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Figure 1.
Pooled diagnostic odds ratio (DOR) (95% confidence interval), with χ2 test for homogeneity. BNP indicates brain natriuretic peptide; LVEF, left ventricular ejection fraction; and MI, myocardial infarction. The abscissa is on a log scale.

Pooled diagnostic odds ratio (DOR) (95% confidence interval), with χ2 test for homogeneity. BNP indicates brain natriuretic peptide; LVEF, left ventricular ejection fraction; and MI, myocardial infarction. The abscissa is on a log scale.

Figure 2
Estimates of diagnostic accuracy from individual studies that measured brain natriuretic peptide vs left ventricular ejection fraction of 40% or less plotted in receiver operating characteristic curve space, ie, sensitivity vs 1 − specificity. Results from different cutoff points within the same study are joined, with the numbers next to the circles being the cutoff point (in picomoles per liter). The pooled diagnostic odds ratio (DOR) is used to estimate the plot of summary receiver operating characteristic curve and the area under the curve (AUC). The area of the circles is proportional to the size of the studies.

Estimates of diagnostic accuracy from individual studies that measured brain natriuretic peptide vs left ventricular ejection fraction of 40% or less plotted in receiver operating characteristic curve space, ie, sensitivity vs 1 − specificity. Results from different cutoff points within the same study are joined, with the numbers next to the circles being the cutoff point (in picomoles per liter). The pooled diagnostic odds ratio (DOR) is used to estimate the plot of summary receiver operating characteristic curve and the area under the curve (AUC). The area of the circles is proportional to the size of the studies.

