Ablation of Persistent and Long-Standing Persistent Atrial Fibrillation

Key Points

Ablation of persistent and long-standing persistent atrial fibrillation (AF) is a potentially complex procedure, which carries a lower success rate than ablation for paroxysmal AF.
Pulmonary vein isolation remains the cornerstone of AF ablation in every AF population with antral isolation having better outcomes than ostial ablation. Further adjunctive ablation comes in many forms.
Currently we favor posterior wall isolation, careful attention to low-voltage areas, and nonpulmonary vein trigger mapping in the persistent and long-standing persistent AF population.
Preprocedural predictors of recurrence include longer duration since persistent AF diagnosis, greater than one year of continuous AF, elevated APPLE score, and fibrosis on delayed-enhancement magnetic resonance imaging.

Introduction

Atrial fibrillation (AF) is a growing health epidemic, with more than 33 million people with the disease worldwide. The prevalence is expected to exceed 12 million in the United States alone by 2050. Within this group, the phenotype of AF varies greatly. Most patients with AF present initially with paroxysmal AF, which is currently defined as AF always terminating in 7 days or less, either spontaneously or with intervention ( Table 19.1 ). If AF sustains for more than 7 days, it is defined as persistent AF, and if AF sustains continuously for more than 1 year, it is defined as long-standing persistent AF. Within the persistent AF group, early persistent AF is now defined as sustaining for less than three months. A Canadian registry enrolling before the widespread adoption of catheter ablation for AF showed that after an initial diagnosis of paroxysmal AF, 8.6%, 24.3%, and 36.3% will progress to persistent AF within 1, 5, and 10 years, respectively.

TABLE 19.1

Key Points for Atrial Fibrillation Ablation

Diagnostic criteria	Paroxysmal atrial fibrillation (PAF) is atrial fibrillation (AF) that terminates within 7 days of onset, spontaneously or with intervention Persistent AF is AF that sustains for >7 days Early persistent AF is AF that sustains >7 days but <3 months Long-standing persistent AF is continuous AF >12 months in duration
Ablation targets	All ablations for AF should include complete pulmonary vein isolation (PVI) Patients with persistent AF have worse ablation-free survival than those with paroxysmal AF after PVI Further ablation may include ablation of nonpulmonary vein (PV) triggers, posterior wall ablation/isolation, left atrial appendage electrical isolation or excision, roof or mitral line, cavotricuspid isthmus line, ablation of complex fractionated atrial electrograms (CFAEs), mapping and ablation of fibrosis, mapping and ablation of ganglionic plexi, and mapping and ablation of rotors
Special equipment	Electroanatomic mapping (EAM) is strongly recommended Intracardiac echocardiography, contact force sensing catheters, general anesthesia with high-frequency ventilation, and deflectable sheaths can all be useful in achieving durable lesions Multipolar catheters can be helpful in determining sources of non-PV triggers
Sources of difficulty	Achieving durable PVI remains challenging and may be necessary but not sufficient for achieving arrhythmia-free survival in many patients with persistent and long-standing persistent AF Contact force and impedance monitoring, adenosine challenge, achieving ablation line unexcitability, and maintaining close lesion spacing may help achieve durable lesions Posterior wall ablation and isolation can be achieved efficiently and safely in most patients with short duration, low-power, low-flow irrigation settings to limit esophageal heating
Predictors of outcome	Longer time since persistent AF diagnosis and longer time in continuous AF predict worsened outcome APPLE score (1 point each for age >65 years, persistent AF, eGFR <60mL/min/1.73m ² , LA diameter ≥43mm, and left ventricular ejection fraction <50%) predicts AF recurrence after ablation with an odds ratio for AF recurrence for scores of 1, 2, or ≥3 equal to 1.73, 2.79, and 4.70 as compared with a score of zero (similar predictive power for repeat ablation) Delayed-enhancement magnetic resonance imaging (DE-MRI) shows linear correlation between left atrial fibrosis burden and postablation recurrence with recurrence rates of 15%, 36%, 46%, and 69% corresponding to <10%, ≥10-<20%, ≥20-<30%, and ≥30% fibrosis of the LA

Not surprisingly, clinical classification of AF type by a treating physician can be at odds with more objective implantable device-recorded data, and clinical factors such as heart failure or structural heart disease may play a role in the physicians’ assessment of treatment options for patients. In addition, there is significant heterogeneity across each group in terms of AF burden, with patients clinically assigned to either group having no AF or continuous AF during 365 days of monitoring.

