Sudden cardiac death (SCD) is the leading cause of mortality in patients with ischemic heart disease and left ventricular dysfunction.1 The second Multicenter Automatic Defibrillator Implantation Trial (MADIT-II) and the Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT) have shown that implantable cardioverter defibrillators (ICDs) reduce mortality in patients with ischemic heart disease and left ventricular ejection fractions (LVEF) <30% and <35%, respectively.2,3 Although ICD implantation may be cost-effective overall,4-7 widespread use of ICDs is likely to be constrained by fixed healthcare budgets. Moreover, the use of LVEF as a sole criterion to identify high-risk patients lacks both sensitivity and specificity. For instance, only one in five patients allocated to ICD therapy in the recently published SCD-HeFT trial received an appropriate ICD shock for ventricular arrhythmia over five years of follow-up, which is the average life of a defibrillator generator before requiring replacement. Clearly, further risk-stratification of the pool of patients considered eligible for ICDs would have broad implications for the healthcare system.
Microvolt T-wave alternans (MTWA) involves the detection of every-other-beat alternations in T-wave morphology. These alternations are thought to represent abnormalities in intracellular calcium handling that may predispose patients to ventricular tachyarrhythmias.8-10 Earlier studies have suggested that MTWA may be a useful, non-invasive method for discriminating between patients with ischemic cardiomyopathy who are at low and high risk for SCD.11,12 While provocative, these studies were primarily limited in their ability to adjust for baseline differences in clinical characteristics (such as age and LVEF) between patients who tested MTWA-negative and non-negative (positive and indeterminate).13 Without adjusting for such baseline differences, it is unclear whether MTWA adds additional prognostic value over traditional clinical characteristics that are often associated with SCD.13,14
We therefore evaluated whether MTWA was an independent predictor of mortality in patients with ischemic cardiomyopathy after adjusting for demographics and clinical characteristics, including ICD status, age, LVEF, prolonged QRS duration, clinical comorbidities, and medication treatment. We also determined if the prognostic utility of MTWA was related to its ability to predict arrhythmic versus non-arrhythmic mortality.
Study Methods
A multicenter prospective cohort with defined ischemic heart disease and left ventricular dysfunction (LVEF <35%) meeting current Centers for Medicare and Medicaid Services (CMS) criteria for ICD therapy was developed. Patients were enrolled between March 2001 and June 2004 and underwent baseline MTWA testing by treadmill exercise (Heartwave system, Cambridge Heart, Inc., Bedford, Massachusetts). All MTWA tests were interpreted according to standard criteria by an expert reader blinded to patient characteristics and clinical outcomes.15 Based on earlier studies,11,12,14,16 we classified both indeterminate and positive tests as 'non-negative' during statistical analyses, but also examined MTWA-positive and -indeteminate results separately during secondary analyses.
Patient data on demographics, clinical comorbidities, medication usage, ICD status, and non-invasive studies (QRS duration, Holter analyses) were collected. The primary end-point for the study was all-cause mortality. Secondary end-points included cause-specific mortality (arrhythmic or non-arrhythmic);17 individual comparisons between the MTWA-positive, -indeterminate, and -negative groups; and the delivery of appropriate ICD shocks in patients with ICDs. Clinical follow-up for end-points through December 2004 was achieved by quarterly office visits, telephone contact with patients, review of office charts, and annual query of the National Death Index.18,19
Because ICDs have been shown to be efficacious in reducing mortality in this population, stratified Cox proportional hazards analyses by ICD status were performed for the study outcomes,20 as there was no significant interaction between the ICD and MTWA variables (p=0.47). The stratified multivariable models adjusted for differences in demographic, clinical, medication usage, and non-invasive study data between the MTWA groups.
Results
Baseline Characteristics and Unadjusted Analyses
Of the 768 patients, 514 (67%) had a non-negative MTWA test. Mean follow-up for the entire cohort was 18 + 10 months. In the non-ICD group, there were 58 deaths (MTWA negative: 15 (8.4%); MTWA non-negative: 43 (21.8%)), of which 28 were arrhythmic deaths (MTWA negative 6 (3.4%); MTWA non-negative 22 (11.2%)]. In the ICD group, there were 41 deaths [MTWA negative: 6 (8.0%) deaths; MTWA non-negative: 35 (11.0%) deaths), of which 14 were arrhythmic deaths (MTWA negative 3 (4.0%); MTWA non-negative 11 (3.5%)) (see Table 1). There were also a total of 26 appropriate ICD therapies not associated with death in the ICD group.
Kaplan-Meier event-free survival curves for all-cause mortality comparing those who tested MTWA-negative and non-negative, stratified by ICD status, are shown in Figure 1. Mortality-free survival for MTWA-negative patients was significantly higher than for MTWA non-negative patients (stratified log-rank statistic = 13.50; p=0.0002).
