Current and Future Use of Insertable Cardiac Monitors

JACC: CLINICAL ELECTROPHYSIOLOGY

VOL.

-, NO. -, 2018

ª 2018 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION PUBLISHED BY ELSEVIER

STATE-OF-THE-ART REVIEW

Current and Future Use of Insertable Cardiac Monitors Shaun Giancaterino, MD, Florentino Lupercio, MD, Marin Nishimura, MD, Jonathan C. Hsu, MD, MAS

ABSTRACT Insertable cardiac monitors (ICMs) are small, subcutaneously implanted devices offering continuous ambulatory electrocardiogram monitoring with a lifespan up to 3 years. ICMs have been studied and proven useful in selected cases of unexplained syncope and palpitations, as well as in atrial fibrillation (AF) management. The use of ICMs has greatly improved our ability to detect subclinical AF after cryptogenic stroke, and application of this technology is growing. Despite this, current stroke and cardiology society guidelines are lacking in recommendations for monitoring of subclinical AF following cryptogenic stroke, including the optimal timing from stroke event, duration, and method of electrocardiogram monitoring. This focused review outlines the current society guidelines, summarizes the latest evidence, and describes current and future use of ICMs with an emphasis on detection of subclinical AF in patients with cryptogenic stroke. (J Am Coll Cardiol EP 2018;-:-–-) © 2018 by the American College of Cardiology Foundation.

A

trial fibrillation (AF) is the most common car-

Cryptogenic strokes are estimated to account for

diac arrhythmia, and it can lead to thrombo-

20% to 30% of all ischemic strokes, equivalent to

embolic

approximately 300,000 cases annually in North

stroke,

most

commonly

from

emboli arising from the left atrial appendage (1). It

America and Europe (5).

is estimated that AF is the source of 1 in 4 ischemic

Critics argue that no universally accepted defini-

strokes (2). Stroke accounts for 1 in every 20 deaths

tion exists for cryptogenic stroke, and diagnostic

in the United States and is a leading cause of serious

criteria have not been standardized. In response to

long-term disability and health care expenditure (3).

this, Hart et al. (5,6) have proposed a similar clinical

Cryptogenic stroke is the current term used to

construct termed embolic stroke of undetermined

describe a symptomatic cerebral infarct for which no

source (ESUS), to identify patients with embolism as

probable cause is identified following an adequate

the likely stroke mechanism. ESUS is defined as a

diagnostic evaluation (2,4). Initial work-up typically

nonlacunar brain infarct without an identified car-

includes echocardiography, a 12-lead electrocardio-

dioembolic source or occurring secondary to occlu-

gram (ECG), inpatient cardiac telemetry, or 24-h

sive atherosclerosis. Diagnostic criteria for ESUS are

Holter monitoring, laboratory screening for hyperco-

specific and include the following: 1) nonlacunar

agulable states (more often performed in patients

brain infarct on imaging; 2) <50% arterial stenosis

younger than 55 years of age), and magnetic reso-

proximal to the infarct; and 3) no major-risk car-

nance imaging or computed tomography imaging of

dioembolic

source

the brain and vasculature of the head and neck (2).

paroxysmal

AF diagnosed by

(including

no

permanent

ECG). Given

or the

From the Cardiac Electrophysiology Section, Division of Cardiology, Department of Medicine, University of California, San Diego, La Jolla, California. Dr. Hsu has received consulting and speaking honoraria from Medtronic, St. Jude Medical, Boston Scientific, and Biotronik; and has received research grants from Biosense-Webster and Biotronik. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. All authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the JACC: Clinical Electrophysiology author instructions page. Manuscript received April 23, 2018; revised manuscript received May 31, 2018, accepted June 4, 2018.

ISSN 2405-500X/$36.00

https://doi.org/10.1016/j.jacep.2018.06.001

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ABBREVIATIONS

ambiguity in the definition of cryptogenic

REVIEW OF INSERTABLE CARDIAC

AND ACRONYMS

stroke, the concept of ESUS may become

MONITORING TECHNOLOGY

ACC = American College of

more widely adopted in both future clinical practice and research. For the purpose of this

There are multiple modalities now available for AECG

review, however, cryptogenic stroke is the

monitoring, and many have been studied for use in

electrocardiogram

preferred term because it is currently better

detection of subclinical AF among patients with

AF = atrial fibrillation

recognized in the cardiology and stroke

cryptogenic stroke and in unexplained syncope

community.

(11,16–18). Most of the external devices available,

Cardiology

AECG = ambulatory

AHA = American Heart

Subclinical AF is variably defined as AF

Association

including Holter, event, and mobile cardiac telemetry

AHRE = atrial high rate event

detected

individuals

monitors, may have limited utility in cases of rare yet

CHA2DS2-VASc = congestive

without a prior diagnosis by ECG (7). Through

recurrent events because of inadequate surveillance

heart failure, hypertension,

improvements in ambulatory ECG (AECG)

duration and potential intermittent monitoring pat-

age, diabetes, stroke, vascular

monitoring,

increasingly

terns. In contemporary practice, small, implantable

evident that subclinical AF is strongly asso-

devices can monitor and record the heart rhythm for

ciated with cryptogenic stroke (7–9). Given

several years (19–21). With the capability of long-term

that newly diagnosed AF after stroke carries a

continuous monitoring, the ICM has been shown to be

higher risk of recurrent stroke, detection of

a sensitive method of detection for subclinical AF,

subclinical AF following cryptogenic stroke

unexplained syncope, and palpitations.

