title: Risk of intracranial hemorrhage with protease-activated receptor-1 antagonists.
abstract: OBJECTIVE
  Recent clinical trial data suggest that protease-activated receptor-1 (PAR-1) antagonists may increase the risk of intracranial hemorrhage. Our objective was to investigate the qualitative and quantitative risks of intracranial hemorrhage in patients receiving PAR-1 antagonist therapy.
  
  
  METHODS
  Pubmed, EMBASE, Cochrane Central Register of Controlled Trials, and Clinicaltrials.gov from 1966 to May 2012, were searched to identify relevant studies. We included randomized controlled trials that included a comparison of PAR-1 antagonist with placebo and in which the total number of patients and intracranial hemorrhage events were reported separately for active treatment and control groups. Summary incidence rates, relative risks, and 95% confidence intervals (CIs) were calculated using random-effects models. Between-study heterogeneity was assessed using the I2 statistic.
  
  
  RESULTS
  In 9 PAR-1 antagonist trials with 42000 patients with a history of thrombotic vascular disease or acute coronary syndrome, PAR-1 antagonist treatment was associated with increased risk of intracranial hemorrhage (0.59% vs 0.30%; relative risk, 1.98; 95% CI, 1.46-2.68; P<0.00001; number needed to harm, 345). There was no heterogeneity across trials (P=0.84; I2=0%), PAR-1 antagonist agent (P=0.52), treatment duration (P=0.38), or trial-qualifying event (P=0.59). Risk of death from any cause or a cardiovascular cause did not differ between active treatment and control groups.
  
  
  CONCLUSIONS
  In a pooled analysis of data from 9 trials, PAR-1 antagonist therapy was associated with an increased risk for intracranial hemorrhage.
authors.affiliation: Department of Neurology, Chang Gung University College of Medicine, Chang Gung Memorial Hospital, Chiayi, Taiwan.
authors.forename: Meng
authors.initials: M
authors.lastname: Lee
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Saver
authors.forename: Keun-Sik
authors.initials: KS
authors.lastname: Hong
authors.forename: Hsiu-Chuan
authors.initials: HC
authors.lastname: Wu
authors.forename: Bruce
authors.initials: B
authors.lastname: Ovbiagele
mesh_terms: D054058:Acute Coronary Syndrome / Q000188:drug therapy / Q000453:epidemiology; D006801:Humans; D007097:Imines / Q000009:adverse effects*; D015994:Incidence; D020300:Intracranial Hemorrhages / Q000139:chemically induced* / Q000453:epidemiology*; D007783:Lactones / Q000009:adverse effects*; D010919:Placebos; D011725:Pyridines / Q000009:adverse effects*; D016032:Randomized Controlled Trials as Topic; D012307:Risk Factors; D013927:Thrombosis / Q000188:drug therapy / Q000453:epidemiology; D010975:Platelet Aggregation Inhibitors
chemical_list: C540445:E 5555; D007097:Imines; D007783:Lactones; D010919:Placebos; D011725:Pyridines; C530299:vorapaxar; D010975:Platelet Aggregation Inhibitors