Implantable cardioverter-defibrillators: a new preventive medical option

Implantable cardioverter-defibrillator (ICD or defibrillator) therapy has revolutionized the fields of cardiology and electrophysiology. Hundreds of thousands of patients at risk for sudden cardiac death receive them each year. The devices are not much larger than a pacemaker, and they have full pacemaker capabilities in addition to being able to shock patients out of life-threatening ventricular arrhythmias. The Multicenter Automatic Defibrillator Implantation Trial (MADIT) in 1996 was a landmark trial that showed for the first time a mortality benefit of ICD therapy over medications in patients at high risk for sudden death. Multicenter Automatic Defibrillator Implantation Trial II, published in 2002, extended these results to all patients with ischemic heart failure with depressed heart function. Candidates for ICD implantation include most patients with an ejection fraction of <30%, especially those with coronary artery disease. More work needs to be done to define those patients with nonischemic cardiomyopathies who will benefit from ICDs and biventricular pacing for heart failure.     

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.     

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.     

Risk stratification for primary implantation of a cardioverter-defibrillator in patients with ischemic left ventricular dysfunction.

OBJECTIVES: The study was designed to develop a simple risk stratification score for primary therapy with an implantable cardioverter-defibrillator (ICD). BACKGROUND: Current guidelines recommend primary ICD therapy in patients with a low ejection fraction (EF). However, the benefit of the ICD in the low EF population may not be uniform. METHODS: Best-subset proportional-hazards regression analysis was used to develop a simple clinical risk score for the end point of all-cause mortality in patients allocated to the conventional therapy arm of MADIT (Multicenter Automatic Defibrillator Implantation Trial)-II after excluding a pre-specified subgroup of very high-risk (VHR) patients (defined by blood urea nitrogen [BUN] >or=50 mg/dl and/or serum creatinine >or=2.5 mg/dl). The benefit of the ICD was then assessed within risk score categories and separately in VHR patients. RESULTS: The selected risk score model comprised 5 clinical factors (New York Heart Association functional class >II, age >70 years, BUN >26 mg/dl, QRS duration >0.12 s, and atrial fibrillation). Crude mortality rates in the conventional group were 8% and 28% in patients with 0 and >or=1 risk factors, respectively, and 43% in VHR patients. Defibrillator therapy was associated with a 49% reduction in the risk of death (p < 0.001) among patients with >or=1 risk factors (n = 786), whereas no ICD benefit was identified in patients with 0 risk factors (n = 345; hazard ratio 0.96; p = 0.91) and in VHR patients (n = 60; hazard ratio 1.00; p > 0.99). CONCLUSIONS: Our data suggest a U-shaped pattern for ICD efficacy in the low-EF population, with pronounced benefit in intermediate-risk patients and attenuated efficacy in lower- and higher-risk subsets.     

Mechanisms of death in the CABG Patch trial: a randomized trial of implantable cardiac defibrillator prophylaxis in patients at high risk of death after coronary artery bypass graft surgery

BACKGROUND: The CABG Patch trial compared prophylactic implantable cardiac-defibrillator (ICD) implantation with no antiarrhythmic therapy in coronary bypass surgery patients who had a left ventricular ejection fraction <0.36 and an abnormal signal-averaged ECG. There were 102 deaths among the 446 ICD group patients and 96 deaths among the 454 control group patients, a hazard ratio of 1.07 (P=0.63). The mechanisms of death were classified, and hypotheses were tested about the effects of ICD therapy on arrhythmic and nonarrhythmic cardiac deaths in the CABG Patch Trial and the Multicenter Automatic Defibrillator Implantation Trial (MADIT). METHODS AND RESULTS: The 198 deaths in the trial were reviewed by an independent Events Committee and classified by the method of Hinkle and Thaler. Only 54 deaths (27%) occurred out of hospital; 145 deaths (73%) were witnessed. Seventy-nine (82%) of the 96 deaths in the control group and 76 (75%) of the 102 deaths in the ICD group were due to cardiac causes. Cumulative arrhythmic mortality at 42 months was 6.9% in the control group and 4.0% in the ICD group (P=0. 057). Cumulative nonarrhythmic cardiac mortality at 42 months was 12. 4% in the control group and 13.0% in the ICD group (P=0.275). Death due to pump failure was significantly associated with death >1 hour from the onset of symptoms, dyspnea within 7 days of death, and overt heart failure within 7 days of death. CONCLUSIONS: In the CABG Patch Trial, ICD therapy reduced arrhythmic death 45% without significant effect on nonarrhythmic deaths. Because 71% of the deaths were nonarrhythmic, total mortality was not significantly reduced.     

