Ablation of Atrial Fibrillation

In Depth

Ablation of Atrial Fibrillation Patient Selection, Periprocedural Anticoagulation, Techniques, and Preventive Measures After Ablation

Mark S. Link, MD Michel Haïssaguerre, MD* Andrea Natale, MD*

STATE OF THE ART

Downloaded from http://circ.ahajournals.org/ by guest on April 26, 2018

ABSTRACT: Atrial fibrillation (AF) is the most common arrhythmia encountered by cardiologists and is a major cause of morbidity and mortality. Risk factors for AF include age, male sex, genetic predisposition, hypertension, diabetes mellitus, sleep apnea, obesity, excessive alcohol, smoking, hyperthyroidism, pulmonary disease, air pollution, heart failure, and possibly excessive exercise. The management of AF involves decisions about rate versus rhythm control. Asymptomatic patients are generally managed with rate control and anticoagulation. Symptomatic patients will desire rhythm control. Rhythm control options are either antiarrhythmic agents or ablation, with each having its own risks and benefits. Ablation of AF has evolved from a rare and complex procedure to a common electrophysiological technique. Selection of patients to undergo ablation is an important aspect of AF care. Patients with the highest success rates of ablation are those with normal structural hearts and paroxysmal AF, although those with congestive heart failure have the greatest potential benefit of the procedure. Although pulmonary vein isolation of any means/energy source is the approach generally agreed on for those with paroxysmal AF, optimal techniques for the ablation of nonparoxysmal AF are not yet clear. Anticoagulation reduces thromboembolic complications; the newer anticoagulants have eased management for both the patient and the cardiologist. Aggressive management of modifiable risk factors (hypertension, diabetes mellitus, sleep apnea, obesity, excessive alcohol, smoking, hyperthyroidism, pulmonary disease, air pollution, and possibly excessive exercise) after ablation reduces the odds of recurrent AF and is an important element of care.

*Drs Haïssaguerre and Natale contributed equally to this work. Correspondence to: Mark S. Link, MD, UTSouthwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390. E-mail: [email protected] Key Words: ablation techniques ◼ anti-arrhythmia agents ◼ anticoagulants ◼ atrial fibrillation ◼ pulsed radiofrequency treatment © 2016 American Heart Association, Inc.

Circulation. 2016;134:339–352. DOI: 10.1161/CIRCULATIONAHA.116.021727

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urrently, in the United States, ≈5 million individuals have a diagnosis of atrial fibrillation (AF), and the American Heart Association AF writing group estimates that the number of patients with AF will double over the next 25 years.1 AF prevalence in Europe is similar.2 AF is a significant contributor to morbidity and mortality: Patients with AF have a 5-fold risk of stroke,3 a 3-fold risk of heart failure,4 and a doubling of mortality.3 The care of patients with AF makes up a significant proportion of a cardiologist’s practice. Options for treatment have exploded over the last decade, particularly with regard to anticoagulation and ablation. Ablation of AF has evolved from a concept difficult to imagine in the early 1990s to a rare, very lengthy procedure in the late 1990s5 to now a generally safe and reasonably successful procedure.1,6,7 Information on the care of patients with AF undergoing ablation has accumulated over the last several years; thus, a comprehensive review is relevant to practicing cardiologists. This review focuses on the management of patients with AF around the time of the procedure, including patient selection for AF ablation, anticoagulation before and after the procedure, various techniques of ablation, and finally postablation pharmacological and nonpharmacological methods to reduce recurrences of AF. The putative mechanisms of AF are directly related to the techniques of ablation. Traditionally, AF was thought to be secondary to spiral depolarization waves in the atria.8,9 Thus, early ablative techniques concentrated on the interruption of the fibrillatory waves in the atria, first with surgical methods10,11 and then with transvenous catheters.12 Subsequently, a landmark study in 1998 demonstrated that AF could be attributable to pulmonary vein (PV) atrial premature beats/tachycardia in atrial musculature lying within the PVs (Figure 1).5 Fur-

thermore, ablation of these triggers could eliminate AF.5 It is now clear that other sites beside the PVs can trigger AF.13–20 Alteration of atrial substrate and elimination of PV and non-PV triggers have remained the 2 basic philosophies in AF ablation. Patients with paroxysmal AF may have triggers only; those with nonparoxysmal AF are more likely to have abnormalities of the atrial substrate. Thus, elimination of triggers may suffice in paroxysmal but not in longer-duration AF. However, it is also clear that the mechanism of AF is more complex than just triggers and substrate and includes autonomic modulation, fibrosis, remodeling, ischemia, dilatation, and stretch, among others.7 A more complete understanding of the mechanism(s) of AF will, we hope, translate into improved treatment.

