Multicenter Automatic Defibrillator Implantation Trial Research Articles

Repolarization variability in the risk stratification of MADIT II patients

QT variability has been reported to be associated with ventricular arrhythmias and sudden cardiac death. There is limited data regarding variability in T-wave morphology and its prognostic value. In this study, we present a novel approach for the measurement of T-wave variability (TWV) reflecting changes in T-wave morphology, and we investigate the prognostic significance of Holter-derived TWV in patients with and without ventricular arrhythmias requiring appropriate implantable cardioverter defibrillator (ICD) therapy from the Multicenter Automatic Defibrillator Implantation Trial II (MADIT II). Methods Study population consisted of 275 ICD patients from MADIT II after excluding patients with intraventricular conduction abnormalities or atrial fibrillation. TWV was measured based on amplitude variance of T-wave amplitude. Results During 2-year follow-up, 58 (21%) patients had appropriate ICD therapy for ventricular tachycardia or fibrillation. Patients with appropriate ICD therapy had higher levels of TWV measures than those without arrhythmic events. After adjustment for heart rate, ejection fraction, and significant clinical predictors of arrhythmic events, a Cox proportional-hazards regression model revealed that dichotomized TWV values were predictive for ventricular tachyarrhythmias requiring appropriate ICD therapy (hazard ratio, 2.0; 95% CI; 1.2-3.5; P=0.01). On the basis of the comprehensive testing, TWV value >59 microV was found predictive for arrhythmic events in MADIT II population. Our newly designed method for the assessment of repolarization variability in ambulatory Holter recordings detected transient variability of T-wave morphology, which was predictive for ventricular tachyarrhythmias in the MADIT II population.

Sudden Death Prevention With Implantable Devices

The “modern” era of the treatment of ventricular tachyarrhythmias with device-based therapy may have begun in 1899, when Prevost and Battelli noted, almost as an afterthought, that direct current shock could terminate ventricular fibrillation (VF) in dogs.1 Three decades later, pioneering work in the field of defibrillation concluded that the passage of electrical current across the heart can both initiate and terminate VF.2,3 Still, little attention was paid to this phenomenon, as evidenced by Paul Dudley White’s Heart Disease , which devoted less than half a page to VF and characterized the arrhythmia as “a condition of little importance so far as we know now.”4 In 1947, the thoracic surgeon Claude Beck saved the first human life by the successful use of cardiac defibrillation in a 14-year-old boy who developed VF during a thoracic surgical procedure and went on to achieve a full recovery.5 These early accomplishments provided the foundation for the landmark work of Mirowski and Mower that ultimately led to the development of the implantable cardioverter-defibrillator (ICD) and its introduction in humans in 1980.6 Pacing may prevent sudden cardiac death due to bradyarrhythmias and in certain circumstances such as torsade de pointes associated with congenital long-QT syndrome (LQTS) and pause-dependent ventricular tachycardia (VT). Although no controlled studies exist, retrospective analyses suggest that recurrent torsade de pointes in patients with LQTS may be prevented by continuous pacing.7 Early clinical data on small numbers of patients suggested that the combination of β-adrenergic blockade plus continuous pacing reduced the number of syncopal events and the anticipated rate of sudden death in high-risk LQTS patients.8 The beneficial effects of pacing may be limited to patients with LQT2 and LQT3, in which the transmural dispersion of repolarization worsens steeply during bradycardia.9 Genotype-phenotype correlation confirms that …

Uncertainty on the Use of Aldosterone Antagonists for Primary Therapy for Sudden Cardiac Death in the Setting of Implanted Devices

In the early development of therapy for acute myocardial infarction, it was thought that once the necrotic process had been completed (usually within 24 hours of coronary artery occlusion), additional therapies could not affect outcome. However, after completion of the necrotic process, the myocardial infarction may thin and stretch (involving lengthwise slippage of myocytes), a phenomenon referred to as myocardial infarct expansion. This process causes local left ventricular cavity dilatation followed by gradual global left ventricular dilatation and lengthwise (eccentric) hypertrophy of the noninfarcted tissue. Apoptosis (programmed cell death) and some attempt of the myocardium to regenerate, especially at the infarct border zone, may also contribute to this remodeling process of the ventricle. If the left ventricle remodels in such a way that it becomes very dilated, then the prognosis is poor, and heart failure is more likely to occur.1 These later processes of myocardial infarct expansion and left ventricular remodeling became the target of therapies such as angiotensin-converting enzyme (ACE) inhibition that could be initiated after 24 hours of coronary occlusion. ACE inhibition, angiotensin receptor blockade, and long-term β-blockade have become standard pharmacological approaches for postinfarction left ventricular dysfunction and heart failure. Response by Pitt and Pitt p 2989 Ventricular arrhythmias can occur in both the acute and chronic phases of acute myocardial infarction and can lead to sudden cardiac death (SCD). Reentrant arrhythmias may arise at the border zone of infarcts, causing monomorphic ventricular tachycardia that may occur years after the index infarction. Recurrent myocardial ischemia resulting in an unstable substrate may contribute to polymorphic ventricular tachycardia or ventricular fibrillation. Agents such as β-blockers that are anti-ischemic may reduce sudden death by quieting this unstable substrate. In the Multicenter Automatic Defibrillator Implantation Trial (MADIT) II, implantable defibrillators were shown to reduce mortality in post–myocardial infarction patients with …

