Bivalirudin is a specific and reversible direct thrombin inhibitor

Direct thrombin inhibitor

Direct thrombin inhibitors are a class of medication that act as anticoagulants by directly inhibiting the enzyme thrombin. Some are in clinical use, while others are undergoing clinical development...

 (DTI).¹

Chemically, it is a synthetic congener

Congener

Congener has several different meanings depending on the field in which it is used. Colloquially, it is used to mean a person or thing like another, in character or action.-Biology:In biology, congeners are organisms within the same genus...

 of the naturally occurring drug hirudin

Hirudin

Hirudin is a naturally occurring peptide in the salivary glands of medicinal leeches that has a blood anticoagulant property...

 (found in the saliva of the medicinal leech Hirudo medicinalis).

Bivalirudin is a DTI that overcomes many limitations seen with indirect thrombin inhibitors, such as heparin

Heparin

Heparin , also known as unfractionated heparin, a highly sulfated glycosaminoglycan, is widely used as an injectable anticoagulant, and has the highest negative charge density of any known biological molecule...

. Bivalirudin is a short, synthetic peptide that is potent, highly specific, and a reversible inhibitor of thrombin

Thrombin

Thrombin is a "trypsin-like" serine protease protein that in humans is encoded by the F2 gene. Prothrombin is proteolytically cleaved to form thrombin in the first step of the coagulation cascade, which ultimately results in the stemming of blood loss...

¹. It inhibits both circulating and clot-bound thrombin, while also inhibiting thrombin-mediated platelet activation and aggregation⁶. Bivalirudin has a quick onset of action and a short half-life.¹ It does not bind to plasma proteins (other than thrombin) or to red blood cells. Therefore it has a predictable antithrombotic response. There is no risk for Heparin Induced Thrombocytopenia

Heparin-induced thrombocytopenia

Heparin-induced thrombocytopenia is the development of thrombocytopenia , due to the administration of various forms of heparin, an anticoagulant...

/Heparin Induced Thrombosis-Thrombocytopenia Syndrome (HIT/HITTS).¹ It does not require a binding cofactor such as antithrombin and does not activate platelets. These characteristics make bivalirudin an ideal alternative to heparin.

Bivalirudin clinical studies demonstrated consistent positive outcomes in patients with stable angina

Angina

Angina pectoris, commonly known as angina, is chest pain due to ischemia of the heart muscle, generally due to obstruction or spasm of the coronary arteries . Coronary artery disease, the main cause of angina, is due to atherosclerosis of the cardiac arteries...

, unstable angina (UA), non-ST segment elevation myocardial infarction (NSTEMI), and ST-segment elevation myocardial infarction (STEMI) undergoing PCI in 7 major randomized trials ¹.

Indications

US (United States) Indications¹:

• 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 aspirin

EU (European) indications¹⁰:

• 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

Mechanism of action¹

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.

Video describing bivalirudin’s mechanism of action: http://www.angiomax.com/AboutAngiomax/mechanismAction.aspx?launch=true

Pharmacokinetics ¹

• 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 mcg/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 ¹

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:¹

• PCI Bolus: 0.75 mg/kg

• PCI Infusion: 1.75 mg/kg/hr

EU dosing¹⁰ :

• UA/NSTEMI

-Bolus: 0.1 mg/kg

-Infusion: 0.25 mg/kg/hr 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/hr for the duration of the procedure.
-Bolus: 0.75 mg/kg

-Infusion: 1.75 mg/kg/hr

• 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. ¹

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.^1,10

Bivalirudin should be administered with optimal antiplatelet therapy (aspirin plus clopidogrel). ^1,10

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. ^1,10

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 [GFR<30 ml/min] and in dialysis-dependent patients.)^1,10

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. ^1,10

Bivalirudin is classified as Pregnancy Category B. ^1,10

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.¹¹

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^1,9 .

HORIZONS-AMI^9,12,13

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%).

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 of major adverse cardiovascular events (11.9% vs. 11.9%)

• A significant reduction in the rate of cardiac mortality in patients treated with bivalirudin monotherapy versus UFH plus a GP IIb/IIIa inhibitor was maintained at 1 year in the HORIZONS AMI trial (2.1% vs. 3.8%)The incidence of stent thrombosis at 1 year was also similar between the 2 treatment groups (3.5% in the Angiomax group vs. 3.2% in the UFH plus GP IIb/IIIa inhibitor group).

