Defibrillators In Non-Ischemic Cardiomyopathy Treatment Evaluation Research Articles

Heart failure patients unresponsive to implantable cardioverter-defibrillator therapy: a neglected problem.

Heart failure patients unresponsive to implantable cardioverter-defibrillator therapy: a neglected problem.

Implantable cardioverter-defibrillators in heart failure patients with reduced ejection fraction and diabetes.

There is limited information on the outcomes after primary prevention implantable cardioverter-defibrillator (ICD) implantation in patients with heart failure (HF) and diabetes. This analysis evaluates the effectiveness of a strategy of ICD plus medical therapy vs. medical therapy alone among patients with HF and diabetes. A patient-level combined-analysis was conducted from a combined dataset that included four primary prevention ICD trials of patients with HF or severely reduced ejection fractions: Multicenter Automatic Defibrillator Implantation Trial I (MADIT I), MADIT II, Defibrillators in Non-Ischemic Cardiomyopathy Treatment Evaluation (DEFINITE), and Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT). In total, 3359 patients were included in the analysis. The primary outcome of interest was all-cause death. Compared with patients without diabetes (n = 2363), patients with diabetes (n = 996) were older and had a higher burden of cardiovascular risk factors. During a median follow-up of 2.6 years, 437 patients without diabetes died (178 with ICD vs. 259 without) and 280 patients with diabetes died (128 with ICD vs. 152 without). ICDs were associated with a reduced risk of all-cause mortality among patients without diabetes [hazard ratio (HR) 0.56, 95% confidence interval (CI) 0.46-0.67] but not among patients with diabetes (HR 0.88, 95% CI 0.7-1.12; interaction P = 0.015). Among patients with HF and diabetes, primary prevention ICD in combination with medical therapy vs. medical therapy alone was not significantly associated with a reduced risk of all-cause death. Further studies are needed to evaluate the effectiveness of ICDs among patients with diabetes.

Wearable Cardioverter-Defibrillator Therapy for the Prevention of Sudden Cardiac Death: A Science Advisory From the American Heart Association.

Sudden cardiac death (SCD) accounts for >300 000 deaths in the United States annually.1 Although the majority of these deaths occur in low-risk populations2 in which aggressive interventions are not practical, some higher-risk populations have been established in whom intervention with an implantable cardioverter-defibrillator (ICD) has been shown in randomized trials to reduce mortality.3–7 Additionally, there is a population of patients who may benefit from automatic emergency cardioversion-defibrillation but are not deemed appropriate candidates for ICD implantation at the time of presentation. This group is defined by 2 populations. The first subgroup comprises those who are at perceived risk but for whom there may be optimism for clinical improvement (eg, patients soon after revascularization or those with a recent diagnosis of myocardial infarction [MI] or cardiomyopathy). Alternatively stated, the optimal management of these patients at risk (or perceived risk) during the waiting period before an ICD is indicated remains unknown. The second subgroup includes those who have a clear indication for ICD but also have a contraindication to immediate ICD placement (eg, active infection or unknown prognosis). The wearable cardioverter-defibrillator (WCD) is a device designed for patients at risk of SCD who are not immediate candidates for ICD therapy. By providing automatic therapy, the WCD does not depend on a second person to defibrillate, as required with a manual or automated external defibrillator (AED). Unlike the ICD (including both transvenous and subcutaneous devices), the WCD requires no surgical operation, can be provided for a short period of time, is temporary, and is easily removed. These characteristics of the WCD, along with safety and efficacy data presented to the US Food and Drug Administration (FDA), resulted in approval in the United States in 2002.8 Because of the increasing use of the WCD and uncertainty of indications …

Outcomes of Implantable Cardioverter-Defibrillator Use in Patients With Comorbidities: Results From a Combined Analysis of 4 Randomized Clinical Trials

