Note: This draft Recommendation Statement is not the final recommendation of the U.S. Preventive Services Task Force. This draft is distributed solely for the purpose of pre-release review. It has not been disseminated otherwise by the USPSTF. It does not represent and should not be interpreted to represent a USPSTF determination or policy.
This draft Recommendation Statement is based on an evidence review that was published on November 12, 2013 (available at http://www.uspreventiveservicestaskforce.org/uspstf14/vitasupp/vitasuppart.htm).
The USPSTF makes recommendations about the effectiveness of specific clinical preventive services for patients without related signs or symptoms.
It bases its recommendations on the evidence of both the benefits and harms of the service, and an assessment of the balance. The USPSTF does not consider the costs of providing a service in this assessment.
The USPSTF recognizes that clinical decisions involve more considerations than evidence alone. Clinicians should understand the evidence but individualize decisionmaking to the specific patient or situation. Similarly, the USPSTF notes that policy and coverage decisions involve considerations in addition to the evidence of clinical benefits and harms.
This draft Recommendation Statement is available for comment from November 12 until December 9, 2013, at 5:00 PM ET. You may wish to read the entire Recommendation Statement before you comment. A fact sheet that explains the draft recommendations in plain language is available here.
Vitamin, Mineral, and Multivitamin Supplements for the Primary Prevention of Cardiovascular Disease and Cancer: U.S. Preventive Services Task Force Recommendation Statement
Summary of Recommendations and Evidence
The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of the use of multivitamins for the prevention of cardiovascular disease or cancer.
This is an I statement.
The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of the use of single- or paired-nutrient supplements (with the exception of beta-carotene and vitamin E) for the prevention of cardiovascular disease or cancer.
This is an I statement.
The USPSTF recommends against the use of beta-carotene or vitamin E supplements for the prevention of cardiovascular disease or cancer.
This is a D recommendation.
Go to the Clinical Considerations section for additional information about suggestions for practice regarding the I statement.
Use of dietary supplements is common in the U.S. adult population. Forty-nine percent of adults used at least one dietary supplement in 2007 to 2010, and 32% of adults reported using a multivitamin-multimineral supplement (1). Supplement use is more common among women than men and among older adults than younger adults (2). Most supplements are used with the intent of preventing illness or slowing the progress of existing disease (1). The substantial impact of cardiovascular disease and cancer on health status and mortality in the United States has been well described (3).
Assessment of Risk Status
This recommendation applies to healthy adult populations without known or suspected nutritional deficiencies. Nutritional deficiency can occur because of lack of access to nutritious food due to geography or poverty, physiologic impairment in absorption of nutrients, or severe restriction of diet despite access to nutritious foods.
Benefits of Vitamin Supplementation
The USPSTF found inadequate evidence on the benefits of supplementation with multivitamins to reduce the risk of cardiovascular disease or cancer.
The USPSTF found inadequate evidence on the benefits of supplementation with individual vitamins, minerals, or functional pairs in healthy populations without nutritional deficiencies to reduce the risk of cardiovascular disease or cancer.
The USPSTF found adequate evidence that supplementation with beta-carotene or vitamin E in healthy populations without nutritional deficiencies does not reduce the risk of cardiovascular disease or cancer.
Harms of Vitamin Supplementation
The USPSTF found inadequate evidence on the harms of supplementation with multivitamins and most single vitamins, minerals, or functional pairs.
The USPSTF found adequate evidence that supplementation with beta-carotene increases the risk of lung cancer in persons who are at increased risk of lung cancer.
The USPSTF found adequate evidence that supplementation with vitamin E has little or no significant harms.
The USPSTF concludes that the evidence is insufficient to determine the balance of benefits and harms of supplementation with multivitamins for the prevention of cardiovascular disease or cancer.
The USPSTF concludes that the evidence is insufficient to determine the balance of benefits and harms of supplementation with single- or paired-nutrients (except beta-carotene or vitamin E) for the prevention of cardiovascular disease or cancer.
