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(Chest. 2005;128:21-29.)
© 2005 American College of Chest Physicians

B-Type Natriuretic Peptide and Echocardiographic Determination of Ejection Fraction in the Diagnosis of Congestive Heart Failure in Patients With Acute Dyspnea*

Philippe Gabriel Steg, MD; Laurence Joubin; James McCord, MD; William T. Abraham, MD; Judd E. Hollander, MD; Torbjorn Omland, MD; France Mentré; Peter A. McCullough, MD; Alan S. Maisel, MD; for the Breathing Not Properly Multinational Study Investigators{dagger}

* From the Department of Cardiology (Dr. Steg), Centre d’Investigation Clinique, Hôpital Bichat-Claude Bernard, Assistance Publique-Hôpitaux de Paris, Paris, France; Department of Epidemiology, Biostatistics and Clinical Research (Drs. Joubin and Mentré), Hôpital Bichat-Claude Bernard, Assistance Publique-Hôpitaux de Paris, Paris, France; Heart and Vascular Institute (Dr. McCord), Detroit, MI; Division of Cardiovascular Medicine (Dr. Abraham), Davis Heart & Lung Research Institute, The Ohio State University, Columbus, OH; Department of Emergency Medicine (Dr. Hollander), University of Pennsylvania, Department of Emergency Medicine, Philadelphia, PA; Department of Medicine (Dr. Omland), Akershus University Hospital, University of Oslo, Oslo, Norway; Department of Medicine (Dr. Maisel), University of California, San Diego School of Medicine, Veterans Affairs Medical Center, San Diego, CA; and Division of Nutrition and Preventive Medicine (Dr. McCullough), William Beaumont Hospital, Royal Oak, MI. {dagger} Additional investigators are listed in the Appendix.

Correspondence to: Philippe Gabriel Steg, MD, Cardiology, Hôpital Bichat-Claude Bernard, Assistance Publique–Hôpitaux de Paris, 46 rue Henri Huchard, 75877 Paris Cedex 18, France; e-mail: gabriel.steg{at}bch.ap-hop-paris.fr


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 Conclusions
 Appendix
 References
 
Background: Echocardiography and B-type natriuretic peptide (BNP) are diagnostic tests for congestive heart failure (CHF), but an emergency diagnosis can be difficult.

Objective: To assess the diagnostic performance of BNP testing and echocardiographic assessment of left ventricular systolic function, separately and combined, for the identification of CHF in patients with acute dyspnea.

Design: Prospective, multinational, multicenter study.

Setting: Patients presenting to emergency departments in seven hospitals between June 1999 and December 2000.

Patients: A total of 1,586 patients with acute dyspnea.

Main outcome measures: Echocardiographic determination of ejection fraction (EF) and point-of care BNP measurement for the diagnosis of CHF.

Results: Seven hundred nine of the 1,586 patients underwent echocardiography; 492 patients (69.4%) had a final diagnosis of CHF. Patients with CHF were older (68.5 years vs 61.6 years, p < 0.0001), had a lower EF (39.5% vs 56.1%, p < 0.0001), and a higher BNP (683 pg/mL vs 129 pg/mL, p < 0.0001) than patients without CHF. Area under the receiver operating characteristic (ROC) curve for the diagnosis of CHF was significantly higher for BNP (0.89) than for EF (0.78; area under the ROC curve difference, 0.12; p < 0.0001). The sensitivity of BNP ≥ 100 pg/mL for the diagnosis of CHF was 89%, and specificity was 73%. Values for EF ≤ 50% had a sensitivity of 70% and a specificity of 77%. Multivariate logistic regression analysis showed that, in combination with clinical, ECG, and chest radiograph data, BNP ≥ 100 pg/mL and EF ≤ 50% remained independent predictors of CHF (odds ratios, 32.1 and 6.2, respectively). The proportions of patients who were correctly classified were 67% for BNP alone, 55% for EF alone, 82% for the two variables together, and 97.3% when clinical, ECG, and chest radiograph data were added.

