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Levine GN, Bates ER, Blankenship JC, Bailey SR, Bittl JA, Cercek B, Chambers CE, Ellis SG, Guyton RA, Hollenberg SM, Khot UN, Lange RA, Mauri L, Mehran R, Moussa ID, Mukherjee D, Nallamothu BK, Ting H. 2011 ACCF/AHA/SCAI guideline for percutaneous coronary intervention: a report of the American College of Cardiology Founda- tion/American Heart Association Task Force on Practice Guidelines. Circulation. In press. 175. Rooke TW, Hirsch AT, Misra S, Sidawy AN, Beckman JA, Findeiss L, Golzarian J, Gornik HL, Halperin JL, Jaff MR, Moneta GL, Olin JW, Stanley JC, White CJ, White JV, Zierler RE. 2011 ACCF/AHA focused update of the guideline for the management of patients with peripheral artery disease (updating the 2005 guideline): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation. 2011;124:2020 2045. 176. Hirsch AT, Haskal ZJ, Hertzer NR, Bakal CW, Creager MA, Halperin JL, Hiratzka LF, Murphy WRC, Olin JW, Puschett JB, Rosenfield KA, Sacks D, Stanley JC, Taylor LM Jr, White CJ, White J, White RA. ACC/AHA 2005 guidelines for the management of patients with peripheral arterial disease (lower extremity, renal, mesenteric, and abdominal aortic): executive summary: a collaborative report from the American Association for Vascular Surgery/Society for Vascular Surgery, Society for Cardiovascular Angiography and Interventions, Society for Vascular Medicine and Biology, Society of Interventional Radiology, and the ACC/AHA Task Force on Practice Guidelines (Writing Committee to Develop Guidelines for the Management of Patients With Peripheral Arterial Disease). Circulation. 2006;113: 1474 1547. KEY WORDS: AHA Scientific Statements n secondary prevention n coronary disease n vascular disease n risk factors Smith et al AHA/ACCF Secondary Prevention: 2011 Update 2473


WRITING COMMITTEE MEMBERS Scott M. Grundy, MD, PhD, FAHA, Chair* Neil J. Stone, MD, FACC, FAHA, Vice Chair* Alison L. Bailey, MD, FACC, FAACVPR Craig Beam, CRE* Kim K. Birtcher, MS, PharmD, AACC, FNLA Roger S. Blumenthal, MD, FACC, FAHA, FNLA Lynne T. Braun, PhD, CNP, FAHA, FPCNA, FNLA Sarah de Ferranti, MD, MPH* Joseph Faiella-Tommasino, PhD, PA-C Daniel E. Forman, MD, FAHA** Ronald Goldberg, MD Paul A. Heidenreich, MD, MS, FACC, FAHA Mark A. Hlatky, MD, FACC, FAHA* Daniel W. Jones, MD, FAHA Donald Lloyd-Jones, MD, SCM, FACC, FAHA* Nuria Lopez-Pajares, MD, MPH Chiadi E. Ndumele, MD, PhD, FAHA* Carl E. Orringer, MD, FACC, FNLA Carmen A. Peralta, MD, MAS* Joseph J. Saseen, PharmD, FNLA, FAHA Sidney C. Smith Jr, MD, MACC, FAHA* Laurence Sperling, MD, FACC, FAHA, FASPC*** Salim S. Virani, MD, PhD, FACC, FAHA* Joseph Yeboah, MD, MS, FACC, FAHA 2018 by the American Heart Association, Inc., and the American College of Cardiology Foundation. CHOLESTEROL CLINICAL PRACTICE GUIDELINES AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines Circulation https://www.ahajournals.org/journal/circ ACC/AHA Task Force Members, see page e1123 *ACC/AHA Representative. AACVPR Representative. ACC/AHA Task Force on Clinical Practice Guidelines Liaison. Prevention Subcommittee Liaison. PCNA Representative. AAPA Representative. **AGS Representative. ADA Representative. PM Representative. ACPM Representative. NLA Representative. APhA Representative. ***ASPC Representative. ABC Representative. The American Heart Association requests that this document be cited as follows: Grundy SM, Stone NJ, Bailey AL, Beam C, Birtcher KK, Blumenthal RS, Braun LT, de Ferranti S, Faiella-Tommasino J, Forman DE, Goldberg R, Heidenreich PA, Hlatky MA, Jones DW, Lloyd-Jones D, Lopez-Pajares N, Ndumele CE, Orringer CE, Peralta CA, Saseen JJ, Smith SC Jr, Sperling L, Virani SS, Yeboah J.


