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Curative Ablation for Atrial Fibrillation: What Clinical Trials DoWe Need to Establish Efficacy?

DIPEN SHAH, M.D.

From the Division of Cardiology, Hopital Cantonal de Geneve, Geneva, Switzerland

Curative Ablation for Atrial Fibrillation. In contrast to other supraventricular tachycardias, cu-rative treatment of atrial fibrillation, although increasingly available and rapidly evolving, is neither aseffective nor the first choice. Until recently, the unavailability of nonsurgical curative treatment may havefueled a debate on the relative importance of restoring sinus rhythm versus controlling the ventricular rateduring atrial fibrillation. Recent randomized trials (PIAF, AFFIRM, and RACE) using very limited atrialfibrillation burden assessment show that pharmacologic ventricular rate control is much safer and possiblymore effective than pharmacologic restoration of sinus rhythm. A clinical trial comparing a truly curativetreatment of atrial fibrillation—such as catheter ablation targeting pulmonary vein isolation—with phar-macologic treatment is required. It should focus on reliable efficacy parameters, use vigilant assessment ofsafety, and, most importantly, be structured to provide all-important prognostic information on long-termoutcome. Atrial fibrillation burden is a theoretically robust efficacy parameter, but accurate quantificationover a sufficiently long period of monitoring will require technologically innovative noninvasive rhythmmonitoring devices. (J Cardiovasc Electrophysiol, Vol. 14, pp. S48-S51, September 2003, Suppl.)

atrial fibrillation, pulmonary vein isolation, atrial fibrillation burden, embolic event

Introduction

The persistent debate about the optimal therapy for atrialfibrillation testifies to the lack of an effective treatment thatmeets with unanimous approval. Clearly, atrial fibrillationis difficult to treat, and many of its defining characteristicsrender it difficult to assess and analyze.

Restoring normalcy is considered synonymous with cur-ing disease, and, in the context of atrial fibrillation, durablerestoration of sinus rhythm should be considered just that. Theincreasing awareness of associated complications, particu-larly cardiovascular morbidity and stroke, has only served tostrengthen the need to eliminate atrial fibrillation. However,the treatment must not be worse than the disease; therefore,it must be weighed in the context of the available standardsof efficacy, safety, and prognostic influence. For a hithertountreatable and lethal condition, even a small improvementin outcome, perhaps at the cost of significant morbidity, maybe considered acceptable, whereas the same is not true forpathologies that have a significantly less malignant course.Consequently, it is the anticipation of incremental benefit of anew treatment for atrial fibrillation over the benefit of existingtreatments that should determine its relevance. Demonstra-tion of such a benefit is necessary to justify its continued andwidespread use.

Atrial fibrillation is known to be intermittent as well asasymptomatic. These characteristics make evidence-basedmanagement guidelines difficult to establish. Considerationof the current recommendations for treatment of nearly allother supraventricular arrhythmias is useful in this context.Until recently, drug therapy had been the mainstay for treat-ment of “paroxysmal supraventricular and junctional” tachy-cardias that, although symptomatic, generally do not havelong-term adverse morbidity and mortality associations (with

Address for correspondence: Dipen Shah M.D., Division of Cardiology, Ho-pital Cantonal de Geneve, 24, Rue Micheli du Crest, 1211 Geneva, Switzer-land. Fax: 4122-472-7229; E-mail: Dipen.Shah@hcuge.ch

perhaps the exception of sudden death in the context of pre-excited atrial fibrillation). The routine availability of curativetreatment that renders the patient “normal” has largely dis-placed pharmacologic therapy as the treatment of choice, withthe proviso that, to account for the risks of an invasive proce-dure, it may be desirable to demonstrate the ineffectivenessof pharmacologic treatment before recourse to catheter ab-lation. Surgical ablation, on the other hand (which precededcatheter ablation and provided an equally curative solution),probably does not have the same efficacy-to-safety ratio andthus has never been a rival of drug treatment. To my knowl-edge, the credentials of catheter ablative treatment for thesesupraventricular arrhythmias have never seriously been re-quired to meet the rigors of evidence-based medicine becausethe virtues of restoring sinus rhythm in this situation have notbeen questioned. The unavailability of curative treatment foratrial fibrillation probably has fueled the debate on the virtuesof restoring normal sinus rhythm.

