Heart Failure in Patients With Stable Atherosclerosis: A Post Hoc Analysis of the TRA 2°P-TIMI 50 Trial

Abstract

Background: Heart failure is a growing public health burden and a morbid complication of atherosclerotic cardiovascular disease. Antiplatelet therapy is commonly used for the secondary prevention of atherothrombotic ischemic events, but its role in mitigating the risk of heart failure is less well characterized. In this study, we examined the epidemiology of heart failure within a previously completed large, randomized trial of the antiplatelet agent vorapaxar, and tested the hypothesis that vorapaxar would reduce the incidence of heart failure relative to placebo. Methods: We performed a nested exploratory analysis within the Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events (TRA 2°P)-Thrombolysis in Myocardial Infarction (TIMI) 50 trial, which randomized 26,449 patients with stable atherosclerotic cardiovascular disease to vorapaxar or placebo on top of standard therapy for a median of 30 months. Heart failure endpoints were adjudicated retrospectively from serious adverse events reported in the TRA 2°P trial, using a definition of heart failure adapted from professional society guidelines. Heart failure incidence was analyzed using Kaplan-Meier analysis, and comparisons were made using a Cox proportional hazards model. Results: Among placebo-treated patients in the TRA 2°P trial, 1.5% experienced heart failure at 3 years of follow-up. By qualifying type of atherosclerosis at randomization, heart failure incidence was highest in those with peripheral artery disease (2.6%), intermediate in those with prior myocardial infarction (1.4%), and tended to be lower in those with prior ischemic stroke (0.6%). Heart failure risk correlated with the risk of recurrent atherothrombosis as quantified by the TIMI Risk Score for Secondary Prevention: heart failure occurred in 5.8% of high-risk, 0.4% of intermediate-risk, and 0.1% of low-risk patients (P<0.0001). The incidence of heart failure did not differ significantly by treatment group (vorapaxar [1.7%] vs. placebo [1.5%]; hazard ratio, 1.15; 95% confidence interval, 0.93-1.42; P=0.19). Conclusions: In this large, well-characterized cohort with established atherosclerosis, heart failure and recurrent atherothrombosis shared similar risk factors. Vorapaxar did not reduce the risk of heart failure among patients with stable atherosclerotic cardiovascular disease in the TRA 2°P trial.