Letter by De Ferrari and Verrier Regarding Article, “Role of Microvolt T-Wave Alternans in Assessment of Arrhythmia Vulnerability Among Patients With Heart Failure and Systolic Dysfunction: Primary Results From the T-Wave Alternans Sudden Cardiac Death in Heart Failure Trial Substudy”
To the Editor:
We read with interest the recent article by Gold et al,1 who concluded that T-wave alternans (TWA) should not be used to make clinical decisions for patients with symptomatic heart failure and left ventricular dysfunction. The accompanying editorial2 underscored as a major limitation the study’s use of an implantable cardioverter-defibrillator (ICD) discharge as a surrogate marker for sudden cardiac death, referencing a meta-analysis3 that demonstrated a dramatic difference in the predictive power of TWA if ICD-detected events were included or excluded.
Although performing a TWA substudy within a large ICD trial was considered a major advantage,1 inclusion of ICD therapy actually prevented the determination of TWA’s prediction of clinical sudden death. An analysis excluding ICD-detected end points could be beneficial. However, end-point rates within the treatment groups are not reported, and their absence prevents the assessment of overestimation caused by ICD interventions. The text indicates that 75 subjects reached primary end points, but 95 primary end points are reported (27 sudden deaths, 3 resuscitated cardiac arrests, 40 sustained ventricular tachycardia [VT] events, and 25 ICD discharges). The accompanying table provides numbers differing from those reported elsewhere in the text. Negative and indeterminate TWA patients are 28% and 35% in the Table but 22% and 41% throughout the text. Sudden deaths are 26 (27 in the text), and all-cause deaths in TWA-negative and nonnegative groups are 16 and 65, respectively (15 and 60 in Figure 2).
Additional aspects should be considered. Patients enrolled were not consecutive, representing 19% of the overall Sudden Cardiac Death in Heart Failure Trial population and 45±22% of patients enrolled at 37 sites (3 patients per year per site). The number of indeterminate tests was atypically high (41%). Also, the strategy to withhold β-blockers has been debated.4
The most frequent end point was sustained VT, which occurred in >8% of patients. This unusually high occurrence requires clarification of the definition of sustained VT. How many episodes were symptomatic? How were they recorded? In the study, 2 events were counted in case of “VT leading to ICD discharge,” suggesting that the end point of sustained VT was attributed to ventricular arrhythmias detected by ICDs and lasting presumably <30 seconds. The clinical significance of short-lasting asymptomatic VTs in patients with heart failure is uncertain.
It is worth placing the study’s conclusions in the context of prior studies, including the T-Wave ALternans in Patients With Heart FAilure (ALPHA)5 study, which is the largest TWA study performed in patients with heart failure, enrolling 446 consecutive nonselected patients with nonischemic cardiomyopathy in New York Heart Association classes II and III. Abnormal TWA was associated with a hazard ratio of 4.01 for cardiac mortality and life-threatening ventricular arrhythmias. After excluding all device-detected end points, abnormal TWA was associated with a hazard ratio of 3.44 (P=0.008). Our meta-analysis of studies performed in patients with nonischemic cardiomyopathy4 determined an overall highly significant relative risk for abnormal TWA (2.99, 95% confidence interval 1.88 to 4.75). If 51% of both population and events reported by Gold1 are added (an imperfect choice but necessitated by lack of cause-related data), the resulting relative risk would remain statistically significant (2.41, 95% confidence interval 1.63 to 3.57).
We commend the authors for their valuable study, which contributes to a better understanding of the potential value of TWA. Overall, we believe that available data still support a role for TWA in clinical decision making for patients with symptomatic heart failure and LV dysfunction, particularly of nonischemic origin.
Dr Verrier has received research grants on T-wave alternans from the National Institutes of Health, the American Heart Association, and Medtronic Inc. He has received royalties for his patent on the modified moving average method for TWA analysis, which was assigned to Beth Israel Deaconess Medical Center and licensed to GE Healthcare. Dr De Ferrari reports no conflicts.
Gold MR, Ip JH, Costantini O, Poole JE, McNulty S, Mark DB, Lee KL, Bardy GH. Role of microvolt T-wave alternans in assessment of arrhythmia vulnerability among patients with heart failure and systolic dysfunction: primary results from the T-Wave Alternans Sudden Cardiac Death in Heart Failure Trial substudy. Circulation. 2008; 118: 2022–2028.
Rosenbaum D. T-Wave Alternans in the Sudden Cardiac Death in Heart Failure Trial population: signal or noise? Circulation. 2008; 118: 2015–2018.
Salerno-Uriarte JA, De Ferrari GM, Klersy C, Pedretti RF, Tritto M, Sallusti L, Libero L, Pettinati G, Molon G, Curnis A, Occhetta E, Morandi F, Ferrero P, Accardi F, ALPHA Study Group Investigators. Prognostic value of T-wave alternans in patients with heart failure due to nonischemic cardiomyopathy: results of the ALPHA Study. J Am Coll Cardiol. 2007; 50: 1896–1904.