2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults

A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines

1.1 Organization of the Panel

The Blood Cholesterol Expert Panel (Expert Panel) was originally convened as the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel IV) appointed by the NHLBI. The Expert Panel was composed of 13 members and 3 ex-officio members, which included primary care physicians, cardiologists, endocrinologists, and experts in clinical lipidology, clinical trials, cardiovascular epidemiology and nutrition, and guideline development. The Expert Panel chair asked all panel members to disclose any conflict-of-interest information to the full panel in advance of the deliberations; members with conflicts were asked to recuse themselves from voting on any aspect of the guideline for which a conflict might exist. All 16 members of the NHLBI Adult Treatment Panel IV Panel transitioned to the ACC/AHA guideline Expert Panel. Independent contractors performed the systematic review with the assistance of the Expert Panel and provided methodological guidance to the Expert Panel.

1.2 Document Review and Approval

A formal peer review process was initially completed under the auspices of the NHLBI and included 23 expert reviewers and representatives of federal agencies. This document was also reviewed by 4 expert reviewers nominated by the ACC and the AHA when the management of the guideline transitioned to the ACC/AHA. The ACC and AHA reviewers’ RWI information is published in this document (Appendix 2).

This document was approved for publication by the governing bodies of the ACC and AHA and endorsed by the American Academy of Physician Assistants, American Association of Cardiovascular and Pulmonary Rehabilitation, American Pharmacists Association, American Society for Preventive Cardiology, Association of Black Cardiologists, Preventive Cardiovascular Nurses Association, and WomenHeart: The National Coalition for Women with Heart Disease.

1.3 Scope of Guideline

This guideline is based on the Full Panel Report, which is provided as an online-only data supplement to the guideline. The Full Panel Report contains background and additional material related to content, methodology, evidence synthesis, rationale, and references and is supported by the NHLBI Systematic Evidence Review, which can be found at http://www.nhlbi.nih.gov/guidelines/cholesterol/ser/. Table 2 provides an overview to facilitate understanding what is new in the present guideline.

The Expert Panel was charged with using data from randomized controlled trials (RCTs) and systematic reviews and meta-analyses of RCTs to update the clinical practice recommendations for the treatment of blood cholesterol levels to reduce ASCVD risk. For this guideline, ASCVD includes coronary heart disease (CHD), stroke, and peripheral arterial disease, all of presumed atherosclerotic origin. These recommendations are intended to provide a strong, evidence-based foundation for the treatment of cholesterol for the primary and secondary prevention of ASCVD in women and men.

Because RCT data were used to identify those most likely to benefit from cholesterol-lowering statin therapy, the recommendations will be of value to primary care clinicians as well as specialists concerned with ASCVD prevention. Importantly, the recommendations were designed to be easy to use in the clinical setting, facilitating the implementation of a strategy of risk assessment and treatment focused on the prevention of ASCVD. The present guideline is intended to address treatment of adults (≥21 years of age) to complement the NHLBI cardiovascular health risk-reduction guideline for children and adolescents (4).

The members of the Expert Panel acknowledge the important contributions arising from decades of genetic and biochemical studies, observational epidemiological and ecological studies, and in vitro and animal experiments that associated higher low-density lipoprotein cholesterol (LDL-C) levels with greater ASCVD risk. These studies provided the rationale for RCTs, which in turn demonstrated that lowering cholesterol levels reduced ASCVD events and thereby established a central, causal role of atherogenic cholesterol-containing lipoprotein particles, particularly LDL, in the genesis of CHD and ASCVD.

Other strategies for using drug therapy to reduce ASCVD events have been advocated, including treat-to-cholesterol target, lowest-is-best, and risk-based treatment approaches. However, only 1 approach has been evaluated in multiple RCTs—the use of fixed doses of cholesterol-lowering drugs to reduce ASCVD risk. Because the overwhelming body of evidence came from statin RCTs, the Expert Panel appropriately focused on these statin RCTs to develop evidence-based guidelines for the reduction of ASCVD risk. We recognize that this represents a significant departure from current strategies. This should not come as a surprise to clinicians. The recent guideline on heart failure has changed long-standing paradigms on the basis of the evidence, and this guideline does as well (5). Future RCTs will be needed to determine the optimal treatment strategy to provide the greatest reduction in ASCVD events with best margin of safety.

The Expert Panel acknowledges that our process did not provide for a comprehensive approach to the detection, evaluation, and treatment of lipid disorders as was done in the prior Adult Treatment Panel III Report (6). However, the present guideline was never intended to be a comprehensive approach to lipid management for purposes other than ASCVD risk reduction. A limited number of expert opinion recommendations were made only when RCT evidence was not present and after a thorough consideration of what the Expert Panel had learned from the RCTs. For the many questions about complex lipid disorders that are beyond the scope of our systematic evidence review, or for which little or no RCT data are available, it is anticipated that clinicians with lipid expertise can contribute to their management.