The USPSTF concludes with moderate certainty that the harms of supplementation with beta-carotene, either alone or in combination, outweigh the benefits.
The USPSTF concludes with moderate certainty that there is no net benefit of supplementation with vitamin E for the prevention of cardiovascular disease or cancer.
Patient Population Under Consideration
The focus of this recommendation is healthy adults without special nutritional needs. Populations studied were typically age 50 years or older. This recommendation does not apply to children, women who are pregnant or may become pregnant, or persons who are chronically ill, hospitalized, or have a clinical nutritional deficiency.
Suggestions for Practice Regarding the I Statements
In deciding whether to use vitamin, mineral, and multivitamin supplements for the prevention of cardiovascular disease and cancer, primary care providers should consider the following.
Potential Preventable Burden
Evidence from in vitro and animal research and population-based epidemiologic studies support the hypothesis that oxidative stress may play a fundamental role in the initiation and progression of both cancer and common cardiovascular diseases (3). If this hypothesis is correct, then some combination of specific supplement(s), specific dose, vulnerable host, and specific timing may be found to be useful.
Important harms have been demonstrated with the use of beta-carotene. There are several known adverse effects caused by excessive doses of vitamins; for example, moderate doses of vitamin A supplements may reduce bone mineral density, but high doses may be hepatotoxic or teratogenic. Otherwise, the vitamins reviewed by the USPSTF had few known risks. Since many of these vitamins are fat soluble, the lifetime impact of high doses should be taken into consideration.
The USPSTF did not address doses higher than the tolerable upper intake level, as determined by the U.S. Food and Nutrition Board. Both vitamins A and D have known harms at doses exceeding the tolerable upper intake level (4), and the potential for harm from other supplements at very high doses should be carefully considered.
The U.S. Pharmacopeia has developed reference standards to aid in quality control of dietary supplement production; however, considerable variability likely exists in the content and concentration of ingredients in commercially available formulations. This variability in the composition of dietary supplements makes it challenging to extrapolate results obtained from controlled clinical trials.
While dietary supplements themselves are not particularly costly, the cumulative impact of this class of agent on spending is significant. In 2010, $28.1 billion was spent on dietary supplements in the United States (5).
Surveys conducted by the dietary supplement industry suggest that many physicians and nurses have recommended dietary supplements to their patients for health and wellness (6).
Additional Approaches to Prevention
Despite the absence of benefit of vitamin supplementation, adequate nutrition by eating a diet rich in fruits, vegetables, whole grains, fat-free and low-fat dairy products, and seafood may play a role in the prevention of cancer or cardiovascular disease. The 2010 Dietary Guidelines for Americans (7) provide guidance on how to consume a nutrient-rich diet.
There may be specific groups of patients with well-defined conditions for whom specific nutrients will provide benefits. For example, women planning or capable of pregnancy should take a daily supplement containing folic acid to help prevent neural tube defects.
The USPSTF has a large portfolio of recommendations for prevention of cardiovascular disease and cancer, including recommendations for smoking cessation, cholesterol screening, hypertension screening, diabetes screening, obesity screening and counseling, aspirin use, and cancer screening (available at www.uspreventiveservicestaskforce.org).
Research Needs and Gaps
A critical gap in the evidence is the lack of studies of multivitamin combinations in groups generalizable to the U.S. population. Two randomized, controlled trials (RCTs) of multivitamin supplements suggest a potential cancer prevention benefit in men but not women. Future trials should be more representative of the general population, including women and minority groups, and have enough power to demonstrate whether there are true subgroup differences.
There are significant challenges to studying nutrient supplementation using methods similar to those used in studying pharmaceutical interventions. New and innovative research methodologies for examining effects of nutrients that account for the unique complexities of nutritional research but maintain rigorous designs should be explored.
The paucity of studies and general lack of effect of any single nutrient or nutrient pair makes it difficult to draw meaningful conclusions on the balance of benefits and harms without a coordinated research effort and focus.
