Pulmonary vein triggers play an important role in the initiation of atrial flutter: Initial results from the prospective randomized Atrial Fibrillation Ablation in Atrial Flutter (Triple A) trial Ralph Schneider, MD,* Joerg Lauschke, MD,* Tina Tischer, MD,* Cindy Schneider, MD,* Wolfgang Voss, MD,* Felix Moehlenkamp,* Aenne Glass,† Doreen Diedrich,† Dietmar Bänsch, PhD* From the *Heart Centre, University Hospital of Rostock, Germany, and †Institute for Biostatistics and Informatics in Medicine, University Rostock, Germany. BACKGROUND The incidence of atrial fibrillation (AF) after ablation of a cavotricuspid isthmus (CTI)–dependent atrial flutter (AFL) is high. OBJECTIVE The purpose of this study was to test the hypothesis that AFL and AF may be initiated by pulmonary vein triggers. This prospective randomized trial tested the efficacy of a standalone pulmonary vein isolation (PVI) in patients with AFL but without AF. METHODS Patients with AFL but without documented AF were randomly assigned to 1 of 3 treatment groups: (1) antiarrhythmic drugs (AAD), (2) CTI ablation, or (3) circumferential PVI. The primary end-point was defined as any recurrent atrial tachyarrhythmia and the secondary end-point as recurrence of AFL. In case of tachyarrhythmia recurrence in the PVI group, a second PVI was performed to close gaps in the ablation lines. RESULTS Of the 60 patients, 17 were randomized to AAD, 23 to CTI ablation, and 20 to PVI. During follow-up of 1.42 ⫾ 0.83 years, 14 of 17 patients (82.4%) in the AAD group, 14 of 23 patients (60.9%)

Introdution Ablation of the cavotricuspid isthmus (CTI) is the therapy of choice for treatment of typical atrial flutter (AFL).1,2 However, many patients also present with atrial fibrillation (AF) at the time of ablation or during follow-up.3–7 In patients with isolated AFL and no documentation of other arrhythmias, the incidence of AF was 12.9% 6 months after CTI ablation5 and increased progressively to 50% after 2.5 Drs. Schneider and Lauschke contributed equally to this manuscript. Dr. Bänsch has received grants from Biotronik, St. Jude Medical, and Medtronic; and has received honoraria from Biotronik, St. Jude Medical, and Medtronic. The study was supported by Biosense Webster and Medtronic. ClinicalTrials.gov Identifier: NCT02051621. Address reprint requests and correspondence: Dr. Dietmar Bänsch, University Clinic, Ernst-Heydemann-Str 6, 18057 Rostock, Germany. E-mail address: dietmar. [email protected].

1547-5271/$-see front matter B 2015 Heart Rhythm Society. All rights reserved.

in the CTI group, and 2 of 20 patients (10%) in the PVI group reached the primary end-point (P o.001) after a mean of 1.4 PVI procedures per patient. AFL reoccurred in 9 patients (52.9.%) in the AAD group, in 2 patients (8.7%) in the CTI group, and after a single PVI in 3 patients (15%) in the PVI group (P ¼ .003). After closure of gaps, 1 patient (5%) in the PVI group presented with recurrent AFL. CONCLUSION Pulmonary vein triggers play an important role in AFL. PVI can prevent the recurrence of AFL, even without CTI ablation. KEYWORDS Atrial fibrillation; Atrial flutter; Radiofrequency ablation; Three-dimensional electroanatomic reconstruction ABBREVIATIONS AAD ¼ antiarrhythmic drug; AF ¼ atrial fibrillation; AFL ¼ atrial flutter; CTI ¼ cavotricuspid isthmus; ECG ¼ electrocardiography; ILR ¼ implantable loop recorder; PV ¼ pulmonary vein; PVI ¼ pulmonary vein isolation (Heart Rhythm 2015;12:865–871) I 2015 Heart Rhythm Society. All rights reserved.

years6 and 82% after 39 months.7 In patients with preexisting AF, the incidence was even higher than in patients with isolated AFL.8,9 A close pathophysiologic interrelationship between both arrhythmias has been suggested for many years10,11 and is backed by current clinical and experimental studies.12 These studies raise the question whether both arrhythmias are initiated by the same electrical trigger.10,12 AF is mainly initiated by triggers from the pulmonary veins (PVs),13 and recent studies demonstrated the benefit of an additional pulmonary vein isolation (PVI) in patients with isolated AFL.14,15 The aim of this study was to examine the efficacy of a standalone PVI in patients with AFL but without AF. We report the initial results of the ongoing prospective randomized Atrial Fibrillation Ablation in Atrial Flutter (Triple A) study. http://dx.doi.org/10.1016/j.hrthm.2015.01.040

