Kelley P. Anderson

Sudden cardiac death unresponsive to implantable defibrillator therapy: an urgent target for clinicians, industry and government.

A major expansion in utilization of implantable cardioverter-defibrillators (ICDs) is anticipated based on the results of randomized clinical trials (RCT) that demonstrate increased survival in a sizable population of patients with reduced left ventricular function. However, if RCT accurately reflect clinical practice, then a substantial proportion of patients will die suddenly despite ICD implantation. ICD-unresponsive sudden cardiac death (SCD) has been recognized since the initial ICD experience. Yet, despite 25 years of technical advances, the frequency of ICD-unresponsive SCD has not declined. Pooled analysis of RCT indicates a crude rate of ICD-unresponsive SCD of 5%. This may not cause alarm in an average practice, but it comprises about 30% of cardiac deaths. Meta-analyses of RCT show that ICD therapy is associated with a relative risk reduction of SCD of approximately 60%, far less than the greater than 90% efficacy that many expect. The suboptimal performance of ICD therapy accounts for the failure of some RCT to achieve statistically significant effects on survival. The number of patients with ICD-unresponsive SCD is highly correlated with the number of cardiac deaths among control patients as well as ICD recipients. Otherwise, no definite patterns have emerged that clearly distinguish this mode of demise from other modes of cardiac death. Retrospective post-hoc analyses have not revealed distinguishing characteristics of patients with ICD-unresponsive SCD with respect to clinical variables, pre-terminal symptoms or to the setting of the terminal event. Despite advanced storage capabilities of implanted devices, almost no information has become available from RCT regarding the terminal rhythm or the response of the ICD. These observations have implications for clinical management and research.Candidates for ICD implantation based on RCT should be accurately informed about the residual risk of SCD. Investigators seeking to identify populations likely to benefit from ICD therapy based on SCD incidence should recognize that a significant fraction may not respond to ICD therapy. Reducing the incidence of ICD-unresponsive SCD would substantially improve survival and cost-effectiveness related to ICD therapy. Close cooperation between clinicians, investigators and representatives of industry and government is urgently needed to develop strategies to identify patients prone to ICD-unresponsive SCD, to determine its mechanisms and to develop methods of prevention and treatment.

Sympathetic Nervous System Activity and Ventricular Tachyarrhythmias: Recent Advances

Sympathetic nervous system activity (SNSA) is believed to participate in the genesis of ventricular tachyarrhythmias (VTA) but understanding has been impeded by the number and complexity of effects and the paucity of data from humans. New information from studies of genetic disorders, animal models, and spontaneous human arrhythmias indicates the importance of the temporal pattern of SNSA in arrhythmia development. The proarrhythmic effects of short‐term elevations of SNSA are exemplified by genetic disorders and include enhancement of early and delayed afterdepolarizations and increased dispersion of repolarization. The role of long‐term elevations of SNSA is suggested by animal models of enhanced SNSA signaling that results in apoptosis, hypertrophy, and fibrosis, and sympathetic nerve sprouting caused by infusion of nerve growth factor. Processes that overlap short‐ and long‐term effects are suggested by changes in R‐R interval variability (RRV) that precede VTA in patients by several hours. SNSA‐mediated alterations in gene expression of ion channels may account for some intermediate‐term effects. The propensity for VTA is highest when short‐, intermediate, and long‐term changes are superimposed. Because the proarrhythmic effects are related to the duration and intensity of SNSA, normal regulatory processes such as parasympathetic activity that inhibits SNSA, and oscillations that continuously vary the intensity of SNSA may provide vital antiarrhythmic protection that is lost in severe heart failure and other disorders. These observations may have therapeutic implications. The recommended use of β‐adrenergic receptor blockers to achieve a constant level of inhibition does not take into account the temporal patterns and regional heterogeneity of SNSA, the proarrhythmic effects of α‐adrenergic receptor stimulation, or the potential proarrhythmic effects of β‐adrenergic receptor blockade. Further research is needed to determine if other approaches to SNSA modulation can enhance the antiarrhythmic effects.

Estimates of Implantable Cardioverter-Defibrillator Complications: Caveat Emptor

Appropriate selection of patients for implantable cardioverter-defibrillator (ICD) therapy requires knowledge of the beneficial effects and adverse consequences of such therapy. Although the randomized clinical trial is the sine qua non for establishing the benefits and exposing the adverse effects of interventions, subjects recruited for ICD trials may not represent the eligible population.1 Moreover, improved treatments of the underlying disorders and comorbid conditions and advances in equipment and implantation techniques could alter the balance of benefits and risks so that information from older clinical trials cannot be assumed to reflect current practice. In this issue of Circulation , Peterson and colleagues provide one of the first peer-reviewed studies using the National ICD Registry (NICDR) to examine gender-related differences in ICD implantation complication rates.2 Two preliminary reports have shown that patients in the NICDR differ significantly from those recruited into 2 of the primary prevention ICD trials that provided the evidence base for current practice guidelines and reimbursement policies of the Center for Medicaid and Medicare Services.3,4 Article p 1078 Participation is voluntary for most registries. Registries that include hospitals that agree to time- and labor-intensive data recording requirements and external scrutiny cannot be expected to represent hospitals that do not. The NICDR is part compulsory and part voluntary. Participation in the NICDR is required to receive reimbursement for primary prevention ICDs in Center for Medicaid and Medicare Services beneficiaries; however, about 75% of hospitals have elected to enroll all ICD patients in the NICDR.5 As of June 2008, data from 1448 hospitals totaling >270 373 implants had been entered in the NICDR. The report by Peterson et al2 is based on 204 700 unique patients accrued between January 2006 and December 2007 from 1224 hospitals. After exclusion of patients with a previous ICD implantation, the …

