Comparison of efficacy of implanted cardioverter-defibrillator in patients with versus without diabetes mellitus

In the second Multicenter Automatic Defibrillator Implantation Trial, patients with a previous myocardial infarction and left ventricular ejection fraction < or =0.30 benefited significantly from prophylactic implantable cardioverter-defibrillator (ICD) placement. Diabetic patients who had a myocardial infarction had a worse prognosis compared with nondiabetics. The present study used data from the second Multicenter Automatic Defibrillator Implantation Trial to assess the efficacy of ICD placement on survival in diabetic patients. Of the 1,232 patients in the second Multicenter Automatic Defibrillator Implantation Trial, 489 were characterized as diabetic. They were more likely to be New York Heart Association class II to IV, be hypertensive, have renal dysfunction, have an increased body mass index, and to take diuretic drugs. Diabetic patients had a 24% greater adjusted risk of death than nondiabetic patients. The hazard ratio (HR) for the risk of death in patients treated with the ICD compared with conventional therapy was similar in diabetics (HR 0.61; 95% confidence interval [CI] 0.38 to 0.98) and nondiabetics (HR 0.71; 95% CI 0.49 to 1.05), with no evidence of interaction. Thus, diabetic patients derive a similar benefit from ICD therapy despite being sicker and having a higher mortality rate overall.     

Implantable cardioverter-defibrillator efficacy in patients with heart failure and left ventricular dysfunction (from the MADIT II population)

The Multicenter Automatic Defibrillator Implantation Trial II demonstrated a significant 31% reduction in the risk of mortality in postinfarction patients with low ejection fraction (EF < or =30%). Recently, results from the Sudden Death in Heart Failure Trial indicated that a subgroup of patients with New York Heart Association (NYHA) class III heart failure had less benefit from an implantable cardioverter-defibrillator (ICD) than patients with less advanced heart failure. This study evaluates the association between NYHA class, EF, and blood urea nitrogen (BUN) levels as measures of heart failure and left ventricular dysfunction, and ICD benefit in reducing mortality as well as the association of these parameters with ICD therapy for ventricular tachyarrhythmias. NYHA class I was identified in 442 patients (36%), class II in 425 (35%), and class III in 350 patients (29%). EF < or =20% was present in 472 patients (38%), EF of 21% to 25% in 359 patients (29%), and EF of 26% to 30% in 401 patients (33%). BUN < or =25 mg/dl was present in 850 patients (70%) and >25 mg/dl in 368 patients (30%). Patients with higher NYHA class and BUN had higher mortality (34%) and a higher risk of arrhythmic events (33% to 35%) than patients in lower functional groups (16% to 20%). EF did not differentiate the risk. There was no evidence for significant interactions between mortality, ICD therapy, and tested parameters. In conclusion, patients with more advanced heart failure have a higher risk of mortality and arrhythmic events than patients with less severe disease. However, there is no significant difference in the benefit from ICD therapy among the above subgroups of patients in the Multicenter Automatic Defibrillator Implantation Trial.     

Implantable cardiac arrhythmia devices--Part II: implantable cardioverter defibrillators and implantable loop recorders

Implantable cardiac devices have become firmly entrenched as important therapeutic tools for a variety of cardiac conditions. The second part of this two-part review discusses the contemporary use and follow-up of implantable cardioverter defibrillators (ICD) and the implantable loop recorder. The ICD has become the standard therapy for protecting patients against sudden cardiac death. Two recent trials, the Multicenter Automatic Defibrillator Trial II (MADIT II) and the Sudden Cardiac Death Heart Failure Trial (SCD-HEFT), demonstrated that the ICD is associated with a significant survival benefit for patients with reduced ejection fraction (< 0.30-0.35), particularly if heart failure symptoms are present. The ICD has an important role in the management of other conditions associated with a high risk for sudden death, such as hypertrophic cardiomyopathy, long QT syndrome, and Brugada syndrome. The implantable loop recorder has become an important diagnostic tool for the patient with unexplained syncope.     

