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`
`THE PRESENT AND FUTURE STATE-OF-THE-ART REVIEW Device-Detected
`Atrial Fibrillation What to Do With Asymptomatic Patients?
`
`Article · January 2015
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`J O U R N A L O F T H E A M E R I C A N C O L L E G E O F C A R D I O L O G Y
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`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
`
`clinically significant heart rhythm disorder
`(1), with an estimated lifetime risk of 22%
`to 26% or about a lifetime risk of 1 in 4 (2). It has
`been diagnosed in >2.5 million people in the United
`States alone (3). In 2010, the incidence of diagnosed
`AF in the United States was 1.2 million, and its
`prevalence is projected to increase to >12 million
`cases by 2030 (4). In the European Union, there
`were 8.8 million adults >55 years of age with AF
`in 2010, with an expected increase to 17.9 million
`by 2060 (5). Globally, AF incidence in 2010 was esti-
`mated at 33.5 million (20.9 million men and 12.6
`million women). Despite a higher
`incidence in
`men, mortality associated with AF is greater
`in
`women, doubling between 1990 and 2010 (6). These
`statistics do not account for silent or undiagnosed
`
`AF, which is thought to affect as many as one-
`third of the U.S. population (3).
`
`MECHANISMS OF AF
`
`The pathophysiology of AF is multifactorial and
`complex, including both genetic and neural mecha-
`nisms. The main mechanism by which autonomic
`activation triggers AF is activation of the sympathetic
`and parasympathetic nervous system, which likely
`interact with the pulmonary vein–left atrial
`(LA)
`junction to trigger atrial ectopy (7). Genetic mecha-
`nisms linked to AF development include alterations
`in potassium or sodium channels, connexin expres-
`sion or function (2), and microRNAs (8). Four major
`mechanisms that promote focal ectopic firing and
`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 re-
`lationships 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.
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`Device-Detected Atrial Fibrillation
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`A B B R E V I A T I O N S
`
`A N D A C R O N Y M S
`
`AF = atrial fibrillation
`
`AHRE = atrial high
`rate episodes
`
`AT = atrial tachyarrhythmia
`
`CIED = cardiac implantable
`electronic device
`
`CRT = cardiac
`resynchronization therapy
`
`CS = cryptogenic stroke
`
`ECG = electrocardiogram
`
`EGM = intracardiac electrogram
`
`ICM = implantable cardiac
`monitor
`
`LA = left atrium/atrial
`
`LAA = left atrial appendage
`
`TE = thromboembolic event(s)
`
`AF: 1) ion channel dysfunction; 2) calcium
`handling abnormalities; 3) structural remod-
`eling (primarily atrial fibrosis); and 4) auto-
`nomic neural dysregulation (2,8). These 4
`conditions not only trigger AF, but may also
`result from episodes of AF, supporting the
`concept that “atrial fibrillation begets atrial
`fibrillation,” first reported in an early animal
`study documenting atrial electrical remodel-
`ing in AF (9). Further advances in knowledge
`of the pathophysiology of AF have revealed
`that electrical remodeling in AF is not limited
`to the atria. More pronounced remodeling
`after brief episodes of induced AF has been
`documented in the pulmonary veins (10),
`thereby extending the concept to “AF begets
`AF in the pulmonary veins”.
`
`AF AND STROKE
`
`AF is a major independent predictor of ischemic
`stroke, resulting in a 5-fold increase in risk (1). Each
`year, approximately 795,000 people experience
`strokes, of which 610,000 are first strokes and
`approximately 87% are ischemic. In the United States,
`someone suffers a stroke every 40 s (that is, approx-
`imately 90 people/h) (1). Among patients with AF, it
`is estimated that every hour, 15 will have a stroke (11),
`and such AF-related strokes impose a higher mortal-
`ity than strokes unrelated to AF (12). The prevalence
`of AF and associated stroke risk are highest among
`elderly patients, with stroke risk independent of
`whether AF is paroxysmal, persistent, or permanent
`(1). A large number of earlier clinical trials (13–15)
`demonstrated that
`systemic
`anticoagulation is
`highly efficacious for stroke prevention in patients
`with AF (16), with a recent meta-analysis doc-
`umenting the efficacy of both direct thrombin in-
`hibitors
`and vitamin K antagonists
`in stroke
`prevention in nonvalvular AF (17).
