Journal of the American College of Cardiology
2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in AdultsA Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines
This article has corrections. Please see:
Author + information
- Published online July 1, 2014.
Author Information
- Neil J. Stone, MD, MACP, FAHA, FACC, Chair, Expert Panel,
- Jennifer G. Robinson, MD, MPH, FAHA, Vice Chair, Expert Panel,
- Alice H. Lichtenstein, DSc, FAHA, Vice Chair, Expert Panel,
- C. Noel Bairey Merz, MD, FAHA, FACC, Expert Panel Member,
- Conrad B. Blum, MD, FAHA, Expert Panel Member,
- Robert H. Eckel, MD, FAHA, Expert Panel Member,
- Anne C. Goldberg, MD, FACP, FAHA, Expert Panel Member,
- David Gordon, MD, Expert Panel Member∗,
- Daniel Levy, MD, Expert Panel Member∗,
- Donald M. Lloyd-Jones, MD, ScM, FACC, FAHA, Expert Panel Member,
- Patrick McBride, MD, MPH, FAHA, Expert Panel Member,
- J. Sanford Schwartz, MD, Expert Panel Member,
- Susan T. Shero, MS, RN, Expert Panel Member∗,
- Sidney C. Smith Jr., MD, FACC, FAHA, Expert Panel Member,
- Karol Watson, MD, PhD, FACC, FAHA, Expert Panel Member and
- Peter W.F. Wilson, MD, FAHA, Expert Panel Member
- ACC/AHA Practice Guideline
- biomarkers, pharmacological
- cardiovascular disease
- cholesterol
- diabetes mellitus
- drug therapy
- hydroxymethylglutaryl-CoA reductase inhibitors/statins
- hypercholesterolemia
- lipids
- patient compliance
- primary prevention
- risk assessment
- risk reduction behavior
- secondary prevention
Methodology Members
Karen M. Eddleman, BS, Nicole M. Jarrett, Ken LaBresh, MD, Lev Nevo, MD, Janusz Wnek, PhD
ACC/AHA Task Force Members
Jeffrey L. Anderson, MD, FACC, FAHA, Chair, Jonathan L. Halperin, MD, FACC, FAHA, Chair-Elect, Nancy M. Albert, PhD, CCNS, CCRN, FAHA, Biykem Bozkurt, MD, PhD, FACC, FAHA, Ralph G. Brindis, MD, MPH, MACC, Lesley H. Curtis, PhD, FAHA, David DeMets, PhD, Judith S. Hochman, MD, FACC, FAHA, Richard J. Kovacs, MD, FACC, FAHA, E. Magnus Ohman, MD, FACC, Susan J. Pressler, PhD, RN, FAAN, FAHA, Frank W. Sellke, MD, FACC, FAHA, Win-Kuang Shen, MD, FACC, FAHA
Subcommittee on Prevention Guidelines
Sidney C. Smith, Jr, MD, FACC, FAHA, Chair, Gordon F. Tomaselli, MD, FACC, FAHA, Co-Chair
Table of Contents
Preamble and Transition to ACC/AHA Guidelines to Reduce Cardiovascular Risk.....2890
1. Introduction.....2891
1.1. Organization of the Panel.....2891
1.2. Document Review and Approval.....2891
1.3. Scope of Guideline.....2892
1.4. Methodology and Evidence Review.....2894
2. Overview of the Guideline.....2895
2.1. Lifestyle as the Foundation for ASCVD Risk-Reduction Efforts.....2895
2.2. Initiation of Statin Therapy.....2897
3. Critical Questions and Conclusions.....2897
3.1. Identification of CQs.....2897
3.1.1. CQ1: LDL-C and Non–HDL-C Goals in Secondary Prevention.....2899
3.1.2. CQ2: LDL-C and Non–HDL-C Goals in Primary Prevention.....2899
3.1.3. CQ3: Efficacy and Safety of Cholesterol-Lowering Medications.....2899
4. Statin Treatment: Recommendations.....2899
4.1. Intensity of Statin Therapy in Primary and Secondary Prevention.....2899
4.2. LDL-C and Non–HDL-C Treatment Goals.....2901
4.3. Secondary Prevention.....2902
4.4. Primary Prevention in Individuals ‡21 Years of Age With LDL-C ‡190 mg/dL.....2903
4.5. Primary Prevention in Individuals With Diabetes.....2905
4.6. Primary Prevention in Individuals Without Diabetes and With LDL-C 70 to 189 mg/dL.....2905
4.7. Risk Assessment in Primary Prevention.....2906
4.8. Heart Failure and Hemodialysis.....2907
5. Safety: Recommendations.....2907
6. Managing Statin Therapy: Recommendations.....2911
6.1. Monitoring Statin Therapy.....2911
6.2. Optimizing Statin Therapy.....2912
6.3. Insufficient Response to Statin Therapy.....2912
6.3.1. Testing.....2912
6.3.2. Nonstatins Added to Statins or in Statin-Intolerant Individuals.....2913
7. Selected Clinical and Population Subgroups.....2913
7.1. Sex and Racial and Ethnic Subgroups.....2913
7.2. Individuals >75 Years of Age.....2913
8. Limitations.....2914
9. Evidence Gaps and Future Research Needs.....2914
10. Conclusions.....2914
References.....2915
Appendix 1. Author Relationships With Industry and Other Entities (Relevant).....2919
Appendix 2. Expert Reviewer Relationships With Industry and Other Entities.....2922
Appendix 3. Abbreviations.....2923
Appendix 4. Evidence Statements.....2923
Appendix 5. Expanded Discussion of What’s New in the Guideline.....2932
Preamble and Transition to ACC/AHA Guidelines to Reduce Cardiovascular Risk
The goals of the American College of Cardiology (ACC) and the American Heart Association (AHA) are to prevent cardiovascular diseases; improve the management of people who have these diseases through professional education and research; and develop guidelines, standards, and policies that promote optimal patient care and cardiovascular health. Toward these objectives, the ACC and AHA have collaborated with the National Heart, Lung, and Blood Institute (NHLBI) and stakeholder and professional organizations to develop clinical practice guidelines for assessment of cardiovascular risk, lifestyle modifications to reduce cardiovascular risk, management of blood cholesterol in adults, and management of overweight and obesity in adults.
In 2008, the NHLBI initiated these guidelines by sponsoring rigorous systematic evidence reviews for each topic by expert panels convened to develop critical questions (CQs), interpret the evidence, and craft recommendations. In response to the 2011 report from the Institute of Medicine on the development of trustworthy clinical guidelines (1), the NHLBI Advisory Council recommended that the NHLBI focus specifically on reviewing the highest-quality evidence and partner with other organizations to develop recommendations (2,3). Accordingly, in June 2013 the NHLBI initiated collaboration with the ACC and AHA to work with other organizations to complete and publish the 4 guidelines noted above and make them available to the widest possible constituency. Recognizing that the Expert Panels/Work Groups did not consider evidence beyond 2011 (except as specified in the methodology), the ACC, AHA, and collaborating societies plan to begin updating these guidelines starting in 2014.
The joint ACC/AHA Task Force on Practice Guidelines (Task Force) appointed a subcommittee to shepherd this transition, communicate the rationale and expectations to the writing panels and partnering organizations, and expeditiously publish the documents. The ACC/AHA and partner organizations recruited a limited number of expert reviewers for fiduciary examination of content, recognizing that each document had undergone extensive peer review by representatives of the NHLBI Advisory Council, key federal agencies, and scientific experts. Each writing panel responded to comments from these reviewers. Clarifications were incorporated where appropriate, but there were no substantive changes because the bulk of the content was undisputed.
Although the Task Force led the final development of these prevention guidelines, they differ from other ACC/AHA guidelines. First, as opposed to an extensive compendium of clinical information, these documents are significantly more limited in scope and focus on selected CQs on each topic, based on the highest-quality evidence available. Recommendations were derived from randomized trials, meta-analyses, and observational studies evaluated for quality and were not formulated when sufficient evidence was not available. Second, the text accompanying each recommendation is succinct, summarizing the evidence for each question. The Full Panel/Work Group Reports include more detailed information about the evidence statements that serve as the basis for recommendations. Third, the format of the recommendations differs from other ACC/AHA guidelines. Each recommendation has been mapped from the NHLBI grading format to the ACC/AHA Classification of Recommendation/Level of Evidence (COR/LOE) construct (Table 1) and is expressed in both formats. Because of the inherent differences in grading systems and the clinical questions driving the recommendations, alignment between the NHLBI and ACC/AHA formats is in some cases imperfect. Explanations of these variations are noted in the recommendation tables, where applicable.
Applying Classification of Recommendation and Level of Evidence
In consultation with NHLBI, the policies adopted by the writing panels to manage relationships of authors with industry and other entities (RWI) are outlined in the methods section of each panel report. These policies were in effect when this effort began in 2008 and throughout the writing process and voting on recommendations, until the process was transferred to ACC/AHA in 2013. In the interest of transparency, the ACC/AHA requested that panel authors resubmit RWI disclosures as of July 2013. Relationships relevant to this guideline are disclosed in Appendix 1. None of the ACC/AHA expert reviewers had relevant RWI (Appendix 2). See Appendix 3 for a list of abbreviations used in the guideline.
Systematic evidence reports and accompanying summary tables were developed by the expert panels and NHLBI. The guideline was reviewed by the ACC/AHA Task Force and approved by the ACC Board of Trustees, and the AHA Science Advisory and Coordinating Committee. In addition, ACC/AHA sought endorsement from other stakeholders, including professional organizations. It is the hope of the writing panels, stakeholders, professional organizations, NHLBI, and Task Force that the guidelines will garner the widest possible readership for the benefit of patients, providers, and the public health.
