Medical, Interventional, and Surgical Treatment Strategies for Atrial Fibrillation

Background: Atrial fibrillation is the most common type of cardiac arrhythmia; the lifetime risk for a 55-year-old person to develop atrial fibrillation is 37%. In recent years, there have been various distinct changes in the clinical management of AF.

Methods: This review is based on a selective search for literature on the treatment of AF and the prevention of thromboembolic complications. The updated guideline of the European Society of Cardiology (ESC) for the diagnosis and treatment of AF was also taken into consideration.

Results: The main components of AF management are the comprehensive treatment of risk factors and concomitant diseases, as well as the prevention of thromboembolic complications, usually with non–vitamin-K-dependent oral anticoagulants or vitamin K antagonists, according to individual risk stratification. Beyond this, either rate or rhythm control are viable treatment concepts. Symptomatic patients in whom reversible causes have been ruled out should be offered rhythm-control therapy early in their course. In patients with risk factors and/or heart failure, an early rhythm control strategy has been found to be beneficial. As antiarrhythmic drugs often prove to be ineffective over the long term, catheter ablation is now becoming increasingly important in AF management.

Conclusion: The clinical management of atrial fibrillation consists of a multimodal approach with risk stratification, lifestyle modification, prevention of thromboembolism, and, if possible, early rhythm control therapy.

Atrial fibrillation (AF) is the most commonly occurring form of persistent cardiac arrhythmia. Currently, one out of three persons aged 55 years can expect to be affected by AF over the course of their lifetime. The incidence of AF increases with age (< 60 years 0.7%, > 85 years 17.8%). Data from Germany show a prevalence of 4.6% for men and 1.9% for women (1).

The presence of classical cardiac risk factors (e.g., smoking, diabetes mellitus, overweight, arterial hypertension) favors the occurrence of AF (e1), and the risk is also increased by a positive family history (odds ratio [OR] 1.85, 95% confidence interval [1.12; 3.06]) (e2).

The technological advances that have given patients access to information about their heart rhythm are accompanied by new technical procedures and proven drug treatments for the management of AF itself and the prevention of thromboembolic complications. Recent randomized studies have yielded the first evidence regarding improvement in the prognosis of AF in patients with risk factors by early rhythm control. An updated version of the ESC guidelines on AF therapy features a pathway for the treatment of this form of cardiac arrhythmia (2).

Learning goals

After completion of this article, readers should:

• Know the definition and diagnostic criteria for AF and be familiar with the treatment pathway for AF and the options for multimodal therapy
• Be aware of the indications for oral anticoagulation and the alternative treatment options in the presence of contraindications.
• Be familiar with the pharmacological, interventional, and surgical treatment concepts and their respective roles in the management of AF.

Basic principles, diagnosis, and clinical findings

Atrial fibrillation is a supraventricular arrhythmia with uncoordinated electrical stimulation of the atria. The electrocardiographic hallmarks of AF are the absence of P-waves; irregular, chaotic waves; and inconsistent R–R intervals (as long as there is no simultaneous third-degree AV block). Persistence of AF for at least 30 s is necessary for diagnosis. A 12-lead ECG should be used for documentation. Single-lead ECG is an alternative (rhythm strip), but documentation must last at least 30 s (2). The typical symptoms of AF include tachycardia, palpitations, shortness of breath, weakness, angina pectoris-like symptoms, dizziness, and syncope. The number and severity of symptoms varies, and some cases (up to 40%) show no symptoms at all (e3). The current guidelines recommend opportunistic screening for AF (e.g., when consulting a physician for another reason) in persons over 65 years of age and in patients with risk factors (such as arterial hypertension or obstructive sleep apnea syndrome) (class I-B indication). Clinical examination, for example palpation of the pulse and auscultation, remains an essential component of the screening process. Alongside the determination of routine laboratory parameters (especially thyroid function), transthoracic echocardiography should be carried out in every newly diagnosed case of AF to detect any secondary causes (e.g., cardiac valve defects) and/or secondary ailments (e.g., heart failure).

