Should Ablation Be First-Line Therapy and for Whom: The Antagonist Position
2005; Lippincott Williams & Wilkins; Volume: 112; Issue: 8 Linguagem: Inglês
10.1161/circulationaha.104.483305
ISSN1524-4539
AutoresBenzy J. Padanilam, Eric N. Prystowsky,
Tópico(s)Cardiac electrophysiology and arrhythmias
ResumoHomeCirculationVol. 112, No. 8Should Ablation Be First-Line Therapy and for Whom: The Antagonist Position Free AccessArticle CommentaryPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessArticle CommentaryPDF/EPUBShould Ablation Be First-Line Therapy and for Whom: The Antagonist Position Benzy J. Padanilam, MD and Eric N. Prystowsky, MD Benzy J. PadanilamBenzy J. Padanilam and Eric N. PrystowskyEric N. Prystowsky Originally published23 Aug 2005https://doi.org/10.1161/CIRCULATIONAHA.104.483305Circulation. 2005;112:1223–1231Atrial fibrillation (AF), the commonest cardiac arrhythmia with an adverse prognosis, has an estimated prevalence of 0.4% in general population.1 The disease is associated with significant morbidity related to symptoms, heart failure, and thromboembolism.2 Although AF is generally considered a non–life-threatening arrhythmia, it was associated with a 1.5- to 1.9-fold excess mortality after adjustment for preexisting cardiovascular conditions in the Framingham Heart Study.3 In the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) study, a strategy of heart rate control was equivalent to heart rhythm control in terms of quality of life and all-cause mortality but superior in reducing hospitalizations.4 Anticoagulation with warfarin is maintained in either strategy if the patient has risk factors for thromboembolism. The major reason to pursue sinus rhythm in patients with AF is to improve their symptoms and quality of life. No studies have shown a reduction in stroke or heart failure when rhythm control is attempted in patients with AF.Once the decision to achieve rhythm control in a given patient has been made, physicians have to determine the best means of achieving this objective. Multiple randomized trials have demonstrated a modest but highly significant efficacy for antiarrhythmic medications.5 The limited long-term efficacy and high incidence of side effects of antiarrhythmic medications have prompted physicians to consider nonpharmacological therapies for AF.6 It has also been postulated, in a retrospective subanalysis of the AFFIRM study, that a strategy to maintain sinus rhythm without the adverse effects of antiarrhythmic medications may confer a survival advantage.7 In a nonrandomized study, Pappone et al8 compared the outcomes in a selected group of 589 patients who underwent circumferential pulmonary vein ablation with 582 age- and gender-matched cohort patients who received antiarrhythmic medications to maintain sinus rhythm. After a median follow-up of 900 days, the observed survival was longer and quality of life was better for patients who underwent ablation. Although these findings are intriguing, they require confirmation in a prospective randomized controlled trial.Determinants of First-Line TherapyThe issue under discussion here is not whether a catheter ablation cure of AF is either possible or useful in many patients but whether it should be used as "first-line" therapy. Thus, it is important to establish reasonable criteria to define first-line therapy. In our view, 3 requisites should be met for any new treatment to attain this status: (1) knowledge of the short-term and long-term risks, (2) knowledge of the short-term and long-term benefits, and (3) an equivalent or superior risk-to-benefit ratio of the proposed treatment compared with established therapies. The following discussion reviews the data on catheter ablation of AF as they pertain to these 3 important issues. As we will show for most patients, the evidence does not support catheter ablation as first-line therapy for AF.Nonpharmacological Therapy for Wolff-Parkinson-White SyndromeNonpharmacological treatment for Wolff-Parkinson-White (WPW) syndrome is a paradigm against which nonpharmacological therapy for other cardiac arrhythmias should be compared. Figure 1 reviews the evolution of the surgical approach to cure WPW syndrome. In 1930, Wolff, Parkinson, and White combined the observations of a bundle-branch block with an abnormally short PR interval in individuals with paroxysms of tachycardia into what we now recognize as the WPW syndrome. Still, it took decades of observations of outstanding electrocardiographers and finally invasive clinical electrophysiologists to unravel the pathophysiology of AV reentry.9Download figureDownload PowerPointFigure 1. Development of surgical therapy for WPW syndrome. See text for details.The path taken to understand this very important arrhythmia solidified 1 certain thing: its clinical relevance in humans. As more knowledge on mapping the location of an accessory pathway became available, the next logical step was for a visionary team of researchers to attempt a surgical cure for this arrhythmia, as was done by Dr Will Sealy and colleagues at Duke University.10 Initially, surgery was used very infrequently, and each case was systematically evaluated. Over many years, the surgical approach was refined until it became an established