doi: 10.1161/CIRCULATIONAHA.107.699918
(Circulation. 2007;116:2984-2991.)
© 2007 American Heart Association, Inc.
Contemporary Reviews in Cardiovascular Medicine |
Is Microvolt T-Wave Alternans the Answer to Risk Stratification in Heart Failure?
From the British Heart Foundation Glasgow Cardiovascular Research Centre, University of Glasgow (R.C.M., C.E.J., I.T., J.J.V.M., S.M.C.) and the Department of Cardiology, Royal Infirmary (M.C.P.), Glasgow, United Kingdom.
Correspondence to Dr Stuart M. Cobbe, Department of Medical Cardiology, Royal Infirmary, Glasgow G31 2ER, UK. E-mail stuart.cobbe{at}clinmed.gla.ac.uk
Key Words: death, sudden • heart failure • implantable cardioverter-defibrillator • T-wave alternans
 |
Introduction |
|---|
 Top Introduction Prevention of Sudden Cardiac...Microvolt T-Wave AlternansPredictive Value of MTWAUnresolved Issues in MTWA...Extrapolation to Primary...Improving the Evidence Base...References |
|---|
Despite recent advances in the prevention and treatment of cardiovascular disease, sudden cardiac death (SCD) still accounts for
50% of all cardiovascular deaths in developed countries, thus accounting for a significant proportion of annual death worldwide.1 Reduction of the incidence of SCD depends on identification of those at most risk. In the present review we will concentrate on the challenges of risk stratification for SCD in chronic heart failure (CHF). We evaluate the utility of microvolt T-wave alternans (MTWA) as a tool for predicting SCD and consider whether MTWA is currently a valid means of selecting which patients should, or should not, receive an implantable cardioverter-defibrillator (ICD). |
Prevention of Sudden Cardiac Death |
|---|
|
TopIntroductionPrevention of Sudden Cardiac...Microvolt T-Wave AlternansPredictive Value of MTWAUnresolved Issues in MTWA...Extrapolation to Primary...Improving the Evidence Base...References |
|---|
Until recently, attempts to prevent SCD relied on pharmacological therapy. β-Blockers,2 angiotensin-converting enzyme inhibitors,3 angiotensin receptor blockers4 and aldosterone antagonists5 modestly reduce the risk of SCD in patients with CHF and after myocardial infarction (MI), whereas antiarrhythmic therapy has largely failed.6 Despite such treatments, these patients remained at high risk until the advent of the ICD. Although ICDs have further reduced the risk of SCD, they are expensive and can be associated with significant morbidity; therefore, precisely targeting their use is crucial. Implantation of ICDs for secondary prevention is clear. Prior sustained ventricular arrhythmia confers high risk and the benefit/risk balance is clearly favorable.7 Also, the secondary prevention population is relatively small and readily identified, thus the financial costs are not insurmountable.
Primary prevention ICD therapy is an entirely different scenario. Large, randomized controlled trials have shown a mortality benefit with ICDs in patients with a low left ventricular ejection fraction (LVEF) and a history of MI or CHF.6,8 However, 2 major concerns have restricted implementation of this strategy. First, although analyses have estimated an acceptable cost-effectiveness profile,9 the immediate cost of implanting devices in this large population is enormous and the workload would exceed the capacity of most cardiology services. Second, the available evidence suggests that selection on the basis of LVEF alone is inefficient. For example, in the largest and longest published trial, the Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT), 79% of patients in the ICD arm did not use their device. In other words, in this landmark study many patients who did not require an ICD received one. The absolute risk reduction in the group randomized to ICD implantation was modest (7.2% over 5 years).6 This suggests that there is room for better definition of the target population and underscores the need for improved risk stratification to achieve substantial mortality benefit without prohibitive cost or the morbidity related to unnecessary device implantation.
In patients with CHF, QRS prolongation is associated with a poor prognosis, but whether this relates to an increased risk of SCD is unclear,10 and patients with a narrow QRS remain at high risk.6,11 Similarly, the presence of nonsustained VT does not specifically predict SCD in CHF.12 Other markers of arrhythmic risk, such as signal-averaged ECG, QT dispersion, and heart rate variability are limited by low sensitivity.1 Recently, MTWA testing has been advocated as a predictor of ventricular arrhythmias in potential candidates for primary prevention ICD therapy. Indeed, the Centers for Medicare and Medicaid Services have recently approved its reimbursement for the evaluation of patients at risk of SCD, stating: "Within patient groups that may be considered candidates for ICD therapy, a negative MTWA test may be useful in identifying low-risk patients who are unlikely to benefit from, and who may experience worse outcomes from, ICD placement."13
|
Microvolt T-Wave Alternans |
|---|
|
TopIntroductionPrevention of Sudden Cardiac...Microvolt T-Wave AlternansPredictive Value of MTWAUnresolved Issues in MTWA...Extrapolation to Primary...Improving the Evidence Base...References |
|---|
T-wave alternans describes beat-to-beat fluctuations in T-wave morphology, which have been anecdotally associated with the onset of ventricular fibrillation (VF). Experimental work has suggested that T-wave alternans is caused by cellular repolarization alternans, which can cause dynamic instability in cardiac repolarization and predispose to VF.14 In initial clinical studies, MTWA during atrial pacing was associated with an increased risk of ventricular arrhythmia.15 MTWA testing is now performed during submaximal exercise, using a commercially available system (CH2000 or HearTwave II, Cambridge Heart, Bedford, Mass). A series of beats recorded at a stable heart rate are aligned and the amplitude of each T-wave at the same time with respect to the QRS complex is plotted. These data then undergo spectral analysis, which determines the magnitude of T-wave fluctuation occurring on alternate beats. If sufficient alternans is sustained at heart rates <110 bpm, the test is positive. Absence of alternans at 110 bpm constitutes a negative test. A test satisfying neither set of criteria is classified as indeterminate. The system presents the data, along with an automated classification, as shown in the Figure. Atrial fibrillation (AF) precludes MTWA testing by this method as unequal R-R intervals confound the frequency analysis. MTWA can also be determined with time-domain methods, which are applicable to Holter data and AF. Although this technology has been evaluated during pacing,16 no prospective data are available regarding the prognostic value of Holter-based MTWA testing.
