Outpatient Management of Atrial Fibrillation

Atrial fibrillation (AF) is becoming an increasingly frequent problem, due in large part to the aging of the population. In patients older than the age of 80 years, the community prevalence approaches 9%. Many patients with new onset of AF present as outpatients, some asymptomatically and others with complaints suggestive of hemodynamic compromise. The first tasks are to ensure adequate rate control and identify and attend to underlying precipitants and etiologies. The focus then shifts to design and implementation of a risk-adjusted program of stroke prophylaxis to counter the high risk of embolic stroke. Emerging advances in achieving rhythm control raise the issue of rate control versus rhythm control.

PATHOPHYSIOLOGY, CLINICAL PRESENTATION, AND COURSE (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 and 20)

The electrophysiology of AF is believed to involve spontaneous reentrant impulses originating from cardiac ganglionic plexuses at the junction of the pulmonary veins and left atrium. These impulses are thought to trigger pulmonary-vein muscle fibers, which, in turn, cause transmission to the left atrium. Enlargement and inflammation of the left atrium may help sustain these impulses. Persistence of AF shortens the refractory period of atrial muscle, which seems to enhance the propensity of the atrium to fibrillate. AF may occur in the context of underlying heart disease or as an isolated phenomenon in the absence of readily identifiable cardiac pathology; it may also arise in the setting of hyperthyroidism. Adverse consequences include systemic embolization and hemodynamic compromise. In the Framingham Study, onset of AF and heart failure were closely linked. Furthermore, the development of chronic AF corresponded with a doubling of cardiovascular mortality.

Often, AF begins as an intermittent process referred to as paroxysmal AF, but increasing frequency and duration can lead to atrial remodeling with fibrosis and myolysis, which is associated with chronic AF and refractoriness to restoration of sinus rhythm.

Atrial Fibrillation in the Context of Underlying Heart Disease

AF due to underlying heart disease may be paroxysmal or chronic. Paroxysms typically occur in patients with the tachycardia-bradycardia (sick sinus) syndrome or Wolff-Parkinson-White (WPW) syndrome and during exacerbations of cardiomyopathic, valvular, and ischemic forms of organic heart disease. Advanced states of these conditions often result in chronic AF.

Tachycardia-bradycardia (sick sinus) syndrome involves dysfunction of both the sinus node and the atrioventricular conducting system, often in conjunction with lack of an adequate escape mechanism in the setting of severe bradycardia. Characteristic presentations include episodes of AF with a slow ventricular response rate and bouts of severe bradycardia leading to syncope or near-syncope.

WPW syndrome presents with paroxysms of rapid AF and other supraventricular tachycardias, consequences of an accessory connection between the atrium and the ventricle (e.g., the Kent bundle) leading to preexcitation (short PR interval, delta waves). The AF may be associated with a very fast ventricular response rate facilitated by rapid antegrade conduction over the accessory conduction pathway. There may be a widening of the QRS, mimicking ventricular fibrillation. In rare instances, the rapid ventricular response can degenerate into true ventricular fibrillation and sudden death. Fortunately, the risk of such serious ventricular dysrhythmias is very low in previously asymptomatic WPW patients, in part because the accessory pathways tend to lose antegrade conductivity over time.

Preexisting valvular, ischemic, or cardiomyopathic heart disease makes for increased risk of AF. Patients with such underlying pathology may experience a paroxysm of AF triggered by an acute insult (e.g., acute heart failure, ischemia, fever, infection, hypoxia, or hypovolemia). Correction of the precipitant often results in at least a temporary return to sinus rhythm. If the underlying condition continues unabated, paroxysms of AF may become more frequent and prolonged, culminating in chronic AF. AF is particularly common in patients with mitral valve disease, due to the early onset of increased left atrial pressure and resultant dilatation. AF is much less common in disease of the aortic valve; its development signifies advanced disease (see Chapter 33). Increases in pulse pressure indicative of aortic stiffness increase the risk of AF, presumably by increasing cardiac load.

