Update on the Management of Pulmonary Hypertension

1. Update on the Management of Pulmonary Hypertension Sarfraz Saleemi MD Pulmonary Hypertension Program King Faisal Specialist Hospital & Research Center Riyadh, Saudi Arabia

2. Treatment of Pulmonary Hypertension  Currently there is no cure for PAH  Those who start therapy in WHO FC I or II demonstrate a better prognosis than those whose therapy is started in the more advanced stages  By recognizing and treating patients as early as possible, disease progression may be delayed Sitbon O et al. J Am Coll Cardiol 2002

3. PAH: Screening high risk population  Key to early diagnosis – screening high risk populations:  Carriers of BMPR gene  Family members of patient with FPAH with positive genetic testing  Patients with systemic sclerosis (SSc)  Symptomatic patients with chronic liver disease and those on liver transplant consideration.  Early diagnosis improves outcome • Hachulla E et al Ann Rheum Dis 2004 • Galie N et al. Eur Heart J 2004 • McGoon M et al. Chest 2004

4. 1% 24% n=674 12% (%) 63% 100 80 60 40 20 0 FC I FC II FC III FC IV WHO FC FC at the time of diagnosis of PAH Humbert et al; Am J Respir Crit Care Med (2006) French National Registry (2002-2003)

5. survival correlates with functional class McLaughlin VV, et al. Chest 2004;126:78S-92S

6. 1-Year Mortality 9 29 46 0 10 20 30 40 50 II III IV WHO FC 1-Yearmortality(%) N=782 McLaughlin et al. Am J Respir Crit Care Med. 2009;179:A1043. Mathier et al. Am J Respir Crit Care Med. 2009;179:A2658

7. Goals of treatment • Prevent disease progression • Improve survival • Improve quality of life • Improve functional class to I or II • Maintain good right ventricular function

8. Treatment of PAH Treatment naive patient PAH confirmed by expert center General measures Supportive therapy Acute vasoreactivity test (iPAH, H-PAH, D-PAH only) Vasoreactive CCB Therapy Non-vasoreactive (or not iPAH/HPAH/DPAH) Low/int Risk High Risk Oral Monotherapy Initial oral Combo Therapy Initial combo including IV PC Inadequate response Double/triple sequential therapy . Galie N, ESC/ERS 2015 Guidelines Lung Transplant Inadequate response

9. PAH Therapy: general Measures  Sodium restriction  Abstinence from smoking  In-flight O2 administration - patients in WHO-FC III and IV and those with arterial pO2 consistently < 8 kPa (60 mmHg)  Supervised exercise training in physically deconditioned PAH patients  Excessive physical activity leading to distressing symptoms is not recommended  Avoid pregnancy (at least two and preferably three forms of birth control)  Update vaccination status – Influenza and Pneumococcal  Psychosocial support  In elective surgery, epidural rather than general anesthesia whenever possible Galie N, ESC/ERS 2015 Guidelines

10. PAH Therapy: Supportive measures  Long-term O2 therapy when arterial pO2 is consistently < 8 kPa (60 mmHg)  Diuretic treatment in patients with signs of RV failure and fluid retention  Anticoagulation should be considered in patients with IPAH, heritable and DPAH  Correction of anemia and/or iron status may be considered  ACE inhibitors, ARB agents and beta-blockers should be avoided unless required by co-morbidities Galie N, ESC/ERS 2015 Guidelines

12. Calcium channel blocker treatment recommendations • High doses CCBs - in patients with vasoreactive IPAH, HPAH and DPAH • Close follow-up & reassessment after 3-4 months of therapy including RHC • Continue high dose CCBs in patients with FC I or II with marked hemodynamic improvement (near normalization) • Initiate specific PAH therapy in patients in FC III or IV or those without marked hemodynamic improvement after high doses of CCBs • CCBs not indicated in patients without a vasoreactivity study or non- responders unless used for other indications (e.g. Raynaud’s phenomenon) Galie N, ESC/ERS 2015 Guidelines

