Although it is long been suggested that antioxidants may have protective effects against cardiovascular disease (CVD), recent studies suggest that cardiovascular benefits are limited specifically to foods that are sources of polyphenol antioxidants, such as flavonoid-rich cocoa (FRC). The body of evidence for a beneficial effect with cocoa is building, but data from long-term randomized controlled trials with CVD endpoints such as death and myocardial infarction are required before recommending cocoa flavonoid intake for the prevention of CVD, stated Eric L. Ding, ScD, of Harvard School of Public Health, Boston, Massachusetts, USA.

Whereas an older meta-analysis found total flavonoid intake to be associated with lower risk of coronary heart disease (CHD) mortality in a 2006 study [Ding EL et al. Nutr Metab (Lond) 2006], higher quality studies in recent years have limited the benefits to cocoa flavonoids. A recent and comprehensive systematic review and meta-analysis of 24 RCTs with 1106 participants and a mean cocoa flavonoid dose of 500 mg daily showed that FRC was associated with improvement in multiple cardiovascular risk factors, including blood pressure (BP), lipids, insulin resistance, and flow-mediated dilation (FMD; Table 1) [Shrime MG et al. J Nutr 2011]. Total cholesterol, triglycerides, and C-reactive protein were unchanged. Of note, there was a nonlinear dose response between FRC and FMD, with the maximum effect achieved with the 500-mg daily dose. This is the first meta-analysis to evaluate the effect of FRC on all CVD risk factors and a dose-response relationship, and its limitations include the trials being short term (2 to 18 weeks) and not having access to patient-level data, said Dr. Ding. In addition, another meta-analysis of cocoa flavonoids performed by researchers from Harvard also found benefits for lowering insulin and improving insulin resistance [Hooper L et al. Am J Clin Nutr 2008].

The Zutphen Elderly Study, a prospective cohort study of 470 men in the Netherlands who were followed for 15 years, was among the high-quality studies that showed an association between cocoa intake and reductions in CVD and total mortality [Buijsse B et al. Arch Intern Med 2006]. Subject who had the highest amount of cocoa intake were associated with reduced risk of CV death (adjusted relative risk, 0.50; 95% CI, 0.32 to 0.78; p = .004) and all-cause death at 15 years (adjusted relative risk, 0.53; 95% CI, 0.39 to 0.72; p<.001) as compared to subjects with the least amount of ingestion.

A systematic review and meta-analysis of 7 nonrandomized studies showed that higher versus lower levels of chocolate consumption were associated with a reduced risk of any CVD (relative risk, 0.63; 95% CI, 0.44 to 0.90) [Buitrago-Lopez A et al. BMJ 2011]. Further evidence for an association between chocolate consumption and reduction in stroke came from the Cohort of Swedish Men study of 37,103 men that found a 17% relative risk reduction in the highest (62.9 g/week) versus the lowest (0 g) quartiles of consumption [Larsson S et al. Neurology 2012] and a meta-analysis of 5 studies that showed a relative risk reduction of 0.81 for stroke (95% CI, 0.73 to 0.90) [Larsson S et al. Neurology 2012].

The evidence of benefit with FRC and chocolate from preclinical, prospective cohort, and short-term clinical studies to prevent CVD has provided the framework for long-term RCTs with hard CVD endpoints. Planning is underway for the Cocoa Supplement and Multivitamins Outcomes Study [COSMOS], led by researchers from Brigham and Women's Hospital and Harvard Medical School, that will begin in 2015 and enroll 18,000 men and women who are free of CVD to determine the effect of high-quality cocoa flavanol supplementation (750 mg daily) and also a multivitamin in a double-blind, placebo-controlled, 2×2 factorial study.