We read with great interest the article by Hosseini et al. entitled “Thrombolysis in Direct Oral Anticoagulant-Treated Stroke Patients: Cross-Sectional Survey of Canadian Practice.” ^{Reference Hosseini, Ganesh, Almekhlafi, Menon and Singh1} The authors are to be congratulated for conducting this timely and highly relevant national survey, addressing one of the most challenging and rapidly evolving areas in contemporary acute stroke care. Systematically capturing real-world Canadian practice patterns regarding intravenous thrombolysis (IVT) in direct oral anticoagulant (DOAC)-treated patients, their work provides important insights into current heterogeneity, resource limitations and persistent clinical uncertainty. This study represents an important contribution that highlights key evidence gaps and reinforces the urgent need for more robust data to guide standardized decision-making.

The authors conducted an invite-only, web-based cross-sectional survey of 13 mostly comprehensive Canadian stroke centers to assess how acute ischemic stroke (AIS) patients on DOACs are managed with respect to IVT. They found marked variability in practice: DOAC level testing was inconsistently available and often time-consuming, and most centers (9/13) did not routinely use these levels to guide IVT decisions. ^{Reference Hosseini, Ganesh, Almekhlafi, Menon and Singh1} Regarding reversal agents, access to the dabigatran antidote idarucizumab was relatively common (69% with ready access), but 8/13 centers (61%) never used idarucizumab during the recent two years, and 5/13 centers (38%) reported using it 1–5 times for AIS patients; by contrast, access to andexanet alfa (AA) for factor Xa inhibitors was limited (only 7% with ready access), and almost all centers (92%) reported never using it. ^{Reference Hosseini, Ganesh, Almekhlafi, Menon and Singh1} This highlights significant uncertainty and evidence gaps in the management of DOAC-treated AIS patients, with a need for prospective clinical trials and clearer guidelines.

Currently, approximately 20% of IVT-eligible AIS patients are taking a DOAC at the time of the event. Historically, these patients have been excluded from trials of IVT. The European Stroke Organisation (ESO) guidelines and similar contemporary recommendations recommend against IVT in the absence of reliable coagulation assays with DOAC intake within 48 h prior to AIS. ^{Reference Berge, Whiteley and Audebert2} A major barrier to safe IVT in this population remains the lack of reliable bedside assessment of anticoagulant effects: current point-of-care assays are promising but not widely available, and mass spectrometry is impractical due to time constraints. The ESO guidelines recommend alteplase in AIS patients with recent dabigatran intake only after administration of idarucizumab or unless the results of specific coagulation tests are normal. ^{Reference Berge, Whiteley and Audebert2} AA, a recombinant decoy factor Xa protein developed to reverse factor Xa inhibitor anticoagulation, has never been endorsed for urgent procedures such as IVT. ^{Reference Berge, Whiteley and Audebert2} Consequently, most patients with recent factor Xa inhibitor ingestion and no other contraindications are excluded from IVT.

However, observational data from the Safe Implementation of Treatments in Stroke-International Stroke Thrombolysis Register (>1300 DOAC-treated AIS patients, >60% on factor Xa inhibitors) showed no differences in outcomes after IVT compared with patients without DOACs, ^{Reference Matusevicius, Säflund and Balestrino3} corroborating prior studies indicating the safety of IVT despite recent DOAC use. ^{Reference Kam, Holmes and Hernandez4} Furthermore, an international retrospective cohort including 832 thrombolysed AIS patients despite documented DOAC ingestion within 48 h found lower odds of symptomatic intracranial hemorrhage (sICH) compared with no anticoagulant use. ^{Reference Meinel, Wilson and Gensicke5} Additional single-center observations highlight that a large subset (≈28%) of patients with recent DOAC ingestion actually have minimal or no measurable anticoagulant activity, yet still remain untreated, ^{Reference Pommeranz, Lehr and Escolà6} underscoring the pharmacokinetic/pharmacodynamic variability in real-world DOAC use. Importantly, sICH rates were low and similar between IVT-treated and untreated patients, supporting the feasibility of IVT in selected DOAC-treated patients, suggesting that exclusion based solely on reported DOAC use may unnecessarily deny reperfusion therapy. Furthermore, similar observational studies suggest comparable sICH rates following tenecteplase vs alteplase in patients with recent DOAC intake and possibly support a more liberalized approach to reperfusion therapies in this setting.

These data motivate prospective trials such as the ongoing multicenter prospective randomized trial “Safety and Efficacy of Intravenous Thrombolysis in Patients With Ischemic Stroke and Direct Oral Anticoagulants Intake (DO-IT)” (NCT06571149) ⁷ that investigates safety and efficacy of IVT (with alteplase or tenecteplase) in AIS patients with recent DOAC ingestion (<48 h), with the primary outcome being a 90-day shift in modified Rankin Scale. The results of DO-IT will be pivotal to definitively inform guideline updates.

In parallel, we would like to highlight an interesting mechanistic perspective on IVT in patients taking DOACs. Drawing on experimental thrombus analyses, clots formed under DOAC exposure may differ structurally – featuring looser fibrin networks, thicker fibrin strands and greater permeability, which may enhance fibrinolytic susceptibility due to reduced thrombin-activatable fibrinolysis inhibitor activity – potentially rendering them more susceptible to IVT. ^{Reference Frol, Pretnar Oblak, Kermer, Ntaios, Papanagiotou and Šabovič8} While these findings are preliminary and derived from laboratory models, they introduce a biologically plausible hypothesis that some DOAC-treated patients might not only tolerate IVT but, under certain circumstances, also respond favorably due to intrinsic clot characteristics. The open question remains whether IVT in DOAC-treated patients could even be more effective than in those not treated with DOACs. Further work is needed before such concepts can be extrapolated clinically, but they may help inform the direction of future studies.

In conclusion, accumulating evidence supports the plausible safety of IVT in carefully selected DOAC-treated AIS patients and challenges current blanket exclusion strategies. At the same time, important uncertainties remain regarding both safety and potential efficacy – particularly with tenecteplase, now increasingly adopted as the preferred thrombolytic and across varying levels of DOAC activity. Addressing these gaps will require well-designed prospective multicenter studies with standardized protocols, systematic DOAC level assessment, predefined clinical and imaging endpoints and ideally integrated mechanistic insights. In this context, the study of Hosseini et al. ^{Reference Hosseini, Ganesh, Almekhlafi, Menon and Singh1} provides an important real-world benchmark and provides an important foundation for future trials to expand evidence-based treatment strategies in this growing patient population. Taken together, there is little doubt that the time has come to move from cautious exclusion toward evidence-based inclusion of DOAC-treated patients in reperfusion strategies.