Article, Emergency Medicine

Good outcome after intravenous thrombolysis for acute stroke in a patient under treatment with dabigatran

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American Journal of Emergency Medicine

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Good outcome after intravenous thrombolysis for acute stroke in a patient under treatment with dabigatran?

Abstract

The Novel oral anticoagulants are indicated for stroke and systemic embolism prophylaxis in patients with nonvalvular Atrial fibrillation . Very few cases of intravenous recombinant tissue plasminogen activator in patients under treatment with NOACs have been described. The decision to thrombolyze 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 predictably residual.

The novel oral anticoagulants (NOACs) dabigatran, rivaroxaban, and apixaban are indicated for prophylaxis against stroke and systemic embolism in patients with nonvalvular Atrial fibrillation . In comparison to warfarin, the NOACs have the advantage of having limited, specific therapeutic targets in the coagulation cascade, a Wide therapeutic window, predictable pharmacokinetics, minimal drug-drug and drug- food interactions, and no need 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 regarding thrombolysis with intravenous recombinant tissue plasminogen activator (IV rt-PA) may be required. The decision whether to thrombolyze patients taking a NOAC is complex and requires a somewhat uninformed judgment about the balance between the benefits of treatment and the risk of symptomatic hemorrhagic complications for the individual patient [2].

A 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 1 week prior to arrival, was admitted to the emergency department because of sudden onset of speech disturbance that had begun 2 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 Institutes of Health Stroke Scale score was 2. His blood pressure was 161/91 mm Hg. Apart from the aphasia and severe central obesity with body mass index of 35.9 kg/m2, the result of the general examination was unremarkable. Electrocardiography confirmed the presence of atrial fibrillation with a

? Disclosure: The authors have nothing to disclose.

controlled ventricular response. His initial blood glucose was 116 mg/dL. The platelet count, activated partial thromboplastin time , thrombin time (TT), and prothrombin time /International normalized ratio were all within normal limits. The patient’s estimated creatinine clearance was 109.7 mL/min (Cockcroft-Gault formula). Brain computed tomographic scan showed early signs of ischemia in territory of the Middle cerebral artery (Fig. A, B). Despite the low National Institutes of Health Stroke Scale score, the presence of a profound cortical language deficit supported the emergency team’s decision to administer thrombo- lytic therapy to the patient, then 13 hours after the last dose of dabigatran, with 90 mg r-tPA intravenously. The patient recovered well with no Bleeding complications and only occasional anomic pauses in the speech as a residual. The brain computed tomographic scan after 24 hours showed a small ischemic cortical stroke in the Broca area (Fig. C, D).

Apart from elevated glycated hemoglobin (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. Dabigatran is an oral direct thrombin (factor IIa) inhibitor. Its use has increased significantly since its approval in 2010 [3]. The risk- benefit ratio for thrombolysis of acute ischemic stroke in patients taking dabigatran is problematic because the degree of anticoagula- tion cannot be readily or reliably determined prior to lysis, raising substantive concern for Hemorrhagic transformation of the stroke [4]. 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 patients with acute ischemic stroke, the extent of anticoagulation can be reliable determined using the INR, allowing a more quantitative assessment of bleeding risk should lysis be attempted. For dabigatran, both the aPTT and the TT give a qualitative assessment of anticoagulation; the dilute thrombin time, 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 contraindications for thrombolysis while on dabigatran treatment, if coagulation times were within or close to the normal limits (TT b 38 seconds and/or aPTT b 37 seconds), IV r-tPA was administered. Based on this protocol, 2 out of 13 patients were deemed eligible and were successfully treated, without hemorrhagic complication, over a period of 8 months [5].

Besides laboratory assays, the other important data to assess in NOAC-treated patients being considered for thrombolysis are renal

0735-6757/(C) 2014

image of Fig

Fig. Brain CT at admission showing loss of insular cortical mantle (A) and hyperdensity in distal left middle cerebral artery (B). Brain CT 24 hours after thrombolysis showing a cortical small frontal ischemic area (C and D).

function and time since last dose. All of the NOACs share a much shorter half-life than warfarin and are usually dosed twice daily (rivaroxaban for venous thromboembolism after 2 weeks 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 the long time elapsed after the last dose of dabigatran supported the decision to thrombo- lyze the patient without exposing him to a high risk of hemorrhagic complications. Furthermore, our patient’s glomerular filtration rate was greater than 80 mL/min, which is associated with a significantly lower rate of major 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 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 the renal function. With dabigatran in particular, TT and aPTT also offer some qualitative guidance.

Catia Diogo, MD Josiana Duarte, MD

Department of Internal Medicine Unidade Local de Saude do Litoral Alentejano (ULSLA)

Hipolito Nzwalo, MD

National Institute of Medical Emergency (INEM)

Department of Neurology Centro Hospitalar do Algarve (CHA) E-mail address: [email protected]

Sofia Sobral, MD

Department of Internal Medicine Unidade Local de Saude do Litoral Alentejano (ULSLA)

Paula Pestana, MD

Department of Internal Medicine Unidade Local de Saude do Litoral Alentejano (ULSLA) National Institute of Medical Emergency (INEM)

Henrique Rita, MD

Department of Internal Medicine Unidade Local de Saude do Litoral Alentejano (ULSLA) National Institute of Medical Emergency (INEM)

Jose Sousa e Costa, MD

Department of Internal Medicine Unidade Local de Saude do Litoral Alentejano (ULSLA)

http://dx.doi.org/10.1016/j.ajem.2014.04.021

References

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