13. (Years) Long-term CCB responders Long-term CCB failure 38 33 30 22 13 8 3 3 2 1 19 12 7 4 0 Subjects at risk, n CumulativeSurvival Long-term CCB responders Long-term CCB failure 0 .2 .4 .6 .8 1 0 2 4 6 8 10 12 14 16 18 Sitbon et al. Circulation 2005;111:3105-3111 Survival in IPAH Long-term CCB responders p=0.0007

15. Risk assessment in PAH Galie N, ESC/ERS 2015 Guidelines

16. Humbert M et al. N Engl J Med. 2004;351:1425-1436. Targets for current PAH-specific therapy Big Endothelin Endothelin- converting Enzyme Endothelin Receptor A Endothelin Receptor B Vasoconstriction and Proliferation Endothelin Receptor Antagonists Endothelin-1 Endothelin Pathway Arginine Nitric Oxide Synthase Vasodilatation and Antiproliferation Nitric Oxide cGMP Exogenous Nitric Oxide Phosphodiesterase Type-5 Phosphodiesterase Type-5 Inhibitors Nitric Oxide Pathway Arachidonic Acid Prostacyclin Synthase Vasodilatation and Antiproliferation Prostacyclin cAMP Prostacyclin Derivatives Prostacyclin Pathway sGC stimulators 16 IP receptor agonist

17. Pregnancy risk: X B X B N Targets for current PAH-specific therapy

18. + + Drug 1 Drug 2 Drug 2Drug 1 Sequential High risk group Low risk group Upfront Combination TherapyMonotherapy PDE5I OR ERA OR PGI2

19. Class of drug Name of drug Route Pregnancy Side effects Endothelin Receptor Antagonist Ambrisentan Bosentan Macitentan Oral Oral Oral X X X Hypotension, headache, nausea, nasal congestion, Hepatotoxicity, decreased sperm counts, edema, wheezing, anemia and metallic taste. PDE5 inhibitors Sildenafil Tadalafil Vardenafil Oral Oral Oral B B B headache, hypotension, visual disturbances, cold symptoms, indigestion. sGC stimulators Riociguat Oral X Headache, nausea Diarrhea, hypotension, bleeding tendency Prostacyclin analogues Epoprostenol Intravenous B headache, nausea, diarrhea, flushing, hypotension, jaw pain, muscle ache, low platelets and rash, flushing, tingling Iloprost Inhaled Intravenous B B Treprostinil Intravenous Subcutaneous Inhaled Oral B B B B Beraprost Oral B IP receptor agonist Selexipag Oral N

20. Choice of Initial PAH Therapy Dependent on many factors – Disease severity – Approval status – Route of administration – Side-effect profile – Patient preference – Cost consideration – Physician experience, clinical judgement Barst RJ, et al. J ACC 2009

21. Upfront Combination Therapy Sequential Combination Therapy Galie N, ESC/ERS 2015 Guidelines

22. PH treatment progress - Historical Controls NIH 68% 48% 34% Bosentan ~90% ~75% Flolan/ Remodulin ~85% ~70% ~60% Survival 1 year 3 year 5 year Gomberg-Maitland et al, JACC 2011; 57: 1053-61.

23. Sitbon et al. JACC 2002 100 Months 80 60 40 20 0 IV epoprostenol Historical control 0 12 24 36 48 60 72 84 96 108 120 Survival% at 1, 2, 3, 5 years: 85%, 70%, 63%, 55% at 1, 2, 3, 5 years: 58%, 43%, 33%, 28% IV Epoprostenol: Long-term Outcome in Idiopathic PAH

24. Reduction in mortality - RCTs in PH As of May 2010. 3780 patients of 23 trials. An overall reduction of mortality of 44% (P = 0.016) Galiè N, Palazzini M, Manes A. Pulmonary arterial hypertension: from the kingdom of the near-dead to multiple clinical trial meta-analyses. European Heart Journal. 2010;31(17):2080-2086.

