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Atrial Fibrillation: Current Management and Best Practices

Atrial Fibrillation: Current Management and Best Practices

Atrial fibrillation (AF) is the most commonly diagnosed cardiac arrhythmia that results from structural or electrophysiological irregularities within the atrial tissue.1,2 Unlike patients in normal sinus rhythm, those with AF have atria that contract rapidly (at approximately 400-600 beats per minute) leading to a heart rhythm commonly referred to as “irregularly irregular.”1 As a result, the heart’s ability to pump blood may be impaired, leading to pooling of blood in the atria in those affected with AF. This pooling of blood puts them at an increased risk of both stroke and systemic embolism.2,3
In the United States, AF affects an estimated 2.7 million to 6.1 million people.4 Its prevalence is projected to rise to more than 12 million by 2030 and to 15.9 million by 2050.4-7 In men and women aged ≥40 years, the lifetime risk for developing AF is 1 in 4.8 The projected increase can be attributed in large part due to the anticipated growth in the US population, but it also reflects the aging US population and improved survivorship.7 One projection indicates that approximately 8 million of those affected by AF in 2050 will be aged ≥80 years.7 Given the significant complications associated with AF such as stroke, heart failure (HF), tachycardia, and myocardial infarction, this will have substantial economic implications.4

Although multiple underlying risk factors and biomarkers exist for developing AF (Table 1)2, the most common risk factors include age greater than 60 years, diabetes, hypertension, coronary artery disease, prior myocardial infarction, HF, structural heart disease, prior open heart surgery, untreated atrial flutter, thyroid disease, chronic lung disease, obstructive sleep apnea, excessive alcohol or stimulant use, and serious illness or infection.2,9

Several longitudinal studies have clearly documented that AF carries an increased risk of morbidity and is an independent risk factor for death. The most serious and disabling complication is thromboembolic stroke; AF serves as an independent risk factor for stroke.7 Estimates suggest that about 15% to 20% of US strokes can be attributed each year to AF.3 In addition to being the fifth leading cause of death for men, and fourth for women, in the United States (Figure10), stroke is also a leading cause of serious long-term disability and is the leading preventable cause of disability.10,11 While longitudinal studies have shown that individuals in their 50s with AF have a relatively low annual risk for stroke, the risk steadily climbs as a person ages. In patients aged ≥80 years, the relative risk of stroke has been shown to be as high as 23.5%.7 HF is another negative outcome associated with AF. Estimates suggest 20% to 50% of AF patients will develop HF, and in patients with established HF, AF worsens outcomes.3,7

The financial impact of AF is significant; its US estimated incremental cost is $26 billion annually. Of this amount, approximately $6 billion is directly attributed to AF, with the remainder linked to other cardiovascular and noncardiovascular expenses.5 In 1 evaluation of Medicare patients, when comparing those with AF to those without, AF patients had higher per-patient costs. In 2008, the excess cost in beneficiaries with AF was $8705 greater than in those without.5 About 75% of AF costs are related to direct and indirect costs associated with hospitalization. Claims data support the finding that the high costs attributed to hospitalizations are driven both by initial hospitalizations and frequent readmissions. One retrospective analysis showed that 42% of patients admitted with an initial diagnosis for AF or atrial flutter were readmitted within 1 year, with inpatient admissions driving more than half the direct costs. This amounted to $22,579 in mean per-patient direct cost from January 2004 through December 2007. Other drivers of the overall cost include prescription drugs, testing, and care in the outpatient setting.7 Additional financial burdens include the overall impact to society and lost productivity. While not often referenced in economic impact studies of AF, the condition contributes to increases in missed workdays and short-term disability.7

Stroke and HF, the key morbidities associated with AF, are the main contributors to AF’s heavy economic burden. The American Heart Association estimates that overall US stroke-related costs in 2016 were $33 billion.7,12 Strokes in AF patients are typically more severe, exhibit greater morbidity, and lead to worse outcomes, so the overall economic burden to the healthcare system is disproportionately higher in this population. For instance, Lee and colleagues examined a randomized sample of Medicare beneficiaries versus a demographically matched control group, and excess treatment costs in the AF population averaged $14,199 more than those of the control group. Additionally, stroke was determined to be as likely in the AF population. The same analysis indicated that incidence of HF was 3 times as likely in the AF group and also increased the total cost of care. In analyzing Medicare beneficiaries aged ≥65 years, Caro and associates developed an economic model to examine stroke in AF patients. The model predicted that, within 1 year, 96,980 strokes would occur, resulting in $2.6 billion in direct costs incurred during the first year after the stroke.7
Management of Atrial Fibrillation
AF can be categorized into several different classifications characterized by duration of AF and the ability to convert to normal sinus rhythm. The classifications include paroxysmal, persistent, long-standing persistent, permanent, and nonvalvular AF (NVAF) (Table 22).2 A patient’s classification can change after attempting new or different treatment strategies.13

