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ADVANCES IN PULMONARY HTN TREATMENT
- 1. Advances in management of pulmonary hypertension Speaker – Dr. Rajeev sharma Preceptor – Dr. Sandeep singh Dr. S ramakrishnan
- 2. Points of Discussion Introduction Approach to patient Management of PAH Recent advances Summary
- 3. Pulmonary circulation Distensible, low pressure Normal PAP: 24/9 mmHg MPAP: 15 mmHg PVR: 50-150 dyn.s/cm5 PCWP : <15 mm Hg PAH is defined as MPAP > 25 mm Hg at rest
- 4. Natural History NIH registry of IPAH patients from 1981-1985 showed a median survival of 2.8 years Recently report suggest 3-year survival < 60% despite current therapy - need for more option Circulation. 2010;122:156-163 Chest. 2004;126:78S–92S.
- 5. Classification 2.4 Congenital/acquired left heart inflow/outflow tract obstruction and congenital cardiomyopathies
- 7. Diagnostic algorithm Suspicion of PAH History, clinical examination, chest X- ray, electrocardiogram
- 8. Diagnostic algorithm TTE (with bubble contrast) PAH : diagnosis, severity, clue to the cause
- 9. Diagnostic algorithm RHC - Confirmation of diagnosis Vasodilator response
- 10. Diagnostic algorithm V/Q Scan Pulmonary angiography Multi-detector CT Coagulation profile Chronic pulmonary embolism
- 11. Diagnostic algorithm Pulmonary function tests Arterial blood gas analysis Overnight polysomnography Gas exchange Ventilatory function
- 12. Diagnostic algorithm CTD work up : ANA/RF/ANCA/ anti DNA Topoisomerase antibody, HIV ELISA LFT,TFT ,serum ACE level Scleroderma, SLE HIV PP Hypertension
- 13. Approach to treatment 1. General measures 2. Primary therapy 3. Supportive therapy 4. Advanced therapy
- 14. Treatment Considerations No Cure with drugs Goals are To decrease PVR & Pressure Reduce symptoms Increase patient activity & longevity
- 15. General measures
- 16. Physical activity Encouraged to be active within symptom limits Study has shown the value of a training programme in improving exercise performance Mereles D et al Circulation 2006;114:1482–1489.
- 17. Pregnany & contraception 30–50% mortality in patients with PAH Barrier contraceptive methods are safe but unpredictable effect Progesterone-only preparations are effective approaches to contraception Bosentan may reduce the efficacy of OCP IUCD- vasovagal reaction - poorly tolerated
- 18. Primary therapy Anticoagulation Thromboendarterectomy Oxygen therapy Treat underlying Heart disease No effective therapy Advanced therapy used 1 4 2 3
- 20. Oxygen Main therapy for Group 3 PAH Maintain SPo2 > 90 % NOTT trial compared continuous (19 hours/ day) to nocturnal (12 hours/ day) oxygen administration Three-year mortality rate was lower with continuous oxygen than nocturnal oxygen (22 versus 42 percent) Ann Intern Med 1980 ;93;391
- 21. NOTT Trial
- 22. Diuretics Symptom benefit Decrease RV filling pressure & wall stress Arrhythmia risk & may decrease CO
- 23. Digoxin No long term studies Used in patients with Rt Heart failure & low CO state PAH with atrial arrhythmias
- 24. Anticoagulation Rationale High prevalence of thrombotic lesions in IPAH Thrombin leads to disease progression Survival advantage with warfarin Chest. 1997;112:714 –21 Circulation. 1984;70:580 –7.
