ATRIAL FIBRILLATION: Modern Concepts and Management

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Annu. Rev. Med. 2005. 65:475–94 doi: 10.1146/annurev.med.56.082103.104656 c 2005 by Annual Reviews. All rights reserved Copyright First published online as a Review in Advance on Oct. 13, 2004

ATRIAL FIBRILLATION: Modern Concepts Annu. Rev. Med. 2005.56:475-494. Downloaded from arjournals.annualreviews.org by Instituto Nacional de Ciencias Medicas & Nutricion Salvador on 10/24/05. For personal use only.

and Management Ashish Agarwal,1 Meghan York,1 Bharat K. Kantharia,2 and Michael Ezekowitz2 1

Department of Internal Medicine, Drexel University College of Medicine, Philadelphia, Pennsylvania 19102; email: [email protected], [email protected] 2 Division of Cardiology, Drexel University College of Medicine, Philadelphia, Pennsylvania 19102; email: [email protected], [email protected]

Key Words ablation

stroke, anticoagulation, antiarrhythmics, sinus rhythm, catheter

■ Abstract Atrial fibrillation (AF) is a common cardiac arrhythmia responsible for significant morbidity and mortality. In recent years, progress has been made in determining the genetic abnormalities that may lead to AF. New trials have shown that rate control and anticoagulation are acceptable as a primary treatment strategy in many patients who have a high risk of recurrence. Newer and safer antiarrhythmics are now available. Pacemaker and implantable cardiac defibrillator technology is rapidly evolving and may play a significant role in future treatment and prevention of AF. Direct thrombin inhibitors are likely to add a user-friendly option to the current standard therapy for stroke prevention.

INTRODUCTION In 1909, the affliction of pulsus irregularis perpetuus was captured electrographically by Einthoven’s galvanometer and linked to a pathophysiology: the fibrillations of the cardiac atria (1). Almost 100 years after this discovery, atrial fibrillation (AF) has become one of the most problematic emerging epidemics in cardiovascular disease because of its powerful impact on morbidity and mortality (2). The understanding and management of AF are evolving as never before owing to the availability of newer technologies and drugs. In this article, we discuss the genetics, mechanism, and causes of AF, the changing basic management strategy, newer concepts of prevention and treatment, and advances in prevention of stroke due to AF.

EPIDEMIOLOGY Atrial fibrillation is the most common sustained cardiac arrhythmia, affecting more than two million people in the United States (3). The increasing prevalence of AF 0066-4219/05/0218-0475$14.00

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Annu. Rev. Med. 2005.56:475-494. Downloaded from arjournals.annualreviews.org by Instituto Nacional de Ciencias Medicas & Nutricion Salvador on 10/24/05. For personal use only.

(4) is largely due an increasing elderly population, comorbidities, and perhaps lifestyle changes. The prevalence of AF increases from 0.5% in the age group 50– 59 y to ∼9% in those older than 70 y (5–7). The rate of hospitalization for AF has increased by 2–3 times in the past two decades (8). Gender and race influence the occurrence, AF being more frequent in male (1.5 times the frequency in female) (3) and Caucasian populations (6). There is some evidence that AF is more common in the winter and that the incidence increases as the temperature decreases (9).

GENOMICS Although AF is typically an acquired disease, ∼5% of patients may have a heritable form. Several studies of multigenerational kindreds have localized mutations to specific chromosomes, identified genes, and even demonstrated the associated functional protein product. The first study of familial AF determined 10q22-q24 as the genetic locus in certain families (10). Although the gene has not yet been identified, genes that code for ion channel proteins are potential candidates. Another group showed linkage to chromosome 6q14-q16 (11), although the exact gene remains to be determined. By working with yet another multigenerational kindred, researchers identified linkage to the KCNQ1 gene located at chromosome 11p15.5 (12). Functional analysis has demonstrated a gain-of-function mutation in KCNQ1 that encodes a potassium ion channel protein. This potassium channel is present on atrial myocytes and causes an increase in current density and faster activation, thereby decreasing both action potential duration and effective refractory period. This supports the hypothesis that alterations in cardiac cellular electrophysiology at the molecular level of ion channels play a role in induction and maintenance of AF. Genetic research in acquired disease has shown an association between the minK38G allele and clinical AF (13). This allele encodes another subunit protein at the same atrial potassium channel implicated in the KCNQ1 research. The identification of multiple genes associated with AF is consistent with the proposition that multiple primary molecular mechanisms are involved in altering the electrophysiological environment of the atria. This advancement in genomic delineation fortifies the notion that AF is both a multifactorial and genetically heterogeneous disease.

