AMSTERDAM — Among patients with atrial high-rate episodes detected by implantable devices, anticoagulation with edoxaban did not significantly reduce the incidence of a composite outcome of cardiovascular death, stroke, or systemic embolism in comparison with placebo but was associated with a higher bleeding risk in the NOAH-AFNET 6 trial.
Dr Paulus Kirchhof
“These results tell us that patients with atrial high-rate episodes with clinical stroke risk factors ― but who do not have clinically defined AF ― do not need blood thinners. They do not need to be anticoagulated. That is a relief,” the lead investigator of the trial, Paulus Kirchhof, MD, University Heart and Vascular Center Hamburg, in Germany, commented to theheart.org | Medscape Cardiology.
Kirchhof pointed out that this result was unexpected. “Many of us thought that because atrial high-rate episodes look like AF when they occur, then they are an indication for anticoagulation. But based on these results from the first-ever randomized trial on this population, there is no need for anticoagulation in these patients.”
Kirchhof presented the NOAH-AFNET 6 trial on Friday at the European Society of Cardiology (ESC) Congress 2023, which is being held here in Amsterdam, the Netherlands. The study was also simultaneously published in The New England Journal of Medicine.
The trial recruited patients with implanted devices that enable continuous monitoring of atrial rhythm, such as pacemakers and defibrillators. “Because we can record the rhythm day and night with these devices, they pick up small abnormalities. About 20% of these patients experience these occasional atrial high-rate episodes ― short episodes that look like AF, but they are rare and brief,” Kirchhof noted.
He explained that whether the occurrence of these atrial high-rate episodes in patients without atrial fibrillation (AF), as documented on a conventional electrocardiogram (ECG), justifies the initiation of anticoagulants has been unclear. “But this trial tells us that these episodes are different to AF that is diagnosed on ECG,” he added.
Another finding in the trial was that among these patients, there was an unexpectedly low rate of stroke, despite the patients’ having a CHADSVASC score of 4.
“Based on the result of this trial, these occasional atrial high-rate episodes do not appear to be associated with stroke. It appears quite benign,” Kirchhof said.
Implications for Wearable Technology?
He said the results may also have implications for wearable devices that pick up abnormal heart rhythm, such as smartwatches.
“We don’t know exactly what these wearable technologies are picking up, but most likely it is these atrial high-rate episodes. But we need more research on the value of these wearable technologies; we need randomized trials in this particular patient population before we consider anticoagulation in these patients,” Kirchhof stated.
The NOAH-AFNET 6 study was an event-driven, double-blind, double-dummy, randomized trial involving 2536 patients aged 65 years or older who had atrial high-rate episodes that lasted for at least 6 minutes and who had at least one additional risk factor for stroke.
Patients were randomly assigned in a 1:1 ratio to receive edoxaban or placebo. The primary efficacy outcome was a composite of cardiovascular death, stroke, or systemic embolism, evaluated in a time-to-event analysis. The safety outcome was a composite of death from any cause or major bleeding.
The mean age of the patients was 78 years, 37.4% were women, and the median duration of atrial high-rate episodes was 2.8 hours. The trial was terminated early, at a median follow-up of 21 months, on the basis of safety concerns and the results of an independent, informal assessment of futility for the efficacy of edoxaban; at termination, the planned enrollment had been completed.
Results showed that a primary efficacy outcome event occurred in 83 patients (3.2% per patient-year) in the edoxaban group and in 101 patients (4.0% per patient-year) in the placebo group (hazard ratio, 0.81; 95% CI, 0.60 – 1.08; P = .15). The incidence of stroke was approximately 1% per patient-year in both groups.
A safety outcome event occurred in 149 patients (5.9% per patient-year) in the edoxaban group and in 114 patients (4.5% per patient-year) in the placebo group (hazard ratio, 1.31; 95% CI, 1.02 – 1.67; P = .03).
ECG-diagnosed AF developed in 462 of 2536 patients (18.2% total, 8.7% per patient-year).
