ARTESIA: Apixaban reduces the risk of stroke in subclinical AF, with an increase in major non-fatal bleeding

By Lucas Marinacci on

Key Points

  • This randomized trial of 4012 patients (median age ~77, mean CHA2DS2VASC ~4, ~65% male) with an implanted pacemaker, defibrillator, or cardiac monitor with subclinical atrial fibrillation (SCAF) found that apixaban significant reduced stroke and systemic embolism compared with aspirin.
  • Major bleeding was higher in the anticoagulation group in both on treatment and intention to treat analyses, but rates of fatal bleeding and symptomatic intracranial hemorrhage were similar and numerically fewer in the apixaban arm.

SCAF is defined as asymptomatic AF detected only with long term continuous monitoring such as pacemakers and defibrillators.  It is associated with a 2.5 fold increase in stroke, but the risk is thought to be 4-5 fold lower than with overt, clinical AF.  Despite this increase in stroke risk, the role of anticoagulation in this population is unclear. 

On November 12, 2023 the results of the “ARTESIA Trial: Apixaban for Stroke Prevention in Subclinical Atrial Fibrillation” were presented at AHA Scientific Sessions 2023 with simultaneous publication in the New England Journal of Medicine.1   

This randomized, double-blind, double-dummy trial compared apixaban (dose per label insert at 5mg or 2.5mg twice a day) with aspirin 80-100mg once a day among patients with device-detected SCAF lasing 6 minutes to 24 hours.  Patients must have been age >=55 with a CHA2DS2-VASC of at least 3 or age >= 75 years, or else have a history of stroke.  The primary endpoint was stroke or systemic embolism.  The safety endpoint was ISTH major bleeding, subclassified by presentation and clinical course. 

The intention to treat population included 4012 patients randomized in 247 centers in 16 countries.  While 99% of the patient took at least 1 dose of study medication, about ¼ of the patient stopped the study medication due to SCAF lasting more than 24 hours or the development of clinical AF at the median follow up of 1.5 years and 1/3 stopped study medications for other reasons.  The mean follow up time was 3.5+/- 1.8 years; 22% of patients died and ~3% withdrew or were lost to follow up.  The authors performed an intention to treat (ITT) analysis with left censoring at time of SCAF > 24 hours or clinical AF, as well as an ITT analysis without censoring.  The primary analysis for bleeding pre-specified an on-treatment analysis, but an ITT was also performed. 

There were 2015 patients in the apixaban arm and 1997 in the aspirin arm.  Baseline characteristics were comparable between the two groups: mean age of ~77, ~36% female, mean CHA2DS2-VASC of ~4, and a ~9% rate of prior stroke, systemic embolism or TIA.  Time of longest episode of SCAF and use of other anti-platelet agent were also similar. 

Apixaban was associated with a significantly lower rate of the primary outcome of strok3 or systemic embolism (0.78% per year versus 1.24% per year [HR 0.69, 95% CI 0.45, 0.88; p = 0.007]).  Rates of hemorrhagic stroke were not significantly different and numerically higher in the aspirin arm. There was no significant difference in rates of cardiovascular death.  For the on-treatment safety analysis, the risk of major bleeding was higher in the apixaban (1.71%/ year) compared to the aspirin (0.94%/year; HR 1.80, 95% CI 1.26,2.57; p=0.001).  There was no significant difference found in the rates of fatal bleeding or symptomatic intracranial hemorrhage (both numerically higher in the aspirin arm) or transfusion requirement (numerically higher in the apixaban arm).  

In a benefit to risk analysis, the authors found every 4.6 strokes or embolic events prevented by apixaban per thousand patient years there were 4.1 more major bleeding events; 45% of strokes on ASA were permanently disabling or fatal, which was reduced by 49% with apixaban.  

Professor Jeff Healey of the Population Health Research Institute of McMaster University in Hamilton, Ontario, Canada concluded: “Apixaban reduces the risk pf stroke or systemic embolism in patients with subclinical AF…and increases major bleeding.  But no increase in fatal or intracranial bleeding was detected.  Anticoagulation should be considered for patients with SCAF who have additional stroke risk factors.”