- Email: [email protected]
Early Initiation of Anticoagulation with Direct Oral Anticoagulants in Patients after Transient Ischemic Attack or Ischemic Stroke
ARTICLE IN PRESS
Early Initiation of Anticoagulation with Direct Oral Anticoagulants in Patients after Transient Ischemic Attack or Ischemic Stroke Kosmas Macha, MD,1 Bastian Volbers, MD,1 Tobias Bobinger, MD, Natalia Kurka, MD, Lorenz Breuer, MD, Hagen B. Huttner, MD, Stefan Schwab, MD, and Martin Köhrmann, MD
Background: Direct oral anticoagulants (DOACs) are increasingly used for secondary prevention of cardioembolic stroke. While DOACs are associated with a long-term reduced risk of intracranial hemorrhage compared to vitamin K antagonists, pivotal trials avoided the very early period after stroke and few data exist on early initiation of DOAC therapy post stroke. Methods: We retrospectively analyzed data from our prospective database of all consecutive transient ischemic attack (TIA) or ischemic stroke patients with atrial fibrillation treated with DOACs during hospital stay. As per our institutional treatment algorithm for patients with cardioembolic ischemia DOACs are started immediately in TIA and minor stroke (group 1), within days 3-5 in patients with infarcts affecting one third or less of the middle cerebral artery, the anterior cerebral artery, or the posterior cerebral artery territories (group 2) as well as in infratentorial stroke (group 3) and after 1-2 weeks in patients with large infarcts (>1⁄3MCA territory, group 4). We investigated baseline characteristics, time to initiation of DOAC therapy after symptom onset, and hemorrhagic complications. Results: In 243 included patients, administration of DOAC was initiated 40.5 hours (interquartile range [IQR] 23.0-65.5) after stroke onset in group 1 (n = 41) and after 76.7 hours (IQR 48.0134.0), 108.4 hours (IQR 67.3-176.4), and 161.8 hours (IQR 153.9-593.8) in groups 2-4 (n = 170, 28, and 4), respectively. Two cases of asymptomatic intracranial hemorrhage (.8%) and 1 case of symptomatic intracranial hemorrhage (.4%) were observed, both in group 2. Conclusions: No severe safety issues were observed in early initiation of DOACs for secondary prevention after acute stroke in our in-patient cohort. Key Words: Oral anticoagulation—ischemic stroke—secondary prevention—hemorrhagic transformation—DOAC—atrial fibrillation. © 2016 National Stroke Association. Published by Elsevier Inc. All rights reserved.
From the Department of Neurology, Universitätsklinikum Erlangen, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Erlangen, Germany. Received April 13, 2016; revision received June 17, 2016; accepted June 21, 2016. Disclosure statement: M.K., S.S., L.B., and B.V. received speakers’ honoraria from Boehringer Ingelheim, Bayer, and BMS Pfizer. Address correspondence to Kosmas Macha, MD, Department of Neurology, Universitätsklinikum Erlangen, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Schwabachanlage 6, 91054 Erlangen, Germany. E-mail: [email protected]. 1 These authors contributed equally to the manuscript. 1052-3057/$ - see front matter © 2016 National Stroke Association. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2016.06.031
Journal of Stroke and Cerebrovascular Diseases, Vol. ■■, No. ■■ (■■), 2016: pp ■■–■■
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ARTICLE IN PRESS K. MACHA ET AL.
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Introduction Patients with atrial fibrillation (AF) and recent transient ischemic attack (TIA) or ischemic stroke are at high risk for recurrent ischemic stroke especially in the early phase after stroke.1 Oral anticoagulation (OAC) is highly effective to prevent further cardioembolic ischemic events; thus, it is desirable to initiate this treatment as early as possible after an ischemic event.2 On the other hand, patients with subacute ischemic stroke are at risk for hemorrhagic transformation of the infarct after early anticoagulation. Pivotal trials of DOACs were mainly carried out in primary stroke prevention, and to maximize safety in patients with ischemic stroke, the study drug could not be started within 7, 14, or even 30 days after an ischemic stroke.3-6 Therefore, safety data regarding early initiation of DOAC therapy in patients with AF after acute ischemic stroke or TIA is sparse. In the present study, we investigated safety of a treatment algorithm for early initiation of DOACs after cerebral ischemia in an in-patient stroke cohort.
