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Publications

Journal Article Ahead of print

PubMed: 42953941 DOI: 10.1161/STROKEAHA.126.056981

Comparative Safety and Efficacy of Oral Anticoagulants in Patients With Atrial Fibrillation and Prior Ischemic Stroke: A Systematic Review and Network Meta-Analysis of Randomized-Controlled Clinical Trials.

Stroke

Authors: Nikolaos M Papageorgiou, Lina Palaiodimou, Aikaterini Theodorou, Maria-Ioanna Stefanou, Evangelos Panagiotopoulos, Aristeidis H Katsanos, Apostolos Safouris, Odysseas Kargiotis, Simona Sacco, Guillaume Turc, Urs Fischer, Pooja Khatri, Shadi Yaghi, Georgios Tsivgoulis

Affiliations

  • Second Department of Neurology, "Attikon" University Hospital, School of Medicine, National & Kapodistrian University of Athens, Greece (N.M.P. L.P. A.T. M.-I.S. E.P. A.S. G. Tsivgoulis).
  • Department of Neurology and Stroke, Eberhard-Karls University of Tübingen, Germany (M.-I.S.).
  • Division of Neurology, McMaster University and Population Health Research Institute, Hamilton, Ontario, Canada (A.Η.K.).
  • Stroke Unit, Metropolitan Hospital, Piraeus, Greece (A.S.).
  • Department of Neurology, University General Hospital of Patras, University of Patras, Rio, Greece (O.K.).
  • Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, Italy (S.S.).
  • Université Paris Cité, Institute of Psychiatry and Neuroscience of Paris (IPNP), INSERM U1266, Team Turc, France (G. Turc).
  • Department of Neurology, GHU Paris Psychiatrie et Neurosciences, France (G. Turc).
  • Department of Neurology, Inselspital Bern University Hospital, University of Bern, Switzerland (U.F.).
  • Department of Neurology, Yale University School of Medicine, New Haven, CT (P.K.).
  • Department of Neurology, The Warren Alpert Medical School of Brown University, Providence, RI (S.Y.).

Abstract

BACKGROUND

Patients with atrial fibrillation (AF) and prior ischemic stroke represent a high-risk population facing competing risks of recurrent thromboembolism and hemorrhagic complications. Although direct oral anticoagulants (DOACs) are recommended over vitamin K antagonists for stroke prevention in AF, no randomized controlled clinical trial has directly compared individual DOACs to each other in this population.

METHODS

We conducted a systematic review and frequentist random-effects network meta-analysis of randomized-controlled clinical trials enrolling patients with AF and prior ischemic stroke or transient ischemic attack. MEDLINE, Scopus, and ClinicalTrials.gov were searched from inception until May 2026. The primary outcome was any stroke. Secondary outcomes included ischemic stroke, hemorrhagic stroke, major bleeding, intracranial hemorrhage (ICH), cardiovascular mortality, and all-cause mortality. Treatment effects were expressed as risk ratios (RR) with 95% CIs.

RESULTS

The evidence network comprised 6 trials (18 395 patients) in a star-shaped structure. Each DOAC was informed by a single warfarin-controlled trial, and 2 trials used aspirin as the comparator. All between-DOAC comparisons were indirect. In the network meta-analysis, compared with warfarin, apixaban was the only agent to significantly reduce both any stroke (RR, 0.72 [95% CI, 0.53-0.97]) and major bleeding (RR, 0.73 [95% CI, 0.54-0.99]). Dabigatran, apixaban, and edoxaban each significantly reduced hemorrhagic stroke and ICH versus warfarin, whereas rivaroxaban did not reach significance for any bleeding outcome. Edoxaban was the only agent associated with significantly lower cardiovascular (RR, 0.79 [95% CI, 0.65-0.97]) and all-cause mortality (RR, 0.84 [95% CI, 0.72-0.99]). Based on indirect comparisons only, no differences between individual DOACs were observed.

CONCLUSIONS

In patients with AF and prior ischemic stroke, individual DOACs reduced intracranial and systemic bleeding relative to warfarin, although not uniformly across agents. Apixaban alone significantly reduced both any stroke and major bleeding versus warfarin, but differences between individual DOACs could not be established given the small number of trials.

REGISTRATION

URL: https://www.crd.york.ac.uk/PROSPERO/; Unique identifier: CRD420261404062.

MeSH

Anticoagulants, Mortality, Safety, Hemorrhage, Ischemic Stroke, Stroke, Hemorrhagic Stroke, Atrial Fibrillation, Secondary Prevention, Cerebrovascular Circulation, Network Meta-Analysis, Cerebrovascular Disorders, Warfarin, Direct-Acting Oral Anticoagulants, Apixaban