Contents lists available atScienceDirect
Contemporary Clinical Trials Communications
journal homepage:www.elsevier.com/locate/conctcIntErnationaL eLeCTRicAl storm registry (ELECTRA): Background,
rationale, study design, and expected results
Federico Guerra
a,∗, Michele Accogli
b, Paolo Bonelli
a, Corrado Carbucicchio
c, Valentina Catto
c,
Laura Cipolletta
a, Gaetano Maria De Ferrari
d, Gabriele Dell
’Era
e, Veronica Dusi
d,
Oscar Fabregat-Andrés
f, Marco Flori
a, Eraldo Occhetta
e, Pietro Palmisano
b, Francesca Patani
a,
Alessandro Proclemer
g, Alessandro Capucci
aaCardiology and Arrhythmology Clinic, Marche Polytechnic University, University Hospital“Ospedali Riuniti”, Ancona, Italy bCardiology Unit,“Card. G. Panico” Hospital, Tricase, Italy
cCardiology Center Monzino IRCCS, Milan, Italy
dLaboratory of Clinical and Experimental Cardiology, Department of Molecular Medicine, Fondazione IRCCS Policlinico San Matteo, University of Pavia, Pavia, Italy eDivision of Cardiology, University of Eastern Piedmont,“Maggiore della Carità” Hospital, Novara, Italy
fCoronary Care Unit, General University Hospital, Valencia, Spain
gCardiology Department, University Hospital“S. Maria della Misericordia”, Udine, Italy
A R T I C L E I N F O
Keywords: Arrhythmia Catheter ablation Electrical storm Implantable cardioverter-defibrillator Ventricularfibrillation Ventricular tachycardiaA B S T R A C T
Electrical storm (ES) is defined as three or more episodes of ventricular fibrillation (VF) or ventricular tachy-cardia (VT) within 24 h and is associated with an increased tachy-cardiac and all-cause mortality. ES is a full ar-rhythmic emergency, its prevalence steadily increasing along with the number of implantable cardioverter-defibrillator implanted every year in developed countries. Nowadays, little evidence exists regarding clinical predictors of ES and their potential association on mortality and heart failure (HF), nor optimal pharmacological and non-pharmacological treatment has ever been codified. The intErnationaL eLeCTRicAl storm registry (ELECTRA) is a multicentre, observational, prospective clinical study with two major aims. First, to create an international database on ES encompassing clinical features, pharmacological management, and interventional treatment strategies. Second, to describe mortality and rehospitalization rates in patients with ES over a long follow-up. The primary endpoint is all-cause mortality 3 years after the ES index event. The main secondary endpoint is hospitalization for all causes 3 years after the ES index event. Other secondary endpoints includes ES recurrences, unclustered VTs/VFs recurrences, and hospitalizations for HF worsening. A minimum of 500 pa-tients will be included in the registry, and all papa-tients will be followed-up for a minimum of three years. The present paper describes the background and current rationale of the ELECTRA study and details the study design, from enrolment strategy to data collection methods to planned data analysis. A brief overview of the expected results and their potential clinical and research implications will also be presented (NCT02882139).
1. Introduction
Ventricular arrhythmias such as ventricular tachycardia (VT) and ventricular fibrillation (VF) represent a major event in the clinical history of a patient and usually lead to hemodynamic instability and sudden cardiac death (SCD). Organized ventricular arrhythmias may be associated with structural heart disease, genetic arrhythmic syndromes or metabolic disorders[1]. In patients at high risk for ventricular ar-rhythmias, the guidelines of the European Society of Cardiology sug-gests the use of an implantable cardioverter-defibrillator (ICD), a sub-cutaneous device that can quickly recognize and treat ventricular
arrhythmias using fast ventricular pacing (ATP) or direct-current shock [2].
Recurrences of ventricular arrhythmias and electrical instability have exponentially increased in the last decades and a new clinical entity called electrical storm (ES) has risen as a major morbidity and mortality factor[3]. ES is usually defined as the occurrence of three or more episodes of VTs/VFs within 24 h requiring either anti-tachycardia pacing (ATP) or cardioversion/defibrillation[4]. Most of the patients presenting with ES are in fact already implanted with an ICD. This is due to three factors. First, as reported before, patients with an ICD have a higher risk to develop ventricular arrhythmias[5]. Second, the ICD is
http://dx.doi.org/10.1016/j.conctc.2017.06.002
Received 10 February 2017; Received in revised form 5 June 2017; Accepted 7 June 2017
∗Corresponding author. Cardiology and Arrhythmology Clinic, Marche Polytechnic University, University Hospital“Ospedali Riuniti”, Via Conca 71, Ancona, Italy.