Lipid-lowering therapy for prevention of ventricular tachyarrhythmias*

In this issue of the Journal , Mitchell et al. [(1)][1]report that lipid-lowering therapy (LLT) was associated with a 36% relative risk reduction (RRR) in all-cause mortality in patients with ischemic heart disease (IHD) enrolled in the Antiarrhythmics Versus Implantable Defibrillator (AVID) trial.

Programmed electrical stimulation for risk assessment in Brugada syndrome: time to change the guidelines?

Brugada syndrome (BrS) is a rare inheritable disorder identified by characteristic abnormalities in the anterior electrocardiographic (ECG) leads ([1][1]). The main clinical problem is sudden cardiac death (SCD). The only accepted form of SCD prevention is an implantable cardioverter defibrillator (

Biological Clocks and Ventricular Tachyarrhythmias

Sudden cardiac death (SCD) due to sustained ventricular tachyarrhythmias (VTA) remains a major public health problem because of poor understanding of the mechanisms. Initiation of VTA in animal models and in patients usually requires intense metabolic or electrical stimuli not often observed for

Ablation for atrial fibrillation: what are acceptable levels of experience, efficacy, and complications?

The 2011 ACCF/AHA/HRS Focused Update on the Management of Patients With Atrial Fibrillation upgraded the indication for atrial fibrillation (AF) catheter ablation from class IIa to class I (level of evidence A) for “selected patients with significantly symptomatic, paroxysmal AF who have failed treatment with an antiarrhythmic drug and have normal or mildly dilated left atria, normal or mildly reduced LV function, and no severe pulmonary disease” [1]. This implies that the members of the guideline committee agree that the benefit of AF catheter ablation outweighs the risks for this group of patients based on the highest level of evidence. The benefits are related to reduction of symptoms and improvement in quality of life. However, the procedure is not known to improve longevity or to reduce complications such as stroke or to eliminate the need for anticoagulation and attendant risks of bleeding complications. Moreover, the benefits are limited by the success rate of the procedure. In order tomake an informed decision, patients, referring clinicians, and AF ablation operators need to have specific information on the efficacy and risks. The ACCF/AHA/HRS guidelines do not specify the efficacy or the risks that justify a class I recommendation. Instead, they stipulate that the procedure be performed in experienced centers defined as performing more than 50 AF catheter ablations per year although they acknowledge that this recommendation is not evidence based [1]. The 2010 Canadian Cardiovascular Society guidelines specify both an efficacy rate (60–75% after one procedure and 75–90% after two procedures) and complication rates (overall 2–3%, vascular access complication 1–2%, cardiac perforation 0.5–1%, thromboembolism 0.5–1%) [2]. However, for evidence, they cite only a worldwide survey that reports a higher complication rate (see below) [3]. The 2010 Guidelines of the European Society of Cardiology suggest a more modest recommendation for catheter ablation of AF (level IIa) [4]. A table of clinical trials of catheter ablation is provided that indicates rates of AF free at 1 year from 56% to 87%. A table describing specific complications is also provided including death (0.7%), thromboembolism [0.93% (transient ischemic attack—TIA 0.2%, stroke 0.3%)], tamponade up to 6% of all procedures, and 0.8% with hypotension or cardiac arrest. There is, therefore, variance among the major American, Canadian, and European guidelines regarding the strength of recommendation for AF ablation, level or grade of evidence, and expectation for procedure experience, efficacy, and complications. In a recent survey, major procedural complications of radiofrequency catheter ablation for AF occurred in 4.5% of 16,309 patients who underwent 20,825 procedures between 2003 and 2006 from 85 centers worldwide [3]. In this survey there were 25 deaths (0.15%), 213 cardiac tamponades (1.31%), 25 permanent diaphragmatic paralyses (0.17%), 6 atrial–esophageal fistulae (0.04%), 37 strokes (0.23%), 115 TIAs (0.71%), 11 valve damages (0.07%), 152 femoral pseudoaneurysms (0.93%), 88 arterial–venous fistulae (0.54%), and 48 pulmonary vein stenoses requiring intervention (0.29%) and assorted other low-frequency but serious complications. Many clinicians would be reluctant to recommend a procedure to reduce symptoms with these many serious complications. The level of experience was not low as the median number of procedures per center was 245, well above the suggested minimum 50 AF ablation procedures per year recommended by the ACCF/AHA/HRS The opinions expressed are entirely those of Dr. Anderson and do not represent those of the JICE. From The Department of Cardiology, Marshfield Clinic, Marshfield, and the Department of Medicine, University of Wisconsin Medical School, Wisconsin, USA. Dr. Anderson has no financial, commercial, or industrial relationships related to this commentary.