REPORTING OF CARDIOVASCULAR EVENTS IN CLINICAL TRIALS SUPPORTING FDA-APPROVAL OF CONTEMPORARY CANCER DRUGS

Abstract

Background: Cardiovascular disease (CVD) is a leading cause of morbidity and mortality among patients treated with anticancer therapies. In the US, novel cancer therapy trials are required to report concerning adverse events prior to Food and Drug Administration (FDA) approval. Yet, the pattern and reported incidence of CVD events in these pivotal clinical trials is unknown. Method(s): From the Drugs@FDA database, MEDLINE, clinicaltrial.gov, and publicly available FDA reviews we identified all pivotal (phase II and III) clinical trials tied to anticancer drug approvals from 1998-2018. The primary outcome was the report of major adverse cardiovascular events (MACE), defined as incident myocardial infarction (MI), stroke, heart failure (HF), coronary or peripheral revascularization, atrial fibrillation (AF) and CVD death, irrespective of treatment arm. Pooled reported annualized incidence-rates of MACE were compared to reported rates in a large contemporary similar-aged general population using relative risks (RR). Population risk difference (RD) for MACE was estimated. Differences in drug efficacy using pooled binary endpoint hazard ratios (HR), based on the presence or absence of reported MACE events were also assessed. Result(s): Overall, there were 189 trials, linked to 123 drugs, enrolling 97,365 participants (58.5+/-5 years, 46.0% female, 80.4% on biologic, targeted or immune-based therapies) with 148,138 person-years of follow-up. Over a median follow-up of 18 months, 954 cases of incident MACE (370 HF, 65 MI, 179 stroke, 29 revascularizations, 65 AF and 246 CVD deaths; 680 in the intervention vs 274 control arm; P<0.01) were reported, from the 48.7% of trials noting any CVD. The overall weighted average incidence was 644 events per 100,000 person-years (777 per 100,000 in the intervention arm), compared to a reported incidence of 1,408 among similar aged non-cancer trial subjects (RR 0.46, P<0.01), translating into an RD of 764. There was no association between reporting CVD events and drug efficacy (HR 0.60 vs 0.65; P =0.22). Conclusion(s): Among pivotal clinical trials linked to contemporary FDA-approved cancer drugs, reported CVD event rates dramatically trail reported population rates. Copyright 2019 American College of Cardiology Foundation. All rights reserved.