Atrial Fibrillation in the Elderly: A Review

This article is the third in a continuing series on cardiovascular issues in the older adult. The second article in the series, “Diagnosis and Treatment of Chronic Orthostatic Hypotension,” was published in the April issue of Clinical Geriatrics. The remaining articles in the series, to be published in future issues of the Journal, will discuss such topics as heart failure, peripheral arterial disease, hypertension, and devices for heart rhythm disorders.
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Introduction

Atrial fibrillation (AF) is the most common sustained arrhythmia encountered in clinical practice. It is responsible for considerable morbidity and mortality in the general population, which is even greater among the elderly population. Current estimates indicate that 2.3 million individuals in the United States are affected by symptomatic AF, with an expected increase to 5.6 million by 2050.¹ The median age of patients with AF is 75 years, and approximately 70% of affected patients are between the ages of 65 and 85 years.² It is clear that the prevalence of AF increases with age (Figure 1), reaching almost 10% in those age 80 to 89 years.³ 

It is likely that age-dependent atrial pathophysiologic changes are responsible for the increased incidence of AF in the elderly. The most credible explanation for the increasing prevalence of AF is likely related to the success in treating chronic cardiovascular conditions that predispose one to AF. Inevitably, aging and longer exposure to these predisposing conditions result in progressive atrial substrate for tachyarrhythmia, producing more candidates for AF in this age group than seen previously.

Although AF itself is not considered to be life-threatening, it is associated with an increased risk of death. In the original Framingham cohort, the odds ratio for total mortality was 1.5 in men with AF and 1.9 in women with AF, even after adjustment for age and other risk factors.⁴ The specific mechanisms for the increased risk of death remain unclear; however, possible factors include increased risks of stroke and heart failure (HF), as well as coronary ischemia, drug toxicities, and systemic thromboembolism related to AF. Furthermore, the morbidity in elderly persons with AF is substantial because of increased HF hospitalizations, strokes, need for pacemaker implantations secondary to sick sinus syndrome or necessary drug therapy, and adverse effects related to antiarrhythmic therapy.

Recent advances in pharmacotherapy and nonpharmacologic treatment options have generated considerable excitement in the field of AF. More importantly, the inclusion of large numbers of elderly patients in these trials has expanded the treatment options for this traditionally excluded group. The purpose of this article is to review the management of AF with a focus on new therapies for the elderly population.

Definition

Atrial fibrillation is defined as a supraventricular tachyarrhythmia characterized by rapid, uncoordinated atrial activity. On electrocardiogram (ECG), AF is recognized by replacement of distinct P waves with fibrillatory waves of varying amplitude and shape, and is associated with an irregular and rapid ventricular response governed by the atrioventricular (AV) node response.

AF is often an electrical manifestation of an associated cardiovascular condition, most commonly hypertension. Additional cardiovascular conditions commonly associated with AF include valvular heart disease (most often mitral valve disease), HF, coronary artery disease (CAD), hypertrophic cardiomyopathy, restrictive cardiomyopathies (eg, amyloid), and pericardial diseases. Noncardiovascular conditions can also predispose individuals to AF, such as acute and chronic pulmonary disease, sepsis, hyperthyroidism, and excess alcohol intake or alcohol withdrawal. AF is extremely common after all forms of cardiac surgery. In fact, AF may occur in 25% to 40% of patients after coronary artery bypass graft surgery and in up to 60% of patients after valvular surgery, with the incidence being the highest in the elderly population.⁵

Classification

The most commonly used classification scheme for AF divides it into 3 categories: paroxysmal, persistent, and permanent AF.² If the arrhythmia terminates spontaneously within 7 days, it is referred to as paroxysmal AF. If the AF terminates spontaneously after a longer period (ie, more than 7 days) or requires termination with pharmacologic or direct current cardioversion, it is termed persistent AF. Recurrent episodes of arrhythmia can be termed paroxysmal or persistent depending on the duration of AF. Long-standing persistent AF refers to AF that has continued for longer than 1 year when efforts are still directed toward maintaining sinus rhythm. When AF has continued longer than 1 year and efforts to restore sinus rhythm are no longer pursued, the arrhythmia is termed permanent. Thus, the determination of permanent AF is partially dependent on the chosen treatment strategy. In clinical practice, efforts directed at restoring sinus rhythm, usually with catheter ablation, are often pursued even in patients with AF durations of greater than 1 year.

