The ΔRL2 and ΔE4 scores mediated 29% of the treatment effect on clinical worsening in PAH trials, outperforming Δ6MWD, which mediated 19%.
Do composite risk assessment scores (ΔRL2, ΔE4, ΔE3, ΔFPHN) serve as stronger surrogate endpoints than Δ6MWD for predicting clinical worsening events in patients with pulmonary arterial hypertension?
Composite risk assessment scores, particularly REVEAL Lite 2 and European Four Strata, are stronger surrogate endpoints than 6-minute walk distance for predicting clinical worsening in PAH trials.
Absolute Event Rate: 0% vs 0%
Abstract Rationale 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. Objectives We investigate whether the change in four 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. Methods 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 five scores between baseline and 12-16 weeks follow-up. We conducted Bootstrap analysis to provide head-to-head comparisons. Measurements and Main Results Our analysis shows that all four composite scores mediate significantly more of the treatment effect compared to 6MWD (29% for ΔRL2 and ΔE4 compared to 19% for Δ6MWD; both p-values 10-15). The drug treatment effect accounted for by all five scores increases with intermediate/high risk patients, and ΔRL2 had the highest % mediation (37% for ΔRL2 versus 28% for Δ6MWD; p-value = 10-15). Conclusions 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.
Liu et al. (Fri,) reported a other. The ΔRL2 and ΔE4 scores mediated 29% of the treatment effect on clinical worsening in PAH trials, outperforming Δ6MWD, which mediated 19%.