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For peer review onlyDiagnostic yield of chest and thumb-ECG after cryptogenic stroke: Transient Electrocardiogram Assessment in Stroke

Evaluation (TEASE) – an observational trial

Journal: BMJ Open

Manuscript ID bmjopen-2020-037573

Article Type: Original research

Date Submitted by the Author: 21-Feb-2020

Complete List of Authors: Magnusson, Peter; Uppsala Universitet, Centre for Research and Development, Uppsala University/Region Gävleborg; Karolinska Institute, Institution of MedicineLyren, Adam; Uppsala UniversitetMattsson, Gustav; Uppsala Universitet

Keywords: Adult cardiology < CARDIOLOGY, STROKE MEDICINE, INTERNAL MEDICINE

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For peer review only

1

Diagnostic yield of chest and thumb-ECG after cryptogenic stroke: Transient

Electrocardiogram Assessment in Stroke Evaluation (TEASE) – an

oberservational trial

Peter Magnusson1,2 Adam Lyrén2 Gustav Mattsson2

5 1. Cardiology Research Unit, Department of Medicine, Karolinska Institutet, Stockholm, SE-171 76,

SWEDEN

2. Centre for Research and Development, Uppsala University/Region Gävleborg, Gävle, SE-801 87,

SWEDEN

10

Correspondence to:

Peter Magnusson

Cardiology Research Unit, Department of Medicine

Karolinska Institutet

15 Karolinska University Hospital/Solna

SE-171 76 Stockholm, SWEDEN

Phone: +46(0)705 089407

Fax: +46(0)26 154255

E-mail: [email protected]

20

Word count: 3245

Keywords: atrial fibrillation, cryptogenic stroke, ECG screening, stroke, thumb-ECG.

Short title: Diagnostic yield of thumb-ECG after stroke

Conflicts of interest and source of funding: The project received free product from Coala Life.

25 Outside this project: PM has received speaker fees or grants from Abbott, Alnylam, Bayer,

AstraZeneca, Boehringer-Ingelheim, Internetmedicin, Lilly, MSD, Novo Nordisk, Octopus Medical,

Orion Pharma, Pfizer, Vifor Pharma, and Zoll. AL has received speaker fees from Pfizer. GM has

received speakers fee from Alnylam, MSD, and Internetmedicin.

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ABSTRACT

Objective: In stroke survivors, atrial fibrillation (AF) is typically evaluated solely by

short-term ECG monitoring in the stroke unit. Prolonged continuous ECG monitoring

or insertable cardiac monitors require substantial resources. Chest and thumb-ECG

5 could provide an alternative means of AF detection, which in turn could allow prompt

anticoagulation to prevent recurrent stroke. The objective of this study was to assess

the yield of newly diagnosed AF during 28 days of chest and thumb-ECG monitoring

twice daily in cryptogenic stroke.

Methods: This study, Transient Electrocardiogram Assessment in Stroke Evaluation

10 (TEASE), included stroke patients from Region Gävleborg, Sweden, between 2017

and 2019. Patients with a recent ischemic stroke without documented AF (or other

reasons for anticoagulation) before or during ECG evaluation in the stroke unit were

evaluated using the Coala Heart MonitorTM connected to a smartphone application for

remote monitoring.

15 Results: The prespecified number of 100 patients (mean age 67.6±10.8 years; 60%

males) was analyzed. In 9 patients (9%, number needed to screen 11) AF but no

other significant atrial arrhythmias was diagnosed. The mean CHA2DS2-VASc score

was similar among patients with AF and no AF (4.9±1.1 vs 4.3±1.3; p=0.224) and

patients with AF were older (74.3±9.0 vs 66.9±10.8; p=0.049). Patients performed on

20 average 90.1±15.0% of scheduled transmissions.

Conclusion: In evaluation of cryptogenic stroke, 9% of patients had AF detected

using chest and thumb-ECG twice daily during one month. In many stroke survivors

this is a feasible approach and they will be protected from recurrent stroke by

anticoagulation treatment.

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Strengths and limitations of this study

• Prospective evaluation of atrial fibrillation using the chest and thumb-ECG after

stroke.

• Pragmatic approach to evaluation of cryptogenic stroke that increase

5 generalizability.

• The Coala Life MonitorTM provides a feasible tool to detect atrial fibrillation after

recent stroke.

10

15

20

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INTRODUCTION

Stroke is a leading cause of death, disability, and morbidity including dementia.1 The

global burden of stroke remains a challenge due to aging populations and the

growing prevalence of risk factors, such as congestive heart failure, hypertension,

5 diabetes, vascular disease, and the interplay with atrial fibrillation (AF).2,3 AF is a

complex condition known to cause stroke and systemic embolization, but these

devastating events can be prevented by anticoagulant therapy.4 A non-vitamin K

antagonist oral anticoagulant (NOAC) is the preferred choice because of superior

efficacy, lower risk of bleeding, and fewer interactions.5 A meta-analysis of the pivotal

10 NOAC trials showed a 19% reduction of stroke/systemic embolism and a 10% lower

mortality compared to warfarin.5 If AF is not diagnosed, then antiplatelet medication is

the current practice following a stroke.6,7 According to the European Society of

Cardiology (ESC), antiplatelet monotherapy should not be considered in the

presence of AF, regardless of the stroke risk.6,7 At least 20-30% of patients with

15 ischemic stroke have a documented episode of AF before, during, or after the stroke,

but in a quarter of patients, the stroke is cryptogenic, meaning that no attributable

cause can be discerned.8-10

The strategies for AF detection after stroke include monitoring using

continuous electrocardiogram (ECG) in the hospital ward, repeated ECGs, Holter

20 monitoring, external event or loop recorders, long-term monitoring using patches, and

handheld devices. Insertable cardiac monitors in cryptogenic stroke yield an AF

diagnosis in 8.9% at 6 months and 12.4% at 12 months, but this invasive strategy

has not been endorsed in routine care; it requires considerable resources and implies

high upfront costs, even though it seems to be cost effective.11,12 Episodes of AF may

25 be silent, thus not recognized or reported by the patient, but are nevertheless

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associated with the same risk of embolization.13-15 In patients with either dual-

chamber pacemakers or implantable defibrillators and with no previously

documented history of AF, atrial high rate episodes are associated with an increased

risk of stroke, although the temporal aspects suggest complex causative

5 pathways.16,17 The cutoff duration for increased risk among patients with implantable

devices is controversial, but episode duration of more than one hour doubles the risk

for ischemic stroke.18,19,20 The current position of the ESC clearly advocates a low

threshold for NOAC in patients with multiple risk factors and especially in secondary

prevention of stroke.21 A handheld ECG device typically monitors for 30 seconds to

10 meet the definition of AF, but captured episodes often reflects longer and repeated

episodes and has become a widely accepted indication to initiate NOAC in newly

detected AF.6,7 Given the fact that prior stroke or transient ischemic attack (TIA) is

the most powerful risk factor for recurrent stroke because it confers a 10% per year

risk, there is clearly an urgent need for accurate detection of AF and prompt

15 therapeutic intervention to prevent recurrent stroke.22

Sequentially stratified ECG monitoring detected AF in 24% of stroke patients.8 The

diagnostic yield was 11.5% in a pooled analysis, but this yield varies with such

factors as timing, length of registration, and the monitoring tool.23 Thus, while ECG

monitoring over an extended period of time is crucial for stroke survivors, post-

20 discharge Holter monitoring or patches are impractical, ECG data storage is limited,

and data interpretation requires considerable resources.

A large multicenter study of stroke patients on Holter monitoring reported new

diagnoses of AF in 2.6% of patients at 24 hours and 4.3% at 72 hours.10 In another

study, AF was detected in 8.3% of stroke patients monitored by continuous ECG for

25 a median of 89 hours in the stroke unit; prolonged monitoring was superior to 24-hour

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monitoring in detecting AF.24 Since ECG monitoring over an extended period of time

is important for stroke survivors, the thumb-ECG offers advantages: a twice-daily

monitoring schedule is convenient for patients, who can also use the device to

capture symptomatic episodes.

5 The chest and thumb-ECG Coala Heart MonitorTM (Coala Life AB, Stockholm,

Sweden) utilizes a smartphone application for remote monitoring through a web-

based platform. The system offers validated algorithms and the additional chest-

ECG, which allows for differentiation between arrhythmias. However, diagnostic yield

and feasibility of this system in patients who recently suffered a stroke need to be

10 evaluated.

