Michel Mirowski and colleagues ABSTRACT CARDIOLOGY. ICD Update: New Evidence and Emerging Clinical Roles in Primary Prevention of Sudden Cardiac Death

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1 ICD Update: New Evidence and Emerging Clinical Roles in Primary Prevention of Sudden Cardiac Death Ronald D. Berger, MD, PhD, FACC ABSTRACT PURPOSE: To review recent major randomized trials of implantable cardioverter-defibrillators (ICDs) and discuss the impact of their results on evolving ICD indications. EPIDEMIOLOGY: Sudden cardiac deaths (SCDs) occur about 6 to 9 more frequently in patients with heart failure (HF) than in patients without HF, and about new HF cases are diagnosed every year. REVIEW SUMMARY: Efficacy of ICDs in patients who have already had life-threatening ventricular arrhythmias is well established. More recent evidence that shows ICD efficacy in primary prevention (ie, patients at high risk of first cardiac arrests, such as patients with prior myocardial infarction [MI] and low left ventricular ejection fraction [LVEF]) has suddenly expanded the potential clinical role of these expensive devices. Most significantly, the Multicenter Automatic Defibrillator Implantation Trial (MADIT)-II showed a 31% reduction in mortality with ICDs in patients with prior MI, LVEF of 30%, and New York Heart Association (NYHA) Class I-III disease; the Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT) demonstrated a 23% reduction in mortality with ICDs in patients with ischemic or nonischemic cardiomyopathy, LVEF of 35%, and NYHA Class II or III disease; and the Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure (COMPAN- ION) trial showed a 36% reduction in mortality with a device that combined ICD functions with resynchronization in patients with intraventricular conduction delays. TYPE OF AVAILABLE EVIDENCE: Unstructured review of randomized-controlled trials. GRADE OF AVAILABLE EVIDENCE: Good. CONCLUSION: ICDs reduce mortality in patients with cardiomyopathy, NYHA Class II-III disease, and LVEF of 35% (or Class I with LVEF of 30%). ICDs with resynchronization functionality reduce mortality in patients with LVEF of 35%, NYHA Class III-IV disease, and ventricular dyssynchrony. Although ICDs are cost effective relative to other common cardiovascular treatments, the societal costs associated with more widespread use of ICDs warrant development of evidence-based patient risk-stratification methods. (Adv Stud Med. 2005;5(9): ) Michel Mirowski and colleagues published the first report of cardiac defibrillator placement in humans 25 years ago. 1 Since that seminal account, the implantable cardioverter-defibrillator (ICD) has undergone a series of major advances in design and function. Most notably, in the past decade there has been a dramatic reduction in device size despite added functionality. Now the size of pacemakers (ie, about the size of a small stopwatch), ICDs no longer require abdominal implantation with general anesthesia and thoracotomy. Instead, the devices can be easily placed under the pectoral skin and now employ much-improved transvenous leads (Figure 1). 2 These modern ICDs last longer, store event electrograms for later interrogation, and include enhancements such as an electrically active device cans, biphasic shock waveform, atrial tachycardia Dr Berger is Professor of Medicine and Professor of Biomedical Engineering, Johns Hopkins University School of Medicine; and Co-Director of Cardiac Electrophysiology, Johns Hopkins Hospital, Baltimore, Maryland. Conflict of Interest: Dr Berger reports that he is a consultant for Guidant Corporation. Off-Label Product Discussion: The author does not include discussion of off-label/unapproved use of products. Correspondence to: Ronald D. Berger, MD, PhD, FACC, Johns Hopkins Hospital, Carnegie 592, Baltimore, MD rberger@jhmi.edu. 468 Vol. 5, No. 9 October 2005

2 IMPLANTABLE CARDIOVERTER-DEFIBRILLATORS Figure 1. The Implantable Cardioverter- Defibrillator* Shock coil Shock coil Pacing electrodes Pulse generator Battery Casing (cut away) Typical single-chamber implantable cardioverter-defibrillator: a pulse generator with battery, integrated circuits, memory, and telemetry is placed in pectoral region; the single lead with shock coil and pacing electrode is sent transvenously to the right ventricle; additional leads for right atrial or left ventricular pacing can be added. *Reprinted with permission from DiMarco. 