Pulmonary Arterial Hypertension (PAH): Emerging Therapeutic Strategies Nick H. Kim, M.D. Clinical Professor of Medicine Director, Pulmonary Vascular Medicine Clinical Service Chief, PCCSM La Jolla Pulmonary, Critical Care, and Sleep Medicine University of California, San Diego
Disclosures: Consultant: Actelion, Arena, Bayer, Johnson & Johnson, Merck Speakers bureau: Actelion, Bayer Research support: Bellerophon, Eiger, Gilead, Lung Biotechnology, SoniVie; NIH R21 Co-Investigator Board member: International CTEPH Association (ICA), CTEPH.com 2
5 th WSPH PH: Diagnostic Classification 1. Pulmonary arterial hypertension (PAH) 1.1. Idiopathic PAH (IPAH) 1.2. Heritable 1.2.1. BMPR2 1.2.2. ALK1, ENG, SMAD9, CAV1, KCNK3 1.2.3. Unknown 1.3. Drug- and toxin-induced 1.4. Associated with 1.4.1. Connective tissue diseases (CTD) 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 PH of the newborn 2. PH 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. PH due to lung diseases and/or hypoxemia 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 diseases 4. Chronic thromboembolic PH 5. PH with unclear multifactorial mechanisms 5.1. Hematologic disorders: chronic hemolytic anemia, myeloproliferative disorders splenectomy 5.2. Systemic disorders: sarcoidosis, pulmonary histiocytosis: lymphangioleiomyomatosis 5.3. Metabolic disorders: glycogen storage disease, Gaucher disease, thyroid disorders 5.4. Others: tumoral obstruction, fibrosing mediastinitis, chronic renal failure, segmental PH Simonneau G, et al. J Am Coll Cardiol. 213;62(25 Suppl):D34-41.
Schematic Progression of PAH Presymptomatic/ Compensated Symptomatic/ Decompensating Declining/ Decompensated PAP PVR
PAH Treatment: When Should We Intervene? Ultimate Goal: No functional impairment, prolonged life, improved QoL Regular monitoring allows treatment escalation Functional Capacity Late Intervention Progressive remodeling and RHF in absence of treatment Time 5 Sitbon O and Galié N. Eur Respir Rev 21; 19: 118, 272 278
Prognosis of ipah: correlation with FC Advanced lung cancer WHO Class IV IPAH 6 months Advanced colorectal cancer Advanced breast cancer WHO Class III IPAH 2.6 years WHO Class I - II IPAH 4.9 years Ischemic cardiomyopathy 1 2 3 4 5 6 Survival (years) 7 Pre-modern treatment era D'Alonzo GE, et al. Ann Intern Med 1991; 115:343-9. Kato I, et al. Cancer 21; 92:2211-9. Felker GM, et al. N Engl J Med 2; 342:177-84.
The Multicenter RePHerral Study: Referral of Patients with PH Diagnoses to Tertiary PH Centers Post Referral Diagnosis Group 1 Group 2 Group 3 No PH Unk. Group 1 41 (73%) 3 (5%) 4 (7%) 7 (12%) 1 (2%) Pre- Referral Diagnosis Group 2 8 (62%) 1 (8%) 4 (31%) Group 3 4 (18%) 3 (14%) 13 (59%) 2 (9%) Unk. 12 (29%) 13 (31%) 1 (2%) 14 (33%) 2 (5%) Correct Pre-Referral Diagnosis Incorrect Pre-Referral Diagnosis N=141 patients referred over a 1-month period for PH evaluation. 45% of patients initiated on PAH-specific meds prior to referral did not have Group I PAH. Deano RC, et al. JAMA Intern Med. 213;173(1):887-93.
Current PAH Therapies Target 3 Pathways camp, cyclic adenosine monophosphate; cgmp, cyclic guanosine monophosphate; ET, endothelin; GTP, guanosine triphosphate; IP, prostacyclin receptor; NO, nitric oxide; PDE5, phosphodiesterase type 5; PGI 2, prostacyclin; sgc, soluble guanylate cyclase. Humbert M et al. Circulation 214;13:2189 28.
