Atrial fibrillation in the elderly population: Challenges and management considerations

Abstract Importance Atrial fibrillation is the most clinically significant arrhythmia in humans when viewed both from a global and also a national perspective. In the United States, approximately 2.7‐6.1 million people are estimated to have atrial fibrillation. With the aging of the population, this prevalence is on an increasing trend and remains an obstacle to cardiovascular health despite significant advancements specific to cardiovascular disease management. Observation In this specific group of patients, healthcare utilization is a concern from the public health perspective. Unfortunately, misconceptions dominate clinical decision making; for instance, the avoidance of safe and effective anticoagulation strategies in patients at the highest risk for embolic strokes continues to be widespread in clinical practice and is often based on a skewed assessment of risk versus benefit. Also, when there are contraindications to standard interventions for atrial fibrillation, a clear and nuanced understanding of second‐ and third‐line interventions with proven benefit is often lacking. Conclusions and Relevance An individualized approach should be followed by physicians when managing atrial fibrillation in the elderly patient, taking into consideration the risk of complications, particularly the embolic stroke and the availability of treatment options for stroke prevention whether through pharmacological anticoagulation or left atrial appendage occluding devices. The following review sets out to clarify these issues.


| Epidemiology and risk factors
A systematic review conducted in 2010 on the number of individuals with AF worldwide reported a prevalence of 33.5 million, while in the United States, there were approximately a prevalence 5.2 million in 2010 with a projected increase to a prevalence of 12.1 million in 2030. [1][2] This prevalence is steadily rising as the population ages. 3,4 These numbers do not take into account subclinical AF, detected incidentally using implantable cardiac devices such as pacemakers, implantable cardioverter defibrillators (ICDs), and loop recorders. For example, in the ASSERT study, which included 2580 patients with pacemakers or ICDs above the age of 65 years and had no history of AF, 10% of patients had subclinical AF at 3 months and 35% at 2.5 years. 5 The true prevalence of AF in the United States is therefore unknown.
The prevalence is greatly dependent on factors such as age, sex, ethnicity, and obesity. AF appears to be more common in men. It appears to be more prevalent in the Caucasian population than in African Americans. 3 AF is quite unusual in infants and young children in the absence of structural/congenital heart disease. In the developed world, age has much to do with the occurrence of AF. As seen In the ATRIA study, out of 1.89 million subjects, the prevalence of AF for individuals under 55 years was 0.1%. 4 The risk of AF increases exponentially with aging; in the Framingham Heart Study, participants who were at least 40 years of age and had no history of AF had a 26% and 23% chance of future AF for men and women, respectively. Figure 1 shows estimated prevalence in accordance with age.
There are associated risk factors that significantly increase the risk of developing AF 6,7 (Table 1). In general, the risk of developing AF increases with any heart disease. 8,9 Among the most common diseases are hypertension, coronary artery disease, and heart failure (HF). 10,11 Valvular disease such as stenosis or regurgitation is another contributing factor to the development of AF by increasing atrial pressure and/or stretch. 12 Twenty percent of adults who have had long-standing atrial septal defects will develop AF. 13 Pathologies that increase the right ventricular afterload, such as pulmonary emboli, chronic obstructive pulmonary disease, and obstructive sleep apnea, can ultimately increase the risk of AF. [14][15][16][17][18][19] According to the Framingham Heart Study, per one unit of BMI increase, the risk of AF increases by 5%. 20,21 A few other known risk factors for the development of AF are thyroid disease, metabolic syndrome, chronic kidney disease, 22 and the stress of surgery or infection. [23][24][25] Inflammation within the atria due to systemic mediators or localized processes can contribute to further worsening of conduction within the atrial tissue, leading to a higher susceptibility of AF. 25

