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Idarucizumab for Intravenous Thrombolysis and Endovascular Thrombectomy in Acute Stroke: A Case Report
The Journal of Emergency Medicine, Vol. -, No. -, pp. 1–4, 2019 Ó 2019 Elsevier Inc. All rights reserved. 0736-4679/$ - see front matter
https://doi.org/10.1016/j.jemermed.2019.09.040
Selected Topics: Neurological Emergencies
IDARUCIZUMAB FOR INTRAVENOUS THROMBOLYSIS AND ENDOVASCULAR THROMBECTOMY IN ACUTE STROKE: A CASE REPORT Yu-Ting Lin, MD,* Yen-Jun Lai, MD,† and Tzu-Hsien Lai, MD, PHD‡§ *Department of Emergency Medicine, Far Eastern Memorial Hospital, New Taipei, Taiwan, †Department of Medical Imaging, Far Eastern Memorial Hospital, New Taipei, Taiwan, ‡Department of Neurology, Far Eastern Memorial Hospital, New Taipei, Taiwan, and §Department of Neurology, National Yang-Ming University School of Medicine, Taipei, Taiwan Reprint Address: Tzu-Hsien Lai, MD, PHD, Department of Neurology, Far Eastern Memorial Hospital, No. 21, Sec. 2, Nanya S. Rd., Banqiao Dist., New Taipei City 220, Taiwan (R.O.C.)
, Keywords—dabigatran; endovascular thrombectomy; idarucizumab; recombinant tissue plasminogen activator; stroke
, Abstract—Background: Non–vitamin K antagonist oral anticoagulants (NOACs), such as dabigatran, are widely used to prevent ischemic stroke in patients with nonvalvular atrial fibrillation. Nonetheless, stroke occurs in 1–2% of patients, and the use of NOACs may increase the bleeding risk for patients who are receiving acute treatment of intravenous thrombolysis (IVT) or endovascular thrombectomy (EVT). Idarucizumab, a monoclonal antibody developed to bind dabigatran, has been proven safe and effective for patients with uncontrolled bleeding or for patients planning to receive emergent procedures. It is now accepted that patients taking dabigatran with recurrent stroke may benefit from IVT after idarucizumab. However, there are limited data regarding idarucizumab use in patients planning to have EVT. Case Report: We present the case of a male patient taking dabigatran who had a stroke and who was treated with idarucizumab followed by combined IVT and EVT. The patient had immediate recanalization of the occluded vessel and near total recovery of function after 3 months. Why Should an Emergency Physician be Aware of This?: Our case report supports the evidence that patients presenting with acute ischemic stroke (AIS) despite being under dabigatran therapy should be evaluated for reversal by idarucizumab which can contribute to the eligibility for IVT as well as EVT. It has also been proved to provide better outcomes for patients with AIS. The availabilities of specific reversal agents for NOACs will probably alter the current management of patients with AIS. Ó 2019 Elsevier Inc. All rights reserved.
INTRODUCTION Non–vitamin K antagonist oral anticoagulants (NOACs) are widely used as alternatives for vitamin K antagonists, including 3 direct factor Xa inhibitors and 1 direct thrombin inhibitor, dabigatran. The common action of NOACs is to prevent stroke in patients with nonvalvular atrial fibrillation (AF). In general, NOACs are associated with better safety and efficacy than vitamin K antagonists (1). However, some patients still experience complications, such as intracerebral hemorrhage (ICH). To reverse these complications, various solutions have been developed, including idarucizumab, andexanet alfa, and ciraparantag (2–4). Some patients taking NOACs still experience stroke and NOAC use may further limit acute stroke treatment because of the higher bleeding risk. Significant progress in the treatment of acute ischemic stroke (AIS) has been made in recent years. Intravenous thrombolysis (IVT), with the addition of a tissue plasminogen activator, is generally recommended for patients within 4.5 h of stroke onset (5). Endovascular thrombectomy (EVT), particularly mechanical thrombectomy with
RECEIVED: 19 June 2019; FINAL SUBMISSION RECEIVED: 5 August 2019; ACCEPTED: 20 September 2019 1
2
Y.-T. Lin et al.
