Proposed Approach to Thrombolysis in Dabigatran-Treated Patients Presenting with Ischemic Stroke Mahesh Kate, MBBS, MD, DM,* Artur Szkotak, MD, PhD, FRCPC,† Adam Witt, MD,* Ashfaq Shuaib, MD, FRCPC, FAHA,* and Kenneth Butcher, MD, PhD, FRCPC*
Background: Acute ischemic stroke thrombolysis in patients taking dabigatran is controversial because of a presumed increased risk of symptomatic hemorrhagic transformation. Using data from our local hematopathology laboratory, we developed a thrombolysis protocol for acute ischemic stroke patients taking dabigatran. Methods: A local thrombin time (TT)–dabigatran concentration relationship was calculated using dabigatran calibrators. The effect of dabigatran on activated partial thromboplastin time (aPTT) and prothrombin time (PT) (international normalized ratio [INR]) was also measured. A protocol was developed, in which a dabigatran concentration less than 10 ng/mL (corresponding to a TT , 38 seconds or a normal aPTT) was selected as the upper limit for thrombolysis. Consecutive patients presenting with acute stroke were then enrolled in this prospective study. Results: In the 8 months after development of the protocol, 13 potential thrombolysis candidates taking dabigatran were assessed at a median (interquartile range) time of 192 (143) minutes. The median National Institutes of Health Stroke Scale score was 18 (20). The mean time from arrival to TT, aPTT, and PT (INR) results were 39 6 4.1 minutes, 21 6 6.5 minutes, and 21 6 6.5 minutes, respectively. Based on TT/aPTT, 4 patients were ineligible for thrombolysis. Six patients were not treated because of minor or resolving symptoms and another presented with intracerebral hemorrhage. Two patients were treated with intravenous tissue plasminogen activator (tPA), without symptomatic hemorrhagic transformation in either case. In 3 patients (42.8%), aPTT was normal, despite a prolonged TT. Conclusions: Administration of intravenous tPA in dabigatran-treated patients is feasible. Although, the relationship between dabigatran concentrations and coagulation measures varies between laboratories, individual protocols, preferably based on TT, can be developed at acute stroke treatment centers. Key Words: Thrombolysis— anticoagulation—stroke—dabigatran—thrombin time—partial thromboplastin time. Ó 2013 by National Stroke Association
From the *Division of Neurology, Department of Medicine, University of Alberta, Edmonton; and †Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Canada. Received July 23, 2013; revision received November 7, 2013; accepted November 13, 2013. Disclosure: None. Address correspondence to Kenneth Butcher, MD, PhD, FRCPC, 2E3 WMC Health Sciences Center, University of Alberta, 8440 112th St, Edmonton, Alberta, Canada T6G 2B7. E-mail: ken.butcher@ ualberta.ca. 1052-3057/$ - see front matter Ó 2013 by National Stroke Association http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2013.11.013
Introduction The use of dabigatran for stroke prevention in patients with atrial fibrillation has increased significantly since its approval in 2010.1 Although clinicians are concerned about dabigatran-related bleeding complications, ischemic stroke presents a significant management challenge because of the absence of tests to measure dabigatran plasma concentrations in a timely manner in most centers. The risk of hemorrhagic transformation after thrombolysis in dabigatran-treated patients is unknown, but presumed to be higher, based on experience with warfarin.2
Journal of Stroke and Cerebrovascular Diseases, Vol. -, No. - (---), 2013: pp 1-5
1
M. KATE ET AL.
2
In warfarin-treated patients, thrombolysis selection is based on international normalized ratios (INRs),3 which are unhelpful in cases of dabigatran treatment. Suggested tests of dabigatran anticoagulant activity include activated partial thromboplastin time (aPTT) and thrombin time (TT).4 At this point, no safe aPTT or TT values have been established for thrombolysis. We hypothesized that aPTT and/or TT can be used to select appropriate patients for stroke thrombolysis and developed a protocol for tissue plasminogen activator (tPA) administration in this setting.