|
|
Predictive Value of MTWA |
|---|
|
TopIntroductionPrevention of Sudden Cardiac...Microvolt T-Wave AlternansPredictive Value of MTWAUnresolved Issues in MTWA...Extrapolation to Primary...Improving the Evidence Base...References |
|---|
The studies that have assessed the predictive value of MTWA testing during exercise are summarized in Table 1.
|
Known or Suspected Arrhythmia
In a population of 313 patients referred for cardiac electrophysiological study (EPS), MTWA predicted the occurrence of ventricular tachyarrhythmic events (VTE) (ie, SCD, VF, sustained ventricular tachycardia (VT), or appropriate ICD therapy) better than EPS (relative risk, 10.9 versus 7.1).17 However, this was a heterogeneous population; some patients were referred after cardiac arrest and others for assessment of supraventricular tachycardia.
Myocardial Infarction
Three studies have investigated the prognostic utility of MTWA after MI regardless of LVEF. Only 1 study has suggested that MTWA may predict SCD. This study enrolled 850 consecutive patients late after MI (mean, 2.7 months post-MI). MTWA was found to predict SCD or resuscitated VF, although the event rate was only 3%.18 The proportion of patients prescribed a β-blocker was low (30%). Two other studies suggested that MTWA is not prognostically useful after MI. In 1 study, 140 consecutive patients were investigated in the first 30 days after MI. Only 3 end points (death/VTE) accrued over 15 months of follow-up19 and MTWA did not predict events. The second study examined the predictive value of MTWA for all-cause death in 323 consecutive patients early after MI (mean, 8 days post-MI). Of these, only 56 (17%) patients were MTWA-positive. None of the 26 deaths occurred in this group.20 Notably, these patients were evaluated while receiving optimal medical therapy (including a β-blocker in 97%). In a cohort of 1041 patients with preserved LVEF after MI (mean, 48 days post-MI), a positive MTWA test did predict VTE, although the number of end points was extremely low (18 over 32 months).21
Two small studies have specifically selected patients who meet Multicenter Automatic Defibrillator Implantation Trial (MADIT)-II entry criteria (previous MI, LVEF 
30% without prior VF/VT) from other cohorts. In 129 such patients, none of the 12 who experienced SCD or resuscitated VF were in the MTWA-negative group.22 In a subgroup analysis of a larger study, 177 patients who meet MADIT-II criteria had MTWA tests classified as abnormal (positive/indeterminate, 68%), or normal (negative, 32%). The hazard ratio associated with an abnormal test (4.8; 95% CI, 1.1 to 20.7) was only adjusted for QRS duration and so does not reflect incremental prognostic value.11
In short, the evidence for the use of MTWA in risk stratification after MI is not robust. The negative predictive value (NPV) may be high in selected patients, but the results are conflicting in more representative cohorts and, in MADIT-II patients, the incremental prognostic value is untested. Preliminary results are now available from the Microvolt T-Wave Alternans Testing for Risk Stratification of Post-MI Patients (MASTER)-I study. In 575 MADIT-II eligible patients undergoing ICD implantation, an abnormal MTWA test did not predict the combined end point of arrhythmic death and ICD discharge.33
Ischemic Left Ventricular Systolic Dysfunction
Three studies have examined the prognostic value of MTWA in patients with ischemic left ventricular systolic dysfunction (LVSD). The first study performed MTWA testing in 144 nonconsecutive patients referred for EPS.23 The cohort was divided into primary (n=88) and secondary (n=56) prevention subgroups, and 111 patients received an ICD. A positive MTWA test did not predict the primary end point (death/VTE) in the primary prevention subgroup.