2 therapies, enhanced discrimination between ventricular tachycardia (VT) and supraventricular tachycardia, dualchamber atrial-ventricular pacing, biventricular pacing capability, and advanced bradycardia pacing algorithms. The recent furious pace of ICD technical innovation has been driven by need. With trials such as the Cardiac Arrhythmia Suppression Trials (CAST and CAST-II) showing that antiarrhythmic drugs actually caused excess deaths in patients at risk of life-threatening arrhythmias after myocardial infarction (MI), 3,4 the search for device-based solutions to sudden cardiac death (SCD) has intensified. In CAST, for example, those on encainide or flecainide had about 3 times the mortality risk of those on placebo. 3 More recent disappointments with newer agents such as amiodarone are noted in this article. With the aging of the American population and cardiologists increasing success in saving the lives but not necessarily the healthy myocardia of more patients, the need for new strategies in heart failure (HF) and SCD has been growing. Today, new cases of HF are diagnosed every year in the United States and these patients die of SCD at 6 to 9 times the rate of the general population. 5 The direct medical costs of managing HF in the United States most of these costs attributable to hospitalization are already estimated at $25.3 billion. 5 Consequently, the lack of effective antiarrhythmic drugs combined with a continuing demographic age wave has increased the clinical and economic demand for safer and more effective therapies. This article will review the past decade s major primary prevention trials with ICDs and describe current strategies for patient selection. Secondary prevention also is an indication for the use of ICDs, but is beyond the scope of this article. PRIMARY PREVENTION TRIALS WITH IMPLANTABLE CARDIOVERTER-DEFIBRILLATORS In the context of the ICD studies described here, primary prevention refers to prevention of death from first cardiac arrest rather than, as in many well-known statin or antihypertensive trials, prevention of first MI. Secondary prevention trials are designed to see whether ICDs prevent a sudden death from a second arrest or life-threatening arrhythmia. All the major studies discussed here are multicenter, randomized, parallel-group studies. In evaluating these classic studies, the reader should pay particular attention to enrolled patient populations (ie, who was included and excluded) and the risk stratifiers (ie, which subgroups had the best or worst outcomes), since these are the study outcomes that have influenced guideline and reimbursement strategies over the past decade. MADIT The Multicenter Automatic Defibrillator Implantation Trial (MADIT) was the first study to demonstrate a survival benefit of ICDs in high-risk patients. 6 This 5- year study enrolled patients with previous MI (>3 weeks prior); left ventricular ejection fraction (LVEF) of 35%, New York Heart Association (NYHA) Class I-III disease, and nonsustained ventricular tachycardia (NSVT), which was considered an important marker of risk for future VT or cardiac arrest. Patients (mean age, 63 years; Figure 2. Multicenter Automatic Defibrillator Implantation Trial (MADIT) Survival Data* Probability of Survival P =.009 Defibrillator Conventional therapy Year 54% reduction in implantable cardioverter-defibrillator group. *Reprinted with permission from Moss AJ, et al. 6 Johns Hopkins Advanced Studies in Medicine 469

3 mean LVEF, 26%) were randomized to ICD or no ICD with conventional therapy, which at that time consisted mainly of β-blockers and amiodarone. After a mean follow-up period of 27 months, there was a significant 54% reduction in mortality in the ICD group (P =.009) (Figure 2). Fifteen of the 95 patients with ICDs died (16%) vs 39 of 101 patients without ICDs (39%). MUSTT The Multicenter Unsustained Tachycardia Trial (MUSTT) did not specifically test ICDs for primary prevention of SCD, but it revealed that antiarrhythmic therapy significantly reduced arrhythmic death or cardiac arrest only with ICD backup. 7 The trial was designed to test the value of electrophysiologically-guided (EP-guided) antiarrhythmic therapy against no therapy in high-risk patients with coronary artery disease. The major inclusion criteria were LVEF of 40% and asymptomatic NSVT. Of 2002 patients enrolled, 704 with inducible, sustained ventricular tachy-arrhythmias were randomly assigned to serial testing of antiarrhythmic drugs, guided by the results of electrophysiological (EP) testing, or to no antiarrhythmic therapy. Implantation of a defibrillator could be recommended after at least 1 unsuccessful drug trial. After 5 years of follow-up, the incidence of cardiac arrest or death from arrhythmia, the primary endpoint, was significantly higher among patients who received no antiarrhythmic therapy than among those assigned to EP-guided therapy (40% vs 34%, P =.05). The investigators attributed the difference solely to the use of ICDs. Among patients assigned