Medical Grand Rounds

Vitamin D and the heart: Why we need large-scale clinical trials

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Randomized clinical trials

A meta-analysis of 18 randomized trials5 of vitamin D supplementation (300–2,000 IU/day, mean 528 IU/day vs placebo), including 57,311 participants, evaluated the rate of death from all causes and found a modest but significant reduction in risk (relative risk 0.93, 95% confidence interval [CI] 0.87–0.99). These were generally trials looking at fracture rates or physical performance, and a dose-response relationship was not evident. A recent systematic review of randomized controlled trials of vitamin D1 that included cardiovascular disease as a secondary outcome found a pooled relative risk for cardiovascular disease of 0.90 (95% CI 0.77–1.05) for vitamin D supplementation compared with placebo and 1.04 (95% CI 0.92–1.18) for combination vitamin D plus calcium supplementation vs placebo.1 Two individual trials are discussed below.

Trivedi et al6 randomized 2,686 British men and women to vitamin D3 100,000 IU given every 4 months over 5 years (equivalent to 800 IU/day) or placebo. The relative risk of cardiovascular events was 0.90 (95% CI 0.77–1.06) and of cardiovascular deaths 0.84 (95% CI 0.65–1.10). Although the results were promising, the trial was designed to assess fracture risk and was not large enough for the differences in cardiovascular outcomes to reach statistical significance.

The Women’s Health Initiative,7,8 which included 36,282 postmenopausal women aged 50 to 79, tested combined vitamin D3 (400 IU/day) with calcium (1,000 mg/day) vs placebo. No benefit was seen for preventing coronary events or stroke, which may be due to the low dosage of vitamin D. The hazard ratio for coronary disease was 1.04 (0.92–1.18). Regarding mortality, the hazard ratio for cardiovascular death was 0.92, for cerebrovascular death 0.89, for cancer death 0.89, and for other deaths 0.95. None of these hazard ratios reached statistical significance.


As is probably true for everything in biological systems, there apparently is an optimal level of intake to meet vitamin D needs.

The Framingham Offspring Study,2 which found a higher risk with vitamin D deficiency, also found a suggestion of a threshold. Participants who had levels of 50 to 65 nmol/L had the lowest risk. Higher levels did not confer lower risk and even suggested a slight upturn.

Evidence from the Women’s Health Initiative8 also indicates that high dosages may not be better than moderate dosages. The meta-analysis of vitamin D and all-cause mortality5 found a relative risk of 0.93, but one of the largest studies in that meta-analysis tested only 400 IU a day and found a similar relative risk of 0.91 (95% confidence interval, 0.83–1.01).

Moreover, the NHANES study found that with increasing serum 25-hydroxyvitamin D3 levels, the risk of all-cause mortality fell until about 100 nmol/L, but then plateaued and even increased with higher serum levels.4


In VITAL, the investigators aim to recruit 20,000 healthy men (age 60 and older) and women (65 and older) who are representative of the US population ( Because it is a primary prevention trial, people with a known history of cardiovascular disease or cancer will be excluded. Participants will be randomized to receive either 2,000 IU of vitamin D3 per day or placebo. Each group will be further randomized to receive either 1 g per day of fish oil (combined eicosapentaenoic acid [EPA] and docosahexaenoic acid [DHA]) or placebo. The mean treatment period will be 5 years. Recruitment began in early 2010.

Blood will be collected in about 80% (ideally 100%) of participants, with follow-up blood collection in at least 2,000.

Primary aims of the trial are to test whether vitamin D3 and the omega-3 fatty acids reduce the risk of total cancer and major cardiovascular events (a composite of myocardial infarction, stroke, and death due to cardiovascular events).

Secondary aims are to test whether these agents lower the risk of:

  • Site-specific cancer, including colorectal, breast, and prostate cancer, and the total cancer mortality rate
  • An expanded composite outcome including myocardial infarction, stroke, cardiovascular death, coronary artery bypass grafting, percutaneous coronary intervention, and its individual components.

Tertiary aims are to explore whether vitamin D3 and omega-3 fatty acids have additive effects on the primary and secondary end points. The trial will also explore whether the effects of vitamin D3 and omega-3 fatty acids on cancer and cardiovascular disease vary by baseline blood levels of these nutrients, and whether race, skin pigmentation, or body mass index modify the effects of vitamin D3.

Ancillary studies will assess the effect of the interventions on risk of diabetes, hypertension, cognitive decline, depression, fracture, infections, respiratory disorders, and autoimmune diseases. The primary sponsor of this trial is the National Cancer Institute, and the secondary sponsor is the National Heart, Lung and Blood Institute. Other institutes and agencies also are cosponsors of the study.

The timing of VITAL is optimal

There is a limited window of opportunity for conducting a randomized clinical trial: the evidence must be strong enough to justify mounting a very large trial with enough power to look at cardiovascular events and cancer, but the evidence must not be so strong that it would be unethical to have a placebo group. Thus, there must be a state of equipoise. Our trial allows the study population to have a background intake of vitamin D that is currently recommended by national guidelines. Therefore, even the placebo group should have adequate intake of vitamin D.

The growing use of vitamin D supplementation by the public underscores the need for conclusive evidence of its benefits and risks. No previous large-scale randomized clinical trial has tested moderate to high doses of vitamin D for the primary prevention of cancer and cardiovascular disease.

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