The American Heart Association requests that this document be cited as follows: Grundy SM, Stone NJ, Bailey AL, Beam C, Birtcher KK, Blumenthal RS, Braun LT, de Ferranti S, Faiella-Tommasino J, Forman DE, Goldberg R, Heidenreich PA, Hlatky MA, Jones DW, Lloyd-Jones D, Lopez-Pajares N, Ndumele CE, Orringer CE, Peralta CA, Saseen JJ, Smith SC Jr, Sperling L, Virani SS, Yeboah J. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/ APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation. 2019;139:e1082 e1143. DOI: 10.1161/CIR.0000000000000625. Key Words: AHA Scientific Statements Guidelines biomarkers, coronary artery calcium score pharmacological cardiovascular disease cholesterol, LDL-cholesterol diabetes mellitus drug therapy hydroxymethylglutaryl- CoA reductase inhibitors/statins hypercholesterolemia lipids patient compliance primary prevention risk assessment risk reduction discussion risk treatment discussion, secondary prevention ezetimibe proprotein convertase subtilisin/kexin type 9 inhibitor (PCSK9) inhibitors CLINICAL STATEMENTS AND GUIDELINES TABLE OF CONTENTS Top 10 Take-Home Messages to Reduce Risk of Atherosclerotic Cardiovascular Disease Through Cholesterol Management e1083 Preamble e1084 1. Introduction e1085 1.1. Methodology and Evidence Review e1085 1.2. Organization of the Writing Committee e1086 1.3. Document Review and Approval e1086 1.4. Scope of the Guideline e1086 1.5. Class of Recommendation and Level of Evidence e1087 1.6. Abbreviations e1087 2. High Blood Cholesterol and ASCVD e1087 2.1. Serum Cholesterol, Lipoproteins, and ASCVD e1087 2.1.1. Cholesterol, Lipoproteins, and Apolipoprotein B e1087 2.1.2. Cholesterol, LDL-C, and ASCVD e1087 2.1.3. LDL-C and Other Risk Factors e1087 2.2. Measurements of LDL-C and Non HDL-C e1088 2.3. Measurements of Apolipoprotein B and Lipoprotein (a) e1089 2.4. Monitoring Response of LDL-C to Statin Therapy e1090 3. Therapeutic Modalities e1090 3.1. Lifestyle Therapies e1090 3.1.1. Diet Composition, Weight Control, and Physical Activity e1090 3.1.2. Lifestyle Therapies and Metabolic Syndrome e1090 3.2. Lipid-Lowering Drugs e1090 3.2.1. Statin Therapy e1090 3.2.2.


Lifestyle Therapies and Metabolic Syndrome e1090 3.2. Lipid-Lowering Drugs e1090 3.2.1. Statin Therapy e1090 3.2.2. Nonstatin Therapies e1091 3.2.3. Nonstatin Add-on Drugs to Statin Therapy e1091 4. Patient Management Groups e1091 4.1. Secondary ASCVD Prevention e1091 4.2. Severe Hypercholesterolemia (LDL-C 190 mg/dL [ 4.9 mmol/L]) e1095 4.3. Diabetes Mellitus in Adults e1097 4.4. Primary Prevention e1099 4.4.1. Evaluation and Risk Assessment e1099 4.4.2. Primary Prevention Adults 40 to 75 Years of Age With LDL-C Levels 4.4.3. Monitoring in Response to LDL-C Lowering Therapy e1106 4.4.4. Primary Prevention in Other Age Groups e1107 4.5. Other Populations at Risk e1111 4.5.1. Ethnicity e1111 4.5.2. Hypertriglyceridemia e1112 5. Statin Safety and Statin-Associated Side Effects e1117 6. Implementation e1120 7. Cost and Value Considerations e1121 7.1. Economic Value Considerations: PCSK9 Inhibitors e1121 8. Limitations and Knowledge Gaps e1122 8.1. Randomized Controlled Trials e1122 8.2. Risk Assessment e1122 8.2.1. Continuing Refinement of PCE e1123 8.2.2. Improvement in Lifetime Risk Estimate e1123 8.2.3. Refinement of Clinician Patient Risk Discussion e1123 8.2.4. Monitoring and Adjustment of Treatment e1123 8.2.5. Prognostic Significance of CAC e1123 References e1124 Appendix 1: Author Relationships With Industry and Other Entities (Relevant) 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol Appendix 2: Reviewer Relationships With Industry and Other Entities (Comprehensive) 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/ AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol TOP 10 TAKE-HOME MESSAGES TO REDUCE RISK OF ATHEROSCLEROTIC CARDIOVASCULAR DISEASE THROUGH CHOLESTEROL MANAGEMENT 1. In all individuals, emphasize a heart-healthy lifestyle across the life course. A healthy lifestyle reduces atherosclerotic cardiovascular disease (ASCVD) risk at all ages. In younger indi- viduals, healthy lifestyle can reduce development of risk factors and is the foundation of ASCVD risk reduction. In young adults 20 to 39 years of age, an assessment of lifetime risk facilitates the clinician patient risk discussion (see No.


In young adults 20 to 39 years of age, an assessment of lifetime risk facilitates the clinician patient risk discussion (see No. 6) and emphasizes intensive lifestyle efforts. In all age groups, lifestyle therapy is the primary interven- tion for metabolic syndrome. 2. In patients with clinical ASCVD, reduce low- density lipoprotein cholesterol (LDL-C) with high-intensity statin therapy or maximally tolerated statin therapy. The more LDL-C is reduced on statin therapy, the greater will be sub- sequent risk reduction. Use a maximally tolerated statin to lower LDL-C levels by 50%. 3. In very high-risk ASCVD, use a LDL-C thresh- old of 70 mg/dL (1.8 mmol/L) to consider addition of nonstatins to statin therapy. Very high-risk includes a history of multiple major ASCVD events or 1 major ASCVD event and multiple high-risk conditions. In very high-risk ASCVD patients, it is reasonable to add ezetimibe to maximally tolerated statin therapy when the LDL-C level remains 70 mg/dL ( 1.8 mmol/L). In patients at very high risk whose LDL-C level CLINICAL STATEMENTS AND GUIDELINES remains 70 mg/dL ( 1.8 mmol/L) on maximally tolerated statin and ezetimibe therapy, adding a PCSK9 inhibitor is reasonable, although the long- term safety (>3 years) is uncertain and cost effec- tiveness is low at mid-2018 list prices. 4. In patients with severe primary hyper- cholesterolemia (LDL-C level 190 mg/dL [ 4.9 mmol/L]), without calculating 10-year ASCVD risk, begin high-intensity statin ther- apy. If the LDL-C level remains 100 mg/dL ( 2.6 mmol/L), adding ezetimibe is reasonable. If the LDL-C level on statin plus ezetimibe remains 100 mg/dL ( 2.6 mmol/L) and the patient has multiple factors that increase subsequent risk of ASCVD events, a PCSK9 inhibitor may be considered, although the long-term safety (>3 years) is uncer- tain and economic value is uncertain at mid-2018 list prices. 5.


