'Promising Signals' With Cocoa Flavanols to Reduce CV Events?

Batya Swift Yasgur, MA, LSW

April 12, 2022

Results of a large, randomized trial of a cocoa flavanol supplement showed a trend toward a reduction in total cardiovascular events, although the reduction did not reach statistical significance in comparison with placebo. However, some secondary endpoints, including cardiovascular disease (CVD) death, did show significant results the researchers called "promising" and that warrant further investigation, they say.

The COcoa Supplement and Multivitamin Outcomes Study (COSMOS) included over 21,000 older adults randomly assigned to receive either treatment or placebo. It showed that 3.6 years of cocoa flavanol supplementation was associated with 10% lower rate of total CV events, including myocardial infarction (MI), stroke, CVD death, revascularization, and unstable angina, but was not statistically significant.

There was, however, a statistically significant 27% reduction in CV death, a secondary endpoint.

Additional analyses comparing participants adherent to cocoa flavanols to those adherent to placebo found a significant 15% reduction in the primary endpoint of total CVD events among participants taking the supplement regularly. Moreover, cocoa flavanols significantly reduced the risk of major cardiovascular events (MI plus stroke plus CVD death) by 16%, compared to placebo in this analysis.

"The COSMOS trial showed promising signals that warrant further research and confirmation in a future trial," lead investigator JoAnn Manson MD, DrPH, professor of epidemiology, Harvard T. H. Chan School of Public Health and the Michael and Lee Bell Professor of Women's Health, Harvard Medical School, told theheart.org | Medscape Cardiology.

"However, because this is the first large-scale, randomized trial of cocoa flavanol supplementation, it would be premature to recommend that everyone begin taking cocoa flavanol supplements at this time," said Manson, who is also the chief of preventive medicine at Brigham and Women's Hospital, Boston.

The study was published online March 16 in The American Journal of Clinical Nutrition.

Long History

Cocoa has a "long history of medicinal use." Its potential health benefits are derived from its flavanol and procyanidin content, but previous studies of cocoa products and CVD have been "inconsistent," the authors state. Other plant-derived sources of dietary flavanols are tea, grapes, berries, and other fruits.

"Earlier small-scale and short-term mechanistic trials had shown favorable effects of high-dose cocoa flavanols on blood pressure, flow-mediated vasodilation, and inflammation," Manson said, but "no previous large-scale trials of cocoa flavanols in reducing clinical CVD events had been done."

The researchers initiated the COSMOS study, a pragmatic, large-scale, 2x2 factorial randomized trial testing a cocoa extract supplement (500 mg/day of cocoa flavanols) and a typical multivitamin in the prevention of CVD and cancer among older adults (n = 21,442: 12,666 women aged ≥65 years and 9776 men aged ≥60 years who were free of MI, stroke, and recently diagnosed cancer at study entry). This current study focused on the cocoa extract component of the trial.

Participants were divided into four arms in equal proportions:

  • Active cocoa extract and active multivitamin

  • Active cocoa extract and multivitamin placebo

  • Active multivitamin and cocoa extract placebo

  • Both placebos

Manson noted that the 500 mg/day dosage of cocoa flavanols tested in COSMOS "exceeds that readily obtained in the diet."

The median follow-up period was 3.6 (interquartile range, 3.2 – 4.2) years, during which participants were sent follow-up questionnaires at 6 and 12 months following randomization and semiannually thereafter, to assess adherence with randomized treatments, use of nontrial cocoa supplements and/or multivitamins, potential side effects of the interventions, updated medical history, and "other relevant lifestyle, clinical, and dietary risk factors."

The primary outcome was a composite of total CVD events, including incident MI, stroke, coronary revascularization, CV mortality, carotid artery surgery, peripheral artery surgery, and unstable angina requiring hospitalization.

Secondary cardiovascular outcomes were a combination of total CVD and all-cause mortality, the individual components of total CVD events, and the original composite CVD outcome of MI, stroke, coronary revascularization, and cardiovascular mortality. That original outcome was expanded to include the other endpoints when "overall rates of CVD were lower than expected," for a variety of reasons, they note.

Other secondary outcomes included the incidence of invasive cancer (excluding nonmelanoma skin cancer) and key site-specific cancers, including breast, colorectal, and lung cancers.

The researchers also conducted per-protocol analyses that censored follow-up when the participant discontinued trial pills, began outside nonstudy use of a cocoa supplement, and/or took <75% of study pills.

