Multicenter Automatic Defibrillator Implantation Trial II Research Articles

Death with an implantable cardioverter-defibrillator: a MADIT-II substudy.

There are limited data regarding factors that identify implantable cardioverter-defibrillator (ICD) patients who will experience either ventricular tachyarrhythmic (VTA) or non-arrhythmic (NA) mortality, and the commonly used clinical classification of sudden cardiac death (SCD) vs. non-sudden cardiac death (NSCD) may not be accurate enough. We aimed to correlate clinical adjudication of mortality events to device interrogation data and to identify risk factors for VTA mortality in Multicenter Automatic Defibrillator Implantation Trial II (MADIT-II). Of the 746 patients who received an ICD in MADIT-II, 44 died from cardiac causes and had available interrogation data at the time of death. Sudden cardiac death vs. NSCD was defined by an adjudication committee. Ventricular tachyarrhythmic and NA arrhythmic deaths were categorized by the presence or absence of ventricular tachycardia or fibrillation (VT/VF) during the terminal event. Mode of death was found to be inaccurate when validated by device interrogation for VTA events: 50% patients adjudicated as SCD did not have a VTA event at the time of death; and 25% of adjudicated NSCD were found to have VT/VF during the mortality event. Multivariate analysis showed that factors independently associated with VTA mortality included: VT/VF >72 h prior to the mortality event [hazard ratio (HR) 8.0; P < 0.001], hospitalization for heart failure (HR 6.7; P = 0.001), and a history of hypertension (HR 4; P = 0.04). Current classification of SCD vs. NSCD fails to identify VTA events at the time of death in a significant proportion of patients, and simple clinical parameters can be used to identify ICD recipients with increased risk for VTA mortality.

Long-Term Survival With Implantable Cardioverter-Defibrillator in Different Symptomatic Functional Classes of Heart Failure

The ACC/AHA/HRS (American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society) guidelines recommend implantable cardioverter-defibrillator (ICD) therapy primary prevention in all patients with severely reduced left ventricular ejection fraction (≤30%) regardless of New York Heart Association (NYHA) functional class, whereas recent European guidelines limit the indication to those with symptomatic heart failure (NYHA ≥ II). We therefore aimed to evaluate the long-term survival benefit of primary ICD therapy among postmyocardial infarction patients with and without heart failure (HF) symptoms who were enrolled in MADIT-II (Multicenter Automatic Defibrillator Implantation Trial II). We classified 1,164 MADIT-II patient groups according to the baseline NYHA class (NYHA I [n = 442], NYHA II [n = 425], and NYHA III [n = 297]); patients with NYHA IV were excluded. Multivariate Cox proportional hazards regression modeling was performed to compare the mortality reduction with ICD versus non-ICD therapy during 8 years of follow-up between the 3 NYHA groups. The median (interquartile range) follow-up time was 7.6 (3.5 to 9) years. At 8 years of follow-up, the cumulative probability of mortality in the non-ICD treatment arm was 57% for NYHA I, 57% for NYHA II, and 76% for NYHA III (p <0.001). Multivariate models demonstrated similar long-term mortality risk reduction with ICD compared with the non-ICD treatment arm regardless of HF symptoms: NYHA I (HR = 0.63, 0.46 to 0.85, p = 0.003), NYHA II (HR = 0.68, 0.50 to 0.93, p = 0.017), and NYHA III (HR = 0.68, 0.50 to 0.94, p = 0.018); p for NYHA class by treatment arm interaction >0.10. In conclusion, primary ICD therapy provides consistent long-term survival benefit among patients with previous myocardial infarction and severe left ventricular dysfunction, regardless of HF symptoms.

Survival benefit of the primary prevention implantable cardioverter-defibrillator among older patients: does age matter? An analysis of pooled data from 5 clinical trials.