a stent retriever, may help in select patients with large vessel occlusion, even up to 16–24 h poststroke (6,7). In eligible patients, the practice of IVT followed by EVT has recently become the standard of care and has been reported to be associated with beneficial outcomes, lower mortality, and similar rates of symptomatic ICH (8). Idarucizumab is a reversal agent for dabigatran. In a recent review, its use for patients with AIS who were receiving IVT was associated with more favorable neurologic outcomes, defined as a National Institutes of Health Stroke Scale (NIHSS) score #1, a modified Rankin scale (mRS) score 0–2, or improvement in the NIHSS score $8 (9). It might also reduce the risk of symptomatic ICH and death, but the results were not statistically significant (9). However, the efficacy and safety of idarucizumab in patients with AIS who plan to have either isolated EVT or combined IVT and EVT have not been validated. We report a case of a patient with AIS undergoing dabigatran therapy who was treated with combined IVT and EVT after the administration of idarucizumab for anticoagulation reversal. CASE REPORT A 71-year-old man presented with a sudden onset of chest tightness. He had lost consciousness for <1 min and reported experiencing dysarthria while playing Mahjong (a traditional Chinese game). He had history of coronary artery disease treated with coronary artery angioplasty and stent placement 5 years ago, persistent AF with dabigatran 110 mg twice a day (last intake within 24 h of the event), and type 2 diabetes mellitus.
The patient arrived in our emergency department 30 min after the onset of symptoms. With clear consciousness and stable vital signs, he was characterized as level 3 at triage. Because of the initial chief complaint of chest pain, stroke was not suspected at first. The physician noted right facial palsy, hemiparesis, and dysarthria, and therefore a domestic AIS protocol was initiated. According to the neurologist, the patient’s right upper and lower limb muscle power were 1 and 4, respectively, on the 0–5 point Medical Research Council scale. The patient’s NIHSS score was 9 and his mRS score was 5. Electrocardiogram results showed AF without acute ischemic change. The patient’s cardiac enzymes were normal, and his coagulation profile was nearly normal, except for a minimally prolonged prothrombin time (international normalized ratio 1.07). A computed tomography scan of his head revealed no ICH and faint hypodensity at the left frontal operculum and insula, indicating possible left middle cerebral artery (MCA) territory infarction. After evaluation, the patient was considered eligible for IVT. Because he had been taking dabigatran within the past 24 h, 5 g of idarucizumab was given as continuous infusion for 15 min before the administration of tissue plasminogen activator. Because of a previous report of idarucizumab reversal of daigatran effect ‘‘within minutes,’’ we decided to start tissue plasminogen activator 10 min after idarucizumab infusion (10). The onset-toneedle time was 3 h and 19 min. The patient then received a computed tomography angiography scan of the head for the evaluation of possible EVT. The computed tomography angiography scan revealed left MCA segment 1 (M1) occlusion with left MCA territory infarction (Figure 1). Angiography confirmed left M1 total occlusion and about
Figure 1. (A) Occlusion at left middle cerebral artery segment 1. (B) Faint hypodensity at the left frontal operculum and the left insula.