`The association between AF and cryptogenic
`stroke (CS) was recently documented using an
`implantable cardiac monitor (ICM). The CRYSTAL-AF
`(CRYptogenic Stroke and underlying Atrial Fibrilla-
`tion) trial, a prospective, randomized, multicenter,
`global study, in which long-term cardiac monitoring
`using an ICM was compared to conventional elec-
`trocardiogram (ECG) monitoring (ECG, 24-h Holter, or
`event monitor) for detection of AF in 441 patients
`with CS, demonstrated that AF was detected in 8.9%
`of ICM patients (compared to 1.4% in the ECG control
`group) at 6 months. Furthermore, on long-term
`follow-up at 3 years, AF was detected in 30% of
`patients by ICM, compared to only 3% in the
`
`conventional ECG group (18). Although anticoagulant
`prescription for AF was higher in the ICM group
`versus the routine ECG monitoring group (10.1% vs.
`4.6%) at 6 months, 97.0% of patients with detected
`AF were receiving oral anticoagulant agents by the
`12-month follow-up (18).
`A similar study, the EMBRACE (30-Day Cardiac
`Event Monitor Belt for Recording Atrial Fibrillation
`After a Cerebral Ischemic Event) study, compared
`new AF detection by noninvasive ambulatory ECG
`monitoring with either a 30-day event-triggered
`recorder (intervention group) or a conventional 24-h
`monitor (control group)
`in 572 patients with CS
`within the preceding 6 months, without a history of
`AF (19). The investigators reported a greater than
`5-fold increase (16.1% vs. 3.2%; p < 0.001) in AF
`detection in the 30-day event monitor group, with a
`subsequent significant increase in anticoagulation
`prescription (18.6% vs. 11.1%; p ¼ 0.01) among the
`30-day event monitor group. At the 90-day follow-
`up, 87% of patients with AF in the event monitor
`group and 100% of patients with AF in the control
`group were on anticoagulant
`therapy (19). Thus,
`both the CRYSTAL-AF and EMBRACE studies docu-
`mented a significant increase in anticoagulant pre-
`scription in CS patients with newly detected AF.
`However, anticoagulation treatment rates are signi-
`ficantly lower for patients without a prior history of
`stroke with newly detected AF on cardiac implantable
`electronic devices (CIEDs). One retrospective study
`reported a 50% incidence of pacemaker-detected
`AF, yet <25% of these patients with pacemaker-
`detected AF were treated with anticoagulant agents
`(20). The temporal relationship between atrial fibril-
`lation and stroke is not as well understood, and in some
`patients, episodes of AF are not detected until
`months after a stroke.
`
`MECHANISMS OF STROKE IN AF
`
`Although AF-related stroke is commonly attributed
`to clot formation resulting from blood stasis in the
`poorly contracting LA during AF, the mechanisms
`of thrombogenesis in AF are much more complex,
`implicating Virchow’s triad reviewed by Watson et al.
`(21) and Iwasaki et al. (22).
`In AF, endothelial and endocardial damage in the
`left atrial appendage (LAA), the presence of complex
`aortic plaque ($4 mm, ulcerated, or mobile) (23), and
`abnormal extracellular matrix turnover (which can
`induce fibrosis) all contribute to vessel wall changes.
`Abnormal blood stasis in the LA and LAA (which
`is promoted by and further worsens LA dilation),
`along with abnormal hemostasis and coagulation
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`Chen-Scarabelli et al.
