Papercut: Apixaban for Stroke prevention in Subclinical Atrial Fibrillation

The first thing you might say is, "Why's should I care about subclinical Atrial Fibrillation, I work in Emergency Medicine?" Perhaps, this will guide us to making better decisions on anticoagulation in patients who present with their first episode of Atrial Fibrillation and we need to cardiovert them. The decision making process, other than for the highest risk patients is not that clear.

Atrial fibrillation is the most common arrhythmia we see in the emergency department. It is the leading cause of stroke(1) and although we reduce that risk with anticoagulation, we then increase the risk of potential bleeding(2). We need to weigh up these two risks and determine if we treat or not.

Subclinical atrial fibrillation is asymptomatic atrial fibrillation, or atrial fibrillation causing non-specific symptoms, that are not clinically detected, unless it is detected in continuous cardiac monitoring by implanted cardiac devices. It has been found to be present in more than 30% of some patient groups, increasing the stroke risk by a factor of 2.5(3). That stroke risk is only increased by about a half ( 1 percent per year) of the risk of patients with clinically detected atrial fibrillation.

Should we be anticoagulating patients with this lower risk?

The Apixaban for the Reduction of Thrombo-Embolism in patients with Device-detected Subclinical Atrial Fibrillation (ARTESIA) Trial(4) asked the question: Would Apixaban result in a lower risk of stroke or systemic embolism compared to aspirin, with an acceptable low risk of bleeding, in patients with subclinical atrial fibrillation, who had risk factors for stroke?

What they did

The trial was conducted in 247 clinical sites in 16 European and North American countries.

N= 4012

Patients were randomised in double-blind, double-dummy* fashion to receive apixaban 5mg bd(or 2.5mg bd) or aspirin 81mg/day.

(*The purpose of the double-dummy approach maintains blinding when comparing different treatments, by giving participants both the active treatment and placebo.)

Patients included in the trial:

• Had to have subclinical atrial fibrillation detected for 6 minutes to 24 hours
• Had a CHA₂DS₂-VASc score of >3
• Minimum age of 55 years (7 patients younger than 55 were included)

Patients were excluded if:

• There was a history of clinical atrial fibrillation or
• The patient developed clinical atrial fibrillation
• The patient was on anticoagulation
• There were bleeding issues
• Creatinine clearance < 25 ml/min
• Subclinical atrial fibrillation > 24 hours

Primary Outcome

There was an efficacy outcome which looked at stroke or systemic embolism.

There was a primary safety outcome which was major bleeding

Other Outcomes

• Cause specific mortality
• TIA with motor deficit, aphasia or duration > 5 minutes.

What they found

Patients with subclinical atrial fibrillation, who also had risk factors for stroke had:

• Risk of stroke or systemic embolism lowered by 37% with apixaban that with aspirin.
• Risk of disabling or fatal stroke lowered by 49% with apixaban
• Risk of major bleeding with apixaban increased by a factor of 1.8, however most cases responded to supportive care.

Comparing the risk of stroke with the risk of bleeding

There were 31 less cases of stroke or systemic embolism in the Apixaban group, compared to aspirin, however there were also 39 more bleeding episodes. 45% of strokes in the aspirin group resulted in death or long term disability, 90% of major bleeding events with apixaban were managed non-procedurally. Therefore more severe stroke events were prevented, than there were bleeding events. The authors believed that oral anticoagulation should be considered.

How does this affect what we do going forward?

There is a degree of uncertainty related to who we start anticoagulation on, when they present to the emergency department with atrial fibrillation. My approach is becoming more and more one of commencing anticoagulation on all patients with a CHADS VASc score > 0. however is this right? Does the risk of stroke outweigh the risk of bleed? In the above study they anticoagulated patients who had a score of 3 or more.

Extra Note

This study needs to be compared with the Non-Vitamin K Antagonist Oral Anticoagulants in patients with Atrial High Rate Episodes) NOAH-AFNET 6 trial (5), where they randomly assigned patients with similar characteristics to this trial to receive edoxaban or placebo and the trial was prematurely terminated for futility ie., edoxaban compared to placebo did not provide benefit. There were however some distinct differences in these two studies that may explain the results.

A Meta-analysis(6) of these two trials may explain the difference. Read the Meta-analysis here.

References

1. Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation as an independent risk factor for stroke: the Framingham Study. Stroke 1991; 22: 983-8.
2. Connolly SJ, Eikelboom J, Joyner C, et al. Apixaban in patients with atrial fibrillation. N Engl J Med 2011; 364: 806-17.
3. Healey JS, Connolly SJ, Gold MR, et al. Subclinical atrial fibrillation and the risk of stroke. N Engl J Med 2012; 366: 120-9.
4. Healy J.S et al. Apixaban for Stroke Prevention in Subclinical Atrial Fibrillation. NEJM. 2024. 390;2: pp 107-117
5. Kirchhof P, et al. Anticoagulation with edoxaban in patients with atrial high-rate episodes. N Engl J Med 2023; 389: 1167-79
6. McIntyre W et al. Direct Oral Anticoagulants for Stroke Prevention in patients with Device -Detected Atrial Fibrillation: A Study-Level Meta-Analysis of the NOAH-AFNET 6 and ARTESIA Trials. Circulation 149:13:981-988.