Conclusion: BNP measurement was superior to two-dimensional echocardiographic determination of EF in identifying CHF, regardless of the threshold value. The two methods combined have marked additive diagnostic value.

Key Words: B-type natriuretic peptide • congestive heart failure • echocardiography


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 Conclusions
 Appendix
 References
 
Acute dyspnea is a common reason for admission to the emergency department. Often dyspnea is caused by congestive heart failure (CHF), which requires specific treatment. Yet, in the context of emergency medicine, accurate diagnosis or exclusion of CHF is often difficult, especially in elderly or obese patients, given the frequency of comorbidities such as COPD. The diagnosis of CHF is further hampered by the lack of specificity or sensitivity of the signs and symptoms1 and the lack of definitive "gold standard" for diagnosis. Echocardiography is a standard method for detecting left ventricular dysfunction and offers an indirect measure of left ventricular filling pressures.23 However, it is not routinely available in the context of emergency medicine, and its performance and interpretation require expertise on behalf of the operator.

B-type natriuretic peptide (BNP) is a cardiac neurohormone secreted from the cardiac ventricles in response to ventricular volume expansion and pressure overload.45 BNP levels are raised in patients with left ventricular dysfunction, and correlate with both New York Heart Association functional class and patient prognosis.67891011 Early studies1213 showed that elevated concentrations of BNP distinguish CHF from other causes of dyspnea more accurately than left ventricular ejection fraction (EF), atrial natriuretic peptide, or N-terminal atrial natriuretic peptide. A pilot study1 using a rapid (15 min), whole-blood assay for BNP demonstrated that point-of-care testing of BNP is a sensitive and specific test for the diagnosis of CHF in the urgent-care setting. A multinational study14 validated the clinical utility of rapid measurement of BNP, used in conjunction with other clinical information, for the diagnosis or exclusion of CHF in the emergency department. The present analysis focuses on the subset of patients in this study14 who underwent echocardiography. The aim of this report is to assess the diagnostic performance of BNP testing and echocardiographic assessment of left ventricular systolic function, separately and combined, for the identification of CHF in a broad population of patients presenting with acute dyspnoea. The methods and rationale for that study14 have been reported.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 Conclusions
 Appendix
 References
 
The study was approved by the institutional review boards of participating study centers. A total of 1,586 patients from seven sites (five in the United States, one in France, and one in Norway) were enrolled from June 1999 to December 2000. To be eligible for inclusion, patients had to have shortness of breath as their most prominent complaint. Patients aged < 18 years, those whose dyspnea was not secondary to CHF (eg, cardiac tamponade), and patients with acute myocardial infarction, renal failure, and obvious trauma were excluded. Patients with unstable angina were excluded unless their predominant presentation was dyspnea.

Potential patients were identified through a review of nurse descriptions of the patient’s principal complaints by a physician or trained research assistant. Patients who fit the inclusion criteria were asked about participating in the study, and written informed consent was obtained. A 5-mL blood sample was collected into a tube containing potassium ethylenediamine tetra-acetic acid (1 mg/mL blood). BNP was measured using a fluorescence immunoassay kit (Triage; Biosite Diagnostics; San Diego, CA). The patient’s medical history, results of physical examination and other blood tests, and interpretations of chest radiographs or other diagnostic tests were collected.

For each patient enrolled in the study, emergency department physicians who were blinded to the results of the BNP measurements assessed the percentage of probability of the patient having CHF as the cause of symptoms. In patients with a history of CHF, physicians classified the patient as having either an acute exacerbation of CHF or another cause of dyspnea with underlying left ventricular dysfunction (eg, patients with left ventricular dysfunction but who presented for bronchitis).

