Chapter 251: Atrial Fibrillation (Harrison's Principles of Internal Medicine)

University of the Philippines ­ Manila Access Provided by:...

University of the Philippines ­ Manila Access Provided by: Harrison's Principles of Internal Medicine, 21e Chapter 251: Atrial Fibrillation William H. Sauer; Paul C. Zei PATHOPHYSIOLOGY AND EPIDEMIOLOGY Atrial fibrillation (AF) is a cardiac arrhythmia characterized by seemingly disorganized, rapid, and irregular atrial electrical activation, resulting in loss of organized atrial mechanical contraction. These rapid and irregular electrical signals input into the atrioventricular (AV) node, which determines ventricular activation and rate. The conducted ventricular rate is variable, resulting in an irregular, usually rapid ventricular rate, ranging typically between 110 and 160 beats/min in most. In some patients, the sustained ventricular rate can exceed 200 beats/min, whereas in others with either high vagal tone or AV nodal conduction disease, the ventricular rate may be excessively slow (Fig. 251­1). FIGURE 251­1 Electrocardiogram of an irregularly irregular heart rhythm without discernable P waves. The disorganized atrial activation is best appreciated in lead V1 for this patient. AF is the most common sustained arrhythmia; as a result, it is a major public health issue. Prevalence increases with age, with >95% of AF patients >60 years of age. The prevalence in humans over age 80 is ~10%. The lifetime risk of developing AF for men aged 40 years old is ~25%. AF is slightly more common in men than women and more common in whites than blacks. Risk factors for developing AF in addition to age and underlying cardiac disease include hypertension, diabetes mellitus, cardiac disease, family history of AF, obesity, and sleep­disordered breathing. AF is not a benign condition, with a 1.5­ to 1.9­fold increased risk of mortality after controlling for underlying cardiac disease. Perhaps the most important consequence of AF is a significantly increased risk of stroke compared to the general population, causing ~25% of all strokes. The risk of dementia is increased in patients with AF, as is the risk of MRI­detected asymptomatic embolic infarct. AF, most often when ventricular rate remains uncontrolled for prolonged periods, increases the risk of developing congestive heart failure and cardiomyopathy. Moreover, as a corollary, patients with underlying heart disease, in particular cardiomyopathy and congestive heart failure, are at higher risk for developing AF. AF is a marker for worsened morbidity and mortality in patients with existing heart disease, although the precise extent of the independent risk increase associated with AF in heart disease is unclear. AF may, on occasion, be associated with an identifiable precipitating factor, such as hyperthyroidism, acute alcohol intoxication, myocardial infarction, pulmonary embolism, pericarditis, and cardiac surgery, where AF occurs in up to 30% of patients postoperatively. AF is clinically most typically defined by the pattern of episodes. Paroxysmal AF is defined as a pattern of AF episodes that occur spontaneously and terminate with a relatively short duration, most commonly defined as 7 days or less. Persistent AF refers to AF that occurs continuously for >7 days but 1 year. These descriptors for AF correlate with the underlying pathophysiology Downloaded of AF. AF 2024­8­4 tends 10:15 A to be aIP Your progressive condition, with, at this point, no definitive “cure” that will completely eliminate AF durably in a is 49.147.196.41 Chapter 251: Atrial Fibrillation, William H. Sauer; Paul predictable fashion. The pathophysiology of AF, however, C.remains Zei incompletely understood. Most data support a multifactorial process that Page 1 / to leads 11 ©2024 McGraw Hill. All Rights Reserved. Terms of Use Privacy Policy Notice Accessibility the development of manifest AF. Clinical and epidemiologic studies have demonstrated that, in addition to cardiovascular disease, obesity, hypertension, diabetes mellitus, and sleep­disordered breathing are associated with higher risk of developing AF. The proposed pathophysiology on occasion, be associated with an identifiable precipitating factor, such as hyperthyroidism, acute alcohol intoxication, myocardial infarction, University of the Philippines ­ Manila pulmonary embolism, pericarditis, and cardiac surgery, where AF occurs in up to 30% of patients postoperatively. Access Provided by: AF is clinically most typically defined by the pattern of episodes. Paroxysmal AF is defined as a pattern of AF episodes that occur spontaneously and terminate with a relatively short duration, most commonly defined as 