While some patients may be predisposed to development of lone AF due to genetic factors that may lead to shortened atrial refractory periods, ectopic foci, or abnormal pulmonary vein (PV) architecture, others develop AF at an advanced age or after prolonged periods of hypertension, obstructive sleep apnea, obesity, chronic kidney disease, and heart failure. In these two scenarios, the existing atrial substrate may be quite different, with the former group displaying uniformly healthy atrial tissue (normal atrial voltage by electroanatomic mapping) and the latter extensive atrial scarring early in the natural history of a patient’s AF. This heterogeneity of substrate, coupled with the wide variation in arrhythmia burden within each classification of AF (paroxysmal, early persistent, persistent, and long-standing persistent) means that these classifications based on time alone cannot fully predict a given patient’s likely benefit from medical or invasive therapies, and can only partially guide the optimal treatment strategy.

Catheter ablation for AF is superior to antiarrhythmic drug therapy in maintaining sinus rhythm across many different patient populations. In 1998, Haissaguerre et al. published the seminal findings that PV triggers often initiate AF, and elimination of these triggers by catheter ablation may eliminate AF in some patients. Nearly 20 years later, pulmonary vein isolation (PVI) remains the foundation of all widely accepted modern catheter ablation techniques for AF, with an expectation that a single-procedure will eliminate paroxysmal AF in approximately 60% to 70% of patients at 1 year (see Table 19.1 ). Interestingly, as technology, technique, and experience have all improved over time, improvements in the availability and usage of ambulatory monitoring has likely led to a greater capture of short and subclinical AF episodes, with a resultant relative stagnation of AF outcomes through time. While efficacy for patients with paroxysmal AF undergoing PVI seem to be consistently greater than 50%, outcomes in those with persistent and long-standing persistent AF are generally worse, though results seem to vary by center and in association with other clinical factors. For this reason, interest has long focused on adjunctive ablation strategies that could be coupled with PVI in the persistent and long-standing persistent AF subgroups to improve results.

Over the last 15 years the most frequently employed adjunctive ablative strategies have been placement of linear ablation lesion sets (typically left atrial roof and mitral lines) and ablation of complex fractionated atrial electrograms (CFAEs). When these additional ablation lesion sets were compared with PVI alone in the multicenter Substrate and Trigger Ablation for Reduction of Atrial Fibrillation (STAR AF2) randomized controlled trial, they showed longer procedure times and a trend toward worse outcomes. Other adjunctive invasive strategies intended to reduce recurrence of persistent AF include mapping and ablation of non-PV triggers, posterior wall ablation/isolation, cavotricuspid isthmus line placement, left atrial appendage isolation or excision, ablation in areas of fibrosis, ablation of ganglionic plexi, mapping and ablation of rotors, and surgical ablation. Rigorous multicenter data is currently limited and/or conflicting for these strategies, as will be discussed below. In addition, all of these techniques require additional time, most require additional expertise, some require extra equipment, and most probably increase procedural risk, with the goal of achieving outcomes similar to what PVI achieves in patients with paroxysmal AF. As such, the 2014 American College of Cardiology/American Heart Association/Heart Rhythm Society (ACC/AHA/HRS) guidelines and 2017 Heart Rhythm Society/European Heart Rhythm Association/European Cardiac Arrhythmia Society/Asia Pacific Heart Rhythm Society/Latin American Society of Electrophysiology and Cardiac Stimulation (HRS/EHRA/ECAS/APHRS/SOLAECE) expert consensus statements have assigned a class I indication for catheter ablation of drug-refractory, symptomatic paroxysmal AF, a class IIa indication for drug-refractory, symptomatic persistent AF, and a class IIb indication for drug-refractory, symptomatic long-standing persistent AF ( Table 19.2 ).

TABLE 19.2

Arrhythmia Diagnostic Criteria

Paroxysmal atrial fibrillation (AF)	AF that terminates within 7 days of onset, spontaneously or with intervention Class I indication for ablation if symptomatic, refractory to at least 1 antiarrhythmic Class IIa indication for ablation before antiarrhythmic
Persistent AF	AF sustains for >7 days Class IIa indication for ablation if symptomatic, refractory to at least 1 antiarrhythmic
Early persistent AF	AF sustains >7 days but <3 months
Long-standing persistent AF	AF is continuous AF >12 months in duration Class IIb indication for ablation if symptomatic, refractory to at least 1 antiarrhythmic
AF recurrence after ablation	AF or atrial tachycardia (AT) documented to last 30 seconds occurring after a 3-month blanking period
Nonpulmonary vein trigger	Early atrial depolarizations leading to AF or sustained AT

