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Enough Is Enough: Stop Wasting Money on Vitamin and Mineral Supplements
 
 
  Download the PDF here
 
Download the PDF here
 
Download the PDF here
 
Download the PDF here
 
Eliseo Guallar, MD, DrPH; Saverio Stranges, MD, PhD; Cynthia Mulrow, MD, MSc, Senior Deputy Editor; Lawrence J. Appel, MD, MPH; and Edgar R. Miller III, MD, PhD
 
Ann Intern Med
Editorial | 17 December 2013 - There are 4 articles below including this Editorial & 3 published reports in Annals on this topic.
 
Three articles in this issue address the role of vitamin and mineral supplements for preventing the occurrence or progression of chronic diseases. First, Fortmann and colleagues (1) systematically reviewed trial evidence to update the U.S. Preventive Services Task Force recommendation on the efficacy of vitamin supplements for primary prevention in community-dwelling adults with no nutritional deficiencies. After reviewing 3 trials of multivitamin supplements and 24 trials of single or paired vitamins that randomly assigned more than 400 000 participants, the authors concluded that there was no clear evidence of a beneficial effect of supplements on all-cause mortality, cardiovascular disease, or cancer.
 
Second, Grodstein and coworkers (2) evaluated the efficacy of a daily multivitamin to prevent cognitive decline among 5947 men aged 65 years or older participating in the Physicians' Health Study II. After 12 years of follow-up, there were no differences between the multivitamin and placebo groups in overall cognitive performance or verbal memory. Adherence to the intervention was high, and the large sample size resulted in precise estimates showing that use of a multivitamin supplement in a well-nourished elderly population did not prevent cognitive decline. Grodstein and coworkers' findings are compatible with a recent review (3) of 12 fair- to good-quality trials that evaluated dietary supplements, including multivitamins, B vitamins, vitamins E and C, and omega-3 fatty acids, in persons with mild cognitive impairment or mild to moderate dementia. None of the supplements improved cognitive function.
 
Third, Lamas and associates (4) assessed the potential benefits of a high-dose, 28-component multivitamin supplement in 1708 men and women with a previous myocardial infarction participating in TACT (Trial to Assess Chelation Therapy). After a median follow-up of 4.6 years, there was no significant difference in recurrent cardiovascular events with multivitamins compared with placebo (hazard ratio, 0.89 [95% CI, 0.75 to 1.07]). The trial was limited by high rates of nonadherence and dropouts.
 
Other reviews and guidelines that have appraised the role of vitamin and mineral supplements in primary or secondary prevention of chronic disease have consistently found null results or possible harms (5-6). Evidence involving tens of thousands of people randomly assigned in many clinical trials shows that ß-carotene, vitamin E, and possibly high doses of vitamin A supplements increase mortality (6-7) and that other antioxidants (6), folic acid and B vitamins (8), and multivitamin supplements (1, 5) have no clear benefit.
 
Despite sobering evidence of no benefit or possible harm, use of multivitamin supplements increased among U.S. adults from 30% between 1988 to 1994 to 39% between 2003 to 2006, while overall use of dietary supplements increased from 42% to 53% (9). Longitudinal and secular trends show a steady increase in multivitamin supplement use and a decline in use of some individual supplements, such as ß-carotene and vitamin E. The decline in use of ß-carotene and vitamin E supplements followed reports of adverse outcomes in lung cancer and all-cause mortality, respectively. In contrast, sales of multivitamins and other supplements have not been affected by major studies with null results, and the U.S. supplement industry continues to grow, reaching $28 billion in annual sales in 2010. Similar trends have been observed in the United Kingdom and in other European countries.
 
The large body of accumulated evidence has important public health and clinical implications. Evidence is sufficient to advise against routine supplementation, and we should translate null and negative findings into action. The message is simple: Most supplements do not prevent chronic disease or death, their use is not justified, and they should be avoided. This message is especially true for the general population with no clear evidence of micronutrient deficiencies, who represent most supplement users in the United States and in other countries (9). The evidence also has implications for research. Antioxidants, folic acid, and B vitamins are harmful or ineffective for chronic disease prevention, and further large prevention trials are no longer justified. Vitamin D supplementation, however, is an open area of investigation, particularly in deficient persons. Clinical trials have been equivocal and sometimes contradictory. For example, supplemental vitamin D, which might prevent falls in older persons, reduced the risk for falls in a few trials, had no effect in most trials, and increased falls in 1 trial. Although future studies are needed to clarify the appropriate use of vitamin D supplementation, current widespread use is not based on solid evidence that benefits outweigh harms (10).
 
