An Inclisiran First Strategy vs Usual Care in Patients with Atherosclerosis

Most patients with atherosclerotic cardiovascular disease (ASCVD) fail to achieve guideline-directed low-density lipoprotein cholesterol (LDL-C) goals. Twice-yearly inclisiran lowers LDL-C by ∼50% when added to statins. To evaluate 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) versus representative usual care in US patients with ASCVD. 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) versus usual care alone. Primary endpoints were percentage change in LDL-C from baseline and statin discontinuation rates. We randomized 450 patients (30.9% female, 12.4% Black, 15.3% Hispanic); mean baseline LDL-C 97.4 mg/dL. The "inclisiran first" strategy led to significantly greater reductions in LDL-C from baseline to Day 330 versus usual care (60.0% vs 7.0%; p<0.001). Statin discontinuation rates with "inclisiran first" (6.0%) were noninferior versus 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 0.5%, respectively). An "inclisiran first" implementation strategy led to greater LDL-C lowering compared with usual care without discouraging statin use or raising new safety concerns.