Technology Assessment Report

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1 ICSI I NSTITUTE FOR CLINICAL S YSTEMS IMPROVEMENT Technology Assessment Report The information contained in this ICSI Technology Assessment Report is intended primarily for health professionals and the following expert audiences: physicians, nurses, and other health care professional and provider organizations; health plans, health systems, health care organizations, hospitals and integrated health care delivery systems; medical specialty and professional societies; researchers; federal, state and local government health care policy makers and specialists; and employee benefit managers. This ICSI Technology Assessment Report should not be construed as medical advice or medical opinion related to any specific facts or circumstances. If you are not one of the expert audiences listed above you are urged to consult a health care professional regarding your own situation and any specific medical questions you may have. In addition, you should seek assistance from a health care professional in interpreting this ICSI Technology Assessment Report and applying it in your individual case. This ICSI Technology Assessment Report is designed to assist clinicians by providing a scientific assessment, through review and analysis of medical literature, of the safety and efficacy of medical technologies and is not intended either to replace a clinician s judgment or to suggest that a particular technology is or should be a standard of medical care in any particular case. Standards of medical care are determined on the basis of all the facts and circumstances involved in a particular case and are subject to change as scientific knowledge and technology advance and practice patterns evolve. Copies of this ICSI Technology Assessment Report may be distributed by any organization to the organization s employees butmay not be distributed outside of the organization without the prior written consent of the Institute of Clinical Systems Improvement. All other copyright rights in this ICSI Technology Assessment Report are reserved by the Institute for Clinical Systems Improvement. The Institute for Clinical Systems Improvement assumes no liability for any adaptations or revisions or modifications made to this ICSI Technology Assessment Report.

2 Report Abstract: B-Type Natriuretic Peptide (BNP) for the Diagnosis and Management of Congestive Heart Failure Description of Test Prepared under the direction of the Technology Assessment Committee by Brent Metfessel, M.D., Staff TA #91 Approved: August 2005 Work Group Leader George Klee, M.D., Ph.D. Pathology Mayo Clinic Work Group Members Joel Holger, M.D. Emergency Medicine HealthPartners Medical Group Thomas E.Kottke, M.D. Cardiology Regions Hospital Farouk Mookadam, M.D. Consulting Cardiology Mayo Clinic This document is a scientific statement of safety and efficacy only. It is not intended to replace a clinician s judgement or to suggest that a particular technology is or should be a standard of medical care in any particular case. With a prevalence of 4.8 to 5 million cases, congestive heart failure (CHF) is a major health problem in the United States, with 550,000 new cases being diagnosed each year. Diagnosis of CHF may be difficult, even in emergency care settings, as the symptoms tend to be non-specific. Other more specific diagnostic and prognostic tools, such as echocardiography and cardiac catheterization, are either too invasive, too costly, or impractical to use for rapid assessment of symptomatic patients. Considering that early medical treatment of CHF may prolong life and reduce symptoms, a search for an inexpensive, readily available, easy to perform, and highly predictive test for CHF has occurred that ultimately has centered around the cardiac natriuretic peptides. The plasma levels of such peptides increase based on the amount of myocardial wall stretch and stress with greater increases in more severe CHF. Thus, natriuretic peptides may be an indicator of severity of CHF. The most commonly discussed natriuretic peptide in the literature is B-type natriuretic peptide (BNP) which is the subject of this assessment. Through the measurement of plasma levels, BNP is proposed to provide additional discriminatory information in terms of the detection, diagnosis, prognosis, and monitoring of CHF. Committee Conclusions With regard to B-type natriuretic peptide (BNP) for the screening, diagnosis and monitoring of congestive heart failure (CHF), the ICSI Technology Assessment Committee concludes: 1) The BNP test is safe, requiring only a routine venipuncture. 2) There are no data to support the use of BNP in the general screening of asymptomatic populations for CHF, and thus BNP testing should not be used for this purpose. 3) BNP measurements are useful as an adjunct to other clinical tools for differentiating cardiac (CHF) causes from other causes of dyspnea presenting in the emergency department or urgent care setting. In particular, the diagnosis of CHF is highly unlikely in patients with normal BNP levels. Care should be taken when measuring BNP within 2 to 4 hours after the onset of acute symptoms as false negatives may occur (Conclusion Grade II). 4) The utility of BNP as a tool to optimize management of heart failure or measure treatment response has yet to be defined. Serial testing of BNP levels has not been shown to have clinical utility. Please see full report for potential uses, contraindications, efficacy, safety, alternatives, and comparative costs. Copyright 2005 by Institute for Clinical Systems Improvement

3 Report: B-Type Natriuretic Peptide (BNP) for the Diagnosis and Management of Congestive Heart Failure Prepared under the direction of the Technology Assessment Committee by Brent Metfessel, M.D., Staff TA #91 Approved: August 2005 James Smith, M.D., Chair HealthPartners Medical Group Merrill Biel, M.D. ENT Specialty Care Bruce Burnett, M.D. Park Nicollet Health Services Craig Christianson, M.D. UCare Thomas Elliott, M.D. St. Mary s/duluth Clinic Health System Keith Folkert, M.D. BlueCross BlueShield MN John Frederick, M.D. PreferredOne Paul Karazija, M.D. Medica George Klee, M.D., Ph.D. Mayo Clinic Richard Kopher, M.D. HealthPartners Medical Group Thomas Kottke, M.D. HealthPartners Medical Group Kirsten Hall Long, Ph.D. Mayo Clinic Thomas Marr, M.D. HealthPartners Lorre Ochs, M.D. HealthPartners Medical Group Jamie Peters, M.D. Fairview Ridges Arthur Puff, M.D. Metropolitan Health Plan Howard Stang, M.D. HealthPartners Medical Group Paul Swan, M.D. HealthPartners Medical Group Rick Wehseler, M.D. Affiliated Community Medical Centers ICSI technology assessment reports are designed to assist clinicians by providing a scientific assessment, through review and analysis of medical literature, of the safety and efficacy of medical technologies and are not intended to replace a clinician s judgement or to suggest that a particular technology is or should be a standard of medical care in any particular case. Standards of medical care are determined on the basis of all the facts and circumstances involved in a particular case and are subject to changes as scientific knowledge and technology advance and practice patterns evolve. Work Group Leader: George Klee, M.D., Ph.D. Pathology Mayo Clinic Joel Holger, M.D. Emergency Medicine HealthPartners Medical Group Thomas E. Kottke, M.D. Cardiology Regions Hospital Farouk Mookadam, M.D. Consulting Cardiology Mayo Clinic ICSI Technology Assessment Report Process: A topic is selected by the Technology Assessment Committee (TAC) based on its relevance to the ICSI Health Care Guidelines and/or interest in the topic by ICSI member or sponsor organizations. A work group of 4 to 6 physicians and other health care professionals is identified. The work group includes a leader who does not perform the procedure/treatment/test that is the focus of the report, a critical reading expert, content expert(s), and, preferably, a primary care physician. Prospective work group members are asked to disclose any potential conflicts of interest relevant to the topic of the report; disclosures are reviewed for unacceptable conflicts. The literature search is completed using MEDLINE; in addition, bibliographies of articles obtained from the literature search are examined to identify articles that may have been missed and work group members are asked to provide key references. The ICSI staff person gets direction on the scope of the report from the work group and prepares a draft report based on the available literature. The evidence is graded according to the system described in the References section of the report. The work group meets to review the draft report and direct the ICSI staff person in revising the report. After approval of the draft report by the work group, the work group leader presents the report to the TAC. Committee members review the report and provide feedback to the work group. The draft report is concurrently distributed to ICSI member organizations and content experts nationwide for their review. All comments received are shared with the work group leader and revisions to the report are made, if necessary. With work group approval of the revisions, the TAC makes the final decision regarding approval of the report for distribution. Reports are approved or not approved based on whether a) the conclusions are supported by the evidence, and b) whether the reviewers' comments were reasonably addressed. Newly approved reports are posted at. Reports are reviewed and revised, if warranted. *See Potential Conflict of Interest Disclosure at the end of the report Copyright 2005 by Institute for Clinical Systems Improvement

4 Description of Test Epidemiology of Congestive Heart Failure Congestive heart failure (CHF) is a major health problem in the United States, affecting about 4.8 to 5 million individuals. Approximately 550,000 new cases of CHF are diagnosed each year (Collins et al., 2003). This condition is highly disabling and is a frequent cause of death especially in those of advanced age. On average, the 5-year mortality among those diagnosed with CHF is 50%, with 90% of CHF patients dead at 10 years (McCullough and Sandberg, 2003). Given that CHF is primarily a disease of those over 65 years of age, the incidence of the disease is expected to increase significantly as the population ages. In addition, CHF is the fourth leading cause of adult hospital admissions and the most frequent cause of hospitalizations for individuals over 65 years of age (McCullough, 2004). Symptoms and signs of CHF may include, among others, dyspnea on exertion or at rest, orthopnea, pulmonary edema, muscle loss due to low cardiac output, palpitations and arrhythmias, and fluid retention with swelling in the ankles or other areas (peripheral edema). Conventional means that may be used to diagnose CHF include history and physical, electrocardiography, echocardiography, and chest X-ray. Although echocardiography may be considered the gold standard in the diagnosis of CHF, the length of time for the test, lack of ready availability in certain settings, and the relatively high cost of the test make echocardiography impractical for screening or diagnosis in large groups of individuals. Cardiac catheterization and hemodynamic monitoring (e.g. Swan-Ganz catheterization) may provide additional information concerning the status of CHF but are not indicated as routine procedures (Ruskoaho, 2003). Furthermore, about 60% of people 55 years and older with a left ventricular ejection fraction (LVEF) of 0.25 or less have been found in the Rotterdam Study (Mosterd et al., 1999) to be asymptomatic. Conversely, individuals with signs and symptoms suggestive of CHF are often found not to have the disease on further investigation (such as echocardiograms and cardiology consults), as the signs and symptoms of CHF tend to be non-specific (Mueller et al., 2004; Collins et al., 2003). Given the diagnostic difficulties in assessing patients for CHF in addition to the fact that early medical treatment of the condition (e.g. with diuretics, angiotensin-converting-enzyme inhibitors, angiotensin receptor blockers, beta-blockers, aldosterone antagonists such as spironolactone, and digitalis) may prolong life and reduce symptoms, a search for an inexpensive, easy-to-perform, highly-predictive test has occurred that distinguishes CHF from other conditions that have a similar clinical presentation. Consequently, the discovery of the natriuretic peptides as candidates for such a test has sparked numerous investigations into their ability to aid in the diagnosis and management of CHF. Description of B-Type Natriuretic Peptide (BNP) Testing BNP was originally cloned from extracts of porcine brain and thus the name brain-type natriuretic peptide, although the peptide is mainly synthesized, stored, and released from the myocardium of the ventricles (Grantham and Burnett, 1997). In the human, the substance originally starts as preprobnp, a 132-amino acid (aa)-long peptide which is then broken down into a 108 aa-long peptide (pro-bnp) and a 26-aa long fragment. Pro-BNP is then enzymatically cleaved into the biologically active BNP (32 amino acids) and the inactive N-terminal fragment (NT-proBNP), both of which circulate in the plasma (McCullough et al., 2003; McCullough, 2004). BNP plasma levels rise in response to an increase in ventricular wall stretch and end-diastolic volume. The half-live of BNP is short (22 minutes) and thus may reflect acute changes in cardiac state to a greater extent than chronic states. Since left ventricular wall stress is increased in CHF, especially in the left ventricle, BNP levels rise in response. Thus, it is proposed that measuring the levels of BNP in the plasma may add important information to the clinical workup in terms of diagnosing, assessing, and managing CHF. In CHF, BNP may have important physiologic roles. It acts as a natriuretic (enhancing sodium excretion), a vasodilator, a diuretic, and is a counter-regulatory hormone to angiotensin II, norepinephrine, and endothelin due to BNP s role in decreasing synthesis of these substances. Thus, the hormone acts as a compensatory hormone in an attempt to decrease the signs and symptoms of CHF. As a result, BNP (known as nesiritide or NatreCor ) has also been given as a treatment for acute exacerbations of CHF. Institute for Clinical Systems Improvement 2

