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. 2023 Jan 7;44(2):129-138.
doi: 10.1093/eurheartj/ehac594.

Inclisiran and cardiovascular events: a patient-level analysis of phase III trials

Kausik K Ray  1 , Frederick J Raal  2 , David G Kallend  3   4 , Mark J Jaros  5 , Wolfgang Koenig  6   7 , Lawrence A Leiter  8 , Ulf Landmesser  9 , Gregory G Schwartz  10 , David Lawrence  11 , Andrew Friedman  12 , Lorena Garcia Conde  11 , R Scott Wright  13 ; ORION Phase III investigators
Affiliations

Inclisiran and cardiovascular events: a patient-level analysis of phase III trials

Kausik K Ray et al. Eur Heart J. .

Abstract

Background: Inclisiran, an siRNA administered twice-yearly, significantly reduced LDL cholesterol (LDL-C) in Phase III trials. Whether lowering LDL-C with inclisiran translates into a lower risk of cardiovascular (CV) events is not yet established.

Methods and results: Patient-level, pooled analysis of ORION-9, -10 and -11, included patients with heterozygous familial hypercholesterolaemia, 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 cardiovascular events (MACEs) included non-adjudicated CV death, cardiac arrest, non-fatal myocardial infarction (MI), and fatal and non-fatal stroke, evaluated as part of safety assessments using a standard Medical Dictionary for Regulatory Activities basket. Although not prespecified, total fatal and non-fatal MI, and stroke were also evaluated. Mean 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 3655 patients over 18 months, 303 (8.3%) experienced MACE, including 74 (2.0%) fatal and non-fatal MIs, and 28 (0.8%) fatal and non-fatal strokes. Inclisiran significantly reduced composite MACE [OR (95% CI): 0.74 (0.58-0.94)], but not fatal and non-fatal MIs [OR (95% CI): 0.80 (0.50-1.27)] or fatal and non-fatal stroke [OR (95% CI): 0.86 (0.41-1.81)].

Conclusion: This analysis offers early insights into the potential CV benefits of lowering LDL-C with inclisiran and suggests potential benefits for MACE reduction. These findings await confirmation in the larger CV outcomes trials of longer duration.

Keywords: Atherosclerotic cardiovascular disease; Inclisiran; LDL-C; Major adverse cardiovascular events.

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Conflict of interest statement

Conflict of interest: K.K.R. receives support from the National Institute for Health Research (NIHR) Imperial Biomedical Research Centre; his institution (Imperial College London) receives support from the NIHR Applied Research Collaboration Northwest London. K.K.R. reports receiving lecture fees from Aegerion Pharmaceuticals, Kowa, Cipla, Algorithm, and Zuelling Pharma, grant support, paid to his institution, lecture fees, and advisory board fees from Amgen, Regeneron Pharmaceuticals/Sanofi, and Pfizer, lecture fees and fees for serving on steering committees for trials from AstraZeneca and Eli Lilly, fees for serving on steering committees for trials from Cerenis Therapeutics, The Medicines Company, and Esperion, advisory board fees from Akcea Therapeutics, Novartis, Silence Therapeutics, Bayer, and Daiichi Sankyo, lecture fees and advisory board fees from Takeda, Boehringer Ingelheim, and Dr Reddy’s Laboratories, grant support and advisory board fees from Merck Sharp & Dohme, fees for serving on a clinical events adjudication committee from AbbVie, and fees for serving as principal investigator for a trial from Resverlogix. F.J.R. reports receiving advisory board fees and lecture fees from Amgen, Sanofi-Aventis, Regeneron Pharmaceuticals, The Medicines Company and Novartis. D.G.K. reports being employed by and holding stock options in the Medicines Company at the time of study and employment with DalCor Pharmaceuticals and LIB Therapeutics at the time of publication. M.J.J. has received fees for providing statistical analysis for trials from The Medicines Company and Novartis. W.K. reports receiving consulting fees and lecture fees from AstraZeneca, Novartis and Amgen, consulting fees from Pfizer, the Medicines Company and Novartis, DalCor Pharmaceuticals, Kowa, Corvidia Therapeutics, Esperion, Genentech, OMEICOS, Novo Nordisk, LIB Therapeutics, and Daiichi Sankyo, lecture fees from Berlin-Chemie, Bristol-Myers Squibb and Sanofi, and grant support and provision of reagents from Singulex, Abbott, Roche Diagnostics, and Dr Beckmann Pharma. L.A.L. grant support paid to his institution, advisory board fees and fees for CME from Amgen, and Novartis; fees for serving on a steering committee and advisory board fees from Esperion; grant support paid to his institution and fees for serving on a steering committee from Kowa, and the Medicines Company and Novartis; advisory board fees and fees for CME from Amarin, Astra Zeneca, HLS, Merck, Pfizer, and Sanofi. U.L. reports receiving lecture and/or advisory fees from AstraZeneca, Boehringer, Sanofi, Berlin Chemie, and Abbott, advisory fees from The Medicines Company, and grant support to institution, lecture fees, and advisory fees from Amgen, Bayer and Novartis. G.G.S. reports receiving research support, paid to his institution, from AstraZeneca, Resverlogix, Sanofi, Silence Therapeutics, and The Medicines Company, and a patent (62/806313) on a method for reducing cardiovascular risk assigned in full to the University of Colorado. D.L. reports being employed by Novartis at the time of publication and holding shares in Novartis. A.F. reports being employed by and holding shares and stock options in The Medicines Company at the time of the clinical study and was employed by Novartis at the time of analysis. L.G.C. reports being employed by Novartis at the time of publication. R.S.W. reports receiving advisory board fees from Boehringer Ingelheim and past fees for consulting on lipid issues with the Medicines Company.