In the NEJM article, the authors say the findings of this trial — the low incidence of stroke that was not further reduced by treatment with edoxaban — may make it appropriate to withhold anticoagulant therapy for patients with atrial high-rate episodes.
They point out that that the main difference between the population studied in this trial and patients with atrial fibrillation (AF), as documented on an ECG, appears to be the paucity and brevity of atrial arrhythmias in patients with atrial high-rate episodes (termed low arrhythmia burden). Published reports show that a low arrhythmia burden contributes to a low incidence of stroke among patients with AF, they note.
They add that the low rate of stroke in this trial suggests that in addition to clinical risk prediction formulas for stroke, methods to improve the estimation of stroke risk among patients with infrequent atrial arrhythmias detected by long-term monitoring are needed to guide decision-making on the use of anticoagulation.
Commenting on the NOAH-AFNET 6 results for theheart.org | Medscape Cardiology, the co-moderator of the ESC HOTLINE session at which they were presented, Barbara Casadei, MD, John Radcliffe Hospital, Oxford, United Kingdom, said: “Finally we know what to with these patients. Before we just had a variety of opinions with no evidence. I think that the trial really highlights that patients who come to the doctor with symptoms of AF or who have ECG-documented AF have a much higher risk of cardioembolic stroke than patients in whom this presumed AF is picked up incidentally from implanted devices.”
She added: “The stroke rates are very low in this trial, so anticoagulation was never going to work. But this is an important finding. We know that anticoagulants are not a free lunch. There is a significant bleeding risk. These results suggest that unless a patient has clinical AF that shows up on an ECG then we need to more cautious in prescribing anticoagulation.”
Also commenting the study, immediate past president of the American College of Cardiology Ed Fry, MD, Ascension Indiana St. Vincent Heart Center, Indianapolis, said the management of patients with implanted cardiac devices or personal wearable technology that has picked up an abnormal rhythm suggestive of AF was a big question in clinical practice.
“These episodes could be AF, which comes with an increased stroke risk, but it could also be something else like atrial tachycardia or supraventricular tachycardia, which do confer an increased stroke risk,” he explained.
“This study shows that without a firm diagnosis of AF on an ECG or some sort of continuous AF monitoring device, we are going to be anticoagulating people who don’t need it. They were exposed to the risk of bleeding without getting the benefit of a reduction in stroke risk,” Fry noted.
“The important outcome from this trial is that it gives comfort in we can be more confident in withholding anticoagulation until we get a firm diagnosis of AF. If we have a high index of suspicion that this could be AF, then we can arrange for a further testing,” he added.
Second Trial Reporting Soon
A trial similar to NOAH-AFNET 6 is currently underway ― the ARTESIA trial, which is expected to be reported later this year.
“We are in close contact with the leadership of that trial, and we hope to do some meta-analysis,” Kirchof said. “But I think today we’ve gone from no evidence to one outcome-based trial which shows there is no reason to use anticoagulation in these patients with atrial high-rate episodes. I think this is reason to change practice now, but yes, of course we need to look at the data in totality once the second trial has reported.”
But the lead investigator of the ARTESIA trial, Stuart Connolly, MD, McMaster University, Hamilton, Canada, does not believe the NOAH-AFNET 6 trial should change practice at this time.
“This trial fails to adequately address the critical issue that drives clinical decision-making in these patients because it is underpowered for the most important endpoint of stroke,” he told theheart.org | Medscape Cardiology.
“The key question is whether anticoagulation reduces stroke in these patients,” he added. “To answer that, a clinical trial needs to have a lot of strokes, and this trial had very few. The trial was stopped early and had way too few strokes to properly answer this key question.”
The NOAH-AFNET 6 trial was an investigator-initiated trial funded by the German Center for Cardiovascular Research and Daiichi Sankyo Europe. Kirchhof reports research support from several drug and device companies active in AF. He is also listed as an inventor on two patents held by the University of Hamburg on AF therapy and AF markers.
European Society of Cardiology (ESC) Congress 2023: Presented August 25, 2023.
N Eng J Med. Published online August 25. Abstract
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