866

Methods Patients The study was approved by the local Ethics Board of the University of Rostock. Consecutive patients with documented typical right AFL on surface 12-lead electrocardiogram (ECG) referred to our hospital between August 2010 and October 2013 were enrolled into the study. Careful evaluations of previous ECGs were performed. Patients with a history of AF or previous CTI ablation at the time of enrollment were excluded. Other exclusion criteria were AV nodal reentrant tachycardia, accessory pathways, left atrial dilation 46 cm, previous valve surgery, and congenital heart disease. Efforts were made to induce AFL during electrophysiologic study. Noninducibility was not an exclusion criterion in this trial because conditions promoting the transition to AFL may be present only temporarily.16–19

Study design Patients were randomly assigned to 1 of the following groups: (1) antiarrhythmic drug (AAD) therapy, (2) ablation of the CTI, or (3) standalone circumferential PVI without additional trigger ablation or substrate modification. All patients gave written informed consent for the study and procedure. Patients randomized to AAD were treated for up to 6 months. Class IC AADs were prescribed in patients without, and amiodarone in patients with, structural heart disease. If patients presented with AFL at time of randomization, electrical cardioversion was performed. Patients randomized to the CTI or PVI group underwent electrophysiologic study under sedation with continuous infusion of propofol. If patients were in AFL, entrainment was performed from the CTI to confirm AFL. Transseptal puncture was performed in all ablation patients with the intention to induce AFL from the PVs. After transseptal puncture, intravenous heparin was administered to maintain an activated clotting time of 250 to 350 seconds. A circular mapping catheter (Lasso, Biosense Webster, Diamond Bar, CA) was positioned via an SL-1 sheath (8Fr or 8.5Fr, St. Jude Medical, St. Paul, MN) in the left superior PV, and repetitive burst pacing up to 30 seconds was performed. To avoid immediate initiation of AF, pacing was started well above the documented clinical AFL cycle length. The initial burst pacing cycle length of 350 ms was decreased by 10 ms every second down to 250 ms and if necessary every 2 to 3 seconds thereafter. The delay in CTI conduction was monitored. If 1:1 left-to-right atrial conduction was lost, pacing was terminated and reinitiated slightly above this cycle length. If AF was induced, pacing was immediately terminated and conversion to AFL was awaited for several minutes. If progression did not occur, AADs (up to 100 mg flecainide or 300 mg amiodarone) were administered intravenously to support conversion of AF into AFL. If AF persisted, cardioversion was performed before ablation.

Heart Rhythm, Vol 12, No 5, May 2015 In the CTI group, the transseptal sheath was retracted and irrigated radiofrequency ablation of the CTI was performed (Celsius, Biosense Webster) with power up to 50 W, flow rate up to 30 mL/min, and temperature limit of 43ºC. Bidirectional conduction block was defined as the endpoint of CTI ablation. In the PVI group, PVI was performed as previously described.20 The end-point of wide circumferential PV ablation was defined as absence of any PV spike within the ipsilateral PVs. Exit block of the left-sided veins was tested to differentiate left atrial appendage signals from residual PV signals. Because gaps in the ablation lines after PVI are frequent, a second procedure to close these gaps was considered an integral part of the ablation if arrhythmias recurred.20 The second ablation was not performed until a minimum time interval of 3 months elapsed from the first procedure.

Monitoring of arrhythmias Implantation of an implantable loop recorder (ILR; Reveal XT, Medtronic, Inc, Minneapolis, MN, USA) was offered to all patients to capture even asymptomatic arrhythmias.21–23 All stored electrograms were carefully evaluated to avoid misclassification of AF.21,22 If patients refused loop recorder implantation, a 7-day Holter ECG was performed 3 and 6 months after randomization and every 6 months thereafter. AF lasting more than 30 seconds and all AFL episodes were documented without blanking period because early recurrence of AF predicts late recurrence.24,25

Postablation procedure After ablation, patients were transferred to the intermediate care unit. Oral anticoagulation was continued after exclusion of pericardial effusion on the day following the ablation procedure.

Study end-points The primary end-point of the study was defined as occurrence of any arrhythmias during follow-up and the secondary end-point as occurrence of AFL after randomization. The starting time point of this analysis was the time of the initial procedure (AAD, CTI ablation, PVI).

