Abstract & Commentary
Synopsis: Data showed a strong trend toward benefit with ICD therapy in patients with nonischemic cardiomyopathy.
Source: Kadish A, et.al. N Engl J Med. 2004;350: 2151-2158.
Most prior trials involving implantable cardioverter defibrillators (ICDs) for the primary prevention of sudden cardiac death have focused on patients with coronary artery disease and prior myocardial infarction. In this study, Kadish and colleagues report the results of a randomized clinical trial in patients with nonischemic cardiomyopathy. The Defibrillators in Nonischemic Cardiomyopathy Treatment Evaluation (DEFINITE) trial reported here is the first large study in this population.
Patients were eligible for the trial if they had a left ventricular ejection fraction of less than 36%, either nonsustained ventricular tachycardia or at least 10 premature ventricular complexes per hour during 24-hour Holter monitoring, a history of symptomatic heart failure and a nonischemic dilated cardiomyopathy. All patients were treated with currently recommended heart failure medication. These included angiotensin converting enzyme inhibitors unless they were contraindicated, beta blockers, and digoxin and diuretics as necessary. Antiarrhythmic drugs were discouraged but could be used to treat symptomatic supraventricular arrhythmias.
Patients were randomly assigned to either ICD therapy or control with 229 patients in each group. The ICD used was a single chamber device which was programmed for back-up ventricular pacing at a rate of 40 bpm and a ventricular fibrillation detection zone at 180 bpm. Patients in the control group who developed either a cardiac arrest or an episode of unexplained syncope could receive an ICD if deemed necessary.
The trial follow-up was 29.0 ± 14.4 months. The total group had a mean age of 58.3 years with a range of 20.3 to 83.9 years. Seventy-one percent were male. Thirtythree percent of the patients were minorities. There was a history of diabetes in 23% and atrial fibrillation in 25% of the patients. Twenty-two percent of the patients were in New York Heart Association class I, 57% in NYHA class II and 21% in NYHA class III. Left bundle branch block was noted in 19.7% and right bundle branch block in 3.3%. The mean left ventricular ejection fraction was 21.4. ACE inhibitors were used in 86% of the patients and beta blockers in 85%. Eighty-seven percent of the patients received a diuretic and 11% an angiotensin II receptor blocker. Amiodarone was used in 5.2% of the patients because of symptomatic arrhythmias. Digoxin was used in 42% of the patients.
There were 229 patients randomized to the ICD group. However, 2 patients declined to undergo ICD implantation and, in response-to-patient requests, 1 patient had the ICD explanted and one patient had the device inactivated. There were 3 implant complications: 1 hemothorax, 1 pneumothorax and 1 cardiac tamponade. All complications resolved with appropriate therapy. There were 10 late complications including 6 lead dislodgements or lead fractures, 3 cases of venous thrombosis and 1 infection. After implant, 2 patients received ICD upgrades to dual chamber devices and eleven received biventricular devices to treat heart failure. Of the 229 patients in the control group, 23 (10%) received ICDs during follow-up primarily for syncope or heart failure with a prolonged QRS duration.
There were 28 deaths in the ICD group vs 40 deaths in the standard therapy group but the difference in survival was not significant (P = 0.08). The unadjusted hazard ratio for deaths among patients who received an ICD was 0.65 (95% confidence interval, 0.4-1.06). Survival analysis showed that the rate of death from any cause at one year was 6.2% in the standard therapy group and 2.6% in the ICD group. At 2 years, it was 14.1% in the standard therapy group and 7.9% in the ICD group. Analysis of mechanism of death suggested that the benefit from the ICD was related to a decrease in arrhythmic deaths.
There were 3 sudden deaths from arrhythmia in the ICD group compared with 14 deaths in the standard therapy group. There were 11 deaths due to heart failure in the standard therapy group and 9 in the ICD group. During follow-up, 41 patients received 91 appropriate ICD shocks. In addition, 49 patients received inappropriate ICD shocks for either atrial fibrillation or other supraventricular arrhythmias. A subgroup analysis was performed. There appeared to be increased benefit among patients with class III congestive heart failure and among men.
Kadish et al conclude that their data showed a strong trend toward benefit with ICD therapy in patients with nonischemic cardiomyopathy. They suggest that since the study did not achieve statistical significance for the entire population, they consider that implantation be approached on a case by case basis.
Comment by John P. DiMarco, MD, PhD
The DEFINITE Trial is the first large study that has shown at least a trend toward benefit with ICD insertion in patients with nonischemic cardiomyopathy. Several studies have shown benefit in patients with ischemic heart disease. However, in 2 prior studies, the Cardiomyopathy Trial (CAT) and the AMIOVIRT Study showed no benefit. However, both of these latter studies were quite small with only about 100 patients in each group.
The findings in DEFINITE are what one should expect. There was a decrease in arrhythmic mortality. The subgroup analysis may however be misleading. There was no benefit demonstrated among women and no benefit demonstrated among patients with class II congestive heart failure. However, the point estimates for both patients with class I and class II heart failure were quite similar at about 0.5 even though the confidence interval for class I heart failure crossed one. We therefore should interpret these data as showing a strong trend toward benefit among all patients with nonischemic cardiomyopathy. As recently reported from the Sudden Cardiac Death Heart Failure Trial, a similar survival benefit was noted in that study in patients with nonischemic cardiomyopathy.
Dr. DiMarco, Professor of Medicine, Division of Cardiology, University of Virginia, Charlottesville, is on the Editorial Board of Clinical Cardiology Alert.