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Atrial Fibrillation: Clinical Features, Mechanisms, and Management
Additional content is available online at Elsevier eBooks for Practicing Clinicians
Electrocardiographic Features
Atrial fibrillation (AF) is a supraventricular arrhythmia characterized electrocardiographically by low-amplitude baseline oscillations (fibrillatory or f waves from the fibrillating atria) and an irregularly irregular ventricular rhythm. The f waves, 300 to 600 beats/min, are variable in amplitude, shape, and timing. Atrial flutter waves have a rate of 250 to 350 beats/min and are constant in timing and morphology ( Fig. 66.1 ). In lead V 1 , f waves sometimes appear uniform and can mimic flutter waves ( Fig. 66.2 ). In some patients, f waves are very small and not perceptible on the electrocardiogram, and the diagnosis of AF is based on the irregularly irregular ventricular rhythm ( Fig. 66.3 ).
The ventricular rate during untreated AF typically is 100 to 160 beats/min. Patients with the Wolff-Parkinson-White (WPW) syndrome can experience ventricular rates during AF exceeding 250 beats/min because of conduction over the accessory pathway (see Chapter 65 ). The ventricular rate during AF can appear more regular when the rate is extremely rapid (>170 beats/min) ( Fig. 66.4 ), when a junctional tachycardia independently controls the ventricles, when there is high-degree atrioventricular (AV) block with a regular escape rhythm ( Fig. 66.5 ), or when the QRS complexes all are paced. In these cases the diagnosis of AF is based on the presence of f waves. Infrequently, a junctional tachycardia can exhibit Wenckebach exit block (often during digitalis toxicity) and cause a regularly irregular ventricular rate.
Classification of Atrial Fibrillation
Atrial fibrillation that terminates spontaneously within 7 days is termed paroxysmal , and AF present continuously for more than 7 days is called persistent . AF that persists for longer than 1 year is termed longstanding persistent . The term permanent AF is used when the patient and clinician jointly decide to abandon further attempts at restoring and/or maintaining sinus rhythm. This “acceptance of AF” represents a therapeutic attitude rather than a pathophysiologic characteristic of the AF and should not be taken literally. Some patients with paroxysmal AF occasionally can have episodes that are persistent and vice versa. The predominant form of AF determines how it should be categorized.
A confounding factor in the classification of AF is cardioversion and antiarrhythmic drug (AAD) therapy. For example, if a patient undergoes transthoracic cardioversion 24 hours after AF onset, it is unknown whether the AF would have persisted for more than 7 days. Furthermore, AAD therapy can change persistent AF into paroxysmal AF. The classification of AF should not be altered on the basis of the effects of electrical cardioversion or AAD therapy.
Lone atrial fibrillation refers to AF that occurs in patients younger than 60 years who do not have hypertension or any evidence of structural heart disease. This designation is a historical descriptor that has been variably applied to different low-risk subsets of AF patients. Because the definitions have not been consistent, and the potentially confusing definitions of this term, this designation should be abandoned.
Paroxysmal AF also can be classified clinically on the basis of the autonomic setting in which it most often occurs. Approximately 25% of patients with paroxysmal AF have vagotonic AF, in which AF is initiated in the setting of high vagal tone, typically in the evening when the patient is relaxing or during sleep. Drugs exerting a vagotonic effect (e.g., digitalis) can aggravate vagotonic AF, and drugs with a vagolytic effect (e.g., disopyramide) may be particularly appropriate for prophylactic therapy. Adrenergic AF occurs in approximately 10% to 15% of patients with paroxysmal AF in the setting of high sympathetic tone, as during strenuous exertion. In patients with adrenergic AF, beta blockers not only provide rate control but may prevent episodes of AF. Most patients have a mixed or random form of paroxysmal AF, with no consistent pattern of onset. In some, alcohol can be a precipitant. ,
Epidemiology of Atrial Fibrillation
Atrial fibrillation is the most common arrhythmia treated in clinical practice and the most common arrhythmia for which patients are hospitalized; approximately 33% of arrhythmia-related hospitalizations are for AF. In 2010 the prevalence of AF was estimated to be between 2.1 and 6.1 million persons. This is predicted to increase to 12.1 million persons by 2030. AF is associated with approximately a fivefold increase in the risk of cerebrovascular accident (stroke), a twofold increase in the risk of all-cause mortality, and a twofold increase in cognitive dysfunction. AF also is associated with the development of heart failure and has been linked to sudden death.
The incidence of AF is related to age and sex, ranging from 0.1% per year before age 40 to more than 1.5% per year in women and more than 2% per year in men older than 80. Advanced age, congestive heart failure, male sex, tall stature, a family history of AF at less than 50 years of age, left atrial enlargement, and hypertension are independent risk factors for the development of AF, as are obesity and obstructive sleep apnea. AF is less common in African Americans.