The objective of this prospective study was to assess the yield of newly diagnosed

AF during 28 days of chest and thumb-ECG for 30 seconds in cryptogenic stroke.

METHODS

Setting and selection

15 Patients with a clinically confirmed diagnosis of ischemic stroke were recruited from

the catchment area of Region Gävleborg, Sweden and its two stroke units in Gävle

and Hudiksvall, respectively. Eligible patients were identified from weekly checks of

the medical records.

Inclusion and exclusion

20 Patients, aged ≥18 years, with a diagnosis of ischemic cryptogenic stroke were

eligible for the study. Cryptogenic stroke is defined as cerebral ischemia of unknown

etiology, i.e. not attributable to a source of cardiac embolism, large artery

atherosclerosis, or small artery disease despite a standard vascular, cardiac, and

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serologic evaluation.24 The exclusion criteria were as follows: previously known atrial

tachycardia with an indication for anticoagulation; an implantable cardioverter

defibrillator, pacemaker or insertable cardiac monitor; pregnancy; indication for

anticoagulation (including low-molecular weight heparin) due to atrial tachycardia,

5 mechanical heart valve, deep vein thrombosis, or pulmonary embolism. Thus, if

outcome is reached the patient should be a candidate for anticoagulation therapy.

Patients with a life expectancy ≤6 months or severe cognitive impairment were

excluded. Patients with a TIA were not included, because this diagnosis is often

uncertain due to being based solely on patient history.25

10 Stroke evaluation

Patients were evaluated with a carefully taken patient history, physical exam, routine

laboratory tests, and standard evaluation using 12-lead ECG, 24-hour Holter, carotid

Doppler ultrasonography and/or computed tomography angiography, computerized

tomography, and, when applicable, magnetic resonance imaging, echocardiography,

15 or transesophageal echocardiography, as well as extended coagulation tests.

Outcome measurements

Atrial tachycardia was defined as AF, atrial flutter, or ectopic atrial tachycardia with a

duration of at least 30 seconds. The date and time of each episode were recorded.

Study endpoint

20 The endpoint was 28-day cumulative incidence of atrial tachycardia.

Chest and thumb-ECG

Patients were asked to use the chest and thumb-ECG monitor device twice daily,

once between the hours of 6:00 and 10:00 a.m. and again between 6:00 and 10:00

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p.m. The monitoring was planned to start within a few days after the diagnosis of

stroke had been confirmed and standard evaluation was complete.

If the patients felt palpitations or other symptoms suggestive of arrhythmia, e.g.

sudden onset of tiredness, dyspnea, syncope, they were asked to record the episode

5 with the smartphone application. Each patient was monitored for four consecutive

weeks (28 days).

Each recording was stored in a web-based application accessible to the

investigators. The investigators checked all recordings daily. In the case of an atrial

tachycardia, a second investigator, an experienced cardiologist within the field of

10 arrhythmia, interpreted the recording. If the outcome was reached, anticoagulation

was promptly started.

Statistics

Descriptive data are reported as frequencies, percentages, means, interquartile

ranges, and percentiles. Continuous variables are summarized as means, standard

15 deviations, and percentiles, and t-tests were used for group comparisons, while chi-

squared test was used for categorical variables. Statistical significance was defined

as a two-sided p-value of <0.05. The data was stored in Excel 2010 (Microsoft

Corporation, Redmond, WA) and imported into SPSS version 25 (IBM, Armonk, NY)

for analyses.

20 Ethics and dissemination

The Regional Ethical Committee in Uppsala approved the study the 20th of

September 2017 (protocol number 2017/321). The study protocol was registered at

Clinical Trial Registration NCT03301662. Each patient was informed by a study

physician and included after written consent.

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RESULTS

As per protocol, 100 patients with a recent history of ischemic stroke were evaluated

between October 2017 and October 2019. The median time from index stroke to

inclusion was 7 days (interquartile range 4-13 days). The mean age at inclusion was

5 67.6±10.8 years. The ages ranged from 27 to 86 years and 25th, 50th, and 75th

percentiles were 61.8, 69.0, 74.9 years, respectively. A majority was male (60.0%)

and the mean age was similar between males and females (66.7±9.7 vs 68.9±12.3

years; p=0.323).

The mean total CHA2DS2-VASc score was 4.4±1.9 points. Because stroke implies 2

10 points per se, all patients had a score of at least 2. No patients had 8 or 9 points and

the scores were normally distributed within the cohort.

Outcome

In total, the 28-days of scheduled chest and thumb-ECG yielded 9% (n = 9) AF

among the participants. An example of AF is shown in Figure 1. No atrial flutter or

15 ectopic atrial tachycardia was diagnosed. The first episode of AF was diagnosed at a

mean of 12.7±7.8 days (range day 1 to 23). The characteristics of the cohort at

baseline and with regard to outcome is summarized in Table 1. The 9 AF episodes

were characterized by a mean frequency of 115±31 (range 72 to 166) beats per

minute. The mean CHA2DS2-VASc score was similar among patients with AF and no

20 AF (4.9±1.1 vs 4.3±1.3; p=0.224) and patients with AF were older (74.3±9.0 vs

66.9±10.8; p=0.049).

No patient died during the monitoring period.

Adherence to protocol

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Among the 111 participants who consented to participate, 11 dropped out because of

cognitive or phycial impairment that made them unable to handle the technology or

they did not wish to participate. Among the 100 participants who completed the

study, a total of 5,249 ECG transmissions were collected during the 28 day period.

5 Patients performed on average 90.1±15.0% (25th, 50th, and 75th percentile 87.5%,

96.4%, and 98.2%, respectively) of scheduled transmissions. The vast majority of

patients (n=86) performed extra transmissions (mean 0.21±0.29/day). The total

number of extra transmission per patient was 4.8±5.2 (range 0 to 24). If an episode

of AF was detected, the study outcome was reached and the patient’s participation in

10 the study was completed.

DISCUSSION

Prolonged monitoring using the Coala Heart MonitorTM detected AF in 9% of patients

with cryptogenic stroke, all of whom received NOAC to prevent recurrent stroke.

Because we targeted solely patients who were candidates for a change in medication

15 regimen in the presence of AF, this led to an actual benefit in the clinical

management of these individual patients. The number needed to screen based on

the yield in our study is 11. The estimated risk of ischemic stroke in AF patients

without anitcoagulation with CHA2DS2-VASc score 4 is 4.8 per 100 years (6.7 if the

composite stroke/TIA/systemic embolism is applied).26 Given the fact that prior

20 stroke/TIA is the most powerful risk factor and confers a 10% per year stroke risk, the

urgent need for rapid identification of AF and subsequent treatment after the first

stroke is underscored.22

Our findings have implications for clinical practice and widespread applicability for

secondary prevention of stroke. The common practice to rely on 24-48 hours of

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monitoring as part of stroke evaluation is insufficient and should be regarded as an

initial screen. Improving the detection of AF will be increasingly important in an aging

population with a considerable burden of other cardiovascular risk factors. Indeed,

the worldwide cardiovascular burden demands a targeted approach to AF and its

5 consequences.27

Compared to a study using ECG chest belt

The largest prospective study of event-triggered recordings of patients (mean age

72.5 years) with a history of cryptogenic stroke used a dry-electrode, nonadhesive,

belt around the chest for 30 days to enable better compliance than skin-contact

10 electrodes; 82% wore it at least 21 days.28 The AF yield was 12.9 percentage points

absolute difference compared to one day of Holter ECG monitoring (16.1% vs 3.2 %).

Compared to our study, these patients were slightly older, such a belt

might be better suited to patients who are unable to handle a smartphone-based

system. Nevertheless, compliance among our patients was better; those who

15 mastered the smartphone-based device are more likely to comply with the protocol

because it is more convenient than wearing a belt. This effect is likely to become

more pronounced over time. Our study has overcome two of the major limitations of

this earlier study. Firstly, the mean time from the index event of stroke to participation

in our study was 11.6±13.7 days, compared to 75.1±38.6 days in the belt study. This

20 late start of monitoring implies that patients were not monitored during the vulnerable

initial period after stroke, which may delay the initiation of protective treatment.

