The direct thrombin inhibitors hirudin and bivalirudin inhibit both fluid-phase and clot-bound thrombin. These agents have been extensively studied in clinical trials in comparison with intravenous unfractionated heparin (UFH), as adjuncts to fibrinolytic therapy for ST-elevation myocardial infarction (STEMI) and in percutaneous coronary intervention (PCI), and they are currently undergoing further evaluation in patients with non-ST elevation acute coronary syndromes (NSTEACS). In angiographic trials there were trends for patients treated with hirudin to be more likely to achieve Thrombolysis In Myocardial Infarction (TIMI) grade 3 flow at 90 minutes than patients treated with UFH (65% versus 57% in TIMI-5; 41% versus 33% in Hirudin for the Improvement of Thrombolysis [HIT]-4; statistically nonsignificant differences in both trials). In Montréal Heart Institute trials and the multicenter Hirulog and Early Reperfusion or Occlusion (HERO)-1 trial the use of bivalirudin was associated with an increased incidence of TIMI grade 3 flow (85% versus 31%, p = 0.006; and 48% versus 35%, p = 0.02, respectively). These studies used streptokinase as the fibrinolytic agent except in TIMI-5 where alteplase was used. The initial clinical outcomes studies (Global Use of Strategies to Open Occluded Coronary Arteries in Acute Coronary Syndromes [GUSTO]-IIA and TIMI-9A) were discontinued early because of a high incidence of intracerebral bleeding (approximately 1.8%). Patients in these studies had either STEMI or NSTEACS, and thus not all were treated with fibrinolytic therapy. These studies were recommenced as GUSTO-IIB and TIMI-9B, using lower dosages of hirudin (0.1 mg/kg bolus + 0.1 mg/kg infusion for 96 hours). Neither TIMI-9B nor GUSTO-IIB showed an improvement in efficacy (death or reinfarction) or an increase in bleeding with hirudin. However, in the 1015 patients with STEMI treated with streptokinase in GUSTO-IIB, there was a 40% reduction in the combined incidence of death or myocardial infarction at 30 days (8.6% versus 14.4%, odds ratio [OR] 0.57, 95% confidence interval [CI] 0.38-0.87, p = 0.004). In the HERO-2 trial, 17073 patients receiving streptokinase for STEMI were randomized to receive either bivalirudin (0.25 mg/kg bolus and 0.5 mg/kg infusion for 12 hours followed by 0.25 mg/kg) or UFH (5000 IU bolus and 800-1000 IU/h infusion titrated to an activated partial thromboplastin time [APTT] of 50-75 seconds) for a total of 48 hours. Thirty-day mortality was similar in both groups (10.8% with bivalirudin versus 10.9% with UFH, OR 0.99, 95% CI 0.90-1.09, p = 0.85). There was a 30% reduction in the incidence of reinfarction before 96 hours (1.6% with bivalirudin versus 2.3% with UFH, OR 0.70, 95% CI 0.56-0.87, p = 0.001). Patients treated with bivalirudin had significantly more moderate bleeding (1.4% versus 1.1% with UFH, OR 1.32, 95% CI 1.0-1.74, p = 0.05). In a meta-analysis of patients with STEMI in the Direct Thrombin Inhibitor Trialists' collaboration, direct thrombin inhibitors were found to reduce the rate of reinfarction at 30 days (3.9% versus 4.8% with UFH, OR 0.80, 95% CI 0.71-0.90, p < 0.001), but did not reduce mortality (9.1% versus 9.0%, OR 1.02, 95% CI 0.94-1.11, p = 0.68) or the combined incidence of death/reinfarction at 30 days (11.8% versus 12.4%, OR 0.95, 95% CI 0.88-1.02, p = 0.18). There was no increase in major bleeding or intracerebral bleeding with direct thrombin inhibitor therapy. In conclusion, direct thrombin inhibitors reduce reinfarction, but not mortality, in patients with STEMI treated with fibrinolytic therapy. The major benefit of direct thrombin inhibitors appears to be in patients undergoing PCI, particularly after STEMI.