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Chronic Care in Cardiology Table 15. Common Secondary Causes of Elevated LDL-C and TG Cause Increase LDL-C Increase TG Medications Amiodarone, cyclosporine, diuretics, glucocorticoids Anabolic steroids, atypical antipsychotics, β-blockers, bile acid sequestrants, glucocorticoids, hormone thera...

Chronic Care in Cardiology Table 15. Common Secondary Causes of Elevated LDL-C and TG Cause Increase LDL-C Increase TG Medications Amiodarone, cyclosporine, diuretics, glucocorticoids Anabolic steroids, atypical antipsychotics, β-blockers, bile acid sequestrants, glucocorticoids, hormone therapy, protease inhibitors, raloxifine, retinoic acid, sirolimus, tamoxifen, thiazides Dietary influences Saturated or trans fats, weight gain, anorexia Very low-fat diets, high carbohydrate intake (refined), excess alcohol, weight gain Disease states and medical conditions Nephrotic syndrome, biliary obstruction, hypothyroidism, obesity, pregnancy Poorly controlled diabetes, hypothyroidism, obesity, pregnancy, nephrotic syndrome, chronic renal failure, lipodystrophies LDL-C = low-density lipoprotein cholesterol; TG = triglycerides. Patient Treatment Group 1. Statin therapy Very high risk (history of several major ASCVD eventsa or one major event + several high-risk conditionsb) ASCVD Patient Severe hypercholester olemia (LDL ≥ 190 mg/dL and age 20–75 yr) Primary prevention (age 40–75 yr and LDL 70– 189 mg/dL) DM Age > 75 yr Management Group Moderate- or highintensity statin Low risk (< 5%) Maximally tolerated statin therapy Calculate 10yr ASCVD risk score using the PCE and Age 20–39 yr determine whether risk estimate + risk enhancers Age 40–75 yr favor statin therapyh Borderline risk (5%–7.4%) LDL ≥ 70 mg/dL or non-HDL ≥ 100 mg/dLd LDL ≥ 70 mg/dL 2. Consider ezetimibe af statin therapy if: 1. Statin therapy Age 30–75 yr with HeFH and LDL ≥ 100 Lifestyle modifications onlymg/dL LDL ↓ ≤ 50% and/or LDL ≥ 100 mg/dLe,f Age 40–75 yr with baseline LDL ≥ 220 If risk enhancers present, mg/dL and LDL ≥ 130 consider moderate-intensity mg/dL statin May be reasonable to initiate statin therapy if several risk factors or risk enhancersg Moderate-intensity statin Intermediate risk (7.5%–19.9%) High-intensity statin for patients with several ASCVD risk factors Continue previously initiated statin therapy Age > 75 yr LDL ≥ 70 mg/dLc 3. Consider PCSK9-I after statin and ezetimibe if: High-intensity statin [goal LDL ↓ ≥ 50%] Age ≤ 75 yr Not very high risk High-intensity statin 2. Consider ezetimibe after statin therapy if: High risk (≥ 20%) Initiate statin therapy if benefits outweigh risks Moderate-intensity statin if benefits > risks 10-yr ASCVD risk ≥ (goal 20%LDL ↓ 30%–49%) If additional LDL lowering is warrantedi but high-intensity statin therapy is not advisable or tolerated, consider ezetimibe or BAS High-intensity statin (goal LDL ↓ ≥ 50%) Figure 7. Statin and nonstatin therapy recommendations according to patient treatment group. Class ClassII(strong) (strong)recommendation. recommendation. Class IIa recommendation; therapy is reasonable. Class IIa(moderate) (moderate) recommendation; therapy is reasonable. Class IIb (weak) recommendation; therapy may considered. Class IIb (weak) recommendation; therapy be may be considered. a Major ASCVD events are acute coronary syndrome (ACS) within the past 12 mo, other history of myocardial infarction stroke, and symptomatic peripheral artery disease. b High-risk conditions are age ≥ 65 yr, HeFH, history of coronary artery bypass surgery or percutaneous coronary interve ASCVD event(s), DM, hypertension, chronic kidney disease (eGFR 15–59 mL/min/1.73 m2), current smoking, histo and persistently elevated LDL ≥ 100 mg/dL despite maximally tolerated statin therapy and ezetimibe. c The 2022 ACC expert consensus pathway on nonstatin therapy suggests a target LDL reduction ≥ 50% and LDL < 55 m d Clinical evidence supports adding a PCSK9 inhibitor after maximally tolerated statin therapy, but adding ezetimibe firs e The 2022 ACC expert consensus pathway on nonstatin therapy suggests a target LDL reduction ≥ 50% and LDL < 70 m clinical ASCVD without FH and a target LDL reduction ≥ 50% and LDL < 55 mg/dL for patients with clinical ASC f Updates in Therapeutics® 2023:and Pharmacotherapy Preparatory Review Recertification MayACCP consider adding a BAS to statin ezetimibe if LDL reduction is <and 50% and fastingCourse TG ≤ 300 mg/dL, especially inhibitor therapy. 1-107 g DM-specific risk enhancers include DM of long duration (≥ 10 yr with type 2 DM or ≥ 20 yr with type 1 DM); microva (albuminuria [≥ 30 mcg/mg creatinine]), eGFR < 60 mL/min/1.73 m2, retinopathy, or neuropathy; or ankle-brachial h If risk decision is uncertain (especially in patients with borderline and intermediate risk), consider measuring coronary Key: Key: Patient Management Group 1. Statin therapy Chronic Care in Cardiology Low risk (< 5%) Patient Management Group Primary prevention (age 40–75 yr and LDL 70– Primary prevention 189 mg/dL) (age 40–75 yr and LDL 70– 189 mg/dL) Calculate 10yr ASCVD risk Low risk (< 5%) score using the PCE and Borderline risk Calculate 10- determine (5%–7.4%) yr ASCVD risk score using whether risk the PCE and estimate + risk determine enhancers whether risk estimate + risk favor statin