5 In response to the interest in BNP measurement in CHF, several laboratory kits have been developed in an effort to measure BNP in a precise, accurate, and efficient manner. There are three main methods for the measurement of BNP: a radioimmunoassay method (RIA), an immunoradiometric assay (IRMA, Shinoria BNP, Shinogi and Co., Ltd., Osaka, Japan), and an immunofluorometric assay (Triage or IMFA method, Biosite Diagnostics, San Diego, CA). The RIA method is the less desirable method due to relatively low sensitivity, specificity, and precision, along with being less practical for the lab technician to use, although it is less costly. The IRMA method utilizes monoclonal antibodies and a solution of I- 125-labeled anti-bnp antibodies that bind BNP and register on a gamma counter. Although precise, the testing is done manually and about 36 hours are needed to perform the test. An automated form of the assay has been recently introduced in a format applicable to hospital clinical laboratories (Bayer Diagnostics, Tarrytown, New Jersey). The Triage method utilizes a kit that resembles a blood glucose meter, although venipuncture rather than a finger prick is needed to provide an adequate blood sample. To measure BNP levels in the Triage system, plasma reacts with fluorescent antibodies which then binds BNP and the BNP-antibody complexes are then counted. The test takes about 15 minutes to complete. Consequently, when rapid diagnosis is needed, the Triage test is usually the preferred test and appears to be the most practical for clinical settings (Howie et al, 2003). The detection range of the assay is from about 5 to 5000 pg BNP/ml with a coefficient of variation of 15% (McCullough, 2004). The Triage assay is similar to others in the ability to discriminate between normal subjects and those with CHF, although it may not be as precise as fully automated assays. The Triage system received FDA approval in 2000 as a diagnostic aid in heart failure and as a prognostic aid in acute coronary syndromes (McCullough and Sandberg, 2003). Additional BNP assays available include the Abbott AxSYM, Bayer ACS:180, Bayer ADVIA Centaur, and the Biosite-Beckman automated ACCESS assay. Other cardiac natriuretic peptides that have been evaluated include atrial natriuretic peptide and a cleavage fragment (ANP and NT-proANP respectively) as well as NT-proBNP (a cleavage fragment of pro-bnp). Since BNP has been the most well-studied of the naturietic peptides, the scope of this report will be limited to BNP only. Relevant Definitions The following are definitions that are relevant to commonly-used statistics in the analysis of the efficacy of BNP testing: Abbreviations include: True positives: TP False positives: FP True negatives: TN False negatives: FN Definitions include (Friis and Sellers, 1996): Sensitivity: The ability of a test to correctly identify all individuals who actually have the disease. Sensitivity can also be defined as TP / (TP + FN) Specificity: The ability of a test to correctly identify only nondiseased individuals who actually do not have the disease. Specificity can also be defined as TN/(TN + FP) Positive predictive value (PPV): The proportion of individuals with a positive test who actually have the disease. PPV can also be defined as TP/(TP + FP) Negative predictive value (NPV): The proportion of individuals with a negative test who actually do not have the disease. NPV can be defined as TN/(TN + FN) Accuracy may be defined as (TP + TN) / (TP + TN+ FP + FN) Receiver Operating Characteristic (ROC) Curve: A plot of sensitivity vs. (1 specificity) for a test. The area under the curve (AUC or C-statistic) may range from 0.5 for a test with poor discriminatory power to 1.0 for a test with optimal discriminatory power. Institute for Clinical Systems Improvement 3

6 Potential Uses Suggested uses for the measurement of plasma BNP levels in CHF include (Rodeheffer, 2004): Screening populations in order to uncover asymptomatic ventricular dysfunction As an aid in the diagnosis of patients with dyspnea or other nonspecific symptoms where CHF is part of the differential diagnosis Monitoring the effectiveness of heart failure treatment and titrating treatment intensity Providing an estimation of prognosis BNP testing is generally used as part of the overall clinical workup and is not normally performed as a stand-alone test. Contraindications Since the only procedure performed on the patient is a venipuncture, there are no known contraindications to BNP testing. Efficacy of Test Use of BNP in Screening for Heart Failure One proposed benefit of BNP measurements is for the screening of asymptomatic populations for left ventricular dysfunction (LVD). Given that a large proportion of patients with LVD do not have symptoms (Mosterd et al., 1999), a screening test that has a high sensitivity and specificity for detecting LVD so that treatment can be started early would be valuable. Vasan et al. (2002) examined the usefulness of BNP as a screening tool for increased left ventricular mass and left ventricular systolic dysfunction (LVSD) in 3177 participants from the Framingham Heart Study who attended a routine examination between Subjects with unavailable BNP levels, creatinine of 2.0 or more, history of heart failure, or inadequate echocardiograms were excluded. At baseline, all participants underwent echocardiographic examination, which was the reference standard. Results showed that the receiver-operating characteristic curve (ROC), where sensitivity is plotted against (1 specificity), showed an area under the curve (AUC) of 0.75 and was higher for men than for women. Plasma BNP levels of 45 pg/ml in men and 50 pg/ml in women resulted in 95% specificity for detecting LVSD. A plasma BNP value of 46 pg/ml in men and 47 pg/ml in women corresponded to a sensitivity of 0.27 for men and 0.13 for women. Lower threshold levels of BNP were associated with an optimization of the sums of sensitivity and specificity, but false positives outnumbered true positives at these thresholds and only identified less than one-third of subjects who had an elevated LV mass and/or LVSD. Risk factors consisted of age > 60 years, hypertension, prevalent cardiovascular disease as well as those with 2 or more high-risk features. Using these risk factors, the AUC increased when the test was considered for high-risk groups in women but not in men. Still, the overall discriminatory power was low. The authors concluded that their findings do not support the use of natriuretic peptides in screening the general population for left ventricular mass and LVSD, and further investigations are warranted to confirm the findings. McDonagh et al. (2001) used the natruiretic peptides N-ANP and BNP as a screening test for 1640 randomly selected men and women aged from an urban population. This population was a subset of the participants in the Glasgow MONICA (monitoring trends and determinants of cardiovascular disease). All patients underwent echocardiography as a reference standard. Left ventricular dysfunction (LVD) was defined as having a left ventricular ejection fraction of 30% or less. The main outcome variable was all-cause mortality after 4 years. The number of subjects that had both an analyzable echocardiogram and a venous sample for measurement of BNP was There were 80 deaths at 4 years (4.9%). Cardiovascular-related deaths accounted for 47% of all deaths. As for all-cause mortality, 21% of those with significant LVD (ejection fraction (LVEF) of 0.30 or less) died (9 out of 43) in Institute for Clinical Systems Improvement 4