If the LDL-C level on statin plus ezetimibe remains 100 mg/dL ( 2.6 mmol/L) and the patient has multiple factors that increase subsequent risk of ASCVD events, a PCSK9 inhibitor may be considered, although the long-term safety (>3 years) is uncer- tain and economic value is uncertain at mid-2018 list prices. 5. In patients 40 to 75 years of age with dia- betes mellitus and LDL-C 70 mg/dL ( 1.8 mmol/L), start moderate-intensity statin therapy without calculating 10-year ASCVD risk. In patients with diabetes mellitus at higher risk, especially those with multiple risk factors or those 50 to 75 years of age, it is reasonable to use a high-intensity statin to reduce the LDL-C level by 50%. 6. In adults 40 to 75 years of age evaluated for primary ASCVD prevention, have a clinician patient risk discussion before starting statin therapy. Risk discussion should include a review of major risk factors (eg, cigarette smoking, ele- vated blood pressure, LDL-C, hemoglobin A1C [if indicated], and calculated 10-year risk of ASCVD); the presence of risk-enhancing factors (see No. 8); the potential benefits of lifestyle and statin therapies; the potential for adverse effects and drug drug interactions; consideration of costs of statin therapy; and patient preferences and values in shared decision-making. 7. In adults 40 to 75 years of age without dia- betes mellitus and with LDL-C levels 70 mg/ dL ( 1.8 mmol/L), at a 10-year ASCVD risk of 7.5%, start a moderate-intensity statin if a discussion of treatment options favors statin therapy. Risk-enhancing factors favor statin ther- apy (see No. 8). If risk status is uncertain, consider using coronary artery calcium (CAC) to improve specificity (see No. 9). If statins are indicated, reduce LDL-C levels by 30%, and if 10-year risk is 20%, reduce LDL-C levels by 50%. 8.


If statins are indicated, reduce LDL-C levels by 30%, and if 10-year risk is 20%, reduce LDL-C levels by 50%. 8. In adults 40 to 75 years of age without dia- betes mellitus and 10-year risk of 7.5% to 19.9% (intermediate risk), risk-enhancing factors favor initiation of statin therapy (see No. 7). Risk-enhancing factors include family history of premature ASCVD; persistently ele- vated LDL-C levels 160 mg/dL ( 4.1 mmol/L); metabolic syndrome; chronic kidney disease; his- tory of preeclampsia or premature menopause (age <40 years); chronic inflammatory disorders (eg, rheumatoid arthritis, psoriasis, or chronic HIV); high-risk ethnic groups (eg, South Asian); persistent elevations of triglycerides 175 mg/dL ( 1.97 mmol/L); and, if measured in selected indi- viduals, apolipoprotein B 130 mg/dL, high-sensi- tivity C-reactive protein 2.0 mg/L, ankle-brachial index <0.9 and lipoprotein (a) 50 mg/dL or 125 nmol/L, especially at higher values of lipoprotein (a). Risk-enhancing factors may favor statin ther- apy in patients at 10-year risk of 5-7.5% (border- line risk). 9. In adults 40 to 75 years of age without diabe- tes mellitus and with LDL-C levels 70 mg/dL to 189 mg/dL ( 1.8-4.9 mmol/L), at a 10-year ASCVD risk of 7.5% to 19.9%, if a decision about statin therapy is uncertain, consider measuring CAC. If CAC is zero, treatment with statin therapy may be withheld or delayed, except in cigarette smokers, those with diabetes mellitus, and those with a strong family history of prema- ture ASCVD. A CAC score of 1 to 99 favors statin therapy, especially in those 55 years of age. For any patient, if the CAC score is 100 Agatston units or 75th percentile, statin therapy is indi- cated unless otherwise deferred by the outcome of clinician patient risk discussion. 10.


For any patient, if the CAC score is 100 Agatston units or 75th percentile, statin therapy is indi- cated unless otherwise deferred by the outcome of clinician patient risk discussion. 10. Assess adherence and percentage response to LDL-C lowering medications and lifestyle changes with repeat lipid measurement 4 to 12 weeks after statin initiation or dose adjustment, repeated every 3 to 12 months as needed. Define responses to lifestyle and statin therapy by percentage reductions in LDL-C levels compared with baseline. In ASCVD patients at very high-risk, triggers for adding nonstatin drug therapy are defined by threshold LDL-C lev- els 70 mg/dL ( 1.8 mmol/L) on maximal statin therapy (see No. 3). PREAMBLE Since 1980, the American College of Cardiology (ACC) and American Heart Association (AHA) have translated scientific evidence into clinical practice guidelines with recommendations to improve cardiovascular health. These guidelines, which are based on systematic meth- ods to evaluate and classify evidence, provide a founda- tion for the delivery of quality cardiovascular care. The ACC and AHA sponsor the development and publica- tion of clinical practice guidelines without commercial CLINICAL STATEMENTS AND GUIDELINES support, and members volunteer their time to the writ- ing and review efforts. Clinical practice guidelines provide recommenda- tions applicable to patients with or at risk of developing cardiovascular disease (CVD). The focus is on medical practice in the United States, but these guidelines are relevant to patients throughout the world. Although guidelines may be used to inform regulatory or payer decisions, the intent is to improve quality of care and align with patients interests. Guidelines are intended to define practices meeting the needs of patients in most, but not all, circumstances, and should not re- place clinical judgment.