1.4 Methodology and Evidence Review

Although the Expert Panel was convened before the Institute of Medicine reports on practice guidelines, our evidence-based process followed most of the standards from the Institute of Medicine report, “Clinical Practice Guidelines We Can Trust” (1). The systematic review was limited to RCTs with ASCVD outcomes and systematic reviews and meta-analyses of RCTs with ASCVD outcomes. Observational studies and those with <18 months (CQ1 and CQ2) or <12 months (CQ3) of follow-up were excluded. Support was provided by a methodology contractor and a systematic review and general support contractor and included the following steps:

• • The Expert Panel constructed CQs relevant to clinical practice.

• • The Expert Panel identified (a priori) inclusion/exclusion criteria for each CQ.

• • An independent contractor developed a literature search strategy, based on inclusion/exclusion criteria, for each CQ.

• • An independent contractor executed a systematic electronic search of the published literature from relevant bibliographic databases for each CQ. The date range for the overall literature search was January 1, 1995, through December 1, 2009. However, RCTs with hard ASCVD outcomes of myocardial infarction (MI), stroke, and cardiovascular death published after that date range were eligible for consideration until the Expert Panel began deliberations on relevant recommendations.

• • RCTs that met the inclusion criteria and were independently graded as fair or good quality were included in the evidence tables for the consideration of the Expert Panel. RCTs that were graded as poor quality were excluded.

• • With the assistance of independent methodologists, this evidence base was used to develop a series of evidence statements graded on the level of the evidence (high, medium, or low).

• • The Expert Panel then synthesized the evidence statements into treatment recommendations/summaries graded as A (strong), B (moderate), C (weak), D (recommend against), E (expert), and N (no recommendation).

• • The final evidence statements and treatment recommendations were approved by at least a majority of voting members of the Expert Panel.

• • Guideline implementability appraisals, planned and coordinated by the NHLBI Implementation Work Group, were performed to identify and address barriers to guideline implementation.

In addition, the Expert Panel was able to include major RCTs and meta-analyses of RCTs published through July 2013 in our discussion and as part of the process of determining ACC/AHA grading of the NHLBI expert-level recommendations.

2.1 Lifestyle as the Foundation for ASCVD Risk-Reduction Efforts

It must be emphasized that lifestyle modification (i.e., adhering to a heart-healthy diet, regular exercise habits, avoidance of tobacco products, and maintenance of a healthy weight) remains a crucial component of health promotion and ASCVD risk reduction, both prior to and in concert with the use of cholesterol-lowering drug therapies. Healthy diet or lifestyle modifications were recommended as background therapy for the RCTs of cholesterol-lowering drug therapy. See the “2013 AHA/ACC Guideline on Lifestyle Management to Reduce Cardiovascular Risk” (10) for lifestyle recommendations for healthy adults. Drug therapy for lifestyle-related risk factors such as hypertension is often needed and smoking should be avoided.

2.2 Initiation of Statin Therapy

The Expert Panel found extensive and consistent evidence supporting the use of statins for the prevention of ASCVD in many higher-risk primary- and all secondary-prevention individuals without New York Heart Association class II–IV heart failure who were not receiving hemodialysis. In the RCTs reviewed, initiation of moderate-intensity therapy (lowering LDL-C by approximately 30% to <50%) or high-intensity statin therapy (lowering LDL-C by approximately ≥50%) is a critical factor in reducing ASCVD events. Moreover, statin therapy reduces ASCVD events across the spectrum of baseline LDL-C levels ≥70 mg/dL. In addition, the relative reduction in ASCVD risk is consistent for primary and secondary prevention and for various patient subgroups. Of note, the absolute reduction in ASCVD events is proportional to baseline absolute ASCVD risk. Therefore, statin therapy is recommended for individuals at increased ASCVD risk who are most likely to experience a net benefit in terms of the potential for ASCVD risk reduction and the potential for adverse effects (Table 3; Figure 2).

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Figure 2

Summary of Statin Initiation Recommendations for the Treatment of Blood Cholesterol to Reduce ASCVD Risk in Adults (See Figures 3, 4, and 5 for More Detailed Management Information)

Colors correspond to the Classes of Recommendation in Table 1. Assessment of the potential for benefit and risk from statin therapy for ASCVD prevention provides the framework for clinical decision making incorporating patient preferences.

*Percent reduction in LDL-C can be used as an indication of response and adherence to therapy, but is not in itself a treatment goal.

†The Pooled Cohort Equations can be used to estimate 10-year ASCVD risk in individuals with and without diabetes. The estimator within this application should be used to inform decision making in primary prevention patients not on a statin.

‡Consider moderate-intensity statin as more appropriate in low-risk individuals.

§For those in whom a risk assessment is uncertain, consider factors such as primary LDL-C ≥160 mg/dL or other evidence of genetic hyperlipidemias, family history of premature ASCVD with onset <55 years of age in a first-degree male relative or <65 years of age in a first-degree female relative, hs-CRP ≥2 mg/L, CAC score ≥300 Agatston units, or ≥75th percentile for age, sex, and ethnicity (for additional information, see http://www.mesa-nhlbi.org/CACReference.aspx), ABI <0.9, or lifetime risk of ASCVD. Additional factors that may aid in individual risk assessment may be identified in the future.

