REVIEW ARTICLE. Accuracy of B-Type Natriuretic Peptide Tests to Exclude Congestive Heart Failure

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1 REVIEW ARTICLE Accuracy of B-Type Natriuretic Peptide Tests to Exclude Congestive Heart Failure Systematic Review of Test Accuracy Studies Markus Battaglia, MD, MPH; Daniel Pewsner, MD; Peter Jüni, MD; Matthias Egger, MD, MSc, MFPHM; Heiner C. Bucher, MD, MPH; Lucas M. Bachmann, MD, PhD Background: Congestive heart failure (CHF) is a major public health problem. The use of B-type natriuretic peptide (BNP) tests shows promising diagnostic accuracy. Herein, we summarize the evidence on the accuracy of BNP tests in the diagnosis of CHF and compare the performance of rapid enzyme-linked immunosorbent assay (ELISA) and standard radioimmunosorbent assay (RIA) tests. Methods: We searched electronic databases and the reference lists of included studies, and we contacted experts. Data were extracted on the study population, the type of test used, and methods. Receiver operating characteristic (ROC) plots and summary ROC curves were produced and negative likelihood ratios pooled. Random-effect metaanalysis and metaregression were used to combine data and explore sources of between-study heterogeneity. Results: Nineteen studies describing 22 patient populations (9 ELISA and 13 RIA) and 9093 patients were included. The diagnosis of CHF was verified by echocardiography, radionuclide scan, or echocardiography combined with clinical criteria. The pooled negative likelihood ratio overall from random-effect meta-analysis was 0.18 (95% confidence interval [CI], ). It was lower for the ELISA test (0.12; 95% CI, ) than for the RIA test (0.23; 95% CI, ). For a pretest probability of 20%, which is typical for patients with suspected CHF in primary care, a negative result of the ELISA test would produce a posttest probability of 2.9%; a negative RIA test, a posttest probability of 5.4%. Conclusions: The use of BNP tests to rule out CHF in primary care settings could reduce demand for echocardiography. The advantages of rapid ELISA tests need to be balanced against their higher cost. Arch Intern Med. 2006;166: Author Affiliations: Department of Social and Preventive Medicine, University of Berne (Drs Battaglia and Egger), MediX General Practice Network, Berne (Dr Pewsner), Basel Institute for Clinical Epidemiology, University Hospital, Basel (Dr Bucher), and Horten Center, University of Zurich, Zurich (Dr Bachmann), Switzerland; and MRC Health Services Research Collaboration, Department of Social Medicine, University of Bristol, Bristol, England (Drs Jüni and Egger). CONGESTIVE HEART FAILure (CHF) is a major public health problem. Incidence and prevalence of CHF increase steeply with age, 1,2 and CHF is a leading cause of hospitalization among people older than 65 years. 3,4 With improvements in the prognosis of CHF, improved survival after acute myocardial infarction, and an aging population, the burden of CHF will continue to increase in the years to come. 3 CME course available at Ruling out CHF early in the diagnostic process is important but difficult. Clinical and signs such as edema, shortness of breath, or persistent coughing or wheezing are unspecific and can be absent. 2,5 Particularly in elderly patients and patients with comorbid disorders that can mimic CHF (eg, obese patients in primary care or patients with acute pulmonary conditions attending emergency departments), diagnostic uncertainty may lead to delayed therapy and unnecessary echocardiograms. See also pages 1063 and 1081 B-type (brain) natriuretic peptide (BNP) is a neurohormone that is secreted in response to volume expansion and pressure overload of cardiac ventricles. 6 In recent years, 2 tests measuring BNP in plasma have been developed, an enzymelinked immunosorbent assay (ELISA) and a radioimmunosorbent assay (RIA). The ELISA test is a bedside test and would be particularly suitable to assist rapid diagnosis on site in primary and emergency care settings. The comparative accuracy of 1073

