Effects of Vitamin D On All-Cause Mortality in Heart Failure
Alan Gaby, MD
Author: Zittermann A, et al.
Reference: Effect of vitamin D on all-cause mortality in heart failure (EVITA): a 3-year randomized clinical trial with 4000 IU vitamin D daily. Eur Heart J 2017;38:2279-2286.
Design: Randomized, double-blind, placebo-controlled trial.
Participants: Four hundred patients (median age, 55 years) with heart failure (New York Heart Association class II or III) and a serum 25-hydroxyvitamin D (25[OH]D) level below 30 ng/ml.
Study Medication and Dosage: Vitamin D (4,000 IU per day) or placebo for 3 years.
Primary Outcome Measures: The primary outcome measure was all-cause mortality. Secondary outcomes included hospitalization, need for implantation of a mechanical circulatory support device, heart transplantation, and hypercalcemia.
Key Findings: At baseline, the median 25(OH)D level was 13 ng/ml; this increased to around 40 ng/ml in the vitamin D group and did not change in the placebo group. The mortality rate was nonsignificantly higher by 9.5% in the vitamin D group than in the placebo group (19.6% vs. 17.9%; p = 0.73). The proportion of patients who needed implantation of a mechanical circulatory support device was significantly higher in the vitamin D group than in the placebo group (15.4% vs. 9.0%; p = 0.03). Other secondary endpoints were similar between groups.
Practice Implications: For the past decade or so, some researchers and practitioners have been recommending routine use of relatively large doses of vitamin D (such as 4,000-10,000 IU per day for prolonged periods of time). They claim that supplementing with enough vitamin D to achieve a purported “optimal” serum 25(OH)D level (such as 36-40 ng/ml or higher) can produce a wide range of health benefits (the average vitamin D dosage needed to achieve a 25(OH)D concentration above 40 ng/ml is about 6,000 IU per day for normal-weight individuals and 7,000 IU per day for overweight individuals). The idea that we should aim for 25(OH)D levels of 36-40 ng/ml or higher is based almost entirely on observational studies, which found that these levels were associated with better health outcomes. However, associations do not prove causation. Serum 25(OH)D levels decline in response to inflammation, sometimes by 40% or more. In patients with one of the many health conditions that have an inflammatory component, serum 25(OH)D may be an unreliable indicator of vitamin D status. The observed association between higher 25(OH)D levels and better health might have nothing to do with vitamin D; it could simply indicate that chronic inflammation is associated with poor health.
A growing body of evidence from randomized controlled trials indicates one of the following: 1) high doses of vitamin D (such as 4,000 IU per day or more) are not more effective, and may actually be less effective in some instances, than moderate doses of the vitamin (such as 800-1,200 IU per day), or 2) high doses of vitamin D are not more effective than placebo. In the present study, supplementation of heart failure patients with 4,000 IU per day of vitamin D did not decrease (and may have increased) mortality, and significantly increased the need for implantation of a mechanical circulatory support device. Heart failure is associated with chronic inflammation, so the very low baseline 25(OH)D levels seen in these patients may not have been indicative of severe vitamin D deficiency. Based on the results of this study, it would seem that moderate doses of vitamin D would be safer for heart failure patients than large doses, even if these moderate doses do not increase 25(OH)D to a level that the laboratory considers normal.