This is the last section of a three-part series on Microvolt T-Wave Alternans. In his article, Dr. Stein discusses the continued role for risk stratification in the modern era.

       We live in an era marked by a dramatic broadening of the indications for implantable cardioverter-defibrillator (ICD) implantation for the prevention of sudden cardiac death. Recent randomized clinical trials including MADIT II, DEFINITE, SCD-HeFT, and COMPANION show that defibrillator implantation may benefit large groups based on simple selection criteria (myocardial infarction, left ventricular dysfunction, congestive heart failure), without the need for traditional risk stratification. The purpose of this presentation is to review the data that support the current paradigm for prophylactic ICD implantation, and critically analyze the trial results. We will review recent data regarding the use of microvolt T-wave alternans for risk stratification, and close with some personal comments and philosophies about risk stratification. One focus will be the potential for good risk stratification to benefit not just the patients who are identified as being at low risk and who therefore might avoid device implantation, but also to benefit the high-risk patients as well.
       William Osler famously wrote, “One of the first duties of a physician is to educate the masses not to take medicine.” In modern times, it is likely that he would have extended that dictum to implantable devices as well.
Nevertheless, there is now a strong imperative to implant ICDs in “the masses.” The first trial that substantially broadened the indications for ICD implantation for primary prevention was MADIT II.¹ MADIT II evaluated patients with a prior myocardial infarction and left ventricular ejection fraction (LVEF) below 30%. There was no requirement for any qualifying arrhythmia (non-sustained left ventricular tachycardia), and there was no systematic assessment of inducibility using electrophysiologic testing prior to randomization. The trial proved that defibrillator implantation resulted in a statistically significant improvement in survival as opposed to conventional therapy. Those treated conventionally had a 78% survival rate after two years vs. 84% survival with ICD implantation.
       More recently, this same stratagem has been evaluated in patients with non-ischemic cardiomyopathies. The DEFINITE Trial enrolled 458 patients with non-ischemic cardiomyopathy and LVEF below 35% (the mean LVEF was 21%).² Patients did need to have a qualifying arrhythmia, either non-sustained ventricular tachycardia, or in a small minority, frequent VPCs. Patients were randomized to ICD therapy versus optimal medical management. The results did not make nominal statistical significance (p = 0.08), but the two-year total mortality was 14% with medical management versus 8% with defibrillator implantation. In other words, there was a 6% absolute survival benefit associated with defibrillator implantation in this population: the magnitude as the survival benefit for the defibrillator in the ischemic population in MADIT II.
       SCD-HeFT, which was recently reported but has not yet been published, is the largest of all the primary prophylactic trials by far, enrolling over 2,500 patients.³ In order to be eligible for the trial, patients had to have an LVEF below 35%, and mild to moderately symptomatic heart failure (NYHA Class II–III). Patients with both ischemic and non-ischemic cardiomyopathies could be enrolled, and the split was just about even: 52% had ischemic cardiomyopathy, and 48% had non-ischemic cardiomyopathy. The mean ejection fraction among this population was 25 percent; 70% of enrollees were in Class II, 30% were in Class III. Of note, if one thinks about the potential benefit of cardiac resynchronization therapy, in addition to defibrillator therapy, the mean QRS duration was 112 milliseconds, and 41% of the patients had a QRS > 120 milliseconds.
       SCD-HeFT employed a three-way randomization between placebo, amiodarone and ICD implantation. The first salient point is that there was no mortality benefit to amiodarone therapy whatsoever, whether analyzed overall or in any individual subgroup. Mortality, with either placebo or amiodarone was approximately 15% at two years, and by the end of five years had reached 33–36%. In comparison, in the group randomized to ICD therapy, total mortality was reduced to approximately 10% at two years; at the end of five years, total mortality was reduced to 28% with the ICD. Similar to MADIT II and DEFINITE, this yields an 8% absolute mortality benefit, albeit now after five years of therapy.
       These are the results, and at face value, they certainly seem to support the concept that widespread application of ICDs in patients with left ventricular dysfunction will improve survival. However, take a closer look at these results, emphasizing the number of patients requiring intervention in order to save one life. In the earliest primary prevention trials (MUSTT and MADIT I) — trials that used an electrophysiologic study for risk stratification prior to ICD implantation — in order to save one life at the end of two to five years, we needed to implant devices in three to four patients. In MADIT II, we have to perform 11 surgeries for every life saved at the end of three years. The SCD-HeFT data suggest a need to implant 17 defibrillators to save one life at the end of three years. As implanting physicians, one cannot be satisfied with a paradigm requiring surgery on 17 patients in order to benefit one. In addition, from a societal perspective, we need to be concerned about the cost implications of such a strategy; ask at what point does the cost outweigh the benefit?