Confirmation of Diagnosis
To confirm the diagnosis, two cardiologists independently reviewed each patient’s medical records and classified them as having dyspnea due to CHF, acute dyspnea due to a noncardiac cause in those with a history of CHF, and dyspnea not due to CHF. The cardiologists were presented with the components and a summary of the Framingham scores for CHF (two major, or one major and two minor criteria), and the National Health and Nutrition and Examination Survey (NHANES) CHF score (≥ 3) calculated from the case report form along with other information from the emergency department data sheets. Both cardiologists were blinded to the results of BNP measurement and the emergency physician’s diagnosis. Additionally, they had access to the emergency department data sheets and any additional information that became available after the initial evaluation. This included a chest radiograph and the electrocardiogram in all patients and, if applicable, the medical history obtained from a medical chart that was not available at presentation to the emergency department; the results of subsequent tests such as echocardiography, radionuclide angiography, or left ventriculography performed at cardiac catheterization; and the in-hospital course for patients admitted to hospital. For patients with a diagnosis other than CHF, confirmation was attempted using normal chest radiograph findings (no heart enlargement or pulmonary venous congestion); radiographic signs of COPD, pneumonia, or lung cancer; normal heart function by further cardiac tests; abnormal pulmonary function test results or follow-up in the pulmonary clinic; response to treatment in the emergency department or hospital with nebulizers, steroids, or antibiotics; and no CHF admissions over the subsequent 30 days.

Echocardiography
Echocardiography was performed according to local practice. Algorithms to calculate left ventricular EF were chosen by the operator, reflecting real-life performance of the test. To compare the diagnostic performance of BNP and echocardiography, echocardiographic left ventricular EF was selected as the quantitative continuous parameter most representative of echocardiographic assessment of left ventricular dysfunction, which would be readily available and accessible even to inexperienced echocardiographers.

Statistical Analysis
All analyses were performed with statistical software (SAS 6.06; SAS Institute; Cary, NC). Qualitative variables were compared using {chi}2 tests, and quantitative variables were compared using Student t test. Receiver operating characteristic (ROC) curves were estimated for both left ventricular EF and BNP. The areas under the ROC curves for BNP and left ventricular EF were compared by a nonparametric test.15

The diagnostic performances of each test for several cutoffs were assessed by computing sensitivity, specificity, positive predictive value and negative predictive value, and likelihood ratios. Positive likelihood ratios are defined as the probability of true-positives/the probability of false-positive results. Negative likelihood ratios are defined as the probability of false-negatives/the probability of true-negative results.

A stepwise multivariate logistic regression was performed. In addition to BNP ≥ 100 pg/mL and EF ≤ 50%, all clinical and then ECG and chest radiograph data significantly associated with CHF in the univariate analysis were tested. This analysis was performed in the subpopulation of patients for whom all of these data were available.


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 Conclusions
 Appendix
 References
 
Patient Characteristics
Of the 1,586 patients enrolled in the study, 709 underwent echocardiography. The median delay between presentation and clinical examination was 43 min (interquartile range, 22 to 80 min). Patients who underwent echocardiography were older than patients who did not (66.4 years vs 62.0 years, p < 0.001) and had more cardiovascular risk factors (Table 1 ). A higher proportion had a Framingham score for CHF (71.7% vs 56.7%, p < 0.0001) and NHANES scores of ≥ 3 (71.4% vs 59.1%, p < 0.0001). Patients who underwent echocardiography had a mean BNP concentration of 513 pg/mL, whereas patients who did not undergo echocardiography had a concentration of 283 pg/mL (p < 0.001) [Table 1].


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  		Table 1. Comparison Between Patients With and Without Echocardiographic Assessment of Left Ventricular Function*

 
Of the 709 patients who underwent echocardiography, 492 patients (69.4%) had a final diagnosis of CHF. These patients were generally older than those with dyspnea from other causes (68.5 years vs 61.6 years, p < 0.0001) [Table 2 ]. They were also more likely to have a history of CHF, myocardial infarction (both p < 0.0001), asthma (p = 0.003), and impaired renal function (p < 0.0001). On clinical examination, patients with CHF were more likely to have symptoms such as shortness of breath and orthopnea (Table 2). They were more likely to have the physical findings of rales, elevated, jugular venous pressure (> 12 cm), and a third heart sound. They also had a higher incidence of abnormal ECG findings, enlarged hearts, pulmonary cephalization, and interstitial or alveolar edema. The proportion of patients who fulfilled the Framingham criteria for CHF (84.6% vs 42.4%, p < 0.0001) or who had a NHANES score of ≥ 3 (82.9% vs 45.2%, p < 0.0001) was significantly higher in patients with CHF. Left ventricular EF was significantly lower in patients with CHF (p < 0.0001), and a larger proportion had an EF of ≤ 50% (p < 0.0001). The mean BNP concentration was 683 pg/mL in patients with a diagnosis of CHF, compared with 129 pg/mL (p < 0.0001) in those with dyspnea from another cause. A greater proportion of patients with CHF had a BNP value > 100 pg/mL (89.0% vs 26.7%, p < 0.0001).