The impact of patient age on the risks of death or rehospitalization after primary prevention implantable cardioverter-defibrillator (ICD) placement is uncertain. Data from 5 major ICD trials were merged: the Multicenter Automatic Defibrillator Implantation Trial I (MADIT-I), the Multicenter UnSustained Tachycardia Trial (MUSTT), the Multicenter Automatic Defibrillator Implantation Trial II (MADIT-II), the Defibrillators in Nonischemic Cardiomyopathy Treatment Evaluation Trial (DEFINITE), and the Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT). Median age at enrollment was 62 (interquartile range 53-70) years. Compared with their younger counterparts, older patients had a greater burden of comorbid illness. In unadjusted exploratory analyses, ICD recipients were less likely to die than nonrecipients in all age groups: among patients aged <55 years: hazard ratio 0.48, 95% posterior credible interval 0.33 to 0.69; among patients aged 55 to 64 years: hazard ratio 0.69, 95% posterior credible interval 0.53 to 0.90; among patients aged 65 to 74 years: hazard ratio 0.67, 95% posterior credible interval, 0.53 to 0.85; and among patients aged ≥75 years: hazard ratio 0.54, 95% posterior credible interval 0.37 to 0.78. Sample sizes were limited among patients aged ≥75 years. In adjusted Bayesian-Weibull modeling, point estimates indicate ICD efficacy persists but is attenuated with increasing age. There was evidence of an interaction between age and ICD treatment on survival (two-sided posterior tail probability of no interaction <0.01). Using an adjusted Bayesian logistic regression model, there was no evidence of an interaction between age and ICD treatment on rehospitalization (two-sided posterior tail probability of no interaction 0.44). In this analysis, the survival benefit of the ICD exists but is attenuated with increasing age. The latter finding may be because of the higher burden of comorbid illness, competing causes of death, or limited sample size of older patients. There was no evidence that age modifies the association between ICD treatment and rehospitalization.

Improving implantable cardioverter defibrillator therapy through better programming

Implantable cardioverter defibrillator (ICD) therapy is a highly efficient, nonpharmacological treatment option that delivers rapid pacing stimuli, antitachycardia pacing (ATP) or shock to reduce death linked to the development of ventricular tachycardia (VT) or ventricular fibrillation among patients at high-risk for ventricular arrhythmias [1–3]. Despite the significant mortality benefit of ICDs, a high incidence (11.5–17.4%) of inappropriate device activation has been reported owing to supraventricular arrhythmias and atrial fibrillation [4,5]. As presented in a substudy of the Multicenter Automatic Defibrillator Implantation Trial-II (MADIT-II), inappropriate ICD therapy predominantly occurs in the 170–190 bpm heart rate range [4]. Inappropriate ICD therapies are associated with impaired quality of life [6] and adverse clinical outcome [7,8]. Some studies suggested an increased mortality with inappropriate ICD activation in this patient population [4,7,8].

Primary Prevention Implantable Cardioverter-Defibrillators

The benefit of implantable cardioverter-defibrillators (ICDs) in improving mortality in populations at risk for sudden cardiac death has been firmly established by multiple randomized controlled trials (RCTs).1–3 However, patients receiving ICDs in clinical practice differ substantially from those enrolled in landmark RCTs. In the most recent report of the US National Cardiovascular Data Registry (NCDR) ICD Registry, including more than half a million ICD implants, ICD recipients were older and sicker, with higher prevalences of diabetes mellitus, hypertension, and atrial fibrillation, than those enrolled in the Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT) and the Multicenter Automatic Defibrillator Implantation Trial II (MADIT-II).1,3,4 Whether these patients enjoy a similar survival benefit to those enrolled in the clinical trials is less well understood. Determining the benefits of ICDs in the real world is a subject of increasing importance, especially as healthcare costs continue to rise. Article see p 706 In this issue of Circulation: Arrhythmias and Electrophysiology , Parkash et al5 compared the mortality rates in real-world patients in Nova Scotia receiving ICDs for primary prevention of ischemic or nonischemic cardiomyopathy (n=290) with comparable patients not receiving ICDs (n=601), using data from 2 registries. The study also described ICD utilization rates. They found that the ICD patients had significantly improved survival and also that ICD referral/implantation rates suggested significant underutilization. …

