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Randomized Controlled Trial
. 2018 Mar 28;13(3):e0193226.
doi: 10.1371/journal.pone.0193226. eCollection 2018.

Association between six-minute walk distance and long-term outcomes in patients with pulmonary arterial hypertension: Data from the randomized SERAPHIN trial

Rogério Souza  1 , Richard N Channick  2 , Marion Delcroix  3 , Nazzareno Galiè  4 , Hossein-Ardeschir Ghofrani  5   6 , Pavel Jansa  7 , Franck-Olivier Le Brun  8 , Sanjay Mehta  9 , Loïc Perchenet  10 , Tomás Pulido  11 , B K S Sastry  12 , Olivier Sitbon  13   14   15 , Adam Torbicki  16 , Lewis J Rubin  17 , Gérald Simonneau  13
Affiliations
Randomized Controlled Trial

Association between six-minute walk distance and long-term outcomes in patients with pulmonary arterial hypertension: Data from the randomized SERAPHIN trial

Rogério Souza et al. PLoS One. .

Abstract

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.

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Conflict of interest statement

Competing Interests: RS reports personal consultancy fees from Actelion Pharmaceuticals Ltd during the conduct of the SERAPHIN study, and personal consultancy fees from Actelion Pharmaceuticals Ltd, Bayer, Eli Lilly, and GlaxoSmithKline outside the submitted work. RNC reports personal consultancy fees from Actelion Pharmaceuticals Ltd during the conduct of the SERAPHIN study, and grants from Actelion Pharmaceuticals Ltd outside the submitted work. MD reports grants from Actelion Pharmaceuticals Ltd during the conduct of the SERAPHIN study, and grants from Actelion Pharmaceuticals Ltd, Bayer, GlaxoSmithKline, and Pfizer outside the submitted work. NG reports grants from Actelion Pharmaceuticals Ltd during the conduct of the SERAPHIN study, and personal consultancy fees and grants from Actelion Pharmaceuticals Ltd, Bayer, Eli Lilly, GlaxoSmithKline, and Pfizer outside the submitted work. H-AG reports personal consultancy fees from Actelion Pharmaceuticals Ltd, Bayer, Ergonex, Gilead, GlaxoSmithKline, Merck, Novartis, and Pfizer outside the submitted work. PJ reports personal consultancy fees from Actelion Pharmaceuticals Ltd during the conduct of the SERAPHIN study, personal consultancy fees from Actelion Pharmaceuticals Ltd, AOP Orphan Pharmaceuticals, Bayer, GlaxoSmithKline, and United Therapeutics, and grants from Actelion Pharmaceuticals Ltd outside the submitted work. F-OLB and LP are employees and hold stock options for Actelion Pharmaceuticals Ltd. SM reports grants and personal consultancy fees from Actelion Pharmaceuticals Ltd during the conduct of the SERAPHIN study, grants from the Heart and Stroke Foundation of Ontario/Canada, Canadian Institute of Health Research, Ontario Thoracic Society, and personal consultancy fees from Bayer Pharmaceuticals Canada, Boehringer Ingelheim Canada, and Takeda-Nycomed outside the submitted work. TP reports grants from the National Heart Institute and personal consultancy fees from Actelion Pharmaceuticals Ltd during the conduct of the SERAPHIN study, personal consultancy fees from Actelion Pharmaceuticals Ltd, Bayer, Eli Lilly, and Pfizer, and grants from Actelion Pharmaceuticals Ltd, Bayer, and United Therapeutics outside the submitted work. BKSS reports personal consultancy fees from Actelion Pharmaceuticals Ltd during the conduct of the SERAPHIN study. OS reports personal consultancy fees from Actelion Pharmaceuticals Ltd during the conduct of the SERAPHIN study, personal consultancy fees from Actelion Pharmaceuticals Ltd, Bayer, Eli Lilly, GlaxoSmithKline, Pfizer, and United Therapeutics, and grants from Actelion Pharmaceuticals Ltd, Bayer, Eli Lilly, GlaxoSmithKline, and Pfizer outside the submitted work. AT reports grants and personal consultancy fees from Actelion Pharmaceuticals Ltd during the conduct of the SERAPHIN study, personal consultancy fees from Actelion Pharmaceuticals Ltd, AOP Orphan Pharmaceuticals, Bayer, Boston Scientific, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Pfizer, and United Therapeutics, and grants from Actelion Pharmaceuticals Ltd, AOP Orphan Pharmaceuticals, Bayer, Boston Scientific, Bristol-Myers Squibb, Pfizer, Sanofi Aventis, and United Therapeutics outside the submitted work. LJR reports personal consultancy fees from Actelion Pharmaceuticals Ltd during the conduct of the SERAPHIN study, and personal consultancy fees from Actelion Pharmaceuticals Ltd, Aires Pharmaceuticals, Arena Pharmaceuticals, Bayer, FDA, GeNO, Gilead, GlaxoSmithKline, Lung LLC, NHLBI, Pfizer, Reata Pharmaceuticals, and United Therapeutics outside the submitted work. GS reports grants and personal consultancy fees from Actelion Pharmaceuticals Ltd during the conduct of the SERAPHIN study, and personal consultancy fees from Actelion Pharmaceuticals Ltd, Eli Lilly, GlaxoSmithKline, Novartis, Pfizer, and United Therapeutics outside the submitted work. F-OLB and LP are employees and hold stock options for Actelion Pharmaceuticals Ltd. F-OLB and LP’s employment with Actelion Pharmaceuticals Ltd does not alter their adherence to PLOS ONE policies on sharing data and materials.

Figures

Fig 1
Fig 1. Association between absolute 6MWD applying a cut-off of 400 m at Month 6 and long-term outcomes in patients with PAH: A. PAH-related death or hospitalization up to end of treatment; B. All-cause death up to end of study.
6MWD, six-minute walk distance; K-M, Kaplan–Meier; PAH, pulmonary arterial hypertension.
Fig 2
Fig 2. Association between absolute 6MWD quartiles at Month 6 and long-term outcomes in patients with PAH: A. PAH-related death or hospitalization up to end of treatment; B. All-cause death up to end of study.
6MWD, six-minute walk distance; K-M, Kaplan–Meier; PAH, pulmonary arterial hypertension.
Fig 3
Fig 3. Association between absolute 6MWD quartiles at baseline and long-term outcomes in patients with PAH: A. PAH-related death or hospitalization up to end of treatment; B. All-cause death up to end of study.
6MWD, six-minute walk distance; K-M, Kaplan–Meier; PAH, pulmonary arterial hypertension.
Fig 4
Fig 4. Association between change in 6MWD from baseline to Month 6 (by quartiles) and long-term outcomes in patients with PAH: A. PAH-related death or hospitalization up to end of treatment; B. All-cause death up to end of study.
6MWD, six-minute walk distance; K-M, Kaplan–Meier; PAH, pulmonary arterial hypertension.
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