BOSTON — Patients who have had a stroke are thought to be at a higher risk for another one, but oral anticoagulation with edoxaban led to no discernible reduction in the risk for a second stroke, and the risk for major bleeding was more than quadruple the risk with no anticoagulation, a subanalysis of a major European trial has shown.
"There is no interaction between prior stroke or TIA (transient ischemic attack) and the treatment effect, and this is true for the primary outcome and the safety outcome," Paulus Kirchoff, MD, director of cardiology at the University Heart and Vascular Center in Hamburg, Germany, said during his presentation of a subanalysis of the NOAH-AFNET 6 trial on May 19 at the annual meeting of the Heart Rhythm Society (HRS) 2024. However, "there is a signal for more safety events in patients randomized to anticoagulation with a prior stroke."
The subanalysis involved 253 patients who had had a stroke or TIA and who had device-detected atrial fibrillation (AF) from the overall NOAH-AFNET 6 population of 2536 patients, which enrolled patients 65 years and older with at least one additional CHA2DS-VASc risk factor and patients 75 years and older with device-detected subclinical AF episodes of at least 6 minutes. Patients were randomized to either edoxaban or no anticoagulation, but 53.9% of the no-anticoagulation group was taking aspirin at trial enrollment. Anticoagulation with edoxaban was shown to have no significant impact on stroke rates or other cardiovascular outcomes.
Subanalysis Results
In the subanalysis, a composite of stroke, systemic embolism, and cardiovascular death — the primary outcome — was similar in the edoxaban and no-anticoagulation groups (14/122 patients [11.5%] vs 16/131 patients [12.2%]; 5.7% vs 6.3% per patient-year).
The rate of recurrent stroke was also similar in the edoxaban and no-anticoagulation groups (four of 122 patients [3.3%] vs six of 131 patients [4.6%]; 1.6% vs 2.3% per patient-year). And there were eight cardiovascular deaths in each group.
However, edoxaban patients had significantly higher rates of major bleeding.
"This is a subanalysis, so what we see in terms of the number of patients with events is not powered for a definitive answer, but we do see that there were 10 major bleeds in the group of patients with a prior stroke or TIA in NOAH," Kirchoff reported. "Eight of those 10 major bleeds occurred in patients randomized to edoxaban."
Results from the NOAH-AFNET 6 trial have been compared with those from the ARTESiA trial, which compared apixaban anticoagulation with aspirin in patients with subclinical AF and was also presented at HRS 2024. ARTESiA showed that apixaban significantly lowered the risk for stroke and systemic embolism.
"In ARTESiA, everyone was on aspirin when they were randomized to no anticoagulation; in NOAH, only about half were on aspirin," Kirchoff said.
Both studies had similar outcomes for cardiovascular death in the anticoagulation and no-anticoagulation groups. "It's not significant; it may be chance, but it's definitely not the reduction in death that we have seen in the anticoagulant trials," Kirchoff said. "When you look at the meta-analyses of the early anticoagulation trials, there's a one-third reduction in death, and here we're talking about a smaller reduction."
This research points to a need for a better way to evaluate stroke risk. "We need new markers," Kirchoff said. "Some of them may be in the blood or imaging, genetics maybe, and one thing that really emerges from my perspective is that we now have the first evidence to suggest that patients with a very low atrial fibrillation burden have a low stroke rate."
More research is needed to better understand AF characteristics and stroke risk, he said.
AF Care Enters a 'Gray Zone'
The NOAH-AFNET 6 results, coupled with those from ARTESiA, are changing the paradigm for anticoagulation in patients with stroke, said Taya Glotzer, MD, an electrophysiologist at the Hackensack University Medical Center in Hackensack, New Jersey, who compiled her own analysis of the studies' outcomes.
"In ARTESiA, the stroke reduction was only 0.44% a year, with a number needed to treat of 250," she said. "In the NOAH-AFNET 6 main trial, the stroke reduction was 0.2%, with the number needed to treat of 500, and in the NOAH prior stroke patients, there was a 0.7% reduction, with a number needed to treat of 143."
None of these device trials would meet the standard for a class 1 recommendation for anticoagulation with a reduction of even 1%-2% per year, she noted, but they do show that the stroke rate "is very, very low" in prior patients with stroke.
"Prior to 2024, we knew what was black and white; we knew who to anticoagulate and who not to anticoagulate. And now we are in a gray zone, trying to balance the risk of stroke and bleeding. We have to individualize or hope for substudies, perhaps using the CHA2DS-VASc score or other information about the left atrium, to help us make decisions in these patients. It's not just going to be black and white," she said.
Kirchoff had no relevant financial relationships to disclose. Glotzer disclosed financial relationships with Medtronic, Abbott, Boston Scientific, and MediaSphere Medical.