Idarucizumab for IVT and EVT
70% stenosis of the left internal carotid artery (Figure 2A). Urgent EVT was performed with a Trevo XP Provue Stentriever (Stryker Neurovascular, Fremont, CA). A thrombolysis in cerebral infarction grade 3 recanalization was achieved 6 h and 14 min after onset of symptoms (Figure 2B). A follow-up computed tomography scan of the head 24 h later revealed a hypodense lesion compatible with partial left MCA infarction. The patient was discharged on day 25 with an NIHSS score of 2 and an mRS score of 3. Three months later, the patient’s NIHSS score was 2 and his mRS was 2; he could manage most activities of daily living without assistance. DISCUSSION In summary, we the report the case of a patient with AF who was receiving dabigatran preventative treatment and experiencing recurrent AIS. After idarucizumab infusion, combined IVT and EVT were applied with successful recanalization and a good clinical outcome. The patient was admitted with an NIHSS score of 9 and an mRS score of 5, and he was discharged with an NIHSS score of 2 and an mRS score of 3. At 3 months postrecanalization, his NIHSS score was 2, his mRS score was 2, and he had independence in carrying out most daily activities. Idarucizumab is a monoclonal antibody fragment that can bind dabigatran irreversibly with an affinity 350 times higher than thrombin (2). In the Study of the REVERSal Effects of Idarucizumab in Patients on Active Dabigatran, the administration of 5 g of idarucizumab produced rapid reversal of the anticoagulant effects of dabigatran in patients who had serious bleeding or those who anticipated needing urgent procedures (10). However, because of the lack of a control group, interpretation of the study should
3
be cautious. According to previous clinical trials, approximately 1–2% of patients with AF taking NOACs are expected to develop AIS. It is commonly accepted that these patients should not receive IVT because of the increased risk of bleeding caused by NOAC use (5). Nonetheless, some latest guidelines of stroke management for anticoagulated patients recommend that IVT could be given in patients with AIS after the reversal of dabigatran effect with idarucizumab (11,12). More evidence is needed to support this practice. Compared to those of IVT, the risks and benefits of EVT in patients with AIS who are taking dabigatran with idarucizumab reversal are less clear, and we were able to find only 4 cases (13–15). Improvement of NIHSS was noted in all 4 of these cases, despite the fact that asymptomatic ICH were noted in 2 cases. All 4 of these patients received both IVT and EVT after idarucizumab. In case series and clinical trials focused on IVT, a few patients also received EVT but outcomes concerning these specific patients were not reported. On the contrary, some case reports support EVT without idarucizumab reversal (16,17). In Japan, a consensus guide suggests that EVT can be considered without idarucizumab pretreatment or IVT (12). Prospective trials will be needed to confirm the efficacy and safety of these treatment regimens. This case report had 3 noteworthy limitations. First, although this patient had successful vessel recanalization and a positive clinical outcome without bleeding, a prospective safety and efficacy trial is needed to generalize the results to patients with similar clinical presentations. Second, because we did not check thrombin time, thrombin clotting time, and dabigatran levels before and after idarucizumab infusion, we cannot be sure of the exact reversal effect of idarucizumab in this patient.
Figure 2. (A) Total occlusion of the left middle cerebral artery segment 1 (M1). (B) Full opening of left M1 after mechanical thrombectomy with stent retriever.
4
Y.-T. Lin et al.
Third, because of the patient’s initial chief complaint of chest tightness, IVT and EVT were delayed, which may have affected the patient’s outcome. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?
6. 7. 8.
Our case report supports the evidence that patients presenting with AIS despite under dabigatran therapy should be evaluated for reversal by idarucizumab which can contribute to the eligibility for IVT as well as EVT. It has also been proved to provide better outcomes for AIS patients. The availabilities of specific reversal agents for NOACs will probably alter current managements of AIS.
9.
10. 11.
REFERENCES
12.
1. Ruff CT, Giugliano RP, Braunwald E, et al. Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials. Lancet 2014;383:955–62. 2. Schiele F, van Ryn J, Canada K, et al. A specific antidote for dabigatran: functional and structural characterization. Blood 2013;121: 3554–62. 3. Heo YA. Andexanet alfa: first global approval. Drugs 2018;78: 1049–55. 4. Bryan L, Sasha B, Solomon S. Ciraparantag safely and effectively reverses apixaban and rivaroxaban in age-matched healthy volunteers as measured by whole blood clotting time. Blood 2018;132: 987. 5. Powers WJ, Rabinstein AA, Ackerson T, et al. American Heart Association Stroke Council. 2018 guidelines for the early management of patients with acute ischemic stroke: a guideline for healthcare
13.