Guidelines are intended to define practices meeting the needs of patients in most, but not all, circumstances, and should not re- place clinical judgment. Recommendations for guideline-directed manage- ment and therapy, which encompasses clinical evalu- ation, diagnostic testing, and both pharmacological and procedural treatments, are effective only when fol- lowed by both practitioners and patients. Adherence to recommendations can be enhanced by shared decision- making between clinicians and patients, with patient engagement in selecting interventions on the basis of individual values, preferences, and associated condi- tions and comorbidities. The ACC/AHA Task Force on Clinical Practice Guidelines strives to ensure that the guideline writ- ing committee both contains requisite expertise and is representative of the broader medical community by selecting experts from a broad array of backgrounds, representing different geographic regions, sexes, races, ethnicities, intellectual perspectives/biases, and scopes of clinical practice, and by inviting organizations and professional societies with related interests and ex- pertise to participate as partners or collaborators. The ACC and AHA have rigorous policies and methods to ensure that documents are developed without bias or improper influence. The complete policy on relation- ships with industry and other entities (RWI) can be found online. Beginning in 2017, numerous modifications to the guidelines have been and continue to be implemented to make guidelines shorter and enhance user friendli- ness. Guidelines are written and presented in a modu- lar knowledge chunk format, in which each chunk in- cludes a table of recommendations, a brief synopsis, recommendation-specific supportive text and, when appropriate, flow diagrams or additional tables. Hyper- linked references are provided for each modular knowl- edge chunk to facilitate quick access and review. More structured guidelines including word limits ( tar- gets ) and a web guideline supplement for useful but noncritical tables and figures are 2 such changes.


More structured guidelines including word limits ( tar- gets ) and a web guideline supplement for useful but noncritical tables and figures are 2 such changes. This Preamble is an abbreviated version, with the detailed version available online. Glenn N. Levine, MD, FACC, FAHA Chair, ACC/AHA Task Force on Clinical Practice Guidelines 1.1. Methodology and Evidence Review The recommendations listed in the present guideline are, whenever possible, evidence based. An initial ex- tensive evidence review, which included literature de- rived from research involving human subjects, published in English, and indexed in MEDLINE (through PubMed), EMBASE, the Cochrane Library, the Agency for Health- care Research and Quality, and other selected databases relevant to the present guideline, was conducted from May 1980 to July 2017. Key search words included but were not limited to the following: hyperlipidemia, cholesterol, LDL-C, HDL-C, ezetimibe, bile acid seques- trants, PCSK9 inhibitors, lifestyle, diet, exercise, medica- tions, child, adolescent, screening, primary prevention, secondary prevention, cardiovascular disease, coronary artery calcium, familial hypercholesterolemia. ASCVD risk-enhancing factors, statin therapy, diabetes melli- tus, women, adherence, Hispanic/Latino, South Asian, African American. Additional relevant studies published through August 2018 during the guideline writing pro- cess, were also considered by the writing committee and added to the evidence tables when appropriate. The final evidence tables are included in the Online Data Supplement and summarize the evidence used by the writing committee to formulate recommendations. References selected and published in the present docu- ment are representative and not all-inclusive. As noted in the detailed version of the Preamble, an independent evidence review committee was commis- sioned to perform a formal systematic review of critical clinical questions related to cholesterol (Table 1), the Table 1.


As noted in the detailed version of the Preamble, an independent evidence review committee was commis- sioned to perform a formal systematic review of critical clinical questions related to cholesterol (Table 1), the Table 1. ERC Questions Question Section Number In adults 20 years of age with clinical atherosclerotic disease (eg, CHD, peripheral artery disease, or CVD) or at high-risk of ASCVD, what are the magnitude of benefit (absolute reduction; NNT) in individual endpoints and composite ischemic events (eg, fatal cardiovascular event, nonfatal MI, nonfatal stroke, unstable angina/revascularization) and magnitude of harm (absolute increase; NNH) in terms of adverse events (eg, cancer, rhabdomyolysis, diabetes mellitus) derived from LDL-C lowering in large RCTs (>1000 participants and originally designed to last >12 months) with statin therapy plus a second lipid-modifying agent compared with statin alone? Clinical atherosclerotic cardiovascular disease (ASCVD) includes acute coronary syndrome (ACS), those with history of myocardial infarction (MI), stable or unstable angina or coronary or other arterial revascularization, stroke, transient ischemic attack (TIA), or peripheral artery disease (PAD) including aortic aneurysm, all of atherosclerotic origin. ASCVD indicates atherosclerotic cardiovascular disease; CHD, coronary heart disease; CVD, cardiovascular disease; ERC, Evidence Review Committee; LDL-C, low-density lipoprotein cholesterol; MI, myocardial infarction; NNH, number needed to harm; NNT number needed to treat; and RCT, randomized controlled trial. CLINICAL STATEMENTS AND GUIDELINES results of which were considered by the writing com- mittee for incorporation into the present guideline. Concurrent with this process, writing committee mem- bers evaluated study data relevant to the rest of the guideline. The findings of the evidence review commit- tee and the writing committee members were formally presented and discussed, and then recommendations were developed. The systematic review for the 2018 Cholesterol Clinical Practice GuidelinesS1.1-1 is published in conjunction with the present guideline, and includes its respective data supplements.


