Validation of 6-Minute Walk Distance as a Surrogate End Point in Pulmonary Arterial Hypertension Trials

Background-Nearly all available treatments for pulmonary arterial hypertension have been approved based on change in 6-minute walk distance (Delta 6MWD) as a clinically important end point, but its validity as a surrogate end point has never been shown. We aimed to validate the difference in Delta 6MWD against the probability of a clinical event in pulmonary arterial hypertension trials. Methods and Results-First, to determine whether Delta 6MWD 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 10 randomized placebo-controlled trials previously submitted to the US Food and Drug Administration (n=2404 patients). Second, to identify a threshold effect for the Delta 6MWD that indicated a statistically significant reduction in clinical events, we conducted a meta-regression among 21 drug/dose-level combinations. Delta 6MWD accounted for 22.1% (95% confidence interval, 12.1%-31.1%) of the treatment effect (P<0.001). The meta-analysis showed an average difference in Delta 6MWD of 22.4 m (95% confidence interval, 17.4-27.5 m), favoring active treatment over placebo. Active treatment decreased the probability of a clinical event (summary odds ratio, 0.44; 95% confidence interval, 0.33-0.57). The meta-regression revealed a significant threshold effect of 41.8 m. Conclusions-Our results suggest that Delta 6MWD does not explain a large proportion of the treatment effect, has only modest validity as a surrogate end point for clinical events, and may not be a sufficient surrogate end point. Further research is necessary to determine whether the threshold value of 41.8 m is valid for long-term outcomes or whether it differs among trials using background therapy or lacking placebo controls entirely. (Circulation. 2012; 126: 349-356.)