EDITORIAL COMMENT
Should Microvolt T-Wave Alternans Be Utilized Routinely in Selecting Patients for Prophylactic Implantable Cardioverter-Defibrillator Insertion in the Setting of Ischemic Heart Disease?*
Andrea M. Russo, MD, FACC*,2 and
Francis E. Marchlinski, MD, FACC2
University of Pennsylvania Health System, Philadelphia, Pennsylvania.
* Reprint requests and correspondence: Dr. Andrea M. Russo, University of Pennsylvania Health System, Penn-Presbyterian Medical Center, 4th Floor PHI, 38th and Market Streets, Philadelphia, Pennsylvania 19104. (Email: andrea.russo{at}uphs.upenn.edu).
Most patients who receive implantable cardioverter-defibrillators (ICDs) for primary prevention never develop sustained ventricular arrhythmias. In addition, the majority of patients in the overall population who die suddenly are not identified by current methods of risk stratification (1). Ejection fraction lacks sufficient sensitivity and specificity to be useful as a single method of risk stratification (1,2). The study by Chow et al. (3) in this issue of the Journal suggests that risk stratification with microvolt T-wave alternans (MTWA) identifies patients who are most and least likely to benefit from ICD therapy.
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MTWA and risk prediction—arrhythmic events and total mortality
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Studies have demonstrated a relationship between MTWA and the inducibility of ventricular arrhythmias during invasive electrophysiologic testing (4,5). A recent meta-analysis examining 19 studies (2,608 subjects) across a wide range of populations identified MTWA as a strong predictor of arrhythmic events, and this predictive value was seen in patients with ischemic and non-ischemic heart disease (6). In a prospective multicenter study of patients potentially eligible for ICD prophylaxis, Bloomfield et al. (7) demonstrated that MTWA can identify high- and low-risk groups among patients with ischemic or nonischemic heart disease and left ventricular ejection fraction (LVEF)  40%, with a primary end point of all-cause mortality or non-fatal sustained ventricular arrhythmias. Other studies have demonstrated that MTWA can also predict total mortality in patients with ischemic heart disease and reduced left ventricular (LV) function without prior history of arrhythmia (8,9).
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MTWA and ICD benefit
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The current study by Chow et al. (3) was performed in patients with ischemic cardiomyopathy and no prior history of ventricular arrhythmias to assess whether ICD benefit differs in MTWA non-negative (positive and indeterminate) versus negative subgroups. The primary end point of the current study was all-cause mortality, and secondary end points included cause-specific mortality and appropriate ICD shocks. The investigators found that mortality reduction with the ICD differs by MTWA status. After multivariable adjustment, ICDs were associated with lower all-cause mortality in MTWA non-negative patients, and this mortality benefit was due largely to a reduction in arrhythmic mortality. The latter is not surprising, as ICDs are anticipated to reduce mortality by reducing arrhythmic death. The authors suggest that MTWA may effectively risk-stratify patients with ischemic cardiomyopathy by identifying subgroups who receive substantial versus minimal benefit from ICD therapy. The reported 70% reduction in arrhythmic mortality is similar to the 62% reduction (from 10% in the conventional therapy group to 3.8% in the ICD group, p < 0.01) seen in the MADIT-II (Multicenter Automatic Defibrillator Implantation Trial) substudy analysis (10).
The current report also suggests that as many as one-third of patients with ischemic heart disease who meet the current criteria for prophylactic ICD insertion may derive minimal benefit from device implantation and that these patients may be identified by MTWA testing. However, it is unclear when to screen patients after infarction and how often to repeat MWTA testing if the initial test is negative. The authors suggest that one option may be to screen patients annually, although data on the conversion rate from MTWA negative to non-negative status is lacking and its prognostic implications are unclear.
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Current study limitations
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Although no significant differences were seen with ICD therapy in the MTWA-negative group, only 75 such patients received an ICD. The authors acknowledge that their study may not have been adequately powered to detect a statistical difference in outcome in this cohort. Patients who have MTWA-negative tests have much lower arrhythmic rates (7–9). Therefore, a larger study might also have found a significant benefit with ICD therapy in the MTWA-negative group. In addition, this was a prospective cohort study, not a randomized prospective study evaluating the benefit of ICD therapy based on MTWA status. Propensity scores for ICD insertion based on variables most likely to influence ICD insertion (such as electrophysiology testing, QRS duration, and abnormal Holter) were developed for each MTWA cohort. Multivariable analyses that controlled for propensity score, demographics, and clinical variables were used to evaluate the degree to which ICDs reduced mortality risk for each MTWA group. As in all cohort studies, the authors acknowledge that there exists the potential for residual confounding factors. In addition, this study evaluated only patients with ischemic heart disease, and results may not apply to patients with non-ischemic disease.