New devices such as smartwatches, pulse monitors, and handy (single-lead) ECG appliances are being used with increasing frequency (Box). Theoretically, this may be useful in making the diagnosis (Table 1). Many of these devices have not yet been validated. There is also uncertainty regarding whether or not brief and asymptomatic episodes of arrhythmia even represent a disease, and whether initiating treatment in such cases is beneficially or harmful (Box). Therefore, such episodes should be assessed by physicians with experience in evaluating ECG findings, and in the case of uncertainty an ECG should be performed to confirm the arrhythmia (2).

Box

Various devices and their mode of function, benefits, and limitations (adapted from [2])

Table 1

Sensitivity and specificity compared with 12-lead ECG (adapted from [2])

The clinical classification of AF can be made on the basis of the duration of the episodes and the pattern of termination. Five subtypes are distinguished: first diagnosis, paroxysmal AF, persistent AF, long-standing persistent AF, and permanent AF (e4). Classification by symptom severity ensues according to the EHRA scoring system (e3).

The treatment pathway of the updated ESC guidelines incorporates a novel characterization for the purpose of structured management. The 4S-AF scheme, comprising evaluation of stroke risk, symptom severity, severity of AF burden, and the nature of the arrhythmogenic substrate, is intended to enable more comprehensive assessment of each individual patient (Figure). Existing classification and scoring systems, such as the CHA₂DS₂-VASc score for estimation of the risk of thromboembolism, should be used. The goal is a more holistic analysis and assessment of the patients in order to enable optimized management according to the ABC treatment pathway (anticoagulation, better control of symptoms, cardiovascular risk factors/comorbidities) in all aspects of care (Figure). However, it has not yet been demonstrated that use of the 4S-AF scheme yields clinical benefits.

Prevention of thromboembolic complications: drug treatment, intervention, surgery

Atrial fibrillation leads to functional and structural modifications of the atrial myocardium that culminate in a prothrombotic milieu favoring thrombus formation, particularly in the left atrial appendage (4). The risk of stroke is increased fivefold by the presence of AF (e5). It is therefore advisable to determine whether administration of oral anticoagulants (OAC) is indicated in each individual case. The CHA₂DS₂-VASc score should be taken into account in making this decision (5). In contrast to previous classifications, “female sex” is counted as a risk modifier rather than a risk factor. OAC are generally not recommended in men with a score of 0 or women with a score of 1. In men with a score ≥ 2 and women with a score ≥ 3, the risk of thromboembolism is so high that OAC are generally recommended, as long as the bleeding risk is not considered to be increased by administration of OAC (HAS-BLED score) (class I-A recommendation). In intermediate cases (a score of 1 for a man or 2 for a woman), OAC are not necessarily recommended but may represent an option in some individuals and should be given, or not, depending on the patient’s circumstances (class IIa recommendation) (2).

The classical OAC were vitamin K antagonists (VKA), with which the risk of stroke could be reduced by 64% (95% confidence interval [49%; 74%]) and that of overall mortality by 26% (95% CI [3%; 43%]) (6). The novel OAC (NOAC) (apixaban, dabigatran, edoxaban, rivaroxaban) are efficacious, safe, and simpler-to-use alternatives (7). Treatment with NOAC lowers the risk of systemic thromboembolic complications and ischemic stroke (OR 0.89, 95% CI [0.82; 0.97]) and also of severe hemorrhagic complications (especially intracranial bleeding: OR 0.50, 95% CI [0.42; 0.59]) compared with VKA therapy (8). The efficacy of optimal VKA treatment (time in therapeutic range, TTR > 70%) has been described as comparable with that of NOAC. The bleeding rates, however, are higher, although the difference in absolute terms is small. When OAC therapy is initiated, or in the event of unstable INR (TTR < 70%), the updated ESC guidelines recommend NOAC in preference to VKA. Effective VKA treatment (TTR > 70%) can be continued (2, 9). AF in patients with moderate or severe mitral valve stenosis or a mechanical heart valve replacement (previously known as valvular AF) requires VKA treatment—NOAC are contraindicated in this scenario. Elevated rates of thromboembolic complications and hemorrhagic complications were observed in patients with mechanical valve replacements who were treated with NOAC (10); for mitral valve stenosis and NOAC, the data are insufficient. Treatment with thrombocyte aggregation inhibitors alone is never advisable for the prevention of thromboembolism.

