CNS Drugs (2017) 31:747–757 DOI 10.1007/s40263-017-0460-x SYSTEMATIC REVIEW Idarucizumab in Dabigatran-Treated Patients with Acute Ischemic Stroke Receiving Alteplase: A Systematic Review of the Available Evidence 1 2 1 1 Slaven Pikija • Laszlo K. Sztriha • J. Sebastian Mutzenbach • Stefan M. Golaszewski • Johann Sellner1,3 Published online: 14 August 2017 Ó The Author(s) 2017. This article is an open access publication Abstract 18/20 patients (90%) had mild or moderate stroke severity. Background and Purpose Current guidelines do not rec- The time from symptom onset to start of tissue plasmino- ommend the use of intravenous recombinant tissue plas- gen activator was 155 min (n = 18, interquartile range minogen activator in patients with acute ischemic stroke 122–214). The outcome was unfavorable in 3/19 patients who receive direct oral anticoagulants. While the human- (16%). There was one fatality as a result of a symptomatic ized monoclonal antibody idarucizumab can quickly post-thrombolysis intracranial hemorrhage, and two reverse the anticoagulant effects of the thrombin inhibitor patients experienced an increase in the National Institute of dabigatran, safety data for subsequent tissue plasminogen Health Stroke Scale compared with baseline. One patient activator treatment are sparse. Here, we review current had a recurrent stroke. No systemic bleeding, venous knowledge about dabigatran reversal prior to systemic thrombosis, or allergic reactions were reported. reperfusion treatment in acute ischemic stroke. Conclusion Experience with idarucizumab administration Methods We performed a systematic review of all pub- prior to tissue plasminogen activator treatment in acute lished cases of intravenous tissue plasminogen activator ischemic stroke is limited. Initial clinical experience in less treatment following the administration of a dabigatran severe stroke syndromes and short time windows seems antidote up to June 2017 and added five unpublished cases favorable. Larger cohorts are required to confirm safety, of our own. We analyzed clinical and radiological out- including bleeding complications and the risk of thrombosis. comes, symptomatic post-thrombolysis intracranial hem- orrhage, and other serious systemic bleeding. Additional endpoints were allergic reaction to idarucizumab, and Key Points venous thrombosis in the post-acute phase. Results We identified a total of 21 patients (71% male) Idarucizumab is a monoclonal antibody fragment with a median age of 76 years (interquartile range 70–84). that quickly reverses the anticoagulant effects of The median National Institute of Health Stroke Scale score dabigatran. at baseline was 10 (n = 20, interquartile range 5–11) and Experience for dabigatran reversal with the aim of intravenous tissue plasminogen activator treatment & Johann Sellner in acute ischemic stroke is limited. [email protected] We summarize 16 published cases and five of our 1 Department of Neurology, Christian Doppler Medical Center, own unpublished cases of systemic thrombolysis in Paracelsus Medical University Salzburg, Ignaz-Harrer-Str. acute ischemic stroke following the administration of 79, 5020 Salzburg, Austria idarucizumab. 2 Department of Neurology, King’s College Hospital, Denmark Hill, London, UK Initial real-life experience for idarucizumab in less severe stroke syndromes and short time windows 3 Department of Neurology, Klinikum rechts der Isar, Technische Universita¨tMu¨nchen, Munich, Germany seems favorable. 748 S. Pikija et al. 1 Introduction anticoagulant effect by dabigatran, some authors would allow i.v. thrombolysis in such scenarios [15]. 1.1 Stroke Prevention in Atrial Fibrillation 1.3 Reversal of Anticoagulant Effect of Dabigatran for Thrombolysis in Acute Ischemic Stroke Atrial fibrillation (AF) is a major and continuously increasing cause of acute ischemic stroke (AIS) [1]. Until Idarucizumab has been approved as a specific antidote of recently, vitamin K antagonists have been the only treat- dabigatran. This antibody fragment demonstrated prompt ment option for the prevention of stroke and systemic and durable reversal of the anticoagulant effects of dabi- embolization arising from AF. The use of vitamin K gatran in animal studies, and in phase I studies of young antagonists (warfarin, phenprocoumon, and aceno- and elderly individuals, as well as in renally impaired coumarol) for non-valvular AF has been decreasing in volunteers [16, 17]. The standard dose of 5 g of this favor of direct oral anticoagulants (DOACs) [2]. In fact, humanized antibody fragment completely reverses the DOACs (apixaban, edoxaban, dabigatran etexilate, and biological activity of dabigatran within a few minutes. It rivaroxaban) are preferentially used because of their has primarily been developed