Implantable defibrillators versus medical therapy for cardiac channelopathies

  • Protocol
  • Intervention

Authors


Abstract

This is the protocol for a review and there is no abstract. The objectives are as follows:

To compare the effectiveness of ICDs with antiarrhythmic drugs, placebo, or usual care in reducing the risk of all-cause mortality, cardiovascular mortality, and adverse events in individuals at increased risk of sudden cardiac death due to cardiac ion channelopathies, including congenital long QT syndrome, congential short QT syndrome, Brugada syndrome and catecholaminergic polymorphic ventricular tachycardia.

Background

Description of the condition

Sudden cardiac death annually claims between 180,000 and 450,000 lives in the United States and an estimated 50,000-70,000 people in the United Kingdom, making it the leading mechanism of death in the United States and a significant worldwide burden of disease (Deo 2012; NICE 2006; Roger 2012). Sudden cardiac death alone accounts for higher annual mortality than other common diseases such as stroke, lung cancer, and colon cancer combined (Go 2014; Roger 2012; Siegel 2013). Though the majority of these deaths are due to ischemic heart disease, an estimated 5-15% of sudden cardiac death victims have no structural abnormalities at autopsy (Bowker 1996; Corrado 2001; Eckart 2011; Puranik 2005). Further investigation into this important subset has revealed a genetic predisposition to sudden cardiac death due to altered cardiac ion channels, collectively known as cardiac ion channelopathies (Goldberger 2014; Napolitano 2012).

Cardiac ion channelopathies are a diverse class of heritable arrhythmias owing to defective ion channels in cardiac cell membranes, which can cause sudden cardiac death in otherwise healthy individuals (Tester 2011). Defective ion channels lead to abnormal electrical rhythms, with a wide range of clinical manifestations ranging from asymptomatic carriers to life-threatening cardiac arrhythmias and death in individuals with structurally normal hearts (Martin 2012). Arrhythmias typically involve ventricular tachycardia degenerating into ventricular fibrillation (Napolitano 2012). If these arrhythmias are not prevented or treated, they may lead to sudden cardiac death, the common mechanism of death for the aforementioned cardiac ion channel deficiencies (Martin 2012).

Beginning in the mid-1990s, several important articles linked well-established heritable syndromes with specific ion channel gene mutations (Ackerman 2004). Currently, four types of inherited cardiac ion channelopathies have been strongly linked to sudden cardiac death in individuals with structurally normal hearts: including congenital long QT syndrome, congential short QT syndrome, Brugada syndrome, and catecholaminergic polymorphic ventricular tachycardia (Napolitano 2012). Since its initial description, a total of 13 susceptible genes have been linked to congenital long QT syndrome (Abriel 2012); three genes in congential short QT syndrome (Gollob 2011); 12 genes in Brugada syndrome (Crotti 2012); and two genes in catecholaminergic polymorphic ventricular tachycardia (Napolitano 2014). Prevalence data has been difficult to estimate for each syndrome, but congenital long QT syndrome and Brugada syndrome are the most common and are each estimated at roughly one in 2,000 individuals (Postema 2012; Schwartz 2009); congential short QT syndrome is estimated to be present in 3 in 10,000 people (Anttonen 2007), and catecholaminergic polymorphic ventricular tachycardia is present at a rate of 1 in 10,000 individuals (Napolitano 2014).

Susceptibility of individuals with these cardiac channelopathies to sudden cardiac death is variable due to a variety of factors including incomplete penetrance and variable expressivity, but the potentially fatal natural history of these diseases highlights the importance of primary and secondary prevention of sudden cardiac death in this high-risk population (Napolitano 2012).

