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1.  Implantable Cardioverter Defibrillators. Prophylactic Use 
Executive Summary
The use of implantable cardiac defibrillators (ICDs) to prevent sudden cardiac death (SCD) in patients resuscitated from cardiac arrest or documented dangerous ventricular arrhythmias (secondary prevention of SCD) is an insured service. In 2003 (before the establishment of the Ontario Health Technology Advisory Committee), the Medical Advisory Secretariat conducted a health technology policy assessment on the prophylactic use (primary prevention of SCD) of ICDs for patients at high risk of SCD. The Medical Advisory Secretariat concluded that ICDs are effective for the primary prevention of SCD. Moreover, it found that a more clearly defined target population at risk for SCD that would be likely to benefit from ICDs is needed, given that the number needed to treat (NNT) from recent studies is 13 to 18, and given that the per-unit cost of ICDs is $32,000, which means that the projected cost to Ontario is $770 million (Cdn).
Accordingly, as part of an annual review and publication of more recent articles, the Medical Advisory Secretariat updated its health technology policy assessment of ICDs.
Clinical Need
Sudden cardiac death is caused by the sudden onset of fatal arrhythmias, or abnormal heart rhythms: ventricular tachycardia (VT), a rhythm abnormality in which the ventricles cause the heart to beat too fast, and ventricular fibrillation (VF), an abnormal, rapid and erratic heart rhythm. About 80% of fatal arrhythmias are associated with ischemic heart disease, which is caused by insufficient blood flow to the heart.
Management of VT and VF with antiarrhythmic drugs is not very effective; for this reason, nonpharmacological treatments have been explored. One such treatment is the ICD.
The Technology
An ICD is a battery-powered device that, once implanted, monitors heart rhythm and can deliver an electric shock to restore normal rhythm when potentially fatal arrhythmias are detected. The use of ICDs to prevent SCD in patients resuscitated from cardiac arrest or documented dangerous ventricular arrhythmias (secondary prevention) is an insured service in Ontario.
Primary prevention of SCD involves identification of and preventive therapy for patients who are at high risk for SCD. Most of the studies in the literature that have examined the prevention of fatal ventricular arrhythmias have focused on patients with ischemic heart disease, in particular, those with heart failure (HF), which has been shown to increase the risk of SCD. The risk of HF is determined by left ventricular ejection fraction (LVEF); most studies have focused on patients with an LVEF under 0.35 or 0.30. While most studies have found ICDs to reduce significantly the risk for SCD in patients with an LVEF less than 0.35, a more recent study (Sudden Cardiac Death in Heart Failure Trial [SCD-HeFT]) reported that patients with HF with nonischemic heart disease could also benefit from this technology. Based on the generalization of the SCD-HeFT study, the Centers for Medicare and Medicaid in the United States recently announced that it would allocate $10 billion (US) annually toward the primary prevention of SCD for patients with ischemic and nonischemic heart disease and an LVEF under 0.35.
Review Strategy
The aim of this literature review was to assess the effectiveness, safety, and cost effectiveness of ICDs for the primary prevention of SCD.
The standard search strategy used by the Medical Advisory Secretariat was used. This included a search of all international health technology assessments as well as a search of the medical literature from January 2003–May 2005.
A modification of the GRADE approach (1) was used to make judgments about the quality of evidence and strength of recommendations systematically and explicitly. GRADE provides a framework for structured reflection and can help to ensure that appropriate judgments are made. GRADE takes into account a study’s design, quality, consistency, and directness in judging the quality of evidence for each outcome. The balance between benefits and harms, quality of evidence, applicability, and the certainty of the baseline risks are considered in judgments about the strength of recommendations.
Summary of Findings
Overall, ICDs are effective for the primary prevention of SCD. Three studies – the Multicentre Automatic Defibrillator Implantation Trial I (MADIT I), the Multicentre Automatic Defibrillator Implantation Trial II (MADIT II), and SCD-HeFT – showed there was a statistically significant decrease in total mortality for patients who prophylactically received an ICD compared with those who received conventional therapy (Table 1).
Results of Key Studies on the Use of Implantable Cardioverter Defibrillators for the Primary Prevention of Sudden Cardiac Death – All-Cause Mortality
MADIT I: Multicentre Automatic Defibrillator Implantation Trial I; MADIT II: Multicentre Automatic Defibrillator Implantation Trial II; SCD-HeFT: Sudden Cardiac Death in Heart Failure Trial.
EP indicates electrophysiology; ICD, implantable cardioverter defibrillator; NNT, number needed to treat; NSVT, nonsustained ventricular tachycardia. The NNT will appear higher if follow-up is short. For ICDs, the absolute benefit increases over time for at least a 5-year period; the NNT declines, often substantially, in studies with a longer follow-up. When the NNT are equalized for a similar period as the SCD-HeFT duration (5 years), the NNT for MADIT-I is 2.2; for MADIT-II, it is 6.3.
GRADE Quality of the Evidence
Using the GRADE Working Group criteria, the quality of these 3 trials was examined (Table 2).
Quality refers to the criteria such as the adequacy of allocation concealment, blinding and follow-up.
Consistency refers to the similarity of estimates of effect across studies. If there is important unexplained inconsistency in the results, our confidence in the estimate of effect for that outcome decreases. Differences in the direction of effect, the size of the differences in effect, and the significance of the differences guide the decision about whether important inconsistency exists.
Directness refers to the extent to which the people interventions and outcome measures are similar to those of interest. For example, there may be uncertainty about the directness of the evidence if the people of interest are older, sicker or have more comorbidity than those in the studies.
As stated by the GRADE Working Group, the following definitions were used to grade the quality of the evidence:
High: Further research is very unlikely to change our confidence n the estimate of effect.
Moderate: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low: Any estimate of effect is very uncertain.
Quality of Evidence – MADIT I, MADIT II, and SCD-HeFT*
MADIT I: Multicentre Automatic Defibrillator Implantation Trial I; MADIT II: Multicentre Automatic Defibrillator Implantation Trial II; SCD-HeFT: Sudden Cardiac Death in Heart Failure Trial.
