title: Reductions in Atherogenic Lipids and Major Cardiovascular Events: A Pooled Analysis of 10 ODYSSEY Trials Comparing Alirocumab With Control.
abstract: BACKGROUND
  A continuous relationship between reductions in low-density lipoprotein cholesterol (LDL-C) and major adverse cardiovascular events (MACE) has been observed in statin and ezetimibe outcomes trials down to achieved levels of 54 mg/dL. However, it is uncertain whether this relationship extends to LDL-C levels <50 mg/dL. We assessed the relationship between additional LDL-C, non-high-density lipoprotein cholesterol, and apolipoprotein B100 reductions and MACE among patients within the ODYSSEY trials that compared alirocumab with controls (placebo/ezetimibe), mainly as add-on therapy to maximally tolerated statin.
  
  
  METHODS
  Data were pooled from 10 double-blind trials (6699 patient-years of follow-up). Randomization was to alirocumab 75/150 mg every 2 weeks or control for 24 to 104 weeks, added to background statin therapy in 8 trials. This analysis included 4974 patients (3182 taking alirocumab, 1174 taking placebo, 618 taking ezetimibe). In a post hoc analysis, the relationship between average on-treatment lipid levels and percent reductions in lipids from baseline were correlated with MACE (coronary heart disease death, nonfatal myocardial infarction, ischemic stroke, or unstable angina requiring hospitalization) in multivariable analyses.
  
  
  RESULTS
  Overall, 33.1% of the pooled cohort achieved average LDL-C <50 mg/dL (44.7%-52.6% allocated to alirocumab, 6.5% allocated to ezetimibe, and 0% allocated to placebo). In total, 104 patients experienced MACE (median time to event, 36 weeks). For every 39 mg/dL lower achieved LDL-C, the risk of MACE appeared to be 24% lower (adjusted hazard ratio, 0.76; 95% confidence interval, 0.63-0.91; P=0.0025). Percent reductions in LDL-C from baseline were inversely correlated with MACE rates (hazard ratio, 0.71; 95% confidence interval, 0.57-0.89 per additional 50% reduction from baseline; P=0.003). Strengths of association materially similar to those described for LDL-C were observed with achieved non-high-density lipoprotein cholesterol and apolipoprotein B100 levels or percentage reductions.
  
  
  CONCLUSIONS
  In a post hoc analysis from 10 ODYSSEY trials, greater percentage reductions in LDL-C and lower on-treatment LDL-C were associated with a lower incidence of MACE, including very low levels of LDL-C (<50 mg/dL). These findings require further validation in the ongoing prospective ODYSSEY OUTCOMES trial.
  
