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Is Bivalirudin a Good Antithrombotic Choice in ACS Patients?

Insights from the Acute Catheterization and Urgent Intervention Triage Strategy (ACUITY) trial

The direct thrombin inhibitor bivalirudin has been studied as an alternative to intravenous heparin during percutaneous coronary intervention (PCI). Its short half-life (25 min) and potential for reduced platelet activation might explain why, compared with unfractionated heparin (UFH) plus planned glycoprotein IIb/IIIa inhibition in the REPLACE-2 trial, bivalirudin plus provisional GPIIb/IIIa inhibition was associated with less bleeding and a similar rate of major adverse outcomes. REPLACE-2 subjects were mostly low- and moderate-risk patients undergoing PCI (Journal Watch Cardiology Mar 28 2003).

Now, in a multinational, open-label, randomized trial funded in part by bivalirudin’s manufacturer, 13,819 acute coronary syndrome (ACS) patients (41% with unstable angina; 59% with non–Q-wave MI) were randomized to receive heparin (either UFH or enoxaparin) plus a GPIIb/IIIa inhibitor, bivalirudin plus a GPIIb/IIIa inhibitor, or bivalirudin alone. Angiography was performed in 99% of patients a mean of 20 hours after hospital admission; 56% underwent PCI. Of the group assigned to bivalirudin alone, 9% received provisional ("bailout") GPIIb/IIIa inhibition. Data from a separate randomization regarding GPIIb/IIIa inhibition (upstream vs. cath-lab administration) are not reported.

Across the three groups, the 30-day incidence of ischemic events (death, MI, or unplanned revascularization for ischemia) ranged narrowly — from 7.3% to 7.8%, demonstrating the noninferiority of the bivalirudin strategies. Findings did not vary according to the type of heparin used. The noninferiority of bivalirudin was consistent whether biomarker results were positive, whether patients underwent PCI, and whether angiography was delayed. Notably, among the 36% of patients who did not receive a thienopyridine before angiography, ischemic events were more common with bivalirudin monotherapy than with heparin + GPIIb/IIIa inhibition (9.1% vs. 7.1%).

The incidence of major bleeding not related to CABG was 5.7% in the heparin + GPIIb/IIIa inhibition group, 5.3% in the bivalirudin + GPIIb/IIIa inhibition group, and just 3.0% in the bivalirudin-alone group. However, according to strict TIMI criteria, the absolute difference in major bleeding between the two GPIIb/IIIa-inhibition strategies and bivalirudin monotherapy narrowed to 1% or less (1.7%–1.9% vs. 0.9%).

Comment: In this large trial known as ACUITY, the best overall strategy for preventing ischemic events and major bleeding in ACS patients was planned bivalirudin monotherapy plus provisional GPIIb/IIIa inhibition. Still, the study has several important limitations: (1) outcomes were inferior with bivalirudin monotherapy when a thienopyridine was not administered before angiography; (2) pre-trial use of heparin and other agents could have influenced the results; (3) major bleeding incidence was only an absolute 1% lower with bivalirudin monotherapy than with the other strategies, according to TIMI criteria; and (4) the trial’s complex noninferiority design might have masked treatment differences in important subgroups. With these caveats, the ACUITY results support a strategy of using bivalirudin as an alternative to heparin plus a GPIIb/IIIa inhibitor in invasively managed ACS patients.

— Howard C. Herrmann, MD

Published in Journal Watch Cardiology November 22, 2006

Citation(s):

Stone GW et al. for the ACUITY Investigators. Bivalirudin for patients with acute coronary syndromes. N Engl J Med 2006 Nov 23; 355:2203-16.

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

Bittl JA. Accounting for ACUITY. N Engl J Med 2006 Nov 23; 355:2249-50.

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