Because administration of OAC is associated with an elevated risk of bleeding, a validated score such as the HAS-BLED score or the ORBIT bleeding risk score should be used (9). A patient with a HAS-BLED score ≥ 3 has an elevated risk of bleeding, which must be considered when deciding on the appropriate treatment (e6). However, this should by no means lead to OAC being denied to suitable patients. Rather, the score should serve to identify and address modifiable risk factors (e.g., uncontrolled arterial hypertension; unstable INR; comedication with non-steroidal antirheumatic drugs [NSAID], thrombocyte aggregation inhibitors, or prednisolone; and alcohol consumption) and to ensure closer monitoring of of patients at risk (2). If the bleeding risk predominates, however, this may speak against OAC.

Severe or recurrent bleeding (e.g., intracranial, gastrointestinal, or urogenital) and advanced renal failure both have the potential to make long-term administration of OAC difficult or even impossible. In such cases, selected patients may benefit from interventional left atrial appendage occlusion (LAAO) (2, 4). In this procedure, an occluder system is introduced into the left atrium via a catheter and anchored in the atrial appendage, thus blocking it. Following implantation, the continuation of oral anticoagulation or dual thrombocyte aggregation inhibition is required for a specific period (at least 1 to 3 months). Randomized comparisons of LAAO and treatment with VKA suggest non-inferiority; however, these studies are limited by, for example, the use of combined endpoints, low case numbers, and inconsistency of results (4, e7, e8, e9). Direct comparison with NOAC treatment is still being evaluated; one small randomized study in high-risk patients has shown non-inferiority, but with a combined endpoint (e10). Currently, therefore, no general benefit of LAA occluders can be assumed.

Surgical occlusion of the atrial appendage is usually performed in the context of planned heart surgery and may comprise suture occlusion or complete amputation of the LAA. Devices are available for occlusion of the appendage by means of a clip (11). Theoretically, these devices offer the option of an isolated intervention via minithoracotomy (e11). However, no randomized direct comparisons with OAC have been performed, so the role of surgical LAA occlusion remains unclarified. Interesting evidence of the potential benefit of combined treatment has emerged from the recently published (randomized) LAAOS-III study (e12), which showed a significant reduction in risk (hazard ratio [HR] 0.67, 95% CI [0.53; 0.85]) after surgical LAAO together with administration of OAC.

Atrial appendage occlusion presents a complementary option for prevention of thromboembolism. Until more robust data from studies are available, however, this procedure should be reserved for selected high-risk patients and used only on an individual basis. The recommendation for interventional and surgical occlusion of the atrial appendage is currently class IIb (B or C).

Lifestyle modification/treatment of comorbidities and risk factors

Patients with AF frequently also have concomitant diseases such as arterial hypertension, coronary heart disease, obesity, or sleep apnea syndrome. After exclusion of secondary causes (e.g., hyperthyroidosis or infection-related events), treatment, particularly of the classical cardiovascular risk factors, should be initiated. For example, the encouragement of moderate exercise, active weight loss (> 10% reduction in weight = sixfold increase in the likelihood of freedom from arrhythmia: 95% CI [3.4; 10.3]) (12), and, in regular drinkers, abstinence from alcohol (HR 0.55, 95% CI [0.36; 0.84]) (13) can reduce the occurrence of AF. Optimization of blood lipid levels, systematic treatment of lipid metabolism disorders and (pre)diabetes, and cessation of smoking constitute appropriate treatment measures (e13, 14). Moreover, screening for suspected obstructive sleep apnea syndrome should be carried out, followed if necessary by treatment. This holistic approach to treatment, embracing the risk factors and comorbidities, should be a fixed component of the treatment pathway (2).

Treatment of atrial fibrillation: rate control or rhythm control?

A central question in the management of AF is whether to strive for rhythm control, with the goal of restoring and maintaining sinus rhythm, or to tolerate AF provided the rate is adequately controlled.

