The activated clotting time (ACT - measured by a Hemochron® device) was measured 5 min after the first bolus of study medication. The percent of patients reaching protocol-specified levels of anticoagulation was greater in the Angiomax with "provisional" GPI group than in the heparin plus GPI group. For patients randomized to Angiomax with "provisional" GPI, the median 5 min ACT was 358 sec (interquartile range 320-400 sec) and the ACT was <225 sec in 3%. For patients randomized to heparin plus GPI, the median 5 min ACT was 317 sec (interquartile range 263-373 sec) and the ACT was <225 sec in 12%. At the end of the procedure, median ACT values were 334 sec (Angiomax group) and 276 sec (heparin plus GPI group).

For the composite endpoint of death, MI, or urgent revascularization adjudicated under double-blind conditions, the frequency was higher (7.6%)(95% confidence interval 6.7%-8.6%) in the Angiomax with "provisional" GPI arm when compared to the heparin plus GPI arm (7.1%)(95% confidence interval 6.1%-8.0%). However, major hemorrhage was reported significantly less frequently in the Angiomax with "provisional" GPI arm (2.4%) compared to the heparin plus GPI arm (4.1%). Study outcomes are shown in Table 2.

At 12 months follow-up, mortality was 1.9% among patients randomized to Angiomax with "provisional" GPIs and 2.5% among patients randomized to heparin plus GPI.

Table 2. Incidences of Clinical Endpoints at 30 Days for REPLACE-2, a Randomized Double-blind Clinical Trial

¹ Defined as intracranial bleeding, retroperitoneal bleeding, a transfusion of ≥2 units of blood/blood products, a fall in hemoglobin >4 g/dL, whether or not bleeding site is identified, spontaneous or non-spontaneous blood loss with a decrease in hemoglobin >3 g/dL.

² p-value <0.001 between groups.

Bivalirudin Angioplasty Trial (BAT)

Angiomax was evaluated in patients with unstable angina undergoing PTCA in two randomized, double-blind, multicenter studies with identical protocols. Patients must have had unstable angina defined as: (1) a new onset of severe or accelerated angina or rest pain within the month prior to study entry or (2) angina or ischemic rest pain which developed between four hours and two weeks after an acute myocardial infarction (MI). Overall, 4312 patients with unstable angina, including 741 (17%) patients with post-MI angina, were treated in a 1:1 randomized fashion with Angiomax or heparin. Patients ranged in age from 29-90 (median 63) years, their weight was a median of 80 kg (39-120 kg), 68% were male, and 91% were Caucasian. Twenty-three percent of patients were treated with heparin within one hour prior to randomization. All patients were administered aspirin 300-325 mg prior to PTCA and daily thereafter. Patients randomized to Angiomax were started on an intravenous infusion of Angiomax (2.5 mg/kg/h). Within 5 min after starting the infusion, and prior to PTCA, a 1 mg/kg loading dose was administered as an intravenous bolus. The infusion was continued for 4 hours, then the infusion was changed under double-blinded conditions to Angiomax (0.2 mg/kg/h) for up to an additional 20 hours (patients received this infusion for an average of 14 hours). The ACT was checked at 5 min and at 45 min following commencement. If on either occasion the ACT was <350 sec, an additional double-blinded bolus of placebo was administered. The Angiomax dose was not titrated to ACT. Median ACT values were: ACT in sec (5th percentile-95th percentile): 345 sec (240-595 sec) at 5 min and 346 sec (range 269-583 sec) at 45 min after initiation of dosing. Patients randomized to heparin were given a loading dose (175 IU/kg) as an intravenous bolus 5 min before the planned procedure, with immediate commencement of an infusion of heparin (15 IU/kg/h). The infusion was continued for 4 hours. After 4 hours of infusion, the heparin infusion was changed under double-blinded conditions to heparin (15 IU/kg/h) for up to 20 additional hours. The ACT was checked at 5 min and at 45 min following commencement. If on either occasion the ACT was <350 sec, an additional double-blind bolus of heparin (60 IU/kg) was administered. Once the target ACT was achieved for heparin patients, no further ACT measurements were performed. All ACTs were determined with the Hemochron® device. The protocol allowed use of open-label heparin at the discretion of the investigator after discontinuation of blinded study medication, whether or not an endpoint event (procedural failure) had occurred. The use of open-label heparin was similar between Angiomax and heparin treatment groups (about 20% in both groups).

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