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Contemporary management of persistent atrial fibrillation
  1. Dhiraj Gupta,
  2. Wern Yew Ding
  1. Liverpool Centre for Cardiovascular Science, University of Liverpool and Liverpool Heart & Chest Hospital, Liverpool, UK
  1. Correspondence to Dr Dhiraj Gupta, Liverpool Centre for Cardiovascular Science, University of Liverpool and Liverpool Heart & Chest Hospital, Liverpool, UK; dhiraj.gupta{at}

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Learning objectives

  • Develop a basic understanding of the underlying mechanisms of atrial fibrillation and classification of the disease.

  • Review the main principles in contemporary management of atrial fibrillation with a focus on persistent atrial fibrillation.

  • Discuss catheter ablation in the context of atrial fibrillation.


Atrial fibrillation (AF) is a multisystemic disorder that is associated with an excess risk of stroke, heart failure and mortality.1 It remains the most common sustained arrhythmia and its significance should not be underestimated. Research focused on unveiling the mechanisms of AF began over a century ago. During this period, several theories have been proposed. More recently, the notion of rotors and spiral waves propagating in the atria was used to address the flaws of prior concepts and enhance our understanding on the development of AF.2 3 Presently, it is believed that the initiation and maintenance of AF is linked to a complex interplay between two crucial components: ‘trigger’ and ‘substrate’. The former refers to one or more ectopic foci that initiate rapid electrical activity resulting in depolarisation of surrounding cardiac myocytes. Maintenance of AF is subsequently dependent on the presence of a suitable substrate in terms of electrophysiological, mechanical and anatomical properties.4 The biggest breakthrough in our understanding of AF occurred two decades ago when Haïssaguerre et al demonstrated the role of pulmonary veins as the most common sites of triggers for the disease.5 This observation serves as the fundamental basis for ablation therapy for AF.

In practice, AF is frequently diagnosed following an incidental finding of uncoordinated atrial activation on a timely surface ECG; subsequent classification of the disease is based on temporal rhythm-based patterns (table 1).6 The latter concept stems from the idea that many patients who develop AF initially suffer from paroxysmal episodes due to triggers that promote substrate remodelling over time to support prolonged episodes of the arrhythmia, thereby progressing to more advanced forms of the disease (eg, persistent AF (persAF)) (figure 1). In this educational review, we will discuss the four pillars of contemporary AF management that comprises risk factor modification, stroke prevention, rhythm control and rate control, with a particular focus on persAF.

Figure 1

Ultra-high-density voltage maps of the left atrium from a posterior view in patients with paroxysmal and persistent AF. Areas with a voltage above 0.5 mV are highlighted in purple and represent healthy myocardium while other areas of lower voltage demonstrate scar tissue. The patient with persistent AF has a globular, dilated left atrium, with a significantly higher proportion of scar tissue that reflects advanced atrial cardiomyopathy. AF, atrial fibrillation; LLPV, left lower pulmonary vein; LUPV, left upper pulmonary vein; RLPV, right lower pulmonary vein; RUPV, right upper pulmonary vein.

Table 1

Classification of atrial fibrillation (AF)6

Limitations of current AF classification

Although the current pattern-based classification of AF is simple, practical and widely adopted, there are several limitations that are worth considering. Foremost, it provides poor discrimination between patients on the basis of stage and severity of the underlying disease, prognosis or indications for therapeutic intervention.7 8 Hence, it does little to encourage an appreciation for the heterogenous nature of this condition and the implications it may have on treatment strategies and outcomes. Second, in the absence of continuous cardiac monitoring, the accuracy of this classification remains questionable. Clinicians are mostly reliant on the presence of patient-reported symptoms and snapshots of electrocardiographic tracings performed at widely spaced intervals to categorise patients. This may result in the misclassification of a significant proportion of patients,9 10 which can have significant clinical implications in terms of treatment strategies. For example, patients with persAF typically only undergo pulmonary vein isolation while those with more advanced disease may receive additional ablation lesion sets (eg, posterior wall isolation). Furthermore, the classification system fails to account for active interventions that may influence the duration of AF episodes, for example, use of antiarrhythmic drugs (AADs). In this regard, a patient with previous persAF who now suffers from paroxysmal episodes after catheter ablation and with ongoing treatment with AADs are classified in the same group as patients with persAF without treatment. Due to the aforementioned reasons, the classification of AF remains a subject of controversy and debate.

