In these patients, additional net benefit from fur- ther LDL-C lowering when LDL-C is 70 mg/dL mmol/L) by ezetimibe and 2 PCSK9 inhibitors (evolocumab and alirocumab) has been dem- This guide- line makes a strong recommendation (COR I) Recommendations for Statin Therapy Use in Patients With ASCVD (Continued) COR LOE Recommendations CLINICAL STATEMENTS AND GUIDELINES for clinicians to add ezetimibe to maximally tolerated statin therapy as a first step in lower- ing 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 inhibi- tor trials (FOURIER, ODYSSEY OUTCOMES). Even so, only very small numbers (3% and 5% respec- tively) were on ezetimibe during these trials. The strategy of ezetimibe before PCSK9 inhibitor is recommended because ezetimibe is widely avail- able as a generic drug and has proven safety and 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 major- ity of patients, leaving a minority eligible for a 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 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 maxi- mal statin ezetimibe. 