title: Varespladib and cardiovascular events in patients with an acute coronary syndrome: the VISTA-16 randomized clinical trial.
abstract: OBJECTIVE
  Secretory phospholipase A2 (sPLA2) generates bioactive phospholipid products implicated in atherosclerosis. The sPLA2 inhibitor varespladib has favorable effects on lipid and inflammatory markers; however, its effect on cardiovascular outcomes is unknown.
  
  
  OBJECTIVE
  To determine the effects of sPLA2 inhibition with varespladib on cardiovascular outcomes.
  
  
  METHODS
  A double-blind, randomized, multicenter trial at 362 academic and community hospitals in Europe, Australia, New Zealand, India, and North America of 5145 patients randomized within 96 hours of presentation of an acute coronary syndrome (ACS) to either varespladib (n = 2572) or placebo (n = 2573) with enrollment between June 1, 2010, and March 7, 2012 (study termination on March 9, 2012).
  
  
  METHODS
  Participants were randomized to receive varespladib (500 mg) or placebo daily for 16 weeks, in addition to atorvastatin and other established therapies.
  
  
  METHODS
  The primary efficacy measure was a composite of cardiovascular mortality, nonfatal myocardial infarction (MI), nonfatal stroke, or unstable angina with evidence of ischemia requiring hospitalization at 16 weeks. Six-month survival status was also evaluated.
  
  
  RESULTS
  At a prespecified interim analysis, including 212 primary end point events, the independent data and safety monitoring board recommended termination of the trial for futility and possible harm. The primary end point occurred in 136 patients (6.1%) treated with varespladib compared with 109 patients (5.1%) treated with placebo (hazard ratio [HR], 1.25; 95% CI, 0.97-1.61; log-rank P = .08). Varespladib was associated with a greater risk of MI (78 [3.4%] vs 47 [2.2%]; HR, 1.66; 95% CI, 1.16-2.39; log-rank P = .005). The composite secondary end point of cardiovascular mortality, MI, and stroke was observed in 107 patients (4.6%) in the varespladib group and 79 patients (3.8%) in the placebo group (HR, 1.36; 95% CI, 1.02-1.82; P = .04).
  
  
  CONCLUSIONS
  In patients with recent ACS, varespladib did not reduce the risk of recurrent cardiovascular events and significantly increased the risk of MI. The sPLA2 inhibition with varespladib may be harmful and is not a useful strategy to reduce adverse cardiovascular outcomes after ACS.
  
  
  BACKGROUND
  clinicaltrials.gov Identifier: NCT01130246.
authors.affiliation: South Australian Health and Medical Research Institute and University of Adelaide, Adelaide, Australia.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Nicholls
authors.affiliation: Academic Medical Center, Amsterdam, the Netherlands.
authors.forename: John J P
authors.initials: JJ
authors.lastname: Kastelein
authors.affiliation: Veterans Affairs Medical Center and University of Colorado, Colorado, Denver.
authors.forename: Gregory G
authors.initials: GG
authors.lastname: Schwartz
authors.affiliation: Cleveland Clinic Coordinating Center for Clinical Research, Cleveland, Ohio.
authors.forename: Dianna
authors.initials: D
authors.lastname: Bash
authors.affiliation: Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Robert S
authors.initials: RS
authors.lastname: Rosenson
authors.affiliation: Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Cavender
authors.affiliation: Cleveland Clinic Coordinating Center for Clinical Research, Cleveland, Ohio.
authors.forename: Danielle M
authors.initials: DM
authors.lastname: Brennan
authors.affiliation: University of Ulm Medical Center, Ulm, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Koenig
authors.affiliation: Leiden University Medical Center, Leiden, and Interuniversity Cardiology Institute of the Netherlands, Utrecht, the Netherlands.
authors.forename: J Wouter
authors.initials: JW
authors.lastname: Jukema
authors.affiliation: Michael E. DeBakey Veterans Affairs Hospital and Baylor College of Medicine, Houston, Texas.
authors.forename: Vijay
authors.initials: V
authors.lastname: Nambi
authors.affiliation: Mayo Clinic, Rochester, Minnesota.
authors.forename: R Scott
authors.initials: RS
authors.lastname: Wright
authors.affiliation: Cleveland Clinic Coordinating Center for Clinical Research, Cleveland, Ohio.
authors.forename: Venu
authors.initials: V
authors.lastname: Menon
authors.affiliation: Cleveland Clinic Coordinating Center for Clinical Research, Cleveland, Ohio.
authors.forename: A Michael
authors.initials: AM
authors.lastname: Lincoff
authors.affiliation: Cleveland Clinic Coordinating Center for Clinical Research, Cleveland, Ohio.
authors.forename: Steven E
authors.initials: SE
authors.lastname: Nissen
mesh_terms: D000085:Acetates / Q000009:adverse effects* / Q000627:therapeutic use*; D054058:Acute Coronary Syndrome / Q000150:complications / Q000188:drug therapy*; D000368:Aged; D000789:Angina, Unstable; D050197:Atherosclerosis; D000069059:Atorvastatin; D004311:Double-Blind Method; D057239:Early Termination of Clinical Trials; D005260:Female; D006538:Heptanoic Acids / Q000627:therapeutic use; D006801:Humans; D007211:Indoles / Q000009:adverse effects* / Q000627:therapeutic use*; D007651:Keto Acids; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction; D010741:Phospholipases A / Q000037:antagonists & inhibitors*; D054497:Phospholipases A2, Secretory / Q000187:drug effects / Q000502:physiology; D011758:Pyrroles / Q000627:therapeutic use; D012306:Risk; D020521:Stroke; D016019:Survival Analysis; D016896:Treatment Outcome
chemical_list: D000085:Acetates; D006538:Heptanoic Acids; D007211:Indoles; D007651:Keto Acids; D011758:Pyrroles; C117948:varespladib; D000069059:Atorvastatin; D010741:Phospholipases A; D054497:Phospholipases A2, Secretory