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European Heart Journal Advance Access originally published online on June 14, 2006
European Heart Journal 2006 27(14):1706-1711; doi:10.1093/eurheartj/ehl100
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© The European Society of Cardiology 2006. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Incidence, time course, and predictors of early malignant ventricular arrhythmias after non-ST-segment elevation myocardial infarction in patients with early invasive treatment

Kazem Rahimi1,2,*, Stefan Watzlawek1, Holger Thiele1, Maria-Anna Secknus1, Bibi-Fatemeh Hayerizadeh1, Josef Niebauer1 and Gerhard Schuler1

1 Department of Internal Medicine/Cardiology, Heart Center, University of Leipzig, Leipzig, Germany
2 Department of General Medicine, King's College Hospital, Bessemer Road, London SE5 9RS, UK

Received 1 March 2006; revised 24 May 2006; accepted 26 May 2006; online publish-ahead-of-print 14 June 2006.

* Corresponding author. Tel: +49 341 865 1428; fax: +49 341 865 1177. E-mail address: krahimi{at}freenet.de


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 Conclusions
 Acknowledgement
 References
 
Aims The incidence of non-ST-segment elevation myocardial infarction (NSTEMI) is increasing. With the limited intensive care facilities, knowledge of the total risk and predictors of acute life-threatening arrhythmias is of major interest to guide the decision on the intensity of care at the time of admission.

Methods and results We continuously monitored 588 consecutive patients with NSTEMI admitted to the coronary care unit of a primary and tertiary care centre for malignant ventricular arrhythmias requiring defibrillation. Ninety-seven per cent of the patients underwent coronary angiography during the index hospital admission. Total rate of malignant ventricular arrhythmias and mortality was 2.6% (n=15) and 3.6% (n=21), respectively. More than two-thirds of arrhythmias occurred within the first 12 h after onset of symptoms. In a bootstrapped multivariable regression analysis, the only factor associated with the occurrence of malignant ventricular arrhythmia was higher white blood cell count on admission. Popular risk assessment tools such as Thrombolysis in Myocardial Infarction, Platelet glycoprotein IIb/IIIa in Unstable angina: Receptor Suppression Using Integrilin Therapy, and Predicting Risk of Death in Cardiac disease Tool were predictive of mortality but not of early arrhythmia.

Conclusion Patients with NSTEMI treated aggressively with early revascularization are at low risk for developing life-threatening arrhythmias. The occurrence of such events remains difficult to predict. The role of baseline inflammatory status as a determinant merits further investigations.

Key Words: Burden of illness • Myocardial infarction • Tachyarrhythmias • Risk factors • Leukocyte


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 Conclusions
 Acknowledgement
 References
 
Patients with acute myocardial infarction are regarded as being at high risk for occurrence of life-threatening arrhythmias in the early phase of the ischaemic event. Therefore, admission to the coronary care unit (CCU) and cardiac monitoring is currently recommended for such patients in the first 24–48 h post-myocardial infarction (MI).1,2 However, these recommendations are largely based on historical data, which do not reflect the recent changes in diagnostic and therapeutic approach towards such patients.

Only the redefinition of MI with the very sensitive and specific biomarker cardiac troponin3 has led to an increase of the incidence of non-ST-segment elevation myocardial infarction (NSTEMI) by 60–100%.4–6 Although the label MI may be justified in these patients due to their poor long-term outcome,4,7 the risk of acute life-threatening arrhythmias may differ from patients with STEMI. New epidemiological data regarding the risk of patients with NSTEMI for major arrhythmia are rare.

Admission of the growing number of patients with uncomplicated NSTEMI to the CCU is often a challenge for hospitals and has a huge impact on treatment costs. Given the fact that the primary benefit of admission of patients with uncomplicated MI to the CCU is prompt resuscitation in the case of cardiac arrest,8 identification of patients with high risk for life-threatening arrhythmic complications would be a helpful tool to guide the clinician in his decision with regard to the appropriate level of care at the time of admission.

Several multivariable models9–12 exist for prediction of early complications in patients with acute coronary events. However, major arrhythmia is not an endpoint in these models. Furthermore, these scores were developed in populations with a low rate of invasive management.