7 days or less. Persistent AF refers to AF that occurs continuously for >7 days but 1 year. These descriptors for AF correlate with the underlying pathophysiology of AF. AF tends to be a progressive condition, with, at this point, no definitive “cure” that will completely eliminate AF durably in a predictable fashion. The pathophysiology of AF, however, remains incompletely understood. Most data support a multifactorial process that leads to the development of manifest AF. Clinical and epidemiologic studies have demonstrated that, in addition to cardiovascular disease, obesity, hypertension, diabetes mellitus, and sleep­disordered breathing are associated with higher risk of developing AF. The proposed pathophysiology suggests a “final common pathway” of these risk factors leading to electrophysiologic changes in atrial tissues. Alterations in regulation of membrane channels and other proteins result in abnormal electrical excitability. Atrial tissues, in particular pulmonary vein musculature, exhibit enhanced automaticity, resulting in ectopic beats (premature atrial contractions), as shown in Fig. 251­2. Bouts of rapid atrial ectopy may then initiate either atrial tachycardia or frank AF. Additional cellular and, eventually, tissue remodeling results in abnormal conduction properties throughout the atria, including, in particular, shortening of atrial tissue refractory periods. This enables sustained AF through a combination of rapid automaticity­based “drivers” and areas of functional reentry. Further remodeling leads to the development of fibrosis and left atrial enlargement (Table 251­1). FIGURE 251­2 Surface electrocardiogram (ECG) of atrial ectopy initiating atrial fibrillation (AF). In this single­lead surface ECG recording, the tracing begins with two conducted sinus beats. A nonconducted premature atrial contraction (PAC) (labeled “blocked PAC”) is shown after the second QRS complex. After the next sinus P wave and QRS, an ectopic beat (PAC) initiates atrial fibrillation, as demonstrated by (somewhat organized) erratic atrial activity and an irregular ventricular response. TABLE 251­1 Categorization of Atrial Fibrillation (AF) by Clinical Temporal Characteristics and Associated Features PAROXYSMAL AF PERSISTENT AF LONG­STANDING PERSISTENT AF Definition Episodes self­terminate or via CV in 1 year in 48 h and in patients at high risk for thromboembolism, such as those with mitral stenosis or hypertrophic cardiomyopathy, conversion to sinus rhythm is associated with an increased risk of thromboembolism. Thromboembolism can occur soon or several days after restoration of sinus rhythm if appropriate anticoagulation measures are not taken. Cardioversion within 48 h of the onset of AF is common practice in patients who have not been anticoagulated, provided that they are not at high risk for stroke due to a prior history of embolic events, rheumatic mitral stenosis, or hypertrophic cardiomyopathy with marked left atrial enlargement. These low­risk patients with occasional episodes of AF can be instructed to notify their physician when AF occurs to arrange for cardioversion to be Downloaded 2024­8­4 10:15 A Your IP is 49.147.196.41 done within 48 h. Chapter 251: Atrial Fibrillation, William H. Sauer; Paul C. Zei Page 4 / 11 ©2024 McGraw Hill. All Rights Reserved. Terms of Use Privacy Policy Notice Accessibility If the duration of AF exceeds 48 h or is unknown, there is greater concern for thromboembolism after cardioversion, even in patients considered low risk (CHA2DS2­VASc of 0 or 1 [see below]) for stroke. There are two approaches to mitigate the risk related to cardioversion. One option is to risk of thromboembolism. Thromboembolism can occur soon or several days after restoration of sinus rhythm if appropriate anticoagulation University of the Philippines ­ Manila measures are not taken. Access Provided by: Cardioversion within 48 h of the onset of AF is common practice in patients who have not been anticoagulated, provided that they are not at high risk for stroke due to a prior history of embolic events, rheumatic mitral stenosis, or hypertrophic cardiomyopathy with marked left atrial enlargement. These low­risk patients with occasional episodes of AF can be instructed to notify their physician when AF occurs to arrange for cardioversion to be done within 48 h. If the duration of AF exceeds 48 h or is unknown, there is greater concern for thromboembolism after cardioversion, even in patients considered low risk (CHA2DS2­VASc of 0 or 1 [see below]) for stroke. There are two approaches to mitigate the risk related to cardioversion. One option is to anticoagulate continuously for 3 weeks before and a minimum of 