma control medication, such as an inhaled
corticosteroid. Once asthma control is achieved and maintained, assess the patient at regular intervals and step
down therapy (e.g., discontinue SEREVENT DISKHALER) if possible without loss of asthma control and maintain
the patient on a long-term asthma control medication, such as an inhaled corticosteroid. Do not use SEREVENT
DISKHALER for patients whose asthma is adequately controlled on low- or medium-dose inhaled corticosteroids.
220 of 369
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Trade name
Active ingredient(s)
Serevent Diskus®
Salmeterol
Singulair®
Accolate®
Zyflo®
ZyfloCR®
Montelukast
Zafirlukast
Zileuton
Zileuton
Xolair®
Omalizumab
Controller medications for asthma
Boxed warnings
Long-acting beta2-agonists (LABAs), such as salmeterol, the active ingredient in SEREVENT DISKUS, increase
the risk of asthma-related death. Currently available data are inadequate to determine whether concurrent use of
inhaled corticosteroids or other long-term asthma control drugs mitigates the increased risk of asthma-related
death from LABA. Because of this risk, use of SEREVENT DISKUS for the treatment of asthma without
concomitant use of a long-term asthma control medication, such as an inhaled corticosteroid, is contraindicated.
Use SEREVENT DISKUS only as additional therapy for patients with asthma who are currently taking but are
inadequately controlled on a long-term asthma control medication, such as an inhaled corticosteroid. Once asthma
control is achieved and maintained, assess the patient at regular intervals and step down therapy (e.g.,
discontinue SEREVENT DISKUS) if possible without loss of asthma control and maintain the patient on a longterm asthma control medication, such as an inhaled corticosteroid. Do not use SEREVENT DISKUS for patients
whose asthma is adequately controlled on low- or medium-dose inhaled corticosteroids.
No Box
No Box
No Box
No Box
Anaphylaxis has been reported to occur after administration of Xolair in premarketing clinical trials and in
postmarketing spontaneous reports. Signs and symptoms in these reported cases have included bronchospasm,
hypotension, syncope, urticaria, and/or angioedema of the throat or tongue. Some of these events have been lifethreatening. In premarketing clinical trials the frequency of anaphylaxis attributed to Xolair use was estimated to be
0.1%. In postmarketing spontaneous reports, the frequency of anaphylaxis attributed to Xolair use was estimated
to be at least 0.2% of patients based on an estimated exposure of about 57,300 patients from June 2003 through
December 2006. Anaphylaxis has occurred as early as after the first dose of Xolair, but also has occurred beyond
one year after beginning regularly scheduled treatment. Administer Xolair only in a healthcare setting by
healthcare providers prepared to manage anaphylaxis that can be life-threatening. Observe patients closely for an
appropriate period of time after administration of Xolair, taking into account the time to onset of anaphylaxis seen
in premarketing clinical trials and postmarketing spontaneous reports [see Adverse Reactions (6)]. Inform patients
of the signs and symptoms of anaphylaxis, and instruct them to seek immediate medical care should signs or
symptoms occur. Discontinue Xolair in patients who experience a severe hypersensitivity reaction [see
Contraindications (4)].
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Trade name
Active ingredient(s)
Advair®
Fluticasone
propionate/Salmeterol
xinafoate
Advair Diskus®
Fluticasone
propionate/Salmeterol
xinafoate
Advair HFA®
Fluticasone
propionate/Salmeterol
xinafoate
Controller medications for asthma
Boxed warnings
Long-acting beta2-agonists (LABAs), such as salmeterol, one of the active ingredients in ADVAIR, increase the
risk of asthma-related death. Currently available data are inadequate to determine whether concurrent use of
inhaled corticosteroids or other long-term asthma control drugs mitigates the increased risk of asthma-related
death from LABAs. Available data from controlled clinical trials suggest that LABAs increase the risk of asthmarelated hospitalization in pediatric and adolescent patients. Therefore, when treating patients with asthma,
physicians should only prescribe ADVAIR for patients not adequately controlled on a long-term asthma-control
medication, such as an inhaled corticosteroid, or whose disease severity clearly warrants initiation of treatment
with both an inhaled corticosteroid and a LABA. Once asthma control is achieved and maintained, assess the
patient at regular intervals and step down therapy (e.g., discontinue ADVAIR) if possible without loss of asthma
control and maintain the patient on a long-term asthma control medication, such as an inhaled corticosteroid. Do
not use ADVAIR for patients whose asthma is adequately controlled on low- or medium-dose inhaled
corticosteroids.
Long-acting beta2-agonists (LABAs), such as salmeterol, one of the active ingredients in ADVAIR DISKUS,
increase the risk of asthma-related death. Currently available data are inadequate to determine whether
concurrent use of inhaled corticosteroids or other long-term asthma control drugs mitigates the increased risk of
asthma-related death from LABAs. Available data from controlled clinical trials suggest that LABAs increase the
risk of asthma-related hospitalization in pediatric and adolescent patients. Therefore, when treating patients with
asthma, physicians should only prescribe ADVAIR DISKUS for patients not adequately controlled on a long-term
asthma-control medication, such as an inhaled corticosteroid, or whose disease severity clearly warrants initiation
of treatment with both an inhaled corticosteroid and a LABA. Once asthma control is achieved and maintained,
assess the patient at regular intervals and step down therapy (e.g., discontinue ADVAIR DISKUS) if possible
without loss of asthma control and maintain the patient on a long-term asthma control medication, such as an
inhaled corticosteroid. Do not use ADVAIR DISKUS for patients whose asthma is adequately controlled on low- or
medium-dose inhaled corticosteroids.
Long-acting beta2-agonists (LABAs), such as salmeterol, one of the active ingredients in ADVAIR HFA, increase
the risk of asthma-related death. Currently available data are inadequate to determine whether concurrent use of
inhaled corticosteroids or other long-term asthma control drugs mitigates the increased risk of asthma-related
death from LABAs. Available data from controlled clinical trials suggest that LABAs increase the risk of asthmarelated hospitalization in pediatric and adolescent patients. Therefore, when treating patients with asthma,
physicians should only prescribe ADVAIR HFA for patients not adequately controlled on a long-term asthmacontrol medication, such as an inhaled corticosteroid, or whose disease severity clearly warrants initiation of
treatment with both an inhaled corticosteroid and a LABA. Once asthma control is achieved and maintained,
assess the patient at regular intervals and step down therapy (e.g., discontinue ADVAIR HFA) if possible without
loss of asthma control and maintain the patient on a long-term asthma control medication, such as an inhaled
corticosteroid. Do not use ADVAIR HFA for patients whose asthma is adequately controlled on low- or mediumdose inhaled corticosteroids.
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Trade name
Active ingredient(s)
Symbicort®
Budesonide/formoterol
Symbicort
Turbuhaler®
Budesonide/formoterol
Spiriva®
Tiotropium
Controller medications for asthma
Boxed warnings
Long-acting beta2-adrenergic agonists, such as formoterol, one of the active ingredients in SYMBICORT, increase
the risk of asthma-related death. Currently available data are inadequate to determine whether concurrent use of
inhaled corticosteroids or other long-term asthma control drugs mitigates the increased risk of asthma-related
death from LABA. Available data from controlled clinical trials suggest that LABA increase the risk of asthmarelated hospitalization in pediatric and adolescent patients. Therefore, when treating patients with asthma,
SYMBICORT should only be used for patients not adequately controlled on a long-term asthma-control
medication, such as an inhaled corticosteroid or whose disease severity clearly warrants initiation of treatment with
both an inhaled corticosteroid and LABA. Once asthma control is achieved and maintained, assess the patient at
regular intervals and step down therapy (e.g. discontinue SYMBICORT) if possible without loss of asthma control,
and maintain the patient on a long-term asthma control medication, such as an inhaled corticosteroid. Do not use
SYMBICORT for patients whose asthma is adequately controlled on low or medium dose inhaled corticosteroids.
Long-acting beta2-adrenergic agonists, such as formoterol, one of the active ingredients in SYMBICORT
TURBUHALER, increase the risk of asthma-related death. Currently available data are inadequate to determine
whether concurrent use of inhaled corticosteroids or other long-term asthma control drugs mitigates the increased
risk of asthma-related death from LABA. Available data from controlled clinical trials suggest that LABA increase
the risk of asthma-related hospitalization in pediatric and adolescent patients. Therefore, when treating patients
with asthma, SYMBICORT TURBUHALER should only be used for patients not adequately controlled on a longterm asthma-control medication, such as an inhaled corticosteroid or whose disease severity clearly warrants
initiation of treatment with both an inhaled corticosteroid and LABA. Once asthma control is achieved and
maintained, assess the patient at regular intervals and step down therapy (e.g. discontinue SYMBICORT
TURBUHALER) if possible without loss of asthma control, and maintain the patient on a long-term asthma control
medication, such as an inhaled corticosteroid. Do not use SYMBICORT TURBUHALER for patients whose asthma
is adequately controlled on low or medium dose inhaled corticosteroids.
No Box
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Appendix D. Labeled and delivered doses
Examples of variation in labeled and delivered doses of inhaled asthma controller
medications
Labeled Dose
(mcg)
“Ex-Valve” Dose
(mcg)
“Ex-Actuator Dose”
(Delivered Dose, mcg)
100/50
250/50
500/50
100/50
250/50
500/50
93/45
233/45
465/45
80
160
100
200
80
160
50
100
250
44
110
220
50
100
250
50
125
250
46
94
229
44
110
220
Foradil Aerolizer® DPI (formoterol)
12
12
10
Pulmicort Flexhaler® (budesonide)
180
90
180
90
160
80
QVAR® HFA (beclomethasone)
40
80
50
100
40
80
Serevent Diskus® (salmeterol)
50
50
47
Serevent® Inhalation Aerosol (salmeterol)
21
25
21
100/6
200/6
100/6
200/6
80/4.5
160/4.5
80/4.5
160/4.5
91/5.1
181/5.1
80/4.5
160/4.5
Brand Name/Product (Generic Name)
Advair Diskus® DPI (fluticasone/salmeterol)
Alvesco® (ciclesonide)
Flovent Diskus® (fluticasone)
Flovent® HFA (fluticasone)
Symbicort Turbuhaler® (budesonide/formoterol)
*Available in Canada*
Symbicort® (budesonide/formoterol)
Controller medications for asthma
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Appendix E. Search strategies
Original Report
#3 Search "Asthma"[Majr]
65353
#4 Search "Asthma"[Majr] Limits: Publication Date from 1990, Humans,
30878
English
#12 Search "inhaled corticosteroids" OR "Beclomethasone"[Mesh] OR qvar
14453
OR vanceril OR "Budesonide"[Mesh] OR pulmicort OR "flunisolide
"[Substance Name] OR aerobid OR aerospan OR bronalide OR
"fluticasone "[Substance Name] OR flovent OR "Triamcinolone"[Mesh]
OR azmacort OR "mometasone furoate "[Substance Name] OR asmanex
#13 Search #4 AND #12
3191
#14 Search ("Randomized Controlled Trials"[MeSH] OR "Randomized
342286
Controlled Trial"[Publication Type]) OR "Single-Blind Method"[MeSH]
OR "Double-Blind Method"[MeSH] OR "Random Allocation"[MeSH]
#15 Search #13 AND #14
1352
#16 Search ("Case-Control Studies"[MeSH] OR "Cohort Studies"[MeSH] OR 959680
"Cross-Sectional Studies"[MeSH] OR "Follow-Up Studies"[MeSH] OR
"Longitudinal Studies"[MeSH] OR "Retrospective Studies"[MeSH] OR
observational studies
#17 Search #13 AND #16
581
#23 Search ("Adrenergic beta-Agonists"[Mesh] AND "long acting") OR
2104
"formoterol "[Substance Name] OR foradil OR oxis OR perforomist OR
"salmeterol "[Substance Name] OR serevent
#24 Search #4 AND #23
1018
#25 Search #24 AND #14
546
#26 Search #24 AND #16
104
#34 Search "Leukotriene Antagonists"[Mesh] OR "montelukast "[Substance
2574
Name] OR singulair OR "zafirlukast "[Substance Name] OR accolate OR
"zileuton "[Substance Name] OR zyflo OR "pranlukast "[Substance
Name] OR onon
#35 Search #4 AND #34
954
#36 Search #14 AND #35
323
#37 Search #16 AND #35
91
#39 Search Anti-IgE OR "omalizumab "[Substance Name] OR xolair
2448
#40 Search #4 AND #39
245
#41 Search #40 AND #14
51
#42 Search #40 AND #16
8
#45 Search "fluticasone-salmeterol combination "[Substance Name] OR
3140
"fluticasone propionate - salmeterol combination "[Substance Name] OR
advair OR budesonide-formoterol OR "symbicort "[Substance Name]
Controller medications for asthma
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#46 Search #4 AND #45
#47 Search #46 AND #14
#48 Search #46 AND #16
#49 Search #15 OR #17 OR #25 OR #26 OR #36 OR #37 OR #41 OR #42 OR
#47 OR #48
1017
544
163
2305
COCHRANE = 46 = 34 NEW
EMBASE =
1. Inhaled Corticosteroids = 445 = 103 NEW
2. LABAs = 232 = 29 NEW
3. LTRAs = 134 = 14 NEW
4. Anti-IgE = 0
5. Combination Studies =5 = 0 NEW
IPA =
1. Inhaled Corticosteroids = 40 = 32 NEW
2. LABAs = 34 = 31 NEW
3. LTRAs = 1 = 0 NEW
4. Anti-IgE = 8 = 8 NEW
5. Combination Studies = 22 = 15 NEW
NEW TOTAL DATABASE = 2571
#1 Search "Asthma"[Majr]
67440
#2 Search "Asthma"[Majr] Limits: added to PubMed in the last 1 year, Humans,
1705
English
#3 Search "inhaled corticosteroids" OR "Beclomethasone"[Mesh] OR qvar OR
15093
vanceril OR "Budesonide"[Mesh] OR pulmicort OR "flunisolide "[Substance
Name] OR aerobid OR aerospan OR bronalide OR "fluticasone "[Substance Name]
OR flovent OR "Triamcinolone"[Mesh] OR azmacort OR "mometasone furoate
"[Substance Name] OR asmanex
#4 Search #2 AND #3
187
#5 Search ("Randomized Controlled Trials"[MeSH] OR "Randomized Controlled
315353
Trial"[Publication Type]) OR "Single-Blind Method"[MeSH] OR "Double-Blind
Method"[MeSH] OR "Random Allocation"[MeSH]
#6 Search #4 AND #5
55
#7 Search ("Case-Control Studies"[MeSH] OR "Cohort Studies"[MeSH] OR "Cross- 1017347
Sectional Studies"[MeSH] OR "Follow-Up Studies"[MeSH] OR "Longitudinal
Studies"[MeSH] OR "Retrospective Studies"[MeSH] OR observational studies
#8 Search #4 AND #7
31
#9 Search ("Adrenergic beta-Agonists"[Mesh] AND "long acting") OR "formoterol
2263
"[Substance Name] OR foradil OR oxis OR perforomist OR "salmeterol
"[Substance Name] OR serevent
Controller medications for asthma
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#10 Search #2 AND #9
#11 Search #10 AND #5
#12 Search #10 AND #7
#13 Search "Leukotriene Antagonists"[Mesh] OR "montelukast "[Substance Name] OR
singulair OR "zafirlukast "[Substance Name] OR accolate OR "zileuton
"[Substance Name] OR zyflo OR "pranlukast "[Substance Name] OR onon
#14 Search #2 AND #13
#15 Search #14 AND #5
#16 Search #14 AND #7
#17 Search Anti-IgE OR "omalizumab "[Substance Name] OR xolair
#18 Search #2 AND #17
#19 Search #18 AND #5
#20 Search #18 AND #7
#21 Search "fluticasone-salmeterol combination "[Substance Name] OR "fluticasone
propionate - salmeterol combination "[Substance Name] OR advair OR
budesonide-formoterol OR "symbicort "[Substance Name]
#22 Search #2 AND #21
#23 Search #22 AND #5
#24 Search #22 AND #7
#25 Search #6 OR #8 OR #11 OR #12 OR #15 OR #16 OR #19 OR #20 OR #23 OR
#24
60
21
6
2702
52
23
10
2545
37
2
2
198
16
10
0
101
PUBMED = 86 new
COCHRANE = 3 = 3 new (protocols)
EMBASE = 33 = 16 new
IPA = 8 = 7 new
NEW TOTAL DATABASE = 112
Systematic Reviews
#1 Search (Anti-IgE OR "omalizumab "[Substance Name] OR xolair) AND
27
systematic[sb]
#2 Search "Asthma"[Majr]
67544
#3 Search "Asthma"[Majr] Limits: Humans, English
45554
#4 Search #1 AND #3
19
#5 Search ("Leukotriene Antagonists"[Mesh] OR "montelukast "[Substance Name] OR
81
singulair OR "zafirlukast "[Substance Name] OR accolate OR "zileuton "[Substance
Name] OR zyflo OR "pranlukast "[Substance Name] OR onon) AND systematic[sb]
#6 Search #5 AND #3
55
#7 Search (("Adrenergic beta-Agonists"[Mesh] AND "long acting") OR "formoterol
89
"[Substance Name] OR foradil OR oxis OR perforomist OR "salmeterol "[Substance
Controller medications for asthma
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Name] OR serevent) AND systematic[sb]
#8 Search #3 AND #7
#9 Search systematic[sb] AND ("inhaled corticosteroids" OR "Beclomethasone"[Mesh]
OR qvar OR vanceril OR "Budesonide"[Mesh] OR pulmicort OR "flunisolide
"[Substance Name] OR aerobid OR aerospan OR bronalide OR "fluticasone
"[Substance Name] OR flovent OR "Triamcinolone"[Mesh] OR azmacort OR
"mometasone furoate "[Substance Name] OR asmanex)
#13 Search #9 AND #3
#14 Search "fluticasone-salmeterol combination "[Substance Name] OR "fluticasone
propionate - salmeterol combination "[Substance Name] OR advair OR budesonideformoterol OR "symbicort "[Substance Name] AND systematic [sb]
52
357
177
12
212 citations
1. Inhaled Corticosteroids = 177 = 87 new
2. LABAs = 52 = 23 new
3. LTRAs = 55 = 33 new
4. Anti-IgE = 27= 10
5. Combination Studies =12 = 9 NEW
131 new citations
Controller medications for asthma
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Search Strategies: Asthma Medication Update 1
19 March 2010
Search
Most Recent Queries
Result
#1 Search "Asthma"[Majr]
73021
#2 Search "inhaled corticosteroids" OR "Beclomethasone"[Mesh] OR qvar OR
18315
vanceril OR "Budesonide"[Mesh] OR pulmicort OR "flunisolide "[Substance
Name] OR aerobid OR aerospan OR bronalide OR "fluticasone "[Substance
Name] OR flovent OR "Triamcinolone"[Mesh] OR azmacort OR "mometasone
furoate "[Substance Name] OR asmanex
#3 Search ("Adrenergic beta-Agonists"[Mesh] AND "long acting") OR "formoterol
3100
"[Substance Name] OR foradil OR oxis OR perforomist OR "salmeterol
"[Substance Name] OR serevent
#4 Search "Leukotriene Antagonists"[Mesh] OR "montelukast "[Substance Name]
3349
OR singulair OR "zafirlukast "[Substance Name] OR accolate OR "zileuton
"[Substance Name] OR zyflo OR "pranlukast "[Substance Name] OR onon
#5 Search Anti-IgE OR "omalizumab "[Substance Name] OR xolair
2926
#6 Search "fluticasone, salmeterol drug combination "[Substance Name] OR
317
"fluticasone propionate - salmeterol combination "[Substance Name] OR advair
OR budesonide-formoterol OR "symbicort "[Substance Name]
#7 Search "tiotropium "[Substance Name] OR Spiriva
514
#8 Search "ciclesonide "[Substance Name] OR Alvesco
204
#9 Search ("Randomized Controlled Trial"[Publication Type] OR "Randomized
413141
Controlled Trials as Topic"[MeSH]) OR "Single-Blind Method"[MeSH] OR
"Double-Blind Method"[MeSH] OR "Random Allocation"[MeSH]
#10 Search "Case-Control Studies"[MeSH] OR "Cohort Studies"[MeSH] OR
1181884
"Cross-Sectional Studies"[MeSH] OR "Follow-Up Studies"[MeSH] OR
"Longitudinal Studies"[MeSH] OR "Retrospective Studies"[MeSH] OR
observational studies
#11 Search #1 AND #2
5414
#12 Search #1 AND #3
1604
#13 Search #1 AND #4
1406
#14 Search #1 AND #5
508
#15 Search #1 AND #6
189
#16 Search #1 AND #7
27
#17 Search #1 AND #8
102
#18 Search #11 AND #9
1924
#19 Search #11 AND #10
896
#20 Search #12 AND #9
752
#21 Search #12 AND #10
186
#22 Search #13 AND #9
419
Controller medications for asthma
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Final Update 1 Report
Drug Effectiveness Review Project
#23 Search #13 AND #10
#24 Search #14 AND #9
#25 Search #14 AND #10
#26 Search #15 AND #9
#27 Search #15 AND #10
#28 Search #16 AND #9
#29 Search #16 AND #10
#30 Search #17 AND #9
#31 Search #17 AND #10
#32 Search #18 OR #19 OR #20 OR #21 OR #22 OR #23 OR #24 OR #25 OR #26
OR #27
#33 Search (#32) AND "2008/01/01"[Entrez Date] : "3000"[Entrez Date]
#34 Search #28 OR #29 OR #30 OR #31
#35 Search #34 OR #33
#36 Search #35 Limits: Animals
#37 Search #35 NOT #36
#38 Search #37 Limits: English Sort by: PublicationDate
160
80
20
112
21
7
2
54
7
3234
387
67
443
8
435
406
PubMed: 406
Cochrane Database: 202 (418-216 duplicates)
IPA: 131 (220-89 duplicates)
EMBASE: 153 (372-219 duplicates)
27 September 2010
Search
Most Recent Queries
#1 Search "Asthma"[Majr]
#2 Search "inhaled corticosteroids" OR "Beclomethasone"[Mesh] OR qvar OR
vanceril OR "Budesonide"[Mesh] OR pulmicort OR "flunisolide "[Substance
Name] OR aerobid OR aerospan OR bronalide OR "fluticasone "[Substance
Name] OR flovent OR "Triamcinolone"[Mesh] OR azmacort OR
"mometasone furoate "[Substance Name] OR asmanex
#3 Search ("Adrenergic beta-Agonists"[Mesh] AND "long acting") OR
"formoterol "[Substance Name] OR foradil OR oxis OR perforomist OR
"salmeterol "[Substance Name] OR serevent
#4 Search "Leukotriene Antagonists"[Mesh] OR "montelukast "[Substance
Name] OR singulair OR "zafirlukast "[Substance Name] OR accolate OR
"zileuton "[Substance Name] OR zyflo OR "pranlukast "[Substance Name]
OR onon
#5 Search Anti-IgE OR "omalizumab "[Substance Name] OR xolair
#6 Search "fluticasone, salmeterol drug combination "[Substance Name] OR
Controller medications for asthma
Result
74620
18893
3272
3477
3017
348
230 of 369
Final Update 1 Report
Drug Effectiveness Review Project
"fluticasone propionate - salmeterol combination "[Substance Name] OR
advair OR budesonide-formoterol OR "symbicort "[Substance Name]
#7 Search "tiotropium "[Substance Name] OR Spiriva
#8 Search "ciclesonide "[Substance Name] OR Alvesco
#9 Search ("Randomized Controlled Trial"[Publication Type] OR "Randomized
Controlled Trials as Topic"[MeSH]) OR "Single-Blind Method"[MeSH] OR
"Double-Blind Method"[MeSH] OR "Random Allocation"[MeSH]
#10 Search "Case-Control Studies"[MeSH] OR "Cohort Studies"[MeSH] OR
"Cross-Sectional Studies"[MeSH] OR "Follow-Up Studies"[MeSH] OR
"Longitudinal Studies"[MeSH] OR "Retrospective Studies"[MeSH] OR
observational studies
#11 Search #1 AND (#2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8)
#12 Search #11 AND #9
#13 Search #11 AND #10
#14 Search #12 OR #13
#15 Search ((#14) AND "2010/01/01"[Entrez Date] : "3000"[Entrez Date]) AND
"0"[Entrez Date] : "3000"[Entrez Date]
#16 Search #15 Limits: Animals
#17 Search #15 NOT #16
#18 Search #17 Limits: English
586
218
427780
1227204
7722
2605
1109
3392
89
4
85
85
PubMed: 85 (85 before duplicates removed)
Cochrane Database: 42 (61 before duplicates removed)
IPA: 16 (36 before duplicates removed)
EMBASE: 63 (125 before duplicates removed)
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Appendix F. Studies of poor quality
The full-text of the following studies were considered for analysis, but were deemed to have fatal flaws in
internal validity.
Sample
size
Study
Design
Intervention
Reason for exclusion
No comparison group, crosssectional analysis of 140
asthmatics with ICS treatment
1
Abuekteish et al.1995
Observational
140
BUD vs. BDP
over 5 years.; no description of
analysis; no adjustment for
duration and dose of ICS;
Insufficient reporting to allow for
2
Acun et al. 2005
appraisal of methods and
RCT
100
BUD vs. FP
analysis; Results not reported.
Comparisons were between
medium dose CIC, high dose
CIC, and low dose BUD; no
information on randomization
scheme; no blinding (BUD
group used a spacer whereas
CIC groups did not); some
3
Adachi et al., 2007
RCT
319
CIC vs. BUD
baseline differences between
groups; no information on
attrition/dropouts for those who
were randomized; no
information on whether intention
to treat or per protocol analysis
used.
Attrition NR, but high in other
BUD vs.
Agertoft et al. 19944
Observational
278
corresponding publication; high
control
potential selection bias
High attrition and differential
attrition; high potential for
selection bias (mainly due to
BUD vs.
Agertoft et al.20005
Observational
338
attrition); 97/270 in the BUD
control
group had not yet attained adult
height and were thus not
analyzed.
Lack of an appropriately
Allen et al. 19946
Meta-analysis
810
BUD
described comprehensive,
systematic literature search...
High potential for selection bias
and confounding, very high
attrition (low participation rate),
unclear how patients were
identified/selected/recruited,
Anthracopoulos et al.
unclear if appropriate dosage
Observational
641
BUD vs. FP
20077
comparison, open-label, unclear
which confounders were
adjusted for in the analyses
(and no mention of parental
height), analysis excluded
children that required more than
Controller medications for asthma
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Drug Effectiveness Review Project
Sample
size
Study
Design
Aubier et al. 19998
RCT
503
FP/SM vs. FP
+ SM vs. FP
Bakhireva et al. 20079
Observational
96
LTRAs vs.
SABAs and
control
Barnes et al. 2007
10
Intervention
RCT
75
MOM vs. BUD
Bleecker et al. 200611
Pooled analysis
183
FP/SM
Davis et al.12
Meta-analysis
NR
Omalizumab
Ferguson et al. 200713
RCT
Kallen et al.14
Observational
Karaman et al. 200715
RCT
67
BUD vs.
BUD+MOM vs.
BUD+FM
Lipworth et al. 199916
Meta-analysis
NR
ICS
Nong et al. 200117
RCT
77
BDP vs. FP
Controller medications for asthma
BUD vs. FP
2014
BBUD
Reason for exclusion
36 months of ICS and those
that entered puberty.
Poor reporting of methods and
results of meaningful outcome
Small sample size (inadequate
to detect differences in adverse
events of interest).
Baseline differences, lack of
reporting of randomization,
blinding, equal assessment of
both groups,
Potential selection bias (from
two different RCTs, just 183
(43%) of subjects had available
genotype information; not clear
how these were chosen;
potential confounding, analyses
don't adjust for baseline SABA
use or symptom scores which
were slightly worse in the B16
Gly/Gly group; sample size-studies not powered to detect
differences among genotypes
Methods not reported
Attrition high (> 40%), potential
selection bias, less than 60% of
subjects completed the 1 year
study; did not account for
greater # of steroid courses in
BUD group (15 vs. 6); postrandomization exclusions
Poor measurement and
uncontrolled confounders
High attrition, masking not
reported at any level, type or
withdrawal/exclusion not
reported and dropout rate
significant, no ITT analysis, no
explanation of why many
randomized subjects not
included in the analyses, no
mention of statistical power
Search terms not specified;
meta-analysis methods not
adequately reported; not
independently reviewed; no
report of publication bias,
heterogeneity, or clear eligibility
criteria; unclear how metaanalysis was carried out other
than multiple regression.
High potential for bias;
233 of 369
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Sample
size
Intervention
RCT
109
BUD vs. BDP
Palmer et al. 200619
Observational
546
SM
Pauwels et al. 199820
RCT
340
RCT
49
FP vs. BDP
BUD vs. BUD+
ZAF
Riccioni et al. 200222
RCT
45
BUD vs. MOM
Scott et al. 199923
Pooled data
670
BUD
Wardlaw et al. 200424
RCT
167
MOM vs. FP
Weiss et al. 200525
RCT
945
BUD vs. TRA
Yurdakul et al. 200226
RCT
64
BUD+FM vs.
BUD+ZAF
Study
Design
Ohaju-Obodo et al.
200518
Perng et al. 2004
21
Reason for exclusion
Completer's analysis; 22% postrandomization exclusions;
incomplete inclusion/exclusion
criteria; not sure it was actually
randomized;
High potential for selection and
measurement bias; no blinding,
analysis not described, unable
to determine attrition, did not
report randomization/allocation
concealment methods
No baseline data given for
comparison of groups so unable
to adequately assess potential
for selection bias
Poor reporting, confounding
High potential for selection bias
and measurement bias
Open-label, no ITT analysis, no
reporting of majority of criteria
for critical appraisal
Pooled data analysis without a
systematic literature search
No blinding, randomisation
method nr, no withdrawal
information reported
High potential for selection and
measurement bias; all groups
unblinded, not ITT analysis, ICS
dosing was left to the discretion
of the physician (starting dose
and subsequent adjustments)
making us unable to determine
if the comparison is appropriate
(nothing reported on actual
dosing received.
Not truly randomized---thus not
really an RCT, allocation,
blinding, etc. Nothing about
withdrawals. Unable to
determine if ITT analysis or
what was done.
References for Appendix F
1.
2.
3.
Abuekteish F, Kirkpatrick JN, Russell G. Posterior subcapsular cataract and inhaled corticosteroid therapy. Thorax. Jun
1995;50(6):674-676.
Acun C, Tomac N, Ermis B, Onk G. Effects of inhaled corticosteroids on growth in asthmatic children: a comparison
of fluticasone propionate with budesonide. Allergy Asthma Proc. May-Jun 2005;26(3):204-206.
Adachi M, Ishihara K, Inoue H, et al. Efficacy and safety of inhaled ciclesonide compared with chlorofluorocarbon
beclomethasone dipropionate in adults with moderate to severe persistent asthma. Respirology. Jul 2007;12(4):573-580.
Controller medications for asthma
234 of 369
Final Update 1 Report
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
Drug Effectiveness Review Project
Agertoft L, Pedersen S. Effects of long-term treatment with an inhaled corticosteroid on growth and pulmonary
function in asthmatic children. Respir Med. May 1994;88(5):373-381.
Agertoft L, Pedersen S. Effect of long-term treatment with inhaled budesonide on adult height in children with asthma.
N Engl J Med. Oct 12 2000;343(15):1064-1069.
Allen DB, Mullen M, Mullen B. A meta-analysis of the effect of oral and inhaled corticosteroids on growth. J Allergy
Clin Immunol. Jun 1994;93(6):967-976.
Anthracopoulos MB, Papadimitriou A, Panagiotakos DB, et al. Growth deceleration of children on inhaled
corticosteroids is compensated for after the first 12 months of treatment. Pediatr Pulmonol. May 2007;42(5):465-470.
Aubier M, Pieters WR, Schlosser NJ, Steinmetz KO. Salmeterol/fluticasone propionate (50/500 microg) in combination
in a Diskus inhaler (Seretide) is effective and safe in the treatment of steroid-dependent asthma. Respir Med. Dec
1999;93(12):876-884.
Bakhireva LN, Jones KL, Schatz M, et al. Safety of leukotriene receptor antagonists in pregnancy. J Allergy Clin
Immunol. Mar 2007;119(3):618-625.
Barnes N, Laviolette M, Allen D, et al. Effects of montelukast compared to double dose budesonide on airway
inflammation and asthma control. Respir Med. Aug 2007;101(8):1652-1658.
Bleecker ER, Yancey SW, Baitinger LA, et al. Salmeterol response is not affected by beta2-adrenergic receptor
genotype in subjects with persistent asthma. J Allergy Clin Immunol. Oct 2006;118(4):809-816.
Davis LA. Omalizumab: a novel therapy for allergic asthma. Ann Pharmacother. Jul-Aug 2004;38(7-8):1236-1242.
Ferguson AC, Van Bever HP, Teper AM, Lasytsya O, Goldfrad CH, Whitehead PJ. A comparison of the relative
growth velocities with budesonide and fluticasone propionate in children with asthma. Respir Med. Jan
2007;101(1):118-129.
Kallen B, Rydhstroem H, Aberg A. Congenital malformations after the use of inhaled budesonide in early pregnancy.
Obstet Gynecol. Mar 1999;93(3):392-395.
Karaman O, Arli O, Uzuner N, et al. The effectiveness of asthma therapy alternatives and evaluating the effectivity of
asthma therapy by interleukin-13 and interferon gamma levels in children. Allergy Asthma Proc. Mar-Apr
2007;28(2):204-209.
Lipworth BJ. Systemic adverse effects of inhaled corticosteroid therapy: A systematic review and meta-analysis. Arch
Intern Med. May 10 1999;159(9):941-955.
Nong BR, Huang YF, Hsieh KS, et al. A comparison of clinical use of fluticasone propionate and beclomethasone
dipropionate in pediatric asthma. Kaohsiung J Med Sci. Jun 2001;17(6):302-311.
Ohaju-Obodo JO, Chukwu C, Okpapi J, et al. Comparison of the efficacy and safety of budesonide turbuhaler
administered once daily with twice the dose of beclomethasone dipropionate using pressurised metered dose inhaler in
patients with mild to moderate asthma. West Afr J Med. Jul-Sep 2005;24(3):190-195.
Palmer CN, Lipworth BJ, Lee S, Ismail T, Macgregor DF, Mukhopadhyay S. Arginine-16 beta2 adrenoceptor genotype
predisposes to exacerbations in young asthmatics taking regular salmeterol. Thorax. Nov 2006;61(11):940-944.
Pauwels RA, Yernault JC, Demedts MG, Geusens P. Safety and efficacy of fluticasone and beclomethasone in
moderate to severe asthma. Belgian Multicenter Study Group. Am J Respir Crit Care Med. Mar 1998;157(3 Pt 1):827832.
Perng DW, Huang HY, Lee YC, Perng RP. Leukotriene modifier vs inhaled corticosteroid in mild-to-moderate asthma:
clinical and anti-inflammatory effects. Chest. May 2004;125(5):1693-1699.