Burden of Disease
Cardiovascular disease and cancer are the largest single contributors to the burden of chronic disease in the developed world. In 2011, these two chronic diseases accounted for 23.7% and 22.8% of all deaths in the United States, respectively (8).
Scope of Review
In order to update its 2003 recommendation, the USPSTF reviewed evidence of the efficacy of multivitamin or mineral supplement use in the general adult population for the prevention of cardiovascular disease and cancer (3, 9). The value of vitamins that naturally occur in food, the use of vitamin supplements for the prevention of other conditions (e.g., neural tube defects), and the use of vitamin supplements for the secondary prevention of complications in patients with existing disease are outside the scope of this review.
Effectiveness of Preventive Medication
Multivitamin and Antioxidant Combinations
The USPSTF reviewed four RCTs and one cohort study assessing health outcomes of a multivitamin supplement (3). The studies varied in the nutrients and dosages used. No effect on all-cause mortality was found in the three trials that assessed this outcome. Two trials assessed cardiovascular disease outcomes. Overall, there was no effect on incidence of cardiovascular disease events. One trial reported a borderline significant decrease in fatal myocardial infarctions.
Two large trials, the Physician's Health Study II (10) and the Supplementation in Vitamins and Mineral Antioxidants Study (11), showed a decrease in overall cancer incidence in men (pooled unadjusted relative risk, 0.93 [95% CI, 0.87 to 0.99]) (3). The Physician's Health Study II included 14,641 male U.S. physicians with an average age of 64.3 years. The intervention used a commercially available multivitamin that contained 30 ingredients. The unadjusted relative risk for total cancer incidence was 0.94 (95% CI, 0.87 to 1.00) after 11.2 years of followup. The homogeneity of this study population (i.e., primarily older, white male physicians) limits its generalizability.
The Supplementation in Vitamins and Mineral Antioxidants Study was conducted in France in 13,017 men and women with an average age of 49 years. The intervention supplement included nutritional doses of vitamins C and E plus beta-carotene, selenium, and zinc. Outcomes were reported for the end of the intervention phase at 7.5 years and again at 12.5 years after randomization. There was no effect on overall cancer incidence in women, but there was a 31% decrease in men (adjusted relative risk, 0.69 [95% CI, 0.53 to 0.91]) during the supplementation period. The lack of effect in women and use of different supplement formulations in the two trials makes it difficult to extrapolate these findings to the general population.
Single and Paired Vitamins and Minerals
The USPSTF reviewed 24 studies of individual vitamins, minerals, or functional nutrient pairs (3). Across all the supplements studied, there was no evidence of beneficial effects on cardiovascular disease, cancer, or all-cause mortality. However, there are only a limited number of studies for most individual nutrients, and differences in study designs make it difficult to pool effects across supplements. Therefore, the USPSTF is not able to conclude with certainty that there is no effect. The evidence for each individual nutrient is discussed below.
The USPSTF reviewed three RCTs and two cohort studies of vitamin A (3). None of the studies reported cardiovascular disease incidence. One good-quality trial showed an increased risk of lung cancer and related death. The baseline population was at high risk of lung cancer (smokers and asbestos-exposed workers), so the increased mortality may be attributable to the beta-carotene component. Two trials reported all-cause mortality, but no significant difference was observed between intervention and control groups at the longest followup. Increased risk of hip fractures was observed in one large prospective cohort study of postmenopausal women.
Two RCTs studied the effects of vitamin C, either alone or in combination, and found no statistically significant effect on cardiovascular disease, cancer, or all-cause mortality (3).
Vitamin D With or Without Calcium
Three trials studied the effects of vitamin D alone on cardiovascular disease and cancer (3). Two trials found no effect on cardiovascular disease incidence or mortality. One trial reported cancer incidence and death and found no difference between intervention and control groups. Two trials reporting all-cause mortality found no statistically significant difference.
