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June 18/25, 2019 Circulation. 2019;139:e1082–e1143. DOI: 10.1161/CIR.0000000000000625 e1096

CLINICAL STATEMENTS AND GUIDELINES Synopsis

Patients with severe hypercholesterolemia have a high lifetime risk, and decisions about statins in these patients do not require ASCVD risk scoring. These patients derive net ASCVD risk reduction benefit from interventions that increase expression of LDL receptors. The strongest data have been derived from statin RCTs, which have demonstrated greater risk reduction with statins than with placebo and greater reduction from higher-intensity statin therapy than with moderateintensity statin therapy. Ezetimibe plus a moderate-intensity statin is associated with greater LDL-C reduction than is statin monotherapy in patients with heterozygous FH, and the combination reduces ASCVD risk more than moderate-intensity statin monotherapy in patients who have had a recent ACS. In selected patients with severe hypercholesterolemia whose LDL-C is inadequately controlled with drug therapy, LDL apheresis is an option. Referral to a lipid specialist may be indicated.

Recommendation-Specific Supportive Text

1.	 Patients with primary severe hypercholesterolemia (LDL-C levels ≥190 mg/dL [≥4.9 mmol/L]) have a high-risk of ASCVDS4.2-2,S4.2-4,S4.2-18 and premature and recurrent coronary events.S4.2-3 Although there have been no randomized, placebo-controlled trials of statin therapy done exclusively in subjects with LDL-C levels ≥190 mg/dL (≥4.9 mmol/L), a placebo-controlled primary prevention study performed in men with a mean baseline LDL-C level of 192±17 mg/dL (4.9±0.4 mmol/L) demonstrated a reduced incidence of MI and cardiovascular death in those receiving pravastatin 40 mg daily.S4.2-5 These findings were extended in a post hoc analysis of 2 560 exclusively primary-prevention subjects in that RCT and in a 20-year observational post-trial long-term follow-up study.S4.2-19 In addition, retrospective cohort studies have demonstrated that statin therapy reduces risk of incident MIS4.2-6 and of CHD and all-cause deathS4.2-1 in patients with phenotypic or genetically confirmed FH. Because moderate- or high-intensity statins have been shown to reduce ASCVD risk in both primary- and secondary-prevention trials and because high-intensity statins provide greater ASCVD risk reduction than moderate-intensity statins or placebo,S4.2-7 maximally tolerated statin therapy should be administered to patients with primary severe hypercholesterolemia. 2.	 A large placebo-controlled RCT examined the effect of simvastatin 80 mg daily, with or without ezetimibe 10 mg daily, on carotid intima-media thickness and plasma lipoproteins over 2 years. Mean LDL-C reduction was greater in the combined-therapy group, but there was no difference in carotid intima-media thickness between the 2 groups. The study was not powered to examine the risk of ASCVD events.S4.2-10 However, a very large placebo-controlled RCT examining ASCVD outcomes in post-ACS patients, performed over a period of 7 years, showed that the addition of ezetimibe 10 mg to simvastatin 40 mg daily resulted in greater ASCVD risk reduction than that produced by statin monotherapy.S4.2-8 Secondaryprevention patients with certain ASCVD risk indicators exhibit greater ASCVD risk reduction from ezetimibe therapy than do patients without these characteristics.S4.2-20 Patients with severe hypercholesterolemia who are adherent to statins, achieve <50% reduction in LDL-C levels with maximally tolerated statin therapy, and have an LDL-C level ≥100 mg/dL (≥2.6 mmol/L) are likely to derive additional ASCVD risk reduction from ezetimibe add-on therapy through additional LDL-C lowering.S4.2-9

3.	 When administered to patients with severe hypercholesterolemia who are taking maximally tolerated statins with or without ezetimibe, bile acid sequestrants have demonstrated LDL-C-lowering efficacy.S4.2-11,S4.2-12 However, the clinical utility of bile acid sequestrants is limited by the absence of ASCVD outcomes data when used in combination with statins, as well as by the issues of twice-daily dosing, high pill burden, the absence of well-tolerated generic formulations, drug interactions, and the potential for triglyceride elevation. Nonetheless, in patients with very severe hypercholesterolemia, adding sequestrants to otherwise maximal cholesterol-lowering therapy in patients who are not eligible for a PCSK9 inhibitor may be considered. 4.	 PCSK9 inhibitors are promising drugs for treatment of FH.S4.2-9,S4.2-13–S4.2-15 Two placebo-controlled RCTs of the efficacy and safety of PCSK9 inhibitors in patients with heterozygous FH who were ≥18 years of age and taking stable, maximally tolerated statin therapy demonstrated favorable safety profiles and an additional ≥50% reduction in LDL-C.S4.2-10,S4.2-15 There are no currently available outcomes trials of PCSK9 inhibitors in patients with ASCVD heterozygous FH. In patients with LDL-C levels ≥190 mg/dL (≥4.9 mmol/L), advancing age is associated with progressively increasing ASCVD risk,S4.2-4 and agerelated risk would likely apply to those with heterozygous FH because of their higher lifetime exposure to increased LDL-C concentration.S4.2-18 A long-term prospective cohort registry study of

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