The 3 trials had 3 different sets of eligibility criteria for implantation of an ICD for primary prevention of SCD. Conclusions
Overall, there is evidence that ICDs are effective for the primary prevention of SCD. Three trials have found a statistically significant decrease in total mortality for patients who prophylactically received an ICD compared with those who received conventional therapy in their respective study populations.
As per the GRADE Working Group, recommendations consider 4 main factors:
The tradeoffs, taking into account the estimated size of the effect for the main outcome, the confidence limits around those estimates, and the relative value placed on the outcome;
The quality of the evidence (Table 2);
Translation of the evidence into practice in a specific setting, taking into consideration important factors that could be expected to modify the size of the expected effects, such as proximity to a hospital or availability of necessary expertise; and
Uncertainty about the baseline risk for the population of interest
The GRADE Working Group also recommends that incremental costs of health care alternatives should be considered explicitly with the expected health benefits and harms. Recommendations rely on judgments about the value of the incremental health benefits in relation to the incremental costs. The last column in Table 3 is the overall trade-off between benefits and harms and incorporates any risk or uncertainty.
For MADIT I, the overall GRADE and strength of the recommendation is “moderate” – the quality of the evidence is “moderate” (uncertainty due to methodological limitations in the study design), and risk/uncertainty in cost and budget impact was mitigated by the use of filters to help target the prevalent population at risk (Table 3).
For MADIT II, the overall GRADE and strength of the recommendation is “very weak” – the quality of the evidence is “weak” (uncertainty due to methodological limitations in the study design), but there is risk or uncertainty regarding the high prevalence, cost, and budget impact. It is not clear why screening for high-risk patients was dropped, given that in MADIT II the absolute reduction in mortality was small (5.6%) compared to MADIT I, which used electrophysiological screening (23%) (Table 3).
For SCD-HeFT, the overall GRADE and strength of the recommendation is “weak” – the study quality is “moderate,” but there is also risk/uncertainty due to a high NNT at 5 years (13 compared to the MADIT II NNT of 6 and MADIT I NNT of 2 at 5 years), high prevalent population (N = 23,700), and a high budget impact ($770 million). A filter (as demonstrated in MADIT 1) is required to help target the prevalent population at risk and mitigate the risk or uncertainty relating to the high NNT, prevalence, and budget impact (Table 3).
The results of the most recent ICD trial (SCD-HeFT) are not generalizable to the prevalent population in Ontario (Table 3). Given that the current funding rate of an ICD is $32,500 (Cdn), the estimated budget impact for Ontario would be as high as $770 million (Cdn). The uncertainty around the cost estimate of treating the prevalent population with LVEF < 0.30 in Ontario, the lack of human resources to implement such a strategy and the high number of patients required to prevent one SCD (NNT = 13) calls for an alternative strategy that allows the appropriate uptake and diffusion of ICDs for primary prevention for patients at maximum risk for SCD within the SCD-HeFT population.
The uptake and diffusion of ICDs for primary prevention of SCD should therefore be based on risk stratification through the use of appropriate screen(s) that would identify patients at highest risk who could derive the most benefit from this technology.
Overall GRADE and Strength of Recommendation for the Use of Implantable Cardioverter Defibrillators for the Primary Prevention of Sudden Cardiac Death
MADIT I: Multicentre Automatic Defibrillator Implantation Trial I; MADIT II: Multicentre Automatic Defibrillator Implantation Trial II; SCD-HeFT: Sudden Cardiac Death in Heart Failure Trial.
NNT indicates number needed to treat. The NNT will appear higher if follow-up is short. For ICDs, the absolute benefit increases over time for at least a 5-year period; the NNT declines, often substantially, in studies with a longer follow-up. When the NNT are equalized for a similar period as the SCD-HeFT duration (5 years), the NNT for MADIT-I is 2.2; for MADIT-II, it is 6.3.
NSVT indicates nonsustained ventricular tachycardia; VT, ventricular tachycardia.
PMCID: PMC3382404  PMID: 23074465
2.  The Relevance of the Primary Prevention Criteria for Implantable Cardioverter Defibrillator Implantation in Korean Symptomatic Severe Heart Failure Patients 
Korean Circulation Journal  2012;42(3):173-183.
Background and Objectives
Implantable cardioverter defibrillator (ICD) therapy is recommended as the primary tool for prevention of sudden cardiac death (SCD) in symptomatic patients with severe left ventricular dysfunction. There is a paucity of information on whether this recommendation is appropriate for the Korean population with severe heart failure.
Subjects and Methods
The study group consisted of 275 consecutive patients (mean age 65 years, 71% male) who met the ICD implantation criteria for primary prevention (left ventricular ejection fraction ≤30% and New York Heart Association functional class II or III). We analyzed the clinical characteristics and outcomes of an ischemic cardiomyopathy (ICMP) group (n=131) and a non-ischemic cardiomyopathy (NICMP) group (n=144). The outcomes of these 2 groups were compared with the Multicenter Automatic Defibrillator Implantation Trial II (MADIT-II) conventional and Defibrillators in the Non-ischemic Cardiomyopathy Treatment Evaluation (DEFINITE) standard therapy groups, respectively.
Eighty patients (29%) died during a follow-up period of 40±17 months. The NICMP group had better all-cause mortality rates than the ICMP group (19% vs. 40%, p<0.001), however both groups had a similar incidence of SCD (7% vs. 10%, p=0.272). The 2-year all-cause mortality and SCD for the ICMP group were similar to those of the MADIT-II conventional therapy group (20% vs. 20%, 7% vs. 10%, respectively, all p>0.05). All-cause mortality and the incidence of SCD in the NICMP group were comparable to those of the DEFINITE standard therapy group (13% vs. 17%, 6% vs. 6%, respectively, all p>0.05).
Korean patients with severe heart failure in both the ICMP and NICMP groups had all-caused mortality and risk of SCD comparable to patients in the MADIT-II and DEFINITE standard therapy groups. Therefore, the primary prevention criteria for ICD implantation would be appropriate in both Korean ICMP and NICMP patients.
