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You are here: HomePublic Comments and NominationsOpportunity for Public CommentDraft Recommendation Statement : Draft Recommendation Statement

Draft Recommendation Statement

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

This opportunity for public comment expired on January 25, 2016 at 8:00 PM EST

Note: This is a Draft Recommendation Statement. This draft is distributed solely for the purpose of receiving public input. It has not been disseminated otherwise by the USPSTF. The final Recommendation Statement will be developed after careful consideration of the feedback received and will include both the Research Plan and Evidence Review as a basis.

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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Draft: Recommendation Summary

PopulationRecommendationGrade
(What's This?)
Adults ages 40–75 years with no symptoms or history of CVD and a calculated 10-year CVD event risk of ≥10%

The USPSTF recommends that adults without a history of cardiovascular disease (CVD) (i.e., symptomatic coronary artery disease or thrombotic stroke) use a low- to moderate-dose statin for the prevention of CVD events when all of the following criteria are met:

  • They are ages 40 to 75 years
  • They have one or more CVD risk factors (i.e., dyslipidemia, diabetes, hypertension, or smoking)
  • They have a calculated 10-year risk of a cardiovascular event of 10% or greater

Identification of dyslipidemia and calculation of 10-year CVD event risk requires universal lipid screening in adults ages 40 to 75 years. Select for the Clinical Considerations section for information on screening.

The USPSTF recommends the service. There is high certainty that the net benefit is moderate or there is moderate certainty that the net benefit is moderate to substantial.
Adults ages 40–75 years with no symptoms or history of CVD and a 10-year CVD event risk of 7.5%–10%

Although statin use may be beneficial for the primary prevention of CVD events in some adults with a 10-year CVD event risk of less than 10%, the likelihood of benefit is smaller due to a lower probability of disease and uncertainty in individual risk prediction. Clinicians may choose to offer a low- to moderate-dose statin to certain adults without a history of CVD when all of the following criteria are met:

  • They are ages 40 to 75 years
  • They have one or more CVD risk factors (i.e., dyslipidemia, diabetes, hypertension, or smoking)
  • They have a calculated 10-year risk of a cardiovascular event of 7.5% to 10%

Considerations: No clinical trials have evaluated statin use in adults on the basis of a specific risk threshold calculated by a CVD risk prediction tool. In addition, the incidence of CVD events in the population increases linearly with CVD risk level; there is no point at which event rates abruptly escalate. The likelihood that an individual will benefit from statin use largely depends on his or her absolute baseline risk of a CVD event. Although regular statin use may reduce the risk of a CVD event when the predicted 10-year risk is less than 10%, the number of persons who will avert a CVD event will be much smaller than when that risk is at least 10%, and clinicians’ ability to accurately identify who will go on to experience a CVD event is limited. Persons who place a higher value on the potential benefits than the potential harms and inconvenience of taking a daily medication may choose to initiate statin use for cardiovascular risk reduction.

The USPSTF recommends against routinely providing the service. There may be considerations that support providing the service in an individual patient. There is at least moderate certainty that the net benefit is small.
Adults age 76 years and older without a history of heart attack or stroke

The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of statin use for the prevention of CVD events in adults age 76 years and older without a history of heart attack or stroke.

The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of the service. Evidence is lacking, of poor quality, or conflicting, and the balance of benefits and harms cannot be determined.

These recommendations apply to adults age 40 years and older without a history of CVD who do not have current signs and symptoms of CVD (i.e., symptomatic coronary artery disease or thrombotic stroke) (select for the Clinical Considerations section).

