This multicenter, open-label study evaluated the safe, effective dose of intravenous argatroban for prophylaxis or treatment of thrombosis in patients ≤16 years of age requiring nonheparin anticoagulation. The protocol-specified argatroban dose for systemic anticoagulation was 1.0 μg/kg/min (0.25 μg/kg/min for patients with impaired hepatic function; 0.5 μg/kg/min for patients <6 months old, reduced to 0.125 μg/kg/min with impaired hepatic function), adjusted to achieve activated partial thromboplastin times (aPTTs) 1.5–3 times the baseline value, or for procedures requiring immediate anticoagulation, an initial bolus then an infusion with doses varying by procedure (eg, 250 μg/kg bolus, then 15 μg/kg/min for cardiac catheterization, adjusted to achieve an activated clotting time of 200–300 seconds, with doses reduced if impaired hepatic function). Primary efficacy endpoints were the occurrence/recurrence of thrombosis and of thromboembolic complications including death and amputations resulting from the complication. Primary safety endpoints were major bleeding and death secondary to bleeding complications. The study population comprised 18 patients (age range: 1.6 weeks to 16.1 years; 12 males) with confirmed (8), suspected (5), or risk of (2) heparin-induced thrombocytopenia (HIT), or conditions such as heparin resistance or antithrombin deficiency (5); 2 patients met 2 inclusion diagnoses, and most had serious comorbidities. Overall, 17 patients received continuous argatroban, 6 underwent procedures, 5 received a bolus [median (range), 250 (11.2–250) μg/kg], and 14 completed the study. The median (range) treatment duration was 2.9 (<0.1–13.8) days. The median (range) infusion dose was 1.5 (0.38–13) μg/kg/min in 13 patients with normal hepatic function and 0.8 (0.4–0.9) μg/kg/min in 4 patients with serum total bilirubin >2.0 mg/dL secondary to hepatic impairment or cardiac complications. Of 11 patients administered 1.0 μg/kg/min initially, target aPTTs were achieved without dose adjustment in 4 patients by 2 h and with no or little dose adjustment in 8 patients by 9 h and all patients by 26 h. Within the 30-day follow up, 5 patients had 6 thrombotic events (2 patients had an event during therapy). No patient required amputation or died due to thrombosis during therapy. In each patient with confirmed HIT, the platelet count recovered during treatment. Two critically ill patients had major bleeding (each event was fatal): 1 patient died 2 days after argatroban cessation due to cerebral infarction and intracranial hemorrhage, and 1 patient on extracorporeal membrane oxygenation for heart failure had fatal subarachnoid bleeding on study day 25. The most frequent treatment-emergent adverse events were hypokalemia, constipation and hypotension (n=5, each). In this first prospective study of direct thrombin inhibition in both infants and children requiring nonheparin anticoagulation, argatroban was well tolerated and rapidly provided adequate levels of anticoagulation for noninterventional or interventional needs in seriously ill pediatric patients.

Disclosure:Research Funding: This study was sponsored by GlaxoSmithKline. Off Label Use: Use of argatroban in children which is off-label.