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  		Table 2. Comparison of Clinical and Paraclinical Characteristics of Patients With and Without CHF*

 
Quantitative Relationships Between BNP and EF
The quantitative relationships between EF and BNP are displayed in Figure 1 , which shows the BNP values for each quartile of EF in patients without (top, a) and with (bottom, b) BNP. When BNP was used to differentiate CHF from other causes of dyspnea, the area under the ROC curve was significantly higher for BNP (0.89) than for EF (0.78). The area under the curve difference was 0.12 (p < 0.0001; Fig 2 ). The intercept of BNP and EF with the 1 – line was at 162 pg/mL for BNP (sensitivity = specificity, 83%) and 53% for EF (sensitivity = specificity, 72%).



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  		Figure 1. Quantitative relationships between left ventricular EF and plasma BNP values. Box plots of BNP values for each quartile of EF in patients without CHF (top, A) or with CHF (bottom, B).

 


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  		Figure 2. ROC curves for BNP and left ventricular EF, differentiating between dyspnea due to CHF and dyspnea due to other causes.

 
Diagnostic Performance of BNP and Echocardiography
The diagnostic performance of selected thresholds of BNP and left ventricular EF is summarized in Table 3 . BNP ≥ 100 pg/mL had the highest sensitivity (89%) and a specificity of 73%. BNP > 162 pg/mL had the highest specificity (83%) and a sensitivity of 83%. While the Framingham criteria and NHANES score showed sensitivity values of 85% and 83%, their specificities were much lower (58% and 55%, respectively). The highest positive likelihood ratio (4.88) was for BNP > 162 pg/mL, which corresponded to a negative likelihood ratio of 0.20. At the lower cutoff (100 pg/mL), BNP had a positive likelihood ratio of 3.29 and a negative likelihood ratio of 0.5. Conversely, the lowest positive likelihood ratios were for the Framingham criteria (2.02) and NHANES score (1.84).


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  		Table 3. Diagnostic Performance of BNP and Left Ventricular EF at Selected Thresholds

 
Multiple logistic regression analysis showed that, when used alone (odds ratio [OR], 22.2; 95% confidence interval [CI], 14.7 to 33.6) or in combination with clinical (OR, 38.0; 95% CI, 17.7 to 81.5), ECG, and chest radiograph readings (OR, 37.6; 95% CI, 14.4 to 98.3), BNP remained a strong independent predictor of CHF. The multivariate logistic regression analysis was performed using all variables significantly associated with CHF (Table 2) in the 371 patients in whom all of these data were available. When only clinical data were entered into the model, BNP ≥ 100 pg/mL and EF ≤ 50% remained independent predictors of CHF (OR, 30.7; 95% CI, 12.7 to 74.4; and OR, 6.7; 95% CI, 3.1 to 14.7, respectively). They also remained significantly associated with CHF when ECG and chest radiograph data were added (ORs, 32.1 and 6.2, respectively). In these models, the proportion of patients who were correctly classified (accuracy) was 67% for BNP alone, 55% for EF alone, 82% for the two variables together, and 97.3% when clinical, ECG, and chest radiograph data are added.