These categories are useful for clinical management because AF is a progressive condition, with patients often passing from one category to the next. In fact, most patients present with paroxysmal AF with recurring episodes that become more frequent and longer over time. This observation gave rise to the concept “AF begets AF.”⁶

Pathophysiology

The electrophysiologic properties underlying the onset and maintenance of AF require both an initiating event (trigger) and an anatomical substrate. The initiating event occurs most often from the pulmonary veins (PVs). The seminal work by Häissaguerre et al⁷ in this field demonstrated that paroxysmal AF often was initiated by focal discharges from the PVs. Since then, it has been shown that the sleeves of atrial myocardium extending into the PVs provide the source for small reentrant circuits or automatic focuses that trigger the arrhythmia.⁸ This observation changed the paradigm of AF and provided the rationale for isolation of PVs during catheter ablation.

A critical mass of abnormal atrial tissue (substrate) is required to sustain AF. Abnormal atrial tissue engenders heterogeneous atrial conduction and refractoriness, whereby impulses propagating from “focal” sources encounter variable lines of block that stabilize reentry and maintain the arrhythmia.^9-11 The presence of structural heart disease promotes atrial chamber enlargement and pathology, explaining the higher prevalence of AF among patients with underlying cardiovascular conditions. Interestingly, AF also promotes atrial remodeling, supporting the pathophysiologic basis of “AF begets AF” and providing insight into how the arrhythmia may evolve from paroxysmal to persistent AF (Figure 2).

Clinical Presentation

As a primary event, AF is often recognized by the sensation of an irregular heartbeat (palpitations) or a fast heart rate. Additional features may include fatigue, shortness of breath, angina-like chest pain, light-headedness, or syncope. Syncope can result from either tachycardia or sick sinus syndrome. Importantly, many patients with new AF have no symptoms or present only after an asymptomatic period of unknown duration. This is particularly true among elderly patients, who often have better-controlled ventricular rates than younger patients.

In some instances, the presence of very rapid ventricular rates can lead to more serious consequences, such as hypotension, syncope, angina, myocardial ischemia, or HF. Prolonged episodes of untreated tachycardia can also result in tachycardia-induced cardiomyopathy. Patients with severe underlying cardiac conditions are more likely to have these serious manifestations because of shortening of diastolic filling periods, loss of AV synchrony, and decreased stroke volumes. This is also true among elderly patients, who, with aging, may have restrictive physiology due to increasing myocardial stiffness.

The most feared complication of AF is cardioembolic stroke. Thrombotic material in AF is most frequently found in the left atrial appendage. Depending on stroke risk factors, the annual risk of nonvalvular AF (ie, absence of rheumatic mitral valve disease or a prosthetic heart valve) among elderly patients can exceed 10%.¹² In the Framingham study, the annual risk of stroke attributable to AF was 1.5% in patients age 50 to 59 years and 23.5% in those age 80 to 89 years.¹³

Clinical Evaluation

Ideally, the 12-lead ECG confirms the diagnosis of AF; however, in the presence of asymptomatic or paroxysmal AF, telemetry or ambulatory monitoring can be useful. A focused history is also important to review symptoms and to identify the presence of underlying heart conditions. As part of the initial evaluation, all patients with AF should have a 2-dimensional echocardiogram to assess for structural or valvular heart disease. Also, blood tests for renal, hepatic, and thyroid function may be considered depending on the clinical situation. Additional testing with either prolonged ambulatory monitoring, exercise testing, transesophageal echocardiography, or electrophysiology study will depend on the clinical findings.

Management

Acute
The acute management of AF requires an assessment of hemodynamic stability. A hemodynamically unstable patient should undergo emergent direct current cardioversion to restore sinus rhythm. Most patients, however, are hemodynamically stable, and the initial goal is to control the ventricular rate. Rate control can be achieved in the vast majority of patients using either beta blockers or calcium-channel blockers, with digoxin sometimes added to either beta blockers or calcium-channel blockers. Amiodarone can also be useful for acute rate control when other agents have failed or are contraindicated during HF exacerbations.