Methods Dabigatran Concentration Assessment Tests A TT (human source serum thrombotic accelerator (STA) thrombin reagent; Diagnostica Stago, Asnieres Sur Seine, France) dabigatran concentration curve (Fig 1) was generated using dabigatran calibrators (courtesy Joachim Stangier, Boehringer Ingelheim Pharma GmbH & Co, KG, Biberach an der Riss, Germany). TT was also measured in patient samples with both normal (n 5 8) and elevated fibrinogen levels (n 5 4). Elevated fibrinogen levels results in a spuriously low or prolonged TT.5 aPTTs were measured at each dabigatran concentration using SynthASil reagent (HemosIL; Instrumentation Laboratory Company, Bedford, MA) and both the STA-R coagulation analyzer (Diagnostica Stago) and STA-comp (Compact) coagulation analyzers (Diagnostica Stago).
Thrombolysis Patient Selection Algorithm An algorithm for selection of tPA candidates was then developed based on TT and aPTT thresholds (Fig 2). Treatment decisions were all made as part of routine stroke care. This was not a research protocol and was, therefore, not submitted to our local Internal Review Board. Similarly, patients were not asked to sign consent as intravenous tPA is standard of care in our centers. The unique situation was discussed with the patients and family when the patients arrived to emergency department. In patients who were aphasic or had decreased consciousness and had no family member available for discussion, the attending physician made the treatment decision and the family/patient were informed later. TT and fibrinogen levels were obtained in patients with a history of dabigatran use. Patients with a TT of less than 38 seconds, corresponding to dabigatran concentrations less than 10 ng/mL, were considered potential tPA candidates. It was not possible to obtain TT at telestroke centers. Thrombolysis decisions were made using aPTT values alone at these sites. As the relationship between aPTT prolongation and dabigatran concentrations is not linear,4 only patients with normal aPTT values were considered eligible for tPA.
Figure 1. Dabigatran concentration–thrombin time and activated thromboplastin time plot. Abbreviations: TTnf, thrombin time (normal fibrinogen); TThf, thrombin time (high fibrinogen); aPTTstar, activated plasma thromboplastin time (STA-R coagulometer); PTTcomp, activated plasma thromboplastin time (compact coagulometer).
All patients underwent noncontrast computed tomography (CT). CT angiography (CTA) of the neck and head arteries and CT perfusion of the brain were performed when possible. The CTA is standard at our tertiary care sites but is not always completed as part of telestroke assessments. The noncontrast CT was evaluated for early signs of ischemia, and if more than one third of the symptomatic vascular territory was involved, then the patient was not considered eligible for intravenous thrombolysis. The treatment algorithm was circulated to attending stroke specialists and fellows. We prospectively collected data from all patients with a history of dabigatran use who presented with acute ischemic stroke.
Results In the 8 months after protocol development, 13 (6 women) potential thrombolysis candidates taking dabigatran with a mean (SD) age of 70.4 6 12.6 years were assessed with CT scan at a median (interquartile range) time of 192 (143) minutes (Table 1). Symptoms resolved to the point of nondebilitating deficits by the time of baseline CT scan in 6 patients. None of these patients had a major arterial occlusion visible on CTA. Three patients presented with a partial anterior circulation syndrome, 1 with a lacunar syndrome, and 2 had posterior circulation syndromes. One patient had dabigatran-associated intracerebral hemorrhage (TT . 120 seconds). The 6 remaining patients had a median (interquartile range) National Institutes of Health Stroke Scale score of 18 (20). The mean time from arrival to TT, aPTT, and prothrombin time (INR) results were 39 6 4.1 minutes, 21 6 6.5 minutes, and 21 6 6.5 minutes, respectively. Based on TT/aPTT, 4 patients were ineligible for thrombolysis (dabigatran concentrations . 10 ng/mL).
THROMBOLYSIS AND DABIGATRAN
3
Figure 2. Acute stroke management algorithm in patients prescribed dabigatran. Abbreviations: CT, computed tomography; IV, intravenous; PTT, plasma thromboplastin time; TT, thrombin time.