   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
Conclusions
 Appendix
 References
 
The results of our study indicate that point-of-care measurement of BNP in the emergency department is superior to echocardiographic determination of EF in the identification of CHF. Indeed, this finding is consistent irrespective of the threshold value of BNP. The calculated area under the ROC curve was 0.89 for BNP, compared with 0.78 for EF. Another important finding from this study is the marked additive diagnostic value of combining both methods, with an accuracy of 82% for diagnosing CHF in patients with shortness of breath seen in the emergency department, much improved compared to either method alone. These findings validate and extend the observations made in previous studies11416 regarding the role of BNP in this context, and strongly suggest the value of combining both methods.

In comparison with our study, in which a simple assessment of left ventricular EF by echocardiography was used, Logeart et al16 used two-dimensional and Doppler echocardiography in their study of emergency patients with dyspnea. They found that both the bedside BNP assay and echocardiography added important diagnostic information to the clinical findings. Echocardiography was more accurate than BNP for establishing the cause of acute dyspnea. Logeart et al16 also found that a BNP value < 80 pg/mL had a high negative predictive value (93%), whereas between 80 pg/mL and 300 pg/mL BNP was poorly predictive of the final diagnosis. The strong negative predictive value at 80 pg/mL is in close agreement with the findings from the multicenter BNP study (92%),14 but a higher cutoff (100 pg/mL) for diagnosing CHF was recommended in view of the sensitivity (90%), specificity (76%), and accuracy (83%). The interstudy differences in optimal threshold values for the diagnosis of CHF1141617 may reflect differences in the study populations. However, despite the value of detailed two-dimensional and Doppler echocardiography,16 this technique is not routinely available round-the-clock in the emergency department, and experienced personnel are needed to perform and evaluate the data. Patients may also be unable to lie still during the evaluation because of dyspnea, and adequate imaging may not be obtained in a substantial fraction of individuals, in particular because of comorbidities such as obesity or lung disease.14

The presence of a cardiac neurohormone that is secreted from the ventricles in response to ventricular volume expansion and pressure overload45 provides a sensitive and specific test for diagnosing or ruling out the presence of CHF. Furthermore, BNP concentration is correlated with severity of CHF,111819, and it can be used as a prognostic indicator across a number of clinical settings.79112021 This and previous studies11416 demonstrate the value of BNP not only in ruling out CHF, but also in identifying the presence of CHF in patients with dyspnea.

Echocardiography, especially when combining two-dimensional imaging and Doppler, provides more data than left ventricular EF, which is a gross simplification of echocardiographic assessment of left ventricular function. Yet, most of the parameters used to approach left ventricular function or filling pressures are complex, require expertise, and are not often used or applicable in an emergency setting, especially in patients with dyspnea. With the availability of portable echocardiographic devices, it is tempting to use a simplified echocardiographic examination to assist diagnosis of patients with dyspnea, in particular focusing on a simple assessment of left ventricular systolic function. However, patients with chronic left ventricular systolic dysfunction may have additional noncardiac causes of dyspnea. In addition, because CHF may occur despite normal systolic function2223 a substantial fraction of patients with CHF will have normal or preserved left ventricular EF. Given that BNP is useful for the diagnosis of CHF both in patients with and without systolic dysfunction,24 the superiority of BNP over EF as a diagnostic tool for CHF in patients with dyspnea is logical.

Study Limitations
As the decision to perform echocardiography was left to the discretion of the clinician, echocardiography was performed in less than half of the patients from the total cohort, and not all patients underwent detailed Doppler echocardiographic analysis, which led us to focus this analysis on two-dimensional imaging-derived left ventricular EF. The subset of patients who underwent echocardiography represents a group at higher cardiac risk, with a greater history of cardiac disease. Therefore, the predictive value of a low EF in this group may differ from that in a broader population, and this may affect generalizability of the findings. However, the 709 patients analyzed in this study all underwent clinical examinations, radiography, ECG, and echocardiography, and therefore have all of these reference tests available for adjudication by an independent expert committee. Because there is no simple "gold standard" available for the diagnosis of CHF, this was chosen as the method for adjudication.