Principles of rate control

Tachycardic conduction via the AV node is a typical finding in AF. In addition to symptoms, it may lead to a reduction in left ventricular ejection fraction or worsening of existing heart failure. If other (e.g., ischemic, valvular, or inflammatory) causes have been ruled out, this is termed arrhythmia-induced cardiomyopathy—a potentially reversible condition. The optimal target rate is not clearly defined. Large randomized studies have shown no difference with regard to clinical events, NYHA stage, or hospitalization between strict control of heart rate (< 80/min at rest and < 110/min during light exercise) and a moderate target rate (< 110/min at rest). A rate of < 110/min thus seems acceptable in patients without arrhythmia-induced heart failure or tachycardia-associated symptoms (15, 16). Beta-blockers, calcium-channel blockers of the non-dihydropyridine type, digoxin/digitoxin, and, in principle, amiodarone can be considered for pharmacological control of heart rate. In this way (under study conditions), a target rate of < 110/min can be achieved in 97% of cases and of < 80/min in 67% (16). In the acute setting, once other causes of tachycardia (such as inflammation or anemia) have been excluded the agents of choice are beta-blockers and calcium-channel blockers, due to their quick response. For longer-term treatment the choice of drugs depends on what concomitant diseases are present. For instance, calcium-channel blockers would be preferred to beta-blockers in a patient with (severe) asthma or COPD (even when there is no strict contraindication), but should not be used in patients with heart failure. Digitalis or amiodarone can be considered for second-line treatment. Digitalis is usually more effective in the elderly due to the lower sympathetic tone in this age group. However, the drug exposure should be kept low. If amiodarone is used, a conversion to sinus rhythm may occur. Therefore, a 3-week period of effective oral anticoagulation is required or a transesophageal echocardiography should be performed to rule out intracardiac thrombi to prevent thromboembolic events. Long-term amiodarone treatment should not be used for rate control because of its pronounced adverse event profile. In such cases, or in the event of inadequate drug treatment, as a last resort rate control can be achieved by means of catheter ablation of the AV node and thus permanent pacemaker treatment or cardiac resynchronization therapy (CRT). Owing to its irreversibility, this option is usually considered only in elderly patients with long-standing persistent AF (e14). His-bundle pacing with consecutive physiological stimulation of the ventricles has been used increasingly often in recent years and appears promising, but still needs to be evaluated in randomized trials (e15).

Principles of rhythm control

Various forms of treatment can be considered for the establishment and maintenance of sinus rhythm: drug treatment, intervention, surgery, or combinations thereof. In the acute scenario electrical cardioversion can rapidly re-establish sinus rhythm and is associated with a high success rate (94.2%) and only few complications (proarrhythymic effects due to lacking R-peak synchronization, bradycardia, cutaneous burns, or sedation-related problems) (e16). In hemodynamically stable patients transesophageal echocardiography should be carried out first to rule out intracardiac thrombi, unless there has been continuous and effective oral anticoagulation for at least 3 weeks or the episode of AF is shorter than 48 h (2). Electrical cardioversion is not a causal treatment, however; > 50% of patients have a recurrence within 1 year (e17, e18).

Drug treatment

Specific pharmacological antiarrhythmic treatment can terminate and and decrease AF burden (Table 2) (17). Nevertheless, AF recurs in 43 to 67% of patients on antiarrhythmic treatment (mean follow-up 10 months). Furthermore, adverse events or proarrhythmic effects occur (Table 2) (17). Even increased mortality has been reported for chinidine and sotalol (17). In Germany, therefore, the class IC antiarrhythmics flecainide and propafenone are frequently used. These substances may also be given, if required, to treat (occasional) AF episodes. However, they should be used only in patients with no structural heart disease (contraindications: heart failure/reduced left ventricular ejection fraction [LVEF], status post myocardial infarction or LV hypertrophy [wall thickness ≥ 14 mm]) (2, 18). Particularly in patients with structural heart disease (especially in the presence of reduced LVEF), therefore, amiodarone is the sole option. Amiodarone is the most effective antiarrhythmic, but, particularly when used in the long term, has the potential to cause adverse events (sometimes severe), e.g., thyroid function disorders, pulmonary fibrosis, corneal deposits, hepatitis, and cutaneous discoloration. When antiarrhythmic therapy is started, ECG monitoring (sometimes in the form of ambulatory ECG) is required, with special attention paid to the QTc time and prevention of proarrhythmic effects (19).

