Aetiology, secondary prevention strategies and outcomes of ischaemic stroke despite oral anticoagulant therapy in patients with atrial fibrillation

Alexandros A Polymeris; Thomas R Meinel; Hannah Oehler; Kyra Hölscher; Annaelle Zietz; Jan F Scheitz; Christian H Nolte; Christoph Stretz; Shadi Yaghi; Svenja Stoll; Ruihao Wang; Karl Georg Häusler; Simon Hellwig; Markus G Klammer; Simon Litmeier; Christopher R Leon Guerrero; Iman Moeini-Naghani; Patrik Michel; Davide Strambo; Alexander Salerno; Giovanni Bianco; Carlo Cereda; Timo Uphaus; Klaus Gröschel; Mira Katan; Susanne Wegener; Nils Peters; Stefan T Engelter; Philippe A Lyrer; Leo H Bonati; Lorenz Grunder; Peter Arthur Ringleb; Urs Fischer; Bernd Kallmünzer; Jan C Purrucker; David J Seiffge

doi:10.1136/jnnp-2021-328391

Aetiology, secondary prevention strategies and outcomes of ischaemic stroke despite oral anticoagulant therapy in patients with atrial fibrillation

J Neurol Neurosurg Psychiatry. 2022 Jun;93(6):588-598. doi: 10.1136/jnnp-2021-328391. Epub 2022 Apr 8.

Authors

Alexandros A Polymeris^#¹, Thomas R Meinel^#², Hannah Oehler³, Kyra Hölscher³, Annaelle Zietz¹, Jan F Scheitz⁴, Christian H Nolte⁴, Christoph Stretz⁵, Shadi Yaghi⁵, Svenja Stoll⁶, Ruihao Wang⁶, Karl Georg Häusler⁷, Simon Hellwig⁴, Markus G Klammer⁴, Simon Litmeier⁴, Christopher R Leon Guerrero⁸, Iman Moeini-Naghani⁸, Patrik Michel⁹, Davide Strambo⁹, Alexander Salerno⁹, Giovanni Bianco¹⁰, Carlo Cereda¹⁰, Timo Uphaus¹¹, Klaus Gröschel¹¹, Mira Katan^{1

12}, Susanne Wegener¹², Nils Peters^{1

13

14}, Stefan T Engelter^{1

14}, Philippe A Lyrer¹, Leo H Bonati¹, Lorenz Grunder¹⁵, Peter Arthur Ringleb³, Urs Fischer^{1

2}, Bernd Kallmünzer⁶, Jan C Purrucker^#³, David J Seiffge^#¹⁶

Affiliations

¹ Department of Neurology and Stroke Center, University Hospital Basel and University of Basel, Basel, Switzerland.
² Department of Neurology, Inselspital University Hospital and University of Bern, Bern, Switzerland.
³ Department of Neurology, Heidelberg University Hospital, Heidelberg, Germany.
⁴ Department of Neurology, Charité-Universitätsmedizin Berlin, Berlin, Germany.
⁵ Department of Neurology, The Warren Alpert Medical School of Brown University, Providence, Rhode Island, USA.
⁶ Department of Neurology, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg (FAU), Erlangen, Germany.
⁷ Department of Neurology, University Hospital Würzburg, Würzburg, Germany.
⁸ Department of Neurology, The George Washington University, Washington, DC, USA.
⁹ Service of Neurology, Department of Clinical Neurosciences, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.
¹⁰ Stroke Center, Neurology Department, Neurocenter of Southern Switzerland EOC, Lugano, Ticino, Switzerland.
¹¹ Department of Neurology, University Hospital Mainz, Mainz, Germany.
¹² Department of Neurology, University Hospital and University of Zurich, Zurich, Switzerland.
¹³ Stroke Center, Klinik Hirslanden Zurich, Zurich, Switzerland.
¹⁴ Neurology and Neurorehabilitation, University Department of Geriatric Medicine Felix Platter, University of Basel, Basel, Switzerland.
¹⁵ Department of Neuroradiology, Inselspital University Hospital and University of Bern, Bern, Switzerland.
¹⁶ Department of Neurology, Inselspital University Hospital and University of Bern, Bern, Switzerland david.seiffge@insel.ch.

^# Contributed equally.

Abstract

Objective: To investigate the aetiology, subsequent preventive strategies and outcomes of stroke despite anticoagulation in patients with atrial fibrillation (AF).

Methods: We analysed consecutive patients with AF with an index imaging-proven ischaemic stroke despite vitamin K-antagonist (VKA) or direct oral anticoagulant (DOAC) treatment across 11 stroke centres. We classified stroke aetiology as: (i) competing stroke mechanism other than AF-related cardioembolism; (ii) insufficient anticoagulation (non-adherence or low anticoagulant activity measured with drug-specific assays); or, (iii) AF-related cardioembolism despite sufficient anticoagulation. We investigated subsequent preventive strategies with regard to the primary (composite of recurrent ischaemic stroke, intracranial haemorrhage, death) and secondary endpoint (recurrent ischaemic stroke) within 3 months after index stroke.

Results: Among 2946 patients (median age 81 years; 48% women; 43% VKA, 57% DOAC), stroke aetiology was competing mechanism in 713 patients (24%), insufficient anticoagulation in 934 (32%) and cardioembolism despite sufficient anticoagulation in 1299 (44%). We found high rates of the primary (27% of patients; completeness 91.6%) and secondary endpoint (4.6%; completeness 88.5%). Only DOAC (vs VKA) treatment after index stroke showed lower odds for both endpoints (primary: adjusted OR (aOR) (95% CI) 0.49 (0.32 to 0.73); secondary: 0.44 (0.24 to 0.80)), but not switching between different DOAC types. Adding antiplatelets showed higher odds for both endpoints (primary: aOR (95% CI) 1.99 (1.25 to 3.15); secondary: 2.66 (1.40 to 5.04)). Only few patients (1%) received left atrial appendage occlusion as additional preventive strategy.

Conclusions: Stroke despite anticoagulation comprises heterogeneous aetiologies and cardioembolism despite sufficient anticoagulation is most common. While DOAC were associated with better outcomes than VKA, adding antiplatelets was linked to worse outcomes in these high-risk patients. Our findings indicate that individualised and novel preventive strategies beyond the currently available anticoagulants are needed.

Trial registration number: ISRCTN48292829.

Keywords: atrial fibrillation; etiology; outcome; prevention strategies; stroke despite anticoagulation.

MeSH terms

Administration, Oral
Aged, 80 and over
Anticoagulants / adverse effects
Atrial Fibrillation* / complications
Atrial Fibrillation* / drug therapy
Brain Ischemia* / etiology
Brain Ischemia* / prevention & control
Female
Humans
Ischemic Stroke*
Male
Secondary Prevention
Stroke* / drug therapy
Stroke* / etiology
Stroke* / prevention & control

Substances

Anticoagulants