Idarucizumab for dabigatran reversal.
Dabigatran etexilate, a direct thrombin inhibitor, has been increasingly used over the last few years, but the lack of antidote has been pointed out as a major risk in case of life-threatening haemorrhage. Although some non-specific reversal therapies have been used (e.g. prothrombin complex concentrates (PCCs), activated PCC or activated factor VII), a specific reversal agent for dabigatran would be beneficial.
Idarucizumab is a monoclonal antibody fragment that has a high affinity to dabigatran and is able to neutralise its activity. Previous studies (see other comments on NATAonline) have assessed the pharmacokinetic profile, the tolerance and the effect of idarucizumab on coagulation parameters in healthy volunteers.
The RE-VERSE AD study (ClinicalTrial.gov, NCT02104947) is an ongoing, multicentre, prospective study that will seek to assess the efficacy of idarucizumab (5 g, two 50-mL infusions of 2.5 g each) in patients treated with dabigatran with uncontrolled bleeding (group A), and those who need to undergo a surgical or any other invasive procedure that cannot be delayed (group B). Although the investigators plan to recruit 300 patients at more than 400 centres in 38 countries, the present article reports the results of an interim analysis including 90 patients (group A = 51, group B = 39). The primary endpoint being the percentage reversal of coagulation parameters following the administration of the antidote, while the secondary endpoints were clinical assessment of bleeding and haemostasis.
This interim analysis reports that idarucizumab was able to completely reverse the effect of dabigatran, assessed by standard and specific coagulation assays. Among patients who underwent a surgical procedure ‘normal’ intraoperative haemostasis was reported in 33/36 patients (92%). Among patients with severe haemorrhage in whom haemostasis was assessed (n = 35), the median time needed to restore haemostasis was 11.4 hours. Despite the complete reversal of anticoagulation, 18 (20%) patients died (9 in each group); 10 deaths were due to vascular causes and there were 5 fatal bleeding events. Finally, early and late thrombotic events, defined by events occurring within 72 h or >72 h, respectively, occurred in 5 (6%) patients.
Although this study highlighted promising perspectives for the specific reversal of dabigatran-induced haemorrhage or the management of patients requiring emergent invasive procedures, further results are needed to better assess the effect of idarucizumab on clinical endpoints and outcomes. Although iduracizumab was highly effective to normalise coagulation parameters, only a few clinical endpoints were assessed. Furthermore, in the absence of control group, it is hard to know whether the administration of idarucizumab significantly improved the management of these patients compared to standard approaches. Although idarucizumab is definitively a crucial therapeutic option in bleeding situations, further evidence is needed to identify the clinical context where idaruzicumab will be more effective than standard therapies.
Last but not least, idarucizumab can antagonise the anticoagulant effect of dabigatran but does not have any procoagulant effect. Standard measures to replace coagulation factors, treat hypovolaemia, and manage a bleeding patient should be recommended.
– David Faraoni