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LETTERS TO EDITOR
Year : 2019  |  Volume : 67  |  Issue : 2  |  Page : 568-570

Acute stroke thrombolysis following dabigatran reversal using idarucizumab


Division of Neurology, Department of Medicine, 2E3 WMC Health Sciences Centre, University of Alberta, Edmonton, Alberta, Canada

Date of Web Publication13-May-2019

Correspondence Address:
Dr. Kenneth Butcher
Division of Neurology, Department of Medicine, 2E3 WMC Health Sciences Centre, University of Alberta, Edmonton, Alberta
Canada
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0028-3886.258032

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How to cite this article:
Harsha KJ, Thirunavukkarasu S, Butcher K. Acute stroke thrombolysis following dabigatran reversal using idarucizumab. Neurol India 2019;67:568-70

How to cite this URL:
Harsha KJ, Thirunavukkarasu S, Butcher K. Acute stroke thrombolysis following dabigatran reversal using idarucizumab. Neurol India [serial online] 2019 [cited 2019 May 20];67:568-70. Available from: http://www.neurologyindia.com/text.asp?2019/67/2/568/258032


Sir,

Novel oral anticoagulants (NOACs) are recommended first-line agents for prevention of ischemic stroke in patients with atrial fibrillation (AF).[1] One of the barriers to adoption of NOACs has been the lack of a reversal agent or antidote. Idarucizumab, a specific reversal agent for one NOAC (dabigatran), was approved for use in Canada in 2016. This is a monoclonal antibody fragment that irreversibly binds to dabigatran and has been shown to completely reverse anticoagulant activity.[2] Idarucizumab is indicated for treatment of bleeding in patients taking dabigatran or in patients in whom reversal is required before urgent medical procedures.

Although it is somewhat counterintuitive, the most common stroke presentation of anticoagulated AF patients is not an intracerebral hemorrhage, but an ischemic stroke. This reflects the high risk of cardioembolism associated with AF, even in patients who are adequately anticoagulated. Thrombolysis in patients taking NOACs is generally not recommended unless it can be established, either through history or through laboratory testing, that therapeutic drug levels are not present. Although unstudied, this reversal agent may also be useful in facilitating thrombolysis in patients presenting with ischemic stroke while taking dabigatran.

A 74-year old female patient presented to the hospital with sudden-onset aphasia and right-sided hemiplegia. Her stroke risk factors were the presence of AF, hypertension, and dyslipidemia. She had been taking dabigatran (150 mg PO BID) for 4 years before presentation. A non-contrast computed tomography (CT) of the brain demonstrated no acute ischemic changes. A CT angiogram revealed occlusion of the inferior division of the left middle cerebral artery [Figure 1]. The thrombin time (TT) was prolonged, indicating compliance with dabigatran, but these laboratory results were not available until 30 min after treatment decisions were made.
Figure 1: (a) Axial CT scan demonstrating subtle early ischemic changes in the left MCA territory. (b-d) CT angiogram source images demonstrating normal left M1 and proximal M2, occlusion of distal M2 (arrow), non-opacification of the left MCA branches (white ellipsoid) and normally opacified right MCA branches (black ellipsoid). (e) Mistar software processed CT perfusion maps demonstrating the ischemic core (red) and penumbra (green) in the left MCA territory. (f) Axial CT scan 4 days post-tPA, demonstrating a small subacute infarct in the left MCA territory, with some petechial hemorrhagic transformation

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The patient was administered idarucizumab 5 g intravenously. Five minutes later, she was treated with intravenous tissue plasminogen activator (tPA). The initial TT was 81.7 s (normal range 14.3–19.7 s). A repeat TT at 7 h after tPA was 20.7 s.

By 48 h after treatment, the motor symptoms had resolved, although she had residual expressive dysphasia. A repeat CT scan of the brain at 24 h demonstrated a moderate sized left middle cerebral artery (MCA) territory infarct with no hemorrhagic transformation. A CT scan head at 96 h revealed a small asymptomatic petechial hemorrhagic transformation within the infarct. A CT scan on day 9 demonstrated resolution of these petechial hemorrhages. She was restarted on dabigatran 150 mg PO bid after a repeat CT scan of the head on day 9 and was discharged.

Anticoagulant reversal to deliver a thrombolytic agent represents a paradigm shift in acute stroke therapy. Although reversal agents for older oral and parenteral anticoagulants are available, this approach is not advocated in patients taking these agents. The primary reason for this is that the time to reversal is long and cannot be assured without repeat coagulation status testing. The prothrombin complex concentrate can theoretically be used before tPA administration in patients taking warfarin. Although rapid international normalized ratio (INR) normalization occurs in a majority of patients, reversal is not always complete.

