Author + information
- Received May 16, 2018
- Revision received September 7, 2018
- Accepted September 20, 2018
- Published online February 18, 2019.
- Ivo Roca-Luque, MD, PhDa,∗ (, )
- Jaume Francisco-Pasqual, MDa,
- Gerard Oristrell, MDb,
- Julián Rodríguez-García, MDa,
- Alba Santos-Ortega, MDa,
- Gabriel Martin-Sanchez, MDa,
- Nuria Rivas-Gandara, MD, PhDa,
- Jordi Perez-Rodon, MD, PhDa,
- Ignacio Ferreira-Gonzalez, MD, PhDc,
- David García-Dorado, MD, PhDb and
- Angel Moya-Mitjans, MD, PhDa
- aArrhythmia Unit, Cardiology Department, Hospital Universitari Vall d’Hebron, Barcelona, Spain
- bCardiology Department, Hospital Universitari Vall d’Hebron, Barcelona, Spain
- cCardiovascular Epidemiology Unit, Cardiology Department, Hospital Universitari Vall d’Hebron, Barcelona, Spain
- ↵∗Address for correspondence:
Dr. Ivo Roca-Luque, Unitat d’ Arítmies, Servei de Cardiologia, Hospital Universitari Vall d’ Hebron, Passeig Vall d’ Hebron 119-129, 08035 Barcelona, Spain.
Objectives This study sought to compare the differences between procainamide and flecainide to stress the His-Purkinje system during electrophysiological study (EPS) in patients with syncope and bundle branch block (BBB).
Background Patients with syncope and BBB are at risk of developing atrioventricular block. EPS is recommended including class I drug challenge to unmask His-Purkinje disease in cases with baseline normal His-ventricular interval. There is little data on differences between different class I drugs.
Methods This was a prospective study of all consecutive patients undergoing EPS for syncope and BBB at a single center (January 1, 2012 to June 30, 2017). Of those patients with negative baseline EPS, 2 cohorts were compared: group A (historical cohort: procainamide) and group B (flecainide).
Results During the study, 271 patients (age 73.9 ± 12.1 years, 64.9% male, QRS duration: 139.4 ± 13.9 ms) underwent EPS. In 166, baseline EPS was negative and class I drug challenge was performed (90 procainamide, 76 flecainide). The final value and percentage increase in the His-ventricular interval (76 ± 16 ms vs. 64 ± 10 ms and 22.5 ± 6.2% vs. 11.8 ± 5.3%; p < 0.001) and diagnostic yield (14.5% vs. 7.8%, p = 0.04) were higher with flecainide. No differences were found in baseline characteristics. During follow-up (25.8 ± 6.3 months), 39 patients (24.8%) with negative EPS (19.2% with flecainide vs. 30.1% with procainamide: relative risk: 5.1; 95% confidence interval: 2.6 to 10.2; p < 0. 001) received a pacemaker.
Conclusions Flecainide has a higher diagnostic yield than does procainamide in patients with BBB, syncope, and negative baseline EPS due to a greater increase of the His-ventricular interval. Additionally, there is a lesser need for pacemaker implantation in patients in whom the class I drug test using flecainide was negative.
The prognosis of patients with syncope is completely different depending on the etiology (1,2) with higher mortality in patients with cardiac syncope. European Society of Cardiology Syncope Guidelines (3) recommend that an electrophysiological study (EPS) be performed in patients with syncope and bundle branch block (BBB) in order to identify those patients at greater risk of developing atrioventricular block (AVB). Patients with prolonged His-ventricular (HV) interval or intra- or infra-Hisian block induced by atrial pacing are at significant risk of developing high-degree AVB (4–8). Permanent pacing is recommended in cases of prolonged HV interval (>70 ms) or induction of AVB by pacing (9). However, baseline EPS has low sensitivity, so, in patients with a normal baseline HV interval, a drug challenge with class I antiarrhythmic agents is recommended to unmask intra- or infra-Hisian conduction abnormalities (10–12). In cases of intra- or infra-Hisian AVB or HV interval >100 ms during class I drug administration, pacing is also indicated (9). The effects of class I drugs on the healthy heart are limited. However, when there is conduction system disease, the resting potential of dysfunctional cells is higher, so the rate at which the voltage-dependent sodium current rises is impaired. The use of sodium channel blockers in these patients further impairs the sodium current and thus electrical conduction (11). Several class I drugs have been used (disopyramide, procainamide, ajmaline, and flecainide) to stress the His-Purkinje system, but no specific recommendation has been made as to which of the drugs should be used. Although it has been demonstrated that the diagnostic yield of these drugs differs in another setting (13), there is very little data on the differences between different class I drugs in unmasking advanced His-Purkinje disease. Due to the low sensitivity of EPS in these patients even after His-Purkinje challenge with class I antiarrhythmic drugs (14), it is essential that research focus its attention on improving the diagnostic yield of EPS. The aim of this study is to analyze the differences between procainamide and flecainide as drugs used to stress the His-Purkinje system during EPS in patients with syncope and BBB.
