Introduction. Methods

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1 Europace (2015) 17, doi: /europace/euu332 CLINICAL RESEARCH Cardiac electrophysiology Electrophysiological studies in patients with paroxysmal supraventricular tachycardias but no electrocardiogram documentation: findings from a prospective registry Joerg Lauschke 1 *, Julia Schneider 1, Ralph Schneider 1, Catharina Nesselmann 2, Tina Tischer 1, Aenne Glass 3, and Dietmar Bänsch 1 1 Department of Cardiology, University Medical Center, Ernst-Heydemann-Str. 6, Rostock 18059, Germany; 2 Department of Cardiac Surgery, University Medical Center, Schillingallee 35, Rostock 18057, Germany; and 3 Institute for Biostatistics and Informatics in Medicine and Ageing Research, University Medical Center, Ernst-Heydemann-Str. 8, Rostock 18057, Germany Received 24 April 2014; accepted after revision 17 October 2014 Aims A significant proportion of patients presenting with paroxysmal supraventricular tachycardia (PSVT) has no electrocardiogram (ECG) documentation. In these patients an electrophysiological study (EPS) may be performed to facilitate the diagnosis.... Methods In a prospective registry we compared the prevalence of inducible arrhythmias and the clinical outcome in 525 patients and results with and without ECG documentation. Compared with patients with a documented PSVT a smaller but substantial proportion of patients (63.7%) without ECG documentation had inducible supraventricular tachycardias (SVT). Atrioventricular nodal reentrant tachycardia was the most common type in both groups. Patients with an inducible SVT and no documentation were significantly younger, had a shorter episode duration and a lower hospitalization rate, which may be the cause for the lacking documentation. Similar to patients with documented PSVTs most of these patients (90.0%) were asymptomatic or clinically improved after the EPS. Even 43% of patients without an inducible tachycardia improved clinically, probably due to a placebo effect of the EPS. In particular, patients between 31 and 60 years of age seemed to benefit from an EPS because they were more likely to have inducible SVTs that could be cured by radiofrequency ablation.... Conclusion Our data show that a substantial proportion of patients with suspected paroxysmal tachycardia, but without ECG documentation, have inducible SVTs and obtain a clear clinical benefit from an EPS. Thus, our data provide justification for using EPS for patients in this category. To the best of our knowledge, ours is the first prospective registry that supports this approach Keywords Paroxysmal supraventricular tachycardia PSVT SVT ECG Ablation Introduction An electrophysiological study (EPS) is recommended for patients with documented symptomatic paroxysmal supraventricular tachycardia (PSVT). 1 However, in clinical practice, a significant proportion of patients with a typical clinical history, but with no previous electrocardiogram (ECG) documentation of the tachycardia, may be referred for an EPS in order to facilitate a definitive diagnosis; however, the outcomes for these patients are unknown. Using a prospective registry, we compared the frequency of inducible and ablated supraventricular tachycardias (SVT) as well as the clinical outcomes among patients referred for suspected paroxysmal supraventricular tachycardia, either with or without ECG documentation. Methods Patients Five hundred and twenty-five consecutive patients, referred to the Rostock University Medical Center for suspected paroxysmal supraventricular * Corresponding author. Tel: ; fax: , address: joerg.lauschke@uni-rostock.de Both authors contributed equally to this work. Published on behalf of the European Society of Cardiology. All rights reserved. & The Author For permissions please journals.permissions@oup.com.

