2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood

2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood

2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: Executive Summary Citation This slide set is adapted from the 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/AP hA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: Executive Summary. Published on [Date], available at: Journal of the American College of Cardiology [(insert full link)] and Circulation [(insert full link)] The full-text guidelines are also available on the following Web sites: ACC (www.acc.org) and AHA (professional.heart.org) 2018 Cholesterol Guideline Writing Committee Scott M. Grundy, MD, PhD, FAHA, Chair Neil J. Stone, MD, FACC, FAHA, Vice Chair Alison L. Bailey, MD, FACC, FAACVPR Daniel W. Jones, MD, FAHA Craig Beam, CRE*

Donald Lloyd-Jones, MD, SCM, FACC, FAHA* Kim K. Birtcher, MS, PharmD, AACC, FNLA Nuria Lopez-Pajares, MD, MPH Roger S. Blumenthal, MD, FACC, FAHA, FNLA Chiadi E. Ndumele, MD, PhD, FAHA* Lynne T. Braun, PhD, CNP, FAHA, FPCNA, FNLA Carl E. Orringer, MD, FACC, FNLA Sarah de Ferranti, MD, MPH* Carmen A. Peralta, MD, MAS* Joseph Faiella-Tommasino, PhD, PA-C Joseph J. Saseen, PharmD, FNLA, FAHA Daniel E. Forman, MD, FAHA**

Sidney C. Smith, Jr, MD, MACC, FAHA* Ronald Goldberg, MD Laurence Sperling, MD, FACC, FAHA, FASPC*** Paul A. Heidenreich, MD, MS, FACC, FAHA Salim S. Virani, MD, PhD, FACC, FAHA* Mark A. Hlatky, MD, FACC, FAHA* Joseph Yeboah, MD, MS, FACC, FAHA *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 Table 1. Applying Class of Recommendation and evel of Evidence to Clinical Strategies, Interventions,

Treatments, or Diagnostic Testing in Patient Care* (Updated August 2015) Top 10 Take-Home Messages 2018 Cholesterol Guidelines Top 10 Take Home Messages 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 individuals, 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 clinicianpatient risk discussion (see No. 6) and emphasizes intensive lifestyle efforts. In all age groups, lifestyle therapy is the primary intervention for metabolic syndrome. Top 10 Take Home Messages 2. In patients with clinical ASCVD, reduce lowdensity lipoprotein cholesterol (LDL-C) with highintensity statin therapy or maximally tolerated

statin therapy. The more LDL-C is reduced on statin therapy, the greater will be subsequent risk reduction. Use a maximally tolerated statin to lower LDL-C levels by 50%. Top 10 Take Home Messages 3. In very high-risk ASCVD, use a LDL-C threshold 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 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 costeffectiveness is low at mid-2018 list prices.

Top 10 Take Home Messages 4. In patients with severe primary hypercholesterolemia (LDL-C level 190 mg/dL[4.9 mmol/L]) without calculating 10-year ASCVD risk, begin high-intensity statin therapy without calculating 10-year ASCVD risk. 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) & 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 uncertain and economic value is low at mid-2018 list prices. Top 10 Take Home Messages 5. In patients 40 to 75 years of age with diabetes 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%. Top 10 Take Home Messages 6. In adults 40 to 75 years of age evaluated for primary ASCVD prevention, have a clinicianpatient risk discussion before starting statin therapy. Risk discussion should include a review of major risk factors (e.g., cigarette smoking, elevated 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 drugdrug interactions; the consideration of costs of statin therapy; and the patient preferences & values in shared decision-making.

Top 10 Take Home Messages 7. In adults 40 to 75 years of age without diabetes 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 therapy (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%. Top 10 Take Home Messages 8. In adults 40 to 75 years of age without diabetes mellitus and 10-year risk of 7.5% to 19.9% (intermediate risk), riskenhancing factors favor initiation of statin therapy (see No. 7). Risk-enhancing factors include family history of premature ASCVD; persistently elevated LDL-C levels 160 mg/dL (4.1 mmol/L); metabolic syndrome; chronic kidney disease; history of preeclampsia or premature menopause (age <40 yrs) chronic inflammatory disorders (e.g., rheumatoid arthritis, psoriasis,

or chronic HIV); high-risk ethnic groups (e.g., South Asian); persistent elevations of triglycerides 175 mg/dL (1.97 mmol/L); Top 10 Take Home Messages 8. In adults 40 to 75 years of age without diabetes mellitus and 10-year risk of 7.5% to 19.9% (intermediate risk), riskenhancing factors favor initiation of statin therapy (see No. 7). Risk-enhancing factors include and, if measured in selected individuals apolipoprotein B 130 mg/dL high-sensitivity C-reactive protein 2.0 mg/L ankle-brachial index <0.9 and l lipoprotein (a) 50 mg/dL or 125 nmol/L, especially at higher values of lipoprotein (a). Risk-enhancing factors may favor statin therapy in patients at 10-year risk of 5-7.5% (borderline risk) Top 10 Take Home Messages 9. In adults 40 to 75 years of age without diabetes mellitus and with LDL-C levels 70 mg/dL- 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 premature 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 indicated unless otherwise deferred by the outcome of clinicianpatient risk discussion. Top 10 Take Home Messages 10. Assess adherence and percentage response to LDLClowering 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 levels 70 mg/dL (1.8 mmol/L) on maximal statin therapy (see No. 3). 2018 Cholesterol Guideline

