Amy Damask1, P Gabriel Steg2, Gregory G Schwartz3, Michael Szarek4, Emil Hagström5, Lina Badimon6, M John Chapman7, Catherine Boileau8, Sotirios Tsimikas9, Henry N Ginsberg10, Poulabi Banerjee1, Garen Manvelian1, Robert Pordy1, Sibylle Hess11, John D Overton1, Luca A Lotta1, George D Yancopoulos1, Goncalo R Abecasis1, Aris Baras1, Charles Paulding1. 1. Regeneron Pharmaceuticals, Inc., Tarrytown, NY. 2. Université de Paris, Hôpital Bichat, Assistance Publique-Hôpitaux de Paris Paris, INSERM U1148, France. 3. University of Colorado School of Medicine, Aurora, CO. 4. Department of Biostatistics and Epidemiology, SUNY Downstate School of Public Health, Brooklyn, NY. 5. Dept of Medical Sciences, Cardiology, Uppsala University, 75185 Uppsala, Sweden. 6. Cardiovascular Program-ICCC, CiberCV, IRHospital de la Santa Creu i Sant Pau, 08025 Barcelona, Spain. 7. Endocrinology Metabolism Division, Pitie-Salpetriere University Hospital, Sorbonne University and National Institute for Health and Medical Research (INSERM), Paris, France. 8. Université de Paris, Inserm U1148 and Genetics Department, APHP-Hospital Bichat-Claude Bernard, Paris, France. 9. Sulpizio Cardiovascular Center, Division of Cardiovascular Medicine, University of California San Diego, La Jolla, CA. 10. Irving Institute for Clinical and Translational Research, Columbia University, New York, NY. 11. Sanofi Aventis Deutschland GmbH, Translational Medicine and Early Development, Biomarkers and Clinical Bioanalyses, Frankfurt 65926, Germany.
Abstract
Background: Alirocumab, an antibody that blocks proprotein convertase subtilisin/kexin type 9 (PCSK9), was associated with reduced major adverse cardiovascular events (MACE) and death in the ODYSSEY OUTCOMES trial. In this study, higher baseline LDL cholesterol (LDL-C) levels predicted greater benefit from alirocumab treatment. Recent studies indicate high polygenic risk scores (PRS) for coronary artery disease (CAD) identify individuals at higher risk who derive increased benefit from statins. Herein we perform post hoc analyses to determine whether high PRS for CAD identifies higher-risk individuals, independently from baseline LDLC and other known risk factors, who might derive greater benefit from alirocumab treatment. Methods: ODYSSEY OUTCOMES was a randomized, double-blind, placebo-controlled trial comparing alirocumab or placebo in 18,924 patients with acute coronary syndrome and elevated atherogenic lipoproteins despite optimized statin treatment. The primary endpoint (MACE) comprised death from CAD, nonfatal myocardial infarction, ischemic stroke, or unstable angina requiring hospitalization. A genome-wide PRS for CAD comprising 6,579,025 genetic variants was evaluated in 11,953 patients with available DNA samples. Analysis of MACE risk was performed in placebo treated patients while treatment benefit analysis was performed in all patients. Results: The incidence of MACE in the placebo group was related to PRS for CAD: 17.0% for high PRS patients (>90th percentile) and 11.4% for lower PRS patients (≤90th percentile) (p<0.001); this PRS relationship was not explained by baseline LDL-C or other established risk factors. Both the absolute and relative reduction of MACE by alirocumab compared to placebo was greater in high versus low PRS patients. There was an absolute reduction by alirocumab in high versus low PRS groups of 6.0% and 1.5%, respectively, and relative risk reduction by alirocumab of 37% in the high PRS group (hazard ratio [HR] 0.63; 95% confidence interval [CI] 0.46-0.86; p = 0.004) versus 13% reduction in the low PRS group (HR 0.87; 95% CI 0.78-0.98; p=0.022; interaction p = 0.04). Conclusions: A high PRS for CAD is associated with elevated risk for recurrent MACE after ACS, and larger absolute and relative risk reduction with alirocumab treatment, providing an independent tool for risk stratification and precision medicine.
