Large Systematic Review of Vitamin and Antioxidant Supplements Finds No Impact on Risk of CVD

Abstract & Commentary

By Dónal P. O’Mathúna, PhD, Senior Lecturer in Ethics, Decision-Making & Evidence, School of Nursing and Human Sciences, Dublin City University, Ireland. Dr. O’Mathúna reports no financial relationships relevant to this field of study.

This article originally appeared in the April 2013 issue of Integrative Medicine Alert.

Synopsis: A systematic review and meta-analysis of 50 randomized controlled trials did not find that vitamin and antioxidant supplements reduce the risk of cardiovascular disease. Numerous subgroup analyses similarly found no benefit from daily supplementation, but also no adverse effects.

Source: Myung SK, et al. Efficacy of vitamin and antioxidant supplements in prevention of cardiovascular disease: Systematic review and meta-analysis of randomised controlled trials. BMJ 2013;346:f10. doi: 10.1136/bmj.f10.

This systematic review and meta-analysis focused on randomized, controlled trials (RCTs) of vitamin and antioxidant supplements for the prevention of cardiovascular disease. A number of previous meta-analyses of such supplementation have reached conflicting conclusions. In contrast, numerous epidemiological studies have found associations between fruit and vegetable intake and reduced risk of cardiovascular diseases. Multivitamin supplementation is commonly practiced and believed to be beneficial as a way of obtaining the benefits of fruit and vegetable consumption. Previous meta-analyses of RCTs had examined individual vitamins or antioxidants, while the meta-analysis reported here examined all supplements containing either vitamins and/or antioxidants, and also conducted several subgroup analyses.

A comprehensive database search yielded more than 2000 articles, of which 50 satisfied the predetermined inclusion criteria. These were RCTs lasting at least 6 months that reported on the efficacy of vitamin or antioxidant supplementation for the primary or secondary prevention of cardiovascular diseases. Of these, 45 were double-blinded while five were open-label trials. The included trials involved 294,478 participants who ranged in age from 49-82 years. Two trials were conducted in China and the rest in Western countries. Supplementation lasted between 6 months and 12 years, involving a wide range of different vitamins, antioxidants, and combinations. Manufacturers funded five of the trials, 42 were funded by public or independent organizations, and three did not report funding source.

Study quality was assessed using the Jadad scale, with the mean score for the 47 assessable trials being 4.3 out of 5 (range 2 to 5). Publication bias was not identified using either the Begg’s funnel plot or the Egger’s test. A fixed effects model was used for meta-analysis of all 50 trials and showed no impact of supplementation on the risk of major cardiovascular events (relative risk [RR] 1.00; 95% confidence interval [CI], 0.98-1.02). Subgroup meta-analysis where vitamins or antioxidants were given singly or in any combination showed no beneficial effects.

Several subgroup analyses were carried out with the majority finding no significant associations with risk of major cardiovascular events. These included meta-analyses by type of supplement, type of cardiac outcome, type of prevention (primary or secondary), methodological quality of trials, duration of treatment, funding source, or supplement provider. Beneficial effects were identified in three subgroup analyses. Low-dose vitamin B6 supplementation slightly decreased the risk of major cardiovascular events (RR 0.92; 95% CI, 0.85-0.99). Vitamin B6 and vitamin E supplementation reduced the risk of cardiovascular death (RR 0.91; 95% CI, 0.83-0.99) and myocardial infarction (RR 0.77; 95% CI, 0.65-0.91). However, these beneficial effects were only seen in trials where the pharmaceutical industry provided the supplements (but no further information was given on whether industry had any influence on the research protocol). In addition, when only high-quality trials were analyzed, these beneficial effects were not identified.

The reviewers concluded that, “In this large-scale meta-analysis of randomised controlled trials, we found no evidence to support the use of vitamin or antioxidant supplements for the primary or secondary prevention of major cardiovascular events.”

Commentary

The meta-analysis reported here satisfied the AMSTAR criteria for high methodological quality of systematic reviews.1 One limitation was their use of the Jadad scale to assess the methodological quality of the included RCTs. The reviewers acknowledged the criticisms of this tool as it places greater emphasis on the quality of the trial’s report rather than the risk of bias in the conduct of the trial. However, this tool is more convenient and efficient to use. Another limitation is the ages of the RCT participants, who were older than 49 years, and the locations of the studies, primarily in Western countries. This limits the generalizability of the findings for other populations.