High Blood Cholesterol and ASCVD Measurements of LDL-C and Non-HDL-C Recommendations for Measurements of LDL-C and Non-HDL-C COR LOE I B-NR I B-NR Recommendations 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 baseline LDL-C. 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 (4.5 mmol/L) or higher,

a repeat lipid profile in the fasting state should be performed for assessment of fasting triglyceride levels and baseline LDL-C. Measurements of LDL-C and Non-HDL-C Recommendations for Measurements of LDL-C and Non-HDL-C COR LOE IIa C-LD IIa C-LD Recommendations For patients 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 Friedewald formula. 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. 2018 Cholesterol Guideline Patient Management Groups Secondary ASCVD Prevention Recommendations for Statin Therapy Use in Patients With ASCVD COR LOE Recommendations In patients who are 75 years of age or younger with clinical ASCVD,* high-intensity statin therapy should be initiated or I A continued with the aim of achieving a 50% or greater reduction in LDL-C levels. I A

In patients with clinical ASCVD in whom high-intensity statin therapy is contraindicated or who experience statinassociated side effects, moderate-intensity statin therapy should be initiated or continued with the aim of achieving a 30% to 49% reduction in LDL-C levels. Secondary ASCVD Prevention Recommendations for Statin Therapy Use in Patients With ASCVD COR LOE Recommendations In patients with clinical ASCVD who are judged to be very high risk and considered for PCSK9 inhibitor therapy, I B-NR maximally tolerated LDL-C lowering therapy should include maximally tolerated statin therapy and ezetimibe. IIa ASR In patients with clinical ASCVD who are judged to be very high risk and who are on maximally tolerated LDL-C lowering therapy with LDL-C 70 mg/dL (1.8 mmol/L) or higher or a

non-HDL-C level of 100 mg/dL (2.6 mmol/L) or higher, it is reasonable to add a PCSK9 inhibitor following a clinician patient discussion about the net benefit, safety, and cost. Secondary ASCVD Prevention Recommendations for Statin Therapy Use in Patients With ASCVD COR LOE Recommendations In patients with clinical ASCVD who are on maximally tolerated statin therapy and are judged to be at very high IIa B-R risk and have an LDL-C level of 70 mg/dL (1.8 mmol/L) or higher, it is reasonable to add ezetimibe therapy. Value Statement: Low Value (LOE: B-NR) At mid-2018 list prices, PCSK9 inhibitors have a low cost value (>$150,000 per QALY) compared to good cost value (<$50,000 per QALY) (Section 7 provides a full discussion of the dynamic interaction of different prices and clinical benefit).

Secondary ASCVD Prevention Recommendations for Statin Therapy Use in Patients With ASCVD COR LOE Recommendations In patients older than 75 years of age with clinical ASCVD, it is reasonable to initiate moderate- or high-intensity statin therapy after evaluation of the potential for ASCVD risk IIa B-R reduction, adverse effects, and drugdrug interactions, as well as patient frailty and patient preferences. IIa C-LD In patients older than 75 years of age who are tolerating high-intensity statin therapy, it is reasonable to continue high-intensity statin therapy after evaluation of the potential for ASCVD risk reduction, adverse effects, and drug-drug interactions, as well as patient frailty and patient preferences.

Secondary ASCVD Prevention Recommendations for Statin Therapy Use in Patients With ASCVD COR LOE Recommendations In patients with clinical ASCVD who are receiving maximally tolerated statin therapy and whose LDL-C level remains 70 IIb B-R mg/dL (1.8 mmol/L) or higher, it may be reasonable to add ezetimibe. IIb B-R In patients with heart failure (HF) with reduced ejection fraction attributable to ischemic heart disease who have a reasonable life expectancy (3 to 5 years) and are not already on a statin because of ASCVD, clinicians may consider initiation of moderate-intensity statin therapy to reduce the occurrence of ASCVD events. Secondary Prevention

Table 4. Very High-Risk* of Future ASCVD Events Major ASCVD Events Recent ACS (within the past 12 mo) History of MI (other than recent ACS event listed above) History of ischemic stroke Symptomatic peripheral arterial disease (history of claudication with ABI <0.85, or previous revascularization or amputation) Table 4 continued High-Risk Conditions Age 65 y Heterozygous familial hypercholesterolemia History of prior coronary artery bypass surgery or percutaneous coronary intervention outside of the major ASCVD event(s) Diabetes mellitus Hypertension CKD (eGFR 15-59 mL/min/1.73 m2) Current smoking Persistently elevated LDL-C (LDL-C 100 mg/dL [2.6 mmol/L]) despite maximally tolerated statin therapy and ezetimibe History of congestive HF

Severe Hypercholesterolemia (LDL-C 190 mg/dL [4.9 mmol/L]) Recommendations for Primary Severe Hypercholesterolemia (LDL-C 190 mg/dL [4.9 mmol/L]) COR LOE I B-R IIa B-R Recommendations In patients 20 to 75 years of age with an LDL-C level of 190 mg/dL (4.9 mmol/L) or higher, maximally tolerated statin therapy is recommended. In patients 20 to 75 years of age with an LDL-C level of 190 mg/dL (4.9 mmol/L) or higher who achieve less than a 50% reduction in LDL-C while receiving maximally tolerated