The Implantable Cardiac Defibrillator

implantable cardioverter-defibrillator (ICD) is one of the great engineering achievements of the twentieth century.1 This electronic device detects potentially lethal cardiac arrhythmia (ventricular fibrillation [VF] or ventricular tachycardia [VT]) and shocks or overdrives the heart to restore normal sinus rhythm. Smaller than the tiniest cell phone, the ICD system consists of a battery, leads to sense rhythm and to deliver the shock, a computer that analyzes cardiac waveforms and initiates a counter-pulsation algorithm, charging circuitry that converts battery power to the voltage and current needed to overcome the arrhythmia, and memory to document cardiac and device activity. Additional components of the system include an external programmer to interrogate the ICD memory and to tailor sensing and firing algorithms to optimize care for a particular patient. Initially approved by the Food and Drug Administration in 1985, the first-generation ICD was bulky, weighing more than 9 ounces. Implantation was a complex open-heart surgical procedure (thoracotomy) with the attendant risks of general anesthesia and surgical site infection. Rudimentary sensing algorithms resulted in occasional false firings, which some patients equated to being kicked by a mule. Battery life was at best 2-3 years and necessitated additional surgery to replace the pulse generator. While Medicare coverage soon became available, eligibility criteria were highly restrictive, framing the device as: ... a treatment of last resort for patients who have documented episodes of life-threatening tachyarrhythmia or cardiac arrest not associated with myocardial infarction. Patients must also be found by electrophysiologic testing to have an inducible tachyarrhythmia that proves unresponsive to medication or surgical therapy . . .2 Over the ensuing 20 years, the technology has steadily evolved.3 The device has shrunk to less than one-fifth the original size, the number of leads has been reduced, and sensing algorithms refined. Battery life has improved to the point where 5-10 years may elapse before pulse generator replacement is required. Most importantly, the smaller and more elegant design facilitated a much simpler implantation procedure that does not require opening the chest, and can be performed in an ambulatory surgery center under local anesthesia. Technological evolution combined with growing evidence for survival benefit has resulted in progressive relaxation of Medicare coverage criteria. From the beginning, controversy has surrounded the ICD because of debate over whether or not the technology is Determinants of ICD cost-effectiveness relative to standard care include the cost of the procedure, the survival benefit of the device, and the risk of cardiac arrhythmic death in the target patient population. Over time, the annualized cost of the ICD has decreased due to less invasive surgery and longer battery life. Lower costs make the device more cost-effective. Conversely, broadening of selection criteria has reduced the relative risk of patients receiving the therapy, which tends to reduce cost-effectiveness. The Multicenter Automatic Defibrillator Implantation Trial II (MADIT II) trial evaluated ICD benefit and cost relative to conventional pharmacologic therapy among myocardial infarction survivors with impaired cardiac pumping ability as evidenced by an

Inverse Relationship of Blood Pressure Levels to Sudden Cardiac Mortality and Benefit of the Implantable Cardioverter-Defibrillator in Patients With Ischemic Left Ventricular Dysfunction

This study was designed to evaluate the relationship among blood pressure (BP) levels, risk of sudden cardiac death (SCD), and benefit of the implantable cardioverter-defibrillator (ICD) in patients with ischemic left ventricular (LV) dysfunction. Low BP has been shown to be associated with increased mortality in patients with LV dysfunction and heart failure. We hypothesized that increasing BP levels are associated with a reduction in the risk of SCD in this population, thereby limiting ICD efficacy in a lower-risk subset. The independent contribution of systolic blood pressure (SBP) and diastolic blood pressure (DBP) to outcome was analyzed in 1,231 patients enrolled in the prospective MADIT-II (Multicenter Automatic Defibrillator Implantation Trial II). Multivariate analysis showed that in the conventional therapy arm of the trial, 10-mm Hg increments in systolic BP were independently associated with a respective 14% (p = 0.01) and 16% (p = 0.04) reduction in the risk of cardiac mortality and SCD; similar trends were shown for DBP. Defibrillator therapy provided the least survival benefit to patients in the lower-risk, upper SBP (>130 mm Hg) and DBP (>/=80 mm Hg) quartiles (hazard ratio 1.04 [p = 0.89] and 1.05 [p = 0.88], respectively), whereas a respective 39% and 38% (p = 0.002) reduction in the risk of death with ICD therapy was observed among patients with lower BP values. In patients with ischemic LV dysfunction, SBP and DBP levels show an inverse correlation with sudden cardiac mortality. These noninvasive hemodynamic parameters may be useful for identifying lower-risk patients, in whom the benefit of primary defibrillator implantation is more limited.

