News:Bivalirudin is no better than heparin in patients pretreated with clopidogrel undergoing PCI: Results from the ISAR-REACT-3 trial

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March 29, 2008 By Vijayalakshmi Kunadian MBBS MD MRCP [1]

SCAI-ACCi2 08-Chicago, IL:Investigators from Germany report today that bivalirudin is not superior to unfractionated heparin (UFH) among stable patients pretreated with 600 mg of clopidogrel undergoing percutaneous coronary intervention (PCI).

The results of the ISAR-REACT-3 trial were presented by Dr. Adnan Kastrati at the SCAI-i2 summit Annual Scientific Sessions in Chicago today.

This study was a randomized double-blind, active controlled, multicenter trial of bivalirudin versus unfractionated heparin in troponin-negative patients undergoing percutaneous coronary intervention (PCI) after pretreatment with 600 mg of clopidogrel.

Antithrombotic agents play a major role in the management of patients with coronary artery disease and during percutaneous coronary intervention. Indirect thrombin inhibitors (unfractionated heparin-UFH, low molecular weight heparin and synthetic pentasaccharide derivatives such as fondoparinux) and direct thrombin inhibitors (bivalirudin) have been evaluated in patients with acute coronary syndromes and those undergoing percutaneous coronary intervention.

The investigators in the ISAR-REACT-3 trial sought to determine if the outcomes among patients treated with bivalirudin were superior to those among patients treated with unfractionated heparin in patients who had been loaded with 600 mg of clopidogrel. Clopidogrel was administered at least 2 hours prior to PCI, and clopidogrel at a dose of 75 mg was continued for at least one month after balloon angioplasty or implantation of bare-metal stents and for at least six months after implantation of drug-eluting stents. Patients were administered aspirin indefinitely.

This study included patients aged 18 years or older undergoing percutaneous coronary intervention. Exclusion criteria included patients with recent ST segment elevation myocardial infarction within the last 48 hours, cardiogenic shock, acute coronary syndrome and positive biomarkers (Troponin T > 0.03 micrograms/Li), malignancies, active bleeding or bleeding diathesis, a history of gastrointestinal or genitourinary bleeding within the last 6 weeks, vascular diseases, recent trauma or surgery, recent bivalirudin or UFH or anticoagulation therapy, heparin induced thrombocytopenia, planned staged PCI procedure, anemia, severe hypertension (>180/110mmHg), renal impairment (GFR <30ml/min), or allergy to study medications.

Bivalirudin was administered as an intravenous bolus of 0.75 mg/kg prior to the start of the intervention, followed by infusion of 1.75 mg/kg per hour for the duration of the procedure. Unfractionated heparin was administered as an intravenous bolus of 140U/kg followed by infusion of placebo 1.75 mg/kg per hour for the duration of the procedure.

The primary endpoint consisted of:

• The composite of death, myocardial infarction (MI), urgent target vessel revascularization (TVR) within 30 days or in-hospital major bleeding

The secondary endpoints consisted of:

• Composite of death, MI, or urgent TVR within 30 days
• Composite of death, MI or TVR at 1 year

This study consisted of 4570 low to intermediate–risk patients who were undergoing PCI with 2,289 randomized to receive bivalirudin and 2,281 patients to receive UFH. Both arms had comparable baseline characteristics. The primary endpoint was similar between the two arms. In the bivalirudin group compared with the UFH group, there was no difference in the incidence of death (0.1% vs. 0.2%, p = 0.7), MI (5.6% vs. 4.8%, p = 0.24), Q-wave myocardial infarction (0.6% vs. 0.4%, p=0.3), definite stent thrombosis rate (0.5% vs. 0.4%, p=0.52) and urgent TVR (0.8% vs. 0.7%, p = 0.75).

There was no difference in the combined endpoint of death/myocardial infarction/TVR (5.9% vs. 5%, RR 1.16, 0.91-1.49, p=0.23). When these endpoints were added to the incidence of major bleeding, bivalirudin did not differ from UFH (8.3% vs. 8.7%, RR 0.94, 0.77-1.15, p=0.57). When the bleeding events were analysed independently, bivalirudin was associated with less major (3.1% vs. 4.6%, p=0.008) and minor bleeds (6.8% vs. 9.9%, p=0.0001) compared to UFH.

Limitations of the study include the fact that the bolus dose of heparin was high (140 U/Kg) and this may account for the higher bleeding rate seen in the heparin arm. The TIMI bleeding criteria may not have been sensitive to smaller bleeds. The criteria for MI required a CK MB elevation > 2 fold rather than 3 fold as has been used in other studies.

Source

Presented at the SCAI Annual Scientific Sessions in partnership with ACC i2 summit, March 29-April 1, 2008 Chicago