Apple Heart Study

Written by: Em Wessling, MD (NUEM ‘22) Edited by: Dana Loke, MD (NUEM ‘19) Expert Commentary by: Rod Passman, MD

---

Chief Complaint: My watch thinks I have Atrial Fibrillation!

 As technology advances, medicine must continue to advance in pace. Wearable technology has been evolving for decades. The information gathered from a wide range of these devices may someday help to provide healthcare workers with valuable information about a patient’s condition. However, for now, there is limited research on their utility within the healthcare field.

 Thus far, both Apple Watch and Fitbit have been shown to correctly identify tachycardia during atrial tachyarrhythmias, but their accuracy to the heart rate varied with the type of arrhythmia (1,2). Apple Watch has been shown to be more accurate than Fitbit (1,2). The WATCH AF trial demonstrated it was possible with reasonable sensitivity (93.7%) and specificity (98.2) to use smart watches to diagnose Atrial Fibrillation (3). 

How Apple Watch is tracking atrial fibrillation:

-        Photoplethysmography: the use of light to determine volume within a structure at a given time

-        Pulse is estimated by time between peak volume seen by photoplethysmography.

-        When the pulse is highly variable between consecutive beats, irregular heart beat is suspected.

Apple Heart Study: The plan and the preliminary data (4, 5)

Study Design: Prospective, single arm pragmatic study

-        Enrolled 419,093 participant  

-        Inclusion Criteria: appropriate Apple technology, Age≥22 years, US resident, proficient in English, valid phone number and email.

-        Exclusion criteria: self-reported atrial fibrillation , atrial flutter, or anticoagulation

-        Methods:  “Irregular Pulse Notification” (indication of possible atrial fibrillation) sent to participants  if 5/6 irregular pulses within  48 hour period, at which point participant was instructed to wear EKG patch for up to 7 days.

-        Primary Outcome: Proportion of patients alerted with “Irregular Pulse Notification” who were found to have atrial fibrillation or atrial flutter on EKG patch, in the 65+ population as well as in all-comers.

-        Secondary Outcomes: Positive predictive value (PPV) of irregular heart rhythm notification; percentage of those with irregular notification who contacted a health care professional within 3 months.

Preliminary Data presented at ACC:

-        Participants who received “Irregular Pulse Notification”:  2,161 (0.52% all comers)

-        Participants age >65 who received “Irregular Pulse Notification”: >3%

-        EKG Patches sent to 658 participants; 450 returned.

• 34% of those returned showed atrial fibrillation

• PPV for Tachogram: 71%

• PPV for “Irregular Pulse Notification”: 84%

-        Notification to doctor - approx. 50%

Limitations:

• Small sample size for EKG patches, despite high enrollment

• Self-reported data

• Self-selecting group, i.e.may not be able to extrapolate prevalence data to those who do not wear smart watches

Potential Impact on Emergency Departments:

As more and more studies validate the accuracy of wearable technology to measure and recognize health conditions, the implications must be analyzed as well.

Prior to 2017, researchers began to predict that there would be an expansive increase in the rates of atrial fibrillation due to “worldwide aging” (6). While this review acknowledged there were “potential applications” for smart phone technology in the diagnosis, their predictions of the expanse of the epidemic of atrial fibrillation preceded definitive research showing increased diagnosis rates with wearable technology, which will likely only further expedite this growing patient population.  The mSToPS Trial showed that immediate in-home monitoring with an EKG patch had 3% greater rates of atrial fibrillation diagnosis compared to delayed EKG monitoring at 4 months. This led to increased use of anticoagulants and increased health care utilization (7). If this increase was seen with EKG patches, consider the influx of patients to primary care and cardiology clinics in addition to emergency departments that can be projected based on the rise of smart watch detection of atrial fibrillation. Researchers in Australia had begun studying this prior to the commencement of the Apple Heart Study (8). When cardiac patients were asked if they trusted smart watches to predict arrhythmia and measure their heart rate only 53% agreed; however, that did not stop 91% from reporting they would seek care if their watch alerted them about an abnormality (8). While the preliminary data from the Apple Heart study shows that a much smaller percentage of those who were not previously cardiac patients sought medical care when alerted by their Apple Watch, further study is needed to see the extent to which advances in smart watch health technology will lead to an influx in patients to the Emergency Department due to concerns of arrhythmia found by a smartwatch (5).