Draft: Rationale

Importance

CVD is a broad term that encompasses a number of atherosclerotic conditions that affect the heart and blood vessels, including coronary heart disease, as ultimately manifested by myocardial infarction (MI), and cerebrovascular disease, as ultimately manifested by stroke. CVD is the leading cause of morbidity and mortality in the United States, accounting for one out of every three deaths among adults.1

Statins are a class of drugs that function by inhibiting the 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) enzyme, the rate-limiting step in the production of cholesterol. Statins reduce total cholesterol, LDL cholesterol, and, to a lesser extent, triglycerides, and probably have anti-inflammatory and plaque stabilization effects.2

Potential Benefits of Statin Use for the Prevention of CVD Events

The USPSTF found adequate evidence that low- to moderate-dose statin use in adults ages 40 to 75 years who have one or more CVD risk factors (dyslipidemia, diabetes, hypertension, or smoking) and a calculated 10-year CVD event risk of at least 10% reduces the probability of a CVD event (MI or thrombotic stroke) by at least a moderate amount.

The USPSTF found adequate evidence that low- to moderate-dose statin use in adults ages 40 to 75 years who have one or more CVD risk factors (dyslipidemia, diabetes, hypertension, or smoking) and a calculated 10-year CVD event risk of 7.5% to 10% reduces the probability of a CVD event by at least a small amount.

The USPSTF found inadequate evidence to conclude whether statins are beneficial in reducing the incidence of CVD events in adults age 76 years and older.

Potential Harms of Statin Use for the Prevention of CVD Events

The USPSTF found adequate evidence that the harms of low- to moderate-dose statin use in adults ages 40 to 75 years are small. Randomized, controlled trials (RCTs) of statin use for the primary prevention of CVD events largely used low and moderate doses; under these conditions, statin use was not associated with serious adverse events. However, evidence concerning the association between statin use and diabetes mellitus is mixed, and limited evidence suggests that there may be a small increased risk of developing diabetes with high-dose statin use. Myalgia is a commonly reported side effect, but trial data do not support the conclusion that statin use plays a major causative role in its occurrence. Evidence on cognitive harms is relatively sparse; further research would more definitively establish the relationship between statin use and cognitive function.

The USPSTF found inadequate evidence about the harms of statin use for the prevention of CVD in adults age 76 years and older without a history of heart attack or stroke.

USPSTF Assessment

The USPSTF concludes with moderate certainty that low- to moderate-dose statin use for the prevention of CVD events in adults ages 40 to 75 years without a history of CVD who have one or more CVD risk factors (dyslipidemia, diabetes, hypertension, or smoking) and a predicted 10-year CVD event risk of 10% or greater has at least a moderate net benefit.

The USPSTF concludes with moderate certainty that low- to moderate-dose statin use for the prevention of CVD events in adults ages 40 to 75 years without a history of CVD who have one or more CVD risk factors (dyslipidemia, diabetes, hypertension, or smoking) and a predicted 10-year CVD event risk of 7.5% to 10% has a small net benefit. The decision to initiate therapy in this population should reflect an assessment of the patient’s specific circumstances and his or her preference for a potential small benefit relative to the potential risks and inconvenience of a lifelong daily medication.

The USPSTF concludes that for adults age 76 years and older without a history of CVD, the evidence is insufficient, and the balance of benefits and harms of statin use to prevent CVD cannot be determined.

Draft: Clinical Considerations

Risk Factors for CVD

Almost all participants enrolled in the trials examining statin use for the primary prevention of CVD had an LDL cholesterol level of 130 to 190 mg/dL or a diabetes diagnosis; hypertension and smoking were also common among trial participants.2 Persons with an LDL cholesterol level of greater than 190 mg/dL were usually excluded from participation, as it was not considered appropriate to randomly assign them to placebo. For the purposes of this recommendation, dyslipidemia is defined as an LDL cholesterol level greater than 130 mg/dL.

A single trial, JUPITER (Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin), excluded persons with dyslipidemia or diabetes and evaluated the effect of high-dose rosuvastatin versus placebo on the incidence of cardiovascular events in participants with elevated C-reactive protein (CRP) levels.3 The USPSTF previously reviewed the evidence on the utility of CRP as a risk predictor of coronary heart disease and found that although there is an association between increased CRP levels and coronary heart disease events, there is insufficient evidence that a reduction in CRP levels results in fewer CVD events.4 Additionally, CRP is not currently included in any of the major risk prediction calculators, and the effects of using CRP in addition to traditional CVD risk factors to guide the prescription of statins for the purposes of CVD risk reduction are uncertain. As such, the USPSTF does not recommend for or against the use of CRP alone as a risk factor in screening to prevent CVD events in asymptomatic adults without a history of CVD.5 In JUPITER, most of the trial participants either also had hypertension or were smokers (57% and 15%, respectively)3—risk factors the USPSTF prioritized for determining potential suitability for statin use.