These guidelines are meant to define practices that meet the needs of patients in most circumstances and are not a replacement for clinical judgment. The ultimate decision about care of a particular patient must be made by the healthcare provider and patient in light of the circumstances presented by that patient. As a result, situations might arise in which deviations from these guidelines may be appropriate. These considerations notwithstanding, in caring for most patients, clinicians can employ the recommendations confidently to reduce the risks of atherosclerotic cardiovascular disease (ASCVD) events.
See Tables 1a and 1b for an explanation of the NHLBI recommendation grading methodology.
NHLBI Grading of the Strength of Recommendations
NHLBI Quality Rating of the Strength of Evidence
1 Introduction
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.
What’s New in the 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 Overview of the Guideline
The RCTs identified in the systematic evidence review indicated a consistent reduction in ASCVD events from 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor (statin) therapy in secondary- and primary-prevention populations, with the exception of no ASCVD event reduction when statin therapy was initiated in those with New York Heart Association class II to IV heart failure or those receiving maintenance hemodialysis. The RCTs either compared fixed doses of statins with placebo or untreated controls, or compared fixed doses of higher-intensity statins with moderate-intensity statins. These trials were not designed to evaluate the effect of titrated (dose-adjusted) statin treatment to achieve prespecified LDL-C or non–HDL-C goals.
Therefore, the Expert Panel was unable to find RCT evidence to support titrating cholesterol-lowering drug therapy to achieve target LDL-C or non–HDL-C levels, as recommended by Adult Treatment Panel III (6–8). Notably, the Expert Panel did find RCT evidence that use of therapy (e.g., niacin) to additionally lower non–HDL-C, once an LDL-C target was achieved, did not further reduce ASCVD outcomes (9). The Expert Panel also found extensive RCT evidence that the appropriate intensity of statin therapy should be used to reduce ASCVD risk in those most likely to benefit. The work of the Expert Panel was informed by the reports of the Lifestyle Management (10) and Risk Assessment Work Groups (11) (Figure 1). A summary of the major recommendations for the treatment of cholesterol to reduce ASCVD risk is provided in Table 3.
Overview of the Expert Panel’s Guideline
RCTs indicates randomized controlled trials.
Summary of Key Recommendations for the Treatment of Blood Cholesterol to Reduce ASCVD Risk in Adults (See Tables 4, 8, 9, and 10 for the complete recommendations; and Table 5 for definition of statin intensity)
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).
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 Critical Questions and Conclusions
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.
3.1.1 CQ1: LDL-C and Non–HDL-C Goals in Secondary Prevention
CQ1: What is the evidence for LDL-C and non–HDL-C goals for the secondary prevention of ASCVD?
The Expert Panel reviewed 19 RCTs to answer CQ1. Although CQ1 is supported conceptually by an extrapolation of observational studies and observational data from RCTs, no data were identified for treatment or titration to a specific LDL-C goal in adults with clinical ASCVD. The majority of studies confirming the efficacy of cholesterol reduction in improving clinical outcomes in patients with clinical ASCVD used a single fixed-dose statin to lower LDL-C levels. In the 4S trial, 37% had the dose of simvastatin raised from 20 mg/d to 40 mg/d to achieve a total cholesterol level <200 mg/dL (16). The Expert Panel was unable to find any RCTs that evaluated titration of all individuals in a treatment group to specific LDL-C targets <100 mg/dL or <70 mg/dL, nor were any RCTs comparing 2 LDL-C treatment targets identified. No statin RCTs reporting on-treatment non–HDL-C levels were identified. (In CQ3, statin-nonstatin combination therapy was evaluated.)
3.1.2 CQ2: LDL-C and Non–HDL-C Goals in Primary Prevention
CQ2: What is the evidence for LDL-C and non–HDL-C goals for the primary prevention of ASCVD?
The Expert Panel reviewed 6 RCTs. The 4 studies confirming the efficacy of cholesterol reduction in improving clinical outcomes in patients without ASCVD used fixed-dose statin therapy to lower LDL-C levels. In the AFCAPS-TEXCAPS (Air Force/Texas Coronary Atherosclerosis Prevention Study) trial (17), in 50% of participants, the lovastatin dose was raised from 20 mg to 40 mg to achieve an LDL-C level <110 mg/dL. In the MEGA (Management of Elevated Cholesterol in the Primary Prevention Group of Adult Japanese) trial (18), the dose of pravastatin could be uptitrated from 10 mg to 20 mg to achieve a total cholesterol level <220 mg/dL. The Expert Panel did not find any RCTs that evaluated titration of all individuals in a treatment group to specific LDL-C targets <100 mg/dL or <70 mg/dL, nor were any RCTs comparing 2 LDL-C treatment targets identified. No trials reported on-treatment non–HDL-C levels.
3.1.3 CQ3: Efficacy and Safety of Cholesterol-Lowering Medications
CQ3: For primary and secondary prevention, what is the impact on lipid levels, effectiveness, and safety of specific cholesterol-modifying drugs used for lipid management in general and in selected subgroups?
The populations examined included primary-prevention adult patients who could not have a diagnosis of CHD or cardiovascular disease. Interventions included pharmacotherapy with single-drug therapies or combination-drug therapies with any drug therapy used for treating blood cholesterol, including statins, fibrates (fenofibrate, gemfibrozil), nicotinic acid (niacin in immediate-, slow-, or extended-release form), bile acid sequestrants, ezetimibe, omega-3 fatty acids (also called marine fatty acids, including eicosapentaenoic acid alone, docosahexanoic acid alone, eicosapentaenoic acid plus docosahexanoic acid, and alpha-linolenic acid). There were no ASCVD outcomes identified for plant sterols, sterol esters, stanols, or stanol esters. A single ASCVD outcomes trial (19) used Xuezhikang, an extract from red yeast Chinese rice, which was not available in the United States during the timeframe for evidence review, so no recommendations were made regarding its use.
The recommendations synthesize the evidence retrieved for answering CQ3, along with the evidence from the trials included in CQ1 and CQ2, to guide the use of cholesterol-lowering drugs for secondary or primary prevention of ASCVD.
4 Statin Treatment: Recommendations
For each recommendation, the grades of the recommendation by both the NHLBI and ACC/AHA methods are provided. Major treatment recommendations are listed in Table 4, and statin intensities are defined in Table 5. The safety (statin and nonstatin) recommendations are in Section 5. A complete listing of the evidence statements supporting each recommendation, along with the references, is provided in Appendix 4.
Recommendations for Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults—Statin Treatment (High, Moderate, and Low Statin Intensities are Defined in Table 5)
High-, Moderate-, and Low-Intensity Statin Therapy (Used in the RCTs Reviewed by the Expert Panel)∗
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.
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).
Secondary Causes of Hyperlipidemia Most Commonly Encountered in Clinical Practice
The flow diagram for the initiation and management of statin therapy in individuals with LDL-C ≥190 mg/dL is provided in 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.
Rationale for the Expert Panel Approach to Primary-Prevention Guidelines
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.
5 Safety: Recommendations
See safety recommendations for statins (Table 8) and nonstatin drugs (Table 9).
Statin Safety Recommendations
Nonstatin Safety Recommendations
RCT data were also used to examine the safety of lipid medications. From the statin RCTs and meta-analyses, patient characteristics and monitoring strategies were identified that should enhance the safe use of high- and moderate-intensity statin therapy. Patient characteristics that may influence statin safety include but are not limited to: multiple or serious comorbidities, including impaired renal or hepatic function; a history of previous statin intolerance or muscle disorders; concomitant use of drugs affecting statin metabolism; a history of hemorrhagic stroke; and age >75 years. Asian ancestry may also influence the initial choice of statin intensity.
This guideline recommends against routine measurement of creatine kinase in individuals receiving statin therapy. This measurement should be reserved for those with muscle symptoms. However, measurement of a baseline creatine kinase may be useful in those at increased risk of adverse muscle events. Such individuals include those with a personal or family history of statin intolerance or muscle disease, clinical presentation, or concomitant drug therapy that might increase the likelihood of myopathy.
Expert recommendations are also provided for managing muscle symptoms while a patient is on statin therapy. These useful management suggestions were derived from other clinical trial data and clinical experience to enhance the safety and tolerability of statin therapy. Consistent with the protocols of the RCTs, patients should be asked at each visit, both before and after initiation of statin therapy, about muscle symptoms such as muscle weakness or fatigue, aching, pain, tenderness, cramps, or stiffness. The recommended approach for management of muscle symptoms is described in Table 8, Recommendation 8.
This guideline recommends that baseline measurement of transaminase (alanine transaminase; ALT) levels should be performed before initiation of statin therapy. This approach was taken in the RCTs reviewed for this report. There is no recommendation to monitor transaminase (ALT) levels because ALT monitoring was performed in the RCTs, and there was no significant difference between placebo groups and statin treatment groups in the rates of ALT elevations. In addition, the U.S. Food and Drug Administration has indicated that if the baseline hepatic transaminases are normal, further hepatic monitoring is not needed. During statin therapy, it is reasonable to measure hepatic function if symptoms suggesting hepatotoxicity arise (e.g., unusual fatigue or weakness, loss of appetite, abdominal pain, dark-colored urine, or yellowing of the skin or sclera).
