Chapter  142:  Testing for BNP and NT-proBNP in the Diagnosis and Prognosis of Heart Failure

What Are the Determinants of Both BNP and NT-proBNP?

A total of 72 studies showed a relationship between B-type natriuretic peptides and a determinant. These determinants have the potential to affect accurate diagnosis, prognosis and the ability to monitor treatment effectively.

For demographic determinants, age was the most frequently reported determinant and in 13 of 15 studies was positively correlated with both BNP and NT-proBNP.^{3– 15} Few functional measures were evaluated. Of these weight,⁸ but not BMI,^{9, 10} showed a negative relationship with B-type natriuretic peptides and these two studies had no,⁹ or very few,¹⁰ patients who were obese.

In general, evidence available on 21 cardiac diseases was associated with an increase in the B-type natriuretic peptides. However, there were differences among diseases within the broad category of cardiac ischemia. The evidence available on 11 non-cardiac diseases and B-type natriuretic peptide levels was mixed; the non-cardiac causes of dyspnea,^{16– 18} diabetic nephropathy,¹⁵ and stroke⁸ were all associated with higher levels of B-type natriuretic peptides. There were 29 biochemical and hematological markers where an association with the B-type natriuretic peptides was made. Markers of myocardial damage, including Tn-I,^{3, 19, 20} Tn-T,^{8, 14, 16, 21– 26} myoglobin,²¹ and CK-MB,^{21, 27– 29} were mostly positively associated with B-type natriuretic peptide levels. There were 23 measures from 14 studies reported for heart function.^{4, 8– 12, 14, 15, 29– 34} Most of the hemodynamic, electrocardiographic and echocardiographic measures were compared to BNP and a few were compared to NT-proBNP. Both positive and negative associations were found. There were 14 studies, including nine different drug treatments, with data on the effect of drug therapy.^{31, 35– 47} All showed a decrease in, or no effect on, B-type natriuretic peptide levels.

What Are the Clinical Performance Characteristics of Both BNP and NT-proBNP Measurement in Patients with Symptoms Suggestive of HF or with Known HF?

There were a total of 27 studies eligible for evaluation of the clinical performance of BNP and NT-proBNP and not all of these reported performance characteristics or were suitable for meta-analysis. We meta-analyzed studies within specific settings and also across all study settings where sufficient data were available to calculate sensitivity, specificity, positive likelihood ratio (LR+) and negative likelihood ratio (LR-), diagnostic odds ratio (DOR) and summary ROC curves. Since there is no guideline for meta-analyzing studies that present results with single and multiple cut points the lowest cut point was chosen in studies with multiple cut points to maximize sensitivity. Summary estimates for studies within setting and across all settings were calculated.

Presenting to emergency department. Fourteen articles^{7, 16– 18, 48– 57} were selected for data abstraction. The 12 studies evaluating BNP utilized several cut point values ranging from 50 to 400 pg/mL and reported sensitivities from 60 to 100 percent, specificities from 27 to 99 percent, and areas under the curve (AUC) of 0.67 to 0.99. In addition, the LR+ ranged from 0.69 to 70 and the LR- from 0 to 0.44. DOR values ranged from 13 to 1635 and based on the meta-analysis of eight studies the summary estimate was 81 (95 percent CI: 29 to 219).

The three studies evaluating NT-proBNP utilized values ranging from 254 to 4567 pg/mL and reported sensitivities from 74 to 98 percent, specificities from 47 to 93 percent, and AUC values of 0.89 to 0.96. The LR+ ranged from 1.85 to 13.43 and the LR- from 0.03 to 0.29. DOR values ranged from 17 to 291 with a summary estimate of 60 (95 percent CI: 9 to 407).

Most studies of the studies scored high on the Quality Assessment of Diagnostic Accuracy Studies (QUADAS) items indicating lack of bias.

Specialized clinic or outpatient setting. There were a total of six studies eligible for review in specialized clinics,^{11, 58– 62} though diagnostic performance data could be abstracted in only three. All studies evaluated BNP except two^{58, 60} which compared both BNP and NT-proBNP. These two studies evaluated BNP using the same method, had similar cut points (135 and 142 pg/mL) and gave similar sensitivities (72 and 73 percent), specificities (73 and 77 percent), AUC (0.79 and 0.83), LR+ (2.7 and 3.17) and LR- (0.38 and 0.35), respectively.

Although different methods and cut points were used for NT-proBNP measurement, the diagnostic performance data were similar to each other and to the BNP data. The cut points were 695 and 4127 pg/mL, with corresponding sensitivities of 85 and 70 percent, specificities of 73 and 77 percent, AUC of 0.82 and 0.79, LR+ of 3.19 and 2.59 and LR- of 0.2 and 0.41.

Methodological quality was high on the QUADAS for these studies.

Primary care setting. There were a total of seven papers^{34, 63– 68} from this setting and data could be abstracted from only five. Two studies evaluated BNP with cut points ranging from 10 to 115 pg/mL and reported sensitivities from 66 to 92 percent, specificities from 18 to 88 percent, AUC from 0.70 to 0.88, LR+ from 1.12 to 5.7, and LR- from 0 to 0.27. Meta-analysis gave a summary DOR of 2 (95 percent CI: 1 to 6).

The three studies evaluating NT-proBNP with cut points from 67 to 338 pg/mL and reported sensitivities from 67 to 100 percent, specificities from 18 to 84 percent, AUC from 0.70 to 0.93, LR+ from 1.22 to 5.7, and LR- from 0 to 0.27. Meta-analysis gave a summary DOR 17 (95 percent CI: 9 to 32).

These studies generally rated well on the QUADAS.

Long term care setting. There were no studies with patients with symptoms suggestive of HF or with known HF presenting in long term care settings.

All settings. From the all settings combined, 15 studies had sufficient data for meta-analysis. The cut points across all settings ranged from 10 to 200 pg/mL (mean = 95 pg/mL) for BNP and 125 to 1691 pg/mL (mean = 642 pg/mL) for NT-proBNP. Sensitivities for BNP and NT-proBNP ranged from 50 to 99 percent and 83 to 99 percent, respectively. Specificities for BNP and NT-proBNP ranged from 19 to 97 percent and 46 to 89 percent, respectively.

We observed significant heterogeneity when the data were meta-analyzed and the sources were subsequently explored. The Moses-Littenberg regression model was not significant indicating that cut point was not a factor in explaining heterogeneity. The meta-analysis indicated the diagnostic parameters remain similar even when results from all settings are combined. The summary estimate of sensitivity was high for both BNP (94 percent; 95 percent CI: 32 to 97) and NT-proBNP (92 percent; 95 percent CI: 87 to 97), whereas the summary estimate for specificity was low for BNP (66 percent; 95 percent CI: 52 to 79) and NT-proBNP (65 percent; 95 percent CI: 51 to 78). The LR- summary estimates for BNP (0.10; 95 percent CI: 0.05 to 0.22) and NT-proBNP (0.14; 95 percent CI: 0.09 to 0.23) were much better than the summary estimates for LR+ for both BNP (2.92; 95 percent CI: 2.09 to 4.09) and NT-proBNP (2.67; 95 percent CI: 1.98 to 3.59).

The summary ROC curves for BNP and NT-proBNP both tended to curve strongly towards the upper left hand corner, signifying high accuracy. Furthermore, the AUC values were 0.86 for both BNP and NT-proBNP, suggesting that regardless of the clinical setting, the cut point chosen, or the test used, measurement of B-type natriuretic peptides is useful in the diagnosis of HF.

Further analysis of heterogeneity was possible to do in six studies from the ED setting that measured BNP by one method with a cut point of 100 (± 5) pg/mL. Even with this uniformity, specificity remained wide (28 to 94 percent). Given that the inclusion and exclusion criteria were not the same in these studies, and are themselves possible determinants of BNP, this heterogeneity is not unexpected.

Overall, there is not clear evidence to suggest the superiority of either BNP or NT-proBNP when all settings are considered.

Does Measurement of BNP or NT-proBNP Add Independent Diagnostic Information to the Traditional Diagnostic Measures of HF in Patients with Suggestive HF?

We first examined the subset of primary papers from Question 2a that performed multivariate logistic regression analysis to determine whether or not BNP or NT-proBNP measurement provided independent information in the diagnosis of HF. Odds ratios for the B-type natriuretic peptides ranged from 9 to 220 and were generally as high as or higher than, other diagnostic variables. This suggests that measurement of the B-type natriuretic peptide does provide information independent from the traditional diagnostic measures.

Secondly, we examined existing systematic reviews of the diagnosis of HF. These reviews considered many diagnostic tests for HF, both alone and in combination. The DOR ranged from 11 to 569 for BNP and 15 to 230 for NT-proBNP.

These data suggest measurement of the BNP or NT-proBNP are as good as, or better than traditional diagnostic measures for ruling out HF.

Do BNP or NT-proBNP Levels Predict Cardiac Events in Populations at Risk of CAD, with Diagnosed CAD and HF?

There were 108 studies eligible for evaluating the ability of BNP or NT-proBNP levels to predict cardiac events. Both B-type natriuretic peptides were found to be independent predictors of mortality and other cardiac composite endpoints in patients, but few evaluated NT-proBNP and even fewer evaluated both. Thus there is limited evidence to suggest that either of these B-type natriuretic peptides is a better prognostic marker of mortality or cardiac events than the other.

At risk of CAD. The prognostic value of BNP or NT-proBNP for mortality and cardiac events was examined in 12 studies^{4, 9, 9, 10, 15, 24, 69– 74} of individuals with risk factors for CAD. These studies differed in terms of the age and gender of their participants, methods of diagnosing risk factors for CAD, lengths of follow up, and outcomes. Multiple regression analyses consistently showed that the level of BNP or NT-proBNP was positively associated (adjusted measures of risk 1.10 to 5.40) with the outcome.

With diagnosed CAD. The 38 studies^{3, 8, 13, 14, 19– 22, 27– 29, 33, 75– 100} evaluating CAD patients varied with respect to the age and gender of participants, sample size, length of follow up, and outcomes. However, consistent positive associations were found between the level of BNP or NT-proBNP and the outcome of interest. For BNP the range of risk estimate is 2.00 to 3.00 and for NT-proBNP it is 1.50 to 3.00. For both these B-type natriuretic peptides, the small number of studies prevents any differential prediction in persons with or without prior cardiac related surgery.

