The U.S. Preventive Services Task Force (USPSTF) grades its recommendations (A, B, C, D, or I) and identifies the Levels of Certainty regarding Net Benefit (High, Moderate, and Low). The definitions of these grades can be found at the end of the “Major Recommendations” field.
Summary of Recommendation and Evidence
The USPSTF recommends that adults without a history of cardiovascular disease (CVD) (i.e., symptomatic coronary artery disease or ischemic stroke) use a low- to moderate-dose statin for the prevention of CVD events and mortality when all of the following criteria are met: (1) they are aged 40 to 75 years; (2) they have 1 or more CVD risk factors (i.e., dyslipidemia, diabetes, hypertension, or smoking); and (3) they have a calculated 10-year risk of a cardiovascular event of 10% or greater (B recommendation).
Identification of dyslipidemia and calculation of 10-year CVD event risk requires universal lipids screening in adults aged 40 to 75 years. See the “Clinical Considerations” section for more information on lipids screening and the assessment of cardiovascular risk.
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, because of 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: (1) they are aged 40 to 75 years; (2) they have 1 or more CVD risk factors (i.e., dyslipidemia, diabetes, hypertension, or smoking); and (3) they have a calculated 10-year risk of a cardiovascular event of 7.5% to 10% (C recommendation).
The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of initiating statin use for the primary prevention of CVD events and mortality in adults 76 years and older without a history of heart attack or stroke (I statement).
Patient Population Under Consideration
These recommendations apply to adults 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 ischemic stroke) (see Figure 2 in the original guideline document). Some individuals in this group may have undetected, asymptomatic atherosclerotic changes; for the purposes of this recommendation statement, the USPSTF considers these persons to be candidates for primary prevention interventions. These recommendations do not apply to adults with a low-density lipoprotein cholesterol (LDL-C) level greater than 190 mg/dL (to convert LDL-C values to mmol/L, multiply by 0.0259) or known familial hypercholesterolemia; these persons are considered to have very high cholesterol levels and may require statin use.
Risk Factors for CVD
For the purposes of this recommendation, dyslipidemia is defined as an LDL-C level greater than 130 mg/dL or a high-density lipoprotein cholesterol (HDL-C) level less than 40 mg/dL (to convert HDL-C values to mmol/L, multiply by 0.0259). Most participants enrolled in trials of statin use for the prevention of CVD had an LDL-C level of 130 to 190 mg/dL or a diabetes diagnosis; hypertension and smoking were also common among trial participants. Persons with an LDL-C level greater than 190 mg/dL were usually excluded from trial participation, as it was not considered appropriate to randomly assign them to placebo. Thus, these recommendations do not pertain to persons with very high cholesterol levels (i.e., LDL-C >190 mg/dL) or familial hypercholesterolemia, as they were excluded from most prevention trials.
One trial, JUPITER (Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin), which excluded persons with dyslipidemia or diabetes, evaluated the effect of high-dose rosuvastatin vs. placebo in participants with elevated C-reactive protein (CRP) levels. 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 elevated CRP levels and coronary heart disease events, there is insufficient evidence that a reduction in CRP levels results in fewer CVD events. 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 reducing CVD risk 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. In JUPITER, most of the trial participants either also had hypertension (57%) or were smokers (15%)—risk factors the USPSTF prioritized for determining potential suitability for statin therapy. In the recent Heart Outcomes Prevention Evaluation 3 (HOPE-3) trial, there was no difference in the effects of statins among participants with or without elevated CRP levels.
10-Year Risk of CVD Events
The USPSTF recommends using the American College of Cardiology (ACC)/American Heart Association (AHA) Pooled Cohort Equations to calculate 10-year risk of CVD events. In 2013, the ACC/AHA released the Pooled Cohort Equations with the publication of new statin therapy guidelines. The calculator derived from these equations takes into account age, sex, race, cholesterol levels, systolic blood pressure level, 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; ischemic stroke and stroke-related death) as the outcomes of interest.
This risk calculator has been the source of some controversy, as several investigators not involved with its development have found that it overestimates risk when applied to more contemporary US cohorts, especially those at the lower end of the risk spectrum. Although other risk prediction tools are available, they address varying populations, risk factors, and outcomes and have their own limitations. The ACC/AHA risk calculator is, to date, the only US-based CVD risk prediction tool that has published external validation studies in other US-based populations. Other advantages are that it can generate sex- and race-specific risk predictions and that it includes ischemic stroke as an outcome.
Nonmodifiable risk factors for CVD include older age, male sex, and race/ethnicity; however, statin trials have not included persons with only these risk factors. 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.
It is important to note that the calculated 10-year CVD event risk derived from the ACC/AHA risk calculator is heavily influenced by age. For example, 41% of men and 27% of women aged 60 to 69 years without a history of CVD will be found to have a calculated 10-year CVD event risk of 10% or greater. Many older adults, particularly those aged 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 evaluated statin use among persons in this age group without CVD risk factors; 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 initiating statin use in this age group should be based on shared decision making between patients and clinicians about the potential benefits and harms. Specific recommendations from other organizations for such individuals are discussed in the “Recommendations of Others” section in the original guideline document.