ObjectivesThe aim of this study was to determine if the benefit of implantable cardioverter-defibrillators (ICDs) is modulated by medical comorbidity. BackgroundPrimary prevention ICDs improve survival in patients at risk for sudden cardiac death. Their benefit in patients with significant comorbid illness has not been demonstrated. MethodsOriginal, patient-level datasets from MADIT I (Multicenter Automatic Defibrillator Implantation Trial I), MADIT II, DEFINITE (Defibrillators in Non-Ischemic Cardiomyopathy Treatment Evaluation), and SCD-HeFT (Sudden Cardiac Death in Heart Failure Trial) were combined. Patients in the combined population (N = 3,348) were assessed with respect to the following comorbidities: smoking, pulmonary disease, diabetes, peripheral vascular disease, atrial fibrillation, ischemic heart disease, and chronic kidney disease. The primary outcome was overall mortality, using the hazard ratio (HR) of time to death for patients receiving an ICD versus no ICD by extent of medical comorbidity, and adjusted for age, sex, race, left ventricular ejection fraction, use of antiarrhythmic drugs, beta-blockers, and angiotensin-converting enzyme inhibitors. ResultsOverall, 25% of patients (n = 830) had <2 comorbid conditions versus 75% (n = 2,518) with significant comorbidity (≥2). The unadjusted hazard of death for patients with an ICD versus no ICD was significantly lower, but this effect was less for patients with ≥2 comorbidities (unadjusted HR: 0.71; 95% confidence interval: 0.61 to 0.84) compared with those with <2 comorbidities (unadjusted HR: 0.59; 95% confidence interval: 0.40 to 0.87). After adjustment, the benefit of an ICD decreased with increasing number of comorbidities (p = 0.004). ConclusionsPatients with extensive comorbid medical illnesses may experience less benefit from primary prevention ICDs than those with less comorbidity; implantation should be carefully considered in sick patients. Further study of ICDs in medically complex patients is warranted.

To the Editor—Should an improvement in left ventricular systolic function preclude ICD generator replacement?

Schliamser et al 1 Schliamser J.E. Kadish A.H. Subacius H. et al. DEFINITE Investigators. Significance of follow-up left ventricular ejection fraction measurements in the Defibrillators in Non-Ischemic Cardiomyopathy Treatment Evaluation trial (DEFINITE). Heart Rhythm. 2013; 10: 838-846 Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar evaluated the effect of left ventricular ejection fraction (LVEF) change on outcome in the DEFINITE (Defibrillators in Non-Ischemic Cardiomyopathy Treatment Evaluation) trial and concluded that LVEF improvement during follow-up was associated with improved survival but not with a significant decrease in appropriate shocks, thus supporting the idea that these patients still derive an important benefit from the implantable cardioverter-defibrillator (ICD). However, despite the novelty of the study, some of their findings may be questionable. Reply to the Editor—Should an Improvement in Left Ventricular Systolic Function Preclude ICD Generator Replacement?Heart RhythmVol. 10Issue 9PreviewIn their Letter to the Editor, Barra and Agarwal present a case supporting an alternative recommendation for the clinical implications of the post hoc analysis of change in left ventricular ejection fraction (LVEF) in the DEFINITE trial.1 Although they eloquently review many of the limitations related to the standards of device programming that existed at the time of the DEFINITE trial, post hoc analyses should be interpreted cautiously and have many caveats. They are rarely, if ever, incorporated in guidelines. Full-Text PDF

Arrhythmia and left ventricular ejection fraction: Once broken, always broken?