statin therapy and/or have an LDL-C level of 100 mg/dL (2.6 mmol/L) or higher, ezetimibe therapy is reasonable. Severe Hypercholesterolemia (LDL-C 190 mg/dL [4.9 mmol/L]) Recommendations for Primary Severe Hypercholesterolemia (LDL-C 190 mg/dL [4.9 mmol/L]) COR LOE IIb B-R IIb B-R Recommendations In patients 20 to 75 years of age with a baseline LDL-C level 190 mg/dL (4.9 mmol/L), who achieve less than a 50% reduction in LDL-C levels and have fasting triglycerides 300 mg/dL (3.4 mmol/L). while taking maximally tolerated statin

and ezetimibe therapy, the addition of a bile acid sequestrant may be considered. In patients 30 to 75 years of age with heterozygous FH and with an LDL-C level of 100 mg/dL (2.6 mmol/L) or higher while taking maximally tolerated statin and ezetimibe therapy, the addition of a PCSK9 inhibitor may be considered. Severe Hypercholesterolemia (LDL-C 190 mg/dL [4.9 mmol/L]) Recommendations for Primary Severe Hypercholesterolemia (LDL-C 190 mg/dL [4.9 mmol/L]) COR LOE IIb C-LD Value Statement: Uncertain Value (B-NR)

Recommendations In patients 40 to 75 years of age with a baseline LDL-C level of 220 mg/dL (5.7 mmol/L) or higher and who achieve an ontreatment LDL-C level of 130 mg/dL (3.4 mmol/L) or higher while receiving maximally tolerated statin and ezetimibe therapy, the addition of a PCSK9 inhibitor may be considered. Among patients with FH without evidence of clinical ASCVD taking maximally tolerated statin and ezetimibe therapy, PCSK9 inhibitors provide uncertain value at 2018 U.S. list prices. Diabetes Mellitus in Adults COR I IIa Recommendations for Patients With Diabetes Mellitus LOE Recommendations In adults 40 to 75 years of age with diabetes mellitus, regardless of estimated 10-year ASCVD risk, moderateA intensity statin therapy is indicated.

In adults 40 to 75 years of age with diabetes mellitus and an LDL-C level of 70 to 189 mg/dL (1.7 to 4.8 mmol/L), it is reasonable to assess the 10-year risk of a first ASCVD event B-NR by using the race and sex-specific PCE to help stratify ASCVD risk. Diabetes Mellitus in Adults COR IIa Recommendations for Patients With Diabetes Mellitus LOE Recommendations In adults with diabetes mellitus who have multiple ASCVD B-R risk factors, it is reasonable to prescribe high-intensity statin therapy with the aim to reduce LDL-C levels by 50% or more. IIa In adults older than 75 years of age with diabetes mellitus B-NR and who are already on statin therapy, it is reasonable to continue statin therapy.

IIb In adults with diabetes mellitus and 10-year ASCVD risk of 20% or higher, it may be reasonable to add ezetimibe to C-LD maximally tolerated statin therapy to reduce LDL-C levels by 50% or more. Diabetes Mellitus in Adults COR IIb IIb Recommendations for Patients With Diabetes Mellitus LOE Recommendations In adults older than 75 years with diabetes mellitus, it may be C-LD reasonable to initiate statin therapy after a clinicianpatient discussion of potential benefits and risks. In adults 20 to 39 years of age with diabetes mellitus that is either of long duration (10 years of type 2 diabetes mellitus, 20 years of type 1 diabetes mellitus), albuminuria (30 mcg

of albumin/mg creatinine), estimated glomerular filtration C-LD rate (eGFR) less than 60 mL/min/1.73 m2, retinopathy, neuropathy, or ankle-brachial index (ABI; <0.9), it may be reasonable to initiate statin therapy. Table 5. Diabetes-Specific Risk Enhancers That Are Independent of Other Risk Factors in Diabetes Mellitus Risk Enhancers Long duration (10 years for type 2 diabetes mellitus (S.4.3-20) or 20 years for type 1 diabetes mellitus) Albuminuria 30 mcg of albumin/mg creatinine eGFR <60 mL/min/1.73 m2 Retinopathy Neuropathy ABI <0.9 Table 6. Risk-Enhancing Factors for ClinicianPatient Risk Discussion Risk-Enhancing Factors

Family history of premature ASCVD (males, age <55 y; females, age <65 y) Primary hypercholesterolemia (LDL-C, 160189 mg/dL [4.14.8 mmol/L); nonHDLC 190219 mg/dL [4.95.6 mmol/L])* Metabolic syndrome (increased waist circumference, elevated triglycerides [>175 mg/dL], elevated blood pressure, elevated glucose, and low HDL-C [<40 mg/dL in men; <50 in women mg/dL] are factors; tally of 3 makes the diagnosis) Chronic kidney disease (eGFR 1559 mL/min/1.73 m2 with or without albuminuria; not treated with dialysis or kidney transplantation) Chronic inflammatory conditions such as psoriasis, RA, or HIV/AIDS History of premature menopause (before age 40 y) and history of pregnancyassociated conditions that increase later ASCVD risk such as preeclampsia High-risk race/ethnicities (e.g., South Asian ancestry) Table 6 continued Risk-Enhancing Factors Lipid/biomarkers: Associated with increased ASCVD risk o Persistently* elevated, primary hypertriglyceridemia (175 mg/dL); o If measured: Elevated high-sensitivity C-reactive protein (2.0 mg/L)

