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Microvolt T-wave alternans for risk stratification of cardiac events in ischemic cardiomyopathy: A meta-analysis
IJCA-14881; No of Pages 5 International Journal of Cardiology xxx (2012) xxx–xxx
Contents lists available at SciVerse ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Microvolt T-wave alternans for risk stratification of cardiac events in ischemic cardiomyopathy: A meta-analysis Zhen Chen a, b, Yue Shi a, Xiaofeng Hou a, Shudong Xu b, Jiangang Zou b,⁎ a b
Division of Cardiology, First Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu, China Division of Cardiology, Taixing Hospital, Taixing, Jiangsu, China
a r t i c l e
i n f o
Article history: Received 27 June 2011 Received in revised form 4 November 2011 Accepted 11 May 2012 Available online xxxx Keywords: Microvolt T-wave alternans Ischemic cardiomyopathy Cardiac mortality Arrhythmia Meta-analysis
a b s t r a c t Background: The ability of microvolt T-wave alternans (MTWA) for risk stratification of cardiac events in patients with ischemic cardiomyopathy (ICM) has not been well established. Methods: The authors systematically reviewed current literature and carried out a meta-analysis to determine the ability of MTWA to predict the outcome severity after ICM. Major endpoints include composite endpoint of cardiac mortality and severe arrhythmic events in primary prevention of patients with ICM, as well as all-cause mortality (cardiac death, and/or non-cardiac death). Results: Seven trials were included by using MTWA for risk stratification of cardiac events in 3385 patients with ICM. All patients were distributed into two groups according to the results of MTWA tests: nonnegative group included positive and indeterminate, and negative group. Compared with the negative group, non-negative group showed increased rates of cardiac mortality or severe arrhythmic events (RR = 1.65, 95%CrI = 1.32, 2.071), sudden cardiac death (SCD) (RR = 2.04 95%CrI = 1.11, 3.75), and allcause mortality (RR = 2.11, 95%CrI = 1.60, 2.79). The funnel plot revealed that there might be bias within current publications. The fail-safe number of composite endpoint and all-cause mortality was 14.42 and 18.93, respectively (when P = 0.01). The fail-safe number of SCD was 1.07 (when P = 0.05), which may be caused by the small case number of included studies and some patients with ICD included. Conclusions: The non-negative group of MTWA had a nearly double risk of severe outcomes compared with the negative group. Therefore, MTWA represents a potential useful tool for judging the severity of ICM. © 2012 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Sudden cardiac death (SCD) is defined as unexpected death resulting from a cardiac cause, usually within one hour after the onset of symptoms. The most common arrhythmias precipitating SCD are ventricular fibrillation and pulseless ventricular tachycardia [1]. Although patients with preserved LV function after myocardial infarction (MI) are at extremely low risk of serious cardiac events [2], for those patients with at least mild LV dysfunction, the outcomes after ischemic cardiomyopathy (ICM) becomes variable and reliable risk assessment method is remained to be developed. Some studies including several meta-analyses [3–7] suggested that MTWA may be helpful for risk stratification of cardiac death or a ventricular tachyarrhymic event and identified subsets of ICM patients least likely to benefit from implantable cardioverter defibrillator (ICD) insertion. These suggest that MTWA may be considered as a practical tool for ICM outcome assessment. However, controversial results ⁎ Corresponding author at: Division of Cardiology, First Affiliated Hospital of Nanjing Medical University, 140 Hanzhong Avenue, Nanjing, Jiangsu 210009, China. Tel.: + 86 025 68136438; fax: + 86 025 83674656. E-mail address: [email protected] (J. Zou).
were obtained in another large scale study [8]. To further clarify whether MTWA is beneficial for evaluating of the severity of ICM or not, we systematically reviewed currently available medical literature, and carried out a meta-analysis to determine the usefulness of MTWA for risk evaluation. 2. Materials and methods 2.1. Search criteria We systematically searched for literature through PubMed, Embase, Web of Science and Cochrane database. The search was limited to full-text English and Chinese publications before March 2011. The following medical subject heading search terms were used: (1) ‘T-wave alternans’, TWA; (2) ‘ischemic’, ‘coronary artery disease’, ‘coronary heart disease’, ‘coronary disease’, ‘myocardial infarction’, or ‘coronary revascularization’. 2.2. Inclusion criteria We defined patients with ICM as cardiac catheterization with ≥50% stenosis in ≥ one coronary vessel, with positive finding nuclear perfusion imaging, with documented myocardial infarction, with history of coronary revascularization as well as left ventricular ejection fraction (LVEF) ≤ 40% [4,9,10]. The studies were included if they met the following criteria [5–7]: 1) were prospective cohort studies of ≥ 50 human subjects who underwent exercise- or pacing‐
0167-5273/$ – see front matter © 2012 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2012.05.050
Please cite this article as: Chen Z., et al, Microvolt T-wave alternans for risk stratification of cardiac events in ischemic cardiomyopathy: A meta-analysis, Int J Cardiol (2012), doi:10.1016/j.ijcard.2012.05.050
2
Z. Chen et al. / International Journal of Cardiology xxx (2012) xxx–xxx
induced MTWA testing for the prediction of clinical outcomes; 2) human participants with ICM without any history of malignant arrhythmic event (excluded nonsustained ventricular tachycardia), cardiac arrest or unexplained syncope; 3) provided primary data on results of MTWA and of clinical outcomes, including all-cause mortality, SCD, cardiac death, sustained ventricular arrhythmias, and/or appropriate ICD discharge; and 4) had a follow-up time of more than six months. We also decided to include those studies which had just mentioned ‘TWA’, other than ‘MTWA’, if the ‘TWA’ could be identified as ‘MTWA’ by testing methods and their conference values [11]. Patients were excluded if they had unstable coronary artery disease, New York Heart Association functional class IV heart failure, myocardial infarction within 28 days, permanent atrial fibrillation or took an antiarrhythmic drug at baseline (β-block agent excluded) [3].
