© 2005 European Society of Cardiology
The diagnostic accuracy of plasma BNP and NTproBNP in patients referred from primary care with suspected heart failure: Results of the UK natriuretic peptide study
a Department of Clinical Cardiology, National Heart & Lung Institute, Imperial College Royal Brompton Campus, London, UK
b Department of Cardiology, Western Infirmary Glasgow, UK
c Department of Cardiovascular Medicine, National Heart & Lung Institute, Charing Cross Hospital London, UK
d Department of Cardiology, Royal Infirmary Glasgow, UK
e Academic & Clinical Department of Cardiovascular Medicine, St. Mary*s Wing, Whittington Hospital & UCL, London, UK
* Corresponding author. Tel. +44 207 3518148. E-mail address: m.cowie{at}imperial.ac.uk
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Abstract |
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 Top Abstract 1. Introduction2. Methods3. ResultsReferences |
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Objectives: To determine the diagnostic accuracy of the measurement of plasma B-type natriuretic peptide (BNP) and N-terminal pro-BNP (NTproBNP) in patients referred by their general practitioners (GPs) with symptoms suggestive of heart failure. Additionally, to compare the diagnostic accuracy of the resting 12-lead electrocardiogram (ECG) with that of the peptides.
Design: A diagnostic accuracy study.
Setting: Rapid-access heart failure clinics in five hospitals.
Participants: 306 patients referred by their GPs with suspected heart failure.
Main outcome measures: Sensitivity, specificity, positive and negative predictive values (PPV and NPV) and positive and negative likelihood ratios for BNP, NTproBNP and the ECG for the diagnosis of heart failure. Area under the receiver operating characteristics (ROC) curves for the two natriuretic peptides.
Results: The diagnosis of heart failure was confirmed in 104 (34%) patients. The area under the ROC curve was 0.84 [95% CI 0.79–0.89] for BNP and 0.85 [0.81–0.90] for NTproBNP. At the manufacturers' recommended decision cut-points, NTproBNP provided a higher NPV (0.97) than BNP (0.87), but at lower PPV (0.44 versus 0.59). An abnormal ECG did not add any further predictive value to that of NTproBNP.
Conclusions: We have confirmed the value of the measurement of plasma BNP or NTproBNP as a ‘rule-out’ test for heart failure in patients currently referred by GPs to rapid access diagnostic clinics. A simple classification of the 12-lead ECG into ‘normal’ or ‘abnormal’ adds little value to ruling out heart failure in these circumstances. Further work is necessary to establish the best decision cut-points for use in clinical practice.
Key Words: B-type natriuretic peptide • NT-proBNP • Heart failure • Diagnosis • Sensitivity and specificity
Received October 20, 2004; Revised December 20, 2004; Accepted January 27, 2005
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1. Introduction |
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TopAbstract1. Introduction2. Methods3. ResultsReferences |
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The clinical diagnosis of heart failure is challenging, particularly for GPs who often deal with more subtle presentations of the syndrome than hospital physicians. Published studies suggest that less than half of patients suspected of having heart failure by a primary care physician have this diagnosis confirmed on further cardiac investigation and evaluation by a specialist [1–3].
It is widely accepted that clinicians should not diagnose heart failure based on clinical grounds alone. This concept is supported by the European [4] and North American [5] guidelines, which advocate the use of cardiac imaging to obtain objective evidence of cardiac dysfunction (most usually by transthoracic echocardiography). However, the low diagnostic yield of echocardiography among patients referred with suspected heart failure from primary care confirms that clinicians require more evidence than from history taking and clinical examination alone in order to select candidates for echocardiography more appropriately. Furthermore, in many health care systems (including the UK) access to echocardiography is restricted—particularly for GPs. The long waiting times for this test and the cost involved may impose additional hurdles. Not surprisingly, a recent survey on the quality of care among patients with heart failure in Europe found that even among hospitalised patients only 66% have had an echocardiogram [6].