Intermediate risk h enhancers (7.5%–19.9%) therapy favor statin therapyh High risk (≥ 20%) 1. Statin therapy Borderline risk (5%–7.4%) Lifestyle modifications only If risk enhancers present, consider moderate-intensity statin Intermediate risk (7.5%–19.9%) Moderate-intensity statin if benefits > risks (goal LDL ↓ 30%–49%) statin HighHigh-intensity risk (≥ 20%) (goal LDL ↓ ≥ 50%) 2. Consider ezetimibe af statin therapy if: Lifestyle modifications only 3. Consider PCSK9 2. Consider ezetimibe after inhibitor after statin and if: Ifstatin risktherapy enhancers present, ezetimibe if: consider moderate-intensity statin Moderate-intensity statin if benefits If additional LDL > risks lowering is warrantedi (goal LDL ↓ 30%–49%) but high-intensity statin therapy is not advisable or tolerated, consider ezetimibe or BAS If additional LDL lowering is warrantedi but high-intensity statin therapy is not advisable or tolerated, consider ezetimibe or BAS High-intensity statin (goal LDL ↓ ≥ 50%) Figure 7. Statin and nonstatin therapy recommendations according to patient treatment group. Figure 7.7.Statin and nonstatin therapy recommendations according to patient group (Cont’d). Figure Statin and nonstatin therapy recommendations according totreatment patient treatment group. Key: Class I (strong) recommendation. Class IIa (moderate) recommendation; therapy is reasonable. Key: Class I (strong) recommendation. Key: Class I (strong) recommendation. Class IIb (weak) recommendation; therapy may be considered. Class IIa (moderate) recommendation; therapy is reasonable. a Class IIaare (moderate) therapy is reasonable. Major ASCVD events acute coronaryrecommendation; syndrome (ACS) within the past 12 mo, other history of myocardial infarction (MI), history of ischemic Class IIb (weak) recommendation; therapy may considered. stroke, and symptomatic peripheral artery disease. Class IIb (weak) recommendation; therapy be may be considered. b a conditions are are age acute ≥ 65 yr, HeFH, history of coronary artery bypass surgery or percutaneous coronary intervention outside(MI), the major aHigh-risk Major ASCVD events coronary syndrome (ACS) within the past 12 mo, other history of myocardial infarction history of Major ASCVD events are acute coronary syndrome within past 12 mo, other history offailure, myocardial infarction ASCVD event(s), hypertension, chronicartery kidneydisease. disease (eGFR 15–59(ACS) mL/min/1.73 m2), the current smoking, history of congestive heart ischemic stroke, andDM, symptomatic peripheral andstroke, persistently elevated LDL ≥ 100 mg/dL despite maximally tolerated statin therapy and ezetimibe. and symptomatic peripheral artery disease. b cHigh-risk conditions are age ≥ 65 yr, HeFH, history of coronary artery bypass surgery or percutaneous coronary intervention outside the major The b 2022 ACC expert consensus pathway on nonstatin therapy suggests a target LDL reduction ≥ 50% and LDL < 55 mg/dL. High-risk conditions are agechronic ≥inhibitor 65kidney yr,after HeFH, history ofstatin coronary artery bypass surgery orofpercutaneous dASCVD event(s), DM, hypertension, disease (eGFR 15–59 mL/min/1.73 m2), current smoking, congestive heart coronary interve Clinical evidence supports adding a PCSK9 maximally tolerated therapy, but adding ezetimibe first history is more cost-effective. e ASCVD event(s), DM, chronic disease (eGFR 15–59 m2with ), current smoking, histo failure, and persistently elevated LDLhypertension, ≥ 100 mg/dL despite maximally tolerated statin therapy and and ezetimibe. The 2022 ACC expert consensus pathway on nonstatin therapy suggestskidney a target LDL reduction ≥ 50% LDL <mL/min/1.73 70 mg/dL for patients clinical ASCVD without FH and a target LDL reduction ≥ 50% and LDL < 55 mg/dL for patients with clinical ASCVD and FH. c andACC persistently elevated LDL ≥ 100therapy mg/dL despite maximally tolerated statin expert consensus pathway on nonstatin suggests a target LDL reduction ≥ 50% and LDL <therapy 55 mg/dL.and ezetimibe. fThe 2022 May consider adding a BAS to statin and ezetimibe if LDL reduction is < 50% and fasting TG ≤ 300 mg/dL, especially if ineligible for PCSK9 dcThe 2022 ACC expert consensus pathway on nonstatin therapy suggests a target LDL reduction ≥ 50% and LDL < 55 m Clinical evidence supports adding a PCSK9 inhibitor after maximally tolerated statin therapy, but adding ezetimibe first is more cost-effective. inhibitor therapy. g DM-specific risk enhancers includepathway DMadding of long duration (≥ 10 yrinhibitor with type 2a DM or LDL ≥maximally 20 yr with type 150% DM); microvascular complications e d Clinical evidence supports a PCSK9 after statin therapy, but adding ezetimibe firs The 2022 ACC expert consensus on nonstatin therapy suggests target reduction ≥tolerated and LDL < 70 mg/dL for patients with (albuminuria [≥ 30 mcg/mg creatinine]), eGFR < 60 mL/min/1.73 m2, retinopathy, or neuropathy; or ankle-brachial index < 0.9. e ASCVD without FH andconsensus a target LDL reduction ≥ 50% and LDL < 55therapy mg/dL forsuggests patients witha clinical ASCVD and FH. hclinical The 2022 ACC expert pathway on nonstatin target LDL reduction ≥ 50% and LDL < 70 m If risk decision is uncertain (especially in patients with borderline and intermediate risk), consider measuring coronary artery calcium. f iMay