Applicability of a Risk Score for Prediction of the Long-Term (8-Year) Benefit of the Implantable Cardioverter-Defibrillator

The present study was designed to explore the 8-year survival benefit of a nonresynchronization implantable cardioverter-defibrillator (ICD) according to a simple risk stratification score. There is limited information regarding factors that predict the benefit of primary prevention with an ICD during long-term follow-up. This study used a previously developed risk score including 5 clinical factors (New York Heart Association functional class >II, age >70 years, blood urea nitrogen >26 mg/dl, QRS duration >0.12 s, and atrial fibrillation) to evaluate 8-year ICD survival benefit within risk score categories among 1,191 MADIT-II (Multicenter Automatic Defibrillator Implantation Trial II) patients. Patients with low (0 risk factors, n = 345) and intermediate risk (1 to 2 risk factors, n = 646) demonstrated a significantly higher probability of survival at 8-year follow-up when treated by ICD as compared with non-ICD therapy (75% vs. 58%, p = 0.004; and 47% vs. 31%, p < 0.001, respectively). By contrast, among high-risk patients (3 or more risk factors, n = 200), there was no significant difference in 8-year survival between the ICD and non-ICD subgroups (19% vs. 17%, p = 0.50). Consistently, multivariate analysis showed that ICD therapy was associated with a significant long-term survival benefit among low- and intermediate-risk patients (hazard ratio [HR]: 0.52, p < 0.001, and HR: 0.66, p < 0.001, respectively), whereas treatment with an ICD was not associated with a significant benefit among high-risk patients (HR: 0.84, p = 0.25). These findings suggest that a simple risk score can identify patients who derive significant long-term benefit from primary ICD therapy. High-risk patients with multiple comorbidities composed 17% of the MADIT-II population and did not derive long-term benefit from nonresynchronization device therapy.

The Relevance of the Primary Prevention Criteria for Implantable Cardioverter Defibrillator Implantation in Korean Symptomatic Severe Heart Failure Patients

Background and ObjectivesImplantable cardioverter defibrillator (ICD) therapy is recommended as the primary tool for prevention of sudden cardiac death (SCD) in symptomatic patients with severe left ventricular dysfunction. There is a paucity of information on whether this recommendation is appropriate for the Korean population with severe heart failure.Subjects and MethodsThe study group consisted of 275 consecutive patients (mean age 65 years, 71% male) who met the ICD implantation criteria for primary prevention (left ventricular ejection fraction ≤30% and New York Heart Association functional class II or III). We analyzed the clinical characteristics and outcomes of an ischemic cardiomyopathy (ICMP) group (n=131) and a non-ischemic cardiomyopathy (NICMP) group (n=144). The outcomes of these 2 groups were compared with the Multicenter Automatic Defibrillator Implantation Trial II (MADIT-II) conventional and Defibrillators in the Non-ischemic Cardiomyopathy Treatment Evaluation (DEFINITE) standard therapy groups, respectively.ResultsEighty patients (29%) died during a follow-up period of 40±17 months. The NICMP group had better all-cause mortality rates than the ICMP group (19% vs. 40%, p<0.001), however both groups had a similar incidence of SCD (7% vs. 10%, p=0.272). The 2-year all-cause mortality and SCD for the ICMP group were similar to those of the MADIT-II conventional therapy group (20% vs. 20%, 7% vs. 10%, respectively, all p>0.05). All-cause mortality and the incidence of SCD in the NICMP group were comparable to those of the DEFINITE standard therapy group (13% vs. 17%, 6% vs. 6%, respectively, all p>0.05).ConclusionKorean patients with severe heart failure in both the ICMP and NICMP groups had all-caused mortality and risk of SCD comparable to patients in the MADIT-II and DEFINITE standard therapy groups. Therefore, the primary prevention criteria for ICD implantation would be appropriate in both Korean ICMP and NICMP patients.

