Introduction
Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a hereditary condition that manifests as arrhythmias induced by adrenergic stimulation.1 Genomic alterations in specific genes disrupt the intricate homeostasis of intracellular calcium in cardiac myocytes.2 3 Consequently, this dysregulation leads to irregular myocardial contractions and poses a substantial risk for severe, potentially life-threatening arrhythmias. Despite unremarkable findings in resting electrocardiograms, individuals with CPVT are susceptible to exertion-induced episodes of ventricular tachycardia (VT).4
Early diagnosis of CPVT is crucial as untreated patients face significant mortality risks. Management typically involves a combination of therapies.5 6 Beta-blockers and flecainide, which are antiarrhythmic medications, effectively reduce the frequency and severity of VT episodes.6–8 In specific situations, the surgical procedure known as left cardiac sympathetic denervation (LCSD), which disrupts sympathetic nerve fibres that can cause arrhythmias, might be required. For high-risk CPVT patients, implantable cardioverter defibrillators (ICD) are often recommended.9 10 These devices can detect and terminate dangerous arrhythmias by delivering an electric shock. However, it is important to note that ICD may not always be effective in preventing arrhythmias and, in some cases, can even trigger electrical storms—sustained episodes of arrhythmias that can be fatal. The criteria for implanting an ICD in patients with CPVT are based on expert consensus and non-randomized studies. Due to the lack of extensive data, it is essential to thoroughly assess the potential benefits and risks for each patient before making the decision to implant an ICD.11 12 Age and lifestyle are crucial considerations, especially for younger, active individuals who may face greater risks of device-related complications and inappropriate shocks.4 Inappropriate shocks from ICDs can lead to physical discomfort, psychological distress and potentially dangerous arrhythmias.13 Therefore, a thorough assessment of the risk-benefit balance is crucial when considering ICD therapy for CPVT patients.
Two meta-analyses have attempted to address this issue. The first, published in 2016, included only 28 CPVT patients, representing a mere 0.6% of the study population, and its early publication date limits its relevance.14 The second article assessed the prognosis for CPVT patients following ICD implantation but failed to include a comparison group of patients without ICDs, omitting essential clinical context.15 Our meta-analysis aims to address these deficiencies by reviewing the most recent data and evaluating all-cause mortality, thus providing a comprehensive perspective on the use of ICDs in CPVT management. Our goal is to examine the rates of both appropriate and inappropriate shocks, as well as ICD-related complications. It is crucial to understand the safety profile of ICD therapy for this patient population to establish realistic expectations about procedural and long-term risk-benefit ratios.
Methods and analysis
Protocol registration
The protocol for this systematic review was formally registered with the PROSPERO database, which is recognized as the International Prospective Register of Systematic Reviews. This registration took place on September 11, 2022, and can be identified by the registration number CRD42022370824. This protocol will be carried out in meticulous adherence to the directives outlined in the Cochrane Handbook for Intervention Reviews. The findings of this systematic review will be reported in line with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) standards.
16
The study is scheduled to commence in October 2023 and conclude in May 2024, which defines the timeframe for data collection and analysis.
Research questions
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What is the impact of ICD implantation on mortality in patients with CPVT?
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How significant are the adverse effects of ICD in individuals with CPVT?
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In CPVT patients, which subgroups are best suited for ICD, and how does this vary based on factors like gender, age and other relevant subgroups?
Eligibility criteria
Eligibility criteria will be established based on the participants, exposures, outcomes and study type strategy.
Type of studies
Our review will include English-language observational studies and randomized controlled trials (RCTs), with potential inclusion of conference abstracts and proceedings that allow for quality assessment. To maintain a focus on rigorous and applicable evidence, we will exclude protocols, case reports, duplicates, single-arm studies, reviews, and animal studies
Populations
Studies will include CPVT patients, whether or not they have undergone ICD implantation. Diagnosing CPVT necessitates the presence of a structurally healthy heart, a resting electrocardiogram that appears normal, and the manifestation of bidirectional or polymorphic ventricular tachycardia triggered by exercise or emotional stress. The confirmation of a CPVT diagnosis involves identifying a heterozygous pathogenic variant in genes such as RYR2, CALM1, CALM2, CALM3 or CASQ2, or detecting biallelic pathogenic variants in CASQ2, TECRL or TRDN.17 18
Interventions
Studies will be included where the intervention group is randomly assigned to receive various types of implantable cardioverter defibrillators (ICDs), encompassing both permanent and temporary devices, along with any supplementary leads for pacing, such as biventricular pacemakers, dual chamber, or single chamber. Moreover, we will also consider trials assessing the effectiveness of vest-style, wearable, or external cardioverter defibrillators.