14. 15. 16. 17.
professionals from the American Heart Association/American Stroke Association. Stroke 2018;49:e46–110. Nogueira RG, Jadhav AP, Haussen DC. Thrombectomy 6 to 24 hours after stroke with a mismatch between deficit and infarct. N Engl J Med 2018;378:11–21. Albers GW, Marks MP, Kemp S. Thrombectomy for stroke at 6 to 16 hours with selection by perfusion imaging. N Engl J Med 2018;378: 708–18. Mistry EA, Mistry AM, Nakawah MO, et al. Mechanical thrombectomy outcomes with and without intravenous thrombolysis in stroke patients: a meta-analysis. Stroke 2017;48:2450–6. Jin C, Huang RJ, Peterson ED, et al. Intravenous tPA (tissue-type plasminogen activator) in patients with acute ischemic stroke taking non-vitamin K antagonist oral anticoagulants preceding stroke. Stroke 2018;49:2237–40. Pollack CV Jr, Reilly PA, Bernstein R, et al. Design and rationale for RE-VERSE AD: a phase 3 study of idarucizumab, a specific reversal agent for dabigatran. Thromb Haemost 2015;114:198–205. Steffel J, Verhamme P, Potpara TS, et al. The 2018 European Heart Rhythm Association Practical Guide on the use of non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation. Eur Heart J 2018;39:1330–93. Toyoda K, Yamagami H, Koga M. Consensus guides on stroke thrombolysis for anticoagulated patients from Japan: application to other populations. J Stroke 2018;20:321–31. Binet Q, Hammer FD, Rocrelle O, et al. Systemic thrombolysis and endovascular thrombectomy in severe acute ischemic stroke after dabigatran reversal with idarucizumab. Clin Case Rep 2018;6: 698–701. Renard A, Mallecourt C, Wilhlem L, et al. Intravenous thrombolysis and thrombectomy in stroke after dabigatran reversal by idarucizumab. Presse Med 2018;47(4 part 1):401–4. Zhao H, Coote S, Pesavento L, et al. Prehospital idarucizumab prior to intravenous thrombolysis in a mobile stroke unit. Int J Stroke 2019;14:265–9. Muller P, Topakian R, Sonnberger M, et al. Endovascular thrombectomy for acute ischemic stroke patients anticoagulated with dabigatran. Clin Neurol Neurosurg 2013;115:2257–9. Javedani PP, Horowitz BZ, Clark WM, et al. Dabigatran etexilate: management in acute ischemic stroke. Am J Crit Care 2013;22: 169–76.
https://doi.org/10.1016/j.jemermed.2019.09.040
Selected Topics: Neurological Emergencies
IDARUCIZUMAB FOR INTRAVENOUS THROMBOLYSIS AND ENDOVASCULAR THROMBECTOMY IN ACUTE STROKE: A CASE REPORT Yu-Ting Lin, MD,* Yen-Jun Lai, MD,† and Tzu-Hsien Lai, MD, PHD‡§ *Department of Emergency Medicine, Far Eastern Memorial Hospital, New Taipei, Taiwan, †Department of Medical Imaging, Far Eastern Memorial Hospital, New Taipei, Taiwan, ‡Department of Neurology, Far Eastern Memorial Hospital, New Taipei, Taiwan, and §Department of Neurology, National Yang-Ming University School of Medicine, Taipei, Taiwan Reprint Address: Tzu-Hsien Lai, MD, PHD, Department of Neurology, Far Eastern Memorial Hospital, No. 21, Sec. 2, Nanya S. Rd., Banqiao Dist., New Taipei City 220, Taiwan (R.O.C.)
, Keywords—dabigatran; endovascular thrombectomy; idarucizumab; recombinant tissue plasminogen activator; stroke
, Abstract—Background: Non–vitamin K antagonist oral anticoagulants (NOACs), such as dabigatran, are widely used to prevent ischemic stroke in patients with nonvalvular atrial fibrillation. Nonetheless, stroke occurs in 1–2% of patients, and the use of NOACs may increase the bleeding risk for patients who are receiving acute treatment of intravenous thrombolysis (IVT) or endovascular thrombectomy (EVT). Idarucizumab, a monoclonal antibody developed to bind dabigatran, has been proven safe and effective for patients with uncontrolled bleeding or for patients planning to receive emergent procedures. It is now accepted that patients taking dabigatran with recurrent stroke may benefit from IVT after idarucizumab. However, there are limited data regarding idarucizumab use in patients planning to have EVT. Case Report: We present the case of a male patient taking dabigatran who had a stroke and who was treated with idarucizumab followed by combined IVT and EVT. The patient had immediate recanalization of the occluded vessel and near total recovery of function after 3 months. Why Should an Emergency Physician be Aware of This?: Our case report supports the evidence that patients presenting with acute ischemic stroke (AIS) despite being under dabigatran therapy should be evaluated for reversal by idarucizumab which can contribute to the eligibility for IVT as well as EVT. It has also been proved to provide better outcomes for patients with AIS. The availabilities of specific reversal agents for NOACs will probably alter the current management of patients with AIS. Ó 2019 Elsevier Inc. All rights reserved.
