BAT: The Bivalirudin Angioplasty Trial1
- 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
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.
In BAT, ANGIOMAX significantly reduced ischemic events1,3
- 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*
|
|
ANGIOMAX
n=2161
|
Heparin
n=2151
|
P value
|
|
No. (%) patients with major hemorrhage†
|
76 (3.5%)
|
199 (9.3%)
|
<.001
|
|
-With >3 g/dL fall in Hgb
|
41 (1.9%)
|
124 (5.8%)
|
<.001
|
|
-With >5 g/dL fall in Hgb
|
14 (0.6%)
|
47 (2.2%)
|
<.001
|
|
-Retroperitoneal bleeding
|
5 (0.2%)
|
15 (0.7%)
|
.026
|
|
-Intracranial bleeding
|
1 (0.05%)
|
2 (0.09%)
|
.624
|
|
-Required transfustion‡ |
43 (2.0%)
|
123 (5.7%)
|
<.001
|
|
* 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.
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.
1Bittl JA, Chaitman BR, Feit F, Kimball W, Topol EJ. Bivalirudin versus heparin during coronary
angioplasty for unstable or postinfarction angina: final report reanalysis of the
Bivalirudin Angioplasty Study. Am Heart J. 2001;142:952-959.
2Angiomax Prescribing Information. The Medicines Company; Parsippany,
NJ, December 6, 2005.
3Data on file. The Medicines Company; Parsippany, NJ.
4Henry TD. Overcoming heparin limitations in high-risk percutaneous coronary
intervention: the alternative strategy — replacing heparin with bivalirudin. J Invas
Cardiol. 2002;14(suppl B):19B-29B.
5Bittl J. Switching from heparin to a thrombin-specific anticoagulant
(bivalirudin) for PTCA in unstable angina patients reduces major clinical events. Circulation.
2000;102(18suppl):813.