Risk factor modification

It is being increasingly recognised that AF may be a ‘lifestyle’ disease for many, as it frequently coexists with obesity, hypertension, diabetes and other comorbidities.11 During previous years, upstream therapy for AF was largely relegated to the sidelines, with most of our attention being directed at stroke prevention and ensuring adequate symptom relief. However, the recent 2020 European Society of Cardiology guidelines emphasise the importance of this approach and provide a much broader perspective on the types of upstream therapy that we should consider.6 Modifiable risk factors in primary and secondary prevention of AF are summarised in box 1. The detection and management of each have previously been described in detail.12

Box 1

Modifiable risk factors associated with atrial fibrillation

  • Hypertension

  • Diabetes mellitus

  • Coronary artery disease

  • Heart failure

  • Valvular heart disease

  • Chronic kidney disease

  • Obesity

  • Obstructive sleep apnoea

  • Hyperthyroidism

  • Smoking

  • Chronic obstructive pulmonary disease

  • Excessive alcohol intake

  • Excessive exercise

In terms of risk factor modification, there is emerging evidence demonstrating the benefits of a structured, focused and tailored approach among patients with AF compared with offering mere general lifestyle advice. For example, a physician-led weight loss programme has been shown to contribute to significantly greater weight reduction in overweight patients or patients with obesity with AF, resulting in lower AF symptom burden and severity scores, plus reduced AF episodes and duration compared with self-directed general lifestyle measures.13 Nonetheless, focusing on weight loss alone may not be sufficient in patients with advanced persAF,14 where the management of other risk factors may be of equal importance.15 Indeed, implementation of a combined weight loss programme (inclusive of dedicated clinic reviews, individualised counselling, a meal plan and exercise prescription) and aggressive management of risk factors (such as hypertension, dyslipidaemia, glucose intolerance, obstructive sleep apnoea, smoking and excess alcohol intake) have been found to reverse the natural progression of AF in a significant proportion of patients.16 This highlights the dynamic nature of AF and the importance of risk factor modification. Overall, AF is in many ways a ‘lifestyle disease’ and we cannot afford to continue to bench risk factor modification as a passive observer.

Stroke prevention

AF is characterised by a prothrombotic state17 and therefore stroke prevention is an integral element to improve the prognosis of these patients, perhaps even more so in those with higher AF burden as is the case in patients with persAF.18 Treatment decisions are based on risk assessments to inform clinicians and patients of the potential risks versus benefit of anticoagulation. Currently, international guidelines recommend that every patient, apart from those at low risk, should be offered anticoagulation therapy.6 The main therapeutic options are between vitamin K antagonists (eg, warfarin and acenocoumarol) and non-vitamin K oral anticoagulants (eg, dabigatran, apixaban, rivoraxoban and edoxaban). An in-depth discussion of these agents is beyond the scope of this review. Nonetheless, there are patients for whom none of these options is appropriate. In this setting, left atrial appendage (LAA) occlusion may be considered among patients with non-valvular AF.

There is emerging evidence for the effectiveness of LAA occlusion as an alternative to oral anticoagulation in certain patients.19 This invasive procedure is predicated on the understanding that the vast majority of systemic emboli in non-valvular AF originate from the LAA and therefore, isolation of this structure from the circulatory system should prevent most embolic events. LAA occlusion may be performed percutaneously using either endocardial or epicardial access, or surgically in conjunction with other cardiac surgery. While numerous observational studies have shown feasibility and efficacy of LAA occlusion in a variety of patients with non-valvular AF for whom long-term oral anticoagulation may not be appropriate,15 data from randomised controlled trials are lacking in these populations. Hence, specialist advice and a multidisciplinary team approach should be implemented whenever a potential candidate is identified. Indications to consider a referral for LAA occlusion are shown in box 2. Importantly, access to percutaneous LAA occlusion is restricted in many healthcare systems, including in the UK, and it should not be offered to patients as an alternative to oral anticoagulants.20

Box 2

Indications to consider referral for left atrial appendage occlusion*

  • Previous life-threatening or major bleeding event(s) due to non-transient causes

  • High risk of major bleeding on oral anticoagulation (eg, cerebral amyloid angiopathy, clotting disorders)

  • Ischaemic stroke despite compliance with oral anticoagulant therapy

  • Severe side effects or allergic reaction to multiple anticoagulant medications

  • *Applies only to patients with atrial fibrillation, where the use of anticoagulation is warranted for stroke prevention.