E-mail address:f.guerra@univpm.it(F. Guerra).
Contemporary Clinical Trials Communications 7 (2017) 69–72
Available online 09 June 2017
2451-8654/ © 2017 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/BY-NC-ND/4.0/).
able to treat brief and asymptomatic arrhythmic episodes that would not be detected by the patient. Third, and more important, the ICD enables the patient to survive thefirst arrhythmic episode, making it possible for the patient to experience further VTs/VFs.
The incidence of ES is debated in different studies and ranges from 4 to 7% in primary prevention and from 10 to 60% in secondary pre-vention[5]. Despite the wealth of data currently available, there are still grey areas regarding predictors and optimal treatment, mostly due to the small samples of the studies available so far[6]. Nonetheless, almost all authors agree in considering ES an independent predictor of poor outcome[7]. More recently, the interest has also shifted towards non patient-related variables as potential predictors of ES. In this con-text, the MADIT-RIT trial has showed that restricting ICD intervention to longer or faster arrhythmias is safe and may reduce patient morbidity and mortality [8], and a multicentre, patient-level meta-analysis has recently demonstrated that ES presents a higher incidence during daytime hours and working days, and is associated with an increase in monthly temperature variation[9].
The aim of the intErnationaL eLeCTRicAl storm registry (ELECTRA) registry is twofold. First, we want to create an international registry on ES encompassing clinical features, pharmacological management, and interventional treatment strategies. Second, we plan to use the data derived from the registry to describe mortality and rehospitalization rates in patients with ES over a long follow-up.
2. Methods 2.1. Study design
The ELECTRA is a multicentre, observational, prospective clinical study aimed at gathering information on a wide cohort of patients af-fected by ES. Enrolment started on August 1st, 2016 and will continue for a minimum of three years. There is no pre-specified date for the end of enrolment, which will continue according to the enrolment rate. A minimum of 500 patients will be included in the present registry, and each patient will be followed-up for a minimum of three years. The exploratory nature intrinsic to the registry characteristics does not allow a sample size calculation (see Statistical analysis below). However, the sample size was selected on the estimated enrolment rates of the participating centres during a 3-year enrolment period. Moreover, the sample size will be large enough to postulate specific subgroup ana-lyses.
The inclusion criteria are:
•Diagnosis of ES, defined as three or more episodes of VTs/VFs within 24-hour and separated by at least 5 min or documentation of sustained VT lasted at least 12 h
•
age≥18 years old•
written informed consentThe exclusion criteria are few, and aimed to gather a representative sample of the“real-world” population:
•
No ICD implantation•
confirmed or suspected use of drugs or narcotics with known direct pro-arrhythmic effect•
inability to express an informed consent for the studyAll patients admitted to the participating centres will be evaluated consecutively by the referent investigators. All patients that meet the above-described criteria will be included in the registry. The study complies with the Declaration of Helsinki; it was approved by the ethic committee of each participating center, and was registered intowww. clinicaltrials.gov (NCT02882139). At enrolment, each patient will be informed on the aim and the design of the study. It will be stated to each patient that his participation to the registry is voluntary, free and
that the consent can be withdrawn at any time and for any reason. All patients will be informed to the results of the study through their en-rolling centres.
2.2. Data collection
All data requested will be collected by the referent investigators at enrolment and during each follow-up visit. Considering that the ICD records all the major arrhythmic events since implantation, patients experiencing an ES previous to the enrolment start can be included retrospectively if they meet the following additional inclusion criteria:
•
Availability of complete and accurate clinical data•
No ICD replacement after the index event, leading to the loss of original data•
Availability of ECG and echocardiography done for routine clinical purposes•
Agreement to subscribe the informed consent during the next rou-tine visitData are saved on a dedicated website in agreement with the Italian regulations on the treatment of personal data. Electronic cards of data collection transmitted to the study responsible are identified by an al-phanumeric code. The list of matches between subjects' data and these codes will be created and kept by local investigators only. The complete list of all collected variables is shown inSupplementary Table 1. Each centre will be asked to report every death and hospital admission of all patients and their causes. Moreover, data about subjects' vital status will be updated every 6 months, either by telephone call or by ambu-latory visit.