Up to one-half of patients with new-onset AF will experience spontaneous cardioversion to sinus rhythm within 24 hours.¹⁴ For others, the decision to pursue electrical or pharmacologic cardioversion depends on the ability to control ventricular rate and the persistence of symptoms.

Chronic
The long-term management of AF involves two potential strategies: control of the ventricular rate (rate control) or restoration of sinus rhythm (rhythm control). Historically, it was assumed that maintaining sinus rhythm was better than rate control alone. This assumption was based on the belief that rhythm control would improve hemodynamics and lower the risk of stroke. In the landmark Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) study,¹⁵ however, no significant difference in survival was found using either strategy in patients older than 65 years with at least one stroke risk factor. There were no significant differences found in exercise tolerance or quality of life between either strategy. Because of a tendency to eliminate or reduce the intensity of anticoagulation in the rhythm-control group, a greater than expected rate of stroke was observed in this group, likely due to recurring asymptomatic AF.¹⁵ This observation makes it clear that regardless of which strategy is chosen, the need for anticoagulation should be based on stroke risk, not on whether restoration of sinus rhythm is pursued. Additionally, the long-term use of antiarrhythmic drugs (AADs) may have contributed to the slightly higher all-cause mortality in the rhythm-control arm. The Atrial Fibrillation and Congestive Heart Failure (AF-CHF) trial¹⁶ evaluated patients specifically with depressed left ventricular (LV) function and New York Heart Association (NYHA) classes II to IV HF and a history of AF. Again, the results demonstrated no advantage to the routine use of a rhythm-control strategy. Catheter ablation of AF was not studied in these trials.

In view of these findings, the decision to use a rhythm-control or rate-control strategy is based on clinical factors and is primarily driven by the desire to improve the patient’s quality of life. Rhythm control is indicated in patients who continue to have troublesome symptoms despite adequate rate control and who can tolerate AADs. AADs are more efficacious than placebo not only in sustaining sinus rhythm, but also in delaying recurrences and reducing prolonged episodes. For some patients with very symptomatic AF, this may prove useful despite recurrences while on AADs. The choice of AAD therapy depends on many clinical factors, including consideration of structural heart disease, hypertension, renal and hepatic function, pulmonary status, and coronary ischemia (Table 1).^2,17 The increased prevalence of these comorbid factors and altered pharmacokinetics among elderly patients make the choice of AAD therapy even more challenging.¹⁸

Currently, the overall effectiveness of AADs in maintaining sinus rhythm at 1 year is approximately 50%, and it is slightly higher with amiodarone (approximately 70%).¹⁹ Because of its adverse-effect profile, however, experts recommend using amiodarone only after other drugs have failed or when there are contraindications to their use. It is important to note that when AADs do not result in symptomatic improvement or if they cause adverse effects, their use should be discontinued.

New AADs are actively being studied. Dronedarone was approved by the US Food and Drug Administration (FDA) in July 2009 to reduce the risk of cardiovascular hospitalizations when treating for AF. These recommendations were based on the findings of A Placebo-Controlled, Double-Blind, Parallel Arm Trial to Assess the Efficacy of Dronedarone 400 mg bid for the Prevention of Cardiovascular Hospitalization or Death From any Cause in Patients With Atrial Fibrillation/Atrial Flutter (ATHENA)²⁰ (patient mean age, 71.6 years), which demonstrated that treatment with dronedarone resulted in a 24% reduction in the risk of cardiovascular complications when compared with placebo. With its approval, the FDA provided a warning against the use of dronedarone in patients with a history of severe HF or those with NYHA class II or III HF and a recent decompensation based on a previous trial indicating harm in these patients.²¹

The Efficacy & Safety of Dronedarone Versus Amiodarone for the Maintenance of Sinus Rhythm in Patients With Atrial Fibrillation (DIONYSOS) trial,²² the only randomized trial comparing dronedarone with amiodarone, found that patients taking dronedarone for the prevention of recurrent AF were half as likely to remain in sinus rhythm as patients taking amiodarone. A trend toward more adverse events in patients taking amiodarone was found, however, emphasizing the need for larger trials to define the role of dronedarone in the management of AF.