Lone Atrial Fibrillation

Lone AF is characterized by the occurrence of AF in the absence of clinically evident heart disease or cardiovascular risk factors. In about two thirds of cases, the condition presents as isolated or recurrent episodes of paroxysmal AF; in the remainder, the AF is chronic. Survival rates and stroke risks are similar regardless of whether the lone AF episodes are paroxysmal or chronic. Lone AF may be annoying and sometimes frightening, but the key question is the risk of embolization that it confers. In patients younger than 60 years, survival and embolic risk are no different from those of a population of similar age; however, in patients older than 60 years, there is nearly a fourfold increase in relative risk of stroke, probably due to the increased probability of underlying cardiovascular risk factors in older patients with seemingly “lone” AF. Thus, lone AF appears to pose little risk, but only if the patient is relatively young and has no other cardiovascular risk factors. Recent study in idiopathic AF patients identified somatic mutations in the connexin 40 gene, which codes for an atrial gap junction protein believed to be important in atrial conduction. Such findings suggest a possible genetic molecular basis for the condition.

Apathetic Hyperthyroidism of the Elderly

Clinically inapparent hyperthyroidism may be mistaken for lone AF because there may be little evidence of organic heart disease, and the typical symptoms and signs of hyperthyroidism can also be absent. Sometimes, the clinical presentation more closely resembles depression or occult malignancy, with significant weight loss, marked apathy, and unexplained AF dominating the clinical picture. Diagnosis is made by ruling out underlying organic heart disease and finding the thyrotropin to be undetectable and the free thyroxin index or total triiodothyronine substantially elevated (see Chapters 8 and 103). Treatment directed at the hyperthyroidism usually terminates the AF. Although uncommon, this eminently treatable form of AF should not be missed. Stroke risk is minimal if there is no accompanying organic heart disease.

Alcohol-Induced AF

Alcohol excess has been implicated as a major precipitant of AF. Binge drinking may induce paroxysms of AF and ventricular dysrhythmias (so-called holiday heart disease). Although there may be no overt evidence of underlying heart disease, there is some debate as to how normal the hearts really are of patients who experience alcohol-induced arrhythmias. Chronic alcohol abuse can lead to alcoholic cardiomyopathy, which may present as paroxysmal AF during binge drinking. As drinking continues, the cardiomyopathy progresses, and the AF becomes more established. The condition is potentially reversible with total abstinence.

Atrial Flutter/Fibrillation

Atrial flutter, when occurring in the context of underlying heart disease, often shares much of the same pathophysiology and adverse consequences as atrial fibrillation. Being a characteristically unstable rhythm, it often degenerates into AF, referred to as “atrial flutter-fibrillation”. Stroke risk is substantial for persons whose atrial flutter is a consequence of hypertensive, valvular, ischemic, or cardiomyopathic heart disease, especially in the setting of reduced ejection fraction or prior AF.

Systemic Embolization and Stroke

Both epidemiologic and prospective studies have documented an increased risk of systemic embolization and stroke in patients with AF. Most emboli derive from thrombus formation due to stasis in the left atrial appendage. The resulting strokes are often large and particularly devastating. It used to be thought that increased risk applied only to patients with AF caused by rheumatic mitral valve disease (relative risk increased nearly 15-fold), but community-based studies have identified lesser but still significant increases (e.g., four- to fivefold) in stroke risk for all AF patients with underlying heart disease. Average stroke risk from AF in the absence of valvular heart disease approaches 5%/year.

Strong independent predictors of risk for stroke or systemic embolization in nonrheumatic AF patients include clinical congestive heart failure or systolic dysfunction, previous thromboembolism, systolic hypertension (>160 mm Hg), and age greater than 75 years in women. Prospective transthoracic echocardiographic (ECG) study confirms that left ventricular (LV) dysfunction is an independent predictor of stroke risk, and transesophageal echocardiographic (TEE) studies find that thrombus in the left atrium or left atrial appendage also powerfully predicts embolic risk.

Atherosclerotic risk factors (e.g., diabetes, smoking) also increase the risk of systemic embolization and stroke in persons with AF, perhaps by contributing to development of complex atherosclerotic plaque in the transverse portion of the thoracic aorta, found in TEE studies to be an independent risk factor for embolic stroke.

