BACKGROUND: Patients with pulmonary arterial hypertension who achieve a six-minute walk distance of 380-440 m may have improved prognosis. Using the randomized controlled trial of macitentan in pulmonary arterial hypertension (SERAPHIN), the association between six-minute walk distance and long-term outcomes was explored. METHODS: Patients with six-minute walk distance data at Month 6 were dichotomized as above or below the median six-minute walk distance (400 m) and assessed for future risk of pulmonary arterial hypertension-related death or hospitalization and all-cause death. Additionally, six-minute walk distance values at baseline, Month 6 and the change from baseline to Month 6 were categorized by quartiles. All associations were analyzed by the Kaplan-Meier method using a log-rank test and Cox regression models. RESULTS: Patients with a six-minute walk distance >400 m vs. ≤400 m at Month 6 have a reduced risk of pulmonary arterial hypertension-related death or hospitalization (hazard ratio 0.48; 95% confidence interval 0.33-0.69). The risk was also lower for patients with higher quartiles of six-minute walk distance at baseline or Month 6 (baseline: hazard ratio [Q4 (>430 m) vs. Q1 (≤300 m)] 0.23; 95% confidence interval 0.15-0.36; Month 6: hazard ratio [Q4 (>455 m) vs. Q1 (≤348 m)] 0.33; 95% confidence interval 0.19-0.55). In contrast, six-minute walk distance changes at Month 6 were not associated with the risk of pulmonary arterial hypertension-related death or hospitalization (p = 0.477). These findings were consistent when adjusted for known confounders. Similar results were observed for the risk of all-cause death up to end of study. CONCLUSIONS: Patients with pulmonary arterial hypertension walking >400 m had better long-term prognosis. Although changes in six-minute walk distance were not associated with long-term outcomes, assessing absolute six-minute walk distance values remains important in the clinical management of patients with pulmonary arterial hypertension.

Assistance Publique Hôpitaux de Paris Service de Pneumologie Hôpital Bicêtre Le Kremlin Bicêtre France

Assistance Publique Hôpitaux de Paris Service de Pneumologie Hôpital Bicêtre Le Kremlin Bicêtre France Université Paris Sud Laboratoire d'Excellence en Recherche sur le Médicament et L'innovation Thérapeutique Le Kremlin Bicêtre France INSERM U 999 Centre Chirurgical Marie Lannelongue Le Plessis Robinson France

Cardiopulmonary Department Ignacio Chávez National Heart Institute Mexico City Mexico

Clinical Department of Cardiology and Angiology 1st Faculty of Medicine 2nd Medical Department Charles University Prague Czech Republic

Department of Biostatistics Actelion Pharmaceuticals Ltd Allschwil Switzerland

Department of Cardiology CARE Hospitals Hyderabad India

Department of Experimental Diagnostic and Specialty Medicine DIMES Bologna University Hospital Bologna Italy

Department of Medicine Division of Respirology London Health Sciences Centre Victoria Hospital Western University London Ontario Canada

Department of Pneumology Gasthuisberg University Hospital Leuven Belgium

Department of Pulmonary Circulation and Thromboembolic Diseases Medical Center of Postgraduate Education Otwock Poland

Global Medical Affairs Actelion Pharmaceuticals Ltd Allschwil Switzerland

Medical Clinic 2 5 University of Giessen and Marburg Lung Center Giessen Germany Department of Medicine Imperial College London London United Kingdom

Pulmonary and Critical Care Massachusetts General Hospital Boston Massachusetts United States of America

Pulmonary Department Heart Institute University of São Paulo Medical School São Paulo Brazil

University of California San Diego School of Medicine La Jolla California United States of America

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