Elevated Lp(a): A relative indication for its measurement is family history of premature ASCVD. An Lp(a) 50 mg/dL or 125 nmol/L constitutes a risk-enhancing factor especially at higher levels of Lp(a). Elevated apoB 130 mg/dL: A relative indication for its measurement would be triglyceride 200 mg/dL. A level 130 mg/dL corresponds to an LDL-C >160 mg/dL and constitutes a risk-enhancing factor ABI <0.9 Primary Prevention Adults 40 to 75 Years of Age With LDL-C Levels 70 to 189 mg/dL (1.74.8 mmol/L) Primary Prevention Recommendations for Adults 40 to 75 Years of Age With LDL Levels 70 to 189 mg/dL (1.74.8 mmol/L) COR I I LOE Recommendations A

In adults at intermediate-risk, statin therapy reduces risk of ASCVD, and in the context of a risk discussion, if a decision is made for statin therapy, a moderate-intensity statin should be recommended. A In intermediate-risk patients, LDL-C levels should be reduced by 30% or more, and for optimal ASCVD risk reduction, especially in high-risk patients, levels should be reduced by 50% or more. Primary Prevention Adults 40 to 75 Years of Age With LDL-C Levels 70 to 189 mg/dL (1.74.8 mmol/L) Primary Prevention Recommendations for Adults 40 to 75 Years of Age With LDL Levels 70 to 189 mg/dL (1.74.8 mmol/L) COR I I LOE

Recommendations For the primary prevention of clinical ASCVD* in adults 40 to 75 years of age without diabetes mellitus and with an LDL-C level of 70 to 189 mg/dL (1.7 to 4.8 mmol/L), the 10-year ASCVD risk of a first hard ASCVD event (fatal and nonfatal MI or stroke) should be estimated by B-NR using the race- and sex-specific PCE, and adults should be categorized as being at low risk (<5%), borderline risk (5% to <7.5%), intermediaterisk (7.5% to <20%), and high-risk (20%). Clinicians and patients should engage in a risk discussion that considers risk factors, adherence to healthy lifestyle, the potential for ASCVD risk-reduction benefits, and the potential for adverse effects and drug B-NR drug interactions, as well as patient preferences, for an individualized treatment decision. Primary Prevention Adults 40 to 75 Years of Age With LDL-C Levels 70 to 189 mg/dL (1.74.8 mmol/L) Primary Prevention Recommendations for Adults 40 to 75 Years of Age With LDL Levels 70 to 189 mg/dL (1.74.8 mmol/L) COR LOE

Recommendations IIa In intermediate-risk adults, risk-enhancing factors favor B-R initiation or intensification of statin therapy. IIa In intermediate-risk or selected borderline-risk adults, if the decision about statin use remains uncertain, it is reasonable to B-NR use a CAC score in the decision to withhold, postpone or initiate statin therapy. Primary Prevention Adults 40 to 75 Years of Age With LDL-C Levels 70 to 189 mg/dL (1.74.8 mmol/L) Primary Prevention Recommendations for Adults 40 to 75 Years of Age With LDL Levels 70 to 189 mg/dL (1.74.8 mmol/L) COR IIa

LOE Recommendations In intermediate-risk adults or selected borderline-risk adults in whom a CAC score is measured for the purpose of making a treatment decision, AND If the coronary calcium score is zero, it is reasonable to withhold statin therapy and reassess in 5 to 10 years, as long as higher risk conditions are absent (diabetes mellitus, family history of premature CHD, cigarette smoking); B-NR If CAC score is 1 to 99, it is reasonable to initiate statin therapy for patients 55 years of age; If CAC score is 100 or higher or in the 75th percentile or higher, it is reasonable to initiate statin therapy. Primary Prevention Adults 40 to 75 Years of Age With LDL-C Levels 70 to 189 mg/dL (1.74.8 mmol/L) Primary Prevention Recommendations for Adults 40 to 75 Years of Age With LDL Levels 70 to 189 mg/dL (1.74.8 mmol/L) COR

IIb IIb LOE Recommendations In intermediate-risk adults who would benefit from more aggressive LDL-C lowering and in whom high-intensity statins are advisable but not acceptable or tolerated, it may be B-R reasonable to add a nonstatin drug (ezetimibe or bile acid sequestrant) to a moderate-intensity statin. In patients at borderline risk, in risk discussion, the presence of B-R risk-enhancing factors may justify initiation of moderateintensity statin therapy. Table 7. Checklist for ClinicianPatient Shared Decision-Making for Initiating Therapy Checklist Item ASCVD risk assessment

Recommendation Assign to statin treatment group; use ASCVD Risk Estimator Plus.* o In lower-risk primary-prevention adults 40-75 y of age with LDL-C 70 mg/dL (1.8 mmol/L). o Not needed in secondary prevention, in those with LDL-C 190 mg/dL (4.9 mmol/L), or in those 40-75 y of age with diabetes mellitus. Assess other patient characteristics that influence risk. See Risk-Enhancing Factors (Section 4.4.1.3. and Table 6) Assess CAC (Section 4.4.1.4.) if risk decision is uncertain and additional information is needed to clarify ASCVD risk. o Use decision tools to explain risk (e.g., ASCVD Risk Estimator Plus,* Mayo Clinic Statin Choice Decision Aid). Lifestyle modifications Review lifestyle habits (e.g., diet, physical activity, weight or body mass index, and tobacco use). Endorse a healthy lifestyle and provide relevant advice, materials, or referrals. (e.g., CardioSmart, AHA Lifes Simple 7, NLA Patient Tear Sheets, PCNA Clinicians Lifestyle Modification Toolbox, cardiac rehabilitation,