Inverse relationship of blood pressure levels to sudden cardiac mortality and benefit of the implantable cardioverter-defibrillator in patients with ischemic left ventricular dysfunction.

OBJECTIVES: 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. BACKGROUND: 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. METHODS: 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). RESULTS: 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. CONCLUSIONS: 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.     

T-wave alternans for risk stratification and prevention of sudden cardiac death

Despite considerable progress in the management of ischemic heart disease, a substantial proportion of patients continue to experience life-threatening arrhythmic events. The Multicenter Automatic Defibrillator Implantation Trial 2 has recently shown the superiority of implantable cardioverter defibrillators (ICDs) over conventional strategies to prevent sudden death in patients with reduced ejection fraction, but at the expense of potentially unnecessary ICD implantation in a large percentage of patients. T-wave alternans (TWA), which reflects alternation of cellular repolarization, results in a substantial increase in dispersion of repolarization, a prerequisite for reentrant arrhythmias. Recent trials, cumulating close to 3000 patients, have established TWA analysis as a powerful tool for arrhythmia prevention. Based on the most recent estimates, at least one third of post-myocardial infarction patients are expected to be tested negative. With a negative predictive value greater than 90%, TWA might allow for targeting of patients most likely to benefit from ICD therapy. Accurate identification of high-risk patients by noninvasive TWA may allow for improved widespread screening for sudden death prevention in the general population.     

ICD therapy for the prevention of sudden cardiac death in post-MI patients

Opinion statement Implantable cardioverter-defibrillators (ICDs) are unequivocally the treatment of choice for patients who have already experienced a near-fatal tachyarrhythmic event. Recently, studies have conclusively demonstrated that extending the benefits of ICD therapy to postinfarction patients with resultant left ventricular dysfunction results in dramatic additional lifesaving without the need for complex riskstratification procedures. The landmark Multicenter Automatic Defibrillator Implantation Trial II (MADIT II) shows that patients with reduced left ventricular function (ejection fraction < 30%) 1 month after a myocardial infarction should receive an ICD to prevent sudden cardiac death.     

Implantable cardioverter defibrillator therapy in postinfarction patients

PURPOSE OF REVIEW: In the past few years, new clinical trials were conducted to determine the effectiveness of implantable cardioverter defibrillators (ICDs) for prevention of mortality in patients with ischemic and nonischemic cardiomyopathies. This paper aims to provide an overview of the current state of knowledge regarding ICD therapy in postinfarction patients. RECENT FINDINGS: Postinfarction patients with severe left ventricular dysfunction are at high risk of sudden cardiac death. Antiarrhythmic therapy does not improve survival in such patients and, therefore, ICDs emerged as treatment of choice for both primary and secondary prevention of mortality after MI. The MADIT (Multicenter Automatic Defibrillator Implantation Trial) and MUSTT (Multicenter Unsustained Tachycardia Trial) trials were the first primary prevention ICD trials documenting a substantial reduction in mortality with an ICD in postinfarction patients with depressed ejection fraction, nonsustained ventricular tachycardia, and inducible sustained ventricular tachycardia. The recently completed MADIT II trial broadened indications for prophylactic use of ICD in postinfarction patients with ejection fraction of 30% or less without a requirement for additional risk stratifiers. The benefit from ICD therapy in patients with low ejection fraction was recently confirmed by results from the SCD-HeFT (Sudden Cardiac Death in Heart Failure) and COMPANION (Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure) trials. SUMMARY: Recent clinical trials established ICD as an important therapeutic modality for primary and secondary prevention of mortality in postinfarction patients.     

New indications for implantable defibrillator therapy

Implantable cardioverter Defibrillator (ICD) therapy has been extensively evaluated in patients at high risk of sudden cardiac death. Most recently, the Sudden Cardiac Death in Heart Failure Trial found that patients with moderate symptoms of congestive heart failure, whether due to an ischemic or a nonischemic cause, have reduced mortality compared with patients treated only with conventional medical therapy for heart failure. The results of this trial confirm those of earlier trials finding a benefit of ICD therapy in patients with coronary artery disease and reduced left ventricular systolic function, and extend the indications for ICD therapy to those without coronary artery disease.     

