title: Long-term Safety and Efficacy of Achieving Very Low Levels of Low-Density Lipoprotein Cholesterol : A Prespecified Analysis of the IMPROVE-IT Trial.
abstract: In the Improved Reduction of Outcomes: Vytorin Efficacy International Trial, intensive low-density lipoprotein cholesterol (LDL-C)-reducing therapy with ezetimibe/simvastatin compared with simvastatin alone was associated with a significant reduction in cardiovascular events in 18 144 patients after acute coronary syndrome. The safety of very low LDL-C levels over the long-term is unknown.
  
  
  
  To assess the safety and clinical efficacy of achieving a very low (<30 mg/dL) level of LDL-C at 1 month using data from the Improved Reduction of Outcomes: Vytorin Efficacy International Trial.
  
  
  
  This prespecified analysis compared outcomes in patients stratified by achieved LDL-C level at 1 month in the Improved Reduction of Outcomes: Vytorin Efficacy International Trial and adjusted for baseline characteristics during 6 years' median follow-up. Patients were enrolled from October 26, 2005, to July 8, 2010, and the data analysis was conducted from December 2014 to February 2017.
  
  
  
  Safety end points included adverse events leading to drug discontinuation; adverse muscle, hepatobiliary, and neurocognitive events; and hemorrhagic stroke, heart failure, cancer, and noncardiovascular death. Efficacy events were as specified in the overall trial.
  
  
  
  Among the 15 281 patients included in the study, 11 645 (76.2%) were men and the median age was 63 years (interquartile range, 56.6-70.7 years). In these patients without an event in the first month, the achieved LDL-C values at 1 month were less than 30 mg/dL, 30 to 49 mg/dL, 50 to 69 mg/dL, and 70 mg/dL or greater in 6.4%, 31%, 36%, and 26% of patients, respectively. Patients with LDL-C values less than 30 mg/dL (median, 25 mg/dL; interquartile range, 21-27 mg/dL) at 1 month were more likely randomized to ezetimibe/simvastatin (85%), had lower baseline LDL-C values, and were more likely older, male, nonwhite, diabetic, overweight, statin naive, and presenting with a first myocardial infarction. After multivariate adjustment, there was no significant association between the achieved LDL-C level and any of the 9 prespecified safety events. The adjusted risk of the primary efficacy composite of cardiovascular death, major coronary events, or stroke was significantly lower in patients achieving an LDL-C level less than 30 mg/dL at 1 month (adjusted hazard ratio, 0.79; 95% CI, 0.69-0.91; P = .001) compared with 70 mg/dL or greater.
  
  
  
  Patients achieving an LDL-C level less than 30 mg/dL at 1 month had a similar safety profile (and numerically the lowest rate of cardiovascular events) over a 6-year period compared with patients achieving higher LDL-C concentrations. These data provide reassurance regarding the longer-term safety and efficacy of the continuation of intensive lipid-lowering therapy in very higher-risk patients resulting in very low LDL-C levels.
  
  
  
  clinicaltrials.gov Identifier: NCT00202878.
authors.affiliation: Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, TIMI Study Group, Boston, Massachusetts.
authors.forename: Robert P
authors.initials: RP
authors.lastname: Giugliano
authors.affiliation: Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, TIMI Study Group, Boston, Massachusetts.
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Wiviott
authors.affiliation: Duke Clinical Research Institute, Durham, North Carolina.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Blazing
authors.affiliation: Policlinico San Matteo, Pavia, Italy.
authors.forename: Gaetano M
authors.initials: GM
authors.lastname: De Ferrari
authors.affiliation: Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, TIMI Study Group, Boston, Massachusetts.
authors.forename: Jeong-Gun
authors.initials: JG
authors.lastname: Park
authors.affiliation: Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, TIMI Study Group, Boston, Massachusetts.
authors.forename: Sabina A
authors.initials: SA
authors.lastname: Murphy
authors.affiliation: Duke Clinical Research Institute, Durham, North Carolina.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: White
authors.affiliation: Merck & Co, Kenilworth, New Jersey.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Tershakovec
authors.affiliation: Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, TIMI Study Group, Boston, Massachusetts.
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Cannon
authors.affiliation: Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, TIMI Study Group, 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 / Q000627:therapeutic use*; D002318:Cardiovascular Diseases / Q000401:mortality*; D008078:Cholesterol, LDL / Q000097:blood*; D004311:Double-Blind Method; D000069499:Ezetimibe, Simvastatin Drug Combination / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D008107:Liver Diseases / Q000453:epidemiology; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009135:Muscular Diseases / Q000453:epidemiology; D009203:Myocardial Infarction / Q000097:blood / Q000188:drug therapy* / Q000453:epidemiology; D009369:Neoplasms / Q000453:epidemiology; D010347:Patient Care Planning; D017410:Practice Guidelines as Topic; D016016:Proportional Hazards Models; D012206:Rhabdomyolysis / Q000453:epidemiology; D020521:Stroke / Q000453:epidemiology*; D016896:Treatment Outcome
chemical_list: D000924:Anticholesteremic Agents; D008078:Cholesterol, LDL; D000069499:Ezetimibe, Simvastatin Drug Combination