Effective Strategies and Clinical Updates in Pulmonary Arterial Hypertension Hap Farber Director, Pulmonary Hypertension Center Boston University School of Medicine Disclosures 1) Honoria: Actelion, Gilead, Bayer 2) Consultant: Actelion, Gilead, United Therapeutics, Bayer, Bellerephon 3) Research Grants: United Therapeutics, Gilead, Actelion 1
Discussion today 1) Identify the latest recommendations and clinical guidelines for the management of patients with PAH 2) Explore the advances in the diagnostic algorithm for PH 3) Evaluate the latest data on oral prostanoids and how they can be incorporated into appropriate treatment plans 4) Discuss effective therapeutic strategies to modify treatment for patients with worsening PAH despite existing therapy 5) Analyze the differences between conventional and emerging PAH therapies based on current evidence for their efficacy, safety, and utility Discussion today Choice of treatment for PAH: what we do and why do we do it this way? 2
Treatment Issues in PAH 1) One, two, or three drugs? Monotherapy Dual combination therapy Triple combination therapy 2) When? Upfront Add-on (stable vs. failing) 3) Which drugs and in what order? Classification of Pulmonary Hypertension (Nice, 2013) 1. Pulmonary arterial hypertension 1.1 Idiopathic PAH 1.2 Heritable PAH 1.2.1 BMPR2 1.2.2 ALK-1, ENG, SMAD9, CAV1, KCNK3 1.2.3 Unknown 1.3 Drug and toxin induced 1.4 Associated with: 1.4.1 Connective tissue disease 1.4.2 HIV infection 1.4.3 Portal hypertension 1.4.4 Congenital heart diseases 1.4.5 Schistosomiasis 1 Pulmonary veno-occlusive disease and/or pulmonary capillary hemangiomatosis 1 Persistent pulmonary hypertension of the newborn (PPHN) 3
Classification of Pulmonary Hypertension (Nice, 2013) 2. Pulmonary hypertension due to left heart disease 2.1 Left ventricular systolic dysfunction 2.2 Left ventricular diastolic dysfunction 2.3 Valvular disease 2.4 Congenital/acquired left heart inflow/outflow tract obstruction and congenital cardiomyopathies 3. Pulmonary hypertension owing to lung diseases and/or hypoxia 3.1 Chronic obstructive pulmonary disease 3.2 Interstitial lung disease 3.3 Other pulmonary diseases with mixed restrictive and obstructive pattern 3.4 Sleep-disordered breathing 3.5 Alveolar hypoventilation disorders 3.6 Chronic exposure to high altitude 3.7 Developmental lung disorders Classification of Pulmonary Hypertension (Nice, 2013) 4. Chronic thromboembolic pulmonary hypertension (CTEPH) 5. Pulmonary hypertension with unclear multifactorial mechanisms 5.1 Hematological disorders: chronic hemolytic anemias, myeloproliferative disorders, splenectomy 5.2 Systemic disorders: sarcoidosis, pulmonary Langerhan s cell histiocytosis, lymphangioleiomyomatosis, neurofibromatosis, vasculitis 5.3 Metabolic disorders: glycogen storage disease, Gaucher s disease, thyroid disease 5.4 Others: tumoral obstruction, fibrosing mediastinitis, chronic renal failure, segmental PH 4
Definition of PAH (Nice, 2013) 1) Mean PAP 25mm Hg at rest; PCWP or LVEDP 15mm Hg; PVR 3 WU (240 dynes). 2)?Exercise PAH 3) Volume loading? 4) What about mpap 21-24? Echocardiographic Estimation of PH in Clinical Practice 1) ACC/ AHA expert consensus recommends further evaluation of patients with dyspnea and an estimated RVsp >40 mm Hg 2) ECHO-estimated measurements of PH are NOT diagnostic (for anything) and should NEVER be the basis for the prescription of PAH specific agents 3) Estimates >60 and/or right ventricular enlargement/dysfunction are cause for significant concern and expedited evaluation by an expert team Rudski LG, et al. J Am Soc Echocardiogr. 2010;23:685-713. McLaughlin VV, et al. Circulation. 2009:119:2250-2294. 5
PAH: Echocardiography ECHO compared to right heart catheterization: False negative rate: <1% False positive rate: 30-40% Treatment Issues in PAH 1) One, two, or three drugs? Monotherapy Dual combination therapy Triple combination therapy 2) When? Upfront Add-on (stable vs. failing) 3) Which drugs and in what order? 6