The role of electrophysiology study in risk stratification of sudden cardiac death

Patients with ischemic heart disease and left ventricular systolic dysfunction are at high risk of sudden cardiac death. However, most of these high-risk patients will never develop potential fatal ventricular arrhythmias. Thus, modalities that stratify patients according to their risk of sudden cardiac death are needed. The electrophysiology study has, for decades, been used to prognosticate on patients' risk of sudden cardiac death. Recent data from the Multicenter Unsustained Tachycardia Trial (MUSTT) and Multicenter Automatic Defibrillator Implantation Trial II (MADIT II) demonstrate that in patients with ischemic heart disease and left ventricular systolic dysfunction, an electrophysiology study can help identify patients who are at high risk of sudden cardiac death. However, in these patient populations, the prognostic ability of an electrophysiology study is only modest and the negative predictive value is poor. In the future, combining the results of noninvasive modalities with invasive electrophysiology testing may improve our prognostic ability. Furthermore, expanding the role of the electrophysiology study to include therapeutic ablations may alter a patient's future risk of sudden cardiac death.     

Value of microvolt T-wave alternans for predicting patients who would benefit from implantable cardioverter-defibrillator therapy

Despite considerable progress in the management of coronary artery disease and dilated cardiomyopathy, a substantial proportion of patients remains at the risk of life-threatening arrhythmic events. The Multicenter Automatic Defibrillator Implantation II and Sudden Cardiac Death Heart Failure studies have conclusively demonstrated that prophylactic implantable cardioverter-defibrillator (ICD) therapy reduces mortality among subjects with ischemic and nonischemic cardiomyopathy but at the expense of potentially unnecessary ICD implantation in a large percentage of patients. Microvolt T-wave alternans (MTWA), with a negative predictive value greater than 90%, holds promise for selecting the patients who would likely and patients not likely to benefit from ICD implantation. Accurate identification of high-risk patients by noninvasive MTWA may allow for improved widespread screening for sudden death prevention in the general population.     

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

BACKGROUND: 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. OBJECTIVES: 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. METHODS: The MADIT II cohort served as the source for data on the clinical course, cardiac events, and effectiveness of ICD therapy in AF patients. RESULTS: 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). CONCLUSION: 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.     

Differences in Outcomes Between Patients Treated with Single‐ versus Dual‐Chamber Implantable Cardioverter Defibrillators: A Substudy of the Multicenter Automatic Defibrillator Implantation Trial II

Objectives: We sought to evaluate the influence of single‐ versus dual‐chamber implantable cardioverter defibrillators (ICDs) on the occurrence of heart failure and mortality as well as appropriate and inappropriate ICD therapy in the Multicenter Automatic Defibrillator Implantation Trial II (MADIT‐II). Background: In MADIT‐II, ICD therapy in patients with a prior myocardial infarction and ejection fraction ≤0.30 was associated with a 31% reduction in risk of mortality when compared to conventionally treated patients. An unexpected finding was an increased occurrence of hospitalization for heart failure in the ICD group. Methods: Data from 717 patients randomized to ICD therapy with single‐ or dual‐chamber pacing devices in MADIT‐II were retrospectively analyzed. Endpoints selected for analysis included death from any cause, new or worsening heart failure requiring hospitalization, death or heart failure, appropriate therapy for ventricular tachycardia (VT) or ventricular fibrillation (VF), and inappropriate ICD therapy for atrial fibrillation or supraventricular tachycardia. Results: A total of 404 single‐chamber ICDs (S‐ICDs) and 313 dual‐chamber ICDs (D‐ICDs) were implanted. Patients receiving D‐ICDs were at a higher risk at baseline than those receiving S‐ICDs, with older age, higher NYHA class, more frequent prior CABG, wider QRS complex, more LBBB, higher BUN level, a history of more atrial arrhythmias requiring treatment, and a longer time interval from their index myocardial infarction to enrollment. While there was a trend toward an increase in adverse outcomes in the D‐ICD group, no statistically significant differences in heart failure or mortality were observed between S‐ICD versus D‐ICD groups. Conclusions: Patients with D‐ICDs had a nonsignificant trend toward higher mortality and heart failure rates than patients with S‐ICDs.     

