Original Investigation
Effect of Alirocumab on Lipoprotein(a) and Cardiovascular Risk After Acute Coronary Syndrome

https://doi.org/10.1016/j.jacc.2019.10.057Get rights and content
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Abstract

Background

Lipoprotein(a) concentration is associated with cardiovascular events. Alirocumab, a proprotein convertase subtilisin/kexin type 9 inhibitor, lowers lipoprotein(a) and low-density lipoprotein cholesterol (LDL-C).

Objectives

A pre-specified analysis of the placebo-controlled ODYSSEY Outcomes trial in patients with recent acute coronary syndrome (ACS) determined whether alirocumab-induced changes in lipoprotein(a) and LDL-C independently predicted major adverse cardiovascular events (MACE).

Methods

One to 12 months after ACS, 18,924 patients on high-intensity statin therapy were randomized to alirocumab or placebo and followed for 2.8 years (median). Lipoprotein(a) was measured at randomization and 4 and 12 months thereafter. The primary MACE outcome was coronary heart disease death, nonfatal myocardial infarction, ischemic stroke, or hospitalization for unstable angina.

Results

Baseline lipoprotein(a) levels (median: 21.2 mg/dl; interquartile range [IQR]: 6.7 to 59.6 mg/dl) and LDL-C [corrected for cholesterol content in lipoprotein(a)] predicted MACE. Alirocumab reduced lipoprotein(a) by 5.0 mg/dl (IQR: 0 to 13.5 mg/dl), corrected LDL-C by 51.1 mg/dl (IQR: 33.7 to 67.2 mg/dl), and reduced the risk of MACE (hazard ratio [HR]: 0.85; 95% confidence interval [CI]: 0.78 to 0.93). Alirocumab-induced reductions of lipoprotein(a) and corrected LDL-C independently predicted lower risk of MACE, after adjustment for baseline concentrations of both lipoproteins and demographic and clinical characteristics. A 1-mg/dl reduction in lipoprotein(a) with alirocumab was associated with a HR of 0.994 (95% CI: 0.990 to 0.999; p = 0.0081).

Conclusions

Baseline lipoprotein(a) and corrected LDL-C levels and their reductions by alirocumab predicted the risk of MACE after recent ACS. Lipoprotein(a) lowering by alirocumab is an independent contributor to MACE reduction, which suggests that lipoprotein(a) should be an independent treatment target after ACS. (ODYSSEY Outcomes: Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab; NCT01663402)

Key Words

acute coronary syndromes
alirocumab
low-density lipoprotein cholesterol
major adverse cardiovascular events
proprotein convertase subtilisin/kexin type 9 inhibition

Abbreviations and Acronyms

ACS
acute coronary syndrome
CI
confidence interval
HR
hazard ratio
IQR
interquartile range
LDL-C
low-density lipoprotein cholesterol
MACE
major adverse cardiovascular events
non−HDL-C
non−high-density lipoprotein cholesterol
PCSK9
proprotein convertase subtilisin/kexin type 9

Cited by (0)

