ALPHA: The Use of T-Wave Alternans to Assess Risk in Patients With Nonischemic Heart Failure

Luis Gruberg, MD, FACC


May 01, 2007

ALPHA extends the earlier findings suggesting that a negative predictive value in patients with ischemic cardiomyopathy can also be applied to a nonischemic patient population.

Presenter: Gaetano De Ferrari, MD (San Matteo Hospital in Pavia, Italy), on behalf of the ALPHA Study Group Investigators


In recent years, indications for the use of implantable cardioverter defibrillators (ICDs) for the primary prevention of sudden cardiac death have expanded the eligible patient population exponentially. However, it is estimated that to prevent 1 death over 5 years with primary prevention ICD therapy, 14 patients have to undergo device implantation. Such a high number needed to treat has placed significant importance on developing ways to identify patients who would or would not otherwise benefit from ICD therapy.

One such method under study for risk stratification is microvolt T-wave alternans (TWA) testing. TWA is a noninvasive, electrocardiographic (ECG)-based test that can be performed in a physician's office with modifications to currently available exercise testing equipment. The test measures beat-to-beat microvolt variations in the shape, amplitude, or timing of the ECG T-wave that have been linked with the development of clinical ventricular arrhythmias. A negative TWA test result is classified as normal and suggests that a patient is not at risk. TWA test results of positive or indeterminate are conventionally grouped together and classified as abnormal.

Prior studies have demonstrated the value of using TWA testing to identify postmyocardial infarction patients with left ventricular dysfunction at low risk and thus not candidates for therapy. However, the applicability of this test in patients with nonischemic cardiomyopathy is less clear.

The T-Wave Alternans in Patients with Heart Failure (ALPHA) trial was designed to assess the capability of TWA to predict cardiac death and life-threatening arrhythmias in patients with nonischemic cardiomyopathy.

Study Design

ALPHA was a multicenter, prospective Italian study that enrolled patients with New York Heart Association class II or III nonischemic cardiomyopathy, impaired left ventricular function (ejection fraction [EF] ≤ 40%) etiology, and no history of malignant arrhythmias. Patients had to be on optimal medical therapy, including beta-blockers, diuretics, and angiotensin-converting enzyme inhibitors. All patients underwent microvolt TWA testing at baseline and were followed for 18-24 months.

Primary endpoint: Composite of cardiac death and life-threatening ventricular arrhythmias.

Secondary endpoints: Total mortality and the composite of arrhythmic death and life-threatening arrhythmias.


Of the 446 patients who were enrolled in the study, 154 patients had a negative (normal) TWA test; 200 were positive; and 92 were indeterminate. The latter 2 groups were combined and classified as having an abnormal TWA test result.

Patients in the abnormal group were significantly older, and were more likely to have NYHA class III heart failure, a poorer quality of life, and a lower EF than patients with normal TWA test results ( Table 1 ).

Over the course of follow-up, the rate of all clinical events was significantly higher in patients with abnormal TWA than patients with normal TWA test results (Figure). In addition, the rates of hospitalization were significantly higher in the abnormal test group (61 vs 24).

Figure 1.

ALPHA: clinical events.

The risk for cardiac death and life-threatening arrhythmias (primary endpoint) in patients with abnormal TWA test results was 4 times higher than in patients with normal test results, with the curves on Kaplan-Meier separating as early as 3 months. In addition, patients with abnormal test results had a 4- and 5-fold greater risk for total mortality and arrhythmic death/arrhythmias, respectively ( Table 2 ). Overall, the negative predictive value at 18 months was 98.7% for the primary endpoint and 99% for patients with an EF of < 35%. This suggests that < 2% of patients with nonischemic cardiomyopathy who have a normal test result would likely experience a clinical event within 18 months, and would thus not benefit from ICD therapy.


  1. In patients with NYHA class II and III nonischemic cardiomyopathy, an abnormal TWA test is associated with a 4-fold higher risk for cardiac death and life-threatening arrhythmias.

  2. The prognosis of patients with a normal TWA test is very good, and these patients are unlikely to benefit from ICD therapy.



ALPHA is a well-designed, simple study that may help us improve the management of very complex patients with nonischemic cardiomyopathy. The finding that patients with a normal test have a good outcome compared with those who have an abnormal test is likely to influence how these patients are selected for primary prevention ICDs. However, before implementing this test on a wide-scale basis, confirmation of these study results will be needed.


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