With respect to multivitamins, the studies published in this issue and previous trials indicate no substantial health benefit. This evidence, combined with biological considerations, suggests that any effect, either beneficial or harmful, is probably small. As we learned from voluminous trial data on vitamin E, however, clinical trials are not well-suited to identify very small effects, and future trials of multivitamins for chronic disease prevention in well-nourished populations are likely to be futile.
 
In conclusion, ß-carotene, vitamin E, and possibly high doses of vitamin A supplements are harmful. Other antioxidants, folic acid and B vitamins, and multivitamin and mineral supplements are ineffective for preventing mortality or morbidity due to major chronic diseases. Although available evidence does not rule out small benefits or harms or large benefits or harms in a small subgroup of the population, we believe that the case is closed- supplementing the diet of well-nourished adults with (most) mineral or vitamin supplements has no clear benefit and might even be harmful. These vitamins should not be used for chronic disease prevention. Enough is enough.
 
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Long-Term Multivitamin Supplementation and Cognitive Function in Men: A Randomized Trial
 
Francine Grodstein, ScD*; Jacqueline O'Brien, ScD*; Jae Hee Kang, ScD; Rimma Dushkes, PhD; Nancy R. Cook, ScD; Olivia Okereke, MD; JoAnn E. Manson, MD, DrPH; Robert J. Glynn, PhD; Julie E. Buring, ScD; J. Michael Gaziano, MD, MPH; and Howard D. Sesso, ScD, MPH
 
Abstract
 
Background:
Despite widespread use of multivitamin supplements, their effect on cognitive health-a critical issue with aging-remains inconclusive. To date, no long-term clinical trials have studied multivitamin use and cognitive decline in older persons.
 
Objective: To evaluate whether long-term multivitamin supplementation affects cognitive health in later life.
 
Design: Randomized, double-blind, placebo-controlled trial of a multivitamin from 1997 to 1 June 2011. The cognitive function substudy began in 1998. Up to 4 repeated cognitive assessments by telephone interview were completed over 12 years.
 
Setting: The Physicians' Health Study II.
Patients: 5947 male physicians aged 65 years or older.
Intervention: Daily multivitamin or placebo.
 
Measurements: A global composite score averaging 5 tests of global cognition, verbal memory, and category fluency. The secondary end point was a verbal memory score combining 4 tests of verbal memory, which is a strong predictor of Alzheimer disease.
 
Results: No difference was found in mean cognitive change over time between the multivitamin and placebo groups or in the mean level of cognition at any of the 4 assessments. Specifically, for the global composite score, the mean difference in cognitive change over follow-up was -0.01 SU (95% CI, -0.04 to 0.02 SU) when treatment was compared with placebo. Similarly, cognitive performance did not differ between the multivitamin and placebo groups on the secondary outcome, verbal memory (mean difference in cognitive change over follow-up, -0.005 SU [CI, -0.04 to 0.03 SU]).
 
Limitation: Doses of vitamins may be too low or the population may be too well-nourished to benefit from a multivitamin.
 
Conclusion: In male physicians aged 65 years or older, long-term use of a daily multivitamin did not provide cognitive benefits.
 
Primary Funding Source: National Institutes of Health, BASF, Pfizer, and DSM Nutritional Products.
 
Discussion
 
In this long-term, randomized, placebo-controlled trial with more than a decade of treatment among 5947 men aged 65 years or older, those assigned to a daily multivitamin had similar overall cognitive performance as those receiving a placebo.
 
Few observational studies have examined multivitamin use and cognition. Some epidemiologic research suggests that moderate doses of antioxidant vitamins (similar to those found in a multivitamin supplement) are associated with a slower rate of cognitive decline (38). For example, in 2889 participants from the Chicago Health and Aging Project with a mean follow-up of 3.2 years, higher total vitamin E and vitamin E from food intake (mean intake of vitamin E was 90 IU and 17% of participants used vitamin E supplements) was associated with slower cognitive decline (10). Nonetheless, findings for antioxidant vitamins are not consistent. An analysis of 16 010 women in the Nurses' Health Study found no association between total antioxidant intake or antioxidant intake from foods alone and cognitive decline over 4 years (39).
 