The purpose of this study was to assess the time-based incidence of life-threatening ventricular arrhythmias and their risk factors in patients with NSTEMI based on routinely collected information. We also set out to assess whether currently available risk scores of early prognosis are able to discriminate between patients with or without sustained ventricular tachycardia or ventricular fibrillation.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 Conclusions
 Acknowledgement
 References
 
Data collection
We designed this study as a prospective registry of patients admitted with the diagnosis of acute MI without ST-elevation from a tertiary and primary care centre.

We collected the data on all consecutive patients from 1 January 2002 to 1 July 2005 with the diagnosis of NSTEMI according to the current European Society of Cardiology/American College of Cardiology (ESC/ACC) definition.3 Patients were eligible if they were admitted to the CCU within 48 h of symptom onset. Patients transferred from other hospitals for further diagnosis and management were also included if they presented within the above time frame. The period of observation ended with the discharge or the death of the patient. The study complies with the Declaration of Helsinki. The institutional review committee approved the study.

Primary outcome of interest included timing and type of in-hospital arrhythmias. According to the hospital policy, all patients were continuously monitored for complex arrhythmia with the use of a multilead and computerized arrhythmia detection system. All potential life-threatening arrhythmias detected by the computerized system were evaluated by trained CCU staff. Malignant ventricular arrhythmia was defined as ventricular fibrillation or ventricular tachycardia with haemodynamic compromise requiring defibrillation.

Following data were also registered from the patient files: age, sex, weight, height, past medical history, medication on admission, administration and type of medication on presentation, heart rate and blood pressure on admission, Killip classification, routinely available laboratory data including potassium, creatinine, urea, glucose, creatine kinase, creatine kinase-MB, troponin, LDL cholesterol, full blood count, international normalized ratio (INR), time of onset of symptoms, time of presentation to hospital, time of coronary angiogram, length of CCU stay, length of hospital stay, and further discharge arrangements. We assessed comorbidity by the Charlson index.13 A trained specialist blinded to the outcome of the study reviewed the electrocardiograms (ECGs) on admission. Coronary angiography data collected were the number of vessels with a stenosis higher than 25% on visual assessment, severity of the stenoses, culprit lesion if applicable, type of intervention, and left ventricular ejection fraction (if no ventriculography available, echocardiography result was taken). We calculated the following risk scores with the use of published methods: Thrombolysis in Myocardial Infarction (TIMI),10 Global Registry of Acute Coronary Events (GRACE),12 Platelet glycoprotein IIb/IIIa in Unstable angina: Receptor Suppression Using Integrilin Therapy (PURSUIT),11 and Predicting Risk of Death in Cardiac disease Tool (PREDICT).9

Data analysis
Mann–Whitney U test and {chi}2 test were used for continuous variables and categorical parameters, respectively. The Kaplan–Meier method was used for the analysis of the event-free survival of patients with events being defined as occurrence of malignant ventricular arrhythmia. Baseline features associated with malignant ventricular arrhythmia in the univariable analysis and clinically plausible interactions were subject to multivariable analysis using stepwise forward logistic regression modelling to identify predictors based on the likelihood ratio test. We performed an internal validation of the predictors by means of bootstrapping with 5000 iterations. Variables included in the multivariable analysis were systolic blood pressure, INR, white blood cell (WBC) count, and serum potassium level. The use of diuretics was not considered for inclusion in the regression analysis despite its association with VT/VF in the univariable analysis, as there was a negative correlation with potassium as another variable in the regression analysis. The assumed linearity between the logit of dependent and independent variables was tested and confirmed by the Box–Tidwell transformation test.The predictive discriminatory capacity of the four risk scores (TIMI, GRACE, PURSUIT, and PREDICT) was measured and compared with the c-statistic representing the area under the receiver operating characteristic (ROC) curves for the prediction of malignant ventricular arrhythmia.

The above analysis was repeated for in-hospital mortality as the secondary outcome. Values of two-sided P<0.05 were considered significant. The Statistical Package for Social Sciences (SPSS Inc., Chicago, IL, USA, Version 11.5) and STATA statistics package (STATA Corp., College Station, TX, USA, Version 9) were used for the statistical analysis.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 Conclusions
 Acknowledgement
 References
 
During the 3.5 years period of the study, 588 consecutive patients admitted to the University of Leipzig, Heart Centre, with acute NSTEMI according to the current ESC/ACC definition3 were entered into the registry. Of these patients, 137 (27%) patients were direct admissions and 374 (73%) patients were early transfers from other hospitals. Ninety-seven per cent of the patients underwent diagnostic angiography during the hospital stay with a median delay of 17.5 h from the onset of symptoms (interquartile range 10.6–25.9 h). Seventy-four per cent of the patients were treated with either interventional or surgical revascularization.

