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Reversal of Dabigatran to Facilitate Lytic Management of Acute Ischemic Stroke

dabigatranAcute ischemic stroke (AIS) occurs when there is a sudden occlusion of the arterial blood supply to part of the brain, and is most commonly manifested clinically by focal neurological deficit/s. In the US, more than 750,000 stroke cases are diagnosed each year, making it the nation’s fifth leading cause of the death and the most common etiology of disability.1 Strokes have a devastating effect on the quality of life of a substantial portion of affected patients and their caregivers, and in the US are responsible for direct and indirect costs exceeding $100 billion annually.

Pathologically, strokes may be ischemic (~80%) or hemorrhagic (~20%).2 The most common cause of ischemic stroke is cardioembolic, most often associated with atrial fibrillation (AF),3 which itself is the most common cardiac arrhythmia. In patients with nonvalvular AF, the oral anticoagulant dabigatran etexilate (PRADAXA®) was shown in the large RE-LY study4 to be associated with a significantly lower risk of cardioembolic ischemic stroke than standard therapy—vitamin K antagonist (warfarin)—and is licensed worldwide for that indication.

Once ischemic stroke occurs, the mainstay restorative therapy is thrombolysis and/or thrombectomy to recanalize the occlusion and reperfuse the brain, with the primary therapy available worldwide being intravenous recombinant tissue plasminogen activator (IV r-tPA) administered 0-4.5 hours after symptomatic expression.2 Even with this approach, prognosis is guarded, with studies showing the absolute reduction in chance of poor outcome in patients treated with IV r-tPA within 3 hours is 10% (NNT=10), and in the 3-4.5 hour window, 7% (NNT=14).1 The primary limitations of intravenous thrombolysis for AIS are delays in achieving reperfusion, inadequately complete recanalization, and hemorrhagic transformation (HT).5 Invasive thrombectomy is also a reperfusion option and is associated with a lower bleeding risk, but is available only at specialized centers and is not feasible in all vessel locations. Thus thrombolysis remains the most common therapy for AIS in North America.1,2

Hemorrhagic transformation, which increases the morbidity and mortality of AIS,6 occurs spontaneously in AIS at a baseline rate without administration of thrombolytic therapy in around 1.5% of cases).7 Case definition of HT varies, as the occurrence of bleeding in the infarcted brain tissue may range from small, petechial, asymptomatic hemorrhages, to large intracerebral hematomas resulting in high intracranial pressure and midline shift.8,9 After IV r-tPA, the rate of HT is more in the range of 7%,7 although it is now appreciated that not all hemorrhagic transformations are deleterious; it has been postulated that small hemorrhagic infarctions could actually be a marker of successful recanalization and are associated with long-term favorable outcome, while delayed recanalization is more often associated with the development of symptomatic hemorrhagic complications.8

Concern for HT is heightened in patients with AIS who are taking oral anticoagulant or antiplatelet therapies. In fact, the most recent ASA/AHA treatment guidelines for AIS list as an absolute exclusion criterion for intravenous thrombolysis “current use of direct thrombin inhibitors or direct factor Xa inhibitors with elevated sensitive laboratory tests (e.g., aPTT, INR, platelet count, ECT, TT, or appropriate factor Xa activity assays).”5 As dabigatran etexilate (PRADAXA®) is a direct thrombin inhibitor, the guidelines clearly exclude IV r-tPA as an accepted therapy for AIS that presents within the eligibility window while on dabigatran therapy, even in the absence of other contraindications. After IV r-tPA, the rate of HT is more in the range of 7%.8

The RE-VERSE AD study established the safety and efficacy of idarucizumab, a Fab-fragment antibody directed specifically against dabigatran, as a reversal agent for the anticoagulant effects of dabigatran.10 Idarucizumab is a humanized monoclonal antibody fragment that binds dabigatran some 350 times more avidly than dabigatran binds thrombin. The standard dose of 5g immediately reverses the anticoagulant activity of dabigatran.10,11 In RE-VERSE AD, idarucizumab rapidly (within minutes), safely, and durably ( > 24 hours) reversed dabigatran-mediated anticoagulation both in dabigatran-treated patients who presented with acute hemorrhage and in dabigatran-treated patients who required reversal for restoration of hemostasis prior to urgent or emergent invasive procedures. While only one subject was enrolled globally in RE-VERSE AD for idarucizumab reversal to facilitate management of acute AIS, subsequent to the licensing of idarucizumab around the world, numerous case reports and case series of the use of this strategy have been published, and in summation have suggested a likely positive benefit:risk balance for it.12–17 In systematic studies of AIS management, lack of reversal agents for anticoagulated patients has excluded patients, who would otherwise have been eligible for IV r-tPA, due to the potential risk of bleeding.18 A “reverse-to-lyse” approach to managing patients on dabigatran with AIS seems reasonable.