MECHANISM Many patients with AF have anatomically and histologically abnormal atria. The atria may be dilated, with fibrosis, abnormal muscle fibers, and healthy atrial muscle fibers coexisting in close proximity (14). This results in a difference in refractory period within the atrial tissue and promotes reentrant mechanisms. A shorter effective refractory period promotes AF. One mechanism of AF is the fractionation of a mother wave into daughter wavelets; in the presence of an enlarged atrium, a short refractory period, and slow conduction, this leads to a sustained AF (15, 16). The other mechanism is the presence of foci that discharge either continuously,

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leading to sustained AF, or in short bursts, triggering AF that is sustained by the first mechanism. These foci are commonly found in patients with paroxysmal AF and a structurally normal heart and are a target for ablation therapy. Depending on the pattern, AF is classified as a single episode, paroxysmal (recurrent but selfterminating), persistent (recurrent and not self-terminating), or permanent (present all the time) (17).

ASSOCIATIONS Atrial fibrillation can have cardiac or noncardiac causes. Elimination of the precipitating cause can lead to conversion to sinus rhythm (SR) without any cardiac intervention. When AF occurs in absence of any demonstrable underlying disease, it is known as “lone AF” (Table 1).

MANAGEMENT Competing Clinical Strategies: Maintenance of Sinus Rhythm Versus Rate Control and Anticoagulation The most common approach to AF is conversion to and maintenance in SR. The justification for this approach is that it should decrease symptoms, increase cardiac output (20), improve exercise tolerance, prevent tachycardia-induced myopathy, TABLE 1 Conditions associated with atrial fibrillation Cardiac causes

Noncardiac causes

Myocardial infarction Inflammation pericarditis and myocarditis Arrhythmias Wolff-Parkinson-White syndrome, atrio-ventricular (AV) reentrant and AV nodal reentrant tachycardia, sick sinus syndrome Enlarged left atrium Valvular disease mitral stenosis, mitral valve prolapse Hypertension especially with left ventricular hypertrophy (19) Cardiomyopathy hypertrophic obstructive, dilated, and restrictive cardiomyopathies Others cardiac tumors, atrial septal defect, cor pulmonale, idiopathic dilation of the right atrium

Hyperthyroidism Sleep apnea syndrome Cardiac-thoracic surgery (18) Alcohol consumption Electrocution Pulmonary embolism Restrictive lung disease Heredity “Lone AF”—no underlying cause

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TABLE 2 Trials comparing rate versus rhythm control in atrial fibrillation Trial∗ (Reference)

Results (rate control versus rhythm control)

AFFIRM (21) n = 4060

No significant difference in primary endpoint (all-cause mortality) (21.3% vs 23.8%) p = 0.08

RACE (22) n = 522

Rate control was not inferior to rhythm control (17.2%–22.6%) in occurrence of primary end point (composite of cardiovascular death, thromboembolism, hospitalization, serious bleeding, pacemaker implantation, severe drug reaction)

PIAF (23) n = 252

No significant difference (60.8% vs 55.1%) in primary end point (improvement in symptoms) p = 0.3

STAF (24) n = 200

No significant difference (6.09%/y vs 5.54%/y) in primary end point (composite of death, cerebrovascular event, CPR, and embolism) p = 0.99

∗ AFFIRM, Atrial Fibrillation Follow-up Investigation of Rhythm Management; RACE, Rate Control versus Electrical Cardioversion; PIAF, Pharmacological Intervention in Atrial Fibrillation; STAF, Strategies of Treatment of Atrial Fibrillation.