2 346 Total Citations Identified to Capture Primary Articles on All Diagnostic Tests Using BNP for Heart Failure Diagnosis (173 Medline; 90 EMBASE; 83 Other; No Hits for Cochrane Database or MEDION) 84 Primary Articles on Diagnostic Accuracy of BNP for Heart Failure Retrieved for Detailed Evaluation 19 Primary Articles Included in Systematic Review 22, Number of Patient Populations in 2 2 Tables Analyzed Figure 1. Study flow diagram. the 2 tests is, however, unclear. We performed a systematic review of the literature and meta-analysis to compare the diagnostic accuracy of ELISA and RIA assays. METHODS We used methods recommended by the Cochrane methods group on systematic reviews of screening and diagnostic tests. 7 IDENTIFICATION OF STUDIES We searched Medline and EMBASE (January 1990 to March 2004), the Cochrane Library (2004, issue 1) and MEDION (a database of diagnostic test reviews set up by Belgian and Dutch colleagues) (December 1971 to March 2004) to identify diagnostic studies evaluating the accuracy of BNP in the diagnosis of CHF. Search strategies combined free text terms and Medical Subject Headings (MeSH) relating to heart failure and diagnostic accuracy studies. The detailed search strategy is available on request. We considered studies in any language. We supplemented electronic searches by hand searching reference lists of relevant articles and reviews and by contacting experts and manufacturers of BNP tests. STUDY SELECTION AND DATA EXTRACTION PROCEDURES Studies were eligible if they compared any type of BNP assay in asymptomatic patients or patients with suspected acute CHF with echocardiographic findings or findings from radionuclide scans, with 262 Citations Excluded After Screening Titles and/or Abstracts 65 Articles Excluded 20 No Test Accuracy Study 1 Duplicate Publication 2 Overlapping Sampling Periods at the Same Institution 13 Lack of Data to Construct 2 2 Table 29 Lack of Original Data Reviews, Letters or without additional clinical criteria. Besides this, the minimum requirement for inclusion was enough information to fill the 2 2 table. Two reviewers independently examined titles and abstracts of all potentially relevant articles and obtained full articles of all citations meeting the selection criteria. When necessary, we contacted authors to clarify issues, for example, when data from the same patients may have been included in several studies. We excluded studies that did not report the number of truepositive, false-positive, true-negative, and false-negative findings, and studies that were restricted to patients with diastolic dysfunction or examined the use of BNP as a prognostic marker. Final decisions on eligibility were made by consensus. We abstracted study characteristics, methodologic quality, and results from each selected article. Study characteristics included the setting and type of population examined, publication year, test type and cutoff, reference standards, and the source of funding (main support from industry vs other). For comparison in statistical calculations we converted BNP levels from picogram per milliliter to picomole per liter where necessary, using a factor of (1/3.463), based on the molecular weight of the BNP. Data were abstracted in duplicate using an electronic data entry form developed for this purpose. 8 Discrepancies were resolved by consensus. ASSESSMENT OF STUDY QUALITY We assessed all articles that met the selection criteria for study quality. We selected items based on theoretical considerations and empirical data, 9 including study design (case-control design or other), type of recruitment (prospective or retrospective, or other), use of different reference tests (yes or no), application of reference tests (applied to all or only a fraction of study participants), and blind interpretation of test results (yes or no). DATA SYNTHESIS We calculated sensitivities, specificities, likelihood ratios, and their standard errors. We examined individual study results and between-study heterogeneity by plotting sensitivity and specificity in the receiver operating characteristics (ROC) space and used the regression model proposed by Moses et al 10 to calculate summary ROC curves for both assays separately. We calculated the I 2 statistic, which describes the percentage of total variation across studies that is due to heterogeneity rather than chance. 