Two patients were treated with intravenous tPA (.9 mg/kg). In 1 case, the decision was made to treat using aPTT alone. This patient presented with significant neurologic deficits to a telestroke site, where TT was unavailable. The mean door-to-needle time for tPA delivery was 84 6 12 minutes. A repeat CT head at 24 hours revealed no hemorrhagic transformation in the patient treated based on TT. Immediate post-tPA magnetic resonance angiography revealed recanalization. In the patient treated with aPTT alone, asymptomatic hemorrhagic transformation (European Co-operative Acute Stroke Study Grade HI26) was seen on the 24-hour post-tPA CT scan. In 3 patients (42.8%, 3 of 7), the TT was prolonged despite a normal aPTT (Table 1).
Discussion This is the first description of a thrombolysis algorithm in acute ischemic stroke patients taking dabigatran. These
preliminary data suggest it may be possible to safely select patients, ideally based on local TT values, provided the dabigatran concentration–TT relationship is known. A quantitative rather than qualitative assessment of dabigatran concentrations is ideal. In this respect, a locally calibrated TT is superior to an aPTT. An alternative is the HEMOCLOT Thrombin inhibitor assay (standardized TT).4 Ecarin clotting time can also be used to assess dabigatran concentrations. These measurements are all linearly related to dabigatran blood concentrations and potentially suitable for emergent assessment of ischemic stroke. In telestroke centers where TT was unavailable, we relied on a normal aPTT. Although aPTT is not linearly related to dabigatran concentration, it is prolonged at therapeutic levels.4 In 3 patients, the aPTT was normal, despite prolonged TT. Our patient treated on the basis of aPTT alone had a hemorrhagic complication (asymptomatic hemorrhagic transformation). This is a single
M. KATE ET AL.
4
Table 1. Baseline characteristics
Characteristics
TIA (n 5 6)
Stroke (n 5 7)
Age (y) 68.2 6 8.6 72.4 6 14.2 Sex (M:F) 2:1 3:4 Hypertension, n (%) 5 (83.3) 5 (71.4) Diabetes mellitus, n (%) 2 (33.3) 3 (42.8) Dyslipidemia, n (%) 4 (66.6) 3 (42.8) Smoking, n (%) 2 (33.3) 2 (28.5) Mean plasma creatinine 93.3 6 11.5 87.4 6 13.3 (mmol/L) 59.2 6 17.3 55.1 6 14.2 Mean glomerular filtration rate (Cockcroft–Gault formula) (mL/min) Coronary artery 1 (16.6) 3 (42.8) disease (%) Baseline NIHSS 0 (0) 14 (9) (median, IQR) Premorbid MRS 1 (1) 1 (1) (median, IQR) CHADS score 2 (2) 2 (2) (median, IQR) Limb weakness as 2 (33.3) 7 (100) presentation Large-artery atherosclerosis 1 (16.6) 1 (14.2) Small-vessel disease 2 (33.3) 3 (42.8) MRS (median, IQR) at 90 d 1 (1) 3 (2) Mortality at 90 d 0 (0) 1 (14.2) Abbreviations: F, female; IQR, interquartile range; M, male; MRS, modified Rankin Scale; NIHSS, National Institutes of Health Stroke Scale.
