Accepted Manuscript. Mass Screening for Atrial Fibrillation: The Hype, The Methods, The Application. James A. Reiffel M.D. S (19)

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1 Accepted Manuscript Mass Screening for Atrial Fibrillation: The Hype, The Methods, The Application James A. Reiffel M.D. PII: S (19) DOI: Reference: AJM To appear in: The American Journal of Medicine Please cite this article as: James A. Reiffel M.D., Mass Screening for Atrial Fibrillation: The Hype, The Methods, The Application, The American Journal of Medicine (2019), doi: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

2 Mass Screening for Atrial Fibrillation: The Hype, The Methods, The Application James A. Reiffel, M.D. Professor Emeritus of Medicine, Columbia University Contact information: James A. Reiffel, M.D. c/o 202 Birkdale Lane Jupiter, FL Phone and fax: Disclosures: During the last 3 years, Dr. Reiffel has been an investigator and consultant for Medtronic, Janssen, Gilead, and Sanofi; a consultant for Portola, Acesion, InCardia Therapeutics; and a member of speaker s bureaus for Janssen and Boehringer Ingelheim. Word Count: 1449 (Text, including references) Funding: None Dr. Reiffel is the sole author and fully responsible for the content Running Head: Smart Watch versus Inserted Monitors for Detecting Atrial Fibrillation Key Words: Atrial Fibrillation, Monitoring, Smart Watch, Implanted Monitors, Thromboembolism

3 Recently, Apple launched new heart-related features for their Apple Watch, with notable excitement in the press, including an FDA-cleared app that notifies wearers if atrial fibrillation has occurred. Apple admits, however, the watch cannot detect all episodes; inconclusive results are possible; and it s not intended for people with known atrial fibrillation. 1 Notably, this comes shortly after the US Preventive Services Task Force published an advisory stating: the current evidence is insufficient to assess the balance of benefits and harms of screening for atrial fibrillation with electrocardiograms (ECG). 2, So, what is the public to do about screening? The answer depends upon whether there s a reason to screen. [Table 1] In patients with unexplained but atrial fibrillation-compatible symptoms, determining if atrial fibrillation is causative is important for diagnosis/therapy. However, this is quite different than mass screening of the public to seek atrial fibrillation when no hint of it exists, risk from atrial fibrillation is low, and treatment implications are uncertain. In contrast, understanding the relationship between atrial fibrillation, thromboembolism, and utility of prophylactic anticoagulation 3 has prompted pre-event identification efforts utilizing progressively advanced monitoring technologies in subjects with demographic, genetic, and/or laboratory risk markers 4 that identify an increased likelihood of having atrial fibrillation with thromboembolic risk, and in whom cost-effective oral anticoagulation reduces thromboembolic events. Monitoring such patients seems appropriate because: atrial fibrillation is often asymptomatic and unrecognized until thromboembolism; symptomatic and asymptomatic atrial fibrillation patients have similar adverse outcome rates; 5 device-detected atrial fibrillation has been linked to increased

4 stroke/death risk; 6 and, most of these atrial fibrillation-linked demographics are also high-risk markers for thromboembolism in atrial fibrillation patients. This contrasts with the uncertain and likely low cost-benefit of mass population screening especially with smart watches most often worn by younger individuals, 7 such as the millennial generation where high-risk markers for thromboembolism in atrial fibrillation are infrequent. If one believes atrial fibrillation detection in subjects with high-risk markers for thromboembolism is an important public health goal and its treatment is warranted, then we should monitor such individuals. Detection may occur fortuitously during an ECG but is more likely via systematic ECG screening at specific time points, such as yearly medical visits; opportunistic ECG screening, such as during vaccinations/pharmacy visits; scheduled ambulatory ECG monitoring with varying devices for variable durations; semi-continuous monitoring with a smart watch; and/or continuous monitoring with an inserted/implanted device. With non-watch external monitoring in differing populations, atrial fibrillation detection has been 0.2% to 5.3% Importantly, atrial fibrillation detection increases with longer durations of monitoring One could assume that general population screening with smart watches (which are not worn continuously) would also yield single digits/year incidences. Of note, not all atrial fibrillation detected by devices is new. In an AFinder Program in Hong Kong, % had atrial fibrillation detected but new detection occurred in only 0.69%. Contrastingly, significantly higher newly detected atrial fibrillation has ranged from 20% to 40% during months of follow up in single arm trials utilizing continuously recording implanted/inserted cardiac monitors in patients without known atrial fibrillation but with