Table 1. 
Accuracy of Brain Natriuretic Peptides for Diagnosis of Heart Failure by Diagnostic Standard
Accuracy of Brain Natriuretic Peptides for Diagnosis of Heart Failure by Diagnostic Standard
Table 2. 
Studies That Compared BNP and ANP
Studies That Compared BNP and ANP
1.
Davies  MHobbs  FDavis  R  et al.  Prevalence of left-ventricular systolic dysfunction and heart failure in the Echocardiographic Heart of England Screening study: a population based study. Lancet. 2001;358439- 444
PubMedArticle
2.
Redfield  M Heart failure: an epidemic of uncertain proportions. N Engl J Med. 2002;3471442- 1444
PubMedArticle
3.
Redfield  MMJacobsen  SJBurnett  JC  JrMahoney  DWBailey  KRRodeheffer  RJ Burden of systolic and diastolic ventricular dysfunction in the community: appreciating the scope of the heart failure epidemic. JAMA. 2003;289194- 202
PubMedArticle
4.
Morgan  SSmith  HSimpson  I  et al.  Prevalence and clinical characteristics of left ventricular dysfunction among elderly patients in general practice setting: cross sectional survey. BMJ. 1999;318368- 372
PubMedArticle
5.
McDonagh  TAMorrison  CELawrence  A  et al.  Symptomatic and asymptomatic left-ventricular systolic dysfunction in an urban population. Lancet. 1997;350829- 833
PubMedArticle
6.
Mosterd  AHoes  AWde Bruyne  MC  et al.  Prevalence of heart failure and left ventricular dysfunction in the general population: the Rotterdam Study. Eur Heart J. 1999;20447- 455
PubMedArticle
7.
Cowie  MRStruthers  ADWood  DA  et al.  Value of natriuretic peptides in assessment of patients with possible new heart failure in primary care. Lancet. 1997;3501349- 1353
PubMedArticle
8.
Fuat  AHungin  APMurphy  JJ Barriers to accurate diagnosis and effective management of heart failure in primary care: qualitative study. BMJ. 2003;326196
PubMedArticle
9.
Baughman  KL B-type natriuretic peptide: a window to the heart. N Engl J Med. 2002;347158- 159
PubMedArticle
10.
DerSimonian  RLaird  N Meta-analysis in clinical trials. Control Clin Trials. 1986;7177- 188
PubMedArticle
11.
Moses  LEShapiro  DLittenberg  B Combining independent studies of a diagnostic test into a summary ROC curve: data-analytic approaches and some additional considerations. Stat Med. 1993;121293- 1316
PubMedArticle
12.
Pepe  M The Statistical Evaluation of Medical Tests for Classification and Prediction.  Oxford, England Oxford University Press2003;108
13.
McDonagh  TARobb  SDMurdoch  DR  et al.  Biochemical detection of left-ventricular systolic dysfunction. Lancet. 1998;3519- 13
PubMedArticle
14.
Bettencourt  PFerreira  APardal-Oliveira  N  et al.  Clinical significance of brain natriuretic peptide in patients with postmyocardial infarction. Clin Cardiol. 2000;23921- 927
PubMedArticle
15.
Choy  AMDarbar  DLang  CC  et al.  Detection of left ventricular dysfunction after acute myocardial infarction: comparison of clinical, echocardiographic, and neurohormonal methods. Br Heart J. 1994;7216- 22
PubMedArticle
16.
Valli  NGeorges  ACorcuff  JBBarat  JLBordenave  L Assessment of brain natriuretic peptide in patients with suspected heart failure: comparison with radionuclide ventriculography data. Clin Chim Acta. 2001;30619- 26
PubMedArticle
17.
Vasan  RSBenjamin  EJLarson  MG  et al.  Plasma natriuretic peptides for community screening for left ventricular hypertrophy and systolic dysfunction: the Framingham Heart Study. JAMA. 2002;2881252- 1259
PubMedArticle
18.
Hutcheon  SDGillespie  NDStruthers  ADMcMurdo  ME B-type natriuretic peptide in the diagnosis of cardiac disease in elderly day hospital patients. Age Ageing. 2002;31295- 301
PubMedArticle
19.
Landray  MJLehman  RArnold  I Measuring brain natriuretic peptide in suspected left ventricular systolic dysfunction in general practice: cross-sectional study. BMJ. 2000;320985- 986
PubMedArticle
20.
Smith  HPickering  RMStruthers  ASimpson  IMant  D Biochemical diagnosis of ventricular dysfunction in elderly patients in general practice: observational study. BMJ. 2000;320906- 908
PubMedArticle
21.
McGeoch  GLainchbury  JTown  GIToop  LEspiner  ERichards  AM Plasma brain natriuretic peptide after long-term treatment for heart failure in general practice. Eur J Heart Fail. 2002;4479- 483
PubMedArticle
22.
Yamamoto  KBurnett  JC  JrBermudez  EAJougasaki  MBailey  KRRedfield  MM Clinical criteria and biochemical markers for the detection of systolic dysfunction. J Card Fail. 2000;6194- 200
PubMedArticle
23.
Yamamoto  KBurnett  JC  JrJougasaki  M  et al.  Superiority of brain natriuretic peptide as a hormonal marker of ventricular systolic and diastolic dysfunction and ventricular hypertrophy. Hypertension. 1996;28988- 994
PubMedArticle
24.
Luchner  ABurnett  JC  JrJougasaki  M  et al.  Evaluation of brain natriuretic peptide as marker of left ventricular dysfunction and hypertrophy in the population. J Hypertens. 2000;181121- 1128
PubMedArticle
25.
Krishnaswamy  PLubien  EClopton  P  et al.  Utility of B-natriuretic peptide levels in identifying patients with left ventricular systolic or diastolic dysfunction. Am J Med. 2001;111274- 279
PubMedArticle
26.
Osca  JQuesada  AArnau  MA  et al.  Brain natriuretic peptide: diagnostic value in heart failure [in Spanish]. Rev Esp Cardiol. 2002;557- 15
PubMedArticle
27.
Davis  MEspiner  ERichards  G  et al.  Plasma brain natriuretic peptide in assessment of acute dyspnoea. Lancet. 1994;343440- 444
PubMedArticle
28.
Hobbs  FDavis  RRoalfe  AHare  RDavies  MKenkre  J Reliability of N-terminal pro-brain natriuretic peptide assay in diagnosis of heart failure: cohort study in representative and high risk community populations. BMJ. 2002;3241498- 1500
PubMedArticle
29.
Maisel  ASKrishnaswamy  PNowak  RM  et al.  Rapid measurement of B-type natriuretic peptide in the emergency diagnosis of heart failure. N Engl J Med. 2002;347161- 167
PubMedArticle
30.
Castro  ADias  PPereira  M  et al.  Type B natriuretic peptide in the diagnosis of heart failure with preserved systolic function [in Portuguese]. Rev Port Cardiol. 2001;201109- 1113
PubMed
31.
Lubien  EDeMaria  AKrishnaswamy  P  et al.  Utility of B-natriuretic peptide in detecting diastolic dysfunction: comparison with Doppler velocity recordings. Circulation. 2002;105595- 601
PubMedArticle
32.
Boyko  EJ Re: "Meta-analysis of Pap test accuracy." Am J Epidemiol. 1996;143406- 407
PubMedArticle
33.
Kalra  PRStruthers  AD More evidence for bedside BNP in heart failure assessment. Int J Cardiol. 2002;86149- 152Article
34.
Del Ry  SGiannessi  DClerico  A Plasma brain natriuretic peptide measured by fully-automated immunoassay and by immunoradiometric assay compared. Clin Chem Lab Med. 2001;39446- 450
PubMed
35.
McCullough  PANowak  RMMcCord  J  et al.  B-type natriuretic peptide and clinical judgment in emergency diagnosis of heart failure: analysis from Breathing Not Properly (BNP) Multinational Study. Circulation. 2002;106416- 422
PubMedArticle
36.
Not Available, Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial. Lancet. 1999;3539- 13
PubMedArticle
37.
Pfeffer  MABraunwald  EMoye  LA  et al. SAVE Investigators, Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction: results of the survival and ventricular enlargement trial. N Engl J Med. 1992;327669- 677
PubMedArticle
38.
Packer  MCoats  AJFowler  MB  et al.  Effect of carvedilol on survival in severe congestive heart failure. N Engl J Med. 2001;3441651- 1658
PubMedArticle
39.
Cheitlin  MD Can clinical evaluation differentiate diastolic from systolic heart failure? if so, is it important? Am J Med. 2002;112496- 497
PubMedArticle
40.
Troughton  RWFrampton  CMYandle  TGEspiner  EANicholls  MGRichards  AM Treatment of heart failure guided by plasma aminoterminal brain natriuretic peptide (N-BNP) concentrations. Lancet. 2000;3551126- 1130
PubMedArticle
41.
Murdoch  DRMcDonagh  TAByrne  J  et al.  Titration of vasodilator therapy in chronic heart failure according to plasma brain natriuretic peptide concentration: randomized comparison of the hemodynamic and neuroendocrine effects of tailored versus empirical therapy. Am Heart J. 1999;1381126- 1132
PubMedArticle
Review Article
October 11, 2004

