Apixaban Versus Aspirin in Subclinical Atrial Fibrillation (SCAF): Major Bleeding Findings from Latest ARTESiA Sub-analysis
While the anticoagulant apixaban significantly increased the risk of major bleeding compared to aspirin in patients with subclinical atrial fibrillation (SCAF), this risk was primarily driven by non-critical gastrointestinal bleeding, according to a new sub-analysis of the ARTESiA randomized clinical trial.
It is noteworthy that the rates of fatal bleeding and serious intracranial bleeding were similar between the two treatment arms, and most major bleeding events were nonemergencies characterized by decreased hemoglobin levels greater than or equal to 2g/dL.
These findings, which characterize the type and severity of bleeding events, were published online in the month of November in the Journal of American Medical Association (JAMA) Cardiology.
Subclinical atrial fibrillation (SCAF), identified in patients using implanted rhythm devices like pacemakers, implantable cardioverter-defibrillators, or cardiac monitors, is associated with an elevated risk of stroke or systemic embolism. Although oral anticoagulation (OAC) is generally recommended for patients with clinical AF who are at high risk of stroke, the role of OAC in managing SCAF is less certain due to the generally lower absolute stroke rates observed in this population compared to the known risk of bleeding. The primary ARTESiA randomized clinical trial previously established that apixaban reduced the risk of stroke or systemic embolism by 37% compared with aspirin in SCAF patients, but this benefit was accompanied by an increased risk of major bleeding. A thorough assessment of the benefits and harms of OAC requires not only analyzing the absolute risks of stroke and major bleeding, but also understanding the specific type and severity of these adverse events.
The original ARTESiA findings indicated that apixaban reduced the risk of disabling or fatal stroke by 49% (hazard ratio [HR], 0.51; 95% CI, 0.29-0.88), suggesting that the severity of events may differ. This pre-specified sub-analysis was conducted to further characterize the major bleeding events.
This research was a pre-specified sub-analysis of the international, double-blind, double-dummy Apixaban for the Reduction of Thromboembolism in Patients with Device-Detected Subclinical Atrial Fibrillation (ARTESiA) randomized clinical trial. The trial was conducted at 247 clinical sites across 16 countries. Participants included patients with at least one SCAF episode detected by an implanted device and lasting between 6 minutes and 24 hours, who also had stroke risk factors (CHA2DS2-VASc score ≥3) or a history of prior stroke without other risk factors. Patients were randomized 1:1 in a double-blind, double-dummy design to receive either apixaban, 5 mg twice daily (with a reduced dose of 2.5 mg twice daily when meeting dose reduction criteria), or aspirin, 81 mg daily, using a web based randomization system.
The primary outcome for this sub-analysis was major bleeding, which was adjudicated by a blinded committee using the International Society on Thrombosis and Hemostasis (ISTH) criteria. The ISTH definition includes overt bleeding accompanied by a decrease in hemoglobin of ≥2 g/dL or the transfusion of ≥2 units of packed red cells, or bleeding occurring at a critical site, or resulting in death. The analysis included patients who received treatment.
The sub-analysis included 3961 patients (mean age, 76.8 years) who received treatment. After a mean follow-up period of 3.5 years, 133 patients experienced at least one major bleeding episode. The major bleeding rate was significantly higher in the apixaban group (1.71 per 100 patient-years) compared to the aspirin group (0.94 per 100 patient-years) resulting in a Hazard Ratio of 1.80 (95% CI, 1.26-2.57). Site analysis revealed that the rate of gastrointestinal bleeding was significantly higher in the apixaban group (0.89% vs 0.40% per 100 patient-years; HR, 2.23; 95% CI, 1.32-3.78). Gastrointestinal bleeding was the single most common site for index major bleeding (48.9%). Conversely, the rates of fatal bleeding (0.10% vs 0.16% per 100 patient-years; HR, 0.63) and symptomatic intracranial bleeding (0.33 vs 0.40 per 100 patient-years; HR, 0.82) were similar in both treatment arms.
Among the 133 index major bleeding events, those occurring with apixaban were less likely to be at a critical site (27.9%) compared to those with aspirin (46.8%) (P=.03). Most major bleeding events were non-emergencies, with the most frequent criterion being a decrease in hemoglobin level of ≥2 g/dL. Multivariable analysis identified four factors independently associated with an increased risk of major bleeding: NSAID use (HR, 10.25; 95% CI, 6.57-15.99), cancer (HR, 2.87; 95% CI, 1.49-5.53), randomization to apixaban (HR, 1.84; 95% CI, 1.29-2.63), and increasing age (HR, 1.47 per 5-year increase).
The findings of this sub-analysis imply that while Apixaban increased the absolute risk of major bleeding compared to aspirin, the severity and location of these bleeding events must be carefully weighed against the benefits of stroke prevention. Most major bleeding events were classified as nonclinical emergencies and required only conservative or supportive measures. Furthermore, index major bleeding events that occurred while taking apixaban were less likely to be at a critical site, including intracranial sites, compared with those taking aspirin. Given that apixaban reduced the risk of disabling or fatal stroke by 49% in the overall ARTESiA trial, understanding the type and lower severity of the most frequent major bleeding events is crucial for facilitating shared clinical decision-making.
The identification of key factors strongly associated with major bleeding, including nonsteroidal anti-inflammatory drug (NSAID) use, cancer, and increasing age, may help physicians and patients understand the spectrum and consequences of potential bleeding complications. These identified risk factors could inform individualized antithrombotic treatment plans, such as emphasizing the discontinuation of NSAIDs, to mitigate bleeding risk in SCAF patients.
Reference: Siegal DM, Sticherling C, Healey JS, et al. Major Bleeding With Apixaban vs Aspirin: A Subanalysis of the ARTESiA Randomized Clinical Trial. JAMA Cardiol. Published online November 12, 2025. doi:10.1001/jamacardio.2025.4151
