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Time to Replace Heparin Use During PCI?

Bivalirudin, a direct thrombin inhibitor, showed promise in a large, randomized comparison.

Unfractionated heparin (UFH) is the standard for indirect inhibition of thrombin during percutaneous coronary intervention (PCI). Recently available direct thrombin inhibitors (DTIs) such as bivalirudin have shown some advantages over UFH in terms of dosing and bleeding complications. Now, researchers have done a large, randomized comparison.

In the REPLACE-2 trial, funded by bivalirudin's manufacturer, 6010 patients were randomized to intravenous bivalirudin (with provisional glycoprotein IIb/IIIa inhibition) or to UFH (with planned GPIIb/IIIa inhibition) during elective or urgent PCI that was unrelated to acute MI or acute coronary syndrome (ACS). For bivalirudin, dosing was a 0.75-mg/kg bolus before PCI, then a 1.75-mg/kg-hour infusion for the duration of PCI; the pre-PCI bolus of heparin was 65 U/kg.

About 85% of both groups received clopidogrel more than 2 hours before PCI. About 97% of the UFH group and about 7% of the bivalirudin group ended up receiving a GPIIb/IIIa inhibitor. In both groups, GPIIb/IIIa-inhibitor use was roughly evenly divided between eptifibatide and abciximab. Five minutes after UFH bolus administration, the median activated clotting time (ACT) in that group was 317 seconds, longer than most current targets.

The bivalirudin and UFH groups had similar 30-day rates of the primary composite endpoint -- death, MI, urgent repeat revascularization (URR), or in-hospital major bleeding (9.2% vs. 10.0%, respectively) -- and of just death, MI, or URR (7.6% vs. 7.1%). Among endpoint components, MI incidence trended slightly higher, and bleeding incidence was significantly lower, with bivalirudin.

Comment: In this large, randomized trial in PCI patients, the DTI bivalirudin, combined with provisional GPIIb/IIIa inhibition, was as safe and effective as UFH with planned GPIIb/IIIa inhibition, suggesting that the former regimen is a suitable alternative to current practice. However, before we have a clear best choice of antithrombin agent, several questions must be answered: Do the REPLACE-2 data apply to high-risk ACS patients? Will the trend toward more MIs with bivalirudin result in more late mortality? Is bivalirudin use cost-effective at roughly $395 per patient (vs. $615 for eptifibatide and $1300 for abciximab)? Did the longer-than-usual ACT in the UFH group increase bleeding risk? Could a strategy of bivalirudin with planned GPIIb/IIIa inhibition add further benefit -- and cost? Finally, were outcome differences related to the choice of GPIIb/IIIa inhibitor?

— Howard C. Herrmann, MD

Published in Journal Watch Cardiology March 28, 2003

Citation(s):

Lincoff AM et al. for the REPLACE-2 Investigators. Bivalirudin and provisional glycoprotein IIb/IIIa blockade compared with heparin and planned glycoprotein IIb/IIIa blockade during percutaneous coronary intervention: REPLACE-2 randomized trial. JAMA 2003 Feb 19; 289:853-63.

• Original article (Subscription may be required)
• Medline abstract (Free)

Antman EM. Should bivalirudin replace heparin during percutaneous coronary interventions? JAMA 2003 Feb 19; 289:903-5.

• Original article (Subscription may be required)
• Medline abstract (Free)