Riccioni G, Ballone E, D'Orazio N, et al. Effectiveness of montelukast versus budesonide on quality of life and
bronchial reactivity in subjects with mild-persistent asthma. International Journal of Immunopathology and
Pharmacology. 2002;15(2):149-155.
Scott MB, Skoner DP. Short-term and long-term safety of budesonide inhalation suspension in infants and young
children with persistent asthma. J Allergy Clin Immunol. Oct 1999;104(4 Pt 2):200-209.
Wardlaw A, Larivee P, Eller J, Cockcroft DW, Ghaly L, Harris AG. Efficacy and safety of mometasone furoate dry
powder inhaler vs fluticasone propionate metered-dose inhaler in asthma subjects previously using fluticasone
propionate. Ann Allergy Asthma Immunol. Jul 2004;93(1):49-55.
Weiss KB, Paramore LC, Liljas B, Revicki DA, Luce BR. Patient satisfaction with budesonide Turbuhaler versus
triamcinolone acetonide administered via pressurized metered-dose inhaler in a managed care setting. J Asthma. Nov
2005;42(9):769-776.
Yurdakul AS, Calisir HC, Tunctan B, Ogretensoy M. Comparison of second controller medications in addition to
inhaled corticosteroid in patients with moderate asthma. Respir Med. May 2002;96(5):322-329.
Controller medications for asthma
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Final Update 1 Report
Drug Effectiveness Review Project
Appendix G. Excluded studies at full-text level
The following full-text publications were considered for inclusion for the update report but failed to meet
the criteria for this report. In addition to the references listed below there were 45 studies excluded
because they were not published in English (2) or they were not an eligible study design (43). A list of
studies excluded from the original report is available as an appendix to that report.
Exclude Reasons
2 = Ineligible outcome(s)
3 = Ineligible drug
4 = Ineligible population
6 = Ineligible design (e.g., small sample size, insufficient study duration)
7 = Ineligible comparison
Excluded Publication
Aballea S, Cure S, Vogelmeier C, Wiren A. A retrospective database study comparing treatment
outcomes and cost associated with choice of fixed-dose inhaled corticosteroid/long-acting beta-agonists
for asthma maintenance treatment in Germany. Int J Clin Pract 2008;62(12):1870-9.
Agertoft L, Pedersen S. Short-term lower-leg growth rate and urine cortisol excretion in children treated
with ciclesonide. J Allergy Clin Immunol 2005;115(5):940-5.
Anonymous, Feb. Ciclesonide (<it>Alvesco</it>) - A new inhaled corticosteroid for asthma. In: Medical
Letter on Drugs and Therapeutics (USA); 2008. p. 75-76.
Anonymous, Jun. Budenosia/formoterol (<it>Symbicort</it>) for asthma. In: Medical Letter on Drugs
and Therapeutics (USA); 2008. p. 9-1.
Anonymous. Long-Acting Beta-2 Agonists in Asthma. Medical Letter on Drugs and Therapeutics (USA)
2009;51:1.
Antoniu SA, Monica Pop C. Ciclesonide therapy in asthma: a potential effect on small airway
inflammation? Expert Opin Pharmacother 2009;10(5):917-9.
Antoniu SA. Effects of montelukast-desloratadine combination on early and late asthma responses.
Expert Opinion on Pharmacotherapy 2009;10(15):2577-2579.
Appleton SL, Ruffin RE, Wilson DH, Taylor AW, Adams RJ. Cardiovascular disease risk associated with
asthma and respiratory morbidity might be mediated by short-acting beta2-agonists. J Allergy Clin
Immunol 2009;123(1):124-130 e1.
Apter AJ. Advances in adult asthma diagnosis and treatment and health outcomes, education, delivery,
and quality in 2008. Journal of Allergy and Clinical Immunology 2009;123:35.
Apter AJ. Advances in the care of adults with asthma and allergy in 2007. Journal of Allergy and Clinical
Immunology 2008;121(4):839-844.
Backman RBCSRK. Fluticasone propionate via Diskus inhaler at half the microgram dose of
budesonide via Turbuhaler inhaler. Clinical Drug Investigation 2001;21(11):735-743.
Baptist AP, Reddy RC. Inhaled corticosteroids for asthma: are they all the same? Journal of Clinical
Pharmacy and Therapeutics (England) 2009;34:1.
Basu K, Palmer CN, Tavendale R, Lipworth BJ, Mukhopadhyay S. Adrenergic beta<INF>2</INF>receptor genotype predisposes to exacerbations in steroid-treated asthmatic patients taking frequent
albuterol or salmeterol. Journal of Allergy and Clinical Immunology 2009;124:1188.
Bateman ED, Bousquet J, Busse WW, Clark TJ, Gul N, Gibbs M, et al. Stability of asthma control with
regular treatment: an analysis of the Gaining Optimal Asthma controL (GOAL) study. Allergy
2008;63(7):932-8.
Berger WE, Bleecker ER, O'Dowd L, Miller CJ, Mezzanotte W. Efficacy and safety of
budesonide/formoterol pressurized metered-dose inhaler: Randomized controlled trial comparing onceand twice-daily dosing in patients with asthma. Allergy and Asthma Proceedings 2010;31(1):49-59.
Bisgaard H, Skoner D, Boza ML, Tozzi CA, Newcomb K, Reiss TF, et al. Safety and tolerability of
montelukast in placebo-controlled pediatric studies and their open-label extensions. Pediatric
Pulmonology 2009;44(6):568-579.
Blais L, Beauchesne MF, Forget A. Acute care among asthma patients using budesonide/formoterol or
fluticasone propionate/salmeterol. Respir Med 2009;103(2):237-43.
Boulet LP, Franssen E. Influence of obesity on response to fluticasone with or without salmeterol in
moderate asthma. Respir Med 2007;101(11):2240-7.
Boulet LP, Turcotte H, Prince P, Lemiere C, Olivenstein R, Laprise C, et al. Benefits of low-dose
Controller medications for asthma
Reason
6
6
6
2
2
6
6
6
6
6
6
6
4
6
6
4
2
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inhaled fluticasone on airway response and inflammation in mild asthma. Respir Med
2009;103(10):1554-63.
Breekveldt-Postma NS, Koerselman J, Erkens JA, Herings RM, Grp CS, et al., et al. Treatment with
inhaled corticosteroids in asthma is too often discontinued. In: Pharmacoepidemiology and Drug Safety
(England); 2008. p. 411-422.
Budesonide/formoterol (Symbicort) for asthma. Med Lett Drugs Ther 2008;50(1279):9-11.
Busse WW, Pedersen S, Pauwels RA, Tan WC, Chen YZ, Lamm CJ, et al. The Inhaled Steroid
Treatment As Regular Therapy in Early Asthma (START) study 5-year follow-up: effectiveness of early
intervention with budesonide in mild persistent asthma. J Allergy Clin Immunol 2008;121(5):1167-74.
Busse WW, Shah SR, Somerville L, Parasuraman B, Martin P, Goldman M. Comparison of adjustableand fixed-dose budesonide/formoterol pressurized metered-dose inhaler and fixed-dose fluticasone
propionate/salmeterol dry powder inhaler in asthma patients. J Allergy Clin Immunol 2008;121(6):140714, 1414 e1-6.
Cabana MD. Long-acting beta - Agonists best option for "step-up" therapy for children with uncontrolled
asthma. Journal of Pediatrics 2010;157 (3):512-513.
Camargo CA, Jr., Barr RG, Chen R, Speizer FE. Prospective study of inhaled corticosteroid use,
cardiovascular mortality, and all-cause mortality in asthmatic women. Chest 2008;134(3):546-51.
Campbell JD, Borish L, Haselkorn T, Rasouliyan L, Lee JH, Wenzel SE, et al. The response to
combination therapy treatment regimens in severe/difficult-to-treat asthma. Eur Respir J
2008;32(5):1237-42.
Carroll WD, Jones PW, Boit P, Clayton S, Cliff I, Lenney W. Childhood evaluation of salmeterol
tolerance - A double-blind randomized controlled trial. Pediatric Allergy and Immunology 2010;21 (2
PART 1):336-344.
Castro Rodriguez JA, Rodrigo GJ. Efficacy of inhaled corticosteroids in infants and preschoolers with
recurrent wheezing and asthma: a systematic review with meta-analysis (Provisional abstract).
Pediatrics 2009;123(3):e519-e525.
Cates CJ, Lasserson TJ. Combination formoterol and inhaled steroid as maintenance and reliever
therapy versus inhaled steroid maintenance for chronic asthma in adults and children. Cochrane
Database of Systematic Reviews 2008;3.
Cates CJ, Lasserson TJ. Combination formoterol and inhaled steroid versus beta2-agonist as relief
medication for chronic asthma in adults and children. Cochrane database of systematic reviews
(Online) 2009(1):CD007085.
Celano MP, Linzer JF, Demi A, Bakeman R, Smith CO, Croft S, et al. Treatment adherence among lowincome, African American children with persistent asthma. J Asthma 2010;47(3):317-22.
Chanez P, Stallaert R, Reznikova E, Bloemen P, Adamek L, Joos G. Effect of salmeterol/fluticasone
propionate combination on airway hyper-responsiveness in patients with well-controlled asthma.
Respiratory Medicine 2010;104 (8):1101-1109.
Christensson C, Thoren A, Lindberg B. Safety of inhaled budesonide: clinical manifestations of
systemic corticosteroid-related adverse effects. Drug Saf 2008;31(11):965-88.
Covar RA, Strunk R, Zeiger RS, Wilson LA, Liu AH, Weiss S, et al. Predictors of remitting, periodic, and
persistent childhood asthma. Journal of Allergy and Clinical Immunology 2010;125(2):359-366.
Dal Negro RW, Borderias L, Zhang Q, Fan T, Sazonov V, Guilera M, et al. Rates of asthma attacks in
patients with previously inadequately controlled mild asthma treated in clinical practice with combination
drug therapy: an exploratory post-hoc analysis. BMC Pulm Med 2009;9:10.
Delea TE, Hagiwara M, Stanford RH, Stempel DA. Effects of fluticasone propionate/salmeterol
combination on asthma-related health care resource utilization and costs and adherence in children and
adults with asthma. Clin Ther 2008;30(3):560-71.
Delea TE, Hagiwara M, Stempel DA, Stanford RH. Adding salmeterol to fluticasone propionate or
increasing the dose of fluticasone propionate in patients with asthma. Allergy and Asthma Proceedings
2010;31 (3):211-218.
Delea TE, Stanford RH, Hagiwara M, Stempel DA. Association between adherence with fixed dose
combination fluticasone propionate/salmeterol on asthma outcomes and costs (Brief record). Current
Medical Research and Opinion 2008;24(12):3435-3442.
Demoly P, Louis R, Soes-Petersen U, Naya I, Carlsheimer A, Worth H, et al. Budesonide/formoterol
maintenance and reliever therapy versus conventional best practice. Respiratory Medicine
2009;103(11):1623-1632.
DiSantostefano RL, Davis KJ, Yancey S, Crim C. Ecologic analysis of asthma-related events and
dispensing of inhaled corticosteroid- and salmeterol-containing products. Ann Allergy Asthma Immunol
2008;100(6):558-65.
Drugs for asthma. Treat Guidel Med Lett 2008;6(76):83-90.
Dyer MJ, Halpin DM, Stein K. Inhaled ciclesonide versus inhaled budesonide or inhaled
Controller medications for asthma
6
7
6
2
6
7
2
4
7
7
2
7
4
4
6
6
6
6
7
6
6
6
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beclomethasone or inhaled fluticasone for chronic asthma in adults: a systematic review (Structured
abstract). BMC Family Practice 2006;7:34.
Dyer MJ, Halpin DM, Stein K. Inhaled ciclesonide versus inhaled budesonide or inhaled
beclomethasone or inhaled fluticasone for chronic asthma in adults: a systematic review. BMC Fam
Pract 2006;7:34.
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Controller medications for asthma
6
4
4
4
6B
6
3
6
6
2
2
7
4
2
6
2
7
4
6
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Appendix H. Strength of evidence
Table H-1. Strength of evidence for the comparative efficacy of inhaled
corticosteroids
No. of
Studies
Result (for
(# of
equipotent
subjects) Design Quality
Consistency Directness
doses)
Beclomethasone compared with Budesonide
1 SR
1 SR
Good
Some
No difference for
(1174)
w/ MA
Direct
inconsistency
most outcomes
2 RCTs
2
Fair
(669)
RCTs
Beclomethasone compared with Ciclesonide
We did not identify any good or fair quality systematic reviews or head-to-head trials
Beclomethasone compared with Flunisolide
We did not identify any good or fair quality systematic reviews or head-to-head trials
Beclomethasone compared with Fluticasone
SR not direct
(compared
2 SRs
2 SRs
Good
FP
( 15,867)
w/ MA
compared
No difference for
Some
Good
most outcomes
inconsistency with
11 RCTs
11
(1), Fair
combined
(3,273)
RCTs
(10)
effect of
BDP/BUD)
Beclomethasone compared with Mometasone
No difference for
2 (592)
RCTs
Fair
Consistent
Direct
all outcomes
Beclomethasone compared with Triamcinolone
2 (668)
RCTs
Fair
Some
inconsistency
Other
modifying
factorsa
Overall
strength
of the
evidence
None
Moderate
None
High
None
Moderate
No difference for
most outcomes
No long-term
data (both
were 8-weeks)
Moderate
Direct
No difference for
equipotent
comparisons
No long-term
data (all were
12-weeks); 3
of the 5 RCTs
compared
equipotent
doses
Moderate
Direct
No difference for
all outcomes
No long-term
data (6-week
trail)
Moderate
No difference for
all outcomes for
equipotent
comparisons
5 of the 8
RCTs
compared
equipotent
doses and
consistently
found no
difference for
most outcomes
High
No difference for
Only 1 RCT
Low
Direct
Budesonide compared with Ciclesonide
5 (2336)
RCTs
Fair
Consistent
Budesonide compared with Flunisolide
1 (179)
RCT
Fair
NA
Budesonide compared with Fluticasone
1 SR
(14,602)
1 SR
w/ MA
Good
Consistent
8 RCTs
(3076)
8
RCTs
Fair
SR not direct
(compared
FP
compared
with
combined
effect of
BDP/BUD)
RCTs were
direct
Budesonide compared with Mometasone
2 (992)
RCTs
Fair
Some
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Table H-1. Strength of evidence for the comparative efficacy of inhaled
corticosteroids
No. of
Studies
(# of
subjects)
Design
Quality
Consistency
inconsistency
Directness
Overall
strength
of the
evidence
Result (for
equipotent
doses)
symptoms, MOM
> BUD for
rescue use
Other
modifying
factorsa
included an
equipotent
comparison
BUD > TAA for
symptoms,
rescue med use,
and quality of life
Starting doses
and dose
adjustments
were left to the
discretion of
the clinical
investigator
Low
7 of 8 RCTs
compared
equipotent
doses
High
Both compared
nonequipotent
doses
Low
No long-term
data (12-week
trials)
Moderate
2 of the 3
RCTs
compared nonequipotent
doses
Low
Budesonide compared with Triamcinolone
1 (945)
RCT
Fair
Consistent
Direct
Ciclesonide compared with Flunisolide
We did not identify any good or fair quality systematic reviews or head-to-head trials
Ciclesonide compared with Fluticasone
8 (4230)
RCTs
Fair
Consistent
Direct
No difference for
equipotent
comparisons
Ciclesonide compared with Mometasone
We did not identify any good or fair quality systematic reviews or head-to-head trials
Ciclesonide compared with Triamcinolone
We did not identify any good or fair quality systematic reviews or head-to-head trials
Flunisolide compared with Fluticasone
2 (653)
RCTs
Fair
Consistent
Direct
NA
Flunisolide compared with Mometasone
We did not identify any good or fair quality systematic reviews or head-to-head trials
Flunisolide compared with Triamcinolone
We did not identify any good or fair quality systematic reviews or head-to-head trials
Fluticasone compared with Mometasone
No difference for
most outcomes
3 (1103)
RCTs
Fair
Consistent
Direct
for equipotent
comparisons
Fluticasone compared with Triamcinolone
FP > TAA for
most outcomes
Some
for equipotent
3 (1275)
RCTs
Fair
Direct
inconsistency
doses (one 12week RCT)
Abbreviations: BDP = beclomethasone dipropionate; BUD = Budesonide; FLUN = Flunisolide; FP = Fluticasone
Propionate; ICS = Inhaled Corticosteroids; MA=meta-analysis; MOM = Mometasone; RCT= randomized controlled
trial; SR=systematic review; TAA = Triamcinolone Acetonide
a
Imprecise or sparse data; a strong or very strong association; high risk of reporting bias; dose response gradient;
effect of plausible residual confounding
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Table H-2. Strength of evidence for the comparative efficacy of leukotriene
modifiers (LMs)
Number
of studies
(# of
subjects)
Design
Quality
Other
modifying
factorsa
Overall
Strength
of the
evidence
Consistency
Directness
Result and
magnitude
of effect
NA
Direct
No difference
None
Low
NA
Direct
No difference
None
Low
Overall total: LM compared with LM
1 (40)
RCT (12 weeks)
Fair
Montelukast compared with Zafirlukast
1 (40)
RCT (12 weeks)
Fair
Montelukast compared with Zileuton
We did not identify any systematic reviews or head-to-head trials
Zafirlukast compared with Zileuton
We did not identify any systematic reviews or head-to-head trials
Abbreviations: LM= Leukotriene Modifiers; MA= meta-analysis; RCT= randomized controlled trial; SR= systematic
review.
a
Imprecise or sparse data; a strong or very strong association; high risk of reporting bias; dose response gradient;
effect of plausible residual confounding.
Table H-3. Strength of evidence for the comparative efficacy of LABAs
Number of
studies (# of
subjects)
Design
Quality
Result and
magnitude
of effect
Other
modifying
factorsa
Overall
strength
of the
evidence
Consistency
Directness
Consistent
Direct
No
difference
None
Moderate
Direct
No
difference
in health
outcomes
None
Moderate
Direct
No
difference
in health
outcomes
None
Moderate
Overall total: LABA compared with LABA
3 (1107)
RCTs
Fair
Eformoterol (eFM) compared with salmeterol (SM)
2 (625)
RCTs (8-week
cross-over; 12week openlabel)
Fair
Consistent
Formoterol (FM) compared with salmeterol (SM)
1 (482)
RCT (openlabel, 6-month
trial)
Fair
Consistent
Formoterol (FM) compared with arformoterol (ARF)
We did not identify any systematic reviews or head-to-head trials that compared FM to ARF
Salmeterol (SM) compared with arformoterol (ARF)
We did not identify any systematic reviews or head-to-head trials that compared SM to ARF
Abbreviations: ARF= Arformoterol; eFM = Eformoterol; FM = Formoterol; LABAs = Long-Acting Beta-2 Agonists;
MA= meta-analysis; RCT= randomized controlled trial; SM= Salmeterol; SR= systematic review.
a
Imprecise or sparse data; a strong or very strong association; high risk of reporting bias; dose response gradient; effect of plausible
residual confounding.
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Table H-4. Strength of evidence for the comparative efficacy of omalizumab and
placebo
Omalizumab compared with placebo
No. of
studies
(# of
subjects) Design Quality Consistency Directness Results and magnitude of effecta
Overall
Other
strength
modifying of
factorsa
evidence
Overall total: Omalizumab compared with placebo
2 SRs
(5,199)
2 SR
w/ MA
8 RCTs
(3480)
6
RCTs
Good Consistent
(1),
Fair (1)
Direct
OM > placebo
None
High
Change in # of exacerbations per
patient: WMD = -0.18, 95% CI: -0.24, 0.11
Good
(2),
Fair (6)
Percentage/number of patients with ≥ 1
exacerbation: OR = 0.51, 95% CI:
0.40, 0.67
Increase in AQLQ scores: SMD = 0.26,
95% CI: 0.18, 0.35
AQLQ = Asthma Quality of Life Questionnaire; CI = confidence interval; MA=meta-analysis; OM= Omalizumab; RCT= randomized
controlled trial; SMD = standard mean difference; SR= systematic review.
a
Selected results from our meta-analyses of included RCTs; the complete meta-analyses is in Appendix I.
Table H-5. Strength of evidence for the comparative efficacy of BUD/FM and
FP/SM
No. of
studies
(# of
subjects) Design Quality Consistency Directness
Overall total: BUD/FM compared with FP/SM
Consistent
when both
Good
BUD/FM and
1 (5,537)
SR
FP/SM
Direct
Good
delivered via
4 (5,818)
RCTs
(3);
a single
Fair (1)
inhaler
BUD/FM compared with FP/SM
1 (5,537)
SR
3 (5,390)
RCTs
Overall
strength
of
evidence
No difference
None
Moderate
No difference;
Moderate
Exacerbations requiring
emergency visit or
hospital admission: OR
(95% CI) = 0.74 (0.53,
1.04)
lack of
precision,
wide
confidence
intervals;
not all
studies
compared
equipotent
steroid
doses
FP/SM > BUD/FM
(despite BUD
administered at higher
dose equipotency than
FP)
Compared
nonequipotent
steroid
components
Low
Exacerbations requiring
oral steroids: OR (95%
CI) = 1.16 (0.95, 1.4)
Good
Good
(2);
Fair (1)
Magnitude of effect
Other
modifying
factors
Consistent
Direct
BUD+FM compared with FP/SM
1 (428)
RCT
Good
NA
Direct
Abbreviations: BUD = budesonide; FM = formoterol; FP = fluticasone propionate; ICS= inhaled corticosteroids; OR = odds ratio;
RCT=randomized controlled trial; SM = salmeterol; SMD = standard mean difference; SR = systematic review
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Table H-6. Strength of evidence for for the comparative efficacy of BUD/FM for
maintenance and as-needed relief (BUD/FM MART) and ICS/LABA with a ShortActing Beta-Agonist (SABA) for relief
No. of
Overall
Studies
Other
strength
(# of
modifyin of
Directn Result and Magnitude of
subjects) Design Quality Consistency
ess
Effect
g factors evidence
Overall total: BUD/FM for maintenance and relief compared with ICS/LABA for maintenance with SABA for
relief
4a
RCTs
Good
Consistent for
Direct
BUD/FM MART associated
Heterogen Moderate
(10,547)
(2);
symptoms and
with lower odds of
eity of
Fair
exacerbations
exacerbations and fewer
study
(2)
Some
nocturnal awakenings:
designs
inconsistency
and dose
Exacerbations requiring
for other
compariso
medical intervention:
outcomes
ns; not
OR (95% CI) = 0.75 (0.66,
always
0.85)
clear
amount of
Exacerbations requiring
FM
emergency visit or hospital
delivered;
admission:
trials
OR (95% CI) = 0.73 (0.60,
using
0.90)
lower total
ICS doses
Nocturnal awakenings: OR
in
(95% CI) = -0.076 (-0.124, BUD/FM
0.027)
for
maintenan
No difference in symptom-free ce and
days, symptom scores,
relief
rescue-free days, or rescue
group
medicine use
reported
similar
outcomes
to other
trials
BUD/FM MART compared with BUD/FM for maintenance with SABA for relief
2 (6,095)
RCTs
Good
Consistent for
Direct
All trials reported lower
Moderate
(1);
symptoms and
exacerbation rates for those
exacerbations
treated with BUD/FM MART
Fair
Some
and no difference in symptom
(1)
measures
inconsistency
for other
outcomes
BUD/FM MART compared with FP/SM for maintenance with SABA for relief
3 (7,787)
RCTs
Good
Consistent for
Direct
All trials reported lower
Moderate
(2);
symptoms and
exacerbation rates for those
Fair
exacerbations
treated with BUD/FM MART
(1)
Some
and no difference in symptom
inconsistency
measures
for other
outcomes
Abbreviations: BUD = Budesonide; CI: =confidence interval; FD=fixed dose; FM = Formoterol; ICS= Inhaled Corticosteroids; LABAs
= Long-Acting Beta-2 Agonists; MART = maintenance and reliever therapy; SABA = Short-Acting Beta-Agonist; SMD = standard
mean difference.
a
The overall total of trials and number of participants do not equal the sum of trials for the two specific comparisons because one
trial contributed to both comparisons
(BUD/FM maintenance and reliever therapy compared with BUD/FM fixed dose and compared with FP/SM fixed dose).
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Table H-7. Strength of evidence for the comparative efficacy of ICSs and LTRAs
Number
of
studies
(# of
subjects) Design Quality Consistency Directness
Overall total of trials: ICS compared with LTRA
22
RCTs
Fair
Consistent
Direct
(9,873)
Other
modifying
factors
Overall
strength
of
evidence
ICS > LTRA; ICSs had less
rescue medicine use (%
rescue free days: SMD 0.25; rescue medicine use
per day: SMD -0.23), fewer
symptoms (% symptom
free days: SMD -0.21;
lower symptom score: SMD
-0.28), less frequent
exacerbations (SMD -0.17),
and increase in quality of
life (AQLQ scores: SMD 0.19). All were statistically
significant favoring ICSs
(Appendix I).
None
High
Results (magnitude of
effect)
FP compared with ML
9 (3,864)
RCTs
Fair
Consistent
Direct
FP > ML; had less rescue
medicine use (% rescue
medicine free days: SMD 0.25), less symptoms (%
symptom-free days: SMD 0.24; lower symptom score:
SMD -0.24), fewer
exacerbations (SMD -0.17),
and greater improvement in
quality of life (AQLQ
scores: SMD -0.15). All
were statistically significant
favoring FP.
None
High
BDP compared with ML
6 (3,823)
RCTs
Fair
Consistent
Direct
BDP > ML; had fewer
exacerbations (SMD -0.15,
95% CI: -0.30, -0.00), and
a trend toward less rescue
medication use (mean
change puffs per day: SMD
-0.08, 95% CI: -0.19, 0.04)
and fewer symptoms (%
symptom-free days: SMD 0.11, 95% CI: -0.25, 0.02)
None
Moderate
Some
inconsistency
Direct
Mixed results: reported
outcomes either not
significantly different or
favored BUD
None
Moderate
Consistent
Direct
FP > ZAF; less rescue
medicine use (rescue
medicine free days: SMD 0.30, 95% CI: -0.40, -0.20);
fewer symptoms (%
symptom free days: SMD 0.29, 95% CI: -0.39, -0.19;
greater improvement in
None
High
BUD compared with ML
3 (520)
RCTs
Fair
FP compared with ZAF
4 (1,666)
RCTs
Fair
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Table H-7. Strength of evidence for the comparative efficacy of ICSs and LTRAs
Number
of
studies
(# of
subjects)
Design
Quality
Consistency
Directness
Results (magnitude of
effect)
symptom score: SMD 0.31, 95% CI: -0.41, -0.21),
and fewer exacerbations
(SMD -0.21, 95% CI: -0.31,
-0.11)
Other
modifying
factors
Overall
strength
of
evidence
Abbreviations: AQLQ = Asthma Quality of Life Questionnaire; BDP = beclomethasone dipropionate; BUD =
Budesonide; CI = confidence interval; FP = Fluticasone Propionate; ICS = Inhaled Corticosteroids; LTRAs =
Leukotriene receptor antagonists; MA=meta-analysis; RCT= randomized controlled trial; SMD = standard mean
difference; SR = systematic review; ZAF = Zafirlukast.
Table H-8. Strength of evidence for the comparative efficacy of ICSs and LABAs
for monotherapy
Number of
studies (#
of
subjects)
Design Quality
Consistency
ICS compared with LABA for monotherapy
13 (4196)
RCTs
Good (1) Some
Fair (12) inconsistency
FP compared with SM
7 (2262)
RCTs
Fair
BDP compared with SM
3 (694)
RCTs
Fair
TAA compared with SM
1 (164)
RCT
Good
(16
weeks)
Controller medications for asthma
Directness
Results, magnitude of
effect
Other
modifying
factorsa
Overall
strength
of
evidence
Direct
LABAs had a
significantly higher odds
of exacerbations than
ICSs (OR = 2.845; 95%
CI = 1.664, 4.863; P <
0.001; 6 studies)); no
statistically significant
difference found in
meta-analyses of other
outcomesb
None
High
Some
inconsistency
Direct
Fewer exacerbations
with FP than SM; mixed
results for other
outcomes, but trials
generally reported no
differences or better
outcomes for those
treated with FP than
with SM
None
High
Some
inconsistency
Direct
Mixed results, but trials
generally reported no
differences or better
outcomes for those
treated with BDP than
with SM
None
High
NA
Direct
Fewer patients having
exacerbations with TAA
(7% compared with
20%, P = 0.04) and
lower treatment failure
rate (6% compared with
24%, P-0.004); no
difference in symptoms,
None
Moderate
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Number of
studies (#
of
subjects)
Design
Drug Effectiveness Review Project
Quality
BUD compared with FM
2 (1076)
RCTs
Fair
(12
weeks)
Consistency
Directness
NA
Direct
Results, magnitude of
effect
rescue use, or QOL
Trend toward fewer
symptoms, nocturnal
awakenings, and
exacerbations; trend
toward less rescue use
Other
modifying
factorsa
Overall
strength
of
evidence
None
Moderate
Abbreviations: BDP = beclomethasone dipropionate; BUD = Budesonide; CI = confidence interval; FM = Formoterol; FP =
Fluticasone Propionate; ICS = Inhaled Corticosteroids; LABAs = Long-Acting Beta-2 Agonists; NR = not reported; QOL = quality of
life; RCT= randomized controlled trial; SM = Salmeterol; SMD = standard mean difference; TAA = triamcinolone acetonide.
a
Imprecise or sparse data; a strong or very strong association; high risk of reporting bias; dose response gradient; effect of plausible
residual confounding.
b
The selected results are from our meta-analyses of included RCTs; the complete meta-analyses are in Appendix I.
Table H-9. Strength of evidence for the comparative efficacy of leukotriene
modifiers and LABAs for monotherapy
Number
of
studies
(# of
subjects) Design
Quality
Consistency
Montelukast compared with Salmeterol
1 (191)
RCT (8
Fair
NA
weeks)
Montelukast compared with Eformoterol
Fair,
1 (58)
RCT;
NA
cross-over
unclear
with
if oneunusual
week
design; 12
washout
weeks
sufficient
contributing
to this
comparison
Directness
Results, magnitude
of effect
Other
modifying
factorsa
Overall
strength
of
evidence
Direct
Zero compared with
one death in one study
(P = NR)
None
Insufficient
Direct
Those treated with
eFM had fewer
symptoms (% of
symptom-free days: 23
compared with 0; P =
0.01; symptom scores:
1.2 compared with 1.6;
P = 0.02), less rescue
medicine use (% of
rescue-free days: 40
compared with 30; P =
0.008), and better
quality of life (QOL
score: 0.4 compared
with 0.6; P = 0.001)
None
Insufficient
Abbreviations: LABAs = Long-Acting Beta-2 Agonists; NR = not reported; QOL = quality of life; RCT= randomized controlled trial.
a
Imprecise or sparse data; a strong or very strong association; high risk of reporting bias; dose response gradient; effect of plausible
residual confounding.
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Table H-10. Strength of evidence for the comparative efficacy of ICS + LABA and
same dose ICS alone as first line therapy
Number
of
studies
(# of
Result (magnitude
subjects) Design
Quality
Consistency
Directness of effect)
Overall total: ICS + LABA compared with ICS alone as first line therapy
1 SR
1 SR w/
Good
Some
Direct
No difference in
(8050a)
MA
inconsistency
number of patients
with exacerbations
9 RCTs
9 RCTs
Fair
requiring systemic
(3,932)
steroids (RR 1.04,
95% CI: 0.73, 1.47) or
with exacerbations
requiring hospital
admissions (RR 0.38,
95% CI 0.09 to 1.65)b
Other
modifying
factors
Overall
strength
of
evidence
None
Moderate
Mixed results:
reported outcomes
found no differences
or favored FP+SM
None
Moderate
Mixed results:
reported outcomes
found no differences
or favored BUD+FM
None
Moderate
Greater improvement
in the % of symptomfree days (SMD =
0.24 , 95% CI: 0.14,
0.33; 6 studies),
symptom scores
(SMD = 0.28, 95% CI:
0.15, 0.41; 4 studies),
% rescue medicinefree days (SMD 0.32,
95% CI 0.20, 0.43; 4
studies), and rescue
medicine use (puffs
per day) (SMD 0.25,
95% CI 0.12, 0.38; 7
studies) for those
treated with
ICS+LABAc
Fluticasone + salmeterol compared with fluticasone
7 (1062)
RCTs
Fair
Consistent
Direct
Budesonide + formoterol compared with budesonide
2 (1036)
RCTs
Fair
Some
Direct
inconsistency
Abbreviations: BUD = Budesonide; CI = confidence interval; FM = Formoterol; FP = Fluticasone Propionate; ICS = Inhaled
Corticosteroids; LABAs = Long-Acting Beta-2 Agonists; MA=meta-analysis; RCT= randomized controlled trial; RR = relative risk; SM
= Salmeterol; SMD = standard mean difference; SR=systematic review.
a
This is the total number of patients for both comparisons (ICS + LABA v ICS (same dose) and ICS + LABA v ICS (higher dose))
153
studied in the systematic review.
b
153
This result is from a previously published systematic review with meta-analysis.
c
Our meta-analysis results and forest plots are in Appendix I.