Decision to Implant a Cardioverter Defibrillator after Myocardial Infarction: The Role of Ejection Fraction v. Other Risk Factor Markers

The Multicenter Automatic Defibrillator Implantation Trial showed that in post-myocardial infarction patients with a left ventricular ejection fraction (EF) 0.30, an implantable cardioverter defibrillator (ICD) resulted in a 31% relative reduction in the risk of death when compared with a conventional therapy group. Whether further refinement in risk estimation could be achieved with additional clinical testing to qualify patients for primary prevention with ICDs remains problematic. The authors analyzed Cardiac Arrhythmia Suppression Trial registry data to estimate sensitivity and specificity of EF, ventricular premature frequency, and nonsustained ventricular tachycardia for predicting death. They combined the results with similar data from the literature and used summarizing receiver operating characteristic (meta-ROC) curves to estimate overall operational values for sensitivity and specificity for each clinical test. They estimated aggregate values for prior probability to project risks when tests were used singly and in combination. The authors used arrhythmia markers and heart rate variability to further stratify low-EF patients (prior risk = 20.3%); proportionately, 20.4% were predicted at high risk (>30%) and 40.5% at low risk (<10%). When heart rate variability is normal, those at high risk reduced proportionately to 9.2%, and those at low risk increased to 51.6%. The combined use of noninvasive markers for arrhythmia substrate and altered autonomic tone can improve risk stratification in low EF without optimal beta-block therapy, whereas for those with optimal beta-block therapy, markers for arrhythmia substrate alone work. Ancillary use of electrophysiologic stimulation can improve results.

Contemporary Pacemaker and Defibrillator Device Therapy

Intracardiac pacemaker and defibrillator implantations were initially described a half century and a quarter century ago, respectively.1,2 Originally conceived as devices for the treatment of symptomatic bradycardia and sustained ventricular tachyarrhythmias, these therapies have subsequently been applied to the management of an increasing host of arrhythmia and other indications, including the treatment of heart failure.3 Although underuse of this technology has occasionally been reported,4 it has become abundantly clear that the number of patients deriving benefit from device therapy has risen exponentially; cardiac electrophysiology and pacing has emerged as a subspecialty within cardiology to address the growing needs of cardiac rhythm management.5 It is, nonetheless, incumbent on the general cardiologist to become proficient in certain aspects of device therapy.6 The goals of the present review are to highlight some of the fundamental areas of knowledge essential for follow-up, to provide an update on newer applications of device therapy, and to address some of the more common challenges and clinical scenarios encountered by the general cardiologist. The implantable cardioverter-defibrillator (ICD) was originally applied to patients surviving life-threatening ventricular tachyarrhythmias—so-called secondary prevention. Subsequently, primary prevention trials identified other patients who were at increased risk for sudden cardiac death but who had yet to manifest such risk,7 thereby expanding the indications for ICD therapy. The most recent iteration of guidelines for device implantation has identified additional conditions in which pacemaker and/or ICD therapy are associated with an enhancement of quality of life and/or survival.3,8 In particular, new ICD indications for primary prevention include prophylactic implantation in patients with ischemic cardiomyopathy and ejection fraction (EF) less than or equal to 30% (MADIT-II [Multicenter Automatic Defibrillator Implantation Trial II] criteria),9 and in patients with Brugada syndrome.10 The potential importance of ICD therapy for patients with nonischemic …

Health-Related Quality of Life Consequences of Implantable Cardioverter Defibrillators

