Effect of Baseline Nutritional Status on Long-term Multivitamin Use and Cardiovascular Disease Risk: A Secondary Analysis of the Physicians' Health Study II Randomized Clinical Trial

JAMA Cardiol. 2017 Jun 1;2(6):617-625. doi: 10.1001/jamacardio.2017.0176.


Importance: Long-term multivitamin use had no effect on risk of cardiovascular disease (CVD) in the Physicians' Health Study II. Baseline nutritional status may have modified the lack of effect.

Objective: To investigate effect modification by various baseline dietary factors on CVD risk in the Physicians' Health Study II.

Design, setting, and participants: The Physicians' Health Study II was a randomized, double-blind, placebo-controlled trial testing multivitamin use (multivitamin [Centrum Silver] or placebo daily) among US male physicians. The Physicians' Health Study II included 14 641 male physicians 50 years or older, 13 316 of whom (91.0%) completed a baseline 116-item semiquantitative food frequency questionnaire and were included in the analyses. This study examined effect modification by baseline intake of key foods, individual nutrients, dietary patterns (Alternate Healthy Eating Index and Alternate Mediterranean Diet Score), and dietary supplement use. The study began in 1997, with continued treatment and follow-up through June 1, 2011.

Interventions: Multivitamin or placebo daily.

Main outcomes and measures: Major cardiovascular events, including nonfatal myocardial infarction, nonfatal stroke, and CVD mortality. Secondary outcomes included myocardial infarction, total stroke, CVD mortality, and total mortality individually.

Results: In total, 13 316 male physicians (mean [SD] age at randomization, 64.0 [9.0] years in those receiving the active multivitamin and 64.0 [9.1] years in those receiving the placebo) were observed for a mean (SD) follow-up of 11.4 (2.3) years. There was no consistent evidence of effect modification by various foods, nutrients, dietary patterns, or baseline supplement use on the effect of multivitamin use on CVD end points. Statistically significant interaction effects were observed between multivitamin use and vitamin B6 intake on myocardial infarction, between multivitamin use and vitamin D intake on CVD mortality, and between multivitamin use and vitamin B12 intake on CVD mortality and total mortality. However, there were inconsistent patterns in hazard ratios across tertiles of each dietary factor that are likely explained by multiple testing.

Conclusions and relevance: The results suggest that baseline nutritional status does not influence the effect of randomized long-term multivitamin use on major CVD events. Future studies are needed to investigate the role of baseline nutritional biomarkers on the effect of multivitamin use on CVD and other outcomes.

Trial registration: clinicaltrials.gov Identifier: NCT00270647.

Publication types

  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Animals
  • Cardiovascular Diseases / mortality*
  • Dairy Products
  • Diet*
  • Dietary Supplements
  • Double-Blind Method
  • Fishes
  • Fruit
  • Humans
  • Male
  • Middle Aged
  • Myocardial Infarction / epidemiology*
  • Nutritional Status*
  • Red Meat
  • Stroke / epidemiology*
  • Vegetables
  • Vitamins / therapeutic use*
  • Whole Grains


  • Vitamins

Associated data

  • ClinicalTrials.gov/NCT00270647