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Clinical Chemistry 52: 1802-1808, 2006. First published July 27, 2006; 10.1373/clinchem.2005.064386
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(Clinical Chemistry. 2006;52:1802-1808.)
© 2006 American Association for Clinical Chemistry, Inc.

Point-of-Care Testing

Rapid Brain Natriuretic Peptide Test and Doppler Echocardiography for Early Diagnosis of Mild Heart Failure

Nadia Aspromonte1,a, Vincenzo Ceci1, Antonella Chiera1, Claudio Coletta1, Alessandra D’Eri2, Mauro Feola3, Prospero Giovinazzo2, Loredano Milani2, Federica Noventa2, Angela Beatrice Scardovi1, Augusto Sestili1 and Roberto Valle2

1 Heart Failure Unit and Department of Cardiology, Santo Spirito Hospital, Rome, Italy.
2 Department of Cardiology, S. Croce-Carle Hospital, Cuneo, Italy.
3 Heart Failure Unit, Department of Cardiology, Civic Hospital, San Donà di Piave (VE), Italy.

aAddress correspondence to this author at: Via Bonaventura Cerretti 18, I-00167 Rome, Italy. Fax 39-06-662950; E-mail naspromonte{at}yahoo.it.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Background: The early identification of patients at risk for the development of clinical heart failure (HF) is a new challenge in an effort to improve outcomes.

Methods: We prospectively evaluated whether the combination of brain natriuretic peptide (BNP) measurements (Triage BNP test, Biosite Diagnostics) and echocardiography would effectively stratify patients with new symptoms in a cost-effective HF program aimed at early diagnosis of mild HF. A total of 252 patients were referred by 100 general practitioners.

Results: Among the study population, the median BNP value was 78 ng/L (range, 5–1491 ng/L). BNP concentrations were lower among patients without heart disease [median 15 ng/L (range, 5–167 ng/L); n = 96] than among patients with confirmed HF [median, 165 ng/L (22–1491 ng/L); n = 157; Mann–Whitney U-test, 12.3; P <0.001]. Patients were grouped into diastolic dysfunction [BNP, 195 (223) ng/L], systolic dysfunction [BNP, 290 (394) ng/L], and both systolic and diastolic dysfunction [BNP, 776 (506) ng/L]. In this model, a cutoff value of 50 ng/L BNP increases the diagnostic accuracy in predicting mild HF, avoiding 41 echocardiograms per 100 patients studied, with a net saving of 14% of total costs.

Conclusions: Blood BNP concentrations, in a costeffective targeted screening, can play an important role in diagnosing mild HF and stratifying patients into risk groups of cardiac dysfunction.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Heart failure (HF)1 is a progressive and lethal disease affecting 1%–2% of the general population(1). Even with recent advances in therapeutics(2)(3), the mortality and morbidity rates remain high. Moreover, this disease is becoming the most costly cardiovascular illness(4), and current strategies of healthcare delivery in HF involve close cooperation between inpatient and outpatient care providers(5). The onset of symptoms is a critical point in the natural development of HF. However, for primary care physicians, identifying patients at risk for developing clinical HF is a new challenge in the effort to improve outcomes. Conventional diagnostic methods, such as echocardiography, have been shown to be useful in detecting impaired left ventricular ejection fraction. However, this test is not yet available for routine diagnostic screening(6)(7). Given the vast investment of resources required for asymptomatic ventricular dysfunction screening programs, a clinical strategy with a more targeted methodology has recently been proposed and adopted. Brain natriuretic peptide (BNP) has emerged as an important diagnostic serum marker in congestive HF. At the early stages, it may play a key role in preserving the compensated state of asymptomatic left ventricular dysfunction(8)(9).

The aim of our study was to evaluate the efficacy and effectiveness of an organizational model based on BNP and Doppler echocardiography testing techniques in early diagnosis of patients with mild HF. This strategy is aimed at patients with a high risk of developing HF, i.e., class B patients with structural heart disorder who have never presented with symptoms or signs of HF, according to the American College of Cardiology/American Heart Association classification system(10).


