The changing paradigm in pulmonary hypertension trials: longer duration, new endpoints

Approved therapies for pulmonary arterial hypertension (PAH) currently consist of 12 agents, the majority of which were approved following short-term randomized clinical trials using change in 6 minute walk distance (6MWD) as the primary outcome. However, there is growing concern that significant improvements in this measure do not translate into morbidity and mortality benefits.

As a result of data questioning the association between improvements in 6 minute walk distance and improvements in outcome, PAH clinical trial design is increasingly utilizing morbidity and mortality events as a composite primary outcome. This concept was recently illustrated in the published phase 3 trial of macitentan versus placebo, during which the clinical worsening event rate was decreased by 45%. Several additional unpublished trials have been similarly designed, all of which will require extended blinded treatment time in order to accrue sufficient event rates. The definition of morbidity events has varied across clinical studies; further standardization of this parameter is necessary.

Although multiple direct and surrogate outcomes have been studied in PAH clinical research, rate of clinical worsening events, using prolonged, event-driven trial design, has emerged as the new standard.