Clinical utility of microvolt T-wave alternans testing in identifying patients at high or low risk of sudden cardiac death.

BACKGROUND: Previous studies have demonstrated that microvolt T-wave alternans (MTWA) testing is a robust predictor of ventricular tachyarrhythmias and sudden cardiac death (SCD) in at-risk patients. However, recent studies have suggested that MTWA testing is not as good a predictor of "appropriate" implantable cardioverter-defibrillator (ICD) therapy as it is a predictor of SCD in patients without ICDs. OBJECTIVE: To evaluate the utility of MTWA testing for SCD risk stratification in patients without ICDs. METHODS: Patient-level data were obtained from 5 prospective studies of MTWA testing in patients with no history of ventricular arrhythmia or SCD. In these studies, ICDs were implanted in only a minority of patients and patients with ICDs were excluded from the analysis. We conducted a pooled analysis and examined the 2-year risk for SCD based on the MTWA test result. RESULTS: The pooled cohort included 2883 patients. MTWA testing was positive in 856 (30%), negative in 1627 (56%), and indeterminate in 400 (14%) patients. Among patients with a left ventricular ejection fraction (LVEF) of ≤35%, annual SCD event rates were 4.0%, 0.9%, and 4.6% among groups with MTWA positive, negative, and indeterminate test results. The SCD rate was significantly lower among patients with a negative MTWA test result than in patients with either positive or indeterminate MTWA test results (P <.001 for both comparisons). In patients with an LVEF of >35%, annual SCD event rates were 3.0%, 0.3%, and 0.3% among the groups with MTWA positive, negative, and indeterminate test results. The SCD rate associated with a positive MTWA test result was significantly higher than that associated with either negative (P <.001) or indeterminate MTWA test results (P = .003). CONCLUSIONS: In patients without ICDs, MTWA testing is a powerful predictor of SCD. Among patients with an LVEF of ≤35%, a negative MTWA test result is associated with a low risk for SCD. Conversely, among patients with an LVEF of >35%, a positive MTWA test result identifies patients at significantly heightened SCD risk. These findings may have important implications for refining primary prevention ICD treatment algorithms.

Intracardiac electrogram T-wave alternans/variability increases before spontaneous ventricular tachyarrhythmias in implantable cardioverter-defibrillator patients: a prospective, multi-center study.

BACKGROUND: T-wave alternans (TWA) increases before ventricular tachycardia (VT) or fibrillation (VF), suggesting that it may warn of VT/VF in implantable cardioverter-defibrillator patients. Recently, we described a method for measuring alternans and nonalternans variability (TWA/V) from electrograms (EGMs) stored in implantable cardioverter-defibrillators before VT/VF. The goal of this prospective, multicenter study was to determine whether EGM TWA/V was greater before VT/VF than at baseline. METHODS AND RESULTS: We enrolled 63 implantable cardioverter-defibrillator patients. TWA/V was computed from stored EGMs before spontaneous VT/VF and from sequential windows of 8 pairs of beats using 4 different control recordings: baseline rhythm, rapid pacing at 105 bpm, segments of ambulatory Holter EGMs matched to the time of VT/VF episodes, and EGMs before spontaneous supraventricular tachycardia. During follow-up, 28 patients had 166 episodes of VT/VF. TWA/V was greater before VT/VF (62.9 ± 3.1 µV; n = 28) than during baseline rhythm (12.8 ± 1.8 µV; P < 0.0001; n = 62), during rapid pacing (14.5 ± 2.0 µV; P < 0.0001; n = 52), before supraventricular tachycardia (27.5 ± 6.1 µV; P < 0.0001; n = 9), or during time-matched ambulatory controls (12.3 ± 3.5 µV; P < 0.0001; n = 16). By logistic regression, the odds of VT/VF increased by a factor of 2.2 for each 10-µV increment in TWA/V (P < 0.0001). CONCLUSIONS: In implantable cardioverter-defibrillator patients, EGM TWA/V is greater before spontaneous VT/VF than in control recordings. Future implantable cardioverter-defibrillators that measure EGM TWA/V continuously may warn patients and initiate pacing therapies to prevent VT/VF.