A Systematic Review of the Diagnostic Accuracy of Natriuretic Peptides for Heart Failure

Author Affiliations

From the Centre for General Practice (Drs Doust, Glasziou, and Pietrzak) and Division of Epidemiology and Social Medicine (Dr Dobson), School of Population Health, University of Queensland, Herston, Australia. The authors have no relevant financial interest in this article.

Arch Intern Med. 2004;164(18):1978-1984. doi:10.1001/archinte.164.18.1978
Abstract

Background  The diagnosis of heart failure is difficult, with both overdiagnosis and underdiagnosis occurring commonly in practice. Natriuretic peptides have been proposed as a possible test for assisting diagnosis. We assessed the diagnostic accuracy of brain natriuretic peptide (BNP), including a comparison with atrial natriuretic peptide (ANP).

Methods  Electronic searches were conducted of MEDLINE and EMBASE from January 1994 to December 2002 and handsearches of reference lists of included studies. We included studies that assessed the diagnostic accuracy of BNP against echocardiographic or clinical criteria or that compared the diagnostic accuracy of BNP with ANP. Two reviewers assessed studies for inclusion and quality and extracted the relevant data. A meta-analysis was performed by pooling the diagnostic odds ratios for studies that used a common reference standard.

Results  Twenty studies were included. For the 8 studies (n = 4086) that measured BNP against the criterion of left ventricular ejection fraction of 40% or less (or equivalent), the pooled diagnostic odds ratio was 11.6 (95% confidence interval, 8.4-16.1). The pooled diagnostic odds ratio was greater, 30.9 (95% confidence interval, 27.0-35.4), in the 7 studies (n = 2374) that measured BNP against clinical criteria (generally a consensus view using all other clinical information). The diagnostic odds ratio was similar in studies conducted in general practice and in hospital settings. Three studies compared BNP with N-terminal–ANP, a precursor form of ANP, and pooling of the results of these studies showed BNP to be a more accurate marker of heart failure than NT-ANP.