 While the accuracy of these methods of arrhythmia detection are still being studied, the potential for ED presentation with this chief complaint will continue to rise. In the fourth quarter of 2017 financial year, Apple alone sold greater than 8 million smart watches worldwide, making it the largest watch vender in the world (9).  With these increased sales, comes the potential for increased recognition of arrythmia by smartwatch. Healthcare organizations throughout the country must strive to develop effective and efficient clinical pathways in order to evaluate, potentially diagnose, and treat this patient population. Upon presentation to the Emergency Department, each patient should receive an EKG, telemetry monitoring while in the Emergency Department and screaming lab work: often including CBC, BMP + Mg, and troponin.  From there, the pathway may vary. Many would agree, if the patient is and has always been asymptomatic, work up is unremarkable, with normal sinus rhythm on their EKG, discharge home with an EKG patch and follow up with cardiology is reasonable. Conversely, an EKG showing atrial fibrillation would constitute a new diagnosis and further work up would proceed as with any other new diagnosis of Atrial Fibrillation. However, for those who fall in-between, the disposition is not as clear. What would you do?

---

Expert Commentary

More than 800 years ago, Maimonides described an irregular pulse that likely represented atrial fibrillation (AF). The development of the electrocardiogram by Einthoven 700 years later allowed surface recordings of human AF for the first time.1 With the recognition that AF is often asymptomatic and paroxysmal, the development of inexpensive, non-invasive, passive monitors for irregular rhythm identification has long been recognized as a potentially important tool for arrhythmia detection and management.

At its core (pun intended), the purpose of the Apple Heart Study was to assess the feasibility of AF screening in large populations by monitoring participants with a wrist-worn photoplethysmography (PPG) monitor.2 The PPG algorithm in the Apple Watch samples the pulse several times daily during periods of physical inactivity and increases the sampling rate if an irregular tachogram is detected. If 5 out of 6 tachograms are consistent with AF (requiring > 60 minutes of AF), the wearer receives an irregular rhythm notification. Since the version of the Apple Watch used in the study did not have the 30-second ECG feature (available in Series 4 watches and later), the Apple Heart Study protocol asked those who received the irregular rhythm notification to wear an ECG patch at a later date. 

Several important facts can be gleaned from the Apple Heart Study.  First, the study virtually enrolled 419,297 individuals in less than a year, a testament to the interest in the subject matter, the ease of remote enrollment when appropriate, and the enormous potential of digital health studies. Second, the fear that the healthcare system would be inundated with false positive AF notifications appears unfounded as 99.8% of participants under age 40 did not receive an irregular rhythm notification.  Third, the positive predictive value for the irregular rhythm notification was surprisingly high (84%) despite that fact that the patch was applied a mean of 13 days following the notification and was worn for less than 7 days on average. This last point is worth emphasizing since with paroxysmal AF, a negative monitor placed two weeks after an irregular rhythm notification may simply mean that AF was not present during both time periods.

The study also has some important caveats.  The Apple Heart Study did not report the sensitivity and specificity of the PPG algorithm for AF detection, a critical piece of missing data needed for clinical care and future research. Furthermore, only a minority of patients who received an irregular rhythm notification actually wore and returned the ECG monitor, showing that virtual enrollment doesn’t always translate into virtual protocol compliance. From a research perspective, wearable AF monitors have allowed for large-scale screening studies such as the Huawei  Heart and Heartline Studies aimed at understanding the true prevalence of AF and the risks and benefits of early detection and treatment.3,4 From a clinical perspective, a patient who says “my watch says I have AF” still requires ECG confirmation, but that too has been made easier with the new generation of wearables.

References

1. Prystowsky EN. The history of atrial fibrillation: the last 100 years. J Cardiovasc Electrophysiol. 2008;19(6):575-582. doi:10.1111/j.1540-8167.2008.01184.

2. Perez MV, Mahaffey KW, Hedlin H, et al. Large-Scale Assessment of a Smartwatch to Identify Atrial Fibrillation. N Engl J Med. 2019;381(20):1909-1917. doi:10.1056/NEJMoa1901183

3. Guo Y, Wang H, Zhang H, et al. Mobile Photoplethysmographic Technology to Detect Atrial Fibrillation. J Am Coll Cardiol. 2019;74(19):2365-2375. doi:10.1016/j.jacc.2019.08.019

4. www.heartline.com

Rod Passman, MD

Professor, Feinberg School of Medicine

Cardiac Electrophysiology

Northwestern Memorial Hospital

---

How To Cite This Post:

[Peer-Reviewed, Web Publication] Wessling, E. Loke, D. (2021, Jan 25). Apple Heart Study. [NUEM Blog. Expert Commentary by Passman, R]. Retrieved from http://www.nuemblog.com/apple-heart.