‖Potential ASCVD risk-reduction benefits. The absolute reduction in ASCVD events from moderate- or high-intensity statin therapy can be approximated by multiplying the estimated 10-year ASCVD risk by the anticipated relative-risk reduction from the intensity of statin initiated (∼30% for moderate-intensity statin or ∼45% for high-intensity statin therapy). The net ASCVD risk-reduction benefit is estimated from the number of potential ASCVD events prevented with a statin, compared to the number of potential excess adverse effects.

¶Potential adverse effects. The excess risk of diabetes is the main consideration in ∼0.1 excess cases per 100 individuals treated with a moderate-intensity statin for 1 year and ∼0.3 excess cases per 100 individuals treated with a high-intensity statin for 1 year. In RCTs, both statin-treated and placebo-treated participants experienced the same rate of muscle symptoms. The actual rate of statin-related muscle symptoms in the clinical population is unclear. Muscle symptoms attributed to statin therapy should be evaluated (see Table 8, Safety Recommendation 8).

ABI indicates ankle-brachial index; ASCVD, atherosclerotic cardiovascular disease; CAC, coronary artery calcium; hs-CRP, high-sensitivity C-reactive protein; LDL-C, low-density lipoprotein cholesterol; MI, myocardial infarction; and RCT, randomized controlled trial.

On the basis of this large and consistent body of evidence, 4 major statin benefit groups were identified for whom the ASCVD risk reduction clearly outweighs the risk of adverse events based on a strong body of evidence. These are 1) secondary prevention in individuals with clinical ASCVD, 2) primary prevention in individuals with primary elevations of LDL-C ≥190 mg/dL, 3) primary prevention in individuals with diabetes 40 to 75 years of age who have LDL-C 70 to 189 mg/dL, and 4) primary prevention in individuals without diabetes and with estimated 10-year ASCVD risk ≥7.5%, 40 to 75 years of age who have LDL-C 70 to 189 mg/dL. Moderate evidence supports the use of statins for primary prevention in individuals with 5% to <7.5% 10-year ASCVD risk, 40 to 75 years of age with LDL-C 70 to 189 mg/dL. Selected individuals with <5% 10-year ASCVD risk, or <40 or >75 years of age may also benefit from statin therapy. Clinicians and patients should engage in a discussion of the potential for ASCVD risk-reduction benefits, adverse effects, drug–drug interactions, and consider patient preferences for treatment. This discussion also provides the opportunity to re-emphasize healthy-lifestyle habits and address other risk factors.

Clinical ASCVD is defined by the inclusion criteria for the secondary-prevention statin RCTs (acute coronary syndromes, a history of MI, stable or unstable angina, coronary or other arterial revascularization, stroke, transient ischemic attack, or peripheral arterial disease presumed to be of atherosclerotic origin). For primary prevention in individuals without clinical ASCVD or diabetes who have an LDL-C 70 to 189 mg/dL, the estimated absolute 10-year risk of ASCVD (defined as nonfatal MI, CHD death, or nonfatal and fatal stroke) should be used to guide the initiation of statin therapy. The 10-year ASCVD risk should be estimated with the Pooled Cohort Equations (Section 4.7). For the primary prevention of ASCVD in individuals with diabetes (diabetes mellitus type 1 and type 2), estimated 10-year ASCVD risk can also be used to guide the intensity of statin therapy. For those with clinical ASCVD or with LDL-C ≥190 mg/dL who are already in a statin benefit group, it is not appropriate to estimate 10-year ASCVD risk. In primary prevention, additional factors may influence ASCVD risk in those for whom a risk-based decision is unclear. These include a primary LDL-C ≥160 mg/dL or other evidence of genetic hyperlipidemias, family history of premature ASCVD with onset <55 years of age in a first-degree male relative or <65 years of age in a first-degree female relative, high-sensitivity C-reactive protein ≥2 mg/L, coronary artery calcium score ≥300 Agatston units or ≥75th percentile for age, sex, and ethnicity (for additional information, see http://www.mesa-nhlbi.org/CACReference.aspx.), ankle-brachial index <0.9, and elevated lifetime risk of ASCVD.

The findings support the use of statins to prevent both nonfatal and fatal ASCVD events. Such an approach can reduce the large burden of disability from nonfatal stroke (for which women are at higher risk than men) and nonfatal CHD events. Primary and secondary prevention of ASCVD with statins can positively impact rising healthcare costs. In addition, a high level of evidence was found that statins reduce total mortality in individuals with a history of prior ASCVD events (e.g., secondary-prevention settings). In individuals with no prior history of ASCVD events (e.g., primary-prevention settings), there is moderate evidence that statins reduce total mortality in individuals at increased ASCVD risk. It should be noted that 2 meta-analyses published after the completion of the Expert Panel’s systematic review provide strong evidence that statins reduce total mortality in primary prevention (12,13).

3.1 Identification of CQs

Although limited to 3 CQs, these questions were considered the most important to answer in order to identify whom to treat and with what treatment(s) and to consider how intensively the treatments should be used. The first 2 CQs evaluated the evidence for LDL-C and non–HDL-C goals for the secondary and primary prevention of ASCVD with cholesterol-lowering drug therapy. Titration to specific LDL-C goals has been considered a fundamental therapeutic strategy in deciding on the adequacy of cholesterol-lowering therapy for secondary and primary prevention. Therefore, a comprehensive systematic review of the evidence base supporting this concept was essential. The third CQ had several objectives:

• • Identify groups of patients who will benefit from pharmacological treatment,

• • Define the pharmacological treatment(s) for which there is the best evidence of net benefit, and

• • Provide guidance on the appropriate intensity of pharmacological treatment to reduce ASCVD risk.

