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Prediction of Arrhythmic Events after Myocardial Infarction Based on Signal-Averaged Electrocardiogram and Ejection Fraction


From the *Department of General Internal Medicine, Inselspital University of Bern Hospital, Bern, Switzerland; †Department of Geriatrics, Inselspital University of Bern Hospital, Bern, Switzerland, ‡Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland; and §Department of Cardiology, Hospital Lucerne, Lucerne, Switzerland

Background: Trials on implantable cardioverter-defibrillators (ICD) for patients after acute myocardial infarction (AMI) have highlighted the need for risk assessment of arrhythmic events (AE). The aim of this study was to evaluate risk predictors based on a novel approach of interpreting signal-averaged electrocardiogram (SAECG) and ejection fraction (EF). Methods: SAECG, interpreted with a new index, and EF were prospectively evaluated to predict AE in 144 patients with AMI. Results: During the mean follow-up period of 4.1 years, 19 AE occurred. The new SAECG index showed a sensitivity of 84%, a specificity of 62%, a positive predictive value (PPV) of 25%, and a negative predictive value (NPV) of 96%. A combination of a normal new SAECG index and an EF >35% resulted in a sensitivity of 100%, a specificity of 47%, a PPV of 22%, and a NPV of 100%; this corresponded to an AE incidence rate of 0%. When both tests were abnormal, the AE incidence rate was 21.3%. Conclusions: This is the first contemporary study reporting predictive values based on a combination of SAECG and EF. If confirmed in an appropriately designed and powered trial, this novel approach might be used to identify both patients at very low risk for AE not requiring further risk assessment and patients at high risk in whom ICD implantation can be considered without further risk assessment. (PACE 2008;


signal-averaged electrocardiogram, ventricular dysfunction, left, arrhythmia, prognosis, mortality

Introduction Arrhythmic events (AE) causing sudden car- diac death (SCD) are a major risk after acute myocardial infarction (AMI). Several large tri- als showed an improved survival of patients with AMI and at high risk for AE after treat- ment with implantable cardioverter-defibrillators (ICD). 13 These trials have highlighted the need for development of tools to identify patients at risk for AE who might benefit from ICD implantation. There are two traditional tests having a proven, albeit limited, ability to predict AE: the signal-averaged electrocardiogram (SAECG) 414 and the ejection fraction (EF). 48,1416 Despite its high negative predictive value, the SAECG is not

Financial support. Andreas Schoenenberger was supported by a grant from the Robert Bosch Foundation (Stuttgart, Germany). All authors disclose all associations (either commercial or in- dustrial) that may pose a conflict of interest.

Address for reprints: Paul Erne, M.D., Department of Cardiol- ogy, Hospital Lucerne, CH-6000 Lucerne 16, Switzerland. Fax:

+41-41-2055109; e-mail: Paul.Erne@KSL.CH

Received April 4, 2007; revised October 5, 2007; accepted October 29, 2007.

commonly used in risk assessment algorithms, predominantly because of its low positive predic- tive value. Furthermore, most ICD trials used the EF rather than the SAECG as a predictor of AE. 13 EF and SAECG have a similar positive predictive value, but the negative predictive value of the EF is lower than that of the SAECG. 48,1417 Currently, no single test precisely predicts AE. Algorithms combining different tests are subject to an ongoing debate. 18 The optimal interpretation of the SAECG has been extensively debated. 414,1922 However, the commonly used algorithm of SAECG interpreta- tion may lead to a substantial information loss by its early dichotomization of the three SAECG vari- ables (the filtered QRS duration (fQRS), the root- mean-square voltage of the terminal QRS complex (RMS), and the duration of low-amplitude signals (LAS)). We hypothesized that a new index combin- ing the continuous information of the three SAECG variables to a new continuous variable would im- prove the prognostic value of the SAECG. One recent meta-analysis proposed combin- ing the SAECG and the EF as first steps of risk assessment because these two tests allow defini- tion of populations at very low risk and at high

C 2008, The Authors. Journal compilation

C 2008, Blackwell Publishing, Inc.

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risk not requiring further risk assessment. 17 The authors concluded that further studies investigat- ing a combination of both methods are needed. We have found only three studies that published quan- titative results on the combined prognostic value of SAECG and EF in patients after AMI. 4,7,14 Since these studies were conducted more than a decade ago with a lower proportion of acute reperfusion therapies, the ndings might not be applicable to- day. This study, therefore, evaluates the prognostic value of a new index for the SAECG interpretation and combines it with the EF as predictors of AE in a contemporary study population after AMI.