Fragmented QRS and mortality risk in patients with left ventricular dysfunction.

BACKGROUND: Fragmented QRS (fQRS) has been shown to predict cardiac events in select patient populations. Whether fQRS improves patient selection for primary prevention patients eligible for implantable cardioverter-defibrillator (ICD) therapy remains unknown. METHODS AND RESULTS: In a prospective, multisite cohort of 842 patients with left ventricular dysfunction (ejection fraction < or =35%) representing both ischemic and nonischemic etiology, the presence of fQRS on ECG was assessed using standardized criteria. The association between fQRS and all-cause and arrhythmic mortality was evaluated overall and stratified by ICD status using multivariable Cox regression models, adjusted for demographic, clinical, and treatment variables. Fragmented QRS was present in 274 (32.5%) patients, and there were 191 (22.7%) deaths during a mean follow-up of 40+/-17 months. Rates of all-cause mortality did not differ between the fQRS+ (19.7%) and fQRS- (24.1%) groups; adjusted hazard ratio, 0.88; 95% confidence interval, 0.63-1.22; P=0.43. Additionally, rates of arrhythmic mortality were similar between the fQRS+ (9.9%) and fQRS- (12.7%) groups: adjusted hazard ratio, 0.77; 95% confidence interval, 0.49-1.31; P=0.38. Subgroup analyses found no association between fQRS and mortality when the cohort was further stratified by ICD status, etiology of left ventricular dysfunction, wide (>/=120 ms) versus narrow (<120 ms) QRS duration, or fQRS myocardial territory. CONCLUSIONS: In this prospective, multisite cohort of primary prevention patients with left ventricular dysfunction, the presence of fQRS on ECG was not associated with a higher risk of either all-cause or arrhythmic mortality. These findings do not provide evidence that fQRS would be effective in risk stratifying primary prevention patients eligible for ICD therapy.

Impact of age and medical comorbidity on the effectiveness of implantable cardioverter-defibrillators for primary prevention.

BACKGROUND: Although implantable cardioverter-defibrillators (ICDs) reduce mortality in primary prevention patients with left ventricular systolic dysfunction, recent studies have questioned their overall role in clinical practice, especially in older patients and those with major comorbid conditions. METHODS AND RESULTS: In a prospective cohort of 965 patients with ischemic and nonischemic cardiomyopathies (ejection fraction or=75), ischemic etiology, ejection fraction (>25% versus 0.05). Incremental cost-effectiveness ratios for ICD therapy were similar between patients aged >or=75 years and younger patients but rose slightly in those with multiple comorbid conditions. CONCLUSIONS: Routine use of ICDs in primary prevention patients with left ventricular systolic dysfunction was associated with lower all-cause mortality, even among older patients and those with major comorbid conditions. Although their use needs to be individualized, our findings suggest that these groups should not be routinely excluded from ICD treatment.

Peri-infarct pacing with CRT in the early postinfarct phase to attenuate long-term remodeling.

Deleterious left ventricular remodeling routinely occurs after myocardial infarction (MI) and novel strategies to attenuate this phenomenon may prove valuable. Here, we describe the potential role of left ventricular (LV) peri-infarct pacing (delivered via biventricular pacemakers) to reduce post-MI remodeling. Regional wall stress in the infarcted area is predictive of remodeling and therefore represents a potential therapeutic target. Using an intrinsic property of pacing to reduce stress and work at the pacing site, there are animal data to suggest that long-term peri-infarct pacing can have a salutary effect on cardiac structure after MI. This concept was tested in a pilot human study, suggesting attenuation of ventricular dilation in post-MI patients treated with LV pacing compared with control. To further characterize this concept, a 110-patient, multicenter, randomized Prevention of Myocardial Enlargement and Dilatation post-Myocardial Infarction Study (MENDMI) has completed enrollment. Inclusion criteria included anterior MI, QRS < 120 ms, ejection fraction 2,000, and wall motion abnormalities in at least five of 16 segments. MENDMI will help to determine whether chronic application of peri-infarct pacing provides structural and clinical benefits and will help in the design of further investigations to modify postinfarction ventricular remodeling.

