The Efficacy of Microvolt T-Wave Alternans Testing and Other Noninvasive Risk Stratification Methods for Identifying Patients at Risk of Sudden Cardiac DeathMichael J. Mirro, MD, Medical Director of the Parkview Health System Clinical Research Center in Fort Wayne, Indiana, describes his use of microvolt t-wave alternans (MTWA) testing and other noninvasive risk stratification methods for identifying patients at risk for sudden cardiac death (SCD). Explain the different methods currently available for screening, such as left ventricular ejection fraction and MTWA. The public health challenge of preventing sudden cardiac death is significant. Various clinical parameters and noninvasive tests have been studied in an attempt to accurately identify patients who do not have a history of SCD, but who are at risk. These include: 1) structural parameters which predispose one to arrhythmias (reduced ejection fraction, myocardial scar); 2) measures of autonomic tone (heart rate variability, baroreceptor sensitivity); 3) assessment of electrical repolarization abnormalities (T-wave alternans, QT dispersion); and 4) screening for ambient rhythm disturbances like NSVT on Holter. One consistent finding from numerous trials is that patients with significant left ventricular (LV) dysfunction fall into a high-risk category. As we know from the MADIT II trial, post-MI patients with ejection fractions of 30 percent or less are at high risk and benefit from ICD therapy.1 Similarly, the SCD-HeFT trial showed that patients with reduced EF in the setting of congestive heart failure should be considered for prophylactic ICD implantation to prevent sudden cardiac death.2 While EF has been the most consistent risk factor identified, there are limitations to this approach. For example, there is often significant variation in EF determination based on the imaging modality utilized. In addition, most patients who receive a prophylactic ICD based on low EF never require therapy from the device, illustrating the modest positive predictive value of this approach. Lastly, the majority of SCD events occur in patients with more preserved EF. For these reasons, there has been keen interest over the years to identify other means of identifying patients at risk for SCD that could potentially complement EF. Microvolt T-wave alternans is a non-invasive diagnostic test that has shown to be predictive of SCD in multiple clinical trials of patients with LV dysfunction.3-5 It has also demonstrated prognostic value in patients with more preserved EF, suggesting that it may be useful in a group that is collectively at lower risk, particularly when combined with other factors that could predispose certain individuals to sudden death.6 For those readers who may be unaware, what is MTWA testing? T-wave alternans (TWA) is a term used to describe an alternating pattern in the T wave of the ECG. Visible TWA has been recognized for many years as a marker of arrhythmic vulnerability. For example, in patients with long QT syndrome, gross alternation in the morphology of the T wave was often noted prior to the onset of ventricular fibrillation.7 In the 1980s, this observation was extended to hypothesize that very subtle, non-visible fluctuations in the T-wave (microvolt T-wave alternans) may be associated with increased risk for life-threatening arrhythmias in the future. Today, the most common method for measuring MTWA, the spectral method, is capable of measuring alternans down to the level of 1-2 microvolts. Because early work on MTWA showed it to be a rate-dependent phenomenon, the test is most often conducted in the context of treadmill exercise while the ECG is continually monitored.8 Laboratory research suggests that MTWA on the ECG is caused by a disturbance in calcium calcium handling at the cellular level.9 This disturbance can lead to heterogeneity of repolarization and subsequent vulnerability to reentrant rhythms like VT or VF. Importantly, this suggests that MTWA is not merely associated with SCD risk, but is mechanistically linked as a cause of SCD. How effective is MTWA testing? Studies report a consistently high negative predictive value (95-99%) in patients with LV dysfunction, making MTWA a valuable tool for identifying those patients who have minimal risk of SCD.3-5 In a recent meta-analysis, the annual SCD risk for patients testing negative for MTWA was only 0.3%.10 The data on MTWA is particularly compelling in the non-ischemic cardiomyopathy population, a group in which other tests do not work well. The ALPHA trial showed that, in non-ischemic patients with EF Why is testing with solely MTWA not generally sufficient? How does MTWA complement other methods used for SCD testing? Today, MTWA is not an indication for ICD implantation but is used to complement other modalities like EF. For example, in the case of conflicting EF measurements, MTWA may help to clarify the best clinical course. In addition, many indicated patients are reluctant to consider ICD therapy or have multiple co-morbidities that make the decision to implant more complicated. In such patients, an MTWA test often helps balance the risks and benefits. Importantly, MTWA may be used to help manage the overall risk of SCD in patients who are not indicated for an ICD. For example, in post-MI patients with a preserved EF, various steps may be taken to reduce the underlying risk in a patient with a positive MTWA test. These include ruling out ischemia, optimizing the pharmacologic regimen or simply making lifestyle changes like quitting smoking. In borderline cases where other risk factors or symptoms are present, invasive testing like EPS may be warranted. What is the protocol of treatment for patients with a negative MTWA result who do not receive an ICD? How is MTWA testing beneficial for patients who test positive? In our program, we routinely use MTWA for post-MI patients or those with recent heart failure hospitalizations.15 The result of the MTWA test is used as an adjunct to EF and other clinical factors. In patients with an EF below 35% and no mitigating factors, an ICD is typically recommended. If the patient refuses or is reluctant to consider implantation, a positive MTWA test may serve as a call to action and present a second chance to educate the patient about the risks of SCD. In patients with borderline EF in the range of 36-40%, MTWA testing may be used to aid in the decision-making process. For example, a positive test may lead to further testing to assess the presence of NSVT, which may, in turn, lead to EP testing. The MTWA test is particularly helpful in borderline cases where conflicting EF measurements are recorded, or multiple co-morbidities are present, or for those with non-ischemic cardiomyopathy. A negative test provides a source of reassurance that the SCD risk is low, while a positive test indicates that a more aggressive approach may be warranted. In all cases, negative tests are routinely repeated on an annual basis. I think that T-wave alternans