Atrial fibrillation (AF) is the most common sustained arrhythmia observed in clinical practice, encountered in a variety of clinical settings including the ambulatory clinic, the emergency room, and inpatient units. It may occur in isolation, be precipitated by an acute and reversible cause, or complicate a chronic cardiovascular or noncardiovascular condition. The current prevalence in the United States is believed to be close to 2.5 million.

The ECG diagnosis of AF is made based on an undulating or oscillating pattern of atrial activity that is inconstant and disorganized and conducted with an irregularly irregular ventricular response. There is a distinct absence of regular, consistent and organized atrial activity. The inferior leads of the ECG are often helpful in distinguishing AF from other atrial arrhythmias that may have irregular ventricular rates such as atrial flutters (AFLs) and tachycardias.

AF is strongly age related. It infrequently presents below the age of 50 or 60, but is extremely common when patients reach the age of 80 and above (about one in ten). Population studies confirm the relationship of age in AF, independent of cardiovascular conditions (Fig. 3-1). It is likely that age-dependent atrial pathophysiologic processes are responsible for the increasing prevalence of AF relative to age. In addition, the success in treating chronic cardiovascular conditions such as hypertension and coronary heart disease makes AF more likely to occur in the elderly. In addition, population studies consistently observe that men are more likely to experience AF than women, with an increased prevalence of approximately twofold.

The development of AF in population-based studies was associated with an increased risk of death. This appeared to be independent of other known predictors of mortality but the specific underlying mechanism of death was unclear. Possible contributing factors may include the increased risk of stroke and heart failure associated with AF. Additional possibilities include coronary ischemia, systemic thromboembolic state, toxic drug therapy, and associated cardiovascular diseases.

Although most patients with AF have an associated cardiovascular condition, some patients have no known precipitating cause or associated cardiovascular disease, and in
these patients, AF is termed “lone” AF or idiopathic AF. Anywhere from 5% to 30% of patients with AF may fall into this category, depending on the setting. Although recent guidelines suggest that this terminology be phased out, it is commonly employed in clinical practice. It is thought that these patients may face a lower long-term risk of cardiovascular complications because of the absence of associated cardiovascular disease, although age-related risks are still important, especially that of age-related stroke risk.

The most common associated cardiovascular cause of AF in the Western world is hypertension, responsible for approximately 40% of cases of AF in most studies. Additional causes (Table 3-1) include coronary heart disease and acute myocardial infarction (MI), valvular heart disease, heart failure and cardiomyopathy, cardiac and valvular surgery, and pericardial diseases. Additionally, some noncardiovascular causes may precipitate AF including hyperthyroidism, acute and chronic pulmonary diseases, and toxic exposure, particularly excess alcohol intake.

Although rheumatic heart disease is seen much less frequently in contemporary medicine, the presence of mitral valvular disease is a potent risk factor for AF. The strongest association is found with mitral stenosis, and a less potent association is seen with mitral regurgitation. Although the risk of developing AF long-term is relatively small with coronary heart disease, its prevalence makes this an important risk factor for AF in the general population. In addition, AF may be seen in approximately 10% of patients in the early period after acute MI, usually in unstable patients with extensive myocardial damage when atrial injury has also occurred. AF in this setting is often short-lived but portends a worse prognosis.

AF is an extremely common postoperative finding in patients who have undergone all forms of cardiac surgery. Following coronary artery bypass surgery, AF may occur in approximately 20% to 25% of patients, but in valvular surgery, it may be seen in up to 40% of patients. Risk factors for the development of AF in this setting include age, left ventricular (LV) hypertrophy, right coronary artery bypass, intra-atrial conduction delay detected on signal-averaged ECG, and absence of β-blocker therapy. AF lengthens
hospital stay and may be associated with thromboembolic events. However, AF in this setting is generally transient, resolving within the hospital stay or shortly thereafter. The peak incidence occurs on postoperative days 2 to 3.

AF may be seen in patients who have overt or subclinical (occult) hyperthyroidism. The latter is particularly important to identify in the elderly patient. AF is associated with the significant risk of thromboembolic events in this clinical setting and rapid ventricular rates are often observed. AF is often difficult to control until the patient is rendered euthyroid.

