High Residual Risk of Recurrent Stroke Seen in AF Patients on Anticoagulants

HELSINKI, Finland—Patients with atrial fibrillation (AF) who have had an ischemic stroke continue to have a high risk of recurrent stroke even when they’re treated with oral anticoagulation, a systematic review and meta-analysis shows.

Roughly one out of every six will have another ischemic stroke over the next 5 years, with about one out of every five at risk for an ischemic or hemorrhagic stroke, according to estimates presented by Jane Buckley, MB (Mater Misericordiae University Hospital, Dublin, Ireland), last week at the European Stroke Organisation Conference (ESOC) 2025.

Recurrent events were even more common among patients whose initial ischemic stroke occurred while they were taking oral anticoagulation, either with a vitamin K antagonist (VKA) or a direct oral anticoagulant (DOAC).

“I think as a community, we’ve actually become a little bit too comfortable with the idea that DOACs are sufficient in our stroke patients,” lead investigator John McCabe, MB BCh, PhD (Mater Misericordiae University Hospital), told TCTMD. “And whilst they do work at reducing stroke, the headline data would really suggest that there’s a high residual risk in these patients.”

There’s always a concern that patients are more vulnerable when they’re not adherent to prescribed treatments, so it’s important that physicians counsel patients on how critical it is to take their medications as prescribed, McCabe said.

Additional measures not related to DOAC therapy are still needed to stave off recurrent events in patients with AF as well, he said, pointing to lifestyle modification, blood pressure control, and management of diabetes as examples.

Andrei Alexandrov, MD (Banner – University Medical Center, Phoenix, AZ), who was not involved in the study, agreed, noting that there could be multiple mechanisms at play in patients who have a stroke.

“One of the messages is even if you have known A-fib and a stroke, this patient should not only see a cardiologist, but also a stroke neurologist to complete a workup for other risk factors,” Alexandrov told TCTMD. “Look at the patient as a whole and if necessary address multiple, often conflicting, stroke pathogenic mechanisms.”

In addition to ensuring patients with AF are taking oral anticoagulation if indicated, physicians need to keep an eye on blood pressure, make sure patients are taking precautions against falls, stress the importance of quitting smoking, and monitor other potential risks, he said. “These are all contributing factors, and the paper just shows that we need to stay on top of patients’ problems.”

Higher Risks in Real-world Cohorts

For the study, published simultaneously online in JAMA Neurology, the investigators collected data from 23 studies that included patients with AF and a prior ischemic stroke, had follow-up lasting at least a year, and provided information on the incidence of recurrent stroke. Together, there were 78,733 patients with 140,307 years of total follow-up. The median proportion of patients across studies who were discharged on oral anticoagulation was 92%.

The primary outcome was recurrent ischemic stroke, with a pooled overall incidence of 3.75% per year. That figure was higher in noninterventional cohort studies than in analyses derived from RCTs (4.20% vs 2.26% per year; P < 0.001 for interaction).

The pooled incidence of any recurrent stroke (ischemic or hemorrhagic) was 4.88% per year, again with a higher rate in noninterventional cohort studies than in RCTs (6.28% vs 2.68%; P < 0.001 for interaction). Intracerebral hemorrhage (ICH) occurred at a rate of 0.58% per year overall.

In the subset of patients whose initial ischemic stroke occurred while they were taking oral anticoagulation, annual rates of recurrent events were even higher—7.20% for ischemic stroke, 8.96% for any stroke, and 1.40% for ICH.

Based on these numbers, the researchers estimated that 5-year cumulative risks of recurrent events were 17.4% for ischemic stroke and 22.1% for any stroke overall and 31.2% and 37.5%, respectively, among patients who had an ischemic stroke despite use of oral anticoagulation.

Implications for Future Research, Risk Stratification

Based on the findings, “there is now a very strong rationale for new trials of prevention therapy in AF-related stroke,” McCabe said. Such studies might explore, he said, whether left atrial appendage occlusion enhances stroke protection in patients who have already had a stroke despite DOAC therapy—an approach being investigated in the ELAPSE trial.

“However, there are other opportunities that are maybe not as high tech,” McCabe said, pointing to interventions to improve DOAC adherence, blood pressure control, and management of lipids and glycemia. “I think [these] could make a big difference to outcomes.”

Along with exploring additional ways to lower recurrent stroke risk, there is a need for the field to improve risk stratification to identify patients who carry the greatest hazard and who might benefit the most from additional treatments, McCabe said, noting that the CHA₂DS₂-VASc score doesn’t perform very well in a post-stroke population.

“If I’m looking after an AF-related patient who’s had an ischemic stroke, we can’t really risk stratify these patients, and I think that’s really important because if it turns out that the best treatment is left atrial appendage occlusion, then we want to make sure that we’re not doing unnecessary invasive procedures in patients that don’t need those therapies,” he said.