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Impact of Biatrial Defragmentation in Patients with Paroxysmal Atrial Fibrillation: Results from A Randomized Prospective Study Jana Nührich M.D., Daniel Steven M.D., Imke Berner M.D., Thomas Rostock M.D., Boris Hoffmann M.D., Helge Servatius M.D., Arian Sultan M.D., Jakob Lüker M.D., András Treszl M.D., Ph. D., M.Sc., Karl Wegscheider Ph.D., Stephan Willems M.D. www.elsevier.com/locate/buildenv

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S1547-5271(14)00629-8 http://dx.doi.org/10.1016/j.hrthm.2014.06.002 HRTHM5806

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Heart Rhythm

Cite this article as: Jana Nührich M.D., Daniel Steven M.D., Imke Berner M.D., Thomas Rostock M.D., Boris Hoffmann M.D., Helge Servatius M.D., Arian Sultan M.D., Jakob Lüker M.D., András Treszl M.D., Ph. D., M.Sc., Karl Wegscheider Ph.D., Stephan Willems M.D., Impact of Biatrial Defragmentation in Patients with Paroxysmal Atrial Fibrillation: Results from A Randomized Prospective Study, Heart Rhythm, http://dx.doi. org/10.1016/j.hrthm.2014.06.002 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Impact of Biatrial Defragmentation in Patients with Paroxysmal Atrial Fibrillation: Results from A Randomized Prospective Study

Jana Nührich, M.D.1, Daniel Steven, M.D.1, Imke Berner, M.D.2, Thomas Rostock, M.D.3, Boris Hoffmann, M.D.1, Helge Servatius, M.D.1, Arian Sultan, M.D.1, Jakob Lüker, M.D.1, András Treszl, M.D., Ph. D., M.Sc.4, Karl Wegscheider, Ph.D.4,Stephan Willems, M.D.1

1

Department of Electrophysiology, University Heart Center, University Hospital Eppendorf, Hamburg, Germany

2

Electrophysiology Bremen, Klinikum Links der Weser, Germany

3

Department of Electrophysiology, University Hospital, Johannes Gutenberg-University Mainz,

Germany 4

Department of Biometrics and Epidemiology, University Hospital Eppendorf, Hamburg, Germany

Address for correspondence: Dr. Jana Mareike Nührich University Heart Center Departement of Electrophysiology Martinistraße 52, O70 20246 Hamburg Germany Tel.: +49-40-7410-54120 Fax: +49-40-7410-54125 email: [email protected]

Short title: PVI vs PVI+CFAE in paroxysmal AF All authors declare no conflicts of interest regarding this manuscript.

Background Single procedure success rates of pulmonary vein isolation (PVI) in patients with paroxysmal atrial fibrillation (PAF) are still unsatisfactory. In patients with persistent atrial fibrillation (AF) ablation of complex fractionated atrial electrograms (CFAE) beyond PVI results in improved outcomes. Objective We hypothesized that PAF-patients with sustained AF acutely after PVI might also benefit from additional CFAE-ablation. Methods Overall 1134 consecutive patients received a first catheter-ablation of PAF between 06/2008-12/2012. In most patients AF was either not inducible or terminated during PVI. In 68 patients (6%) AF sustained after successful PVI. These patients were randomized to either cardioversion (PVI-alone, n=33) or additional CFAE-ablation (PVI+CFAE, n=35) and followed every 1-3 months including serial Holter recordings. Primary endpoint was recurrence of AF/atrial tachycardia (AT) after a blanking period of 3 months. Results Procedure-duration (127±6 vs 174±10 min), radiofrequency-application- (44±3 vs 74±5 min) and fluoroscopy-time (26±2 vs 41±3 min) were longer in PVI+CFAE (all p10 minutes. Since CFAE ablation can only be performed during AF, patients were included to the study if AF sustained after PVI >10 minutes without reinducing. Patients were then randomized

(figure 1, study protocol) either to electrical cardioversion to sinus

rhythm (PVI-alone) or CFAE-ablation with the endpoint of AF-termination (PVI+CFAE). Primary endpoint of the study was defined as recurrence of any atrial tachyarrhythmia (> 30 seconds) during 12 months FU with a blanking period of 3 months. During the initial 3 months period arrhythmia recurrences were treated conservatively by cardioversion and/or AAD therapy.5 The study has been approved by the Institutional Review Board and the local ethics committee. All patients gave informed written consent.