Decreasing the statin dose may be considered when 2 consecutive values of LDL-C are <40 mg/dL. This recommendation was based on the approach taken in 2 RCTs. However, no data were identified that suggest an excess of adverse events occurred when LDL-C levels were below this level.
Statins modestly increase the excess risk of type 2 diabetes in individuals with risk factors for diabetes. The potential for an ASCVD risk-reduction benefit outweighs the excess risk of diabetes in all but the lowest-risk individuals (Section 4.5). All individuals receiving statins should be counseled on healthy-lifestyle habits. Individuals receiving statin therapy should be evaluated for new-onset diabetes according to the current diabetes screening guidelines (91). Those who develop diabetes during statin therapy should be encouraged to adhere to a heart-healthy dietary pattern, engage in physical activity, achieve and maintain a healthy body weight, cease tobacco use, and continue statin therapy to reduce their risk of ASCVD events.
Statins are listed as pregnancy category X and should not be used in women of childbearing potential unless these women are using effective contraception and are not nursing.
For individuals taking any dose of statins, it is reasonable to use caution in individuals >75 years of age, as well as in individuals who are taking concomitant medications that alter drug metabolism, taking multiple drugs, or taking drugs for conditions that require complex medication regimens (e.g., those who have undergone solid organ transplantation or are receiving treatment for HIV). A review of the manufacturer’s prescribing information might be useful before initiation of any cholesterol-lowering drug, because RCTs considered defined populations and many patients in everyday practice would not qualify for clinical trials. Thus, clinicians should also consult other sources of safety data, such as pharmacists, drug information centers, and manufacturers’ prescribing information on a regular basis for up-to-date guidance about lipid medications and medication interactions.
Statins used in combination with other cholesterol-lowering drug therapies might require more intensive monitoring. The safety of nonstatin agents was reviewed, and that information is included in Table 9 and the Full Panel Report Supplement. Warnings about the use of cholesterol-lowering agents in pregnancy and lactation also apply to nonstatins, and the manufacturer's prescribing information should be consulted.
6 Managing Statin Therapy: Recommendations
See Table 10 for a summary of recommendations for monitoring, optimizing, and addressing insufficient response to statin therapy.
Recommendations for Monitoring, Optimizing, and Addressing Insufficient Response to Statin Therapy
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.
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
6.3.1 Testing
The evidence is less clear with regard to the most appropriate tests for determining whether an anticipated therapeutic response to statin therapy has occurred on the maximally tolerated dose. RCT evidence to support the use of specific LDL-C or non–HDL-C targets was not identified. The focus is on the intensity of the statin therapy, but as an aid to monitoring response to therapy and adherence, it is reasonable to use the following as indicators of anticipated therapeutic response to statin therapy:
• High-intensity statin therapy generally results in an average LDL-C reduction of ≥50% from the untreated baseline.
• Moderate-intensity statin therapy generally results in an average LDL-C reduction of 30% to <50% from the untreated baseline.
• LDL-C levels and percent reduction are to be used only to assess response to therapy and adherence. They are not to be used as performance standards.
In those already on a statin, in whom the baseline LDL-C is unknown, an LDL-C <100 mg/dL was observed in most individuals receiving high-intensity statin therapy in RCTs.
However, there are many limitations of using LDL-C <100 mg/dL as a fixed target. If a moderate- or low-intensity statin results in an LDL-C level <100 mg/dL in a patient with ASCVD, the evidence suggests that a high-intensity statin, if tolerated, provides a greater reduction in ASCVD events. Conversely, in those with LDL-C levels slightly >100 mg/dL on a high-intensity statin, some options such as niacin might require down-titration of the statin intensity in an effort to improve safety. This would result in a suboptimal intensity of evidence-based statin therapy. Additional limitations to using LDL-C treatment targets are discussed in the Full Panel Report Supplement.
No evidence was found that titration or combination-drug therapy to achieve specific LDL-C or non–HDL-C levels or percent reductions improved ASCVD outcomes. Therefore, this guideline does not recommend their use as performance measures.
The percent LDL-C reduction may not only indicate adherence, but also may reflect biological variability in the response to statin therapy. This acknowledges that some individuals may have less than an average response. Attention to adherence of statin and lifestyle therapy and evaluation and treatment of secondary causes (Table 6) that might elevate LDL-C, may address less-than-anticipated responses to a specific statin dosage. Whether the dose of statin therapy should be increased on the basis of a less-than-anticipated average response should be left to clinical judgment.
6.3.2 Nonstatins Added to Statins or in Statin-Intolerant Individuals
Adherence to lifestyle changes and to statin therapy should be reemphasized before the addition of a nonstatin drug is considered (Figure 5). RCTs evaluating the ASCVD event reductions from nonstatins used as monotherapy were reviewed, as were RCTs evaluating the additional reduction in ASCVD events from nonstatin therapy added to statin therapy. The Expert Panel could find no data supporting the routine use of nonstatin drugs combined with statin therapy to further reduce ASCVD events. In addition, no RCTs that assessed ASCVD outcomes in statin-intolerant patients were found.
Clinicians treating high-risk patients who have a less-than-anticipated response to statins, who are unable to tolerate a less-than-recommended intensity of a statin, or who are completely statin intolerant, may consider the addition of a nonstatin cholesterol-lowering therapy. High-risk individuals include those with ASCVD, those with LDL-C ≥190 mg/dL, and those with diabetes 40–75 years of age. In this situation, this guideline recommends clinicians preferentially prescribe drugs that have been shown in RCTs to provide ASCVD risk-reduction benefits that outweigh the potential for adverse effects and drug–drug interactions, and consider patient preferences.
7 Selected Clinical and Population Subgroups
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.
8 Limitations
The evidence-based recommendations in this guideline focus on patient groups who are well represented in RCTs and/or are highly likely to have high-risk genetic conditions, so the recommendations are designed to inform rather than replace clinical judgment. However, there are other patient groups for which a robust evidence base is lacking but that may nevertheless include some persons for whom statin treatment should be considered (after taking patient preferences into account) on the basis of the potential for ASCVD benefits to exceed the risk of adverse events and drug–drug interactions. Clinician judgment is especially important for several patient groups for which the RCT evidence is insufficient for guiding clinical recommendations. These patient groups include younger adults (<40 years of age) who have a low estimated 10-year ASCVD risk but a high lifetime ASCVD risk based on single strong factors or multiple risk factors. Other groups include those with serious comorbidities and increased ASCVD risk (e.g., individuals with HIV or rheumatologic or inflammatory diseases, or who have undergone a solid organ transplantation). This guideline encourages clinicians to use clinical judgment in these situations, weighing potential benefits, adverse effects, drug–drug interactions, and consider patient preferences.
Previous guidelines have taken less rigorous approaches to identifying the evidence to support their recommendations. In contrast, to minimize various sources of bias, the present recommendations are based on data available from RCTs and systematic reviews and meta-analyses of RCTs that were graded as fair to good quality by an independent contractor and were reviewed by the Expert Panel, with the assistance of an independent methodologist. To avoid biases, evidence from post-hoc analyses of included RCTs, from poor-quality RCTs, and from observational studies was not considered. This approach resulted in a comprehensive set of evidence-based clinical recommendations for the treatment of blood cholesterol to reduce ASCVD risk.
9 Evidence Gaps and Future Research Needs
After a systematic review of the literature, several research priorities are suggested that address existing evidence gaps and offer the greatest potential to inform and influence clinical practice and reduce ASCVD morbidity and mortality. High-priority research areas are:
1. Outcomes of RCTs to evaluate statins for the primary prevention of ASCVD in adults >75 years of age.
2. Outcomes of RCTs to evaluate alternative treatment strategies for ASCVD risk reduction. These RCTs may compare titration to specific cholesterol or apolipoprotein goals versus fixed-dose statin therapy in high-risk patients.
3. RCTs to determine whether submaximal statin doses, combined with nonstatin therapies, reduce ASCVD risk in statin-intolerant patients.
4. Evaluation of the incidence, pathophysiology, clinical course, and clinical outcomes of new-onset diabetes associated with statin therapy.
5. Outcomes of RCTs of new lipid-modifying agents to determine the incremental ASCVD event-reduction benefits when added to evidence-based statin therapy.
Additional research recommendations are included in the Full Panel Report Supplement.
10 Conclusions
These recommendations arose from careful consideration of an extensive body of higher-quality evidence derived from RCTs and systematic reviews and meta-analyses of RCTs. Rather than LDL-C or non–HDL-C targets, this guideline used the intensity of statin therapy as the goal of treatment. Through a rigorous process, 4 groups of individuals were identified for whom an extensive body of RCT evidence demonstrated a reduction in ASCVD events with a good margin of safety from moderate- or high-intensity statin therapy:
Four Statin Benefit Groups:
1. Individuals with clinical ASCVD
2. Individuals with primary elevations of LDL-C ≥190 mg/dL
3. Individuals 40 to 75 years of age with diabetes and LDL-C 70 to 189 mg/dL without clinical ASCVD
4. Individuals without clinical ASCVD or diabetes who are 40 to 75 years of age and have LDL-C 70 to 189 mg/dL and an estimated 10-year ASCVD risk of ≥7.5%. This requires a clinician-patient discussion.
Individuals in the last group can be identified by using the Pooled Cohort Equations for ASCVD risk prediction developed by the Risk Assessment Work Group. Lifestyle counseling should occur at the initial and follow-up visits as the foundation for statin therapy and may improve the overall risk factor profile.