AF may occur when patients have consumed large amounts of alcohol, i.e., binge drinking, giving rise to a “holiday heart syndrome.” There may be no underlying cardiac disease and the AF may be a transient phenomenon.

AF may occur episodically with spontaneous termination or prolonged and continuous requiring pharmacologic or electrical therapy for termination. The former is termed paroxysmal AF and generally self-terminates within 24 to 48 h. On other occasions, the AF may spontaneously terminate after a more prolonged period, often when the patient is on an antiarrhythmic drug program. AF that continues without spontaneous termination is categorized based on the duration of AF or the intentions of therapy. When AF has been present continuously for more than 7 days and up to 1 year, it is termed persistent AF. When AF has continued for longer than 1 year, when there has been failed efforts to restore and maintain sinus rhythm, and/or when sinus rhythm is no longer sought, this form of AF is termed permanent. A more recently developed category, long-lasting persistent AF, is reserved for a group of patients whose AF has lasted from 1 to 3 years but in whom efforts are being made to restore sinus rhythm usually by catheter ablation.

These categories are useful for clinical management because AF is a progressive condition, with patients often passing from one phase to another. Hence, AF patients can be further classified based on the first occurrence of AF or when a pattern is recurrent. Most, but not all, patients present with paroxysmal AF. The frequency and duration of AF is quite variable but often the AF burden increases over time and the patient will pass into a phase of persistent AF.

Because of underlying atrial pathophysiology (defined above), the overall pattern of AF opens a window into the likely progression of atrial remodeling; that is, the longer the AF has been present or the greater the burden, the more likely there has been progression of pathophysiologic substrate. The pace of progression of AF is highly variable, even among similar clinical conditions or even in the absence of underlying cardiovascular disease. However, paroxysmal AF will progress to more long-lived or permanent forms at a rate that may be in the range of about 5% per year.

AF may complicate the course of patients with a number of serious medical illnesses especially pneumonia, MI, viral pericarditis, and sepsis. The clinical presentation is dominated by these underlying conditions.

Much more frequently, patients present with AF as the primary event. They may be seen in the emergency room, an ambulatory care clinic, or be hospitalized. The most common symptoms include a sense of irregular or rapid heart beating, fatigue or weakness, dyspnea especially with exertion, angina-like chest discomfort, and light-headedness. Less frequently, patients describe polyuria and near syncope, and very rarely, syncope. Syncope may result from tachyarrhythmia but also from associated bradyarrhythmia, especially sinus bradycardia and pauses posttermination (“tachy-brady syndrome”).

Symptoms of AF are due to the underlying arrhythmic condition, namely irregular ventricular activation, rapid ventricular rate, and loss of atrioventricular (AV) synchrony. Any one or a combination of these three underlying mechanisms may play a role. In other words, some patients may not be tachycardic, and yet experience severe symptoms due to loss of atrial kick.

In particular, patients with severe cardiac conditions may have a more profound presentation. Irregular ventricular rates can compromise ventricular function. Rapid ventricular rates shorten diastole and thus interfere with ventricular filling and coronary perfusion. Loss of AV synchrony, and thus, the atrial kick can decrease stroke volume by up to 40% in patients who are dependent upon atrial systole for ventricular filling, such as patients with hypertrophic cardiomyopathy and congestive heart failure. Patients with hypertrophic cardiomyopathy sometimes present with extremely serious and life-threatening findings including hypotension and shock.

Many patients can describe the onset of symptoms, and thus with reasonable accuracy, clinicians can gauge the duration of the AF. Other patients have a more vague recollection of when symptoms had started and it is difficult to determine how long AF has been present. In these situations, concerns are increased regarding the development of atrial thrombus. Very importantly, up to one third of patients with AF have no symptoms whatsoever. In these patients, it is impossible to know how long they have had AF and in fact they may have had a varying pattern and long history of AF without diagnosis. In these patients, it is helpful to determine if they have had medical examinations and ECGs in the past so a window of AF duration can be calculated. This is an important issue because the longevity of AF, especially if present for more than 1 year, will greatly influence the likelihood for successful restoration and maintenance of sinus rhythm. Finally, even patients who have clearcut symptoms will have asymptomatic episodes intermixed with symptomatic ones; indwelling pacing devices have made this scenario abundantly clear.