Implantable cardioverter defibrillators (ICDs) improve survival and extend lives of patients with severe heart disease. We sought to evaluate the impact of ICDs on health-related quality of life (HRQOL) during the first 3 years after implantation. A total of 1089 patients from the Multicenter Automatic Defibrillator Implantation Trial II (MADIT II) were randomized to an ICD or medical treatment only. Health Utility Index (HUI3) at baseline, 3, 12, 24, and 36 months following randomization; survival data. We constructed mean profiles of HRQOL for living patients, estimated overall quality-adjusted life years (QALYs), separately by treatment arm, and calculated cumulative QALY gains/losses as the difference between the areas under the treatment specific HRQOL profiles. Multivariate fixed effect regression models were developed to impute the missing HRQOL data using baseline patient characteristics (age, gender, treatment, HUI3 score, diabetes, diuretics use, and NYHA class). Bootstrapped standard errors were calculated for the estimated differences in HRQOL gains/losses between treatment arms. Similarly, we performed subgroup analyses (by gender, age, and baseline NYHA class, blood urine nitrogen, ejection fraction, and QRS). There were no differences in QALYs loss for living patients by treatment group (-0.037, P = 0.64) or in overall QALYs loss by treatment group (0.043, P = 0.37) over 3 years. In subgroup analysis, female subjects demonstrated a trend towards greater survival benefit (0.298, P = 0.07) and overall QALYs (0.261, P = 0.14). Adverse effects of the ICD on HRQOL together with lower HRQOL among survivors may offset the 3-year survival benefits of ICDs.

Time Dependence of Defibrillator Benefit After Coronary Revascularization in the Multicenter Automatic Defibrillator Implantation Trial (MADIT)-II

Time Dependence of Defibrillator Benefit After Coronary Revascularization in the Multicenter Automatic Defibrillator Implantation Trial (MADIT)-II

Response to Abraham

More than 4000 patients have been evaluated in randomized controlled trials of cardiac resynchronization therapy (CRT). These studies have demonstrated that CRT with or without an implantable cardioverter-defibrillator (ICD) consistently improves quality of life, functional status, exercise capacity, and cardiac structure and function and reduces morbidity and mortality in heart failure patients with ventricular dyssynchrony. The magnitude of benefit seen with CRT is comparable to or exceeds that seen with evidence-based drug therapies for heart failure but occurs in patients who are already receiving such medications. Thus, CRT has been added to the list of evidence-based therapies that make heart failure patients feel better and live longer (the Table). Consequently, a strong ethical mandate exists for the use of CRT in heart failure. This mandate is reflected in our current practice guidelines for the management of chronic heart failure, which state that all eligible patients should receive CRT unless contraindicated.1,2 End of debate! CRT should be a routine part of any evidence-based treatment regimen for heart failure. View this table: Major Benefits of Evidence-Based Heart Failure Therapies Of course, things are never quite so simple, so let us take a look at the evidence supporting this clinical mandate for CRT and address patient selection, some of the limitations of CRT, and some of the unanswered questions about the use of CRT in heart failure. None of this discussion will lessen the role of CRT in the treatment of heart failure; rather, it will guide the selection of appropriate patients and speculate on the future application of CRT to an even broader group of heart failure patients. Response by Greenberg and Mehra p 2698 Approximately one third of patients with systolic heart failure exhibit ventricular dyssynchrony, defined as a QRS duration >120 ms on the surface ECG.3,4 Ventricular dyssynchrony produces suboptimal ventricular …

Physical functioning and mental well-being in association with health outcome in patients enrolled in the Multicenter Automatic Defibrillator Implantation Trial II

The association of psychosocial and physical factors with health outcome in patients with congestive heart failure (CHF) has not been fully explored. The aim of this study was to assess the physical and mental health in relationship to health outcome in post-infarction patients with advanced left ventricular dysfunction. A total of 1058 patients enrolled in the Multicenter Automatic Defibrillator Implantation Trial II (MADIT II) completed the Medical Outcome Trust Short Form (SF-12) at baseline. Physical component summary (PCS) and mental component summary (MCS) of SF-12 were analysed in relationship to survival, hospitalization due to CHF, and implantable cardioverter-defibrillator (ICD) therapy. Both baseline PCS and MCS were significantly associated with death (P < 0.001 and P < 0.016, respectively) and hospitalization due to CHF (P <or= 0.001). After adjustment for significant clinical covariates and treatment group, low PCS and low MCS groups remained significant predictors of mortality and CHF hospitalization. Neither PCS nor MCS was associated with appropriate ICD therapy for ventricular tachyarrhythmias. Patients who experienced appropriate ICD shocks had a statistically significant deterioration of PCS but not MCS from baseline to 12 months. Lower baseline PCS and MCS are associated with unfavourable health outcome in MADIT II patients, but not with appropriate ICD therapy for ventricular tachyarrhythmias. Patients who experience ICD shock reported a decrease in PCS, but little or no changes in MCS.