consider adding a BAS to statin and ezetimibe if LDL reduction is < 50% and fasting TG ≤ 300 mg/dL, especially if ineligible for PCSK9 The 2022 ACC expert consensus pathway on nonstatin therapy suggests a target of LDL reduction ≥ 50% and LDL < 70 mg/dL. clinical ASCVD without FH and a target LDL reduction ≥ 50% and LDL < 55 mg/dL for patients with clinical ASC inhibitor therapy. f May consider adding a BAS to statin and ezetimibe if LDL reduction is < 50% and fasting TG ≤ 300 mg/dL, especially DM-specific risk enhancers include DM of long duration (≥ 10 yr with type 2 DM or ≥ 20 yr with type 1 DM); microvascular complications inhibitor therapy. (albuminuria [≥ 30 mcg/mg creatinine]), eGFR < 60 mL/min/1.73 m2, retinopathy, or neuropathy; or ankle-brachial index < 0.9. g g DM-specific risk enhancers include DM of long duration (≥ 10 yr with type 2 DM or ≥ 20 yr with type 1 DM); microva (albuminuria [≥ 30 mcg/mg creatinine]), eGFR < 60 mL/min/1.73 m , retinopathy, or neuropathy; or ankle-brachial i The h 2022 ACC expert consensus pathway on nonstatin therapy suggests a target of LDL reduction ≥ 50% and LDL < 70 mg/dL. If risk= decision is uncertain (especially in patients with borderline and intermediate risk), consider measuring coronary ASCVD atherosclerotic cardiovascular disease; BAS = bile acid sequestrant; DM = diabetes mellitus; HeFH = heterozygous familial hyperi The 2022 ACC consensus on nonstatin therapy suggests of LDL reduction ≥ 50% and LDL < 7 cholesterolemia; PCE =expert pooled cohort equation;pathway PCSK9 = proprotein convertase subtilisin kexin/typea9target serine protease. If risk decision is uncertain (especially in patients with borderline and intermediate risk), consider measuring coronary artery calcium. 2 h Information from: Grundy SM, Stone NJ, Bailey AL, et al. 2018 ACC/AHA/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 Foundation/American Heart Association Task Force on Clinical Practice Guidelines. Circulation 2019;139:e1082-43; Lloyd-Jones D, Morris P, Ballantyne CM, et al. 2022 ACC expert consensus decision pathway on the role of nonstatin therapies for LDL-cholesterol lowering in the management of atherosclerotic cardiovascular disease risk. J Am Coll Cardiol 2022;80:1366-418. iii. M  oderate hypertriglyceridemia (triglycerides [TG] 175-499 mg/dL) (a) Address and treat lifestyle factors, comorbidities, and medications which increase TGs (b) If persistently elevated and ASCVD risk ≥7.5%, consider initiation or intensification of statin therapy iv. Severe hypertriglyceridemia (TG ≥ 500 mg/dL) (a) If persistently elevated and ASCVD risk ≥7.5%, consider initiation or intensification of statin therapy (b) Reasonable to implement a very low-fat diet and reasonable to initiate fibrate or omega-3 fatty acid therapy to prevent acute pancreatitis, especially if fasting TG ≥ 1000 mg/dL ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-108 Chronic Care in Cardiology v. Expected changes in TG concentrations with drug therapy (Table 16) Table 16. Effect of Lipid-Lowering Medications on TG Medication Statins Fibrates Niacin Ezetimibe Omega-3 fatty acids % Decrease in TG 7–30 20–50 20–50 5–11 19–44 TG = triglycerides E. Risk assessment tools for primary prevention 1. Risk discussions and shared decision making with patients should consider whether lifestyle and ASCVD risk factors have been addressed, cost considerations, and a discussion of the potential benefits and adverse events of drug therapy. Patients and health care professionals should work together to establish a customized cholesterol management plan. 2. Pooled Cohort Equation (PCE) to estimate 10-year ASCVD risk a. Measures hard ASCVD events: fatal and nonfatal MI and stroke b. Assists with identifying higher-risk patients for statin therapy c. Should not be used for patients with clinical ASCVD d. Available at http://tools.acc.org/ASCVD-Risk-Estimator/ e. Components of PCE: i. Sex ii. Age iii. Race iv. TC v. HDL-C vi. SBP vii. Receiving treatment for high BP viii. DM ix. Smoker 3. Risk-enhancing factors a. Family history of premature ASCVD (males <55 years, females <65 years) b. Primary hypercholesterolemia (LDL-C 160-189 mg/dL or non-HDL-C 190-219 mg/dL) c. Metabolic syndrome d. CKD e. Chronic inflammatory conditions such as psoriasis, rheumatoid arthritis, HIV/AIDS f. History of premature menopause (age <40 years) g. History of preeclampsia h. High-risk race/ethnicity (e.g., South Asian ancestry) i. Elevated TG ≥175 mg/dL j. Elevated biomarkers such as high-sensitivity C-reactive protein, lipoprotein (a), apolipoprotein B k. Ankle-brachial index <0.9 4. Coronary artery calcium (CAC) score for additional risk-stratification a. If risk decision is uncertain (especially borderline and intermediate risk patients), consider measuring coronary artery calcium b. Score = 0: consider no statin (unless DM, family history of premature coronary heart disease, or cigarette smoking present) ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-109 Chronic Care in Cardiology c. d. F. Score = 1-99: favors statin if age ≥55 Score ≥100 or ≥75th percentile: favors statin Monitoring 1. Measure fasting lipids 4-12 weeks after therapy initiation 2. Measure fasting lipids every 3-12 months thereafter 3. Periodically re-assess risk factors for ASCVD G. 