DESCRIPTION

Angiomax® (bivalirudin) is a specific and reversible direct thrombin inhibitor. The active substance is a synthetic, 20 amino acid peptide. The chemical name is D-phenylalanyl-L-prolyl-L-arginyl-L-prolyl-glycyl-glycyl-glycyl-glycyl-L-asparagyl-glycyl-L-aspartyl-L-phenylalanyl-L-glutamyl-L-glutamyl-L-isoleucyl-L-prolyl-L-glutamyl-L-glutamyl-L-tyrosyl-L-leucine trifluoroacetate (salt) hydrate (Figure 1). The molecular weight of Angiomax is 2180 daltons (anhydrous free base peptide). Angiomax is supplied in single-use vials as a white lyophilized cake, which is sterile. Each vial contains 250 mg bivalirudin, 125 mg mannitol, and sodium hydroxide to adjust the pH to 5-6 (equivalent of approximately 12.5 mg sodium). When reconstituted with Sterile Water for Injection the product yields a clear to opalescent, colorless to slightly yellow solution, pH 5-6.

CLINICAL PHARMACOLOGY

General:

Angiomax directly inhibits thrombin by specifically binding both to the catalytic site and to the anion-binding exosite of circulating and clot-bound thrombin. Thrombin is a serine proteinase that plays a central role in the thrombotic process, acting to cleave fibrinogen into fibrin monomers and to activate Factor XIII to Factor XIIIa, allowing fibrin to develop a covalently cross-linked framework which stabilizes the thrombus; thrombin also activates Factors V and VIII, promoting further thrombin generation, and activates platelets, stimulating aggregation and granule release. The binding of Angiomax to thrombin is reversible as thrombin slowly cleaves the Angiomax-Arg3-Pro4 bond, resulting in recovery of thrombin active site functions.

In in vitro studies, Angiomax inhibited both soluble (free) and clot-bound thrombin, was not neutralized by products of the platelet release reaction, and prolonged the activated partial thromboplastin time (aPTT), thrombin time (TT), and prothrombin time (PT) of normal human plasma in a concentration-dependent manner. The clinical relevance of these findings is unknown.

Pharmacokinetics:

Angiomax exhibits linear pharmacokinetics following intravenous (IV) administration to patients undergoing percutaneous transluminal coronary angioplasty (PTCA). In these patients, a mean steady state Angiomax concentration of 12.3 ± 1.7 mcg/mL is achieved following an IV bolus of 1 mg/kg and a 4-hour 2.5 mg/kg/h IV infusion. Angiomax is cleared from plasma by a combination of renal mechanisms and proteolytic cleavage, with a half-life in patients with normal renal function of 25 min. The disposition of Angiomax was studied in PTCA patients with mild and moderate renal impairment and in patients with severe renal impairment. Drug elimination was related to glomerular filtration rate (GFR). Total body clearance was similar for patients with normal renal function and with mild renal impairment (60-89 mL/min). Clearance was reduced approximately 20% in patients with moderate and severe renal impairment and was reduced approximately 80% in dialysis-dependent patients. See Table 1 for pharmacokinetic parameters. For patients with renal impairment the activated clotting time (ACT) should be monitored. For dosing instructions, refer to the DOSAGE AND ADMINISTRATION section. Angiomax is hemodialyzable. Approximately 25% is cleared by hemodialysis.

Angiomax does not bind to plasma proteins (other than thrombin) or to red blood cells.

Pharmacodynamics:

In healthy volunteers and patients (with ≥ 70% vessel occlusion undergoing routine angioplasty), Angiomax® (bivalirudin) 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 eva luated 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 7 days 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).

The activated clotting time (ACT – measured by a Hemochron® device) was measured 5 min after the first bolus of study medication. The percent of patients reaching protocol-specified levels of anticoagulation was greater in the Angiomax with provisional GPI group than in the heparin plus GPI group. For patients randomized to Angiomax® (bivalirudin) with provisional GPI, the median 5 min ACT was 358 sec (interquartile range 320-400 sec) and the ACT was <225 sec in 3%. For patients randomized to heparin plus GPI, the median 5 min ACT was 317 sec (interquartile range 263-373 sec) and the ACT was <225 sec in 12%. At the end of the procedure, median ACT values were 334 sec (Angiomax group) and 276 sec (heparin plus GPI group).

For the composite endpoint of death, MI, or urgent revascularization adjudicated under double-blind conditions, the frequency was higher (7.6%) (95% confidence interval 6.7%-8.6%) in the Angiomax with “provisional” GPI arm when compared to the heparin plus GPI arm (7.1%) (95% confidence interval 6.1%-8.0%). However, major hemorrhage was reported significantly less frequently in the Angiomax with provisional GPI arm (2.4%) compared to the heparin plus GPI arm (4.1%). Study outcomes are shown in Table 2. 

At 12 months follow-up, mortality was 1.9% among patients randomized to Angiomax with “provisional” GPIs and 2.5% among patients randomized to heparin plus GPI.

Bivalirudin Angioplasty Trial (BAT):

Angiomax® (bivalirudin) was eva luated in patients with unstable angina undergoing PTCA in two randomized, double-blind, multicenter studies with identical protocols. Patients must have had unstable angina defined as: (1) a new onset of severe or accelerated angina or rest pain within the month prior to study entry or (2) angina or ischemic rest pain which developed between four hours and two weeks after an acute myocardial infarction (MI). Overall, 4312 patients with unstable angina, including 741 (17%) patients with post-MI angina, were treated in a 1:1 randomized fashion with Angiomax or heparin. Patients ranged in age from 29-90 (median 63) years, their weight was a median of 80 kg (39-120 kg), 68% were male, and 91% were Caucasian. Twenty-three percent of patients were treated with heparin within one hour prior to randomization. All patients were administered aspirin 300-325 mg prior to PTCA and daily thereafter. Patients randomized to Angiomax were started on an intravenous infusion of Angiomax (2.5 mg/kg/h). Within 5 min after starting the infusion, and prior to PTCA, a 1 mg/kg loading dose was administered as an intravenous bolus. The infusion was continued for 4 hours, then the infusion was changed under double-blinded conditions to Angiomax (0.2 mg/kg/h) for up to an additional 20 hours (patients received this infusion for an average of 14 hours). The ACT was checked at 5 min and at 45 min following commencement. If on either occasion the ACT was <350 sec, an additional double-blinded bolus of placebo was administered. The Angiomax dose was not titrated to ACT. Median ACT values were: ACT in sec (5th percentile-95th percentile):  345 sec (2