ARTICLE IN PRESS

Case Studies

Systemic Thrombolysis in Acute Ischemic Stroke after
Dabigatran Etexilate Reversal with Idarucizumab—A Case
Report
Derya Tireli, MD,* Jun He, MD,* Mette Maria Nordling, MD,† and
Troels Wienecke, MD, PhD*,‡

Introduction: Idarucizumab is a reversal agent for dabigatran etexilate. By reversing the anticoagulating effect of dabigatran etexilate with idarucizumab (Praxbind),
patients presenting with an acute ischemic stroke can now be eligible for thrombolysis.
Patient: We describe our experience with idarucizumab in a 71-year-old male patient
pretreated with dabigatran etexilate. The patient arrived with a hemiparesis, central
facial palsy, and dysarthria. Method: Dabigatran etexilate was antagonized with
idarucizumab, approximately 2.5 hours after the patient’s last dose. Immediately
after the infusion of idarucizumab, the patient received thrombolytic therapy. Results:
The hemiparesis and the central facial palsy were fully remitted 3 days after the
onset of symptoms, and the dysarthria was remitted 2 days afterwards. Discussion: Non-vitamin K oral anticoagulants (NOACs) are widely used for the prevention
of embolic stroke in patients with atrial fibrillation. Dabigatran etexilate is an oral
thrombin inhibitor that can be reversed by idarucizumab. Idarucizumab, a monoclonal antibody fragment, directly binds dabigatran etexilate and neutralizes its
activity. Conclusion: Reversal of dabigatran etexilate using idarucizumab was safe
and successful with no recombinant tissue plasminogen activator interactions.
Key Words: Stroke—dabigatran—systemic thrombolysis—idarucizumab.
© 2017 National Stroke Association. Published by Elsevier Inc. All rights reserved.

Introduction
Dabigatran etexilate (Pradaxa) is a specific and reversible thrombin inhibitor approved for stroke prevention
From the *Neurovascular Center, Department of Neurology, Zealand
University Hospital, Roskilde, Denmark; †Department of Radiology, Research Center for Advanced Imaging, Zealand University
Hospital, Roskilde, Denmark; and ‡Faculty of Health and Medical
Sciences, University of Copenhagen, Copenhagen, Denmark.
Received January 7, 2017; accepted March 29, 2017.
Address correspondence to Derya Tireli, MD, Neurovascular Center,
Department of Neurology, Zealand University Hospital, DK-4000
Roskilde, Denmark. E-mail: deti@regionsjaelland.dk, deryatireli@
gmail.com.
1052-3057/$ - see front matter
© 2017 National Stroke Association. Published by Elsevier Inc. All
rights reserved.
http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2017.03.039

in patients with atrial fibrillation. Idarucizumab, a monoclonal antibody fragment, binds dabigatran etexilate and
neutralizes its activity within a few minutes.1

Case Report
A 71-year-old male patient was admitted to our department with dysarthria, a left-sided central facial palsy,
and a left-sided hemiparesis. The patient was treated with
dabigatran etexilate (Pradaxa) 150 mg twice daily because
of paroxysmal atrial fibrillation and hypertension. In addition, the patient had known cardiovascular risk factors2;
hypercholesterolemia, active smoker and suffered from
chronic obstructive pulmonary disease.
Morning medication, including dabigatran etexilate
(Pradaxa), was administered at 11:00 am in the morning,
and stroke symptoms started at 11:30 am. The patient

Journal of Stroke and Cerebrovascular Diseases, Vol. ■■, No. ■■ (■■), 2017: pp ■■–■■

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D. TIRELI ET AL.

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Figure 1. (Left): Primary CT of the brain shows no infarction. (Middle) CT brain perfusion MTT shows small perfusion defect in the right frontal lobe.
(Right) CT brain 24-hour control shows no infarction or hemorrhage. Abbreviations: CT, computed tomography; MTT, mean transit time.