With diagnosed HF. There were 58 studies eligible for evaluating BNP or NT-proBNP levels in predicting cardiac events in HF patients. The majority of the 38 studies^{12, 23, 25, 30, 32, 36, 41, 48, 101– 130} found baseline BNP levels to be independent predictors of mortality across various cut points and six studies evaluated both BNP and NT-proBNP tests. The adjusted hazard ratio (HR) showed a 2.5 to a 7.2 fold increase relative to those subjects with lower levels of BNP. Baseline BNP values were independent predictors of composite outcomes with HR estimates from 1.7 to 3.2. Studies comparing baseline and predischarge BNP levels suggest differences in the prediction of mortality. More research is required to establish the relative contribution of these two measurements of BNP. Primarily single studies evaluated the combined use of baseline BNP levels with other markers of cardiac dysfunction (e.g., troponin I and T, or percent VO2 max) as predictors of mortality and composite outcomes. Although the findings may suggest that the combined markers increase the ability to predict future outcomes, more research is needed to establish their relative benefit.

The majority of the 18 NT-proBNP studies^{26, 35, 41, 103, 112, 125, 126, 128, 131– 140} found this marker to be a significant independent predictor of death or composite endpoints at various cut points. The adjusted risk estimates varied from 2.17 to 9.35 for mortality outcomes, and 2.11 to 5.96 for cardiac composite outcomes.

What Are the Screening Performance Characteristics of the BNP or NT-proBNP in General Asymptomatic Populations?

A screening test was defined as being used to detect preclinical cardiac dysfunction, systolic or diastolic, in the general population. There were eight studies^{5, 74, 122, 141– 145} in populations without established or overt disease; two studies had no sensitivity or specificity data.^{74, 122} BNP generally shows poor screening test characteristics for both the detection of moderate to severe LVSD and of diastolic dysfunction. It is even less accurate for the detection of milder degrees of systolic dysfunction. There was a single NT-proBNP study¹⁴⁵ and it showed the screening highest for those with LVEF > 40, and over 70 years of age.

Can BNP or NT-proBNP Measurement Be Used To Monitor Response to Therapy?

There were 18 studies meeting the eligibility criteria.^{31, 37– 47, 110, 146– 150} The studies included chronic HF patients with at least three B-type natriuretic peptide measurements over time. Only half these studies reported the change in BNP or NT-proBNP and related the change to other outcomes including cardiac function, exercise capacity, symptoms or clinical events.

A number of these studies demonstrated a relationship between the change in BNP or NT-proBNP and either mortality, morbidity or other clinical parameters. Although promising, the findings have not been uniform and the majority of studies were of poor methodological quality; overall this suggests limited evidence that BNP or NT-proBNP may be useful to monitor therapy in HF patients.

Determinants

Numerous factors have been found to be associated with the levels of B-type natriuretic peptides. However, the value of these associations for clinical use is not clear and future research should explore these associations, particularly as a function of HF severity.

Diagnostic Properties for HF

In all settings (ED, specialized clinics, and primary care) both BNP and NT-proBNP have high sensitivity and lower specificity. This would suggest that these measurements could serve as a test for ruling out cardiac dysfunction. Measurement of B-type natriuretic peptide levels adds independent information relative to traditional diagnostic measures for this condition. Large multicentre trials (especially in ED with complex clinical patients) that allow for multivariate analyses to evaluate variables that contribute to low specificity should be undertaken in the future.

Prognosis

BNP and NT-proBNP have been shown to be independent predictors of mortality and other cardiac composite endpoints for populations with risk of CAD, diagnosed CAD, and diagnosed HF. There were few studies which evaluated B-type natriuretic peptides in populations without known heart failure. All but a single study suggest these are not sufficiently accurate to be an effective screening test for unrecognized left ventricular dysfunction. Future research should explore the relative merits of B-type natriuretic peptides compared to and combined with other markers of cardiac dysfunction to predict future outcomes.

Monitoring Treatment

There is insufficient evidence to demonstrate that BNP and NT-proBNP levels show change in response to therapies to manage stable chronic HF patient. Future research could include large randomized trials to show whether therapy guided by changes in B-type natriuretic peptides affect outcome.

Refinement of the Topic and the Research Questions

The first step during the topic assessment and refinement process was to organize a teleconference with partner organizations. The Task Order Officer (TOO) invited topic experts and the McMaster multidisciplinary research team to define the magnitude of the topic to be addressed and to refine/clarify the preliminary research questions for this evidence report. An international Technical Expert Panel (TEP) was assembled to provide high-level content expertise on this topic (Appendix E) and to participate in conference calls on an as-needed basis throughout the data refinement and extraction phase.

Search Strategy

Two search strategies were undertaken, one for the main report (Appendix A) and a second one for the review of reviews (Appendix A) for Question 2b. The bibliographic databases searched included MEDLINE^®, EMBASE, CINAHL, Cochrane Central and AMED (Allied and Complementary Medicine) from 1989 to February 2005. Hand searching was not undertaken for this systematic review.

For Question 2b, which compared other diagnostic tests relative to BNP and NT-proBNP, a review of reviews was undertaken in MEDLINE^® and EMBASE from January 2000 to September 2005. The start date of 2000 was chosen in order to identify only the most recent reviews.

Eligibility Criteria

A list of eligibility criteria was developed in Systematic Review Software (SRS) for the purposes of this systematic review. Details of the eligibility criteria can be found in Appendix B.

Assay method

Table 1

Details of BNP test characteristics

Table 1

Details of BNP test characteristics

Table row #	Company Name	Test / Instrument Name	Date Available
1	Shionogi & Co. Ltd, Osaka, Japan	Shionoira-IRMA	1993
2	Biosite, Inc., San Diego, CA, United States	Triage® B-Type Natriuretic Peptide (BNP)	Nov. 2002
3	Bayer Diagnostics Corporation, Tarrytown, NY, United States	ADVIA Centaur® B-Type Natriuretic Peptide (BNP)	June 2003
4	Beckman Coulter Inc, Fullerton CA, United States	Access	Oct 2003
5	Abbott Laboratories. Abbott Park, IL, United States	Abbott AxSYM ® B-Type Natriuretic Peptide (BNP)	Feb 2004

Table 2

Details of NT-proBNP test characteristics

Table 2

Details of NT-proBNP test characteristics

Table row #	Company Name / Reference	Test / Instrument Name	Date Available
6	Christchurch, New Zealand referenced to: Hunt PJ, Richards AM, Nicholls MG, Yandle TG, Doughty RN, Espiner EA. Immunoreactive aminoterminal probrain natriuretic peptide (NT-proBNP): A new marker for cardiac impairment. Clin Endocrinol 1997; 47:287–296	NT-proBNP	1997
7	Roche Diagnostics GmbH, Tutzing, Germany, referenced to: Karl J, Borgya A, Gallusser A, Huber E, Krueger K, Rollinger W, Schenk J. Development of a novel, N-terminal-proBNP (NT-proBNP) assay with a low detection limit. Scand J Clin Lab Invest Suppl. 1999; 230:177–81	NT-proBNP	1999
8	Biomedica, Vienna, Austria	NT-proBNP ELISA	2001a
9	Roche Diagnostics Corporation, Indianapolis, IN, United States	Elecsys® NT-proBNP Immunoassay	Nov. 2002
10	Dade Behring, Inc., Newark, DE, United States	Dimension® NT-proBNP (PBNP)	July 2004

a

For research purposes only.

Measurement of BNP or NT-proBNP. This systematic review included only those studies that measured BNP by methods that were available commercially for diagnostic use in a clinical setting up to February 2005 (Table 1). However, for NT-proBNP methods, three methods were included that were not commercially available for use in clinical settings for the purposes of diagnosis (see Table 2). One of these methods was the early generation assay to the Roche NT-proBNP method (ELISA method). The other two methods (Biomedica and Christchurch) were included because of their frequent use and because comparison studies have been done with the Roche NT-proBNP method.^{147, 164} The purpose of these restrictions was to ensure that results from this systematic review were not unduly affected by the test method used. The goal was to reduce the variability and thus uncertainty in the analysis of our results and for them to be directly applicable for clinical use (since these will be the methods clinical laboratories will use). One limitation with this approach is the possible exclusion of studies with important information not available in any of the included studies. Also, the strength of some findings may be weakened due to a smaller number of studies reporting similar findings but using different test methods. Tables 1 and 2 provide the details of the assays used in this review to measure BNP or NT-proBNP.

Number of measurements of BNP or NT-proBNP. For Question 4, BNP or NT-proBNP was to be measured at a minimum of 3 time points. This restriction was not applied to any other question in this review.

Data Collection and Reliability of Study Selection

A team of trained research assistants evaluated the title, abstract and full text screening. Standardized forms and a guide explaining the criteria were developed. Two reviewers were required to achieve consensus on the identification, selection, validity and abstraction of articles and information. Disagreements that were not resolved by consensus were settled by one or more members of the local expert team.

Quality Assessment of Included Studies

To assess the quality of primary studies we utilized standardized rating scales with acceptable reliability and validity. The specific scale to be used was dependent on the study design and the research question. The Quality Assessment of Diagnostic Accuracy Studies (QUADAS)¹⁶⁵ was selected to evaluate studies chosen for the research question addressing diagnostic accuracy of the BNP or NT-proBNP test. The QUADAS was developed specifically to take into account biases unique to the design of diagnostic studies. Quality items were considered individually rather than as a composite score as recommended by the developers of this tool.¹⁶⁶ The Jadad scale was used for studies that were RCTs.¹⁶⁷ For non-randomized study designs the only two criteria selected for evaluation were consecutive sampling and blinding to the outcome.¹⁶⁸ For quality assessment of systematic reviews, the Screening and Test Evaluation Program (STEP) checklist was used.¹⁶⁹ Appendix B shows the instruments used to evaluate quality.

Summarizing Our Findings: Descriptive and Analytic Approaches

Both descriptive and quantitative approaches were used to summarize study characteristics and outcomes. Multiple publications on the same study cohort were grouped together and treated as a single study for statistical analysis. Standardized summary tables explicating important study population and BNP or NT-proBNP test characteristics, as well as study results, were created. Results for BNP and NT-proBNP measurements were reported using the units pg/mL. Conversions were made to pg/mL, using the factor 1 pmol/L = 3.46 pg/mL for BNP and 1 pmol/L = 8.457 pg/mL for NT-proBNP.

Meta-analysis was only carried out for Question 2a. Meta-analysis for the remaining questions was not considered for several reasons including lack of data, too few studies and significant clinical heterogeneity. Quality scores were not used for weighting data in any of the analyses; rather, the inverse of the variance was used to weight studies.