- 25. Anticoagulation COMPERA Registry Prospective registry To assess role of OAC in various forms of PAH 1283 patients ( n=738 (58%) received OAC ) 800 patients are of IPAH ( including 34 patients with heritable & drug-associated PAH ) Target INR was 2-3 Circulation 2014
- 26. Anticoagulation COMPERA registry Anticoagulation used in 66% of IPAH and in 43% of other forms of PAH OAC in IPAH was associated with significantly better 3-year- survival (p=0.006) The survival difference at 3 years remained statistically significant(p=0.017) OAC not associated with a survival benefit in other forms of PAH
- 27. Anticoagulation Recommended in IPAH Heritable PAH Anorexigen associated PAH CTEPH
- 28. Advanced therapy CCB Prostanoid ERB PDE 5 I
- 29. CCB Oldest class of drugs Only in patients with definite vasoreactivity A retrospective analysis of 557 patients with IPAH showed that only 13% of patients had vasoreactivity, of these only 50% benefitted from CCB Circulation. 2005 Jun 14;111(23):3105-3111. Epub 2005 Jun 6. Drug Starting Dose Usual Dose Maximum Daily Dose Amlodipine 2.5mg OD 20 mg OD 20-30 mg Nifedipine 30 mg BD(SR) 120-240 mg per day 240 mg Diltiazem 60 mg TDS 240-720 mg per day 920 mg
- 30. PDE-5 Inhibitor Sildenafil Tadalafil Verdanafil Vasodilation Antiproliferative action Headache,flushing,epistaxis impaired colour vision
- 31. PDE-5 Inhibitor PHIRST- Tadalafil RCT on 405 patients of PAH showed favorable effects on hemodynamics & exercise capacity at largest doses(40 mg OD) Significantly improved 6 MWD at 16 week both in treatment naïve and on baseline bosentan therapy group Circulation 2009;119:2894–2903.
- 32. ERA Drug Route Dose Advantage Disadvant Bosentan oral 62.5-125 mg BD •6MWT •NYHA •Heamod Elevation OT/PT Ambrisentan oral 5-10 mg OD -DO- Sitaxentan Withdrawn due to fatal hepatic failure
- 33. Prostanoids Drug Route Dose Advantage Disadvanta ge Epoprostenol IV (infusion) •25-40 ng/kg/min •6 MWT •NYHA class • Survival •Long term IV access •Rebound •Jaw pain Iloprost Inhaled • 9-10 doses/day -Do- •Frequent dosing
- 34. Riociguat Soluble GC stimulator Dual action In RCT( n-443 ) – PATENT 1 Trial - Riociguat significantly improved exercise capacity (Both in naïve and baseline B or E) FDAApproved for Class II-IV Dose – 2.5 mg TDS
- 36. Riociguat
- 38. Vardenafil More potent PDE 5 Inhibitor Evaluation study RCT – 70 patient Dose - 5 mg Bid for 12 week Improved 6MWD , hemodyanamics Improved clinical outcomes Not Approved
- 39. Macitentan Sustained receptor binding and enhanced tissue penetration In RCT ( SERAPHIN)- 742 pt ( 1:1:1 - P : M3: M10 ) 64 % on baseline PDE-5 I or prostanoid Reduced morbidity and mortality Well tolerated FDAApproved for Class II-IV with Dose – 10 mg
- 42. Oral Treprostinil Freedom –M trial RCT - 349 patient (Treprostinil - 233 , placebo - 116) not on ERA or PDE -5 I At 12 week 6MWD improved significantly (P=0.0125) Improves exercise capacity in patient not receiving other treatment Based on this trial oral Treprostinil was approved in dec 2013 Circulation 2013;127:624-633.
