MUSTT

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Buxton AE et al. "A randomized study of the prevention of sudden death in patients with coronary artery disease". New Engl J Med. 1999. 341(25):1882-90.
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Clinical Question

In patients ischemic cardiomyopathy, EF<40%, and asymptomatic nonsustained ventricular tachycardia, does an EPS-guided approach (including ICD and/or antiarrhythmic drugs) reduce the risk of cardiac arrest or arrhythmic death compared to no intervention?

Bottom Line

In patients with ischemic cardiomyopathy, EF <40%, and NSVT, EPS-guided therapy resulted in a 7% absolute reduction in the primary endpoint of cardiac arrest or arrhythmic death versus no intervention, driven primarily by ICD use. Patients with a known indication for ICD were not excluded, obscuring the degree to which benefit was derived for those with NSVT or by using EPS-guided therapy to direct ICD placement.

Major Points

Multiple RCTs including SCD-HeFT and MADIT-II have established the role of ICD use as primary prophylaxis to reduce arrhythmic mortality in patients with significant systolic dysfunction (LVEF < 35% with symptoms in SCD-HeFT and LVEF < 30% in the setting of ischemic cardiomyopathy regardless of symptoms in MADIT-II). Other patients with ischemic cardiomyopathy, particularly those who experience nonsustained VT, are thought to remain at higher risk of arrhythmic events. This is a large population of patients, many of whom will never experience a significant arrhythmic event. It was thought that the use of EPS-guided therapy, or the attempted induction of sustained VT by delivering provocative stimuli, may be able to identify a subset of patients at higher risk and therefore more likely to benefit from ICD or AAD use versus those with negative induction testing.

The 1999 Multicenter Unsustained Tachycardia Trial (MUSTT) trial randomized 704 patients to either EPS-guided therapy (if positive, protocolized to antiarryhthmic therapy vs. ICD) versus no antiarrhythmic therapy. At 5 years, EPS-guided therapy was associated with a 7% absolute reduction in the primary outcome of cardiac arrest and arrhythmic death, with similar benefit in overall mortality. This benefit was driven exclusively by ICD therapy. In fact, within the EPS-guided therapy group, patients receiving ICD had a 75% relative risk reduction for the primary outcome compared to those receiving AAD therapy. Importantly, the average EF was 30%, making it difficult to assess if patients benefited from a known indication or this novel one.

The MUSTT trial sought to identify a subset of patients with ischemic cardiomyopathy, those with NSVT and positive EP study, who may benefit from ICD for primary prevention. However, it is difficult to attribute the benefit of ICD to the NSVT or positive EPS, or to quantify the benefit of ICD given the lack of randomization post-positive EP study. Further studies are needed to confirm this finding and ensure that these results from 1999 are still valid on modern maximal medical therapies.

Guidelines

ACCF/AHA/HRS Guidelines for Device-Based Therapy (2012, adapted)[1]
  • ICD therapy is indicated in patients with nonsustained VT due to prior MI, LVEF less than or equal to 40%, and inducible VF or sustained VT at electrophysiological study (Class 1, Level of Evidence B)

Design

  • Multicenter, open-label, randomized, controlled trial
  • N=704
    • EPS-guided therapy (n=351)
      • AAD (n=158)
      • ICD (n=161)
    • No antiarrhythmic therapy (n=353)
  • Setting: 85 sites in the US and Canada
  • Enrollment: November 1, 1990 to October 31, 1996
  • Median follow-up: 39 months
  • Analysis: Intention-to-treat
  • Primary outcome: Cardiac arrest or arrhythmic death

Population

Inclusion Criteria

  • Coronary artery disease present defined as:
    • Reversible ischemia on exercise testing
    • Obstructive CAD on coronary angiogram
  • LVEF ≤ 40%
  • Asymptomatic NSVT (3 or more beats)

Exclusion Criteria

  • History of syncope
  • Sustained ventricular tachycardia or fibrillation 48 hours or more after the onset of MI
  • NSVT occurred solely in the setting of acute ischemia, metabolic disorders, or drug toxicity

Baseline Characteristics

From the EPS arm

  • Demographics: Age 67, male 90%, white 90%
  • Cardiac: LVEF 30%, Hx MI 96%, Hx CABG 56%, NYHA I 37%, NYHA II 39%, NYHA III 24%, NYHA IV 0%
  • EP: Sustained VT inducible 88%, VT cycle length 245ms
  • Medications: Beta blocker 29%, ACE/ARB 72%, ASA 64%, digitalis 52%, diuretic 58%

Interventions

  • 1:1 randomization to EPS-guided therapy or no antiarrhythmic therapy
    • Among patients randomized to EPS-guided therapy, patients underwent the following protocol
    • Initial programmed stimulation with delivery of 1-3 extrastimuli and burst pacing at two RV sites during two paced cycle lengths in the absence of AADs. Stimulation was stopped after sustained VT was induced.
    • If EPS positive, randomized AAD titration with loading of AAD followed by repeat programmed stimulation. If fewer than 15 complexes induced with stimulation, long-term therapy with that AAD was undertaken. If no drug resulted in fewer than 15 complexes, patients could be discharged with an AAD that resulted in hemodynamically tolerated VT at stimulation.
    • ICD therapy could be recommended after at least one failed AAD drug test
  • Treatment with beta blockers and ACEi/ARB recommended for all patients
  • Patients were evaluated one month after discharge and every three months thereafter

Outcomes

Comparisons are EPS-guided approach vs no antiarrhythmic treatment unless specified.

Primary Outcomes

Cardiac arrest or arrhythmic death (5 years)
25% vs. 32% [RR 0.73; 95% CI 0.53-0.99; P=0.04]

Secondary Outcomes

Overall mortality (5 years)
42% vs. 48% [RR 0.80; 95% CI 0.64-1.01; P=0.06]
Cardiac death (5 years)
34% vs. 40% [P=0.05]
Cardiac arrest or arrhythmic death (5 years, among EPS-guided patients, ICD vs. AAD without ICD)
9% vs. 37% [P<0.001]
Overall mortality (5 years, among EPS-guided patients, ICD vs. AAD without ICD)
24% vs. 55% [RR 0.40; 95% CI 0.27-0.59; P<0.001]

Adverse Events

Complication related to initial EP study
0.7% (all nonfatal)

Criticisms

  • Mean EF was ~30%, suggesting the benefit of ICD may not be related to NSVT or positive EP study
  • Patients with positive EPS study not randomized to either ICD or AAD, allowing for potential bias
  • Study performed in 1999; results may not generalize well to current EP and ICD technology
  • Patients were not on maximal medical therapy, which may have nullified benefit of ICD in this population
  • Secondary outcomes evaluating benefit of ICD therapy may be reflecting harm from AAD (or be exaggerated by it)

Funding

  • Study supported by grants from the National Heart, Lung, and Blood Institute, C.R. Bard, Berlex Laboratories,Boehringer–Ingelheim Pharmaceuticals, Guidant–Cardiac Pacemakers, Knoll Pharmaceutical, Medtronic, Searle, Ventritex–St. Jude Medical, and Wyeth–Ayerst Laboratories

Further Reading

  1. Epstein AE et al. 2012 ACCF/AHA/HRS focused update incorporated into the ACCF/AHA/HRS 2008 guidelines for device-based therapy of cardiac rhythm abnormalities: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. J. Am. Coll. Cardiol. 2013. 61:e6-75.