Statistical analysis The sample size was determined using the computer software nQuery Advisor 7.0. For the type I error α = 0.05 (2-sided), a power of 1-β = 0.80 and the expected reduction of arrhythmia recurrence after follow-up of 3 years from 100% (AAD group) to 60% (CTI group) and 30% (PVI group) were calculated; patient recruitment was set for 50 patients per group. Calculation was realized by using module PTT2-1 in nQuery for a 2-group Fisher exact test of equal proportions because of the most important question regarding a relevant difference between the CTI and PVI groups. For a global comparison between the 3 groups (100% vs

Schneider et al

Ablation of Atrial Fibrillation for Treatment of Atrial Flutter

60% vs 30%), far fewer patients would be necessary (cp. module PGT0-2 [χ2 test of equal proportions in 3 groups]). After enrollment of 60 patients, a prespecified interim analysis was performed in order to stop the trial in case the outcome of the PVI group was unfavorable. All data were stored and analyzed using the Windowsbased statistical software SPSS (version 21, IBM SPSS Statistics, Inc, Chicago, IL, USA). Descriptive statistics were computed for continuous and categorical variables. All continuous variables are presented as mean ⫾ SD. Categorical variables are presented as frequency and percentage. Testing for differences of continuous variables between the 3 study groups, created by therapy, was accomplished by 1-way analysis of variance or the Kruskal–Wallis test, as appropriate. For significant differences post hoc least significance difference tests or Mann–Whitney U tests were used to compare 2 groups in each case. Test selection was based on evaluating the variables for normal distribution using the Kolmogorov–Smirnov test. For categorical variables, comparisons were made using the χ2 test or Fisher exact test. Period of time until AF occurred or time until last observation was analyzed using the Kaplan–Meier method. Between-group differences were assessed by the Mantel log rank test for censored survival data. All P values resulting from 2-sided statistical tests and P o.05 were considered significant.

Results Patients A total of 60 patients (48 men [80%]) were included in the study at the time of the prespecified interim analysis. Of these patients, 17 (28.3%) were randomized to AAD therapy, 23 (38.3%) to CTI ablation, and 20 (33.3%) to PVI alone. All groups were well balanced; baseline characteristics are given in Table 1. A mean time of 6.7 ⫾ 14.5 months elapsed between first documentation of AFL and randomization. Table 1

867

Enrollment and electrophysiologic data At the time of randomization, 26 patients had persistent AFL. Eight patients were randomized to the AAD group and were successfully cardioverted. At the time of electrophysiologic study, 4 patients (17.4%) in the CTI group had persistent AFL, and AFL was inducible in 16 patients (69.6%); 2 patients (10%) in the PVI group had persistent AFL, and AFL was inducible in 11 patients (55%, P ¼ .669). AF was inducible in 1 patient in the CTI group and in 5 patients in the PVI group (P ¼ .081). All episodes of induced AF/AFL were initiated by burst pacing. Electrophysiologic data are summarized in Table 2. In 23 of 27 patients (85.2%), AFL was induced by burst pacing from the left superior PV and in the remaining 4 patients from the distal coronary sinus. An episode of AF preceded induced episodes of AFL in 12 patients (44.4%; 8 in the CTI group and 4 in the PVI group). Clockwise AFL was induced in only 1 patient. AADs were used to convert AF to AFL in 7 patients. The cycle length of induced AFL was significantly longer than the cycle length of spontaneous AFL (P o.001). The primary end-point of bidirectional conduction block of the CTI (CTI group) or PVI (PVI group) was achieved in all patients.

Postprocedural monitoring Forty-eight patients (80%) received or had a device for arrhythmia monitoring (45 ILR, 2 pacemaker, 1 ICD). In 2 other patients, the ILR was explanted. In these 2 patients and the remaining 10 patients (3 AAD, 4 CTI, 3 PVI) follow-up was completed with 7-day Holter ECG.

Complications One patient had a pericardial effusion after the second PVI that needed drainage. In 1 AAD patient the ILR was explanted because of confirmed infection. Atriovenous

Baseline characteristics

No. Male Age (years) Spontaneous atrial flutter cycle length (ms) Hypertension [n (%)] Diabetes mellitus Structural heart disease Revascularization Ejection fraction (%) Left atrial diameter (mm) Implanted rhythm device (%) Follow-up (years) Follow-up after successful first ablation or after closure of gaps in second ablation (years)

All patients

AAD group

CTI group

PVI group

P value

60 48 (80) 62.3 ⫾ 8.8 229 ⫾ 28 51 (85) 21 (35) 23 (38.3) 14 (23.3) 54.8 ⫾ 12.1 44.7 ⫾ 7.2 48 (80) 1.42 ⫾ 0.83

17 12 (70.6) 61.7 ⫾ 8.7 236 ⫾ 36 13 (76.5) 5 (29.4) 6 (35.3) 4 (23.5) 55.1 ⫾ 11.4 44.8 ⫾ 8.1 12 (70.6) 1.50 ⫾ 0.75