dietitian, smoking cessation program). Table 7 continued Checklist Item Recommendation Potential net clinical Recommend statins as first-line therapy. Consider the combination of statin and nonstatin benefit of therapy in selected patients. pharmacotherapy Discuss potential risk reduction from lipid-lowering therapy. Discuss the potential for adverse effects or drug drug interactions. Table 7 continued Checklist Item Cost considerations Recommendation Discuss potential out-of-pocket cost of therapy to the patient (e.g., insurance plan coverage, tier level,

copayment). Encourage the patient to verbalize what was heard (e.g., Shared patients personal ASCVD risk, available options, and decision-making risks/benefits). Invite the patient to ask questions, express values and preferences, and state ability to adhere to lifestyle changes and medications. Refer patients to trustworthy materials to aid in their understanding of issues regarding risk decisions. Collaborate with the patient to determine therapy and follow-up plan. Table 8. Selected Examples of Candidates for CAC Measurement Who Might Benefit From Knowing Their CAC Score Is Zero CAC Measurement Candidates Who Might Benefit from Knowing Their CAC Score Is Zero Patients reluctant to initiate statin therapy who wish to understand their risk and potential for benefit more precisely Patients concerned about need to reinstitute statin therapy after discontinuation for statin-associated symptoms

Older patients (men, 55-80 y of age; women, 60-80 y of age) with low burden of risk factors who question whether they would benefit from statin therapy Middle-aged adults (40-55 y of age) with PCE-calculated 10-year risk of ASCVD 5% to <7.5% with factors that increase their ASCVD risk, although they are in a borderline risk group Monitoring in Response to LDL-CLowering Therapy COR I Recommendation for Monitoring LOE Recommendation Adherence to changes in lifestyle and effects of LDL-C lowering medication should be assessed by measurement of fasting lipids and appropriate safety indicators 4 to 12 weeks A after statin initiation or dose adjustment and every 3 to 12 months thereafter based on need to assess adherence or safety.

Primary Prevention in Other Age Groups (Older Adults) COR LOE IIb B-R IIb IIb Recommendations for Older Adults Recommendations In adults 75 years of age or older with an LDL-C level of 70 to 189 mg/dL (1.7 to 4.8 mmol/L), initiating a moderate-intensity statin may be reasonable. B-R In adults 75 years of age or older, it may be reasonable to stop statin therapy when functional decline (physical or cognitive),

multimorbidity, frailty, or reduced life-expectancy limits the potential benefits of statin therapy. B-R In adults 76 to 80 years of age with an LDL-C level of 70 to 189 mg/dL (1.7 to 4.8 mmol/L), it may be reasonable to measure CAC to reclassify those with a CAC score of zero to avoid statin therapy. Primary Prevention in Other Age Groups (Children and Adolescents) Recommendations for Children and Adolescents COR I I LOE A Recommendations

In children and adolescents with lipid disorders related to obesity, it is recommended to intensify lifestyle therapy, including moderate caloric restriction and regular aerobic physical activity. B-NR In children and adolescents with lipid abnormalities, lifestyle counseling is beneficial for lowering LDL-C. Primary Prevention in Other Age Groups (Children and Adolescents) Recommendations for Children and Adolescents COR IIa IIa LOE B-R B-NR Recommendations

In children and adolescents 10 years of age or older with an LDL-C level persistently 190 mg/dL (4.9 mmol/L) or higher or 160 mg/dL (4.1 mmol/L) or higher with a clinical presentation consistent with FH (see Section 4.2.) and who do not respond adequately with 3 to 6 months of lifestyle therapy, it is reasonable to initiate statin therapy. In children and adolescents with a family history of either early CVD* or significant hypercholesterolemia, it is reasonable to measure a fasting or nonfasting lipoprotein profile as early as age 2 years to detect FH or rare forms of hypercholesterolemia. Primary Prevention in Other Age Groups (Children and Adolescents) Recommendations for Children and Adolescents COR IIa IIa LOE Recommendations

In children and adolescents found to have moderate or severe hypercholesterolemia, it is reasonable to carry out reverse-cascade screening of family members, which B-NR includes cholesterol testing for first-, second-, and when possible, third-degree biological relatives, for detection of familial forms of hypercholesterolemia. C-LD In children and adolescents with obesity or other metabolic risk factors, it is reasonable to measure a fasting lipid profile to detect lipid disorders as components of the metabolic syndrome. Primary Prevention in Other Age Groups (Children and Adolescents) Recommendations for Children and Adolescents COR IIb LOE

Recommendations In children and adolescents without cardiovascular risk factors or family history of early CVD, it may be reasonable to measure a fasting lipid profile or nonfasting non HDL-C B-NR once between the ages of 9 and 11 years, and again between the ages of 17 and 21 years, to detect moderate to severe lipid abnormalities. Table 9. Normal and Abnormal Lipid Values in Childhood* Acceptable, mg/dL Borderline, mg/dL Abnormal, mg/dL TC <170 (<4.3 mmol)

170-199 (4.3-5.1 mmol) 200 (5.1 mmol) Triglycerides (0-9 y) <75 (<0.8 mmol) 75-99 (0.8-1.1 mmol) 100 (1.1 mmol) Triglycerides (1019 y) <90 (<1.0 mmol) 90-129 (1.0-1.5 mmol) 130 (1.4 mmol) HDL-C >45 (>1.2 mmol) 40-45 (1.0-1.2 mmol)

