Effect of cocoa flavanol supplementation for the prevention of cardiovascular disease events: the COcoa Supplement and Multivitamin Outcomes Study (COSMOS) randomized clinical trial

Abstract

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, 2-by-2 factorial trial of cocoa extract supplementation and multivitamins for prevention of CVD and cancer among 21,442 US adults (12,666 women aged ≥65 y and 8776 men aged ≥60 y), free of major CVD and recently diagnosed cancer. The 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 flavanols/d, including 80 mg (-)-epicatechin] 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 y, 410 participants taking cocoa extract and 456 taking placebo had confirmed total cardiovascular events (HR: 0.90; 95% 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.

Conclusions: 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. This trial is registered at www.clinicaltrials.gov as NCT02422745.

Keywords: cancer; cardiovascular disease; cocoa extract; flavanols; multivitamin; randomized clinical trial.

FIGURE 1

Screening, randomization, and follow-up of the participants. ¹Eligibility was determined by medical history, age, and willingness to forego personal use of cocoa extract and multivitamin pills. ²Eligibility was determined by medical history, age, willingness to forego personal use of cocoa extract and multivitamin pills, caffeine sensitivity, and willingness to limit calcium and vitamin D supplement use. ³Included subjects who never completed the screening phase (n = 2914), eligibility could not be determined (n = 5), and enrollment goal already met (n = 55). ⁴Included subjects who never completed screening phase (n = 168) and enrollment goal already met (n = 54).

FIGURE 2

HRs and 95% CIs¹ for the primary and secondary CVD outcomes, according to randomized assignment, in intention-to-treat analyses. ¹Summary statistics were from Cox regression models that stratified baseline hazard functions by multivitamin trial randomization group, age, sex, and recruitment cohort. CIs were not adjusted for multiple comparisons. ²This outcome was a composite of myocardial infarction, stroke, CVD death, CABG/PCI, unstable angina including hospitalization, carotid artery surgery, and peripheral artery surgery. ³This outcome was a composite of myocardial infarction, stroke, and CVD death. CABG/PCI, coronary artery bypass graft and percutaneous coronary intervention; CVD, cardiovascular disease.

FIGURE 3

Cumulative incidence rates of total cardiovascular events¹ and CVD death, according to year of follow-up, in the cocoa extract group and placebo group. ¹Primary outcome (left panel): a composite of myocardial infarction, stroke, CVD death, CABG/PCI, unstable angina including hospitalization, carotid artery surgery, and peripheral artery surgery. Secondary outcome (right panel): CVD death. Summary statistics were from Cox regression models that stratified baseline hazard functions by multivitamin trial randomization group, age, sex, and recruitment cohort (intention-to-treat analyses). P value was for the effect of randomization group, based on a stratified score (log-rank) test. Rates (%) were annualized. CABG/PCI, coronary artery bypass graft and percutaneous coronary intervention; CVD, cardiovascular disease.

FIGURE 4

HRs and 95% CIs¹ for the primary and secondary CVD outcomes, according to randomized assignment, where follow-up of noncompliant participants was censored. ¹Summary statistics were from weighted Cox regression models that stratified baseline hazard functions by multivitamin trial randomization group, age, sex, and recruitment cohort, and used the robust sandwich estimator for variance. Time-dependent weights were calculated as the inverse probability of compliance, where probabilities were estimated from a Cox regression model with baseline hazard functions stratified by age, sex, recruitment source, multivitamin-trial arm and cocoa extract trial arm, and included baseline history of CVD and hypertension status (time-dependent) as covariates. CIs were not adjusted for multiple comparisons. ²A participant's follow-up was censored at the first time they reported having missed >8 d of cocoa extract study pills per month, took personal nonstudy cocoa extract, or did not respond to a semiannual questionnaire. ³Total cardiovascular event was a composite of myocardial infarction, stroke, CVD death, CABG/PCI, unstable angina including hospitalization, carotid artery surgery, and peripheral artery surgery. ⁴Major cardiovascular event was a composite of myocardial infarction, stroke, and CVD death. CABG/PCI, coronary artery bypass graft and percutaneous coronary intervention; CVD, cardiovascular disease.