Response to Letter Regarding Article, “Pathogenesis of Sudden Unexpected Death in a Clinical Trial of Patients With Myocardial Infarction and Left Ventricular Dysfunction, Heart Failure, or Both”

We thank Dr McEvoy for his interest in our article.1 Despite an increased risk of sudden death in the first weeks after myocardial infarction (MI), a retrospective analysis of Multicenter Automatic Defibrillator Implantation Trial II (MADIT-II),2 the prospective randomized Defibrillator in Acute Myocardial Infarction (DINAMIT),3 and the Immediate Risk Stratification Improves Survival (IRIS)4 trials did not show a benefit of early implantable cardioverter-defibrillator (ICD) implantation after MI in patients with low ejection fraction. As pointed out by Dr McEvoy, the DINAMIT and IRIS trials also concluded that, although ICD therapy was associated with a reduction in the rate of arrhythmic death that was offset by an increase in the rate of nonarrhythmic death, high rates of cardiac mortality in the ICD group were from mechanisms other than tachyarrhythmia. Because the results of these trials were neutral, it is important to …

Risk Factors for Recurrent Heart Failure Events in the Multicenter Automatic Defibrillator Implantation Trial II (MADIT‐II)

Risk Factors for Recurrent Heart Failure. This study was designed to identify risk factors for recurrent heart failure (HF) events in patients with ischemic left ventricular dysfunction enrolled in the Multicenter Automatic Defibrillator Implantation Trial II (MADIT-II). The Prentice, Williams, and Peterson (PWP) statistical model was utilized to identify and compare risk factors for 1 or ≥ 2 HF hospitalizations among 1,218 patients with ischemic left ventricular dysfunction enrolled in the MADIT-II trial. Risk factors for a first HF hospitalization included treatment with an ICD (HR = 1.31; P = 0.05), New York Heart Association class > II (HR = 1.95; P < 0.001), female gender (HR = 1.38; P = 0.05), atrial fibrillation (HR = 1.90; P = 0.001), QRS >120 ms (HR = 1.41; P = 0.01), diabetes mellitus (HR = 1.51; P = 0.003), heart rate ≥ 80 (HR = 1.35; P = 0.04), diuretic therapy (HR = 1.82; P < 0.001), and the presence of prerenal azotemia (defined as blood urea nitrogen:creatinine > 20; HR = 1.45; P = 0.01). In contrast, prerenal azotemia was the only risk factor that was independently associated with a significant increase in the risk of ≥ 2 HF hospitalizations (HR = 1.52; P = 0.027). The occurrence of 1 HF event after enrollment was associated with a 2.8-fold (P < 0.001) increase in the risk of death, whereas after the occurrence of a second event there was a 6.7-fold (P < 0.001) increase in the risk of subsequent mortality. In MADIT-II, prerenal azotemia was the only significant and independent risk factor for HF progression after a first event, and recurrent HF was the most powerful predictor of mortality. These findings stress the importance of identifying risk factors for HF progression among patients who receive an ICD for primary prevention.

Long-Term Benefit of Primary Prevention With an Implantable Cardioverter-Defibrillator