for the reversal of antico- favorable risk–benefit profile. Four randomized, controlled, agulant effects of dabigatran for emergency surgery and phase III trials supported the approval of these drugs, life-threatening bleeding [18]. Whether idarucizumab which individually demonstrated non-inferiority to war- could be used to safely perform systemic thrombolysis with farin for stroke prevention in non-valvular AF [3–6]. Each tPA has not been evaluated in clinical trials so far. Of year, approximately 1–2% of patients with non-valvular importance, additional questions such as the efficacy of AF are expected to develop AIS despite treatment with tPA after antagonization of dabigatran, the risk of intrac- DOACs [7, 8]. Thrombolytic treatment with intravenous erebral and systemic bleeding, as well as the potential (i.v.) recombinant tissue plasminogen activator (tPA) is occurrence of procoagulant effects need to be answered contraindicated in patients taking a DOAC. [19]. In addition, the significance of potential adverse reactions including hypokalemia, delirium, constipation, 1.2 Dabigatran and Treatment with Tissue- pyrexia, and pneumonia in AIS needs to be established Plasminogen Activator in Acute Ischemic Stroke [20]. Since the approval of idarucizumab for the manage- ment of bleeding complications related to dabigatran use, Dabigatran etexilate is a prodrug of dabigatran. Dabigatran there have been case reports of off-label use in the context inhibits the function of thrombin, which stabilizes clots by of i.v. thrombolysis in AIS. Here, we review the current catalyzing the conversion of fibrinogen to fibrin [9]. Severe evidence by analyzing all published cases and our addi- hemorrhagic complications, similar to those seen with tional five unpublished cases of patients with AIS who vitamin K antagonists, can be anticipated in the context of received tPA after reversal of dabigatran with tPA treatment in patients receiving anticoagulation treat- idarucizumab. ment with dabigatran, and, in fact, a case of fatal intrac- erebral hemorrhage has been reported among seven tPA- treated patients also receiving dabigatran [10, 11]. Drug 2 Materials and Methods labeling suggests a 48-h gap following the last intake of dabigatran, or at least the elapse of two half-lives since the 2.1 Inclusion and Exclusion Criteria most recent dose [12, 13]. The use of tPA may be justified if the patient had not taken dabigatran for the previous The inclusion criteria were as follows: adult patients 12 h, and anticoagulation assays are consistent with an (age [18 years) with acute-onset focal neurological defi- absence or a very low level of dabigatran activity [14]. cits suggestive of AIS; receiving treatment with dabigatran Normal kidney function is a prerequisite in both situations. (110 or 150 mg twice a day); and the administration of Determination of dabigatran serum concentrations, how- idarucizumab prior to treatment with tPA. The exclusion ever, is not possible at many centers in a reasonable time criterion was the a final diagnosis of a stroke mimic. frame, and the absolute safety margins for tPA treatment have not been established yet. 2.2 Search Strategy Traditional tests of coagulation, including International Normalized Ratio and activated partial thromboplastin time The literature review was performed via a comprehensive (aPTT), have somewhat limited reliability in measuring the search on MEDLINE, SCOPUS, and Web of Science anticoagulant effects of dabigatran. As normal thrombin databases up to 12 June, 2017. We used the following time (TT, \38 s) and aPTT (\37 s) exclude the significant terms and keywords: ‘ischemic stroke’, ‘stroke’, ‘brain Idarucizumab in Dabigatran-Treated Patients with Acute Ischemic Stroke Receiving Alteplase 749 infarction’, ‘thrombolysis’, ‘thrombolysis therapy’, 2.6 Statistical Analysis ‘thrombolytic therapy’, ‘recombinant tissue plasminogen activator’, ‘rtPA’, ‘tPA’, ‘t-PA’, ‘alteplase’, ‘new oral Continuous variables are presented as median with anticoagulant’, ‘NOAC’, ‘DOAC’, ‘direct thrombin inhi- interquartile range (IQR). GraphPad Prism Version 6.0 bitor’, ‘DTI’, ‘pradaxa’, ‘dabigatran’, ‘idarucizumab’, and (GraphPad Software, Inc., La Jolla, CA, USA) was used for ‘praxbind’, with different Boolean operators. All English statistical analyses. abstracts and full texts of the relevant articles were studied. We also manually searched reference lists of the retrieved articles to identify additional sources. 3 Results 2.3 Quality Assessment and Data Extraction 3.1 Systematic Review No additional rating of the quality was performed because A total of 13 eligible papers, reporting on 16 patients, were the publications were entirely case reports. Cases were also identified based on the inclusion and exclusion