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
We designed a coordinated program of care shared by 2 Italian primary cardiological centers (Santo Spirito, center 1, and San Donà di Piave, center to identify patients with new on-set HF whose condition had deteriorated from class B to class C. After a training course focused on HF guidelines, a total of 100 general practitioners (GPs) operating within the referral hospital environment were involved in this program between January 2001 and January 2003. The total population served by GPs was composed of 110 333 inhabitants (male/female = 49/51; age distribution: <10 years, 2%; 10–19 years, 10%; 20–29 years, 15%; 30–39 years, 19%; 40–49 years, 18%; 50–59 years, 14%; 60–69 years, 11%; 70–79 years, 8%; 80–89 years, 2%; > 90 years, 1%), drawn from a wide geographical area that was representative of urban and rural communities. In a preliminary study, the prevalence of clinical HF in a sample population of 10 000 inhabitants was 1.1%(11). The eligibility criteria for targeted screening consisted of (a) documented history of cardiopathy (patients with known risk factors and/or structural heart diseases predisposing to HF, such as left ventricular hypertrophy, left ventricular dilation, or hypocontractility; asymptomatic valvular heart disease; or previous myocardial infarction)(10); (b) symptoms suggestive of HF [dyspnea on exertion, orthopnea, paroxysmal nocturnal dyspnea, lower extremity edema, or rapid weight gain (defined as a 2 kg increase over 48 h or less)](12); and (c) no previous diagnosis.

The protocol included a description of patient assessment, indications for relevant investigations (electrocardiogram, echocardiography, and biochemistry/BNP) and visit to the dedicated outpatient clinic. The study was approved by the local research ethics committee, and informed consent was obtained from patients. Blood samples were obtained from patients after 30 min of bed rest. Venous blood samples were collected into tubes containing potassium EDTA (1 mg/mL of blood). Samples were immediately analyzed with a point-of-care testing method (Triage® BNP test, Biosite Diagnostics) to measure BNP concentrations in whole blood. This method correlates the fluorescence measurement with the BNP concentration by use of an internal calibration curve. The assay results were complete after 15 min. We calculated that eliminating the need to deliver samples to the central laboratory and centrifugation, enables a turnaround time of <30 min (the turnaround time, is defined as the time from blood collection to the reporting of results). The lowest detectable measurement for this assay was 5 ng/L (range, 5–1300 ng/L). Total CV values for the BNP Biosite Diagnostics assay were <15% (10.1% at a mean concentration of 28 ng/L and 13.9% at 1180 ng/L, determined with controls provided by the manufacturer)(13)(14). Throughout this report, the BNP values are reported as the range, median, and 25th and 75th percentiles.

Echocardiography tests were carried out at the initial evaluation phase with a Sonos 5000 Philips MS system (center 1) and a Vingmed System Five device (center 2). Two specialists interpreted all the echocardiograms, blinded to the results of the BNP assay; controversies were resolved by consensus. We categorized patients as having ventricular systolic dysfunction if they had an ejection fraction (EF) ≤45% and diastolic dysfunction in the presence of one of the following patterns(15)(16): (a) abnormal relaxation [peak protodiastolic transmitral velocity (E)/peak late diastolic transmitral velocity (A) <1 and deceleration time of the mitral E wave (EDT) >140 ms in patients less than 55 years of age, or E/A <0.8 and EDT >140 ms in subjects more than 55 years of age]; (b) pseudonormal (1 < E/A <2 and EDT >140 ms; diastolic wave of pulmonary veins on Doppler test superior to the systolic wave for differentiation from the normal pattern); (c) restrictive (E/A >2 and EDT <140 ms).

The presence of one of these patterns in patients with normal EF (≥45%) was defined as isolated diastolic dysfunction. Following the method of Lubien et al.(16), we categorized as having "normal ventricular function" patients with a normal LVEDD, no major wall abnormalities, an EF >45%, and no abnormalities of diastolic function. Patients were classified on the basis of their symptoms to establish the prevalence of clinically manifested HF, namely the presence of 2 major criteria or 1 major criterion + 2 minor criteria according to the Framingham score(12). After clinical and instrumental investigations(17), all patients were classified as follows: (a) patients with a confirmed diagnosis of HF; (b) patients with heart disease, excluding HF; (c) patients free from heart disease, but suffering from dyspnea related to chronic obstructive pulmonary disease (COPD); (d) patients free from heart or lung diseases.

Only direct costs were measured. To quantify the cost of instrumental examinations, the Italian Health Ministry Registry system(18) was used. Regarding BNP-related costs (reagent cost per test, quality control, calibration, equipment rental, and staff time) an estimate recently published in the literature(19) was used ({euro}28 for single assay). We compared the cost of screening by an echocardiogram ({euro}103) (cost = number in population x price of echocardiogram) to the cost of combined screening with BNP first and an echocardiogram second (number in population x price of echocardiogram + number in population with a "positive" BNP x price of echocardiogram)(20). Different calculations were made to illustrate the effect of various BNP cutoff values on the cost–efficacy ratio.