Electrophysiological study The detailed procedural protocol was

described before.11 Briefly,

surface

electrocardiograms and bipolar endocardial electrograms were continuously 5

monitored and stored on a computer based digital amplifier/recorder system (Bard Electrophysiology, Lowell, MA). The following catheters were introduced via a femoral vein access: (1) a steerable decapolar catheter (Inquiry, IBI, Irvine Biomedical, Irvine, CA) positioned within the CS; (2) a circumferential decapolar diagnostic catheter (Lasso, Biosense-Webster, Diamond Bar, CA) for mapping of the PV; (3) a nonsteerable quadripolar diagnostic catheter (Inquiry, IBI, Irvine Biomedical) placed in the right atrial appendage (RAA); and (4) a 3.5-mm external irrigated-tip ablation catheter (Biosense-Webster). Access to the left atrium (LA) was achieved by a single transseptal puncture with the two catheters placed into the LA via the same puncture. A nonfluoroscopic 3-dimensional mapping was performed using the Carto (Biosense Webster, Diamond Bar, California) or Ensite NavX (St. Jude Medical, St. Paul, Minnesota) system at the operator's discretion.

Ablation protocol Pulmonary Vein Isolation Electrical isolation of the PV was performed in all patients. An ablation line was initially created on the posterior wall along the ipsilateral veins. This line was continued around the ipsilateral PV including the anterior aspect as required to achieve complete electrical isolation. PVI was defined as elimination or dissociation of PV potentials recorded by the Lasso catheter.

CFAE-ablation In the CFAE-group after complete electrical PVI, mapping and ablation was routinely continued in the LA. For the purpose of AF cycle length (AFCL) measurement, the Lasso catheter was placed in the LA appendage (LAA). After brief exploration of the individual AF behavior, electrogram-guided ablation targeting specific electrogram 6

patterns was performed as described previously.9,

18

The first step was usually

ablation along the roof, LA septum, and inferior and lateral LA. Electrogram-guided ablation was performed at virtually all aspects of the LA displaying the described electrogram characteristics. After that, ablation of the CS was the next step. Mapping and ablation using the same criteria were then continued in the right atrium (RA) if AF did not terminate during LA and CS ablation and the RAA demonstrated a shorter AFCL than the LAA. The desired procedural endpoint was AF-termination and, whenever neccessary, mapping and ablation of subsequent atrial tachycardias (AT) aiming at achievement of sinus rhythm (SR) by ablation only. Linear ablation was only performed in case of conversion to AT with a macroreentrant mechanism. Linear lesions were created with the aim of achieving a bidirectional block.19 When AF termination had not been achieved, the procedure was stopped after a maximum of 6 hours or if a maximum of 5l of fluid had been administrated to the patient due to catheter irrigation. The patient was then externally cardioverted.

Ablation parameters Ablation was performed with a maximum power output of 30 W using an irrigation rate of 10–30 ml/min (0.9% saline infused with the Cool Flow Pump, Biosense Webster) for the PV, 35 W and an irrigation rate between 30 and 60 ml/min in the LA, and up to 30 W in the RA. Power output at the posterior wall was limited to 28 W. Radiofrequency (RF) current was applied within the CS with a maximum of 20 W and a manually adjusted irrigation rate to keep the tip temperature below 42°C.

Follow-up All patients were seen regularly every 1-3 months in our outpatient clinic. Before visits, the patients received at least one 24h-Holter electrocardiogram (ECG). A 7

detailed history of the patients’ symptoms suggestive for potential arrhythmia recurrences was taken. In case of symptoms suspicious for arrhythmia recurrences, documentation by additional tele-ECG

recordings

was

obtained. Individual

antiarrhythmic drug treatment, including amiodarone, was continued at month 1-3 after the procedure and than stopped in all patients. Patients with arrhythmia recurrences after a 3-month blanking period were offered and scheduled for a repeat procedure. However, a minimal interval of 3 months was required between the two procedures. Depending on individual symptoms, AAD therapy was restarted until the repeat procedure was performed.

Repeat procedures As a first step electrical conduction of the PV was assessed by confirmation of entrance block after restoration of SR proving dissociation or complete abolition of the PV potential as shown in the circumferential mapping catheter sequentially for each vein. Differentiation between far field vs PV potentials was performed by stimulation if required. Reisolation of PV was then performed, as described above. If AF persisted (>10 minutes), electrogram-guided ablation was applied in all patients with the same techniques as described for the index procedure. Mapping and ablation of AT was also performed using the techniques described above. The procedural endpoint was termination of AF and/or AT upon achievement of SR.

Statistical analysis The planned sample size of 75 patients per group was designed to provide a 90% power with an alpha-error of 5%, assuming an absolute risk reduction of 25% by additional CFAE-ablation compared to PVI alone in the primary outcome. Statistical

8

analysis was specified after either inclusion of 150 patients or as an interimsanalysis after 3 years of inclusion. Stochastic curtailment with conditional power calculation was applied to investigate whether an early stop of the trial for futility may be adopted.