patient, and we cannot exclude the possibility that this would have occurred even if we had determined TT was less than 38 seconds. Nonetheless, TT can be prolonged, even in the presence of a normal aPTT (Fig 1). We, therefore, conclude that TT permits a more informed thrombolysis decision. Nonetheless, in cases where a TT is unavailable, and other treatment options, such as endovascular therapy, are unavailable, it may be reasonable to consider thrombolysis in patients with normal aPTT. Based on our initial experience, we have extended TT measurements to our telestroke centers. Although aPTT may be considered redundant in the presence of a TT assessment, assessment of standard coagulation parameters (INR and aPTT) is standard in most centers, and we measure all 3 in acute stroke patients with a history of dabigatran use. Our upper TT (38 seconds) and dabigatran concentration (,10 ng/mL) thresholds for treatment were conservative but arbitrary. In fact, we cannot exclude the possibility that concentrations less than 10 ng/mL are not associated with an increased risk of hemorrhagic transformation. Although dabigatran concentrations less than 50 ng/mL are subtherapeutic,4,7 they may still be associated with elevated hemorrhagic transformation
risk. With experience, the recognized safe threshold for thrombolysis in dabigatran-treated patients may increase, as did the INR limit in patients taking warfarin.3 In this series of patients, symptoms resolved spontaneously by the time of assessment in the emergency department in nearly 50% of cases. This is consistent with a previous observational study, indicating that stroke severity at admission is reduced in patients taking warfarin and, to a lesser extent, antiplatelet agents.8 It is plausible that even at subtherapeutic plasma concentrations, dabigatran and other antithrombotic agents exert a protective effect by reducing clot burden and/or increasing the likelihood of spontaneous recanalization. Six case reports of thrombolysis in dabigatran-treated patients have been published.9-14 The majority of patients appear to have been treated on clinical grounds, without reference to markers of dabigatran concentration. In most cases, aPTT values were normal or slightly prolonged, suggesting minimal dabigatran concentrations. Symptomatic hemorrhagic transformation occurred in 1 case.14 In another case, TT was measured, but the relationship between this value and dabigatran concentration was unknown and did not inform the treatment decision.9 The annual risk of ischemic stroke in dabigatrantreated patients in the Randomised Evaluation of Long Term Anticoagulant Therapy (RE-LY) with Dabigatran Etexilate study, was .92% (150 mg BID) to 1.43% (110 mg BID) versus 1.2% in patients on warfarin.15 Thus, although dabigatran is effective, stroke rates will never be zero, particularly in noncompliant patients. As the number of dabigatran-treated patients increases, thrombolysis decisions will become more common. In a survey assessing physician attitudes to thrombolysis in dabigatran-treated patients, approximately 50% of physicians reported they would not treat patients with tPA, irrespective of the aPTT.16 This reflects the need for a reliable measure of dabigatran concentrations, and TT appears to fulfill this role.
Conclusion Acute stroke thrombolysis in selected dabigatrantreated patients is feasible. We recommend development of TT-based protocols in acute stroke centers. Acknowledgment: K.B. holds a Canada Research Chair in Cerebrovascular Disease and the Heart and Stroke Foundation of Alberta Professorship in Stroke Medicine.
References 1. Kirley K, Qato DM, Kornfield R, et al. National trends in oral anticoagulant use in the United States, 2007 to 2011. Circ Cardiovasc Qual Outcomes 2012;5:615-621. 2. Ruecker M, Matosevic B, Willeit P, et al. Subtherapeutic warfarin therapy entails an increased bleeding risk after stroke thrombolysis. Neurology 2012;79:31-38.
THROMBOLYSIS AND DABIGATRAN 3. Xian Y, Liang L, Smith E, et al. Risks of intracranial hemorrhage among patients with acute ischemic stroke receiving warfarin and treated with intravenous tissue plasminogen activator. JAMA 2012;307:2600-2608. 4. van Ryn J, Stangier J, Haertter S, et al. Dabigatran etexilate—a novel, reversible, oral direct thrombin inhibitor: interpretation of coagulation assays and reversal of anticoagulant activity. Thromb Haemost 2010;103:1116-1127. 5. Carr ME Jr, Gabriel DA. Hyperfibrinogenemia as a cause of prolonged thrombin clotting time. Southern Med J 1986;79:563-570. 6. Trouillas P, von Kummer R. Classification and pathogenesis of cerebral hemorrhages after thrombolysis in ischemic stroke. Stroke 2006;37:556-561. 7. Van De Werf F, Brueckmann M, Connolly SJ, et al. A comparison of dabigatran etexilate with warfarin in patients with mechanical heart valves: the randomized, phase II study to evaluate the safety and pharmacokinetics of oral dabigatran etexilate in patients after heart valve replacement (RE-ALIGN). Am Heart J 2012; 163:931-937.e1. 8. O’Donnell M, Oczkowski W, Fang J, et al. Preadmission antithrombotic treatment and stroke severity in patients with atrial fibrillation and acute ischaemic stroke: an observational study. Lancet Neurol 2006; 5:749-754. 9. Sangha N, El Khoury R, Misra V, et al. Acute ischemic stroke treated with intravenous tissue plasminogen activator in a patient taking dabigatran with radiographic
5
10.