Idarucizumab is the first true anticoagulant antidote. A 5 g intravenous (IV) bolus has been shown to normalize TT, which is linearly correlated with dabigatran concentrations, within minutes of administration.[2],[3],[4] This results in a completely normal coagulation status in a timely fashion. This unique aspect of idarucizumab made it feasible to consider a staged reversal followed by thrombolysis. This approach has been used in 23 other cases in Europe and Australia [Table 1].[8],[9],[10],[11],[12],[13]
Table 1: Case reports of patients treated with thrombolysis after dabigatron reversal using idarucizumab

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Approximately 50% of patients taking an anticoagulant who present with ischemic stroke will have transient or mild symptoms that do not require therapy.[5] Patients presenting with large vessel occlusion can be treated with endovascular clot retrieval.[6] Although, a vast majority of patients treated with this highly effective therapy were administered intravenous tPA initially, a consensus paper has suggested that this may not be warranted in patients taking anticoagulants.[7] Patients presenting with disabling symptoms without a proximal large vessel occlusion, such as our patient, are the optimal tPA candidates, provided any coagulopathy can be reversed. This remains an empiric therapeutic approach at this point. A clinical trial in this select group of patients is unlikely to be completed in the near future, but a prospective registry may be feasible.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Verma A, Cairns JA, Mitchell LB, Macle L, Stiell IG, Gladstone D, et al. Focused update of the Canadian Cardiovascular Society Guidelines for the management of atrial fibrillation. Can J Cardiol 2014;30:1114-30.  Back to cited text no. 1
    
2.
Pollack CV, Reilly PA, Eikelboom J, Glund S, Verhamme P, Bernstein RA, et al. Idarucizumab for dabigatran reversal. N Engl J Med 2015;373:511-20.  Back to cited text no. 2
    
3.
Glund S, Stangier J, Schmohl M, Gansser D, Norris S, van Ryn J, et al. Safety, tolerability, and efficacy of idarucizumab for the reversal of the anticoagulant effect of dabigatran in healthy male volunteers: A randomised, placebo-controlled, double-blind phase 1 trial. Lancet 2015;386:680-90.  Back to cited text no. 3
    
4.
Glund S, Moschetti V, Norris S, Stangier J, Schmohl M, van Ryn J, et al. A randomised study in healthy volunteers to investigate the safety, tolerability and pharmacokinetics of idarucizumab, a specific antidote to dabigatran. Thromb Haemost 2015;113:943-51.  Back to cited text no. 4
    
5.
Kate M, Szkotak A, Witt A, Shuaib A, Butcher K. Proposed approach to thrombolysis in dabigatran-treated patients presenting with ischemic stroke. J Stroke Cerebrovasc Dis 2014;23:1351-5.  Back to cited text no. 5
    
6.
Goyal M, Menon BK, van Zwam WH, Dippel DWJ, Mitchell PJ, Demchuk AM, et al. Endovascular thrombectomy after large-vessel ischaemic stroke: A meta-analysis of individual patient data from five randomised trials. Lancet 2016;387:1723-31.  Back to cited text no. 6
    
7.
Diener HC, Bernstein R, Butcher K, Campbell B, Cloud G, Davalos A, et al. Thrombolysis and thrombectomy in patients treated with dabigatran with acute ischemic stroke: Expert opinion. Int J Stroke 2017;12:9-12.  Back to cited text no. 7
    
8.
Schulz JG, Kreps B. Idarucizumab elimination of dabigatran minutes before systemic thrombolysis in acute ischemic stroke. J Neurol Sci 2016;370:44.  Back to cited text no. 8
    
9.
Mutzenbach JS, Pikija S, Otto F, Halwachs U, Weymayr F, Sellner J. Intravenous thrombolysis in acute ischemic stroke after dabigatran reversal with idarucizumab – A case report. Ann Clin Transl Neurol 2016;3:889-92.  Back to cited text no. 9
    
10.
Ng FC, Bice J, Rodda A, Lee-Archer M, Crompton DE. Adverse clinical outcomes after dabigatran reversal with idarucizumab to facilitate acute stroke thrombolysis. J Neurol 2017;264:591-4.  Back to cited text no. 10
    
11.
Kerman P, Eschenfelder CC, Diener HS, Grond M, Abdalla Y, Althaus K, et al. Antagonizing dabigatran by idarucizumab in cases of ischemic stroke or intracranial hemorrhage in Germany – A national case collection. Int J Stroke 2017;12:383-91.  Back to cited text no. 11
    
12.
Tireli D, He J, Nordling MM, Wienecke T. Systemic thrombolysis in acute ischemic stroke after dabigatran etexilate reversal with idarucizumab – A case report. J Stroke Cerebrovasc Dis 2017;26:e123-5.  Back to cited text no. 12
    
13.
Bissig D, Manjunath R, Traylor BR, Richman DP, Ng KL. Acute stroke despite dabigatran anticoagulation treated with idarucizumab and intravenous tissue plasminogen activator. J Stroke Cerebrovasc Dis 2017;26:e102-4.  Back to cited text no. 13
    


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