Mechanisms of Atrial Fibrillation
The mechanisms responsible for AF are complex and incompletely understood. The three main mechanistic concepts that have emerged over time consist of multiple reentrant wavelets, rapidly discharging autonomic foci, and a single reentrant circuit with fibrillatory conduction. Considerable progress has been made in defining the mechanisms underlying initiation, perpetuation, and progression of AF. A key breakthrough that had an immediate therapeutic impact was the recognition that in many patients, AF is triggered and/or maintained by rapidly firing foci in the pulmonary veins. It is now well accepted the focal firing is the key mechanism underlying initiation and perpetuation of paroxysmal AF. In contrast, the mechanisms that underlie maintenance of persistent AF appear far more complex. In persistent AF, changes in the atrial substrate, including interstitial fibrosis that contributes to slow, discontinuous, and anisotropic conduction, may give rise to wandering or stationary reentry. It is for this reason that the outcomes of AF ablation targeted at the pulmonary veins (PVs) alone results in lower efficacy than in patients with paroxysmal AF.
Genetic Factors
It is now well established that susceptibility to AF is heritable. , Individuals who have a first-degree relative with AF have a 40% increased risk of developing AF. In the last decade, considerable progress has been made in identifying the genetic determinants of AF. Population-based studies have been used to identify many AF risk loci. A recent study tested the association between AF genetic susceptibility and recurrence of AF after AF ablation using a polygenic risk score. A higher AF genetic susceptibility was associated with younger age and fewer clinical risk factors, but not AF recurrence. Although progress has been made, studies continue to better define the link between genetic factors and AF and how these genetic factors impact the response to therapy.
Causes of Atrial Fibrillation
The majority of patients with AF have hypertension (usually with left ventricular hypertrophy; Chapter 26 ) or some other form of structural heart disease. In addition to hypertensive heart disease, the most common cardiac abnormalities associated with AF are ischemic heart disease ( Chapter 37, Chapter 38, Chapter 39, Chapter 40 ), mitral valve disease ( Chapter 75, Chapter 76 ), hypertrophic cardiomyopathy ( Chapter 54 ), and dilated cardiomyopathy ( Chapter 52 ). Less common causes of AF are restrictive cardiomyopathies such as amyloidosis ( Chapter 53 ), constrictive pericarditis ( Chapter 86 ), and cardiac tumors (see Chapter 98 ). Severe pulmonary hypertension often is associated with AF ( Chapter 88 ).
Obstructive sleep apnea and obesity are associated with each other, and both independently increase the risk of AF (see Chapter 89 ). The possible mechanisms of AF in patients with sleep apnea include hypoxia, surges in autonomic tone, and hypertension. Available data suggest that atrial dilation and an increase in local and systemic inflammatory factors are responsible for the relationship between obesity and AF. Obesity is associated with increased deposits of epicardial fat (see Chapter 30 ). A growing body of data has demonstrated that epicardial fat is strongly associated with the presence, severity, and recurrence of AF in many clinical settings. The most likely arrhythmogenic mechanisms by which epicardial fat predisposes to AF include adipocyte infiltration, profibrotic effects, proinflammatory effects. The LEGACY study demonstrated that sustained weight loss and exercise can reduce the AF burden.
AF is sometimes caused by tachycardia. Patients with tachycardia-induced AF most often have AV nodal reentrant tachycardia or a tachycardia related to WPW syndrome that degenerates into AF. AF in a patient with a history of rapid and regular palpitations before the onset of irregular palpitations or with a WPW electrocardiographic pattern suggest that the patient may have tachycardia-induced AF. Treatment of the tachycardia that triggers the AF often (but not always) prevents recurrences of AF.
Clinical Features
The symptoms of AF range from none to severe and functionally disabling. The most common symptoms are palpitations, fatigue, dyspnea, effort intolerance, and lightheadedness. Polyuria can occur because of release of atrial natriuretic peptide. Many patients with symptomatic paroxysmal AF also have asymptomatic episodes, and some patients with persistent AF have symptoms only intermittently, making it difficult to assess accurately the frequency and duration of AF on the basis of symptoms.
An estimated 25% of patients with AF are asymptomatic, more often elderly patients and patients with persistent AF. Such patients sometimes are erroneously classified as being “asymptomatic” despite having symptoms of fatigue or effort intolerance. Because fatigue is a nonspecific symptom, it may not be clear that the cause is persistent AF. Many elderly patients incorrectly assume that their effort intolerance is attributable to aging. A “diagnostic cardioversion” may be helpful by maintaining sinus rhythm for at least a few days to determine whether a patient feels better in sinus rhythm. This strategy is especially valuable in a patient under the age of 80 years who presents for a routine physical examination and is found to be in AF. Rather than quickly declaring the patient “asymptomatic,” many experienced clinicians will restore sinus rhythm with a cardioversion to evaluate symptomatic improvement. This strategy also is useful in patients with newly diagnosed persistent AF as the longer a patient is in continuous AF, the more difficult it is to restore and maintain sinus rhythm. This approach can provide a basis to pursue a rhythm-control versus rate-control strategy.
Syncope, an uncommon symptom of AF, can be caused by a long sinus pause on termination of AF in a patient with the sick sinus syndrome. Syncope also can occur during AF with a rapid ventricular rate because of neurocardiogenic (vasodepressor) syncope triggered by the tachycardia or because of a severe drop in blood pressure caused by a reduction in cardiac output.
Asymptomatic or minimally symptomatic AF patients are not prompted to seek medical care and can present with a thromboembolic complication such as stroke or the insidious onset of heart failure symptoms, eventually presenting in florid congestive heart failure caused by tachycardia-induced cardiomyopathy.
