This is an open-access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work, first published in JMIR Research Protocols, is properly cited. The complete bibliographic information, a link to the original publication on https://www.researchprotocols.org, as well as this copyright and license information must be included.
Paroxysmal atrial fibrillation (AF) is a probable cause of cryptogenic stroke (CS), and its detection and treatment are important for the secondary prevention of stroke. Insertable cardiac monitors (ICMs) are clinically effective in screening for AF and are superior to conventional short-term cardiac monitoring. Japanese guidelines for determining clinical indications for ICMs in CS are stricter than those in Western countries. Differences between Japanese and Western guidelines may impact the detection rate and prediction of AF via ICMs in patients with CS. Available data on Japanese patients are limited to small retrospective studies. Furthermore, additional information about AF detection, including the number of episodes, cumulative episode duration, anticoagulation initiation (type and dose of regimen and time of initiation), rate of catheter ablation, role of atrial cardiomyopathy, and stroke recurrence (time of recurrence and cause of the recurrent event), was not provided in the vast majority of previously published studies.
In this study, we aim to identify the proportion and timing of AF detection and risk stratification criteria in patients with CS in real-world settings in Japan.
This is a multicenter, prospective, observational study that aims to use ICMs to evaluate the proportion, timing, and characteristics of AF detection in patients diagnosed with CS. We will investigate the first detection of AF within the initial 6, 12, and 24 months of follow-up after ICM implantation. Patient characteristics, laboratory data, atrial cardiomyopathy markers, serial magnetic resonance imaging findings at baseline, 6, 12, and 24 months after ICM implantation, electrocardiogram readings, transesophageal echocardiography findings, cognitive status, stroke recurrence, and functional outcomes will be compared between patients with AF and patients without AF. Furthermore, we will obtain additional information regarding the number of AF episodes, duration of cumulative AF episodes, and time of anticoagulation initiation.
Study recruitment began in February 2020, and thus far, 213 patients have provided written informed consent and are currently in the follow-up phase. The last recruited participant (May 2021) will have completed the 24-month follow-up in May 2023. The main results are expected to be submitted for publication in 2023.
The findings of this study will help identify AF markers and generate a risk scoring system with a novel and superior screening algorithm for occult AF detection while identifying candidates for ICM implantation and aiding the development of diagnostic criteria for CS in Japan.
UMIN Clinical Trial Registry UMIN000039809; https://tinyurl.com/3jaewe6a
DERR1-10.2196/39307
Stroke is a leading cause of mortality and disability worldwide. A primary goal of stroke management is to clarify the stroke etiology to optimize secondary prevention. Despite standard extensive diagnostic workups, approximately 15%-40% of all ischemic stroke cases are of unknown etiologies and are classified as cryptogenic [
The term “embolic stroke of undetermined source” (ESUS) has been proposed to describe CS that is not lacunar and is not associated with proximal arterial stenosis or a recognizable cardioembolic source [
This study aims to clarify the proportion and timing of AF detection via ICMs in patients diagnosed with CS in Japan. Additionally, we aim to identify risk stratification criteria using real-world data, which could then be used in clinical practice to predict occult AF, identify optimal candidates for ICM implantation, and inform the development of diagnostic criteria.
The LOOK (a multicenter observational study on the detection of AF using insertabLe cardiac mOnitors in patients with cryptOgenic stroKe) registry is an observational, multicenter, prospective registry of patients who have been diagnosed with CS and implanted with an ICM. The Medtronic CareLink Network is being used to remotely transmit the device data.
Ethical approval for this study was obtained from the ethics review committee of Nippon Medical School (B-2019-043) and from the relevant ethics committees of all participating centers. Written informed consent is required from all patients or their family members before study participation. This study is registered with the University hospital Medical Information Network (UMIN) Clinical Trial Registry (UMIN000039809).