PMCID: PMC3318089  PMID: 22493612
Heart failure; Implantable defibrillators; Death, sudden, cardiac
The Multicenter Automatic Defibrillator Implantation Trial-Cardiac Resynchronization Therapy (MADIT-CRT) trial demonstrated that cardiac resynchronization therapy (CRT) when added to the implantable cardiac defibrillator (ICD) reduces risk of heart failure (HF) or death in minimally symptomatic patients with reduced cardiac ejection fraction and wide QRS complex.
To evaluate 4-year cost-effectiveness of CRT-ICD compared to ICD alone using MADIT-CRT data.
Research Design
Patients enrolled in the trial were randomized to implantation of either ICD or CRT-ICD in a 2:3 ratio, with up to 4-year follow-up period. Cost-effectiveness analyses were conducted, and sensitivity analyses by age, gender and left bundle branch block (LBBB) conduction pattern were performed.
1271 patients with ICD or CRT-ICD (U.S. centers only) who reported healthcare utilization and health-related quality of life data (HRQOL).
We used the EQ-5D (U.S. weights) to assess patient HRQOL and translated utilization data to costs using national Medicare reimbursement rates.
Average 4-year healthcare expenditures in CRT-ICD patients were higher than costs of ICD patients ($62,600 vs. 57,050, p=0.015), mainly due to the device and implant-related costs. The incremental cost-effectiveness ratio of CRT-ICD compared to ICD was $58,330/quality-adjusted life years (QALY) saved. The cost effectiveness improved with longer time horizon and for the LBBB subgroup ($7,320/QALY), with no cost-effectiveness benefit being evident in the non-LBBB group.
In minimally symptomatic patients with low ejection fraction and LBBB, CRT-ICD is cost effective within 4-year horizon when compared to ICD-only
PMCID: PMC3711178  PMID: 22913474
implantable cardioverter-defibrillator (ICD); cardiac resynchronization therapy (CRT); cost-effectiveness; health-related quality-of-life (HRQOL); survival; MADIT-CRT
4.  Risk Stratification for Sudden Cardiac Death In Patients With Non-ischemic Dilated Cardiomyopathy 
Non ischemic dilated cardiomyopathy (NIDCM) is a disorder of myocardium. It has varying etiologies. Albeit the varying etiologies of this heart muscle disorder, it presents with symptoms of heart failure, and rarely as sudden cardiac death (SCD). Manifestations of this disorder are in many ways similar to its counterpart, ischemic dilated cardiomyopathy (IDCM). A proportion of patients with NIDCM carries a grave prognosis and is prone to sudden cardiac death from sustained ventricular arrhythmias. Identification of this subgroup of patients who carry the risk of sudden cardiac death despite adequate medical management is a challenge .Yet another method is a blanket treatment of patients with this disorder with anti arrhythmic medications or anti tachyarrhythmia devices like implantable cardioverter defibrillators (ICD). However this modality of treatment could be a costly exercise even for affluent economies. In this review we try to analyze the existing data of risk stratification of NIDCM and its clinical implications in practice.
PMCID: PMC1502083  PMID: 16943952
Non Ischemic Dilated Cardiomyopathy; Ischemic Dilated Cardiomyopathy; Risk Stratification; Implantable cardioverter defibrillator; Sudden Cardiac Death
5.  Angiotensin Receptor Type 1 Single Nucleotide Polymorphism A1166C is Associated with Malignant Arrhythmias and Altered Circulating miR-155 Levels in Patients with Chronic Heart Failure 
Journal of cardiac failure  2012;18(9):717-723.
Sudden cardiac death (SCD) due to ventricular tachyarrhythmias accounts for approximately 450,000 annual deaths in the U.S.; many of these cases involve patients with chronic heart failure (HF). Prediction of which HF patients are most susceptible to SCD is difficult, and it is uncertain whether gene polymorphisms associated with HF outcomes are also linked to arrhythmic risk.
We evaluated 485 patients with chronic HF to see whether the Angiotensin Receptor Type 1 (AT1) A1166C or Angiotensin Converting Enzyme Insertion/Deletion (ACE I/D) polymorphisms were associated with a higher rate of ventricular arrhythmias requiring implantable cardioverter defibrillator (ICD) therapies over a 5-year period. We assessed the correlation between polymorphisms and antitachycardia pacing (ATP) and/or ICD shocks.
Patients with AT1-1166 CC genotype had an increased rate of all events: ATP plus ICD shocks (p=0.02). There was no association between ACE I/D genotype and ICD therapies. Furthermore, circulating levels of microRNA-155 (miR-155), a microRNA known to posttranscriptionally regulate AT1R expression, were significantly decreased in the CC compared to the AC and AA genotypes and were associated with ICD events.
Our study suggests that the AT1R-1166 CC genotype is associated with increased ICD therapies in patients with chronic HF, and the level of circulating miR-155 may be a potential marker for arrhythmic risk. While these findings are novel, they will need replication and validation in larger cohorts of chronic HF patients.
PMCID: PMC3640363  PMID: 22939041
Genetic Polymorphisms; Angiotensin; Angiotensin Type 1 Receptor; Sudden Cardiac Death; Heart Failure; microRNA
6.  Wearable defibrillator use in heart failure (WIF): results of a prospective registry 
Heart failure (HF) patients have a high risk of death, and implantable cardioverter defibrillators (ICDs) are effective in preventing sudden cardiac death (SCD). However, a certain percentage of patients may not be immediate candidates for ICDs, particularly those having a short duration of risk or an uncertain amount of risk. This includes the newly diagnosed patients, as well as those on the cardiac transplant list or NYHA class IV heart failure patients who do not already have an ICD. In these patients, a wearable cardioverter defibrillator (WCD) may be used until long term risk of SCD is defined. The purpose of this study was to determine the incidence of SCD in this population, and the efficacy of early defibrillation by a WCD.
Ten enrolling centers identified 89 eligible HF patients who were either listed for cardiac transplantation, diagnosed with dilated cardiomyopathy, or receiving inotropic medications. Data collected included medical history, device records, and outcomes (including 90 day mortality).