The hallmark of AF on physical examination is an irregularly irregular pulse. Short R-R intervals during AF do not allow adequate time for left ventricular diastolic filling, resulting in a low stroke volume and the absence of palpable peripheral pulse. This results in a “pulse deficit,” during which the peripheral pulse is not as rapid as the apical rate. Other manifestations of AF on the physical examination are irregular jugular venous pulsations and variable intensity of the first heart sound.
Diagnostic Evaluation
The history should be directed at determination of the type and severity of symptoms, the first onset of AF, whether the AF is paroxysmal or persistent, the triggers of AF, whether the episodes are random or occur at particular times (e.g., during sleep), and the frequency and duration of episodes. When it is unclear from the history, 2 to 4 weeks of continuous or autotrigger ambulatory monitoring, or by mobile cardiac outpatient telemetry, is useful to determine whether AF is paroxysmal or persistent and to quantitate the AF burden in patients with paroxysmal AF. The history also should be directed at identification of potentially correctable causes (e.g., hyperthyroidism, excessive alcohol intake), structural heart disease, and comorbidities.
In a patient who describes irregular or rapid palpitations suggestive of paroxysmal AF, ambulatory monitoring is useful to document whether AF is responsible for the symptoms. If the symptoms occur on a daily basis, a 24-hour Holter recording is appropriate. However, extended monitoring for 2 to 4 weeks with an event monitor or continuous rhythm monitor or by mobile cardiac outpatient telemetry is appropriate for patients whose symptoms are sporadic (see Chapter 61 ). Another option is an insertable monitor, which is placed subcutaneously and has a battery life of approximately 3 years. A recent trial demonstrated that among patients with a cryptogenic stroke and no AF seen on a 24-hour Holter monitor, AF was detected in 8.9% of patients who had an implantable cardiac monitor within 6 months. One of the most important benefits of a continuous monitor over weeks to years is that the burden of AF can be precisely defined.
Laboratory testing should include thyroid, liver, and renal function blood tests. Echocardiography always is appropriate to evaluate atrial size and left ventricular function and to look for left ventricular hypertrophy, congenital heart disease (see Chapter 82 ), and valvular heart disease ( Chapter 72, Chapter 73, Chapter 74, Chapter 75, Chapter 76, Chapter 77 ). Chest radiography is appropriate if the history or physical examination is suggestive of pulmonary disease ( Chapter 17 ). A stress test is appropriate for evaluation of ischemic heart disease in at-risk patients ( Chapter 15 ).
Prevention of Thromboembolic Complications
Risk Stratification
The most important therapeutic goal in AF patients is to prevent thromboembolic complications, especially stroke. , Anticoagulants (warfarin or one of the direct oral anticoagulants) are far more effective than antiplatelet agents (e.g., aspirin or clopidogrel) for prevention of thromboembolic complications. , However, because of the risk of hemorrhage from anticoagulants, their use should be limited to patients whose risk of thromboembolic complications is greater than the risk of hemorrhage. Therefore, it is useful to risk stratify patients with AF to identify appropriate candidates for anticoagulation. The guidelines for use of anticoagulants to prevent thromboembolism are outlined in eTable 66.G1 and eTable 66.G2 (see Chapter 95 ).
The strongest predictors of ischemic stroke and systemic thromboembolism are a history of stroke or transient ischemic episode and mitral stenosis. When patients with AF and a prior ischemic stroke are treated with aspirin, the risk of another stroke is very high, in the range of 10% to 12% per year. At the other end of the risk spectrum are younger patients with AF and no comorbidities whose cumulative 15-year risk of stroke is in the range of 1% to 2%. Aside from prior stroke, the best-established risk factors for stroke in patients with nonvalvular AF are diabetes (relative risk [RR], 1.7), hypertension (RR, 1.6), heart failure (RR, 1.4), and age 70 or older (RR, 1.4 per decade). , ,
Renal failure also is an independent risk factor for stroke in patients with AF. The RR of a thromboembolic event in the absence of anticoagulation was 1.4 in patients with non–end-stage chronic kidney disease and 1.8 in patients requiring hemodialysis or a renal transplant. The predictive strength of chronic kidney disease for a thromboembolic event appears to be equivalent to that of heart failure and advanced age. Therefore, it may be appropriate to take into account chronic kidney disease when evaluating the risk profile of a patient with AF.
At present the CHA 2 DS 2 -VASc score is recommended for estimation of stroke risk (cardiac failure, hypertension, age >75 years; diabetes, stroke, or transient ischemic attack (TIA), age 65 to 74 years, vascular disease, female sex category). , Each risk factor counts as 1 point, with the exception of prior stroke or transient ischemic events and age ≥75 years, which count for 2 points. Correction for the inclusion of female sex is accomplished in the updated 2019 AF Guidelines by specifying a higher CHA 2 DS 2 -VASc score in women than in men (i.e., ≥3 in women and ≥2 in men to achieve a class I recommendation for anticoagulation) for each anticoagulation cutoff. When considering the CHA 2 DS 2 -VASc score, it is important to recognize that there are risk factors for stroke that are not included in the CHA 2 DS 2 -VASc score. These include left atrial size, mitral annular calcification, and AF burden (see eTable 66G.1 ).