Even with these limitations, this meta-analysis joins a growing list of meta-analyses of RCTs that have not found support for the use of vitamin and antioxidant supplements to prevent cardiovascular disease or cancer, or reduce overall mortality.2 However, the results conflict with the results of in vitro and animal studies, and highlight concerns about the applicability of these studies for clinical decision-making.

In spite of the widespread use of multivitamins, controversy has raged over their efficacy. The December 2012 issue of Integrative Medicine Alert reviewed the results of the Physicians’ Health Study II (PHSII).3 This 15-year, double-blind, RCT compared the effects of a multivitamin (Centrum Silver) with placebo on male physicians age 50 years or older. This limits the applicability of its results to this product, and there is debate over the best formulation for a multivitamin. The primary endpoints were incidence of cancer and major cardiovascular events, with secondary endpoints of site-specific cancers. The reviewed article reported on cancer endpoints, noting a statistically significant 8% reduction in the rate of total cancer in the multivitamin group compared to the placebo group. However, other RCTs have not found such beneficial effects, and hence national and international cancer prevention guidelines do not (as yet) recommend multivitamins for cancer prevention. Some of the reasons for this were reviewed in the commentary as it examined the strengths and weakness of PHSII, and the general challenges of conducting RCTs with multivitamins (particularly the impossibility of having a true placebo group since vitamins are readily available in people’s diets, but to varying degrees).

In another recent publication, the PHSII reported its findings for cardiovascular endpoints.4 These found no significant benefit from multivitamin use compared to placebo on major cardiovascular events (hazard ratio [HR] 1.01; 95% CI 0.91-1.10; P = 0.91). In addition, a daily multivitamin had no beneficial effects on total MI, total stroke, cardiovascular disease mortality, or total mortality.

In contrast, the January 2013 issue of Integrative Medicine Alert reviewed a cross-sectional study of the daily dietary intake of flavonoids on risk factors for coronary artery disease.5 The endpoints measured were blood pressure and arterial stiffness. The flavonoids were obtained primarily from wine, grapes, and berries, which are good sources of vitamins and antioxidants. The study found that higher intake of only the anthocyanin subclass of flavonoids was associated with significantly lower blood pressure and arterial stiffness.

These reports, coupled with the meta-analysis reported here, exemplify the conflicting results of studies examining the efficacy of multivitamins. They also point to some of the reasons for these different results and toward some ways to interpret these contradictory results for patients. Cross-sectional studies like the one reviewed in January use food frequency questionnaires to record people’s dietary consumption, while RCTs like the PHSII and those reviewed in the meta-analysis focus on a multivitamin intervention. They are, so to speak, examining apples and oranges. Multivitamin preparations are synthetically produced with controlled amounts of specific vitamins and other components. Questions abound over the combination of vitamins, the dose of each, their bioavailability, and how they have been manufactured and stored. In contrast, fruits and vegetables contain a wide variety of different natural products in varying proportions. Although many case-control and cohort studies of fruit and vegetable consumption find beneficial results, the RCTs of multivitamin products have tended to have less beneficial effects. The meta-analysis reported here is thus in keeping with this general trend.

While at first glance the results of these studies may appear to conflict, they are in keeping with current guidelines. Thus, consumption of fruit and vegetables is recommended as part of an overall healthy lifestyle to reduce the risk of cardiovascular disease. Consumption of daily multivitamin and antioxidant supplements is not part of such guidelines and is not warranted by the most recent meta-analysis of RCTs. It is not looking like a daily multivitamin is going to take the place of an apple a day.

References

1. Shea BJ, et al. Development of AMSTAR: A measurement tool to assess the methodological quality of systematic reviews. BMC Med Res Methodol 2007;7:10.

2. Myung SK, et al. Effects of antioxidant supplements on cancer prevention: Meta-analysis of randomized controlled trials. Ann Oncol 2010;21:166-179.

3. Quick M, Kiefer DK. Do multivitamins prevent cancer in men? Integrative Med Alert 2012;15:141-144.

4. Sesso HD, et al. Multivitamins in the prevention of cardiovascular disease in men: The Physicians’ Health Study II randomized controlled trial. JAMA 2012;308:1751-1760.

5. Marcolina ST. Dietary anthocyanins for coronary artery disease: Berry good results. Integrative Med Alert 2013; 16:3-6.