method of treatment.9 Long-term safety and efficacy were established, and the quality of life for up to 18 years after surgery was excellent.11 Even with the short-term and long-term risks and benefits known, many, if most, electrophysiologists still did not recommend it as first-line therapy for most patients with WPW syndrome, although it clearly was a first-line treatment for high-risk groups and younger patients.In Figure 2, the nonpharmacological treatment paradigm for WPW syndrome shifts to the development of catheter ablation to cure patients with these arrhythmias. The surgical experience provided the electrophysiologist with an in-depth understanding of an anatomic approach to ablate accessory pathways, and the major hurdles were to develop deflectable tipped catheters with appropriate electrode surfaces and energy sources that would enable a catheter-based approach for ablation. The technical challenges were resolved rather quickly, and short-term safety and efficacy were established.12 Because the long-term safety and efficacy of the surgical approach had been established, it was presumed that a similar outcome could be expected from the catheter-based approach. Thus, the marked reduction in morbidity and mortality of catheter ablation compared with surgery advanced catheter ablation as first-line therapy of patients with the WPW syndrome even in the absence of prospective randomized clinical trials. Download figureDownload PowerPointFigure 2. Development of catheter ablation therapy for WPW syndrome. See text for details.Nonpharmacological Therapy for AFThe journey to a surgical approach to cure patients with AF took a strikingly different course than that for patients with WPW syndrome (Figure 3). There were nearly no reasonable experimental models to study WPW syndrome, but a plethora of models, including computer simulations, were used to investigate the pathophysiological basis for AF.2 Sherf and coworkers13,14 proposed that AF was caused by an ectopic focus, but most investigators sided with Moe et al,15,16 who advanced the concept of the multiple wavelet hypothesis. In this concept, AF is maintained by multiple independent wavelets moving around functionally refractory tissue. The maintenance of AF depends on the probability that electrical activity can be sustained by a sufficient number of active wavelets at any point in time. The pioneering surgical approach to cure AF developed by Dr Cox17 was based on the pathophysiological mechanism of the multiple wavelet hypothesis. The surgical approach was designed to make critical incisions in the right and left atria that would develop barriers to conduction and thereby prevent maintenance of AF. The atrial incisions direct sinus impulses to a path or a "maze" to reach the AV node, and the surgical approach has been called the maze procedure. This procedure was refined over time, and short-term safety and efficacy are reasonably well established. For example, among the 178 patients undergoing several iterations of the maze procedure from 1987 to 1996, 93% were arrhythmia free in the absence of antiarrhythmic medications with a 3-month to 8.5-year follow-up.17 Thus, both short-term and long-term safety and efficacy appear reasonable with this technique. Despite a high success rate of the surgical maze procedure to cure AF, the requirement of open heart surgery with its attendant risks have clearly limited the acceptance of this procedure as a first-line therapy, and it is rarely used for this purpose. Surgical approaches using the maze and the more current pulmonary vein isolation procedures are very reasonable "add-on" techniques in patients undergoing other forms of cardiac surgery. Download figureDownload PowerPointFigure 3. Development of surgical therapy to cure AF. See text for details.Catheter Ablation to Cure AFFigure 4 summarizes the odyssey of the development of a catheter ablation approach to cure AF. Based on the success of the surgical maze procedure, the initial catheter ablation approach attempted to create a series of linear ablation lines in the right and left atrium to mimic the surgical maze approach.18,19 The use of linear ablation lines within the left atrium yielded a success rate often in the 40% to 50% range, but the relatively high complication rates dampened enthusiasm for this ablation approach.18,19 Linear ablations in the right atrium have demonstrated limited success on follow-up.20–22Download figureDownload PowerPointFigure 4. Development of catheter ablation therapy to cure AF. See text for details.The long buried and forgotten observations on an ectopic focus theory for AF suddenly reemerged with the seminal observation of Haissaguerre and colleagues23 on the existence of pulmonary vein ectopy that caused AF. The majority of focal sources of AF occur within ≥1 of the pulmonary veins, and elimination of these ectopic areas can prevent AF.21 The importance of this observation by Haissaguerre et al that the clinical occurrence of AF was often related to an ectopic focus cannot be overstated. Although this observation does not negate the contribution of reentry in maintaining AF in patients, it swiftly caused a sea change in the clinical ablation approach to cure patients with AF. Furthermore, it