BUD = Budesonide; CI = confidence interval; FM = Formoterol; FP = Fluticasone Propionate; ICS = Inhaled Corticosteroids; LABAs
= Long-Acting Beta-2 Agonists; MA=meta-analysis; RCT= randomized controlled trial; RR = relative risk; SM = Salmeterol; SMD =
standard mean difference; SR=systematic review
Controller medications for asthma
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Table H-11. Strength of evidence for the comparative efficacy of ICS + LABA
compared with higher dose ICS
Study
design
(Number
Number
of studies using 1
inhaler
(Number
for ICS+
Result,
of
subjectsa) LABAb )
Quality Consistency Directness magnitude of effectc
Overall total: ICS + LABA compared with higher dose of ICS RCTs
33d
33 RCTs Good
Some
Direct
ICS+LABA had greater
(18,153)
(2)
inconsistency
improvement in the
Fair
percentage of symptom(31)
free days (SMD = -0.20,
95% CI: -0.25, -0.14),
symptom scores (SMD =
-0.22, 95% CI: -0.34, 0.11), % rescue-free
days (SMD = -0.24, 95%
CI: -0.31, -0.16), and
rescue medicine use
(SMD = -0.22, 95% CI: 0.28, -0.16)
Other
modifying
factors
Overall
strength
of
evidence
None
High
No statistically significant
difference in the
percentage of subjects
with exacerbations, but
trend favors those
treated with ICS+LABA
(OR = 0.89, 95% CI:
0.78, 1.01)
FP+SM compared with FP
14 (7,091) RCTs
Fair
(11)
Some
inconsistency
Direct
no statistically significant
difference in the number
of people with
exacerbations, but the
pooled odds ratio favors
FP+SM (OR = 0.86, 95%
CI: 0.67, 1.10, 8 studies)
High
meta-analyses for
symptom-free days,
symptom scores,
rescue-free days, and
rescue medicine use
show a trend toward
results similar to those in
the overall meta-analysis
for ICS+LABA compared
with higher dose ICS
BUD+FM compared with BUD
7 (6,460)
RCTs
Fair
(5)
Some
inconsistency
Direct
Meta-analyses show
trends consistent with
the overall ICS+LABA
compared with higher
dose ICS meta-analyses
BDP+SM compared with BDP
6 (2,574)
RCTs
Fair
(0)
Some
inconsistency
Direct
greater reduction in
rescue medicine use
Controller medications for asthma
High
None
High
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Table H-11. Strength of evidence for the comparative efficacy of ICS + LABA
compared with higher dose ICS
Number
of studies
(Number
of
subjectsa)
Study
design
(Number
using 1
inhaler
for ICS+
LABAb )
Quality
Consistency
Directness
Result,
magnitude of effectc
(SMD = 0.18, 95% CI:
0.05, 0.31; 3 studies)
and trend toward greater
improvement in the
percentage of symptomfree days with BDP+SM
Other
modifying
factors
Overall
strength
of
evidence
No difference in
exacerbations (OR =
0.84, 95% CI: 0.65, 1.10)
BDP+FM compared with BDP
3 (982)
RCT
Fair
(2)
Consistent
Direct
Better symptom and
rescue medicine use
outcomes for BDP+FM
in all trials; results
showed a trend toward
fewer exacerbations with
BDP+FM
None
Moderate
FP+SM compared with BUD
2 (702)
RCTs
Fair (1)
(2)
Good
(1)
Some
inconsistency
Direct
Mixed results between
studies; No statistically
significant difference in
exacerbations for both;
other outcomes show no
difference or favor
FP+SM
None
Moderate
BUD+FM compared with FP
1 (344)
RCT
Fair
(1)
NA
Direct
No difference in
symptoms or nocturnal
awakenings, but fewer
exacerbations and less
rescue medicine for
BUD+FM
None
Moderate
FP+SM compared with TAA
1 (680)
RCT
Fair
(0)
NA
Direct
Greater improvement in
symptoms, nocturnal
awakenings, and rescue
medicine use for FP+SM
None
Moderate
Abbreviations: AQLQ = Asthma Quality of Life Questionnaire; BDP = beclomethasone dipropionate; BUD = Budesonide; CI =
confidence interval; FP = Fluticasone Propionate; ICS = Inhaled Corticosteroids; LABAs = Long-Acting Beta-2 Agonists; MA=metaanalysis; OCS = oral corticosteroids; QOL = quality of life; RCT= randomized controlled trial; RR = relative risk; SM = Salmeterol;
SMD = standard mean difference; SR=systematic review; TAA = Triamcinolone Acetonide; WMD = weighted mean difference.
a
This is the total number of asthma subjects randomized in the trial. Some subjects may have received other treatments as several
trials had multiple treatment arms.
b
This is the number of trials that administered the ICS/LABA in 1 inhaler for this comparison.
c
This includes the selected results of meta-analyses presented; see Appendix I and text for complete results.
d
The total number of studies and subjects are less than the sum of the trials and subjects for each comparison because some trials
included multiple comparisons.
e
165
These results are from a previously published meta-analysis.
f
167
These are selected results from a previously published meta-analysis;Ducharme, 2010 , which is an update to Greenstone,
201
2005 .
g
This is the total number of patients for both comparisons included in the review. The review looked at two groups of studies, ICS +
LABA v same dose ICS and ICS + LABA v higher dose ICS.
Controller medications for asthma
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Table H-12. Strength of evidence for the comparative efficacy of addition of LABA
to ICS compared with continuing same dose ICS
Study
design
(Number
Number
of studies using
single
(Number
combo
of
subjectsa ) inhalerb ) Quality Consistency
ICS + LABA compared with same dose of ICS
32
RCTs
Good
Consistent
(14,737)
(2),
Fair
(31)
Directness
Result (magnitude of
effect)
Other
modifying
factors
Overall
strength
of
evidence
Direct
ICS+LABA > ICS for
symptom free days
(SMD 0.27, 95% CI:
0.22, 0.32), symptom
scores (SMD -0.27, 95%
CI: -0.33, -0.21), rescue
medicine use (SMD 0.29, 95% CI: -0.36, 0.23), and quality of life
(AQLQ scores; SMD
0.26, 95% CI: 0.14,
0.37)c
None
High
Direct
BUD+FM > BUD
None
High
Direct
FP+SM > FP
None
High
Direct
ICS+SM > ICS for
symptoms and rescue
medicine use in all trials
None
High
Some
inconsistency
Direct
ICS+FM > ICS for some
outcomes and no
difference for others
None
Low
BDP+SM compared with BDP
1 (177)
RCT
Fair
(0)
NA
Direct
No difference in
symptoms,
exacerbations, or rescue
medicine use
None
Low
BDP+FM compared with BDP
1 (645)
RCT
Fair
(0)
NA
Direct
Rescue medication use
was significantly reduced
from baseline in the
BDP+FM group (mean
difference: -0.36 95% CI
-0.52 to -0.19) and
unchanged in the BDP
along group. No between
group difference was
reported.
None
Low
BUD+FM (or eFM) compared with BUD
16 (9,456) RCTs
Good
Consistent
(13) e
(2) Fair
(14)
FP+SM compared with FP
9 (3029)
RCTs
Fair
Consistent
(9)
ICS+SM compared with ICS
3 (835)
RCTs
Fair
Consistent
(0)
ICS+FM compared with ICS
2 (541)
RCTs
Fair
(0)
Abbreviations: AQLQ = Asthma Quality of Life Questionnaire; BDP = beclomethasone dipropionate; BUD = Budesonide; CI =
confidence interval; eFM = Eformoterol; FM = Formoterol; FP = Fluticasone Propionate; ICS = Inhaled Corticosteroids; LABAs =
Long-Acting Beta-2 Agonists; MA=meta-analysis; OCS= oral corticosteroids; RCT= randomized controlled trial; RR = relative risk;
SM = Salmeterol; SMD = standard mean difference; SR=systematic review.
a
Total number of asthma subjects randomized in the trial. Some subjects may have received other treatments as several trials had
multiple treatment arms.
b
Number of trials for this comparison that administered the ICS/LABA in 1 inhaler.
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c
See Appendix I for complete results of meta-analyses.
Results from previously published meta-analysis.
e
Five trials had an arm with BUD+FM in single inhaler and an arm with them in separate inhalers.
d
Table H-13. Strength of evidence for the comparative efficacy of ICS + LTRA and
ICS
Number
of
studies
(Number
of
subjects) Design Quality Consistency
LTRA + ICS compared with ICS same dose
1 (5,871)
1 SR
Good
Some
w/ MA
inconsistency
Directness
Direct
Result, magnitude of
effect
Exacerbations: nonstatistically significant
reduction in the risk of
exacerbations requiring
systemic steroids: RR
0.64, 95% CI: 0.38, 1.07
Symptoms: No
difference
Rescue medicine use:
LTRA+ICS > ICS [SMD
-0.15, 95% CI: -0.24, 0.05]
Other
modifying
factors*
Overall
strength
of
evidence
Few trials
tested
licensed
doses of
LTRAs: just 4
trials did so
for the
primary
outcome:
exacerbations
requiring
systemic
steroids
Low
Quality of Life: No
difference [WMD 0.08,
95% CI: -0.03, 0.20]
BUD + ML compared with BUD same dose
1 (639)
RCT
Fair
Some
(16
inconsistency
weeks)
BDP + ML compared to BDP same dose
1 (642)
RCT
Fair
Some
(16
inconsistency
weeks)
Direct
Mixed results: BUD+ML
> BUD for most
outcome measures; no
difference for some
None
Low
Direct
Mixed results: BDP+ML
> BDP for most
outcome measures; no
difference for some
None
Low
Symptoms: No
difference
[change from baseline
in symptoms score
(WMD 0.01, 95% CI: 0.09, 0.10)]
Only 3 trials
in the MA
compared
licensed
doses of
LTRAs with
increasing the
dose of ICSs
Moderate
LTRA + ICS compared with ICS increased dose
1 (5,871)
1 SR
Good
Some
Direct
w/ MA
inconsistency
Exacerbations: No
difference [risk of
exacerbation requiring
systemic steroids: RR
0.92, 95% CI: 0.56,
1.51]
Power of the
MA is
insufficient to
confirm the
equivalence
Rescue medicine use:
No difference
BUD + ML compared with BUD increased dose
2 (960)
RCTs
Fair
Some
Direct
(12-16
inconsistency
Controller medications for asthma
No difference for most
outcomes (one trial);
None
Low
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Table H-13. Strength of evidence for the comparative efficacy of ICS + LTRA and
ICS
Number
of
studies
(Number
of
subjects)
Result, magnitude of
effect
One trial reported fewer
exacerbations with
increased dose BUD
Fluticasone (FP)+Montelukast (ML) compared with Fluticasone (FP) increased dose
1 (182)
RCT
Fair
Not
Direct
No difference in
(48
applicable
hospitalizations due to
weeks,
asthma symptoms; 43
triple
(FP+ML) vs. 47 (FP)
crossoral steroid courses
over)
Design
weeks)
Quality
Consistency
Directness
Other
modifying
factors*
Primary
outcome was
a composite
outcome
including
FEV1
Overall
strength
of
evidence
Low
Abbreviations: BUD = Budesonide; CI = confidence interval; ICS = Inhaled Corticosteroids; LTRAs = Leukotriene receptor
antagonists; MA=meta-analysis; ML = Montelukast; QOL = quality of life; RCT= randomized controlled trial; RR= Risk Ratio; SMD =
standard mean difference; SM = Salmeterol;; SR=systematic review; WMD = weighted mean difference.
Table H-14. Strength of evidence for the comparative efficacy of LABA + ICS and
LTRA
Number
of
studies
(# of
subjects) Design Quality Consistency
Overall total: ML compared with FP + SM
5 (2,188)
RCTs
Good
Consistent
(12 to
(1)
Fair (4)
48
weeks)
Directness
Magnitude of effect
Other
modifying
factors
Direct
FP+SM > ML
None
Overall
strength
of
evidence
High
Greater improvement in
symptom-free days (SMD 0.25, 95% CI: -0.35, -0.15)
and percentage of rescue
medicine-free days (SMD 0.27, 95% CI: -0.37, -0.17)
Fewer exacerbations (SMD
0.26, 95% CI: 0.16, 0.35)
Abbreviations: CI = confidence interval; FP = Fluticasone Propionate; ICS = Inhaled Corticosteroids; LABAs = Long-Acting Beta-2
Agonists; LTRAs = Leukotriene receptor antagonists; ML = Montelukast; RCT= randomized controlled trial; SM = Salmeterol;
SMD=standard mean difference.
Symbol use: Drug X > Drug Y = statistically significant difference in outcomes favoring Drug X; Drug X > Drug Y trend = point
estimate favors Drug X, but the difference is not statistically significant or tests of statistical significance were NR; No difference = no
statistically significant difference or tests of statistical significance were not reported and outcomes are similar.
Table H-15. Strength of evidence for the comparative efficacy of LTRA + ICS and
LABA + ICS
Number
of
studies
(# of
subjects) Design Quality Consistency Directness Magnitude of effect
Overall total: LTRA plus ICS compared with LABA plus ICS
Controller medications for asthma
Other
modifying
factors
Overall
strength
of
evidence
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1 (6,030)
1 SR
w/ MA
8 (5,459)
8
RCTs
Drug Effectiveness Review Project
Good
Consistent
Good
(1);
Fair (7)
ML + FP compared with SM + FP
7 (5,411)
RCTs
Good
Consistent
(1) Fair
(6)
ML + BUD compared with FM + BUD
1 (48)
RCT
Fair
NA
Direct
ICS+LABA > ICS+LTRA
None
High
Exacerbations requiring
systemic steroids (RR 0.83;
a
95% CI: 0.71, 0.97)
Direct
ICS+LABA > ICS+LTRA for
most reported outcomes
None
High
Direct
FM+BUD > ML+BUD
None
Moderate
Abbreviations: BUD = Budesonide; CI = confidence interval;; FM = Formoterol; FP = Fluticasone Propionate; ICS =
Inhaled Corticosteroids; LABAs = Long-Acting Beta-2 Agonists; LTRAs = Leukotriene receptor antagonists;
MA=meta-analysis; RCT= randomized controlled trial; SM = Salmeterol; SR=systematic review.
Table H-16. Strength of evidence for the comparative efficacy of ICS + LABA and
LTRA + LABA
Number
of
studies
(# of
Result (magnitude of
subjects) Design Quality Consistency Directness effect)
Montelukast plus Salmeterol compared with Beclomethasone plus Salmeterol
RCT,
ICS+LABA >
1 (192)
crossFair
NA
Direct
LTRA+LABA
over
Other
modifying
factors
Overall
strength of
evidence
Composite
outcome
Moderate
Abbreviations: ICS = Inhaled Corticosteroids; LABAs = Long-Acting Beta-2 Agonists; LTRAs = Leukotriene receptor
antagonists; RCT= randomized controlled trial.
Table H-17. Strength of evidence for tolerability and frequency of adverse events
of BUD/FM compared with FP/SM
No. of
studies
(# of
subjects) Design Quality Consistency
Overall total: BUD/FM compared with FP/SM
Directness
Magnitude of effect
Other
modifying
factors
Overall
strength
of
evidence
No differenceb:
2 (5,935)
a
4 (5,818)
SRs
RCTs
Good
(2)
Good
(3); Fair
(1)
Consistent
when both
BUD/FM and
FP/SM
delivered via
a single
inhaler
Direct
All-cause non-fatal
SAEs: OR (95%CI)
= 1.14 (0.82, 1.59);
Asthma-related nonfatal SAEs: OR 0.69
(0.37, 1.26)
imprecise
results and not
all studies
compared
equipotent
steroid doses
Moderate
Moderate
Low
BUD/FM compared with FP/SM
2 (5,935)
a
c
SRs
Consistent
Direct
imprecise
results and not
all studies
compared
equipotent
steroid doses
NA
Direct
Compared nonequipotent
steroid
Good
(2)
Good
(2); Fair
(1)
BUD+FM compared with FP/SM
3 (5,390)
RCTs
1 (428)
RCT
Good
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Table H-17. Strength of evidence for tolerability and frequency of adverse events
of BUD/FM compared with FP/SM
No. of
studies
(# of
subjects)
Design
Quality
Consistency
Directness
Magnitude of effect
Other
modifying
factors
components,
only study that
administered
BUD+FM in
separate
inhalers
Overall
strength
of
evidence
BUD = budesonide; FM = formoterol; FP = fluticasone propionate; OR = odds ratio; RCT = randomized controlled
trial; SAE = serious adverse event; SM = salmeterol; SR = systematic review
a
This number is from the larger SR281 that includes the same studies as the other SR94 plus three others
b
These results are from the larger SR281
c
One of the SRs281 includes trials of BUD/FM and BUD+FM
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Appendix I. Meta-analyses
Ciclesonide Meta-Analysis Results
Ciclesonide compared with fluticasone
Summary of outcomes evaluated:
1.
Exacerbations
2.
Rescue medication use (puffs per day)
3.
Change in symptom score
4.
Oral Candidiasis (Thrush)
Results
Exacerbations (studies using the same definition of exacerbation)
Studies included:
Bateman et al. 2008
Boulet et al. 2007
Magnussen et al. 2007a
Magnussen et al. 2007b
Dahl et al. 2010
Ciclesonide v Fluticasone - Exacerbations
Study name
Statistics for each study
Odds ratio and 95%CI
Odds Lower Upper
ratio limit limit Z-Valuep-Value
Bateman, 2008
0.934
Boulet, 2007
0.610
Magnussen, 2007a1.870
Magnussen, 2007b1.918
Dahl, 2010
1.000
0.969
0.309 2.818
0.144 2.584
0.16920.742
0.17321.283
0.286 3.500
0.500 1.878
-0.122
-0.670
0.510
0.531
0.000
-0.094
0.903
0.503
0.610
0.596
1.000
0.925
0.01
0.1
Favors CIC
Results for Heterogeneity among studies:
Q-value
d.f. (Q)
P value
0.99658
4
0.910314
1
10
100
Favors FP
I-squared
0
Only includes studies in which exacerbations were defined as worsening asthma that required treatment with oral steroids.
Includes all doses (Magnussen (a) is CIC 80 mcg v FP 88 mcg Bateman and Boulet are CIC 320 mcg v FP 330 or 200
mcg; Magnussen (b) is CIC 160 mcg once/day v FP 88 mcg bid; Dahl is CIC 80 mcg once/day v 100mcg FP bid).
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Exacerbations (All studies, regardless of definition)
Studies included:
Bateman et al. 2008
Boulet et al. 2007
Magnussen et al. 2007a
Magnussen et al. 2007b
Pederson et al. 2009a
Pederson et al. 2009b
Pederson et al. 2006
Dahl et al. 2010
Ciclesonide v Fluticasone - Exacerbations
Study name
Statistics for each study
Odds ratio and 95%CI
Odds Lower Upper
ratio limit limit Z-Valuep-Value
Bateman, 2008 0.934
Boulet, 2007
0.610
Magnussen, 2007a1.870
Magnussen, 2007b1.918
Pederson, 2009a 3.836
Pederson, 2009b 1.485
Pederson, 2006 1.270
Dahl, 2010
1.000
1.444
0.309 2.818
0.144 2.584
0.16920.742
0.17321.283
1.40110.501
0.465 4.746
0.337 4.785
0.286 3.500
0.905 2.304
-0.122
-0.670
0.510
0.531
2.616
0.667
0.353
0.000
1.541
0.903
0.503
0.610
0.596
0.009
0.505
0.724
1.000
0.123
0.01
0.1
Favors CIC
Results for Heterogeneity among studies:
Q-value
d.f. (Q)
P value
6.047684
7
0.534193
Controller medications for asthma
1
10
100
Favors FP
I-squared
0
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Exacerbations (excluding studies using low-dose CIC)
Studies included:
Bateman et al. 2008
Boulet et al. 2007
Magnussen et al. 2007b
Pederson et al. 2009b
Pederson et al. 2006
Excluded studies (low-dose CIC):
Magnussen et al. 2007a
Pederson et al. 2009a
Dahl et al. 2010
Ciclesonide v Fluticasone - Exacerbations
Study name
Statistics for each study
Odds ratio and 95%CI
Odds Lower Upper
ratio limit limit Z-Valuep-Value
Bateman, 2008 0.934
Boulet, 2007
0.610
Magnussen, 2007b1.918
Pederson, 2009b 1.485
Pederson, 2006 1.270
1.093
0.309 2.818
0.144 2.584
0.17321.283
0.465 4.746
0.337 4.785
0.600 1.991
-0.122
-0.670
0.531
0.667
0.353
0.292
0.903
0.503
0.596
0.505
0.724
0.771
0.01
0.1
Favors CIC
Results for Heterogeneity among studies:
Q-value
d.f. (Q)
P value
1.230898
4
0.872986
Controller medications for asthma
1
10
100
Favors FP
I-squared
0
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Rescue medication use (puffs per day)
Studies included:
Bateman et al. 2008
Buhl et al. 2006
Magnussen et al. 2007a
Magnussen et al. 2007b
Pederson et al. 2009a
Pederson et al. 2009b
Pederson et al. 2007
Note: Data from included studies are reported as median number of puffs per day. The overall effect measure should be
interpreted cautiously.
Ciclesonide v Fluticasone - Rescue medication puffs per day
Study name
Statistics for each study
Std diff in means and 95% CI
Std diff Standard
Lower Upper
in means error Variance limit limit Z-Valuep-Value
Bateman, 2008
Buhl, 2006
Magnussen, 2007a
Magnussen, 2007b
Pederson, 2009a
Pederson, 2009b
Pederson, 2007
0.150
0.046
-0.004
0.000
0.018
0.033
-0.016
0.032
0.089
0.087
0.086
0.087
0.090
0.091
0.088
0.033
0.008-0.025
0.008-0.124
0.007-0.173
0.008-0.170
0.008-0.158
0.008-0.145
0.008-0.189
0.001-0.034
0.325
0.216
0.165
0.170
0.194
0.211
0.158
0.097
1.680
0.529
-0.048
0.000
0.202
0.368
-0.177
0.956
0.093
0.597
0.961
1.000
0.840
0.713
0.859
0.339
-0.50
-0.25
Favors CIC
Results for Heterogeneity among studies:
Q-value
d.f. (Q)
P value
2.39888006
6
0.879609
Controller medications for asthma
0.00
0.25
0.50
Favors FP
I-squared
0
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Symptom score
Studies included:
Bateman et al. 2008
Boulet et al. 2007
Buhl et al. 2006
Magnussen et al. 2007a
Magnussen et al. 2007b
Pederson et al. 2009a
Pederson et al. 2009b
Note: Data from included studies are reported as median changes in asthma symptom score. The overall effect measure should
be interpreted cautiously.
Ciclesonide v Fluticasone - Symptom Score
Study name
Statistics for each study
Std diff in means and 95% CI
Std diff Standard
Lower Upper
in means error Variance limit limit Z-Valuep-Value
Bateman, 2008
Boulet, 2007
Buhl, 2006
Magnussen, 2007a
Magnussen, 2007b
Pederson, 2009a
Pederson, 2009b
0.000
0.000
0.033
0.010
0.025
0.020
0.020
0.016
0.090
0.092
0.087
0.086
0.087
0.091
0.092
0.034
0.008-0.176
0.008-0.180
0.008-0.137
0.007-0.159
0.008-0.145
0.008-0.159
0.008-0.160
0.001-0.050
0.176
0.180
0.204
0.180
0.196
0.198
0.200
0.082
0.000
0.000
0.381
0.121
0.290
0.219
0.218
0.468
1.000
1.000
0.703
0.904
0.772
0.827
0.827
0.640
-0.25
-0.13
Favors CIC
Results for Heterogeneity among studies:
Q-value
d.f. (Q)
P value
0.11983843
6
0.999966
Controller medications for asthma
0.00
0.13
0.25
Favors FP
I-squared
0
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Oral Candidiasis (Thrush) – Odds Ratio – New Analysis
FP vs. CIC: Odds Ratios for Oral Candidiasis-Thrush
Study name
Statistics for each study
Odds
ratio
Bateman 2008 0.400
Boulet 2007
0.052
Dahl 2010
0.404
Lipworth 2005 0.087
Pederson 2009 1.048
0.325
Lower
limit
Upper
limit
0.141 1.138
0.003 0.898
0.140 1.166
0.010 0.720
0.065 16.851
0.166 0.639
Odds ratio and 95% CI
Z-Value p-Value
-1.717
-2.034
-1.676
-2.264
0.033
-3.260
0.086
0.042
0.094
0.024
0.974
0.001
0.01
0.1
Favors CIC
1
10
100
Favors FP
Heterogeneity
Q-value
df (Q)
P-value
I-squared
4.082539064
4
0.394950636
2.021758103
Sensitivity analyses indicate no difference in overall meta-analysis conclusions with single studies removed.
Controller medications for asthma
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Omalizumab Meta-Analysis Results
All studies compare Omalizumab with Placebo.
Summary of outcomes evaluated:
1.
Number of exacerbations per patient
2.
Percentage of patients with one or more exacerbation
3.
Change in AQLQ score
Results
Number of Exacerbations per Patient: Updated Analysis
Studies included:
Busse et al. 2001; Finn et al 2003; Lanier et al. 2005 (single study population)
Holgate et al. 2004
Humbert et al. 2005
Soler et al. 2001; Buhl et al 2002; Buhl et al. 2002 (single study population)
Vignola et al. 2004
Milgrom et al. 2001
Lanier et al. 2009
Omalizumab v Placebo: Number of Exacerbations per Patient
Study name
Statistics for each study
Difference in means and 95% CI
Difference Standard
Lower Upper
in means
error Variance limit
limit Z-Value p-Value
Busse, 2001
Holgate, 2004
Soler, 2001
Milgrom, 2001
Humbert, 2005
Vignola, 2004
Lanier, 2009
-0.260
-0.080
-0.380
-0.100
-0.230
-0.150
-0.190
-0.178
0.094
0.141
0.115
0.059
0.113
0.064
0.070
0.033
0.009
0.020
0.013
0.004
0.013
0.004
0.005
0.001
-0.445
-0.356
-0.605
-0.216
-0.451
-0.276
-0.328
-0.241
-0.075
0.196
-0.155
0.016
-0.009
-0.024
-0.052
-0.114
-2.759
-0.569
-3.309
-1.685
-2.040
-2.336
-2.707
-5.450
0.006
0.569
0.001
0.092
0.041
0.020
0.007
0.000
-1.00
-0.50
Favors Omalizumab
0.00
0.50
1.00
Favors Placebo
Results for Heterogeneity among studies:
Value of Q-statistic
d.f. (Q)
P value
I-squared
6.487
6
0.371
7.506
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Odds Ratio for 1 or more Exacerbations per patient
Studies included:
Busse et al 2001; Finn et al 2003; Lanier et al 2005 (single study population)
Ohta et al. 2009
Soler et al 2001; Buhl et al 2002; Buhl et al., 2002 (single study population)
Milgrom et al 2001
Vignola et al 2004
Holgate, 2004
Studies that reported outcome, but are not included: NA
Omalizumab v Placebo: Proportion of Patients with One or More Exacerbation
Study name
Statistics for each study
Odds ratio and 95% CI
Odds Lower Upper
ratio limit
limit Z-Value p-Value
Busse, 2001 0.563
Ohta, 2009 0.337
Soler, 2001 0.334
Milgrom, 2001 0.622
Vignola, 2004 0.603
Holgate, 2004 0.805
0.514
0.360
0.130
0.216
0.351
0.383
0.366
0.396
0.879
0.871
0.519
1.105
0.948
1.772
0.668
-2.528
-2.244
-4.896
-1.620
-2.190
-0.538
-4.973
0.011
0.025
0.000
0.105
0.028
0.591
0.000
0.1 0.2
0.5 1
Favors Omalizumab
2
5 10
Favors Placebo
Results for Heterogeneity among studies:
Value of Q-statistic
d.f. (Q)
P value
I-squared
6.743
5
0.240
25.847
Controller medications for asthma
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Change in AQLQ Score: Updated Analysis
Studies included:
Busse et al. 2001; Finn et al. 2003; Lanier et al. 2005 (single study population)
Holgate et al. 2004
Humbert et al. 2005
Soler et al. 2001; Buhl et al. 2002; Buhl et al. 2002 (single study population)
Vignola et al. 2004
Studies that reported outcome, but are not included: NA
Omalizumab v Placebo - Change in AQLQ Score
Study name
Statistics for each study
Std diff in means and 95% CI
Std diff Standard
Lower Upper
in means error Variance limit limit Z-Valuep-Value
Busse, 2001 0.226
Holgate, 2004 0.310
Humbert, 2005 0.324
Soler, 2001 0.283
Vignola, 2004 0.195
0.263
0.088
0.128
0.098
0.086
0.100
0.043
0.008
0.016
0.010
0.007
0.010
0.002
0.054
0.059
0.131
0.115
0.000
0.178
0.397
0.561
0.517
0.452
0.391
0.349
2.577
2.416
3.293
3.292
1.961
6.066
0.010
0.016
0.001
0.001
0.050
0.000
-1.00
-0.50
Favours Placebo
0.00
0.50
1.00
Favours Omalizumab
Results for Heterogeneity among studies:
Value of Q-statistic
d.f. (Q)
P value
I-squared
1.212
4
0.876
0.000
Controller medications for asthma
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ICS+LABA VS. ICS+LABA (Combination products)
Meta-Analysis Results
Summary of Outcomes Evaluated:
1.
Exacerbations requiring oral steroids
2.
Exacerbations requiring emergency visit/hospital admission
Study compares fixed Dose Combo of BUD/FM with Fixed Dose Combo FP/SM
Data were gathered from the individual articles when possible; when exacerbation data were not reported in the articles,
available data were gathered by contacting the authors or from a published systematic review (Lasserson, 2008).
Exacerbations requiring oral steroids
Studies included:
Aalbers et al. 2004 ; Aalbers et al. 2010
Dahl et al. 2006
Kuna et al. 2007 and Price et al. 2007
Studies that reported outcome, but are not included:
Ringdal et al. 2002: Administered BUD and FM in separate inhalers; daily BUD dose was twice the BUD dose in included
studies.
Budesonide+Formoterol vs. Fluticasone+Salmeterol - Exacerbations (requiring oral steroids)
Study name
Statistics for each study
Odds
ratio
Odds ratio and 95% CI
Lower
limit
Upper
limit
p-Value
Aalbers et al 2004; Aalbers et al 2010
1.142
0.669
1.950
0.626
Dahl et al 2006
1.280
0.903
1.815
0.165
Kuna et al 2007; Price et al 2007; Kuna 2010
1.090
0.824
1.441
0.547
1.158
0.946
1.417
0.155
0.5
Favors BUD/FM
Q-value
0.501296225
df (Q)
2
Heterogeneity
P-value
0.778296196
1
2
Favors FP/SM
I-squared
0
Sensitivity analyses indicate no difference in overall meta-analysis conclusions with single studies removed.
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Exacerbations requiring emergency visit/hospital admission
Studies included:
Aalbers et al. 2004; Aalbers et al. 2010
Dahl et al. 2006
Kuna et al. 2007 and Price et al. 2007
Studies that reported outcome, but are not included:
Ringdal et al. 2002 :
Administered BUD and FM in separate inhalers; daily BUD dose was twice the BUD dose in included studies
Budesonide+Formoterol vs. Fluticasone+Salmeterol - Exacerbations (requiring ER/hospital admission)
Study name
Statistics for each study
Odds
ratio
Odds ratio and 95% CI
Lower
limit
Upper
limit
p-Value
Aalbers et al 2004; Aalbers et al 2010
0.429
0.109
1.680
0.224
Dahl et al 2006
1.252
0.491
3.191
0.638
Kuna et al 2007; Price et al 2007; Kuna 2010
0.713
0.491
1.035
0.075
0.743
0.531
1.040
0.083
0.5
1
Favors BUD/FM
Q-value
1.864494918
Heterogeneity
P-value
0.393667963
df (Q)
2
2
Favors FP/SM
I-squared
0
Sensitivity analyses indicate no difference in overall meta-analysis conclusions with single studies removed with the exception of
removing Dahl et al, 2006. The overall result became significant in favor of BUD + FM when Dahl et al, 2006 [OR 0.688 (9% CI
0.480 to 0.986)] was removed.
Sensitivity Analyses – Exacerbations (requiring ER/hospital admission – BUD+FM vs. FP+SM
BUD+FM vs. FP+SM - Exacerbations (requiring ER/hospital admission) Sensitivity Analysis
Studyname
Statistics with studyremoved
Point
Lower
limit
Upper
limit
Z-Value
Odds ratio (95%CI) with studyremoved
p-Value
Aalbers et al 2004; Aalbers et al 2010
0.797
0.514
1.236
-1.014
0.311
Dahl et al 2006
0.688
0.480
0.986
-2.036
0.042
Kuna et al 2007; Price et al 2007; Kuna 2010
0.826
0.297
2.299
-0.366
0.714
0.743
0.531
1.040
-1.732
0.083
0.5
Favors BUD+FM
Controller medications for asthma
1
2
Favors FP+SM
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BUD/FM (MART) compared with ICS+LABA (fixed
dose) Meta-Analysis Results
All studies compare BUD/FM MART vs. BUD/FM except Kuna et al 2007 and price et al 2007, which in addition, compares
BUD/FM MART vs. FP/SM. denoted with *
Summary of outcomes evaluated
1. Severe exacerbations requiring medical intervention
2. Severe exacerbations requiring emergency visit or hospital admission
3. Rescue medication use (puffs/day)
4. Rescue medication use (% rescue-free days)
5. Symptoms (% symptom-free days)
6. Symptoms (score)
7. Nocturnal Awakenings
Severe exacerbations requiring medical intervention
Studies included:
Vogelmeier et al. 2005
O’Byrne et al. 2005
Bousquet et al. 2007
Kuna et al. 2007; Price et al. 2007 ; Kuna 2010 vs FP/SM
Kuna et al. 2007; Price et al. 2007 ; Kuna 2010 vs BUD/FM
Studies that reported outcome, but are not included:
Bisgaard et al. 2006:
Post-hoc subset analysis of O’Byrne et al. 2005 ; inclusion would result in double-counting data
Severe Exacerbations (requiring medical intervention) - BUD/FM MART vs. ICS/LABA
Study name
Statistics for each study
Odds
ratio
Bousquet 2007
Vogelmeier, 2005
O'Byrne 2005
Kuna 2007; Price 2007; Kuna 2010 vs FP/SM
Kuna 2007; Price 2007; Kuna 2010 vs BUD/FM
0.815
0.749
0.509
0.662
0.806
0.746
Odds ratio and 95% CI
Lower Upper
limit
limit
p-Value
0.622
0.596
0.244
0.502
0.609
0.656
0.136
0.012
0.072
0.003
0.131
0.000
1.067
0.939
1.062
0.873
1.067
0.848
1
0.5
Favors MART
2
Favors ICS/LABA
Heterogeneity
Q-value
df (Q)
P-value
I-squared
2.453449782
4
0.652990274
0
Sensitivity analyses indicate no difference in overall meta-analysis conclusions with single studies removed.
Controller medications for asthma
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Severe exacerbations requiring emergency visit or hospital admission
Studies included:
Vogelmeier et al. 2005
Bousquet et al. 2007
Kuna et al. 2007; Price et al. 2007 ; Kuna 2010 vs FP/SM
Kuna et al. 2007; Price et al. 2007 ; Kuna 2010 vs BUD/FM
Studies that reported outcome, but are not included: NA
Severe Exacerbations (requiring emergency department visits or hospital admission) - BUD/FM MART vs. ICS/LABA
Study name
Statistics for each study
Odds
ratio
Odds ratio and 95% CI
Lower
limit
Upper
limit
p-Value
Bousquet 2007
0.650
0.430
0.983
0.041
Vogelmeier, 2005
0.670
0.421
1.065
0.090
Kuna 2007; Price 2007; Kuna 2010 vs FP/SM
0.682
0.468
0.994
0.047
Kuna 2007; Price 2007; Kuna 2010 vs BUD/FM
0.956
0.638
1.434
0.829
0.733
0.597
0.900
0.003
0.5
1
Favors MART
2
Favors ICS/LABA
Heterogeneity
Q-value
df (Q)
P-value
I-squared
2.264524
3
0.519351
0
Sensitivity analyses indicate no difference in overall meta-analysis conclusions with single studies removed.