7 four years, as compared to 4% in those with a LVEF of greater than 0.30 (p < ). There was no significant difference between 4-year all-cause mortality in participants with symptomatic versus asymptomatic LVD of any degree (whether LVEF was defined as an LVEF of 0.40 or less or LVEF of 0.35 or less). The median BNP level in those who died from any cause was 16.9 pg/ml as compared to 7.8 pg/ml in survivors (p < ). Using a stepwise Cox regression model resulted in inclusion of four variables: advancing age (hazard ratio 1.5, p < per 5-year increment), BNP concentration of 17.9 pg/ml or greater (hazard ratio 2.2, p < 0.006), presence of ischemic heart disease (hazard ratio 1.9, p < 0.03), and male gender (hazard ratio 1.8, p < 0.04). Participants with a LVEF of 0.40 or less that also had a BNP concentration of 17.9 pg/ml or greater had a 4-year mortality rate of 17% as compared to participants in the same LVEF range who also had a BNP level below this value (6.8% 4-year mortality rate, p < 0.013). Patients with preserved left ventricular function also had a significantly increased mortality rate if their BNP level was greater than or equal to 17.9 pg/ml (8.5% mortality rate) as compared to subjects with a BNP level below this value (2% mortality rate, p < ). The authors conclude that the study shows for the first time in a general population aged years that BNP is an independent predictor of all-cause mortality. They state that in addition to its role as a diagnostic aid in LVD, BNP also has prognostic information. However, the number of deaths was relatively small, which may make generalization of the findings difficult. Also unknown is whether the results of such screening can be used to guide treatment. Thus, application of the findings, while promising, is limited in the clinical setting. Maisel et al. (2001) studied patients who were referred for echocardiography due to suspected LV dysfunction. The study population was drawn from the San Diego Veteran s Health Care System and included 200 consecutive patients. Patients with known LV dysfunction were excluded. Both outpatients and inpatients were included in the study, with about 24% of the population consisting of inpatients. Fifty-two had unsubstantiated claims of dyspnea with the rest being asymptomatic. Almost all patients had risk factors for heart disease, with 46% having a history of coronary artery disease. In the 105 patients in whom echocardiography returned a normal result, average (mean) BNP levels were 29.5 pg/ml. In those with diastolic dysfunction (n = 42) BNP levels averaged 391 pg/ml (p < 0.001); in those with systolic dysfunction (n = 53) BNP averaged 567 pg/ml (p < 0.001), and in those with both a diastolic restrictive filling pattern and systolic dysfunction, BNP averaged 1077 pg/ml (p < ). The overall mean average BNP for all patients with abnormal left ventricular function (n = 95) is 489 pg/ml. The area under the ROC curve was A BNP cutoff level at 38.5 pg/ml had a negative predictive value of 93%. A BNP threshold of 75 pg/ml resulted in the highest specificity (98%), best positive predictive value (98%) and highest accuracy (93%). BNP levels of > 100 pg/ml were seen in only 1% of patients with normal LV function compared with 80% of those with abnormal ventricular function (p < 0.001). The authors concluded that BNP can reliably predict the presence or absence of LV dysfunction on echocardiography, and may assist in determining the appropriateness of patient referral. Limitations include possible lack of generalizability of the results since the population was drawn entirely from a Veteran s Health Care System in a single city. In addition, the sample size was relatively small for a screening study. Epshteyn et al. (2003) examined the use of BNP as a screening tool for left ventricular dysfunction in diabetics. A total of 486 patients were studied, also from the Veteran s Administration health care system. BNP levels were compared with echocardiographic findings in 263 patients. Patients were divided into two groups: one group was comprised of participants with a clinical indication for echocardiography (CIE, n=172), and the other group consisted of patients with no clinical indication for echocardiography (no-cie, n=91). The latter group was taken from a random sample of 306 clinic patients with no-cie. The patients with no-cie that were not given echocardiography acted as an additional comparison group. Cardiologists assessing left ventricular function were blinded to the results of the BNP testing. Abnormal results on echocardiography included a LVEF of < 50% and/or wall abnormalities and/or impaired relaxation and restrictive and pseudonormal patterns (diastolic dysfunction). The patients with no-cie who were randomly selected to receive echocardiography had a mean average BNP level of 83 pg/ml compared to 63 pg/ml for no-cie patients without echos (p = 0.10). Patients with CIE had higher BNP levels on average (301 pg/ml) than those with no-cie (p < 0.001). Patients with CIE also had higher rates of hypertension, coronary artery disease, and myocardial infarction. In patients found to have normal left ventricular function, BNP levels were low regardless of whether a CIE was present (51 pg/ml and 47 pg/ml respectively). Patients with CIE who were found to Institute for Clinical Systems Improvement 5

8 have abnormal left ventricular function (n=112) had a mean BNP level of 435 pg/ml. Patients with no- CIE but who were found to have abnormal left ventricular function on echocardiogram (n=32) had BNP values of 161 pg/ml. Differences in BNP concentrations between patients with normal versus abnormal left ventricular function were significant for both groups (p < 0.001). Using ROC analysis the AUC was 0.91 (p < 0.001) for CIE patients and 0.81 for no-cie patients (p < 0.001). A BNP threshold of 79 pg/ml had a sensitivity of 86%, a specificity of 92%, an accuracy of 82%, and a positive predictive value of 95%. Levels at 60 pg/ml or less had a negative predictive value of 90%. On logistic regression, history of CHF, coronary artery bypass graft, atrial fibrillation, and BNP were all predictors of left ventricular dysfunction, with BNP being the strongest (p < 0.001). The authors concluded that the rapid whole blood test for BNP can reliably detect the presence or absence of left ventricular dysfunction in diabetics, regardless of the presence of symptomatology of LV dysfunction, although BNP should not replace imaging in the diagnosis of CHF since they provide complementary information. However, normal BNP levels make significant LV dysfunction unlikely. The authors pointed out limitations that include possible lack of generalizability of results from an older, largely male Veteran s Administration Medical Center population, and the use of BNP to uncover any impairment of ventricular dysfunction rather than significant impairment, which may make correlation between clinical signs, symptoms, and BNP levels problematic. A comparison between BNP as a screening device to 12-lead electrocardiography was performed by Hedberg et al. (2004) in year old men and women. Echocardiography was used as the reference standard for LVEF and wall motion index determinations. LVEF was possible to obtain in 276 participants. The mean LVEF was 59% (SD, 10.5%). For the wall motion index to detect an LVEF of less than 0.40, the AUC under the ROC curve was making the wall motion index an accurate measure of LVEF. The prevalence of left ventricular dysfunction (wall motion index less than 1.7) was 6.9%. The 12-lead EKG showed significant abnormalities in 25.8% of the participants, including atrial fibrillation, bundle branch blocks, ST-segment depression, and others. On multivariate analysis ST-segment changes, Q-wave abnormalities, major conduction disturbances, and T-wave inversion were independent EKG changes associated with LV dysfunction. The median concentration of BNP was 108 pg/ml (interquartile range (IQR), pg/ml) in those with LV dysfunction and 25 pg/ml (IQR pg/ml) in those without systolic dysfunction (p < 0.001). The area under the ROC curve for BNP to detect LV systolic dysfunction was (95% CI, ). A BNP concentration of greater than 28 pg/ml gave a 93% sensitivity, 55% specificity, 99% negative predictive value, and 13% positive predictive value. The corresponding values for the EKG to detect LV systolic dysfunction are 96%, 79%, 100%, and 26% respectively. A higher BNP cutoff (73 pg/ml) showed a higher specificity rate but did not detect 21% of the participants with LV dysfunction. As for the ability of BNP to detect LV systolic dysfunction in subjects with major EKG abnormalities, the sensitivity, specificity, negative and positive predictive values were 96%, 38%, 97%, and 35% respectively. Although BNP and the EKG were nearly equivalent in identifying LV systolic dysfunction (high sensitivities), and in excluding the condition (high negative predictive value) the number of false positives was considerably higher with BNP than with the EKG. The authors state that the 12-lead resting EKG is an effective screening tool for LV systolic dysfunction, with plasma BNP being nearly equivalent to the EKG in excluding systolic dysfunction, but BNP measurement yields more false-positive results. In reference to the use of BNP as a screening test, the studies show that BNP is not useful as a screening tool, in particular as a tool for screening the general population as the prevalence of asymptomatic LV dysfunction is low. Use of BNP in the Diagnosis of Heart Failure Whereas screening for left ventricular dysfunction pertains largely to the asymptomatic population, this section examines the ability of BNP to diagnose heart failure in those with symptoms and signs that present problematic differential diagnoses. In an early study Cowie and Struthers (1997) enrolled 122 consecutive patients (59 male, 63 female, age range years) referred to a rapid-access heart failure clinic with a new primary-care diagnosis of heart failure. The natriuretic peptides ANP, N-terminal ANP, and BNP were measured using radioimmunoassay. The reference standard was a 3-cardiologist panel that examined findings from Institute for Clinical Systems Improvement 6

9 clinical assessment, chest radiographs, and echocardiography. Using these criteria, 29% of patients in the study were diagnosed with heart failure. BNP results were available in 106 patients (29 with heart failure). The BNP geometric means of the heart failure patients were much higher than those with other diagnoses (63.9 vs pmol/l, p < 0.001). The AUC for the ROC analysis showed that BNP had the largest AUC (0.96) as compared to ANP (0.93) and NT-ANP (0.89). At threshold values chosen to give a 98% negative predictive value for heart failure, BNP levels were noted to have a sensitivity of 97%, a specificity of 84%, and a positive predictive value of 70%. In a logistic regression model, the addition of ANP or NT-ANP did not improve the predictive power in comparison to a model containing BNP alone. When the size of the heart based on chest radiographs was added to the model, only BNP was predictive of heart failure. The authors concluded that in patients with symptoms suggestive of heart failure in the primary care setting, BNP levels appear to be a useful indicator in delineating which patients are likely to have heart failure and need further assessment. However, this is an early study with a relatively small sample size and thus does not permit definitive conclusions regarding the clinical efficacy of BNP in the primary care setting. Yamamoto et al. (2000) compared BNP to a 5-point clinical score derived from patient history, electrocardiogram, and chest radiogram in 466 outpatients referred for echocardiography to further evaluate heart failure in patients who were symptomatic or have risk factors for systolic dysfunction. Systolic dysfunction was defined as an ejection fraction (EF) less than 0.45 and was noted in 10.9% of patients. The AUC for ROC analysis concerning BNP was 0.79 for detecting an EF of less than 0.45, showing a weak to moderate relationship between BNP levels and prediction of LVEF (statistical significance not reported). An abnormal BNP assay occurred in 41% of patients and identified a group with a relatively high proportion of patients with systolic dysfunction (21% had an EF of less than 0.45). A normal BNP identified a group with a low risk of systolic dysfunction (4% with an EF of less than 0.45). As for the clinical score, the score was positive in 43% of the population, of which 24% had a EF of less than A normal score identified a group with a low risk of systolic dysfunction (1% with an EF of 0.45 or less). The investigators concluded that the sensitivity and specificity of BNP levels was acceptable but also underscores the importance of accompanying clinical criteria in making the diagnosis. Lubien et al. (2002) studied 294 patients from the Veteran s Administration health care system that were referred for echocardiography in order to assess left ventricular function. The target of the study was an evaluation of diastolic function (in patients with preserved systolic function) and thus patients with systolic dysfunction were excluded. All echocardiograms were interpreted by cardiologists blinded to the BNP levels. For patients without diastolic dysfunction (n = 175), the average age was 60 years; for patients with diastolic dysfunction (n = 119) the average age was 71 years. About 90% of patients were male. Patient were classified into 4 classes which included normal, impaired relaxation, pseudonormal, and restrictive-like filling patterns. In patients with diastolic dysfunction, the mean BNP level was 286 pg/ml with the normal group having a BNP of 33 pg/ml (p < 0.001). In addition, all 3 clinical subgroups had a higher BNP concentration than normals (p < 0.001). Participants with restrictive-like filling patterns had the highest average BNP value (408 pg/ml) (p < 0.001) and symptomatic patients had higher BNP concentrations for all diastolic filling categories. The AUC for BNP to detect diastolic dysfunction overall was 0.92 (p < 0.001), although the restrictivelike filling patterns, which often correlates with more severe symptoms, showed an AUC of BNP levels were not able to discriminate the various diastolic filling patterns from each other. A cutoff BNP value of 62 pg/ml was noted to have a sensitivity of 85%, a specificity of 83%, and an accuracy of 84% in detecting abnormal diastolic filling patterns. In multivariate analysis using logistic regression, age, history of CHF, and BNP values were found to be significantly associated with the identification of diastolic dysfunction. The odds ratio (OR) for BNP > 62 pg/ml was 26.8 (p < 0.001). The investigators suggest that low BNP levels may preclude the need for echocardiography in relevant patients, especially in high-risk patients that are asymptomatic. Elevated BNP levels may indicate a high suspicion of LV dysfunction even in asymptomatic patients and thus helps select patients in need of further workup. However, the sample was not randomized and the conclusions are only generalizable to those with diastolic dysfunction, although preserved systolic function occurs in as many as 40% to 50% of patients with heart failure, implying a high incidence and prevalence of diastolic ventricular dysfunction. Also, the population was from the Veteran s Administration healthcare system and thus care needs to be taken in applying the conclusions to other populations. Institute for Clinical Systems Improvement 7

