CACHET: Comparison of Abciximab Complications With Hirulog for Ischemic Events Trial (CACHET)¹

• Summary
• Trial Design
• Clinical Outcomes

Summary

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 amongst 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

Trial Design

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.

Trial Design

A total of 268 patients were enrolled. There were no significant differences in baseline or procedural variables among the ANGIOMAX and heparin treatment groups.

CACHET– Part A: Patients received ANGIOMAX (1 mg/kg bolus followed by 2.5 mg/kg/h for 4 hours) and abciximab (0.25 mg/kg bolus followed by 0.125 µg/kg/min infusion for 12 hours). In the heparin plus abciximab arm, patients received low-dose weight-adjusted heparin (initial bolus of 70 units/kg, maximum 7000 units) with additional boluses to maintain activated clotting time (ACT) >200 seconds. The abciximab dose was the same as for the ANGIOMAX treatment arm. Sixty patients (30 per treatment group) were randomized.

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.

Clinical Outcomes

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

* 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.

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.

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.