European Heart Journal

European Heart Journal Advance Access originally published online on May 5, 2007
European Heart Journal 2007 28(17):2126-2133; doi:10.1093/eurheartj/ehm116

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Role of programmed ventricular stimulation in patients with Brugada syndrome: a meta-analysis of worldwide published data

Matthias Paul^1,*,, Joachim Gerss^3,, Eric Schulze-Bahr^1,2, Thomas Wichter¹, Christian Vahlhaus¹, Arthur A.M. Wilde⁴, Günter Breithardt^1,2 and Lars Eckardt¹

¹ Department of Cardiology and Angiology, University Hospital of Muenster, Albert-Schweitzer-Str. 33, D-48149 Muenster, Germany
² Leibniz-Institute for Arteriosclerosis Research at the University of Muenster, Muenster, Germany
³ Coordinating Centre for Clinical Trials, University Hospital of Muenster, Muenster, Germany
⁴ Experimental and Molecular Cardiology Group, Academic Medical Centre, Amsterdam, The Netherlands

Received 13 October 2006; revised 15 March 2007; accepted 22 March 2007; online publish-ahead-of-print 5 May 2007.

^* Corresponding author. Tel: +49 251 83 47581; fax: +49 251 83 47864. E-mail address: mapaul{at}uni-muenster.de

	Abstract

Top Abstract Introduction Methods Results Discussion Conclusion Acknowledgements References

 
Aims: Brugada syndrome (BS) is an ion channelopathy with the risk of sudden cardiac death. The role of programmed ventricular stimulation (PVS) in risk stratification has been controversially discussed. Therefore, we performed a meta-analysis on the prognostic role of PVS in BS.

Methods and results: A Medline^® search until July 2006 documented 822 entries for BS. Only English publications with > 10 patients and a follow-up period were considered (n = 15). Patients [n = 1217; 974 males (80%)] were divided into three groups: survived sudden cardiac arrest (SCA) [n = 222 (18%)], syncope (Syncope) [n = 275 (23%)], and asymptomatic patients (Asympt) [n = 720 (59%)]. PVS was conducted in 1036 patients (85%). In 548 patients (53%), sustained ventricular tachyarrhythmias (VT) or ventricular fibrillation (VF) was inducible. During follow-up (34 ± 40 months), VT/VF occurred in 141 patients. SCA bore the highest chance for a VT/VF occurrence during follow-up [odds ratio (OR) 14.4 compared with asymptomatic patients; P < 0.0005]. However, except for one study, the OR for VT/VF during follow-up in relation to VT/VF inducibility was non-significant (OR 1.5; P = ns).

Conclusion: The main finding is that we were unable to identify a significant role of PVS with regard to arrhythmic events during follow-up in BS, thus questioning the role of PVS for risk stratification in patients with BS. Patients with BS and survived SCA show the highest chance for VT/VF occurrence during follow-up.

Key Words: Brugada syndrome • Programmed ventricular stimulation • Sudden cardiac death • Meta-analysis

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These authors contributed equally to this manuscript.

An editorial comment on this article has been published in Europace (doi:10.1093/europace/eum174)

	Introduction

Top Abstract Introduction Methods Results Discussion Conclusion Acknowledgements References

 
Initially described in 1992,¹ the Brugada syndrome (BS) has been recognized as a major cause of sudden cardiac death in young apparently healthy individuals.² It is characterized by an atypical right bundle branch block with ST segment elevation in the right precordial leads, which may be documented spontaneously or after administration of class I antiarrhythmic agents.^1–3 Mutations in the SCN5A gene, coding the alpha subunit of the cardiac sodium channel, have been found in about 20% of patients with BS.^4,5 Though many efforts have been undertaken to optimize risk stratification in affected patients and their relatives, there is an ongoing controversy on the prognostic impact of programmed ventricular stimulation (PVS) in these patients.^6–8 This issue harbours far-reaching implications in terms of clinical care, management, and follow-up strategies. Considering the discrepant findings resulting from analyses in sometimes small patient cohorts, we sought to evaluate the significance of PVS by a combined analysis of available trials on this topic.

	Methods

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Study objectives
The primary aim of this meta-analysis was to evaluate the prognostic role of PVS in patients with reported BS. BS was defined according to the published criteria.^1,2 It was recognized that there would be a significant heterogeneity in the studies selected as to patient selection, availability of case-specific data, eligibility to as well as the individual protocol of PVS, length of follow-up, and event rates. Nonetheless, by combining the studies, the explanatory power to evaluate the impact of PVS in this rare disease would be greatly increased.