Controller medications for asthma
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Rescue medication use (puffs/day) – Updated Analysis
Studies included:
Vogelmeier et al. 2005
O’Byrne et al. 2005
Bousquet et al. 2007
Kuna et al. 2007; Price et al. 2007 ; Kuna 2010 vs FP/SM
Kuna et al. 2007; Price et al. 2007 ; Kuna 2010 vs BUD/FM
Studies that reported outcome, but are not included:
Bisgaard et al. 2006:
Post-hoc subset analysis of O’Byrne et al. 2005 ; inclusion would result in double-counting data
Rescue medication use (puffs/day) - BUD/FM MART vs. ICS/LABA
Study name
Statistics for each study
Std diff
in means
Standard
error
Lower
limit
Variance
Upper
limit
Std diff in means and 95% CI
Z-Value
p-Value
Vogelmeier, 2005
-0.142
0.043
0.002
-0.227
-0.058
-3.291
0.001
O'Byrne, 2005
-0.154
0.047
0.002
-0.246
-0.062
-3.291
0.001
Bousquet, 2007
-0.038
0.042
0.002
-0.120
0.044
-0.915
0.360
Kuna 2007; Price 2007; Kuna 2010 vs FP/SM 0.065
0.042
0.002
-0.018
0.148
1.525
0.127
Kuna 2007; Price 2007; Kuna 2010 vs BUD/FM
-0.028
0.043
0.002
-0.111
0.056
-0.654
0.513
-0.058
0.040
0.002
-0.137
0.020
-1.461
0.144
-1.00
-0.50
0.00
0.50
1.00
Favors BUD/FM MART Favors ICS+LABA
Heterogeneity
Q-value
df (Q)
P-value
I-squared
17.090854
4
1.86E-03
76.5956697
Sensitivity analyses indicate no difference in overall meta-analysis conclusions with single studies removed.
Controller medications for asthma
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Rescue medication use (% rescue-free days): Updated Analysis
Studies included:
O’Byrne et al. 2005
Bousquet et al. 2007
Kuna et al. 2007; Price et al. 2007 ; Kuna 2010 vs FP/SM
Kuna et al. 2007; Price et al. 2007 ; Kuna 2010 vs BUD/FM
Studies that reported outcome, but are not included:
Bisgaard et al. 2006:
Post-hoc subset analysis of O’Byrne et al. 2005; inclusion would result in double-counting data
Percent Rescue Free Days - BUD/FM MART vs. ICS/LABA
Study name
Statistics for each study
Std diff
Standard
error
Bousquet 2007,
-0.024
Kuna 2007; Price 2007; Kuna vs FP/SM -0.097
Kuna 2007; Price 2007; Kuna vs BUD/FM
-0.054
O'Byrne, 2005
0.024
-0.040
0.042
0.042
0.043
0.047
0.025
in means
Lower
Variance
0.002
0.002
0.002
0.002
0.001
Std diff in means and 95% CI
Upper
limit
-0.106
-0.180
-0.137
-0.067
-0.088
limit
Z-Value
p-Value
0.058
-0.014
0.030
0.116
0.009
-0.570
-2.281
-1.260
0.524
-1.593
0.568
0.023
0.208
0.600
0.111
-1.00
-0.50
0.00
Favors MART
0.50
1.00
Favors ICS/LABA
Heterogeneity
Q-value
df (Q)
P-value
I-squared
3.945357456
3
0.26742531
23.96126248
Sensitivity analyses indicate no difference in overall meta-analysis conclusions with single studies removed with the exception of
removing O’Byrne. The overall result becomes significant in favor of BUD/FM MART (SMD -0.058 (95% CI -0.106 to -010).
Sensitivity Analysis - % Rescue-free days BUD/FM MART vs. ICS/LABA MART
BUD/FM MART vs. ICS/LABA- Rescue-free days
Study name
Statistics with study removed
Upper
limit
Std diff in means (95% CI) with study removed
Point
Standard
error
Variance
Lower
limit
Z-Value
p-Value
Bousquet,
-0.044
0.035
0.001
-0.112
0.024
-1.278
0.201
Kuna 2007; Price 2007; Kuna vs FP/SM
-0.020
0.025
0.001
-0.069
0.029
-0.805
0.421
Kuna 2007; Price 2007; Kuna vs BUD/FM
-0.034
0.035
0.001
-0.102
0.034
-0.976
0.329
O'Byrne
-0.058
0.024
0.001
-0.106
-0.010
-2.368
0.018
-0.040
0.025
0.001
-0.088
0.009
-1.593
0.111
-2.00
-1.00
Favors BUD/FM MART
Controller medications for asthma
0.00
1.00
2.00
Favors ICS + LABA
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Symptoms (% symptom-free days): Updated Analysis
Studies included:
O’Byrne et al. 2005
Bousquet et al. 2007
Kuna et al. 2007; Price et al. 2007 ; Kuna 2010 vs FP/SM
Kuna et al. 2007; Price et al. 2007 ; Kuna 2010 vs BUD/FM
Studies that reported outcome, but are not included:
Bisgaard et al. 2006:
Post-hoc subset analysis of O’Byrne et al. 2005; inclusion would result in double-counting data
Percent Symptom Free Days - BUD/FM MART vs. ICS/LABA
Study name
Statistics for each study
Std diff in means and 95% CI
Std diff Standard
Lower Upper
in means error Variance limit
limit Z-Value p-Value
Bousquet 2007
O'Byrne 2005
0.014
-0.030
Kuna 2007; Price 2007; Kuna 2010 vs FP/SM
0.074
Kuna 2007; Price 2007; Kuna 2010 vs BUD/FM
0.024
0.023
0.042
0.047
0.042
0.043
0.022
0.002
0.002
0.002
0.002
0.000
-0.068
-0.122
-0.009
-0.060
-0.019
0.096 0.345
0.061 -0.643
0.157 1.750
0.107 0.560
0.065 1.058
0.730
0.520
0.080
0.575
0.290
-1.00
-0.50
0.00
Favors BUD/FM MART
0.50
1.00
Favors ICS/LABA
Heterogeneity
Q-value
df (Q)
P-value
I-squared
2.790543715
3
0.42505896
0
Sensitivity analyses indicate no difference in overall meta-analysis conclusions with single studies removed.
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Symptoms (score) – Updated Analysis
Studies included:
Vogelmeier et al. 2005
O’Byrne et al. 2005
Bousquet et al. 2007
Kuna et al. 2007; Price et al. 2007 ; Kuna 2010 vs FP/SM
Kuna et al. 2007; Price et al. 2007 ; Kuna 2010 vs BUD/FM
Studies that reported outcome, but are not included:
Bisgaard et al. 2006:
Post-hoc subset analysis of O’Byrne et al. 2005; inclusion would result in double-counting data
Symptom Score - BUD/FM MART vs. ICS/LABA
Study name
Statistics for each study
Std diff
Standard
in means
error
Upper
limit
Std diff in means and 95% CI
Z-Value
p-Value
Vogelmeier, 2005
-0.079
0.043
0.002
-0.163
0.006
-1.819
0.069
O'Byrne, 2005
-0.073
0.047
0.002
-0.164
0.019
-1.555
0.120
0.004
0.042
0.002
-0.078
0.086
0.100
0.920
Kuna 2007; Price 2007; Kuna 2010 vs FP/SM 0.051
0.042
0.002
-0.032
0.134
1.207
0.228
Kuna 2007; Price 2007; Kuna 2010 vs BUD/FM
0.000
0.043
0.002
-0.083
0.083
0.000
1.000
-0.018
0.025
0.001
-0.066
0.031
-0.714
0.475
Bousquet, 2007
Variance
Lower
limit
-1.00
-0.50
0.00
Favors BUD/FM MART
0.50
1.00
Favors ICS/LABA
Heterogeneity
Q-value
df (Q)
P-value
I-squared
6.453186856
4
0.16776399
38.01512199
Sensitivity analyses indicate no difference in overall meta-analysis conclusions with single studies removed.
Controller medications for asthma
276 of 369
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Drug Effectiveness Review Project
Nocturnal Awakenings: Updated Analysis
Studies included:
Bosquet at al 2007
O'Byrne et al 2005
Kuna et al 2007; Price at al 2007; Kuna 2010
Studies that reported outcome, but are not included: NA
Nocturnal awakenings - BUD/FM MART vs. ICS/LABA
Study name
Statistics for each study
Std diff
in means
Standard
error
Variance
Lower
limit
Upper
limit
Std diff in means and 95% CI
Z-Value
p-Value
Bousquet 2007
-0.069
0.042
0.002
-0.151
0.013
-1.644
0.100
Kuna 2007; Price 2007; Kuna 2010 vs FP/SM
-0.040
0.042
0.002
-0.123
0.043
-0.951
0.342
Kuna 2007; Price 2007; Kuna 2010 vs BUD/FM -0.051
0.043
0.002
-0.134
0.033
-1.188
0.235
O'Byrne 2005
-0.154
0.047
0.002
-0.246
-0.062
-3.291
0.001
-0.076
0.025
0.001
-0.124
-0.027
-3.073
0.002
-1.00
-0.50
0.00
0.50
1.00
Favors BUD/FM MART Favors ICS/LABA
Q-value
3.872799
Heterogeneity
df (Q)
P-value
3
0.275531
I-squared
22.53664
Sensitivity analyses indicate no difference in overall meta-analysis conclusions with single studies removed.
Controller medications for asthma
277 of 369
Final Update 1 Report
Drug Effectiveness Review Project
Inter-class comparisons (Between classes)
Leukotriene Receptor Antagonist Meta-Analysis Results
LTRA compared with ICS Results
Summary of Outcome Measures Analyzed:
1.
Rescue medication use (percent improved rescue free days)
2.
Rescue medication use (decrease in puffs)
3.
Symptom control (percent improved symptom free days)
4.
Symptom control (change in score)
5.
Percent Exacerbations
6.
Change in AQLQ Scores
Results
Rescue Medication Use (percent rescue free days): Updated Analysis
Included studies:
Baumgartner et al. 2003
Bleeker et al. 2000
Brabson et al. 2002
Busse et al. 2001a
Busse et al. 2001b
Garcia et al. 2005
Meltzer et al. 2002
Ostrom 2005
Kim et al. 2000
Peters et al. 2007
Zeiger et al. 2005
Zeiger et al. 2006
Studies that reported outcome, but are not included:
Study
Ducharme et al 2004
Halpern et al. 2003
Malmstrom et al. 1999
Controller medications for asthma
Reason
Review paper
Review paper
P values reported are for placebo comparisons
278 of 369
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Drug Effectiveness Review Project
ICS v LTRA: Rescue Medication Use (Percent Rescue Free Days)
Study name
Statistics for each study
Std diff in means and 95% CI
Std diff Standard
Lower Upper
in means
error Variance limit
limit Z-Value p-Value
Baumgartner 2003
Bleeker 2000
Brabson 2002
Busse 2001 #715
Busse 2001 #673
Garcia 2005
Meltzer 2002
Ostrom 2005
Peters 2007
Kim 2000
Zeiger 2005
Zeiger 2006
-0.157
-0.312
-0.296
-0.287
-0.263
-0.189
-0.290
-0.337
-0.186
-0.317
-0.051
-0.511
-0.251
0.080
0.095
0.096
0.087
0.134
0.064
0.088
0.109
0.110
0.096
0.103
0.131
0.029
0.006
0.009
0.009
0.008
0.018
0.004
0.008
0.012
0.012
0.009
0.011
0.017
0.001
-0.314
-0.498
-0.484
-0.457
-0.526
-0.313
-0.462
-0.550
-0.400
-0.506
-0.252
-0.768
-0.308
-0.000
-0.126
-0.109
-0.116
-0.000
-0.064
-0.117
-0.123
0.029
-0.128
0.150
-0.254
-0.194
-1.961
-3.292
-3.092
-3.292
-1.962
-2.968
-3.292
-3.093
-1.697
-3.292
-0.499
-3.895
-8.624
0.050
0.001
0.002
0.001
0.050
0.003
0.001
0.002
0.090
0.001
0.618
0.000
0.000
-1.00
-0.50
Favors ICS
0.00
0.50
1.00
Favors LTRA
Sensitivity analyses indicate no difference in overall meta-analysis conclusions with single studies removed.
Results for Heterogeneity among studies:
Q-value
d.f. (Q)
P value
I-squared
12.509
11
0.327
12.062
Controller medications for asthma
279 of 369
Final Update 1 Report
Drug Effectiveness Review Project
Rescue Medication Use (puffs per day): Updated Analysis
Included studies:
Bleeker et al. 2000
Brabson et al. 2002
Busse et al. 2001a
Busse et al. 2001b
Israel et al. 2002
Kim et al. 2000
Lu et al. 2009
Meltzer et al. 2002
Ostrom et al. 2005
Stelmach et al. 2005
Yurdukal et al. 2003
Zeiger et al. 2005
Zeiger et al. 2006
Studies that reported outcome, but are not included:
Study
Ducharme et al 2004
Halpern et al 2003
Malmstrom et al 1999
Reason
Review paper
Review paper
p-values reported are for placebo comparisons
ICS v LTRA: Rescue Medication Use (Mean Change in Puffs per Day)
Study name
Std diff
in means
Bleeker 2000
-0.312
-0.316
-0.287
Busse 2001 #673 -0.263
Israel 2002
-0.038
Kim 2000
-0.317
Lu 2009
-0.115
Meltzer 2002
-0.290
Ostrom 2005
-0.257
Stelmach 2005
-0.549
Yurdakul 2003
0.000
Zeiger 2005
-0.102
Zeiger 2006
-0.281
-0.228
Brabson 2002
Busse 2001 #715
Statistics for each study
Lower
Upper
Standard
error
Variance
limit
limit
0.095
0.009 -0.498 -0.126
0.096
0.009 -0.504 -0.128
0.087
0.008 -0.457 -0.116
0.134
0.018 -0.526 -0.000
0.077
0.006 -0.190 0.113
0.096
0.009 -0.506 -0.128
0.108
0.012 -0.327 0.097
0.088
0.008 -0.462 -0.117
0.109
0.012 -0.470 -0.044
0.350
0.122 -1.235 0.137
0.283
0.080 -0.554 0.554
0.103
0.011 -0.303 0.099
0.130
0.017 -0.535 -0.027
0.001 -0.291 -0.165
0.032
Std diff in means and 95% CI
Z-Value p-Value
-3.292
0.001
-3.292
0.001
-3.292
0.001
-1.962
0.050
-0.495
0.621
-3.292
0.001
-1.061
0.289
-3.292
0.001
-2.367
0.018
-1.568
0.117
0.000
1.000
-0.995
0.320
-2.166
0.030
-7.099
0.000
-1.00
-0.50
Favors ICS
0.00
0.50
1.00
Favors LTRA
The results of this meta-analysis show a significant reduction in the use of rescue medication (measured in puffs per day) with
ICS over LTRA.
Sensitivity analyses indicate no difference in overall meta-analysis conclusions with single studies removed.
Results for Heterogeneity among studies:
Q-value
d.f. (Q)
P-value
I-squared
13.862
12
0.310
13.433
Controller medications for asthma
280 of 369
Final Update 1 Report
Drug Effectiveness Review Project
Percent Improved Symptom Control (symptom free days): Updated Analysis
Included studies:
Baumgartner et al. 2003
Bleeker et al. 2000
Brabson et al. 2002
Busse et al. 2001a
Busse et al. 2001b
Israel et al. 2002
Kim et al. 2000
Malmstrom et al. 1999
Meltzer et al. 2002
Ostrom et al. 2005
Peters et al. 2007
Sorkness et al. 2007
Yurdukal et al. 2003
Zeiger et al. 2005
Studies that reported outcome, but are not included:
Study
Ducharme et al. 2004
Halpern et al. 2003
Zeiger et al. 2006
Reason
Review paper
Review paper
Measured different outcomes
ICS v LTRA: Symptom Control (Percent Symptom Free Days)
Study name
Statistics for each study
Std diff in means and 95% CI
Std diff Standard
Lower Upper
in means error Variance limit limit Z-Value p-Value
Baumgartner 2003-0.157
Bleeker 2000
-0.312
Brabson 2002
-0.316
Busse 2001 #715 -0.287
Busse 2001 #673 -0.263
Israel 2002
0.006
Malmstrom 1999 -0.209
Meltzer 2002
-0.290
Ostrom 2005
-0.186
Peters 2007
-0.180
Sorkness 2007 -0.422
Zeiger 2005
-0.121
Kim 2000
-0.259
-0.214
0.080
0.095
0.096
0.087
0.134
0.063
0.081
0.088
0.108
0.109
0.146
0.103
0.096
0.033
0.006
0.009
0.009
0.008
0.018
0.004
0.007
0.008
0.012
0.012
0.021
0.011
0.009
0.001
-0.314
-0.498
-0.504
-0.457
-0.526
-0.119
-0.369
-0.462
-0.398
-0.395
-0.708
-0.322
-0.448
-0.279
-0.000
-0.126
-0.128
-0.116
-0.000
0.130
-0.050
-0.117
0.027
0.034
-0.135
0.081
-0.071
-0.149
-1.961
-3.292
-3.292
-3.292
-1.962
0.089
-2.577
-3.292
-1.713
-1.646
-2.882
-1.176
-2.698
-6.421
0.050
0.001
0.001
0.001
0.050
0.929
0.010
0.001
0.087
0.100
0.004
0.240
0.007
0.000
-1.00
-0.50
Favors ICS
0.00
0.50
1.00
Favors LTRA
Sensitivity analyses indicate no difference in overall meta-analysis conclusions with single studies removed.
Results for Heterogeneity among studies:
Q-value
d.f. (Q)
P value
19.244
12
0.083
Controller medications for asthma
I-squared
37.644
281 of 369
Final Update 1 Report
Drug Effectiveness Review Project
Percent Improved Symptom Control (symptom score)
Included studies:
Bleeker et al. 2000
Brabson et al. 2002
Busse et al. 2001a
Busse et al. 2001b
Laviolette et al. 1999
Malmstrom et al. 1999
Meltzer et al. 2002
Ostrom et al. 2005
Zeiger et al. 2005
Kim et al. 2000
Studies that reported outcome, but are not included:
Study
Ducharme et al 2004
Halpern et al 2003
Reason
Review paper
Review paper
Composite measure that includes more than just symptom
score
P-value only reported as NS, no measures of variation
reported
Stelmack et al 2005
Yurdulak et al 2003
ICS v LTRA: Symptom Control (Change in Symptom Score)
Study name
Statistics for each study
Std diff in means and 95% CI
Std diff Standard
Lower Upper
in means error Variance limit limit Z-Value p-Value
Bleeker 2000
-0.312
Brabson 2002
-0.316
Busse 2001 #715-0.287
Busse 2001 #673-0.263
Laviolette 1999 -0.498
Malmstrom 1999 -0.209
Meltzer 2002
-0.290
Ostrom 2005
-0.138
Zeiger 2005
-0.174
Kim 2000
-0.317
-0.281
0.095
0.096
0.087
0.134
0.102
0.081
0.088
0.108
0.103
0.096
0.031
0.009
0.009
0.008
0.018
0.010
0.007
0.008
0.012
0.011
0.009
0.001
-0.498
-0.504
-0.457
-0.526
-0.699
-0.369
-0.462
-0.350
-0.376
-0.506
-0.340
-0.126
-0.128
-0.116
-0.000
-0.297
-0.050
-0.117
0.074
0.027
-0.128
-0.221
-3.292
-3.292
-3.292
-1.962
-4.860
-2.577
-3.292
-1.277
-1.697
-3.292
-9.183
0.001
0.001
0.001
0.050
0.000
0.010
0.001
0.202
0.090
0.001
0.000
-1.00
-0.50
Favors ICS
0.00
0.50
1.00
Favors LTRA
Sensitivity analyses indicate no difference in overall meta-analysis conclusions with single studies removed.
Results for Heterogeneity among studies:
Q-value
d.f. (Q)
P-value
8.483
9
0.486
Controller medications for asthma
I-squared
0.000
282 of 369
Final Update 1 Report
Drug Effectiveness Review Project
Percent Exacerbations: Updated Analysis
Included studies:
Baumgartner et al. 2003
Bleeker et al. 2000
Brabson et al. 2002
Busse et al. 2001a
Busse et al. 2001b
Garcia et al. 2005
Malmstrom et al. 1999
Meltzer et al. 2002
Peters et al. 2007
Sorkness et al. 2007
Szefler et al. 2005
Kim et al. 2000
Yurdukal et al. 2003
Studies that reported outcome, but are not included:
Study
Ducharme et al. 2004
Halpern et al. 2003
Reason
Review paper
Review paper
ICS v LTRA: Percent Exacerbations
Study name
Statistics for each study
Std diff in means and 95% CI
Std diff Standard
Lower Upper
in means error Variance limit limit Z-Value p-Value
Baumgartner 2003-0.052
Bleeker 2000
-0.123
Brabson 2002
-0.269
Busse 2001 #715 -0.153
Busse 2001 #673 -0.263
Garcia 2005
-0.150
Malmstrom 1999 -0.209
Meltzer 2002
-0.023
Peters 2007
-0.238
Sorkness 2007 -0.382
Szefler 2005
-0.278
Kim 2000
-0.202
Yurdakul 2003
-0.429
-0.171
0.080
0.094
0.096
0.087
0.134
0.064
0.081
0.088
0.110
0.146
0.118
0.096
0.286
0.027
0.006
0.009
0.009
0.008
0.018
0.004
0.007
0.008
0.012
0.021
0.014
0.009
0.082
0.001
-0.208
-0.308
-0.457
-0.323
-0.526
-0.275
-0.369
-0.195
-0.453
-0.668
-0.510
-0.390
-0.990
-0.223
0.105
0.061
-0.081
0.017
-0.000
-0.026
-0.050
0.148
-0.023
-0.096
-0.046
-0.014
0.132
-0.119
-0.650
-1.308
-2.809
-1.763
-1.962
-2.366
-2.577
-0.268
-2.172
-2.616
-2.348
-2.110
-1.499
-6.454
0.516
0.191
0.005
0.078
0.050
0.018
0.010
0.789
0.030
0.009
0.019
0.035
0.134
0.000
-1.00
-0.50
Favors ICS
0.00
0.50
1.00
Favors LTRA
Sensitivity analyses indicate no difference in overall meta-analysis conclusions with single studies removed.
Results for Heterogeneity among studies:
Q-value
d.f. (Q)
P value
11.410
12
0.494
Controller medications for asthma
I-squared
0.000
283 of 369
Final Update 1 Report
Drug Effectiveness Review Project
Change in AQLQ Score: Updated Analysis
Studies included:
Busse et al. 2001a
Garcia et al. 2005
Malmstrom et al. 1999
Meltzer et al. 2002
Peters et al. 2007
Zeiger et al. 2005
Kim et al. 2000
ICS v LTRA: Change in AQLQ Score
Study name
Statistics for each study
Std diff in means and 95% CI
Std diff Standard
Lower Upper
in means error Variance limit limit Z-Value p-Value
Busse 2001 #673-0.287
Garcia 2005
-0.133
Malmstrom 1999 -0.209
Meltzer 2002
-0.290
Peters 2007
-0.025
Zeiger 2005
-0.132
Kim 2000
-0.317
-0.193
0.134
0.064
0.081
0.088
0.109
0.103
0.096
0.037
0.018
0.004
0.007
0.008
0.012
0.011
0.009
0.001
-0.550
-0.258
-0.369
-0.462
-0.239
-0.333
-0.506
-0.266
-0.023
-0.009
-0.050
-0.117
0.189
0.070
-0.128
-0.121
-2.135
-2.097
-2.577
-3.292
-0.228
-1.282
-3.292
-5.201
0.033
0.036
0.010
0.001
0.820
0.200
0.001
0.000
-1.00
-0.50
Favors ICS
0.00
0.50
1.00
Favors LTRA
Sensitivity analyses indicate no difference in overall meta-analysis conclusions with single studies removed.
Results for Heterogeneity among studies:
Q-value
d.f. (Q)
P value
7.001
6
0.321
Controller medications for asthma
I-squared
14.301
284 of 369
Final Update 1 Report
Drug Effectiveness Review Project
ML compared with ICS Results
Summary of Outcome Measures Analyzed:
1.
Rescue medication use (percent improved)
2.
Rescue medication use (puffs)
3.
Symptom control (percent improved)
4.
Symptom score
5.
Percent Exacerbations
6.
Change in AQLQ Scores
Results
Rescue Medication Use (percent improved symptom free days): Updated
Analysis
Studies that reported outcome, but are not included:
Study
Yurdukal et al 2003
Becker et al. 2006
Malmstrom et al. 1999
Reason
P value nonsignificant, no variance reported
Outcome is reported as a median
P-Value for comparison of interest not reported
ICS v ML: Rescue Medication Use (Percent Rescue Free Days)
Study name
Statistics for each study
Std diff
Standard
in means
error
Baumgartner 2003 -0.157
0.080
Busse 2001 #715 -0.287
0.087
Garcia 2005
-0.189
0.064
Meltzer 2002
-0.290
0.088
Ostrom 2005
-0.337
0.109
Peters 2007
-0.186
0.110
Zeiger 2005
-0.051
0.103
Zeiger 2006
-0.511
0.131
-0.235
0.041
Lower
Variance
0.006
0.008
0.004
0.008
0.012
0.012
0.011
0.017
0.002
limit
-0.314
-0.457
-0.313
-0.462
-0.550
-0.400
-0.252
-0.768
-0.315
Std diff in means and 95% CI
Upper
limit
-0.000
-0.116
-0.064
-0.117
-0.123
0.029
0.150
-0.254
-0.155
Z-Value p-Value
-1.961
0.050
-3.292
0.001
-2.968
0.003
-3.292
0.001
-3.093
0.002
-1.697
0.090
-0.499
0.618
-3.895
0.000
-5.758
0.000
-1.00
-0.50
Favors ICS
0.00
0.50
1.00
Favors ML
Sensitivity analyses indicate no difference in overall meta-analysis conclusions with single studies removed.
Results for Heterogeneity among studies:
Q-value
d.f. (Q)
P value
10.884
7
0.144
Controller medications for asthma
I-squared
35.686
285 of 369
Final Update 1 Report
Drug Effectiveness Review Project
Rescue Medication Use (puffs per day): Updated Analysis
ICS v ML: Rescue Medication Use (Mean Change in Puffs per Day)
Study name
Statistics for each study
Std diff in means and 95% CI
Std diff Standard
Lower Upper
in means error Variance limit limit Z-Value p-Value
Busse 2001 #715-0.287
Israel 2002
-0.038
Lu 2009
-0.115
Meltzer 2002
-0.290
Ostrom 2005
-0.257
Stelmach 2005 -0.549
Yurdakul 2003 0.000
Zeiger 2005
-0.102
Zeiger 2006
-0.281
-0.189
0.087
0.077
0.108
0.088
0.109
0.350
0.283
0.103
0.130
0.042
0.008
0.006
0.012
0.008
0.012
0.122
0.080
0.011
0.017
0.002
-0.457
-0.190
-0.327
-0.462
-0.470
-1.235
-0.554
-0.303
-0.535
-0.271
-0.116
0.113
0.097
-0.117
-0.044
0.137
0.554
0.099
-0.027
-0.108
-3.292
-0.495
-1.061
-3.292
-2.367
-1.568
0.000
-0.995
-2.166
-4.557
0.001
0.621
0.289
0.001
0.018
0.117
1.000
0.320
0.030
0.000
-1.00
-0.50
Favors ICS
0.00
0.50
1.00
Favors ML
Sensitivity analyses indicate no difference in overall meta-analysis conclusions with single studies removed.
Results for Heterogeneity among studies:
Q-value
d.f. (Q)
P-value
9.962
8
0.268
Controller medications for asthma
I-squared
19.699
286 of 369
Final Update 1 Report
Drug Effectiveness Review Project
Percent Improved Symptom Control (symptom free days): Updated Analysis
ICS v ML: Symptom Control (Percent Symptom Free Days)
Study name
Statistics for each study
Std diff in means and 95% CI
Std diff Standard
Lower Upper
in means error Variance limit limit Z-Value p-Value
Baumgartner 2003-0.157
Busse 2001 #715 -0.287
Israel 2002
0.006
Malmstrom 1999 -0.209
Meltzer 2002
-0.290
Ostrom 2005
-0.186
Peters 2007
-0.180
Sorkness 2007 -0.422
Zeiger 2005
-0.121
-0.187
0.080
0.087
0.063
0.081
0.088
0.108
0.109
0.146
0.103
0.042
0.006
0.008
0.004
0.007
0.008
0.012
0.012
0.021
0.011
0.002
-0.314
-0.457
-0.119
-0.369
-0.462
-0.398
-0.395
-0.708
-0.322
-0.268
-0.000
-0.116
0.130
-0.050
-0.117
0.027
0.034
-0.135
0.081
-0.105
-1.961
-3.292
0.089
-2.577
-3.292
-1.713
-1.646
-2.882
-1.176
-4.475
0.050
0.001
0.929
0.010
0.001
0.087
0.100
0.004
0.240
0.000
-1.00
-0.50
Favors ICS
0.00
0.50
1.00
Favors ML
Sensitivity analyses indicate no difference in overall meta-analysis conclusions with single studies removed.
Results for Heterogeneity among studies:
Q-value
d.f. (Q)
P value
14.794
8
0.063
Controller medications for asthma
I-squared
45.923
287 of 369
Final Update 1 Report
Drug Effectiveness Review Project
Percent Improved Symptom Control (symptom score): Updated Analysis
ICS v ML: Symptom Control (Change in Symptom Score)
Study name
Statistics for each study
Std diff in means and 95% CI
Std diff Standard
Lower Upper
in means error Variance limit limit Z-Value p-Value
Busse 2001 #715-0.287
Laviolette 1999 -0.498
Malmstrom 1999 -0.209
Meltzer 2002
-0.290
Ostrom 2005
-0.138
Zeiger 2005
-0.174
-0.266
0.087
0.102
0.081
0.088
0.108
0.103
0.048
0.008
0.010
0.007
0.008
0.012
0.011
0.002
-0.457
-0.699
-0.369
-0.462
-0.350
-0.376
-0.361
-0.116
-0.297
-0.050
-0.117
0.074
0.027
-0.171
-3.292
-4.860
-2.577
-3.292
-1.277
-1.697
-5.507
0.001
0.000
0.010
0.001
0.202
0.090
0.000
-1.00
-0.50
Favors ICS
0.00
0.50
1.00
Favors ML
Sensitivity analyses indicate no difference in overall meta-analysis conclusions with single studies removed.
Results for Heterogeneity among studies:
Q-value
d.f. (Q)
P-value
7.924
5
0.160
Controller medications for asthma
I-squared
36.899
288 of 369
Final Update 1 Report
Drug Effectiveness Review Project
Percent Exacerbations: Updated Analysis
ICS v ML: Percent Exacerbations
Study name
Statistics for each study
Std diff in means and 95% CI
Std diff Standard
Lower Upper
in means error Variance limit limit Z-Value p-Value
Baumgartner 2003-0.052
Busse 2001 #715 -0.153
Garcia 2005
-0.150
Malmstrom 1999 -0.209
Meltzer 2002
-0.023
Peters 2007
-0.238
Sorkness 2007 -0.382
Szefler 2005
-0.278
Yurdakul 2003
-0.429
-0.162
0.080
0.087
0.064
0.081
0.088
0.110
0.146
0.118
0.286
0.034
0.006
0.008
0.004
0.007
0.008
0.012
0.021
0.014
0.082
0.001
-0.208
-0.323
-0.275
-0.369
-0.195
-0.453
-0.668
-0.510
-0.990
-0.229
0.105
0.017
-0.026
-0.050
0.148
-0.023
-0.096
-0.046
0.132
-0.094
-0.650
-1.763
-2.366
-2.577
-0.268
-2.172
-2.616
-2.348
-1.499
-4.687
0.516
0.078
0.018
0.010
0.789
0.030
0.009
0.019
0.134
0.000
-1.00
-0.50
Favors ICS
0.00
0.50
1.00
Favors ML
Sensitivity analyses indicate no difference in overall meta-analysis conclusions with single studies removed.
Results for Heterogeneity among studies:
Q-value
d.f. (Q)
P value
I-squared
9.354
8
0.313
14.473
Controller medications for asthma
289 of 369
Final Update 1 Report
Drug Effectiveness Review Project
Change in AQLQ Score: Updated Analysis
ICS v ML: Change in AQLQ Score
Study name
Statistics for each study
Std diff in means and 95% CI
Std diff Standard
Lower Upper
in means error Variance limit limit Z-Value p-Value
Garcia 2005
-0.133
Malmstrom 1999-0.209
Meltzer 2002
-0.290
Peters 2007
-0.025
Zeiger 2005
-0.132
-0.165
0.064
0.081
0.088
0.109
0.103
0.039
0.004
0.007
0.008
0.012
0.011
0.002
-0.258
-0.369
-0.462
-0.239
-0.333
-0.242
-0.009
-0.050
-0.117
0.189
0.070
-0.088
-2.097
-2.577
-3.292
-0.228
-1.282
-4.201
0.036
0.010
0.001
0.820
0.200
0.000
-1.00
-0.50
Favors ICS
0.00
0.50
1.00
Favors ML
Sensitivity analyses indicate no difference in overall meta-analysis conclusions with single studies removed.
Results for Heterogeneity among studies:
Q-value
d.f. (Q)
P value
4.306
4
0.366
Controller medications for asthma
I-squared
7.112
290 of 369
Final Update 1 Report
Drug Effectiveness Review Project
Zaf compared with ICS Results
Summary of Outcome Measures Analyzed:
1.
Rescue medication use (percent improved)
2.
Rescue medication use (puffs per day)
3.
Symptom control (percent improved)
4.
Symptom control (score)
5.
Percent Exacerbations
Results
Rescue Medication Use (percent improved): Updated Analysis
ICS v Zafirlukast: Rescue Medication Use (Percent Rescue Free Days)
Study name
Statistics for each study
Std diff in means and 95% CI
Std diff Standard
Lower Upper
in means error Variance limit limit Z-Value p-Value
Bleeker 2000
-0.312
Brabson 2002
-0.296
Busse 2001 #673-0.263
Kim 2000
-0.317
-0.302
0.095
0.096
0.134
0.096
0.051
0.009
0.009
0.018
0.009
0.003
-0.498
-0.484
-0.526
-0.506
-0.402
-0.126
-0.109
-0.000
-0.128
-0.202
-3.292
-3.092
-1.962
-3.292
-5.913
0.001
0.002
0.050
0.001
0.000
-1.00
-0.50
Favors ICS
0.00
0.50
1.00
Favors Zafirlukast
Sensitivity analyses indicate no difference in overall meta-analysis conclusions with single studies removed.
Results for Heterogeneity among studies:
Q-value
d.f. (Q)
P value
I-squared
0.122
3
0.989
0.000
Controller medications for asthma
291 of 369
Final Update 1 Report
Drug Effectiveness Review Project
Rescue Medication Use (change in puffs per day): New Analysis
ICS v Zafirlukast: Rescue Medication Use (Mean Change in Puffs per Day)
Study name
Statistics for each study
Std diff in means and 95% CI
Std diff Standard
Lower Upper
in means error Variance limit limit Z-Value p-Value
Bleeker 2000
-0.312
Brabson 2002
-0.316
Busse 2001 #673-0.263
Kim 2000
-0.317
-0.307
0.095
0.096
0.134
0.096
0.051
0.009
0.009
0.018
0.009
0.003
-0.498
-0.504
-0.526
-0.506
-0.408
-0.126
-0.128
-0.000
-0.128
-0.207
-3.292
-3.292
-1.962
-3.292
-6.020
0.001
0.001
0.050
0.001
0.000
-1.00
-0.50
Favors ICS
0.00
0.50
1.00
Favors Zafirlukast
Sensitivity analyses indicate no difference in overall meta-analysis conclusions with single studies removed.
