1. A Randomized Trial of a Multivitamin in the Prevention of Cardiovascular Disease in Men: The Physicians’ Health Study II HD Sesso, WC Christen, V Bubes, JP Smith, J MacFadyen, M Schvartz, JE Manson, RJ Glynn, JE Buring, JM Gaziano Division of Preventive Medicine Brigham and Women’s Hospital Boston, MA Funding: NIH (NCI, NHLBI, NIA, and NEI) and an investigator-initiated grant from BASF Corporation. Pills and/or packaging were provided by BASF, Pfizer and DSM Nutritional Products.

2. Background More than half of US adults take vitamin supplements, with common multivitamins (MVM) the most widely used. Basic research suggests that some components of MVMs might reduce the risk of cardiovascular disease (CVD). Observational studies have not clearly demonstrated an association between MVMs and a lower risk of CVD. There are no large-scale, long-term randomized trials of a MVM in the prevention of CVD and other chronic diseases.

3. Physicians’ Health Study (PHS) 1982 – 1996: PHS I enrolled 22,071 male physicians in a trial by mail of aspirin and beta-carotene 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 by mail.

4. Randomized, double-blind, placebo- controlled, factorial trial conducted by mail among 14,641 male physicians aged 50 years and older. Evaluated the long-term risks and benefits of vitamin E, vitamin C, and a multivitamin (Centrum Silver daily) Primary outcomes: CVD and cancer Secondary outcomes: Eye disease and cognitive function Physicians’ Health Study II: Design

5. Phase I: Mailed Invitations to 18,763 PHS I participants Phase II: Mailed invitations to 254,597 new physicians 11,128 Enrolled in a Placebo Run-in 14,641 Randomized Participants Active Vitamin EVitamin E Placebo Active Vitamin C Vitamin C Placebo Active Multi- Vitamin Multi- Vitamin Placebo Active Multi- Vitamin Multi- Vitamin Placebo Active Multi- Vitamin Multi- Vitamin Placebo Active Multi- Vitamin Multi- Vitamin Placebo Active Vitamin C Vitamin C Placebo PHYSICIANS’ HEALTH STUDY II RANDOMIZATION SCHEME 7,6417,000

6. Monthly Calendar Pack

8. Physicians’ Health Study II: Follow-up Mean follow-up was 11.2 years, with a total of more than 164,000 person-years of follow-up. MVM compliance: 77% at 4 years, 72% at 8 years, and 67% at study end Primary CVD Outcome: Major cardiovascular events (nonfatal myocardial infarction (MI), nonfatal stroke, and CVD death) Other CVD Outcomes: Total and fatal MI, total and fatal stroke, ischemic and hemorrhagic stroke, CVD mortality, and total mortality

9. Age, mean (SD) 64.2 (9.1)64.3 (9.2) BMI, mean (SD) 25.9 (3.4)26.0 (3.4) Current smoker, % 3.53.7 Exercise ≥1 time/wk, % 62.260.7 Current aspirin use, % 77.577.3 History of hypertension, % 41.842.7 History of high cholesterol, % 36.037.3 History of diabetes, % 6.55.9 Plasma TC, mean (SD) 203.5 (35.5)203.7 (36.0) Fruits & vegetables, servings/d (IQR) 4.26 (2.95-5.75)4.19 (2.94-5.77) Whole grains, servings/d (IQR) 1.13 (0.49-2.00)1.07 (0.49-1.99) Active (n = 7317) Placebo (n = 7324) JAMA 2012 In press Baseline Characteristics by Multivitamin Treatment Assignment P>.05 for all comparisons between multivitamin and placebo groups

10. JAMA 2012 In press Crude log-rank P =.69

11. JAMA 2012 In press Crude log-rank P =.44

12. Major cardiovascular events 8768561.01 (0.91-1.10).91 Total MI 3173350.93 (0.80-1.09).39 MI death 27430.61 (0.38-0.995).048 Total stroke 3323111.06 (0.91-1.23).48 Stroke death 89761.16 (0.85-1.58).34 Ischemic stroke 2772501.10 (0.92-1.30).29 Hemorrhagic stroke 49451.08 (0.72-1.63).69 Cardiovascular death 4084210.95 (0.83-1.09).47 Total mortality 134514120.94 (0.88-1.02).13 Cardiovascular Events by Multivitamin Treatment Assignment Active (n = 7317) Placebo (n = 7324) HR (95% CI) Outcome JAMA 2012 In press P

13. Crude log-rank P =.71Crude log-rank P =.94

14. Age, years.04 50-591361091.27 (0.99-1.63) 60-692442251.09 (0.91-1.31) ≥704965220.91 (0.81-1.03) Smoking status.49 Never4124140.95 (0.83-1.09) Former4194011.06 (0.92-1.21) Current45411.11 (0.72-1.70) Current aspirin use.07 No1991691.20 (0.98-1.48) Yes6546630.96 (0.86-1.07) History of high cholesterol.65 No5114721.03 (0.91-1.16) Yes3533690.98 (0.85-1.13) Effect Modification by Selected Baseline Characteristics on Major Cardiovascular Events Active (n = 7317) Placebo (n = 7324) HR (95% CI)Baseline Characteristic JAMA 2012 In press P int

15. History of diabetes.33 No7657401.02 (0.92-1.13) Yes1091160.89 (0.68-1.16) History of CVD.62 No7457281.02 (0.92-1.13) Yes1311280.96 (0.75-1.22) Plasma TC ≥240 mg/dL.77 No4574431.02 (0.89-1.16) Yes83821.07 (0.79-1.46) Fruit and vegetable intake.32 <4 servings/d3303081.09 (0.93-1.27) 4 to <7 servings/d3183000.99 (0.85-1.17) ≥7 servings/d1071200.87 (0.67-1.13) Effect Modification by Selected Baseline Characteristics on Major Cardiovascular Events Active (n = 7317) Placebo (n = 7324) HR (95% CI)Baseline Characteristic JAMA 2012 In press P int

16. Total cancer 129013790.92 (0.86-0.998).04 Total epithelial cell cancer 115812440.92 (0.85-0.997).04 Prostate cancer 6836900.98 (0.88-1.09).76 Total cancer minus prostate 6417150.88 (0.79-0.98).02 Cancer mortality 4034560.88 (0.77-1.01).07 Total mortality 134514120.94 (0.88-1.02).13 By baseline history of cancer Yes (n=1312) 951260.73 (0.56-0.96).02 No (n=13329) 119512530.94 (0.87-1.02).15 Cancer Events by Multivitamin Treatment Assignment Active (n = 7317) Placebo (n = 7324) HR (95% CI) Outcome JAMA 2012; Online October 17, 2012 P

17. Conclusions PHS II is the only large-scale randomized trial testing long-term MVM use, finding no effect on major cardiovascular events in men. The main reason to take a daily MVM remains to prevent vitamin and mineral deficiency. The decision to take a MVM should also consider its modest beneficial effects on cancer. We will be providing additional trial results for the effects of a MVM on other important outcomes along with extending follow-up of the PHS II cohort.

18. HD Sesso and coauthors Multivitamins in the Prevention of Cardiovascular Disease in Men: The Physicians’ Health Study II Randomized Controlled Trial Available at www.jama.com jamanetwork.com