A blood test for heart failure that was simple and easy to interpret would have enormous appeal, particularly among GPs. BNP (and its N-terminal counterpart NTproBNP) are secreted chiefly by the ventricular heart muscle. BNP causes natriuresis, diuresis and smooth muscle relaxation, whereas NTproBNP is biologically inactive [7]. The production and plasma concentration of these peptides are increased in patients with heart failure [8]. A small, single-centre study raised hopes that the measurement of plasma BNP could be used as ‘rule-out— test for heart failure in patients referred from primary care [9]. Another study reported that ECG could be used for the same purpose, albeit with a lower positive predictive value [10]. Both tests have been recommended as suitable ‘rule-out— tests in the recent guidance on the management of heart failure for the NHS in England and Wales from the National Institute for Clinical Excellence (NICE) [11].
We conducted a multi-centre study to determine the diagnostic utility of plasma BNP and NTproBNP in patients presenting to their GP with new symptoms suggestive of heart failure. Additionally, we compared the diagnostic value of the resting 12-lead ECG as a "rule-out" test for heart failure with BNP and NTproBNP.
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2. Methods |
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TopAbstract1. Introduction2. Methods3. ResultsReferences |
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2.1. Assessment and investigation
Between July 2001 and May 2003, we recruited 306 consecutive patients referred by their GPs to the rapid access heart failure clinics in the five participating centres: Aberdeen Royal Infirmary; Western General and Royal Infirmary, Glasgow; Whittington Hospital, London; and Charing Cross Hospital, London. Aberdeen and Charing Cross withdrew from the study after recruiting only 18 and 14 patients, respectively, due to staff changes and operational reasons.
A cardiologist examined all referred individuals and recorded their medical history. An ECG, chest radiograph and transthoracic echocardiogram were performed. Venous blood was drawn for measurement of full blood count, serum urea, creatinine, and electrolytes, and plasma BNP and NTproBNP. Patients with a previously documented history of heart failure were excluded from the study.
2.2. Plasma natriuretic peptide concentration measurement
A 10 ml venous blood sample was drawn into an EDTA tube. BNP was assayed using a point-of-care fluorescence immunoassay (Biosite Diagnostics, Velizy, France [12]) at each centre. Samples for NT proBNP were posted to the core laboratory in Glasgow for analysis using an automated ELISA assay on the ElecsysTM system (Roche Diagnostics, Basel, Switzerland) [13].
2.3. Resting 12-lead ECG
The ECG was recorded and reported according to routine practice at the participating centres. For the purposes of this report, only ECGs that were completely normal were classified as ‘normal—. All other ECGs (including those with atrial fibrillation, paced rhythm, bundle branch block, Q waves, ST/T wave abnormalities, and those fulfilling the Sokolow criteria for left ventricular hypertrophy [14] were classified as ‘abnormal—).
2.4. Echocardiography
All centres used their local protocols for transthoracic Doppler 2D echocardiography, based on the ACC/AHA guidelines [15]. Left ventricular systolic function was graded semi-quantitatively (normal, mild/moderately impaired, severely impaired), and quantitatively by calculation of fractional shortening and ejection fraction.
2.5. Diagnosis of heart failure
Heart failure was diagnosed by the cardiologist only if there was at least one symptom of heart failure (shortness of breath, fatigue, leg oedema) at rest or on exertion and objective evidence of cardiac dysfunction at rest on assessment including echocardiography, as recommended by the European Society of Cardiology [16]. The diagnosing physicians were blind to the BNP and NTproBNP results.