AF can be classified under different subtypes as defined by the 2014
American Heart Association guidelines 26,27 (Table 2). Paroxysmal AF is defined as AF that terminates spontaneously or by intervention (cardioversion) within 7 days. Most patients who have subclinical AF also are categorized under paroxysmal AF. Subclinical AF is typically diagnosed via ambulatory cardiac monitoring since the episodes of AF can occur randomly and often lack symptomology.
Persistent AF is a failure of the arrhythmia to terminate within a 7-day period. Long-standing persistent AF is when it lasts for over 12 months, and permanent AF is a term used when rate control is the preferred long-term strategy for managing the AF following a discussion between the clinician and the patient. 26 Additionally, there is an ongoing long-term prospective, randomized, nationwide study conducted by Apple and Johnson & Johnson. One arm of the study will be using the Heartline app on their iPhone, whereas the other arm will be using an Apple Watch Series 5. The primary outcome of this study is to assess the relationship of using technology such as an iPhone with the Heartline app and the Apple Watch in the detection of AF while also assessing if the clinical outcome is improved, such as mitigation of stroke risk. Other desired secondary outcomes of this study consist of determining whether a heart health engagement program and medication adherence intervention would benefit those with previously diagnosed AF, understanding the overall impact of technology in identifying or managing other health problems beyond the heart, and lastly to support the advancement of clinical studies in this field of medicine where technology intersects with medicine.

| FINAN CIAL IMPAC T OF AF
The prevalence of AF is expected to significantly increase over the next few years. This is partially explained by the improved survival  32 During that year, the estimated total cost was about $6.65 billion; 44% of which was for hospitalizations, and 4% was for prescription medications.

| MANAG EMENT OF AF
Management of AF in the elderly population consists of an inte- factors. 33 Furthermore, the management of AF in the elderly population requires an increased understanding of its relationship with falls and HF, two very common comorbidities that often lead to clinical confusion in the management of AF in this population.

| Impact of AF management in the elderly population
AF is the most common arrhythmia to occur in the elderly population   During acute decompensation, beta blockers and calcium channel blockers should be avoided until euvolemia is achieved due to the negative inotropic effects of these medications. Digoxin is effective at rate control and is particularly useful in the setting of acute decompensated HF. Careful monitoring of digoxin levels and renal function should be employed in order to avoid digoxin toxicity, given its narrow therapeutic index.

| Cognitive impairment and AF management
Cognitive impairment is a common ailment affecting the elderly; 20% of individuals over the age of seventy have mild cognitive impairment, 45 and over 500 000 people develop dementia on a yearly basis in the United States. 46 Globally, there are about 7.7 million new cases every year. AF and cognitive impairment often coexist.

Anticoagulation therapy in patients who have AF and dementia has
shown clear benefit. In the Swedish Dementia Registry, 8096 patients were found to have concomitant AF. 47 Of these, one third were treated with warfarin, one third with antiplatelet medications, and the remainder were treated with no anticoagulation. Patients treated with warfarin had a lower rate of ischemic stroke and death compared to patients who received antiplatelet therapy or no anticoagulation.
These findings highlight the importance of anticoagulation in patients with AF regardless of the degree of cognitive impairment.

| Frailty and its impact on treatment
Frailty is a common clinical syndrome in older adults that carries an increased risk for poor health outcomes including falls, incident disability, hospitalization, and mortality. Frailty is defined as a clinically recognizable state of increased vulnerability resulting from an aging-

| Rate versus rhythm control
The optimal approach to managing AF, whether it be a focus on rate control or restoring sinus rhythm, has been long the subject of

debate. A variety of studies have shown clear benefits with either
therapy. Therefore, therapy should be individualized based on the clinical scenario and associated comorbidities. 33 Rate control therapy is favored in patients over the age of 80 years old, which accounts for 35% of patients with AF. 51 This age group is at a greater risk of adverse effects from rhythm control medications, which tend to have proarrhythmic side effects. These patients have a higher rate of long standing persistent AF and permanent AF with significant left atrial enlargement, which leads to failure of antiarrhythmic therapy in restoring sinus rhythm. Rate control is a safe and effective approach in these patients as has been shown in the AFFIRM and RACE trials, which showed no difference between a rhythm control strategy and a rate control strategy in terms of improvement in the quality of life. 52 In fact, a rhythm control strategy has been shown to be associated with a higher rate of hospitalization.
More recently, the EAST-AFNET 4 trial has shown that an early rhythm control strategy within the first year of AF diagnosis in patients with AF and associated cardiovascular disease is associated with improved outcomes and reduction in the risk of stroke and cardiovascular death. This is a practice changing trial that could lead to a paradigm shift in the management of AF, particularly in younger patients with cardiovascular comorbidities. 53 Additionally, a rhythm control strategy is associated with greater exercise capacity and improved quality of life in younger patients. Patients who fail rate control therapy, HF patients, or patients with new-onset AF can all be considered for a rhythm control strategy. 52