11 Mild heterogeneity will account for less than 30% of the variation, and pronounced heterogeneity will account for more than 50%. Because the BNP test is mainly used to rule out CHF, we were particularly interested in the likelihood ratio of a negative result. The likelihood ratio is a measure of a test result s ability to modify pretest probabilities and is used to convert the estimated probability of the suspected diagnosis before the test result was known (pretest probability) into a posttest probability, which takes the result into account. 12 METAREGRESSION ANALYSIS We used random-effects metaregression 13 to investigate sources of variation in the negative likelihood ratios. The following variables were considered: type of test (ELISA or RIA), mean age of study population, proportion of male participants, presence of typical of heart failure, type of setting, and year of publication. We also examined the following items on study quality: patient recruitment (consecutive or other), blinding of test results (yes or no), study design (prospective or retrospective), and funding source (industry or other). Finally, we explored whether the type of reference test (echocardiography, radionuclide scan, or echocardiography combined with clinical criteria) influenced results. Results are presented as sensitivities, specificities, negative likelihood ratios, and summary ROC curves, with 95% confidence intervals (CIs). All analyses were 1074

3 Table 1. Characteristics of Studies on Test Accuracy of BNP Tests for the Diagnosis of Congestive Heart Failure Source Choy et al, Davis et al, Davidson et al, Cowie et al, McDonagh et al, Bettencourt et al, Landray et al, Smith et al, Yamamoto et al, Dao et al, Maisel et al, Valli et al, Quality of Study* Prospective, Individuals Tested, No. Mean Age, y Proportion Male, % Type of Test Cutoff, pg/ml (pmol/l) Reference Standard Setting RIA 52 (15) ECHO Postmyocardial infarction patients in tertiary care RIA 77 (22) ECHO Acute dyspnea and urgent admission Test described RIA 14 (4) RN scan Referred by general practice for suspected ventricular dysfunction 106 NR 48 RIA 77.7 (22) ECHO and Primary care patients with newly suspected heart failure diagnosis Prospective, RIA 17.9 (5.2) ECHO General population, random sample RIA 93.8 (27) ECHO Postmyocardial infarction patients in tertiary care Test described RIA 17.9 (5.2) ECHO Clinically suspected heart failure by general practice Test described NR RIA 65.5 (19) ECHO and Consecutive, RIA 37 (11) ECHO and ELISA 80 (23) ECHO and ELISA 75 (22) ECHO and General population from primary care practices aged 70 to 84 y Outpatients referred for assessment of systolic function with or risk factors Veterans, convenience sample with acute dyspnea Mainly outpatient veterans, referred for suspected left ventricular dysfunction RIA 52 (15) RN scan Referrals for evaluation of ventricular function Proportion With Heart Failure, % (continued) performed using Stata Statistical software (version 8.2; Stata Corp, College Station, Tex). RESULTS IDENTIFICATION OF STUDIES AND STUDY QUALITY Figure 1 summarizes the process of identifying and selecting studies. *References 14, 15, 18, 22, 24, 25, 27-29, 32. Nineteen studies, which described 22 study populations, met our inclusion criteria. Study characteristics are listed in Table 1. Among the 19 studies, 10 had a prospective design,* 8 enrolled patients consecutively, 17,19,22,24-28 and 11 reported blind interpretation of test results. 14,17,19,22-24,26,28-31 There were no diagnostic case-control studies, and reference tests were applied equally to all study participants. Thirteen studies examined the accuracy of the RIA assay 14-22,25,27,30,32 ; 5, the ELISA test 23,24,28,29,31 ; and 1, the ELISA N-terminal pro-bnp (NT-pro-BNP) test. 26 Studies used either the ejection fraction determined by echocardiography (cutoff, 30%-50%) or ra- 1075

