Indications
US (United States)
*Bivalirudin is indicated for use as an anticoagulant in patients with unstable angina undergoing percutaneous transluminal coronary angioplasty (PTCA). *Bivalirudin with provisional use of glycoprotein IIb/IIIa inhibitor (GPI) is indicated for use as an anticoagulant in patients undergoing percutaneous coronary intervention (PCI). *Bivalirudin is indicated for patients with, or at risk of HIT/HITTS undergoing PCI. *Bivalirudin is intended for use with aspirin and has been studied only in patients receiving concomitant aspirinEU (European)
*Percutaneous Coronary Intervention (PCI), including patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary PCI. *Bivalirudin is also indicated for the treatment of adult patients with unstable angina/non-ST segment elevation myocardial infarction (UA/NSTEMI) planned for urgent or early intervention. *Bivalirudin should be administered with aspirin and clopidogrel.Basic chemical and pharmacological properties
Chemistry
Bivalirudin is a 20 amino acid long peptide with the sequence D-Phe-Pro-Arg-Pro-Gly-Gly-Gly-Gly-Asn-Gly-Asp-Phe-Glu-Glu-Ile-Pro-Glu-Glu-Tyr-Leu (FPRPGGGGNGDFEEIPEEYL), where the first residue is D-phenylalanine instead of the natural L-phenylalanine.Mechanism of action
Bivalirudin 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. It cleaves fibrinogen into fibrin monomers, activates Factor V, VIII, and XIII, allowing fibrin to develop a covalently cross-linked framework that stabilizes the thrombus. Thrombin also promotes further thrombin generation, and activates platelets, stimulating aggregation and granule release. The binding of bivalirudin to thrombin is reversible as thrombin slowly cleaves the bivalirudin-Arg3-Pro4 bond, resulting in recovery of thrombin active site functions.Pharmacokinetics
*Following an IV bolus of bivalirudin of 1 mg/kg and a 4-hour 2.5 mg/kg/h IV infusion a mean steady state concentration of 12.3 ± 1.7 µg/mL is achieved *Bivalirudin is cleared from plasma by a combination of renal mechanisms and proteolytic cleavage *Half-life: -Normal renal function (≥ 90 mL/min) = 25 minutes -Mild renal dysfunction (60–89 mL/min) = 22 minutes -Moderate renal dysfunction (30-59 mL/min) = 34 minutes -Severe renal dysfunction (≤ 29 mL/min) = 57 minutes -Dialysis-dependent = 3.5 hours *Clearance is reduced approximately 20% in patients with moderate and severe renal impairment and by 80% in dialysis-dependent patients *Bivalirudin is hemodialyzable and approximately 25% is cleared by hemodialysis. Pharmacodynamics Coagulation times return to baseline approximately 1 hour following cessation of bivalirudin administration.Dosing and administration
Bivalirudin is intended for IV use only and is supplied as a sterile, lyophilized product in single-use, glass vials. After reconstitution, each vial delivers 250 mg of bivalirudin. ''US dosing'': *PCI Bolus: 0.75 mg/kg *PCI Infusion: 1.75 mg/kg/h ''EU dosing'': *UA/NSTEMI -Bolus: 0.1 mg/kg -Infusion: 0.25 mg/kg/h for up to 72 hours for medical management -If patient proceeds to PCI, an additional bolus of 0.5 mg/kg of bivalirudin should be administered before the procedure and the infusion increased to 1.75 mg/kg/h for the duration of the procedure. *PCI -Bolus: 0.75 mg/kg -Infusion: 1.75 mg/kg/h *Coronary Artery Bypass Graft (CABG) -Patients proceeding to CABG surgery off-pump: The IV infusion of bivalirudin should be continued until the time of surgery. Just prior to surgery, a 0.5 mg/kg bolus dose should be administered followed by a 1.75 mg/kg/h infusion for the duration of the surgery. -Patients proceeding to CABG surgery on-pump: The IV infusion of bivalirudin should be continued until 1 hour prior to surgery after which the infusion should be discontinued Five minutes after the bolus dose has been administered, an activating clotting time (ACT) should be performed and an additional bolus of 0.3 mg/kg should be given if needed. Continuation of the bivalirudin infusion following PCI for up to 4 hours post-procedure is optional, at the discretion of the treating physician. After 4 hours, an additional IV infusion of bivalirudin may be initiated at a rate of 0.2 or 0.25 mg/kg/h for up to 20 hours, if needed. Bivalirudin should be administered with optimal antiplatelet therapy (aspirin plus clopidogrel). ''Renal impairment'' A reduction in the infusion dose of bivalirudin should be considered in patients with moderate or severe renal impairment. If a patient is on hemodialysis, the infusion should be reduced to 0.25 mg/kg/h. No reduction in the bolus dose is needed.Safety information
