How Much AF Warrants Anticoagulation? NOAH-AFNET 6 Provides Clues

John M. Mandrola, MD


August 26, 2023

An example of medical science done well is an unbiased, well-conducted, randomized controlled trial that addresses a clinically relevant question. Its "success" does not depend on finding a positive result; any result helps clinicians and patients alike.

Yesterday at the European Society of Cardiology (ESC) Congress 2023, we learned the results of such a trial. In NOAH-AFNET 6, use of edoxaban (vs placebo) in patients with short-duration atrial high-rate episodes detected on an implantable cardiac device was associated with a higher rate of adverse events and no significant reduction in stroke, systemic embolism, or cardiovascular death.

Whether to use oral anticoagulation in short-duration atrial fibrillation (AF) detected on a cardiac device is a question that comes up almost every day in my practice. My colleagues have stopped asking me my threshold AF duration for starting anticoagulation because I always give the same answer: "I have no idea; no one does." 

Primary investigator of NOAH-AFNET 6, Paulus Kirchhoff, MD, gave us strong clues that when it comes to treating short-duration AF, less beats more.

The NOAH-AFNET 6 Trial

Slightly more than 2500 patients with atrial high-rate episodes detected on an implantable cardiac device were randomly assigned to edoxaban or placebo. Their mean age was 78 years, and their median CHA2DS2-VASc score was 4. Of note, 54% of patients in the control arm received aspirin for standard indications. 

The primary endpoint was a composite of stroke, systemic embolism, and cardiovascular death.

The investigators terminated the trial prematurely after a median follow-up of 21 months for two reasons: likely futility of efficacy and harm. At the time of termination, 184 of 220 planned primary outcome events had occurred.


A primary endpoint occurred at a rate of 3.2% per patient-year in the edoxaban group vs 4.0% in the placebo group. This difference did not reach statistical significance (HR, 0.81; 95% CI, 0.60 - 1.08; P = .15).

The incidence of stroke was low and similar for both groups: 0.9% vs 1% per patient-year in the edoxaban vs placebo arms, respectively.

Adverse events, defined as major bleeding or death, occurred at a significantly higher rate in the edoxaban group (5.9% vs 4.5% per patient-year; HR, 1.31; 95% CI, 1.02 - 1.67).

The rate of electrocardiography (ECG)-diagnosed AF in the entire cohort was 18.2%, or 8.7% per patient-year.

Subgroup analyses showed no significant interactions; these included the duration of episodes, baseline stroke risk, and aspirin use.

Six Take-Homes Lessons

First, this is strong evidence against using oral anticoagulation in patients with short-duration AF. It will affect the decisions I make next week. These were older patients with many stroke risk factors and a median duration of 3 hours of AF; yet, oral anticoagulation was associated with more harm than benefit.

Second, primary investigator Paulus Kirchhoff, MD, called the results "practice changing." He may be correct, albeit slightly premature.

We should leave room for the ARTESiA trial results, which are coming soon. ARTESiA tests apixaban vs aspirin in similar patients but has a more focused primary endpoint: stroke, transient ischemic attack with imaging-confirmed cerebral infarction, and systemic embolism. Compared with NOAH, ARTESiA enrolled more patients and will follow them for longer. These design differences favor higher rates of stroke and, thus, more power to detect differences. 

The problem I foresee with ARTESiA is the choice to use aspirin in the control arm. This will create higher bleeding rates in the control group and may blunt the harm signal seen with oral anticoagulation in NOAH, where approximately half the control arm was receiving aspirin.

Third, do not be confused by the terminology atrial high-rate episodes. Electrically speaking, this is AF. Kirchhoff showed a picture of a typical episode. The atrial channel had super-fast irregular activity in the atrium. In other words, fibrillation.

Fourth, NOAH advances our knowledge of the prognosis of AF. What we called AF in the predigital age is different from what we now label AF. In the past, AF had to last long enough (or create enough symptoms) to trigger a clinician to order a standard ECG. Continuous monitoring requires neither symptoms nor long-duration AF. NOAH proves that short-duration AF is a lower-risk condition than a 12-lead ECG-defined AF. (I am beginning to believe that short-duration AF might be a condition of aging—akin to gray hair and wrinkles.)

Fifth, NOAH also demonstrates the power of randomization. I have heard people argue that trials can't be done for all clinical questions because of costs. Now consider the costs of using oral anticoagulation in millions of people with short-duration AF. Trials, I believe, pay for themselves and likely improve cost efficacy in the long run.

My sixth and final point is that NOAH enhances my pessimism about screening for AF—especially with digital devices in lower-risk patients.

Anticoagulants always come with an increase in major bleeding, so for an anticoagulant to create a net benefit, you need baseline stroke rates to be above some threshold. If the stroke rate is this low in older patients with a median CHA2DS2-VASc of 4, it would be even lower in younger smartwatch owners.

If you are going to screen for AF to reduce stroke, you will need a different parameter than short-duration AF episodes.

John Mandrola practices cardiac electrophysiology in Louisville, Kentucky, and is a writer and podcaster for Medscape. He espouses a conservative approach to medical practice. He participates in clinical research and writes often about the state of medical evidence. 

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