2.6. Publication bias analysis The funnel plot was used to discriminate the publication bias. Fail-safe number was calculated by following methods, when P = 0.05 or 0.01. 2
2
Nfs0:05 ¼ ð∑Z=1:64Þ −S; Nfs0:01 ¼ ð∑Z=2:33Þ −S
3. Results 3.1. Study characteristics
A quality analysis was performed based on the following assessment of the articles: 1) the follow-up completed was beyond 90% of the cohort, 2) the outcome judgment was blinded to the results of MTWA testing, and 3) a multivariate analysis using other standard predictors of cardiac events was performed. A study was considered fair quality if it fulfilled the first criteria. A study was considered good if one of the other two was met [6].
After screening of all literature, we identified 7 prospective cohort studies involving a total of 3385 participants (Fig. 1). Besides which, we tried to contact the authors of two other studies [12,13] to resolve important ambiguities, but failed to receive the original data. Therefore, these two studies were not included in our current analysis. The characteristics of included studies are presented in Table 1. No randomized controlled trials examining MTWA in primary prevention were identified. In one study [14], there were two sub-groups of which included patients received ICD or no ICD respectively. There was no data of VT/VF in the group of no ICD, so we analyzed the study as two studies: Chow et al. [14]—ICD, and Chow et al. [14]— non ICD. Six of these studies were classified as being of good quality, and the remaining one was of moderate quality. Differences existed in the categorization schemes of MTWA test results and in the percentage of patients in the different MTWA categories (Table 1). Of all patients, 2277 had a non-negative MTWA test, 1108 had a negative test.
2.5. Statistical analysis
3.2. Results of the meta-analyses
Our primary analysis examined MTWA as a predictor of a composite endpoint of cardiac mortality or severe arrhythmic events in primary prevention of patients with ICM. In a secondary analysis, we examined the use of MTWA uniquely as a predictor of all-cause mortality (cardiac death, and/or non-cardiac death). We carried out separate meta-analyses compared with each pair of MTWA categories in terms of risk ratios for each endpoint. Statistical analysis was performed using the Review Manager 5.0 free ware package. A test for homogeneity using the Mantel–Haenszel method was performed for all summary estimates to evaluate the uniformity of findings across studies. A p value b 0.10 was considered statistically significant to reject the null hypothesis of the test of homogeneity.
In our primary analysis of the composite endpoint of mortality and malignant arrhythmia, we pooled data across studies to investigate the predictive ability of MTWA. The risk of cardiac mortality or malignant arrhythmic events with non-negative MTWA was increased compared to negative test group (RR = 1.65, 95%CrI = 1.32, 2.071) (Fig. 2). Similar results were obtained about the risk of sudden cardiac death between non-negative MTWA group and negative MTWA group (SCD RR = 2.04 95%CrI = 1.11, 3.75) (Fig. 3). When we examined MTWA as a predictor of all-cause mortality in the second
2.3. Data abstraction Two authors (Chen and Shi) selected those articles systematically (Fig. 1), and extracted the data which included study design, study finding, inclusion and exclusion criteria, details regarding MTWA testing (including definition of abnormal test) and classification of results, baseline demographic and clinical characteristics of participants, duration of follow-up, endpoints evaluated, multivariable analyses, and main conclusions. When there were different estimated results from more than one follow-up time periods in one study (e.g. at 1 year and 2 years), we used the ones from the longer follow-up period.
2.4. Quality analysis of study
Fig. 1. Flow diagram of systematic literature search, study selection, and reasons for exclusion.