Results for Heterogeneity among studies:
Q-value
d.f. (Q)
P value
I-squared
0.128
3
0.622
0.000
Controller medications for asthma
292 of 369
Final Update 1 Report
Drug Effectiveness Review Project
Symptom Control (percent improved symptom free days): Updated Analysis
Studies that reported outcome, but are not included: NA
ICS v Zafirlukast: Symptom Control (Percent Symptom Free Days)
Study name
Statistics for each study
Std diff in means and 95% CI
Std diff Standard
Lower Upper
in means error Variance limit limit Z-Value p-Value
Bleeker 2000
-0.312
Brabson 2002
-0.316
Busse 2001 #673-0.263
Kim 2000
-0.259
-0.291
0.095
0.096
0.134
0.096
0.051
0.009
0.009
0.018
0.009
0.003
-0.498
-0.504
-0.526
-0.448
-0.391
-0.126
-0.128
-0.000
-0.071
-0.191
-3.292
-3.292
-1.962
-2.698
-5.705
0.001
0.001
0.050
0.007
0.000
-1.00
-0.50
Favors ICS
0.00
0.50
1.00
Favors Zafirlukast
Sensitivity analyses indicate no difference in overall meta-analysis conclusions with single studies removed.
Results for Heterogeneity among studies:
Q-value
d.f. (Q)
P value
I-squared
.268
3
.966
0.000
Controller medications for asthma
293 of 369
Final Update 1 Report
Drug Effectiveness Review Project
Symptom Control (change in score): Updated Analysis
ICS v Zafirlukast:Symptom Control (Change in Symptom Score)
Study name
Statistics for each study
Std diff in means and 95% CI
Std diff Standard
Lower Upper
in means error Variance limit limit Z-Value p-Value
Bleeker 2000
-0.312
Brabson 2002
-0.316
Busse 2001 #673-0.263
Kim 2000
-0.317
-0.307
0.095
0.096
0.134
0.096
0.051
0.009
0.009
0.018
0.009
0.003
-0.498
-0.504
-0.526
-0.506
-0.408
-0.126
-0.128
-0.000
-0.128
-0.207
-3.292
-3.292
-1.962
-3.292
-6.020
0.001
0.001
0.050
0.001
0.000
-1.00
-0.50
Favors ICS
0.00
0.50
1.00
Favors Zafirlukast
Sensitivity analyses indicate no difference in overall meta-analysis conclusions with single studies removed.
Results for Heterogeneity among studies:
Q-value
d.f. (Q)
P value
0.128
3
0.988
Controller medications for asthma
I-squared
0.000
294 of 369
Final Update 1 Report
Drug Effectiveness Review Project
Percent Exacerbations: Updated Analysis
Studies that reported outcome, but are not included: NA
ICS v Zafirlukast: Percent Exacerbations
Study name
Statistics for each study
Std diff in means and 95% CI
Std diff Standard
Lower Upper
in means error Variance limit limit Z-Value p-Value
Bleeker 2000
-0.123
Brabson 2002 -0.269
Busse 2001 #673-0.263
Kim 2000
-0.202
-0.207
0.094
0.096
0.134
0.096
0.051
0.009
0.009
0.018
0.009
0.003
-0.308
-0.457
-0.526
-0.390
-0.307
0.061
-0.081
-0.000
-0.014
-0.107
-1.308
-2.809
-1.962
-2.110
-4.064
0.191
0.005
0.050
0.035
0.000
-1.00
-0.50
Favors ICS
0.00
0.50
1.00
Favors Zafirlukast
Sensitivity analyses indicate no difference in overall meta-analysis conclusions with single studies removed.
Results for Heterogeneity among studies:
Q-value
d.f. (Q)
P value
1.385
3
0.709
Controller medications for asthma
I-squared
0.000
295 of 369
Final Update 1 Report
Drug Effectiveness Review Project
ML compared with BDP Results
Summary of Outcome Measures Analyzed:
1.
Rescue medication use (change in puffs per day)
2.
Symptom control (percent improved)
3.
Percent Exacerbations
Results
Rescue Medication Use (puffs per day): Updated Analysis
Montelukast v Beclomethasone: Rescue Medication Use (Mean Change in Puffs per Day)
Study name
Statistics for each study
Std diff in means and 95% CI
Std diff Standard
Lower Upper
in means error Variance limit limit Z-Value p-Value
Israel 2002
-0.038
Lu 2009
-0.115
Stelmach 2005 -0.549
Yurdakul 2003 0.000
-0.076
0.077
0.108
0.350
0.283
0.060
0.006
0.012
0.122
0.080
0.004
-0.190
-0.327
-1.235
-0.554
-0.194
0.113
0.097
0.137
0.554
0.043
-0.495
-1.061
-1.568
0.000
-1.251
0.621
0.289
0.117
1.000
0.211
-1.00
-0.50
0.00
Favors Beclomethasone
0.50
1.00
Favors Montelukast
Sensitivity analyses indicate no difference in overall meta-analysis conclusions with single studies removed.
Results for Heterogeneity among studies:
Q-value
d.f. (Q)
P value
I-squared
2.266
3
0.519
0.000
Controller medications for asthma
296 of 369
Final Update 1 Report
Drug Effectiveness Review Project
Symptom Control (Percent Improvement in Symptom Free Days)
Studies that reported outcome, but are not included: NA
Montelukast v Beclomethasone: Symptom Control (Percent Symptom Free Days)
Study name
Statistics for each study
Std diff in means and 95% CI
Std diff Standard
Lower Upper
in means error Variance limit limit Z-Value p-Value
Baumgartner 2003-0.157
Israel 2002
0.006
Malmstrom 1999 -0.209
-0.112
0.080
0.063
0.081
0.069
0.006
0.004
0.007
0.005
-0.314
-0.119
-0.369
-0.247
-0.000 -1.961
0.130 0.089
-0.050 -2.577
0.022 -1.636
0.050
0.929
0.010
0.102
-1.00
-0.50
0.00
0.50
1.00
Favors Beclomethasone Favors Montelukast
Sensitivity analysis results:
Statistics with study removed
Z-value
-0.8930
-3.2051
-0.8439
-1.6356
Study Name
Baumgartner 2004
Israel 2002
Malmstrom 1999
Overall Model
Results for Heterogeneity among studies:
Q-value
d.f. (Q)
P value
5.090
2
0.078
Controller medications for asthma
P value
0.3718
0.0014
0.3987
0.1019
I-squared
60.707
297 of 369
Final Update 1 Report
Drug Effectiveness Review Project
Percent Exacerbations
Montelukast v Beclomethasone: Percent Exacerbations
Study name
Statistics for each study
Std diff Standard
in means
error
Lower
Variance
limit
Std diff in means and 95% CI
Upper
limit Z-Value p-Value
Baumgartner 2003 -0.052
0.080
0.006 -0.208
0.105
-0.650
0.516
Malmstrom 1999
-0.209
0.081
0.007 -0.369 -0.050
-2.577
0.010
Yurdakul 2003
-0.429
0.286
0.082 -0.990
0.132
-1.499
0.134
-0.149
0.075
0.006 -0.297 -0.002
-1.984
0.047
-1.00
-0.50
0.00
0.50
1.00
Favors Beclomethasone Favors Montelukast
Heterogeneity
Q-value
df (Q)
P-value
I-squared
2.965
2
0.227
32.537
**Sensitivity analysis: Baumgartner is influential.
Study name
Statistics with study removed
Standard
error
Point
Variance
Lower
limit
Upper
limit
Z-Value
p-Value
Baumgartner 2003
-0.2258
0.0782
0.0061
-0.3790
-0.0726
-2.8884
0.0039
Malmstrom 1999
-0.1403
0.1597
0.0255
-0.4533
0.1727
-0.8785
0.3797
Yurdakul 2003
-0.1299
0.0787
0.0062
-0.2843
0.0244
-1.6504
0.0989
-0.1493
0.0753
0.0057
-0.2968
-0.0018
-1.9838
0.0473
Controller medications for asthma
298 of 369
Final Update 1 Report
Drug Effectiveness Review Project
Montelukast compared with Fluticasone Results
Summary of Outcome Measures Analyzed:
1.
Rescue medication use (percent improved rescue free days)
2.
Rescue medication use (decrease in puffs)
3.
Symptom control (percent improved symptom free days)
4.
Symptom control (change in score)
5.
Percent Exacerbations
6.
Change in AQLQ Scores
Results
Rescue Medication Use (% rescue free days): Updated Analysis
Fluticasone v Montelukast: Rescue Medication Use (Percent Rescue Free Days)
Study name
Statistics for each study
Std diff in means and 95% CI
Std diff Standard
Lower Upper
in means error Variance limit limit Z-Value p-Value
Busse 2001 #715-0.287
Garcia 2005
-0.189
Meltzer 2002
-0.290
Ostrom 2005
-0.337
Peters 2007
-0.186
Zeiger 2005
-0.051
Zeiger 2006
-0.511
-0.250
0.087
0.064
0.088
0.109
0.110
0.103
0.131
0.046
0.008
0.004
0.008
0.012
0.012
0.011
0.017
0.002
-0.457
-0.313
-0.462
-0.550
-0.400
-0.252
-0.768
-0.340
-0.116
-0.064
-0.117
-0.123
0.029
0.150
-0.254
-0.159
-3.292
-2.968
-3.292
-3.093
-1.697
-0.499
-3.895
-5.407
0.001
0.003
0.001
0.002
0.090
0.618
0.000
0.000
-1.00
-0.50
0.00
Favors Fluticasone
0.50
1.00
Favors Montelukast
Sensitivity analyses indicate no difference in overall meta-analysis conclusions with single studies removed.
Results for Heterogeneity among studies:
Q-value
d.f. (Q)
P value
9.939
6
0.127
Controller medications for asthma
I-squared
39.633
299 of 369
Final Update 1 Report
Drug Effectiveness Review Project
Rescue Medication Use (puffs per day): Updated Analysis
Fluticasone v Montelukast: Rescue Medication Use (Mean Change in Puffs per Day)
Study name
Statistics for each study
Std diff in means and 95% CI
Std diff Standard
Lower Upper
in means error Variance limit limit Z-Value p-Value
Busse 2001 #715-0.287
Meltzer 2002
-0.290
Ostrom 2005
-0.257
Zeiger 2005
-0.102
Zeiger 2006
-0.281
-0.247
0.087
0.088
0.109
0.103
0.130
0.045
0.008
0.008
0.012
0.011
0.017
0.002
-0.457
-0.462
-0.470
-0.303
-0.535
-0.334
-0.116
-0.117
-0.044
0.099
-0.027
-0.159
-3.292
-3.292
-2.367
-0.995
-2.166
-5.518
0.001
0.001
0.018
0.320
0.030
0.000
-1.00
-0.50
0.00
0.50
1.00
Favors FluticasoneFavors Montelukast
Sensitivity analyses indicate no difference in overall meta-analysis conclusions with single studies removed.
Results for Heterogeneity among studies:
Q-value
d.f. (Q)
P-value
2.511
4
0.643
Controller medications for asthma
I-squared
0.000
300 of 369
Final Update 1 Report
Drug Effectiveness Review Project
Percent Improved Symptom Control (symptom free days): Updated Analysis
Fluticasone v Montelukast: Symptom Control (Percent Symptom Free Days)
Study name
Statistics for each study
Std diff in means and 95% CI
Std diff Standard
Lower Upper
in means error Variance limit limit Z-Value p-Value
Busse 2001 #715-0.287
Meltzer 2002
-0.290
Ostrom 2005
-0.186
Peters 2007
-0.180
Sorkness 2007 -0.422
Zeiger 2005
-0.121
-0.240
0.087
0.088
0.108
0.109
0.146
0.103
0.042
0.008
0.008
0.012
0.012
0.021
0.011
0.002
-0.457
-0.462
-0.398
-0.395
-0.708
-0.322
-0.322
-0.116
-0.117
0.027
0.034
-0.135
0.081
-0.158
-3.292
-3.292
-1.713
-1.646
-2.882
-1.176
-5.741
0.001
0.001
0.087
0.100
0.004
0.240
0.000
-1.00
-0.50
0.00
0.50
1.00
Favors FluticasoneFavors Montelukast
Sensitivity analyses indicate no difference in overall meta-analysis conclusions with single studies removed.
Results for Heterogeneity among studies:
Q-value
d.f. (Q)
P value
4.047
5
0.543
Controller medications for asthma
I-squared
0.000
301 of 369
Final Update 1 Report
Drug Effectiveness Review Project
Percent Improved Symptom Control (symptom score): Updated Analysis
Fluticasone v Montelukast: Symptom Control (Change in Symptom Score)
Study name
Statistics for each study
Std diff in means and 95% CI
Std diff Standard
Lower Upper
in means error Variance limit limit Z-Value p-Value
Busse 2001 #715-0.287
Meltzer 2002
-0.290
Ostrom 2005
-0.138
Zeiger 2005
-0.174
-0.235
0.087
0.088
0.108
0.103
0.048
0.008
0.008
0.012
0.011
0.002
-0.457
-0.462
-0.350
-0.376
-0.328
-0.116
-0.117
0.074
0.027
-0.141
-3.292
-3.292
-1.277
-1.697
-4.929
0.001
0.001
0.202
0.090
0.000
-1.00
-0.50
0.00
0.50
1.00
Favors FluticasoneFavors Montelukast
Sensitivity analyses indicate no difference in overall meta-analysis conclusions with single studies removed.
Results for Heterogeneity among studies:
Q-value
d.f. (Q)
P value
1.885
3
0.597
Controller medications for asthma
I-squared
0.000
302 of 369
Final Update 1 Report
Drug Effectiveness Review Project
Percent Exacerbations: Updated Analysis
Fluticasone v Montelukast: Percent Exacerbations
Study name
Statistics for each study
Std diff in means and 95% CI
Std diff Standard
Lower Upper
in means error Variance limit limit Z-Value p-Value
Busse 2001 #715-0.153
Garcia 2005
-0.150
Meltzer 2002
-0.023
Peters 2007
-0.238
Sorkness 2007 -0.382
Szefler 2005
-0.278
-0.171
0.087
0.064
0.088
0.110
0.146
0.118
0.043
0.008
0.004
0.008
0.012
0.021
0.014
0.002
-0.323
-0.275
-0.195
-0.453
-0.668
-0.510
-0.256
0.017
-0.026
0.148
-0.023
-0.096
-0.046
-0.087
-1.763
-2.366
-0.268
-2.172
-2.616
-2.348
-3.970
0.078
0.018
0.789
0.030
0.009
0.019
0.000
-1.00
-0.50
0.00
0.50
1.00
Favors FluticasoneFavors Montelukast
Sensitivity analyses indicate no difference in overall meta-analysis conclusions with single studies removed.
Results for Heterogeneity among studies:
Q-value
d.f. (Q)
P value
I-squared
6.250
5
0.283
19.996
Controller medications for asthma
303 of 369
Final Update 1 Report
Drug Effectiveness Review Project
Change in AQLQ Score: Updated Analysis
Fluticasone v Montelukast: Change in AQLQ Score
Study name
Statistics for each study
Std diff in means and 95% CI
Std diff Standard
Lower Upper
in means
error Variance limit
limit Z-Value p-Value
Garcia 2005 -0.133
Meltzer 2002-0.290
Peters 2007 -0.025
Zeiger 2005 -0.132
-0.153
0.064
0.088
0.109
0.103
0.050
0.004
0.008
0.012
0.011
0.002
-0.258
-0.462
-0.239
-0.333
-0.250
-0.009
-0.117
0.189
0.070
-0.055
-2.097
-3.292
-0.228
-1.282
-3.054
0.036
0.001
0.820
0.200
0.002
-1.00
-0.50
0.00
0.50
1.00
Favors FluticasoneFavors Montelukast
Sensitivity analyses indicate no difference in overall meta-analysis conclusions with single studies removed.
Results for Heterogeneity among studies:
Q-value
d.f. (Q)
P value
I-squared
3.928
3
0.269
23.623
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ICS compared with LABA Monotherapy
Summary of Outcome Measures Analyzed:
1) % Rescue medication free days
2) Rescue medication reduction in puffs
3) % Symptom free days
4) Change in symptom scores
5) Percent Exacerbations
Results
% Rescue Medication Free Days – Updated Analysis
Studies not included because of lack of appropriate data: Lazarus et al, 2001 and Deykin et al 2005; Simons et al 1997; Kavuru et
al 2000 and Nathan et al 2003; Murray et al 2004; Noonan et al 2006; Shapiro et al 2000 and Nathan et al 2003; Corren et al
2007; Verberne et al 1997.
%Rescue Free Days - ICS v. LABA
Studyname
Statistics for each study
Std diff in means and 95% CI
Std diff
in means
Standard
error
Variance
Lower
limit
Upper
limit
Z-Value
p-Value
Nathan et al 1999
-0.303
0.125
0.016
-0.548
-0.057
-2.411
0.016
Lundbacket al 2006
0.289
0.147
0.022
0.000
0.577
1.963
0.050
Nathan et al 2006 and Edin et al 2009
-0.279
0.149
0.022
-0.571
0.013
-1.873
0.061
Nelson et al 2003
-0.203
0.146
0.021
-0.490
0.083
-1.391
0.164
Pearlman et al 2004 and Edin et al 2009
-0.200
0.149
0.022
-0.492
0.092
-1.340
0.180
-0.142
0.108
0.012
-0.354
0.069
-1.321
0.186
-1.00
-0.50
0.00
Favors LABA
Q-value
11.36999371
Heterogeneity
P-value
2.27E-02
df (Q)
4
0.50
1.00
Favors ICS
I-squared
64.81968151
Sensitivity analyses indicate no difference in overall meta-analysis conclusions with single studies removed with the exception of
removing Lundback et al. The overall result becomes significant in favor of LABA (SMD -0.25 (95% CI -0.39, -0.11).
Sensitivity Analyses - % Rescue Free Days – ICS v. LABA
% Rescue Free Days - ICS v. LABA
Studyname
Statistics with studyremoved
Std diff in means (95% CI) with studyremoved
Point
Standard
error
Variance
Lower
limit
Upper
limit
Nathan et al 1999
-0.098
0.131
0.017
-0.354
0.158
Z-Value
-0.749
0.454
Lundbacket al 2006
-0.251
0.071
0.005
-0.390
-0.113
-3.553
0.000
p-Value
Nathan et al 2006 and Edin et al 2009
-0.109
0.132
0.017
-0.367
0.150
-0.821
0.411
Nelson et al 2003
-0.126
0.137
0.019
-0.396
0.143
-0.920
0.358
Pearlman et al 2004 and Edin et al 2009
-0.128
0.137
0.019
-0.396
0.141
-0.931
0.352
-0.142
0.108
0.012
-0.354
0.069
-1.321
0.186
-1.00
-0.50
Favors LABA
Controller medications for asthma
0.00
0.50
1.00
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Rescue Medication Use (puffs per day) – Updated Analysis
Included Studies:
Kavuru et al 2000 and Nathan et al 2003
Murray et al 2004
Nathan et al 2006 and Edin et al 2009
Nelson et al 2003
Shapiro et al 2000 and Nathan et al 2003
Corren et al 2007
Verberne et al 1997
Studies not included because of lack of applicable data:
Lazarus et al 2001 and Deykin et al, 2005
Nathan et al, 1999
Simons et al, 1997
Lundback et al, 2006
Noonan et al, 2006
Verberne et al, 1997
Pearlman et al, 2004 and Edin et al, 2009
Change in Rescue Medicine Puffs per Day - ICS v. LABA
Study name
Statistics for each study
Std diff
in means
Standard
error
Variance
Lower
limit
Upper
limit
Std diff in means and 95% CI
Z-Value
p-Value
Kavuru et al 2000 and Nathan et al 2003
0.046
0.153
0.023
-0.254
0.345
0.299
0.765
Murray et al 2004
-0.329
0.150
0.023
-0.624
-0.034
-2.189
0.029
Nathan et al 2006 and Edin et al 2009-0.164
0.149
0.022
-0.456
0.127
-1.108
0.268
Nelson et al 2003
0.100
0.146
0.021
-0.186
0.387
0.687
0.492
Shapiro et al 2000 and Nathan et al 2003
0.384
0.154
0.024
0.082
0.685
2.493
0.013
Corren et al 2007
0.207
0.135
0.018
-0.058
0.472
1.531
0.126
Verberne et al 1997
1.014
0.260
0.067
0.505
1.523
3.903
0.000
0.144
0.128
0.016
-0.108
0.395
1.119
0.263
-2.00
-1.00
0.00
Favors LABA
Q-value
27.82665345
df (Q)
6
Heterogeneity
P-value
1.01E-04
1.00
2.00
Favors ICS
I-squared
78.43793896
Sensitivity analyses indicate no difference in overall meta-analysis conclusions with single studies removed.
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% Symptom free days – Updated Analysis
Included Studies:
Kavuru et al 2000 and Nathan et al 2003
Murray et al 2004
Nathan et al 2006 and Edin et al 2009
Nelson et al 2003
Shapiro et al 2000 and Nathan et al 2003
Corren et al 2007
Pearlman et al 2004 and Edin et al 2009
Studies not included:
Lazarus et al 2001; Deykin 2005Nathan et al 1999Simons et al 1997Lundback 2006Noonan 2006Verberne et al 1997
% Symptom Free Days - ICS v. LABA
Study name
Statistics for each study
Std diff in means and 95% CI
Std diff Standard
Lower Upper
in means
error
Variance limit
limit Z-Value p-Value
Kavuru et al 2000 and Nathan et al 2003
-0.023
0.153
0.023 -0.323
0.276
-0.153
0.879
Murray et al 2004
-0.026
0.149
0.022 -0.319
0.267
-0.177
0.860
0.028
0.148
0.022 -0.262
0.319
0.190
0.849
-0.125
0.146
0.021 -0.411
0.161
-0.856
0.392
Shapiro 2000 and Nathan 2003
0.365
0.154
0.024
0.064
0.667
2.375
0.018
Corren et al 2007
0.308
0.135
0.018
0.043
0.574
2.275
0.023
-0.170
0.149
0.022 -0.462
0.122
-1.142
0.254
0.053
0.079
0.006 -0.102
0.207
0.671
0.503
Nathan et al 2006 and Edin et al 2009
Nelson 2003
Pearlman et al 2004 and Edin et al 2009
-1.00
-0.50
0.00
Favors LABA
Q-value
11.95317722
df (Q)
6
Heterogeneity
P-value
0.063021552
0.50
1.00
Favors ICS
I-squared
49.80414084
Sensitivity analyses indicate no difference in overall meta-analysis conclusions with single studies removed.
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Symptom control (symptom score) – Update Analysis
Included studies:
Kavuru et al 2000 and Nathan et al 2003
Murray et al 2004
Nathan et al 2006 and Edin et al 2009
Nelson et al 2003
Shapiro et al 2000 and Nathan et al 2003
Corren et al 2007
Studies not included:
Lazarus et al 2001 and Deykin et al 2005
Nathan et al 1999
Simons et al 1997
Lundback et al 2006
Noonan et al 2006
Verberne et al 1997
Pearlman et al 2004 and Edin 2009
Change in Symptom Score - ICS v. LABA
Study name
Statistics for each study
Std diff Standard
Lower
in means
error
Variance limit
Std diff in means and 95% CI
Upper
limit Z-Value p-Value
Kavuru et al 2000 and Nathan et al0.113
2003
0.153
0.023 -0.187
0.413
0.741
0.459
Murray et al 2004
0.000
0.149
0.022 -0.293
0.293
0.000
1.000
Nathan et al 2006 and Edin et al 2009
-0.099
0.148
0.022 -0.390
0.192
-0.668
0.504
Nelson et al 2003
0.146
0.021 -0.286
0.286
0.000
1.000
Shapiro et al 2000 and Nathan et al
0.568
2003
0.154
0.024
0.266
0.869
3.691
0.000
Corren et al 2007
0.285
0.135
0.018
0.020
0.551
2.107
0.035
0.144
0.098
0.010 -0.048
0.337
1.468
0.142
0.000
-1.00
-0.50
Favors LABA
Q-value
13.30378884
df (Q)
5
Heterogeneity
P-value
2.07E-02
0.00
0.50
1.00
Favors ICS
I-squared
62.41672158
Sensitivity analyses indicate no difference in overall meta-analysis conclusions with single studies removed.
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Exacerbations (Odds Ratio): Updated Analysis
Note:
Studies included in this analysis were those that provided definitions of “exacerbation” and reported a measure of patients
experiencing exacerbations. Three studies reported numbers of patients experiencing clearly defined exacerbations;{Lazarus,
2001 #694; Corren, 2007 #4799; Noonan, 2006 #38} two reported the numbers of patients receiving oral steroids for
exacerbations;{Nathan, 1999 #907; Verberne, 1997 #1082} and one reported the number of patients experiencing at least two
defined exacerbations.{Lundback, 2006 #168} Studies reporting only withdrawals from the trial due to exacerbations and those
failing to clearly define “exacerbation” were not included in our analysis.
Studies not included:
Simons et al. 1997
Kavuru et al. 2000; Nathan et al. 2003
Murray et al. 2004
Nathan et al. 2006; Edin et al. 2009
Nelson et al. 2003
Shapiro et al. 2000; Nathan et al. 2003
Pearlman et al. 2004; Edin et al. 2009
ICS v. LABA - Exacerbations (see notes)
Study name
Statistics for each study
Odds
ratio
Lower
limit
Odds ratio and 95% CI
Upper
limit Z-Value p-Value
Lazarus et al 2001 and Deykin et al 2005
3.198
0.949 10.775
1.875
0.061
Nathan et al 1999
1.367
0.634
2.944
0.797
0.425
Lundback et al 2006
3.167
1.608
6.236
3.334
0.001
Noonan et al 2006
3.336
1.187
9.374
2.285
0.022
Corren et al 2007
1.804
0.421
7.729
0.795
0.427
2.977 71.193
3.307
0.001
1.664
3.821
0.000
Verberne et al 1997
14.559
2.845
4.863
0.1
0.2
0.5
1
Favors LABA
Q-value
8.095029256
df (Q)
5
Heterogeneity
P-value
0.151075559
2
5
10
Favors ICS
I-squared
38.23370068
Sensitivity analyses indicate no difference in overall meta-analysis conclusions with single studies removed.
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LABA + ICS compared with ICS (same dose, first line
therapy)
Summary of Outcome Measures Analyzed:
1) Rescue medication reduction in puffs
2) Rescue medicine free days (percent improved)
3) Symptom Control (percent improved symptom free days)
4) Symptom Control (percent improved symptom score)
Results
Rescue Medication Use (puffs per day): Updated Analysis
Studies not included: Boonsawat et al 2008; Rojas et al 2007
ICS + LABA vs. ICS (same dose, 1st line therapy) - Rescue medicine use, puffs per day
Study name
Statistics for each study
Std diff
in means
Standard
error
Upper
limit
Std diff in means and 95% CI
Variance
Lower
limit
Z-Value
p-Value
Chuchalain 2002
0.528
0.136
0.018
0.262
0.794
3.895
0.000
Murray 2004
0.391
0.152
0.023
0.094
0.689
2.580
0.010
Nelson 2003
0.362
0.146
0.021
0.077
0.647
2.487
0.013
O'Byrne 2001
0.004
0.093
0.009
-0.179
0.186
0.038
0.970
Renzi, 2010
0.194
0.088
0.008
0.021
0.367
2.198
0.028
Kerwin, 2008
0.200
0.098
0.010
0.008
0.391
2.045
0.041
Strand, 2007
0.242
0.164
0.027
-0.079
0.564
1.478
0.139
0.251
0.066
0.004
0.121
0.381
3.790
0.000
-1.00
-0.50
0.00
Favors ICS
Q-value
12.91750977
df (Q)
6
Heterogeneity
P-value
4.44E-02
0.50
1.00
Favors ICS + LABA
I-squared
53.5514189
Sensitivity analyses indicate no difference in overall meta-analysis conclusions with single studies removed.
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% Rescue Medication Free Days – Updated Analysis
Included studies:
Nelson et al 2003
Rojas et al 2007
Renzi et al 2010
Strand 2007
(Note: Rojas et al reported the outcome as median % rescue free days; sensitivity analyses show that removing this study does
not change the overall conclusion.)
Studies not included:
Chuchalain et al 2002
Boonsawat et al 2008
O’Byren et al 2001
Kerwin et al 2008
Murray et al 2004
ICS + LABA vs. ICS (same dose, 1st line therapy) - % Rescue Free Days
Study name
Statistics for each study
Std diff
in means
Standard
error
Upper
limit
Std diff in means and 95% CI
Variance
Lower
limit
Z-Value
p-Value
Nelson 2003
0.320
0.145
0.021
0.035
0.604
2.200
0.028
Rojas et al 2007
0.349
0.106
0.011
0.141
0.556
3.293
0.001
Renzi, 2010
0.291
0.089
0.008
0.118
0.465
3.292
0.001
Strand, 2007
0.323
0.164
0.027
0.001
0.646
1.966
0.049
0.317
0.058
0.003
0.204
0.430
5.497
0.000
-1.00
-0.50
0.00
Favors ICS
Q-value
0.175064302
df (Q)
3
Heterogeneity
P-value
0.981510689
0.50
1.00
Favors ICS + LABA
I-squared
0
Sensitivity analyses indicate no difference in overall meta-analysis conclusions with single studies removed.
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% Symptom free days: Updated Analysis
Included studies:
Murray et al. 2004
Nelson et al. 2003
O’Byrne et al. 2001
Rojas et al. 2007
Strand et al. 2007
Renzi et al. 2010
Studies not included:
Chuchalain et al 2002
Boonsawat et al 2008
Kerwin et al 2008
ICS + LABA vs. ICS (same dose, 1st line therapy) - % Symptom free days
Study name
Statistics for each study
Std diff
in means
Murray 2004
Nelson 2003
O'Byrne 2001
Rojas et al 2007
Strand, 2007
Renzi, 2010
0.391
0.246
0.066
0.305
0.378
0.231
0.236
Standard
error
0.152
0.145
0.093
0.106
0.165
0.088
0.050
Variance
0.023
0.021
0.009
0.011
0.027
0.008
0.002
Std diff in means and 95% CI
Lower
limit
Upper
limit
Z-Value
p-Value
0.094
-0.038
-0.117
0.097
0.055
0.058
0.139
0.689
0.530
0.249
0.512
0.701
0.404
0.333
2.580
1.698
0.707
2.880
2.294
2.613
4.750
0.010
0.090
0.480
0.004
0.022
0.009
0.000
-1.00
-0.50
0.00
Favors ICS
Q-value
5.532061896
df (Q)
5
Heterogeneity
P-value
0.354442985
0.50
1.00
Favors ICS + LABA
I-squared
9.617786394
Sensitivity analyses indicate no difference in overall meta-analysis conclusions with single studies removed.
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Symptom Control (symptom score): Updated Analysis
Included Studies
Murray et al 2004
Nelson et al 2003
Kerwin et al 2008
Strand et al 2007
Studies not included:
Chuchalain et al 2002
Boonsawat et al 2008
Rojas et al 2007
O’Byrne 2001
Renzi et al 2010
ICS + LABA vs. ICS (same dose, 1st line therapy) - Change in Symptom Score
Statistics for each study
Std diff
in means
Standard
error
Upper
limit
Std diff in means and 95% CI
Variance
Lower
limit
Z-Value
p-Value
Murray, 2004
0.391
0.152
0.023
0.094
0.689
2.580
0.010
Nelson, 2003
0.214
0.145
0.021
-0.069
0.498
1.482
0.138
Kerwin, 2008
0.191
0.098
0.010
0.000
0.383
1.961
0.050
Strand, 2007
0.469
0.166
0.027
0.144
0.794
2.832
0.005
0.277
0.066
0.004
0.148
0.405
4.224
0.000
-1.00
-0.50
0.00
Favors ICS
Q-value
2.870736346
df (Q)
3
Heterogeneity
P-value
0.411987437
0.50
1.00
Favors ICS + LABA
I-squared
0
Sensitivity analyses indicate no difference in overall meta-analysis conclusions with single studies removed.
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ICS compared with LABA+ICS (Higher Dose) MetaAnalysis Results
Summary of Outcome Measures Analyzed:
1) Rescue medication use (percent rescue free days)
2) Rescue medication use (puffs per day)
3) Symptom control (percent symptom free days)
4) Symptom control (symptom score)
5) Exacerbations
Results
% Rescue free days – Updated analysis
Studies that reported outcome but that are not included: Verberne et al, 1998 (no p-value); Jenkins et al, 2000 (data in graph
only); Gappa et al, 2009 (no p-value); van Noord et al, 1999 (reported outcome as odds ratio)
ICS+LABA v ICS (higher dose) - % Rescue Free Days
Study name
Statistics for each study
Std diff
in means
Lower
limit
Upper
limit
Std diff in means and 95% CI
p-Value
Baraniuk et al 1999a
-0.201
-0.385
-0.016
0.033
Baraniuk et al 1999b
-0.271
-0.455
-0.086
0.004
Bateman et al 2003
-0.358
-0.571
-0.145
0.001
Bisgaard et al 2006
-0.115
-0.379
0.148
0.389
Busse et al 2003
-0.225
-0.392
-0.059
0.008
deBlic et al 2009
-0.259
-0.485
-0.033
0.025
Ind et al 2003
-0.362
-0.578
-0.147
0.001
Jarjour et al 2006
-0.581
-1.010
-0.153
0.008
0.001
-0.209
0.211
0.994
O'Byrne et al 2005
-0.153
-0.244
-0.062
0.001
Peters et al 2008
-0.409
-0.652
-0.166
0.001
-0.235
-0.309
-0.160
0.000
Johansson et al 2001
-1.00
-0.50
0.00
Favors ICS+LABA
Q-value
15.678
df (Q)
10
Heterogeneity
P-value
0.109
0.50
1.00
Favors ICS (higher dose)
I-squared
36.217
Sensitivity analyses indicate no difference in overall meta-analysis conclusions with single studies removed.