4.1 Intensity of Statin Therapy in Primary and Secondary Prevention

The Expert Panel defines the intensity of statin therapy on the basis of the average expected LDL-C response to a specific statin and dose. “High-intensity,” “moderate-intensity,” and “low-intensity” statin therapy definitions were derived from the systematic reviews for CQ1 and CQ2. The basis for differentiation among specific statins and doses arose from the RCTs included in CQ1, where there was a high level of evidence that high-intensity statin therapy with atorvastatin 40 mg to 80 mg reduced ASCVD risk more than moderate-intensity statin therapy with atorvastatin 10 mg, pravastatin 40 mg, or simvastatin 20 mg to 40 mg twice daily. Classifying specific statins and doses by the percent reduction in LDL-C level is based on evidence that the relative reduction in ASCVD risk from statin therapy is related to the degree by which LDL-C is lowered. However, no variation in the relative reduction in ASCVD risk was observed after the data were adjusted for LDL-C reduction. Furthermore, there is no differentiation between the specific statins and doses used in primary- and secondary-prevention RCTs, according to a high level of evidence that statins reduce ASCVD risk similarly in both populations.

Percent reductions in LDL-C for a specific statin and dose were calculated for the RCTs included in individual meta-analyses conducted by the Cholesterol Treatment Trialists (CTT) in 2010 (20), in which statin therapy reduced ASCVD events. High-intensity statin therapy on average lowers LDL-C by approximately ≥50%, moderate-intensity statin therapy lowers LDL-C by approximately 30% to <50%, and lower-intensity statin therapy lowers LDL-C by <30% (Table 5).

4.2 LDL-C and Non–HDL-C Treatment Goals

The Expert Panel did not find evidence to support titrating cholesterol-lowering drug therapy to achieve optimal LDL-C or non–HDL-C levels because the clinical trials were essentially fixed-dose trials (CQ1 and CQ2). Dosage increases did occur in a few RCTs with the intent of maximizing statin therapy. Therefore, these were not truly tests of defining optimal goals for LDL-C in primary and secondary prevention because not all individuals in the statin treatment groups received drug therapy titrated to achieve a specific LDL-C or non–HDL-C goal, nor were specific treatment targets compared. One RCT in CQ3 was identified that showed no additional ASCVD event reduction from the addition of nonstatin therapy to further lower non–HDL-C levels once an LDL-C goal had been reached. In AIM-HIGH (Atherothrombosis Intervention in Metabolic Syndrome With Low HDL/High Triglycerides and Impact on Global Health Outcomes), the additional reduction in non–HDL-C levels (as well as further reductions in apolipoprotein B, lipoprotein[a], and triglycerides in addition to HDL-C increases) with niacin therapy did not further reduce ASCVD risk in individuals treated to LDL-C levels of 40 to 80 mg/dL (9).

Therefore, given the absence of data on titration of drug therapy to specific goals, no recommendations are made for or against specific LDL-C or non–HDL-C goals for the primary or secondary prevention of ASCVD.

4.3 Secondary Prevention

Women and men with clinical ASCVD (defined from the RCT inclusion criteria as acute coronary syndromes; history of MI, stable or unstable angina, coronary or other arterial revascularization, stroke, transient ischemic attack, or peripheral arterial disease presumed to be of atherosclerotic origin) arterial revascularization, stroke, transient ischemic attack, or peripheral arterial disease presumed to be of atherosclerotic origin are at increased risk for recurrent ASCVD and ASCVD death. An extensive body of evidence demonstrates that high-intensity statin therapy reduces ASCVD events more than moderate-intensity statin therapy (Table 4) in individuals with clinical ASCVD.

High-intensity statin therapy should be initiated for adults ≤75 years of age with clinical ASCVD who are not receiving statin therapy, or the intensity should be increased in those receiving a low- or moderate-intensity statin, unless they have a history of intolerance to high-intensity statin therapy or other characteristics that could influence safety (Section 5). This is consistent with RCT data. In 2 trials, patients were previously treated with a moderately intensive statin (46,47), and in 2 trials, 75% to 97% of patients had not received prior statin therapy (48,78). The high-intensity statins atorvastatin 80 mg and rosuvastatin 20 mg daily reduce LDL-C ≥50% on average and have been shown to reduce ASCVD events in RCTs.

Although atorvastatin 40 mg reduces LDL-C by approximately ≥50%, this dose was used in only 1 RCT if the participant was unable to tolerate atorvastatin 80 mg/dL. Whether an individual receiving atorvastatin 40 mg should be uptitrated to atorvastatin 80 mg should be based on the potential for an ASCVD risk-reduction benefit and the potential for adverse effects, drug–drug interactions, and consider patient preferences.

