Prim Care Clin Office Pract 32 (2005) Atrial Fibrillation. 830 Chalkstone Avenue, Providence, RI 02908, USA

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1 Prim Care Clin Office Pract 32 (2005) Atrial Fibrillation Ohad Ziv, MD a,b, Gaurav Choudhary, MD a,c, * a Brown Medical School, Box G-A, Providence, RI 02912, USA b Division of Cardiology, Rhode Island Hospital, 593 Eddy Street, Providence, RI 02903, USA c Division of Cardiology, Providence Veterans Administration Medical Center, 830 Chalkstone Avenue, Providence, RI 02908, USA The American College of Cardiology Practice Guidelines defines atrial fibrillation as uncoordinated atrial activation with consequent deterioration of atrial mechanical function [1]. The primary care physician will undoubtedly face the management of patients who have atrial fibrillation, because it is the most common cardiac arrhythmia. Evolving knowledge about the natural history, clinical effects, and treatment efficacy of atrial fibrillation has made this task more challenging. Recently, large, randomized, placebocontrolled trials have yielded powerful and surprising results that have forced clinicians to reassess previous atrial fibrillation management practices. In this article, the authors review the current understanding of atrial fibrillation and its appropriate treatment, highlight the major recent investigations that have changed our approach to atrial fibrillation, and describe the potential for exciting treatment options in the near future. Epidemiology Population-based studies suggest that 2 to 3 million people in the United States are affected by atrial fibrillation [2,3]. The incidence of atrial fibrillation increases with age, and approximately doubles with each decade of life [4,5]. Generally, men have a higher age-adjusted prevalence of atrial fibrillation [6]. From the Framingham database, we know that the overall biennial incidence is 6.2 cases per 1000 persons for men and 3.8 cases per 1000 persons for women [7]. The biennial incidence is over 30 per 1000 persons 75 to * Corresponding author. Division of Cardiology, Providence Veterans Administration Medical Center, 830 Chalkstone Avenue, Providence, RI address: Gaurav_Choudhary@brown.edu (G. Choudhary) /05/$ - see front matter. Published by Elsevier Inc. doi: /j.pop primarycare.theclinics.com

2 1084 ZIV & CHOUDHARY 84 years of age, and near 80 per 1000 persons 85 to 94 years of age [7]. One percent of those younger than 60 years of age and 6% of those older than 80 years of age have been diagnosed as having atrial fibrillation [1,4]. Recent observational studies have suggested that the overall prevalence of atrial fibrillation is increasing across gender and age groups, accompanied by an increase in the prevalence of hypertension, coronary artery disease, heart failure, and diabetes [8]. The incidence of atrial fibrillation is affected by the presence of both chronic illnesses and acute precipitating factors (Box 1). The presence of disease states mentioned in Box 1 increases the risk of developing recurrent atrial fibrillation. Alternatively, reversible precipitants of atrial fibrillation do not carry the same prognosis for recurrence. Although myocardial Box 1. Chronic illnesses and acute triggers associated with the development of atrial fibrillation Cardiac and noncardiac illnesses associated with atrial fibrillation Underlying heart disease Valvular heart disease Left ventricular hypertrophy Diastolic dysfunction Cardiomyopathy Pulmonary disease Pulmonary hypertension Pulmonary embolism Chronic obstructive pulmonary disease Obstructive sleep apnea Precipitants of atrial fibrillation Inflammatory or infiltrative atrial disease Pericarditis Amyloidosis Myocarditis Intoxicants Alcohol Cocaine Amphetamines Increased sympathetic activity Hyperthyroidism Pheochromocytoma Anxiety Postoperative (especially cardiac surgery) Exertion-induced

3 ATRIAL FIBRILLATION 1085 infarction can be complicated by atrial fibrillation, patients presenting with atrial fibrillation without chest pain or anginal equivalent are unlikely to have silent acute coronary syndrome and need not be worked up for ischemia. Classification The American College of Cardiology (ACC)/American Heart Association (AHA) classification for atrial fibrillation is outlined in Table 1. The initial distinction that must be made is whether the episode of atrial fibrillation is secondary to a reversible underlying cause, because these episodes may behave and be treated differently. Next, the approach to a patient who has atrial fibrillation depends on whether the patient is having a first-detected episode, or whether the episode is recurrent. Finally, lone atrial fibrillation is a distinct classification that carries a lower risk for thromboembolic disease, and therefore different treatment implications. Mechanism and pathophysiology The electrophysiological mechanism of atrial fibrillation is commonly explained by the theory of multiple wavelets. In this model, atrial fibrillation is a manifestation of multiple small re-entrant circuits in the atria. The continued propagation of these microcircuits is facilitated by large atrial mass and heterogeneous atrial myocardium that ensures that the wave-front of depolarization continuously finds nonrefractory atrial tissue [4]. Another theory proposes that atrial fibrillation is the result of a single rapidly firing focus within the atrium [9,10]. In some cases, the initiation of atrial Table 1 Classification of atrial fibrillation outlines in the 2001 ACC/AHA guidelines for the management of patients with atrial fibrillation Secondary atrial fibrillation Atrial fibrillation due to an underlying reversible cause First detected atrial fibrillation The first time a patient s atrial fibrillation comes to medical attention Recurrent atrial fibrillation The occurrence of two or more episodes of atrial fibrillation Paroxysmal atrial fibrillation A recurrent episode of atrial fibrillation that is self-limited Persistent atrial fibrillation An episode of atrial fibrillation that is sustained Permanent atrial fibrillation Persistent atrial fibrillation in a patient that has failed conversion or is not a candidate for conversion to sinus rhythm Lone atrial fibrillation Atrial fibrillation in a patient under 60 years of age with no clinical or echocardiographic evidence of cardiopulmonary disease