23 21 (91.3) 63.9 ⫾ 7.9 226 ⫾ 27 21 (91.3) 10 (43.5) 8 (34.8) 5 (21.7) 55.5 ⫾ 11.5 43.2 ⫾ 6.7 19 (82.6) 1.39 ⫾ 0.81 1.35 ⫾ 0.79

20 15 (75%) 61.1 ⫾ 10 226 ⫾ 19 17 (85) 6 (30) 9 (45) 5 (25) 53.7 ⫾ 13.6 46.1 ⫾ 7.0 17 (85) 1.40 ⫾ 0.94 1.03 ⫾ 0.88

.213* .517† .590† .430* .554* .754* .968* .924† .504† .509* .871† .177‡

Values are given as no. (%) or mean ⫾ SD unless otherwise indicated. AAD ¼ antiarrhythmic drug; CTI ¼ cavotricuspid isthmus; PVI ¼ pulmonary vein isolation. * χ2 test. † Kruskal–Wallis test. ‡ Mann–Whitney U test.

868 Table 2

Heart Rhythm, Vol 12, No 5, May 2015 Electrophysiologic data of the ablation groups

AFL at EPS [n (%)] Induced AFL [n (%)] Induced AFL cycle length at EPS (ms) (mean ⫾ SD) Antecedent AF at EPS induction [n (%)] Only AF inducible [n (%)] Ablation in AFL [n (%)]

CTI group

PVI group

P value†

20 (87) 16 (69.6) 262 ⫾ 32 8 (34.8) 1 (4.3) 12 (60)

13 (65) 11 (55) 279 ⫾ 73 4 (20) 5 (25) 0 (0)

.148† .361† .671* .327† .081† o.001†

AAD ¼ antiarrhythmic drug; AF ¼ atrial fibrillation; AFL ¼ atrial flutter; CTI ¼ cavotricuspid isthmus; EPS ¼ electrophysiologic study; PVI ¼ pulmonary vein isolation. * Mann–Whitney U test. † Fisher exact test.

fistula with groin hematoma requiring surgical intervention occurred in 2 patients (1 after coronary angiography).

Outcome After mean follow-up of 1.42 ⫾ 0.83 years, 14 of 17 patients (82.4%) reached the primary end-point in the AAD group, 14 of 23 patients (60.9%) in the CTI group, and 2 of 20 patients (10%) in the PVI group after a mean of 1.4 PVI procedures per patient (Figure 1A; χ2 test, P o.001; log rank test overall 0.001, log rank test for AAD vs CTI P ¼ .216, for AAD vs PVI P o.001, for CTI vs PVI P ¼ .005). However, after a single PVI procedure, 8 of 20 patients (40%) developed atrial tachyarrhythmias (87.5% at least 1 episode of AF); there was no significant difference between the 3 groups after a single PVI (Figure 1B; log rank test overall P ¼ .144, for AAD vs CTI P ¼ .26, for AAD vs PVI P ¼ .067, for CTI vs PVI P ¼ .294). Early recurrences during the first 3 months after ablation were noted in 5 of 8 PVI patients. All experienced late recurrences. In the CTI group, 7 of 14 patients had newonset AF during the first 3 months after ablation, and all experienced late recurrences of AF. In the AAD group with arrhythmia recurrences, 7 patients had only AFL, 5 had only AF, and 2 had AF that organized intermittently to AFL. There was no difference in arrhythmia detection between patients with Holter or ILR (χ2 test, P ¼ .598). The secondary end-point (recurrence of AFL) was reached in 9 patients (52.9%) in the AAD group, and after a single ablation procedure in 2 patients (8.7%) in the CTI group and in 3 patients (15%) in the PVI group (χ2 test, P ¼ .003; log rank test overall P ¼ .005, for AAD vs CTI P ¼ .005, for AAD vs PVI P ¼ .034). Of 8 patients with recurrent arrhythmias after PVI, 7 had at least 1 gap in the circumferential PV lines during a second PVI procedure. Including this second ablation, only 1 patient in the PVI group reached the secondary end-point (Figure 2). There was no significant difference concerning the secondary end-point between the CTI and PVI groups after closing the gaps in the initial ablation lines (log rank test P ¼ .226). Patients in the PVI and CTI groups experienced recurrences of AFL less frequently than did patients in the AAD group (log rank test P o.001 for CTI and P ¼ .008 for PVI). Both patients with reablation of the CTI experienced AF during follow-up. In 1 patient with recurrent AFL after a

second PVI, a third procedure revealed a remaining gap in the ablation line around the left-sided veins. After closure of this gap the patient remained free of any arrhythmia for 12 months. In the other patient with AF recurrence, the PVs were isolated but a variety of extra-PV triggers were noted during both procedures.

