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Observational Study
. 2019 Jun;85(6):823-834.
doi: 10.1002/ana.25489. Epub 2019 Apr 30.

Direct oral anticoagulants versus vitamin K antagonists after recent ischemic stroke in patients with atrial fibrillation

David J Seiffge  1   2   3 , Maurizio Paciaroni  4 , Duncan Wilson  2 , Masatoshi Koga  5 , Kosmas Macha  6 , Manuel Cappellari  7 , Sabine Schaedelin  8 , Clare Shakeshaft  2 , Masahito Takagi  5 , Georgios Tsivgoulis  9   10 , Bruno Bonetti  7 , Bernd Kallmünzer  6 , Shoji Arihiro  5 , Andrea Alberti  4 , Alexandros A Polymeris  1 , Gareth Ambler  11 , Sohei Yoshimura  5 , Michele Venti  4 , Leo H Bonati  1 , Keith W Muir  12 , Hiroshi Yamagami  5 , Sebastian Thilemann  1 , Riccardo Altavilla  4 , Nils Peters  1   13 , Manabu Inoue  5 , Tobias Bobinger  6 , Giancarlo Agnelli  4 , Martin M Brown  2 , Shoichiro Sato  5 , Monica Acciarresi  4 , Hans Rolf Jager  14 , Paolo Bovi  7 , Stefan Schwab  6 , Philippe Lyrer  1 , Valeria Caso  4 , Kazunori Toyoda  5 , David J Werring  2 , Stefan T Engelter  1   13 , Gian Marco De Marchis  1 ; CROMIS-2, RAF, RAF-DOAC, SAMURAI, NOACISP LONGTERM, Erlangen and Verona registry collaborators
Affiliations
Observational Study

Direct oral anticoagulants versus vitamin K antagonists after recent ischemic stroke in patients with atrial fibrillation

David J Seiffge et al. Ann Neurol. 2019 Jun.

Abstract

Objective: We compared outcomes after treatment with direct oral anticoagulants (DOACs) and vitamin K antagonists (VKAs) in patients with atrial fibrillation (AF) and a recent cerebral ischemia.

Methods: We conducted an individual patient data analysis of seven prospective cohort studies. We included patients with AF and a recent cerebral ischemia (<3 months before starting oral anticoagulation) and a minimum follow-up of 3 months. We analyzed the association between type of anticoagulation (DOAC versus VKA) with the composite primary endpoint (recurrent ischemic stroke [AIS], intracerebral hemorrhage [ICH], or mortality) using mixed-effects Cox proportional hazards regression models; we calculated adjusted hazard ratios (HRs) with 95% confidence intervals (95% CIs).

Results: We included 4,912 patients (median age, 78 years [interquartile range {IQR}, 71-84]; 2,331 [47.5%] women; median National Institute of Health Stroke Severity Scale at onset, 5 [IQR, 2-12]); 2,256 (45.9%) patients received VKAs and 2,656 (54.1%) DOACs. Median time from index event to starting oral anticoagulation was 5 days (IQR, 2-14) for VKAs and 5 days (IQR, 2-11) for DOACs (p = 0.53). There were 262 acute ischemic strokes (AISs; 4.4%/year), 71 intracranial hemorrrhages (ICHs; 1.2%/year), and 439 deaths (7.4%/year) during the total follow-up of 5,970 patient-years. Compared to VKAs, DOAC treatment was associated with reduced risks of the composite endpoint (HR, 0.82; 95% CI, 0.67-1.00; p = 0.05) and ICH (HR, 0.42; 95% CI, 0.24-0.71; p < 0.01); we found no differences for the risk of recurrent AIS (HR, 0.91; 95% CI, 0.70-1.19; p = 0.5) and mortality (HR, 0.83; 95% CI, 0.68-1.03; p = 0.09).

Interpretation: DOAC treatment commenced early after recent cerebral ischemia related to AF was associated with reduced risk of poor clinical outcomes compared to VKA, mainly attributed to lower risks of ICH. ANN NEUROL 2019;85:823-834.

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Conflict of interest statement

The following companies manufacture drugs involved in this study: Bayer (BY, rivaroxaban), Boehringer Ingelheim (BI, dabigatran), Pfizer/Bristol Meyer Squibb (PB, apixaban), and Daiichi Sankyo (DS, edoxaban). D.J.S.: scientific advisory boards: BY and PB. M.P.: honoraria as a member of the speaker bureau of BI, BY, and PB. M.K.: speaker honoraria from DS, BY, and PB. K.M. speaker honoraria from BY, travel grant from PB. L.H.B.: consultancy or advisory board fees or speaker's honoraria from BY, PB. K.W.M.: participated in advisory boards for DS and BY; member of trial steering committee for BY‐sponsored NAVIGATE‐ESUS trial. G.T.: scientific advisory boards: BY, DS, and BI. S.A.: speaker honoraria from DS, BI, and BMS/PB. H.Y.: speaker honoraria from DS, BY, BI, and BMS/PB. Research funding: PB. S.S.: employment by BY HealthCare Pharmaceuticals’ Japanese subsidiary, BY Yakuhin, from January 2018 (all his contributions to this study were made during his employment at the National Cerebral and Cardiovascular Center). N.P.: advisory boards BI, BY, and DS. K.T.: speaker honoraria from DS, BY, BI, and PB. P.A.L.: scientific advisory boards: BY, DS, and BI. Funding for travel or speaker honoraria: BY and BI. Research funding: BI. D.J.W.: speaking honoraria: BY. S.T.E.: funding for travel or speaker honoraria: BY and BI. Scientific advisory boards: BY, BI, and PB. Educational grant from PB. G.M.D.M.: travel honoraria: BY; speaker honoraria: PB.

Figures

Figure 1
Figure 1
Study flow chart.
Figure 2
Figure 2
Kaplan‐Meier curves for the composite endpoint (A), recurrent AIS (B), ICH (C), and mortality (D) for patients in both groups (VKA vs DOAC). AIS = acute ischemic stroke; DOAC = direct oral anticoagulant; ICH = intracranial hemorrhage; VKA = vitamin K antagonist. [Color figure can be viewed at www.annalsofneurology.org]
Figure 3
Figure 3
Cumulative incidence function. DOAC = direct oral anticoagulant; VKA = vitamin K antagonist.
Figure 4
Figure 4
Subgroup analyses of treatment effect in predefined subgroups for the composite endpoint (A), recurrent AIS (B), ICH (C), and mortality (D). AIS = acute ischemic stroke; DOAC = direct oral anticoagulant; HR = hazard ratio; ICH = intracranial hemorrhage; NIHSS = National Institute of Health Stroke Severity Scale; VKA = vitamin K antagonist. [Color figure can be viewed at www.annalsofneurology.org]
See this image and copyright information in PMC

References

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