`Device-Detected Atrial Fibrillation
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`283
`
`(activation of platelets and the coagulation cascade),
`complete Virchow’s
`triad (21). Virchow’s
`triad
`(described
`by
`the German
`physician, Rudolf
`Virchow), identified 3 main factors contributing to
`thrombosis: alterations in blood flow (stasis), the
`vessel wall (injury to the vascular endothelium), and
`blood
`constituents
`(hypercoagulability). When
`applied to thrombogenesis in AF, blood stasis occurs
`in the LA/LAA, atrial structural remodeling (including
`endothelial damage) ensues, and there is hypercoag-
`ulability due to activation of platelets and the coag-
`ulation cascade. Atrial hypocontractility and loss of
`atrial kick, along with LA enlargement, lead to blood
`stasis, which promotes endothelial damage and hy-
`percoagulability. Up-regulation of inflammatory and
`growth factors leads to endothelial damage, which in
`turn, promotes hypercoagulability with subsequent
`abnormal fibrinolysis (22).
`Due to its anatomical morphology, the LAA, a
`vestigial remnant of the original embryonic LA, has a
`predilection for thrombus formation.
`In fact, the
`LAA is the most common site of thrombus formation
`in patients with nonvalvular AF (24), accounting
`for >90% of thrombi (Figure 1). This thrombogenic
`tendency has led to targeted interventions to occlude
`the LAA in an attempt to reduce stroke risk in AF, as
`reported in trials such as the PLAATO (Percutaneous
`Left Atrial Appendage Transcatheter Occlusion) trial
`in 2002 (25) and, most recently, the PROTECT AF
`(Watchman Left Atrial Appendage System for Embolic
`Protection in Patients With Atrial Fibrillation) study,
`which documented noninferiority of LAA occlusion to
`systemic anticoagulation (26). In fact, the PROTECT
`AF trial was credited with being the first trial to
`demonstrate involvement of the LAA in the patho-
`genesis of stroke in AF (27).
`Significant safety concerns for WATCHMAN im-
`plantation, including pericardial effusions and device
`embolization, were addressed in a subsequent trial,
`the PREVAIL (Watchman LAA Closure Device in Pa-
`tients With Atrial Fibrillation Versus Long Term
`Warfarin Therapy) trial, which documented a signifi-
`cantly lower rate of adverse events compared to the
`PROTECT AF trial (4.2% vs. 8.7%; p ¼ 0.004) (28).
`Although the third review by the Food and Drug
`Administration Circulatory System Devices Advisory
`Panel in October 2014 (29) resulted in a unanimous
`vote on safety of the device, analysis of the updated
`June 2014 PREVAIL dataset demonstrated new
`ischemic strokes occurring more than 1 year after
`WATCHMAN device implant. Furthermore, neither
`the first primary endpoint of
`the PREVAIL trial
`(composite 18-month rate of stroke, cardiovascular or
`unexplained death, and systemic embolism) nor the
`
`second primary endpoint (composite 18-month rate of
`stroke and systemic embolism) were met, raising
`the question regarding long-term efficacy, with the
`committee split on the benefit-risk profile. At the
`present time, the fate of the WATCHMAN device
`remains uncertain (29).
`Recent studies reported a significant association
`between the type of LAA morphology and silent ce-
`rebral ischemia as well as stroke risk, suggesting a
`potential role for LAA morphology in stroke risk
`stratification schemes. Among the 4 major types of
`LAA morphology (chicken wing, cactus, windsock,
`and cauliflower), cauliflower LAA morphology carried
`the highest risk of stroke, whereas chicken wing car-
`ried the lowest in a study of 932 patients undergoing
`catheter ablation of AF (30). A significant association
`between LAA morphology and burden of silent cere-
`bral ischemia was reported in 348 patients undergo-
`ing catheter ablation of AF (31). Although LAA
`exclusion does not prevent AF-related strokes due to
`other causes (i.e., noncardioembolic origin), because
`the LAA accounts for >90% of thrombi in AF (25), it
`may be a significant strategy in stroke prevention
`in nonvalvular AF.