---

Other Posts You May Enjoy

References

1. Koshy, Anoop N., et al. "Smart watches for heart rate assessment in atrial arrhythmias." International journal of cardiology 266 (2018): 124-127.

2. Koshy, A., et al. "Heart Rate Assessment by Smart Watch: Utility or Futility?." Heart, Lung and Circulation 26 (2017): S280-S281.

3. Dörr, Marcus, et al. "The WATCH AF trial: SmartWATCHes for detection of atrial fibrillation." JACC: Clinical Electrophysiology5.2 (2019): 199-208.

4. Turakhia, Mintu P., et al. "Rationale and design of a large-scale, app-based study to identify cardiac arrhythmias using a smartwatch: The Apple Heart Study." American heart journal207 (2019): 66-75.

5. ACC News Story. “Apple Heart Study Identifies AFib in Small Group of Apple Watch Wearers.” American College of Cardiology: Latest in Cardiology, American College of Cardiology, 16 Mar. 2019, www.acc.org/latest-in-cardiology/articles/2019/03/08/15/32/sat-9am-apple-heart-study-acc-2019.

6. Morillo CA, Banerjee A, Perel P, Wood D, Jouven X. Atrial fibrillation: the current epidemic. J Geriatr Cardiol. 2017;14(3):195–203. doi:10.11909/j.issn.1671-5411.2017.03.011

7. Steinhubl SR, Waalen J, Edwards AM, et al. Effect of a Home-Based Wearable Continuous ECG Monitoring Patch on Detection of Undiagnosed Atrial Fibrillation: The mSToPS Randomized Clinical Trial. JAMA.2018;320(2):146–155.

8. Koshy, A., et al. "Cardiac Patients Likely to Seek Medical Assistance Based on Abnormal Heart Rate Readings on Smart Watches or Smartphone ECG Monitors." Heart, Lung and Circulation 26 (2017): S280.

9. Canalys Press Team. “18 Million Apple Watches Ship in 2017, up 54% on 2016.” Canalys Newsroom, Canalys, 6 Feb. 2018, www.canalys.com/newsroom/18-million-apple-watches-ship-2017-54-2016.

A “Pill-in-the-Pocket” Approach to Paroxysmal Atrial Fibrillation

Written by: David Feiger, MD (NUEM ‘22) Edited by: Jon Andereck, MD, MBA NUEM ‘19) Expert Commentary by: Kaustubha Patil, MD

---

The Case

A healthy 65-year-old male with paroxysmal atrial fibrillation presents to the emergency department in atrial fibrillation with rapid ventricular rate. His blood pressure is 135/83, heart rate 135, respirations 15 with an O2 saturation of 98% on room air. He states that he took his “pill-in-the-pocket” four hours prior to presentation and his symptoms did not resolve.

Atrial fibrillation

A study in the Western Journal of Emergency Medicine in 2013 observed the costs associated with emergency department (ED) treatment and discharge of patients presenting with atrial fibrillation (AF) or atrial flutter was $5,460 [10]. Those admitted to the hospital naturally incur far higher costs. For those eligible, a visit to the ED could be avoided with the “pill-in-the-pocket” approach.

What is the “pill-in-the-pocket” approach?

The “pill-in-the-pocket” approach is the administration of a prescribed class IC antiarrhythmic, either flecainide or propafenone, following recent onset of episodes of palpitations in patients with paroxysmal AF. It is generally initiated by the patient’s cardiologist after extensive cardiac evaluation to rule out structural disease and other conduction abnormalities. The idea is to terminate the suspected episode of AF without having to present to an ED or clinic. Several studies have investigated the safety of this approach and supported this method of outside-the-hospital termination of paroxysmal AF events [2, 14].

Who is eligible for the “pill-in-the-pocket” approach?

In a study in the New England Journal of Medicine supporting the feasibility and safety of this out-of-hospital treatment, only specific patients were selected to participate. Inclusion criteria included:

• healthier patients between 18 and 75 years old

• a history of infrequent AF not associated with chest pain, hemodynamic instability, dyspnea, or syncope

• no significant electrocardiographic abnormalities (pre-excitations, bundle branch blocks, long QT interval, etc.)