has the greatest potential in helping us with post-MI patients with preserved LV function (EF 40-50%). These patients are a real challenge. Cardiologists often see patients who present to the hospital with acute MI, receive revascularization and, assuming the problem is now resolved, they are discharged home — only to suffer from SCD two months later. Looking back, we are beginning to wonder if we could have done a better job of identifying those patients who are at risk. I believe the best way to approach such patients is to perform more prolonged monitoring to routinely assess EF and to look for risk markers like MTWA and nonsustained VT. In such patients, a combination of positive tests, particularly when accompanied by symptoms, may result in an EP referral. Let me give you a specific example. A patient who was revascularized following an MI with a pre-discharge EF of 35% is now stable on optimal medical therapy and returns after cardiac rehab with an EF of 42%. This patient still has some risk for sudden death, but doesn’t qualify for an ICD implant per the guidelines. If the patient has a negative MTWA test, that provides further information that the clinical risk based on EF improvement is low and suggests that the patient can be safely managed without defibrillator implant. On the other hand, if that patient had a positive MTWA test, I would counsel the patient about the residual risk and recommend that they be monitored more carefully for drug compliance, risk factor modification and ECG abnormalities. For example, we may review the ECG for evidence of a fragmented QRS complex, an indication of slow conduction, or perform a Holter to look for NSVT or assess HRV. If they had evidence of nonsustained VT or developed symptoms, we would perform invasive EP testing to see if they indeed needed an implantable defibrillator. What components are needed for an effective SCD screening program? I believe that an effective SCD training program requires a systematic non-invasive testing protocol, an educational component for patients and their families, and a reliable health information technology system. Most practices in community settings in the United States do not have a good post-hospitalization protocol set up to routinely assess risk factors like EF. In our hospital, we focus our SCD screening efforts on the post-discharge period for MI and heart failure patients. During the first 90 days, patients are titrated on optimal pharmacologic therapy, receive training on cardiopulmonary resuscitation and automated external defibrillator (AED) use, and are prescribed to cardiac rehab when appropriate. Patients with additional risk factors including low LVEF may receive a wearable defibrillator during this time while awaiting final determination of ICD candidacy. The protocol then requires all patients to return within 60-90 days for EF measurement (via echo), stress test and MTWA. We have an in-depth discussion with the patient and family about the potential risk of SCD that may linger after the initial hospitalization. Based on the outcome of the various tests, a clinical course is determined and routine follow-ups are scheduled. An electronic medical records system is used during the discharge process and in follow-up to identify candidates for ICD therapy and additional testing. Features include EF alerts, routine checks for compliance with optimal pharmacologic therapy and automatic reminders for all tests in the SCD screening battery. Why was it important to create this screening process for sudden cardiac death at your hospital? Because SCD occurs abruptly and without warning, prediction and prevention programs are very important. Many patients can fall through the cracks without a systematic screening protocol. By scheduling patients for routine assessments, you can make sure that they do not drop out of the system and that they return for cardiac rehab and periodic follow-ups. Because cardiovascular disease evolves over time, annual screening is particularly important for tests like MTWA. Why is it important for hospitals to have a screening program in place? How can hospitals create similar programs? From a practical standpoint, the hospitalization experience not only for post MI but for acute congestive heart failure patients is a great opportunity for cardiology practices to have a sudden cardiac death screening/prevention program in place. Once the patients leave the hospital, it should be part of their discharge process to schedule patients for a repeat echocardiogram at 60-90 days post-hospitalization. This is also an ideal time for adjunct testing like MTWA. Hospitals can use existing electronic health records to set up alerts and automatic reminders for various tests. Ideally, this information should be linked to the ambulatory cardiology clinic, to make sure these patients are getting proper follow-up. What further research is needed in MTWA testing going forward? Data from observational studies has consistently demonstrated the predictive value of MTWA. Prospective randomized trials will help to confirm these findings and clarify the role of MTWA in directing therapy. Going forward, I believe future risk stratification approaches will likely involve a combination of clinical factors and parameters derived from diagnostic testing. This strategy, where multiple factors are combined to form a powerful composite clinical risk score, is likely to outperform any single test in terms of SCD prediction. Various noninvasive techniques may prove to be useful including ECG-derived parameters like MTWA, QRS duration, heart rate variability, SAECG and heart rate turbulence. Promising imaging modalities include cardiac MRI to assess scar size and geometry, and there is considerable interest in identifying genetic and biochemical markers that could be incorporated into a screening paradigm. The ABCD trial recently showed the benefit of a combined testing approach in a population of ischemic cardiomyopathy patients with EF Is there anything you’d like to add? Obviously we are all interested in reducing the impact of sudden cardiac death. It is a significant clinical challenge, and new data is constantly emerging, making it confusing at times. However, one thing that concerns me is that there have been some poorly conducted studies that have added to the confusion, including certain industry-sponsored trials like MASTER I. This trial should be critically considered based on 1) the impact of ICD firings as a surrogate endpoint for SCD, and 2) the role of industry in funding and managing the trial. The development of sophisticated risk stratification tools may be threatening to ICD manufacturers, because they have the potential to reduce the total number of devices implanted. However, as physicians, our goal is to deliver ICD therapy to the most appropriate high-risk patients, while ensuring that patients at nominal risk for SCD are not exposed to the attendant risks and complications associated with implantation.