Good outcome after intravenous thrombolysis for acute stroke in a patient under treatment with dabigatran C´atia Diogo MD, Josiana Duarte MD, Sofia Sobral MD, Paula Pestana MD, Hip´olito Nzwalo MD, Henrique Rita MD, Jos´e Sousa Costa MD PII: DOI: Reference:
S0735-6757(14)00265-4 doi: 10.1016/j.ajem.2014.04.021 YAJEM 54251
To appear in:
American Journal of Emergency Medicine
Received date: Revised date: Accepted date:
4 March 2014 23 March 2014 7 April 2014
Please cite this article as: Diogo C´ atia, Duarte Josiana, Sobral Sofia, Pestana Paula, Nzwalo Hip´olito, Rita Henrique, Costa Jos´e Sousa, Good outcome after intravenous thrombolysis for acute stroke in a patient under treatment with dabigatran, American Journal of Emergency Medicine (2014), doi: 10.1016/j.ajem.2014.04.021
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Title: “Good outcome after intravenous thrombolysis for acute stroke in a patient under treatment with dabigatran”
T
Authors:
RI P
Cátia Diogo,MD1 Josiana Duarte, MD1 Sofia Sobral, MD1
SC
Paula Pestana, MD 1,2 Hipólito Nzwalo, MD 2,3
MA NU
Henrique Rita, MD 1,2 José Sousa e Costa, MD1
Department of Internal Medicine, Unidade Local de Saúde do Litoral Alentejano (ULSLA) 1
3Department
ED
National Institute of Medical Emergency (INEM) of Neurology, Centro Hospitalar do Algarve (CHA)
PT
2
Corresponding author:
CE
Hipólito Nzwalo
AC
Address: Hospital de Faro, Department of Neurology, Rua Leao Penedo, 8000386 Faro E-mail:[email protected] Disclosure: The authors have nothing to disclose. Key Words : “acute stroke” , thrombolysis , dabigatran Abstract: The novel oral anticoagulants (NOACs) are indicated for stroke and systemic embolism prophylaxis in patients with non valvular atrial fibrillation (AF). Very few cases of intravenous recombinant tissue plasminogen activator (IV rt-PA) in patients under treatment with NOACs have been described. The decision to thrombolyse patients under NOACs is complex and requires a balance between the benefits of treatment and the risk of symptomatic hemorrhagic complications. We describe an unusual case of treatment IV rt-PA for acute ischemic stroke in a patient receiving dabigatran for AF. The decision to treat the patient with IV rt-PA was based on the combination of normal coagulation times with the long time elapsed after the last dose of dabigatran, when the drug effect was predictable residual.
ACCEPTED MANUSCRIPT The novel oral anticoagulants (NOACs), dabigatran, rivaroxaban and apixaban are indicated for prophylaxis against stroke and systemic embolism in patients
T
with non valvular atrial fibrillation (AF). In comparison to warfarin, the
RI P
NOACs have the advantage of having limited, specific therapeutic targets in the coagulation cascade, a wide therapeutic window, predictable
SC
pharmacokinetics, minimal drug-drug and drug-food interactions, and no need
MA NU
for routine laboratory monitoring of anticoagulation (1). However, the lack of availability of rapid and accurate laboratory assays of pharmacological activity of the NOACs creates an additional challenge in cases of acute ischemic stroke occurring in patients taking these drugs, where urgent decision making
ED
regarding thrombolysis with intravenous recombinant tissue plasminogen
PT
activator (IV rt-PA) may be required. The decision whether to thrombolyse patients taking a NOAC is complex and requires a somewhat uninformed
CE
judgment about the balance between the benefits of treatment and the risk of
A
AC
symptomatic hemorrhagic complications for the individual patient (2). 61-year-old man, with a medical history of type 2 diabetes mellitus,
hypertension, moderate alcohol consumption, and AF on dabigatran treatment (150 mg twice a day) for one week prior to arrival,
was admitted to the
emergency department because of sudden onset of speech disturbance that had begun two hours before. He had taken his last dose of dabigatran 10 hours before the symptoms began. On neurological examination he had an expressive aphasia. There were no ocular, motor, sensory or coordination deficits. His National Institute of Health Stroke Scale (NIHSS) score was 2. His blood
ACCEPTED MANUSCRIPT pressure was 161/91 mm Hg. Apart from the aphasia and severe central obesity with body mass index of 35,9 kg/m2, the general examination was
T
unremarkable. Electrocardiography confirmed the presence of atrial fibrillation
RI P
with a controlled ventricular response. His initial blood glucose was 116 mg/dL. The platelet count, activated partial thromboplastin time (aPTT),
SC
thrombin time (TT), and prothrombin time (PT)/international normalized ratio
MA NU
