TEC Assessment Index

Radiofrequency Catheter Ablation of the Pulmonary Veins for Treatment of Atrial Fibrillation

Executive Summary

Background

Atrial fibrillation is a common cardiac arrhythmia that is associated with serious cardiovascular morbidities, decreased quality of life, and decreased survival. The current treatment approach for atrial fibrillation is primarily pharmacologic, with invasive interventions reserved for small subsets of patients. Catheter ablation of the pulmonary veins, also known as pulmonary vein isolation (PVI) or circumferential pulmonary vein ablation (CPVA), is a nonpharmacologic alternative treatment for patients with atrial fibrillation. Radiofrequency catheter ablation offers potential benefits compared to current pharmacologic treatments, including the potential to improve a variety of clinical outcomes and to avoid the need for long-term antiarrhythmic medications and anticoagulation.

Objective

The objective of this Assessment is to determine whether radiofrequency catheter ablation improves health outcomes when used as a treatment for patients with atrial fibrillation. Three indications for radiofrequency catheter ablation are addressed: 1) patients with recent onset paroxysmal atrial fibrillation, as first-line treatment; 2) patients with symptomatic paroxysmal or persistent atrial fibrillation, who have failed treatment with antiarrhythmic drugs; 3) patients with class II or III congestive heart failure and symptomatic atrial fibrillation, in whom heart rate is poorly controlled by standard medications, as an alternative to atrioventricular (AV) nodal ablation and pacemaker implantation.

Search Strategy

MEDLINE® was searched (via PubMed) from March 2006 to January 2009, using the terms "pulmonary vein isolation," "PVI," "CPVA," "circumferential pulmonary vein ablation," and "catheter ablation." These terms were cross-referenced with the terms "atrial fibrillation," and "a fib." Search was limited to English language articles on human subjects. This search supplemented a prior search performed over the period of 1990 through March 2006 for the 2006 TEC Assessment.

Selection Criteria

Randomized, controlled trials published in the peer-reviewed, English-language literature that compared catheter ablation of the pulmonary veins with alternative treatment(s).

Main Results

Six randomized, controlled trials met the inclusion criteria and were reviewed in-depth for this Assessment. The trials differed in their patient populations, the specific catheter ablation techniques used, and the comparisons made; all trials used radiofrequency energy for the catheter ablation energy source. The trials addressed three distinct indications for catheter ablation: 1) patients with paroxysmal atrial fibrillation, as a first-line treatment option (1 trial); 2) patients with symptomatic paroxysmal or persistent atrial fibrillation, who have failed treatment with antiarrhythmic drugs (4 trials); 3) patients with symptomatic atrial fibrillation and class II or III congestive heart failure, in whom heart rate is poorly controlled by standard medications as an alternative to AV nodal ablation and pacemaker insertion (1 trial).

All 6 trials reported that maintenance of sinus rhythm was improved for the catheter ablation group. Recurrence rates of atrial fibrillation at 1 year ranged from 11–44% for the catheter ablation groups in these trials, compared with 63–96% for the medication groups. Four of the 6 trials reported quality of life (QOL) outcomes. One of these only reported within-group comparisons, as opposed to between-group comparisons. The other 3 trials reported improvements in QOL associated with catheter ablation. These QOL measures were self-reported, and since the trials were unblinded, there is the possibility of reporting bias due to placebo effect. For the population of patients with recent onset paroxysmal atrial fibrillation, one trial reported improvements in atrial fibrillation recurrences and QOL.

For the population of patients with symptomatic atrial fibrillation who have failed antiarrhythmic medications, 4 trials reported improvements in atrial fibrillation recurrence, and one trial reported the outcomes of QOL, symptom scores, and exercise duration. For the population of patients with symptomatic atrial fibrillation and class II or III congestive heart failure, one trial reported improvements for the catheter ablation group on a wider range of outcomes, i.e., recurrence of atrial fibrillation, left ventricular ejection fraction, functional status, and QOL. None of the trials report meaningful data on mortality, thromboembolic complications, or other cardiovascular outcomes.

