Elsevier

The Lancet

Volume 398, Issue 10310, 23–29 October 2021, Pages 1507-1516
The Lancet

Articles
Implantable loop recorder detection of atrial fibrillation to prevent stroke (The LOOP Study): a randomised controlled trial

https://doi.org/10.1016/S0140-6736(21)01698-6Get rights and content

Summary

Background

It is unknown whether screening for atrial fibrillation and subsequent treatment with anticoagulants if atrial fibrillation is detected can prevent stroke. Continuous electrocardiographic monitoring using an implantable loop recorder (ILR) can facilitate detection of asymptomatic atrial fibrillation episodes. We aimed to investigate whether atrial fibrillation screening and use of anticoagulants can prevent stroke in individuals at high risk.

Methods

We did a randomised controlled trial in four centres in Denmark. We included individuals without atrial fibrillation, aged 70–90 years, with at least one additional stroke risk factor (ie, hypertension, diabetes, previous stroke, or heart failure). Participants were randomly assigned in a 1:3 ratio to ILR monitoring or usual care (control) via an online system in permuted blocks with block sizes of four or eight participants stratified according to centre. In the ILR group, anticoagulation was recommended if atrial fibrillation episodes lasted 6 min or longer. The primary outcome was time to first stroke or systemic arterial embolism. This study is registered with ClinicalTrials.gov, NCT02036450.

Findings

From Jan 31, 2014, to May 17, 2016, 6205 individuals were screened for inclusion, of whom 6004 were included and randomly assigned: 1501 (25·0%) to ILR monitoring and 4503 (75·0%) to usual care. Mean age was 74·7 years (SD 4·1), 2837 (47·3%) were women, and 5444 (90·7%) had hypertension. No participants were lost to follow-up. During a median follow-up of 64·5 months (IQR 59·3–69·8), atrial fibrillation was diagnosed in 1027 participants: 477 (31·8%) of 1501 in the ILR group versus 550 (12·2%) of 4503 in the control group (hazard ratio [HR] 3·17 [95% CI 2·81–3·59]; p<0·0001). Oral anticoagulation was initiated in 1036 participants: 445 (29·7%) in the ILR group versus 591 (13·1%) in the control group (HR 2·72 [95% CI 2·41–3·08]; p<0·0001), and the primary outcome occurred in 318 participants (315 stroke, three systemic arterial embolism): 67 (4·5%) in the ILR group versus 251 (5·6%) in the control group (HR 0·80 [95% CI 0·61–1·05]; p=0·11). Major bleeding occurred in 221 participants: 65 (4·3%) in the ILR group versus 156 (3·5%) in the control group (HR 1·26 [95% CI 0·95–1·69]; p=0·11).

Interpretation

In individuals with stroke risk factors, ILR screening resulted in a three-times increase in atrial fibrillation detection and anticoagulation initiation but no significant reduction in the risk of stroke or systemic arterial embolism. These findings might imply that not all atrial fibrillation is worth screening for, and not all screen-detected atrial fibrillation merits anticoagulation.

Funding

Innovation Fund Denmark, The Research Foundation for the Capital Region of Denmark, The Danish Heart Foundation, Aalborg University Talent Management Program, Arvid Nilssons Fond, Skibsreder Per Henriksen, R og Hustrus Fond, The AFFECT-EU Consortium (EU Horizon 2020), Læge Sophus Carl Emil Friis og hustru Olga Doris Friis' Legat, and Medtronic.

Introduction

Stroke constitutes a major health problem worldwide.1, 2 The risk of stroke is five-times higher in individuals with atrial fibrillation than those without.2 Approximately 20% of strokes are linked to atrial fibrillation, and strokes secondary to atrial fibrillation are associated with a poor outcome compared with strokes without atrial fibrillation.3, 4, 5 Furthermore, 30% of strokes are so-called cryptogenic, potentially caused by undetected atrial fibrillation.6, 7 As with stroke, the increasing prevalence of atrial fibrillation can be attributed to population ageing and accumulation of other risk factors.8, 9, 10

Anticoagulation treatment is highly effective in reducing the risk of stroke in patients diagnosed with atrial fibrillation.11 A major challenge is that patients with atrial fibrillation are often asymptomatic and thus remain undiagnosed, and the proportion of asymptomatic cases increases with age.12 In patients with cryptogenic stroke, approximately 30% will have atrial fibrillation detected if continuous heart rhythm monitoring is applied with an implantable loop recorder (ILR).7 Studies of patients with cardiac implantable electronic devices have found that even short, subclinical atrial fibrillation episodes are associated with increased stroke risk.13