The second study examined 768 consecutive patients with coronary heart disease and LVSD.24 The authors analyzed positive and indeterminate tests together and separately, addressed cause-specific death as a secondary end point, and performed a more extensive multivariable analysis than has been seen in other studies. However, the follow-up was relatively short (mean, 18±10 months) and the event rate (n=99) was arguably low for a population of this kind, limiting the power of the study. A nonnegative MTWA test independently predicted all-cause mortality (hazard ratio, 2.24; 95% CI, 1.34 to 3.75) and arrhythmic mortality (hazard ratio, 2.29; 95% CI, 1.0 to 5.24) in the whole population. However, when positive and indeterminate results were analyzed separately, positive results did not predict arrhythmic death, whereas indeterminate results predicted both all-cause and arrhythmic death. Therefore, indeterminate rather than positive tests accounted for the majority of the predictive value for arrhythmia, which counters the proposition that MTWA identifies a specific proarrhythmic substrate.
The Alternans Before Cardioverter Defibrillator (ABCD) study recruited 566 patients with ischemic LVSD and nonsustained VT and compared the ability of MTWA and EPS to predict VTE. Preliminary results show that the 1-year event rate was lowest when both tests were negative (2.3%), highest when both were abnormal (12.6%), and intermediate when only 1 test was abnormal (MTWA nonnegative, 5%; EPS abnormal, 7.5%). Use of an ICD (shock or pacing) accounted for the majority (55 of 65) of end points. However, ICD implantation was not mandated if both tests were normal, and so patients in this group (n=99) may have been less likely to reach an end point. Furthermore, because ICD therapies occur more frequently than SCD in patients without ICDs, a significant proportion of the end points in this study may have been attributable to subclinical arrhythmias.34
Left Ventricular Systolic Dysfunction Irrespective of Etiology
One study recruited 549 patients with LVSD, including patients with ischemic (n=267) and nonischemic (n=282) cardiomyopathy.25 The primary end point was a composite of death and VTE. Over 20 months, there were 2 deaths and 2 ICD discharges in the normal MTWA group (n=189) compared with 38 deaths and 9 ICD discharges in the abnormal group (n=360) (the proportion with an ICD in each group was the same). After multivariable adjustment, an abnormal MTWA test was associated with an increased risk of VTE.
Nonischemic Left Ventricular Systolic Dysfunction
Three studies have examined the prognostic utility of MTWA in nonischemic cardiomyopathy. The first study performed MTWA testing in 104 patients and concluded that a positive MTWA test was independently associated with VTE.26 However, this study has many limitations. The number of end points was very small (n=12), as was the sample size, limiting the multivariable analysis. Many screened patients were ineligible because of AF, but no information was given regarding their number or characteristics. No patient was prescribed an angiotensin-converting enzyme inhibitor or β-blocker before entry into the study (ie, MTWA testing was carried out on suboptimal medical therapy). The second study recruited 137 patients and compared MTWA with other arrhythmic markers.27 MTWA was the only independent predictor of VTE after a mean follow-up of 14 months. However, the multivariable model did not include age or LVEF. The cohort included patients with an ICD (27%), mostly for prior VF/VT, and 11 of 18 end points occurred in those patients. This limits extrapolation of these results to a primary prevention population. The largest study (n=263) excluded patients with prior VF/VT and had a longer duration of follow-up (52 months).28 A positive MTWA test was not associated with the occurrence of VTE.
The available evidence does not suggest that MTWA is a reliable indicator of arrhythmia in patients who have nonischemic LVSD. There appears to be little to recommend a strategy of using MTWA in this population to determine which patients should have an ICD.
Symptomatic Heart Failure With Low LVEF
The evidence, such as it is, for the prognostic utility of MTWA in LVSD cannot simply be extrapolated to patients with symptomatic CHF, which is a clinically distinct entity. Three small studies (n=73, n=46, n=107) have assessed the predictive value of MTWA testing in patients with low ejection fraction heart failure.29–31 On initial review these studies suggest that MTWA predicts clinical outcome in this population. However, they do have several limitations beyond their size.
The first selected 73 patients with New York Heart Association II CHF after excluding those with LVEF 20% "because of high risk of death." An additional 17 patients were excluded after indeterminate MTWA testing, leaving a small and highly selected group in which a positive MTWA test was associated with an increased risk of VTE over 17 months.29 In another study, of 46 patients with New York Heart Association II/III CHF, MTWA predicted cardiac death (n=7) but not SCD (n=1).30 In the third study, of 107 patients with CHF, none of the 13 end points occurred in MTWA-negative patients and MTWA was the only independent predictor of VTE.31 However, the multivariable adjustment included only 7 arrhythmia markers.