10-Year Risk of CVD Events

The USPSTF recommends using the American College of Cardiology/American Heart Association (ACC/AHA) pooled cohort equations to calculate 10-year risk of CVD events (available at http://professional.heart.org/professional/GuidelinesStatements/PreventionGuidelines/UCM_457698_SubHomePage.jsp).

In 2013, the ACC/AHA released pooled cohort equations with the publication of new statin therapy guidelines.6 The calculator derived from these equations includes age, sex, race, cholesterol, systolic blood pressure, antihypertension treatment, presence of diabetes, and smoking status as risk factors in the prediction model, and focuses on hard clinical outcomes (heart attack and death from coronary heart disease, as well as ischemic stroke and stroke-related death) as the outcomes of interest.

This risk calculator has been the source of some controversy since its publication, as several investigators not involved with its development have found that it overestimates risk when applied to a series of external U.S. cohorts, especially at the lower end of the risk spectrum.7 Although other risk prediction tools are available, they vary in the populations, risk factors, and outcomes addressed and have their own limitations. The ACC/AHA calculator is, to date, the only U.S.-based CVD risk prediction tool that has published external validations in other U.S.-based populations. Another advantage is that it can generate sex- and race-specific risk predictions. Of particular importance, it is the only tool that includes ischemic stroke as an outcome.

It is important to note that the predicted 10-year risk of CVD events derived from the ACC/AHA risk calculator is heavily influenced by age. For example, 41% of men and 27% of women ages 60 to 69 years without a history of CVD will be found to have a 10% or greater calculated 10-year risk of a CVD event.8 Many older adults, particularly those ages 65 to 75 years, may meet the recommended risk threshold for treatment with statins in spite of the absence of dyslipidemia, diabetes, hypertension, or smoking. No trial data evaluate the use of statins in this age group; thus, the evidence is insufficient to know whether statin use provides them the same or less benefit than in similarly aged adults with CVD risk factors. Decisions about statin use in this age group should be based on shared decisionmaking between clinicians and patients about the potential benefits and harms. Specific recommendations from other organizations for such individuals are discussed in the “Recommendations of Others” section.

Periodic assessment of cardiovascular risk factors from ages 40 to 75 years, including measurement of total, LDL, and high-density lipoprotein cholesterol, is required to implement this recommendation. The optimal intervals for cardiovascular risk assessment are uncertain. On the basis of other guidelines and expert opinion, reasonable options include annual assessment of blood pressure9 and smoking status10 and measurement of lipid levels every 5 years.6 Shorter intervals may be useful for persons whose risk levels are close to those warranting therapy, and longer intervals are appropriate for those who are not at increased risk and have repeatedly normal levels.

The USPSTF systematically searched for evidence on the effect of screening for dyslipidemia in adults ages 20 to 39 years (and in children and adolescents). It found no evidence that screening for dyslipidemia in adults before age 40 years has an effect on either short- or longer-term cardiovascular outcomes;11 thus, the USPSTF neither recommends for or against screening in this age group. A separate recommendation statement addresses screening in children and adolescents;12 it also found insufficient evidence to assess the balance of benefits and harms of screening.