This is a single-center observational prospective study that includes all consecutive patients undergoing EPS for syncope and BBB at Vall d’ Hebron University Hospital between January 1, 2012 and June 30, 2017. Patients with an established indication for pacing (third-degree, Mobitz II, or advanced 2nd second-degree AVB) or with severely depressed left ventricular ejection fraction (≤35%) were excluded. Clinical data and the number of syncopal episodes were collected from the clinical history. Detailed analysis of the 12-lead electrocardiogram was performed, and several data items were collected: sinus versus nonsinus rhythm; PR interval; QRS duration; right BBB; left BBB; left posterior fascicular block; and left anterior fascicular block. For EPS, 2 femoral venous accesses were gained. Two tetrapolar catheters (Supreme, Abbott, St. Jude Medical, St. Paul, Minnesota) were used for basic measurements, atrial stimulation, and ventricular stimulation in cases of structural heart disease. Sinus node recovery time was obtained after 30 s of atrial pacing at 600 and 500 ms, and the highest value was corrected by basal heart rate. In cases where the HV interval was <70 ms, a class I drug (group A: procainamide 10 mg/kg intravenously, from June 2012 to June 2015; group B: flecainide 2 mg/kg intravenously, from June 2015 to June 2017; 10 min infusion in both cases) was administered. The dose equivalence between both drugs was extrapolated from doses used in other scenarios (15) and maximum dose was used in all patients. Continuous monitoring of the HV interval and atrial pacing were performed during the class I drug infusion and for 10 min after the infusion. EPS was considered positive according to current European Society of Cardiology guidelines (3) in the following cases: corrected sinus node recovery time >525 ms; baseline HV interval ≥70 ms or ≥100 ms after class I drug administration; second- or third-degree infra- or intra-Hisian block (with pacing cycle length above 400 ms) before or during incremental atrial pacing or after class I drug administration. A cardiac pacemaker was implanted in all patients with positive EPS and an implantable loop recorder was inserted in the rest of the population. Figure 1 shows the study flowchart. The study was approved by our institution’s ethics review board.
Continuous variables are expressed as mean ± SD and range. Categorical variables are represented by frequencies and percentages. A descriptive analysis of clinical, electrocardiographic, echocardiographic, and procedure-related variables was performed. Chi-square or Fisher exact test was used for dichotomous categorical variables (with calculation of 95% confidence interval [CI]), analysis of variance test for nondichotomous categorical variables, and Student's t-test for continuous variables. Two-tailed values of p ≤ 0.05 were considered statistically significant. Analyses were performed with SPSS software (Mac OS version 20.0; IBM SPSS Statistics, Chicago, Illinois).
A total of 271 consecutive patients (64.9% male, age: 73.95 ± 12.2 years) undergoing EPS were included. In 105 patients, the baseline EPS was positive, so a pacemaker was implanted. Of the remaining 166 patients with a negative baseline EPS, a pharmacological challenge was performed with procainamide in 90 patients (group A, historical cohort) and with flecainide in 76 patients (group B). Comorbidities, syncope characteristics, cardiac ultrasound data, and electrocardiographic abnormalities are listed in Table 1. The mean number of syncopal episodes and left ventricular ejection fraction were 2.44 ± 2.6% and 57.2 ± 8.6%, respectively. The most frequent conduction disturbance patterns were right BBB plus left fascicular block (41%), left BBB (34.3%) and isolated right BBB (22.3%). The mean QRS duration was 139.4 ± 14 ms. No differences in baseline characteristics were observed between the groups with the exception that the proportion of patients without prodromal symptoms preceding syncope was higher in the procainamide group (82.2% vs. 64.4%, p < 0.001).
EPS results and follow-up
The baseline HV interval was similar in both groups. EPS was positive in 10.8% of the patients. Diagnostic yield was significantly higher in the flecainide group (14.5% vs. 7.8%, p = 0.004) (Figure 2). A pacemaker was implanted in all patients with positive EPS after the class I drug test. The final HV interval, absolute value, and percentage increase in HV interval were significantly higher in the flecainide group (Figure 3). Details of the EPS results are listed in Table 2. After a mean follow-up of 25.8 ± 6.3 months, 39 patients (24.8%) with nondiagnostic EPS after drug challenge (19.2% in the flecainide group vs. 30.1% in the procainamide group) received a pacemaker because advanced AVB with a significant higher relative risk in procainamide group (relative risk [RR]: 5.1; 95% CI: 2.6 to 10.2; p < 0.001) (Figure 4). Any parameter of the EPS after class I drug challenge could predict the occurrence of late AVB. No arrhythmia-related deaths or severe trauma secondary to syncope were observed in patients with negative EPS.