Implantable Cardioverter-Defibrillators for Primary Prevention of Sudden Death in Heart Failure

The demonstrated efficacy of implantable cardioverter-defibrillators (ICDs) for reducing sudden death in heart failure trial populations presents a critical challenge to those responsible for the allocation of healthcare resources.1–3 The current cost, multiplied by the prevalence of heart failure deemed high-risk, threatens to make this one enterprise the highest priced intervention for the Medicare population. The elegant cost-effectiveness analysis contributed by Dr Mark and colleagues from the Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT) in this issue of Circulation provides an exemplary insight into this challenge.4 These investigators’ favorable conclusions are consistent with those from a meta-analysis by Sanders et al5 and with the slightly more conservative implications from the recent cost-effectiveness analysis of the Multicenter Automatic Defibrillator Implantation Trial (MADIT)-II by Zwanziger et al.6 Article p 135 This editorial will offer an alternative conclusion based on both back-of-the-envelope estimations and scrutiny of model assumptions regarding different phases of survival for heart failure populations. ICDs for primary prevention of sudden death in the heart failure population may be less cost-effective than other recommended heart failure therapies, which are prescribed to modify disease progression and symptoms, decreasing costly hospitalizations as well as mortality. Formal cost-effectiveness analysis is complex, but it may be illustrative to begin from simple considerations. A reasonable threshold for cost-effective intervention is often assigned as $40 000 per life-year saved, in line with the present article4 suggesting a cost of $38 389 per life-year saved and $41 530 per quality-adjusted life-year saved. This is approximately equal to the cost of the defibrillator device and implantation, as currently assessed for reimbursement. (The costs would be lower for the simpler device used in SCD-HeFT, which is not available now, and for outpatient implantation, which was common in SCD-HeFT but not the current standard.) This …

Causes and Consequences of Heart Failure After Prophylactic Implantation of a Defibrillator in the Multicenter Automatic Defibrillator Implantation Trial II

Implantable cardioverter-defibrillator (ICD) therapy may be associated with an increased risk for heart failure (HF). The present study evaluated the frequency, causes, and consequences of HF after ICD implantation. We performed a retrospective analysis of the clinical factors and outcomes associated with postenrollment HF events in 1218 patients enrolled in the Multicenter Automatic Defibrillator Implantation Trial II. The adjusted hazard ratios (HRs) of ICD:conventional therapy for first and recurrent HF events were 1.39 (P=0.02) and 1.58 (P<0.001), respectively. The risk was increased among patients who received single-chamber or dual-chamber ICDs. Development of HF was associated with an increased mortality risk (HR, 3.80; P<0.001). Among patients who received a single-chamber ICD, there was a similar survival benefit before and after the development of HF (HR, 0.59 and 0.61, respectively; P=0.92 for difference), whereas among patients with dual-chamber devices, there was a significant reduction in survival benefit after HF (HR, 0.26 and 0.83, respectively; P=0.01 for difference). Within the defibrillator arm of the trial, patients who received life-prolonging therapy from the ICD had an increased risk for first and recurrent HF events (HR, 1.90; P=0.01 and 1.74; P<0.001, respectively). Patients with chronic ischemic heart disease who are treated with either single-chamber or dual-chamber ICDs have improved survival but an increased risk of HF. The present data suggest that ICD therapy transforms sudden death risk to a subsequent HF risk. These findings should direct more attention to the prevention of HF in patients who receive an ICD.

Cost-Effectiveness of a Microvolt T-Wave Alternans Screening Strategy for Implantable Cardioverter-Defibrillator Placement in the MADIT-II–Eligible Population

This study was designed to compare the cost-effectiveness of implantable cardioverter-defibrillator (ICD) placement with and without risk stratification with microvolt T-wave alternans (MTWA) testing in the MADIT-II (Second Multicenter Automatic Defibrillator Implantation Trial) eligible population. Implantable cardioverter-defibrillators have been shown to prevent mortality in the MADIT-II population. Microvolt T-wave alternans testing has been shown to be effective in risk stratifying MADIT-II-eligible patients. On the basis of published data, cost-effectiveness of three therapeutic strategies in MADIT-II-eligible patients was assessed using a Markov model: 1) ICD placement in all; 2) ICD placement in patients testing MTWA non-negative;, and 3) medical management. Outcomes of expected cost, quality-adjusted life-years (QALYs), and incremental cost-effectiveness were determined for patient lifetime. Under base-case assumptions, providing ICDs only to those who test MTWA non-negative produced a gain of 1.14 QALYs at an incremental cost of 55,700 dollars when compared to medical therapy, resulting in an incremental cost-effectiveness ratio (ICER) of 48,700 dollars/QALY. When compared with a MTWA risk-stratification strategy, placing ICDs in all patients resulted in an ICER of 88,700 dollars/QALY. Most (83%) of the potential benefit was achieved by implanting ICDs in the 67% of patients who tested MTWA non-negative. Results were most sensitive to the effectiveness of MTWA as a risk-stratification tool, MTWA negative screen rate, cost and efficacy of ICD therapy, and patient risk for arrhythmic death. Risk stratification with MTWA testing in MADIT-II-eligible patients improves the cost-effectiveness of ICDs. Implanting defibrillators in all MADIT-II-eligible patients, however, is not cost-effective, with one-third of patients deriving little additional benefit at great expense.

