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European Journal of Heart Failure 2007 9(3):272-279; doi:10.1016/j.ejheart.2006.07.004
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© 2007 European Society of Cardiology

B-type natriuretic peptide levels predict event-free survival in patients with implantable cardioverter defibrillators

Michael Christa,c,*, Julia Sharkovaa, Somer Bayrakcioglua, Ileana Herzumb, Christian Muellerc and Wolfram Grimma

a Klinik für Innere Medizin Kardiologie, Germany
b Klinik für Innere Medizin, Institut für Klinische Chemie Universität Marburg, Germany
c Departement Medizin, Med. Klinik A Universitätsspital Basel, Switzerland

* Corresponding author. Department of Internal Medicine, Medical Division A, University of Basel, Petersgraben 4, CH-4031 Basel, Switzerland. Tel.: +41 0 61 265 2525; fax: +41 49 0 69 13303154027. E-mail address: ChristMic{at}uhbs.ch


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
Introduction: We examined whether B-type natriuretic peptide (BNP) levels predict outcome in heart failure patients with implantable cardioverter defibrillators (ICD) using a combined endpoint of malignant tachyarrhythmias, death or heart transplantation.

Methods and results: BNP levels were measured in 123 ICD patients with chronic heart failure (age: 63±12years, ejection fraction: 29±10%). After a median follow-up of 25months, the combined endpoint was reached in 28 patients (first tachyarrhythmic event, n=16; death, n=11; heart transplantation, n=1). BNP levels were significantly lower in patients with event-free survival compared to patients reaching the combined endpoint of this study (median: 140 vs. 373pg/ml; p<0.001). Multivariable Cox regression analysis revealed that BNP levels predict adverse outcome (RR 1.002 per pg/ml increment; 95% CI: 1.001–1.003; p<0.001) and use of beta-blockers was associated with favourable outcome (RR 0.319; 95% CI 0.151–0.670; p=0.004). LV ejection fraction (p=0.66) did not significantly predict event-free survival in multivariable analysis.

Conclusions: BNP plasma levels are useful markers to predict event-free survival in ICD patients with heart failure. Of note, malignant tachyarrhythmias appear responsible for about 50% of fatal outcomes. Our findings suggest that determination of BNP plasma levels is more valuable than determining LV ejection fraction to anticipate event-free survival in this population.

Key Words: Brain natriuretic peptide • Ventricular tachyarrhythmias • Implantable cardioverter defibrillator • Cardiac death • Sudden arrhythmic death

Received January 9, 2006; Revised May 17, 2006; Accepted July 13, 2006


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 References
 
Individual risk prediction is mandatory in order to identify patients at increased risk for heart failure related events including progression of cardiac failure and/or malignant ventricular arrhythmias. In particular, pathogenesis of sudden arrhythmic death is complex, including conduction and repolarization abnormalities, genetic predisposition, myocardial ischaemia and neurohumoral activation [1,2]. Stretch of myocardial tissue modulates the acute and chronic electrophysiological properties of the myocardium via the activation of mechano-sensitive or stretch-activated ion channels [3]. This mechano-electrical feedback triggers ectopic ventricular beats, slows conduction and enhances refractoriness in heart failure patients with LV dysfunction [4].

Implantable cardioverter defibrillators (ICD) can effectively terminate episodes of ventricular fibrillation (VF) and ventricular tachycardia (VT), subsequently averting sudden arrhythmic death. However, malignant tachyarrhythmic events are usually rare in heart failure patients. In addition, the costs of ICD implantation including follow-up care are substantial [5]. Therefore, the cost-effectiveness of the prophylactic implantation of an ICD has been questioned and risk stratification for proper indication of device implantation is desirable.

B-type natriuretic peptide (BNP) has been demonstrated to indicate increased risk of death in several populations with cardiovascular disease [6]. BNP is mainly secreted in the cardiac ventricles in response to myocardial stretch attributable to volume overload, indicating both progression of cardiac failure and susceptibility for arrhythmic events. Thus, it is tempting to speculate that BNP plasma levels are attractive risk predictors in heart failure patients planned for ICD implantation. We therefore examined whether measurement of BNP plasma levels could predict event-free survival, including malignant ventricular arrhythmias, death or heart transplantation, in ICD patients with heart failure and LV dysfunction.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 References
 
2.1. Patients, study design
Between December 1992 and September 2003, 362 patients received an ICD at our institution (University of Marburg, Germany). In 111 patients (prophylactic group), this was due to asymptomatic ventricular tachycardia (VT) in the presence of systolic LV dysfunction (LV ejection fraction ≤30%). In 251 patients (symptomatic group), this was due to unexplained syncope, syncope or a history of sustained VT or ventricular fibrillation (VF) (Fig. 1). Devices were checked every three to six months at the defibrillator outpatient clinic and consecutive patients were prospectively recruited from June 2002 to September 2003. The study was conducted according the principles of Good Clinical Practice and the Declaration of Helsinki, and patients gave written informed consent before enrolment into the study. Patient history was obtained at the date of enrolment and a thorough physical examination was performed. All patients were stable with regard to symptoms and drug treatment for at least 1 month.