20

The conditional power

of the interimsanalysis was set to a pre-defined level of 0.2.21 Computations were performed using the %CondPowerLSH SAS Macro.22 Categorical variables are reported as absolute and relative values. Continuous variables are reported as mean and standard error of the mean in case of normal distribution or median and interquartile range in case of other distribution. Event-free survival was displayed with Kaplan-Meier curves. Throughout all calculations, a twotailed probability p-value of .05 was considered statistically significant.

Results

Baseline data In 68 out of 1134 patients (6%) undergoing a first ablation of PAF, AF persisted during the procedure after PVI. Those patients where eligible for the study and therefore randomized: 33 patients to the group PVI-alone, and 35 to the group PVI+CFAE, respectively The remaining patient cohort (1066 patients) had to be excluded due to non-inducibility (681, 60%) of AF or AF-termination during PVI (385, 34%). The baseline data of the randomized patients are shown in table 1. There were no group differences with respect to age, sex, AF history, AF episode length as well as LA diameter or left ventricular ejection fraction. Moreover AAD therapy and cardiovascular risk factors were comparable in both groups. Due to two outliers there

9

was a trend towards longer AF-history in PVI+CFAE, however, this difference was not significant. None of the patients were lost-to-FU.

Procedural data Angiography and 3D mapping revealed normal anatomy in most patients (91%), while a persistent foramen ovale was found in 1 patient, a common ostium of left PV in 3 patients, an additional, third right PV in 1 patient and an atypical cardiac axis due to diaphragmatic elevation in 1 patient. Overall 1013 (89%) of the 1134 screened patients had SR at the beginning of the procedure, in 332/1013 (33%) AF >10 minutes was inducible. The procedural data of the finally included patients are shown in table 2. Eight of these patients presented in and maintained AF throughout the procedure. In the remaining 60 patients AF was inducible and persisted >10 minutes after successful PVI. The number of RF-impulses for the initial PVI was comparable in both groups (24±2 vs 21±1, p=0.15). Due to the adjunctive CFAE-ablation procedure- and flouroscopy duration as well as RF-time were significantly longer in the group PVI+CFAE. Termination of AF was achieved in 30/35 (86%) CFAE-procedures. Direct termination into sinus rhythm occurred in 22/30 (73%) and via atrial tachycardia in 8/30 (27%). In 12/35 (34%) patients CFAE-ablation in the LA was sufficient to achieve AF termination. 23 patients (66%) received further CFAE-ablation in the CS and RA. A mean of 1.5 intraprocedural consecutive AT in patients without termination directly to SR were observed, most commonly common-type atrial flutter (in 4/8 patients), roofdependent flutter (2/8), perimitral flutter (2/8) and tachycardia from the CS (2/8). Most frequently AF could be terminated in the CS (7/30, 23%), followed by anteroseptal LA (6/30, 20%), anterior LA wall (3/30, 10%) and the LAA (3/30, 10%). 10

One patient in the PVI+CFAE group experienced a cardiac tamponade which was successfully treated by pericardiocentesis. No other procedure-related complication occurred in either group.

Outcome The prespecified interim analysis was performed after 3 years of inclusion. Due to highly symptomatic recurrence of AF one patient in each group received an early repeat-procedure within the blanking period. According to the study protocol, these recurrences and repeat procedures were not included into final analysis. The conditional power of the one year event rates was 17.9% falling below the predefined level of 0.2.21 As a consequence, further randomization was stopped. Regarding the primary endpoint, freedom of any atrial tachyarrhythmia without AAD, no significant difference between the two groups was observed (figure 2). The different types of recurring atrial tachyarrhythmias are depicted in table 3. Recurrence of PAF tended to be more common in the group PVI-alone, atrial tachycardia occured slightly more often in the group PVI+CFAE. Emergence of persistent AF appeared only in 3 patients (1 in PVI-alone, 2 in PVI+CFAE). However, none of these conditions reached statistical significance

Repeat procedures Almost all patients with recurrences underwent repeat ablation during further FU (10/11, 91% in the group PVI-alone, 11/13, 85% in the group PVI+CFAE, p=1.00), after a mean of 9.2±1.6 vs 10.3±1.6 months (p=0.63), respectively. Due to highly symptomatic AF episodes AAD therapy was restarted in 2 patients in the group PVIalone (1 patient class Ic AAD, 1 patient class III AAD) and in 8 patients in the group PVI+CFAE (7 patients class Ic AAD, 1 class III AAD). 11

In only one patient in the group PVI+CFAE all PV were still isolated. Therefore a reisolation of one or more PV during first re-intervention due to PV-reconnection was performed in all patients in the group PVI-alone and in 10/11, 91%, (p=1.00) in the group PVI+CFAE. A mean of 2.6±0.3 vs 2.0±0.4 (p=0.26) PV showed reconnection in the group PVI-alone and the group PVI+CFAE, respectively. Further ablation (mapping and ablation of CFAE and ablation of consecutive occuring AT as described for the initial procedure) due to sustained AF after re-isolation was required in 7/10, 70%, vs 11/11, 100%, (p=0.09), in the groups PVI-alone and PVI+CFAE, respectively. Two patients in each group received more than one repeat procedure. No procedure-related complication occurred during repeat procedures in either group.