For each primary study included in Question 2a, we calculated the following measures of test results accuracy: sensitivities, specificities, likelihood ratios (positive LR⁺ and negative LR^-) and diagnostic odds ratios (DOR). For those papers where the actual numbers of true and false positive and negative results (TP, FP, TN, FN) were presented, or where enough information was given to allow us to calculate and estimate these numbers, we recalculated the sensitivities, specificities and calculated the LR+, LR- and DOR with the accompanying 95 percent confidence intervals (CI).

These measures were calculated across different cut points and by study setting (emergency, outpatient, primary care and long term care settings) for BNP and NT-proBNP separately. Overall estimates of the diagnostic accuracy of the test were obtained by pooling the sensitivities, specificities and LRs obtained from each primary study. These different analyses were assessed for publication bias (graphical as well as statistical). We used sensitivity analysis to examine the influence of one study at a time and Galbraith plots for assessing heterogeneity across studies.

Our initial analyses considered the level of heterogeneity across the individual studies that were included in the meta-analysis. The Cochrane's Q test was used as a measure of heterogeneity in all the meta-analyses and the I² as a measure of inconsistency. We observed some heterogeneity in many of our meta-analyses and as a result, analyses using the random effects models were selected. Subgroup analysis and stratification were carried out to further explore the causes. As a part of these, meta-regression methods were employed to study the effects of a few covariates on the respective diagnostic test measures. Due to the number of studies available, we were only able to carry out univariate meta-regressions in most cases. We also assessed the correlation between sensitivities and specificities. However, no significant correlations were observed. All statistical analyses were carried out using Stata/SE 8.0 for Windows (Stata Corporation) and Meta Package.

Pooled estimates were also calculated for DORs and summary receiver operator characteristic (SROC) curves were created in our analyses to assess the effect of different cut points. A DOR is a simple measure used when combining sensitivities and specificities from different studies. It is easy to calculate and less sensitive to diagnostic thresholds.¹⁷⁰ The DOR makes use of the sensitivity and specificity pair by comparing the odds of one to the other. It compares the odds of positive test results in the trial participants with the outcome of interest, to the odds for positive test results for those without the outcome of interest (Equation 1).

Equation 1: DOR

DOR= sensitivity/( 1 -sensitivity)/( 1 -specificity)/(specificity)

The standard error of the log DOR is approximately given by:

Where TP is true positive, FP is false positive, TN is true negative and FN is false negative. Appropriate adjustments are made in cases of zero counts.

An alternative formulation of the DOR is given in Equation 2:

Equation 2: Alternative calculation for DOR.

DOR= sensitivity/( 1 -specificity)/( 1 -sensitivity)/(specificity) =LR ⁺ /LR ^-

Where the LRs are the positive and negative likelihood ratios.

Using this definition, a DOR is a measure of the spread between the two LRs. The SROC curve mimics the receiver operator characteristic (ROC) curve and is a way to measure the diagnostic accuracy across different studies. It is based on logit transformation of the data, which plots D, the difference between the logit of the true-positive rates (TPR, sensitivity) and the logit of the false-positive rates (FPR, 1 - specificity) on the y axis against their sum S on the x axis i.e., D = logit TPR — logit FPR against S = logit TPR + logit FPR. The y axis (D) is equivalent to the log (DOR), and the x axis (S) is a way to measure how the test characteristics vary with respect to the thresholds of the diagnostic tests. A regression equation (D = α + β * S) derived from the SROC curve analysis can be used to assess the heterogeneity among study results.171. It is possible to get spurious SROC plots based on regression analysis when individual studies have homogeneity in their results since regression analysis with small variations in both the independent and dependent variables can result in misleading results.

Population Criteria for Each Question

Question 2a: criteria for population inclusion. A study was also eligible if it considered one of the following symptoms or signs as a marker for HF: anginal pain, anginal syndrome, ankle swelling, bilateral leg edema, breathlessness, cardiac dysfunction, cardiac insufficiency, cardiomegaly on chest x-ray, diastolic distensibility, diastolic dysfunction, diastolic dysfunction on cardiac catheterization, diastolic stiffness, dyspnea, ejection fraction (EF), elevated jugular venous pressure, fatigue, fluid retention, hepatomegaly, left ventricular (LV) relaxation, filling, LV systolic function (or dysfunction), nocturnal cough, orthopnea, palpitation, paroxysmal nocturnal dyspnea, peripheral edema, pleural effusion, pulmonary congestion, pulmonary rales, tachycardia (heart rate ≥ 120 beats/min), third heart sound, ventricular dysfunction, weight loss.

Question 2a: criteria for population exclusion. For emergency of primary care settings only, studies were excluded if the population had subjects with known HF, and samples that only included subjects with any of the following: heart transplantation, obesity clinic patients, hypertrophic cardiomyopathy, mitral valve regurgitation patients. Inpatient hospital or community settings were excluded.

Question 2b: criteria for population inclusion. Primary studies with traditional diagnostic tests of HF included the following: chest x-ray, echocardiography, myocardial radionuclide angiogram (MRNA), dobutamine echo, cardiac catheter, magnetic resonance imaging (MRI), computerized tomography (CT), and pulmonary/vascular measures.

Question 3a: criteria for population inclusion. All patients with: i) at risk of CAD; ii) with diagnosed CAD; iii) with diagnosed HF. The citation was required to use at least one of the following terms to indicate HF: i) HF; ii) congestive HF; iii) New York Heart Association (NYHA) criteria, NYHA functional class, American College of Cardiology (ACC), American Heart Association (AHA), Canadian Cardiovascular Society (CCS), Modified Framingham Clinical Criteria for diagnosis of Heart Failure, and European Study Group on Diastolic Heart Failure; iv) cardiac dysfunction.

Question 3a: criteria for population exclusion. Studies were excluded if the population had any of the following health conditions: heart transplant, stenosis, renal disease, pulmonary embolism, cardiomyopathy, tumour, amyloid, leukemia, atrial fibrillation after pacemaker implant, respiratory disease, pulmonary hypertension, ischemic stroke, sepsis, perimyocarditis, intensive care unit patients.

Question 3b: criteria for population inclusion. General populations with no known cardiac dysfunction.

Question 4: criteria for population inclusion. Studies evaluating treatments for HF had to have identified the subjects using one of the following criteria: ACC / AHA, NYHA, CCS, Modified Framingham Clinical Criteria for the Diagnosis of Heart Failure, European Study Group on Diastolic Heart Failure.

Question 4: criteria for population exclusion. Studies were excluded if the patients' HF was not stable.

Intervention for Each Question

Selection of interventions was not relevant for research Questions 1, 2 and 3.

Question 4: criteria for intervention inclusion. Treatments for HF could include any of the following:

• Medications: angiotensin converting enzyme (ACE) inhibitors; angiotensin receptor blocker therapy; beta blockers; cardiac glycosides; diuretics; nitrates; spironolactone

• Surgeries, Procedures and Medical Devices: balloon valvuloplasty catheter; enhanced counterpulsation; heart valve replacement surgery; automatic implantable cardiac defibrillator; cardiac resynchronization therapy; intra-aortic balloon pump insertion; prosthetic heart valve; ventricular assist device; valvuloplasty (balloon or surgical).

• Healthy Lifestyles: Exercise; maintain a healthy weight; eat a healthy diet; control blood pressure; control blood cholesterol; prevent and manage diabetes mellitus; quit smoking; manage stress.

Outcome Criteria for Each Question

Question 2a and 2b outcomes criteria for outcomes inclusion. Any measure of the degree or presence of HF was accepted, including: clinical diagnosis, left ventricular ejection fraction (LVEF), change in NYHA class, left ventricular end-diastolic pressure, left ventricular end-diastolic dimension, left ventricular end-systolic dimension, end-diastolic thicknesses of the inter-ventricular septum.

Question 3a and 3b outcomes criteria for outcomes inclusion. Admission to hospital for any of the following outcomes: angina requiring a minimum 24 hour hospitalization (acute coronary syndrome), angiographic percutaneous coronary interventions (including terms angioplasty, bypass surgery, coronary artery bypass graft, cardiac revascularization, percutaneous transluminal coronary angioplasty, stent), atrial fibrillation (arrhythmias), cerebrovascular event (e.g., stroke), composite endpoint, congestive heart failure (CHF), isolated diastolic ventricular dysfunction, mortality (all cause), myocardial infarction (MI).

Question 4 outcomes. criteria for outcomes inclusion. No a priori outcomes were identified for inclusion.

Criteria for outcomes exclusion. Non-cardiac events

Study Characteristics

Table 3

The effect and association of various biological determinants (more...)

Table 3

The effect and association of various biological determinants on BNP and NT-proBNP levels.*

Determinant	Increase		None		Decrease
	BNP	NT-proBNP	BNP	NT-proBNP	BNP	NT-proBNP
Demographic Characteristics
African-American			1
Age	8	4	2
Female	2	3	2	4
Smoker, current				2
Cardiac Disease
Acute coronary syndrome		1
Acute right heart failure (no CPE group)			1
Angina, stable		1		1
Aortic stenosis		3
Arrhythmia		1
Atrial fibrillation			1
Cardiac decompensation		1
Cardiogenic pulmonary edema (CPE)	1
Diastolic dysfunction	3	1			2a	1a
Dilated cardiomyopathy			1
Hypertension, with diastolic dysfunction	2
Ischemic heart disease		1	1
LAD culprit lesion	1
LAD lesion, proximal vs mid	1
Left ventricular mass	1
Multi-vessel disease		1
Myocardial infarction	1	2
Myocardial infarction, history		2
Previous CHF		1
Revascularization		1
Valvular disease		1
Non-cardiac Disease
Diabetes		1		3
Diabetic nephropathy		1
Diabetic retinopathy				1
Dyspnea, non-cardiac	2	1
Hyperlipidemia				1		1
Hypertension	2	3		1
Hypertension, duration			1
Lung disease					1b	1c
Peripheral vascular disease				1
Stroke		1
Stroke and TIA				1
Biochemical and Hematological Markers
ACE genotype DD		1
Adrenomedullin				1
Aldosterone			1
ANP	3	1
Big endothelin-1	2
cGMP	1	1
Cholesterol			1	1
Creatinine kinase			1
Creatinine kinase-MB	2	1	1
C-reactive protein		3
Creatinine	2	3	2
Endothelin-1		1
Epinephrine	1
Glucose, random	1
Glucose, fasting				1
HbA1c			1	1
Hemoglobin						1
Interleukin-6		1
Lymphocytes			1		1
Myoglobin		1
Norepinephrine	5	1
NT-proANP	5	2
Osteoprotegerin		1
Plasma renin activity					1
Relaxin				1
ST2, soluble receptor			1
Total protein			1
Troponin-I	3			1
Troponin-T	2	9
Functional and Physiologic Measures
Activities of daily living score	1
BMI			2
Creatinine clearance			1
Exercise						1d
Glomerular filtration rate					2
Weight						1
Hemodynamic, echocardiographic and electrocardiographic measures
Blood pressure			3
Blood pressure, systolic		2	2
Cardiac index			1
E/A ratio			2
Fibrosis			1
Fractional shortening			2
Heart rate	2	1	2
Left ventricular diastolic dimension	1
Left ventricular end-systolic diameter	1
Left ventricular mass index	6
Left ventricular relative wall thickness			1
MIBG activity					1
Mid-wall left ventricular fractional shortening			1
PCWP	1
Perfusion defect size	1
Pulmonary arterial pressure	1
Pulse pressure	1
Restrictive filling pattern of deceleration time					1
Right atrial pressure	1
ST-segment depression		2
Telesystolic volume			1
Drug treatment
Amiodarone					2
Atenolol					1
Beta-blockers			1		1
Carvedilol			2	1		2
Enalapril					3
Furosemide, dosage			1
Lisinopril, dosage					1
Metoprolol			1
Perindopril				1
Valsartan					4
Treatment-Nondrug
Left ventricular assist device					1