lower the risk of stroke and thromboembolism, reduce mortality, and improve quality of life. However, this traditional strategy is associated with a significant failure rate and side effects. It has been challenged by newer trials (Table 2) comparing the strategy of SR maintenance to heart rate control and anticoagulation. The results of these trials have consistently shown that in patients who are likely to have recurrent AF, rate control is as acceptable as rhythm control. Attempts to maintain SR resulted in more adverse reactions and hospitalization in the rhythm-control group (21). It is also noted that a large proportion of patients in the rhythm-control group were not in SR. In both groups, the majority of strokes occurred after warfarin had been stopped or when anticoagulation was inadequate, with subtherapeutic international normalized ratio (INR). Based on these trials, in patients who are likely to have recurrent AF, rate control and anticoagulation seems to be the most appropriate strategy.

Cardioversion New-onset AF (24–48 h) has the highest rate of spontaneous cardioversion to SR—as high as 50%–70% (25, 26)—and may not require intervention for rhythm control. Thus, any intervention should have a high efficacy and rapid action to result in a clinically meaningful outcome for these patients. However, patients with persistent AF have a low rate of spontaneous cardioversion and may benefit from electrical or pharmacological cardioversion. Electrical cardioversion is recommended if the patient is unstable because of hypotension, cardiac ischemia, or heart failure attributable to AF. It requires hospitalization and sedation, and can cause myocardial injury, arrhythmias, and local side effects such as skin burns and muscle injury. Pharmacological cardioversion is less effective and more time-consuming than electrical cardioversion. Pharmacological

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agents such as sotalol generally need to be initiated in the hospital. The drugs can cause arrhythmias such as torsades de pointes and bradycardia. Pharmacological cardioversion is best if used within seven days of the onset of AF and is less effective in persistent AF. Any form of cardioversion is associated with risks of thromboembolism. The main agents available for pharmacological cardioversion are the class Ic, III, and Ia antiarrhythmics (Table 3). The important issues to consider before using these drugs are patient profile, duration of AF, and efficacy and safety of the drug. These agents are more effective in recent-onset AF than in persistent AF. Their efficacy may be related to the route of administration, dose, and rapidity of administration. It is, however, difficult to compare different agents because various trials have used different agents at different dosages. Flecainide and propafenone are commonly used class Ic agents. Both drugs have similar efficacy, and their intravenous forms act more quickly than oral forms. Propafenone is superior to oral amiodarone or quinidine. Class Ic drugs are the most efficacious drugs in cardioversion of recent-onset AF; however, their efficacy is much lower in cardioversion of persistent AF. Patients need to be carefully selected to avoid proarrythmic side effects. Class Ic drugs should not be used in patients


PHARMACOLOGICAL CARDIOVERSION

TABLE 3 Pharmacological agents for conversion of atrial fibrillation (AF) to sinus rhythm ∗

Drug (References)

Efficacy in cardioversion

Comments

Propafenone (27–32)

79%–86% in recent-onset AF

Avoid in structural heart disease, low LVEF, COPD, unstable patients

Flecainide (33–36)


Avoid in structural heart disease and low LVEF

Amiodarone (37–38)

26% in persistent AF

Successful within 24 h; patients need monitoring for side effects if on long-term therapy; may be used in CHF

Dofetilide (39–42)

30% in persistent AF

May be used in patients with MI and CHF; needs in-hospital initiation

Ibutilide (43–47)

27%–31%

Pretreatment with ibutilide can lead to more successful electrical cardioversion

Quinidine (48–49)


Not a first-line agent owing to side effects

∗ Abbreviations: LVEF, left ventricular ejection fraction; COPD, chronic obstructive pulmonary disease; MI, myocardial infarction; CHF, congestive heart failure.