immediately managed to call for help and an ambulance arrived. Standard operational procedures prescribe
telephone contact from the ambulance to the stroke centre,
whereby the stroke physician is notified regarding time
of stroke onset and dabigatran etexilate (Pradaxa) treatment and compliance.
The patient arrived at 12:49 pm, 79 minutes after stroke
onset, with a National Institute of Health Stroke Score
of 6 points. Based on muscle strength rating from a score
between 5 and 0,3 the patient was scored to 5 minus in
the left shoulder and elbow, 4 in the wrist, and 2-3 points
in the fingers. In the left lower extremity, the patient had
a score of 5 minus.
Brain computed tomography (CT) showed neither intracranial bleeding nor previous stroke, or early signs of
acute ischemic stroke. However, CT perfusion imaging
showed a small perfusion defect in the right frontal lobe
at the area of the middle cerebral artery (Fig 1).
The international normalized ratio was 1.3 and the activated partial thromboplastin time was 62 seconds (normal
range 20-29 seconds), indicating dabigatran etexilate
(Pradaxa) treatment.4 The patient and family were informed regarding the rationale for idarucizumab (Praxbind)
and the following systemic intravenous thrombolysis treatment using recombinant tissue plasminogen activator
(r-tPA) (alteplase) and accepted treatment. The plasmadabigatran value was measured to .01 after the treatment,
confirming idarucizumab efficacy on dabigatran etexilate
(Pradaxa) reversal.
Idarucizumab (Praxbind) 2.5 g/50 mL, initiated at 1:19
pm and ended at 1:47 pm, was infused intravenously twice,
with a 15-minute interval. Immediately after the second infusion of idarucizumab, systemic intravenous r-tPA was
initiated. After 24 hours, the National Institute of Health
Stroke Score was 2 for a slight dysarthria and a left-sided
central facial palsy. The patient had regained full muscle
strength over all joints in the previously hemiparetic left
side. The follow-up CT scan 24 hours after the start of
alteplase treatment showed no signs of cerebral infarction
or hemorrhagic transformation. Follow-up brain magnetic

resonance imaging 10 days after stroke onset showed no
signs of acute or subacute infarction corresponding to the
perfusion deficit or in any other part of the brain (Fig 2).
There was an old, small lacunar infarct in the left cerebellar hemisphere, and nonspecific white-substance gliosis
subcortical bilateral, defined as small-vessel ischemia.
Ultrasound of the carotid arteries revealed no atherosclerotic lesions or stenosis. The symptoms were fully
remitted in no time, and 3 days after the onset of symptoms, discrete dysarthria was the only thing left at the
discharge. The dysarthria was fully remitted 2 days after
the discharge.

Discussion
Idarucizumab is a humanized monoclonal antibody fragment binding dabigatran etexilate approximately 350fold stronger than dabigatran etexilate binding to thrombin,
thereby neutralizing the anticoagulant activity of dabigatran
etexilate. The biochemical composition of idarucizumab
is the main reason for this mechanism of action. The molecular composition has structural similarities to thrombin,
but idarucizumab lacks enzymatic activity. The binding
to dabigatran etexilate is mediated by hydrophobic

Figure 2. MRI day 10 shows no restricted diffusion or infarction on T2FLAIR. Abbreviations: MRI, magnetic resonance imaging; T2-FLAIR, T2fluid-attenuated inversion recovery.

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REVERSAL OF DABIGATRAN ETEXILATE USING IDARUCIZUMAB

interactions, H-bonds, and a salt bridge, resulting in high
affinity for dabigatran etexilate.5 Idarucizumab does not
bind to FV, FVIII, FXIII, or fibrinogen. It directly inhibits dabigatran etexilate and does not potentiate coagulation
further. There are no interactions between idarucizumab
and r-tPA-induced thrombolysis in human plasma in vitro.
According to the RE-LY study,5 a study based on a cohort
of patients 65 years or more and with a moderate to high
comorbidity status, the average peak concentrations of
dabigatran etexilate observed in patients with atrial fibrillation who received dabigatran etexilate 150 mg twice
dailyvaried by more than 5-fold. An idarucizumab dose
of 2 g completely binds and reverses 70% of dabigatran
etexilate. An idarucizumab dose of 5 g causes dabigatran
etexilate reversal of 99% and is therefore the choice for
standard dose.5
Thus, when a patient treated with dabigatran etexilate
suffers a thrombotic event, which is procoagulant in nature,
r-tPA may be initiated rapidly after dabigatran etexilate
reversal.2,4
To our knowledge, there are 6 previously published
cases1,2,6-9 describing an identical treatment in acute ischemic stroke followed with intravenous r-tPA. Cases with
positive and negative treatment outcomes should be reported until consensus guidelines or randomized trials
are published.

Conclusion
In the present case, idarucizumab neutralized dabigatran
etexilate, and the following r-tPA treatment was safe,
leaving the patient fully remitted and satisfied.

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References
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