Left ventricular ejection fraction (LVEF) occupies a central place within current guidelines for implantable cardioveter-defibrillator (ICD) therapy in patients with nonischemic cardiomyopathy. The 2 largest trials recruited patients with an LVEF of ≤35% that was “stable” or “irreversible.” 1,2 Patients undergoing long-term treatment for nonischemic cardiomyopathy often have substantial improvements in LVEF, although the association with reduced arrhythmia risk has not been extensively studied. The Defibrillators in Non-Ischemic Cardiomyopathy Treatment Evaluation (DEFINITE) study included 458 patients with nonischemic cardiomyopathy, New York Heart Association class (NYHA) I–III symptoms, LVEF ≤35%, and ambient arrhythmias on Holter monitoring (ventricular ectopy or nonsustained ventricular tachycardia [NSVT]). All patients received optimal medical therapy and were randomized to receive an ICD or no device therapy. The trial reported a trend toward reduced mortality in the ICD arm, but did not achieve statistical significance. This may have been due to unexpectedly low mortality in the control arm. In this issue of HeartRhythm, Schliamser et al 3 investigate the relationship between changes in LVEF and clinical events in a post hoc analysis of the DEFINITE study. The protocol specified that LVEF should be assessed at yearly intervals, but only 17% patients had these data available. However, some repeated LVEF measurements were available in 197 of 449 (44%) patients and therefore these were studied. The patients were grouped according to the change in LVEF: 45% increase (group I), o5% change (group II), or 45% decrease (group III). An LVEF improvement was associated with substantial survival benefit (deaths in each group were 3.2%, 12.6%, and 33%, respectively). An improvement in NYHA class was also associated with improved survival. However, although group I had a tendency toward reduced arrhythmic events, this did not reach statistical significance. In 70 of 197 (36%) patients, LVEF increased to an absolute value of 435% but 4 of these patients went on to have an arrhythmic event after this improvement had occurred. The results of this retrospective analysis must be interpreted with caution. A large number of patients had to be excluded because follow-up LVEF assessments were not made. The patients in whom follow-up data were available had a higher incidence of ICD shocks, were more likely to be young and white, have diabetes, and have better 6-minute walk test results. Patients were categorized according to changes in LVEF of just 5%, with LVEF determination being performed according to the local hospital’s preference. Mostly, echocardiography was used, which has variable reproducibility and the assessors of LVEF were not blinded to other clinical information. While this is a technical limitation to the study, the data have been obtained within the context of standard clinical practice and, in this sense, may be more realistic. Why might recovery of LVEF not fully predict a reduction in arrhythmia risk? Nonischemic cardiomyopathy is an umbrella term that encompasses a wide range of pathological processes, with the end result being mechanical and electrical dysfunction. LVEF is just one marker of these disease processes. Electrolyte disturbances and stretch-induced arrhythmia may also contribute to arrhythmogenicity. Histological studies have shown increased fibrosis between cardiac muscle fibers and bundles that may enhance anisotropy and promote electrical uncoupling. This can provide the substrate for reentry during ventricular fibrillation. 4 In another small study of 29 patients undergoing ablation for ventricular arrhythmias in the presence of nonischemic cardiomyopathy, fibrosis was detected with magnetic resonance imaging in approximately half of the patients. 5 It is probable that fibrosis might persist even in patients whose LVEF improves. Other clinical parameters are also known to give an indication of arrhythmia risk. Left bundle branch block may be related to the presence of fibrosis.InthestudybySchliamser et al, there was a significantly lower proportion of patients with left bundle branch block in those with LVEF improvement. Other factors such as the presence of pulmonary hypertension, hyponatremia, NYHA class, and coexistent right-sided heart failure have prognostic significance. Logically, these additional pieces of information could contribute to risk stratification for

Significance of follow-up left ventricular ejection fraction measurements in the Defibrillators in Non-Ischemic Cardiomyopathy Treatment Evaluation trial (DEFINITE)

As left ventricular ejection fraction (LVEF) may improve, worsen, or remain the same over time, patients' prognosis may also be expected to change because of the change in LVEF, among other factors. To evaluate the effect of LVEF change on outcome in the Defibrillators in Non-Ischemic Cardiomyopathy Treatment Evaluation (DEFINITE) trial. Patients with nonischemic cardiomyopathy with LVEF<36%, history of symptomatic heart failure, and the presence of significant ventricular ectopic activity were enrolled in the DEFINITE trial. Follow-up LVEF measurements were obtained annually in only a minority (17%) of trial participants. This study therefore evaluated survival and arrhythmic end points in patients whose LVEF was reassessed between 90 and 730 days after enrollment. During the 90-730-day postrandomization period, 187 of 449 (42%) enrolled patients who survived at least 90 days had at least 1 follow-up LVEF measurement; these patients were younger and white; had diabetes, better 6-minute walk test results, and higher BMI; were more likely to have appropriate shocks; and had fewer deaths compared to those without follow-up LVEF measurements. Patients whose LVEF improved had reduced mortality compared to patients whose LVEF decreased (hazard ratio 0.09; 95% confidence interval 0.02-0.39; P = .001). Survival free of appropriate shocks was not significantly related to LVEF improvement during follow-up. LVEF improvement was associated with improved survival, but not with a significant decrease in appropriate shocks. These data highlight that appropriate caution should be exercised not to extrapolate the positive effect of improved LVEF to the elimination of arrhythmic events.