disease, sex

CI = confidence interval DOAC = direct oral anticoagulant agent

ECG = electrocardiogram EHRA = European Heart

in

asymptomatic

it

has

become

has the potential to change management. In

ICMs, also known as implantable loop recorders,

patients with clinical AF, treatment with an

are small devices requiring a minor invasive proced-

Cardiology

oral anticoagulant agent (OAC) such as

ure for implantation in the subcutaneous tissue. Most

ESO = European Stroke

warfarin or a direct oral anticoagulant agent

contemporary models weigh less than 3 g, are

Organization

(DOAC) has been shown to be superior to

one-third the size of an AAA battery, and offer

ESUS = embolic stroke of

aspirin or no therapy in primary and sec-

continuous monitoring with a life span up to 3 years

undetermined source

ondary prevention of stroke (1,10,11). A

(17,19–21). Devices are inserted near the left 4th

HRS = Heart Rhythm Society

similar benefit for starting OAC for patients

intercostal space corresponding to the V 2 -V3 ECG lead

ICM = insertable cardiac

with

location, and an ECG tracing is measured between 2

monitor

demonstrated.

Rhythm Association

ESC = European Society of

ISHNE = International Society for Noninvasive and Holter Electrocardiology

OAC = oral anticoagulant

subclinical

AF

has

not

yet

been

electrodes at the ends (Figure 1). The implantable

Because of the intermittent nature of

monitors available at the time of this writing are the

paroxysmal AF and often poor correlation

Reveal XT and Reveal LINQ models (Medtronic,

between symptoms and episodes, subclinical

Minneapolis, Minnesota) (Figures 2A and 2B), the SJM

agent

AF can be difficult to detect and diagnose

Confirm and Confirm Rx models (St. Jude Medical,

TIA = transient ischemic attack

(12). The development of long-term ECG

Saint Paul, Minnesota) (Figures 2C and 2D), and the

monitoring through insertable cardiac moni-

BioMonitor2 model (Biotronik, Berlin, Germany)

tors (ICMs) has greatly improved the ability to detect

(Figures 2E and 2F).

AF after cryptogenic stroke, evidenced most notably

ICMs are capable of recording the cumulative AF

in the landmark CRYSTAL-AF (Cryptogenic Stroke

burden, as well as storing a fixed number of ECG

and Underlying Atrial Fibrillation) study (13) (Central

waveforms. The latest models are now capable of

Illustration). ICMs have also proven useful in pa-

wirelessly transmitting device data and ECG wave-

tients with recurrent unexplained syncope and carry

forms automatically by cell phone technology to the

class I and II recommendations for this indication

clinician’s inbox for review. Automated AF detection

from major society guidelines (14,15).

algorithms have been developed using R-R wave in-

Despite a growing body of evidence on the inci-

terval variability over 2-min periods (22). Advanced

dence of AF detection in patients who have had

algorithms have added p-wave detection to improve

cryptogenic stroke, current stroke and cardiology

specificity for AF (as in the Reveal LINQ model) (23).

society guidelines are lacking in recommendations for

Small, industry-funded studies have demonstrated

monitoring of subclinical AF, including the optimal

favorable performance in the identification of AF

timing from stroke event, duration, and method of

when compared with the gold standard of Holter

AECG monitoring recommended. This review seeks to

monitoring

outline the current use of ICM for syncope and AF

(24,25). Published reports on sensitivity, specificity,

detection, summarize the latest guidelines and evi-

positive predictive value, and negative predictive

dence, and describe future implications of ICM use

value using an AF duration analysis were as follows:

specifically for detection of subclinical AF in patients

98.1%, 98.5%, 91.9%, and 99.7% (Medtronic Reveal

with cryptogenic stroke.

XT) and 83.9%, 99.4%, 97.3%, and 98.5% (St. Jude

with

expert

adjudication

of

events

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C ENTR AL I LL U STRA T I O N An Insertable Cardiac Monitor Detects Subclinical Atrial Fibrillation Following Cryogenic Stroke

Giancaterino, S. et al. J Am Coll Cardiol EP. 2018;-(-):-–-. This diagram illustrates 1) Subclinical atrial fibrillation leading to development of left atrial appendage thrombus formation and cardioembolic stroke; 2) Subcutaneous placement of an insertable cardiac monitor (ICM) near the left 4th intercostal space; and 3) ICM detection of subclinical atrial fibrillation and wireless cellular transmission of arrhythmia alert.

Confirm), respectively. The BioMonitor2 master study

respectively, when using a similar AF duration-based

is pending publication; however, preliminary data

analysis (Master Study of the Insertable Cardiac

from the manufacturer (Biotronik) report sensitivity,

Monitor BioMonitor 2; NCT02565238).

specificity, positive predictive value, and negative

ICM monitoring does have certain limitations,

predictive value of 93.6%, 99.2%, 93.4%, and 99.3%,

including a significant cost of the device and procedure

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F I G U R E 1 ICM Implantation Site Near Left 4th Intercostal

Space

(estimated initial cost $4,000), with additional ongoing monitoring costs. The need for a small, invasive procedure, although unlikely to cause significant harm to patients, can result in rare complications. The Reveal In-Office (RIO) and Reveal LINQ In-Office 2 (RIO 2) studies demonstrated a favorable safety profile of ICM device insertion, with the most common (albeit rare) complications being incision site hemorrhage and device dislocation (26,27). RIO 2 investigators reported procedure-

or

device-related

complication

rates

of <1% for Reveal LINQ ICM devices inserted in either the hospital or office setting, a finding suggesting that this procedure can be safely performed in the clinic A and B correspond to common ICM implant sites. ICM ¼ insertable cardiac monitor.