10 Krishnaswamy et al. (2001) studied 400 Veterans (96 to 97% male and an average age of 60 to 69 depending on subgroup) that were referred for echocardiography to evaluate ventricular function. Based on echocardiography results, patients were assigned to groups which included patients with normal ventricular function (n = 147), systolic dysfunction only (n = 155), diastolic dysfunction only (n = 98), and both systolic and diastolic dysfunction (n = 70). When all patients with abnormal LV function were grouped together, the average BNP level was 416 pg/ml as compared to the values in patients with normal LV function (p < 0.001). The AUC for the ROC curve was 0.95, with a level of 75 pg/ml or greater showing a sensitivity of 85%, a specificity of 97%, and an accuracy of 90% in detecting LV dysfunction. A level of < 107 pg/ml had a 90% predictive value. BNP could not differentiate patients with systolic dysfunction from patients with diastolic dysfunction alone (AUC = 0.61). However, patients with both systolic and diastolic dysfunction had the highest average BNP levels (675 pg/ml). In patients with heart failure symptoms and normal systolic function, BNP levels of 57 pg/ml had a positive predictive value of 100% for diastolic dysfunction. Overall, patients with an abnormal LV function and symptoms of heart failure had a higher average level of BNP (581 pg/ml) as compared to patients with abnormal LV function but without symptoms (236 pg/ml, p < 0.001). A level < 107 pg/ml had a negative predictive value of 90%. The authors conclude that BNP measurements may be a useful way of distinguishing patients with abnormal ventricular function from patients without LV dysfunction. Dao et al. (2001) enrolled a convenience sample of 250 predominately male (94%) patients who presented to urgent care and emergency departments of an academic Veteran s Affairs hospital with dyspnea. As a reference standard, 2 cardiologists reviewed all medical records and independently assessed the patients condition (blinded to the patients BNP levels). This reference standard was used to evaluate the discriminatory power of BNP for the diagnosis of CHF. Reference standard assessment revealed that 39% had acute CHF, 6% had baseline LV dysfunction without acute exacerbation of CHF, and 55% had non- CHF causes for their dyspnea. Patients with acute CHF had an average BNP value of 1,076 as compared to 38 pg/ml for patients without CHF (p < 0.001). Using a threshold of 80 pg/ml, BNP performed with an accuracy of 95% and a sensitivity of 98%, specificity of 92%, positive predictive value of 90% and negative predictive value of 98%. A threshold of 100 pg/ml performed similarly but with a slightly reduced sensitivity and negative predictive value and a slightly increased specificity and positive predictive value. Although the treating physicians performed well, having a C-statistic of 0.884, BNP measurements appeared to perform better with a C-statistic of Fifteen patients were mistakenly given the diagnosis of CHF by the treating physicians, yet had a mean BNP level of 46 pg/ml. In addition, 15 patients with the final diagnosis of CHF were not diagnosed as such during their visit yet had a mean BNP of 742 pg/ml. Assuming a cutoff BNP value of 80 pg/ml, 29 of the 30 misdiagnoses would have been corrected. The authors concluded that BNP testing is sensitive and specific for the identification of CHF in urgent or emergency care settings. They note that the sample characteristics may be a limitation to generalizability as they are primarily a convenience sample from a Veteran s Affairs population. Wieczorek et al. (2002) evaluated the performance of a point-of-care assay (Triage BNP assay) for the diagnosis and assessment of CHF on the basis of the New York Heart Association functional classification scheme. The prospective, multicenter trial enrolled 1050 inpatients, outpatients, and healthy controls. Patients were divided into 6 subgroups: patients without CHF or hypertension (n = 473), patients with hypertension but no CHF (n = 168), NYHA class I CHF (n = 73), class II CHF (n = 135), class III CHF (n = 141) and class IV CHF (n = 60). The coefficient of variation (CV) for intraassay precision ranged from 9.5% at 28.8 pg/ml to 13.9% at 1180 pg/ml. The CV or interassay variation ranged from 10% at 28.8 pg/ml to 14.8% at 1180 pg/ml. For participants without cardiac disease, median BNP concentrations were higher for women than for men (12.8 pg/ml compared to 5.47 pg/ml respectively). BNP concentrations also increased with age, ranging from about 7.0 pg/ml in 35 year olds to 23 pg/ml in individuals 75 years of age or greater (without cardiac disease). Although BNP increased with increasing NYHA functional class severity, the values could not be used to predict class due to considerable overlap in BNP values between classes. However, the AUC for BNP levels as a discriminator between CHF and non-chf patients was found to be 0.93 (p < 0.001). At a cutpoint of 100 pg/ml (corresponding to the elbow of the ROC curve and the FDA-approved diagnostic threshold level) the sensitivity was 82% and specificity was 97%. The authors also suggest lower cutoffs when an increase in sensitivity and negative predictive value is desired. Institute for Clinical Systems Improvement 8

11 Logeart et al. (2002) enrolled 163 patients with severe dyspnea in a comparison of the accuracy of BNP measurements and bedside Doppler echocardiography obtained on admission. Patients with acute MI, chest injury, or recent surgeries were excluded. A group of 30 inpatients all over 65 years of age without cardiac disease, pulmonary disease, hypertension, or diabetes served as a control group for BNP values and a group of 30 outpatients with chronic stable CHF (NYHA class II or III) served as an additional control. Two cardiologists and one pulmonologist blinded to the BNP and echocardiographic results determined the final diagnosis (reference standard). The final diagnosis was CHF in 115 patients and non-chf in 48 cases. Twenty-four patients (15%) were misdiagnosed by the attending physician on admission, with CHF wrongly diagnosed in 13 patients and missed in 11 patients. Mean BNP concentrations were 1,022 pg/ml in the acute CHF group as compared to 187 pg/ml in the non-chf group, along with 44 pg/ml in the control group and 144 pg/ml in the chronic stable CHF group. The intergroup difference was significant (p < 0.001). A BNP threshold value of 300 pg/ml correctly classified 88% of patients (p < ) but a threshold of 80 pg/ml obtained a high negative predictive value (93%). The discriminatory value of BNP appeared to be relatively low in patients with levels between 80 pg/ml and 300 pg/ml as well as in patients studied very soon (less than 4 hours) after the onset of acute dyspnea. For the Doppler analysis, the best results occurred with analysis of mitral inflow; the restrictive pattern of inflow had an accuracy of 91%. On multivariate analysis, both BNP measurements (above 300 pg/ml) (p < ) and Doppler studies (p < ) added incremental predictive value for diagnosis of CHF. The authors state that both BNP and Doppler testing add important independent diagnostic information to the clinical workup in emergency patients with acute dyspnea. The addition of Doppler information became particularly relevant in the gray areas for BNP values (80 to 300 pg/ml) where discriminatory information from BNP measurements appeared to be lowest. Mueller et al. (2004) presented results of a study on the use of BNP in the evaluation and management of acute dyspnea. A prospective, randomized controlled study of 452 patients who presented to the emergency department with acute dyspnea was performed, allocating 225 patients to a diagnostic strategy including the measurement of BNP using a rapid bedside assay and 227 patients to a standard workup (control group). The mean age was 71 years, with women making up slightly more than 40% of the patients. Fifty percent of patients had coronary artery disease; hypertension was present in 52%; pulmonary disease was noted in 50%, including 31% with chronic obstructive pulmonary disease (COPD); and diabetes was present in 23%. The cutoff value for the separation of CHF-related dyspnea from other causes of dyspnea was 100 pg/ml. As for results, the median time from presentation to initiation of therapy was 90 minutes in the control group and 63 minutes in the BNP group (p = 0.03). As for hospitalizations, 75% of patients in the BNP group were hospitalized, compared with 85% of those in the control group (p = 0.008). Fifteen percent of patients in the BNP group were admitted to intensive care as compared with 24% of patients in the control group (p = 0.01). For patients that were hospitalized, the median time to discharge was shorter in the BNP group as compared to the control group (8.0 days vs days, p = 0.001). There was no significant difference between the groups in hospital mortality (21 in the control group vs. 13 in the BNP group, p = 0.19). Exacerbation of COPD was more commonly diagnosed as the cause of dyspnea in the BNP group as compared to controls (23%vs. 11%, p = 0.001). On follow-up, the rates or readmission within 30 days for the BNP and the control group (12 % vs. 10% respectively) and mortality within 30 days of discharge (10% vs. 12%) were not significantly different between groups. All patients were available for 30-day follow-up data collection. The authors concluded that the use of BNP along with other clinical information reduced the time to treatment initiation, the need for hospitalization or intensive care, and time to discharge. An additional advantage of the study design was the fact that BNP results were used along with other clinical variables to affect the management of the patient; consequently, the effect of the BNP result could be seen in the clinical disposition of the patient, although event rates (mortality and morbidity) were not affected. McCullough et al. (2002) presented the results of an analysis of the Breathing Not Properly (BNP) Multinational Study, which enrolled 1586 participants in 7 centers who presented with acute dyspnea. Average age of the cohort was 64 years and 55.7% were men. Of the enrollees, 1538 (97%) had the level of clinical certainty of CHF determined by the emergency department attending physician, which consisted of low (0% to 20%), intermediate (21% to 79%), and high (80% to 100%) diagnostic certainties. Of note, 33.2% of patients had a prior history of CHF by self-report and/or by records available to the ER physician. All participants had an EKG and 96% had a chest x-ray. In addition, 44.8% of patients had Institute for Clinical Systems Improvement 9