4 Table 1. Characteristics of Studies on Test Accuracy of BNP Tests for the Diagnosis of Congestive Heart Failure (cont) Source Hobbs et al, 26 1 Quality of Study* Individuals Tested, No. Mean Age, y Proportion Male, % Type of Test ELISA NT-pro-BNP Cutoff, pg/ml (pmol/l) NR (36) Reference Standard ECHO Setting Randomly sampled patients, general population aged over NR (36) Patients with existing heart failure diagnosis NR (36) Patients taking diuretics NR (36) Patients at high risk for heart failure Hutcheon et al, 27 Jourdain et al, 28 Maisel et al, 29 McGeoch et al, 30 Morrison et al, 31 Vasan et al, 32 Consecutive, 299 NR 35 RIA 170 (49) ECHO Referrals for suspected cardiovascular disease ELISA 300 (87) ECHO and Referrals for acute dyspnea by general practice or cardiologist to emergency department ELISA 100 (29) ECHO Acute dyspnea patients in emergency setting RIA (35) ECHO Selected heart failure patients from 2 practices in primary care 321 NR 95 ELISA 94 (27) ECHO and Veterans, convenience sample, all dyspnea on exertion, 75% at rest RIA NR ECHO General population, Framingham offspring Proportion With Heart Failure, % Abbreviations: BNP, B-type natriuretic peptide; ECHO, echocardiography; ELISA, enzyme-linked immunosorbent assay; NR, not reported; NT-pro-BNP, N-terminal pro-bnp assay (not converted into picograms per milliliter); RIA, radioimmunosorbent assay; RN, radionuclide. *Only quality items that were met by the study are listed. The following items could be met: prospective recruitment of study participants, consecutive recruitment, adequate description of test, blind interpretation of test results. There were no diagnostic case-control studies; in all studies, reference tests were applied to all study participants. Numbers indicate different subgroups of patients as defined by setting dionuclide scans (cutoff, 35%-40%) as the reference standard; 8 studies used a combination of echocardiography and clinical. The median sample size of the 19 studies was 139 patients (range, ); the analysis was based on 9093 patients. Five studies were sponsored by industry. 23,25,27,29,31 CHARACTERISTICS OF STUDY POPULATIONS AND PRETEST PROBABILITIES Study populations and settings were heterogeneous (Table 1). The mean age of participants ranged from 51 to 79 years; the percentage of men, from 35% to 95%. Five studies were conducted in patients with acute dyspnea in tertiary care settings, with the prevalence (pretest probability) of heart failure ranging from 39% to 72%. 15,23,28,29,31 Similarly high prevalences were observed in patients examined after a myocardial infarction and in patients with an existing diagnosis of heart failure. 14,19,26,30 Among outpatients who were referred by general practitioners, prevalence of heart failure ranged from 10% to 31%. 16,17,20,22,27 In screening studies of patients with risk factors for coronary heart disease and CHF, the prevalence was below 10%. 18,21,32 TEST PERFORMANCE CHARACTERISTICS Table 2 lists for each study population the number of true-positive, false-positive, false-negative, and true-negative test findings, as well as sensitivity, specificity, and negative likelihood ratio. The median sensitivity was 87% (range, 68%- 98%). Specificity tended to be lower and more heterogeneous (median, 1076