Please cite this article as: Chen Z., et al, Microvolt T-wave alternans for risk stratification of cardiac events in ischemic cardiomyopathy: A meta-analysis, Int J Cardiol (2012), doi:10.1016/j.ijcard.2012.05.050
Z. Chen et al. / International Journal of Cardiology xxx (2012) xxx–xxx
3
Table 1 Characteristics of prospective cohort studies examining microvolt T-wave alternans and baseline patient characteristics. Included study
Sample size
Men (%)
Age (mean ± SD, year)
LVEF (mean ± SD, %)
Follow-up (mean ± SD, months)
Quality score
Rashba et al. [15] Bloomfield et al. [16] Chow et al. [14]—ICD Chow et al. [14]—no ICD Zacks et al. [10] Chow et al. [8] Chan et al. [9] Costantini et al. [3]
144 177 382 376 387 575 768 566
81 85 86 79 66 84 82 84
64 ± 10 61 ± 9.6 66.9 ± 9.8 67.5 ± 10.8 66.3 ± 11.7 65 ± 11 67.1 ± 10.4 65.4 ± 10
28 ± 7 23 ± 6 26.3 ± 6.0 28.3 ± 6.1 29.8 ± 8.6 24.0 ± 4.8 27.2 ± 6.1 28 ± 8
42 ± 32 20 ± 6 18 ± 10
Good Good Good
33 ± 17 25 ± 11 18 ± 10 19 ± 7
Moderate Good Good Good
analysis, again similar results were obtained. Compared to negative MTWA, the risk of all-cause mortality with non-negative MTWA was increased significantly (RR = 2.11, 95%CrI = 1.60, 2.79) (Fig. 4). 3.3. Discriminate the publication bias The funnel plot revealed that there may be publication bias. The number of fail-safe of composite endpoint and all-cause mortality was 14.42 and 18.93, respectively (P = 0.01). The number of failsafe of SCD was 1.07 (P = 0.05). 4. Discussion Our current systematic review and meta-analysis examined MTWA as a predictor of mortality and malignant arrhythmic events for primary prevention in patients with ICM. And our data demonstrated that nonnegative MTWA predicts an increased risk of mortality and malignant arrhythmic events as compared to negative counterpart. MTWA may therefore have some clinical utility as a stratification tool to assess short- to moderate-term risk in high-risk primary prevention populations. It may be helpful to reduce the economic burden associated with the prevention of arrhythmic events by ICD implantation. Several meta-analyses tried to demonstrate the correlation between MTWA and the risk of mortality and/or arrhythmic events [5–7]. These meta-analyses included a wide variety of patient populations, such as ICD recipients, nonischemic congestive heart failure (CHF), CHF, post-myocardial infarction (MI), healthy and athletic heart. In comparison with these previous meta-analyses, our current report included only patient populations with ICM. This study is therefore more homogenous and specifically addresses the usefulness of MTWA in high-risk primary prevention. The credible interval of RR in the study of van der Avoort et al. [5], was wide. This suggested the clinical value of MTWA may range from very modest to substantial and highlighted the need for additional high-quality studies to better
Study or Subgroup
refine these estimates. However, the credible interval in our analysis is narrow due to the homogeneousness of the patient populations included. Our meta-analysis is the first systematic review and meta-analysis that focuses on the use of MTWA in the setting of primary prevention in patients with ICM. By excluding studies of healthy and nonischemic individuals, we provide a more valid measurement of MTWA predictive value as it pertains to clinical practice. There was a meta-analysis [6] which found no difference in the predictive value of MTWA between patients with ischemic and nonischemic CHF. But that analysis included only two studies [15,16] and it had a low credit. The present analysis demonstrated that non-negative MTWA increased SCD with a low fail-safe number, 1.07 (when P = 0.05). This may be caused by the small case number of included studies and the characters of patients included. Chow T, 2006-ICD [14] and Chow T, 2008 [8] studied the patients with ICD implant, while the Chow T, 2006-non ICD [14] without the ICD. Fig. 3 showed that there was no significant difference between non-negative and negative MTWA with ICD, but to those patients without ICD, SCD increased in non-negative MTWA group substantially. So ICD attenuated the prognosis of MTWA to SCD. The potential mechanism for this result might be that ICDs stopped VT/VF, and reduced SCD. More studies should be performed to examine the effects of ICD on the predictive value of MTWA to SCD. MTWA is a predictor of cardiac events, but whether the predictive value of MTWA is time-dependent remains unclear. One study [3] showed that the prognostic ability of MTWA appeared to diminish after 1 year of follow-up. However, another study [9] showed no significant difference of the prognostic ability during 3 years of followup. There was no formal statistical testing for an interaction between MTWA and time period, and it may not be realistic to expect a single MTWA test to predict outcome in patients with a changing disease state [17,18]. Although some have recommended rescreening at
non-negative negative
Risk Ratio
Risk Ratio
Events
M-H, Fixed, 95% CI
M-H, Fixed, 95% CI
Total Events Total Weight
Chan PS, 2008
51
514
7
254
8.2%
3.60 [1.66, 7.82]
Chow T 2006-ICD
35
317
5
75
7.1%
1.66 [0.67, 4.08]
Chow T, 2008
67
361
28
214
30.9%
1.42 [0.94, 2.13]
Costantini O, 2009
49
401
16
165
19.9%
1.26 [0.74, 2.15]
Rashba EJ, 2004
37
106
6
38
7.8%
2.21 [1.01, 4.82]
Zacks ES, 2007
65
260
22
127
26.0%
1.44 [0.93, 2.23]
873 100.0%
1.65 [1.32, 2.07]
Total (95% CI) Total events
1959 304
84
Heterogeneity: Chi² = 6.31, df = 5 (P = 0.28); I² = 21% Test for overall effect: Z = 4.34 (P < 0.0001)
0.05 0.2 1 5 20 Favours negative Favours non-negative
Fig. 2. Forest plot of the risk of composite endpoint (cardiac mortality or severe arrhythmias) among those with a non-negative microvolt T-wave alternans test compared with those with a negative microvolt T-wave alternans test.
Please cite this article as: Chen Z., et al, Microvolt T-wave alternans for risk stratification of cardiac events in ischemic cardiomyopathy: A meta-analysis, Int J Cardiol (2012), doi:10.1016/j.ijcard.2012.05.050
4
Z. Chen et al. / International Journal of Cardiology xxx (2012) xxx–xxx
non-negative Study or Subgroup
Events
negative
Risk Ratio
Total Events Total Weight
Risk Ratio
M-H, Fixed, 95% CI
Chow T 2006-ICD
11
317
3
75
32.6%
0.87 [0.25, 3.03]
Chow T 2006-no ICD
22
197
6
179
42.2%
3.33 [1.38, 8.03]
7
361
3
214
25.3%
1.38 [0.36, 5.29]
468 100.0%
2.04 [1.11, 3.75]
Chow T, 2008 Total (95% CI) Total events
875 40
M-H, Fixed, 95% CI
12
Heterogeneity: Chi² = 3.31, df = 2 (P = 0.19); I² = 40%
0.05
Test for overall effect: Z = 2.28 (P = 0.02)
0.2 1 5 20 Favours negative Favours non-negative
Fig. 3. Forest plot of the risk of SCD among those with a non-negative microvolt T-wave alternans test compared with those with a negative microvolt T-wave alternans test.
regular time intervals, the optimal timing for retesting has not been established.