INTRODUCTION Non–vitamin K antagonist oral anticoagulants (NOACs) are widely used as alternatives for vitamin K antagonists, including 3 direct factor Xa inhibitors and 1 direct thrombin inhibitor, dabigatran. The common action of NOACs is to prevent stroke in patients with nonvalvular atrial fibrillation (AF). In general, NOACs are associated with better safety and efficacy than vitamin K antagonists (1). However, some patients still experience complications, such as intracerebral hemorrhage (ICH). To reverse these complications, various solutions have been developed, including idarucizumab, andexanet alfa, and ciraparantag (2–4). Some patients taking NOACs still experience stroke and NOAC use may further limit acute stroke treatment because of the higher bleeding risk. Significant progress in the treatment of acute ischemic stroke (AIS) has been made in recent years. Intravenous thrombolysis (IVT), with the addition of a tissue plasminogen activator, is generally recommended for patients within 4.5 h of stroke onset (5). Endovascular thrombectomy (EVT), particularly mechanical thrombectomy with
RECEIVED: 19 June 2019; FINAL SUBMISSION RECEIVED: 5 August 2019; ACCEPTED: 20 September 2019 1
2
Y.-T. Lin et al.
a stent retriever, may help in select patients with large vessel occlusion, even up to 16–24 h poststroke (6,7). In eligible patients, the practice of IVT followed by EVT has recently become the standard of care and has been reported to be associated with beneficial outcomes, lower mortality, and similar rates of symptomatic ICH (8). Idarucizumab is a reversal agent for dabigatran. In a recent review, its use for patients with AIS who were receiving IVT was associated with more favorable neurologic outcomes, defined as a National Institutes of Health Stroke Scale (NIHSS) score #1, a modified Rankin scale (mRS) score 0–2, or improvement in the NIHSS score $8 (9). It might also reduce the risk of symptomatic ICH and death, but the results were not statistically significant (9). However, the efficacy and safety of idarucizumab in patients with AIS who plan to have either isolated EVT or combined IVT and EVT have not been validated. We report a case of a patient with AIS undergoing dabigatran therapy who was treated with combined IVT and EVT after the administration of idarucizumab for anticoagulation reversal. CASE REPORT A 71-year-old man presented with a sudden onset of chest tightness. He had lost consciousness for <1 min and reported experiencing dysarthria while playing Mahjong (a traditional Chinese game). He had history of coronary artery disease treated with coronary artery angioplasty and stent placement 5 years ago, persistent AF with dabigatran 110 mg twice a day (last intake within 24 h of the event), and type 2 diabetes mellitus.