Patient Selection Patient selection for ablation is a shared decision by the patient and physician. This decision is to be placed in context of the frequency of AF, symptoms during AF, age and comorbidities of the patient, and other available options for AF management. For asymptomatic or minimally symptomatic individuals, especially if elderly or frail, rate control may be appropriate. For more symptomatic individuals, a rhythm control strategy will be preferred. In this group of patients, the decision is between antiarrhythmic agents and ablation. The risks and benefits of antiarrhythmic agents must be balanced against the risks and benefits of ablation. The odds of a successful ablation not only are related to the technique of the procedure but also are critically to patient characteristics. The ideal patient with the highest likelihood of procedural success is

Figure 1. Locations of atrial tachycardia that initiated atrial fibrillation in 45 patients reported in 1998.

Note that the majority of focal atrial tachycardias that precipitated atrial fibrillation lie within the pulmonary veins. Adapted with permission from Haïssaguerre et al5 with permission from the publisher. Copyright © 1998 Massachusetts Medical Society.

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Ablation of Atrial Fibrillation

Figure 2. Selection of patients with no or minimal structural heart disease for atrial fibrillation (AF) ablation. AAD indicates antiarrhythmic drug; LoE, Level of Evidence; LSPAF, long-standing persistent atrial fibrillation; PAF, paroxysmal atrial fibrillation; and PerAF, persistent atrial fibrillation.


wish to pursue ablation as an initial strategy. Importantly, these guidelines give a Class III (causes harm) warning for pursuing AF ablation for the sole purpose of discontinuing anticoagulation. The European Society of Cardiology (ESC) guidelines for paroxysmal AF are remarkably similar.6 Patients with paroxysmal AF who fail antiarrhythmic agents are given a Class I indication. It is a Class IIa indication for patients with paroxysmal AF who prefer ablation before an antiarrhythmic agent. The 2012 ESC guidelines did not change the 2010 recommendations for ablation of persistent AF, which remained Class IIa if patients are resistant to antiarrhythmic agents and Class IIb as initial strategy.27 Repeat ablations are necessary in many patients, particularly in those with underlying heart disease. In general, a younger age, greater severity of symptoms, and contribution of AF to heart failure/cardiomyopathy factor into the decision for repeat ablations. In many of these individuals, repeat ablations should be performed.

Figure 3. Selection of patients with structural heart disease (SHD) for atrial fibrillation (AF) ablation. AAD indicates antiarrhythmic drug.

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one with paroxysmal AF, no underlying cardiac disease, and a nondilated left atrium (Figure 2). Paroxysmal AF is defined as AF 7 days) and long-standing persistent (continuous AF >1 year) AF may also benefit from AF ablation.1,6,7 In addition, patients with congestive heart failure or decreased left ventricular ejection fraction may be candidates for AF ablation (Figure 3).24–26 However, it is clear that the odds of a successful ablation are diminished with greater underlying heart disease. In particular, left atrial enlargement, mitral valve disease, and chronic heart failure are associated with poorer outcomes.1,6,7 It was once believed that patients need to fail at least 1 antiarrhythmic agent before AF ablation. However, given the known toxicities of antiarrhythmic agents and the success of ablation, ablation is now acceptable as an initial rhythm control strategy, at least for paroxysmal AF.1,6 The latest AF ablation guidelines were updated in the United States in 20141 and in Europe in 2012 (Table 1).6 For patients with symptomatic paroxysmal AF, the latest American Heart Association/American College of Cardiology recommendations give a Class I recommendation (is useful) for catheter ablation in patients with paroxysmal AF who have failed or are intolerant of class I or III antiarrhythmic agents.1 These same guidelines give a IIa recommendation (is reasonable) for those symptomatic patients with paroxysmal AF who wish to pursue ablation as an initial rhythm strategy and patients with symptomatic persistent AF who have failed or are intolerant to a class I or III antiarrhythmic agent. For patients with long-standing persistent AF, the recommendation drops to a IIb (may be considered), and this recommendation is applicable regardless of whether they have failed or are intolerant of class I or III antiarrhythmic agents or

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Table 1. Patient Selection for AF Ablation According to US1 and European2,67 Guidelines US Guidelines Paroxysmal, failed AAD

European Guidelines

I

I

Paroxysmal, initial strategy

IIa

IIa

Persistent, failed AAD

IIa

IIa

Persistent, initial strategy

IIb

IIb

Long-standing persistent (>12 mo)

IIb

IIb

Heart failure

IIb

IIb

Sole purpose of discontinuation of anticoagulation

III: harm

AAD indicates antiarrhythmic drugs; and AF, atrial fibrillation. I=benefit>>>risk, should be performed; IIa=benefit>>risk, is reasonable; IIb=benefit≥risk, may be considered; and III=no benefit or harm. Downloaded from http://circ.ahajournals.org/ by guest on April 26, 2018