In patients with asymptomatic AF or minimal symptoms following appropriate rate control, continuation of AV nodal agents alone is appropriate. In the Rate Control Efficacy in Permanent Atrial Fibrillation: a Comparison Between Lenient Versus Strict Rate Control II (RACE II) trial,²³ treatment with lenient rate control (target resting heart rate <110 bpm) was just as clinically effective as strict rate control (target resting heart rate <80 bpm and <110 bpm during moderate exercise) in patients 80 years or younger with regard to a composite of cardiovascular events and adverse events related to rate-control drugs. This indicates that lenient rate control can be adopted as a first-choice strategy with an option for more strict control if the patient remains symptomatic or if HF develops. This is especially helpful in elderly patients, who may not tolerate high doses of beta blockers or calcium-channel blockers because of adverse effects.

Stroke Prevention
A key component of managing AF involves preventing thromboembolic complications, especially stroke. As previously stated, nearly one-fourth of all strokes among octogenarians are attributable to AF.¹³ Consequently, elderly patients should receive anticoagulation therapy for AF provided there are no strong contraindications.

The most effective means to prevent strokes is anticoagulation with warfarin. Hart et al²⁴ found that adjusted-dose warfarin decreased the risk of stroke by 62% (95% confidence interval [CI], 48%-72%). In direct comparison with aspirin, warfarin decreased the relative risk of stroke by 36% (95% CI, 14%-52%).²⁴ Hylek and Singer²⁵ found that the use of warfarin was associated with a 2-fold increase in intracranial hemorrhage. Maintaining international normalized ratio (INR) levels within a range of 2.0 to 3.0 minimizes the incidence of both ischemic and hemorrhagic strokes.²⁵

Several risk stratification schemes exist to calculate an individual’s stroke risk and determine the need for oral anticoagulation therapy. The CHADS₂ score is the most widely used system and has been validated in elderly patients. The sum of the points determines the CHADS₂ score and provides an estimate for the adjusted annual stroke rate (Table 2, Figure 3).²⁶ The American College of Cardiology, American Heart Association, and European Society of Cardiology have established guidelines on administering anticoagulation based on the individual CHADS₂ score.² For example, recommended therapy for persons with no risk factors for stroke is aspirin 81 to 325 mg; for persons with a CHADS₂ score of 1, it is aspirin or dose-adjusted warfarin (INR, 2.0-3.0 with a target of 2.5); and for persons with any high risk factor (ie, previous transient ischemic attack or stroke, prosthetic heart valve, or mitral stenosis) or a CHADS₂ score of greater than 1 it is dose-adjusted warfarin (INR, 2.0-3.0 with a target of 2.5 or > 2.5 if mechanical mitral valve).²

The past decade has seen a sharp rise in the treatment of CAD with intracoronary stents, in particular drug-eluting stents, requiring prolonged periods of dual antiplatelet therapy. In general, aspirin use has been found to increase an elderly patient’s absolute risk for serious bleeding by 0.6%, and observational data suggest that triple therapy with aspirin, clopidogrel, and warfarin is also associated with a high risk of bleeding.^27,28 There are no adequate studies that have specifically addressed the issue of patients undergoing percutaneous coronary intervention (PCI) who also require chronic anticoagulation for AF. In the Atrial Fibrillation Clopidogrel Trial With Irbesartan for Prevention of Vascular Events (ACTIVE-W),²⁹ however, the combination of clopidogrel and aspirin was shown to provide inferior protection against stroke versus INR-directed therapy with warfarin. Therefore, all patients undergoing PCI with a documented need for chronic anticoagulation should continue to receive warfarin with a goal INR based on individual stroke risks. In this setting, most practicing cardiologists will add dual antiplatelet therapy to warfarin therapy for a limited time period. After the acute period, for most patients with AF and stable CAD, warfarin anticoagulation (plus clopidogrel, depending on the use of drug-eluting stents) should provide satisfactory antithrombotic therapy to prevent both cerebral and myocardial ischemic events.²

Despite the clear superiority of warfarin over aspirin in the prevention of strokes, anticoagulation is underused in the elderly. This is, in part, due to an overestimation of bleeding risks in elderly candidates. The Birmingham Atrial Fibrillation Treatment of the Aged Study (BAFTA)³⁰ demonstrated that even among very elderly patients with AF, anticoagulation with warfarin was superior to aspirin for primary stroke prevention. In this trial, patients age 75 years or older with AF were randomized to adjusted-dose warfarin or aspirin 75 mg. The results demonstrated that even in the highest age groups, warfarin was more effective and there was no significant increased risk of bleeding with its use. Thus, in patients with a strong indication for anticoagulation therapy and no significant contraindications, adjusted-dose warfarin is strongly encouraged.

In October 2010, the FDA approved dabigatran for the prevention of stroke and systemic embolism in patients with AF. In the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) study,³¹ patients (mean age, 71 years) with nonvalvular AF were randomized to either adjusted-dose warfarin or dabigatran. The rates of the primary outcome (stroke or systemic embolism) were significantly lower among patients taking dabigatran 150 mg twice daily (relative risk 0.66; 95% CI, 0.53-0.82; P < .001). The rate of major bleeding was similar to that seen with warfarin at this dosage, and intracranial hemorrhage was reduced by 60%. In addition to its superior efficacy, dabigatran requires no anticoagulant monitoring and has few interactions, which makes it particularly attractive for elderly patients taking multiple medications. Adoption of dabigatran into wide clinical practice is expected given the enthusiasm surrounding the results of the RE-LY study; however, insurance coverage of dabigatran remains in question.

Novel developments in nonpharmacologic approaches to stroke prevention in AF are also being investigated. A left atrial appendage occlusion device delivered percutaneously holds promise. The Randomized Prospective Trial of Percutaneous LAA [left atrial appendage] Closure vs Warfarin for Stroke Prevention in AF (PROTECTAF)³² demonstrated noninferiority with the device in comparison to warfarin, although adverse events were higher with the device. The FDA has requested a new trial from the manufacturer to better examine the efficacy and safety profile of the device. Nonetheless, the technology does provide hope that patients with strong contraindications to oral anticoagulation therapy may soon have an option to reduce stroke risk without the cost of bleeding.

Catheter Ablation
In a post hoc analysis of the AFFIRM study, the presence of sinus rhythm was associated with an approximately 50% reduced risk of death.³³ This effect was counterbalanced by an increased risk of death with the use of AADs; however, this analysis suggested a theoretical benefit of maintaining sinus rhythm and has spurred the development of alternative pharmacologic and nonpharmacologic therapies directed at restoring sinus rhythm.

Catheter ablation of AF is one such technique and involves the delivery of heat (radiofrequency ablation) or cooling (cryoablation) to eliminate arrhythmogenic substrate in the atrium that triggers and sustains AF. The realization that paroxysmal AF is initiated from triggers within the PVs facilitated the development of catheter ablation strategies. Today, isolation of the PVs from the left atrium forms the cornerstone of ablation therapy. Published trials indicate successful maintenance of sinus rhythm in 70% to 80% of patients at 12 months.^34,35 In one long-term analysis, approximately 70% of patients who were free of AF recurrence 1 year after catheter ablation and were not taking AADs remained free of AF at 5 years.³⁷ The ongoing Catheter Ablation versus Anti-arrhythmic Drug Therapy for Atrial Fibrillation (CABANA) trial addresses this question prospectively, and also addresses whether catheter ablation has a prognostic benefit.