Ventricular Arrhythmia Inducibility Predicts Subsequent ICD Activation in Nonischemic Cardiomyopathy Patients: A DEFINITE Substudy

We evaluated whether electrophysiologic (EP) inducibility predicts the subsequent occurrence of spontaneous ventricular tachycardia (VT) or ventricular fibrillation (VF) in the Defibrillators in Nonischemic Cardiomyopathy Treatment Evaluation (DEFINITE) trial. Inducibility of ventricular arrhythmias has been widely used as a risk marker to select implantable cardioverter defibrillator (ICD) candidates, but is believed not to be predictive in nonischemic cardiomyopathy patients. In DEFINITE, patients randomized to the ICD arm, but not the conventional arm, underwent noninvasive EP testing via the ICD shortly after ICD implantation using up to three extrastimuli at three cycle lengths plus burst pacing. Inducibility was defined as monomorphic or polymorphic VT or VF lasting 15 seconds. Patients were followed for a median of 29 +/- 14 months (interquartile range = 2-41). An independent committee, blinded to inducibility status, characterized the rhythm triggering ICD shocks. Inducibility, found in 29 of 204 patients (VT in 13, VF in 16), was associated with diabetes (41.4% vs 20.6%, P = 0.014) and a slightly higher ejection fraction (23.2 +/- 5.9 vs 20.5 +/- 5.7, P = 0.021). In follow-up, 34.5% of the inducible group (10 of 29) experienced ICD therapy for VT or VF or arrhythmic death versus 12.0% (21 of 175) noninducible patients (hazard ratio = 2.60, P = 0.014). In DEFINITE patients, inducibility of either VT or VF was associated with an increased likelihood of subsequent ICD therapy for VT or VF, and should be one factor considered in risk stratifying nonischemic cardiomyopathy patients.

Sex differences in outcome after implantable cardioverter defibrillator implantation in nonischemic cardiomyopathy

Women have been underrepresented in randomized trials of implantable cardioverter defibrillator (ICD) therapy, and limited data suggest that women may not benefit from prophylactic ICD implantation to the same extent as men. In the Defibrillators in Non-Ischemic Cardiomyopathy Treatment Evaluation (DEFINITE) trial, a reduction in all-cause mortality was seen in men (P = .018) but not for women (P = .76). Sex-specific cumulative probabilities of event-free survival from total, arrhythmic, and noncardiac mortality as well as appropriate shocks were calculated, and log-rank tests were performed. Interaction terms in multivariable Cox proportional hazards models were used to test the hypothesis that the effectiveness of the ICD differed between men and women. Among 458 patients (326 men and 132 women) with nonischemic cardiomyopathy enrolled in the DEFINITE trial, the test for an interaction between sex and ICD treatment on total mortality was not significant in unadjusted (P = .11) or in multivariable adjusted (P = .18) analyses. When we examined cause-specific mortality, we found no sex difference in the incidence of arrhythmic death. Instead, we documented a relative excess of noncardiac death among women randomized to the ICD (P = .02) as compared with women randomized to standard medical therapy. With respect to device use, there was a trend for women to have fewer appropriate ICD shocks after multivariable adjustment (P = .06). Among patients with nonischemic cardiomyopathy enrolled in DEFINITE, we found no conclusive evidence for a sex difference in the effectiveness of the ICD; however, the trial was not adequately powered to detect such interaction effects. Larger studies are required to definitively address whether the benefit of ICD therapy differs between men and women.

Prognostic Value and Temporal Behavior of the Planar QRS-T Angle in Patients With Nonischemic Cardiomyopathy

