Presenter: Alan H. Kadish, MD, Northwestern University Feinberg School of Medicine (Chicago, Ilinois)
Approximately one third of all cases of heart failure are of a non-ischemic etiology. Patients with non-ischemic dilated cardiomyopathy and left ventricular (LV) dysfunction are at increased risk for sudden cardiac death (SCD). While both beta-blockers and ACE inhibitors reduce the incidence of both sudden and nonsudden death, SCD still remains a major cause of mortality in selected patients with non-ischemic dilated cardiomyopathy. Implantable cardioverter defibrillators (ICDs) have been shown to be effective in the primary prevention of SCD in a selected population of patients with coronary artery disease. However, to date, no large-scale studies have examined the use of ICDs in patients with non-ischemic dilated cardiomyopathy.Aim
The Defibrillators in Non-ischemic Cardiomyopathy Treatment Evaluation (DEFINITE) trial was conducted to evaluate the prophylactic implantation of an ICD to prevent sudden death in patients with non-ischemic dilated cardiomyopathy.Study Design
A total of 458 patients with LV dysfunction (ejection fraction [EF] ≤ 35%) and non-ischemic dilated cardiomyopathy were randomized to either standard oral medical therapy (n = 229) or standard oral medical therapy plus ICD implantation (n = 229). Patients were randomized at 48 centers in the United States and Israel between July 1998 and May 2003.
All patients received standard pharmacologic treatment with beta-blockers (carvedilol or metoprolol), ACE inhibitors, digoxin, and diuretics as needed. Single-chamber ICDs (St. Jude Medical; Minneapolis, Minnesota) programmed VVI 40 bpm, VF Zone only; 180 bpm were used in the study.
The study's primary endpoint was total mortality; secondary endpoint was arrhythmic death. In designing the trial, investigators determined that in order to demonstrate a significant difference between the 2 groups, the use of ICDs would have to reduce the incidence of mortality by 50% compared with conventional therapy. A P value of .0367 was needed in order to achieve significance. The prospective design of the trial called for data analysis upon the 56th death in the study cohort.Enrollment Criteria
Inclusion criteria included:
Age 21-80 years
Non-ischemic cardiomyopathy with LVEF ≤ 35%
Symptomatic heart failure
Documented nonsustained ventricular tachycardia (VT) or an average of 10 PVCs/hour on Holter monitor
Patients excluded from the study included those with:
Coronary artery disease
Unexplained syncope in the previous 6 months
Prior cardiac arrest, VT of more than 15 beats at a rate of 120 bpm
New York Heart Association (NYHA) class IV failure at enrollment
Electrophysiologic study within the last 3 months
Amiodarone treatment for ventricular arrhythmias
Baseline clinical characteristics were similar between the 2 groups; however, patients in the standard therapy group had a longer history of cardiomyopathy (Table 1).Table 1. DEFINITE: Baseline Characteristics
(n = 229)
(n = 229)
|White race (%)||68||68|
|Atrial fibrillation (%)||26||23|
|Duration of disease (yrs)*||3.3||2.4|
|NYHA class I-II (%)||79||79|
|NYHA class III (%)||21||21|
|NSVT only (%)||23||22|
|PVC only (%)||10||9|
|Ejection fraction (%)||22||21|
|Walk distance (m)||328||311|
ICD, implantable cardioverter defibrillator; LBBB, left bundle branch block; NSVT, nonsustained ventricular tachycardia; NYHA, New York Heart Association; PVC, premature ventricular complex
*P < .05.
All patients were on optimal medical therapy, and there was no significant difference between the 2 groups with respect to concomitant drug treatment. Importantly, it should be noted that > 85% of patients were treated with ACE inhibitors and beta-blockers, respectively (Table 2).Table 2. DEFINITE: Concomitant Drug Therapy
(n = 229)
(n = 229)
|ACE inhibitor (%)||87||84|
ACE, angiotensin converting enzyme; ARB, angiotensin receptor blocker; ICD, implantable cardioverter defibrillatorOutcomes
Patients were followed for a mean of 26 ± 4 months. A total of 56 deaths occurred in the study (prespecified); 33 in the standard therapy arm and 23 deaths in the ICD arm. Arrhythmic death accounted for 33% of deaths that occurred in the therapy arm and 13% of deaths that occurred in the ICD arm (Figure 1).
