Lancet (London, England)Systematic Review - Meta-Analysis
05 Jul 2025
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).
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).
COI Statement
Declaration of interests UF reports research support from the Swiss National Science Foundation and the Swiss Heart Foundation; is a principal investigator of the ELAN trial and co-principal investigator of the DISTAL, TECNO, SWIFT DIRECT, SWITCH, ELAPSE, and ICARUS trial; is a steering committee member of the DO_IT trial; declares research grants from Medtronic (BEYOND SWIFT and SWIFT DIRECT), Stryker, Rapid medical, Penumbra, Medtronic, and Phenox (DISTAL), and Boehringer Ingelheim (TECNO) with all fees paid to the institution; reports consultancies for Medtronic, Stryker, and CSL Behring (fees paid to institution); declares participation on an advisory board for AstraZeneca (formerly Alexion/Portola), Boehringer Ingelheim, Biogen, AbbVie, and Acthera (fees paid to institution); is a member of a clinical event committee of the COATING study (Phenox) and a member of the data and safety monitoring committee of the TITAN, LATE_MT, and IN EXTREMIS trials; and is the president of the Swiss Neurological Society and president-elect of the European Stroke Organisation. TJM reports consulting fees from AstraZeneca, CLS Behring, and Octapharma. NF reports grants and contracts from the British Heart Foundation, National Institute for Health and Care Research, Medical Research Council, Cure Parkinson's Trust, and the European Union; declares consulting fees from ALK-Abelló, Sanofi Aventis, Gedeon Richter, Abbot, Galderma, AstraZeneca, Ipsen, Vertex, Thea, Novo Nordisk, Aimmune Therapeutics, and Gilead; and declares participation on a data safety monitoring board (DSMB) for Orion. TG reports research grants from the Austrian Science Fund; speakers' honoraria from Bristol Myers Squibb, Novartis, and AstraZeneca; and participation on advisory boards for Novartis and AstraZeneca. ZH reports research grants from the Swedish Society for Medical Research (S17-0133), the Swedish Heart-Lung Foundation (20200722), and Uppsala University Hospital (Upssala, Sweden); declares lecture and consulting fees from Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Pfizer, and Roche Diagnostics; and is a member of the Precision Medicine and Diagnostics expert group for SciLifeLab (Uppsala, Sweden). MK reports research support from the Intramural Research Fund (20-4-5) for Cardiovascular Diseases of the National Cerebral and Cardiovascular Center, Japan; research funding from Boston Scientific and Nippon Boehringer Ingelheim; research funding and speaker fees from Daiichi-Sankyo; consulting fees from Bristol Myers Squibb/Janssen Pharmaceuticals; and speaker fees from AstraZeneca, Bayer Yakuhin, Bristol Myers Squibb/Pfizer, and Mitsubishi Tanabe Pharma Corporation. PL reports institutional research grants from Lone Star Stroke Consortium. RL reports payments and honoraria to his institution from Boehringer Ingelheim, Bristol Myers Squibb, Medtronic, and Pfizer. GYHL reports consultant and speaker fees for Anthos, Bristol Myers Squibb/Pfizer, Boehringer Ingelheim, and Daiichi Sankyo (paid to institution); and is the senior investigator of the National Institute for Health and Care Research. PSN declares research funding from the British Heart Foundation but declares no competing interests. BN reports payments from Symbec-Orion for participation on the DSMB for the HOVID trial. GT reports grants from the European Union, the German Research Foundation, and the German Innovation Fund; consulting fees and honoraria from Acandis, AstraZeneca, Bayer, and Boehringer Ingelheim; honoraria from Bristol Myers Squibb/Pfizer, Daiichi Sankyo, and Stryker; participation on the DSMB for the TEA-Stroke Study; and is chair of the board of directors for the European Stroke Organisation and Speaker of the Commission Cerebrovascular Diseases of the German Neurological Society. PW reports payments from Abbott for participation in the Clincial Event Adjudication Committee for the PORTICO studies. SJW reports institutional research grants from Lone Star Stroke Consortium and the State of Texas. JO reports institutional research grants from Amgen, AstraZeneca, Bayer, and Roche Diagnostics; and institutional honoraria from Pfizer. JD reports institutional research grants from the Stroke Association for the ELAN and OASIS trials, from National Institute for Health and Care Research for the CLASP study, and a Medicines Development Fellowship from the UK Medical Research Council; speaker fees from Medtronic; participation on the DSMB for INTERACT4; is on an advisory board for AstraZeneca; and is the treasurer of the European Stroke Organisation. DJW reports grant funding from the Stroke Association, British Heart Foundation, and a National Institute for Health and Care Research Senior Investigator Award; speaking honoraria from Bayer; speaking and chairing honoraria from Alexion and Novo Nordisk; consultancy fees from Alnylam, Bayer, and Novo Nordisk; is chief investigator for the PROHIBIT-ICH and OPTIMAS trials; and participated on DSMB or advisory boards for OXHARP DSMB, and the LACI-2, TICH-2, TICH-3, RESTART, MACE-ICH, and PLINTH Trial Steering Committees. All other authors report no competing interests.
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