2 802 J. Lauschke et al. What s new? A substantial proportion of patients with suspected paroxysmal supraventricular tachycardias but without an electrocardiogram documentation have inducible tachycardias that are curable by ablation. These patients clearly benefit from an electrophysiological study. The clinical outcome is comparable to patients with a documented tachycardia. tachycardia between 2009 and 2013, were included in the prospective registry. All of them presented with a history of paroxysmal regular tachycardia (regular palpitations, on/off-phenomenon, termination after vagal manoeuvres), either with or without ECG documentation, as assessed by 12 lead ECG, Holter, or an implantable loop recorder. All patients received at least one 24 h Holter by the referring physician. After confirmation of typical symptoms, a physical examination, a 12-lead-ECG, a routine laboratory test, and an EPS were performed in all patients. All patients gave written informed consent prior to the EPS. Patients with overt pre-excitation were excluded from the registry because the diagnosis of atrio-ventricular reentrant tachycardia (AVRT) could be made from the resting 12 lead ECG without an ECG-documented tachycardia. Patients with irregular palpitations highly suggestive of paroxysmal atrial fibrillation were also excluded. Electrophysiological study The EPS was performed under conscious sedation. An octapolar catheter (Webster D-Type, Biosense Webster) was advanced to the coronary sinus (CS) via the left subclavian vein. A second octapolar catheter was placed at the bundle of His via the right femoral vein. A quadripolar catheter (Soloist, Medtronic) was placed in the right ventricular apex via the left femoral vein. For SVT induction, programmed ventricular and atrial stimulation was performed (basic cycle length: 600 ms, 1 3 extra stimuli, stimulation at the Wenckebach point). In the absence of inducible SVT, stimulation was repeated under isoprenaline and atropine. However, when a sustained SVT was induced reproducibly, differentiation of the type of tachycardia was achieved by overdrive ventricular pacing (using atrial entrainment as a proof of principle for reentrant tachycardias), His synchronous PVCs during tachycardia (preceding the A in case of AVRT) and the response to entrainment (VAV vs. VAAV). For right atrial tachycardia, an additional 10 polar catheter was placed in the high right atrium or along the crista terminalis, as required. As a standard procedure, the site of earliest activation under atrial tachycardia (AT) was mapped with a 4 mm tip ablation catheter guided by fluoroscopy. If these attempts failed, a 3D activation map was achieved using Carto 3 (Biosense Webster, Diamond Bar). Ablation of accessory pathways, AV-node modulation, ablation of AT, or atrial flutter was performed according to current guidelines. 1 All ablation catheters had a 4 mm platinum tip. For atrio-ventricular nodal reentrant tachycardia (AVNRT) and AT ablation a non-irrigated catheter was used with a power of W, and a temperature limit of 558C. For ablation of accessory pathways, a non-irrigated catheter with a power of W and a temperature limit of 558C was used. For atrial flutter and atrial fibrillation, an irrigated catheter was used with 40 W/458C and W/438C, respectively. Post-ablation, the stimulation protocol described above was repeated. Follow-up Clinical follow-ups were scheduled in our outpatient clinic at 6, 12, and 18 months after the ablation. Patients who lived far away were monitored by referring physicians who provided reports to our institution. Patients were advised to schedule additional visits if symptoms recurred. Long-term data on the clinical course following the ablation were collected through additional phone calls with the patients, and the patient records were updated accordingly. A recurrent PSVT after ablation was defined as any PSVT lasting longer than 10 s. These recurrences were differentiated into the initially ablated PSVT and other types of PSVT not diagnosed during the first procedure. In the case of a recurrent symptomatic PSVT, a re-ablation was performed if appropriate. Patients who declined a second procedure were treated medically. Statistics Statistical analysis was performed with IBM SPSS Statistics for Windows, version 21.0 (IBM Corp). Descriptive statistics were computed for variables of interest. The statistics computed included means and standard deviations of continuous variables, frequencies, and relative frequencies of categorical factors. Because