Table 2

A selection of antiarrhythmic drugs: efficacy, proarrhythmia, and adverse effects; from (17)

Catheter ablation

The primary indication for catheter ablation is failure of antiarrhythmic treatment (class I recommendations [Figure 1]). Recent studies have focused on ablation as the primary treatment option (Table 3). The principal reason for this is the superior rhythm control, although no general improvement in prognosis has yet been shown (20). The ESC guidelines give a class IIa recommendation for catheter ablation as primary treatment (no prior drug therapy) in symptomatic paroxysmal AF and a class IIb recommendation for symptomatic persistent AF. In the presence of arrhythmia-induced cardiomyopathy, there is a class I recommendation for primary catheter ablation (Figure 1) (2). The goal of catheter ablation is electrical isolation of the pulmonary veins from the left atrium (e19). This is usually achieved by means of radiofrequency (RF) ablation or the cryoballoon technique (Figure 2). Randomized trials (e20, e21) have shown that these two procedures are equally effective in symptomatic paroxysmal AF (53% versus 65% freedom from recurrence, > 98% lower AF burden; RR 0.84 [0.65; 1.07]) (21). Cryoballoon ablation is associated with shorter procedure times but a tendency towards longer imaging times; more phrenic nerve lesions (almost always reversible) and fewer pericardial effusions occur than with RF ablation (22). Alternative energy forms are being evaluated (e22). The treatment of paroxysmal AF is associated with higher success rates than that of persistent AF (23, e23). Because catheter ablation may be followed by asymptomatic episodes (ca. 15%) (e24) and late episodes of AF, long-term continuation of OAC is recommended following catheter ablation, guided by the CHA₂DS₂-VASc score. To date there are no robust data from randomized controlled trials enabling adequate stroke risk assessment after catheter ablation.

Figure 1

Management of patients with atrial fibrillation

Figure 2

Catheter ablation for isolation of the pulmonary veins using high-frequency ablation (a) or the cryoballoon technique (b)

Table 3

A selection of recent and relevant randomized controlled trials on rhythm-preserving treatment

The rate of periprocedural complications associated with catheter ablation is low at experienced centers. Complications at the puncture sites occur most frequently and can be severe in 2–4% of cases. The periprocedural mortality is < 0.2%. The principal potentially serious complications are pericardial tamponade (1–2%), stroke (< 1%), and esophageal fistula/perforation (< 0.5%) (2).

Randomized studies have shown that catheter ablation is superior to drug treatment with regard to amelioration of the symptoms, with better quality of life (24), better maintenance of sinus rhythm, and lower rates of hospitalization. A meta-analysis of six randomized controlled trials found that symptomatic atrial arrhythmias occurred in 11.8% of cases after ablation, compared with 26.4% after drug treatment (RR 0.44 [0.27; 0.72], p = 0.001) (Table 3) (25, 26). The prognostic benefit indicated in one meta-analysis (26) was determined largely by patients with heart failure. While the prognosis of the patients who had restricted left ventricular function was better with catheter ablation than with drug treatment, this result cannot be extrapolated to the “general” patient population (20, 27, 28, e25). Also after catheter ablation, lifestyle modification on the part of obese patients is crucial in reducing the risk of recurrence (29).

Surgical treatment options

The development of the Cox maze procedure has provided a surgical option for the treatment of AF (30). In this technique the pulmonary veins are isolated and other segments of the atrium are electrically separated from one another by means of multiple incisions. Bipolar high-frequency ablation forceps and cryobased instruments are used for this purpose (30). To date, the Cox maze procedure has mostly been performed intraoperatively during planned open heart surgery (31). One randomized study reporting 5 years’ follow-up has been published. The authors describe superiority of the procedure regarding sinus rhythm maintenance, but the study had no statistical validity for assessment of stroke risk (e26). Surgical ablation as an accompaniment to heart surgery is accorded a class IIa-A indication (2).