Nonmodifiable risk factors for CVD include older age, male sex, and race/ethnicity. Trials of statins have not included persons whose only risk factors were age, sex, or race/ethnicity. Other risk factors, such as family history of premature coronary artery disease, have not been demonstrated to improve risk prediction in a clinically meaningful way.13

Statin Use for the Primary Prevention of CVD Events

Eighteen RCTs evaluated the effects of statins versus placebo or no statin in adults ages 40 to 75 years without known CVD. Most of the trials enrolled participants on the basis of an elevated LDL cholesterol level or a diabetes diagnosis. Low- or moderate-dose statin use was associated with a reduced risk of all-cause mortality (pooled risk ratio [RR], 0.83 [95% confidence interval (CI), 0.76 to 0.92]), cardiovascular mortality (RR, 0.64 [95% CI, 0.49 to 0.84]), ischemic stroke (RR, 0.72 [95% CI, 0.61 to 0.84]), heart attack (RR, 0.63 [95% CI, 0.56 to 0.71]), and a composite cardiovascular outcome (RR, 0.69 [95% CI, 0.61 to 0.77]).2

Among the study populations, the proportion of CVD events prevented (i.e., the relative risk reduction) was similar across age, sex, race, lipid level, and other risk factor categories.2 Among trials that stratified patients according to a baseline global cardiovascular risk score, similar relative risk estimates were observed among those classified at a higher versus lower assessed CVD event risk.3, 14

However, the absolute magnitude of benefit that an intervention with demonstrated efficacy can have in a specific population—even with similar relative risk reduction estimates across groups—directly depends on the incidence of disease over time in that group. In other words, the more likely it is that a certain population will have a heart attack or ischemic stroke, the greater the potential reduction in the number of CVD events with statin use in that population. This is one of the fundamental reasons for the distinction between a “B” and “C” recommendation for the population that presents with dyslipidemia, diabetes, hypertension, or smoking and a 7.5% to 10% versus 10% or greater 10-year CVD event risk.

In the absence of other risk factors, adults with an LDL cholesterol level greater than 190 mg/dL may still fall below the risk threshold for statin use for CVD prevention.  As noted previously, this group was generally excluded from the primary prevention trials evaluating the effects of statin use on health outcomes, as expert opinion strongly favors intervention. It is possible that the relative risk reduction in this group is higher than in adults with a lower LDL cholesterol level, and the absolute benefit greater than would be predicted from risk calculators. High-dose statin use may still be considered in this group, irrespective of predicted risk.15

Dosage

As previously noted, available RCTs evaluating statins for the primary (as opposed to secondary or tertiary) prevention of CVD events largely used low and moderate doses. The Table lists the drug regimens used in the available trials.

There is limited information available about high-dose statin use in a primary prevention population. As such, the harms of statin use for the primary prevention of CVD events in adults ages 40 to 75 years can only be bounded as small for low- or moderate-dose statin regimens. There may be individual clinical circumstances that warrant consideration of high-dose statin use; however, the most directly applicable body of evidence for patients without a history of CVD demonstrates benefits with low- to moderate-dose statin use.

Available information about high-dose statin use in a primary prevention population comes from the JUPITER trial. The trial found an increased risk of physician-reported incident diabetes with statin use compared with placebo after 2 years of followup (3.2% vs. 2.4%; RR, 1.25 [95% CI, 1.05 to 1.49]).3 Post-hoc analysis subsequently suggested that many of the diabetes cases may have occurred in participants who had other risk factors for diabetes at baseline (e.g., impaired fasting blood glucose or obesity).16

Summary

The incidence of CVD events in the population increases linearly with CVD risk level; there is no threshold at which event rates abruptly escalate. As such, any cutpoint for assessing where the net benefit of statin use shifts from small to moderate for a population requires judgment. Issues to consider include the uncertainty of current risk prediction methods, the overall probability of CVD events occurring in that population, the known and unknown associated harms of statin use, and patient preferences.

The USPSTF concludes that adults who smoke or have dyslipidemia, diabetes, or hypertension and at least a 10% 10-year CVD event risk should be offered a low- to moderate-dose statin. Adults with diabetes or dyslipidemia and a 20% or greater 10-year CVD event risk are most likely to benefit from statin use.

Clinicians may selectively offer adults who smoke or have dyslipidemia, diabetes, or hypertension and a 7.5% to 10% 10-year CVD event risk a low- to moderate-dose statin. Fewer individuals in this population will benefit from the intervention, so the decision to initiate low- to moderate-dose statin use should reflect shared decisionmaking that weighs the potential benefits and harms, the uncertainty about risk prediction, and individual patient preferences, including the acceptability of long-term daily medication use.