to EP-guided therapy, the 5-year cardiac mortality rate was 9%, compared with 37% for those who did not receive a defibrillator (P <.001). Figure 3. Multicenter Automatic Defibrillator Implantation Trial (MADIT)-II Survival Data* Probability of Survival Conventional Defibrillator P = Year 31% reduction in mortality with implantable cardioverter-defribrillator. *Reprinted with permission from Moss AJ, et al. 8 MADIT-II Based on MADIT, post-mi patients with a relatively low LVEF ( 30%) but no other risk markers (eg, no NSVT, no inducible VT) were randomized in a 3:2 ratio to ICD or no ICD with conventional therapy, which by this time had expanded to include angiotensin-converting enzyme (ACE) inhibitors and statins. 8 Basically, these were patients who had had an MI at least 1 month earlier (mean time from last MI, 81 months) and who had left ventricular damage (mean LVEF, 23%), but who lacked the standard EP-laboratory-based red flags for VT risk. The 1232 enrolled patients were a mean age of 65 years. Whereas about half had undergone a previous coronary artery bypass graft (CABG) procedure or percutaneous transluminal coronary angioplasty (PTCA), per entry criteria, none had been revascularized within the previous 3 months. In this lower-risk MADIT-II group, the relative reduction in mortality owing to ICD was still significant at 31% (P =.016) (Figure 3). The overall mortality rates at a mean follow-up of 20 months were 14.2% in the defibrillator group and 19.8% in the conventional therapy group. Survival results were similar in all MADIT-II subgroups stratified by age, sex, LVEF, NYHA Class, and QRS interval. Despite the statistical nonsignificance of the QRS width in predicting outcomes, the trend toward better ICD outcomes in those with longer intervals prompted the Centers for Medicare and Medicaid Services (CMS) to use the QRS interval as a criterion for defibrillator reimbursement. As discussed below, such criteria have since evolved, and the search for improved markers of VT risk and ICD benefit has expanded to consider noninvasive serum, genomic, and proteomic markers, as well as a range of improved EP markers such as QT interval variability, inducibility at the time of ICD implantation, heart rate variability, and T-wave alternans. While these potential risk stratifiers are worthy of continued study, LVEF remains the only risk stratifier with which survival benefit from ICDs has been proven. One additional and perhaps counterintuitive piece of evidence emerging from MADIT-II involved the impact of length of time since MI as a factor in survival and defibrillator benefit. Clinicians may be tempted to think that a patient is out of the danger zone 5 or 10 years after an MI and therefore less in need of an ICD. In fact, MADIT-II data suggest just the opposite. In a subsequent retrospective analysis of those data, patients with remote MIs derived the greatest benefit (Figure 4). 9 The hazard ratio (HR) for risk of death with ICD vs no ICD was only 0.97 (95% confidence interval [CI], ; P =.92) for recent MIs, whereas it was 0.55 (95% CI, ; P =.001) for MIs occurring more than 18 months in the past. This analysis should be interpreted 470 Vol. 5, No. 9 October 2005

4 IMPLANTABLE CARDIOVERTER-DEFIBRILLATORS with caution because of its retrospective nature. Nonetheless, these data suggest that post-mi deaths attributable to HF tend to occur early and that with each passing year, the relative risk of SCD in survivors increases, which explains the progressively greater benefit over time with ICD. DINAMIT The ideal timing of defibrillator implantation was also explored in the Defibrillator in Acute Myocardial Infarction Trial (DINAMIT). 10 In this study, 647 patients were randomized to ICD or no ICD early after their infarction (6-40 days post-mi). All patients had LVEFs of 35% or less plus other risk indicators, including a high resting average 24-hour heart rate (>80 bpm) or a depressed heart rate variability (ie, standard deviation in normal regular rate [interbeat] intervals [SDNN] of <70 msec). In this group, the mean age was 62 years and the mean LVEF was 28%. In DINAMIT, patients with a recent MI had no survival benefit from prompt ICD placement (Figure 5). This supports the retrospective analysis of MADIT- II, 9 which showed that defibrillators have the most profound benefit in the years not the months following an MI. It is conceivable, however, that the entry criteria for the DINAMIT study selected for a patient population that responded differently than the population in the MADIT-II study. DEFINITE Although most LV dysfunction and related VT is caused by obstructive coronary artery disease, nonischemic dilated cardiomyopathy can also lead to SCD. The