Figure 1 Kaplan–Meier curve for the primary end-point, including a second ablation (A) and after a single ablation procedure (B). AAD ¼ antiarrhythmic drug; CTI ¼ cavotricuspid isthmus; PVI ¼ pulmonary vein isolation.

Schneider et al

Ablation of Atrial Fibrillation for Treatment of Atrial Flutter

869

prevent AFL recurrence is supported by the observation that 1 patient with AFL recurrence after the second PVI still needed closure of a gap during a third procedure. However, we did not assess PV reconnections in patients without arrhythmia recurrence. Thus, it is possible that some of these patients, if studied, would have reconnections even though they did not have clinical arrhythmia recurrence. Although CTI ablation has proved to be superior to drug therapy for treatment of AFL,2 we included an AAD group in order to investigate the prevalence of AF in these patients with an intensified monitoring. In previous studies, the term isolated Aflut was derived from the medical record databases, and an intensified preablation monitoring has never been reported in patients with isolated AFL.5–7 Our results confirm the additional existence of AF in many patients with supposed “isolated” AFL. Interestingly, there was a cycle length difference between documented AFL and cycle length at electrophysiologic study. This may be attributed to a combination of rough estimation from surface ECG of clinical AFL as well as sedation and use of AADs during electrophysiologic study.

Pathophysiologic implications

Figure 2 Kaplan–Meier curve for the secondary end-point, including a second cavotricuspid isthmus (CTI) or pulmonary vein isolation (PVI) procedure (A) and after a single procedure (B). The antiarrhythmic drug (AAD) group is shown for comparison.

In both ablation groups, all patients with recurrent AFL after the index procedure experienced episodes of AF organizing to AFL, except for 1 patient in the PVI group. In the AAD group, 7 patients (41.2%) with a recurrent arrhythmia experienced at least 1 short episode of AF. All patients in the ablation groups except for 1 in the CTI group were off AAD.

Discussion

AF is often a coexisting arrhythmia in patients with AFL.26,27 The question has been raised whether AFL is a potential trigger for AF or AF is the underlying clinical arrhythmia for AFL.10 Our results strongly suggest that for the initiation of both arrhythmias, the PVs play an important role. Accordingly, PVI can prevent AF and AFL. This is in line with results from other studies.26,27 Although our patients did not show a history of AF at the time of enrollment, 41.2% of patients in the AAD group, 60.9% in the CTI group, and 35% in the PVI group after a single ablation procedure had AF during follow-up. With the exception of 1 patient who had a variety of extra-PV triggers, all patients who had new documented AF after the first PVI had at least 1 gap in the circumferential lines. After closure of all gaps in a second PVI procedure, freedom from AF increased to 90% and freedom from AFL to 95% during follow-up of 1.03 ⫾ 0.88 years. In our series, the 2 patients with AFL recurrence in the CTI group showed recurrent CTI conduction. After closing this gap, they continued to develop paroxysmal AF. It seems reasonable to assume that after CTI ablation AF wavefronts cannot “reorganize” to stable AFL, leading to either AF persistence or termination to sinus rhythm.

Outcome We report the initial results of an ongoing single-center randomized trial with different treatment strategies in patients with isolated AFL. All patients had no history of AF and no documented AF at the time of first clinical presentation. Patients were assigned to 1 of 3 treatment arms. We found that PVI can prevent the recurrence of AFL even without CTI ablation. A completion of PVI with repetitive procedures was a prerequisite of arrhythmia suppression in some patients. The assumption that a PVI was mandatory to

Clinical implications Several clinical trials assessed the relationship between AFL and AF.7,15,26 Ellis et al7 reported a high incidence of AF (up to 82%) after CTI ablation in patients with isolated AFL during mean follow-up time of 39 months. Wazni et al26 demonstrated that in patients with both AF and AFL, PVI is sufficient to control both arrhythmias, although in the blanking period 55% of patients still had episodes of typical AFL and some patients had antiarrhythmic therapy or