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Rescue medication use (puffs per day): Updated Analysis
Studies that reported outcome but that are not included: Pauwels et al, 1997 (no p-value); Chuchalin et al 2008 (compares once
daily ICS+LABA to twice daily ICS)
ICS+LABA v ICS (higher dose) - Rescue Medication Use - Puffs per day
Study name
Statistics for each study
Std diff
in means
Baraniuk et al 1999a
Baraniuk et al 1999b
Bateman et al 2003
Bateman et al 2006
Bergmann et al 2004
Bisgaard et al 2006
Busse et al 2003
Condemi et al 1999
Greening et al 1994
Jarjour et al 2006
Lalloo et al 2003
Mitchell et al 2003
O'Byrne et al 2001
O'Byrne et al 2005
Peters et al 2008
Vermetten et al 1999
-0.201
-0.271
-0.222
-0.220
-0.423
0.048
-0.194
-0.317
-0.058
-0.346
-0.208
-0.469
-0.109
-0.153
-0.409
-0.258
-0.218
Lower
limit
-0.385
-0.455
-0.434
-0.399
-0.636
-0.215
-0.361
-0.506
-0.248
-0.768
-0.390
-0.748
-0.265
-0.244
-0.652
-0.516
-0.275
Upper
limit
-0.016
-0.086
-0.010
-0.041
-0.210
0.311
-0.028
-0.128
0.132
0.077
-0.026
-0.190
0.047
-0.062
-0.166
-0.000
-0.161
Std diff in means and 95% CI
p-Value
0.033
0.004
0.040
0.016
0.000
0.720
0.022
0.001
0.553
0.109
0.025
0.001
0.170
0.001
0.001
0.050
0.000
-1.00
-0.50
0.00
Favors ICS+LABA
Q-value
21.222
Heterogeneity
df (Q)
P-value
15
0.130
0.50
1.00
Favors ICS (higher dose)
I-squared
29.317
Sensitivity analyses indicate no difference in overall meta-analysis conclusions with single studies removed.
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% Symptom free days: Updated Analysis
Studies that reported outcome but that are not included: Greening et al, 1994 (no p-value); Peters et al, 2007 (compares once
daily ICS+LABA to twice daily ICS); Chuchalin et al, 2008 (compares once daily ICS+LABA to twice daily ICS); Gappa et al,
2009 (no p-value); Jarjour et al, 2006 (no p-value)
ICS+LABA v ICS (higher dose) - % Symptom Free Days
Study name
Statistics for each study
Baraniuk et al 1999a
Baraniuk et al 1999b
Bateman et al 2003
Bergmann et al 2004
Bisgaard et al 2006
Busse et al 2003
Ind et al 2003
Jenkins et al 2000
Johansson et al 2001
Kelsen et al 1999
Kips et al 2000
Lalloo et al 2003
O'Byrne et al 2001
O'Byrne et al 2005
Peters et al 2008
Std diff in means and 95% CI
Std diff
in means
Lower
limit
Upper
limit
p-Value
-0.184
-0.271
-0.056
-0.313
-0.276
-0.149
-0.340
-0.353
0.000
-0.179
-0.162
-0.251
-0.091
-0.153
-0.409
-0.198
-0.369
-0.455
-0.267
-0.525
-0.540
-0.316
-0.555
-0.564
-0.210
-0.358
-0.670
-0.433
-0.247
-0.244
-0.652
-0.252
-0.000
-0.086
0.156
-0.101
-0.012
0.017
-0.124
-0.143
0.210
-0.000
0.345
-0.069
0.064
-0.062
-0.166
-0.144
0.050
0.004
0.607
0.004
0.041
0.078
0.002
0.001
1.000
0.050
0.530
0.007
0.250
0.001
0.001
0.000
-1.00
-0.50
Favors ICS+LABA
Q-value
17.2683
Heterogeneity
df (Q)
P-value
14
0.2421633
0.00
0.50
1.00
Favors ICS (higher dose)
I-squared
18.92646
Sensitivity analyses indicate no difference in overall meta-analysis conclusions with single studies removed.
Controller medications for asthma
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Symptom control (symptom score): Updated Analysis
Studies that reported outcome but that are not included: Lalloo et al, 2003 (no p-value); Pauwels et al 1997 (no p-value); Peters et
al, 2007 (compares once daily ICS+LABA to twice daily ICS); Chuchalin et al, 2008 (compares once daily ICS+LABA to twice
daily ICS)
ICS+LABA v ICS (higher dose) - Symptom Score
Study name
Statistics for each study
Std diff
in means
Baraniuk et al 1999a
Baraniuk et al 1999b
Bateman et al 2006
Bergmann et al 2004
Bisgaard et al 2006
Busse et al 2003
Condemi et al 1999
Jarjour et al 2006
Mitchell et al 2003
O'Byrne et al 2005
0.184
-0.271
-0.185
-0.377
-0.305
-0.101
-0.317
-0.564
-0.469
-0.153
-0.223
Lower
limit
0.000
-0.455
-0.364
-0.590
-0.569
-0.267
-0.506
-0.992
-0.748
-0.244
-0.335
Std diff in means and 95% CI
Upper
limit
0.369
-0.086
-0.007
-0.165
-0.040
0.065
-0.128
-0.136
-0.190
-0.062
-0.112
p-Value
0.050
0.004
0.042
0.000
0.024
0.232
0.001
0.010
0.001
0.001
0.000
-1.00
-0.50
0.00
Favors ICS+LABA
0.50
1.00
Favors ICS (higher dose)
Heterogeneity with Baraniuk et al, 1999a
df (Q)
P-value
I-squared
9
0.000
70.502
Heterogeneity w/o Baraniuk et al, 1999a
Q-value
df (Q)
P-value
I-squared
13.512
8
0.095
40.792
Q-value
30.511
Sensitivity analyses indicate no difference in overall meta-analysis conclusions with single studies removed.
Controller medications for asthma
317 of 369
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Exacerbations: Updated Analysis
Studies that reported the number of patients or the percent of patients in each group who experienced exacerbations are included.
ICS+LABA v ICS (higher dose) - Exacerbations (all)
Study name
Statistics for each study
Odds
ratio
Bateman et al 2003
0.584
Bergmann et al 2004
0.256
Bisgaard et al 2006
1.679
Bouros et al 1999
0.941
Busse et al 2003
1.324
Condemi et al 1999
0.627
deBlic et al 2009
1.020
Ind et al 2003
0.847
Jarjour et al 2006
0.619
Jenkins et al 2000
0.997
Johansson et al 2001
0.935
Kelsen et al 1999
0.859
Lalloo et al 2003
0.681
Mitchell et al 2003
0.718
Murray et al 1999
0.920
O'Byrne et al 2005
1.131
Pauwels et al 1997; O'Byrne et al 2008 1.110
Peters et al 2008
0.603
van Noord et al 1999
1.041
Verberne et al 1998
1.514
Vermetten et al 1999
0.524
Woolcock et al 1996
0.762
0.885
Lower
limit
Upper
limit
0.374
0.028
0.948
0.058
0.453
0.348
0.142
0.529
0.189
0.633
0.511
0.534
0.473
0.288
0.582
0.900
0.706
0.319
0.493
0.535
0.224
0.456
0.779
0.912
2.313
2.973
15.365
3.865
1.129
7.338
1.357
2.024
1.572
1.710
1.383
0.981
1.786
1.457
1.421
1.747
1.140
2.199
4.286
1.230
1.272
1.007
Odds ratio and 95% CI
p-Value
0.018
0.225
0.075
0.966
0.608
0.120
0.984
0.490
0.428
0.991
0.827
0.533
0.039
0.476
0.723
0.290
0.651
0.120
0.917
0.434
0.138
0.299
0.063
0.1
0.2
0.5
Favors ICS+LABA
Q-value
23.8841
Heterogeneity
df (Q)
P-value
21
0.301
1
2
5
10
Favors ICS (higher dose)
I-squared
11.916
Sensitivity analyses indicate no difference in overall meta-analysis conclusions with single studies removed.
Controller medications for asthma
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FP/SM v FP Analyses (ICS+LABA v ICS – higher dose)
1)
2)
3)
4)
5)
% Symptom Free Days
Symptom Score
% Rescue Free Days
Rescue Medication Use – Puffs per Day
Exacerbations (all)
Results
Note: For the following analyses for FP/SM v FP, see the notes above for the ICS + LABA v higher dose ICS analyses
regarding studies not included.
% Symptom Free Days
FP/SMv FP(higher dose) - %SymptomFree Days
Studyname
Statistics for each study
Std diff in means and 95%CI
Stddiff
inmeans
Lower
limit
Upper
limit
p-Value
Baraniuk et al 1999a
-0.184
-0.369
-0.000
0.050
Bergmannet al 2004
-0.313
-0.525
-0.101
0.004
Busseet al 2003
-0.149
-0.316
0.017
0.078
Indet al 2003
-0.340
-0.555
-0.124
0.002
-0.230
-0.325
-0.134
0.000
-1.00
-0.50
Favors FP/SM
0.00
0.50
1.00
Favors FP
Heterogeneity
Q-value
df (Q)
P-value
I-squared
2.725
3
0.436
0
Controller medications for asthma
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Symptom Score
FP/SMv FP(higher dose) - SymptomScore
Studyname
Statistics for each study
Std diff in means and 95%CI
Stddiff
inmeans
Lower
limit
Upper
limit
p-Value
Baraniuk et al 1999a
0.184
0.000
0.369
0.050
Batemanet al 2006
-0.185
-0.364
-0.007
0.042
Bergmannet al 2004
-0.377
-0.590
-0.165
0.000
Busseet al 2003
-0.101
-0.267
0.065
0.232
Condemi et al 1999
-0.317
-0.506
-0.128
0.001
Jarjour et al 2006
-0.564
-0.992
-0.136
0.010
-0.197
-0.382
-0.013
0.036
-1.00
-0.50
Favors FP/SM
0.00
0.50
1.00
Favors FP
Heterogeneity
Q-value
df (Q)
P-value
I-squared
24.07566
5
2.10E-04
79.23213
Controller medications for asthma
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% Rescue Free Days – Updated Analysis
FP/SMv FP(higher dose) - %Rescue Free Days
Studyname
Statistics for each study
Std diff in means and 95%CI
Stddiff
inmeans
Lower
limit
Upper
limit
p-Value
Baraniuk et al 1999a
-0.201
-0.385
-0.016
0.033
Busseet al 2003
-0.225
-0.392
-0.059
0.008
deBlic et al 2009
-0.259
-0.485
-0.033
0.025
Indet al 2003
-0.362
-0.578
-0.147
0.001
Jarjour et al 2006
-0.581
-1.010
-0.153
0.008
-0.268
-0.363
-0.174
0.000
-1.00
-0.50
Favors FP/SM
0.00
0.50
1.00
Favors FP
Heterogeneity
Q-value
df (Q)
P-value
I-squared
3.558817
4
0.468992
0
Controller medications for asthma
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Rescue Medication Use – Puffs per Day
FP/SMv FP(higher dose) - Rescue MedicationPuffs per Day
Studyname
Statistics for each study
Std diff in means and 95%CI
Stddiff
inmeans
Lower
limit
Upper
limit
p-Value
Baraniuk et al 1999a
-0.201
-0.385
-0.016
0.033
Batemanet al 2006
-0.220
-0.399
-0.041
0.016
Bergmannet al 2004
-0.423
-0.636
-0.210
0.000
Busseet al 2003
-0.194
-0.361
-0.028
0.022
Condemi et al 1999
-0.317
-0.506
-0.128
0.001
Jarjour et al 2006
-0.346
-0.768
0.077
0.109
-0.262
-0.343
-0.181
0.000
-1.00
-0.50
Favors FP/SM
0.00
0.50
1.00
Favors FP
Heterogeneity
Q-value
df (Q)
P-value
I-squared
3.938899
5
0.558246
0
Controller medications for asthma
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Exacerbations (all) – Updated Analysis
FP/SM v FP (higher dose) - Exacerbations (all)
Study name
Statistics for each study
Odds
ratio
Lower
limit
Upper
limit
p-Value
Bergmann et al 2004 0.256
0.028
2.313
0.225
Busse et al 2003
1.324
0.453
3.865
0.608
Condemi et al 1999
0.627
0.348
1.129
0.120
deBlic et al 2009
1.020
0.142
7.338
0.984
Ind et al 2003
0.847
0.529
1.357
0.490
Jarjour et al 2006
0.619
0.189
2.024
0.428
Jenkins et al 2000
0.997
0.633
1.572
0.991
van Noord et al 1999 1.041
0.493
2.199
0.917
0.861
0.670
1.104
0.238
Odds ratio and 95% CI
0.1 0.2
0.5
1
Favors FP/SM
2
5
10
Favors FP
Heterogeneity
Q-value
df (Q)
P-value
I-squared
3.8808829
7
0.7933907
0
Controller medications for asthma
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BUD/FM v BUD Analyses (ICS+LABA v ICS – higher dose)
1)
2)
3)
4)
5)
Exacerbations
% Rescue medicine free days
Rescue medicine use – puffs per day
% Symptom free days
Symptom Score
Results
Note: For the following analyses for BUD/FM v BUD, see the notes above for the ICS + LABA v higher dose ICS analyses
regarding studies not included.
Exacerbations (all) – Updated Analysis
BUD/FM v BUD (higher dose) - Exacerbations (all)
Study name
Statistics for each study
Odds
ratio
Lower
limit
Upper
limit
p-Value
Bisgaard et al 2006
1.679
0.948
2.973
0.075
Lalloo et al 2003
0.681
0.473
0.981
0.039
O'Byrne et al 2005
1.131
0.900
1.421
0.290
Pauwels et al 1997; O'Byrne et al 2008
1.110
0.706
1.747
0.651
Peters et al 2008
0.603
0.319
1.140
0.120
0.979
0.717
1.336
0.892
Odds ratio and 95% CI
0.1 0.2
0.5
1
Favors BUD/FM
Q-value
11.16073
Controller medications for asthma
df (Q)
4
Heterogeneity
P-value
2.48E-02
2
5
10
Favors BUD
I-squared
64.16005
324 of 369
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% Rescue Medicine Free Days – Updated Analysis
BUD/FM v BUD (higher dose) - % Rescue medicine free days
Study name
Statistics for each study
Std diff in means and 95% CI
Std diff
in means
Lower
limit
Upper
limit
p-Value
Bisgaard et al 2006
-0.115
-0.379
0.148
0.389
O'Byrne et al 2005
-0.153
-0.244
-0.062
0.001
Peters et al 2008
-0.409
-0.652
-0.166
0.001
-0.208
-0.363
-0.054
0.008
-0.50
-0.25
0.00
Favors BUD/FM
0.25
0.50
Favors BUD
Heterogeneity
Q-value
df (Q)
P-value
I-squared
3.9591837
2
0.1381256
49.484536
Controller medications for asthma
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Final Update 1 Report
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Rescue Medicine Use – Puffs per day – Updated Analysis
BUD/FM v BUD (higher dose) - Rescue medicine use - Puffs per day
Study name
Statistics for each study
Std diff
in means
Bisgaard et al 2006
Lower
limit
Std diff in means and 95% CI
Upper
limit
p-Value
0.048
-0.215
0.311
0.720
Lalloo et al 2003
-0.208
-0.390
-0.026
0.025
O'Byrne et al 2001
-0.109
-0.265
0.047
0.170
O'Byrne et al 2005
-0.153
-0.244
-0.062
0.001
Peters et al 2008
-0.409
-0.652
-0.166
0.001
-0.163
-0.265
-0.062
0.002
-0.50
-0.25
0.00
Favors BUD/FM
0.25
0.50
Favors BUD
Heterogeneity
Q-value
df (Q)
P-value
I-squared
7.1278688
4
0.1292833
43.882244
Controller medications for asthma
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% Symptom Free Days – Updated Analysis
BUD/FM v BUD (higher dose) - % Symptom free days
Study name
Statistics for each study
Std diff in means and 95% CI
Std diff
in means
Lower
limit
Upper
limit
p-Value
Bisgaard et al 2006
-0.276
-0.540
-0.012
0.041
Kips et al 2000
-0.162
-0.670
0.345
0.530
Lalloo et al 2003
-0.251
-0.433
-0.069
0.007
O'Byrne et al 2001
-0.091
-0.247
0.064
0.250
O'Byrne et al 2005
-0.153
-0.244
-0.062
0.001
Peters et al 2008
-0.409
-0.652
-0.166
0.001
-0.192
-0.273
-0.111
0.000
-0.50
-0.25
0.00
Favors BUD/FM
0.25
0.50
Favors BUD
Heterogeneity
Q-value
df (Q)
P-value
I-squared
6.0596263
5
0.3004602
17.486661
Controller medications for asthma
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Final Update 1 Report
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Symptom Score
BUD/FM v BUD (higher dose) - Symptom Score
Study name
Statistics for each study
Std diff in means and 95% CI
Std diff
in means
Lower
limit
Upper
limit
p-Value
Bisgaard et al 2006
-0.305
-0.569
-0.040
0.024
O'Byrne et al 2005
-0.153
-0.244
-0.062
0.001
-0.176
-0.283
-0.070
0.001
-0.50
-0.25
0.00
Favors BUD/FM
0.25
0.50
Favors BUD
Heterogeneity
Q-value
df (Q)
P-value
I-squared
1.1283463
1
0.2881284
11.374725
Controller medications for asthma
328 of 369
Final Update 1 Report
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BDP/SM v BDP Analyses (ICS+LABA v ICS – higher dose)
1) Rescue medicine use – Puffs per day
2) % Symptom free days
3) Exacerbations
Results
Note: For the following analyses for BDP/SM v BDP, see the notes above for the ICS + LABA v higher dose ICS analyses
regarding studies not included.
Rescue medicine use – Puffs per day
BDP/SM v BDP (higher dose) - Rescue medicine use - Puffs per day
Study name
Statistics for each study
Std diff in means and 95% CI
Std diff
in means
Lower
limit
Upper
limit
p-Value
Greening et al 1994
-0.058
-0.248
0.132
0.553
Kelsen et al 1999
-0.246
-0.426
-0.067
0.007
Vermetten et al 1999
-0.258
-0.516
-0.000
0.050
-0.178
-0.294
-0.062
0.003
-0.50
-0.25
0.00
Favors BDP/SM
0.25
0.50
Favors BDP
Heterogeneity
Q-value
df (Q)
P-value
I-squared
2.4764914
2
0.2898923
19.240583
Controller medications for asthma
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Final Update 1 Report
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% Symptom free days
BDP/SM v BDP (higher dose) - % Symptom Free Days
Study name
Statistics for each study
Std diff in means and 95% CI
Std diff
in means
Lower
limit
Upper
limit
p-Value
Kelsen et al 1999
-0.179
-0.358
-0.000
0.050
Vermetten et al 1999
-0.437
-0.697
-0.177
0.001
-0.290
-0.540
-0.039
0.023
-0.50
-0.25
0.00
Favors BDP/SM
0.25
0.50
Favors BDP
Heterogeneity
Q-value
df (Q)
P-value
I-squared
2.5711752
1
0.1088269
61.107279
Controller medications for asthma
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Exacerbations (all)
BDP/SM v BDP (higher dose) - Exacerbations (all)
Study name
Statistics for each study
Odds
ratio
Odds ratio and 95% CI
Lower Upper
limit
limit p-Value
Kelsen et al 1999
0.859
0.534
1.383
0.533
Murray et al 1999
0.920
0.582
1.457
0.723
Verberne et al 1998
1.514
0.535
4.286
0.434
Vermetten et al 1999
0.524
0.224
1.230
0.138
Woolcock et al 1996
0.762
0.456
1.272
0.299
0.843
0.653
1.089
0.192
0.1 0.2 0.5 1
Favors BDP/SM
2
5 10
Favors BDP
Heterogeneity
Q-value
df (Q)
P-value
I-squared
2.7049752
4
0.6083443
0
Controller medications for asthma
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ICS compared with LABA+ICS (Higher Dose) MetaAnalysis Results – Sensitivity Analyses
1)
2)
3)
4)
5)
Rescue medicine use – Puffs per day
% Rescue free days
Symptom Score
% Symptom free days
Exacerbations
Rescue medicine use – Puffs per day
ICS/LABA v ICS (higher dose) - Rescue medicine use - Puffs per day - Sensitivity Analyses
Study name
Baraniuk et al 1999a
Baraniuk et al 1999b
Bateman et al 2003
Bergmann et al 2004
Bisgaard et al 2006
Condemi et al 1999
Greening et al 1994
Lalloo et al 2003
Mitchell et al 2003
O'Byrne et al 2001
O'Byrne et al 2005
Peters et al 2008
Vermetten et al 1999
Statistics for each study
Std diff in means and 95% CI
Std diff
in means
Lower
limit
Upper
limit
p-Value
-0.201
-0.271
-0.222
-0.423
0.048
-0.317
-0.058
-0.208
-0.469
-0.109
-0.153
-0.409
-0.258
-0.221
-0.385
-0.455
-0.434
-0.636
-0.215
-0.506
-0.248
-0.390
-0.748
-0.265
-0.244
-0.652
-0.516
-0.290
-0.016
-0.086
-0.010
-0.210
0.311
-0.128
0.132
-0.026
-0.190
0.047
-0.062
-0.166
-0.000
-0.151
0.033
0.004
0.040
0.000
0.720
0.001
0.553
0.025
0.001
0.170
0.001
0.001
0.050
0.000
-1.00
-0.50
0.00
Favors ICS/LABA
0.50
1.00
Favors ICS (higher dose)
Heterogeneity
Q-value
df (Q)
P-value
I-squared
20.759591
12
5.40E-02
42.195393
Controller medications for asthma
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% Rescue free days
ICS/LABA v ICS (higher dose) - % Rescue free days - Sensitivity Analyses
Study name
Statistics for each study
Std diff in means and 95% CI
Std diff
in means
Lower
limit
Upper
limit
p-Value
Baraniuk et al 1999a
-0.201
-0.385
-0.016
0.033
Baraniuk et al 1999b
-0.271
-0.455
-0.086
0.004
Bateman et al 2003
-0.358
-0.571
-0.145
0.001
Bisgaard et al 2006
-0.115
-0.379
0.148
0.389
deBlic et al 2009
-0.259
-0.485
-0.033
0.025
Ind et al 2003
-0.362
-0.578
-0.147
0.001
0.001
-0.209
0.211
0.994
O'Byrne et al 2005
-0.153
-0.244
-0.062
0.001
Peters et al 2008
-0.409
-0.652
-0.166
0.001
-0.225
-0.306
-0.145
0.000
Johansson et al 2001
-1.00
-0.50
0.00
Favors ICS/LABA
0.50
1.00
Favors ICS (higher dose)
Heterogeneity
Q-value
df (Q)
P-value
I-squared
12.797355
8
0.1190148
37.487082
Controller medications for asthma
333 of 369
Final Update 1 Report
Drug Effectiveness Review Project
LABA + ICS compared with Continuing Same Dose ICS
Summary of Outcome Measures Analyzed:
1. Rescue medication reduction in puffs
2. Rescue medicine free days (percent improved)
3. Symptom Control (percent improved symptom free days)
4. Symptom Control (percent improved symptom score)
5. Change in AQLQ score
Note* - exacerbations were recorded in inconsistent measures
Results
Rescue Medication Use – Puffs per day – Updated Analysis
ICS+LABAv. ContinueSameDoseICS- RescueMedicationUse- PuffsPer Day
Studyname
Statistics for eachstudy
Stddiff
inmeans
Bailey 2008
Boyd1995
Buhl 2003a
Buhl 2003b
Corren2007; Murphy 2008
Eid2010a
Kavuru2000
Kemp1998
Koopmans 2006
Morice2007a
Morice2007b
Nathan2006
Noonan2006; Chervinsky 2008a
O'Byrne2001a
O'Byrne2001b
Peters 2008
Russell 1995
vander Molen1997
Verberne1998
Zetterstorm2001a
Zetterstorm2001b
-0.009
-0.371
-0.278
-0.356
-0.283
-0.210
-0.335
-0.294
-0.949
-0.314
-0.312
-0.492
-0.352
-0.308
-0.313
-0.330
-0.301
-0.432
0.351
-0.330
-0.336
-0.294
Stddiff inmeans and95%CI
Lower
limit
Upper
limit
p-Value
-0.189
-0.740
-0.490
-0.568
-0.558
-0.420
-0.628
-0.469
-1.512
-0.501
-0.498
-0.784
-0.620
-0.464
-0.470
-0.527
-0.576
-0.688
-0.014
-0.581
-0.592
-0.357
0.171
-0.001
-0.067
-0.144
-0.008
-0.000
-0.042
-0.119
-0.387
-0.127
-0.126
-0.199
-0.084
-0.153
-0.155
-0.134
-0.026
-0.175
0.717
-0.079
-0.081
-0.230
0.925
0.049
0.010
0.001
0.044
0.050
0.025
0.001
0.001
0.001
0.001
0.001
0.010
0.000
0.000
0.001
0.032
0.001
0.059
0.010
0.010
0.000
-1.00
-0.50
Favors ICS+LABA
0.00
0.50
1.00
Favors ICS
Heterogeneity
Q-value
df (Q)
P-value
I-squared
31.58152
20
4.80E-02
36.671825
Sensitivity analyses indicate no difference in overall meta-analysis conclusions with single studies removed.
Controller medications for asthma
334 of 369
Final Update 1 Report
Drug Effectiveness Review Project
% Rescue Medication Free Days – Updated Analysis
ICS+LABAv. ContinueSameDoseICS- %RescueFreeDays
Studyname
Statistics for eachstudy
Stddiff
inmeans
Bateman2001a
Bateman2001b
Buhl 2003a
Buhl 2003b
Corren2007; Murphy 2008
Eid2010a
Ind2003
Jenkins 2006a
Jenkins 2006b
Kuna2006a
Kuna2006b
Lundback2006
Morice2007a
Morice2007b
Nathan2006
Noonan2006; Chervinsky 2008a
Peters 2008
Pohunek2006a
Zetterstorm2001a
Zetterstorm2001b
0.329
0.328
0.278
0.356
0.467
0.355
0.365
0.380
0.440
0.194
0.326
0.000
0.314
0.312
0.290
0.452
0.327
-0.081
0.424
0.431
0.307
Stddiff inmeans and95%CI
Lower
limit
Upper
limit
p-Value
0.112
0.112
0.067
0.144
0.189
0.144
0.148
0.154
0.178
0.000
0.132
-0.287
0.127
0.126
0.000
0.183
0.132
-0.270
0.172
0.175
0.246
0.546
0.545
0.490
0.568
0.744
0.566
0.583
0.607
0.701
0.389
0.520
0.287
0.501
0.498
0.580
0.721
0.522
0.107
0.676
0.688
0.368
0.003
0.003
0.010
0.001
0.001
0.001
0.001
0.001
0.001
0.050
0.001
1.000
0.001
0.001
0.050
0.001
0.001
0.398
0.001
0.001
0.000
-1.00
-0.50
0.00
Favors ICS
Q-value
28.37722
Heterogeneity
df (Q) P-value
19
7.64E-02
0.50
1.00
Favors ICS+LABA
I-squared
33.04488
Sensitivity analyses indicate no difference in overall meta-analysis conclusions with single studies removed.
Controller medications for asthma
335 of 369
Final Update 1 Report
Drug Effectiveness Review Project
% Symptom Free Days – Updated Analysis
ICS+LABAv. ContinueSameDoseICS- %SymptomFreeDays
Studyname
Statisticsfor eachstudy
Bateman2001a
Bateman2001b
Boyd1995
Buhl 2003a
Buhl 2003b
Corren 2007; Murphy2008
Ind 2003
Jenkins2006
Kavuru2000
Kuna2006
Morice2007
Nathan 2006
Noonan2006; Chervinsky2008a
Noonan2006a
Noonan2006b
OByrne2001b
O'Byrne2001a
Peters2008
Pohunek2006a
Pohunek2006b
Shapiro2000
Tal 2002
Verberne1998
Zetterstorm2001a
Zetterstorm2001b
Stddiff inmeans and95%CI
Stddiff
inmeans
Lower
limit
Upper
limit
p-Value
0.366
0.364
0.342
0.211
0.211
0.012
0.343
0.380
0.335
0.194
0.245
0.077
0.452
0.438
0.446
0.313
0.308
0.327
-0.011
0.012
0.379
0.255
0.161
0.315
0.431
0.270
0.148
0.148
-0.027
0.000
0.000
-0.262
0.125
0.154
0.042
0.000
0.059
-0.211
0.183
0.177
0.181
0.155
0.153
0.132
-0.201
-0.180
0.074
0.022
-0.202
0.064
0.175
0.216
0.583
0.581
0.712
0.422
0.422
0.286
0.560
0.607
0.628
0.389
0.431
0.366
0.721
0.698
0.711
0.470
0.464
0.522
0.178
0.205
0.684
0.488
0.524
0.566
0.688
0.323
0.001
0.001
0.069
0.050
0.050
0.930
0.002
0.001
0.025
0.050
0.010
0.600
0.001
0.001
0.001
0.000
0.000
0.001
0.906
0.900
0.015
0.032
0.384
0.014
0.001
0.000
-1.00
-0.50
Favors ICS
0.00
0.50
1.00
Favors ICS+LABA
Heterogeneity
Q-value
df (Q)
P-value
I-squared
33.2345
24
9.92E-02
27.78589
Sensitivity analyses indicate no difference in overall meta-analysis conclusions with single studies removed.
Controller medications for asthma
336 of 369
Final Update 1 Report
Drug Effectiveness Review Project
Symptom Score – Updated Analysis
ICS+LABAv. Continue Same DoseICS- SymptomScore
Studyname
Statisticsfor eachstudy
Baileyet al, 2008
Boyd1995
Buhl 2003
Corren et al, 2007; Murphyet al, 2008
Jenkins2006
Kavuru2000
Kemp 1998
Koopmans2006
Morice2007a
Morice2007b
Noonan2006a
Noonan2006b
Noonanet al, 2006; Chervinskyet al, 2008a
Shapiro2000
vander Molen1997
Zetterstorm2001a
Zetterstorm2001b
Stddiff inmeans and95%CI
Stddiff
inmeans
Lower
limit
Upper
limit
p-Value
-0.034
-0.342
-0.211
-0.037
-0.380
-0.335
-0.294
-0.653
-0.245
-0.312
-0.259
-0.263
-0.452
-0.379
-0.269
-0.315
-0.336
-0.268
-0.214
-0.712
-0.422
-0.311
-0.607
-0.628
-0.469
-1.201
-0.431
-0.498
-0.517
-0.527
-0.721
-0.684
-0.524
-0.566
-0.592
-0.326
0.145
0.027
-0.000
0.237
-0.154
-0.042
-0.119
-0.106
-0.059
-0.126
-0.000
-0.000
-0.183
-0.074
-0.014
-0.064
-0.081
-0.210
0.708
0.069
0.050
0.793
0.001
0.025
0.001
0.019
0.010
0.001
0.050
0.050
0.001
0.015
0.039
0.014
0.010
0.000
-1.00
-0.50
Favors ICS+LABA
0.00
0.50
1.00
Favors ICS
Heterogeneity
Q-value
df (Q)
P-value
I-squared
15.78496
16
0.4680673
0
Sensitivity analyses indicate no difference in overall meta-analysis conclusions with single studies removed.
Controller medications for asthma
337 of 369
Final Update 1 Report
Drug Effectiveness Review Project
AQLQ – Updated Analysis
ICS+LABAv. Continue Same Dose ICS- AQLQ
Studyname
Statisticsfor eachstudy
Stddiff inmeans and95%CI
Stddiff
inmeans
Lower
limit
Upper
limit
p-Value
Moriceet al, 2007a
0.314
0.127
0.501
0.001
Moriceet al, 2007b
0.312
0.126
0.498
0.001
Priceet al 2002
0.147
-0.028
0.321
0.100
Kemp et al, 1998
0.064
-0.110
0.239
0.470
Berger et al, 2010
0.518
0.210
0.826
0.001
Corren et al, 2007; Murphyet al, 2008
0.167
-0.108
0.441
0.233
Noonanet al, 2006; Chervinskyet al, 2008a
0.452
0.183
0.721
0.001
0.259
0.144
0.374
0.000
-1.00
-0.50
Favors ICS
0.00
0.50
1.00
Favors ICS+LABA
Heterogeneity
Q-value
df (Q)
P-value
I-squared
11.96621
6
6.27E-02
49.85882
Sensitivity analyses indicate no difference in overall meta-analysis conclusions with single studies removed.
Controller medications for asthma
338 of 369
Final Update 1 Report
Drug Effectiveness Review Project
LTRA compared with LABA+ICS Results
Summary of Outcome Measures Analyzed:
1.
Rescue medication use (rescue free days)
2.
Symptom control (symptom-free days)
3.
Percent Exacerbations
Results
Rescue Medication Use – Rescue-Free Days
Studies that reported outcome, but are not included: NA
LTRA v ICS + LABA - Rescue medication - Rescue free days
Study name
Statistics for each study
Std diff
in means
Calhoun 2001
Pearlman 2002
Peters 2007
Koenig 2008
-0.322
-0.319
-0.207
-0.215
-0.272
Standard
error
Variance
0.098
0.097
0.110
0.109
0.052
0.010
0.009
0.012
0.012
0.003
Lower
limit
-0.514
-0.509
-0.424
-0.429
-0.373
Std diff in means and 95% CI
Upper
limit
-0.130
-0.129
0.009
-0.000
-0.171
Z-Value
p-Value
-3.292
-3.292
-1.882
-1.961
-5.287
0.001
0.001
0.060
0.050
0.000
-1.00
-0.50
0.00
Favors ICS+LABA
0.50
1.00
Favors LTRA
Heterogeneity
Q-value
df (Q)
P-value
I-squared
1.114178
3
0.773653
0
Controller medications for asthma
339 of 369
Final Update 1 Report
Drug Effectiveness Review Project
Symptom-Free Days
Studies that reported outcome, but are not included: NA
LTRA v ICS + LABA - Symptom control - Symptom free days
Study name
Statistics for each study
Std diff
in means
Calhoun 2001
Pearlman 2002
Peters 2007
Koenig 2008
-0.322
-0.319
-0.103
-0.215
-0.249
Standard
error
Std diff in means and 95% CI
Variance
Lower
limit
Upper
limit
Z-Value
0.010
0.009
0.012
0.012
0.003
-0.514
-0.509
-0.318
-0.429
-0.350
-0.130
-0.129
0.113
-0.000
-0.148
-3.292
-3.292
-0.935
-1.961
-4.844
0.098
0.097
0.110
0.109
0.051
p-Value
0.001
0.001
0.350
0.050
0.000
-1.00
-0.50
0.00
Favors ICS + LABA
0.50
1.00
Favors LTRA
Heterogeneity
Q-value
df (Q)
P-value
I-squared
2.942463
3
0.400582
0
Controller medications for asthma
340 of 369
Final Update 1 Report
Drug Effectiveness Review Project
Exacerbations
Studies that reported outcome, but are not included: NA
LTRA v ICS + LABA - Exacerbations
Study name
Statistics for each study
Std diff in means and 95% CI
Std diff Standard
Lower Upper
in means
error Variance limit
limit Z-Value p-Value
Calhoun 2001
Pearlman 2002
Peters 2007
Maspero 2008
0.322
0.155
0.240
0.294
0.255
0.098
0.096
0.110
0.089
0.049
0.010
0.009
0.012
0.008
0.002
0.130
-0.034
0.023
0.119
0.159
0.514
0.343
0.456
0.469
0.350
3.292
1.604
2.172
3.292
5.215
0.001
0.109
0.030
0.001
0.000
-0.50
-0.25
Favors LTRA
0.00
0.25
0.50
Favors ICS + LABA
Heterogeneity
Q-value
1.770616
df (Q)
3
P-value
0.62135
Controller medications for asthma
I-squared
0
341 of 369
Final Update 1 Report
Drug Effectiveness Review Project
Appendix J. Tolerability and overall adverse events of ICSs
Summary table of ICS adverse events and tolerability from head-to-head RCTs
Study
design
Country
Population
N
Study
Duration Setting
Beclomethasone compared with budesonide
Molimard et al.