Most importantly, our focus is on those individuals most likely to benefit from evidence-based statin therapy to reduce ASCVD risk. Implementation of these ASCVD risk-reduction guidelines will help to substantially address the large burden of fatal and nonfatal ASCVD in the United States. We realize that these guidelines represent a change from previous guidelines, but clinicians have become accustomed to change when that change is consistent with the current evidence. Continued accumulation of quality trial data will inform future cholesterol treatment guidelines.
Presidents and Staff
American College of Cardiology
John Gordon Harold, MD, MACC, President
Shalom Jacobovitz, Chief Executive Officer
William J. Oetgen, MD, MBA, FACC, Executive Vice President, Science, Education, & Quality
Charlene May, Senior Director, Science and Clinical Policy
American College of Cardiology/American Heart Association
Lisa Bradfield, CAE, Director, Science and Clinical Policy
Emily Schiller, Specialist, Science and Clinical Policy
American Heart Association
Mariell Jessup, MD, FACC, FAHA, President
Nancy Brown, Chief Executive Officer
Rose Marie Robertson, MD, FAHA, Chief Science Officer
Gayle R. Whitman, PhD, RN, FAHA, FAAN, Senior Vice President, Office of Science Operations
Marco Di Buono, PhD, Vice President of Science and Research
Jody Hundley, Production Manager, Scientific Publications, Office of Science Operations
National Heart, Lung, and Blood Institute
Glen Bennett, MPH
Denise Simons-Morton, MD, PhD
Appendix 1 Author Relationships With Industry and Other Entities (Relevant)— 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol in Adults to Reduce Atherosclerotic Cardiovascular Risk
Panel Member | Employment | Consultant | Speakers Bureau | Ownership/ Partnership/ Principal | Personal Research | Expert Witness |
---|---|---|---|---|---|---|
Neil J. Stone Chair | Northwestern Memorial Hospital—Bonow Professor of Medicine, Feinberg School of Medicine, Northwestern University | 2008–2012: None | 2008–2012: None | 2008–2012: None | 2008–2012: None | 2008–2012: None |
2013: None | 2013: None | 2013: None | 2013: None | 2013: None | ||
Jennifer G. Robinson Co-Chair | University of Iowa—Professor of Epidemiology and Medicine; Prevention Intervention Center—Director | 2008–2012: None | 2008–2012: None | 2008–2012: None | 2008–2012: | 2008–2012: None |
2013: None | 2013: None | 2013: None | 2013: | 2013: None | ||
Alice H. Lichtenstein Co-Chair | Tufts University, USDA Human Nutrition Research Center on Aging—Gershoff Professor of Nutrition Science and Policy; Professor of Public Health and Family Medicine | 2008–2012: None | 2008–2012: None | 2008–2012: None | 2008–2012: None | 2008–2012: None |
2013: None | 2013: None | 2013: None | 2013: None | 2013: None | ||
C. Noel Bairey Merz | Cedars-Sinai Medical Center—Women's Guild Endowed Chair in Women's Health Barbara Streisand Women's Heart Center—Director; Preventive Cardiac Center—Professor of Medicine | 2008–2012:
| 2008–2012: None | 2008–2012:
| 2008–2012:
| 2008–2012: None |
2013:
| 2013: None | 2013: None | 2013:
| 2013: None | ||
Conrad Blum | Columbia University Medical Center, Columbia University College of Physicians and Surgeons—Professor of Medicine | 2008–2012: None | 2008–2012: None | 2008–2012: None | 2008–2012: None | 2008–2012: None |
2013: None | 2013: None | 2013: None | 2013: None | 2013: None | ||
Robert H. Eckel | University of Colorado, Denver School of Medicine—Professor of Medicine; Professor of Physiology and Biophysics; and Charles A. Boettcher II Chair in Atherosclerosis | 2008–2012:
| 2008–2012: None | 2008–2012: None | 2008–2012: None | 2008–2012: None |
2013:
| 2013: None | 2013: None | 2013:
| 2013: None | ||
Anne Carol Goldberg | Washington University School of Medicine—Associate Professor of Medicine | 2008–2012:
| 2008–2012: None | 2008–2012: None | 2008–2012: | 2008–2012: None |
2013:
| 2013: None | 2013: None | 2013: | 2013: None | ||
David Gordon, Ex-Officio | NHLBI—Special Assistant for Clinical Studies, Division of Cardiovascular Diseases | 2008–2012: None | 2008–2012: None | 2008–2012: None | 2008–2012: None | 2008–2012: None |
2013: None | 2013: None | 2013: None | 2013: None | 2013: None | ||
Daniel Levy, Ex-Officio | NHLBI—Director of the Center for Population Studies | 2008–2012: None | 2008–2012: None | 2008–2012: None | 2008–2012: None | 2008–2012: None |
2013: None | 2013: None | 2013: None | 2013: None | 2013: None | ||
Donald M. Lloyd-Jones | Northwestern University Feinberg School of Medicine—Senior Associate Dean; Chair and Professor of Preventive Medicine; Professor of Medicine (Cardiology) | 2008–2012: None | 2008–2012: None | 2008–2012: None | 2008–2012: None | 2008–2012: None |
2013: None | 2013: None | 2013: None | 2013: None | 2013: None | ||
Patrick McBride | University of Wisconsin School of Medicine and Public Health—Professor of Medicine and Family Medicine | 2008–2012: None | 2008–2012: None | 2008–2012: None | 2008–2012: None | 2008–2012: None |
2013: None | 2013: None | 2013: None | 2013: None | 2013: None | ||
J. Sanford Schwartz | University of Pennsylvania School of Medicine— Leon Hess Professor of Internal Medicine, Health Management and Economics | 2008–2012:
| 2008–2012: None | 2008–2012: None | 2008–2012:
| 2008–2012: None |
2013:
| 2013: None | 2013: None | 2013:
| 2013: None | ||
Susan T. Shero Ex-Officio | NHLBI—Public Health Advisor | 2008–2012: None | 2008–2012: None | 2008–2012: None | 2008–2012: None | 2008–2012: None |
2013: None | 2013: None | 2013: None | 2013: None | 2013: None | ||
Sidney C. Smith, Jr | University of North Carolina—Professor of Medicine; Center for Cardiovascular Science and Medicine—Director | 2008–2012: None | 2008–2012: None | 2008–2012: None | 2008–2012: None | 2008–2012: None |
2013: None | 2013: None | 2013: None | 2013: None | 2013: None | ||
Karol Watson | University of California, Los Angeles School of Medicine—Co-Director | 2008–2012:
| 2008–2012: None | 2008–2012: None | 2008–2012:
| 2008–2012: None |
2013: None | 2013: None | 2013: None | 2013:
| 2013: None | ||
Peter W.F. Wilson | Atlanta VA Medical Center and Emory University School of Medicine—Professor of Medicine | 2008–2012:
| 2008–2012: None | 2008–2012: None | 2008–2012:
| 2008–2012: None |
2013: None | 2013: None | 2013: None | 2013:
| 2013: None |
This table reflects the relevant healthcare-related relationships of authors with industry and other entities provided by the panels during the document development process (2008–2012). Both compensated and uncompensated relationships are reported. These relationships were reviewed and updated in conjunction with all meetings and conference calls of the Expert Panel during the document development process. Authors with relevant relationships during the document development process recused themselves from voting on recommendations relevant to their relationships. In the spirit of full transparency, the ACC and AHA asked Expert Panel members to provide updates and approve the final version of this table, which includes current relevant relationships (2013).
To review the NHLBI and ACC/AHA’s current comprehensive policies for managing relationships with industry and other entities, please refer to http://www.nhlbi.nih.gov/guidelines/cvd_adult/coi-rwi_policy.htm and http://www.cardiosource.org/Science-And-Quality/Practice-Guidelines-and-Quality-Standards/Relationships-With-Industry-Policy.aspx.
Per ACC/AHA policy:
A person is deemed to have a significant interest in a business if the interest represents ownership of ≥5% of the voting stock or share of the business entity, or ownership of ≥$10,000 of the fair market value of the business entity; or if funds received by the person from the business entity exceed 5% of the person’s gross income for the previous year. Relationships that exist with no financial benefit are also included for the purpose of transparency. Relationships in this table are modest unless otherwise noted.
ACC indicates American College of Cardiology; AHA, American Heart Association; NHLBI, National Heart, Lung, and Blood Institute; and USDA, U.S. Department of Agriculture.
↵∗ Significant relationship.