870 cardioversion. These results were recently confirmed in another study.27 In contrast to these 2 studies, our patients did not show a history of AF, and we were able to demonstrate that even in the absence of documented AF the PVs play an important role in the initiation of AFL and that PVI is sufficient to control AF and AFL without antiarrhythmic therapy. Our study confirmed the benefit of additional PVI in patients without documented AF as shown by Navarrete et al.15 They demonstrated that in patients with isolated AFL and no history of AF, a combination of CTI ablation and PVI reduced the rate of any tachyarrhythmias during follow-up compared with a standalone CTI ablation.15 Although there was a comparable recurrence rate of AFL after CTI ablation, the recurrence rate after standalone PVI in our study is higher than that reported by Navarrete et al15 in their CTI plus PVI group. However, as previously described,21,22 implantable rhythm devices in our series allowed more detailed follow-up with identification of even asymptomatic arrhythmia episodes, possibly not recorded during 48-hour Holter monitoring. In addition, we performed complete arrhythmia monitoring without any blanking period after the ablation procedure. We believe that AFL is an early indicator of AF, indicating that the PVs and most likely AF are the true triggering mechanisms for the initiation of AFL. If AF is indeed the underlying electrical problem, it may also explain the comparable risk for thromboembolic events in patients with AF and AFL.28–30 Therefore, with a higher risk of thromboembolic complications with AFL, oral anticoagulation should be considered even after successful CTI ablation in these patients or subclinical AF must be excluded by intensified ECG monitoring.31 This study aimed to prove the role of the PVs and the electrophysiologic interrelationship of AFL and AF in patients who present with AFL as their first clinical arrhythmia event. We want to emphasize that we do not conclude from our results that CTI ablation is unnecessary in case of clinical AFL. On the contrary, an important message from this study is that even if PVI is performed in patients with typical AFL, it is reasonable to perform CTI ablation as well because PV reconnection is likely and patients still are vulnerable to AFL. We agree with Navarrete et al15 that clinicians must be aware of a strong link between AFL and AF, indicating that CTI ablation for interruption of isolated AFL may require additional PVI to abolish AF in order to reduce the high thromboembolic risk, even if AF is not clinically present.

Study limitations This is a single-center randomized study with only a limited number of patients. Larger randomized multicenter trials after standalone PVI are necessary to prove the need for additional PVI in patients with AFL. All of our patients showed ECG criteria of typical counterclockwise CVIdependent right AFL. Nonetheless, the diagnosis of AFL based on 12-lead ECG may be limited, and other atrial

Heart Rhythm, Vol 12, No 5, May 2015 tachycardias may have similar ECG morphologies. However, in our series a considerable portion of patients had typical AFL at the time of the ablation procedure, which was confirmed with entrainment during the study. There was a trend toward more induction of AF in the PVI group. Although we carefully evaluated all documented arrhythmia ECGs in all patients before inclusion into the study, subclinical AF may have been present in more patients in the PVI group but not documented before enrollment. We cannot exclude that additional effects other than PVI associated to left atrial debulking or effects of ganglionated plexuses contributed to the ablation success. One may criticize that we included a second PVI ablation procedure in the overall outcome evaluation to prove the effect of standalone PVI to prevent AFL. Because recurrence rates after a single AF ablation procedure are high even at experienced ablation centers,32,33 a second AF ablation is often required in a relevant number of patients and should be viewed as an integral part of PVI.

Conclusion Our data support the electrophysiologic concept that the PVs play an important role in the initiation of AFL. AFL may be the earliest manifestation of AF and manifests as a different electrophysiologic manifestation because of the functional line of block between the venae cavae. Successful PVI with circumferential PV block seems to prevent the recurrence of both AF and AFL.

References 1. Gula LJ, Redfearn DP, Veenhuyzen GD, Krahn AD, Yee R, Klein GJ, Skanes AC. Reduction in atrial flutter ablation time by targeting maximum voltage: results of a prospective randomized clinical trial. J Cardiovasc Electrophysiol 2009;20:1108–1112. 2. Natale A, Newby KH, Pisanó E, Leonelli F, Fanelli R, Potenza D, Beheiry S, Tomassoni G. Prospective randomized comparison of antiarrhythmic therapy versus firstline radiofrequency ablation in patients with atrial flutter. J Am Coll Cardiol 2000;35:1898–1904. 3. Winter JB, Crijns HJ. Atrial flutter and atrial fibrillation: two sides of a coin or one coin? J Cardiovasc Electrophysiol 2000;11:859–860. 4. Laurent V, Fauchier L, Pierre B, Grimard C, Babuty D. Incidence and predictive factors of atrial fibrillation after ablation of typical atrial flutter. J Interv Card Electrophysiol 2009;24:119–125. 5. Ng DW, Altemose GT, Wu Q, Srivasthan K, Scott LR. Typical atrial flutter as a risk factor for the development of atrial fibrillation in patients without otherwise demonstrable atrial tachyarrhythmias. Mayo Clin Proc 2008;83:646–650. 6. Chinitz JS, Gerstenfeld EP, Marchlinski FE, Callans DJ. Atrial fibrillation is common after ablation of isolated atrial flutter during long-term follow-up. Heart Rhythm 2007;4:1029–1033. 7. Ellis K, Wazni O, Marrouche N, et al. Incidence of atrial fibrillation postcavotricuspid isthmus ablation in patients with typical atrial flutter: left-atrial size as an independent predictor of atrial fibrillation recurrence. J Cardiovasc Electrophysiol 2007;18:799–802. 8. Paydak H, Kall JG, Burke MC, Rubenstein D, Kopp DE, Verdino RJ, Wilber DJ. Atrial fibrillation after radiofrequency ablation of type I atrial flutter: time to onset, determinants, and clinical course. Circulation 1998;98:315–322. 9. Philippon F, Plumb VJ, Epstein AE, Kay GN. The risk of atrial fibrillation following radiofrequency catheter ablation of atrial flutter. Circulation 1995;92: 430–435. 10. Waldo AL. Mechanisms of atrial flutter and atrial fibrillation: distinct entities or two sides of a coin? Cardiovasc Res 2002;54:217–229. 11. Waldo AL. More musing about the inter-relationships of atrial fibrillation and atrial flutter and their clinical implications. Circ Arrhythm Electrophysiol 2013;6: 453–454.

