New England Journal of Medicine MARCH 21, 2002

Prophylactic Implantation of a Defibrillator in Patients with Myocardial Infarction and Reduced Ejection Fraction (MADIT-II)

Arthur J. Moss, Wojciech Zareba, W. Jackson Hall, et al.

Bottom Line

In patients with a prior myocardial infarction and a left ventricular ejection fraction of 30% or less, prophylactic implantation of an implantable cardioverter-defibrillator (ICD) significantly reduces all-cause mortality compared to conventional medical therapy.

Key Findings

1. The study demonstrated a 31% relative reduction in the risk of all-cause mortality in the ICD group compared to the conventional therapy group (hazard ratio 0.69; 95% confidence interval, 0.51 to 0.93; P=0.016).

2. At an average follow-up of 20 months, mortality rates were 14.2% in the ICD arm versus 19.8% in the conventional therapy arm.

3. The survival benefit did not begin to diverge until approximately 9 months after implantation, after which the curves continued to separate.

4. Hospitalization for heart failure occurred more frequently in the ICD group (19.9%) compared to the conventional therapy group (14.9%), though this trend did not reach statistical significance.

Study Design

Design

RCT

Open-Label

Sample

1,232

Patients

Duration

20 mo

Median

Setting

Multicenter, North America

Population Patients with a prior myocardial infarction occurring more than 30 days before enrollment and a left ventricular ejection fraction of 30% or less.

Intervention Implantation of an implantable cardioverter-defibrillator (ICD).

Comparator Conventional medical therapy alone.

Outcome All-cause mortality.

Study Limitations

• The trial was terminated early by the Data and Safety Monitoring Board, which may have led to an overestimate of the treatment effect.

• The study did not require electrophysiological testing for risk stratification, leading to a broader inclusion criteria than prior studies but potentially including patients at lower arrhythmic risk.

• The follow-up period was relatively short (average 20 months) for a prophylactic device meant to provide long-term protection, though subsequent extended follow-up analyses addressed this.

• Concomitant medical therapy was left to the discretion of treating physicians rather than strictly mandated, which may not reflect modern standardized guideline-directed medical therapy.

Clinical Significance

MADIT-II established the implantable cardioverter-defibrillator (ICD) as a standard of care for the primary prevention of sudden cardiac death in high-risk patients with prior myocardial infarction and significantly reduced left ventricular function, fundamentally changing clinical practice guidelines.

Historical Context

Following the original MADIT trial, which focused on patients with inducible arrhythmias, MADIT-II extended the application of prophylactic ICDs to a much broader population of post-MI patients with low ejection fraction, removing the requirement for invasive electrophysiological testing.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

What is the primary pathophysiological mechanism by which a prior myocardial infarction (MI) increases the risk of sudden cardiac death, and how does an implantable cardioverter-defibrillator (ICD) address this risk?

Key Response

An MI creates a fibrotic myocardial scar which serves as an anatomical substrate for macro-reentrant ventricular tachycardia. In patients with low ejection fractions, the risk of these lethal arrhythmias is high. An ICD monitors the heart rhythm and delivers a high-energy shock to terminate ventricular tachycardia or fibrillation, thereby preventing sudden cardiac death.

Resident

Based on the MADIT-II trial and subsequent clinical guidelines, what is the mandatory waiting period after an acute myocardial infarction before a patient becomes eligible for a primary prevention ICD, and why?

Key Response

Guidelines require a 40-day waiting period post-MI. This is because trials like DINAMIT showed that early ICD implantation did not reduce all-cause mortality, as early deaths were often due to non-arrhythmic causes (like pump failure), and some patients experience myocardial recovery (stunning vs. necrosis) during the subacute phase.

Fellow

MADIT-II showed a benefit in patients with LVEF ≤30% regardless of their QRS duration. How should this finding be integrated with the results of the SCD-HeFT and COMPANION trials when deciding between an ICD and a Cardiac Resynchronization Therapy Defibrillator (CRT-D)?

Key Response

While MADIT-II utilized LVEF alone as a criterion, CRT-D (from COMPANION/MADIT-CRT) provides additional benefit for those with QRS ≥150ms and Left Bundle Branch Block (LBBB). Fellows must distinguish between patients who simply need an 'insurance policy' against SCD (ICD) and those who need heart failure symptom management and reverse remodeling (CRT-D).

Attending

Considering the 'competing risk of death' in the MADIT-II population, which clinical biomarkers or comorbidities most significantly attenuate the survival benefit of a prophylactic ICD in an elderly patient with a prior MI?

Key Response

Patients with advanced age, severe renal insufficiency (CrCl <30 mL/min), and NYHA Class IV symptoms often have a high risk of non-arrhythmic death. In these cases, the ICD may never fire before the patient dies of other causes, making the procedure high-risk for complications with minimal actuarial benefit.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

The MADIT-II trial utilized a 3:2 randomization ratio favoring the ICD group. What are the statistical and ethical justifications for using an unequal randomization scheme in large-scale device trials, and how does it affect the power of the study?

Key Response

Unequal randomization is often used to gain more safety and performance data on the experimental intervention (ICD). While a 1:1 ratio is statistically most powerful, a 3:2 ratio only minimally reduces power while providing a larger denominator for identifying device-related adverse events and complications.

Journal Editor

If you were reviewing the MADIT-II manuscript, how would you address the potential bias introduced by the study being terminated early by the Data and Safety Monitoring Board (DSMB) after a median follow-point of only 20 months?

Key Response

Early termination for efficacy often results in an 'overestimation' of the treatment effect (the 'Winner's Curse'). Editors would flag the need for longer-term follow-up data to ensure that the early survival benefit is sustained and not eclipsed by late device complications or the exhaustion of the survival benefit over time.

Guideline Committee

How did MADIT-II fundamentally shift the Class of Recommendation for ICDs in primary prevention compared to the previous MADIT-I criteria, and what is the current ACC/AHA Level of Evidence for this population?

Key Response

MADIT-I required a positive electrophysiology study (EPS) for inclusion. MADIT-II proved that LVEF ≤30% post-MI was sufficient evidence of risk on its own. Consequently, the 2017 AHA/ACC/HRS guidelines moved this to a Class I, Level of Evidence: A recommendation for patients at least 40 days post-MI with LVEF ≤30%.

Clinical Landscape

Noteworthy Related Trials

1999

MUSTT Trial

n = 704 · NEJM

Tested

Electrophysiologically guided antiarrhythmic therapy

Population

Patients with prior MI, EF less than or equal to 40%, and inducible ventricular tachycardia

Comparator

No antiarrhythmic therapy

Endpoint

Cardiac arrest or arrhythmic death

Key result: Electrophysiologically guided antiarrhythmic therapy did not improve survival in patients with asymptomatic nonsustained ventricular tachycardia.

2004

DINAMIT Trial

n = 674 · NEJM

Tested

ICD implantation

Population

Patients within 6 to 40 days after acute myocardial infarction

Comparator

Optimal medical therapy

Endpoint

All-cause mortality

Key result: Early ICD implantation after myocardial infarction did not improve survival compared to medical therapy.

2005

SCD-HeFT Trial

n = 2,521 · NEJM

Tested

Single-lead ICD or amiodarone

Population

Patients with NYHA class II or III heart failure and reduced ejection fraction

Comparator

Placebo

Endpoint

All-cause mortality

Key result: ICD therapy significantly reduced mortality by 23% compared to placebo in patients with mild to moderate heart failure.

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