Data from the Framingham Study suggest that risk of stroke is greatest at the onset of AF, with greater than 25% of AF-associated strokes occurring shortly after onset. In addition, patients with AF have twice the likelihood of having a recurrence of stroke within the first 6 months compared with patients with stroke and no AF. Patients with paroxysmal AF have roughly the same stroke risk as those with chronic AF. Stroke risk with atrial flutter is lower than with AF, but many persons with atrial flutter subsequently go on to develop AF. Patients with pacemakers detecting runs of subclinical AF as brief as 6 minutes have a significantly increased risk of ischemic stroke and systemic embolization (hazard ratio, 2.46). Even in the absence of clinical stroke, AF is associated with a significantly increased risk of cognitive impairment.

Reduction in Cardiac Output and Risk of Death

The decrease in ventricular filling and loss of atrial contraction that result from AF lead to a fall in cardiac output and a rise in pulmonary capillary wedge pressure. When these are substantial, shortness of breath and reduced exercise tolerance may ensue. Rapid AF is especially likely to trigger hemodynamic compromise and heart failure. Cardiomyopathic changes are sometimes a consequence of rapid AF, further compromising cardiac output and exacerbating symptoms.

AF is often a predictor of reduced long-term survival. In the Framingham community study, persons with new onset of AF had a risk-factor-adjusted odds ratio for mortality of 1.5 for men and 1.9 for women compared with those in sinus rhythm. Similarly, in the Woman’s Health Study of otherwise healthy middle-aged women, new-onset of AF was independently associated with increased risks of all-cause, cardiovascular, and noncardiovascular mortality (hazard ratios, 1.42 to 2.57).

PRINCIPLES OF MANAGEMENT (21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62 and 63)

Before proceeding to address issues of management, it is important to confirm the diagnosis of AF (see Chapter 25). Many ECG recorders now come with software algorithms that automatically produce reports of rhythm disorders. Errors in diagnosis of AF are frequent; reported false-positive rates by such software algorithms approach 20%. Any automated reading needs confirmation by manual review of the relevant tracing.

Once AF is confirmed, the immediate tasks are determination of ventricular response rate, assessment of its hemodynamic consequences (heart rate being an important determinant of hemodynamic state and myocardial oxygen demand), and establishment of rate control. Whether to continue with rate control or attempt cardioversion requires consideration. Attention then turns to determining stroke risk and selecting an appropriate means of stroke prophylaxis.

Assessment of Ventricular Response Rate and Hemodynamic State

The acute assessment starts with checking quickly for symptoms and signs of hemodynamic compromise (e.g., exertional dyspnea, chest pain, light-headedness, systolic hypotension, tachycardia, tachypnea, vasoconstricted extremities, jugular venous distention, rales, third heart sound) in conjunction with ECG and chest x-ray. One needs to evaluate heart rate by checking the apical pulse (radial pulse may not be accurate) both at rest and after mild exertion (e.g., 5 to 10 sit-ups or standing up 5 to 10 times from a chair). Ventricular rate may appear wellcontrolled at rest when there is little adrenergic stimulation but rise markedly with mild effort.

Patients with little evidence of hemodynamic compromise and only modest elevation in ventricular response rate can continue their evaluation and management planning on an outpatient basis (see Chapter 25, Appendix). Cardiac ultrasound can be scheduled, being very informative for more detailed assessment of functional status and stroke risk (see later discussion). Those with evidence of hemodynamic compromise (e.g., hypotension, acute heart failure, acute ischemia) or extremely rapid ventricular response rate (>150 beats/min) require immediate hospitalization for consideration of intravenous pharmacotherapy or, if severely compromised, electrical cardioversion.

