B-type Natriuretic Peptide for Diagnosis of Heart Failure in Emergency Department Patients: A Critical Appraisal

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1 686 Schwam d BNP FOR DIAGNOSIS OF HF B-type Natriuretic Peptide for Diagnosis of Heart Failure in Emergency Department Patients: A Critical Appraisal Abstract The diagnosis of heart failure in the outpatient setting can be difficult. A rapid assay for B-type natriuretic peptide (BNP) has been advocated for the diagnosis of heart failure, using a single cutoff of 100 pg/ml. BNP is produced by both the right and left cardiac ventricles and is elevated in a variety of conditions, including heart failure, pulmonary hypertension, cor pulmonale, pulmonary embolism, left ventricular hypertrophy, renal failure, circulatory overload, Eric Schwam, MD acute coronary syndromes, atrial fibrillation, lung cancer, and sepsis. This multitude of causes of BNP elevation imposes limits on its diagnostic use for heart failure. The literature on the use of BNP testing for diagnosis of heart failure is reviewed, and improved guidelines for its interpretation are suggested. Key words: heart failure; B-type natriuretic peptide; BNP testing. ACADEMIC EMER- GENCY MEDICINE 2004; 11: The clinical diagnosis of heart failure (HF) can be difficult. 1 Although echocardiography can be very helpful in this regard, its use in the acute setting is often limited by lack of availability and by technical factors. A rapid test for B-type natriuretic peptide (BNP) (Biosite, San Diego, CA) has become available to aid in the clinical diagnosis of HF. The latest (2001) American College of Cardiology/American Heart Association Guidelines on the evaluation and management of HF have stated that more research was needed to determine the place of BNP testing. 2 This article explores the question of whether the assay for BNP is a useful test for the diagnosis of HF in emergency department (ED) patients based on literature review and analysis. STUDY SELECTION A literature search of Medline (accessed October 20, 2003, and limited to human studies published in English) using the PubMed interface was conducted. The search strategy congestive heart failure and ( BNP or natriuretic peptide or natriuretic peptide brain or natriuretic peptide type b ) and ( dyspnea or emergency department ) yielded 55 From the Emergency Care Center, Sturdy Memorial Hospital, Attleboro, MA, and Department of Medicine, Division of Emergency Medicine, Brown University School of Medicine, Providence, RI (ES). Received September 30, 2003; revision received October 23, 2003; accepted December 2, Address for correspondence: Eric Schwam, MD, Emergency Care Center, Sturdy Memorial Hospital, P.O. Box 2963, 211 Park Street, Attleboro, MA schwam@massmed.org. Reprints are not available. doi: /j.aem articles. The abstracts of these articles were scanned for clinical studies that enrolled ED patients with dyspnea and reported sensitivities and specificities for the diagnosis of HF by the triage BNP test. Ten articles met these specifications and were reviewed further. The largest trial was the Breathing Not Properly (BNP) Multinational Study reported by Maisel et al. 3 Of the other articles, four described subsets of the BNP Multinational Study patients, 4 7 two were pilot studies by members of the same research group, 8,9 and three were published by other groups The 250 convenience patients in the study by Dao et al. 8 served as the pilot study for the Multinational Study group, and Morrison et al. 9 reported on 321 similar patients. The study sites and patient enrollment dates of Dao s study were encompassed by those of Morrison s study, and both were encompassed by those of the Multinational Study. Maisel et al. have confirmed in an on October 30, 2003, that Dao s patients were, in fact, a subset of Morrison s but maintain that they were not included in the Multinational Study, because of a possible error in the publication of the latter s enrollment dates. The other Multinational Study subset articles were reviewed, but they did not contribute additional relevant information. Ultimately, six articles were included for further analysis: two from the Multinational Study, 3,4 and the studies by Morrison et al., 9 Villacorta et al., 10 Lainchbury et al., 11 and Logeart et al. 12 A systematic, quantitative synthesis of all data was precluded because only two studies (the Multinational Study 3,4 and Lainchbury et al. 11 ) met the criteria of being a prospective study of ED patients, defined by explicit and applicable inclusion criteria with blinded assessment of diagnosis using

