European Journal of Heart Failure

European Journal of Heart Failure 2002 4(4):479-483; doi:10.1016/S1388-9842(02)00027-2

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© 2002 European Society of Cardiology

Plasma brain natriuretic peptide after long-term treatment for heart failure in general practice

Graham McGeoch^a,*, John Lainchbury^b, G.Ian Town^c, Les Toop^a, Eric Espiner^b and A.Mark Richards^b

^a Department of Public Health and General Practice, The Christchurch School of Medicine University of Otago, Christchurch, New Zealand
^b Christchurch Cardioendocrine Research Group, The Christchurch School of Medicine University of Otago, Christchurch, New Zealand
^c Canterbury Respiratory Research Group, The Christchurch School of Medicine University of Otago, Christchurch, New Zealand

^* Corresponding author. Fax: +64-33-299616 E-mail address: graham_m{at}pegasus.org.nz

	Abstract

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

 
Aim: Plasma brain natriuretic peptide (BNP) concentrations are known to have high sensitivity and specificity in the diagnosis of heart failure in newly symptomatic patients. The relationship of plasma BNP to cardiac function in stable patients on long-term established treatment for heart failure is unknown. Plasma BNP was assessed for its ability to predict echocardiographic abnormality in 100 patients receiving long-term treatment in general practice for a provisional diagnosis of heart failure.

Methods and results: BNP >35 pmol/l had a sensitivity and specificity of 69% and 67%, respectively, for a left ventricular ejection fraction of <45%. However, 19% of patients had an LVEF of below 45% whilst BNP was below 35 pmol/l. These patients, in whom a diagnosis of heart failure had been made years previously (mean 3.9 years), were all clinically stable on treatment.

Conclusion: These findings support the view that BNP can be restored to normal levels in well-compensated patients despite persisting significant systolic dysfunction and suggest that BNP assays may be helpful for monitoring adequacy of therapy. BNP assays will have limited utility in the diagnosis of cardiac impairment once anti-failure therapy is well established and symptoms have been abolished.

Key Words: Heart failure • Brain natriuretic peptide • General practice

Received August 2, 2001; Revised November 5, 2001; Accepted January 17, 2002

	1. Introduction

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

 
Accurate diagnosis is essential for the provision of good management of heart failure. The assessment of milder heart failure in subjects not requiring admission to hospital is frequently inaccurate, reflecting the lack of sensitivity and specificity of symptoms and signs for this diagnosis [1]. Symptoms may be mild and of slow onset. The elderly, obese and those with chronic obstructive pulmonary disease frequently present with non-specific symptoms (fatigue, shortness of breath) or signs (for example, peripheral oedema) which may reflect a wide range of conditions other than, or in addition to, heart failure. Misdiagnosis may lead to unnecessary long-term treatment for heart failure or failure to treat when needed. Monitoring progress and titrating treatment for heart failure can also be problematic given the difficulty of clinical assessment. In New Zealand and other countries, chest X-rays and echocardiography may not be easily accessible to doctors in primary care. Reasons for this include cost, distance and scarcity of facilities, which may further contribute to inaccurate diagnosis of heart failure. Studies based in general practice using echocardiography to confirm clinically diagnosed chronic heart failure show a false positive rate of 53–74% depending on inclusion criteria [2–4]. Hence the availability of a reliable blood test to assist in diagnosis and monitoring of heart failure in general practice would be of great value.

Plasma brain natriuretic peptide (BNP) is currently the most promising cardiac marker under investigation. This 32 amino acid peptide is secreted from cardiomyocytes in response to transmural stress. Plasma concentrations are related to concurrent left ventricular function and to cardiovascular prognosis, both after acute myocardial infarction and in chronic left ventricular impairment [5,6]. Plasma BNP has proven useful in diagnosing heart failure in patients admitted to hospital with acute dyspnoea, and also in a specialist rapid access outpatient clinic examining patients with recent onset symptoms suggestive of heart failure [7,8]. The relationship of plasma BNP to cardiac function in stable patients on long-term established anti-failure therapy in general practice is unknown.

We hypothesised that plasma BNP would have high sensitivity and specificity for the detection of significant, on-going systolic and diastolic cardiac dysfunction in a population of patients treated for heart failure in general practice. Accordingly, we have assessed the ability of plasma BNP measurement to recognise cardiac dysfunction, as indicated by echocardiography, in 100 clinically stable patients receiving long-term treatment for presumed heart failure in the community.

The Health Funding Authority (Canterbury) Ethics Committee approved the study protocol and participants gave signed informed consent.