• no structural or functional cardiac diseases

• no history of thromboembolic episodes

• no current use of an antiarrhythmic medication

• not currently pregnant

• no significant chronic disease including but not limited to muscular dystrophies, systemic collagen disease, and renal or hepatic insufficiency

These patients were then admitted to the hospital for a cardiac workup and were trialed on either flecainide or propafenone with successful pharmacologic cardioversion in the inpatient setting. Both flecainide and propafenone are proarrhythmic, thus structural heart diseases must be ruled out before their use and patients should be monitored during initiation of therapy [2].

How do flecainide and propafenone work?

Flecainide and propafenone are both powerful class IC antiarrhythmics that strongly bind fast sodium channels with a slower association and dissociation than other class I antiarrhythmics. These drugs slow phase 0 during sodium-dependent depolarization in cardiac muscle cells of the atrial and ventricular myocardium (Figure 1). This effect is primarily important in prolonging atrial refractoriness, thus aiding in the conversion and termination of AF. Flecainide’s use in tachyarrhythmias comes from its rate-dependence property in which its efficacy is greater at faster heart rates. Propafenone has additional beta blocker activity which may enhance its overall clinical effectiveness in treating tachyarrhythmias [3, 5, 6, 13].

What are treatment options for patients presenting to the ED in AF?

For all comers presenting in AF with rapid ventricular rate to the ED, the literature has not elicited a perfect treatment modality, and no distinction is made for patients on the “pill-in-the-pocket” approach prior to arrival. Despite this, general practice guidelines are highlighted in many textbooks.

In hemodynamically-stable patients, rate control in the ED is the generally the treatment of choice. Diltiazem is often preferred as compared to beta blockers like metoprolol, which may cause hemodynamic instability in patients with underlying heart or lung disease. In otherwise healthy patients, metoprolol is a reasonable choice [1]. Digoxin is also appropriate, but onset takes several hours and is inferior to beta-blockers for rate control within 6 hours of treatment [11].

Patients who have been in AF for > 48 hours are at a greater risk of new intracardiac thrombus formation and cardioversion-induced embolization. Newer data from a study in 2014 suggests that there is an increased risk of thrombus formation with > 12 hours of AF [8] though the original guidelines for electric cardioversion within 48 hours of symptom onset have not changed. Patients who are hemodynamically stable who have been in AF for > 48 hours (and considered if > 12 hours) should be admitted from the ED for transesophageal echo to rule out intracardiac thrombus prior to cardioversion, or alternatively for initiation of anticoagulation [7].

In hemodynamically unstable patients, electrical cardioversion should be pursued regardless of a patient’s anticoagulation status [7].

Are there any treatment considerations in the ED for patients in AF taking flecainide or propafenone?

Treatment failure to the “pill-in-the-pocket” approach may be a marker of progression of the patient’s clinical disease. However, if a patient presents within an hour or two of taking their “pill-in-the-pocket,” remember the four to six-hour onset of these medications suggests they may convert during their ED stay. As in the case initially presented, the patient spontaneously converted while waiting for a provider. For those that do not, these patients warrant evaluation for new structural cardiac disease and may no longer benefit from the “pill-in-the-pocket” approach and may require daily maintenance prophylactic therapy [2].

A subset of stable patients presenting to the ED with AF with rapid ventricular rate may be taking flecainide or propafenone as maintenance therapy and not as part of the “pill-in-the-pocket” approach. In this instance, some literature has suggested that these patients can take an extra dose or two up to the maximum daily dose of flecainide (400mg) or propafenone (900mg for immediate release and 850mg for sustained release) to attempt pharmacological conversion, and it would be reasonable to attempt this in the ED [9].

To admit or not admit, that is the question.

The patient’s clinical picture should guide the provider as to the patient’s disposition. A patient’s comorbidities, current stability following conversion to normal sinus rhythm, plan for possible ablation, necessity for starting anticoagulation or maintenance medication, and means for close cardiology or PCP follow up on an outpatient basis should be factored when dispositioning the patient. Certainly, if a patient is requiring continuous IV infusion of rate controlling medications or has poor rate control, he or she should be admitted to the hospital [1]. Recent literature suggests that discharging stable patients home is safe following successful electrical, pharmacologic, or spontaneous cardioversion in the ED [4].