4 weeks after cardioversion. A second approach is to start anticoagulation and perform a TEE or high­resolution cardiac CT scan to detect the presence of thrombus in the left atrial appendage. If thrombus is absent, cardioversion can be performed and anticoagulation continued for a minimum of 4 weeks to allow time for recovery of atrial mechanical function. In either case, cardioversion of AF is associated with a substantial risk of recurrence, which may not be symptomatic. Longer­term maintenance of anticoagulation is considered based on the patient’s individual risk for stroke, commonly assessed using the CHA2DS2­VASc score. Acute Rate Control The goal of rate control in AF is to allow more diastolic filling time, improving cardiac output and reducing patient symptoms. In the longer term, adequate rate control will minimize the risk of congestive heart failure and tachycardia­induced cardiomyopathy. Acute rate control can be achieved with beta blockers and/or the calcium channel blockers verapamil and diltiazem administered either intravenously or orally, as warranted by the urgency of the clinical situation. Digoxin has been used for many years for rate control, particularly in patients susceptible to congestive heart failure, because it lacks the negative inotropic effect seen in calcium channel blockers and beta blockers. It acts synergistically with beta blockers and calcium channel blockers and, therefore, may be useful as an added agent when rate control is inadequate. However, recent evidence suggests increased mortality with its use, and so its utilization has declined. Chronic Rate Control For patients who remain in AF chronically, the goal of rate control is to both alleviate symptoms and prevent deterioration of ventricular function from excessive rates. β­Adrenergic blockers and calcium channel blockers are often used either alone or in combination. Exertion­related symptoms are often an indication of inadequate rate control. Rate should be assessed with exertion and medications adjusted accordingly. Adequate rate control is defined as a resting heart rate of 2), requires monitoring of PT/INR to adjust dose, and has many drug and food interactions that can hinder patient compliance and render maintaining a therapeutic effect challenging. The direct­acting agents are easier to use and achieve reliable anticoagulation promptly without requiring dosage adjustment based on blood tests. Dabigatran, rivaroxaban, and apixaban have renal excretion, cannot be used with severe renal insufficiency (creatinine clearance 65–75 years, heart failure, renal insufficiency, prior bleeding, and excessive alcohol or nonsteroidal anti­inflammatory drug use. In patients who require dual antiplatelet therapy (e.g., aspirin and clopidogrel) after coronary or peripheral arterial stenting, there is a substantially increased bleeding risk when standard oral anticoagulation with warfarin or a direct­acting anticoagulant is added. The optimal combination of agents for patients with AF who also require antiplatelet therapy remains unclear. Chronic anticoagulation is contraindicated in some patients due to bleeding risks. Because most atrial thrombi likely originate in the left atrial appendage, surgical removal of the appendage, combined with atrial maze surgery, may be considered for patients undergoing surgery, although removal of the appendage has not been unequivocally shown to reduce the risk of thromboembolism. Percutaneously deployed devices that occlude or ligate the left atrial appendage are also available, appear to be noninferior to warfarin in reducing stroke risk, and are considered in patients who have a high risk of thromboembolism but serious bleeding risk from chronic oral anticoagulation (Table 251­2). TABLE 251­2 Novel Oral Anticoagulant Dosing DABIGATRAN RIVAROXABAN APIXABAN EDOXABAN Standard 150 mg bid 20 mg qd 5 mg bid 60 mg qd dose Reduced 110 mg bid 15 mg qd 2.5 mg bid 30 mg qd dose Dose Dabigatran 110 mg bid in patients Creatine At least 2 of 3 criteria: age ≥80 If any of the following: creatinine clearance 30–50 reduction with: age ≥80 years, concomitant clearance 15–49 years, body weight ≤60 kg, or mL/min, body weight ≤60 kg, or concomitant use criteria use of verapamil, or increased mL/min serum creatinine ≥1.5 mg/dL of dronedarone, cyclosporine, erythromycin, or bleeding risk (133 mol/L) ketoconazole Note: As of publication, four novel or direct oral anticoagulants are available and indicated for stroke prevention for atrial fibrillation. The standard dosing, reduced dosing, and criteria for reduced dosing are shown for each agent. Rhythm Control The decision to administer antiarrhythmic drugs or perform