2 ACAD EMERG MED d June 2004, Vol. 11, No. 6 d high-quality criterion standard for HF. Accordingly, instead of presenting the data in aggregated fashion, each study must be individually summarized and critically analyzed to allow a summary recommendation. ARTICLE SUMMARIES The BNP Multinational Study 3 included 1,586 patients from seven sites in three countries. Eligible patients were over 18 years of age seen in an ED or urgent care clinic with a complaint of shortness of breath as the most prominent symptom. The authors explicitly excluded patients with acute myocardial infarction, renal failure, trauma, or cardiac tamponade, as well as patients with unstable angina unless their predominant symptom at presentation was dyspnea. Young patients with a history of asthma were also excluded at some centers (Maisel AS, written communication, Oct 28, 2003). Emergency physicians (EPs) were blinded to BNP levels. They treated patients in standard fashion and recorded their estimates of the probability of HF (from 0 to 100% by deciles). The criterion standard for patient diagnosis was determined by two cardiologists who reviewed all clinical information, including prior medical records and subsequent testing. They were also blinded to the BNP levels and the ED diagnosis. Patients were categorized as having 1) dyspnea due to HF (47%), 2) dyspnea not due to HF (49%), or 3) left ventricular dysfunction with dyspnea not due to HF (5%). For a binary analysis of HF versus non-hf, groups 2 and 3 were combined, as was appropriate. The two cardiologists independently agreed on the final diagnosis 90% of the time, and the other 10% were adjudicated by a panel that sought consensus. The BNP measurements were made in triplicate, and the average value was reported (up to 1,300 pg/ml, the test s maximum validated value at the time). No details of the non-hf diagnoses were provided, other than the statement that 21 patients were considered to have cor pulmonale. The investigators also reported the subset of patients (1,538 of 1,586) in whom the treating EPs had estimated (by deciles) the clinical probability of HF (using history, physical, electrocardiography [ECG], radiology, and other routine laboratory tests). 4 They divided the physician estimates into groups of low (0 20%), intermediate (21 79%), and high (80 100%) pretest probability of HF. The authors concluded that a BNP of 100 pg/ml with a positive likelihood ratio (LR) of 3.8 (95% confidence interval [95% CI] = 3.3 to 4.2) was the optimal cutoff for diagnosis of HF. Using logistic regression, the authors also constructed an HF nomogram that combined clinical judgment and specific BNP levels. Among patients who had a clinical probability estimate for HF recorded, a BNP greater than 100 pg/ ml produced a binary positive LR of only 3.4 (95% CI = 3.1 to 3.9), which would confer a clinically insignificant revision in diagnostic certainty for low intermediate probabilities. However, if the EP was % certain of the diagnosis of HF, the positive LR was 11.5 (95% CI = 8.6 to 17.1). Although this is excellent, it applies to only a limited number of patients. In an attempt to combine clinical judgment with BNP testing, the investigators chose a strategy of incorporating a high pretest probability or BNP greater than 100 pg/ml, although the advantage of the combined strategy had a similar positive LR of 3.2 (95% CI = 2.8 to 3.5) as using a BNP cutoff of 100 pg/ ml alone. With the application of either the derived HF nomogram or the standard Fagan nomogram relating disease probability and LRs, 13,14 it can be shown that patients with either very high or low probabilities of HF require substantially contrary BNP values to cast doubt on the clinical diagnosis and extremely discordant (and improbable) BNP values to completely alter it. Patients within the authors intermediate probability group also require very high or low BNP levels to establish or exclude a diagnosis of HF. A cutoff of 100 pg/ml is not useful in any of these situations. Morrison et al. 9 reported on 321 convenience patients presenting to the ED and urgent care center of a single medical center. Two hundred fifty of these patients were also described by Dao et al. 8 The methods were similar to those of the Multinational Study, because this was a pilot study for the latter. Forty-two percent of patients were diagnosed with HF. A breakdown of non-hf diagnoses was provided, as well as a table of sensitivities and specificities. The area under the curve (AUC) was Morrison s data may have been subject to significant selection bias, because the first 250 of the 321 patients enrolled represented only 57% of those eligible. 8 Morrison and colleagues sensitivities for BNP are similar to the other studies, but their specificities are much higher. This might be accounted for by their practice of counting all 28 patients with cor pulmonale (mean BNP pg/ml) as having HF. Villacorta et al. 10 studied 70 consecutive patients presenting to the ED of a single referral cardiology hospital in Brazil. The EPs and the adjudicating cardiologist were both blinded to the BNP data. Patients with HF and another disease were categorized as having HF. Fifty-one percent of patients had HF as a cause of their dyspnea. A breakdown of non- HF diagnoses was provided, but only one (post hoc) cutoff was reported; a BNP of 200 pg/ml was 100% sensitive and 97% specific for the diagnosis of HF. The results from the study by Villacorta et al. are unusually impressive, to the extent of being an outlier in relation to the other studies. Several factors (including the small sample size) may account for this. Seventy-two percent of the HF patients were in NYHA Class 4, as opposed to 17% of the Multinational Study