12 echocardiography with reported ejection fractions. Two independent cardiologists blinded to the results of the BNP testing provided the reference standard for CHF diagnosis. Initial agreement between the cardiologists occurred in 89.3% of cases. The final diagnosis was CHF in 722 of the participants (47%). At an 80% cutoff of certainty of CHF based on the emergency department attending s impression, clinical judgment had a sensitivity of 49% and a specificity of 96%. At a cutoff of 100 pg/ml, BNP had a sensitivity of 90% and a specificity of 73%. Adding BNP to clinical judgment enhanced the diagnostic accuracy (CHF vs. no CHF) from 74% to 81%. In addition, for subjects with an intermediate probability of CHF based on emergency department diagnosis, BNP correctly classified 74% of cases. The AUC of the ROC curve was 0.86, 0.90, and 0.93 for clinical judgment, BNP, and a combination of clinical judgment and BNP respectively (p < for all pairwise comparisons). The authors state that this is the first study that incorporates the emergency department attending s pretest probability of CHF. The emergency department s diagnosis has a reasonably high rate of accuracy that may be enhanced with BNP determinations. The present study underscores the value of a careful history, physical, and other diagnostic testing when using BNP levels as an additional tool in the repertoire. However, further research needs to be performed concerning what weight to give the BNP levels in comparison to other clinical tools in making the final diagnosis. Maisel et al. (2002) extended the analysis of the BNP Multinational Study (1586 patients) and noted that BNP measurements by themselves were the single most accurate predictor of the presence or absence of CHF based on the area under the ROC curve (0.91 for BNP, p < 0.001) for a cutoff of 100 pg/ml. BNP also appeared to correlate with the New York Heart Association (NYHA) functional class, with a range from an average of 244 pg/ml for class I CHF to 817 pg/ml for class IV CHF. The BNP cutoff of 100 pg/ml appeared to be more accurate (83%) than either the NHANES criteria (67%) or the Framingham criteria (73%) for diagnosing CHF. Maisel et al. (2003) used the BNP Multinational Study data to evaluate the ability of BNP to detect CHF with preserved systolic function (non-systolic or diastolic heart failure). A subset of 452 patients with a final adjudicated diagnosis of CHF underwent echocardiography within 30 days of their emergency department visit. A LVEF of 0.45 or greater was consistent with preserved systolic function. Based on these findings, 63.5% had systolic dysfunction and 36.5% had preserved LV function. Patients with nonsystolic CHF (NS-CHF) had significantly lower BNP values 413 pg/ml than those with systolic CHF (S- CHF) (821 pg/ml, p < 0.001). Comparing BNP values for patients with NS-CHF to those of patients without CHF, a BNP value of 100 pg/ml had a sensitivity of 86%, a negative predictive value of 96%, and an accuracy of 75% for detection of abnormal diastolic LV function. As for a comparison of S-CHF to NS- CHF, the difference between the two designations in terms of BNP value was not significant for males but was significantly higher for S-CHF than for NS-CHF in women (p = 0.03). The authors note a high overlap between BNP levels in S-CHF and NS-CHF and concluded that although BNP may provide some modest discriminatory value in differentiating S-CHF and NS-CHF, the main function of BNP is to separate patients with CHF from those without CHF. McCullough et al. (2003) evaluated a 417 patient subgroup in the BNP Multinational Study that had no history of cardiac failure but had a history of asthma or COPD. The reference standard was two independent cardiologists that evaluated history, physical, and other diagnostic test results but were blinded to the BNP results. Using the reference standard, 20.9% of patients were found to have CHF. The emergency physicians identified only 36.8% of the patients. The mean BNP values were pg/ml for those with CHF and pg/ml for those without CHF. At a threshold of 100 pg/ml, BNP had a sensitivity of 93.1%, a specificity of 77.3%, a positive predictive value of 51.9%, a negative predictive value of 97.7%, and an accuracy of 80.6%. If BNP were added to clinical judgment where the emergency department attending assessed the probability of CHF as 80% or higher, BNP would have correctly identified 83/87 (95.4%) of patients. For patients where the emergency physician gave low probabilities of CHF (less than or equal to 20%), BNP would have correctly identified 20/22 cases as having CHF. On multivariate analysis, BNP was found to be the most important predictor of CHF (odds ratio (OR) = 12.1, p < ). Other independent predictors include a third heart sound (p < 0.03), pulmonary edema on chest x-ray (p = 0.001), and elevated jugular venous pressure (p < 0.05). The study showed the value of BNP in diagnosing acutely dyspneic patients with a history of lung disease but without a clear history of CHF. Of note is the high negative predictive value, which refers to the ability of BNP to act as a ruleout for CHF; that is, CHF becomes quite unlikely given a BNP value of less than 100 pg/ml. Overall, Institute for Clinical Systems Improvement 10

13 BNP testing increased the detection of newly diagnosed or previously unrecognized CHF by about 20%. Limitations included the possibility of classification bias by the reference standard cardiologists and that the measurement of BNP may have been confounded by other conditions such as moderate renal failure or subclinical ischemia. BNP may be secreted by the right ventricle as well in the setting of right heart failure. Although an early and correct diagnosis of CHF can theoretically aid treatment decisions, the study did not test that hypothesis directly. Knudsen et al. (2004) compared chest radiographs and plasma BNP levels in a multicenter study of 880 patients presenting with acute dyspnea. Two blinded cardiologists served as the reference standard and evaluated clinical data to make a final diagnostic determination. Patients were categorized as to whether they had acute heart failure (n = 447) or not (n = 433). Data analysis showed that BNP levels of 100 pg/ml or more contributed significantly in discriminatory value for diagnosing CHF compared to radiographic indicators. Multivariate logistic regression analysis depicted that BNP levels added independent information to the radiographic findings of cardiomegaly, cephalization, and interstitial edema (all statistically significant predictors as well), which also added information to historical and other clinical predictors of CHF. Doust et al. (2004) conducted a systematic review of the diagnostic accuracy of the natriuretic peptides for heart failure. Twenty studies were included. For the eight studies (n = 4086) that measured BNP against an echocardiographic standard (LVEF of 0.40 or less or equivalent) the pooled diagnostic odds ratio was 11.6 (95% CI, 8.4 to 16.1). In the 7 studies that measured BNP against a consensus clinical determination, the diagnostic odds ratio was greater at 30.9 (95% CI, 27.0 to 35.4). The authors state that the results of the studies show that BNP is accurate in the diagnosis of heart failure. It was also felt that the quality of the studies were generally high. However, considerable variation exists in diagnostic accuracy between studies that cannot be accounted for by variation in the clinical setting used. They state that prior to the routine application of the test for diagnostic purposes, more needs to be learned about the causes of the variation. At present, the most likely use of BNP would be as a rule-out in order to assess which patients do or do not need further testing such as echocardiography. The threshold BNP level would need to be low enough such that false negatives would be kept to a minimum. The authors briefly stated that a role for BNP in CHF prognosis and/or in monitoring the response to treatment has been proposed based on early study results. However, further research is needed to determine how BNP compares to other testing such as echocardiography in predicting prognosis and evaluating response to treatment. Of note is that a large portion of the evidence comes from a relatively homogenous population (Veteran s Affairs enrollees) who are mostly male. Thus, although the evidence appears strong overall, care needs to be taken prior to applying the results to other populations. However, data from non-veterans Affairs studies such as the Breathing Not Properly studies provides additional support for the efficacy of BNP testing to aid in the diagnosis of CHF, particularly in the emergency department setting. Use of BNP in the Monitoring and Management of CHF Patients and the Prediction of Cardiac Events Cheng et al. (2001) conducted a pilot study that investigated the value of BNP in the prediction of treatment outcomes in decompensated heart failure. The investigators followed 72 Veterans Affairs patients admitted with decompensated NYHA classes III and IV CHF and measured BNP levels daily. Of the admitted patients, 22 end points (death or readmission) occurred within 30 days of discharge (death in 13 patients, readmission in 9 patients). All surviving patients received complete follow-up at 30 days. In patients who died or were readmitted, BNP concentrations increased during the index hospitalization (mean increase of 233 pg/ml, p < 0.001). In patients without the occurrence of end-point events, BNP levels decreased between admission and discharge (mean decrease of 215 pg/ml, p < 0.05). Patients who had successful outcomes were characterized by decreases in BNP concentration and improvement in NYHA class. Overall, patients with a decrease in BNP levels during their hospital stay had a 16% event rate as compared to a 52% event rate for patients with rising levels (Chi-square analysis: p < 0.001). Although admission BNP values and change in BNP values during the hospital stay were both significant outcome predictors, the last BNP measurement (the discharge BNP) was the single variable most strongly correlated with death and/or readmission (1,801 pg/ml compared to 690 pg/ml in those with successful outcomes). In examining patients who survived to discharge, NYHA class was the strongest predictor of readmission (p = ). Discharge BNP was also correlated to 30-day readmission (p = 0.02). A final Institute for Clinical Systems Improvement 11