The systematic review for the 2018 Cholesterol Clinical Practice GuidelinesS1.1-1 is published in conjunction with the present guideline, and includes its respective data supplements. Numerical values for triglycerides, total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high- density lipoprotein cholesterol (HDL-C), and non HDL- C are given in both mg/dL and mmol/L. To convert to mmol/L, the values in mg/dL for TC, LDL-C, HDL-C, and non HDL-C were divided by 38.6 and for triglycerides, by 88.6. On May 10, 2018 a writing committee member discussed their participation in an industry-supported, multicenter study, which they had thought was not rel- evant to this prevention guideline. However, when this was reviewed using specific ACC/AHA criteria it was considered to represent a relevant relationship with in- dustry. Given the current policy that a prevention guide- line writing committee member must be free of any relevant relationships with industry, this member was removed from the committee. The 2 sections authored by the writing committee member were removed and replaced by new material written by the guideline chairs, and the revised sections reviewed and approved by all remaining writing committee members. The writ- ing committee member did not participate in any fur- ther guideline discussions or review of the manuscript or recommendations. 1.2. Organization of the Writing Committee The writing committee consisted of medical experts including cardiologists, internists, interventionalists, a nurse practitioner, pharmacists, a physician assistant, a pediatrician, a nephrologist, and a lay/patient repre- sentative.


Organization of the Writing Committee The writing committee consisted of medical experts including cardiologists, internists, interventionalists, a nurse practitioner, pharmacists, a physician assistant, a pediatrician, a nephrologist, and a lay/patient repre- sentative. The writing committee included represen- tatives from the American Heart Association (AHA), American College of Cardiology (ACC), American Association of Cardiovascular and Pulmonary Reha- bilitation (AACVPR), American Association Academy of Physician Assistants (AAPA), Association of Black Cardiologists (ABC), American College of Preventive Medicine (ACPM), American Diabetes Association (ADA), American Geriatrics Society (AGS), American Pharmacists Association (APhA), American Society for Preventive Cardiology (ASPC), National Lipid As- sociation (NLA), and Preventive Cardiovascular Nurses Association (PCNA). Appendix 1 of the present docu- ment lists writing committee members relevant re- lationships with industry and other entities. For the purposes of full transparency, the writing committee members comprehensive disclosure information is available online. 1.3. Document Review and Approval This document was reviewed by 21 official reviewers each nominated by the ACC, AHA, AAPA, ABC, ACPM, ADA, AGS, APhA, ASPC, NLA, and PCNA, as well as 27 individual content reviewers. Reviewers RWI informa- tion was distributed to the writing committee and is published in this document (Appendix 2). This document was approved for publication by the governing bodies of the AHA, the ACC, AAPA, ABC, ACPM, ADA, AGS, APhA, ASPC, NLA, and PCNA. 1.4. Scope of the Guideline The purpose of the present guideline is to address the practical management of patients with high blood cholesterol and related disorders. The writing com- mittee reviewed previously published guidelines, evi- dence reviews, and related statements. Table S1 in the Web Supplement contains a list of publications and statements deemed pertinent. The primary sources of evidence are randomized controlled trials (RCTs).


The primary sources of evidence are randomized controlled trials (RCTs). Most RCTs in this area have been performed with statins as the only cholesterol-lowering drug.S1.4-1 S1.4-3 Since the 2013 ACC/AHA cholesterol guideline,S1.4-4 newer cholesterol-lowering agents (nonstatin drugs) have been introduced and subjected to RCTs. They include ezetimibe and PCSK9 inhibitors, and their use is lim- ited mainly to secondary prevention in patients at very high-risk of new atherosclerotic cardiovascular disease (ASCVD) events. Most other patients with ASCVD are treated with statins alone. In primary prevention, statins are recommended for patients with severe hy- percholesterolemia and in adults 40 to 75 years of age either with diabetes mellitus or at higher ASCVD risk. Throughout these guidelines similar to the 2013 guidelines, consistent attention is given to a clinician patient risk discussion for making shared decisions. Besides major risk factors of the pooled cohort equa- tions (PCE), the clinician patient risk discussion can in- clude other risk-enhancing factors, and when risk sta- tus is uncertain, a coronary artery calcium (CAC) score is an option to facilitate decision-making in adults 40 years of age. In children, adolescents, and young adults, identifying those with familial hypercholester- olemia (FH) is a priority. However, most attention is given to reducing lifetime ASCVD risk through lifestyle therapies. CLINICAL STATEMENTS AND GUIDELINES 1.5. Class of Recommendation and Level of Evidence Recommendations are designated with both a class of recommendation (COR) and a level of evidence (LOE). The class of recommendation indicates the strength of recommendation, encompassing the estimated magni- tude and certainty of benefit in proportion to risk.


The class of recommendation indicates the strength of recommendation, encompassing the estimated magni- tude and certainty of benefit in proportion to risk. The level of evidence rates the quality of scientific evidence supporting the intervention on the basis of the type, quantity, and consistency of data from clinical trials and other sources (Table 2).S1.5-1 Abbreviation Meaning/Phrase ABI ankle-brachial index ACS acute coronary syndrome AIDS acquired immunodeficiency syndrome apoB apolipoprotein B ARR absolute risk reduction ASCVD atherosclerotic cardiovascular disease CAC coronary artery calcium CHD coronary heart disease CK creatine kinase CKD chronic kidney disease COR Class of Recommendation CTT Cholesterol Treatment Trialists CVD cardiovascular disease eGFR estimated glomerular filtration rate FH familial hypercholesterolemia HDL high-density lipoprotein HF heart failure HIV human immunodeficiency virus LDL-C low-density lipoprotein cholesterol LOE Level of Evidence Lp(a) lipoprotein (a) MI myocardial infarction PCE pooled cohort equations QALY quality-adjusted life-year RA rheumatoid arthritis RCT randomized controlled trials RRR relative risk reduction RWI relationships with industry and other entities SAMS statin-associated muscle symptoms SR systematic review TC total cholesterol VLDL very low-density lipoprotein VLDL-C very low-density lipoprotein cholesterol 2. HIGH BLOOD CHOLESTEROL AND ASCVD 2.1. Serum Cholesterol, Lipoproteins, and ASCVD 2.1.1. Cholesterol, Lipoproteins, and Apolipoprotein B Serum cholesterol and its lipoprotein carriers (LDL, very low-density lipoprotein [VLDL], and HDL) are known to be related to ASCVD. LDL-C is the dominant form of atherogenic cholesterol. VLDL is the chief carrier of triglycerides, and VLDL cholesterol (VLDL-C) is also ath- erogenic. HDL-C is seemingly not atherogenic. Chylo- microns transport dietary fat; chylomicron atherogenici- ty is uncertain. The combination of LDL-C and VLDL-C is called non HDL-C and is more atherogenic than either lipoprotein alone.