Adverse events from the procedure can occur, including pulmonary vein stenosis, tamponade, thromboembolism, and perforation of the esophageal wall. The rates of these complications cannot be determined accurately from the available data. The available studies are small in size and do not include sufficient numbers of patients to adequately address uncommon complications. Furthermore, the rates of complications in the available studies reflect the specific procedures performed and may not be generalizable to variations on the procedure. There have been numerous modifications to the original catheter ablation technique, mainly with the intention of reducing pulmonary vein stenosis and other complications, and currently there is little standardization of the procedure across medical centers.

Author's Conclusions and Comments

All 6 trials report substantial differences in favor of the catheter ablation group on some relevant outcomes, particularly recurrence of atrial fibrillation. The consistency of this finding establishes that catheter ablation is more effective than medications in maintaining sinus rhythm across a wide spectrum of patients with atrial fibrillation, and across different variations of catheter ablation. However, the recurrence rate varied widely in these trials from 13–44%, indicating that there may be differences in absolute efficacy for different populations of patients with atrial fibrillation. Also, while the comparison of recurrence rates between treatment groups is valid in these trials, it is not possible to conclude with confidence that the lack of recurrence reported in trials represents the elimination of atrial fibrillation. Atrial fibrillation is often intermittent and of brief duration, thus creating difficulties in assessing recurrence when assessed over short periods of time, as is done in the available trials.

The relevance of maintaining sinus rhythm as a health outcome is variable for different populations of patients with atrial fibrillation. For the broad population of patients with atrial fibrillation who do not have specific reasons to pursue a rhythm control strategy, the value of this outcome is questionable. The goals of therapy in this population are to control ventricular rate, ameliorate symptoms, and prevent complications of atrial fibrillation, such as stroke. These goals can usually be accomplished with medications to control heart rate, with or without anticoagulation. Maintenance of sinus rhythm may not offer any further advantage over rate control in these patients.

For patients in whom symptoms are not adequately controlled with a rate control strategy (Indication 2), maintenance of sinus rhythm becomes a more important goal. In these patients, the alternative to catheter ablation is pharmacologic management with antiarrhythmic medications and anticoagulation. Antiarrhythmic medications are only partially effective in maintaining sinus rhythm and have a variety of adverse effects, including proarrhythmic properties that can lead to serious, life-threatening ventricular arrhythmias. Anticoagulation also has the potential to cause serious hemorrhagic adverse effects. Therefore, maintenance of sinus rhythm by nonpharmacologic methods is a particularly attractive option for this patient group. In addition, it is reasonable to extrapolate that a decrease in the frequency and/or duration of atrial fibrillation episodes will result in a decrease in symptoms. While the available data do not establish the degree of symptom improvement associated with catheter ablation, the large reported difference in the percent of patients maintaining sinus rhythm is likely to translate to a clinically important reduction in symptoms.

For patients with class II or III congestive heart failure and symptomatic atrial fibrillation in whom heart rate is poorly controlled by standard medications (Indication 3), one trial reports benefit on maintenance of sinus rhythm, improved ejection fraction, improved functional status, and improved QOL. While this trial is small, it was judged to be high quality on formal quality assessment and the magnitude of difference on all the outcome measures was relatively large. As a result, it is possible to conclude that radiofrequency catheter ablation of the pulmonary veins is superior to AV nodal ablation and pacemaker insertion for this population.

Data on the most important clinical outcomes is lacking. None of the trials reports on the most relevant clinical outcomes such as mortality, thromboembolic events, and cardiovascular complications. Maintenance of sinus rhythm has the potential to substantially improve important clinical outcomes, but this remains to be determined. This is a major gap in the literature that precludes conclusions on the impact of radiofrequency catheter ablation in the broader population of patients with atrial fibrillation.

Another potential benefit of maintaining sinus rhythm is avoidance of the need for anticoagulation. While anticoagulation is effective in reducing the risk of embolic stroke, it also can lead to serious bleeding complications, such as gastrointestinal or intracranial hemorrhage. Treatment decisions based on the benefits and risks of anticoagulation are challenging for clinicians and patients alike. This is particularly true for elderly patients, in whom both the risks of complications from atrial fibrillation and the risk of complications from anticoagulation are increased. Embolic stroke in elderly patients can lead to severe disability and loss of independence. On the other hand, hemorrhagic complications from anticoagulation, for example, intracranial bleeds in elderly patients at risk for falls, can have devastating consequences. Maintaining sinus rhythm has the potential to reduce the risk for both types of complications.

Larger trials with longer follow-up periods are therefore required to provide useful information on important clinical outcomes and complication rates. The CABANA study (ClinicalTrials.gov Identifier NCT00578617) is an ongoing trial of approximately 4,000 patients that compares radiofrequency catheter ablation with antiarrhythmic medications, and includes the endpoints of mortality, complications of catheter ablation, and other clinical outcomes. This is a 5-year trial that is expected to be completed in 2011. Numerous other smaller randomized, controlled trials are currently underway as well, these should add to the overall evidence base for catheter ablation.

Based on the available evidence, the Blue Cross and Blue Shield Association Medical Advisory Panel made the following judgments about whether radiofrequency catheter ablation as a treatment for atrial fibrillation meets the Blue Cross and Blue Shield Association Technology Evaluation Center (TEC) criteria.

1. The technology must have final approval from the appropriate governmental regulatory bodies.

Radiofrequency catheter ablation is a percutaneous procedure, and as such is not itself subject to U.S. Food and Drug Administration (FDA) approval. However, the devices used for catheter ablation are subject to FDA approval. On February 6, 2009, the FDA granted approval via the premarket application (PMA) approval process for the NaviStar® ThermoCool® saline irrigated radiofrequency ablation catheter and the EZ Steer ThermoCool® Nav Catheter (both from Biosense Webster Inc., Diamond Bar, CA), for the treatment of medication-refractory atrial fibrillation. The FDA has also granted PMA approval to numerous catheter ablation systems for other ablation therapy for arrhythmias such as supraventricular tachycardia, atrial flutter, and ventricular tachycardia.

2. The scientific evidence must permit conclusions concerning the effect of the technology on health outcomes.

The evidence is sufficient to conclude that radiofrequency catheter ablation is superior to pharmacologic treatment for maintaining sinus rhythm in certain patient populations. Four randomized, controlled trials reported decreased recurrence of atrial fibrillation in patients with symptomatic paroxysmal or persistent atrial fibrillation who have failed antiarrhythmic medications, as an alternative to continued medical management. In each case, the magnitude of difference was relatively large, with the absolute risk reduction ranging from 47–70% at 1-year follow-up.

For patients with class II or III congestive heart failure and symptomatic atrial fibrillation in whom heart rate was uncontrolled with standard medications, who would otherwise be candidates for AV nodal ablation and pacemaker insertion, one small randomized, controlled trial reported improvements in QOL, functional status, left ventricular ejection fraction, and recurrences of atrial fibrillation associated with radiofrequency catheter ablation. While small and of short duration, this trial was otherwise a high-quality study, and is sufficient to permit conclusions that outcomes will be improved following catheter ablation for this subgroup of patients.

The evidence is not sufficient to permit conclusions on the impact of radiofrequency catheter ablation on other outcomes in the broader population of patients with paroxysmal atrial fibrillation (e.g., as first-line treatment of recent onset arrhythmia or in patients who are adequately managed with a rate control strategy). While there is some evidence suggesting that catheter ablation may improve QOL, this is not adequately robust to permit conclusions. Only two trials provided comparative data on QOL, with each using a different instrument. In addition, the data on QOL are self reported, and thus prone to bias given that these trials were not double blinded. None of the available trials provided data on clinical outcomes such as cardiovascular morbidity and mortality.

3. The technology must improve the net health outcome.

For patients who have symptomatic paroxysmal or persistent atrial fibrillation uncontrolled by standard medications, radiofrequency catheter ablation will improve outcomes. In this case, reduction or elimination of atrial fibrillation episodes will lead to a corresponding improvement in symptoms. Serious complications of catheter ablation in this group of patients is uncertain, but likely to be low, and is balanced against the risk of long-term, suboptimal medication management, including the adverse effects of antiarrhythmic medications and anticoagulation.

For patients with class II or III congestive heart failure and symptomatic atrial fibrillation in whom heart rate is poorly controlled by standard medications, catheter ablation leads to improvements in left ventricular ejection fraction, QOL, and functional status that are greater than those achieved with AV nodal ablation and pacemaker insertion. Serious complications of both procedures can occur, but are uncommon, and there is no definitive evidence that either procedure is substantially more risky than the other.

For the majority of patients whose condition is adequately controlled with a rate control strategy, maintenance of sinus rhythm is not by itself sufficient to demonstrate improved outcomes. For these patients, it is necessary to demonstrate improvements on other outcomes in order to determine benefit, and therefore, it is not possible to conclude that catheter ablation improves health outcomes for the broader population of patients with atrial fibrillation.

4. The technology must be as beneficial as any established alternatives.

Alternative treatments generally involve pharmacologic management. For patients with symptomatic paroxysmal or persistent atrial fibrillation despite medications, catheter ablation is more beneficial than medications in reducing symptoms. In patients who do not have uncontrolled symptoms (i.e., who are adequately maintained on a rate control strategy) or who have new onset paroxysmal atrial fibrillation, it is not possible to conclude that catheter ablation is more beneficial than medications.

For patients with class II or III congestive heart failure and symptomatic atrial fibrillation in whom heart rate is poorly controlled by standard medications, AV nodal ablation and pacemaker insertion is an alternative treatment. One small, high-quality trial establishes that catheter ablation is more effective than AV nodal ablation in improving QOL, functional status, and left ventricular ejection fraction.

5. The improvement must be attainable outside the investigational settings.

Catheter ablation of the pulmonary veins is a technically complex procedure that requires specialized training and has a substantial learning curve. Currently, expertise to perform these procedures is widely available among interventional cardiologists in the U.S. Therefore, the improvement seen in the clinical trials of patients with symptomatic paroxysmal or persistent atrial fibrillation who have failed antiarrhythmic medications or in patients with class II or III congestive heart failure and symptomatic atrial fibrillation in whom heart rate is poorly controlled by standard medications, is expected to be attainable outside the investigational setting.

Whether radiofrequency catheter ablation improves outcomes for other patients with atrial fibrillation, including patients whose condition is adequately controlled using a rate control strategy or as first-line treatment for patients with paroxysmal atrial fibrillation, has not been established in the investigational setting.

Based on the above, radiofrequency catheter ablation of the pulmonary veins as a treatment for atrial fibrillation meets the TEC criteria for:

*  patients with symptomatic paroxysmal or persistent atrial fibrillation who have failed antiarrhythmic medications, as an alternative to continued medical management; and

*  patients with class II or III congestive heart failure and symptomatic atrial fibrillation in whom heart rate is poorly controlled by standard medications, as an alternative to AV nodal ablation and pacemaker insertion.

For other patients with atrial fibrillation, including first-line treatment for paroxysmal atrial fibrillation, radiofrequency catheter ablation of the pulmonary veins does not meet the TEC criteria.

TEC Assessment Index

ablate; ablation; AF; amiodarone; antiarrhythmic; anticoagulation; arrhythmia; arrhythmic; atrial; atrioventricular; AV node; beta blockers; calcium channel blockers; cardiology; cardiomyopathy; cardiovascular disease; cardioversion; catheter; CHF; chronic; circumferential; composite; congestive heart failure; CPVA; DC; digoxin; direct current; EF; ejection fraction; fibrillation; flecainide; foci; heart; heart rate; implant; implantation; insertion; isolation; isthmus;; left atrium; left ventricular ejection fraction; LVEF; MAZE; mitral; myocardial; New York Heart Association; nodal; NYHA; ostia; pacemaker; paroxysmal; PCI; percutaneous coronary intervention; potentials; pulmonary vein; PVI; QOL; quality of life; radiofrequency; rate control; RF; rhythm control; sinus rhythm; stenosis; tamponade; targeting; thoracotomy; thromboembolic; thromboembolism; warfarin;