Collected data will be processed, analysed and reported according the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) Initiative international guidelines[10]. 2.3. Statistical analysis
The primary endpoint will be estimated annually and it will be expressed as absolute and relative numbers. Survival curves free from study endpoint, eventually adjusted according to variables of interest such as gender, age, underlying heart disease, comorbidities and pro-gramming mode will be calculated according to the Kaplan-Meier method and compared by Log-rank test for primary and secondary endpoints. Primary endpoint subgroup analyses for each of the afore-mentioned variables will be performed too. According to the number of centres involved, we expect to recruit at least 500 patients. Considering an annual incidence of the primary endpoint (death from all causes) of 11% according to our experience[7], we expect about 55 deaths at 1-year follow-up and about 165 deaths at the end of the 3-1-year follow-up. The statistical analysis will be conducted using the SPSS 21.0 for Windows software (SPSS Inc. Chicago, IL, USA). Every test will be two-tailed and a value of p > 0.05 will be considered significant. Multi-plicity between the different endpoints will be controlled by the step-wise Holm procedure.
2.4. Expected results
The primary endpoint of the ELECTRA registry will be all-cause mortality 3 years after the ES index event. The main secondary end-point will be hospitalization for all causes 3 years after the ES index event. Survival and new hospitalizations will be documented through ICD remote monitoring, internal database checking, and direct phone interview. Deaths will be classified according to a modified Hinkle-Thaler classification[11]and categorized into three predefined groups: sudden death, non-sudden death for cardiovascular causes, and death for other causes. Non-sudden death for cardiovascular causes will be divided into HF-related death, coronary death, and death for other
F. Guerra et al. Contemporary Clinical Trials Communications 7 (2017) 69–72
cardiovascular causes. Other secondary endpoints will be: number of ES recurrences and time tofirst recurrence; number of unclustered VTs/ VFs recurrences and time tofirst recurrence; number of hospitalizations for HF worsening and time tofirst HF-related hospitalization.
Thefinal report will also include the following data:
•
Prevalence of cardiovascular risk factors (arterial hypertension, diabetes mellitus, prior stroke or TIA, atrial fibrillation, coronary artery disease, peripheral vascular disease)•
Concomitant pharmacological therapy at the time of the index event•
Acute and chronic pharmacological management•
Non-pharmacological therapy, including catheter ablation [12,13] and sympathetic denervation[14].•
Centrality and dispersion measures regarding laboratory, echo-cardiograph, and electrophysiological parameters•
Centrality and dispersion measures regarding ES inherent variables, such as total number of arrhythmias, cycle length, and ICD pro-gramming3. Discussion 3.1. Open questions
The ELECTRA registry aims to give a solid answer to many open questions. Thefirst is to estimate with good precision the incidence of death and cardiovascular events after ES over a long follow-up. The large sample size will help in define the impact that ES has on overall survival, and whether ES patients experience more frequently non-sudden cardiac death and HF-related cardiovascular events, as postu-lated before [7,15]. In fact, recent evidence links ES and HF quite tightly, supporting the notion that, in patients with structural heart disease, ES could be considered among the plethora of HF-related signs and symptoms rather than an innocent bystander[16].
Second, the present registry will delineate which baseline char-acteristics are more commonly associated with ES. While clinical pre-dictors for ES such as secondary prevention, monomorphic VT, reduced EF, and concomitant therapy with class I anti-arrhythmic drugs are already known, these data mostly come from retrospective studies [6,15,17]and meta-analyses[4,5]and still have to be confirmed in a large, prospective, observational study. Moreover, the ELECTRA will offer the opportunity to confirm on a larger basis the non-homogeneous temporal presentation of ES recently postulated by a patient-level meta-analysis on the subject[9].
Third, data from the ELECTRA registry will define the contemporary standard of care for ES. The reported prevalence of different pharma-cological and non-pharmapharma-cological treatments will help delineate how referring centres treat ES nowadays. The ELECTRA will also offer in-sights on the optimal strategy in ICD programming. A focus on how to setup the device after the implant is critical, as patients with ES had a more aggressive ICD, including lower detection rates, shorter detection times, and no ATP during capacitors charge[18]. Therefore, optimizing the detection of ventricular arrhythmia could help in reduce ES in-cidence and its related increased mortality. Data from the present registry could also become a solid foundation for phase III randomized clinical trial on non-conventional treatment of ES, such as pharmaco-logical sedation and sympathetic denervation[14,19].
Funding sources
The ELECTRA registry is supported by the Marche Polytechnic University (Grant number 27/2017).
Disclosures
All authors declare no conflict of interests related to the present manuscript.
Appendix A. Supplementary data
Supplementary data related to this article can be found athttp://dx. doi.org/10.1016/j.conctc.2017.06.002.
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