Background— The Multicenter Automatic Defibrillator Implantation Trial II (MADIT-II) showed a significant 31 reduction in the risk of death with primary implantable cardioverter-defibrillator (ICD) therapy during a median follow-up of 1.5 years. However, currently there are no data on the long-term efficacy of primary defibrillator therapy. Methods and Results— MADIT-II enrolled 1232 patients with ischemic left ventricular dysfunction who were randomized to ICD and non-ICD medical therapy and were followed up through November 2001. For the present long-term study, we acquired posttrial mortality data through March 2009 for all study participants (median follow-up, 7.6 years). Multivariate Cox proportional hazards regression modeling was performed to calculate the hazard ratio for ICD versus non-ICD therapy during long-term follow-up. At 8 years of follow-up, the cumulative probability of all-cause mortality was 49 among patients treated with an ICD compared with 62 among non-ICD patients ( P &lt;0.001). Multivariate analysis demonstrated that ICD therapy was associated with a significant long-term survival benefit (hazard ratio for 0- through 8-year mortality=0.66 [95 confidence interval, 0.56 to 0.78]; P &lt;0.001). Treatment with an ICD was shown to be associated with a significant reduction in the risk of death during the early phase of the extended follow-up period (0 through 4 years: hazard ratio=0.61 [95 confidence interval, 0.50 to 0.76]; P &lt;0.001) and with continued life-saving benefit during the late phase of follow-up (5 through 8 years: hazard ratio=0.74 [95 confidence interval, 0.57 to 0.96]; P =0.02). Conclusions— Our findings demonstrate a sustained 8-year survival benefit with primary ICD therapy in the MADIT-II population.

Clinical Summaries

Clinical Summaries

ICD shocks: Not just the “straw that broke the camel's back”

ICD shocks: Not just the “straw that broke the camel's back”

Relation of Body Mass Index to Sudden Cardiac Death and the Benefit of Implantable Cardioverter–Defibrillator in Patients With Left Ventricular Dysfunction After Healing of Myocardial Infarction

Obesity has been identified as a risk factor for cardiovascular disease and heart failure. However, data regarding the relation of body mass index (BMI) to outcome in patients with established heart failure are conflicting. We examined the risk of all-cause mortality and sudden cardiac death (SCD) in 1,231 patients after myocardial infarction with left ventricular dysfunction enrolled the Multicenter Automatic Defibrillator Implantation Trial-II (MADIT-II). Interaction-term analysis was used to assess the benefit of the implantable cardioverter-defibrillator (ICD) in upper (obese > or =30 kg/m(2), n = 361) and lower (nonobese <30 kg/m(2), n = 870) BMI categories. Mean BMI in the study population was 27.9 +/- 5.1 kg/m(2). In multivariate analysis, decreased BMI was shown to be independently associated with an increase in the risk of all-cause mortality (23% risk increase per 5-U BMI decreased, p = 0.009) and SCD (41% risk increase per 5-U BMI decrease, p = 0.01). Consistently, patients with BMI <30 kg/m(2) exhibited 46% (p = 0.03) and 76% (p = 0.04) increases in risk of all-cause mortality and SCD, respectively, compared to patients who had higher BMI values. The benefit of the ICD was pronounced in higher-risk patients with BMI <30 kg/m(2) (hazard ratio 0.68, p = 0.017) and maintained in the lower-risk subgroup of patients with BMI > or =30 kg/m(2) (hazard ratio 0.73, p = 0.32; p = 0.86 for ICD-by-BMI interaction). In conclusion, our findings suggest an independent inverse association between BMI values and risk of all-cause mortality and SCD in patients after myocardial infarction with left ventricular dysfunction enrolled in the MADIT-II trial.

Does Microvolt T-Wave Alternans Testing Predict Ventricular Tachyarrhythmias in Patients With Ischemic Cardiomyopathy and Prophylactic Defibrillators?: The MASTER (Microvolt T Wave Alternans Testing for Risk Stratification of Post-Myocardial Infarction Patients) Trial

