Direct Thrombin Inhibitors

argatroban	Bivalirudin (Angiomax ®)
lepirudin (Refludan ®):

argatroban

Mechanism of Action
Argatroban is a direct thrombin inhibitor that reversibly binds to the thrombin active site. Argatroban does not require the co-factor antithrombin III for antithrombotic activity. Argatroban exerts its anticoagulant effects by inhibiting thrombin-catalyzed or -induced reactions, including fibrin formation; activation of coagulation factors V, VIII, and XIII; activation of protein C; and platelet aggregation.

Argatroban is highly selective for thrombin with an inhibitory constant (Ki) of 0.04 µM. At therapeutic concentrations, Argatroban has little or no effect on related serine proteases (trypsin, factor Xa, plasmin, and kallikrein).

Argatroban is capable of inhibiting the action of both free and clot-associated thrombin.

Argatroban does not interact with heparin-induced antibodies. Evaluation of sera in 12 healthy subjects and 8 patients who received multiple doses of Argatroban did not reveal antibody formation to Argatroban

INDICATIONS AND USAGE
Argatroban is indicated as an anticoagulant for prophylaxis or treatment of thrombosis in patients with heparin-induced thrombocytopenia.

Argatroban is indicated as an anticoagulant in patients with or at risk for heparin-induced thrombocytopenia undergoing percutaneous coronary intervention (PCI).

CONTRAINDICATIONS
Argatroban is contraindicated in patients with overt major bleeding, or in patients hypersensitive to this product or any of its components

DOSAGE AND ADMINISTRATION
Each 2.5-mL vial contains 250 mg of Argatroban; and, as supplied, is a concentrated drug (100 mg/mL), which must be diluted 100-fold prior to infusion. Argatroban should not be mixed with other drugs prior to dilution in a suitable intravenous fluid.

Preparation for Intravenous Administration
Argatroban should be diluted in 0.9% Sodium Chloride Injection, 5% Dextrose Injection, or Lactated Ringer’s Injection to a final concentration of 1 mg/mL. The contents of each 2.5-mL vial should be diluted 100-fold by mixing with 250 mL of diluent. Use 250 mg (2.5 mL) per 250 mL of diluent or 500 mg (5 mL) per 500 mL of diluent. The constituted solution must be mixed by repeated inversion of the diluent bag for 1 minute. Upon preparation, the solution may show slight but brief haziness due to the formation of microprecipitates that rapidly dissolve upon mixing. The pH of the intravenous solution prepared as recommended is 3.2 to 7.5

Dosage - I.V.: Adults:
Heparin-induced thrombocytopenia:

Initial dose: 2 mcg/kg/minute.

Maintenance dose: Measure aPTT after 2 hours, adjust dose until the steady-state aPTT is 1.5-3.0 times the initial baseline value, not exceeding 100 seconds; dosage should not exceed 10 mcg/kg/minute

Conversion to oral anticoagulant: Because there may be a combined effect on the INR when argatroban is combined with warfarin, loading doses of warfarin should not be used. Warfarin therapy should be started at the expected daily dose.

Patients receiving </= 2 mcg/kg/minute of argatroban: Argatroban therapy can be stopped when the combined INR on warfarin and argatroban is >4; repeat INR measurement in 4-6 hours; if INR is below therapeutic level, argatroban therapy may be restarted. Repeat procedure daily until desired INR on warfarin alone is obtained.

Patients receiving >2 mcg/kg/minute of argatroban: Reduce dose of argatroban to 2 mcg/kg/minute; measure INR for argatroban and warfarin 4-6 hours after dose reduction; argatroban therapy can be stopped when the combined INR on warfarin and argatroban is >4. Repeat INR measurement in 4-6 hours; if INR is below therapeutic level, argatroban therapy may be restarted. Repeat procedure daily until desired INR on warfarin alone is obtained.

Note: Critically-ill patients with normal hepatic function became excessively anticoagulated with FDA-approved or lower starting doses of argatroban (Reichert MG, 2003). Doses between 0.15-1.3 mcg/kg/minute were required to maintain aPTTs in the target range. Another report of a cardiac patient with anasarca secondary to acute renal failure had a reduction in argatroban clearance similar to patient with hepatic dysfunction (de Denus S, 2003). Reduced clearance may have been attributed to reduced perfusion to the liver. Consider reducing starting dose to 0.5-1 mcg/kg/minute in critically-ill patients who may have impaired hepatic perfusion (eg, patients requiring vasopressors, having decreased cardiac output, having fluid overload).