       COMPANION, a trial of resynchronization therapy (CRT) for congestive heart failure is also instructive in this regard. COMPANION was a randomized trial of a CRT-ICD versus a CRT-pacemaker versus “optimal” medical therapy.⁴ In order to be enrolled in COMPANION, patients needed to have a QRS > 120 milliseconds, an LVEF < 35%, and Class III or IV congestive heart failure with a hospitalization or ER visit for CHF management within a year prior to enrollment. As with SCD-HeFT, COMPANION included both ischemic and non-ischemic cardiomyopathy patients. Patients had to be on a medical regimen that included ACE inhibitors, beta-blockers, and spironolactone.
       The results from COMPANION, with respect to mortality, were striking. One-year total mortality in patients treated with “optimal” medical management was 19%. That is an astonishingly poor prognosis and an indicator of just how far we have to go in improving therapy for these patients. Survival was somewhat better, although not statistically significantly better, with a CRT-pacemaker, and was statistically significantly reduced with the CRT-ICD compared with medical management.
       The one-year mortality with CRT-pacemakers was about 14% in COMPANION; the one-year mortality with the CRT-ICD was about 11%. If one wanted to play the role of devil’s advocate, one might point out that although the CRT-pacemaker arm did not do (statistically) significantly better than optimal medical management, it is likewise true that the CRT-pacemaker arm did not differ in a statistically meaningful manner from the CRT-ICD arm. The absolute mortality difference between the CRT-pacemaker and the CRT-ICD was low: only a 3% absolute mortality difference at the end of 1 year, meaning that one would need to implant 100 CRT-ICDs as opposed to CRT-pacemakers in order to save three lives by 1 year.
       These analyses immediately raise the issue of whether we can improve matters performing some form of risk stratification, in particular by using the microvolt T-wave alternans test. Before getting into the numbers, though, it is very important to shift perspective on what we demand of a prognostic test. We are used to asking whether a given diagnostic test can identify patients needing an intervention: does the stress test mean that someone needs to go on to cardiac catheterization? Does the echocardiogram mean that someone needs to go on to have valve surgery? However, in the case of risk stratification for sudden death prophylaxis, this sort of risk stratification — the positive predictive value of the test — is only of secondary importance. Perhaps instead of using risk stratification to identify who needs a defibrillator, we should be using our tools to identify the patients who do not need the ICD. Although this difference is subtle, it may have profound significance. In this case, what is important is the negative predictive value of a test: if we can find a population that would otherwise need an ICD but who we can now identify as being at low risk, we can potentially save a lot of people from device implantation who would otherwise undergo the surgery.
       The negative predictive value of microwave T-wave alternans testing was evaluated in a multicenter trial that included 215 patients with ischemic heart disease who were undergoing EP studies and T-wave alternans testing for known or suspected arrhythmias.⁵ Sixty percent of patients in this trial had a history of syncope or pre-syncope, and 27% had a history of prior or sustained ventricular arrhythmia. Interestingly, only 6% of patients in this population were being studied for primary indication of non-sustained VT. If the EP study was positive, there was a 25% rate of sustained ventricular tachycardia or death within 400 days (in other words, a positive predictive value of 25%). That was comparable to a positive predictive value of t-wave alternans at 26% in the same population. However, those patients with a negative EP study still had a 10% risk of sustained VT or death — not a number anyone can be comfortable with. On the other hand, if the T-wave alternans test was negative, the 400-day risk of either sustained VT or death was only 3%.
       A recent study by Hohnloser et al.⁶ pooled data from two previously reported trials and analyzed the subset of 129 “MADIT II” type patients (those with a prior myocardial infarction and LVEF < 30%). Those who had a positive T-wave alternans test had 30% mortality at the end of one year. In contrast, the mortality was only about 5% at 1 year in those patients with a negative alternans test. Results for patients with non-ischemic cardiomyopathy have been similar. Kitamura and colleagues analyzed 104 patients with non-ischemic dilated cardiomyopathy and found that those patients who had a positive T-wave alternans test with an onset heart rate below 100 had a 1-year risk of sudden death, VF, or VT of 30%.⁷ In contrast, the risk in patients with a negative T-wave alternans test was extremely low.
