October 31st, 2013
EUROMAX Meets Primary Endpoint But Editorialist Raises Questions
When started during transport to the hospital during a heart attack, bivalirudin (Angiox, Medicines Company) improves clinical outcomes and reduces major bleeding, though at the cost of a small but significant risk in stent thrombosis. The results of the European Ambulance Acute Coronary Syndrome (ACS) Angiography) Trial (EUROMAX) were presented on Wednesday by Phillippe Gabriel Steg at the TCT conference in San Francisco and published simultaneously in the New England Journal of Medicine.
A role for bivalirudin in primary PCI was established years ago in the HORIZONS-AMI trial, but clinical practice has evolved since then, including more prehospital treatment (especially in Europe), less use of glycoprotein IIb/IIIa inhibitors, and the advent of novel antiplatelet agents. EUROMAX, the investigators write, “was designed to determine whether [the] benefits of bivalirudin would persist in the contemporary setting.”
While in the ambulance on their way to the hospital for a primary PCI, 2218 patients with ST-segment elevation myocardial infarction (STEMI) were randomized to either bivalirudin or a control strategy of either unfractionated or low-molecular-weight heparin with optional adjunctive IIb/IIIa inhibitors.
At 30 days, the rate of death or major bleeding not associated with CABG was significantly lower in the bivalirudin group compared with the control group:
- 5.1% vs. 8.5%, relative risk 0.60, CI 0.43 – 0.82, p=0.001
A similar reduction was observed in the secondary composite endpoint of death, reinfarction, or non-CABG major bleeding:
- 6.6% vs. 9.2%, RR 0.72, CI 0.54 – 0.96, p=0.02
There were no significant differences in mortality (2.9% and 3.1%) or reinfarction (1.7% and 0.9%), but bivalirudin therapy did result in a significant reduction in major bleeding:
- 2.6% vs. 6.0%; RR 0.43, CI 0.28 – 0.66, p<0.001
The chief drawback to bivalirudin was a significant increase in the rate of acute stent thrombosis:
- 1.1% vs. 0.2%, RR 6.11. CO 1.37 – 27.24, p=0.007
The entire difference between the groups in stent thrombosis occurred in the first 24 hours of treatment. It should be noted that a similar elevation in stent thrombosis was observed in the HORIZONS-AMI trial. The EUROMAX investigators reported that none of the acute stent thromboses were fatal. Two thirds of the patients with stent thrombosis had reinfarction, and all of them had ischemia-driven revascularization.
In an accompanying editorial, Shamir Mehta writes that EUROMAX is “a timely and important second randomized study evaluating bivalirudin in primary PCI.” However, he points out that the definition of major bleeding in the study “did not actually require the occurrence of overt clinical bleeding,” and there were no significant differences in TIMI major bleeding or GUSTO severe or life-threatening bleeding.
In his conclusion, Mehta raises question about the value of bivalirudin in the clinical setting:
Thus, the clearest findings in the two trials evaluating bivalirudin in primary PCI are that bivalirudin increases the risk of acute stent thrombosis while reducing bleeding complications. Whether there is a true mortality reduction with bivalirudin among patients with STEMI is much less certain, since the EUROMAX study did not show even a trend toward a reduction in this outcome.
Is the tradeoff of reduced procedural bleeding worth the increased risk of acute stent thrombosis? This depends on the relative incidence of major bleeding versus that of stent thrombosis and the association between these events and subsequent mortality and morbidity. Few observers would dispute that stent thrombosis is a serious, albeit infrequent, event that results in either reinfarction or death in most cases. On the other hand, major bleeding occurs more frequently but varies widely in severity, depending on how the term is defined. Severe bleeding is prognostically more important but far less frequent than less serious bleeding, which has little or no long-term importance. Thus, it is critical that clinicians weigh the relative importance of these events before selecting an antithrombotic strategy for their patients.