To Treat or Not to Treat: Low‐Dose Alteplase for Patients With Acute Ischemic Stroke Taking Direct Oral Anticoagulants Within 24 Hours

Intravenous thrombolytic therapy with recombinant tissue‐type plasminogen activator (alteplase) is the mainstay of treatment for patients with acute ischemic stroke. However, the safety of alteplase in patients with recent use of direct oral anticoagulants (DOACs) remains a matter of significant debate. Most societal guidelines recommend against the use of intravenous alteplase in patients who have taken a DOAC within the preceding 48 hours, owing to the perceived increased risk of hemorrhage, ¹ , ² though the evidence for this has never been firmly established. ³ , ⁴ , ⁵

In this issue of the Journal of the American Heart Association (JAHA), Okada et al report data that help define the safety profile of low‐dose alteplase among patients taking DOACs within 24 hours before stroke. ⁶ Unlike the United States and European guidelines, the approved dose of alteplase in Japan is 0.6 mg per kilogram owing to results of the Japan Alteplase Clinical Trial, which showed similar efficacy and a lower risk of intracerebral hemorrhage when low‐dose alteplase was used. ⁷ Moreover, the Japanese guidelines are more liberal and do not advise against the use of intravenous alteplase unless the time of the last DOAC dose is <4 hours, international normalized ratio >1.7, or activated partial thromboplastin clotting time (aPTT) exceeds at least 1.5 times the baseline value. ⁸ This unique recommendation provides an unprecedented opportunity to evaluate the safety and efficacy of intravenous thrombolysis in patients with ischemic stroke taking DOACs.

The authors used data from a single‐center stroke registry and identified patients with acute ischemic stroke who received low‐dose alteplase between March 2011 and January 2021. Among them, 40 patients had taken DOACs within 24 hours before alteplase treatment and 753 patients were on no oral anticoagulants. There were no patients who took DOACs within 24 to 48 hours before alteplase treatment. The rate of symptomatic intracranial hemorrhage was 2.5% among patients taking DOACs compared with 2.4% among patients not taking any oral anticoagulants, with no statistically significant difference between groups (adjusted odds ratio [OR], 0.95 [95% CI, 0.17–5.28]). Additional analyses showed no significant differences in rates of any intracranial hemorrhage within 36 hours (12.5% versus 16.2%; adjusted OR, 0.61 [95% CI, 0.24–1.59]) or mortality at 3 months (5.0% versus 5.7%; adjusted OR, 0.56 [95% CI, 0.10–3.14]). Moreover, the rate of favorable outcomes was comparable between groups (modified Rankin Scale of 0–2 at 3 months, 59.4% versus 58.2%; adjusted OR, 1.33 [95% CI, 0.62–2.82]), even though patients taking DOACs were older, had more cardiovascular risk factors, and experienced more severe strokes in terms of higher National Institutes of Health Stroke Scale score at baseline (median 15 versus 9). Based on these findings, it appears safe to administer low‐dose alteplase to selected patients who had taken DOACs within 24 hours before stroke onset.

The study from Okada et al has several strengths, including the exact timing of the last DOAC and prespecified statistical analysis with adjustment for potential confounders associated with outcomes. However, caution is needed in interpreting these results. First, it was an observational cohort and not a randomized clinical trial. There were several significant differences in baseline characteristics between patients taking DOACs and those who were not on any anticoagulants. Although the authors used regression analyses to adjust for variables such as age, sex, baseline National Institutes of Health Stroke Scale, and ASPECTS (Alberta Stroke Program Early CT Score) scores, adjustment for differences in medical comorbidities did not occur, and the presence of any residual or unmeasured confounding between groups may bias comparisons and outcomes. Having said that, patients on DOACs had higher prevalence of cardiovascular risk factors including atrial fibrillation, heart failure, prior ischemic stroke, and transient ischemic attack than patients not on any anticoagulants. Therefore, it could be argued that the odds of symptomatic intracranial hemorrhage would be even lower and the odds of favorable outcomes would be even higher in the DOAC group if further adjustments could be made. Second, there is strong potential for selection bias related to which patients on DOACs received alteplase. It is possible that patients on DOACs were not given thrombolysis for reasons not fully captured in the registry. The authors tried to mitigate this concern by exploring the reasons for not administering alteplase in patients on DOACs. Overall, only <5% was not treated because of elevated prothrombin time ‐international normalized ratio, aPTT, or last DOAC use immediately before stroke onset. In contrast, the large majority of patients did not receive thrombolytic therapy because of late arrival beyond 4.5 hours from stroke onset, mild stroke, rapid improvement, or large early ischemic change on admission imaging.

Third, the authors did not measure DOAC plasma levels. Therefore, it remains unknown whether additional selection criteria based on drug‐specific plasma level or other point‐of‐care laboratory test may improve selection for thrombolysis. Fourth, this study was a single‐center study and had a relatively small sample size. More importantly, low‐dose alteplase is only used in Japan and a few Asian countries. Therefore, it would be difficult to extrapolate these findings to non‐Asian populations whose metabolism and therapeutic effects of alteplase may differ or to other countries where standard dose of alteplase at 0.9 mg per kilogram is commonly used.

Although this study did not provide a definite answer to the safety of intravenous alteplase for patients with ischemic stroke with recent use of DOACs, its findings partially affirm the recommendations set forth by the Japan Stroke Society. Given the established benefit and relatively low risk of harm associated with low‐dose alteplase, future guidelines may consider omitting recent use of DOACs within 48 hours as an absolute contraindication to intravenous alteplase for patients with acute ischemic stroke.

Disclosures

Dr Xian reported receiving grants from the American Heart Association, Genentech, and receiving personal fees from Boehringer Ingelheim. Dr Kam has no disclosures to report.