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European Journal of Heart Failure 2007 9(6-7):651-659; doi:10.1016/j.ejheart.2007.01.010
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© 2007 European Society of Cardiology

Comparison of B-type natriuretic peptide assays for identifying heart failure in stable elderly patients with a clinical diagnosis of chronic obstructive pulmonary disease

Frans H. Ruttena,*, Maarten-Jan M. Cramerb, Nicolaas P.A. Zuithoffa, Jan-Willem J. Lammersb, Wim Verweijc, Diederick E. Grobbeea and Arno W. Hoesa

a Utrecht Heart Failure Organisation (UHFO), Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, The Netherlands
b Utrecht Heart Failure Organisation (UHFO), Heart Lung Center Utrecht, Department of Cardiology, University Medical Center Utrecht, The Netherlands
c Utrecht Heart Failure Organisation (UHFO), SALTRO, Department of Clinical Chemistry, PO Box 9300, 3506 GH Utrecht, The Netherlands

* Corresponding author. Utrecht Heart Failure Organisation (UHFO), Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, PO Box 85060, Stratenum 6.131, 3508 AB Utrecht, The Netherlands. Tel: +31 30 2538193; fax: +31 30 2539028. E-mail address: F.H.Rutten{at}umcutrecht.nl (F.H. Rutten). URL: http://www.juliuscenter.nl (F.H. Rutten).


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
Aims: To compare the ability of different B-type natriuretic peptide (BNP) assays to identify heart failure in stable elderly patients with a diagnosis of chronic obstructive pulmonary disease (COPD).

Methods: 200 patients aged ≥65 years with COPD according to their general practitioner and without known heart failure, underwent a diagnostic work-up. The final diagnosis of heart failure was established by a panel using the diagnostic principles of the European Society of Cardiology. All available diagnostic results, including echocardiography, but not BNP or NT-proBNP measurements, were used. The ability of different B-type natriuretic peptide assays to identify heart failure was estimated using the area under the receiver operating characteristic curves (ROC-area).

Results: The ROC-areas did not differ significantly between the various assays of NT-proBNP and BNP, and ranged from 0.68 (95%CI 0.60–0.73) to 0.73 (95%CI 0.64–0.81). For NT-proBNP the age- and gender-independent "optimal" cut-point was 15 pmol/l (125 pg/ml) and for BNP 10 pmol/l (35 pg/ml). All assays were much better at excluding than detecting heart failure.

Conclusions: All assays of B-type natriuretic peptide showed reasonable and comparable accuracy in recognising heart failure. At "optimal" cut-points, all assays performed better at excluding than detecting new cases of heart failure in this population.

Key Words: Heart failure • B-type natriuretic peptides • Diagnosis • Chronic obstructive pulmonary disease

Received April 15, 2006; Revised November 29, 2006; Accepted January 18, 2007


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 References
 
Heart failure is a complex clinical syndrome and clinical diagnosis is notoriously difficult in the early phases and in elderly patients with co-morbid chronic obstructive pulmonary disease (COPD) due to an overlap in signs and symptoms [1]. B-type natriuretic peptides have been shown to be useful in the diagnostic assessment of patients suspected of having heart failure by their general practitioner [2,3] and in patients with acute dyspnoea [4]. In addition, B-type natriuretic peptide assays are more readily available than other tests such as echocardiography. However, studies designed to assess the diagnostic utility of B-type natriuretic peptides for detecting or ruling out heart failure in COPD patients are scarce [5,6].

Most diagnostic studies are performed with either B-type natriuretic peptide (BNP) or the amino-terminal fragment of pro-BNP (NT-proBNP). Few data, however, are available on the comparative performance of these assays in clinical decision-making [7,8]. Comparative data on the performance of different B-type natriuretic peptides are also lacking for the difficult to assess population of patients with a diagnosis of COPD.

After release, pro-BNP splits into two fragments, that is, the biologically active BNP and inactive NT-proBNP. Both of these B-type natriuretic peptides are stable (i.e. no degradation when applying up to four freeze/thaw cycles or storage for several months frozen below –20 °C) and can easily be detected and quantified by immunometric assays in serum or plasma. The molecular weight of these B-type natriuretic peptides differ, and because NT-proBNP is not cleared actively, it has a longer half-life, with plasma levels 2-10 times higher than BNP [9]. BNP Centaur (Bayer Inc.) and BNP AxSYM (Abbott Inc.) are both sandwich-type immunoassays based on two monoclonal antibodies, with the same detection antibody, but a different capture antibody [10]. Whether the biological and clearance differences between NT-proBNP and BNP on the one hand, and the differences in capture antibodies between the two BNP assays on the other hand have diagnostic implications for identifying heart failure in patients with a clinical diagnosis of COPD is unknown. In addition, it is unclear whether plasma and serum measurements of NT-proBNP are interchangeable. The latter is important in view of the discrepancies in the recommendations of the producer (Roche Inc.) and clinical practice regarding NT-proBNP assessment [11,12].