11.
12.
13.
14.
15.
16.
evidence of recanalization. J Stroke Cerebrovas Dis 2012;21:917.e5-917.e9. Matute MC, Guillan M, Garcia-Caldentey J, et al. Thrombolysis treatment for acute ischaemic stroke in a patient on treatment with dabigatran. Thromb Haemost 2011; 106:178-179. De Smedt A, De Raedt S, Nieboer K, et al. Intravenous thrombolysis with recombinant tissue plasminogen activator in a stroke patient treated with dabigatran. Cerebrovasc Dis 2010;30:533-534. Marrone LC, Marrone AC. Thrombolysis in an ischemic stroke patient on dabigatran anticoagulation: a case report. Cerebrovasc Dis 2012;34:246-247. Lee VH, Conners JJ, Prabhakaran S. Intravenous thrombolysis in a stroke patient taking dabigatran. J Stroke Cerebrovas Dis 2012;21:916.e11-916.e12. Casado Naranjo I, Portilla-Cuenca JC, Jimenez Caballero PE, et al. Fatal intracerebral hemorrhage associated with administration of recombinant tissue plasminogen activator in a stroke patient on treatment with dabigatran. Cerebrovasc Dis 2011;32:614-615. Connolly SJ, Ezekowitz MD, Yusuf S, et al, the RE-LY Steering Committee and Investigators. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009;361:1139-1151. Rybinnik I, Mullen MT, Messe S, et al. Treatment of acute stroke in patients on dabigatran: A survey of us stroke specialists. J Stroke Cerebrovas Dis 2013; 22:1312-1316.
Background: Acute ischemic stroke thrombolysis in patients taking dabigatran is controversial because of a presumed increased risk of symptomatic hemorrhagic transformation. Using data from our local hematopathology laboratory, we developed a thrombolysis protocol for acute ischemic stroke patients taking dabigatran. Methods: A local thrombin time (TT)–dabigatran concentration relationship was calculated using dabigatran calibrators. The effect of dabigatran on activated partial thromboplastin time (aPTT) and prothrombin time (PT) (international normalized ratio [INR]) was also measured. A protocol was developed, in which a dabigatran concentration less than 10 ng/mL (corresponding to a TT , 38 seconds or a normal aPTT) was selected as the upper limit for thrombolysis. Consecutive patients presenting with acute stroke were then enrolled in this prospective study. Results: In the 8 months after development of the protocol, 13 potential thrombolysis candidates taking dabigatran were assessed at a median (interquartile range) time of 192 (143) minutes. The median National Institutes of Health Stroke Scale score was 18 (20). The mean time from arrival to TT, aPTT, and PT (INR) results were 39 6 4.1 minutes, 21 6 6.5 minutes, and 21 6 6.5 minutes, respectively. Based on TT/aPTT, 4 patients were ineligible for thrombolysis. Six patients were not treated because of minor or resolving symptoms and another presented with intracerebral hemorrhage. Two patients were treated with intravenous tissue plasminogen activator (tPA), without symptomatic hemorrhagic transformation in either case. In 3 patients (42.8%), aPTT was normal, despite a prolonged TT. Conclusions: Administration of intravenous tPA in dabigatran-treated patients is feasible. Although, the relationship between dabigatran concentrations and coagulation measures varies between laboratories, individual protocols, preferably based on TT, can be developed at acute stroke treatment centers. Key Words: Thrombolysis— anticoagulation—stroke—dabigatran—thrombin time—partial thromboplastin time. Ó 2013 by National Stroke Association
From the *Division of Neurology, Department of Medicine, University of Alberta, Edmonton; and †Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Canada. Received July 23, 2013; revision received November 7, 2013; accepted November 13, 2013. Disclosure: None. Address correspondence to Kenneth Butcher, MD, PhD, FRCPC, 2E3 WMC Health Sciences Center, University of Alberta, 8440 112th St, Edmonton, Alberta, Canada T6G 2B7. E-mail: ken.butcher@ ualberta.ca. 1052-3057/$ - see front matter Ó 2013 by National Stroke Association http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2013.11.013
Introduction The use of dabigatran for stroke prevention in patients with atrial fibrillation has increased significantly since its approval in 2010.1 Although clinicians are concerned about dabigatran-related bleeding complications, ischemic stroke presents a significant management challenge because of the absence of tests to measure dabigatran plasma concentrations in a timely manner in most centers. The risk of hemorrhagic transformation after thrombolysis in dabigatran-treated patients is unknown, but presumed to be higher, based on experience with warfarin.2
Journal of Stroke and Cerebrovascular Diseases, Vol. -, No. - (---), 2013: pp 1-5
