Ischemic Heart Disease

The Multicenter Unsustained Tachycardia Trial (MUSTT) was a multi-center prospective study that enrolled 2202 patients with significant CAD, reduced LVEF (<40%), and nonsustained VT and subjected patients to programmed ventricular stimulation.⁸ VT was induced in just over one third of patients. These patients were then randomized to either no AAD therapy or AAD therapy guided by repeated stimulation. If VT remained inducible despite AAD therapy, an ICD was implanted. Patients in whom sustained monomorphic VT was induced were monitored by a registry. Although this study confirmed that patients with inducible VT off AADs had a higher rate of arrhythmic events over the following 5 years compared with those without inducible VT (36% vs. 24%; P = .005), the event rate in patients without inducible VT at the time of invasive EPS was not insignificant (Figure 25-2).⁹

FIGURE 25-2 The role of invasive electrophysiological testing in patients with ischemic cardiomyopathy from the Multicenter Unsustained Tachycardia Trial (MUSTT). Shown are Kaplan-Meier estimates of the rates of cardiac arrest or death from arrhythmia in the registry patients and the patients with inducible ventricular tachyarrhythmias who were not assigned to antiarrhythmic therapy.

(From Buxton AE, Lee KL, DiCarlo L, et al: Electrophysiologic testing to identify patients with coronary artery disease who are at risk for sudden death. Multicenter Unsustained Tachycardia Trial Investigators, N Engl J Med 342:1937–1945, 2000.)

As just stated, it is not uncommon to induce polymorphic VT and VF at shorter extrastimulus coupling intervals and with multiple extrastimuli. In the MUSTT trial, induction of polymorphic VT or VF was considered positive only if this occurred with up to two extrastimuli. In a retrospective analysis of the Multicentre Automatic Defibrillator Trial II (MADIT-II), for which patients had to have an LVEF less than 30% and a prior MI, programmed ventricular stimulation was prognostic only when a positive result was taken—that is, not when polymorphic VT or VF had been induced with aggressive pacing.^9,10 Although many studies were performed on acute arrhythmia suppression with AADs, the long-term use of AADs to prevent VT and VF has been disappointing, and it is now common to implant ICDs in patients at risk. However, this is mainly based on the patient’s LVEF, not on invasive testing.^8,9,11,12

Current guidance for the use of programmed ventricular stimulation is based largely on the MADIT-I and MADIT-II trials and the results of the Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT).^11–13 In the United Kingdom, the National Institute for Health and Clinical Excellence updated the guidelines for ICD implantation, which are used in other health care systems throughout the world. These evidence-based guidelines suggest that the role of programmed ventricular stimulation in the decision to implant an ICD is restricted to patients with a previous MI (>6 weeks), an LVEF of 30% to 35%, a lack of New York Heart Association (NYHA) class IV symptoms, and nonsustained VT on monitoring. These criteria were derived from the enrollment criteria to the MADIT-I study. Patients who were enrolled in the MADIT-II study with an LVEF less than 30% did not need to undergo invasive EPS. Although it appears that programmed ventricular stimulation has quite a narrow indication in the decision of when to implant an ICD, it still remains a useful tool. The absolute benefit from ICD implantation in the MADIT trial was 12% per year in which patients had to have a “positive” test result compared with a more modest absolute benefit of approximately 3% and 1.5% per year, respectively, in the MADIT-II and SCD-HeFT populations, in whom programmed ventricular stimulation was not used to determine ICD implantation.

On the basis of the MUSTT trial results, patients with clinically significant CAD and an LVEF of 30% to 40% and nonsustained VT would also benefit from ICDs if they had a positive programmed ventricular stimulation test result.^8,9 Again, a large absolute benefit was demonstrated in this patient population, although for most patients the clinically significant CAD was a prior MI.

A recent study has shown that performing programmed ventricular stimulation may be beneficial when patients presented within the first few weeks after an MI and with an LVEF of less than 40% (Figure 25-3).¹⁴ ICD implantation is not routinely considered in these patients as a result of the Defibrillator in Acute Myocardial Infarction Trial (DINAMIT), which demonstrated that patients with an ICD implanted within the first month of an MI with an LVEF of less than 35% and depressed autonomic function, as assessed by heart rate variability, actually had a worse outcome.¹⁵ Although fewer patients died of arrhythmic events, the rate of nonarrhythmic death was substantially high. These data, as well as those from the Immediate Risk Stratification Improves Survival (IRIS) trial, which also investigated early implantation of an ICD in high-risk patients (as assessed by reduced LVEF <40%, depressed autonomic function, or nonsustained VT on Holter monitoring), demonstrated no absolute mortality benefit from implantation.¹⁴ This has led to the current situation in which high-risk patients do not receive ICDs after an MI.^16,17

FIGURE 25-3 The role of invasive electrophysiological study after myocardial infarction. Shown are Kaplan-Meier curves for sudden death or ventricular tachycardia or ventricular fibrillation (VT or VF) stratified by those with inducible VT or VF at invasive electrophysiological (EP) study 9 days after successful revascularization. HR, Hazard ratio.