Appendix 2 Expert Reviewers Relationships With Industry and Other Entities—2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol in Adults to Reduce Atherosclerotic Cardiovascular Risk
Reviewer | Employment | Representation | Consultant | Speakers Bureau | Ownership/ Partnership/ Principal | Personal Research | Expert Witness |
---|---|---|---|---|---|---|---|
Roger Blumenthal | Johns Hopkins Hospital Ciccarone Preventive Cardiology Center—Professor of Medicine | ACC/AHA | None | None | None | None | None |
William Virgil Brown | Emory University School of Medicine | NLA |
| None | None | None | None |
Linda Hemphill | Massachusetts General Hospital—Director, LDL Apheresis Program | NLA |
| None | None | None | None |
Matthew Ito | Oregon Health & Science University, Department of Pharmacy Practice—Professor | NLA |
| None | None | None | None |
Terry Jacobson | Emory University | NLA |
| None | None |
| None |
Andrew Kates | Washington University School of Medicine in St. Louis—Cardiovascular Fellowship Program Director | ACC/AHA | None | None | None | None | None |
James M. McKenney | Virginia Commonwealth University—Professor Emeritus | NLA | None | None | None | None | None |
E. Magnus Ohman | Duke Clinical Research Institute—Professor of Medicine; Program for Advanced Coronary Disease—Director | ACC/AHA Task Force on Practice Guidelines | None | None | None | None | None |
Carl E. Orringer | Case Western Reserve University School of Medicine—Associate Professor of Medicine | NLA | None | None | None | None | None |
Robert S. Rosenson | Mount Sinai Hospital—Director, Preventive Cardiology; Professor of Medicine, Cardiology | NLA |
| None |
| None | None |
John Rumsfeld | Denver VA Medical Center, University of Colorado—National Director of Cardiology, U.S. Veterans Health Administration | ACC/AHA | None | None | None | None | None |
Robert A. Wild | University of Oklahoma, College of Medicine, Department of Obstetrics and Gynecology—Professor | NLA |
| None | None | None | None |
This table represents the relationships of reviewers with industry and other entities that were self-disclosed at the time of peer review. It does not necessarily reflect relationships with industry at the time of publication. To review the NHLBI and ACC/AHA’s current comprehensive policies for managing relationships with industry and other entities, please refer to http://www.nhlbi.nih.gov/guidelines/cvd_adult/coi-rwi_policy.htm and http://www.cardiosource.org/Science-And-Quality/Practice-Guidelines-and-Quality-Standards/Relationships-With-Industry-Policy.aspx.
ACC indicates American College of Cardiology; AHA, American Heart Association; NLA, National Lipid Association; and VA, Veterans Affairs.
Appendix 3 Abbreviations
ALT = alanine transaminase
ASCVD = atherosclerotic cardiovascular disease
CHD = coronary heart disease
COR = Class of Recommendation
CQ = critical question
HDL-C = high-density lipoprotein cholesterol
LDL-C = low-density lipoprotein cholesterol
LOE = Level of Evidence
MI = myocardial infarction
NHLBI = National Heart, Lung, and Blood Institute
RCT = randomized controlled trial
RWI = relationships with industry and other entities
Appendix 4 Evidence Statements
ES No. | Evidence Statement | Level of Evidence | Recommendation(s)/ Section | References |
---|---|---|---|---|
1 | Data are not available regarding treatment or titration to a specific LDL-C goal in adults with CHD/CVD. The Expert Panel found insufficient evidence to support setting LDL-C goals in CHD/CVD patients. | I | Secondary Prevention | Conclusion after reviewing 19 RCTs in CQ1 Evidence Table: 4D (87), A–Z (117), ACCORD (14), ALLIANCE (118), ASPEN (119), AURORA (84), CARE (73), CORONA (85), GREACE (120), HATS (121), HPS (16), IDEAL (47), LIPID (74), LIPS (122), MIRACL (93), MUSHASHI-AMI (123), PROVE-IT (48), SPARCL (78,107), TNT (46) |
2 | The Expert Panel did not identify any trials in adults with CHD/CVD reporting mean or median on-treatment non–HDL-C levels in adults with CHD/CVD. | Secondary Prevention | N/A | |
3 | LDL-C goals <130 mg/dL or <100 mg/dL in patients without CHD/CVD. Randomized trial data are not available regarding dose titration to achieve a specific LDL-C goal. | I | Primary Prevention | Conclusion after reviewing 6 RCTs included in CQ2: AFCAPS (17), ASPEN (119), AURORA (84), CARDS (75), JUPITER (49), MEGA (18) |
4 | There was insufficient evidence in women without CHD/CVD to evaluate the reduction in CVD risk with achieved LDL-C levels <130 mg/dL or <100 mg/dL. | I | Primary Prevention | N/A |
5 | The Expert Panel did not identify any trials in adults without CHD/CVD reporting on-treatment non–HDL-C levels in adults with CHD/CVD. | Primary Prevention | N/A | |
6 | In adults with CHD/CVD, fixed high-intensity statin treatment (atorvastatin 40–80 mg) that achieved a mean LDL-C 67–79 mg/dL reduced the RR for CHD/CVD events more than fixed lower-dose statin treatment that achieved a mean LDL-C 97–102 mg/dL. In these trials, the mean LDL-C levels achieved differed by 23–30 mg/dL, or 22%–32%, between the 2 groups. Simvastatin 80 mg did not decrease CVD events compared with simvastatin 20–40 mg. See Table 4 for definitions of high, moderate, and low intensity for statins. Higher intensity = atorvastatin 40–80 mg Moderate intensity = atorvastatin 10 mg, pravastatin 40 mg, or simvastatin 20–40 mg | H | Secondary Prevention | Benefit: TNT (46), IDEAL (47), PROVE-IT (48) Lower LDL-C reductions, no benefit: A–Z (117), ACCORD (14) No difference in LDL-C between groups: (SEARCH (124) not included in CQ1) |
7 | In adults with CHD/CVD who do not have Class II–IV heart failure, fixed high-intensity statin (atorvastatin 80 mg) or statin-niacin treatment that achieved a mean LDL-C 72–79 mg/dL reduced the RR for CHD/CVD events compared with placebo with a mean LDL-C 112–135 mg/dL. In these trials, the mean LDL-C levels were reduced by 45–57 mg/dL or by 45% (HATS [121]) to 53% (SPARCL [107]). | H | Secondary Prevention | SPARCL (107) HATS (121) MIRACL (93) CORONA (85)–no benefit |
8 | In adults with CHD/CVD and diabetes, fixed high-intensity statin treatment (atorvastatin 80 mg) that achieved a mean LDL-C of 57–77 mg/dL reduced the RR for CHD/CVD events more than fixed lower-intensity statin treatment that achieved a mean LDL-C of 81–99 mg/dL. In these trials, the mean LDL-C levels achieved differed by 22–24 mg/dL, or 22%–30%, between the 2 groups. | M to H | Secondary Prevention (diabetes subgroup included) | TNT (46,94), PROVE-IT (48,125) No diabetes subgroup publications found for MIRACL (93) or IDEAL (47) |
9 | In adults ≥65 years of age with CHD/CVD, fixed high-intensity statin treatment (atorvastatin 80 mg) that achieved a mean LDL-C of 72 mg/dL reduced CHD/CVD events more than fixed lower-intensity statin treatment that achieved a mean LDL-C of 97 mg/dL. In this trial, the mean LDL-C levels achieved differed by 25 mg/dL, or 26%, between the 2 groups. In adults ≥65 years of age with a history of stroke or TIA, higher fixed-dose statin treatment that achieved a mean LDL-C of 72 mg/dL reduced CHD events more than placebo, with a mean LDL-C of 129 mg/dL. In this trial, the mean LDL-C level was reduced by 61 mg/dL, or 46%, from baseline in those ≥65 years of age. | L | Secondary Prevention (age subgroups included) | TNT (46,126), SPARCL (107,127) No publications by age included for: PROVE-IT (48) IDEAL (47) HATS (121) |
10 | In adults with CHD/CVD and CKD (excluding hemodialysis), fixed high-intensity statin treatment (atorvastatin 80 mg) that achieved a mean LDL-C of 79 mg/dL reduced CHD/CVD events more than fixed lower-dose statin treatment that achieved a mean LDL-C of 99 mg/dL. In this trial, the mean LDL-C levels achieved differed by 20 mg/dL, or 20% between the 2 groups. | L | Secondary Prevention (CKD subgroup included) | TNT (46,128) TNT (46,129) No publications included for CKD: PROVE-IT (48) IDEAL (47) |
11 | In adults with CHD or acute coronary syndromes, more intensive-dose statin therapy reduced LDL-C to a greater degree (by 20 mg/dL or an additional 20%) than less intensive-dose statin therapy or placebo and produced a greater reduction in CVD events. Each 1-mmol/L (38.7-mg/dL) reduction in LDL-C reduced the RR for CVD events by approximately 28%. See Table 4 for definitions of high-, moderate-, and low-intensity statin therapy. More intensive statin therapy = atorvastatin 80 mg, simvastatin 80 mg. Less intensive statin therapy = atorvastatin 10 mg, pravastatin 40 mg, or simvastatin 20–40 mg. | H | Secondary Prevention | CTT 2010 (20)—data from 5 trials TNT (46) IDEAL (47) PROVE-IT (48) A–Z (117) SEARCH (124) (not included in CQ1) |
12 | In trials of more intensive statin therapy (atorvastatin 80 mg, simvastatin 80 mg) compared with less intensive statin therapy (atorvastatin 10 mg, pravastatin 40 mg, or simvastatin 20–40 mg), women with CHD or acute coronary syndromes experienced a similar (approximately 25%) magnitude of relative CVD reduction as men (approximately 29%). Women also experienced a similar magnitude of absolute risk reduction as men. | H | Secondary Prevention (women included) | CTT 2010 (20)—5 trials TNT (46) IDEAL (47) PROVE-IT (48) A–Z (117) SEARCH (124) (not included in CQ1) |