14 BNP level of 430 pg/ml or less was a strong negative predictor for readmission. Using BNP discharge values, the area under the ROC curve in terms of prediction of readmission was 0.72, indicating fair to good discriminating power. The AUC for all end points (readmission and death) was Although the study suggests that changes in BNP levels during treatment is an important prognostic indicator and possibly useful in monitoring and guiding treatment in patients with decompensated CHF, the authors noted that the study was an observational study using a convenience sample of largely male patients and that the data should be interpreted with caution. The sample size was also small, precluding multivariate analysis. Anand et al. (2003) evaluated whether BNP and/or norepinephrine (NE) levels are associated with changes in morbidity and mortality in the Valsartan Heart Failure Trial (Val-HeFT). Val-HeFT was a randomized placebo-controlled double-blind trial. Enrolled patients needed to have an LVEF of < 0.40 and an LV internal diameter in diastole of 2.9 cm/m 2 or more after adjustment for body surface area. Plasma BNP and NE were measured prior to randomization and during follow-up in about 4300 patients meeting the above criteria. Baseline hormone measurements were available in 4284 patients. The risk ratio of all-cause mortality and first morbid event (M and M) with baseline NE or BNP above the median was significantly higher than for patients whose values were below the median (relative risk (RR) 2.1 and 2.2 for mortality and morbidity, respectively, p < ). RR for NE was also significant but less so than for BNP. In quartile analysis, baseline BNP and NE showed a quartile-dependent increase in M and M, with BNP having a stronger association with M and M as compared to NE. In terms of change in hormone levels over time, patients with the largest percent decrease in BNP and NE from baseline to 4 and 12 months follow-up had the lowest M and M whereas patients with the largest percent increase in BNP and NE had the highest M and M (the relationship of BNP changes at 4 months to M and M occurrences were all significant; no significance data were available for the 12-month evaluation). BNP increased progressively over the duration of the study by an average of 23 pg/ml in the placebo group, with the valsartan group showing a sustained decrease in BNP over time (average decrease of 21 pg/ml). The authors concluded that BNP (and NE) are associated with increases or decreases in the risk of subsequent mortality and morbidity and may act as important surrogate markers in heart failure. More work needs to be performed in terms of longer-term follow-up and in correlating pathophysiological events to BNP level changes, as well as more precisely correlating BNP changes with treatment effects. Berger et al. (2002) studied BNP as a predictor of sudden death in patients with chronic heart failure. BNP levels were obtained from 452 ambulatory patients who had a LVEF of 0.35 or less. Only patients without heart transplantation or a mechanical assist device were included in the study. Deaths were categorized as sudden death, pump failure, or from other causes. At up to 3 years of follow-up, 293 patients survived without heart transplant or a mechanical assist device, 89 patients died, and 65 patients received a heart transplant. Sudden death was the cause of death in 44 patients, 31 patients had pump failure, and 14 patients had a mode of death from other causes. In a univariate model, significant risk factors for sudden death were log BNP (p = ), log N-ANP (p = 0.003), LVEF (p = 0.005), log N-BNP (p = 0.006), systolic blood pressure (p = 0.01), big endothelin (p = 0.03), and NYHA functional class (p = 0.04). In a multivariate model, log BNP was the only independent significant predictor of sudden death (p = ). Using a threshold of 130 pg/ml, Kaplan-Meier sudden death-free survival rates were significantly higher in patients with values below the threshold point (99%) compared with patients above the point (81%, p = ). The authors conclude that BNP, as a predictor of sudden death, may be useful as a way to identify patients that may benefit most from an implantable cardioverterdefibrillator (ICD) device. They also suggest the need for additional studies in larger CHF populations to confirm the result. Ishii et al. (2002) evaluated laboratory methods for risk stratification in patients with acutely decompensated CHF. Ninety-eight consecutive patients (mean age 69 years, 51 men and 47 women) admitted to the coronary care unit with worsening CHF were evaluated. Patients with acute coronary syndrome in the 3 months preceding admission and those with renal failure were excluded. Serum concentrations of cardiac troponin T (ctnt), serum cardiac troponin I (ctni), and plasma ANP and BNP were measured on admission to the coronary care unit (93 patients were NYHA class III or IV). During a mean follow-up of 451 days (follow-up was complete in all patients), there were 37 cardiac events, which included 21 cardiac deaths (14 in-hospital deaths) in addition to 16 readmissions for worsening of heart failure. The causes of cardiac deaths were pump failure in 18 patients, acute myocardial infarction in 1, Institute for Clinical Systems Improvement 12

15 and sudden death in 2 patients. All 14 in-hospital deaths were due to heart failure. Ninety-two percent of cardiac deaths occurred within 12 months after the index admission. Significant univariate predictors of cardiac events and deaths were NYHA class, LVEF, ctnt levels, ctni levels, and log BNP. Multivariate predictors included ctnt and log BNP. The AUC for ctnt was 0.63 for detection of patients with and without cardiac events. The AUC for BNP was A ctnt level > micrograms/l (sensitivity and specificity of 65% and 64%) and a BNP > 440 pg/ml (sensitivity and specificity of 74% and 59% respectively) on admission were correlated with an increase in in-hospital mortality, overall cardiac mortality, and rate of cardiac events. Based on Kaplan-Meier analysis, the combination of ctnt and BNP could reliably stratify patients into low-risk, intermediate-risk, and high-risk groups for cardiac events. In the study, rates of cardiac events were 13% in the low-risk group, 42% in the intermediate risk group, and 59% in the high-risk group. The investigators concluded that measuring the admission concentration of ctnt and BNP together may aid in the stratification of patients in terms of risk for future cardiac mortality and morbidity. However, the sample size was small and BNP did not perform well on its own. Consequently, this investigation casts some doubt in terms of the ability of BNP alone as a prognosticator in terms of cardiac events for acutely ill CHF patients. Logeart et al. (2004) studied the use of BNP to predict post-discharge outcome of patients who were admitted due to decompensated heart failure. Serial measurements of BNP were performed from admission to discharge in two samples of consecutive patients. Patients were followed for 6 months for the occurrence of death or first readmission. In the derivation study (patients admitted for CHF exacerbation), 114 patients were included. In the validation study, 109 CHF patients were included from another center. About 30% of patients had preserved LVEF (> 0.45) values (diastolic heart failure). Patients who required emergent transplantation were excluded. Average age in both groups was about 70 years, and the derivation study had 79:35 male to female ratio, with the validation study having approximately a 50:50 ratio. In the derivation group, 9 patients died of treatment-refractory CHF resulting in 105 patients available for follow-up. Mean BNP levels were 1,015 ng/l on admission with a level of 457 ng/l near discharge. During the 6 months of monitoring, 12 patients died and 39 were readmitted for CHF exacerbations. In univariate analysis, inotropic use was the only clinical variable related to adverse outcomes. As for echocardiographic variables, LVEF was poorly predictive of adverse outcomes while the predischarge Doppler mitral pattern had a strong association with adverse outcomes. The predischarge BNP assay (given near time of discharge) was the variable most strongly predictive of adverse cardiac events, with an AUC of 0.80 (95% CI, 0.71 to 0.89). In multivariate analysis, only the predischarge BNP value remained significant (hazard ratio = 1.14, p = 0.027). A BNP level of 350 ng/l resulted in the best compromise between sensitivity and specificity for predicting death or readmission. In the validation study patients, 12 died during the hospital stay, nine died during the 6-month monitoring period, and 26 were rehospitalized for exacerbation of CHF. Mean BNP levels were 941 ng/l at admission and 441 ng/l at discharge. Predischarge BNP concentrations remained a strong predictor of adverse events (death or cardiac readmission), with an AUC of At a BNP cutoff level of 350 ng/l, sensitivity was 80% and specificity was 88% in predicting death or readmission at six months. On Kaplan-Meier analysis, predischarge BNP levels showed strong predictive power for death or readmission (p < ). The study suggests that BNP levels are a strong predictor of adverse events after acute admission for CHF, with a graded relationship between BNP concentrations and outcome. The authors suggest that BNP values may have greater predictive values than clinical variables and Doppler echocardiographic results. However, further study is needed that utilizes larger sample sizes and longer-term follow up to confirm the results, as well as to investigate the application of BNP results to patient management. Tsutamoto et al. (2001) investigated the effect of spironolactone on BNP and left ventricular remodeling in patients with CHF. Thirty-seven patients with mild to moderate nonischemic CHF were randomly allocated into a spironolactone group (n=20) or a placebo group (n=17). Average age was 63 to 65 years old (depending on group) and 28 of the participants were men. Left ventricular volume and mass were measured prior to treatment and after 4 months of treatment. Left ventricular volume and mass were significantly decreased (p < 0.05) and LVEF was significantly increased after spironolactone treatment (p < 0.05). The corresponding values were unchanged in the placebo group. Plasma levels of ANP, BNP, and plasma procollagen type III aminoterminal peptide (PIIINP, a peptide marker of myocardial fibrosis) were decreased in the spironolactone group (P < 0.05 for ANP, p < 0.01 for PIIINP and BNP) but not in the placebo group. The authors suggest that the reduction of BNP level with spironolactone treatment Institute for Clinical Systems Improvement 13

16 may be a marker of treatment benefit. However, the study does not compare the prognostic value of BNP to that of any other reference standard to show relative prediction strength as to the level of benefit of treatment. Maisel et al. (2004) evaluated the value of BNP levels in terms of offering independent information that can aid decision-making with regard to outcomes in emergency medicine. The sample consisted of 464 patients (median age 64 years, including 46.1% females and 63.4% African-Americans from the Rapid Emergency Department Heart Failure Outpatient Trial (REDHOT)). The subjects were seen in the emergency room for shortness of breath and had BNP levels of > 100 pg/ml. Physicians were blinded to the BNP levels. Patients were monitored for up to 90 days after discharge. Of the 464 patients, 90% were hospitalized. Two-thirds were noted to be at NYHA class III or IV. BNP levels did not differ significantly between participants who were discharged home from the emergency department versus those admitted to the hospital (976 pg/ml vs. 776 pg/ml, p = 0.6). On logistic regression analysis, the emergency physician s decision to admit to the hospital or discharge a patient did not influence 90-day outcomes. However, the BNP level was a strong predictor of 90-day outcome. The 90 day combined event rate (CHF visits or admissions or mortality) in patients with BNP < 200 pg/ml was 9% and in those with BNP > 200 pg/ml was 29% (p = 0.006). The investigators concluded that there may be a disconnect in terms of the severity as perceived by emergency physicians and severity as determined by BNP plasma concentrations, and that BNP levels may aid physicians in making triage decisions concerning inpatient admissions. Further data are needed in order to refine biomarker-guided therapeutic and monitoring strategies. The prediction of future cardiac events in patients presenting with dyspnea in the emergency department setting was evaluated by Harrison et al. (2002). In 325 patients recruited from the Veterans Administration health care system (average age 65 years, 95% men) who presented with dyspnea to the emergency department, BNP levels were measured. For the next 6 months, patients were followed in order to determine the frequency of end-points including death (cardiac and non-cardiac), hospital admissions (cardiac), and repeat emergency department visits for CHF. There were 23 cardiac deaths (including 15 CHF deaths) and 13 noncardiac deaths. The AUC using BNP to detect a CHF end point (CHF-related death, hospital admission, or repeat emergency department visit) was (95% CI, to 0.915). Using a BNP cutoff value of 480 pg/ml, the sensitivity was 68%, the specificity was 88%, and the accuracy was 85% for prediction of a subsequent CHF adverse event. Patients with a BNP of > 480 pg/ml have a 51% 6-month probability of CHF-related event. The AUC for detecting death from cardiac causes was (95% CI, to 0.933) and for detecting subsequent death from CHF was (95% CI, to 0.954). BNP was not associated with death from non-cardiac causes. Kaplan-Meier plot analysis for all CHF events showed that a rising BNP was associated with a worsening prognosis. Patients with a BNP of less than 230 pg/ml had only a 2.5% incidence of CHF-related end points. The authors state that a high BNP level in patients presenting with acute dyspnea in the emergency department setting was predictive of subsequent cardiac events, with a low BNP value having a high negative predictive value. However, the fact that the study was an observational study performed in predominantly male patients may limit the generalizability of the findings. In addition, the overall low absolute number of deaths in this population may make interpretation of the results for other populations difficult. In a randomized controlled trial with 68 hypertensive subjects with dilated cardiomyopathy, NYHA class III to IV CHF, and a LVEF of 0.40 or less, Falcao et al. (2004) investigated the association of diagnostic and predictive markers (BNP and ANP) to clinical and functional parameters of CHF in an outpatient population. Twenty-six normal controls also took part in the study. The 68 patients were randomly allocated into either a group treated with an angiotensin receptor blocker (ARB, irbesartan) or an ACEinhibitor (ACE-I, captopril). BNP and ANP were measured in both groups and correlated with clinical and functional parameters during a follow-up of six months. The average age in the CHF group was 66 years and consisted of 81% men. The normal control group had an average age of 58 years and consisted of 38% men. The mean LVEF was 0.33 in the patient groups and 0.62 in the controls. The mean BNP level was pmol/l in the patient groups and 7.12 pmol/l in the controls (p = ). Significant correlations were found between BNP levels and LVEF. Between the baseline phase and the final month of follow-up (sixth months), BNP and ANP decreased significantly in the ARB group but not in the ACE-I group. More specifically, BNP concentration was pmol/l lower in the ARB group than in the ACE-I Institute for Clinical Systems Improvement 14