(From Kumar S, Sivagangabalan G, Zaman S, et al: Electrophysiology-guided defibrillator implantation early after ST-elevation myocardial infarction, Heart Rhythm 7:1589–1597, 2010.)

In the latest study, however, programmed ventricular stimulation has been used to risk stratify patients, in contrast to the noninvasive measures in the IRIS and DINAMIT studies. In the study by Kumar et al, patients with previous MI and an LVEF less than 40% had programmed ventricular stimulation at an average of 9 days after the acute event. An ICD was implanted in patients in whom VT could be induced with a cycle length greater than 200 ms with up to four extrastimuli. In this study, patients with a positive test result were at a substantially higher risk (hazard ratio [HR], 14.3) compared with those who had a negative test result, and implantation of an ICD seemed to confer benefit in this patient population. An important distinction in this study compared with the earlier DINAMIT and IRIS trials was that patients had to have been successfully revascularized before enrollment.

The results of MUSTT, taken together with the more recent work on early programmed ventricular stimulation after successful revascularization, suggest that programmed ventricular stimulation is a useful tool in risk stratifying patients with a reduced ejection fraction after MI (Table 25-2). Compared with signal-averaged electrocardiograms (ECGs) and LVEF, programmed ventricular stimulation is the best predictor of spontaneous ventricular arrhythmia late after MI in patients with reduced ejection fraction.^18,19

Table 25-2 Use of Invasive Electrophysiological Testing after Myocardial Infarction

Idiopathic Dilated Cardiomyopathy

The role of programmed ventricular stimulation in the risk assessment of patients with idiopathic dilated cardiomyopathy (IDCM) is not well studied. Approximately 50% of patients with IDCM will have SCD caused by ventricular arrhythmia as opposed to progressive heart failure.²⁰ Impairment of left ventricular function alone does not appear to be a specific marker for risk.^11,21,22 In the Cardiomyopathy Trial (CAT), 104 patients with IDCM and an LVEF less than 30% were randomized to either medical or ICD therapy.²³ This trial had a very low rate of β-blocker use, which makes interpretation more difficult in the contemporary era. Despite this, overall mortality was very low, and the trial was stopped early because of futility.

In the Amiodarone Versus Implantable Cardioverter-Defibrillator: Randomized Trial in Patients With Nonischemic Dilated Cardiomyopathy and Asymptomatic Nonsustained Ventricular Tachycardia (AMIOVIRT), 103 patients were enrolled, but this trial was also stopped early after just over 2 years because of a failure to show any benefit of an ICD. Again, there was a relatively low mortality rate of 12%.²¹ Although the use of β-blockers was better, only 53% of patients were taking them at the time of the study. Invasive EPS was again not used to risk stratify patients. In the Defibrillators in Non-Ischaemic Cardiomyopathy Treatment Evaluation (DEFINITE) trial, a much larger number of patients were enrolled compared with either CAT or AMIOVIRT, with similar inclusion criteria.²² In addition, a greater population was on optimal medical therapy, with 84% of the population on β-blockers and 86% on angiotensin-converting enzyme (ACE) inhibitors, although spironolactone was not then part of the standard therapy. However, patients were excluded if they had undergone invasive EPS within 3 months. Although implantation of an ICD led to a significant reduction in the rate of SCD (HR, 0.2), it did not lead to an overall reduction in death from any cause.

A smaller study did investigate the use of programmed ventricular stimulation in this patient population as well as the presence of nonsustained VT on ambulatory monitoring.²⁴ Although more than 80% of patients enrolled in the study were taking β-blockers, fewer than one fourth of patients were taking β-blockers at the start of the study. With a stimulation protocol of a six-beat drive train with two or three extrastimuli from a single site, monomorphic VT was inducible in 7% of patients. The addition of the third extrastimulus increased overall inducibility, but this was caused by the induction of polymorphic VT, ventricular flutter, and VF. During a mean follow-up of just over 2 years, the positive predictive value (PPV) was poor at 29%. Although the negative predictive value (NPV) of programmed ventricular stimulation was high, there was a very low event rate in the overall study population.

A more recent study looked at inducibility of ventricular tachyarrhythmias and subsequent therapy from an ICD implanted for secondary prevention.²⁵ By using a different stimulation protocol from the previous study, with four basic drive train cycle lengths, up to two ventricular stimulation sites, and up to three extrastimuli, the investigators found that induction of polymorphic VT or VF was more predictive of subsequent fast VT or VF events than if sustained monomorphic VT was induced. They also found that these patients had a worse overall mortality rate despite having a similar left ventricular systolic function.²⁶ However, this was a retrospective study, and the data collection took place over a long period, from 1994 to 2007, limiting the clinical application of this study.

In conclusion, programmed ventricular stimulation is of limited value for risk assessment in patients with IDCM and has no randomized controlled trial data to support its use.