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

Comment on ‘Apixaban for stroke prevention in subclinical atrial fibrillation’ which was presented at the 2023 American Heart Association Scientific Sessions and published in the New England Journal of Medicine, https://doi.org/10.1056/NEJMoa2310234. 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 CHA2DS2-VASc score ≥3; age ≥75; or a history of stroke). Overall, 4012 patients (mean age ± standard deviation 77 ±8 years; 36% women; mean CHA2DS2-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). Subclinical atrial fibrillation (AF), consisting of brief asymptomatic episodes of AF, detected by continuous arrhythmia monitoring and lasting 6 min or longer but <24 h, can be diagnosed in approximately one-third of patients with a cardiac pacemaker, defibrillator, or implantable cardiac monitor and is associated with a 2.5-fold greater risk of stroke.2,3 However, the absolute increase in stroke risk in patients with subclinical AF is substantially lower than the risk increase observed among those with clinical AF,4 so there is an open question as to whether oral anticoagulation should be used in patients with subclinical AF and other atrial high-rate episodes (AHREs).5 Although the terms subclinical AF and AHREs are sometimes used interchangeably, they may not reflect the same pathophysiology.5 Clinical guidelines and consensus statements have proposed considering oral anticoagulant treatment in high-risk or very high-risk patients based on clinical characteristics or long AHREs, when a clinical benefit is expected. At the same time, given the lack of data, the guidelines called for further randomized trials in this clinical setting.6 The Apixaban for the Reduction of Thrombo-Embolism in Patients with Device-Detected Subclinical Atrial Fibrillation (ARTESIA) trial was designed to address this uncertainty and found that oral anticoagulation with apixaban significantly reduced the risk of ischaemic stroke or systemic embolism and the severity of stroke when compared to antiplatelet therapy with low-dose aspirin. As expected, there was a higher rate of major bleeding in patients randomized to anticoagulant therapy, as reported by previous major studies in AF.4 In the ARTESIA trial, the comparator was aspirin, known to be effective in preventing stroke in patients with previous stroke, but whether it reduces the risk of stroke among patients with AF is controversial.7 The use of aspirin in the control group probably mitigated the signal for harm, because aspirin is known to increase bleeding. Although the severity of the averted strokes and the caused major bleeds cannot be easily compared, it should be emphasized that both all-cause mortality and death from cardiovascular causes were comparable in the two treatment groups. Moreover, the risk of the composite of stroke, systemic embolism, or death from cardiovascular causes was similar for patients assigned to receive apixaban and those assigned to receive aspirin.1 The results of the ARTESIA trial must be seen vis-à-vis the recently published NOAH-AFNET 6 (Non–vitamin K antagonist Oral anticoagulants in patients with Atrial High-rate episodes) trial, which randomized 2538 participants with AHREs and clinical risk factors for stroke to edoxaban or control (aspirin or placebo according to clinical indication).8 It should be emphasized that both trials were stopped prematurely, a fact responsible for the statistical uncertainty surrounding their point estimates for the primary efficacy endpoint. Although there were differences in the study population, randomized treatments, and primary efficacy outcomes, with NOAH-AFNET 6 including death from cardiovascular causes, a meta-analysis of NOAH-AFNET 6 and ARTESIA found that the two studies gave consistent results and that oral anticoagulation with edoxaban or apixaban may reduce the risk of stroke by approximately one-third and increase the risk of major bleeding by ∼60%.9 The annual rate of stroke was lower than expected in both trials (1.1% in the control group in the NOAH-AFNET 6 trial and 1.2% in the aspirin group in the ARTESIA trial).1,8 These values are about two-thirds lower than the ischaemic stroke risk reported among patients with clinical AF.4 Therefore, a key message from both trials is that the incidence of stroke among (mostly, aspirin-treated) patients with subclinical AF is relatively low. However, it should be emphasized that about one-quarter of participants in the ARTESIA study converted to open-label anticoagulation therapy due to the development of device-detected AF episodes lasting >24 h or clinical AF. These findings support the consideration of oral anticoagulation for patients with device-detected AF through a process of shared decision-making that takes into account predicted risks and modifiable risk factors of the individual patient, as well as his/her values and preferences. The study findings had been expected to have broader implications for the role of population-based AF screening, given the proliferation of wearable cardiac monitors and direct-to-consumer devices.10–12 However, the ARTESIA results directly apply only to patients who are already at increased risk of stroke in whom subclinical AF is detected by an implanted device and in a predominantly White population. Future randomized trials and real-world data may provide information on specific subgroups of patients in whom the benefits of anticoagulation clearly outweigh the risks of bleeding. At present, the substantially uncertain balance between reducing the risk of stroke and increasing the risk of major bleeding suggests caution before routine implementation of this strategy in clinical practice. G.L. reports personal fees for speaker bureau from Astra Zeneca, Boehringer Ingelheim, Novo Nordisk, Daiichi Sankyo, Sanofi, and Novartis, outside the submitted work. C.P. reports personal fees from AbbVie, Acticor Biotech, Bayer, Eli Lilly, and Tremeau and grant support (to the Institution) for investigator-initiated research from AIFA (Italian Drug Agency), Bayer, Cancer Research UK, and European Commission; he chaired the Scientific Advisory Board of the International Aspirin Foundation.

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