Acknowledgment The authors of this manuscript have certified that they comply with the principles of ethical publishing in the International Journal of Cardiology [19].
4.1. Limitations of the trial First, there is slight difference in inclusion criteria between different studies. For example, patients of the ABCD trial [3] were selected on the basis of LVEF ≤ 0.40, raising the possibility that these patients might have been at somewhat lower risk than those currently selected for ICD insertion on the basis of LVEF ≤ 0.35. In addition, some patients have the history of non-continuous ventricular tachycardia, this will increase the risk of cardiac events. Second, we could not analyze the end points of ventricular arrhythmias because there were not enough data. However, we avoided another limitation which existed in prior meta-analyses [5–7]. In those analyses, the outcomes in individual studies were variable (e.g., cardiac death, SCD/VT/VF, syncope or ICD events). It may be more clinically applicable for future studies of MTWA to use the end point of ventricular arrhythmias.
5. Conclusions After studying the usefulness of MTWA as a risk predictor of ICM in a meta-analysis of 3385 subjects, we found that the non-negative of MTWA predicted a nearly double the risk of serious heart events compared with the absence of MTWA. Therefore, MTWA represents a potential useful tool for judging the severity of ICM. Our study helps to understand the value and the disadvantage of MTWA testing. Further study of the combined predictive value of several methods of risk stratification including MTWA with adequate follow-up and appropriate end points is required.
non-negative
negative
References [1] Zipes DP, Camm J, Borggrefe M, et al. ACC/AHA/ESC 2006 guidelines for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: a report of the American College of Cardiology/American Heart Association Task Force and the European Society of Cardiology Committee for Practice Guidelines (writing committee to develop guidelines for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death). Circulation 2006;114:e385–484. [2] Exner DV, Kavanagh KM, Slawnych MP, et al. Noninvasive risk assessment early after a myocardial infarction the REFINE study. J Am Coll Cardiol 2007;50: 2275–84. [3] Costantini O, Hohnloser SH, Kirk MM, et al. The ABCD (Alternans Before Cardioverter Defibrillator) Trial: strategies using T-wave alternans to improve efficiency of sudden cardiac death prevention. J Am Coll Cardiol 2009;53:471–9. [4] 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;263:125–6. [5] van der Avoort CJ, Filion KB, Dendukuri N, Brophy JM. Microvolt T-wave alternans as a predictor of mortality and severe arrhythmias in patients with leftventricular dysfunction: a systematic review and meta-analysis. BMC Cardiovasc Disord 2009;28(9):5. [6] 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. [7] Calò L, De Santo T, Nuccio F, et al. Predictive value of microvolt T-wave alternans for cardiac death or ventricular tachyarrhythmic events in ischemic and nonischemic cardiomyopathy patients: a meta-analysis. Ann Noninvasive Electrocardiol 2011;16:388–402. [8] Chow T, Kereiakes DJ, Onufer J, et al. 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. J Am Coll Cardiol 2008;52:1607–15.
Risk Ratio
Study or Subgroup
Events
Bloomfield DM, 2004
21
121
2
56
3.8%
4.86 [1.18, 20.01]
Chan PS, 2008
78
514
21
254
38.7%
1.84 [1.16, 2.90]
Chow T 2006-ICD
35
317
6
75
13.4%
1.38 [0.60, 3.16]
Chow T 2006-no ICD
43
197
15
179
21.7%
2.60 [1.50, 4.52]
Chow T, 2008
46
361
13
214
22.5%
2.10 [1.16, 3.79]
778 100.0%
2.11 [1.60, 2.79]
Total (95% CI) Total events
Total Events Total Weight
1510 223
Risk Ratio M-H, Fixed, 95% CI
57
Heterogeneity: Chi² = 3.26, df = 4 (P = 0.51); I² = 0% Test for overall effect: Z = 5.29 (P < 0.00001)
M-H, Fixed, 95% CI
0.05 0.2 1 5 20 Favours negative Favours non-negative
Fig. 4. Forest plot of the risk of all-cause mortality among those with a non-negative microvolt T-wave alternans test compared with those with a negative microvolt T-wave alternans test.