Management of AF from a rate control or rhythm control perspective has been studied via a meta-analysis of 5 randomized trials.7 Rate control in combination with anticoagulation as front-line treatment has been shown to be as effective as rhythm control. A follow-up cost-effectiveness analysis from the AFFIRM study showed savings in the rate control group based on less utilization of hospital days. The HOT CAFÉ study, along with its subanalysis, the RACE study, also demonstrated lower costs in rate control groups, primarily due to drug costs and the use of cardioversion in the rhythm control group.7

The decision to either restore normal sinus rhythm or control ventricular rate is crucial to AF management. The selected treatment approach should be based on the patient’s clinical evaluation, including a detailed medical history, physical exam, echocardiography, and thyroid function tests, to rule out the presence of certain underlying factors that could render some treatments potentially harmful.13,14 Management approaches for rate and rhythm control include pharmacologic therapy, (Table 32); invasive electrophysiologic interventions such as electrical cardioversion, catheter-based ablation, and surgery.13,15

Pharmacologic Therapy
Rate Control

The goal of pharmacologic therapy for rate control is to decrease the ventricular rate, both at rest and during exertion, without causing excessive bradycardia. Beta blockers, non-dihydropyridine (DHP) calcium channel blockers, and digoxin all have different mechanisms of action but the same effect on ventricular rate—conduction through the atrioventricular node is slowed down.14 Of these 3 drug classes, beta-blockers are the most effective when used alone to achieve rate control. The AFFIRM study demonstrated that 70% of patients taking a beta blocker achieved their target heart rate goal, compared with 54% of patients taking a non-DHP calcium channel blocker.14 Non-DHP calcium channel blockers, such as verapamil and diltiazem, are preferred for AF patients with preserved left ventricular systolic function and severe chronic obstructive pulmonary disease. Verapamil and diltiazem are equally effective to control ventricular rate.14 The 2014 American Heart Association (AHA)/American College of Cardiology (ACC)/Heart Rhythm Society (HRS) Guideline for the Management of Patients with AF recommends using a beta blocker or non-DHP calcium channel blocker to control ventricular rate in patients with paroxysmal, persistent, or permanent AF.2 Less effective for achieving rate control is digoxin, a third option. Patients treated with pharmacologic therapy to achieve rate control may require the use of more than 1 drug.14

Rhythm Control

The AHA/ACC/HRS guideline recommends treating AF with an antiarrhythmic drug, to maintain sinus rhythm. Once risks have been assessed (class I recommendation), choices include amiodarone, dofetilide, dronedarone, flecainide, propafenone, and sotalol, depending on underlying heart disease and comorbidities.2

The most commonly prescribed antiarrhythmic drug for AF is amiodarone, even though it does not have FDA approval for this indication. Amiodarone is the most effective antiarrhythmic drug available; however, its use is limited by potential pulmonapary, liver, and thyroid toxicities.16 Amiodarone is only recommended after those toxicities have been taken into careful consideration, and after other antiarrhythmics have failed or been contraindicated (class I recommendation).2

Dronedarone has a similar structure to amiodarone; its use is associated with fewer noncardiovascular adverse events (AEs), and at the time of its FDA approval, it was believed to have been associated with a decreased stroke risk in AF patients.16 However, further review led to the addition of an FDA black box warning of increased risk of death, stroke, and HF in patients with decompensated HF or permanent atrial fibrillation and other contraindications. Dronedarone must not be used in patients with symptomatic HF with recent decompensation requiring hospitalization, or with New York Heart Association Class IV HF; both, in combination with dronedarone, can increase the risk for death. It is also contraindicated in AF patients who will not or cannot be cardioverted into normal sinus rhythm. In patients with permanent AF, dronedarone doubles the risk of death, stroke, and hospitalization for HF.17

Flecainide and propafenone should be used in AF patients without structural heart damage. However, they are contraindicated in patients with prior myocardial infarction (MI) and reduced left ventricular function, because ventricular proarrhythmia may occur.16

Sotalol is a highly utilized antiarrhythmic drug, popular likely due to minimal noncardiovascular AEs associated with its use. Approach higher doses with caution, however, as they are associated with a higher risk of ventricular proarrhythmia.