Two trials studied vitamin D and calcium combined. One small, fair-quality study found a statistically significant decreased risk of cancer with supplement use (12). The Women's Health Initiative, a larger, good-quality trial using lower doses of vitamin D and calcium supplements, found no effect on cancer incidence or mortality (13). A post hoc subgroup analysis of women who were not taking supplements at baseline showed an association between vitamin D and calcium supplement use and lower total and breast cancer incidence (14). Only the Women's Health Initiative reported cardiovascular disease incidence and mortality and all-cause mortality, and found no effect after 7 years of followup.
Four trials of calcium supplementation found no effects on overall cardiovascular disease, cancer, or all-cause mortality (3).
Six RCTs assessed vitamin E supplementation (3). Three trials reported cardiovascular disease incidence and mortality. One trial in women reported a lower cardiovascular disease mortality rate in the intervention group, but mortality rates for myocardial infarction and stroke were not statistically different. One trial found an increased risk of hemorrhagic stroke in the intervention group.
Four RCTs reported cancer incidence, with inconsistent results. The Alpha-Tocopherol Beta-Carotene Cancer Prevention trial (15) reported a decreased prostate cancer incidence rate, but the effect did not persist with longer followup. Conversely, the Selenium and Vitamin E Cancer Prevention Trial (16) reported an increased risk of prostate cancer after extended followup. Overall, there was no significant effect on incidence of all cancers or other site-specific cancers or in cancer mortality rates. No effect on all-cause mortality was observed in the five trials reporting this outcome.
A consistent body of evidence from six clinical trials suggests that beta-carotene supplementation does not decrease the risk of cardiovascular disease events, overall cancer incidence, or cancer mortality (3). Two trials, the Alpha-Tocopherol Beta-Carotene Cancer Prevention trial (15) and the Carotene and Retinol Efficacy Trial (17), showed an increased risk of lung cancer incidence and mortality and all-cause mortality in participants with a high baseline risk of lung cancer. A meta-analysis of beta-carotene trials reported an increased risk of lung cancer (pooled odds ratio, 1.24 [95% CI, 1.10 to 1.39]) in current smokers (18).
Two trials studied selenium alone or in combination with other nutrients and found no effect on cardiovascular disease or all-cause mortality (3). The effects on cancer were mixed. One trial found a decrease in risk of cancer incidence and mortality. The other found no significant difference. Additional analyses showed cancer benefits only in men with the lowest levels of selenium, suggesting a potential effect resulting from treatment of selenium deficiency. No differences in all-cause mortality were found in either trial.
Only one trial studied folic acid (3). It found no effect on cardiovascular disease incidence or all-cause mortality. There was an increased incidence of cancer, attributed to an excess number of prostate cancer deaths in the intervention group.
Potential Harms of Preventive Medication
Overall, few significant harms were reported from these interventions, with the exception of beta-carotene. As described previously, two trials reported increased risk of lung cancer and lung cancer mortality in smokers, especially heavy smokers. Increased cancer risk from beta-carotene supplementation in nonsmokers has not been observed in trials.
There are reports in the literature of less serious harms, such as hypercarotenemia or yellowing of the skin (multivitamins, beta-carotene), rashes (multivitamins), minor bleeding events (multivitamins), and gastrointestinal symptoms (calcium and selenium). Rare but more serious harms were associated with some nutrient trials, including hip fractures (vitamin A), prostate cancer (folic acid), and kidney stones (vitamin D and calcium).
Estimate of Magnitude of Net Benefit
The USPSTF found inadequate evidence on the effectiveness of multivitamin supplements to prevent cardiovascular disease or cancer. Therefore, the USPSTF concludes that the evidence on benefits is lacking and the balance of benefits and harms cannot be determined. The USPSTF also found inadequate evidence on the effectiveness of most single or paired vitamin or mineral supplements and is unable to determine the balance of benefits and harms for their use to prevent cardiovascular disease or cancer.
Only two vitamin supplements have sufficient data to estimate net benefit. Beta-carotene has been associated with a statistically significant increased risk of lung cancer incidence in smokers. The USPSTF concludes with moderate certainty that the net benefit of beta-carotene supplementation is negative (i.e., there is a net harm).