4 1086 ZIV & CHOUDHARY fibrillation can be attributed to premature beats that arise from the pulmonary vein ostia in the left atrium [11]. Ablation of these foci can be successful in preventing recurrence of the arrhythmia [12]. The disorganized electrical activity of the fibrillating atria precludes mechanical contraction. This loss of mechanical activity likely leads to blood pooling and the formation of thrombus, especially in the left atrial appendage [1]. The exact pathogenesis of thrombus formation in atrial fibrillation is complex and not well-understood; however, clinical data strongly link the arrhythmia with thromboembolic phenomenon. The loss of atrial contraction also leads to the loss of the atrial kick d the atrial contribution to ventricular filling. The atrial kick can augment the stroke volume by up to 20% [13,14]. Patients who have pre-existing severe systolic or diastolic dysfunction rely on this atrial augmentation of stroke volume, and can develop symptoms of worsening dyspnea, hypotension, or hypoxemia. In addition to the loss of atrial kick, rapid and irregular ventricular rate leads to variable time in diastole, and therefore to variable stroke volume. Hemodynamic compromise is more likely with higher rates. Most patients who have normal hearts can tolerate high ventricular rates, but patients who have significant valvular disease, or diastolic or systolic dysfunction can become severely dyspneic and develop pulmonary congestion. Finally, consistently high ventricular rates can lead to tachycardia-induced cardiomyopathy. This myopathy is believed to be mediated through neurohormonal activation and myocyte calcium overload. It is generally reversible with aggressive rate control [4]. Prognosis The effect of atrial fibrillation on mortality has been variable in trials, and is not clearly defined; however, with the presence of cardiovascular disease, patients have about a twofold increase in all-cause mortality [15] attributable to cardiovascular events [16]. It is still unclear whether the increase in mortality is secondary to atrial fibrillation itself, to associated rapid ventricular rates, or is a confounding effect of more significant underlying cardiovascular disease. Atrial fibrillation is an independent risk factor for stroke. In the Framingham database, the presence of atrial fibrillation in patients without rheumatic heart disease conferred a 4.8 relative risk of thromboembolic stroke. This increase in risk was greater than the risk conferred by the presence of hypertension, coronary artery disease, or congestive heart failure [17]. Factors that increase the risk of stroke in patients who have atrial fibrillation are outlined in Table 2. They include age, structural heart disease, previous stroke, hypertension, diabetes, and coronary artery disease. Some studies suggest that hyperthyroidism in the presence of atrial fibrillation is also a risk for thromboembolism [1].

5 ATRIAL FIBRILLATION 1087 Table 2 Risk factors for ischemic stroke and systemic embolism in patients with nonvalvular atrial fibrillation Risk factors (control groups) Relative risk a Previous stroke or TIA 2.5 History of hypertension 1.6 Congestive heart failure 1.4 Advanced age (continuous, per decade) 1.4 Diabetes mellitus 1.7 Coronary artery disease 1.5 Abbreviation: TIA, transient ischemic attack. a Relative risk refers to comparison with atrial fibrillation patients without these risk factors. From Fuster V, Ryden LE, Asinger RW, et al. ACC/AHA/ESC guidelines for the management of patients with atrial fibrillation. J Am Coll Cardiol 2001;38(4):1266xlii; with permission. These risk factors are additive. The compilation of data from the Stroke Prevention in Atrial Fibrillation trials (SPAF) supplies the clinician with a stroke risk model for patients who have atrial fibrillation [18]. Patients under the age of 75 who do not have the above risk factors are low-risk patients, and had an annual stroke rate of less than 1%. Patients at moderate risk, including those who had hypertension or diabetes and who were under 75 years of age, had a 2.5% annual stroke rate. Patients over 75 years of age who had not had a previous stroke and had a history of hypertension carried a high risk of a first event, reaching 7% per year. Patients who had previous stroke were at highest risk of a recurrent event, having a 13% annual risk of recurrence. Approach to management First detected atrial fibrillation Diagnosis Before formulating a plan for management, the clinician must be sure of the diagnosis. A recent study from Michigan [19] demonstrated that in over 2000 electrocardiograms, a computer-generated interpretation misdiagnosed the rhythm as atrial fibrillation. In a quarter of these misdiagnosed cases, the physician did not correctly identify the rhythm, which led to the ordering of additional tests, and in 10% of these patients to the initiation of either antiarrhythmic agents or anticoagulation. This study underscores the importance of appropriately diagnosing atrial fibrillation, and the need for careful analysis of the rhythm on an electrocardiogram. Other atrial rhythms that may mimic fibrillation, such as multifocal atrial tachycardia, sinus rhythm or sinus tachycardia with multiple, premature atrial beats, or sinus rhythm with sinus arrhythmia, do not carry the same clinical implications.