Out of 89 patients, final data on 82 patients has been collected. Patients wore the device for 75±58 days. Mean age was 56.8±13.2, and 72% were male. Most patients (98.8%) were diagnosed with dilated cardiomyopathy with a low ejection fraction (<40%) and twelve were listed for cardiac transplantation. Four patients were on inotropes. There were no sudden cardiac arrests or deaths during the study. Interestingly, 41.5% of patients were much improved after WCD use, while 34.1% went on to receive an ICD.
In conclusion, the WCD monitored HF patients until further assessment of risk. The leading reasons for end of WCD use were improvement in left ventricular ejection fraction (LVEF) or ICD implantation if there was no significant improvement in LVEF.
PMCID: PMC3574049  PMID: 23234574
Heart failure; Wearable cardioverter defibrillator; Sudden cardiac death
7.  Quality of Life with Defibrillator Therapy or Amiodarone in Heart Failure 
The New England journal of medicine  2008;359(10):999-1008.
Implantable cardioverter defibrillator (ICD) therapy significantly prolongs life in patients at increased risk of sudden cardiac death from depressed left ventricular function. However, it is unclear whether this increased longevity is accompanied by deterioration in quality of life.
The Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT) compared ICD therapy or amiodarone versus state-of-the-art medical therapy alone in 2521 stable heart failure patients with depressed left ventricular function. Quality of life, a secondary end point of the trial, was prospectively measured at baseline, 3, 12, and 30 months and was 93% to 98% complete. The Duke Activity Status Index (which measures cardiac physical functioning) and the SF-36 Mental Health Inventory (which measures psychological well-being or distress) were prespecified principal quality-of-life outcomes. Multiple additional quality-of-life outcomes were also examined.
Compared with medical therapy alone, psychological well-being in the ICD arm significantly improved at 3 months (p=0.01) and 12 months (p=0.004) but not at 30 months. No clinically or statistically significant differences in physical functioning by treatment were observed. Some other quality-of-life measures improved in the ICD arm at 3 and/or 12 months but none differed significantly at 30 months. ICD shocks within the month preceding a scheduled assessment were associated with decreased quality of life in multiple domains. Amiodarone had no significant effects on the principal quality-of-life outcomes.
In a large primary prevention population with moderately symptomatic heart failure, single lead ICD therapy was not associated with any detectable adverse quality-of-life effects over 30 months of follow-up.
PMCID: PMC2823628  PMID: 18768943
Sudden cardiac death; congestive heart failure; implantable cardioverter-defibrillator; quality of life
8.  An ECG Index of Myocardial Scar Enhances Prediction of Defibrillator Shocks: An Analysis of the Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT) 
Only a minority of patients receiving implantable cardioverter-defibrillators (ICDs) for the primary prevention of sudden death receive appropriate shocks, yet almost as many are subjected to inappropriate shocks and device complications. Identifying and quantifying myocardial scar, which forms the substrate for ventricular tachyarrhythmias, may improve risk-stratification.
To determine if the absence of myocardial scar detected by novel 12-lead ECG Selvester QRS-scoring criteria identifies patients with low risk for appropriate ICD shocks.
We applied QRS-scoring to 797 patients from the ICD arm of the Sudden Cardiac Death in Heart Failure Trial. Patients were followed for a median of 45.5 months for ventricular tachycardia/fibrillation treated by the ICD or sudden tachyarrhythmic death (combined group referred to as VT/VF).
Increasing QRS-score scar size predicted higher rates of VT/VF. Patients with no scar (QRS-score=0) represented a particularly low-risk cohort with 48% fewer VT/VF events than the rest of the population (absolute difference 11%; hazard ratio 0.52, 95% CI=0.31–0.88). QRS-score scar absence vs. presence remained a significant prognostic factor after controlling for 10 clinically-relevant variables. Combining QRS-score (scar absence vs. presence) with ejection fraction (≥25% vs. <25%) distinguished low-, middle-, and high-risk subgroups with 73% fewer VT/VF events in the low- vs. high-risk group (absolute difference 22%; hazard ratio=0.27, 95% CI=0.12–0.62).
Patients with no scar by QRS-scoring have significantly fewer VT/VF events. This inexpensive 12-lead ECG tool provides unique, incremental prognostic information and should be considered in risk-stratifying algorithms for selecting patients for ICDs.
PMCID: PMC3010478  PMID: 20884379
9.  Incidence and electrophysiological characteristics of spontaneous ventricular tachyarrhythmias in high risk coronary patients and prophylactic implantation of a defibrillator 
Heart  2004;90(6):667-671.
Objectives: To assess the incidence and electrophysiological characteristics of spontaneous ventricular tachyarrhythmias after implantable cardioverter-defibrillator (ICD) implantation for primary prevention.
Design: Prospective observational study.
Patients: 41 consecutive patients, who fulfilled MADIT (multicenter automatic defibrillator implantation trial) I criteria, except for suppressibility by procainamide, and who received a prophylactic ICD.
Interventions: Subpectoral implantation of an ICD.
Main outcome measures: Incidence of ventricular tachyarrhythmias and their electrophysiological characteristics with respect to timing of the arrhythmia, tachyarrhythmia cycle length, mode of termination, and clinical relevance.
Results: During a mean (SD) follow up of 30 (21) months 18 of 41 (43.9%) patients experienced 142 appropriate ICD treatments. The mean (SD) time to first event was 9.6 (15.1) months. One patient had ventricular fibrillation (VF), 12 patients ventricular tachycardia (VT), and five both VT and VF. The mean (SD) cycle length of monomorphic VT was 306 (42) ms. Of 142 episodes, 117 (82.3%) were terminated by antitachycardia pacing and another 25 (17.6%) by ICD discharges. Cumulative survival of hypothetical death, defined as treated VT with a cycle length < 260 ms or VF, was 83.2% after one year and 78.4% after two years.
Conclusions: Patients with a left ventricular ejection fraction < 35%, a history of myocardial infarction, non-sustained VT, and inducible VT/VF are at high risk of VT/VF early after implantation. Therefore, implantation of a tiered treatment defibrillator seems to be justified.
PMCID: PMC1768244  PMID: 15145875
implantable cardioverter-defibrillator; MADIT; arrhythmia risk
10.  Genomics, heart failure and sudden cardiac death 
Heart failure reviews  2008;15(3):229-238.