Figure 1. DEFINITE: overall mortality.
The trial's primary endpoint failed to reach statistical significance. At 2 years, all-cause mortality was 13.8% in the standard therapy group vs 8.1% in the ICD arm (P = .06) (Figure 2). Although it did not reach the predicted 50% reduction, use of an ICD was associated with a 34% relative reduction in risk of all-cause death, and the absolute mortality benefit at 2 years was 5.7%.
Figure 2. DEFINITE: all-cause mortality.
However, ICDs were associated with a significantly lower rate of arrhythmic death, the study's secondary endpoint. There were 14 arrhythmic deaths, 11 in the standard therapy group and 3 in the ICD arm (P = < .05). Use of an ICD was associated with a 74% reduction in the relative risk of arrhythmic deaths.
Subgroup analyses were conducted to determine the relative risk of mortality in patients based on gender, EF, QRS duration, heart association class, and history of atrial fibrillation. Interestingly, investigators found that patients of male gender with EF < 20%, NYHA class III, and QRS > 120 ms were most likely to derive the greatest benefit from ICD implantation. Specifically, the use of an ICD in patients with NYHA class III heart failure was associated with a 67% relative risk reduction in all-cause mortality compared with standard medical therapy alone (P = .009) (Figure 3).
Figure 3. DEFINITE: all-cause mortality in NYHA class III.Conclusions
The investigators drew the following conclusions from the results of the DEFINITE trial:
Patients with non-ischemic cardiomyopathy, severe LV dysfunction, and an arrhythmia marker have an annual mortality of only 6% to 7% when treated with ACE inhibitors and beta-blockers.
On drug therapy, arrhythmic SCD accounts for only one third of all deaths, a lower proportion than expected.
Despite this, ICD implantation reduced arrhythmic death.
ICD implantation tended to reduce all-cause mortality. The absolute mortality benefit was 5.7% at 2 years. The relative risk reduction was 34% (P = .06).
Commenting on the DEFINITE trial, Arthur J. Moss, MD, University of Rochester Medical Center (Rochester, New York), acknowledged the significant advances in the field that have taken place in the 23 years since the first ICD implantation was performed by Dr. Mirowsky in 1980 . Dr. Moss believes that DEFINITE, was a well-performed study that fills an existing void in the role of ICDs in patients with non-ischemic cardiomyopathy.
According to Dr. Moss, the P value of .06 was "meaningfully significant" and was in line with the P values found in other ICD trials. In addition, he stated that the entry criteria used in this trial were similar to those used in other ICD trials, such as the Multicenter Automatic Defibrillator Implantation Trial (MADIT) I (enrollment criteria in MADIT I included EF ≤ 35%, ventricular arrhythmias, and no programmed electrical stimulation). Sicker patients (low EF, NYHA class III) seemed to derive the greatest benefit, which, according to Moss is in concordance with results of previous trials. He found it interesting that women did not obtain so much benefit and believed that this may very well be a particularity for patients with non-ischemic cardiomyopathy. Future interrogation of the devices will provide more knowledge on the appropriateness of discharge of the device, he concluded.Reference
Moss AJ, Hall WJ, Cannom DS, et al. Improved survival with an implanted defibrillator in patients with coronary disease at high risk for ventricular arrhythmia. N Engl J Med. 1996;335:1933-1940.
Medscape Cardiology © 2003
Cite this: Luis Gruberg. DEFINITE: Defibrillators in Non-ischemic Cardiomyopathy Treatment Evaluation - Medscape - Nov 18, 2003.