Observational studies of B vitamins and cognitive status have also been inconsistent (40). Some studies have shown better cognitive performance among persons with higher blood levels of folate (41-42) or other B vitamins (43-45), but other studies have shown no association (46-48). Studies of dietary intake and supplements have also varied. One cohort study of 321 participants with a mean follow-up of 3 years found that dietary folate (mean intake, 440 μg), vitamin B6 (mean intake, 3.98 mg), and vitamin B12 (mean intake, 9.57 μg) from food and supplement sources were related to better performance on a spatial copying task but not other memory-related tests (49). Another study found that vitamin B12 intake was not related to cognitive decline in 3718 participants with a median follow-up of 5.5 years, except for a potential benefit limited to the oldest participants (50).
 
Results from previous randomized, controlled trials of multivitamin supplements and cognition have not found clear benefits in well-nourished populations. In a recent meta-analysis of 10 smaller, shorter-term, randomized, controlled trials of multivitamin supplements, there was no effect on 7 cognitive domains except for immediate free recall memory, which was not a specific a priori hypothesis (12). Trials testing high doses of individual vitamin supplements have generally had null results for cognition as well, including large-scale trials of antioxidant supplements (51-55) and B vitamins (56-59).
 
Yet, one issue with many of the trials is that supplementation may be administered too late or for an inadequate duration to prevent cognitive decline, which is a process that begins years before symptoms are detected. In a cognitive substudy of the SU.VI.MAX (Supplementation in Vitamins and Mineral Antioxidants) trial (n = 4447), investigators assessed cognition 6 years after the conclusion of an 8-year trial of antioxidant supplementation and found better performance for the supplement group on a test of episodic memory (17).
 
However, results were not significant for the 5 other cognitive outcomes tested. Therefore, findings are difficult to interpret. Stronger evidence comes from a report of the ß-carotene component from the PHS II trial. Participants randomly assigned to ß-carotene had significantly better performance on global cognitive and verbal memory after an average of 18 years of supplementation, suggesting that very long-term vitamin supplementation or exposure at younger ages before substantial neuropathology has accumulated may be required to maintain brain health (20, 60).
 
A limitation of this study is that the male physician participants may have been too well-nourished to observe benefits of supplementation. When cognitive benefits have been observed in other trials of nutriceuticals, these benefits are usually in groups with inadequate dietary intakes of the relevant vitamin (52, 61). Future studies are needed to clarify whether multivitamin supplementation may be more beneficial in persons with less optimal nutritional status or vitamin deficiencies. This is of particular interest in an aging population because older persons are often at risk for nutritional deficiencies due to reduced micronutrient intake, altered absorption, and the metabolic requirements of vitamins (62).
 
This population is also unique in that the participants are all highly educated men, so it is possible that effects of multivitamins could have been different in a study population with varying levels of educational attainment. Nevertheless, our large sample size gave us sufficient power to detect the effects of the multivitamin supplement on changes in cognition, and we have identified many risk factors for cognitive decline in previous studies using PHS II data, including ß-carotene treatment and type 2 diabetes mellitus (20, 63).
 
Furthermore, cognitive testing began an average of 2.5 years (range, 0.18 to 5.3 years) after randomization. This prevented evaluating change in performance from randomization, and it is possible that we missed acute benefits of multivitamins during initial follow-up. However, risk factors for cognitive decline were similarly distributed among treatment groups at randomization, and cognition was similar at the initial cognitive assessment (including among newly recruited participants with a mean of only 1 year from randomization to initial cognitive testing). Therefore, it is likely that cognitive function was similar between the 2 groups at randomization. Given the length of time over which cognitive changes occur, it is unlikely that we missed any meaningful changes due to multivitamin supplementation in the period between randomization and initial cognitive testing.
 