Periodic assessment of cardiovascular risk factors from ages 40 to 75 years, including measurement of total cholesterol, LDL-C, and HDL-C levels, is required to implement this recommendation. The optimal intervals for cardiovascular risk assessment are uncertain. Based on other guidelines and expert opinion, reasonable options include annual assessment of blood pressure and smoking status and measurement of lipid levels every 5 years. Shorter intervals may be useful for persons whose risk levels are close to those warranting therapy, and longer intervals are appropriate for persons who are not at increased risk and have repeatedly normal levels.
Screening and Statin Use in Adults Aged 21 to 39 Years
The USPSTF systematically searched for evidence on the effect of screening for dyslipidemia in adults aged 21 to 39 years. It found insufficient evidence that screening for dyslipidemia before age 40 years has an effect on either short- or longer-term cardiovascular outcomes. The USPSTF found no studies that evaluated the effects of screening vs. no screening, treatment vs. no treatment, or delayed vs. earlier treatment in adults in this age group. Thus, the USPSTF recommends neither for nor against screening for dyslipidemia in this age group. A separate recommendation statement also found insufficient evidence to assess the balance of benefits and harms of screening for dyslipidemia in children and adolescents.
The USPSTF recognizes the rationale for screening for dyslipidemia in adults aged 20 to 39 years to identify those at risk for the development of early atherosclerosis, including those with familial hypercholesterolemia. Unfortunately, the evidence is lacking in this age group. The USPSTF found 4 trials of statin use for primary prevention that enrolled patients younger than 40 years. However, results were not reported separately for this age group, and it comprised a small part of the overall population. One cohort study compared the effects of statins vs. no statins for the treatment of familial hypercholesterolemia. However, the mean age of patients in this study was 44 years. Given the lack of data on the efficacy of screening for or treatment of dyslipidemia in adults aged 20 to 39 years, the USPSTF encourages clinicians to use their clinical judgment for patients in this age group.
Statin Use in Adults Aged 40 to 75 Years
Nineteen RCTs evaluated the effects of statins vs. placebo or no statins in adults aged 40 to 75 years without known CVD. Most of the trials, including the recently published HOPE-3 trial, enrolled participants based on an elevated LDL-C level, a diabetes diagnosis, or at least 1 CVD risk factor. Use of low- or moderate-dose statins was associated with a reduced risk of all-cause mortality (pooled risk ratio [RR], 0.86 [95% CI, 0.80-0.93]), cardiovascular mortality (RR, 0.69 [95% CI, 0.54-0.88]), ischemic stroke (RR, 0.71 [95% CI, 0.62- 0.82]), heart attack (RR, 0.64 [95% CI, 0.57-0.71]), and a composite cardiovascular outcome (RR, 0.70 [95% CI, 0.63-0.78]).
Among the study populations, the proportion of CVD events prevented (i.e., the relative risk reduction) was similar across age, sex, race/ethnicity, lipid level, and other risk factor categories. Among trials that stratified participants according to a baseline global cardiovascular risk score, similar relative risk estimates were observed among those classified at a higher vs. lower CVD event risk.
Given similar relative risk reductions, the absolute magnitude of benefit that an intervention with demonstrated efficacy can have in a specific population directly depends on the incidence of disease over time in that population. In other words, the more likely it is that persons in 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 will be in that population. This is one of the fundamental reasons for the distinction between a grade B and C recommendation for the population that presents with dyslipidemia, diabetes, hypertension, or smoking and a 10% or greater vs. 7.5% to 10% 10-year CVD event risk.
In the absence of other risk factors, adults with an LDL-C level greater than 190 mg/dL may still fall below the risk threshold for statin use for CVD prevention. As noted previously, these persons were generally excluded from the prevention trials evaluating the effects of statin use on health outcomes, because expert opinion strongly favors intervention for these individuals. It is possible that the relative risk reduction in this group is higher than in adults with a lower LDL-C level and that the absolute benefit is greater than would be predicted from a risk calculator.
As previously noted, available RCTs evaluating statins for the prevention of CVD events largely used low and moderate doses. There were no clear differences in estimates of effect when the trials were stratified according to statin dose (see the table for the drug regimens used in the available trials in the original guideline document). The Cholesterol Treatment Trialists meta-analysis showed that greater degree of LDL-C reductions achieved were associated with proportional reductions in major cardiovascular events. However, these analyses were based not on randomized comparisons but on the degree of LDL-C reduction achieved. The degree of cholesterol reduction may be attributable, in part, to interindividual variability in response to statins, not just statin dosage.
Limited information is available about use of high-dose statins in a primary prevention population. As such, the harms of statin use for the prevention of CVD events in adults aged 40 to 75 years can only be bounded as small for low- or moderate-dose statins. There may be individual clinical circumstances that warrant consideration of use of high-dose statins; decisions about dose should be based on shared decision making between patients and clinicians. However, the most directly applicable body of evidence for patients without a history of CVD demonstrates benefits with use of low- to moderate-dose statins.