catheter ablation to attempt maintenance of sinus rhythm (commonly referred to as the Downloaded 2024­8­4 10:15 A Your IP is 49.147.196.41 rhythm Chaptercontrol strategy 251: Atrial ) is mainly Fibrillation, guidedH.bySauer; William patient symptoms Paul C. Zei and preferences regarding the benefits and risks of therapies. In general, patients Page 7who / 11 maintain ©2024 sinus rhythm McGraw Hill. Allhave better Rights survival than Reserved. those Terms who continue of Use to have Notice Privacy Policy AF. This may be because continued AF is a marker of disease severity. In Accessibility older randomized trials, administration of antiarrhythmic medications to maintain sinus rhythm did not improve survival or symptoms compared to a rate control strategy, and the drug therapy group had more hospitalizations. Disappointing efficacy and toxicities of available antiarrhythmic drugs  Note: As of publication, four novel or direct oral anticoagulants are available and indicated for stroke prevention for atrial fibrillation. The standard dosing, reduced dosing, and criteria for reduced dosing are shown for each agent. University of the Philippines ­ Manila Access Provided by: Rhythm Control The decision to administer antiarrhythmic drugs or perform catheter ablation to attempt maintenance of sinus rhythm (commonly referred to as the rhythm control strategy) is mainly guided by patient symptoms and preferences regarding the benefits and risks of therapies. In general, patients who maintain sinus rhythm have better survival than those who continue to have AF. This may be because continued AF is a marker of disease severity. In older randomized trials, administration of antiarrhythmic medications to maintain sinus rhythm did not improve survival or symptoms compared to a rate control strategy, and the drug therapy group had more hospitalizations. Disappointing efficacy and toxicities of available antiarrhythmic drugs and patient selection bias may be factors that influenced the results of these trials. Recently, a randomized trial evaluating an early rhythm control strategy (within 1 year of initial presentation) compared to standard rate control demonstrated a reduction in cardiovascular events, including death from cardiovascular causes and stroke. Differences between this study and earlier randomized trials that failed to show a significant difference in outcomes in rate versus rhythm control included the use of catheter ablation and a high adherence rate to anticoagulation despite apparent rhythm control. In patients with heart failure due to depressed left ventricular function, a catheter ablation–based strategy to maintain sinus rhythm appears to provide mortality benefit compared with a medical rhythm control strategy. In a broader population of patients with AF, a large, randomized, prospective study comparing catheter ablation rhythm control medications demonstrated a nonsignificant trend toward reduced hospitalizations and improved mortality, mostly driven by patients with heart failure. A rhythm control strategy is usually selected for patients with symptomatic paroxysmal AF, recurrent episodes of symptomatic persistent AF, AF with difficult rate control, and AF that has resulted in depressed ventricular function or that aggravates heart failure. A rhythm control strategy is more likely to be favored in younger patients than in sedentary or elderly patients in whom rate control is more easily achieved. Even if sinus rhythm is apparently maintained, anticoagulation is recommended according to the CHA2DS2­VASc stroke risk profile because asymptomatic episodes of AF are common. Following a first episode of persistent AF, a strategy using AV nodal–blocking agents, cardioversion, and anticoagulation is reasonable, in addition to addressing possible aggravating factors. If recurrences are infrequent, periodic cardioversion is reasonable. However, if a patient has frequent symptomatic AF despite rate control, then a rhythm control strategy incorporating catheter ablation and/or antiarrhythmic medications is indicated. Based on recent randomized trial data demonstrating superiority of ablation over medications for maintenance of sinus rhythm and benefits of an early rhythm control strategy, there is a trend toward offering ablation earlier in the course of treatment, especially for individuals with paroxysmal AF. PHARMACOLOGIC THERAPY FOR MAINTAINING SINUS RHYTHM The goal of pharmacologic therapy is to maintain sinus rhythm or reduce episodes of AF. Risks and side effects of antiarrhythmic drugs are a major consideration in selecting therapy. Drug therapy can be instituted once sinus rhythm has been established or in anticipation