of no normal distributions, testing for differences of continuous variables between two study groups was accomplished by the Mann Whitney U test by ranks. For categorical factors comparisons between groups were performed by Fisher s exact test or x 2 test. For all tests a ¼ 0.05 was set as statistically significant. For 65 patients with an inducible SVT, but without any documentation, the logistic regression model was used to assess the independence of SVT inducibility from the prognostic factors age, gender, structural heart disease, duration and frequency of symptoms. First, bivariate analyses were performed to look for a significant influence of variables on SVT inducibility. For the parameter episode duration, a dichotomy value of 50 min was used because this was the mean episode duration in 65 patients with inducible SVTs but without ECG documentation. Second, variables yielding P values 0.20 in the bivariate analysis were entered into the multivariate models to highlight some possible associations between the outcome and some covariates that were of borderline significance. All P values resulted from two-sided statistical tests and P 0.05 was considered to be significant. Results In this study, 423 of 525 patients (80.6%) presented with an ECGdocumented PSVT, while 102 patients (19.4%) had a typical history of a PSVT but without any ECG-documented tachycardia. Patients without any ECG documentation had shorter episodes of PSVT (P ¼ 0.02), were younger at presentation for EPS (P, 0.01) and less frequently hospitalized (P, 0.01) than patients with an ECG documented PSVT. The duration of symptoms did not differ significantly between the two groups (P ¼ 0.17). Both groups included more women than men (61.5% in the group with ECG documentation; 70.6% in the group without), but this difference was not statistically significant (P ¼ 0.11). All baseline characteristics are presented in Tables 1 and 2. The mean follow-up period was 30 months. Complete follow-up was recorded for 467 patients (89%). Supraventricular tachycardias could be induced during the EPS in 378 of 423 (89.4%) patients with ECG documentation. The most common type of induced SVTs were AVNRT (249 patients, 58.9%) followed by AVRT (87 patients, 20.6%) and AT (28 patients, 6.6%). The foci of AT were crista terminalis (13 patients, 46.4%), lateral free wall of the right atrium (three patients, 10.7%), right atrial

3 Electrophysiological studies in patients with paroxysmal supraventricular tachycardias 803 Table 1 Baseline characteristics of all patients recruited in the clinical cohort Characteristic All (mean + SD) ECG documentation No ECG documentation P values (mean + SD) (mean + SD)... Gender Female, n (%) 332 (63.2) 260 (61.5) 72 (70.6) 0.11 a Duration of symptoms (years) b Episodes per month b Episode duration (min) b Age at EPS (years) ,0.01 b Age at first symptomatic episode (years) b Hospitalizations ,0.01 b Emergency calls ,0.01 b a Fisher s exact test. b Mann Whitney U test. Table 2 Prevalence of structural heart disease Structural heart disease All (n 5 525) ECG documentation No ECG documentation (n 5 423) (n 5 102)... CAD 57 (10.8%) 50 (11.8%) 7 (6.9%) DCM 4 (0.8%) 4 (1.0%) 0 HCM 2 (0.4%) 2 (0.5%) 0 Other 4 (0.8%) 3 (0.7%) 1 (1.0%) None 452 (86.1%) 361 (85.3%) 91 (89.2%) No data available 6 (1.1%) 3 (0.7%) 3 (2.9%) Distribution not significantly different between patients with and without ECG documentation (x 2 test, P ¼ 0.47). CAD, coronary artery disease; DCM, dilated cardiomyopathy; HCM, hypertrophic cardiomyopathy. appendage (two patients, 7.1%), atrial septum (two patients, 7.1%), CS ostium (one patient, 3.6%), sinus node area (one patient, 3.6%), and mitral annulus (six patients, 21.5%). Supraventricular tachycardia could not be induced in 45 patients (10.6%). Supraventricular tachycardia was reproducibly induced in 65 of 102 patients without any documentation (63.7%). As with the ECGdocumented patient group, AVNRT was found to be the most common SVT (57 patients, 55.9%) among those without documentation. We found low AVRT (two patients, 2.0%), but a comparable rate of AT (five patients, 4.9%). The foci of AT were crista terminalis (three patients, 60%), lateral free wall of the right atrium (1 patient, 20%), and multiple right atrial sites in one patient (20%). In conclusion, the distribution of inducible SVTs differed between patients with and without ECG documentation (x 2 test for the whole 6 2 contingency table, P, 0.01, Table 3). For individual types of inducible SVTs, we found for AVRT