The purpose of this trial was to determine whether microvolt T-wave alternans (MTWA) predicts ventricular tachyarrhythmic events (VTEs) in post-myocardial infarction patients with left ventricular ejection fraction (LVEF) < or =30%.Previous studies have established MTWA as a predictor for total and arrhythmic mortality, but its ability to identify prophylactic implantable cardioverter-defibrillator (ICD) recipients most likely to experience VTEs remains uncertain.This prospective trial was conducted at 50 U.S. centers. Patients were eligible if they met MADIT-II (Multicenter Automatic Defibrillator Implantation Trial II) indications for device implant. All patients underwent MTWA testing followed by ICD implantation, with pre-specified programming to minimize the likelihood of therapies for non-life-threatening VTE. Minimum follow-up was 2 years with annual MTWA testing. Initially indeterminate MTWA tests were repeated.Analyses were conducted on 575 patients (84% male; average age +/- SD = 65 +/- 11 years; average LVEF +/- SD = 0.24 +/- 0.05). The final distribution of MTWA results were: MTWA positive in 293 (51%), MTWA negative in 214 (37%), and indeterminate in 68 patients (12%). Over an average follow-up of 2.1 +/- 0.9 years, there were 70 VTEs. A VTE occurred in 48 of 361 (13%, 6.3%/year) MTWA non-negative and 22 of 214 (10%, 5.0%/year) MTWA negative patients. A non-negative MTWA test result was not associated with VTE (hazard ratio: 1.26; 95% confidence interval: 0.76 to 2.09; p = 0.37), although total mortality was significantly increased (hazard ratio: 2.04; 95% confidence interval: 1.10 to 3.78; p = 0.02).In MADIT-II-indicated ICD-treated patients, the risk of VTE does not differ according to MTWA classification, despite differences in total mortality. (MASTER I-Microvolt T Wave Alternans Testing for Risk Stratification of Post MI Patients; NCT00305240).

Should patients with congenital heart disease and a systemic ventricular ejection fraction less than 30% undergo prophylactic implantation of an ICD?

A number of important prospective studies have firmly validated the idea that patients at elevated risk for sudden cardiac death (SCD) can have that risk reduced by the use of implantable cardioverter defibrillators (ICDs). Among patients resuscitated from a potentially lethal cardiac event, ICD placement is termed secondary prevention. Primary prevention is the extension of this protective principle to groups of patients who have yet to experience a cardiac arrest, but who by virtue of specific and carefully defined clinical characteristics are determined to be at elevated risk for this event. Response by Silka and Bar-Cohen see p 317 Given the cost of ICD therapy and the number of patients who may meet primary prevention indications, the potential societal cost of this approach to cardiac risk management is high. In the past decade, this has driven a vigorous debate within the fields of heart rhythm management and health care economics as to the optimal ways to delineate patient groups that will most benefit from ICD therapy. The Multicenter Automatic Defibrillator Implantation Trial II (MADIT-II) study1 was a milestone in the evolution of this debate, providing evidence that a large group of patients—those with ischemic cardiomyopathy—could be rapidly and noninvasively sorted on the basis of left ventricular (LV) ejection fraction, with those having severe LV dysfunction realizing a clear survival benefit from ICD therapy. In this article, I challenge the proposition that MADIT-II and subsequent studies of the efficacy of ICD therapy in patients with acquired LV dysfunction can be applied to patients with moderate to severe systemic ventricular dysfunction in congenital heart disease (CHD). To make this argument, several topical areas must be considered. These include the current state of clinical knowledge of the natural history of CHD in adolescents and adults, the known rates of sudden death in …

Risk stratification of patients with prior myocardial infarction and advanced left ventricular dysfunction by gated myocardial perfusion SPECT imaging