Conclusions  Brain natriuretic peptide is an accurate marker of heart failure. Use of a cutoff value of 15 pmol/L achieves high sensitivity, and BNP values below this exclude heart failure in patients in whom disease is suspected. As the diagnostic odds ratio for BNP is greater when assessed against clinical criteria than against left ejection fraction alone, BNP may also be detecting patients with "diastolic" heart failure.

The rising prevalence1 and cost2 of heart failure and increasing treatment options3 have made the accurate diagnosis of heart failure increasingly important. Heart failure is difficult to diagnose correctly, with both overdiagnosis and underdiagnosis occurring commonly in practice. Studies that have investigated the prevalence of echocardiographic abnormalities in populations have found that at least half of patients with significant left ventricular dysfunction on echocardiogram are asymptomatic or have not previously been diagnosed as having heart failure.4,5 In the Rotterdam Study, a population-based cohort study of chronic disease in persons aged 55 years or older, 60% of people with a left ventricular ejection fraction of 25% or less were asymptomatic.6 Conversely, patients with signs and symptoms suggestive of heart failure are frequently found not to have the disease when measured against more objective criteria. One study investigated all suspected new cases of heart failure referred by general practitioners during a 15-month period against a consensus decision of 3 cardiologists, including the results of further investigations such as echocardiogram. Against this definition, only 30% of the referred patients had heart failure.7

The diagnosis of heart failure is hindered if access to further investigations is limited. It is especially difficult for general practitioners, who are faced with many patients at high risk of the disease and who must make decisions regarding appropriate further investigation, treatment, and referral. General practitioners in the United Kingdom identified a lack of confidence in establishing an accurate diagnosis as a major barrier to treating patients with heart failure.8 Both in general practice and in emergency departments, many patients presenting with symptoms of heart failure have comorbidities that may also account for their symptoms.

The myocardium releases neuropeptides that serve to maintain circulatory homeostasis. A-type (atrial) natriuretic peptide (ANP) is secreted primarily by the atrial myocardium in response to dilation, and B-type (brain) natriuretic peptide (BNP) is secreted by the ventricles in response to end-diastolic pressure and volume.9 Both ANP and BNP and various precursor forms, such as N-terminal (NT)–ANP, have been evaluated as potential diagnostic tests for heart failure. We performed a systematic review of the literature and meta-analysis to quantify the diagnostic accuracy of BNP for the diagnosis of heart failure and to compare it with the diagnostic accuracy of ANP.

METHODS

We searched MEDLINE and EMBASE from January 1994 to December 2002 for all studies of the diagnostic accuracy of natriuretic peptides for heart failure. The search strategy for MEDLINE is available fom the authors. The reference lists of primary studies and review articles identified by the search were checked for further relevant studies. We included all studies that compared the diagnostic accuracy of natriuretic peptides against a reference standard and where the results were reported so that a 2 × 2 table of results could be constructed. Several studies that examined the association between natriuretic peptide levels and heart failure were excluded, as were case-control studies. Six studies involving overlapping or duplicate cohorts of patients were also excluded.

Two reviewers (J.A.D. and E.P.) assessed independently the quality of each study and extracted data. Disagreements were resolved by consensus or by consulting a third reviewer (P.P.G.). Each reviewer extracted the data to construct a 2 × 2 table for every cutoff point that was published in each study. To allow for changes in the cutoff points used both within and between studies, the diagnostic odds ratio (DOR) = {[Sensitivity/(1 − Sensitivity)]/[(1 − Specificity)/Specificity]} was chosen as the measure of diagnostic accuracy. If there was more than one cutoff point within a study, we took the average of the DORs for each cutoff point. This was done by taking the average of the natural logarithm of the odds ratio and the average of the variance of the natural logarithm of the odds ratio for cutoff points within a study (unweighted, because the study size was the same in each case), and back-transforming to calculate the average DOR and confidence interval (CI). The studies were grouped so that a DOR was calculated against each reference standard, using a DerSimonian and Laird random-effects model10 on a logarithmic scale with a corresponding test of heterogeneity. Where possible, the positive and negative likelihood ratios were calculated where studies had used similar cutoff levels and the same reference standard, again using a DerSimonian and Laird random-effects model.