Patients with persistent or long-standing persistent AF require more extensive ablation and adjunctive procedures to PV isolation that target substrate. “Substrate” ablation creates linear lines by connecting various regions of the left atrium to the existing PV lines, as well as targeting high-frequency atrial activity and ganglionated plexi to alter parasympathetic and sympathetic activity. Reported findings demonstrate that ablation is significantly less effective for persistent AF as compared with paroxysmal AF.^37,38

An expert consensus statement from the American College of Cardiology Foundation, American Heart Association, and Heart Rhythm Society consider AF ablation to be a class I indication in highly symptomatic patients who have failed at least one AAD or inthose who do not wish to take drug therapy.¹⁷ Major complications of AF ablation, including tamponade, PV stenosis; and vascular complications, occur in 4% to 6% of cases. The mortality rate is less than 1%.² In general, existing data support the notion that catheter ablation for paroxysmal AF can be performed with similar efficacy and safety in elderly patients and in younger patients and should be considered a treatment option for highly symptomatic patients.^39,40 It should be noted, however, that 20% to 40% of patients will continue to experience symptoms after a single procedure and will either require a second procedure or have to remain on antiarrhythmic therapies.⁴⁰ It is also important to note that no trial has evaluated the need for long-term anticoagulation after catheter ablation. Thus, continuation of anticoagulants is determined by an individual’s stroke risk based on CHADS₂.²

A proportion of patients remain symptomatic despite best medical therapy or attempts at catheter ablation to maintain sinus rhythm. In these cases, ablation of the AV node to create heart block and implantation of a pacemaker may be warranted. This option can be particularly attractive in elderly patients who are less physically active or those who prefer a more definitive treatment. However, limitations include persistent need for anticoagulation, pacemaker dependence, and risk of infection with pacemaker implantation. There are no prospective trials in elderly patients addressing AV node ablation and pacing versus catheter ablation for AF in medically refractory AF. In some elderly patients, successful treatment with either option has been associated with improved quality of life, LV function, and exercise capacity.^39-42

Conclusion

AF is the most common arrhythmia in clinical practice and occurs most frequently in the elderly. The past decade has seen rapid developments in the management of AF and its complications using both pharmacologic and nonpharmacologic measures. Primary care physicians, cardiologists, and other healthcare providers involved in the care of elderly patients should have an appreciation of these new therapies and be prepared to individualize these options based on patients’ symptoms and the benefits expected with treatment.

The authors report no relevant financial relationships. Dr. Siddiqi is Cardiology Fellow, University of Maryland, and Dr. Dickfeld is Chief of Electrophysiology, VA Baltimore, and Associate Professor, University of Maryland, Baltimore.

References

1. Go AS, Hylek EM, Phillips KA, et al. Prevalence of diagnosed atrial fibrillation in adults: national implications for rhythm management and stroke prevention: the AnTicoagulation and Risk Factors in Atria Fibrillation (ATRIA) study. JAMA. 2001;285(18):2370-2375.

2. European Heart Rhythm Association; Heart Rhythm Society; Fuster V, Rydén LE, Cannom DS, et al; American College of Cardiology; American Heart Association Task Force on Practice Guidelines; European Society of Cardiology Committee for Practice Guidelines; Writing Committee to Revise the 2001 Guidelines for the Management of Patients With Atrial Fibrillation. ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation—executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients With Atrial Fibrillation) [published correction appears in J Am Coll Cardiol. 2007;50(6):562]. J Am Coll Cardiol. 2006;48(4):854-906.

3. Feinberg WM, Blackshear JL, Laupacis A, Kronmal R, Hart RG. Prevalence, age distribution, and gender of patients with atrial fibrillation. Arch Intern Med. 1995;155(5):469-473.

4. Benjamin EJ, Wolf PA, D’Agostino RB, Silbershatz H, Kannel WB, Levy D. Impact of atrial fibrillation on the risk of death: the Framingham Study. Circulation.1998;98(10):946-952.

5. Maisel WH, Rawn JD, Stevenson WG. Atrial fibrillation after cardiac surgery. Ann Intern Med. 2001;135(12):1061-1073.

6. Wijffels MC, Kirchhof CJ, Dorland R, Allessie MA. Atrial fibrillation begets atrial fibrillation. A study in awake chronically instrumented goats. Circulation. 1995;92(7):1954-1968.

7. Häissaguerre M, Jaïs P, Shah DC, et al. Spontaneous initiation of atrial fibrillation by ectopic beats originating in the pulmonary veins. N Engl J Med. 1998;339(10):659-666.

8. de Bakker JM, Ho SY, Hocini M. Basic and clinical electrophysiology of pulmonary vein ectopy. Cardiovasc Res. 2002;54(2):287-294.

