Expanding use of ICDs in nonischemic cardiomyopathy patients: No DEFINITE answers yet

November 11, 2003

Orlando, FL - The results of the first large-scale, primary-prevention trial investigating the prophylactic use of internal cardioverter defibrillators (ICDs) in patients with severe left ventricular dysfunction due to nonischemic cardiomyopathy showed that while the use of ICDs trended toward a convincing reduction in all-cause mortality in these patients, the results did not achieve statistical significance.

The investigators note that the use of ICDs in nonischemic cardiomyopathy patients did result in a statistically significant reduction in mortality due to arrhythmias and that high-risk patientsNYHA class 3 patientsalso appear to benefit from the addition of a defibrillator to standard medical therapy.

The results of the study—Defibrillators in Nonischemic Cardiomyopathy Treatment Evaluation (DEFINITE)—were presented here today at the American Heart Association Scientific Sessions.

"The defibrillator clearly prevents arrhythmic sudden death, and there is a suggestion that it improves survival, but to draw that conclusion firmly will require additional follow-up and additional studies," said Dr Alan K Kadish (Northwestern University Feinberg School of Medicine, Chicago, IL).

Expanding patient population for ICDs

The DEFINITE trial was a multicenter, randomized study that enrolled 458 patients with left ventricular dysfunction due to nonischemic dilated cardiomyopathy. In addition to ejection fractions <35%, patients included in the study also had a history of spontaneous premature ventricular complexes or nonsustained ventricular tachycardia.

 
The defibrillator clearly prevents arrhythmic sudden death, and there is a suggestion that it improves survival, but to draw that conclusion firmly will require additional follow-up and additional studies.
 

"The best estimates are that about one third of the patients in the US who have congestive heart failure have congestive heart failure due to a primary disease of the heart muscle as opposed to narrowing of the arteries," said Kadish.

Patients in the study were randomized into two groups: one receiving standard medical therapy, including ACE inhibitors and beta blockers, and the other receiving standard medical therapy plus an ICD.

The prospective design of the trial called for the study to be stopped after 56 deaths in the study cohort. To achieve significance, investigators estimated the trial would have to reduce mortality by 50% relative to standard therapy, a benchmark similar to other studies when the DEFINITE trial was designed, said Kadish.

Overall, there were 33 deaths in the standard-therapy group and 23 deaths in the ICD group, resulting in a 34% reduction in all-cause mortality in patients randomized to ICD therapy. Of the total deaths, there were 14 deaths resulting from arrhythmias11 in the standard-medical-therapy group and three in the ICD study armtranslating into a statistically significant 74% relative reduction in risk in patients receiving an ICD (p<0.05).

DEFINITE: Primary end point of all-cause mortality at two years

Primary end point Standard medical therapy, n=229 (%) Standard medical therapy plus ICD, n=229 (%) p
All-cause mortality  13.8 8.1 0.06

Investigators predicted more than half of the 56 deaths in the study cohort would be arrhythmic, but only one third of total deaths were caused by arrhythmias, said Kadish. As a result, the lack of arrhythmic deaths affected the statistical analysis.

"We did a great job preventing arrhythmic mortality," Kadish told heartwire . "But arrhythmic death was just a small percentage of the overall deaths, so that when you looked at total mortality, the numbers were there, but they didn't achieve significance because we only had a 33% arrhythmic mortality rate in the standard-therapy group as opposed to our predicted 50% mortality."

Kadish noted that one of the major issues when designing defibrillator trials is the advance of pharmacology in treating patients with nonischemic cardiomyopathy. Compliance rates with beta blockers and ACE inhibitors were both greater than 85%, said Kadish, possibly resulting in a relatively low rate of all-cause and arrhythmic mortality in the control group.

 
We did a great job preventing arrhythmic mortality.
 

"It could be that the reason the control-group mortality in this study was lower than in some of the other studies is related to the fact that we didn't have patients with coronary artery disease, but it could also be that we had a much higher compliance rate with beta blockers and ACE inhibitors," said Kadish.

Will high-risk patients benefit most?

Kadish also presented data suggesting that patients at highest risk for sudden cardiac death may benefit most from an ICD. In a subgroup analysis of NYHA class 3 patients, Kadish said that the implantation of an ICD resulted in a 67% relative reduction in all-cause mortality compared with standard medical therapy alone.

"There was a suggestion that patients with class 3 congestive heart failure had greater benefit from the ICD," said Kadish. "That comparison was highly significant, but the study was not powered to detect differences specifically in the different classes of heart failure, so that conclusion at this point is perhaps somewhat tentative."

Kadish said that despite not achieving statistical significance with the primary end point of all-cause mortality, the results are promising and hint at the benefit to be gained in patients with nonischemic cardiomyopathy.

"I think that because we did not achieve statistical significance, the primary end point is going to require additional follow-up analysis and perhaps additional studies before we can be absolutely certain of what role the ICD will play," he said. "The fact that the ICD did reduce arrhythmic mortality and tended to reduce overall mortality suggests the possibility that the ICD may benefit this patient population in the primary prevention of sudden death."

Kadish added that cost-effectiveness analyses are currently being conducted.

Results still meet scientific and statistical scrutiny

During the discussion period following the presentation of the results, Dr Arthur Moss (University of Rochester Medical Center, NY) congratulated the investigators for the first study examining the prophylactic use of ICDs in patients with nonischemic cardiomyopathy.

"This fills a very important gap in our treatment of patients at risk for sudden cardiac death," said Moss. "The findings are important and provide data on an incremental group of patients who will benefit from ICD therapy."

 
This fills a very important gap in our treatment of patients at risk for sudden cardiac death.
 

Moss added that the results are in line with other major ICD trials, including the MADIT trials, MUSTT, and COMPANION. He is not particularly concerned about the statistical significance of the DEFINITE results.

"I'm sure [the p value] was very troublesome for the investigators," said Moss. "But I have to tell you that I consider the results meaningfully significant and I have to tell you that I do not discriminate between p equals 0.05 and p equals 0.06." He did note that for the primary end point of all-cause mortality to be statistically significant, p would need to be 0.037.

Moss said investigators more than likely hurt themselves in designing the trial with the assumption of achieving a 50% reduction in all-mortality. When asked by heartwire if investigators set the bar too high, Kadish said the 50% relative risk reduction was designed to be impressive.

"We thought that to have a therapy that would be utilized in the medical community, we would have to show an impressive benefit," said Kadish. "At the time we designed this study in 1997, two other studies, MADIT I and MUSTT, both showed a 50% reduction. We estimated that the ICD should be able to do as well as that in patients without coronary artery disease."

Moss added that the benefit seen in sicker patients is consistent with previous trials but was disappointed that investigators limited the study to patients less than 80 years old. He also took issue with the categorization of arrhythmic death, noting that no interrogation data are available on the peripheral event in these patients. Still, Moss concluded the trial does start to expand the potential use of ICD therapy.

He concluded by stating the trial is highly important as it expands "the patient population that will benefit from an ICD," and the trial meets statistical and scientific scrutiny.

More data regarding the prophylactic use of ICDs in nonischemic cardiomyopathy patients should come next year with the results of the National Heart, Lung, and Blood Institute's Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT). SCD-HeFT is evaluating the use of ICDs and amiodarone hydrochloride for the prevention of sudden death in 2500 ischemic and nonischemic heart-failure patients.

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