Data are expressed as mean (SD). A value of P <0.05 was set as the significance threshold. For data with nongaussian distribution we used the Mann–Whitney U-test for cross-sample comparisons, whereas association between variables was verified by Fisher exact test. Because BNP circulating concentrations have nongaussian distribution in reference individuals, both the original and the logarithmic transformation of data were used for statistical analysis (ANOVA). A characteristic ROC was used to test whether BNP values could be used to identify patients with left ventricular dysfunction among those consulting their GP for new-onset dyspnea and/or lower-extremity edema.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Overall, the study population (Table 1 ) comprised relatively elderly patients (median age, 73 years; age range, 32–96 years), with both sexes equally represented (51% female), presenting dyspnea compatible with a moderately advanced functional class (NYHA median, 2; range, 1–3) and worsened by numerous comorbidities, particularly diabetes mellitus (18%), atrial fibrillation (17%), COPD (13%), and renal insufficiency [creatinine concentrations >176.8 µmol/L (>2.0 mg/dL), 4%]. Ischemic cardiopathy and arterial hypertension were present in 32% and 41% of all cases, respectively. Nine percent of the population had valve dysfunction. The majority of the study patients consulted their GP for dyspnea on exertion and/or lower-extremity edema (71%), whereas only 29% complained of dyspnea at rest and/or orthopnea. The number of patients receiving effective medication was high among the class B population, with a high prevalence of cardiovascular illness recorded at both participating health centers.


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  		Table 1. Demographic, clinical, and instrumental characteristics of the 253 patients in the study sample.1

A total of 157 patients of 253 (62%) HF was diagnosed in, whereas another 5 patients (2%) presented with other heart disorders or acute vascular disorders, and 13 (5%) with COPD. A total of 78 (31%) were found to be free from both heart and lung disorders (Fig. 1 ). Table 1Up illustrates the demographic characteristics (clinical, laboratory, and instrumental) of patients identified as suffering from HF symptoms, and the rest of the study sample. There was a statistical difference between patients with HF and those without, in terms of age (older) and more advanced functional class. Among HF patients, there was a higher incidence of ischemic cardiopathy, hypertension, and atrial fibrillation; a lower incidence of COPD; and a greater number of prescribed pharmacological therapies. The etiology of HF was largely attributable to ischemic cardiopathy (in 37% of cases) and hypertension (32%); in a few cases, it was attributable to valve disorders. In 14% of cases, the etiology was unknown (Table 1Up ). The 157 patients with overt HF were distributed as follows (NYHA classification): 46% in class II and 54% in class III. Among those patients with symptomatic left ventricular dysfunction, 32% showed systolic failure, 47% had isolated diastolic dysfunction, and 21% had combined systolic-diastolic dysfunction.


Figure 1
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  		Figure 1. BNP concentrations according to the final diagnosis in the four patient groups (A), according to NYHA class in patients with confirmed diagnosis of heart failure (B), and within cardiac function categories (C). Box and lines plot with median, 25th percentile, and 75th percentile.

Among the study population, the median BNP value was 78 ng/L (range, 5–1491 ng/L). BNP concentrations were lower among patients without heart disease [median, 15 ng/L (range, 5–167 ng/L); n = 96] compared with patients with confirmed HF [median, 165 ng/L (22–1491 ng/L); n = 157; Mann–Whitney U-test, 12.3; P <0.001]. In the subgroup of 5 patients presenting with heart disorders in whom HF was not diagnosed, 3 had new-onset atrial fibrillation, and 2 had subacute myocardial infarction. The median BNP values of 119 ng/L (range, 17–167 ng/L) in this group were intermediate and not substantially different in comparison with patients having a confirmed diagnosis, patients with COPD, and patients free from lung and heart disorders (ANOVA one-way, not significant; Fig. 1AUp ). A significant correlation between BNP and NYHA class (Pearson r = 0.28; P <0.001): NYHA II = 105 ng/L (range, 22–1491 ng/L; n = 73), NYHA III = 247 ng/L (range, 43–1470 ng/L; n = 84), (Mann–Whitney U-test –5.3; P <0.001) was observed (Fig. 1BUp ). We did not observe any significant relation between BNP concentrations and use of ß blockers, renin-angiotensin inhibitor, or diuretics. Multivariate regression identified only 2 predictors of HF: atrial fibrillation (P = 0.001) and BNP concentrations (P = 0.001), whereas renal failure, age, sex, COPD, diuretic treatment, and ischemic heart disease were excluded (Table 2 ).