- 43. Selexipag Selective prostacyclin receptor agonist Chemically distinct from prostacyclin Oral Long acting - Twice daily dosing & less fluctua
- 44. Selexipag GRIPHON trial RCT to assess safety and efficacy of selexipag N – 1156 ( placebo (n=582) or selexipag (n=574) Selexipag reduced risk of M/M event vs placebo (p<0.0001)by 40% Effect was observed irrespective of background treatment The most frequent adverse events were headache, diarrhea, nausea, jaw pain JACC 2015
- 45. Imatinib mesylate Rationale : PAH Vasoconstriction + Remodeling PDGF and c-KIT Proliferation of VSMC Imatinib
- 46. Impres study 24-week RCT ( n – 202 ) PVR > 800 and on ≥ 2 drugs Primary outcome - change in 6MWD Dose – 200 - 400 mg / day
- 47. Impres study
- 48. Impres study Placebo-corrected effect on 6MWD - 32m (P=0.002) PVR decreased by 379 dynes·sec ( P<0.001) Functional class, TTCW and mortality did not differ Effect maintained in the extension study Adverse events and discontinuation more Subdural hematoma more ( 2+6 ) - imatinib and anticoagulation
- 49. Impres study Study suggest imatinib improves exercise capacity and hemodynamics in patients with Advanced PAH who remain symptomatic on at least 2 drugs of the currently available 3 drug classes
- 50. Combination Therapy Use of more than 1 class of drugs Now recommended Multiple combinations effective and well tolerated Patient should be reassessed every 3–6 months and addition of new therapy considered when goals have not met
- 51. Sequential Combination Therapy Well studied Class 1 A recommendation SERAPHIN PATENT GRIPHON PHIRST
- 52. COMPASS 1 COMPASS 2 COMPASS 3 Pt on B > 12 week Single oral S dose of 25mg Sig decrease in PVR & MPAP Pt on S for > 12 week Placebo / B No effect on mortality Improved 6MWD and NT-pro BNP More LFT abnor ( B >P) Naïve pt B till 16 week / B 0r B + S ( based on achievement of 6 MWD of 380 m at 16 week ) Showed that B+S result in more achievement of predefined 6MWD ( 31 % at 28 week c/f B alone 16 % at 16 week ) Well tolerated J Am Coll Cardiol. 2013 Chest. 2010J Clin Pharma 2009
- 53. Upfront Combination Therapy Commencing > 1 therapies in treatment naive patients Less data WHO functional class III/IV -- IIb-C
- 54. BREATHE-2 AMBITION • 33 patient • B + E / E + P in 2:1 manner • Trend toward improvement but no sig difference in Hemody or clinical • Less s/e of Epo in combination group • RCT – 500 patients • 253 A+ T , 247 A or T • Combination therapy superior to monotherapy • Less hospitalization • improved 6 MWD • Eur Respir J 2004 Euro Resp J 2014
- 55. Triple Upfront Combination • E + B + S in severe PAH ( class III/IV) • A prospective analysis of 19 patients of idiopathic or heritable PAH • Significant improvements in haemodynamics, func class and 6MWD • 3-year survival rate of 100%( Expected- 49% ) • Achievement of WHO functional class I or II in all Eur Respir J 2014; 43: 1691–1697
- 57. Indications Patients with persistent RHF or recurrent syncope despite medical therapy Bridge to transplant Palliation
- 58. Rationale Improved CO RV decompression Reduced sympathetic activity Improved o2 transport ( despite fall in spo2) Most favorable results patient with RAP 10-20mmHg
- 59. BAS 2.Mean RAP 3. Size of BAS 4.LA pressur e 5.LV Functio n
- 60. BAS Graded dilatation End-points LV EDP reaches 18mmHg SpO2 80% or 10% from baseline 16mm dilatation is achieved
- 62. Stent fenestration technique Control degree of shunt & Maintain patency Free of thrombotic complications ( c/f Fenestrated ASO ) Mounted on balloon catheter that is constricted by loop Full balloon inflation result in diabolo-shaped stent
- 63. Diabolo Fenestrated Stent Technique
- 64. Stent Across the Atrial Septum
- 65. ASO With Self-Made Fenestration
- 66. BAS BAS at early stage of disease (mean RAP of 9 ± 5 mm Hg and syncope rather than overt RHF ) may offer a survival advantage Timing of BAS should be before RAP ≥20 mm Hg LV EDP >18 mm Hg PVRI >55 U/m2 Baseline SPO2 <90% Eur Respir J 2011;38:1343–8