3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) 1. General approach to initiating statin therapy: a. Fasting lipid panel i. If baseline LDL-C is higher than 190 mg/dL, evaluate for secondary causes. If primary, screen for familial hypercholesterolemia. b. Alanine aminotransferase (ALT) i. Evaluate patients with unexplained ALT more than 3x upper limit of normal c. Hemoglobin A1C d. Creatine kinase (if indicated) e. Evaluate for secondary causes or conditions that may affect statin safety 2. Efficacy a. First line for high LDL-C or CHD risk b. When selecting a statin, consider its intensity (Table 17). c. Reduce LDL-C by 24%–60%. d. Reduce TG by 7%–30%. e. Raise HDL-C by 5%–15%. f. Reduce major coronary events. g. Reduce CHD mortality. h. Reduce coronary procedures (percutaneous coronary intervention [PCI] or coronary artery bypass grafting). i. Reduce stroke. j. Reduce total mortality. Table 17. Relative LDL-C-Lowering Efficacy of Statins Atorva (mg) — 10 20 40 80 — Fluva (mg) 20–40 80 — — — — Pitava (mg) 1 2 4 — — — Lova (mg) 20 40 80 — — — Prava (mg) 10–20 40 80 — — — Rosuva (mg) — — 5 10 20 40 Simva (mg) 10 20 40 — — — %↓ LDL 30 38 41 47 55 63 Denotes low-intensity statin; lowers LDL-C by < 30%. Denotes moderate-intensity statin; lowers LDL-C by 30% to < 50%. Denotes high-intensity statin; lowers LDL-C by ≥ 50%. Atorva = atorvastatin; Fluva = fluvastatin; LDL-C = low-density lipoprotein cholesterol; Lova = lovastatin; Pitava = pitavastatin; Prava = pravastatin; Rosuva = rosuvastatin; Simva = simvastatin. Adapted from: Stone NJ, Robinson J, Lichtenstein AH, et al. 2013 ACC/AHA guidelines on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults. Circulation 2014;129(suppl 2):S1-45. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-110 Chronic Care in Cardiology 3. 4. 5. 6. 7.  echanism of action: Inhibits enzyme responsible for converting HMG-CoA to mevalonate (rateM limiting step in production of cholesterol) Main adverse effects and monitoring a. Myopathy (can check creatine kinase [CK] at baseline and then only if muscle symptoms occur; no regular monitoring) b. Elevated liver enzymes i. Obtain LFTs at baseline in all patients ii. Perform repeated LFTs only when clinically indicated. iii. Monitor for symptoms of hepatic injury. Absolute contraindications a. Active liver disease, unexplained persistent elevations in hepatic transaminases b. Nursing mothers c. Certain medications (agent-specific; see drug interactions below) d. In 2021, the FDA requested removal of the contraindication against statin use in pregnancy. However, statins are teratogenic and should be discontinued in most patients who are pregnant or breastfeeding. Select drug interactions (see Table 18) a. Fibrates: Increased risk of myopathy and rhabdomyolysis when coadministered with statins. Risk is greater with gemfibrozil than with fenofibrate. b. Niacin: Doses greater than 1 g/day increase the risk of myopathy and rhabdomyolysis when used concomitantly with statins; risk is lower than with fibrates; statins and niacin are commonly used together; monitor for muscle pain. c. Canagliflozin: A case report of a myopathy attributed to a drug interaction between canagliflozin and rosuvastatin was recently reported. Differences exist between statins in regard to pharmacokinetics and renal dosing (Tables 19 and 20) Table 18. Select Drug Interactions with Statins Lovastatin Amiodarone Pravastatin Daily dose NTE 40 mg Amlodipine Azole antifungals CI (itraconazole, ketoconazole, posaconazole, and voriconazole) Bempedoic acid Cobicistatcontaining products Colchicine Cyclosporine Daily dose NTE 40 mg CI Simvastatin Daily dose NTE 20 mg Daily dose NTE 20 mg CI (itraconazole, ketoconazole, posaconazole, and voriconazole) Daily dose NTE 20 mg CI Fluvastatin Daily dose NTE 20 mg BID (fluconazole) Pitavastatin Atorvastatin Rosuvastatin Daily dose NTE 20 mg (itraconazole) Use with caution Use with caution Use with caution Use with caution Use with caution Use with caution Use with caution Avoid use Daily dose CI Daily dose CI Avoid use Daily dose NTE 20 mg NTE 20 mg BID NTE 5 mg Danazol Daily dose CI NTE 20 mg Diltiazem Daily dose Daily dose Verapamil NTE 20 mg NTE 10 mg Dronedarone Daily dose Daily dose NTE 20 mg NTE 10 mg BID = twice daily; CI = contraindicated; HIV = human immunodeficiency virus; NTE = not to exceed. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-111 Chronic Care in Cardiology Table 18. Select Drug Interactions with Statins (Cont’d) Lovastatin Pravastatin Simvastatin Erythromycin Clarithromycin CI CI Gemfibrozil Avoid use Daily dose NTE 40 mg (clarithromycin) Avoid use Grapefruit juice Avoid use (> 1 quart per day) Lomitapide Consider lovastatin dose reduction Nefazodone Niacin HIV protease inhibitors Ranolazine CI Avoid doses of niacin ≥ 1 g/day CI CI Fluvastatin Pitavastatin Atorvastatin Avoid use Daily dose NTE 1 mg (erythromycin) Avoid use Daily dose NTE 20 mg (clarithromycin) Avoid use Avoid use Avoid doses of niacin ≥ 1 g/day Consider dose adjustment Rosuvastatin Daily dose NTE 10 mg Avoid excess quantities (> 1.2 L/day) Daily dose NTE 20 mg (or 40 mg if tolerated 80 mg for ≥1 yr) CI Avoid doses of niacin ≥ 1 g/day CI Avoid doses of niacin ≥ 1 g/day Avoid doses of niacin ≥ 1 g/day Avoid doses of niacin ≥ 1 g/day Avoid use with tipranavir plus