1
M. KATE ET AL.
2
In warfarin-treated patients, thrombolysis selection is based on international normalized ratios (INRs),3 which are unhelpful in cases of dabigatran treatment. Suggested tests of dabigatran anticoagulant activity include activated partial thromboplastin time (aPTT) and thrombin time (TT).4 At this point, no safe aPTT or TT values have been established for thrombolysis. We hypothesized that aPTT and/or TT can be used to select appropriate patients for stroke thrombolysis and developed a protocol for tissue plasminogen activator (tPA) administration in this setting.
Methods Dabigatran Concentration Assessment Tests A TT (human source serum thrombotic accelerator (STA) thrombin reagent; Diagnostica Stago, Asnieres Sur Seine, France) dabigatran concentration curve (Fig 1) was generated using dabigatran calibrators (courtesy Joachim Stangier, Boehringer Ingelheim Pharma GmbH & Co, KG, Biberach an der Riss, Germany). TT was also measured in patient samples with both normal (n 5 8) and elevated fibrinogen levels (n 5 4). Elevated fibrinogen levels results in a spuriously low or prolonged TT.5 aPTTs were measured at each dabigatran concentration using SynthASil reagent (HemosIL; Instrumentation Laboratory Company, Bedford, MA) and both the STA-R coagulation analyzer (Diagnostica Stago) and STA-comp (Compact) coagulation analyzers (Diagnostica Stago).
Thrombolysis Patient Selection Algorithm An algorithm for selection of tPA candidates was then developed based on TT and aPTT thresholds (Fig 2). Treatment decisions were all made as part of routine stroke care. This was not a research protocol and was, therefore, not submitted to our local Internal Review Board. Similarly, patients were not asked to sign consent as intravenous tPA is standard of care in our centers. The unique situation was discussed with the patients and family when the patients arrived to emergency department. In patients who were aphasic or had decreased consciousness and had no family member available for discussion, the attending physician made the treatment decision and the family/patient were informed later. TT and fibrinogen levels were obtained in patients with a history of dabigatran use. Patients with a TT of less than 38 seconds, corresponding to dabigatran concentrations less than 10 ng/mL, were considered potential tPA candidates. It was not possible to obtain TT at telestroke centers. Thrombolysis decisions were made using aPTT values alone at these sites. As the relationship between aPTT prolongation and dabigatran concentrations is not linear,4 only patients with normal aPTT values were considered eligible for tPA.
Figure 1. Dabigatran concentration–thrombin time and activated thromboplastin time plot. Abbreviations: TTnf, thrombin time (normal fibrinogen); TThf, thrombin time (high fibrinogen); aPTTstar, activated plasma thromboplastin time (STA-R coagulometer); PTTcomp, activated plasma thromboplastin time (compact coagulometer).
All patients underwent noncontrast computed tomography (CT). CT angiography (CTA) of the neck and head arteries and CT perfusion of the brain were performed when possible. The CTA is standard at our tertiary care sites but is not always completed as part of telestroke assessments. The noncontrast CT was evaluated for early signs of ischemia, and if more than one third of the symptomatic vascular territory was involved, then the patient was not considered eligible for intravenous thrombolysis. The treatment algorithm was circulated to attending stroke specialists and fellows. We prospectively collected data from all patients with a history of dabigatran use who presented with acute ischemic stroke.