  
  BACKGROUND
  URL: https://www.clinicaltrials.gov. Unique identifiers: NCT01507831, NCT01623115, NCT01709500, NCT01617655, NCT01644175, NCT01644188, NCT01644474, NCT01730040, NCT01730053, and NCT01709513.
authors: From Imperial Centre for Cardiovascular Disease Prevention, Department of Primary Care and Public Health, Imperial College, London, UK (K.K.R.); Columbia University, New York, NY (H.N.G.); Department of Medicine, University of Chicago Medicine, Chicago, IL (M.H.D.); Regeneron Pharmaceuticals, Inc Tarrytown, NY (R.P.); Sanofi, Paris, France (L.B.); Biostatistics and Programming, Sanofi, Chilly-Mazarin, France (P.M.); University of Colorado, Anschutz Medical Campus, Aurora (R.H.E.); and Harvard Clinical Research Institute, Boston, MA (C.P.C.). k.ray@imperial.ac.uk.
authors: Kausik K
authors: KK
authors: Ray
authors: From Imperial Centre for Cardiovascular Disease Prevention, Department of Primary Care and Public Health, Imperial College, London, UK (K.K.R.); Columbia University, New York, NY (H.N.G.); Department of Medicine, University of Chicago Medicine, Chicago, IL (M.H.D.); Regeneron Pharmaceuticals, Inc Tarrytown, NY (R.P.); Sanofi, Paris, France (L.B.); Biostatistics and Programming, Sanofi, Chilly-Mazarin, France (P.M.); University of Colorado, Anschutz Medical Campus, Aurora (R.H.E.); and Harvard Clinical Research Institute, Boston, MA (C.P.C.).
authors: Henry N
authors: HN
authors: Ginsberg
authors: From Imperial Centre for Cardiovascular Disease Prevention, Department of Primary Care and Public Health, Imperial College, London, UK (K.K.R.); Columbia University, New York, NY (H.N.G.); Department of Medicine, University of Chicago Medicine, Chicago, IL (M.H.D.); Regeneron Pharmaceuticals, Inc Tarrytown, NY (R.P.); Sanofi, Paris, France (L.B.); Biostatistics and Programming, Sanofi, Chilly-Mazarin, France (P.M.); University of Colorado, Anschutz Medical Campus, Aurora (R.H.E.); and Harvard Clinical Research Institute, Boston, MA (C.P.C.).
authors: Michael H
authors: MH
authors: Davidson
authors: From Imperial Centre for Cardiovascular Disease Prevention, Department of Primary Care and Public Health, Imperial College, London, UK (K.K.R.); Columbia University, New York, NY (H.N.G.); Department of Medicine, University of Chicago Medicine, Chicago, IL (M.H.D.); Regeneron Pharmaceuticals, Inc Tarrytown, NY (R.P.); Sanofi, Paris, France (L.B.); Biostatistics and Programming, Sanofi, Chilly-Mazarin, France (P.M.); University of Colorado, Anschutz Medical Campus, Aurora (R.H.E.); and Harvard Clinical Research Institute, Boston, MA (C.P.C.).
authors: Robert
authors: R
authors: Pordy
authors: From Imperial Centre for Cardiovascular Disease Prevention, Department of Primary Care and Public Health, Imperial College, London, UK (K.K.R.); Columbia University, New York, NY (H.N.G.); Department of Medicine, University of Chicago Medicine, Chicago, IL (M.H.D.); Regeneron Pharmaceuticals, Inc Tarrytown, NY (R.P.); Sanofi, Paris, France (L.B.); Biostatistics and Programming, Sanofi, Chilly-Mazarin, France (P.M.); University of Colorado, Anschutz Medical Campus, Aurora (R.H.E.); and Harvard Clinical Research Institute, Boston, MA (C.P.C.).
authors: Laurence
authors: L
authors: Bessac
authors: From Imperial Centre for Cardiovascular Disease Prevention, Department of Primary Care and Public Health, Imperial College, London, UK (K.K.R.); Columbia University, New York, NY (H.N.G.); Department of Medicine, University of Chicago Medicine, Chicago, IL (M.H.D.); Regeneron Pharmaceuticals, Inc Tarrytown, NY (R.P.); Sanofi, Paris, France (L.B.); Biostatistics and Programming, Sanofi, Chilly-Mazarin, France (P.M.); University of Colorado, Anschutz Medical Campus, Aurora (R.H.E.); and Harvard Clinical Research Institute, Boston, MA (C.P.C.).
authors: Pascal
authors: P
authors: Minini
authors: From Imperial Centre for Cardiovascular Disease Prevention, Department of Primary Care and Public Health, Imperial College, London, UK (K.K.R.); Columbia University, New York, NY (H.N.G.); Department of Medicine, University of Chicago Medicine, Chicago, IL (M.H.D.); Regeneron Pharmaceuticals, Inc Tarrytown, NY (R.P.); Sanofi, Paris, France (L.B.); Biostatistics and Programming, Sanofi, Chilly-Mazarin, France (P.M.); University of Colorado, Anschutz Medical Campus, Aurora (R.H.E.); and Harvard Clinical Research Institute, Boston, MA (C.P.C.).
authors: Robert H
authors: RH
authors: Eckel
authors: From Imperial Centre for Cardiovascular Disease Prevention, Department of Primary Care and Public Health, Imperial College, London, UK (K.K.R.); Columbia University, New York, NY (H.N.G.); Department of Medicine, University of Chicago Medicine, Chicago, IL (M.H.D.); Regeneron Pharmaceuticals, Inc Tarrytown, NY (R.P.); Sanofi, Paris, France (L.B.); Biostatistics and Programming, Sanofi, Chilly-Mazarin, France (P.M.); University of Colorado, Anschutz Medical Campus, Aurora (R.H.E.); and Harvard Clinical Research Institute, Boston, MA (C.P.C.).
authors: Christopher P
authors: CP
authors: Cannon
mesh_terms: D000368:Aged; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000924:Anticholesteremic Agents / Q000627:therapeutic use*; D053299:Apolipoprotein B-100 / Q000097:blood; D015992:Body Mass Index; D002318:Cardiovascular Diseases / Q000188:drug therapy* / Q000517:prevention & control*; D008078:Cholesterol, LDL / Q000097:blood; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D000069438:Ezetimibe / Q000627:therapeutic use; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008055:Lipids / Q000097:blood; D008297:Male; D008875:Middle Aged; D015990:Placebo Effect; D011446:Prospective Studies; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000924:Anticholesteremic Agents; D053299:Apolipoprotein B-100; D008078:Cholesterol, LDL; D008055:Lipids; D000069438:Ezetimibe; C571059:alirocumab
keywords: apolipoproteins; cardiovascular diseases; cholesterol, LDL; risk