Heart-Healthy Diet

During the intervention period, 866 participants experienced the primary outcome of total cardiovascular events, 410 in the cocoa extract group and 456 in the placebo group (hazard ratio [HR], 0.90; 95% CI, 0.78 – 1.02; P = .11), and 3.5% of participants (n = 750) died.

The annualized rates of total cardiovascular events were 1.08% and 1.20% in the active and placebo cocoa extract groups, respectively — a difference that was not statistically significant.

Among secondary outcomes, notably, CVD death was significantly reduced (HR, 0.73; 0.54 – 0.99).

However, there were no significant reductions in MI, stroke, and revascularizations in the cocoa vs the placebo group (HR, 0.87; 95% CI, 0.66 – 1.16; HR, 0.91; 95% CI, 0.77 – 1.17; and HR, 0.95; 95% CI, 0.77 – 1.17, respectively). The HR for all-cause mortality was 0.89 (95% CI, 0.77 – 1.03).

Still, the per-protocol analyses "supported a lower risk of total cardiovascular events (HR, 0.85; 95% CI, 0.72 – 0.99)," the authors report.

Compliance, defined as missing ≤8 days/month of study pills, remained high throughout the study period in both active cocoa extract and placebo groups, at 83.1% and 84.2%, respectively, at study closeout.

Taking cocoa extract had no significant effect on the secondary outcomes of total cancer, specific cancers, or cancer death.

"For the more rigorous MACE endpoint of MI plus stroke plus CVD death, cocoa flavanols significantly reduced risk by 16% compared to placebo, although this endpoint was not a focus of the trial," Manson summarized. She added that they saw no CV benefits in the multivitamin supplement.

There were no safety concerns for either the cocoa flavanol or multivitamin interventions.

The findings "support striving to have a heart-healthy dietary pattern high in plant-derived flavanols, including tea, grapes, berries, and other fruits," Manson said.

She cautioned that dietary supplements are "meant to complement, not replace, a healthy, balanced diet" and emphasized that COSMOS "was not a chocolate trial, and chocolate is not a reliable source of cocoa flavanols, which can be destroyed in the processing of many types of chocolates."

Additionally, "to achieve intakes of flavanols at this level through chocolate would require excessive calories, sugar, and fat. Chocolate is a wonderful treat, but it shouldn't be perceived as a health food."

"Novel" Bioactive

Commenting for theheart.org | Medscape Cardiology, Mary McGrae McDermott, MD, Jeremiah Stamler Professor of Medicine, Division of General Internal Medicine and Geriatrics and Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, said the study findings suggest "that cocoa flavanols appear to have a small beneficial effect on the prevention of cardiovascular events in older healthy people, but the effect is small, and this trial seems to have lacked adequate statistical power to show a definitive benefit."

However, "because cocoa flavanols were not associated with significant adverse effects, I think that it would be reasonable for an interested person to take them," said McDermott, whose research focuses on cocoa flavanols and peripheral artery disease.

McDermott, who was not involved with the present study, added that it would be "interesting to study cocoa flavanols in patients at higher risk of cardiovascular events, where the intervention has the potential to have a more potent effect."

Manson said, "For now, the results are encouraging and support further research on this novel bioactive, including longer-term follow-up of the COSMOS trial cohort, ongoing COSMOS mechanistic studies, and a potential additional trial to reproduce these findings. Such studies will further elucidate the relationship between cocoa flavanol supplementation and clinical CVD events."

COSMOS is supported by an investigator-initiated grant from Mars Edge, a segment of Mars dedicated to nutrition research and products, which included infrastructure support and the donation of study pills and packaging. Pfizer Consumer Healthcare (now part of GSK Consumer Healthcare) provided support through the partial provision of study pills and packaging. COSMOS is also supported in part by grants from the National Institutes of Health (NIH). The Women's Health Initiative (WHI) program is funded by the National Heart, Lung, and Blood Institute, the NIH, and the US Department of Health and Human Services. Manson reports receiving investigator-initiated grants from Mars Edge, a segment of Mars Inc dedicated to nutrition research and products, for infrastructure support and donation of COSMOS study pills and packaging, The other authors' disclosures are listed on the original article. McDermott reports that her group is currently conducting a trial of cocoa flavanols for peripheral artery disease (COCOA PAD study), which is supported by Mars.

Am J Clin Nutr. Published online March 16, 2022. Abstract

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