Primary and Secondary Prevention of Ischemic Stroke and Cerebral Hemorrhage: JACC Focus Seminar

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.

/pdf/timing-of-anticoagulation-after-recent-ischaemic-stroke-in-2o4hpst1g5.pdf

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

Patients with ischemic stroke or transient ischemic attack and non-valvular atrial fibrillation have a high risk of recurrent stroke and other vascular events. The aim of this guideline is to provide recommendations on antithrombotic medication for secondary prevention of stroke and other vascular outcomes in these patients. The working group identified questions and outcomes, graded evidence, and developed recommendations according to the Grading of Recommendations Assessment, Development, and Evaluation approach and the European Stroke Organisation (ESO) standard operating procedure for guidelines. The guideline was reviewed and approved by the ESO guideline board and the ESO executive committee. In patients with atrial fibrillation and previous stroke or transient ischemic attack, oral anticoagulants reduce the risk of recurrence over antiplatelets or no antithrombotic treatment. Non-vitamin K antagonist oral anticoagulants are preferred over vitamin K antagonists because they have a lower risk of major bleeding and death. Recommendations are weak regarding timing of treatment, (re-)starting oral anticoagulants in patients with previous intracerebral haemorrhage, and treatment in specific patient subgroups of those of older age, with cognitive impairment, renal failure or small vessel disease, because of a lack of strong evidence. In conclusion, for patients with atrial fibrillation and ischemic stroke or transient ischemic attack, non-vitamin K antagonist oral anticoagulants are the preferred treatment for secondary prevention of recurrent stroke or thromboembolism. Further research is required to determine the best timing for initiating oral anticoagulants after an acute ischemic stroke, whether or not oral anticoagulants should be (re)started in patients with a history of intracerebral haemorrhage, and the best secondary preventive treatment in specific subgroups.

https://journals.sagepub.com/doi/pdf/10.1177/2396987319841187

Antithrombotic treatment for secondary prevention of stroke and other thromboembolic events in patients with stroke or transient ischemic attack and non-valvular atrial fibrillation: A European Stroke Organisation guideline

Background In patients with acute ischemic stroke and atrial fibrillation, early anticoagulation prevents ischemic recurrence but with the risk of hemorrhagic transformation (HT). The aims of this ...

/pdf/hemorrhagic-transformation-in-patients-with-acute-ischemic-1ofpjttk60.pdf

Hemorrhagic transformation in patients with acute ischemic stroke and atrial fibrillation: Time to initiation of oral anticoagulant therapy and outcomes

The aims of this article are to review the evidence regarding the use of non-vitamin K oral anticoagulants (NOACs) for secondary stroke prevention as compared to vitamin K antagonists in patients with atrial fibrillation (AF) and in patients with embolic strokes of uncertain source (ESUS), and when to initiate or resume anticoagulation after an ischaemic stroke or intracranial haemorrhage. Four large trials compared NOACs with warfarin in patients with AF. In our meta-analyses, the rate of all stroke or systemic embolism (SE) was 4.94% with NOACs vs. 5.73% with warfarin. Among the patients with AF and previous transient ischaemic attack or ischaemic stroke, the rate of haemorrhagic stroke was halved with a NOAC vs. warfarin, and the rate of major bleeding was 5.7% with a NOAC vs. 6.4% with warfarin. There was no significant difference in mortality. In a trial comparing apixaban with aspirin in patients with AF, the rate of stroke or SE was 2.4% at 1 year with apixaban vs. 9.2% at 1 year with aspirin and the rates of major bleeding were 4.1% with apixaban vs. 2.9% with aspirin. Data from registries confirmed the results from the randomized trials. Initiation or resumption of anticoagulation after ischaemic stroke or cerebral haemorrhage depends on the size and severity of stroke and the risk of recurrent bleeding. Two large trials tested the hypothesis that NOACs are more effective than 100 mg aspirin in patients with ESUS. Neither trial showed a significant benefit of the NOAC over aspirin. In the meta-analysis, the rate all stroke or SE was 4.94% with NOACs vs. 5.73% with warfarin and the rate of haemorrhagic stroke was halved with a NOAC. The four NOACs had broadly similar efficacy for the major outcomes in secondary stroke prevention.

Non-vitamin K oral anticoagulants for secondary stroke prevention in patients with atrial fibrillation.

Background and Purposes—This study was designed to derive and validate a score to predict early ischemic events and major bleedings after an acute ischemic stroke in patients with atrial fibrillati...

Prediction of Early Recurrent Thromboembolic Event and Major Bleeding in Patients With Acute Stroke and Atrial Fibrillation by a Risk Stratification Schema: The ALESSA Score Study.

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Prediction of Early Recurrent Thromboembolic Event and Major Bleeding in Patients With Acute Stroke and Atrial Fibrillation by a Risk Stratification Schema: The ALESSA Score Study.