Suggestions for Practice Regarding the I Statement

Potential Preventable Burden

Adults age 76 years and older were not included in any of the randomized trials of statin use for the primary prevention of CVD.2 Thus, understanding of the potential benefits of statin use in this age group is limited.

Potential Harms

Evidence on the potential harms of statin use for the primary prevention of CVD events in this age group is very limited. Observational evidence suggests there may be an association between lower cholesterol levels and an increased risk of mortality with advanced age, after adjusting for other risk factors.17, 18

Current Practice

The most current data from the National Health and Nutrition Examination Survey indicate that nearly half (47.6%) of adults age 75 years and older in the United States use prescription cholesterol-lowering medications. The majority (>80%) use a statin alone.19 The survey did not distinguish between the use of cholesterol-lowering medications for the purposes of primary versus secondary prevention, so it is not possible to determine how many of these individuals have had a previous heart attack or ischemic stroke. Another study using data from the Medical Expenditure Panel Survey, which did allow for the differentiation of individuals with and without vascular disease (defined as coronary heart disease, stroke, or peripheral vascular disease), found that the rate of statin use among adults age 80 years and older for the purposes of primary prevention increased from about 9% in 1999–2000 to 34% in 2011–2012.20

The Society for Post-Acute and Long-Term Care Medicine, as part of the Choosing Wisely® campaign, highlighted among its “Top 5 Things Physicians and Patients Should Question” the use of cholesterol-lowering medications in adults with limited life expectancy (i.e., at age 70 and, most particularly, 85 years and older). The Society points to the increased likelihood of an overall unfavorable risk-to-benefit ratio.21

Other Approaches to Prevention

The USPSTF has made other recommendations relevant to the prevention of CVD in adults, including the use of aspirin to prevent CVD, screening for coronary heart disease, screening for hypertension, behavioral counseling on a healthful diet and physical activity in adults at average and high risk of CVD, and screening for and management of obesity in adults (available at www.uspreventiveservicestaskforce.org).

Draft: Other Considerations

Research Needs and Gaps

Additional research is needed to better understand the true predictive accuracy of the pooled cohort equations to predict cardiovascular risk, in order to optimally guide methods for cardiovascular risk assessment. Research to evaluate the optimal frequency of cardiovascular risk assessment, including serum lipid screening, should be performed. There are limited data on different statin dosing strategies; trials that directly compare titrated statin therapy to target lipid levels versus fixed-dose therapy would be of great value, as would studies that directly compare higher- versus lower-dose statin regimens. Such trials should use hard clinical outcomes as endpoints, rather than intermediate markers.

Additional research on the potential harms of statin therapy is also warranted, particularly with respect to the possible association with increased diabetes incidence. Finally, research is needed to assess the balance of benefits and harms of statin use for the primary prevention of cardiovascular events in adults age 76 years and older. At present, there is no trial evidence to evaluate the net benefit of statin therapy in this population.

Draft: Discussion

Burden of Disease

In 2011, there were an estimated 375,000 deaths from coronary heart disease and 130,000 deaths from cerebrovascular disease.22 Coronary heart disease is responsible for approximately one-fifth of deaths among adults ages 45 to 64 years and a quarter of deaths among those age 65 years and older.23 The prevalence of coronary heart disease increases with age, ranging from about 7% in 45- to 64-year-olds to 20% in those age 65 years and older; it is somewhat higher in men (8%) than in women (5%).24

Scope of Review

The USPSTF commissioned two systematic evidence reviews to update its 2008 recommendation on screening for lipid disorders in adults. The reviews addressed the following: 1) the benefits and harms of screening for and treatment of dyslipidemia in asymptomatic adults ages 21 to 29 years on CVD-related morbidity and mortality; 2) the benefits and harms of statin use in reducing the incidence of CVD-related morbidity and mortality or all-cause mortality in asymptomatic adults without a history of CVD events; 3) how the benefits of statin use vary by subgroup, clinical characteristics, or potency; and 4) the benefits of treatment-to-target versus other treatment strategies in asymptomatic adults age 40 and older without a history of CVD events.

