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

Abstract

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.

Figure 1:. Risk of recurrent ischaemic stroke and intracranial haemorrhage in patients with atrial fibrillation and a recent ischaemic stroke

Annualised event frequencies (percentage per year with 95% CIs) of recurrent ischaemic stroke and intracranial haemorrhage in prospective observational studies^– of patients treated with direct oral anticoagulants with at least3 months of clinical follow-up.

Figure 2:. Timing for initiation of direct oral anticoagulant administration

Enrolment of eligible patients with ischaemic stroke and atrial fibrillation in ongoing randomised controlled trials is suggested on the basis of current guidelines and evidence from observational studies and clinical trials. If enrolment in a trial is not possible, clinicians will need to use the data to weigh potential risks and benefits of early DOAC administration although evidence is currently scarce to make strong recommendations. DOAC=direct oral anticoagulant. HT=haemorrhagic transformation. NIHSS= National Institutes of Health Stroke Scale. *Parenchymal haematoma Type 2 (homogeneous hyperdensity with mass effect >30% of infarct volume or extending beyond the infarct). †Petechial haemorrhage Type 1 (petechial heterogeneous hyperdensity), petechial haemorrhage Type 2 (diffuse heterogeneous hyperdensity), or parenchymal haemorrhage Type 1 (homogeneous hyperdensity <30% of infarct). ‡If oral anticoagulants are not contraindicated. ¶Prospective observational data and one small randomised controlled trial; grade of recommendation B, level of evidence 2a.