<40 (<1.0 mmol) LDL-C <110 (<2.8 mmol) 110-129 (2.8-3.3 mmol) 130 (3.4 mmol) Non-HDL-C <120 (<3.1 mmol) 120-144 (3.1-3.7 mmol) 145 (3.7 mmol) Other Populations at Risk (Ethnicity) Recommendation for Other Populations at Risk COR

IIa LOE Recommendation For clinical decision-making in adults of different race/ethnicities, it is reasonable for clinicians to review B-NR race/ethnic features that can influence ASCVD risk so as to adjust choice of statin or intensity of treatment. Table 10. Racial/Ethnic Issues in Evaluation, Risk Decisions, and Treatment of ASCVD Risk Asian Americans* Evaluation ASCVD issues informed by race/ethnicity ASCVD risk in people of South Asian and East Asian origin varies by country of origin; individuals from South Asia (see below)

have increased ASCVD risk. Racial/Ethnic Groupings Hispanic/Latino Americans Blacks Race/ethnicity and country of origin, together with socioeconomic status and acculturation level, may explain risk factor burden more precisely (e.g., ASCVD risk is higher among individuals from Puerto Rico than those from Mexico). Lipid issues informed by race/ethnicity Asian Americans have lower Hispanic/Latino women have higher levels of HDL-C than whites. prevalence of low HDL-C compared There is higher prevalence of with Hispanic/Latino men. LDL-C among Asian Indians, Filipinos, Japanese, and

Vietnamese than among whites. An increased prevalence of high TG was seen in all Asian American subgroups. Metabolic issues informed by race/ethnicity Increased MetS is seen with lower waist circumference than in whites. DM develops at a lower lean body mass and at earlier ages. Majority of risk in South Asians is explained by known risk factors, especially those related to insulin resistance. Comments ASCVD risk assessment in black women shows increased ASCVD risk compared with their otherwise similar white

counterparts. There is heterogeneity in risk according to racial/ethnic group and within racial/ethnic groups. Native American/ Alaskan populations have high rates of risk factors for ASCVD compared to non-Hispanic whites. Blacks have higher levels of HDL-C and lower levels of triglycerides than non-Hispanic whites or Mexican Americans. All ethnic groups appear to be at greater risk for dyslipidemia, but important to identify those with more sedentary behavior and less favorable diet. DM is disproportionately present There is increased DM and compared with whites and blacks. hypertension.

There is increased prevalence of MetS and DM in Mexican Americans compared with whites and Puerto Ricans. There is increased prevalence of DM. Features of MetS vary by race/ethnicity. Waist circumference, not weight, should be used to determine abdominal adiposity when possible. Table 10 continued Asian Americans* Treatment Lifestyle counseling (use Use lifestyle counseling to principles of Mediterranean recommend a heart-healthy diet and DASH diets) consistent with racial/ethnic preferences to avoid weight gain and address BP and lipids. Racial/Ethnic Groupings

Hispanic/Latino Americans Blacks Use lifestyle counseling to recommend a heart-healthy diet consistent with racial/ethnic preferences to avoid weight gain and address BP and lipids. Use lifestyle counseling to recommend a heart-healthy diet consistent with racial/ethnic preferences to avoid weight gain and address BP and lipids. Comments Asian and Hispanic/Latino groups need to be disaggregated because of regional differences in lifestyle preferences. Challenge is to avoid increased sodium, sugar, and calories as groups acculturate. Intensity of statin therapy and response to LDL-C lowering

Japanese patients may be No sensitivity to statin dosage is seen, No sensitivity to statin dosage is sensitive to statin dosing. In an as compared with non-Hispanic white seen, as compared with nonopen-label, randomized primary- or black individuals. Hispanic white individuals. prevention trial, Japanese participants had a reduction in CVD events with low-intensity doses of pravastatin as compared with placebo. In a secondary-prevention trial, Japanese participants with CAD benefitted from a moderateintensity dose of pitavastatin. Using a lower statin intensity in Japanese patients may give results similar to those seen with higher intensities in non-Japanese patients. Safety Higher rosuvastatin plasma There are no specific safety issues with levels are seen in Japanese,

statins related to Hispanic/Latino Chinese, Malay, and Asian ethnicity. Indians as compared with whites. FDA recommends a lower starting dose (5 mg of rosuvastatin in Asians versus 10 mg in whites). Caution is urged as dose is uptitrated. Clinicians should take Asian race into account when prescribing dose of rosuvastatin (See package insert). In adults of East Asian descent, other statins should be used preferentially over simvastatin. Baseline serum CK values are higher in blacks than in whites. The 95th percentile race/ethnicity- specific and sexspecific serum CK normal levels are available for assessing changes in serum CK.

Table 10 continued Asian Americans* Risk Decisions PCE CAC score No separate PCE is available; use PCE for whites. PCE may underestimate ASCVD risk in South Asians. PCE may overestimate risk in East Asians. Racial/Ethnic Groupings Hispanic/Latino Americans Blacks Comments No separate PCE is available; Use PCE for blacks. use PCE for non-Hispanic whites. If African-American ancestry is also present,

then use PCE for blacks. Country-specific race/ethnicity, along with socioeconomic status, may affect estimation of risk by PCE. In terms of CAC burden, CAC predicts similarly in South Asian men were whites and in those who similar to non-Hispanic identify as Hispanic/Latino. white men, but higher CAC when than blacks, Latinos, and Chinese Americans. South Asian women had similar CAC scores to whites and other racial/ethnic women, although CAC burden higher in older age. In MESA, CAC score was highest in white and

