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Background
About 20–30% of all ischaemic strokes are associated with atrial fibrillation (AF) [1]. Although the long-term net benefit of oral anticoagulation for stroke prevention in AF is well-established [2, 3], when to start anticoagulation in the acute phase after ischaemic stroke—balancing the risks of early recurrent ischaemic stroke and haemorrhagic transformation of the acute infarct—is a frequent and important dilemma in stroke medicine [2]. Indeed, the first large-scale phase 3 DOAC AF trials excluded patients with recent ischaemic stroke due to concerns about a potential increased risk of intracranial bleeding [4, 5–6].
Although numerous observational studies [7] and two randomised controlled trials [8, 9] have investigated this question, substantial clinical uncertainty remains due to biases and confounding inherent in the observational data and limited statistical power in the randomised trials. Thus, uncertainty remains about the superiority of early anticoagulation and the effects of DOAC timing in key subgroups such as infarct size or stroke severity. In particular, the limited number of participants with moderate-to-severe strokes limits generalisability to the full population of patients with acute ischaemic stroke and atrial fibrillation. The ELAN [9] trial also excluded the key high-risk group of patients taking oral anticoagulation at the time of their stroke, and those with parenchymal haemorrhage types 1 and 2 (but not those with haemorrhagic infarction types 1 and 2).
Statistical framework
OPTIMAS utilises a gatekeeper approach, investigating whether, in patients with acute ischaemic stroke and AF, early initiation of DOAC treatment (within 4 days (96 h) of onset) is non-inferior to, or better than later initiation of DOAC (Direct (non-vitamin K antagonist [VKA]) oral anticoagulants treatment, no sooner than day 7 (> 144 h) and no later than day 14 (< 336 h) after onset, in preventing recurrent ischaemic stroke, systemic embolism and symptomatic intracranial haemorrhage (sICH). Table 1 below provides our estimand framework with respect to potential intercurrent events (an event of interest occurring after treatment initiation which can affect the interpretation of the endpoint) [10].
Table 1. Estimand
Characteristic of estimand (primary outcome) | Definition and method of analysis |
|---|---|
Population | Participants aged 18 years or over, clinical diagnosis of acute ischaemic stroke, AF (including paroxysmal, persistent or permanent AF, or atrial flutter). Eligibility to commence DOAC in accordance with approved prescribing recommendations and SmPC... |