Reporting of Cardiovascular Events in Clinical Trials Supporting FDA Approval of Contemporary Cancer Therapies

Abstract

Background: Cardiovascular disease (CVD) has become an increasingly common limitation to effective anticancer therapy. Yet, whether CVD events were consistently reported in pivotal trials supporting contemporary anticancer drugs is unknown.

Objectives: The authors sought to evaluate the incidence, consistency, and nature of CVD event reporting in cancer drug trials.

Methods: From the Drugs@FDA, clinicaltrials.gov, MEDLINE, and publicly available U.S. Food and Drug Administration (FDA) drug reviews, all reported CVD events across latter-phase (II and III) trials supporting FDA approval of anticancer drugs from 1998 to 2018 were evaluated. The primary outcome was the report of major adverse cardiovascular events (MACE), defined as incident myocardial infarction, stroke, heart failure, coronary revascularization, atrial fibrillation, or CVD death, irrespective of treatment arm. The secondary outcome was report of any CVD event. Pooled reported annualized incidence rates of MACE in those without baseline CVD were compared with reported large contemporary population rates using relative risks. Population risk differences for MACE were estimated. Differences in drug efficacy using pooled binary endpoint hazard ratios on the basis of the presence or absence of reported CVD were also assessed.

Results: Overall, there were 189 trials, evaluating 123 drugs, enrolling 97,365 participants (58.5 ± 5 years, 46.0% female, 72.5% on biologic, targeted, or immune-based therapies) with 148,138 person-years of follow-up. Over a median follow-up of 30 months, 1,148 incidents of MACE (375 heart failure, 253 myocardial infarction, 180 strokes, 65 atrial fibrillation, 29 revascularizations, and 246 CVD deaths; 792 in the intervention vs. 356 in the control arm; p < 0.01) were reported from the 62.4% of trials noting any CVD. The overall weighted-average incidence was 542 events per 100,000 person-years (716 per 100,000 in the intervention arm), compared with 1,408 among similar-aged non-cancer trial subjects (relative risk: 0.38; p < 0.01), translating into a risk difference of 866. There was no association between reporting CVD events and drug efficacy (hazard ratio: 0.68 vs. 0.67; p = 0.22).

Conclusions: Among pivotal clinical trials linked to contemporary FDA-approved cancer drugs, reported CVD event rates trail expected population rates.

Keywords: U.S. Food and Drug Administration; cancer clinical trials; cardio-oncology; cardiovascular disease; reporting of adverse events.

FIGURE 1. Reported Cardiovascular Events During Follow-Up

Events are stratified by cancer type (A), and therapeutic class (B), respectively. *The percentages reported reflect a denominator of the total number of trials within the subgroup considered. CVD = cardiovascular disease; GI = gastrointestinal; GU = genitourinary.

CENTRAL ILLUSTRATION. Cardiovascular Events in Pivotal Cancer Trials

(A) Proportional frequency of incident reported cardiovascular disease(CVD)events during cancer trial follow-up, compared with reported contemporary nontribal population estimates (–27) Plots stratified by CVD event types (hypertension not shown to due to high variation in rates based on drug type). (B) Reported versus observed cumulative CVD incidence rates, depicted in events per 100,000 person-years of available follow-up. Estimates reflect major adverse cardiovascular events from supporting anticancer trials compared with observed rates in a similar-aged contemporary population. *There were zero events reported for myocarditis