17 group at the sixth month (p = 0.001). Clinical benefit was noted for both treatment groups throughout the six month monitoring period, with patients moving to NYHA class II CHF. The increase in LVEF from both drugs was statistically significant. However, LVEF was significantly higher in the ARB group than the ACE-I group at the end of the follow-up period. No participants died during the follow-up period. Although this study suggested a significant correlation of BNP levels with improvement in clinical and functional parameters, more work is needed with larger sample sizes and longer follow-up times to ascertain more precisely the level of correlation and predictive value of BNP for treatment response from a variety of CHF drug regimens. Plasma BNP levels were used to titrate therapy in a small study (Murdoch et al., 1999) that enrolled 20 patients with mild to moderate CHF. The participants were randomly assigned to a group where the titration of therapy was based on plasma BNP levels and a group that titrated ACE inhibitor doses through clinical means. The trial lasted 8 weeks. Only the BNP-based approach was associated with a significant decrease in plasma BNP throughout the duration of the study. The suppression in plasma BNP was significantly greater for the BNP-based approach as compared to the clinical group after 4 weeks (p = 0.03). Although both treatment methods resulted in a favorable hemodynamic effect, mean heart rate fell (p = 0.02) and plasma renin activity increased (p = 0.03) in the BNP group as compared to the clinical group. It was concluded that titration of vasodilator therapy using BNP levels resulted in a more favorable inhibition of the renin-angiotensin-aldosterone system along with a heart rate decrease. However, further studies with larger sample sizes and longer-term follow-up are needed to confirm these results, especially as they apply to variables that are clinically and functionally based. Wang et al. (2004) prospectively studied 3346 individuals without CHF from the Framingham Offspring Study. The average age was about 58.5 years with a male:female ratio of about 47:53. The relationship of plasma BNP and NT-proANP to the risk of death from any cause, a first major cardiovascular event, CHF, atrial fibrillation, stroke or transient ischemic attack, and coronary artery disease were analyzed. With a mean follow-up period of 5.2 years, 119 subjects died and 79 had a first cardiovascular event. After adjusting for cardiovascular risk factors, each 1 standard deviation increment in log BNP concentration was associated with a 27% increase in the risk of death (p = 0.009), a 28% increase in the risk of a first cardiovascular event (p = 0.03), a 77% increase in the risk of developing CHF (p < 0.001), a 66% increase in the risk of developing atrial fibrillation (p < 0.001), and a 53% increase in stroke and transient ischemic attack risk (p = 0.002). BNP levels were not associated with the risk of developing coronary artery disease. Multivariate analysis showed that BNP values greater than the 80 th percentile (20.0 pg/ml for men and 23.3 pg/ml for women) were associated with hazard ratios of 1.62 for death (p = 0.02), 1.76 for first cardiovascular event (p = 0.03), 1.91 for an atrial fibrillation diagnosis (p = 0.02), 1.99 for incidence of stroke or transient ischemic attack (p = 0.02), and 3.07 for incidence of CHF (p = 0.002). As for secondary analysis, after adjusting for left ventricular mass, left atrial diameter, and LV systolic dysfunction, the association of BNP with death and the occurrence of a first major cardiovascular event became non-significant. However, BNP was still a significant predictor of the risk of heart failure (p < 0.02) and atrial fibrillation (p < 0.03). The association between BNP values and the risk of transient ischemic attack or stroke remained significant. The authors concluded that plasma natriuretic peptide levels predicted a range of cardiovascular outcomes and provided additional information to that of other established risk factors. The association was strongest for heart failure and atrial fibrillation. Strengths of the study include a large sample size, the comprehensiveness of the multivariate analysis, and the long follow-up period. However, additional investigation is needed in non-framingham study cohorts, in cohorts with pre-existing risk factors such as diabetes or hypertension, and to more precisely define cutoff values for BNP. It is also unknown at this point how elevated BNP values in the general population should affect patient management and the need for further diagnostic testing. Doust et al. (2005) wrote a systematic review detailing the potential for BNP to be used as a predictor of cardiac events and death in patients with heart failure. Nineteen studies that used BNP values to estimate the relative risk of death or other cardiovascular events in heart failure patients and five studies that predicted risk in asymptomatic patients were included in the analysis. In heart failure patients, each increment of 100 pg/ml in BNP values was associated with a 35% increase in the relative risk of death. In 35 multivariate analysis models, BNP or NT-proBNP was the only variable to reach significance as a predictor in nine of them, meaning that other variables did not contain further prognostic information beyond the information provided by BNP/NT-proBNP. The systematic review concluded by stating that Institute for Clinical Systems Improvement 15

18 although systematic reviews of prognostic studies have difficulties such as publication bias (lack of publication of negative results), BNP is a strong predictor of adverse outcomes in both asymptomatic and heart failure patients. Safety of Test Morbidity Rate: Since the test requires only a routine venipuncture, there is a minimal risk of side effects such as minor bleeding or bruising; there were no reported side effects in the literature. Mortality Rate: No mortality has been reported that is associated with collecting the blood sample for analysis. Training and Experience Required to Perform the Procedure: BNP is not stable on a long-term basis and thus needs to be assayed within 2 hours of collection. Conditions and Setting of BNP Testing: The test may be done in nearly any medical setting that has access to a laboratory that is capable of performing the test. A bedside version of the BNP test is also available that provides results in about 15 minutes. In some settings such as flash pulmonary edema, more than one hour may be needed since the onset of symptoms to see elevations in BNP measures (Maisel, 2002). Another study suggested that up to 4 hours after symptom onset may be needed prior to determining BNP levels (Logeart et al., 2002). Factors that Increase the Risk Associated with BNP testing: Other than bleeding or clotting disorders that are significant enough to affect venipuncture, there are no factors that increase the risk of BNP testing. Potential for Inappropriate Use of BNP testing: There remain controversial uses of the BNP test such as how to titrate therapy in response to BNP levels. If used for this purpose, there is the possibility that therapy may be misguided. Other inappropriate uses of the test, such as for population-based screening, may lead to false positives and unnecessary diagnostic procedures. However, widespread abuse of the test appears unlikely. When the patient is being treated with nesiritide for CHF, testing should not be performed during the infusion of the drug as this will confound the BNP levels. Alternative Tests NT-proBNP, the other cleavage product in the genesis of BNP is another neuropeptide that has been studied in relation to diagnostic and prognostic predictive ability. The longer half-life of NT-proBNP (120 minutes vs. 22 minutes for BNP) led to studies of NT-proBNP as an indicator of more meaningful hemodynamic changes, such as with serial measurements every 12 hours (McCullough and Sandberg, 2003). However, NT-proBNP is more influenced by age and renal function than is BNP, and there is a large gray zone for NT-proBNP for which interpretation of results may be difficult. Assays for NTproBNP have also been approved by the Food and Drug Administration, although the cut point for detecting CHF jumps from 125 pg/ml to 450 pg/ml after age 75 years. In addition, in head to head comparisons, BNP has been found to be slightly more accurate than NT-proBNP in diagnosing decreased left ventricular dysfunction (Hammerer-Lercher et al., 2001). Furthermore, due to the greater use of BNP in the literature and the fact that NT-proBNP may not reflect the patient s status at time of examination due to its longer half-life, BNP is typically considered the gold standard natriuretic peptide for clinical applications (McCullough and Sandberg, 2003). Comparative Costs The cost of performing the Biosite Triage BNP bedside testing is small and is of the order of about $50 per assessment. Some laboratory-based BNP assays, used for specialized testing, may cost up to $165. Institute for Clinical Systems Improvement 16

19 Committee Conclusions With regard to B-type natriuretic peptide (BNP) for the screening, diagnosis and monitoring of congestive heart failure (CHF), the ICSI Technology Assessment Committee concludes: 1) The BNP test is safe, requiring only a routine venipuncture. 2) There are no data to support the use of BNP in the general screening of asymptomatic populations for CHF, and thus BNP testing should not be used for this purpose. 3) BNP measurements are useful as an adjunct to other clinical tools for differentiating cardiac (CHF) causes from other causes of dyspnea presenting in the emergency department or urgent care setting. In particular, the diagnosis of CHF is highly unlikely in patients with normal BNP levels. Care should be taken when measuring BNP within 2 to 4 hours after the onset of acute symptoms as false negatives may occur (Conclusion Grade II based on Class A, C, M evidence. See Appendix). 4) The utility of BNP as a tool to optimize management of heart failure or measure treatment response has yet to be defined. Serial testing of BNP levels has not been shown to have clinical utility. Potential Conflict of Interest Disclosure In the interest of full disclosure, ICSI has adopted the policy of revealing relationships work group members have with companies that sell products or services that are relevant to this technology assessment report topic. The reader should not assume that these financial interests will have an adverse impact on the content of the technology assessment report, but they are noted here to fully inform readers. Readers of the technology assessment report may assume that only work group members listed below have potential conflicts of interest to disclose. Dr. George Klee (workgroup leader) had previously received grants from Biosite and Beckman Coulter, both manufacturers of B-type nauriuretic peptide (BNP) test equipment. ICSI's conflict of interest policy and procedures are available for review on ICSI's Web site at. Evidence Grading System Evidence is classed and graded as described below. I. CLASSES OF RESEARCH REPORTS A. Primary Reports of New Data Collection: Class A: Class B: Class C: Class D: Randomized, controlled trial Cohort study Non-randomized trial with concurrent or historical controls Case-control study Study of sensitivity and specificity of a diagnostic test Population-based descriptive study Cross-sectional study Case series Case report Institute for Clinical Systems Improvement 17