Results In the 8 months after protocol development, 13 (6 women) potential thrombolysis candidates taking dabigatran with a mean (SD) age of 70.4 6 12.6 years were assessed with CT scan at a median (interquartile range) time of 192 (143) minutes (Table 1). Symptoms resolved to the point of nondebilitating deficits by the time of baseline CT scan in 6 patients. None of these patients had a major arterial occlusion visible on CTA. Three patients presented with a partial anterior circulation syndrome, 1 with a lacunar syndrome, and 2 had posterior circulation syndromes. One patient had dabigatran-associated intracerebral hemorrhage (TT . 120 seconds). The 6 remaining patients had a median (interquartile range) National Institutes of Health Stroke Scale score of 18 (20). The mean time from arrival to TT, aPTT, and prothrombin time (INR) results were 39 6 4.1 minutes, 21 6 6.5 minutes, and 21 6 6.5 minutes, respectively. Based on TT/aPTT, 4 patients were ineligible for thrombolysis (dabigatran concentrations . 10 ng/mL).
THROMBOLYSIS AND DABIGATRAN
3
Figure 2. Acute stroke management algorithm in patients prescribed dabigatran. Abbreviations: CT, computed tomography; IV, intravenous; PTT, plasma thromboplastin time; TT, thrombin time.
Two patients were treated with intravenous tPA (.9 mg/kg). In 1 case, the decision was made to treat using aPTT alone. This patient presented with significant neurologic deficits to a telestroke site, where TT was unavailable. The mean door-to-needle time for tPA delivery was 84 6 12 minutes. A repeat CT head at 24 hours revealed no hemorrhagic transformation in the patient treated based on TT. Immediate post-tPA magnetic resonance angiography revealed recanalization. In the patient treated with aPTT alone, asymptomatic hemorrhagic transformation (European Co-operative Acute Stroke Study Grade HI26) was seen on the 24-hour post-tPA CT scan. In 3 patients (42.8%, 3 of 7), the TT was prolonged despite a normal aPTT (Table 1).
Discussion This is the first description of a thrombolysis algorithm in acute ischemic stroke patients taking dabigatran. These
preliminary data suggest it may be possible to safely select patients, ideally based on local TT values, provided the dabigatran concentration–TT relationship is known. A quantitative rather than qualitative assessment of dabigatran concentrations is ideal. In this respect, a locally calibrated TT is superior to an aPTT. An alternative is the HEMOCLOT Thrombin inhibitor assay (standardized TT).4 Ecarin clotting time can also be used to assess dabigatran concentrations. These measurements are all linearly related to dabigatran blood concentrations and potentially suitable for emergent assessment of ischemic stroke. In telestroke centers where TT was unavailable, we relied on a normal aPTT. Although aPTT is not linearly related to dabigatran concentration, it is prolonged at therapeutic levels.4 In 3 patients, the aPTT was normal, despite prolonged TT. Our patient treated on the basis of aPTT alone had a hemorrhagic complication (asymptomatic hemorrhagic transformation). This is a single
M. KATE ET AL.
4
Table 1. Baseline characteristics
Characteristics
TIA (n 5 6)
Stroke (n 5 7)
Age (y) 68.2 6 8.6 72.4 6 14.2 Sex (M:F) 2:1 3:4 Hypertension, n (%) 5 (83.3) 5 (71.4) Diabetes mellitus, n (%) 2 (33.3) 3 (42.8) Dyslipidemia, n (%) 4 (66.6) 3 (42.8) Smoking, n (%) 2 (33.3) 2 (28.5) Mean plasma creatinine 93.3 6 11.5 87.4 6 13.3 (mmol/L) 59.2 6 17.3 55.1 6 14.2 Mean glomerular filtration rate (Cockcroft–Gault formula) (mL/min) Coronary artery 1 (16.6) 3 (42.8) disease (%) Baseline NIHSS 0 (0) 14 (9) (median, IQR) Premorbid MRS 1 (1) 1 (1) (median, IQR) CHADS score 2 (2) 2 (2) (median, IQR) Limb weakness as 2 (33.3) 7 (100) presentation Large-artery atherosclerosis 1 (16.6) 1 (14.2) Small-vessel disease 2 (33.3) 3 (42.8) MRS (median, IQR) at 90 d 1 (1) 3 (2) Mortality at 90 d 0 (0) 1 (14.2) Abbreviations: F, female; IQR, interquartile range; M, male; MRS, modified Rankin Scale; NIHSS, National Institutes of Health Stroke Scale.
