Abstract 10351: Validity and Relevance of Clinical Worsening as a Composite Endpoint in Pulmonary Arterial Hypertension Trials

Abstract

Background: Clinical worsening (CW) is commonly used as an endpoint in pulmonary arterial hypertension (PAH) trials. The use of composite endpoints is based on the assumption that each component is interchangeable. Objectives: We aimed to assess the trial-level surrogacy of CW for predicting overall mortality (considered adequate when coefficient of determination R 2 trial >0.70) in PAH trials. We also assessed whether the various CW components were similar in terms of: 1) frequency of occurrence; 2) treatment-related relative risk (RR) reduction and; 3) importance to patients. Methods: We searched MEDLINE, Embase, and the Cochrane Library (01/1990-12/2020) for RCTs evaluating the effects of PAH treatment on CW. The R 2 trial between the RR for CW and mortality (including after censoring) was analysed by regression analysis. The frequency of occurrence of the CW components, as well as the RR reduction of the CW components and those considered of critical, major and mild-to-moderate importance determined through a web-based survey on 257 PAH patients were assessed. Results: From 4,778 references, we included 35 studies (7,744 pts). The effects of PAH-specific therapies on CW modestly correlated with mortality (R 2 trial 0.32). Most of the CW defining-events were PAH-related hospitalizations (30.5%) and symptomatic progressions (48.0%), whereas deaths (14.1%), treatment escalations (6.8%) and transplantations or atrial septostomies (0.6%) were unusual. The RR across components differed by >0.4 in 20/35 studies (57%). Furthermore, the composite endpoints combined components of both critical to moderate importance to patients in 31/35 studies (89%). The pooled treatment effects only became significant when endpoints of major (RR 0.67;95%CI 0.60-0.74;p<0.01) and moderate (RR 0.61;0.52-0.70;p<0.01) importance to patients were added to critical outcomes (RR 1.02;95%CI 0.78-1.32;p=0.91). Consistently, 8/12 (67%) trials with documented decreases in CW were no longer significant when outcomes of moderate importance to patients were excluded. Conclusion: CW is not a surrogate outcome for mortality in PAH trials. Moreover, components of CW largely vary in frequency, response to therapy and importance to patients and are thus not interchangeable.