2.6. Data analysis
Categorical variables are described as proportions, and continuous variables using mean and standard deviation for normally distributed variables, and median and 90% range for non-normal distributions. Differences between groups were examined using 
2 test for categorical variables, and unpaired t-tests for continuous variables. The plasma concentration of the natriuretic peptides are reported using the raw data, but due to the positively skewed distributions differences between groups were compared using parametric statistics on log-transformed values. Spearman's correlation coefficient was used to compare the concentrations of BNP and NT-proBNP. Diagnostic utilities were calculated using the sensitivity, specificity, negative and positive predictive values, and negative and positive likelihood ratios. Receiver operating characteristic (ROC) curves were drawn for both peptides using the diagnosis of the examining cardiologist as the ‘gold standard— and the area under the curve (AUC) was calculated. The independent contribution of the two peptides, and the ECG, to the diagnosis of heart failure was assessed using logistic regression. SPSS v11.5 and STATA 7.0 were used for the analyses.
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3. Results |
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TopAbstract1. Introduction2. Methods3. ResultsReferences |
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The characteristics of the 306 patients enrolled in this study are shown in Table 1. The median age was 74 years. More women (176; 58%) than men were referred for assessment. A history of hypertension, diabetes, and coronary artery disease was common. The 12-lead ECG was abnormal in 163 (53%) patients.
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After full assessment, the diagnosis of heart failure was confirmed in 104 (34%) patients. Of these 104 individuals, 79 (76%) had impaired left ventricular (LV) systolic dysfunction and 24 (23%) had preserved systolic LV function [data missing for one patient (1%)]. Valve disease was thought to be responsible for the development of heart failure in 17 (16%) cases and other causes in 14 (13%). The total exceeds 100% as some patients had more than one cardiac abnormality.
Plasma BNP concentration was available for 301 patients, and NTproBNP in 302 patients. The correlation between the plasma concentrations of both peptides was very high (r=0.92, P<0.001). BNP was higher in patients with a confirmed diagnosis of heart failure (median and 90% range 285 [29–1300] pg/ml) compared with the other patients (51 [7–350] pg/ml, P<0.001). A similar difference was found for NTproBNP (1537 [166–21 854] pg/ml compared with 202 [22–2323] pg/ml, P<0.001).
The ROC curves for both peptides are shown in Fig. 1. The AUC was similar at 0.84 [95% CI 0.79–0.89] for BNP and 0.85 [0.81–0.90] for NTproBNP. The AUC was also similar when stratified by median age at presentation, or by gender (data not shown). Visual inspection of the curves fails to reveal an obvious ‘shoulder— but BNP did not reach as high a sensitivity as NTproBNP for a range of specificities, suggesting that it may be of less value as a ‘rule-out— test. This is confirmed in a multivariate logistic regression model, where comparison of the two peptides suggests that BNP does not provide independent diagnostic information to that provided by NTproBNP alone (Table 2a).
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Currently, the manufacturers recommended decision cut-points for ‘rule-out— of heart failure in patients with new symptoms are 100 pg/ml for BNP, and 125 pg/ml for NTproBNP. The diagnostic utility at these cut-points is shown in Table 3. At these recommended levels, NTproBNP has considerably higher sensitivity (and hence negative predictive value) but slightly lower positive predictive value. A lower decision cut point for BNP would provide better diagnostic utility.
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Classifying the ECG as ‘normal— or ‘abnormal— provided a sensitivity of 0.81, indicating that nearly 20% of patients with heart failure may have a normal ECG. In our cohort of patients, 20 out of the 104 patients who were found to have heart failure had normal ECGs. Importantly, 17 out of these 20 patients had abnormal NTproBNP and 14 had abnormal BNP concentrations, using cut-points of 166 pg/ml and 65 pg/ml respectively. Negative predictive value was 0.86, positive predictive value 0.51, specificity 0.60, positive likelihood ratio 2.00, and negative likelihood ratio 0.31(Table 3). The logistic models in Table 2b show that the ECG adds independent diagnostic information (as to whether an individual has heart failure or not) to that provided by BNP, but not NTproBNP.