I cited above case studies and case series that have reported on the clinician-driven use of this strategy. There have been no formal trials of reverse-to-lyse. But now we have the largest case series yet, from New Zealand, which as a nation was a stalwart enroller for RE-VERSE AD. Barber et al published “Stroke reperfusion therapy following dabigatran reversal with idarucizumab in a national cohort” in Neurology.19 They evaluated the stroke care (complications, outcomes, and door-to-needle times) of patients given idarucizumab for dabigatran reversal prior to lytic therapy for stroke, to those of patients not requiring or not given idarucizumab in a nationwide cohort of thrombolyzed patients over a 24-month period. They included all New Zealand patients with stroke treated with stroke reperfusion entered into a mandatory online national registry (what an amazing resource!).19

In New Zealand in 2017 and 2018, 1,336 patients received thrombolysis for AIS. Fifty-one patients received idarucizumab prior to thrombolysis, while 386 patients had stroke clot retrieval, of whom 8 (2.1%) were first treated with idarucizumab. Idarucizumab-treated patients had slower door-to-needle times (83 [54–110] minutes vs 61 [43–85] minutes, p = 0.0006). Symptomatic intracerebral hemorrhage occurred in 2 (3.9%) of the idarucizumab-treated patients and 49 (3.8%) of the other thrombolyzed patients (p = 0.97). None of the idarucizumab-treated patients had significant thrombotic complications. At 7 days, 3 (5.9%) idarucizumab-treated and 101 (7.9%) of the other thrombolyzed patients had died (p = 0.61). The showed that idarucizumab was used in 6% of all thrombolyzed AIS patients in a national cohort during 2018, up from 1.3% in 2017. Idarucizumab appeared to be safe with similar clinical outcomes to routinely managed patients, despite a 22-minute door-to-needle time delay. Idarucizumab can facilitate thrombolysis in patients with stroke taking dabigatran.

I couldn’t agree more! We don’t have similar published observational data for andexanet alfa, the reversal agent for the anti-Factor Xa NOACs, which is unfortunate because dabigatran, the only anticoagulant for which idarucizumab is helpful, not commonly used now in the US. If it happens, though, clinicians should strongly consider reverse-to-lyse with idarucizumab in appropriate patients seen!

Resources

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2. Powers William J., Rabinstein Alejandro A., Ackerson Teri, et al. 2018 Guidelines for the Early Management of Patients With Acute Ischemic Stroke: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke. 2018;49(3):e46-e99. doi:10.1161/STR.0000000000000158
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10. Pollack CV, Reilly PA, van Ryn J, et al. Idarucizumab for Dabigatran Reversal – Full Cohort Analysis. N Engl J Med. 2017;377(5):431-441. doi:10.1056/NEJMoa1707278
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12. Kermer P, Eschenfelder CC, Diener H-C, et al. Antagonizing dabigatran by idarucizumab in cases of ischemic stroke or intracranial hemorrhage in Germany – A national case collection. Int J Stroke Off J Int Stroke Soc. 2017;12(4):383-391. doi:10.1177/1747493017701944
13. Berrouschot J, Stoll A, Hogh T, Eschenfelder CC. Intravenous Thrombolysis With Recombinant Tissue-Type Plasminogen Activator in a Stroke Patient Receiving Dabigatran Anticoagulant After Antagonization With Idarucizumab. Stroke. 2016;47(7):1936-1938. doi:10.1161/STROKEAHA.116.013550
14. Kafke W, Kraft P. Intravenous Thrombolysis after Reversal of Dabigatran by Idarucizumab: A Case Report. Case Rep Neurol. 2016;8(2):140-144. doi:10.1159/000447531
15. Schäfer N, Müller A, Wüllner U. Systemic Thrombolysis for Ischemic Stroke after Antagonizing Dabigatran with Idarucizumab-A Case Report. J Stroke Cerebrovasc Dis Off J Natl Stroke Assoc. 2016;25(8):e126-127. doi:10.1016/j.jstrokecerebrovasdis.2016.05.006
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19. Barber PA, Wu TY, Ranta A. Stroke reperfusion therapy following dabigatran reversal with idarucizumab in a national cohort. Neurology. February 2020. doi:10.1212/WNL.0000000000009155

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