Benefits of Statin Use for the Primary Prevention of CVD Events

Eighteen randomized trials evaluated the effects of statins in adults at increased cardiovascular risk but without a history of CVD events. The median duration of followup was 3 years, and three trials were stopped early due to observed benefits in the intervention arm. A majority of participants were male and white.2

Most of the available trials relied on a composite outcome of CVD events as the primary outcome of interest; the exact composition of this combined endpoint varied across trials. In general, statin therapy was statistically significantly associated with a reduced incidence of composite CVD outcomes compared with placebo; pooled analysis of 12 trials found a relative risk of 0.69 (95% CI, 0.61 to 0.77) after 1 to 5 years. Fourteen trials reported on all-cause mortality after 1 to 5 years, and pooled analysis demonstrated a relative risk estimate of 0.83 (95% CI, 0.76 to 0.92). Although this estimate was heavily influenced by the JUPITER and ASCOT-LLA (Anglo-Scandinavian Cardiac Outcomes Trial—Lipid Lowering Arm) trials3, 25 due to their large sizes (both were stopped early), the estimate was robust to multiple sensitivity analyses.2

Nine trials reported on cardiovascular mortality. Pooled analysis revealed a relative risk of 0.64 (95% CI, 0.49 to 0.84) after 2 to 5 years, although statistical heterogeneity was present and there was some inconsistency in the individual trials.2 Eleven trials provided information about fatal and nonfatal MI. Results were mixed, but most large trials found that statin use led to a statistically significantly reduction in the incidence of any MI; the pooled relative risk after 2 to 5 years of followup was 0.63 (95% CI, 0.56 to 0.71).2 Twelve trials reported on the incidence of fatal and nonfatal stroke. After 6 months to 5 years of followup, statin use was associated with a decreased risk of any stroke (RR, 0.72 [95% CI, 0.61 to 0.84]), although none of the trials were designed to evaluate this outcome, given their relatively small sample sizes and short duration of followup. When stratified by fatal and nonfatal stroke, the pooled estimate only showed a statistically significant effect for nonfatal stroke, although few trials reported these outcomes separately, making results imprecise.2

Across these outcomes, benefits appeared consistent across different demographic and clinical subgroups, including those without severe dyslipidemia at baseline.2 Given similar relative risk estimates across a population, the absolute degree of benefit will be greatest in those individuals at higher baseline risk of experiencing a CVD event.

Fourteen trials used fixed-dose statin therapy, of which the majority was a moderate dose. Two trials directly compared different statin doses, but both were underpowered to draw reliable conclusions about clinical outcomes. No studies were identified that directly compared treatment with statins titrated to attain target cholesterol levels versus fixed-dose or other strategies. Although three trials used high-dose statin therapy, only one (JUPITER) investigated hard clinical outcomes (e.g., fatal or nonfatal MI or death from CVD).2, 3 Given the above, direct evidence about how different doses of statin therapy or treatment-to-target strategies might affect clinical outcomes is extremely limited.

Harms of Statin Use for the Primary Prevention of CVD Events

In randomized trials of statin use for the purposes of CVD primary prevention, compared with placebo, statin therapy was not associated with an increased risk of withdrawal due to adverse events, and there were no statistically significant differences in the risk of experiencing any serious adverse event. The trials also found no evidence of an increase in cancer or aminotransferase elevation with statin use.2

Evidence on the association between statin use and adverse cognitive effects is very limited, but no clear increase in risk was observed.2 A systematic review of RCTs and observational studies on the effects of statin use for any indication on cognition found no statistically significant differences in performance scores on tests of attention, visuoperception, motor and processing speed, memory, cognitive performance, or executive function; it also found no effect on the incidence of Alzheimer’s disease or dementia.26