The key to diagnosis is of course the electrocardiogram. Ideally, a 12-lead ECG should be obtained during symptomatic and asymptomatic arrhythmias. Multiple recordings are useful as many patients can experience more than one type of arrhythmia, for example, AF, AFL, atrial tachycardia (AT), and atrial ectopic beats. In some patients, ambulatory monitoring including transtelephonic ECG is useful to diagnose paroxysmal arrhythmias that occur in the outpatient setting. Prolonged monitoring is also useful to document the patterns of AF including whether AF is persistent, and the ventricular rates, especially during activities of daily living. Single-lead ECG recordings are less useful because at times they can be misleading and the underlying fibrillatory wave pattern may not be apparent or in other circumstances an organized atrial arrhythmia may be difficult to discern. Thus, multilead recordings or 12-lead ECGs are most useful.

Historical variables are critical to review including the symptoms described in the previous section and the AF frequency, duration, and initial onset. Classification of AF as described in a preceding section is critical for planning management. It should be recognized that even patients with symptomatic episodes will frequently have asymptomatic events as well. Additional historical variables that should be sought include the presence of cardiovascular conditions that can promote AF as well as noncardiovascular conditions that are associated with AF. The potential complications of AF, including neurologic incidents, should be elicited.

Besides historical variables, it is important to determine whether the patient has underlying heart disease, which at times may be occult or a secondary phenomenon related to the AF (e.g., tachycardia-induced cardiomyopathy). Thus, it is typically useful to perform an echocardiogram to evaluate ventricular function, valvular heart disease, and LA dimension. The latter will give insight into the mechanism of AF or may be indicative of the duration of AF as patients with prolonged AF often have progressive atrial dilatation. The LA has been shown to enlarge by about 5 mm in diameter over a 1-year observation period. LA enlargement (especially greater than 55 to 60 mm) has been associated with failure to maintain sinus rhythm after successful cardioversion.

Transesophageal echocardiography may be required to exclude the presence of atrial thrombus, specifically LA appendage thrombus, when a cardioversion is required and a patient has not yet had the requisite three consecutive weeks of therapeutic anticoagulation. The transesophageal echo is particularly useful to detect the presence of thrombus and more frequently the presence of spontaneous echo contrast or “smoke” which is a marker of stasis in the atrial chamber. The presence of thrombus is a contraindication for cardioversion but the presence of smoke is not. Nonetheless, stroke risk is increased in the presence of smoke and also in the presence of reduced LA appendage emptying velocity. Up to approximately 25% of patients with AF of more than a few days duration may have LA appendage thrombus if they have not been inadequately anticoagulated.

Additional cardiac tests can be individualized and include exercise testing, cardiac catheterization, cardiac magnetic resonance imaging (MRI), etc. EP study is generally not required for most patients with AF unless another primary arrhythmia is suspected (e.g., supraventricular tachycardia [SVT], Wolff-Parkinson-White [WPW] syndrome, AFL, or tachycardia) or if catheter ablation of AF or associated arrhythmias is planned (see below).

AF can have adverse consequences but the nature and frequency of complications vary, primarily related to underlying heart disease and age. Population studies such as the Framingham cohort have determined that patients with AF have an increased rate of death compared to counterparts in the population without AF. For men, the death rate is increased 1.5-fold and for women, 1.9-fold (Fig. 3-3). The cause-specific mortality composition is uncertain but may be related to an increased risk of stroke and its consequences, aggravation or precipitation of heart failure, worsening of coronary ischemia, development of a hypercoagulable state, ventricular electrical instability, complications and proarrhythmia from drug therapy, and other causes.

AF by virtue of rapid and/or irregular ventricular rates can contribute to LV dysfunction. A pure form of tachycardia-induced cardiomyopathy can exist when patients’ heart rates are excessive for much or all of the 24-h period. However, the proportion of
time and the degree of tachycardia that is required to precipitate LV dysfunction in a clinical environment is uncertain. Indeed, the diagnosis of tachycardia-induced cardiomyopathy must be made in retrospect; that is, when rate or rhythm control is achieved, there is improvement of the LV dysfunction and/or resolution of cardiomyopathy. A high index of suspicion should be maintained in all patients. An even more difficult scenario unfolds when patients have preexisting heart disease and superimposed AF, which can aggravate rather than create a cardiomyopathic process. This “impure” form of tachycardia-induced cardiomyopathy is even more difficult to recognize but should be considered possible in all such patients with a high index of suspicion. Thus, patients should not be allowed to have excessive ventricular rates without adequate control.

