Objective: To investigate the timing of DOAC initiation to decrease mortality rate in the acute phase of cardioembolic stroke. Methods: This multicenter retrospective observational study using a national administrative database included 24,179 patients with acute cardioembolic stroke who received a direct oral anticoagulant (DOAC) during hospitalization between April 1st, 2012 and March 31st, 2019. Patients were divided into four groups based on the interval between admission and DOAC initiation and, according to the “1-3-6-12 day” rule. The primary outcome was 90-day in-hospital mortality. Secondary outcomes were functional disability at discharge (modified Rankin Scale ≥3) and major bleeding. The generalized estimated equation model adjusted with entropy balance weighting was used to compare the risk of outcomes. Subgroup analyses were performed by stratifying levels of consciousness on hospital admission. Results: The risk of 90-day in-hospital mortality did not vary between groups according to DOAC initiation timing. Initiation at day 3 or later was associated with an increased risk of functional disability at discharge (highest risk group: day 12-21 vs day 1-2, adjusted OR 2·99 [2·48–3·60]), and an increased risk of major bleeding (highest risk group: day 12-21 vs day 1-2, adjusted OR 2·66 [1·77–3·98]). In the subgroup analysis, patients with spontaneous arousal in whom DOAC initiation occurred at day 12 or later had an increased risk of 90-day in-hospital mortality (day 12-21 vs day 1-2, adjusted OR 1·58 [1·07–2·32]). Patients without spontaneous arousal in whom DOAC administration occurred at day 3 or later had a lower risk of 90-day in-hospital mortality (day 12-21 vs day 1-2, adjusted OR 0·57 [0·40–0·81]). Interpretation: In patients with acute cardioembolic stroke and spontaneous arousal, it may be safe and effective initiate DOAC within 2 days of hospitalization. Patients without spontaneous arousal may benefit from a delay in DOAC initiation to day 3 or later.
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