Results from a large randomized study of a cocoa flavanol supplement showed a trend towards a reduction in total cardiovascular events, although the reduction did not reach statistical significance compared to placebo. However, some secondary endpoints, including death from cardiovascular disease (CVD), showed significant results that the researchers called “promising” and warrant further investigation, they say.
The COcoa Supplement and Multivitamin Outcomes Study (COSMOS) included over 21,000 seniors randomly assigned to receive either treatment or a placebo. It showed that 3.6 years of cocoa flavanol supplementation was associated with a 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 analyzes comparing cocoa flavanol adherents to placebo adherents found a significant 15% reduction in the primary endpoint of total CVD events among participants who regularly took the supplement. Furthermore, in this analysis, cocoa flavanols significantly reduced the risk of major cardiovascular events (MI plus stroke plus cardiovascular death) by 16% compared to placebo.
“The COSMOS study has shown promising signs that warrant further research and confirmation in a future study,” said lead researcher JoAnn Manson MD, DrPH, professor of epidemiology, Harvard TH Chan School of Public Health and Michael and Lee Bell Professor of Women’s Health, Harvard School of Medicine, said theheart.org | Medscape Cardiology.
“However, as this is the first large-scale randomized study of cocoa flavanol supplementation, it would be premature to recommend that everyone start taking cocoa flavanol supplements at this time,” said Manson, who is also the head of medicine. preventive at Brigham and Women’s Hospital, Boston.
The study was published online on March 16 in The American Journal of Clinical Nutrition.
Cocoa has a “long history of medicinal use”. Its potential health benefits stem from its flavanol and procyanidin content, but previous studies on cocoa products and cardiovascular disease have been “inconsistent,” the authors say. Other plant sources of food flavanols are tea, grapes, berries, and other fruits.
“Previous small-scale and short-term mechanistic studies had shown favorable effects of high-dose cocoa flavanols on blood pressure, flow-mediated vasodilation and inflammation,” Manson said, but “no previous large-scale study of cocoa flavanols in the reduce clinical events of CVD had been done “.
Researchers initiated the COSMOS study, a pragmatic, large-scale, randomized 2×2 factorial study that tested a cocoa extract supplement (500 mg / day of cocoa flavanols) and a typical multivitamin in the prevention of cardiovascular disease and cancer. among the elderly (n = 21,442: 12,666 women aged ≥65 years and 9776 men aged ≥60 years who were free from newly diagnosed myocardial infarction, stroke and cancer at study entry). This current study focused on the cocoa extract component of the test.
The participants were divided into four arms in equal proportions:
Active cocoa extract and active multivitamin
Active cocoa extract and multivitamin placebo
Active multivitamin placebo and cocoa extract
Manson noted that the 500 mg / day dosage of cocoa flavanols tested in COSMOS “exceeds that easily obtained in the diet.”
The median follow-up period was 3.6 (interquartile range, 3.2 – 4.2) years, during which follow-up questionnaires were sent to participants at 6 and 12 months after randomization and thereafter. every six months, to assess adherence to randomized treatments, use of non-experimental cocoa supplements and / or multivitamins, potential side effects of interventions, updated medical history and “other lifestyle, clinical and dietary risk factors” .
The primary outcome was a composite of total CVD events, including incident myocardial infarction, 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 the total CVD events, and the original composite CVD outcome of myocardial infarction, stroke, coronary revascularization, and cardiovascular mortality. That original finding was expanded to include the other endpoints when “overall CVD rates were lower than expected,” for a variety of reasons, they note.
Other secondary outcomes included the incidence of invasive cancer (excluding non-melanoma skin cancer) and key site-specific cancers, including breast, colorectal and lung cancers.
The researchers also conducted per-protocol analyzes that censored follow-up when the participant stopped taking the test pills, started using a cocoa supplement outside of the study, and / or took less than 75% of the pills. study.
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 cocoa extract and placebo groups, respectively, a difference not statistically significant.
Among the secondary outcomes, in particular, CVD death was significantly reduced (HR, 0.73; 0.54 – 0.99).
However, there were no significant reductions in myocardial infarction, stroke, and revascularizations in the cocoa group compared to 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).
However, the per-protocol analyzes “supported a lower risk of total cardiovascular events (HR, 0.85; 95% CI, 0.72-0.99),” the authors report.
Compliance, defined as the lack of ≤8 days / month of study pills, remained high throughout the study period in both the active cocoa extract and placebo groups at 83.1% and placebo, respectively. 84.2% at the close of the study.
Intake of cocoa extract had no significant effect on secondary outcomes of total cancer, specific cancers, or cancer death.
“For the stricter MACE endpoint of myocardial infarction plus stroke plus CVD death, cocoa flavanols significantly reduced the risk by 16% compared to placebo, although this endpoint was not the focus of the study,” Manson summarized. She added that they saw no CV benefits in the multivitamin supplement.
There were no safety issues for either cocoa flavanol or multivitamin interventions.
The findings “support the effort to have a heart-healthy dietary model rich in plant-derived flavanols, including tea, grapes, berries and other fruits,” Manson said.
He warned that dietary supplements “are intended to complement, not replace, a healthy and balanced diet” and stressed that COSMOS “was not a chocolate trial and chocolate is not a reliable source of cocoa flavanols, which can be destroyed during the processing of many types of chocolates. “
Additionally, “to achieve flavanol intake 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.”
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 results suggest “that cocoa flavanols appear to have a small beneficial effect on the prevention of cardiovascular events in healthy older people, but the effect is small and this study does not appear to have adequate statistical power to show definitive benefit. “
However, “since cocoa flavanols were not associated with significant adverse effects, I think it would make sense for an affected person to take them,” said McDermott, whose research focuses on cocoa flavanols and peripheral artery disease.
McDermott, who was not involved in the present study, added that it would be “interesting to study cocoa flavanols in patients at higher risk for 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 new bioactive, including the long-term follow-up of the COSMOS study cohort, ongoing COSMOS mechanistic studies, and a potential additional study to reproduce these findings. Such studies will further illustrate the relationship between cocoa flavanol supplementation and the clinical events of CVD. “
COSMOS is supported by a researcher-initiated grant from Mars Edge, a segment of Mars dedicated to research and nutritional 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 partial supply 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 United States Department of Health and Human Services. Manson reports receiving investigator-initiated grants from Mars Edge, a segment of Mars Inc dedicated to nutritional research and products, for infrastructure support and the donation of pills and packaging for the COSMOS study. The revelations of the other authors are listed in 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.
I’m J Clin Nutr. Published online March 16, 2022. Abstract
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