Hispanic men, with blacks having significantly lower prevalence and severity of CAC. Risk factor differences in MESA between ethnicities did not fully explain variability in CAC. However, CAC predicted ASCVD events over and above traditional risk factors in all ethnicities. Hypertriglyceridemia Recommendations for Hypertriglyceridemia COR LOE I B-NR

IIa B-R Recommendations In adults 20 years of age or older with moderate hypertriglyceridemia (fasting or nonfasting triglycerides 175 to 499 mg/dL [1.9 to 5.6 mmol/L]), clinicians should address and treat lifestyle factors (obesity and metabolic syndrome), secondary factors (diabetes mellitus, chronic liver or kidney disease and/or nephrotic syndrome, hypothyroidism), and medications that increase triglycerides. In adults 40 to 75 years of age with moderate or severe hypertriglyceridemia and ASCVD risk of 7.5% or higher, it is reasonable to reevaluate ASCVD risk after lifestyle and secondary factors are addressed and to consider a persistently elevated triglyceride level as a factor favoring initiation or intensification of statin therapy (see Section 4.4.2.). Hypertriglyceridemia Recommendations for Hypertriglyceridemia COR LOE

IIa B-R IIa B-NR Recommendations In adults 40 to 75 years of age with severe hypertriglyceridemia (fasting triglycerides 500 mg/dL [5.6 mmol/L]) and ASCVD risk of 7.5% or higher, it is reasonable to address reversible causes of high triglyceride and to initiate statin therapy. In adults with severe hypertriglyceridemia (fasting triglycerides 500 mg/dL [5.7 mmol/L]), and especially fasting triglycerides 1000 mg/dL (11.3 mmol/L)), it is reasonable to identify and address other causes of hypertriglyceridemia), and if triglycerides are persistently elevated or increasing, to further reduce triglycerides by implementation of a very low-fat diet, avoidance of refined carbohydrates and alcohol, consumption of omega-3 fatty acids, and, if necessary to prevent acute pancreatitis, fibrate therapy.

Issues Specific to Women COR LOE I B-NR I I C-LD C-LD Recommendations for Issues Specific to Women Recommendations Clinicians should consider conditions specific to women, such as premature menopause (age <40 years) and history of pregnancyassociated disorders (hypertension, preeclampsia, gestational diabetes mellitus, small-for-gestational-age infants, preterm deliveries), when discussing lifestyle intervention and the potential for benefit of statin therapy.

Women of childbearing age who are treated with statin therapy and are sexually active should be counseled to use a reliable form of contraception. Women of childbearing age with hypercholesterolemia who plan to become pregnant should stop the statin 1 to 2 months before pregnancy is attempted, or if they become pregnant while on a statin, should have the statin stopped as soon as the pregnancy is discovered. Adults With Chronic Kidney Disease COR LOE IIa B-R IIb III: No Benefit Recommendations for Adults With CKD Recommendations

In adults 40 to 75 years of age with LDL-C 70 to 189 mg/dL (1.7 to 4.8 mmol/L) who are at 10-year ASCVD risk of 7.5% or higher, CKD not treated with dialysis or kidney transplantation is a risk-enhancing factor and initiation of a moderate-intensity statin or moderate-intensity statins combined with ezetimibe can be useful. C-LD In adults with advanced kidney disease that requires dialysis treatment who are currently on LDL-lowering therapy with a statin, it may be reasonable to continue the statin. B-R In adults with advanced kidney disease who require dialysis treatment, initiation of a statin is not recommended. Adults With Chronic Inflammatory Disorders and HIV Recommendations for Adults With Chronic Inflammatory Disorders and HIV COR LOE Recommendations

In adults 40 to 75 years of age with LDL-C 70 to 189 mg/dL (1.7 to 4.8 mmol/L) who have a 10-year ASCVD risk of 7.5% or higher, chronic inflammatory disorders and HIV are risk-enhancing factors and in risk IIa B-NR discussion favor moderate-intensity statin therapy or high-intensity statin therapy. IIa IIa B-NR B-NR In patients with chronic inflammatory disorders or HIV, a fasting lipid profile and assessment of ASCVD risk factors can be useful as a) a guide to benefit of statin therapy and b) for monitoring or adjusting lipidlowering drug therapy before and 4 to 12 weeks after starting inflammatory diseasemodifying therapy or antiretroviral therapy. In adults with RA who undergo ASCVD risk assessment with measurement of a lipid profile, it can be useful to recheck lipid values and other major ASCVD risk factors 2 to 4 months after the patients inflammatory disease has been controlled.

2018 Cholesterol Guideline Statin Safety and Statin-Associated Side Effects Statin Safety and Statin-Associated Side Effects Recommendations for Statin Safety and Statin-Associated Side Effects COR LOE Recommendations A clinicianpatient risk discussion is recommended before initiation of statin therapy to review net clinical benefit, weighing the potential for ASCVD risk reduction against the potential for statin-associated side effects, statindrug I A interactions, and safety, while emphasizing that side effects can be addressed successfully. I A