The patient arrived in our emergency department 30 min after the onset of symptoms. With clear consciousness and stable vital signs, he was characterized as level 3 at triage. Because of the initial chief complaint of chest pain, stroke was not suspected at first. The physician noted right facial palsy, hemiparesis, and dysarthria, and therefore a domestic AIS protocol was initiated. According to the neurologist, the patient’s right upper and lower limb muscle power were 1 and 4, respectively, on the 0–5 point Medical Research Council scale. The patient’s NIHSS score was 9 and his mRS score was 5. Electrocardiogram results showed AF without acute ischemic change. The patient’s cardiac enzymes were normal, and his coagulation profile was nearly normal, except for a minimally prolonged prothrombin time (international normalized ratio 1.07). A computed tomography scan of his head revealed no ICH and faint hypodensity at the left frontal operculum and insula, indicating possible left middle cerebral artery (MCA) territory infarction. After evaluation, the patient was considered eligible for IVT. Because he had been taking dabigatran within the past 24 h, 5 g of idarucizumab was given as continuous infusion for 15 min before the administration of tissue plasminogen activator. Because of a previous report of idarucizumab reversal of daigatran effect ‘‘within minutes,’’ we decided to start tissue plasminogen activator 10 min after idarucizumab infusion (10). The onset-toneedle time was 3 h and 19 min. The patient then received a computed tomography angiography scan of the head for the evaluation of possible EVT. The computed tomography angiography scan revealed left MCA segment 1 (M1) occlusion with left MCA territory infarction (Figure 1). Angiography confirmed left M1 total occlusion and about
Figure 1. (A) Occlusion at left middle cerebral artery segment 1. (B) Faint hypodensity at the left frontal operculum and the left insula.
Idarucizumab for IVT and EVT
70% stenosis of the left internal carotid artery (Figure 2A). Urgent EVT was performed with a Trevo XP Provue Stentriever (Stryker Neurovascular, Fremont, CA). A thrombolysis in cerebral infarction grade 3 recanalization was achieved 6 h and 14 min after onset of symptoms (Figure 2B). A follow-up computed tomography scan of the head 24 h later revealed a hypodense lesion compatible with partial left MCA infarction. The patient was discharged on day 25 with an NIHSS score of 2 and an mRS score of 3. Three months later, the patient’s NIHSS score was 2 and his mRS was 2; he could manage most activities of daily living without assistance. DISCUSSION In summary, we the report the case of a patient with AF who was receiving dabigatran preventative treatment and experiencing recurrent AIS. After idarucizumab infusion, combined IVT and EVT were applied with successful recanalization and a good clinical outcome. The patient was admitted with an NIHSS score of 9 and an mRS score of 5, and he was discharged with an NIHSS score of 2 and an mRS score of 3. At 3 months postrecanalization, his NIHSS score was 2, his mRS score was 2, and he had independence in carrying out most daily activities. Idarucizumab is a monoclonal antibody fragment that can bind dabigatran irreversibly with an affinity 350 times higher than thrombin (2). In the Study of the REVERSal Effects of Idarucizumab in Patients on Active Dabigatran, the administration of 5 g of idarucizumab produced rapid reversal of the anticoagulant effects of dabigatran in patients who had serious bleeding or those who anticipated needing urgent procedures (10). However, because of the lack of a control group, interpretation of the study should
3
be cautious. According to previous clinical trials, approximately 1–2% of patients with AF taking NOACs are expected to develop AIS. It is commonly accepted that these patients should not receive IVT because of the increased risk of bleeding caused by NOAC use (5). Nonetheless, some latest guidelines of stroke management for anticoagulated patients recommend that IVT could be given in patients with AIS after the reversal of dabigatran effect with idarucizumab (11,12). More evidence is needed to support this practice. Compared to those of IVT, the risks and benefits of EVT in patients with AIS who are taking dabigatran with idarucizumab reversal are less clear, and we were able to find only 4 cases (13–15). Improvement of NIHSS was noted in all 4 of these cases, despite the fact that asymptomatic ICH were noted in 2 cases. All 4 of these patients received both IVT and EVT after idarucizumab. In case series and clinical trials focused on IVT, a few patients also received EVT but outcomes concerning these specific patients were not reported. On the contrary, some case reports support EVT without idarucizumab reversal (16,17). In Japan, a consensus guide suggests that EVT can be considered without idarucizumab pretreatment or IVT (12). Prospective trials will be needed to confirm the efficacy and safety of these treatment regimens. This case report had 3 noteworthy limitations. First, although this patient had successful vessel recanalization and a positive clinical outcome without bleeding, a prospective safety and efficacy trial is needed to generalize the results to patients with similar clinical presentations. Second, because we did not check thrombin time, thrombin clotting time, and dabigatran levels before and after idarucizumab infusion, we cannot be sure of the exact reversal effect of idarucizumab in this patient.
