T-Wave Alternans is Interesting, but More Trials are Necessary to Permit Subselection of MADIT II Patients

Todd J. Cohen, MD
Todd J. Cohen, MD
Dr. Hohnloser and colleagues recently published the results of a 24-month follow-up of 129 patients who met MADIT II criteria in the Lancet (Volume 362, July 12, 2003). The prospective evaluation showed that patients who were T-wave alternans negative had no episodes of sudden cardiac death or cardiac arrest, whereas those who were T-wave alternans positive had a 15.6% event rate. Although these results are promising, the number of patients are too few and the follow-up period is too short to come to the conclusion that this technique can subselect MADIT II patients who are low risk and do not need a device. This type of conclusion is reminiscent of early studies from the late 1980s with the implantable defibrillator, which surmised that if there were no firings over a similar period, the device may be unnecessary.  Subsequent studies with longer follow-up periods demonstrated that even though the defibrillator may not fire over a 2.5-year period, there was still a significant chance of ventricular tachycardia/fibrillation over the next 2.5 years (total 5-year follow-up period). This study is premature and inconclusive. T-wave alternans is not the mainstay for selection of device implantation in 2003-2004. In conclusion, further prospective studies with many more patients and much longer follow-up are needed before we can come to a solid conclusion on the utility of T-wave alternans as an additional screening tool for patients who meet MADIT II criteria. At the present time, I would be very leery at not implanting a defibrillator in a patient who meets MADIT II criteria solely on the results of T-wave alternans.
Lancet Study Points to Utility of Microvolt T-Wave Alternans Test in Predicting which MADIT II Type Patients may not Benefit from a Defibrillator Implant Growing Body of Evidence Supports Use of Microvolt T-Wave Alternans Test as Risk Stratification Tool for Defibrillator Implantation July 12, 2003: Cambridge Heart, Inc. announced that the results of a study assessing the utility of Microvolt T-Wave Alternans (MTWA) in predicting risk of sudden death among MADIT II type patients have been reported in the Lancet. The results indicate that the MTWA Test, using the Cambridge Heart proprietary Analytic Spectral Method during exercise stress, identifies which MADIT II type patients are at low risk for sudden cardiac death, and therefore may not benefit from implantation of a defibrillator. Cardiologists, payers and regulators have struggled to find a way to accurately determine which MADIT II type patients will and will not benefit from invasive defibrillator therapy. MADIT II type patients are people who have had a previous heart attack and have diminished heart function as measured by left ventricular ejection fraction (LVEF) the Lancet identified 129 MADIT II type patients from two previously published clinical trials which prospectively evaluated Microvolt T-Wave Alternans testing in a larger population of 957 heart patients. Twenty-seven percent of the MADIT II type patients tested MTWA negative, while 73% were non-negative. The primary endpoint of the study was sudden cardiac death and cardiac arrest. Kaplan-Meier analysis at 24 months of follow-up revealed an event rate of zero for patients who tested MTWA negative and an event rate of 15.6% for the remaining patients. Thus, there were neither sudden cardiac deaths nor cardiac arrests among the MADIT II type patients who tested MTWA negative. We have compelling evidence here that Microvolt T-Wave Alternans testing can identify a subgroup of MADIT II type patients who are at low risk of dying suddenly and therefore should not require defibrillator therapy, said Stefan Hohnloser, MD, the lead author of the study and Professor of Medicine at J.W. Goethe University in Frankfurt, Germany. MADIT II criteria alone are not sufficient to mandate defibrillator implantation. We now have a simple, non-invasive tool that can help us eliminate both the cost and the risk of implanting patients unnecessarily. The publication of this study confirms the results of two previously presented studies, including an NIH-sponsored trial presented at the late-breaking clinical trials session of the American College of Cardiology in March, said David Chazanovitz, President and CEO of Cambridge Heart, Inc. We now have consistent data on almost 500 MADIT II patients which suggests that patients testing negative for MTWA may not benefit from an implantable defibrillator. Conversely, patients testing not negative may achieve a greater benefit from ICD therapy than demonstrated in the MADIT II trial. An accompanying editorial in the Lancet cited the benefits that would accrue from effective risk stratification of MADIT II patients and suggested further evaluation of MTWA. The company continues studying MTWA in two large, multi-center trials being sponsored by St. Jude Medical (ABCD trial) and Medtronic (MASTER trial). The Cambridge Heart Microvolt T-Wave Alternans Test measures extremely subtle beat-to-beat fluctuations in a person s heartbeat called T-wave alternans. These tiny heartbeat variations measured at one millionth of a volt are detected in any clinical setting where titration of the heart rate is possible. The preparation for the test consists of placing proprietary sensors on a patient s chest. Extensive clinical research has shown that patients with symptoms of or at risk of life-threatening arrhythmias who test positive for T-wave alternans are at significant risk for subsequent sudden cardiac events including sudden death, while those who test negative are at minimal risk.

Microvolt T-Wave Alternans Is an Effective Risk Stratifier in the MADIT II Population The MADIT II study (Moss et al, New England Journal of Medicine, Volume 346, March 21, 2002) demonstrated that ICD implantation in patients with prior myocardial infarction and left ventricular ejection fraction >= 0.30 resulted in an absolute mortality reduction of 5.6%. The MADIT II study has sparked a quest for a non-invasive risk stratifier that can effectively identify a subset of MADIT II patients who will benefit from ICD therapy and a subset of patients who will not. Medicare has currently opted for QRS width as a measure for identifying the group of MADIT II patients for which it will reimburse for ICD therapy, in the absence of prospective data demonstrating the utility of QRS as a risk stratifier in this regard. Microvolt T-wave alternans (MTWA) testing has been demonstrated to be an effective stratifier for ventricular tachyarrhythmic risk in a range of patient populations. Hohnloser et al (the Lancet, Volume 362, July 12, 2003), in an analysis of 129 MADIT II patients drawn from two studies in which MTWA was prospectively evaluated as a risk stratifier, demonstrated that MTWA was specifically effective in the MADIT II population. During a two-year follow-up, there were no sudden cardiac deaths nor cardiac arrests among the patients who tested MTWA negative, and the corresponding event rate was 15.6% among the remaining patients. Furthermore, two additional prospective studies have now been presented at national meetings (by Dr. Daniel Bloomfield at the American College of Cardiology March 2003, and by Dr. Theodore Chow at the American Heart Association November 2003) with essentially identical results. Collectively, these two studies together with the study reported in the Lancet comprise approximately 500 patients. The recently launched MASTER trial is also prospectively examining the use of MTWA in patients with prior MI and reduced ejection fraction. The studies reported to date have had follow-up periods of two years. Longer duration follow-up data are not required in order to use MTWA clinically, provided that MTWA testing is repeated at least every two years in MADIT II patients who test negative in order to reassess their arrhythmic risk. MTWA is an inexpensive non-invasive test and thus repeating this test on an annual or biannual basis is not a problem clinically. As the additional studies come to publication, the data supporting the use of MTWA to risk stratify MADIT II patients will be established. MTWA testing in the MADIT II population, and in other at risk populations, can provide a call to action for ICD implantation in those patients who will benefit from such therapy. Simultaneously, MTWA testing may allow patients to avoid ICD therapy if they do not require it. Richard J. Cohen, M.D., Ph.D.* Whitaker Professor, Harvard-MIT Division of Health Sciences and Technology *Dr. Cohen has a financial interest in Cambridge Heart, Inc. a manufacturer of equipment for the measurement of MTWA.