Newer Diagnostic and Cost-Effective Ways to Identify Asymptomatic Atrial Fibrillation for the Prevention of Stroke

Atrial fibrillation (Afib) is the most common and underestimated cardiac arrhythmia with a lifetime risk of >35% after the age of 55 years and the risk continues to rise exponentially. Afib leads to stasis of blood within the atria allowing clot formation and increasing the risk for systemic embolization leading to strokes. Outcomes due to Afib can improve significantly with appropriate treatment. Thus, the need for convenient, well‐tolerated, cost‐effective cardiac monitoring for Afib is needed. The study aims to evaluate the various newer devices and compare them with traditional Holter monitoring, keeping diagnostic yield, cost-effectiveness, and patients' convenience in mind. Though Holter monitoring is simple and non-expensive, it has major limitations including limited recording capacity, inability for real-time recordings, and inconvenience to patients. Zio Patch (iRhythm Technologies, Inc; San Francisco, CA) and other loop recording devices are patient-friendly, inexpensive, and can offer real-time data for longer days. More prospective studies are needed to evaluate the sensitivity, specificity, and the actual number of patients getting benefits from newer devices by diagnosing Afib sooner and start early prevention therapy.


Introduction And Background
Atrial fibrillation (Afib) is the most common sustained cardiac arrhythmia, with a lifetime risk of 37% occurrence after the age of 55 years [1]. The causal relation between atrial fibrillation and stroke has been known for many years. Uncoordinated and rapid myocyte activity due to hyperactive electric stimulation from the SA node results in impaired contraction of the atria. This impairment leads to stasis of blood within the atria that allows clot formation to occur, thus increasing the risk for systemic embolization leading to cardio-embolic strokes [2].
Afib has been a major burden on the healthcare system. Though incidence throughout the general population has been relatively stable over time, the prevalence of Afib continues to rise exponentially [3]. Some of the increasing prevalence may be attributable to a modest improvement in Afib-related survival (e.g., three-year mortality rate reduction from 45% in 1993 to 42% in 2005), which is related to earlier detection and treatment of underlying conditions such as hypertension, coronary artery disease (CAD), and heart failure (HF) [3]. Afib accounts for 3-4% of all emergency department visits, with typical symptoms like syncope, palpitations, dizziness attributable to arrhythmias, etc. [4]. There are half a million hospitalizations annually in the United States for which Afib is the primary diagnosis. Afib is estimated to contribute to >100,000 deaths per year in the United States. Outpatient cardiac rhythm monitoring is an integral part of the early diagnosis and management of Afib, which is the priority in successful secondary stroke prevention [5]. This stresses the use of ambulatory cardiac monitoring devices for earlier detection of Afib.
The true epidemiological profile of Afib is incomplete and underestimated because a substantial proportion of Afib patients can be asymptomatic or without clinical manifestations ("clinically silent or subclinical Afib") [6]. Clinically silent Afib diagnosed often during routine checkups, leaves difficult decisions for physicians on how to treat and to what extent. Currently, researchers have been focused on clinically silent and asymptomatic Afib which has shown equal outcomes regarding stroke and death. In the most recent data reported by EurObservational Research Programme (EORP)-Atrial Fibrillation Pilot General Registry, mortality at one year was more than twofold higher in asymptomatic patients than their symptomatic counterparts and was associated independently with older age and comorbidities [7].
Additionally, undiagnosed Afib can have immense complications and morbidity. Outcomes due to Afib can improve significantly with appropriate treatment, including anticoagulation to prevent systemic embolization and stroke, rhythm, and rate control for the restoration of normal rhythm. Despite guidelines from multiple societies, there is a significant gap in the care of Afib. Earlier and improved methods of detection can allow earlier initiation of appropriate therapies to prevent adverse health outcomes. Furthermore, monitored individuals, compared with non-monitored controls, had higher rates of Afib diagnosis, greater initiation of anticoagulants, but also increased health care resource utilization at one year. Better detection of paroxysmal atrial fibrillation (PAF) by prolonged cardiac monitoring can be expected to improve secondary prevention through optimized secondary preventive regimens, like oral anticoagulation for stroke patients [8]. The improved cost-effectiveness is attributable to the fact that these newly detected patients benefit from anticoagulation therapy to prevent stroke recurrence which in turn saves future costs and reduces the impairment of quality of life.
The need for convenient, well-tolerated, cost-effective cardiac monitoring for Afib is likely to increase as Afib becomes more prevalent [4]. Traditionally monitoring of arrhythmias has been done by a continuous electrocardiogram (ECG) monitor known as a Holter monitor, which is given to patients with a recent history of acute coronary syndrome and daily symptoms such as syncope, dizziness, and palpitations. Continuous ECG monitoring records data such as average heart rate, RR interval, and ST-segment changes for a period of 24-48 hours. Alternatively, in recent years there have been many technological advancements in this field of study. For example, we now have single and double lead ECG that can be placed directly on the chest, smartwatches, and handled devices that pair directly with your phone. These devices have automated algorithms within their specifically designed optical sensors to detect irregularities in pulse to notify the user in real-time of possible atrial fibrillations without the use of electrodes or wires. However, due to its very limited data and accuracy, it still remains unknown when this technology may be used as a primary diagnostic tool in medicine. Lastly, non-invasive continuous monitoring patch such as the Zio Patch (iRhythm Technologies, Inc; San Francisco, CA) is a single-lead ECG monitor that provides up to 14 days of continuous ECG data from a single vector. These devices are single-use, water-resistant, and allow for long term cardiac monitoring. Although this may be a promising technology, larger studies will be required to determine the efficacy of these devices in detecting arrhythmias [9].
Hence, the literature review aims to evaluate the effectiveness of various ambulatory devices in detecting asymptomatic Afib to prevent stroke.