of cardioversion. However, antiarrhythmic medications may in some instances pharmacologically cardiovert the patient into sinus rhythm. Therefore, an appropriate anticoagulation strategy approach similar to electrical cardioversion is recommended, particularly at the time of initiation of therapy. β­Adrenergic blockers and calcium channel blockers help control ventricular rate, improve symptoms, and possess a low­risk profile, but have low efficacy for preventing or terminating AF episodes. Class I sodium channel–blocking agents (e.g., flecainide, propafenone, disopyramide) are options for patients without significant structural heart disease, but negative inotropic and proarrhythmic effects warrant avoidance in patients with coronary artery disease or heart failure. The class III agents sotalol and dofetilide can be administered to patients with coronary artery disease or structural heart disease but have ~3% risk of inducing excessive QT prolongation and torsades des pointes. Dofetilide should be initiated only in a hospital with ECG monitoring, and many physicians take this approach with sotalol as well. Dronedarone increases mortality in patients with heart failure or long­ standing persistent AF. All of these agents have modest efficacy in patients with paroxysmal AF, of whom ~30–50% will benefit. Amiodarone is more effective, maintaining sinus rhythm in approximately two­thirds of patients. It can be administered to patients with heart failure and coronary artery disease. However, >40% of patients experience amiodarone­related toxicities during long­term therapy, and thus, careful monitoring of potential toxicities, including liver, lung, and thyroid abnormalities, must be accompanied with this therapy. CATHETER AND SURGICAL ABLATION FOR MAINTAINING SINUS RHYTHM Successful catheter ablation avoids antiarrhythmic drug toxicities, but procedural risks and efficacy depend on operator experience. For patients with previously untreated but recurrent paroxysmal AF, catheter ablation has superior efficacy compared to antiarrhythmic drug therapy, and ablation is even more clearly superior to antiarrhythmic drugs for patients who have recurrent AF despite drug treatment. Long­term control of AF is more difficult to achieve in patients with persistent AF, likely because of more extensive atrial abnormalities and associated greater comorbidities in these patients (Fig. 251­4). FIGURE 251­4 Downloaded 2024­8­4 A. Electroanatomic map10:15 A Your IP superimposed onisan 49.147.196.41 MRI reconstruction of a left atrium with mapping catheter in the left common pulmonary vein and Chapter ablation catheter at the pulmonary vein–left atriumPaul 251: Atrial Fibrillation, William H. Sauer; C. Zei junction. Page 8 / 11 B. Spontaneous pulmonary vein (PV) ectopy initiating fibrillatory conduction contained ©2024 McGraw Hill. All Rights Reserved. Terms of Use Privacy Policy Notice Accessibility within the isolated vein. even more clearly superior to antiarrhythmic drugs for patients who have recurrent AF despite drug treatment. Long­term control of AF is more difficult to achieve in patients with persistent AF, likely because of more extensive atrial abnormalities and associated greaterofcomorbidities University in these the Philippines ­ Manila patients (Fig. 251­4). Access Provided by: FIGURE 251­4 A. Electroanatomic map superimposed on an MRI reconstruction of a left atrium with mapping catheter in the left common pulmonary vein and ablation catheter at the pulmonary vein–left atrium junction. B. Spontaneous pulmonary vein (PV) ectopy initiating fibrillatory conduction contained within the isolated vein. Catheter ablation involves percutaneous venous access (typically via the femoral veins), trans(atrial) septal puncture, and radiofrequency ablation or cryoablation to electrically isolate the left atrial regions around the pulmonary vein antra, abolishing the ability of triggering foci in these regions to initiate AF and also likely impacting the substrate for reentry in the left atrium. Extensive areas of ablation are required, and gaps in healed ablation areas or emergence of new trigger sites outside the pulmonary veins necessitate a repeat procedure in 10–30% of patients. Several alternative energy sources to create ablative lesions are being evaluated for ablation of AF and other arrhythmias, including laser, external beam radiation, and pulsed field electroporation. In patients with paroxysmal AF, sinus rhythm is maintained for >1 year after a single ablation procedure in ~70% of patients and is achieved in >90% of patients after multiple procedures in some studies. Many patients become more responsive to antiarrhythmic