Methods Study Population and Data Acquisition

All patients treated at the Hospital of Lucerne (Switzerland) for an AMI and examined by SAECG after the AMI during two time periods (May 1995 to July 1998 and November 2003 to October 2005) were included in this study. AMI was dened as having typical chest pain of >30 minutes du- ration or ECG changes compatible with AMI, or both, and total serum creatin kinase levels at least twice the upper limit of normal range with ab- normal creatin kinase-MB or troponin levels. Dur- ing the rst time period, 82 patients were eligi- ble for inclusion. In this subsample 1, the SAECG of 69 patients (84.1%) qualied for the analysis; 11 patients (13.4%) with bundle-branch block or intraventricular conduction abnormalities (> 120 ms) and two patients (2.4%) with unreadable trac- ings (noise level > 0.7 µV) were excluded. Dur- ing the second time period, 89 patients were eligi- ble. In this subsample 2, the SAECG of 79 patients (88.8%) qualied for the analysis; eight patients (9.0%) with bundle-branch block or intraventric- ular conduction abnormalities (> 120 ms) and 2 patients (2.2%) with unreadable tracings (noise level > 0.7 µV) were excluded. All SAECG trac- ings were recorded with a commercially available system (CS 100, Schiller AG, Baar, Switzerland) 3 to 30 days after the AMI. 23 The three quantita- tive SAECG variables, fQRS, RMS, and LAS, were calculated by computer-derived algorithms. The EF was assessed by transthoracic echocardiogra- phy (Agilent SONOS 5500, Philips Medical Sys- tems, Zurich,¨ Switzerland). The regional ethical committee approved the study and each patient gave oral (subsample 1) or written (subsample 2) informed consent in order to comply with the Dec- laration of Helsinki.

Scoring of the SAECG and the EF

First, the SAECG was interpreted accord- ing to the commonly used algorithm that di- chotomizes the three SAECG variables at standard

cut points and then denes an abnormal SAECG as at least one abnormal SAECG variable. 414,1922 Dichotomization of the three SAECG variables was made according to the dened standards at fQRS > 114 ms, RMS < 20 µ V, and LAS > 37 ms. 414,1922 This denition was termed conventional scoring method. Second, the SAECG was scored with a new index, because the conventional scoring method may lead to a substantial information loss by di- chotomizing on the level of the single SAECG vari- ables. Based on the conventional scoring method,

a patient with the three SAECG variables near the

cut points, but just within the normal range, is classied as normal, whereas a patient with two clearly normal variables and one borderline patho- logical variable is classied as abnormal. To ad- dress this limitation, we derived a new index com- bining the continuous information of the three SAECG variables to a new continuous variable. It combines fQRS, RMS, and LAS by simple logarith- mic functions, which can be easily implemented in spreadsheet programs. This new index was de- veloped based on previous studies without using data from this study. 414,1922 The function con- tains two terms, one for fQRS and one for RMS and LAS combined, giving fQRS the approximate weight of RMS and LAS combined. The variable fQRS was attributed to this relatively high weight because in previous studies the duration of fQRS was found to be the most important predicting pa- rameter. 6,7,14,22 The exponents of the logarithmic functions contain the three variables of the SAECG and the corresponding cut point values (114 ms for fQRS, 20 µV for RMS, and 37 ms for LAS). The new index was dened as

Index = log(1.5 f QRS114 + 1)

+ log( (20RMS) 4 RMS 3.2

+ 1) log(1.1 L AS37 + 1).

This equation was developed based on the fol- lowing rationale: The rst-term results in rapidly increasing values for fQRS durations near 114 ms according to the decreasing survival with increas- ing fQRS. For RMS values, a lower survival was reported with low (< 20 µV) and with high volt- ages (> 50 µV); a better survival was found at inter- mediate levels. 6 The second term therefore shows

a U-shaped curve with high values for RMS volt-

ages below 20 µV and with slowly increasing val- ues for RMS voltages above 50 µ V. High LAS val- ues were found to be associated with an increased risk of AE. Therefore, low LAS values decrease the overall value of the second term while high LAS values increase it. For the analysis of its prog-

nostic value, the index was dichotomized at 0.12. This cut point was derived by determining the