Does microvolt T-wave alternans testing predict ventricular tachyarrhythmias in patients with ischemic cardiomyopathy and prophylactic defibrillators? The MASTER (Microvolt T Wave Alternans Testing for Risk Stratification of Post-Myocardial Infarction Patients) trial.

OBJECTIVES: The purpose of this trial was to determine whether microvolt T-wave alternans (MTWA) predicts ventricular tachyarrhythmic events (VTEs) in post-myocardial infarction patients with left ventricular ejection fraction (LVEF) < or =30%. BACKGROUND: Previous studies have established MTWA as a predictor for total and arrhythmic mortality, but its ability to identify prophylactic implantable cardioverter-defibrillator (ICD) recipients most likely to experience VTEs remains uncertain. METHODS: This prospective trial was conducted at 50 U.S. centers. Patients were eligible if they met MADIT-II (Multicenter Automatic Defibrillator Implantation Trial II) indications for device implant. All patients underwent MTWA testing followed by ICD implantation, with pre-specified programming to minimize the likelihood of therapies for non-life-threatening VTE. Minimum follow-up was 2 years with annual MTWA testing. Initially indeterminate MTWA tests were repeated. RESULTS: Analyses were conducted on 575 patients (84% male; average age +/- SD = 65 +/- 11 years; average LVEF +/- SD = 0.24 +/- 0.05). The final distribution of MTWA results were: MTWA positive in 293 (51%), MTWA negative in 214 (37%), and indeterminate in 68 patients (12%). Over an average follow-up of 2.1 +/- 0.9 years, there were 70 VTEs. A VTE occurred in 48 of 361 (13%, 6.3%/year) MTWA non-negative and 22 of 214 (10%, 5.0%/year) MTWA negative patients. A non-negative MTWA test result was not associated with VTE (hazard ratio: 1.26; 95% confidence interval: 0.76 to 2.09; p = 0.37), although total mortality was significantly increased (hazard ratio: 2.04; 95% confidence interval: 1.10 to 3.78; p = 0.02). CONCLUSIONS: In MADIT-II-indicated ICD-treated patients, the risk of VTE does not differ according to MTWA classification, despite differences in total mortality. (MASTER I-Microvolt T Wave Alternans Testing for Risk Stratification of Post MI Patients; NCT00305240).

Usefulness of microvolt T-wave alternans to predict outcomes in patients with ischemic cardiomyopathy beyond one year.

Previous studies have demonstrated that microvolt T-wave alternans (MTWA) screening effectively risk-stratifies patients with ischemic cardiomyopathy. Whether the prognostic utility of MTWA diminishes over 3 years of follow-up remains unknown. In this study, a prospective cohort of 768 patients with ischemic cardiomyopathy (left ventricular ejection fraction <35%) and no previous sustained ventricular arrhythmia was developed, of whom 514 (67%) screened MTWA nonnegative (positive and indeterminate). The mean follow-up period was 18 +/- 11 months. The primary end point was all-cause mortality and appropriate implantable cardioverter-defibrillator shocks. Stratified Cox regression analyses (by implantable cardioverter-defibrillator status) estimated the predictive power of MTWA within each year of follow-up and determined whether this diminished over time. There were 99 deaths (MTWA negative: 21 [8.3%]; MTWA nonnegative: 78 [15.2%]) and 33 appropriate implantable cardioverter-defibrillator shocks (MTWA negative: 3 [4.0%]; MTWA nonnegative: 30 [9.5%]). After multivariate adjustment, a nonnegative MTWA test result was associated with a greater than twofold increased risk for events in each of the 3 years of follow-up (year 1: stratified hazard ratio 2.19, 95% confidence interval 1.10 to 4.34, p = 0.03; year 2: stratified hazard ratio 3.36, 95% confidence interval 1.28 to 8.83, p = 0.01; year 3: stratified hazard ratio 2.06, 95% confidence interval 0.81 to 5.22, p = 0.13). There were no significant interactions between the time periods (year 1 vs year 2: p = 0.47; year 1 vs year 3: p = 0.92). In conclusion, MTWA reliably and consistently predicts mortality and arrhythmic risk throughout the first 2 to 3 years of follow-up. Although these findings need further validation, they suggest that rescreening with MTWA may not need to be performed more frequently than once every 2 years.