Obtain baseline aPTT prior to start of therapy. Check aPTT 2 hours after start of therapy to adjust dose, keeping the steady-state aPTT 1.5-3 times the initial baseline value (not exceeding 100 seconds). Monitor hemoglobin, hematocrit, signs and symptoms of bleeding.

Percutaneous coronary intervention (PCI):
Initial: Begin infusion of 25 mcg/kg/minute and administer bolus dose of 350 mcg/kg (over 3-5 minutes). ACT should be checked 5-10 minutes after bolus infusion; proceed with procedure if ACT >300 seconds. Following initial bolus:

ACT <300 seconds: Give an additional 150 mcg/kg bolus, and increase infusion rate to 30 mcg/kg/minute (recheck ACT in 5-10 minutes)

ACT >450 seconds: Decrease infusion rate to 15 mcg/kg/minute (recheck ACT in 5-10 minutes)

Once a therapeutic ACT (300-450 seconds) is achieved, infusion should be continued at this dose for the duration of the procedure.

Impending abrupt closure, thrombus formation during PCI, or inability to achieve ACT >300 sec: An additional bolus of 150 mcg/kg, followed by an increase in infusion rate to 40 mcg/kg/minute may be administered.

Dosage adjustment in hepatic impairment: Decreased clearance and increased elimination half-life are seen with hepatic impairment; dose should be reduced. Initial dose for moderate hepatic impairment is 0.5 mcg/kg/minute. Note: During PCI, avoid use in patients with elevations of ALT/AST (>3 times ULN); the use of argatroban in these patients has not been evaluated.

Elderly: No adjustment is necessary for patients with normal liver function

Supplied
Injection, solution: 100 mg/mL (2.5 mL)

Bivalirudin (Angiomax ®)

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

INDICATIONS AND USAGE
Angiomax is indicated for use as an anticoagulant in patients with unstable angina undergoing percutaneous transluminal coronary angioplasty (PTCA).

Angiomax with provisional use of glycoprotein IIb/IIIa inhibitor (GPI) as listed in the CLINICAL TRIALS REPLACE-2 section (see package insert) is indicated for use as an anticoagulant in patients undergoing percutaneous coronary intervention (PCI).

Angiomax is indicated for patients with, or at risk of, HIT/HITTS undergoing PCI.

Angiomax is intended for use with aspirin and has been studied only in patients receiving concomitant aspirin.

The safety and effectiveness of Angiomax have not been established in patients with acute coronary syndromes who are not undergoing PTCA or PCI.

CONTRAINDICATIONS
Angiomax is contraindicated in patients with:

active major bleeding;

hypersensitivity to Angiomax or its components.

WARNINGS
Angiomax is not intended for intramuscular administration. Although most bleeding associated with the use of Angiomax in PCI occurs at the site of arterial puncture, hemorrhage can occur at any site. An unexplained fall in blood pressure or hematocrit, or any unexplained symptom, should lead to serious consideration of a hemorrhagic event and cessation of Angiomax administration.

An increased risk of thrombus formation has been associated with the use of Angiomax in gamma brachytherapy, including fatal outcomes.

There is no known antidote to Angiomax. Angiomax is hemodialyzable

Dosage
Adults: Anticoagulant in patients with unstable angina undergoing PTCA (treatment should be started just prior to PTCA): I.V.: Initial: Bolus: 1 mg/kg, followed by continuous infusion: 2.5 mg/kg/hour over 4 hours; if needed, infusion may be continued at 0.2 mg/kg/hour for up to 20 hours; patients should also receive aspirin 300-325 mg/day

Administration
For I.V. administration only. To prepare infusion, reconstitute each 250 mg vial with 5 mL sterile water for injection; further dilute with 5% dextrose in water or 0.9% sodium chloride for injection; final concentration should be 0.5-5 mg/mL. Do not mix with other medications.

Renal Dosing
Dosage adjustment in renal impairment: Infusion dose should be reduced based on degree of renal impairment. Initial bolus dose remains unchanged. Monitor activated coagulation time (ACT).
CRCL 60 ml/min: No adjustment required
CRCL 30-59 ml/min: Decrease infusion dose by 20%
CRCL 10-29 ml/min: Decrease infusion dose by 60%
Dialysis-dependent patients (off dialysis): Decrease infusion dose by 90%.