Calcium Channel Blockers 1) Small subset (<<10%) of patients with IPAH have favorable long-term response to high-dose CCB 2) Potential patients identified by reduction in mpap 10 with absolute mpap <40 and increased or unchanged CO 3) Vasoreactivity testing only performed with short-acting pulmonary vasodilators (ino currently agent of choice) 4) Slow up-titration with CCB required with high level maintenance doses (Diltiazem, 240 720mg; nifedipine, 120 240mg) 5) Patients without sustained hemodynamic response to NYHA FC I or II require other PAH therapy Humbert M, et al. Circulation 2014; 130:2189-2208 Sitbon O, et al. Circulation 2005; 111:3105 11 REVEAL: Monotherapy and Combination Therapy in Patients with PAH Percent (%) 100% 80% 60% 40% 20% 0% Monotherapy Dual Combination Triple Combination 48% of patients were receiving monotherapy at the time of study enrollment. 18.50% 21.10% 24.40% 17.10% 16.10% 7.40% 7.50% 11.10% 4.80% 5.80% 0.90% 3.00% ERA PDE51 IV/SC Prostacyclin Inhaled Prostacyclin N = 2438. Treatment reported at time of enrollment in REVEAL Badesch DB, et al. Chest 2010; 137;376-87. 7
Use of Parenteral Prostanoids at Time of Death in the REVEAL Registry Total IV/SC prostanoid therapy use = 43.0% 16% 12% 8% 4% 0% 7.6% 8.4% 14.4% 11.2% 1.1% 5.6% 3.0% 12.4% 15.1% 4.6% 11.2% 5.3% N=909. All-cause mortality. Farber H, et al. J Heart Lung Transpl 2013; 32:1114-22. REVEAL: Under-use of Parental Prostanoids in FC IV PAH IV Prostacyclin Use 1 Day Prior to Designation as FC IV 5.8% PGI Monotherapy PGI Combination Therapy No PGI IV/SC Prostacyclin Use 90 Days After Designation as FC IV PGI Therapy No PGI 51.0% 43.2% 48.0% 52.0% N=294 patients worsening to FC IV. Farber H, et al. J Heart Lung Transpl 2013; 32:1114-22. 8
PAH Long-term Monotherapy Trials: Caveats 1) Most long-term data come from open-label extensions of placebo-controlled trials (no comparator arm) 2) These trials allowed add-on therapy after initial blinded treatment phase; thus, some or all of the efficacy seen in open-label phase could be due to add-on therapy, not primary study medication 3) Some trials defined add-on therapy as a clinical endpoint; others did not 4) Results cannot be compared across studies because each trial was unique, with fundamental protocol differences (study size, FC, outcomes definitions, use of additional medications without reaching trial endpoint, etc.) PAH Long-term Combination Therapy Trials: Caveats 1) Only AMBITION prospectively studied the question of monotherapy versus de novo combination therapy 2) All other currently reported trials featured add-on protocols 3) Relative contribution of individual agents to treatment success difficult to assess 4) Combination therapy trials often have only a short-term component, with no long-term follow-up 9
AMBITION: Ambrisentan-Tadalafil Combination Therapy. Primary Study Endpoint: Time To Clinical Worsening Primary Endpoint: Time to First Clinical Failure Event Event-Free (%) 100 75 50 25 0 1 year 88.9% 1 year 75.5% Combination therapy Pooled monotherapy 2 year 79.7% 2 year 63.2% 3 year 67.6% 3 year 56.1% Number at risk: 0 24 48 72 96 120 144 168 192 Time (weeks) Combination: 253 229 186 145 106 71 36 4 Pooled monotherapy: 247 209 155 108 77 49 25 5 Nazzareno G, et al. ERS 2014 Kaplan Meier Curves for the Probability of a First Adjudicated Primary End-Point Event. Galiè N et al. N Engl J Med 2015;373:834-844. 10
AMBITION: Subgroup Analysis Combination Therapy Pooled Monotherapy Subgroup n Events n Events Hazard Ratio (95% CI) IPAH/HPAH 134 25 (19%) 145 46 (32%) 0.535 (0.329-0.871) 13 Favors Combination Favors Monotherapy APAH 119 21 (18%) 102 31 (30%) 0.453 (0.259-0.790) WHO FC II 76 4 (5%) 79 17 (22%) 0.211 (0.071-0.629) WHO FC III 177 42 (24%) 168 60 (36%) 0.576 (0.388-0.855) 10 Age <57 years 124 13 (10%) 120 31 (26%) 0.367 (0.192-0.701) Age 57 years 129 33 (26%) 127 46 (36%) 0.581 (0.371-0.910) BL 6MWD <363.7 m 129 35 (27%) 121 51 (42%) 0.537 (0.349-0.827) 7 BL 6MWD 363.7 m 124 11 (9%) 126 26 (21%) 0.380 (0.187-0.769) North America 116 22 (19%) 112 34 (30%) 0.505 (0.295-0.866) 3 Rest of world 137 24 (18%) 135 43 (32%) 0.506 (0.307-0.834) Female 188 32 (17%) 200 61 (31%) 0.473 (0.308-0.726) Male 65 14 (22%) 47 16 (34%) 0.581 (0.283-1.194) 0 0.125 0.25 0.5 1 2 4 Hazard Ratio (95% CI) Rubin L, et al. Chest 2014; 146:339A. AMBITION: Comparison of Initial Combination Therapy in WHO FC II and WHO FC III Patients 40% Primary Endpoint Clinical Failure Events 36% 30% * 22% 24% 20% 10% 5% 0% FC II Combination FC II Pooled Monotherapy FC III Combination FC III Pooled Monotherapy Frost A, et al. Am J Respir Crit Care Med 2015; 191:A4781. 11