value of ICDs in preventing SCD in such patients was explored in the Defibrillators in Non-Ischemic Cardiomyopathy Treatment Evaluation (DEFINITE) study, 11 which enrolled 458 patients with NYHA Class I- III nonischemic cardiomyopathy and LVEF of 35%. Patients had a mean LVEF of 21% and were followed for a mean of 29 months after 1:1 randomization to ICD or no ICD. Standard medical therapy in both groups included β-blockers, ACE inhibitors, and loop diuretics. The ICD led to a 35% reduction in mortality, with 28 deaths in the ICD group and 40 in the standardtherapy group (HR, 0.65; 95% CI, ; P =.08). This overall mortality benefit was not statistically significant, probably because of the small patient population size; however, there were only 3 sudden deaths in the ICD group vs 14 in the non-icd group (HR, 0.20; 95% CI, ; P =.006). Furthermore, one post-hoc subgroup analysis showed that the mortality benefit was largely confined to the Class III patients. SCD-HEFT The Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT) investigators included patients with nonischemic or ischemic cardiomyopathy in a 3-way comparison of ICDs, amiodarone, and placebo in patients with mild to moderate HF. 12 This large population (N = 2521) with mean age of 60 years, LVEF of 35% (mean 25%), and NYHA Class II or III disease was followed for a mean of 45 months after randomization. In SCD-HeFT, there was no difference between amiodarone and placebo in mortality (HR, 1.06; Figure 4. Multicenter Automatic Defibrillator Implantation Trial (MADIT)-II: Effect of Time from Myocardial Infarction on Implantable Cardioverter-Defibrillator Efficacy* Q1 Q2 Q3 Q4 < 18 mo mo mo 120 mo Time From MI Conv (n) ICD (n) Conv ICD ICD = implantable cardioverter-defibrillator; MI = myocardial infarction. *Reprinted with permission from Wilber DJ, et al. 9 Figure 5. Defibrillator in Acute Myocardial Infarction Trial (DINAMIT) Risk Data* Cumulative Risk of Death From Any Cause P =.66 ICD group Control group Months After Randomization No. at Risk ICD group Control group ICD = implantable cardioverter-defibrillator. *Reprinted with permission from Hohnloser SH, et al. 10 Johns Hopkins Advanced Studies in Medicine 471

5 Figure 6. Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT) Mortality Data* Mortality 0.4 HR 97.5% CI P-Value Amiodarone vs Placebo , ICD Therapy vs Placebo , Amiodarone ICD therapy Placebo Months of Follow-up HR = hazard ratio; CI = confidence interval; ICD = implantable cardioverter-defibrillator. 23% reduction in mortality in implantable cardioverter-defibrillator group. *Reprinted with permission from Bardy GH, et al. 12 Figure 7. COMPANION Study Survival Data* % Survival CRT vs OPT: RR = 24%, P =.060 (Critical boundary =.014) CRT-D vs OPT: RR = 36%, P =.003 (Critical boundary =.022) 12-month Event Rates OPT: 19% CRT: 15% (AR=4%) CRT-D: 12% (AR=7%) OPT (no device) CRT HR 0.76 (CI: ) CRT-D HR 0.64 (CI: ) Days From Randomization CRT = cardiac resynchronization therapy; RR = relative risk; HR = hazard ratio. *Reprinted with permission from Bristow MR, et al % CI, ; P =.53), but the defibrillator group had a 23% relative reduction in mortality compared with placebo (HR,.77; 97.5% CI, ; P =.007) and an absolute decrease in mortality of 7.2% after 5 years in the overall population (Figure 6). Results did not vary according to either ischemic or nonischemic causes of HF, but quite to the converse of the findings in the DEFINITE study, patients with Class II HF benefited from the ICD, whereas those with Class III HF did not. These disparate results indicate, if nothing else, the dangers of basing practice decisions on post-hoc study outcomes. Though posthoc and secondary outcomes may be of interest for hypothesis-generating purposes, the designated primary outcomes must remain the bellwether guide for evidence-driven ICD placement decisions. CARDIAC RESYNCHRONIZATION Many patients with HF have intraventricular conduction delays that exacerbate LV dysfunction and lead to related hemodynamic effects. To improve the coordination of ventricular contractions in these patients, special ICDs have been designed for cardiac resynchronization therapy (CRT). These CRT-Ds combine the defibrillation function with extra pacing leads in the atrium and ventricles to improve the synchrony of the heart. Pacemakers that lack the ICD function are now commonly referred to as CRT-Ps. COMPANION The Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure (COMPANION) study evaluated the ability of ICD/CRTs to improve survival. 