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

Abstract

ImportanceCurrent guidelines advise against intravenous alteplase therapy for treatment of acute ischemic stroke in patients previously treated with non–vitamin K antagonist oral anticoagulants (NOACs).ObjectiveTo 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 ParticipantsThis 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.ExposuresNOAC treatment within 2 days prior to stroke, compared to either no anticoagulant treatment or warfarin treatment.Main Outcomes and MeasuresThe 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.ResultsOf 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 RelevanceIn 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.

Inconclusive Findings in Non-Vitamin K Antagonist Oral Anticoagulants Study

“…To the Editor We read with interest the nationwide population-based cohort study with meta-analysis by Tsai et al The study findings showed that patients who received non-vitamin K antagonist oral anticoagulants (NOACs) before a stroke, compared with those receiving warfarin and those without oral anticoagulant treatment (non-OAC), did not experience a higher risk of intracranial hemorrhage (ICH), major bleeding events, or mortality when treated with intravenous alteplase for acute ischemic stroke. In comparison with the active comparator (warfarin group), the odds ratios (ORs) were 0.88 (95% CI, 0.32-2.40) for ICH, 0.82 (95% CI, 0.34-1.97) for major bleeding, and 0.31 (95% CI, 0.08-1.18) for in-hospital mortality.…”

Inconclusive Findings in Non-Vitamin K Antagonist Oral Anticoagulants Study—In Reply

“…Regarding the results on intracranial hemorrhage (ICH) development, the primary outcome measure in our study was the development of any type of ICH, including symptomatic or asymptomatic ICH. We used codes 433 and 434 from the International Classification of Diseases, Ninth Revision, Clinical Modification and codes I63 and I64 from the International Statistical Classification of Diseases, Tenth Revision, Clinical Modification during the index hospitalization per the Taiwan National Health Insurance Research Database records.…”

Inconclusive Findings in Non-Vitamin K Antagonist Oral Anticoagulants Study

“…To the Editor In their population-based cohort study using Taiwan’s National Health Insurance Research Database, Tsai et al report no excess risk of intracranial hemorrhage (ICH) associated with treatment compared with no treatment with non-vitamin K antagonist oral anticoagulants (NOACs) in patients with acute ischemic stroke receiving intravenous alteplase. We applaud the authors’ efforts to build on the evidence on the safety of thrombolysis in patients receiving NOACs; however, we wonder about potential issues of exposure and outcome misclassification producing results that are biased toward the null hypothesis.…”

“…The authors used prescriptions for anticoagulants from insurance claims data to identify exposed and unexposed groups of patients who were treated compared with untreated with NOACs, respectively . Although these data are relatively complete and generally superior to self-reported use of medication, they do not capture medication nonadherence.…”

“…When patients miss 1 or 2 doses of their anticoagulant, the prescription remains active, but the patient is not actually anticoagulated. In the analysis by Tsai et al, this potential exposure misclassification may have artificially inflated the number of patients in the exposure group without the outcome given that they were never at any putative increased risk of ICH—producing bias toward the null. In other words, if there is substantive misclassification of patients untreated with NOACs (by nonadherence) as treated with NOACs (by active prescription), the magnitude of the relative effect of NOAC treatment on ICH risk may have been underestimated in this study.…”