and for none significant differences in probabilities between both groups (Fisher s exact test, P, 0.01). In the group with ECG-documented PSVTs, 376 patients (88.9%) were ablated: [249 for AVNRT (58.9%), 87 for concealed accessory pathways (20.6%), 25 for AT (5.9%)]. Fifteen patients (3.5%) received a cavo-tricuspid isthmus ablation for common type atrial flutter, whereas two patients (0.5%) received a pulmonary vein isolation plus lines for left atrial reentrant tachycardias and atrial fibrillation. Thirty-seven of 249 patients ablated for AVNRT (14.8%) presented with a recurrent PSVT, and four of these (1.6%) were AVNRT. Thirtythree patients had other types of PSVT not previously documented or induced: mostly AT and atrial fibrillation. All patients with a recurrent AVNRT were successfully reablated. Sixteen of 87 patients (18.4%) ablated for accessory pathways presented with a recurrent PSVT, 5 of them (5.7%) with the initiallyablatedavrt, and 11 patients with other types of PSVT, mostly AF. Two of the five patients with ablated AVRT were successfully reablated. In one patient, two ablations remained ineffective, whereas two other patients did not show up for a second repetition. Nine of 25 patients (36%) ablated for AT presented with a recurrent PSVT. However, none of these recurrent PSVTs were documented or initially ablated. Most of them had atrial fibrillation or atrial flutter. All 15 patients ablated for common type atrial flutter remained free of atrial flutter. However, five of these developed atrial fibrillation. Two hundred seventy-six patients (71.1%) were free of any symptoms during follow-up, whereas 70 patients (18.0%) had milder symptoms, and 42 patients (10.8%) did not improve clinically (Figure 1). Sixty-four of the 102 patients (62.7%) without ECG documentation were ablated [57 for AVNRT (55.9%), two for a concealed accessory pathway (2.0%) and five for AT (4.9%)]. Eight of the 57 patients (14%) ablated for AVNRT presented with a recurrent PSVT. Seven of

4 804 J. Lauschke et al. Table 3 Types and frequencies of induced SVTs All (n 5 525) ECG documentation No ECG documentation P values a (n 5 423) (n 5 102)... AVNRT 306 (58.3%) 249 (58.9%) 57 (55.9%) 0.66 AVRT 89 (17.0%) 87 (20.6%) 2 (2.0%),0.01 AT 33 (6.3%) 28 (6.6%) 5 (4.9%) AFlut 12 (2.3%) 12 (2.8%) AFib 3 (0.6%) 2 (0.5%) 1 (1.0%) none 82 (15.6%) 45 (10.6%) 37 (36.2%),0.01 Significantly different distribution between patients with and without ECG documentation (chi-square test for the 6 2 contingency table, P, 0.01). AFlut, atrial flutter; AFib, atrial fibrillation. a Fisher s exact test. Number of patients (%) 11% 11% 10% 19% 18% 70% 71% 26% 64% All ECG docu No ECG docu Asymptomatic Improved No change Figure 1 Clinical outcomes in all patients and those with or without ECG documentation. these recurrences were different types of PSVT not addressed in the initial procedure. One patient had a recurrent AVNRT and was successfully reablated. Overall, the recurrence rate after AVNRT ablation was 1.8%. Patients ablated for an accessory pathway were free of any recurrent arrhythmia. One of five patients ablated for AT presented with a recurrent PSVT which was not the initially ablated tachycardia. Supraventricular tachycardia could not be induced in 37 patients (36.2%) without any ECG documentation. Interestingly, 16 (43.2%) of these patients showed no symptoms or milder symptoms after the EP study. Fifty patients (63.7%) were asymptomatic during follow-up, and 21 patients (26.3%) improved clinically. However, eight patients (10.0%) did not show clinical improvement (Figure 1). For all 102 patients without ECG documentation, we compared the markers of age at EPS, and duration of symptoms, between the groups of patients with and without an inducible SVT. Patients with an inducible SVT were significantly older ( vs years, P ¼ 0.01), and were symptomatic for a longer period ( vs years, P, 0.01; Figure 2). Figures 3 and 4 show the inducibility rates for SVTs with respect to age at EPS and the duration of symptoms. Since we were looking for markers of SVT inducibility, we used a logistic regression model for age, gender, structural heart disease, duration, and frequency of symptoms in the group of 65 patients with an inducible SVT, but without any documentation. Additionally, multivariate analysis was performed for the parameters of age at EPS, and duration of symptoms. In patients between 31 and 60 yearsof age at the time of EPS, an inducible SVTwassignificantly more likely than in patients younger than 31 years