ritonavir. Daily dose NTE 20 mg (saquinavir/ ritonavir, darunavir/ ritonavir, fosamprenavir or fosamprenavir/ ritonavir) Daily dose NTE 40 mg (nelfinavir) Use with caution Daily dose NTE 10 mg (lopinavir/ ritonavir or atazanavir/ ritonavir) Daily dose NTE 20 mg Rifampin Daily dose NTE 2 mg BID = twice daily; CI = contraindicated; HIV = human immunodeficiency virus; NTE = not to exceed. Table 19. Pharmacokinetic Differences Between Statins Atorvastatin Fluvastatin Lovastatin Pitavastatin Pravastatin Simvastatin Rosuvastatin Bioavailability (%) 14 24 <5 43-51 17 <5 20 Half-life (hr) 14 3 2–3 12 1.8 2 19 Elimination/ Metabolism 3A4 2C9 3A4 2C9 N/A 3A4 2C9 Prodrug No No Yes No No Yes No Solubility Lipophilic Lipophilic Lipophilic Lipophilic Hydrophilic Lipophilic Hydrophilic N/A = not applicable. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-112 Chronic Care in Cardiology Table 20. Dosing of Statin Agents in CKD Dose Recommended by KDIGO Guidelinesa Drug Comments Atorvastatin Fluvastatin Lovastatin Pitavastatin Pravastatin — Doses > 40 mg/day not studied in severe renal impairment CrCl <30 mL/min: NTE 20 mg/day CrCl 15-59 mL/min: NTE 2 mg/day CrCl <30 mL/min: Initial dose = 10 mg/day CrCl < 30 mL/min: Initial dose = 5 mg/day Simvastatinb Rosuvastatin CrCl < 30 mL/min: NTE 10 mg/day 20 mg/day 80 mg/day Not studied 2 mg/day 40 mg/day 40 mg/day (ezetimibe/simvastatin 10/20 mg/day) 10 mg/day Recommendations for Stage 3a through Stage 5 CKD (from Kidney Disease: Improving Global Outcomes Lipid Work Group. KDIGO clinical practice guidelines for lipid management in chronic kidney disease. Kidney Int 2013;3:1-56). b The 80-mg dose of simvastatin should be reserved for patients who have been taking simvastatin 80 mg long term (e.g., ≥ 12 mo) and who are without evidence of muscle toxicity. CrCl = creatinine clearance; NTE = not to exceed a H. Ezetimibe 1. Efficacy a. Lowers LDL-C by 18%–20% b. Can raise HDL-C by 1%–5% c. Lowers TG by 5%–10% 2. Mechanism of action: Inhibition of cholesterol absorption 3. Adverse effects and monitoring: Diarrhea, upper respiratory tract symptoms; no monitoring necessary 4. Data suggest that combination with simvastatin is superior to simvastatin alone in prevention of CV events. I. PCSK9 Inhibitors 1. Monoclonal antibodies (mAbs) a. Agents: Alirocumab, evolocumab b. Efficacy: Lower LDL-C by an additional 45%–68% when combined with statin therapy; reduce CV events when added to statin therapy (FOURIER and ODYSSEY OUTCOMES trials) c. Mechanism of action: Monoclonal antibodies that inhibit a protein called PCSK9, increasing cholesterol clearance from the liver d. Both indicated for heterozygous familial hypercholesterolemia or clinical ASCVD; evolocumab also indicated for homozygous familial hypercholesterolemia e. According to the 2018 AHA/ACC management of blood cholesterol guidelines, PCSK9 mAbs are only indicated for select patients already receiving maximally tolerated statin therapy and ezetimibe with either clinical ASCVD at very high risk or severe hypercholesterolemia in the 2018 ACC/ AHA cholesterol guidelines (Figure 7). According to the 2022 ACC expert consensus pathway on nonstatin therapy, either PCSK9 mAbs or ezetimibe may be considered as first-line adjuvants to maximally tolerated statin therapy. f. Adverse effects: Injection-site reactions, respiratory infections g. Dose: i. Evolocumab: (a) Heterozygous familial hypercholesterolemia or clinical ASCVD: 140 mg subcutaneously every 2 weeks or 420 mg subcutaneously once monthly (b) Homozygous familial hypercholesterolemia: 420 mg subcutaneously once monthly ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-113 Chronic Care in Cardiology 2. J. ii. A  lirocumab: Initial dose, 75 mg subcutaneously every 2 weeks or 300 mg subcutaneously every 4 weeks; if LDL-C reduction inadequate, can adjust dose to 150 mg subcutaneously every 2 weeks iii. PCSK9 inhibitor mAbs are preferred to inclisiran because of availability of CV outcomes data. Inclisiran a. Efficacy: Reduces LDL by 51% b. Mechanism of action: Small synthetic interfering ribonucleic acid that inhibits translation of PCSK9 proteins, up-regulating hepatic LDL receptor density c. Indicated as an adjunct to maximally tolerated statin therapy in adults with heterozygous familial hypercholesterolemia or ASCVD who require additional LDL lowering d. Adverse effects: Injection site reactions e. Dose: 284 mg subcutaneously at months 0 and 3, then every 6 months thereafter f. Clinical outcomes trials are ongoing. To date, the effect of inclisiran on CV morbidity and mortality is unknown. Bile acid sequestrants (cholestyramine, colestipol, colesevelam) 1. Efficacy a. Reduce LDL-C by 15%–27%. b. Raise HDL-C by 3%–5%. c. May increase TG concentrations. d. Reduce major coronary events. 2. Mechanism of action: Bind to bile acids to disrupt enterohepatic recirculation of bile acids. Liver is stimulated to convert hepatocellular cholesterol to bile acids. 