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Inclisiran and Cardiovascular Events
Quick Takes
- This pooled analysis reports that the addition of inclisiran to background lipid-lowering therapies was associated with a 26% lower probability of MACE and favorable trends towards a lower risk of fatal and nonfatal MI.
- Of note, ascertainment of MACE was based on investigator-reported adverse event reporting rather than blinded adjudication by a panel of experts, and these potential benefits of inclisiran should be considered hypothesis generating and confirmed in larger CV outcomes trials of longer duration.
Study Questions:
What is the relationship between inclisiran treatment or placebo on the risk of cardiovascular (CV) events?
Methods:
The investigators conducted a patient-level, pooled analysis of ORION-9, ORION-10, and ORION-11, and included patients with heterozygous familial hypercholesterolemia, atherosclerotic CV disease (ASCVD), or ASCVD risk equivalent on maximally tolerated statin therapy, randomized 1:1 to receive 284 mg inclisiran or placebo on days 1, 90, and 6-monthly thereafter for 18 months. Prespecified exploratory endpoint of major CV events (MACEs) included nonadjudicated CV death, cardiac arrest, nonfatal myocardial infarction (MI), and fatal and nonfatal stroke, evaluated as part of safety assessments using a standard Medical Dictionary for Regulatory Activities basket. Although not prespecified, total fatal and nonfatal MI and stroke were also evaluated.
Results:
Mean low-density lipoprotein cholesterol (LDL-C) at baseline was 2.88 mmol/L. At day 90, the placebo-corrected percentage reduction in LDL-C with inclisiran was 50.6%, corresponding to an absolute reduction of 1.37 mmol/L (both p < 0.0001). Among 3,655 patients over 18 months, 303 (8.3%) experienced MACE, including 74 (2.0%) fatal and nonfatal MIs, and 28 (0.8%) fatal and nonfatal strokes. Inclisiran significantly reduced composite MACE (odds ratio [OR], 0.74; 95% confidence interval [CI], 0.58–0.94), but not fatal and nonfatal MIs (OR, 0.80; 95% CI, 0.50–1.27) or fatal and nonfatal stroke (OR, 0.86; 95% CI, 0.41–1.81).
Conclusions:
The authors concluded that this analysis offers early insights into the potential CV benefits of lowering LDL-C with inclisiran and suggests potential benefits for MACE reduction.
Perspective:
This patient-level, pooled analysis reported that the addition of inclisiran to background lipid-lowering therapies was associated with a 26% lower probability of MACE and favorable trends towards a lower risk of fatal and nonfatal MI compared with placebo. The reported rate of adverse events (AEs) with inclisiran was similar to that of placebo, apart from bronchitis and clinically relevant AEs at the injection site, which were more frequent with inclisiran but were mild, and none were persistent. Of note, ascertainment of MACE was based on investigator-reported AE-reporting rather than blinded adjudication by a panel of experts, and these benefits of inclisiran should be considered hypothesis generating and confirmed in larger prospective CV outcomes trials of longer duration.
Clinical Topics: Arrhythmias and Clinical EP, Diabetes and Cardiometabolic Disease, Dyslipidemia, Prevention, Implantable Devices, SCD/Ventricular Arrhythmias, Lipid Metabolism, Nonstatins, Novel Agents, Primary Hyperlipidemia, Statins
Keywords: Atherosclerosis, Bronchitis, Cholesterol, LDL, Dyslipidemias, Heart Arrest, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Hyperlipoproteinemia Type II, Myocardial Infarction, Primary Prevention, Stroke, Vascular Diseases
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