Journal ClubHallie LeePharmD Candidate 2013Mercer University COPHSPHA 618 Geriatrics-Continuous Care

Multivitamins in the Prevention of Cardiovascular Disease in Men; The Physicians’ Health

Study II Randomized Controlled Trial

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)

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

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.

Base

line

Chara

cteristics

MethodsPrimary endpoint:

Major cardiovascular events (nonfatal MI, nonfatal stroke, and CVD mortality) Secondary

endpoints:

MI and Stroke individually

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

Results: Cumulative Incidence Curves • A summary curve showing the cumulative failure

rates over time due to a particular cause

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

Sta

tistics 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 point stratified 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 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

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

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

Conclu

sion

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

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

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.