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.     

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.     

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.     

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.     

Amiodarone: clinical trials

Amiodarone is an antiarrhythmic agent commonly used in the treatment of supraventricular and ventricular tachyarrhythmias. This article reviews the results and clinical implications of primary and secondary prevention trials in which amiodarone was used in one of the treatment arms. Key post-myocardial infarction primary prevention trials include the European Myocardial Infarct Amiodarone Trial (EMIAT) and the Canadian Amiodarone Myocardial Infarction Trial (CAMIAT), both of which demonstrated that amiodarone reduced arrhythmic but not overall mortality. In congestive heart failure patients, amiodarone was studied as a primary prevention strategy in two pivotal trials: Grupo de Estudio de la Sobrevida en la Insuficiencia Cardiac en Argentina (GESICA) and Amiodarone in Patients With Congestive Heart Failure and Asymptomatic Ventricular Arrhythmia (CHF-STAT). Amiodarone was associated with a neutral overall survival and a trend toward improved survival in nonischemic cardiomyopathy patients in CHF/STAT and improved survival in GESICA. In post-myocardial infarction patients with nonsustained ventricular tachycardia and a depressed ejection fraction, the Multicenter Automatic Defibrillator Implantation Trial (MADIT) demonstrated that implantable cardioverter-defibrillators (ICD) statistically improved survival compared to the antiarrhythmic drug arm, most of whose patients were taking amiodarone. In patients with histories of sustained ventricular tachycardia or ventricular fibrillation, the Cardiac Arrest Study in Seattle: Conventional Versus Amiodarone Drug Evaluation (CASCADE) trial demonstrated that empiric amiodarone lowered arrhythmic recurrence rates compared to other drugs guided by serial Holter or electrophysiologic studies. However, arrhythmic death rates were high in both treatment arms of the study. Several secondary prevention trials, including the Antiarrhythmics Versus Implantable Defibrillators Study (AVID), the Canadian Implantable Defibrillator Study (CIDS), and the Cardiac Arrest Study Hamburg (CASH), have demonstrated the superiority of ICD therapy compared to empiric amiodarone in improving overall survival. Based on the above findings, amiodarone is safe to use in post-myocardial infarction and congestive heart failure patients that need antiarrhythmic therapy. Although amiodarone is effective in treating malignant arrhythmias, high-risk patients should be considered for an ICD as frontline therapy.     

Clinical course and implantable cardioverter defibrillator therapy in postinfarction women with severe left ventricular dysfunction

BACKGROUND: There are limited data regarding implantable cardioverter defibrillator (ICD) therapy in postinfarction women with severe left ventricular dysfunction. The aim of this study was to evaluate the risk of cardiac events and effects of ICD therapy in women as compared to men enrolled in the Multicenter Automatic Defibrillator Implantation Trial II (MADIT II). METHODS AND RESULTS: Among 1,232 patients enrolled in MADIT II, there were 192 (16%) women and 1,040 (84%) men. When compared to men, women had an increased frequency of NYHA class > or =II (70 vs 63%; P = 0.067), hypertension (60% vs 52%; P = 0.047), diabetes (42% vs 34%; P = 0.027), and LBBB (25% vs 17%; P = 0.011), and less frequent CABG surgery (42% vs 60%; P < 0.001). The 2-year cumulative mortality in patients randomized to conventional therapy was not significantly different in women and men (30% and 20%, respectively; P = 0.19). Adjusting for relevant clinical covariates, the hazard ratios for ICD effectiveness were similar in women (0.57; 95% CI = 0.28-1.18; P = 0.132) and men (0.66; 95% CI = 0.48-0.91; P = 0.011). The risk of appropriate ICD therapy for VT/VF was lower in women than in men (hazard ratio = 0.60 for female vs male gender; 95% CI = 0.37-0.98; P = 0.039). CONCLUSIONS: MADIT II women had similar mortality and similar ICD effectiveness when compared to men. MADIT II women with ICDs had a lower risk of arrhythmic events with fewer episodes of ventricular tachycardia than men.     

