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 (Δ6MWD) 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 Δ6MWD against the probability of a clinical event in pulmonary arterial hypertension trials.


RESULTS
First, to determine whether 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 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 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% confidence interval, 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% 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 Δ6MWD 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.
Center for Clinical Epidemiology and Biostatistics, Philadelphia, PA, USA. gabler@upenn.edu
Nicole B
NB
Gabler
Benjamin
B
French
Brian L
BL
Strom
Harold I
HI
Palevsky
Darren B
DB
Taichman
Steven M
SM
Kawut
Scott D
SD
Halpern
D000328:Adult; D004185:Disability Evaluation; D016903:Drug Monitoring / Q000379:methods / Q000592:standards*; D065128:Endothelin Receptor Antagonists; D065627:Familial Primary Pulmonary Hypertension; D005260:Female; D006801:Humans; D006976:Hypertension, Pulmonary / Q000188:drug therapy* / Q000503:physiopathology*; D008297:Male; D008875:Middle Aged; D010726:Phosphodiesterase Inhibitors / Q000627:therapeutic use*; D011453:Prostaglandins / Q000627:therapeutic use*; D016032:Randomized Controlled Trials as Topic / Q000379:methods / Q000592:standards; D020127:Recovery of Function / Q000187:drug effects / Q000502:physiology; D015203:Reproducibility of Results; D016896:Treatment Outcome; D016138:Walking
D065128:Endothelin Receptor Antagonists; D010726:Phosphodiesterase Inhibitors; D011453:Prostaglandins