Trial search strategy
We performed an extensive Medline^® database search (National Library of Medicine, Bethesda, MD, USA) to identify all trials concerning PVS in patients with BS until 31 July 2006 using the query terms ‘Brugada syndrome’ and ‘Brugada syndrome stimulation’.

Study inclusion criteria
Trials to be selected for further analyses had to be in English language and had to comprise 10 or more patients. Clinical data as well as information on length of follow-up and event-rates during follow-up were additional prerequisites. In the case of numerous reports by the same group of authors, only the one with the largest number of patients was considered. Trial eligibility was assessed in consensus by two authors (M.P. and L.E.). In addition, the corresponding authors of those studies with incomplete information regarding patients' characteristics and follow-up data were contacted and asked to help clarify missing values.

Endpoint and definitions
The occurrence of ventricular tachyarrhythmias (VTs) served as the primary endpoint. Patients were divided into three groups according to their initial clinical manifestation: Patients with a survived cardiac arrest (group ‘SCA’), patients with a history of unexplained syncope (group ‘Syncope’), and asymptomatic patients (group ‘Asymptomatic’). Acknowledging the fact that group-specific information on the length of follow-up would presumably not be available in all studies, the overall mean length of the follow-up period was considered for statistical analyses.

Statistical analyses
Statistical analyses were conducted by means of hierarchical logistic regression in order to analyse available data most efficiently.⁹ A two-step model was applied. In the first level, the event rate of a certain patient group was modelled using a logistic regression approach, which comprised the co-factors ‘past medical history’ and ‘inducibility of sustained VTs’. In order to account for within-study effects, co-factors were modelled via random components with study-specific realizations. Systematic between-study variation in event rates due to different follow-up was accounted for by means of an additional fixed co-variate. In the second level of the statistical model, all random components were modelled to be normally distributed with fixed expected values and variance components. Estimated model parameters were obtained by means of a restricted maximum likelihood approach and were interpreted in terms of a population-average formulation. P-values of significance tests are to be interpreted in an explorative way and are regarded significant in case P < 0.05. No adjustment for multiple testing was conducted. Statistical analyses were performed with the HLM software (version 6.0 Scientific Software International Lincolnwood, IL, USA).

	Results

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Included trials, patient characteristics and study designs
Out of the 822 entries on BS between 1999 and 31 July 2006, 15 studies comprising a total of 1217 patients (80% males) with BS were eligible for this meta-analysis.^8,10–23 Among these were 10 single-center^{10–12,16–19,21–23} and five multi-center studies^8,13–15,20 (Table 1). A complete data set was available in four studies.^10,11,16,22 After personal communication with the corresponding authors, we were able to obtain additional information on six studies^{8,14,18,20,21,23} which were marked in Tables 1 and 2.

View this table: [in this window] [in a new window]   Table 1 Clinical profile of study patients: I

 

View this table: [in this window] [in a new window]   Table 2 Clinical profile of study patients: II

 
The mean age of the study patients was 44 ± 14 years; 222 patients (18%) had survived an episode of SCA (range 5%¹⁰ to 90%¹⁵) and in 275 patients (23%; range 10%¹⁵ to 38%¹⁰), an unexplained syncope had triggered further cardiological work-up resulting in the final diagnosis of BS. The majority of study patients (n = 720; 59%; range 0^11,15 to 80%¹⁷) were asymptomatic but had either a spontaneous abnormal surface ECG compatible with BS or were asymptomatic relatives of a patient with BS. A positive family history of sudden unexplained cardiac death was reported in 157 patients. The proportion of patients with a positive family history varied between the studies from 0²² to 47%.¹⁶ In addition, in two studies, no specific data on family history were mentioned.^12,14

Detailed information on characteristic Brugada-type ECGs were available in 750 patients (62%): 503 patients exhibited a typical Brugada-ECG spontaneously (range 30²³ to 100%,^{11,12,15–17}), and in 247 patients, these could only be recorded after administration of a class I antiarrhythmic agent. The choice of drug, its dose, and administration protocol differed between the studies. Intravenous flecainide administration (2 mg/kg body weight) over 6 min¹⁸ or 10 min^{8,10,19,20,23} was used in the majority of trials.^{8,10,13,18–20} In some studies,^8,13 intravenous ajmaline (1 mg/kg body weight), procainamide (10–15 mg/kg body weight^8,15,23) or pilsicainide (1 mg/kg body weight or 150 mg orally^21,22) was applied. Information on spontaneous or provoked Brugada-ECGs were provided in all but one study.¹⁴

Molecular genetic screening for the presence of SCN5A mutations in index patients was reported in eight studies^{8,10,13,15,19–22} comprising a total of 469 patients (39% of all patients; range of genotyped patients: 37%²² to 100%¹⁰). Mutations were found in 87 (19%) of these patients (range 9%¹⁹ to 38%¹⁰).