In individuals with clinical ASCVD in whom high-intensity statin therapy would otherwise be used, either when high-intensity statin therapy is contraindicated or when characteristics predisposing to statin-associated adverse effects are present, moderate-intensity statin should be used as the second option, if tolerated (Section 5). In the relatively few individuals >75 years of age who were included in RCTs of high- versus moderate-intensity statin therapy, there was no clear evidence of an additional reduction in ASCVD events from high-intensity statin therapy. In contrast, individuals >75 years of age did experience a reduction in ASCVD events in the trials of mostly moderate-intensity statin therapy, as compared with control. Therefore, moderate-intensity statin therapy should be considered for individuals >75 years of age with clinical ASCVD. However, in acknowledgment that older participants in RCTs were likely to be healthier than many older individuals in the general population, the use of statin therapy should be individualized in persons >75 years of age with clinical ASCVD, according to the potential for ASCVD risk-reduction benefits, adverse effects, drug–drug interactions, and consider patient preferences. The Expert Panel considers it reasonable to continue statin therapy in persons >75 years of age who have clinical ASCVD and are tolerating statin therapy.

The flow diagram for the initiation and management of statin therapy in individuals with clinical ASCVD is provided in Figure 3.

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Figure 3

Initiating Statin Therapy in Individuals With Clinical ASCVD

Colors correspond to the Classes of Recommendation in Table 1.

*Fasting lipid panel preferred. In a nonfasting individual, a non–HDL-C level ≥220 mg/dL could indicate genetic hypercholesterolemia that requires further evaluation or a secondary etiology. If nonfasting triglycerides are ≥500 mg/dL, a fasting lipid panel is required.

†It is reasonable to evaluate the potential for ASCVD benefits and for adverse effects, and to consider patient preferences, in initiating or continuing a moderate- or high-intensity statin in individuals with ASCVD who are >75 years of age.

ALT indicates alanine transaminase; ASCVD, atherosclerotic cardiovascular disease; CK, creatine kinase; FH, familial hypercholesterolemia; LDL-C, low-density lipoprotein cholesterol; and ULN, upper limit of normal.

4.4 Primary Prevention in Individuals ≥21 Years of Age With LDL-C ≥190 mg/dL

This guideline recognizes that individuals ≥21 years of age with primary, severe elevations of LDL-C (≥190 mg/dL) have a high lifetime risk for ASCVD events. This is due to their lifetime exposure to markedly elevated LDL-C levels arising from genetic causes. Thus, at age 21, these individuals should receive statin therapy if they have not already been diagnosed and treated before this age. Although in most clinical trials individuals with LDL-C ≥190 mg/dL were not included because of their need for treatment, extensive evidence shows that each 39-mg/dL reduction in LDL-C by statin therapy reduces ASCVD risk by about 20%. Patients with primary elevations of LDL-C ≥190 mg/dL require even more substantial reductions in their LDL-C levels and intensive management of other risk factors to reduce their ASCVD event rates. Therefore, it is reasonable to use high-intensity statin therapy to achieve at least a 50% reduction. It is recognized that maximal statin therapy might not be adequate to lower LDL-C sufficiently to reduce ASCVD event risk in individuals with primary severe elevations of LDL-C. In addition to a maximally tolerated dose of statin, nonstatin cholesterol-lowering medications are often needed to lower LDL-C to acceptable levels in these individuals. Because the hypercholesterolemia in these high-risk individuals is often genetically determined, family screening is especially important in this group to identify additional family members who would benefit from assessment and early treatment.

Secondary causes of severe elevations of LDL-C ≥190 mg/dL and triglycerides ≥500 mg/dL often contribute to the magnitude of the hyperlipidemia and should be evaluated and treated appropriately. For guidance, we note that in a lipid specialty clinic, the most frequently encountered secondary conditions were excessive alcohol intake, uncontrolled diabetes, and overt albuminuria (79). Table 6 focuses on secondary causes of hyperlipidemia most likely encountered in clinical practice (80). Management of individuals with fasting triglycerides ≥500 mg/dL has been addressed in an AHA statement (45).

The flow diagram for the initiation and management of statin therapy in individuals with LDL-C ≥190 mg/dL is provided in Figure 4.

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Figure 4

Initiating Statin Therapy in Individuals Without Clinical ASCVD

Colors correspond to the Classes of Recommendation in Table 1.

*Fasting lipid panel preferred. In a nonfasting individual, a non–HDL-C level ≥220 mg/dL could indicate genetic hypercholesterolemia that requires further evaluation or a secondary etiology. If nonfasting triglycerides are ≥500 mg/dL, a fasting lipid panel is required.

†The Pooled Cohort Equations can be used to estimate 10-year ASCVD risk in individuals with and without diabetes.

A downloadable spreadsheet enabling estimation of 10-year and lifetime risk for ASCVD and a Web-based calculator are available at http://my.americanheart.org/cvriskcalculator and http://www.cardiosource.org/en/Science-And-Quality/Practice-Guidelines-and-Quality-Standards/2013-Prevention-Guideline-Tools.aspx.