`
`DEVICE-DETECTED AF
`
`can be
`(AT)
`tachyarrhythmias
`Subclinical atrial
`detected by various cardiac monitoring methods,
`including external surface monitoring (e.g., standard
`12-lead electrocardiogram, ambulatory Holter moni-
`tors, event monitors) and by CIEDs (e.g., implantable
`cardiac monitors, dual-chamber pacemakers, dual-
`chamber implantable cardioverter-defibrillators, car-
`diac resynchronization therapy [CRT] devices), many
`of which enable remote monitoring. This review
`addresses only CIEDs, given their continuous moni-
`toring capability. AT commonly occurs in patients
`with CIEDs and is associated with an increased risk
`of thromboembolism (TE) (1). Several studies have
`correlated TE risk with the total duration or burden
`of device-detected AT (32–34). However, there are
`presently no published randomized clinical studies
`investigating treatment of AT detected by CIEDs.
`All cardiac rhythm recordings obtained from CIEDs
`require adjudication or review by a qualified clinician
`to verify diagnostic accuracy. Retrospective review of
`device-derived data has confirmed that most of these
`tachyarrhythmias represent paroxysmal AF or atrial
`flutter. However, false detection may occur due to
`far-field R-wave (Figure 2) oversensing by the atrial
`lead (35–37) or runs of premature atrial complexes.
`False negative or missed AF has been reported when
`episodes of AF are very brief (35,37). In addition,
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`
`antitachycardia responses of CIEDs are not spe-
`cific for AF (35,37) and may be triggered by other
`forms of AT,
`including atrial tachycardia or atrial
`flutter. Thus, intracardiac electrograms (EGMs) must
`be reviewed to verify the accuracy of the device di-
`agnostics. Device-stored data based solely on marker
`channels, without EGMs, cannot be used to verify AF
`due to the potential for diagnostic errors caused by
`oversensing or undersensing by the atrial
`lead.
`Furthermore, atrial tachycardia detection rate pro-
`gramming and the duration of the post-ventricular
`atrial blanking interval can also influence the num-
`ber of automatic mode-switching episodes in the
`setting of AT (38). Although ICM are also susceptible
`to false AF detection due to oversensing or missed AF
`detection due to undersensing, 2 ICM with AF algo-
`rithms (Medtronic Reveal XT, Model 9529, Medtronic
`Inc., Minneapolis, Minnesota, and, SJM Confirm
`Implantable Cardiac Monitor Model DM2102, St. Jude
`Medical, Inc., Sunnyvale, California) are currently
`available on the market, with the Medtronic Reveal
`XT reported to have an overall accuracy of 98.5% in
`AF detection (39) (Figure 3). Although atrial high rate
`episodes (AHRE) have been used as a surrogate for
`AF, the data must be interpreted with caution. In the
`ASSERT (ASymptomatic AF and Stroke Evaluation in
`
`Pacemaker Patients and the AF Reduction Atrial
`Pacing) trial, the positive predictive value of AHREs
`for EGM-confirmed AF was examined in 2,850 sub-
`jects with implanted pacemakers. In 17.3% of cases,
`AHRE episodes at >190 beats/min lasting >6 min
`were found to be falsely positive, due predominantly
`to repetitive non–re-entrant ventriculoatrial syn-
`chrony
`(40),
`also
`known as
`atrioventricular-
`desynchronization arrhythmia (Figure 4). Repetitive
`non–re-entrant ventriculoatrial synchrony is trig-
`gered by retrograde ventriculoatrial conduction with
`functional atrial undersensing. It results from retro-
`grade atrial activation during the post-ventricular
`atrial refractory period and functional atrial non-
`capture due to atrial stimulation during the absolute
`refractory period, with the potential to trigger mode
`switching (41–45).
