By searching databases (PubMed, Embase, the Cochrane Library, Scopus, CINAHL, and ClinicalTrials.gov) and hand searching relevant bibliographies, we identified 2240 articles (fig 1). After excluding 573 duplicated articles, two of authors independently reviewed and excluded 1593 articles that did not satisfy the predetermined selection criteria based on each article’s title and abstract. We reviewed the full texts of the 74 remaining articles and excluded 24 articles (16 were identical trials within the same population; five were not related to the subject of this study; two were replies or comments; and one reported insufficient data). A total of 5011
trials were included in the final analysis. The full details of all included trials are in appendix 1. The 50 trials included 294
478 participants with 156
663 in intervention groups and 137
815 in control groups. In the trials reporting age, the mean age of the participants ranged from 49 to 82. The year of publication of the included trials ranged between 1989 and 2012, spanning 23 years. Twelve trials were conducted in the United State, four in the United Kingdom, three in Finland, three in France, three in Italy, two in Canada, two in Israel, two in Australia, two in China, two in Germany, two in Norway, one in Sweden, one in Switzerland, one in the Netherlands, one in US/Canada, one in US/Canada/Scotland), one in Germany/the Netherlands, one in Canada/US, one in 13 countries, and one in 20 countries. The range of supplementation and follow-up periods was 6 months to 12 years. The number of participants ranged from 61 to 39
Fig 1 Flow diagram for identification of relevant clinical trials examining effect of vitamins and supplements in prevention of cardiovascular disease
Among the 50 trials, 30 were primary prevention trials (general populations, smokers and workers exposed to asbestos, patients with oesophageal dysplasia, male physicians, patients with non-melanoma skin cancer, postmenopausal women, patients undergoing chronic haemodialysis, patients with end stage renal disease, ambulatory elderly women with vitamin D insufficiency, patients with chronic renal failure, older people with femoral neck fractures, patients with diabetes mellitus, elderly women with a low serum 25-hydroxyvitamin D concentration, health professionals, people with a high fasting plasma total homocysteine concentration, or kidney transplant recipients), and 20 were secondary prevention trials (patients with cardiovascular disease, coronary heart disease, acute myocardial infarction, unstable angina, transient ischaemic attack, stroke, angiographically proved coronary atherosclerosis, vascular disease, or aortic valve stenosis).
Forty five trials were randomised, double blind, placebo controlled trials, and five were open label, randomised controlled trials. All vitamin or antioxidant supplements and placebos were administered orally either singly or in combination with other vitamin or antioxidant supplements.
The dose regimens used in each trial were as follows: vitamin A (10
000 or 25
000 IU daily), vitamin B6
(3, 6, 10, 12.5, 25, 40, 48, 50, or 100 mg daily; 20 mg three times weekly), vitamin B12
(0.4, 0.5, 1, or 2 mg daily; 6, 18, 20, 60, or 400 µg daily; 50 µg three times weekly), vitamin C (60, 120, 180, 250, 500, or 1000 mg daily), vitamin D (800 or 1000 IU daily; 200 IU twice daily; 400 IU twice daily; 300 IU daily and 100 IU daily; 100
000 IU every four months), vitamin E (60, 200, 400, 600, 800 IU daily; 400 or 600 IU alternate day; 400 IU twice daily; 30, 50, 300, 600 mg daily), β carotene (6, 15, 20, 25, 30, or 50 mg daily; 50 mg alternate day), folic acid (560 or 800 µg daily; 0.5, 0.8, 1, 1.2, 2, 2.5, 5, 15, or 40 mg daily; 5 mg three times weekly), and selenium (50, 75, 100, 122, or 122 µg daily).
Thirty nine trials used vitamin supplements only, and 22 trials used antioxidant supplements only. The additional nutritional supplements or drugs used in each trial were aspirin (325 mg daily); coenzyme Q10 (100 mg daily); calcium (93 mg daily) with or without hormone replacement therapy; application of a sun protection factor 15+ sunscreen; ramipril (angiotensin converting enzyme inhibitor; with or without aspirin (100 mg daily); zinc (20 mg daily); multivitamins and minerals; calcium carbonate (500 mg twice daily); calcium (1000 mg daily); calcium citrate (1000 mg daily); omega 3 fatty acids (eicosapentaenoic acid and docosahexaenoic acid at a ratio of 2:1). The main outcomes used in each trial were fatal or non-fatal acute myocardial infarction, unstable angina, coronary heart disease, ischaemic heart disease, major coronary events, cardiovascular death, sudden death, transient ischaemic stroke, stroke, and cardiovascular disease.
Out of 47 trials reporting funding source, five were funded by pharmaceutical companies and 42 were funded mainly by public or governmental organisations or independent scientific foundations. Also, in 29 trials, vitamin or antioxidant supplements were provided at no cost from the pharmaceutical industry, while 18 trials paid for them or did not mention whether the pharmaceutical industry charged for them.
In the fixed effects meta-analysis of all 50 trials, use of vitamin or antioxidant supplements was not associated with reduced risks of major cardiovascular events (relative risk 1.00; 95% confidence interval 0.98 to 1.02; I2
=42%) (fig 2). Overall, the effect sizes of the smaller randomised controlled trials tend to be less than 1.0, while the effect sizes of the larger ones tend to be null. In the 48 selected trials, the Begg’s funnel plot was symmetrical, and P for bias was 0.11 in the Egger’s test (two12
of the 50 trials were not included because of “zero” cells in the 2×2 table) (the Begg’s funnel plot is not shown in the figure).