3 688 Schwam d BNP FOR DIAGNOSIS OF HF patients. The greater severity of HF would result in higher BNP values, which may explain the higher sensitivity. Patients with HF and another cause for dyspnea were classified as having HF, which artificially elevates the specificity. Lainchbury et al. 11 studied 205 nonconsecutive ED patients presenting with dyspnea to a New Zealand hospital for a study comparing multiple BNP assays. A panel of adjudicating cardiologists was blinded to BNP data. The AUC for the triage BNP test was reported at 0.89, very similar to the Multinational Study. They selected a post hoc optimum cutoff of 208 pg/ml, which had a sensitivity of 94%, a specificity of 70%, and a positive LR of 3.1 (95% CI = 2.4 to 4.0). In an echocardiography study at a single hospital in France, Logeart et al. 12 enrolled 235 consecutive patients admitted through the ED with severe dyspnea. Seventy-two patients were excluded for mostly technical reasons; of the remaining 163 patients, 90% were admitted to the intensive care unit and 21% required mechanical ventilation. The admitting physician and a panel of two cardiologists and a pulmonologist who were blinded to BNP assigned each patient a diagnosis. Seventy percent of the patients had HF, 23% had decompensated lung disease, and 7% had pulmonary embolism. For HF, the AUC was 0.93, and multiple cutoffs were reported. The authors found that a BNP of 80 pg/ml was 97% sensitive but only 27% specific for the diagnosis of congestive HF. They concluded that BNP results between 80 and 300 pg/ml were nondiagnostic, but that a level more than 300 was due to either HF or a severe pulmonary embolism. Although the sensitivity of BNP for the diagnosis of HF (at 100 pg/ml) was 96% (95% CI = 93% to 99%) overall, in the 12 patients presenting with less than four hours of dyspnea, the sensitivity declined to 71% (95% CI = 47% to 95%), illustrating that in flash pulmonary edema, BNP elevations to diagnostic levels may be delayed by several hours. This patient population does not represent the majority of patients evaluated for possible HF in most EDs. Large numbers of patients were excluded, the prevalence of HF was exceedingly high, and the severity of illness of the patient population was higher than in other studies. ANALYSIS Despite their varied patient populations, the receiver operating characteristic (ROC) curves and AUCs generated by the Multinational Study, Lainchbury et al., and Logeart et al. are quite similar. However, these authors come to very different conclusions regarding the optimal application of BNP testing. Consequently, I propose the following analytic protocol to define the rational use for the BNP assay in the diagnosis of HF: 1. The diagnostic accuracy of EPs estimates of HF should first be evaluated for each decile. From this, one could determine those patients for whom clinical acumen is sufficiently accurate so that BNP testing is noncontributory. The patients whose probability estimates are either indecisive or imprecise are the population for which BNP is potentially helpful. This range of probabilities (10 90%, 20 80%, etc.) is the zone of diagnostic uncertainty Interval LRs should be calculated. With continuous data such as BNP levels, much diagnostic information is lost when applying a single cutoff LR. For example, given a BNP cutoff of 100 pg/ ml, it is intuitively obvious that levels of 101 and 1300 pg/ml have vastly different clinical implications. A better approach uses LRs calculated for various interval ranges ( pg/ml, pg/ml, etc.). These interval LRs more accurately reflect the diagnostic significance of values within intervals than does the single binary cutoff. 16 This process will be performed for all three studies. 3. Upper and lower interval cutoffs could then be selected to obtain optimal positive and negative LRs with consideration of the consequences of over- and underdiagnosis. 4. The percentage distribution of BNP levels into the diagnostic and nondiagnostic groups could be calculated to determine how often the test provides useful information. 