We compared the diagnostic ability of two assay systems for BNP (Centaur and AxSYM), and plasma versus serum NT-proBNP in detecting or ruling out heart failure in a diagnostically difficult population of stable elderly patients with COPD according to their general practitioner.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 References
 
2.1. Participants
In this cross-sectional study, 200 patients aged 65 years or over, with a general practitioner's diagnosis of COPD, and without known heart failure (i.e. heart failure with objective evidence of (systolic and/or diastolic) ventricular dysfunction), were enrolled in the study. This was a random sample (every second patient was included) of a total study population of 405 elderly patients with a GP's diagnosis of COPD, in a stable phase of their disease [13]. The study was conducted between April 2001 and June 2003.

The Medical Ethics Committee of the University Medical Center Utrecht, the Netherlands, approved the study protocol and all participants gave written informed consent. The investigation conformed with the principles outlined in the Declaration of Helsinki.

2.2. Diagnostic work-up
All participants underwent an extensive diagnostic work-up at our out-patient clinic, including patient history, physical examination, electrocardiography, chest radiography, laboratory measurements, pulmonary function tests, and echocardiography. Standard 12-lead electrocardiograms (ECG) were recorded and classified according to the Minnesota coding criteria [14]. Chest radiographs were taken according to standard radiological criteria. Blood samples were taken and analysed the same day, and after centrifugation specimens of serum and plasma were stored at –70 °C. Lung function measurements were performed with a fixed-volume body plethysmograph and Masterscreen (Masterlab Jaeger, Würzburg, Germany). Finally, echocardiographic studies were performed by two experienced cardiac sonographers using a Philips Sonos 5500 imaging system (Andover, MA., USA) and interpreted by a single cardiologist (M-J.M.C.) specialised in echocardiography. Parameters from Doppler analysis, M-mode, and two-dimensional transthoracic echocardiography were used. Where image quality was sufficient, the left-ventricular ejection fraction (LVEF) was calculated using Simpson's rule (disc summation method) [15]. Alternatively, the single plane area-length method or 2D visual estimate method was applied [16,17]. Left atrial volume was assessed by the biplane area-length method from apical 4- and 2-chamber views [18]. After correction for body surface area, cut-off values for normal and definitely increased left atrial volume index of 28 ml/m2 and 32 ml/m2 respectively, were used [18]. Pulsed-wave Doppler mitral inflow and pulmonary venous inflow was assessed, and the E/A velocity ratio and ratio of systolic to diastolic forward flow (S/D ratio) was calculated. Diastolic function was categorised as normal, impaired relaxation (grade I), pseudonormal filling (grade II), or restrictive filling (grade III) by a combination of transmitral and pulmonary flow patterns and left atrial volume indexes [19]. (Appendix). We measured the peak velocity of the tricuspid regurgitant signal with continuous-wave Doppler and calculated the systolic pulmonary artery pressure with the modified Bernoulli equation [20].

2.3. B-type natriuretic peptide measurements
At the end of the study, NT-proBNP and BNP levels were measured for all patients in a single batch, after the frozen specimens were thawed. NT-proBNP was measured with an automated non-competitive immunoradiometric assay (Roche Inc., Mannheim, Germany) on an Elecsys 1010 analyser. Both EDTA-plasma and serum were analysed. During analysis, laboratory measurements of one serum and eight plasma samples of NT-proBNP were accidentally omitted. Results are given in pmol/l, to convert to pg/ml, multiply by 8.457.

For plasma BNP measurements we used the automated Abbott AxSYM BNP immuno-assay (Abbott Inc., Park Ill, USA) and Bayer Centaur BNP immuno-assay (Bayer Inc., Leverkusen, Germany), using the Advia Centaur analyser. Results are given in pmol/l, to convert to pg/ml, multiply by 3.467.