The combination of LDL-C and VLDL-C is called non HDL-C and is more atherogenic than either lipoprotein alone. The main protein embedded in LDL and VLDL is apolipoprotein B (apoB), and like non HDL- C, apoB is a stronger indicator of atherogenicity than LDL-C alone. 2.1.2. Cholesterol, LDL-C, and ASCVD Evidence that serum cholesterol contributes to ASCVD comes from several sources: animal studies, genetic forms of hypercholesterolemia, epidemiological stud- ies, and RCTs. US population studiesS2.1.2-1,S2.1.2-2 suggest that optimal total cholesterol levels are about 150 mg/ dL (3.8 mmol/L), which corresponds to an LDL-C level of about 100 mg/dL (2.6 mmol/L). Adult populations with cholesterol concentrations in this range manifest low rates of ASCVD.S2.1.2-3 RCTs of cholesterol-lowering drugs in high-risk patients confirm that LDL-C lowering produces marked reductions in ASCVD. This confirms the general principle that lower is better for LDL- The present guideline looks to evidence from new RCTs to aid in the translation of RCT data to the individual patient to provide net benefit.S2.1.2-7 2.1.3. LDL-C and Other Risk Factors Although LDL-C is a primary cause of atherosclero- sis, other risk factors contribute, as well. The major risk factors include cigarette smoking, hypertension, dysglycemia, and other lipoprotein abnormalities. Be- cause atherosclerosis progresses with advancing age, a person s age also counts as a risk factor. By combin- ing all major risk factors into a prediction equation, an individual s probability of developing ASCVD can be estimated. The Framingham Heart StudyS2.1.3-1 took the lead in creating risk-prediction equations. These were improved in the 2013 ACC/AHA cholesterol guideli- by compiling data from 5 community-based cohorts that were broadly representative of the US population.


These were improved in the 2013 ACC/AHA cholesterol guideli- by compiling data from 5 community-based cohorts that were broadly representative of the US population. These so-called population cohort equa- tions have been validated in a large community-based Initially, data from the Women s CLINICAL STATEMENTS AND GUIDELINES Health Initiative, a contemporary multiethnic cohort of postmenopausal women, appeared to indicate that these pooled cohort equations overestimated ASCVD risk. However, when event surveillance was improved by data from Centers for Medicare & Medicaid Servic- es, the authors found that the equations discriminated Several other factors associate with ASCVD, and in the present document these are called risk-enhancing factors. Projections of future risk derived from major risk factors and risk-enhancing factors can be used to adjust the intensity of LDL-lowering therapy. 2.2. Measurements of LDL-C and Non HDL-C Recommendations for Measurements of LDL-C and Non HDL-C Referenced studies that support recommendations are summarized in Online Data Supplement 1. COR LOE Recommendations I B-NR In adults who are 20 years of age or older and not on lipid-lowering therapy, measurement of either a fasting or a nonfasting plasma lipid profile is effective in estimating ASCVD risk and documenting Table 2.


COR LOE Recommendations I B-NR In adults who are 20 years of age or older and not on lipid-lowering therapy, measurement of either a fasting or a nonfasting plasma lipid profile is effective in estimating ASCVD risk and documenting Table 2. Applying Class of Recommendation and Level of Evidence to Clinical Strategies, Interventions, Treatments, or Diagnostic Testing in Patient Care* (Updated August 2015) CLINICAL STATEMENTS AND GUIDELINES I B-NR In adults who are 20 years of age or older and in whom an initial nonfasting lipid profile reveals a triglycerides level of 400 mg/dL or higher ( 4.5 mmol/L), a repeat lipid profile in the fasting state should be performed for assessment of fasting triglyceride levels and IIa C-LD For adults with an LDL-C level less than 70 mg/dL (<1.8 mmol/L), measurement of direct LDL-C or modified LDL-C estimate is reasonable to improve accuracy over the IIa C-LD In adults who are 20 years of age or older and without a personal history of ASCVD, but with a family history of premature ASCVD or genetic hyperlipidemia, measurement of a fasting plasma lipid profile is reasonable as part of an initial evaluation to aid in the understanding and identification of familial lipid disorders. Synopsis The standard calculation method for LDL-C is the Friedewald formula: LDL-C=(TC) (triglycerides/5) (HDL-C). When triglyceride levels are not elevated, this equation is sufficiently accurate. In hypertri- glyceridemia, however, Friedewald-calculated LDL- C can be erroneous. After normal food intake, LDL-C differs minimally with time.S2.2-10 Fasting and nonfasting TC and HDL-C levels appear to have fairly similar prognostic value and associations with CVD Thus, nonfasting samples can be used for risk assessment in primary prevention and for assessment of baseline LDL-C levels before the ini- tiation of a statin in primary and secondary prevention.