123

Abbreviations: ACE=angiotensin converting enzyme; ANP=atrial natriuretic peptide; BMI=body mass index; E/A=early to late(atrial) echocardiographic phases of ventricular filling; cGMP=cyclic guanosine mononucleotide phosphate; CHF=congestive heart failure; CPE=cardiogenic pulmonary edema; HbA1c=hemoglobin A1c; LAD=left anterior descending coronary artery; MIBG=I-etaiodobenzylguanidine; PCWP=pulmocapillary wedge pressure; TIA=transient ischemic attack

*

Study details for the determinants in alphabetical order including sample size, method, type, statistical method and values can be found in Evidence Tables 1 in Appendix C.

**

The numbers given for each determinant refer to the number of associations abstracted from the studies according to effect and type of B-type natriuretic peptide.

a

= Compared to systolic dysfunction;

b

= Compared to CHF;

c

= CHF and CHF + lung disease;

d

= Increased physical activity

Demographic Characteristics

Age was the most frequently reported determinant and in 13 of 15 studies was positively correlated with both BNP and NT-proBNP.^{3– 15} There were two studies that did not show a relationship with age,^{31, 34} but these studies had the smallest number of patients (n = 21 and 36, respectively) as compared to the other studies (range = 85 to 6809). One study reported no difference between African Americans and Caucasians.⁴⁹ The association of B-type natriuretic peptides with gender was examined in 11 studies, with an almost equal number reporting either a higher level (n=5), or no difference in males (n = 6). There were no obvious similarities among studies with respect to observed association and patient population. However, larger studies were more likely than smaller studies to report a higher B-type natriuretic peptide level in females compared to males. Two studies looked at current smoking and reported no association.^{8, 85}

Cardiac Disease

In general, all cardiac diseases (n = 21) were associated with an increase in the B-type natriuretic peptides. These included diastolic dysfunction,^{5, 11, 16, 33, 34, 65} cardiac decompensation,²⁶ acute right HF,⁵⁷ and cardiac pulmonary edema (CPE).⁵⁷ Acute right HF without cardiac pulmonary decompensation was not related to BNP concentration. Cardiac decompensation, however, was related to an increase in NT-proBNP. Patients with CPE had higher levels of BNP than patients with obstructive lung disease. Patients with diastolic dysfunction had elevated B-type natriuretic peptide levels but not as elevated as patients with systolic dysfunction.^{11, 16, 172}

There were differences among diseases within the broad category of cardiac ischemia. Patients with acute coronary syndrome (ACS) had elevated NT-proBNP levels,⁸⁵ but there was no difference between patients with and without ischemic heart disease unless the patients had cardiovascular risk factors.^{4, 116} Acute myocardial infarction (MI)^{4, 8, 29} or historical MI^{14, 85} were associated with increased levels of B-type natriuretic peptides. Stable angina was not associated with a difference in B-type natriuretic peptides in one study⁴ that included hypertensive patients, but was positively associated in patients with Non ST-elevation myocardial infarction (NSTEMI) ACS.⁵⁷ Patients with left anterior descending (LAD) coronary artery lesions had elevated BNP and those with proximal lesions had higher levels than those with mid-lesions.⁹⁵ Multi-vessel disease was associated with higher NT-proBNP levels.⁸⁵ Also NT-proBNP levels were positively associated with patients who had previous revascularization.⁸ There was no difference between patients with dilated cardiomyopathy and old MI.¹²⁴ Arrhythmia⁶⁵ was associated with elevated levels of B-type natriuretic peptides; however, there was no difference between atrial fibrillation and sinus rhythm¹¹⁵ valvular disease⁶⁵ and all severities of aortic stenosis⁶ were positively associated with B-type natriuretic peptides levels.

Non-cardiac Diseases

The effect of non-cardiac diseases (n = 11) on B-type natriuretic peptide levels was mixed. Non-cardiac causes of dyspnea,^{16– 18} diabetic nephropathy,¹⁵ and stroke⁸ were all associated with higher levels of B-type natriuretic peptides. Lung disease compared to HF,⁵⁶ or HF plus lung disease,⁶⁵ had lower BNP and NT-proBNP levels respectively. Diabetic retinopathy¹⁵ and cerebrovascular disease (including stroke and transient ischemic attack)^{4, 8} did not show association with B-type natriuretic peptide levels. For diabetes, one study showed a positive association with NT-proBNP⁸ but in three studies^{4, 14, 85} there was no association. Four of five studies that evaluated hypertension^{8, 10, 34, 89} showed a positive association with B-type natriuretic peptides. The one study⁸⁵ that did not show a difference used a statistical test for the difference in medians whereas the other studies used mean difference tests or regression analysis. Duration of hypertension was also not associated with BNP levels.¹⁰ There was no difference in NT-proBNP levels between patients with peripheral vascular disease as compared to patients without risk factors for cardiovascular disease (CVD).⁴ Two studies reported hyperlipidemia as a determinant. One of these studies showed an inverse relationship with NT-proBNP levels⁸⁵ using the Wilcoxon rank sum test, whereas the other study showed no relationship⁸ using multiple linear regression analysis.

Biochemical and Hematological Markers

There were 29 biochemical and hematological markers where an association with the B-type natriuretic peptides was made. Markers of myocardial damage, including Tn-I,^{3, 19, 20} Tn-T,^{8, 14, 16, 21– 26} myoglobin,²¹ and CK-MB,^{21, 27– 29} were mostly positively associated with B-type natriuretic peptide levels. One study did not show a statistically significant correlation with CK-MB.²⁷ This study included only ST-segment elevation myocardial infarction (STEMI) patients, whereas the other studies excluded STEMI patients, or included MI patients admitted to the coronary care unit. No significant association was found in one study with Tn-I.²⁰ This study included only NSTEMI and unstable angina patients in contrast to the other studies that included STEMI and ACS patients. Total creatine kinase showed no significant association with BNP but this may be because no patients in this study had elevated levels of this marker.²⁶ Furthermore, the cardiac hormones ANP,^{12, 13, 25, 84} NT-proANP,^{13, 20, 41, 74, 84, 144, 144} and second messenger cGMP,^{12, 84} were positively associated with B-type natriuretic peptide levels. However, relaxin, also a cardiac hormone, showed no association with NT-proBNP.¹³⁶ Several markers of inflammation including C-reactive protein,^{8, 14, 21} interleukin-6,²² the ST2 receptor protein⁹⁰ and osteoprotegerin⁹⁸ were positively associated with B-type natriuretic peptide levels. The association with lymphocytes was patient group specific.¹⁰⁵ There was no statistically significant association between BNP and lymphocytes observed in the patient group with hypertensive heart disease, mitral stenosis, atrial fibrillation and hypertrophic cardiomyopathy, but a negative association was observed in a group composed of patients with ischemic heart disease, dilated cardiomyopathy aortic stenosis, aortic regurgitation and mitral regurgitation. There was a mixed association with markers of the renin-angiotensin-aldosterone system (RAAS). Plasma renin activity¹⁰⁶ was inversely associated with BNP, whereas andromedullin⁸⁴ and aldosterone¹⁰⁶ showed no significant relationship with NT-proBNP and BNP, respectively. The ACE genotype DD,⁸¹ endothelin-1,¹⁰⁶ big endothelin-1,^{41, 106} epinephrine⁸⁴ and norepinephrine^{12, 25, 39, 41, 84, 106} were all positively associated with the B-type natriuretic peptides. Creatinine, an indirect marker of renal function, increased in five of eight studies with increasing levels of B-type natriuretic peptides.^{8, 9, 13, 29, 34, 36, 76, 100} The reason why two studies^{29, 34} did not show a correlation with creatinine is unknown; however, these two studies had the smallest sample size (n = 64 and 36, respectively) compared to the other studies (n = 84 to 6809). There was also no significant relationship observed between total protein⁹ and BNP. Fasting glucose¹⁵ and HbA1c^{9, 15} tests for diabetes showed no significant relationship with B-type natriuretic peptides, but random glucose¹³⁵ was positively associated with BNP. Cholesterol,^{9, 15} a marker of HF, showed no significant relationship with BNP or NT-proBNP. However, hemoglobin,¹⁵ a marker of anemia, was negatively associated with NT-proBNP.

Functional and Physiologic Measure

Two measures of renal function, glomerular filtration rate¹⁵ and creatinine clearance,¹²² showed an inverse relationship with B-type natriuretic peptides. Weight,⁸ but not BMI,^{9, 10} showed a negative relationship with B-type natriuretic peptides. Exercise testing also showed that a decrease in physical endurance was related to higher B-type natriuretic peptide levels.¹¹⁶ Two studies which evaluated BMI as a determinant had no,⁹ or very few,¹⁰ patients who were obese.