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optimal cut-off based on the Cox proportional haz- ards model and corresponded to the cut-off that maximized the hazard ratio. The EF was dichotomized at the commonly used cut point of 35% with values below indicat- ing an abnormal EF. 13,15,16

Follow-Up and Definition of End-Point

The follow-up was obtained from several sources. In surviving patients, patient interviews were conducted. If there was evidence for a pos- sible AE, additional information was obtained from the general practitioner and/or hospital case records. In those patients who died during the follow-up period, additional information on the circumstances of death was collected by interview- ing the patients relatives (closest family member) and/or consulting national death registry records. In patients treated with an ICD, the ICD protocol was studied. AE constituted the end-point deni- tion, including SCD or documented conversions of a sustained ventricular tachycardia (VT) by an ICD or during resuscitation. Based on the Hinkle- Thaler method, 24 deaths from heart failure or car- diogenic shock due to AMI were not considered SCD. AE were independently classied by two specially trained physicians (blinded to baseline SAECG and EF information). In case of disagree- ment, a third physician was consulted.

Statistical Analysis

Data were analyzed using STATA software (Stata 8, StataCorp LP, College Station, TX, USA). The level of statistical signicance was xed at P < 0.05. Comparisons between groups were per- formed using the Students t-test for normally dis- tributed continuous variables and chi-square anal- ysis for categorical variables. Sensitivity, speci- city, positive predictive value (PPV), and neg- ative predictive value (NPV) were calculated for all dichotomized variables (conventional scoring method, new index, and EF). Kaplan-Meier func- tions were generated to illustrate the ability to stratify the risk. 25 Log-rank test was used to test equality of survivor functions. Cox proportional hazards models were used to calculate relative risks and 95% condence intervals for the com- parison of event rates. 25

Results Patient Characteristics

The mean age of all study participants was 59.4 ± 9.1 years (age range from 29.4 to 84.6 years) and 15 study participants (10.4%) were female. The clinical characteristics of all study partici- pants and separated for both subsamples are sum- marized in Table I. Both subsamples were similar except for differences in positive family history for

Table I.

Patient Characteristics


Both Subsamples (n = 144)

Subsample 1 (n = 69)

Subsample 2 (n = 75)

Mean age (years)

Heart rate (/min)

59.4 (± 9.1)

59.1 (± 9.5)

59.7 (± 8.8)

Male (%)




Height (cm) Weight (kg) BMI (kg/m 2 )

Cardiovascular risk factors

171.2 (± 7.4) 79.4 (± 12.2) 27.2 (± 3.6) 72.3 (± 17.0)

171.6 (± 7.5) 78.7 (±11.2) 26.7 (± 3.1) 70.4 (± 17.2)

170.8 (±7.5) 80.1 (± 14.1) 27.7 (± 4.3) 75.4 (± 16.6)

- Hypertension (%)




- Diabetes (%)




- Smoking (%)




- Hyperlipidemia (%)




- Family history (%)




Ejection fraction (%) Maximum CK (U/L)

42.5 (±11.3) 2,196 (± 2,179)

44.0 (± 11.1) 1,738 (± 1,710)

41.1 (± 11.4) 2,638 (± 2,664)

Acute PCI * (%)




Values are means (± standard deviation) or as indicated. * PCI within 24 hours after hospital admission. BMI = body mass index; CK = creatine kinase; PCI = percutaneous coronary intervention.

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coronary artery disease (P = 0.01) and rates of acute percutaneous coronary interventions (PCI) (P < 0.001). In subsample 1, 19 patients (27.5%) under- went acute PCI within 24 hours after hospital ad- mission; a further 34 patients (49.3%) had this in- tervention subsequently within the rst month af- ter AMI. The proportion of patients receiving acute PCI increased to 58.7% in subsample 2; a further

29 patients in subsample 2 (38.7%) had this inter-

vention within the rst month after AMI. The mean length of time between AMI and SAECG recording

was 8.6 days (± 7.2 days) in subsample 1, and 6.8 days (± 6.1 days) in subsample 2. In subsample 1, follow-up for AE was com- pleted in all 69 patients. The mean length of follow-up duration after administration of the SAECG was 6.7 (± 2.3) years with a total observa- tion time of 461 person-years. During follow-up,

10 patients (14.5%) had an AE: ve patients with

SCD, four patients with documented conversions of a sustained VT by an ICD, and one patient with a converted VT during resuscitation. Overall, 13 pa- tients died during follow-up: in addition to the ve SCD, three patients died of a recurrent AMI, two of congestive heart failure, and one patient died each of cancer, pneumonia, and ischemic colitis. In subsample 2, four patients who were lost to follow-up had to be excluded, resulting in a to- tal of 75 patients suitable for analysis. The mean length of follow-up duration in these patients was 1.7 (± 0.7) years with a total observation time of 128 person-years. During follow-up, nine patients (12.0%) had an AE: two patients with SCD and seven patients with documented conversions of a sustained VT by an ICD. There were no further deaths among subsample 2.