An unweighted least-squares regression model using the method of Moses et al11 was used to assess whether the odds ratio was independent of the cutoff point. The model is D = a + bS, where the difference D is defined as the logit true-positive rate minus the logit false-positive rate, which is equivalent to the log of the DOR, and the sum S is defined as the logit true-positive rate plus the logit false-positive rate, which is a measure in the variation of the threshold. For each study, the values D and S were calculated, then the regression line was fitted. An unpaired, 2-tailed t test was used to see whether the slope of the line was significantly different from zero, which would imply that the overall diagnostic accuracy of the test varied with the cutoff point used.

In studies that compared the diagnostic accuracy of BNP with ANP, the estimated area under the curve (AUC) for each study was pooled by an inverse variance method. The diagnostic accuracy of the 2 natriuretic peptides was assessed by comparing the difference between the 2 pooled AUCs divided by the variance of the AUC, Image description not available. with a standard normal distribution.12 This method will underestimate the true measure of difference, as the data are derived from paired study designs, but would require individual patient data to estimate the true difference.

RESULTS

We identified 20 studies with published data that met the inclusion criteria of the review1331 (Table 1).

The quality of the studies was generally high, with most satisfying the following criteria (with the number reporting each criterion in parentheses): (1) patients were a consecutive series or random sample (15/20); (2) the index and reference tests were assessed independently and blinded to the other test result (15/20); (3) all patients received both tests (16/20); (4) the methods for performing both tests were described (20/20); (5) the characteristics of the study population were described (20/20); and (6) there was no time delay between the measurement of the 2 tests (14/20). The details of the first 2 quality criteria are also shown in Table 1.

The DORs of BNP against each reference standard are shown in Figure 1. In the 8 studies that measured BNP against a left ventricular ejection fraction of 40% or less, the pooled DOR was 11.6 (95% CI, 8.4-16.1). The results of the studies were consistent, with no evidence of heterogeneity. With less restrictive echocardiographic criteria, the DOR was smaller and the degree of heterogeneity greater, as would be expected with studies with a more imperfect reference standard and varying levels for the reference threshold. Using a reference standard of left ventricular ejection fraction of 40% or less and pooling studies that used a cutoff between 14 and 19 pmol/L gave an estimated positive likelihood ratio of 4.1 (95% CI, 2.6-6.6) and a negative likelihood ratio of 0.35 (95% CI, 0.17-0.72).

In the 7 studies that measured BNP against a consensus clinical opinion, generally using all other diagnostic information available, the DOR was greater (30.9; 95% CI, 27.0-35.4). The degree of heterogeneity between the studies was also low. This result suggests that BNP and clinical diagnosis are in greater agreement than BNP and left ventricular function, assuming no other differences between the 2 groups of studies. The results were heavily weighted by the results of one study, however, the Breathing Not Properly study reported by Maisel et al in 2002.29 This was a multicenter study with 1586 patients that assessed the diagnostic accuracy of BNP in patients presenting to 7 emergency departments against the diagnosis by 2 cardiologists who had access to all clinical data, including results of radiology and echocardiography. In this study, using a cutoff level of 14.4 pmol/L, the positive likelihood ratio was 2.6 (95% CI, 2.3-2.8) and the negative likelihood ratio was 0.05 (95% CI, 0.03-0.07).

In the 2 studies that measured BNP against echocardiographic criteria for both systolic and diastolic heart failure, the DOR (37.7; 95% CI, 5.9-237.2) was again greater than in studies that measured only systolic function, but the results of the 2 studies were different.

Of the studies that investigated BNP vs systolic or systolic plus diastolic function, 7 studies were conducted in general practice or community settings and 11 were conducted in hospital settings. The DOR from the studies in the 2 settings showed similar results (Figure 1). As these groups of studies pool results using different reference standards, they both showed highly statistically significant levels of heterogeneity.