Hemodynamic, Electrocardiographic and Echocardiographic Measures

There were 23 measures from 14 studies reported for heart function.^{4, 8– 12, 14, 15, 29– 34} Most of the hemodynamic, electrocardiographic and echocardiographic measures were compared to BNP and a few were compared to NT-proBNP. Nine were positively associated with the B-type natriuretic peptides whereas eight showed no association. I-123 — metaiodobenzylquanidine (MIBG) activity,³⁰ was negatively associated with B-type natriuretic peptides. Deceleration time of early mitral inflow was also negatively associated with BNP (the lower the deceleration time, the higher the plasma BNP).³² Heart rate and systolic blood pressure were the only two measurements that showed discrepant effects on B-type natriuretic levels. Heart rate was associated with both an increase^{8, 12, 31} and no change^{9, 34} in B-type natriuretic peptides. Of the two studies that did not show an association, one included only hypertensive patients³⁴ and in the other, the association was in elderly subjects (> 80 years).⁹ Systolic blood pressure was either positively^{4, 15} associated with NT-proBNP, or showed no association with BNP.^{10, 31} In one of these studies³¹ the association changed to positive after the patients were treated with a beta blocker.

Drug Treatment

There were 14 studies, including nine different drug treatments, with data on the effect of drug treatment.^{31, 35– 47} The effect of these drugs was a decrease or no effect on B-type natriuretic peptide levels. Studies involving therapy with amiodarone,³⁷ atenolol,⁴¹ enalapril^{40, 42} and valsartan^{39, 43, 45, 46} all showed a decrease in B-type natriuretic peptides. Studies that assessed B-type natriuretic peptide levels after therapy with perindopril⁴⁷ or metoprolol⁴⁴ showed no difference compared to baseline. There was no dose dependent change in B-type natriuretic peptide levels with lisinopril³⁶ or furosemide.³⁶ The effect of carvedilol therapy on B-type natriuretic peptide levels, compared to baseline or a placebo group, showed either a decrease,^{31, 36, 47} or no change.^{35, 44} There were two studies^{38, 44} that treated patients with beta blockers but did not differentiate between the two drugs (carvedilol or metoprolol). One study reported a decrease in NT-proBNP concentration³⁸ whereas the other study reported no change in BNP concentration⁴⁴ after treatment.

Non-drug Treatment

There was only one study in this group of papers that reported a non-drug therapy. In this study the concentration of BNP decreased after implantation of a left ventricular device.¹⁵⁰

Question 2ai: Emergency Department

Sample and Design Characteristics of Studies

Table 4

Diagnostic properties of studies that evaluated BNP (more...)

Table 4

Diagnostic properties of studies that evaluated BNP and NT-proBNP in patients with symptoms suggestive of HF in emergency or urgent care settings

Report	Study Design	Study Population	n Age** % Male	Prevalence %	Reference test	Reference standard	Index test	Index cut point (pg/mL)	Sens %	Spec %	LR+	LR-	AU ROC
Barcarse48 2004	Prospective Cohort	Convenience sample VA with SOB	98	58	1 Cardiologist review	clinical	BNP(2)	110	96*	91*	10.67	0.04	0.979
			65 y					170	82	94	13.67	0.19	0.979
			100%					300	70	99	70.00	0.30	0.979
Bayes-Genis16 2004	Prospective Cohort	SOB NYHA III or IV	89	83	2 Cardiologists review	clinical	NT-ProBNP (9)	>254	98.6	46.7	1.85	0.03	0.957
			71 y					>423	95.7	73.3	3.58	0.06	0.957
			54%					>592	94.3	73.3	3.53	0.08	0.957
								>761	91.4	73.3	3.42	0.12	0.957
								>973	91.4	93.3	13.64	0.09	0.957
								>1099	90	93.3	13.43	0.11	0.957
Dao56 2001	Cross-sectional	SOB	250	39	2 Cardiologists review	clinical	BNP(2)	80	98	92	12.25	0.02	0.98
			63 y					100	94	94	15.67	0.06	0.98
			94%					115	90	96	22.50	0.10	0.98
								120	90	96	22.50	0.10	0.98
								150	87	97	29	0.13	0.98
Jose53 2003	Cross-sectional	SOB of > 6 m	119	61	NR	Framingham Echo	NT-ProBNP (8)	1691	97	89	8.82	0.03	0.94
			54 y
			66%
Knudsen50 2004	Diagnostic	SOB Male	69	58	2 Cardiologists review	clinical	BNP(2)	≥50	95	37.9	1.53	0.13	0.9
			74 y					≥100	90	55.2	2.01	0.18	0.9
			100%					≥150	92.5	62.1	2.44	0.12	0.9
								≥200	90	72.4	3.26	0.14	0.9
		SOB Female	86	41	2 Cardiologists review	clinical	BNP(2)	≥50	100	37.3	1.59	0.00	0.86
			78 y					≥100	94.3	54.9	2.09	0.10	0.86
			0%					≥150	91.4	58.8	2.22	0.15	0.86
								≥200	88.6	62.7	2.38	0.18	0.86
		SOB Age ≥ 76 y	NR	NR	2 Cardiologists review	clinical	BNP(2)	NR	NR	NR	NR	NR	0.82
			NR
			NR
		SOB Age < 76 y	NR	NR	2 Cardiologists review	clinical	BNP(2)	NR	NR	NR	NR	NR	0.88
			NR
			NR
Knudsen51 2004	Cross-sectional	SOB	880	51	2 Cardiologists review	clinical	BNP(2)	≥100	90	75	3.66	0.14	NR
			64 y					≥200	80	87	6.08	0.23	NR
			55%					≥300	71	90	7.18	0.32	NR
								≥400	64	92	8.1	0.39	NR
Lainchbury7 2003	Diagnostic	SOB	205	34	2 Cardiologists review	clinical	NT-ProBNP (9)	1184	87	71	3	0.18	0.89
			70 y					2030	83	82	4.61	0.21	0.89
			49%					2906	80	87	6.15	0.23	0.89
								3721	74	90	7.40	0.29	0.89
								4567	92	68	2.88	0.12	0.89
							BNP(2)	69	97	44	1.73	0.07	0.89
								104	97	49	1.90	0.06	0.89
								208	94	70	3.13	0.09	0.89
								277	83	78	3.77	0.22	0.89
								346	77	84	4.81	0.27	0.89
Logeart17 2002	Cross-sectional	SOB	163	71	2 Cardiologists and 1 Pneumologist review	clinical	BNP(2)	80	97	27	1.33	0.11	0.93
			67 y					100	96	31	1.39	0.13	0.93
			67%					150	93	45	1.69	0.16	0.93
								200	93	56	2.11	0.13	0.93
								250	91	68	2.84	0.13	0.93
								300	88	87	6.77	0.14	0.93
								400	79	93	11.29	0.23	0.93
Maisel18 2002	Cross-sectional	SOB	1586	47	2 Cardiologists review	clinical	BNP(2)	≥50	97	62	2.55	0.05	0.91
			64 y					≥80	93	74	3.58	0.09	0.91
			56%					≥100	90	76	3.75	0.13	0.91
								≥125	87	79	4.14	0.16	0.91
								≥150	85	83	5.00	0.18	0.91
Maisel49 2004	Prospective Cohort	SOB	1586	47	2 Cardiologists review	clinical	BNP(2)	≥100	90.4	72.9	3.34	0.13	NR
			64 y					≥200	81.4	85.1	NR	NR	NR
			56%					≥300	72.5	88.6	NR	NR	NR
								≥400	62.7	91.1	NR	NR	NR
		SOB 18–69 y	NR	NR	2 Cardiologists review	clinical	BNP(2)	≥100	86	82	0.69	0.17	0.915
			NR					≥200	77	91	8.45	0.25	0.915
			NR					≥300	69	94	11.10	0.33	0.915
								≥400	60	95	11.23	0.43	0.915
		SOB 70–105 y	NR	NR	2 Cardiologists review	clinical	BNP(2)	≥100	94	53	2.00	0.12	0.844
			NR					≥200	85	72	3.03	0.21	0.844
			NR					≥300	75	77	3.27	0.32	0.844
								≥400	65	83	3.85	0.42	0.844
		SOB Male	883	48	2 Cardiologists review	clinical	BNP(2)	≥100	92	76	3.84	0.10	0.918
			NR					≥200	83	88	6.93	0.18	0.918
			100%					≥300	73	90	7.49	0.30	0.918
								≥400	64	93	9.00	0.39	0.918
		SOB Female	703	46	2 Cardiologists review	clinical	BNP(2)	≥100	88	59	2.16	0.20	0.87
			NR					≥200	78	82	4.27	0.27	0.87
			0%					≥300	72	87	5.40	0.32	0.87
								≥400	61	89	5.55	0.44	0.87
		SOB White race	773	50	2 Cardiologists review	clinical	BNP(2)	≥100	93	69	2.96	0.10	0.888
			NR					≥200	82	82	4.63	0.21	0.888
			NR					≥300	72	86	5.11	0.33	0.888
								≥400	60	90	5.86	0.44	0.888
		SOB Black race	715	44	2 Cardiologists review	clinical	BNP(2)	≥100	87	76	3.61	0.17	0.903
			NR					≥200	81	88	6.45	0.22	0.903
			NR					≥300	74	91	8.24	0.28	0.903
								≥400	66	93	8.79	0.37	0.903
McCullough54 2002	Diagnostic	SOB	1538	47	2 Cardiologists review	clinical	BNP(2)	≥100	90	73	3.33	0.14	0.9
			64 y
			56%
Morrison55 2002	Cross-sectional	SOB	321	42	2 Cardiologists review	clinical	BNP(2)	94	98	86	7.0	.023	0.99
			NR					105	94	86	6.71	.069	0.99
			NR					135	90	90	9.00	0.11	0.99
								195	85	94	14.16	.159	0.99
								240	79	96	19.75	.218	0.99
Ray57 2004	Cross-sectional	SOB > 65 y Respiration measures cutoffs	308	45.7	2 of: Cardiologist Pulmonologist GM Internist Geriatrician ED Physician	clinical	BNP(2)	≥100	90	59	2.20	0.17	0.67
			80 y					≥150	85	71	2.93	0.21	0.67
			49%					≥200	82	84	5.13	0.21	0.67
								≥250	78	90	7.80	0.24	0.67
								≥300	72	92	9.00	0.30	0.67
								≥350	67	92	8.38	0.36	0.67
								≥400	60	95	12.00	0.42	0.67
Villacorta52 2002	Cross-sectional	SOB	70	51	1 Cardiologist review	clinical	BNP(2)	200	100	97	33.33	0.00	0.99
			72 y
			47%

Abbreviations: ACS=acute coronary syndrome, AU ROC=area under the receiver operator characteristics curve, ED=emergency department, LR- =negative likelihood ratio, LR+ =positive likelihood ratio, NR=not reported, Sens% =sensitivity(%), SOB=shortness of breath, Spec% =specificity, uLL=unadjusted log likelihood, VA=Veterans Administration., y=years.

