Background, Outcome, and Clinical Implications of the Multicenter Automatic Defibrillator Implantation Trial (MADIT)

M ventricular tachyarrhythmias account for approximately one half of the estimated 1,000,000 people who die from cardiac causes annually. In 1990, the Multicenter Automatic Defibrillator Implantation Trial (MADIT) group of investigators set out to determine if an implanted cardioverter defibrillator (ICD) would improve survival in patients with coronary disease at high risk for ventricular arrhythmias. The recently reported results from the MADIT study indicate that the ICD does save lives in high-risk coronary patients with left ventricular dysfunction and nonsustained ventricular tachycardia.1 To properly understand MADIT, it is important to go back to the 1980s and the investigations that related to the risks posed by left ventricular dysfunction, repetitive ventricular premature beats, and antiarrhythmic agents, and the findings from electrophysiologic studies in patients with acute and subacute coronary artery disease. In 1983, the Multicenter Postinfarction Research Group reported their findings on the role of physiologic measurements of heart function in predicting mortality in the Multicenter Postinfarction Program (MPIP).2 A striking finding was the exponential increase in 1-year cardiac mortality as the left ventricular ejection fraction (LVEF) decreased to ,0.35 (Figure 1). This inverse relationship between LVEF and mortality has been substantiated in many subsequent studies by other investigators, both before and after the introduction of thrombolytic therapy, revascularization procedures, and pharmacologic treatment with angiotensin-converting enzyme (ACE) inhibitors in high-risk coronary patients. A reduced LVEF reflects significant and extensive myocardial disease with an increased propensity for heart failure and reentrant ventricular tachyarrhythmias. Another important report from MPIP was the quantitative analysis of the relationships between ventricular arrhythmias recorded on a 24-hour Holter, and mortality in the 2 years after myocardial infarction.3 Bigger et al3 showed a stepwise reduction in survival as one progressed from single, to paired, to $3 ventricular premature beats in a row (nonsustained ventricular tachycardia [NSVT]), with a 2-year mortality of almost 30% in patients with NSVT. Furthermore, the risk from NSVT was further accentuated in the presence of left ventricular dysfunction with LVEF ,0.35. Other relevant developments that served as background for MADIT included the findings from the Cardiac Arrhythmia Suppression Trial (CAST) reported in 19894 and the publication by Wilber et al5 in 1990 on the risk implications of induced and nonsuppressed ventricular tachyarrhythmias at electrophysiologic testing. The CAST trial found that 2 major antiarrhythmic drugs, encainide and flecainide, were associated with an increased cardiac mortality when compared to placebo in coronary patients at high risk for sudden arrhythmic death. This study raised serious questions about the safety and efficacy of antiarrhythmic drugs in patients with coronary disease. Wilber et al5 carried out electrophysiologic testing in 100 consecutive patients with spontaneous asymptomatic NSVT, chronic coronary disease, and LVEF ,0.40. The 1and 2-year actuarial incidence of aborted cardiac arrest or sudden death was 34% and 50%, respectively, in patients with inducible and sustained (not suppressed by antiarrhythmic challenge) ventricular tachyarrhythmia in this high-risk population. These findings from studies during the timeframe 1983–1990 provided the rationale for MADIT and set the stage for the multicenter investigation to evaluate the safety and efficacy of ICD therapy in a randomized trial of high-risk coronary patients.