5 Table 2. Results of Studies on Test Accuracy of BNP Tests for the Diagnosis of Congestive Heart Failure* Study Test Type True Positive Test Finding, No. False Positive False Negative True Negative Sensitivity,% Specificity,% Negative Likelihood Ratio (95% CI) This systematic review and metaanalysis is based on 9093 participants from 22 separate study populations, 1854 (20%) of whom were diagnosed as having CHF. Studies were generally of good methodo- Choy et al, RIA ( ) Davis et al, RIA ( ) Davidson et al, RIA ( ) Cowie et al, RIA ( ) McDonagh et al, RIA ( ) Bettencourt et al, RIA ( ) Landray et al, RIA ( ) Smith et al, RIA ( ) Yamamoto et al, RIA ( ) Dao et al, ELISA ( ) Maisel et al, ELISA ( ) Valli et al, RIA ( ) Hobbs et al, 26 ELISA 1 NT-pro ( ) 2 BNP ( ) ( ) ( ) Hutcheon et al, 27 RIA ( ) Jourdain et al, 28 ELISA ( ) Maisel et al, 29 ELISA ( ) McGeoch et al, 30 RIA ( ) Morrison et al, 31 ELISA ( ) Vasan et al, 32 RIA ( ) Abbreviations: BNP, B-type natriuretic peptide; CI, confidence interval; ELISA, enzyme-linked immunosorbent assay; NT-pro-BNP, N-terminal pro-bnp assay (not converted into picograms per milliliter); RIA, radioimmunosorbent assay. *To 0 cells, 0.5 was added to allow calculation of sensitivity, specificity, and other statistics. Numbers indicate different subgroups of patients as defined by setting. In cases of 0 false negatives, 0.5 was added to 0 to allow calculation of sensitivity, specificity, and other statistics. 72%; range, 19%-98%). The combined negative likelihood ratio overall from random-effect metaanalysis was 0.18 (95% CI, ). It was lower for the ELISA test (0.12; 95% CI, ) than for the RIA test (0.23; 95% CI, ) (Figure 2). This difference was unlikely to be a chance finding (P from test of interaction=.009). The type of test explained a substantial proportion of between study heterogeneity in the negative likelihood ratio: the I 2 statistic was reduced from 66% to 45% when including type of test system in the metaregression model. The difference in the performance of the 2 test systems is also evident from the summary ROC curves shown in Figure 3. The other variables considered in metaregression analyses were not strongly associated with the negative likelihood ratio, with the exception of presence of and type of test. The presence of was associated with a lower negative likelihood ratio (P=.07); however, the association was much attenuated and became nonsignificant (P=.62) when the type of test system was entered into the model. Figure 4 shows the estimated posttest probabilities for different pretest probabilities assuming constancy of the negative likelihood ratio. For example, for a pretest probability of 20% (which is typical for patients with suspected heart failure in primary care), a negative result of the ELISA test would produce a posttest probability of 2.9%, and a negative RIA test would produce a posttest probability of 5.4%. Conversely, the corresponding posttest probabilities among patients with acute in an emergency setting, assuming a pretest probability of 60%, would be 15% and 26%, respectively. COMMENT We summarized the accuracy of the 2 available BNP screening tests for excluding CHF in different study populations, ranging from asymptomatic patients in the community to patients presenting with acute dyspnea in emergency departments. We found that negative results of both tests accurately rule out the diagnosis if patients are at relatively low risk of CHF. The use of BNP tests in low-risk patients in primary care settings could reduce demand for echocardiography and referrals of patients to specialists. The ELISA tests, which allow bedside testing and provide results in a few minutes, performed somewhat better than the RIA tests, which must be sent to a laboratory. However, the ELISA advantages must be weighed against its higher cost compared with RIA ($55 vs $11). STRENGTHS AND LIMITATIONS 1077