Finally, the formulation of the multivitamin used in PHS II has changed since it began, reflecting evolving perspectives and priorities in nutrition. For example, vitamin D increased from 400 to 500 IU, vitamin A (percentage as ß-carotene) decreased from 5000 IU (50%) to 2500 IU (40%), and 250 μg of lutein and 300 μg of lycopene were added. However, the formulation of the multivitamin used throughout PHS II (Appendix Table 1) has remained the same throughout its duration.
 
Strengths of this trial include the large population of men with a long duration of randomized treatment. Additional strengths include completion of 4 repeated cognitive assessments over nearly a decade, with high rates of follow-up and a validated neuropsychological test battery covering various cognitive domains based on the same cognitive domains used in the National Institute on Aging's Uniform Data Set Neuropsychological Test Battery (64). The PHS II also benefited from high levels of adherence to multivitamin treatment, with two thirds of men still adherent to their treatment regimen after more than a decade of follow-up.
 
In this large, randomized, placebo-controlled trial among 5947 men aged 65 years or older, we saw no benefit of a daily multivitamin in slowing cognitive decline after more than a decade of treatment and follow-up. These data do not provide support use of multivitamin supplements in the prevention of cognitive decline. However, it is important to consider other health effects of multivitamin supplementation, including modest protection against overall cancer risk in the PHS II with long-term use (3) and any potential effects on other important health outcomes yet to be evaluated. Moreover, further research is needed in other populations, such as those with nutrient deficiencies, to determine whether there are cognitive benefits specific to daily multivitamin use.
 
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17 December 2013
 
Vitamin and Mineral Supplements in the Primary Prevention of Cardiovascular Disease and Cancer: An Updated Systematic Evidence Review for the U.S. Preventive Services Task Force
 
Abstract
 
Background:
Vitamin and mineral supplements are commonly used to prevent chronic diseases.
 
Purpose: To systematically review evidence for the benefit and harms of vitamin and mineral supplements in community-dwelling, nutrient-sufficient adults for the primary prevention of cardiovascular disease (CVD) and cancer. Data Sources: MEDLINE, Embase, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and Database of Abstracts of Reviews of Effects were searched from January 2005 to 29 January 2013, with manual searches of reference lists and gray literature.
 
Study Selection: Two investigators independently selected and reviewed fair- and good-quality trials for benefit and fair- and good-quality trials and observational studies for harms.
 
Data Extraction: Dual quality assessments and data abstraction.
 
Data Synthesis: Two large trials (n = 27 658) reported lower cancer incidence in men taking a multivitamin for more than 10 years (pooled unadjusted relative risk, 0.93 [95% CI, 0.87 to 0.99]). The study that included women showed no effect in that group. High-quality studies (k = 24; n = 324 653) of single and paired nutrients (such as vitamins A, C, or D; folic acid; selenium; or calcium) were scant and heterogeneous and showed no clear evidence of benefit or harm. Neither vitamin E nor ß-carotene prevented CVD or cancer, and ß-carotene increased lung cancer risk in smokers.
 
Limitations: The analysis included only primary prevention studies in adults without known nutritional deficiencies. Studies were conducted in older individuals and included various supplements and doses under the set upper tolerable limits. Duration of most studies was less than 10 years. Conclusion: Limited evidence supports any benefit from vitamin and mineral supplementation for the prevention of cancer or CVD. Two trials found a small, borderline-significant benefit from multivitamin supplements on cancer in men only and no effect on CVD.
 
Primary Funding Source: Agency for Healthcare Research and Quality.
 
Vitamins and minerals are commonly used as dietary supplements to promote health and prevent chronic diseases (1). In the National Health and Nutrition Examination Survey III (1988-1994), nearly half of the U.S. population reported using a dietary supplement. A "multivitamin" was the most frequently used supplement (2). Americans spend an estimated $11.8 billion each year on vitamin and mineral supplements (3).
 
Cardiovascular disease (CVD) and cancer are the leading causes of illness and death in the United States (4). Cancer and CVD have several shared risk factors, including inflammation, oxidative stress, and methionine metabolism. The rationale for using these supplements is supported by many in vitro and animal studies showing that they protect against these damaging cellular mechanisms. In 2003, the U.S. Preventive Services Task Force (USPSTF) concluded that there was insufficient evidence to recommend for or against the use of vitamins A, C, and E; multivitamins with folic acid; or antioxidant combinations for the prevention of CVD or cancer (5). The USPSTF recommended against the use of ß-carotene supplements, either alone or in combination, because they found good-quality evidence that they not only carried no benefit but in fact caused harm among adults at an increased risk for lung cancer. To help the USPSTF update its recommendation, we identified and reviewed additional evidence on the benefits and harms of vitamin and mineral supplementation to prevent CVD and cancer in the general adult population.
 