The prospective randomized controlled trial is sacrosanctto the proponents of evidence-based medicine. Three recentstudies that have been well received by peer-reviewed jour-nals present an interesting starting point for the debate. PIAF(Pharmacological Intervention in Atrial Fibrillation)1 ran-domized patients with symptomatic atrial fibrillation persist-ing for 7 to 360 days to pharmacologic rate control with dil-tiazem versus rhythm control incorporating oral amiodaroneand external DC cardioversion. The PIAF Investigators ex-cluded patients with many conditions in which sinus rhythmis considered essential (e.g., congestive heart failure, hyper-trophic cardiomyopathy), and patients underwent follow-upfour times in the subsequent 12 months, including 24-hourHolter monitoring at each visit. They found 56% of patients inthe rhythm control arm were in sinus rhythm at the end of theobservation period. The investigators concluded that the twotherapeutic strategies achieved similar symptomatic improve-ment, but they also found that exercise tolerance was betterin the rhythm control arm. From the title, the study is clearlyabout a pharmacologic intervention, although its relevance

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in the context of truly curative treatment was not discussed.Two more recent studies—Rate Control versus ElectricalCardioversion for Persistent Atrial Fibrillation (RACE)2 andAtrial Fibrillation Follow-up Investigation of Rhythm Man-agement (AFFIRM)3—have titles indicating that they test abroad and provocative concept in the treatment of atrial fib-rillation: Is ventricular rate control better than eliminationof atrial fibrillation? These studies leave the strong impres-sion that (ventricular) rate-controlled atrial fibrillation is anacceptable endpoint compared to rhythm control. RACE andAFFIRM compare drug control of ventricular rate (successfulin 92%) with drug treatment intended to eliminate atrial fib-rillation, the latter having poor or mediocre efficacy, withoutemphasizing the basic pharmacologic modality of treatmentused with its attendant limitations.

Verification of arrhythmia burden was limited to intermit-tent “snapshot” ECGs, typically a few seconds every monthor even less frequently, so that maintenance of stable sinusrhythm in both studies would be expected to be less than thereported 40% to 60%. To claim that restoring sinus rhythm isno better or even harmful compared to tolerating atrial fibril-lation with a controlled ventricular rate when the means usedto restore sinus rhythm are scarcely effective is no better thancircular reasoning!

In addition, the conclusion in RACE that elimination ofatrial fibrillation does not reduce thromboembolic risk is pre-mature and unsupported by evidence from the current stud-ies. The presence of sinus rhythm following a thromboem-bolic event (which, in all probability, is when the rhythmfirst would be monitored after a cerebrovascular accident)does not exclude thrombus formation as a consequence ofatrial mechanical dysfunction after an episode of atrial fibril-lation, which may require 3–4 weeks (or more) for completerecovery. Thus, both AFFIRM and RACE are misleadingwhen they suggest that the virtues of sinus rhythm over thatof tolerating atrial fibrillation (with a controlled ventricularrate) are being tested when these studies, at best, succeedin comparing two different categories of presently availablecardioactive drugs. The conclusion that emerges is not thatatrial fibrillation (albeit with a controlled ventricular rate) isas acceptable as sinus rhythm, but that antiarrhythmic drugs(mainly types I and III) are poor at eliminating atrial fibril-lation and frequently are toxic. In contrast, the CAST studyhas appropriately been interpreted as evidence of the toxicityof the drugs used and not of the futility of eliminating ven-tricular premature complexes in reducing the risk of suddendeath.