These studies are small, appear to be highly selected, and lack proper multivariable adjustment. Their limited relevance to real-life populations with CHF is exemplified by the mean ages of the patients enrolled (64 years, 59 years, and 56 years, respectively). The average age of unselected heart failure populations is 75 years.35
Results are now available from 2 larger studies of MTWA in CHF. The Microvolt T-Wave Alternans in Patients with Heart Failure (ALPHA) study recruited 446 patients with nonischemic cardiomyopathy (LVEF40%) and stable New York Heart Association II/III CHF on optimal medical therapy. A nonnegative MTWA test was associated with an increased risk of cardiac death or VTE over 18 to 24 months.32 However, these patients were older, more symptomatic, and had a lower mean LVEF, imbalances that highlight the need for careful multivariable adjustment in such studies. In the SCD-HeFT T-wave alternans substudy, MTWA testing was performed in 490 patients with LVEF 35% and New York Heart Association II/III CHF; 41% of tests were indeterminate and over 35 months there was no difference in the rate of VTE between MTWA groups for patients who received either ICD or placebo.36 These studies are larger than those published so far and their contradictory results mean that doubt remains regarding the value of MTWA for predicting arrhythmic risk in CHF.
|
Unresolved Issues in MTWA Testing |
|---|
|
TopIntroductionPrevention of Sudden Cardiac...Microvolt T-Wave AlternansPredictive Value of MTWAUnresolved Issues in MTWA...Extrapolation to Primary...Improving the Evidence Base...References |
|---|
Does MTWA Have Incremental Prognostic Value?
There are few data regarding the true incremental prognostic value of MTWA testing because of the lack of detailed multivariable analysis undertaken in the studies to date (Table 2). A number of powerful predictors of outcome in CHF have recently been identified,37 including plasma B-type natriuretic peptide (BNP) levels, which have an established prognostic significance in CHF with reduced LVEF.37 BNP has also been found to be an independent predictor of SCD.39 The prognostic value of MTWA testing has not been compared with that of BNP. It is certainly conceivable that a low BNP could confer as good a prognosis as a negative MTWA test. If this were the case, then the cost and small risk to the patient associated with MTWA testing would be unjustified. Although some may argue that BNP is not suitable for risk stratification because it varies over relatively short time scales, it should be noted that there is no evidence regarding the reproducibility of MTWA results over time scales greater than a few hours.40
|
Atrial Fibrillation
MTWA exercise testing cannot be performed in patients with AF. Only 2 studies have reported the proportion of screened patients ineligible because of AF (23%28 and 22%32). In MADIT-II, 9% of patients had AF,8 and in populations with CHF 25% to 30% have concurrent AF.4 If sufficient evidence was accrued to allow MTWA to be used to identify appropriate candidates for ICD therapy in populations with sinus rhythm, attention should remain on alternative strategies in the large population ineligible for testing.
Inability to Exercise
Tapanainen et al reported that 15% of 379 consecutive MI patients in sinus rhythm could not exercise due to co-morbidity or physical frailty.20 Although a positive MTWA test failed to predict all-cause mortality, inability to exercise was found to be an independent predictor of death (relative risk, 5.62; 95% CI, 1.76 to 15.99).20 Implementation of a risk-stratification tool that requires exercise is likely to be problematic in CHF, where the incidence of frailty and comorbidity is high.
Medical Therapy
Despite the fact that pharmacological therapy can reduce SCD, in only 1 of the studies described is optimal medical therapy mandated. In 1 post-MI study18 and 2 CHF studies,30,31 fewer than half of patients were prescribed a β-blocker. Many studies discontinued β-blockers for at least 24 hours to reduce indeterminate tests. However, as acute β-blockade reduces MTWA magnitude, in some cases converting a positive to a negative test,41 omission of β-blockers may not only reduce the number of indeterminate tests but may also increase the number of positive tests. We would argue that MTWA testing is only clinically valuable if shown to be independently predictive of outcome in patients on optimal tolerated medical therapy, including a β-blocker.
Indeterminate Testing
MTWA tests are classified as indeterminate in a defined set of circumstances: if there is significant noise or ectopy, if alternans is unsustained, or if the patient cannot attain a heart rate of 110 bpm for 1 minute. In early studies, indeterminate MTWA tests were assumed to be of no significance to arrhythmic events and were excluded. However, in the first report by Bloomfield et al, indeterminate MTWA tests accounted for the majority of nonnegative tests and were grouped together with positive tests as abnormal,11 which is now common practice. Table 3 shows outcomes in MTWA-positive and indeterminate groups from studies that have examined all-cause death. In each, the rate of death was higher in the indeterminate group. Clearly, an indeterminate test indicates an unfavorable prognosis, but the nature of this risk is unclear. Only 1 study enrolled a sufficiently large cohort to examine cause-specific death (Table 4). Indeterminate tests accounted for 159 of 514 abnormal MTWA tests and predicted both arrhythmic and nonarrhythmic death, whereas a positive test only predicted all-cause death.24 In another study, the rate of major arrhythmic events was highest in the indeterminate group (24%) compared with the MTWA-positive (13%) or MTWA-negative (10%) groups.28
|
|
This raises the possibility that an indeterminate test may actually predict both nonarrhythmic and arrhythmic risk. Although this may seem counterintuitive, it is possible that patients with nonsustained alternans or ectopy on exercise are prone to ventricular arrhythmia. Recent analyses of indeterminate tests concluded that such patients were at high risk, distinct from the tests ruled as indeterminate because of noise, artifact, or a sharp rise in heart rate,42,43 suggesting that the prognostic value of MTWA may be improved by reclassification of indeterminate tests.43
|
Extrapolation to Primary Prevention ICD Therapy |
|---|
|
TopIntroductionPrevention of Sudden Cardiac...Microvolt T-Wave AlternansPredictive Value of MTWAUnresolved Issues in MTWA...Extrapolation to Primary...Improving the Evidence Base...References |
|---|
There has been much speculation that MTWA could improve risk stratification for the primary prevention of SCD, and many commentators have argued that the current evidence regarding the favorable prognosis conferred by a negative test is sufficient to justify using MTWA to identify a subgroup of primary prevention ICD candidates who would not benefit.11,44 This could reduce the number of primary prevention implants and thereby reduce the cost of therapy.
