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CLINICAL STATEMENTS AND GUIDELINES

April 1, 2025 Circulation. 2025;151:e771–e862. DOI: 10.1161/CIR.0000000000001309 e798

demonstrated in those patients enrolled closer to their ACS event.20,21 Evolocumab effectively reduces LDL-C levels early after ACS and has demonstrated favorable changes on plaque components by intracoronary imaging in patients with NSTEMI.22–24 Greater plaque regression has also been reported by intracoronary imaging for patients treated with alirocumab after AMI.25 Inclisiran is a small interfering RNA targeting synthesis of the PCSK9 protein that is administered at 6-month intervals after an initial 3-month dose. Inclisiran lowers LDL-C levels by approximately 50% and is well tolerated,26 but clinical outcome studies are not yet available. Bempedoic acid works upstream from statins in the liver and leads to approximately 20% reduction in LDL-C levels. It reduces MACE

Table 11.  Nonstatin Treatment Options for LDL-C Lowering in Patients With ACS Who Are Not at LDL-C Goal on Maximally Tolerated Statin Therapy

Drug Mechanism of Action LDL-C Lowering (%) Outcomes Study Performed in Patients With Recent ACS? Potential Adverse Effects Ezetimibe* Blocks NPC1L1 cholesterol absorption 15-25 Yes (<10 d post ACS) Liver function test abnormalities Evolocumab Monoclonal antibody to PCSK9 ∼60 Established ASCVD (>1 mo post ACS) Injection site reaction Alirocumab Monoclonal antibody to PCSK9 ∼60 Yes (1-12 mo post ACS) Injection site reaction Inclisiran Inhibitor of PCSK9 synthesis (small interfering RNA) ∼50 Clinical outcomes trials in ASCVD are ongoing Injection site reaction Bempedoic acid† ATP-citrate lyase inhibitor ∼20 With or at high risk for CVD (>90 d post ACS) Gout; gallstones; liver function test abnormalities All agents are approved by the FDA. *The LDL-C lowering potency of ezetimibe is greater when used in combination with statin therapy (approximately 25% LDL-C reduction) than when used as monotherapy (15%-20%). †Coadministration of bempedoic acid with simvastatin at a dose >20 mg and pravastatin at a dose >40 mg is not recommended due to the increased risk of musclerelated adverse effects from statins. ACS indicates acute coronary syndromes; ASCVD, atherosclerotic cardiovascular disease; CVD, cardiovascular disease; FDA, US Food and Drug Administration; LDL- C, low-density lipoprotein cholesterol; NPC1L1, Niemann-Pick C1-Like 1 protein; and PCSK9, proprotein convertase subtilisin/kexin type 9.

Figure 5. Management of Lipid-Lowering Therapy for Patients With ACS. Colors correspond to Class of Recommendation in Table 2. *Nonstatin LDL-lowering therapy: ezetimibe, PCSK9 inhibitor (alirocumab, evolocumab and inclisiran), and/or bempedoic acid. ACS indicates acute coronary syndromes; LDL, low-density lipoprotein; LDL-C, low-density lipoprotein cholesterol; and PCSK9, proprotein convertase subtilisin/kexin type 9.

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