Schneider et al

Ablation of Atrial Fibrillation for Treatment of Atrial Flutter

12. Waldo AL. Inter-relationships of atrial fibrillation and atrial flutter mechanisms and clinical implications. J Am Coll Cardiol 2008;51:779–786. 13. Haïssaguerre M, Jaïs P, Shah DC, Takahashi A, Hocini M, Quiniou G, Garrigue S, Le Mouroux A, Le Métayer P, Clémenty J. Spontaneous initiation of atrial fibrillation by ectopic beats originating in the pulmonary veins. N Engl J Med 1998;339:659–666. 14. Steinberg JS, Romanov A, Musat D, Preminger M, Bayramova S, Artyomenko S, Shabanov V, Losik D, Karaskov A, Shaw RE, Pokushalov E. Prophylactic pulmonary vein isolation during isthmus ablation for atrial flutter: the PReVENT AF Study I. Heart Rhythm 2014;11:1567–1572. 15. Navarrete A, Conte F, Moran M, Ali I, Milikan N. Ablation of atrial fibrillation at the time of cavotricuspid isthmus ablation in patients with atrial flutter without documented atrial fibrillation derives a better long-term benefit. J Cardiovasc Electrophysiol 2011;22:34–38. 16. Cosio FG, Arribas F, Barbero JM, Kallmeyer C, Goieolea A. Validation of double-spike electrograms as markers of conduction delay or block in atrial flutter. Am J Cardiol 1988;61:775–780. 17. Matsuo K, Uno K, Khrestian CM, Waldo AL. Conduction from left-to-right and right-to-left across the crista terminalis. Am J Physiol Heart Circ Physiol 2001;280:H1683–H1691. 18. Schumacher B, Jung W, Schmidt H, Fischenbeck C, Lewalter T, Hagendorff A, Omran H, Wolpert C, Lüderitz B. Transverse conduction capabilities of the crista terminalis in patients with atrial flutter and atrial fibrillation. J Am Coll Cardiol 1999;34:363–373. 19. Arenal A, Almendral J, Alday JM, Villacastín J, Ormaetxe JM, Sande JL, PerezCastellano N, Gonzalez S, Ortiz M, Delcán JL. Rate-dependent conduction block of the crista terminalis in patients with typical atrial flutter. Influence on evaluation of cavotricuspid isthmus conduction block. Circulation 1999;99:2771–2778. 20. Bänsch D, Bittkau J, Schneider R, Schneider C, Wendig I, Akin I, Nienaber CA. Circumferential pulmonary vein isolation: wait or stop early after initial successful pulmonary vein isolation? Europace 2013;15:183–188. 21. Kapa S, Epstein AE, Callans DJ, et al. Assessing arrhythmia burden after catheter ablation of atrial fibrillation using an implantable loop recorder: the ABACUS study. J Cardiovasc Electrophysiol 2013;24:875–881. 22. Verma A, Champagne J, Sapp J, Essebag V, Novak P, Skanes A, Morillo CA, Khaykin Y, Birnie D. Discerning the incidence of symptomatic and asymptomatic episodes of atrial fibrillation before and after catheter ablation (DISCERN AF): a prospective, multicenter study. JAMA Intern Med 2013;173:149–156. 23. Ziegler PD, Koehler JL, Mehra R. Comparison of continuous versus intermittent monitoring of atrial arrhythmias. Heart Rhythm 2006;3:1445–1452.

