Multivitamins in the Prevention of Cardiovascular Disease in Men

Incomplete

Sesso HD, et al. "Multivitamins in the prevention of cardiovascular disease in men: the Physicians' Health Study II randomized controlled trial". JAMA. 2012. 308(17):1751-1760.
PubMed • Full text

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Clinical Question

In men at risk for cardiovascular disease, does the use of daily multivitamins reduce the risk of cardiovascular-related morbidity and mortality?

Bottom Line

In men at risk for cardiovascular disease, the use of daily multivitamins was not shown to prevent cardiovascular disease (CVD) or cardiovascular events including myocardial infarction (MI), stroke, or cardiovascular (CV) mortality. Due to the increased tablet burden, incurred cost, risk for potential side effects, and lack of evidence, the use of daily multivitamin supplements for prevention of cardiovascular disease in men is not recommended.

Major Points

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. Randomized clinical trials have tested the effect of high-dose individual vitamins and minerals with the vast majority showing no effect on CVD endpoints.

In this randomized, double-blind, placebo-controlled trial, 14,641 male physicians were given a once daily multivitamin or placebo and followed for a median of 11.2 years. The primary outcomes being addressed were major cardiovascular events and mortality. Ultimately, the study found that multivitamins do not work to prevent cardiovascular events or mortality in men who were at high risk.

The study’s findings are consistent with other studies done on the effects of multivitamins in cardiovascular disease. The study analyzed endpoints via self-reported information from the participants; this is subject to response bias. Additionally, the study does not mention how they assessed adherence.

Guidelines

• 2010 Dietary Guidelines stated that there is no evidence to support use of a daily multivitamin in disease prevention, including CVD.
• American Heart Association and American College of Cardiology (AHA/ACC) Guidelines do not address the use of multivitamins for prevention or treatment of CVD

Design

• Trial Type: randomized, double-blind, placebo-controlled trial, 2x2x2x2 factorial design
• N= 14,641
• Experimental n= 7,324 (daily multivitamin)
• Standard n= 7,317 (placebo)
• Setting: United States
• Enrollment years: Phase I (1997-1999), Phase II (1997-2001)
• Mean follow-up years: 11.2 years (ended in 2011), follow-up conducted by yearly questionnaires and calendar packs mailed to participants
• Analysis: intention to treat
• Primary Outcomes: Composite endpoint of major cardiovascular events, including nonfatal MI, nonfatal stroke, and CVD mortality. Secondary outcomes included MI and stroke individually.

Population

Inclusion Criteria

• Males physicians age 50 or older as identified by the American Medical Association (AMA)they were recruited via mail
• Agreed to stop current use of all multivitamins or supplements containing >100% RDA of vitamin E, vitamin C, B-carotene, or vitamin A
• History of MI, stroke, or cancer were eligible.

Exclusion Criteria

• History of cirrhosis or active liver disease, taking anticoagulants, or reported a serious illness that might preclude participation.

Baseline Characteristics (all comparisons are multivitamin vs placebo)

• Mean age: 64.2 years vs 64.3 years
• BMI: 3.4% vs. 3.4%
• Current cigarette smoker: 3.5% vs. 3.7%
• Exercise >1 time/ week: 62.2% vs. 60.7%

Interventions

Randomization via computer-generated list of random numbers, stratified according to age in blocks of 16

• Experimental: Participants were randomized into one of four groups to take one Centrum Silver or Vitamin E or Vitamin C or Beta Carotene daily
• Control: Take one placebo tab daily

Outcomes

Primary Outcomes

Composite endpoint of major CV events; defined as nonfatal MI, nonfatal stroke, and CVD mortality.

• Major CV events
  • No baseline history of CVD
    • Placebo (10.4%), Multivitamin (10.7%), Hazard ratio (HR) 1.02, 95% CI (0.92-1.13)
  • Baseline history of CVD
    • Placebo (33.8%), Multivitamin (34.8%), HR 0.96, 95% CI (0.75-1.22)

Secondary Outcomes

• Total MI
  • No baseline history of CVD
    • Placebo (4.3%), Multivitamin (4.1%), HR 0.93, 95% CI (0.79-1.09)
  • Baseline history of CVD
    • Placebo (8.8%), multivitamin (9.0%), HR 0.99, 95% CI (0.61-1.60)
• Total Stroke
  • No baseline history of CVD
    • Placebo (3.8%), Multivitamin (4.0%), HR 1.06, 95% CI (0.86-1.25)
  • Baseline history of CVD
    • Placebo (12.2%), Multivitamin (13.6%), HR 1.05, 95% CI (0.70-1.56)
• CVD mortality
  • No baseline history of CVD
    • Placebo (4.8%), Multivitamin (4.6%), HR 0.96, 95% CI (0.82-1.12)
  • Baseline history of CVD
    • Placebo (24.6%), Multivitamin (24.5%), HR 0.96, 95% CI (0.71-1.29)
• Total mortality
  • No baseline history of CVD
    • Placebo (17.8%), Multivitamin (16.8%), HR 0.95, 95% CI (0.88-1.03)
  • Baseline history of CVD
    • Placebo (47.4%), Multivitamin (47.6%), HR 0.90, 95% CI (0.73-1.11)

Adverse Events

• Skin rash
  • Multivitamin (29.0%), Placebo (27.3%), Number needed to harm (NNH) 59, HR 1.07, 95% CI (1.02-1.18)
• Epistaxis
  • Multivitamin (21.6%), Placebo (19.8%), NNH 56, HR 1.10, 95% CI (1.02-1.18)
• No significant effects on gastrointestinal (GI) symptoms (peptic ulcer, constipation, diarrhea, gastritis, and nausea), fatigue, drowsiness, skin discoloration, migraine, easy bruising or other bleeding.
• Minor bleeding was inconsistent, and could have been due to chance.
• Hematuria
  • Multivitamin (16.3%), Placebo (17.6%), NNT 76, HR 0.91, 95% CI (0.84-0.98)

Criticisms

Self-reported endpoints are subject to response bias. This can compromise the results of the study as certain measures are dependent on the honesty of the participants and their ability to correctly recall any events. Also, the study only analyzed the effects of multivitamins in prevention of CVD in healthy, nutrient sufficient individuals. This does not take into account another portion of the population that could potentially show benefit.

Funding

This study was supported by grants CA 097193, CA 34944, CA 40360, HL 26490, and HL 34595 from the NIH (Bethesda, Maryland) and an investigator-initiated grant from BASF Corporation (Florham Park, New Jersey). Study agents and packaging were provided by BASF Corporation and Pfizer (formerly Wyeth, American Home Products, and Lederle) (New York, New York), and study packaging was provided by DSM Nutritional Products Inc (formerly Roche Vitamins) (Parsippany, New Jersey).