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 with systolic dysfunction (LVEF < 40%) due to ischemic cardiomyopathy and asymptomatic nonsustained ventricular tachycardia (VT), does an EPS-guided approach including antiarrhythmic therapy with either ICD and/or antiarrhythmic drugs (AADs) if sustained VT is inducible at EP study reduce cardiac arrest or arrhythmic death compared to no intervention?

Bottom Line

In patients with systolic dysfunction (LVEF < 40%) due to ischemic cardiomyopathy and asymptomatic nonsustained ventricular tachycardia (VT), EPS-guided therapy (use of AAD and/or ICD therapy in patients with inducible sustained VT) resulted in a 7% absolute reduction in the primary endpoint of cardiac arrest or arrhythmic death versus no intervention. The benefit of EPS-guided therapy was solely due to ICD use, with a 28% absolute reduction in cardiac arrest or arrhythmic death at 5 years in those with an ICD implanted versus no EPS-guided therapy. Patients randomized to EPS-guided therapy who received AAD but not ICD experienced similar event rates to those not randomized to EPS-guided therapy.

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). Nevertheless, patients with ischemic cardiomyopathy without more severe systolic dysfunction, particularly those who experience nonsustained VT, are thought to remain at higher risk of arrhythmic events. At the same time, this is a large population of patients many of whom will never experience a significant arrhythmic event. It is possible 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 (subsequently underwent AAD titration and/or ICD placement if sustained VT inducible on EPS) versus no antiarrhythmic therapy and assessed for a primary outcome of cardiac arrest or arrhythmic death. At 5 years, EPS-guided therapy was associated with a 7% absolute reduction in cardiac arrest and arrhythmic death as well as a similar benefit in terms of overall mortality. This benefit was driven exclusively by ICD therapy as the rate of the primary outcome was similar in patients randomized to EPS-guided therapy followed by AAD without ICD and those randomized to no antiarrhythmic therapy at all. Specifically, 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 without ICD.

Ultimately, the results of MUSTT suggest that even patients with very mild systolic dysfunction due to ischemic cardiomyopathy, including those with LVEF 35-39% which would be too high to qualify for either SCD-HeFT or MADIT-II, still appear to benefit from ICD therapy if they have asymptomatic NSVT and EP study is notable for inducible sustained VT. Although this is a relatively circumscribed population of patients, the magnitude of benefit suggests that these patients should be risk stratified with EPS and receive ICD therapy if sustained VT is inducible.

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

  • Patients randomized to EPS-guided therapy not randomized to either ICD or AAD, allowing for potential bias (i.e., patients who ultimately received ICD therapy were potentially less sick to begin with) and possible overestimation of ICD benefit
  • Mean LVEF among patients in the study approximately 30%. As a result, the proportion of patients with LVEF 35-39% is likely small (not actually reported) even though this is the subgroup of greatest interest as ICD therapy is already known to be beneficial in most patients with LVEF < 35%

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.