871

24. Calkins H, Kuck KH, Cappato R, et al. 2012 HRS/EHRA/ECAS Expert Consensus Statement on Catheter and Surgical Ablation of Atrial Fibrillation: recommendations for patient selection, procedural techniques, patient management and follow-up, definitions, endpoints, and research trial design. Europace 2012;14:528–606. 25. Pedrote A, Arana-Rueda E, García-Riesco L, Sánchez-Brotons J, Durán-Guerrero M, Gómez-Pulido F, Arce-León A, Frutos-López M. Paroxysmal atrial fibrillation burden before and after pulmonary veins isolation: an observational study through a subcutaneous leadless cardiac monitor. J Cardiovasc Electrophysiol 2013;24:1075–1082. 26. Wazni O, Marrouche NF, Martin DO, et al. Randomized study comparing combined pulmonary vein-left atrial junction disconnection and cavotricuspid isthmus ablation versus pulmonary vein-left atrial junction disconnection alone in patients presenting with typical atrial flutter and atrial fibrillation. Circulation 2003;108:2479–2483. 27. Mohanty S, Mohanty P, Di Biase L, et al. Results from a single-blind, randomized study comparing the impact of different ablation approaches on long-term procedure outcome in coexistent atrial fibrillation and flutter (APPROVAL). Circulation 2013;127:1853–1860. 28. Seidl K, Hauer B, Schwick NG, Zellner D, Zahn R, Senges J. Risk of thromboembolic events in patients with atrial flutter. Am J Cardiol 1998;82: 580–583. 29. Grönefeld GC, Wegener F, Israel CW, Teupe C, Hohnloser SH. Thromboembolic risk of patients referred for radiofrequency catheter ablation of typical atrial flutter without prior appropriate anticoagulation therapy. Pacing Clin Electrophysiol 2003;26:323–327. 30. Hernández Madrid A, Peña Pérez G, González Rebollo JM, Gómez Bueno M, Marín Marín I, Bernal Morell E, Escobar Cervantes C, Camino López A, Peng J, Moro Serrano C. Systemic embolism after reversion to sinusal rhythm of persistent atrial flutter. Rev Clin Esp 2003;203:230–235. 31. Heidbuchel H, Verhamme P, Alings M, Antz M, Hacke W, Oldgren J, Sinnaeve P, Camm AJ, Kirchhof P. EHRA practical guide on the use of new oral anticoagulants in patients with non-valvular atrial fibrillation: executive summary. Eur Heart J 2013;34:2094–20106. 32. Weerasooriya R, Khairy P, Litalien J, et al. Catheter ablation for atrial fibrillation: are results maintained at 5 years of follow-up? J Am Coll Cardiol 2011;57: 160–166. 33. Rostock T, Salukhe TV, Steven D, et al. Long-term single- and multipleprocedure outcome and predictors of success after catheter ablation for persistent atrial fibrillation. Heart Rhythm 2011;8:1391–1397.

CLINICAL PERSPECTIVES In our prospective randomized study, we evaluated different treatment strategies in patients with atrial flutter but without atrial fibrillation. We demonstrated that the pulmonary veins are an important trigger site for induction of atrial flutter, as already known for atrial fibrillation, and that pulmonary vein isolation (PVI) can prevent atrial flutter recurrences even without cavotricuspid isthmus (CTI) ablation and in the absence of known atrial fibrillation. We also showed that by using intensified preablation continuous ECG monitoring, additional atrial fibrillation can be revealed in patients with suspected “isolated” atrial flutter. With this knowledge, clinicians should be aware that after CTI ablation, the atria still are susceptible to pulmonary vein triggers and atrial fibrillation may occur. Thus, oral anticoagulation has to be continued in selected patients. If possible, preablation screening for atrial fibrillation should be considered. However, even without documented atrial fibrillation, a combined ablation procedure of CTI and PVI may be offered to patients with atrial flutter to eliminate the underlying trigger and prevent future atrial fibrillation. In this way, the need for antiarrhythmic therapy, prolonged anticoagulation treatment, or repeated ablation procedures could be spared to the patient. To obtain reliable information and to avoid underestimation of recurrent arrhythmias after ablation procedures, continuous ECG monitoring provides a basis for treatment decisions.

Pulmonary vein triggers play an important role in the initiation of atrial flutter: Initial results from the prospective randomized Atrial Fibrillation Ablation in Atrial Flutter (Triple A) trial.

The incidence of atrial fibrillation (AF) after ablation of a cavotricuspid isthmus (CTI)-dependent atrial flutter (AFL) is high...
465KB Sizes 0 Downloads 9 Views