Direct Thrombin Inhibitors

argatroban

Heparin-Induced Thrombocytopenia (HIT/HITTS)
Initial Dosage: Before administering Argatroban, discontinue heparin therapy and obtain a baseline aPTT. The recommended initial dose of Argatroban for adult patients without hepatic impairment is 2 µg/kg/min, administered as a continuous infusion. Monitoring therapy: In general, therapy with Argatroban is monitored using the aPTT. Tests of anticoagulant effects (including the aPTT) typically attain steady-state levels within 1-3 hours following initiation of Argatroban. Dose adjustment may be required to attain the target aPTT. Check the aPTT 2 hours after initiation of therapy to confirm that the patient has attained the desired therapeutic range. Dosage adjustment: After the initial dose of Argatroban, the dose can be adjusted as clinically indicated (not to exceed 10 µg/kg/min), until the steady-state aPTT is 1.5 to 3 times the initial baseline value (not to exceed 100 seconds).

Percutaneous Coronary Interventions (PCI) in HIT/HITTS Patients
Initial Dosage: An infusion of Argatroban should be started at 25 µg/kg/min and a bolus of 350 µg/kg administered via a large bore intravenous (IV) line over 3 to 5 minutes. Activated clotting time (ACT) should be checked 5 to 10 minutes after the bolus dose is completed. The procedure may proceed if the ACT is greater than 300 seconds.
Dosage Adjustment: If the ACT is less than 300 seconds, an additional IV bolus dose of 150 µg/kg should be administered, the infusion dose increased to 30 µg/kg/min, and the ACT checked 5 to 10 minutes later. If the ACT is greater than 450 seconds, the infusion rate should be decreased to 15 µg/kg/min, and the ACT checked 5 to 10 minutes later. Once a therapeutic ACT (between 300 and 450 seconds) has been achieved, this infusion dose should be continued for the duration of the procedure. In case of dissection, impending abrupt closure, thrombus formation during the procedure, or inability to achieve or maintain an ACT over 300 seconds, additional bolus doses of 150 µg/kg may be administered and the infusion dose increased to 40 µg/kg/min. The ACT should be checked after each additional bolus or change in the rate of infusion.

Bivalirudin (Angiomax ®)

Anticoagulant in patients with unstable angina undergoing PTCA (treatment should be started just prior to PTCA): Initial: Bolus: 1 mg/kg IV, 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.

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%.

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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