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Systemic Thrombolysis in Acute Ischemic Stroke after Dabigatran Etexilate Reversal with Idarucizumab—A Case Report
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, Troels Wienecke, MD, PhD*,‡
MD,†
and
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: [email protected], 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 ■■–■■
1
ARTICLE IN PRESS D. TIRELI ET AL.
2
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.
ARTICLE IN PRESS 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.
3
References 1. Schäfer N, Müller A, Wüllner U. Systemic thrombolysis for ischemic stroke after antagonizing dabigatran with idarucizumab—a case report. J Stroke Cerebrovasc Dis 2016;25:e126-e127. 2. Berrouschot J, Stoll A, Hogh T, et al. Intravenous thrombolysis with recombinant tissue-type plasminogen activator in a stroke patient receiving dabigatran anticoagulant after antagonization with idarucizumab. Stroke 2016;47:1936-1938. 3. Florence JM, Pandya S, King WM, et al. Intrarater reliability of manual muscle test (Medical Research Council scale) grades in Duchenne’s muscular dystrophy. Phys Ther 1992;72:115-122, discussion 122-126. 4. Diener HC, Bernstein R, Butcher K, et al. Thrombolysis and thrombectomy in patients treated with dabigatran with acute ischemic stroke: expert opinion. Int J Stroke 2017;12:9-12. 5. Reilly PA, van Ryn J, Grottke O, et al. Idarucizumab, a specific reversal agent for dabigatran: mode of action, pharmacokinetics and pharmacodynamics, and safety and efficacy in phase 1 subjects. Am J Emerg Med 2016;34(11S):26-32. 6. Mutzenbach JS, Pikija S, Otto F, et al. Intravenous thrombolysis in acute ischemic stroke after dabigatran reversal with idarucizumab—a case report. Ann Clin Transl Neurol 2016;3:889-892. 7. Kafke W, Kraft P. Intravenous thrombolysis after reversal of dabigatran by idarucizumab: a case report. Case Rep Neurol 2016;8:140-144. 8. Gawehn A, Ayari Y, Heuschkel C, et al. Successful thrombolysis with recombinant tissue plasminogen activator after antagonizing dabigatran by idarucizumab: a case report. J Med Case Rep 2016;10:269. 9. Schulz JG, Kreps B. Idarucizumab elimination of dabigatran minutes before systemic thrombolysis in acute ischemic stroke. J Neurol Sci 2016;370:44.
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, Troels Wienecke, MD, PhD*,‡
MD,†
and
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: [email protected], 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 ■■–■■
1
ARTICLE IN PRESS D. TIRELI ET AL.
2
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.
ARTICLE IN PRESS 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.
3
References 1. Schäfer N, Müller A, Wüllner U. Systemic thrombolysis for ischemic stroke after antagonizing dabigatran with idarucizumab—a case report. J Stroke Cerebrovasc Dis 2016;25:e126-e127. 2. Berrouschot J, Stoll A, Hogh T, et al. Intravenous thrombolysis with recombinant tissue-type plasminogen activator in a stroke patient receiving dabigatran anticoagulant after antagonization with idarucizumab. Stroke 2016;47:1936-1938. 3. Florence JM, Pandya S, King WM, et al. Intrarater reliability of manual muscle test (Medical Research Council scale) grades in Duchenne’s muscular dystrophy. Phys Ther 1992;72:115-122, discussion 122-126. 4. Diener HC, Bernstein R, Butcher K, et al. Thrombolysis and thrombectomy in patients treated with dabigatran with acute ischemic stroke: expert opinion. Int J Stroke 2017;12:9-12. 5. Reilly PA, van Ryn J, Grottke O, et al. Idarucizumab, a specific reversal agent for dabigatran: mode of action, pharmacokinetics and pharmacodynamics, and safety and efficacy in phase 1 subjects. Am J Emerg Med 2016;34(11S):26-32. 6. Mutzenbach JS, Pikija S, Otto F, et al. Intravenous thrombolysis in acute ischemic stroke after dabigatran reversal with idarucizumab—a case report. Ann Clin Transl Neurol 2016;3:889-892. 7. Kafke W, Kraft P. Intravenous thrombolysis after reversal of dabigatran by idarucizumab: a case report. Case Rep Neurol 2016;8:140-144. 8. Gawehn A, Ayari Y, Heuschkel C, et al. Successful thrombolysis with recombinant tissue plasminogen activator after antagonizing dabigatran by idarucizumab: a case report. J Med Case Rep 2016;10:269. 9. Schulz JG, Kreps B. Idarucizumab elimination of dabigatran minutes before systemic thrombolysis in acute ischemic stroke. J Neurol Sci 2016;370:44.