6 ELISA Test Dao et al, Maisel et al, Hobbs et al 1, 26 Hobbs et al 4, 26 Hobbs et al 3, 26 Jourdain et al, 28 Hobbs et al 2, 26 Morrison et al, 31 Maisel et al, 29 Overall Negative LR (95% CI) Positive LR (95% CI) 0.02 ( ) ( ) 0.14 ( ) 7.17 ( ) 0.10 ( ) 9.90 ( ) 0.27 ( ) 3.75 ( ) 0.38 ( ) 2.60 ( ) 0.06 ( ) ( ) 0.10 ( ) 9.91 ( ) 0.14 ( ) 6.95 ( ) 0.13 ( ) 7.64 ( ) 0.12 ( ) 8.22 ( ) RIA Test Choy et al, ( ) 4.34 ( ) Davis et al, ( ) ( ) Davidson et al, ( ) ( ) Cowie et al, ( ) ( ) McDonagh et al, ( ) 3.58 ( ) Bettencourt et al, ( ) 4.27 ( ) Landray et al, ( ) 2.63 ( ) Yamamoto et al, ( ) 2.97 ( ) Smith et al, ( ) 7.80 ( ) Valli et al, ( ) 5.29 ( ) Vasan et al, ( ) 6.31 ( ) McGeoch et al, ( ) 2.13 ( ) Hutcheon et al, ( ) 4.19 ( ) Overall 0.23 ( ) 4.37 ( ) Negative LR Positive LR 100 Figure 2. Forest plots showing the negative and positive likelihood ratios (LRs) for enzyme-linked immunosorbent assay (ELISA) and radioimmunosorbent assay (RIA) testing along with the corresponding pooled estimates using a random-effects model. CI indicates confidence interval; numbers following Hobbs et al indicate different subgroups of patients in that study, as defined by setting (Table 1). Sensitivity RIA ELISA SROC for RIA SROC for ELISA Specificity that the difference in performance observed between the ELISA and RIA test was explained by differences in study populations. Studies used different reference tests and criteria for the diagnosis of CHF. Different reference standards could have introduced heterogeneity in test accuracy, but this was not confirmed by our analyses. We acknowledge that we could only adjust for information that was aggregated at the study level. Individual patient data would have been preferable but were not available. Individual patient data would also have allowed us to examine the effect of the choice of different BNP cutoffs. Despite a comprehensive literature search, we could not identify any studies that directly compared the 2 test systems. We therefore believe that our study makes an important contribution to the best available evidence on the accuracy of BNP tests for the diagnosis of CHF. Figure 3. Receiver operating characteristic (ROC) plot along with the summary ROC (SROC) curves stratified for studies of the enzyme-linked immunosorbent assay (ELISA) and radioimmunosorbent assay (RIA). RESULTS IN CONTEXT WITH OTHER STUDIES logic quality, although reporting was sometimes incomplete. Both tests had been examined in a range of populations, but there was little evidence that test performance depended on patient characteristics or Doust and colleagues 33 recently did a systematic review of the diagnostic accuracy of natriuretic peptides in the diagnosis of heart failure. This review differs in several respects: we excluded 6 studies that were in- 1078

7 Posttest Probability, % RIA ELISA Pretest Probability, % Figure 4. Nomograms of the relation between the pretest and posttest probabilities after a negative finding on enzyme-linked immunosorbent assay (ELISA) or radioimmunosorbent assay (RIA). cluded by Doust et al but did not meet our inclusion criteria. In 3 of these, the definition of the reference standard was inadequate, and the other 3 were of patients with diastolic heart failure. Conversely, we identified 5 additional studies and obtained unpublished information from some authors. 34 Furthermore, in contrast to Doust et al, 33 we compared the characteristics of the bedside ELISA test with the RIA assay. IMPLICATIONS AND FURTHER RESEARCH It is widely acknowledged that CHF is a major public health problem. Recent data from the Framingham Heart Study indicate that the lifetime risk of CHF is 1 in 5, for both men and women. 1 In the United Kingdom and elsewhere, CHF is a leading cause of hospitalization among people older than 65 years. 3,4 Although prognosis has improved in recent decades, mortality remains high: the 5-year mortality from 1990 to 1999 was 59% for men and 45% for women aged 65 to 74 years in the Framingham study. 35 With further improvements in the prognosis of CHF, improved survival after acute myocardial infarction, and an aging population, the burden of CHF will continue to increase in the years to come. 3 B-type natriuretic peptide tests have the potential to guide clinical decisions, particularly in patients at lower risk in primary care and emergency departments. Applied early in the diagnostic process in patients with suspected cardiac failure, negative BNP test findings can help rule out CHF and thus avoid unnecessary referral to echocardiography. If the test result is positive, confirmation by echocardiography