Assessment of the Patient with Persistent and Long-Standing Persistent Atrial Fibrillation

Patients with persistent AF may have a wide range of symptomatology, arrhythmia burden, and comorbidities. Many patients with persistent AF are initially encountered by the electrophysiologist in the outpatient setting, often in the midst of a prolonged episode of AF. A few questions are important to consider when evaluating a patient with persistent or long-standing persistent AF:

Is the patient symptomatic? Can that be determined if it is unclear?
Is the patient presenting in sinus rhythm or AF?
What is the AF burden, and how long is the current episode? How long since diagnosis?
Are other diseases worsened by the presence of AF (i.e., heart failure, sick sinus syndrome, hypertrophic cardiomyopathy)?
Are there factors precluding certain antiarrhythmic drug therapy (heart failure, coronary artery disease, renal disease, lung disease)?
Are there factors precluding catheter ablation (high anesthesia risk, intolerance of anticoagulation, left atrial appendage thrombus)?
Is the patient expected to have open heart surgery, which could potentially be paired with a surgical ablation for AF?

Assessing and Defining Symptomatology

Patients with persistent AF often complain of nonspecific symptoms such as fatigue or exercise intolerance, making it difficult to ascertain whether a concomitant problem such as obesity, sleep apnea, or clinical heart failure is the major instigator. In addition, patients are often unaware when AF started and may feel minimal palpitations, which may give the false impression that AF is asymptomatic. In that sense, symptomatology attributable to AF may be in the eye of the beholder. In this circumstance one should consider direct current cardioversion (DCCV) with or without an antiarrhythmic medication for the purpose of determining improvement in symptomatology when in sinus rhythm. The patient is encouraged to keep a literal or mental symptom diary for the days and weeks preceding and following cardioversion. Most patients with persistent AF will experience some improvement of symptoms after cardioversion. If a patient with persistent AF experiences no symptomatic improvement with a trial of sinus rhythm, rhythm control is less appealing, given that multiple ablations and/or continuation of antiarrhythmic drugs may be needed to achieve long-term success. More than 10% of patients will fail to have even momentary restoration of sinus rhythm, even at 360 J, in which case placement of two sets of defibrillator pads (one in anteroposterior configuration and one in anterolateral configuration) connected to two separate external defibrillators can be synchronized and fired simultaneously (by a single operator) with near universal success. We recommend very firm pressure on the two anterior patches (this can best be done from on top of the stretcher or with the bed very low) with dry towels and rubber gloves to ensure no current is leaked through the operator applying pressure. In addition, pretreatment with ibutilide can also be used to aid cardioversion. Of note, amiodarone may raise the defibrillation threshold.

Presenting Rhythm

Among patients with a clinical diagnosis of persistent AF, those who present to the electrophysiology (EP) lab in sinus rhythm, or who have early conversion to sinus rhythm during the procedure (before the completion of the planned ablation), have a significantly greater likelihood of long-term success. This is probably because, at least in part, of the presence of sinus rhythm being a marker of a phenotype, which is likely to have improved outcomes. Arriving to the lab in sinus rhythm, all other things being equal, is statistically more likely in patients with a lower AF burden. Conversion early during the procedure could be a marker of a patient with a more paroxysmal, self-terminating phenotype, which may have terminated even in the absence of ablation. By the same reasoning a patient with persistent AF, who presents to clinic in sinus rhythm, may be expected to have better outcomes with ablation than one who does not.

Atrial Fibrillation Burden and Chronicity

As discussed earlier, patients with persistent AF are more likely to experience recurrence than those with paroxysmal AF (see Table 19.1 ). Among patients with persistent AF, those classified as persistent AF for more than 1 year seem to be approximately twice as likely to have recurrence as compared to those diagnosed with persistent AF for less than 1 year. Additionally, those with long-standing persistent AF (>1 year of continuous AF) have worsened outcomes as compared with those who have been in AF less than twelve months.

