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. 2023 Jul;94(1):43-54.
doi: 10.1002/ana.26654. Epub 2023 Apr 13.

Atrial Fibrillation Detected before or after Stroke: Role of Anticoagulation

Flurina Lyrer  1 , Annaelle Zietz  1   2 , David J Seiffge  3 , Masatoshi Koga  4 , Bastian Volbers  5 , Duncan Wilson  6   7 , Bruno Bonetti  8 , Sabine Schaedelin  9 , Henrik Gensicke  1   2 , Sohei Yoshimura  4 , Kosmas Macha  5 , Gareth Ambler  10 , Sebastian Thilemann  1 , Tolga Dittrich  1 , Manabu Inoue  4 , Kaori Miwa  4 , Ruihao Wang  5 , Gabriela Siedler  5 , Luise Biburger  5 , Martin M Brown  6 , Rolf H Jäger  11 , Keith Muir  12 , Christopher Traenka  1   2 , Kanta Tanaka  4 , Masayuki Shiozawa  4 , Leo H Bonati  1   13 , Nils Peters  1   2   14 , Gregory Y H Lip  15   16 , Philippe A Lyrer  1 , Manuel Cappellari  8 , Kazunori Toyoda  4 , Bernd Kallmünzer  5 , Stefan Schwab  5 , David J Werring  6 , Stefan T Engelter  1   2 , Gian Marco De Marchis  1 , Alexandros A Polymeris  1 ; NOACISP-LONGTERM, Erlangen Registry, CROMIS-2, SAMURAI-NVAF and Verona Registry collaborators
Affiliations

Atrial Fibrillation Detected before or after Stroke: Role of Anticoagulation

Flurina Lyrer et al. Ann Neurol. 2023 Jul.

Abstract

Background: Atrial fibrillation (AF) known before ischemic stroke (KAF) has been postulated to be an independent category with a recurrence risk higher than that of AF detected after stroke (AFDAS). However, it is unknown whether this risk difference is confounded by pre-existing anticoagulation, which is most common in KAF and also indicates a high ischemic stroke recurrence risk.

Methods: Individual patient data analysis from 5 prospective cohorts of anticoagulated patients following AF-associated ischemic stroke. We compared the primary (ischemic stroke recurrence) and secondary outcome (all-cause death) among patients with AFDAS versus KAF and among anticoagulation-naïve versus previously anticoagulated patients using multivariable Cox, Fine-Gray models, and goodness-of-fit statistics to investigate the relative independent prognostic importance of AF-category and pre-existing anticoagulation.

Results: Of 4,357 patients, 1,889 (43%) had AFDAS and 2,468 (57%) had KAF, while 3,105 (71%) were anticoagulation-naïve before stroke and 1,252 (29%) were previously anticoagulated. During 6,071 patient-years of follow-up, we observed 244 recurrent strokes and 661 deaths. Only pre-existing anticoagulation (but not KAF) was independently associated with a higher hazard for stroke recurrence in both Cox and Fine-Gray models. Models incorporating pre-existing anticoagulation showed better fit than those with AF category; adding AF-category did not result in better model fit. Neither pre-existing anticoagulation nor KAF were independently associated with death.

Conclusion: Our findings challenge the notion that KAF and AFDAS are clinically relevant and distinct prognostic entities. Instead of attributing an independently high stroke recurrence risk to KAF, future research should focus on the causes of stroke despite anticoagulation to develop improved preventive treatments. ANN NEUROL 2023;94:43-54.

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Conflict of interest statement

D.J.S.: research support from Daiichi‐Sankyo (the manufacturer of the DOAC edoxaban); advisory boards and consultancy for Bayer (the manufacturer of the DOAC rivaroxaban), Portola/Alexion/AstraZeneca and VarmX (the manufacturers of the DOAC reversal agents andexanet alfa and VMX‐COO1, respectively). M.K.: speaker honoraria from Bayer Yakuhin, Daiichi‐Sankyo, research support from Daiichi‐Sankyo, Nippon Boehringer‐Ingelheim (the manufacturer of the DOAC dabigatran). B.V.: personal fees from BMS/Pfizer (the manufacturer of the DOAC apixaban), personal fees from Bayer. H.G.: advisory board honoraria from Daiichi‐Sankyo; funding for travel from BMS/Pfizer. S.T.: travel grants from BMS/Pfizer. C.T.: travel grants from Bayer. L.H.B.: consultancy or advisory board fees or speaker's honoraria from Bayer and BMS. N.P.: scientific advisory boards for Boehringer‐Ingelheim, AstraZeneca. P.A.L.: advisory boards for Boehringer‐Ingelheim, Bayer, Daiichi‐Sankyo; travel support from Pfizer. M.C.: consulting fees from Boehringer‐Ingelheim, BMS/Pfizer; advisory board Daiichi‐Sankyo. K.T.: lecture honoraria (modest) from Daiichi‐Sankyo, Bayer Yakuhin, BMS. D.J.W.: personal fees from Bayer. S.T.E.: funding for travel or speaker honoraria from Bayer, Boehringer‐Ingelheim and Daiichi‐Sankyo; scientific advisory boards for Bayer, Boehringer‐Ingelheim, BMS/Pfizer; research funding to his institutions from Pfizer (educational grant), Daiichi‐Sankyo. G.M.D.M.: travel honoraria from Bayer, BMS/Pfizer; speaker honoraria from Bayer; consultant honoraria from Bayer; member of the Steering Committee of PACIFIC Stroke (NCT04304508; investigational product: factor XIa inhibitor asundexian); Industry payments made to the research fund of the University Hospital Basel. The remaining authors declare no relevant conflicts.

Figures

FIGURE 1
FIGURE 1
Study flowchart.
FIGURE 2
FIGURE 2
Kaplan–Meier and cumulative incidence curves for recurrent ischemic stroke according to (A) AF category and (B) anticoagulation before stroke. [Color figure can be viewed at www.annalsofneurology.org]
FIGURE 3
FIGURE 3
Adjusted hazard ratio estimates for the effect of AF category and anticoagulation before stroke on ischemic stroke recurrence from Cox and Fine‐Gray models. When modelled separately, AF category shows a weaker association with ischemic stroke recurrence than anticoagulation before stroke. In the combined model, only anticoagulation before stroke but not AF category retains a strong association with ischemic stroke recurrence.
See this image and copyright information in PMC

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