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AMSTERDAM -- Edoxaban (Savaysa) didn't improve outcomes for high-risk patients with subclinical atrial fibrillation (Afib)-like episodes detected by implanted cardiac devices, the NOAH-AFNET 6 trial showed.

The direct oral anticoagulant (DOAC) yielded a 3.2% per patient-year rate of the primary composite endpoint of cardiovascular death, stroke, or systemic embolism, similar to the 4.0% per patient-year rate with a no-anticoagulation placebo (HR 0.81, 95% CI 0.60-1.08, P=0.15).

Strokes occurred in about 1% of patients in both groups, Paulus Kirchhof, MD, of the University Heart and Vascular Center Hamburg in Germany, reported here at the European Society of Cardiology (ESC) Congress.

The results were also published in the .

And, as expected, edoxaban led to an excess in the composite risk of all-cause mortality or major bleeding compared with placebo (5.9% vs 4.5% per patient-year, HR 1.31, 95% CI 1.02-1.67, P=0.03).

"We think that we have good news for our patients with atrial high-rate episodes [AHREs]," Kirchhof said at a press conference where the findings were discussed. "This trial demonstrates that anticoagulation should not be used in patients with atrial high-rate episodes until atrial fibrillation is documented by ECG. And that is a practice-changing finding, at least for many clinicians."

The cardiac electrical activity recorded during these AHREs looks like the activity recorded during Afib, and indeed 97% of the episodes were over 200 bpm with a median duration of nearly 3 hours. Presuming that this would contribute to stroke risk, some clinicians have initiated oral anticoagulant therapy, particularly for high-stroke-risk patients and for those with long-lasting AHREs.

"Will this change the guidelines?" posited ESC study discussant Elena Arbelo, MD, PhD, of the University of Barcelona. "I think the guidelines nowadays just recommend asking for ECG documentation of the arrhythmias. I think this will need to stay this way, and we must be careful indicating anticoagulation without ECG documentation."

Press conference moderator Martin Halle, MD, of the Technical University of Munich, noted that "we all expected a different result here. This is clearly changing also the mind on pathophysiology and also the way we think of how emboli develop in the left atrium," setting up further research needs.

The event-driven trial fully enrolled with 2,536 patients ages 65 and older (mean age 78 years, 37.4% women) before it 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," the researchers noted.

Enrollment required AHREs (an atrial rate of ≥170 bpm as captured on a pacemaker, defibrillator, resynchronization device, or implanted loop recorder capable of long-term rhythm monitoring) lasting for at least 6 minutes and at least one additional risk factor for stroke but no history of clinical Afib on electrocardiogram. Median CHA₂DS₂-VASc score was 4.

Participants were randomly assigned to double-blind, double-dummy treatment with edoxaban at standard doses for Afib or placebo with aspirin according to clinical indications (which 54% received).

The researchers noted that stopping early after the accrual of 184 of the 220 originally planned primary efficacy outcome events left the trial with insufficient power to detect or rule out a small beneficial effect of oral anticoagulation on the prevention of stroke, which occurred at a lower rate than expected from prior trials.

Limitations also included the trial population of predominantly white patients in Europe.

Generalizability to other DOACs was unclear, Kirchhof cautioned. There are other trials underway, notably the with apixaban for device-detected sub-clinical Afib, which is due to report results soon.

Another big question clinically is how to address atrial arrhythmias as detected by consumer wearables when no Afib is documented on an ECG.

"With these results, we may speculate that we need also to be cautious" in prescribing anticoagulation in that setting, Arbelo added.

While acknowledging that more data are coming, Kirchhof told 麻豆传媒 at a press conference that there's no reason to wait to act. "I do think that it is time to change practice, because we didn't have evidence before and now we have evidence. Whether the conclusion coming from our data is the same that we'll see in 3 or 4 years time is hard to predict, but I do think we have a robust trial. We have a clear signal for harm."

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