Rhythm control

Rhythm control in AF comprises several approaches, each with an aim of establishing sinus rhythm. It encompasses direct current cardioversion (DCCV), pharmacological medications with AADs and invasive procedures such as catheter or surgical ablation. Historical studies performed at the end of the last century had failed to demonstrate any prognostic advantage with rhythm control over rate control in persAF21 or otherwise.22 However, these studies had several limitations, including high rates of anticoagulation discontinuation in patients randomised to the rhythm control arm. Furthermore, many patients in these studies were those who would have been classified today as being in long-standing persistent AF or permanent AF. Indeed, the recently published EAST trial has shown that early institution of rhythm control in patients with newly diagnosed AF of <12 months reduced the composite end point of death from cardiovascular causes, stroke and hospitalisation with worsening heart failure or acute coronary syndrome.23 As such, while the current mainstay purpose for rhythm control is to provide symptom-relief and improve quality of life, it may have additional prognostic benefits in carefully selected patient groups.

Direct current cardioversion is frequently reserved for acute situations with evidence of active (or imminent) haemodynamic compromise or to offer temporary respite during interim periods of illness or while awaiting long-term treatment. This is because while effective in the immediate setting, its effects are short-lived as demonstrated by high failure rates in excess of 40% by 1 month.24

Unlike DCCV, use of AADs provides more sustained effects with better maintenance of sinus rhythm over an extended period of time. The therapeutic options and dosing regimes of AADs vary between countries. In the UK, flecainide, sotalol and amiodarone are the three most common AADs employed. Amiodarone is generally considered the most effective agent but carries a wide array of potential side effects, including photosensitivity, lung fibrosis, liver damage, peripheral neuropathy and thyroid abnormalities. Moreover, as with all AADs, there is a risk of inducing prolongation of the QT interval with associated serious ventricular arrhythmia. There are also numerous considerations on the suitability of AADs in patients with comorbidities. For example, flecainide is contraindicated in the presence of structural heart disease. Hence, it is important that patients maintained on AADs are kept under specialist review, and undergo regular 12-lead ECG monitoring, especially when doses are altered.

Regardless of the rhythm control strategy, there is a risk of propagating any pre-existing thrombi which may have formed during the interval between AF onset and diagnosis. The risk of this occurrence can be minimised by instituting adequate anticoagulation and/or high-quality imaging of the left atrium, typically with trans-oesophageal echocardiography, prior to treatment. In the event that thrombus is detected, any rhythm control strategy is extremely high-risk and should not be undertaken in most cases.

Catheter ablation

Catheter ablation is a minimally invasive procedure, typically performed percutaneously using a variety of mapping and ablation catheters positioned in the heart via the femoral vein(s). The cornerstone of AF ablation is to achieve durable electrical isolation of the pulmonary veins (figure 2). The procedure is undertaken with either intravenous sedation or general anaesthesia.

Figure 2

Ultra-high-density voltage maps of the left atrium from a posterior view in a patient with paroxysmal atrial fibrillation before and immediately after pulmonary vein isolation. Areas with a voltage above 0.5 mV are highlighted in purple and represent healthy myocardium, while the grey areas represent the pulmonary veins which have been electrically isolated from the left atrium. The coloured orbs indicate individual RF lesions placed sequentially to ablate underlying tissue. LLPV, left lower pulmonary vein; LUPV, left upper pulmonary vein; PVI, pulmonary vein isolation; RF, radiofrequency; RLPV, right lower pulmonary vein; RUPV, right upper pulmonary vein.


Although AF ablation is used primarily for symptom relief, there are promising data to suggest that its benefits may extend beyond this in selected patients. In particular, catheter ablation has been shown to reduce mortality and hospitalisation in AF patients with coexisting heart failure.25 26 Moreover, in studies of patients with AF and heart failure, those who received catheter ablation had a significant improvement to their left ventricular systolic function compared with rate control alone.27 28 This benefit was greater in those with an absence of ventricular scar on MRI.28 The difference in outcomes observed with catheter ablation that was not demonstrated in other methods of rhythm control may be secondary to its superiority in reducing burden of atrial arrhythmias, including in those with persAF.29 Overall, factors influencing the risk and benefit of catheter ablation in patients with AF with heart failure are shown in figure 3. In contrast, the CABANA (Catheter Ablation vs Antiarrhythmic Drug Therapy for Atrial Fibrillation) trial failed to demonstrate prognostic benefit with catheter ablation over AADs in terms of a composite of mortality, disabling stroke, serious bleeding and cardiac arrest among the general AF population.30 A caveat was that there was significant crossover following randomisation which may have had an impact on the effects of catheter ablation.

Figure 3

Factors influencing the risk versus benefit ratio of catheter ablation in patients with AF and heart failure. AF, atrial fibrillation; DCCV, direct current cardioversion; LA, left atrial; LV, left ventricular; LVSD, left ventricular systolic dysfunction; NYHA, New York Heart Association. Created with

Modalities used for catheter ablation

The two most frequently used modalities of catheter ablation in AF are focal radiofrequency (RF) ablation and cryoballoon ablation. The former uses the delivery of RF current in a point-by-point manner to heat tissues and create cellular necrosis. In contrast, the latter uses a balloon that is filled with pressurised gas to freeze tissues and induce scarring. Broadly speaking, both modalities are interchangeable in terms of efficacy, although this equivalence has strictly only been shown in patients with persAF.31

Advantages of cryoablation include ease of equipment set up, no requirement for three-dimensional mapping, reduced need for general anaesthesia due to better patient tolerance, a shorter procedure time and a shorter learning curve for the operator. These advantages have allowed more widespread uptake of catheter ablation in AF. Nevertheless, there are trade-offs with cryoablation in that it lacks the versatility and diagnostic capability that is afforded by RF ablation. In this regard, RF ablation facilitates tailored lesion prescription that may be particularly crucial in patients with severely dilated atria or with anatomical variants of the pulmonary veins. Moreover, RF permits adjunctive ablation of non-pulmonary vein targets such as the cavo-tricuspid isthmus, posterior wall of the left atrium and LAA, and is less reliant on fluoroscopy, thereby decreasing radiation exposure for patients and the operator.


High-quality durable pulmonary vein isolation remains the cornerstone of successful catheter ablation and may provide 12-month freedom from atrial arrhythmias in up to 80% in patients with persAF.32 However, among those with more advanced disease and/or unfavourable characteristics (box 3), the success rate of pulmonary vein isolation alone is significantly lower, prompting the pursuit for additional ablation targets to improve long-term outcomes. These targets may be fixed structures (eg, posterior wall of the left atrium, LAA, superior vena cava) or dynamic substrates (eg, complex fractionated atrial activity). Presently, this is an area of ongoing research and the optimal lesion set in persAF remains ill-defined. Regardless, risk factor modification should continue to be emphasised in these patients, and those with a high-risk of AF recurrence postablation, identified using clinical tools such as the DR-FLASH score (based on diabetes mellitus, renal dysfunction, persAF, left atrial diameter >45 mm, age >65 years, female sex, and hypertension),33 may benefit from more aggressive intervention.

Box 3

Factors that predict suboptimal outcomes in catheter ablation of atrial fibrillation

  • Increased age

  • Severely dilated left atrium

  • Long duration of persistent atrial fibrillation prior to ablation

  • Non-paroxysmal atrial fibrillation

  • Chronic kidney disease

  • Heart failure

  • Untreated structural heart disease

  • Uncontrolled hypertension

  • Poorly controlled diabetes mellitus

  • Severe obesity


Given the elective nature of catheter ablation in AF, safety is an important element to consider. Overall, the procedure is associated with a higher upfront risk of complications compared with AAD therapy but over long-term follow-up, it may negate the requirement for medications (and thereby side effects) in a substantial number of patients. With new developments in technology, such as three-dimensional mapping, contact force-sensing catheters and steerable sheaths, percutaneous catheter ablation for AF is becoming increasingly safe. In a meta-analysis of 140 recent studies, the acute complication rates of AF ablation were 2.6% which included vascular complications (1%), cardiac tamponade (<1%), stroke (<0.5%) and death (<0.1%).34 Serious late complications such as atrio-oesophageal fistula and pulmonary vein stenosis are rare, and may be under-recognised as patients often present weeks to months following the procedure. In general, there appears to be a close relationship between procedural volume and safety outcomes, with high-volume centres and operators performing better in this regard.35