- 67. Pott shunt Rationale Decompression Blood is shunted into the dAo, which avoids exposing the brain and myocardium to desaturated blood Reliable shunting than ASD
- 68. Pott shunt In a series of 8 children of IPAH NYHA IV with repeated syncope or signs RHF Six of 8 patients survived and remained well ( func class 1 /2 ) at a mean follow-up of 63 months Improved 6MWD & BNP levels Ann Thorac Surg 2012;94:817–24
- 69. TPS Percutaneous Pott shunt in a series of 4 adults ( total 7 critically ill ) Brockenbrough needle and the "stiff" end of a 0.014-inch wire used to puncture the dAo and LPA. After balloon dilation, an iCAST 7 × 22-mm covered stent Two patient died Remaining 2 did well over 4 month follow up J Heart Lung Transplant 2013;32:381–7
- 70. TPS
- 71. TPS In 3 patients with IPAH and severe PH having small PDA PDA allowed easy insertion of covered stent After a mean follow-up of 14 ± 9 months, all 3 patients showed improved functional capacity and improved RV function No major complications or deaths Circ Cardiovasc Interv 2013
- 72. TPS The optimal timing – Not clear Should be reserved for patients in whom BAS or lung transplantation is contraindicated
- 73. Balloon pulmonary angioplasty PEA in CTEPH is contraindicated in the presence of Severe underlying lung disease Lesions located in distally BPA improves pulmonary blood flow distribution and increases pulmonary vascular capacitance, decreasing RV afterload
- 74. Balloon pulmonary angioplasty Feinstein et al. - BPA in 18 patients with CTEPH Gradually dilated using balloons - sized to be 75% to 100% of vessel diameter Improved in NYHA class, 6MWD and mean PAP Repeat angiography demonstrated that all previously treated vessels remained patent at 1 to 40 months after initial BPA Circulation 2001;103:10–3.
- 75. Balloon pulmonary angioplasty Kataoka et al. BPA in 29 patients with CTEPH Significant improvements in hemodynamic parameters, functional capacity and BNP levels at 6 months Circ Cardiovasc Interv 2012;5:756–62
- 76. Balloon pulmonary angioplasty Mizoguchi et al. performed BPA in 68 inoperable CTEPH. All patients showed significant improvements in PAP, BNP levels, and functional exercise capacity 66 patients were alive at 2.2 ± 1.4 years Follow-up at 1 year confirmed improved angiographic appearance of the pulmonary arteries Circ Cardiovasc Interv 2012;5:748–55
- 78. Balloon pulmonary angioplasty Reperfusion pulmonary injury can be a fatal complication Limit dilation to no more than 2 vessels per sitting IVUS & OCT to ensure that the maximal size is not >90% of the original size of the vessel diameter In candidates found to be unsuitable for PEA, BPA can be considered an alternative
- 79. Pulmonary artery denervation Rationale Increased β1-adrenoreceptor RNA expression on pulmonary blood vessels Increased sympathetic activity demonstrated by higher MSNA Post-BAS, MSNA levels decrease compared with controls Baroreceptors near bifurcation of the MPA and are involved in facilitating a neural reflex
- 80. PADN-1 Study
- 81. PADN-1 Study Patient -21 ( 13 - PADN ) PADN at bifurcation of MPA and at ostial RPA & LPA Significant improvement of Mean PAP (p<0.01) 6 MWT ( p < 0.006) Tei index (p < 0.001)
- 82. PADN
- 83. PADN
- 84. EPC BM derived Involved in endothelial homeostasis & angiogenesis Junhui et al. Found decreased EPCs in IPAH Act through paracrine mechanism
- 85. EPC
- 86. EPC RCT comparing effects of early EPC transplantation plus conventional therapy with those of conventional therapy alone in 31 patients with IPAH EPC significantly improved exercise tolerance and pulmonary haemodynamics J Am Coll Cardiol 2007; 49:1566–1571
- 87. EPC A pilot study showed that EPC transplantation was associated with significant improvements in exercise capacity, NYHA class and pulmonary haemodynamics in children with IPAH Pediatr Transplant 2008; 12: 650–655
- 88. Hemoptysis remains a major cause of morbidity in patients of PAH ( sp. ES ) AIIMS data – 41 patients of ES studied 24 had no hemoptysis and 17 patients had hemoptysis Mean age of the patients was 23.7 ± 7.9 years with a range from 13 – 50 years Bronchial artery embolization
