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Circulation. 2019;139:e1082–e1143. DOI: 10.1161/CIR.0000000000000625 June 18/25, 2019 e1095 CLINICAL STATEMENTS AND GUIDELINES

higher discontinuation rates with high-intensity therapy,S4.1-45 a moderate-intensity statin may be preferable. Nevertheless, the decision to initiate moderate- or high-intensity statin therapy in patients >75 years of age with ASCVD should be based on expected benefit versus competing comorbidities.S4.1-23–S4.1-31 8.	 This recommendation is based on the observation that the age reported in clinical trials of statin therapy in patients with ASCVD represents the patient’s age at study entry. Therefore, it is reasonable to consider continuation of high-intensity therapy in patients >75 years of age with ASCVD if they are tolerating the statin and have a low risk of competing morbidities.S4.1-23,S4.1-26,S4.1-31 RCTsS4.1-32,S4.1-33,S4.1-35,S4.1-36 have not shown an adverse effect of statin therapy on cognition. 9.	 Although moderate-intensity statin therapy reduces ASCVD events, it is less effective than high-intensity therapy.S4.1-3 This difference presumably is due to differences in LDL-C–lowering potency. Hence, if ezetimibe were to be added to a moderate-intensity therapy to compensate for the difference in LDL-C–lowering ability between moderate- and high-intensity statins, the combination of moderate-intensity statin and ezetimibe could potentially produce a level of ASCVD risk reduction similar to that produced by high-intensity therapy alone. This hypothesis is supported by the finding that ezetimibe enhanced risk reduction when combined with moderate-intensity therapy in patients after ACS.S4.1-15 Thus, it may be reasonable to add ezetimibe to moderate-intensity therapy in patients with ASCVD for whom high-intensity therapy is indicated but cannot be used, provided their LDL-C level remains ≥70 mg/ dL (≥1.8 mmol/L) on moderate-intensity therapy. The same reasoning holds for any patient whose LDL-C level remains ≥70 mg/dL (≥1.8 mmol/L) on maximally tolerated statin therapy 10.	 The CORONA (Controlled Rosuvastatin Multi­ national Trial in Heart Failure) trialS4.1-38 (patients with ischemic HF and left ventricular ejection fraction <40%) and GISSI HF trial (Effects of n-3 PUFA and Rosuvastatin on Mortality-Morbidity of Patients With Symptomatic CHF)S4.1-39 (patients with ischemic and nonischemic HF, 9.8% with left ventricular ejection fraction >40%) evaluated the efficacy and safety of initiation of 10 mg of rosuvastatin daily compared with placebo. Neither trial met its primary outcome. Rosuvastatin reduced the risk of total hospitalizations, hospitalizations for a cardiovascular cause, and hospitalizations for worsening HF in CORONA. A subsequent analysis accounting for repeat HF hospitalizations showed significant reduction in HF hospitalizations.S4.1-46 Post hoc analyses from CORONA showed that patients randomized to rosuvastatin with less advanced HF with reduced ejection fraction (lowest tertile of NT-proBNP) had a significant reduction in the primary outcome, but no benefit was seen among patients with more advanced HF.S4.1-47 The CORONA and GISSI studies were notable for high overall and cardiovascular mortality rates, with MI occurring in a small minority. A subsequent patient-level analysisS4.1-37 that pooled data from both these trials and accounted for competing causes of death showed a significant 19% reduction in the risk of MI with rosuvastatin in patients with ischemic HF, although the ARR was small.

4.2 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]) Referenced studies that support recommendations are summarized in Online Data Supplements 9 and 10.

COR LOE Recommendations

I B-R 1.  In patients 20 to 75 years of age with an LDL-C level of 190 mg/dL or higher (≥4.9 mmol/L), maximally tolerated statin therapy is recommended.S4.2-1–S4.2-7

IIa B-R 2.  In patients 20 to 75 years of age with an LDL-C level of 190 mg/dL or higher (≥4.9 mmol/L) 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 or higher (≥2.6 mmol/L), ezetimibe therapy is reasonable.S4.2-8–S4.2-10

IIb B-R 3.  In patients 20 to 75 years of age with a baseline LDL-C level of 190 mg/dL or higher (≥4.9 mmol/L), who achieve less than a 50% reduction in LDL-C levels and have fasting triglycerides 300 mg/dL or lower (≤3.4 mmol/L), while taking maximally tolerated statin and ezetimibe therapy, the addition of a bile acid sequestrant may be considered.S4.2-11,S4.2-12

IIb B-R 4.  In patients 30 to 75 years of age with heterozygous FH and with an LDL-C level of 100 mg/dL or higher (≥2.6 mmol/L) while taking maximally tolerated statin and ezetimibe therapy, the addition of a PCSK9 inhibitor may be considered.S4.2-9,S4.2-13–S4.2-15

IIb C-LD 5.  In patients 40 to 75 years of age with a baseline LDL-C level of 220 mg/dL or higher (≥5.7 mmol/L) and who achieve an on-treatment LDL-C level of 130 mg/ dL or higher (≥3.4 mmol/L) while receiving maximally tolerated statin and ezetimibe therapy, the addition of a PCSK9 inhibitor may be considered.S4.2-13–S4.2-17

Value Statement: Uncertain Value

(B-NR) 6.  Among patients with FH without evidence of clinical ASCVD taking maximally tolerated statin and ezetimibe therapy, PCSK9 inhibitors provide uncertain value at mid- 2018 US list prices.

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