2.4. Presence or absence of heart failure
The final diagnosis of heart failure was determined by an expert panel, in accordance with previous studies [2,4]. As stated by the Standards for Reporting of Diagnostic Accuracy (STARD) initiative, consensus diagnosis is the best proxy reference in the absence of an ideal standard, such as in heart failure [21]. The panel used the diagnostic principles for heart failure defined by the ESC, that is, symptoms of heart failure and echocardiographic evidence of (systolic and/or diastolic) ventricular dysfunction [22]. The panel comprised two cardiologists, a pulmonologist and a general practitioner. In case of no consensus, the majority decided whether the case definition was met. In case of evenly split votes (which occurred in three patients) we used the majority decision of the two cardiologists and the general practitioner. The panel had at its disposal the results of all non-invasive diagnostic tests in all patients (i.e. patient's history, physical examination, ECG, blood tests (except BNP and NT-proBNP), chest X-ray, pulmonary function tests, and echocardiography.

Patients with heart failure were further classified as systolic, ‘isolated’ diastolic, or ‘isolated’ right sided heart failure. For systolic heart failure, patients had to have indicative symptoms of heart failure (i.e. orthopnoea, paroxysmal nocturnal dyspnoea, fatigue, peripheral oedema, nycturia ≥2 times a night, or any combination of these symptoms) in combination with an echocardiographic LVEF≤45%. ‘Isolated’ diastolic dysfunction was defined as echocardiographic diastolic dysfunction (grade I, II, or III) (Appendix) in combination with LVEF>45%. For ‘isolated’ diastolic heart failure patients had to have in addition to echocardiographic diastolic dysfunction (i) indicative symptoms and signs (i.e. peripheral or pulmonary fluid retention and/or elevated jugular venous pressure) of heart failure [20], or (ii) indicative symptoms and echocardiographic left ventricular hypertrophy, atrial fibrillation, or anginal complaints [23]. ‘Isolated’ right sided heart failure was defined as increased systolic pulmonary arterial or right ventricular dysfunction assessed semiquantatively by the 2D visual estimate method, or both, and a LVEF>45%.

Because nearly all participants experienced dyspnoea (98%), and dyspnoea is indicative of both heart failure and COPD, this symptom was not useful in identifying heart failure in this patient population.

2.5. Data analysis
The association between NT-proBNP and BNP and the presence or absence of previously unrecognised heart failure was quantified applying univariate and multivariate logistic regression analysis. The ability of NT-proBNP and BNP to discriminate between patients with and without heart failure was estimated using the area under the receiver operating characteristic curve (ROC-area) [24]. Different cut-off levels for NT-proBNP and BNP were used to calculate positive and negative predictive values, and sensitivity and specificity, with 95% confidence intervals [25]. For assessment of the ‘optimal’ cut-off value we depicted the ROC-curve and adopted the value of BNP or NT-proBNP closest to optimal sensitivity and specificity (i.e. highest sum of sensitivity and specificity). For ease of use, values of BNP and NT-proBNP were rounded to the nearest integer. When cut-off values had equal sums of sensitivity and specificity we took the cut-off value with the highest negative predictive value.

Because natriuretic peptide measurements had a skewed distribution, natural logarithmic transformation was applied before assessing Pearson's correlation coefficient. All data showed a Gaussian distribution after log transformation. Bland-Altman plots were applied to investigate the influence of the levels of B-type natriuretic peptide on the observed differences between the assays [26].


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 References
 
The mean age of the participants was 73 (SD 5.4) years, and 58% were male. Baseline demographics and clinical characteristics are presented in Table 1. In 51 (25.5%) participants previously unrecognised heart failure was diagnosed by the panel. Twenty-nine had (14.5%) systolic, 22 (11%) had ‘isolated’ diastolic, and none had ‘isolated’ right sided heart failure. Cardiovascular medication (ACE inhibitors, angiotensin-II blockers, β-blockers and diuretics) was more commonly received by patients who were eventually classified as heart failure patients, although not significantly. One participant had a serum creatinine concentration greater than 200 µmol/l (i.e. 243 µmol/l), and no participants had a blood urea greater than 20 mmol/l. Nearly all participants (98%) suffered from dyspnoea and more than one third had a history of ischaemic heart disease or hypertension. Abnormal pulmonary sounds were common (36%) and it was difficult to distinguish rhonchi from crepitations on physical examination.