RCT Entities:
Background: Alirocumab, an antibody that blocks proprotein convertase subtilisin/kexin type 9 (PCSK9), was associated with reduced major adverse cardiovascular events (MACE) and death in the ODYSSEY OUTCOMES trial. In this study, higher baseline LDL cholesterol (LDL-C) levels predicted greater benefit from alirocumab treatment. Recent studies indicate high polygenic risk scores (PRS) for coronary artery disease (CAD) identify individuals at higher risk who derive increased benefit from statins. Herein we perform post hoc analyses to determine whether high PRS for CAD identifies higher-risk individuals, independently from baseline LDLC and other known risk factors, who might derive greater benefit from alirocumab treatment. Methods: ODYSSEY OUTCOMES was a randomized, double-blind, placebo-controlled trial comparing alirocumab or placebo in 18,924 patients with acute coronary syndrome and elevated atherogenic lipoproteins despite optimized statin treatment. The primary endpoint (MACE) comprised death from CAD, nonfatal myocardial infarction, ischemic stroke, or unstable angina requiring hospitalization. A genome-wide PRS for CAD comprising 6,579,025 genetic variants was evaluated in 11,953 patients with available DNA samples. Analysis of MACE risk was performed in placebo treated patients while treatment benefit analysis was performed in all patients. Results: The incidence of MACE in the placebo group was related to PRS for CAD: 17.0% for high PRS patients (>90th percentile) and 11.4% for lower PRS patients (≤90th percentile) (p<0.001); this PRS relationship was not explained by baseline LDL-C or other established risk factors. Both the absolute and relative reduction of MACE by alirocumab compared to placebo was greater in high versus low PRS patients. There was an absolute reduction by alirocumab in high versus low PRS groups of 6.0% and 1.5%, respectively, and relative risk reduction by alirocumab of 37% in the high PRS group (hazard ratio [HR] 0.63; 95% confidence interval [CI] 0.46-0.86; p = 0.004) versus 13% reduction in the low PRS group (HR 0.87; 95% CI 0.78-0.98; p=0.022; interaction p = 0.04). Conclusions: A high PRS for CAD is associated with elevated risk for recurrent MACE after ACS, and larger absolute and relative risk reduction with alirocumab treatment, providing an independent tool for risk stratification and precision medicine.
Authors: Minxian Wang; Ramesh Menon; Sanghamitra Mishra; Aniruddh P Patel; Mark Chaffin; Deepak Tanneeru; Manjari Deshmukh; Oshin Mathew; Sanika Apte; Christina S Devanboo; Sumathi Sundaram; Praveena Lakshmipathy; Sakthivel Murugan; Krishna Kumar Sharma; Karthikeyan Rajendran; Sam Santhosh; Rajesh Thachathodiyl; Hisham Ahamed; Aniketh Vijay Balegadde; Thomas Alexander; Krishnan Swaminathan; Rajeev Gupta; Ajit S Mullasari; Alben Sigamani; Muralidhar Kanchi; Andrew S Peterson; Adam S Butterworth; John Danesh; Emanuele Di Angelantonio; Aliya Naheed; Michael Inouye; Rajiv Chowdhury; Ramprasad L Vedam; Sekar Kathiresan; Ravi Gupta; Amit V Khera Journal: J Am Coll Cardiol Date: 2020-08-11 Impact factor: 24.094
Authors: Vincent Plagnol; Peter Donnelly; Fernando Riveros-Mckay; Michael E Weale; Rachel Moore; Saskia Selzam; Eva Krapohl; R Michael Sivley; William A Tarran; Peter Sørensen; Alexander S Lachapelle; Jonathan A Griffiths; Ayden Saffari; John Deanfield; Chris C A Spencer; Julia Hippisley-Cox; David J Hunter; Jack W O'Sullivan; Euan A Ashley Journal: Circ Genom Precis Med Date: 2021-03-02