A Proposed Randomized Trial of Cocoa Flavanols and Multivitamins in the Prevention of Cardiovascular Disease and Cancer JoAnn E. Manson, MD, DrPH Howard D. Sesso, ScD, MPH Brigham and Women's Hospital Harvard Medical School Garnet L. Anderson, PhD Fred Hutchinson Cancer Research Center WHI Nutrition SIG Call April 5, 2013
Rationale for the Trial Emerging evidence that cacao (cocoa, dark chocolate) reduces risk of CVD and that multivitamins may reduce risk of cancer. Growing intake of, and health claims related to, these foods/supplements underscore the need for conclusive evidence on benefits and risks. No previous large-scale RCTs of these agents have been conducted in primary prevention in women. A prevention trial among women in WHI would be highly cost-effective.
Proposed Trial Design WHI women aged 65 years and free of CVD and recently diagnosed cancer N=12,000 Cocoa extract (750 mg/d flavanols) N=6,000 Placebo N=6,000 Multivitamins N=3000 Placebo N=3000 Multivitamins N=3000 Placebo N=3000 Mean Treatment Period = 4 years Primary Outcomes: CVD (MI, stroke, CVD death and coronary revascularization); cancer. Baseline Blood collection in ~1,500, follow-up bloods in 1,000.
Primary Aims 1) To test whether cocoa reduces risk of major CVD events (MI, stroke, and CVD mortality) and coronary revascularization. 2) To test whether multivitamins reduce risk of cancer (excluding non-melanoma skin cancer). Secondary Aims Specific Aims 1) To test whether cocoa and/or multivitamins reduce risk of CVD composite plus all-cause mortality. 2) To test whether cocoa and/or multivitamins reduce risk of individual components of above composite or of cancer.
Specific Aims (cont d) Tertiary Aims 1) To explore whether cocoa and multivitamins have synergistic or additive effects on the risk of major CVD events, all-cause mortality, or cancer. 2) To explore whether effects of these agents on CVD or cancer vary by (a) baseline dietary intake of these nutrients (from FFQ and/or blood levels), (b) age, or (c) BMI.
Estimated Number of Potentially Eligible WHI Participants Recruited for the Proposed Trial 77,011 Initial mailing to potentially eligible women free of CVD and recently diagnosed cancer 20,793 Willing and eligible respondents 17,500 Willing and eligible women sign informed consent Invitational letter, screening questionnaire Consent, brochure, baseline questionnaire Placebo run-in 12,000 Compliant, willing, and eligible women randomized to take cocoa and/or multivitamin supplements
Trial Cohort Follow-up Will be fully integrated into the WHI follow-up mailings, data collection, and outcomes confirmation system. Leverages the WHI infrastructure for cohort follow-up (regional center mailings, CCC, project office). Utilizes leadership and scientific committee structure of WHI (P & P, ancillary study committee, outcomes adjudication, scientific interest groups, etc.). Utilizes the current DSMB/OSMB, with additional members as needed. Very cost-effective design and follow-up structure (~$125 per participant per year direct costs; ~$62.50 per agent tested).
N = 12,000 women Cohort Size/Power With 4 years of treatment, power of 84% to detect RR=0.85 for primary CVD endpoint of MI, stroke, CVD mortality, and coronary revascularization. Power = 97% for CVD composite plus all-cause mortality. Power is also >90% for RR of 0.80 for total cancer.
Partial List of Potential Ancillary Studies Cognitive Function Diabetes/Glucose Tolerance Hypertension Physical Performance Site-specific Cancers Mood Disorders/Depression Autoimmune Diseases Biomarkers and Genetic Studies Non-invasive Vascular Imaging
Cocoa The cocoa bean comes from the cacao plant, Theobroma cacao, which when processed forms cocoa and chocolate. High-cacao chocolate, typically as dark chocolate, has been associated with health benefits. Beneficial effects of cocoa have been attributed to its high polyphenol and flavonoid content: Catechins Epicatechins Theobromine Procyanidins
Multiple Mechanisms through which Cocoa Products May Lower the Risk of CVD Cocoa Products Platelet adhesion and aggregation Antioxidant capacity LDL oxidation Blood pressure LDL Triglycerides HDL Endothelial function Flow-mediated dilation Insulin sensitivity Glucose metabolism Inflammation CVD Risk
Meta-Analysis of Cohort Studies on Chocolate Consumption and CVD Source: Buitrago-Lopez A et al. BMJ 2011.
Cocoa: Effects on CVD Risk Factors Smaller, short-term clinical trials examining various doses of chocolate, cocoa, or polyphenols have identified beneficial effects on intermediate cardiovascular endpoints, including: Improvements in flow-mediated dilation Improvements in lipids Lowering of blood pressure Other intermediate cardiovascular endpoints Recent meta-analyses have summarized these findings and provided support for specific mechanisms through which cocoa and chocolate consumption may reduce CVD.