Disease Processes Exacerbated by Atrial Fibrillation

When determining how aggressively to treat AF, it is reasonable to consider comorbidities. In patients with heart failure and AF, AF ablation has been associated with an improvement in left ventricular ejection fraction (LVEF) of 8.5%, as well as an improvement in 6-minute walk and quality of life when compared with rate control. Additionally, AF ablation compared favorably to atrioventricular (AV) node ablation with biventricular pacing in heart failure patients with significantly greater quality of life, 6-minute walk, and left ventricular (LV) ejection fraction in the AF ablation group. Most notably, recent evidence from the randomized controlled Catheter Ablation for Atrial Fibrillation with Heart Failure (CASTLE-AF) trial showed a significant reduction in the primary composite end point of death or hospitalization for worsening heart failure (hazard ratio [HR] 0.62; P =.007) among patients with LVEF 35% or less randomized to ablation as opposed to medical therapy (rate or rhythm control) for AF. The study also showed significant reductions in the individual end points of all-cause mortality (HR 0.53; P =.010), cardiac mortality (HR 0.49; P =.009), and hospitalization for worsened heart failure (HR 0.56; P =.004) in the ablation group. Similar to prior studies, LVEF and 6-minute walk also showed significant improvements in the ablation group. Interestingly, these effects were seen in the setting of a 50% recurrence rate in the ablation group, but a reduction in AF burden (rather than complete elimination) to around 25% as opposed to 60% for those receiving medical therapy alone.

In addition, patients with tachy-brady syndrome plagued by symptomatic sinus bradycardia or long postconversion pauses in the setting of needed rate or rhythm control medications for AF, may benefit from an early ablative approach to avoid or postpone the need for placement of a permanent pacemaker.

Lastly, observational data suggests that AF ablation is associated with a reduced incidence of stroke or TIA as compared to propensity-matched patients with AF who do not undergo ablation. This effect seems to be greater in patients without recurrence of arrhythmia after ablation. However, despite propensity matching, it is possible that the decision to perform ablation and also ablation success may be a marker of a healthier patient population, who would be less likely to suffer a stroke regardless of ablation. Therefore a randomized trial will be needed to determine the true effect, if any, that AF ablation has on long-term stroke risk. Notably, recent guidelines state that “a patient’s desire to eliminate the need for long-term anticoagulation by itself should not be considered an appropriate selection criterion for AF ablation.”

Antiarrhythmic Drug Options

In many patients with persistent AF, antiarrhythmic drug options are limited. Patients with persistent AF and structural heart disease should not be prescribed class 1c antiarrhythmic medications. In this group sotalol, dofetilide, dronedarone, and amiodarone are options. For those with heart failure dronedarone, and to some extent sotalol, are also contraindicated. In addition, patients with poor or fluctuating renal function or serum potassium levels are at elevated risk of Torsades de Pointes with the class III antiarrhythmic drugs sotalol and dofetilide. For those who do qualify for a class III drug, several days of hospitalization for drug loading is recommended. Finally, any patients with advanced lung disease or those with an expected lifespan of a decade or more are not ideal candidates for amiodarone, given the risk of long-term, potentially fatal, toxicities. After all of these considerations are taken into account, there is a significant cohort of persistent AF patients with few or no good antiarrhythmic drug options. Despite this, operators should be aware that patients with persistent AF, and especially those with long-standing persistent AF, may require continuation or initiation of antiarrhythmic drug therapy after ablation to maintain sinus rhythm.

Potential Contraindications to Ablation

Ablation of AF is contraindicated or certainly riskier in certain populations. Given the elevated incidence of periprocedural stroke in the absence of anticoagulation, intraprocedural heparin, and oral anticoagulation is recommended for at least 2 months after ablation in all patients, regardless of baseline stroke risk. The 2014 ACC/AHA/HRS guidelines state that “AF catheter ablation should not be performed in patients who cannot be treated with anticoagulant therapy during and following the procedure.” In patients with heparin-induced thrombocytopenia or other specific contraindication to heparin, bivalirudin can be used for the acute procedure.

In addition, those with an exceptionally high risk for general anesthesia, such as those with advanced lung disease and concomitant morbid obesity, should warrant special consideration and attention prior to referral for ablation. Most patients with inferior vena cava (IVC) filters can safely undergo AF ablation. Fluoroscopy, and occasionally contrast venography, should be used to ensure safe passage of wires and sheaths. Occasionally chronic thrombus may prevent access through a filter.

Patients with congenital heart disease are at significantly elevated risk of AF, and the risk increases as one ages. Simple congenital heart disease, in which the atrial septum has been repaired, requires extra care to perform transseptal puncture. This has been performed in high-volume centers using intracardiac echocardiography, with a high degree of success and few complications. AF ablation in complex congenital heart disease, which may include surgical baffles and severely distorted anatomy, should be referred to an operator experienced with these patients.

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