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Uwe Zeymer

According to the current guidelines of the European Society of Cardiology for patients with acute myocardial infarction with persistent ST-segment elevation intravenous anticoagulation is recommended in all patients undergoing primary percutaneous coronary intervention (PCI).Unfractionated heparin (UFH) has traditionally been used in the catheterization laboratory as the anticoagulant of choice during primary PCI to prevent thrombosis and ischemic events. However, UFH has several pharmacologic limitations including a high intra- and inter-individual variability.  Bivalirudin is a thrombin-specific anticoagulant, which has the ability to inactivate both free and fibrin-bound thrombin. In several randomized clinical trials bivalirudin has demonstrated efficacy and safety in patients undergoing PCI.4- In the HORIZONS trial, bivalirudin reduced the primary combined endpoint including death, myocardial infarction and bleeding complications compared to heparin plus routine glycoprotein IIb/IIIa inhibitors (GPI) in patients undergoing primary PCI. Moreover cardiovascular mortality was reduced after 30 days and at 3-year follow-up.  However, the use of GPI is not always routine in clinical practice anymore and might have contributed to the increase in bleeding complications seen in the control arm. In the EUROMAX trial, the use of GPI was not mandated, but was left to the standard practice of participating centers. The EUROMAX trial tested the hypothesis that bivalirudin, started upstream before primary PCI, is beneficial in the context of the use of the new antiplatelet drugs prasugrel and ticagrelor and a high use of radial access.
In EUROMAX 2218 patients with ST-segment elevation myocardial infarction (STEMI) during transfer for primary PCI were randomized  to bivalirudin (with prolonged infusion after PCI) or to heparins (unfractionated or low-molecular-weight heparin) with optional GPI. Primary and key secondary outcomes were the composites of death or non–CABG-related major bleeding, and death, reinfarction or non–CABG-related major bleeding, respectively, at 30 days.
Bivalirudin reduced the risk of both the primary (5.1% vs. 8.5%; relative risk, 0.60; 95% confidence interval [CI], 0.43 to 0.82; P=0.001) and key secondary (6.6% vs. 9.2%; relative risk, 0.72; 95% CI, 0.54 to 0.96; P=0.03) outcomes. Bivalirudin also reduced major bleeding (2.6% vs. 6.0%; relative risk, 0.43; 95% CI, 0.28 to 0.66; P<0.001) and net adverse clinical events (7.8% vs. 10.6%; relative risk, 0.73; 95% CI, 0.56 to 0.96; P=0.02). Acute stent thrombosis was higher with bivalirudin (1.1% vs. 0.2%; relative risk 6.11; 95% CI, 1.37 to 27.24; P=0.007). There was no difference in death (2.9% vs. 3.1%) or reinfarction (1.7% vs. 0.9%). Results were consistent across subgroups, including access site or choice of P2Y12 inhibitor.



Prof Gregg Stone (USA)
Numerous randomized trials demonstrated that in patients with STEMI undergoing primary PCI (on a background of aspirin and clopidogrel), adding a glycoprotein IIb/IIIa inhibitor (GPI) such as abciximab to heparin reduces stent thrombosis, reinfarction and mortality compared to heparin alone. The HORIZONS-AMI trial subsequently demonstrated that compared to heparin + GPI, bivalirudin with provisional GPI use results in similar rates of composite ischemic events with 40-50% reductions in major bleeding and thrombocytopenia. Acute stent thrombosis, however, within the first 24 hours after PCI, occurred in ~1% more patients treated with bivalirudin. Thereafter the rates of stent thrombosis in bivalirudin-treated patients were decreased compared to UFH+GPI. This overall favorable balance of ischemia and bleeding, plus other non-hematologic benefits of bivalirudin, resulted in a marked reduction in cardiac mortality at 30 days with bivalirudin, results which were sustained to 3 years.
The EUROMAX trial incorporated several advances in PCI not available or routinely used during HORIZONS-AMI, including more potent P2Y12 inhibitors, more frequent use of radial intervention, and pre-hospital medication administration. EUROMAX also made GPI use optional in the control arm, a practice which has of late become more common in Europe. Nonetheless, the results of EUROMAX were consistent with HORIZONS-AMI. A pooled patient-level meta-analysis of the HORIZONS-AMI and EUROMAX trials presented at the recent American College of Cardiology annual scientific sessions reported that bivalirudin compared to heparin ± GPI resulted in reduced 30-day rates of major bleeding, thrombocytopenia and cardiac mortality, with non-significantly different rates of reinfarction, ischemia-driven revascularization, stroke and non-cardiac mortality. Bivalirudin resulted in greater rates of acute stent thrombosis, with non-significantly different rates of subacute stent thrombosis. Composite net adverse clinical events (all-cause death, reinfarction, stroke, ischemia-driven revascularization or major bleeding) were substantially lower with bivalirudin. No significant heterogeneity was present between the 2 trials for these outcome measures, and the results were consistent across major subgroups. These results support use of bivalirudin for anticoagulation of STEMI patients undergoing primary PCI, independent of vascular access site, choice of P2Y12 inhibitor, and timing of drug initiation and discontinuation.