Implantable loop recorder (ILR) is recommended to detect subclinical atrial fibrillation (AF) after cryptogenic stroke; however, the clinical outcomes of this practice is unclear. We conducted a systematic review and meta-analysis of randomized controlled trials to evaluate 12-month AF detection, change in oral anticoagulation (OAC), and recurrent stroke in ILR versus usual care after ischemic stroke. We searched Medline, Embase, Web of Science, Cochrane Library for randomized controlled trials comparing ILR with usual care after any ischemic stroke. Primary outcomes were cumulative AF detection and recurrent stroke (ischemic or hemorrhagic) or transient ischemic attack over 12 months. Secondary outcome was OAC initiation. Meta-analysis was performed with Mantel-Haenszel pooled odds ratios (ORs) and random effects models. Of 200 identified articles, 3 trials were included (1,233 participants). Cryptogenic stroke and underlying AF included cryptogenic stroke only, stroke of known cause and underlying-AF included small or large vessel stroke only, and post embolic rhythm detection with implantable vs external monitoring included all ischemic strokes. The 12-month AF detection was 13% in the ILR group and 2.4% in controls. ILR was more likely to detect AF compared with usual care (OR 5.8, 95% confidence interval 3.2 to 10.2). Stroke or transient ischemic attack occurred in 7% with ILR and 9% with usual care (OR 0.8, 95% confidence interval 0.5 to 1.2). In patients with detected AF, 97% and 100% were started on OAC in cryptogenic stroke and underlying AF and post embolic rhythm detection with implantable vs external monitoring, respectively, compared with 68% in stroke of known cause and underlying-AF. In conclusion, ILR was superior to usual care in AF detection, but the relative low incidence of AF and the nondifferential risk of stroke between the ILR and usual care arms may suggest that most patients do not benefit from ILR implantation. Further studies are warranted to understand if patient selection can be improved to increase the diagnostic yield of ILR.
Of 795,000 ischemic strokes occurring annually in the United States, 20% to 25% are recurrent. Detection of subclinical AF as the etiology of the index stroke is critical for prevention of recurrent stroke because it identifies patients in whom oral anticoagulation (OAC) is highly effective for secondary stroke prophylaxis. Implantable loop recorder (ILR) placement was endorsed by the 2019 American Heart Association/American College of Cardiology /Heart Rhythm Society AF guideline for detection of subclinical AF in cryptogenic stroke. However, cryptogenic stroke is a diagnosis of exclusion and its definition is nebulous. Clinically, the decision to implant ILRs may be partly arbitrary and made at the clinician’s discretion. It is also not well known if cryptogenic stroke in reality is enriched for AF compared with other stroke subtypes. Although it is posited that ILR reduces the risk of recurrent stroke through greater AF detection followed by OAC, the clinical significance of occult AF detected by extended rhythm monitoring is uncertain , and the randomized clinical trials (RCTs) were not powered to answer this question. Therefore, we conducted a meta-analysis of RCTs to quantify the incremental change in AF detection, initiation of OAC, and subsequent risk of stroke associated with ILR use versus usual care in poststroke settings.
The authors declare that all supporting data are available within the article and its online supplementary files. We performed our meta-analysis of RCTs using a protocol designed based on the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. The protocol, including our search strategies, is registered in International Prospective Register of Systematic Reviews. We searched Medline, Embase, Web of Science, and the Cochrane Library for RCTs comparing ILR with usual care in adults aged 18 years or older who received a diagnosis of ischemic stroke or transient ischemic attack (TIA) and without known history of AF. Original studies published in the English language in 1990 or later and those with AF detection and stroke (ischemic or hemorrhagic) or TIA as outcomes with a minimum of 12 months of follow-up were eligible for inclusion. We included all ischemic stroke subtypes and any form of non-ILR external rhythm monitoring performed in the control group (e.g., 12-lead electrocardiogram, Holter monitor, 30-day event monitor, patch monitor, external loop recorder, mobile cardiac outpatient telemetry). D.K. and D.F. designed the search strategies using the Peer Review of Electronic Search Strategies standard. All titles and abstracts were independently reviewed for inclusion by 2 investigators (D.K. and Q.D.). We used Endnote (Endnote; Clarivate Analytics, Philadelphia, Pennsylvania), and Rayyan (Qatar Computing Research Institute [Data Analytics], Doha, Qatar) for the screening process.