       The available data thus suggest that the negative predictive value of T-wave alternans testing may be sufficient to take patients who would have been eligible for defibrillators based on a MADIT II/SCD-HeFT criterion and identify a group of patients who do not require ICD implantation. What I want to propose is that excluding the low-risk patients not only benefits them, it also benefits the high-risk patients. In order to explain why I believe that, it is first necessary to acknowledge the underutilization of ICDs for primary prevention. Ruskin and colleagues analyzed Medicare and managed care claims data in 2002 and estimated there was somewhere between 736–1140 ICD candidates per 1 million population of the United States.⁸ However, the actual implant rate in the US at that time was only 416 per million population.
       Thus, only one-half to one-third of potential ICD candidates in the U.S. are actually getting the implant. Why should that be? There are three barriers to ICD implantation in potential candidates, all of which can be favorably impacted by doing good risk stratification. One barrier is reluctance among referring physicians to address the issue of sudden cardiac death in patients who are feeling “OK.” This may be a very difficult conversation to have with a patient who may have had a heart attack many years ago, but who has been feeling well over the intervening years. The availability of a test like the microvolt T-wave alternans test provides an entry point to discuss the risk of sudden death with a patient and to explain the utility of ICD implantation. A second barrier is the concern about quality of life in ICD recipients — in particular, concerns about risk of inappropriate therapies in these patients. The best available estimates are that about 20% of ICD recipients experience inappropriate shock at some point. It is one thing if patients also experience appropriate life-saving shocks. However, it is quite another thing to have a series of inappropriate shocks and never need to use the device to treat VT or ventricular fibrillation. Therefore, risk stratification that enables one to pull out the low-risk population swings the quality of life benefit in favor of the ICD recipient. A third barrier concerns the issue of cost. The ability to pull out low-risk patients obviously improves the cost benefit trade-off in the high-risk patient, and therefore facilitates implantation of devices in the high-risk patient.
       Thus, a series of benefits accrue with risk stratification: risk stratification benefits the members of the low-risk group, who avoid an unnecessary medical procedure. However, it also benefits the high-risk group by providing an entry point for discussion of sudden cardiac death and the utility of defibrillator implantation. The greater benefit in the high-risk patients allays important patient/physician concerns regarding cost, quality of life, and procedural morbidity. Not only is there a continued role for risk stratification in the modern era — if anything, results of trials like MADIT II and SCD-HeFT have made the development of tools for accurate risk stratification imperative.

Patients With a Nonischemic Cardiomyopathy and a Negative T-Wave Alternans Stress Test Are at a Low Risk of Death

-Otto Costantini, Elizabeth S. Kaufman, Metrohealth Med. Ctr./Case Western Reserve Univ., Cleveland, OH; Daniel M. Bloomfield, Richard C. Steinman, Pearila B. Namerow, Michael K. Parides, J. Thomas Bigger Jr., Columbia Univ. College of Physicians and Surgeons, New York City, NY; for the “CHF-TWA” Investigators Abstract Oral Sessions: American Heart Association Scientific Sessions Wednesday, November 10, 2004 ECG and Noninvasive Arrhythmia Testing Program Number 3093 Background: Patients with dilated non-ischemic cardiomyopathy (NI-CM) are at increased risk for sudden cardiac death. Because of low specificity, traditional risk-stratifying measures poorly predict which of these patients are at lowest risk and would least benefit from ICD prophylaxis. T-Wave Alternans (TWA) exercise testing has been shown to identify patients with coronary artery disease at low risk of death. We therefore hypothesized that a negative TWA test would identify patients with NI-CM at low risk of death. Methods: We conducted a prospective epidemilologic study of 282 patients with a left ventricular ejection fraction (LVEF) <= 0.40 and dilated NI-CM. Patients with atrial fibrillation, New York Heart Association Class IV heart failure, or sustained ventricular tachyarrhythmias were excluded. All patients had a TWA test. The primary endpoint of the study was actuarial all-cause mortality at 2 years. Results: Mean age was 51 ± 13 years, mean LVEF was 0.23 ± 0.08, and the mean follow-up was 16.4 months. TWA testing was normal (negative) in 95 patients (34%), and abnormal (positive or indeterminate) in 187 patients (66%). None of the patients with a normal TWA test and 12 patients with an abnormal TWA test (8.6%) died (P <= 0.02, Figure 1). Conclusions: In patients with NI-CM, a normal TWA test predicts a low 2-year all-cause mortality. ICD prophylaxis in these patients may not be needed.