13 | In adults with and without CVD, in trials comparing more intensive to less intensive statin therapy or statin therapy with placebo/control, the relative CVD risk reduction was similar for those <65 years, 65 to ≤75, or >75 years of age. There is less information to estimate the magnitude of benefit in those under age 45 or over age 75 years, because fewer participants in these age groups were enrolled in clinical trials. More intensive statin therapy did not appear to reduce CVD risk, compared with less intensive statin therapy, in those with ASCVD and age >75 years. Statin therapy, compared with control (most RCTs evaluated moderate-intensity statin therapy), had a similar magnitude of RR reduction in those >75 as in those ≤75 years of age with and without ASCVD. Statin therapy vs. control trials = atorvastatin (A) 10–20 mg, fluvastatin (F) 80 mg, lovastatin (L) 40–80 mg, pravastatin (P) 40 mg, rosuvastatin (R) 10–20 mg, simvastatin (S) 40 mg. See Table 4 for the Expert Panel’s definitions for high-, moderate-, and low-intensity statin therapy. The Panel uses moderate intensity to refer to statin drugs and doses that lower LDL-C by 30% to approximately 50%. This dose refers to atorvastatin 10 mg, fluvastatin 80 mg, lovastatin 40 mg, pravastatin 40 mg, rosuvastatin 10 mg, and simvastatin 40 mg. | H | Primary Prevention, Secondary Prevention | CTT 2010 (20)—26 trials Included: More vs. less statin TNT (46) IDEAL (47) PROVE-IT (48) A–Z (117) SEARCH (124) Statin vs. control (statin/dose, percent LDL-C reduction) 4S (47) S20–40, –36% WOSCOPS (72) P40, –22% CARE (130) P40, –29% AFCAPS/TexCAPS (17) L20-40, –24% LIPID (74) P40, –27% GISSI-P (86) P20, –9% LIPS (122) F40 BID, –27% HPS (16) S40, –38% PROSPER (38) P40, –27% ALLHAT-LLT (131) P40, –14% ASCOT-LLA (132) A10, –31% ALERT (133) F40, –20% CARDS (75) A10, –38% ALLIANCE (118)—NA 4D (87)—A20, –27% ASPEN (119) A10, –34% MEGA (18) P10–20, –17% JUPITER (49) R20, –40% GISSI-HF (86) R10, –30% AURORA (84) R10, –38% |
14 | In adults with CHD (including acute coronary syndromes, or a history of MI, stable or unstable angina, coronary revascularization), statin therapy reduced the RR for CVD events by approximately 21% per 1-mmol/L (38.7-mg/dL) LDL-C reduction. This relationship was similar for more intensive compared with less intensive statin therapy and for statin therapy compared with placebo/control. | H | Secondary Prevention | CTT 2010 (20)—26 trials—see above |
15 | In adults with CVD other than CHD (including stroke, TIA presumed to be of atherosclerotic origin, or peripheral arterial disease or revascularization), statin therapy reduced the RR for CVD events by approximately 19% per 1-mmol/L (38.7-mg/dL) LDL-C reduction. This relationship was similar for more intensive compared with less intensive statin therapy and for statin therapy compared with placebo/control. | H | Secondary Prevention | CTT 2010 (20)—26 trials |
16 | In adults with diabetes and CHD or other CVD, moderate-dose statin therapy reduced CVD events by approximately 20% per 1-mmol/L (38.7-mg/dL) LDL-C reduction. | H | Secondary Prevention (diabetes subgroup included) | CTT 2008 (134)—14 trials |
17 | In adults with and without CVD, statin therapy reduced CVD events in both men and women. | H | Primary Prevention, Secondary Prevention | CTT 2010 (20)—26 trials |
18 | In adults with and without CVD, in trials comparing more* intensive with less intensive statin therapy, or statin therapy with placebo/control, there were no clinically important differences in the CVD risk reduction between the subgroups listed below:
| H | Primary Prevention, Secondary Prevention | CTT 2010 (20)—26 trials |
19 | In more vs. less statin and statin vs. control trials combined, each 1-mmol/L (38.7-mg/dL) reduction in LDL-C resulted in approximately 22% reductions in CVD risk across baseline LDL-C levels [<2 mmol/L (77 mg/dL), ≥2 to <2.5 mmol/L (97 mg/dL), ≥2.5 to <3.0 mmol/L (116 mg/dL), ≥3.0 to <3.5 mmol/L (135 mg/dL), and ≥3.5 mmol/L, either untreated or on statin therapy]. In the statin vs. placebo/control trials, those with LDL-C <2 mmol/L may have experienced less benefit than those with higher LDL-C level. | M | CTT 2010 (20)—26 trials | |
20 | In adults, statins reduce the RR for CVD, CHD, and fatal CHD similarly in those with or without hypertension. This benefit applies across all levels of baseline systolic and diastolic blood pressure and in those with treated hypertension. | H | Primary Prevention, Secondary Prevention | CTT 2010 (20), Messerli AJC 2008 (135) |
21 | In adults with and without CVD who received more intensive compared with less intensive statin therapy, or statin therapy compared with placebo/control, the RR for first stroke was reduced by approximately 16% per 1-mmol/L (38.7-mg/dL) LDL-C reduction, primarily because of an approximately 21% reduction in the RR for ischemic stroke. | M to H | Primary Prevention, Secondary Prevention | CTT 2010 (20)—26 trials |
22 | In adults with and without CHD/CVD who received more intensive compared with less intensive statin therapy, or statin therapy compared with placebo/control:
| H | Primary Prevention, Secondary Prevention | CTT 2010 (20)—26 trials |
23 | In adults with CHD or acute coronary syndromes who received more intensive compared with less intensive statin therapy, the RR for coronary revascularization was reduced by approximately 34% per 1-mmol/L (38.7-mg/dL) LDL-C reduction. | H | Secondary Prevention | CTT 2010 (20)—5 trials |
24 | In adults with and without CVD who received statin therapy compared with placebo/control, the RR for coronary revascularization was reduced by approximately 24% per 1-mmol/L (38.7-mg/dL) LDL-C reduction. | H | Primary Prevention, Secondary Prevention | CTT 2010 (20)—21 trials |
25 | In adults with and without CVD who received statin therapy, a larger absolute reduction in LDL-C (mmol/L or mg/dL) was associated with a greater reduction in the risk for CVD. | M | Primary Prevention, Secondary Prevention | CTT2010 (20), Kizer 2010 (136) |
26 | In adults with and without CVD who received statin therapy, there was no variation in the relative reduction of CVD risk among the trials after adjustment for LDL-C reduction. Thus, LDL-C reduction appeared to account for the reduction in CVD risk. | M | Primary Prevention, Secondary Prevention | CTT 2010 (20) |
27 | Consistent 23%–28% relative reductions in CVD risk per 39-mg/dL (1-mmol/L) reduction in LDL-C were observed after 1 year to beyond 5 years of statin treatment. | H | Secondary Prevention, Primary Prevention | CTT 2008 (134), 2005 (50) CTT 2010 (96) |
28 | Statins reduce the RR for CVD similarly in primary- and secondary-prevention populations. | H | Primary Prevention; Secondary Prevention | CTT 2010 (20) CTT 2010 Web appendix (50) |
29 | In adults with diabetes (some of whom had CHD), statin therapy reduced the RR for CVD events by approximately 20% per 1-mmol/L (38.7-mg/dL) LDL-C reduction. This 1-mmol (20%) risk-reduction relationship was similar for more intensive compared with less intensive statin therapy and for statin therapy compared with placebo/control. | H | Secondary Prevention (includes diabetes subgroup) Primary Prevention in Individuals With Diabetes | CTT 2010 (20) CTT 2008 (134) |
30 | Adults with type 2, type 1, and no diabetes had similar RRRs in CVD per 1-mmol/L (38.7-mg/dL) LDL-C reduction. | H | Primary Prevention in Individuals With Diabetes | CTT 2010 (20) |
31 | In adults with diabetes without CVD, moderate-dose statin therapy, compared with placebo/control, reduced the RR for CVD events by approximately 27% per 1-mmol/L (38.7-mg/dL) LDL-C reduction. | H | Primary Prevention in Individuals With Diabetes | CTT 2008 (134)—14 trials |
32 | In adults with diabetes, statin therapy reduced the RR for CVD by a similar magnitude for subgroups of diabetic men and women, <65 and ≥65 years of age; treated hypertension; body mass index <25, >25 to <30, and ≥30; systolic blood pressure <160 and ≥160 mm Hg; diastolic blood pressure <90 and ≥90 mm Hg; current smokers and nonsmokers; estimated GFR <60, ≥60 to <90, and ≥90 mL/min/1.73 m2; and predicted annual risk for CVD <4.5%, >4.5% to <8.0%, and ≥8.0%. Whereas RRRs are similar across these subgroups, absolute risk reductions may differ for various subgroups. | H | Primary Prevention in Individuals With Diabetes | CTT 2008 (134)—14 trials |
33 | In adults 40 to 75 years of age with diabetes and ≥1 risk factor, fixed moderate-dose statin therapy that achieved a mean LDL-C of 72 mg/dL reduced the RR for CVD by 37% (in this trial, LDL-C was reduced by 46 mg/dL or 39%). | M | Primary Prevention in Individuals With Diabetes | CARDS (75) |
34 | In men and postmenopausal women 40 to 73 years of age without CHD/CVD, the majority of whom did not have diabetes and had baseline LDL-C levels <190 mg/dL, fixed low- to moderate-dose statin therapy that achieved a mean LDL-C of 115–127 mg/dL reduced the RR for CVD by 24%–25%, compared with placebo, with mean LDL-C levels of 153–156 mg/dL. (In these trials, LDL-C was reduced by 29–35 mg/dL and 19%–25% from baseline with a low- to moderate-dose statin.) | H | Primary Prevention | AFCAPS (17); MEGA (18) |
