Author + information
- Shaun G. Goodman, MD, MSc∗ (, )
- Philippe Gabriel Steg, MD@gabrielsteg,
- Michael Szarek, PhD,
- Deepak L. Bhatt, MD, MPH,
- Vera A. Bittner, MD, MSPH,
- Rafael Diaz, MD,
- Robert A. Harrington, MD,
- J. Wouter Jukema, MD, PhD,
- Harvey D. White, DSc,
- Andreas M. Zeiher, MD,
- Gregory G. Schwartz, MD, PhD,
- for the ODYSSEY OUTCOMES Investigators†
- ↵∗Division of Cardiology, St Michael’s Hospital, 30 Bond Street, Room 6-034, Toronto, Ontario M5B 1W8, Canada
In the ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) trial, 18,924 patients with a recent acute coronary syndrome (ACS) not at lipid goals despite maximally tolerated statin therapy were randomized to alirocumab or placebo (1). Alirocumab produced a marked reduction of low-density lipoprotein cholesterol (LDL-C) levels and significantly reduced the primary composite cardiovascular endpoint (1).
On an intention-to-treat basis, LDL-C levels among alirocumab-assigned patients increased over time (Figure 1A) (1). Factors contributing to the rise in LDL-C among alirocumab-treated patients included 1 or more of the following: study treatment discontinuation (14.2%), protocol-specified blinded substitution of placebo to avoid sustained LDL-C <15 mg/dl (7.7%), background statin dose reduction (16.7%), or decreased adherence to statin or study treatment. A remaining question is whether rising LDL-C levels over time in alirocumab-assigned patients could also reflect time-dependent “attenuation” of the lipid-lowering efficacy of alirocumab (2).
We addressed this question in ODYSSEY OUTCOMES (using a similar approach as in the FOURIER (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk) trial of evolocumab ) by examining LDL-C levels in a subset of the trial cohort with sustained and consistent lipid-lowering therapy. To do so, we excluded patients with 1 or more of the following characteristics: follow-up <3 years (58.3% of the study cohort), at least 1 missing protocol-specified LDL-C measurement through 3 years (18.7%), a change in prescribed background statin treatment (7.1%), discontinuation of study treatment prior to 3 years (5.6%), or protocol-specified blinded substitution of placebo for alirocumab prior to 3 years (3.5% of the alirocumab group). The remaining subset of the trial population thus defined (n = 1,879 placebo, n = 1,672 alirocumab) demonstrated a consistent and sustained reduction in median LDL-C levels with alirocumab, from month 1 (first post-randomization evaluation; absolute 47 mg/dl and relative 53% reductions vs. placebo), through month 36 (absolute 55 mg/dl and relative 62% reductions vs. placebo) and through 3 years (Figure 1B).
Maintenance of LDL-C lowering with alirocumab observed in this subset of ODYSSEY OUTCOMES is similar to previous studies of shorter duration (4). Assessment of previous ODYSSEY trials suggested that 99% (n = 3,120) of patients had ≥15% LDL-C lowering with alirocumab and, among the <1% with apparent “hypo-responsiveness,” the majority had undetectable or missing alirocumab levels, absence of pharmacokinetic analyses, or early treatment discontinuation (5). In ODYSSEY OUTCOMES, “neutralizing” antidrug antibodies were detected infrequently (0.5% alirocumab, <0.1% in the placebo group) (1); the current sustained treatment analysis included LDL-C measurements in patients who had positive titers for antialirocumab antibodies. Previous data indicate that the presence of these antibodies rarely accounts for attenuation of LDL-C lowering (5); therefore, neutralizing antibodies would be expected to have minimal impact on the LDL-C levels, as observed in ODYSSEY OUTCOMES. None of the ODYSSEY trials collected data to assess adherence to prescribed background lipid-lowering therapy. If such adherence decreased over time in the ODYSSEY OUTCOMES trial—as would be expected in a population in whom two-thirds of patients were recently initiated with statin therapy at the time of the index ACS—it might explain the slight upward drift in LDL-C in the placebo group and in the continuous treatment subset of the alirocumab group in Figure 1A. The subgroup of patients analyzed represents only 18.8% of the trial population; thus, the generalizability to the broader cohort may be limited.
In conclusion, we observed sustained LDL-C lowering without apparent attenuation over 3 years in ODYSSEY OUTCOMES participants who had all LDL-C measurements, did not discontinue alirocumab or have blinded substitution of placebo, and did not change background lipid-lowering therapy. These findings are consistent with previous, shorter-duration trials with alirocumab and indicate no clinically meaningful diminution of its lipid-lowering efficacy over several years.