However, the current evidence is lacking in many respects. Most of the studies are limited by small sample size or by low event rates, which reduces power, and there is a lack of detailed multivariable analysis. We cannot, at present, extrapolate the prevalence data for a negative test to unselected populations, because the proportion of patients who would be ineligible for testing because of AF or an inability to exercise is unknown. In addition, a high NPV has only been demonstrated over relatively short time scales, and because the arrhythmic substrate changes over time it is likely that serial MTWA testing would be required. The corollary of not implanting in MTWA negative patients would be to implant in all nonnegative patients, including those with indeterminate tests. Given the lack of proven incremental prognostic value of MTWA and the conflicting results in some studies, we have serious doubts regarding the benefit of this strategy and believe that the decision of the Centers for Medicare and Medicaid Services to reimburse for MTWA testing in all potential candidates for ICD implantation is premature. Indeed, the Blue Cross Blue Shield Technology Evaluation Center has not approved MTWA testing for this indication on the basis of insufficient evidence.45
|
Improving the Evidence Base for MTWA |
|---|
|
TopIntroductionPrevention of Sudden Cardiac...Microvolt T-Wave AlternansPredictive Value of MTWAUnresolved Issues in MTWA...Extrapolation to Primary...Improving the Evidence Base...References |
|---|
Further investigation is required to address the shortcomings and contradictions apparent in the data pertaining to MTWA and arrhythmic risk. A meta-analysis has already been conducted and, although it confirmed the high NPV of MTWA across many smaller studies, it could not address the lack of multivariable adjustment or the unrepresentative nature of the study populations.46
Prospective MTWA testing in all patients undergoing ICD implantation could provide valuable evidence as to whether MTWA can predict arrhythmic events. This may be achievable through the US National ICD Registry, which includes the improvement of risk stratification among its aims.47
In addition, further observational studies should be carried out in well-defined, representative populations. In these studies, multivariable models should be designed carefully to test incremental prognostic value over established predictors, and attention should be paid to the characteristics and outcomes of those ineligible for MTWA testing. The possibility that the high NPV of MTWA could be utilized in combination with other markers as part of a risk stratification algorithm should also be explored. A carefully designed trial of MTWA-guided ICD therapy would provide the most robust evidence. In this approach, patients who meet evidence-based criteria for ICD implantation would be assigned to medical therapy only, and such selection would therefore require careful ethical consideration. This is certainly conceivable, given that not all patients who meet the criteria receive an ICD at present. However, to justify such a trial, the evidence derived from observational studies should first be improved.
In conclusion, the evidence for the use of MTWA in risk stratification of patients at risk of SCD is compelling in some aspects, principally its NPV in patients with ischemic LVSD. However, the available evidence is not yet sufficient to allow its extrapolation to routine clinical use in large numbers of patients to determine whether primary prevention ICD implantation is indicated. To plan the most clinically and cost-effective method of SCD prevention, MTWA needs to be investigated in more detail.
|
Acknowledgments |
|---|
Sources of Funding
Dr Myles and Dr Cobbe are supported by the British Heart Foundation.
Disclosures
All authors are now investigators on a Chief Scientist Office project grant entitled, "Microvolt T-Wave Alternans in Chronic Heart Failure: A Study of Prevalence and Incremental Prognostic Value" (Ref CZH/4/439).
|
References |
|---|
|
TopIntroductionPrevention of Sudden Cardiac...Microvolt T-Wave AlternansPredictive Value of MTWAUnresolved Issues in MTWA...Extrapolation to Primary...Improving the Evidence Base...References |
|---|
- Huikuri HV, Castellanos A, Myerburg RJ. Sudden death due to cardiac arrhythmias. N Engl J Med. 2001; 345: 1473–1482.
[Free Full Text] - Kendall MJ, Lynch KP, Hjalmarson A, Kjekshus J. Beta-blockers and sudden cardiac death. Ann Intern Med. 1995; 123: 358–367.
[Abstract/Free Full Text] - Domanski MJ, Exner DV, Borkowf CB, Geller NL, Rosenberg Y, Pfeffer MA. Effect of angiotensin-converting enzyme inhibition on sudden cardiac death in patients following acute myocardial infarction: a meta-analysis of randomized clinical trials. J Am Coll Cardiol. 1999; 33: 598–604.