Sudden cardiac death (SCD) is among the most common causes of death in developed countries throughout the world. Despite decreased overall cardiac mortality, SCD vrates appear to be increasing in concert with escalating global prevalence of coronary disease and heart failure, the two major conditions predisposing to SCD. This unfavorable trend is a consequence of our inability to identify those who will die suddenly from lethal ventricular arrhythmias and to develop effective therapies for all populations at risk. The known risk factors for SCD lack the predictive power needed to generate preventive strategies for the large number of fatal arrhythmic events that occur among lower-risk subsets of the population. Even among recognized high-risk subsets, prediction of SCD remains challenging. With the exception of the implantable cardioverter defibrillator (ICD) there are few effective strategies for the prevention and treatment of SCD. This article discusses the prospect of genomic science as an approach to the identification of patients at high-risk for SCD. While the final common pathway for SCD is malignant ventricular arrhythmias, there are many potential contributors, pathways, and mechanisms by which common genetic variants (polymorphisms) could affect initiation and propagation of life-threatening cardiac arrhythmias. Recent advances in genomic medicine now provide us with novel approaches to both identify candidate genes/pathways and relatively common polymorphisms which may predispose patients to increased risk for SCD. Improved understanding of the relationship between common polymorphisms and SCD will not only improve risk stratification such that ICDs can be targeted to those patients most likely to benefit from them but also provide new insight into the pathophysiology of SCD.
PMCID: PMC2851840  PMID: 18437561
Sudden cardiac death; Genomics; Heart failure; Single nucleotide polymorphisms
11.  Clinical Utility of Microvolt T-wave Alternans Testing In Identifying Patients at High or Low Risk of Sudden Cardiac Death 
Previous studies have demonstrated that microvolt T-wave alternans (MTWA) testing is a robust predictor of ventricular tachyarrhythmias and sudden cardiac death (SCD) in at-risk patients. However, recent studies have suggested that MTWA testing is not as good a predictor of “appropriate” implantable cardioverter-defibrillator (ICD) therapy as it is a predictor of SCD in patients without ICDs.
We sought to evaluate the utility of MTWA testing for SCD risk stratification in patients without ICDs.
Patient-level data were obtained from five prospective studies of MTWA testing in patients with no history of ventricular arrhythmia or SCD. In these studies, ICDs were implanted in only a minority of patients and patients with ICDs were excluded from the analysis. We conducted a pooled analysis and examined the 2-year risk for SCD based on MTWA test result.
The pooled cohort included 2883 patients. MTWA testing was positive in 856 (30%), negative in 1627 (56%) and indeterminate in 400 (14%) patients. Among patients with LVEF ≤ 35%, annual SCD event rates were 4.0%, 0.9% and 4.6% among the MTWA positive, negative and indeterminate groups. The SCD rate was significantly lower among patients with a negative MTWA test compared to either the positive or the indeterminate groups (p<0.001 for both comparisons). In patients with LVEF > 35%, annual SCD event rates were 3.0%, 0.3% and 0.3% among the MTWA positive, negative and indeterminate groups. The SCD rate associated with a positive test was significantly higher than either the negative (p<0.001) or the indeterminate groups (p=0.003).
In patients without ICDs, MTWA testing is a powerful predictor of SCD. Among patients with LVEF ≤ 35%, a negative MTWA test is associated with a low risk for SCD. Conversely, among patients with LVEF > 35%, a positive MTWA test identifies patients at significantly heightened SCD risk. These findings may have important implications for refining primary prevention ICD treatment algorithms.
PMCID: PMC3411866  PMID: 22406384
T-wave alternans; arrhythmia; sudden death; risk stratification; electrophysiology; defibrillation
12.  T Wave Alternans And Ventricular Tachyarrhythmia Risk Stratification: A Review 
Sudden cardiac death (SCD) is one of the leading causes of mortality in industrialized countries. Thus, identifying patients at high risk of SCD is an important goal. T wave alternans (TWA) is a new method for identifying patients with lethal ventricular tachyarrhythmias, and is dependent on heart rate. The maximal predictive accuracy is achieved at heart rates between 100 and 120 bpm, so that TWA is usually measured during exercise, phamacological stress, or atrial pacing. It has been shown that TWA has high sensitivity and negative predictive value for predicting SCD after myocardial infarction and is also useful for predicting SCD in patients with nonischemic cardiomyopathy. Although the implantable cardioverter defibrillator (ICD) is now the primary therapy for preventing SCD, it is difficult to identify those patients who are susceptible to lethal ventricular tachyarrhythmias for primary prevention. In the prediction of SCD, TWA can be used as a screening test of appropriate patients for further electrophysiological examination and therapy.
PMCID: PMC1513519  PMID: 16943959
T wave alternans; sudden cardiac death; ventricular tachyarrhythmia
13.  Impact of Implantable Cardioverter-Defibrillator, Amiodarone, and Placebo on the Mode of Death in Stable Patients With Heart Failure 
Circulation  2009;120(22):2170-2176.
The Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT) demonstrated that implantable cardioverterdefibrillator (ICD) therapy reduces all-cause mortality in patients with New York Heart Association class II/III heart failure and a left ventricular ejection fraction ≤35% on optimal medical therapy. Whether ICD therapy reduced sudden death caused by ventricular tachyarrhythmias without affecting heart failure deaths in this population is unknown.
Methods and Results
SCD-HeFT randomized 2521 subjects to placebo, amiodarone, or shock-only, single-lead ICD therapy. Over a median follow-up of 45.5 months, a total of 666 deaths occurred, which were reviewed by an Events Committee and initially categorized as cardiac or noncardiac. Cardiac deaths were further adjudicated as resulting from sudden death presumed to be ventricular tachyarrhythmic, bradyarrhythmia, heart failure, or other cardiac causes. ICD therapy significantly reduced cardiac mortality compared with placebo (adjusted hazard ratio, 0.76; 95% confidence interval, 0.60 to 0.95) and tachyarrhythmia mortality (adjusted hazard ratio, 0.40; 95% confidence interval, 0.27 to 0.59) and had no impact on mortality resulting from heart failure or noncardiac causes. The cardiac and tachyarrhythmia mortality reductions were evident in subjects with New York Heart Association class II but not in subjects with class III heart failure. The reduction in tachyarrhythmia mortality with ICD therapy was similar in subjects with ischemic and nonischemic disease. Compared with placebo, amiodarone had no significant effect on any mode of death.