Prediction of AE

Table II depicts the diagnostic accuracy of the risk-predictive dichotomized variables of SAECG and EF for both subsamples combined and for each subsample separately. The new index resulted in a signicantly higher sensitivity, specicity, PPV, and NPV than the conventional scoring method in both subsamples combined (P = 0.04) and subsam- ple 1 (P = 0.02). In subsample 2, there was no sta- tistically signicant difference between new index and conventional scoring method (P = 0.50). In both subsamples combined, the yearly in- cidence rate of AE for patients with normal con- ventional score was 1.5% as compared to 6.8% in those with an abnormal conventional score (P = 0.002). The incidence rate of AE with normal and abnormal new index was 1.2% and 8.9%, re- spectively (P < 0.001). The Kaplan-Meier survivor functions of the conventional scoring method and the new index differed signicantly (P = 0.02). In both subsamples combined, the combina- tion of a normal index and a normal EF compared to an abnormal index and/or an abnormal EF re- sulted in a sensitivity of 100%, a specicity of 47%, a PPV of 22%, and a NPV of 100%. On the other hand, the combination of an abnormal index and an abnormal EF compared to a normal index and/or a normal EF had a sensitivity of 58%, a specicity of 90%, a PPV of 46%, and a NPV of 93%. The combination of the new index and the EF was signicantly better than the conventional scoring method (P < 0.001) and the EF alone (P < 0.001), and there was a statistical trend (P = 0.08) that the combination was better than the new index alone. Figure 1 shows the Kaplan-Meier estimates

Table II.

Diagnostic Accuracy of Risk-Predictive Dichotomized Variables for Both Subsamples Combined and for Each Subsample Separately

Patient Group


Method of Interpretation





Both subsamples


Conventional scoring method New index
















Subsample 1


Conventional scoring method New index
















Subsample 2


Conventional scoring method New index
















Values are percentages. EF = ejection fraction; NPV = negative predictive value; PPV = positive predictive value; SAECG = signal-averaged electrocardiogram.


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PREDICTION OF ARRHYTHMIC EVENTS Figure 1. Kaplan-Meier estimates of event-free survival as predicted by: (A) the
PREDICTION OF ARRHYTHMIC EVENTS Figure 1. Kaplan-Meier estimates of event-free survival as predicted by: (A) the
PREDICTION OF ARRHYTHMIC EVENTS Figure 1. Kaplan-Meier estimates of event-free survival as predicted by: (A) the

Figure 1. Kaplan-Meier estimates of event-free survival as predicted by: (A) the new index of the signal-averaged electrocardiogram, (B) the ejection fraction (EF), and (C) the combination of the new index and EF.

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Table III.

Association of Risk-Predictive Dichotomized Variables with Arrhythmic Events in Univariable and Multivariable Analysis of Both Subsamples Combined


Hazard Ratio (Univariable Analysis)


Hazard Ratio (Multivariable Analysis)*


fQRS > 114 ms RMS < 20 µV

5.4 (95% CI: 2.1, 14.0)


6.0 (95% CI: 2.3, 16.1) 4.9 (95% CI: 1.9, 12.7) 4.9 (95% CI: 1.8, 13.1)


4.1 (95% CI: 1.6, 10.3)



LAS > 37 ms Conventional scoring method

3.4 (95% CI: 1.4, 8.4)




3.5 (95% CI: 1.3, 0.4) 5.9 (95% CI: 2.1, 16.8) 7.7 (95% CI: 2.8, 21.6)


4.1 (95% CI: 1.5, 11.3) 6.8 (95% CI: 2.3, 19.7) 9.3 (95% CI: 3.2, 27.0)


New index > 0.12 EF 35%





Values correspond to the hazard ratio (95% confidence interval (CI)).

* After adjustment for age and gender. EF = ejection fraction; fQRS = filtered QRS duration; LAS = duration of low-amplitude signals; RMS = root-mean-square voltage of the terminal QRS complex.

of event-free survival as predicted by the new in- dex and the EF. The yearly incidence rate was 0% for patients with a normal new index and a normal EF, and 7.7% for patients with an abnormal new index and/or an abnormal EF (P < 0.001). When both new index and EF were abnormal, the inci- dence rate was 21.3% (19.0% in subsample 1, and 23.7% in subsample 2). In both subsamples combined, all di- chotomized risk-predictive variables were sig- nicant predictors in uni- and multivariable

analysis adjusted for age and gender (Table III). In

a further multivariable analysis comprising all di-

chotomized predictive variables and adjusting for age and gender, only new index and EF remained signicant (P = 0.01 and P = 0.006, respectively) and independent predictors of AE.

Discussion This study contributes three relevant new ndings to the risk assessment of AE in patients after AMI. First, this study shows that a newly de- veloped index probably improves the prognostic value of the SAECG as compared to the conven- tional scoring method for the prediction of AE in patients after AMI. Second, a normal new index combined with a normal EF allowed identifying patients at very low risk for AE after AMI in this study. Third, patients with an abnormal new in- dex and a concurrently abnormal EF had a high incidence rate of AE (21.3%) in this study. In most previous studies investigating the prognostic value of the SAECG in the prediction of AE after AMI, the negative predictive value was high (81% to 99%), but the positive predic- tive value remained low (8% to 29%); sensitiv-

ity ranged from 39% to 93% and specicity from 62% to 91%. 21 In this study, test characteristics of the new index were in the upper range of the reported previous results found for the conven- tional scoring method of SAECG interpretation. However, test characteristics were still not suf- cient to base treatment decisions on the new index alone. The same applied to the EF when it was used as single risk-predictive variable. In this study, the combination of SAECG and EF allowed an excellent identication of patients at low and at high risk of AE. This nding is in concordance with a recent meta-analysis 17 and the previous studies having prospectively combined SAECG and EF in similar study populations. 4,7,14 For patients with normal SAECG and normal EF, the meta-analysis reported a 2-year probability of AE of 2.2%. When both tests were abnormal, a 2- year probability of 38.7% was found in the meta- analysis as compared to a 1-year probability of 21.3% in our study. The meta-analysis suggested using SAECG and EF as the rst steps of risk as- sessment after AMI and excluding patients when the tests were either both negative or both positive. The meta-analysis is limited by the fact that it com- bined heterogeneous populations and the prospec- tive studies by the fact that they were conducted more than one decade ago. Meanwhile, the increas- ing percentage of acute reperfusions in recent years was shown to decrease the prognostic power of the SAECG. 26 However, this topic remained controver- sial as the SAECG was also found to be a powerful indicator of arrhythmic events in the present era of active treatment. 27 Recent studies did not eval- uate the SAECG in combination with the EF. In this study, the identication of patients at low and


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at high risk using the combination of new index and EF was maintained in the subsample of pa- tients with an increased percentage of acute reper- fusions. Our study exhibits potential limitations. First, our sample size was relatively small. However, sample size was adequate to perform analyses of the combined subsamples, as shown by the condence intervals found for tests of main hy- potheses. On the other hand, due to the lim- ited sample size, statistical testing within subsam- ples separately, or subgroup analyses, was limited. Therefore, the nonsignicant result for the com- parison of new index and conventional scoring method in subsample 2 was probably due to the limited sample size in this subsample. Second, this study was based on an outcome combining mortal- ity and a surrogate end-point with ICD interven- tion. Furthermore, the follow-up duration in sub- sample 2 was rather short. Third, we might have overestimated the predictive value of the new in- dex because the cut-off of the new index was de- rived from subsample 1 in this study. Therefore, fu- ture studies in other populations need to conrm the improved predictive value of the new index. Fourth, all participants were recruited in one sin- gle Swiss hospital and the study population con- sisted of a predominantly male population. The generalizability to other populations is therefore limited. Fifth, patients with intraventricular con- duction defects were excluded. Consequently, our results apply only to patients with a QRS 120 ms on standard ECG. This study has research implications. The role of the SAECG as a predictor of AE has not been clar- ied in the large ICD intervention trials. 13 Only the coronary artery bypass grafting (CABG) Trial


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February 2008

PACE, Vol. 31