The data for the individual studies and the curve derived from the pooled odds ratio for studies comparing BNP with a reference standard of left ventricular ejection fraction of 40% or less are shown in Figure 2. This figure illustrates the variation seen between studies in terms of the sensitivity and specificity for various cutoff points. The Moses et al11 regression model was estimated for studies that used a reference standard of left ventricular ejection fraction of 40% or less and clinical diagnosis. These both showed a significant negative relationship, implying that the diagnostic accuracy decreases with increases in the cutoff.32

Six studies compared the diagnostic accuracy of BNP and ANP. The results of these studies are shown in Table 2.7,13,15,17 The BNP was generally more accurate as a diagnostic marker of heart failure than ANP. The AUCs for the receiver operating characteristic curves were available for 3 studies that compared NT-ANP with BNP. The pooled AUC for the 3 studies that compared NT-ANP with echocardiogram was 0.78 (95% CI, 0.73-0.84). The pooled AUC for BNP in the same studies was 0.84 (95% CI, 0.80-0.89). The test statistic for the difference between the 2 measures shows a marginally statistically significant difference with a z score of 1.66 (P = .048). This calculation underestimates the true significance because the original data were from paired study designs.

COMMENT

The results of these 20 studies show that BNP is accurate in the diagnosis of heart failure. However, there is considerable variation in the estimates of diagnostic accuracy between studies, and this variation does not seem to be accounted for by differences in the clinical setting or the type of test used. It would be helpful to understand the sources of this variation before recommending the routine clinical use of the test.

Measurement of BNP is cheaper and is potentially more accessible than echocardiography. Results of BNP testing can be obtained within 20 minutes of blood collection.33,34 As echocardiography provides additional information that may be important in the clinical treatment of patients with heart failure, the most likely use of BNP will be in the ambulatory care setting to determine which patients require further testing with echocardiogram. The cutoff level will therefore need to be sufficiently low that patients who have heart failure are not excluded from further testing. In the Breathing Not Properly study, combining BNP with clinical judgment improved diagnostic accuracy across the entire range of diagnostic certainty. Even when the clinician had a high degree of certainty in his or her diagnosis, combining this judgment with the BNP result improved diagnostic accuracy.35

Measurement of BNP may play a role in the diagnosis of patients with diastolic heart failure. The diagnostic accuracy of BNP was greater when the definition of disease used as the reference standard included patients who were diagnosed as having heart failure but who had "preserved left ventricular systolic dysfunction." This raises the question of whether BNP could be a better marker of disease, prognosis, and response to treatment than left ventricular function and whether comparison with echocardiographic criteria of left ventricular function may, in fact, be a comparison with a "silver" standard. To date, almost all of the trials of treatment for heart failure have been conducted in patients with impaired left ventricular function.3638 Although there is a group of patients who have heart failure with preserved left ventricular systolic function (diastolic heart failure), it is not clear how these patients could be identified or how patients chosen by alternative criteria would respond to treatment.39

Using a cutoff value of 15 pmol/L achieves high sensitivity, and BNP values below this are able to exclude heart failure in patients in whom disease is suspected. Early studies have also shown a potential role for BNP in monitoring the response to treatment.40,41 Future research will need to further define BNP's role in clinical management, and to determine whether it is better at predicting prognosis and response to treatment than echocardiography.

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Article Information

Correspondence: Jenny A. Doust, BMBS, FRACGP, Centre for General Practice, School of Population Health, University of Queensland, Herston Road, Herston Qld 4006, Australia (j.doust@uq.edu.au).

Accepted for publication March 23, 2004.

We thank Jon Deeks, Senior Medical Statistician, Centre for Statistics in Medicine, Oxford, England, for comments on an earlier draft of this article.