Rate Control (21, 22, 23, 24, 25, 26, 27, 28 and 29)

Rate control will improve cardiac function, help alleviate symptoms, and improve prognosis. By allowing for longer diastolic filling time and improving cardiac hemodynamics, one aims to reduce the stimulus for tachycardia-related remodeling and resultant cardiomyopathy. The traditional goal for ventricular response rate has been a resting apical pulse of less than 85 beats/min and of less than 110 beats/min after mild exercise. However, when more “lenient” rate control (<110 beats/min at rest) is compared in randomized controlled trial to strict rate control (<80 beats/min at rest) with respect to a composite cardiovascular outcome, patients in the “lenient” group fare just as well if not slightly better and require fewer visits. The finding underscores the importance of managing rate control with respect to clinical status and ejection fraction rather than treating to a target heart rate. Excessive rate-control efforts that make the patient symptomatic are as unwise as those that ignore rate control and put the patient at risk for tachycardia-related worsening of LV function.

Treatment is largely pharmacologic, although nonpharmacologic measures (e.g., atrioventricular node ablation with ventricular pacing) provide options in refractory situations. Pharmacologic options include beta-blockade, calcium channel blockers, and digoxin. Choice of agent is informed by consideration of the patient’s underlying pathophysiology.

Beta-Blockers

Beta-blocking agents and calcium channel blockers have supplanted digoxin as the drugs of choice for rate control in AF largely because of their superior efficacy in settings of high adrenergic stimulation. Beta-blockers slow ventricular response by increasing the refractoriness of the atrioventricular node and blocking the β-adrenergic effect of catecholamines on heart rate. Unlike digoxin, they do not require vagal tone to slow ventricular response rate, making them particularly useful when exercise, situational stress, hyperthyroidism, fever, hypoxemia, or ischemia is responsible for the tachyarrhythmia. Although negatively inotropic, beta-blockers may even be used with benefit (albeit cautiously) for AF in the setting of congestive heart failure (see Chapter 32).

Calcium-Channel Blockers

Like beta-blockers, a number of calcium channel blockers have proven useful for AF rate control, especially in the acute setting. Verapamil is the prototypical calcium channel blocker used in AF; its ability to prolong the refractory period and the conduction time of atrioventricular nodal tissue reduces the ventricular response rate. Diltiazem acts similarly, although not quite as potently; its advantage is less negative inotropy. Unlike digoxin, calcium channel blockers do not require vagal tone to be maximally effective, and consequently they control AF under circumstances that ordinarily would be refractory to digoxin (i.e., high sympathetic tone). Caution is required when using these calcium channel blockers in the setting of underlying LV failure or conduction system disease (e.g., sick sinus syndrome) because they may exacerbate failure or lead to extreme bradycardia. These agents are contraindicated in WPW syndrome due to their tendency to enhance conduction through the accessory pathway (see later discussion). Use of short-acting preparations in the setting of congestive heart failure is associated with an increased risk of cardiac death (see Chapter 32). In general, sustainedrelease formulations appear to be better-tolerated than shortacting ones (see Chapter 26), especially for continuous use.

Digoxin

Although no longer considered the cornerstone of pharmacologic therapy for AF, digoxin can still play an important role in rate control, especially in persons whose AF is a consequence of LV dysfunction (see Chapter 32). In the setting of a failing left ventricle, digoxin’s positive inotropic effects may help to lessen the stimulus for fibrillation. However, the drug’s dependence on vagal tone for full effect and the high level of adrenergic stimulation common to situations that trigger paroxysms of AF or worsen rate control conspire to limit its utility.

Limitations.

Digoxin tends to be ineffective in slowing heart rate when vagal tone is low and adrenergic stimulation is high, such as during exercise, stress, fever, hypovolemia, hyperthyroidism, ischemia, or hypoxia. Control may appear adequate at rest, but with exercise or other forms of sympathetic stimulation, the ventricular response rate rises precipitously. Moreover, in the absence of heart failure, digoxin neither restores sinus rhythm nor maintains sinus rhythm and does little to reduce the frequency and severity of paroxysmal AF episodes. Electrophysiologic studies show that the drug actually shortens the atrial refractory period and may contribute to the persistence of AF. By facilitating conduction through the bypass tract and shortening its refractory period, digoxin may exacerbate AF due to WPW syndrome. Careful case selection and close monitoring of therapy are critical to safe and effective digoxin use (see also Chapter 32).

Adverse Effects.