ICD therapy reduced cardiac mortality and sudden death presumed to be ventricular tachyarrhythmic in SCD-HeFT and had no effect on heart failure mortality. Amiodarone had no effect on all-cause mortality or its cause-specific components, except an increase in non-cardiac mortality in class III patients.
PMCID: PMC2922511  PMID: 19917887
cardiomyopathy; death, sudden; heart failure; mortality; tachyarrhythmias
14.  Maximizing Survival Benefit With Primary Prevention ICD Therapy in a Heart Failure Population 
Circulation  2009;120(10):835-842.
Although implantable cardioverter defibrillator (ICD) therapy reduces mortality in moderately symptomatic heart failure patients with an ejection fraction ≤35%, many such patients do not require ICD shocks over long-term follow-up.
Using a modification of a previously validated risk prediction model based on routine clinical variables, we examined the relationship between baseline predicted mortality risk and the relative and absolute survival benefits of ICD treatment in the primary prevention Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT).
In the placebo arm, predicted 4-year mortality grouped into 5 equal-sized risk groups varied from 12% to 50% (c statistic=0.71), while the proportion of SCD in those same risk groups decreased from 52% to 24% of all deaths. ICD treatment decreased relative risk of SCD by 88% in the lowest risk group vs. 24% in the highest risk group (p =0.009 for the interaction), and relative risk of total mortality by 54% in the lowest risk group vs. no benefit (2%) in the highest risk group (p =0.014 for the interaction). Absolute 4-year mortality reductions were 6.6%, 8.8%, 10.6%, 14.0% and −4.9% across risk quintiles. In highest risk patients (predicted annual mortality >20%), no benefit of ICD treatment was seen. Projected over each patient’s predicted life span, ICD treatment added 6.3, 4.1, 3.0, 1.9, and 0.2 additional years of life in the lowest to highest risk groups, respectively.
A clinical risk-prediction model identified subsets of moderately symptomatic heart failure patients in SCD-HeFT in whom single lead ICD therapy was of no benefit and other subsets in which benefit was substantial.
PMCID: PMC3774781  PMID: 19704100
Arrhythmias; clinical electrophysiology; drugs; Congestive Heart Failure; Ablation/ICD/surgery; Health policy and outcome research
15.  Prolonged QRS Duration on the Resting ECG is Associated with Sudden Death Risk in Coronary Disease, Independent of Prolonged Ventricular Repolarization 
Abnormalities of ventricular repolarization as well as depolarization have been associated with increased risk of ventricular arrhythmias.
We evaluated the relative contribution of these predictors to risk of sudden cardiac death (SCD) among patients with coronary artery disease (CAD).
In the ongoing Oregon Sudden Unexpected Death Study (Oregon SUDS), adult residents of Portland, OR metropolitan area (population ~1 million) who suffered SCD were identified prospectively (2002-2007). Of these, we analyzed the subgroup of SCDs that had a resting 12-lead ECG prior to SCD and also had associated CAD. Comparisons were conducted with a control group of subjects with known CAD, but no history of SCD from the same geographic region. Corrected QT interval (QTc), JT interval (JTc), QRS duration (QRSd) and other parameters were measured from ECG prior and unrelated to SCD. Analysis of LV function was limited to those subjects that had echocardiography performed prior to and remote from SCD.
A total of 642 SCD cases (71±13 yrs, 62% male) were compared to 450 controls (66±12 yrs, 64% male). SCD cases had significantly longer QRSd (102±25 vs. 97±20 ms, p=0.0008) as well as JTc (348±44 vs. 339±34 ms, p=0.0006) vs. controls. In cases with prolonged QRSd, 38% had severe LV systolic dysfunction (LVSD) and 62% had normal, mild or moderately decreased LV systolic function. In a multivariable model, QRSd, JTc, age and severe LVSD were independent predictors. There was minimal overlap between prolonged QRSd and JTc in both case and control groups (3% and 4%, respectively).
Prolonged QRSd, JTc and severe LVSD had independent contributions to risk of SCD in coronary disease, in this community-based setting.
PMCID: PMC3183321  PMID: 21699869
Epidemiology; risk; stratification; predictor; population; sudden cardiac death; electrocardiogram; ventricular fibrillation; prevention
16.  Prospective Observational Study of Implantable Cardioverter‐Defibrillators in Primary Prevention of Sudden Cardiac Death: Study Design and Cohort Description 
Primary‐prevention implantable cardioverter‐defibrillators (ICDs) reduce total mortality in patients with severe left ventricular systolic function. However, only a minority of patients benefit from these devices. We designed the Prospective Observational Study of Implantable Cardioverter‐Defibrillators (PROSE‐ICD) to identify risk factors and enhance our understanding of the biological mechanisms that predispose to arrhythmic death in patients undergoing ICD implantation for primary prevention of sudden death.
Methods and Results
This is a multicenter prospective cohort study with a target enrollment of 1200 patients. The primary end point is ICD shocks for adjudicated ventricular tachyarrhythmias. The secondary end point is total mortality. All patients undergo a comprehensive evaluation including history and physical examination, signal‐averaged electrocardiograms, and blood sampling for genomic, proteomic, and metabolomic analyses. Patients are evaluated every 6 months and after every known ICD shock for additional electrocardiographic and blood sampling. As of December 2011, a total of 1177 patients have been enrolled with more nonwhite and female patients compared to previous randomized trials. A total of 143 patients have reached the primary end point, whereas a total of 260 patients died over an average follow‐up of 59 months. The PROSE‐ICD study represents a real‐world cohort of individuals with systolic heart failure receiving primary‐prevention ICDs.
Extensive electrophysiological and structural phenotyping as well as the availability of serial DNA and serum samples will be important resources for evaluating novel metrics for risk stratification and identifying patients at risk for arrhythmic sudden death.
Clinical Trial Registration
URL: Unique Identifier: NCT00733590.