(27). Despite good sensitivity, the use of AF detection algorithms has the potential to lead to an elevated number of false-positive results because of motion and myopotential artifacts, as well as misclassification from ectopic beats, necessitating that a physician

F I G U R E 2 ICM Devices and Event Report

personally review all possible AF tracings to ensure an accurate diagnosis. Given the large numbers of patient data stored on these devices, there is the potential for data overload from a clinician perspective (28).

INDICATIONS FOR INSERTABLE CARDIAC MONITORS Established indications for ICM use in current practice include unexplained syncope, palpitations, and management of AF (22). With regard to AF management, ICMs have been studied for AF monitoring in rhythm

control

strategies,

for

AF

monitoring

following catheter ablation, and for detection of subclinical AF after cryptogenic stroke. The primary focus of this review is detection of subclinical AF after cryptogenic stroke, and this indication is discussed in greatest detail.

GUIDELINES FOR INSERTABLE CARDIAC MONITORS IN SYNCOPE The following organizational guidelines discuss the use of ICMs for evaluation of syncope: 1) 2017 International Society for Noninvasive and Holter Electrocardiology

(ISHNE)/Heart

Rhythm

Society

(HRS) expert consensus statement on ambulatory ECG and external cardiac monitoring (29); 2) 2017 American College of Cardiology (ACC)/American Heart (A) Medtronic Reveal XT and (B) Reveal LINQ. (Reproduced with permission of Medtronic, Inc., Minneapolis, Minnesota.) (C) St. Jude/Abbott Confirm and (D)

Association

(AHA)/Heart

Rhythm

Society

(HRS) guideline for the evaluation and management

Confirm Rx. (Reproduced with permission of St. Jude/Abbott, St. Paul,

of patients with syncope (14); 3) 2009 European

Minnesota.) (E) Biotronik Biomonitor2. (Reproduced with permission of

Society of Cardiology (ESC)/European Heart Rhythm

Biotronik, Berlin, Germany.) ICM ¼ insertable cardiac monitor.

Association (EHRA) guideline for the diagnosis and management of syncope (15). These guidelines are

Continued on the next page

summarized in Table 1 (14,15,29).

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F I G U R E 2 Continued

(F) Event report showing atrial fibrillation tracing. (Reproduced with permission of Biotronik, Berlin, Germany.)

All guidelines are in general agreement that the

class IIa, B-R recommendation for ICM use in selected

decision to use an ICM for syncope is highly dependent

patients with syncope of suspected arrhythmic origin.

on patients’ characteristics, frequency of syncopal

The joint ESC/EHRA syncope guidelines provide

events, and pre-test probability of arrhythmic cause.

class I, B recommendations for ICM use in both 1) early

The ACC/AHA/HRS syncope guidelines provide a

phase of evaluation in patients without high-risk

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(Place of Reveal in the Care Pathway and Treatment

T A B L E 1 Guideline Recommendations for ICMs in Syncope

of Patients with Unexplained Recurrent Syncope)

Recommendation

Class

Level of Evidence

2017 ISHNE/HRS expert consensus statement on AECG monitoring

“Much longer monitoring using ILRs can further improve the diagnostic yield for syncope, as high as 85% in some studies”

N/A

N/A

2017 ACC/AHA/HRS guideline for the evaluation and management of patients with syncope

“To evaluate selected ambulatory patients with syncope of suspected arrhythmic etiology, an ICM can be useful”

IIa

2009 ESC/EHRA guideline for the diagnosis and management of syncope

“ILR is indicated in: 1) An early phase of evaluation in patients with recurrent syncope of uncertain origin, absence of high risk criteria, and a high likelihood of recurrence within battery longevity of the device 2) High risk patients in whom a comprehensive evaluation did not demonstrate a cause of syncope or lead to a specific treatment”

1) I 2) I

Year/Organization

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study used ICMs in 570 patients with unexplained syncope and followed them for a mean of 10 months (31). ICMs assisted in diagnosis of syncope in 30% of these patients. A 2016 systematic review and meta-

B-R

analysis including 4 studies and 579 patients found that patients who underwent ICM implantation experienced higher rates of diagnosis (relative risk: 0.61; confidence interval [CI]: 0.54 to 0.68) (18). A

B B

cost-analysis study by Krahn et al. (32) showed that an ICM strategy was more expensive per participant, but the cost was lower per diagnosis when compared with conventional testing in cases of recurrent unexplained syncope. The ISSUE-3 (Third International Study on Syncope of Uncertain Etiology) trial investigators implanted

ACC/AHA/HRS ¼ American College of Cardiology/American Heart Association/Heart Rhythm Society; ESC/ EHRA ¼ European Society of Cardiology/European Heart Rhythm Association; ICM ¼ insertable cardiac monitor; ILR ¼ implantable loop recorder; ISHNE/HRS ¼ International Society for Noninvasive and Holter Electrocardiology/Heart Rhythm Society; N/A ¼ not applicable.