Comparisons
We will incorporate studies in which the comparator group receives standard care or antiarrhythmic medications from any class of drugs based on the Singh-Vaughan Williams classification system: class I, class II (including beta-blockers), class III (including amiodarone), class IV and class V (including digoxin).
Outcomes
Main outcomes
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All-cause (total) mortality.
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Cardiovascular incidents, both fatal and non-fatal, encompass sudden cardiac death, patients who have survived sudden cardiac arrest, strokes, and myocardial infarctions.
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ICD harm and ICD-related mortality. Mortality associated with ICDs was characterized by fatalities resulting from complications related to ICDs, deaths induced by electrical storms caused by inappropriate shocks, sudden unexplained deaths occurring with the ICD still in place, and instances of sudden cardiac death stemming from ICD failure.
Additional outcomes
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Appropriate/inappropriate shocks. Appropriate shocks refer to those initiated by ventricular tachycardia or ventricular fibrillation. On the other hand, inappropriate shocks are characterized by those caused by supraventricular tachycardia, which includes conditions like atrial fibrillation or physiological sinus tachycardia, as well as discharges resulting from the oversensing of either cardiac or noncardiac signals, or due to a malfunction in the device.
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Other ICD-related complications. Additional complications associated with ICDs include infections, malfunctions of the lead or device, dislodgement of the lead, pericardial effusion or cardiac tamponade, thrombotic events, reoperations due to pocket-related issues or hematomas, and occurrences of pneumothorax.
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Quality of life.
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Cost.
Information sources
A systematic search will be conducted across the Cochrane Library, Web of Science, EMBASE and PubMed, covering the entire history of each database up to the current date. This search will continue to be updated until the submission of our manuscript. The search approach will utilize medical subject headings alongside suitable Boolean operators like ‘NOT’, ‘AND’ and ‘OR’. Tailored search strategies will be crafted for every database.
Additionally, trial registers will be consulted. If we discover a pertinent conference abstract,
we will contact the authors to obtain the complete article. To broaden the scope of eligible studies, we will additionally investigate
grey literature, examine reference lists from included
research, and consider studies published within the review timeframe.
Search strategy
The primary literature review will be conducted by two authors, ZY.D and S.S, using the PubMed scientific database. The search will include the following terms: ‘catecholaminergic polymorphic ventricular tachycardia,’ ‘CPVT,’ ‘subcutaneous implantable cardioverter defibrillator,’ ‘implantable cardioverter defibrillator’ and ‘ICD.’ These search terms were selected based on a preliminary literature review, database queries and consensus among the authors. An experienced information specialist will support the development of the search strategy. Moreover, we will utilize 15 potentially relevant test articles to evaluate and improve our search strategy. Our searches will have no limitations regarding publication date or language. The search strategy will be presented in Supplementary Materials (online supplemental table 1).
Supplemental material
Data records and management
Following the completion of the search, the references from the study will be transferred to Mendeley referencing software to facilitate initial management and removal of duplicates. The deduplicated references will then be imported into Covidence for further literature management and screening to ensure a rigorous review process. Two independent reviewers, ZY.D and S.S, will evaluate the titles and abstracts, and subsequently the complete texts of all records
identified. Should any
conflicts or discrepancies arise
at any point, a third reviewer, YM.L, will participate in discussions to resolve these issues. Throughout the screening process, the reviewers will follow the eligibility criteria based on Population, Intervention, Comparators, Outcomes, Publication year, and Study design (PICOTS). We will document the reasons for excluding studies during the full-text review phase
. Included studies, both at the title/abstract and full-text stages, will be independently extracted by ZY.D and S.S. A member of the technical team will help reach a consensus on the extracted data. ZY.D and S.S will verify that each publication meets the inclusion criteria through discussion. The main analysis will encompass studies that report: (1) basic demographic information, (2) a minimum of two CPVT patients and (3) at least one patient who underwent ICD implantation. Data presented only in abstract form will not be included. The detailed selection process will be depicted in a PRISMA flow diagram, which will be shown as
figure 1
.
Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow chart.
The details to be gathered from the studies included will involve characteristics like the title, primary author, name of the journal, year of publication, type of study, and size of the sample. The predetermined variables will be recorded and analysed using Microsoft Excel (Microsoft Excel for Mac V.16.75.2). Data to be extracted from eligible studies will include all-cause mortality, fatal and non-fatal cardiovascular events, ICD-related mortality, appropriate and inappropriate shocks, other ICD-related complications, cost, administration of anti-arrhythmic drugs and LCSD therapies, demographic data and indications for ICD implantation. Should any necessary data be absent from the studies included, the authors will be reached out to for further information. If no response is received, the available data will be analysed. The specific data to be extracted are presented in table 1.
Data extraction
Risk of bias assessment
The evaluation of potential bias in the studies that are included will be conducted using the Cochrane Risk of Bias tool,19 ROBINS-120 or RoB 2,21 tailored to the design of each study. This assessment will be conducted by two independent investigators, ZY.D and S.S, focusing on areas pertinent to randomised trials such as the generation of random sequences, the concealment of allocation, the blinding of both participants and personnel, the blinding of outcome assessments, incomplete outcome data, selective reporting and various potential biases. Non-randomised studies will be evaluated for bias using ROBINS-I or RoB 2, depending on their alignment with the criteria of these tools. Risk of bias scores will be summarised in tables, and their impact on findings will be discussed to ensure transparency.
Data synthesis and reporting
We will start by performing a qualitative synthesis, reviewing the context, methods and findings of studies to highlight key patterns and insights. Integrating results from different studies is challenging due to variations in study design, methods and outcome measures. Sufficient homogeneity will be determined by factors such as the indication for ICD implantation, follow-up time, outcome measures and study design. The meta-analysis will be conducted using statistical software (RevMan V.5.4.1), applying a homogeneity threshold of I² <50% to indicate acceptable homogeneity among studies. For significant heterogeneity, identified by I² ≥50%, results will be presented through tables and narrative synthesis instead of a pooled quantitative analysis. We will use Cochran’s Q tests alongside I² to assess study heterogeneity. For studies presenting various models, the one with the most comprehensive adjustments will be reported. In cases of multiple publications from the same cohort, we will select the publication providing the most complete or pertinent data for our analysis.
Outcomes measured by time-to-event will be assessed through hazard ratios (HRs), while dichotomous outcomes will be evaluated using risk ratios (RRs) or odds ratios (ORs), all accompanied by 95% confidence intervals (CIs) presented in forest plots. Statistical tests are two-sided, considering p<0.05 as significant.
Missing data
Missing or ambiguous data with an uncertain risk of bias will be addressed by attempting to contact the article authors. If doubts remain after contacting them, the analysis will proceed using the data that is available, and a discussion on the potential consequences of the missing information will be included.
Meta-regression
Random effect meta-regression will be conducted to analyse variables affecting pooled results.
Subgroup analysis
Subgroup analysis is planned for age, percentage of male patients, study design, administration of anti-arrhythmic drugs and LCSD therapies, and indications for ICD implantation if significant heterogeneity exists among studies.
Sensitivity analysis
The leave-one-out approach will be used to evaluate the reliability and robustness of the findings. High-risk studies will be excluded first based on evidence-based critical appraisal, followed by low-certainty studies that impact the interpretation.
Publication bias
A funnel plot will be used to assess potential publication bias, provided there are a minimum of 10 studies in the meta-analysis. Additionally, both Egger’s and Begg’s tests will be performed to quantify publication bias and adjust the effect size, ensuring reliable meta-analysis results. In cases where there are fewer than 10 studies, the application of Egger’s and Begg’s tests will still be taken into account.
Summary of evidence
According to GRADE guidelines (Grading of Recommendations Assessment, Development, and Evaluation), the quality of evidence will be assessed independently by ZY.D and S.S.22
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