	2. Methods

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

 
Currently or previously symptomatic patients with a provisional diagnosis of heart failure (excluding long-term hospital residents) and currently receiving diuretic or converting enzyme inhibitor drugs or both were serially identified from the databases of seven general practitioners in two practices until 100 had been recruited. Demographic variables and medical history were recorded for each patient. Investigations included a 12-lead electrocardiogram, echocardiography and plasma BNP.

Venous samples for BNP assay were drawn into cooled EDTA tubes, promptly centrifuged and the separated plasma frozen to –20° pending assay. BNP radioimmunoassay was configured to produce a result within 24 h [9]. The coefficients of variation for the RIA were: intra-assay 8.1% at 15 pmol/l, 5.2% at 32 pmol/l, and 8.6% at 60 pmol/l; and interassay: 29.2% at 18 pmol/l, 9.9% at 41 pmol/l, and 5.6% at 66 pmol/l. The normal range for this BNP assay (when configured for a result in 24 h) is 4–35 pmol/l as assessed from samples acquired from 200 healthy subjects (both genders and across a wide age range) randomly selected from the Christchurch electoral role.

Echocardiograms were all performed by a single operator (J.L.) who was blinded to the plasma BNP level. M-Mode echocardiographic variables were measured using the recommendations of the American Society of Echocardiography [10]. Left ventricular mass was calculated from the M-mode measurements. Left ventricular ejection fraction was calculated by the biplane disc summation method. Transmitral flow velocity signals were obtained by placing a pulsed Doppler sample volume at the tips of the valve leaflets. Valvular regurgitation was assessed semi-quantitatively by colour Doppler imaging and valvular stenosis was assessed using standard Doppler techniques.

2.1. Statistical analysis
Relationships between BNP and echocardiographic variables were tested using Pearson's correlation coefficient. The ability of BNP to predict ejection fractions less than 35, 40 and 45% was assessed using receiver operator characteristic curve analysis [11]. Relevant variables in sub-groups defined according to BNP and ejection fraction were compared using ANOVA and the Kruskal Wallis non-parametric ANOVA. A P-value of <0.05 (two-tailed) was taken to indicate statistical significance. Where significant effects were found these were further explored using Fishers least significant difference test.

	3. Results

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

 
Demographic details, medical history and drug treatment are indicated on Table 1. Patients living in long-term hospital level residential care or unable to give informed consent were excluded (n=53). A satisfactory echocardiogram was obtained in 91 of the 100 patients. Sixty percent of the group had an ejection fraction of <45%, and 77% had some abnormality on echocardiography or had atrial fibrillation. The prevalence of atrial fibrillation and flutter was 25%. Significant valve disease was diagnosed in four subjects and pacemakers were present in four patients.

View this table: [in this window] [in a new window]   Table 1 Demographic details, medical history and drugs (n=100)

 
Plasma BNP and echocardiographic left ventricular ejection fraction were significantly and inversely correlated (r=–0.30, P=0.004, n=91, Fig. 1). Plasma BNP of >50 pmol/l (a value previously found to have high sensitivity and specificity for diagnosis of dyspnoea of cardiac origin in patients admitted urgently to hospital [9]) had a sensitivity of only 38% but a specificity of 83%, positive predictive value of 78% and negative predictive value of 47% for prediction of echocardiographic ejection fractions below 45%. A plasma BNP level of 35 pmol/l had 69 and 67% sensitivity and specificity, respectively, for detection of an ejection fraction below 45% (with a positive predictive value of 76% and a negative predictive value of 59%). The area under the receiver–operator characteristic curves for detection of left ventricular ejection fractions at the three thresholds of 35%, 40% and 45% (Fig. 2) differed significantly from the line of zero information with values of 0.72, 0.76 and 0.75, respectively (P<0.001 in each case).

View larger version (10K): [in this window] [in a new window] [Download PowerPoint slide]   Fig. 1 Echocardiographic ejection fraction (LVEF) plotted against plasma BNP (n=91) with diagnosis of heart failure.

 

View larger version (8K): [in this window] [in a new window] [Download PowerPoint slide]   Fig. 2 ROC for plasma BNP as a test for LVEF of <45%. The point of maximum specificity and sensitivity is taken as optimal for the test in this population and lies at 35 pmol/l. 50 pmol/l is marked as the optimal cut-point from previous studies [9] defined by clinical presence or absence of heart failure not ejection fraction as in this study.

