p.13 抽出テキスト

June 18/25, 2019 Circulation. 2019;139:e1082–e1143. DOI: 10.1161/CIR.0000000000000625 e1094

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 efficacy, 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 administration 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), excluding 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 longterm 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 addition 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. TRS 2°P includes 9 readily available clinical high-risk features and was initially developed in a population of patients with MI within 2 weeks to 1 year of randomization to a thrombin receptor agonistS4.1-44 and further validated in IMPROVE-IT.S4.1-14 A higher number of these high-risk features was associated with a higher risk of recurrent ASCVD events. In post- ACS patients with ≥3 high-risk features, addition of ezetimibe was associated with substantial risk reduction (19% RRR; 6.3% ARR; number needed to treat, 16); those with 2 high-risk features had some benefit, whereas those with 0 or 1 additional features had no benefit.S4.1-14 Therefore, it is reasonable to initiate ezetimibe in patients with ASCVD who are on maximally tolerated statin therapy and judged to be at very high risk. For the present guideline, a definition of very high risk is amalgamated from TRS 2°P and the recruitment criteria of 2 trials with PCSK9 inhibitors (Table 4). 6.	 The cost-effectiveness of using PCSK9 inhibitors for the secondary prevention of ASCVD has been evaluated in 7 published simulation models, as detailed in Section 7 (and Online Data Supplements 44 and 45). The reported incremental cost-effectiveness ratios range from $141 700 to $450 000 per added (QALY), with all but 1 model reporting “low value” (>$150 000 per QALY added). All models agree that the value provided by PCSK9 inhibitors would be significantly improved by price reductions of 70% to 85% from the mid-2018 US list price of roughly $14 000 a year. 7.	 When high-intensity stain therapy was compared with moderate-intensity statin therapy in patients >75 years of age with ASCVD,S4.1-3 there was no heterogeneity of effect among age groups >75, >65 to ≤75, and ≤65 years. However, analyses of RCTs that compared statin therapy (mostly moderate intensity) with placebo among patients >75 years of age with ASCVD showed statistically significant reduction in major vascular events.S4.1-3 Because older adults may have a higher risk of adverse events (eg, liver function test abnormalities), lower statin adherence, and

Table 4.  Very High-Risk* of Future ASCVD Events

Major ASCVD Events Recent ACS (within the past 12 mo) History of MI (other than recent ACS event listed above) History of ischemic stroke Symptomatic peripheral arterial disease (history of claudication with ABI

<0.85, or previous revascularization or amputationS4.1-40) High-Risk Conditions Age ≥65 y Heterozygous familial hypercholesterolemia History of prior coronary artery bypass surgery or percutaneous coronary

intervention outside of the major ASCVD event(s) Diabetes mellitus Hypertension CKD (eGFR 15-59 mL/min/1.73 m2)S4.1-15,S4.1-17 Current smoking Persistently elevated LDL-C (LDL-C ≥100 mg/dL [≥2.6 mmol/L]) despite

maximally tolerated statin therapy and ezetimibe History of congestive HF *Very high-risk includes a history of multiple major ASCVD events or one major ASCVD event and multiple high-risk conditions. ABI indicates ankle-brachial index; ACS, acute coronary syndrome; ASCVD, atherosclerotic cardiovascular disease; CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; HF, heart failure; LDL, low-density lipoprotein cholesterol; and MI, myocardial infarction.

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