Vitamins E and C in the Prevention of Cardiovascular Disease in Men

The Physicians' Health Study II Randomized Controlled Trial

Howard D. Sesso, ScD, MPH; Julie E. Buring, ScD; William G. Christen, ScD; Tobias Kurth, MD, ScD; Charlene Belanger, MA;Jean MacFadyen, BA; Vadim Bubes, PhD; JoAnn E. Manson, MD, DrPH; Robert J. Glynn, ScD; J. Michael Gaziano, MD, MPH JAMA. 2008;300(18):(doi:10.1001/jama.2008.600).

Context  Basic research and observational studies suggest vitamin E or vitamin C may reduce the risk of cardiovasculardisease. However, few long-term trials have evaluated men at initially low risk of cardiovascular disease, and no previous trial in men has examined vitamin C alone in the prevention of cardiovascular disease.

Objective  To evaluate whether long-term vitamin E or vitamin C supplementation decreases the risk of major cardiovascular events among men.

Design, Setting, and Participants  The Physicians' Health Study II was a randomized, double-blind, placebo-controlled factorial trial of vitamin E and vitamin C that began in 1997 and continued until its scheduled completion on August 31, 2007. There were 14 641 US male physicians enrolled, who were initially aged 50 years or older, including 754 men (5.1%) with prevalent cardiovascular disease at randomization.

Intervention  Individual supplements of 400 IU of vitamin E every other day and 500 mg of vitamin C daily.

Main Outcome Measures  A composite end point of major cardiovascular events (nonfatal myocardial infarction, nonfatal stroke, andcardiovascular disease death).

Results  During a mean follow-up of 8 years, there were 1245 confirmed major cardiovascular events. Compared with placebo, vitamin E had no effect on the incidence of major cardiovascular events (both active and placebo vitamin E groups, 10.9 events per 1000 person-years; hazard ratio [HR], 1.01 [95% confidence interval {CI}, 0.90-1.13]; P = .86), as well as total myocardial infarction (HR, 0.90 [95% CI, 0.75-1.07];P = .22), total stroke (HR, 1.07 [95% CI, 0.89-1.29]; P = .45), and cardiovascular mortality (HR, 1.07 [95% CI, 0.90-1.28]; P = .43). There also was no significant effect of vitamin C on major cardiovascular events (active and placebo vitamin E groups, 10.8 and 10.9 events per 1000 person-years, respectively; HR, 0.99 [95% CI, 0.89-1.11]; P = .91), as well as total myocardial infarction (HR, 1.04 [95% CI, 0.87-1.24]; P = .65), total stroke (HR, 0.89 [95% CI, 0.74-1.07]; P = .21), and cardiovascular mortality (HR, 1.02 [95% CI, 0.85-1.21]; P = .86). Neither vitamin E (HR, 1.07 [95% CI, 0.97-1.18]; P = .15) nor vitamin C (HR, 1.07 [95% CI, 0.97-1.18]; P = .16) had a significant effect on total mortality but vitamin E was associated with an increased risk of hemorrhagic stroke (HR, 1.74 [95% CI, 1.04-2.91]; P = .04).

Conclusions  In this large, long-term trial of male physicians, neither vitamin E nor vitamin C supplementation reduced the risk of major cardiovascular events. These data provide no support for the use of these supplements for the prevention of cardiovascular disease in middle-aged and older men.

Trial Registration  clinicaltrials.gov Identifier: NCT00270647