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  		Table 1 Characteristics of 200 patients with a clinical diagnosis of COPD and according to the presence or absence of heart failure

 
Of the participants 118 (59.0%) were classified as COPD according to the GOLD criteria (a ratio of forced expiratory volume in 1 second and forced vital capacity (FEV1/FVC) <70%) [27]. The prevalence of heart failure was similar in patients with COPD according to the GOLD-criteria (30/118, 25.4%) and in those with a clinical diagnosis of COPD based on pulmonary complaints (i.e. complaints of dyspnoea, cough and/or sputum production) who did not fulfil the GOLD criteria for COPD (21/82, 25.6%). Of the patients with COPD according to GOLD, 37 (31.4%) had mild COPD (GOLD I), 64 (54.2%) moderate (GOLD II), and 17 (14.4%) severe COPD (GOLD III) [28]. There was no clear relation between severity of COPD and presence of heart failure (Fig. 1).


Figure 01
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  		Fig. 1 Severity of COPD according to GOLD classification, and LV ejection fraction in relation to serum NT-proBNP and plasma BNP Centaur.

 
Median values of all B-type natriuretic peptide assays differed significantly between those patients with and those without heart failure (Table 2). Median serum levels of NT-proBNP (15.5 pmol/l, IQR 9.3-30.6) were 0.96 pmol/l higher than plasma levels of NT-proBNP. Median plasma levels of BNP AxSYM (13.2 pmol/l, IQR 5.6-19.3) were 3.57 pmol/l higher than the levels of BNP Centaur.


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  		Table 2 Serum and plasma NT-proBNP measurements and BNP measurements (AxSYM and Centaur) in 200 patients with a general practitioner's diagnosis of COPD and their association with presence or absence of heart failure

 
Patients with systolic heart failure had higher natriuretic peptide levels and larger ROC-area's than those with ‘isolated’ diastolic heart failure (Table 2). The ROC-areas of the four B-type natriuretic peptide assays did not differ significantly, but was highest for NT-proBNP measured in serum (0.73 (95% CI 0.64-0.81), and lowest for plasma BNP AxSYM (0.68 (95% CI 0.60-0.73) (Table 2, Fig. 1). The ROC-areas in men (ROC-area 0.68-0.75) and those aged >75 years (ROC-area 0.72-0.74) tended to be higher, although the difference was not statistically significant, to that in women (ROC-area 0.65-0.69) and those aged ≤75 years (ROC-area 0.66-0.73), respectively. The four BNP assays had ROC-areas of around 0.60 for establishing presence or absence of ‘isolated’ diastolic heart failure, and ROC-areas of 0.75-0.80 for systolic heart failure (Table 2). The ROC-areas for detecting a LVEF <30% (8 (4%) patients) were 0.95-0.96, while the ROC-areas for detecting a LVEF of 30-45% (21 (11%) patients) were 0.66-0.72. Separate analyses restricted to patients with COPD according to the GOLD-criteria (N=118) provided similar ROC-areas for BNP and NT-proBNP as for the total population of patients with a clinical diagnosis of COPD (N=200).

The ‘optimal’ cut-point for NT-proBNP was 15 pmol/l (125 pg/ml) and for BNP 10 pmol/l (35 pg/ml) (Table 3). These cut-points were age and gender independent. All four B-type natriuretic peptide assays had a negative predictive value of 0.85 to 0.89 and a positive predictive value of 0.34 to 0.40 for identifying heart failure at the ‘optimal’ cut-point, depending on the applied assay system. The negative predictive values for identifying ‘isolated’ diastolic heart failure and systolic heart failure separately at the ‘optimal’ cut-point were 0.91 to 0.93 and 0.93 to 0.96, respectively, and the positive predictive values 0.12 to 0.15 and 0.21 to 0.25, respectively, depending on the assay system used.


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  		Table 3 Sensitivity, specificity, positive and negative predictive value, and accuracy of serum NT-proBNP and plasma BNP Centaur in identifying heart failure at different cut-off points

 
After log transformation, Pearson's correlation coefficients between measurements of NT-proBNP in serum and plasma were very high (r=0.998, p<0.001). The correlation between plasma measurements of BNP AxSYM (Abbott Inc.) and BNP Centaur (Bayer Inc.) (r=0.818, p<0.001) was also high (Table 4). Correlation between NT-proBNP measured in serum and BNP AxSYM (r=0.744, p<0.001) was somewhat lower. Bland-Altman plots showed that differences between log transformed NT-proBNP serum and plasma levels were small, with consistently higher levels for serum measurements. Differences between log transformed BNP AxSYM and Centaur were less small, with higher levels for BNP AxSYM. The Bland-Altman plot showed that for higher BNP levels, BNP Centaur tended to be higher than BNP AxSYM.