Available information about use of high-dose statins in a 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 follow-up (3.2% vs 2.4%; RR, 1.25 [95% CI, 1.05-1.49]), which was not reported in trials evaluating use of moderate- or low-dose statins. Post hoc analysis subsequently suggested that many of the diabetes cases in JUPITER may have occurred in participants who had other risk factors for diabetes at baseline (e.g., impaired fasting blood glucose or obesity).
The incidence of CVD events in a population increases linearly with CVD risk level; there is no threshold at which event rates abruptly escalate. As such, any cut point for assessing where the net benefit of statin use shifts from small to moderate for a population requires judgment. Evidence indicates that currently available risk calculators tend to overestimate CVD risk, suggesting that actual benefits may be lower than estimated. Issues to consider include the uncertainty of current risk prediction methods, the overall probability of CVD events occurring in the 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 a 10% or greater 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 persons in this population will benefit from the intervention, so the decision to initiate use of low- to moderate-dose statins should reflect shared decision making that weighs the potential benefits and harms, the uncertainty about risk prediction, and individual patient preferences, including the acceptability of long-term use of daily medication.
Suggestions for Practice Regarding the I Statement for Initiating Statin Therapy for Primary Prevention in Adults 76 Years and Older
Potential Preventable Burden
Adults 76 years and older were not included in any of the randomized trials of statin use for the primary prevention of CVD. Thus, understanding of the potential benefits of initiating statin use for primary prevention in this age group is limited.
Evidence on the potential harms of statin use for the primary prevention of CVD events in adults 76 years and older is very limited. Observational evidence suggests there may be an association between very low cholesterol levels and an increased risk of mortality with advanced age, after adjusting for other risk factors.
The most current data from the National Health and Nutrition Examination Survey indicate that nearly half (47.6%) of adults 75 years and older in the United States use prescription cholesterol-lowering medications. The majority (>80%) use a statin alone. The survey did not distinguish between the use of cholesterol-lowering medications for the purposes of primary vs. secondary prevention, so it is not possible to determine how many of these persons 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 80 years and older for the purposes of primary prevention increased from about 9% in 1999-2000 to 34% in 2011-2012.
The Society for Post-Acute and Long-Term Care Medicine, as part of the Choosing Wisely campaign, highlighted the use of cholesterol-lowering medications in adults with limited life expectancy (i.e., 70 years and, most particularly, 85 years and older) among its “10 Things Physicians and Patients Should Question” because of the increased likelihood of an overall unfavorable risk-to-benefit ratio.
Other Approaches to Prevention
The USPSTF has made other recommendations relevant to the prevention of CVD in adults, including aspirin use for the prevention of CVD, screening for coronary heart disease using electrocardiography, use of nontraditional risk factors in CVD risk assessment, screening for high blood pressure, screening for abnormal blood glucose levels and type 2 diabetes mellitus, interventions for tobacco smoking cessation, behavioral counseling to promote a healthful diet and physical activity for CVD prevention in adults, and screening for and management of obesity in adults.
What the United States Preventive Services Task Force (USPSTF) Grades Mean and Suggestions for Practice
||Suggestions for Practice
||The USPSTF recommends the service. There is high certainty that the net benefit is substantial.
||Offer or provide this service.
||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.
||Offer or provide this service.
||The USPSTF recommends selectively offering or providing this service to individual patients based on professional judgment and patient preferences. There is at least moderate certainty that the net benefit is small.
||Offer or provide this service for selected patients depending on individual circumstances.
||The USPSTF recommends against the service. There is moderate or high certainty that the service has no net benefit or that the harms outweigh the benefits.
||Discourage the use of this service.
||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.
||Read the “Clinical Considerations” section of the USPSTF Recommendation Statement (see the “Major Recommendations” field). If the service is offered, patients should understand the uncertainty about the balance of benefits and harms.
USPSTF Levels of Certainty Regarding Net Benefit
Definition: The U.S. Preventive Services Task Force defines certainty as “likelihood that the USPSTF assessment of the net benefit of a preventive service is correct.” The net benefit is defined as benefit minus harm of the preventive service as implemented in a general, primary care population. The USPSTF assigns a certainty level based on the nature of the overall evidence available to assess the net benefit of a preventive service.
|Level of Certainty
||The available evidence usually includes consistent results from well-designed, well-conducted studies in representative primary care populations. These studies assess the effects of the preventive service on health outcomes. This conclusion is therefore unlikely to be strongly affected by the results of future studies.
||The available evidence is sufficient to determine the effects of the preventive service on health outcomes, but confidence in the estimate is constrained by factors such as:
- The number, size, or quality of individual studies
- Inconsistency of findings across individual studies
- Limited generalizability of findings to routine primary care practice
- Lack of coherence in the chain of evidence
As more information becomes available, the magnitude or direction of the observed effect could change, and this change may be large enough to alter the conclusion.
||The available evidence is insufficient to assess effects on health outcomes. Evidence is insufficient because of:
- The limited number or size of studies
- Important flaws in study design or methods
- Inconsistency of findings across individual studies
- Gaps in the chain of evidence
- Findings not generalizable to routine primary care practice
- A lack of information on important health outcomes
More information may allow an estimation of effects on health outcomes.