Multivitamins in the prevention of cardiovascular disease in men: the Physicians' Health Study II randomized controlled trial

Abstract

Context: Although multivitamins are used to prevent vitamin and mineral deficiency, there is a perception that multivitamins may prevent cardiovascular disease (CVD). Observational studies have shown inconsistent associations between regular multivitamin use and CVD, with no long-term clinical trials of multivitamin use.

Objective: To determine whether long-term multivitamin supplementation decreases the risk of major cardiovascular events among men.

Design, setting, and participants: The Physicians' Health Study II, a randomized, double-blind, placebo-controlled trial of a common daily multivitamin, began in 1997 with continued treatment and follow-up through June 1, 2011. A total of 14,641 male US physicians initially aged 50 years or older (mean, 64.3 [SD, 9.2] years), including 754 men with a history of CVD at randomization, were enrolled.

Intervention: Daily multivitamin or placebo.

Main outcome measures: Composite end point of major cardiovascular events, including nonfatal myocardial infarction (MI), nonfatal stroke, and CVD mortality. Secondary outcomes included MI and stroke individually.

Results: During a median follow-up of 11.2 (interquartile range, 10.7-13.3) years, there were 1732 confirmed major cardiovascular events. Compared with placebo, there was no significant effect of a daily multivitamin on major cardiovascular events (11.0 and 10.8 events per 1000 person-years for multivitamin vs placebo, respectively; hazard ratio [HR], 1.01; 95% CI, 0.91-1.10; P = .91). Further, a daily multivitamin had no effect on total MI (3.9 and 4.2 events per 1000 person-years; 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), or CVD mortality (5.0 and 5.1 events per 1000 person-years; HR, 0.95; 95% CI, 0.83-1.09; P = .47). A daily multivitamin was also not significantly associated with total mortality (HR, 0.94; 95% CI, 0.88-1.02; P = .13). The effect of a daily multivitamin on major cardiovascular events did not differ between men with or without a baseline history of CVD (P = .62 for interaction).

Conclusion: Among this population of US male physicians, taking a daily multivitamin did not reduce major cardiovascular events, MI, stroke, and CVD mortality after more than a decade of treatment and follow-up.

Trial registration: clinicaltrials.gov Identifier: NCT00270647.

Figure 1

Flow diagram of participants from screening to completion of the multivitamin component of the Physicians' Health Study (PHS) II.* * Those classified as “unforwardable” were not able to be contacted by mail.

Figure 2

Cumulative incidence rates of (part A) major cardiovascular events, (part B) total myocardial infarction, and (part C) total stroke by randomized multivitamin assignment in the Physicians' Health Study II. * The reduction in the number at risk from 10 to 11 years reflects the two phases of PHS II recruitment; PHS I physicians initially enrolled in Phase 1 starting in 1997 were followed longer on average (mean of 13 years) than new physicians recruited in Phase 2 starting in 1999 (mean of 10 years). Crude log-rank P=0.69 for major cardiovascular events, P=0.44 for total myocardial infarction, and P=0.44 for total stroke.

Figure 2

Cumulative incidence rates of (part A) major cardiovascular events, (part B) total myocardial infarction, and (part C) total stroke by randomized multivitamin assignment in the Physicians' Health Study II. * The reduction in the number at risk from 10 to 11 years reflects the two phases of PHS II recruitment; PHS I physicians initially enrolled in Phase 1 starting in 1997 were followed longer on average (mean of 13 years) than new physicians recruited in Phase 2 starting in 1999 (mean of 10 years). Crude log-rank P=0.69 for major cardiovascular events, P=0.44 for total myocardial infarction, and P=0.44 for total stroke.

Figure 2

Cumulative incidence rates of (part A) major cardiovascular events, (part B) total myocardial infarction, and (part C) total stroke by randomized multivitamin assignment in the Physicians' Health Study II. * The reduction in the number at risk from 10 to 11 years reflects the two phases of PHS II recruitment; PHS I physicians initially enrolled in Phase 1 starting in 1997 were followed longer on average (mean of 13 years) than new physicians recruited in Phase 2 starting in 1999 (mean of 10 years). Crude log-rank P=0.69 for major cardiovascular events, P=0.44 for total myocardial infarction, and P=0.44 for total stroke.

Figure 3

Hazard ratios (HRs) and 95% confidence intervals (CIs) of major cardiovascular events among 13,887 men with no baseline history of cardiovascular disease (part A; Primary Prevention) and 754 men with a baseline history of cardiovascular disease (part B; Secondary Prevention) in the Physicians' Health Study II. * Crude log-rank P=0.71 for 13,887 men with no baseline history of cardiovascular disease, and crude log-rank P=0.94 for 754 men with a baseline history of cardiovascular disease.