(INR) were all within normal limits. The patient’s estimated creatinine clearance was 109.7 ml/min (Cockcroft-Gault formula). Brain computed tomographic (CT) scan showed early signs of ischemia in territory of the middle cerebral artery (Figure 1A, 1B). Despite the low NIHSS score, the presence of a profound
ED
cortical language deficit supported the emergency team’s decision to administer
PT
thrombolytic therapy to the patient, then 13 hours after the last dose of dabigatran, with 90mg r-tPA intravenously. The patient recovered well with no
CE
bleeding complications and only occasional anomic pauses in the speech as a
AC
residual. The brain CT after 24 hours showed a small ischemic cortical stroke in Broca's area (1C, 1D). Apart from elevated glycated hemoglobin (HbA1c of 11%) and the presence of discrete hypokinesis of the left inferior ventricular wall on transthoracic echocardiography, the rest of the diagnostic workup, including Doppler of cervical vessels, carotid angiogram, thyroid hormones, and thrombophilia screen, yielded negative results. After treatment adherence reinforcement, the patient was discharged home, and he largely resumed his normal life.
ACCEPTED MANUSCRIPT Dabigatran is an oral direct thrombin (Factor IIa) inhibitor. Its usage has increased significantly since its approval in 2010 (3). The risk:benefit ratio for
T
thrombolysis of acute ischemic stroke in patients taking dabigatran is
RI P
problematic because the degree of anticoagulation cannot be readily or reliably determined prior to lysis, raising substantive concern for
SC
transformation of the stroke (4).
hemorrhagic
MA NU
Very few cases of thrombolysis in dabigatran-treated patients have been published (5, 6), but one can anticipate an increase in the number of eligible patients for thrombolysis under treatment with dabigatran or other NOACs as the use (and number) of these agents continues to expand. In warfarin-treated
ED
patients with acute ischemic stroke, the extent of anticoagulation can be reliable
PT
determined using the International Normalized Ratio (INR), allowing a more For
CE
quantitative assessment of bleeding risk should lysis be attempted.
dabigatran, both the aPTT and the TT give a qualitative assessment of
AC
anticoagulation; the dilute thrombin time (dTT), available in Europe, is more quantitative.
A thrombolysis patient selection algorithm for routine clinical practice in patients under dabigatran treatment was recently published (5). For patients without contra-indications for thrombolysis while on dabigatran treatment, if coagulation times were within or close to the normal limits (TT less than 38 seconds and/or aPTT less than 37 seconds), IV r-tPA was administered. Based on this protocol two out of 13 patients were deemed eligible and were
ACCEPTED MANUSCRIPT successfully treated, without hemorrhagic complication, over a period of 8 months (5).
T
Besides lab assays, the other important data to assess in NOAC-treated patients
RI P
being considered for thrombolysis are renal function and time since last dose.
SC
All of the NOACs share a much shorter half-life than warfarin and are usually dosed twice daily (rivaroxaban for venous thromboembolism after two weeks
MA NU
of twice-daily treatment being the notable exception). Therefore, in the setting of normal renal function, the extent of anticoagulation can be expected to wane significantly by the time the next dose is due, even if that cannot be directly measured. In our patient, the combination of normal coagulation times with
ED
the long time elapsed after the last dose of dabigatran supported the decision to
Furthermore, our patient glomerular filtration rate was above
CE
complications.
PT
thrombolyse the patient without exposing him to a high risk of hemorrhagic
≥80 mL/min which is associated with a significantly lower rates of major
AC
bleeding (7). In fact, a shorter time interval between the last dabigatran dose and r-tPA administration (or similar time but in the setting of reduced clearance due to impaired renal function) may be a critical factor in an increased risk of bleeding with thrombolysis and invasive procedures. In one reported case of fatal hemorrhagic complication after IV r-tPA in a dabigatran-treated patient, the patient had taken the last dose only 3 hours earlier (4). With the use of NOACs, clinicians should be aware of these risk considerations regarding thrombolysis decision making.
Contrary to warfarin treated
patients, where the INR is sufficiently quantitative to guide the decision, the
ACCEPTED MANUSCRIPT essential information required in NOAC-treated patients within the time window for thrombolysis is the time of the last dose of the specific NOAC and
T
the renal function. With dabigatran in particular, TT and aPTT also offer some
RI P
qualitative guidance.