`
`REVIEW OF PUBLICATIONS ON
`DEVICE-DETECTED AF
`
`Because the advent of dual-chamber devices and
`ventricular leads with atrial sensing capability, the
`clinical implications of device-detected AT have been
`considered in the context of anticoagulation for
`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.
`
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`
`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
`MOST (MOde Selection) trial in patients with sinus
`node dysfunction, the TRENDS study: A Prospective
`Study of the Clinical Significance of Atrial Arrhyth-
`mias Detected by Implanted Device Diagnostics, and
`
`the ASSERT trial are among the more comprehensive
`efforts to provide guidance. Although these studies
`varied with regard to rate thresholds for detection
`of AT (including AT and AHRE), duration of epi-
`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
`
`True AT/AF
`
`False AT/AF triggered
`due to PVC
`
`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).
`
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`tachyarrhythmias and risk of ischemic stroke was
`consistently found.
`The MOST trial, a 6-year randomized trial of DDDR
`versus VVIR pacing in patients with sinus node
`dysfunction, documented a 50% reduction in newly
`diagnosed AF with dual-chamber pacing compared to
`ventricular pacing alone (hazard ratio: 0.50; 95%
`confidence interval: 0.32 to 0.76; p ¼ 0.001) (47). A
`subgroup analysis of 316 patients correlated AHRE
`with clinical outcomes, but found no significant as-
`sociation of pacing mode (dual-chamber vs. single-
`chamber ventricular pacing) on the presence or
`absence of AHRE (48). The presence of AHRE (atrial
`rate >220 beats/min for 10 consecutive beats) was an
`independent predictor of mortality (HR: 2.48), death
`or nonfatal stroke (HR: 2.79), and AF (HR: 5.93),
`indicating that pacemaker patients with sinus node
`dysfunction and AHRE were more than 2.5 times as
`likely to die or have a stroke, and were 6 times
`as likely to develop AF than those without AHRE
`(32). Limitations of this substudy were its retro-
`spective design, small sample size, and that 81%
`(129 of 160) of patients with AHRE had prior su-
`praventricular arrhythmias (32). A prospective study
`Search AV Extension and Managed Ventricular Pacing
`for Promoting Atrio-Ventricular Conduction (SAVE
`PACe) measured the time to persistent AF with
`
`com-
`dual-chamber minimal ventricular pacing
`pared to conventional dual-chamber pacing (49). By
`measuring AF with stored diagnostic data from
`the pacemaker, the SAVE PACe trial showed a mod-
`erate reduction of the risk of persistent AF in patients
`with sinus node disease (49). These observations
`motivated a prospective study (TRENDS) to investi-
`gate the relationship between device-detected AT
`(including atrial flutter, AF, and atrial tachycardia)
`and stroke risk (50). The TRENDS study was a pro-
`spective, observational study of 2,486 patients with
`1 or more risk factors for stroke who had implanted
`devices. Patients with either a low (#5.5 h on any
`single day within a 30-day period) or a high burden of
`AT ($5.5 h) had a higher risk of stroke than those
`without AT (HR: 2.20; 95% CI: 0.96 to 5.05; p ¼ 0.06)
`(33). However, the difference in hazard ratio between
`the groups with low and high AHRE burdens was
`not statistically significant (51).
`The ASSERT trial evaluated whether detection of
`asymptomatic AHRE predicted an increased risk of
`stroke and systemic embolism in pacemaker patients
`without a history of AF, as well as whether overdrive
`atrial pacing would reduce the risk of symptomatic
`AF (52). Although overdrive atrial pacing failed to
`reduce the risk of symptomatic AF, subclinical epi-
`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).
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`J A N U A R Y 2 7 , 2 0 1 5 : 2 8 1 – 9 4
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`Chen-Scarabelli et al.
