Systematic review of trials using vasodilators in pulmonary arterial hypertension: Why a new approach is needed

Background In a previous metaanalysis on the approved treatments for pulmonary hypertension, we reported that all therapies caused small changes in 6-minute walk distance over a short period, with minimal effects on hemodynamics and no effect on survival. Since that last review, 10 new clinical trials with about 1,500 patients have been published, which has increased the statistical power of our observations. Methods A systematic review of all clinical trials in pulmonary arterial hypertension was done. Results The pooled effect of all treatments strategies (relative risk [95% CI], P) now shows a significant reduction of 39% (2%-62%, P = .041) in all-cause mortality. The benefits were confined only to patients with advanced disease for 16 weeks, regardless of which class of drug is used. When considering the effects within each drug family, no class of drug produced a statistically significant reduction in all-cause mortality. The improved survival bore no relationship with the change in 6-minute walk, the primary end point in most of the trials. Conclusions The impact of vasodilators on long-term survival in pulmonary arterial hypertension remains uncertain. Future trials need to (a) adopt new trial designs that can better address clinical benefits, (b) use new end points that incorporate our best understanding of the disease rather than the ones that are easy to administer, and (c) include longer durations of study and other strategies to clarify if survival is affected. (Am Heart J 2010;159:245-57.)