35 | In men ≥50 years and women ≥60 years of age without CHD/CVD with LDL <130 mg/dL and hs-CRP ≥2 mg/L, fixed intensive-dose statin that achieved a mean LDL-C of 53 mg/dL reduced the RR for CVD events by 44% compared with placebo, which had a mean LDL-C 110 mg/dL. In this trial, LDL-C was reduced by 53 mg/dL, or 49%. | M | Primary Prevention | JUPITER (49) |
36 | In adults without CVD (some of whom had diabetes) who received more intensive or less intensive statin therapy, or statin therapy compared with placebo/control, the RR for CVD events was reduced by approximately 25% per 1-mmol/L LDL-C reduction. This was similar to the CVD RRR observed in those with CHD or CVD. | H | Primary Prevention | CTT 2010 (20) |
37 | Statin therapy reduces CHD and stroke events in adults ≥40 years of age without CHD/CVD, and with a wide range of baseline LDL-C levels. | H | Primary Prevention | CTT 2010 (20) JUPITER (49) AFCAPS (17) MEGA (18) |
38 | Statin therapy, with a range of LDL-C lowering, reduces all-cause mortality, compared with placebo, in primary-prevention clinical trials of adults who were in general ≥40 years of age and had at least 1 risk factor, and with a wide range of baseline LDL-C levels. | M | Primary Prevention | CTT 2010 (20) |
39 | There is insufficient evidence to determine the benefit of statins in primary prevention on all-cause mortality separately for women and men or with advancing age. | I | Primary Prevention | CTT 2010 (20) |
40 | In MEGA (18), AFCAPS (17), JUPITER (49), and CARDS (75), the 10-year NNTs to prevent 1 hard CVD event were 82, 56, 30, and 15, respectively. These reflect RRRs of 24%, 26%, 44%, and 37%, respectively, and placebo event rates for major CVD calculated at 10 years of 5.1%, 6.9%, 7.6%, and 18%, respectively. | M | Primary Prevention | CTT 2010 (20) appendix individual trials—projected calculation |
41 | In adults without CVD (some of whom had diabetes) overall, who received statin therapy compared with placebo/control, the RR for CVD events was reduced by approximately 25% per 1-mmol/L LDL-C reduction. This was similar to the CVD RRR observed in those with CHD or CVD. | H | Primary Prevention, Primary Prevention in Individuals With Diabetes | CTT 2010 (20) |
42 | Statin therapy, with a range of LDL-C lowering, reduces all-cause mortality by about 10%, compared with placebo, in primary-prevention clinical trials of adults who were ≥40 years of age and in general who had at least 1 risk factor, and with a wide range of baseline LDL-C levels. | M | Primary Prevention, efficacy | Cochrane (15), Ray (137), Brugts (138), Bukkapatnam (139), JUPITER (49) MEGA—women (140) |
43 | In adults with and without CVD, intensive- and moderate-dose statins do not increase the risk for death from noncardiovascular causes, regardless of baseline LDL-C. Statins do not increase (or decrease) the risk for incident cancer overall or cancer of any type, or the risk for cancer death. | H | Primary Prevention, Secondary Prevention, Safety of Statins | CTT 2010 (20), Mills 2008 (97), Cochrane (15), Bonovas (141) |
44 | In adults with or without CVD, statin therapy is associated with an excess risk for incident diabetes.
| M | Primary Prevention, Secondary Prevention, Safety of Statins | Sattar 2010 (81) Preiss (142), PROVE-IT (48), A–Z (117), TNT (46), IDEAL (47), SEARCH (124), JUPITER (49) |
45 | In trials of high-intensity compared with moderate-intensity statins (clinical CVD), moderate-intensity statin compared with placebo (diabetes—primary prevention), high-intensity statin compared with placebo (secondary and primary prevention), or statin-niacin versus placebo, participants were:
| H | Statin Adherence | Reflects review of TNT (46), IDEAL (47), PROVE-IT (48), CARDS (75), JUPITER (49), SPARCL (107), MEGA (18), AFCAPS (17) baseline and main papers; these were statin trials that demonstrated significant CVD risk reduction (and were the basis of recommendations arising from CQ1 and CQ2) HATS (121) |
46 | Most RCTs of moderate-intensity statin therapy and all RCTs of high-intensity statin therapy excluded subjects with serious comorbidities and other conditions or concomitant drug therapy predisposing to adverse events from statin therapy (see Table 9). | H | Primary Prevention, Secondary Prevention, Safety of Statins, Safety of Nonstatins | RCTs included in CQ1, 2, and 3: A–Z (117), ACCORD (14), AIM-HIGH (9), ASPEN (119), CARE (130), CDP (101), FIELD (115), GREACE (120), HATS (121), HHS (111), HPS (16), IDEAL (47), JUPITER (49), LIPID (74), LIPS (122), LRC (113), MIRACL (93), MUSHASHI-AMI (123), PROVE-IT (48), SEAS (108), SHARP (109), SPARCL (107), TNT (46) |
47 | In adults with and without CVD who received more intensive compared with less intensive statin therapy, or statin therapy compared with placebo/control, overall the RR for first hemorrhagic stroke was not increased. Hemorrhagic stroke comprised 11% of total strokes in the more intensive/statin group, compared with 8% in the less intensive/control groups. | M | Primary Prevention, Secondary Prevention, Safety of Statins | CTT 2010 (20) |
48 | In adults with and without CVD, statin-treated individuals in clinical trials are not more likely to discontinue treatment than placebo-treated individuals. | H | Primary Prevention, Secondary Prevention, Safety of Statins | Cochrane—14 trials (15), CTT 2010 (20) |
49 | In adults with and without CVD in clinical trials, low- to moderate-dose statins do not increase the risk for myalgias or muscle pain. | H | Primary Prevention, Secondary Prevention, Safety of Statins | Cochrane—14 trials (15), CTT 2010 (20) |
50 | In adults selected for participation in clinical trials of statin therapy, rhabdomyolysis occurred rarely (<0.06% over a mean 4.8- to 5.1-year treatment period). | H | Primary Prevention, Secondary Prevention, Safety of Statins | CTT 2010 (20) |
51 | In adults with CHD, the rate of creatine kinase elevation ≥3 times ULN occurs infrequently and at a similar rate in those treated with intensive- or moderate-dose statin therapy. | H | Primary Prevention, Secondary Prevention, Safety of Statins | Dale (98), CTT 2010 (20) |
52 | In adults with CHD, although uncommon (<1.5% over 5 years), intensive statin therapy increases the risk for elevated hepatic transaminase (ALT and/or AST) levels ≥2–3 times ULN more than moderate-dose statin therapy. No cases of hepatic failure were reported. | H | Primary Prevention, Safety of Statins | Dale (98), Cochrane (15), CTT 2010 (20), TNT (46), IDEAL (47), PROVE-IT (48), JUPITER (49) |
53 | Low- to moderate-dose statin therapy has similar rates of elevated hepatic transaminase levels as placebo/no statin treatment. In general, clinical trials tend to underestimate those likely to have side effects, often related to selection procedures. | H | Primary Prevention, Safety of Statins | CTT 2010 (20) |
54 | With the exception of simvastatin 80 mg, intensive- and moderate-dose statins did not increase the risk for rhabdomyolysis. | L | Safety of Statins | CTT 2010 (20), Cochrane (15), Mills (97) |
55 | In adults with CHD, CK elevation ≥3 times ULN occurs infrequently and at a similar rate in those treated with intensive- or moderate-dose statin therapy (0.02% [moderate-dose statin] to 0.1% [higher-dose statin]) over a 1- to 5-year treatment period (RR 2.63, 95% CI 0.88–7.85). | H | Secondary Prevention, Safety | Dale 2007 (98) |
56 | The Expert Panel did not find evidence that statins had an adverse effect on cognitive changes or risk of dementia. | I | Safety of Statins | Reviewed RCTs in CQ1, CQ2; assessment of cognitive function only reported in HPS (16) |
57 | In men with CHD who are 30 to 64 years of age, immediate-release niacin (with an approximately 2-g dose):
| L | Secondary Prevention, Safety, Monotherapy, Safety, Efficacy | CDP (101,143) |
58 | In a trial in 67 adults with CHD and low HDL-C, slow-release niacin (at a mean 2.4-g dose) plus low-dose simvastatin resulted in the following:
| L | Secondary Prevention, Combination Treatment | HATS Investigators (121) |
59 | In adults 45 years of age and older with established CVD and low HDL-C (<40 mg/dL in men or <50 mg/dL in women), elevated triglycerides (150–400 mg/dL), and LDL-C <180 mg/dL off statin, in whom the dose of simvastatin was adjusted, or ezetimibe was added, to maintain LDL-C in a range of 40–80 mg/dL, extended-release niacin 1,500–2,000 mg/day plus simvastatin (9.5% also on ezetimibe 10 mg) compared with placebo (with 50 mg immediate-release niacin) plus simvastatin (21.5% also on ezetimibe 10 mg:
| M | Secondary Prevention, Combination Treatment | AIM-HIGH Investigators (9) |
60 | In men 35–59 years of age without CHD, hypertension, diabetes, or obesity and with LDL-C ≥175 mg/dL and triglycerides <300 mg/dL, cholestyramine:
| L | Primary Prevention, Safety, Efficacy | LRC (113) |
61 | Insufficient data to evaluate the efficacy and safety of ezetimibe monotherapy. | I | Efficacy, Safety, Nonstatin | |