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with structural heart disease or abnormal ventricular function because of the high risk of arrhythmias. Amiodarone, dofetilide, and ibutilide are the commonly used class III drugs (Table 3). Amiodarone and dofetilide are more useful in cardioversion in persistent AF. Although amiodarone is used frequently, it is only modestly effective in cardioversion (∼25%), and cardioversion may not occur for days to weeks. Its long-term use is associated with side effects that lead to withdrawal from treatment and needs regular monitoring, but it can be highly effective in some cases. Dofetilide is administered orally, and its efficacy for cardioversion (∼30%) is similar to that of amiodarone. In-hospital initiation is necessary so that QTc interval and arrhythmias can be monitored. Dofetilide is faster acting than amiodarone (90% of patients cardiovert within 36 h with dofetilide) and has been shown to be safe in patients with myocardial infarction (MI) or congestive heart failure (CHF), the two groups that are at a higher risk of developing proarrhythmic side effects. Intravenous ibutilide is moderately effective (30%–40%) in cardioverting AF (43). An effect may be expected within 1 h after administration. It has been shown to be superior to procainamide (44) and sotalol (45) but has no advantage over amiodarone in terms of efficacy (46). Pretreatment with ibutilide prior to electrical cardioversion can lead to a very high (100% in one study) rate of conversion to SR and at the same time decrease the amount of energy needed for cardioversion (47). Quinidine is a class Ia drug used orally after ventricular response has been controlled. It is effective in cardioverting 60%–80% of episodes of recent AF. Clinical response may be expected 2–6 h after administration. However, it is not used routinely because it is associated with significant adverse effects (including sudden death), and drugs with similar efficacy and fewer side effects are now available. Esmolol is a short-acting intravenous beta blocker that can be used in postoperative patients with high adrenergic tone (50). Digoxin (51–53), calcium channel blockers, and other beta blockers have not been shown to be effective in cardioversion. Sotalol is currently not recommended for cardioversion athough a recent trial has yielded promising results. Electrical cardioversion has been used since the 1960s for managing arrhythmias. Direct-current cardioversion involves delivery of an electrical shock synchronized with the intrinsic activity of the heart, usually by sensing the R wave of the electrocardiogram. Successful cardioversion of AF depends on the nature of the underlying heart disease and the current density delivered to the atrial myocardium. Rates of electrical cardioversion of AF vary from 70% to 90%. Rectilinear biphasic waveform is more likely to be successful and requires less energy than sine-wave monophasic waveform in cardioversion (94% versus 79%) (54). Using higher initial energy (200 J for biphasic and 300– 360 J for monophasic) (55) also results in fewer shocks and less energy overall. Pretreatment with ibutilide just before cardioversion increases the success rate to as high as 100%. Short duration of AF, presence of atrial flutter, and younger age

ELECTRICAL CARDIOVERSION

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are predictors of success, whereas left atrial enlargement, atrial ectopy, underlying heart disease, and cardiomegaly are predictors of immediate recurrence. Transesophageal echocardiography (TEE) is the most sensitive and specific technique for detection of left atrial thrombus (56). Compared to transthoracic echocardiogram, TEE provides a much better view of the left atria/left atrial appendage (LA/LAA). TEE is used in AF to stratify the risk of stroke and to guide cardioversion. Traditionally, patients are anticoagulated for 3–4 weeks prior to cardioversion to prevent embolism. Now, LA/LAA thrombus can be easily ruled out using TEE, and patients can undergo immediate cardioversion. Both strategies have similar rates of thromboembolism (90% of selected patients. The principle behind the procedure is that the creation of barriers to conduction in the atrium will prevent the propagation of reentrant wavefronts, thereby inhibiting sustained AF. This is generally achieved by surgically creating scars in the left atrium and isolating pulmonary veins. The maze-III procedure is a more refined version that is currently used (70). The mortality rate of an isolated maze operation is 1%–2%. Sinus node dysfunction due to disruption of blood supply may occur, necessitating permanent pacemaker implantation. This procedure is indicated in highly symptomatic, drug-resistant AF or in patients with thromboembolism due to AF while on warfarin. It can also be done as an add-on to other cardiothoracic surgery.