Microvolt T-wave alternans testing for ventricular arrhythmia risk stratification.

Extensive research and clinical interest has focused recently on use of microvolt T-wave alternans (MTWA) as a means for sudden death risk stratification in patients with cardiomyopathy. Emphasis has been placed on determining whether MTWA testing can more accurately identify high-risk patients from the broad population who are potentially eligible for prophylactic implantable cardioverter defibrillators. More recent studies seek to determine if additional patients not currently covered by primary prevention implantable cardioverter defibrillator guidelines could be defined using MTWA. Unfortunately, accumulation of clinical data has not necessarily led to clarity in the minds of the end-users as to the role of MTWA in clinical practice. This article serves to provide background information, selective review of relevant studies, and a perspective on where the field stands today. A general framework for incorporating MTWA into clinical practice is presented.

Usefulness of microvolt T-wave alternans on predicting outcome in patients with ischemic cardiomyopathy with and without defibrillators.

Microvolt T-wave alternans (MTWA) was proposed as an effective tool to identify high-risk patients with ischemic cardiomyopathy. However, previous studies suggested that the prognostic utility of MTWA may be limited to only patients with normal QRS duration. It therefore was assessed whether MTWA and QRS duration >120 ms independently predict mortality in patients with ischemic cardiomyopathy and whether the prognostic utility of MTWA differs by QRS duration. A total of 768 consecutive patients with ischemic cardiomyopathy (left ventricular ejection fraction < or =35%) and no history of ventricular arrhythmia were enrolled, of whom 514 (67%) screened MTWA non-negative (positive or indeterminate) and 223 (29%) had a QRS >120 ms on resting electrocardiogram. After multivariable adjustment, a non-negative MTWA test result was associated with a significantly higher risk for all-cause mortality in patients without an implantable cardioverter-defibrillator (ICD) (hazard ratio [HR] 2.27, 95% confidence interval [CI] 1.22 to 4.24, p = 0.01) and for all-cause mortality and appropriate ICD shocks in patients with an ICD (HR 2.42, 95% CI 1.07 to 5.41, p = 0.04). In contrast, a QRS >120 ms was not associated with all-cause mortality and ICD shocks in patients without (HR 0.96, 95% CI 0.52 to 1.75, p = 0.88) or with an ICD (HR 1.25, 95% CI 0.76 to 2.08, p = 0.40). No significant interaction was found between MTWA and QRS >120 ms (non-ICD p = 0.19, ICD p = 0.73). In conclusion, MTWA, but not QRS duration, predicted mortality outcomes in patients with ischemic cardiomyopathy. Moreover, the prognostic utility of MTWA did not appear to differ by QRS duration.

Prognostic implication of redefining indeterminate microvolt T-wave alternans studies as abnormal or normal.