6 1088 ZIV & CHOUDHARY Natural history Observational studies have demonstrated that over two thirds of patients who have acute onset atrial fibrillation convert spontaneously. Two thirds of these spontaneous conversions occur within the first 24 hours. Half of the remaining patients who will spontaneously convert to sinus rhythm will do so within 48 hours of onset [20]. Indications for hospitalization Often, the first question that a clinician must ask when dealing with a newly diagnosed case of atrial fibrillation is whether the patient warrants in-hospital evaluation and treatment. Patients who demonstrate hemodynamic or cardiovascular instability certainly require immediate stabilization and hospitalization for management. In addition, patients who are difficult to rate-control, are at high risk for thromboembolism, or are highly symptomatic with their arrhythmia should be considered for hospitalization. Furthermore, if a patient is a candidate for early cardioversion, hospitalization can facilitate a rapid workup and either chemical or electrical conversion to sinus rhythm. Initial workup The initial workup of a patient presenting with a first detected episode of atrial fibrillation begins with a detailed history and physical examination (Box 2). The history should focus on symptoms associated with the arrhythmia, including any shortness of breath, dizziness, palpitations, or change in exertional capacity and their timing. Such a history helps the clinician gauge the severity of symptoms, as well as the duration of this and perhaps other previous episodes of atrial fibrillation. It is important to elucidate any precipitating factors and patient characteristics that increase the risk of thromboembolism with the presence of atrial fibrillation. The physical examination is focused on signs of atherosclerosis and heart failure, including arterial bruits and jugular venous distension, and a detailed heart examination. An electrocardiogram verifies the presence of atrial fibrillation. In addition, the electrocardiogram is checked for evidence of old myocardial infarcts, left ventricular hypertrophy, pre-excitation in the form of a delta wave, and baseline QT and QRS intervals in the event that an anti-arrhythmic drug is used. Blood is tested for thyroid function. If anti-arrhythmic drugs are to be used, renal and liver function are also checked. Chest radiograph is used to evaluate the lung parenchyma and pulmonary vasculature. Finally, a transthoracic echocardiogram is part of the basic evaluation of a patient who has newly identified atrial fibrillation. Echocardiographic evaluation of the pericardium, valvular structures, left ventricular size and function, and atrial sizes can provide clues regarding the underlying cause, and help assess the risk of thromboembolism, and the risk of future recurrence [1].

7 ATRIAL FIBRILLATION 1089 Box 2. Initial workup for patients with first detected atrial fibrillationdminimum evaluation 1. History and physical examination, to define The presence and nature of symptoms associated with arterial fibrillation (AF) The clinical type of AF (first episode, paroxysmal, persistent, or permanent) The onset of the first symptomatic attack or date of discovery of AF The frequency, duration, precipitating factors, and modes of termination of AF The response to any pharmacological agents that have been administered The presence of any underlying heart disease or other reversible conditions (eg, hyperthyroidism or alcohol consumption) 2. Electrocardiogram, to identify Rhythm (verify AF) Left ventricular (LV) hypertrophy P-wave duration and morphology or fibrillatory waves Pre-excitation Prior myocardial infarction (MI) To measure and follow the RR, QRS, and QT intervals in conjunction with anti-arrhythmic drug therapy 3. Chest radiograph, to evaluate The lung parenchyma, when clinical findings suggest an abnormality The pulmonary vasculature, when clinical findings suggest an abnormality 4. Echocardiogram, to identify Valvular heart disease Left and right atrial size LV size and function Peak right ventricular (RV) pressure (pulmonary hypertension) LV hypertrophy Left atrial (LA) thrombus (low sensitivity) Pericardial disease 5. Blood tests of thyroid function For a first episode of AF, when the ventricular rate is difficult to control, or when AF recurs unexpectedly after cardioversion From Fuster V, Ryden LE, Asinger RW, et al. ACC/AHA/ESC guidelines for the management of patients with atrial fibrillation. J Am Coll Cardiol 2001; 38(4):1266xvii; with permission.

8 1090 ZIV & CHOUDHARY Management The main decisions in the management of atrial fibrillation involve therapy for rate control, conversion to sinus rhythm, and need for anticoagulation (see Fig. 1). Rate control. In the absence of obvious instability, the initial focus is rate control (Table 3). The majority of patients require therapy for rate control First Detected Atrial Fibrillation Work-up for reversible causes Hemodynamic instability, Chest pain, suspicion for WPW Patient is stable Urgent Cardioversion Heart rate control with IV calcium channel blockers or beta-blockers Spontaneous Cardioversion Continued atrial fibrillation; start anticoagulation Low likelihood of remaining in sinus High likelihood of remaining in sinus Duration <48 hours and low suspicion for paroxysmal atrial fibrillation Duration > 48 hours or high suspicion for paroxysmal atrial fibrillation Cardioversion Unable to undergo TEE TEE pursued 4 weeks anticoagulation Atrial clot No atrial clot Cardioversion 4 weeks anti-coagulation post cardioversion Assessment of recurrence, stroke risk and Long-term anticoagulation Fig. 1. Approach to a first detected episode of atrial fibrillation. IV, intravenous; TEE, transesophageal; WPW, Wolff-Parkinson-White.

9 Table 3 Pharmocological heart rate control in atrial fibrillation Drug Control of acute episode Control of sustained atrial fibrillation Comments Calcium-channel blockers Diltiazem Verapamil Beta-blockers Esmolol Metoprolol 20-mg bolus followed, if necessary, by 25 mg given 15 min later. Maintenance infusion of 5 15 mg/hr 5 10 mg IV over 2 3 min, repeated once, 30 min later. Maintenance infusion rate is not reliably documented. 0.5 mg/kg of body weight IV, repeated if necessary. Follow with infusion at 0.05 mg/kg/min, increasing as needed to 0.2 mg/kg/min. 5-mg bolus IV, repeated twice at intervals of 2 min. No data on maintenance infusion. Oral controlled-release formulation, mg daily. Slow-release formulation mg once or twice daily. Not available in oral forms mg daily in divided doses. Propranolol 1 5 mg IV, given over 10 min mg in divided doses or in long-acting form. Digoxin mg IV or orally over 24 hrs in doses of 0.25 to 0.5 mg. Long-term control may be better with the addition of digoxin. Causes elevation in digoxin level. May be more negatively inotropic than diltiazem. Hypotension may be troublesome but responds to drug discontinuation. Useful if there is concomitant coronary disease. Non-cardioselective: use cautiously in patients with a history of bronchospasm mg daily. Renally excreted. Slow onset even if given IV, with less effective control than other agents, although may be synergistic with them. Poor efficacy for exertional heart-rate control. ATRIAL FIBRILLATION 1091