The ODYSSEY OUTCOMES trial was funded by Sanofi and Regeneron Pharmaceuticals. Dr. Bittner serves on the Executive Steering Committee of the ODYSSEY OUTCOMES trial (Sanofi), as National Coordinator for STRENGTH (AstraZeneca), DalGene (Dalcor), CLEAR (Esperion), and as site investigator for ORION IV (The Medicines Company), all contracted through the University of Alabama at Birmingham; has previously served as site investigator for ARTEMIS (Astra Zeneca) and COMPASS (Bayer Healthcare), both contracted through the University of Alabama at Birmingham; and has consulted for Sanofi. Dr. Szarek has served as a consultant or on Advisory Boards (or both) for CiVi, Resverlogix, Baxter, Esperion, and Regeneron Pharmaceuticals. Dr. Aylward has received research support, speaker fees, and served on Advisory Boards for Sanofi, Amgen, AstraZeneca, CSL, Bayer, Novartis, and Boehringer Ingelheim. Dr. Bhatt has served on Advisory Board for Cardax, Cereno Scientific, Elsevier Practice Update Cardiology, Medscape Cardiology, PhaseBio, and Regado Biosciences; has served on the Board of Directors for Boston VA Research Institute, Society of Cardiovascular Patient Care, and TobeSoft; has served as Chair for American Heart Association Quality Oversight Committee; has served on Data Monitoring Committees for Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute, for the PORTICO trial, funded by St. Jude Medical, now Abbott), Cleveland Clinic (including for the ExCEED trial, funded by Edwards), Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine (for the ENVISAGE trial, funded by Daiichi-Sankyo), and the Population Health Research Institute; has received honoraria from American College of Cardiology (Senior Associate Editor, Clinical Trials and NewsACC.org; Vice-Chair, ACC Accreditation Committee), Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute; RE-DUAL PCI clinical trial steering committee funded by Boehringer Ingelheim; AEGIS-II executive committee funded by CSL Behring), Belvoir Publications (Editor-in-Chief, Harvard Heart Letter), Duke Clinical Research Institute (clinical trial steering committees, including for the PRONOUNCE trial, funded by Ferring Pharmaceuticals), HMP Global (Editor-in-Chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (Guest Editor; Associate Editor), Medtelligence/ReachMD (CME steering committees), Population Health Research Institute (for the COMPASS operations committee, publications committee, steering committee, and USA national co-leader, funded by Bayer), Slack Publications (Chief Medical Editor, Cardiology Today’s Intervention), Society of Cardiovascular Patient Care (Secretary/Treasurer), and WebMD (CME steering committees); has other relationships with Clinical Cardiology (Deputy Editor), NCDR-ACTION Registry Steering Committee (Chair), and VA CART Research and Publications Committee (Chair); has received research funding from Abbott, Afimmune, Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Chiesi, CSL Behring, Eisai, Ethicon, Ferring Pharmaceuticals, Forest Laboratories, Fractyl, Idorsia, Ironwood, Ischemix, Lilly, Medtronic, PhaseBio, Pfizer, PLx Pharma, Regeneron, Roche, Sanofi, Synaptic, and The Medicines Company; has received royalties from Elsevier (Editor, Cardiovascular Intervention: A Companion to Braunwald’s Heart Disease); has served as site co-investigator for Biotronik, Boston Scientific, CSI, St. Jude Medical (now Abbott), and Svelte; has served as a trustee for American College of Cardiology; and has performed unfunded research for FlowCo, Merck, Novo Nordisk, and Takeda. Dr Diaz has received research grants from Sanofi, DalCor Pharmaceuticals, Population Health Research Institute, Duke Clinical Research Institute, the TIMI group, Amgen, Cirius, Montreal Health Innovations Coordinating Center, and Lepetit; and has received personal fees, as a member of the Executive Steering Committee, from Amgen and Cirius. Dr. Edelberg was an employee of Sanofi during the conduct of the study and is now an employee of Myokardia. Dr. Fras serves as National Coordinator for the ODYSSEY OUTCOMES Trial (Sanofi); and has received research support and speaker/consulting fees from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Krka, Novo Nordisk, Pfizer, and Sanofi. Dr. Goodman has received research grant support (e.g., steering committee or data monitoring committee) and/or speaker/consulting honoraria (e.g., advisory boards) from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, CSL Behring, Daiichi-Sankyo/American Regent, Eli Lilly, Esperion, Ferring Pharmaceuticals, GlaxoSmithKline, HLS Therapeutics, Janssen/Johnson & Johnson, Merck, Novartis, Novo Nordisk A/C, Pfizer, Regeneron, Sanofi, and Servier; and has received salary support from the Heart and Stroke Foundation of Ontario/University of Toronto (Polo) Chair, Canadian Heart Research Centre and MD Primer, Canadian VIGOUR Centre, Duke Clinical Research Institute, New York University Clinical Coordinating Centre, and PERFUSE. Dr. Halvorsen has received consultant fees and speaking honoraria from AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Merck, Novartis, Pfizer, and Sanofi. Dr. Hanotin is an employee of Sanofi. Dr. Harrington has received research grants from Apple, CSL, Sanofi, AstraZeneca, Portola, Janssen, Bristol-Myers Squibb, Novartis, and The Medicines Company; has served as a consultant or on the Advisory Board for Amgen, Bayer, Gilead, MyoKardia, and WebMD; and is on the Board of Directors (unpaid) for AHA and Stanford HealthCare. Dr. Jukema has received research grants from the Netherlands Heart Foundation, the Interuniversity Cardiology Institute of the Netherlands, and the European Commission Seventh Framework Programme; and has received research support from Amgen, Astellas, AstraZeneca, Daiichi-Sankyo, Lilly, Merck-Schering-Plough, Pfizer, Roche, and Sanofi. Ms. Loizeau is an employee of and holds shares in Sanofi. Dr. Moriarty has received research grants from and/or has consulted for Regeneron, Sanofi, Amgen, Esperion, Kaneka, Gemphire, Ionis, Novartis, Stage II