Research in context

Evidence before this study

Stroke constitutes a growing health challenge worldwide. Atrial fibrillation is a well known risk factor for stroke, but the risk can be mitigated by anticoagulation treatment. The LOOP Study was initiated on the basis that individuals with atrial fibrillation are often asymptomatic and thus remain undiagnosed and untreated. Studies of patients with cardiac implantable electronic devices, such as pacemakers, reported a high prevalence of subclinical atrial fibrillation and evidence was growing that this type of atrial fibrillation was associated with increased stroke risk. In 2014, the Cryptogenic Stroke and Underlying Atrial Fibrillation study reported that 30% of patients with cryptogenic stroke had atrial fibrillation detected when continuous heart rhythm monitoring was applied. These findings sparked a growing interest in atrial fibrillation screening, while new technologies emerged to detect the arrhythmia. The effect on hard outcomes, such as incidence of stroke, remains to be determined.

Added value of this study

This study presents outcomes of long-term continuous screening for atrial fibrillation versus usual care in individuals with risk factors for stroke. We found that although atrial fibrillation was detected and treated much more often, systematic, intensive screening did not have a significant effect on stroke risk, and there was no effect on mortality. However, the time-to-event curves for stroke overlapped during the first 2–3 years after which they appeared to diverge due to increasing event rates in the control group, and a sensitivity analysis suggested that screening might prevent strokes if done per protocol—ie, continuous implantable loop recorder monitoring for 3 years. The study also showed high rates of atrial fibrillation diagnosis without active screening, high acceptance of anticoagulation, and modest bleeding rates.

Implications of all the available evidence

In this randomised trial of individuals with stroke risk factors, continuous implantable loop recorder monitoring for atrial fibrillation, and subsequent anticoagulation if atrial fibrillation was detected, did not significantly reduce the risk of stroke or systemic arterial embolism. This result was seen despite a high proportion of atrial fibrillation detection and a high acceptance of anticoagulation therapy and might imply that not all atrial fibrillation is worth screening for, and not all screen-detected atrial fibrillation merits anticoagulation.

European and US guidelines recommend opportunistic screening for atrial fibrillation in people aged 65 years and older using pulse-palpation or standard electrocardiogram (ECG), whereas systematic or more intense screening is recommended in individuals at high risk of stroke.14, 15, 16 These recommendations are based on studies showing that screening is feasible and will detect more cases of atrial fibrillation, whereas the effect on stroke prevention remains unknown.

Given the scarcity of evidence on health benefits of screening for atrial fibrillation, we aimed to investigate whether systematic, intensive atrial fibrillation screening and use of anticoagulants can prevent stroke in individuals at high risk.

Section snippets

Study design and participants

Atrial Fibrillation Detected by Continuous ECG Monitoring Using Implantable Loop Recorder to Prevent Stroke in High-risk Individuals (The LOOP Study) was an investigator-initiated, multicentre, unblinded, randomised controlled trial done at four centres (Rigshospitalet, Bispebjerg and Frederiksberg Hospital, Zealand University Hospital, and Odense University Hospital) covering three of Denmark's five regions. The trial design has been published previously.17

Eligible participants were aged 70–90

Results

From Jan 31, 2014, to May 17, 2016, 6205 individuals were screened for inclusion and, of these, 6004 were included and randomly assigned. The most frequent reason for exclusion was history of atrial fibrillation or atrial fibrillation on the initial screening ECG (figure 1). 6004 participants were randomly assigned into the trial; 1501 (25·0%) were assigned to the ILR group, and 4503 (75·0%) to control (table 1). The mean age of the participants was 74·7 years (SD 4·1), and 2837 (47·3%) were

Discussion

In this randomised trial of individuals with stroke risk factors, continuous ILR monitoring for atrial fibrillation, and subsequent anticoagulation if atrial fibrillation was detected, did not significantly reduce the risk of stroke or systemic arterial embolism. This result was despite a high proportion of diagnosed atrial fibrillation and a high acceptance of anticoagulation therapy and adherence to the treatment. The rates of bleeding were modest despite the low threshold for

Data sharing

The LOOP Study data will be part of the AFFECT-EU consortium (supported from EU-Horizon 2020 programme) in which studies on screening for atrial fibillation will be included in a future meta-analysis. Applications for other collaborations can be submitted to the consortium via JHS.

Declaration of interests

JHS is a member of Medtronic advisory boards and has received speaker honoraria and research grants from Medtronic in relation to this work and outside the submitted work. SZD is a part-time employee of Vital Beats outside the submitted work. DWK is a member of a Medtronic advisory board on stroke and has received speaker honoraria and travel grants from Medtronic, St Jude Medical, and Boehringer Ingelheim, outside the submitted work. AB reports research grants from The Region of Southern

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