 
A significant proportion of the group (37%) exhibited plasma BNP below the previously established threshold for this assay in newly symptomatic patients (less than 50 pmol/l) despite ejection fractions below 45% [9]. Nineteen percent had BNP less than 35 pmol/l and ejection fraction less than 45%. Conversely, a smaller minority (12%) had elevated plasma BNP levels (greater than 35 pmol/l) despite ejection fractions in excess of 45% (Fig. 1). Twenty-five percent of subjects showed plasma BNP less than 35 pmol/l and ejection fractions greater than 45%. Fifteen of 33 subjects with BNP <35 pmol/l had abnormal renal function and 15/67 subjects with BNP >35 pmol/l had abnormal renal function. Mean BNP levels in the 25 subjects with atrial fibrillation (overall mean 49 pmol/l with average LVEF 39%) were not markedly influenced by concurrent LVEF with no significant difference in BNP for group with LVEF above vs. below 45% [n=19 with LVEF below 45% (mean 32%) with mean BNP 52 pmol/l and n=6 with LVEF above 45% (mean 57%) with mean BNP 45 pmol/l].

Echocardiographic variables (Table 2) significantly (P<0.01 for all) correlated with concurrent plasma BNP levels included left ventricular diastolic volume (r=0.39), systolic volume (0.40), ejection fraction (–0.30) and left ventricular mass (0.31).

View this table: [in this window] [in a new window]   Table 2 BNP and echo data (mean±S.D.)

 

	4. Discussion

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

 
In patients in general practice receiving long-term treatment for a provisional clinical diagnosis of heart failure, plasma BNP >35 pmol/l had reasonable sensitivity and specificity for predicting echocardiographic left ventricular ejection fraction of <45%. These patients had been diagnosed in both primary and secondary care and treated over varying periods of time. They are representative of patients currently treated in general practice for heart failure. Data providing the basis for the original diagnosis were frequently incomplete as is often the case in daily practice. It is accepted that the group was likely to include subjects with incorrect initial diagnoses of heart failure with other conditions such as obesity and lung disease. However, at the threshold of 50 pmol/l (a level shown by the same assay method to have high sensitivity and specificity for diagnosis of cardiac-based dyspnoea in patients admitted urgently to hospital) [9], sensitivity was only 38% although specificity was sustained at 83%. The positive predictive value was 78% and negative predictive value 47%. These findings therefore contrast with those of studies of newly symptomatic patients in which plasma BNP has demonstrated sensitivity and specificity as high as 93% and 90%, respectively, and a negative predictive value of 98% for a final diagnosis of an exacerbation of heart failure [7,8]. Hence, the value of BNP (50 pmol/l) most powerful in the diagnosis of newly symptomatic heart failure has less ability to predict left ventricular systolic dysfunction in stable patients on long-term treatment. Several factors may contribute to the difference. First, the correlates differ (LVEF and the presence of symptomatic heart failure) and are not always closely related. Second, plasma BNP (but not LVEF) is likely to return towards normal with prolonged and adequate treatment. This suggestion is also supported by findings of studies in survivors of myocardial infarction. BNP measured in the first 4 days is a powerful predictor of left ventricular dysfunction [5,12] but may have less ability to identify mild and moderate left ventricular impairment in stable survivors [13]. A study employing aminoterminal pro-BNP as a guide to heart failure treatment has recently been published [14] and also indicates that adequate treatment (as corroborated by improved outcomes) is reflected in falls in plasma aminoterminal BNP.

BNP was not strongly related to LVEF in the group with atrial fibrillation presumably reflecting the small group size and effective treatment. Adequate treatment and lower BNP secretion may also reduce the influence of mild degrees of renal impairment on elevating BNP levels.

The subgroup with raised BNP in the presence of a preserved ejection fraction may have had diastolic dysfunction. This suggestion is consistent with reports of elevation of plasma BNP in the presence of diastolic dysfunction [15,16] and will be a major reason for the relative weakness of the correlation between BNP and LVEF. The group with normal BNP and ejection fraction had presumably recovered or been misdiagnosed.

In conclusion, in stable patients who have received prolonged therapy for suspected heart failure, plasma BNP has a sensitivity and specificity, positive predictive value and negative predictive value at a plasma concentration of 35 pmol/l of 69%, 67%, 76% and 59%, respectively, for significant left ventricular systolic dysfunction (LVEF <45%). This contrasts with the greater diagnostic power for newly symptomatic heart failure. The data suggest prolonged adequate treatment will be reflected in falls in plasma BNP towards normal and may be useful in confirming adequacy of treatment.

Plasma BNP is not sufficiently sensitive or specific for general practitioners to reliably be able to detect significant systolic dysfunction in a stable population on long-term treatment for cardiac failure. Further studies are awaited to determine whether plasma BNP is useful for diagnosing suspected exacerbations of heart failure in untreated, non-hospitalised general practice patients and whether general practitioners can titrate adequate treatment against plasma BNP.

	Acknowledgments

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

 
Funding Source: Canterbury Medical Research Foundation.

	References

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

 

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