Although muscle pain, soreness, or weakness are commonly reported by patients using statins, there were no statistically significant differences between the intervention and control groups in the RCTs of statin use for primary prevention purposes for myalgia (seven trials; pooled RR, 0.96 [95% CI, 0.79 to 1.16]), myopathy (two trials; pooled RR, 1.10 [95% CI, 0.47 to 2.59]), or rhabdomyolysis (three trials; pooled RR, 1.33 [95% CI, 0.30 to 5.95]), although the CIs for the latter two conditions were very wide due to a low number of reported events.2

Data from five RCTs and two observational studies of statin use for the primary prevention of CVD provided evidence on its potential association with diabetes incidence. Pooled analysis of the RCTs demonstrated no association between statin use and an increased risk of diabetes compared with placebo (RR, 1.04 [95% CI, 0.88 to 1.24]);2 however, the only trial to use a high-dose statin (JUPITER) reported a statistically significant increased risk of diabetes with statin use.3 In post-hoc stratified analysis, participants with one or more risk factors for diabetes (e.g., obesity or metabolic syndrome) were at higher risk of developing diabetes than those without such factors (hazard ratio, 1.28 [95% CI, 1.07 to 1.54] vs. 0.99 [95% CI, 0.45 to 2.21]).16 Observational studies also reported mixed findings; a U.K. case-control study found no association with statin use,27 but an analysis from the Women’s Health Initiative noted an increased diabetes risk (adjusted hazard ratio, 1.48 [95% CI, 1.38 to 1.59]).28

Estimate of Magnitude of Net Benefit

No direct evidence from RCTs is available to guide the choice of a specific CVD risk threshold for statin use. However, in the available trials of statin use among adults at increased risk of CVD but without a history of CVD events, benefits have been generally consistent across different clinical and demographic subgroups (even in those without marked hyperlipidemia). As such, the likelihood that an individual will benefit from statin use is directly associated with his or her absolute baseline risk of experiencing a CVD event.

The USPSTF concludes that adults who smoke or have dyslipidemia, diabetes, or hypertension and at least a 10% 10-year CVD event risk should be offered a low- to moderate-dose statin. In this population, the higher the underlying 10-year risk of a CVD event, the greater the likelihood of benefit from statin use. Because the absolute underlying risk is lower, fewer adults who smoke or have dyslipidemia, diabetes, or hypertension and a 7.5% to 10% 10-year CVD risk will benefit from statin use. As such, any decision to start low- to moderate-dose statin use in this population should involve shared decisionmaking that weighs the potential benefits and harms and the uncertainty surrounding individual CVD risk prediction. It should also take into consideration the personal preferences of each patient, including the acceptability of long-term daily medication use.

For adults age 76 years and older without a history of CVD, the USPSTF concludes that the balance of benefits and harms of statin use to prevent CVD cannot be determined.

Draft: Previous USPSTF Recommendation

This recommendation replaces the USPSTF 2008 recommendation on screening for lipid disorders in adults. The USPSTF makes recommendations about preventive services that fall generally into one of three categories: screening, counseling, and preventive medication. For preventive medication topics, a major purpose of the systematic evidence review is to determine how to identify individuals in the general population for whom the USPSTF can be moderately certain about the balance of benefits and harms of a preventive medication on health outcomes.

Accumulating evidence on the role of statins in preventing CVD events across different populations led the USPSTF to reframe its clinical question of “whom to screen for elevated lipid levels” to “whom to prescribe statin therapy.” Testing for elevated lipid levels is a necessary (but not sufficient) step in the overall assessment of CVD risk to help identify those individuals who may benefit from statin therapy. In the age range in which statins have been studied for primary prevention, universal screening for elevated lipid levels is required to make this determination. Therefore, the screening framework used in the last USPSTF recommendation statement is no longer relevant and has been replaced by a preventive medication framework. This recommendation statement focuses on the assessment of overall CVD risk to identify adults ages 40 to 75 years without a history of CVD who can benefit most from statin use to reduce their risk of experiencing a CVD event. The USPSTF found no studies that evaluated the effects of statin use on health outcomes in disease-free adults younger than age 40 years. The research plan developed for the systematic evidence review that served as the foundation of this draft recommendation statement did not consider reduction in LDL cholesterol to be a sufficient surrogate for health outcomes.

