Rationale and design of the Apixaban for the Reduction of Thrombo-Embolism in Patients With Device-Detected Sub-Clinical Atrial Fibrillation (ARTESiA) trial

doi:10.1016/j.ahj.2017.04.008

American Heart Journal

Volume 189, July 2017, Pages 137-145

https://doi.org/10.1016/j.ahj.2017.04.008 Get rights and content

Background

Device-detected subclinical atrial fibrillation (AF) refers to infrequent, short-lasting, asymptomatic AF that is detected only with long-term continuous monitoring. Subclinical AF is common and associated with an increased risk of stroke; however, the risk of stroke with subclinical AF is lower than for clinical AF, and very few patients with subclinical AF alone have been included in large AF anticoagulation trials. The net benefit of anticoagulation in patients with subclinical AF is unknown.

Design

ARTESiA is a prospective, multicenter, double-blind, randomized controlled trial, recruiting patients with subclinical AF detected by an implanted pacemaker, defibrillator, or cardiac monitor, and who have additional risk factors for stroke. Patients with clinical AF documented by surface electrocardiogram will be excluded from the study. Participants will be randomized to receive either apixaban (according to standard AF dosing) or aspirin 81 mg daily. The primary outcome is the composite of stroke, transient ischemic attack with diffusion-weighted magnetic resonance imaging evidence of cerebral infarction, and systemic embolism. Approximately 4,000 patients will be enrolled from around 230 clinical sites, with an anticipated mean follow-up of 36 months until 248 adjudicated primary outcome events have occurred.

Summary

ARTESiA will determine whether oral anticoagulation therapy with apixaban compared with aspirin reduces the risk of stroke or systemic embolism in patients with subclinical AF and additional risk factors.

Section snippets

Subclinical AF and stroke risk

Several studies have shown an association between the presence of subclinical AF and the risk of stroke. The summarized results of the trials that have investigated the risk of stroke associated with subclinical AF have recently been published.⁴ In the Mode Selection Trial in Sinus Node Dysfunction study, patients with sinus node dysfunction were randomized to dual-chamber rate-modulated or single-chamber ventricular pacing. In a subgroup analysis of this study, the presence of subclinical AF,

Anticoagulation therapy for stroke prevention in AF and subclinical AF

The overall efficacy of anticoagulation therapy for stroke prevention in AF has been well established.⁷ More recently, the efficacy and safety of non–vitamin K antagonist oral anticoagulants for stroke prevention have been established in pivotal phase 3 trials with thousands of patients.8., 9., 10., 11. Overall, when compared with warfarin, non–vitamin K antagonist oral anticoagulants significantly reduced the risk of stroke, intracranial hemorrhage, and mortality, with similar risk for major

Study overview

ARTESiA (ClinicalTrials.govNo. NCT01938248) is a prospective, multicenter, double-blind, randomized controlled trial that will recruit patients with subclinical AF detected by either a pacemaker, ICD, or insertable cardiac monitor, and who also have other risk factors for stroke and no requirement for anticoagulation therapy. Eligible, consenting patients will be enrolled and randomized to receive aspirin or apixaban. The study will be conducted at approximately 230 sites in the United States,

Discussion

Subclinical AF is characterized by relatively short episodes of atrial high-rate arrhythmias that are detected only with continuous monitoring and are mostly asymptomatic. Subclinical AF differs from clinically overt AF, which occurs more often, with symptoms, and is documented on ECG. Several studies have shown an association between the presence of subclinical AF and the risk of stroke.2., 3., 4., 5.

However, there is debate on the minimum duration of subclinical AF that is required to confer

Conclusions

The ARTESiA trial will compare apixaban with aspirin to reduce the risk of stroke in patients with subclinical AF and additional risk factors for stroke. The study findings will generate evidence to address this gap in scientific knowledge and will help inform antithrombotic strategies for these patients.