Patient enrollment for this ongoing study started in February 2020 in 24 medical institutions throughout Japan. The inclusion criteria for this study are as follows: (1) patients who have been diagnosed with CS according to the Japanese diagnostic criteria and have been implanted with an ICM (Reveal LINQ), and (2) patients aged 40-90 years. The main exclusion criterion is the presence of contraindications for MRI. A full description of the inclusion and exclusion criteria is presented in
Patients of either sex, between 40 and 90 years of age
Patients diagnosed with cryptogenic stroke and implanted with an insertable cardiac monitor
Patients (or their legal representatives) who have given written consent
Patients with a history of atrial fibrillation and atrial flutter
Patients with permanent contraindications or indications for oral anticoagulants
Applicable patients with pacemaker or implantable defibrillator implantation
Magnetic resonance imaging–contraindicated patients
Patients diagnosed with life expectancy within 2 years due to some disease
An inappropriate decision made by the investigator
The study data, such as patient background, laboratory data, coagulation test, B-type natriuretic peptide, physiological examination (electrocardiogram [ECG], transthoracic echocardiography, transesophageal echocardiography [TEE], and carotid echocardiography), neuroimaging examination, Mini-Mental State Examination (MMSE), modified Rankin Scale (mRS), and presence of cardiovascular events, gastrointestinal bleeding, and other adverse events, or death (
Overview of study schedule.
Survey items | Baseline survey | 6 months (±30 days) | 12 months (±30 days) | 24 months (±30 days) |
Consent withdrawal/visit status/health confirmation |
|
✔ | ✔ | ✔ |
Patient background/history | ✔ |
|
|
|
Blood count, biochemistry, coagulation test, BNPa | ✔ | ✔ | ✔ | ✔ |
Physiological examination (ECG,b TTE,c TEE,d carotid echocardiography) | ✔ |
|
|
|
Brain MRIe examination | ✔ | ✔ | ✔ | ✔ |
MMSEf | ✔ |
|
✔ | ✔ |
mRSg | ✔ | ✔ | ✔ | ✔ |
Presence of cardiovascular events, gastrointestinal bleeding, other adverse events, or death |
|
✔ | ✔ | ✔ |
aBNP: B-type natriuretic peptide.
bECG: electrocardiogram.
cTTE: transthoracic echocardiography.
dTEE: transesophageal echocardiography.
eMRI: magnetic resonance imaging.
fMMSE: Mini-Mental State Examination.
gmRS: modified Rankin Scale.
Age, sex, body mass index, prestroke modified Rankin Scale (mRS) score, antithrombotic therapy before the index case, previous stroke, hypertension, dyslipidemia, diabetes mellitus, alcohol intake, smoking, peripheral artery disease, history of cancer, education level, and CHA2DS2-VASc (Congestive Heart Failure, Hypertension, Age [≥75 years], Diabetes, Stroke/Transient Ischemic Attack, Vascular Disease, Age [65-74 years], Sex [Female]) score
Distribution of infarct lesions, infarct size, number of infarcts, major vessel occlusion, intra-arterial signal signs, susceptibility vessel signs, Diffusion-Weighted Imaging—Alberta Stroke Program Early Computed Tomography Scores, natural recanalization, hemorrhagic transformation, number and location of cerebral microbleeds, old cortical lesions, and recurrence of stroke after magnetic resonance imaging
Deep terminal negativity of the P-wave V1, P-wave terminal force in lead V1, P axis, PR interval, heart rate–corrected QT interval, and the number and percentage of atrial premature contractions and ventricular premature contractions
Routine blood biochemistry examinations, including creatinine clearance and measurements of D-dimers, C-reactive protein, brain natriuretic peptide (BNP), and N-terminal prohormones of the BNP
Left atrium diameter, left atrial volume index, valvular disease, right to left shunt, aortic plaque thickness and morphology, spontaneous echo contrast, left atrial appendage filling and emptying velocity, left ventricular ejection fraction, atrial septal aneurysm, and strand readings
Max intima-media thickness, plaque morphology, internal carotid artery stenosis as assessed by the European Carotid Surgery Trial method, peak systolic velocity, and end diastolic velocity
Recent retrospective observational ICM studies have demonstrated that major vessel occlusion (n=84) and frequent premature atrial contractions (n=66) were associated with AF detection after adjustment for risk factors and comorbidities, respectively [
The LOOK study has been organized by a central coordinating center at the Department of Neurology, Nippon Medical School, and is being conducted at 24 medical centers throughout Japan. A steering committee is managing the trial.
Study recruitment started in February 2020, and thus far, 213 patients have provided written informed consent in May 2021 and are currently in the follow-up phase. The last recruited participant will have completed the 24-month follow-up in May 2023. Data cleanup and analyses are projected to be completed by September 2023, and the results are expected to be submitted for peer-reviewed publication in 2023.
