Risk factors for major bleeding in patients with heparin-induced thrombocytopenia treated with argatroban: a retrospective study.

We retrospectively characterized major bleeding events and their risk factors among 269 patients with clinically diagnosed heparin-induced thrombocytopenia (HIT) treated using argatroban (2 microg x kg(-1) x min(-1) initially, adjusted to achieve activated partial thromboplastin times (aPTTs) 1.5-3 times the baseline) in a prospective multicenter study. Patients received a median (range) dose of 1.9 (0.2-9.7) microg x kg(-1) x min(-1) for 5.6 (0.1-61) days. Average aPTTs during therapy were 61.6 (37-183) seconds. Major bleeding, most commonly gastrointestinal, occurred in 19 patients (7.1%) during therapy. Another patient suffered from intracranial hemorrhage 4 days after argatroban cessation. Bleeding was fatal in 2 patients (0.7%); each received multiple anticoagulants and thrombolytic therapy. Major bleeding was more likely to occur in patients with HIT-related thrombosis (odds ratio = 2.9, P = 0.039), pulmonary impairment (odds ratio = 20.3, P < 0.001), or an aPTT >100 seconds (odds ratio = 3.7, P = 0.010). Major bleeding rates associated with average aPTTs of <45, 45-67.5, 67.6-90, and >90 seconds, respectively, were 5.0% (1 of 20 patients), 5.6% (9 of 162 patients), 8.7% (6 of 69 patients), and 22% (4 of 18 patients). No significant effect of patient demographics, other baseline illnesses including hepatic or renal impairment, argatroban dose, or treatment duration was detected on major bleeding. Risk factors for major bleeding in argatroban-treated patients with HIT include baseline HIT-related thrombosis and pulmonary impairment. For minimizing bleeding risk during argatroban therapy for HIT, the aPTT should be routinely monitored and maintained at <90 seconds.

Argatroban anticoagulation in pediatric patients: a literature analysis.

Argatroban, a direct thrombin inhibitor, is approved in the United States in adults as an anticoagulant for prophylaxis or treatment of thrombosis in heparin-induced thrombocytopenia (HIT) and in adults with or at risk for HIT undergoing percutaneous coronary intervention. The authors conducted a literature analysis to characterize the uses, dosing patterns, and safety of argatroban anticoagulation in pediatric patients. A comprehensive literature search identified nine articles describing 34 patients aged 1 week to 16 years who received argatroban anticoagulation for prophylaxis or treatment of thrombosis, cardiac catheterization, hemodialysis, extracorporeal membrane oxygenation or ventricular assist device support, or cardiopulmonary bypass. Most (85%) patients had HIT, a history of HIT, and/or HIT antibodies. For HIT thromboprophylaxis or treatment, argatroban dosing varied widely (0.1-12 mcg/kg/min), with no obvious relationship between patient age and dosage requirement. Overall, in these pediatric patients, therapeutic levels of anticoagulation were achieved despite the wide range of doses used. For pediatric patients undergoing cardiac catheterization, argatroban doses lower than those recommended in adults appeared to provide therapeutic anticoagulation. There was an unacceptably high bleeding risk with argatroban anticoagulation during pediatric cardiopulmonary bypass. Due to the limitations of case reports and/or case series, prospective studies with pharmacokinetic analyses are needed to evaluate the use of argatroban in pediatric patients.

Argatroban dosing in patients with heparin-induced thrombocytopenia.

OBJECTIVE: To retrospectively evaluate clinical experiences with argatroban dosing, particularly incremental dosage adjustments, during a clinical trial of argatroban anticoagulation in heparin-induced thrombocytopenia (HIT). METHODS: Records of 304 patients with HIT administered argatroban during a prospective study were reviewed to determine each dose, incremental dosage adjustment, and duration of therapy. Dosing information (stratified by patient initial dose) and incremental adjustments (overall, and stratified by dose from which adjustment occurred) were summarized. The relationship between median incremental adjustments and adverse outcomes, including bleeding, was investigated. RESULTS: Two hundred seventy-one (89%) patients received initial doses of 1.9-2.1 micro g/kg/min (group B). Twenty-six (9%) patients were started at a lower dose. Group B's median (5-95th percentile) final dose was 1.6 (0.25-4.0) micro g/kg/min. During a median of 6 days of argatroban therapy, patients underwent a median of 3.0 dosage adjustments using a median and mode incremental adjustment of 0.5 micro g/kg/min (5-95th percentile, 0.1-2.0 micro g/kg/min). Fifty-two (17%) patients required no dosage adjustment. Incremental adjustments decreased with decreasing current dose (e.g., median 0.25 micro g/kg/min from doses of 0.26-0.75 micro g/kg/min). Outcomes were similar between patients with no adjustment or with median incremental adjustments of 0.75 micro g/kg/min. CONCLUSIONS: Based on this clinical experience, together with the established linear pharmacokinetics and pharmacodynamics of argatroban, appropriate dosage increments may be proposed for argatroban-treated patients with HIT. Incremental adjustments of 0.5 micro g/kg/min are reasonable for most patients. Smaller adjustments (e.g., 0.25 micro g/kg/min) should be used when modifying lower doses, such as those recommended for use in hepatically impaired patients.