20 B. Reports that Synthesize or Reflect upon Collections of Primary Reports: II. Class M: Class R: Class X: Meta-analysis Systematic review Decision analysis Cost-effectiveness analysis Consensus statement Consensus report Narrative review Medical opinion CONCLUSION GRADES Key conclusions (as determined by the work group) are supported by a conclusion grading worksheet that summarizes the important studies pertaining to the conclusion. Individual studies are classed according to the system defined in Section I, above, and are assigned a designator of +, -, or ø to reflect the study quality. Conclusion grades are determined by the work group based on the following definitions: Grade I: The evidence consists of results from studies of strong design for answering the question addressed. The results are both clinically important and consistent with minor exceptions at most. The results are free of any significant doubts about generalizability, bias, and flaws in research design. Studies with negative results have sufficiently large samples to have adequate statistical power. Grade II: The evidence consists of results from studies of strong design for answering the question addressed, but there is some uncertainty attached to the conclusion because of inconsistencies among the results from the studies or because of minor doubts about generalizability, bias, research design flaws, or adequacy of sample size. Alternatively, the evidence consists solely of results from weaker designs for the question addressed, but the results have been confirmed in separate studies and are consistent with minor exceptions at most. Grade III: The evidence consists of results from studies of strong design for answering the question addressed, but there is substantial uncertainty attached to the conclusion because of inconsistencies among the results from different studies or because of serious doubts about generalizability, bias, research design flaws, or adequacy of sample size. Alternatively, the evidence consists solely of results from a limited number of studies of weak design for answering the question addressed. Grade Not Assignable: the conclusion. There is no evidence available that directly supports or refutes References The symbols +,, ø, and N/A found on the conclusion grading worksheets are used to designate the quality of the primary research reports and systematic reviews: + indicates that the report or review has clearly addressed issues of inclusion/exclusion, bias, generalizability, and data collection and analysis; indicates that these issues have not been adequately addressed; ø indicates that the report or review is neither exceptionally strong or exceptionally weak; N/A indicates that the report is not a primary reference or a systematic review and therefore the quality has not been assessed. Anand IS, Fisher LD, Yann-Tong C, et al. Changes in brain natriuretic peptide and norepinephrine over time and mortality and morbidity in the valsartan heart failure trial (Val-HeFT). Circulation 2003;107: (Class A) Berger R, Huelsman M, Strecker K, et al. B-type natriuretic peptide predicts sudden death in patients with heart failure. Circulation 2002;105: (Class B) Institute for Clinical Systems Improvement 18

21 Cardarelli R, Lumicao Jr. TG. B-type natriuretic peptide: a review of its diagnostic, prognostic, and therapeutic monitoring value in heart failure for primary care physicians. J Am Board Fam Pract 2003;16: Cheng V, Kazanagra R, Garcia A, et al. A rapid bedside test for B-type peptide predicts treatment outcomes in patients admitted for decompensated heart failure: a pilot study. J Am Coll Cardiol 2001;37: (Class B) Collins SP, Ronan-Bentle S, Storrow AB. Diagnostic and prognostic usefulness of natriuretic peptides in emergency department patients with dyspnea. Ann Emerg Med 2003;41: (Class R) Cowie MR and Struthers AD. Value of natriuretic peptides in assessment of patients with possible new heart failure in primary care. Lancet 1997;350: (Class C) 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: (Class C) 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: (Class M) Doust JA, Pietrzak E, Dobson A, et al. How well does B-type natriuretic peptide predict death and cardiac events in patients with heart failure: systematic review. BMJ 2005;330:625. (Class M) Emdin M, Clerico A, Clemenza F, et al. Consensus document: recommendations for the clinical use of cardiac natriuretic peptides. Ital Heart J 2005;6: Epshteyn V, Morrison K, Krishnaswamy P, et al. Utility of B-type natriuretic peptide (BNP) as a screen for left ventricular dysfunction in patients with diabetes. Diabetes Care 2003;26: (Class C) Falcao LM, Pinto F, Ravara L, van Zwieten PA. BNP and ANP as diagnostic and predictive markers in heart failure with left ventricular systolic dysfunction. J Renin Angiotensin Aldosterone Syst 2004;5: (Class A) Friis RH, and Sellers, TA. Epidemiology for Publich Health Practice. Gaithersburg, Maryland: Aspen Publishers, Inc (Class R) Grantham JA, Burnett JC Jr. BNP: increasing importance in the pathophysiology and diagnosis of congestive heart failure. Circulation Jul 15;96(2): (Class R) Hammerer-Lercher A, Neubauer E, Muller S, et al. Head-to-head comparison of N-terminal pro-brain natriuretic peptide, brain natriuretic peptide and N-terminal pro-atrial natriuretic peptide in diagnosing left ventricular dysfunction. Clin Chim Acta 2001;310: (Class C) Harrison A, Morrison LK, Krishnaswamy P, et al. B-type natriuretic peptide predicts future cardiac events in patients presenting to the emergency department with dyspnea. Ann Emerg Med 2002;39: (Class C) Hedberg P, Lonnberg I, Jonason T, Nilsson G, Pehrsson K, Ringqvist I. Electrocardiogram and B-type natriuretic peptide as screening tools for left ventricular systolic dysfunction in a population-based sample of 75-year-old men and women. Am Heart J 2004;148: (Class C) Howie JN, Caldwell MA, Dracup K. The measurement of brain natriuretic peptide in heart failure: precision, accuracy, and implications for practice. AACN Clin Issues 2003;14: (Class R) Ishii J, Nomura M, Nakamura Y, et al. Risk stratification using a combination of cardiac troponin T and brain natriuretic peptide in patients hospitalized for worsening chronic heart failure. Am J Cardiol 2002;89: (Class C) Knudsen CW, Omland T, Clopton P, et al. Diagnostic value of B-Type natriuretic peptide and chest radiographic findings in patients with acute dyspnea. Am J Med 2004;116: (Class C) Institute for Clinical Systems Improvement 19

22 Krishnaswamy P, Lubien E, Clopton P, et al. Utility of B-natriuretic peptide levels in identifying patients with left ventricular systolic or diastolic dysfunction. Am J Med 2001;111: (Class C) Logeart D, Saudubray C, Beyne P, et al. Comparative value of Doppler echocardiography and B-type natriuretic peptide assay in the etiologic diagnosis of acute dyspnea. J Am Coll Cardiol 2002;40: (Class C) Logeart D, Thabut G, Jourdain P, et al. Predischarge B-type natriuretic peptide assay for identifying patients at high risk of re-admission after decompensated heart failure. J Am Coll Cardiol 2004;43: (Class C) Lubien E, DeMaria A, Krishnaswamy P, et al. Utility of B-natriuretic peptide in detecting diastolic dysfunction: comparison with Doppler velocity recordings. Circulation 2002;105: (Class C) Maisel A. B-type natriuretic peptide measurements in diagnosing congestive heart failure in the dyspneic emergency department patient. Reviews in Cardiovascular Medicine 2002;3(Suppl 4):S10-S17. (Class R) 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: (Class C) 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 2002;347: (Class C) Maisel AS, McCord J, Nowak RM, et al. Bedside B-Type natriuretic peptide in the emergency diagnosis of heart failure with reduced or preserved ejection fraction. Results from the Breathing Not Properly Multinational Study. J Am Coll Cardiol 2003;41: (Class C) Maisel A, Hollander JE, Guss D, et al. Primary results of the Rapid Emergency Department Heart Failure Outpatient Trial (REDHOT). A multicenter study of B-type natriuretic peptide levels, emergency department decision making, and outcomes in patients presenting with shortness of breath. J Am Coll Cardiol 2004;44: (Class B) McCullough PA, Nowak RM, McCord J, et al. B-type natriuretic peptide and clinical judgment in emergency diagnosis of heart failure: analysis from the Breathing Not Properly (BNP) Multinational Study. Circulation 2002;106: (Class C) McCullough PA, Sandberg KR. Sorting out the evidence on natriuretic peptides. Rev Cardiovasc Med 2003;4 Suppl 4:S (Class R) McCullough PA, Hollander JE, Nowak RM, et al. Uncovering heart failure in patients with a history of pulmonary disease: rationale for the early use of B-type natriuretic peptide in the emergency department. Acad Emerg Med 2003;10: (Class C) McCullough PA. B-type natriuretic peptide and its clinical implications in heart failure. Am Heart Hosp J 2004;2: (Class R) McDonagh TA, Cunningham AD, Morrison CE, et al. Left ventricular dysfunction, natriuretic peptides, and mortality in an urban population. Heart 2001;86: (Class C) Mosterd A, Hoes AW, de Bruyne MC, et al. Prevalence of heart failure and left ventricular dysfunction in the general population; The Rotterdam Study. Eur Heart J 1999;20: (Class C) Mueller C, Scholer A, Laule-Kilian K, et al. Use of B-type natriuretic peptide in the evaluation and management of acute dyspnea. N Engl J Med 2004;350: (Class A) Murdoch DR, McDonagh TA, Byrne J, et al. Titration of vasodilator therapy in chronic heart failure according to plasma brain natriuretic peptide concentration: randomized comparison of the hemodynamic and neuroendocrine effects of tailored versus empirical therapy. Am Heart J 1999;138: (Class A) Institute for Clinical Systems Improvement 20

23 Rodeheffer RJ. Measuring plasma B-type natriuretic peptide in heart failure: good to go in 2004? J Am Coll Cardiol 2004;44: (Class R) Ruskoaho H. Cardiac hormones as diagnostic tools in heart failure. Endocrine Reviews 2003;24: (Class R) Silver MA, Maisel A, Yancy CW, et al. BNP Consensus Panel 2004: a clinical approach for the diagnostic, prognostic, screening, treatment monitoring, and therapeutic roles of natriuretic peptides in cardiovascular diseases. Congestive Heart Failure 2004;10:1-30. Tsutamoto T, Wada A, Maeda K, et al. Effect of spironolactone on plasma brain natriuretic peptide and left ventricular remodeling in patients with congestive heart failure. J Am Coll Cardiol 2001;37: (Class A) 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 2002;288: (Class B) Wang TJ, Larson MG, Levy D, et al. Plasma natriuretic peptide levels and the risk of cardiovascular events and death. N Engl J Med Feb 12;350: (Class B) Wieczorek SJ, Wu AH, Christenson R, et al. A rapid B-type natriuretic peptide assay accurately diagnoses left ventricular dysfunction and heart failure: a multicenter evaluation. Am Heart J 2002;144: (Class C) Yamamoto K, Burnett JC Jr., Bermudez EA, et al. Clinical criteria and biochemical markers for the detection of systolic dysfunction. J Card Fail 2000;6: (Class C) Appendix See next pages Institute for Clinical Systems Improvement 21

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