BACKGROUND: Age affects disease severity and patient outcomes in pulmonary arterial hypertension. This post-hoc analysis identified prognostic age groups and associated macitentan/selexipag treatment effects. METHODS: Randomized trials evaluated macitentan (SERAPHIN; NCT00660179) and selexipag (GRIPHON; NCT01106014) versus placebo (primary endpoint: time to morbidity/mortality [M/M]). This analysis defined age thresholds differentiating M/M risk in patients randomized to placebo (Cox regression determining treatment effect by age). RESULTS: Three age groups (< 35, 35-64, ≥ 65 years) showed good M/M risk discrimination (c-statistic 0.69, SERAPHIN; 0.66, GRIPHON). M/M risk was higher in placebo patients < 35 versus 35-64 years (SERAPHIN: hazard ratio [HR] 1.73, 95% confidence interval [CI] 1.10-2.72, p = 0.02; GRIPHON: HR 1.81, 95% CI 1.28-2.56, p < 0.001). M/M risk trended higher in patients ≥ 65 versus 35-64 years (SERAPHIN: HR 1.55, 95% CI 0.89-2.69, p = 0.12; GRIPHON (HR 1.08, 95% CI 0.75-1.55, p = 0.69). M/M risk was lower with macitentan/selexipag versus placebo: macitentan < 35 (HR 0.44, 95% CI 0.25-0.78; p = 0.005), 35-64 (HR 0.50, 95% CI 0.33-0.76; p < 0.001), ≥ 65 years (HR 0.69, 95% CI 0.30-1.58; p = 0.38); selexipag < 35 (HR 0.50, 95% CI 0.32-0.78; p = 0.002), 35-64 (HR 0.72, 95% CI 0.54-0.96; p = 0.03), ≥ 65 years (HR 0.55, 95% CI 0.33-0.91; p = 0.02). Adverse-event discontinuations were similar. CONCLUSIONS: The benefit (vs placebo) of macitentan/selexipag on reducing risk of M/M events was consistent across all ages, including the younger group where significant treatment effects were observed.

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

Actelion Pharmaceuticals US Inc Titusville NJ

CARE Hospitals Hyderabad India

Centre of Postgraduate Medical Education European Health Centre ECZ Otwock Poland

Clinical Research Department National Heart Institute Mexico City Mexico

David Geffen School of Medicine at University of California Los Angeles Los Angeles CA

Department of Internal Medicine 2 Cardiology and Center of Cardiovascular Medicine Medical University of Vienna Währinger Gürtel 18 20 1090 Vienna Austria

InCor Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo São Paulo Brazil

Janssen Research and Development LLC Raritan NJ

National Pulmonary Hypertension Unit Mater Misericordiae University Hospital Dublin Ireland

Respirology Division Department of Medicine Schulich School of Medicine and Dentistry Western University London ON Canada

Université Paris Saclay APHP Hôpital Bicêtre Le Kremlin Bicêtre France

University Hospitals of Leuven Leuven Belgium

University of Michigan Ann Arbor MI

University of New Mexico Albuquerque NM

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