Discussion
 
This review included 26 studies (24 randomized, controlled trials and 2 cohort studies) that examined the benefits and harms of using vitamin and mineral supplements for primary prevention of CVD, cancer, or all-cause mortality in healthy individuals without known nutritional deficiencies. We found no consistent evidence that the included supplements affected CVD, cancer, or all-cause mortality in healthy individuals without known nutritional deficiencies. Other systematic reviews have arrived at this same conclusion (56-66). The certainty of this result is tempered, however, because few fair- or good-quality studies are available for all supplements except vitamin E and ß-carotene. For vitamin E, we identified 6 fair- to good-quality trials that produced clearly null effects on these end points. This result is consistent with the conclusions of other systematic reviews and meta-analyses of vitamin E (67-71). Our review also confirmed the established harm of ß-carotene supplementation on lung cancer incidence and death for individuals at high risk for lung cancer (24, 29, 72). Further, we identified 6 trials that failed to detect any benefit from ß-carotene supplementation for any individuals.
 
The results of vitamin supplementation trials have been disappointing at best, despite having a solid mechanistic basis (73). One explanation for this result could be that the physiologic systems affected by vitamins and other antioxidant supplements are so complex that the effects of supplementing with only 1 or 2 components is generally ineffective or actually does harm (74). This hypothesis is compatible with our finding that the best support for benefit of supplementation came from 2 multivitamin trials that used physiologic doses of a wider variety of agents.
 
Two good-quality trials of multivitamin supplementation found lower cancer incidence in men (19, 54). The SU.VI.MAX trial included women and did not find an effect in this subgroup (19). We found a statistically significant protective effect from multivitamin supplementation when we pooled data for men in these 2 trials. The borderline significance level in both studies and the lack of an effect in women in SU.VI.MAX suggest we should not try to overgeneralize these results. The SU.VI.MAX investigators speculate that the observed sex difference in multivitamin effects on cancer incidence in their trial may have been due to lower baseline antioxidant status in men than women (19). A baseline difference in blood levels, however, was found only for ß-carotene and not for vitamins E and C, selenium, or zinc (19), although blood levels may not fully reflect nutritional status. Other behavioral or biological factors might modify the effects of antioxidant supplements on men and women; however with only 1 study available it would be better to reconfirm the sex difference before speculating on its cause.
 
The simplest way to interpret the vitamin D and calcium results is that these vitamins have no effect on CVD or cancer. A systematic review by Wang and colleagues came to a similar conclusion (59). Our data do suggest, however, that the effects of calcium on these end points may differ from the effects of vitamin D. When we pooled the 2 vitamin D trials (40-41), for example, we found lower mortality in the supplement groups (unadjusted relative risk, 0.94 [CI, 0.87 to 1.01]). In contrast, the point estimates for calcium were all greater than 1, although CIs for all estimates were wide. These findings support the idea that future research should include separate studies of calcium and vitamin D.
 
Recently, several investigators have posited that calcium intake or supplementation has harmful effects on CVD outcomes (75-80). Much of this speculation, however, derives from 2 meta-analyses that used different sets of trials (75-76) and were heavily influenced by data from a reanalysis of the Women's Health Initiative (WHI) trial (77). The WHI reanalysis identified harms only in the subgroup of women not taking calcium or vitamin D at baseline. Such post hoc subgroup analyses, however, can be misleading (81). Indeed, the WHI investigators found no evidence of harm for CVD or cancer in their own reanalysis of their trial results, even when results were stratified by baseline supplement use and the results of their large observational study were added (78). Two other recent studies included only observational data. These studies did not show consistent findings across studies, between sexes, or between dietary and supplemental calcium use (79-80). Although available studies are insufficiently consistent to permit the conclusion that calcium supplementation is harmful, future controlled trials should address this question.
 