Cost Effectiveness of the Implantable Cardioverter‐Defibrillator: Better in Higher‐Risk Patients and Extended Duration

Recent clinical trials have demonstrated the efficacy of implantable cardioverter-defibrillators (ICDs) for preventing arrhythmic death in patients at high risk for this outcome.1 However, the high cost of the ICD and estimates of over 50,000 new candidates for the device each year2 continue to concern clinicians and payors, which has stimulated interest in refining the criteria for patient selection for this form of therapy. The cost effectiveness of ICDs is addressed in a recent analysis of results from the Multicenter Automatic Defibrillator Implantation Trial (MADIT)-II by Zwanziger et al.3 continue to concern clinicians and payors, which has stimulated interest in refining the criteria for patient selection for this form of therapy. The cost effectiveness of ICDs is addressed in a recent analysis of results from the Multicenter Automatic Defibrillator Implantation Trial (MADIT)-II by Zwanziger et al.3 in a detailed study based on clinical outcome and economic data to elucidate this issue. MADIT-II was a randomized trial of ICD compared with conventional medical therapy in patients with a prior myocardial infarction and left ventricular ejection fraction ≤30%.4 No electrophysiologic testing was required. The cost-effectiveness analysis included 1095 US patients with complete data relating to clinical costs. The study group included 664 patients who received an ICD and 431 patients in the medical treatment arm, a distribution that was based on the 3:2 randomization process in the clinical trial. The results demonstrated an all-cause mortality of 21% (n=90) in the medically treated patients and 15% (n=97) in the ICD arm, yielding an estimated hazard ratio (HR) of 0.677. Extensive information was collected for analysis of cost effectiveness, including number of office visits, diagnostic tests and procedures, hospitalizations, emergency department visits, medications, and other health care services. The cost effectiveness of ICD therapy during a 3.5-year interval was $235,000 per year of life saved. However, three alternate projections extrapolated to 12 years of follow-up revealed incremental cost-effectiveness ratios ranging from $78,600 to $114,000. The authors concluded that the estimated cost per year of life saved by ICD therapy in the MADIT-II study was high at 3.5 years, but it was considerably lower based on projections for longer intervals. For a perspective, the authors note that the current National Cholesterol Education Program Adult Treatment Panel III report (NCEP ATP III) guidelines for management of elevated cholesterol are associated with incremental cost-effectiveness ratios of $100,000 per quality-adjusted life year.5 Cost effectiveness in MADIT-II patients was clearly better in the higher-risk patients. The latter group was characterized by age older than 65 years, New York Heart Association (NYHA) class II or higher, electrocardiographic QRS duration ≥120 milliseconds, and blood urea nitrogen >25 mg/mL. Analysis of cost effectiveness is complex and involves multiple factors. As Zwanziger et al.3 note, a major element in the high initial cost of ICD therapy is implantation of the device. Additionally, as would be anticipated, their findings suggest that the incremental cost-effectiveness ratio increases in the higher-risk patients. The significance of this issue is reflected in the estimate by the authors that application of ICD therapy to all patients with MADIT-II criteria in this country would cost more than $5 billion annually. Studies such as this and methods to improve identification of patients most likely to benefit from ICD therapy will further enhance the application of these remarkable devices. In this regard, the utility of T-wave alternans testing for assessment of susceptibility to ventricular arrhythmias in candidates for ICD therapy is awaited with keen anticipation.6

The Cost Effectiveness of Implantable Cardioverter-Defibrillators: Results From the Multicenter Automatic Defibrillator Implantation Trial (MADIT)-II

We sought to evaluate the cost implications of the implantable cardioverter-defibrillator (ICD), using utilization, cost, and survival data from the Multicenter Automatic Defibrillator Implantation Trial (MADIT)-II. This trial showed that prophylactic implantation of a defibrillator reduces the rate of mortality in patients who experienced a previous myocardial infarction and low left ventricular ejection fraction. Given the size of the eligible population, the cost effectiveness of the ICD has substantial implications. Our research comprises the cost-effectiveness component of the randomized controlled trial, MADIT-II, based on utilization, cost, and survival information from 1,095 U.S. patients who were assigned randomly to receive an ICD or conventional medical care. Utilization data were converted to costs using a variety of national and hospital-specific data. The incremental cost-effectiveness ratio (iCER) was calculated as the difference in discounted costs divided by the difference in discounted life expectancy within 3.5 years. Secondary analyses included projections of survival (using three alternative assumptions), corresponding cost assumptions, and the resulting cost-effectiveness ratios until 12 years after randomization. During the 3.5-year period of the study, the average survival gain for the defibrillator arm was 0.167 years (2 months), the additional costs were 39,200 dollars, and the iCER was 235,000 dollars per year-of-life saved. In three alternative projections to 12 years, this ratio ranged from 78,600 dollars to 114,000 dollars. The estimated cost per life-year saved by the ICD in the MADIT-II study is relatively high at 3.5 years but is projected to be substantially lower over the course of longer time horizons.