10 1092 ZIV & CHOUDHARY for atrial fibrillation with a rapid ventricular response. Older patients who have intrinsic conduction system disease may have rates under 100 beats per minute, and may even manifest bradycardia. Nondihydropyridine calcium channel blockers are widely used in their intravenous form to emergently control rapid ventricular rates associated with atrial fibrillation. Both verapamil and diltiazem can act to reduce heart rates immediately and safely [21,22]; however, both agents can produce hypotension and act as negative inotropes. Verapamil may have more negative inotropic effects than diltiazem [13], and is therefore often used as a second-line agent, when diltiazem therapy has failed. In patients who have systolic dysfunction, both agents should be avoided. Beta-blockers are also very effective in immediate rate control. They are often the first line of therapy in patients who have concomitant coronary artery disease caused by their anti-ischemic effects and in patients whose atrial fibrillation is driven by high sympathetic activity or hyperthyroidism [23]. Their use can be limited by bronchospasm in patients who have chronic obstructive pulmonary disease or asthma. In patients who have systolic dysfunction, betablockers are preferred over verapamil or diltiazem for immediate rate control because they have relatively less negative inotropic effect. Digitalis can be used for rate control without worsening systolic dysfunction or worsened hypotension. When it is used, digitalis should be loaded with a one milligram dose in the first 24 hours in divided doses of 0.25 or 0.5 mg. Its onset of action can take hours, and therefore initial use of beta-blocker or calcium channel blockers may be necessary. Furthermore, in the acutely ill patient who has a high sympathetic tone, the parasympathetically driven effect of digitalis may be minimal. Often this drug is used more successfully in combination with beta-blocking agents or calcium channel-blocking agents [24,25]. When rate-controlling atrial fibrillation with a rapid ventricular response, the clinician must be alert to the presentation of atrial fibrillation in a patient who has Wolff-Parkinson-White syndrome. These patients are often younger and present with an irregular wide-complex tachycardia. Use of atrioventricular (AV) nodal blocking agents in this circumstance is contraindicated, because it may cause preferential conduction down the accessory pathway. The accessory pathway usually has a short refractory period and allows extremely rapid ventricular rates that may degenerate into ventricular fibrillation. In this circumstance, the consultation of a cardiologist and use of intravenous procainamide is preferred. A scenario that most clinicians have faced is the presentation of a patient who has borderline low blood pressures and atrial fibrillation with a rapid ventricular response. Patients who have systolic blood pressures of 90 to 100 mm Hg and who demonstrate signs of sufficient end-organ perfusion and rapid ventricular rates present a dilemma. They appear stable currently, thus acute and emergent cardioversion seems inappropriately aggressive. Yet, there is concern that nodal blocking agents will create further

11 ATRIAL FIBRILLATION 1093 hypotension and destabilize the patient. In this circumstance, low-dose parenteral or intravenous beta-blockers or calcium channel blockers used cautiously can often reduce the ventricular rate and paradoxically improve blood pressure as a result of improved ventricular filling. Intravenous continuous drip of esmolol or diltiazem can be useful for careful titration with rapid termination in the case that hypotension is exacerbated. Alternatively, digitalis can be used if the patient is stable. Cardioversion. If atrial fibrillation is contributing to either hemodynamic or cardiovascular instability, including the presence of unstable angina, urgent cardioversion to sinus rhythm should be performed. Although no prospective studies can be used to guide the decision to cardiovert, most experts believe that all stable patients deserve at least one attempt at restoring sinus rhythm [26]. Restoration of sinus rhythm can simplify a patient s medical regimen and reduce symptoms. The initial consideration with cardioversion is whether the patient has a high likelihood of maintaining sinus rhythm. If the specific precipitant of atrial fibrillation is still present, cardioversion to sinus rhythm is often futile, with early recurrence of atrial fibrillation. Hyperthyroidism and sepsis exemplify presentations in which early recurrence is often seen. In addition, echocardiography can identify patients who have a high likelihood of recurrence by assessing left atrial size, which is an independent predictor of recurrent atrial fibrillation. Compared to patients with normal left atrial size, patients with a left atrial diameter of 4 to 5 cm and greater than 5 cm have a 1.6 times and 4.5 times greater risk of atrial fibrillation recurrence respectively [27]. In patients who have an acceptable chance of remaining in sinus rhythm, the second consideration must be the safety of conversion to sinus rhythm. The concern is that if a clot exists in the left atrium, restoring sinus rhythm will facilitate the propelling of clot systemically. Furthermore, serial transesophageal echocardiography has demonstrated that even in patients who do not have left atrial thrombus at cardioversion, atrial stunning after cardioversion led to new thrombus formation [28]. When the duration of the fibrillation episode is known to be less than 48 hours, the risk of thromboembolic events after cardioversion, even without anticoagulation, is less than 1% [29]; however, most clinicians will anticoagulate such patients for 4 weeks after cardioversion, because the cardioversion itself is believed to create a prothrombotic state [30]. In patients whose duration of atrial fibrillation is uncertain or is believed to be greater than 48 hours, restoration of atrial fibrillation can only be safely pursued by two means. The more conservative approach includes systemic anticoagulation for 1 month, followed by cardioversion and the continuation of anticoagulation for at least 1 month thereafter. Alternatively, patients can be safely cardioverted after excluding the presence of left atrial thrombus by transesophageal echocardiography, followed by systemic anticoagulation for 1 month [31]. In the Assessment of Cardioversion Using Transesophageal

