Effect of cocoa flavanol supplementation for prevention of cardiovascular disease events: The COSMOS randomized clinical trial

Background Cocoa extract is a source of flavanols that favorably influence vascular risk factors in small and short-term trials, yet effects on clinical cardiovascular events are untested. Objectives We examined whether cocoa extract supplementation decreases total cardiovascular disease (CVD) among older adults. Methods We conducted a randomized, double-blind, placebo-controlled, two-by-two factorial trial of cocoa extract supplementation and multivitamins for prevention of CVD and cancer among 21,442 U.S. adults (12,666 women aged >= 65 years and 8,776 men aged >= 60 years) free of major CVD and recently diagnosed cancer. Intervention phase was June 2015 through December 2020. This article reports on the cocoa extract intervention. Participants were randomly assigned to a cocoa extract supplement (500 mg/d flavanols, including 80 mg (-)-epicatechins) or placebo. The primary outcome was a composite of confirmed incident total cardiovascular events, including myocardial infarction (MI), stroke, coronary revascularization, cardiovascular death, carotid artery disease, peripheral artery surgery, and unstable angina. Results During a median follow-up of 3.6 years, 410 participants taking cocoa extract and 456 taking placebo had confirmed total cardiovascular events (hazard ratio [HR], 0.90; 95% confidence interval [CI], 0.78, 1.02; P = 0.11). For secondary endpoints, HRs were 0.73 (95% CI, 0.54, 0.98) for CVD death, 0.87 (95% CI, 0.66, 1.16) for MI, 0.91 (95% CI, 0.70, 1.17) for stroke, 0.95 (95% CI, 0.77, 1.17) for coronary revascularization, neutral for other individual cardiovascular endpoints, and 0.89 (95% CI, 0.77, 1.03) for all-cause mortality. Per-protocol analyses censoring follow-up at nonadherence supported a lower risk of total cardiovascular events (HR, 0.85; 95% CI, 0.72, 0.99). There were no safety concerns. Conclusion Cocoa extract supplementation did not significantly reduce total cardiovascular events among older adults but reduced CVD death by 27%. Potential reductions in total cardiovascular events were supported in per-protocol analyses. Additional research is warranted to clarify whether cocoa extract may reduce clinical cardiovascular events.