The Multicenter Automatic Defibrillator Implantation Trial II (MADIT-II) has shown that the prophylactic implantable cardiac defibrillator improves the survival rate of patients with prior myocardial infarction and advanced left ventricular (LV) dysfunction. However, a more accurate noninvasive predictor should be found to identify subgroups at high risk, one that would allow implantable cardiac defibrillator therapy to be directed specifically to the patients who would benefit most. To elucidate whether technetium 99m tetrofosmin electrocardiogram-gated single photon emission computed tomography (SPECT) imaging at rest can determine the risk of arrhythmic death, 106 patients who met the MADIT-II criteria (LV ejection fraction <or=0.3, myocardial infarction >1 month earlier, and no sustained ventricular tachyarrhythmia) were recruited from a pool of 4628 consecutive patients who had undergone resting Tc-99m tetrofosmin SPECT imaging. By use of the endpoints of lethal arrhythmic events, which included documentation of sustained ventricular tachycardia, ventricular fibrillation, or diagnosis of sudden cardiac death, we performed follow-up for a mean of 30 months. Lethal arrhythmic events occurred in 14 patients. Patients with lethal arrhythmic events had a lower LV ejection fraction, greater LV end-systolic and end-diastolic volume indices, and a greater perfusion defect volume than the remaining patients. By receiver operating characteristic curve analysis, myocardial defect volume was the strongest predictor for the development of lethal arrhythmic events. Our results confirm that perfusion defect volume by Tc-99m tetrofosmin scintigraphy is the most pivotal predictor of the future occurrence of lethal arrhythmic events and of sudden cardiac death. Tc-99m tetrofosmin SPECT images may assist in identifying subsets of patients with a greater likelihood of arrhythmic death among patients with LV dysfunction.

Life Versus Death

Randomized clinical trials have clearly shown that the implanted cardiac defibrillator (ICD) saves lives1–3 and that cardiac resynchronization therapy (CRT) and combined ICD and CRT devices reduce both heart failure and mortality.4–6 However, during long-term follow-up of patients with these implanted devices, only a minority will use appropriate ICD therapy for life-threatening ventricular tachyarrhythmic events. For example, in the Multicenter Automatic Defibrillator Implantation Trial II (MADIT-II), only 35% of the patients in the ICD arm received appropriate ICD therapy (shock or antitachycardia pacing) during 3-year follow-up.7 The challenge facing the medical profession is how to better identify and select patients who will benefit from implanted ICD or combined ICD and CRT devices so as to achieve greater therapeutic efficacy without losing patients. During recent years, several noninvasive and invasive electrophysiological tests have been evaluated, including signal-averaged ECG, heart rate variability, heart rate turbulence, T-wave alternans, and programmed electrophysiological testing, but the risk-stratification results from these tests have not been very encouraging. Recently, Goldenberg et al demonstrated that the ICD:conventional therapy hazard ratio in patients with advanced renal disease (blood urea nitrogen >50 mg/dL) and in good-risk patients without adverse clinical factors such as heart failure, atrial fibrillation, older age, and wide QRS complex, renal dysfunction was close to 1.0 in 35% of the …

Association of prolonged QRS duration with ventricular tachyarrhythmias and sudden cardiac death in the Multicenter Automatic Defibrillator Implantation Trial II (MADIT-II)

There is conflicting literature on the relationship between prolonged QRS duration (QRSd) and arrhythmic events, including sudden cardiac death (SCD), in heart failure patients with or without implantable cardioverter-defibrillators (ICDs). The purpose of this study was to evaluate the prognostic significance of prolonged QRSd relative to arrhythmic outcomes in medically and ICD-treated patients enrolled in the Multicenter Automatic Defibrillator Implantation Trial (MADIT) II. Using a Cox proportional hazards model adjusting for ejection fraction, heart failure class, and blood urea nitrogen, we estimated the association of prolonged QRSd >/=140 ms with SCD in the medically treated arm and SCD or first appropriate ICD therapy for rapid ventricular tachycardia/fibrillation (VT/VF; cycle length </=260 ms) in the ICD-treated arm. In the medically treated arm, prolonged QRSd was a significant independent predictor of SCD (hazard ratio 2.12; 95% confidence interval 1.20-3.76; P = .01). However, in the ICD-treated arm, prolonged QRSd did not predict SCD or rapid VT/VF (hazard ratio 0.77; 95% CI 0.47-1.24; P = .28). The difference in the prognostic effect of prolonged QRSd in these two groups was significant (P<.01). These results were not affected by varying the cycle length that defines rapid VT/VF or the duration that defines QRSd prolongation. In patients with prior myocardial infarction and EF </=30%, prolonged QRSd does not predict SCD/VT/VF in ICD-treated patients but does predict SCD in medically treated patients. This underscores the nonequivalence of VT/VF and SCD and the need for caution in inferring risk of SCD when using nonrandomized databases that include only patients with ICDs.