1.
Pollack CV Jr: New oral anticoagulants in the ED setting: a review. Am J
MA NU
Emerg Med. 2012 Nov;30(9):2046-54. 2.
SC
References
Folyovich A, Varga V, Béres-Molnár KA, et al. Dilemma of Indication for
Thrombolysis in a Patient with Acute Ischemic Stroke Treated with a Novel
Kirley K, Qato DM, Kornfield R, et al. National trends in oral
PT
3.
ED
OralAnticoagulant. J Stroke Cerebrovasc Dis. 2013 May 27.
anticoagulant use in the United States, 2007 to 2011. Circ Cardiovasc Qual
Casado Naranjo I, Portilla-Cuenca JC, Jimenez Caballero PE, et al. Fatal
AC
4.
CE
Outcomes 2012;5:615-621.
intracerebral hemorrhage associatedwith administration of recombinant tissue plasminogen activator in a stroke patient on treatment with dabigatran. Cerebrovasc Dis 2011;32:614-615. 5.
Kate M, Szkotak A, Witt A, et al. Proposed Approach to Thrombolysis in
Dabigatran-Treated Patients Presenting with Ischemic Stroke. J Stroke Cerebrovasc Dis. 2014 Jan 6. pii: S1052-3057(13)00479-5. 6.
Breuer L, Ringwald J, Schwab S, Köhrmann M. Ischemic stroke in an
obese patient receiving dabigatran. N Engl J Med. 2013 Jun 20;368(25):2440-2.
ACCEPTED MANUSCRIPT
7.
Hijazi Z1, Hohnloser SH, Oldgren J, et al. Efficacy and Safety of
T
Dabigatran Compared With Warfarin in Relation to Baseline Renal Function in
RI P
Patients With Atrial Fibrillation: A RE-LY (Randomized Evaluation of Long-
SC
term Anticoagulation Therapy) Trial Analysis. Circulation. 2014 Mar
ED
MA NU
4;129(9):961-70.
Legend:
PT
Figure 1A-D: Brain TC at admission showing loss of insular cortical mantle
CE
(1A), hyperdensity in distal left MCA (1B); Brain TC, 24 hours after
AC
thrombolysis showing a cortical small frontal ischemic area (1C, 1D).
S0735-6757(14)00265-4 doi: 10.1016/j.ajem.2014.04.021 YAJEM 54251
To appear in:
American Journal of Emergency Medicine
Received date: Revised date: Accepted date:
4 March 2014 23 March 2014 7 April 2014
Please cite this article as: Diogo C´ atia, Duarte Josiana, Sobral Sofia, Pestana Paula, Nzwalo Hip´olito, Rita Henrique, Costa Jos´e Sousa, Good outcome after intravenous thrombolysis for acute stroke in a patient under treatment with dabigatran, American Journal of Emergency Medicine (2014), doi: 10.1016/j.ajem.2014.04.021
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Title: “Good outcome after intravenous thrombolysis for acute stroke in a patient under treatment with dabigatran”
T
Authors:
RI P
Cátia Diogo,MD1 Josiana Duarte, MD1 Sofia Sobral, MD1
SC
Paula Pestana, MD 1,2 Hipólito Nzwalo, MD 2,3
MA NU
Henrique Rita, MD 1,2 José Sousa e Costa, MD1
Department of Internal Medicine, Unidade Local de Saúde do Litoral Alentejano (ULSLA) 1
3Department
ED
National Institute of Medical Emergency (INEM) of Neurology, Centro Hospitalar do Algarve (CHA)
PT
2
Corresponding author:
CE
Hipólito Nzwalo
AC
Address: Hospital de Faro, Department of Neurology, Rua Leao Penedo, 8000386 Faro E-mail:[email protected] Disclosure: The authors have nothing to disclose. Key Words : “acute stroke” , thrombolysis , dabigatran Abstract: The novel oral anticoagulants (NOACs) are indicated for stroke and systemic embolism prophylaxis in patients with non valvular atrial fibrillation (AF). Very few cases of intravenous recombinant tissue plasminogen activator (IV rt-PA) in patients under treatment with NOACs have been described. The decision to thrombolyse patients under NOACs is complex and requires a balance between the benefits of treatment and the risk of symptomatic hemorrhagic complications. We describe an unusual case of treatment IV rt-PA for acute ischemic stroke in a patient receiving dabigatran for AF. The decision to treat the patient with IV rt-PA was based on the combination of normal coagulation times with the long time elapsed after the last dose of dabigatran, when the drug effect was predictable residual.