•

estimated from ROC curve

Number in bracket refers to row number in Table 1 or Table 2 2 describing method used to measure B-type natriuretic peptide

**

Mean age if given in report

Fourteen articles met all of the inclusion criteria and were selected for data abstraction.^{7, 16– 18, 48– 57} Of the 14 selected studies, four were from the Breathing Not Properly Multinational Study.¹⁸ The data from the sub-studies^{49, 51, 54} were excluded from the meta- analyses. This study and seven others examined only BNP.^{17, 48, 50, 52, 55– 57} Two other studies examined only NT-proBNP, ^{16, 53} and one study examined variations of both BNP and NT-proBNP.⁷ The included studies were published over a period of four years (2001 - 2004) with the majority published in 2002 and 2004 (Table 4). The patients enrolled in all studies presented to emergency departments with shortness of breath and were over 18 years of age. One study⁵⁷ limited enrolment to patients over 65 years of age while another¹⁶ limited enrolment to patients between 44 and 88 years of age.

Diagnosis of HF in studies. All studies except two^{52, 53} selected for data abstraction employed a cohort design and a reference standard agreed upon by consensus of at least two physicians (mostly cardiologists). Two studies based the diagnosis on the opinion of a single cardiologist^{48, 52} and the third only stated that the definitive diagnosis was based on the Framingham criteria and echocardiography results.⁵³ The adjudicating physicians each arrived at a diagnosis of HF based on their interpretation of all available clinical data, often including echocardiography results. The Boston Criteria were employed in the diagnosis in one study⁵² and the Framingham criteria in three studies,^{18, 53, 55} one of which also applied the National Health and Nutrition Examination Survey (NHANES).¹⁸

Diagnostic properties. Table 4 presents the results to answer the question “What are the clinical performance characteristics of both BNP and NT-proBNP measurement in patients with symptoms suggestive of HF or with known HF presenting to an emergency department?”

Table 7

Diagnostic odds ratios for studies that evaluated BNP (more...)

Table 7

Diagnostic odds ratios for studies that evaluated BNP and NT-proBNP in patients with symptoms suggestive of or with HF across all settings

Report	Setting	Test	Cut point(pg/mL)	Sensitivity			Specificity			Diagnostic Odds Ratio
					Lower 95% CI	Upper 95% CI		Lower 95% CI	Upper 95% CI		Lower 95% CI	Upper 95% CI	n
Seino58 2004	Clinic	BNP(1)	135	0.723	0.613	0.800	0.731	0.614	0.822	7	5.58	14	172
		NT-proBNP(9)	695	0.857	0.777	0.911	0.731	0.614	0.822	16	8	35	172
Barcarse48 2004	ED	BNP(2)	110	0.958	0.830	0.980	0.940	0.830	0.970	360	58	2257	98
			170	0.842	0.726	0.914	0.928	0.809	0.975	69	18	274	98
			300	0.701	0.573	0.809	0.976	0.876	0.995	96	12	759	98
Dao56 2001	ED	BNP(2)	80	0.979	0.927	0.994	0.921	0.869	0.954	558	122	2250	250
			100	0.912	0.839	0.954	0.941	0.892	0.968	167	63	441	250
			115	0.896	0.820	0.943	0.960	0.917	0.981	213	75	607	250
			120	0.869	0.820	0.943	0.960	0.917	0.981	213	75	607	250
			150	0.875	0.794	0.927	0.970	0.930	0.987	231	76	705	250
Logeart17 2002	ED	BNP(2)	80	0.969	0.920	0.988	0.270	0.165	0.410	12	3	41	163
			100	0.960	0.908	0.983	0.282	0.173	0.425	10	3	30	163
			150	0.930	0.868	0.964	0.458	0.325	0.597	11	5	28	163
			200	0.930	0.868	0.964	0.562	0.422	0.693	17	7	43	163
			250	0.913	0.847	0.952	0.687	0.546	0.800	23	9	56	163
			300	0.878	0.806	0.926	0.875	0.753	951.000	50	18	140	163
Maisel18 2002	ED	BNP(2)	50	0.970	0.955	0.980	0.620	0.586	0.652	54	34	84	1586
			80	0.930	0.909	0.946	0.739	0.709	0.768	38	27	52	1586
			100	0.901	0.876	0.920	0.760	0.730	0.787	27	22	38	1586
			125	0.869	0.843	0.891	0.890	0.761	0.816	25	19	33	1586
			150	0.849	0.822	0.873	0.830	0.803	0.854	28	21	36	1586
Morrison55 2002	ED	BNP(2)	94	0.977	0.936	0.992	0.855	0.798	0.898	258	77	872	321
			105	0.940	0.866	0.969	0.855	0.798	0.898	93	41	213	321
			135	0.903	0.841	0.942	0.898	0.846	0.934	82	39	173	321
			195	0.850	0.780	0.901	0.941	0.897	0.966	91	42	197	321
			540	0.791	0.714	0.851	0.962	0.924	0.981	97	41	231	321
Ray57 2004	ED	BNP(2)	100	0.900	0.84	0.939	0.592	0.517	0.664	13	7	25	308
			150	0.851	0.783	0.900	0.712	0.639	0.775	14	8	25	308
			200	0.822	0.751	0.876	0.838	0.775	0.886	24	13	44	308
			250	0.780	0.704	0.840	0.898	0.843	0.935	31	16	59	308
			300	0.732	0.644	0.790	0.922	0.871	0.953	31	15	61	308
			350	0.673	0.592	0.745	0.922	0.871	0.953	24	13	48	308
Villacorta52 2002	ED	BNP(2)	200	0.99	0.88	1.00	0.96	0.83	0.99	1635	64	4135	70
Lainchbury7 2003	ED	BNP(2)	69	0.971	0.901	0.992	0.437	0.356	0.521	26	6	112	205
			104	0.971	0.901	0.992	0.511	0.427	0.594	36	8	151	205
			208	0.942	0.862	0.977	0.703	0.621	0.774	39	13	115	205
			277	0.828	0.723	0.899	0.777	0.7	0.839	17	8	36	205
			346	0.771	0.660	0.854	0.837	0.765	0.889	17	8	36	205
		NT-proBNP(9)	1184	0.871	0.773	0.93	0.711	0.629	0.78	17	76	37	205
			2030	0.828	0.723	0.899	0.822	0.749	0.877	22	10	48	205
			2875	0.800	0.691	0.877	0.866	0.799	0.914	26	12	56	205
			3721	0.742	0.629	0.830	0.903	0.842	0.942	27	12	59	205
Bayes-Genis16 2004	ED	NT-proBNP(9)	254	0.986	0.925	0.997	0.467	0.248	0.698	62	7	572	87
			423	0.958	0.884	0.985	0.6	0.357	0.801	35	7	163	87
			592	0.944	0.865	0.978	0.8	0.855	0.929	68	13	343	87
			972	0.902	0.812	0.952	0.933	0.701	0.988	130	15	1142	87
			1099	0.917	0.83	0.916	0.933	0.702	0.988	154	17	1382	87
Jose 53 2003	ED	NT-proBNP(8)	1691	0.972	0.905	0.992	0.891	0.769	0.952	291	54	1569	119
Landray66 2000	Primary Care	BNP(1)	10	0.925	0.801	0.974	0.186	0.118	0.281	3	1	10	126
			17.9	0.875	0.738	0.945	0.348	0.256	0.454	4	1	11	126
			76	0.675	0.52	0.799	0.872	0.785	0.927	14	6	36	126
Hobbs63 2004	Primary Care	BNP(1)	115	0.5	0.237	0.763	0.667	0.579	0.744	2	1	7	133
		NT-proBNP(9)	338	0.952	0.667	0.995	0.463	0.378	0.551	17	1	302	133
Gustafsson68 2003	Primary Care	NT-proBNP(9)	125	0.969	0.846	0.994	0.458	0.405	0.511	27	4	201	367
Wright64 2003	Primary Care	NT-proBNP(6)	211	0.831	0.732	0.898	0.771	0.713	0.821	17	9	33	305

Abbreviations: HF=heart failure, ED=emergency department, CI=confidence interval

Number in bracket refers to row number in Table 1 or Table 2 describing method used to measure B-type natriuretic peptide.

Figure 3. Forest plots for BNP in all settings using (more...)

   Figure 3. Forest plots for BNP in all settings using the lowest cut point provided in each study: a) sensitivity, b) specificity, c) LR+, d) LR-, e) DOR

Figure 4. Forest plots for NT-proBNP in all settings (more...)

   Figure 4. Forest plots for NT-proBNP in all settings using the lowest cut point provided in each study: a) sensitivity, b) specificity, c) LR+, d) LR-, e) DOR

The 12 studies evaluating BNP utilized several cut point values ranging from 50 to 400 pg/mL and reported sensitivities from 60 percent to 100 percent, specificities from 27 to 99 percent, and areas under the curve (AUC) of 0.67 to 0.99.^{7, 17, 18, 48– 52, 54– 57} In addition, the reported positive likelihood ratio (LR+) ranged from 0.69 to 70 and the negative likelihood ratio (LR-) ranged from 0.00 to 0.44 (Table 4). The three studies evaluating NT-proBNP utilized several values ranging from 254 to 4567 pg/mL and reported sensitivities from 74 percent to 98.6 percent, specificities from 47 to 93 percent, and AUC values of 0.89 to 0.96. It was possible to do meta-analysis on eight studies for BNP^{7, 17, 18, 48, 52, 55– 57} and three studies for NT-proBNP.^{7, 16, 53} To maximize sensitivity the lowest cut point was used if multiple cut point data were given. The data are summarized in Table 7 and Figures 3 and 4. The sensitivities of the BNP studies were similar with a summary sensitivity of 97 percent and a CI of 96 to 98 percent. In contrast, the specificity data was very heterogeneous with a summary estimate of 70 percent and a CI ranging from 56 to 85 percent (see Appendix C, Table 13–15 for results of tests for heterogeneity with regards to setting). The corresponding likelihood ratios (LRs) showed that the LR- (0.06, 95 percent CI: 0.03 to 0.10) was better than the LR+ (3.63, 95 percent CI: 2.49 to 5.31) in terms of diagnostic value. The diagnostic odds ratio (DOR) for BNP ranged from 13 to 1635 with a summary estimate of 81 (95 percent CI: 29 to 219). With the exception of the pooled sensitivity estimates (Figure 3a) for BNP in the ED, all other combined estimates (for specificity, LR+, LR-, and DOR) had positive tests for heterogeneity; as such our confidence in these pooled estimates is decreased.