Figure 01
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  		Fig. 1 Enrolment of heart failure patients with an implantable cardioverter defibrillator and a LV ejection fraction ≤45% at the defibrillator outpatient clinic of Marburg University, Germany.

 
2.2. Electrocardiography and echocardiography
Standardised 12-lead electrocardiograms (ECGs) were recorded at a paper speed of 50 mm/s from each patient after 5 min of supine rest. The ECGs were interpreted by a single experienced researcher blinded to patient baseline characteristics and outcome. Patients were classified to have pacemaker rhythm, if more than 50% of beats were paced during the ECG recording.

Two-dimensional echocardiographic images of the heart were obtained at the end of the expiratory period using a Vingmed Vivid Five machine (GE Medical Systems, Solingen, Germany). Parameters of LV dimension were measured by a single experienced echocardiographer using standard procedures. LV end diastolic volume and LV ejection fraction were determined using Simpson's method according to current recommendations using standard procedures in all patients [7]. The intra-observer variability for all parameters was <10%.

2.3. Laboratory procedures
Following an overnight fast, venous blood samples were drawn between 8:30 h and 10:30 h with patients resting supine for at least 15 min prior to sampling. Samples were drawn through a 21-gauge cannula inserted into an antecubital vein using ethylenediamine tetraacetic acid (EDTA) containing monovettes (Sarstedt, Nuembrecht, Germany). Blood samples were immediately transferred onto ice, plasma was separated by centrifugation and stored at –80 °C for a maximum of 3 months prior to analysis. BNP levels were determined using a chemiluminescence immunoassay (Bayer AG, Fernwald, Germany [8]). The analytical detection limit of the assay was 2 pg/ml. The intra-assay coefficient of variations (CVs) were 1.8-4.3% at 29.4-1763 pg/ml and the inter-assay CVs were 2.3-4.7% at 29.4-1736 pg/ml BNP [8]. BNP measurements were performed at a different site by a technician blinded to the characteristics of the patients.

2.4. Defibrillator implantation and device programming
ICDs with non-thoracotomy lead systems and biphasic shock waveforms with a maximum shock energy of 27 to 34 J were used exclusively. Device programming was performed as reported previously [9]. All ICD systems used provided stored intra-cardiac electrocardiograms in addition to beat-to-beat intervals of episodes triggering device action (Guidant, St. Paul, Minnesota; Medtronic, Minneapolis, Minnesota). The time interval for VF detection ranged from 1 to 3 s in Guidant devices; the Medtronic devices were programmed to require 18 out of 24 beats below the programmed detection cycle length (range 240-280 ms) in order to initiate capacitor charging in the VF zone. Slower ventricular tachyarrhythmias were detected and treated in one or two separate VT zones with anti-tachycardia burst pacing followed by up to four cardioversion shocks [9].

2.5. Follow-up
All baseline clinical characteristics, including the results of cardiac evaluation and implantation data, was collected prospectively in the Marburg Defibrillator Database [9]. Follow-up was completed in all patients enrolled and was started at the time of BNP measurement. Patients were followed primarily in our defibrillator outpatient clinic at three-to six months intervals or as soon as possible after spontaneous ICD shocks for device interrogation and retrieval of stored electrocardiograms. All stored electrocardiograms of episodes triggering ICD therapy were classified by two experienced electrophysiologists, as appropriate or inappropriate, using previously described criteria [10,11].