2-Year Results

• At 2-year follow-up, a reduction in the incidence of net adverse clinical events (22.3 % vs. 24.8%) and major bleeding (6.4% vs. 9.6%) was maintained in the bivalirudin monotherapy group versus UFH plus a GP IIb/IIIa inhibitor group, with no difference in the rate of major adverse cardiovascular events (18.7% vs. 18.8%)

• A significant reduction in the rate of cardiac mortality in patients treated with bivalirudin monotherapy versus UFH plus a GP IIb/IIIa inhibitor was maintained at 2 year in the HORIZONS AMI trial (2.5% vs. 4.2%)

• At 2-year follow-up, treatment with bivalirudin monotherapy resulted in a 25% reduction in all-cause mortality, representing 15 lives saved per 1000 patients treated (number needed to treat [NNT] = 67 to save 1 life).

• The incidence of stent thrombosis (ARC definite/probable) at 2 years was also similar between the 2 treatment groups (4.6% in the Angiomax group vs. 4.3% in the UFH plus GP IIb/IIIa inhibitor group).

ACUITY

ACUITY was a large multicenter, prospective, open-label, 3-arm trial designed to establish the optimal antithrombotic treatment regimens in patients with UA/NSTEMI undergoing early invasive management.

30-Day Results

• Bivalirudin monotherapy provided superior net clinical outcomes compared to any heparin regimen with GP IIb/IIIa inhibitor (10.1% vs 11.7%) at 30 days.

• The incidence of ACUITY scale major bleeding (non-CABG) was decreased significantly by 47% in the bivalirudin monotherapy group vs the heparin with GP IIb/IIIa inhibitor group (3.0% vs 5.7%) at 30 days.

1-Year Results

• Bivalirudin alone demonstrated no difference in the rates of composite ischemic complications (death, MI, unplanned revascularization for ischemia) versus heparin with GP IIb/IIIa inhibition (16.4% vs 16.3%) at 12 months.

REPLACE-2

REPLACE-2 was a multicenter, double-blind, triple dummy randomized clinical trial in patients with low to moderate risk for ischemic complications undergoing PCI.

30 Days

• The incidence of net adverse clinical events (9.2% vs. 10.0%) and major adverse cardiovascular events (7.6% vs. 7.1%) was reduced by bivalirudin monotherapy versus unfractionated heparin (UFH) plus a GP IIb/IIIa inhibitor with significant reduction in rates of major bleeding (2.4 vs. 4.1%) at 30 days.

1-Year Results

• Differences in mortality favoring bivalirudin at 30 days and 6 months was maintained at 12 months and demonstrated a 24% risk reduction in death compared to heparin plus GP IIb/IIIa inhibition.

BAT

The Phase III Bivalirudin Angioplasty Trial (BAT) was a randomized, prospective, double blind, multicenter study in patients with unstable angina undergoing PTCA.

• The composite endpoint of death, MI or revascularization occurred in 6.2% of patients treated with bivalirudin and in 7.9% of patients treated with heparin.

• Significant reductions in clinical events were maintained at 90 days with absolute benefits being sustained through 180 days.

• The incidence of major hemorrhage for the entire hospitalization period in patients assigned bivalirudin was 3.7% compared to 9.3% in patients randomized to heparin.

Guidelines

Bivalirudin has Class I recommendations in multiple national guidelines.

US guidelines^14-16

Patient Type	Guidelines	Recommendations
STEMI and primary PCI	ACC/AHA/SCAI 2009 Joint STEMI/PCI Focused Update	Class I-B, IIa-B
UA/NSTEMI	ACC/AHA 2007 guidelines for UA/NSTEMI patients	Class I-B, IIa-B
NSTE-ACS patients	ACCP 2008 clinical practice guidelines for patients with NSTE-ACS	Grade 1A, 2B
PCI	ACCP 2008 clinical practice guidelines for patients with NSTE-ACS	Grade 1B

EU guidelines^17-19

Patient Type	Guidelines	Recommendations
STEMI	European Society of Cardiology 2008	Class IIa – B
NSTE-ACS	European Society of Cardiology 2007	Class IIa-B, IB
PCI	European Society of Cardiology 2005	Class IIa C, IC