Final Research Plan

Statin Use for the Primary Prevention of Cardiovascular Disease in Adults: Preventive Medication

November 05, 2020

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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This figure depicts the analytic framework, which outlines the evidence areas covered in the review, including the population, interventions and related harms, and outcomes. The population includes adults age 18 years and older without prior cardiovascular disease events. An arrow from the population leads to risk assessment, including cardiovascular risk factors and 10-year or lifetime individualized cardiovascular disease risk level. A line representing statin treatment then proceeds from risk assessment to the outcomes examined in the review, which include morbidity or mortality related to coronary heart disease or cerebrovascular accident (stroke), all-cause mortality, and quality of life (Key Questions 1 and 3). A subsequent arrow from the intervention assesses resulting harms (Key Questions 2 and 3).

Abbreviations: CHD=coronary heart disease; CVA=cerebrovascular accident (stroke); CVD=cardiovascular disease; KQ=key question.

1. a. What are the benefits of statins in reducing the incidence of cardiovascular disease (CVD)–related morbidity or mortality or all-cause mortality in asymptomatic adults without prior CVD events?
    b. Do the benefits of statin treatment vary in subgroups defined by demographic, clinical, or socioeconomic characteristics?
    c. What are the benefits of statin treatment titrated to achieve target low-density lipoprotein cholesterol levels vs. a fixed dose strategy?
2. a. What are the harms of statin treatment?
    b. Do the harms of statin treatment vary in subgroups defined by demographic, clinical, or socioeconomic characteristics?
3. How do the benefits and harms of statin treatment vary according to its intensity?

Contextual questions will not be systematically reviewed and are not shown in the Analytic Framework. 

  1. What are the effects of initiating statins for primary prevention at different cardiovascular risk thresholds on the number of persons eligible for treatment and potential benefits and harms (including modeling studies)?
  2. How do patient preferences regarding use of statins for primary prevention vary at different cardiovascular risk thresholds?
  3. What are the effects on mortality and cardiovascular events of use of the coronary artery calcium score alone or in addition to the Pooled Cohort Equations vs. the Pooled Cohort Equations alone to guide decisions regarding use of statins for primary prevention?
  4. What are the effects of consideration of coronary artery calcium score, C-reactive protein, ankle-brachial index, lipoprotein(a), socioeconomic status, race/ethnicity, or family history in addition to the Pooled Cohort Equations vs. the Pooled Cohort Equations alone on patient preferences regarding use of statins for primary prevention?
  5. In persons with similar assessed cardiovascular risk, how does use of statins for primary prevention differ according to demographic, clinical, or socioeconomic characteristics?

Note: A Contextual Question on risk prediction instruments is currently being addressed in a separate USPSTF review on aspirin use for the primary prevention of CVD and colorectal cancer: “Are there patient populations for whom CVD risk is underestimated or overestimated using the Pooled Cohort Equations?” Patient populations include those defined by demographic, clinical, and socioeconomic characteristics.

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 Review. Criteria are overarching as well as specific to each of the key questions.

  Include Exclude
Populations Asymptomatic adults without prior CVD events (e.g., myocardial infarction, angina, revascularization, CVA, or transient ischemic attack), including persons at increased risk for CVD events based on 10-year or lifetime individualized CVD risk level or presence of specific CVD risk factors

Subgroups of interest: Age, sex, race/ethnicity, CVD risk factors, estimated CVD risk, comorbidities, socioeconomic status

 Populations younger than age 18 years or with a prior CVD-related event or familial hyperlipidemia
Interventions Statin therapy Other drugs or non-drug interventions (e.g., diet, exercise)
Comparators KQs 1a, 1c, 2: Placebo, no statin

KQ 1b: Dosing statin to target low-density lipoprotein cholesterol level vs. fixed dose therapy

KQ 3: Higher- vs. lower-intensity statin therapy

 Other comparisons
Outcomes KQs 1, 3: CHD- and/or CVA-related morbidity or mortality; all-cause mortality; quality of life

KQ 2: Myopathy, rhabdomyolysis, myalgia, cognitive loss, diabetes, cataracts, elevations in liver function tests or creatinine phosphokinase levels

 Intermediate outcomes (e.g., lipid levels, measures of atherosclerosis such as intima media thickness or coronary artery calcium score)
Settings Primary care or primary care–generalizable settings Settings not generalizable to primary care
Study Designs KQs 1–3: RCTs, without publication date limitations

KQ 2: Large cohort studies (n>10,000) and case-control studies on harms of statins vs. no statin for primary prevention

 Case series, case reports; poor-quality studies

Abbreviations: CHD=coronary heart disease; CVA=cerebrovascular accident (stroke); CVD=cardiovascular disease; KQ=key question; RCT=randomized, controlled trial.

The draft Research Plan was posted for comment on the USPSTF website from July 9, 2020, to August 5, 2020. After reviewing public comments, the USPSTF revised the Research Plan in the following ways: changed the word “potency” to “intensity” in Key Question 3; added quality of life as an outcome and updated the Analytic Framework to reflect this change; and added cataracts as a potential harm. The USPSTF also added socioeconomic status as a factor defining subgroups of interest and added a contextual question on how use of statins in persons at similar assessed cardiovascular risk varies by demographic, clinical, and socioeconomic characteristics.