Atlanta, GA - Final results of the Multicenter Autonomic Defibrillator Implantation Trial II (MADIT II) trial confirm a survival benefit from implantable cardioverter defibrillator (ICD) implantation in a vastly enlarged group of patients, those with any history of MI and left ventricular dysfunction with an ejection fraction (EF) of 0.30 or less. Although good news clinically, the results raise difficult questions about the potentially crippling economic impact of this added healthcare cost.
The MADIT II findings were reported here at the American College of Cardiology 51st Annual Scientific Session, coinciding with its publication in the March 21, 2002 issue of the New England Journal of Medicine. The Journal allowed an early embargo lift for the morning of the trial's presentation here.
"Our findings show that the implantation of a defibrillator improves survival in patients with a prior MI and advanced left ventricular dysfunction," the researchers, led by Dr Arthur J Moss (University of Rochester Medical Center, Rochester, NY) conclude in their publication. "Prophylactic ICD therapy is now ready for prime time use in patients with coronary heart disease and left ventricular dysfunction," Moss told a press conference here.
It is estimated 3 to 4 million patients in the US currently fit these inclusion criteria, the researchers note in their paper, and there are about 400000 new cases annually. "If a meaningful number of these patients receive an implantable defibrillator prophylactically, the cost to the healthcare system would be substantial. We hope that market forces will drive down the cost of this therapy," the authors conclude.
Moss told reporters, "This is the first time in the history of the New England Journal they've cooperated with the American College of Cardiology for a joint release - most unusual."
Expanded inclusion criteria
Previous results from the first MADIT and the Multicenter Unsustained Tachycardia Trial (MUSTT), both primary prevention trials, had shown a benefit from ICD implantation in patients with heart disease, reduced ventricular function, unsustained ventricular tachycardia, and inducible ventricular tachycardia. In both of those studies, patients underwent EP testing to determine their risk of arrhythmia, Moss et al write, but the prognostic value of EP testing in identifying patients at risk for ventricular arrhythmias is "uncertain."
In MADIT II, the inclusion criteria for implantation of an ICD was expanded, requiring only that patients had a prior MI at least 30 days previous to implantation, and that they have an EF of 0.30 or less. The trial, supported entirely by Guidant (Indianapolis, IN), randomized 1232 patients from 71 US centers and 5 European centers to receive either an ICD, or to continue on conventional medical therapy.
Initially, the paper notes, eligible patients were required to have frequent or repetitive ventricular ectopic beats on 24-hour Holter monitoring, but this requirement was eliminated after enrollment of 23 patients, "because almost all eligible patients had such arrhythmias," the researchers said.
Randomization was done in a 3:2 ratio: 742 patients were assigned to receive an ICD, and 490 to conventional therapy. (During the presentation, Moss noted that this randomization design was important, meant to allow substudies at the conclusion of the trial to determine if any of the electrophysiologic parameters studied at the time of implantation might show a high-risk subset of patients that would benefit most from an ICD. They expect to present this data at the NASPE meeting in May.) The primary endpoint was death from any cause.
On November 20, 2001, the investigators announced that the trial had been halted by the Data Safety and Monitoring Board for efficacy in the ICD arm, as reported by heartwire . During an average follow-up of 20 months, the mortality rate was 19.8% in the conventional therapy group, reduced to 14.2% with implantation of the ICD, a 31% reduction in the risk of death.
MADIT II: All-cause mortality
|Endpoint||ICD group||Conventional therapy group||Hazard ratio (95% CI)||p value|
|All-cause mortality||105 (14.2%)||97 (19.8%)||0.69 (0.51-0.93)||0.016|
The survival benefit was similar across subgroups stratified by age, sex, EF, NYHA class and the QRS interval, the researchers added.
Looking at causes of death, they found that the benefit seen was largely driven by prevention of sudden death, Moss told the meeting here.
MADIT II: Mortality events
|Cause of death||ICD group||Conventional therapy group|
|Arrhythmic||27 (3.6%)||46 (9.4%)|
Of note, benefit from the ICD, which manifested itself within only a few months in the MADIT trial, was not evident until about 9 months after implantation in MADIT II. Moss and colleagues speculated that the delay might be related to differences between the populations studied.
Increase in new heart failure?
The researchers reported that serious complications with defibrillator therapy were "infrequent," but did note that the incidence of new or worsened heart failure was slightly higher in the defibrillator group. A total of 73 (14.9%) patients in the conventional therapy group were hospitalized with heart failure, compared to 148 (19.9%) in the defibrillator group, they write. This represented 9.4 and 11.3 patients hospitalized per 1000 months on active therapy respectively, they added (nominal p=0.09).
Moss et al write that they were "concerned" by this finding. They speculate on a variety of possible explanations, including the possibility that these patients, saved from malignant ventricular arrhythmias by their ICD, may have more time for heart failure to develop. Conversely, it's possible that ICD shocks may contribute to rehospitalization or myocardial injury, or that the backup ventricular pacing may impair ventricular function.
"Patients with a reduced ejection fraction who receive an implantable defibrillator should be carefully monitored for the development or exacerbation of heart failure," the researchers write.
ICD for everyone? "Maybe, maybe not"
In an editorial accompanying the publication, Dr J Thomas Bigger (Columbia University College of Physicians and Surgeons), struck a note of caution about the results.
"A key question raised by the trial is whether the results indicate that all patients with a previous myocardial infarction and a left ventricular ejection fraction of 0.30 or less should receive a defibrillator," Bigger writes. "Maybe, but maybe not."
Future analyses will determine whether patients can be identified who may benefit more than others, Bigger suggested. He called the finding of increased heart failure in the ICD group "worrisome," but added that if the cause of the deterioration could be found, that it could perhaps be modified.
Like many have done before in discussions of the potential impact of this study on clinical practice - including the investigators themselves - Bigger brought up the issue of cost. "The cost-effectiveness of defibrillator prophylaxis remains in question and looms as a barrier to the wider use of this approach," he writes. Although the devices may become cheaper, the new finding that ICDs were associated with more hospitalizations complicates the equation further.
Conversely, a key part of the calculation is the expected increase in life-expectancy with the device. This initial MADIT II report suggests only a moderate increase in survival, he writes, but the average follow-up was only about 20 months, shorter than the 4- to 5-year life of the device. "Accordingly, the full benefit of defibrillator therapy in MADIT II has not yet accrued, and continued follow up should lead to a more precise estimate."
In the end, Bigger concludes that the evidence to use the device in every patient has not been established with this trial.
"The findings of MADIT II represent a substantial advance in the prophylactic use of defibrillators, but do not in themselves confirm that this approach should be used in all patients with coronary heart disease and severe left ventricular dysfunction," Bigger writes. "It is possible that more careful screening of potential candidates for the prophylactic implantation of a defibrillator would decrease the risk of complications, inconvenience, and expense, yet save almost as many lives as did the criteria used by MADIT II."
Click here to see related story: Round two MADIT II: the experts react
Heartwire from Medscape © 2002 Medscape, LLC
Cite this: MADIT II: Mortality reduction with ICD implantation for patients with prior MI, LV dysfunction - Medscape - Mar 19, 2002.