Methods Study Design With respect to possible contraindications, DOACs are initiated early as per the following institutional algorithm dividing patients into 4 groups: (1) In patients with TIA and minor stroke (symptoms lasting more than 24 hours without correlates in cerebral imaging) DOACs are started without delay after initial evaluation (group 1); (2) In patients with supratentorial infarcts affecting one third or less of the middle cerebral artery (MCA), the anterior cerebral artery (ACA), or the posterior cerebral artery (PCA) territories (group 2) as well as (3) in patients with infratentorial infarcts (group 3) DOACs are started within 3-5 days; (4) In patients with larger infarcts (>1⁄3MCA infarction) (group 4) OAC is delayed for 1-2 weeks. We extracted data from our prospective database of consecutive TIA or ischemic stroke patients admitted between September 2011 and December 2013. Patients were included using the following inclusion criteria: (1) AFassociated acute ischemic event and (2) treatment with DOACs during in-patient hospital stay. Patients receiving several different anticoagulation regimens were excluded (n = 29); 2 patients were excluded due to early cessation of DOAC therapy for other reasons than intracranial hemorrhage (ICH). Antiplatelets were administered according to the discretion of the treating physician (e.g., condition after coronary or neurovascular stenting) but are not routinely used in patients with AF as per an institutional protocol. Infarct size was measured based on computed tomography (CT) imaging or magnetic resonance imaging (MRI) as performed in clinical routine. We investigated baseline characteristics, time to initiation of DOAC therapy, coadministration of antiplatelets, and occurrence of asymptomatic intracranial hemorrhage (aICH) or symptomatic
intracranial hemorrhage (sICH). Cerebral imaging was performed in case of clinical deterioration (National Institutes of Health Stroke Scale [NIHSS] score ≥4 points) and for other diagnostic reasons according to the discretion of the treating physician. Intracranial hemorrhages were graded according to European Cooperative Acute Stroke Study III (ECASS III) criteria.7
Statistical Analysis Dichotomous variables were presented as number and percentage, and ordinal variables as median and interquartile range (IQR) if the Kolmogorov–Smirnov test showed no normal distribution. Statistical analyses were performed using the IBM SPSS Statistics 21 software package (SPSS Inc., Chicago, IL).
Results Overall 401 patients received OAC during in-hospital stay for TIA or acute ischemic stroke. DOACs were administered in 243 of these patients (60.6%) and in 93 of 107 patients (86.9%) with newly detected AF. Demographic and baseline characteristics are given in Table 1. The median NIHSS scores on admission in patient groups are shown in Figure 1. DOAC therapy was initiated 40.5 hours (IQR 23.0-65.5) after stroke onset in group 1 and after 76.7 hours (IQR 48.0-134.0), 108.4 hours (IQR 67.3176.4), and 161.8 hours (IQR 153.9-593.8) in groups 2-4, respectively. Median time from symptom onset to initiation of DOAC therapy in days is given in Figure 2. Overall, 89.7% of patients received DOACs within 7 days, and 98.4% within the first 14 days. Thirteen CTs and 12 MRIs were performed after the initiation of DOAC therapy; two of the CTs were due to clinical deterioration. Two cases of aICH (.8%, one HI1 and one HI2) and 1 case of sICH (.4%, PH2) were detected, both in group 2 (see Table 2).
