Device-Detected Atrial Fibrillation

JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY

VOL. 65, NO. 3, 2015

ª 2015 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION

ISSN 0735-1097/$36.00

PUBLISHED BY ELSEVIER INC.

http://dx.doi.org/10.1016/j.jacc.2014.10.045

THE PRESENT AND FUTURE STATE-OF-THE-ART REVIEW

Device-Detected Atrial Fibrillation What to Do With Asymptomatic Patients? Carol Chen-Scarabelli, PHD,* Tiziano M. Scarabelli, MD, PHD,y Kenneth A. Ellenbogen, MD,z Jonathan L. Halperin, MDy

ABSTRACT Atrial fibrillation (AF) is the most common clinically significant arrhythmia and conveys an increased risk of stroke, regardless of whether it is symptomatic. Despite multiple studies supporting an association between subclinical atrial tachyarrhythmias (ATs) detected by cardiac implantable electronic devices and increased risk of thromboembolic events, clinical intervention for device-detected AT remains sluggish, with some clinicians delaying treatment and instead opting for continued surveillance for additional or longer episodes. However, the 2014 updated clinical practice guidelines on AF recommend use of the CHA2DS2-VASc stroke risk score for nonvalvular AF, with oral anticoagulation recommended for scores $2, regardless of whether AF is paroxysmal, persistent, or permanent. This paper reviews the epidemiology of AF and mechanisms of stroke in AF, and discusses device-detected AF and its clinical implications. (J Am Coll Cardiol 2015; 65:281–94) © 2015 by the American College of Cardiology Foundation.

A

trial fibrillation (AF) is the most common

AF, which is thought to affect as many as one-

clinically significant heart rhythm disorder

third of the U.S. population (3).

(1), with an estimated lifetime risk of 22%

to 26% or about a lifetime risk of 1 in 4 (2). It has

MECHANISMS OF AF

been diagnosed in >2.5 million people in the United States alone (3). In 2010, the incidence of diagnosed

The pathophysiology of AF is multifactorial and

AF in the United States was 1.2 million, and its

complex, including both genetic and neural mecha-

prevalence is projected to increase to >12 million

nisms. The main mechanism by which autonomic

cases by 2030 (4). In the European Union, there

activation triggers AF is activation of the sympathetic

were 8.8 million adults >55 years of age with AF

and parasympathetic nervous system, which likely

in 2010, with an expected increase to 17.9 million

interact with the pulmonary vein–left atrial (LA)

by 2060 (5). Globally, AF incidence in 2010 was esti-

junction to trigger atrial ectopy (7). Genetic mecha-

mated at 33.5 million (20.9 million men and 12.6

nisms linked to AF development include alterations

million women). Despite a higher incidence in

in potassium or sodium channels, connexin expres-

men, mortality associated with AF is greater in

sion or function (2), and microRNAs (8). Four major

women, doubling between 1990 and 2010 (6). These

mechanisms that promote focal ectopic firing and

statistics do not account for silent or undiagnosed

reentry substrate formation have been implicated in

From the *Veterans Affairs Ann Arbor Health Care System, University of Michigan, Ann Arbor, Michigan; yZena and Michael A. Wiener Cardiovascular Institute, Mount Sinai Medical Center, New York, New York; and the zDepartment of Medicine, Virginia Commonwealth University School of Medicine, Richmond, Virginia. Dr. Ellenbogen has served as a consultant for Medtronic, Boston Scientific and St. Jude Medical, and has received research, honorarium, and fellowship support from Medtronic and Boston Scientific. Dr. Halperin has served as a consultant for Bayer Healthcare, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Pfizer, Inc., Biotronik, Boston Scientific, and Medtronic. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Drs. Ellenbogen and Halperin contributed equally to this work as senior authors. Sumeet Chugh, MD, served as Guest Editor for this paper. Manuscript received June 29, 2014; revised manuscript received October 14, 2014, accepted October 14, 2014.

Downloaded From: http://content.onlinejacc.org/ by Tiziano Scarabelli on 01/20/2015

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Chen-Scarabelli et al.

JACC VOL. 65, NO. 3, 2015 JANUARY 27, 2015:281–94

Device-Detected Atrial Fibrillation

ABBREVIATIONS

AF: 1) ion channel dysfunction; 2) calcium

conventional ECG group (18). Although anticoagulant

AND ACRONYMS

handling abnormalities; 3) structural remod-

prescription for AF was higher in the ICM group

eling (primarily atrial fibrosis); and 4) auto-

versus the routine ECG monitoring group (10.1% vs.

nomic neural dysregulation (2,8). These 4

4.6%) at 6 months, 97.0% of patients with detected

conditions not only trigger AF, but may also

AF were receiving oral anticoagulant agents by the

result from episodes of AF, supporting the

12-month follow-up (18).

