Current Clinical Applications of Bivalirudin: An Overview

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Nicolas W. Shammas, MS, MD

Clinical Pharmacology of Bivalirudin
Bivalirudin is a direct thrombin inhibitor with specific and reversible actions.1–6 It is a synthetic, 20-amino acid peptide with a molecular weight of 2180 daltons. Bivalirudin directly inhibits both circulating and bound thrombin by binding to its catalytic site and anion-binding exosite. The binding to thrombin is reversible, as the latter cleaves the bivalirudin-Arg3-Pro4 bond, resulting in recovery of the active site. Bivalirudin does not activate platelets and is not inhibited by platelet products. It produces a linear dose and concentration-dependent anticoagulation with subsequent prolongation of partial thromboplastin time (PTT) and prothrombin time (PT). At the most commonly utilized dose of 0.75 mg/kg IV bolus and 1.75 mg/kg/hour infusion during percutaneous coronary interventions (PCI), bivalirudin yields a mean activated clotting time (ACT) of 358 sec, 5 minutes after the initial bolus. If bivalirudin needs to be administered beyond the post procedural 4-hour infusion window, it can be continued at a rate of 0.2 mg/kg/hour. However, the administration of bivalirudin beyond the procedure time is optional and in fact, infrequently used.
Bivalirudin is also partly cleared by renal mechanisms, and therefore, dose administration needs to be adjusted in patients with severe renal impairment (creatinine clearance 10–29 mL/min) (maintenance rate reduced to 1 mg/kg/hour), or in patients on hemodialysis (maintenance rate of 0.25 mg/kg/hour). The bolus dose is not altered with renal function. Once administered, there is no antidote to reverse bivalirudin anticoagulation effect. However, bivalirudin can be partly dialyzed (25% of the drug is cleared by hemodialysis).

Clinical Applications of Bivalirudin Bivalirudin in Percutaneous Coronary Interventions
Bivalirudin is currently approved as an anticoagulant in patients with unstable angina undergoing percutaneous transluminal coronary angioplasty, or with the provisional use of glycoprotein (GP) IIb/IIIa inhibitors in elective non-emergent PCI. A review of the clinical trials of bivalirudin in PCI is presented below.

Bivalirudin Angioplasty Study Trial (BAT)
In the BAT trial,7 patients (n = 4312) with unstable angina and undergoing percutaneous transluminal angioplasty were randomized to bivalirudin versus high dose heparin. In this multi-center, double-blind trial, patients treated with bivalirudin (n = 2161) had a 22% reduction in the 7-day composite endpoint of death, myocardial infarction (MI) and repeat revascularization as compared to the heparin-treated patients (n = 2151) (6.2% versus 7.9%, p = 0.0386). The composite endpoint difference was sustained at 90 days (p = 0.012) and 180 days (p = 0.153). Major bleeding was significantly reduced by 62% with bivalirudin compared to heparin (9.3% versus 3.5%, p < 0.001). Based on this study, the Food and Drug Administration (FDA) approved the use of bivalirudin in patients undergoing percutaneous coronary angioplasty. The BAT trial, however, was done prior to the era of stents and GP IIb/IIIa inhibitors, and therefore, its conclusions do not apply to today’s interventional practice.

Randomized Evaluation of PCI Linking Angiomax to Reduced Clinical Events (REPLACE)-1 trial
In the REPLACE-1 trial,8 1056 patients at 77 sites in the U.S. undergoing contemporary coronary interventions were randomized in a large-scale pilot study to unfractionated heparin (70 U/kg initial bolus) versus bivalirudin (0.75 mg/kg bolus, 1.75 mg/kg/hour infusion during the procedure). In contrast to the BAT trial, stents and GP IIb/IIIa inhibitors were used in 85% and 72% of patients, respectively. Furthermore, 56% of patients were pretreated with clopidogrel. The composite incidence of death, MI or urgent revascularization (before hospital discharge or within 48 hours) in the heparin group (n = 524) was 6.9% compared to 5.6% in the bivalirudin group (n = 532) (p = 0.4). Bivalirudin showed less major bleeding compared to heparin (2.1% versus 2.7%, respectively, p = 0.52). This trial confirmed the safety of the combined approach of bivalirudin with GP IIb/IIIa inhibition and demonstrated that bivalirudin can be effective in contemporary PCI. This study was not designed to address bivalirudin as a replacement to the combined therapy of heparin and GPIIb/IIIa inhibition during angioplasty.

Randomized Evaluation of PCI Linking Angiomax to Reduced Clinical Events (REPLACE)-11 trial.
In the REPLACE-2 trial,9 6,010 patients undergoing elective or urgent PCI at 233 sites in the United States, Canada, Europe and Israel were randomized in a double-blind, active-controlled trial of bivalirudin monotherapy (0.75 mg/kg bolus plus 1.75 mg/kg/hour for the duration of the PCI) with provisional GP IIb/IIIa inhibition (n = 2999) versus unfractionated heparin (65 U/kg bolus) with planned GP IIb/IIIa inhibition (eptifibatide or abciximab) (n = 3011). The primary 30-day composite endpoint of death, MI, urgent repeat revascularization and in-hospital major bleeding was 9.2% in the bivalirudin arm versus 10% in the heparin-GP IIb/IIIa arm (p = 0.32). The secondary 30-day composite endpoint of death, MI and urgent revascularization in the bivalirudin group met the prespecified statistical criteria for non-inferiority to the heparin-GP IIb/IIIa group. Provisional GP IIb/IIIa inhibitors were administered to 7.2% of bivalirudin patients. Also, bivalirudin led to significantly less in-hospital major bleeding when compared to the heparin-GP IIb/IIIa inhibitor combination (2.4% versus 4.1%, p < 0.001).

References: 

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