Please cite this article as: Chen Z., et al, Microvolt T-wave alternans for risk stratification of cardiac events in ischemic cardiomyopathy: A meta-analysis, Int J Cardiol (2012), doi:10.1016/j.ijcard.2012.05.050
Z. Chen et al. / International Journal of Cardiology xxx (2012) xxx–xxx [9] Chan PS, Kereiakes DJ, Bartone C, Chow T. Usefulness of microvolt T-wave alternans to predict outcomes in patients with ischemic cardiomyopathy beyond one year. Am J Cardiol 2008;102:280–4. [10] Zacks ES, Morin DP, Ageno S, et al. Effect of oral beta-blocker therapy on microvolt T-wave alternans and electrophysiology testing in patients with ischemic cardiomyopathy. Am Heart J 2007;153:392–7. [11] Bloomfield DM, Hohnloser SH, Cohen RJ. Interpretation and classification of microvolt T wave alternans tests. J Cardiovasc Electrophysiol 2002;13:502–12. [12] Rashba EJ, Osman AF, MacMurdy K, et al. Exercise is superior to pacing for T wave alternans measurement in subjects with chronic coronary artery disease and left ventricular dysfunction. J Cardiovasc Electrophysiol 2002;13:845–50. [13] Huikuri HV, Raatikainen MJ, Moerch-Joergensen R, et al. Prediction of fatal or near-fatal cardiac arrhythmia events in patients with depressed left ventricular function after an acute myocardial infarction. Eur Heart J 2009;30:689–98. [14] Chow T, Kereiakes DJ, Bartone C, et al. Prognostic utility of microvolt T-wave alternans in risk stratification of patients with ischemic cardiomyopathy. J Am Coll Cardiol 2006;47:1820–7.
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[15] Rashba EJ, Osman AF, Macmurdy K, et al. Enhanced detection of arrhythmia vulnerability using T wave alternans, left ventricular ejection fraction, and programmed ventricular stimulation: a prospective study in subjects with chronic ischemic heart disease. J Cardiovasc Electrophysiol 2004;15:170–6. [16] Bloomfield DM, Steinman RC, Namerow PB, et al. 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: 1885–9. [17] Madias JE. Letter by Madias regarding article, “Role of microvolt T-wave alternans in assessment of arrhythmia vulnerability among patients with heart failure and systolic dysfunction: primary results from the T-wave alternans sudden cardiac death in heart failure trial substudy”. Circulation 2009;120:e21. [18] Madias JE. Microvolt T-wave alternans: is there anything that can be done to save it? J Am Coll Cardiol 2009;53:1245–6. [19] Coats AJ, Shewan LG. Ethics in the authorship and publishing of scientific articles. Int J Cardiol 2011;153:239–40.
Please cite this article as: Chen Z., et al, Microvolt T-wave alternans for risk stratification of cardiac events in ischemic cardiomyopathy: A meta-analysis, Int J Cardiol (2012), doi:10.1016/j.ijcard.2012.05.050
Contents lists available at SciVerse ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Microvolt T-wave alternans for risk stratification of cardiac events in ischemic cardiomyopathy: A meta-analysis Zhen Chen a, b, Yue Shi a, Xiaofeng Hou a, Shudong Xu b, Jiangang Zou b,⁎ a b
Division of Cardiology, First Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu, China Division of Cardiology, Taixing Hospital, Taixing, Jiangsu, China
a r t i c l e
i n f o
Article history: Received 27 June 2011 Received in revised form 4 November 2011 Accepted 11 May 2012 Available online xxxx Keywords: Microvolt T-wave alternans Ischemic cardiomyopathy Cardiac mortality Arrhythmia Meta-analysis
a b s t r a c t Background: The ability of microvolt T-wave alternans (MTWA) for risk stratification of cardiac events in patients with ischemic cardiomyopathy (ICM) has not been well established. Methods: The authors systematically reviewed current literature and carried out a meta-analysis to determine the ability of MTWA to predict the outcome severity after ICM. Major endpoints include composite endpoint of cardiac mortality and severe arrhythmic events in primary prevention of patients with ICM, as well as all-cause mortality (cardiac death, and/or non-cardiac death). Results: Seven trials were included by using MTWA for risk stratification of cardiac events in 3385 patients with ICM. All patients were distributed into two groups according to the results of MTWA tests: nonnegative group included positive and indeterminate, and negative group. Compared with the negative group, non-negative group showed increased rates of cardiac mortality or severe arrhythmic events (RR = 1.65, 95%CrI = 1.32, 2.071), sudden cardiac death (SCD) (RR = 2.04 95%CrI = 1.11, 3.75), and allcause mortality (RR = 2.11, 95%CrI = 1.60, 2.79). The funnel plot revealed that there might be bias within current publications. The fail-safe number of composite endpoint and all-cause mortality was 14.42 and 18.93, respectively (when P = 0.01). The fail-safe number of SCD was 1.07 (when P = 0.05), which may be caused by the small case number of included studies and some patients with ICD included. Conclusions: The non-negative group of MTWA had a nearly double risk of severe outcomes compared with the negative group. Therefore, MTWA represents a potential useful tool for judging the severity of ICM. © 2012 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Sudden cardiac death (SCD) is defined as unexpected death resulting from a cardiac cause, usually within one hour after the onset of symptoms. The most common arrhythmias precipitating SCD are ventricular fibrillation and pulseless ventricular tachycardia [1]. Although patients with preserved LV function after myocardial infarction (MI) are at extremely low risk of serious cardiac events [2], for those patients with at least mild LV dysfunction, the outcomes after ischemic cardiomyopathy (ICM) becomes variable and reliable risk assessment method is remained to be developed. Some studies including several meta-analyses [3–7] suggested that MTWA may be helpful for risk stratification of cardiac death or a ventricular tachyarrhymic event and identified subsets of ICM patients least likely to benefit from implantable cardioverter defibrillator (ICD) insertion. These suggest that MTWA may be considered as a practical tool for ICM outcome assessment. However, controversial results ⁎ Corresponding author at: Division of Cardiology, First Affiliated Hospital of Nanjing Medical University, 140 Hanzhong Avenue, Nanjing, Jiangsu 210009, China. Tel.: + 86 025 68136438; fax: + 86 025 83674656. E-mail address: [email protected] (J. Zou).
were obtained in another large scale study [8]. To further clarify whether MTWA is beneficial for evaluating of the severity of ICM or not, we systematically reviewed currently available medical literature, and carried out a meta-analysis to determine the usefulness of MTWA for risk evaluation. 2. Materials and methods 2.1. Search criteria We systematically searched for literature through PubMed, Embase, Web of Science and Cochrane database. The search was limited to full-text English and Chinese publications before March 2011. The following medical subject heading search terms were used: (1) ‘T-wave alternans’, TWA; (2) ‘ischemic’, ‘coronary artery disease’, ‘coronary heart disease’, ‘coronary disease’, ‘myocardial infarction’, or ‘coronary revascularization’. 2.2. Inclusion criteria We defined patients with ICM as cardiac catheterization with ≥50% stenosis in ≥ one coronary vessel, with positive finding nuclear perfusion imaging, with documented myocardial infarction, with history of coronary revascularization as well as left ventricular ejection fraction (LVEF) ≤ 40% [4,9,10]. The studies were included if they met the following criteria [5–7]: 1) were prospective cohort studies of ≥ 50 human subjects who underwent exercise- or pacing‐
0167-5273/$ – see front matter © 2012 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2012.05.050
Please cite this article as: Chen Z., et al, Microvolt T-wave alternans for risk stratification of cardiac events in ischemic cardiomyopathy: A meta-analysis, Int J Cardiol (2012), doi:10.1016/j.ijcard.2012.05.050
2
Z. Chen et al. / International Journal of Cardiology xxx (2012) xxx–xxx
induced MTWA testing for the prediction of clinical outcomes; 2) human participants with ICM without any history of malignant arrhythmic event (excluded nonsustained ventricular tachycardia), cardiac arrest or unexplained syncope; 3) provided primary data on results of MTWA and of clinical outcomes, including all-cause mortality, SCD, cardiac death, sustained ventricular arrhythmias, and/or appropriate ICD discharge; and 4) had a follow-up time of more than six months. We also decided to include those studies which had just mentioned ‘TWA’, other than ‘MTWA’, if the ‘TWA’ could be identified as ‘MTWA’ by testing methods and their conference values [11]. Patients were excluded if they had unstable coronary artery disease, New York Heart Association functional class IV heart failure, myocardial infarction within 28 days, permanent atrial fibrillation or took an antiarrhythmic drug at baseline (β-block agent excluded) [3].
2.6. Publication bias analysis The funnel plot was used to discriminate the publication bias. Fail-safe number was calculated by following methods, when P = 0.05 or 0.01. 2
2
Nfs0:05 ¼ ð∑Z=1:64Þ −S; Nfs0:01 ¼ ð∑Z=2:33Þ −S
3. Results 3.1. Study characteristics
A quality analysis was performed based on the following assessment of the articles: 1) the follow-up completed was beyond 90% of the cohort, 2) the outcome judgment was blinded to the results of MTWA testing, and 3) a multivariate analysis using other standard predictors of cardiac events was performed. A study was considered fair quality if it fulfilled the first criteria. A study was considered good if one of the other two was met [6].
After screening of all literature, we identified 7 prospective cohort studies involving a total of 3385 participants (Fig. 1). Besides which, we tried to contact the authors of two other studies [12,13] to resolve important ambiguities, but failed to receive the original data. Therefore, these two studies were not included in our current analysis. The characteristics of included studies are presented in Table 1. No randomized controlled trials examining MTWA in primary prevention were identified. In one study [14], there were two sub-groups of which included patients received ICD or no ICD respectively. There was no data of VT/VF in the group of no ICD, so we analyzed the study as two studies: Chow et al. [14]—ICD, and Chow et al. [14]— non ICD. Six of these studies were classified as being of good quality, and the remaining one was of moderate quality. Differences existed in the categorization schemes of MTWA test results and in the percentage of patients in the different MTWA categories (Table 1). Of all patients, 2277 had a non-negative MTWA test, 1108 had a negative test.
2.5. Statistical analysis
3.2. Results of the meta-analyses
Our primary analysis examined MTWA as a predictor of a composite endpoint of cardiac mortality or severe arrhythmic events in primary prevention of patients with ICM. In a secondary analysis, we examined the use of MTWA uniquely as a predictor of all-cause mortality (cardiac death, and/or non-cardiac death). We carried out separate meta-analyses compared with each pair of MTWA categories in terms of risk ratios for each endpoint. Statistical analysis was performed using the Review Manager 5.0 free ware package. A test for homogeneity using the Mantel–Haenszel method was performed for all summary estimates to evaluate the uniformity of findings across studies. A p value b 0.10 was considered statistically significant to reject the null hypothesis of the test of homogeneity.
In our primary analysis of the composite endpoint of mortality and malignant arrhythmia, we pooled data across studies to investigate the predictive ability of MTWA. The risk of cardiac mortality or malignant arrhythmic events with non-negative MTWA was increased compared to negative test group (RR = 1.65, 95%CrI = 1.32, 2.071) (Fig. 2). Similar results were obtained about the risk of sudden cardiac death between non-negative MTWA group and negative MTWA group (SCD RR = 2.04 95%CrI = 1.11, 3.75) (Fig. 3). When we examined MTWA as a predictor of all-cause mortality in the second
2.3. Data abstraction Two authors (Chen and Shi) selected those articles systematically (Fig. 1), and extracted the data which included study design, study finding, inclusion and exclusion criteria, details regarding MTWA testing (including definition of abnormal test) and classification of results, baseline demographic and clinical characteristics of participants, duration of follow-up, endpoints evaluated, multivariable analyses, and main conclusions. When there were different estimated results from more than one follow-up time periods in one study (e.g. at 1 year and 2 years), we used the ones from the longer follow-up period.
2.4. Quality analysis of study
Fig. 1. Flow diagram of systematic literature search, study selection, and reasons for exclusion.
Please cite this article as: Chen Z., et al, Microvolt T-wave alternans for risk stratification of cardiac events in ischemic cardiomyopathy: A meta-analysis, Int J Cardiol (2012), doi:10.1016/j.ijcard.2012.05.050
Z. Chen et al. / International Journal of Cardiology xxx (2012) xxx–xxx
3
Table 1 Characteristics of prospective cohort studies examining microvolt T-wave alternans and baseline patient characteristics. Included study
Sample size
Men (%)
Age (mean ± SD, year)
LVEF (mean ± SD, %)
Follow-up (mean ± SD, months)
Quality score
Rashba et al. [15] Bloomfield et al. [16] Chow et al. [14]—ICD Chow et al. [14]—no ICD Zacks et al. [10] Chow et al. [8] Chan et al. [9] Costantini et al. [3]
144 177 382 376 387 575 768 566
81 85 86 79 66 84 82 84
64 ± 10 61 ± 9.6 66.9 ± 9.8 67.5 ± 10.8 66.3 ± 11.7 65 ± 11 67.1 ± 10.4 65.4 ± 10
28 ± 7 23 ± 6 26.3 ± 6.0 28.3 ± 6.1 29.8 ± 8.6 24.0 ± 4.8 27.2 ± 6.1 28 ± 8
42 ± 32 20 ± 6 18 ± 10
Good Good Good
33 ± 17 25 ± 11 18 ± 10 19 ± 7
Moderate Good Good Good
analysis, again similar results were obtained. Compared to negative MTWA, the risk of all-cause mortality with non-negative MTWA was increased significantly (RR = 2.11, 95%CrI = 1.60, 2.79) (Fig. 4). 3.3. Discriminate the publication bias The funnel plot revealed that there may be publication bias. The number of fail-safe of composite endpoint and all-cause mortality was 14.42 and 18.93, respectively (P = 0.01). The number of failsafe of SCD was 1.07 (P = 0.05). 4. Discussion Our current systematic review and meta-analysis examined MTWA as a predictor of mortality and malignant arrhythmic events for primary prevention in patients with ICM. And our data demonstrated that nonnegative MTWA predicts an increased risk of mortality and malignant arrhythmic events as compared to negative counterpart. MTWA may therefore have some clinical utility as a stratification tool to assess short- to moderate-term risk in high-risk primary prevention populations. It may be helpful to reduce the economic burden associated with the prevention of arrhythmic events by ICD implantation. Several meta-analyses tried to demonstrate the correlation between MTWA and the risk of mortality and/or arrhythmic events [5–7]. These meta-analyses included a wide variety of patient populations, such as ICD recipients, nonischemic congestive heart failure (CHF), CHF, post-myocardial infarction (MI), healthy and athletic heart. In comparison with these previous meta-analyses, our current report included only patient populations with ICM. This study is therefore more homogenous and specifically addresses the usefulness of MTWA in high-risk primary prevention. The credible interval of RR in the study of van der Avoort et al. [5], was wide. This suggested the clinical value of MTWA may range from very modest to substantial and highlighted the need for additional high-quality studies to better
Study or Subgroup
refine these estimates. However, the credible interval in our analysis is narrow due to the homogeneousness of the patient populations included. Our meta-analysis is the first systematic review and meta-analysis that focuses on the use of MTWA in the setting of primary prevention in patients with ICM. By excluding studies of healthy and nonischemic individuals, we provide a more valid measurement of MTWA predictive value as it pertains to clinical practice. There was a meta-analysis [6] which found no difference in the predictive value of MTWA between patients with ischemic and nonischemic CHF. But that analysis included only two studies [15,16] and it had a low credit. The present analysis demonstrated that non-negative MTWA increased SCD with a low fail-safe number, 1.07 (when P = 0.05). This may be caused by the small case number of included studies and the characters of patients included. Chow T, 2006-ICD [14] and Chow T, 2008 [8] studied the patients with ICD implant, while the Chow T, 2006-non ICD [14] without the ICD. Fig. 3 showed that there was no significant difference between non-negative and negative MTWA with ICD, but to those patients without ICD, SCD increased in non-negative MTWA group substantially. So ICD attenuated the prognosis of MTWA to SCD. The potential mechanism for this result might be that ICDs stopped VT/VF, and reduced SCD. More studies should be performed to examine the effects of ICD on the predictive value of MTWA to SCD. MTWA is a predictor of cardiac events, but whether the predictive value of MTWA is time-dependent remains unclear. One study [3] showed that the prognostic ability of MTWA appeared to diminish after 1 year of follow-up. However, another study [9] showed no significant difference of the prognostic ability during 3 years of followup. There was no formal statistical testing for an interaction between MTWA and time period, and it may not be realistic to expect a single MTWA test to predict outcome in patients with a changing disease state [17,18]. Although some have recommended rescreening at
non-negative negative
Risk Ratio
Risk Ratio
Events
M-H, Fixed, 95% CI
M-H, Fixed, 95% CI
Total Events Total Weight
Chan PS, 2008
51
514
7
254
8.2%
3.60 [1.66, 7.82]
Chow T 2006-ICD
35
317
5
75
7.1%
1.66 [0.67, 4.08]
Chow T, 2008
67
361
28
214
30.9%
1.42 [0.94, 2.13]
Costantini O, 2009
49
401
16
165
19.9%
1.26 [0.74, 2.15]
Rashba EJ, 2004
37
106
6
38
7.8%
2.21 [1.01, 4.82]
Zacks ES, 2007
65
260
22
127
26.0%
1.44 [0.93, 2.23]
873 100.0%
1.65 [1.32, 2.07]
Total (95% CI) Total events
1959 304
84
Heterogeneity: Chi² = 6.31, df = 5 (P = 0.28); I² = 21% Test for overall effect: Z = 4.34 (P < 0.0001)
0.05 0.2 1 5 20 Favours negative Favours non-negative
Fig. 2. Forest plot of the risk of composite endpoint (cardiac mortality or severe arrhythmias) among those with a non-negative microvolt T-wave alternans test compared with those with a negative microvolt T-wave alternans test.
Please cite this article as: Chen Z., et al, Microvolt T-wave alternans for risk stratification of cardiac events in ischemic cardiomyopathy: A meta-analysis, Int J Cardiol (2012), doi:10.1016/j.ijcard.2012.05.050
4
Z. Chen et al. / International Journal of Cardiology xxx (2012) xxx–xxx
non-negative Study or Subgroup
Events
negative
Risk Ratio
Total Events Total Weight
Risk Ratio
M-H, Fixed, 95% CI
Chow T 2006-ICD
11
317
3
75
32.6%
0.87 [0.25, 3.03]
Chow T 2006-no ICD
22
197
6
179
42.2%
3.33 [1.38, 8.03]
7
361
3
214
25.3%
1.38 [0.36, 5.29]
468 100.0%
2.04 [1.11, 3.75]
Chow T, 2008 Total (95% CI) Total events
875 40
M-H, Fixed, 95% CI
12
Heterogeneity: Chi² = 3.31, df = 2 (P = 0.19); I² = 40%
0.05
Test for overall effect: Z = 2.28 (P = 0.02)
0.2 1 5 20 Favours negative Favours non-negative
Fig. 3. Forest plot of the risk of SCD among those with a non-negative microvolt T-wave alternans test compared with those with a negative microvolt T-wave alternans test.
regular time intervals, the optimal timing for retesting has not been established.
Acknowledgment The authors of this manuscript have certified that they comply with the principles of ethical publishing in the International Journal of Cardiology [19].
4.1. Limitations of the trial First, there is slight difference in inclusion criteria between different studies. For example, patients of the ABCD trial [3] were selected on the basis of LVEF ≤ 0.40, raising the possibility that these patients might have been at somewhat lower risk than those currently selected for ICD insertion on the basis of LVEF ≤ 0.35. In addition, some patients have the history of non-continuous ventricular tachycardia, this will increase the risk of cardiac events. Second, we could not analyze the end points of ventricular arrhythmias because there were not enough data. However, we avoided another limitation which existed in prior meta-analyses [5–7]. In those analyses, the outcomes in individual studies were variable (e.g., cardiac death, SCD/VT/VF, syncope or ICD events). It may be more clinically applicable for future studies of MTWA to use the end point of ventricular arrhythmias.
5. Conclusions After studying the usefulness of MTWA as a risk predictor of ICM in a meta-analysis of 3385 subjects, we found that the non-negative of MTWA predicted a nearly double the risk of serious heart events compared with the absence of MTWA. Therefore, MTWA represents a potential useful tool for judging the severity of ICM. Our study helps to understand the value and the disadvantage of MTWA testing. Further study of the combined predictive value of several methods of risk stratification including MTWA with adequate follow-up and appropriate end points is required.
non-negative
negative
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Risk Ratio
Study or Subgroup
Events
Bloomfield DM, 2004
21
121
2
56
3.8%
4.86 [1.18, 20.01]
Chan PS, 2008
78
514
21
254
38.7%
1.84 [1.16, 2.90]
Chow T 2006-ICD
35
317
6
75
13.4%
1.38 [0.60, 3.16]
Chow T 2006-no ICD
43
197
15
179
21.7%
2.60 [1.50, 4.52]
Chow T, 2008
46
361
13
214
22.5%
2.10 [1.16, 3.79]
778 100.0%
2.11 [1.60, 2.79]
Total (95% CI) Total events
Total Events Total Weight
1510 223
Risk Ratio M-H, Fixed, 95% CI
57
Heterogeneity: Chi² = 3.26, df = 4 (P = 0.51); I² = 0% Test for overall effect: Z = 5.29 (P < 0.00001)
M-H, Fixed, 95% CI
0.05 0.2 1 5 20 Favours negative Favours non-negative
Fig. 4. Forest plot of the risk of all-cause mortality among those with a non-negative microvolt T-wave alternans test compared with those with a negative microvolt T-wave alternans test.
Please cite this article as: Chen Z., et al, Microvolt T-wave alternans for risk stratification of cardiac events in ischemic cardiomyopathy: A meta-analysis, Int J Cardiol (2012), doi:10.1016/j.ijcard.2012.05.050
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Please cite this article as: Chen Z., et al, Microvolt T-wave alternans for risk stratification of cardiac events in ischemic cardiomyopathy: A meta-analysis, Int J Cardiol (2012), doi:10.1016/j.ijcard.2012.05.050