MADIT II Trial -- Prophylactic Implantation of a Defibrillator in Patients with Myocardial Infarction and Reduced Ejection Fraction
Brian McGovern, M.D.
Massachusetts General Hospital; Chairman, Atrial Fibrillation Foundation
Over the last decades, there has been great progress in reducing death from cardiovascular causes, but there is much to be done. Cardiovascular disease is still the single most common cause of death in the United States. Patients with myocardial infarction (MI) and reduced left ventricular function are at the highest risk for congestive heart failure (CHF) and arrhythmia-related sudden cardiac death (SCD). Statistics show that there are 340,000 out-of-hospital or emergency room cardiac arrests per year in the United States — 50 percent in absence of acute MI. There is a 95 percent out-of-hospital mortality for these patients. This extremely low survival rate has motivated the prophylactic implantation of a defibrillator for primary prevention.
For treatment of patients at risk for SCD due to ventricular tachyarrhythmias, the implantable cardioverter/defibrillator (ICD) has revolutionized treatment. Advances in technology have improved ICDs, making them easier to implant and safer for patients. They are smaller, much more complex and have improved battery life from the days of their inception in 1980 and approval by the Food and Drug Administration (FDA) in 1985.
The second Multicenter Automatic Defibrillator Implantation Trial (MADIT II) was conducted to help better identify patients with coronary heart disease who would benefit from an ICD. MADIT II is the latest in a series of trials involving the use of ICDs to improve management and clinical treatment of arrhythmia patients. The Antiarrhythmics versus Implantable Defibrillators (AVID) Trial compared ICDs with antiarrhythmic-drug therapy (amiodarone or sotalol, predominantly the former) in patients who had survived life-threatening ventricular arrhythmias. Once it was established that defibrillator therapy had a clear advantage over drug therapy, the trial was stopped. (1)
Previous trials examined the role of the ICD as primary therapy in patients who have never experienced symptomatic arrhythmias but have risk markers for sudden death. The first Multicenter Automatic Defibrillator Implantation Trial (MADIT) and the Multicenter Unsustained Tachycardia Trial (MUSTT) showed that patients with coronary heart disease, a reduced left ventricular ejection fraction, unsustained ventricular tachycardia and inducible sustained ventricular tachyarrhythmias in the electrophysiology lab benefited from ICD implantation. (2) Read brief reviews of all trials.
The Coronary Artery Bypass Graft (CABG) Patch Trial evaluated the prophylactic use of ICDs in patients undergoing coronary revascularization surgery. A high risk of death due to arrhythmia was considered to be indicated by a noninvasive marker — an abnormal signal-averaged electrocardiogram — plus an ejection fraction below 36 percent. (3) The CABG Patch Trial showed no benefit to ICD therapy.
In MADIT II patients with a prior MI and a left ventricular ejection fraction of 0.30 or less were randomly assigned in a 3:2 ratio to receive an ICD (742 patients) or conventional medical therapy (490 patients), with all-cause mortality as the primary end point. Electrophysiologic testing or inducible ventricular arrhythmias were not eligibility criteria for MADIT II. The findings revealed that in patients with a previous MI and reduced left ventricular ejection fraction, the prophylactic use of an ICD, in addition to medications, significantly reduced the risk of death.
Results from MADIT II have been widely anticipated because the trial was well designed with excellent follow-up. Other strong features of the trial included:
- Low rate of crossover
- High frequency of adjunctive medications in both groups
- Primary endpoint of all-cause mortality
- Timing of mortality benefit
- CHF admissions and other long-term risks
During 20 months of follow-up of the study group, there was a 31 percent reduction in the relative risk of mortality among patients in the ICD group compared with those in the conventional therapy group. Because of the reduced risk of mortality seen in the trial, the Data Safety and Monitoring Board stopped the trial early (November 2001). The results are especially significant because ICD therapy was “on top of optimal medical management.” Use of beta-blockers in both treatment arms, for example, was 70 percent, and use of statins was 67 percent in the ICD group and 64 percent in the conventional therapy group.
ICD therapy was associated with the expected rates of device-related complications, but, more importantly, was also associated with a higher rate of new or worsened heart failure than was conventional therapy. While this was a troublesome finding, the research team speculated that effective treatment of potential lethal arrhythmias leads to longer survival, thus allowing heart failure to develop. It is possible that other explanations, such as adverse effects of chronic pacing, may have contributed to this observation.
In general, the conclusion of MADIT II is:
- In patients with reduced EF and history of MI, ICD implantation confers a mortality benefit.
- There is a concerning trend toward an increase in CHF admissions in the ICD group.
- Cost considerations are substantial, but will require an assessment of full survival benefit.
- Subgroup analysis, in particular, assessment of EPS in risk stratification, may be helpful in transitioning these results into clinical practice.