Discussion In meta-analyses of the randomized trials, DOACs are uniformly associated with an overall reduced risk of ICH; however, early therapy initiation post stroke was precluded by study design in all pivotal trials.8,9 In the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial (apixaban), a minimum of 7 days was needed between an ischemic stroke and study inclusion, whereas in both Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) (dabigatran) and Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET-AF) (rivaroxaban), 14 days were required.3-5 In addition, patients with TIA could not be included in the ROCKETAF trial within 3 days of the event. 4 The Effective Anticoagulation with Factor Xa Next Generation in Atrial
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Table 1. Demographic and baseline characteristics
Characteristics
TIA or minor stroke (group 1, n = 41)
Nonextensive supratentorial infarction (group 2, n = 170)*
Infratentorial infarction (group 3, n = 28)
Extensive supratentorial infarction (group 4, n = 4)
Age median (IQR) Age more than 80 years Sex (female) Arterial hypertension Diabetes mellitus Dyslipidemia NIHSS score, median (IQR) Thrombolysis
78.0 (73.5-84.5) 17 (41.5) 23 (56.1) 34 (82.9) 9 (22.0) 23 (56.1) 0 (0-1) —
78.0 (72.0-84.0) 65 (38.2) 77 (45.3) 153 (90.0) 57 (33.5) 103 (61.3) 5 (2-9) 56 (32.9)
78.0 (67.8-80.0) 6 (21.4) 14 (50.0) 27 (96.4) 10 (35.7) 24 (85.7) 3 (1-5) 5 (17.9)
68.5 (63.0-71.8) 0 (.0) 3 (75.0) 3 (75.0) 0 (.0) 1 (25.0) 15 (9-16) 2 (50.0)
Abbreviations: IQR, interquartile range; NIHSS, National Institutes of Health Stroke Scale. Number of patients (%). *Twelve patients with additional infratentorial infarction.
Fibrillation–Thrombolysis in Myocardial Infarction 48 (ENGAGE AF-TIMI 48) trial (edoxaban) even precluded inclusion of patients within 30 days of any ischemic stroke.6 In contrast to previous therapies, this exclusion criterion of pivotal trials is not reflected in the official license. In our cohort, DOAC therapy was initiated on day 2 in patients with TIA or minor stroke (group 1) and on days
4 and 5 in patients with nonextensive supratentorial (group 2) and infratentorial (group 3) infarctions. The comparably early initiation of OAC found in group 4 of our study is most likely caused by small numbers and the fact that many patients with large infarctions were transferred to rehab units prior to initiation of DOAC and were therefore excluded from analysis. The vast majority of our patients
Figure 1. NIHSS score distribution in patient groups. *Twelve patients with additional infratentorial infarction. Abbreviations: NIHSS, National Institutes of Health Stroke Scale; TIA, transient ischemic attack.
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Figure 2. Time of DOAC initiation. *Twelve patients with additional infratentorial infarction. Abbreviations: DOAC, direct oral anticoagulant; TIA, transient ischemic attack.
received OAC within the time frame not covered by the large trials. Overall, 89.7% of the patients received DOACs within 7 days (ARISTOTLE), 98.4% within the first 14 days (RE-LY and ROCKET-AF), and 99.6% within 30 days (ENGAGE AF-TIMI 48).3-6 Of the patients with imagingconfirmed infarction (groups 2-4), 87.6%, 98.0%, and 99.5%
received OAC within 7, 14, and 30 days, respectively. All patients with TIA or minor stroke (group 1) received OAC within 7 days; in 82.9% of patients in group 1, OAC was initiated within 3 days (patients with TIA in ROCKET-AF).4 Initiation of dabigatran therapy within 24 hours after symptom onset in patients with minor stroke was shown
Table 2. Therapy, occurrence of ICH, and length of hospital stay Nonextensive TIA or minor stroke supratentorial infarction (group 1, n = 41) (group 2, n = 170)* Onset DOAC† (h), median (IQR) Co-antiplatelet therapy (mono) Co-antiplatelet therapy (dual) aICH sICH Length of hospital stay (days), median (IQR)
40.5 (23.0-65.5) 0 (.0) 2 (4.9) 0 (.0) 0 (.0) 5 (4-5)
76.7 (48.0-134.0) 12 (7.1) 2 (1.2) 2 (.8) 1 (.4) 7 (5-10)
Infratentorial infarction (group 3, n = 28)
Extensive supratentorial infarction (group 4, n = 4)
108.4 (67.3-176.4) 3 (10.7) 0 (.0) 0 (.0) 0 (.0) 9 (6-10)
161.8 (153.9-593.8) 0 (.0) 0 (.0) 0 (.0) 0 (.0) 13 (9-27)
Abbreviations: aICH, asymptomatic intracranial hemorrhage; DOAC, direct oral anticoagulant; ICH, intracranial hemorrhage; IQR, interquartile range; sICH, symptomatic intracranial hemorrhage; TIA, transient ischemic attack. Number of patients (%). *Twelve patients with additional infratentorial infarction. †Time from symptom onset or last seen normal to initiation of OAC.