Time dependence of defibrillator benefit after coronary revascularization in the Multicenter Automatic Defibrillator Implantation Trial (MADIT)-II.

OBJECTIVES: 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. BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.     

A critical appraisal of indications for the implantable cardioverter defibrillator (ICD).

The implantable cardioverter defibrillator (ICD) is a remarkably effective therapy for reducing sudden cardiac death in patients with malignant ventricular arrhythmias. The indications for implantation of the ICD were approved in 1985 by the United States Food and Drug Administration; it could be implanted in patients who have experienced cardiac arrest or in those with recurrent ventricular arrhythmias which are not suppressed by anti-arrhythmic drugs in the electrophysiology laboratory. These established indications have not changed in the last seven years. In the near future, the release of third-generation ICDs (with antitachycardia pacing) will likely further expand indications for the device. Many patients with stable ventricular tachycardia who have not had syncope or cardiac arrest will receive a third-generation defibrillator. Also, three clinical trials now in progress--CABG-PATCH, Multicenter Automatic Defibrillator Implantation Trial (MADIT) and Multicenter Unsustained Tachycardia Trial (MUSTT)--are studying "pre-event" patients with low ejection fraction and electrical instability; some of the patients in each trial are being prospectively randomized to the ICD. Within the next five years we will have a better understanding of the role of ICD therapy in such patients. Until these studies are completed, it is important that the indications for the ICD not be expanded.     

Arrhythmias in heart failure

Opinion statement  

Survival benefit with an implanted defibrillator in relation to mortality risk in chronic coronary heart disease

Although improved patient survival has been reported in several randomized trials with the implanted cardioverter-defibrillator, <15% of patients treated with defibrillators during trials receive life-saving benefit from this therapy. We evaluated the survival benefit from defibrillator therapy in relation to the severity of the mortality risk in patients with coronary heart disease. Using data from the Multicenter Automatic Defibrillator Implantation Trial, we partitioned the study population into high- and low-risk subsets for each of 3 physiologically meaningful risk factors (ejection fraction, QRS duration, and history of heart failure requiring therapy). Risk of death was evaluated by Cox proportional-hazards regression analyses in patients with single and multiple risk factors. The defibrillator was associated with a significant (p = 0.002) reduction in mortality only in high-risk subsets with ejection fraction <0.26, QRS duration > or =0.12 second, and history of heart failure requiring treatment. The Cox hazard ratio for the risk of death progressively increased >1.0 as a function of the number of risk factors present. Defibrillator therapy was associated with a progressive reduction in the hazard ratio <1.0 (improved survival) at each increased level of mortality risk. Patients at the highest mortality risk (all 3 risk factors; hazard ratio 4.33) achieved the largest mortality reduction (hazard ratio 0.20) from defibrillator therapy. In patients with chronic coronary heart disease, the magnitude of the survival benefit from the implanted defibrillator is directly related to the severity of cardiac dysfunction and its associated mortality risk.     

The clinical implications of cumulative right ventricular pacing in the multicenter automatic defibrillator trial II

INTRODUCTION: This study was designed to assess whether right ventricular pacing in the implantable cardioverter defibrillator (ICD) arm of the Multicenter Automatic Defibrillator Implantation Trial (MADIT) II was associated with an unfavorable outcome. METHODS AND RESULTS: Data on the number of ventricular paced beats were available in 567 (76%) of 742 MADIT II patients with ICDs. The number of ventricular paced beats over the total number of beats showed a bimodal distribution with patients being predominantly paced or nonpaced. Therefore, patients were dichotomized at 0-50% and 51-100% of cumulative pacing with median pacing rate 0.2% and 95.6%, respectively. Endpoints included new or worsening heart failure, appropriate ICD therapy for VT/VF, and the combined endpoint of heart failure or death. Clinical features associated with frequent ventricular pacing included age >or=65 years, advanced NYHA heart failure class, LVEF < 0.25, first degree AV and bundle branch block, and amiodarone use. During follow-up, 119 patients (21%) had new or worsened heart failure, 130 (23%) had new or worsened heart failure or death, and 142 (25%) had appropriate therapy for VT/VF. In comparison to patients with infrequent pacing, those with frequent pacing had significantly higher risk of new or worsened heart failure (hazard ratio = 1.93; P = 0.002) and VT/VF requiring ICD therapy (HR = 1.50; P = 0.02). CONCLUSIONS: Patients in MADIT II who were predominantly paced had a higher rate of new or worsened heart failure and were more likely to receive therapy for VT/VF. These results suggest the deleterious consequences of RV pacing, particularly in the setting of severe LV dysfunction.     

