Atrial fibrillation (AF) accounts for approximately 20-30% of ischaemic strokes and is more likely to result in disability compared to other types of ischaemic stroke. Direct oral anticoagulants (DOACs) are better tolerated as long-term stroke-preventive treatment in AF patients than vitamin K antagonists (VKAs), with approximately 50% fewer intracranial haemorrhages. However, the optimal timing for initiating DOACs after an acute ischaemic stroke remains unanswered.
The prospect of stroke reduction using early DOAC initiation therefore exists, but early dosing of DOACs leads to a risk of infarction or haemorrhagic conversion. A recent meta-analysis of aggregate data from observational and randomized studies suggested that early DOAC administration may be safe; however, the findings were limited due to confounding variables and potential biases.
A systematic review and meta-analysis were conducted according to a pre-registered protocol on PROSPERO (CRD42024522634). In this review, the researchers searched PubMed, Cochrane Central, and Embase through March 16, 2025, for randomised controlled trials (RCTs) that specifically compared the early (≤4 days) versus delayed (≥5 days) initiation of DOAC in patients with acute ischemic stroke and AF.
The primary outcome was a combination of recurrent ischaemic stroke, symptomatic intracerebral haemorrhage, or unclassifiable stroke within 30 days. A one-stage individual patient data meta-analysis (IPDMA) was employed to estimate treatment effects, utilizing a generalised linear mixed-effects model that accounted for variability between trials. The outcomes were displayed in the form of odds ratios (ORs) and corresponding 95% confidence intervals (CIs).
Four trials met the inclusion criteria: TIMING, ELAN, OPTIMAS, and START. There were 5441 participants with a mean age of 77.7 years (45.4% females). The average score of the National Institutes of Health Stroke Scale (NIHSS) was 5 (Interquartile range [IQR]: 3-10). The primary outcome data were available for 5429 patients. Among patients who received early DOACs (n=2683), the primary outcome occurred in 2.1% (n=57), compared to 3.0% (n=83) in 2746 patients of the delayed treatment groups (OR 0.70, 95% CI 0.50-0.98, p=0.039).
Further analysis showed a significantly reduced rate of recurrent ischaemic stroke in the early treatment group (1.7% vs 2.6%; OR 0.66, 95% CI 0.45-0.96, p=0.029). In addition, there was no significant difference observed in the rate of symptomatic intracerebral haemorrhage with early treatment (0.4% in both groups; OR 1.02, 95% CI 0.43-2.46, p=0.96).
The findings from CATALYST IPDMA strongly support the early initiation of DOACs (within four days) as a safe and effective strategy to reduce stroke recurrence in AF patients post-stroke. Over time, as both groups receive effective anticoagulation, the relative advantage of early initiation diminishes.
There was no statistically significant difference observed at the 90-day point between early and delayed initiation, which aligns with expectations, given that the acute phase is the highest-risk period. Beyond the clinical efficacy, early DOAC initiation may also promote improved patient adherence and shorter hospital stays.
This study is also beneficial in terms of the theoretical use of DOACs, as it has previously demonstrated potential benefits to patient adherence and shorter hospitalizations. CATALYST analyses in the future will examine even more detailed subgroups at higher risk, such as haemorrhagic transformation or large infarct size, to further tailor their treatment. Overall, these findings represent a significant advancement toward the timing of anticoagulation for secondary stroke prevention in patients with AF.
References: Dehbi HM, Fischer U, Ă…sberg S, et al. Collaboration on the optimal timing of anticoagulation after ischaemic stroke and atrial fibrillation: a systematic review and prospective individual participant data meta-analysis of randomised controlled trials (CATALYST). Lancet. 2025;406(10498):43-51. doi:10.1016/S0140-6736(24)01234-5