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  		Table 4 Pearson's correlation coefficients between natural logarithmic transformed B-type natriuretic peptide measurements

 
Separate analyses restricted to patients with COPD according to the GOLD-criteria (N=118) provided the same ‘optimal’ cut-points for BNP and NT-proBNP as for the total population of patients with a clinical diagnosis of COPD (N=200).

B-type natriuretic peptide levels were not influenced by the severity of COPD (according to the GOLD-classification) (Fig. 1). With increasing severity of left ventricular dysfunction (decreasing LV ejection fraction) B-type natriuretic peptide levels increased, with a significant difference between LVEF≤30% and other LV ejection fractions (Fig. 1).


   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
References
 
Our study shows that different NT-proBNP and BNP assays are helpful diagnostic indicators for selecting patients who should undergo echocardiographic screening to detect previously unknown heart failure, in a population of stable elderly patients with a primary care diagnosis of chronic obstructive pulmonary disease (COPD). The four natriuretic peptide assays were comparable overall in their ability to detect or rule out heart failure in these patients. In addition, serum and EDTA-plasma measurements of NT-proBNP (Roche Inc.) were interchangeable because differences were extremely small and not clinically significant. The overall diagnostic ability of the four assay systems was reasonable to good for detecting or excluding heart failure. Due to low positive predictive values, the overall diagnostic ability of the BNP assays was moderate in identifying heart failure patients with moderate left ventricular dysfunction (i.e. LVEF 30-45%) and poor for identifying those with ‘isolated’ diastolic heart failure. Importantly, however, the four assay systems performed adequately in ruling out severe (i.e. those with a LVEF <30%) or less severe (LVEF 30-45% and ‘diastolic’ ventricular dysfunction) heart failure at the age- and gender-independent ‘optimal’ cut-points of 15 pmol/l (125 pg/ml) for NT-proBNP and 10 pmol/l (35 pg/ml) for BNP, with all negative predictive values above 0.85.

BNP Centaur tends to have higher concentrations than BNP AxSYM in patients with low BNP values, whereas in patients with high BNP values, BNP Centaur concentrations tend to be lower. Differences in capturing antibodies between these two commercially available BNP assays could cause this difference in diagnostic performance at variable BNP values. In the overall diagnostic performance this difference between the two BNP assays, however, seems not to be of clinical relevance.

Natriuretic peptide levels were clearly influenced by left ventricular ejection fraction (severity of LV dysfunction), but not by the severity of COPD (according to the GOLD-classification). A limitation, however, is the low number of patients with severe COPD in our study. Moreover, the limited number of patients with severe COPD could also be the reason for the absence of ‘isolated’ right sided heart failure in our study.

The overall diagnostic accuracy of the natriuretic peptide measurements in detecting or ruling out heart failure in our study was lower than in previous studies in patients suspected of heart failure [2] or patients with acute dyspnoea visiting an emergency department [4,7]. The age- and gender-independent ‘optimal’ cut-points in our stable patients with a clinical diagnosis of COPD are relatively low and of the same value as suggested by the manufacturer in case of NT-proBNP; however, they are much lower than the manufacturer's advised cut-point for normal in the case of BNP. Our ‘optimal’ cut points are comparable with other studies performed in relatively stable primary care patients [2,29], but much lower than should be applied in patients with acute dyspnoea presenting at the emergency department [4,30]. Differences in the patient population, that is, stable patients with chronic dyspnoea instead of patients with acute dyspnoea necessitating an emergency department visit is the most obvious reason for the lower diagnostic accuracy and cut-points for B-type natriuretic peptides in our study [31]. It is plausible that participants in our study overall had much lower intracardiac pressures than patients with acute dyspnoea (acute increase in intracardiac pressure) or patients suspected of heart failure (recent increase in dyspnoea and most often signs of volume overload). Since the production of B-type natriuretic peptides in the ventricular myocytes depends on intracardiac pressure, lower concentrations of B-type natriuretic peptides could be expected in our population [32,33]. Thus, B-type natriuretic peptide assays can be expected to accurately detect the presence of heart failure in those with severe left ventricular dysfunction (i.e. a LVEF <30%), but to perform less accurately in those with moderate left ventricular dysfunction (i.e. LVEF 30-45% or ‘isolated’ diastolic heart failure). There was no clear difference between the assay systems from different companies in this respect.

