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Randomized controlled trials: a solid platform for observational research

Although it remains serious and life-threatening, there has been steady progress in pulmonary arterial hypertension (PAH) treatment over the last few decades. Physicians can now target several different pathways with a range of pulmonary vasodilators, either alone or in combination. The bulk of pulmonary vasodilators were approved using 6-min walk distance, a surrogate outcome, as the primary study endpoint. This has led to a robust conversation about the use of surrogates in PAH and their place in clinical trials. In particular, concerns have been raised as to whether haemodynamic surrogates reflect clinically relevant outcomes in PAH. A meta-analysis of PAH trials found that, while change in haemodynamics over 12 weeks was correlated with both treatment and outcomes, only a small fraction of improvement in clinical outcomes could be explained by the change in haemodynamics. If this meta-analysis is true and generalizable, reliance on haemodynamic surrogates could provide misleading impressions when evaluating drug efficacy. Pharmaceutical companies and regulators have subsequently moved away from short-term trials using surrogates and towards longer trials with a focus on clinically relevant endpoints. The best approach to identifying clinically relevant endpoints in PAH trials should be considered a work in progress. Composite outcomes, such as are used in SERAPHIN, have several merits including increased study efficiency, diminished impact of competing risks, and the ability to capture multiple aspects of a treatment effect. On the other hand, powering studies for a composite outcome diminishes the ability to discriminate differences in components of the composite and may create a false sense of equivalency. Important differences in death or hospitalization may be obscured, especially if a component of the composite outcome is driven by a surrogate endpoint with intermediate relevance to clinical progression. Nevertheless, the paradigm shift in PAH trials away from surrogate endpoints and toward clinically relevant outcomes is an important step toward further improving the quality of trials in PAH. The move toward clinically relevant endpoints in trials does not imply that surrogate endpoints are irrelevant in PAH. Proactive clinicians try not to wait for clinically relevant events, such as hospitalization or death, to make changes in therapy. Instead, for better or worse, functional, haemodynamic, or biochemical metrics are used clinically as surrogates to inform prognosis and determine whether treatment is adequate.