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)

 Didn't this earlier research prompt your competent? doctor and hospital to have this done already?

anticoagulation (24 posts to November 2014)

Do you prefer your doctor and hospital incompetence NOT KNOWING? OR NOT DOING? And they've been completely incompetent for almost two years already. Why haven't they been fired yet!

The latest here:

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)

Hakim-Moulay Dehbi, PhDa,† ∙ Prof Urs Fischer, MD MScb,† ∙ Signild Åsberg, MD PhDc,† ∙ Truman J Milling, MDd,† ∙ Stefanie Abend, BScb ∙ Norin Ahmed, MSca ∙ et al. Show more

Cover Image - The Lancet, Volume 406, Issue 10498

Background

The optimal timing of oral anticoagulation for prevention of early ischaemic stroke recurrence in people with acute ischaemic stroke and atrial fibrillation remains uncertain. We aimed to estimate the effects of starting a direct oral anticoagulant (DOAC) early (≤4 days) versus later (≥5 days) after onset of ischaemic stroke.

Methods

For this systematic review and meta-analysis we searched the electronic databases PubMed, Cochrane Central Register of Controlled Trials, and Embase for randomised controlled trials published from inception until March 16, 2025. We included clinical trials if they were pre-registered, randomised, investigated clinical outcomes, and included participants with acute ischaemic stroke and atrial fibrillation who were assigned to either early or later initiation (≤4 days vs ≥5 days) of a DOAC in approved doses. The primary outcome was a composite of recurrent ischaemic stroke, symptomatic intracerebral haemorrhage, or unclassified stroke within 30 days of randomisation. Secondary outcomes included components of the primary composite within 30 days and 90 days. We did a one-stage individual patient data meta-analysis with the use of a generalised linear mixed-effects model, accounting for between-trial differences, to generate treatment effects, which are presented as odds ratios (ORs) and 95% CIs. This study is registered with PROSPERO, CRD42024522634.

Findings

We identified four eligible trials: TIMING (NCT02961348), ELAN (NCT03148457), OPTIMAS (NCT03759938), and START (NCT03021928). After excluding participants who opted out of data sharing or were not randomly assigned to DOAC initiation within 4 days or at day 5 or later, we included 5441 participants (mean age 77·7 years [SD 10·0], 2472 [45·4%] women, median National Institutes of Health Stroke Scale 5 [IQR 3–10]) in the individual patient data meta-analysis. We obtained primary outcome data for 5429 participants. The primary outcome occurred in 57 (2·1%) of 2683 participants who started DOAC early versus 83 (3·0%) of 2746 participants who started later (OR 0·70, 95% CI 0·50–0·98, p=0·039). Early DOAC reduced the risk of recurrent ischaemic stroke (45 [1·7%] of 2683 vs 70 [2·6%] of 2746, OR 0·66, 0·45–0·96, p=0·029). There was no evidence of an increase in symptomatic intracerebral haemorrhage with early DOAC initiation (10 [0·4%] of 2683 vs 10 [0·4%] of 2746, OR 1·02, 0·43–2·46, p=0·96).

Interpretation

For people with acute ischaemic stroke and atrial fibrillation, early DOAC initiation (within 4 days) reduced the risk of the composite outcome of recurrent ischaemic stroke, symptomatic intracerebral haemorrhage, or unclassified stroke within 30 days. These findings support early DOAC initiation in clinical practice.

Funding

The CATALYST collaboration was facilitated by a British Heart Foundation grant for OPTIMAS (grant reference number CS/17/6/33361), with support from researchers at the National Institute for Health and Care Research University College London Hospitals Biomedical Research Centre, and a Swiss National Science Foundation grant for ELAN (32003B_197009; 32003B_169975).

Introduction

Atrial fibrillation causes about 20–30% of ischaemic strokes, which are generally more disabling than strokes associated with other causes.1 Direct oral anticoagulants (DOACs) are highly effective in long-term secondary prevention after ischaemic stroke associated with atrial fibrillation and are associated with about half the risk of intracranial haemorrhage compared with vitamin K antagonists.2 However, the optimal timing of initiation of anticoagulation after acute ischaemic stroke in atrial fibrillation is a persisting clinical dilemma, since the pivotal DOAC trials excluded participants with recent acute ischaemic stroke (ie, within 7–30 days). Although early DOAC might reduce the risk of early ischaemic stroke recurrence due to cardiac embolism, early use of DOACs must be balanced against concerns regarding haemorrhagic transformation of the acute infarct which could, if severe, worsen clinical outcomes. A recent aggregate data meta-analysis3 including observational and randomised studies suggested that early DOAC treatment might be safe, but these data are limited by potential biases and confounding.

Research in context

Evidence before this study

Pivotal randomised controlled trials showed that direct oral anticoagulants (DOACs) are highly effective for the prevention of ischaemic stroke in people with atrial fibrillation, but did not include participants soon after acute ischaemic stroke (within about 1–2 weeks). Early DOAC use might reduce the risk of early ischaemic stroke recurrence due to cardiac embolism but might also increase haemorrhagic transformation of the acute infarct that could, if severe, worsen clinical outcomes. We searched the electronic databases PubMed, Cochrane Central Register of Controlled Trials, and Embase on May 16, 2024 (with an additional updated search on March 16, 2025), for randomised controlled trials comparing early versus delayed start of DOAC. The main search terms were “acute ischaemic stroke” AND “atrial fibrillation” AND “anticoagulants” AND “timing” AND “randomised”. We identified four published trials (TIMING, ELAN, OPTIMAS, and START). The risk of bias, assessed according to the revised Cochrane risk-of-bias tool for randomised trials, was low. None of the four trials alone provided unequivocal evidence that early DOAC treatment was preferable to delayed initiation.

Added value of this study

We performed an individual patient data meta-analysis including 5441 participants from TIMING, ELAN, OPTIMAS, and START (mean age 77·7 years [SD 10·0], 2472 [45·4%] women, median National Institutes of Health Stroke Scale score at admission 5 [IQR 3–10]) to investigate the effects of early DOAC initiation within 4 days versus later DOAC initiation (at day 5 or later). Our results showed a reduction of the primary outcome, a composite of recurrent ischaemic stroke, symptomatic intracerebral haemorrhage, or unclassified stroke within 30 days. The primary outcome occurred in 57 (2·1%) of 2683 participants who started a DOAC early versus 83 (3·0%) of 2746 in the delayed DOAC group. The benefits were consistent across key prespecified subgroups including clinical stroke severity, reperfusion treatment, and previous use of oral anticoagulants.

Implications of all the available evidence

Our findings suggest that clinicians should initiate DOAC treatment within 4 days and do not support the practice of delaying DOAC initiation after acute ischaemic stroke with atrial fibrillation. Future CATALYST subgroup analyses will further explore the risks and benefits of early initiation of DOACs.