Abstract 205: Risk of Intracranial Hemorrhage with Protease-activated Receptor-1 Antagonists

Abstract

Background: Recent clinical trial data suggest that protease-activated receptor-1 (PAR-1) antagonists may increase the risk of intracranial hemorrhage (ICH). Our objective was to investigate the qualitative and quantitative risk of ICH in patients receiving PAR-1 antagonist therapy. Methods: Pubmed and EMBASE 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 ICH events were reported separately for active treatment and control groups. Summary incidence rates, relative risks (RRs), and 95% confidence intervals (CIs) were calculated using random-effects models. Between-study heterogeneity was assessed using the I 2 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 ICH (0.59% vs. 0.30%; RR 1.98, 95% CI 1.46 to 2.68, P < 0.00001) (Figure). There was no heterogeneity across trials (P=0.84, I 2 =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: This meta-analysis showed that patients with a history of thrombotic vascular disease or acute coronary syndrome treated with PAR-1 antagonists are at higher risk of experiencing ICH, a dreaded form of stroke, associated with high mortality and greater loss of health over a survivor’s lifetime than ischemic stroke.