Further FU Regarding outcome during further FU including repeat procedures, also no significant difference could be observed between the two groups. After a mean of 1.4±0.1 vs 1.4±0.2 procedures, (p=0.88) 29/33, 88%, vs 30/35, 86%, (p=1.00) were free from recurrence of any atrial tachyarrhythmia. 2/29 patients in the group PVI-alone remained arrhythmia free while on AAD (both class III AAD), in contrast none of the 30 arrhythmia free patients in the group PVI+CFAE were on any AAD. Overall mean FU was 21±1 months.

Discussion

Main findings First of all, only 6% of patients with clinical PAF had persistent AF beyond successful PVI. As this was not expected, patient recruitment took several years. Even though 12

intraprocedural sustained AF may suggest the presence of a PV-independent substrate, these patients did not benefit from further CFAE-ablation after PVI, as arrhythmia-free survival after the initial procedure did not differ between the two groups, although AF-termination was achieved in the vast majority. Moreover, additional CFAE-ablation led to significantly longer procedure-, flouroscopy- and RFduration, potentially associated with higher procedural risks. Thus, this randomized prospective study was terminated after the predefined interimsanalysis.

Arrhythmia-recurrence The mechanism leading to PAF has been well understood since the detection of initiating triggers confined to the PV.1 In contrast, in persistent AF an additional PVindependent substrate contributes to the maintainance of the arrhythmia.5, 6 In this setting PVI aimes to eliminate the AF trigger, while the altered atrial substrate is addressed by several techniques of substrate modification such as CFAE-ablation.18 Thus, PVI alone achieves acceptable single procedural success rates in paroxysmal, but not persistent AF.4,

5, 14, 23

On the other hand, CFAE-ablation alone is not

reasonable, as the trigger should always be eliminated first, underscoring PVI as the cornerstone of all AF-ablation procedures.5 Of note, recently published data implicate, that the advantage of reverse remodeling with prolonged time in SR prior to any catheter ablation reduces the need for additional ablation even in persistent AF. Thus, the substrate may not be necessarily fixed.24 The small number of actual randomized patients in our study, i.e. patients with PAF and intraprocedural sustained AF after successful PVI, confirmes the predominant PV-dependent mechanism in most patients with PAF. In this majority of patients, inducible AF at the beginning of the procedure most often terminates during successful PVI. Moreover, the PV reconnection rate in our cohort was rather high. 13

This also suggests the PV to be the main trigger for arrhythmia recurrence in PAF and is supported by previous data of patients undergoing invasive check for persistence of PV-Isolation, published in 2010. In this study we showed a high rate of PV-reconnection, even in asymptomatic patients (43% overall, 100% in patients with symptomatic recurrence).25 Nevertheless, there still might remain a very small subgroup of PAF-patients with a PV-independent substrate. Our approach to identify these patients differed from previous studies. First of all, previous studies12, 26-28 selected patients based on the AF-inducibility after successful PVI as suggested earlier.29, 30 In those studies additional CFAE-ablation failed to show a benefit. Indeed, AF may be induced even in healthy subjects. Thus, inducibility after ablation does not seem to be an optimal selection criterion. Therefore we only induced at the beginning of the procedure and exclusively included those patients with sustained AF after successful PVI without reinducing. Deisenhofer et al. randomized patients already prior to the procedure leading to inclusion of patients without AF-inducibility after PVI.27 After excluding those patients in a subgroup analysis the study was no longer powered to detect group differences. In line with our findings, two meta-analyses also showed that there seems to be no benefit of additional CFAE-ablation in patients with PAF.23, 31 However, most of the prior studies again used AF-inducibility after PVI as a selection criterion to identify patients at risk for a PV-independent substrate or performed randomization in advance, thus limiting the number of patients with a potential benefit from more extensive ablation strategies.27 Only Verma et. al found a trend towards a better outcome in a subgroup of patients with PAF and additional ablation beyond PVI. 14 Of note, this study included only patients with a high burden of AF, which could explain these findings. Indeed, there are different subgroups within the group of patients with 14

PAF. Nattel recently suggested to differentiate two types of PAF-patients:32 one typical form with “recent-onset” AF with little or no history of AF and a second form with very frequent usually short-lasting AF episodes. In our study AF episodes

Impact of biatrial defragmentation in patients with paroxysmal atrial fibrillation: results from a randomized prospective study.

Single procedure success rates of pulmonary vein isolation (PVI) in patients with paroxysmal atrial fibrillation (PAF) are still unsatisfactory. In pa...
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