RCT,
France
20051
openlabel
Age 18-60,
moderate to
460
severe persistent,
not controlled on
12
ICS, smoking
weeks
status NR
Comparison
(total daily
dose in
mcg)
BDP MDI
(800)
vs.
BUD DPI
(1600)
vs.
FP DPI
(1000)
Equivale
nt dosing
Yes (all
high)
RCT,
open
label
Multinational
(France, New
Zealand, Spain,
UK)
377
24
months
Age 20-60, mild,
no ICS for
previous 3
months
Multicenter (19)
Overall AEs(%): 38 vs
35 vs 37, P = 0.791
between all
Quality
rating
Fair
Withdrawals due to AEs
(#):
1 vs 1 vs 2
Dysphonia (%): 13 vs 16
vs 20
Multicenter,
subspecialty
clinics
Tattersfield et
al. 20012
Results
Respiratory
infection (%):
19 vs 14 vs 16
BUD DPI
(adjustable
dosing; range
133-1729)
vs
BDP MDI
with spacer
(176-1906)
vs.
non-steriod
treatment
"placebo"
Yes
(range
low to
high
for both)
Central and peripheral
nervous system
disorders (%):
18 vs 19 vs 20
Overall AEs(%): NR
Fair
Withdrawals due to AEs
(%):
4.6 vs 2.7 vs 6.4
Oral candidiasisthrush (%):
3 vs 2 vs 0
Dysphonia (%): 2 vs 1
vs 1
Upper respiratory tract
infection (%): 20 vs 23
vs 12
Back pain (%): 7 vs 8 vs
2
Fractures (%): 1.1 vs 0
vs 0
Reduction in bone
mineral density (%): did
not differ among
treatment groups over
the 2 years
No difference in
BMD/fractures between
BDP, BUD, and placebo
over 2 years
Controller medications for asthma
342 of 369
Final Update 1 Report
Study
Worth et al.
20013
Drug Effectiveness Review Project
Study
design
N
Duration
RCT,
openlabel
209
8 weeks
Country
Population
Setting
Germany,
France,
Netherlands
Age 18-75,
moderate to
severe, on ICS,
smoking status
NR
Comparison
(total daily
dose in
mcg)
BDP MDI
(800)
vs.
BUD DPI
(1600)
Equivale
nt dosing
Yes (high)
Age ≥ 18,
moderate to
severe, on ICS,
excluded
smokers
Quality
rating
Fair
Withdrawals due to
AEs(%):
3 vs. 5
Dysphonia (%): 5.4 vs.
4.08
fungal infection (%): 2.7
vs. 4.08
Multicenter (39)
Beclomethasone compared with ciclesonide
Chylack 20084
RCT
Multinational (US,
Poland, South
1,568
Africa)
Results
Overall AEs (%): 24.3
vs. 26.5
CIC HFAMDI (640)
vs.
BDP HFAMDI (640)
Yes (high)
Overall AEs (%):
incidence of treatment
emergent AEs: 83.5 vs.
85.6
Fair
Withdrawals due to
AEs(%): 3.7 vs. 2.8
Oral candidiasisthrush (%): 1.4 vs. 6.3
Multicenter
Dysphonia (%): 2.2 vs.
1.5
Pharyngitis (%): 8.0 vs.
8.4
Beclomethasone compared with flunisolide
No systematic reviews or head-to-head trials found
Beclomethasone compared with fluticasone
Barnes et al.
RCT, DB Multinational (7
FP MDI
19935
countries
(1000)
154
worldwide)
vs.
BDP MDI
6 weeks
Age ≥ 18, severe, (2000)
20% smokers
Multicenter (18
outpatient clinics)
Yes (high)
Overall AEs: 52% vs.
51%, P > 0.15
Fair
Withdrawals due to
AEs(%):
2.4% vs. 4.2%
Oral candidiasisthrush (%):
6% vs. 4%
Cough (%): 2% vs. 3%
Sore throat (%): 5% vs.
6%
Headache (%): 4% vs.
1%
Upper respiratory tract
infection (%): 6% vs. 3%
Rhinitis (%): 7% vs. 3%
Additional adverse
Controller medications for asthma
343 of 369
Final Update 1 Report
Drug Effectiveness Review Project
Study
Study
design
N
Duration
Country
Population
Setting
Boe et al. 19946
RCT, DB
Norway
134
Age ≥ 18, poorly
controlled, 34%
smokers
12
weeks
Comparison
(total daily
dose in
mcg)
FP DPI
(1600)
vs.
BDP DPI
(2000)
Equivale
nt dosing
Yes (high)
Results
events and comments:
no significant differences
(P > 0.15) between
treatments in the
incidence or nature of
AEs
Overall AEs: NR
Quality
rating
Fair
Withdrawals due to AEs
(%): 8 vs. 2
Oral candidiasisthrush (%):
31 vs. 30
Multicenter
Sore throat (%): 28 vs.
14
Upper respiratory tract
infection (%): 27 vs. 38
Respiratory
infection (%): 14 vs. 10
Hoarseness (%): 14 vs.
5
GI disorders(%): 13 vs.
19
de Benedictis et
al. 20017
RCT, DB
343
52
weeks
Multinational (7
countries:
Holland,
Hungary, Italy,
Poland,
Argentina, Chile,
South Africa)
Age 4-11,
prepubertal,
severity and
smoking status
NR
Multicenter (32)
FP DPI (400)
vs.
BDP DPI
(400)
Yes
(medium)
Muscoskeletal
disorders(%): 13 vs. 25
Overall AEs(%): 80 vs.
80.9
Fair
Withdrawals due to AEs:
NR
Growth: Adjusted mean
growth velocity greater
in FP treated subjects
(4.76 cm/year (0.28))
than BDP treated
subjects (4.06 cm/year
(0.29) (Difference 0.70
(95% CI: 0.13, 1.26 cm,
P < 0.02))
Cough (%): 5.3 vs. 8.1
Upper respiratory tract
infection (%): 13.5 vs.
14.5
Rhinitis (%): 25.3 vs.
11.6
Bronchitis (%): 14.1 vs.
Controller medications for asthma
344 of 369
Final Update 1 Report
Study
Drug Effectiveness Review Project
Study
design
N
Duration
Country
Population
Setting
Comparison
(total daily
dose in
mcg)
Equivale
nt dosing
Results
11.6
Quality
rating
Ear, nose, and throat
infection (%): 14.1 vs.
9.2
Pharyngitis/throat
infection(%): 12.4 vs.
14.5
Viral infection(%): 11.8
vs. 7.5
Fabbri et al.
19938
RCT, DB
Multinational (10
European)
274
12
months
(daily
symptom
outcome
s
collected
for initial
12
weeks)
Age 12-80,
moderate to
severe, not
controlled on
ICS, 11%
smokers
FP MDI
(1500)
vs.
BDP MDI
(1500)
Yes (high)
Viral respiratory
infection(%): 9.4 vs. 10.4
Overall AEs(%):
70% vs. 73% of pts
Fair
Withdrawals due to AEs
(%):
8 vs. 8
Deaths (#): 2 deaths, not
asthma related vs. 1
death, not asthma
related
Multicentre (25)
Oral candidiasisthrush (%):
4 vs. 7
Sore throat (%):
5 vs. 2
Headache (%):
4 vs. 5
Upper respiratory tract
infection (%): 6 vs. 5
Respiratory
infection (%):
15 vs. 11
Hoarseness (%):
6 vs. 3
Fairfax et al.
20019
RCT,
DB, DD
172
6 weeks
UK and Ireland
Age 18-65, mild
to severe,
symptomatic on
ICS, 24% current
smokers
BDP MDI
(extrafine
HFA, 400)
vs.
FP MDI
(CFC, 400)
Yes
(medium)
influenza (%):
4 vs. 5
Overall AEs(%): 41 vs.
37
Fair
Withdrawals due to AEs:
NR
Deaths: 0 vs. 0
Multicenter (30
Controller medications for asthma
345 of 369
Final Update 1 Report
Study
Lorentzen et al.
199610
Drug Effectiveness Review Project
Study
design
N
Duration
RCT, DB
Country
Population
Setting
general practice
sites)
Multinational (7,
Europe)
213
12
months
Age 18-77,
severe, well
controlled on high
dose ICS, 19%
smokers
Comparison
(total daily
dose in
mcg)
FP MDI
(1000)
vs.
BDP MDI
(2000)
Equivale
nt dosing
Yes (high)
Results
Overall AEs(%): 72 vs.
72
Quality
rating
Fair
Withdrawals due to AEs
(%):
13 vs. 9
Oral candidiasisthrush (%):
4 vs. 4
Multicenter (20
outpatient clinics)
Cough (%): 7 vs. 2
Sore throat (%): 4 vs. 7
Headache (%): < 1 vs.
7, P = 0.03
Respiratory
infection (%):
6 vs. 9
Rhinitis (%):
10 vs. 1
Hoarseness (%):
6 vs. 7
Lundback et al.
199311
RCT, DB
Multinational (10)
585
Age 15-90,
moderate, not
controlled on
ICS, smoking
status NR
6 weeks
(N =
48989
continue
d an
additiona
l 46
weeks)
FP MDI (500)
vs.
FP DPI (500)
vs.
BDP MDI
(1000)
No, only
for FP
MDI vs.
BDP MDI
(high); FP
DPI 500
is medium
Multicenter (47)
influenza (%):
5 vs. 13
Overall AEs: NR
Fair
Withdrawals due to AEs
(%):
3.6 vs 4.0 vs 2.6
Oral candidiasisthrush (%):
2 vs 2 vs 4
Sore throat (%): 5 vs 2
vs 1
Headache (%): 5 vs 7 vs
7
Upper respiratory tract
infection (%): 6 vs 9 vs 7
Rhinitis (%): 2 vs 5 vs 2
Malo et al.
199912
RCT,
DB,
crossove
Controller medications for asthma
Canada
Age ≥18, severity
FP MDI (4001000)
vs.
No
(medium
– high vs.
Hoarseness (%): 2 vs 2
vs < 1
Overall AEs: NR
Fair
Withdrawals due to AEs:
346 of 369
Final Update 1 Report
Study
Drug Effectiveness Review Project
Study
design
N
Duration
r
69
Medici et al.
200013
Country
Population
Setting
NR, excluded
current or former
smokers
16
weeks
multicenter
RCT, DB
Switzerland
69
Age 20-55, mild
to moderate, on
ICS for 6 months,
5-23% current
smokers
12
months
Multicenter (7
outpatient sites)
Comparison
(total daily
dose in
mcg)
BDP MDI
(800- 2000)
FP MDI (400)
vs.
FP MDI (750)
vs.
BDP MDI
(800)
vs.
BDP MDI
(1500)
Equivale
nt dosing
medium really
high)
Yes
(medium
vs high vs
medium
vs high)
Results
NR
Skin bruising:
was not significantly
different in terms of the
number of subjects
affected; its severity and
frequency, as well as the
number of bruises on
direct examination were
significantly greater in
subjects taking BDP
(mean 1.64 lesions on
BDP and 1.24 lesions on
FP)
Overall AEs: NR
Quality
rating
Fair
Adverse events caused
withdrawal (%): 0 vs 0
vs 0 vs 7.7
Hoarseness/dysphonia
(#):
1 vs 1 vs 1 vs 0
Oral candidiasis: 0 for all
Allergic skin reactions: 0
for all
Rash/skin eruptions: 0
for all
Molimard, M et
al. 20051
RCT,
openlabel
460
12
weeks
France
Age 18-60,
moderate to
severe persistent,
not controlled on
ICS, smoking
status NR
Multicenter,
subspecialty
clinics (69
pulmonologists)
BDP MDI
(800)
vs.
BUD DPI
(1600)
vs.
FP DPI
(1000)
Yes (all
high)
Reduction in bone
mineral density (%):No
difference in BMD
between BDP- and FPtreated patients over 1
year
Overall AEs(%): 38 vs
35 vs 37, P = 0.791
between all
Fair
Withdrawals due to AEs
(#):
1 vs 1 vs 2
Dysphonia (%): 13 vs 16
vs 20
Respiratory
infection (%):
19 vs 14 vs 16
Central and peripheral
nervous system
disorders (%):
18 vs 19 vs 20
Controller medications for asthma
347 of 369
Final Update 1 Report
Study
Raphael et al.
199914
Drug Effectiveness Review Project
Study
design
N
Duration
RCT,
DB, DD
399
12
weeks
Country
Population
Setting
US
Age ≥ 12 years,
mild to severe,
not controlled on
ICS, smokers
excluded
Multicenter,
specialty asthma
and primary care
centers (23)
Comparison
(total daily
dose in
mcg)
FP MDI (164)
vs
FP MDI (440)
vs
BDP MDI
(336)
vs
BDP MDI
(672)
Equivale
nt dosing
Yes (low,
medium,
low,
medium)
Results
FP all vs. BDP all
reported for those with
two percentages
Quality
rating
Fair
Overall AEs (%): 9 vs.
15, P = 0.664
Withdrawals due to AEs
(%):
3 vs 3 vs 4 vs 2
Oral candidiasisthrush (%):
1 vs. 4, P = 0.472
Dysphonia (%):
3 vs. 7, P = 0.577
Sore throat (%):
1 vs. 3, P = 0.797
Headache (%):
1 vs. 3, P = 0.721
Beclomethasone compared with mometasone
Bernstein et al.
US
RCT,
199915
DB, DD
Age ≥12, mild to
moderate, on
365
ICS, smokers
12
excluded
weeks
Multicenter (20)
Mometasone
DPI (200)
vs
Mometasone
DPI (400)
vs
Mometasone
DPI (800)
vs
BDP MDI
(336)
vs
placebo
No; only
for MOM
400 vs.
BDP 336
(both
medium)
Overall AEs(%): 18 vs
26 vs 28 vs 21 vs 22
Fair
Withdrawals due to AEs
(%):
5 vs 3 vs 4 vs 8 vs 11
Oral candidiasisthrush (%):
4 vs 6 vs 15 vs 3 vs 1
Dysphonia (%):
1 vs 1 vs 3 vs 1 vs 1
Cough (%): 1 vs 0 vs 0
vs 0 vs 3
Nathan et al.
200116
RCT,
DB, DD
227
12
weeks
US
Age ≥12,
moderate, on
ICS, smokers
excluded
Multicenter (15)
Placebo
vs
Mometasone
DPI (200)
vs
Mometasone
DPI (400)
vs
BDP MDI
(336)
No; only
for MF
200 vs.
BDP
(both
low), MF
400 is
medium
Headache (%): 3 vs 4 vs
4 vs 4 vs 5
Overall AEs: NR
Fair
Withdrawals due to
AEs(%):
8.8 vs 1.8 vs 3.6 vs 1.8
Oral candidiasisthrush (%):
0 vs 4 vs 11 vs 5
Dysphonia (%):
0 vs 4 vs 4 vs 2
Headache (%):
2 vs 5 vs 2 vs 4
Controller medications for asthma
348 of 369
Final Update 1 Report
Study
Drug Effectiveness Review Project
Study
design
N
Duration
Country
Population
Setting
Comparison
(total daily
dose in
mcg)
Equivale
nt dosing
Results
Quality
rating
Hoarseness (%):
2 vs 7 vs 2 vs 0
Beclomethasone compared with triamcinolone
RCT,
US
Berkowitz et al.
17
DB, DD
1998
Age 18-65, mild
339
to moderate, on
ICS, smokers
8weeks
excluded
BDP MDI
(336)
vs
TAA MDI
(800)
vs
placebo
Yes
(medium)
Overall AEs(%): 50 vs
57.4 vs 55.5
Fair
Withdrawals due to AEs
(%):
9.8 vs 8.3 vs 16.3
Multicenter (17),
asthma/allergy
centers
Oral
candidiasis/thrush (%):
1.8 vs 0 vs 0
Dysphonia (%): 1.8 vs
1.9 vs 0
Cough (%): 3.6 vs 2.8 vs
2.7
Dry throat (%): 0 vs 0.9
vs 0
Death (%): 0 vs 0 vs 0
Bronsky et al.
199818
RCT,
DB, DD
329
8 weeks
US
Age 18-65, mild
to severe, on
ICS, smokers
excluded
BDP MDI
(336)
vs
TAA MDI
(800)
vs
placebo
Yes
(medium)
Pharyngitis (%): 2.7 vs
0.9 vs 2.7
Overall AEs(%): 48.2 vs
50.9 vs 59.8, P = 0.786
BDP vs. TAA
Fair
Withdrawals due to
AEs(%):
2.7 vs 8.4 vs 17.9
Multicenter
Oral candidiasisthrush (%):
0.0 vs 0.9 vs 0.0
Dysphonia (%): 0.9 vs
1.9 vs 0.0
Cough: 0.9 vs 0.9 vs 1.8
Upper respiratory tract
infection (%): 2.7 vs 10.4
vs NR, P = 0.027
Death (%): 0.0 vs 0.0 vs
0.0
Budesonide compared with ciclesonide
Boulet et al.
RCT,
Multinational 200619
DB, DD
Canada and
Europe
359
Age 12-75, mild
Controller medications for asthma
CIC HFAMDI (320)
vs.
BUD DPI
(320)
No
(medium
vs. low)
Overall AEs(%): 42 vs.
52
Fair
Withdrawals due to
AEs(%): NR
349 of 369
Final Update 1 Report
Study
Drug Effectiveness Review Project
Study
design
N
Duration
12
weeks
Country
Population
Setting
to moderate, on
ICS, heavy
smokers or exsmokers
excluded (>10
cigarettes/day)
Comparison
(total daily
dose in
mcg)
Equivale
nt dosing
Results
Quality
rating
Oral candidiasisthrush (%):
0.0 vs 0.0
Dysphonia (%): 2 vs. 1
Multicenter
Cough: NR
Sore throat (%): 2 vs. 1
Hansel et al.
200620
RCT
Multinational Europe
554
12
weeks
Age 12-75, mild
to severe, on
ICS, 9% smokers
Multicenter
CIC HFAMDI (80)
vs.
CIC HFAMDI (320)
vs.
BUD DPI
(400)
Yes for
CIC 80
vs. BUD
400
No for
CIC 320
vs. BUD
(low vs.
medium
vs. low)
Upper respiratory tract
infection (%): 12 vs. 19
Overall AEs(%): 36.8
Fair
vs. 40.8 vs. 33.9
Withdrawals due to
AEs(%): 4.4 vs. 2.1 vs.
1.7
Oral candidiasisthrush (%): NR
Dysphonia (%): NR
Increased cough (%): 0
vs. 3.1 vs. 0
Sore throat (%): NR
Headache (%): 3.3 vs.
3.6 vs. 0
p=NR
Ukena et al.
200721
RCT,
DB, DD
399
12
weeks
Vermeulen et
22
al. 2007
RCT,
DB, DD
403
12
weeks
Controller medications for asthma
Germany
Age 12-75, mild
to severe,
smokers
excluded
Multicenter
Multinational Hungary, Poland,
Serbia/Monteneg
ro, South Africa,
Spain
Age 12-17,
severe, not
controlled on
ICS, excluded
smokers
CIC HFAMDI (320)
vs.
BUD DPI
(400)
No
(medium
vs. low)
CIC HFAMDI (320)
vs.
BUD DPI
(800)
Yes
(medium)
Upper respiratory tract
infection (%): 11.5 vs.
5.1 vs. 7.9
p=NR
See Evidence Table
Overall AEs(%): 26.5%
of patients vs. 18.3%
Fair
Fair
Withdrawals due to
AEs(%): NR
Oral candidiasisthrush (%): 0 vs. 0
Dysphonia, cough, sore
throat, and
350 of 369
Final Update 1 Report
Study
Drug Effectiveness Review Project
Study
design
N
Duration
Country
Population
Setting
Comparison
(total daily
dose in
mcg)
Equivale
nt dosing
Results
headache (%): NR
Quality
rating
Multicenter
Upper respiratory tract
infection (%): 2.2 vs. 2.3
von Berg et al.
200723
RCT,
DB, DD
621
12
weeks
Multinational Australia,
Germany,
Hungary, Poland,
Portugal, Serbia
and Montenegro,
South Africa and
Spain
CIC HFAMDI (160)
vs.
BUD DPI
(400)
Yes (low)
Deaths: 0 vs. 0
Overall AEs(%):38% of
patients (n=158 in G1,
n=78 in G2) experienced
an AE
Fair
Withdrawals due to
AEs(%): 2.9 vs. 1
Oral candidiasis/thrush
and dysphonia
combined (%): 0.2 vs.
1.5
Age 6-11,
moderate to
severe, smoking
status NR
Cough, sore throat, and
headache: NR
Multicenter
Upper respiratory tract
infection (%): 3.6% vs.
6.3%
Mean body height
increase, in centimeters:
1.18 (p<.0001) vs. 0.70
(p<.0001);
Increase in body height
significantly greater in
G1 than G2 (difference
b/t groups = 0.481 cm, p
= .0025, two-sided)
Budesonide compared with flunisolide
Canada
Newhouse et al. RCT
24
2000
179
Age 18-75,
moderate, on
6 weeks
ICS, 5% current
smokers
Multicenter (17)
Flunisolide
MDI +
AeroChambe
r (1500)
vs.
BUD DPI
(1200)
Yes
(medium)
Overall AEs(%): 48 vs.
54.4
Fair
Withdrawals due to AEs:
NR
Headache (%): 6.7 vs.
3.8
flu syndrome (%): 4.0
vs. 6.3
Paresthesia (%): 2.7 vs.
0.0
Migraine (%): 2.7 vs. 0.0
Emesis (%): 2.7 vs. 0.0
Insomnia (%): 1.3 vs.
2.5
Controller medications for asthma
351 of 369
Final Update 1 Report
Study
Drug Effectiveness Review Project
Study
design
N
Duration
Country
Population
Setting
Budesonide compared with fluticasone
Ayres et al.
RCT,
Multinational (13
199525
DB, DD
countries
worldwide)
671
Age 18-70,
6 weeks
severe, on ICS,
smokers
excluded
Comparison
(total daily
dose in
mcg)
FP MDI
(1000)
vs
FP MDI
(2000)
vs
BUD MDI
(1600)
Equivale
nt dosing
No (high
vs high vs
medium)
Results
Back pain (%): 1.3 vs.
2.5
Overall AEs: NR
Quality
rating
Fair
Withdrawals due to AEs:
NR
Overall adverse events
(%): 61 vs 49 vs 51
Oral candidiasisthrush (%):
3 vs 4 vs 5
Multicenter (66)
Cough (%): 3 vs 6 vs 5
Sore throat (%): 4 vs 4
vs 2
Headache (%): 5 vs 7 vs
6
Upper respiratory tract
infection (%): 11 vs 10
vs 6
Respiratory
infection (%): 4 vs 1 vs 2
Rhinitis (%): 4 vs 1 vs 3
Ferguson et al.
199926
RCT,
DB, DD
Multinational (6
countries
worldwide)
333
20
weeks
FP DPI (400)
vs.
BUD DPI
(800)
Yes
(medium)
RCT,
DB, DD
Ages 4-12,
moderate to
severe, on ICS,
smoking status
NR
Controller medications for asthma
Multinational
(Belgium,
Canada,
Fair
Withdrawals due to
AEs(%): NR
Oral candidiasisthrush (%):
0 vs. 0
Upper respiratory tract
infection (%): 28 vs. 32
Multicenter
Heinig et al.
199927
Hoarseness (%): 6 vs 3
vs 3
Overall AEs(%): NR
FP DPI
(2000)
vs.
No (both
are high
doses,
Growth: linear growth
velocity was statistically
greater for FP compared
to BUD (adjusted mean
increase in height: 2.51
cm vs. 1.89; difference
was 6.2 mm (95% CI:
2.9-9.6, P = .0003)
Overall AEs(%): 78 vs.
77
Fair
352 of 369
Final Update 1 Report
Study
Drug Effectiveness Review Project
Study
design
N
Duration
395
24
weeks
Hoekx et al.
28
1996
RCT,
DB, DD
229
Country
Population
Setting
Denmark,
Netherlands)
Comparison
(total daily
dose in
mcg)
BUD DPI
(2000)
Age 18-75,
severe, not
controlled on
ICS, 15% current
smokers
Multicenter (47)
Multinational (4:
Netherlands,
Sweden,
Denmark,
Finland)
FP DPI (400)
vs.
BUD DPI
(400)
Equivale
nt dosing
but
relative
potency
of
fluticason
e is
greater at
the given
doses)
No
(medium
vs. low)
Results
Withdrawals due to AEs:
NR
Overall AEs(%): 63 vs.
69
Quality
rating
Fair
Withdrawals due to AEs
(%):
2 (1.7%) vs. 3 (2.7%)
8 weeks
Children up to 13,
mild to moderate,
on ICS, smoking
status NR
Oral candidiasisthrush (%):
3 vs. < 1
Multicenter (22)
Cough (%): 6 vs. 4
Sore throat (%): 4 vs. 5
Headache (%): 3 vs. 7
Upper respiratory tract
infection (%): 12 vs. 15
Rhinitis (%): 11 vs. 12
Hoarseness (%): 0 vs. 4
Kannisto et al.
200029
RCT
Finland
75
Age 5-15,
severity NR, new
onset of asthma
6 months
for lab
outcome
s, 12
months
for
growth
outcome
Molimard et al.
20051
RCT,
openlabel
Controller medications for asthma
tertiary center,
University clinic
France
Age 18-60,
moderate to
BUD DPI
(800 for 2
months, then
400)
vs.
FP DPI (500
for 2 months,
then 200)
vs.
Cromone
(non-ICS
control)
At 4 months,
a subgroup
were
switched to
cromones
BDP MDI
(800)
vs
BUD DPI
Yes
allergic skin reaction
(%): < 1 vs. 5
Overall AEs: NR
Steroid
dosing
range:
medium,
low vs.
medium,
low
Withdrawals due to AEs
(%): NR
Yes (all
high)
Overall AEs(%): 38 vs
35 vs 37, P = 0.791
between all
Fair
Growth: Greater growth
velocity in FP than in
BUD group
[FP treated children had
less growth reduction
than BUD treated
children (height SD
score: 0.03 vs. 0.23; P <
0.05)
Fair
353 of 369
Final Update 1 Report
Study
Drug Effectiveness Review Project
Study
design
N
Duration
460
12
weeks
Country
Population
Setting
severe persistent,
not controlled on
ICS, smoking
status NR
Comparison
(total daily
dose in
mcg)
(1600)
vs
FP DPI
(1000)
Equivale
nt dosing
RCT,
DB, DD
518
12
weeks
Multinational
Age 18-75,
moderate to
severe, not
controlled on
ICS, 19%
smokers
Quality
rating
Dysphonia (%): 13 vs 16
vs 20
Multicenter,
subspecialty
clinics (69
pulmonologists)
Ringdal et al.
199630
Results
Withdrawals due to AEs
(#):
1 vs 1 vs 2
Respiratory
infection (%):
19 vs 14 vs 16
FP DPI (800)
vs.
BUD DPI
(1600)
Yes (high)
Central and peripheral
nervous system
disorders (%):
18 vs 19 vs 20
Overall AEs(%): 61.7 vs.
61.5
Fair
Withdrawals due to AEs
(%):
3.9 vs. 5.0
Sore throat (%):
5.9 vs. 4.2
Multicenter
Upper respiratory tract
infection (%):
21.5 vs. 24.9
Rhinitis (%):
11.3 vs. 8.0
Budesonide compared with mometasone
Bousquet et al.
RCT,
Multinational (17)
200031
singleblind
Age ≥ 12,
moderate, on
ICS, smokers
730
excluded
12
Multicenter (57)
weeks
Corren et al
200332
RCT,
DB, DD
Controller medications for asthma
US
Mometasone
DPI (200)
vs
Mometasone
DPI (400)
vs
Mometasone
DPI (800)
vs
Budesonide
DPI (800)
No (only
for MF
400 vs.
BUD,
both
medium)
Mometasone
DPI (400)
No
(medium
Overall AEs: NR
Fair
Withdrawals due to AEs
(%):
3 vs < 1 vs 2 vs 4 vs 2
Dysphonia (%):
4.3 vs 2.8 vs 4.8 vs 2.2
The most common
treatment-related
adverse events were
headache (4-8%),
pharyngitis (4-5%), and
dysphonia (2-5%). Oral
candidiasis was
uncommon in this study,
reported by only 16
patients overall, and had
a similar incidence
among the treatment
groups (N = 4, 6, 4, and
3)
Overall AEs(%): 8 vs 9
vs 8
Fair
354 of 369
Final Update 1 Report
Study
Drug Effectiveness Review Project
Study
design
N
Duration
262
8 weeks
Country
Population
Setting
Age ≥12,
moderate, on
ICS, smokers
excluded
Comparison
(total daily
dose in
mcg)
vs
BUD DPI
(320)
vs
placebo
Equivale
nt dosing
vs. low)
Results
Quality
rating
Withdrawals due to AEs:
NR
Most frequently reported
treatment-related AEs
were headache and
pharyngitis (both 4% or
less: data by treatment
arm NR).
Multicenter (17)
There was only one
report of oral candidiasis
in one MF-reated
patient.
Budesonide compared with triamcinolone
Weiss et al.
RCT
US
200433
945
Age ≥18, mild to
severe, smoking
52
status NR
weeks
Multicenter,
patients from 25
managed care
plans
Ciclesonide compared with flunisolide
No systematic reviews or head-to-head trials found
Ciclesonide compared with fluticasone
Bateman
RCT
Multinational 200834
Europe, North
528
America, South
Africa
6 months
Age 12-75,
moderate to
severe, on ICS,
33% ex-smokers
or current
smokders
Multicenter
BUD DPI
(mean dose
at start and
end: 941.9
and 956.8
mcg/d)
vs.
TAA pMDI
(1028.2/1042
.9 mcg/d)
Yes, on
average
both are
medium
CIC HFAMDI (640)
vs.
FP HFA-MDI
(660)
Yes (high)
Overall AEs (%): 85 vs.
86
Fair
Withdrawals due to AEs
(%):
3.0 vs. 2.5
The most frequently
reported AEs were
respiratory tract
infection, sinusitis,
bronchitis, and
accident/injury.
Overall AEs (N): 373 vs.
401
Fair
Withdrawals due to AEs
(%): NR
Oral candidiasisthrush (%): 2.0
vs. 4.8 (numbers from
safety set)
Dysphonia (%): 3.1 vs.
9.2 (numbers from
safety set)
Cough (%): NR
Sore
throat (%):Pharyngolary
ngeal pain (numbers
from safety set) 4.3 vs.
4.4
Headache (%):2.4 vs.
4.4 (numbers from
Controller medications for asthma
355 of 369
Final Update 1 Report
Study
Drug Effectiveness Review Project
Study
design
N
Duration
Country
Population
Setting
Comparison
(total daily
dose in
mcg)
Equivale
nt dosing
Results
safety set)
Quality
rating
Upper respiratory tract
infection (%): 8.2 vs.
7.3% (numbers from
safety set)
Hoarseness (%): NR
Boulet 200735
RCT
474
12
weeks
Multinational Austria, Canada,
Germany,
Hungary, South
Africa, Spain
CIC HFAMDI (320)
vs.
FP DPI (400)
Yes
(medium)
Deaths: 0
Overall AEs(%): 36.1 vs.
39.3
Fair
Withdrawals due to AEs
(%): 1.7 vs. 4.2
Age 12-75,
moderate, 30%
ex-smokers or
current smokders
Oral candidiasisthrush (%): 0 vs. 3.8;
p=0.002 (1-sided)
Dysphonia (N): 5 vs. 6
Multicenter
Cough (%): NR
Sore throat (%): 3.4 vs.
1.7
Headache (%): NR
Upper respiratory tract
infection (%): NR
Buhl 200636
RCT
529
12
weeks
Multinational Germany,
Austria, The
Netherlands,
Spainn, Hungary,
Poland, South
Africa
Age 12-75,
moderate, on
ICS, smoking
status NR
Multicenter
CIC HFAMDI (160)
vs.
FP HFA-MDI
(176)
Yes (low)
Hoarseness (%): NR
Overall AEs (%): 36 vs.
34
Fair
Withdrawals due to AEs
(%): 2.26 vs. 1.14
Oral candidiasis/thrush
or dysphonia: Oral
candidiasis or voice
alteration occurred in 3
patients treated with
fluticasone proprionate
but neither occurred in
patients treated with
ciclesonide
Cough or sore throat:
NR
Headache (%): 3 vs. 4
Upper respiratory tract
infection (%): 8 vs. 8
Deaths: 0 vs. 0
Controller medications for asthma
356 of 369
Final Update 1 Report
Study
Dahl 201037
Drug Effectiveness Review Project
Study
design
N
Duration
RCT,
DB, DD
480
24
weeks
Knox 200738
RCT
Country
Population
Setting
Multinational –
Austria, Canada,
Germany,
Poland, and
South Africa
Equivale
nt dosing
Yes (low)
Multicenter
United Kingdom,
Belgium
Age 17-75, on
ICS, severity NR,
2-3% smokers
Results
Overall AEs(%): 44 vs.
43
Quality
rating
Fair
Withdrawals due to AEs
(N): 4. Vs. 8
Oral candidiasisthrush (%): 2.1 vs. 5.0
Age 12-75, on
ICS, mild to
moderate,
excluded current
and ex-smokers
with ≥ 10 packyear history, 2231% current or
ex-smokers
enrolled
111
12
weeks
Comparison
(total daily
dose in
mcg)
CIC HFAMDI (80)
vs.
FP HFA-MDI
(200)
Cough, sore throat, or
headache (%): NR
Upper respiratory tract
infection (%): 6.7 vs. 5.0
Hoarseness (%): NR
CIC HFAMDI (160)
vs.
FP HFA-MDI
(500)
No (low
vs.
medium)
Deaths (%): 0 vs. 0
Overall AEs(n):
Treatment-emergent AE
(TEAE) 42 vs. 49
Fair
Withdrawals due to AEs
(n): 1 vs. 0
Oral candidiasisthrush (n): 0 vs. : 1
Multicenter
Cough (%): NR
Sore throat (%): 3.4 vs.
3.8
Headache (%): NR
Upper respiratory tract
infection (%): 3.4 vs. 9.4
Lipworth 200539
RCT
United States
164
Age >18, mild to
moderate,
smoking status
NR
12
weeks
Multicenter
Placebo
vs.
CIC HFAMDI (320)
vs.
CIC HFAMDI (640)
vs.
