Internal Medicine Journal | 2021
Failure of dabigatran following idarucizumab and omeprazole administration
Abstract
The widespread use of direct oral anticoagulants (DOAC) over recent years has led to several reports describing treatment failure, defined as the development of cardiac or venous thrombus, or thromboembolic event while on therapeutic anticoagulation. A recent review reported 79 cases of DOAC failure, a quarter in those taking dabigatran and two-thirds in rivaroxaban users. The cause of treatment failure was unknown in threequarters of cases, while drug–drug interactions were responsible for 18%. An 81-year-old man with atrial fibrillation presented with left hemiparesis and dysarthria. His medications included diltiazem 360 mg OD and dabigatran 110 mg BD. National Institutes of Health Stroke Scale (NIHSS) on admission was 12, thrombin time (TT) was >100 s, serum creatinine was 150 μmol/L and non-contrast computed tomography (CT) of the brain was unremarkable. The patient received idarucizumab 5 mg, followed 11 min later by intravenous alteplase (total dose 63.9 mg). He responded well and post thrombolysis NIHSS was 0. Non-contrast CT of the brain did not demonstrate any new changes. Carotid imaging demonstrated 50–69% stenosis of the right internal carotid artery and he underwent endarterectomy. Dabigatran 110 mg BD, aspirin 100 mg OD and omeprazole 20 mg OD were started 48 h after the stroke (and administration of idarucizumab) and he was discharged home. He re-presented 2 days later (5 days after restarting dabigatran) with two episodes of left hemiparesis and dysarthria. He reported good adherence to his prescribed medication including dabigatran since discharge. The antithrombotic regimen was continued and dispensed by nursing staff during admission. Neurovascular magnetic resonance imaging demonstrated areas of restricted diffusion in the right pons and right cerebellum (Fig. 1), and usual post-endarterectomy changes. TT was 41 and 66 s the following day. Due to the subtherapeutic readings, the patient was transitioned to warfarin. At follow up 1 month later, the patient remained well. Dabigatran etexilate (DE) is a direct thrombin inhibitor and used for stroke prevention in non-valvular atrial fibrillation. Following ingestion, gastric acid facilitates the absorption of DE, followed by conversion by esterases to active dabigatran. Elevations in gastric pH, as occurs with proton-pump inhibitors, could result in reduced absorption and suboptimal anticoagulation; however, studies demonstrate conflicting effects on coagulation and the clinical relevance is unknown. DE prolongs TT, which is the most sensitive and commonly used assay to determine anticoagulant effect. TT increases with serum dabigatran concentrations in a linear manner up to 100 s (correlating to 40 ng/mL of dabigatran), beyond which it becomes unreliable. The expected peak plasma steady state concentration of dabigatran in patients on 150 mg twice daily is approximately 180 ng/mL with a trough of 90 ng/mL. The TT measured in our patient reliably reflects subtherapeutic anticoagulation. Idarucizumab is a monoclonal antibody fragment that binds dabigatran, resulting in immediate and complete reversal of anticoagulant activity. In Phase 2 studies, DE efficacy is preserved when reinstituted following Idarucizumab treatment.