5 demographic/laboratory markers common to atrial fibrillation. 15 Recognizing that atrial fibrillation is often intermittent/transient, one can understand why intermittent monitoring will miss many atrial fibrillation events identifiable with inserted monitors. [Figure 1] Inherently, given the greater likelihood of atrial fibrillation in patients with demographic/laboratory markers prevalent in the atrial fibrillation population, 4 continuous monitoring should detect atrial fibrillation more frequently in such subjects than in the general public and with a higher incidence than is possible with any external monitors, including smart watches. To this end, various intermittent monitoring approaches were modeled against continuous monitoring using the implanted/inserted cardiac monitors in REVEAL AF. 16 The monitor recordings allowed multiple non-continuous models to be extracted from its continuous data set. Atrial fibrillation lasting 6 minutes on the monitors was 27.1% at 12 months. This exceeded estimated rates from all simulated intermittent monitoring approaches: 0.8% with 24 hours of monitoring to 6.2% with 30 days of continuous monitoring one time. For repeated monitoring strategies, 12-month atrial fibrillation detection ranged from 3.5%, with quarterly 24-hour Holter monitoring to 10.6% with quarterly 7-day monitoring. Modeling of the smart watch was not performed, but would certainly be lower than continuous implanted/inserted monitor recordings though it should be greater in this demographically-enriched population than in the general public.

6 Finally, while the smart watch/smart phone app provides an opportunity to screen for atrial fibrillation, for most general population subjects in whom atrial fibrillation is detected, its value and the need for treatment is uncertain. In contrast, in subjects with demographic/laboratory characteristics giving them a higher likelihood of having atrial fibrillation 4 and an indication for therapy if atrial fibrillation is found, 15 optimal screening is now via easily inserted, very low risk subcutaneous monitors. Moreover, only continuous monitoring allows for determination of atrial fibrillation burden, recently recognized an important parameter, 17 as thromboembolic risk appears related not simply to atrial fibrillation as present/absent but also to the quantity of fibrillation present. Because atrial fibrillation may be symptom free, have poor symptom-arrhythmia correlation, and/or be intermittent, timely diagnosis of atrial fibrillation often requires active detection efforts. The smart watch can overcome some of these limitations but not as well as an insertable cardiac monitor. No doubt the smart watch capable of detecting atrial fibrillation will become a marketplace hit, like all new technological advances, but to what importance other than to the stock market and device sales? Detection is only needed in subjects where it matters.

7 REFERENCES 1. Baig EC. Apple watch s ECG app could help save lives. USA Today. Friday December 7, 2018, page 3B. 2. Jonas DE, Kahwati LC, Yun JDY, Middleton JC, Coker-Schwimmer M, Asher GN. Screening for atrial fibrillation with electrocardiography: evidence report and systematic review for the US Preventive Services Task Force. JAMA 2018; 320: Lin HJ, Wolf PA, Kelly-Hayes M, Beiser AS, Kase CS, Benjamin EJ, D'Agostino RB. Stroke severity in atrial fibrillation. The Framingham Study. Stroke 1996;27: Reiffel JA. Optimum risk assessment for stroke in atrial fibrillation: should we hold the status quo or consider magnitude synergism and left atrial appendage anatomy. Arrhythmia & Electrophysiology Review 2017; 6: Thind M, DaJuanicia NH, Badri M, et al. Embolic and other adverse outcomes in symptomatic versus asymptomatic patients with atrial fibrillation (from the ORBIT-AF Registry). Am J Cardiol 2018; 122: Reiffel J, Verma A, Halperin JL, et al. Rationale and design of REVEAL AF: a prospective study of previously undiagnosed atrial fibrillation as documented by an insertable cardiac monitor in high-risk patients. Am Heart J 2014; 167: Rowland C. Apple now says its smartwatch tech to detect atrial fibrillation is not for those with atrial fibrillation. The Washington Post, Business Section, December 6,