For NT-proBNP the summary estimates were similar to BNP in that the sensitivity (95 percent, 95 percent CI: 90 to 101) was much higher than the specificity (72 percent, 95 percent CI: 53 to 90). The LR- (0.07, 95 percent CI: 0.02 to 0.27) was also better than the LR+ (3.35, 95 percent CI: 1.75 to 6.41). The DOR from these three studies assessing NT-proBNP ranged from 17 to 291 with a summary estimate of 60 (94 percent CI: 9 to 407). All pooled estimates of NT-proBNP diagnostic accuracy measures were significant for heterogeneity for ED studies.

Figure 5. Forest plots for BNP in the ED using a cut (more...)

   Figure 5. Forest plots for BNP in the ED using a cut point of 100 (±5) pg/mL: a) sensitivity, b) specificity, c) LR+, d) LR-, e) DOR

There were six studies that provided diagnostic information at a BNP cut point of 100 (±5) pg/mL.^{7, 17, 18, 55– 57} The meta-analysis on these studies shows a similar pattern to that described for varying cut points (Figure 5); with the exception of LR-, all other diagnostic pooled estimates were positive for heterogeneity. The sensitivity summary estimation is 95 percent (95 percent CI: 91 to 96) with a lower and broader specificity summary estimation (67 percent, 95 percent CI: 53 to 80). The LR+ was 3.4 (95 percent CI: 2.14 to 5.42) and the LR- was 0.11 (95 percent CI: 0.08 to 0.15), which is higher than the lowest cut point summary estimate. The overall DOR for this group of studies was reduced to 38 but the 95 percent CI was tighter (17 to 85) compared to the lowest cut point summary estimate.

Quality assessment of studies. Results from the application of the QUADAS Question 14, quality assessment tool are as follows (see also Appendix C Evidence Figures, Figure 1): one (9.1 percent) of the studies clearly addressed the issue of disease progression bias (QUADAS Question 4); the reference standard was independent of the index test result (QUADAS Question 7) in 10 (90.9 percent) of the studies; the reference standard was described in sufficient detail (QUADAS Question 9) in seven (63.6 percent) of the studies; interpretation of the peptide marker (BNP or NT-proBNP) measurement was clearly without knowledge of the reference test results (QUADAS Question 10) in one (9.1 percent) of the studies; interpretation of the reference test results was clearly without knowledge of the B-type natriuretic peptide marker results (QUADAS Question 11) in seven (63.6 percent) of the studies; none (100 percent) of the studies stated whether or not the clinical data was available when the B-type natriuretic peptide test results were interpreted as would be the case when the test is used in practice (QUADAS Question 12); one (9.1 percent) of the studies reported uninterpretable or intermediate test results (QUADAS Question 13) and; withdrawals were not explained in two (18.2 percent) of the studies (QUADAS Question 14). Overall, the quality of these studies was good.

Question 2aii: Specialized Clinic or Outpatient Setting

Sample and Design Characteristics of Studies

There were a total of six papers eligible for review published between 1997 and 2004.^{11, 58– 62} All studies evaluated BNP with the exception of two^{58, 60} which compared both BNP and NT-proBNP. The studies were conducted in Austria, Japan, Portugal and USA. Two studies were based on patients referred to a HF clinic^{11, 59} and the remaining, to outpatient settings.^{58, 60– 62} All studies provided evaluation on BNP and two compared BNP and NT-proBNP.^{58, 60} Three of these papers provided data on sensitivity, specificity, and ROC curves for BNP or NT-proBNP ^{11, 58, 60}. Three of these papers did not provide ROC characteristics or sensitivity or specificity data; instead, only correlation data for BNP or NT-proBNP with different variables of cardiac structure, function and symptoms were provided.

Diagnosis of HF in studies. Three studies^{58, 60, 62} used echocardiography as the reference standard, one study used echocardiography plus clinical criteria¹¹ and two studies^{59, 61} used the NYHA classification.

Table 5

Diagnostic properties of studies that evaluated BNP (more...)

Table 5

Diagnostic properties of studies that evaluated BNP and NT-proBNP in patients with symptoms suggestive of or with HF in outpatient or specialty clinic settings

Report	Study design	Study population	n Age** % Male	Prevalence %	Reference test	Reference standard	Index Test	Index cut point (pg/mL)	Sens %	Spec %	LR+	LR-	AU ROC
Bettencourt 11 2000	Cross-sectional	Suspected HF	100	100	Clinical by 2 Internists and 1 Cardiologist	HF	BNP(1)	NR	NR	NR	NR	NR	0.92
			69 y			Systolic HF	BNP(1)	NR	NR	NR	NR	NR	0.78
			54%			Diastolic HF	BNP(1)	NR	NR	NR	NR	NR	0.89
Hammerer60 2001	Cross-sectional	Stable chronic HF	57	100	LVEF	impaired (< 48% by 3D echo and <55% by RNV)	BNP(1)	142	NR	NR	NR	NR	0.75
			45–80 y				NT-proBNP(8)	4127	NR	NR	NR	NR	0.67
			NR			resting LVEF <40%	BNP(1)	142	0.73	0.77	3.17	0.35	0.83
							NT-proBNP(8)	4127	0.7	0.73	2.59	0.41	0.79
Lee59 2002	Prospective cohort	HF	41	100	Change in NYHA Class	none (correlation)	BNP(1)	NR	NR	NR	NR	NR	NR
			23–85 y
			70%
Maeda61 1998	Cross-sectional	LVD (LVEF <50%)	72	100	LVEDP	NR	BNP(1)	NR	NR	NR	NR	NR	NR
			61 y
			74%
Seino58 2003	Cross-sectional	Chronic HF and Controls	105	100	LVEF	< 40%	BNP(1)	NR	NR	NR	NR	NR	0.77
			64 y			< 50%	BNP(1)	135	72.3	73.2	2.7	0.38	0.794
			80%			< 40%	NT-proBNP(9)	NR	NR	NR	NR	NR	0.754
						< 50%	NT-proBNP(9)	695	85.4	73.2	3.19	0.2	0.82
Yamada62 1997	Cross-sectional	various cardiovascular diseases	122	NR	LVEDD	> 56mm	BNP(1)	NR	NR	NR	NR	NR	NR
			71 y		LVESD	≥ 40mm	BNP(1)	NR	NR	NR	NR	NR	NR
			66%		LVEF	< 50%	BNP(1)	NR	NR	NR	NR	NR	NR
					IVS	< 11mm	BNP(1)	NR	NR	NR	NR	NR	NR

Abbreviations: AU ROC=area under the receiver operating characteristics curve, HF=heart failure, IVS=Interventricular septum,LR+=positive likelihood ratio, LR-=negative likelihood ratio, LVD=left ventricular dysfunction, LVEDD= left ventricular ejection diastolic dysfunction, LVEDP=left ventricular end-diastolic pressure, LVEF=left ventricular ejection fraction, LVESD= left ventricular ejection systolic dysfunction, NR=not reported, NYHA=New York Heart Association, SE=standard error, sens=sensitivity, spec=specificity, RNV=radionuclide ventriculography. y= years.

Number in bracket refers to row number in Table 1 or Table 2 describing method used to measure B-type natriuretic peptide.

**

Mean age if given in report

Diagnostic properties. Hammerer-Lercher et al.⁶⁰ directly compared the diagnostic values of NT-proBNP with BNP in 57 patients with stable chronic HF. In the analysis of normal (echocardiographic ejection fraction (EF) ≤ to 48 percent or radionuclide angiographic EF ≤ to 55 percent) versus impaired (echocardiographic EF < 48 percent or radionuclide angiographic EF < 55 percent) LVEF the AUC for BNP was 0.75 (SE ± 0.06), and for NT-proBNP was 0.67 (SE ± 0.07) (Table 5). In the analysis of LVEF less than 40 percent versus greater than or equal to 40 percent, the AUC for BNP was 0.83 (SE ± 0.06), and for NT-proBNP was 0.79 (SE ± 0.07). Positive and negative LRs were 3.17 and 0.35, respectively for BNP and 2.59 and 0.41, respectively for NT-proBNP. NT-proBNP did not differ significantly from BNP in either of the analyses. The optimal discriminator values were 142 pg/mL for BNP, and 4127 pg/mL for NT-proBNP for the detection of LVEF less than 40 percent compared to greater than or equal to 40 percent. For these discriminators the sensitivity was 73 percent for BNP, and 70 percent for NT-proBNP. The specificities were 77 percent for BNP, and 73 percent for NT-proBNP.

Bettencourt et al.¹¹ studied 100 patients with symptoms suggestive of HF referred to a HF clinic. These patients had suspected or not previously investigated HF. Since healthy controls were included in this study, this suggested the potential for spectrum bias, although it was not clear if the control data was used in the estimates of diagnostic accuracy. For a cut point value of 39.7 pg/mL, the positive predictive value was 95.5 percent. For the diagnosis of HF regardless of LVEF, the AUC was 0.92 (95 percent CI: 0.86 to 0.99; p < 0.0001). The accuracy of BNP for the detection of systolic dysfunction was slightly less with an AUC of 0.78 (95 percent CI: 0.69 to 0.88; p < 0.0001). The BNP performance for detection of diastolic dysfunction expressed by the AUC was 0.89 (95 percent CI: 0.78 to1.00; p < 0.0001) for the patients without systolic dysfunction. Multiple regression analysis demonstrated that age, left ventricular mass index, and LVEF were independently associated with BNP.

Seino et al.⁵⁸ compared BNP and NT-proBNP relative to LVEF less than 40 percent and less than 50 percent in patients with HF. Their data indicate that detection of LVEF less than 50 percent was slightly greater for NT-proBNP than BNP (AUC 0.820 and 0.794, respectively). The reverse was true for LVEF less than 40 percent, with BNP having slightly greater AUC (0.770) compared to NT-proBNP (0.754). The optimum cut point values were determined to be 135 pg/mL for BNP and 695 pg/mL for NT-proBNP. There were four papers 11,59,61,62 that examined the relationship between BNP only and other HF variables but did not provide any data about the sensitivity, specificity or accuracy of these measurements. In general, it was demonstrated that BNP was related to cardiac function measured either as LVEF⁶² or left ventricular end diastolic pressure.⁶¹ One study⁵⁹ examined 41 HF patients and found BNP was related to the NYHA class.