13 Enrolled patients were randomized to an ICD/CRT, a resynchronization biventricular pacemaker alone, or no device in a 2:2:1 ratio. These patients were very sick, with NYHA Class III or IV disease, LVEF of 35%, and hospitalization for HF in the previous year; they also had enlarged heart with dyssynchrony as evidenced by a QRS duration of >120 msec and a PR interval of >150 msec. The average age in the COMPANION patient population was 67 years and the mean LVEF was 21%. Compared with optimal pharmacologic therapy alone, the CRT-P device decreased the risk of death from any cause by 24% (P =.059), and the CRT-D reduced the risk by 36% (P =.003) (Figure 7). The risk of death or hospitalization resulting from HF was reduced by 34% in the pacemaker-only (CRT-P) group (P <.002) and by 40% in the CRT-D group (P <.001). Accordingly, patients with advanced HF and prolonged QRS interval benefit from pacing with or without defibrillation, but they have significantly reduced mortality when the ICD is combined with CRT functionality. These results extended those of a previous 6-month trial that showed that CRT improves quality of life, LVEF, and exercise tolerance in high-risk HF patients. 14 PUTTING IT ALL TOGETHER: WHO BENEFITS FROM AN ICD? Based on the major studies just reviewed, the overall survival benefit of the ICD or the CRT-D is in the range of 20% to 50% (Figure 8). The same studies provide guidance on which patients are most appropriate for ICD placement. A defibrillator is generally indicated in patients with an LVEF of <35% and NYHA Class II or III HF (Figure 9), based on the SCD-HeFT trial results. 12 Based on MADIT-II, 8 Class I asymptomatic patients with ischemic disease and an LVEF of <30% may also benefit. 472 Vol. 5, No. 9 October 2005

6 IMPLANTABLE CARDIOVERTER-DEFIBRILLATORS The CRT-D is most appropriate for those patients who are Class III or IV with a marker of dyssynchrony, such as a wide QRS. 13,14 The most recently published practice guidelines 15 are from 2002 and do not reflect the findings of the SCD-HeFT and COMPANION trials, because they had not yet been reported at that time. These guidelines will likely be revised shortly. Until 2005, the standard CMS coverage policies on ICDs had remained fairly constant, including use in (1) documented ventricular fibrillation arrest not due to transient or reversible causes; (2) documented sustained VT, spontaneous or induced, not associated with acute MI and not due to transient or reversible causes; (3) familial or inherited conditions with high risk of life-threatening arrhythmias; and (4) prior MI, LVEF of 35%, and inducible or sustained VT or ventricular fibrillation at EP study. For primary prevention indications for ICDs, the CMS exclusion criteria have also remained fairly consistent in recent years and still include: Cardiogenic shock while in a stable baseline rhythm CABG or PTCA within past 3 months Enzyme-positive MI within past 40 days Symptoms of findings that indicate candidacy for coronary revascularization Coexisting disease with expected survival of <1 year In early 2005, however, the CMS reimbursement guidance in primary prevention evolved to reflect the new evidence just reviewed. Of particular importance, the CMS recently abandoned its requirement that MI patients with LVEF of 30% must also have a wide QRS in order to qualify for an ICD. In addition, based on SCD-HeFT, the CMS now covers ICDs in Class II or III HF patients with LVEF 35% whether the cause is ischemic or nonischemic. In nonischemic cardiomyopathy, patients must be at least 9 months from diagnosis to rule out reversible causes. Patients with Class IV HF who meet the other requirements for CRTs are also now eligible for an ICD, according to the CMS. Finally, to establish a larger database on ICDs, CMS now requires that all patients who receive an ICD for primary prevention must be enrolled in a new national registry. BUT, CAN WE AFFORD IT? As just reviewed, several well-designed clinical trials now indicate that ICDs provide benefits to patients who in previous years would not have received the device. With national expenditures on ICDs expected to reach more than $6 billion in 2005 (based on one manufacturer s estimate of ICD implants at $ each) and with more aging baby boomers moving into an age of higher risk for life-threatening arrhythmias, the question becomes: Can our society afford ICDs in these new primary prevention settings? One of the main measures of cost effectiveness is the cost per life-year saved (CLYS), which is calculated by taking the difference in cost between the treatment in question and the accepted standard of care (in this case, medical therapy) and dividing that number by the incremental years of life saved. Lower values are more cost effective, and procedures that cost less than $ for each additional year of life generally are considered cost effective. For example, in the early 