Another factor that decreased the discriminatory ability (‘contrast’) of B-type natriuretic peptides between those with and without heart failure was the relatively high median B-type natriuretic peptide levels (at the upper level or even above that of the suggested ‘normal’ range) of the participants without heart failure [25]. Previous studies have suggested that COPD patients without heart failure can have increased B-type natriuretic peptide levels, possibly due to some degree of right ventricular wall stress [34,35].

The diagnostic accuracy of all tested B-type natriuretic peptides was significantly lower for ‘isolated’ diastolic heart failure than for systolic heart failure. An earlier study showed that the diagnostic accuracy of BNP and NT-proBNP was lower for detecting diastolic dysfunction than systolic dysfunction [32]. Since BNP and NT-proBNP levels are positively correlated with intracardiac pressures and severity of heart failure [8], lower predictability of diastolic compared to systolic heart failure could be expected in our population.

Since our aim was to study possible differences in diagnostic performance between available B-type natriuretic peptide assays, the exact role of these measurements in the complete diagnostic process of identifying heart failure was not assessed. To address this issue, a study in a larger population sample is needed in which findings from history and physical examination should be included to determine the additional value of B-type natriuretic peptides [36].

The presence of heart failure was established by consensus evaluation, using all available diagnostic information [2]. This is an established method as reference standard, since a true ‘gold’ standard is lacking for assessing heart failure [37]. Moreover, our study and earlier studies showed that a panel diagnosis of heart failure was highly reproducible [38]. Re-presenting (blinded to the original decision) a random sample of 10% of our patients to the panel showed disagreement in one case only.

A considerable proportion (41%) of patients with a clinical diagnosis of COPD did not fulfil the GOLD-criteria of COPD. This proportion is comparable with the results of a recent study in a tertiary hospital in the US showing that only 31% of patients with a hospital discharge diagnosis of COPD had a confirmatory spirometry during hospital admission or in the eight years prior to admission, and of those who did have spirometry, 30% did not fulfil the GOLD-criteria of COPD [39]. Thus, although GOLD-criteria are widely accepted, implementation of spirometry in clinical practice is not yet very common in either general practice or hospitals. Importantly, we showed that the overall diagnostic capacity of BNP and NT-proBNP was essentially the same, revealing similar ROC-areas and the same ‘optimal’ cut-points in patients with COPD according to GOLD compared to the total population of patients with a clinical diagnosis of COPD. Thus, the results of our study are applicable to the large population of patients with a diagnosis of COPD, comprising about 15% of all persons aged 65 years or over.

In conclusion, NT-proBNP and BNP assays did not differ significantly in their overall diagnostic ability to detect or rule out previously unknown heart failure in stable patients (i.e. chronic dyspnoea) with a diagnosis of COPD. B-type natriuretic peptide measurements could serve as selection criteria for those patients requiring echocardiography because BNP and NT-proBNP had high negative predictive values in this large population. Importantly, this high negative predictive value occurred at low ‘optimal’ cut-points compared to those suggested for patients with acute dyspnoea presenting at the emergency department. The overall diagnostic ability of both NT-proBNP and BNP are lower for detecting heart failure in stable patients with chronic dyspnoea and a diagnosis of COPD than in patients with acute dyspnoea presenting at the emergency department.

Doppler echocardiographic criteria used for classification of diastolic function


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E/A, early-to-atrial left ventricular filling ratio; DT, deceleration time; IVRT, isovolumetric relaxation time; S/D, systolic-to-diastolic pulmonary venous flow ratio; LA volume index, left atrial volume indexed for body surface area.


   Acknowledgement
 
We thank the participating patients, general practitioners, and their assistants, including the general practices connected to the General Practice Network Utrecht (HNU), the cardiac sonographers Elly Lutgert-Hagman and Ineke Kasteleijn, the pulmonology technicians, especially Paul Munnik, and Pieter Zanen, the lung physiologist. Frances Verheij assisted us with the data management. SALTRO, the department of clinical chemistry was helpful with the blood analyses. We thank Roche Inc. (Mannheim, Germany), Abbott Inc. (Illinois, USA), and Bayer Inc. (Leverkusen, Germany) for supplying the assays for analysis of NT-proBNP, BNP AxSYM and BNP Centaur, respectively.

This study was financially supported by a grant (number 904-61-144) from the Netherlands Organisation for Scientific Research (NWO).

Conflict of interest: FHR received funding for an educational symposium and lecturing from Roche Inc.


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

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