The planar QRS-T angle can be easily obtained from standard 12-lead ECGs, but its predictive ability is not established. We sought to determine the predictive ability of the planar QRS-T angle in patients with nonischemic cardiomyopathy and to assess QRS-T angle behavior over time. Baseline QRS-T angles from 455 patients in the Defibrillators in Nonischemic Cardiomyopathy Treatment Evaluation (DEFINITE) trial were measured. All patients had nonischemic cardiomyopathy, New York Heart Association class I to III heart failure, and nonsustained ventricular tachycardia or frequent ventricular ectopy. The primary end point (a composite of total mortality, appropriate implantable cardioverter-defibrillator shock, or resuscitated cardiac arrest) occurred in 25 of 172 patients (14.5%) with a QRS-T angle < or =90 degrees and in 72 of 283 patients (25.4%) with a QRS-T angle >90 degrees (hazard ratio, 1.93; 95% confidence interval, 1.23 to 3.05; P=0.002). A QRS-T angle >90 degrees remained a significant predictor of the primary end point (P=0.039) after adjustment for treatment group, age, gender, QRS duration, left bundle-branch block, left ventricular ejection fraction, New York Heart Association class III, atrial fibrillation, and diabetes mellitus. The secondary end point (total mortality) occurred in 17 of the 172 patients (9.9%) with a QRS-T angle < or =90 degrees and in 49 of the 283 patients (17.3%) with a QRS-T angle >90 degrees (hazard ratio, 1.79; 95% confidence interval, 1.03 to 3.10; P=0.016). A sample of 152 patients with multiple follow-up ECGs was analyzed to assess temporal QRS-T angle behavior. Changes in the QRS-T angle correlated with changes in left ventricular ejection fraction and QRS duration over time (P<0.001). A planar QRS-T angle >90 degrees is a significant predictor of a composite end point of death, appropriate implantable cardioverter-defibrillator shock, or resuscitated cardiac arrest in nonpaced, mild to moderately symptomatic patients with nonischemic cardiomyopathy with frequent or complex ventricular ectopy. QRS-T angles changed predictably with left ventricular ejection fraction and QRS duration.

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

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

Effects of Statin Therapy on Arrhythmic Events and Survival in Patients With Nonischemic Dilated Cardiomyopathy

We sought to evaluate whether statins were associated with a survival benefit and significant attenuation in life-threatening arrhythmias in patients with nonischemic dilated cardiomyopathy. Statins are associated with a reduction in appropriate implantable cardioverter-defibrillator (ICD) therapy in patients with coronary artery disease and improved clinical status in nonischemic dilated cardiomyopathy. The effect of statin use on time to death or resuscitated cardiac arrest and time to arrhythmic sudden death was evaluated in 458 patients enrolled in the DEFINITE (DEFIbrillators in Non-Ischemic cardiomyopathy Treatment Evaluation) study. The effect of statin use on time to first appropriate shock was analyzed only in the 229 patients who were randomized to ICD therapy. The unadjusted hazard ratio (HR) for death among patients on versus those not on statin therapy was 0.22 (95% confidence interval [CI] 0.09 to 0.55; p = 0.001). When controlled for statin effects, ICD therapy was associated with improved survival (HR 0.61; 95% CI 0.38 to 0.99; p = 0.04). There was one arrhythmic sudden death in the 110 patients receiving statin therapy (0.9%) versus 18 of 348 patients not receiving statins (5.2%; p = 0.04). The unadjusted HR for arrhythmic sudden death among patients on versus those not on statin therapy was 0.16 (95% CI 0.022 to 1.21; p = 0.08). The HR for appropriate shocks among patients on versus those not on statin therapy was 0.78 (95% CI 0.34 to 1.82) after adjustment for baseline differences in the two groups. Statin use in the DEFINITE study was associated with a 78% reduction in mortality. This reduction was caused, in part, by a reduction in arrhythmic sudden death. These findings should be confirmed in a prospective, randomized clinical trial.

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

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

Patients With Recently Diagnosed Nonischemic Cardiomyopathy Benefit From Implantable Cardioverter-Defibrillators

