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.