However, there is no direct evidence to support the superiority of a single approach for intensification of lipid-lowering therapy between: a) maximizing statin dose; b) adding ezetimibe to moderate- or high-dose statin (in patients already on high-dose statins); or c) adding PCSK9 inhibitors to maximum-dose statin with or without ezetimibe Table 1. Evidence on Reducing Recurrent CVD Events with Moderate- or High-dose Statins Clinical Trial Intervention/Population (Maximize Statin or Add Non-statin) Results for Primary Composite Endpoint Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab (ODYSSEY OUTCOMES) [86] Alirocumab added to maximum-dose statin in patients 1 12 months after ACS over 2.8 years Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk (FOURIER) Evolocumab added to maximum-dose statins with or without ezetimibe in patients with clinically evident ASCVD and one major risk factor or two minor risk factors IMProved Reduction of Outcomes: Vytorin Efficacy International Trial Ezetimibe added to moderate-dose statins in patients after ACS The Pravastatin or Atorvastatin Evaluation and Infection Therapy- Thrombolysis In Myocardial Infarction 22 Moderate-dose (pravastatin 40 mg) versus high-dose (atorvastatin 80 mg) statin in patients with ACS Treating to New Targets (TNT) [89] Moderate-dose (10 mg) versus high-dose (atorvastatin 80 mg) in patients with stable CAD over 4.9 years Abbreviations: ACS: acute coronary syndrome; ASCVD: atherosclerotic cardiovascular disease; CAD: coronary artery disease; mg: milligrams; NNT: number needed to treat; PCSK9: proprotein convertase subtilisin/kexin type 9; RRR: relative risk reduction Summary We recommend the combination of maximally tolerated statins and ezetimibe before PCSK9 inhibitors because high-dose statins and ezetimibe have evidence of long-term safety and reduction in CV events. Statins and ezetimibe are also administered orally and are widely available as generic products. 