Indeed, most AF episodes occur around the time of the index event. However,

studies using implantable devices show that the cumulative incidence of AF

continues to increase after the first month.11,19 Secondly, as the authors suggested,

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including patients with TIA might dilute the cohort with low-risk patients if TIA was not

the correct diagnosis. This, in turn, could affect outcome.25

Comparison of chest-ECG

In a Danish cohort of 95 patients with stroke/TIA, using the Zenicor™ handheld

5 device twice daily for 30 days yielded 20 patients with AF but concurrent Holter

monitoring detected 11 of these episodes during the first day.29 Thus, in 10 out of 95

patients, the thumb-ECG detected AF that was not diagnosed by Holter. The median

time from index event to AF diagnosis was 4 days. The mean age was 79 years,

considerablly higher than in our study, which may have compensated for the

10 inclusion of TIA to result in similar yield as in our study. The finding that 13% of

tracings were not usable because poor quality may reflect the older age of the study

population, but also stresses the importance of thorough patient education at the time

of inclusion and support during follow-up, if needed. Of all eligible patients, 22%

could not be included because of cognitive and physical impairment. We share the

15 experience that not all patients are suitable for using a thumb-ECG in this type of

evaluation.

In another post stroke/TIA study (n=249) using thumb-ECG twice daily,

the yield was 6.8% and 11.8% in patients aged 75 years and older.30 The age

distribution of AF is in line with epidemiological data and previous findings. It should

20 be noted that recording capabilities of the devices at that time caused the definition of

AF to be limited to episodes of 10 seconds, which is shorter than the generally

accepted definition of AF episodes of 30 seconds, endorsed by current guidelines.7

Moreover, patients with a suspected TIA were included, in contrast to our study.

Interestingly, 94% of all detected AF episodes occurred during the first 20 days.

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In a single-center retrospective analysis, 13 out of 114 patients (11.4%) with

stroke/TIA had AF detected by a Zenicor™ ECG during a 21-day follow-up with

recordings scheduled twice daily.31 Episodes of less than 30 seconds were not

considered as AF. Notably, the mean age of the patients was 70.3 years and 27.2%

5 had a diagnosis of TIA. This study adds data about yield and feasibility in real-world

care, outside of a clinical trial. As in our study, patients in this single-center study

received their handheld ECG system soon after stroke, in this case a mean of 4.1

days from the stroke.

Limitations

10 Although the overall benefit of anticoagulation in AF patients based on current risk

assessment is unequivocal, the cause of stroke in an individual case is often hard to

prove. The mechanisms of ischemic stroke may be multifactorial. AF, especially

recurrent and extended episodes, may cause remodeling of the atrial anatomy and

structural changes. Even if AF is detected, consideration of other causes should not

15 necessarily be ruled out. Therefore, an overall assessment of risk factors and

treatment options is warranted in conjunction with a team-based approach, which is

crucial to improve stroke managment.

The incidence of AF in this trial is likely underestimated. The largest and

most severe strokes often occur in the elderly, who are likely to be underrepresented

20 in clinical trials. However, the target population for this trial had to be able to handle

the equipment and be followed by remote system in a outpatient setting after

discharge. Patients with milder, less disabling stroke constitute an ideal group for

prevention of recurrent stroke and death. Although a thumb-ECG is an attractive

method of noninvasive AF detection, there remain some controversies with regard to

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anticoagulation for short-term AF. The duration of an AF episode captured by

snapshot is unknown, but it is assumed to represent longer or multiple episodes. The

potential benefits of anticoagulation therapy for short-term AF would be challenging

to study, because it would require long-term follow-up, demands a large sample size,

5 a randomized controlled design, and raises ethical concerns about withholding

anticoagulation from stroke survivors.

Future perspectives

Guidelines already allow for prolonged monitoring of these patients: “In stroke

patients, additional ECG monitoring by long-term noninvasive or implanted loop

10 recorders should be considered to document silent atrial fibrillation” (class IIa

recommendation, level of evidence B).7 Despite the landmark trial,11 current practice

remains unchanged in that invasive monitoring is rarely used for AF detection in

stroke patients. The benefit of the thumb-ECG in secondary stroke prevention has

been demonstrated by our study, in addition to previous efforts in this setting. Yet,

15 cost effectiveness in this setting from both healthcare and societal viewpoint remains

to be elucidated.

Furthermore, a large-scale, multicenter, international, prospective observational trial

is welcome in order to confirm diagnostic yield and would allow for subgroup

analyses; and assessment of predictors for increased probability of AF. Artifical

20 intelligence is tempting to consider in order to personalize evaluations, based on the

presence of well-known markers of AF such as extrasystoles, clinical risk factors, and

possibly laboratory markers. Moreover, the feasibility of different devices and the

length of evaluation time need to be further refined and adapted to possible

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subgroups of stroke patients. In addition to advances in technology, the availability of

devices as an integral part of stroke assessment needs to be increased.

CONCLUSION

In patients with cryptogenic stroke, 9% have AF detected using chest and thumb-

5 ECG twice daily over a period of four weeks. In many stroke survivors this is a

feasible approach and can protect them from recurrent stroke by allowing for prompt

initiation of NOAC treatment.

DECLARATIONS

10 Ethics: The study was approved by The Regional Ethical Committee in Uppsala

(2017/321) and registered at Clinical Trial Registration NCT03301662.

Consent for publication

Not applicable.

Acknowledgements

15 The authors acknowledge editing by Jo Ann LeQuang of LeQ Medical who reviewed

the manuscript for American English. Adrian Kling, Titti Lundgren, Ulf Tossman,

Magnus Samuelsson, and Philip Siberg from Coala Life are acknowledged for

support regarding the Coala Life Monitor.TM The authors also wish to thank the staff

at the stroke unit in Gävle and Hudiksvall for their participation in the study.

20 Author contributions

PM: idea, design, data collection, analyses and interpretation, administration,

supervision, project management, and writing of the manuscript. AL: data collection,

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critical revision. GM: design, data collection, analyses and interpretation,

administration, project co-management, critical revision.

Funding

Region Gävleborg funded this research project and Coala Life provided free product

5 Coala Heart MonitorTM during the study period.

Competing interests

The project received free product from Coala Life.

Outside this project: PM has received speaker fees or grants from Abbott, Alnylam,

Bayer, AstraZeneca, Boehringer-Ingelheim, Internetmedicin, Lilly, MSD, Novo

10 Nordisk, Octopus Medical, Orion Pharma, Pfizer, Vifor Pharma, and Zoll. AL has

received speaker fees from Pfizer. GM has received speakers fee from Alnylam,

MSD, and Internetmedicin.

Ethics approval

The study was approved by the Regional Ethical committee in Uppsala (Dnr

15 2017/321).

Patient consent for publication

Not required.

Data sharing statement

No additional data sharing available.

20 Patient and Public Involvement

Patients were not involved in the design, or condict, or reporting, or dissemination

plan of our research.

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ORCID

Peter Magnusson: 0000-0001-7906-7782

Adam Lyrén: 0000-0001-5557-9345

Gustav Mattsson: 0000-0002-4317-0443

5 REFERENCES

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5. Ruff CT, Giugliano RP, Braunwald E, et al. Comparison of the efficacy and safety

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analysis of randomised trials. Lancet 2014;383:955-62.

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11. Sanna T, Diener HC, Passman RS, et al. CRYSTAL AF Investigators.

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13. Savelieva I, Camm AJ. Clinical relevance of silent atrial fibrillation: prevalence,

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14. Friberg L, Hammar N, Rosenqvist M. Stroke in paroxysmal atrial fibrillation: report

5 from the Stockholm Cohort of Atrial Fibrillation. Eur Heart J 2010;31:967-75.

15. Vanassche T, Lauw MN, Eikelboom JW, et al. Risk of ischaemic stroke according

to pattern of atrial fibrillation: analysis of 6563 aspirin-treated patients in ACTIVE-A

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16. Healey JS, Connolly SJ, Gold MR, et al. ASSERT Investigators. Subclinical atrial

10 fibrillation and the risk of stroke. N Engl J Med 2012;366:120-9.