Multivariable Cox Proportional Hazards Models
Patients with a non-negative MTWA result had a greater than two-fold higher risk of all-cause mortality after multivariable adjustment (stratified hazards ratio (HR)=2.24 (1.34, 3.75); p=0.002) (see Table 2). This mortality difference was mediated primarily through an increase in arrhythmic mortality (stratified HR=2.29 (1.00, 5.24); p=0.049), as no significant relationship was found for non-arrhythmic mortality (stratified HR=1.77 (0.84, 3.74); p=0.13). Moreover, a non-negative MTWA was an independent predictor of event-free survival (all-cause mortality and appropriate ICD shock) in the ICD group (HR=2.42 (1.07, 5.48) with p=0.035). Finally, an indeterminate MTWA test (vs MTWA negative test) was found to be as predictive for mortality as a positive MTWA test result (see Table 3)
Comment
This study is the largest series to date to examine the predictive ability of MTWA to risk-stratify patients with ischemic heart disease and left ventricular dysfunction. We found that patients with ischemic cardiomyopathy and a non-negative MTWA test result have more than a two-fold higher risk of all-cause mortality compared with patients with a negative MTWA result. Although one could argue that the presence of MTWA may simply represent a composite risk profile from a patient's joint distribution of clinical and comorbid conditions, our study found that MTWA remained an independent predictor even after controlling for demographics, clinical comorbidities, ICD status, and medication treatment. Importantly, we also demonstrated that the increased risk associated with a non-negative MTWA result is mediated primarily through higher rates of arrhythmic mortality. A recent meta-analysis of MTWA found that a non-negative MTWA test result was associated with a univariate risk ratio for cardiac arrhythmic events of 2.42 (95% CI: 1.30 to 4.50) in patients with ischemic cardiomyopathy.14 However, the authors reported that the major limitation of most studies examining MTWA in various patient populations has been the lack of adjustment for known risk factors (such as age and LVEF) or other potential confounders. This has prevented a true assessment of the incremental prognostic utility of MTWA in predicting mortality.13,14
Moreover, many prior studies have reported cardiac arrhythmic events as their primary outcome without providing analyses for all-cause mortality. This leaves open the possibility that competing risks (whereby a non-negative MTWA test predicts arrhythmic mortality but not all-cause mortality) or misclassification bias (for cause-specific mortality) may have confounded prior results.13 To our knowledge, our study is the first to assess the prognostic utility of MTWA for both all-cause and arrhythmic rates of mortality after adjusting for baseline differences in age and LVEF, as well as for ICD status, medication usage and clinical variables.
Because of the large sample size in our study, we were able to assess whether a MTWA indeterminate test was an independent predictor of outcome. Prior studies have combined MTWA-positive and -indeterminate patients into a MTWA non-negative category without being able to adequately assess whether MTWA indeterminate patients had similar mortality hazard ratios as MTWA-positive patients, when compared with MTWA negative patients. To our knowledge, our study is the first to specifically examine this in patients with ischemic cardiomyopathy, and we found no significant differences in all-cause or cause-specific mortality risks between the MTWA-indeterminate and -positive groups, suggesting that our decision to combine them into one 'non-negative' category in this study was statistically appropriate. In fact, the mortality hazard ratio was non-significantly higher for MTWA-indeterminate patients than for MTWA-positive patients. As the majority of patients (77%) had frequent ectopy or inability to reach adequate heart rate as the primary reason for an indeterminate MTWA result, this may reflect underlying heart substrates or physical deconditioning that may predispose MTWA indeterminate patients to similar or higher mortality rates than MTWA positive patients.
The potential implication of MTWA testing in patients at high-risk for SCD is far-reaching. CMS has recently extended coverage for prophylactic ICD implantation to the SCD-HeFT and MADIT-II eligible population.21 However, this comes at considerable financial cost, and it is likely that ICD therapy will continue to be withheld from many 'appropriate' candidates because of barriers to treatment, including lack of hospital and physician resources, or a perception that the existing criteria are too broad.22,23 The ability to more selectively target devices in high-risk individuals using a screening test such as MTWA might lead to more complete treatment of those who are most likely to benefit.6,24 Our findings raise the possibility that, in patients with ischemic cardiomyopathy and without prior history of ventricular arrhythmia, those who test MTWA non-negative will have a higher absolute and relative risk of mortality from arrhythmic deaths compared with those who test MTWA negative, and may therefore derive more benefit with ICD therapy.
Conclusion
MTWA is a strong and independent predictor of all-cause and arrhythmic mortality in patients with ischemic cardiomyopathy. MTWA adds incremental prognostic utility to presently known risk factors for mortality in this population, with significant implications for future risk-stratification models.