Description of the intervention

Previous research has focused on preventing and treating potentially fatal arrhythmias in high-risk individuals to prevent sudden cardiac death. The first prevention strategy includes medical management with antiarrhythmic drugs as prophylaxis for prevention of sudden cardiac death. Antiarrhythmic drugs can suppress ventricular arrhythmias, including asymptomatic or mildly symptomatic non-sustained ventricular tachycardia, which may serve as a nidus potentially leading to sudden cardiac death (Burkart 1990; Friedman 1986). Their actions are often classified based on their primary mechanism of action on the cardiac action potential. The Singh-Vaughan Williams classification scheme is widely used to separate antiarrhythmic drugs into five main categories: class I agents modulate myocardial sodium channels; class II agents inhibit sympathetic activity, primarily via beta adrenergic blockade; class III agents block myocardial potassium channels; class IV agents block myocardial calcium channels; class V agents work via other or unknown mechanisms (Bonow 2011). However, many of the antiarrhythmic drugs have well-described potential adverse side effects limiting their widespread use (Malhotra 2011).

Two early landmark randomized controlled trials (RCTs), the 'Cardiac Arrhythmia Suppression Trial' I and II (CAST I 1989; CAST II 1992), investigated the antiarrhythmic effects of class Ic antiarrhythmic agents in participants with coronary artery disease. While these antiarrhythmic drugs were able to suppress arrhythmias, they were associated with increased rates of all-cause mortality (CAST I 1989; CAST II 1992). Beta blockers are considered the mainstay of medical management of ventricular ectopic beats and arrhythmias and are suggested as first-line therapy in patients with ventricular tachyarrhythmias (Zipes 2006). Non-beta blocker antiarrhythmic drugs such as amiodarone and sotalol have been used primarily as adjunctive therapy in individuals at higher risk for arrhythmias and their benefit remains unclear (Malhotra 2011).

A second prevention strategy utilizes implantable cardioverter-defibrillator (ICDs) to treat patients with potentially fatal heart rhythms. Originally developed in the 1980s, ICDs are small battery-powered devices capable of delivering electrical impulses to the heart capable of terminating arrhythmias with rapid overdrive pacing, cardioversion, or defibrillation.

However, ICDs carry both short and long term risks. Procedural adverse events associated with ICD implantation include hematoma (1.1%), lead dislodgment (1.0%), and pneumothorax (0.5%); with a cumulative major complication rate of 1.5% during hospitalization (Curtis 2009). Long-term risks also include inappropriate shocks at rates recently documented at approximately 11% after three and a half years post-implantation, and implant-related complications including infection, lead failure, risks associated with generator change (Alter 2005). Thus the potential benefits of ICDs need to be carefully weighed against their potential risks of ICD placement for prevention in individuals with cardiac channelopathies.

How the intervention might work

Originally introduced in the 1980s, ICDs are relatively small, 40 cm3 devices that are usually implanted subcutaneously in the upper chest. The ICD consists of two components: a pulse generator and electrode leads. The pulse generator includes a battery, energy delivery components, microprocessors, and electronic circuit contained in a case. This case is then connected to the heart via bipolar coated electrode wires placed in veins leading to the heart. Via these electrodes, ICDs scan an individual's intrinsic heart rhythm in real time to detect tachyarrhythmias and can deliver electrical pacing signals, if necessary. If pre-programmed criteria are met for ventricular tachycardia or ventricular fibrillation, ICDs attempt to terminate the arrhythmia via electrical treatments including rapid overdrive pacing, cardioversion, or defibrillation. In defibrillation, the electrical impulse generated by ICDs induce global cardiac depolarization and halts specific abnormal rhythms using predetermined electrical rhythm evaluation algorithms (DiMarco 2003). ICDs are very effective at converting individuals out of shockable rhythms, including ventricular tachycardia and ventricular fibrillation, with estimated rates as high as 97% (Epstein 2013; Zipes 2006).

Since 1990, ICD implantation rates have rapidly increased worldwide. ICD implantation rates have increased nearly 20-fold in the United States from approximately 30 implants per million population to 577 implants per million population in 2006. In Europe, absolute ICD implantation rates lag behind those in the United States but have increased from under 10 implants per million population to 155 implants per million population in 2006 (Camm 2010). However, the prevalence nor incidence of ICD implantation for cardiac channelopathies is not known.

