Early Apixaban Use Following Stroke in Patients With Atrial Fibrillation

Abstract

Background and Purpose: It is unknown when to start anticoagulation after acute ischemic stroke (AIS) from atrial fibrillation (AF). Early anticoagulation may prevent recurrent infarctions but may provoke hemorrhagic transformation as AF strokes are typically larger and hemorrhagic transformation-prone. Later anticoagulation may prevent hemorrhagic transformation but increases risk of secondary stroke in this time frame. Our aim was to compare early anticoagulation with apixaban in AF patients with stroke or transient ischemic attack (TIA) versus warfarin administration at later intervals. Methods: AREST (Apixaban for Early Prevention of Recurrent Embolic Stroke and Hemorrhagic Transformation) was an open-label, randomized controlled trial comparing the safety of early use of apixaban at day 0 to 3 for TIA, day 3 to 5 for small-sized AIS (<1.5 cm), and day 7 to 9 for medium-sized AIS (≥1.5 cm, excluding full cortical territory), to warfarin, in a 1:1 ratio at 1 week post-TIA, or 2 weeks post-AIS. Results: Although AREST ended prematurely after a national guideline focused update recommended direct oral anticoagulants over warfarin for AF, it revealed that apixaban had statistically similar yet generally numerically lower rates of recurrent strokes/TIA (14.6% versus 19.2%, P =0.78), death (4.9% versus 8.5%, P =0.68), fatal strokes (2.4% versus 8.5%, P =0.37), symptomatic hemorrhages (0% versus 2.1%), and the primary composite outcome of fatal stroke, recurrent ischemic stroke, or TIA (17.1% versus 25.5%, P =0.44). One symptomatic intracerebral hemorrhage occurred on warfarin, none on apixaban. Five asymptomatic hemorrhagic transformation occurred in each arm. Conclusions: Early initiation of anticoagulation after TIA, small-, or medium-sized AIS from AF does not appear to compromise patient safety. Potential efficacy of early initiation of anticoagulation remains to be determined from larger pivotal trials. REGISTRATION: URL: https://www.clinicaltrials.gov/ ; Unique identifier: NCT02283294.

Rationale, Design and Methods of the Prospective Record of the Use of Dabigatran in Patients with Acute Stroke or TIA (PRODAST) Study

“…Five asymptomatic haemorrhagic transformations were found in each group. 14 However, due to the very small sample size, no meaningful conclusion regarding the risk of an early administration of anticoagulants after stroke can be drawn from this investigation.…”

“…The ‘Apixaban for Early Prevention of Recurrent Embolic Stroke and Hemorrhagic Transformation’ (AREST) trial randomly assigned patients with acute TIA, small- or medium-sized stroke to an early administration of Apixaban at day 0 to 3 for TIA, day 3 to 5 for small-sized IS and day 7 to 9 for medium-sized IS or to warfarin at 1 week after TIA, or 2 weeks after IS. 14 After the guideline recommendations regarding anticoagulation after stroke due to AF were changed in favour of administration of DOAC, the AREST trial was prematurely stopped after enrolment of only 91 patients. No symptomatic haemorrhages were observed in apixaban-treated patients, while one occurred in the warfarin study arm.…”

“…Data on early use of NOAC after acute IS derived from RCTs are currently limited to only few and small studies. 13,14 According to observational studies, a starting interval between 4 and 14 d after acute IS is recommended. 15 However, this finding could not be confirmed in a more recent study.…”

“…Data on early use of NOAC after acute IS derived from RCTs are currently limited to only few and small studies. 13 , 14 …”

Acute Secondary Prevention of Ischemic Stroke: Overlooked No Longer

“…The optimal timing of anticoagulation with direct-acting oral anticoagulants (DOACs) following ischemic stroke in atrial fibrillation is the focus of ongoing trials. Existing evidence shows that anticoagulation with DOACs in the early period (3-5 days) following ischemic stroke at least can be applied with a low frequency of associated symptomatic intracranial hemorrhage events (21,22). Analysis of multicenter observational data comparing different strategies for anticoagulation following atrial fibrillation-associated stroke supports the use of DOACs over warfarin and supports direct initiation of oral treatment rather than bridging with heparin or heparinoids (23).…”