‡For those in whom a risk assessment is uncertain, consider factors such as primary LDL-C ≥160 mg/dL or other evidence of genetic hyperlipidemias; family history of premature ASCVD with onset <55 years of age in a first-degree male relative or <65 years of age in a first-degree female relative, high-sensitivity C-reactive protein ≥2 mg/L; CAC ≥300 Agatston units or ≥75th percentile for age, sex, and ethnicity (for additional information, see http://www.mesa-nhlbi.org/CACReference.aspx); ABI <0.9; or lifetime risk of ASCVD. Additional factors that may aid in individual risk assessment could be identified in the future.

§1) Potential ASCVD risk-reduction benefits. The absolute reduction in ASCVD events from moderate- or high-intensity statin therapy can be approximated by multiplying the estimated 10-year ASCVD risk by the anticipated relative-risk reduction from the intensity of statin initiated (∼30% for moderate-intensity statin or ∼45% for high-intensity statin therapy). The net ASCVD risk-reduction benefit is estimated from the number of potential ASCVD events prevented with a statin, compared to the number of potential excess adverse effects. 2) Potential adverse effects. The excess risk of diabetes is the main consideration in ∼0.1 excess cases per 100 individuals treated with a moderate-intensity statin for 1 year and ∼0.3 excess cases per 100 individuals treated with a high-intensity statin for 1 year. In RCTs, both statin-treated and placebo-treated participants experienced the same rate of muscle symptoms. The actual rate of statin-related muscle symptoms in the clinical population is unclear. Muscle symptoms attributed to statin therapy should be evaluated (see Table 8, Safety Recommendation 8).

ABI indicates ankle-brachial index; ALT, alanine transaminase; ASCVD, atherosclerotic cardiovascular disease; CAC, coronary artery calcium; CK, creatine kinase; FH, familial hypercholesterolemia; LDL-C, low-density lipoprotein cholesterol; MI, myocardial infarction; RCT, randomized controlled trial; and ULN, upper limit of normal.

4.5 Primary Prevention in Individuals With Diabetes

A high level of evidence supports the use of moderate-intensity statin therapy in persons with diabetes who are 40 to 75 years of age. The only trial of high-intensity statin therapy in primary prevention was performed in a population without diabetes. However, a high level of evidence existed for event reduction with statin therapy in individuals with a ≥7.5% estimated 10-year ASCVD risk (Section 4.6) who did not have diabetes to recommend high-intensity statin therapy preferentially for individuals with diabetes and a ≥7.5% estimated 10-year ASCVD risk (Section 4.7). This consideration for those with diabetes who are 40 to 75 years of age recognizes that these individuals are at substantially increased lifetime risk for ASCVD events and death. Moreover, individuals with diabetes experience greater morbidity and worse survival after the onset of clinical ASCVD. In persons with diabetes who are <40 years of age or >75 years of age, or whose LDL-C is <70 mg/dL, statin therapy should be individualized on the basis of considerations of ASCVD risk-reduction benefits, the potential for adverse effects and drug–drug interactions, and patient preferences (Figure 4).

4.6 Primary Prevention in Individuals Without Diabetes and With LDL-C 70 to 189 mg/dL

In individuals 40 to 75 years of age with LDL-C 70 to 189 mg/dL who do not have clinical ASCVD or diabetes, initiation of statin therapy based on estimated 10-year ASCVD risk is recommended, regardless of sex, race, or ethnicity (Section 4.7). Point estimates of statin-associated reductions in the relative risk of ASCVD in primary prevention are similar for both women and men. There also is no evidence that the ASCVD risk-reduction benefit or adverse-effect profiles differ by race.

To better identify those individuals without ASCVD who would most benefit from statin therapy to reduce ASCVD risk, data were used from the 3 exclusively primary-prevention RCTs that included individuals with LDL-C levels <190 mg/dL, almost all of whom had LDL-C levels ≥70 mg/dL (17,18,49). From these trials, an estimate of the expected 10-year ASCVD event rates was derived from the placebo groups. The rates of excess adverse events in the statin treatment groups were obtained from meta-analyses of statin RCTs. A high level of evidence for an ASCVD risk-reduction benefit from initiation of moderate- or high-intensity statin therapy in individuals 40 to 75 years of age with ≥7.5% estimated 10-year ASCVD risk was found (Section 4.7). The reduction in ASCVD risk clearly outweighs the potential for adverse effects (Table 7). Thus, it is recommended that individuals 40 to 75 years of age, who are not already candidates for statin therapy on the basis of the presence of clinical ASCVD, diabetes, or LDL-C ≥190 mg/dL, receive statin therapy if they have a ≥7.5% estimated 10-year risk for ASCVD and LDL-C 70 to 189 mg/dL. Although only 1 exclusively primary-prevention RCT included individuals with LDL-C 70 to <100 mg/dL, the Cholesterol Treatment Trialists 2010 meta-analysis found a relative reduction in ASCVD events of similar magnitude across the spectrum of LDL-C levels ≥70 mg/dL (20). Given that the relative risk reduction is similar across the range of LDL-C 70 to 189 mg/dL, the absolute benefit of statin therapy in primary prevention is determined by the global risk estimate using all the risk factor information and is reflected in the estimated 10-year ASCVD risk.