25. Efficacy and Safety of Pulmonary Arterial Hypertension-specific Therapy in Pulmonary Arterial Hypertension A Meta-analysis of Randomized Controlled Trials CHEST 2016; 150(2):353-366 PAH-specific monotherapy could improve mortality, exercise capacity, functional class, and hemodynamic status compared with placebo or conventional therapy. (OR, 0.50 [95% CI, 0.33 to 0.76]; P. .001)

26. Combination therapy improve exercise capacity, functional class, and hemodynamic status compared with monotherapy, No proven effect on mortality compared to monotherapy. Combination therapy had a much higher incidence of withdrawal due to adverse effects than monotherapy. Efficacy and Safety of Pulmonary Arterial Hypertension-specific Therapy in Pulmonary Arterial Hypertension A Meta-analysis of Randomized Controlled Trials CHEST 2016; 150(2):353-366 (OR, 0.98 [95% CI, 0.57 to 1.68]; P. .94)

27. Meta-Analysis of Monotherapy Versus Combination Therapy for Pulmonary Arterial Hypertension Benjamin D. Fox, et al. Am J Cardiol 2011;108:1177–1182 Combination Therapy did not decrease the combined end point of mortality, admission for worsening PAH, lung transplantation, or escalation of PAH therapy (RR 0.42, 95% CI 0.17 to 1.04). In conclusion, PAH Combination Therapy does not offer an advantage over Monotherapy apart from modestly increasing exercise capacity.

28. Conclusion: Combination therapy improve exercise capacity, functional class, and hemodynamic status compared with monotherapy although there was no effect on mortality.

29. Suggested assessment and timing of follow up in PAH Clinical assessment for heat failure, functional assessment, biomarkers and hemodynamics Galie N, ESC/ERS 2015 Guidelines

30. PH treatment in specific conditions

31. Treatment of Group 2 PH (PH-LHD) Optimization of treatment of underlying condition before assessment of PH-LHD (i.e. treating structural heart disease) Identify other causes of PH (i.e. COPD, sleep apnea syndrome, PE, CTEPH) and to treat them when appropriate before assessment of PH-LHD Invasive assessment of PH in patients on optimized volume status Patients with PH-LHD and a severe pre-capillary component should be referred to an expert PH center for a complete assessment and an individual treatment decision Use of PAH-approved therapies is not recommended in PH-LHD Galie N, ESC/ERS 2015 Guidelines

32. Group 2 PH: ERA and Prostacyclin Packer et al, J Card Fail 2005; 11: 12-20 Anand et al, Lancet 2004; 364: 347-54. Packer et al – Abstract at ACC 2002 in Atlanta. Calif et al, Am Heart J 1997; 134:44-54. Endothlin-receptor antagonists REACH-1, EARTH, ENABLE: - no benefit Prostacyclin analogues (epoprostenol) FIRST: stopped early for excess heart failure

33. - EF <40%, RCT of sildenafil (n=34) increased HRQOL and exercise capacity - EF<40%, RCT of sildenafil (n=55): improved EF, left atrial volume index and LV mass index -EF >50%, RCT of sildenafil (n=44): reduced lung water, PCWP, PA pressures, etc at 12 months - EF >50%, Riociguat (n=21) improved stroke volume Lewis et al, Circulation 2007; 116: 1555-62; Guazzi et al, Circ-HF 2011; 4: 8-17; Group 2 PH: PDE5i and sGC stimulator

34. Effect of Phosphodiesterase-5 Inhibition on Exercise Capacity and Clinical Status in Heart Failure With Preserved Ejection Fraction A Randomized Clinical Trial (RELAX TRIAL) JAMA, March 27, 2013—Vol 309, No. 12 Conclusion and Relevance: Among patients with HFPEF, Sildenafil for 24 weeks, compared with placebo, did not result in significant improvement in exercise capacity or clinical status. 216 patients 103 placebo 113 Sildenafil

35. Eur Heart J. 2017 Dec 21 Sildenafil for improving outcomes in patients with corrected valvular heart disease and persistent pulmonary hypertension: a multicenter, double-blind, randomized clinical trial (SIOVAC TRIAL) Off-label indication of sildenafil in patients with LHD-PH due to valvular disease should be discouraged

