Acute stroke thrombolysis following dabigatran reversal using idarucizumab
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0028-3886.258032
Source of Support: None, Conflict of Interest: None
Novel oral anticoagulants (NOACs) are recommended first-line agents for prevention of ischemic stroke in patients with atrial fibrillation (AF). One of the barriers to adoption of NOACs has been the lack of a reversal agent or antidote. Idarucizumab, a specific reversal agent for one NOAC (dabigatran), was approved for use in Canada in 2016. This is a monoclonal antibody fragment that irreversibly binds to dabigatran and has been shown to completely reverse anticoagulant activity. Idarucizumab is indicated for treatment of bleeding in patients taking dabigatran or in patients in whom reversal is required before urgent medical procedures.
Although it is somewhat counterintuitive, the most common stroke presentation of anticoagulated AF patients is not an intracerebral hemorrhage, but an ischemic stroke. This reflects the high risk of cardioembolism associated with AF, even in patients who are adequately anticoagulated. Thrombolysis in patients taking NOACs is generally not recommended unless it can be established, either through history or through laboratory testing, that therapeutic drug levels are not present. Although unstudied, this reversal agent may also be useful in facilitating thrombolysis in patients presenting with ischemic stroke while taking dabigatran.
A 74-year old female patient presented to the hospital with sudden-onset aphasia and right-sided hemiplegia. Her stroke risk factors were the presence of AF, hypertension, and dyslipidemia. She had been taking dabigatran (150 mg PO BID) for 4 years before presentation. A non-contrast computed tomography (CT) of the brain demonstrated no acute ischemic changes. A CT angiogram revealed occlusion of the inferior division of the left middle cerebral artery [Figure 1]. The thrombin time (TT) was prolonged, indicating compliance with dabigatran, but these laboratory results were not available until 30 min after treatment decisions were made.
The patient was administered idarucizumab 5 g intravenously. Five minutes later, she was treated with intravenous tissue plasminogen activator (tPA). The initial TT was 81.7 s (normal range 14.3–19.7 s). A repeat TT at 7 h after tPA was 20.7 s.
By 48 h after treatment, the motor symptoms had resolved, although she had residual expressive dysphasia. A repeat CT scan of the brain at 24 h demonstrated a moderate sized left middle cerebral artery (MCA) territory infarct with no hemorrhagic transformation. A CT scan head at 96 h revealed a small asymptomatic petechial hemorrhagic transformation within the infarct. A CT scan on day 9 demonstrated resolution of these petechial hemorrhages. She was restarted on dabigatran 150 mg PO bid after a repeat CT scan of the head on day 9 and was discharged.
Anticoagulant reversal to deliver a thrombolytic agent represents a paradigm shift in acute stroke therapy. Although reversal agents for older oral and parenteral anticoagulants are available, this approach is not advocated in patients taking these agents. The primary reason for this is that the time to reversal is long and cannot be assured without repeat coagulation status testing. The prothrombin complex concentrate can theoretically be used before tPA administration in patients taking warfarin. Although rapid international normalized ratio (INR) normalization occurs in a majority of patients, reversal is not always complete.
Idarucizumab is the first true anticoagulant antidote. A 5 g intravenous (IV) bolus has been shown to normalize TT, which is linearly correlated with dabigatran concentrations, within minutes of administration.,, This results in a completely normal coagulation status in a timely fashion. This unique aspect of idarucizumab made it feasible to consider a staged reversal followed by thrombolysis. This approach has been used in 23 other cases in Europe and Australia [Table 1].,,,,,
Approximately 50% of patients taking an anticoagulant who present with ischemic stroke will have transient or mild symptoms that do not require therapy. Patients presenting with large vessel occlusion can be treated with endovascular clot retrieval. Although, a vast majority of patients treated with this highly effective therapy were administered intravenous tPA initially, a consensus paper has suggested that this may not be warranted in patients taking anticoagulants. Patients presenting with disabling symptoms without a proximal large vessel occlusion, such as our patient, are the optimal tPA candidates, provided any coagulopathy can be reversed. This remains an empiric therapeutic approach at this point. A clinical trial in this select group of patients is unlikely to be completed in the near future, but a prospective registry may be feasible.
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