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  		Table 2. Predictors of heart failure in multivariate logistic regression analysis.

Within the population examined, BNP values were inversely correlated to the EF (Pearson r = –0.30; P <0.01). Ninety-eight patients (39%) showed systolic dysfunction [median BNP concentrations, 119 ng/L (range, 6–1491 ng/L)]; 102 (40%) showed isolated diastolic dysfunction [median BNP concentrations,138 ng/L (range, 8–1300 ng/L)]; and 53 (21%) showed normal ventricular function [BNP median,10 ng/L (range, 5–60 ng/L)]. The values obtained are significantly different for both types of dysfunction from normal subjects [ANOVA (F = 16; P <0.001)] for all Tukey’s test comparisons (Fig. 1CUp ). Thirteen patients with both (combined) systolic dysfunction and restrictive diastolic pattern had higher BNP values than the rest of the study population [median, 726 ng/L (range, 97–1421 ng/L) vs median, 67 ng/L (range, 5–170 ng/L); Mann–Whitney U-test Z = –3.8; P <0.001]. Among this group, patients with BNP concentrations >175 ng/L (16 of 74; 22%) had evidence of advanced diastolic dysfunction compared with subjects with concentrations ≤175 pg/mL (3 of 179; 2%) ({chi}2 = 30.0; P <0.001).

The usefulness of BNP concentrations for detecting HF patients is illustrated by the ROC in Fig. 2 . The area under the curve value of 0.96 (confidence interval, 0.94–0.98) indicates a satisfactory discriminating power. Several cutoff values were tested. Notably, a BNP value of 50 ng/L showed both statistical sensitivity and specificity of 90%. BNP demonstrates a reasonable discriminating power for identifying patients with systolic dysfunction and a restrictive diastolic pattern. The area under the curve for the ROC with BNP values to detect combined systolic dysfunction and/or restrictive diastolic pattern in the study sample was 0.88 (confidence interval, 0.81–0.94). A BNP value ≥175 ng/L had sensitivity of 85% and specificity of 74% for identifying patients at high risk.


Figure 2
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  		Figure 2. ROC analysis comparing sensitivity and specificity of BNP values to detect mild heart failure in 253 patients studied.

The cost of screening by echocardiography ({euro}10 300) per 100 patients examined was compared with the approach combining both BNP and echocardiography. A screening program combining Doppler ultrasound techniques with a BNP result >50 ng/L would mean a false-negative diagnosis in no more then 10 patients per 100 tested. Furthermore, this approach would render unnecessary 41 echocardiograms per every 100 patients studied, representing a cost saving for the entire model of 14% [({euro}10 300 – {euro}8887)/{euro}10 300]. Moreover, the application of a cutoff value of 70 ng/L, which identifies the 79% of cases, would mean "missing" 21 cases of 100 among the patients identified with clinical criteria. However, this approach would avoid 49 echocardiograms for every 100 patients studied, with a cost saving of 22% ([{euro}10 300– {euro}8053]/{euro}10 300).


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
In the real world, correct diagnosis of HF remains problematic, in that the signs and symptoms have a low specificity (particularly in the initial phases); diagnosis is also difficult whenever HF is mild(21)(22). Natriuretic peptides [BNP and N-terminal proBNP (NT-proBNP)] are taking their place in the new generation of neurohormonal markers used to diagnose HF(23)(24). From a clinical application viewpoint, most comparative clinical studies did not show notable diagnostic differences for NT-proBNP and BNP measurements in structural heart disease with symptoms of HF (stage C), even if the diagnostic accuracy of the neurohormonal marker strictly depends on the criteria by which patients were selected(25)(26)(27). On the other hand, Mueller et al.(28) reported that NT-proBNP seems to be minimally advantageous compared with BNP for the detection of structural heart disease without symptoms of HF (stage B) because of a slower plasma clearance of NT-proBNP compared with the biologically active peptide BNP.

Existing studies in primary care have examined populations in which the 2 markers performed similarly in the detection of decreased left ventricular ejection fraction in symptomatic and asymptomatic patients(29)(30)(31)(32). Because of their physiological profile, B-type peptides are generally more accurate in identifying HF and rapidly changing in an evolving response to recent clinical instability(25)(26)(32), but their use in helping to delineate less specific symptoms of HF in primary care is not yet fully realized.