PMCID: PMC3603235  PMID: 23525420
cardiomyopathy; implantable cardioverter‐defibrillator; sudden death; ventricular tachyarrhythmias
17.  Ventricular arrhythmias in congestive heart failure: clinical significance and management. 
Texas Heart Institute Journal  1999;26(1):42-59.
The benefit of defibrillator therapy has been well established for patients with LV dysfunction (ejection fraction less than 35%), coronary artery disease, NSVT, and inducible and nonsuppressible ventricular tachycardia. Implantable cardioverter-defibrillator therapy is also indicated for all CHF patients in NYHA functional classes I, II, and III who present with aborted sudden cardiac death, or ventricular fibrillation, or hemodynamically unstable ventricular tachycardia--and also in patients with syncope with no documented ventricular tachycardia but with inducible ventricular tachycardia at electrophysiology study. The ongoing MADIT II trial was designed to evaluate the benefit of prophylactic ICD implantation in these patients (ejection fraction less than 30%, coronary artery disease, and NSVT) without prior risk stratification by PES. The CABG Patch trial concluded that prophylactic placement of an ICD during coronary artery bypass grafting in patients with low ejection fraction and abnormal SAECG is not justifiable. Except for the indications described above, ICD implantation has not been proved to be beneficial as primary or secondary therapy. Until more data are available, patients should be encouraged to enroll in the ongoing clinical trials.
PMCID: PMC325598  PMID: 10217470
18.  Genetic Polymorphisms as Risk Stratification Tool in Primary Preventive ICD Therapy 
ISRN Cardiology  2011;2011:457247.
More and more implantable cardioverter-defibrillators (ICDs) are implanted as primary prevention of sudden cardiac death (SCD). However, major problem in practice is to identify high-risk patients for SCD. Different methods for noninvasive risk stratification do not have a sufficient positive or negative predictive value. Since current approaches lead to implantation of ICDs in a large number of patients who will never suffer an arrhythmic event and simultaneously patients still die of SCD who currently did not seem eligible for primary preventive ICD implantation, there is a need for additional tools for risk stratification. Epidemiological studies point to a hereditary risk of SCD. Different susceptibility of each person concerning arrhythmogenic events might be explained by genetic polymorphisms. By obtaining an individual “pattern” of polymorphisms of genes encoding for proteins which are important in arrhythmogenesis in one patient, risk stratification in primary prevention of SCD might by improved.
PMCID: PMC3262511  PMID: 22347643
19.  Primary Prevention of Fatal Ventricular Arrhythmias With Implantable Cardioverter-Defibrillator Therapy – An Analysis of Implications Based on MADIT II Criteria 
The primary aim of this retrospective study was to determine the proportion of patients with myocardial infarction (MI) who fulfil the criteria of the Multicenter Automatic Defibrillator Implantation Trial (MADIT) II and the implications of MADIT II criteria in practice.
We performed a retrospective analysis of three hundred and ninety four admissions to the Coronary Care Unit (CCU) of the Royal Infirmary of Edinburgh. We selected those with myocardial infarction (MI) and attempted to retrieve electronic copies of their echocardiogram reports. When available, these were used to assess requirement for primary-prevention Implantable Cardioverter Defibrillator (ICD) therapy based on reported left ventricular function.
One hundred and ninety patients were admitted to the CCU with a diagnosis of MI. Of these, 100 patients (51.5%) had an echocardiogram. Requirement for ICD therapy was unlikely in 87 (87%), probable in 6 (6%) and necessary in 7 (7%). Since a significant number of patients in the probable category were also likely to meet MADIT II criteria, we concluded that the proportion of patients requiring primary-prevention ICD therapy would be no less than 7% and more likely to be 13%.
In the context of a busy teaching hospital, a figure of 13% for the requirement of ICD therapy in MI patients represents annual implantation activity of at least 100 per million. This is likely to have very significant resource implications.
PMCID: PMC2687889  PMID: 19529803
20.  The prediction of ICD therapy in multicenter automatic defibrillator implantation trial (MADIT) II like patients: a retrospective analysis 
MADIT II like patients have not been compared to patients without an electrophysiological study, patients in whom ventricular tachycardia or fibrillation were induced in an electrophysiological study (EPS) and patients without an inducibility in EPS in one study.
The multicenter automatic defibrillator implantation trial (MADIT) II showed a benefit of ICD implantation in patients with ischemic heart disease.
We performed a retrospective analysis in 93 patients with an ischemic heart disease and an ejection fraction ≤30% who had an ICD implanted with a follow-up at least an 18 months. Patients were divided into 3 groups according to the primary indication for ICD implantation: without EPS (group I), patients in whom ventricular tachycardia or fibrillation were inducible in EPS (group II) or patients without an inducibility in EPS (group III).
During the mean follow-up of 32.9 ± 16.1 months 289 appropriate ICD therapies and 10 deaths occurred. The incidence of appropriate ICD therapies did not differ significantly between the groups (group I 40%, group II 54% and group III 48% of patients). We found in group II a higher risk of appropriate ICD therapies with occurrence of a specific constellation of EPS values. These patients showed a 15-fold risk (P = 0.005) of an appropriate ICD therapy. Furthermore a brain natriuretic peptide value of 265 pg/ml also predicted an appropriate ICD therapy with a 3.5-fold risk (P = 0.017).
In the present retrospective study the results of MADIT II were affirmed in the case of incidence of ventricular arrhythmias in patients with an EF < 30% and coronary heart disease. The prediction of an appropriate ICD therapy with EPS was only achieved in patients with inducibility in the EPS.
PMCID: PMC2267892  PMID: 18379653
MADIT II; electrophysiologic study; appropriate ICD therapy
21.  Predictors of appropriate therapy in patients with implantable cardioverter-defibrillator for primary prevention of sudden cardiac death 
Heart International  2010;5(1):e4.