PAH Trials Evolution 25
Current Medical Therapies for PAH: Indications and Usage Class/Drug Trade Name FDA Approval Phase III Trials Primary Endpoint Approved Indication Black Box/ Contraindication Key Citation Prostacyclin epoprostenol Flolan, Veletri 1995, 28 NA PPH Study Δ 6MWD,12wk WHO Group 1 CHF, pulm edema Barst 1996 iloprost Ventavis 24 AIR Δ 6MWD,12wk WHO Group 1 None Olschewski 22 treprostinil ETRA Remodulin (sc,iv) Tyvaso (inhaled) Orenitram (oral) 22 (sc,iv) 29 (inh) 213 (po) TRIUMPH FREEDOM-M Δ 6MWD,12wk WHO Group 1 Remodulin: hypersensitivity Tyvaso-None Orenitram-hepatic imp bosentan Tracleer 21 BREATHE-1, -5 Δ 6MWD,12wk WHO Group 1 Teratogenicity/ Hepatotoxicity Simmoneau 22 McLaughlin 21 Jing 213 Rubin 22 ambrisentan Letairis 27 ARIES-1, -2 Δ 6MWD,12wk WHO Group 1 Fetal toxicity Galiè 28 macitentan Opsumit 213 SERAPHIN Combined Morb/Mort PDE5i WHO Group 1 Fetal toxicity/ Pregnancy Pulido 213 sildenafil Revatio 25 Super-1, -2 Δ 6MWD,12wk WHO Group 1 nitrates Galiè 25 tadalafil Adcirca 29 PHIRST Δ 6MWD,12wk WHO Group 1 nitrates Galiè 29 sgc Stimulator riociguat Adempas 213 PATENT CHEST IP Receptor Agonist selexipag Uptravi 215 GRIPHON Combined Morb/Mort Δ 6MWD,16wk WHO Group 1 +4 (CTEPH) WHO Group 1 (FC II/III) Fetal toxicity PDE5i Ghofrani 213 Ghofrani 213 None SItbon 215
ipah Survival Reports on Epoprostenol According to Functional Class 1. 1 Cumulative survival.8.6.4.2 NYHA I or II p<.1 NYHA III or IV 12 24 36 48 6 72 84 96 18 Survival (%) 8 6 4 2 12 24 36 48 6 72 FC I FC II FC III FC IV 84 No. at risk Months NYHA I or II: 91 84 69 48 32 17 7 3 1 NYHA III or IV: 75 45 16 9 4 4 No. at risk 115 112 86 Months 63 46 3 2 1 Sitbon O et al. J Am Coll Cardiol. 22;4:78-788. McLaughlin V et al. Circulation. 22;16:1477-1482.
Drug tested Sequential combination therapy Study Background N Duration (weeks) Primary endpoint Bosentan EARLY None or sildenafil (16%) 185 24 PVR +, Δ6MWD Bosentan COMPASS-2 Sildenafil 334 92 Morbi-mortality (NS) Iloprost STEP Bosentan 67 12 Δ6MWD (NS) Iloprost COMBI Bosentan 4 12 Δ6MWD (NS) Imatinib Phase II Bosentan &/or sildenafil &/or prostanoids 59 24 Δ6MWD (NS) Imatinib IMPRES Bosentan &/or sildenafil &/or prostanoids 22 24 Δ6MWD + Macitentan SERAPHIN None, PDE5i or inhaled iloprost 742 13.9 mean Morbi-mortality + Riociguat PATENT None, bosentan or prostanoids 443 12 Δ6MWD + Selexipag GRIPHON None, ERA and/or PDE5i 1156 7.7 median Morbi-mortality + Selexipag Phase II Bosentan &/or sildenafil 43 17 PVR + Sildenafil PACES Epoprostenol 264 16 Δ6MWD + Sildenafil NCT323297 Bosentan 14 12 Δ6MWD (NS) PAH Tadalafil RCTs that PHIRST have included at None least or bosentan one subgroup (54%) treated with 45 combination 16 Δ6MWD therapy (NS) Trepostinil Inhaled- TRIUMPH Bosentan or sildenafil 235 12 Δ6MWD + Trepostinil Oral- FREEDOM C1 Bosentan &/or sildenafil 354 16 Δ6MWD (NS) Trepostinil Oral- FREEDOM C2 Bosentan &/or sildenafil 31 16 Δ6MWD (NS)
Up Front Combination Therapy Reduces Events in New PAH Patients (AMBITION) Participants with No Event (%) Combination Therapy vs. Pooled Monotherapy 1 8 6 4 2 Combination therapy Pooled monotherapy Hazard ratio,.5 (95% CI,.35-.72) P<.1 24 48 72 96 12 144 168 192 Weeks No. at Risk Combination Therapy 253 229 186 145 16 71 36 4 Pooled monotherapy 247 29 155 18 77 49 25 5 13 Galiè N, Barberå JA, Frost AE, et al. Initial Use of Ambrisentan plus Tadalafil in Pulmonary Arterial Hypertension N Engl J Med. 215;373:834-844.