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to be safe in a small number of patients recently, as only 3 of 53 patients had evidence of asymptomatic petechial transformation on follow-up MRI on day 7, which remained stable at day 30 on continued dabigatran therapy; no sICH occurred.10 The median length of hospital stay in our patient cohort was 5, 7, 9, and 13 days in groups 1-4, respectively, and therefore patients were monitored in the acute phase of DOAC initiation. We observed 2 cases of aICH and 1 case of sICH. One aICH was detected in a 1⁄3MCA territory stroke patient (NIHSS score on admission: 13) initially treated with antiplatelet therapy. Treatment was switched to DOAC after detection of AF on day 4; follow-up MRI on day 5 showed hemorrhagic transformation of the infarction (HI2), while the patient showed no clinical deterioration. The second aICH was detected in a patient with stroke in the PCA territory (initial NIHSS score: 3) who was switched from antiplatelet therapy to DOACs after detection of AF on day 4. Followup CT on day 6 showed slight hemorrhagic transformation (HI1), while the patient showed no clinical deterioration. The sICH occurred 14 days post stroke (<1⁄3MCA territory, initial NIHSS score: 2) and 2 days after carotid revascularization. The patient previously had been on dualantiplatelet therapy because of recent coronary artery baremetal stenting but had been perioperatively switched to dual therapy (DOAC and acetylsalicyclic acid (ASA)). Noncontrast CT revealed a fatal large left-sided hemorrhage (PH2). The exact etiology of sICH development in this patient remains unclear, but may be multifactorial because of dual therapy in the context of reperfusion injury. Similar to our results, the Stroke Acute Management with Urgent Risk-factor Assessment and Improvement (SAMURAI) Study on Anticoagulant Therapy in Nonvalvular Atrial Fibrillation (NVAF) study demonstrated the safety of early DOAC initiation in a large Japanese cohort as the investigators detected no ICH after DOAC initiation (median: 4 days post stroke).11 Our study has obvious limitations, mainly its retrospective, monocenter design as well as limited patient number. However, no safety issues were encountered in our cohort. While our cohort was older than patients in the pivotal trials (median or mean: 70-73 years) and SAMURAI-NVAF (mean: 74.5 years), only 36.2% of our patients were aged above 80 years.3-6,11 Therefore, data
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regarding early DOAC initiation, especially in elderly patients, are still sparse. Larger datasets are needed to assess the efficacy and safety of early initiation of DOAC in secondary prevention in patients with AF post stroke. Acknowledgment: This work was performed in fulfillment of the requirements for obtaining the degree “Dr. med.”.