Disclosures

Dr Lopes's disclosures are available at https://dcri.org/about-us/conflict-of-interest. Dr Alings has served on advisory boards/speaker bureau for Bayer, Bristol-Myers Squib, Boehringer Ingelheim, Daiichi Sankyo, and Pfizer. Dr Connolly has received consulting fees and research support from Boehringer Ingelheim, Pfizer, Bristol-Myers Squibb, Bayer, Portola, Medtronic, St Jude Medical, and Daiichi Sankyo. Dr Granger has received consulting and research funding from Bristol-Myers Squibb/Pfizer,

References (26)

C.T. Ruff et al.
Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials
Lancet
(2014)
A. Verma et al.
2014 Focused update of the Canadian Cardiovascular Society Guidelines for the management of atrial fibrillation
Can J Cardiol
(2014)
E.S. Kaufman et al.
Positive predictive value of device-detected atrial high-rate episodes at different rates and durations: an analysis from ASSERT
Heart Rhythm
(2012)
S. Schulman et al.
Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients
J Thromb Haemost
(2005)
P.A. Wolf et al.
Atrial fibrillation as an independent risk factor for stroke: the Framingham Study
Stroke
(1991)
T.V. Glotzer et al.
The relationship between daily atrial tachyarrhythmia burden from implantable device diagnostics and stroke risk: the TRENDS study
Circ Arrhythm Electrophysiol
(2009)
J.S. Healey et al.
Subclinical atrial fibrillation and the risk of stroke
N Engl J Med
(2012)
P.L. Hess et al.
The role of cardiovascular implantable electronic devices in the detection and treatment of sublinical atrial fibrillation: a review
JAMA Cardiol
(2017)
T.V. Glotzer et al.
Atrial high rate episodes detected by pacemaker diagnostics predict death and stroke: report of the Atrial Diagnostics Ancillary Study of the MOde Selection Trial (MOST)
Circulation
(2003)
B.F. Gage et al.
Validation of clinical classification schemes for predicting stroke: results from the National Registry of Atrial Fibrillation
JAMA
(2001)

Risk factors for stroke and efficacy of antithrombotic therapy in atrial fibrillation. Analysis of pooled data from five randomized controlled trials

Arch Intern Med

(1994)

C.B. Granger et al.

Apixaban versus warfarin in patients with atrial fibrillation

N Engl J Med

(2011)

M.R. Patel et al.

Rivaroxaban versus warfarin in nonvalvular atrial fibrillation

N Engl J Med

(2011)

Cited by (240)