Overall, 1036 patients (85%) underwent PVS. In 548 patients (53%), sustained VTs were inducible. The proportion of patients with inducible sustained VTs varied between the studies from 34%¹⁹ to 91%.²² In the majority of studies (11 studies^{8,10–12,16–22}), the protocol of PVS encompassed two stimulation sites with up to three extra-stimuli and at least two basic cycle lengths. No information on stimulation sites were reported in two studies,^13,15 and additional details of applied basic cycle lengths were not available in four studies.^13–15,17

An automatic implantable cardioverter-defibrillator (ICD) was implanted in 353 patients (range 15%¹² to 88%²²). During a mean follow-up period of 34 ± 40 months, recurrences of VTs was reported in 141 patients.

Inducibility of sustained VTs was highest in SCA patients (66%; Table 2). Eighty SCA patients (36%) had a recurrence of life-threatening VTs during follow-up, and in 73% of these patients, VTs were inducible. In 55% of patients with a history of syncope, sustained VTs were inducible during PVS (n = 151 patients; Table 2). Among the 30 patients (11%) of this group with an arrhythmic event during follow-up, 23 patients (77%) had inducible sustained VTs. In contrast, sustained VTs inducibility in asymptomatic patients was low (n = 182; 25%). Among the 23 initially asymptomatic individuals (3%) who experienced a life-threatening arrhythmic event during follow-up, 14 patients (61%) had inducible sustained VTs.

Calculating the odds ratio (OR) for inducibility of sustained VTs during PVS depending on the initial clinical disease manifestation, no difference between patients with survived SCA and those with syncope prior diagnosis [OR 1.1; P = 0.821; 95% confidence interval (CI) 0.52–2.27] was apparent. However, when compared to asymptomatic individuals with the typical Brugada ECG, patients of the former groups exhibited inducible sustained VTs more frequently (P < 0.04; Table 3). In detail, patients with SCA had a 3.1-fold (OR 3.1; 95% CI 1.08–9.14; P = 0.038) and those with syncope a 2.9-fold (OR 2.9; 95% CI 1.14–7.38; P = 0.029) higher chance for inducible sustained VTs than asymptomatic patients (Table 3).

View this table: [in this window] [in a new window]   Table 3 Odds ratios for the inducibility of sustained ventricular tachyarrhythmias during programmed ventricular stimulation

 
Analysing the event rate of recurrent VTs during follow-up, patients with SCA had a 14-fold higher incidence of life-threatening arrhythmias when compared with asymptomatic individuals (OR 14.4; 95% CI 6.81–30.53; P < 0.0005; Table 4). When compared with patients with syncope, the odds of future life-threatening arrhythmias in SCA patients were also significantly increased (OR 3.1; 95% CI 1.63–5.78; P = 0.003). However, investigating the impact of inducible sustained VTs during PVS on the occurrence of VTs during follow-up, inducibility of sustained VTs was of no statistical significant value (OR 1.5; 95% CI 0.55–4.06; P = 0.399; Table 4). The length of follow-up was entered into the statistical model as a co-variable demonstrating an OR of 1.0 (95% CI 0.91–1.00; P = 0.068).

View this table: [in this window] [in a new window]   Table 4 Odds ratios for the occurrence of ventricular tachyarrhythmias during follow-up depending on the past medical history and that of life-threatening ventricular arrhythmias depending on the results of the programmed ventricular stimulation

 
Noteworthy, the data reported by Brugada et al.¹⁴ showed in parts significantly divergent results. The differences in inducibility of sustained VTs between the groups SCA and Syncope proved to be highly significant, whereas it was not significant in the other studies (OR 2.8; 95% CI 1.39–5.53; P = 0.0034; Table 3). The most prominent difference between the results of Brugada et al.¹⁴ and all other studies in this meta-analysis becomes apparent when analysing the impact of sustained VTs inducibility on the arrhythmia recurrence: only in the study by Brugada et al. a highly significant OR (10.0; 95% CI 3.81–26.23; P < 0.0001; Table 4) was found.

	Discussion

Top Abstract Introduction Methods Results Discussion Conclusion Acknowledgements References

 
Clinical characteristics and published follow-up data of 1217 patients with BS were analysed in this meta-analysis to evaluate the role of PVS for risk stratification. The main finding is that we were unable to identify a significant role of PVS with regard to arrhythmic events during follow-up in BS.