ICMs in 511 patients with more than 3 episodes of unexplained syncope within 2 years (33). Patients with recurrence of syncope and device-detected asystole for longer than 3 s, or asystole for longer than 6 s without syncope, received dual-chamber

features and 2) high-risk patients after negative find-

pacemakers and were randomized to pacing with

ings of a preliminary evaluation.

rate-drop response or to sensing only. Risk of syncope recurrence in patients who had pacing was reduced

EVIDENCE FOR INSERTABLE CARDIAC

by 57% (CI: 4 to 81). In the recently presented

MONITORS IN SYNCOPE

SPRITELY (Syncope: Pacing or Recording in the Later Years) trial, investigators randomized 115 patients

Unexplained syncope is defined by the ACC as syn-

with at least 1 episode of syncope and with bifascic-

cope for which a cause is undetermined after initial

ular block to either empirical pacemaker implantation

evaluation, including but not limited to a thorough

or ICM implantation for further rhythm monitoring

history, physical examination, and ECG (14). The

(34). After mean follow-up time of 30 months, the

goals of AECG monitoring in the evaluation of

empirical pacemaker group experienced lower pri-

unexplained syncope are to capture and identify

mary composite outcome rates of death, syncope,

any bradyarrhythmias, conduction block, or tachyar-

symptomatic bradycardia, asymptomatic actionable

rhythmias

(29).

bradycardia, and device complications (63% event-

Following initial diagnostic work-up with 12-lead ECG

free survival rate) compared with the ICM group

and inpatient telemetry, ICMs may be used for syn-

(22% event-free survival rate) with a p value <0.001.

cope evaluation in patients with recurrent yet infre-

In the ICM group, 59% of patients crossed over to

quent symptoms when other diagnostic test results

receive a pacemaker. These key studies are summa-

have been inconclusive (22). Several randomized

rized in Table 2 (18,30–34).

that

correlate

with

symptoms

controlled trials and observational studies have demonstrated utility of ICMs in the diagnosis of

PALPITATIONS

unexplained syncope (14). The RAST (Randomized Assessment of Syncope Trial) was among the first

AECG monitoring has an important role in the work-

randomized

ICM

up of palpitations, where studies have demonstrated

versus conventional testing in these patients (30).

that initial history, physical examination, and 12-lead

Investigators randomized 60 patients with unex-

ECG are nondiagnostic in roughly two-thirds of pa-

plained syncope to ICM versus conventional testing

tients (29). The 2017 ISHNE/HRS expert consensus

(including external loop recorder, tilt testing, and

statement recommended a range from 24 to 48 h to 2

electrophysiological testing) and followed them for a

weeks of AECG monitoring for unexplained palpita-

mean of 10.5 months. Diagnosis was made in 55% in

tions, depending on symptom frequency; therefore,

controlled

trials

to

compare

the ICM arm compared with 19% in the control

ICMs are not routinely indicated (29). The 2009 EHRA

(p ¼ 0.0014). The multicenter prospective PICTURE

position paper on indications for the use of diagnostic

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implantable and external ECG loop recorders provided a class IIA recommendation for ICM use in select cases of severe infrequent palpitations when other ECG monitoring systems fail to document cause (35).

GUIDELINES FOR MONITORING FOR ATRIAL FIBRILLATION AFTER STROKE

T A B L E 2 Evidence for ICMs in Syncope

Study (yr) and Reference

Study Type

Number of Patients

Randomized controlled trial

60

Diagnosis in 55% of patients in the ICM arm compared with 19% in the control (p ¼ 0.0014)

PICTURE (2011) (31)

Multicenter prospective

570

ICMs assisted in diagnosis in 30% of patients

Solbiati et al. (2016) (18) Systematic review

579

Patients with ICM implantation experienced higher rates of diagnosis (RR: 0.61; CI: 0.54–0.68)

Krahn et al. (2003) (32)

Randomized crossover study

60

ICM strategy was more expensive per participant but cost lower per diagnosis when compared with conventional testing

ISSUE-3 (2012) (33)

Randomized controlled trial

511

Risk of syncope recurrence in patients with ICM-detected syncope randomized to pacing arm was reduced by 57% (CI: 4–81)

SPRITELY (2018) (34)

Randomized pragmatic trial

115

Empirical pacemaker arm experienced lower rates of primary composite outcomes

The following organizational guidelines discuss AECG monitoring for AF after stroke: 1) 2017 ISHNE/HRS expert consensus statement on ambulatory ECG and external cardiac monitoring or telemetry (29); 2) 2016

ESC/EHRA/European

Stroke

Organization

(ESC/EHRA/ESO) guidelines for the management of AF (36); 3) 2014 AHA/American Stroke Association (AHA/ASA) guidelines for the prevention of stroke in patients with stroke and transient ischemic attack (TIA) (10); 4) 2014 Canadian Stroke best practice guidelines for the secondary prevention of stroke

Results

RAST (2001) (30)

(37); and 5) 2014 Canadian Cardiovascular Society focused update of guidelines for the management of AF (38). The 2014 AHA/ACC/HRS guidelines for the management of patients with atrial fibrillation sum-

CI ¼ confidence interval; ICM ¼ insertable cardiac monitor; ISSUE -3 ¼ Third International Study on Syncope of Uncertain Etiology; PICTURE ¼ Place of Reveal in the Care Pathway and Treatment of Patients with Unexplained Recurrent Syncope; RAST ¼ Randomized Assessment of Syncope Trial; RR ¼ relative risk; SPRITELY ¼ Syncope: Pacing or Recording in the Later Years.

marize the evidence behind subclinical AF and stroke but do not further discuss ECG monitoring for AF detection in patients with cryptogenic stroke (1). The

detect paroxysmal AF in cases where the initial ECG

guideline

or 24 to 48 h of ECG monitoring does not show AF but

recommendations

are

summarized

in

Table 3 (10,29,36–38).

a cardioembolic mechanism is suspected. The Cana-

As the most contemporary guideline, the 2017

dian stroke guidelines specify selecting patients who

ISHNE/HRS expert consensus statement offers 1 of

are potential candidates for anticoagulation, but they

the strongest endorsements for the use of ICMs, by

do not further comment on duration or method of

stating that external AECG monitoring may be limited

monitoring. The 2014 Canadian Cardiovascular Soci-

by noncompliance and an [ICM] may be more effec-

ety guidelines, published after CRYSTAL-AF, also

tive, citing the 6-fold increased detection rate of AF

suggest “additional” ambulatory monitoring beyond

>30 s at 6 months of follow-up as reported in the

24 h for AF detection for “selected older patients”