Impact of Atrial Fibrillation Burden on Health Care Costs and Utilization
2024, JACC: Clinical Electrophysiology
Integrating patient-specific cardiac implantable electronic device (CIED)-detected atrial fibrillation (AF) burden with measures of health care cost and utilization allows for an accurate assessment of the AF-related impact on health care use.
The goal of this study was to assess the incremental cost of device-recognized AF vs no AF; compare relative costs of paroxysmal atrial fibrillation (pAF), persistent atrial fibrillation (PeAF), and permanent atrial fibrillation (PermAF) AF; and evaluate rates and sources of health care utilization between cohorts.
Using the de-identified Optum Clinformatics U.S. claims database (2015-2020) linked with the Medtronic CareLink database, CIED patients were identified who transmitted data ≥6 months postimplantation. Annualized per-patient costs in follow-up were analyzed from insurance claims and adjusted to 2020 U.S. dollars. Costs and rates of health care utilization were compared between patients with no AF and those with device-recognized pAF, PeAF, and PermAF. Analyses were adjusted for geographical region, insurance type, CHA₂DS₂-VASc score, and implantation year.
Of 21,391 patients (mean age 72.9 ± 10.9 years; 56.3% male) analyzed, 7,798 (36.5%) had device-recognized AF. The incremental annualized increased cost in those with AF was $12,789 ± $161,749 per patient, driven by increased rates of health care encounters, adverse clinical events associated with AF, and AF-specific interventions. Among those with AF, PeAF was associated with the highest cost, driven by increased rates of inpatient and outpatient hospitalization encounters, heart failure hospitalizations, and AF-specific interventions.
Presence of device-recognized AF was associated with increased health care cost. Among those with AF, patients with PeAF had the highest health care costs. Mechanisms for cost differentials include both disease-specific consequences and physician-directed interventions.
Association of Device-Detected Atrial High-Rate Episodes With Long-term Cardiovascular and All-Cause Mortality: A Cohort Study
2024, Canadian Journal of Cardiology
Device-detected atrial high-rate episodes (AHREs) were associated with an increased thromboembolic risk. Although limited data regarding the long-term prognosis of patients with AHRE were controversial, this study aimed to identify the association of device-detected AHRE with mortality.
This observational study included patients with implantable cardioverter defibrillator (ICD) or cardiac resynchronization therapy defibrillator (CRT-D) placement and no history of atrial fibrillation (AF), atrial flutter (AFL), or atrial tachycardia (AT). During follow-up, patients with at least 1 day of AHRE duration ≥ 15 minutes were identified. The primary endpoint was cardiovascular mortality, and the secondary endpoint was all-cause mortality.
During a mean follow-up period of 4.2 years, AHREs were detected in 124 of 343 (36.2%) patients. Of these, 44 deaths (35.5%) occurred in 124 patients with AHREs, which was significantly higher than those without AHREs (43 of 219; 19.6%; P = 0.001). The multivariate analysis revealed that patients with AHRE had a significantly higher risk of cardiovascular (hazard ratio [HR], 2.40; 95% confidence interval [CI], 1.23-4.67; P = 0.010), and all-cause mortality (HR, 2.31; 95% CI, 1.49-3.59; P < 0.001). Further analysis indicated that this association remained significant in patients with higher burden (≥ 6 hours) but not in patients with lower burden (≥ 15 minutes to 6 hours). Notably, even after excluding the patients diagnosed with clinical AF during follow-up, the remaining patients with AHREs still exhibited a higher risk of cardiovascular and all-cause mortality compared with patients without AHREs.
AHREs were prevalent in ICD or CRT-D recipients with no history of clinical AF, AFL, or AT and were associated with more than twice the risk of cardiovascular and all-cause mortality.
No. ChiCTR-ONRC-13003695.
Les épisodes de haute fréquence auriculaire (EHFA) détectés par dispositif ont été associés à un risque thromboembolique accru. Bien que les quelques données concernant le pronostic à long terme des patients avec EHFA soient controversées, cette étude visait à identifier l'association des EHFA détectés par dispositif avec la mortalité.
Cette étude observationnelle incluait des patients ayant reçu un implant de défibrillateur cardioverteur implantable (DCI) ou une thérapie de resynchronisation cardiaque avec défibrillateur (TRC-D) et n'ayant pas d'antécédents de fibrillation auriculaire (FA), de flutter auriculaire (FLA) ou de tachycardie auriculaire (TA). Lors du suivi, les patients présentant au moins un jour d'EHFA d'une durée ≥ 15 minutes étaient identifiés. Le critère d'évaluation principal était la mortalité cardiovasculaire et le critère d'évaluation secondaire était la mortalité toutes causes confondues.
Sur une période de suivi moyenne de 4,2 ans, des EHFA ont été détectés chez 124 des 343 (36,2 %) patients. Parmi ceux-ci, 44 décès (35,5 %) ont eu lieu chez les 124 patients avec EHFA, ce qui était significativement plus élevé que chez ceux sans EHFA (43/219, 19,6 %, P = 0,001). L'analyse multivariée a révélé que les patients avec EHFA avaient un risque significativement plus élevé de mortalité cardiovasculaire (rapport de risque [RR] 2,40, intervalle de confiance [IC] à 95 %, 1,23-4,67, P = 0,010) et de mortalité toutes causes confondues (RR 2,31, IC à 95 %, 1,49-3,59, P < 0,001). Une analyse plus approfondie a indiqué que cette association restait significative chez les patients avec un stress plus élevé (≥ 6 heures), mais pas chez les patients avec un stress plus faible (≥ 15 minutes-6 heures). Notamment, même après avoir exclu les patients diagnostiqués avec une FA clinique pendant le suivi, les patients restants montrant des EHFA présentaient toujours un risque plus élevé de mortalité cardiovasculaire et de mortalité toutes causes confondues par rapport aux patients sans EHFA.
Les EHFA étaient prévalents chez les patients ayant reçu un DCI ou une TRC-D sans antécédents de FA, FLA ou TA cliniques et étaient associés à un risque plus que doublé de mortalité cardiovasculaire et de mortalité toutes causes confondues.
ChiCTR-ONRC-13003695.
Direct oral anticoagulants are associated with lower risk of dementia in patients with atrial fibrillation
2024, European Journal of Internal Medicine
Atrial fibrillation (AF) is associated with increased risk of dementia. Whether direct oral anticoagulation (DOAC) reduce this risk compared to vitamin-K antagonist (VKA) is unclear. The aim of this study was to assess the risk of new all-cause dementia and vascular dementia in AF patients, treated with either DOAC or VKAs.