The clinical value of the CHA 2 DS 2 -VASc score lies in its simplicity and predictive value. There is a direct relationship between the CHA 2 DS 2 -VASc score and the annual risk of stroke in the absence of aspirin or anticoagulant therapy. The annual risk of stroke is zero or close to zero when the CHA 2 DS 2 -VASc score is 0, compared with approximately 3% when the CHA 2 DS 2 -VASc score is 3 ( Fig. 66.6 ). Other risk scores that incorporate other metrics include biomarkers that have been developed and calibrated and may improve risk benefit assessment in AF patients that are candidates for anticoagulation.
The AF burden in persistent AF is 100% and always higher than in patients with paroxysmal AF. It may seem reasonable to assume that the risk of stroke is higher in patients with persistent AF. This recently has been confirmed by several studies, which reported a higher stroke risk in patients with persistent than paroxysmal AF. , Despite the results of these recent studies, neither the CHA 2 DS 2 -VASc score nor the current United States and European AF management guidelines have incorporated AF burden as a risk factor for stroke or into anticoagulation recommendations. ,
Pacemakers and implantable cardioverter-defibrillators (ICDs) that incorporate an atrial lead are capable of detecting short episodes of asymptomatic AF that are subclinical. Subclinical atrial tachyarrhythmias were independently associated with a 2.5-fold increase in the risk of stroke. Long-term intracardiac monitoring in patients with recently implanted pacemakers or ICDs has detected subclinical AF (SCAF) in up to 50% of patients. In a multicenter prospective study, electrocardiographic monitors were implanted in patients ≥65 years of age with left atrium (LA) enlargement or elevated pro-BNP but no history of AF with either CHA 2 DS 2 -VASc ≥2, sleep apnea or body mass index (BMI) >30 kg/m 2 . About half of the patients had a history of stroke or TIA. SCAF (>5 minutes duration) was detected in 40% of patients who suffered a stroke or TIA and 30% of those who did not over 16 months of follow-up. SCAF is common in older adults and more frequently detected due to the widespread use of implanted electrocardiographic monitoring devices. However, whether anticoagulation lowers stroke risk in this subset of AF patients currently is unknown; SCAF may be a risk marker, not a cause of stroke. The 2019 AHA/ACC/HRS AF Guidelines provides a class I level of evidence (LOE) B recommendation that the presence of recorded atrial high rate episodes on an implanted device should prompt further evaluation to document clinically relevant AF to guide treatment decisions (see eTable 66G.6 ). It is important to recognize that not all mode switch events that are classified as AF by an implanted device are truly AF. In the absence of data from clinical trials, most clinicians today would advise anticoagulation for patients with device-detected AF who have episodes of at least 5 hours in duration and have an elevated stroke risk profile.
An important consideration in patients treated with an oral anticoagulant is the risk of bleeding. Several risk-scoring systems have been developed to assess a patient’s susceptibility to hemorrhagic complications. The scoring system with the best balance of simplicity and accuracy is the HAS-BLED score. The components of this score are hypertension, abnormal renal or liver function, stroke, bleeding history or predisposition, labile international normalized ratio (INR), older adults (>75 years), and concomitant drug (antiplatelet agent or nonsteroidal anti-inflammatory drug) or alcohol use. Each of these components is 1 point. As the score increases from 0 to the maximum of 9, there is a stepwise increase in the risk of bleeding in patients treated with warfarin. While these scores may be helpful in identifying patients at elevated breeding risk, their clinical utility was deemed insufficient to be included as a formal recommendation in the 2014 ACC/AHA/HRS AF Guidelines. ,
The 2019 AHA/ACC/HRS AF Guidelines give a class I LOE A recommendation for anticoagulation of men with a CHA 2 DS 2 -VASc score of 2 or higher and women with a CHA 2 DS 2 -VASc score of 3 or higher. For men with a CHA 2 DS 2 -VASc score of 1 and women with a CHA 2 DS 2 -VASc score of 2, anticoagulation should be considered (class IIa, LOE A). While the CHA 2 DS 2 -VASc score provides a valuable guideline for anticoagulation, other factors should be considered, including patient preference. Some patients may prefer to accept an increased risk of stroke instead of long-term anticoagulation. Other patients with a low CHA 2 DS 2 -VASc score of 0 to 1 may prefer to take an anticoagulant to protect against even the small risk of a stroke (see eTable 66G.1 ).
Aspirin
Aspirin is not effective for preventing thromboembolic complications in patients with AF. In a meta-analysis of five randomized clinical trials, aspirin did not significantly reduce the risk of stroke compared with placebo in patients with AF. In a large cohort study of patients with nonvalvular AF, aspirin had no therapeutic efficacy for preventing strokes. In several network meta-analyses, the variable and modest reduction in stroke risk with aspirin is not greater than that expected for reduction of risk for vascular stroke. It is notable that a major update of the 2019 ACC/AHA/HRS AF Guidelines, as compared with the 2014 AHA/ACC/HRS AF Guidelines, is that aspirin is no longer recommended for stroke prevention in AF patients. , In patients with a low CHA 2 DS 2 -VASc score, the recommended options for stroke prevention are now an anticoagulant versus no therapy (see eTable 66G.1 ).