Time Dependence of Defibrillator Benefit After Coronary Revascularization in the Multicenter Automatic Defibrillator Implantation Trial (MADIT)-II

The study was designed to assess the effect of elapsed time from coronary revascularization (CR) on the benefit of the implantable cardioverter-defibrillator (ICD) and the risk of sudden cardiac death (SCD) in patients with ischemic left ventricular dysfunction. The ICD improves survival in appropriately selected high-risk cardiac patients by 30% to 54%. However, in the Coronary Artery Bypass Graft (CABG)-Patch trial no evidence of improved survival was shown among a similar population of patients in whom an ICD was implanted prophylactically at the time of elective CABG. The outcome by time from CR was analyzed in 951 patients in whom a revascularization procedure was performed before enrollment in the Multicenter Automatic Defibrillator Implantation Trial (MADIT)-II. The adjusted hazard ratio (HR) of ICD versus conventional therapy was 0.64 (p = 0.01) among patients enrolled more than six months after CR, whereas no survival benefit with ICD therapy was shown among patients enrolled six months or earlier after CR (HR = 1.19; p = 0.76). In the conventional therapy group, the risk of cardiac death increased significantly with increasing time from CR (p for trend = 0.009), corresponding mainly to a six-fold increase in the risk of SCD among patients enrolled more than six months after CR. In patients with ischemic left ventricular dysfunction, the efficacy of ICD therapy after CR is time dependent, with a significant life-saving benefit in patients receiving device implantation more than six months after CR. The lack of ICD benefit when implanted early after CR may be related to a relatively low risk of SCD during this time period.

Implantable cardioverter-defibrillator therapy and risk of congestive heart failure or death in MADIT II patients with atrial fibrillation

Atrial fibrillation (AF) contributes to increased risk of morbidity and mortality. Data regarding the effectiveness of implantable cardioverter-defibrillator (ICD) therapy in AF patients are limited. The purpose of this study was to evaluate the effectiveness of ICD therapy in patients with AF enrolled in the Multicenter Automatic Defibrillator Implantation Trial II (MADIT II) and to identify their risk for the combined endpoint of hospitalization for congestive heart failure or death. The MADIT II cohort served as the source for data on the clinical course, cardiac events, and effectiveness of ICD therapy in AF patients. AF was found as baseline rhythm at enrollment in 102 (8%) MADIT II patients. In comparison to 1,007 patients in sinus rhythm, AF patients were older, more frequently were males, had wider QRS complex, and had higher blood urea nitrogen and creatinine levels (P <.05 for all parameters). ICD therapy was effective in reducing 2-year mortality in AF patients from 39% in 41 conventionally treated patients to 22% in 61 ICD-treated patients (hazard ratio = 0.51, P = .079). However, the combined endpoint of hospitalization for heart failure or death at 2 years was 69% and 59%, respectively (NS). AF was predictive for the combined endpoint of heart failure hospitalization or death (hazard ratio = 1.68, P = .040). New-onset AF in patients with baseline sinus rhythm was associated with increased risk of mortality (hazard ratio = 2.70, P <.001). MADIT II patients with AF benefit from ICD therapy, which reduces their mortality. MADIT II patients with AF are at high risk for developing heart failure.

Reduction in Ventricular Tachyarrhythmias With Statins in the Multicenter Automatic Defibrillator Implantation Trial (MADIT)-II

