Direct Thrombin Inhibitors

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

argatroban

Prophylaxis or treatment of thrombosis in adults with heparin-induced thrombocytopenia; adjunct to percutaneous coronary intervention (PCI) in patients who have or are at risk of thrombosis associated with heparin-induced thrombocytopenia

Mechanism of Action
A direct, highly selective thrombin inhibitor. Reversibly binds to the active thrombin site of free and clot-associated thrombin. Inhibits fibrin formation; activation of coagulation factors V, VIII, and XIII; protein C; and platelet aggregation.

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).

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

Administration
Solution must be diluted to 1 mg/mL prior to administration.

Monitoring Parameters
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.

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

Bivalirudin (Angiomax ®)

Anticoagulant used in conjunction with aspirin for patients with unstable angina undergoing percutaneous transluminal coronary angioplasty (PTCA)

Mechanism of Action
Bivalirudin acts as a specific and reversible direct thrombin inhibitor, binding to circulating and clot-bound thrombin. Shows linear dose- and concentration-dependent prolongation of ACT, aPTT, PT and TT.

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 ®):

Lepirudin provides more stable level of anticoagulation than heparin. Lepirudin does not require endogenous cofactors and acts independently of antithrombin-III.

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.

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