ACCEPTED MANUSCRIPT The novel oral anticoagulants (NOACs), dabigatran, rivaroxaban and apixaban are indicated for prophylaxis against stroke and systemic embolism in patients
T
with non valvular atrial fibrillation (AF). In comparison to warfarin, the
RI P
NOACs have the advantage of having limited, specific therapeutic targets in the coagulation cascade, a wide therapeutic window, predictable
SC
pharmacokinetics, minimal drug-drug and drug-food interactions, and no need
MA NU
for routine laboratory monitoring of anticoagulation (1). However, the lack of availability of rapid and accurate laboratory assays of pharmacological activity of the NOACs creates an additional challenge in cases of acute ischemic stroke occurring in patients taking these drugs, where urgent decision making
ED
regarding thrombolysis with intravenous recombinant tissue plasminogen
PT
activator (IV rt-PA) may be required. The decision whether to thrombolyse patients taking a NOAC is complex and requires a somewhat uninformed
CE
judgment about the balance between the benefits of treatment and the risk of
A
AC
symptomatic hemorrhagic complications for the individual patient (2). 61-year-old man, with a medical history of type 2 diabetes mellitus,
hypertension, moderate alcohol consumption, and AF on dabigatran treatment (150 mg twice a day) for one week prior to arrival,
was admitted to the
emergency department because of sudden onset of speech disturbance that had begun two hours before. He had taken his last dose of dabigatran 10 hours before the symptoms began. On neurological examination he had an expressive aphasia. There were no ocular, motor, sensory or coordination deficits. His National Institute of Health Stroke Scale (NIHSS) score was 2. His blood
ACCEPTED MANUSCRIPT pressure was 161/91 mm Hg. Apart from the aphasia and severe central obesity with body mass index of 35,9 kg/m2, the general examination was
T
unremarkable. Electrocardiography confirmed the presence of atrial fibrillation
RI P
with a controlled ventricular response. His initial blood glucose was 116 mg/dL. The platelet count, activated partial thromboplastin time (aPTT),
SC
thrombin time (TT), and prothrombin time (PT)/international normalized ratio
MA NU
(INR) were all within normal limits. The patient’s estimated creatinine clearance was 109.7 ml/min (Cockcroft-Gault formula). Brain computed tomographic (CT) scan showed early signs of ischemia in territory of the middle cerebral artery (Figure 1A, 1B). Despite the low NIHSS score, the presence of a profound
ED
cortical language deficit supported the emergency team’s decision to administer
PT
thrombolytic therapy to the patient, then 13 hours after the last dose of dabigatran, with 90mg r-tPA intravenously. The patient recovered well with no
CE
bleeding complications and only occasional anomic pauses in the speech as a
AC
residual. The brain CT after 24 hours showed a small ischemic cortical stroke in Broca's area (1C, 1D). Apart from elevated glycated hemoglobin (HbA1c of 11%) and the presence of discrete hypokinesis of the left inferior ventricular wall on transthoracic echocardiography, the rest of the diagnostic workup, including Doppler of cervical vessels, carotid angiogram, thyroid hormones, and thrombophilia screen, yielded negative results. After treatment adherence reinforcement, the patient was discharged home, and he largely resumed his normal life.
ACCEPTED MANUSCRIPT Dabigatran is an oral direct thrombin (Factor IIa) inhibitor. Its usage has increased significantly since its approval in 2010 (3). The risk:benefit ratio for
T
thrombolysis of acute ischemic stroke in patients taking dabigatran is
RI P
problematic because the degree of anticoagulation cannot be readily or reliably determined prior to lysis, raising substantive concern for
SC
transformation of the stroke (4).
hemorrhagic
MA NU
Very few cases of thrombolysis in dabigatran-treated patients have been published (5, 6), but one can anticipate an increase in the number of eligible patients for thrombolysis under treatment with dabigatran or other NOACs as the use (and number) of these agents continues to expand. In warfarin-treated
ED
patients with acute ischemic stroke, the extent of anticoagulation can be reliable
PT
determined using the International Normalized Ratio (INR), allowing a more For
CE
quantitative assessment of bleeding risk should lysis be attempted.
dabigatran, both the aPTT and the TT give a qualitative assessment of
AC
anticoagulation; the dilute thrombin time (dTT), available in Europe, is more quantitative.