BACKGROUND: Prior studies involving microvolt T-wave alternans (MTWA) have combined positive and indeterminate studies into a high-risk "nonnegative" category. However, studies examining the prognostic utility of specific reasons for an indeterminate study are limited. The objective of this study was to assess if patients have differences in survival prognosis based on the reasons for an indeterminate MTWA result. METHODS: We enrolled 768 consecutive patients with ischemic cardiomyopathy (left ventricular ejection fraction < or = 35%) and no prior history of sustained ventricular arrhythmia. Microvolt T-wave alternans studies were classified as positive, negative, or indeterminate. Prespecified multivariable Cox regression analyses, stratified by implantable cardioverter/defibrillator status, were used to determine whether there was heterogeneity in survival prognosis among the individual reasons for an indeterminate study. RESULTS: We identified 159 (21%) patients with an indeterminate MTWA test. Reasons for indeterminate studies included frequent ectopy (46%), inability to reach adequate heart rate (IHR) (32%), unsustained alternans (9%), and excessive noise (13%). After multivariable adjustment, indeterminate studies due to ectopy/IHR were associated with a significantly higher risk for all-cause (stratified hazard ratio [HR] 4.63, 95% CI 1.32-16.18, P = .02) and arrhythmic mortality (stratified HR 17.57, 95% CI 1.62-190.50, P = .02) but not for nonarrhythmic mortality (stratified HR 1.30, 95% CI 0.27-6.29, P = .75). The prognostic utility of MTWA testing was improved when indeterminate studies were reclassified as abnormal (positive + ectopy/IHR) or normal (negative + unsustained alternans), with only 3% of all studies thereafter remaining inconclusive (noise). CONCLUSION: Patients with indeterminate MTWA studies exhibit heterogeneity in survival prognosis. Reclassifying indeterminate studies as abnormal or normal improves the predictive power of MTWA.

Feasibility of biventricular pacing in patients with recent myocardial infarction: impact on ventricular remodeling.

To test the hypothesis that biventricular pacing after a myocardial infarction with reduced ejection fraction can attenuate left ventricular (LV) remodeling, the authors studied 18 patients (myocardial infarction within 30-45 days, ejection fraction

Microvolt T-wave alternans identifies patients with ischemic cardiomyopathy who benefit from implantable cardioverter-defibrillator therapy.

OBJECTIVES: This study sought to assess whether implantable cardioverter-defibrillators (ICDs) have different mortality benefits among patients with ischemic cardiomyopathy who screen negative and non-negative (positive and indeterminate) for microvolt T-wave alternans (MTWA). BACKGROUND: Microvolt T-wave alternans has been proposed as an effective tool for risk stratification. However, no studies have examined whether ICD benefits differ by MTWA group. METHODS: We developed a prospective cohort of 768 patients with ischemic cardiomyopathy (left ventricular ejection fraction < or =35%) and no prior sustained ventricular arrhythmia, of which 392 (51%) received ICDs. The mean follow-up time was 27 +/- 12 months. Propensity scores for ICD implantation based on the variables most likely to influence defibrillator implantation were developed for each MTWA cohort. Multivariable Cox analyses that controlled for propensity score, demographics, and clinical variables evaluated the degree to which ICDs decreased mortality risk for each MTWA group. RESULTS: We identified 514 (67%) patients with a non-negative MTWA test result. After multivariable adjustment, ICDs were associated with lower all-cause mortality in MTWA-non-negative patients (hazard ratio [HR] 0.45, 95% confidence interval [CI] 0.27 to 0.76, p = 0.003) but not in MTWA-negative patients (HR 0.85, 95% CI 0.33 to 2.20, p = 0.73) (for interaction, p = 0.04), with the mortality benefit in MTWA-non-negative patients largely mediated through arrhythmic mortality reduction (HR 0.30, 95% CI 0.13 to 0.68, p = 0.004). The number needed to treat with an ICD for 2 years to save 1 life was 9 among MTWA-non-negative patients and 76 among MTWA-negative patients. CONCLUSIONS: In patients with ischemic cardiomyopathy and no prior history of ventricular arrhythmia, mortality reduction with ICD implantation differs by MTWA status, with implications for risk stratification and health policy.

Effectiveness of implantable cardioverter-defibrillators in patients with ischemic heart disease and left ventricular dysfunction.