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Cost and reimbursement
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If ICDs were inserted in all patients meeting the MADIT-II (Multicenter Automatic Defibrillator Implantation Trial II) or SCD-HeFT (Sudden Cardiac Death in Heart Failure Trial) study indications, the cost implications would be substantial. For example, in the SCD-HeFT study, only a limited percentage of patients (5.1% per year) in the ICD treatment arm received appropriate shocks for rapid ventricular tachycardia/ventricular fibrillation during follow-up (11). Analysis of a model to evaluate treatment strategies for a hypothetical MADIT II-like patient revealed that risk stratification with MTWA testing would improve the cost-effectiveness of ICDs (12). The findings of the current study would support this hypothesis, as the number of patients needed to treat for 2 years with an ICD to save 1 life would be 9 among MTWA non-negative patients and 76 among MTWA-negative patients.
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Conclusions
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At present, there is no single test or known series of tests that have been prospectively evaluated that provide a high predictive value in identifying high- and low-risk patients for primary prevention ICD insertion. Inserting ICDs in all patients who currently meet guidelines, based on LV function, leads to implantation of devices in many patients who will never need them. Not only does this have implications with respect to the cost, but, in addition, a realistic assessment of potential adverse events and quality of life should be considered.
On the basis of the results of the current study, MWTA appears promising in predicting patients who might be most likely and least likely to benefit from ICD therapy. Microvolt T-wave alternans has utility in predicting risk in diverse populations, including patients with coronary artery disease, nonischemic cardiomyopathy, congestive heart failure, and patients who already have ICDs. Although MWTA testing has a low specificity and predictive accuracy, there is a high negative predictive value. Patients with reduced LV function who are being considered for prophylactic ICD implantation but have a negative MTWA test might avoid, or at least postpone, ICD insertion.
Because of limitations of the current cohort study, subsequent validation in larger cohort studies or future randomized studies is definitely needed before MTWA can be used routinely as a screening test to determine the need for prophylactic ICD insertion. Future study should focus on a larger scale prospective evaluation of MTWA in prediction of arrhythmic events and mortality in ICD recipients. Although risk stratification using MTWA could have important implications with respect to health care policy and reimbursement, the results of the current study should not be overinterpreted. Additional prospective data collection must be acquired before major policy decisions are made.
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Future study
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The role of MTWA testing in selection of the best candidates for ICD insertion awaits the results of large multicenter trials. The MASTER (Microvolt T-wave AlternanS Testing for Risk Stratification) trials are ongoing and will evaluate the role of MTWA in predicting risk of ventricular arrhythmias in patients with coronary artery disease and reduced LV function who are indicated for primary prevention ICDs. The objective of the ABCD (Alternans Before Cardioverter Defibrillator) trial is to demonstrate that MTWA is at least as effective as invasive electrophysiologic testing in determining which patients with ischemic heart disease are at increased risk for life-threatening arrhythmic events. The REFINE (Risk Estimation Following Infarction-Noninvasive Evaluation) study will evaluate the role of MTWA testing in risk stratification of a lower risk post-MI group with an LVEF of up to 50%.
Although the results of ongoing trials will add to our current information about the ability of MTWA to predict events in ICD patients, they will not answer all questions. Other non-invasive tools, such as signal averaging, heart rate variability, and baroreflex sensitivity, have been shown to have prognostic value in helping to identify high-risk patients, but these techniques have not become standard in clinical practice owing to low positive predictive values. Magnetic resonance assessment of scar can identify substrate for inducible ventricular tachycardia in patients with nonischemic cardiomyopathy, independent of LVEF, and could prove to be a valuable tool for risk assessment (13). Future studies evaluating the utility of the combined predictive value of several methods of risk stratification, including MTWA, with long-term follow-up in a variety of patient populations is warranted.
Perhaps one benefit of potentially avoiding ICD insertion in the negative-MTWA group is that we may increase resources for newer, yet-to-be-defined populations who may derive greater benefit. The majority of patients who die suddenly do not meet current implantation criteria, and these patients have not been included in previous primary prevention trials. The average LVEF in survivors of cardiac arrest in 2 multicenter randomized secondary prevention trials was 32% and 45% (14,15). In the future, MTWA might demonstrate utility in expanding ICD indications to better identify newer populations with an LVEF >35% at increased arrhythmic risk.