Our analysis has some limitations. We considered only primary prevention interventions in generally healthy people and excluded secondary and tertiary prevention trials and treatment studies. Thus, our results do not apply to the targeted use of nutrients in deficient or higher-risk individuals. Only 2 trials of multivitamin supplements were included for efficacy, even though we broadly defined a multivitamin as 3 or more ingredients. Those 2 trials studied very different supplements (19, 21). Because the only multivitamin trial to include women used a supplement with 5 ingredients (19), it could be argued that there are no data on a "true" multivitamin in women. Most of the included vitamin trials provided less than a decade of follow-up, and vitamin effects on CVD and cancer may take longer to manifest. The small number of studies in each pooled analysis made it difficult to evaluate between-study heterogeneity. We limited our examination of harms to fair- and good-quality trials and observational studies and thus may have underestimated harms. In addition, we did not assess harms from higher doses of vitamins and minerals than the upper tolerable limit set by the U.S. Food and Nutrition Board.
 
This is a review of trials, a study design used primarily to evaluate drug therapy. The design might not be ideally suited to evaluating nutrients (82). The control group in a placebo-controlled trial of medications is not exposed to the medication. In a nutrient supplementation study, however, the control group is exposed to some level of the nutrient because it is designed to answer a different question: Does exposure to an optimal level of the nutrient produce better health outcomes than exposure to the usual level? To conduct this type of study, one must know both the usual and optimal level of exposure. In practice, however, exposure to the nutrient in the control group may change during the course of a trial as societal norms change, complicating interpretation of the trial results. Women in the WHI control group, for example, had twice the average calcium intake of that anticipated when the trial was designed, and the vitamin D dose was lower than many now think is necessary to achieve optimal blood levels.
 
Few studies have evaluated the effectiveness of vitamin and mineral supplements in the primary prevention of CVD and cancer in nutrient-sufficient adults.
 
Published studies have used a wide variety of supplements, in different doses, with different study objectives and populations, and usually for short duration. Although 2 relatively large trials examined the efficacy of a multivitamin in the primary prevention of CVD and cancer in a general population, population selection and potential sex-specific findings limit the applicability of their results. Future studies of multivitamin supplements should recruit from a general population with representation of multiple minority groups and both sexes, use a multivitamin that is reasonably similar to the popular brands in the current market, continue for at least a decade, and include enough participants to provide adequate power to detect benefits and harms within important subgroups, including men and women. This is a tall order, and any such study would also face other difficulties, including agreement on the content of the multivitamin, so the results of the trial might be dismissed by observers who felt that an important ingredient was omitted. The wide availability of multivitamins could result in substantial crossover, and the large number of participants and long follow-up needed would result in an expensive trial.
 
Still, the U.S. public is devoting major financial resources to multivitamins, so such a trial could have a large public health impact, whatever the outcome. Despite its limitations, the current literature on single or paired vitamins and minerals is sufficient to discourage additional studies of ß-carotene or vitamins A, C, and E in general populations not deficient in the nutrients. Future studies of selenium should clearly separate individuals with adequate and low baseline selenium levels. Future studies of vitamin D should be done separately from studies of calcium. Vitamin D and calcium studies should include the full range of hypothesized benefits, including fracture prevention, to allow a comprehensive comparison of overall benefits and harms.
 
In conclusion, we found no evidence of an effect of nutritional doses of vitamins or minerals on CVD, cancer, or mortality in healthy individuals without known nutritional deficiencies for most supplements we examined. In most cases data are insufficient to draw any conclusion, although for vitamin E and ß-carotene a lack of benefit is consistent across several trials. We identified 2 multivitamin trials that both found lower overall cancer incidence in men (19, 21). Both trials were methodologically sound, but the lack of an effect for women (albeit in 1 trial), the borderline significance in men in both trials, and the lack of any effect on CVD in either study makes it difficult to conclude that multivitamin supplementation is beneficial.
 
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Oral High-Dose Multivitamins and Minerals After Myocardial Infarction: A Randomized Trial
 
Gervasio A. Lamas, MD; Robin Boineau, MD, MA; Christine Goertz, DC, PhD; Daniel B. Mark, MD, MPH; Yves Rosenberg, MD; Mario Stylianou, PhD; Theodore Rozema, MD; Richard L. Nahin, PhD, MPH; Lauren Lindblad, MS; Eldrin F. Lewis, MD; Jeanne Drisko, MD; Kerry L. Lee, PhD, for the TACT (Trial to Assess Chelation Therapy) Investigators
 
Abstract
 
Background:
Whether high-dose multivitamins are effective for secondary prevention of atherosclerotic disease is unknown.
 
