Balancing the benefits and risks of anticoagulation in patients with subclinical atrial fibrillation

Key points• The Apixaban for the Reduction of Thrombo-Embolism in Patients with Device-Detected Subclinical Atrial Fibrillation trial is a double-blind, double-dummy, randomized clinical trial funded by the Canadian Institutes of Health Research and an industrial partner. 1 The aim was to determine whether apixaban would result in a lower risk of stroke or systemic embolism than low-dose aspirin, with an acceptable risk of major bleeding, among patients with subclinical atrial fibrillation, detected by a pacemaker, defibrillator, or implantable cardiac monitor and lasting 6-24 h, who also had risk factors for stroke (age ≥ 55 plus a CHA 2 DS 2 -VASc score ≥3; age ≥75; or a history of stroke).• Overall, 4012 patients (mean age ± standard deviation 77 ±8 years; 36% women; mean CHA 2 DS 2 -VASc score of 3.9 ± 1.1 indicating a moderate to high risk of stroke) were randomized at 247 clinical sites in 16 European and North American countries to receive apixaban at a dose of 5 mg twice daily (or 2.5 mg twice daily in patients meeting criteria for dose reduction) or aspirin at a dose of 81 mg daily.Trial medication was to be discontinued, and anticoagulation started, if subclinical atrial fibrillation lasting >24 h or clinical atrial fibrillation developed.This occurred in 490 patients (24%) in the apixaban group and 476 patients (24%) in the aspirin group.Trial medication was discontinued for other reasons in 687 patients (34%) in the apixaban group and 697 patients (35%) in the aspirin group.The primary efficacy outcome, a composite of stroke or systemic embolism, was assessed in the intention-to-treat population.The primary safety outcome, major bleeding according to the definition of the International Society on Thrombosis and Haemostasis, was assessed in the on-treatment population.• The sample size calculation assumed a risk of 2.8% per patient-year in the control group, a crossover frequency of 8.5%, and the occurrence of 248 primary outcome events in the two groups.The trial was stopped prematurely, before reaching this number of events, because the industrial partner could no longer re-supply trial medication.• After a mean follow-up of 3.5 ± 1.8 years, the primary efficacy outcome occurred in 55 patients in the apixaban group (0.8% per patient-year) and 86 patients in the aspirin group [1.2% per patient-year; hazard ratio (HR), 0.63; 95% confidence interval (CI), 0.45-0.88;P = .007],with severe strokes (modified Rankin Scale score, 3-6) reduced by about half (HR = 0.51; 95% CI, 0.29-0.88) in the apixaban group.All-cause death (5.1% vs. 4.8%; HR 1.04; 95% CI 0.90-1.21)or cardiovascular death (1.5% vs. 1.5%;HR 0.96; 95% CI 0.73-1.25)did not differ between groups.• The major bleeding rate was 1.7% per patient-year in the apixaban group and 0.9% per patient-year in the aspirin group (HR, 1.80; 95% CI, 1.26-2.57;P = .001),with gastrointestinal bleeding explaining ∼60% of the excess risk, but no difference in less frequent symptomatic intracranial haemorrhage or fatal bleeding.• In a benefit-to-risk analysis, the use of apixaban instead of aspirin was responsible for 46 fewer strokes/emboli and 77 more major bleeds per 10 000 patient-years (number-needed-to-treat = 217 vs. number-needed-to-harm = 130).