title: Efficacy and safety of alirocumab vs ezetimibe in statin-intolerant patients, with a statin rechallenge arm: The ODYSSEY ALTERNATIVE randomized trial.
abstract: BACKGROUND
  Statin intolerance limits many patients from achieving optimal low-density lipoprotein cholesterol (LDL-C) concentrations. Current options for such patients include using a lower but tolerated dose of a statin and adding or switching to ezetimibe or other non-statin therapies.
  
  
  METHODS
  ODYSSEY ALTERNATIVE (NCT01709513) compared alirocumab with ezetimibe in patients at moderate to high cardiovascular risk with statin intolerance (unable to tolerate ≥2 statins, including one at the lowest approved starting dose) due to muscle symptoms. A placebo run-in and statin rechallenge arm were included in an attempt to confirm intolerance. Patients (n = 361) received single-blind subcutaneous (SC) and oral placebo for 4 weeks during placebo run-in. Patients reporting muscle-related symptoms during the run-in were to be withdrawn. Continuing patients were randomized (2:2:1) to double-blind alirocumab 75 mg SC every 2 weeks (Q2W; plus oral placebo), ezetimibe 10 mg/d (plus SC placebo Q2W), or atorvastatin 20 mg/d (rechallenge; plus SC placebo Q2W) for 24 weeks. Alirocumab dose was increased to 150 mg Q2W at week 12 depending on week 8 LDL-C values. Primary end point was percent change in LDL-C from baseline to week 24 (intent-to-treat) for alirocumab vs ezetimibe.
  
  
  RESULTS
  Baseline mean (standard deviation) LDL-C was 191.3 (69.3) mg/dL (5.0 [1.8] mmol/L). Alirocumab reduced mean (standard error) LDL-C by 45.0% (2.2%) vs 14.6% (2.2%) with ezetimibe (mean difference 30.4% [3.1%], P < .0001). Skeletal muscle-related events were less frequent with alirocumab vs atorvastatin (hazard ratio 0.61, 95% confidence interval 0.38-0.99, P = .042).
  
  
  CONCLUSIONS
  Alirocumab produced greater LDL-C reductions than ezetimibe in statin-intolerant patients, with fewer skeletal-muscle adverse events vs atorvastatin.
authors.affiliation: Division of Clinical Pharmacology, Department of Internal Medicine, University of Kansas Medical Center, Kansas City, KS, USA. Electronic address: pmoriart@kumc.edu.
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Moriarty
authors.affiliation: Hartford Hospital, Hartford, CT, USA.
authors.forename: Paul D
authors.initials: PD
authors.lastname: Thompson
authors.affiliation: Harvard Clinical Research Institute, Boston, MA, USA; Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, MA, USA.
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Cannon
authors.affiliation: Duke University Medical Center, Durham, NC, USA.
authors.forename: John R
authors.initials: JR
authors.lastname: Guyton
authors.affiliation: Lipid Clinic, Centre Hospitalier Universitaire de Québec, Laval University, Québec, Canada.
authors.forename: Jean
authors.initials: J
authors.lastname: Bergeron
authors.affiliation: McGuire VA Medical Center, Richmond, VA, USA.
authors.forename: Franklin J
authors.initials: FJ
authors.lastname: Zieve
authors.affiliation: Groupe Hospitalier Pitié-Salpêtrière (Assistance Publique-Hôpitaux de Paris), Paris, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Bruckert
authors.affiliation: Department of Medicine, Emory University, Atlanta, GA, USA.
authors.forename: Terry A
authors.initials: TA
authors.lastname: Jacobson
authors.affiliation: Mayo Clinic, Department of Cardiovascular Diseases, Rochester, MN, USA.
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Kopecky
authors.affiliation: PCSK9 Development and Launch Unit, Sanofi, Montpellier, France.
authors.forename: Marie T
authors.initials: MT
authors.lastname: Baccara-Dinet
authors.affiliation: Department of Biostatistics, Regeneron Pharmaceuticals, Inc., Tarrytown, NY, USA.
authors.forename: Yunling
authors.initials: Y
authors.lastname: Du
authors.affiliation: Department of Clinical Sciences, Cardiovascular & Metabolism Therapeutics, Regeneron Pharmaceuticals, Inc., Tarrytown, NY, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Pordy
authors.affiliation: Department of Clinical Sciences, Cardiovascular & Metabolism Therapeutics, Regeneron Pharmaceuticals, Inc., Tarrytown, NY, USA.
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Gipe
mesh_terms: D001384:Azetidines / Q000009:adverse effects* / Q000627:therapeutic use*; D004311:Double-Blind Method; D000069438:Ezetimibe / Q000009:adverse effects* / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000009:adverse effects* / Q000627:therapeutic use; D006937:Hypercholesterolemia / Q000188:drug therapy; D008297:Male; D008875:Middle Aged; D012449:Safety
chemical_list: D001384:Azetidines; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D000069438:Ezetimibe
keywords: Clinical trials; Lipid-lowering drugs; Lipoproteins; Monoclonal antibodies; PCSK9