17. Brambatti M, Connolly SJ, Gold MR, et al; ASSERT Investigators. Temporal

relationship between subclinical atrial fibrillation and embolic events. Circulation

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18. Boriani G, Glotzer TV, Santini M, et al. Device-detected atrial fibrillation and risk

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19. Glotzer TV, Hellkamp AS, Zimmerman J, et al; MOST Investigators. Atrial high

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20. Glotzer TV, Daoud EG, Wyse DG, et al. The relationship between daily atrial

tachyar-rhythmia burden from implantable device diagnostics and stroke risk: the

TRENDS study. Circ Arrhythmia Electrophysiol 2009;2(5):474-80.

21. Gorenek B, Bax J, Boriani G, et al; ESC Scientific Document Group. Device-

5 detected subclinical atrial tachyarrhythmias: definition, implications and management

– an European Heart Rhythm Association (EHRA) consensus document, endorsed

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Sociedad Latinoamericana de Estimulación Cardíaca y Electrofisiología (SOLEACE).

Europace 2017;19(9):1556-78.

10 22. Stroke Risk in Atrial Fibrillation Working Group. Independent predictors of stroke

in patients with atrial fibrillation: a systematic review. Neurology 2007;69(6):546-54.

23. Sposato LA, Cipriano LE, Saposnik G, et al. Diagnosis of atrial fibrillation after

stroke and transient ischaemic attack: a systematic review and meta-analysis. Lancet

Neurol 2015;14:377-87.

15 24. Rizos T, Guntner J, Jenetzky E, et al. Continuous stroke unit electrocardiographic

monitoring versus 24-hour Holter electrocardiography for detection of paroxysmal

atrial fibrillation after stroke. Stroke 2012;43:2689-94.

25. Servaas Dolmans L, Lebedeva E, Veluponnar D, et al. Diagnostic Accuracy of

the Explicit Diagnostic Criteria for Transient Ischemic Attack. Stroke 2019;50:2080–

20 85.

26. Friberg L, Rosenqvist M, Lip GY. Evaluation of risk stratification schemes for

ischaemic stroke and bleeding in 182 678 patients with atrial fibrillation: the Swedish

Atrial Fibrillation cohort study. Eur Heart J 2012;33:1500-10.

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27. Healey JS, Oldgren J, Ezekowitz M, et al; RE-LY Atrial Fibrillation Registry and

Cohort Study Investigators. Occurrence of death and stroke in patients in 47

countries 1 year after presenting with atrial fibrillation: a cohort study. Lancet

2016;388:1161-9.

5 28. Gladstone DJ, Spring M, Dorian P; EMBRACE Investigators and Coordinators.

Atrial fibrillation in patients with cryptogenic stroke. N Engl J Med 2014;370:2467-77.

29. Poulsen MB, Binici Z, Dominguez H. Performance of short ECG recordings twice

daily to detect paroxysmal atrial fibrillation in stroke and transient ischemic attack

patients. Int J Stroke 2017;12:192-6.

10 30. Doliwa Sobocinski P, Anggårdh Rooth E, Frykman Kull V, et al. Improved

screening for silent atrial fibrillation after ischaemic stroke. Europace 2012;14:1112-6.

31. Orrsjö G, Cederin B, Bertholds E, et al. Screening of Paroxysmal Atrial Fibrillation

after Ischemic Stroke: 48-Hour Holter Monitoring versus Prolonged Intermittent ECG

Recording. ISRN Stroke 2014 Article ID 208195, 6 pages.

15

20

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● Table 1. Characteristics of 100 patients at baseline.

All (%) No atrial fibrillation (%)

Atrial fibrillation (%)

Patients 100 (100) 91 (91) 9 (9)Mean age (years) 67.6 ± 10.8 66.9 ± 10.8 74.3 ± 9.0Median time from index stroke to inclusion (days)

7.0 (IQR 4.0-12.8) 7.0 (IQR 4.0-13.0) 6.0 (IQR 3.0-8.0)

Congestive heart failure 1 (1) 1 (1.1) 0 (0)Hypertension 78 (78.0) 71 (78.0) 7 (77.8)Age≥ 75 years 24 (24.0) 20 (22.0) 4 (44.4)Diabetes mellitus 19 (19.0) 18 (19.8) 1 (11.1)Stroke 100 (100.0) 91 (100.0) 9 (100.0)Vascular disease 17 (17.0) 16 (17.6) 1 (11.1)Age 65-74 years 37 (37.0) 34 (37.4) 3 (33.3)Sex category (female) 40 (40.0) 34 (37.4) 6 (66.7)CHA2DS2-VASc score Mean total score 4.4 ± 1.9 4.3 ± 1.3 4.9 ± 1.1 0 point 0 (0.0) 0 (0.0) 0 (0.0) 1 point 0 (0.0) 0 (0.0) 0 (0.0) 2 points 6 (6.0) 6 (6.6) 0 (0.0) 3 points 22 (22.0) 22 (24.2) 0 (0.0) 4 points 24 (24.0) 20 (22.0) 4 (44.4) 5 points 28 (28.0 25 (27.5) 3 (33.3) 6 points 15 (15.0) 14 (15.4) 1 (11.1) 7 points 5 (5.0) 4 (4.4) 1 (11.1) 8 points 0 (0.0) 0 (0.0) 0 (0.0) 9 points 0 (0.0) 0 (0.0) 0 (0.0)

Data presented as frequencies (percentage in parenthesis)

IQR = interquartile range

5

● Figure 1. Example of an ECG transmission from a Coala Heart Monitor™ for an episode of atrial fibrillation.

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Figure 1. Example of an ECG transmission from a Coala Heart Monitor™ for an episode of atrial fibrillation.

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STROBE Statement—checklist of items that should be included in reports of observational studies

Item No Recommendation

Page No

(a) Indicate the study’s design with a commonly used term in the title or the abstract

1Title and abstract 1

(b) Provide in the abstract an informative and balanced summary of what was done and what was found

2

IntroductionBackground/rationale 2 Explain the scientific background and rationale for the investigation being

reported4

Objectives 3 State specific objectives, including any prespecified hypotheses 5

MethodsStudy design 4 Present key elements of study design early in the paper 1,2,6Setting 5 Describe the setting, locations, and relevant dates, including periods of

recruitment, exposure, follow-up, and data collection6,7

(a) Cohort study—Give the eligibility criteria, and the sources and methods of selection of participants. Describe methods of follow-upCase-control study—Give the eligibility criteria, and the sources and methods of case ascertainment and control selection. Give the rationale for the choice of cases and controlsCross-sectional study—Give the eligibility criteria, and the sources and methods of selection of participants

6,7Participants 6

(b) Cohort study—For matched studies, give matching criteria and number of exposed and unexposedCase-control study—For matched studies, give matching criteria and the number of controls per case

Variables 7 Clearly define all outcomes, exposures, predictors, potential confounders, and effect modifiers. Give diagnostic criteria, if applicable

6,7,8

Data sources/ measurement

8* For each variable of interest, give sources of data and details of methods of assessment (measurement). Describe comparability of assessment methods if there is more than one group

6

Bias 9 Describe any efforts to address potential sources of bias 6Study size 10 Explain how the study size was arrived at 6Quantitative variables 11 Explain how quantitative variables were handled in the analyses. If

applicable, describe which groupings were chosen and why6,7

(a) Describe all statistical methods, including those used to control for confounding

8

(b) Describe any methods used to examine subgroups and interactions 8(c) Explain how missing data were addressed 8(d) Cohort study—If applicable, explain how loss to follow-up was addressedCase-control study—If applicable, explain how matching of cases and controls was addressedCross-sectional study—If applicable, describe analytical methods taking account of sampling strategy

8

Statistical methods 12

(e) Describe any sensitivity analysesContinued on next page

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Results(a) Report numbers of individuals at each stage of study—eg numbers potentially eligible, examined for eligibility, confirmed eligible, included in the study, completing follow-up, and analysed

9

(b) Give reasons for non-participation at each stage 9

Participants 13*

(c) Consider use of a flow diagram NA(a) Give characteristics of study participants (eg demographic, clinical, social) and information on exposures and potential confounders

9

(b) Indicate number of participants with missing data for each variable of interest 9

Descriptive data

14*

(c) Cohort study—Summarise follow-up time (eg, average and total amount)Cohort study—Report numbers of outcome events or summary measures over time 9,10Case-control study—Report numbers in each exposure category, or summary measures of exposure

