MADIT-II

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Moss AJ, et al. "Prophylactic Implantation of a Defibrillator in Patients with Myocardial Infarction and Reduced Ejection Fraction". The New England Journal of Medicine. 2002. 346(12):877-883.
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Clinical Question

In patients with ischemic cardiomyopathy, does prophylactic ICD placement improve survival?

Bottom Line

In post-MI patients with systolic dysfunction (EF ≤30%), prophylactic ICD reduced all-cause mortality compared to standard medical therapy.

Major Points

The Multicenter Automatic Defibrillator Implantation Trial II (MADIT-II) randomized 1,232 post-MI patients with systolic dysfunction (LVEF ≤30%) to prophylactic ICD or conventional medical therapy. Unlike the earlier MADIT-I (1996) and MUSTT (1999) trials, MADIT-II did not require electrophysiologic testing for inducible VT prior to enrollment. After a mean follow-up of 20 months, the trial was terminated early because prophylactic ICD reduced all-cause mortality (14.2% vs. 19.8%; P=0.016; NNT=18). A post-hoc analysis demonstrated that the mortality reduction appeared to be entirely attributed to a reduction in SCD (3.8% vs. 10.0%; P<0.01)[1]. The reason is not entirely clear, but ICD placement was also associated with a higher rate of heart failure (20% vs. 15%).

Subsequently, SCD-HeFT (2005) demonstrated mortality benefit of ICD in patients with either ischemic or nonischemic cardiomyopathy (LVEF≤35%) compared to amiodarone and to placebo.

Guidelines

AHA/ACCF Heart Failure (2013, adapted)[2]

  • ICD if nonischemic dilated cardiomyopathy or ICM ≥40 days post MI with LVEF ≤35% and NYHA class II or III symptoms on OMT with expected survival >1 year (class I, level A)
  • ICD for ICM >40 days post MI with LVEF ≤30%, NYHA class I symptoms on OMT with expected survival >1 year (class I level B)

Design

  • Multicenter, non-blinded, parallel group, randomized, controlled trial
  • N=1,232 patients with previous MI and LVEF ≤30%
    • ICD (n=742)
    • Conventional medical therapy (n=490)
  • Setting: 76 centers in the US and Europe
  • Enrollment: 1997-2001 (stopped early)
  • Mean follow-up: 20 months
  • Analysis: Intention-to-treat
  • Primary outcome: All-cause mortality

Population

Inclusion Criteria

  • Age >21 years
  • History of MI ≥1 month prior, as documented by abnormal Q wave on EKG, elevated cardiac enzymes, fixed defect on thallium scanning, or localized akinesia on ventriculography with evidence of obstructive CAD on angiography
  • LVEF ≤30% within 3 months

Exclusion Criteria

  • FDA approved indication for ICD
  • NYHA Class IV symptoms at enrollment
  • Coronary revascularization in previous 3 months
  • MI in previous month
  • Advanced cerebrovascular disease
  • High likelihood of death during trial

Baseline Characteristics

  • Demographics: Age 64 years, male 84%
  • PMH: HTN 53%, DM 35%, AF 9%, Current or former smoker 81%
  • CABG: 57%
  • PCI: 44%
  • LVEF: 23%
  • NYHA Class
    • I: 37%
    • II: 35%
    • III: 24%
    • IV: 5%
  • QRS ≥0.12: 50%
    • RBBB: 8%
    • LBBB: 19%

Baseline Therapy

  • ACE-inhibitors: 70%
  • Beta-blockers: 70%
  • Diuretics: 76%
  • Digoxin: 57%
  • Class I antiarrhythmic agents: 3%
  • Amiodarone: 12%
  • CCB: 9%
  • Statins: 66%

Interventions

Randomized in 3:2 ratio to either ICD or conventional medical therapy

Outcomes

Comparisons are ICD vs. conventional medical therapy.

Primary Outcome

All-cause mortality
14.2% vs. 19.8% (HR 0.69; 95% CI 0.51-0.93; P=0.016; NNT=18)

Secondary Outcome

New or worsened HF
19.9% vs. 14.9% (P=0.09)

Subgroup Analysis

No differences in effect of ICD on survival in subgroup analyses stratified according to age, gender, LVEF, NYHA class, QRS interval, HTN, DM, LBBB, AF, interval since MI, single vs dual chamber ICD, or BUN.

Criticisms

  • Lack of blinding[3]
  • Use of antiplatelet therapy was unclear[3]
  • Reasons for worsening HF with ICD placement are unclear and concerning[4]

Funding

  • Guidant
  • Multiple disclosures

Further Reading

  1. Analysis of mortality events in the Multicenter Automatic Defibrillator Implantation Trial (MADIT-II)
  2. Yancy CW, et al. "2013 ACCF/AHA guideline for the management of heart failure." Circulation. 2013;128:e240-e327.
  3. 3.0 3.1 NEJM Letters to the Editor
  4. Concurrent editorial