Clinical Worsening is Predictive of Future Mortality in PAH (REVEAL) 1-y survival in patients with and without prior clinical worsening Survival (%) 1 8 6 4 1 Survival Estimate Not Worsened (n = 1,511) Worsened (n = 1,34) 94.1 ±.6% 77.1 ± 1.1% 3 6 9 12 Time From Worsening/Day 365 (Months) Patients, who clinically worsened in the 1 st year follow-up after diagnosis of PAH, had poorer survival in subsequent year of follow-up than those who did not show clinical worsening (77.7% +1.1% vs 94.1% +.6%, respectively; P<.1) 14 Frost AE, Badesch DB, Miller DP, et al. Evaluation of the Predictive Value of a Clinical Worsening Definition Using 2-Year Outcomes in Patients With Pulmonary Arterial Hypertension: A REVEAL Registry Analysis. CHEST 213; 144(5):1521 1529
PAH Risk: The REVEAL Risk Calculator APAH=associated PAH; BNP=brain natriuretic peptide; BPM=beats per minute; CTD=connective tissue disease; Dlco=carbon monoxide diffusing capacity; FPAH=familial PAH; HR=heart rate; mrap=mean right atrial pressure; NYHA=New York Heart Association; PoPH=portopulmonary hypertension; PVR=pulmonary 15 vascular resistance; SBP=systolic blood pressure. Calculated risk scores can range from (lowest risk) to 22 (highest risk). Benza RL, et al. Chest. 212;141(2):354-362.
215 ESC/ERS Guidelines: Risk Stratification in PAH 16 Clinical assessment Exercise tests Biochemical markers Echocardiographic evaluations Hemodynamic evaluations Determinants of prognosis Clinical signs of right heart failure Progression of symptoms Estimated 1-year mortality Low risk < 5% Intermediate risk 5-1% High risk > 1% Absent Absent Present No Slow Rapid Syncope No Occasional syncope Repeated syncope FC I, II III IV 6MWD > 44 m 165-44 m < 165 m CPET NT-proBNP plasma levels Imaging (echo, CMR) Hemodynamics Peak VO 2 > 15 ml/min/ kg (> 65% pred.) VE/VCO 2 slope < 36 BNP < 5 ng/l NT-proBNP < 3 ng/l RA area < 18 cm 2 No pericardial effusion RAP < 8 mmhg CI 2.5 l/min/m 2 SvO 2 > 65% Peak VO 2 11-15 ml/ min/kg (35-65% pred.) VE/VCO 2 slope 36-44.9 BNP 5 3 ng/l NT-proBNP 3 14 ng/l RA area 18 26 cm 2 No or minimal pericardial effusion RAP 8 14 mmhg CI 2. 2.4 l/min/m 2 SvO 2 6 65% Peak VO 2 < 11ml/min/kg (< 35% pred.) VE/VCO 2 slope 45 BNP > 3 ng/l NT-proBNP > 14 ng/l RA area > 26 cm 2 Pericardial effusion RAP > 14 mmhg CI < 2. l/min/m 2 SvO 2 < 6% Galiè N, et al. Eur Respir J 215 Galiè N, et al. Eur Heart J 216
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Patients with a higher proportion of low risk variables at both baseline and follow up have a significantly reduced risk of mortality Swedish PAH Registry (n = 53, incident, 28-216) Methodology: Assigned a score of 1 (low-risk), 2 (intermediate-risk) or 3 (high-risk) for each variable available; calculated average score, rounded to nearest integer to define the patient s risk group. Survival 1.. 8. 6 Baseline (at diagnosis). 4 Low risk. Intermediate risk 2 High risk. Log rank, p <.1 1 2 3 4 5 Number at risk Years 12 1 86 73 58 42 355 246 176 124 8 51 55 35 22 13 5 4 Survival 1.. 8. 6 Follow up risk assessment (within a year of diagnosis). 4 Low risk. 2 Intermediate risk High risk. Log rank, p <.1 1 2 3 4 5 Number at risk Years 111 96 8 65 48 33 229 18 127 85 54 36 43 24 9 5 2 1 Survival 1.. 8. 6. 4. 2 Stable low risk Improved to low risk Stable intermediate or high risk Worsened to intermediate or high risk. Log rank, p <.1 1 2 3 4 5 Years Number at risk 57 5 44 37 28 21 54 46 36 28 2 12 213 163 18 69 41 26 59 41 28 21 15 11 Kylhammar D, et al. Eur Heart J 217