patient, and we cannot exclude the possibility that this would have occurred even if we had determined TT was less than 38 seconds. Nonetheless, TT can be prolonged, even in the presence of a normal aPTT (Fig 1). We, therefore, conclude that TT permits a more informed thrombolysis decision. Nonetheless, in cases where a TT is unavailable, and other treatment options, such as endovascular therapy, are unavailable, it may be reasonable to consider thrombolysis in patients with normal aPTT. Based on our initial experience, we have extended TT measurements to our telestroke centers. Although aPTT may be considered redundant in the presence of a TT assessment, assessment of standard coagulation parameters (INR and aPTT) is standard in most centers, and we measure all 3 in acute stroke patients with a history of dabigatran use. Our upper TT (38 seconds) and dabigatran concentration (,10 ng/mL) thresholds for treatment were conservative but arbitrary. In fact, we cannot exclude the possibility that concentrations less than 10 ng/mL are not associated with an increased risk of hemorrhagic transformation. Although dabigatran concentrations less than 50 ng/mL are subtherapeutic,4,7 they may still be associated with elevated hemorrhagic transformation
risk. With experience, the recognized safe threshold for thrombolysis in dabigatran-treated patients may increase, as did the INR limit in patients taking warfarin.3 In this series of patients, symptoms resolved spontaneously by the time of assessment in the emergency department in nearly 50% of cases. This is consistent with a previous observational study, indicating that stroke severity at admission is reduced in patients taking warfarin and, to a lesser extent, antiplatelet agents.8 It is plausible that even at subtherapeutic plasma concentrations, dabigatran and other antithrombotic agents exert a protective effect by reducing clot burden and/or increasing the likelihood of spontaneous recanalization. Six case reports of thrombolysis in dabigatran-treated patients have been published.9-14 The majority of patients appear to have been treated on clinical grounds, without reference to markers of dabigatran concentration. In most cases, aPTT values were normal or slightly prolonged, suggesting minimal dabigatran concentrations. Symptomatic hemorrhagic transformation occurred in 1 case.14 In another case, TT was measured, but the relationship between this value and dabigatran concentration was unknown and did not inform the treatment decision.9 The annual risk of ischemic stroke in dabigatrantreated patients in the Randomised Evaluation of Long Term Anticoagulant Therapy (RE-LY) with Dabigatran Etexilate study, was .92% (150 mg BID) to 1.43% (110 mg BID) versus 1.2% in patients on warfarin.15 Thus, although dabigatran is effective, stroke rates will never be zero, particularly in noncompliant patients. As the number of dabigatran-treated patients increases, thrombolysis decisions will become more common. In a survey assessing physician attitudes to thrombolysis in dabigatran-treated patients, approximately 50% of physicians reported they would not treat patients with tPA, irrespective of the aPTT.16 This reflects the need for a reliable measure of dabigatran concentrations, and TT appears to fulfill this role.
Conclusion Acute stroke thrombolysis in selected dabigatrantreated patients is feasible. We recommend development of TT-based protocols in acute stroke centers. Acknowledgment: K.B. holds a Canada Research Chair in Cerebrovascular Disease and the Heart and Stroke Foundation of Alberta Professorship in Stroke Medicine.
References 1. Kirley K, Qato DM, Kornfield R, et al. National trends in oral anticoagulant use in the United States, 2007 to 2011. Circ Cardiovasc Qual Outcomes 2012;5:615-621. 2. Ruecker M, Matosevic B, Willeit P, et al. Subtherapeutic warfarin therapy entails an increased bleeding risk after stroke thrombolysis. Neurology 2012;79:31-38.
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