5. After these cutoffs have been determined, ideally, they should be validated in a second prospective study. Because the Multinational Study raw data set was not available for this analysis, it could be conducted only on published information. CLINICAL JUDGMENT The EPs estimates of the probability of HF were calculated from the data in McCullough et al. 4 and are shown in Table 1. When the pretest probability of HF was judged to be very high (95 100%), then the actual rate of HF was 95%. When the pretest probability of HF was judged to be very low (0 4%), the actual rate of HF was 7%. It may seem that a substantial (7%) rate of misdiagnosis was seen in patients in whom physicians were certain that HF was absent. However, it must be remembered that the average patient age was 64 years, and most young patients were explicitly excluded from the study, so for an unselected patient population overall, a 0 4% pretest probability estimate of HF is likely very accurate. Thus, for pretest probabilities of 0 4% or %, BNP testing is unnecessary and, as Table 1 also shows, actually performs worse than clinical judgment. For all other pretest probabilities (5 94%), however, clinical

4 ACAD EMERG MED d June 2004, Vol. 11, No. 6 d TABLE 1. Calculations from Multinational Study Data: Emergency Physician Estimate of Probability of Heart Failure (HF), Compared with Actual Rate of HF ED Estimate of Probability of HF (%)* Actual Rate of HF in Group (%) Accuracy of Clinical Diagnosis (%) Accuracy of BNP (100 pg/ml cutoff) (%) Percent of Total Patients in Group (%) NA NA NA Comparison of accuracy of clinical diagnosis and B-type natriuretic peptide (BNP) for diagnosis of HF. Data calculated from Ref. 4 *The authors allocated the physician estimates of 0%, 10%, 20%, 30%, etc., to bins of 0 9%, 10 19%, 20 30%, etc., but the proper allocation is 0 4%, 5 14%, 15 24%, 25 34%, etc., which is what is used here. NA = data not available. judgment alone is insufficiently accurate, and further testing is required. The ideal diagnostic test would give definitive results for patient presentations covering the entire range of pretest probabilities for the target disease. Unfortunately, many real-world diagnostic tests give definitive results for the extremes of pretest probability but more equivocal answers for patients with intermediate pretest probabilities. In this regard, BNP is no exception. The author compared BNP results from all patients with those in the intermediate (20 80%) pretest probability group. For all patients (using the 100 pg/ml cutoff), the positive LR was 3.4, but for the intermediate group, the sensitivity and specificity were 88% and 55%, respectively, giving a lower positive LR of 2. Thus, in the patients in whom the test has the greatest potential diagnostic benefits, it tends not to give definitive results. SPECTRUM BIAS Many patients with very low pretest probability may have been excluded from the test population, whereas most patients with very high pretest probability were included. If, in clinical practice, one would not order a BNP test on a patient with clinically obvious HF, then such a patient should not be included in the test population. This spectrum bias would be expected to inflate the sensitivity. Because only 7% of the test population fell into the % pretest probability group, the magnitude of this spectrum bias may be limited. INTERVAL LIKELIHOOD RATIOS Hohl et al. 17 calculated interval LRs for the Multinational Study data set. I calculated two additional interval LRs for this study 18,19 and for the data from Lainchbury et al. and Logeart et al. (Table 2). Despite the differing patient populations, the results are remarkably similar. BNP levels less than pg/ ml effectively rule out the diagnosis of HF. Levels between 400 and 1,000 pg/ml have moderate ability to diagnose HF, and with levels more than 1,000 pg/ ml, there is a large likelihood of HF. The BNP levels between 80 and 400 pg/ml have little utility for the diagnosis of HF. Overall, these results are consistent with those generated by application of the HF and Fagan nomograms and with the pathophysiological data showing that many diseases cause BNP levels in this range. CUTOFFS The most meaningful way to use BNP would be to combine an accurate pretest probability with an interval LR to generate a posttest probability using TABLE 2. Calculated Interval Likelihood Ratios for Diagnosis of HF by BNP BNP Range (pg/ml) LR (95% CI) 28 Multinational Study 3 \ ( )* ( ) ( ) ( ) ( ) ( ) 400 1,000 18, ( ) [1, (10 26)* Lainchbury et al. 11 \ ( )* Indeterminant ( ) ( ) ( ) [ ( ) Logeart et al. 12 \ ( ) ( ) ( ) Indeterminant ( ) ( ) ( ) [ (4 33)* LR $5 or#0.2 (test result produces moderate shifts in disease probability). *LR $10 or #0.1 (test result produces large shifts in disease probability). HF = heart failure; CI = confidence interval; BNP = B-type natriuretic peptide; LR = likelihood ratio.

