title: Reduction in Total Cardiovascular Events With Ezetimibe/Simvastatin Post-Acute Coronary Syndrome: The IMPROVE-IT Trial.
abstract: BACKGROUND
  Intensive low-density lipoprotein cholesterol therapy with ezetimibe/simvastatin in IMPROVE-IT (IMProved Reduction of Outcomes: Vytorin Efficacy International Trial) significantly reduced the first primary endpoint (PEP) in patients post-acute coronary syndrome (ACS) compared to placebo/simvastatin.
  
  
  OBJECTIVE
  This analysis tested the hypothesis that total events, including those beyond the first event, would also be reduced with ezetimibe/simvastatin therapy.
  
  
  METHODS
  All PEP events (cardiovascular [CV] death, myocardial infarction [MI], stroke, unstable angina [UA] leading to hospitalization, coronary revascularization ≥30 days post-randomization) during a median 6-year follow-up were analyzed in patients randomized to receive ezetimibe/simvastatin or placebo/simvastatin in IMPROVE-IT. Negative binomial regression was used for the primary analysis.
  
  
  RESULTS
  Among 18,144 patients, there were 9,545 total PEP events (56% were first events and 44% subsequent events). Total PEP events were significantly reduced by 9% with ezetimibe/simvastatin vs placebo/simvastatin (incidence-rate ratio [RR]: 0.91; 95% confidence interval [CI]: 0.85 to 0.97; p = 0.007), as were the 3 pre-specified secondary composite endpoints and the exploratory composite endpoint of CV death, MI, or stroke (RR: 0.88; 95% CI: 0.81 to 0.96; p = 0.002). The reduction in total events was driven by decreases in total nonfatal MI (RR: 0.87; 95% CI: 0.79 to 0.96; p = 0.004) and total NF stroke (RR: 0.77; 95% CI: 0.65 to 0.93; p = 0.005).
  
  
  CONCLUSIONS
  Lipid-lowering therapy with ezetimibe plus simvastatin improved clinical outcomes. Reductions in total PEP events, driven by reductions in MI and stroke, more than doubled the number of events prevented compared with examining only the first event. These data support continuation of intensive combination lipid-lowering therapy after an initial CV event. (IMProved Reduction of Outcomes: Vytorin Efficacy International Trial [IMPROVE-IT]; NCT00202878).
authors.affiliation: TIMI Study Group, Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts. Electronic address: smurphy15@partners.org.
authors.forename: Sabina A
authors.initials: SA
authors.lastname: Murphy
authors.affiliation: TIMI Study Group, Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Cannon
authors.affiliation: Duke Clinical Research Institute, Durham, North Carolina.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Blazing
authors.affiliation: TIMI Study Group, Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Robert P
authors.initials: RP
authors.lastname: Giugliano
authors.affiliation: Duke Clinical Research Institute, Durham, North Carolina.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: White
authors.affiliation: Duke Clinical Research Institute, Durham, North Carolina.
authors.forename: Yuliya
authors.initials: Y
authors.lastname: Lokhnygina
authors.affiliation: Duke Clinical Research Institute, Durham, North Carolina.
authors.forename: Craig
authors.initials: C
authors.lastname: Reist
authors.affiliation: TIMI Study Group, Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: KyungAh
authors.initials: K
authors.lastname: Im
authors.affiliation: TIMI Study Group, Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Erin A
authors.initials: EA
authors.lastname: Bohula
authors.affiliation: Fundacion Cardioinfantil, Instituto de Cardiología, Bogotá, Cundinamarca, Colombia.
authors.forename: Daniel
authors.initials: D
authors.lastname: Isaza
authors.affiliation: Hospital Universitario La Paz, Cardiology Department, Madrid, Spain.
authors.forename: Jose
authors.initials: J
authors.lastname: Lopez-Sendon
authors.affiliation: Sahlgrenska University Hospital/Ostra and Sahlgrenska Academy, University of Gothenburg, Gotenburg, Sweden.
authors.forename: Mikael
authors.initials: M
authors.lastname: Dellborg
authors.affiliation: Merck and Company, Inc., Kenilworth, New Jersey.
authors.forename: Uma
authors.initials: U
authors.lastname: Kher
authors.affiliation: Merck and Company, Inc., Kenilworth, New Jersey.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Tershakovec
authors.affiliation: TIMI Study Group, Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Eugene
authors.initials: E
authors.lastname: Braunwald
mesh_terms: D054058:Acute Coronary Syndrome / Q000097:blood / Q000188:drug therapy*; D000368:Aged; D000924:Anticholesteremic Agents / Q000008:administration & dosage; D008078:Cholesterol, LDL / Q000097:blood / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D000069438:Ezetimibe / Q000008:administration & dosage*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage; D015994:Incidence; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction / Q000097:blood / Q000453:epidemiology / Q000517:prevention & control*; D019821:Simvastatin / Q000008:administration & dosage*; D015996:Survival Rate / Q000639:trends; D013997:Time Factors; D016896:Treatment Outcome; D014481:United States / Q000453:epidemiology
chemical_list: D000924:Anticholesteremic Agents; D008078:Cholesterol, LDL; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D019821:Simvastatin; D000069438:Ezetimibe
keywords: ezetimibe; low-density lipoprotein cholesterol; simvastatin; total events