36. Treatment of PH-CHD Bosentan in FC III patients with Eisenmenger syndrome Other ERAs, PDE-5is and prostanoids may be considered in patients with Eisenmenger syndrome In the absence of significant hemoptysis, oral anticoagulant treatment may be considered in patients with PA thrombosis or clinical signs of heart failure Supplemental O2 in cases in which it produces a consistent increase in SO2 and reduces symptoms Phlebotomy with isovolumic replacement when the Hct is >65% and symptoms of hyperviscosity Supplemental iron in patients with low ferritin plasma levels Combination drug therapy may be considered in patients with Eisenmenger syndrome The use of CCBs is NOT recommended in patients with Eisenmenger syndrome Galie N, ESC/ERS 2015 Guidelines

37. Correction of congenital heart diseases PVR (WU) CORRECTABLE <2.3 YES >4.6 NO 2.3-4.6 Individual patient assessment in tertiary care centers Galie N, ESC/ERS 2015 Guidelines

38. Treatment of PH-PVOD/PCH Referral of patients with PVOD/PCH to a transplant center for evaluation is indicated as soon as the diagnosis is established Patients with PVOD/PCH should be managed only in centers with extensive experience in PH due to the risk of pulmonary edema after the initiation of PAH therapy Pulmonary vasodilator therapy should be cautiously started especially prostacyclin due to risk of pulmonary edema High dose diuretics are usually needed to maintain euvolemia Galie N, ESC/ERS 2015 Guidelines

39. Treatment of CTD-PAH • Same treatment algorithm as for patients with IPAH is recommended • Doppler echocardiography is recommended as a screening test in asymptomatic patients with SSc, followed by annual screening with echocardiography, DLCO and biomarkers • RHC in all cases of suspected PAH associated with CTD • Oral anticoagulation may be considered on an individual basis and in the presence of thrombosis risk Galie N, ESC/ERS 2015 Guidelines

40. Source PAH agent Number of patients Number (%) of CTD-PAH patients Galiè et al (SUPER-1) Sildenafil 278 84 (30) Simonneau et al (PACES) Sildenafil 267 55 (21 Galiè et al (PHIRST) Tadalafil 405 95 (24) Rubin et al20 (BREATHE-1) Bosentan 213 63 (30) Galiè et al (EARLY) Bosentan 185 33 (18) Galiè et al (ARIES) Ambrisentan 393 124 (32) Badesch et al Epoprostenol 111 111 (100) Galiè et al (ALPHABET) Beraprost 130 13 (10) Simonneau et al Treprostinil 469 90 (19) Hiremath et al Treprostinil 44 2 (5) CTD-PAH patients included in major RCTs

41. Respir Med. 2016 Aug;117:254-63. Ambrisentan response in connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH) A subgroup analysis of the ARIES-E clinical trial. J Am Coll Cardiol. 2009 Nov 17;54(21):1971-81 ARIES-E trial124 patients with CTD-PAH were evaluated. 62.6%, 57.3%, and 58.2% of CTD-PAH patients treated with ambrisentan exhibited increases in 6MWD at 1-, 2-, and 3- years respectively. At 3 years, 64% of patients were free from clinical worsening . And 76% of patients were still alive.

42. Riociguat for the treatment of pulmonary arterial hypertension associated with connective tissue disease: results from PATENT-1 and PATENT-2 Humbert M, et al. Ann Rheum Dis 2016;0:1–5 • 443 patients • 111 patients had PAH-CTD (66 SSc,18 SLE; 11 RA 10 MCTD), and 6 unspecified CTD) • Riociguat improved mean 6MWD, WHO FC, PVR, CI. • Improvements in 6MWD and WHO FC persisted at 2 years. • Two-year survival of patients with PAH-CTD was the same as for idiopathic PAH (93%). • Riociguat had a similar safety profile in patients with PAH-CTD to that of the overall population

43. Ambition study Galie E. et al. N Engl J Med. 2015 Aug 27;373(9):834-44. Pooled monotherapy 103/253 (41%) had CTD-PAH Combination therapy 84/247 (34%) had CTD-PAH Outcome Combination (n = 103) Monotherapy (n = 84) Any event, % 21 40 Improvement in 6-minute walking, m 40 12

44. Ambrisentan and Tadalafil Up-front Combination Therapy in Scleroderma-associated Pulmonary Arterial Hypertension Paul M. Hassoun et al. American Journal of Respiratory and Critical Care Medicine Volume 192 Number 9 | November 1 2015 Open labeled – 36 weeks 19 patient with treatment naïve SSc-PH Tadalfil 40 mg plus Abrisartan 10 mg