The narrow therapeutic index for digoxin also discourages its use. Subtle dysrhythmic manifestations of digitalis toxicity in the setting of AF include regularization of AF, a manifestation of junctional tachycardia, and frequent ventricular premature beats. The latter should not be confused on electrocardiogram with the widened QRS complexes caused by the Ashman phenomenon (prolonged relative refractory period in the beat after a long RR interval). Although ventricular response rate provides a “bioassay” of digitalis effect and makes frequent sampling of digoxin levels unnecessary, watching for changes in rhythm can be very informative. Whenever there is suspicion of digitalis toxicity, digoxin should be held and a serum level checked.

Choice of Agent

Selection of the proper agent for rate control requires an etiologic diagnosis (see Chapter 25). As noted previously, empiric therapy without regard for the underlying pathophysiology risks hemodynamic worsening. The importance of this principle is underscored by the approaches required to establish rate control in heart failure, WPW syndrome, sick sinus syndrome, and hyperthyroidism.

WPW Syndrome.

WPW syndrome requires special mention because of the small but important risk of hemodynamic compromise associated with the disorder and standard approaches to rate control. WPW patients with very rapid ventricular rates and hemodynamic deterioration during an attack of AF should be hospitalized, promptly referred to a cardiologist, and treated with urgent electrical cardioversion. WPW patients with occasional bouts of AF that are well-tolerated and self-limited require no treatment so long as the shortest RR interval during an attack is greater than 180 msec; a shorter interval is associated with an increased risk of ventricular fibrillation. No restrictions on activity are necessary. Digoxin and calcium channel blockers should not be used because they encourage conduction through the accessory pathway by blocking conduction through the atrioventricular node. Future episodes of AF are prevented by the use of antiarrhythmic agents such as amiodarone or radiofrequency ablation. Inpatient electrophysiologic testing is used to help judge which agent is most likely to provide optimal control of ventricular rate during AF. Beta-blockers are sometimes helpful in protecting against recurrent episodes of AF but should also be subjected to electrophysiologic study before being used in patients with potentially serious attacks of AF. Cardiac consultation is essential.

Tachycardia—Bradycardia (Sick Sinus) Syndrome.

Patients with the tachycardia-bradycardia form of sick sinus syndrome pose a therapeutic dilemma: Although their AF usually responds well to beta-blockade, verapamil, or digoxin, these therapies may seriously exacerbate episodes of bradycardia by further suppressing conduction through the atrioventricular node. Consequently, implantation of a demand pacemaker is often necessary for patients with symptomatic tachycardia-bradycardia syndrome.

Hyperthyroidism.

AF caused by hyperthyroidism responds best to beta-blockade, although definitive treatment of the underlying thyroid disease (see Chapter 103) is essential to successful prevention of future episodes of AF. At times, elective cardioversion (see later discussion) is necessary to restore sinus rhythm after successful treatment of the hyperthyroidism.

Heart Failure.

Patients with AF due to congestive failure may benefit from the judicious application of digoxin and betablockade. Both agents can slow ventricular response rate and enhance myocardial performance. Digoxin’s directly positive inotropic effects improve cardiac output in the failing heart while slowing conduction through the junction. Although betablockade is negatively inotropic, its ability to slow ventricular response rate and lessen myocardial oxygen demand may have the net effect of improving ventricular performance, particularly in persons with AF due to underlying ischemic heart disease (see Chapter 32).

Refractory Rapid AF.

Patients who fail to respond to or cannot tolerate pharmacologic therapy for rate control and remain symptomatic pose a problem. Options include cardioversion followed by measures to maintain sinus rhythm (so-called rhythm control; see later discussion) and ablation of the atrioventricular node in conjunction with placement of a permanent ventricular pacemaker. Ablation of the atrial reentrant circuit causing AF has been performed both surgically (the maze procedure) and by radiofrequency techniques during electrophysiologic study. With ablation, the atria continue to fibrillate (necessitating stroke prophylaxis; see later discussion), but ventricular function, exercise tolerance, and quality of life all improve, and there is no adverse effect on longterm survival. For pharmacologically refractory patients who require rate control but do not need the atrial boost to cardiac output, ablation remains an option if other measures fail.

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