PVS has been reported to identify patients at high risk for life-threatening VTs. However, except for a selected group of post-myocardial infarction patients (depressed left ventricular function and ventricular tachycardia²⁴), PVS has failed to be relevant for risk stratification in cardiomyopathies (e.g. dilative cardiomyopathy, hypertrophic cardiomyopathy), or ion channelopathies such as long QT syndrome.²⁴ In addition, the recently published ACC/AHA/ESC guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death refer to PVS as a class IIb indication. This reflects the fact that most studies on this topic have failed to demonstrate a predictive role of PVS.²⁵

There is an ongoing controversy as to the role and protocol of PVS in patients with BS.^6,7,26,27 Both the number of patients who underwent PVS and of those who had inducible sustained VTs varied between studies which may in part be attributed to study-specific inclusion criteria. To minimize potentially false-positive or non-specific results of PVS, the Second BS Consensus Report² suggested a stimulation protocol involving up to three extra-stimuli first applied to the right ventricular apex, followed by the right ventricular outflow-tract in the case of non-inducibility from the apex site. Stimulation at two sites was performed in 11 studies; in two studies, the stimulation site was not mentioned.^13,15

Calculating the ORs for inducibility and event rates between the three different clinical groups, it became apparent that the study by Brugada et al.¹⁴ showed partly highly divergent results when compared with all other studies. Thus, it seemed appropriate not only to calculate the overall but also to separate ORs for the aforementioned and the other studies.

Overall, survivors of an SCA as well as patients with prior syncope had a three-fold higher chance for inducible sustained VTs when compared with previously asymptomatic Brugada individuals (Table 3; P = 0.038 and P = 0.029, respectively). However, inducibility between SCA and Syncope was only significantly different in the study by Brugada et al.¹⁴ without even an indication of a trend towards significance among the other studies (Table 3; OR 0.9; P = 0.744). Finally, the overall inducibility of sustained VT during PVS also failed to predict future arrhythmic events in all studies except for Brugada et al.,¹⁴ in which it was highly significant (OR 10.002; 95% CI 3.81–26.23; P < 0.0001; Table 4).

The reasons for these discrepancies cannot be attributed to divergent demographic patient characteristics (i.e. age, proportion of male gender, past medical history) between the study by Brugada et al.¹⁴ and the other studies. The number of patients who underwent PVS, stimulation protocol, and outcome of stimulation procedure differed slightly between both aforementioned groups. However, the existing differences are not pronounced enough to account for relevant discrepancies between the study results. Duration of follow-up and the proportion of arrhythmic events during follow-up were comparable. Thus, there may be other confounding factors that account for the observed differences. First of all, if one considers the spontaneous type I, coved-type Brugada ECG as the more characteristic, rather ‘malignant’ variant,² seven studies involving 201 patients (17% of all patients) included patients with both type I and type II Brugada ECG.^{11,12,16,17,20,22,23} However, the proportion of patients with a type II ECG in these studies was relatively low ranging between 14% (seven patients²⁰) and 70% patients (14 patients²³). In one study,¹¹ the proportion of type II Brugada ECGs has not been explicitly mentioned. Even if one assumes a possible 70% proportion of type II Brugada ECG in this study, the overall number of patients in this meta-analysis with only a type II ECG would have reached 7.2% (i.e. 87 patients). Therefore, this appears unlikely to be of distinct relevance.

Second, the role of genetic factors attributing to a potentially different proportion of electrical instability in affected patients has yet to be defined. Given the genetic heterogeneity and incomplete penetrance reported for SCN5A mutations in BS,^2,28 an involvement of other genes or modifiers appears to be very likely. In the present meta-analysis, genetic data were provided in 53% of the studies. None of these studies reported a correlation between SCN5A mutations and future arrhythmic events.

Other modulating factors encompass a circadian sympathovagal variation and altered autonomic balance² contributing to the fact that characteristic ECG repolarization abnormalities may vary even from day-to-day. This in turn suggests a possible intermittent electrical instability, which at least theoretically may argue against a potential role of PVS for risk stratification. In addition, we have previously reported a correlation between body surface area of ST elevation (measured with body surface potential maps) and the inducibility of VTs in patients with BS.²⁹

Finally, one may also raise the question whether the population within the Brugada registry is possibly biased towards more severe cases. This is reflected in the decreasing number of arrhythmic events in asymptomatic patients in consecutive publications on the same registry (Figure 1).

View larger version (28K): [in this window] [in a new window] [Download PowerPoint slide]   Figure 1 Development of arrhythmic events during follow-up in asymptomatic Brugada individuals within the Brugada registry in different publications on the same registry when compared with the meta-analysis.