BACKGROUND: Implantable cardioverter-defibrillators (ICDs) have been shown in primary prevention efficacy trials to reduce mortality in patients with ischemic heart disease and left ventricular dysfunction. To investigate the generalizabilty of this mortality reduction, we examined the effectiveness of ICDs in clinical practice. METHODS: We developed a prospective multicenter cohort of 770 patients with ischemic left ventricular dysfunction (ejection fraction < or =35%) and without a history of ventricular arrhythmia, of whom 395 (52%) received ICDs. Mean +/- SD follow-up was 27 +/- 12 months. We assessed the degree to which ICDs decreased mortality risk using Cox proportional hazards analyses that controlled for clinical predictors of death, receipt of ICD (a propensity score analysis), and predictors of arrhythmic death (including electrophysiologic variables). RESULTS: Multivariate Cox analyses showed that those with ICDs had significantly lower all-cause mortality (hazard ratio [HR], 0.53; 95% confidence interval [CI], 0.33-0.86). This mortality reduction was mediated through dramatically lower arrhythmia-related mortality (HR, 0.35; 95% CI, 0.17-0.73), with no significant effect on cardiovascular nonarrhythmic (HR, 0.81; 95% CI, 0.34-1.96) and noncardiovascular (HR, 0.76; 95% CI, 0.29-2.05) mortality. No differences were found between the ICD and non-ICD groups for a composite outcome of all-cause mortality, appropriate ICD shocks, or documented symptomatic ventricular arrhythmia, which suggests that the 2 groups had similar baseline risk for life-threatening arrhythmic events (HR, 0.96; 95% CI, 0.63-1.45). CONCLUSION: In clinical practice, ICDs appear to reduce all-cause and arrhythmic rates of mortality at levels similar to those found in primary prevention trials.

Early revascularization and ACC/AHA guideline-compliant medical management improve left ventricular function and short-term prognosis in patients presenting with acute myocardial infarction and severe left ventricular dysfunction.

BACKGROUND: Myocardial infarction (MI) complicated by severe left ventricular (LV) dysfunction is associated with significant morbidity and mortality. The natural history of this population with contemporary revascularization and guideline-based medical therapies is poorly defined. We sought to determine the impact of contemporary treatment strategies on LV function and prognosis in patients with MI and severe LV dysfunction. METHODS: Consecutive MI patients were prospectively followed as part of an ongoing internal database. The current report comprises 75 patients with first MI and severe LV systolic dysfunction (EF less than or equal to 3%). Initial demographic and clinical data were collected during hospitalization and at 1-, 3- and 6-month follow up. RESULTS: Patients were 71% male, 36% diabetic and 51% had prior coronary disease with a mean (+/- SD) age of 65 +/- 14 years. The average hospital stay was 5.7 days for ST-elevation (CPK range 424 to 5,250) and 2.4 days for non-ST-elevation MI (CPK range 175 to 705). Revascularization in-hospital was performed in 87% of patients (62 percutaneous, 3 surgical). At hospital discharge, treatment included beta-blockers (84%), ACE-inhibitors (73%), statins (81%), aspirin (88%) and clopidogrel (84%). Mean (+/- SD) LVEF was 25.7 +/- 5.9% in hospital, 36.6 +/- 11.8% by 1 to 3 months (p < 0.01), and 37.6 +/- 9.3% at 6 months (p < 0.01). By 1 to 3 months, 63% had improved LVEF, 24% were unchanged and 14% were worse. One patient died in the hospital and 3 died by 6-month follow up (mortality 5.3%). CONCLUSION: A strategy of early revascularization combined with guideline-based medical management favorably impacts LV function and short-term prognosis in MI patients with severe LV systolic dysfunction. With contemporary treatment strategies, the majority (> 60%) of patients demonstrate improvement in LVEF and mortality is low (5.3%).

Cost-effectiveness of a microvolt T-wave alternans screening strategy for implantable cardioverter-defibrillator placement in the MADIT-II-eligible population.