Bivalirudin is contraindicated in patients with active major bleeding and hypersensitivity to bivalirudin or its components. (In the EU bivalirudin is also contraindicated in patients with an increased risk of bleeding due to hemostasis disorders and/or irreversible coagulation disorders, severe uncontrolled hypertension, subacute bacterial endocarditis, and severe renal impairment FR<30 ml/minand in dialysis-dependent patients). Bivalirudin is an anticoagulant. Therefore, bleeding is an expected adverse event. In clinical trials, bivalirudin treated patients exhibited statistically significantly lower rates of bleeding than patients treated with heparin plus a GP IIb/IIIa inhibitor. The most common (≥10%) adverse events of bivalirudin are back pain, pain, nausea, headache, and hypotension. Bivalirudin is classified as Pregnancy Category B.Pediatric experience
The U.S. Food and Drug Administration (FDA) granted pediatric exclusivity for bivalirudin, based on studies submitted in response to a written request by the FDA to investigate the use of bivalirudin in pediatric patients aged birth to 16-years old. The submission was based on a prospective, open-label, multi-center, single arm study evaluating bivalirudin as a procedural anticoagulant in the pediatric population undergoing intravascular procedures for congenital heart disease. Study outcomes suggest that the pharmacokinetic (PK) and pharmacodynamic (PD) response of bivalirudin in the pediatric population is predictable and behaves in a manner similar to that in adults.Comparative results
Bivalirudin is supported by 7 major randomized trials. These trials include REPLACE-2 (Randomized Evaluation of PCI Linking Angiomax to Reduced Clinical Events-2), BAT (Bivalirudin Angioplasty Trial), ACUITY (Acute Catheterization and Urgent Intervention Triage Strategy Trial), and HORIZONS AMI (Harmonizing Outcomes With Revascularization and Stents in AMI). A total of 25,000 patients with a low to high risk for ischemic complications undergoing PCI were evaluated. Bivalirudin with or without provisional GPIIb/IIIa demonstrated similar angiographic and procedural outcomes and improved clinical outcomes when compared with heparin plus GPIIb/IIIa. HORIZONS-AMI HORIZONS AMI was a prospective, randomized, open-label, double-arm multicenter trial in STEMI patients undergoing primary PCI. ''30 Day Results'' *The incidence of net adverse clinical events (9.2% vs. 12.1%) and major bleeding (4.9% vs. 8.3%) was significantly reduced by bivalirudin monotherapy versus unfractionated heparin (UFH) plus a GP IIb/IIIa inhibitor with similar rates of major adverse cardiovascular events (5.4 vs. 5.5%) at 30 days. *A significant reduction in the rate of cardiac mortality in patients treated with bivalirudin monotherapy versus UFH plus a GP IIb/IIIa inhibitor was observed (1.8% vs. 2.9%) at 30 days. *Patients receiving Angiomax monotherapy had similar rates of overall stent thrombosis (Academic Research Consortium (ARC) definition) at 30 days versus UFH plus a GP IIb/IIIa inhibitor (2.5% vs. 1.9%), with the exception of acute stent thrombosis (<24 hours), which was higher for the bivalirudin-treated patients at 1.3% vs 0.3% for the UFH-GP IIb/IIIa-inhibitor-treated patients. ''1-Year Results'' *At 1-year follow-up, a reduction in the incidence of net adverse clinical events (15.7% vs. 18.3%) and major bleeding (5.8% vs. 4.9%) was maintained in the bivalirudin monotherapy group versus UFH plus a GP IIb/IIIa inhibitor group, with no difference in the rate ofGuidelines
Bivalirudin has Class I recommendations in multiple national guidelines. US guidelines EU guidelinesReferences
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