 
The interaction of all these factors and those to be still identified contribute to the divergent results of PVS and the occurrence of arrhythmic events during follow-up leaving both patients and their relatives as well as the attending physicians in a dilemma. In symptomatic Brugada patients, the implantation of an automatic cardioverter-defibrillator is unanimously recommended.² However, management of asymptomatic patients remains highly difficult. The inducibility of sustained VTs during PVS failed to identify high-risk patients in 14 of 15 studies enrolled in this meta-analysis and might therefore rather be considered as a diagnostic tool of uncertain value. Therefore, in the light of the current data, the indication to perform a PVS may not be considered as strict as previously recommended.² However, due to the described occurrence of symptomatic supraventricular tachyarrhythmias in some patients with BS,⁸ invasive-electrophysiologic testing may still play a role in selected patients.

The decision whether or not to recommend an ICD to asymptomatic patients should be made deliberately weighing the potential individual risk for future arrhythmic events against procedure-related risk, risk of inappropriate shocks, and quality of life. There is no doubt that asymptomatic patients should be monitored very carefully and that the avoidance of potential triggers of VTs in these patients is essential.

Study limitations
In the present meta-analysis, as individual effect measures are not available in most cases, assessment of publication bias cannot be performed with standard methods, and although trial eligibility was assessed in consensus by two authors, there might yet be a potential publication bias. As an inherent problem to all studies on BS, the mean duration of follow-up of 34 ± 40 months is too short and the number of arrhythmic events during follow-up too small for final conclusion. Clearly, longer follow-up periods will finally elucidate the natural history of BS but in the meantime, the present data cast a light on important trends that are of clinical relevance.

Because of the restricted availability of required data and the relatively low number of arrhythmic events during follow-up, we could not analyse the impact of clinical variables such as gender (male vs. female), family history, spontaneous Brugada-type ECG, and the presence/absence of SCN5A mutations on subsequent arrhythmic events. In addition, we could not control for a potentially underlying impact of site-specific VT/ventricular fibrillation (VF) inducibility on the occurrence of future VTs as well as for possible group-specific differences in the mean length of follow-up.

During the process of conducting this meta-analysis with preliminary data first presented at Heart Rhythm 2006,³⁰ another meta-analysis of BS has been published by Gehi et al.,³¹ which also indicated a limited role of PVS in patients with BS. However, there are some distinct differences to our study as to study objective and methodology that should be addressed. First of all, in contrast to our study, Gehi et al. used a more traditional methodological approach to assess predictors of future arrhythmic events by calculating the relative risk of several potential risk factors. The univariate approach by Gehi et al. does not allow controlling for potential confounders (e.g. differences in past medical history, inducibility during PVS, and the inter-study variation in the follow-up duration). In addition, the applied univariate models imply that only those study results can be included in the meta-analysis that allow relative risk estimation within the individual study. Consequently, in certain cases, only few studies could be integrated (e.g. two studies for SCN5A mutation).³¹ Second, they did not perform sensitivity analyses to elucidate potential inter-study differences. Third, Gehi et al.³¹ included in their analyses several reports by the same group of authors (e.g. Kakishita et al., Takenaka et al., Morita et al.; n = 71 patients) as well as four studies without PVS performed (Hermida et al., Atarashi et al., Nanke et al., and Sakabe et al.). Together with additional minor differences, this eventually results in an overall slightly lower number of patients in comparison to our meta-analysis (Paul et al.: 1217 patients vs. Gehi et al.: 1157 patients).

	Conclusion

Top Abstract Introduction Methods Results Discussion Conclusion Acknowledgements References

 
Patients with BS and survived SCA bear the highest chance for a life-threatening arrhythmia occurrence during follow-up. However, divergent results of PVS in the literature highly question the role of this diagnostic tool for reliable risk stratification in patients with BS.

	Acknowledgements

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The authors wish to thank all the corresponding authors of the studies enrolled in this meta-analysis who contributed formerly not available details from their studies.

Supported in part by grants form the Deutsche Forschungsgemeinschaft (DFG), Bonn, Germany [Sonderforschungsbereich 556, Project C4: M.P., T.W.; E.S.-B. (Schu1082/3-1 and 3-2)], from the Fondation Leducq, Paris, France [E.S.-B., L.E., A.A.M.W. ((‘Alliance against sudden cardiac death’)], and the Peter Osypka foundation (L.E. holds the Peter Osypka professorship of clinical and experimental electrophysiology).

Conflict of interest: none declared.

	Footnotes

 
These authors contributed equally to this manuscript.

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Top Abstract Introduction Methods Results Discussion Conclusion Acknowledgements References

 

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