The timing of echocardiography differed from that of BNP measurements. As a consequence, transient left ventricular systolic dysfunction may have been missed when echocardiography was performed (days after the acute episode) because systolic dysfunction may have been transient and/or relieved by medical therapy. However, it is unlikely that early regression of left ventricular dysfunction could account for the marked difference in diagnostic performance encountered in the present study, especially as, outside of acute myocardial infarction, transient systolic dysfunction is rare and EF appears stable even after acute pulmonary edema.22 Finally, echocardiography was often performed in an elective fashion by experienced personnel, which may result in a more reliable assessment of regional and global wall motion and EF than might be achieved in a real-time emergency setting.


   Conclusions
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Conclusions
Appendix
 References
 
In this large study of an emergency-department population seeking medical attention for dyspnea, in whom echocardiography was performed, BNP measurement was consistently superior to a single echocardiographic determination of left ventricular EF in identifying patients with CHF, regardless of the threshold value. Two-dimensional echocardiography was less sensitive than a single determination of BNP in diagnosing CHF. However, even more importantly, the two variables have marked additive diagnostic value and when combined have a much-improved accuracy compared to either method alone. This strongly suggests that, where applicable, they should be used together.


   Appendix
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Conclusions
 Appendix
References
 
BNP Multinational Study Investigators
Alan S. Maisel, MD (Principal Investigator), University of California, and Veteran’s Affairs Medical Center, Department of Medicine, Division of Cardiology, San Diego, CA; Peter A. McCullough, MD, MPH (Co-Principal Investigator, Chair, Publications Committee), University of Missouri-Kansas City School of Medicine, Truman Medical Center, Departments of Basic Science and Internal Medicine, Cardiology Section, Kansas City, MO; James McCord, MD, and Richard M. Nowak, MD, MBA, Henry Ford Hospital, Department of Emergency Medicine, Detroit, MI; Patricia Hlavin, MD, Radmila Kaznegra, MD, Paul Clopton, BS, and Ralph Shabetai, MD, University of California, San Diego, Veteran’s Affairs Medical Center, Department of Medicine, Division of Cardiology, San Diego, CA; Judd E. Hollander, MD, Department of Emergency Medicine, and Evan Loh, MD, Department of Medicine and Heart Failure and Cardiac Transplantation Program, University of Pennsylvania Health System, Philadelphia, PA; Marie-Claude Aumont, MD, Phillippe Duc, MD, PhD, and Philippe Gabriel Steg, MD, Cardiology Department, Lamia Hafi, MD, and Valérie Beaumesnil, MD, Clinical Investigation Center, and Armelle Desplanques MD, Emergency Department, Hôpital Bichat-Claude Bernard, Assistance Publique-Hôpitaux de Paris, Paris, France; Arne Westheim, MD, Department of Cardiology, and Torbjorn Omland, MD, Department of Medicine, Ullevål University Hospital, Oslo, Norway; and William T. Abraham, MD (Endpoints Committee), Division of Cardiovascular Medicine, Gill Heart Institute, University of Kentucky College of Medicine, Lexington, KY.


   Acknowledgements
 
We are indebted to the emergency department staff at the following study centers for their efforts: San Diego Veterans Affairs Medical Center, San Diego, CA; Henry Ford Hospital, Detroit, MI; Hospital of the University of Pennsylvania, Philadelphia, PA; Hôpital Bichat, Paris, France; Ullevål University Hospital, Oslo, Norway; the University of Cincinnati Medical Center, Cincinnati, OH; and Hartford Hospital, Hartford, CT.


   Footnotes
 
Abbreviations: BNP = B-type natriuretic peptide; CHF = congestive heart failure; CI = confidence interval; EF = ejection fraction; NHANES = National Health and Nutrition and Examination Survey; OR = odds ratio; ROC = receiver operating characteristic

This study was supported by an unrestricted grant from Biosite Diagnostics, Inc., San Diego, CA.

Drs. Maisel and McCullough are consultants to Biosite Diagnostics, Inc.

Received for publication October 22, 2004. Accepted for publication January 12, 2005.


   References
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Conclusions
 Appendix
 References
 

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Evid. Based Med., February 1, 2006; 11(1): 31 - 32.
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