CACHET: Comparison of Abciximab Complications With Hirulog
for Ischemic Events Trial (CACHET)1
The overall results of CACHET (Parts A, B, & C) showed that administration of
Angiomax® (bivalirudin) with or without provisional abciximab:
- Achieved rapid and manageable anticoagulation
- Showed no apparent pharmacological interaction with abciximab
- Was associated with a lower combined incidence of major adverse clinical outcomes,
myocardial infarction (MI), revascularization, and major hemorrhage compared with
heparin plus abciximab
Based on parts B and C of CACHET and REPLACE-12,
an ANGIOMAX bolus of 0.75 mg/kg and an infusion of 1.75 mg/kg/h (with or without
provisional abciximab) appears to maintain adequate anticoagulation throughout the
duration of a typical percutaneous coronary intervention (PCI).
CACHET and the results from REPLACE-12
formed the clinical basis for the REPLACE-2 trial, which was designed to compare
clinical and economic outcomes among patients undergoing contemporary PCI and receiving
ANGIOMAX as the foundation anticoagulant (with provisional use of glycoprotein [GP]
IIb/IIIa inhibitors) against the outcomes of patients receiving unfractionated heparin
plus routine GP IIb/IIIa inhibitors as the antithrombotic regimen.3
CACHET was a randomized, open-label trial designed to assess the safety and efficacy
of ANGIOMAX with provisional abciximab versus low-dose heparin and abciximab in
patients undergoing angioplasty and stenting.
A sequence of randomized, open-label trials (CACHET–Parts A, B, & C)1 evaluated ANGIOMAX plus planned or provisional
abciximab versus heparin plus abciximab to assess in a preliminary manner the safety
and effectiveness of ANGIOMAX with planned or provisional abciximab. Sequential
phases were planned, first focusing on the safety (bleeding risk) of ANGIOMAX combined
with abciximab and subsequently assessing the efficacy of ANGIOMAX alone, with abciximab
given only as needed, in suppressing ischemic complications.
|
|
Phase
|
|
|
A
|
B
|
C
|
|
Patients Randomized
|
60
|
129
|
80
|
Randomization ratio
(control arm/study
arm)
|
1:1
|
1:2
|
1:3
|
|
Control arm
|
Low dose, weight-adjusted heparin
+ planned abciximab
|
|
Study arm
|
|
|
|
|
ANGIOMAX bolus (mg/kg)
|
1.0
|
0.50
|
0.75
|
|
ANGIOMAX infusion (mg/kg/h)
|
2.5
|
1.75
|
1.75
|
|
ANGIOMAX infusion duration
|
4h
|
In laboratory
|
In laboratory
|
|
Abciximab
|
Planned
|
Provisional
|
Provisional
|
Adapted from Lincoff et al, Am Heart J, 2002.
A total of 268 patients were enrolled. There were no significant differences in
baseline or procedural variables among the ANGIOMAX and heparin treatment groups.
Results from CACHET Part A showed that administration of the labeled dose of ANGIOMAX
concomitantly with full-dose abciximab (n = 30), resulted in:
- Predictable and manageable anticoagulation
- No excessive risk of hemorrhage or clinical ischemia events
- Clinically meaningful inhibition of thrombin
- 80% to 90% inhibition of adenosine diphosphate (ADP)-induced platelet aggregation
The CACHET Part A study established the safety of combining ANGIOMAX with abciximab
without excessive risk of hemorrhage or clinical ischemia.
CACHET–Part B/C:This portion of CACHET examined the effects of different
doses of ANGIOMAX with provisional abciximab. Patients undergoing elective PCI were
randomized to receive either low-dose heparin (70 units/kg bolus, maximum 7000 units)
with abciximab (0.25 mg/kg bolus and 0.125 µg/kg/min infusion) (control group) or
ANGIOMAX at 2 different doses with provisional abciximab. In the heparin group,
additional weight-adjusted boluses were administered as needed for the duration
of the procedure to maintain an ACT level >200 seconds. The first 85 ANGIOMAX patients
(Part B) received a bolus of 0.5 mg/kg. The next 59 ANGIOMAX patients (Part C) received
a bolus of 0.75 mg/kg. Following the boluses, ANGIOMAX patients also received an
infusion of 1.75 mg/kg/h for the duration of the procedure and provisional abciximab
at the discretion of the PCI operator.
Abciximab was used in 34 (24%) patients randomized to ANGIOMAX. All patients received
aspirin. Patients were also treated with a thienopyridine after stent placement.
Stents were deployed in 184/208 (88%) patients.
No death or stroke occurred in any group. The combined incidence of death, MI, revascularization,
or major hemorrhage reported within 7 days was 3.5% (5/144) in the ANGIOMAX patients
and 14.1% (9/64) in the heparin plus abciximab group.
CACHET B/C TRIAL: Clinical Outcomes at 7 days
|
Clinical Outcome
|
Control heparin plus abciximab
(n=64)
(Parts B/C)
|
Parts B ANGIOMAX (bolus 0.5mg/kg,
infusion 1.75 mg/kg/h) (n=85)
|
Parts C ANGIOMAX (bolus 0.75mg/kg,
infusion 1.75 mg/kg/h) (n=59)
|
Parts B/C ANGIOMAX (combined)
(n=144)
|
|
|
II
|
%
|
II
|
%
|
II
|
%
|
II
|
%
|
|
Death/MI/Revasc |
5
|
7.8
|
4
|
4.7
|
0
|
0.0
|
4
|
2.8
|
|
Major hemorrhage* |
4
|
6.3
|
2
|
2.4
|
0
|
0.0
|
2
|
1.4
|
|
Any clinical event* |
9
|
14.1
|
5
|
5.9
|
0
|
0.0
|
5
|
3.5
|
Use of ANGIOMAX and provisional abciximab resulted in a 75% reduction in the risk
of death, MI, revascularization, and major bleeding* compared with patients administered
heparin and abciximab.
|
* Major hemorrhage defined as intracranial, retroperitoneal or intraocular bleeding,
or overt bleeding associated with fall in hemoglobin concentration of >3 g/dL or
transfusion of ≥2 units of blood.
† Death, MI, revascularization, or major hemorrhage.
|
CACHET – Net Clinical Benefit
Use of ANGIOMAX and provisional abciximab resulted in a 78% reduction in the risk
of major bleeding* vs heparin plus planned abciximab (1.4% vs 6.3%, respectively).
|
* Major bleeding defined as intracranial, intraocular, or retroperitoneal hemorrhage,
blood loss resulting in a decrease in hemoglobin level by >3 g/dL, or clinically
overt bleeding leading to transfusion of ≥2U of blood.
|
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.
1Lincoff AM, Kleiman NS, Kottke-Marchant K, et al. Bivalirudin with planned
or provisional abciximab versus low-dose heparin and abciximab during percutaneous
coronary revascularization: results of the Comparison of Abciximab Complications
With Hirulog for Ischemic Events Trial (CACHET). Am Heart J . 2002;143:847-853.
2Lincoff AM, Bittl JA, Kleiman NS, et al. Comparison of bivalirudin versus
heparin during percutaneous coronary intervention (the Randomized Evaluation of
PCI Linking Angiomax to Reduced Clinical Events [REPLACE-1] trial). Am J Cardiol.
2004;93:1092-1096.
3Lincoff AM, Bittl JA, Harrington RA, et al. Bivalirudin and provisional
glycoprotein IIb/IIIa blockade compared with heparin and planned glycoprotein IIb/IIIa
blockade during percutaneous coronary intervention: REPLACE-2 randomized trial.
JAMA. 2003;289:853-863.