Draft: Recommendations of Others

The ACC/AHA jointly recommend statin use in asymptomatic adults ages 40 to 75 years without a history of CVD who have an LDL cholesterol level of 70 to 189 mg/dL if they also have diabetes (moderate- to high-dose statin use is recommended, depending on their 10-year CVD event risk) or an estimated 10-year CVD event risk of 7.5% or greater, as calculated on the pooled cohort equations risk calculator (shared decisionmaking is recommended before initiating moderate- to high-dose statin use). Instead of treating to a specific LDL cholesterol target, the ACC/AHA recommend fixed-dose statin therapy.15 In response, the Mayo Clinic established a task force; it has generally consistent recommendations, although it emphasizes lifestyle modifications over statin therapy in adults age 40 years and older with an LDL cholesterol level of 70 to 189 mg/dL and who do not have diabetes, in cases where the patient presents with an LDL cholesterol level of less than 100 mg/dL or is sufficiently motivated to reduce their CVD event risk to less than 7.5%.29

The Canadian Cardiovascular Society recommends statin therapy combined with health behavior modification in men age 40 years and older and women age 50 years and older without CVD risk factors, or in adults of any age with CVD risk factors who also have a 20% or greater 10-year CVD event risk or an LDL cholesterol level of 135 to 190 mg/dL and a 10% to 20% CVD event risk based on the Framingham risk score. Statin therapy in adults with a Framingham risk score of less than 10% is reserved for those with genetic hyperlipidemia or an LDL cholesterol level of 193 mg/dL or greater. The treatment strategy is treatment-to-target rather than by therapy dose (e.g., ≥50% reduction in LDL cholesterol).30

The U.K. National Institute for Health Care and Excellence recommends that statin therapy (specifically, atorvastatin 20 mg) be offered for the primary prevention of CVD events to adults age 40 years and older with a 10% or greater 10-year CVD risk, as estimated by the QRISK2 assessment tool. Before offering statin therapy, providers should discuss the benefits of lifestyle modification and optimize the management of all other modifiable CVD risk factors.31

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

Comment period is not open at this time.

References:

1. Mensah GA, Brown DW. An overview of cardiovascular disease burden in the United States. Health Aff (Millwood). 2007;26(1):38-48.
2. Chou R, Dana T, Blazina I, Daeges M, Bougatsos C, Grusing S, Jeanne TL. Statins for Prevention of Cardiovascular Disease in Adults: Systematic Review for the U.S. Preventive Services Task Force. Evidence Synthesis No. 139. AHRQ Publication No. 14-05206-EF-2. Rockville, MD: Agency for Healthcare Research and Quality; 2015.
3. Ridker PM, Danielson E, Fonseca FA, Genest J, Gotto AM Jr, Kastelein JJ, et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med. 2008;359(21):2195-207.
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Draft: Table. Low- and Moderate-Dose Statin Regimens

Low-Dose Statins Moderate-Dose Statins
Fluvastatin 20 to 40 mg Atorvastatin 10 to 20 mg
Lovastatin 20 mg Fluvastatin 40 mg BID
Pitavastatin 1 mg Fluvastatin XL 80 mg
Pravastatin 10 to 20 mg Lovastatin 40 mg
Simvastatin 10 mg Pitavastatin 2 to 4 mg
Pravastatin 40 to 80 mg
Rosuvastatin 5 to 10 mg
Simvastatin 20 to 40 mg

Note: “Low-” and “moderate-” dose categories are from the ACC/AHA 2013 guideline15 on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults.

Current as of: December 2015

Internet Citation: Draft Recommendation Statement: Statin Use for the Primary Prevention of Cardiovascular Disease in Adults: Preventive Medication. U.S. Preventive Services Task Force. November 2016.
https://www.uspreventiveservicestaskforce.org/Page/Document/draft-recommendation-statement175/statin-use-in-adults-preventive-medication1

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