- 89. Bronchial artery embolization Highly successful in acute termination of hemoptysis Polyvinyl alcohol particles of 250–500 microns size Complications- rare and include Non-target embolization Subintimal dissection Arterial perforation
- 90. Bronchial artery embolization In study of 21 patient BAE procedure was successful in 96% patients 14 in BAE therapy group and 7 in the conservative group 28-day mortality was 14% in the BAE group and 28.5% in the conservatively managed group (p= 0.57) Recurrence rate 43% Int J Clin Pract Suppl. 2012
- 91. PAH mangement
- 92. PAH mangement
- 93. PAH mangement
- 94. Older • Sildenafil • Tadalafil • Bosentan • Ambrisentan • Epoprostenol Newer • Riociguat • Vardenafil • Macitentan • Oral Treprostinil • Selexipag • Imatinib Intervention • BAS with stenting • BPA • TPS • PADN • EPC Combination therapy – sequential/ upfront
- 95. Thank you
Editor's Notes
- PAH (see Table 5 for definition) represents the type of PH in which the most important advances in the understanding and treatment have been achieved in the past decade. It is also the group in which PH is the ‘core’ of the clinical problems and may be treated by specific drug therapy.
- Because procedure related mortality was high esp in patients who either had a very small septostomy with no benefit and in patients who had large septostomy which led to severe desaturation and death, the concept of graded BAS was introduced.
- for Mounting a Stent (A) A loop of defined diameter is created using a temporary pacing wire. This is placed over a standard balloon valvuloplasty catheter. (B) The stent, mounted and crimped with the loop centered. (C) The stent is placed across the fenestration, and the balloon catheter is fully inflated
- (A) A snare is positioned in the left pulmonary artery (LPA). A descending aortogram demonstrates proximity of the descending thoracic aorta (DAo) to the LPA. (B) The aortic wall has been engaged and stained (black arrow) with a transseptal needle. The sharpened end of a Stabilizer wire has been advanced through the vessel walls into the lumen of the LPA. (C) With a Maverick balloon used as a ‘‘dilator,’’ the long sheath is advanced from DAo into the LPA. The Stabilizer wire has been snared to allow the balloon-sheath complex to be both pulled and pushed across the vessel walls. (D) Descending aortogram after covered stent placement delineates the newly created Potts shunt (white arrow).
- A Dedicated 7.5-F Triple-Function Catheter (A) The catheter had a tapered (to 5-F) circular tip with 10 pre-mounted electrodes (each electrode has a width of 0.75mm and is separated by 2 mm [B]). Electrodes are connected with a connect-cable and a connect-box (C). There are 10 knobs on the surface of connect-box (D), and each is consistent with the electrode on the circular tip of the ablation catheter. Sequential ablation was performed by selecting the knob on the generator after the whole system is set up (E).
- An 8-F Long Sheath Was Inserted Through the Femoral Vein and Advanced to the MPA (A) The same patient as in Figure 1 is shown. The PADN catheter was advanced along this long sheath (B). After gently withdrawing the sheath and pushing the PADN catheter, the circular tip would be released from the sheath (C). Then, slight clockwise rotation and pushing the handle would allow the circular tip into the ostial left PA (Level 1 of ablation, <2 mm distal to orifice [D]). After ablation at Level 1, counterclockwise rotation and withdrawing of the handle would allow the circular tip to slide down to the distal bifurcation area of MPA (Level 2 of ablation, <2 mm proximal to the bifurcation level [E]). Finally, continuously rotation and pushing the handle was performed until the circular tip jumped into the Level 3 of ablation (<2 mm distal to ostial right PA [F]). When the electrodes tightly contacted the inner arterial surface, there existed the inability to advance distally (G) or to ease in withdrawing proximally (H)
- The endothelial progenitor cell loop in the pathobiology of pulmonary hypertension