Why it is important to do this review

Although the physiology of cardiac channelopathies has been elucidated over the past decade, these diseases remain both lethal and potentially treatable. Expert guidelines suggesting genetic testing for certain subsets of individuals with these cardiac channelopathies and their family members has ensured increasing numbers of individuals will be diagnosed (Ackerman 2011). However, the appropriate treatment for individuals diagnosed with these deficiencies remains uncertain and lags behind for a variety of reasons. First, risk factors predisposing individuals with ion channelopathies to sudden cardiac death are not well described, making it difficult to match the intensity of treatment with the level of risk. It is, however, well recognized individuals with prior cardiac arrest or syncope are at high risk for future arrhythmias (Epstein 2013; Gehi 2006). In fact, the 2012 American College of Cardiology, American Heart Association, and Heart Rhythm Society guidelines for individuals with congenital long QT syndrome, congential short QT syndrome, Brugada syndrome and catecholaminergic polymorphic ventricular tachycardia recommend ICD consideration for those with prior episodes of sustained ventricular tachycardia or ventricular fibrillation and for primary prevention for some patients with a very strong family history of early mortality with C level of evidence (Epstein 2008; Epstein 2013). Given the increased risk of sudden cardiac death and increasing number of genetic variants being discovered in individuals with cardiac channelopathies, it is important to understand which strategy, antiarrhythmic drugs or ICDs, can reduce the risk of sudden cardiac death. We know of no systematic reviews that have evaluated RCTs for the effect of these interventions on individuals with cardiac channelopathies.

Objectives

To compare the effectiveness of ICDs with antiarrhythmic drugs, placebo, or usual care in reducing the risk of all-cause mortality, cardiovascular mortality, and adverse events in individuals at increased risk of sudden cardiac death due to cardiac ion channelopathies, including congenital long QT syndrome, congential short QT syndrome, Brugada syndrome and catecholaminergic polymorphic ventricular tachycardia.

Methods

Criteria for considering studies for this review

Types of studies

We will include RCTs of any length in which participants with diagnosed ion channelopathies were randomized to either ICD implantation versus antiarrhythmic drugs or ICD implantation versus usual care. We will exclude non-randomized studies.

Types of participants

We will include adult participants (18 years of age or older) who are diagnosed by study investigators with one of the following cardiac ion channelopathies: congenital long QT syndrome, congential short QT syndrome, Brugada syndrome or catecholaminergic polymorphic ventricular tachycardia.

Types of interventions

We will include studies where the intervention group is randomized to receive any ICD, including permanent and temporary with any additional leads for pacing, including single chamber, dual chamber, and biventricular pacemakers. We will include trials evaluating the effect of any external, wearable, or vest cardioverter defibrillators.

We will include studies where the comparator group is randomized to receive usual care or antiarrhythmic drugs from any drug class according to the Singh-Vaughan Williams classification system: class I, class II (including beta-blockers), class III (including amiodarone), class IV, and class V (including digoxin).

Types of outcome measures

Primary outcomes
  1. All-cause (total) mortality

  2. Fatal and non-fatal cardiovascular events, including sudden cardiac death, survived sudden cardiac arrest, myocardial infarction, stroke

  3. Adverse events, including: ICD site, generator, or lead infection; inappropriate firing; ICD malfunction; lead extraction; pocket hematoma; pneumothorax; ICD removal; drug discontinuation due to side effect, toxicity, intolerance, or adverse reaction

Secondary outcomes
  1. Non-fatal cardiovascular events, including survived sudden cardiac arrest, myocardial infarction, stroke

  2. Inappropriate ICD firing

  3. Quality of life

  4. Cost

Search methods for identification of studies

Electronic searches

We will search the Database of Abstracts of Reviews of Effectiveness (DARE) (The Cochrane Library) to identify existing systematic reviews. We will use the following sources for the identification of published trials:

  1. Cochrane Central Register of Controlled Trials (CENTRAL) (T he Cochrane Library);

  2. MEDLINE via Ovid;

  3. EMBASE via http://embase.com/;

  4. Conference Proceedings Citation Index - Science (CPCI-S) via Thomson Reuters Web of Science.

See Appendix 1 for a detailed MEDLINE search strategy. We will adapt search strategies for CENTRAL, EMBASE, and other databases from the MEDLINE search strategy to conform to the differing controlled vocabularies, thesauri, and search syntax associated with each database. We will use the sensitivity-maximizing Cochrane RCT filter for MEDLINE and also the adaptations of it to EMBASE and CPCI-S (Lefebvre 2011). We will not apply any language limits to the searches and relevant papers will be included regardless of the language in which they are published. We will run searches from the earliest date available in each database to the present and we will not apply any limits on date.

Searching other resources

We will also search the following clinical trial registers for ongoing and additional unpublished studies:

  1. ClinicalTrials.gov (http://clinicaltrials.gov/);

  2. the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) search portal (http://apps.who.int/trialsearch/).

In addition to the above electronic searches, we will attempt to discover additional studies by searching the reference lists of included trials as well as reference lists of relevant systematic reviews, and meta-analyses retrieved during the search process. We will attempt to contact authors of included studies to locate missing data and other unpublished or ongoing studies meeting the inclusion criteria.

Data collection and analysis

Selection of studies

We will identify eligible studies by the search strategy. Two authors (DM, MH) will review the title and abstract of each paper for potential relevancy. Of the studies initially deemed relevant by either author, we will retrieve the full text and will evaluate it for inclusion based on our inclusion criteria. In the case of disagreement, studies we will initially be resolve this by consensus, and if necessary, arbitrated by a third author (JG) for final inclusion.

Data extraction and management

Two authors (DM, MH) will independently abstract information using standardized data abstraction forms on each study including study design, participant characteristics, intervention and control information, outcome data, cost, quality of life, adverse events, and risks of bias. We will resolve disagreements by consensus. When needed, a third author (JG) will arbitrate in any disagreements. We will use the Cochrane Collaboration's statistical software, Review Manager 2014, for our analyses.

Assessment of risk of bias in included studies

Two authors (DM, MH) will independently assess risk of bias for each study using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We will resolve any disagreements by discussion or by involving a third author (JG). We will assess the risk of bias according to the following domains:

  1. random sequence generation;

  2. allocation concealment;

  3. blinding of participants and personnel;

  4. blinding of outcome assessment;

  5. incomplete outcome data;

  6. selective outcome reporting;

  7. other bias (e.g. industry funding).

We will grade each potential source of bias as high, low or unclear and provide a quote from the study report together with a justification for our judgment in the 'Characteristics of included studies' tables. We will summarize the risk of bias judgements across different studies for each of the domains listed. Where information on risk of bias relates to unpublished data or correspondence with a trialist, we will note this in the 'Characteristics of included studies' tables.

When considering treatment effects, we will take into account the risk of bias for the studies that contribute to that outcome.

Measures of treatment effect

We will present data according to the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We will calculate the relative risks (RRs) and associated 95% confidence intervals (CIs) for each study with dichotomous outcomes using inverse variance weighting of studies. For studies with continuous variables, we will calculate the weighted mean differences (WMDs) between the intervention and control groups with associated 95% CIs using inverse variance weighting of studies. We will calculate and report the number needed to treat (NNT), if possible.

Dealing with missing data

We will contact investigators or study sponsors in order to verify key study characteristics and obtain missing numerical outcome data where possible (e.g. when a study is identified as "abstract only"). Where this is not possible, and the missing data are thought to introduce serious bias, we will explore the impact of including such studies in the overall assessment of results by a sensitivity analysis

Assessment of heterogeneity

We will evaluate the presence and degree of heterogeneity between studies by the Mantel-Haenszel Chi2 test and the I2 statistic, respectively, for each outcome. In the presence of no or minimal heterogeneity, we will use fixed-effect analytical models. However, when significant heterogeneity is present (I2 > 50%), we will search for possible explanations, including both participants and interventions, and will use random-effects models with cautious interpretation.