will generally be required. Early diagnosis of left ventricular dysfunction or CHF may be important: treatment with angiotensin-converting enzyme inhibitors can improve the prognosis of patients with left ventricular dysfunction without overt heart failure and patients with symptomatic CHF Future diagnostic accuracy studies should model the probability of CHF given the BNP test result and also take into account relevant clinical data (such as the presence of and age). Such studies should be adequately powered so that the influence of clinical indicators on test performance can be examined. The resulting prediction rules should then be validated in other populations, and their costeffectiveness should ideally be investigated in randomized trials. 39 Indeed, although our review indicates that BNP tests are useful to rule out CHF in patients at lower risk, the effect of the introduction of such tests on clinical outcomes or costs remains unclear. Accepted for Publication: January 10, Correspondence: Matthias Egger, MD, MSc, MFPHM, Department of Social and Preventive Medicine, University of Berne, Finkenhubelweg 11, CH-3012 Berne, Switzerland Financial Disclosure: None. Funding/Support: This study was funded by Gesellschaft für das Gemeinnützige und Gute and the Swiss Academy of Medical Science (Käthe Zingg-Schwichtenberg-Foundation), Basel, Switzerland, and grants 3233B , 3200B (Dr Bachmann), , and (Dr Jüni) from the Swiss National Science Foundation, Berne, Switzerland. Acknowledgment: We thank Fritz Grossenbacher, MD, for help with the literature searches. REFERENCES 1. Lloyd-Jones DM, Larson MG, Leip EP, et al. Lifetime risk for developing congestive heart failure: the Framingham Heart Study. Circulation. ;106: McDonagh TA, Morrison CE, Lawrence A, et al. Symptomatic and asymptomatic left-ventricular systolic dysfunction in an urban population. Lancet. 1997;350: Braunwald E. Shattuck lecture cardiovascular medicine at the turn of the millennium: triumphs, concerns, and opportunities. N Engl J Med. 1997;337: Cowie MR, Fox KF, Wood DA, et al. Hospitalization of patients with heart failure: a populationbased study. Eur Heart J. ;23: Redfield MM, Jacobsen SJ, Burnett JC, Mahoney DW, Bailey KR, Rodeheffer RJ. Burden of systolic and diastolic ventricular dysfunction in the community. JAMA. 2003;289: de Lemos JA, McGuire DK, Drazner MH. B-type natriuretic peptide in cardiovascular disease. Lancet. 2003;362: Irwig L, Glasziou P. Cochrane Methods Group on Systematic Review of Screening and Diagnostic Tests: Recommended Methods (1996). Accessed February 2,. 8. Horvath AR, Pewsner D. Systematic reviews in laboratory medicine: principles, processes and practical considerations. Clin Chim Acta. 2004; 342: Lijmer JG, Mol BW, Heisterkamp S, et al. Empirical evidence of design-related bias in studies of diagnostic tests. JAMA. 1999;282: Moses LE, Shapiro D, Littenberg B. Combining independent studies of a diagnostic test into a summary ROC curve: data-analytic approaches and some additional considerations. Stat Med. 1993; 12: Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ. 2003;327: Pewsner D, Battaglia M, Minder C, Marx A, Bucher 1079

8 HC, Egger M. Ruling a diagnosis in or out with SpPIn and SnNOut : a note of caution. BMJ. 2004;329: Thompson SG, Sharp SJ. Explaining heterogeneity in meta-analysis: a comparison of methods. Stat Med. 1999;18: Choy AM, Darbar D, Lang CC, et al. Detection of left ventricular dysfunction after acute myocardial infarction: comparison of clinical, echocardiographic, and neurohormonal methods. Br Heart J. 1994;72: Davis M, Espiner E, Richards G, et al. Plasma brain natriuretic peptide in assessment of acute dyspnoea. Lancet. 1994;343: Davidson NC, Naas AA, Hanson JK, Kennedy NS, Coutie WJ, Struthers AD. Comparison of atrial natriuretic peptide, B-type natriuretic peptide, and N-terminal proatrial natriuretic peptide as indicators of left ventricular systolic dysfunction. Am J Cardiol. 