12 1094 ZIV & CHOUDHARY Echocardiography (ACUTE) trial, these two methods were compared in a randomized prospective manner. There was no difference in mortality or thromboembolic events between the two treatment groups, suggesting that either method is acceptable. In both groups, the stroke rate was less than 1% [32]. If a patient suffers from few symptoms with good rate control and there are concerns about the efficacy or safety of a cardioversion attempt, it is acceptable to opt for rate control only. Cardioversion requires the consultation of a cardiologist, and can be achieved through either electrical or pharmacological means. Electrical cardioversion requires conscious sedation, and therefore the appropriate facilities and personnel to safely offer conscious sedation. Pharmacological cardioversion has been less effective than electrical cardioversion, and the medications used do carry a small risk of serious ventricular tachyarrhythmias; however, any facility with telemetry capability is adequate for pharmacological cardioversion [1]. Electrical cardioversion requires the delivery of direct current in synchrony with the native depolarization of the ventricle. Synchronization avoids the danger of delivering a shock on the terminal portion of the T wave, the R on T phenomenon, associated with the development of torsade de pointes. Success rates for electrical cardioversion vary from 70% to 90% for most patients. These success rates drop drastically for patients who have longstanding, persistent atrial fibrillation and severely enlarged left atria [1,4]. Patients who revert to atrial fibrillation are more likely to remain in sinus rhythm with subsequent cardioversion attempts if an anti-arrhythmic agent is used [33]. Pharmacological cardioversion is less effective in achieving sinus rhythm, but often may be more practical. All anti-arrhythmic medications carry a risk for pro-arrhythmia, and must be administered in a monitored setting with access to a defibrillator. Although there are few data to support the efficacy of AV nodal blocking agents such as calcium channel blockers or digoxin in cardioversion, there are sufficient data to support the use of Class Ia, Class Ic, and Class III anti-arrhythmic agents for the restoration of sinus rhythm (Table 4). Intravenous procainamide has been a popular choice for cardioversion because of its relative safety, and an efficacy of 20% to 60% in recent onset atrial fibrillation [1,4]. The Class Ic drugs, such as flecainide and propafenone, have demonstrated efficacy of 50% to 80% with oral loading [4]; however, Class Ic drugs are associated with increased mortality in patients who have structural heart disease [34]. The Class III anti-arrhythmic agents have a better safety profile in patients who have structural disease. Intravenous ibutilide has demonstrated nearly a 50% conversion rate, compared with a placebo conversion rate of less than 5%. It is more efficacious in atrial flutter than fibrillation. Cardioversion occurs within 30 minutes in 80% of successful cases. Its use is limited by the development of sustained torsade de pointes that occurs in about 2% of patients. Hence, it should be avoided in patients who have prolonged QT intervals [35]. Other Class III agents have lower success rates with cardioversion. Amiodarone is very safe in the

13 ATRIAL FIBRILLATION 1095 Table 4 Typical doses of drugs used to maintain sinus rhythm in patients with atrial fibrillation and possible side effects Drug Daily dosage Potential adverse effects Amiodarone a mg Photosensitivity, pulmonary toxicity, polyneuropathy, GI upset, bradycardia, torsade de pointes (rare), hepatic toxicity, thyroid dysfunction Disopyramide mg Torsade de pointes, HF, glaucoma, urinary retention, dry mouth Dofetilide b mg Torsade de pointes Flecainide mg Ventricular tachycardia, congestive HF, enhanced AV nodal conduction (conversion to atrial flutter) Procainamide mg Torsade de pointes, lupus-like syndrome, GI symptoms Propafenone mg Ventricular tachycardia, congestive HF, enhanced AV nodal conduction (conversion to atrial flutter) Quinidine mg Torsade de pointes, GI upset, enhanced AV nodal conduction Sotalol b mg Torsade de pointes, congestive HF, bradycardia, exacerbation of chronic obstructive or bronchospastic lung disease The drugs and doses given here have been determined by consensus based on published studies. Abbreviations: AV, atrioventricular; GI, gastrointestinal; HF, heart failure. a A loading dose of 600 mg per day is usually given for 1 month or 1000 mg per day over 1 week. b Dose should be adjusted for renal function and QT-interval response during in-hospital initiation phase. From Fuster V, Ryden LE, Asinger RW, et al. ACC/AHA/ESC guidelines for the management of patients with atrial fibrillation. J Am Coll Cardiol 2001;38(4):1266xxx; with permission. short term, but requires a long loading period and can be initiated in the outpatient setting. Its maximum efficacy may be seen in days rather than hours [1]. New pharmacological approaches to cardioversion in the future may allow for more effective and safer means of conversion. Anticoagulation. Finally, the clinician must decide whether to start longterm anticoagulation. This can be a difficult decision, because prospective data on the risk of thromboembolism with atrial fibrillation are based on paroxysmal or persistent atrial fibrillation. As the authors outline below, patients who have recurrent atrial fibrillation who do not have lone atrial fibrillation, should be considered for anticoagulation. The clinician is therefore forced to judge whether the patient is likely to have recurrence of fibrillation and is thus at risk for thromboembolism in the future. A common practice with a first-episode atrial fibrillation is to withhold long-term anticoagulation and follow the patient with serial Holter monitors to assess for recurrence of atrial fibrillation and quantify the atrial fibrillation burden. Intermittent rhythm monitoring, however, is likely to grossly underestimate

