Pharmacodynamics:

In healthy volunteers and patients (with ≥ 70% vessel occlusion undergoing routine angioplasty), Angiomax exhibits linear dose- and concentration-dependent anticoagulant activity as evidenced by prolongation of the ACT, aPTT, PT, and TT. Intravenous administration of Angiomax produces an immediate anticoagulant effect. Coagulation times return to baseline approximately 1 hour following cessation of Angiomax administration.

In 291 patients with ≥ 70% vessel occlusion undergoing routine angioplasty, a positive correlation was observed between the dose of Angiomax and the proportion of patients achieving ACT values of 300 sec or 350 sec. At an Angiomax dose of 1.0 mg/kg IV bolus plus 2.5 mg/kg/h IV infusion for 4 hours, followed by 0.2 mg/kg/h, all patients reached maximal ACT values >300 sec.

CLINICAL TRIALS:

Angiomax has been evaluated in five randomized, controlled interventional cardiology trials reporting 11,422 patients. Stents were deployed in 6062 of the patients in these trials - mainly in trials performed since 1995. Percutaneous transluminal coronary angioplasty (PTCA), atherectomy or other procedures were performed in the remaining patients.

REPLACE-2 Trial

This was a randomized double-blind multicenter study reporting 6002 (intent-to-treat) patients undergoing percutaneous coronary intervention (PCI). Patients were randomized to treatment with Angiomax with the "provisional" use of platelet glycoprotein IIb/IIIa inhibitor (GPI) or heparin plus planned use of GPI. GPIs were added on a "provisional" basis to patients who were randomized to Angiomax in the following circumstances:

1.    decreased TIMI flow (0 to 2) or slow reflow;

2.    dissection with decreased flow;

3.    new or suspected thrombus;

4.    persistent residual stenosis;

5.    distal embolization;

6.    unplanned stent;

7.    suboptimal stenting;

8.    side branch closure;

9.    abrupt closure; clinical instability; and

10.  prolonged ischemia.

During the study, one or more of these circumstances occurred in 12.7% of patients in the Angiomax with "provisional" GPI arm. GPIs were administered to 7.2% of patients in the Angiomax with "provisional" GPI arm (62.2% of eligible patients).

Patients ranged in age from 25-95 years (median 63); weight ranged from 35-199 kg (median 85.5): 74.4% were male and 25.6% were female. Indications for PCI included unstable angina (35% of patients), myocardial infarction within 7days prior to intervention (8% of patients), stable angina (25%) and positive ischemic stress test (24%). Stents were deployed in 85% of patients. Ninety-nine percent of patients received aspirin and 86% received thienopyridines prior to study treatment.

Angiomax was administered as a 0.75 mg/kg bolus followed by a 1.75 mg/kg/h infusion for the duration of the procedure. At investigator discretion, the infusion could be continued following the procedure for up to 4 hours. The median infusion duration was 44 min. Heparin was administered as a 65 U/kg bolus. GPIs (either abciximab or eptifibatide) were given according to manufacturers' instructions. Both randomized groups could be given "provisional" treatments during the PCI at investigator discretion, but under double-blind conditions. "Provisional" treatment with GPI was requested in 5.2% of patients randomized to heparin plus GPI (they were given placebo) and 7.2% patients randomized to Angiomax with "provisional" GPI (they were given abciximab or eptifibatide according to pre-randomization investigator choice and patient stratification).

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