A thrombolysis patient selection algorithm for routine clinical practice in patients under dabigatran treatment was recently published (5). For patients without contra-indications for thrombolysis while on dabigatran treatment, if coagulation times were within or close to the normal limits (TT less than 38 seconds and/or aPTT less than 37 seconds), IV r-tPA was administered. Based on this protocol two out of 13 patients were deemed eligible and were
ACCEPTED MANUSCRIPT successfully treated, without hemorrhagic complication, over a period of 8 months (5).
T
Besides lab assays, the other important data to assess in NOAC-treated patients
RI P
being considered for thrombolysis are renal function and time since last dose.
SC
All of the NOACs share a much shorter half-life than warfarin and are usually dosed twice daily (rivaroxaban for venous thromboembolism after two weeks
MA NU
of twice-daily treatment being the notable exception). Therefore, in the setting of normal renal function, the extent of anticoagulation can be expected to wane significantly by the time the next dose is due, even if that cannot be directly measured. In our patient, the combination of normal coagulation times with
ED
the long time elapsed after the last dose of dabigatran supported the decision to
Furthermore, our patient glomerular filtration rate was above
CE
complications.
PT
thrombolyse the patient without exposing him to a high risk of hemorrhagic
≥80 mL/min which is associated with a significantly lower rates of major
AC
bleeding (7). In fact, a shorter time interval between the last dabigatran dose and r-tPA administration (or similar time but in the setting of reduced clearance due to impaired renal function) may be a critical factor in an increased risk of bleeding with thrombolysis and invasive procedures. In one reported case of fatal hemorrhagic complication after IV r-tPA in a dabigatran-treated patient, the patient had taken the last dose only 3 hours earlier (4). With the use of NOACs, clinicians should be aware of these risk considerations regarding thrombolysis decision making.
Contrary to warfarin treated
patients, where the INR is sufficiently quantitative to guide the decision, the
ACCEPTED MANUSCRIPT essential information required in NOAC-treated patients within the time window for thrombolysis is the time of the last dose of the specific NOAC and
T
the renal function. With dabigatran in particular, TT and aPTT also offer some
RI P
qualitative guidance.
1.
Pollack CV Jr: New oral anticoagulants in the ED setting: a review. Am J
MA NU
Emerg Med. 2012 Nov;30(9):2046-54. 2.
SC
References
Folyovich A, Varga V, Béres-Molnár KA, et al. Dilemma of Indication for
Thrombolysis in a Patient with Acute Ischemic Stroke Treated with a Novel
Kirley K, Qato DM, Kornfield R, et al. National trends in oral
PT
3.
ED
OralAnticoagulant. J Stroke Cerebrovasc Dis. 2013 May 27.
anticoagulant use in the United States, 2007 to 2011. Circ Cardiovasc Qual
Casado Naranjo I, Portilla-Cuenca JC, Jimenez Caballero PE, et al. Fatal
AC
4.
CE
Outcomes 2012;5:615-621.
intracerebral hemorrhage associatedwith administration of recombinant tissue plasminogen activator in a stroke patient on treatment with dabigatran. Cerebrovasc Dis 2011;32:614-615. 5.
Kate M, Szkotak A, Witt A, et al. Proposed Approach to Thrombolysis in
Dabigatran-Treated Patients Presenting with Ischemic Stroke. J Stroke Cerebrovasc Dis. 2014 Jan 6. pii: S1052-3057(13)00479-5. 6.
Breuer L, Ringwald J, Schwab S, Köhrmann M. Ischemic stroke in an
obese patient receiving dabigatran. N Engl J Med. 2013 Jun 20;368(25):2440-2.
ACCEPTED MANUSCRIPT
7.
Hijazi Z1, Hohnloser SH, Oldgren J, et al. Efficacy and Safety of
T
Dabigatran Compared With Warfarin in Relation to Baseline Renal Function in
RI P
Patients With Atrial Fibrillation: A RE-LY (Randomized Evaluation of Long-
SC
term Anticoagulation Therapy) Trial Analysis. Circulation. 2014 Mar
ED
MA NU
4;129(9):961-70.
Legend:
PT
Figure 1A-D: Brain TC at admission showing loss of insular cortical mantle
CE
(1A), hyperdensity in distal left MCA (1B); Brain TC, 24 hours after
AC
thrombolysis showing a cortical small frontal ischemic area (1C, 1D).