Outcome data 15*

Cross-sectional study—Report numbers of outcome events or summary measures(a) Give unadjusted estimates and, if applicable, confounder-adjusted estimates and their precision (eg, 95% confidence interval). Make clear which confounders were adjusted for and why they were included

9

(b) Report category boundaries when continuous variables were categorized

Main results 16

(c) If relevant, consider translating estimates of relative risk into absolute risk for a meaningful time period

Other analyses 17 Report other analyses done—eg analyses of subgroups and interactions, and sensitivity analyses

10

DiscussionKey results 18 Summarise key results with reference to study objectives 11,12Limitations 19 Discuss limitations of the study, taking into account sources of potential bias or

imprecision. Discuss both direction and magnitude of any potential bias13

Interpretation 20 Give a cautious overall interpretation of results considering objectives, limitations, multiplicity of analyses, results from similar studies, and other relevant evidence

12,13

Generalisability 21 Discuss the generalisability (external validity) of the study results 13

Other informationFunding 22 Give the source of funding and the role of the funders for the present study and, if

applicable, for the original study on which the present article is based16

*Give information separately for cases and controls in case-control studies and, if applicable, for exposed and unexposed groups in cohort and cross-sectional studies.

Note: An Explanation and Elaboration article discusses each checklist item and gives methodological background and published examples of transparent reporting. The STROBE checklist is best used in conjunction with this article (freely available on the Web sites of PLoS Medicine at http://www.plosmedicine.org/, Annals of Internal Medicine at http://www.annals.org/, and Epidemiology at http://www.epidem.com/). Information on the STROBE Initiative is available at www.strobe-statement.org.

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Journal: BMJ Open

Manuscript ID bmjopen-2020-037573.R1


Date Submitted by the Author: 15-Jun-2020


<b>Primary Subject Heading</b>: Cardiovascular medicine

Secondary Subject Heading: Cardiovascular medicine



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observational trial



SWEDEN


SWEDEN

10

Correspondence to:

Peter Magnusson





Phone: +46(0)705 089407

Fax: +46(0)26 154255


20

Word count: 3245



25

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ABSTRACT













remote monitoring.



other significant atrial arrhythmias (>30 seconds) was diagnosed. The mean

CHA2DS2-VASc score was similar among patients with AF and no AF (4.9±1.1 vs

4.3±1.3; p=0.224) and patients with AF were older (74.3±9.0 vs 66.9±10.8; p=0.049).

20 Patients performed on average 90.1±15.0% of scheduled transmissions.



this is a feasible approach and they will be protected from recurrent stroke by

anticoagulation treatment.

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• Prospective evaluation of atrial fibrillation using the chest and thumb-ECG after

stroke.


5 generalizability.

• Use of the Coala Life MonitorTM which is connected to a webbased portal

10

15

20 INTRODUCTION

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diabetes, vascular disease, and the interplay with atrial fibrillation (AF).2,3 AF is a

5 complex condition known to cause stroke and systemic embolization, but these




NOAC trials showed a 19% reduction of stroke/systemic embolism and a 10% lower

10 mortality compared to warfarin.5 If AF is not diagnosed, then antiplatelet medication is




ischemic stroke have a documented episode of AF before, during, or after the stroke,

15 but in a quarter of patients, the stroke is cryptogenic, meaning that no attributable




monitoring, external event or loop recorders, long-term monitoring using patches, and

20 handheld devices. Insertable cardiac monitors in cryptogenic stroke yield an AF




be silent, thus not recognized or reported by the patient, but are nevertheless

25 associated with the same risk of embolization.13-15 In patients with either dual-

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pathways.16,17 The cutoff duration for increased risk among patients with implantable

5 devices is controversial, but episode duration of more than one hour doubles the risk




meet the definition of AF, but captured episodes often reflects longer and repeated

10 episodes and has become a widely accepted indication to initiate NOAC in newly




therapeutic intervention to prevent recurrent stroke.22

15 Sequentially stratified ECG monitoring detected AF in 24% of stroke patients.8 The




discharge Holter monitoring or patches are impractical, ECG data storage is limited,

20 and data interpretation requires considerable resources.




a median of 89 hours in the stroke unit; prolonged monitoring was superior to 24-hour

25 monitoring in detecting AF.24 Since ECG monitoring over an extended period of time

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The chest and thumb-ECG Coala Heart MonitorTM (Coala Life AB, Stockholm,

5 Sweden) utilizes a smartphone application for remote monitoring through a web-


ECG, which allows for differentiation between arrhythmias.25 However, diagnostic

yield and feasibility of this system in patients who recently suffered a stroke need to

be evaluated.

10 The objective of this prospective study was to assess the yield of newly diagnosed


METHODS


Patients with a clinically confirmed diagnosis of ischemic stroke were recruited from

15 the catchment area of Region Gävleborg, Sweden and its two stroke units in Gävle




Patients, aged ≥18 years, with a diagnosis of ischemic cryptogenic stroke were

20 eligible for the study. Cryptogenic stroke is defined as cerebral ischemia of unknown




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mechanical heart valve, deep vein thrombosis, or pulmonary embolism. Thus, if

5 outcome is reached the patient should be a candidate for anticoagulation therapy.



uncertain when being based solely on patient history.26 While the more recent tissue-

based definition of TIA utilizing magnetic resonance diffusion weighted imaging

10 improves the diagnostic accuracy, this is not always done in routine clinical

practice.27

Stroke evaluation


laboratory tests, and standard evaluation using 12-lead ECG, 24-hour Holter, carotid

15 Doppler ultrasonography and/or computed tomography angiography, computerized


or transesophageal echocardiography, as well as extended coagulation tests.


Atrial fibrillation or atrial flutter with a duration of at least 30 seconds. The date and

20 time of each episode were recorded.

Study endpoint

The endpoint was 28-day cumulative incidence of atrial fibrillation or atrial flutter.

Chest and thumb-ECG

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stroke had been confirmed and standard evaluation was complete.

5 If the patients felt palpitations or other symptoms suggestive of arrhythmia, e.g.


with the smartphone application. Each patient was monitored for four consecutive

weeks (28 days).

Each recording was stored in a web-based application accessible to the

10 investigators. The investigators checked all recordings daily. In the case of an

arrhythmia that would imply outcome, a second investigator, an experienced

cardiologist within the field of arrhythmia, interpreted the recording. If the outcome

was reached, anticoagulation was promptly started.

Statistics

15 Descriptive data are reported as frequencies, percentages, means, interquartile


deviations, and percentiles, and t-tests were used for group comparisons, while chi-


as a two-sided p-value of <0.05. The data was stored in Excel 2010 (Microsoft

20 Corporation, Redmond, WA) and imported into SPSS version 25 (IBM, Armonk, NY)

for analyses.

Ethics and dissemination



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Clinical Trial Registration NCT03301662 and published.28 Each patient was informed

by a study physician and included after written consent.

RESULTS


5 (out of 111 who consented to participate) between October 2017 and October 2019.

The median time from index stroke to inclusion was 7 days (interquartile range 4-13

days). The mean age at inclusion was 67.6±10.8 years. The ages ranged from 27 to

86 years and 25th, 50th, and 75th percentiles were 61.8, 69.0, 74.9 years, respectively.

A majority was male (60.0%) and the mean age was similar between males and

10 females (66.7±9.7 vs 68.9±12.3 years; p=0.323).


points per se, all patients had a score of at least 2. No patients had 8 or 9 points and


Outcome

15 In total, the 28-days of scheduled chest and thumb-ECG yielded 9% (n = 9) AF

among the participants. An example of AF is shown in Figure 1 (as a comparison

sinus rhythm is shown in Figure 2). No atrial flutter or ectopic atrial tachycardia was

diagnosed. The first episode of AF was diagnosed at a mean of 12.7±7.8 days (range

day 1 to 23). The characteristics of the cohort at baseline and with regard to outcome

20 is summarized in Table 1. The 9 AF episodes were characterized by a mean

frequency of 115±31 (range 72 to 166) beats per minute. The mean CHA2DS2-VASc

score was similar among patients with AF and no AF (4.9±1.1 vs 4.3±1.3; p=0.224)

and patients with AF were older (74.3±9.0 vs 66.9±10.8; p=0.049).

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Out of 9 patients with detected atrial fibrillation, 1 patient had come into contact with

health care due to the episode, he reported that he experienced symptoms in the

form of palpitations and dizziness the night before atrial fibrillation was detected. He

had experienced similar symptoms previously but this time after seeing that the

5 automated report of the scheduled ECG in the morning was abnormal he went to the

emergency department and was admitted due to rapid atrial fibrillation. Out of the

other 8 patients with detected atrial fibrillation; 1 reported feeling palpitations, 1

reported feeling stressed as well as dizzy and 6 reported feeling well with no

symptoms in conjunction with the episode.

10 There was no adverse event related to the use of the ECG device. No patient died

during the monitoring period.




15 they did not wish to participate. Among the 100 participants who completed the


Patients performed on average 90.1±15.0% (25th, 50th, and 75th percentile 87.5%,



20 number of extra transmission per patient was 4.8±5.2 (range 0 to 24). If an episode


the study was completed.

DISCUSSION

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Prolonged monitoring using the Coala Heart MonitorTM detected AF in 9% of patients



regimen in the presence of AF, this led to a potential benefit in the clinical

5 management of these individual patients. The number needed to screen based on

the yield in our study is 11. The estimated risk of ischemic stroke in AF patients



stroke/TIA is the most powerful risk factor and confers a 10% per year stroke risk, the

10 urgent need for rapid identification of AF and subsequent treatment after the first

stroke is underscored.22




15 initial screen. Improving the detection of AF will be increasingly important in an aging

population with a considerable burden of other cardiovascular risk factors. Indeed,


consequences.30


20 The largest prospective study of event-triggered recordings of patients (mean age



electrodes; 82% wore it at least 21 days.31 The AF yield was 12.9 percentage points

absolute difference compared to one day of Holter ECG monitoring (16.1% vs 3.2 %).

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mastered the smartphone-based device are more likely to comply with the protocol

5 because it is more convenient than wearing a belt. This effect is likely to become




late start of monitoring implies that patients were not monitored during the vulnerable

10 initial period after stroke, which may delay the initiation of protective treatment.





15 the correct diagnosis. This, in turn, could affect outcome.25



device twice daily for 30 days yielded 20 patients with AF but concurrent Holter


20 patients, the thumb-ECG detected AF that was not diagnosed by Holter. The median



inclusion of TIA to result in similar yield as in our study. The finding that 13% of

tracings were not usable because poor quality may reflect the older age of the study

25 population, but also stresses the importance of thorough patient education at the time

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experience that not all patients are suitable for using a thumb-ECG in this type of

evaluation.

5 In another post stroke/TIA study (n=249) using thumb-ECG twice daily

for 30 days, the yield was 6.8% and 11.8% in patients aged 75 years and older.33

The age distribution of AF is in line with epidemiological data and previous findings. It

should be noted that recording capabilities of the devices at that time caused the

definition of AF to be limited to episodes of 10 seconds, which is shorter than the

10 generally accepted definition of AF episodes of 30 seconds, endorsed by current

guidelines.7 Moreover, patients with a suspected TIA were included, in contrast to our

study. Interestingly, 94% of all detected AF episodes occurred during the first 20

days.

In a single-center retrospective analysis, 13 out of 114 patients (11.4%) with

15 stroke/TIA had AF detected by a Zenicor™ ECG during a 21-day follow-up with



had a diagnosis of TIA. This study adds data about yield and feasibility in real-world

care, outside of a clinical trial. As in our study, patients in this single-center study

20 received their handheld ECG system soon after stroke, in this case a mean of 4.1


Limitations

Although the overall benefit of anticoagulation in AF patients based on current risk

assessment is unequivocal, the cause of stroke in an individual case is often hard to

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prove. We used a pragmatic approach based on current practice, even though a

more detailed classification, based on imaging, of cryptogenic stroke has been

suggested.27 The mechanisms of ischemic stroke may be multifactorial. AF,

especially recurrent and extended episodes, may cause remodeling of the atrial

5 anatomy and structural changes. Even if AF is detected, consideration of other

causes should not necessarily be ruled out. Therefore, an overall assessment of risk

factors and treatment options is warranted in conjunction with a team-based

approach, which is crucial to improve stroke management.


10 most severe strokes often occur in the elderly, who are likely to be underrepresented

in clinical trials. However, the target population for this trial had to be able to handle



prevention of recurrent stroke and death. In patients not eligible for thumb ECG, a

15 device with adhesive electrodes would be an alternative.35 Although a thumb-ECG is

an attractive method of noninvasive AF detection, there remain some controversies

with regard to anticoagulation for short-term AF. The duration of an AF episode

captured by snapshot is unknown, but it is assumed to represent longer or multiple

episodes. The potential benefits of anticoagulation therapy for short-term AF would

20 be challenging to study, because it would require long-term follow-up, demands a

large sample size, a randomized controlled design, and raises ethical concerns about

withholding anticoagulation from stroke survivors.

Future perspectives

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Guidelines already allow for prolonged monitoring of these patients: “In stroke


recorders should be considered to document silent atrial fibrillation” (class IIa


5 remains unchanged in that invasive monitoring is rarely used for AF detection in

stroke patients. The benefit of the thumb-ECG in secondary stroke prevention has


cost effectiveness in this setting from both healthcare and societal viewpoint remains

to be elucidated.

10 Furthermore, a large-scale, multicenter, international, prospective observational trial

is welcome in order to confirm diagnostic yield and would allow for subgroup


intelligence is tempting to consider in order to personalize evaluations, based on the


15 possibly laboratory markers. Moreover, the feasibility of different devices and the

length of evaluation time need to be further refined and adapted to possible



CONCLUSION

20 In patients with cryptogenic stroke, 9% have AF detected using chest and thumb-

ECG twice daily over a period of four weeks. In many stroke survivors this is a

feasible approach and can protect them from recurrent stroke by allowing for prompt

initiation of NOAC treatment.

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DECLARATIONS

Ethics: The study was approved by The Regional Ethical Committee in Uppsala



5 Not applicable.

Acknowledgements

The authors acknowledge editing by Jo Ann LeQuang of LeQ Medical who reviewed



10 support regarding the Coala Life Monitor.TM The authors also wish to thank the staff

at the stroke unit in Gävle and Hudiksvall for their participation in the study.

Author contributions



15 critical revision. GM: design, data collection, analyses and interpretation,

administration, project co-management, critical revision.

Funding

Region Gävleborg funded this research project and Coala Life provided free product

Coala Heart MonitorTM during the study period.

20 Competing interests


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Outside this project: PM has received speaker fees or grants from Abbott, Alnylam,


Nordisk, Octopus Medical, Orion Pharma, Pfizer, Vifor Pharma, and Zoll. AL has


5 MSD, and Internetmedicin.

Ethics approval


2017/321).


10 Not required.

Data sharing statement


Patient and Public Involvement


15 plan of our research.

ORCID

Peter Magnusson: 0000-0001-7906-7782

Adam Lyrén: 0000-0001-5557-9345

Gustav Mattsson: 0000-0002-4317-0443

20 REFERENCES

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Cardiovascular Diseases for 10 Causes, 1990 to 2015. J Am Coll Cardiol 2017;70:1-

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11. Sanna T, Diener HC, Passman RS, et al. CRYSTAL AF Investigators.

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15 12. Diamantopoulos A, Sawyer LM, Lip GY, et al. Cost-effectiveness of an insertable


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13. Savelieva I, Camm AJ. Clinical relevance of silent atrial fibrillation: prevalence,


20 82.


from the Stockholm Cohort of Atrial Fibrillation. Eur Heart J 2010;31:967-75.

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and AVERROES. Eur Heart J 2015;36:281-87.


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Eur Heart J 2014;35(8):508-16.

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tachyar-rhythmia burden from implantable device diagnostics and stroke risk: the


20 21. Gorenek B, Bax J, Boriani G, et al; ESC Scientific Document Group. Device-

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Europace 2017;19(9):1556-78.

22. Stroke Risk in Atrial Fibrillation Working Group. Independent predictors of stroke


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24. Rizos T, Guntner J, Jenetzky E, et al. Continuous stroke unit electrocardiographic


10 atrial fibrillation after stroke. Stroke 2012;43:2689-94.

25. Insulander P, Carnlöf C, Schenck-Gustafsson K, Jensen-Urstad M. Device profile

of the Coala Heart Monitor for remote monitoring of the heart rhythm: overview of its

efficacy. Expert Rev Med Devices. 2020 Mar;17(3):159-165.


15 the Explicit Diagnostic Criteria for Transient Ischemic Attack. Stroke 2019;50:2080–

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27. Hart RG, Catanese L, Perera KS, et al. Embolic stroke of undetermined source: A

systematic review and clinical update. Stroke 2017 48(4), 867– 72.

28. Magnusson P, Koyi H, Mattsson G. A Protocol for a Prospective Observational

20 Study Using Chest and Thumb ECG: Transient ECG Assessment in Stroke

Evaluation (TEASE) in Sweden. BMJ Open. 2018 Apr 3;8(4):e019933.

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5 Cohort Study Investigators. Occurrence of death and stroke in patients in 47


2016;388:1161-9.

31. Gladstone DJ, Spring M, Dorian P; EMBRACE Investigators and Coordinators.


10 32. Poulsen MB, Binici Z, Dominguez H. Performance of short ECG recordings twice



33. Doliwa Sobocinski P, Anggårdh Rooth E, Frykman Kull V, et al. Improved


15 34. Orrsjö G, Cederin B, Bertholds E, et al. Screening of Paroxysmal Atrial Fibrillation



35. Lumikari TJ, Putaala J, Kerola A, et al. Continuous 4-week ECG Monitoring With

Adhesive Electrodes Reveals AF in Patients With Recent Embolic Stroke of

20 Undetermined Source. Ann Noninvasive Electrocardiol 2019;24(5):e12649.

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7.0 (IQR 4.0-12.8) 7.0 (IQR 4.0-13.0) 6.0 (IQR 3.0-8.0)




5

10

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● Figure 2. Example of an ECG transmission from a Coala Heart Monitor™ showing normal 5 sinus rhythm.

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● Figure 2. Example of an ECG transmission from a Coala Heart Monitor™ showing normal sinus rhythm.

79x26mm (300 x 300 DPI)

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Page No




2


reported4





6,7Participants 6



6,7,8



6




8


8



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9


Participants 13*


9


Descriptive data

14*


Outcome data 15*


9


Main results 16



10




12,13






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Journal: BMJ Open

Manuscript ID bmjopen-2020-037573.R2


Date Submitted by the Author: 05-Aug-2020


<b>Primary Subject Heading</b>: Cardiovascular medicine

Secondary Subject Heading: Cardiovascular medicine



BMJ Open on F


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1



observational trial



SWEDEN


SWEDEN

10

Correspondence to:

Peter Magnusson





Phone: +46(0)705 089407

Fax: +46(0)26 154255


20

Word count: 3245



25

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2

ABSTRACT













remote monitoring.



other significant atrial arrhythmias (>30 seconds) was diagnosed. The mean

CHA2DS2-VASc score was similar among patients with AF and no AF (4.9±1.1 vs

4.3±1.3; p=0.224) and patients with AF were older (74.3±9.0 vs 66.9±10.8; p=0.049).

20 Patients performed on average 90.1±15.0% of scheduled transmissions.



this is a feasible approach and they will be potentially protected from recurrent stroke

by anticoagulation treatment.

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• Prospective study design.

• Evaluation of atrial fibrillation using a combined chest and thumb-ECG after stroke.


5 generalizability.

• Use of the Coala Life MonitorTM which is connected to a webbased portal.

• Limited sample size based on stroke units at two centers.

10

15

20

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4

INTRODUCTION




5 diabetes, vascular disease, and the interplay with atrial fibrillation (AF).2,3 AF is a

complex condition known to cause stroke and systemic embolization, but these




10 NOAC trials showed a 19% reduction of stroke/systemic embolism and a 10% lower

mortality compared to warfarin.5 If AF is not diagnosed, then antiplatelet medication is




15 ischemic stroke have a documented episode of AF before, during, or after the stroke,

but in a quarter of patients, the stroke is cryptogenic, meaning that no attributable




20 monitoring, external event or loop recorders, long-term monitoring using patches, and

handheld devices. Insertable cardiac monitors in cryptogenic stroke yield an AF




25 be silent, thus not recognized or reported by the patient, but are nevertheless

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5

associated with the same risk of embolization.13-15 In patients with either dual-




5 pathways.16,17 The cutoff duration for increased risk among patients with implantable

devices is controversial, but episode duration of more than one hour doubles the risk




10 meet the definition of AF, but captured episodes often reflects longer and repeated

episodes and has become a widely accepted indication to initiate NOAC in newly




15 therapeutic intervention to prevent recurrent stroke.22

Sequentially stratified ECG monitoring detected AF in 24% of stroke patients.8 The




20 discharge Holter monitoring or patches are impractical, ECG data storage is limited,

and data interpretation requires considerable resources.




25 a median of 89 hours in the stroke unit; prolonged monitoring was superior to 24-hour

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6

monitoring in detecting AF.24 Since ECG monitoring over an extended period of time




5 The chest and thumb-ECG Coala Heart MonitorTM (Coala Life AB, Stockholm,

Sweden) utilizes a smartphone application for remote monitoring through a web-


ECG, which allows for differentiation between arrhythmias.25 However, diagnostic

yield and feasibility of this system in patients who recently suffered a stroke need to

10 be evaluated.

The objective of this prospective study was to assess the yield of newly diagnosed


METHODS


15 Patients with a clinically confirmed diagnosis of ischemic stroke were recruited from

the catchment area of Region Gävleborg, Sweden and its two stroke units in Gävle




20 Patients, aged ≥18 years, with a diagnosis of ischemic cryptogenic stroke were

eligible for the study. Cryptogenic stroke is defined as cerebral ischemia of unknown



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5 mechanical heart valve, deep vein thrombosis, or pulmonary embolism. Thus, if

outcome is reached the patient should be a candidate for anticoagulation therapy.



uncertain when being based solely on patient history.26 While the more recent tissue-

10 based definition of TIA utilizing magnetic resonance diffusion weighted imaging

improves the diagnostic accuracy, this is not always done in routine clinical

practice.27

Stroke evaluation


15 laboratory tests, and standard evaluation using 12-lead ECG, 24-hour Holter, carotid

Doppler ultrasonography and/or computed tomography angiography, computerized


or transesophageal echocardiography, as well as extended coagulation tests.


20 Atrial fibrillation or atrial flutter with a duration of at least 30 seconds. The date and

time of each episode were recorded.

Study endpoint

The endpoint was 28-day cumulative incidence of atrial fibrillation or atrial flutter.

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8

Chest and thumb-ECG




5 stroke had been confirmed and standard evaluation was complete.

If the patients felt palpitations or other symptoms suggestive of arrhythmia, e.g.


with the smartphone application. Each patient was monitored for four consecutive

weeks (28 days).

10 Each recording was stored in a web-based application accessible to the

investigators. The investigators checked all recordings daily. In the case of an

arrhythmia that would imply outcome, a second investigator, an experienced

cardiologist within the field of arrhythmia, interpreted the recording. If the outcome

was reached, anticoagulation was promptly started.

15 Statistics

Descriptive data are reported as frequencies, percentages, means, interquartile


deviations, and percentiles, and t-tests were used for group comparisons, while chi-


20 as a two-sided p-value of <0.05. The data was stored in Excel 2010 (Microsoft

Corporation, Redmond, WA) and imported into SPSS version 25 (IBM, Armonk, NY)

for analyses.

Ethics and dissemination

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Clinical Trial Registration NCT03301662 and published.28 Each patient was informed

by a study physician and included after written consent.

5 Patient and public involvement



RESULTS


10 (out of 111 who consented to participate) between October 2017 and October 2019.

The median time from index stroke to inclusion was 7 days (interquartile range 4-13

days). The mean age at inclusion was 67.6±10.8 years. The ages ranged from 27 to

86 years and 25th, 50th, and 75th percentiles were 61.8, 69.0, 74.9 years, respectively.

