Boehringer Ingelheim Ltd. is pleased to announce that Praxbind (idarucizumab), a treatment to rapidly and specifically reverse the anticoagulant effects of Pradaxa (dabigatran etexilate) in cases of emergency surgery/urgent procedures or in situations of life-threatening or uncontrolled bleeding, is now available in Ireland. Idarucizumab is the first specific reversal agent for a novel oral anticoagulant (NOAC) to receive European approval.
Four NOACs, including dabigatran (a direct thrombin inhibitor), are currently licensed as alternatives to warfarin for the prevention and treatment of venous thromboembolism and for the prevention of stroke in patients with non-valvular atrial fibrillation. All of the NOACs are at least as effective as warfarin for the prevention of stroke in patients with atrial fibrillation and for the treatment of venous thromboembolism. They are associated with less life-threatening bleeding, and in particular less intracranial haemorrhage. However, serious bleeding can occur with NOACs. In addition, patients taking NOACs may sustain trauma and may require urgent surgery or interventions. The availability of specific reversal agents for NOACs could improve patient management during emergency situations.1-3
Idarucizumab is a humanised monoclonal antibody fragment that has been developed as a specific reversal agent for dabigatran. It binds dabigatran with an affinity that is 350 times higher than the affinity of dabigatran for thrombin. Consequently, idarucizumab binds free and thrombin-bound dabigatran and neutralises its activity.2-4
Marketing approval for idarucizumab is based on data from healthy volunteers (three phase I, randomised, double-blind, placebo-controlled studies), as well as results from an interim analysis of a phase III, prospective, cohort study (RE-VERSE AD). In healthy young volunteers, idarucizumab produced immediate and complete reversal of the anticoagulant effects of dabigatran without procoagulant effects. Given these findings, RE-VERSE AD was undertaken to examine the efficacy and safety of idarucizumab for the reversal of the anticoagulant effects of dabigatran in patients who presented with serious bleeding or who required an urgent procedure.2,4
Study design
The RE-VERSE AD study is an ongoing phase III, global, prospective, cohort study investigating idarucizumab in 2 groups of dabigatran-treated patients. Patients in group A are those with serious bleeding. Patients in group B are those who require an urgent procedure. These inclusion criteria were chosen to mirror the real world population in which the reversal agent would be used.
A cohort design was chosen because it was considered unethical to include a control group to receive a placebo or no active treatment. All patients receive 5g of intravenous idarucizumab, administered as two 50ml bolus infusions, each containing 2.5g of idarucizumab, no more than 15 minutes apart. The 5g dose was calculated to reverse the total body load of dabigatran that was associated with the highest range of plasma concentrations measured in the RE-LY trial.
The primary end point is maximum percentage reversal of the anticoagulant effect of dabigatran within 4 hours of completion of the idarucizumab infusions on the basis of central laboratory measurement of the dilute thrombin time (dTT) or ecarin clotting time (ECT). These assays were chosen because they showed excellent correlation with dabigatran concentrations measured by mass spectrometry. Time to cessation of bleeding and assessment of haemostasis during interventions are key secondary end points in groups A and B, respectively.2-4
Data for the first 90 patients receiving idarucizumab in this trial have been reported (51 patients in group A and 39 in group B). More than 90% of patients had a diagnosis of atrial fibrillation and were receiving dabigatran for stroke prevention. The median age of patients was 76.5 years, and the median patient-reported time since the last dose of dabigatran was 15.4 hours. Median plasma concentrations of total dabigatran were 132 and 114ng/ml in groups A and B, respectively.2,4
Idarucizumab rapidly and completely reversed the anticoagulant activity of dabigatran
Among 68 patients with an elevated dTT and 81 with an elevated ECT at baseline, the median maximum reduction in these assays within 4 hours was 100% (95% confidence interval, 100–100). Reversal was evident immediately after the first vial of idarucizumab was given, and 100% reversal was achieved in all but 1 patient. Idarucizumab normalised the test results in 88% (ECT) to 98% (dTT) of patients who had elevated levels at baseline. By 24 hours, 79% of patients had plasma concentrations of unbound dabigatran that were <20 ng/ml (a level that produces little or no anticoagulant activity).2,4
Key secondary end points
In group A patients, bleeding cessation could be determined in 35 patients. The investigator-reported median time to cessation of bleeding was 11.4 hours. In group B, normal intraoperative haemostasis was reported in 92% of the 36 patients who underwent procedures, and mild to moderate impairment was reported in the remaining 8%. The median time between administration of idarucizumab and the start of the procedure was 1.7 hours, and no post-surgical bleeding complications were reported within the 24 hours after surgery.2,4
Serious adverse events
Thrombotic events (including deep vein thrombosis, pulmonary embolism, myocardial infarction, or ischaemic stroke) occurred in 5 patients; in 1 patient 48 hours after idarucizumab administration and the rest >72 hours after dosing. None of these patients were receiving anti-thrombotic therapy when the events occurred. Of the 90 patients, 18 died (9 in each group). Half of the deaths occurred >96 hours after idarucizumab administration. All deaths appeared to be associated with pre-existing medical conditions.2,4
Conclusion
In the RE-VERSE AD study, idarucizumab was shown to rapidly and completely reverse the anticoagulant activity of dabigatran in 88% to 98% of patients. There were no safety concerns among the 90 patients involved in this study (including patients who were given idarucizumab for clinical reasons but were later found to have had normal results on clotting tests at baseline), or among the >200 healthy volunteers who were administered idarucizumab in previous studies.4
References: 1. Sarich et al. Am Heart J 2015;169:751-57. 2. Eikelboom et al. Circulation. 2015;132:2412-2422. 3. Pollack et al. Thromb Haemost 2015;114:198-205. 4. Pollack et al. N Engl J Med 2015;373:511-20.
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