Switching oral anticoagulant therapy following breakthrough ischemic stroke was not associated with a clinically meaningful short-term advantage compared with continuing the same direct oral anticoagulant in patients with atrial fibrillation, according to findings published in JAMA Network Open.
In a multicenter, registry-based cohort study using an emulated target trial design, researchers analyzed 1,006 patients with atrial fibrillation who experienced ischemic stroke while receiving uninterrupted direct oral anticoagulant (DOAC) therapy. Breakthrough stroke was defined as occurring despite documented DOAC intake within the 7 days preceding the event, with the last dose taken within 48 hours of stroke onset.
Patients were treated at 35 stroke centers across nine countries in Europe and North Africa between February 2020 and February 2025. Following the index event, 543 patients (54%) switched to an alternative oral anticoagulant, including another DOAC or a vitamin K antagonist, and 463 (46%) continued the same DOAC.
The primary outcome was 90-day net clinical benefit, defined as recurrent ischemic stroke and moderate to severe bleeding. After adjustment using inverse probability of treatment weighting to balance baseline differences between groups, event rates were similar: 5% among patients who switched therapy and 5% among those who continued the same DOAC.
The study was designed as a noninferiority analysis, meaning it tested whether continuing the same DOAC was not unacceptably worse than switching therapy within a prespecified margin of 3 percentage points. Results met this criterion, indicating no clinically meaningful difference in short-term outcomes between strategies.
Secondary outcomes were also comparable. Recurrent ischemic stroke occurred in approximately 3% of patients in both groups, while symptomatic intracerebral hemorrhage occurred in about 1% of patients. Rates of moderate to severe bleeding were similarly low.
Noninferiority was not formally demonstrated for the broader composite of new ischemic events, defined as stroke or systemic embolism, as the upper bound of the confidence interval crossed the prespecified margin, though absolute differences between groups remained small.
Noninferiority was also not established for mortality outcomes. All-cause mortality occurred in 8.7% of patients who switched therapy and 9.3% of those who continued the same DOAC, while vascular death occurred in 4.9% and 4.4%, respectively. The researchers attributed this to wide confidence intervals rather than a signal of meaningful excess risk, as absolute differences between groups were small.
Findings were generally consistent across different switching strategies. Notably, outcomes were similar whether patients switched to another DOAC with the same mechanism of action or to one with a different pharmacologic target. This finding challenges the common clinical assumption that mechanistic switching—for example, from a factor Xa inhibitor to a direct thrombin inhibitor—may reduce residual cardioembolic risk.
Switching from a DOAC to a vitamin K antagonist was evaluated in a smaller subgroup, and although point estimates suggested lower event rates, the analysis included relatively few patients and wide uncertainty, limiting its reliability for clinical decision-making.
Approximately one-quarter of patients had a competing stroke etiology other than cardioembolism, most commonly large artery atherosclerosis. A prespecified sensitivity analysis excluding these patients yielded similar results, supporting the robustness of the findings.
The study has several limitations. As an observational analysis, treatment assignment was not randomized, and residual confounding cannot be excluded. Treatment changes during follow-up were not systematically captured, which may have reduced differences between groups. In addition, participating centers were predominantly high-volume tertiary stroke units with structured follow-up pathways, which may limit generalizability to other settings.
Overall, the findings suggest that routine switching of anticoagulant therapy solely in response to breakthrough ischemic stroke may not provide additional short-term benefit when patients are receiving appropriate and uninterrupted treatment. Clinical decisions to switch therapy may still be warranted in the context of adherence concerns, drug interactions, or alternative stroke mechanisms.
“Switching anticoagulation treatment was not associated with clinically meaningful short-term benefit compared with continuation,” wrote lead study author Lucio D’Anna, MD, PhD, of Imperial College London, and colleagues.
Disclosures: Several researchers reported relationships with pharmaceutical companies, including Bayer, Daiichi Sankyo, Boehringer Ingelheim, AstraZeneca, Pfizer, and others. No other disclosures were reported.
Source: JAMA Network Open