[Abstract/Free Full Text] - Pfeffer MA, Swedberg K, Granger CB, Held P, McMurray JJ, Michelson EL, Olofsson B, Ostergren J, Yusuf S, Pocock S. Effects of candesartan on mortality and morbidity in patients with chronic heart failure: the CHARM-Overall programme. Lancet. 2003; 362: 759–766.[CrossRef][Medline]
[Order article via Infotrieve]
- Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A, Palensky J, Wittes J. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. N Engl J Med. 1999; 341: 709–717.
[Abstract/Free Full Text] - Bardy GH, Lee KL, Mark DB, Poole JE, Packer DL, Boineau R, Domanski M, Troutman C, Anderson J, Johnson G, McNulty SE, Clapp-Channing N, Davidson-Ray LD, Fraulo ES, Fishbein DP, Luceri RM, Ip JH. Amiodarone or an implantable cardioverter-defibrillator for congestive heart failure. N Engl J Med. 2005; 352: 225–237.
[Abstract/Free Full Text] - The Antiarrhythmics versus Implantable Defibrillators Investigators. A comparison of antiarrhythmic-drug therapy with implantable defibrillators in patients resuscitated from near-fatal ventricular arrhythmias. N Engl J Med. 1997; 337: 1576–1583.
[Abstract/Free Full Text] - Moss AJ, Zareba W, Hall WJ, Klein H, Wilber DJ, Cannom DS, Daubert JP, Higgins SL, Brown MW, Andrews ML. Prophylactic implantation of a defibrillator in patients with myocardial infarction and reduced ejection fraction. N Engl J Med. 2002; 346: 877–883.
[Abstract/Free Full Text] - Mushlin AI, Hall WJ, Zwanziger J, Gajary E, Andrews M, Marron R, Zou KH, Moss AJ. The cost-effectiveness of automatic implantable cardiac defibrillators: results from MADIT. Circulation. 1998; 97: 2129–2135.
[Abstract/Free Full Text] - Kashani A, Barold SS. Significance of QRS complex duration in patients with heart failure. J Am Coll Cardiol. 2005; 46: 2183–2192.
[Abstract/Free Full Text] - Bloomfield DM, Steinman RC, Namerow PB, Parides M, Davidenko J, Kaufman ES, Shinn T, Curtis A, Fontaine J, Holmes D, Russo A, Tang C, Bigger JT Jr. Microvolt T-wave alternans distinguishes between patients likely and patients not likely to benefit from implanted cardiac defibrillator therapy: a solution to the Multicenter Automatic Defibrillator Implantation Trial (MADIT) II conundrum. Circulation. 2004; 110: 1885–1889.
[Abstract/Free Full Text] - Teerlink JR, Jalaluddin M, Anderson S, Kukin ML, Eichhorn EJ, Francis G, Packer M, Massie BM. Ambulatory ventricular arrhythmias in patients with heart failure do not specifically predict an increased risk of sudden death. Circulation. 2000; 101: 40–46.
[Abstract/Free Full Text] - Centers for Medicare and Medicaid Services. Decision memo for microvolt T-wave alternans (CAG-00293N). Available at: https://www.cms.hhs.gov/mcd/viewdecisionmemo.asp?id=165. Accessed June 27, 2006.
- Pastore JM, Girouard SD, Laurita KR, Akar FG, Rosenbaum DS. Mechanism linking T-wave alternans to the genesis of cardiac fibrillation. Circulation. 1999; 99: 1385–1394.
[Abstract/Free Full Text] - Rosenbaum DS, Jackson LE, Smith JM, Garan H, Ruskin JN, Cohen RJ. Electrical alternans and vulnerability to ventricular arrhythmias. N Engl J Med. 1994; 330: 235–241.
[Abstract/Free Full Text] - Cox V, Patel M, Kim J, Liu T, Sivaraman G, Narayan SM. Predicting arrhythmia-free survival using spectral and modified-moving average analyses of T-wave alternans. Pacing Clin Electrophysiol. 2007; 30: 352–358.[CrossRef][Medline]
[Order article via Infotrieve]
- Gold MR, Bloomfield DM, Anderson KP, El Sherif NE, Wilber DJ, Groh WJ, Estes NA 3rd, Kaufman ES, Greenberg ML, Rosenbaum DS. A comparison of T-wave alternans, signal averaged electrocardiography and programmed ventricular stimulation for arrhythmia risk stratification. J Am Coll Cardiol. 2000; 36: 2247–2253.