has led to a resurgence in basic research directed at understanding the pathophysiological mechanisms of AF.Most focal sources of AF have been found within the pulmonary veins. However, foci have been described in the left atrial posterior wall, superior vena cava, crista terminalis, vein of Marshall, coronary sinus, and interatrial septum in as many as 28% of patients.24 Focal ablation within the pulmonary vein was guided by activation mapping. In the first series of 45 patients with paroxysmal AF undergoing focal ablation, 62% were free of symptomatic AF after a mean follow-up of 8 months, and ≈70% of these patients required >1 procedure.23 In another series of 79 patients, Chen et al25 reported an 86% success rate at a mean follow-up of 6 months. The long procedure times, absence of good end points, frequent recurrences, and relatively high incidence of complications such as pulmonary vein stenosis prompted further research into ablation approaches.The most recent techniques target electrical isolation of the entire pulmonary vein musculature from the left atrium as the end point, and several approaches have been proposed. Electrophysiological breakthroughs from the pulmonary veins to the left atrium are often multiple and were identified by circumferential mapping at the venous ostia. Radiofrequency ablation at sites of earliest activation eliminated all pulmonary vein potentials.26,27 In a study of 70 patients and a mean follow up of 4±5 months, 73% were free of AF without antiarrhythmic medications, although 29 patients had a second ablation procedure to obtain these results.26 There were no instances of pulmonary vein stenosis, and elimination of pulmonary vein potentials was suggested as an ablation end point.26An anatomic approach, guided by a nonfluoroscopic navigation system (CARTO), was described by Pappone et al.28 Radiofrequency ablations are delivered circumferentially outside the pulmonary vein ostium. Of the 26 patients who underwent this procedure at a mean follow up of 9±3 months, 85% were free of AF, including 62% without antiarrhythmic medications.28 In a subsequent study of 251 patients from the same group, the overall success was 80%, and only 13 of these patients were taking antiarrhythmic medications.29 The success rate was higher for paroxysmal AF (85%) compared with persistent AF (68%). Modification of these techniques with electrogram-based pulmonary vein antrum isolation has also reported high success rates.30 Another approach recently described has involved targeting complex fractionated electrograms for ablation.31 At a 1-year follow-up, 110 of 121 patients (91%) were free of AF, including 10 patients still taking antiarrhythmic medications.Long-Term EfficacyThe concept of "cure" for a chronic disease like AF should be approached with caution. Epidemiological studies indicate an increased incidence of AF with increasing age and diseases such as hypertension. Aging can lead to electrophysiological and electroanatomic changes in the atria that may provide a substrate for maintenance of AF. Thus, AF may be a disease in which multiple mechanisms are operative, and eliminating triggers and possible modification of substrates with pulmonary vein isolation procedures may not result in long-term cure after initial clinical success.An area of concern is the lack of long-term efficacy of pulmonary vein ablation techniques. Relatively high cure rates using only right atrial linear ablations at initial follow-ups did not hold up over time.20–22 Similarly, high success rates of 86% were reported with focal pulmonary vein ablation in an initial report of a 6-month follow-up, and subsequent follow-up reported lower success.25,32 Several reports have claimed >80% cure rates with circumferential pulmonary vein ablation techniques during relatively short mean follow-up periods ranging from 6 to 14 months.29,30,33 Whether these results will stand the test of time is unknown.Another troubling problem is the significant variance of success among laboratories using similar techniques of ablation.34,35 The procedures are technically challenging and highly operator dependent, which may explain the differences in outcomes. Because initial data are usually reported from very experienced centers, the risk-to-benefit ratio for the same procedure may be quite different at other institutions.36Making efficacy of AF ablation even harder to define is the well-known occurrence of asymptomatic AF.37 Studies reporting only symptomatic AF episodes after ablation could overestimate success, especially during short-term follow-up. In a study of 60 patients who became asymptomatic after pulmonary vein ablation, 12% reported symptoms and documented AF when given an event recorder almost 2 years after the ablation.38 Some patients may have an apparent threshold burden of AF below which it remains asymptomatic, and AF during sleep often goes undetected. It is possible that radiofrequency ablation may change symptomatic AF to asymptomatic AF in some patients. This is important not only to quantify the true success of the procedure but also to make decisions regarding anticoagulation in patients at high risk for stroke. In the AFFIRM trial, the risk of thromboembolism persisted in patients