Correlation of risk classification at baseline and follow up with survival 1 Baseline 1 Follow up risk assessment* 8 8 Survival (%) 6 4 Survival (%) 6 4 2 p <.1; n = 1588 Low-risk Intermediate-risk High-risk 1 2 3 4 5 Time since PAH diagnosis (years) COMPERA Registry: Same methodology as the Swedish registry *Follow-up risk assessment between 3 months and 2 years after treatment initiation. 2 p <.1; n = 1355 Low-risk Intermediate-risk High-risk 1 2 3 4 5 Time since follow up risk assessment (years) Hoeper MM, et al. Eur Respir J 217
Association between the number low-risk criteria achieved within 1 year of diagnosis and long-term prognosis Retrospective study from French Registry Incident patients with idiopathic, heritable and drug-induced PAH between 26-216 were analysed The number of low-risk criteria present at diagnosis and at first re-evaluation were assessed: 1. WHO/NYHA functional class I or II 2. 6-minute walk distance (6MWD) > 44m 3. right atrial pressure < 8 mmhg 4. cardiac index 2.5 L/min/m 2 117 / 1591 patients having all parameters available at both baseline and first re-evaluation Determinants of prognosis Clinical signs of right heart failure Progression of symptoms Syncope FC 6MWD CPET NT-proBNP plasma levels Imaging (echo, CMR) Hemodynamics Low risk < 5% Absent No No I, II > 44 m Peak VO 2 > 15 ml/ min/kg (> 65% pred.) VE/VCO 2 slope < 36 BNP < 5 ng/l NT-proBNP < 3 ng/l RA area < 18 cm 2 No pericardial effusion RAP < 8 mmhg CI 2.5 l/min/m 2 SvO 2 > 65% Boucly A., et al. Eur Resp J 217
Achievement of multiple low risk criteria is associated with improved long-term outcomes Transplant-free survival according to the number of low-risk criteria present at first re-evaluation within the first year after diagnosis 1. 4 criteria Survival. 8. 6. 4.2 p <.1 3 criteria 2 criteria 1 criteria criteria 1 2 Yea 3 4 5 4 criteria 175 153 rs 128 12 63 48 3 criteria 247 24 175 14 12 72 2 criteria 275 219 171 122 78 49 1 criterion 225 183 128 91 62 45 criterion 95 61 44 22 18 14 Low risk criteria: WHO FC I or II; 6MWD >44 m; cardiac index > 2.5 L/min/m²; mrap <8 mmhg Boucly A., et al. Eur Resp J 217
Achievement of multiple low risk criteria is associated with improved long-term outcomes Transplant-free survival according to the number of non-invasive low-risk criteria present at first re-evaluation within the first year after diagnosis Transplant free survival 1.8.6.4.2 p <.1 1 2 3 4 5 Patients at risk, n = 63 Years 3 criteria 1 5 97 81 63 38 26 2 criteria 14 5 1 6 95 72 36 21 1 criteria 17 5 13 6 1 1 62 38 24 criteria 16 8 1 7 76 39 23 1 3 criteria 2 criteria 1 criteria criteria Low risk criteria: WHO FC I or II; 6MWD >44 m; BNP <5 ng/l or NT-proBNP < 3 ng/l Boucly A., et al. Eur Resp J 217
Summary of 3 Reports Swedish 1 COMPERA 2 French 3 Number of patients at baseline Number of patients at follow up 53 1588 117 383 194 117 Associated-PAH included Yes Yes No Definition of low-risk 1-year mortality % by risk group Average score <1.5 Average score < 1.5 3-4 of 4 low-risk criteria 1 / 7 / 26 2.8 / 9.9 / 21.2 1 / NA / 13-3 % low-risk at baseline 23% 12.3% 17% % low-risk at follow-up 29% 24% 41.5% Initial combination therapy 12% 17% 48% Initial monotherapy 86% 83% 52% 1.Kylhammar, D., et al. Eur Heart J 217 2. Hoeper MM, et al. Eur Respir J 217 3. Boucly A., et al. Eur Resp J 217
Key Points Early and accurate PAH diagnosis Proactive combination strategy works Risk assessment at baseline and at follow-up Treat to low risk and avoidance of clinical events 24