Anonymized electronic medical records from the TriNetX federated research network were used. AF patients treated with DOACs within 1 month of AF diagnosis, were 1:1 propensity score-matched with those treated with a VKA. The analysis included patients who completed 5 and 10 years of follow-up and were assessed for all-cause dementia and vascular dementia. Cox proportional hazard models were used to hazard ratios (HR), respectively with 95% confidence intervals (CIs).
Among patients who completed 5 years of follow-up, after propensity score matching the final cohort consisted of 215,404 well-matched AF patients. All-cause dementia was diagnosed in 4,153 (3.9%) patients among those treated with DOACs and 4,150 (3.9%) among the VKA-treated patients (HR: 1.01, 95%CI: 0.96–1.05). Among patients 65–74 years old who were followed, DOAC treatment was associated with lower risk of dementia compared to VKAs (HR: 0.72; 95%CI: 0.59–0.86). Among patients who completed 10 years of follow-up, after propensity score matching the final cohort consisted of 19,208 well-matched AF patients. All-cause dementia was diagnosed in 314 (3.3%) patients among those treated with DOACs and 451 (4.7%) among the VKA-treated patients. DOAC treatment was associated with significantly lower risk of all-cause dementia during a follow-up period of 10 years compared to VKA treatment (HR: 0.72, 95%CI: 0.62–0.83), which remained consistent in patiens ≥65 years old.
This propensity-score matched analysis showed that among AF patients, treatment with a DOACs for a period of 10 years was associated with lower risk of all-cause dementia and vascular dementia compared to VKA treatment, an effect which was not apparent in those treated for shorter duration. This finding requires confirmation in ongoing randomised controlled trials.
Use of Anticoagulation for Thromboembolic Prophylaxis in Patients With Atrial High-Rate Episodes on Device Monitoring: A Narrative Review
2024, American Journal of Cardiology
Ischemic stroke and systemic thromboembolism are primary drivers of significant morbidity and mortality in patients with atrial fibrillation (AF). Although stroke is commonly the first index presentation of clinically silent AF, the growing use of continuous rhythm monitoring through cardiac implanted electronic devices has enabled earlier and increased detection of AF in patients who are otherwise asymptomatic before stroke development. Atrial high-rate episodes (AHREs) are atrial tachyarrhythmias frequently detected by cardiac implanted electronic devices; these events represent subclinical AF and other atrial tachyarrhythmias that can lead to stroke development and AF. Although the presence of AHREs increases the risk of developing both clinical AF and stroke compared with absence of AHREs, there has been a significant clinical variability in anticoagulation initiation in these subjects. In this narrative review, we explore the current evidence and published research surrounding the association between AHREs and stroke development in addition to the utility of anticoagulation in this population for thromboembolic prophylaxis.
The incidence of atrial fibrillation, new oral anticoagulation, stroke, and significant bleeds in patients receiving a new dual-chamber pacemaker
2023, IJC Heart and Vasculature
Atrial fibrillation and flutter (AF/AFL) can be easily detected in patients who have a dual-chamber pacemaker (PM). This can result in a high detection rate of these arrhythmias especially if patients are monitored remotely and detection limits are sensitive.
A single-center retrospective registry analysis of 1,285 consecutive AF/AFL and anticoagulation naïve patients from a limited geographical area undergoing implantation of a new dual-chamber PM (between 2013 and 2019). Seven-year follow-up data for incident AF/AFL, initiation of new oral anticoagulation and for incident strokes and bleeds was obtained from an in-depth review of all relevant patient records including written medical records and death certificates detailing causes of death.
During the follow-up, mortality reached 22.2 % and cumulative incidence of AF/AFL, new anticoagulation, strokes, and bleeds were 52.6 %, 40.4 %, 4.7 % and 10.4 %. In 92.6 % of the cases, AF/AFL was discovered by PM. Remote monitoring was initiated in 67 % (n = 856). Risk factor adjusted mortality in this group was significantly lower when compared to patients in regular out-patient clinic controls (HR 0.45, 95 % CI 0.35–0.57). Despite of their better overall prognosis, the AF/AFL was discovered, and oral anticoagulation was initiated more often in remote monitoring group (HR 1.58, 95 % CI 1.23–1.79 for AF/AFL and HR 1.67, 95 % CI 1.33–2.09 for anticoagulation). There was no significant difference in the incidence of strokes or bleeds.
The incidence of new AF/AFL is high in this population. Remote monitoring is associated with higher diagnostic yields of AF/AFL and initiated anticoagulation, but not with stroke and significant bleeds.
Atrial cardiomyopathy: An entity of emerging interest in the clinical setting
2023, European Journal of Internal Medicine
Since 1995, the concept of atrial cardiomyopathy (ACM) has been associated with myocardial fibrosis. Despite a consensus document in 2016, ACM's definition primarily relies on histopathological findings. The focus on diagnostic criteria for ACM is driven by the potential link to thromboembolic events even independently on atrial fibrillation (AF). The complexity of the mutual relationships between ACM and AF makes difficult any assessment of the thromboembolic risk associated to ACM per se. ACM's thrombogenicity is a multifaceted clinical phenomenon involving electrical, functional, and structural modifications. Factors such as cardiovascular risk factors (e.g., hypertension), common cardiac comorbidities (e.g., heart failure), and extracardiac conditions (e.g., neuromuscular disorders) can promote atrial derangement, triggering atrial fibrillation (AF) and increasing the risk of thromboembolic events. Several diagnostic methods are available to detect the key features of ACM, including electrical changes assessed by surface and intracavitary ECG, and structural and functional alterations evaluated through echocardiography and cardiac magnetic resonance (CMR). These methods can be complemented by electro-anatomical mapping (EAM) to enhance the accuracy of myocardial tissue characterization and assessment of atrial fibrosis. Although certain clinical conditions (e.g., atrial high-rate episodes, AHREs; embolic stroke of undetermined source, ESUS) often exhibit atrial alterations in their thromboembolic presentations, recent randomized trials have failed to demonstrate the benefits of oral anticoagulation in patients with ACM without AF. However, ACM constitutes the substrate for the development of AF, as proposed in the AF European guidelines under the 4S-AF scheme. This review emphasizes the lack of a diagnostic gold standard and the need for clinical criteria for ACM, aiming to better understand the potential therapeutic implications of atrial structural and functional derangements, even in the absence of clinical evidence of AF.

