Validation of Six-Minute-Walk Distance as a Surrogate Endpoint in Pulmonary Arterial Hypertension Trials
Background—Nearly all available treatments for pulmonary arterial hypertension (PAH) have been approved based on change in six-minute-walk distance (Δ6MWD) as a clinically important endpoint, but validity as a surrogate endpoint has never been shown. We aimed to validate the difference in Δ6MWD against the probability of a clinical event in PAH trials.
Methods and Results—First, to determine if Δ6MWD between baseline and 12 weeks mediated the relationship between treatment assignment and development of clinical events, we conducted a pooled analysis of patient-level data from the ten randomized placebo-controlled trials previously submitted to the U.S. Food and Drug Administration (n=2404). Second, to identify a threshold effect for the Δ6MWD that indicated a statistically significant reduction in clinical events, we conducted a meta-regression among 21 drug/dose level combinations. Δ6MWD accounted for 22.1% (95% CI: 12.1%, 31.1%) of the treatment effect (p<0.001). The meta-analysis showed an average difference in Δ6MWD of 22.4 m (95% CI: 17.4 to 27.5), favoring active treatment over placebo. Active treatment decreased the probability of a clinical event (summary OR: 0.44; 95% CI: 0.33, 0.57). The meta-regression revealed a significant threshold effect of 41.8 meters.
Conclusions—Our results suggest that Δ6MWD does not explain a large proportion of the treatment effect, has only modest validity as a surrogate endpoint for clinical events, and may not be a sufficient surrogate endpoint. Further research is necessary to determine whether the threshold value of 41.8 m is valid for long-term outcomes or if it differs among trials using background therapy or lacking placebo controls entirely.
- Received March 20, 2012.
- Accepted May 16, 2012.
- Copyright © 2012, American Heart Association, Inc. All rights reserved. Unauthorized use prohibited