A large and consistent body of evidence has demonstrated that vitamin E supplementation has no effect on cardiovascular disease, cancer, or all-cause mortality. The USPSTF concludes with moderate certainty that the net benefit of vitamin E supplementation is zero.
How Does Evidence Fit With Biological Understanding?
The risk factors for cardiovascular disease are well established. Risk factors for cancer are considerably more complex because of the heterogeneous nature of different cancer types and environmental and genetic influences. Inflammation, oxidative stress, and methionine metabolism have been theorized as common pathologic mechanisms for both cardiovascular disease and cancer. The potential antioxidant and anti-inflammatory effects of many nutrient supplements are the basis for their proposed use to prevent cardiovascular disease and cancer (3). Although not fully understood, research has suggested that the oxidative properties of antioxidants may vary in relation to other factors, such as the concentration of the nutrient and presence of other oxidants/antioxidants. The harmful association between beta-carotene and lung cancer suggests that other variables may influence whether beta-carotene acts as an antioxidant versus a pro-oxidant.
Update of Previous Recommendation
This recommendation updates the 2003 USPSTF recommendation on vitamin supplementation to prevent cardiovascular disease or cancer. At that time, the USPSTF concluded that the evidence was insufficient to recommend for or against the use of supplements of vitamins A, C, or E; multivitamins with folic acid; or antioxidant combinations for the prevention of cardiovascular disease or cancer (I statement). The USPSTF also recommended against the use of beta-carotene supplements, either alone or in combination, for the prevention of cardiovascular disease or cancer (D recommendation).
In the current recommendation, the USPSTF considered evidence on additional nutrient supplements, including vitamin D, calcium, selenium, and folic acid, for the primary prevention of cardiovascular disease and cancer. New evidence on the use of vitamin E increased the USPSTF's certainty about its lack of effectiveness in preventing cardiovascular disease or cancer.
Recommendations of Others
The National Institutes of Health have determined that the present evidence is insufficient to recommend for or against the use of multivitamins to prevent chronic disease (19). The Academy of Nutrition and Dietetics (formerly the American Dietetic Association) noted in a 2009 position statement that although multivitamin supplements may be useful in meeting the recommended levels of some nutrients, there is no evidence that they are effective in preventing chronic disease (20). The American Institute for Cancer Research determined in 2007 that dietary supplements are not recommended for cancer prevention and recommends a balanced diet with a variety of foods rather than supplements (21). The American Heart Association recommends that healthy people receive adequate nutrients by eating a variety of foods rather than supplementation (22).
Table 1: What the Grades Mean and Suggestions for Practice
Table 2: Levels of Certainty Regarding Net Benefit
|Level of Certainty*||Description|
|High||The available evidence usually includes consistent results from well-designed, well-conducted studies in representative primary care populations. These studies assess the effects of the preventive service on health outcomes. This conclusion is therefore unlikely to be strongly affected by the results of future studies.|
|Moderate||The available evidence is sufficient to determine the effects of the preventive service on health outcomes, but confidence in the estimate is constrained by factors such as:
As more information becomes available, the magnitude or direction of the observed effect could change, and this change may be large enough to alter the conclusion.
|Low||The available evidence is insufficient to assess effects on health outcomes. Evidence is insufficient because of:
More information may allow an estimation of effects on health outcomes.
*The U.S. Preventive Services Task Force defines certainty as "likelihood that the USPSTF assessment of the net benefit of a preventive service is correct." The net benefit is defined as benefit minus harm of the preventive service as implemented in a general, primary care population. The USPSTF assigns a certainty level based on the nature of the overall evidence available to assess the net benefit of a preventive service.
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AHRQ Publication No. 14-05199-EF-2
Current as of November 2013
U.S. Preventive Services Task Force. Vitamin, Mineral, and Multivitamin Supplements for the Primary Prevention of Cardiovascular Disease and Cancer: Draft Recommendation Statement. AHRQ Publication No. 14-05199-EF-2. http://www.uspreventiveservicestaskforce.org/draftrec2.htm