OBJECTIVES: This study was designed to compare the cost-effectiveness of implantable cardioverter-defibrillator (ICD) placement with and without risk stratification with microvolt T-wave alternans (MTWA) testing in the MADIT-II (Second Multicenter Automatic Defibrillator Implantation Trial) eligible population. BACKGROUND: Implantable cardioverter-defibrillators have been shown to prevent mortality in the MADIT-II population. Microvolt T-wave alternans testing has been shown to be effective in risk stratifying MADIT-II-eligible patients. METHODS: On the basis of published data, cost-effectiveness of three therapeutic strategies in MADIT-II-eligible patients was assessed using a Markov model: 1) ICD placement in all; 2) ICD placement in patients testing MTWA non-negative;, and 3) medical management. Outcomes of expected cost, quality-adjusted life-years (QALYs), and incremental cost-effectiveness were determined for patient lifetime. RESULTS: Under base-case assumptions, providing ICDs only to those who test MTWA non-negative produced a gain of 1.14 QALYs at an incremental cost of 55,700 dollars when compared to medical therapy, resulting in an incremental cost-effectiveness ratio (ICER) of 48,700 dollars/QALY. When compared with a MTWA risk-stratification strategy, placing ICDs in all patients resulted in an ICER of 88,700 dollars/QALY. Most (83%) of the potential benefit was achieved by implanting ICDs in the 67% of patients who tested MTWA non-negative. Results were most sensitive to the effectiveness of MTWA as a risk-stratification tool, MTWA negative screen rate, cost and efficacy of ICD therapy, and patient risk for arrhythmic death. CONCLUSIONS: Risk stratification with MTWA testing in MADIT-II-eligible patients improves the cost-effectiveness of ICDs. Implanting defibrillators in all MADIT-II-eligible patients, however, is not cost-effective, with one-third of patients deriving little additional benefit at great expense.

Prognostic utility of microvolt T-wave alternans in risk stratification of patients with ischemic cardiomyopathy.

OBJECTIVES: The purpose of this study was to assess if microvolt T-wave alternans (MTWA) is an independent predictor of mortality in patients with ischemic cardiomyopathy. BACKGROUND: Microvolt T-wave alternans has been proposed as an effective tool for identifying high-risk patients with ischemic cardiomyopathy who are likely to benefit from implantable cardioverter-defibrillator (ICD) therapy. However, earlier studies have been limited in their ability to control for baseline differences between MTWA-negative and -non-negative (positive and indeterminate) patients. METHODS: We enrolled 768 consecutive patients with ischemic cardiomyopathy (left ventricular ejection fraction < or =35%) and no prior history of ventricular arrhythmia. All patients underwent baseline MTWA testing and were classified as MTWA negative or non-negative. Multivariable Cox regression analyses, stratified by ICD status, were used to determine the association between MTWA testing and mortality after adjusting for demographic, clinical, and treatment differences between MTWA-negative and -non-negative patients. RESULTS: We identified 514 (67%) patients with a non-negative MTWA test. After multivariable adjustment, a non-negative MTWA test was associated with a significantly higher risk for all-cause (stratified hazard ratio [HR] = 2.24 [95% confidence interval 1.34 to 3.75]; p = 0.002) and arrhythmic mortality (stratified HR = 2.29 [1.00 to 5.24]; p = 0.049) but not for nonarrhythmic mortality (stratified HR = 1.77 [0.84 to 3.74]; p = 0.13). In subgroup analyses, a non-negative MTWA test was also associated with a higher risk for all-cause mortality in patients with ejection fractions < or =30% (stratified HR = 2.10 [1.18 to 3.73]; p = 0.01) and after excluding those with indeterminate MTWA tests (stratified HR = 2.08 [1.18 to 3.66]; p = 0.01). CONCLUSIONS: Microvolt T-wave alternans is a strong and independent predictor of all-cause and arrhythmic mortality in patients with ischemic cardiomyopathy.