2.6. Statistical analysis
Continuous variables are expressed as mean±standard deviation (S.D.). Results are expressed as median (range) and point estimate (95% confidence intervals) as indicated. The primary objective of the study was to examine whether brain natriuretic peptide (BNP) levels could predict the combined endpoint of (malignant tachyarrhythmic events, death or heart transplantation). Malignant tachyarrhythmic events were defined as fast ventricular tachyarrhythmias (VT or VF) with cycle lengths ≤250 ms (heart rate ≥240 bpm) probably leading to death if not terminated by the device [12]. Univariate and multivariable Cox proportional hazards models were used to evaluate the association between the outcome measures (primary endpoint: time to death, heart transplantation or first malignant tachyarrhythmic event as a combined endpoint). Evaluation of univariate grouped Kaplan-Meier plots did not provide any suggestions for a crude violation of the assumption of proportional hazard rates. For examined variables included in the models, no information is given that they should be transformed before inclusion into the Cox regression models.

For building a first Cox regression model, we thereby used a stepwise procedure with an entry level of 0.10. The p-value for staying in the model was set at 0.05. Event-free survival probabilities were estimated with the Kaplan-Meier method and the log rank test was used for comparisons of curves. Additional statistical analyses were used for exploration, description and interpretation. Comparisons between groups were done by the Student's t-test, U-test or chi-square test as applicable. All p-values reported are two-sided, a p-value <0.05 was considered significant; a p-value ≤0.10 was defined to indicate a statistical trend.

Receiver operator characteristic (ROC) curves were constructed to assess the sensitivity and specificity of BNP throughout the concentrations to detect the combined endpoint (critical arrhythmic events, death or heart transplantation), respectively. All statistical calculations were performed using the SPSS statistical software package (version 12.0, SPSS Inc., Chicago, IL).


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 References
 
Demographic characteristics of the 123 heart failure patients enrolled (Fig. 1) are displayed in Tables 1 and 2. During a follow-up of up to 36 months (median 25 months) after enrolment, 16 patients had malignant tachyarrhythmic events, 14 patients died and 2 patients received heart transplantation. First malignant tachyarrhythmic events were recorded in 4 heart failure patients 1 to 30 months before death or heart transplant during follow-up (Fig. 1). Cause of death was progression of heart failure (n=11), vascular death (n=1), suicide (n=1) or unknown (n=1). Thus, the primary combined endpoint was reached in 28 patients (death, n=11; heart transplantation, n=1; first malignant tachyarrhythmic event, n=16). BNP levels were significantly lower in patients with event-free survival compared to patients reaching the combined endpoint of this study (median: 140 vs. 373 pg/ml; p<0.001).


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  		Table 1 Clinical characteristics of patients with implantable cardioverter/defibrillator implantation at study entry

 


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  		Table 2 Concomitant medication at baseline

 
3.1. Predictors of event-free survival
B-type natriuretic peptide levels, body mass index, heart rate, creatinine clearance and treatment with beta-blockers significantly contributed in univariate Cox regression models to predict the primary endpoint (malignant arrhythmias, death or heart transplantation), while only a trend was seen for systolic blood pressure, LV end diastolic diameter and LV ejection fraction. In addition, the presence of a left bundle branch block (LBBB) did not predict event-free survival (Table 3). Heart failure patients were stratified into two groups according to B-type natriuretic peptide (BNP) levels and Kaplan-Meier analysis was performed. Event-free survival was significantly lower in patients with BNP plasma levels ≥183 pg/ml (median) than in patients with BNP values below this cut-off point (log rank test, p=0.008, Fig. 2A). There was a statistical trend that patients with BNP plasma levels <183 pg/ml had a better outcome than patients with BNP levels ≥183 pg/ml levels using transplant-free survival as endpoint (log rank test, p=0.10, Fig. 2B). Indication for device implantation (prophylactic vs. secondary prevention) did not contribute in the Cox regression model to predict the combined endpoint. Similarly, malignant tachyarrhythmic events occurring after device implantation, but before study enrolment, did not predict the combined endpoint during follow-up (Table 3).


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  		Table 3 Event-free survival in ICD patients during follow-up

 


Figure 02
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  		Fig. 2 Heart failure patients were stratified into two groups according to B-type natriuretic peptide (BNP) levels and Kaplan-Meier analyses performed. (A) Patients with BNP plasma levels ≥183 pg/ml (median) had a significantly worse outcome than patients with BNP values below this cut-off point (log rank test) regarding event-free survival (composite endpoint of death, heart transplantation or first occurrence of malignant tachyarrhythmias). (B) A statistical trend was seen, when transplant-free survival was used as the endpoint (log rank test).