References 1. Stroke Risk in Atrial Fibrillation Working Group. Independent predictors of stroke in patients with atrial fibrillation: a systematic review. Neurology 2007;69:546554. 2. Kernan WN, Ovbiagele B, Black HR, et al. Guidelines for the prevention of stroke in patients with stroke and transient ischemic attack: a guideline for healthcare professionals from the American Heart Association/ American Stroke Association. Stroke 2014;45:2160-2236. 3. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009;361:1139-1151. 4. Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011;365:883-891. 5. Granger CB, Alexander JH, McMurray JJV, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011;365:981-992. 6. Giugliano RP, Ruff CT, Braunwald E, et al. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2013;369:2093-2104. 7. Hacke W, Kaste M, Bluhmki E, et al. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med 2008;359:1317-1329. 8. Chatterjee S, Sardar P, Biondi-Zoccai G, et al. New oral anticoagulants and the risk of intracranial hemorrhage: traditional and Bayesian meta-analysis and mixed treatment comparison of randomized trials of new oral anticoagulants in atrial fibrillation. JAMA Neurol 2013;70:1486-1490. 9. 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;383:955-962. 10. Kate M, Gioia L, Buck B, et al. Dabigatran therapy in acute ischemic stroke patients without atrial fibrillation. Stroke 2015;46:2685-2687. 11. Toyoda K, Arihiro S, Todo K, et al. Trends in oral anticoagulant choice for acute stroke patients with nonvalvular atrial fibrillation in Japan: the SAMURAINVAF study. Int J Stroke 2015;10:836-842.
Early Initiation of Anticoagulation with Direct Oral Anticoagulants in Patients after Transient Ischemic Attack or Ischemic Stroke Kosmas Macha, MD,1 Bastian Volbers, MD,1 Tobias Bobinger, MD, Natalia Kurka, MD, Lorenz Breuer, MD, Hagen B. Huttner, MD, Stefan Schwab, MD, and Martin Köhrmann, MD
Background: Direct oral anticoagulants (DOACs) are increasingly used for secondary prevention of cardioembolic stroke. While DOACs are associated with a long-term reduced risk of intracranial hemorrhage compared to vitamin K antagonists, pivotal trials avoided the very early period after stroke and few data exist on early initiation of DOAC therapy post stroke. Methods: We retrospectively analyzed data from our prospective database of all consecutive transient ischemic attack (TIA) or ischemic stroke patients with atrial fibrillation treated with DOACs during hospital stay. As per our institutional treatment algorithm for patients with cardioembolic ischemia DOACs are started immediately in TIA and minor stroke (group 1), within days 3-5 in patients with infarcts affecting one third or less of the middle cerebral artery, the anterior cerebral artery, or the posterior cerebral artery territories (group 2) as well as in infratentorial stroke (group 3) and after 1-2 weeks in patients with large infarcts (>1⁄3MCA territory, group 4). We investigated baseline characteristics, time to initiation of DOAC therapy after symptom onset, and hemorrhagic complications. Results: In 243 included patients, administration of DOAC was initiated 40.5 hours (interquartile range [IQR] 23.0-65.5) after stroke onset in group 1 (n = 41) and after 76.7 hours (IQR 48.0134.0), 108.4 hours (IQR 67.3-176.4), and 161.8 hours (IQR 153.9-593.8) in groups 2-4 (n = 170, 28, and 4), respectively. Two cases of asymptomatic intracranial hemorrhage (.8%) and 1 case of symptomatic intracranial hemorrhage (.4%) were observed, both in group 2. Conclusions: No severe safety issues were observed in early initiation of DOACs for secondary prevention after acute stroke in our in-patient cohort. Key Words: Oral anticoagulation—ischemic stroke—secondary prevention—hemorrhagic transformation—DOAC—atrial fibrillation. © 2016 National Stroke Association. Published by Elsevier Inc. All rights reserved.
From the Department of Neurology, Universitätsklinikum Erlangen, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Erlangen, Germany. Received April 13, 2016; revision received June 17, 2016; accepted June 21, 2016. Disclosure statement: M.K., S.S., L.B., and B.V. received speakers’ honoraria from Boehringer Ingelheim, Bayer, and BMS Pfizer. Address correspondence to Kosmas Macha, MD, Department of Neurology, Universitätsklinikum Erlangen, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Schwabachanlage 6, 91054 Erlangen, Germany. E-mail: [email protected]. 1 These authors contributed equally to the manuscript. 1052-3057/$ - see front matter © 2016 National Stroke Association. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2016.06.031
Journal of Stroke and Cerebrovascular Diseases, Vol. ■■, No. ■■ (■■), 2016: pp ■■–■■
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ARTICLE IN PRESS K. MACHA ET AL.
