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An "Inclisiran First" Strategy vs Usual Care in Patients With Atherosclerotic Cardiovascular Disease
Michael J Koren1, Fatima Rodriguez2, Cara East3
1Jacksonville Center for Clinical Research, Jacksonville, Florida, USA.
Insights
An "inclisiran first" strategy significantly lowered LDL-C in atherosclerotic cardiovascular disease patients compared to usual care. This approach achieved greater LDL-C reduction without increasing statin discontinuation or major safety concerns.
Area of Science:
- Cardiology
- Pharmacology
- Clinical Trials
Background:
- Atherosclerotic cardiovascular disease (ASCVD) patients often fail to meet low-density lipoprotein cholesterol (LDL-C) targets with standard therapies.
- Inclisiran, a twice-yearly therapy, demonstrates significant LDL-C reduction when added to statins.
Purpose of the Study:
- To evaluate the effectiveness of an "inclisiran first" strategy versus usual care in ASCVD patients with elevated LDL-C despite maximally tolerated statins.
- To compare LDL-C goal attainment and statin discontinuation rates between the two treatment strategies.
Main Methods:
- The VICTORION-INITIATE trial was a prospective, randomized, 1:1 trial comparing "inclisiran first" (inclisiran added immediately) plus usual care to usual care alone.
- Primary endpoints included percentage change in LDL-C from baseline and statin discontinuation rates.
- Patients received inclisiran 284 mg at days 0, 90, and 270, with lipid management at physician's discretion in the usual care arm.
Main Results:
- The "inclisiran first" strategy resulted in a significantly greater LDL-C reduction (60.0%) compared to usual care (7.0%) by day 330 (P < 0.001).
- More patients in the "inclisiran first" group achieved LDL-C goals (<70 mg/dL: 81.8% vs 22.2%; <55 mg/dL: 71.6% vs 8.9%; P < 0.001).
- Statin discontinuation rates were noninferior (6.0% vs 16.7%), and treatment-emergent adverse event rates were similar between groups, although injection-site events were more common with inclisiran.
Conclusions:
- An "inclisiran first" implementation strategy is effective in significantly lowering LDL-C in ASCVD patients.
- This strategy achieves superior LDL-C reduction without negatively impacting statin use or introducing new safety concerns.
- The findings support "inclisiran first" as a viable option for managing hyperlipidemia in high-risk cardiovascular patients.
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 ∼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 significantly 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).
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