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Circulation. 2019;139:e1082–e1143. DOI: 10.1161/CIR.0000000000000625 June 18/25, 2019 e1093 CLINICAL STATEMENTS AND GUIDELINES

for clinicians to add ezetimibe to maximally tolerated statin therapy as a first step in lowering LDL-C further. Although no RCT specifically tested the strategy of ezetimibe first and then a PCSK9 inhibitor, ezetimibe was allowed at entry along with statin therapy in both PCSK9 inhibitor trials (FOURIER, ODYSSEY OUTCOMES). Even so, only very small numbers (3% and 5% respectively) were on ezetimibe during these trials. The strategy of ezetimibe before PCSK9 inhibitor is recommended because ezetimibe is widely available as a generic drug and has proven safety and tolerability.S4.1-15 This approach is supported by 2 simulation studies from large populations of very high-risk patients; these reports showed that addition of ezetimibe to statin therapy will lower LDL-C to <70 mg/dL (1.8 mmol/L) in the majority of patients, leaving a minority eligible for a PCSK9 inhibitor.S4.1-42,S4.1-43 These 2 well-designed simulation studies favor the strategy of addition of ezetimibe before PCSK9 inhibitor and warrants an LOE of B-NR. 4.	 The FOURIER trial (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk) evaluated the PCSK9 inhibitor evolocumab among patients with ASCVD who met at least 1 major or 2 minor criteria.S4.1-17 Recruitment was limited to patients who had LDL-C ≥70 mg/dL (≥1.8 mmol/L) (or non–HDL-C ≥100 mg/dL (≥2.6 mmol/L)) on maximal statin ± ezetimibe. At a median follow-up of 2.2 years, evolocumab significantly reduced composite ASCVD (15% RRR; 1.5% AAR) without neurocognitive side effects,S4.1-16,S4.1-17 The ODYSSEY OUTCOMES trial (ODYSSEY Outcomes: Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab), tested alirocumab in patients on maximal statin ± ezetimibe with ACS over a median of 2.8 years, observed a 15% RRR (1.6%

Figure 1. Secondary prevention in patients with clinical ASCVD. Colors correspond to Class of Recommendation in Table 2. Clinical ASCVD consists of ACS, those with history of MI, stable or unstable angina or coronary other arterial revascularization, stroke, transient ischemic attack (TIA), or peripheral artery disease (PAD) including aortic aneurysm, all of atherosclerotic origin. Very high-risk includes a history of multiple major ASCVD events or 1 major ASCVD event and multiple high-risk conditions (Table 4). ACS indicates acute coronary syndrome; ASCVD, atherosclerotic cardiovascular disease; LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol; MI, myocardial infarction; and PCSK9-I, PCSK9 inhibitor.

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