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.

Trial Design

Study Methods: All patients were given aspirin in an oral dose of 300-325 mg prior to PTCA and daily thereafter.

• 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)^1,3
• Patients assigned to heparin therapy were treated with 175 U/kg, followed by 18- to 24-hour infusion of 15 U/kg/h

Clinical End Points: The final analysis of adjudicated data presented here is based on a clinical efficacy end point defined as a composite of death, clinical or enzymatically defined MI, or repeat revascularization. Safety end points consisted of 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

Efficacy
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%.

Significant reductions in clinical events were maintained at 90 days (P = .012) with absolute benefits being sustained through 180 days.

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).

Incidence of in-hospital clinical end points through 7 days in BAT

* Efficacy end point from original study protocol included in composite end point and primary end point (clinical deterioration of cardiac origin requiring revascularization, aortic balloon pump, or angiographically shown decreased coronary blood flow implying abrupt vessel closure).
^† Defined as: Q-wave MI; creatinine kinase-myocardial band (CK-MB) elevation >2 x  the upper limit of normal, new ST- or T-wave abnormality, and chest pain >30 min; or new left bundle branch block with chest pain >30 min and/or elevated CK-MB enzymes; or elevated CK-MB and new ST- or T-wave abnormality without chest pain; or elevated CK-MB only.
^‡ Defined as: any revascularization procedure, including angioplasty, coronary artery bypass grafting, stenting, or placement of an intra-aortic balloon pump.
^§ 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.

• At 30 days, ANGIOMAX demonstrated a 51% reduction of death, MI, or revascularization vs heparin in prestratified, post-MI patients (4.9% vs 9.9%, respectively; P = .009)

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 covariables, 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 patients⁴

Treatment With Heparin Is the Most Important Risk Factor for Bleeding⁵

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).

• 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.

• ANGIOMAX reduced the risk of major bleeding complications by 62% vs heparin
• ANGIOMAX patients exhibited lower rates of major bleeding and fewer requirements for blood transfusions than patients receiving heparin
• Reductions in bleeding complications were clinically significant (P <.001) for both the intent-to-treat population and the post-MI cohort
• The incidence of clinically significant hemorrhage at 7 days in patients assigned ANGIOMAX was 3.5% compared to 9.3% (P =< .001) in patients randomized to heparin
• Overt hemorrhage from the arterial access site was the most frequent underlying cause of major hemorrhage
• Retroperitoneal hemorrhage also occurred more frequently in association with heparin treatment than with ANGIOMAX treatment. There were few intracranial hemorrhages in either randomized group

Safety Considerations

ANGIOMAX with provisional use of glycoprotein IIb/IIIa inhibitor is indicated for use as an anticoagulant in patients undergoing percutaneous coronary intervention (PCI), and in patients with or at risk for heparin-induced thrombocytopenia and thrombosis syndrome (HIT/HITTS) undergoing PCI. ANGIOMAX is intended for use with aspirin and has been studied only in patients receiving concomitant aspirin. ANGIOMAX is contraindicated in patients with active major bleeding or hypersensitivity to ANGIOMAX or its components. The most common (10%) adverse events for ANGIOMAX were back pain, pain, nausea, headache, and hypotension. An unexplained fall in blood pressure or hematocrit, or any unexplained symptom, should lead to serious consideration of a hemorrhagic event and cessation of ANGIOMAX administration. Please see complete prescribing information.