In our series, flecainide is superior to procainamide as a class IC drug to unmask severe His-Pukinje disease in patients with syncope, BBB, and negative baseline EPS (positivity rate: 14.5% vs. 7.2%, p = 0.004), and there is clear reduction in the need of follow-up in patients with negative EPS using flecainide. As far as we know, this is first study comparing the diagnostic yield of different class IC drugs in this setting. Moreover, we have analyzed the effect of both drugs on the HV interval in terms of the absolute and relative increase in its value. Flecainide increases the HV interval from basal values by 42% versus 22%.
As mentioned, the overall diagnostic yield of EPS in patients with BBB and syncope, even when using a class I drug in cases of negative baseline EPS, is not high. In previous observational studies (16), 17 of 54 patients (31.4%) with nondiagnostic EPS after drug challenge and implanted insertable loop recorder required pacemaker implantation during the follow-up. These findings were confirmed in the B4 (Bradycardia Detection in Bundle Branch Block) study (14). In both studies, pharmacological provocation was performed when the baseline EPS was negative, with ajmaline for the Brignole et al. study (16) and with an unspecified class I drug for the B4 study (14). Due to these low predictive values, some investigators suggest that a pacemaker should be implanted in patients with syncope and BBB even after negative EPS. In this regard, a recent randomized trial (17) suggests the superiority of DDD60 beats/min versus DDD30 beats/min pacemakers in patients with syncope, BBB and negative EPS. However, in this study, only the reduction in a combined endpoint (syncope, presyncope, and asymptomatic AVB) was demonstrated, whereas the syncope rate (14.3% vs. 13.6%, p = NS) was similar in both groups. Moreover, no details about EPS are explained in the study, so no information about the use of class I drugs to stress the His-Purkinje system can be analyzed. Moreover, in the B4 study (14), the mortality of patients with negative EPS was similar to that in patients with positive EPS in whom treatment (mostly pacemaker implantation) was given. In this sense, it seems reasonable to continue with a stepwise approach to management with EPS and insertable loop recorder when the EPS after drug challenge is nondiagnostic. Actually, in 10 of 52 patients (19.2%) with syncope, BBB, and nondiagnostic EPS after drug challenge, a nonbradyarrhythmic mechanism of syncope was documented during follow-up, and so systematic pacemaker implantation in these patients has no clear recommendation in the current guidelines (IIb) (9). All of these data justify the need for research into increasing the diagnostic yield of EPS in this setting.
The most commonly used class I antiarrhythmic drug to unmask advanced His-Purkinje disease is procainamide. However, the sensitivity of EPS using this drug has not been systematically analyzed and varies from 50% to 75% (10,18) and the population sizes of the studies are small. Ajmaline (not available in some European countries) has been widely used for this purpose (12,18) with a greater increase in HV interval than that reported with procainamide (although none of the studies compared both drugs directly). Disopyramide has also been tested to unmask Hisian or infra-Hisian defects in patients with a normal HV interval (19) with a range of HV interval increase between that of procainamide and ajmaline and a sensitivity of 70%. Again, no direct comparison has been made between disopyramide and other drugs. Although some of the studies with disopyramide analyze a larger population than studies with ajmaline and procainamide, many patients without syncope were included and the indication for EPS in asymptomatic patients with BBB is not clear in current guidelines. Finally, only 1 study (20) used flecainide in these patients, but the study population was very small (15 patients). As far as we know, this is the largest prospective study analyzing the effect of flecainide in patients with syncope and BBB. Class IC drugs block both open and inactivated state sodium channels and have the slowest kinetics of unbinding during diastole. On the other hand, class IA drugs such as procainamide exhibit open state block and have intermediate effects on sodium channels. This different effect on sodium channels could explain the result of our study. In our population, HV interval increase is much greater in the flecainide group (22.5 ± 6.2% ms or 42.2 ± 24.1% vs. 12 ± 5.3% ms or 23 ± 12.1%, p < 0.001). This increase in the HV interval in a population with similar basal HV interval leads to higher proportion of patients reaching an HV interval ≥100 ms, which, indeed, according to current guidelines is an established indication for pacemaker implantation.
Finally, our study confirms that the stepwise strategy used in the B4 study and detailed in the guidelines is safe, as no arrhythmia-related death or severe trauma occurred in patients with nondiagnostic EPS after drug challenge. Additionally, although a randomized trial should be conducted to confirm our data, after follow-up, a clear, lesser need for pacemaker implantation was observed in the flecainide group (19.2% vs. 30.1%; RR: 5.1; 95% CI: 2.6 to 10.2; p < 0.001). This difference, if confirmed in a larger randomized trial could be, from our point of view, a key finding that could confirm flecainide as the first choice class I drug (when available) over procainamide.