However, the likelihood of success decreases after successive ablations. After 3 or 4 ablations, the likelihood of ultimate success is quite low, and most would look to alternative options at that time. Operator experience and center experience are especially important with repeat ablations.1,6,7

Anticoagulation The vitamin K antagonist warfarin has been the gold standard for anticoagulation in AF. Its ability to lower the risk of thromboembolism has been established by large randomized, controlled trials (RCTs) in the 1980s and early 1990s.28 However, warfarin therapy is complicated by the need for dietary compliance, sensitivity to multiple medications, frequent blood draws for monitoring, and often unexplained INR (international normalized ratio) fluctuations. Thus, there has been a widespread desire to develop warfarin substitutes that are safer and easier to administer. Ximelagatron, a direct thrombin inhibitor, was the first of these warfarin replacements subjected to an RCT. It met the efficacy goal of preventing thromboembolism, but an adverse safety signal of liver toxicity prevented its approval for widespread use.29 Subsequently, dabigatran,30 a direct thrombin inhibitor, and the direct factor Xa inhibitors rivaroxaban,31 apixaban,32 and edoxaban33 are currently available (Table 2). All of these newer/direct anticoagulants were tested against warfarin; they have not been directly compared with one another in a clinical trial. Although the clinical results of the trials are similar, there are differences in trial design, patient thromboembolic risk, and end points that prevent their direct comparison. The CHA2DS2-VASc score has largely supplanted the CHADS score for the estimation of stroke risk in patients with AF.1,6 The CHA2DS2-VASc score includes 7 clinical 342

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characteristics (congestive heart failure, hypertension, age, diabetes mellitus, stroke/transient ischemic attack, vascular disease, female sex) to stratify stroke risk. In the US guidelines, individuals with a CHA2DS2-VASc score of ≥2 are recommended to undergo anticoagulation.1 ESC guidelines recommend anticoagulation for those with a CHA2DS2-VASc score of ≥1 (IIa; should be considered for those with a score of 1).6 The data on the risk of stroke in individuals with AF with a CHA2DS2-VASc score of 1 are conflicting and thus underlie the different recommendations in the United States and Europe.34–36 Periprocedural prescription of anticoagulation is evolving. Initially, warfarin was held either with or without heparin bridging. Subsequent data emerged that showed that bleeding complications were actually lower with uninterrupted warfarin compared with a bridging strategy.37–40 In addition, uninterrupted strategies reduce both clinical and silent thromboembolic events.41 This pattern of withholding anticoagulation around the time of the ablation also applied to the direct anticoagulants, with some studies advocating bridging and others not. There is more concern about the treatment of bleeding complications with the direct anticoagulants because of the previous lack of reversal agents. Registry data have suggested that ablation can be performed without discontinuation of these agents,42–46 although often 1 or 2 doses are held before the procedure. In addition, the development of reversal agents for these direct anticoagulants should provide more justification for uninterrupted anticoagulation at the time of the ablation.47,48 Continuation of anticoagulants should persist for at least 2 months after the procedure.1,6 Continuing anticoagulation for an extended time period depends on the CHA2DS2-VASc score.1 The 2012 ESC guidelines state that long-term anticoagulation is recommended in all patients with a CHA2DS2-VASc score of ≥2,6 and the US guidelines agree that the decision for continued anticoagulation largely hinges on the CHA2DS2-VASc score.1 In the US guidelines, individuals with a low CHA2DS2-VASc score and successful ablation can likely stop anticoagulation after 2 to 3 months. Current guidelines do not recommend AF ablation for the sole purpose of discontinuation of anticoagulation.1,6,27 In addition, AF is more likely to be asymptomatic after ablation, so relying on symptoms alone for the discontinuation of anticoagulation is not recommended.49

Techniques Techniques for AF ablation are maturing, and differences are not completely resolved. Techniques for the ablation of AF vary by energy source and location of atrial lesions (ie, lesion sets). A full discussion of the different techniques for the ablation of AF is beyond the scope of this review, but at least some knowledge of the different techniques is useful for the nonelectrophysiologist. Circulation. 2016;134:339–352. DOI: 10.1161/CIRCULATIONAHA.116.021727

Ablation of Atrial Fibrillation

Table 2. Comparison of Warfarin With the 4 Novel Anticoagulants Available for Administration in the Prevention of Thromboembolism in Patients With AF Rivaroxaban, ROCKET-AF31