Patients with AF may have a risk of stroke and systemic thromboemboli. Cardioemboli resulting from AF are usually cerebrovascular rather than systemic (peripheral, splenic, etc). The risk of stroke is extremely variable and relates in large part to the presence of cardiovascular diseases and the patient’s age. In its most benign context, AF in the absence of cardiovascular disease and in a young patient, particularly when paroxysmal without atrial remodeling, is not associated with an increased risk of stroke relative to the general population (Fig. 3-4). Thus these patients with lone AF do not necessarily require chronic anticoagulation. However, in the setting of cardiovascular disease and advanced age (age 65 years and above), there is a measurably increased risk of stroke. The projected stroke risk is related to a number of risk factors (see below), and guidelines have been published based on a vast literature confirming the importance of chronic anticoagulation in these patients. AF is the most important cardiac cause for stroke and may account for approximately 15% of all strokes. The annual stroke rate in high-risk patients is estimated to be 5% to 8% per year. Stroke risk was historically thought to be similar for paroxysmal and persistent patterns of AF, although some recent data from anticoagulation trials have suggested paroxysmal AF may have lower stroke rates. Strokes that complicate AF are often dense, large, and permanent. Once a patient has experienced a stroke, the long-term prognosis is compromised. A stroke that occurs despite anticoagulation is often smaller than anticipated and more reversible, and these patients will have an improved prognosis relative to those who are unanticoagulated.

Because oxygen demand is governed in large part by heart rate, patients with underlying coronary artery disease may have aggravation of ischemia in the presence of AF. Patients who have AF have activation of the coagulation cascade, and it is conceivable that this hypercoagulable state may contribute to coronary thrombosis as well.

Antiarrhythmic drug therapy which is sometimes used for patients with AF may have a distinct long-term risk as well. Many antiarrhythmic drugs possess potent channel
blocking properties and may be associated with pro-arrhythmia in specific contexts. For example, class Ic antiarrhythmic drugs have a potent negative effect on outcome in patients with underlying coronary heart disease and LV dysfunction, but this concern should probably be extended to patients with LV dysfunction from any cause, coronary artery disease without LV dysfunction, and perhaps any patient with structural heart disease. Drugs that block the potassium channels may have a risk of torsade de pointes which can be life-threatening. Finally, the AFFIRM trial has indicated that a rhythm control strategy that employs antiarrhythmic drugs may be associated with an increased risk of noncardiovascular death over time in older patients treated for AF.

In most patients identified as having an increased risk of stroke and systemic thromboemboli, chronic anticoagulation is the cornerstone of therapy. An initial assessment of stroke risk is mandatory when the diagnosis of AF is made, repeatedly during follow-up as underlying cardiovascular conditions may change or as the patient ages. Multiple risk stratification schemes have been created, generally based on data accumulated in large multicenter trials of anticoagulation, and should be applied in clinical practice. One of the best validated schemas is the CHA₂DS₂-VASc risk index (Table 3-2). Using risk factors of congestive heart failure, hypertension, age 75 years or older, diabetes prior stroke or other thromboembolism, vascular disease, age 65 to 74 years, and female sex category, patients can have risk scores calculated between 0 and 9 points correlating with annual stroke risk (Fig. 3-5). One point is awarded for each one of these risk factors except for the presence of prior stroke/TIA and age > 75 years which are counted as two points. Current guidelines (Table 3-3) suggest that a risk score of 2 or greater necessitates long-term anticoagulation unless there is a specific and validated contraindication. A risk score of 1 is considered an optional indication for chronic anticoagulation.

Echocardiographic risk factors were not consistently obtained in large-scale clinical trials but may be of additional value as well. LA enlargement and LV dysfunction
have been identified as risk factors. The former may develop in patients with long standing AF who have no other risk factors, and some would consider this an indication that the LA is becoming structurally abnormal and may become a potential nidus for atrial thrombus.