AF = atrial fibrillation AHRE = atrial high rate episodes

AT = atrial tachyarrhythmia CIED = cardiac implantable electronic device

concept that “atrial fibrillation begets atrial

A similar study, the EMBRACE (30-Day Cardiac

fibrillation,” first reported in an early animal

Event Monitor Belt for Recording Atrial Fibrillation

study documenting atrial electrical remodel-

After a Cerebral Ischemic Event) study, compared

resynchronization therapy

ing in AF (9). Further advances in knowledge

new AF detection by noninvasive ambulatory ECG

CS = cryptogenic stroke

of the pathophysiology of AF have revealed

monitoring with either a 30-day event-triggered

that electrical remodeling in AF is not limited

recorder (intervention group) or a conventional 24-h

to the atria. More pronounced remodeling

monitor (control group) in 572 patients with CS

after brief episodes of induced AF has been

within the preceding 6 months, without a history of

monitor

documented in the pulmonary veins (10),

AF (19). The investigators reported a greater than

LA = left atrium/atrial

thereby extending the concept to “AF begets

5-fold increase (16.1% vs. 3.2%; p < 0.001) in AF

AF in the pulmonary veins”.

detection in the 30-day event monitor group, with a

AF AND STROKE

prescription (18.6% vs. 11.1%; p ¼ 0.01) among the

CRT = cardiac

ECG = electrocardiogram EGM = intracardiac electrogram ICM = implantable cardiac

LAA = left atrial appendage

subsequent significant increase in anticoagulation

TE = thromboembolic event(s)

30-day event monitor group. At the 90-day followAF is a major independent predictor of ischemic

up, 87% of patients with AF in the event monitor

stroke, resulting in a 5-fold increase in risk (1). Each

group and 100% of patients with AF in the control

year,

experience

group were on anticoagulant therapy (19). Thus,

strokes, of which 610,000 are first strokes and

both the CRYSTAL-AF and EMBRACE studies docu-

approximately 87% are ischemic. In the United States,

mented a significant increase in anticoagulant pre-

someone suffers a stroke every 40 s (that is, approx-

scription in CS patients with newly detected AF.

imately 90 people/h) (1). Among patients with AF, it

However, anticoagulation treatment rates are signi-

is estimated that every hour, 15 will have a stroke (11),

ficantly lower for patients without a prior history of

and such AF-related strokes impose a higher mortal-

stroke with newly detected AF on cardiac implantable

ity than strokes unrelated to AF (12). The prevalence

electronic devices (CIEDs). One retrospective study

of AF and associated stroke risk are highest among

reported a 50% incidence of pacemaker-detected

approximately

795,000

people

elderly patients, with stroke risk independent of

AF, yet 90% of thrombi in AF (25), it

in patients with nonvalvular AF (24), accounting

may be a significant strategy in stroke prevention

for >90% of thrombi (Figure 1). This thrombogenic

in nonvalvular AF.

tendency has led to targeted interventions to occlude the LAA in an attempt to reduce stroke risk in AF, as

DEVICE-DETECTED AF

reported in trials such as the PLAATO (Percutaneous Left Atrial Appendage Transcatheter Occlusion) trial

Subclinical atrial tachyarrhythmias (AT) can be

in 2002 (25) and, most recently, the PROTECT AF

detected by various cardiac monitoring methods,

(Watchman Left Atrial Appendage System for Embolic

including external surface monitoring (e.g., standard

Protection in Patients With Atrial Fibrillation) study,

12-lead electrocardiogram, ambulatory Holter moni-

which documented noninferiority of LAA occlusion to

tors, event monitors) and by CIEDs (e.g., implantable

systemic anticoagulation (26). In fact, the PROTECT

cardiac monitors, dual-chamber pacemakers, dual-

AF trial was credited with being the first trial to

chamber implantable cardioverter-defibrillators, car-

demonstrate involvement of the LAA in the patho-

diac resynchronization therapy [CRT] devices), many

genesis of stroke in AF (27).

of which enable remote monitoring. This review

Significant safety concerns for WATCHMAN im-

addresses only CIEDs, given their continuous moni-

plantation, including pericardial effusions and device

toring capability. AT commonly occurs in patients

embolization, were addressed in a subsequent trial,

with CIEDs and is associated with an increased risk

the PREVAIL (Watchman LAA Closure Device in Pa-

of thromboembolism (TE) (1). Several studies have

tients With Atrial Fibrillation Versus Long Term

correlated TE risk with the total duration or burden

Warfarin Therapy) trial, which documented a signifi-

of device-detected AT (32–34). However, there are

cantly lower rate of adverse events compared to the

presently no published randomized clinical studies

PROTECT AF trial (4.2% vs. 8.7%; p ¼ 0.004) (28).

investigating treatment of AT detected by CIEDs.