After normal food intake, LDL-C differs minimally with time.S2.2-10 Fasting and nonfasting TC and HDL-C levels appear to have fairly similar prognostic value and associations with CVD Thus, nonfasting samples can be used for risk assessment in primary prevention and for assessment of baseline LDL-C levels before the ini- tiation of a statin in primary and secondary prevention. If more precision is necessary, fasting lipids can be mea- sured, but a nonfasting sample is reasonable for most situations. The unreliability of the Friedewald-calculated LDL-C levels appears to be greatest at lower levels of Mar- tin et al. have validated an approach to estimating LDL- C levels from a standard lipid panel when LDL-C levels is <70 mg/dL (<1.8 mmol/L) and triglycerides levels are Recommendation-Specific Supportive Text 1. If an individual has ingested an extremely high-fat meal in the preceding 8 hours, it may be prudent to assess lipids on another day after counseling the patient to avoid such meals. Documentation of the baseline LDL-C level will be useful in assessing the patient s response to the initiation of statin therapy, if that is undertaken.S2.2-1 S2.2-6 Similarly, given relatively modest differences in LDL-C levels associated with the postprandial state, use of a nonfasting sample is effective to document baseline lipid levels before initia- tion of statin therapy in individuals with clinical In adults with a family history of premature ASCVD or genetic hyperlipidemia, a fasting lipid profile is reasonable for initial evaluation. 2. Given relatively modest differences in LDL-C lev- els between fasting and non-fasting samples, the latter is generally adequate to document baseline lipid levels prior to initiation of statin 3. The unreliability of the Friedewald-calculated LDL-C levels rises at lower levels of LDL-C, par- ticularly <70 mg/dL (<1.8 mmol/L).


The unreliability of the Friedewald-calculated LDL-C levels rises at lower levels of LDL-C, par- ticularly <70 mg/dL (<1.8 mmol/L). If accurate measurements of LDL-C levels are needed at very low LDL-C, calculation adjustments can be Measurement of apoB may be use- ful in determining whether hypertriglyceridemia is an atherogenic condition.S2.2-12,S2.2-13 4. In adults with a family history of premature ASCVD or genetic hyperlipidemia, a fasting lipid profile is reasonable for initial evaluation to aid in the understanding and identification of familial 2.3. Measurements of Apolipoprotein B and Lipoprotein (a) Two lipoprotein entities related to LDL-C are apoB and lipoprotein (a) [Lp(a)]. Because apoB is the major apoli- poprotein embedded in LDL and VLDL, several investiga- tors identify strength of association between apoB and Others report a high correlation between apoB and non HDL-C.S2.3-2 Under certain circumstanc- es, particularly in patients with hypertriglyceridemia, the measurement of apoB may have advantages.S2.3-3 Nevertheless, apoB measurement carries extra expense, and its measurement in some laboratories may not be A relative indication for its measurement would be triglyceride 200 mg/dL. A level >130 mg/dL corresponds to an LDL-C level 160 mg/dL and consti- tutes a risk-enhancing factor. A persistent elevation of apoB can be considered a risk-enhancing factor. Sepa- rately, Lp(a) is a modified form of LDL that appears to possess atherogenic potential.S2.3-5 Relative indications for its measurement are family history of premature ASCVD or personal history of ASCVD not explained by major risk factors. Lp(a) increases ASCVD risk especially at higher levels.


Sepa- rately, Lp(a) is a modified form of LDL that appears to possess atherogenic potential.S2.3-5 Relative indications for its measurement are family history of premature ASCVD or personal history of ASCVD not explained by major risk factors. Lp(a) increases ASCVD risk especially at higher levels. Thus, if a decision is made to measure Lp(a), an Lp(a) 50 mg/dL or 125 nmol/L, Lp(a) may be considered a risk-enhancing factor.S2.3-6 Current evi- dence shows that it should be considered in women only in the presence of hypercholesterolemia and Recommendations for Measurements of LDL-C and Non HDL-C (Continued) COR LOE Recommendations CLINICAL STATEMENTS AND GUIDELINES with the understanding that the improvement in risk prediction in adult women in a large clinical trial was In the present document, an elevation of Lp(a) is considered to be a risk-enhancing factor.S2.3-6 This is especially in those with higher Lp(a) values and, if used in women, only in the presence of hypercholes 2.4. Monitoring Response of LDL-C to Statin Therapy In large RCTs of cholesterol-lowering therapy, LDL-C lowering has been consistently shown to reduce the risk of ASCVD. One large meta-analysisS2.4-1 of statin clinical trials showed a progressive reduction in risk of major ASCVD events with lower on-treatment LDL-C levels. In another larger meta-analysisS2.4-2 of 14 statin trials, it was observed that a 38.7-mg/dL (1-mmol/L) reduction of LDL-C levels is accompanied by a 21% reduction in ASCVD risk. In clinical practice, howev- er, absolute responses in LDL-C to statin therapy de- pend on baseline LDL-C concentrations. A given dose of statins produces a similar percentage reduction in LDL-C levels across a broad range of baseline LDL- C levels. For this reason, a more reliable indicator of statin efficacy is percentage reduction.


For this reason, a more reliable indicator of statin efficacy is percentage reduction. In the present document, the percentage reduction is used in follow- up monitoring of patients to estimate the efficacy of statin therapy. As a rough guide, a lowering of LDL-C levels of 1% gives an approximate 1% reduction in the risk of ASCVD somewhat more at higher base- line LDL-C levels and somewhat less at lower baseline 3. THERAPEUTIC MODALITIES 3.1. Lifestyle Therapies 3.1.1. Diet Composition, Weight Control, and Physical Activity For many years, the AHA and ACC have recommend- ed essentials of a healthy diet for the general public and for patients at risk for ASCVD. The current docu- ment supports evidence-based recommendations pro- vided in the 2013 AHA/ACC guidelines on lifestyle Patients should consume a dietary pattern that emphasizes intake of vegetables, fruits, whole grains, legumes, healthy protein sources (low-fat dairy products, low-fat poultry (without the skin), fish/seafood, and nuts), and nontropical vegetable oils; and limits intake of sweets, sugar-sweetened bev- erages, and red meats. This dietary pattern should be adjusted to appropriate calorie requirements, personal and cultural food preferences, and nutritional therapy for other medical conditions including diabetes. Caloric intake should be adjusted to avoid weight gain, or in overweight/obese patients, to promote weight loss. In general, adults should be advised to engage in aerobic physical activity 3-4 sessions per week, lasting on aver- age 40 minutes per session and involving moderate-to vigorous-intensity physical activity. 3.1.2. Lifestyle Therapies and Metabolic Syndrome Lifestyle therapies are particularly indicated for the metabolic syndrome, which is a cluster of risk factors associated with an increased risk of ASCVD, diabetes mellitus, and all-cause death.S3.1.2-1,S3.1.2-2 Metabolic syndrome is a risk-enhancing factor for ASCVD.


