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Final Research Plan

Final Research Plan for Vitamin, Mineral, and Multivitamin Supplementation to Prevent Cardiovascular Disease and Cancer: Preventive Medication

Recommendations made by the USPSTF are independent of the U.S. government. They should not be construed as an official position of the Agency for Healthcare Research and Quality or the U.S. Department of Health and Human Services.

Preface

The final Research Plan will be used to guide a systematic review of the evidence by researchers at an Evidence-based Practice Center. The resulting Evidence Review will form the basis of the USPSTF Recommendation Statement on this topic.

The draft Research Plan was available for comment from May 23 until June 19, 2019 at 5:00 p.m., ET.

Analytic Framework

Figure 1 is the analytic framework that depicts the four Key Questions to be addressed in the systematic review. The figure illustrates how multivitamin/mineral supplementation (Key Question 1) or single nutrients and functionally related pairs of vitamins and nutrients (Key Question 3) may result in improved health outcomes (cardiovascular disease incidence and events, cancer incidence, and all-cause and disease-specific mortality) in adults without known nutritional deficiencies. There are an additional two questions related to potential harms resulting from multivitamin/mineral supplementation (Key Question 2) or single nutrients and functionally related pairs of vitamins and nutrients (Key Question 4) in adults without known nutritional deficiencies.

Key Questions to be Systematically Reviewed

  1. What is the efficacy of multivitamin supplementation for reducing cardiovascular disease, cancer, and mortality in the general adult population?
  2. What are the harms of multivitamin supplementation in the general adult population?
  3. What is the efficacy of supplementation with single nutrients or functionally related nutrient pairs for reducing cardiovascular disease, cancer, and mortality in the general adult population?
  4. What are the harms of supplementation with single nutrients in the general adult population?

Contextual Questions

The contextual question will not be systematically reviewed and is not shown in the Analytic Framework.

  1. What is the effect of vitamin and mineral supplementation on cardiovascular disease risk factors (e.g., high blood pressure, abnormal lipid levels, metabolic syndrome, atrial fibrillation, renal disease, or type 2 diabetes mellitus) and precancerous outcomes (e.g., adenoma or cervical dysplasia)?

Research Approach

The Research Approach identifies the study characteristics and criteria that the Evidence-based Practice Center will use to search for publications and to determine whether identified studies should be included or excluded from the Evidence Report. Criteria are overarching as well as specific to each of the key questions (KQs).

  Included Excluded
Populations KQs 1, 3: Community-dwelling adults (age ≥18 years), including those:
  • Without chronic disease and without nutritional deficiencies
  • With high blood pressure or abnormal lipid levels without known cardiovascular disease (e.g., coronary, cerebrovascular, or peripheral artery disease) or type 2 diabetes mellitus

KQs 2, 4: Community-dwelling adults without chronic disease

Populations that only include pregnant women, infants, persons with chronic diseases other than overweight or obesity (e.g., cancer, cardiovascular disease, type 2 diabetes mellitus, HIV, end-stage renal disease, tuberculosis, arthritis, or chronic pain), persons with known clinical nutritional deficiencies, persons taking prescribed medications, persons who had intestinal or stomach surgery or have known malabsorption syndromes that may influence nutritional absorption or status, or persons who are institutionalized or hospitalized

Studies will be excluded if ≥50% of patients have known nutritional deficiencies, cardiovascular disease, type 2 diabetes mellitus, personal history of cancer (other than nonmelanoma skin cancer) or are taking prescription medications that may influence nutritional absorption or status

Setting Trials conducted in countries rated as “very high” on the 2017 Human Development Index (as defined by the United Nations Development Programme) Trials conducted in countries not categorized as “very high” on the 2017 Human Development Index, as there is concern for nutritional deficiencies in developing countries
Interventions KQs 1, 2: Supplementation with multivitamins/minerals, defined as three or more vitamins, minerals, or combinations of both without added herbs, hormones, or drugs, each at a dose less than the tolerable upper intake level, as determined by the Food and Nutrition Board

KQs 3, 4: Supplementation with single nutrients and functionally related pairs (i.e., calcium; folic acid; vitamins B1, B2, B6, B12, D, E, C, and A; iron; zinc; magnesium; niacin; calcium/vitamin D; calcium/magnesium; folic acid/vitamin B12; selenium; beta-carotene; and folic acid/vitamin D6), each at a dose less than the tolerable upper intake level, as determined by the Food and Nutrition Board

Supplementation with other types of dietary supplements (e.g., herbal supplements, omega-3 fatty acids, amino acids, enzymes, proprietary products, fiber, garlic, or turmeric), or vitamin-derived agents with dermatologic indication (i.e., tretinoin, isotretinoin); interventions to increase dietary intake of a single nutrient (e.g., iron)
Comparisons Placebo, no intervention, or usual diet Supplementation with other vitamins or minerals
Outcomes KQs 1, 3:
  • Cancer incidence (any cancer or site-specific)
  • Cardiovascular disease incidence (including coronary heart disease, peripheral artery disease, and cerebrovascular disease)
  • Cardiovascular disease events (myocardial infarction and ischemic and hemorrhagic stroke), heart failure
  • Mortality (all-cause, cardiovascular disease–related, cancer-related)

KQs 2, 4:

  • Serious adverse events (as defined by the study, or those likely requiring medical attention, such as kidney stones, sarcoidosis, and hip fracture)
  • Withdrawals due to adverse events
  • Nonserious adverse events based on self-report or objective measurements, reported by at least 5% of the study sample taking the supplement
  • Paradoxical effects on main outcomes (from trial evidence included for KQs 1 and 3)
KQs 1, 3: Intermediate measures of cardiovascular disease risk factors (i.e., systolic and diastolic blood pressure, lipid measures, and glucose measures), precancerous lesions

Nonmelanoma skin cancer will not be considered in studies that target populations with a history of previous skin cancer

KQs 2, 4: Intermediate or laboratory measures (e.g., hypercalciuria)

Timing All-cause mortality: Minimum of 1 year of followup

All other outcomes: No minimum followup

Less than 1 year of followup (all-cause mortality only)
Study Designs KQs 1, 3: Randomized controlled trials

KQs 2, 4: Randomized, controlled trials or, for serious harms only, large (n ≥1,000) comparative observational studies (cohort or case-control) or postmarket surveillance data

Only randomized, controlled trials will be considered for studies showing paradoxical harmful effects on main outcomes (cancer incidence and cardiovascular disease incidence or events)
All other study designs

Response to Public Comment

The draft Research Plan was posted for comment on the USPSTF website from May 23, 2019 to June 19, 2019. In response to public comment, the USPSTF made a few minor clarifications to which populations, interventions, and outcomes will be included or excluded. For example, populations with overweight or obesity will be included in the evidence review, but populations with known malabsorption syndromes or a history of intestinal or stomach surgery will be excluded. In addition, interventions to increase dietary intake of a single nutrient will be excluded. The USPSTF revised the language in the key questions to clarify that the health outcomes of interest are cardiovascular disease and cancer, as is consistent with the title. The USPSTF further clarified that incidence of site-specific cancers will be included and added metabolic syndrome, atrial fibrillation, and renal disease to the list of cardiovascular disease risk factors to be reviewed for the contextual question.

Current as of: September 2019

Internet Citation: Final Research Plan: Vitamin, Mineral, and Multivitamin Supplementation to Prevent Cardiovascular Disease and Cancer: Preventive Medication. U.S. Preventive Services Task Force. September 2019.
https://www.uspreventiveservicestaskforce.org/Page/Document/final-research-plan/vitamin-supplementation-to-prevent-cvd-and-cancer-preventive-medication

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