The importance of clarifying the message of these stud-ies to all interested in this area cannot be ignored. A trialcomparing a truly curative treatment versus drug control ofventricular rate is necessary to properly address the question:Is atrial fibrillation as acceptable as normal (sinus) rhythm?To determine the best treatment option, a logical extensionwould be to include a third comparative arm of drug-basedrhythm control in the context of the demonstrated parity ofpharmacologic maintenance of sinus rhythm. Catheter-basedablation treatment already being used in many electrophys-iology laboratories around the world is the obvious curativetreatment that could readily be formally compared with drugtreatment.

When contemplating such a comparison, the main consid-erations that come to mind can be grouped under the follow-ing headings: efficacy, safety, and prognostic effect.

Efficacy

Because atrial fibrillation can be both intermittent andasymptomatic, efforts to correlate atrial fibrillation and mea-sures of its prevalence/severity with outcome parameters havenot yet been convincing. Demonstration of a relationshipbetween increasing arrhythmia and worse outcome wouldstrengthen the case for elimination of atrial fibrillation as adesirable therapeutic goal.

In the absence of data establishing such a relationship, theideal form of evaluation would be to perform an assessmentof the temporal atrial fibrillation burden at baseline and afterthe intervention or during drug treatment. Atrial fibrillationburden, if optimally assessed, conceptually is clearly suitedto overcome the pitfalls of intermittent arrhythmia, as well asthe frequent absence of symptoms.

Periodic ECGs as used in RACE and AFFIRM are clearlytoo small a sample to be representative, and periodic 24-hourHolter monitoring, although better, also may not be enough.The ideal surveillance period is undefined, however, and mayeven differ among patient groups. Any device that directlyrecords the rhythm must have either a sufficiently large mem-ory or accurate intelligent algorithms that allow it to retainonly the arrhythmia events. To permit an extended periodof surveillance, it must be unobtrusive and capable of be-ing integrated in all routine activities, such as showering andswimming.

Because no such ideal device exists, compromises mustbe made. Two approaches have been described recently. Atranstelephonic ECG monitor can allow the transmission ofrelatively short-duration recordings without having to storethem in resident memory or requiring skin electrodes for ex-tended periods. A recent study used these devices to allowpatients to transmit ECGs periodically at a fixed time irre-spective of symptoms in order to determine the incidenceof asymptomatic arrhythmias.4 As the authors acknowledge,even with this approach they underestimated the arrhyth-mia burden, although they succeeded in providing an indi-cation of the extent of the problem of asymptomatic atrialfibrillation.

With increasing sophistication of both hardware and soft-ware, implantable devices (whether for brady or tachy man-agement) have begun to incorporate increasingly more elab-orate and extensive forms of rhythm monitoring capabilities.One study looked at “high rate atrial episodes” in patientswith pacemakers for bradycardic indications and found thatpatients with these episodes, whether symptomatic or asymp-tomatic, were twice as likely to die or have a stroke and sixtimes more likely to develop (conventionally detected) atrialfibrillation.5 Along these lines, implantable rhythm monitor-ing devices have been developed, but the invasive implanta-tion of a foreign body that currently is large and possesses alimited memory prevents its wider use. Although one shouldtake advantage of already implanted and sophisticated rhythmmanagement devices, an invasive strategy solely for arrhyth-mia burden assessment probably cannot be envisaged.

A technologically conceivable and practical adaptationcould involve an easily wearable (and removable) electrode-bearing loop or strap, wound around the neck, chest, thigh,arm, or other location relatively free from movement arti-facts, that could wirelessly transmit electrograms to a belt-borne device and periodically be downloaded to free up itsmemory.

S50 Journal of Cardiovascular Electrophysiology Vol. 14, No. 9, Supplement, September 2003

Such technology-based solutions are motivated by the de-sire to evaluate atrial fibrillation burden as completely as pos-sible, but an interim strategy could be to establish the totalelimination of demonstrable atrial fibrillation using frequentHolter or transtelephonic event monitoring without necessar-ily quantitating the total burden. The subgroup of patientswith no recordable atrial fibrillation could be candidates totest the hypothesis that catheter ablation for sinus rhythmmaintenance is better than pharmacologic rhythm control,the latter known to be ineffective at eliminating atrial fibril-lation even with imperfect “snapshot” monitoring. Certainlysuch a strategy is not perfect, but it represents an advance overother criteria based on “reducing” a highly variable arrhyth-mia burden. Again it must be acknowledged that a minimumsurveillance period is difficult to define, although a longeror more frequent sampling period is better than a shorterone.