Figure 2. (A) Total occlusion of the left middle cerebral artery segment 1 (M1). (B) Full opening of left M1 after mechanical thrombectomy with stent retriever.
4
Y.-T. Lin et al.
Third, because of the patient’s initial chief complaint of chest tightness, IVT and EVT were delayed, which may have affected the patient’s outcome. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?
6. 7. 8.
Our case report supports the evidence that patients presenting with AIS despite under dabigatran therapy should be evaluated for reversal by idarucizumab which can contribute to the eligibility for IVT as well as EVT. It has also been proved to provide better outcomes for AIS patients. The availabilities of specific reversal agents for NOACs will probably alter current managements of AIS.
9.
10. 11.
REFERENCES
12.
1. Ruff CT, Giugliano RP, Braunwald E, et al. Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials. Lancet 2014;383:955–62. 2. Schiele F, van Ryn J, Canada K, et al. A specific antidote for dabigatran: functional and structural characterization. Blood 2013;121: 3554–62. 3. Heo YA. Andexanet alfa: first global approval. Drugs 2018;78: 1049–55. 4. Bryan L, Sasha B, Solomon S. Ciraparantag safely and effectively reverses apixaban and rivaroxaban in age-matched healthy volunteers as measured by whole blood clotting time. Blood 2018;132: 987. 5. Powers WJ, Rabinstein AA, Ackerson T, et al. American Heart Association Stroke Council. 2018 guidelines for the early management of patients with acute ischemic stroke: a guideline for healthcare
13.
14. 15. 16. 17.
professionals from the American Heart Association/American Stroke Association. Stroke 2018;49:e46–110. Nogueira RG, Jadhav AP, Haussen DC. Thrombectomy 6 to 24 hours after stroke with a mismatch between deficit and infarct. N Engl J Med 2018;378:11–21. Albers GW, Marks MP, Kemp S. Thrombectomy for stroke at 6 to 16 hours with selection by perfusion imaging. N Engl J Med 2018;378: 708–18. Mistry EA, Mistry AM, Nakawah MO, et al. Mechanical thrombectomy outcomes with and without intravenous thrombolysis in stroke patients: a meta-analysis. Stroke 2017;48:2450–6. Jin C, Huang RJ, Peterson ED, et al. Intravenous tPA (tissue-type plasminogen activator) in patients with acute ischemic stroke taking non-vitamin K antagonist oral anticoagulants preceding stroke. Stroke 2018;49:2237–40. Pollack CV Jr, Reilly PA, Bernstein R, et al. Design and rationale for RE-VERSE AD: a phase 3 study of idarucizumab, a specific reversal agent for dabigatran. Thromb Haemost 2015;114:198–205. Steffel J, Verhamme P, Potpara TS, et al. The 2018 European Heart Rhythm Association Practical Guide on the use of non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation. Eur Heart J 2018;39:1330–93. Toyoda K, Yamagami H, Koga M. Consensus guides on stroke thrombolysis for anticoagulated patients from Japan: application to other populations. J Stroke 2018;20:321–31. Binet Q, Hammer FD, Rocrelle O, et al. Systemic thrombolysis and endovascular thrombectomy in severe acute ischemic stroke after dabigatran reversal with idarucizumab. Clin Case Rep 2018;6: 698–701. Renard A, Mallecourt C, Wilhlem L, et al. Intravenous thrombolysis and thrombectomy in stroke after dabigatran reversal by idarucizumab. Presse Med 2018;47(4 part 1):401–4. Zhao H, Coote S, Pesavento L, et al. Prehospital idarucizumab prior to intravenous thrombolysis in a mobile stroke unit. Int J Stroke 2019;14:265–9. Muller P, Topakian R, Sonnberger M, et al. Endovascular thrombectomy for acute ischemic stroke patients anticoagulated with dabigatran. Clin Neurol Neurosurg 2013;115:2257–9. Javedani PP, Horowitz BZ, Clark WM, et al. Dabigatran etexilate: management in acute ischemic stroke. Am J Crit Care 2013;22: 169–76.