Figures

Structured Graphical Abstract
Structured Graphical Abstract
AE, adverse event; HR, hazard ratio; LDL-C, low-density lipoprotein cholesterol; mRNA, messenger ribonucleic acid; OR, odds ratio; PCSK9, proprotein convertase subtilisin/kexin type 9; siRNA, small interfering ribonucleic acid.
Figure 1
Figure 1
Mean placebo-corrected percentage and absolute changes in LDL-C from baseline to (intention-to-treat population): (A) Day 90 and (B) Day 540. Values shown are mean treatment difference (inclisiran vs. placebo) and error bars represent the 95% confidence interval (mixed model repeated measures analysis); P < 0.0001 for all.
Figure 2
Figure 2
Kaplan–Meier curves depicting the cumulative event rate (safety population): (A) major adverse cardiovascular event, (B) fatal and non-fatal myocardial infarction, and (C) fatal and non-fatal stroke. *The hazard ratio and 95% confidence interval are from a Cox model with treatment and study ID as factors. †The major adverse cardiovascular event count includes both non treatment-emergent adverse events and treatment-emergent adverse events. In the placebo arm, three non treatment-emergent adverse events occurred on or after the Screening date, within seven days of first dose, but prior to first dose. To avoid a ‘negative time-to-first event’ for these three patients, these events were not included in the time-to-first event analysis; instead, these patients were treated as missing.
Figure 3
Figure 3
Fixed effects meta-analysis of the safety population: (A) major adverse cardiovascular event, fatal and non-fatal myocardial infarction and fatal and non-fatal stroke (pooled data from ORION-9, ORION-10 and ORION-11), and (B) major adverse cardiovascular event by individual study. *Inclisiran, n = 1833; †Placebo, n = 1822. The meta-analysis used the Peto method for pooling studies to ensure that patients enrolled in ORION-9 were included in the analysis, although there were no reported stroke events in the ORION-9 trial. The model used for the meta-analysis included study as a fixed effect. The major adverse cardiovascular event count included treatment emergent adverse events and non- treatment emergent adverse events. Fatal and non-fatal stroke counts included only serious adverse events. Definitions of major adverse cardiovascular event, fatal and non-fatal myocardial infarction, and fatal and non-fatal stroke are provided in the Supplementary material online, Table S2. Test of heterogeneity and I2for major adverse cardiovascular event or adverse cardiovascular event, Q = 0.48 P = 0.79; I2 = 0.00%.
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