Very high-risk patients include those with history of multiple major ASCVD events or 1 major ASCVD event and multiple high-risk conditions. In these patients, additional benefit from LDL-C lower- ing when LDL-C is > 70 mg/dL (1.8 mmol/L) or non high-density lipoprotein >100 mg/dL (2.6 mmol/L) by ezetimibe and 2 PCSK9 inhibitors (evo- locumab and alirocumab) was demonstrated by 3 This guideline strongly recommends (COR 1) that ezetimibe be added to maximally tol- erated statin as a first step to further lower LDL-C. Although no RCT tested the strategy of ezetimibe first and then a PCSK9 inhibitor, ezetimibe was allowed at entry with statin therapy in both PCSK9 inhibitor trials (FOURIER [Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk] and ODYSSEY OUTCOMES [Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab]), but only 3% and 5% received ezetimibe during these trials. Ezetimibe use before PCSK9 inhibitor is recom- mended because ezetimibe is available as a generic drug and has proven safety.211 This approach is supported by 2 simulation studies from large popu- lations of very high-risk patients showing that ezeti- mibe plus statin therapy lowers LDL-C to <70 mg/ dL (1.8 mmol/L) in most patients, leaving a minority eligible for a PCSK9 inhibitor.217,218 In addition, the TST trial of patients with ischemic stroke used ezeti- mibe as second-line therapy to achieve the LDL-C Table 5. 