3. Adverse effects: GI distress, constipation 4. Decreased absorption of many drugs including: warfarin, amiodarone, levothyroxine, ezetimibe, digoxin, and thiazides; administer drugs 1–2 hours before or 4 hours after bile acid sequestrant 5. Contraindications: Complete biliary obstruction, raised TG concentrations (especially greater than 400 mg/dL) K. Niacin (Table 21) 1. Efficacy a. Lowers LDL-C by 5%–25% b. Lowers TG by 20%–50% c. Raises HDL-C by 15%–35% d. Reduces major coronary events e. Lowers lipoprotein (a) 2. Mechanism of action: Inhibits mobilization of free fatty acids from peripheral adipose tissue to the liver and reduces synthesis of TG, very-low-density lipoproteins, and LDL-C 3. Adverse effects and monitoring: Flushing, hyperglycemia, hyperuricemia, myopathy, upper GI distress, increased hepatic transaminases; monitor LFTs at baseline, every 6–12 weeks for first year and then yearly 4. Sustained release appears to be more hepatotoxic than extended-release or immediate-release preparations. 5. Extended-release niacin is less likely to cause flushing. 6. Contraindications: liver disease and active peptic ulcer disease. Caution in patients predisposed to gout 7. Flushing can be minimized by taking aspirin or an NSAID 30–60 minutes before niacin, taking at bedtime with food, using slow titration, and avoiding hot beverages, spicy foods, and hot showers around the time of administration. 8. According to the 2018 AHA/ACC cholesterol guidelines, there are no clear indications for routine niacin use for reduction of LDL-C. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-114 Chronic Care in Cardiology Table 21. Niacin Formulations Drug Form Immediate release Extended release Sustained release Brand Name Niacin, Niacor Niaspan Slo-Niacin Dose Range (g) 1.5–6 1–2 1–2 L. Fibrates 1. Efficacy a. Lower LDL-C by 5%–20% (with normal TG) b. May raise LDL-C with very high TG c. Lower TG by 20%–50% d. Raise HDL-C by 10%–20% 2. Mechanism of action: Reduces rate of lipogenesis in the liver 3. Adverse effects and monitoring: Dyspepsia, gallstones, myopathy, increased hepatic transaminases. Monitor LFTs every 3 months during first year and then periodically. 4. Contraindications: Severe renal or hepatic disease, pre-existing gallbladder disease 5. Indicated for the treatment of severe hypertriglyceridemia (TGs 500 mg/dL or greater), especially in patients with TGs 100 mg/dL or greater M. Omega-3 fatty acids 1. Contain varying ratios of EPA and DHA a. Omega-3 acid ethyl esters: DHA and EPA b. Icosapent ethyl: EPA only c. Omega-3 carboxylic acid: DHA and EPA 2. Efficacy a. Lowers TG by 26%–45% b. Can raise LDL-C when TG concentrations are high c. Raises HDL-C by 5%–14% d. Icosapent ethyl reduced the composite of CV death, nonfatal MI, nonfatal stroke, coronary revascularization, or unstable angina in the REDUCE-IT trial. 3. Mechanism of action: Reduction of hepatic production of very-low-density lipoproteins; possible reduction in hepatic synthesis of TG; increased hepatic β-oxidation 4. Adverse effects: Arthralgia, GI effects (e.g., burping, taste perversion, dyspepsia); at more than 3 g/day, bleeding (because of inhibition of platelet aggregation) 5. Dose: 2–4.8 g/day as a single dose or in two divided doses N. Bempedoic Acid 1. Efficacy a. Lowers LDL-C by 15%–25% b. Reduces HDL-C by 5% 2. Mechanism of action: Inhibits ATP-citrate lyase, which inhibits cholesterol synthesis in the liver 3. Adverse effects and monitoring: Gout, hyperuricemia, leukopenia, thrombocytopenia, tendon rupture. Monitor for signs/symptoms of hyperuricemia and tendon rupture. 4. Indicated for use as an adjunct to statin therapy in heterozygous familial hypercholesterolemia or known CV disease in patients who require additional LDL-C reduction 5. Also available as combination product with ezetimibe 6. Results of clinical outcomes trials were not yet available at the time of publication. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-115 Chronic Care in Cardiology Patient Cases 8. M.M. is a 63-year-old white woman who just finished 6 months of diet and exercise for dyslipidemia. She has a history of hypertension, DM, and asthma. She smokes one pack of cigarettes and drinks three beers per day. Her mother had HTN and suffered an MI at age 42 years. Her father had HTN and DM. Her medications are albuterol metered dose inhaler, lisinopril, metformin, linagliptin, and calcium carbonate antacids. Her vital signs include BP 134/84 mm Hg and HR 75 beats/minute. Her laboratory results are as follows: HDL-C 38 mg/dL, LDL-C 134 mg/dL, TG 186 mg/dL, TC 209 mg/dL, and hemoglobin A1C 8.6%. Her pooled cohort equation estimates a 10-year ASCVD risk of 27.8%. What is the most appropriate next step for M.M.? A. Initiate a low-intensity statin B. Initiate a moderate-intensity statin C. Initiate a high-intensity statin D. Initiate a high-intensity statin plus ezetimibe 9.  ccording to the ACC/AHA blood cholesterol guidelines, which is best described as a high-intensity statin dose? A A. Pravastatin 20 mg/day. B. Lovastatin 20 mg/day. C. Atorvastatin 40 mg/day. D. Rosuvastatin 10 mg/day. 10. Which best describes a potential secondary cause of high TG concentrations? A. Amiodarone. B. Biliary obstruction. C. Sirolimus. D. Saturated fats. V. CHRONIC CORONARY HEART DISEASE AND CHRONIC STABLE ANGINA CHD is a general term that does not discriminate between the various phases the individual may cycle between for several decades. These phases include asymptomatic disease, stable angina, progressive angina, unstable angina, non–ST-segment elevation MI, and ST-segment elevation MI.  epending on the patient’s manifestations, some therapies may be added or modified. However, several basic D treatment rules apply to all individuals with CHD, regardless of the symptoms they may experience. The following mnemonic, developed for patients with chronic stable angina, can be applied to all patients with CHD. A = Aspirin and antianginal therapy B = β-Blocker and BP C = Cigarette smoking and cholesterol D = Diet and DM E = Education and exercise  lthough not all patients with CHD have DM or smoke cigarettes, the mnemonic is a way to remember the A primary areas that should be addressed, as applicable, in all patients with CHD. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-116 Chronic Care in Cardiology Some important recommendations: • Weight reduction and maintenance to a body mass index of 18.5–24.9 kg/m 2 and a waist circumference less than 40 inches for male patients and less than 35 inches for female patients • Physical activity for 30–60 minutes/day, 7 days/week (minimum of 5 days/week) • BP control • Alcohol consumption should be limited to 1 drink (120 mL [4 ounces] of wine, 360 mL [12 ounces] of beer, or 30 mL [1 ounce] of spirits) per day for women and 1 or 2 drinks per day for men. • No smoking and no environmental exposure to smoke • Reduced intake of saturated fats (to less than 7% of total calories), trans fatty acids (to less than 1% of total calories), and cholesterol (to less than 200 mg/day) • If a patient has DM, A1C less than 7%; a goal A1C of 7%–9% is reasonable in certain patients according to age, history of hypoglycemia, presence of microvascular or macrovascular complications, or comorbid conditions. • A nnual influenza vaccine Patient Case 11. A 66-year-old man with a medical history of HTN and acute coronary syndrome with a drug-eluting coronary stent placement 14 months ago presents to the primary care clinic. Current medications include aspirin 81 mg/day, prasugrel 10 mg/day, nitroglycerin 0.4-mg sublingual tablets as needed for chest pain, metoprolol succinate 75 mg/day, ramipril 10 mg/day, and atorvastatin 20 mg/day. He asks you how long he will need to take prasugrel. What is the best answer? A. Call your physician because you may be able to stop prasugrel now. B. Y  our prasugrel should have been discontinued 6 months after acute coronary syndrome; discontinue it now. C. You will need to take prasugrel indefinitely. D. You will need to take prasugrel for at least 18 months after your MI and stent placement. Therapeutic Management of CHD A. Aspirin for Stable CHD 1. Indicated in all patients with CHD unless contraindicated 2. Dose: 75–162 mg/day 3. Decreases CV events by about one third 4. Clopidogrel 75 mg/day can be used if aspirin contraindicated (e.g., allergy) B. Antiplatelet therapy for stable CHD for patients undergoing PCI 1. Aspirin is indicated in all patients. 2.  A P2Y12 is indicated in patients who undergo PCI with stenting; clopidogrel is the only P2Y12 inhibitor recommended in the stable ischemic heart disease (SIHD) guidelines. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-117 Chronic Care in Cardiology Table 22. Recommendations for Dosing and Duration of Antiplatelet Therapy in SIHD Aspirin Clinical Scenario SIHD treated with PCI and BMS placed SIHD treated with PCI and DES placed Initial Dose 325 mg before PCI 325 mg before PCI P2Y12 Inhibitors Subsequent Doses Recommended (Starting Day 2) Minimum Treatment and Therapy Duration (Class I)a Duration 75–100 mg/day indefinitely 75–100 mg/day indefinitely Alternative Treatment Options (Class IIb)b,c Clopidogrel for 1 month Reasonable to extend clopidogrel for > 1 month for those at low risk of bleeding Clopidogrel for 6 months Reasonable to discontinue clopidogrel after 3 months in those at high risk of bleeding or those who experience significant overt bleedingd Reasonable to extend clopidogrel for > 6 mo for those at low risk of bleedingd Class I recommendation; defined as “should be given.” Class IIb recommendation; defined as “may be considered.” c Each patient should be evaluated for his or her individual ischemic/bleeding risk, preferences, cost, etc., to determine the ideal duration of dual antiplatelet therapy. d The DAPT Score detailed in Acute Care in Cardiology I may be used to guide decisions regarding thrombotic versus bleeding risk BMS = bare metal stent; DAPT = dual antiplatelet therapy; DES = drug-eluting stent; PCI = percutaneous coronary intervention; SIHD = stable ischemic heart disease. Fihn SD, Gardin JM, Abrams J, et al. 2012 ACCF/AHA/ACP/AATS/PCNA/SCAI/STS guideline for the diagnosis and management of patients with stable ischemic heart disease: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines, and the American College of Physicians, American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. Circulation 2012;126:3097-137. Levine GN, Bates ER, Bittl JA, et al. 2016 ACC/AHA guideline focused update on duration of dual antiplatelet therapy in patients with coronary artery disease: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol 2016;68:1082-115. a b C. Lipid-lowering therapy (see section IV: Dyslipidemia) 1. Counsel on healthy lifestyle habits 2. Lipid panel, baseline alanine aminotransferase; consider secondary causes of dyslipidemia, evaluate for conditions that may influence statin safety 3. High-intensity statin therapy if without contraindications, drug–drug interactions, or history of statin intolerance (class I recommendation) D. ACE Inhibitors 1. Greatly decrease CV events in patients with CHD (and no left ventricular dysfunction) at high risk of subsequent CV events. 