Dofetilide, although reasonably safe in HF and post-MI patients, is not widely utilized to maintain sinus rhythm.16 The FDA has eliminated the Risk Evaluation and Mitigation Strategy criteria for dofetilide, but its use is still associated with serious ventricular arrhythmias; also, initiation requires an inpatient hospital stay.16,18


In patients who are candidates for anticoagulation therapy, the AHA/ACC/HRS Atrial Fibrillation practice guideline provides warfarin with an international normalized ratio (INR) goal of 2.0 to 3.0, with dabigatran, rivaroxaban, and apixaban as treatment options (class I recommendation).2 Warfarin, a vitamin K antagonist (VKA) oral anticoagulant, has been the gold standard for many years. However, non-VKA oral anticoagulants (NOACs) entered the market in 2010 and are increasingly preferred for certain patient populations.

Dabigatran etexilate is a prodrug which is converted by serum esterases to dabigatran.19 This competitive direct thrombin inhibitor is approved to reduce the risk of stroke and systemic embolism in patients with NVAF.20 In the RE-LY study, dabigatran 150 mg administered twice daily was associated with lower rates of strokes and embolism than observed with warfarin in patients with AF and a risk for stroke; however, rates of major bleeding were similar.21

Rivaroxaban and apixaban, both NOACs, exert their anticoagulant effects via a different mechanism than that of dabigatran. These drugs work by directly inhibiting factor Xa in the coagulation cascade.22,23

The ROCKET AF trial demonstrated that when rivaroxaban was used in AF patients at moderate to high risk for stroke, the drug was found to be noninferior to warfarin for the prevention of stroke or systemic embolism. Fatal bleeding or bleeding at a critical anatomical site occurred less frequently than with warfarin; however, rivaroxaban patients had more gastrointestinal bleeding, bleeding leading to a decrease in hemoglobin level, and bleeding leading to the need for transfusion.22 Apixaban, also a direct oral factor Xa inhibitor, was evaluated in the ARISTOTLE trial in AF patients with at least 1 other risk factor for stroke using a 5-mg twice-daily dose in most patients; fewer than 5% of patients received a lower dose. Apixaban demonstrated superiority over warfarin for the primary outcome of stroke or systemic embolism and reduced major bleeding by 31%.23

As demonstrated in the aforementioned studies, there are benefits to anticoagulating with NOACs. These include the lack of necessity for routine blood monitoring requirement and dose adjustments; fewer drug-food and drug-drug interactions than warfarin has; and lower rates of intracranial bleeding, compared with warfarin.24

In the past, clinicians were cautious about using NOACs because no reversal agent was available—idarucizumab, however, has changed that. Idarucizumab is a monoclonal antibody fragment that binds to free dabigatran and to thrombin-bond dabigatran, which leads to neutralization of dabigatran’s activity.25 While no antidotes are commercially available to reverse the anticoagulant effects of factor Xa inhibitors, the protein andexanet alfa is in the pipeline, though not yet FDA-approved. Clinical data about this potential reversal agent were presented at the 2017 American College of Cardiology’s Annual Scientific Session.26 Drawbacks to NOAC therapy include higher cost; lack (so far) of data relating to efficacy and safety in those with severe chronic kidney disease; its inadvisability of use in AF patients with a mechanical heart valve; and lack of a reversal for certain drugs.2,19,24 In patients who cannot afford the newer agents and when VKA is not an option, data from the Atrial Fibrillation Clopidogrel Trial with Irbesartan for Prevention of Vascular Events-Aspirin (ACTIVE-A) Trial suggest that the combination of aspirin and clopidogrel is superior for stroke prevention than aspirin alone.7

Pharmacologic and direct cardioversion are 2 options for patients needing rhythm control. If no contraindications are present, flecainide, dofetilide, propafenone, and intravenous ibutilide can be used to pharmacologically convert a patient back into normal sinus rhythm (class I recommendation). Amiodarone may also be used; however, it is important to note that practice guidelines do not consider this a first-line choice (class IIa recommendation).2 Direct, or electrical, cardioversion is among the most effective means for converting a patient back to normal sinus rhythm.27 To restore normal sinus rhythm, direct cardioversion employs an electrical current delivered by a defibrillator during the QRS complex (the Q, R, and S waves) to depolarize cardiac cells.13 Success rates for this method of cardioversion range from 75% to 93%, declining to approximately 50% when AF has been present for more than 5 years. Advantages of direct cardioversion compared with pharmacological conversion include a decreased procedure duration, higher success rate, and a lower risk of prorhythmia.27 Direct-current cardioversion is also a class I recommendation for AF patients requiring rhythm control.2

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