Effect of Chocolate/Cocoa Flavan-3-ols on Flow-mediated Dilation Source: Hooper L et al. Am J Clin Nutr 2012;740-751.
Justification of Cocoa Dose The 750 mg/day cocoa supplement is a patented cocoa extract containing the compounds associated with its many health benefits, but without the calories, caffeine, fat or dairy, found in chocolate. Each 750 mg dose includes at least: 75 mg(-) catechins 90 mg theobromine Equivalent content: 14 grams (or 1.5 teaspoons) of cocoa mix powder 1 bar (1.55 ounces or 43.9 grams) per day of dark chocolate
Multivitamins: Background More than one-third of adults in the US take multivitamins (MVM). Basic research suggests how some components of MVM might reduce the risk of cancer and CVD. Observational studies have not clearly demonstrated associations of MVM with lower risk of either outcome. A large-scale randomized trial of multivitamins in men (the Physicians Health Study II) suggested benefits for cancer prevention, but no randomized trials have been done in women.
Content of Centrum Silver Multivitamins to be Tested in WHI Vitamin or Mineral Amount Vitamin A (40% as ß-carotene) 2500 IU Vitamin C 60 mg Vitamin D Vitamin E 500 IU 50 IU Vitamin K 30 µg Thiamin Riboflavin Niacin 1.5 mg 1.7 mg 20 mg Vitamin B 6 3 mg Folic acid 400 µg Vitamin B 12 25 µg Vitamin or Mineral Amount Biotin 30 µg Pantothenic acid 10 mg Calcium 220 mg Phosphorus 20 mg Iodine 150 µg Magnesium 50 mg Zinc 11 mg Selenium 55 µg Potassium 80 mg Lutein 250 µg Lycopene 300 µg Other minerals include copper, nickel, manganese, chromium, molybdenum, chloride, boron, silicon, and vanadium.
Physicians Health Study (PHS) 1982 1996: PHS I enrolled 22,071 male physicians in a trial by mail of aspirin and betacarotene in the prevention of CVD and cancer. 1997 present: PHS II enrolled 7,641 PHS I participants and 7,000 new physicians in a new trial. N = 14,641
Physicians Health Study II HR=0.92 (0.86-0.998) Source: Gaziano JM, et al. JAMA 2012; 308(18):1871.
Cancer Events by MVM Treatment Assignment Outcome Total cancer* 1290 1379 0.92 (0.86-0.998).04 Total epithelial cell cancer 1158 1244 0.92 (0.85-0.997).04 Total cancer minus prostate Active (n = 7317) Placebo (n = 7324) HR (95% CI) 641 715 0.88 (0.79-0.98).02 Prostate cancer 683 690 0.98 (0.88-1.09).76 Colorectal cancer 99 111 0.89 (0.68-1.17).39 Cancer mortality 403 456 0.88 (0.77-1.01).07 Total mortality 1345 1412 0.94 (0.88-1.02).13 P *For men aged 70, HR (95%CI) = 0.82 (0.72-0.93); p for interaction by age = 0.06. Source: Gaziano JM, et al. JAMA 2012; 308(18):1871.
HR=0.94 (0.87-1.02) HR=0.73 (0.56-0.96) Source: Gaziano JM, et al. JAMA 2012; 308(18):1871.
Source: Sesso HD, et al. JAMA 2012; 308(17):1751. Crude log-rank P =.69
Cardiovascular Events by Multivitamin Treatment Assignment Outcome Active (n = 7317) Placebo (n = 7324) HR (95% CI) P Major cardiovascular events 876 856 1.01 (0.91-1.10).91 Total MI 317 335 0.93 (0.80-1.09).39 MI death 27 43 0.61 (0.38-0.995).048 Total stroke 332 311 1.06 (0.91-1.23).48 Cardiovascular death 408 421 0.95 (0.83-1.09).47 Total mortality 1345 1412 0.94 (0.88-1.02).13 Source: Sesso HD, et al. JAMA 2012; 308(17):1751.
Physicians Health Study II Effect Modification by Age on Major Cardiovascular Events Baseline Characteristic Active (n = 7317) Placebo (n = 7324) HR (95% CI) P-value Interaction Age, years.04 50-59 136 109 1.27 (0.99-1.63) 60-69 244 225 1.09 (0.91-1.31) 70 496 522 0.91 (0.81-1.03) Source: Sesso HD, et al. JAMA 2012; 308(17):1751.
Conclusions Cocoa and multivitamins are promising interventions for prevention of CVD and cancer, but conclusive evidence for their efficacy is lacking. The proposed trial would be the first large-scale randomized clinical trial of cocoa in either men or women and the first large-scale trial of multivitamins in women, and will be exceptionally cost-effective. Thank You!