 
The area under the ROC curve using B-type natriuretic peptide levels to predict the occurrence of the combined endpoint was 0.711 (95% CI 0.595 to 0.827, Fig. 3). The optimum concentration of BNP for the calculation of positive and negative predictive accuracy as obtained from the ROC curve was 268 pg/ml (sensitivity 64.3%, specificity 29.3%, negative predictive value 86.3% and positive predictive value 38.3%). Using a cut-off point of 100 pg/ml BNP, a cut point clinically used to exclude the diagnosis of heart failure in patients with acute dyspnoea, decision statistics were the following: sensitivity 82.1%, specificity 32.6%, positive predictive value 27.1% and negative predictive value 85.7%.


Figure 03
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  		Fig. 3 Receiver operating characteristics (ROC) curve using B-type natriuretic peptide levels to predict event-free survival. The area under the ROC curve was 0.711 (95% CI 0.595 to 0.827).

 
B-type natriuretic peptide levels significantly contributed to multivariable Cox regression models predicting the combined endpoint (death, heart transplantation or malignant ventricular tachyarrhythmias). The hazard ratio was been calculated per pg/ml increment of BNP levels (Table 3). Using log BNP in the statistical analysis did not change the results. Multivariable Cox regression analysis revealed that treatment with beta-blockers indicates favourable prognosis (Table 3).

3.2. BNP levels and malignant tachyarrhythmic events
Malignant tachyarrhythmias occurred at a median of 47 months after implantation of the ICD (range: 22-133 months). The number of arrhythmic events observed during follow-up was insufficient to provide statistically robust results on the value of BNP to predict the occurrence of malignant tachyarrhythmias. Exploratory analysis indicated a statistical trend that BNP plasma levels were higher in patients with (median: 299 pg/ml) vs. those without malignant tachyarrhythmias (median: 151 pg/ml; p=0.10). Comparably, a trend was shown that patients with BNP plasma levels ≥183 pg/ml (median) had a higher rate of malignant ventricular tachyarrhythmic events than patients below this cut-off point (log rank test, p=0.08). Using 100 pg/ml BNP as cut point, the negative predictive value of BNP to exclude malignant arrhythmic events was 91.4% in this cohort of patients. The length of time after ICD implantation did not contribute to univariate Cox regression models to predict occurrence of malignant arrhythmias during follow-up (point estimate: 0.998 per month after ICD implantation; 95% CI: 0.982-1.015; p=0.82).


   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
References
 
Increased B-type natriuretic peptide levels may indicate increased risk for adverse events due to progression of heart failure and sudden arrhythmic death in heart failure patients with implantable cardioverter defibrillators (ICD). The major results of this study are as follows: (i) BNP plasma levels significantly predict event-free survival including major arrhythmic events, death, or heart transplantation as endpoints. Only a trend was seen, when death or heart transplantation was used as a combined endpoint. (ii) The use of beta-blockers indicates a favourable outcome in this cohort of ICD patients. (iii) Exploratory statistical analyses suggest a trend towards BNP having predictive value for occurrence of major tachyarrhythmic events in ICD patients with chronic heart failure and a LV ejection fraction ≤45% during follow-up.

Current mortality in patients with chronic heart failure is high with an annual risk of death up to 10% even in optimally treated patients [13,14]. Death in heart failure patients is comparably attributable to progressive cardiac dysfunction and sudden arrhythmic death [15]. Of note, implantable cardioverter defibrillators can effectively terminate episodes of malignant tachyarrhythmias, subsequently averting sudden arrhythmic death [13] indicating interesting treatment opportunities in this patient group. However, financial resources are limited and proper risk stratification appears mandatory to identify patients at increased risk. The predictive value of neurohormonal activation, including BNP levels, in patients with chronic heart failure is well established (for review, see [6]). The present study corroborates and extends previous findings on the predictive value of BNP [16,17] in this selected group of patients. Increased BNP plasma levels indicate an increased risk for death and malignant tachyarrhythmias in heart failure patients with an ICD.

BNP plasma level at baseline and use of beta-blockers, but not LV dysfunction or the presence of a LBBB, significantly contribute to Cox regression models predicting death, heart transplantation or major arrhythmic events. At present, an ejection fraction <30% to 35% is assumed to be a valuable parameter to predict increased risk for both, sudden and non-sudden cardiac death [2]. However, reduced LV ejection fraction is not associated with adverse outcome in multivariable analysis. Additionally, LBBB indicates structural changes in the left ventricle and has consistently been shown to be a powerful predictor of cardiovascular disease and mortality in the general population [18,19]. Although LBBB obviously predicts mortality in stable outpatients with chronic heart failure [20], the presence of LBBB in this population did not provide additional prognostic information. Possibly, this is due to selection of heart failure patients with advanced cardiac disease. In contrast, BNP plasma levels are strongly associated with adverse events. Increased BNP plasma levels may reflect haemodynamic compromise in heart failure patients, and other prognostic variables including LV-ejection fraction obviously do not contain prognostic information beyond that of BNP plasma levels [6]. Thus, BNP plasma levels should be included in the overall risk evaluation of heart failure patients potentially requiring an ICD.