Abstract 2429: ICD Efficacy In Patients Who Developed New Onset Atrial Fibrillation After Enrollment In The MADIT-II Trial

Introduction: In the Multicenter Automatic Defibrillator Implantation Trial-II (MADIT-II), the presence of atrial fibrillation (AF) at baseline was associated with an increased risk of death, and these patients received a substantial benefit from ICD therapy. In the current study, we evaluated the risk of death and the efficacy of ICD therapy in patients who developed new-onset AF after enrollment in the MADIT-II study. Methods/Results: Hazard ratios (HR) were determined using multivariate Cox proportional hazards method. Age ≥ 65 (HR 3.02, p &lt; 0.01), QRS duration &gt; 120 ms (HR 2.30, p &lt; 0.01), and NYHA functional class ≥ 2 (HR 1.78, p = 0.03) were independent predictors of new-onset AF. In both treatment arms, there was a significant increase in the risk of death after developing new-onset AF (Post-AF) (n = 25 in conventional arm, n = 51 in ICD arm) than among patients before or without AF (Pre-AF) (n = 416 in conventional arm, n = 624 in ICD arm) as shown in the Mantel-Byar graphs. After adjusting for relevant covariates (including age, BUN, EF, and beta-blocker use), ICD therapy was associated with a greater reduction in the risk of death in patients who developed new-onset AF (HR 0.31, p = 0.013) compared to patients with no interim AF (HR 0.73, p = 0.055) [p = 0.085 for interaction between interim AF and ICD therapy]. Conclusions: The development of new-onset AF is associated with a significant increase in mortality and this group may be a target for closer follow-up and more aggressive treatment. ICD therapy was highly effective in reducing mortality in MADIT-II patients who developed new-onset AF after enrollment in the trial.

Ventricular arrhythmia storms in postinfarction patients with implantable defibrillators for primary prevention indications: A MADIT-II substudy

Much of prognostic implications of ventricular arrhythmia storms remain unclear. We evaluated the risk associated with electrical storm in patients with defibrillators in the Multicenter Automatic Defibrillator Implantation Trial II (MADIT-II) study. Electrical storm was defined as > or =3 episodes of ventricular tachycardia (VT) or ventricular fibrillation (VF) in 24 hours. Of the 719 patients who received internal cardiac defibrillator (ICD) implants and had follow-up in the MADIT-II, 27 patients (4%) had electrical storm, 142 (20%) had isolated episodes of VT/VF, and the remaining 550 patients had no ICD-recorded VT events. Baseline clinical characteristics among the groups were similar. Patients who experienced electrical storm had a significantly higher risk of death. After adjustments for relevant clinical covariates, the hazard ratio (HR) for death in the first 3 months after the storm event was 17.8 (95% confidence interval [CI] 8.0 to 39.5, P <.01) in comparison with those with no VT/VF. This risk continued even after 3 months for those with electrical storm (HR of 3.5, 95% CI 1.2 to 9.8, P = .02). Study patients with isolated VT/VF episodes also were at an increased risk of dying (HR = 2.5, 95% CI 1.5 to 4.0, P <.01) when compared with patients without VT/VF episodes. Statistically significant predictors of electrical storm were interim postenrollment coronary events (myocardial infarction or angina) HR 3.1 (95% CI 1.2 to 8.1, P = .02) and isolated VT or VF HR 9.2 (95% CI 4.0 to 20.9, P <.01). Postinfarction patients with severe left ventricular dysfunction in whom electrical storm developed have significantly higher mortality than patients with only isolated VT/VF as well as those without any episodes of VT/VF. Patients who experienced postenrollment ventricular arrhythmias and/or interim coronary events during follow-up were at higher risk for VT/VF storms.