45. Association Between Initial Oral Therapy and Outcome in SSc-PAH DATA FROM PHAROS REGISTRY - 98 patients 24=ERA, 59=PDE5, 15=ERA/PDE5 Arthritis Rheumatol. 2016 Mar;68(3):740-8 Percentage of patients with qualifying events for time to clinical worsening Kaplan-Meier curves showing time to clinical worsening At 1 year free of CW ERA=63.0% PDE5=85.9% PDE5+ERA=85.7%

46. Treatment of Portopulmonary Hypertension (POPH) • Echo screening in symptomatic patients with liver disease or portal hypertension and in all candidates for liver transplantation • Patients with POPH should be referred to centers with expertise in managing both conditions • Treatment algorithm for PAH should be applied to patients with POPH, taking into account the severity of liver disease • Anticoagulation is not recommended in patients with POPH • Liver transplantation may be considered in selected patients responding well to PAH therapy • Liver transplantation is contraindicated in patients with severe and uncontrolled PAH Galie N, ESC/ERS 2015 Guidelines

47. Liver Transplant & PoPH Moderate riskLow risk High risk Usual risk for liver transplant Vasodilator therapy Re-evaluate hemodynamics mPAP < 35 mmHg liver transplant Contraindication for liver transplant Vasodilator therapy mPAP <35 mPAP >35 mPAP >50 In-hospital LiverTransplant mortality in PoPH - 36% A report of the multicenter liver transplant database: Liver Transpl 2004; 10: 174-82

48. Treatment of PAH-HIV • Echocardiographic screening in asymptomatic HIV patients to detect PH is not recommended • Same PAH treatment algorithm taking into consideration co-morbidities and drug–drug interactions • Anticoagulation is not recommended because of a lack of data on the efficacy : risk ratio Galie N, ESC/ERS 2015 Guidelines

49. Medical treatment of CTEPH

50. Riociguat for the Treatment of Chronic Thromboembolic Pulmonary Hypertension Primary end point (p< 0.001) CHEST-1 Study

51. CHEST-2 STUDY 6 min walk distance

52. Right ventricle area Right atrial area 27 patients on Riociguat

53. MERIT-1 Macitentan for the treatment of inoperable chronic thromboembolic pulmonary hypertension Ghofrani et al; Lancet Respir Med 2017; 5: 785–94 phase 2, randomised, double-blind, placebo-controlled study PVR 6MWD

54.  Pulmonary endarterectomy (PEA)  Balloon Pulmonary Angioplasty CTEPH  Atrial Septostomy  Lung Transplant  Heart and Lung Transplant  PA denervation by a radiofrequency ablation catheter Non-Pharmacological Treatment

55. • Identify and treat triggering factors • Optimize fluid balance • Reduce RV afterload • Optimize cardiac output • Optimize perfusion pressure Adapted from Hoeper et al, AJRCCM, 184: 1114-24, 2011 Acute management in PAH Crisis

56. • AVOID INTUBATION IF POSSIBLE! • If you do intubate: • Low tidal volume ventilation - PVR may be lowest at FRC • PEEP increases PVR and should be minimized • Permissive hypercapnia can increase PVR by more than 50% and mPAP by more than 30% Dezube et al, Adv in PH, 12: 24-30, 2013 Acute management in PAH Crisis - Ventilation issues

57. Pulmonary Arterial Hypertension Cellular Processes Newman JH. Circulation 2004;109:2947-2952

58. Future directions for the management of PH  Mitochondrial modulators Dichloroacetate (DCA), Ranolazine, Trimetazidine  Anti-inflammatory and immune modulatory therapy Mycophenolate mofetil,, Leukotriene inhibitors, Rituximab  Anti-proliferative therapy Imatinib (TKI) – IMPRES study  Hormonal manipulation Targeting estrogen pathway such as CYP19A1 (AN) or estrogen receptors (tamoxifen).  Inhaled vasoactive intestinal peptide  Rho-kinase inhibitors  Personalized medicine Gene therapy

59. Current Clinical Trials

60. Thank You

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