`Device-Detected Atrial Fibrillation
`
`287
`
`T A B L E 1 CHADS2 and Associated Stroke Risk in the NRAF and ASSERT Trials
`
`NRAF
`
`ASSERT
`
`CHADS2 ¼ 0
`CHADS2 ¼ 1
`CHADS2 ¼ 2
`
`n ¼ 1,733
`120
`463
`523
`
`Number of
`CVAs (94)
`
`Adjusted
`Stroke Risk
`
`n ¼ 259
`
`Number of
`CVAs (11)
`
`Adjusted
`Stroke Risk
`
`2
`17
`23
`
`1.9 (1.2–3.0)
`2.8 (2–3.8)
`4.0 (3.1–5.1)
`
`—
`
`68
`119
`
`—
`
`1
`4
`
`—
`
`2.11 (0.23–18.9)
`1.83 (0.62–5.4)
`
`Values are n or hazard ratio (95% confidence interval).
`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.
`
`Resynchronization Devices) trial, which hypothesized
`that remote monitoring for AT with a predefined
`anticoagulation plan would prove superior to con-
`ventional methods for
`identification of AT with
`physician-directed anticoagulation (56). Patients with
`ICDs or CRT defibrillators were randomized 1:1 to
`either office visits or remote monitoring for detection
`of AT ($200 beats/min for 36 of 48 beats) and, when
`AT was detected, an anticoagulation protocol was
`initiated in the intervention group on the basis of
`the CHADS2 risk score. Patients with CHADS2 risk
`score #2 were to initiate oral anticoagulation if AT
`lasted $48 h, with discontinuation if there were
`no AT recurrences detected for 30 days. Those with
`CHADS2 scores of $3 to 4 would initiate anti-
`coagulation for device-detected AT $24 h in 2 days,
`with discontinuation if there were no AT recurrences
`detected for 90 days. Those with CHADS2 scores $5
`to 6, or with a history of TE were prescribed anti-
`coagulant therapy for any AT, without discontinua-
`tion, regardless of AT recurrence. Exclusion criteria
`included a history of stroke,
`transient
`ischemic
`attack, or systemic embolism, and documented AF
`or atrial flutter. A total of 2,718 patients were
`
`lasting >6 min, were associated with an increased risk
`of ischemic stroke (HR: 1.76; 95% CI: 0.99 to 3.11;
`p ¼ 0.05). Longer episodes of AT were associated with
`incremental stroke risk, but AT of 6 to 24 h (HR: 2.00;
`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
`of subclinical AT episodes, with annual rates of
`TE ranging from 1.20 with a single episode to 1.93
`with $4 episodes. Subclinical AT was almost 8 times
`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).
`Although the stroke risk on the basis of the CHADS2
`(Congestive heart failure, Hypertension, Age $ 75
`years, Diabetes Mellitus, Stroke or transient ischemic
`attack) score appeared lower in the ASSERT trial than
`that published by Gage et al. (53) (HR of 1.82 in the
`ASSERT trial vs. HR of 4.0 in the NRAF [National Reg-
`istry of Atrial Fibrillation] trial, for CHADS2 score of 2)
`(Table 1), the ASSERT trial was a prospective, ran-
`domized trial with lower-risk patients whereas the
`NRAF was a registry trial with a higher-risk patient
`population. Furthermore, the NRAF trial had a greater
`population of females, which was not factored into
`risk stratification with the CHADS2 score system.
`However, female sex has been recognized as a risk
`factor for cerebrovascular accident and is included in
`the currently recommended stroke risk stratification
`scheme, CHA2DS2-VASc (54). In addition to a higher
`proportion of females, the NRAF trial population
`(in comparison to the ASSERT trial population) had
`a significantly greater incidence of congestive heart
`failure, prior cerebrovascular accident or transient
`ischemic attack, and lower utilization of aspirin ther-
`apy (all p values <0.0001) (Table 2). Thus, the lower
`stroke risk in the ASSERT trial may be due to lower-
`risk population, despite similar mean CHADS2 scores
`(2.1 in the NRAF trial vs. 2.2 in the ASSERT trial). An
`editorial accompanying the ASSERT trial contended
`that the hypothesis of causation required AF to pre-
`cede TE events, along with existence of a time-
`threshold effect, whereby longer episodes or greater
`burden of AT conferred greater risk. Clinical trials
`were deemed warranted to determine whether pa-
`tients with brief, asymptomatic AT had significant
`stroke risk and whether anticoagulation would
`benefit this population (55).