9. Moe GK, Abildskov JA. Atrial fibrillation as a self-sustaining arrhythmia independent of focal discharge. Am Heart J. 1959;58(1):59-70.

10. Peters NS, Schilling RJ, Kanagaratnam P, Markides V. Atrial fibrillation: strategies to control, combat, and cure. Lancet. 2002;359(9306):593-603.

11. Everett TH 4th, Olgin JE. Atrial fibrosis and the mechanisms of atrial fibrillation. Heart Rhythm. 2007;4(3 suppl):S24-S27.

12. Hart RG, Pearce LA, Rothbart RM, McAnulty JH, Asinger RW, Halperin JL. Stroke with intermittent atrial fibrillation: incidence and predictors during aspirin therapy. Stroke Prevention in Atrial Fibrillation Investigators. J Am Coll Cardiol. 2000;35(1):183-187.

13. Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation as an independent risk factor for stroke: the Framingham Study. Stroke. 1991;22(8):983-988.

14. Capucci A, Lenzi T, Boriani G, et al. Effectiveness of loading oral flecainide for converting recent-onset atrial fibrillation to sinus rhythm in patients without organic heart disease or with only systemic hypertension. Am J Cardiol. 1992;70(1):69-72.

15. Wyse DG, Waldo AL, DiMarco JP, et al; Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) Investigators. A comparison of rate control and rhythm control in patients with atrial fibrillation. N Engl J Med. 2002;347(23):1825-1833.

16. Roy D, Talajic M, Nattel S, et al; Atrial Fibrillation and Congestive Heart Failure Investigators. Rhythm control versus rate control for atrial fibrillation and heart failure. N Engl J Med. 2008;358(25):2667-2677.

17.Wann LS, Curtis AB, January CT, et al; 2006 Writing Committee Members; ACCF/AHA Task Force Members. 2011 ACCF/AHA/HRS focused update on the management of patients with atrial fibrillation (updating the 2006 Guideline): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Heart Rhythm. 2011;8(1):157-176.

18. Wyse DG. Pharmacotherapy for rhythm management in elderly patients with atrial fibrillation. J Interv Card Electrophysiol. 2009;25(1):25-29.

19. Lafuente-Lafuente C, Mouly S, Longás-Tejaro MA, Mahé I, Benjamin JF. Antiarrhythmic drugs for maintaining sinus rhythm after cardioversion of atrial fibrillation: a systematic review of randomized controlled trials. Arch Intern Med. 2006;166(7):719-728.

20. Hohnloser SH, Crijns HJ, Van Eickels M, et al; ATHENA Investigators. Effect of dronedarone on cardiovascular events in atrial fibrillation [published correction appears in N Engl J Med. 2009;360(23):2487]. N Engl J Med. 2009;360(7):668-678.

21. Køber L, Torp-Pedersen C, McMurray JJ, et al. Increased mortality after dronedarone therapy for severe heart failure [published correction appears in N Engl J Med. 2010;363(14):1384]. N Engl J Med. 2008;358(25):2678-2687.

22. DIONYSIS study results showed the respective profiles of dronedarone and amiodarone [press release]. Paris, France: Sanofi-aventis; December 23, 2008

23. Van Gelder IC, Groenveld HF, Crijns HJ, et al; RACE II Investigators. Lenient versus strict rate control in patients with atrial fibrillation. N Engl J Med. 2010;362(15):1363-1373.

24. Hart RG, Benavente O, McBride R, Pearce LA. Antithrombotic therapy to prevent stroke in patients with atrial fibrillation: a meta-analysis. Ann Intern Med. 1999;131(7):492-501.

25. Hylek EM, Singer DE. Risk factors for intracranial hemorrhage in outpatients taking warfarin. Ann Intern Med. 1994;120(11)897-902.

26. Gage BF, Waterman AD, Shannon W, Boechler M, Rich MW, Radford MJ. Validation of clinical classification schemes for predicting stroke: results from the National Registry of Atrial Fibrillation. JAMA. 2001;285(22):2864-2870.

