Bivalirudin during percutaneous coronary interventions in patients with ST segment elevation myocardial infarction

Abstract

Bivalirudin is a direct thrombin inhibitor that seems to be a promising anticoagulation treatment in patient with ST elevation myocardial infarction (STEMI) treated with primary percutaneous coronary intervention (PCI). We discuss several issues that were raised from the use of Bivalirudin during primary PCI.

Despite that primary percutaneous coronary intervention (PCI) is widely accepted as the treatment of choice in patients with ST segment elevation myocardial infarction (STEMI), the optimal anticoagulation treatment during this procedure is a topic of debate. The combination of unfranctionated heparin and a IIb–IIIa platelet receptor inhibitor is proved to be more effective than unfranctionated heparin alone in both large randomized trials and meta analyses (1,2). Three different IIb-IIIa inhibitors are commercially available today: Abciximab (Reopro®, Eli Lilly & Co, Indianapolis, IN, USA), Eptifibatide (Integrillin®, Milleniun Pharmaceuticals, Inc, Cambridge, MA, USA) and Tirofiban (Aggrastat®, Iroko, Philadelphia, PA, USA). Abciximab is the most well documented from all three, but a meta-analysis failed to show superiority over the other two regimens (3). Abciximab is also much more expensive than the other two, small molecule IIb–IIIa platelet receptor inhibitors, a fact that makes their use even more attractive (4).

The recently conducted HORIZONS-AMI study (5) compared the direct thrombin inhibitor Bivalirudin with the combination of unfranctionated heparin plus a IIb–IIIa inhibitor during primary PCI. The two primary endpoints of the study were major bleedings and the combined end point of major bleedings or major adverse cardiovascular events, including death, reinfarction, target vessel revascularization due to ischemia and stroke within 30 days. Bivalirudin significantly reduced the net adverse clinical events from 12.1% in the heparin plus IIb–IIIa platelet inhibitor group to 9.2% (relative risk 0.76, 95% confidence interval (CI): 0.63–0.92, P = 0.005). This beneficial effect of Bivalirudin was mainly due to a significant reduction of major bleedings from 8.3% to 4.9% (relative risk 0.60, 95% CI: 0.46–0.77, P <0.001). Bivalirudin was associated also with an increase of acute (≤24 h from PCI) stent thrombosis (1.3% versus 0.3%, P <0.001), but this unfavorable effect of Bivalirudin was disappeared at 30 days (stent thrombosis 2.5% versus 1.9%, P = 0.30). Bivalirudin treated patients had also lower cardiac death rates at 30 days (1.8% versus 2.9%, P = 0.03) and lower all cause death rates (2.1% versus 3.1%, P = 0.047) at 30 days post procedure.

This study is the larger primary PCI study ever conducted and naturally had a major effect on patients’ treatment. This effect was clearly pointed out on the European Society of Cardiology Guidelines for patients with STEMI (6), were Bivalirudin received a IIa level of recommendation and a B level of evidence.

However, there are several issues regarding HORIZONS-AMI trial that need to be mentioned. Although Bivalirudin was presented as monotherapy during primary PCI in STEMI patients, the administration of unfranctionated heparin in the ambulance or in the Emergency Room was not in the exclusion criteria, as long there was a 30-min interval between unfranctionated heparin and Bivalirudin administration. Although bolus unfranctionated heparin was similarly administrated in both study groups (65.8% in Bivalirudin group and 76.3% in glycoprotein IIb–IIIa inhibitor group), this resulted in a systematic violation of monotherapy with Bivalirudin. This administration was performed in a non randomized way, but it seems to have a positive effect on patients’ outcomes. Dangas et al, recently presented during the i2 Summit at the American College of Cardiology 58th Scientific Session more results from HORIZONS-AMI showing that patients randomized to Bivalirudin and treated with an additional bolus heparin dose had lower acute stent thrombosis than those not received a bolus heparin dose (0.9% versus 2.6%, P = 0.006).

A second consideration about this trial is that a small, but considerable group of patients initially randomized to Bivalirudin received a IIb–IIIa inhibitor (7.5% of all Bivalirudin patients). The criteria for switching therapies are unclear and this fact raises considerations about the indications for this change.

As the main beneficial effect of Bivalirudin was due to major bleedings reduction, a reasonable question is if this effect is sustained in patients treated with primary through the radial approach, which minimizes access site bleeding complications (approximately 50% from all bleeding complications observed in patients treated with PCI).

In conclusion, Bivalirudin is a very attractive regimen in the setting of primary PCI, especially in groups of patients with high risk of bleeding, but there are several issues to be solved before the generalization of this treatment strategy in a large scale.

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.