Safety and Efficacy of Prophylactic Intravenous Administration of Recombinant Human Antithrombin (rhAT) to Hereditary AT Deficient Patients in High-Risk Situations.

Abstract

Congenital antithrombin (AT) deficiency is a major cause of thrombophilia. Prophylactic AT replacement in high risk situations may be considered for these patients as AT deficiency may lead to insufficient anticoagulation resulting in acute deep venous thrombosis (DVT), which cannot be treated by higher doses of heparin. This multicenter, multinational treatment study is the first to investigate rhAT, derived from transgenic goats, in patients with a personal or family history of DVT and previously documented AT activity < 60% of normal undergoing elective surgery, delivery or Cesarean section. IV rhAT was administered as continuous infusion to maintain AT activity between 80% and 120% of normal. Dose adjustments could be made based on AT assessments. Treatment was initiated prior to the high risk situation and continued for the duration of the high-risk period, with a minimum of 3 days. Standardized duplex ultrasound scans (US) were done prior to treatment, at fixed time points after initiation of treatment and when clinically indicated. Scans were assessed for the presence of DVT locally and videotaped for blinded central evaluation. Primary efficacy assessment was the incidence of acute DVT in the first 30 days after the high risk situation. Fourteen patients (4 hip replacements, 1 bilateral breast reduction, and 9 deliveries) were included. Loading and maintenance rhAT dosing increased and sustained AT activity levels within or close to the normal AT activity range. At central evaluation, one patient suffered from acute DVT at baseline, prior to administration of rhAT and was excluded from the evaluation of efficacy. None of the patients showed clinical symptoms of DVT or other thromboembolic events at any time during rhAT administration or up to 30 days after last day of dosing. One patient, who was clinically asymptomatic, was diagnosed by local and central evaluation with acute DVT by scheduled US evaluation at the intended last day of dosing. Although the patient was asymptomatic, treatment with rhAT was continued. The patient remained asymptomatic and the DVT resolved at follow-up US. At 7 days follow-up one patient was diagnosed as having an acute DVT by central evaluation but not by local evaluation. The patient was asymptomatic during the whole treatment and follow-up, and no action was taken. Thus, the frequency of acute DVT assessed by blinded central and local review was 1/13 (7%). Treatment with rhAT was well tolerated. None of the reported adverse events in patients or newborns was assessed as related to rhAT treatment. There were no signs of allergic or anaphylactic reactions to rhAT and no evidence of antibodies to rhAT up to 90 days follow-up. This is the first study to evaluate AT replacement in hereditary AT deficient patients with screening US determinations. However, the lack of clinically apparent DVT in this study is similar to other comparable AT replacement studies. We therefore conclude that prophylactic administration of rhAT to hereditary AT deficient patients in high-risk situations is safe and effective for the prevention of thromboembolic events.