The purpose of this study was to evaluate predictors of appropriate therapy in patients with implantable cardioverter-defibrillators (ICD) for primary prevention of sudden cardiac death. A retrospective cohort of 321 patients with systolic heart failure undergoing ICD placement for primary prevention of sudden cardiac death was queried with a mean follow-up period of 2.6 years. Appropriate ICD therapy was defined as therapy delivered for termination of a ventricular tachyarrhythmia. Appropriate ICD therapy was delivered in 142 (44%) of the patients. In a multivariate model, body mass index ≥28.8 kg/m2, chronic kidney disease, left ventricular ejection fraction ≤20% and metabolic syndrome were found to be independent predictors of appropriate ICD therapy. Appropriate ICD therapy was associated with higher cardiovascular mortality. These findings show the importance of identification of risk factors, especially metabolic syndrome, in patients following ICD implantation as aggressive treatment of these co-morbidities may decrease appropriate ICD therapy and cardiovascular mortality.
PMCID: PMC3184703  PMID: 21977289
metabolic syndrome; ICD therapy; chronic kidney disease; systolic heart failure.
22.  QRS duration: a simple marker for predicting cardiac mortality in ICD patients with heart failure 
Heart  2003;89(10):1157-1162.
Background: Patients resuscitated from ventricular tachyarrhythmias benefit from implantable cardioverter-defibrillators (ICDs) as opposed to medical treatment. Patients with increased QRS duration receiving an ICD in the presence of heart failure are at greatest risk of cardiac death and benefit most from ICD therapy.
Objective: To determine whether an increased QRS duration predicts cardiac mortality in ICD recipients.
Design: Consecutive patients with heart failure in New York Heart Association functional class III were grouped according to QRS duration (< 150 ms, n = 139, group 1; v ⩾ 150 ms, n = 26, group 2) and followed up for (mean (SD)) 23 (20) months.
Patients: 165 patients were studied (80% men, 20% women); 73% had coronary artery disease and 18% had dilated cardiomyopathy. Their mean age was 62 (10) years and mean ejection fraction (EF) was 33 (14)%. They presented either with ventricular tachycardia (VT) or ventricular fibrillation (VF).
Main outcome measures: Overall and cardiac mortality; recurrence rates of VT, fast VT, or VF.
Results: Mean left ventricular EF did not differ between group 1 (33 (13)%) and group 2 (31 (15)%). Forty patients died (34 cardiac deaths). There was no difference in survival between patients with EF > 35% and ⩽ 35%. Cardiac mortality was significantly higher in group 2 than in group 1 (31.3% at 12 months and 46.6% at 24 months, v 9.5% at 12 months and 18.2% at 24 months, respectively; p = 0.04). The recurrence rate of VT was similar in both groups.
Conclusions: Within subgroups at highest risk of cardiac death, QRS duration—a simple non-invasive index—predicts outcome in ICD recipients in the presence of heart failure.
PMCID: PMC1767911  PMID: 12975406
heart failure; arrhythmia; implantable cardioverter-defibrillator; risk factors
23.  The Need for Studies to Evaluate the Reproducibility of the T-Wave Alternans (TWA), and the Rationale for a Correction Index of the TWA 
Sudden cardiac death (SCD) due to various cardiomyopathies is currently prevented by the implantation of an automated cardioverter/defibrillator (ICD). ICD impalntation in patients who are not survivors of SCD, or have not suffered potentially lethal ventricular arrhythmias, are based on the presence of cardiomyopathy with a reduced left ventricular ejection fraction. The bulk of patients who are considered suitable for an ICD implantation and receive such devices, do not experience device therapy shocks at follow-up ("false positives"), thus creating a climate of uncertainty among patients and physicians about the soundness of our current eligibility criteria for ICDs. In addition the cost of inappropriate ICDs is staggering, and the undue exposure of "false positive" patients to complications, and hardships is disconcerting. T-wave alternans (TWA) has emerged as a possible "risk detection of SCD" technology, but its reproducibility has not been tested. Peripheral edema (extracardiac) or other cardiac mechanisms, unrelated to the degree of SCD risk, alter the amplitude, and other attributes, of the T-waves. Since TWA may be T-wave amplitude-, or other T-wave attributes-dependent (this is still a speculation), a need may be emerging for its correction by the T-wave amplitude (TWA index); such an index may enhance the reproducibility, and evaluate the true sensitivity, specificity and predictive accuracy of the TWA in detecting future victims of SCD.
PMCID: PMC1939870  PMID: 17684576
T-wave alternans; correction index
24.  Chronic Kidney Disease and Mortality in Implantable Cardioverter-Defibrillator Recipients 
Incidence of sudden cardiac death (SCD) in end-stage renal disease (ESRD) remains high. Limited data is available about whether implantable cardioverter-defibrillators (ICDs) can prevent arrhythmic death in patients with chronic kidney disease (CKD). The purpose of this retrospective study was to determine the impact of CKD on all-cause and sudden cardiac death in ICD recipients. We evaluated 441 consecutive patients who underwent ICD implantation at our center between 1994 and 2002. We found that mortality rate was higher in patients with eGFR <60 mL/min and those with ESRD on hemodialysis (43%, n = 69/162 and 54%, n = 12/22, resp.) than in patients with eGFR ≥60 mL/min (23%, n = 58/257; P < .0005). The SCD rate was also higher in the patients with ESRD (50%) than in CKD patients not on dialysis (10.2%; P < .0005). Mortality rate for single-chamber ICDs was 56.8% in comparison with dual-chamber ICDs (38.1%) and for biventricular ICDs (5.0%) (P < .0005).
PMCID: PMC2929581  PMID: 20811610
25.  First experience with the wearable cardioverter defibrillator in the Netherlands 
Netherlands Heart Journal  2011;20(2):77-81.
The implantable cardioverter defibrillator (ICD) has significantly improved survival in patients with an increased risk of sudden cardiac death (SCD). The wearable cardioverter defibrillator (WCD) is an alternative to the ICD in patients with a transient ICD indication or those in whom an ICD temporarily cannot be implanted. We describe here the technical details of the WCD and report three patients who were treated with a WCD in an outpatient setting. The WCD allowed the cardiac condition of two patients to improve to such an extent that permanent ICD implantation was deemed unnecessary. This new form of therapy may result in significant cost reduction, avoidance of unnecessary ICD implantation, and increased patient satisfaction.
PMCID: PMC3265699  PMID: 22144231
Wearable cardiac defibrillator

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