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1/25/2001

Thrombin Inhibitor Approved for Anticoagulation During Angioplasty

Tzipora R. Lieder

The Medicines Company has begun marketing bivalirudin (Angiomax [PDF]) injection as an alternative to heparin for anticoagulation in patients with unstable angina undergoing percutaneous transluminal coronary angioplasty (PTCA). The drug is intended for use in patients also receiving aspirin. ICS distributes the product.

Bivalirudin binds specifically to the catalytic and the external anion-binding sites of circulating and clot-bound thrombin, thereby inhibiting the functions of thrombin crucial to promoting thrombus formation. The binding of bivalirudin to thrombin is reversible.

In two double-blind clinical trials, over 4300 patients with unstable angina undergoing PTCA were randomly assigned to receive bivalirudin or heparin as anticoagulant therapy. All patients received an intravenous (i.v.) injection of anticoagulant before the start of PTCA, followed by i.v. infusion of the agent for up to 24 hours. They also received aspirin 300–325 mg daily. The primary endpoint of the studies was a composite called procedural failure, encompassing clinical (occurrence of death, myocardial infarction, or urgent revascularization) and angiographic (evidence of impending or abrupt vessel closure) elements measured during hospitalization. The bivalirudin and heparin treatment groups had similar frequencies of the composite and individual clinical endpoints and the same median duration of hospitalization.

Limited information is available on the use of bivalirudin during PTCA in patients with heparin-induced thrombocytopenia, with or without thrombosis syndrome. FDA has asked the company to conduct postmarketing research in this patient population.

Although the results of drug-interaction studies of bivalirudin with low-molecular-weight heparin, ticlopidine, or abciximab did not suggest a change in anticoagulant activity, there is insufficient data to draw conclusions about the safety and efficacy of bivalirudin when used with these agents. In clinical trials, administration of bivalirudin with heparin, warfarin, or a thrombolytic agent was associated with increased risk of a major bleeding event compared with the use of bivalirudin alone.

Patients treated with bivalirudin had lower rates of major hemorrhage and lower requirements for blood transfusion than patients treated with heparin. During the clinical trials, the most common adverse events in patients treated with bivalirudin were back pain, general pain, nausea, headache, and hypotension; reported frequencies of these events were comparable in the bivalirudin and heparin treatment groups.

Bivalirudin is cleared by a combination of renal mechanisms and proteolytic cleavage. In patients undergoing PTCA, bivalirudin’s rate of elimination correlated with glomerular filtration rate. Total body clearance was reduced in patients with moderate or severe renal impairment and unaided dialysis-dependent patients. Therefore, the dosage of bivalirudin should be decreased in these types of patients, and activated clotting time should be monitored. About 25% of a bivalirudin dose is cleared by hemodialysis.

Bivalirudin treatment should start just before PTCA, with an i.v. bolus dose of 1.0 mg/kg followed by a four-hour i.v. infusion at a rate of 2.5 mg/kg/hr. After this infusion, another one may be given at a rate of 0.2 mg/kg/hr for up to 20 hours if needed.

Angiomax is available in single-use glass vials containing 250 mg of bivalirudin. Unopened vials must be stored at 2–8 degrees Celsius. Each vial should be reconstituted with 5 mL of sterile water for injection (gently swirl the contents) and diluted in 5% dextrose injection or 0.9% sodium chloride injection. To prepare an admixture for delivery at 1.0 mg/kg, each reconstituted vial should be diluted to achieve a final drug concentration of 5 mg/mL. For delivery at 0.2 mg/kg/hr, the drug should be diluted to 0.5 mg/mL. The product labeling includes a weight-based dosing table.