Assessment of reporting biases

We will create funnel plots to evaluate for publication bias based on our primary outcomes. We will perform tests of asymmetry and create funnel plots where applicable to assess for publication bias (Egger 1997).

Subgroup analysis and investigation of heterogeneity

If sufficient data exist, we will conduct the following subgroup analyses:

  1. age;

  2. sex;

  3. channelopathy subtype (congenital long QT syndrome, congential short QT syndrome, Brugada syndrome or catecholaminergic polymorphic ventricular tachycardia);

  4. implanted vs. non-implanted cardioverter defibrillator.

We will use the formal test for subgroup interactions in Review Manager 2014.

Sensitivity analysis

We will perform sensitivity analyses by excluding studies with high risk of bias and those with unclear risk of bias.

Reaching conclusions

We will base our conclusions only on findings from the quantitative or narrative synthesis of included studies for this review. We will avoid making recommendations for practice and our implications for research will suggest priorities for future research and outline what the remaining uncertainties are in the area.

Appendices

Appendix 1. MEDLINE search strategy

1. exp ion channels/

2. ((cardiac or ion or sodium or calcium or potassium or chloride) adj3 channel*).tw.

3. Channelopathies/

4. channelopath*.tw.

5. exp Long QT Syndrome/

6. (long qt syndrome* or long q-t syndrome* or lqts).tw.

7. timothy syndrome*.tw.

8. (andersen adj3 (syndrome* or tawil or cardiodysrythmic or paralysis)).tw.

9. ((Jervell-Lange Nielsen or surdo cardiac or cardioauditory) adj2 syndrome*).tw.

10. ((romano ward or ward romano) adj syndrome).tw.

11. (short qt syndrome* or short-qt syndrome* sqts).tw.

12. Brugada Syndrome/

13. (brugada or sudden unexplained nocturnal death syndrome* or sunds or right bundle branch block).tw.

14. idiopathic ventricular fibrillation.tw.

15. cardiac conduction disease.tw.

16. (Catecholaminergic Polymorphic Ventricular Tachycardia or CPVT).tw.

17. Ankyrin-B Syndrome*.tw.

18. or/1-17

19. Defibrillators, Implantable/

20. Electric Countershock/

21. "Prostheses and Implants"/

22. (defibrillator* adj5 implant*).tw.

23. cardioverter*.tw.

24. electric countershock*.tw.

25. electric defibrillat*.tw.

26. electroversion therap*.tw.

27. cardiac electroversion*.tw.

28. cardioversion*.tw.

29. or/19-28

30. randomized controlled trial.pt.

31. controlled clinical trial.pt.

32. randomized.ab.

33. placebo.ab.

34. drug therapy.fs.

35. randomly.ab.

36. trial.ab.

37. groups.ab.

38. or/30-37

39. exp animals/ not humans.sh.

40. 38 not 39

41. 18 and 29

42. 40 and 41

Contributions of authors

All authors contributed to the development of concept and writing the protocol.

Declarations of interest

Dr. Goldberger is the Director of the Path to Improved Risk Stratification, NFP and reports unrestricted educational grants-Boston Scientific, Medtronic, St. Jude Medical and consulting/Honoraria–Medtronic, GE Healthcare, Zoll; all of which are unrelated to this review.

Dr. McNamara receives no grant support and has no declarations of interest.

Dr. Mark Huffman receives grant support from the National Heart, Lung, and Blood Institute and World Heart Federation through unrestricted educational grants from AstraZeneca and Boehringer Ingelheim on research and a research training program, respectively, both of which are unrelated to this review

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