A minimally invasive thoracoscopic technique is also available and can be carried out alone in selected patients. This procedure is associated with a 66–90% rate of freedom from arrhythmia after 12 months, but involves higher procedural risk than catheter ablation; however, the published randomized studies are few in number and heterogeneous (class IIa-B indication) (e27). The guidelines give a class I recommendation for continuation of OAC according to the CHA₂DS₂-VASc score even after surgical treatment of AF and, if performed, atrial appendage occlusion.

Prognostic aspects/perspective

The randomized AFFIRM trial, published in 2002, showed that rhythm control conferred no survival benefit while causing a higher rate of adverse events (32). However, the study included a large number of asymptomatic elderly patients with long-standing persistent AF—a group of patients that, from today’s point of view, are not favorable candidates for a rhythm control strategy. Catheter ablation was not a commonly used treatment strategy at that time, and follow-up of subgroups revealed a mortality advantage for patients with sinus rhythm (e28).

The recently published randomized EAST-AFNET 4 trial makes a major contribution to this topic (33). The crucial point is early initiation of therapy, immediately after diagnosis, in patients at elevated risk of stroke. After 5 years’ follow-up, a treatment regimen targeting rhythm control, including drug treatment and/or catheter ablation, was superior to conventional drug treatment (rate control) with regard to the primary combined endpoint (cardiovascular death, stroke, hospitalization due to heart failure or acute coronary syndrome: HR 0.79, 96% CI [0.66; 0.94]; p = 0.005). Other recent randomized studies reinforce the evidence for early interventional management by means of catheter ablation versus drug treatment (34, 35), and the progression of paroxysmal AF to persistent AF also seems to be controlled more effectively by an interventional procedure than by antiarrhythmics (Table 2) (36, e29). However, the intention-to-treat analysis in the CABANA trial (Catheter Ablation vs. Anti-arrhythmic Drug Therapy for Atrial Fibrillation) showed no reduction in cardiovascular events or mortality compared with drug treatment (20).

The results of recent studies confirm the role of catheter ablation in the treatment of atrial fibrillation. This procedure should therefore be offered at an early stage in the management of the patients concerned, as part of a holistic approach with the appropriate treatment of cardiovascular risk factors and prevention of thromboembolism with oral anticoagulants.

Conflict of interest statement
Dr. Gunawardene has received reimbursement of congress registration charges and travel and accommodation costs from Boston Scientific Fellowship and of lecture fees from CTI.

Dr. Eickholt has received consultancy fees from Abbott, Biosense Webster, Biotronik, and Daiichi Sankyo; reimbursement of congress registration charges from Biotronik and Biosense Webster; and lecture fees from Abbott, Biotronik, Medtronic, and Boston Scientific.

Prof. Willems has received consultancy fees from Boston Scientific, Abbott, BMS, Boehringer Ingelheim, and Daiichi Sankyo.

Dr. Hartmann has received reimbursement of congress registration charges from Boston Scientific and Biosense Webster and of travel and accommodation costs from Boston Scientific.

The remaining authors declare that no conflict of interest exists.

Manuscript received on 4 March 2021, revised version accepted on 14 July 2021

Translated from the original German by David Roseveare

Corresponding author
Prof. Dr. med. Stephan Willems
Klinik für Kardiologie und Internistische Intensivmedizin
Asklepios Klinik St. Georg
Lohmühlenstr. 5, 20099 Hamburg, Germany

Cite this as:
Willems S, Gunawardene MA, Eickholt C, Hartmann J, Schmoeckel M, Schäffer B: Medical, interventional, and surgical treatment strategies for atrial fibrillation. Dtsch Arztebl Int 2022; 119: 11–22. DOI: 10.3238/arztebl.m2022.0002

►Supplementary material

eReferences:
www.aerzteblatt-international.de/m2022.0002

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