A conservative estimate of adverse events includes excess cases of new-onset diabetes and rare cases of myopathy and hemorrhagic stroke. The rate of excess diabetes varies by statin intensity. For moderate-intensity statins, approximately 0.1 excess case of diabetes per 100 statin-treated individuals per year has been observed, and for high-intensity statins, approximately 0.3 excess case of diabetes per 100 statin-treated individuals per year has been observed (52,81). The long-term adverse effects of statin-associated cases of diabetes over a 10-year period are unclear and are unlikely to be equivalent to an MI, stroke, or ASCVD death. Myopathy (∼0.01 excess case per 100) and hemorrhagic stroke (∼0.01 excess case per 100) make minimal contributions to excess risk from statin therapy (13).

Although a similar level of evidence of a reduction in ASCVD events from moderate- and high-intensity statin therapy is present for those with a 5% to <7.5% estimated 10-year ASCVD risk, the potential for adverse effects may outweigh the potential for ASCVD risk-reduction benefit when high-intensity statin therapy is used in this risk group. However, for moderate-intensity statin therapy, the ASCVD risk reduction clearly exceeds the potential for adverse effects.

Before initiating statin therapy for the primary prevention of ASCVD in adults with ≥7.5% or 5% to <7.5% estimated 10-year ASCVD risk, it is reasonable for clinicians and patients to engage in a discussion of the proposed therapy. This discussion should include the potential for ASCVD benefit, the potential for adverse effects and drug–drug interactions, and consideration of patient preferences for treatment.

No primary-prevention RCT data were available for individuals 21 to 39 years of age, and few data were available for individuals >75 years of age. Additionally, in individuals 40 to 75 years of age with <5% estimated 10-year ASCVD risk, the net benefit from statin therapy over a 10-year period may be small. Therefore, in adults with LDL-C <190 mg/dL who are not otherwise identified in a statin benefit group or for whom a risk-based treatment decision is uncertain after quantitative risk assessment, clinician knowledge, experience, and skill (“the art of medicine”) and patient preferences all contribute to the decision to initiate statin therapy (82). Before initiation of statin therapy, the clinician-patient discussion should include consideration of the potential for ASCVD risk-reduction benefits, adverse effects, and drug–drug interactions. Additional factors may also be considered to inform treatment decision making in selected individuals. Factors that can contribute to assessment of ASCVD risk include primary LDL-C ≥160 mg/dL or other evidence of genetic hyperlipidemias; family history of premature ASCVD with onset <55 years of age in a first-degree male relative or <65 years of age in a first-degree female relative; high-sensitivity C-reactive protein ≥2 mg/L, coronary artery calcium score ≥300 Agatston units or ≥75th percentile for age, sex, and ethnicity (for additional information, see http://www.mesa-nhlbi.org/CACReference.aspx); ankle-brachial index <0.9; or elevated lifetime risk of ASCVD. Additional factors that might aid in individual risk assessment could be identified in the future.

For an individual <40 years of age, the 10-year horizon might not be optimal for predicting lifetime risk of ASCVD (see 2013 ACC/AHA Guideline on the Assessment of Cardiovascular Risk) (11). Future RCTs will be needed to determine the optimal age at which to initiate statin therapy to reduce ASCVD risk, as well as to determine the optimum duration of statin therapy.

4.7 Risk Assessment in Primary Prevention

To estimate more closely the total burden of ASCVD, this guideline recommends a comprehensive assessment of the estimated 10-year risk for an ASCVD event that includes both CHD and stroke. This is in contrast to the use of an estimated 10-year risk for hard CHD (defined as nonfatal MI and CHD death) (83).

This guideline recommends using the new Pooled Cohort Risk Assessment Equations developed by the Risk Assessment Work Group to estimate the 10-year ASCVD risk (defined as first-occurrence nonfatal and fatal MI and nonfatal and fatal stroke) for the identification of candidates for statin therapy (see http://my.americanheart.org/cvriskcalculator and http://www.cardiosource.org/en/Science-And-Quality/Practice-Guidelines-and-Quality-Standards/2013-Prevention-Guideline-Tools.aspx for risk calculator). These equations should be used to predict stroke as well as CHD events in non-Hispanic, Caucasian, and African-American women and men 40 to 79 years of age with or without diabetes who have LDL-C levels 70 to 189 mg/dL and are not receiving statin therapy. A more complete discussion of risk assessment is provided in the Full Panel Report Supplement.

This guideline does not require specific risk factor counting for risk assessment or the use of RCT risk factor inclusion criteria to determine statin eligibility. Rather, a global ASCVD risk assessment to guide initiation of statin therapy was chosen for several important reasons (see rationale in Table 7 and further discussion in Section 7.3 of the Full Panel Report Supplement): 1) The Cholesterol Treatment Trialists individual-level meta-analyses were used to evaluate the effect of statins in various important patient subgroups, including risk factor cutpoints used for RCT eligibility. The Expert Panel found that statin therapy reduces ASCVD events regardless of risk factor characteristics in both primary and secondary prevention. Therefore, the rationale for using fixed cutpoints to determine whether statin therapy should be used is refuted by a consideration of the total body of evidence. 2) Use of absolute ASCVD risk facilitates a quantitative assessment of the potential for an ASCVD risk-reduction benefit as compared with the potential for adverse effects. 3) Use of an RCT eligibility criteria–based approach results in failure to identify a substantial proportion of higher-risk individuals who could benefit from statin therapy and overidentification of very-low-risk individuals who might not experience a net benefit from statin therapy over a 10-year period.