Please note: †The complete list of the ODYSSEY OUTCOMES Investigators is provided in Szarek M, White HD, Schwartz GG, et al. Alirocumab reduces total nonfatal cardiovascular and fatal events: the ODYSSEY OUTCOMES trial. J Am Coll Cardiol 2019;5;387–96. The trial was funded by Sanofi and Regeneron Pharmaceuticals. Dr. Goodman has received research grants from Daiichi-Sankyo, Luitpold Pharmaceuticals, Merck, Novartis, Servier, Regeneron Pharmaceuticals, Sanofi, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, CSL Behring, Eli Lilly, Esperion, Ferring, Pfizer, Novo Nordisk, and Tenax Therapeutics; has received honoraria from Bristol-Myers Squibb, Eli Lilly, Esperion, Fenix Group International, Ferring Pharmaceuticals, Merck, Novartis, Novo Nordisk, Pfizer, Servier, Regeneron Pharmaceuticals, Sanofi, Amgen, AstraZeneca, Bayer, and Boehringer Ingelheim; and has served as a consultant and/or on the advisory board for AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, HLS Therapeutics, Pfizer, Servier, Tenax Therapeutics, Sanofi, Amgen, and Bayer. Dr. Steg has received research grants from Amarin, Bayer, Merck, Sanofi, and Servier; and has received speaking or consulting fees from Amarin, Amgen, AstraZeneca, Bayer/Janssen, Boehringer Ingelheim, Bristol-Myers Squibb, Lilly, Merck, Novartis, Novo Nordisk, Pfizer, Regeneron Pharmaceuticals, Inc., Sanofi, and Servier. Dr. Szarek has served as a consultant and/or on the advisory board for CiVi, Resverlogix, Baxter, Esperion, and Regeneron Pharmaceuticals; and is co-inventor on the patent (number 15712241.7) to use alirocumab as a “Method for Reducing Cardiovascular Risk” (no royalties or financial benefits received from this patent). Dr. Bhatt has served on Advisory Boards for Cardax, 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 of the American Heart Association Quality Oversight Committee; has served on data monitoring committees for Baim Institute for Clinical Research, 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 the American College of Cardiology, Baim Institute for Clinical Research (RE-DUAL PCI clinical trial steering committee funded by Boehringer Ingelheim), Belvoir Publications, Duke Clinical Research Institute (clinical trial steering committees), HMP Global, Journal of the American College of Cardiology, 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, Society of Cardiovascular Patient Care, and WebMD; has served as Deputy Editor of Clinical Cardiology; has served on the NCDR-ACTION Registry Steering Committee and the VA CART Research and Publications Committee; has received research funding from Abbott, Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Chiesi, Eisai, Ethicon, Forest Laboratories, Idorsia, Ironwood, Ischemix, Lilly, Medtronic, PhaseBio, Pfizer, Regeneron Pharmaceuticals, Roche, Sanofi Aventis, Synaptic, and The Medicines Company; has received royalties from Elsevier; has served as a site co-investigator for Biotronik, Boston Scientific, St. Jude Medical, and Svelte; has served as a trustee for the American College of Cardiology; and has completed unfunded research for FlowCo, Fractyl, Merck, Novo Nordisk, PLx Pharma, and Takeda. Dr. Bittner has received research grants from Amgen, DalCor, Esperion, Sanofi, AstraZeneca, Bayer Healthcare, and The Medicines Company; has received honoraria from the American College of Cardiology, American Heart Association, and National Lipid Association; has served as a consultant and on an advisory board for Sanofi; has served as National Coordinator for trials for AstraZeneca, Esperion, and Dalcor (contracted through UAB), has served as Site PI for ORION 4 for The Medicines Company (contracted through UAB), and has performed Pharmacoepidemiology research for Amgen (contracted through UAB School of Public Health); and is a Senior Guest Editor for Circulation. Dr. Diaz has received research grants from Sanofi, Amgen, Bayer, Dalcor, PHRI, and DCRI; and has received honoraria from 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 and/or on the Advisory Board for Amgen, Bayer, Gilead, MyoKardia, Element Science, and WebMD; and has served on the board of directors (unpaid) for AHA, SignalPath, and Stanford HealthCare. Dr. Jukema has received research grants from the Netherlands Heart Foundation, CardioVascular Research the Netherlands (CVON), the Interuniversity Cardiology Institute of the Netherlands, and the European Community Framework KP7 Program; and has received other research support from Amgen, Astellas, AstraZeneca, Athera, Biotronik, Boston Scientific, Daiichi-Sankyo, Lilly, Medtronic, Merck-Schering-Plough, Pfizer, Roche, Sanofi, and The Medicines Company. Dr. White has received grant support paid to the institution and fees for serving on a steering committee for the ODYSSEY OUTCOMES trial from Sanofi and Regeneron Pharmaceuticals, for the ACCELERATE study from Eli Lilly, for the STRENGTH Trial from Omthera Pharmaceuticals, for the SPIRE Trial from Pfizer USA, for the HEART-FID Study from American Regent, for the CAMELLIA-TIMI Study from Eisai Inc., for the DalGenE Study from DalCor Pharma UK Inc., for the AEGIS-II study from CSL Behring, for the SCORED and SOLOIST-WHF Trials from Sanofi-Aventis Australia Pty Ltd, and for the CLEAROUT Study from Esperion Therapeutics; has received advisory board fees from Sirtex, Actelion, and Lytics Post PCI; has received lecture fees from AstraZeneca; and has received accommodation funding from Sanofi and SAHMRI. Dr. Zeiher has served as a scientific advisor for Sanofi, Amgen, Pfizer, and Boehringer Ingelheim; and has served as a speaker for Boehringer Ingelheim, AstraZeneca, Servier, Bayer, Novartis, and Vifor. Dr. Schwartz is co-inventor of pending U.S. patent 62/806,313 “Method for Reducing Cardiovascular Risk,” assigned in full to the University of Colorado; and has received research grants to University of Colorado from Resverlogix, Sanofi, The Medicines Company, and Roche. The authors thank the patients, study coordinators, and investigators who participated in this trial. Sophie Rushton-Smith, PhD (MedLink Healthcare Communications, London) provided editorial assistance in the preparation of the manuscript (limited to editing for style, referencing, and figure editing) and was funded by Fondation Assistance Publique−Hôpitaux de Paris.
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