The total rate of malignant ventricular arrhythmia was 2.6% (n=15). Another 12 patients were recorded to have non-sustained ventricular arrhythmia (2%). The proportion of patients having malignant arrhythmias was similar in the group of direct admissions compared with early transfers. Twenty-one patients (3.6%) died during the period of observation. The cause of death was non-arrhythmogenic in all but one patient.

Patients' characteristics stratified by the occurrence of malignant ventricular arrhythmia are summarized in Table 1. The long-term and acute medications are summarized in Table 2. In univariable analyses, lower systolic blood pressure on admission, lower serum potassium, higher WBC count, higher INR, and use of diuretics were associated with an increased risk of malignant ventricular arrhythmias requiring defibrillation. Factors associated with occurrence of malignant ventricular arrhythmia in the multivariable analysis were total WBC count and the serum potassium on admission (Table 3). After internal validation by means of bootstrapping with 5000 repeated samples, WBC count remained the only predictor of malignant ventricular arrhythmia (OR 1.145, CI 1.01–1.30, P=0.040).


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  		Table 1 Patients' characteristics

 

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  		Table 2 Patients' medical treatment

 

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  		Table 3 Multivariable regression analysis (likelihood ratio) for malignant arrhythmia

 
A time-based risk assessment showed that 80% of malignant ventricular arrhythmias requiring defibrillation occurred within the first 12 h following the onset of symptoms with no events being recorded after 2 days (Figure 1). We did not observe any malignant ventricular arrhythmias during or after the coronary angiogram in the period of observation.


Figure 1001
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  		Figure 1 The Kaplan–Meier survival curve for occurrence of malignant arrhythmia after non-ST-segment myocardial infarction.

 
In a multivariable regression analysis, factors independently associated with death were higher creatinine level, lower left ventricular ejection fraction, presence of Q-wave on admission ECG, lower systolic blood pressure, and higher Killip class (Table 4).


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  		Table 4 Multivariable regression analysis (likelihood ratio) for death

 
Comparison of the selected risk scores showed a good predictive value of three of the models (TIMI, PURSUIT, and PREDICT) for death but none of them was able to discriminate between patients with early malignant ventricular arrhythmias and those without. (Table 5).


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  		Table 5 ROC curve analysis for the predictive value of selected risk scores for in-hospital mortality and early malignant ventricular arrhythmia

 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
Conclusions
 Acknowledgement
 References
 
Despite the evidence for the safety of early discharge of patients with uncomplicated MI, the length of stay in most countries is still too high.14 Shortening or omitting the time spent on CCU or intensive care units, which accounts for almost half of the total hospital stay,15,16 will have major implications on discharge planning and total treatment cost.

This study shows that the incidence of life-threatening tachyarrhythmias in patients with NSTEMI and early invasive treatment is with 2.6% generally low, being about one quarter to one-third of the risk of patients with STEMI in the Global Utilization of Streptokinase and TPA for Occluded coronary arteries (GUSTO-I), Global Use of Strategies to Open occluded coronary arteries population (GUSTO III),17 and the Euro Heart Survey of Acute Coronary Syndromes,18 or when the risk is compared with the whole spectrum of acute coronary syndromes in GRACE.15 The time course of the events is similar to the STEMI population with more than 80% of the events being recorded within the first 12 h after symptom onset.17

Even though these findings support the current recommendation that cardiac monitoring and CCU admission are not warranted beyond 24–48 h after the ischaemic event in stable patients, the question remains how to risk stratify patients potentially eligible for direct admission to less-intensive care units on presentation. The Euro Heart Survey of Acute Coronary Syndrome showed that 50% of the patients with acute NSTEMI were admitted to the CCU.18 Because of the lack of appropriate risk assessment tools, the decision is mainly determined by the availability of beds, the local hospital policy and physician's judgement.

Although there are several scores for risk stratification of patients admitted with acute coronary syndromes, none of these assesses the risk of early ventricular arrhythmias. Indeed, our study shows that the most popular risk scores are good at predicting in-hospital mortality but they failed to predict early malignant ventricular arrhythmias post-NSTEMI.