14 1096 ZIV & CHOUDHARY the occurrence of atrial fibrillation. Recent comparison of data from implantable devices and intermittent rhythm monitoring suggests that 24- hour monitoring done every 3 months still failed to detect 8% of patients who had more than an hour a day of atrial fibrillation recorded on an implantable device [36]. This significant underdetection compels the clinician to give serious consideration to anticoagulation in any patient presenting with a first episode of atrial fibrillation, and who demonstrates characteristics of increased thromboembolic risk. Postoperative atrial fibrillation The risk of atrial fibrillation after cardiac surgery ranges from 20% to 50% [1]. Although less is known about the risks of atrial fibrillation after noncardiac surgery, it is considered to be significantly less common [1,37]. After cardiac surgery, the peak incidence of atrial fibrillation reaches around 30% at day three and drops to less than 1% after day ten. Predictors of postoperative fibrillation include age, valvular disease, lung disease, previous atrial fibrillation, left atrial enlargement, withdrawal of beta-blockers or angiotensin-converting enzyme inhibitors preoperatively, use of adrenergic medication, and high levels of serum brain natriuretic peptide [1,38 40]. The tenuous hemodynamic state of postoperative patients and the surgical limitation on the use of anticoagulants render the care of these patients challenging at times. Furthermore, the high adrenergic state postoperatively can make the rate control extremely difficult. Use of perioperative beta-blockers is quite effective in reducing postoperative atrial fibrillation, achieving a threefold reduction in incidence [41]. In high-risk patients, oral loading doses of amiodarone for a week before surgery can be used as prophylaxis. [42,43]. Correcting low potassium and magnesium serum levels may help in preventing atrial fibrillation [37,38]. The recommendations for the treatment of postoperative atrial fibrillation are similar to those of any other first-detected or recurrent atrial fibrillation. If the episode lasts more than 48 hours, anticoagulation is highly recommended for the prevention of thromboembolic events. The risks of bleeding must be weighed against the risk of stroke. The decision to anticoagulate is usually made with the collaboration of the medical and surgical teams. Over 90% of patients who have atrial fibrillation after surgery convert to sinus rhythm spontaneously within 2 months [44]. For this reason, cardioversion is reserved for patients who exhibit hemodynamic compromise, or who are known to have had less than 48 hours of atrial fibrillation and are poor anticoagulation candidates. Recurrent atrial fibrillation Rate versus rhythm control When atrial fibrillation recurs, as in paroxysmal or persistent atrial fibrillation, two fundamental questions arise about long-term management:

15 ATRIAL FIBRILLATION 1097 whether to anticoagulate and whether to attempt to maintain sinus rhythm, the latter termed rhythm control. Until recently, anticoagulation and rhythm control were considered as alternative approaches. Patients who successfully reverted to sinus rhythm with therapy were usually taken off their anticoagulation regimen. Other patients who continued to be in atrial fibrillation were placed on long-term anticoagulation, and their ventricular rates were controlled. This approach was termed rate-control. Recently, two large trials, RAte Control versus Electrical cardioversion for persistent atrial fibrillation (RACE) and Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM), compared the cardiovascular event rates and overall survival of patients in rate and rhythm controlled groups [45,46]. In AFFIRM, no difference was found in mortality or ischemic stroke between the rate- and rhythm-controlled groups. The majority of patients in both groups were kept on warfarin through the trial. Furthermore, over two thirds of strokes in both groups occurred in patients who were taken off anticoagulation or whose anticoagulation was subtherapeutic. Indeed, a post hoc analysis of AFFIRM [47] revealed that warfarin use was associated with a twofold reduction in mortality. That same study found that sinus rhythm was also associated with a significant reduction in mortality, but the use of anti-arrhythmic drugs was not beneficial. In their discussion, the study authors postulate that the toxicity of current anti-arrhythmic drugs negates their mortality benefit of preserving sinus rhythm [47]. In the RACE trial, the rate-controlled group derived a benefit in the primary end point, a composite of death, stroke, and heart failure, driven by the difference in thromboembolic events. A post hoc analysis of RACE that has yet to be published is investigating the relationship between cardiovascular event rates and adequate anticoagulation in both patients who were in atrial fibrillation and those who were in sinus rhythm. Most experts believe that current means of rhythm control are inadequate, and that most patients who are being maintained in sinus rhythm have undetected episodes of atrial fibrillation, and thus are still at risk for thromboembolic events [48,49]. These two studies have important implications. First, anticoagulation and rhythm control are two separate issues. All patients who have recurrent atrial fibrillation who do not have lone atrial fibrillation should be considered for systemic anticoagulation for the reduction in their risk of stroke. The decision to attempt the maintenance of sinus rhythm is based on the patient s symptoms. If a patient is very symptomatic despite adequate rate control, reversion to sinus rhythm should be the goal. As one creates a new paradigm for the management goals of recurrent atrial fibrillation, however, one limitation of both RACE and AFFIRM must be carefully addressed. These studies included few patients who have New York Heart Association Class III and IV heart failure. These are the patients who suffer the most from the hemodynamic consequences of chronic atrial fibrillation. Therefore, in this population, rhythm control may confer a survival benefit. An ongoing trial