Objective: To assess whether oral multivitamins reduce cardiovascular events and are safe.
 
Design: Double-blind, placebo-controlled, 2 x 2 factorial, multicenter, randomized trial.
 
Setting: 134 U.S. and Canadian academic and clinical sites.
 
Patients: 1708 patients aged 50 years or older who had myocardial infarction (MI) at least 6 weeks earlier and had serum creatinine levels of 176.8 μmol/L (2.0 mg/dL) or less.
 
Intervention: Patients were randomly assigned to an oral, 28-component, high-dose multivitamin and multimineral mixture or placebo.
 
Measurements: The primary end point was time to total death, recurrent MI, stroke, coronary revascularization, or hospitalization for angina.
 
Results: The median age was 65 years, and 18% of patients were women. The qualifying MI occurred a median of 4.6 years (interquartile range [IQR], 1.6 to 9.2 years) before enrollment. Median follow-up was 55 months (IQR, 26 to 60 months). Patients received vitamins for a median of 31 months (IQR, 13 to 59 months) in the vitamin group and 35 months (IQR, 13 to 60 months) in the placebo group (P = 0.65). Totals of 645 (76%) and 646 (76%) patients in the vitamin and placebo groups, respectively, completed at least 1 year of oral therapy (P = 0.98), and 400 (47%) and 426 (50%) patients, respectively, completed at least 3 years (P = 0.23). Totals of 394 (46%) and 390 (46%) patients in the vitamin and placebo groups, respectively, discontinued the vitamin regimen (P = 0.67), and 17% of patients withdrew from the study. The primary end point occurred in 230 (27%) patients in the vitamin group and 253 (30%) in the placebo group (hazard ratio, 0.89 [95% CI, 0.75 to 1.07]; P = 0.21). No evidence suggested harm from vitamin therapy in any category of adverse events.
 
Limitation: There was considerable nonadherence and withdrawal, limiting the ability to draw firm conclusions (particularly about safety).
 
Conclusion: High-dose oral multivitamins and multiminerals did not statistically significantly reduce cardiovascular events in patients after MI who received standard medications. However, this conclusion is tempered by the nonadherence rate.
 
Discussion
 
TACT found that a 28-component, high-dose oral multivitamin and multimineral regimen used as secondary prevention in patients who have had MI did not statistically significantly reduce cardiovascular events. The complex mixture seemed safe. However, these conclusions must be interpreted cautiously because of a high rate of withdrawal and nonadherence.
 
Our study adds to the existing literature on vitamin therapy in 3 ways. First, complementary and alternative medicine practitioners rather than clinical researchers or supplement companies designed the specific components of the oral treatment regimen, leading to a unique high-dose mixture (Table 7 of the Supplement). Second, an English-language MEDLINE search up to August 2013 showed only 1 other large-scale trial of a multivitamin preparation focusing on cardiovascular outcomes (15) that tested more than 4 components. That trial, the Physicians Health Study II, included only 5.1% (n = 754) of patients with self-reported vascular disease. Thus, our multivitamin study, with its multiple high-dose components and enrollment of 1708 patients who have had MI, adds to the knowledge base of multivitamin therapy as secondary prevention. Finally, and most relevant to the complementary and alternative medicine community, the 2 x 2 factorial design permitted the determination that vitamin therapy did not interact with intravenous chelation, an intervention that had a modestly positive effect on cardiovascular outcomes (8).
 
Cardiovascular disease remains the principal cause of death and disability in the United States. Among the interventions used by patients to treat or prevent heart disease are those supported by an evidence base and prescribed by physicians and over-the-counter nutritional supplements, vitamins, and minerals advertised by the vitamin and supplement industry and purchased by many patients. Clinical trials have randomly assigned thousands of patients to trials testing only a few antioxidant vitamins and minerals, typically vitamin C, vitamin E, ß-carotene, and selenium, alone or in factorial groups and combinations.
 
