For patients with atrial fibrillation (AF) who sustained an ischaemic stroke while receiving direct oral anticoagulant (DOAC) therapy, switching to another anticoagulation agent does not yield significant improvements in most clinical outcomes compared with staying on the same agent, according to the results of an emulated target trial.
The primary outcome of 90-day net clinical benefit, defined as recurrent ischaemic stroke and moderate to severe bleeding, did not differ between the switching and continuation groups (4.9 percent vs 5.1 percent, respectively), with a risk difference of −0.3 percentage points (90 percent confidence interval [CI], −2.7 to 2.1) that met the prespecified noninferiority criterion. [JAMA Netw Open 2026;9:e269584]
Recurrent ischaemic stroke rates at 90 days were also similar (2.9 percent vs 3.1 percent; risk difference, −0.2 percentage points, 90 percent CI, −2.1 to 1.7). However, new ischemic events 90 days after the index event occurred more frequently in the switching group than in the continuation group (8 percent vs 7.4 percent; risk difference, 0.6 percentage points, 90 percent CI, −2.4 to 3.7).
In terms of safety, the 90-day symptomatic intracranial haemorrhage (ICH) event rates were low and similar between the switching and continuation groups, at 0.9 percent and 1.2 percent, respectively (risk difference, −0.4 percentage points, 90 percent CI, −1.7 to 1.0). The 90-day moderate to severe extracranial bleeding event rates were also comparable between the two groups (2.2 percent vs 2.7 percent; risk difference, −0.6 percentage points, 90 percent CI, −2.3 to 1.2). The differences were within the predefined noninferiority margins.
The risk of all-cause mortality was lower in the switching group (8.7 percent vs 9.3 percent; risk difference, −0.6 percentage points, 90 percent CI, −4.0 to 2.7), whereas the risk of vascular death was lower in the continuation group (4.9 percent vs 4.4 percent; risk difference, 0.5 percentage points, 90 percent CI, −1.9 to 2.9).
Similar results were observed regardless of whether the alternative agent patients switched to had the same mechanism of action as their initial DOAC or had a different pharmacologic target.
“In other words, no clinically meaningful differences in 90-day net clinical benefit emerged between switching within the same class and switching across mechanisms,” the investigators pointed out.
“These strategy-specific analyses reinforce the overall finding that no alternative anticoagulation strategy demonstrated clear clinical advantage over continuation of the same DOAC following a breakthrough ischaemic stroke. Thus, mechanistic switching—for example, from a factor Xa inhibitor to a direct thrombin inhibitor—is unlikely to mitigate the residual cardioembolic risk underlying breakthrough strokes,” they added.
A simpler strategy
“Our results challenge the empirical practice of switching anticoagulants after a breakthrough stroke,” the investigators said.
“When poor adherence, inappropriate dosing, and alternative stroke mechanisms have been ruled out, continuation of the same DOAC may represent a safer and simpler strategy, avoiding the transient loss of anticoagulant protection, dosing errors, and uncertainty associated with switching,” they added.
The investigators emphasized that while transitions in anticoagulant therapy may be warranted to accommodate patient preference, manage drug-drug interactions, or navigate specific contraindications, switching agents after a breakthrough stroke does not represent an established strategy for reducing the risk of further recurrences.
“The noninferiority framework allowed us to address the clinically relevant question of whether switching anticoagulation confers a meaningful advantage over continuation, rather than merely testing for statistical differences between groups. In this context, the key concern is not whether the two strategies differ, but whether continuation results in an excess risk beyond a clinically acceptable threshold. This approach [of prespecifying margins of tolerable risk] provides a direct and interpretable assessment of clinical equivalence in practice,” they explained.
The study included 1,006 consecutive adult patients (median age 80.4 years, 50 percent male) with AF who experienced a breakthrough ischaemic stroke while receiving uninterrupted DOAC therapy and subsequently resumed anticoagulation therapy. These patients were enrolled across 35 stroke centres in nine countries in Europe and North Africa and underwent a standardized 90-day follow-up.
Of the patients, 463 (46 percent) continued the same DOAC therapy and 543 (54 percent) switched to another agent following a breakthrough stroke. The median NIHSS score was 9.
Randomized controlled trials are needed to define subgroups who may benefit from treatment modification, according to the investigators.