or older than 60 years of age (odds ratio 3.27, P ¼ 0.03). For the marker duration of symptoms, the differences were not significant. Likewise, no clear differences were noted for all other parameters mentioned above (Tables 4 and 5; Figures 3 and 4). Discussion Compared with patients with a documented PSVT, a smaller but still substantial proportion of patients (63.7%) without ECG documentation had inducible SVTs which could eventually be cured with radiofrequency (RF) ablation. Atrio-ventricular nodal reentrant tachycardia was the most common type of inducible SVT in both groups. Patients with an inducible SVT but with no ECG documentation were significantly younger and also had shorter episode durations and lower hospitalization rates, which may be the cause for the lack of ECG documentation. Among the patients with documented PSVTs, 89.0% were asymptomatic or clinically improved after the EPS. In the group without documentation 90% of patients were asymptomatic or clinically improved after the EPS. Interestingly, 43% of patients without PSVT documentation and without inducible SVT also improved clinically, probably due to a placebo effect from the reassuring information provided by the EPS that no tachycardia could be induced. Considering the clinical outcome following the EPS, 90.0% of all patients who presented with a typical history of paroxysmal SVT, but without a tachycardia ECG showed a clear benefit. In particular, patients between 31 and 60 years of age seem to have benefited most from an EPS, because they were more likely to have inducible SVTs. Surprisingly, our approach did not shorten the time between first symptoms and therapy as the patients without a documented tachycardia probably had milder symptoms. In addition, there was no electrophysiological laboratory available in the area prior to 2009, and patients might have accumulated over a long period of time. The clinical outcome in our registry (AVNRT recurrence rate: 1.8%, AVRT recurrence rate: 5.7%) is in line with published data from a single-centre study and meta-analyses. Feldman et al. 2 reported an acute success rate of 98.1% for AVNRT ablation.

5 Electrophysiological studies in patients with paroxysmal supraventricular tachycardias 805 Age at EPS (years) Not inducible Inducible Not inducible Inducible Figure 2 Comparison of age at EPS (left panel) and duration of symptoms (right panel) between patients with and without an inducible SVT among patients without ECG documentation (n ¼ 102). Shown are the median, the interquartile range (IQR), and minimum and maximum values that are no outliers. Values beyond the quartiles by.1.5 IQRs were defined as outliers, by more than 3.0 IQRs as extreme outliers. Inducibility rate (%) < 31 years years years Age at EPS (years) Figure 3 Inducibility rates for SVTs in 102 patients without ECG documentation according to age at EPS (P ¼ 0.06). Inducibility rate (%) < 11 years years > 20 years Duration of symptoms (years) Figure 4 Inducibility rates for SVTs in 102 patients without ECG documentation according to duration of symptoms (P ¼ 0.20). A meta-analysis by Spector et al 3 found a single-procedure success rate of 93.2% for AVNRT and AVRT ablation, and 91.7% for ablation of atrial flutter with recurrence rates of 6.5% and 13.2%, respectively. Single-centre data published by Schlaepfer and Fromer 4 showed Duration of symptoms (years) Table 4 Univariate logistic regression analysis of predictors of inducibility in 102 patients without ECG documentation Parameter OR 95% CI P values... Duration of symptoms vs. 10 years a vs. 10 years a Episodes per month vs. 1 a vs. 1 a vs. 1 a Episode duration vs. 50 min a Gender 0.34 Female vs. male a Age at EPS vs. 30 years a vs. 30 years a Age at first symptomatic episode vs. 30 years a vs. 30 years a Structural heart disease 0.53 Yes vs. no a OR, odds ratio; CI, confidence interval. a Reference category. that 93% of patients who underwent accessory pathway ablation were asymptomatic or showed clinical improvement during a mean follow-up period of 48 months. They reported a recurrence rate of 4%. In our registry, we noted symptomatic improvement in 89.1% of patients with documented PSVT, and in 90.0% of patients without documented PSVTs, respectively. These results are comparable to the data published by Bathina et al., 5 who reported symptomatic improvement in 84% of patients who underwent RF ablation for documented PSVTs. These findings therefore seem to justify the use of an EP study, even if no paroxysmal SVT has been documented.