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Introduction Patients with atrial fibrillation (AF) and recent transient ischemic attack (TIA) or ischemic stroke are at high risk for recurrent ischemic stroke especially in the early phase after stroke.1 Oral anticoagulation (OAC) is highly effective to prevent further cardioembolic ischemic events; thus, it is desirable to initiate this treatment as early as possible after an ischemic event.2 On the other hand, patients with subacute ischemic stroke are at risk for hemorrhagic transformation of the infarct after early anticoagulation. Pivotal trials of DOACs were mainly carried out in primary stroke prevention, and to maximize safety in patients with ischemic stroke, the study drug could not be started within 7, 14, or even 30 days after an ischemic stroke.3-6 Therefore, safety data regarding early initiation of DOAC therapy in patients with AF after acute ischemic stroke or TIA is sparse. In the present study, we investigated safety of a treatment algorithm for early initiation of DOACs after cerebral ischemia in an in-patient stroke cohort.
Methods Study Design With respect to possible contraindications, DOACs are initiated early as per the following institutional algorithm dividing patients into 4 groups: (1) In patients with TIA and minor stroke (symptoms lasting more than 24 hours without correlates in cerebral imaging) DOACs are started without delay after initial evaluation (group 1); (2) In patients with supratentorial infarcts affecting one third or less of the middle cerebral artery (MCA), the anterior cerebral artery (ACA), or the posterior cerebral artery (PCA) territories (group 2) as well as (3) in patients with infratentorial infarcts (group 3) DOACs are started within 3-5 days; (4) In patients with larger infarcts (>1⁄3MCA infarction) (group 4) OAC is delayed for 1-2 weeks. We extracted data from our prospective database of consecutive TIA or ischemic stroke patients admitted between September 2011 and December 2013. Patients were included using the following inclusion criteria: (1) AFassociated acute ischemic event and (2) treatment with DOACs during in-patient hospital stay. Patients receiving several different anticoagulation regimens were excluded (n = 29); 2 patients were excluded due to early cessation of DOAC therapy for other reasons than intracranial hemorrhage (ICH). Antiplatelets were administered according to the discretion of the treating physician (e.g., condition after coronary or neurovascular stenting) but are not routinely used in patients with AF as per an institutional protocol. Infarct size was measured based on computed tomography (CT) imaging or magnetic resonance imaging (MRI) as performed in clinical routine. We investigated baseline characteristics, time to initiation of DOAC therapy, coadministration of antiplatelets, and occurrence of asymptomatic intracranial hemorrhage (aICH) or symptomatic
intracranial hemorrhage (sICH). Cerebral imaging was performed in case of clinical deterioration (National Institutes of Health Stroke Scale [NIHSS] score ≥4 points) and for other diagnostic reasons according to the discretion of the treating physician. Intracranial hemorrhages were graded according to European Cooperative Acute Stroke Study III (ECASS III) criteria.7
Statistical Analysis Dichotomous variables were presented as number and percentage, and ordinal variables as median and interquartile range (IQR) if the Kolmogorov–Smirnov test showed no normal distribution. Statistical analyses were performed using the IBM SPSS Statistics 21 software package (SPSS Inc., Chicago, IL).
Results Overall 401 patients received OAC during in-hospital stay for TIA or acute ischemic stroke. DOACs were administered in 243 of these patients (60.6%) and in 93 of 107 patients (86.9%) with newly detected AF. Demographic and baseline characteristics are given in Table 1. The median NIHSS scores on admission in patient groups are shown in Figure 1. DOAC therapy was initiated 40.5 hours (IQR 23.0-65.5) after stroke onset in group 1 and after 76.7 hours (IQR 48.0-134.0), 108.4 hours (IQR 67.3176.4), and 161.8 hours (IQR 153.9-593.8) in groups 2-4, respectively. Median time from symptom onset to initiation of DOAC therapy in days is given in Figure 2. Overall, 89.7% of patients received DOACs within 7 days, and 98.4% within the first 14 days. Thirteen CTs and 12 MRIs were performed after the initiation of DOAC therapy; two of the CTs were due to clinical deterioration. Two cases of aICH (.8%, one HI1 and one HI2) and 1 case of sICH (.4%, PH2) were detected, both in group 2 (see Table 2).