`The latest clinical trial on device-detected AF is
`the IMPACT (Randomized Trial of Anticoagulat-
`ion Guided by Remote Rhythm Monitoring in Pa-
`tients With Implanted Cardioverter-Defibrillator and
`
`T A B L E 2 Comparison of Patient Characteristics Between NRAF and ASSERT Trials
`ASSERT (N ¼ 261
`[With Subclinical AT])
`77  7
`14.9%
`
`Age, yrs
`CHF
`HTN
`Male
`Female
`DM
`Prior CVA or TIA
`ASA therapy
`Mean CHADS2 score
`
`NRAF
`(N ¼ 1,733)
`81
`56%
`56%
`42%
`58%
`23%
`25%
`31%
`2.1 (without aspirin)
`2.3 (with aspirin)
`
`Comparison of
`Proportions (p Value)
`
`<0.0001
`
`—
`
`56.3%
`43.7%
`22.6%
`11.9%
`61.3%
`2.2  1.1
`
`<0.0001
`<0.0001
`0.9487
`<0.0001
`<0.0001
`0.1711
`
`ASA ¼ acetylsalicylic acid; AT ¼ atrial tachyarrhythmia; CHF ¼ congestive heart failure; DM ¼ diabetes mellitus;
`HTN ¼ hypertension; TIA ¼ transient ischemic attack; other abbreviations as in Table 1.
`
`Downloaded From: http://content.onlinejacc.org/ by Tiziano Scarabelli on 01/20/2015
`
`AliveCor Ex. 2029 - Page 8
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`288
`
`Chen-Scarabelli et al.
`Device-Detected Atrial Fibrillation
`
`J A C C V O L . 6 5 , N O . 3 , 2 0 1 5
`
`J A N U A R Y 2 7 , 2 0 1 5 : 2 8 1 – 9 4
`
`enrolled, with no significant differences in baseline
`demographics between the 2 groups, except that a
`slightly higher percent of the intervention arm was
`treated with antiplatelet drugs other than aspirin
`(34.5% vs. 30.7%; p ¼ 0.037). The incidence of AT was
`similar for the 2 groups (33.2%, control vs. 36.3%,
`interventional group; p ¼ 0.09), and adjudication of
`device-based atrial EGMs verified 60.5% of AT events
`as AF, 30% as atrial flutter, and the remaining 9.5% as
`false positive, with no significant differences between
`groups. Patients were followed up to 5 years, when
`the Data Monitoring Committee recommended trial
`termination on the basis of failure to demonstrate a
`meaningful difference in outcome with the inter-
`ventional strategy.
`During a median follow-up of 701 days, 225 pa-
`tients in the control group met criteria for oral anti-
`coagulation versus 126 in the intervention group.
`There were no statistically significant differences
`between groups in the proportion of patients starting
`or stopping anticoagulant agents, nor in the mean
`duration of anticoagulant
`therapy. However,
`the
`intervention group started treatment earlier (mean 3
`vs. 54 days; p < 0.001),
`indicating that remote
`monitoring facilitated earlier intervention for AT.
`Nonetheless, there was no significant difference be-
`tween groups in the primary outcome, which was the
`composite of ischemic stroke, systemic embolic, and
`major hemorrhagic events, or in all-cause mortality.
`Although compliance with the oral anticoagulation
`protocol in the interventional group was suboptimal,
`the overall primary event rate was low. The in-
`vestigators concluded that initiation of oral antico-
`agulant therapy on the basis of device-detected AF
`and subsequent discontinuation of therapy on the
`basis of the absence of AT did not improv