Final Thoughts

The “pill-in-the-pocket” approach is a great way for eligible patients to self-terminate episodes of AF in the comfort of their home, potentially preventing a costly and lengthy ED visit. While this approach has been shown to be a safe and effective for terminating paroxysmal AF, there is a significant lack of data on how to treat these patients who do not respond to these medications at home. General principals should be followed–electric cardioversion if the patient is hemodynamically unstable and rate control medications if the patient is hemodynamically stable (or rhythm control if you happen to practice in Canada [14]. Patients may be discharged home with close cardiology or PCP follow up if successfully cardioverted.

---

Expert Commentary

Atrial fibrillation (AF) is the most common cardiac arrhythmia and worldwide prevalence and incidence are increasing.1 It is estimated that by 2050 more than 12 million Americans will suffer from this debilitating and dangerous arrhythmia.1-2  AF presentations to Emergency Departments are certainly not without cost and the overall burden on the healthcare system will undoubtedly increase as the prevalence of atrial fibrillation continues to rise. A “pill in the pocket” approach for treatment of symptomatic atrial fibrillation has been well-described.

Class IC (sodium channel blockers) antiarrhythmic drugs (flecainide and propafenone) are the drugs of choice for “pill in the pocket” chemical cardioversion of symptomatic atrial fibrillation. There are some important considerations for this approach to be safe and effective:

1. The patient should have a history of infrequent paroxysmal atrial fibrillation, not persistent atrial fibrillation (episodes of AF that last greater than 7 days).

2. We reserve this approach for patients with symptomatic atrial fibrillation (palpitations, mild dyspnea, or mild lightheadedness) with rapid ventricular rates who do not experience dangerous symptoms such as chest pain or syncope.

3. As anti-arrhythmic drugs can also be pro-arrhythmic, we do not recommend Class IC antiarrhythmic drugs in patients with known structural heart disease, reduced left ventricular systolic function, or known coronary artery disease, due to the increased risk of inducing dangerous arrhythmias.

4. In patients who are not on therapeutic anticoagulation, we only recommend this approach when it has been less than 24 hours since onset of the AF episode. If the AF episode has lasted beyond 24 hours or it is unknown when the episode started, the risk of formation of intracardiac thrombus during AF and subsequent risk of stroke after a successful chemical cardioversion from a Class IC drug would be prohibitively high.

5. Due to the use-dependent nature of Class IC antiarrhythmics (more effective with more sodium channel blockade at faster ventricular rates), there is a chance of slowing conduction throughout the heart to the point that atrial fibrillation can organize into rapid atrial flutter with 1:1 AV conduction, leading to an aberrant wide complex tachycardia. For this reason, we recommend that the patient receive a beta-blocker or calcium channel blocker at least 30 minutes prior to administration of flecainide or propafenone.

6. Some practitioners recommend that if the patient is not already on anticoagulation, that they initiate anticoagulation at the time of beta-blocker or calcium channel blocker administration to reduce the risk of intracardiac thrombus formation if the patient does not convert to sinus rhythm within 24-48 hours.

7. Some practitioners recommend that the first attempt at “pill in the pocket” dosing be performed in the emergency department so that safety and efficacy can be monitored.

8. If patients report a progressively increasing need for “pill in the pocket” use or there is a suggestion of increasing burden of AF episodes, I recommend consultation with the patient’s cardiologist or electrophysiologist to discuss alternative options for rhythm control of symptomatic atrial fibrillation. Potential options at that time could include initiation of maintenance antiarrhythmic drug therapy versus invasive management with catheter ablation of atrial fibrillation. 

When used in the right patient, a “pill in the pocket” approach can be a very effective strategy for rhythm control of infrequent symptomatic paroxysmal atrial fibrillation. Appropriate patient factors to consider prior to recommending this approach are nicely highlighted in the post above. “Pill in the pocket” management for AF can resolve patient symptoms, improve patient’s quality of life, and reduce unnecessary emergency room visits and subsequent hospitalizations.

References

1. Chugh SS, Havmoeller R, Narayanan K, et al. Worldwide epidemiology of atrial fibrillation: a Global Burden of Disease 2010 Study. Circulation. 2014 Feb 25; 129(8):837-47.

2. Miyasaka Y, Barnes M, Gersh B, et al. Secular Trends in Incidence of Atrial Fibrillation in Olmsted County, Minnesota, 1980 to 2000, and Implications on the Projections for Future Prevalence. Circulation. 2006 Jul 11;114(2):119-25.