Discussion In meta-analyses of the randomized trials, DOACs are uniformly associated with an overall reduced risk of ICH; however, early therapy initiation post stroke was precluded by study design in all pivotal trials.8,9 In the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial (apixaban), a minimum of 7 days was needed between an ischemic stroke and study inclusion, whereas in both Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) (dabigatran) and Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET-AF) (rivaroxaban), 14 days were required.3-5 In addition, patients with TIA could not be included in the ROCKETAF trial within 3 days of the event. 4 The Effective Anticoagulation with Factor Xa Next Generation in Atrial
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Table 1. Demographic and baseline characteristics
Characteristics
TIA or minor stroke (group 1, n = 41)
Nonextensive supratentorial infarction (group 2, n = 170)*
Infratentorial infarction (group 3, n = 28)
Extensive supratentorial infarction (group 4, n = 4)
Age median (IQR) Age more than 80 years Sex (female) Arterial hypertension Diabetes mellitus Dyslipidemia NIHSS score, median (IQR) Thrombolysis
78.0 (73.5-84.5) 17 (41.5) 23 (56.1) 34 (82.9) 9 (22.0) 23 (56.1) 0 (0-1) —
78.0 (72.0-84.0) 65 (38.2) 77 (45.3) 153 (90.0) 57 (33.5) 103 (61.3) 5 (2-9) 56 (32.9)
78.0 (67.8-80.0) 6 (21.4) 14 (50.0) 27 (96.4) 10 (35.7) 24 (85.7) 3 (1-5) 5 (17.9)
68.5 (63.0-71.8) 0 (.0) 3 (75.0) 3 (75.0) 0 (.0) 1 (25.0) 15 (9-16) 2 (50.0)
Abbreviations: IQR, interquartile range; NIHSS, National Institutes of Health Stroke Scale. Number of patients (%). *Twelve patients with additional infratentorial infarction.
Fibrillation–Thrombolysis in Myocardial Infarction 48 (ENGAGE AF-TIMI 48) trial (edoxaban) even precluded inclusion of patients within 30 days of any ischemic stroke.6 In contrast to previous therapies, this exclusion criterion of pivotal trials is not reflected in the official license. In our cohort, DOAC therapy was initiated on day 2 in patients with TIA or minor stroke (group 1) and on days
4 and 5 in patients with nonextensive supratentorial (group 2) and infratentorial (group 3) infarctions. The comparably early initiation of OAC found in group 4 of our study is most likely caused by small numbers and the fact that many patients with large infarctions were transferred to rehab units prior to initiation of DOAC and were therefore excluded from analysis. The vast majority of our patients
Figure 1. NIHSS score distribution in patient groups. *Twelve patients with additional infratentorial infarction. Abbreviations: NIHSS, National Institutes of Health Stroke Scale; TIA, transient ischemic attack.
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Figure 2. Time of DOAC initiation. *Twelve patients with additional infratentorial infarction. Abbreviations: DOAC, direct oral anticoagulant; TIA, transient ischemic attack.