5 690 Schwam d BNP FOR DIAGNOSIS OF HF simple mathematics or the Fagan nomogram. Because this method is not currently feasible, an acceptable alternative might be to select upper and lower cutoffs to balance the consequences of over- and underdiagnosis of HF and its differentials and to consider the meaning of a result in the gray zone. To rule out HF, a lower cutoff of pg/ml has excellent diagnostic value with a negative LR of This finding virtually rules out HF in all patients with low or intermediate pretest probabilities. Selection of the upper cutoff is more problematic. The lowest acceptable limit would be 400 pg/ml, with an associated positive LR of about 5. Recently, several Multinational Study investigators have also suggested or 500 pg/ml 20 as the upper limit. The 1,000- pg/ml cutoff has a positive LR of 16.5, which is excellent. Although data for intermediate levels are not available, the linearity of the ROC curve between 400 and 1,000 pg/ml suggests that the interval LR remains about 5 between these two values. 3,21 Thus, there is no diagnostic advantage to using a value between 400 and 1,000 pg/ml, suggesting that 400 pg/ml is the preferred cutoff. In deciding on the optimal cutoff, it is helpful to consider the consequences of a false-positive diagnosis of HF. Both pulmonary embolism 22 and sepsis 23 can produce BNP concentrations well above 1,000 pg/ml. If the pretest probability of either disease is intermediate to high, then even an extremely elevated BNP cannot discriminate these from HF, and no cutoff is adequate. Failure to treat either sepsis or pulmonary embolism would have substantial adverse effects. GRAY ZONE It is instructive to consider the diagnostic contents of the gray zone between 50 and 400 pg/ml: HF, asymptomatic left ventricular dysfunction, 24 chronic pulmonary hypertension, 9 myocardial ischemia, 25 atrial fibrillation, 26 pulmonary embolism, 22 left ventricular hypertrophy, 27 lung cancer, 9 renal failure, 7 sepsis, 23 and a small percentage of healthy elders. 27 The next step in this analysis is to tabulate the percentage of BNP values that fall above and below the cutoffs and within the pg/ml nondiagnostic gray zone. In the Multinational Study, 40% of all BNP values fell within the nondiagnostic range, and roughly 50% of patients with HF were also in this zone. As a diagnostic test, BNP may be analogous to the ventilation perfusion scan, in which normal and high-probability scans are very useful, but most scans are indeterminate. Sometimes, the physician will find the BNP assay to be very helpful, but at least 40% of the time, it will be inconclusive. CONCLUSIONS B-type natriuretic peptide is a useful test for the clinical diagnosis of HF, but its limitations must be understood to apply it properly. Using the history, physical examination, electrocardiography, and chest radiography, physicians in the ED setting can accurately categorize many patients with very low (0 4%) or very high (95 100%) pretest probability of HF, where no further testing can be justified. For patients with intermediate probability estimates (5 94%), BNP levels under pg/ml have good ability to rule out HF. A BNP level above 400 pg/ml has moderate ability, and a BNP of more than 1,000 pg/ml has substantial ability to rule in the diagnosis of HF. However, sepsis and pulmonary embolism can also cause levels above 1,000 pg/ml. For these reasons, at least 40% of the time, BNP testing will be nondiagnostic. References 1. Badgett RG, Lucey CR, Mulrow CD. Can the clinical examination diagnose left-sided heart failure in adults? 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