16 1098 ZIV & CHOUDHARY comparing rate and rhythm control in this heart failure population will aim at addressing this issue [48]. Finally, if less toxic means of maintaining sinus rhythm become available in the future, a repetition of these trials may yield different outcomes. Management An algorithm that can be used to approach patients who have recurrent atrial fibrillation is outlined in Fig. 2. Pharmacological therapies Rate control. If the decision is made to rate control the atrial fibrillation, oral nondihydropyridine calcium channel blockers or beta-blockers can be used as first-line therapy, with digitalis as a second-line therapy. Although it is easy to conceive how such strict rate control improves cardiovascular outcomes, currently no data exist to demonstrate improvement in morbidity or mortality. RACE II, which is currently under way, will compare clinical outcomes for more lenient rate control goals with strict rate control [48,50]. It is not infrequent to see patients who have adequate heart rates at rest but significant symptoms associated with minimal exercise. In such cases, use of an exercise treadmill test can unmask rapid ventricular rates and help in assessment of adequacy of rate control. In AFFIRM, the goal of rate control Recurrent Atrial Fibrillation Poor anti-coagulation candidate Good anti-coagulation candidate Start aspirin therapy Start warfarin Begin rate control with a betablocker or calcium channel blocker. Digoxin can be added for synergy. Rate control achieved and patient is symptom free Failure to achieve adequate rate control with conventional therapy Rate control achieved, but patient still suffers Monitor for heart failure symptoms or worsening Refer to cardiology for re-evaluation of rate control regimen and consideration for pacemaker placement or AV nodal ablation Refer to cardiology for assessment of anti-arrhythmic drug suitability Fig. 2. Approach to recurrent atrial fibrillation.

17 ATRIAL FIBRILLATION 1099 was resting heart rates less than 80 beats per minute, exercise heart rates of less than 110 beats per minute, and average rates of 100 beats per minute or less [50]. Anticoagulation. Regardless of the choice to rate or rhythm control, stroke prevention is a key component of the management of recurrent atrial fibrillation. A number of prospective trials have demonstrated the benefit in stroke prevention of systemic anticoagulation in patients who have atrial fibrillation [49]. Current recommendations state that patients 65 years of age and older or patients who have any of the risk factors for thromboembolic events noted earlier, who are considered safe for systemic anticoagulation, should be started on warfarin with the goal international normalized ratio (INR) of two to three (Table 5). An INR of 1.5 has been shown to be associated with a threefold increase in stroke rate, whereas no additional benefit was conferred by an INR of greater than 3 [51]. Patients who have valvular disease or mechanical valves are at highest risk of stroke with concurrent atrial fibrillation. These patients have a goal INR of 2.5 to 3.5. It is important to note that patients at high risk for bleeding complications and poor compliance were excluded from most trials [52,53]; therefore, the clinician must always balance the risk of life-threatening bleeding with the risk of stroke. In patients that are not candidates for warfarin, a daily 325 mg aspirin is recommended. The efficacy of aspirin in stroke prevention is not clear. Most of the initial stroke prevention trials included aspirin-treated arms as well as warfarin-treated arms. Several meta-analyses of these trials have since been undertaken. The results of these meta-analyses vary, depending on the methods used in pooling the data. Although most clinicians believe that there is benefit in the use of aspirin, the benefit is small, varying from 0% to 30% relative risk reduction. This marginal benefit is in contrast to the two- to fourfold reduction with warfarin use. When comparing warfarin directly with aspirin, the benefit of full-dose warfarin is still apparent, despite the increased risk of major bleeding risk. The use of full-dose warfarin over aspirin would prevent 23 strokes at the cost of nine major bleeds [49]. Table 5 ACC/AHA recommendations for warfarin or aspirin use for patients with atrial fibrillation based on age and associated risk factors Age Risk factors for stroke a Recommended therapy!65 None Aspirin therapy 65 or older None Warfarin therapy if bleeding risk is acceptable Any age One or more risk factors for stroke Warfarin therapy if bleeding risk is acceptable a Risk factors include: hypertension, diabetes, structural heart disease, previous stroke or transient ischemic attack, hyperthyroidism, and coronary artery disease.

18 1100 ZIV & CHOUDHARY With the small therapeutic window [51] but clear benefit in stroke reduction of warfarin when used appropriately, there continues to be great interest in safer alternatives. The direct thrombin inhibitors have recently gained much attention. Ximelagatran is a direct thrombin inhibitor that is renally excreted and has a dependable bioavailability with twice-a-day dosing. The Stroke Prevention Using Oral Thrombin Inhibitor in Atrial Fibrillation (SPORTIF) III trial demonstrated the equivalence of ximelagatran with dose-adjusted warfarin in stroke prevention [54]. Unfortunately, real concerns about the potential liver toxicity of this medication have halted its approval for long-term use by the Food and Drug Administration [55]. Clinical trials with other direct thrombin inhibitors, indirect thrombin inhibitors, and Factor Xa inhibitors are currently under way [56]. Lone atrial fibrillation. Lone atrial fibrillation is defined as atrial fibrillation in a patient less than 60 years of age who has no clinical or echocardiographic evidence of cardiopulmonary disease. This distinction is made because lone atrial fibrillation carries a lower risk for thromboembolic disease, and therefore has treatment implications. In the SPAF database, patients under the age of 65 without hypertension, diabetes, or previous stroke had an annual stroke rate of 1% and did not benefit from the use of anticoagulation therapy. These patients, who truly have lone atrial fibrillation, are kept on aspirin. Meta-analyses demonstrate that the benefit of aspirin appears more prominent in the younger populations in these trials [57 59]. Rhythm control. Some patients remain symptomatic despite adequate rate control. These patients tend to be the young, who may find that the loss of atrial contraction impairs their exertional tolerance; or the congestive heart failure patients, who rely on the atrial contribution to cardiac output. For these patients, chronic rhythm control may be an attractive option. Although a cardiologist is usually involved in most of the management decisions made in effort to maintain a patient in sinus rhythm, the authors will briefly review the current approaches to rhythm control of atrial fibrillation. If the decision has been made to pursue chronic rhythm control, the initial step is the restoration of sinus rhythm. Unfortunately, relapse of atrial fibrillation can occur as commonly as in 80% of those who successfully return to sinus rhythm [33]. When the maintenance of sinus to control of symptoms is viewed as essential, the use of chronic anti-arrhythmic agents may be needed. Because there are currently no data to support a mortality benefit from the maintenance of sinus rhythm, the efficacy and potential toxicities of antiarrhythmic agents must be carefully weighed to find a suitable regimen for each individual patient (Fig. 3). For long-term maintenance of sinus rhythm, amiodarone is likely the most effective agent. In a prospective randomized trial, amiodarone had half the recurrence rates of sotalol or propafenone. In this same trial, however, 2% of patients receiving amiodarone were taken off the drug because

