A trial involving Birmingham researchers showed that patients with atrial high-rate episodes (AHREs) detected by implanted cardiac devices, but no diagnosed atrial fibrillation (AF), have worse outcomes when given a direct oral anticoagulant (DOAC).
Anticoagulant medication edoxaban, in fact, did not reduce the incidence of a composite of cardiovascular death, stroke, or systemic embolism in the patients who took part in the trial. And not only did anticoagulation not have any benefits: patients who took the medication showed a greater risk of all-cause death or major bleeding.
The findings, published in the New England Journal of Medicine, are important because they could change clinical practice: many physicians have so far been treating patients with AHRE episodes but no diagnosed AF with anticoagulation to prevent strokes. The study, called NOAH-AFNET 6, concluded that this is not only not needed, but potentially harmful – and until atrial fibrillation is documented by an electrocardiogram (ECG), anticoagulation should not be used.
“All anticoagulants increase bleeding to a certain extent, so the increased bleeding rate in patients with AHRE treated with anticoagulation was expected. However, the low stroke rate without anticoagulation was unexpected. Hence, our results can be considered practice-changing in an area where we lacked evidence. . . .”
– Professor Paulus Kirchhof
The NOAH-AFNET 6 trial
The NOAH-AFNET 6 trial, conducted at 206 sites across 18 European countries, was designed to assess whether prescribing oral anticoagulation in patients with AHRE but without AF is beneficial.
AHREs are found in about one-fifth of patients with implanted cardiac devices, including pacemakers, defibrillators, resynchronization devices, or implanted loop recorders. Many physicians have been prescribing these patients anticoagulants because stroke rate is increased in patients with AHRE, and a sizeable portion of them develops clinically detected AF over time. However, even though there are proven benefits of blood thinners in patients with AF, there wasn’t evidence of the advantages of using them in patients not yet diagnosed with AF.
Aiming to fill this gap in knowledge, the trial recruited over 2600 patients aged 65 and older, with AHREs detected by implanted devices and no history of atrial fibrillation as documented on an ECG. Patients were either given edoxaban at the dose approved for prevention of stroke in AF, or aspirin if they were in the placebo group.
The results showed that edoxaban did not significantly reduce the incidence of a composite of cardiovascular death, stroke, or systemic embolism compared with placebo, but it led to a higher incidence of a composite of death or major bleeding. As a consequence, the trial was stopped early due to safety concerns and an assessment of futility for the efficacy of edoxaban in this group of patients.
Paulus Kirchhof, Honorary Professor and former Director of the University of Birmingham’s Institute of Cardiovascular Sciences, member of the NIHR Birmingham Biomedical Research Centre (BRC), and lead author of the study, said: “All anticoagulants increase bleeding to a certain extent, so the increased bleeding rate in patients with AHRE treated with anticoagulation was expected. However, the low stroke rate without anticoagulation was unexpected. Hence, our results can be considered practice-changing in an area where we lacked evidence until NOAH-AFNET 6 reported.”
The study also involved Melanie Calvert, Professor of Outcomes Methodology at the University of Birmingham’s Institute of Applied Health Research and co-lead of the NIHR Birmingham BRC Patient-reported Outcomes research theme.