| Pharmacological anticoagulation
Thrombus development within the left atrium can be associated with disastrous outcomes, with a higher risk in those who are inadequately  Table 3. 59 The clinical significance of these interactions is vital for the patient's well-being since warfarin's therapeutic range is quite narrow. For example, a highly elevated INR may hold serious risks of bleeding events.
Although genetic variation (hepatic cytochrome P-450 variance or Vitamin K epoxide reductase complex) in the population plays a role in varying responses to treatment with warfarin, pharmacogenetic testing is not routinely recommended. Two large metaanalyses of randomized trials demonstrated that testing for genetic variation and incorporating this data into the dosing regimen has not reduced the amount of bleeding or thromboembolic episodes. 60 Diet pattern may lead to abnormalities in adequate INR control. Certain foods 61 that contain high, medium, and low amounts of Vitamin K are portrayed in Table 4. The goal seen in patients on warfarin therapy is to maintain a constant level of dietary Vitamin K intake. Avoiding a significant decrease or increase in Vitamin K containing foods may alter the INR pattern seen on the agreed warfarin dose. Therefore, this is another reason of many why INR monitoring is mandatory while on warfarin. This is also another limiting factor for warfarin use, especially in the elderly population.

| Appendage occlusion for stroke prevention
The left atrial appendage is the site of thrombus formation in patients with AF. 67 In certain patients who are not candidates for pharmacological anticoagulation (recurrent bleeding episodes), appendage exclusion using occluder or ligation devices could be considered, 68 as seen in Table 5. In

| COMPLI C ATI ON S OF AF
AF management is vital for maintaining the well-being of patients.
Inadequate treatment of AF, which is more frequently encountered in the elderly population, may lead to catastrophic sequelae.
Complications of AF include ischemic stroke, silent cerebral ischemia, transient ischemic attack, and systemic embolization. 69 The annual incidence of strokes in the United States is estimated to be around 795 000/year, most commonly in the elderly population. 70,71 Individualized risk factors that add to this risk profile are prior stroke or transient ischemic attack, HF, hypertension, diabetes mellitus, or older age (>65 years old). Strokes as a result of AF have been known to be associated with worse outcomes when compared to strokes from other etiologies. 72 This is believed to be due to a greatersized thrombus that develops in the atrial cavity, which is relatively bigger than emboli from other sources. This finding has been supported by comparing the rates of hemispheric versus retinal events in patients with and without AF, concluding at 25:1 and 2:1, respectively. 72 Silent cerebral ischemia may also occur which would be evident only by imaging since there is a lack of clinical manifestations. Occurrence of this finding in patients with AF reported by a meta-analysis of 17 different studies has been shown to be about 40% when using magnetic resonance imaging (MRI). 73 This form of cerebral ischemia is also more prevalent in patients with known diagnosis of persistent AF, which is more common in the elderly population. 74 Patients that are currently in sinus rhythm have better overall long-term outcomes. In the Framingham Heart Study, an episode of AF was associated with an increased risk of death even with adjustment for pre-existing cardiovascular disease. 75

| SUMMARY
In the past few years, there have been many advances in the management of AF. However, reluctance to treat AF in the elderly population is still a prevailing issue. AF is a significant public health crisis that is more common among the elderly and the management in this population has been limited due to the hesitancy of healthcare providers to initiate these patients on adequate anticoagulation. Less than two third of the elderly population with AF are on anticoagulation, increasing their vulnerability to tragic outcomes.
There is a clear overestimation of the bleeding risk in these patients with an underestimation of the thromboembolic risk, leading to poor management. Physicians should take an individualized approach when managing the elderly patient with AF, taking into consideration the high risk of embolic stroke and the multitude of options available for stroke prevention whether through pharmacological anticoagulation or LAA occluding devices.

CO N FLI C T O F I NTE R E S T
Authors declare no conflict of interests for this article.