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.
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.
Key Questions to be Systematically Reviewed
- What is the efficacy of multivitamin supplementation for reducing cardiovascular disease, cancer, and mortality in the general adult population?
- What are the harms of multivitamin supplementation in the general adult population?
- 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?
- What are the harms of supplementation with single nutrients in the general adult population?
The contextual question will not be systematically reviewed and is not shown in the Analytic Framework.
- 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)?
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).
|Populations||KQs 1, 3: Community-dwelling adults (age ≥18 years), including those:
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:
KQs 2, 4:
|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 dataOnly 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.
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.