1990s the CLYS for PTCA and CABG were calculated in specific populations at $ and $18 200, respectively, 16 whereas the CLYS for cardiac transplantation for HF and peritoneal dialysis Figure 8. Relative Reduction in Mortality With Implantable Cardioverter-Defibrillators % Mortality Reduction Figure 9. When Are Implantable Cardioverter- Defibrillators Indicated? Ischemic HD AVID MADIT MADIT-II DEFIN ITE SCD-HeFT COM PAN ION 2 Prevention IV I II EF 30% III 1 Prevention CRT Indicated QRS 130 ms EF 35% III ICD Indicated IV II Nonischemic HD HD = heart disease; CRT = cardiac resynchronization therapy; EF = ejection fraction; ICD = implantable cardioverter-defibrillator. I CRT-D AVID = Antiarrhythmics Versus Implantable Defibrillators; MADIT = Multicenter Automatic Defibrillator Implantation Trial; DEFINITE = Defibrillators in Non- Ischemic Cardiomyopathy Treatment Evaluation; SCD-HeFT = Sudden Cardiac Death in Heart Failure Trial; COMPANION = Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure. Johns Hopkins Advanced Studies in Medicine 473

7 were reported to be $ and $57 300, respectively. 16,17 Three of the ICD efficacy studies reviewed in this article also performed cost-effectiveness analyses. In MADIT, each year of life saved by an ICD was calculated to cost $ and in SCD-HeFT the CLYS was $ In the most recent cost analysis based on the generally lower-risk MADIT-II population (MI history, LVEF of <30%), the incremental cost effectiveness ratio was $ per life-year gained and the device was projected to increase a patient s life by an average of 1.8 years. 20 Thus, the ICD is at least as cost effective as other accepted therapies in this patient population. If, as estimated by the CMS, total US healthcare expenditures are $1.9 trillion in 2005, then the estimated $6 billion for ICD placement will represent 0.3% of national health spending. By comparison, the total national hospitalization costs for HF are estimated at $14.7 billion per year (2005) and the charges for PTCA are estimated at $18.8 billion per year (2002). 5 Whether or not such an allocation of finite resources for ICDs to prevent SCD is justifiable is a topic that must be debated in coming years. Because ICD therapy will always be more cost effective in higher-risk patients, 21 this economic debate will necessarily occur in parallel with development of methods and evidence related to patient risk stratification and selection. Eventually, noninvasive risk markers may also play a role in developing risk models for ICD use. Until such tools demonstrate value in large clinical trials, however, the patient history and LVEF remain the best guides to patient selection for ICD placement. CONCLUSION Several recent primary prevention studies have expanded the size of the patient population that stands to gain a survival benefit from defibrillator placement. In patients with ischemic cardiomyopathy, ICDs reduce mortality in patients with NYHA Class II or III disease and LVEF of 35%, or with Class I disease and LVEF of 30% (excluding MI within 1 month, or CABG/PTCA within 3 months). In nonischemic cardiomyopathy, ICDs reduce mortality in patients with NYHA Class II or III disease and LVEF of 35%. And in patients with NYHA Class III or IV disease, LVEF of 35%, and ventricular dyssynchrony whether the cause of the cardiomyopathy is ischemic or nonischemic CRT-Ds reduce mortality. REFERENCES 1. Mirowski M, Reid PR, Mower MM, et al. Termination of malignant ventricular arrhythmias with an implanted automatic defibrillator in human beings. N Engl J Med. 1980;303: DiMarco JP. Implantable cardioverter-defibrillators. N Engl J Med. 2003;349: The Cardiac Arrhythmia Suppression Trial (CAST) Investigators. Preliminary report: effect of encainide and flecainide on mortality in a randomized trial of arrhythmia suppression after myocardial infarction. 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An analysis of the cost-effectiveness of the implantable defibrillator. Circulation. 1990;81: Mushlin AI, Hall WJ, Zwanziger J, et al. The cost-effectiveness of automatic implantable cardiac defibrillators: results from MADIT. Multicenter Automatic Defibrillator Implantation Trial. Circulation. 1998;97: Mark DB. Late-breaking clinical trial session at the American Heart Association Scientific Sessions 2004, New Orleans, Louisiana. Available at: Accessed June 1, Al-Khatib SM, Anstrom KJ, Eisenstein EL, et al. Clinical and economic implications of the Multicenter Automatic Defibrillator Implantation Trial-II. Ann Intern Med. 2005;142: Lynd LD, O Brien BJ. Cost-effectiveness of the implantable cardioverter defibrillator: a review of current evidence. J Cardiovasc Electrophysiol. 2003;14(9, suppl):s99-s Vol. 5, No. 9 October 2005