We evaluated whether statins have anti-arrhythmic effects by exploring the association of statin use with appropriate implantable cardioverter-defibrillator (ICD) therapy for ventricular tachycardia/ventricular fibrillation (VT/VF) in the Multicenter Automatic Defibrillator Implantation Trial (MADIT)-II. A few studies have suggested that lipid-lowering drugs may have anti-arrhythmic effects in patients with coronary artery disease. Patients receiving an ICD (n = 654; U.S. centers only) in the MADIT-II study were categorized by the percentage of days each patient received statins during follow-up (90% to 100%, n = 386; 11% to 89%, n = 116; and 0% to 10%, n = 152). The Kaplan-Meier method with significance testing by the log-rank statistic and time-dependent proportional hazards regression analysis were used to evaluate the effect of statin use on the probability of ICD therapy for the combined end point VT/VF or cardiac death and for the end point VT/VF. The cumulative rate of ICD therapy for VT/VF or cardiac death, whichever occurred first, was significantly reduced in those with > or =90% statin usage compared to those with lower statin usage (p = 0.01). The time-dependent statin:no statin therapy hazard ratio was 0.65 (p < 0.01) for the end point of VT/VF or cardiac death and 0.72 (p = 0.046) for VT/VF after adjusting for relevant covariates. Statin use in patients with an ICD was associated with a reduction in the risk of cardiac death or VT/VF, whichever occurred first, and was associated with a reduction in VT/VF episodes. These findings suggest that statins have anti-arrhythmic properties.

Antiarrhythmic Drugs for All Patients With an ICD?

IN THE EARLY STAGES OF IMPLANTABLE CARDIOVERTER DEfibrillator (ICD) use, the combination of antiarrhythmic drug concurrent with the device seemed redundant, akin to “a belt plus suspenders.” Before long it was discovered that, over time, most patients eventually required antiarrhythmic medication in addition to the ICD. In this issue of JAMA, the results of the Optimal Pharmacological Therapy in Cardioverter Defibrillator Patients (OPTIC) trial reported by Connolly and colleagues raise the issue of whether antiarrhythmic therapy, plus a -blocker, should be initiated at the time of initial ICD implantation in an effort to reduce the likelihood of ICD shock. To respond to this question, it is important to examine the interaction of antiarrhythmic drug therapy with the ICD, and the consequences of such a combination. Antiarrhythmic medication is administered in patients with an ICD for a number of reasons. Most importantly, drug therapy can reduce or eliminate ICD shocks by suppressing ventricular arrhythmias, or by slowing ventricular tachycardia (VT) to such a degree that it can be terminated with programmed antitachycardia pacing. In addition to the suppression of such “appropriate” shocks, antiarrhythmic therapy may suppress the “inappropriate” shocks precipitated by supraventricular arrhythmias (primarily atrial fibrillation). Because ICD shocks have been associated with reduced physical capacity and impaired quality of life, suppression of such events may have important clinical benefits. Antiarrhythmic agents may also be added to suppress symptomatic ventricular and supraventricular arrhythmias that are neither fast enough nor sustained to the degree that they cause the ICD to discharge. A further benefit is that, in some cases, these drugs may reduce the defibrillation threshold (defined as the energy required to defibrillate the ventricles) and as such allow for successful defibrillation when the defibrillation threshold is otherwise increased to a level that does not provide an adequate margin of safety (the difference between the defibrillation threshold and maximum output). On the other hand, antiarrhythmic drugs can interfere with ICD function. Proarrhythmic effects of such drugs include torsades de pointes and stabilization of otherwise nonsustained VT. Furthermore, the cycle length of VT can become prolonged to a point that the heart rate no longer exceeds the programmed rate cutoff of the ICD, leaving the arrhythmia unrecognized by the device. In addition, the pharmacological agent may increase, rather than decrease, the defibrillation threshold, in the worst case rendering the ICD ineffective in defibrillating the ventricles. Whenever an antiarrhythmic agent is administered to a patient with an ICD, the effect on device function must be considered. Both animal and clinical studies provide insights to help predict such interactions. As a drug class effect, the category III antiarrhythmic agents (potassium channel blockers), such as sotalol, tend to lower defibrillation threshold, although this finding is variable. In a human study, the defibrillation threshold was lowered acutely by 32% with the addition of D-sotalol (the pure class III enantiomer of D,L-sotalol). This property of lowering the defibrillation threshold may be used clinically to improve the defibrillation threshold when the margin of safety is insufficient. In contrast with potassium channel blocking drugs, the category IC sodium channel blocking agents (flecainide acetate, propafenone hydrochloride) have shown variable effects in animal and human defibrillation threshold. Amiodarone, which shares membrane properties of all the antiarrhythmic drug classes, has been shown to increase the defibrillation threshold in animal models and in some (but not all) human studies. Owing to the often unpredictable effects of antiarrhythmic drugs on ICD function and defibrillation threshold, some clinical electrophysiologists advocate testing of the ICD, and even induction of VT in patients with clinical arrhythmia, before discharging a patient with a new antiarrhythmic agent. In general, -adrenergic blocking agents are considered to have a neutral effect on defibrillation threshold. In routine practice, adjunctive antiarrhythmic therapy is administered to between 49% and 69% of patients who have an ICD. In the Multicenter Automatic Defibrillator Implantation Trial (MADIT) I study, which compared standard therapy with the ICD, 46% of the patients enrolled in