CLINICAL STATEMENTS AND GUIDELINES ARR) in composite ASCVD events.S4.1-18 Together, FOURIER and ODYSSEY OUTCOMES justify a COR of IIa for PCSK9 inhibitors (acknowledging effi- cacy, but at the same time recognizing that there is limited experience with long-term tolerance of expensive monoclonal antibodies that is also inconvenient because it requires repetitive admin- istration via the parenteral route). Because of the statistically significant results in 2 large RCTs showing reductions in ASCVD events in patients who had very high risk and LDL-C 70 mg/dL ( 1.8 mmol/L) while on maximally tolerated LDL-C lowering therapy this recommendation warrants an LOE of A. There are 2 alternative pathways to initiation of PCSK9 inhibitors: (a) in patients on maximally tolerated statin + ezetimibe; and (b) in those on maximally tolerated statin alone. The strategy of (a) statin + ezetimibe before PCSK9 inhibitor, was graded COR I for reasons given in Recommendation 3. Second, strategy (b), exclud- ing ezetimibe, would expose more patients to the inconvenience of antibody therapy and reduce overall cost effectiveness. If patients develop 2 consecutive LDL-C levels <25 mg/dL while on a PCSK9 inhibitor, clinical judgment should be used to determine whether de-intensification of lipid lowering regimen is warranted as long- term safety of such low levels of LDL-C remains unknown. 5. In IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial),S4.1-15 addi- tion of ezetimibe to moderate-intensity statin therapy among patients with ACS and LDL-C levels 50 mg/dL ( 1.3 mmol/L) resulted in a significant ASCVD risk reduction (7% relative risk reduction [RRR]; 2% absolute risk reduction [ARR]) at a median follow-up of 6 years. The TIMI (Thrombolysis in Myocardial Infarction) Risk Score for Secondary Prevention (TRS 2 P) is an integer-based risk stratification tool for patients with ASCVD. 