title: Effect of darapladib on major coronary events after an acute coronary syndrome: the SOLID-TIMI 52 randomized clinical trial.
abstract: OBJECTIVE
  Lipoprotein-associated phospholipase A2 (Lp-PLA2) has been hypothesized to be involved in atherogenesis through pathways related to inflammation. Darapladib is an oral, selective inhibitor of the Lp-PLA2 enzyme.
  
  
  OBJECTIVE
  To evaluate the efficacy and safety of darapladib in patients after an acute coronary syndrome (ACS) event.
  
  
  METHODS
  SOLID-TIMI 52 was a multinational, double-blind, placebo-controlled trial that randomized 13,026 participants within 30 days of hospitalization with an ACS (non-ST-elevation or ST-elevation myocardial infarction [MI]) at 868 sites in 36 countries.
  
  
  METHODS
  Patients were randomized to either once-daily darapladib (160 mg) or placebo on a background of guideline-recommended therapy. Patients were followed up for a median of 2.5 years between December 7, 2009, and December 6, 2013.
  
  
  METHODS
  The primary end point (major coronary events) was the composite of coronary heart disease (CHD) death, MI, or urgent coronary revascularization for myocardial ischemia. Kaplan-Meier event rates are reported at 3 years.
  
  
  RESULTS
  During a median duration of 2.5 years, the primary end point occurred in 903 patients in the darapladib group and 910 in the placebo group (16.3% vs 15.6% at 3 years; hazard ratio [HR], 1.00 [95% CI, 0.91-1.09]; P = .93). The composite of cardiovascular death, MI, or stroke occurred in 824 in the darapladib group and 838 in the placebo group (15.0% vs 15.0% at 3 years; HR, 0.99 [95% CI, 0.90-1.09]; P = .78). There were no differences between the treatment groups for additional secondary end points, for individual components of the primary end point, or in all-cause mortality (371 events in the darapladib group and 395 in the placebo group [7.3% vs 7.1% at 3 years; HR, 0.94 [95% CI, 0.82-1.08]; P = .40). Patients were more likely to report an odor-related concern in the darapladib group vs the placebo group (11.5% vs 2.5%) and also more likely to report diarrhea (10.6% vs 5.6%).
  
  
  CONCLUSIONS
  In patients who experienced an ACS event, direct inhibition of Lp-PLA2 with darapladib added to optimal medical therapy and initiated within 30 days of hospitalization did not reduce the risk of major coronary events.
  
  
  BACKGROUND
  clinicaltrials.gov Identifier: NCT01000727.
authors.affiliation: TIMI Study Group, Cardiovascular Division, Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Michelle L
authors.initials: ML
authors.lastname: O'Donoghue
authors.affiliation: TIMI Study Group, Cardiovascular Division, Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Eugene
authors.initials: E
authors.lastname: Braunwald
authors.affiliation: Green Lane Cardiovascular Service, Auckland City Hospital, Auckland University, Auckland, New Zealand.
authors.forename: Harvey D
authors.initials: HD
authors.lastname: White
authors.affiliation: TIMI Study Group, Cardiovascular Division, Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Dylan P
authors.initials: DP
authors.lastname: Steen
authors.affiliation: Metabolic Pathways and Cardiovascular Therapeutic Area, GlaxoSmithKline, Philadelphia, Pennsylvania.
authors.forename: Mary Ann
authors.initials: MA
authors.lastname: Lukas
authors.affiliation: Metabolic Pathways and Cardiovascular Therapeutic Area, GlaxoSmithKline, King of Prussia, Pennsylvania.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Tarka
authors.affiliation: Département Hospitalo-Universitaire FIRE, Hôpital Bichat, Assistance Publique-Hôpitaux de Paris, and Université Paris-Diderot, Paris, France6NHLI Imperial College, ICMS Royal Brompton Hospital, United Kingdom.
authors.forename: P Gabriel
authors.initials: PG
authors.lastname: Steg
authors.affiliation: Department of Medicine, NYU Langone Medical Center, New York.
authors.forename: Judith S
authors.initials: JS
authors.lastname: Hochman
authors.affiliation: Heart Center, Department for Cardiology and Angiology I, University of Freiburg, Freiburg, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Bode
authors.affiliation: ANMCO Research Center, Florence, Italy.
authors.forename: Aldo P
authors.initials: AP
authors.lastname: Maggioni
authors.affiliation: TIMI Study Group, Cardiovascular Division, Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: KyungAh
authors.initials: K
authors.lastname: Im
authors.affiliation: Metabolic Pathways and Cardiovascular Therapeutic Area, GlaxoSmithKline, Research Triangle Park, North Carolina.
authors.forename: Jennifer B
authors.initials: JB
authors.lastname: Shannon
authors.affiliation: Metabolic Pathways and Cardiovascular Therapeutic Area, GlaxoSmithKline, King of Prussia, Pennsylvania.
authors.forename: Richard Y
authors.initials: RY
authors.lastname: Davies
authors.affiliation: TIMI Study Group, Cardiovascular Division, Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Sabina A
authors.initials: SA
authors.lastname: Murphy
authors.affiliation: TIMI Study Group, Cardiovascular Division, Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Sharon E
authors.initials: SE
authors.lastname: Crugnale
authors.affiliation: TIMI Study Group, Cardiovascular Division, Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Wiviott
authors.affiliation: TIMI Study Group, Cardiovascular Division, Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Marc P
authors.initials: MP
authors.lastname: Bonaca
authors.affiliation: Metabolic Pathways and Cardiovascular Therapeutic Area, GlaxoSmithKline, Research Triangle Park, North Carolina.
authors.forename: David F
authors.initials: DF
authors.lastname: Watson
authors.affiliation: Henry Ford Heart and Vascular Institute, Detroit, Michigan.
authors.forename: W Douglas
authors.initials: WD
authors.lastname: Weaver
authors.affiliation: Erasmus University, Thoraxcentrum, Rotterdam, the Netherlands13International Center for Circulatory Health, Imperial College, London, United Kingdom.
authors.forename: Patrick W
authors.initials: PW
authors.lastname: Serruys
authors.affiliation: TIMI Study Group, Cardiovascular Division, Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Cannon
authors.forename: Dylan L
authors.initials: DL
authors.lastname: Steen
mesh_terms: D054058:Acute Coronary Syndrome / Q000188:drug therapy*; D000368:Aged; D001547:Benzaldehydes / Q000009:adverse effects / Q000627:therapeutic use*; D001798:Blood Proteins / Q000009:adverse effects / Q000627:therapeutic use*; D002318:Cardiovascular Diseases / Q000401:mortality; D004311:Double-Blind Method; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D015994:Incidence; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000453:epidemiology; D017202:Myocardial Ischemia / Q000453:epidemiology / Q000517:prevention & control / Q000628:therapy; D010091:Oximes / Q000009:adverse effects / Q000627:therapeutic use*; D055502:Secondary Prevention; D001713:Biphenyl Compounds; D004048:Diethylamines; D011744:Pyrimidinones; D013440:Sulfides
chemical_list: D001547:Benzaldehydes; D001798:Blood Proteins; D010091:Oximes; C400481:PLIalpha; C529040:darapladib; D001713:Biphenyl Compounds; D004048:Diethylamines; D011744:Pyrimidinones; D013440:Sulfides