This study sought to determine whether the time from diagnosis to randomization was related to outcome in a clinical trial of implantable cardioverter-defibrillator (ICD) insertion in nonischemic cardiomyopathy. Whether the duration of nonischemic cardiomyopathy is related to arrhythmic risk and the possible benefit of ICD insertion is unknown. The Defibrillators in Nonischemic Cardiomyopathy Treatment Evaluation (DEFINITE) trial randomized 458 patients with nonischemic dilated cardiomyopathy and a left ventricular ejection fraction <36% to receive standard medical therapy with or without an ICD. Patients were randomized regardless of the duration of known cardiomyopathy as long as a reversible cause of left ventricular dysfunction was not present. Patients were divided into recently and remotely diagnosed nonischemic cardiomyopathy groups based on the time from diagnosis of cardiomyopathy to randomization. To categorize patients, cut points of three and nine months were used. Patients with recently diagnosed cardiomyopathy who received an ICD had better survival than those treated with standard therapy at both cut points. This difference in survival was significant at three months (p < 0.05) and was borderline significant at nine months (p = 0.058). Patients with remotely diagnosed cardiomyopathy did not have a significant survival benefit with ICD insertion, but there were no significant differences between ICD benefit in the recent and remote diagnosis groups (p = 0.17 and 0.25). Patients who have a recent cardiomyopathy diagnosis do not have any less ICD benefit than those with a remote diagnosis. Thus, ICD therapy should be considered in such patients as soon as they are identified as long as a reversible cause of left ventricular dysfunction is excluded.

Preserved heart rate variability identifies low-risk patients with nonischemic dilated cardiomyopathy: Results from the DEFINITE trial

The recent expansion of indications for prophylactic implantable cardioverter-defibrillator (ICD) placement in subjects with nonischemic dilated cardiomyopathy has raised concerns about the cost-effectiveness of this therapy. The purpose of this study was to identify low-risk patients with nonischemic dilated cardiomyopathy who may not require prophylactic ICD placement. This was a prospective study of 274 participants in the Defibrillators in Non-Ischemic Cardiomyopathy Treatment Evaluation (DEFINITE) trial, a randomized controlled trial that evaluated the role of prophylactic ICD placement in patients with nonischemic dilated cardiomyopathy. The patients underwent 24-hour Holter recording for analysis of heart rate variability (HRV). The primary HRV variable was the standard deviation of normal R-R intervals (SDNN). Patients with atrial fibrillation and frequent ventricular ectopy (>25% of beats) were excluded from HRV analysis (23% of patients). SDNN was categorized in tertiles, and Kaplan-Meier analysis was performed to compare survival in the three tertiles and excluded patients. The study population was 73% male, with a mean age of 59 +/- 12 years and mean left ventricular ejection fraction of 21% +/- 6%. After 3-year follow-up, significant differences in mortality rates were observed: SDNN >113 ms: 0 (0%), SDNN 81-113 ms: 5 (7%), SDNN <81 ms: 7 (10%), excluded patients: 11 (17%) (P = .03). There were no deaths in the tertile with SDNN >113 ms regardless of treatment assignment (ICD vs control). Patients with nonischemic dilated cardiomyopathy and preserved HRV have an excellent prognosis and may not benefit from prophylactic ICD placement. Patients with severely depressed HRV and patients who are excluded from HRV analysis because of atrial fibrillation and frequent ventricular ectopy have the highest mortality.

Are Implantable Cardioverter Defibrillator Shocks a Surrogate for Sudden Cardiac Death in Patients With Nonischemic Cardiomyopathy?

Ventricular tachyarrhythmias long enough to cause implantable cardioverter defibrillator (ICD) shocks are generally thought to progress to cardiac arrest. In previous ICD trials, shocks have been considered an appropriate surrogate for sudden cardiac death (SCD) because the number of shocks has been thought to be equivalent to the mortality excess in patients without ICDs. The practice of equating ICD shocks with mortality is controversial and has not been validated critically. The Defibrillators in Non-Ischemic Cardiomyopathy Treatment Evaluation (DEFINITE) trial was a prospective, randomized, multicenter trial of ICD therapy in 458 patients with nonischemic cardiomyopathy. Patients were randomized to receive standard medical therapy (STD) or STD plus an ICD. Shock electrograms were reviewed, and the cause of death was evaluated by a separate blinded events committee. There were 15 SCD or cardiac arrests in the STD group and only 3 in the ICD arm. In contrast, of the 229 patients randomized to an ICD, 33 received 70 appropriate ICD shocks. Patients in the ICD arm were more likely to have an arrhythmic event (ICD shock plus SCD) than patients in the STD arm (hazard ratio 2.12, 95% CI 1.153 to 3.893, P=0.013). The number of arrhythmic events when one includes syncope as a potential arrhythmic event was similar in both groups (hazard ratio 1.20, 95% CI 0.774 to 1.865, P=0.414). Approximately the same number of total events was noted in each arm when we compared syncope plus SCD/cardiac arrest in the STD arm with SCD plus ICD shocks plus syncope in the ICD arm. Appropriate ICD shocks occur more frequently than SCD in patients with nonischemic cardiomyopathy. This suggests that episodes of nonsustained ventricular tachycardia frequently terminate spontaneously in such patients.

