Comparison of an “Inclisiran First” Strategy With Usual Care in Patients With Atherosclerotic Cardiovascular Disease - VICTORION-INITIATE

Apr 06, 2024
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Author/Summarized by Author:
Amit Saha, MD
Summary Reviewer:
Dharam J. Kumbhani, MD, SM, FACC
Trial Sponsor:
Novartis Pharmaceuticals Corporation
Date Presented:
04/06/2024
Date Published:
04/06/2024
Original Posted Date:
04/06/2024
References

Contribution To Literature:

The VICTORION-INITIATE trial showed that in patients with ASCVD on maximally tolerated statin therapy with inadequate lipid control, inclisiran was superior to usual care in achieving a clinically significant reduction in LDL-C.

Description:

The goal of the trial was to determine the effect of adding inclisiran, a small interfering RNA targeting hepatic proprotein convertase subtilisin/kexin type 9 (PCSK9), versus usual care in achieving adequate lipid lowering in patients with atherosclerotic cardiovascular disease (ASCVD) on maximally tolerated statin therapy or with statin intolerance.

Study Design

  • Randomized
  • Multicenter
  • Open-label
  • Phase 3b

Patients with established ASCVD and low-density lipoprotein-cholesterol (LDL-C) ≥70 mg/dL or non–high-density lipoprotein cholesterol (non–HDL-C) ≥100 mg/dL despite maximally tolerated statin therapy alone were randomized in a 1:1 fashion to an “inclisiran-first” (n = 225) or usual care (n = 225) strategy. The experimental group received inclisiran sodium 300 mg subcutaneous injections on days 0, 90, and 270. The usual care arm was prescribed other lipid-lowering therapies (LLTs) at the treating provider’s judgment.

  • Total number of enrollees: 450
  • Duration of follow-up: 330 days
  • Median patient age: 67 years
  • Percentage female: 31%

Inclusion criteria:

  • Age ≥18 years
  • Prior ASCVD defined as:
  • Coronary artery disease: myocardial infarction (MI), revascularization, or >70% stenosis in ≥1 epicardial vessel by invasive or computed tomography angiography
  • Cerebrovascular disease: ischemic stroke, carotid artery stenosis >70%, or carotid revascularization
  • Peripheral artery disease: resting ankle-brachial index <0.85, revascularization at or above the popliteal artery, or nontraumatic amputation
  • LDL-C ≥70 mg/dL or non-HDL-C ≥100 mg/dL
  • Fasting triglyceride <500 mg/dL
  • Maximally tolerated statin dose or no statin with documented side effects to ≥2 statins, including 1 at the lowest available dose
  • Estimated glomerular filtration rate >30 mL/min/1.73 m2

Exclusion criteria:

  • Left ventricular ejection fraction <30%
  • New York Heart Association class III-IV heart failure
  • Major adverse cardiovascular event (MACE) <6 months prior
  • Life expectancy <2 years due to non-ASCVD comorbidities
  • Treatment with another PCSK9 inhibitor or ezetimibe <3 months prior
  • Active liver disease or aminotransferase levels >3x or total bilirubin >2x upper limit of normal

Other salient features/characteristics:

  • Mean LDL-C: 97.4 mg/dL
  • Active health insurance: 97%
  • Annual income ≤$50,000: 58%
  • Prior MI, coronary revascularization, or ischemic stroke: 95%
  • Statin intolerance: 26%

Principal Findings:

Co-primary outcomes for inclisiran-first vs. usual care at 330 days:

  • Percent change in LDL-C: -60.0% vs. -7.0% (p < 0.001)
  • Discontinuation of statin ≥30 days prior without prior statin intolerance: 6.0% vs. 16.7%, treatment difference -10.6% (97.5% confidence interval [CI] -18.3% to -3.0%) (noninferiority CI margin +15.0%)

Secondary outcomes for inclisiran-first vs. usual care at 330 days:

  • LDL-C reduction ≥50%: 69.8% vs. 5.3% (p < 0.001)
  • LDL-C <70 mg/dL: 81.8% vs. 22.2% (p < 0.001)
  • LDL-C <55 mg/dL: 71.6% vs. 8.9% (p < 0.001)
  • No background LLT: 10.2% vs. 11.6%
  • Statin-only background LLT: 88.4% vs. 73.4%
  • Treatment-related adverse events for inclisiran-first vs. usual care: 14.5% vs. 0.5%
  • Injection site adverse events for inclisiran-first: 10.3%
  • Composite MACE for inclisiran-first vs. usual care at 330 days: 2.7% vs. 2.2%

Interpretation:

VICTORION-INITIATE demonstrated that employing inclisiran directly after maximizing statin therapy was more effective than usual, real-world practices at both absolute LDL-C reduction and achieving guideline-recommended LDL-C levels associated with ASCVD risk reduction. The study was designed to actively recruit from socioeconomic groups historically under-represented in clinical trials to better reflect actual community practice patterns. This is reflected in the usual care arm’s low rates of combination LLT and achieving satisfactory LDL-C reduction, with over 10% of patients on no LLT despite prior ASCVD.

Importantly, only the study drug was provided by the sponsor, while all other LLT was to be obtained at the participants’ own expense. Moreover, only 3% of the study population was uninsured. Inclisiran certainly possesses practical advantages to alternative therapies due to clinic-based (vs. self-) administration and twice-yearly maintenance dosing. However, the current data do not account for the financial barriers patients may ultimately face to accessing inclisiran, particularly as a readily available and immediate second-line therapy to statins. MACE, which are the primary endpoint of the ongoing ORION-4 trial, were an exploratory endpoint and rare during the study period. Interpretation of clinical benefit is therefore limited to that expected to be associated with LDL-C treatment targets in secondary prevention.

References:

Koren MJ, Rodriguez F, East C, et al. An Inclisiran First Strategy vs Usual Care in Patients With Atherosclerosis. J Am Coll Cardiol 2024;Apr 6:[Epub ahead of print].

Presented by Dr. Michael J. Koren at the American College of Cardiology Annual Scientific Session (ACC.24), Atlanta, GA, April 6, 2024.

Clinical Topics: Vascular Medicine, Atherosclerotic Disease (CAD/PAD), Acute Coronary Syndromes, Stable Ischemic Heart Disease

Keywords: ACC24, ACC Annual Scientific Session, Atherosclerosis, Inclisiran, Novel Agents, PCSK9 Inhibitors, Peripheral Arterial Disease


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