Rate control

AF is by definition a state of rapid atrial activity. However, ‘rate control’ in this setting refers to the ventricular rather than atrial rate. Ventricular rates in AF are governed by the atrioventricular node which in some patients may be able to sustain high rates of conduction, therefore resulting in average heart rates well above 100 beats per minute and leading to misnomers such as ‘fast AF’ (or ‘slow AF’ in the opposite scenario). Patients with poorly controlled rates in AF may be symptomatic and suffer from reduced exercise tolerance. Furthermore, these rapid rates may induce left ventricular dysfunction (tachycardiomyopathy), which is usually reversible after adequate rate control.

Therapeutic options for rate control include beta-blockers, non-dihydropyridine calcium channel blockers and digoxin. Importantly, rate and rhythm control in AF should not be regarded as mutually exclusive and in fact, most AADs have some rate control properties too. The target heart rate in AF should be <110 beats per minute, as aiming for stricter rate control beyond this does not appear to confer prognostic advantage even though it may be associated with fewer hospitalisations.36 37

In some patients who are refractory or intolerant to pharmacological therapy, and continue to exhibit high ventricular rates, the ‘pace-and-ablate’ strategy may be a reasonable option (box 4). This involves a staged approach of implantation of a permanent pacemaker followed by ablation of the atrioventricular node, effectively producing complete heart block. The latter procedure is irreversible and renders patients dependent on the pacemaker for the remainder of their life. It is important to bear in mind that as the atria continue to fibrillate, the loss of mechanical atrial transport persists after ‘pace-and-ablate’ treatment. As such, patients can continue to be symptomatic with associated symptoms such as breathlessness. Also, in a small minority of patients, the electrical and mechanical dyssynchrony induced by continuous right ventricular pacing can result in heart failure; unfortunately, it is impossible to predict this serious complication. For this reason, some specialists feel that implantation of a biventricular pacemaker device at the outset may be preferable, especially if there is any suggestion of pre-existing left ventricular systolic dysfunction.

Box 4

Factors that may favour a palliative pace-and-ablate strategy

  • Elderly patients (eg, aged >80 years), especially those with limited activity levels

  • Severe frailty

  • Long duration of persistent AF (eg, >12 months)

  • Prior failed catheter AF ablation procedure(s)

  • Severe left atrial enlargement

  • Significant left atrial fibrosis on LGE-MRI or invasive electrophysiological study

  • Severe chronic kidney disease

  • Multiple comorbidities

  • Significant obesity (eg, BMI >40)

  • Low-volume centre/operator in terms of catheter AF ablation

  • AF, atrial fibrillation; BMI, body mass index; LGE, late gadolinium enhancement.


Contemporary management of persistent AF should encompass a holistic, individualised approach towards risk factor modification, stroke prevention, rhythm control and rate control. Several specialist cardiac interventions including catheter ablation, pace-and-ablate treatment and LAA occlusion are available that can be used for appropriately selected patients (figure 4).

Figure 4

Proposed flow chart for the long-term management of persistent atrial fibrillation. Created with

Key messages

  • The four pillars to contemporary management of atrial fibrillation are risk factor modification, stroke prevention, rhythm control and rate control.

  • Catheter ablation improves symptoms and quality of life in most patients, and may have an additional prognostic benefit in selected patients, especially those with coexisting heart failure.

  • A palliative ‘pace-and-ablate’ strategy should be considered in patients for whom catheter ablation is either unsuitable and/or unsuccessful, or who are refractory to pharmacological rate-control therapies.

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  • Twitter @dhirajguptaBHRS

  • Contributors WYD drafted the manuscript and prepared the Figures/Tables. DG revised the manuscript.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests DG: speaker for Boehringer Ingelheim, Biosense Webster and Boston Scientific. Proctor for Abbott. Research Grants from Medtronic, Biosense Webster and Boston Scientific. WYD: None declared.

  • Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

  • Provenance and peer review Commissioned; externally peer reviewed.

  • Author note References which include a * are considered to be key references.

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