62 | Insufficient data to evaluate the additional efficacy and safety of ezetimibe in combination with a statin compared with a statin alone. | I | Safety, Efficacy, Combination Treatment | |
63 | In adults 45–85 years of age with mild to moderate aortic stenosis and without CVD or diabetes, simvastatin 40 mg coadministered with ezetimibe 10 mg, compared with placebo:
| L | Safety, Efficacy, Combination Treatment | SEAS (108) |
64 | In adults ≥40 years of age with CKD, of whom 33% were receiving dialysis (peritoneal or hemodialysis), ezetimibe 10 mg coadministered with simvastatin 20 mg, compared with placebo:
| L | Safety, Efficacy, Combination Treatment, CKD | SHARP (109) |
65 | Ezetimibe coadministered with simvastatin does not appear to increase the risk for cancer compared with placebo. | L | Safety, Combination Treatment | SHARP (109) |
66 | In adults 50–75 years of age with diabetes—with total cholesterol <250 mg/dL, and total cholesterol/HDL ratio ≥4.0 or triglycerides <450 mg/dL—fenofibrate, compared with placebo:
| L | Safety, Efficacy, Nonstatin Treatment | FIELD (115) |
67 | In adults 40–79 years of age with diabetes, CVD, and/or CVD risk factors, with LDL-C 60–180 mg/dL, HDL-C <55 mg/dL in women and black individuals, HDL-C <50 mg/dL for all others, and triglycerides <750 mg/dL on no medication or <400 mg/dL on medication:
| M | Safety, Efficacy, Nonstatin Treatment | ACCORD (14) |
68 | In men 40–55 years of age without CHD or CHF and non–HDL-C ≥200 mg/dL, gemfibrozil:
| M | Safety, Efficacy, Nonstatin Treatment | Helsinki Heart Study (111) |
69 | In men with CHD who were <74 years of age with HDL-C ≤40 mg/dL and LDL-C ≤140 mg/dL, and triglycerides ≤300 mg/dL, gemfibrozil, compared with placebo:
| M | Efficacy, Nonstatin Treatment | VA-HIT (114) |
70 | In Japanese men who were 40–75 years of age and postmenopausal women ≤75 years of age with and without CHD and LDL-C ≥170 mg/dL, EPA 1,800 mg added to statin therapy:
| M | Efficacy, Safety, Combination Treatment | JELIS (110) |
71 | In individuals with NYHA Classes II–IV systolic or ischemic heart failure, initiation of a statin did not change the absolute or RR for CVD compared with placebo. | M | Efficacy, Selected Population Subgroups | CORONA (85) from CQ1 |
72 | In individuals receiving maintenance hemodialysis, initiation of a statin did not change the relative or absolute risk for CVD compared with placebo. | M | Efficacy, Selected Population Subgroups | 4D (87) and AURORA (84) CQ1 & CQ2, SHARP (109)—HD subgroup |
73 | In men and women of mean age 58 to 68 years with aortic stenosis, treatment with statin or statin plus ezetimibe for a mean of 2.1–4.4 years resulted in a reduction in LDL-C of 50%–55% (67–73 mg/dL) from a baseline LDL-C of 123–140 mg/dL and did not alter the progression of aortic stenosis as assessed by change in valve area, peak aortic valve jet velocity, peak or mean aortic valve gradient, or need for aortic valve surgery. | H | Aortic Stenosis, Combination Treatment | Parolari (144) |
74 | Women who were pregnant or nursing were excluded from statin, fenofibrate, niacin-statin, and ezetimibe-statin RCTs. Only men were enrolled in RCTs of niacin, BAS, and gemfibrozil. | H | Primary Prevention, Secondary Prevention | All RCTs CQ1, CQ2, and CQ3 |
75 | Only individuals with primary hypercholesterolemia were included in RCTs. | H | Primary Prevention, Secondary Prevention | AFCAPS (17) JUPITER (49) JELIS (110) HATS (121) FIELD (115) ACCORD (14) MEGA (18) |
76 | In the 3 exclusively primary-prevention RCTs, low-, moderate-, and high-intensity statin therapy reduced the risk for ASCVD when LDL-C levels were approximately 70–130 mg/dL, 130–190 mg/dL, and 160–200 mg/dL. | H | Primary Prevention | JUPITER (49) MEGA (18) AFCAPS (17) |
77 | Lipids, liver function, uric acid, and glucose tests were obtained at baseline, during up-titration, and every 2–12 months thereafter. | H | Secondary Prevention | CDP (101) (fair) 4–12 months; HATS (121) (good) 2–4 months; AIM-HIGH (9) (good) 3–12 months |
78 | Immediate- and extended-release niacin increase cutaneous adverse effects. | M | Secondary Prevention | CDP (101), AIM-HIGH (9) (not HATS [121]—Slo-Niacin) |
79 | When used as monotherapy or with a statin, niacin increases:
| H M M M | Secondary Prevention, Safety | (CDP [101], HATS [121], AIM-HIGH [9]) (CDP [101], AIM-HIGH [9]—niacin dose reduced or discontinued) (CDP [101], AIM-HIGH [9]—niacin dose reduced or discontinued) Gout (CDP [101]) Increased uric acid (HATS [121]) |
80 | Niacin increases the incidence of atrial fibrillation and weight loss. | L | Secondary Prevention, Safety | CDP (101) (atrial fibrillation not reported in AIM-HIGH [9] or HATS [121]) |
ALT indicates alanine transaminase; ASCVD, atherosclerotic cardiovascular disease; BAS, bile acid sequestrant; BID, twice daily; CHD, coronary heart disease; CHF, congestive heart failure; CK, creatine kinase; CKD, chronic kidney disease; CVD, cardiovascular disease; EPA, eicosapentaenoic acid; GFR, glomerular filtration rate; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; LFT, liver function test; MI, myocardial infarction; NNH, number needed to harm; NNT, number needed to treat; NYHA, New York Heart Association; RCT, randomized controlled trial; RR, relative risk; RRR, relative risk reduction; TIA, transient ischemic attack; and ULN, upper limit of normal.
Appendix 5 Expanded Discussion of What’s New in the Guideline
Focus on ASCVD Risk Reduction: 4 Statin Benefit Groups |
|
A New Perspective on LDL-C and/or Non–HDL-C Goals |
|
Global Risk Assessment for Primary Prevention |
|
Safety |
|
Role of Biomarkers and Noninvasive Tests |
|
Future Updates to the Blood Cholesterol Guideline |
|
∗For additional information, see http://www.mesa-nhlbi.org/CACReference.aspx.
AIM-HIGH indicates Atherothrombosis Intervention in Metabolic Syndrome With Low HDL/High Triglycerides and Impact on Global Health Outcomes; ACCORD, Action to Control Cardiovascular Risk in Diabetes; Apo B, apolipoprotein B; ASCVD, atherosclerotic cardiovascular disease; CAC, coronary artery calcium; CQ, critical question; FDA, U.S. Food and Drug Administration; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; Lp(a), lipoprotein(a); NHANES, National Health and Nutrition Examination Survey; and RCTs, randomized controlled trials.
Footnotes
↵∗ Ex-Officio Members.
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
☆ The Journal of the American College of Cardiology is published on behalf of the American College of Cardiology Foundation by Elsevier Inc.; Circulation is published on behalf of the American Heart Association, Inc., by Wolters Kluwer. This is an open access article under the terms of the Creative Commons Attribution Non-Commercial-NoDervis License, which permits use, distribution, and reproduction in any medium, provided that the Contribution is properly cited, the use is noncommercial, and no modifications or adaptations are made.
This document was approved by the American College of Cardiology Board of Trustees and the American Heart Association Science Advisory and Coordinating Committee in November 2013. The Academy of Nutrition and Dietetics affirms the value of this guideline.
The American College of Cardiology requests that this document be cited as follows: Stone NJ, Robinson JG, Lichtenstein AH, Bairey Merz CN, Blum CB, Eckel RH, Goldberg AC, Gordon D, Levy D, Lloyd-Jones DM, McBride P, Schwartz JS, Shero ST, Smith SC Jr, Watson K, Wilson PWF. 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. J Am Coll Cardiol 2014;63:2889–934.
This article is copublished in Circulation.
Copies: This document is available on the World Wide Web sites of the American College of Cardiology (http://www.cardiosource.org) and the American Heart Association (my.americanheart.org). For copies of this document, please contact the Elsevier Inc. Reprint Department, fax (212) 462-1935, e-mail reprints{at}elsevier.com.
- The Expert Panel Members
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Article Outline
- Top
- Methodology Members
- ACC/AHA Task Force Members
- Subcommittee on Prevention Guidelines
- Table of Contents
- Preamble and Transition to ACC/AHA Guidelines to Reduce Cardiovascular Risk
- 1 Introduction
- 2 Overview of the Guideline
- 3 Critical Questions and Conclusions
- 4 Statin Treatment: Recommendations
- 5 Safety: Recommendations
- 6 Managing Statin Therapy: Recommendations
- 7 Selected Clinical and Population Subgroups
- 8 Limitations
- 9 Evidence Gaps and Future Research Needs
- 10 Conclusions
- Presidents and Staff
- Appendix 1 Author Relationships With Industry and Other Entities (Relevant)— 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol in Adults to Reduce Atherosclerotic Cardiovascular Risk
- Appendix 2 Expert Reviewers Relationships With Industry and Other Entities—2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol in Adults to Reduce Atherosclerotic Cardiovascular Risk
- Appendix 3 Abbreviations
- Appendix 4 Evidence Statements
- Appendix 5 Expanded Discussion of What’s New in the Guideline
- Footnotes
- References