Types of ambulatory devices
Atrial fibrillation is the most underestimated cardiac arrhythmia with a lifetime risk of >35% after the age of 55 years and the causal relationship between atrial fibrillation and stroke has been known for many years [10]. In addition to atrial fibrillation, arrhythmias such as sinus tachycardia, premature ventricular contractions, and ventricular tachycardia can all cause palpitations. Usually benign, palpitations can be a manifestation of potentially life-threatening conditions, especially if associated with dizziness, nearsyncope, or syncope. Therefore, ambulatory electrocardiogram monitoring is an invaluable tool to assess and establish the diagnosis of a patient's symptoms. There are a variety of possible ambulatory monitors to choose from such as Holter monitors, implantable loop recorders, and external loop recorders. Table 1 showed details on various ambulatory electrocardiography devices and their applications.

Holter Monitor
Traditionally, monitoring of arrhythmias has been done by a continuous ECG monitor known as a Holter monitor. The most common monitors allow for continuous registration of three or more leads for 24-48 hours while newer monitors allow for continuous ECG monitoring for up to two weeks [11]. A benefit in extending the time of ECG registration helps improve the diagnostic yield of Holter monitoring, especially for infrequent but recurrent rhythm disturbances [12]. The Holter monitor aids in the detection of arrhythmias and ST-segment changes help to assess the therapeutic efficiency of antiarrhythmic agents and helps to evaluate pacemaker malfunctions [13]. A primary advantage of using Holter monitoring is that it aids in quantifying the real burden of arrhythmia and could help the clinician in making therapeutic decisions for disabling arrhythmias that occur frequently [14]. However, despite this advantage, some limitations include the relatively brief duration of monitoring, limited recording capacity, and inability to transmit real-time data to the attending cardiac unit, and the need for close collaboration between the patient and the healthcare professional [14]. Additionally, these may cause physical discomfort for patients due to the large size of the monitor and electrodes that need to be taped to various areas on the skin that may irritate.

Loop Recorders
Loop recorders are event recorders that work by continually analyzing the ECG and retaining information pertinent to relevant arrhythmias. This is possible through predefined algorithms and registration of the ECG a few minutes prior to the onset of the arrhythmia [14]. These recorders can be activated by the patient when he/she experiences the symptoms and can therefore reliably document a correlation between symptoms and arrhythmia.

Internal Loop Recorders
Implantable loop recorders is a subcutaneous monitoring device used to monitor electrical activity of the heart over an extended period of time, compared to the fixed picture of electrical activity seen with ECGs [15]. These devices can record for up to three years. An implantable loop recorder can store patient-activated episodes, automatically activated episodes or a combination of the two. Some benefits of an implantable loop recorder are that it does not need to be removed during certain activities such as showering or swimming and it can help identify significant cardiac rhythm abnormalities when the patient is sleeping [15]. Additionally, unlike the Holter monitor, an implantable loop recorder has a higher likelihood of detecting arrhythmias due to prolonged monitoring and the ability to detect atrial fibrillation recurrences, as they can be silent and unpredictable [16]. However, it may be affected by false episode detection due to artifacts and they only allow the registration of one lead, rendering the interpretation of the ECG difficult in some cases [14]. Likewise, unlike the Holter monitor, it is far more efficient and reliable at identifying abnormal rhythms [15] and data transmission to a distant diagnostic station is simple [14]. This device may be useful for noncompliant patients, as there are no external parts to be worn [17].

