Unstable Angina and Acute MI

Some of the largest experience with bivalirudin is with patients who have had an acute MI or unstable angina. Two open-label, uncontrolled trials were performed to evaluate the efficacy and tolerability of bivalirudin in patients with unstable angina. Sharma et al. (1993) utilized a 5-day infusion of bivalirudin in patients with unstable angina. Their primary endpoints included death, development of an MI, or the need for coronary intervention. Lidon and coworkers (1993) studied 55 patients with unstable angina in a dose-ranging study. As a result of favorable findings in these two trials, the Thrombin Inhibition in Myocardial Infarction (TIMI) 7 trial comparing four different doses of bivalirudin in combination with aspirin was performed in over 400 patients (Fuchs and Cannon, 1995). The TIMI-8 study compared bivalirudin in a single dose with heparin in patients with unstable angina. This study was prematurely discontinued when Biogen suspended product development. The primary endpoint (all cause mortality and nonfatal MI at 14 days) was lower, and no major bleeding occurred in the bivalirudin group (Antman et al., 2002). These trials suggested that there is a role for bivalirudin in the management of unstable angina.

A number of trials have evaluated the concomitant use of bivalirudin in patients who received streptokinase and aspirin for an acute MI. Lidon et al. (1994) compared bivalirudin to heparin in 45 patients who suffered an acute MI, while Theroux and colleagues (1995) utilized this same strategy in 68 patients. Higher early patency rates and a lower incidence of serious hemorrhage were noted (Nawarskas and Anderson, 2001).

The Hirulog Early Reperfusion/ Occlusion (HERO) trial randomized 412 patients with acute MI to receive low-dose bivalirudin, high-dose bivalirudin, or heparin (White et al., 1997). Bivalirudin was found to be more effective than heparin in producing early patency rates at a reduced risk for bleeding.

The HERO-2 trial randomized 17,073 patients who received streptokinase to heparin or bivalirudin for 48 h in patients who presented with an acute ST-elevation MI. Bivalirudin did not reduce mortality compared to heparin, but was associated with a 30% reduction in repeat MI, without significant increase in severe or life-threatening bleeding (White, 2001).

A meta-analysis by the Direct Thrombin Inhibitor Trialists' Collaborative Group (2002) based on individual patients' data reported on 11 studies (35,970 patients) receiving either heparin or DTI therapy (relative number of patients treated: hirudin > bivalirudin > argatroban > inogatran > efegatran). Overall, DTI therapy appeared to be superior over heparin for the prevention of MI in patients with acute coronary syndromes (ACS) (although the larger number of patients treated with hirudin meant that this DTI contributed most to the overall result reported). Bivalirudin was associated with a 56% reduction in major bleeding risk.

The Acute Catheterization and Urgent Intervention Triage StrategY (ACUITY) trial prospectively randomized 13,819 patients with non-ST segment elevation (NSTE) MI/ACS to one of three antithrombotic regiments; UFH or LMWH (enoxaparin) plus IIb/IIIa inhibition; bivalirudin plus GPIIb/IIIa inhibition; or bivalirudin alone. Primary endpoints were a composite ischemia endpoint (death, MI, or unplanned revascularization for ischemia), major bleeding, and the net clinical outcome, defined as the combination of composite ischemia or major bleeding. Coronary angiography was performed in 99% of patients. In this trial, bivalirudin plus GPIIb/IIIa inhibition was associated with rates of ischemia and bleeding that were similar to those of heparin plus GPIIb/IIIa inhibitor. Bivalirudin given without GPIIb/IIIa inhibition was also associated with similar rates of ischemia compared to the heparin plus GPIIb/IIIa inhibitor study arm, but with a significantly lower major bleeding rate (3.0% vs. 5.7%; p < 0.001) (Stone et al., 2004, 2006).

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