8 now-says-its-smartwatch-app-to-detect-atrial-fibrillation-is-not-for-those-with- atrial-fibrillation/2018/12/06/cb5c46bc-f978-11e8-8c9a- 860ce2a8148f_story.html?utm_term=.94ae53fa7a50 8. Mairesse GH, Moran P, Van Gelder IC, et al. Screening for atrial fibrillation: a EHRA consensus document, endorsed by HRS, APHRS, and SOLAECE. Europace 2017; 19: Fitzmaurice DA, Hobbs FD, Jowett S, Mant J, Murray ET, Holder R, Raftery JP, Bryan S, Davies M, Lip GY, Allan TF. Screening versus routine practice in detection of atrial fibrillation in patients aged 65 or over: cluster randomised controlled trial. Brit Med J 2007;335: Halcox JPJ, Wareham K, Cardew A, Gilmore M, Barry JP, Phillips C, Gravenor MB. Assessment of Remote Heart Rhythm Sampling Using the AliveCor Heart Monitor to Screen for Atrial Fibrillation The REHEARSE-AF Study. Circulation 2017;136: Omboni S, Verberk WJ. Opportunistic screening of atrial fibrillation by automatic blood pressure measurement in the community. BMJ Open 2016;6:e Sandhu RK, Dolovich L, Deif B, Barake W, Agarwal G, Grinvalds A, Lim T, Quinn FR, Gladstone D, Conen D, Connolly SJ, Healey JS. High prevalence of modifiable stroke risk factors identified in a pharmacy-based screening programme. Open Heart 2016;3:e Chan NY, Choy CC, Chan CK, Siu CW. Effectiveness of a nongovernmental organization-led large-scale community atrial fibrillation screening program using

9 the smartphone electrocardiogram: An observational cohort study. Heart Rhythm 2018; 15: Steinhubl SR, Waalen J, Edwards AM, Ariniello LM, Mehta RR, Ebner GS, Carter C, Baca-Motes K, Felicione E, Sarich T, Topol EJ. Effect of a Home-Based Wearable Continuous ECG Monitoring Patch on Detection of Undiagnosed Atrial Fibrillation: The mstops Randomized Clinical Trial. JAMA 2018; 320: Reiffel JA. When silence isn t golden: the case of silent atrial fibrillation. J Innovations in Cardiac Rhythm Management. 2017; 8: Reiffel JA, Verma A, Kowey P, et al. A comparison of atrial fibrillation monitoring strategies in patients at high risk for atrial fibrillation and stroke: Results from the REVEAL AF study. JACC 2018; 69(suppl March 2018). Am Coll Cardiol Ann Sci Sessions, Orlando, FL March 12, 2018; #18-A ACC. DOI: /S (18) Chen LY, Chung MK, Allen LA et al. Atrial Fibrillation Burden: AHA Scientific Statement. Circulation 2018; 137: e623-e644.

10 FIGURE LEGEND Figure 1. Clinical presentation patterns of atrial fibrillation versus likelihood of detection with monitoring. ECV = elective cardioversion. Dark bars indicate times that AF is present. Table 1: Reasons and Methods to Screen for Atrial Fibrillation (AF) in Patients with No AF History Reasons: Methods: None proven in the general population. Symptom assessment. Presumptive in patients with increased likelihood of AF: Prevent abnormal atrial remodeling, symptoms, hospitalizations, morbidity/mortality via post-detection prophylactic therapy. Pulse palpation. Electrocardiograms: Ambulatory Monitoring.

11 Including, Holter monitors, auto-triggered loop recorders, hand-held, or other self-applied, smart watch/smart phone app, etc. Implanted/inserted devices: Implanted pacemakers and defibrillators can be interrogated to assess detected arrhythmias. Newer miniaturized cardiac monitors are insertable, and optimal for long-term continuous monitoring in patients where maximal identification of AF and AF burden is desired.