Timing of anticoagulation after recent ischaemic stroke in patients with atrial fibrillation

Abstract

Summary Background About 13–26% of all acute ischaemic strokes are related to non-valvular atrial fibrillation, the most common cardiac arrhythmia globally. Deciding when to initiate oral anticoagulation in patients with non-valvular atrial fibrillation is a longstanding, common, and unresolved clinical challenge. Although the risk of early recurrent ischaemic stroke is high in this population, early oral anticoagulation is suspected to increase the risk of potentially harmful intracranial haemorrhage, including haemorrhagic transformation of the infarct. This assumption, and current treatment guidelines, are based on historical, mostly observational data from patients with ischaemic stroke and atrial fibrillation treated with heparins, heparinoids, or vitamin K antagonists (VKAs) to prevent recurrent ischaemic stroke. Randomised controlled trials have subsequently shown that direct oral anticoagulants (DOACs; ie, apixaban, dabigatran, edoxaban, and rivaroxaban) are at least as effective as VKAs in primary and secondary prevention of atrial fibrillation-related ischaemic stroke, with around half the risk of intracranial haemorrhage. However, none of these DOAC trials included patients who had experienced ischaemic stroke recently (within the first few weeks). Clinicians therefore remain uncertain regarding when to commence DOAC administration after acute ischaemic stroke in patients with atrial fibrillation. Recent developments Prospective observational studies and two small randomised trials have investigated the risks and benefits of early DOAC-administration initiation (most with a median delay of 3–5 days) in mild-to-moderate atrial fibrillation-associated ischaemic stroke. These studies reported that early DOAC treatment was associated with a low frequency of clinically symptomatic intracranial haemorrhage or surrogate haemorrhagic lesions on MRI scans, whereas later DOAC-administration initiation (ie, >7 days or >14 days after index stroke) was associated with an increased frequency of recurrent ischaemic stroke. Where next? Adequately powered randomised controlled trials comparing early to later oral anticoagulation with DOACs in ischaemic stroke associated with atrial fibrillation are justified to confirm the acceptable safety and efficacy of this strategy. Four such randomised controlled trials (collectively planned to include around 9000 participants) are underway, either using single cutoff timepoints for early versus late DOAC-administration initiation, or selecting DOAC-administration timing according to the severity and imaging features of the ischaemic stroke. The results of these trials should help to establish the optimal timing to initiate DOAC administration after recent ischaemic stroke and whether the timing should differ according to stroke severity. Results of these trials are expected from 2021.

Atrial fibrillation and stroke: a practical guide

“…Four large randomised controlled trials, OPTIMAS, TIMING, START and ELAN, will assess the benefit of early anticoagulation (<4 days) in patients with AF-related stroke, with OPTIMAS (due to recruit ~3500 participants throughout the UK from early 2019 (ClinicalTrials.gov identifier: NCT03759938). 93 …”

Direct oral anticoagulants versus vitamin K antagonists after recent ischemic stroke in patients with atrial fibrillation

“…Interpretation: DOAC treatment commenced early after recent cerebral ischemia related to AF was associated with reduced risk of poor clinical outcomes compared to VKA, mainly attributed to lower risks of ICH. In clinical practice, DOACs are often commenced earlier than in the aforementioned RCTs, 13 yet little is known about safety and effectiveness of this approach. 1,2 Vitamin K antagonists (VKAs) inhibiting the production of several coagulation factors in the liver have been the only option for long-term oral anticoagulation for many years.…”

“…Results: We included 4,912 patients (median age, 78 years [interquartile range {IQR}, 71-84]; 2,331 [47.5%] women; median National Institute of Health Stroke Severity Scale at onset, 5 [IQR, [2][3][4][5][6][7][8][9][10][11][12]); 2,256 (45.9%) patients received VKAs and 2,656 (54.1%) DOACs. Median time from index event to starting oral anticoagulation was 5 days (IQR, [2][3][4][5][6][7][8][9][10][11][12][13][14] for VKAs and 5 days (IQR, [2][3][4][5][6][7][8][9][10][11] for DOACs (p = 0.53). There were 262 acute ischemic strokes (AISs; 4.4%/year), 71 intracranial hemorrrhages (ICHs; 1.2%/year), and 439 deaths (7.4%/year) during the total follow-up of 5,970 patient-years.…”

“…11 Actually, in patients with a history of ischemic stroke enrolled in one of the RCTs, [14][15][16][17] the delay between the stroke and enrollment in the trial was rather long: In ROCKET-AF 16 (Rivaroxabanonce daily, oral, direct factor Xa inhibition compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation), median delay was 551 days, and in ARISTOTLE 15 (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation), only 33% of patients were enrolled within 1 year of stroke. In clinical practice, DOACs are often commenced earlier than in the aforementioned RCTs, 13 yet little is known about safety and effectiveness of this approach. [18][19][20][21][22][23][24][25] Thus, we compared the clinical benefit of DOAC and VKA in patients having AF with a recent ischemic stroke or transient ischemic attack (TIA).…”

Intravenous Thrombolysis after Reversal of Dabigatran with Idarucizumab in Acute Ischemic Stroke: A Case Report

“…Acute ischemic stroke is a serious threatto the health of Chinese residentsand increased yearly.It is the leading cause of death for urban residents in China and characterisedby high morbidityandlethality, high rateof recurrence and disability, and high treatment cost.Cardiac embolism secondary to non-valvular atrial brillation (NVAF) accounts for 13-26% of ischemic stroke patiants for whom long-term and stable anticoagulant therapy is very important [1,2] . Compared with warfarin, DOACsigni cantly reduced the incidence of stroke by 19%, among which dabigatran signi cantly reduced the incidence of stroke by 34%.There was no signi cant difference in the overall incidence of major bleeding between the two [3] .…”