Study of risk assessment scores as surrogate endpoints in pulmonary arterial hypertension trials

Pulmonary arterial hypertension (PAH) clinical trials largely rely on clinically relevant intermediate outcomes, as mortality and lung transplant are infrequent and remote outcomes. The change in 6-minute walk distance (Δ6MWD) is utilized as an intermediate endpoint and is used as a surrogate for clinical worsening events.

We investigate whether the change in 4 composite risk assessment scores-REVEAL Lite 2 (ΔRL2), European Four Strata (ΔE4), European Three Strata (ΔE3), and French Noninvasive score (ΔFPHN)-are potentially stronger surrogate endpoints than the single-component Δ6MWD in PAH studies.

Using data from the AMBITION and FREEDOM-EV trials, we estimated the percentage of treatment effect in reducing clinical worsening events within 1 year that is attributed to the change on each of the 5 scores between baseline and 12-16 weeks' follow-up. We conducted bootstrap analysis to provide head-to-head comparisons.

Our analysis shows that all 4 composite scores mediate significantly more of the treatment effect compared to 6MWD (29% for ΔRL2 and ΔE4 compared to 19% for Δ6MWD; both P <10-15). The drug treatment effect accounted for by all 5 scores increases with intermediate/high-risk patients, and ΔRL2 had the highest % mediation (37% for ΔRL2 vs 28% for Δ6MWD; P < 10-15).

RL2 and E4 were the strongest mediators, with RL2 showing the highest mediation in intermediate/high-risk patients. Until better surrogates are found that mediate over 50% of the treatment effect, RL2 or E4 may serve as alternatives to the 6MWD as intermediate endpoints.