Recent meta-analyses demonstrate that, compared with short-term monitoring, prolonged cardiac rhythm monitoring is associated with higher rates of AF detection, a higher incidence of anticoagulation initiation, and reduced stroke recurrence in patients with CS [
Some testing biases are affected by geographic location; for example, brain MRI is used less frequently in European patients with ESUS [
Recent evidence indicates that atrial cardiomyopathy, diagnosed by the presence of serum or electrocardiographic biomarkers, leads to AF and may result in thromboembolism even before AF manifests [
A previous retrospective study reported that plasma brain natriuretic peptide (BNP) levels were elevated in the acute phase of stroke but were substantially reduced in patients with cardioembolic stroke [
By conducting this prospective LOOK multicenter study, the characteristics of patients with occult AF detected by ICMs will be clarified in more detail than previously reported by analyzing imaging studies on admission and during follow-up, serial measurements of blood markers, and various physiological findings. We hope that our findings will contribute to the identification of markers and enable the development of a risk scoring system with a new and better screening algorithm, which could inform future guidelines for stroke screening in patients with CS as well as the development of comprehensive clinical trials.
atrial fibrillation
branch atheromatous disease
brain natriuretic peptide
cryptogenic stroke
electrocardiogram
embolic stroke of undetermined source
insertable cardiac monitor
Mini-Mental State Examination
magnetic resonance imaging
modified Rankin Scale
N-terminal prohormone of brain natriuretic peptide
transesophageal echocardiography
We would like to thank all collaborators and LOOK investigators for their help with participant recruitment. The LOOK study received funding support from Medtronic Japan Co, Ltd.
Deidentified participant data will be shared on request. Researchers who make the request should include a methodologically sound proposal on how the data will be used. They will also need to sign a data access agreement. The corresponding author can be contacted directly to request data sharing.
SS reports research funding from the All Japan Coffee Association and Pfizer Co, Ltd, and lecture fees from EISAI Co, Ltd. K Kitagawa reports lecture fees from Daiichi Sankyo Co, Ltd and Kyowa Kirin Co, Ltd, and received research funding from Daiichi Sankyo Co, Ltd. YI reports lecture fees from Bayer Healthcare Co, Ltd, Pfizer Japan Inc, Nippon Boehringer Ingelheim Co, Ltd, Takeda Pharmaceutical Co, Ltd, Otsuka Pharmaceutical Co, Ltd, and Daiichi Sankyo Co, Ltd, outside of the submitted work and research funding from Sanofi Co, Ltd. SF reports lecture fees from Takeda Pharmaceutical Co, Ltd, Bayer Yakuhin Co, Ltd, Otsuka Pharmaceutical Co, Ltd, Bristol-Myers Squibb Co, Ltd, Pfizer Co, Ltd, and Daiichi Sankyo Co, Ltd. KO reports lecture fees from Daiichi Sankyo Co, Ltd. HT received lecture fees from Pfizer Co, Ltd and Daiichi Sankyo Co, Ltd. MK reports research funding from Daiichi Sankyo Co, Ltd and Nippon Boehringer Ingelheim Co, Ltd. MI reports lecture fees from Daiichi Sankyo and EISAI, and grant support from Panasonic, GE Precision Healthcare LLC, Bristol-Myers Squibb, and Shimadzu Corporation. HY reports lecture fees from Stryker Co, Ltd, Bayer Yakuhin Co, Ltd, and Daiichi Sankyo Co, Ltd, and research funding from Bristol-Myers Squibb Co, Ltd. KY reports lecture fees from Daiichi Sankyo Co, Ltd. YU received lecture fees from OHARA Pharmaceutical Co, Ltd, and research funds from Bristol-Myers Squibb. YK reports lecture fees from Daiichi Sankyo Co, Ltd. Bayer Healthcare Co, Ltd, and Medtronic Japan Co, Ltd, and research funding and remuneration from Bristol-Myers Squibb Co, Ltd and Nippon Boehringer Ingelheim Co, Ltd. K Kimura reports lecture fees from Bristol-Myers Squibb Co, Ltd, Nippon Boehringer Ingelheim Co, Ltd, Bayer Healthcare Co, Ltd, and Daiichi Sankyo Co, Ltd, and research funding from Teijin Pharma Co, Ltd, Nippon Boehringer Ingelheim Co, Ltd, and Daiichi Sankyo Co, Ltd.