The asymptomatic condition is short-lasting and is detected only by long-term continuous monitoring with pacemakers or defibrillators. The New England Journal of Medicine recently reported the results of a trial including patients with SAF lasting 6 minutes to 24 hours.
Canadian researchers from the Population Health Research Institute at McMaster University and international colleagues randomly assigned patients in a double-blind, double-dummy design to receive apixaban at a dosage of 5 mg twice daily (2.5 mg twice daily when indicated) or aspirin at a dosage of 81 mg daily. If SAF lasting more than 24 hours or clinical atrial fibrillation (AF) developed, protocols called for the trial medication to be discontinued and anticoagulation initiated.
The study team assessed the primary efficacy outcome—stroke or systemic embolism—in the intention-to-treat population, which encompassed all of the patients who had undergone randomization. Major bleeding, the primary safety outcome, was assessed in the on-treatment population, which included all patients who had undergone randomization and received at least one dose of the assigned trial drug, with follow-up censored 5 days after permanent discontinuation of trial medication for any reason.
The 4,012 participants had a mean (±SD) age of 76.8±7.6 years and a mean CHA2DS2-VASc (congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, stroke, vascular disease, age 65 to 74 years, sex category) score of 3.9±1.1; 36.1% of them were women. After a mean follow-up of 3.5±1.8 years, stroke or systemic embolism occurred in 55 patients in the apixaban group (0.78% per patient-year) and in 86 patients in the aspirin group (1.24% per patient-year; hazard ratio [HR], 0.63; 95% CI, 0.45-0.88; P = .007), according to the study.
As for safety issues, the researchers said that in the on-treatment population, the rate of major bleeding was 1.71% per patient-year in the apixaban group and 0.94% per patient-year in the aspirin group (HR, 1.80; 95% CI, 1.26-2.57; P = .001). Fatal bleeding occurred in five patients in the apixaban group and eight patients in the aspirin group, the researchers added.
“Among patients with subclinical atrial fibrillation, apixaban resulted in a lower risk of stroke or systemic embolism than aspirin but a higher risk of major bleeding,” the authors advised.
Background information noted that AF is typically diagnosed by means of electrocardiography in patients with symptoms. In that case, vitamin K antagonists and direct-acting oral anticoagulants reduce the risk of stroke among patients with clinical AF, while increasing the risk of bleeding.
When the use of pacemakers and implantable cardioverter-defibrillators that could continuously detect and characterize atrial arrhythmias became more common 2 decades ago, clinicians noticed that short episodes of asymptomatic AF were common, even in patients with no other evidence of clinical AF and no symptoms.
The current researchers proposed the term SAF to describe AF that is asymptomatic or that produces such short-lasting, nonspecific symptoms that is not readily diagnosed by standard clinical means but is identified only with the use of long-term, continuous cardiac rhythm monitoring by an implanted cardiac pacemaker or defibrillator.
They pointed out that SAF was present in more than one-third of older patients with hypertension who had received a pacemaker and was associated with an increased risk of ischemic stroke or systemic embolism by a factor of 2.5.
“However, the absolute increase in stroke risk with subclinical atrial fibrillation was 1 percentage point per year, approximately half the risk increase observed among patients with clinically detected atrial fibrillation,” the authors wrote. “Given the bleeding risk associated with oral anticoagulants, particularly among older persons, the role of oral anticoagulation in the management of subclinical atrial fibrillation is uncertain.”
The Apixaban for the Reduction of Thrombo-Embolism in Patients with Device-Detected Subclinical Atrial Fibrillation (ARTESIA) trial was designed to determine whether apixaban would result in a lower risk of stroke or systemic embolism than aspirin and had an acceptably low risk of major bleeding in patients with risk factors for stroke who also had SAF detected by a pacemaker, defibrillator, or implantable cardiac monitor.
“The ARTESIA trial showed that among patients with episodes of subclinical atrial fibrillation and risk factors for stroke, the risk of stroke or systemic embolism was lower by 37% (95% CI, 12 to 55) with apixaban than with aspirin, and the risk of disabling or fatal stroke was lower by 49% (95% CI, 12 to 71),” the researchers wrote. “These findings are supported by the intention-to-treat analysis, in which data were not censored after the development of subclinical atrial fibrillation lasting more than 24 hours or clinical atrial fibrillation, and by the on-treatment analysis. The data make a strong case that apixaban prevents stroke in this population, given the high rate of trial-drug discontinuation in this trial. The risk of major bleeding in the on-treatment analysis was increased by a factor of 1.8 (range, 1.3 to 2.6) in the apixaban group as compared with the aspirin group.”
Since the risks are lower in these patients than in those with clinical AF, patients “…should not lead to complacency, because 37 of the 82 strokes (45%) with available data for scores on the modified Rankin scale in the aspirin group resulted in permanent disability or death,” the researchers added.
Looking at both benefits and risks, the study noted, “With apixaban as compared with aspirin, 31 fewer cases of stroke or systemic embolism were seen in the intention-to-treat analysis, as compared with 39 more major bleeding events in the on-treatment analysis. However, strokes involve permanent loss of brain tissue, whereas major bleeding is usually reversible, with most patients having complete recovery.”
The researchers added, “In the ARTESIA trial, apixaban did not results in substantially higher rates of transfusion, fatal bleeding, hemorrhagic stroke, or other intracranial hemorrhage than aspirin. In addition, although 45% of strokes among patients assigned to receive aspirin resulted in death or clinically significant long-term disability, nearly 90% of all major bleeding events in patients who received apixaban were managed with nonprocedural measures only (including blood transfusion).”
Based on the considerably greater severity of the stroke events prevented than the bleeding events caused, the researchers concluded, “We believe that these findings favor consideration of the use of oral anticoagulation for patients with risk factors for stroke in whom subclinical atrial fibrillation develops.”
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