Pharmacy & Therapeutics - November 2008 - (Page 649)

Heparin-Induced Thrombocytopenia Argatroban (Novastan) Argatroban, a small synthetic direct thrombin inhibitor derived from L-arginine, is highly selective and reversibly binds to thrombin. Its antithrombotic effects are exerted by its inhibition of thrombin-mediated fibrin formation; activation of coagulation factors V, VII, and XIII; and platelet activation. Argatroban is approved for both preventing and treating HIT with or without associated thrombosis and for promoting anticoagulation in patients with or at risk for HIT who are undergoing percutaneous coronary intervention (PCI).29 Argatroban has several important advantages over other direct thrombin inhibitors. Unlike the hirudin derivatives (lepirudin and bivalirudin), it is not antigenic. It has a rapid onset of action (one to three hours), a short half-life (39 to 51 minutes), a low molecular weight, and a predictable pharmacokinetic dose response; furthermore, argatroban does not interact with or induce heparin-dependent antibodies, and it can inhibit both free and clot-bound thrombin.29 Thrombin bound to fibrin is protected from inactivation, and heparin’s inability to inactivate bound thrombin is instrumental in its limitation to inhibit propagation of venous thrombi and prevent subsequent rethrombosis.30 It is argatroban’s ability to inactivate bound thrombin that is particularly advantageous, and in addition to preventing further thrombotic events, it can also reduce the extension of existing thromboses. In two prospective, multicenter studies with a total of 722 patients presenting with HIT with or without thrombosis, argatroban therapy was associated with significant reductions in the composite outcome (all-cause mortality, amputation, or new thrombosis) at 37 days, compared with historical controls. In the ARG-911 study, the incidence of the composite endpoint was reduced in argatroban-treated patients, compared with control subjects with HIT (25.6% vs. 38.8%; P = 0.014) and in those with thrombosis (43.8% vs. 56.5%, P = 0.13).31 In the ARG-915 study, similar significant reductions were noted in the incidence of the composite endpoint in subjects with HIT who received argatroban (28.0 vs. 38.8; P = 0.04) and in subjects who had HIT with thrombosis (41.5 vs. 56.5; P = 0.07).32 Major bleeding events in this study were defined as overt bleeding, associated with a hemoglobin decrease of 2 g/dL or greater, that led to a transfusion of 2 units or more or that was intracranial, retroperitoneal, or into a major prosthetic joint. Although the incidence of major bleeding events did not differ significantly between the two groups in either study (5.3% vs. 6.7%), the decrease was still much lower than that for lepirudin. The recommended initial dose for argatroban is 2 mcg/kg per minute administered as a continuous IV infusion. A baseline aPTT should be obtained before the drug is given and should be re-checked two hours after the initiation of therapy. The dose should then be adjusted until a target aPTT of 1.5 to 3.0 times the baseline value is achieved (in 100 seconds or less). Doses should not exceed 10 mcg/kg per minute.29 Argatroban is metabolized hepatically, and a dose reduction is required for patients with significant liver disease. An approximate four-fold decrease in clearance (in contrast to normal) has been observed, leading to drug accumulation. The primary parameter used to monitor argatroban therapy is the aPTT, which achieves steady state within one to three hours after therapy begins and which must be monitored carefully. If argatroban is used in a patient with HIT who presents with concomitant moderate hepatic impairment, the recommended initial dose is 0.5 mcg/kg per minute. The dose is titrated until the aPTT at steady state is 1.5 to 3.0 times the baseline level.29 It may also take longer to reverse the anticoagulant effects in these patients. Caution must be taken because, like other direct thrombin inhibitors, argatroban lacks a specific antidote. Unlike the case with lepirudin, renal adjustments are not required for argatroban, which may be a safer alternative in patients with renal impairment. Bivalirudin (Angiomax) A small semisynthetic analogue of hirudin, bivalirudin has several benefits when compared with other direct thrombin inhibitors. It is FDA-approved for anticoagulation in patients with or at risk for HIT thrombosis syndrome (HITTS) who are undergoing PCI, but it is not approved for treating HIT in other settings.33 It is intended to be used concomitantly with aspirin, as reflected in its utility in study populations. Its advantages are that it undergoes dual elimination via a combination of renal clearance (20%) and plasma proteolytic cleavage (80%). Bivalirudin also has a shorter half-life (25 minutes), reduced immunogenicity, and minimal prolongation of the International Normalized Ratio (INR). The initial recommended dose for bivalirudin is a 0.75mg/kg IV bolus, followed by a continuous infusion of 1.75 mg/kg per hour for the duration of the PCI procedure. However, lower doses are recommended for pre-PCI dosing in patients with acute coronary syndromes. If necessary, clinicians can choose to continue the initial infusion four hours after PCI at a lower dose of 0.2 mg/kg per hour (up to 20 hours); however, a lower-concentration IV bag of 0.5 mg/ml (instead of the 5-mg/mL concentration used in the initial infusion IV bag) must be prepared. Bivalirudin has been safely and successfully used in lower doses in patients with combined hepatic and renal failure.34 For patients with renal impairment, activated clotting time should be monitored. The manufacturer does not recommend bolus dose reductions in renal impairment, but the infusion rate should be reduced to 1 mg/kg per hour in patients with a creatinine clearance (CrCl) of less than 30 mL/minute. Bivalirudin is hemodialyzable, and infusion rates for patients receiving hemodialysis should be even lower (i.e., to 0.25 mg/kg per hour).33 Factor Xa Inhibitors Danaparoid (Orgaran) Danaparoid is a mixture of glycosaminoglycans derived from porcine intestinal mucosa. Despite the extensive experience with the use of this agent in HIT, the agent’s crossreactivity potential (approximately 10%) and its long half-life (24 hours) remain major drawbacks.35 Although danaparoid was voluntarily removed from the U.S. market in April 2002, it remains available for the treatment and prevention of HIT in Canada, Europe, New Zealand, Australia, and Japan. Its removal from the market was soon followed by the release of another factor Xa inhibitor, fondaparinux. Vol. 33 No. 11 • November 2008 • P&T® 649

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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