Innovations, Kowa, Akcea, Pfizer, FH Foundation, University of Penn, and Aegerion; and is a speaker for Regeneron, Sanofi, Amgen, and Amarin. Dr. Moryusef is an employee of Sanofi. Dr. Pordy is an employee of Regeneron Pharmaceuticals. Dr. Roe has received research grant funding from Sanofi, AstraZeneca, Patient Centered Outcomes Research Institute, Ferring Pharmaceuticals, Myokardia, Familial Hypercholesterolemia Foundation, and Bayer; and has received consulting fees or honoraria from AstraZeneca, Amgen, Cytokinetics, Eli Lilly, Roche-Genentech, Janssen Pharmaceuticals, Regeneron, Novo Nordisk, Pfizer, Sanofi, Signal Path, and Elsevier Publishers. Dr. Sinnaeve has received personal fees from Sanofi, Abbott, Boehringer Ingelheim, Bristol-Myers Squibb, Pfizer, and Amgen; has received personal fees and nonfinancial support from AstraZeneca and Merck Sharp Dohme; and has received grants and personal fees from Daiichi-Sankyo and Bayer. Dr. Tsimikas has served as a consultant to Boston Heart Diagnostics; is a co-inventor and receives royalties from patents owned by UCSD on oxidation-specific antibodies and of biomarkers related to oxidized lipoproteins; has a dual appointment at UCSD and Ionis Pharmaceuticals; and is a co-founder of and has an equity interest in Oxitope, Inc. and Kleanthi Diagnostics, LLC; (Although these relationships have been identified for conflict of interest management based on the overall scope of the project and its potential benefit to Oxitope and Kleanthi Diagnostics LLC, the research findings included in this particular publication may not necessarily relate to the interests of Oxitope, Inc. and Kleanthi Diagnostics, LLC. The terms of this arrangement have been reviewed and approved by the University of California, San Diego in accordance with its conflict of interest policies.). Dr. Vogel has received grants and personal fees from Sanofi. Dr. White has received grant support paid to the institution and fees for serving on a steering committee for the ODYSSEY OUTCOMES trial (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) from Sanofi and Regeneron Pharmaceuticals, for the ACCELERATE study (A Study of Evacetrapib in High-Risk Vascular Disease) from Eli Lilly, for the STRENGTH trial (Outcomes Study to Assess Statin Residual Risk Reduction With EpaNova in High CV Risk Patients With Hypertriglyceridemia) from Omthera Pharmaceuticals, for the SPIRE trial (The Evaluation of Bococizumab [PF-04950615; RN 316] in Reducing the Occurrence of Major Cardiovascular Events in High Risk Subjects) from Pfizer USA, for the HEART-FID study (Randomized Placebo-Controlled Trial of FCM as Treatment for Heart Failure With Iron Deficiency) from American Regent, for the CAMELLIA-TIMI study (A Study to Evaluate the Effect of Long-term Treatment With BELVIQ [Lorcaserin HC] on the Incidence of Major Adverse Cardiovascular Events and Conversion to Type 2 Diabetes Mellitus in Obese and Overweight Subjects With Cardiovascular Disease or Multiple Cardiovascular Risk Factors) from Eisai Inc, for the dal-GenE study (Effect of Dalcetrapib vs Placebo on CV Risk in a Genetically Defined Population With a Recent ACS) from DalCor Pharma UK Inc., for the AEGIS-II study from CSL Behring, for the SCORED trial (Effect of Sotagliflozin on Cardiovascular and Renal Events in Patients With Type 2 Diabetes and Moderate Renal Impairment Who Are at Cardiovascular Risk) and the SOLOIST-WHF trial (Effect of Sotagliflozin on Cardiovascular Events in Patients With Type 2 Diabetes Post Worsening Heart Failure) from Sanofi-Aventis Australia Pty. Ltd., and for the CLEAR Outcomes Study (Evaluation of Major Cardiovascular Events in Patients With, or at High Risk for, Cardiovascular Disease Who Are Statin Intolerant Treated With Bempedoic Acid [ETC-1002] or Placebo) from Esperion Therapeutics Inc.; has served on the Advisory Board for Acetelion, Sirtex, and Genentech, Inc. (an affiliate of F. Hoffmann-La Roche Ltd., “Roche”; Lytics Post-PCI Advisory Board at European Society of Cardiology); and has received lecture fees from AstraZeneca. Dr. Zahger serves as National Coordinator for the ODYSSEY OUTCOMES trial and the SCORED trial, both funded by Sanofi; and has consulted for Bayer, AstraZeneca, Boehringer Ingelheim, NovoNordisk, and Sanofi. Dr. Zeiher has received fees for serving on a steering committee for the ODYSSEY OUTCOMES trial from Sanofi; and has received Advisory Board and speaker fees from Sanofi, Amgen, Boehringer Ingelheim, Bayer, Novartis, Pfizer, AstraZeneca, and Vifor. Dr. Baccara-Dinet is an employee of and holds shares in Sanofi. Dr. Steg has received grants and nonfinancial support (co-chair of the ODYSSEY OUTCOMES trial; as such he received no personal fees, but his institution has received funding for the time he has devoted to trial coordination, and he has received support for some travel related to trial meetings) from Sanofi; has received research grants and personal fees from Bayer (Steering Committee MARINER, grant for epidemiological study), Merck (speaker fees, grant for epidemiological studies), Sanofi (co-chair of the ODYSSEY OUTCOMES trial; cochair of the SCORED trial; consulting, speaking), Servier (Chair of the CLARIFY registry; grant for epidemiological research), and Amarin (executive steering committee the REDUCE-IT trial [Disease Reduction of Cardiovascular Events With Icosapent Ethyl–Intervention Trial]; consulting); has received personal fees from Amgen, Bristol-Myers Squibb, Boehringer Ingelheim, Pfizer, Novartis, Regeneron Pharmaceuticals, Lilly, and AstraZeneca; and has a European application number/patent number, issued on October 26, 2016 (No. 15712241.7), for a method for reducing cardiovascular risk. Dr. Schwartz has received research grants to the University of Colorado from Resverlogix, Roche, Sanofi, and The Medicines Company; and is co-inventor of pending U.S. patent 62/806313 “Methods for Reducing Cardiovascular Risk,” assigned in full to University of Colorado. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

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