[Abstract/Free Full Text] - Ikeda T, Saito H, Tanno K, Shimizu H, Watanabe J, Ohnishi Y, Kasamaki Y, Ozawa Y. T-wave alternans as a predictor for sudden cardiac death after myocardial infarction. Am J Cardiol. 2002; 89: 79–82.[CrossRef][Medline]
[Order article via Infotrieve]
- Schwab JO, Weber S, Schmitt H, Steen-Mueller MK, Coch M, Tillmanns H, Becker M, Lenzen C, Waldecker B. Incidence of T-wave alternation after acute myocardial infarction and correlation with other prognostic parameters. Pacing Clin Electrophysiol. 2001; 24: 957–961.[CrossRef][Medline]
[Order article via Infotrieve]
- Tapanainen JM, Still AM, Airaksinen KE, Huikuri HV. Prognostic significance of risk stratifiers of mortality, including T-wave alternans, after acute myocardial infarction: results of a prospective follow-up study. J Cardiovasc Electrophysiol. 2001; 12: 645–652.[CrossRef][Medline]
[Order article via Infotrieve]
- Ikeda T, Yoshino H, Sugi K, Tanno K, Shimizu H, Watanabe J, Kasamaki Y, Yoshida A, Kato T. Predictive value of microvolt T-wave alternans for sudden cardiac death in patients with preserved cardiac function after acute myocardial infarction. J Am Coll Cardiol. 2006; 48: 2268–2274.
[Abstract/Free Full Text] - Hohnloser SH, Ikeda T, Bloomfield DM, Dabbous OH, Cohen RJ. T-wave alternans negative coronary patients with low ejection and benefit from defibrillator implantation. Lancet. 2003; 362: 125–126.[CrossRef][Medline]
[Order article via Infotrieve]
- Rashba EJ, Osman AF, Macmurdy K, Kirk MM, Sarang SE, Peters RW, Shorofsky SR, Gold MR. Enhanced detection of arrhythmia vulnerability using T-wave alternans, left ventricular ejection fraction, and programmed ventricular stimulation. J Cardiovasc Electrophysiol. 2004; 15: 170–176.[CrossRef][Medline]
[Order article via Infotrieve]
- Chow T, Kereiakes DJ, Bartone C, Booth T, Schloss EJ, Waller T, Chung ES, Menon S, Nallamothu BK, Chan PS. Prognostic utility of microvolt T-wave alternans in risk stratification of patients with ischemic cardiomyopathy. J Am Coll Cardiol. 2006; 47: 1820–1827.
[Abstract/Free Full Text] - Bloomfield DM, Bigger JT, Steinman RC, Namerow PB, Parides MK, Curtis AB, Kaufman ES, Davidenko JM, Shinn TS, Fontaine JM. Microvolt T-wave alternans and the risk of death or sustained ventricular arrhythmias in patients with left ventricular dysfunction. J Am Coll Cardiol. 2006; 47: 456–463.
[Abstract/Free Full Text] - Kitamura H, Ohnishi Y, Okajima K, Ishida A, Galeano E, Adachi K, Yokoyama M. Onset heart rate of microvolt-level T-wave alternans provides clinical and prognostic value in nonischemic dilated cardiomyopathy. J Am Coll Cardiol. 2002; 39: 295–300.
[Abstract/Free Full Text] - Hohnloser SH, Klingenheben T, Bloomfield D, Dabbous O, Cohen RJ. Usefulness of microvolt T-wave alternans for prediction of ventricular tachyarrhythmic events in patients with dilated cardiomyopathy: results from a prospective observational study. J Am Coll Cardiol. 2003; 41: 2220–2224.
[Abstract/Free Full Text] - Grimm W, Christ M, Bach J, Muller HH, Maisch B. Noninvasive arrhythmia risk stratification in idiopathic dilated cardiomyopathy: results of the Marburg Cardiomyopathy Study. Circulation. 2003; 108: 2883–2891.
[Abstract/Free Full Text] - Baravelli M, Salerno-Uriarte D, Guzzetti D, Rossi MC, Zoli L, Forzani T, Salerno-Uriarte JA. Predictive significance for sudden death of microvolt-level T-wave alternans in New York Heart Association class II congestive heart failure patients. Int J Cardiol. 2005; 105: 53–57.[CrossRef][Medline]
[Order article via Infotrieve]
- Sarzi BS, Vaninetti R, Laporta A, Picozzi A, Pedretti RF. T wave alternans is a predictor of death in patients with congestive heart failure. Int J Cardiol. 2004; 93: 31–38.[CrossRef][Medline]
[Order article via Infotrieve]
- Klingenheben T, Zabel M, D’Agostino RB, Cohen RJ, Hohnloser SH. Predictive value of T-wave alternans for arrhythmic events in patients with congestive heart failure. Lancet. 2000; 356: 651–652.[CrossRef][Medline]
[Order article via Infotrieve]
- Salerno-Uriarte JA, De Ferrari GM, Klersy C, Pedretti RFE, Tritto M, Sallusti L, Libero L, Pettinati G, Molon G, Curnis A, Occhetta E, Morandi F, Ferrero P, Accardi F, for the ALPHA Study Group Investigators. Prognostic value of T-wave alternans in patients with heart failure due to nonischemic cardiomyopathy. J Am Coll Cardiol. 2007; 50: 1896–1904.
[Abstract/Free Full Text] - Chow T, Kereiakes DJ, Onufer J, Woelfel A, Gursoy S, Peterson BJ, Brown ML, Pu W, Benditt DG. Primary results from the Microvolt T Wave Alternans Testing for Risk Stratification of Post MI Patients (MASTER I) trial. Circulation. 2007; 116: 2631. Abstract.
