BAT: The Bivalirudin Angioplasty Trial¹

• Summary|
• Trial Design|
• Clinical Outcomes

Summary

• The Bivalirudin Angioplasty Trial (BAT) demonstrated a 22% relative risk reduction with Angiomax^® (bivalirudin) in the rate of death, myocardial infarction (MI), or repeat revascularization at 7 days versus heparin monotherapy (6.2% vs 7.9%, respectively; P = .039)
• ANGIOMAX significantly reduced major bleeding vs heparin at 7 days in the intent-to-treat population (3.5% vs 9.3%, respectively; P <.001), which equates to a 62% reduction in major bleeding
• ANGIOMAX is the only antithrombotic with proven efficacy and reduced bleeding complications in percutaneous transluminal coronary angioplasty (PTCA)¹

Trial Design

BAT was a double-blind, randomized, multicenter trial that enrolled 4312 patients with chest pain scheduled for coronary angioplasty in 1993 to 1994. This patient population included 741 independently randomized patients with post-MI angina.¹

Patients were eligible for the study if they were over 21 years of age; were urgently scheduled to undergo angioplasty for unstable angina defined as crescendo angina, angina of new onset, or angina at rest; or were scheduled to undergo angioplasty for postinfarction angina less than 2 weeks after MI. Patients were excluded if serum creatinine concentrations exceeded 3 g/dL; if thrombolytic therapy had been administered within 24 hours; if the patient was scheduled to undergo coronary atherectomy, stenting, laser angioplasty, or a staged angioplasty procedure, or was possibly pregnant; or if there was aspirin or heparin intolerance.

• Patients randomized to ANGIOMAX were given a bolus of 1 mg/kg of body weight, followed by a 4-hour infusion of 2.5 mg/kg/h, followed by a 0.2 mg/kg/h infusion for up to an additional 20 hours at physician discretion (patients received this infusion for an average of 14 hours)^1,2
• Patients assigned to heparin therapy were treated with 175 U/kg, followed by 18- to 24-hour infusion of 15 U/kg/h
• All patients were given aspirin in an oral dose of 300-325 mg prior to PTCA and daily thereafter.

Inclusion Criteria

• Patients were over 21 years of age; were urgently scheduled to undergo angioplasty for unstable angina defined as crescendo angina, angina of new onset, or angina at rest;
• Or were scheduled to undergo angioplasty for postinfarction angina less than 2 weeks after MI.

Major Exclusion Criteria

• serum creatinine concentrations exceeded 3 g/dL;
• thrombolytic therapy had been administered within 24 hours;
• scheduled to undergo coronary atherectomy, stenting, laser angioplasty, or a staged angioplasty procedure,
• were pregnant;
• or if there was aspirin or heparin intolerance.

Clinical End Points:

• Composite of death, clinical or enzymatically defined MI, or repeat revascularization.
• Major hemorrhage, defined as the occurrence of intracranial bleeding, retroperitoneal bleeding, or overt bleeding resulting in a decrease in hemoglobin of >3 g/dL or the need for transfusion of >2 units of blood.

Clinical Outcomes

In BAT, ANGIOMAX significantly reduced ischemic events^1,3

• Major bleeding* at 7 days for patients treated with ANGIOMAX was 3.5% vs 9.3% (P<.001) for heparin
• In BAT, ANGIOMAX infusion was continued after PTCA for up to 4 hours, then followed by a 0.2 mg/kg/h infusion for up to 20 additional hours

* Please see important safety information and bleeding definitions.

Ischemic benefits vs heparin maintained at 180 days in BAT

• Estimates of composite ischemia at 180 days demonstrate consistent outcomes with ANGIOMAX vs heparin¹

A total of 4,312 patients were enrolled into the BAT trial.

The composite end point of death, MI, or revascularization occurred in 169/2151 (7.9%) of patients treated with heparin and in 135/2161(6.2%) of patients treated with ANGIOMAX (P = .039), equivalent to a relative risk reduction of 22%.

The incidence of this composite end point for the cohort of prestratified post-MI patients was also reduced in patients treated with ANGIOMAX versus heparin at 7 days (4.9% vs 9.9%, P = .009).

Consistent outcomes with ANGIOMAX regardless of risk level³

• ANGIOMAX benefits vs heparin were most evident among UA patients, patients treated with prior heparin, post-MI patients, and patients with both risk factors⁴

Adapted from Henry TD. J Invas Cardiol, 2002. P < .001 for all comparisons of ANGIOMAX vs heparin. * Prespecified. † Patients undergoing PTCA within 1 hour of UFH therapy. ‡ Patients developing angina between 4 hours and 2 weeks after acute MI.

Safety

Based on a multivariate analysis, treatment with heparin was the most important bleeding risk variable after accounting for the independent effects of all other co variables, including activated clotting time (ACT) level. Duration of anticoagulation was comparable between the 2 treatment arms and modest differences in levels of anticoagulation do not account for the difference in hemorrhage rates between the 2 treatment arms.

Major Hemorrhage and Transfusions at 7 Days*

* No monitoring of ACT (or PTT) was done after a target ACT was achieved. † Major hemorrhage was defined as the occurrence of any of the following: intracranial bleeding, retroperitoneal bleeding, clinically overt bleeding with a decrease in hemoglobin ≥3 g/dL or leading to a transfusion of ≥2 units of blood. ‡ ≥2 units of blood.

• ANGIOMAX significantly reduced major bleeding vs heparin at 7 days in the intent-to-treat population (3.5% vs 9.3%, respectively; P <.001), which equates to a 62% reduction in major bleeding
• ANGIOMAX demonstrated an 66% reduction in the risk of major bleeding complications vs heparin in prestratified, high-risk patients⁵

Treatment With Heparin Is the Most Important Risk Factor for Bleeding³

Consistent with REPLACE-2, treatment with heparin is one of the most important risk factors for bleeding in BAT. In a multivariate logistic regression analysis to identify patient and treatment variables that were able to predict the risk of major hemorrhage, randomization to treatment with heparin was the most important independent predictor of risk of major hemorrhage (odds ratio 2.9; 95% CI: 2.2–3.8, for risk of major hemorrhage adjusted for covariables).

Other independent covariables predicting risk of major hemorrhage (though with less certainty) were:

• Age ≥70 years (odds ratio 2.1; 95% CI: 1.6–2.7)
• Female gender (odds ratio 2.3; 95% CI: 1.8–2.9)
• Small body surface area (odds ratio 1.5; 95% CI: 1.2–2.0)
• Prior heparin within 1 hour of angioplasty (odds ratio 1.4; 95% CI: 1.1–1.9)

The intensity of anticoagulation as measured by ACT levels was not found to be predictive of risk of major hemorrhage in any univariate or multivariate analysis performed.