Using controlled and real-world data in concert to assess survival benefits in pulmonary arterial hypertension: Insights from SERAPHIN and REVEAL

Designing a randomized controlled trial (RCT) to investigate a survival benefit in a rare disease such as pulmonary arterial hypertension (PAH) has considerable logistical and ethical constraints. In the SERAPHIN RCT, a 23% non-significant reduction in the risk of all-cause mortality was observed with macitentan 10mg vs placebo. As SERAPHIN enrolled patients in the same time frame as the US REVEAL registry, a prediction model based on REVEAL data was used to further explore the effect of macitentan on mortality. From REVEAL (N=3515), 1013 patients who would have met SERAPHIN eligibility criteria were selected (REVEAL analysis cohort [RAC]). Using the RAC, a prediction model for time to death up to 3 years was constructed based on 10 baseline prognostic variables. The model was used to predict survival of each of the 742 SERAPHIN patients had they received real-world treatment in the RAC. The average temporal profile of these patients was then compared with the observed survival of the macitentan 10mg group (n=242) using a log-rank test and Cox’s proportional hazard model. Over 3 years, the risk of mortality observed with macitentan 10mg was 31% lower than that predicted (p=0.033) (Fig). Real-world observational data can complement RCT data to provide a means of evaluating survival benefits in rare diseases. Merits and limitations of this approach will be discussed.