FP HFA-MDI
(880)
Mixed
(NA vs.
medium
vs. high
vs. high)
Hoarseness (%): NR
Overall AEs(n): No. of
pts/n having at least 1
tx-emergent AE: G1:
35/41 vs. G2/G3: 53/82
vs. G4: 32/41
Fair
Withdrawals due to AEs
(%): G1: 7 vs. G2/G3:
1.2 vs. G4: 2.4
Oral candidiasisthrush (%): 0 vs. 2.5%
vs. 2.4% vs. 22.0%
Cough, sore throat, URI,
or headache (%): NR
Hoarseness (n): G1: 0
vs. G2/G3: 2/82 vs. G4:
Controller medications for asthma
357 of 369
Final Update 1 Report
Study
Magnussen
200740
Drug Effectiveness Review Project
Study
design
N
Duration
RCT
808
12
weeks
Country
Population
Setting
Multinational Germany,
Poland, Czech
Republic, France,
Italy, The
Netherlands,
Slovakia, Spain
Comparison
(total daily
dose in
mcg)
CIC HFAMDI (80)
vs.
CIC HFAMDI (160)
vs.
FP HFA-MDI
(176)
Equivale
nt dosing
Yes (low)
744
12
weeks
Multinational Brazil, Germany,
Hungary, Poland,
Portugal, South
Africa
Age 6-11, mild to
severe, smoking
status NR
Upper respiratory tract
infection (%): Reported
similar %s for the three
groups (from 0.4 to
5.8%) for bronchitis,
nasopharyngitis,
pharyngitis, and allergic
rhinitis
CIC HFAMDI (80)
vs.
CIC HFAMDI (160)
vs.
FP HFA-MDI
(176)
Yes (low)
RCT
Multinational - 8
countries
556
12
weeks
Age 6-15, mild to
severe, excluded
current smokers
Multicenter
CIC HFAMDI (160)
vs.
FP HFA-MDI
(176)
Overall AEs(%): 46.4 vs.
41.7 vs. 47.6
Fair
Withdrawals due to AEs
(%): 5.2% vs. 2.1 vs. 0.8
Oral candidiasisthrush (%): 0 vs. 0.43
vs. 0.41
Multicenter
Pedersen
200642
Fair
Oral candidiasis- thrush,
cough, sore throat,
headache, or
hoarseness (%): NR
Multicenter
RCT
Quality
rating
Withdrawals due to AEs
(n): 3 vs. 5 vs. 3
Age >12, mild to
severe, 21-24%
ex- and current
smokers
Pedersen
200941
Results
3/41
Overall AEs(%): 25.2 vs.
24.4 vs. 27.4
Yes (low)
Cough, sore throat,
headache, URI, or
hoarseness (%): NR
Overall AEs (n): 277 vs.
279
Fair
Withdrawals due to AEs
(n): 0 vs. 1
Oral candidiasisthrush (%): NR
Cough, sore throat, or
hoarseness (%): NR
Headache (%): 3.6 vs.
2.5
Upper respiratory tract
infection (%): 6.9 vs. 6.5
Ciclesonide compared with mometasone
No systematic reviews or head-to-head trials found
Ciclesonide compared with triamcinolone
No systematic reviews or head-to-head trials found
Flunisolide compared with fluticasone
Controller medications for asthma
358 of 369
Final Update 1 Report
Drug Effectiveness Review Project
Study
Comparison
design
Country
(total daily
Population
dose in
N
Study
Duration Setting
mcg)
No systematic reviews or head-to-head trials found for KQ2
Flunisolide compared with mometasone
No systematic reviews or head-to-head trials found
Flunisolide compared with triamcinolone
No systematic reviews or head-to-head trials found
Fluticasone compared with mometasone
O’Connor et al.
RCT, DB Multi-national
MF DPI (200)
200143
(20)
vs
733
MF DPI (400)
Age ≥12,
vs
moderate, on
12
MF DPI (800)
ICS, excluded
weeks
vs
smokers
FP DPI (500)
Multicenter,
University
hospitals
Fluticasone compared with triamcinolone
Baraniuk et al.
RCT,
US
199944
DB,
tripleAge ≥12, not
dummy
controlled on
ICS, excluded
680
smokers
12
weeks
Equivale
nt dosing
No (only
for
medium
doses of
each: MF
400 vs.
FP 500)
Results
Overall AEs (%):
20 vs 26 vs 30 vs 29
Quality
rating
Fair
Withdrawals due to AEs
(%):
5 vs 3 vs 5 vs 4
Oral candidiasisthrush (%):
1 vs 7 vs 10 vs 10
FP MDI (196)
+ Salmeterol
(84) vs
FP MDI (440)
vs
TAA MDI
(1200)
Yes
(medium
for both
ICS-only
arms)
Multicenter,
Pulmonary/allerg
y medicine clinics
(50)
Overall AEs(%):
Drug-related: 14 vs 13
vs 8
Fair
Withdrawals due to AEs
(%):
4 vs 1 vs 2
Oral candidiasisthrush (%):
2 vs 2 vs 1
Dysphonia (%): 3 vs 4
vs < 1
Condemi et al.
199745
RCT,
DB, DD
291
24
weeks
US
Age ≥12,
persistent
asthma, on ICS,
excluded
smokers
Multicenter (24
outpatient
centers)
FP DPI (500)
vs
TAA MDI
(800)
vs
placebo
No
(medium
vs low)
Sore throat (%): 3 vs <
1 vs 2
Overall AEs(%):
15 vs 8 vs 13, P = 0.174
Fair
Withdrawals due to AEs:
4 vs 5 vs 8
Oral candidiasisthrush (%):
8 vs 3 vs 1
Sore throat (%): 3 vs 1
vs 0
Headache (%): 1 vs 0 vs
2
Hoarseness (%): 3 vs 0
vs 0
Candidiasis, unspecified
site (%):
2 vs 0 vs 0
Controller medications for asthma
359 of 369
Final Update 1 Report
Study
Gross et al.
199846
Drug Effectiveness Review Project
Study
design
N
Duration
RCT,
DB, DD
304
24
weeks
Country
Population
Setting
US
Age ≥12, mild to
moderate, on
ICS, excluded
smokers
Multicenter (24
respiratory care
or allergy
University
Clinics)
Comparison
(total daily
dose in
mcg)
FP DPI (500)
vs
TAA MDI
(800)
vs
placebo
Equivale
nt dosing
No
(medium
vs low)
Results
Overall AEs (%):
20 vs 5 vs 5, P < 0.001
FP vs TAA
Quality
rating
Fair
Withdrawals due to AEs
(%):
9 vs 7 vs 9
Oral candidiasisthrush (%):
5 vs 0 vs 0
Sore throat (%): 3 vs 2
vs 2
Headache (%): 1 vs 1
vs2
Hoarseness (%): 3 vs 0
vs 0
Migraine(%): 2 vs 0 vs 0
References for Appendix J
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
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beclomethasone extrafine aerosol compared to fluticasone and budesonide. Respir Med. Jun 2005;99(6):770-778.
Tattersfield AE, Town GI, Johnell O, et al. Bone mineral density in subjects with mild asthma randomised to treatment
with inhaled corticosteroids or non-corticosteroid treatment for two years. Thorax. Apr 2001;56(4):272-278.
Worth H, Muir JF, Pieters WR. Comparison of hydrofluoroalkane-beclomethasone dipropionate Autohaler with
budesonide Turbuhaler in asthma control. Respiration. 2001;68(5):517-526.
Chylack LT, Jr., Gross GN, Pedinoff A. A randomized, controlled trial to investigate the effect of ciclesonide and
beclomethasone dipropionate on eye lens opacity. J Asthma. Dec 2008;45(10):893-902.
Barnes NC, Marone G, Di Maria GU, Visser S, Utama I, Payne SL. A comparison of fluticasone propionate, 1 mg
daily, with beclomethasone dipropionate, 2 mg daily, in the treatment of severe asthma. International Study Group. Eur
Respir J. Jun 1993;6(6):877-885.
Boe J, Bakke P, Rodolen T, Skovlund E, Gulsvik A. High-dose inhaled steroids in asthmatics: moderate efficacy gain
and suppression of the hypothalamic-pituitary-adrenal (HPA) axis. Research Council of the Norwegian Thoracic
Society. Eur Respir J. Dec 1994;7(12):2179-2184.
de Benedictis FM, Teper A, Green RJ, Boner AL, Williams L, Medley H. Effects of 2 inhaled corticosteroids on
growth: results of a randomized controlled trial. Arch Pediatr Adolesc Med. Nov 2001;155(11):1248-1254.
Fabbri L, Burge PS, Croonenborgh L, et al. Comparison of fluticasone propionate with beclomethasone dipropionate in
moderate to severe asthma treated for one year. International Study Group. Thorax. Aug 1993;48(8):817-823.
Fairfax A, Hall I, Spelman R. A randomized, double-blind comparison of beclomethasone dipropionate extrafine
aerosol and fluticasone propionate. Ann Allergy Asthma Immunol. May 2001;86(5):575-582.
Lorentzen KA, Van Helmond JL, Bauer K, Langaker KE, Bonifazi F, Harris TA. Fluticasone propionate 1 mg daily
and beclomethasone dipropionate 2 mg daily: a comparison over 1 yr. Respir Med. Nov 1996;90(10):609-617.
Lundback B, Alexander M, Day J, et al. Evaluation of fluticasone propionate (500 micrograms day-1) administered
either as dry powder via a Diskhaler inhaler or pressurized inhaler and compared with beclomethasone dipropionate
(1000 micrograms day-1) administered by pressurized inhaler. Respir Med. Nov 1993;87(8):609-620.
Malo JL, Cartier A, Ghezzo H, et al. Skin bruising, adrenal function and markers of bone metabolism in asthmatics
using inhaled beclomethasone and fluticasone. Eur Respir J. May 1999;13(5):993-998.
Medici TC, Grebski E, Hacki M, Ruegsegger P, Maden C, Efthimiou J. Effect of one year treatment with inhaled
fluticasone propionate or beclomethasone dipropionate on bone density and bone metabolism: a randomised parallel
group study in adult asthmatic subjects. Thorax. May 2000;55(5):375-382.
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26.
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29.
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31.
32.
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Raphael GD, Lanier RQ, Baker J, Edwards L, Rickard K, Lincourt WR. A comparison of multiple doses of fluticasone
propionate and beclomethasone dipropionate in subjects with persistent asthma. J Allergy Clin Immunol. May
1999;103(5 Pt 1):796-803.
Bernstein DI, Berkowitz RB, Chervinsky P, et al. Dose-ranging study of a new steroid for asthma: mometasone furoate
dry powder inhaler. Respir Med. Sep 1999;93(9):603-612.
Nathan RA, Nayak AS, Graft DF, et al. Mometasone furoate: efficacy and safety in moderate asthma compared with
beclomethasone dipropionate. Ann Allergy Asthma Immunol. Feb 2001;86(2):203-210.
Berkowitz R, Rachelefsky G, Harris AG, Chen R. A comparison of triamcinolone acetonide MDI with a built-in tube
extender and beclomethasone dipropionate MDI in adult asthmatics. Chest. Sep 1998;114(3):757-765.
Bronsky E, Korenblat P, Harris AG, Chen R. Comparative clinical study of inhaled beclomethasone dipropionate and
triamcinolone acetonide in persistent asthma. Ann Allergy Asthma Immunol. Apr 1998;80(4):295-302.
Boulet LP, Drollmann A, Magyar P, et al. Comparative efficacy of once-daily ciclesonide and budesonide in the
treatment of persistent asthma. Respir Med. May 2006;100(5):785-794.
Hansel TT, Benezet O, Kafe H, et al. A multinational, 12-week, randomized study comparing the efficacy and
tolerability of ciclesonide and budesonide in patients with asthma. Clin Ther. Jun 2006;28(6):906-920.
Ukena D, Biberger C, Steinijans V, et al. Ciclesonide is more effective than budesonide in the treatment of persistent
asthma. Pulm Pharmacol Ther. 2007;20(5):562-570.
Vermeulen JH, Gyurkovits K, Rauer H, Engelstatter R. Randomized comparison of the efficacy and safety of
ciclesonide and budesonide in adolescents with severe asthma. Respir Med. Oct 2007;101(10):2182-2191.
von Berg A, Engelstatter R, Minic P, et al. Comparison of the efficacy and safety of ciclesonide 160 microg once daily
vs. budesonide 400 microg once daily in children with asthma. Pediatr Allergy Immunol. Aug 2007;18(5):391-400.
Newhouse M, Knight A, Wang S, Newman K. Comparison of efficacy and safety between flunisolide/AeroChamber
and budesonide/turbuhaler in patients with moderate asthma. AER-MD-04 Study Group. Ann Allergy Asthma Immunol.
Mar 2000;84(3):313-319.
Ayres JG, Bateman ED, Lundback B, Harris TA. High dose fluticasone propionate, 1 mg daily, versus fluticasone
propionate, 2 mg daily, or budesonide, 1.6 mg daily, in patients with chronic severe asthma. International Study Group.
Eur Respir J. Apr 1995;8(4):579-586.
Ferguson AC, Spier S, Manjra A, Versteegh FG, Mark S, Zhang P. Efficacy and safety of high-dose inhaled steroids in
children with asthma: a comparison of fluticasone propionate with budesonide. J Pediatr. Apr 1999;134(4):422-427.
Heinig JH, Boulet LP, Croonenborghs L, Mollers MJ. The effect of high-dose fluticasone propionate and budesonide
on lung function and asthma exacerbations in patients with severe asthma. Respir Med. Sep 1999;93(9):613-620.
Hoekx JC, Hedlin G, Pedersen W, Sorva R, Hollingworth K, Efthimiou J. Fluticasone propionate compared with
budesonide: a double-blind trial in asthmatic children using powder devices at a dosage of 400 microg x day(-1). Eur
Respir J. Nov 1996;9(11):2263-2272.
Kannisto S, Korppi M, Remes K, Voutilainen R. Adrenal suppression, evaluated by a low dose adrenocorticotropin
test, and growth in asthmatic children treated with inhaled steroids. J Clin Endocrinol Metab. Feb 2000;85(2):652-657.
Ringdal N, Swinburn P, Backman R, et al. A blinded comparison of fluticasone propionate with budesonide via powder
devices in adult patients with moderate-to-severe asthma: A clinical evaluation. Mediators of Inflammation.
1996;5(5):382-389.
Bousquet J, D'Urzo A, Hebert J, et al. Comparison of the efficacy and safety of mometasone furoate dry powder inhaler
to budesonide Turbuhaler. Eur Respir J. Nov 2000;16(5):808-816.
Corren J, Berkowitz R, Murray JJ, Prenner B. Comparison of once-daily mometasone furoate versus once-daily
budesonide in patients with moderate persistent asthma. Int J Clin Pract. Sep 2003;57(7):567-572.
Weiss KB, Liljas B, Schoenwetter W, Schatz M, Luce BR. Effectiveness of budesonide administered via dry-powder
inhaler versus triamcinolone acetonide administered via pressurized metered-dose inhaler for adults with persistent
asthma in managed care settings. Clin Ther. Jan 2004;26(1):102-114.
Bateman ED, Linnhof AE, Homik L, Freudensprung U, Smau L, Engelstatter R. Comparison of twice-daily inhaled
ciclesonide and fluticasone propionate in patients with moderate-to-severe persistent asthma. Pulm Pharmacol Ther.
2008;21(2):264-275.
Boulet LP, Bateman ED, Voves R, Muller T, Wolf S, Engelstatter R. A randomized study comparing ciclesonide and
fluticasone propionate in patients with moderate persistent asthma. Respir Med. Aug 2007;101(8):1677-1686.
Buhl R, Vinkler I, Magyar P, et al. Comparable efficacy of ciclesonide once daily versus fluticasone propionate twice
daily in asthma. Pulm Pharmacol Ther. 2006;19(6):404-412.
Dahl R, Engelstatter R, Trebas-Pietras E, Kuna P. A 24-week comparison of low-dose ciclesonide and fluticasone
propionate in mild to moderate asthma. Respiratory Medicine. August 2010;104 (8):1121-1130.
Knox A, Langan J, Martinot JB, Gruss C, Hafner D. Comparison of a step-down dose of once-daily ciclesonide with a
continued dose of twice-daily fluticasone propionate in maintaining control of asthma. Curr Med Res Opin. Oct
2007;23(10):2387-2394.
Lipworth BJ, Kaliner MA, LaForce CF, et al. Effect of ciclesonide and fluticasone on hypothalamic-pituitary-adrenal
axis function in adults with mild-to-moderate persistent asthma. Ann Allergy Asthma Immunol. Apr 2005;94(4):465472.
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41.
42.
43.
44.
45.
46.
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Magnussen H, Hofman J, Staneta P, Lawo JP, Hellwig M, Engelstatter R. Similar efficacy of ciclesonide once daily
versus fluticasone propionate twice daily in patients with persistent asthma. J Asthma. Sep 2007;44(7):555-563.
Pedersen S, Engelstatter R, Weber HJ, et al. Efficacy and safety of ciclesonide once daily and fluticasone propionate
twice daily in children with asthma. Pulm Pharmacol Ther. Jun 2009;22(3):214-220.
Pedersen S, Garcia Garcia ML, Manjra A, Theron I, Engelstatter R. A comparative study of inhaled ciclesonide 160
microg/day and fluticasone propionate 176 microg/day in children with asthma. Pediatr Pulmonol. Oct
2006;41(10):954-961.
O'Connor B, Bonnaud G, Haahtela T, et al. Dose-ranging study of mometasone furoate dry powder inhaler in the
treatment of moderate persistent asthma using fluticasone propionate as an active comparator. Ann Allergy Asthma
Immunol. Apr 2001;86(4):397-404.
Baraniuk J, Murray JJ, Nathan RA, et al. Fluticasone alone or in combination with salmeterol vs triamcinolone in
asthma. Chest. Sep 1999;116(3):625-632.
Condemi JJ, Chervinsky P, Goldstein MF, et al. Fluticasone propionate powder administered through Diskhaler versus
triamcinolone acetonide aerosol administered through metered-dose inhaler in patients with persistent asthma. J Allergy
Clin Immunol. Oct 1997;100(4):467-474.
Gross GN, Wolfe JD, Noonan MJ, et al. Differential effects of inhaled corticosteroids: Fluticasone propionate versus
triamcinolone acetonide. American Journal of Managed Care. 1998;4(2):233-244.
Controller medications for asthma
362 of 369
Final Update 1 Report
Drug Effectiveness Review Project
Appendix K. Tolerability and overall adverse events of LABAs
Summary of head to head studies comparing tolerability and overall adverse
events of LABAs
Study
Study design
N
Duration
Country
Comparison
Study population (total daily
Setting
dose)
Results
Quality
rating
Direct evidence (formoterol compared with salmeterol)
Cates and
Lasserson
20091
Systematic
review with
meta-analysis
4 RCTs (3
adult, 1
children)
Multinational
FM DPI (24)
vs.
Adults (age >18) and SM DPI (100)
children (age 6-17),
most with moderate
persistent asthma
N= 1272
At least 12
weeks
All-cause mortality: (N=4, OR Good
not calculated, one adult nonasthma-related death in SM
group, no deaths in children)
All-cause SAEs in adults: (N=
3, OR 0.77; 95% CI 0.46 to
1.28,
All-cause SAEs in children:
(N=1, OR 0.95, 95% CI 0.06
to 15.33)
Asthma-related SAEs in
adults: (N=3, OR 0.86 95% CI
0.29 to 2.57),
Asthma-related SAEs in
children: (N=1, OR notcalculated, no asthma-related
adverse events)
Cates and
Lasserson
2010 2
Systematic
review with
meta-analysis
8 RCTs (all
adult and
adolescent)
Multinational
Age >12, most with
mild to moderate
persistent asthma
(variably defined).
N=6163
SM (variable
dose) and
fluticasone or
beclomethasone
vs.
FM (variable
dose) and
budesonide
All cause mortality: (N=7, OR Good
1.03, 95% CI 0.06 to 16.44)
eFM DPI (24)
vs.
SM DPI (100)
vs.
SM MDI (100)
Hospital admission or
ED visit, number (%):
1 (4) vs. 1 (7) vs. 2 (15)
All cause SAEs: (N=7, OR
1.14, 95% CI 0.82 to 1.59)
Asthma-related SAEs: (N=7,
OR 0.69, 95% CI 0.37 to
1.26)
At least 12
weeks
Campbell et al.
RCT, cross19993
over
469
8 weeks
UK & Republic of
Ireland
Age≥ 12, mild to
moderate, not
controlled on ICS,
20-24% current
smokers in each
group
Fair
Withdrawals due to AE:
Not reported
General practice &
hospital centers
Controller medications for asthma
363 of 369
Final Update 1 Report
Drug Effectiveness Review Project
Summary of head to head studies comparing tolerability and overall adverse
events of LABAs
Study
Condemi et al.
20014
Everden et al.
20045
Study design
N
Duration
Country
Comparison
Study population (total daily
Setting
dose)
FM (24)
vs.
Adults with moderate SM (100)
to moderately severe
N = 528
asthma already
24 wks
taking low dose ICS
(monthly visits (400ug/ day or FP
in which pts
200 ug/d) smoking
could volunteer status=NR
adverse
events);
Multi-center,
symptom
outpatient practices
diaries
collected only
for first 4
weeks.
RCT; openlabel
RCT; open;
USA
UK & Republic of
Ireland
N = 156
12wk
eFM DPI (24)
vs.
SM DPI (100)
Children and
adolescents age 617, moderate
persistent, not
controlled on ICS,
smoking status=NR
Results
Withdrawals due to AE:
FM 5.7% vs. SM 3.4%
Quality
rating
Fair
No. (%) with at least 1
adverse event
202 (77.1) vs. 201 (75.6)
Withdrawals due to AE no.
(%):
4 (5.1) vs. 2 (2.6)
Poor
Overall adverse events
reported (%): 55 vs. 59
General practice
outpatient clinics
Vervolet et al.
19986
RCT, open
label
and
Rutten-van
Molken 19987
N = 482
France, Italy, Spain, FM DPI (24)
Sweden, Switzerland vs.
& UK
SM DPI (100)
Hospitalizations (mean
inpatient days): 0.58 vs. 0.43
P = 0.996
Age ≥ 18, moderatesevere, not controlled
on ICS, 14-16%
current smokers
Withdrawals due to AEs (%)
(4.6) vs. (5.0)
6 mo.
Outpatient centers
Fair
Drug related AEs (%)
32 (13%) vs. 21 (9%)
(headache most common)
Indirect evidence (LABA compared with placebo)
Controller medications for asthma
364 of 369
Final Update 1 Report
Drug Effectiveness Review Project
Summary of head to head studies comparing tolerability and overall adverse
events of LABAs
Study
Cates and
Cates 2010 8
Study design
N
Duration
Systematic
Review with
meta-analysis
Country
Comparison
Study population (total daily
Setting
dose)
Multinational
Patients of any age,
any asthma severity
SM
vs.
Placebo
34 RCTs
Or
N= 62,815
SM
vs.
SABA
Results
Quality
rating
SM vs Placebo:
Good
All-cause mortality in adults:
(N=10 trials, OR 1.33, 95%
CI: 0.85 to 2.08)
All-cause mortality in children:
(N=4, OR nonestimable, zero
deaths reported in 793
patient-years)
Non-fatal SAEs in adults:
(N=13, OR 1.14, 95% CI:
1.01 to 1.28)
Non-fatal SAEs in children
(N=5, OR 1.3, 95% CI: 0.82
to 2.05)
Asthma-related mortality in
adults: (N=10, OR 3.49, 95%
CI 1.31 to 9.31)
Asthma-related non-fatal
SAEs in adults: (N=12, OR
1.42; 95% CI 0.75 to 2.71)
Asthma-related non-fatal
SAEs in children: (N=5, OR
1.72, 95% CI 1.0 to 2.98)
SM vs Salbutamol
All-cause mortality in adults:
(N=4, OR 1.28, 95% CI 0.79
to 2.05)
All-cause mortality in children:
(N=3, OR 0.04, 95% CI 0 to
2.97)
All-cause non-fatal SAEs in
adults and adolescents: (N=5,
OR 0.96, 95% CI 0.85 to 1.1)
All-cause non-fatal SAEs in
children (N=3, OR 1.37, 95%
CI 0.71 to 2.64)
Asthma-related mortality in
adults and adolescents: (N=4,
OR 2.36, 95% CI 0.78 to
7.16)
Asthma-related non-fatal
SAEs in adults and
adolescents: (N=3, OR 0.94,
95% CI 0.37 to 2.34)
Asthma-related non-fatal
SAEs in children: (N=3, OR
1.04, 95% CI 0.47 to 2.31)
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Summary of head to head studies comparing tolerability and overall adverse
events of LABAs
Study
Ni Chroinin et
al. 20049
Study design
N
Duration
Systematic
review and
meta-analysis
N = 1061
Duration: at
least 30 d.
Country
Comparison
Study population (total daily
Setting
dose)
Multinational
Initiating
combined
Adults and/or
ICS+LABA vs.
children aged two
ICS alone at
years and above with same (or
persistent asthma of equivalent).
any severity and who
were steroid-naïve.
18 trials met the
inclusion criteria; 9
(N = 1061 adults)
contributed sufficient
data to be analyzed.
Ni Chroinin et
10
al. 2005
Systematic
review and
meta-analysis
N = 8147
26 RCTs
Duration: at
least 30 days
(most less than
4 mo.)
Multinational
RCTs conducted in
adults or children
aged 2 or above in
whom LABA were
added to ICS.
Results
Any adverse effects (N = 5
trials: RR 1.09, 95% CI: 0.81
to 1.48).
Quality
rating
Good
Withdrawals due to AEs (N =
3 trials: RR 1.71, 95% CI:
0.68 to 4.27),
Specific side effects:
Oral candidiasis (N = 2 trials,
RR 0.43, 95% CI: 0.07 to
2.84). Headache (N = 2 trials,
RR 1.92, 95% CI: 0.54 to
6.85). Tremor (N = 2 trials,
RR 5.05, 95% CI: 1.33 to
19.17).
addition LABA to Overall adverse effects: no
ICS vs. placebo difference (N = 11, RR 0.98,
added to ICS
95% CI: 0.92 to 1.05),
Good
Serious adverse events: no
difference (N = 4 studies, RR
1.16, 95% CI: 0.30 to 4.42) or
Specific side effects:
headache (N = 12, RR 1.13,
95% CI: 0.92 to 1.41);
hoarseness (N = 3
comparisons, RR 0.71, 95%
CI: 0.16 to 3.18, randomeffects model); oral thrush (N
= 4, RR 1.04, 95% CI: 0.35 to
3.06); tachycardia or
palpitations (N = 5, RR 2.13,
95% CI: 0.77 to 5.88);
cardiovascular adverse
effects such as chest pain (N
= 3, RR 0.90, 95% CI: 0.32 to
2.54); tremor (N = 7, RR 2.48,
95% CI: 0.78 to 7.89).
Effect on growth, adrenal
function and methacholine
challenge could not be
aggregated due to insufficient
number of trials (fewer than
2) reporting these outcomes.
Only one study reported
deaths, with three deaths
reported overall.
Withdrawals due to adverse
effects: no difference (N = 19,
RR 1.29, 95% CI: 0.96 to
Controller medications for asthma
366 of 369
Final Update 1 Report
Drug Effectiveness Review Project
Summary of head to head studies comparing tolerability and overall adverse
events of LABAs
Study
Study design
N
Duration
Country
Comparison
Study population (total daily
Setting
dose)
Results
Quality
rating
1.75).
Salpeter et al.
200611
Walters et al.
200712
Systematic
review with
meta-analysis
Adults and children
with asthma
19 RCTs (N =
33826)
Mean age 37 years;
51% men; 15%
African American.
Duration: at
least 3 mo.
53% of subjects on
ICS.
Systematic
review with
meta-analysis
Multinational
67 RCTs
(N = 42,333).
Duration: at
least4 wks.
Regular inhaled
LABA (either
Adults and children
salmeterol or
with asthma who
formoterol)
were not uniformly on administered
ICS. (Studies in
twice daily vs.
which all subjects
placebo.
were uniformly taking
ICS excluded from
.
this review.)
11 studies included
children under 12
yrs.
Asthma severity: of
67 RCTs, number
with mild -moderate
asthma, 28; mild
asthmatics, 9;
moderate - severe
disease, 1; persistent
or symptomatic
disease, 11;
unknown disease
severity, 18.
Controller medications for asthma
LABA vs.
placebo
Hospitalization: OR 2.6 (CI:
1.6 to 4.3). Risk difference
attributed to LABA 0.7% (CI:
0.1% to 1.3%) over 6 months.
Risk increased in children
(OR, 3.9 [CI: 1.7 to 8.8]) and
in adults (OR, 2.0 [CI: 1.0 to
3.9]). Risk increased with SM
(OR, 1.7 [CI: 1.1 to 2.7]) and
with FM (OR, 3.2 [CI: 1.7 to
6.0])
Life-threatening asthma
attacks: OR 1.8 (CI: 1.1 to
2.9). Risk difference 0.12%
(CI: 0.01% to 0.3%) over 6
months.
Asthma-related deaths: (OR,
3.5 [CI: 1.3 to 9.3]). Pooled
risk difference of 0.07% (CI:
0.01% to 0.1%)
Good
Asthma-related death: for
those taking ICS at baseline
RR 1.34 (95% CI: 0.30 to
5.97). For those not taking
ICS at baseline the Relative
Risk is 18.98 (95% CI: 1.1 to
326).
Good
Respiratory-related death: RR
for total population of 2.18
(95% CI: 1.07 to 4.05), N =
26355. No difference
between subgroups using
ICS vs. not using ICS at
baseline (test for interaction P
= 0.84).
All-cause mortality: no
significant difference (RR
1.33, 95% CI: 0.76 to 2.35;
three studies using the nonICS subgroup from SMART,
N = 14534 and RR 1.37, 95%
CI: 0.87 to 2.14 using all
participants from SMART, N
= 26799).
Serious adverse events:
Increased odds of asthmarelated serious AE with LABA
(OR 7.46, 95% CI: 2.21 to
25.16; three studies, N =
895). However, OR for lifethreatening AE from SMART
367 of 369
Final Update 1 Report
Drug Effectiveness Review Project
Summary of head to head studies comparing tolerability and overall adverse
events of LABAs
Study
Study design
N
Duration
Country
Comparison
Study population (total daily
Setting
dose)
Results
Quality
rating
for both mixed and ICS treated populations were not
significantly different. LABA
treatment led to a significant
increase in the odds of
serious AE where this was
reported for ’total events’ in
three pediatric studies (OR
2.11, 1.03 to 4.31; N = 973).
Total AE: No difference
between LABA and placebo
(OR 1.15, 95% CI: 0.99 to
1.33; 18 studies, N = 3447).
Drug-related AE: more in
LABA groups (OR 1.37, 95%
CI: 1.01 to 1.87; seven
studies, N = 2130),
Specific side effects:
“Nervousness”: (OR 5.11,
95% CI: 1.72 to 15.22; two
studies, N = 546). Tremor:
(OR 3.86, 95% CI: 1.91 to
7.78; eight studies, 2257
participants), Headache: (OR
1.28, 95% CI: 1.04 to 1.57; 23
studies, N = 5667). Throat
irritation (OR 1.68, 95% CI:
1.10 to 2.56; eight studies, N
= 1170).
Other AEs: NS difference for
pharyngitis, cough, cramps,
myalgia/ fatigue, insomnia,
upper respiratory infection,
musculo-skeletal pain or
palpitations.
Withdrawal (due to AE): NS
(OR 1.11, 95% CI: 0.93 to
1.32; 21 studies, N = 30943).
Abbreviations: AE = adverse events; CI = confidence interval; DPI = dry powder inhaler; eFM = Eformoterol; FM = Formoterol; ICS =
Inhaled Corticosteroids; LABAs = Long-Acting Beta-2 Agonists; MDI = metered dose inhaler; NS = not statistically significant; OR=
odds ratio; RCT= randomized controlled trial.
No difference = no statistically significant difference or tests of statistical significance were not reported and outcomes are similar.
Note: All results are listed in the same order as the comparison column lists the medications.
References for Appendix K
1.
Cates CJ, Lasserson TJ. Regular treatment with formoterol versus regular treatment with salmeterol for chronic asthma:
serious adverse events. Cochrane Database Syst Rev. 2009(4):CD007695.
Controller medications for asthma
368 of 369
Final Update 1 Report
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
Drug Effectiveness Review Project
Cates CJ, Lasserson TJ. Regular treatment with formoterol and an inhaled corticosteroid versus regular treatment with
salmeterol and an inhaled corticosteroid for chronic asthma: serious adverse events. Cochrane Database Syst Rev.
2010(1):CD007694.
Campbell LM, Anderson TJ, Parashchak MR, Burke CM, Watson SA, Turbitt ML. A comparison of the efficacy of
long-acting beta 2-agonists: eformoterol via Turbohaler and salmeterol via pressurized metered dose inhaler or
Accuhaler, in mild to moderate asthmatics. Force Research Group. Respir Med. Apr 1999;93(4):236-244.
Condemi JJ. Comparison of the efficacy of formoterol and salmeterol in patients with reversible obstructive airway
disease: a multicenter, randomized, open-label trial. Clin Ther. Sep 2001;23(9):1529-1541.
Everden P, Campbell M, Harnden C, et al. Eformoterol Turbohaler compared with salmeterol by dry powder inhaler in
asthmatic children not controlled on inhaled corticosteroids. Pediatr Allergy Immunol. Feb 2004;15(1):40-47.
Vervloet D, Ekstrom T, Pela R, et al. A 6-month comparison between formoterol and salmeterol in patients with
reversible obstructive airways disease. Respir Med. Jun 1998;92(6):836-842.
Rutten-van Molken MP, van Doorslaer EK, Till MD. Cost-effectiveness analysis of formoterol versus salmeterol in
patients with asthma. Pharmacoeconomics. Dec 1998;14(6):671-684.
Cates CJ, Cates MJ. Regular treatment with salmeterol for chronic asthma: serious adverse events. Cochrane Database
Syst Rev. 2008(3):CD006363.
Ni Chroinin M, Greenstone IR, Ducharme FM. Addition of inhaled long-acting beta2-agonists to inhaled steroids as
first line therapy for persistent asthma in steroid-naive adults. Cochrane Database Syst Rev. 2004(2):CD005307.
Ni Chroinin M, Greenstone IR, Danish A, et al. Long-acting beta2-agonists versus placebo in addition to inhaled
corticosteroids in children and adults with chronic asthma. Cochrane Database Syst Rev. 2005(4):CD005535.
Salpeter SR, Buckley NS, Ormiston TM, Salpeter EE. Meta-analysis: effect of long-acting beta-agonists on severe
asthma exacerbations and asthma-related deaths. Ann Intern Med. Jun 20 2006;144(12):904-912.
Walters EH, Gibson PG, Lasserson TJ, Walters JA. Long-acting beta2-agonists for chronic asthma in adults and
children where background therapy contains varied or no inhaled corticosteroid. Cochrane Database Syst Rev.
2007(1):CD001385.
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