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Footnotes
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* Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology. 
2 Drs. Russo and Marchlinski participate in clinical device research trials (Medtronic, Guidant, St. Jude) and speaking engagements with honoraria.
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References
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- Huikuri HV, Castellanos A, Myerburg RJ. Sudden death due to cardiac arrhythmias N Engl J Med 2001;345:1473-1482.[Free Full Text]
- Buxton AE. Risk stratification for sudden death: do we need anything more than ejection fraction? Card Electrophysiol Rev 2003;7:434-437.[CrossRef][Medline]
- Chow T, Kereiakes DJ, Bartone C, et al. Microvolt T-wave alternans identifies patients with ischemic cardiomyopathy who benefit from implantable cardioverter-defibrillator therapy J Am Coll Cardiol 2007;49:50-58.[Abstract/Free Full Text]
- Rosenbaum DS, Jackson LE, Smith JM, et al. Electrical alternans and vulnerability to ventricular arrhythmias N Engl J Med 1994;330:235-241.[Abstract/Free Full Text]
- Gold MR, Bloomfield DM, Anderson KP, et al. A comparison of T-wave alternans, signal averaged electrocardiography and programmed ventricular stimulation for arrhythmia risk stratification J Am Coll Cardiol 2000;36:2247-2253.[Abstract/Free Full Text]
- Gehi AK, Stein RH, Metz LD, Gomes A. Microvolt T-wave alternans for the risk stratification of ventricular tachyarrhythmic events: a meta-analysis J Am Coll Cardiol 2005;46:75-82.[Abstract/Free Full Text]
- Bloomfield DM, Bigger JT, Steinman RC, et al. Microvolt T wave alternans and risk of death or sustained ventricular arrhythmias in patients with left ventricular dysfunction J Am Coll Cardiol 2006;47:456-463.[Abstract/Free Full Text]
- Chow T, Kereiakes DJ, Bartone C, et al. Prognostic utility of microvolt T-wave alternans in risk stratification of patients with ischemic cardiomyopathy J Am Coll Cardiol 2006;47:1820-1827.[Abstract/Free Full Text]
- Bloomfield DM, Steinman RC, Namerow PB, et al. Microvolt T wave alternans distinguishes between patients likely and patients not likely to benefit from implanted cardiac defibrillator therapy: a solution to the Multicenter Automatic Defibrillator Implantation Trial II conundrum Circulation 2004;110:1885-1889.
- Greenberg H, Case RB, Moss AJ, et al. MADIT II Investigators Analysis of mortality events in the Multicenter Automatic Defibrillator Implantation Trial (MADIT II) J Am Coll Cardiol 2004;43:1459-1465.[Abstract/Free Full Text]
- Bardy GH, Lee KL, Mark DB, et al. SCD-HeFT Investigators Amiodarone or an implantable cardioverter defibrillator for congestive heart failure N Engl J Med 2005;352:225-237.[Abstract/Free Full Text]
- Chan PS, Stein K, Chow T, et al. Cost-effectiveness of a microvolt T wave alternans screening strategy for implantable cardioverter defibrillator placement in the MADIT II-eligible population J Am Coll Cardiol 2006;48:112-121.[Abstract/Free Full Text]
- Nazarian S, Bluemke DA, Lardo AC, et al. Magnetic resonance assessment of the substrate for inducible ventricular tachycardia in nonischemic cardiomyopathy Circulation 2005;112:2821-2825.
- The Antiarrhythmics Versus Implantable Defibrillaors (AVID) Investigators A comparison of antiarrhythmic drug therapy with implantable defibrillators in patients resuscitated from near-fatal ventricular arrhythmias N Engl J Med 1997;337:1576-1583.[Abstract/Free Full Text]
- Kuck KH, Cappato R, Siebels J, Ruppel R, CASH Investigators Randomized comparison of antiarrhythmic drug therapy with implantable defibrillators in patients resuscitated from cardiac arrest: the Cardiac Arrest Study Hamburg (CASH) Circulation 2000;102:748-754.
Related Article
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Microvolt T-Wave Alternans Identifies Patients With Ischemic Cardiomyopathy Who Benefit From Implantable Cardioverter-Defibrillator Therapy
- Theodore Chow, Dean J. Kereiakes, Cheryl Bartone, Terri Booth, Edward J. Schloss, Theodore Waller, Eugene Chung, Santosh Menon, Brahmajee K. Nallamothu, and Paul S. Chan
J. Am. Coll. Cardiol. 2007 49: 50-58.
[Abstract]
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