Another issue that must be addressed is the time frameof assessment. It is increasingly acknowledged that a sig-nificant proportion of recurrences after catheter ablation isfollowed by lasting elimination of atrial fibrillation even af-ter antiarrhythmic drugs are withdrawn. Arrhythmia burdenevaluation after ablation should envisage an intervening pe-riod of 4 to 12 weeks to allow for electrical remodeling, aswell as resolution of inflammatory changes.

Safety

The safety issues associated with catheter ablation are es-sentially procedure related. Thus, thromboembolic compli-cations and tamponade are classically related to preexistingor procedure-generated thromboembolic debris and cathetermanipulation, respectively, and are generally obvious. Con-ventional reporting probably is adequate, but silent throm-boemboli (e.g., to the lungs or brain) may be an issue. Ifthey do occur, however, the persistent silence of such eventsprobably is reassuring.

Pulmonary vein stenosis is a complication unique to thepulmonary vein isolation procedure and can result in recal-citrant symptoms, including pulmonary edema, particularlyif multiple veins are involved. Although not definitively es-tablished, a small incidence of late stenosis or worsening hasbeen reported. Any trial design should take into account sucha possibility by including MRI or CT imaging at a distancefrom the intervention.

Transformation of atrial fibrillation into an incessant formof reentrant arrhythmia is a proarrhythmic complication, but itis not as serious as ventricular proarrhythmia (which is amongthe most serious complications of antiarrhythmic drug treat-ment). The transformation of paroxysmal atrial fibrillationto an incessant atrial tachycardia can be troublesome symp-tomatically and may even favor the development of a tachy-cardiomyopathy. It is necessary to recognize this rhythm andto determine its prognostic significance.

Prognostic Significance

In some ways, this is the most difficult but most importantpart of any evidence-based evaluation for catheter ablationof atrial fibrillation. Assessing the effect of the interventionbeyond that of stabilizing the rhythm and the implications of

eliminating fibrillation using the present technique of catheterablation will determine the wider applicability of this or anyother curative technique.

The embolic event rate after the procedure is the mostimportant determining parameter but may require a signifi-cant number of patient-years of follow-up. That the numberof patients freed of atrial fibrillation is less than the num-ber of patients enrolled in the interventional arm also maymake it more difficult to demonstrate a difference. Symp-tomatic improvement, including documentation of improvedeffort tolerance, is important and requires standardized eval-uation. Allied to that should be the aim to document remod-eling, with mechanical remodeling easier to document non-invasively using echocardiography. Reductions in atrial size,improvements in Doppler transvalvular flows, and improve-ment in systolic ventricular function have all been shown insmaller observational studies.

Important to the study design is standardization of the ab-lation procedure, which implies a certain proficiency in orderto prevent complications related to the learning curve. It is notthe process of learning the technique that should be evaluatedbut the effect of a consistent given set of ablation lesions. Aconfounding factor is the discrepancy between the desiredand the achieved lesions, which is difficult to minimize un-less the procedure has clearly defined reproducible and stableendpoints. To this end, objective parameters (e.g., activationcriteria vs voltage criteria for conduction block) are essential.The lesions making up the catheter ablation procedure itselfhave been somewhat of a moving target. Pulmonary vein iso-lation has been considered by many to be an integral partof the procedure, although other adjunctive measures (isola-tion of the superior vena cava, vein of Marshall ablation, andlinear left atrial ablation) have been proposed and are underevaluation for evidence of incremental benefit. The efficacyof the currently commonly used catheter ablation procedure(pulmonary vein isolation or peri-pulmonary vein circumfer-ential ablation) has been reported to range from about 50% to85%, with pulmonary vein stenosis as the main adverse effect(range 0%–6%). Identifying the subset of patients who ben-efit from adjunctive procedures will improve results, hope-fully without increasing risks. As indicated earlier, however,the weight of evidence at present supports the evaluationof pulmonary vein isolation as the basis of curative treat-ment. In most laboratories, the efficacy of catheter ablation issignificantly lower for patients with persistent or permanentatrial fibrillation; therefore, patients with paroxysmal atrialfibrillation undoubtedly are more frequent candidates for acatheter-based procedure. The curative treatment of parox-ysmal atrial fibrillation at present is significantly more at-tractive and likely to show greater symptomatic benefit; onthe other hand, it is likely that patients cured of persistent orpermanent atrial fibrillation will show the greatest prognosticbenefit.