Warfarin
A meta-analysis of the major randomized clinical trials that compared warfarin with placebo for prevention of thromboembolism in patients with AF demonstrated that warfarin reduced the risk of all strokes (ischemic and hemorrhagic) by approximately 60%. , The target INR should be 2.0 to 3.0. This range of INRs provides the best balance between stroke prevention and hemorrhagic complications. In clinical practice, maintenance of the INR in therapeutic range has been challenging, and a large proportion of patients often have an INR of less than 2.0. A large prospective study of community-based practices demonstrated that the mean time in therapeutic range (TTR) in patients treated with warfarin was only 66% and that the TTR was less than 60% in 34% of patients. Even in clinical trials there are significant lapses in maintaining warfarin TTR. Maintaining the INR at a level of 2.0 or higher is important because even a relatively small decrease in INR from 2.0 to 1.7 more than doubles the risk of stroke.
The annual risk of a major hemorrhagic complication during anticoagulation with warfarin is in the range of 1% to 2%, and a strong predictor of major bleeding events is an INR greater than 3.0. For example, the risk of intracranial bleeding is approximately twice as high at an INR of 4.0 than 3.0. This emphasizes the importance of maintaining the INR in the range of 2.0 to 3.0.
Some studies have indicated that advanced age can be a risk factor for intracranial hemorrhage in patients with AF treated with warfarin. However, the available data indicate that warfarin and the direct-acting oral anticoagulants (DOACs) have a favorable risk-to-benefit ratio even in patients older than 75.
Direct-Acting Oral Anticoagulants
Direct thrombin inhibitors and factor Xa inhibitors have several advantages over vitamin K antagonists such as warfarin: (1) a fixed dosing regimen that eliminates the need for monitoring the INR, (2) rapid onset and offset, (3) equal or greater efficacy for stroke prevention, (4) a lower risk of intracranial hemorrhage, (5) no interactions with dietary factors such as alcohol or vitamin-K containing foods, and (6) far fewer drug interactions.
Dabigatran, an oral direct thrombin inhibitor, and rivaroxaban, apixaban, and edoxaban, which are factor Xa inhibitors, are approved by the U.S. Food and Drug Administration (FDA) for prevention of stroke/embolism in patients with nonvalvular AF. Randomized clinical trials demonstrated that each of these four DOACs is noninferior or superior to warfarin in efficacy and safety in patients with nonvalvular AF who had risk factors for stroke. One of the most serious risks of anticoagulation is intracranial hemorrhage. The trials, which were performed for FDA approval of each of these NOACs, revealed that the risk of intracranial hemorrhage is about 50% lower with DOACs compared with warfarin.
Because of these major advantages, the 2019 ACC/AHA/HRS AF Guidelines recommend the use of DOACs over warfarin for prevention of thromboembolic complications in patients with AF (see eTable 66G.1 ).
DOACs also have some disadvantages compared with warfarin: higher cost, more gastrointestinal side effects in the case of dabigatran, twice-daily dosing for dabigatran and apixaban, the absence of a readily available laboratory test to verify compliance, and restricted use in patients with prosthetic valves. Furthermore, use of these agents requires great care in patients with severe renal disease. The pharmacokinetics of apixaban suggest it could be used in severe renal disease and recent studies have demonstrated safety/efficacy, but randomized controlled trials are needed.
Until recently another limitation of DOACs was that there were no specific reversal agents. However, reversal agents now are available for all DOACs. , The first reversal agent to receive FDA approval, both for uncontrolled bleeding and the need for urgent surgery, was idarucizumab, an antibody fragment that reverses the anticoagulant effects of dabigatran within minutes. , Since that time andexanet alfa has been approved for acute major bleeding in patients taking a factor Xa inhibitor. A limitation of andexanet alfa is high cost compared with a prothrombin concentrate.
When a reversal agent is not available or not desired, administration of prothrombin complex concentrate can reverse the anticoagulant effect of the DOACs (see eTable 66G.2 ).
Older studies demonstrated the frequent underutilization of warfarin in patients with AF and risk factors for stroke. The inconvenience and potential risks of warfarin likely contributed to its underutilization. However, the underutilization of and low adherence to oral anticoagulant use in patients with AF has continued to be the case even with the advent of DOACs.
The major professional societies have incorporated recommendations regarding the use of the factor Xa- and direct thrombin-inhibitors into their most recent guidelines for the management of AF. , As noted above, the ACC/AHA/HRS AF guidelines recommend DOACs over warfarin for prevention of stroke and systemic embolism in patients with nonvalvular paroxysmal or persistent AF and risk factors for stroke. This recommendation is limited to patients without valvular AF. Valvular AF is defined as AF in patients with a prosthetic valve or with moderate to severe mitral stenosis. Based on recent data, the 2019 ACC/AHA/HRS AF Guidelines provide a 2B recommendation for reduced-dose DOAC therapy in patients with moderate to severe kidney disease. These guidelines also state that dabigatran, rivaroxaban, and edoxaban are not recommended in patients with end-stage kidney disease or patients on dialysis. Recent studies indicate the apixaban may be safe to use in such patients.