Kaustubha Patil, MD

Clinical Cardiac Electrophysiology

Bluhm Cardiovascular Institute Northwestern Medicine

Assistant Professor of Medicine

Northwestern University Feinberg School of Medicine

---

How To Cite This Post:

[Peer-Reviewed, Web Publication] Feiger, D. Andereck, J. (2020, Nov 2). A “Pill-in-the-Pocket” approach to paroxysmal atrial fibrillation. [NUEM Blog. Expert Commentary by Patil, K]. Retrieved from http://www.nuemblog.com/blog/pill-in-pocket.

---

Other Posts You May Enjoy

References

1. Adams, James, et al. “Tachydysrhythmias.” Emergency Medicine: Clinical Essentials, Elsevier Health Sciences, 2013, pp. 497–513.

2. Alboni, Paolo, et al. “Outpatient Treatment of Recent-Onset Atrial Fibrillation with the ‘Pill-in-the-Pocket’ Approach.” New England Journal of Medicine, vol. 351, no. 23, 2004, pp. 2384–2391., doi:10.1056/nejmoa041233.

3. Aliot, E., et al. “Twenty-Five Years in the Making: Flecainide Is Safe and Effective for the Management of Atrial Fibrillation.” Europace, vol. 13, no. 2, 2010, pp. 161–173., doi:10.1093/europace/euq382.

4. Besser, Kiera Von, and Angela M. Mills. “Is Discharge to Home After Emergency Department Cardioversion Safe for the Treatment of Recent-Onset Atrial Fibrillation?” Annals of Emergency Medicine, vol. 58, no. 6, 2011, pp. 517–520., doi:10.1016/j.annemergmed.2011.06.014.

5. Dan, Gheorghe-Andrei, et al. “Antiarrhythmic Drugs–Clinical Use and Clinical Decision Making: a Consensus Document from the European Heart Rhythm Association (EHRA) and European Society of Cardiology (ESC) Working Group on Cardiovascular Pharmacology, Endorsed by the Heart Rhythm Society (HRS), Asia-Pacific Heart Rhythm Society (APHRS) and International Society of Cardiovascular Pharmacotherapy (ISCP).” EP Europace, vol. 20, no. 5, 2018, doi:10.1093/europace/eux373.

6. Dukes, I.d., and E.m Vaughan Williams. “The Multiple Modes of Action of Propafenone.” European Heart Journal, vol. 5, no. 2, 1984, pp. 115–125., doi:10.1093/oxfordjournals.eurheartj.a061621.

7. January, Craig T., et al. “2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation.” Journal of the American College of Cardiology, vol. 64, no. 21, 2014, doi:10.1016/j.jacc.2014.03.022.

8. Nuotio, Ilpo, et al. “Time to Cardioversion for Acute Atrial Fibrillation and Thromboembolic Complications.” Jama, vol. 312, no. 6, 2014, p. 647., doi:10.1001/jama.2014.3824.

9. “Pill-in-a-Pocket Dosing Safely Converts Breakthrough Atrial Fib.” Family Practice News, vol. 35, no. 18, 2005, p. 20., doi:10.1016/s0300-7073(05)71733-3.

10. Sacchetti, Alfred, et al. “Impact of Emergency Department Management of Atrial Fibrillation on Hospital Charges.” Western Journal of Emergency Medicine, vol. 14, no. 1, 2013, pp. 55–57., doi:10.5811/westjem.2012.1.6893.

11. Sethi, Naqash J., et al. “Digoxin for Atrial Fibrillation and Atrial Flutter: A Systematic Review with Meta-Analysis and Trial Sequential Analysis of Randomised Clinical Trials.” Plos One, vol. 13, no. 3, 2018, doi:10.1371/journal.pone.0193924.

12. Stiell, Ian G., et al. “Association of the Ottawa Aggressive Protocol with Rapid Discharge of Emergency Department Patients with Recent-Onset Atrial Fibrillation or Flutter.” Cjem, vol. 12, no. 03, 2010, pp. 181–191., doi:10.1017/s1481803500012227.

13. Wang, Z, et al. “Mechanism of Flecainide's Rate-Dependent Actions on Action Potential Duration in Canine Atrial Tissue.” American Society for Pharmacology and Experimental Therapeutics, vol. 267, no. 2, 1 Nov. 1993, pp. 575–581.

14. Yao, R., et al. “Real-World Safety And Efficacy Of A ‘Pill-In-The-Pocket' Approach For The Management Of Paroxysmal Atrial Fibrillation.” Canadian Journal of Cardiology, vol. 33, no. 10, 2017, doi:10.1016/j.cjca.2017.07.371.