References
1.
Davies  MHobbs  FDavis  R  et al.  Prevalence of left-ventricular systolic dysfunction and heart failure in the Echocardiographic Heart of England Screening study: a population based study. Lancet. 2001;358439- 444
PubMedArticle
2.
Redfield  M Heart failure: an epidemic of uncertain proportions. N Engl J Med. 2002;3471442- 1444
PubMedArticle
3.
Redfield  MMJacobsen  SJBurnett  JC  JrMahoney  DWBailey  KRRodeheffer  RJ Burden of systolic and diastolic ventricular dysfunction in the community: appreciating the scope of the heart failure epidemic. JAMA. 2003;289194- 202
PubMedArticle
4.
Morgan  SSmith  HSimpson  I  et al.  Prevalence and clinical characteristics of left ventricular dysfunction among elderly patients in general practice setting: cross sectional survey. BMJ. 1999;318368- 372
PubMedArticle
5.
McDonagh  TAMorrison  CELawrence  A  et al.  Symptomatic and asymptomatic left-ventricular systolic dysfunction in an urban population. Lancet. 1997;350829- 833
PubMedArticle
6.
Mosterd  AHoes  AWde Bruyne  MC  et al.  Prevalence of heart failure and left ventricular dysfunction in the general population: the Rotterdam Study. Eur Heart J. 1999;20447- 455
PubMedArticle
7.
Cowie  MRStruthers  ADWood  DA  et al.  Value of natriuretic peptides in assessment of patients with possible new heart failure in primary care. Lancet. 1997;3501349- 1353
PubMedArticle
8.
Fuat  AHungin  APMurphy  JJ Barriers to accurate diagnosis and effective management of heart failure in primary care: qualitative study. BMJ. 2003;326196
PubMedArticle
9.
Baughman  KL B-type natriuretic peptide: a window to the heart. N Engl J Med. 2002;347158- 159
PubMedArticle
10.
DerSimonian  RLaird  N Meta-analysis in clinical trials. Control Clin Trials. 1986;7177- 188
PubMedArticle
11.
Moses  LEShapiro  DLittenberg  B Combining independent studies of a diagnostic test into a summary ROC curve: data-analytic approaches and some additional considerations. Stat Med. 1993;121293- 1316
PubMedArticle
12.
Pepe  M The Statistical Evaluation of Medical Tests for Classification and Prediction.  Oxford, England Oxford University Press2003;108
13.
McDonagh  TARobb  SDMurdoch  DR  et al.  Biochemical detection of left-ventricular systolic dysfunction. Lancet. 1998;3519- 13
PubMedArticle
14.
Bettencourt  PFerreira  APardal-Oliveira  N  et al.  Clinical significance of brain natriuretic peptide in patients with postmyocardial infarction. Clin Cardiol. 2000;23921- 927
PubMedArticle
15.
Choy  AMDarbar  DLang  CC  et al.  Detection of left ventricular dysfunction after acute myocardial infarction: comparison of clinical, echocardiographic, and neurohormonal methods. Br Heart J. 1994;7216- 22
PubMedArticle
16.
Valli  NGeorges  ACorcuff  JBBarat  JLBordenave  L Assessment of brain natriuretic peptide in patients with suspected heart failure: comparison with radionuclide ventriculography data. Clin Chim Acta. 2001;30619- 26
PubMedArticle
17.
Vasan  RSBenjamin  EJLarson  MG  et al.  Plasma natriuretic peptides for community screening for left ventricular hypertrophy and systolic dysfunction: the Framingham Heart Study. JAMA. 2002;2881252- 1259
PubMedArticle
18.
Hutcheon  SDGillespie  NDStruthers  ADMcMurdo  ME B-type natriuretic peptide in the diagnosis of cardiac disease in elderly day hospital patients. Age Ageing. 2002;31295- 301
PubMedArticle
19.
Landray  MJLehman  RArnold  I Measuring brain natriuretic peptide in suspected left ventricular systolic dysfunction in general practice: cross-sectional study. BMJ. 2000;320985- 986
PubMedArticle
20.
Smith  HPickering  RMStruthers  ASimpson  IMant  D Biochemical diagnosis of ventricular dysfunction in elderly patients in general practice: observational study. BMJ. 2000;320906- 908
PubMedArticle
21.
McGeoch  GLainchbury  JTown  GIToop  LEspiner  ERichards  AM Plasma brain natriuretic peptide after long-term treatment for heart failure in general practice. Eur J Heart Fail. 2002;4479- 483
PubMedArticle
22.
Yamamoto  KBurnett  JC  JrBermudez  EAJougasaki  MBailey  KRRedfield  MM Clinical criteria and biochemical markers for the detection of systolic dysfunction. J Card Fail. 2000;6194- 200
PubMedArticle
23.
Yamamoto  KBurnett  JC  JrJougasaki  M  et al.  Superiority of brain natriuretic peptide as a hormonal marker of ventricular systolic and diastolic dysfunction and ventricular hypertrophy. Hypertension. 1996;28988- 994
PubMedArticle
24.
Luchner  ABurnett  JC  JrJougasaki  M  et al.  Evaluation of brain natriuretic peptide as marker of left ventricular dysfunction and hypertrophy in the population. J Hypertens. 2000;181121- 1128
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