Date Published: March 28, 2018
Publisher: Public Library of Science
Author(s): Rogério Souza, Richard N. Channick, Marion Delcroix, Nazzareno Galiè, Hossein-Ardeschir Ghofrani, Pavel Jansa, Franck-Olivier Le Brun, Sanjay Mehta, Loïc Perchenet, Tomás Pulido, B. K. S. Sastry, Olivier Sitbon, Adam Torbicki, Lewis J. Rubin, Gérald Simonneau, Yoshihiro Fukumoto.
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.
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.
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.
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.
Pulmonary arterial hypertension (PAH) is a relentlessly progressive disease characterized by an increase in pulmonary artery pressure and pulmonary vascular resistance, leading to right ventricular failure and poor survival [1, 2]. As a consequence of the pulmonary hemodynamic abnormalities, there is also a progressive decline in the functional and exercise capacity of patients with PAH.
The 742 patients randomized in the SERAPHIN study were well-matched in terms of demographic, clinical, and disease characteristics at baseline. In total, 76.5% of patients were female, mean (SD) age and time since diagnosis were 45.6 (16.1) years and 2.7 (4.0) years, respectively. Mean (SD) 6MWD was 360 (100.2) meters, approximately half of patients were in WHO FC I/II (52.5%) and WHO FC III/IV (47.5%) and background therapy included phosphodiesterase type 5 inhibitor (61.4%) and oral or inhaled prostanoid therapy (5.4%) . Three patients had missing 6MWD values at baseline.
SERAPHIN was the first prospective, long-term, randomized controlled study to assess disease progression in more than 700 patients with PAH over a median treatment period of 2.2 years . Patients with a 6MWD of ≥400 m at Month 6 were at reduced risk of future clinical events, such as PAH-related death or hospitalization, and all-cause death. Patients with higher absolute values of 6MWD at baseline or at Month 6 were confirmed as having better prognosis, whereas the magnitude of change in 6MWD during this period was not associated with long-term clinical outcomes.
In the SERAPHIN study, patients with PAH walking more than 400 m had a lower risk of disease progression, including PAH-related death or hospitalization and all-cause death. Although changes in 6MWD were not associated with long-term outcome in patients with PAH, assessing the absolute 6MWD values remains important in the clinical management of patients with PAH.