who were clinically maintaining sinus rhythm with antiarrhythmic medications, perhaps because of clinically undetected episodes of AF in these patients.4 Patients cured of symptomatic AF after a radiofrequency ablation procedure could be in an analogous situation.In summary, short-term efficacy of the various pulmonary vein ablation techniques appears to be reasonably good but often requires >1 procedure and temporary or prolonged antiarrhythmic medication use. Long-term efficacy defined in years is still lacking.Comparison of TechniquesAt present, most investigators are using techniques to isolate electrically the pulmonary veins from the left atrium or to modify the left atrial substrate around the pulmonary veins. Different methods have been proposed,39–41 but few comparative data have been published. There is debate whether isolation of pulmonary veins is essential to cure AF.42 Oral et al33 compared segmental ostial ablation and circumferential pulmonary vein ablation. Success rates were reported to be 88% with circumferential pulmonary vein ablation compared with 67% for segmental isolation of pulmonary veins. However, the follow-up period was short (164±100 days), and the number of patients small (40 in each group). Variable use of antiarrhythmic medications after ablation in different studies further complicates meaningful comparisons of procedural success.In addition to the pulmonary vein ablation techniques, some investigators propose isolation of the superior vena cava, cavotricuspid isthmus ablation, or addition of linear ablation lesions in the left atrium. Whether these adjunctive ablations improve outcome and which patients should be targeted for them need more investigation. No prospective studies have been performed comparing any of these ablation techniques with medical therapy.Complications of AblationFew therapies, pharmacological or otherwise, can be administered without safety concerns. Potassium channel blocking antiarrhythmic medications (class III) can cause torsade de pointes, amiodarone is associated with a variety of organ toxicities, and sodium channel blocking agents (class I) can increase mortality when used in patients with structurally abnormal hearts and coronary artery disease.2 However, the use of antiarrhythmic medications other than amiodarone is rarely associated with organ toxicity or life-threatening proarrhythmia in patients with structurally normal hearts. Unfortunately, complications of ablation can occur in any patient, including those with normal hearts, and previously unknown complications may emerge with changes in techniques, wider ablation experience, or longer follow-up.Pulmonary Vein StenosisPulmonary vein stenosis of variable degrees was commonly seen after focal ablation inside the pulmonary veins.25,27 The incidence of this complication has been dramatically reduced by changes in technique. In one study, a reduction in power delivery and limiting ablations to the pulmonary vein ostia eliminated acute pulmonary vein stenosis (defined as >50% diameter reduction) detected by venography immediately after ablation.26 In another study, no patients had pulmonary vein stenosis on follow-up transesophageal echocardiograms when ablations were delivered outside the pulmonary vein ostium under CARTO guidance.29 However, a relatively high incidence of pulmonary vein stenosis was reported by another group (36% overall and 17% severe) using the CARTO-based circumferential pulmonary vein ablation approach.35 Titration of radiofrequency energy delivery by visualizing microbubble formation with intracardiac echocardiography is also reported to reduce the incidence of pulmonary vein stenosis.30,43 The true incidence is likely underreported unless postprocedure imaging techniques are used because pulmonary vein stenosis can be asymptomatic.43 The long-term effects of even mild to moderate pulmonary vein stenosis are unclear.ThromboembolismEmbolic stroke is a well-recognized complication of pulmonary vein ablation. The incidence has varied from 0% to 5%23,44; one group recently reported a 2.5% incidence of stroke.45 Intracardiac echocardiography has documented left atrial thrombus attached to the mapping catheter or sheath in 24 of 232 patients (10.3%) even when activated clotting time was maintained >250 seconds.46 Newer, more aggressive anticoagulation strategies and use of intracardiac echocardiography30 may reduce the frequency of this dire complication.Atrioesophageal FistulaLeft atrium to esophagus fistulas have occurred after intraoperative radiofrequency ablation of AF47 and recently have been reported after catheter ablation.48,49 Patients usually present with sudden neurological symptoms or endocarditis after an initial unremarkable postoperative course. Atrio-esophageal fistula, thus far reported only after circumferential pulmonary vein ablations,48,49 may be related to the more extensive ablation lesions applied to the posterior left atrium. In the surgical series, 4 of 387 patients undergoing intraoperative radiofrequency ablation developed atrioesophageal fistula.47 Three patients survived after extensive esophageal resection, and 1 died of massive air embolism. Among the 3 reported cases after catheter ablation, 2 patients died, and 1 survived after emergency cardiac and esophageal surgery. Risk factors for this potentially fatal complication have not been established.47 The true incidence and strategies to prevent this complication with catheter ablation require further study.Left Atrial FlutterReentrant rhythms may originate in the left atrium related to scars of catheter ablation of AF. In a series of 44 patients who underwent linear left atrial ablations, left atrial flutter appeared in 31 patients on follow-up.19,50 Interestingly, left atrial flutter was not inducible at the end of the initial ablation procedure. Left atrial flutter has also been reported after circumferential pulmonary vein ablation procedures in 2.5% to 20% of patients33,35 and may appear months after the initial ablation. Late appearance of atrial flutter may indicate remodeling or extension of ablation scars setting up macroreentry.Other ComplicationsFigure 5 shows the major complications with pulmonary vein ablation in >1000 patients studied.18 Complications additional to those listed above include air embolism, cardiac tamponade, phrenic nerve damage, and mitral valve damage. It should be noted that a variety of ablation techniques were used over time and that the incidence of various complications is likely to be less with refinement of techniques and more experience. Download figureDownload PowerPointFigure 5. Major complications associated with pulmonary vein (PV) ablation procedure to cure AF. TIA indicates transient ischemic attack; CVA, cerebrovascular accident. Reproduced with permission from Reference 18.In summary, the short-term safety of the newer ablation techniques has improved, but serious and life-threatening complications persist. The long-term safety is unknown.Publication BiasPublication bias is a widely recognized phenomenon that occurs because of the influence of study results on the chances of publication. Studies with positive results are more likely to be published than studies with negative results, leading to a preponderance of positive results in the literature.51 Journals with a high citation impact factor are more likely to publish studies with positive results, and tendency toward publication bias is greater with observational studies than with randomized clinical trials.52 Thus, conclusions based only on a review of published data should be interpreted cautiously, especially for observational studies like AF ablation. Underreporting of complications and low procedural success is certainly a possibility.ConclusionsOur requisites for a first-line therapy are known short-term and long-term risks and benefits and a demonstrated risk-to-benefit ratio equivalent or superior to that of alternative treatments. Ultimately, the cost-effectiveness of the treatment should also be taken into account. As shown in Figure 4, we think that long-term safety and efficacy of catheter ablation to cure AF are unknown, and we do not feel that it should be recommended as first-line therapy for most patients with AF. Unlike catheter ablation of WPW syndrome, where excellent short-term and long-term efficacy and minimal procedural complications enabled it to become first-line therapy even in the absence of prospective randomized controlled trials, catheter ablation of AF is associated with variable short-term efficacy, unknown long-term efficacy, and significant procedure-related complications. Our position should not be taken as an indictment against catheter ablation of AF, which we do routinely at our institution. Rather, it reflects the current state of the art of this procedure. We fully expect future advances in techniques and technology and demonstration of the outcomes of ablation in prospective randomized trials to move ablation to a first-line therapy for AF.Are there circumstances in which catheter ablation might be considered as an initial therapy? We think there are, and exceptions to the general rule might include patients with very symptomatic AF who refuse antiarrhythmic medications, patients in whom the only antiarrhythmic choice is long-term amiodarone, and possibly patients at high risk for stroke who refuse or cannot take long-term warfarin therapy. Regarding the last group, one has to recognize that there is no long-term follow-up showing a reduction in stroke risk in patients apparently cured of AF with catheter ablation. Such patients may require constant long-term rhythm monitoring, eg, with an implanted loop recorder.Other less common situations might be young patients with paroxysmal AF and sinus node dysfunction who may not tolerate antiarrhythmic medications without a permanent pacemaker. Significant improvement in sinus node function was reported, eliminating the need for pacing, after curative ablation of AF in such patients.53 The long-term morbidity associated with a pacemaker, in addition to the risks related to antiarrhythmic drug therapy, might tilt the balance in favor of ablation as a first-line treatment in these selected patients. Although clinical judgment is important in deciding the best course of therapy in these individual circumstances, catheter ablation should not be the first-line therapy for most AF patients at the present time. 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