A majority was male (60.0%) and the mean age was similar between males and

15 females (66.7±9.7 vs 68.9±12.3 years; p=0.323).


points per se, all patients had a score of at least 2. No patients had 8 or 9 points and


Outcome

20 In total, the 28-days of scheduled chest and thumb-ECG yielded 9% (n = 9) AF

among the participants. An example of AF is shown in Figure 1 (as a comparison

sinus rhythm is shown in Figure 2). No atrial flutter or ectopic atrial tachycardia was

diagnosed. The first episode of AF was diagnosed at a mean of 12.7±7.8 days (range

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day 1 to 23). The characteristics of the cohort at baseline and with regard to outcome

is summarized in Table 1. The 9 AF episodes were characterized by a mean

frequency of 115±31 (range 72 to 166) beats per minute. The mean CHA2DS2-VASc

score was similar among patients with AF and no AF (4.9±1.1 vs 4.3±1.3; p=0.224)

5 and patients with AF were older (74.3±9.0 vs 66.9±10.8; p=0.049).

Out of 9 patients with detected atrial fibrillation, 1 patient had come into contact with

health care due to the episode, he reported that he experienced symptoms in the

form of palpitations and dizziness the night before atrial fibrillation was detected. He

had experienced similar symptoms previously but this time after seeing that the

10 automated report of the scheduled ECG in the morning was abnormal he went to the

emergency department and was admitted due to rapid atrial fibrillation. Out of the

other 8 patients with detected atrial fibrillation; 1 reported feeling palpitations, 1

reported feeling stressed as well as dizzy and 6 reported feeling well with no

symptoms in conjunction with the episode.

15 There was no adverse event related to the use of the ECG device. No patient died

during the monitoring period.




20 they did not wish to participate. Among the 100 participants who completed the


Patients performed on average 90.1±15.0% (25th, 50th, and 75th percentile 87.5%,



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11

number of extra transmission per patient was 4.8±5.2 (range 0 to 24). If an episode


the study was completed.

DISCUSSION

5 Prolonged monitoring using the Coala Heart MonitorTM detected AF in 9% of patients



regimen in the presence of AF, this led to a potential benefit in the clinical

management of these individual patients. The number needed to screen based on

10 the yield in our study is 11. The estimated risk of ischemic stroke in AF patients



stroke/TIA is the most powerful risk factor and confers a 10% per year stroke risk, the

urgent need for rapid identification of AF and subsequent treatment after the first

15 stroke is underscored.22




initial screen. Improving the detection of AF will be increasingly important in an aging

20 population with a considerable burden of other cardiovascular risk factors. Indeed,


consequences.30


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The largest prospective study of event-triggered recordings of patients (mean age



electrodes; 82% wore it at least 21 days.31 The AF yield was 12.9 percentage points

5 absolute difference compared to one day of Holter ECG monitoring (16.1% vs 3.2 %).




mastered the smartphone-based device are more likely to comply with the protocol

10 because it is more convenient than wearing a belt. This effect is likely to become




late start of monitoring implies that patients were not monitored during the vulnerable

15 initial period after stroke, which may delay the initiation of protective treatment.





20 the correct diagnosis. This, in turn, could affect outcome.25



device twice daily for 30 days yielded 20 patients with AF but concurrent Holter


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patients, the thumb-ECG detected AF that was not diagnosed by Holter. The median



inclusion of TIA to result in similar yield as in our study. The finding that 13% of

5 tracings were not usable because poor quality may reflect the older age of the study

population, but also stresses the importance of thorough patient education at the time



experience that not all patients are suitable for using a thumb-ECG in this type of

10 evaluation.

In another post stroke/TIA study (n=249) using thumb-ECG twice daily

for 30 days, the yield was 6.8% and 11.8% in patients aged 75 years and older.33

The age distribution of AF is in line with epidemiological data and previous findings. It

should be noted that recording capabilities of the devices at that time caused the

15 definition of AF to be limited to episodes of 10 seconds, which is shorter than the

generally accepted definition of AF episodes of 30 seconds, endorsed by current

guidelines.7 Moreover, patients with a suspected TIA were included, in contrast to our

study. Interestingly, 94% of all detected AF episodes occurred during the first 20

days.

20 In a single-center retrospective analysis, 13 out of 114 patients (11.4%) with

stroke/TIA had AF detected by a Zenicor™ ECG during a 21-day follow-up with



had a diagnosis of TIA. This study adds data about yield and feasibility in real-world

25 care, outside of a clinical trial. As in our study, patients in this single-center study

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received their handheld ECG system soon after stroke, in this case a mean of 4.1


Limitations

Although the overall benefit of anticoagulation in AF patients based on current risk

5 assessment is unequivocal, the cause of stroke in an individual case is often hard to

prove. We used a pragmatic approach based on current practice, even though a

more detailed classification, based on imaging, of cryptogenic stroke has been

suggested.27 The mechanisms of ischemic stroke may be multifactorial. AF,

especially recurrent and extended episodes, may cause remodeling of the atrial

10 anatomy and structural changes. Even if AF is detected, consideration of other

causes should not necessarily be ruled out. Therefore, an overall assessment of risk

factors and treatment options is warranted in conjunction with a team-based

approach, which is crucial to improve stroke management.


15 most severe strokes often occur in the elderly, who are likely to be underrepresented

in clinical trials. However, the target population for this trial had to be able to handle



prevention of recurrent stroke and death. In patients not eligible for thumb ECG, a

20 device with adhesive electrodes would be an alternative.35 Although a thumb-ECG is

an attractive method of noninvasive AF detection, there remain some controversies

with regard to anticoagulation for short-term AF. The duration of an AF episode

captured by snapshot is unknown, but it is assumed to represent longer or multiple

episodes. The potential benefits of anticoagulation therapy for short-term AF would

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be challenging to study, because it would require long-term follow-up, demands a

large sample size, a randomized controlled design, and raises ethical concerns about

withholding anticoagulation from stroke survivors.

Future perspectives

5 Guidelines already allow for prolonged monitoring of these patients: “In stroke


recorders should be considered to document silent atrial fibrillation” (class IIa


remains unchanged in that invasive monitoring is rarely used for AF detection in

10 stroke patients. The benefit of the thumb-ECG in secondary stroke prevention has


cost effectiveness in this setting from both healthcare and societal viewpoint remains

to be elucidated.

Furthermore, a large-scale, multicenter, international, prospective observational trial

15 is welcome in order to confirm diagnostic yield and would allow for subgroup


intelligence is tempting to consider in order to personalize evaluations, based on the


possibly laboratory markers. Moreover, the feasibility of different devices and the

20 length of evaluation time need to be further refined and adapted to possible



CONCLUSION

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In patients with cryptogenic stroke, 9% have AF detected using chest and thumb-

ECG twice daily over a period of four weeks. In many stroke survivors this is a

feasible approach, which can potentially protect them from recurrent stroke by

allowing for prompt initiation of NOAC treatment.

5 DECLARATIONS

Ethics: The study was approved by The Regional Ethical Committee in Uppsala



Not applicable.

10 Acknowledgements

The authors acknowledge editing by Jo Ann LeQuang of LeQ Medical who reviewed



support regarding the Coala Life Monitor.TM The authors also wish to thank the staff

15 at the stroke unit in Gävle and Hudiksvall for their participation in the study.

Author contributions



critical revision. GM: design, data collection, analyses and interpretation,

20 administration, project co-management, critical revision.

Funding

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Region Gävleborg funded this research project (grant number 20170220) and Coala

Life provided free product Coala Heart MonitorTM during the study period.

Competing interests


5 Outside this project: PM has received speaker fees or grants from Abbott, Alnylam,


Nordisk, Octopus Medical, Orion Pharma, Pfizer, Vifor Pharma, and Zoll. AL has


MSD, and Internetmedicin.

10 Ethics approval


2017/321).


Not required.

15 Data sharing statement


Patient and public involvement



20 ORCID

Peter Magnusson: 0000-0001-7906-7782

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Adam Lyrén: 0000-0001-5557-9345

Gustav Mattsson: 0000-0002-4317-0443

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7.0 (IQR 4.0-12.8) 7.0 (IQR 4.0-13.0) 6.0 (IQR 3.0-8.0)




5

10

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● Figure 2. Example of an ECG transmission from a Coala Heart Monitor™ showing normal 5 sinus rhythm.

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● Figure 2. Example of an ECG transmission from a Coala Heart Monitor™ showing normal sinus rhythm.

79x26mm (300 x 300 DPI)

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