The present study demonstrates that B-type natriuretic peptide measurement can effectively rule out HF in mild but symptomatic patients. By ROC analysis, BNP showed good diagnostic power to detect HF (area under the curve, 0.94–0.98), with similar performance described for NT-proBNP in 2 previous studies involving primary care patients with dyspnea referred for echocardiography(33)(34). Furthermore, our data confirm that decisional values should vary also according to the population of patients tested(35). In our study, the population identified represents a well-defined and highly selected group (referred in a structured manner by GPs who completed training course) of symptomatic elderly patients with comorbidities. In this setting, a cutoff value of 50 ng/L BNP increases the diagnostic accuracy in predicting mild HF with high discriminating power to detect a true decompensated state, even in the presence of other high-risk heart disorders and multidrug treatment. Similar findings have also been reported in a recent study by Fuat et al.(36) comparing the diagnostic accuracy of BNP testing vs NT-proBNP in 297 patients with suspected HF referred by GPs for clinical assessment or for echocardiography. The use of cutoffs of 40 and 150 pg/mL for BNP and NT-proBNP could have prevented 24% and 25% of referrals to the clinic, respectively. As in most studies published on this topic, our data confirm a correlation between BNP and NYHA functional class(25) and degree of ventricular dysfunction(37), both systolic and diastolic(15)(16). In our population, a cutoff BNP value of 175 ng/L shows a moderate discriminating power in identifying high-risk patients with systolic dysfunction and a restrictive diastolic pattern. The prognosis for this type of patient, reported previously by Gustafsson et al.(33), is poor.

The best combination of tests for HF detection and the most cost-effective model of their use in the primary care setting are not yet known(38). Nielsen et al.(20) reported that BNP would be most useful as an intermediary between clinical exam and echocardiography in the high-risk group because of minimal false negative and cost-effective cost decrease (–21%/–26%). Our work suggests that use of the BNP bedside assay as the main test for screening symptomatic patients would allow healthcare professionals to rule out the presence of new-onset mild HF and could act as a guide in requests for further diagnostic investigation. From a strictly economic viewpoint, a cutoff value of 50 ng/L would allow healthcare professionals to identify 90% of HF patients, thus decreasing healthcare expenditure by 14% (considering this test as an essential diagnostic tool within the context of a dedicated organizational model, such as the one proposed). In our model, results obtained with BNP point-of-care testing, compared with those of central laboratories, have suggested notable declines in turnaround time and in waiting time, thus improving patient satisfaction.

Several limitations deserve comments. First, the present data confirm and extend previous results, suggesting that BNP results are method-dependent and that a single predefined common cutoff value cannot be used(14). We found notable heterogeneity among patients with suspected HF seen in our community-based family practice center, with a high frequency of diastolic abnormalities in elderly patients with mild impairment of functional capacity. This setting may affect the BNP values reported in the study and the substantial SD of the results. Furthermore, the cost analysis based on local costs for supplies and services could limit the applicability to a broader healthcare system. Second, healthcare professionals may use BNP testing as part of the clinical evaluation process. Because of its suboptimal specificity, the implementation of this test would lead to a burden of false-positive results, thus obliging cardiologists to substantiate their diagnosis with further examinations. Third, although several training courses focused on HF guidelines had been developed for transferring newer therapeutic technologies to the community practice, implementation of such guidelines is slow, reflecting concerns over applicability of clinical evidence(39). This may in part explain the observation that, for a community-based study, the final population sample of patients identified and enrolled in the study was modest. Fourth, although the prevalence of HF may differ in other settings, this model in an outpatient practice raises important issues for further research.

In conclusion, targeted screening may be a practical method of evaluation because diagnostic testing is restricted to individuals who are at risk for having undiagnosed HF. The preliminaries cost analysis results obtained from our study suggest that it would be appropriate to use an approach combining BNP testing and echocardiographic techniques in the initial diagnostic work-up of patients with signs and symptoms suggestive of new-onset HF.


   Acknowledgments
 
We thank the nurses Tiziana Di Giacomo and Sabrina Barro for their cooperation and the GPs of Local Health Unit Rome E, Rome, Italy and the Basic Health Services District 1, San Donà di Piave, Italy, who partecipated in this study.


   Footnotes
 
1 Nonstandard abbreviations: HF, heart failure; BNP, brain natriuretic peptide; GP, general practitioner; EF, ejection fraction; EDT, deceleration time of the mitral E wave; LVEDD, left ventricular end-diastolic diameter; COPD, chronic obstructive pulmonary disease; ROC, receiver operating curve; NYHA, New York Heart Association; NT-proBNP, N-terminal proBNP.


   References
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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