Direct thrombin inhibitors in acute coronary syndromes: principal results of a meta-analysis based on individual patientsʹ data

To obtain more reliable and precise estimates of the effect of direct thrombin inhibitors in the management of acute coronary syndromes, including patients undergoing percutaneous coronary intervention, we undertook a meta-analysis based on individual patientsʹ data from randomised trials comparing a direct thrombin inhibitor (hirudin, bivalirudin, argatroban, efegatran, or inogatran) with heparin. Methods We included trials that involved at least 200 patients. The primary efficacy outcome was death or myocardial infarction, and the primary safety outcome was major bleeding. Data from individual trials were combined by use of a modified Mantel-Haenszel method. Findings In 11 randomised trials, 35970 patients were assigned up to 7 daysʹ treatment with a direct thrombin inhibitor or heparin and followed up for at least 30 days. Compared with heparin, direct thrombin inhibitors were associated with a lower risk of death or myocardial infarction at the end of treatment (4•3% vs 5•1%; odds ratio 0•85 [95% CI 0•77–0•94]; p=0•001) and at 30 days (7•4% vs 8•2%; 0•91 [0•84–0•99]; p=0•02). This was due primarily to a reduction in myocardial infarctions (2•8% vs 3•5%; 0•80 [0•71–0•90]; p<0•001) with no apparent effect on deaths (1•9% vs 2•0%; 0•97 [0•83–1•13]; p=0•69). Subgroup analyses suggested a benefit of direct thrombin inhibitors on death or myocardial infarction in trials of both acute coronary syndromes and percutaneous coronary interventions. A reduction in death or myocardial infarction was seen with hirudin and bivalirudin but not with univalent agents. Compared with heparin, there was an increased risk of major bleeding with hirudin, but a reduction with bivalirudin. There was no excess in intracranial haemorrhage with direct thrombin inhibitors. Interpretation Direct thrombin inhibitors are superior to heparin for the prevention of death or myocardial infarction in patients with acute coronary syndromes. This information should prompt further clinical development of direct thrombin inhibitors for the management of arterial thrombosis.