The results of a large number of clinical trials have indicated that the DOACs are as effective as warfarin for prevention of thromboembolic complications associated with cardioversion. This is the case regardless of whether or not a transesophageal echocardiogram is performed before cardioversion to look for left atrial thrombus.
The onset of action of the DOACs is approximately 1.5 to 2 hours after a dose. Their half-life is approximately 12 hours. The rapid onset of action and washout eliminates the need for bridging therapy with heparin when treatment with one of the DOACs is interrupted for a surgical or invasive medical procedure. Recent data indicate that the risk of major periprocedural complications does not differ significantly between patients who undergo radiofrequency catheter ablation of AF during uninterrupted therapy with warfarin and patients anticoagulated with an uninterrupted DOAC. ,
Low-Molecular-Weight Heparin
Low-molecular-weight heparin (LMWH) has a longer half-life than unfractionated heparin and a predictable antithrombotic effect that is attained with a fixed dosage administered subcutaneously twice daily. Because LMWH can be self-injected outside the hospital, it is a practical alternative to unfractionated heparin for initiation of anticoagulation with warfarin in patients with AF. Bridging therapy with LMWH should be continued until the INR is 2.0 or higher.
Because of its high cost, LMWH rarely is used in clinical practice as a substitute for long-term conventional anticoagulation. In the past, LMWH typically was used as a temporary bridge to therapeutic anticoagulation when therapy with warfarin was initiated or in high-risk patients for a few days before and after a medical or dental procedure when anticoagulation with warfarin was been suspended. In contemporary practice, the use of DOACs has greatly limited the need for LMWH in patients with nonvalvular AF.
Excision or Closure of the Left Atrial Appendage
Approximately 90% of left atrial thrombi form in the left atrial appendage (LAA), and therefore successful excision or closure of the LAA should greatly reduce the risk of thromboembolic complications in patients with AF. Surgical techniques consist of either excision or closure by suturing or stapling. The efficacy of these techniques is variable and probably dependent on both the technique and the operator. Transesophageal echocardiography (TEE) should be performed after surgical closure of the LAA to confirm successful closure before discontinuation of anticoagulation.
In recent years, several percutaneous LAA occlusion and ligation devices have been developed as alternatives to surgical closure techniques. These devices have their greatest utility in high-risk AF patients who cannot tolerate or who refuse to take an oral anticoagulant.
The only percutaneous occlusion device approved by the FDA specifically for stroke prevention as an alternative to warfarin is the WATCHMAN (Boston Scientific, Marlborough, Massachusetts). This nitinol plug covered with fenestrated fabric became widely available for clinical use after FDA approval in 2015 ( Fig. 66.7 ). After implantation of the WATCHMAN using femoral vein access and transeptal catheterization, anticoagulation with warfarin is recommended for at least 45 days, at which time anticoagulation can be discontinued if there is no TEE evidence of peridevice flow. Since initial release of this device, considerable evidence has demonstrated that DOACs can be used instead of warfarin. ,
Another device used in the United States for LAA occlusion is the LARIAT (Sentreheart, Redwood City, California). This device has FDA approval for soft tissue approximation (not stroke prevention) and has been used off-label in clinical practice in the United States and elsewhere for LAA occlusion. A guidewire with a magnetic tip is inserted into the left atrium after transseptal catheterization and is positioned at the tip of the LAA. It functions as a rail for an epicardial snare. Entry into the pericardial space is attained using a percutaneous approach. A snare with a pretied suture is inserted into the pericardial space and guided toward the LAA ( Fig. 66.8 ). The pretied suture then is tightened to occlude the LAA. In a large multicenter registry, complete LAA closure was achieved in 94% of 712 patients. There was one procedure-related death, and cardiac perforation occurred in 3.4% of patients, with open heart surgery required to repair the perforation in 1.4% of patients. Clinical trial data establishing the efficacy of the LARIAT for stroke prevention are lacking. At present, this device is being used in the AMAZE clinical trial, which is seeking to determine whether PV isolation plus appendage ligation with the LARIAT device is superior to PV isolation alone in patients with persistent AF. The study has completed enrollment and the results should be available in 2021. Percutaneous or surgical LAA occlusion are considered class IIa and IIb recommendations, respectively, in situations where anticoagulation is contraindicated or the patient is undergoing cardiac surgery (see eTable 66G.2 ).
Acute Management of Atrial Fibrillation
Patients who present to the emergency department because of AF often have a rapid ventricular rate, and control of the ventricular rate is most rapidly achieved with intravenous diltiazem or esmolol ( eTable 66G.3 ). If the patient is hemodynamically unstable, immediate transthoracic cardioversion may be appropriate. Cardioversion should ideally be preceded by TEE to rule out a left atrial thrombus if the AF has been present for longer than 48 hours or if the duration is unclear and the patient is not already anticoagulated. However, if the patient has marked hemodynamic compromise, immediate cardioversion without a TEE is advised.
If the patient is hemodynamically stable, the decision to restore sinus rhythm by cardioversion is based on several factors, including symptoms, prior AF episodes, age, left atrial size, and current AAD therapy. For example, in an elderly patient whose symptoms resolve once the ventricular rate is controlled and who already has had early recurrences of AF despite rhythm-control drug therapy, further attempts at cardioversion usually are not appropriate. On the other hand, cardioversion usually is appropriate for patients with symptomatic AF who present with a first episode of AF or who have had long intervals of sinus rhythm between prior episodes.
