DEFINITE

Published

Kadish A, et al. "Prophylactic Defibrillator Implantation in Patients with Nonischemic Dilated Cardiomyopathy". The New England Journal of Medicine. 2004. 350(21):2151-2158.
PubMed • Full text • PDF

Clinical Question

In patients with nonischemic dilated cardiomyopathy and NYHA class II-IV symptoms, what is the effect of an implantable cardioverter-defibrillator (ICD) on the risk of sudden death?

Bottom Line

ICD placement in addition to standard medical therapy was associated with a trend towards decreased mortality among symptomatic patients with moderate nonischemic dilated cardiomyopathy, LVEF ≤35%, NSVT, and NYHA class II-III symptoms.

Major Points

Sudden cardiac death is the leading cause of death among patients with symptomatic HF. Several trials, including MADIT-I, MADIT-II, MUSTT, and SCD-HeFT demonstrated a mortality benefit of prophylactic ICD placement in various patient groups, including both ischemic and nonischemic cardiomyopathy.

The 2004 Defibrillators in Non-Ischemic Cardiomyopathy Treatment Evaluation (DEFINITE) trial studied 458 patients with nonischemic dilated cardiomyopathy with LVEF ≤35%, NYHA class II-III symptoms, and a history of NSVT. Patients were treated with optimal medical therapy including ACE inhibitors and beta-blockers. ICD placement in addition to standard medical therapy was associated with a trend towards decreased mortality than with standard medical therapy alone, but this did not reach statistical significance. Subgroup analysis showed that the reduction was significant among patients with NYHA class III (HR 0.37; 95% CI 0.15-0.90).

Guidelines

AHA/ACCF Heart Failure Guidelines (2013, adapted)

• 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, reviewer-blinded, parallel-group, randomized, controlled trial
• N=458
  • ICD (n=229)
  • Medical management (n=229)
• Enrollment: July 1998 to June 2002
• Mean follow-up: 2.4 years

Population

Inclusion Criteria

• LVEF ≤35%
• History of symptomatic HF
• Ambient arrhythmias on Holter monitoring, either:
  • Nonsustained ventricular tachycardia (NSVT) of 3-15 beats at ≥120bpm, or
  • ≥10 PVCs/hr
• Absence of CAD based upon angiography or cardiac stress imaging

Exclusion Criteria

• NYHA class IV symptoms
• Poor surgical candidates for ICD placement
• Electrophysiological testing within the prior 3 months
• Permanent pacemakers
• Imminent cardiac transplantation
• Familial cardiomyopathy associated with sudden death
• Acute myocarditis
• Congenital heart disease

Baseline Characteristics

• Mean age: 58.3 years
• Male: 71%
• Race or ethnic group:
  • White: 67%
  • Black: 26%
  • Hispanic: 6%
• History of DM: 23%
• History of AF: 22.7% vs. 26.2%
• Duration of HF: 2.4 vs. 3.3 years (P=0.04)
• NYHA I (22%), II (57%), III (21%)
• QRS interval: 115ms
• LBBB: 19.7%
• RBBB: 3.3%
• NSVT only: 22.5%
• PVCs only 9.4%
• NSVT and PVCs: 68%
• LVEF: 21.4%
• 6MWT: 319 meters

Interventions

• Patients received either standard oral medical therapy or standard oral medical therapy plus an ICD; randomization was stratified by center and amiodarone use
• Standard medical therapy included:
  • ACE inhibitor titrated to the highest dose tolerated or a level most appropriate for HF
    • If ACE inhibitor was contraindicated, patients received ARB, hydralazine, or nitrates
  • Beta-blocker (carvedilol preferred) when tolerated, titrated to the highest dose tolerated or most appropriate for HF
  • Digoxin and diuretics as needed to manage clinical symptoms
  • Amiodarone and other antiarrhythmic drugs were discouraged (the authors cite the inability to titrate beta-blockers to therapeutic doses), but was allowed at a clinician's discretion (the authors cite atrial fibrillation or supraventricular arrhythmias as potential processes requiring an antiarrhythmic agent)
• ICD group had a single-chamber device (St. Jude Medical)
  • Back up VVI pacing occurred at a rate of 40bpm
  • Devices were programmed to detect VF at 180bpm
• Patients were evaluated at 3-month intervals
• Patients in the medical management group who experienced cardiac arrest or unexplained syncope likely due to an arrhythmia received ICDs
• Blinded reviewers determined causes of death by examination of medical records stripped of identification of an ICD
• Pump failure with progressive symptomatic deterioration leading to an arrhythmia was not considered to be an arrhythmogenic death

Pharmacologic Therapy

• ACE inhibitor: 86%
• β-blocker: 85%
• Diuretic: 87%
• ARB: 13.5% vs. 8.7%
• Amiodarone: 4% vs. 6.6%
• Digoxin: 42%
• Nitrate: 9.2% vs. 13.1%

Outcomes

Comparisons are ICD vs. medical management.

Primary Outcome

All-cause mortality

9.4% vs. 17.5% (HR 0.65; 95% CI 0.40-1.06; P=0.08)

Secondary Outcomes

Arrhythmogenic sudden deaths

1% vs. 6% (HR 0.20; 95% CI 0.06-0.71; P=0.006)

HF deaths

3% vs. 4.8% (No P-value given)

Subgroup Analysis

Men with an ICD had a reduced mortality

RR 0.49 95% CI 0.27-0.90; P=0.018

NYHA class III patients with an ICD had a reduced mortality

RR 0.37; 95% CI 0.15-0.90; P=0.02

Adverse Events

• ICD implantation complications included one hemothorax, one pneumothorax, and one cardiac tamponade; all which resolved with appropriate therapy
• ICD complications included six lead dislodgements or fractures, three venous thromboses, and one infection

Criticisms

• No amiodarone group

Funding

Funding from St. Jude Medical, the makers of the ICD.