To assess short-term intracerebral hemorrhage (ICH) and 30-day mortality following intravenous thrombolysis in patients with acute ischemic stroke (AIS) who had taken direct oral anticoagulants (DOACs) within 48 hours prior to symptom onset.

The safety of intravenous thrombolysis in patients with AIS receiving active DOAC therapy remains unclear. Although current guidelines advise against its use because of potential bleeding risks, real-world evidence supporting this recommendation is limited.

We performed a retrospective comparative analysis using the TriNetX Research Network, which includes data from 111 healthcare organizations. Patients with cerebral infarction, NIHSS ≥2, and DOAC use within 48 hours before stroke onset were divided into two cohorts: those treated with intravenous thrombolysis (alteplase or tenecteplase) and those who were not. Patients with outcomes preceding the index event were excluded. Propensity score matching (1:1) was applied across 55 variables, including demographics, stroke severity, coagulation parameters, renal function, and antithrombotic therapy. Intracerebral hemorrhage and mortality were evaluated within 30 days of stroke onset.

After propensity score matching, both cohorts included 16,696 patients with comparable baseline characteristics (mean age ≈ 68 years; 50% male). Within 30 days, intracerebral hemorrhage occurred in 12.5% of the DOAC + IVT group versus 15.3% of the DOAC alone group (risk ratio 0.82, 95% CI 0.78–0.87, p < 0.001), indicating a −2.7% absolute risk reduction with thrombolysis. Mortality was also lower among thrombolysed patients (4.9% vs. 6.7%; risk ratio 0.73, 95% CI 0.67–0.80, p < 0.001). Both cohorts had a median follow-up of 30 days, ensuring uniform outcome evaluation.

Intravenous thrombolysis within 48 hours of DOAC use was not associated with higher risks of intracerebral hemorrhage or early mortality. Both outcomes were lower among treated patients, suggesting that selected anticoagulated individuals may safely benefit from reperfusion therapy. However, further studies are needed to confirm these results and refine eligibility criteria.