If cardioversion is decided upon for a hemodynamically stable patient who presents with AF that does not appear to be self-limited, two management decisions must be made: early versus delayed cardioversion and pharmacologic versus electrical cardioversion.
The advantages of early cardioversion are rapid relief of symptoms, avoidance of the need for TEE or therapeutic anticoagulation for 3 to 4 weeks before cardioversion if cardioversion is performed within 48 hours of AF onset, and possibly a lower risk of early AF recurrence because of less atrial remodeling (see Chapter 64 ). A reason to defer cardioversion is the unavailability of TEE in a patient who has not been anticoagulated with AF of unclear duration or duration more than 48 hours. Other reasons include a left atrial thrombus by TEE (see Chapter 16 ), a suspicion (based on prior AF episodes) that AF will convert spontaneously within a few days, or in rare cases, a correctable cause of AF such as hyperthyroidism.
When cardioversion is performed early in the course of an episode of AF, there is the option of either pharmacologic or electrical cardioversion. Pharmacologic cardioversion has the advantage of not requiring general anesthesia or deep sedation. In addition, the probability of an immediate recurrence of AF is lower with pharmacologic cardioversion than with electrical cardioversion. However, pharmacologic cardioversion is associated with the risk of adverse drug effects and is not as effective as electrical cardioversion. Pharmacologic cardioversion is unlikely to be effective if the duration of AF is longer than 7 days.
Drugs that can be administered intravenously for cardioversion of AF consist of ibutilide, procainamide, and amiodarone. For AF episodes fewer than 2 to 3 days in duration, efficacy is approximately 60% to 70% for ibutilide, 40% to 50% for amiodarone, and 30% to 40% for procainamide. To minimize the risk of QT prolongation and polymorphic ventricular tachycardia (torsades de pointes; see Chapter 67 ), the use of ibutilide should be limited to patients with an ejection fraction greater than 35%.
Acute pharmacologic cardioversion of AF also can be attempted with oral drugs in patients without structural heart disease. The most common oral agents for acute conversion of AF are propafenone (300 to 600 mg) and flecainide (100 to 200 mg). When flecainide is used, patients generally take a beta blocker on AF onset and then take the flecainide one or more hours later. It is recommended that these drugs be administered under surveillance upon first use, as patients may have a pronounced postconversion pause. If no adverse drug effects are observed, the patient may then be an appropriate candidate for episodic, self-administered AAD therapy on an outpatient basis (the “pill-in-the-pocket” approach).
The efficacy of transthoracic cardioversion exceeds 95%. Biphasic waveform shocks convert AF more effectively than monophasic waveform shocks and allow the use of lower energy shocks, resulting in less skin irritation. An appropriate first-shock strength using a biphasic waveform is 150 to 200 J, followed by higher output shocks if needed. If a 360-J biphasic shock is unsuccessful, ibutilide should be infused before another shock is delivered because it lowers the defibrillation energy requirement and improves the success rate of transthoracic cardioversion.
Transthoracic cardioversion can fail to restore sinus rhythm. An increase in shock strength, an infusion of ibutilide, or repeat CV with greater pressure applied to the defibrillation patches, often results in successful repeat cardioversion. The second type of failure is an immediate recurrence of AF within a few seconds of successful conversion to sinus rhythm. This occurs in approximately 25% of AF episodes less than 24 hours in duration and 10% of episodes more than 24 hours in duration. For this type of cardioversion failure, an increase in shock strength is of no value. If the patient has not been receiving an oral rhythm-control agent, infusion of ibutilide may be helpful to prevent an immediate recurrence of AF.
Regardless of whether cardioversion is performed pharmacologically or electrically, therapeutic anticoagulation is necessary for 3 weeks or more before cardioversion to prevent thromboembolic complications if the AF has been ongoing for more than 48 hours. If the time of onset of AF is unclear, for the sake of safety, the AF duration should be assumed to be more than 48 hours. These patients should be therapeutically anticoagulated for 4 weeks after cardioversion to prevent thromboembolic complications that may occur because of atrial stunning. If the patient’s stroke risk profile is elevated, anticoagulation should be continued indefinitely. If the duration of AF is known to be less than 48 hours, cardioversion can be performed without anticoagulation. However, if the patient’s stroke risk profile is elevated and long-term anticoagulation is advised, immediate initiation of anticoagulation with a DOAC is recommended.
When AF duration exceeds 48 hours or is unclear, an alternative to 3 weeks of therapeutic anticoagulation before cardioversion is anticoagulation with heparin and a TEE to check for a left atrial thrombus. If no thrombi are seen, the patient can be cardioverted safely but still requires 4 weeks of therapeutic anticoagulation after cardioversion to prevent thromboembolism related to atrial stunning. The major clinical benefit of the TEE-guided approach over the conventional approach is that sinus rhythm is restored several weeks sooner. Compared with the conventional approach, the TEE approach has not been found to reduce the risk of stroke or major bleeding or to affect the proportion of patients still in sinus rhythm at 8 weeks after cardioversion. The guidelines for pharmacologic and electrical cardioversion, pharmacologic enhancement of direct current cardioversion of AF and prevention of thromboembolism with acute cardioversion are summarized in eTable 66G.4 .
