Journal Club

1. Multivitamins in the Prevention of Cardiovascular Disease in Men; The Physicians’ Health Study II Randomized Controlled Trial Journal Club Hallie Lee PharmD Candidate 2013 Mercer University COPHS PHA 618 Geriatrics-Continuous Care

2. Introduction: The PHS • PHS = Physicians’ Health Study II • Multivitamins,the most common supplement taken by US adults, are used to prevent vitamin and mineral deficiency • Perception that they may prevent cardiovascular disease • Observational studies have shown inconsistent associations • There are no long-term clinical trials of their use for CVD • TO DETERMINE WHETHER LONG-TERM MULTIVITAMIN SUPPLEMENTATION DECREASES THE RISK OF MAJOR CARDIOVASCULAR EVENTS AMONG MEN (Results for cancer, eye disease, and cognitive decline are to be published separately)

3. Methods • Randomized, double-blind, placebo-controlled 2x2x2x2 factorial trial of common daily multivitamin • Phase 1: July 1997 • 18,763 men from PHS I • Phase 2: July 1999 • By July 2011 42,165 recruited • In total 14,641 male US physicians initially aged 50 • 754 with a history of CVD at randomization

4. Methods • Stratified by age, prior cancer or CVD, & PHS I assignment • Multivitamin • Vitamin E • Vitamin C • Beta carotene • Exclusion Criteria • History of cirrhosis or acute liver disease • Taking anticoagulants • Reported serious illness • Willing to forgo current use of multivitamins or supplements with >100% the RDA Funded by National Institutes of Health, BASF Corp., Pfizer, and DSM Nutritional Products Inc.

5. Baseline Characteristics

6. Methods • Primary endpoint: Major cardiovascular events (nonfatal MI, nonfatal stroke, and CVD mortality) • Secondary endpoints: MI and Stroke individually

7. Results • Rates of major CV events: • 11.0 per 1000 person-years in the multivitamin group • 10.8 per 1000 person-years in the placebo group • Men taking a daily multivitamin experienced no benefit for the primary end point of major CV events (HR, 1.01; 95% CI, 0.91- 1.10; P = .91) • Lack of significant benefit for the secondary end points • Total MI (3.9 and 4.2 events per 1000 person-years for multivitamin and placebo, respectively; HR, 0.93; 95% CI, 0.80-1.09; P = .39) • Total stroke (4.1 and 3.9 events per 1000 person-years; HR, 1.06; 95% CI, 0.91-1.23; P = .48) compared to placebo

8. Results: Cumulative Incidence Curves • A summary curve showing the cumulative failure rates over time due to a particular cause

9. Results Subgroup analyses examined whether baseline clinical, lifestyle, familial, biochemical, and dietary risk factors for CVD, along with the other randomized PHS II interventions, modified the effect of a daily multivitamin on major cardiovascular events Suggestion of a differential effect across age groups with possible differences among men aged 50 to 59 years and men 70 years or older No other evidence was found of effect modification by baseline risk factors on major CV events

10. The PHS II was estimated to have 80% power to detect a 12% reduction in the primary end point of major CV events • Primary analyses were based on the intention-to-treat principle • All analyses performed using SAS version 9.2 (SAS Institute Inc) and S-Plus (Insightful Corp), with statistical significance set at P <.05 using 2-sided tests • Cox proportional hazards models estimated hazard ratios (HRs) and 95% CIs • Each pre-specified end pointstratified on the presence of CVD at randomization and adjusted for PHS II study design variables, including age, PHS cohort (original PHS I participant, new PHS II participant), and randomized vitamin E, vitamin C, and beta carotene assignments Statistics

11. Statistics • Relative Risk/Hazard Ratio • (876/7317) / (856/7324) = 1.01 • Relative Risk Reduction • 1- 1.01 = 0.01 • Absolute Risk Reduction • (856/7324) – (876/7317) = 0.003 • Number Needed to Treat • 1/0.003 = 333.33 • Odds Ratio • (876/6441) / (856/6468) = 1.03

12. Statistics: A look at “Power” • Power is defined by beta () • Indicates the probability of the statistical test detecting significant differences when they exist • Analogous to sensitivity • Defined as 1 -  • Power of 80% is minimal • Power of  90% is ideal • A power of 80% means there is a 20% chance of a type II error • To falsely conclude that no significant difference exists between populations/samples • Due to chance or small sample size

13. Power Higher power is achieved by increasing the sample size Often overlooked by researchers Tabulated values and formulas are available for calculating the required sample size The smaller the difference between two interventions, the larger the sample size needed

14.  DAILY MULTIVITAMIN SUPPLEMENTATION DID NOT REDUCE THE RISK OF MAJOR CARDIOVASCULAR EVENTS • Whether to take a daily multivitamin requires consideration of an individual’s nutritional status, because the aim of supplementation is to prevent vitamin and mineral deficiency, plus consideration of other potential effects, including a modest reduction in cancer and other important outcomes in PHS II that will be reported separately Conclusion

15. Discussion • Limitations • Only one multivitamin formulation • Study population was confined to middle-aged and older, predominantly white, male physicians • Long-term multivitamin use may be more effective when initiated earlier in life to counter the initiation and progression of atherosclerosis that often begins at an earlier age • No recommendation or change in practice should be made based on the information found in this trial • Additional trials are necessary • Class Ib level of evidence

16. References Sesso H., Christen W., Bubes V., et al. Multivitamins in the Prevention of Cardiovascular Disease in Men; The Physicians’ Health Study II Randomized Controlled Trial. JAMA November 7, 2012; 308(17):1751-1760.