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.     

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.     

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.     

Repolarization variability in the risk stratification of MADIT II patients.

AIMS: 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. CONCLUSION: 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.     

Arrhythmias in heart failure

Opinion statement  

Prognostic significance of nonsustained ventricular tachycardia after revascularization

INTRODUCTION: Two randomized trials (Multicenter Automatic Defibrillator Implantation Trial [MADIT] and Multicenter Unsustained Tachycardia Trial [MUSTT]) suggest that implantable cardioverter defibrillator (ICD) placement is associated with improved survival in patients with coronary artery disease, depressed left ventricular function, and nonsustained ventricular tachycardia (VT) who also have inducible sustained VT. However, neither study directly addresses the management of such patients who develop nonsustained VT early after revascularization. METHODS AND RESULTS: We evaluated 109 consecutive patients who underwent electrophysiologic testing to evaluate nonsustained VT, which occurred 5 +/- 4 days following revascularization. Sustained monomorphic VT was inducible in 46 (42%) patients; these patients received an ICD. The remaining 63 (58%) noninducible patients received neither antiarrhythmic drug therapy nor an ICD. During 27 +/- 12 months of follow-up, 15 (33%) of 45 patients with an implanted ICD received at least one appropriate therapy from the device and 26 (24%) of the 109 study patients died. The 1- and 2-year freedom from ventricular tachycardia/fibrillation or sudden death in noninducible patients (97% and 93%) was significantly greater than that of inducible patients (84% and 71%; P = 0.001). However, no difference was observed in total mortality. CONCLUSION: Patients with nonsustained VT during the early postrevascularization period who have inducible VT have a high incidence of arrhythmic events. Although this study was not designed to assess the impact of ICD placement on the total mortality of inducible patients, the finding that one third of these patients received appropriate ICD therapy suggests that the device may have a protective effect in these patients.     

Risk Stratification Using Heart Rate Turbulence and Ventricular Arrhythmia in MADIT II: Usefulness and Limitations of a 10‐Minute Holter Recording

Background: We evaluated the usefulness of heart rate turbulence (HRT) parameters and frequency of ventricular premature beats (VPBs) for risk‐stratifying postinfarction patients with depressed left ventricular function enrolled in Multicenter Automatic Defibrillator Trial II (MADIT II). Methods: In 884 MADIT II patients, 10‐minute Holter monitoring at enrollment was used to evaluate HRT parameters and frequency of VPBs. The primary endpoints were defined as all‐cause mortality in patients randomized to conventional treatment and as appropriate therapy for ventricular tachycardia or fibrillation in patients randomized to implantable cardioverter defibrillator (ICD) therapy. Results: The median turbulence slope was lower in patients who died in comparison to survivors in the conventional arm (2.3 vs 4.5 ms/RR; P < 0.05); but it was not a significant predictor of mortality after adjustment for clinical covariates (age, ejection fraction, beta‐blocker use, and BUN levels). There was no association between HRT parameters and arrhythmic events in ICD patients. Conventionally treated patients who died and ICD patients who had appropriate ICD therapy had significantly more frequent VPBs than those without such adverse events. After adjustment for clinical covariates, frequent VPBs>3/10 min were associated with death in the conventional arm (HR = 1.63; P = 0.070) and were predictive for appropriate ICD therapy in the ICD arm (HR = 1.75; P = 0.003). Conclusion: In postinfarction patients with severe left ventricular dysfunction, frequent VPBs are associated with increased risk of mortality and with appropriate ICD therapy. HRT obtained from 10‐min Holter ECG showed a trend toward the association with mortality in univariate analysis but HRT parameters were not predictive of the outcome in multivariate analyses.     

