INTRODUCTION: In SERAPHIN, a long-term, event-driven, double-blind randomised controlled trial in pulmonary arterial hypertension (PAH), macitentan 10 mg significantly reduced the risk of morbidity/mortality compared with placebo. Its open-label extension study (SERAPHIN OL) further assessed long-term safety and tolerability of macitentan 10 mg in PAH patients. METHODS: Patients in SERAPHIN who completed the double-blind treatment period or experienced a morbidity event during the study could enter SERAPHIN OL. Patients received macitentan 10 mg once daily, and safety and survival were assessed until end of treatment (+ 28 days). Two overlapping sets were analysed for safety: (1) all patients in SERAPHIN OL (OL safety set); (2) patients randomised to macitentan 10 mg in SERAPHIN (long-term safety/survival set). Survival was evaluated as an exploratory endpoint in the latter set. RESULTS: Of 742 patients randomised in SERAPHIN, 550 (74.1%) entered SERAPHIN OL (OL safety set); 242 patients were randomised to macitentan 10 mg in SERAPHIN (long-term safety/survival set). Median (min, max) exposure to macitentan 10 mg was 40.1 (0.1, 130.5) months (2074.7 patient-years; OL safety set) and 54.7 (0.1, 141.3) months (1151.0 patient-years; long-term safety/survival set). Safety in both analysis sets was comparable to the known safety profile of macitentan. Kaplan-Meier survival estimates (95% CI) at 1, 5, 7 and 9 years were 95.0% (91.3, 97.1), 73.3% (66.6, 78.9), 62.6% (54.6, 69.6) and 52.7% (43.6, 61.0), respectively (long-term safety/survival set; median follow-up: 5.9 years). CONCLUSIONS: This analysis provides the longest follow-up for safety and survival published to date for any PAH therapy. The safety profile of macitentan 10 mg over this extensive treatment period was in line with that observed in SERAPHIN. As the majority of patients were receiving other PAH therapy at macitentan initiation, our study provides additional insight into the long-term safety of macitentan, including as part of combination therapy. TRIAL REGISTRATION: ClinicalTrials.gov Identifiers: NCT00660179 and NCT00667823.

2nd Department of Internal Medicine Department of Cardiovascular Medicine 1st Faculty of Medicine Charles University and General University Hospital Prague Czech Republic

Actelion Pharmaceuticals Ltd Allschwil Switzerland

BREATHE Department of Chronic Diseases and Metabolism KU Leuven Leuven Belgium

CARE Hospitals Hyderabad India

Clinical Department of Respiratory Diseases Centre of Pulmonary Vascular Diseases University Hospitals of Leuven Leuven Belgium

David Geffen School of Medicine at UCLA Los Angeles CA USA

Department of Clinical Research Ignacio Chávez National Heart Institute Mexico City Mexico

Department of Pulmonary Circulation Thromboembolic Disease and Cardiology Centre for Postgraduate Medical Education ECZ Otwock Otwock Poland

Hôpital Bicêtre Université Paris Sud Le Kremlin Bicêtre France

IRCCS S Orsola University Hospital Bologna Italy

Pulmonary Division Heart Institute University of Sao Paulo Av Dr Eneás de Carvalho Aguiar 255 sala 7079 Sao Paulo SP CEP 06 403 010 Brazil

Southwest Ontario PH Clinic Respirology Division London Health Sciences Centre Western University London ON Canada

University of California San Diego Medical School San Diego CA USA

VALOS S r L Genoa Italy

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ClinicalTrials.gov
NCT00660179, NCT00667823