Risk of Intracranial Hemorrhage With Protease-Activated Receptor-1 Antagonists
Background—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, 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 42 000 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%;, 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.
Conclusion—PAR-1 antagonist therapy was associated with an increased risk for intracranial hemorrhage.
- acute coronary syndrome
- intracranial hemorrhage
- protease-activated receptor-1 antagonists
- thrombin antagonists
- Received July 9, 2012.
- Revision received August 22, 2012.
- Accepted September 10, 2012.
- © 2012 American Heart Association, Inc.