drugs or become less symptomatic with a reduced AF burden after a pulmonary vein isolation procedure, and thus, repeat ablation may not be required for symptom control in some. Ablation is less effective in patients with persistent AF, particularly long­standing persistent AF, especially when associated with more extensive cardiac disease, comorbidities, and evidence of left atrial enlargement. More extensive ablation is often required, targeting areas that likely support reentry and/or AF maintenance and regions outside but adjacent to the pulmonary venous antra. There is no proven strategy for selecting ablation targets outside the pulmonary vein antral regions, and a variety of approaches have been pursued. Ablation of areas of rapid activity during AF and creation of ablation lines to block conduction across regions of the atria have not been proven to improve outcomes in unselected patients. Other ablation targets include non–pulmonary vein foci that fire in response to high­dose isoproterenol, areas of atrial fibrosis, and regions with repetitive rotational or focal activation during AF. More than one ablation procedure is often required to maintain sinus rhythm in patients with persistent and long­standing persistent AF because of lack of lesion durability and complex atrial substrate with non–pulmonary vein sources that may be incompletely treated at the initial ablation session (Fig. 251­5). FIGURE 251­5 Rhythm control strategy for symptomatic atrial fibrillation (AF). This chart outlines the guideline­based management of patients with Downloaded symptomatic 2024­8­4 10:15 AAsYour atrial fibrillation. IP isin49.147.196.41 outlined Table 251­1, the first step is determination of the temporal nature of the patient’s AF (paroxysmal vs Chapter 251: Atrial Fibrillation, William H. Sauer; Paul C. Zei Page 9 / 11 persistent) and any associated risk factors for AF recurrence, such as left atrial anatomic dimensions. A decision is then made regarding medical versus ©2024 McGraw Hill. All Rights Reserved. Terms of Use Privacy Policy Notice Accessibility catheter ablation–based rhythm control, with recommendations for when to consider catheter ablation based on guideline recommendations (class IIa for paroxysmal, IIb for persistent without major risks for recurrence, or AF of any sort in patients with heart failure with reduced ejection fraction persistent AF because of lack of lesion durability and complex atrial substrate with non–pulmonary vein sources that may be incompletely treated at University of the Philippines ­ Manila the initial ablation session (Fig. 251­5). Access Provided by: FIGURE 251­5 Rhythm control strategy for symptomatic atrial fibrillation (AF). This chart outlines the guideline­based management of patients with symptomatic atrial fibrillation. As outlined in Table 251­1, the first step is determination of the temporal nature of the patient’s AF (paroxysmal vs persistent) and any associated risk factors for AF recurrence, such as left atrial anatomic dimensions. A decision is then made regarding medical versus catheter ablation–based rhythm control, with recommendations for when to consider catheter ablation based on guideline recommendations (class IIa for paroxysmal, IIb for persistent without major risks for recurrence, or AF of any sort in patients with heart failure with reduced ejection fraction [EF], class I). Note the importance of patient choice, as well as the subsequent decisions to consider catheter ablation if drugs have failed. (G Hindricks et al: 2020 ESC Guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association of Cardio­ Thoracic Surgery (EACTS). Eur Heart J 42:17, 2020. (Translated and) Reprinted by permission of Oxford University Press on behalf of the European Society of Cardiology.) Catheter ablation has a 2–7% risk of major procedure­related complications, with the long­term trend suggesting steady improvement in complication rates. Complication rates are clearly lowest with high­volume operators and centers. Complications including stroke (0.5–1%), cardiac tamponade (1%), phrenic nerve paralysis, bleeding from femoral access sites, and fluid overload with heart failure, which can emerge 1–3 days after the procedure. It is important to recognize the potential for delayed presentation of some complications. Ablation within the PV can lead to PV stenosis, presenting weeks to months after the procedure with dyspnea or hemoptysis. The esophagus abuts the posterior wall of the left atrium where it is subject to injury, and esophageal ulcers can form immediately after the procedure and may rarely lead to a fistula between the left atrium and esophagus (estimated incidence of