SURGICAL TECHNIQUES

Arrhythmogenic foci in pulmonary veins, right atrium, left atrium, superior vena cava, and coronary sinus may initiate AF (71). The selection

CATHETER ABLATION

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of catheter-based radiofrequency ablation of these foci (Figure 1), pulmonary vein isolation, or compartmentalization of atrium using linear ablation (72) depends on the underlying electrophysiology. Pulmonary vein isolation can be done using either three-dimensional nonfluoroscopic electroanatomical mapping (CARTO) (73) or circular mapping (74, 75). These procedures can be successful in up to 80% of patients who have a structurally normal heart and undergo single-focus ablation or pulmonary vein isolation (76). The success rate in more persistent AF is ∼60%. The risk of recurrent AF could be as high as 30%–40%, primarily in the first few months after ablation, and is more common in patients with multiple foci or abnormal atrium. Thus, patients may continue to require antiarrhythmic medications after radiofrequency ablation. Complications of catheter ablation for AF include pericardial effusion and tamponade, systemic embolism, pulmonary vein stenosis, and phrenic nerve palsy. In recent years, catheter ablation has been made easier with the introduction of intracardiac echocardiography (ICE). Use of ICE has led to better definition of intracardiac anatomy, easier transseptal puncture, precise positioning of catheters at pulmonary vein ostium, detection of catheter migration during ablation, detection of pulmonary vein stenosis, and early detection of pericardial effusion. ICE also allows titration of radiofrequency energy. Overdrive pacing is one of several methods of AF suppression that are currently being investigated. Atrial pacing influences the pattern of atrial depolarization and suppresses premature atrial beats, which trigger episodes of AF. Initial trials have shown that atrial pacing reduces the number of episodes of AF in patients with paroxysmal AF. In patients with standard indications for pacemaker therapy, the risk of AF decreases more with atrial than with ventricular pacing. There are a multitude of trials involving atrial pacing but so far no conclusive evidence has emerged about its role in AF prevention (77). This mode of therapy remains controversial.

SUPPRESSION OF AF BY ATRIAL PACING

The idea of an atrial defibrillator has been investigated for the past few years. It is known that delivering a synchronous shock between the high right atrium and coronary sinus is effective for the termination of AF (78). Implantable cardiac defibrillator (ICD) technology has improved significantly in recent years. The addition of atrial tachyarrhythmia detection, preventive pacing algorithms, and atrial defibrillation has led to the development of ICD devices that can not only detect and treat AF but also prevent it. These ICDs differentiate between atrial tachycardia and AF and treat them with different algorithms. AF is treated with either 50-Hz burst pacing or a series of programmable defibrillating shocks. Recent clinical trials (79, 80) evaluating different devices have shown that these devices have a positive predictive value of >90% for detection of AF. High-frequency burst pacing was effective in terminating AF in 23%–30% of AF episodes, whereas defibrillation was effective in 74%–86%. Dual atrioventricular defibrillators have been demonstrated to be safe and effective in treating AF

INTERNAL ATRIAL DEFIBRILLATORS

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patients with and without coexisting ventricular tachyarrhythmias. Patients with recurrent, drug-resistant, highly symptomatic AF are potential candidates for these devices. Dual atrioventricular defibrillators are not indicated for short or frequent paroxysms of AF. One common problem is the discomfort and resulting anxiety associated with the shock. However, the devices can be programmed for manual cardioversion (in which the patient uses a small, handheld activator) or for automatic timed cardioversion. This flexibility has reduced the incidence of anxiety associated with shock and pain. Although clinical experience so far is limited, this promising technology may provide relief to a small but significant number of eligible patients. Recently, there has been a growing interest in the “hybrid approach” (81) to treatment of drug-refractory AF. This approach uses a varying combination of pharmacological agents, ablation, pacing, and atrial defibrillation. Initial pilot studies, though methodologically different, are encouraging. The hybrid approach is still in development and will require further refinement of both the protocol and technology, better definition of the eligible patient population, analysis of cost and benefits, and determination of long-term adverse effects.

