Pharmacy & Therapeutics - November 2008 - (Page 648)

Heparin-Induced Thrombocytopenia Table 5 Non-heparin Alternatives for the Treatment of Heparin-Induced Thrombocytopenia (HIT) Agent Therapeutic Dose Clearance Half-Life Monitoring Adverse Effects Direct Thrombin Inhibitors Lepirudin (Refludan) 0.4 mg/kg IV bolus (up to 110 kg), followed by 0.15 mg/kg per hour (up to 110 kg) Renal 80 minutes • Measure aPTT 2 hours after initiation of therapy and after each dose adjustment • Therapeutic range: 1.5 to 2.5 x baseline (optimal aPTT, <65 seconds) Bleeding with therapeutic dose in 17.6% of patients; antilepirudin antibodies develop in 30% of patients Argatroban (Novastan) 2 mcg/kg per minute continu- Hepatic ous infusion; maximal infusion: 10 mcg/kg per minute 40–50 minutes • Measure aPTT 2 hours Bleeding with theraafter initiation of therapy peutic dose in 6% to and after each dose 7% of patients adjustment • Therapeutic range: 1.5 to 3 x baseline (≤100 seconds) Measure ACT 5 minutes after completing IV bolus Bleeding with dose used in PCI in 2.4% of patients Bivalirudin (Angiomax) For PCI: 0.75 mg/kg IV bolus, followed by continuous infusion 1.75 mg/kg per hour for remainder of procedure; infusion may be continued for 4 hours after the procedure or administered as a low-dose infusion (0.2 mg/kg per hour) for an additional 20 hours Enzymatic (80%) and renal (20%) 25 minutes Factor Xa Inhibitors Fondaparinux (Arixtra) Not established for HIT Renal 17–20 hours Anti-factor Xa (calibrated to fondaparinux) Bleeding with doses 2.5–7.5 mg every 24 hours (1.2%–2.7%) ACT = activated clotting time; aPTT = activated partial thromboplastin time; PCI = percutaneous coronary intervention. Data from references 13, 23, 26, 30, 33, 34, and 36. bin. Lacking any structural similarity with heparin, it therefore does not cross-react with heparin, PF4, or HIT antibodies.25 It is approved by the Food and Drug Administration (FDA) for the treatment of HIT complicated by thrombosis, but it has also shown efficacy in preventing new thromboses in patients with isolated HIT and with no clinically apparent thromboembolic complications.26 However, the potential for increased bleeding has prevented approval for other indications such as use in acute coronary syndromes. Lepirudin treatment is associated with a rapid and sustained increase in platelet counts and a greater than 50% reduction in the rate of death, amputation, and new thrombotic events in patients with HIT when compared with historical controls.27 In a combined analysis of three prospective observational studies that included 403 patients and 120 historical controls, the combined outcome of death, amputation, and thrombosis at 35 days was lower in the lepirudin patients; however, there was a significantly higher bleeding rate compared with controls (17.6% vs. 5.8%, respectively). Bleeding was the cause of death in 1.2% of these patients.28 The current recommended dosing of lepirudin for the acute HIT management is 0.4 mg/kg as an initial bolus, followed by 0.15 mg/kg per hour (up to 110 kg), adjusted to a target activated partial thromboplastin time (aPTT) between 1.5 and 2.5 times the baseline value. Lepirudin has the longest half-life of all the direct thrombin inhibitors (approximately 80 minutes). Lepirudin undergoes renal elimination and, as a result, can accumulate in patients with renal insufficiency.26 Because of the lack of an antidote, complete avoidance or reduction in the dose with careful monitoring is required in these patients to prevent major bleeding. In one-third of patients receiving lepirudin, a serum creatinine level above 1.0 mg/dL was associated with major bleeding.28 In patients with renal insufficiency, another potent direct thrombin inhibitor, argatroban can be considered. As a foreign substance, lepirudin is immunogenic in some patients. Approximately 30% to 40% of patients with HIT develop IgG anti-hirudin antibodies,25 which paradoxically enhance the agent’s anticoagulant effects by impairing renal clearance and causing drug accumulation. 648 P&T® • November 2008 • Vol. 33 No. 11

Table of Contents Feed for the Digital Edition of Pharmacy & Therapeutics - November 2008

Pharmacy & Therapeutics - November 2008 Contents Editorial Medication Errors Prescription: Washington New Drugs/Drug News/New Medical Devices Drug Forecast Heparin-Induced Thrombocytopenia Medication Utilization Patterns and Hypertension-Related Expenditures among Patients Who Were Switched From Fixed-Dose to Free-Combination Antihypertensive Therapy European Society for Medical Oncology and Association for the Study of Bone and Mineral Research Pharmaceutical Approval Update

Pharmacy & Therapeutics - November 2008

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