External Loop Recorders
External loop recorders can be connected to a belt around the chest, without the need for traditional electrodes, and can monitor the ECG for a maximum of 30 days [18]. Additionally, because this device relies on the patient activating it, it is not suitable for syncope or other conditions in which the patient is unable to activate the device. An advantage of using this device is that ECG data can be transmitted continuously over wireless networks to a remote monitoring system for evaluation.

Zio Patch
The Zio Patch is a single-lead ECG monitor that has no external leads or wires. The patch adheres to the patient's left pectoral region and can record a continuous beat-to-beat ECG, making it useful for monitoring cardiac rhythm, for up to fourteen days. Similar, to the Holter monitor, the data from the Zio Patch is analyzed offline after the completion of the monitoring. However, the Zio Patch has a higher diagnostic yield than the Holter monitor [19]. The patch provides a high diagnostic yield for arrhythmia because the diagnostic yield of continuous loop-recording decreases rapidly after two weeks of monitoring and monitoring beyond seven days provides only an additional 3.9% of patients with a diagnosis [20]. In an epidemiologic study done on the older general population, it was found that atrial fibrillation was detected in 4% of those with no prior history, and 38% of newly detected atrial fibrillation was first found on days three-14 of monitoring with the Zio Patch [21]. Additionally, a single monitoring episode of 12 days was adequate for estimating the extent of supraventricular and ventricular ectopy [21].

Cost-effectiveness
Early detection and timely treatment of arrhythmias are important to reduce the burden of cardiac disease and lower healthcare costs. ECG monitoring beyond the 24-48-hours Holter monitor can improve the detection of arrhythmias, however, prolonged monitoring beyond eight to 14 days is generally not costeffective [4,9,[22][23][24][25][26][27][28][29][30][31]. Therefore, wearable patch monitors such as the Zio Patch, that record at least eight days of ECG data are cost-effective alternatives to the traditional Holter monitors and loop recorders.
In an economic model derived from a randomized controlled study comparing the efficacy of a Holter monitor to the Zio Patch for the detection of PAF after a transient ischemic attack/ischemic stroke, it was found that the implementation of the Zio Patch would prevent 10.8 more strokes per year when compared to the current practice with Holter monitoring [23]. This would result in a yearly saving in direct medical costs of £113,630 ($146,963), increasing to £162,491 ($210,157) over five years [23]. Additionally, Brignole et al. noted that while the 24-48 hours Holter monitor has a relatively low set-up cost, it is expensive in terms of cost per diagnosis [32]. Arnold et al. also state that although it is fairly common to repeat Holter monitoring after the first Holter procedure due to inconclusive results, repeat monitoring did not yield a diagnosis, and patients continued to experience clinical events that led to substantial health costs [33]. In another study comparing the efficacy of the Holter monitor to a 14-day adhesive patch, it was found that the adhesive patch monitor detected 96 arrhythmia events compared with 61 arrhythmia events by the Holter monitor (p<0.001) [34]. This emphasizes the importance of effective diagnosis and treatment in reducing healthcare costs, morbidity, and mortality associated with cardiac arrhythmias. Additionally, the study comparing seven-day-Holter monitoring (7-d-Holter) to a standard 24-hour-Holter to detect PAF, it was found that the seven-day-Holter in patients with cerebral ischemia is cost-effective [8]. The costeffectiveness is due to the increased detection which leads to the implementation of improved antithrombotic regimes that work to avoid recurrent strokes and decrease quality of life impairment. This also emphasizes the role that a seven to 14-day monitoring modality, such as the Zio Patch, can play in reducing healthcare costs.
In addition to the increased healthcare costs associated with the use of the Holter monitor, studies have found that there is an increased cost in monitoring periods beyond two weeks. For instance, the costs can range up to $5832 per new diagnosis versus a $98 cost per patient diagnosis over an initial seven days and $576 over a 14-day period [34]. Therefore, the Zio Patch is likely to achieve a reasonable diagnostic yield compared to loop recorders which typically monitor from up to a month to three years.

Conclusions
Our knowledge of the true ("clinically silent or subclinical Afib") prevalence of Afib is underestimated and represents the tip of the iceberg. Holter monitoring is helpful yet limited by duration, recording capacity, and inability to transmit real-time data. External loop recorder and Zio Patch are better alternatives due to convenient and accurate recording and portability. These newer devices would result in more stroke prevention per year and are more cost-effective in comparison with Holter monitoring. Although these newer devices are proven effective to identify Afib, more prospective studies should be planned to evaluate sensitivity, specificity, and the role of these devices to begin early management in the direction of stroke prevention, and patients' satisfaction.

Conflicts of interest:
In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.