Temporal aspects of improved survival with the implanted defibrillator (MADIT-II)

The present study retrospectively explored the reasons for delay in the onset of survival benefit from the implanted cardioverter defibrillator (ICD) in the Second Multicenter Automatic Defibrillator Implantation Trial. The cumulative probability of cause-specific death over time was estimated by the Kaplan-Meier method and by proportional hazards regression analysis. Early cardiac death survival curves were similar by treatment assignment in the 0- to 12-month period (p = 0.76). Late cardiac death survival curves by treatment assignment in the >12- to 52-month follow-up period were divergent with a lower probability of late cardiac death in the ICD arm compared with conventional therapy group (p <0.001). The time-specific hazard ratios of ICD to conventional therapy for cardiac death in the early and late periods were significantly different from each other (nominal p = 0.004). There was a significant decrease in sudden cardiac death with ICD therapy in the early (p = 0.012) and late (p <0.001) groups. In the early period, the rate of nonsudden cardiac death was significantly higher in the ICD group than in the conventional therapy group (p = 0.003). Rates of late nonsudden cardiac death were similar in the 2 treatment arms (p = 0.11).     

Risk stratification for arrhythmic death after myocardial infarction: current perspective and future direction

The number of patients eligible for implantable cardioverter defibrillator implantation is large and growing. Results of the Multicenter Automatic Defibrillator Implantation Trial-II, Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure trial, and Sudden Cardiac Death in Heart Failure Trial will have a major impact on health care expenditure and economics in all countries. Therefore, one of the most important challenges in today's cardiology is finding more specific and accurate risk stratification strategies (rather than simply ejection fraction) for primary prevention of sudden cardiac death in patients who have suffered myocardial infarction. We hereby reviewed the existing data on potential risk stratifiers and assessed their impact on every day decision making and patient selection for ICD implantation.     

Analysis of mortality events in the Multicenter Automatic Defibrillator Implantation Trial (MADIT-II)

OBJECTIVES: The purpose of this study was to determine the efficacy of implantable cardiac defibrillator (ICD) therapy in preventing sudden cardiac death (SCD) in post-infarction patients with advanced left ventricular (LV) dysfunction. BACKGROUND: The Multicenter Automatic Defibrillator Implantation Trial (MADIT-II) randomized 1,232 post-infarction patients with an ejection fraction of < or =30% to ICD or conventional therapy. In the ICD group, there was a 31% decrease in the risk of total mortality. However, a better understanding of the mode of death is desirable in order to refine therapeutic interventions in high-risk populations. METHODS: We evaluated the 202 deaths, using a variation of the Hinkle-Thaler classification system as well as a clinical classification system to determine the incidence of SCD and the incidence of cardiac death due to progressive LV failure. RESULTS: The SCD rates were 10.0% in the conventional group and 3.8% in the ICD group (p < 0.01). The hazard ratio for the risk of SCD in the ICD group compared with the conventional therapy group was 0.33 (95% confidence interval 0.20 to 0.53, p < 0.0001). The ICD had no meaningful effect on non-sudden death (p = 0.32). The effect of defibrillator therapy in reducing SCD was similar in subgroup analyses stratified according to relevant baseline characteristics. CONCLUSIONS: The decrease in mortality with ICD therapy in MADIT-II is entirely due to a reduction in SCD, with similar reductions in SCD in a spectrum of subgroups stratified according to relevant baseline characteristics.