Cost-Effectiveness of Implantable Cardioverter–Defibrillators

Eight randomized trials have evaluated whether the prophylactic use of an implantable cardioverter-defibrillator (ICD) improves survival among patients who are at risk for sudden death due to left ventricular systolic dysfunction but who have not had a life-threatening ventricular arrhythmia. We assessed the cost-effectiveness of the ICD in the populations represented in these primary-prevention trials. We developed a Markov model of the cost, quality of life, survival, and incremental cost-effectiveness of the prophylactic implantation of an ICD, as compared with control therapy, among patients with survival and mortality rates similar to those in each of the clinical trials. We modeled the efficacy of the ICD as a reduction in the relative risk of death on the basis of the hazard ratios reported in the individual clinical trials. Use of the ICD increased lifetime costs in every trial. Two trials--the Coronary Artery Bypass Graft (CABG) Patch Trial and the Defibrillator in Acute Myocardial Infarction Trial (DINAMIT)--found that the prophylactic implantation of an ICD did not reduce the risk of death and thus was both more expensive and less effective than control therapy. For the other six trials--the Multicenter Automatic Defibrillator Implantation Trial (MADIT) I, MADIT II, the Multicenter Unsustained Tachycardia Trial (MUSTT), the Defibrillators in Non-Ischemic Cardiomyopathy Treatment Evaluation (DEFINITE) trial, the Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure (COMPANION) trial, and the Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT)--the use of an ICD was projected to add between 1.01 and 2.99 quality-adjusted life-years (QALY) and between 68,300 dollars and 101,500 dollars in cost. Using base-case assumptions, we found that the cost-effectiveness of the ICD as compared with control therapy in these six populations ranged from 34,000 dollars to 70,200 dollars per QALY gained. Sensitivity analyses showed that this cost-effectiveness ratio would remain below 100,000 dollars per QALY as long as the ICD reduced mortality for seven or more years. Prophylactic implantation of an ICD has a cost-effectiveness ratio below 100,000 dollars per QALY gained in populations in which a significant device-related reduction in mortality has been demonstrated.

Definite trial is not definitive after all

The result of the DEFINITE trial was published recently [1]. It was another negative trial with a positive-sounding acronym [2]. The DEFINITE (DEFibrillators In Non-Ischemic cardiomyopathy Treatment Evaluation) trial failed to demonstrate a significant reduction in the risk of death from any cause. When the investigators and the device manufacturer launched the trial and invented the acronym DEFINITE, they obviously were expecting a positive result. The negative result must be a big disappointment for them.

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DEFibrillators In Non-Ischemic Cardiomyopathy Treatment Evaluation (DEFINITE)

The DEFibrillators In Non-Ischemic Cardiomyopathy Treatment Evaluation (DEFINITE) was a multi-center, randomized, investigator-initiated trial. Patients enrolled in the trial had non-ischemic cardiomyopathy (LVEF <or=35%), a history of symptomatic heart failure and spontaneous arrhythmia (>10 PVCs/hr or non-sustained ventricular tachycardia defined as 3 to 15 beats at a rate of >120 bpm) on Holter monitor or telemetry within the past 6 months. All patients received standard oral medical therapy for heart failure including angiotensin converting enzyme inhibitors and beta-blockers. Patients were randomized to implantable cardioverter defibrillator (ICD) versus no ICD. Patients were followed for 2 to 3 years. The primary endpoint was total mortality. Quality of life and pharmacoeconomics analysis was also performed. A registry tracked patients who met basic inclusion criteria but were not randomized. We estimated an annual total mortality of 15% at 2 years in the treatment arm that did not receive an ICD. The ICD was expected to reduce mortality by 50%. Approximately 229 patients were required in each treatment group. Forty-five centers were included in this trial that was designed to last an estimated 4 years. Enrollment was projected to occur over 2 1/2 years with a post enrollment follow-up of 1 1/2 years.