Fig 2 Efficacy of vitamin and antioxidant supplements in prevention of major cardiovascular events in meta-analysis of 50 randomised controlled trials sorted in ascending order of number of participants
Based on the Jadad scales, the mean score for the 47 trials assessed was 4.3, ranging from 2 to 5 (table 1).
Table 1 Methodological quality, based on Jadad scale, of 47* included trials on efficacy of vitamin and antioxidant supplements in prevention of cardiovascular diseases
show the efficacy of vitamin or antioxidant supplements in the prevention of the major cardiovascular events in subgroup meta-analysis by various factors. Overall, subgroup meta-analyses by type of supplement (table 2) showed that there was no significant association between vitamin or antioxidant supplements and the risk of the major cardiovascular events (figs 3-6,
and table 2), while low dose vitamin B6 supplementation slightly decreased the risk of major cardiovascular events (relative risk 0.92, 95% confidence interval 0.85 to 0.99; I2=35%; fig 7) in the fixed effects meta-analysis. Similarly, we found no significant association in the overall subgroup meta-analysis by type of outcome (cardiovascular death, fatal or nonfatal myocardial infarction, stroke, or transient ischaemic attack; table 3), type of prevention (primary v secondary; table 2), type of study design, methodological quality (high v low by score of 5), duration of treatment (<5 years v ≥5 years), funding source (independent organisation v pharmaceutical industry) (table 4), and provider of the supplements (pharmaceutical industry v at cost or no mention), while vitamin B6 and vitamin E supplements were associated with a reduced risk of cardiovascular death (relative risk 0.91, 95% confidence interval 0.83 to 0.99; I2=0%) and myocardial infarction (0.77, 0.65 to 0.91; I2=76%), respectively, and vitamin and antioxidant supplementation marginally increased the risk of angina pectoris (1.04, 1.00 to 1.08; I2=36%) (table 3).
Table 2 Efficacy of vitamin and antioxidant supplements in the prevention of the major cardiovascular events in subgroup meta-analysis by type of prevention and type of supplement
Table 3 Efficacy of vitamin and antioxidant supplements in prevention of major cardiovascular events in subgroup meta-analysis by outcome
Table 4 Efficacy of vitamin and antioxidant supplements in prevention of major cardiovascular events in subgroup meta-analysis by various factors
Fig 3 Efficacy of vitamin A supplements in prevention of major cardiovascular events in subgroup meta-analysis of randomised controlled trials
Fig 4 Efficacy of vitamins B6 and B12 and folic acid supplements in prevention of major cardiovascular events in subgroup meta-analysis of randomised controlled trials
Fig 5 Efficacy of vitamins C, D, and E supplements in prevention of major cardiovascular events in subgroup meta-analysis of randomised controlled trials. For subgroup meta-analysis of vitamin C and vitamin E, we used data from 2008 PHS2 article83 because (more ...)
Fig 6 Efficacy of β carotene and selenium supplements in prevention of major cardiovascular events in subgroup meta-analysis of randomised controlled trials
Fig 7 Efficacy of low dose vitamin B6 supplements in prevention of major cardiovascular events in subgroup meta-analysis of randomised controlled trials by study quality according to Jadad scale
In the subgroup meta-analysis of high quality randomised controlled trials within each category of low dose vitamin B6 (relative risk 0.94, 95% confidence interval 0.87 to 1.02; I2=39%; fixed effects model, table 2 and fig 7) and angina (1.01, 0.86 to 1.18; I2=57%; random effects model, table 3), however, beneficial or harmful effects disappeared. Also, even though vitamin B6 supplementation was associated with decreased risks of cardiovascular death in high quality trials, and vitamin E supplementation with a decreased risk of myocardial infarction, those beneficial effects were seen only in trials supplied with supplements by pharmaceutical industry (fig 8 and table 3).
Fig 8 Efficacy of vitamin E supplements in prevention of myocardial infarction in subgroup meta-analysis of randomised controlled trials according to provider of supplements (pharmaceutical industry or other). For subgroup meta-analysis of vitamin E, (more ...)
In the subgroup meta-analysis by the number of participants in each trial, vitamin or antioxidant supplements showed a trend toward a decreased (but not significant) risk of major cardiovascular events (relative risk 0.97, 95% confidence interval 0.94 to 1.01; I2
=40%) in the subgroup meta-analysis of trials with <10
000 participants, while those supplements showed an increased (but not significant) risk of the major cardiovascular events (1.02, 0.99 to 1.04; I2
=39%) in the subgroup meta-analysis of those with ≥10
000 participants (table 4).
Table 5 shows the efficacy of vitamin and antioxidant supplements given singly or in combination with other vitamin or antioxidant supplements on major cardiovascular events in subgroup meta-analyses. We found no significant beneficial effect of vitamin and antioxidant supplements in most of the subgroup meta-analyses, while only vitamin E supplements had a marginally significant decreased efficacy for the major cardiovascular events in high quality trials (relative risk 0.95, 95% confidence interval 0.90 to 1.00; I2=45%).
Table 5 Efficacy of vitamin and antioxidant supplements given singly or combined with other vitamin or antioxidant supplements in prevention of major cardiovascular events in subgroup meta-analysis