Dabigatran, RELY30

Warfarin

Apixaban, ARISTOTLE32

Edoxaban, ENGAGE33

Mechanism

Vitamin K antagonist

Direct thrombin inhibitor

Direct factor Xa inhibitor



Time to peak levels

Days

3h

3h

3h

2h

Half life, h

NA

12–17

5–13

9–14

10–14

Renal excretion, %

NA

80

36

27

50

Dose

Variable

150 mg twice daily

20 mg once daily

5 mg twice daily

For CrCl 50–95 mL/ min, 60 mg once daily (do not use if CrCl >95 mL/min

Dose decrease

Based on INR

75 mg twice daily if CrCl is 15–30 mL/min

15 mg once daily if CrCl is 15–50 mL/min

2.5 mg twice daily if 2 of 3 of the following: Age ≥80 y

30 mg once daily if CrCl 15–50 mL/min

SCr >1.5 mg/dL Common drug interactions

CYP3A4 inhibitors or P-GP inhibitors inducers (erythromycin (dronedarone, ketoconazole) ketoconazole)

P-GP inhibitors Combined P-GP and (dronedarone, CYP3A4 inhibitors (ketoconazole, ritonavir) ketoconazole)

CYP2C9 (amiodarone)

Combined P-GP and CYP3A4 inducers (carbamazepine, phenytoin, rifampin)

CYP1A2 (fluvoxamine, cimetidine, OCPs)

Combined P-GP and CYP3A4 inhibitors (ketoconazole, P-GP inducer (rifampin) ritonavir), Combined P-GP and CYP3A4 inhibitors (carbamazepin, phenytoin, rifampin)

P-GP inducers (rifampin)

Food interactions

Vitamin K (eg, kale, spinach, Brussel sprouts, cabbage, asparagus)

None

Take with evening meal None

None

Reversal agent

Vitamin K

Idarucizumab

Andexanet alfa*

Andexanet alfa*

Andexanet alfa*

STATE OF THE ART


Weight ≤60 kg

FFP PCC AF indicates atrial fibrillation; ARISTOTLE, Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation; CrCl, creatinine clearance; ENGAGE, Global Study to Assess the Safety and Effectiveness of Edoxaban (DU-176b) vs Standard Practice of Dosing With Warfarin in Patients With Atrial Fibrillation; FFP, fresh-frozen plasma; INR, international normalized ratio; NA, not applicable; OCP, oral contraceptive; PCC, prothrombin complex concentrate; P-GP, phosphorylated glycoprotein; RELY, Randomized Evaluation of Long-Term Anticoagulation Therapy; ROCKET-AF, Rivaroxaban Once-Daily oral Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation; and SCr, serum creatinine. *Not approved by the US Food and Drug Administration.

Energy sources available for AF ablation include radiofrequency, cryoablation, and laser. Radiofrequency and cryoablation are currently most commonly used. Radiofrequency creates a lesion with heat (typically up to 60°C) and can be delivered with or without saline irrigation at the tip of the catheter. Irrigated-tip catheters reduce the risk of char formation and improve lesion depth and size; in general, they are the most commonly used catheters for radiofrequency ablation. New catheters with the ability to quantify the force of contact have recently been developed and appear to give more consistent lesions than prior catheters.50 Cryoablation is administered via a left atrial balloon that occludes each PV individually and Circulation. 2016;134:339–352. DOI: 10.1161/CIRCULATIONAHA.116.021727

freezes to −50°C.23 Laser ablation is performed with special catheters designed to create a circumferential lesion set around each PV.51,52 In the United States, only cryoablation and radiofrequency are approved for ablation; in Europe, all 3 are available. The location of ablation lesions is where the major controversies in AF ablation lie. It is reasonably acknowledged that for individuals with paroxysmal AF and no underlying heart failure, electric isolation of the PVs at the antral level is associated with a high degree of elimination of AF (Figures 4 and 5). This isolation can be accomplished with radiofrequency, cryoablation, or laser energy. Randomized, clinical trials in this patient population generally July 26, 2016

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Figure 4. Anatomy of the left atrium and pulmonary veins relative to other cardiac structures.

Left, Posterior view. Note the proximity of the esophagus to the posterior left atrium, which accounts for the risk of atrial-esophageal fistula. Right, Left anterior oblique view. Access to the left atrium is transseptal from the right atrium.

compare an ablative technique with antiarrhythmic drug therapy. In the RAAFT (Radiofrequency Ablation Versus Antiarrhythmic Drugs for Atrial Fibrillation Trial), an RCT largely of patients with paroxysmal AF, those randomized to catheter ablation had a higher 2-year likelihood of sinus rhythm (45% versus 28%; P=0.02).53 In the A4 randomized study, patients in the ablation arm had a 1-year sinus rhythm incidence of 89% compared with 23% (P1.5 mV is shown in purple; tissue with a voltage