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Draft Research Plan

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

This opportunity for public comment expired on June 19, 2019 at 8:00 PM EST

Note: This is a Draft Research Plan. This draft is distributed solely for the purpose of receiving public input. It has not been disseminated otherwise by the USPSTF. 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.

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.

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In an effort to maintain a high level of transparency in our methods, we open our draft Research Plans to a public comment period before we publish the final version.

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Draft: Proposed 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

Draft: Proposed Key Questions to Be Systematically Reviewed

  1. What is the efficacy of multivitamin supplementation on health outcomes 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 on health outcomes in the general adult population?
  4. What are the harms of supplementation with single nutrients in the general adult population?

Draft: Proposed 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, or type 2 diabetes mellitus) and precancerous outcomes (e.g., adenomas or cervical dysplasia)?

Draft: Proposed Research Approach

The Proposed 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
  • With a history of nonmelanoma skin cancer (i.e., squamous cell or basal cell carcinoma) without current cancer

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

Populations that only include pregnant women, infants, persons with chronic diseases (e.g., cancer, cardiovascular disease, type 2 diabetes mellitus, HIV, end-stage renal disease, tuberculosis, arthritis, or chronic pain), persons with clinical nutritional deficiencies, persons taking prescribed medications that may influence nutritional absorption or status, or institutionalized or hospitalized persons

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 rated as “very high” on the 2017 Human Development Index (as defined by the United Nations Development Programme)
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)
Comparisons Placebo or no intervention Supplementation with other vitamins or minerals
Outcomes KQs 1, 3:
  • Cancer incidence
  • 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)
  • 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)
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, 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
Current as of: May 2019

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

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