Monitoring Parameters
Depending upon indication for use of bivalirudin: ACT, aPTT, PT

Supplied:
Injection, powder for reconstitution: 250 mg

lepirudin (Refludan ®):

INDICATIONS AND USAGE
Refludan is indicated for anticoagulation in patients with heparin-induced thrombocytopenia (HIT) and associated thromboembolic disease in order to prevent further thromboembolic complications.

CONTRAINDICATIONS
REFLUDAN is contraindicated in patients with known hypersensitivity to hirudins or to any of the components in REFLUDAN [lepirudin (rDNA) for injection

Dosing: Initially give bolus: 0.4 mg/kg (use maximum weight of 110kg) over 15-20 seconds followed by maintenance dose of 0.15 mg/kg/hr (use maximum weight of 110kg) x 2-10 days as needed.
Monitoring: Monitor aPTT 4 hours after beginning treatment and at least daily (Target aPTT: 1.5 to 2.5x control) Dose adjustments: If aPTT ratio > 2.5, hold infusion for 2 hours, and decrease rate by 50%. Repeat aPTT in 4hrs. If aPTT ratio < 1.5, increase rate by 20% and repeat aPTT in 4 hrs.

Maximum dose: Do not exceed 0.21 mg/kg/hour unless an evaluation of coagulation abnormalities limiting response has been completed. Dosing is weight-based, however, patients weighing >110 kg should not receive doses greater than the recommended dose for a patient weighing 110 kg (44 mg bolus and initial maximal infusion rate of 16.5 mg/hour).

Heparin-induced thrombocytopenia: Bolus dose: 0.4 mg/kg IVP (over 15-20 seconds), followed by continuous infusion at 0.15 mg/kg/hour; bolus and infusion must be reduced in renal insufficiency.
Concomitant use with thrombolytic therapy: Bolus dose: 0.2 mg/kg IVP (over 15-20 seconds), followed by continuous infusion at 0.1 mg/kg/hour

Dosing adjustments during infusions: Monitor first aPTT 4 hours after the start of the infusion. Subsequent determinations of aPTT should be obtained at least once daily during treatment. More frequent monitoring is recommended in renally impaired patients. Any aPTT ratio measurement out of range (1.5-2.5) should be confirmed prior to adjusting dose, unless a clinical need for immediate reaction exists. If the aPTT is below target range, increase infusion by 20%. If the aPTT is in excess of the target range, decrease infusion rate by 50%. A repeat aPTT should be obtained 4 hours after any dosing change.

Use in patients scheduled for switch to oral anticoagulants: Reduce lepirudin dose gradually to reach aPTT ratio just above 1.5 before starting warfarin therapy; as soon as INR reaches 2.0, lepirudin therapy should be discontinued.

Renal Dosing
Dosing adjustment in renal impairment: All patients with a creatinine clearance of <60 ml/min or a serum creatinine of >1.5 mg/dl should receive a reduction in lepirudin dosage. There is only limited information on the therapeutic use of lepirudin in HIT patients with significant renal impairment; the following dosage recommendations are mainly based on single-dose studies in a small number of patients with renal impairment.
Initial: Bolus dose: 0.2 mg/kg IVP (over 15-20 seconds), followed by adjusted infusion based on renal function.
[CRCL 45-60 ml/min or Scr 1.6-2.0]: Adjust rate to 50% of standard infusion rate: 0.075 mg/kg/hour
[CRCL 30-44ml/min ; Scr 2.1-3.0]: Adjust rate to 30% of standard infusion rate: 0.045 mg/kg/hour.
[CRCL 15-29ml/min ; Scr 3.1-6.0]: Adjust rate to 15% of standard infusion rate: 0.0225 mg/kg/hour.
[CRCL <15ml/min ; Scr >6.0]: Avoid or STOP infusion. Note: Acute renal failure or hemodialysis: Infusion is to be avoided or stopped. Following the bolus dose, additional bolus doses of 0.1 mg/kg may be administered every other day (only if aPTT falls below lower therapeutic limit).

Supplied: 50 mg (powder for reconstitution).

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David F. McAuley, Pharm.D., R.Ph. GlobalRPh Inc.