Baroreflex sensitivity and heart rate variability in the identification of patients at risk for life-threatening arrhythmias: implications for clinical trials

BACKGROUND: The need for accurate risk stratification is heightened by the expanding indications for the implantable cardioverter defibrillator. The Multicenter Automatic Defibrillator Implantation Trial (MADIT) focused interest on patients with both depressed left ventricular ejection fraction (LVEF) and the presence of nonsustained ventricular tachycardia (NSVT). Meanwhile, the prospective study Autonomic Tone and Reflexes After Myocardial Infarctio (ATRAMI) demonstrated that markers of reduced vagal activity, such as depressed baroreflex sensitivity (BRS) an heart rate variability (HRV), are strong predictors of cardiac mortality after myocardial infarction. METHODS AND RESULTS: We analyzed 1071 ATRAMI patients after myocardial infarction who had data on LVEF, 24-hour ECG recording, and BRS. During follow-up (21 +/- 8 months), 43 patients experienced cardiac death, 5 patients had episodes of sustained VT, and 30 patients experienced sudden death and/or sustained VT. NSVT, depressed BRS, or HRV were all significantly and independently associated with increased mortality. The combination of all 3 risk factor increased the risk of death by 22x. Among patients with LVEF<35%, despite the absence of NSVT, depressed BRS predicted higher mortality (18% versus 4.6%, P = 0.01). This is a clinically important finding because this grou constitutes 25% of all patients with depressed LVEF. For both cardiac and arrhythmic mortality, the sensitivity of lo BRS was higher than that of NSVT and HRV CONCLUSIONS: BRS and HRV contribute importantly and additionally to risk stratification. Particularly when LVEF is depressed, the analysis of BRS identifies a large number of patients at high risk for cardiac and arrhythmic mortalit who might benefit from implantable cardioverter defibrillator therapy without disproportionately increasing the number of false-positives.     

Relations among renal function, risk of sudden cardiac death, and benefit of the implanted cardiac defibrillator in patients with ischemic left ventricular dysfunction

Implanted cardioverter defibrillator therapy has been shown to be associated with a significant reduction in the risk of sudden cardiac death (SCD) in patients with ischemic left ventricular dysfunction. However, data on the relation between renal function and SCD in this population are limited, and the effect of renal dysfunction on the implanted cardioverter defibrillator benefit has not been determined. We performed a retrospective analysis of the outcome associated with renal dysfunction, as determined by the estimated glomerular filtration rate (eGFR), in patients enrolled in the Multicenter Automatic Defibrillator Implantation Trial-II. Multivariate analysis in conventionally treated patients showed that for each 10-U reduction in eGFR, the risk of all-cause mortality and SCD increased by 16% (p = 0.005) and 17% (p = 0.03), respectively. Defibrillator therapy was associated with a survival benefit in each eGFR category of > or = 35 ml/min/1.73 m2 (overall risk reduction for all-cause mortality 32%, p = 0.01 and for SCD 66%, p < 0.001). However, no implanted cardioverter defibrillator benefit was shown among patients with an eGFR < 35 ml/min/1.73 m2 (all-cause mortality hazard ratio 1.09, p = 0.84; SCD hazard ratio 0.95, p = 0.95). In conclusion, in patients with high-risk cardiac disease enrolled in the Multicenter Automatic Defibrillator Implantation Trial-II, a significant increase was found in the risk of SCD with declining renal function. Defibrillator therapy was associated with a significant survival benefit among the study patients with mild to moderate or no renal disease, but no benefit was shown among patients with more advanced renal dysfunction.