received OAC within the time frame not covered by the large trials. Overall, 89.7% of the patients received DOACs within 7 days (ARISTOTLE), 98.4% within the first 14 days (RE-LY and ROCKET-AF), and 99.6% within 30 days (ENGAGE AF-TIMI 48).3-6 Of the patients with imagingconfirmed infarction (groups 2-4), 87.6%, 98.0%, and 99.5%
received OAC within 7, 14, and 30 days, respectively. All patients with TIA or minor stroke (group 1) received OAC within 7 days; in 82.9% of patients in group 1, OAC was initiated within 3 days (patients with TIA in ROCKET-AF).4 Initiation of dabigatran therapy within 24 hours after symptom onset in patients with minor stroke was shown
Table 2. Therapy, occurrence of ICH, and length of hospital stay Nonextensive TIA or minor stroke supratentorial infarction (group 1, n = 41) (group 2, n = 170)* Onset DOAC† (h), median (IQR) Co-antiplatelet therapy (mono) Co-antiplatelet therapy (dual) aICH sICH Length of hospital stay (days), median (IQR)
40.5 (23.0-65.5) 0 (.0) 2 (4.9) 0 (.0) 0 (.0) 5 (4-5)
76.7 (48.0-134.0) 12 (7.1) 2 (1.2) 2 (.8) 1 (.4) 7 (5-10)
Infratentorial infarction (group 3, n = 28)
Extensive supratentorial infarction (group 4, n = 4)
108.4 (67.3-176.4) 3 (10.7) 0 (.0) 0 (.0) 0 (.0) 9 (6-10)
161.8 (153.9-593.8) 0 (.0) 0 (.0) 0 (.0) 0 (.0) 13 (9-27)
Abbreviations: aICH, asymptomatic intracranial hemorrhage; DOAC, direct oral anticoagulant; ICH, intracranial hemorrhage; IQR, interquartile range; sICH, symptomatic intracranial hemorrhage; TIA, transient ischemic attack. Number of patients (%). *Twelve patients with additional infratentorial infarction. †Time from symptom onset or last seen normal to initiation of OAC.
ARTICLE IN PRESS EARLY INITIATION OF DOAC—THERAPY AFTER STROKE
to be safe in a small number of patients recently, as only 3 of 53 patients had evidence of asymptomatic petechial transformation on follow-up MRI on day 7, which remained stable at day 30 on continued dabigatran therapy; no sICH occurred.10 The median length of hospital stay in our patient cohort was 5, 7, 9, and 13 days in groups 1-4, respectively, and therefore patients were monitored in the acute phase of DOAC initiation. We observed 2 cases of aICH and 1 case of sICH. One aICH was detected in a 1⁄3MCA territory stroke patient (NIHSS score on admission: 13) initially treated with antiplatelet therapy. Treatment was switched to DOAC after detection of AF on day 4; follow-up MRI on day 5 showed hemorrhagic transformation of the infarction (HI2), while the patient showed no clinical deterioration. The second aICH was detected in a patient with stroke in the PCA territory (initial NIHSS score: 3) who was switched from antiplatelet therapy to DOACs after detection of AF on day 4. Followup CT on day 6 showed slight hemorrhagic transformation (HI1), while the patient showed no clinical deterioration. The sICH occurred 14 days post stroke (<1⁄3MCA territory, initial NIHSS score: 2) and 2 days after carotid revascularization. The patient previously had been on dualantiplatelet therapy because of recent coronary artery baremetal stenting but had been perioperatively switched to dual therapy (DOAC and acetylsalicyclic acid (ASA)). Noncontrast CT revealed a fatal large left-sided hemorrhage (PH2). The exact etiology of sICH development in this patient remains unclear, but may be multifactorial because of dual therapy in the context of reperfusion injury. Similar to our results, the Stroke Acute Management with Urgent Risk-factor Assessment and Improvement (SAMURAI) Study on Anticoagulant Therapy in Nonvalvular Atrial Fibrillation (NVAF) study demonstrated the safety of early DOAC initiation in a large Japanese cohort as the investigators detected no ICH after DOAC initiation (median: 4 days post stroke).11 Our study has obvious limitations, mainly its retrospective, monocenter design as well as limited patient number. However, no safety issues were encountered in our cohort. While our cohort was older than patients in the pivotal trials (median or mean: 70-73 years) and SAMURAI-NVAF (mean: 74.5 years), only 36.2% of our patients were aged above 80 years.3-6,11 Therefore, data
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regarding early DOAC initiation, especially in elderly patients, are still sparse. Larger datasets are needed to assess the efficacy and safety of early initiation of DOAC in secondary prevention in patients with AF post stroke. Acknowledgment: This work was performed in fulfillment of the requirements for obtaining the degree “Dr. med.”.
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