Contraindications to chronic therapy are generally few or temporary. Multiple surveys have determined that physicians are overly cautious in administering anticoagulation therapy to patients at risk of stroke due to AF and may overestimate the risk of potential bleeding complications. This is especially true in the elderly who, although often at slightly greater risk of bleeding complications, also have a much greater risk of stroke due to their age and associated cardiovascular conditions. Contraindications to chronic anticoagulant therapy include rare hypersensitivity reactions, active bleeding or recent surgical procedures, bleeding diatheses, or serious hemorrhagic complication during therapeutic anticoagulation.

On the basis of the results of multiple randomized clinical trials chronic warfarin therapy had been the only antithrombotic therapy of choice in patients at risk of stroke. It has been determined that the INR is ideally maintained in a range of 2.0 to
3.0 to maximize therapeutic efficacy and limit bleeding risk. In general, these clinical trials have indicated an approximate two-thirds risk reduction of stroke if patients are treated with warfarin. If patients can be maintained on the therapeutic dose of warfarin on a consistent basis, the risk reduction may range as high as 80%. The risk of major bleeding is in the range of approximately 1% per year, most notably including intracerebral hemorrhage. Thus, clearly, the use of warfarin in patients must include a stroke risk that significantly outweighs this potential bleeding risk, and thus the use of the risk stratification schemes. The flip side of this argument is that patients who have little or no risk, such as those with lone AF at a younger age, are generally not candidates for anticoagulation except preceding (for 3 weeks) and following cardioversion (for 4 weeks).

Several clinical trials also tested the value of aspirin alone as an antithrombotic regimen and in general these trials found that aspirin did not provide statistically significant risk reduction although one large-scale trial found otherwise. A meta-analysis of all published data suggests modest benefit from aspirin but more recent population data refutes this notion. Thus aspirin has been demoted from genuine second-line therapy in patients who have a bona fide contraindication to warfarin or in patients who are at low risk and do not require warfarin therapy. More recent clinical trial data have tested other potent antiplatelet regimens, specifically combining clopidogrel with aspirin therapy. In the ACTIVE studies, this combination was shown to provide inferior protection against stroke versus targeted warfarin therapy, and the trial was prematurely terminated.

It is important to recognize that challenges exist to warfarin usage including multiple drug interactions, food interactions, inconstant INR results, and a narrow therapeutic window. Frequent INR testing is required to ensure a consistent therapeutic action. In the early phases of warfarin initiation, INR values will need to be determined approximately twice weekly. As the therapeutic level is maintained on a stable warfarin dose regimen, this can be initially decreased to once weekly and later, once monthly. This of course is subject to change should new medications be introduced that have the potential to alter the INR, notably amiodarone that potentiates the therapeutic effect of warfarin. It is crucial to maintain the INR value within the targeted range because values consistently below 2.0 are associated with an increased stroke risk, and as values rise above 3.0, there is no additional benefit of stroke protection but there is much greater risk of bleeding.

The recent introduction of the non-vitamin K antagonist oral anticoagulants (NOACs), which includes the direct thrombin inhibitor, dabigatran, and the factor Xa inhibitors, rivaroxaban, apixaban, and edoxaban, has dramatically changed treatment algorithms. Designed to overcome the limitations of warfarin, the NOACs have revolutionized oral anticoagulation because they are at least as effective as warfarin, but are more convenient to administer because the NOACs can be given in fixed doses (Fig. 3-6) without routine coagulation monitoring, and have far fewer drug interaction and no dietary issues. Moreover, as a class, the NOACs are associated with significantly less intracranial bleeding than warfarin. This is an important advantage because bleeding into the brain is the most feared complication of anticoagulation therapy. Compared with warfarin, a meta-analysis of the phase 3 clinical trial data involving more than 70,000 patients revealed that the NOACs are noninferior for prevention of stroke and systemic embolism and as a class, are associated with an approximately 10% reduction in all-cause mortality and a similar reduction in cardiovascular mortality. Rates of major bleeding were similar or lower than those with warfarin and all the NOACs produced less intracranial bleeding than warfarin, but with the exception of apixaban, were associated with more gastrointestinal bleeding.
Because of their more favorable benefit-to-risk profile relative, several guidelines give preference to NOACs over warfarin in eligible patients with AF.