SERAPHIN: Effect of Macitentan on Composite Primary End Point of a First Event Related to PAH or Death from Any Cause Pulido T et al. N Engl J Med 2013;369:809-818. SERAPHIN: Effect of Macitentan on Composite Secondary End Point of Death Due to PAH or Hospitalization for PAH as First Event Pulido T et al. N Engl J Med 2013;369:809-818. 12
GRIPHON: Primary Composite End Point. Sitbon O et al. N Engl J Med 2015;373:2522-2533. COMPASS-2: No Benefit of Bosentan Added to Stable Sildenafil Patients Without an Event (%) Primary Endpoint: Time to First Morbidity or Mortality Event 100 75 50 25 0 Bosentan: Risk reduction = 17%; HR = 0.831; log-rank P = 0.2508 Placebo Bosentan 0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 Time From Randomization (months) Patients at risk: Placebo 175 154 140 123 118 107 90 76 68 61 55 48 43 36 32 26 Bosentan 159 144 128 114 103 97 88 82 69 57 50 42 32 24 21 15 N=334. Randomized placebo-controlled event-driven trial of bosentan added to stable sildenafil. McLaughlin VV, et al. Chest 2014; 146:860A. 13
Upfront triple combination therapy in PAH: a pilot study Sitbon O, et al. Eur Resp J 2014; 43:1691-7. ESC/ERS 2015 treatment algorithm for PAH Galiè N et al. Eur Heart J 2015:doi:10.1093/eurheart/ehv317. 28 14
ESC/ERS 2015 recommendations for monotherapy in PAH Galiè N et al. Eur Heart J 2015:doi:10.1093/eurheart/ehv317. 29 ESC/ERS 2015 recommendations for upfront and sequential combination therapy in PAH Upfront Sequential Consideration: Dose adjustments and potential side effects may be simpler to manage with sequential administration of combination partners Galiè N et al. Eur Heart J 2015:doi:10.1093/eurheart/ehv317. 30 15
Treatment Issues in PAH 1) One, two, or three drugs? Monotherapy Dual combination therapy Triple combination therapy 2) When? Upfront Add-on (stable vs. failing) 3) Which drugs and in what order? Anticoagulation 1) Anticoagulation recommended in PAH with vitamin K antagonist 1 (INR of 1.5-2.5, unless contraindicated). No evidence for NAC. 2) Small observational studies support survival benefit of anticoagulation in IPAH 2-4 3) Survival benefit recently suggested by COMPERA trial in EU 5 4) Improvement in survival not observed in other forms of APAH (such as SSc) 5) Anticoagulation warranted to minimize catheter-related thrombosis in those receiving continuous intravenous prostanoid therapy 1. Humbert M, et al. Circulation 2014;130: 2189-2208 2. Rich S, et al. NEMJ 1992; 327:76 81 3. Frank H, et al. Chest 1997; 112:714 21 4. Fuster V, et al. Circulation 1984; 70:580 7 5. Olsson KM, et al. Circulation 2014; 129:57 65 16
Anticoagulation: Kaplan-Meier estimates of survival at 36 months for IPAH patients. IPreston et al. Circulation 2015; 132:2403-11 Anticoagulation: Kaplan-Meier estimates of survival at 36 months for SSc-PAH patients. Preston et al. Circulation 2015; 132:2403-11 17
5/1/2017 Summary: Long-term Management of Patients With PAH 1) Availability of oral, inhaled, and parenteral PAH therapies provides multiple treatment strategies for patients with PAH; trend toward multi-drug therapy 2) Long-term data on choice of initial medical therapy, de novo combination therapy, or therapy sequencing are still incomplete 3) Considerations for initial therapy selection and for combining therapies should take into account consensus recommendation/guidelines, long-term efficacy and safety data, second-line choices, and patient characteristics, with an individualized approach for each patient 4) In patients with severe disease or in those failing medical therapy, early referral to PAH centers for advanced therapy important 5) Anticoagulation: not sure for IPAH; definite no for scleroderma/ctd 18