View all citing articles on Scopus

: Kenneth Bilchick, MD, MS served as guest editor for this article.

: RCT No. NCT01938248.

View full text

Trial DesignRationale and design of the Apixaban for the Reduction of Thrombo-Embolism in Patients With Device-Detected Sub-Clinical Atrial Fibrillation (ARTESiA) trial

Background

Design

Summary

Section snippets

Subclinical AF and stroke risk

Anticoagulation therapy for stroke prevention in AF and subclinical AF

Study overview

Discussion

Conclusions

Disclosures

Lancet

Can J Cardiol

Heart Rhythm

J Thromb Haemost

Atrial fibrillation as an independent risk factor for stroke: the Framingham Study

Stroke

The relationship between daily atrial tachyarrhythmia burden from implantable device diagnostics and stroke risk: the TRENDS study

Circ Arrhythm Electrophysiol

Subclinical atrial fibrillation and the risk of stroke

N Engl J Med

The role of cardiovascular implantable electronic devices in the detection and treatment of sublinical atrial fibrillation: a review

JAMA Cardiol

Atrial high rate episodes detected by pacemaker diagnostics predict death and stroke: report of the Atrial Diagnostics Ancillary Study of the MOde Selection Trial (MOST)

Circulation

Validation of clinical classification schemes for predicting stroke: results from the National Registry of Atrial Fibrillation

JAMA

Risk factors for stroke and efficacy of antithrombotic therapy in atrial fibrillation. Analysis of pooled data from five randomized controlled trials

Arch Intern Med

Apixaban versus warfarin in patients with atrial fibrillation

N Engl J Med

Rivaroxaban versus warfarin in nonvalvular atrial fibrillation

N Engl J Med

Trial Design
Rationale and design of the Apixaban for the Reduction of Thrombo-Embolism in Patients With Device-Detected Sub-Clinical Atrial Fibrillation (ARTESiA) trial