- Cleland JG, Coletta AP, Abdellah AT, Nasir M, Hobson N, Freemantle N, Clark AL. Clinical trials update from the American Heart Association 2006: OAT, SALT 1 and 2, MAGIC, ABCD, PABA-CHF, IMPROVE-CHF, and percutaneous mitral annuloplasty. Eur J Heart Fail. 2007; 9: 92–97.[CrossRef][Medline]
[Order article via Infotrieve]
- MacIntyre K, Capewell S, Stewart S, Chalmers JWT, Boyd J, Finlayson A, Redpath A, Pell JP, McMurray JJV. Evidence of improving prognosis in heart failure: trends in case fatality in 66 547 patients hospitalized between 1986 and 1995. Circulation. 2000; 102: 1126–1131.
[Abstract/Free Full Text] - Gold MR, Chilson D, Ip JH, Constantini O, Bloomfield D, Poole J, McNulty S, Lee K, Bardy G. T-wave Alternans SCD-HeFT Study: primary events analysis. Circulation. 2006; 114 (suppl II): II-428–II-429. Abstract.
- Pocock SJ, Wang D, Pfeffer MA, Yusuf S, McMurray JJ, Swedberg KB, Ostergren J, Michelson EL, Pieper KS, Granger CB. Predictors of mortality and morbidity in patients with chronic heart failure. Eur Heart J. 2006; 27: 65–75.
[Abstract/Free Full Text] - Koglin J, Pehlivanli S, Schwaiblmair M, Vogeser M, Cremer P, von Scheidt W. Role of brain natriuretic peptide in risk stratification of patients with congestive heart failure. J Am Coll Cardiol. 2001; 38: 1934–1941.
[Abstract/Free Full Text] - Berger R, Huelsman M, Strecker K, Bojic A, Moser P, Stanek B, Pacher R. B-type natriuretic peptide predicts sudden death in patients with chronic heart failure. Circulation. 2002; 105: 2392–2397.
[Abstract/Free Full Text] - Madias JE. Reproducibility of T-wave alternans in congestive heart failure: a theoretical argument. Pacing Clin Electrophysiol. 2006; 29: 800–802.[CrossRef][Medline]
[Order article via Infotrieve]
- Klingenheben T, Gronefeld G, Li YG, Hohnloser SH. Effect of metoprolol and d,l-sotalol on microvolt-level T-wave alternans: results of a prospective, double-blind, randomized study. J Am Coll Cardiol. 2001; 38: 2013–2019.
[Abstract/Free Full Text] - Kaufman ES, Bloomfield DM, Steinman RC, Namerow PB, Costantini O, Cohen RJ, Bigger JT Jr. "Indeterminate" microvolt T-wave alternans tests predict high risk of death or sustained ventricular arrhythmias in patients with left ventricular dysfunction. J Am Coll Cardiol. 2006; 48: 1399–1404.
[Abstract/Free Full Text] - Chan PS, Bartone C, Booth T, Kereiakes D, Chow T. Prognostic implication of redefining indeterminate microvolt T-wave alternans studies as abnormal or normal. Am Heart J. 2007; 153: 523–529.[CrossRef][Medline]
[Order article via Infotrieve]
- Cohen RJ. Enhancing specificity without sacrificing sensitivity: potential benefits of using microvolt T-wave alternans testing to risk stratify the MADIT-II population. Card Electrophysiol Rev. 2003; 7: 438–442.[CrossRef][Medline]
[Order article via Infotrieve]
- Blue Cross Blue Shield Technology Evaluation Center. Microvolt T-wave alternans testing to risk-stratify patients being considered for ICD therapy for primary prevention of sudden death. Assessment program, volume 21, no 14, May 2007. Available at: http://www.bcbs.com/betterknowledge/tec/vols/21/21_14.pdf. Accessed June 19, 2007.
- Gehi AK, Stein RH, Metz LD, Gomes JA. Microvolt T-wave alternans for the risk stratification of ventricular tachyarrhythmic events: a meta-analysis. J Am Coll Cardiol. 2005; 46: 75–82.
[Abstract/Free Full Text] - Hammill S, Phurrough S, Brindis R. The National ICD Registry: now and into the future. Heart Rhythm. 2006; 3: 470–473.[CrossRef][Medline]
[Order article via Infotrieve]
This article has been cited by other articles:
 |
|
 |
|
  M. M. Scheinman and E. Keung The Year in Review of Clinical Cardiac Electrophysiology J. Am. Coll. Cardiol., May 27, 2008; 51(21): 2075 - 2081. [Full Text] [PDF]
|
|
|
|
 |
|
 P. Ferrero, D. Castagno, R. Massa, A. De Luca, M. Castellano, C. Chirio, and R. Grimaldi Spinal cord stimulation affects T-wave alternans in patients with ischaemic cardiomyopathy: a pilot study Europace, April 1, 2008; 10(4): 506 - 508. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||