THE HYBRID APPROACH

Heart Rate Control An alternative to maintenance of SR in patients with paroxysmal or persistent AF is control of ventricular rate. The rate is considered controlled when it is between 60 and 80 beats per minute at rest and between 90 and 115 beats per minute during moderate exercise. The adequacy of rate control during AF can be determined from clinical symptoms and ECG recordings. Control of heart rate at rest does not ensure the same during exercise, and excessive rate acceleration can occur during even mild exercise. Rate control therapy of AF depends mainly on suppression of conduction across the AV node, and hence drugs that prolong the effective refractory period of the AV node are the ones that are generally effective. Sinus bradycardia and heart block may occur in some patients, particularly the elderly, as an unwanted effect of pharmacological intervention with beta blockers, digoxin, or calcium channel antagonists. For rapid control of ventricular response in acute AF, short-acting intravenous agents are used. Calcium channel blockers (generally diltiazem) and beta blockers are the first choice but digoxin and amiodarone are also used. The response to diltiazem is transient, and repeated doses or a continuous intravenous infusion may be necessary to maintain heart rate control. It should be used cautiously in patients with heart failure or low left ventricular ejection fraction (LVEF), but is preferred in chronic obstructive pulmonary disease (COPD). Intravenous beta blockers may be particularly useful in states of increased sympathetic activity. Short-acting esmolol in particular helps careful titration of heart rate. This class should not be used in patients with severe COPD or decompensated

PHARMACOLOGICAL AGENTS

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heart failure. Intravenous digoxin may effectively slow the ventricular rate at rest, but there is a delay in the onset of a therapeutic effect in most patients, and a peak effect does not develop for up to 6 h. The combination of digoxin and atenolol can be used to control ventricular rate. Intravenous amiodarone is effective and well tolerated in critically ill patients and those with heart failure who develop rapid AF. In persistent AF, when rate control is the mainstay of treatment, oral forms of beta blocker, calcium channel blocker, and digoxin are generally used. Because digoxin is unable to control heart rate during exercise, it is generally combined with beta blocker (82) or a calcium channel blocker. Given the availability of more effective agents, digoxin is no longer the first choice except in patients with heart failure or LV dysfunction.

Some patients may have a variable heart rate (e.g., sick sinus syndrome) or may develop bradycardia in response to rate control treatment. These patients may be candidates for ventricular pacing combined with rate control agents. AV nodal ablation with permanent pacemaker implantation is highly effective in controlling heart rate and improving symptoms. This approach is generally indicated for patients who are inadequately rate-controlled on drugs (refractory AF), who develop unacceptable side effects to medications, or who are noncompliant. The strategy of AV nodal ablation and pacemaker decreases the incidence of palpitations, dyspnea, and fatigue by controlling the ventricular rate. It increases exercise tolerance (83, 84) but does not affect mortality (85). The limitations of this technique include the persistent need for anticoagulation, lifelong pacemaker dependency, and complications associated with permanent pacemaker insertion.

NONPHARMACOLOGICAL METHODS

Stroke Prevention The most worrisome complication of AF is stroke. The risk of stroke in patients with AF is 5.6 times greater than in patients in SR (86), and an estimated 60,000 people have strokes associated with AF each year in the United States alone. Approximately 70% of individuals with AF are between 65 and 85 years of age. This group is also at the highest risk of developing a stroke. The risk of stroke from AF increases significantly with age. In the age group 50–59 years, the risk of stroke is 1.5%; between 60 and 69 years it is 2.8%; between 70 and 79 years it is 9.9%; and between 80 and 89 years it is 23.5%. The risk of stroke is the same for paroxysmal and persistent AF. However, individuals younger than 65 years with lone AF do not have increased risk (0.5%–1.0% per year). AF is also associated with an increase in silent cerebral infarcts (87) and may be associated with cognitive dysfunction (88). The cognitive dysfunction may be related to the cerebral infarcts or may involve a mechanism that remains to be determined.

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AGARWAL ET AL. TABLE 5 Stratification of stroke risk in patients with atrial fibrillation and recommended prophylaxis Risk stratification

Prophylaxis

Any one of the following: Rheumatic valvular disease, hypertension, diabetes mellitus, age >75 y, prior TIA/CVA,∗ systemic embolus, moderate-to-severe left ventricular dysfunction

High risk

Warfarin

Age 65–75 y and no other risk factors

Intermediate risk

Warfarin or aspirin

Age