By Michael H. Crawford, MD, Editor
SYNOPSIS: A randomized controlled trial of apixaban vs. low-dose aspirin therapy for subclinical atrial fibrillation detected by implanted electrophysiologic devices showed that apixaban is associated with fewer strokes, but more major bleeding episodes compared to aspirin.
SOURCE: Healey JS, Lopes RD, Granger CB, et al. Apixaban for stroke prevention in subclinical atrial fibrillation. N Engl J Med 2023; Nov 12. doi: 10.1056/NEJMoa2310234. [Online ahead of print]. Presented at the American Heart Association Annual Scientific Sessions, Nov. 11-13, 2023.
Implanted electrophysiologic devices have the capability of continuous monitoring of the heart rhythm, much like an externally worn electrocardiogram (ECG) monitor. This monitoring has revealed that short asymptomatic bursts of atrial fibrillation (AF) are common and increase the risk of stroke or systemic embolism (SSE) by 2.5% for an absolute increase in risk of about 1% per year. Because of the bleeding risk of oral anticoagulants and aspirin, it is unclear whether to treat such patients. Hence, a randomized controlled trial, Apixaban for the Reduction of Thrombo-Embolism in Patients with Device-Detected Subclinical Atrial Fibrillation (ARTESiA) was conducted in 247 centers in 16 European or North American countries.
Entry criteria included an asymptomatic atrial fibrillation (AF) episode lasting ≥ 6 minutes but < 24 hours, age ≥ 55 years, and a CHA2DS2-VASc score ≥ 3. Excluded were patients with a history of AF, another indication for anticoagulation, uncorrected major bleeding in the last six months, and a creatinine clearance of < 25 mL/min. Open-label aspirin use was permitted but discouraged, but dual antiplatelet therapy was not permitted. The subjects were randomized to apixaban per the label or aspirin 81 mg/day. If an AF episode lasted more than two hours or if clinical AF developed, the study drug was discontinued and oral anticoagulation started, but the patients were followed.
The primary outcome was SSE, and the primary safety outcome was major bleeding. Secondary outcomes included mortality and the type of stroke. The study was stopped early because of low enrollment and withdrawal of support. A total of 4,012 patients with a mean CHA2DS2-VASc score of 4 (mean age 77 years, 36% women) were enrolled in ARTESiA between 2015 and 2023 and followed for a median of 3.5 years in the intention to treat (ITT) group and 2.5 years in the on-treatment (OT) group. The median duration of detected AF was 1.5 hours. The primary outcome in the ITT group occurred in 55 patients in the apixaban group and in 86 patients in the aspirin group (hazard ratio [HR], 0.63; 95% confidence interval [CI], 0.45-0.88; P = 0.007).
Severe stroke occurred in 19 patients in the apixaban group and in 37 patients in the aspirin group (HR, 0.51; 95% CI, 0.29-0.88). There was no difference in mortality. In the OT group, major bleeding occurred in 1.7% of the apixaban group and in 0.94% of the aspirin group (HR, 1.8; 95% CI, 1.26-2.57; P < 0.001). The authors concluded that among high-risk patients with subclinical AF (SCAF), apixaban significantly reduced the incidence of SSE, but it increased major bleeding compared to aspirin therapy.
COMMENTARY
The most important thing to remember in applying the results of this trial to clinical practice is that the patients studied were at high risk for stroke. All had a CHA2DS2-VASc score ≥ 3 and 81% had hypertension. Also, they had considerable cardiovascular disease, hence the presence of an implanted device that could detect AF. These were not the worried-well-fixated-on-their-Apple-watch-reported rhythm disturbances. Second, these investigators performed a previous study comparing those with SCAF to those without and showed that the risk of SSE was 0.69% per patient year (PPY) without SCAF vs. 1.69% PPY with SCAF. In comparison, this group’s study of patients with clinical AF on aspirin therapy had an SSE risk of 3.7% PPY. In ARTESiA, the aspirin group had an SSE risk of 1.24% PPY. Thus, SCAF carries a much lower risk of SSE than clinical AF. However, the authors reminded us that in the aspirin group of ARTESiA, 45% of those with an SSE had a permanent disability or died. So, SCAF deserves our attention.
ARTESiA showed that apixaban therapy in patients with SCAF was associated with 31 fewer SSE and 39 more major bleeding events compared to aspirin therapy. Accordingly, one could conclude that the results with apixaban are neutral regarding net clinical benefit. However, the authors pointed out that 90% of the major bleeding episodes were managed with conservative measures, including transfusion, rather than an invasive procedure. On the other hand, an SSE is another matter, with the reported high rates of disability and death. Thus, they argued that oral anticoagulant therapy should be considered in high-risk patients with SCAF.
There are several weaknesses to ARTESiA. They did not meet their enrollment goal, and the SSE rate was low. Also, 35% of the patients enrolled dropped out of the trial for non-protocol reasons, about 24% dropped out per protocol, and 22% died, leaving a small number of patients in each group at the end of the follow-up period. In addition, the study population was 94% white, and women were underrepresented (36%). In the apixaban group, 58% were on aspirin at baseline. We are told that aspirin use was discouraged but not prohibited, but the number continuing aspirin in the apixaban group is not provided.
My takeaway is that the incidental detection of SCAF is an occasion for shared decision-making with the patient so that the pros and cons of the decision to treat with oral anticoagulants or not is understood by all. Also, if treatment is decided upon, then efforts to mitigate any modifiable bleeding risk are warranted. Finally, especially if no treatment if decided upon, periodic surveillance for the transition to clinical AF should be done.