6 806 J. Lauschke et al. Table 5 Multivariate logistic regression analysis of predictors of inducibility in 102 patients without ECG documentation Parameter Adjusted 95% CI P values OR... Duration of symptoms vs. 10 years a vs. 10 years a Age at EPS vs. 30 years a vs. 30 years a OR, odds ratio; CI, confidence interval. a Reference category. We observed a recurrence rate for PSVTs not inducible and therefore not ablated in the first procedure (mainly AT, atrial flutter and atrial fibrillation) of 15.4% in patients with and of 12.5% in patients without ECG documentation, respectively. These rather high rates may be due to the strict definition of PSVT recurrence which was any PSVT lasting longer than 10 seconds. Additionally, 33% of patients in our cohort were older than 60 years. Therefore, one might expect a higher incidence of atrial flutter and atrial fibrillation during follow-up. Alternative strategies to force ECG documentation could include either telemetry or an implantable loop recorder (ILR). Although telemetry is non-invasive, the use of telemetry or ILR may be time consuming and the use of ILR in particular may cause additional costs. Conclusion Our data show that a substantial proportion of patients with suspected paroxysmal tachycardias, but without ECG documentation, have inducible SVTs and obtain a clear clinical benefit from an EP study. Thus, our data provide justification for using EPS for patients in this category. To the best of our knowledge, ours is the first prospective registry which supports this approach. Conflict of interest: None declared. References 1. Blomstroem-Lundqvist C, Scheinman MM, Aliot EM, Alpert JS, Calkins H, Camm AJ et al. European Society of Cardiology Committee, NASPE-Heart Rhythm Society. ACC/AHA/ESC guidelines for the management of patients with supraventricular arrhythmias executive summary. A report of the American College of Cardiology/ American Heart Association Task Force on Practice Guidelines and the European Society Of Cardiology Committee For Practice Guidelines (writing committee to develop guidelines for the management of patients with supraventricular arrhythmias) developed in collaboration with NASPE-Heart Rhythm Society. J Am Coll Cardiol 2003; 42: Feldman A, Voskoboinik A, Kumar S, Spence S, Morton JB, Kistler PM et al. Predictors of acute and long-term success of slow pathway ablation for atrioventricular nodal reentrant tachycardia: a single centre series of 1,419 consecutive patients. Pacing Clin Electrophysiol 2011;34: Spector P, Reynolds MR, Calkins H, Sondhi M, Xu Y, Martin A et al. Meta-analysis of ablation of atrial flutter and supraventricular tachycardia. Am J Cardiol 2009; 104: SchlaepferJ, FromerM. Lateclinicaloutcomeaftersuccessful radiofrequencycatheter ablation of accessory pathways. Eur Heart J 2001;22: Bathina MN, Mickelsen S, Brooks C, Jaramillo J, Hepton T, Kusumoto FM. Radiofrequency catheter ablation versus medical therapy for initial treatment of supraventricular tachycardia and its impact on quality of life and healthcare costs. Am J Cardiol 1998;82: