Antithrombin Alfa in Hereditary Antithrombin Deficient Patients at High Risk for Thromboembolic Complications

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Antithrombin alfa (ATryn®) is approved in EU for the prophylaxis of venous thromboembolism in patients with hereditary AT deficiency (HD) undergoing surgery. Pregnant HD patients are often also treated with AT replacement therapy, as the peri-partum period provides a high risk of developing venous thromboembolic complications. Population PK analysis of the peri-partum and peri-operative data of HD patients treated in a previous study of antithrombin alfa found that a significantly different pharmacokinetic profile exists in pregnancy compared to surgery, suggesting pregnant HD patients would require a revised dosing algorithm to achieve and maintain the target AT activity level (80–120%). Additionally, the therapeutic drug monitoring (TDM) guidelines were optimized for all patients. Both these revisions were applied in a multi-center, multinational, single arm, open label study with antithrombin alfa treatment for the prevention of peri-operative and peri-partum thromboembolic events in HD patients. Adult patients with HD, who had a personal history of venous thromboembolic events (VTE) and were in a high-risk situation for the occurrence of VTE were included. Pregnant women about to deliver (spontaneous, induced or cesarean section) were given a 15 minute IV loading dose calculated as: Loading dose (IU/kg) = (100 minus pretreatment antithrombin activity in %) divided by 1.25. Maintenance dose immediately followed loading dose: Maintenance dose (IU/hour/kg) = (100 minus pretreatment antithrombin activity in %) divided by 5.43. Loading and maintenance dose for surgical patients were calculated as: Loading dose (IU/kg) = (100 minus pretreatment antithrombin activity in %) divided by 2.28; Maintenance dose (IU/hour/kg) = (100 minus pretreatment antithrombin activity in %) divided by 10.22. TDM was used to check plasma AT activity and adjust infusion rate accordingly. AT activity had to be checked 2 and 6 hours after start of loading dose or change of infusion rate, and thereafter 1 or 2 times per day. When AT activity levels were <80% or >120%, infusion rate was respectively increased or decreased by 30%. Twelve pregnant HD patients and 6 surgical patients (M/F=14/4) were treated in the study. Median age was 34.5 (range 21–62). Delivery procedures included 4 cesarean sections. Surgical procedures included major joint replacement (2), neurosurgery, femoropopliteal bypass, laparoscopic cholecystectomy and pulmonary thromboendarterectomy (on cardiopulmonary bypass). Patients were treated for a median of 3.2 days (range 0.9–14) and needed a median of 1 (range 0–6) infusion rate adjustments. All but 1 patient used other anticoagulants (17 heparin, 9 Vit K antagonist, 1 platelet aggregation inhibitor). All patients were examined for VTE during treatment and on the 7th day post-treatment. Signs and symptoms indicative for a VTE had to be followed up with appropriate diagnostic assessment tools. Patient sera were collected up to 90 days post-treatment to test for an immunological reaction to antithrombin alfa or goat milk proteins. One pregnant patient was only treated for 1 day and therefore excluded from the per protocol population. No patient (per protocol or ITT) suffered a confirmed VTE during treatment or up to 7 days post-treatment. Adverse events were usually mild, and as can be expected in surgical and delivery patients. Serious adverse events assessed related to study drug were haemarthrosis and intra-abdominal hemorrhage, both recovered. No confirmed specific immune reaction to antithrombin alfa or goat milk proteins occurred in the 17 patients tested. It was concluded that antithrombin alfa is safe and efficacious in preventing VTE and the revised dosing algorithm performed well in pregnant patients. This abstract is presented by the authors on behalf of the “antithrombin alfa study group”.