3.1. Discussion
Heart failure is difficult to diagnose in the community. Our study supports the evidence from studies in London [1,17], Scotland [3] and Finland [2] that only about a third of patients suspected to have heart failure in primary care (and referred to secondary care) have this diagnosis confirmed following full cardiac assessment including echocardiography. In practice many patients with suspected heart failure receive treatment without appropriate confirmation of the diagnosis [6]. However, if all patients with suspected heart failure were referred for echocardiography, services in some countries would not easily cope with the increased demand. This has been recognised in the recent guidance to the National Health Service in England and Wales from NICE, where the recommendation is made that a normal ECG and/or BNP(NTproBNP) measurement can be used to ‘rule-out— heart failure in the first instance [11].
The measurement of BNP is now available as a point-of-care test and samples for NTproBNP can be sent unprocessed through the post to the hospital laboratory for testing. Both tests can be used in routine primary care practice with minimal training.
In our study, the conditions under which the patients were referred and diagnosed reflected the routine, every-day practice of the participating centres. In particular the ‘gold standard— to which we compared the performance of the measurement of these natriuretic peptides as tests for heart failure accurately mirrors the standard practice for patients referred to hospital: the examining cardiologist (or other physician) confirms or refutes the diagnosis of heart failure following the full assessment of the patient, including echocardiography.
Both peptides have an overall favourable diagnostic utility, but if used as a ‘rule-out— test NTproBNP appears to hold a small advantage, at least in our population. This may be because the plasma concentration of NTproBNP is more stable, and is more likely to reflect an ‘average— circulating concentration of peptide than BNP-which can vary relatively rapidly in response to exercise or ischaemia [18,19]. The additional value of performing an ECG solely as a ‘rule-out— test appears to be relatively small, although if the measurement of natriuretic peptides is not available this may still be considered. It should be remembered, however, that the ECG may provide other useful information such as the presence of a cardiac arrhythmia or evidence of previous myocardial infarction.
This study provides important evidence in support of the growing persuasion that B-type natriuretic peptides can be useful tools in determining whether new symptoms are likely due to heart failure or not, and is entirely consistent with the recent recommendations of both the European Society of Cardiology [4] and the National Institute for Clinical Excellence [11]. A high plasma concentration does not confirm the diagnosis of heart failure, nor does it provide specific information about any underlying cardiac abnormality. Further cardiological investigation will be required. Adoption of such an approach, however, is likely to increase the efficiency with which more sophisticated cardiological testing (including echocardiography) is used. This is likely to be of particular importance in health care systems where access to such testing is limited or slow.
3.2. Limitations of the study
The performance of a diagnostic test depends on the prevalence of the disease in the examined population. The prevalence of heart failure in our cohort of referred patients was 34%, in line with previous studies. Our study centres have a strong background and expertise in heart failure, and this may have positively influenced the accuracy of the diagnosis of heart failure on assessment. Furthermore, the awareness and ability of participating GPs to diagnose heart failure may have been above the usual standard.
3.3. Conclusions
Only a third of patients referred by general practitioners for assessment of new symptoms possibly due to heart failure have this diagnosis confirmed on full assessment. We have confirmed the value of measurement of plasma BNP or NTproBNP as a rule-out test in such patients presenting in primary care. A simple classification of the 12-lead ECG into ‘normal— or ‘abnormal— adds little value to ruling out heart failure in these circumstances. The choice of which natriuretic test to perform is likely to be determined by local factors relating to the relative merits of point-of-care testing compared with conventional laboratory testing. Further work is necessary to establish the best decision cut-points for use in clinical practice.
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Acknowledgements |
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The cost of the assays were met by Biosite Diagnostics (BNP) and Roche Diagnostics (NT-proBNP).
Competing interests statement: TMcD, HD and MRC have been reimbursed by Biosite Diagnostics and Roche Diagnostics for attending scientific conferences; running educational meetings; and have received funding for the cost of assays. SMCH, GM and KF have received funding for the cost of assays from both companies. None has shares in either company. AZ, SR and TMT have no competing interests to declare. The design, conduct and analysis were independent of both companies.
Ethical considerations: All patients provided written fully informed consent for enrolment in the study. The study protocol was approved by the Local Research Ethics Committees of the participating centres.
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