CRYSTAL-AF study. The official guideline favors

with cryptogenic stroke who would be candidates for

“extended” AECG monitoring in patients with cryp-

OAC therapy. This guideline does not further specify

togenic stroke and undiagnosed AF; however, it does

a method of monitoring. Currently, there is lack of

not specify duration or method. The 2016 ESC/EHRA/

expert consensus in North America and Europe

ESO guidelines recommend consideration of “long-

regarding the optimal timing, duration, and method

term” monitoring with either noninvasive ECG mon-

of cardiac monitoring for occult AF in stroke patients.

itors or ICMs to document silent AF in stroke patients. These guidelines do not specify duration of moni-

EVIDENCE FOR SUBCLINICAL ATRIAL

toring. The 2017 ISHNE/HRS expert consensus and

FIBRILLATION AND STROKE RISK

the 2016 ESC/EHRA/ESO guidelines were published after the release of the CRYSTAL-AF study results.

Studies have shown that even brief episodes of sub-

The 2014 AHA/ASA guidelines offer the most specific

clinical AF are associated with ischemic stroke; how-

recommendations, suggesting “prolonged, 30-day

ever, a causal relationship between subclinical AF

rhythm monitoring” within 6 months of acute

and the risk of stroke has yet to be established. Much

ischemic stroke or TIA with no apparent cause. This

of the evidence for subclinical AF and stroke risk

guideline does not specify a method of monitoring.

comes from observational studies of atrial tachyar-

The 2014 Canadian stroke best practice recommen-

rhythmia detection in patients with existing pace-

dations suggest “prolonged” ECG monitoring to

maker or defibrillator devices without a history of

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T A B L E 3 Guideline Recommendations on ECG Monitoring for AF After Cryptogenic Stroke

Year, Organization, and Reference

Recommendation

Class

Level of Evidence

2017 ISHNE/HRS expert consensus statement on AECG monitoring (29)

“A strategy of AECG monitoring is recommended in patients with cryptogenic stroke to detect undiagnosed AF”

I

B-R

2016 ESC/EHRA/ESO guidelines for the management of AF (36)

“Additional ECG monitoring by long-term non-invasive ECG monitors or implanted loop recorders should be considered to document silent atrial fibrillation”

IIa

C

2014 AHA/ASA guidelines for the prevention of stroke in patients with stroke and TIA (10)

“Prolonged rhythm monitoring (w30 days) for AF is reasonable within 6 months of the index event”

IIa

C

2014 Canadian stroke best practice recommendations: secondary prevention of stroke (37)

“Prolonged ECG monitoring is recommended in selected patients for the detection of paroxysmal atrial fibrillation”

N/A

B

2014 CCS guidelines for the management of atrial fibrillation (38)

“We suggest additional ambulatory monitoring (beyond 24 hours) for AF detection, where available, if it is likely that OAC therapy would be prescribed if prolonged AF is detected”

Conditional recommendation.

Moderate quality

AECG ¼ ambulatory electrocardiogram; AF ¼ atrial fibrillation; CCS ¼ Canadian Cardiovascular Society; ECG ¼ electrocardiogram; ISHNE/HRS ¼ International Society for Noninvasive and Holter Electrocardiology/Heart Rhythm Society; OAC ¼ oral anticoagulant agent; TIA ¼ transient ischemic attack; other abbreviations as in Table 1.

stroke or TIA (7,38,39). A subgroup analysis of pa-

individual study cutoffs had a 2.4-fold increased risk

tients in the MOST (Atrial Diagnostics Ancillary Study

of stroke, with an overall absolute annual risk of 1.89

of the Mode Selection) trial showed that patients with

per 100 person-years; 3) patients with subclinical AF

asymptomatic pacemaker-detected atrial high rate

and a mean CHADS2 (congestive heart failure, hy-

events (AHRE) lasting at least 5 min had a 6 times

pertension, age, diabetes, stroke) score of 2.1 had an

higher risk of AF and more than 2 times higher risk of

estimated annual stroke rate of 2.76 per 100 person-

composite endpoint of stroke and death (40). The

years; and 4) short episodes of subclinical AF not

ASSERT (Asymptomatic Atrial Fibrillation and Stroke

meeting individual study cutoffs were associated

Evaluation in Pacemaker Patients and the Atrial

with a lower stroke risk of 0.93 per 100 person-years.

Fibrillation

Reduction

Atrial

Pacing

Trial)

in-

Taken together, these studies suggest that sub-

vestigators found that device-detected episodes of

clinical AF, and especially AF of longer duration, is

AHRE >190 beats/min for >6 min were associated

associated with an increased risk of ischemic stroke,

with a more than 5 times increased risk of AF and a

but they do not prove causality. More data are needed

more than 2-fold increased yearly rate of ischemic

to quantify what amount of subclinical AF may be

stroke or systemic embolism (7).

clinically significant and demonstrate that detection

In a secondary analysis of patients in ASSERT, Van

and treatment of this condition prevents strokes.

Gelder et al. (41) studied the effect of subclinical AF

duration

on

subsequent

stroke

risk

using

time-dependent covariate Cox models. These in-

DETECTION OF SUBCLINICAL ATRIAL FIBRILLATION IN CRYPTOGENIC STROKE

vestigators found that subclinical AF duration longer than 24 h was associated with a significant increase in

Growing numbers of AECG modalities are available

risk of stroke (hazard ratio: 3.24; 95% CI: 1.5 to 6.95;

and have been studied for detection of subclinical AF

p ¼ 0.003). Patients with subclinical AF duration less

in patients with cryptogenic stroke. A discussion and

than 24 h had no statistically significant difference in

comparison of the various external devices can be

stroke risk compared with patients with no evidence

found in many of the contemporary review articles of

of subclinical AF.

both

AECG

monitoring

and

cryptogenic

stroke

Mahajan et al. (42) performed a systematic review

(11,16,17). This section focuses specifically on the ev-

and meta-analysis including 11 studies, analyzing

idence for ICMs in the detection of subclinical AF in

subclinical device-detected AF and stroke risk. The

cryptogenic stroke. Several small, prospective studies

cutoff point for significant subclinical AF duration

evaluated AF detection in patients with cryptogenic

that was used to predict stroke risk varied among

stroke with ICMs before the release of CRYSTAL-AF

studies (from >6 min to 1 h to >5.5 h total daily

(43–48). These results are summarized in Table 4

burden). Notable results of this analysis included the

(13,43–50).

following: 1) subclinical AF was strongly associated

The landmark CRYSTAL-AF trial was among the

with an almost 6-fold risk of future clinical AF;

first randomized controlled trials in the study of

2) patients with subclinical AF duration meeting

subclinical AF in patients with cryptogenic stroke and

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T A B L E 4 Detection of AF With ICMs in Cryptogenic Stroke

Number of Patients

Study (yr), Reference

AF Definition

Monitoring Duration Mean (SD)

Time to AF Detection

AF Detection Yield

Patients With AF Prescribed OAC

N/A

Dion et al. (2010) (43)

24

30 s

14.5 months

N/A

0

Cotter et al. (2013) (44)

51

2 min

229 (116) days

48 days (median)

25.5%

N/A

Ritter et al. (2013) (45)

60

2 min

1 yr

64 days (mean)

16.7%

N/A

Etgen et al. (2013) (46)

22

6 min

1 yr

153 days (mean)

27.3%

N/A

Rojo-Martinez et al. (2013) (47)

101

2 min

281 (212) days

102 days (median)

33.7%

N/A

SURPRISE (2014) (48)

85

2 min

569 (310) days

109 days (mean)

16.1%

N/A

CRYSTAL-AF (2014) (13,49)

221

0.25 min (30 s)

3 yr

1,247

2 min

2 yr

Ziegler et al. (2017) (50)

84 days in original study 8.9% at 6 months 90.5% at 36 months 8.4 months in the 3-year follow-up 12.4% at 12 months (median) 21.1% at 24 months 30.0% at 36 months 112 days (median)

4.6% at 1 month 12.2% at 6 months 16.3% at 12 months 21.5% at 24 months

N/A

CRYSTAL-AF ¼ Cryptogenic Stroke and Underlying Atrial Fibrillation; SURPRISE ¼ Stroke Prior to Diagnosis of Atrial Fibrillation Using Long-term Observation with Implantable Cardiac Monitoring Apparatus Reveal; other abbreviations as in Tables 1 and 3.

the largest study of ICMs at the time. CRYSTAL-AF

In response to the CRYSTAL-AF study results, a

randomized 441 patients with cryptogenic stroke or

prospective observational study was initiated by

TIA in a 1:1 ratio of ICM versus control (standard of

Ziegler et al. (50) to investigate the incidence of

care monitoring) for detection of AF (13). Primary and

subclinical AF in a real-world group of patients who

secondary endpoints were time to detection of AF

had cryptogenic stroke. Investigators used a database

lasting 30 s or longer at 6 and 12 months, respectively.

of more than 1,200 patients (Medtronic Reveal LINQ

ICMs detected AF in 8.9% of patients by 6 months and

Insertable Cardiac Monitor Registry) who received an

in 12.4% of patients by 12 months, compared with

ICM for the purpose of AF detection following cryp-

1.4% and 2.0%, respectively, in the control group. A

togenic stroke and were monitored for up to 2 years of

follow-up study of the CRYSTAL-AF ICM cohort found

follow-up. The primary endpoint was adjudicated AF

a cumulative AF detection rate of 21.1% at 24 months

lasting longer than 2 min. The rate of AF detection at

and 30.0% at 3 years in the ICM arm versus 3.0% and

1, 6, 12, and 24 months was 4.6%, 12.2%, 16.3%, and

3.0%, respectively, in the control arm (49). The me-

21.5%, respectively, with a median time to AF detection

dian time to AF detection in the ICM arm was 84 days

of 112 days. These results are summarized in Table 4.

in the original study and 8.4 months in the 3-year

The results of CRYSTAL-AF and Ziegler et al. (50)

follow-up study. OAC therapy was prescribed for

have shown that subclinical AF in a cryptogenic

94.7%, 96.6%, and 90.5% of ICM-treated patients

stroke group is much more prevalent than previously

with detectable AF at 6, 12, and 36 months, respec-

thought. AF detection rates were remarkably similar

tively. These results are summarized in Table 4.

between

these

2 studies. At 24

months

after

T A B L E 5 Detection of AF With ICMs in Patients at High Risk for Stroke

Number of Patients

AF Definition

PREDATE-AF (2017) (51)

245

6 min

18 months

ASSERT-II (2017) (52)

256

5 min

16.3 (3.8) months

REVEAL AF (2017) (53)

385

6 min

30 months

Study (yr), Reference

Monitoring Duration [Mean (SD)]

Time to AF Detection

AF Detection Yield

Patients With AF Prescribed OAC

141 days (mean)

22.4% at 18 months

76.4%

5.1(5.5) months

34.4% at 12 months

74%*

123 days (median)

6.2% at 1 month 20.4% at 6 months 27.1% at 12 months 29.3% at 18 months 33.6% at 24 months 40.0% at 36 months

56.3%

*OAC started in 7 patients for indications other than AF. ASSERT- II ¼ Prevalence of Sub-Clinical Atrial Fibrillation Using an Implantable Cardiac Monitor; PREDATE-AF ¼ Predicting Determinants of Atrial Fibrillation or Flutter for Therapy Elucidation in Patients at Risk for Thromboembolic Events; REVEAL AF ¼ Incidence of Atrial Fibrillation in High Risk Patients; other abbreviations as in Tables 1 and 3.

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showed statistically significant reductions in stroke or systemic embolism in the ICM and OAC trial arms. Second is the lack of temporal association between AF detection by ICM and subsequent ischemic stroke. The median time to AF detection after cryptogenic stroke of 84 and 112 days, respectively, in CRYSTALAF and the study by Ziegler et al. (50) does not prove causality or delineate a definitive temporal association between the 2.

DETECTION OF SUBCLINICAL ATRIAL FIBRILLATION IN PATIENTS AT HIGH RISK FOR ATRIAL FIBRILLATION AND STROKE With growing knowledge from studies of subclinical AF in patients with pacemakers or implantable cardioverter-defibrillators and cryptogenic stroke, investigators have now begun studying the incidence of AF in patients at high risk for AF and stroke by using

ICMs.

The

PREDATE-AF

(Predicting

De-

terminants of Atrial Fibrillation or Flutter for Therapy Elucidation in Patients at Risk for Thromboembolic Events) study enrolled 245 subjects with no history of AF and a CHA2DS 2-VASc (congestive heart failure, hypertension, age, diabetes, stroke, vascular disease, sex) score of 2 or greater to be screened for new onset AF with an ICM (51). The primary endpoint was adjudicated AF lasting longer than 6 min, and subAF ¼ atrial fibrillation; CBC ¼ complete blood count; CHA2DS2-Vasc ¼ congestive heart failure, hypertension, age, diabetes, stroke, vascular disease, sex CT ¼ computed tomog-

jects were followed for 18 months. Subclinical AF was detected in 22.4% of patients with a mean time to

raphy; ECG ¼ electrocardiogram; ESUS ¼ embolic stroke of undetermined source; ICM ¼

detection of 141 days. Investigators compared this

insertable cardiac monitor; INR ¼ international normalized ratio; MRI ¼ magnetic reso-

with the range of overall AF prevalence in the estab-

nance imaging.

lished literature (3.0% to 7.5%). A total of 76.4% of patients with newly diagnosed AF were prescribed OAC. In light of these results, the investigators sugcryptogenic stroke, 1 of every 5 patients monitored

gest that the use of ICMs for AF screening may be

with ICM had a diagnosis of AF. The median time to

appropriate in subjects with a CHA2DS 2-VASc score of

AF detection in both studies (84 days in the original

2 or greater.

CRYSTAL-AF study and 112 days in the study by Zie-

The ASSERT-II trial implanted ICMs to define the

gler et al. [50]) was past the 30 days of monitoring

prevalence of subclinical AF in 256 patients >65 years

suggested by the current ASA/AHA guidelines. Of

of age without a history of AF, with an average

patients who ultimately had a diagnosis of AF, 88% of

follow-up of 16 months (52). Eligibility also required

those in CRYSTAL-AF and 79% of patients in the

at least 1 of the following: CHA 2 DS2-VASc score of 2 or

study by Ziegler et al. (50) would have been missed if

greater, sleep apnea, body mass index >30, left atrial

monitoring had been performed for only up to 30

enlargement, or increased N-terminal pro–B-type

days. In light of these findings, expert panels have

natriuretic peptide. The primary endpoint was adju-

suggested consideration of longer-term monitoring

dicated AF lasting more than 5 min. In this overall

with an ICM if initial monitoring results are negative

group, subclinical AF was detected in 34.4% per year

in the first 30 days (17).

and in 39.4% per year in patients with a history of

Significant limitations of these data are worth

stroke, TIA, or systemic embolism. The mean time to

mentioning. First is the lack of proven clinical benefit

AF detection was 5.1 months, and 74% of these pa-

of higher rates of subclinical AF detection and sub-

tients were prescribed OACs. Investigators concluded

sequent OAC use to reduce stroke risk in these

that detection of subclinical AF in older patients with

studies. Neither CRYSTAL-AF nor Ziegler et al. (50)

cardiovascular risk factors is relatively common after

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T A B L E 6 Future Randomized Controlled Trials Involving ICMs for Detection of Subclinical AF

Study Acronym

Target Enrollment

Study Group

Treatment Arms

Primary Endpoint

ARTESiA

4,000

Subclinical AF detected by ICM, pacemaker, or ICD

1. Apixaban 2. Aspirin

Primary prevention of stroke, TIA, or SE

LOOP

6,000

High stroke risk*

1. ICM and subsequent OAC if new AF 2. Standard of care

Time to stroke or SE episode

NOAH

3,400

AHRE and 2þ stroke risk factors without AF diagnosis

1. Edoxaban 2. Standard of care

Primary prevention of stroke or SE

500

Ischemic stroke secondary to large- or small-vessel disease

1. ICM 2. Standard of care

Incidence rate of AF through 12 months†

STROKE AF

*Defined as age >70 years and at least 1 of: the following diabetes; hypertension; heart failure; or previous stroke. †Defined as any AF event lasting more than 30 s. AHRE ¼ atrial high rate event; ARTESiA ¼ Apixaban for the Reduction of Thrombo-Embolism in Patients With Device-Detected Sub-Clinical Atrial Fibrillation; ICD ¼ implantable cardioverter-defibrillator; LOOP ¼ Atrial Fibrillation Detected by Continuous ECG Monitoring; NOAH ¼ Non-vitamin K antagonist Oral anticoagulants in patients with Atrial High rate episodes; SE ¼ systemic embolism; STROKE AF ¼ Rate of Atrial Fibrillation Through 12 Months in Patients With Recent Ischemic Stroke of Presumed Known Origin; other abbreviations as in Tables 1 and 3.

a period of long-term monitoring with an ICM. These

FUTURE DIRECTIONS

investigators suggested the need for randomized clinical trials of anticoagulation in patients with

A proposed flow diagram has been included for ICM

recent stroke who have detectable subclinical AF.

device implantation in select patients with crypto-

The REVEAL AF trial investigators implanted ICMs

genic stroke on the basis of high-quality evidence

to define the incidence of AF in 385 patients with a

discussed in this review and summarized in Tables 3,

CHA 2 DS2-VASc score of 2 or greater with an average

4, and 5 (Figure 3).

follow-up of 22.5 months (53). The primary endpoint

An association between subclinical AF and cryp-

was adjudicated AF lasting longer than 6 min. AF

togenic stroke exists, but no causality has been

detection rates at 1, 6, 12, 24, and 30 months were

proven. Questions that need answering include the

6.2%, 20.4%, 27.1%, 33.6%, and 40.0%, respectively.

following: 1) What cutoff of (ICM or other) device-

Median time to first AF episode detection was 123

detected duration of subclinical AF is clinically sig-

days. OAC therapy was prescribed for 56.3% of pa-

nificant? 2) Can the use of OAC therapy in patients

tients overall. Of patients who had a diagnosis of AF

with subclinical AF (detected by ICM) demonstrate a

in this study, 85% would have been missed if they

reduction in stroke rates? Further studies are needed

had been monitored for only 30 days. The in-

to better understand to what extent, if any, subclin-

vestigators of this trial stressed the importance of

ical AF is similar to clinical AF.

ongoing OAC trials for subclinical AF to direct management of these patients further.

FUTURE STUDIES

The following 3 recent trials, as summarized in Table 5 (51–53), demonstrate a substantial incidence

Many future studies relating to ICMs for subclinical

of undiagnosed subclinical in patients with AF and

AF are currently enrolling, with future results that

multiple risk factors for AF and stroke. Much as in

will add to current knowledge. Some involve the use

patients with cryptogenic stroke who were monitored

of ICMs to determine the prevalence of subclinical

with ICMs, the average time to AF detection in these

AF in different stroke groups. Others are studying

high-risk patients was well past the 30-day cutoff, a

OAC therapy for the primary and secondary pre-

finding suggesting a future role for ICMs beyond

vention of stroke in patients with ICM-detected

existing traditional external monitoring strategies.

subclinical AF. Of particular relevance to ICMs are

Increasing use of cardiac implantable devices such as

the forthcoming ARTESiA (Apixaban for the Reduc-

ICMs for AECG monitoring is likely to increase

tion of Thrombo-Embolism in Patients With Device-

established knowledge of the epidemiology and nat-

Detected

ural history of AF. The overall prevalence of any form

(Atrial Fibrillation Detected by Continuous ECG

of AF in the population is likely much higher than

Monitoring; NCT02036450), NOAH (Non-vitamin K

previously thought. Higher prevalence of subclinical

antagonist Oral anticoagulants in patients with Atrial

AF may not correlate with higher stroke rates, and

High rate episodes, and STROKE AF (Rate of Atrial

therefore OAC therapy may not always be necessary.

Fibrillation Through 12 Months in Patients With

Further studies of OAC for subclinical AF are needed.

Recent Ischemic Stroke of Presumed Known Origin;

Sub-Clinical

Atrial

Fibrillation),

LOOP

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NCT02700945) trials, as summarized in Table 6

CONCLUSIONS

(54,55). ARTESiA is studying the use of OAC in the primary prevention of stroke in patients with sub-

Long-term continuous monitoring with ICMs in both

clinical AF detected by long-term continuous moni-

clinical trials and real-world patients has signifi-

toring with an ICM, pacemaker, or implantable

cantly increased our ability to detect subclinical AF

cardioverter-defibrillator (54). LOOP is studying the

and aid in the diagnosis of unexplained syncope.

use of ICMs and subsequent OAC therapy for new AF

Contemporary

in the primary prevention of stroke in patients with

duration of monitoring may be needed to detect AF

significant risk factors for stroke. NOAH is comparing

in selected patients after cryptogenic stroke than

edoxaban versus current standard of care in the

supported by current guidelines, and future studies

primary prevention of stroke and systemic embolism

should inform the guidelines on use of ICMs in

in patients without AF but with AHRE and at least 2

these patients.

evidence

suggests

that

a

longer

stroke risk factors (55). STROKE AF is studying ICMs for the detection of subclinical AF in patients

ADDRESS FOR CORRESPONDENCE: Dr. Jonathan C.

with noncryptogenic acute ischemic strokes. The

Hsu, Cardiac Electrophysiology Section, Division of

results of these clinical trials will provide further

Cardiology, Department of Medicine, University of

guidance in the use of ICMs for detection and man-

California, San Diego, 9452 Medical Center Drive, 3rd

agement of detected subclinical AF in the context of

Floor, Room 3E-417, La Jolla, California, 92037.

stroke.

E-mail: [email protected].

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KEY WORDS atrial fibrillation, cryptogenic stroke, implantable loop recorder, insertable cardiac monitor, syncope

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