Statins are first-line therapy for reducing atherosclerotic cardiovascular disease (ASCVD) risk. Some patients remain at high ASCVD risk despite maximizing statin therapy. Ezetimibe and proprotein convertase subtilisin/kexin type 9 (PCSK9) monoclonal antibodies (mAbs) have been shown to reduce ASCVD events in randomized trials and may be of benefit in selected high-risk patients with cardiovascular disease (CVD) or familial hypercholesterolemia (FH). Number-needed-to-treat (NNT) to prevent one ASCVD event can help identify groups of patients who may gain a net benefit from added nonstatin therapy. Patient groups with NNTs <25 (in whom PCSK9 mAbs may approach cost effectiveness with discounting) include extremely high-risk patients (those with CVD with FH, polyvascular disease, or recurrent ASCVD events) with lowdensity lipoprotein cholesterol (LDL-C) levels ≥70 mg/dL, very high-risk patients (those with CVD with diabetes [and no polyvascular disease], chronic kidney disease, or acute coronary syndromes, or CVD or FH with poorly controlled risk factors) with LDL-C levels ≥100 mg/dL, and high-risk patients (those with CVD or FH with well-controlled risk factors) with LDL-C ≥130 mg/dL. Ezetimibe, which is generic in the United States, is reasonable for patient groups with NNTs <30, the level considered reasonable by most patients. This includes extremely high-risk patients with LDL-C levels ≥130 mg/dL, or very high-risk patients with LDL-C ≥190 mg/dL. All guidelines recommend statin therapy for the prevention of ASCVD.