An “inclisiran First” Strategy Vs Usual Care in Patients with Atherosclerotic Cardiovascular Disease

BACKGROUND Most patients with atherosclerotic cardiovascular disease fail to achieve guideline-directed low-density lipoprotein cholesterol (LDL-C) goals. Twice-yearly inclisiran lowers LDL-C by similar to 50% when added to statins. OBJECTIVES This study evaluated the effectiveness of an "inclisiran first " implementation strategy (adding inclisiran immediately upon failure to reach LDL-C <70 mg/dL despite receiving maximally tolerated statins) vs representative usual care in U.S. patients with atherosclerotic cardiovascular disease. METHODS VICTORION-INITIATE, a prospective, pragmatically designed trial, randomized patients 1:1 to inclisiran (284 mg at days 0, 90, and 270) plus usual care (lipid management at treating physician 's discretion) vs usual care alone. Primary endpoints were percentage change in LDL-C from baseline and statin discontinuation rates. RESULTS We randomized 450 patients (30.9% women, 12.4% Black, 15.3% Hispanic); mean baseline LDL-C was 97.4 mg/dL. The "inclisiran first " strategy led to signi ficantly greater reductions in LDL-C from baseline to day 330 vs usual care (60.0% vs 7.0%; P < 0.001). Statin discontinuation rates with "inclisiran first " (6.0%) were noninferior vs usual care (16.7%). More "inclisiran first" patients achieved LDL-C goals vs usual care (<70 mg/dL: 81.8% vs 22.2%; <55 mg/dL: 71.6% vs 8.9%; P < 0.001). Treatment-emergent adverse event (TEAE) and serious TEAE rates compared similarly between treatment strategies (62.8% vs 53.7% and 11.5% vs 13.4%, respectively). Injection-site TEAEs and TEAEs causing treatment withdrawal occurred more commonly with "inclisiran first " than usual care (10.3% vs 0.0% and 2.6% vs 0.0%, respectively). CONCLUSIONS An "inclisiran first " implementation strategy led to greater LDL-C lowering compared with usual care without discouraging statin use or raising new safety concerns. (A Randomized, Multicenter, Open-label Trial Comparing the Effectiveness of an "Inclisiran First " Implementation Strategy to Usual Care on LDL Cholesterol [LDL-C] in Patients With Atherosclerotic Cardiovascular Disease and Elevated LDL-C [$70 mg/dL] Despite Receiving Maximally Tolerated Statin Therapy [VICTORION-INITIATE]; NCT04929249) (c) 2024 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).