Two investigators (D.K. and Q.D.) independently extracted data from the selected RCTs. All quantitative data were extracted from the trials’ intention-to-treat analyses. We extracted relevant data into a predefined data extraction form. Extracted data included the number of sites and location, the specific ILR used for intervention, types of external rhythm monitoring used in control group, primary, secondary, and post hoc end points, inclusion and exclusion criteria, and follow-up duration. We performed a meta-analysis comparing the relative risks of AF detection and stroke (ischemic or hemorrhagic) or TIA in patients who had a stroke monitored with ILR versus those without ILR using Mantel-Haenszel pooled odds ratios (ORs) with alpha 0.05 from random effects models (Review Manager Version 5.4.1, The Cochrane Collaboration, Copenhagen, Denmark). We used the intention-to-treat principle for analyses. We used random effects models to account for variation in the true effect sizes and the size of study sample across the studies.
We used the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach to assess the quality of the evidence, and our assessment was summarized using GRADEpro. We qualitatively assessed for risk of bias using the Cochrane Collaboration’s risk of bias tool based on the following elements: random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective reporting, and other biases.
Among the 200 records identified from the search strategy, 3 RCTs including 1,233 participants (613 ILR and 620 control) using the intention-to-treat principle for analyses met the inclusion criteria ( Supplementary Figure 1 ). Study characteristics are shown in Table 1 . Patients had median or mean age of 61 to 68 years and 467 were women (38%). One trial reported race/ethnicity of the participants, and 87% were White. In 2 of the trials, there was no specific criteria for definition of usual care for control group, , whereas the third trial specifically compared ILR with 30-day external loop recorder. In all 3 trials, ischemic strokes were manually subtyped by study investigators using the Trial of ORG in Acute Stroke Treatment classification system, with cryptogenic stroke and underlying AF (CRYSTAL AF) including only cryptogenic strokes, stroke of known cause and underlying AF (STROKE-AF) including only small and large artery strokes and post embolic rhythm detection with implantable vs external monitoring (PER DIEM) including all ischemic stroke subtypes, 25% of which were small or large artery strokes and 66% of which were cryptogenic.
| Trial Name | Enrollment Period | No. Sites & Countries | No. Of Participants | Inclusion Criteria | Control Group | Primary (1 ° ), Secondary (2 ° ), Post hoc Outcomes | |
|---|---|---|---|---|---|---|---|
| CRYSTAL AF, 2014 11 | 6/2009−4/2012 | 55 sites, Europe, Canada, US | ILR: 221 Control: 220 | ≥40 y, CS | ECG, Holter, event monitor | 1 ° : AF at 6 mo | 2 ° : AF at 12-mo, stroke/TIA, change in OAC use |
| STROKE-AF, 2021 12 | 5/2015-11/2017 | 33 sites, US | ILR: 242 Control: 250 | ≥60 y LAA or lacunar | ECG, Holter, event monitor, MCT | 1 ° : AF at 12 mo | 2 ° : AF at 36 mo. post hoc: AF at 6-mo, stroke/TIA, OAC use |
| PER DIEM, 2021 13 | 4/2016-7/2019 | 3 sites, Canada | ILR: 150 Control: 150 | ≥18 y All strokes | 30-d external loop recorder | 1 ° : AF at 12 mo | 2 ° : AF or death, time to AF, stroke/TIA, ICH, MB ≤12-mo |
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