The systematic analyses of trials testing a few vitamins and minerals to prevent cardiovascular disease can be characterized as negative and have suggested that some supplements may be harmful in high doses and for some patients (4-5, 16).
 
However, the U.S. public has increased its adoption of more complex multivitamin and multimineral supplements to prevent cardiac disease and maintain health (17). The use of multicombination supplements has increased from 30% of the overall supplement market between 1988 and 1994 to 39% between 2003 and 2006. The supplement industry has increased from $4 billion in 1994 to $23.7 billion in 2008 (18-19). Clinical trials have not kept pace with the use of these multiple-agent supplements.
 
Admittedly, some observations correlate diets rich in varied micronutrients to cardiovascular health and show plausible mechanisms by which complex mixtures of vitamins, minerals, and micronutrients could improve cardiovascular outcomes (1-3). Micronutrients, including vitamin C (20), some bioflavonoids, and others (21), may improve endothelial function. Vitamin E is an antioxidant vitamin and may even repair iron handling within the atherosclerotic plaque, thereby influencing oxidant damage (22). Many other mechanisms have been described that are beyond the scope of this discussion. Moreover, the safety concerns raised by clinical trials with single antioxidant vitamins have not been addressed with complex multivitamin and multimineral mixtures (4, 23-24). Thus, it is reasonable to expand the reach of vitamin trials and test complex mixtures to elucidate efficacy and safety.
 
The high-dose vitamins used in TACT showed an 11% relative reduction in the primary composite end point relative to the placebo group that was not statistically significant. This difference was substantially smaller than the trial was powered to measure. Thus, although this trial does not support the routine use of this high-dose oral multivitamin regimen for all patients who have had MI, the reduced statistical power due to a small difference between groups, as well as nonadherence to the study regimen, limits the conclusion of nonefficacy. Future studies of this particular regimen would have to consider a smaller effect size than we estimated, as well as the barriers to adherence that were identified.
 
We found a significant interaction of vitamin therapy with statin use, reflecting a greater effect of high-dose vitamins in patients not receiving a statin. This finding, which addressed a prespecified subset of patients intolerant to statins or self-selected not to receive statins, should not be interpreted as evidence that vitamin therapy can safely be substituted for statins in patients who have had MI. This finding requires additional mechanistic research and independent replication before the clinical implications can be understood. We also did not replicate the results of Brown and colleagues (25), who observed that a reduction in clinical events associated with simvastatin was attenuated by the concomitant use of vitamins E and C, ß-carotene, and selenium.
 
Despite our conclusions that high-dose oral vitamins and minerals alone do not seem to have a role in the management of patients who have had MI, these persons will probably continue using vitamins for cardiovascular health. It is, therefore, important to comment further on the safety of the TACT vitamins. Despite the doses used (higher in most components than those used by Sesso and associates [15]), serious adverse events and incident cases of cancer did not differ between the groups. However, this conclusion must be tempered by a high rate of discontinuation of the randomly assigned therapy or placebo.
 
Our study had important limitations. The statistical plan was based on an effect size (25% reduction) that may have been overly optimistic for the oral vitamins. The TACT vitamin regimen, requiring 6 large caplets daily, imposed a barrier to patient adherence.
 
In addition, the patient burden of the chelation component of the factorial trial was high. Combining an oral vitamin regimen with intravenous therapy probably increased the nonadherence rate for the oral therapy reported here. This nonadherence rate reduced the ability to definitively comment about the potential toxicity of such a high-dose vitamin and mineral mixture.
 
Nevertheless, the loss of outcomes data is at least partially mitigated because the death status of all patients was checked at the end of the study using the Social Security Death Index and the Canadian death registry. In addition, although more patients withdrew from the study than expected, some did so after having a primary end point. Patients who discontinued vitamins or placebo continued to be followed (unless they withdrew from the study); therefore, we obtained follow-up information for those who discontinued vitamins or placebo but remained in the trial.
 
In stable patients with a history of MI receiving appropriate, evidence-based medical therapy, use of high-dose oral multivitamins and multiminerals seemed safe but did not statistically significantly reduce cardiovascular events. These conclusions must be interpreted cautiously because of a high rate of nonadherence to the study regimen.
 
 
 
 
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