Risk of Bleeding Following Non-Vitamin K Antagonist Oral Anticoagulant Use in Patients With Acute Ischemic Stroke Treated With Alteplase

Abstract

Importance: Current guidelines advise against intravenous alteplase therapy for treatment of acute ischemic stroke in patients previously treated with non-vitamin K antagonist oral anticoagulants (NOACs).

Objective: To evaluate the risk of bleeding and mortality after alteplase treatment for acute ischemic stroke among patients treated with NOACs compared to those not treated with NOACs.

Design, setting, and participants: This nationwide, population-based cohort study was conducted in Taiwan using data from Taiwan's National Health Insurance Research Database from January 2011 through November 2020 and included 7483 patients treated with alteplase for acute ischemic stroke. A meta-analysis incorporating the results of the study with those of previous studies was performed, and the review protocol was prospectively registered with PROSPERO.

Exposures: NOAC treatment within 2 days prior to stroke, compared to either no anticoagulant treatment or warfarin treatment.

Main outcomes and measures: The primary outcome was intracranial hemorrhage after intravenous alteplase during the index hospitalization (the hospitalization subsequent to alteplase administration). Secondary outcomes were major bleeding events and mortality during the index hospitalization. Propensity score matching was used to control potential confounders. Logistic regression was used to estimate the odds ratio (OR) of outcome events. Meta-analysis was performed using a random-effects model.

Results: Of the 7483 included patients (mean [SD] age, 67.4 [12.7] years; 2908 [38.9%] female individuals and 4575 [61.1%] male individuals), 91 (1.2%), 182 (2.4%), and 7210 (96.4%) received NOACs, warfarin, and no anticoagulants prior to their stroke, respectively. Compared to patients who were not treated with anticoagulants, those treated with NOACs did not have significantly higher risks of intracranial hemorrhage (risk difference [RD], 2.47% [95% CI, -4.23% to 9.17%]; OR, 1.37 [95% CI, 0.62-3.03]), major bleeding (RD, 4.95% [95% CI, -2.56% to 12.45%]; OR, 1.69 [95% CI, 0.83-3.45]), or in-hospital mortality (RD, -4.95% [95% CI, -10.11% to 0.22%]; OR, 0.45 [95% CI, 0.15-1.29]) in the propensity score-matched analyses. Furthermore, the risks of bleeding and mortality were not significantly different between patients treated with NOACs and those treated with warfarin. Similar results were obtained in the meta-analysis.

Conclusions and relevance: In this cohort study with meta-analysis, compared to no treatment with anticoagulants, treatment with NOACs prior to stroke was not associated with a higher risk of intracranial hemorrhage, major bleeding, or mortality in patients receiving intravenous alteplase for acute ischemic stroke.

Figure 1.. Patient Selection Flowchart

NOAC indicates non–vitamin K antagonist oral anticoagulant; OAC, oral anticoagulant; PS, propensity score. ^aThere were 28 individuals with missing data for age, sex, or income information, accounting for 0.37% of the initial eligible study population; these individuals were excluded from subsequent data extraction and analyses.

Figure 2.. Literature Search and Article Selection Flowchart

^aThe following 5 studies were included in the previous systematic review conducted by Shahjouei et al in 2020: Shahjouei et al, 2015; Seiffge et al, 2017; Suzuki et al, 2017; Xian et al, 2017; and Mowla et al, 2018. ^bThe following 3 studies were published after the last systematic review: Kam et al, 2022; Okada et al, 2022; and Meinel et al, 2023.

Figure 3.. Forest Plot of the Risk of Intracranial Hemorrhage (ICH) and Other Events According to Anticoagulation Therapy Before Stroke

NOAC indicates non–vitamin K antagonist oral anticoagulant; OAC, oral anticoagulant; OR, odds ratio.