title: Effect of alirocumab, a monoclonal antibody to PCSK9, on long-term cardiovascular outcomes following acute coronary syndromes: rationale and design of the ODYSSEY outcomes trial.
abstract: BACKGROUND
  Following acute coronary syndrome (ACS), the risk for future cardiovascular events is high and is related to levels of low-density lipoprotein cholesterol (LDL-C) even within the setting of intensive statin treatment. Proprotein convertase subtilisin/kexin type 9 (PCSK9) regulates LDL receptor expression and circulating levels of LDL-C. Antibodies to PCSK9 can produce substantial and sustained reductions of LDL-C. The ODYSSEY Outcomes trial tests the hypothesis that treatment with alirocumab, a fully human monoclonal antibody to PCSK9, improves cardiovascular outcomes after ACS.
  
  
  METHODS
  This Phase 3 study will randomize approximately 18,000 patients to receive biweekly injections of alirocumab (75-150 mg) or matching placebo beginning 1 to 12 months after an index hospitalization for acute myocardial infarction or unstable angina. Qualifying patients are treated with atorvastatin 40 or 80 mg daily, rosuvastatin 20 or 40 mg daily, or the maximum tolerated and approved dose of one of these agents and fulfill one of the following criteria: LDL-C ≥ 70 mg/dL, non-high-density lipoprotein cholesterol ≥ 100 mg/dL, or apolipoprotein B ≥ 80 mg/dL. The primary efficacy measure is time to first occurrence of coronary heart disease death, acute myocardial infarction, hospitalization for unstable angina, or ischemic stroke. The trial is expected to continue until 1613 primary end point events have occurred with minimum follow-up of at least 2 years, providing 90% power to detect a 15% hazard reduction. Adverse events of special interest include allergic events and injection site reactions. Interim analyses are planned when approximately 50% and 75% of the targeted number of primary end points have occurred.
  
  
  CONCLUSIONS
  ODYSSEY Outcomes will determine whether the addition of the PCSK9 antibody alirocumab to intensive statin therapy reduces cardiovascular morbidity and mortality after ACS.
authors.affiliation: University of Colorado School of Medicine, Denver, CO. Electronic address: Gregory.Schwartz@va.gov.
authors.forename: Gregory G
authors.initials: GG
authors.lastname: Schwartz
authors.affiliation: Sanofi-Aventis Recherche et Développement S.A., Paris, France; Sanofi-Aventis Recherche et Développement S.A., Bridgewater, NJ.
authors.forename: Laurence
authors.initials: L
authors.lastname: Bessac
authors.affiliation: Duke Clinical Research Institute, Durham, NC.
authors.forename: Lisa G
authors.initials: LG
authors.lastname: Berdan
authors.affiliation: Brigham and Women's Hospital and Harvard Medical School, Boston, MA.
authors.forename: Deepak L
authors.initials: DL
authors.lastname: Bhatt
authors.affiliation: University of Alabama at Birmingham, Birmingham, AL.
authors.forename: Vera
authors.initials: V
authors.lastname: Bittner
authors.affiliation: Estudios Cardiológicos Latinoamérica, Rosario, Argentina.
authors.forename: Rafael
authors.initials: R
authors.lastname: Diaz
authors.affiliation: Canadian VIGOUR Centre, University of Alberta, Toronto, Canada.
authors.forename: Shaun G
authors.initials: SG
authors.lastname: Goodman
authors.affiliation: Sanofi-Aventis Recherche et Développement S.A., Paris, France; Sanofi-Aventis Recherche et Développement S.A., Bridgewater, NJ.
authors.forename: Corinne
authors.initials: C
authors.lastname: Hanotin
authors.affiliation: Stanford University, Stanford, CA.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Harrington
authors.affiliation: Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: J Wouter
authors.initials: JW
authors.lastname: Jukema
authors.affiliation: Stanford University, Stanford, CA.
authors.forename: Kenneth W
authors.initials: KW
authors.lastname: Mahaffey
authors.affiliation: Sanofi-Aventis Recherche et Développement S.A., Paris, France; Sanofi-Aventis Recherche et Développement S.A., Bridgewater, NJ.
authors.forename: Angèle
authors.initials: A
authors.lastname: Moryusef
authors.affiliation: Regeneron Therapeutics, Tarrytown, NY.
authors.forename: Robert
authors.initials: R
authors.lastname: Pordy
authors.affiliation: Duke Clinical Research Institute, Durham, NC.
authors.forename: Matthew T
authors.initials: MT
authors.lastname: Roe
authors.affiliation: Duke Clinical Research Institute, Durham, NC.
authors.forename: Tyrus
authors.initials: T
authors.lastname: Rorick
authors.affiliation: Regeneron Therapeutics, Tarrytown, NY.
authors.forename: William J
authors.initials: WJ
authors.lastname: Sasiela
authors.affiliation: Covance, Inc.,Maidenhead, and Oxford University Hospitals NHS Trust, Oxford, United Kingdom.
authors.forename: Cheerag
authors.initials: C
authors.lastname: Shirodaria
authors.affiliation: State University of New York Downstate Medical Center, Brooklyn, NY.
authors.forename: Michael
authors.initials: M
authors.lastname: Szarek
authors.affiliation: Sanofi-Aventis Recherche et Développement S.A., Paris, France; Sanofi-Aventis Recherche et Développement S.A., Bridgewater, NJ.
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Tamby
authors.affiliation: Duke Clinical Research Institute, Durham, NC.
authors.forename: Pierluigi
authors.initials: P
authors.lastname: Tricoci
authors.affiliation: Auckland City Hospital and University of Auckland, Auckland, New Zealand.
authors.forename: Harvey
authors.initials: H
authors.lastname: White
authors.affiliation: Johann Wolfgang Goethe University, Frankfurt, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Zeiher
authors.affiliation: Assistance Publique-Hôpitaux de Paris, INSERM U-1148, Université Paris Diderot, Paris, France.
authors.forename: Philippe Gabriel
authors.initials: PG
authors.lastname: Steg
mesh_terms: D054058:Acute Coronary Syndrome / Q000150:complications / Q000188:drug therapy*; D000789:Angina, Unstable / Q000517:prevention & control*; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000924:Anticholesteremic Agents / Q000627:therapeutic use*; D001055:Apolipoproteins B / Q000097:blood; D000069059:Atorvastatin; D008078:Cholesterol, LDL / Q000097:blood; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005464:Fluorobenzenes / Q000627:therapeutic use; D006538:Heptanoic Acids / Q000627:therapeutic use; D006760:Hospitalization; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use*; D006937:Hypercholesterolemia / Q000150:complications / Q000188:drug therapy*; D009203:Myocardial Infarction / Q000517:prevention & control*; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases / Q000037:antagonists & inhibitors*; D011743:Pyrimidines / Q000627:therapeutic use; D011758:Pyrroles / Q000627:therapeutic use; D000068718:Rosuvastatin Calcium; D012697:Serine Endopeptidases; D020521:Stroke / Q000517:prevention & control*; D013449:Sulfonamides / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000924:Anticholesteremic Agents; D001055:Apolipoproteins B; D008078:Cholesterol, LDL; D005464:Fluorobenzenes; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011743:Pyrimidines; D011758:Pyrroles; D013449:Sulfonamides; D000068718:Rosuvastatin Calcium; D000069059:Atorvastatin; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases; C571059:alirocumab