2. Should be considered in all patients who also have an LVEF of 40% or less, HTN, DM, and/or CKD (class I recommendation) 3. Consider using in lower-risk patients with a mildly reduced or normal LVEF in whom CV risk factors are well controlled and revascularization has been performed (class IIb recommendation). E. A  RBs: Recommended as an alternative to ACE inhibitors in patients who also have an LVEF of 40% or less, HTN, DM, or CKD or who are unable to tolerate an ACE inhibitor (e.g., cough or angioedema; class IIa recommendation) ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-118 Chronic Care in Cardiology F. Additional therapies for chronic stable angina 1. Definition: Predictable angina symptoms with exertion 2. Goals: Reduce symptoms of ischemia, increase physical function, and improve quality of life. In general, achieved by either decreasing myocardial oxygen demand or increasing myocardial oxygen supply 3. Specific agents a. β-Blockers i. Pharmacologic effects: Decreased inotropy and HR (decrease oxygen demand) ii. Goal resting HR 55–60 beats/minute (less than 50 beats/minute if angina symptoms continue) iii. Goal exercise HR of no more than 75% HR associated with angina symptoms iv. Place in therapy: May be considered chronic therapy for all patients with coronary or other vascular disease. Should be prescribed first-line for relief of angina symptoms in patients with stable ischemic heart disease (class I). Also a class I indication for first 3 years post-MI v. Contraindications: Severe bradycardia (HR less than 50 beats/minute), high-degree AV block or sick sinus syndrome (in absence of a pacemaker) b. CCBs i. Pharmacologic effects (a) Decrease coronary vascular resistance and increase coronary blood flow (increase oxygen supply) (b) Negative inotropy, to varying degrees; nifedipine much greater than amlodipine and felodipine (decrease oxygen demand) (c) Decrease HR (verapamil and diltiazem only; decrease oxygen demand) ii. Place in therapy (a) Non-DHP CCBs may be added to β-blocker therapy to achieve HR goals (caution advised; combination can cause heart block). (b) Instead of β-blocker therapy when unacceptable adverse effects emerge or if treating Prinzmetal’s angina (c) Short-acting CCBs (nifedipine) have been associated with increased CV events; should be avoided (except in slow-release formulations) iii. Contraindications for non-DHP CCBs: HFrEF, severe bradycardia, high-degree AV block or sick sinus syndrome (in absence of a pacemaker) c. Nitrates i. Pharmacologic effects: (a) Endothelium-dependent vasodilation, dilates epicardial arteries and collateral vessels (increase oxygen supply) (b) Decreased left ventricular volume because of decreased preload mediated by venodilation (decrease oxygen demand) ii. Place in therapy (a) A scheduled long-acting nitrate is useful in conjunction with a β-blocker or non-DHP CCB, or both (to blunt the reflex sympathetic tone with nitrate therapy). (b) As-needed sublingual tablets, powder, or spray nitroglycerin is necessary to relieve effort or rest angina. (c) In addition, as-needed sublingual tablets, powder, or spray nitroglycerin can be used before exercise to avoid ischemic episodes. iii. Caution: Hypertrophic obstructive cardiomyopathy, inferior wall MI, severe aortic valve stenosis, avanafil within 12 hours, sildenafil and vardenafil within 24 hours, tadalafil within 48 hours ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-119 Chronic Care in Cardiology d. Ranolazine i. Pharmacologic effects (a) Inhibits the late phase of the inward Na channel in ischemic myocytes during repolarization, leading to a reduction in intracellular Na concentrations. This reduction in Na concentrations leads to reduced calcium influx, which decreases ventricular tension and myocardial oxygen consumption. (b) Increases “oxygen efficiency” ii. Place in therapy (a) Ideal role is unclear (b) Use in combination with β-blockers, CCBs, and/or nitrates when initial management with these drugs is unsuccessful. (c) Use when BP or HR is too low to add β-blockers, CCBs, and/or nitrates (d) Modest reduction in hemoglobin A1C (e) Important points (1) No significant effects on HR or BP; thus, bradycardia and hypotension are not of concern (2) Dose-related QT interval prolongation (3) Metabolized by CYP3A; P-gp substrate (A) Avoid in hepatic dysfunction. (B) Avoid use with strong CYP3A inhibitors, including ketoconazole, itraconazole, clarithromycin, nefazodone, nelfinavir, ritonavir, indinavir, and saquinavir. (C) Avoid use with CYP3A inducers such as rifampin, rifabutin, rifapentine, phenobarbital, phenytoin, carbamazepine, or St. John’s wort. (D) Limit the dose to 500 mg twice daily in patients receiving moderate CYP3A4 inhibitors, including diltiazem, verapamil, erythromycin, fluconazole, and grapefruit juice. Acknowledgments: ACCP gratefully acknowledges the contribution of previous authors Drs. Jo Ellen Rodgers, Robert Page, Sheryl Chow, and Karen J. McConnell to this chapter. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-120