4.8 Heart Failure and Hemodialysis

No recommendation was made with regard to the initiation or continuation of statin therapy in 2 specific groups: 1) individuals with New York Heart Association class II–IV heart failure, and 2) individuals undergoing maintenance hemodialysis. In the 4 RCTs reviewed that specifically addressed statin treatment in these groups, there were individuals with and without heart disease (84–87). Although statin therapy did not reduce ASCVD events in 2 RCTs for each condition (84–87), there was insufficient information on which to base recommendations for or against statin treatment. Future research may identify subgroups of patients with these conditions that may benefit from statin therapy. In individuals with these conditions, the potential for ASCVD risk-reduction benefits, adverse effects, and drug–drug interactions, along with other cautions and contraindications to statin therapy and choice of statin dose, must also be considered by the treating clinician.

6.1 Monitoring Statin Therapy

A high level of RCT evidence supports the use of an initial fasting lipid panel (total cholesterol, triglycerides, HDL-C, and calculated LDL-C), followed by a second lipid panel 4 to 12 weeks after initiation of statin therapy, to determine a patient’s adherence. Thereafter, assessments should be performed every 3 to 12 months as clinically indicated. Adherence to both medication and lifestyle regimens are required for ASCVD risk reduction. After statin therapy has been initiated, some individuals experience unacceptable adverse effects when taking the recommended intensity of statin therapy. Once the severity and association of adverse effects with statin therapy has been established, and once factors potentially contributing to statin intolerance are resolved, the patient should be given lower doses of the same statin or an alternative appropriate statin, until a statin and dose that have no adverse effects have been identified (Table 8, Recommendation 8).

See Figure 5 for a flow diagram on monitoring statin response for the initiation of nonstatin therapy.

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Figure 5

Statin Therapy: Monitoring Therapeutic Response and Adherence

Colors correspond to the Classes of Recommendation in Table 1.

*Fasting lipid panel preferred. In a nonfasting individual, a non–HDL-C level ≥220 mg/dL may indicate genetic hypercholesterolemia that requires further evaluation or a secondary etiology. If nonfasting triglycerides are ≥500 mg/dL, a fasting lipid panel is required.

†In those already on a statin, in whom baseline LDL-C is unknown, an LDL-C <100 mg/dL was observed in most individuals receiving high-intensity statin therapy in RCTs.

‡See Section 6.3.1.

HDL-C indicates high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; and RCTs, randomized clinical trials.

6.2 Optimizing Statin Therapy

Although high-intensity statin therapy reduces ASCVD events more than moderate-intensity statin therapy, lower-intensity statin therapy has also been shown to reduce ASCVD events, although to a lesser degree. Therefore, individuals who merit guideline-recommended statin therapy should be treated with the maximum-appropriate intensity of a statin that does not cause adverse effects.

6.3 Insufficient Response to Statin Therapy

7.1 Sex and Racial and Ethnic Subgroups

Because the RCT evidence shows that the absolute benefit of statin treatment is proportional to baseline ASCVD risk, treatment decisions for women and racial and ethnic subgroups should be based on the level of ASCVD risk. This conclusion is a departure from previous approaches that focused on LDL-C levels to guide treatment decisions. Statin treatment based on estimated 10-year ASCVD risk avoids the overtreatment of lower-risk groups, such as younger, non-Hispanic white women who, despite moderate elevations in LDL-C, are typically not at significantly increased risk for ASCVD in the next 10 years in the absence of substantial risk factor burden. However, ignoring the increased ASCVD risk in African American women and men might result in the undertreatment of some individuals who are at significantly higher ASCVD risk at the same LDL-C level. Thus, this guideline recommends statin therapy for individuals in whom it is most likely to provide ASCVD risk reduction on the basis of the estimated 10-year risk of ASCVD.

7.2 Individuals >75 Years of Age

Fewer people >75 years of age were enrolled in the statin RCTs reviewed. RCT evidence does support the continuation of statins beyond 75 years of age in persons who are already taking and tolerating these drugs. A larger amount of data supports the use of moderate-intensity statin therapy for secondary prevention in individuals with clinical ASCVD who are >75 years of age. However, the limited information available did not clearly support initiation of high-intensity statin therapy for secondary prevention in individuals >75 years of age.

Few data were available to indicate an ASCVD event reduction benefit in primary prevention among individuals >75 years of age who do not have clinical ASCVD. Therefore, initiation of statins for primary prevention of ASCVD in individuals >75 years of age requires consideration of additional factors, including increasing comorbidities, safety considerations, and priorities of care. The Pooled Cohort Equations can also provide information on expected 10-year ASCVD risk for those 76 to 79 years of age that may inform the treatment decision. These factors may influence decisions about cholesterol-lowering drug therapy, especially in the primary-prevention setting. Accordingly, a discussion of the potential ASCVD risk-reduction benefits, risk of adverse effects, drug–drug interactions, and consideration of patient preferences should precede the initiation of statin therapy for primary prevention in older individuals.