THERAPEUTICS IN PULMONARY ARTERIAL HYPERTENSION Evidences & Guidelines

Transcription

1 THERAPEUTICS IN PULMONARY ARTERIAL HYPERTENSION Evidences & Guidelines Vu Nang Phuc, MD Dinh Duc Huy, MD Pham Nguyen Vinh, MD, PhD, FACC Tam Duc Cardiology Hospital

2 Faculty Disclosure No conflict of interest

3 Hemodynamic Definition of PAH PH PAH Mean PAP 25 mm Hg Mean PAP 25 mm Hg plus PCWP/LVEDP 15 mm Hg PVR >3 Wood Units ACCF/AHA 29 Expert Consensus Document on Pulmonary Hypertension McLaughlin et al. J Am Coll Cardiol. 29;53:

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5 Percent survival Chest. 24;126:78S-92S. Survival in PAH Portopulmonary CTD HIV Median survival 2.8 yrs from diagnosis Congenital heart disease Years IPAH

6 ACCF/AHA Diagnostic Algorithm Pivotal Tests Contingent Tests Contribute to Assessment of History Exam CXR ECG Echocardiogram VQ Scan TEE Exercise Echo Pulmonary Angiography Chest CT Angiogram Coagulopathy Profile Index of Suspicion of PH RVE, RAE, RVSP, RV Function Left Heart Disease VHD, CHD Chronic PE PFT s ABG s Ventilatory Function Gas Exchange Overnight Oximetry Polysomnography Sleep Disorder HIV ANA LFT s Other CTD Serologies HIV Infection Scleroderma, SLE, RA Portopulmonary Htn Functional Test (6MWT, CPET) RH Cath McLaughlin VV et al. J Am Coll Cardiol. 29;53: Vasodilator Test Exercise RH Cath Volume Loading Left Heart Cath Establish Baseline Prognosis Confirmation of PH Hemodynamic Profile Vasodilator Response

7 Treatment Goals in PAH Improved exercise capacity Improved function Improved hemodynamics Improved survival Prevention of clinical worsening

8 ACCF/AHA 29 Expert Consensus Document on Pulmonary Hypertension McLaughlin et al. J Am Coll Cardiol. 29;53:

9 PAH Determinants of Risk LOWER RISK DETERMINANTS OF RISK HIGHER RISK No Clinical evidence of RV failure Yes Gradual Progression of symptoms Rapid II, III WHO class IV Longer (>4 m) 6MWD Shorter (<3 m) Peak VO 2 >1.4 ml/kg/min CPET Peak VO 2 <1.4 ml/kg/min Minimal RV dysfunction RAP <1 mm Hg; CI >2.5 L/min/m 2 Echocardiography Hemodynamics Pericardial effusion, significant RV enlargement/dysfunction; RA enlargement RAP >2 mm Hg; CI <2. L/min/m 2 Minimally elevated BNP Significantly elevated McLaughlin et al. J Am Coll Cardiol. 29;53:

10 Long-term CCB Responders: Survival in IPAH 1..8 Long-term CCB responders Cumulative survival.6.4 Long-term CCB failure p=.7.2. Subjects at risk, n Years Sitbon O et al. Circulation. 25;111: Long-term CCB responders Long-term CCB failure

11 Epoprostenol Requires constant IV administration Kept cold prior to infusion Initial dose: 1 2 ng/kg/min Gradually titrating in increments of 1-2 ng/kg/min, based upon side effects and tolerance to reach a plateau between 2 4 ng/kg/min

12 Survival (%) Epoprostenol vs Conventional Therapy: Survival in IPAH Epoprostenol (n=41) p=.3* Conventional therapy (n=4) 8 patients died during 12 weeks, all in conventional Rx Week *Two-sided, by log-rank test. Barst RJ et al. N Engl J Med. 1996;334:

13 TRUST study: IV Treprostinil vs Placebo for sypmtomatic PAH Mean 6MWD (m) Placebo (n=14) Treprostinil IV (n=3) * Mean dose (ng/kg/min) Baseline Week 1 Week 2 Week 3 Week 4 *p=.22. 6MWD values are mean+se. Hiremath J et al. J Heart Lung Transplant. 21;29:

14 TRIUMPH with inhaled Treprostinil 6MWD median change from baseline (m) p=ns 6 p=.1 19 p=.4 2 p< Day 1 Week 6 peak Week 12 peak Week 12 trough McLaughlin VV et al. J Am Coll Cardiol. 21;55:

15 Mean change from baseline (m) Inhaled Iloprost in AIR Trial 4 3 Placebo (n=12) Iloprost (n=11) p= Week 4 Week 8 Week 12 6MWD was not the primary end point in the AIR trial. Olschewski H et al. N Engl J Med. 22;347:

16 Bosentan Orally active nonpeptide antagonist of both endothelin receptor subtypes Prevent and even reverse the development of PH, pulmonary vascular remodelling and RV hypertrophy Initial dose of 62.5 mg bid for first 4 weeks and followed by target dose of 125 mg bid Side effects: hepatotoxicity and teratogenicity

17 Event-free (%) Patients with no clinical worsening (%) Bosentan: BREATHE-1 and EARLY 1 75 BREATHE-1 p=.38 89% p=.15 63% 1 75 p=.114 EARLY Bosentan (n=144) Placebo (n=69) Bosentan (n=35) Placebo (n=13) Time (wk) 25 Bosentan Placebo Time (wk) Rubin LJ et al. N Engl J Med. 22;346; Galiè N et al. Lancet. 28;371:

18 Patients with no clinical worsening (%) % baseline PVR at Month 6 Mean change in 6MWD (m) Earlier is Better? EARLY Study p<.1 Placebo (n=88) Bosentan (n=8) Bosentan (n=86) Placebo (n=91) p= months 6 months 1 75 p= Bosentan Placebo Time (wk) Galiè N et al. Lancet. 28;371:

19 Event-free (%) Ambrisentan in PAH: ARIES studies 1 ARIES-1 ARIES-2 8 p< mg ambrisentan 1 mg ambrisentan 5 and 1 mg ambrisentan Placebo Time (wk) Galiè N et al. Circulation. 28;117: mg ambrisentan 5 mg ambrisentan 2.5 and 5 mg ambrisentan Placebo Time (wk)

20 Phosphodiesterase Inhibitors Sildenafil: potent and highly specific PDE5 inhibitor Inhibits degradation of cgmp by phosphodiesterases Prevent rebound pulmonary vasoconstriction after acute withdrawal of inhaled NO

21 SUPER : Effect of Sildenafil on 6MWD Placebo 2 mg of sildenafil 4 mg of sildenafil 8 mg of sildenafil Change In 6MWD (m) p< Week Galiè N et al. N Engl J Med. 25;353:

22 Change in 6MWD (m) PHIRST trial: Tadalafil vs Placebo effect on 6MWD Placebo Tadalafil 2.5 mg Tadalafil 1 mg Tadalafil 2 mg Tadalafil 4 mg p<.1 p<.5 p< Weeks Galiè N et al. Circulation. 29;119;

23 Mixed Treatment Prostanoids?? Endothelin Receptor Antagonists? Phosphodiesterase Inhibitors

24 Combination Therapy: Other Clinical Trials Current therapy Added therapy Patients (n) Study duration Primary end point FREEDOM-C AMBITION Bosentan and/ or sildenafil Ambrisentan/ tadalafil/combo Treprostinil oral 3 16 weeks 6MWD Combo vs mono 3 Event-driven Morbidity/mortality event Pfizer Bosentan Sildenafil weeks 6MWD COMPASS-1 Bosentan Sildenafil 45 Single dose PVR COMPASS-2 Sildenafil Bosentan 25 Event-driven Morbidity/mortality event COMPASS-3 Bosentan Sildenafil 1 16 weeks 6MWD ATHENA-1 SERAPHIN Sildenafil or tadalafil Naïve/PDE- 5/PGI/combo Ambrisentan 4 24 weeks PVR Macitentan 742 Event-driven Morbidity/mortality event PATENT Naïve/PGI/ERA Riociguat weeks 6MWD IMPRES ATPAHSS 2 current therapies Ambrisentan/ tadalafil/combo Imatinib 2 24 weeks 6MWD Combo vs mono weeks RV mass/pvr GRIPHON ERA, PDE5 or both Selexipag 67 Event-driven Novartis Stable PAH therapy Morbidity/mortality event Nilotinib 66 6 months PVR

25 STEP: Inhaled Iloprost Added to Bosentan Mean 6MWD Change from Baseline (m) Bosentan + Iloprost (n=32) p=.51 Bosentan + Placebo (n=33) Proportion Free of Clinical Worsening Time (d) Iloprost Placebo p=.2* *log-rank test. McLaughlin VV et al. Am J Respir Crit Care Med. 26;174:

26 Mean 6MWD change from baseline (95% CI), m No. clinical worsening event (%) PACES: Sildenafil Added to Epoprostenol p< p=.2 Epoprostenol + sildenafil Epoprostenol + placebo -1 Baseline Study time (wk) Simonneau G et al. Ann Intern Med. 28;149: Erratum: Ann Intern Med. 29;15:63; 29;151:435. Baseline Time from randomization (d) Persons at Risk (Censored), n Baseline Day 28 Day 56 Day 84 Day 112 Epo + placebo (1) 116() 111(2) 7(36) Epo + sildenafil () 128(2) 125(2) 78(44)

27 Heart -Lung Transplantation 1 year survival of 7% 5 year survival of 5% Effective therapy for patients with end stage pulmonary vascular disease

28 Conclusions 1. PAH pathogenesis: pulmonary arterial obstruction by vascular proliferation and remodelling 2. Need thorough diagnostic evaluation 3. Require right heart catheterization prior to initiating therapy 4. Early and combined therapy may benefit

29 Thank you for your attention!