1996;77: Cowie MR, Struthers AD, Wood DA, et al. Value of natriuretic peptides in assessment of patients with possible new heart failure in primary care. Lancet. 1997;350: McDonagh TA, Robb SD, Murdoch DR, et al. Biochemical detection of left-ventricular systolic dysfunction. Lancet. 1998;351: Bettencourt P, Ferreira A, Pardal-Oliveira N, et al. Clinical significance of brain natriuretic peptide in patients with postmyocardial infarction. Clin Cardiol. 2000;23: Landray MJ, Lehman R, Arnold I. Measuring brain natriuretic peptide in suspected left ventricular systolic dysfunction in general practice: crosssectional study. BMJ. 2000;320: Smith H, Pickering RM, Struthers A, Simpson I, Mant D. Biochemical diagnosis of ventricular dysfunction in elderly patients in general practice: observational study. BMJ. 2000;320: Yamamoto K, Burnett JC, Bermudez EA, Jugasaki M, Bailey KR, Redfield MM. Clinical criteria and biochemical markers for the detection of systolic dysfunction. J Card Fail. 2000;6: Dao Q, Krishnaswamy P, Kazanegra R, et al. Utility of B-type natriuretic peptide in the diagnosis of congestive heart failure in an urgent-care setting. J Am Coll Cardiol. 2001;37: Maisel AS, Koon J, Krishnaswamy P, et al. Utility of B-natriuretic peptide as a rapid, point-of-care test for screening patients undergoing echocardiography to determine left ventricular dysfunction. Am Heart J. 2001;141: Valli N, Georges A, Corcuff JB, Barat JL, Bordenave L. Assessment of brain natriuretic peptide in patients with suspected heart failure: comparison with radionuclide ventriculography data. Clin Chim Acta. 2001;306: Hobbs FD, Davis RC, Roalfe AK, Hare R, Davies MK, Kenkre JE. Reliability of N-terminal probrain natriuretic peptide assay in diagnosis of heart failure: cohort study in representative and high risk community populations. BMJ. ; 324: Hutcheon SD, Gillespie ND, Struthers AD, McMurdo ME. B-type natriuretic peptide in the diagnosis of cardiac disease in elderly day hospital patients. Age Ageing. ;31: Jourdain P, Funck F, Canault E, et al. Value of type B natriuretic peptide in the emergency management of patients with suspected cardiac failure: report of 125 cases [in French]. Arch Mal Coeur Vaiss. ;95: Maisel AS, Krishnaswamy P, Nowak RM, et al. Rapid measurement of B-type natriuretic peptide in the emergency diagnosis of heart failure. N Engl J Med. ;347: McGeoch G, Lainchbury J, Town GI, Toop L, Espiner E, Richards AM. Plasma brain natriuretic peptide after long-term treatment for heart failure in general practice. Eur J Heart Fail. ; 4: Morrison LK, Harrison A, Krishnaswamy P, Kazanegra R, Clopton P, Maisel A. Utility of rapid B- natriuretic peptide assay in differentiating congestive heart failure from lung disease in patients presenting with dyspnea. J Am Coll Cardiol. ; 39: Vasan RS, Benjamin EJ, Larson MG, et al. Plasma natriuretic peptides for community screening for left ventricular hypertrophy and systolic dysfunction: the Framingham Heart Study. JAMA. ; 288: Doust JA, Glasziou PP, Pietrzak E, Dobson AJ. A systematic review of the diagnostic accuracy of natriuretic peptides for heart failure. Arch Intern Med. 2004;164: Battaglia M, Bachmann LM, Egger M. Diagnostic accuracy of natriuretic peptides for heart failure. Arch Intern Med. 2005;165: Levy D, Kenchaiah S, Larson MG, et al. Long-term trends in the incidence of and survival with heart failure. N Engl J Med. ;347: Pfeffer MA, Braunwald E, Moyé LA, Basta L, Brown E, Cuddy TE. 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;327: Jong P, Yusuf S, Rousseau MF, Ahn SA, Bangdiwala SI. Effect of enalapril on 12-year survival and life expectancy in patients with left ventricular systolic dysfunction: a follow-up study. Lancet. 2003; 361: Garg R, Yusuf S; Collaborative Group on ACE Inhibitor Trials. Overview of randomized trials of angiotensin-converting enzyme inhibitors on mortality and morbidity in patients with heart failure. JAMA. 1995;273: Bossuyt PM, Lijmer JG, Mol BW. Randomised comparisons of medical tests: sometimes invalid, not always efficient. Lancet. 2000;356: