According to a rapid review published in Lancet Neurology, recent observational studies indicate that the initiation of direct oral anticoagulants (DOACs) between 3 and 5 days after ischemic stroke in patients with atrial fibrillation (Afib) is associated with fewer clinically symptomatic intracranial hemorrhage or surrogate hemorrhagic lesions on subsequent magnetic resonance imaging scans, whereas initiation of DOACs >7 or >14 days after stroke is associated with a higher risk for recurrent ischemic stroke.1
Current guidelines are imprecise and inconsistent with regard to when and how to start oral anticoagulation after the onset of Afib-related ischemic stroke. Although there is scarce evidence from randomized controlled trials of vitamin K antagonist (VKA) efficacy in acute ischemic stroke, VKAs are still recommended as first-line therapy in patients with AF in many countries. In fact, none of the guidelines distinguish between use of VKAs and DOACs, despite the substantial differences in the pharmacodynamics of these compounds. Moreover, findings from Cochrane reviews and meta-analyses have shown that DOACs have similar efficacy to VKAs in primary and secondary prevention of stroke, but are associated with about half the frequency of intracranial hemorrhage.2,3
Several nonrandomized, prospective, observational studies have explored the potential risks and benefits of early DOAC anticoagulation. In 1 study, there was a lower proportion of recurrent ischemic stroke in patients who started DOAC before 7 days vs after 7 days (5.1% per year vs 9.3% per year, respectively; P =.53).4 Another study demonstrated a significantly lower rate of recurrent ischemic stroke in patients who started DOACs within 3 to 14 days of the index stroke vs 14 days (2.1% per year vs 9.1% per year, respectively; P <.001).5 In addition, 4 single-centered observational studies have reported the potential safety of early DOAC initiation.6-9
Although all the observational studies reviewed here were prone to selection bias and featured nonstandardized administration of DOACs, all suggest that early DOAC administration in patients with mild ischemic stroke across different countries and ethnicities has a low frequency of intracranial hemorrhage (including hemorrhagic transformation).
The promising results of the observational studies and persisting clinical uncertainty have prompted several randomized controlled clinical trials investigating early vs late initiation of DOAC administration: ELAN (ClinicalTrials.gov identifier: NCT03148457), OPTIMAS (ClinicalTrials.gov identifier: NCT03759938), TIMING (ClinicalTrials.gov identifier: NCT02961348), and START (ClinicalTrials.gov identifier: NCT03021928). These 4 trials aim to recruit up to 9000 patients; all trials are ongoing, and results are expected in 2021.
The researchers also note that there are unresolved questions concerning starting anticoagulation in patients with renal impairment, as DOACs are eliminated by the kidneys. To their knowledge, there is only 1 trial ongoing (ClinicalTrials.gov identifier: NCT02942407), and without further insights, DOACs should be avoided and VKAs should be used instead in patients with severe renal impairment or those undergoing dialysis.
“The ongoing clinical trials should help to establish whether early initiation of DOAC treatment in patients with atrial fibrillation is safe, prevents recurrent ischemic stroke, shortens hospital stay, and improves the continuity of anticoagulant treatment,” concluded the researchers. In the meantime, “decisions for individual patients must be made on the basis of careful consideration of the risks of ischaemic stroke and intracranial haemorrhage.”
1. Seiffge DJ, Werring DJ, Paciaroni M, et al. Timing of anticoagulation after recent ischaemic stroke in patients with atrial fibrillation. Lancet Neurol. 2019;18(1):117-126.
2. Salazar CA, del Aguila D, Cordova EG. Direct thrombin inhibitors versus vitamin K antagonists for preventing cerebral or systemic embolism in people with non-valvular atrial fibrillation. Cochrane Database Syst Rev. 2014;3:CD009893.
3. Bruins Slot KM, Berge E. Factor Xa inhibitors versus vitamin K antagonists for preventing cerebral or systemic embolism in patients with atrial fibrillation. Cochrane Database Syst Rev. 2018;3:CD008980.
4. Seiffge DJ, Traenka C, Polymeris A, et al. Early start of DOAC after ischemic stroke: risk of intracranial hemorrhage and recurrent events. Neurology. 2016;87(18):1856-1862.
5. Paciaroni M, Agnelli G, Falocci N, et al. Early recurrence and major bleeding in patients with acute ischemic stroke and atrial fibrillation treated with non-vitamin-K oral anticoagulants (RAF-NOACs) study. J Am Heart Assoc. 2017;6(12):e007034.
6. Macha K, Volbers B, Bobinger T, et al. Early initiation of anticoagulation with direct oral anticoagulants in patients after transient ischemic attack or ischemic stroke. J Stroke Cerebrovasc Dis. 2016;25:2317-2321.
7. Cappellari M, Carletti M, Danese A, Bovi P. Early introduction of direct oral anticoagulants in cardioembolic stroke patients with non-valvular atrial fibrillation. J Thromb Thrombolysis. 2016;42:393-398.
8. Gioia LC, Kate M, Sivakumar L, et al. Early rivaroxaban use after cardioembolic stroke may not result in hemorrhagic transformation: a prospective magnetic resonance imaging study. Stroke. 2016;47:1917-1919.
9. Deguchi I, Tanahashi N, Takao M. Timing of treatment initiation with oral anticoagulants for acute ischemic stroke in patients with nonvalvular atrial fibrillation. Circ J. 2017;81:180-184.