In patients with statin-associated muscle symptoms (SAMS), a thorough assessment of symptoms is recommended, in addition to an evaluation for nonstatin causes and predisposing factors. Statin Safety and Statin-Associated Side Effects Recommendations for Statin Safety and Statin-Associated Side Effects COR LOE Recommendations In patients with indication for statin therapy, identification of potential predisposing factors for statin-associated side I B-R effects, including new-onset diabetes mellitus and SAMS, is recommended before initiation of treatment. I B-R In patients with statin-associated side effects that are not severe, it is recommended to reassess and to rechallenge to achieve a maximal LDL-C lowering by modified dosing

regimen, an alternate statin or in combination with nonstatin therapy. Statin Safety and Statin-Associated Side Effects Recommendations for Statin Safety and Statin-Associated Side Effects COR LOE Recommendations In patients with increased diabetes mellitus risk or new-onset diabetes mellitus, it is recommended to continue statin therapy, with added emphasis on adherence, net clinical benefit, and the core principles of regular moderate-intensity physical activity, I B-R maintaining a healthy dietary pattern, and sustaining modest weight loss. I C-LD In patients treated with statins, it is recommended to measure creatine kinase levels in individuals with severe statin-associated

muscle symptoms, objective muscle weakness, and to measure liver transaminases (aspartate aminotransferase, alanine aminotransferase) as well as total bilirubin and alkaline phosphatase (hepatic panel) if there are symptoms suggesting hepatotoxicity. Statin Safety and Statin-Associated Side Effects Recommendations for Statin Safety and Statin-Associated Side Effects COR LOE Recommendations In patients at increased ASCVD risk with chronic, stable liver disease (including non-alcoholic fatty liver disease) when appropriately indicated, it is reasonable to use I B-R statins after obtaining baseline measurements and determining a schedule of monitoring and safety checks. IIa B-R In patients at increased ASCVD risk with severe statinassociated muscle symptoms or recurrent statin-associated

muscle symptoms despite appropriate statin rechallenge, it is reasonable to use RCT proven nonstatin therapy that is likely to provide net clinical benefit. Statin Safety and Statin-Associated Side Effects Recommendations for Statin Safety and Statin-Associated Side Effects COR LOE Recommendations Coenzyme Q10 is not recommended for routine use in III: No B-R patients treated with statins or for the treatment of SAMS. Benefit In patients treated with statins, routine measurements of III: No C-LD creatine kinase and transaminase levels are not useful. Benefit Table 11. Statin-Associated Side Effects Statin-Associated Side Effects

Frequency Predisposing Factors Quality of Evidence Statin-associated muscle symptoms (SAMS) Myalgias (CK Normal) Infrequent (1% to 5%) in RCTs; frequent (5% to 10%) in observational studies and clinical setting Myositis/myopathy (CK > ULN) with concerning symptoms or objective weakness Rare RCTs cohorts/observational

Rhabdomyolysis (CK >10 ULN + renal injury) Rare RCTs cohorts/observational Statin-associated autoimmune myopathy (HMGCR antibodies, incomplete resolution) Rare Case reports New-onset diabetes mellitus Depends on population; more Diabetes mellitus risk

frequent if diabetes mellitus risk factors/metabolic syndrome factors are present, such as body High-intensity statin therapy mass index 30, fasting blood sugar 100 mg/dL; metabolic syndrome, or A1c 6%. RCTs/meta-analyses Age, female sex, low body mass RCTs index, high-risk medications cohorts/observational (CYP3A4 inhibitors, OATP1B1 inhibitors), comorbidities (HIV, renal, liver, thyroid, preexisting myopathy), Asian ancestry, excess alcohol, high levels of physical activity, and trauma Table 11. Statin-Associated Side Effects Statin-Associated Side Effects

Frequency Liver Transaminase elevation 3 ULN Infrequent Hepatic failure Rare Central nervous system Memory/cognition Rare/unclear Cancer No definite association Predisposing Factors Quality of Evidence RCTs/ cohorts/observational Case reports

Case reports; no increase in memory/cognition problems in 3 large-scale RCTs RCTs/meta-analyses Table 11. Statin-Associated Side Effects Statin-Associated Side Effects Other Renal function Cataracts Tendon rupture Hemorrhagic stroke Interstitial lung disease Low testosterone Frequency Unclear/unfounded Unclear

Unclear/unfounded Unclear Unclear/unfounded Unclear/unfounded Predisposing Factors Quality of Evidence 2018 Cholesterol Guideline Implementation Implementation COR LOE I A

I I Recommendations for Implementation Recommendations Interventions focused on improving adherence to prescribed therapy are recommended for management of adults with elevated cholesterol levels, including telephone reminders, calendar reminders, integrated multidisciplinary educational activities, and pharmacist-led interventions, such as simplification of the drug regimen to once-daily dosing. B-NR Clinicians, health systems, and health plans should identify patients who are not receiving guideline-directed medical therapy and should facilitate the initiation of appropriate guideline-directed medical therapy, using multifaceted strategies to improve guideline implementation. B-NR Before therapy is prescribed, a patient-clinician discussion should take place to promote shared decision-making and should include the potential for ASCVD risk-reduction benefit, adverse effects, drug-drug interactions, and

patient preferences. 2018 Cholesterol Guideline Cost and Value Considerations Table 12. Proposed Integration of Level of Value Into Clinical Guideline Recommendations* Level of Value Level of Value High value: Better outcomes at lower cost or ICER <$50,000 per QALY gained Intermediate value: $50,000 to <$150,000 per QALY gained Low value: $150,000 per QALY gained Uncertain value: Value examined, but data are insufficient to draw a conclusion because of absence of studies, low-quality studies, conflicting studies, or prior studies that are no longer relevant Not assessed: Value not assessed by the writing committee Proposed abbreviations for each value recommendation: Level of value: H to indicate high value; I, intermediate value; L, low value; U, uncertain value; and NA, value not assessed. Figure 3. Cost-Effectiveness Analysis for PCSK9 Inhibitors

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