There was only one study⁵⁸ that contained sufficient information to conduct meta-analysis by clinic setting alone. Therefore, no overall estimates for the individual clinic setting are possible. However, this one study was used to conduct meta-analysis for all sites combined (Figure 3 and 4). The results of this analysis are described elsewhere.

Quality assessment of studies. Results from the application of the QUADAS Question 14 quality assessment tool are as follows (see also Appendix C Evidence Figures - Figure 2): three (50.0 percent) of the studies clearly addressed the issue of spectrum bias(QUADAS Question 1); the selection criteria were only described in four (66.7 percent) of the studies (QUADAS Question 2) and in remaining two (33.3 percent) of the studies it was difficult to assess the selection criteria; four (66.7 percent) of the studies described if the reference standard was likely to correctly classify the HF (QUADAS Question 3); three (50 percent) of the studies clearly described the issue of disease progression (QUADAS Question 4); the reference standard was described in sufficient detail (QUADAS Question 9) in five (83.3 percent) of the studies; interpretation of the peptide marker (BNP or NT-proBNP) measurement was clearly made without knowledge of the reference test results (QUADAS Question 10) in five (83.3 percent) of the studies; interpretation of the reference test results was clearly made without knowledge of the B-type natriuretic peptide marker results (QUADAS Question 11) in all of the studies; five (83.3 percent) of the studies stated whether or not the clinical data was available when the B-type natriuretic peptide test results were interpreted as would be the case when the test is used in practice (QUADAS Question 12); one (16.7 percent) of the studies reported uninterpretable or intermediate test results (QUADAS Question 13); and withdrawals were explained in five (83.3 percent) of the studies (QUADAS Question 14). Overall, the quality of these studies was good.

Question 2aiii: Primary Care

Sample and Design Characteristics of Studies

There were seven papers eligible for review that selected patients from a primary care setting. Five of these studies were cross-sectional in design^{34, 65– 68} and one was a RCT⁶⁴. There was one study that selected patients randomly and identified a high risk cohort group.⁶³

Two of the studies restricted their recruitment by age; one to 40 years of age and above,⁶⁴ and one to more than 45 years of age.⁶³ One study presented data stratified by gender.⁶⁵ The RCT⁶⁴ examined the effect of BNP measurement on diagnostic accuracy in primary care. All patients had BNP measured, but the groups were randomized as to whether or not the primary care physician received the results. Nevertheless, this paper is useful because the BNP concentrations can be compared against the reference standard of HF (expert diagnosis) in both arms of the study.

Two studies^{34, 67} either did not provide estimates of the diagnostic performance of the BNP test, or presented the data in a manner such that these diagnostic characteristics could not be calculated.

Diagnosis of HF in studies. Four studies used evaluation of left ventricular systolic function by echocardiogram as the reference standard for HF.^{63, 65, 67, 68} Three used LVEF of less than or equal to 40 percent,^{63, 67, 68} one used LVEF less than or equal to 45 percent,⁶⁵ and one³⁴ did not state the reference cut point. Another study used x-ray or echocardiogram with evidence of pulmonary edema or cardiomegaly as the reference cut point.⁶⁶ The European Society of Cardiology criteria were used as the reference standard for the RCT study.⁶⁴

Table 6

Diagnostic properties of studies that evaluated BNP (more...)

Table 6

Diagnostic properties of studies that evaluated BNP and NT-proBNP in patients with symptoms suggestive of HF in primary care settings

Report	Study Design	Study Population	n Age**% Male	Prevalence %	Reference test	Reference standard	Index test	Index cut point(pg/mL)	Sens %	Spec %	LR+	LR-	AU ROC
Alehagen67 2002	Cross-sectional	65–82 years Symptoms of HF	415	48	Clinical and Echo	LVEF ≤ 40%	BNP(1)	NR	NR	NR	NR	NR	NR
			72 y 52%
Bettencourt34 1999	Cross-sectional	Community HT and normal controls	47	33	Doppler Echo	LV diastolic dysfunction	BNP(1)	NR	NR	NR	NR	NR	0.874
			65 y 47%
Gustafsson68 2003	Cross-sectional	Dyspnea referred for echo	367	10	Doppler Echo	LVEF ≤ 40 %	NT- proBNP(9)	125	97	46	1.79	0.06	0.93
			69 y 46%
Hobbs63 2004	Diagnostic	General population	307	1	LVSD by Doppler Echo	LVEF < 40%	BNP(1)	>115	80	88	6.71	0.23	0.88
			>45 y NR
		HF diagnosis	103	20					71	52	1.5	0.54	0.7
			>45 y NR
		On diuretics	87	8					86	65	2.44	0.022	0.8
			>45 y
			NR
		High risk of HF	133	8					50	67	1.51	0.75	0.7
			>45 y
			NR
		General population	307	1			NT-proBNP(9)	>338	80	73	2.95	0.27	0.76
			>45 y
			NR
		HF diagnosis	103	20					100	18	1.22	0	0.7
			>45 y
			NR
		On diuretics	87	8					86	40	1.43	0.036	0.81
			>45 y
			NR
		High risk of HF	133	8					100	46	1.86	0	0.73
			>45 y
			NR
Landray66 2000	Cross-sectional	Suspected HF	126	32	X-Ray or Echo VSD	LVEF NR	BNP(1)	>10	92	18	1.12	0.097	NR
			74 y					>17.9	88	34	1.32	0.35	NR
			0.54					>76	66	87	5.07	0.39	NR
Nielsen65 2004	Cross-sectional	Dyspnea Male	176	27	HF	ESC HF definition LSVD by Echo	NT-proBNP(9)	93	96	67	2.9	0.06	0.93
			> 50 y
			100%
		Dyspnea Female	169	20				143	94	69	3	0.09	0.9
			> 50 y
			0%
		Dyspnea Male	176	27				76	100	60	2.5	0.00	0.93
			> 50 y
			100%
		Dyspnea Female	169	20				67	100	27	1.37	0	0.9
			> 50 y
			0%
		Dyspnea Male	176	27				152	89	79	4.2	0.14	0.93
			> 50 y
			100%
		Dyspnea Female	169	20				219	91	84	5.7	0.11	0.9
			> 50 y
			0%
Wright64 2003	RCT	Dyspnea and/or edema	305	25	HF	ESC definition of HF	NT-proBNP(6)	211	90	63	2.43	0.16	0.85
			72 y
			35%

Abbreviations: AU ROC=area under the receiver operator characteristics curve, Clin=clinical, Dx= diagnosis, ESC=European Society of Cardiology working group, HF=heart failure, HT=hypertension, LVEF=left ventricular ejection fraction, LVSD=left ventricular systolic dysfunction, LR+=positive likelihood ratio, LR-=negative likelihood ratio, LV=left ventricular, NR=not reported, RCT=randomized controlled trial, Sens%=sensitivity (%), Spec%=specificity(%), y=years.

•

Estimated from the ROC curve

Number in bracket refers to row number in Table 1 or Table 2 describing method used to measure B-type natriuretic peptide.

**

Mean age, if given in report

Diagnostic properties. Table 6 presents the results to answer the question, “What are the clinical performance characteristics of both BNP and NT-proBNP measurement in patients with symptoms suggestive of HF or with known HF presenting to a primary care physician?” Three papers evaluated only BNP,^{34, 66, 67} three evaluated only NT-proBNP,^{64, 65, 68} and one evaluated both.⁶³ Two of seven failed to indicate the cut point for BNP or NT-proBNP used. Two studies presented data for more than one cut point.^{65, 66} The range in cut points were 10 to 115 pg/mL for BNP and 67 to 338 pg/mL for NT-proBNP. Where possible, sensitivities, specificities, and LRs, either reported or calculated, are presented. Area under the ROC curve is presented when reported. Sensitivity ranged from 66 to 92 percent for BNP and 80 to 100 percent for NT-proBNP. Specificity ranged from 18 to 88 percent for BNP and 18 to 84 percent for NT-proBNP. For BNP, LR+ ranged from 1.12 to 6.71 and LR- ranged from 0.022 to 0.75. For NT-proBNP the LR+ ranged from 1.22 to 5.7 and the LR- ranged from 0 to 0.27.

Meta-analysis was done on two studies^{63, 66} for BNP and three studies for NT-proBNP.^{63– 65} To maximize sensitivity the lowest cut point was used if data for multiple cut points were given. The data for the meta-analysis are summarized in Table 7 and the results presented in Figures 3 and 4. Since there were few studies available, the accompanying pooled summary statistics must be interpreted with caution. However, looking at the three studies for NT-proBNP the DOR summary estimate was 17 (95 percent CI: 9 to 32) whereas it was only 2 (95 percent CI: 1 to 6) for BNP. Furthermore, in the Hobbs study⁶³where both BNP and NT-proBNP were measured, the DOR was about eight times higher (2 and 17 for BNP and NT-proBNP, respectively). Tests for heterogeneity were not significant for either of the B-type natriuretic peptides for the pooled LR- or DOR.

Quality assessment of studies. Results from the application of the QUADAS Question 14 quality assessment tool are as follows (see also Appendix C Evidence Figures - Figure 3): six (85.7 percent) of the studies clearly addressed the issue of spectrum bias(QUADAS Question 1); the selection criteria were only described in six (85.7 percent) of the studies (QUADAS Question 2); all of the studies described if the reference standard was likely to classify the HF properly (QUADAS Question 3); five (71.4 percent) of the studies clearly described the issue of disease progression (QUADAS Question 4); the reference standard was described in sufficient detail (QUADAS Question 9) in six (85.7 percent) of the studies; interpretation of the peptide marker (BNP or NT-proBNP) measurement was clearly without knowledge of the reference test results (QUADAS Question 10) in all of the studies; interpretation of the reference test results was clearly without knowledge of the B-type natriuretic peptide marker results (QUADAS Question 11) in all of the studies; six (85.7 percent) of the studies stated whether or not the clinical data was available when the B-type natriuretic peptide test results were interpreted as would be the case when the test is used in practice (QUADAS Question 12); five (71.4 percent) studies reported uninterpretable or intermediate test results (QUADAS Question 13) and; withdrawals were explained in five (71.4 percent) studies (QUADAS Question 14). Overall, the quality of these studies was good.