Although the third review by the Food and Drug

All cardiac rhythm recordings obtained from CIEDs

Administration Circulatory System Devices Advisory

require adjudication or review by a qualified clinician

Panel in October 2014 (29) resulted in a unanimous

to verify diagnostic accuracy. Retrospective review of

vote on safety of the device, analysis of the updated

device-derived data has confirmed that most of these

June 2014 PREVAIL dataset demonstrated new

tachyarrhythmias represent paroxysmal AF or atrial

ischemic strokes occurring more than 1 year after

flutter. However, false detection may occur due to

WATCHMAN device implant. Furthermore, neither

far-field R-wave (Figure 2) oversensing by the atrial

the first primary endpoint of the PREVAIL trial

lead (35–37) or runs of premature atrial complexes.

(composite 18-month rate of stroke, cardiovascular or

False negative or missed AF has been reported when

unexplained death, and systemic embolism) nor the

episodes of AF are very brief (35,37). In addition,


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antitachycardia responses of CIEDs are not spe-

Pacemaker Patients and the AF Reduction Atrial

cific for AF (35,37) and may be triggered by other

Pacing) trial, the positive predictive value of AHREs

forms of AT, including atrial tachycardia or atrial

for EGM-confirmed AF was examined in 2,850 sub-

flutter. Thus, intracardiac electrograms (EGMs) must

jects with implanted pacemakers. In 17.3% of cases,

be reviewed to verify the accuracy of the device di-

AHRE episodes at >190 beats/min lasting >6 min

agnostics. Device-stored data based solely on marker

were found to be falsely positive, due predominantly

channels, without EGMs, cannot be used to verify AF

to repetitive non–re-entrant ventriculoatrial syn-

due to the potential for diagnostic errors caused by

chrony

oversensing or undersensing by the atrial lead.

desynchronization arrhythmia (Figure 4). Repetitive

Furthermore, atrial tachycardia detection rate pro-

non–re-entrant ventriculoatrial synchrony is trig-

gramming and the duration of the post-ventricular

gered by retrograde ventriculoatrial conduction with

atrial blanking interval can also influence the num-

functional atrial undersensing. It results from retro-

ber of automatic mode-switching episodes in the

grade atrial activation during the post-ventricular

setting of AT (38). Although ICM are also susceptible

atrial refractory period and functional atrial non-

to false AF detection due to oversensing or missed AF

capture due to atrial stimulation during the absolute

detection due to undersensing, 2 ICM with AF algo-

refractory period, with the potential to trigger mode

rithms (Medtronic Reveal XT, Model 9529, Medtronic

switching (41–45).

(40),

also

known

as

atrioventricular-

Inc., Minneapolis, Minnesota, and, SJM Confirm Implantable Cardiac Monitor Model DM2102, St. Jude

REVIEW OF PUBLICATIONS ON

Medical, Inc., Sunnyvale, California) are currently

DEVICE-DETECTED AF

available on the market, with the Medtronic Reveal XT reported to have an overall accuracy of 98.5% in

Because the advent of dual-chamber devices and

AF detection (39) (Figure 3). Although atrial high rate

ventricular leads with atrial sensing capability, the

episodes (AHRE) have been used as a surrogate for

clinical implications of device-detected AT have been

AF, the data must be interpreted with caution. In the

considered in the context of anticoagulation for

ASSERT (ASymptomatic AF and Stroke Evaluation in

stroke prevention (46), but the question of what to

F I G U R E 1 Mechanisms of Stroke in Atrial Fibrillation

Cardioembolic sources, almost exclusively represented by left atrial appendage thrombi, account for >90% of embolic events. Noncardioembolic origin, more often embolic material dislodged from thoracic and or carotid plaques, account for the remaining 10% of events. Graphics source: National Institutes of Health/National Heart, Lung, and Blood Institute.





F I G U R E 2 EGM Representative of AT/AF Due to Far-Field R-Wave Sensing

Far-field R-wave sensing on the atrial lead: AR on EGM 1 (atrial EGM) correlates with VS on EGM 2 (ventricular EGM). R-wave is sensed on the atrial channel, triggering false AT/AF.

Note: R-R interval is regular, therefore this is not AF.

Intracardiac electrogram (EGM) demonstrating sensing of the R-wave on the atrial lead, resulting in false detection of atrial tachycardia (AT)/atrial fibrillation (AF). AR ¼ atrial refractory event.

do about device-detected AF remains unsettled. The

the ASSERT trial are among the more comprehensive

MOST (MOde Selection) trial in patients with sinus

efforts to provide guidance. Although these studies

node dysfunction, the TRENDS study: A Prospective

varied with regard to rate thresholds for detection

Study of the Clinical Significance of Atrial Arrhyth-

of AT (including AT and AHRE), duration of epi-

mias Detected by Implanted Device Diagnostics, and

sodes, and follow-up, an association between these

F I G U R E 3 Implantable Cardiac Monitor Strips Exemplifying True and False AT/AF

False AT/AF

False AT/AF triggered due to PVC

True AT/AF

Note: irregular R-R intervals.

Examples of true and false detection of atrial tachycardia (AT)/atrial fibrillation (AF) by implantable cardiac monitors. False AT/AF detection due to irregular R-R intervals in a patient with frequent premature ventricular contractions (PVC).


285

286




tachyarrhythmias and risk of ischemic stroke was

dual-chamber

consistently found.

pared to conventional dual-chamber pacing (49). By

minimal

ventricular

pacing

com-

The MOST trial, a 6-year randomized trial of DDDR

measuring AF with stored diagnostic data from

versus VVIR pacing in patients with sinus node

the pacemaker, the SAVE PACe trial showed a mod-

dysfunction, documented a 50% reduction in newly

erate reduction of the risk of persistent AF in patients

diagnosed AF with dual-chamber pacing compared to

with sinus node disease (49). These observations

ventricular pacing alone (hazard ratio: 0.50; 95%

motivated a prospective study (TRENDS) to investi-

confidence interval: 0.32 to 0.76; p ¼ 0.001) (47). A

gate the relationship between device-detected AT

subgroup analysis of 316 patients correlated AHRE

(including atrial flutter, AF, and atrial tachycardia)

with clinical outcomes, but found no significant as-

and stroke risk (50). The TRENDS study was a pro-

sociation of pacing mode (dual-chamber vs. single-

spective, observational study of 2,486 patients with

chamber ventricular pacing) on the presence or

1 or more risk factors for stroke who had implanted

absence of AHRE (48). The presence of AHRE (atrial

devices. Patients with either a low (#5.5 h on any

rate >220 beats/min for 10 consecutive beats) was an

single day within a 30-day period) or a high burden of

independent predictor of mortality (HR: 2.48), death

AT ($5.5 h) had a higher risk of stroke than those

or nonfatal stroke (HR: 2.79), and AF (HR: 5.93),

without AT (HR: 2.20; 95% CI: 0.96 to 5.05; p ¼ 0.06)

indicating that pacemaker patients with sinus node

(33). However, the difference in hazard ratio between

dysfunction and AHRE were more than 2.5 times as

the groups with low and high AHRE burdens was

likely to die or have a stroke, and were 6 times

not statistically significant (51).

as likely to develop AF than those without AHRE

The ASSERT trial evaluated whether detection of

(32). Limitations of this substudy were its retro-

asymptomatic AHRE predicted an increased risk of

spective design, small sample size, and that 81%

stroke and systemic embolism in pacemaker patients

(129 of 160) of patients with AHRE had prior su-

without a history of AF, as well as whether overdrive

praventricular arrhythmias (32). A prospective study

atrial pacing would reduce the risk of symptomatic

Search AV Extension and Managed Ventricular Pacing

AF (52). Although overdrive atrial pacing failed to

for Promoting Atrio-Ventricular Conduction (SAVE

reduce the risk of symptomatic AF, subclinical epi-

PACe) measured the time to persistent AF with

sodes of AT, defined as atrial rates $190 beats/min

F I G U R E 4 Example of Automatic Mode-Switching Due to Repetitive Non–Re-Entrant Ventriculoatrial Synchrony

Blue oval: P-wave falls in the post-ventricular atrial refractory period and is not sensed [functional atrial undersensing], with subsequent atrial pacing [in red rectangle] occurring in the absolute refractory period [functional atrial non-capture].

Electrogram documenting false detection of atrial tachycardia/atrial fibrillation due to retrograde ventriculoatrial conduction, with P-wave falling into the post-ventricular atrial refractory period (functional atrial undersensing), with subsequent atrial pacing during the absolute refractory period (functional noncapture).




lasting >6 min, were associated with an increased risk of ischemic stroke (HR: 1.76; 95% CI: 0.99 to 3.11;

T A B L E 1 CHADS 2 and Associated Stroke Risk in the NRAF and ASSERT Trials

p ¼ 0.05). Longer episodes of AT were associated with

NRAF

incremental stroke risk, but AT of 6 to 24 h (HR: 2.00;

Number of CVAs (94)

95% CI: 1.13 to 3.55; p ¼ 0.02) and episodes >24 h (HR: 1.98; 95% CI: 1.11 to 3.51; p ¼ 0.02) carried a similar risk. Stroke risk increased with the number

287


n ¼ 1,733

ASSERT Adjusted Stroke Risk

n ¼ 259

Number of CVAs (11)

Adjusted Stroke Risk

CHADS2 ¼ 0

120

2

1.9 (1.2–3.0)

—

—

CHADS2 ¼ 1

463

17

2.8 (2–3.8)

68

1

2.11 (0.23–18.9)

—

CHADS2 ¼ 2

523

23

4.0 (3.1–5.1)

119

4

1.83 (0.62–5.4)

of subclinical AT episodes, with annual rates of TE ranging from 1.20 with a single episode to 1.93

Values are n or hazard ratio (95% confidence interval).

with $4 episodes. Subclinical AT was almost 8 times

ASSERT ¼ ASymptomatic AF and Stroke Evaluation in Pacemaker Patients and the AF Reduction Atrial Pacing; CHADS2 ¼ Congestive heart failure, Hypertension, Age 75 years or older, Diabetes Mellitus, and history of Stroke or transient ischemic attack; CVA ¼ cerebrovascular accident; NRAF ¼ National Registry of Atrial Fibrillation.

more common than clinical AF, which developed in 15.7% of patients with subclinical AT. The 2.5-fold greater risk of TE associated with subclinical AT was independent of the appearance of clinical AF and other stroke risk factors (52).

Resynchronization Devices) trial, which hypothesized that remote monitoring for AT with a predefined

Although the stroke risk on the basis of the CHADS 2

anticoagulation plan would prove superior to con-

(Congestive heart failure, Hypertension, Age $ 75

ventional methods for identification of AT with

years, Diabetes Mellitus, Stroke or transient ischemic

physician-directed anticoagulation (56). Patients with

attack) score appeared lower in the ASSERT trial than

ICDs or CRT defibrillators were randomized 1:1 to

that published by Gage et al. (53) (HR of 1.82 in the

either office visits or remote monitoring for detection

ASSERT trial vs. HR of 4.0 in the NRAF [National Reg-

of AT ($200 beats/min for 36 of 48 beats) and, when

istry of Atrial Fibrillation] trial, for CHADS2 score of 2)

AT was detected, an anticoagulation protocol was

(Table 1), the ASSERT trial was a prospective, ran-

initiated in the intervention group on the basis of

domized trial with lower-risk patients whereas the

the CHADS 2 risk score. Patients with CHADS 2 risk

NRAF was a registry trial with a higher-risk patient

score #2 were to initiate oral anticoagulation if AT

population. Furthermore, the NRAF trial had a greater

lasted $48 h, with discontinuation if there were

population of females, which was not factored into

no AT recurrences detected for 30 days. Those with

risk stratification with the CHADS2 score system.

CHADS2 scores of $3 to 4 would initiate anti-

However, female sex has been recognized as a risk

coagulation for device-detected AT $24 h in 2 days,

factor for cerebrovascular accident and is included in

with discontinuation if there were no AT recurrences

the currently recommended stroke risk stratification

detected for 90 days. Those with CHADS2 scores $5

scheme, CHA2DS2 -VASc (54). In addition to a higher

to 6, or with a history of TE were prescribed anti-

proportion of females, the NRAF trial population

coagulant therapy for any AT, without discontinua-

(in comparison to the ASSERT trial population) had

tion, regardless of AT recurrence. Exclusion criteria

a significantly greater incidence of congestive heart

included a history of stroke, transient ischemic

failure, prior cerebrovascular accident or transient

attack, or systemic embolism, and documented AF

ischemic attack, and lower utilization of aspirin ther-

or atrial flutter. A total of 2,718 patients were

apy (all p values