27. Hart RG, Benavente O, Pearce LA. Increased risk of intracranial hemorrhage when aspirin is combined with warfarin: a meta-analysis and hypothesis. Cerebrovasc Dis. 1999;9(4):215-217.

28. Francescone S, Halperin JL. “Triple therapy” or triple threat? Balancing the risks of antithrombotic therapy for patients with atrial fibrillation and coronary stents. J Am Coll Cardiol. 2008;51(8):826-827.

29. ACTIVE Investigators, Connolly S, Pogue J, Hart R, et al. Effect of clopidogrel added to aspirin in patients with atrial fibrillation. N Engl J Med. 2009;360(20):2066-2078.

30. Mant J, Hobbs FD, Fletcher K, et al; BAFTA Investigators; Midland Research Practices Network (MidReC). Warfarin versus aspirin for stroke in prevention in an elderly community population with atrial fibrillation (the Birmingham Atrial Fibrillation Treatment of the Aged Study, BAFTA): a randomized controlled trial. Lancet. 2007;370(9586):493-503.

31. Connolly SJ, Ezekowitz MD, Yusuf S, et al; RE-LY Steering Committee and Investigators. Dabigatran versus warfarin in patients with atrial fibrillation [published correction appears in N Engl J Med. 2010;363(19):1877]. N Engl J Med. 2009;361(2):1139-1151.

32. Holmes DR, Reddy VY, Turi ZG, et al; PROTECT AF Investigators. Percutaneous closure of the left atrial appendage versus warfarin therapy for prevention of stroke in patients with atrial fibrillation: a randomised non-inferiority trial (published correction appears in Lancet. 2009;374(9701):1596]. Lancet. 2009;374(9689):534-542.

33. Corley SD, Epstein AE, DiMarco JP, et al; AFFIRM Investigators. Relationships between sinus rhythm, treatment, and survival in the Atrial Fibrillation Follow-Up Investigation of Rhythm Management (AFFIRM) study. Circulation. 2004;109(12):1509-1513.

34. Pappone C, Augello G, Sala S, et al. A randomized trial of circumferential pulmonary vein ablation versus antiarrhythmic drug therapy in paroxysmal atrial fibrillation: the APAF study. J Am Coll Cardiol. 2006;48(11):2340-2347.

35. Jaise P, Cauchemez B, MacLe L, et al. Atrial fibrillation ablation versus antiarrhythmic drugs: a multicenter randomized trial. Presented at: Heart Rhythm Society 2006 Annual Scientific Sessions. May 17-20, 2006; Boston, MA.

36. Tzou WS, Marchilinski FE, Zado ES, et al. Long-term outcome after successful catheter ablation of atrial fibrillation. Circ Arrhythm Electrophysiol. 2010;3(3):237-242.

37. Häissaguerre M, Hocini M, Sanders P, et al. Catheter ablation of long-lasting persistent atrial fibrillation: clinical outcome and mechanisms of subsequent arrhythmias. J Cardiovasc Electrophysiol. 2005;16(11):1138-1147.

38. Earley MJ, Abrams DJ, Staniforth AD, Sporton SC, Schilling RJ. Catheter ablation of permanent atrial fibrillation: medium term results. Heart. 2006;92(2):233-238.

39. Hsieh MH, Tai CT, Lee SH, et al. Catheter ablation of atrial fibrillation versus atrioventricular junction ablation plus pacing therapy for elderly patients with medically refractory paroxysmal atrial fibrillation. J Cardiovasc Electrophysiol. 2005:16(5):457-461.

40. Hsu LF, Jais P, Sanders P, et al. Catheter ablation of permanent atrial fibrillation in the elderly. Heart Rhythm. 2005;2(5 suppl):S313-S314.

41. Zado E, Callans DJ, Riley M, et al. Long-term clinical efficacy and risk of catheter ablation for atrial fibrillation in the elderly. J Cardiovasc Electrophysiol. 2008;19(6):621-626.

42.Corrado A, Patel D, Riedlbauchova L, et al. Efficacy, safety, and outcome of atrial fibrillation ablation in septuagenarians. J Cardiovasc Electrophysiol. 2008;19(8):807-811.