The only predictors of malignant ventricular arrhythmia in our study population were higher WBC count and hypokalemia on presentation. WBC count was the only predictor remaining in the model after bootstrapped internal validation. This finding confirms the historical observations from Julian et al.19 in the early 1960s that post-MI patients developing heart failure or shock on the one hand and ventricular arrhythmia on the other hand are two distinct groups and that ventricular arrhythmia seems to occur in patients with apparently stable condition, making such events difficult to predict.

Pathophysiological mechanisms leading to malignant arrhythmias after MI are complex20 but among others the electrolyte imbalance, particularly hypokalemia seems to be important.21 Thus, it is not surprising that patients with lower potassium level were at higher risk for occurrence of malignant ventricular arrhythmia. However, this weak association in our study was not validated in the bootstapped multivariate regression analysis.

After internal validation, higher WBC count on admission was the only independent determinant of early malignant ventricular arrhythmias in patients with NSTEMI. Although there is growing evidence for the role of inflammation in the formation and maintenance of supraventricular arrhythmia, mainly atrial fibrillation,22,23 to the best of our knowledge, a correlation between inflammation and ventricular arrhythmia in post-MI patients has not yet been demonstrated. Higher WBC count has been shown to be related to higher rates of adverse events and mortality in patients after MI simply as a surrogate of infarct size but also independently from it.24,25 Although in studies assessing the prognostic value of WBC count in AMI, the rate of malignant arrhythmia has not been reported, there is a possibility that a proportion of the fatal events were due to arrhythmic complications. This hypothesis is also supported by the fact that in the same studies the higher WBC count was associated with death but not with non-fatal MI during the follow-up period.

Indirect evidence from a post mortem analysis of patients with sudden cardiac death also supports the potential role of inflammation in the genesis of arrhythmia. Although there are various pathophysiological mechanisms in sudden cardiac death, the two major postulated causes are acute coronary thrombosis and primary ventricular arrhythmia mainly arising from scarred myocardium.20 Burke et al.26 demonstrated that patients with sudden cardiac death have an increased level of C-reactive protein compared with a control group irrespective of the presence of coronary thrombi. This suggests that increased inflammation is evident in patients with sudden cardiac death even in those with stable plaques who may have died from arrhythmia unrelated to plaque rupture. But the interpretation of our findings should be cautious and requires confirmation in further studies.

Interestingly, markers of severity of infarct such as Killip class, creatine kinase and cardiac troponin levels, or LV function were not of any prognostic value for occurrence of malignant ventricular arrhythmia, but they were strong predictors of mortality. Patients with NSTEMI are more likely to have suffered from MI in the past and they also present with relatively lower rate of total vessel occlusion. In such a setting, it seems possible that in contrast to patients with STEMI, for the occurrence of arrhythmia, the extent of the new MI plays a less important role, whereas other factors such as interaction between the scar tissue and the ischaemic area20 as well as electrolyte imbalance and inflammation are the major determinants for the genesis of arrhythmia.


   Conclusions
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusions
Acknowledgement
 References
 
Cardiac monitoring after acute NSTEMI in patients with early invasive strategy identified only 2.6% of the patients having acute malignant ventricular arrhythmias with the majority of arrhythmias occurring during the first 12 h after onset of symptoms. With such events being difficult to predict, better scoring models are needed for risk stratification of apparently stable patients after MI at risk for developing ventricular arrhythmias. WBC count on admission may convey important predictive information. However, these findings need to be validated in further prospective studies.


   Acknowledgement
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusions
 Acknowledgement
References
 
We greatly appreciate the critical review and comments of Dr Selva Saman and Dr Jörg Steier regarding this manuscript.

Conflict of interest: none declared.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusions
 Acknowledgement
 References
 

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Authors/Task Force Members, J.-P. Bassand, C. W. Hamm, D. Ardissino, E. Boersma, A. Budaj, F. Fernandez-Aviles, K. A.A. Fox, D. Hasdai, E. M. Ohman, et al.
Guidelines for the diagnosis and treatment of non-ST-segment elevation acute coronary syndromes: The Task Force for the Diagnosis and Treatment of Non-ST-Segment Elevation Acute Coronary Syndromes of the European Society of Cardiology
Eur. Heart J., July 1, 2007; 28(13): 1598 - 1660.
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V. Nkolic-Heitzler and Z. Babic
Incidence, time course, and predictors of early malignant ventricular arrhythmias after non-ST-segment elevation myocardial infarction in patients with early invasive treatment
Eur. Heart J., December 1, 2006; 27(23): 2906 - 2907.
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