Regrettably, the identification of risk factors predicting future malignant ventricular tachyarrhythmias is challenging [2,21]. Innumerable studies emphasise the arrhythmogenicity of neurohumoral activation. Specifically, Berger et al. reported that BNP levels determined at a single time point were significantly increased in heart failure patients with a LV ejection fraction ≤35% suffering sudden cardiac death [22]. Risk of sudden cardiac death was almost absent in heart failure patients with BNP levels below the cut-off point of 130 pg/ml. However, data analysis was conducted retrospectively in this study. In addition, determination of the clinical endpoint "sudden arrhythmic death" is known to be problematic [23], and the risk of sudden arrhythmic death is highly time-variant reflecting temporal heterogeneity of both, the myocardial substrate and potential triggers. Thus, conclusions drawn from this and other studies [24] should be interpreted with caution.

The monitoring function of ICD devices may help to clarify whether natriuretic peptide levels are arrhythmia risk predictors. In a cohort of 35 heart failure patients with a LV ejection fraction <35% post-myocardial infarction, 11 patients with major arrhythmic events had significantly increased NT-proBNP levels (determined at baseline) compared to patients without arrhythmias [25]. In another study, BNP levels above the 50% percentile were reported to be independent predictors of adequate ICD device therapy in a heart failure cohort (n=345, 71% of patients with coronary artery disease; [26]). In our cohort of heart failure patients with an ICD, exploratory analysis revealed a statistical trend that BNP levels predict the occurrence of major arrhythmic events in univariate analysis. However, several issues require further consideration. Previous studies predominantly enrolled patients with coronary artery disease [25,26], while ~ 50% of our cohort had chronic heart failure due to non-ischaemic cardiomyopathy. Therefore, the dependence of the potential predictive role of natriuretic peptides on the pathogenesis of LV dysfunction cannot be excluded. In addition, in our study, major arrhythmic events were defined as fast ventricular tachyarrhythmias (cycle length ≤250 ms), which supposedly lead to arrhythmic death if not terminated immediately [9,12]. Arrhythmic endpoints have not been precisely defined in other studies [25] and therefore the association of these endpoints with arrhythmic death are questionable [27].

For primary prevention, a reduced LV ejection fraction is considered to be a useful marker to identify patients at increased risk of sudden arrhythmic death [13,28]. Of interest, reduced LV ejection fraction does not discriminate between modes of death or identify patients for whom death is more likely to be the result of ventricular tachyarrhythmias [29,30]. Myocardial ischaemia is proposed to be the most important risk predictor for sudden cardiac death in patients with coronary artery disease and incomplete revascularization indicates increased arrhythmic risk [31]. Complete revascularization obviously dissociates the arrhythmic substrate from arrhythmic death [32].

Several limitations of this study merit consideration. (i) The study cohort was of moderate size and a limited number of endpoints were reached, limiting the power of our statistical analysis. (ii) Patient data were collected from a single tertiary referral centre. As patient demographics were very similar to recent multinational studies enrolling patients for ICD implantation [13], we consider our results are also valid in other settings. However, the predictive value of BNP for the incidence of malignant arrhythmias in the general heart failure population needs to be prospectively evaluated. (iii) Allocation to medical therapy was done by the attending physician and was non-randomised. (iv) BNP plasma levels were not determined at the time of ICD implantation in several patients. Thus, selection of patients with better prognosis may have occurred distorting some of our conclusions. However, patients with aborted arrhythmic death have also been included in previous studies [25,26], and statistical analysis did not suggest any association between previous major arrhythmic events or device activation and the arrhythmic endpoint in this study.

In summary, our findings indicate that BNP plasma levels are useful markers to predict event-free survival in ICD patients with chronic heart failure indicating that determination of BNP plasma levels should be considered for the overall risk evaluation of heart failure patients potentially requiring an ICD. Furthermore, our data suggest that measurement of BNP plasma levels is more valuable than determining LV ejection fraction to anticipate event-free survival in ICD patients with heart failure.


   Acknowledgement
 
Y.S. is supported by a grant of the "Deutsche Herzstiftung", Frankfurt, Germany.


   References
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 

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