Lifestyle Therapies and Metabolic Syndrome Lifestyle therapies are particularly indicated for the metabolic syndrome, which is a cluster of risk factors associated with an increased risk of ASCVD, diabetes mellitus, and all-cause death.S3.1.2-1,S3.1.2-2 Metabolic syndrome is a risk-enhancing factor for ASCVD. The most widely used clinical definition of metabolic syn- drome is that proposed by an international consortium of cardiovascular and diabetes organizations.S3.1.2-3 The diagnosis is made by the presence of any 3 of the fol- lowing 5 risk factors: elevated waist circumference, elevated serum triglycerides, reduced HDL-C, elevated blood pressure, and elevated fasting glucose (Table S2 in the Web Supplement). Metabolic syndrome is closely linked to excess weight and particularly to abdominal Therefore, the prevalence of metabolic syndrome has risen sharply among both adults and children as levels of overweight and obesity have risen. Metabolic syndrome is now found in approximately one-third of the adults in the United StatesS3.1.2-5 and is likely underrecognized because of insufficient rates of screening. The prevalence of metabolic syndrome in- creases with age and very commonly occurs in patients with type 2 diabetes mellitus. See Table S2 in the Web Supplement. 3.2. Lipid-Lowering Drugs Among lipid-lowering drugs, statins are the cornerstone of therapy, in addition to healthy lifestyle interventions. Other LDL-lowering drugs include ezetimibe, bile acid sequestrants, and PCSK9 inhibitors. Triglyceride-lower- ing drugs are fibrates and niacin; they have a mild LDL- lowering action, but RCTs do not support their use as add-on drugs to statin therapy.S3.2-1 Characteristics of LDL-lowering drugs are summarized in Table S3 in the Web Supplement. 3.2.1. Statin Therapy The intensity of statin therapy is divided into 3 cat- egories: high-intensity, moderate-intensity, and low- High-intensity statin therapy typically lowers LDL-C levels by 50%, moderate-intensity statin therapy by 30% to 49%, and low-intensity statin therapy by <30% (Table 3).


Statin Therapy The intensity of statin therapy is divided into 3 cat- egories: high-intensity, moderate-intensity, and low- High-intensity statin therapy typically lowers LDL-C levels by 50%, moderate-intensity statin therapy by 30% to 49%, and low-intensity statin therapy by <30% (Table 3). Of course, the magnitude of LDL-C lowering will vary in clinical practice.S3.2.1-2 Certain Asian populations may have a greater re- sponse to certain statins.S3.2.1-18 Pharmacokinetic pro- files among statins are heterogeneous (Table S4 in the Web Supplement). Statin safety has been extensively CLINICAL STATEMENTS AND GUIDELINES Statin-associated side effects are dis- cussed in Section 5. Common medications that may potentially interact with statins are listed in Table S5 in the Web Supplement. More information on statin drug drug interactions can be obtained from the ACC 3.2.2. Nonstatin Therapies Ezetimibe is the most commonly used nonstatin agent. It lowers LDL-C levels by 13% to 20% and has a low in- cidence of side effects.S3.2.2-1,S3.2.2-2 Bile acid sequestrants reduce LDL-C levels by 15% to 30% depending on the dose. Bile acid sequestrants are not absorbed and do not cause systemic side effects, but they are associated with gastrointestinal complaints (eg, constipation) and can cause severe hypertriglyceridemia when fasting tri- glycerides are 300 mg/dL ( 3.4 mmol/L). PCSK9 inhibi- tors are powerful LDL-lowering drugs. They generally are well tolerated, but long-term safety remains to be Two categories of triglyceride-lower- ing drugs, niacin and fibrates, may also mildly lower LDL-C levels in patients with normal triglycerides. They may be useful in some patients with severe hypertri- glyceridemia, but in the present document they are not listed as LDL-lowering drugs. See Table S4 in the Web Supplement. 3.2.3.


They may be useful in some patients with severe hypertri- glyceridemia, but in the present document they are not listed as LDL-lowering drugs. See Table S4 in the Web Supplement. 3.2.3. Nonstatin Add-on Drugs to Statin Therapy Under certain circumstances, nonstatin medications (ezetimibe, bile acid sequestrants, and PCSK9 inhibi- tors) may be useful in combination with statin therapy. The addition of a bile acid sequestrant or ezetimibe to a statin regimen increases the magnitude of LDL-C lower- ing by approximately 15% to 30% and 13% to 20%, The addition of a PCSK9 inhibi- tor to a statin regimen has been shown to further re- duce LDL-C levels by 43% to 64%.S3.2.3-3,S3.2.3-4 See Table S5 in the Web Supplement. 4. PATIENT MANAGEMENT GROUPS 4.1. Secondary ASCVD Prevention Recommendations for Statin Therapy Use in Patients With ASCVD Referenced studies that support recommendations are summarized in Online Data Supplements 6 to 8 and in the Systematic Review Report.