This is an observational study, so a randomized trial should be conducted to confirm our results. Moreover, the drug testing has not been concurrent. However, the only difference between the 2 groups is that the procainamide group had a greater proportion of patients with no prodromal symptoms. This difference may have been relevant in the sense that, in some studies, the absence of prodromes has been associated with higher chance of cardiac syncope (21). In this sense, it is possible that, had the proportion of patients with no prodromal symptoms been the same in both groups (as it should be in a randomized trial), diagnostic yield in the procainamide group would have been even lower. Although our data suggest higher sensitivity of flecainide in this setting, specificity should be studied during larger follow-up of these patients, also analyzing the rate of ventricular pacing to evaluate the real need for pacing. Moreover, despite the higher EPS positivity rate and the lesser need for pacemaker implantation in the group with negative EPS after class I drug challenge with flecainide, these results need to be confirmed in a larger randomized trial. Another potential limitation of this study is the possible different effect of both drugs in sinus rate (flecainide produces higher depression of sinus node than procainamide does) or in adrenergic tone (due to potential vasodilation of procainamide and subsequent increase in adrenergic tone). However, in our series any pacemaker has been implanted only due to abnormal sinus node recovery time and any patient presented clinically relevant hypotension during procainamide infusion. Finally, it must be considered that some hospitals and some guidelines (22) suggest that the role of EPS in these patients is very limited. However, the most recent guidelines (3) maintain a level I of recommendation of performing EPS in syncope patients with BBB so research in this topic is still important.
In our population of patients with syncope and BBB, the use of flecainide has a higher diagnostic yield than procainamide in patients with a normal baseline HV interval and conduction parameters. This is the first study comparing different class I drugs in this setting. Additionally, there is a lesser need for pacing in cases where the class I drug test with flecainide was negative. If these results are confirmed by larger and randomized trials, flecainide could become the class I drug of choice in these patients.
COMPETENCY IN MEDICAL KNOWLEDGE: Patients with syncope and BBB are at risk of developing AVB. EPS is recommended including class I drug challenge to unmask His-Purkinje disease in cases with baseline normal HV interval. There is little data on differences between different class I drugs. In this study we demonstrate that flecainide has a higher diagnostic yield than procainamide in these patients with negative baseline EPS due to a greater increase of the HV interval. Additionally, there is a lesser need (RR: 5.1; 95% CI: 2.6 to 10.2; p < 0.001) for pacemaker implantation in patients in whom the class I drug test using flecainide was negative.
TRANSLATIONAL OUTLOOK: This is the first study that compares 2 different class I drug in this setting. Our findings can have immediate clinical application and flecainide could become the class I drug of choice in these patients due to its higher diagnostic yield and, more important, the lesser need of pacing during follow-up in case of negative test.
This work was partially supported by the Instituto de Salud Carlos III—Centro de Investigación Biomédica En Red- Cardio Vascular (CIBER-CV) Fondos Fondo Europeo de Desarrollo Regional (FEDER). The authors have reported that they have no relationships relevant to the contents of this paper to disclose.
All authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the JACC: Clinical Electrophysiology author instructions page.
- Abbreviations and Acronyms
- atrioventricular block
- bundle branch block
- confidence interval
- electrophysiological study
- relative risk
- Received May 16, 2018.
- Revision received September 7, 2018.
- Accepted September 20, 2018.
- 2019 American College of Cardiology Foundation
- Ruwald M.H.,
- Hansen M.L.,
- Lamberts M.,
- et al.
- Brignole M.,
- Moya A.,
- de Lange F.J.,
- et al.
- Scheinman M.M.,
- Peters R.W.,
- Modin G.,
- Brennan M.,
- Mies C.,
- O’Young J.
- Dhingra R.C.,
- Denes P.,
- Wu D.,
- et al.
- Dhingra R.C.,
- Palileo E.,
- Strasberg B.,
- et al.
- Dhingra R.C.,
- Wyndham C.,
- Bauernfeind R.,
- et al.
- Pentimalli F.,
- Bacino L.,
- Ghione M.,
- Siri G.,
- Gazzarata M.,
- Bellotti P.
- Antzelevitch C.,
- Brugada P.,
- Borggrefe M.,
- et al.
- Brignole M.,
- Menozzi C.,
- Moya A.,
- et al.,
- for the ISSUE Investigators
- Santini M.,
- Castro A.,
- Giada F.,
- et al.
- Englund A.,
- Bergfeldt L.,
- Rosenqvist M.
- Vardas P.E.
- Shen W.K.,
- Sheldon R.S.,
- Benditt D.G.,
- et al.