With these requirements in mind, at least one multicenterstudy currently is enrolling patients (P. Jais, personal com-munication, 2002). This study is designed as an open butrandomized comparison of antiarrhythmic drug therapy withcatheter ablation for patients with symptomatic, frequent, anddrug-resistant paroxysmal atrial fibrillation. Inclusion crite-ria include at least two episodes within the last month despitethe use of one type I or III antiarrhythmic drug. After ran-domization, a 3-month lead-in period is allowed to permit

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optimization of antiarrhythmic drug therapy (different drugsand combinations) or catheter ablation (up to three interven-tions permitted), after which evaluation includes a symptomlog, and ECG and Holter monitoring at relatively frequentintervals during a 12-month follow-up. The persistence ofsinus rhythm noted in the patient diary, as well as at eachconsultation and Holter, will be used to indicate a successfuloutcome. Secondary evaluation criteria include the burden ofatrial fibrillation, adverse events, mortality, and withdrawalof oral anticoagulation. Late monitoring for asymptomaticpulmonary vein stenosis is scheduled at the end of the obser-vation period.

The above study, as well as others investigations, will tryto answer the questions raised by recent data obtained frompharmacologic attempts to control atrial fibrillation. It is im-portant to be able to distinguish a poor tool (pharmacother-apy) from an erroneous premise. With recent progress in thearea of curative ablation of atrial fibrillation, we finally maybe able to justify to evidence-based purists that restoration ofstable sinus rhythm represents more than an electrocardio-graphic transformation.

References

1. Hohnloser SH, Kuck KH, Lilienthal J, for the PIAF Investigators: Rhythmor rate control in atrial fibrillation: Pharmacological intervention in atrialfibrillation (PIAF): A randomized trial. Lancet 2000;356:1789-1794.

2. Van Gelder I, Hagens VE, Bosker HA, Kingsma JH, Kamp O, Kingma T,Said SA, Darmanata JI, Timmermans AJM, Tijssen JGP, Crijns HJGM,for the Rate Control versus Electrical Cardioversion for Persistent atrialfibrillation (RACE) Study Group: A comparison of rate control andrhythm control in patients with recurrent atrial fibrillation. N Engl J Med2002;347:1834-1840.

3. The Atrial Fibrillation Follow-up Investigation of Rhythm Management(AFFIRM) Investigators: A comparison of rate control and rhythm controlin patients with atrial fibrillation. N Engl J Med 2002;347:1825-1833.

4. Page RL, Tilsch TW, Connolly SJ, Schnell DJ, Marcello SR, Wilkin-son WE, Pritchett ELC, for the Azimilide Supraventricular ArrhythmiaProgram (ASAP) Investigators: Asymptomatic or “silent” atrial fibrilla-tion. Frequency in untreated patients and patients receiving azimilide.Circulation 2003;107:1141-1145.

5. Glotzer TV, Hellkamp AS, Zimmerman J, Sweeney MO, Yee R, Marin-chak R, Cook J, Paraschos A, Love J, Radoslovich G, Lee KL, LamasGA for the MOST Investigators: Atrial high rate episodes detected bypacemaker diagnostics predict death and stroke. Report of the atrial diag-nostics ancillary study of the Mode selection trial (MOST). Circulation2003;107:1614-1619.