19 ATRIAL FIBRILLATION 1101 Heart disease? No (or minimal*) Yes Disopyramide Procainamide Quinidine Flecainide Propafenone Sotalol Amiodarone, Dofetilide Consider nonpharmacological options HF CAD Hypertension Amiodarone Dofetilide Sotalol Amiodarone Dofetilide Disopyramide Procainamide Quinidine Yes Amiodarone LVH greater than or equal to 1.4 cm No Flecainide Propafenone Amiodarone Dofetilide Sotabol Disopyramide, Procainamide, Quinidine *For adrenergic atrial fibrillation, beta-blockers or sotalol are the initial drugs of choice. Consider nonpharmacological options to maintain sinus rhythm if drug failure occurs. HF indicates heart failure; CAD, coronary artery disease; and LVH, left ventricular hypertrophy. Fig. 3. Antiarrhythmic drug therapy to maintain sinus rhythm with recurrent atrial fibrillation. Approach based on the presence and type of heart disease. From Fuster V, Ryden LE, Asinger RW, et al. ACC/AHA/ESC guidelines for the management of patients with atrial fibrillation. J Am Coll Cardiol 2001;38(4):1266xxiii; with permission. of suspected pulmonary toxicity [60]. Indeed, the toxicity of long-term amiodarone use, though usually dose-dependent and reversible, has limited its use [4]. Recent data suggest that in long-term maintenance of sinus rhythm, propafenone is twice as effective as sotalol [61]; however, the use of propafenone, a Class Ic drug, is limited to patients who do not have structural heart disease. Sotalol, as a Class III agent and beta-blocker, is preferred in patients who have coronary artery disease, but should be avoided in heart failure patients because of its negative inotropic effects,. With congestive heart failure, amiodarone and dofetilide, another Class III drug, have demonstrated safety and constitute appropriate choices for treatment [1]. The use of dofetilide is limited to authorized practitioners and involves inpatient monitoring for a minimum of 3 days. Recently, a new Class III agent, azimilide, has demonstrated efficacy in cardioversion and maintenance of sinus rhythm in the heart failure population [62]. Although its safety profile and appropriate use still need to be delineated, it is a promising addition to the treatment options for the growing population who have concurrent heart failure and atrial fibrillation. The use of non-anti arrhythmic agents for the prevention of recurrent atrial fibrillation has also been a recent topic of great interest. In post hoc analyses of ACE inhibitor studies in heart failure patients, the use of ACE inhibitors was associated with a reduction in atrial fibrillation recurrence

20 1102 ZIV & CHOUDHARY [63,64]. It is difficult to discern whether this effect is a result of improved blood pressure control or of effects of ACE inhibitors on myocardial remodeling. Prospective randomized trials are currently underway to investigate this possible treatment modality. Nonpharmocological therapies Rate control: atrio-ventricular nodal ablation. Occasionally, patients either fail adequate rate control with maximized dosing of AV nodal blocking agents, or have too narrow a therapeutic window, alternating between symptomatic bradycardia and rapid ventricular rates. In these extreme cases, catheter ablation of the AV node and implantation of a permanent pacemaker can achieve heart rate control and improve patients symptoms [65]. In a post hoc analysis of the AFFIRM data set, 5% of patients required nodal ablation for to achieve adequate rate control [50]. Stroke risk reduction: atrial appendage isolation. Nonpharmocological methods of reducing stroke risk have focused on the occlusion of the left atrial appendage. As discussed earlier, transesophageal echocardiography data suggest the importance of the left atrial appendage in the pathogenesis of atrial clot in atrial fibrillation. Patients undergoing open heart surgery, who are poor candidates for warfarin therapy, can receive a surgical isolation of the left atrial appendage [1]. A percutaneous equivalent of such an isolation is currently being investigated. The Percutaneous Left Atrial Appendage Transcatheter Closure (PLAATO) trials have revealed promising early data with percutaneous left atrial appendage occlusion device [66,67]. This technique is very attractive for the atrial fibrillation patient who is at high risk for bleeding with any systemic anticoagulation. Rhythm control. With the toxicity profiles of these anti-arrhythmic agents and limited success in maintaining sinus rhythm, nonpharmacological means of maintaining sinus rhythm have recently received more interest. Atrial pacing can limit the occurrence of atrial fibrillation in patients who have permanent pacemakers in place. Pacing in the atrium may suppress potential sources of triggered activity and prevent the onset of fibrillation [4]. Implantable atrial defibrillators are being investigated, but remain impractical for wide use because of the discomfort associated with internal defibrillation and the large number of defibrillations that an individual would require [1,4]. In patients undergoing open heart surgery, the Maze procedure can be performed to prevent atrial fibrillation. By using a combination of incisions or cauterization to create barriers within the left atrium, the surgeon can reduce the left atrial tissue available for the propagation of fibrillation waves. It has demonstrated up to a 90% success rate in controlling atrial fibrillation [1]. Along with the risk of increased surgical and cardiopulmonary bypass time, the procedure can result in sinus and AV node dysfunction, at times requiring the implantation of a permanent pacemaker.