Long-Term Management of Atrial Fibrillation
Pharmacologic Rate Control Versus Rhythm Control
Several randomized studies have compared a rate-control strategy with a rhythm-control strategy in patients with AF. Overall, these studies have demonstrated a significantly lower rate of rehospitalization with a rate-control strategy but no significant differences in other major outcomes, such as all-cause mortality, strokes, bleeding events, worsening heart failure, or quality of life.
The results of these randomized studies should not be applied systematically to all patients with AF. It is important to note that many patients in the rhythm-control arms of these studies continued to have AF, and that the possible beneficial effects of sinus rhythm over AF could have been negated by adverse effects of the AADs. Furthermore, most patients enrolled in these studies were elderly and had few AF symptoms, and the duration of follow-up was several years. It remains uncertain what the implications are of decades of continuous AF in terms of the risks of stroke, heart failure, dementia, and death.
The decision to pursue a rhythm-control strategy versus a rate-control strategy should be individualized based on several factors. These include the nature, frequency, and severity of symptoms; the length of time that AF has been present continuously in patients with persistent AF; left atrial size; comorbidities; the response to prior cardioversions; age; the side effects and efficacy of the AADs already used to treat the patient; patient age and activity level; and the patient’s preference.
The duration of continuous AF is a predictor of the ability to restore and maintain sinus rhythm. The chance of successful AF rhythm control is higher in patients with paroxysmal or early persistent AF (<6 months) than for patients who have been in continuous AF for one or more years. This is an important consideration when faced with asymptomatic or minimally symptomatic patients with newly diagnosed persistent AF . It is well established that the presence of AF is associated with a higher risk of stroke risk, heart failure risk, cognitive dysfunction, and mortality. Recent studies indicate that the stroke risk is higher in a patient with continuous AF than paroxysmal AF. , While no study has shown that restoration of sinus rhythm with AF ablation impacts any of these complications of AF, it may. Of particular note is the CABANA trial. This prospective randomized clinical trial randomized 2204 patients with AF to catheter ablation or medical therapy. The primary endpoint was a composite of death, disabling stroke, serious bleeding, or cardiac arrest. No difference in the primary endpoint was present after a median follow-up of 48.5 months. But the secondary endpoint of death or cardiovascular hospitalizations was significantly lower in the ablation arm than in the medical therapy arm (51.7% vs. 58.1%, p = 0.001). For this reason, the 2017 HRS/EHRA/ECAS Consensus Document on AF ablation provides a class IIb recommendation for catheter ablation of AF in patients who are asymptomatic.
Pharmacologic Rate Control
An excessively rapid ventricular rate during AF often results in uncomfortable symptoms and decreased effort tolerance and can cause a tachycardia-induced cardiomyopathy if it is sustained for several weeks to months. Optimal heart rates during AF vary with age and should be similar to the heart rates that a patient would have at a particular degree of exertion during sinus rhythm. Heart rate control must be assessed both at rest and during exertion. The 2014 and 2019 ACC/AHA/HRS AF Guidelines advise that the optimal metric for rate control is a resting heart rate <80 beats/min. , Based on a single European clinical trial, a more lenient rate control metric of <110 beats/min is provided with a class IIb recommendation. , Assessment of the degree of heart rate control can be obtained with a 24-hour Holter monitor. A 12-lead ECG provides an indication of the resting ventricular rate but fails to provide information on the ventricular rate during a patient’s daily activities.
Oral agents available for long-term heart rate control in patients with AF are digitalis, beta blockers, calcium channel antagonists, and amiodarone (see Chapter 64 ). The first-line agents for rate control are beta blockers and the calcium channel antagonists verapamil and diltiazem. A combination is often used to improve efficacy or to limit side effects by allowing the use of smaller dosages of the individual drugs. In patients with sinus node dysfunction and tachycardia-bradycardia syndrome, the use of a beta blocker with intrinsic sympathomimetic activity (pindolol, acebutolol) may provide rate control without aggravating sinus bradycardia.
Digitalis may adequately control the rate at rest but often does not provide adequate rate control during exertion as it works mainly by increasing vagal tone. Digitalis is no longer recommended for rate control except in patients with heart failure because digitalis has been shown to increase the risk of all-cause mortality, particularly among patients with AF. The 2014 and 2019 AHA/ACC/HRS Guidelines recommend digoxin for rate control only in patients with heart failure (see eTable 66G.3 ). ,
Amiodarone is much less frequently used for rate control than the other negative dromotropic agents because of the risk of organ toxicity associated with long-term therapy. Amiodarone can be an appropriate choice for rate control if the other agents are not tolerated or are ineffective. For example, amiodarone would be an appropriate choice for a patient with persistent AF, heart failure, and reactive airway disease who cannot tolerate either a calcium channel antagonist or a beta blocker and who has a rapid ventricular rate despite treatment with digitalis. Amiodarone as a rate-control medication is provided with a class IIb recommendation in the 2014 ACC/AHA/HRS AF Guidelines. ,
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