BNP: Data, Diagnosis and Applications
M Lamberta PGY-3
What are the Biomarkers?
Natriuretic Peptide (NP) assays gained approval by the FDA around the year 2000 for the evaluation of undifferentiated dyspnea and suspected ADHF. The first commercially available test detected the biologically active hormone BNP, but many more recent assays also detect the inert Amino-terminal cleavage product of the BNP prohormone: N-Terminal proBNP (NT-proBNP). (Table 1) Both biomarkers are comparable in their diagnostic accuracy demonstrated by Receiver Operating Characteristic (ROC) curves.
From 1999 to 2000, Maisel et al. recruited 1,586 participants in the first large multinational randomized control trial (RCT) to evaluate BNP for the diagnosis of heart failure in ED patients presenting with acute dyspnea.. The Breathing Not Properly (BNP) study analyzed a subgroup from this cohort to conclude that adding BNP to clinical judgment would have enhanced diagnostic accuracy from 74% to 81%. This trial supported BNP as a good rule-out test for Acute Decompensated Heart Failure (ADHF) with a sensitivity of 90% for BNP < 100 pg/mL when compared to the gold standard: blinded assessment of two independent cardiologists. The authors also argued that BNP ruled-in 14 of the 19 patients that were erroneously diagnosed by clinicians as “CHF improbable,” thereby reducing false negatives from 2% to 0.6%. The improved sensitivity, however, inevitably reduced specificity to near 74% for a cut-off of BNP ≥100 pg/mL.  Furthermore, a secondary analysis pointed out the limited application of this biomarker as clinical judgment seemed to outperform BNP assay when applied to the dyspneic patient at the extremes of pretest probability ie greater than 95% or less than 5% certainty of ADHF.  Therefore, a higher rule-in threshold (BNP > 500 pg/mL improved specificity of this assay but also opened up a “gray-zone” in the interpretation of BNP where the test could neither rule-in nor rule-out with good certainty.
By the mid-2000s, the rule-out and rule-in cut-offs for CHF began to gain modest support by professional organizations including ACEP.  Wang et al. contributed to JAMA’s Rational Clinical Examination series by conducting a meta-analysis of these preceding data in addition to 20 smaller studies on BNP to determine Likelihood ratios for BNP. The meta-analysis calculated a negative likelihood ratio (LR-) near 0.9 (cut-off <100 pg/mL) again promoting BNP as a strong test to rule-out ADHF. Yet, comparing BNP to patient history “significant for heart failure” (LR+ 5.8) or “interstitial edema” on chest X-Ray (LR+ 12), BNP stood as an equivocal test to rule-in HF with LR+ 2.7 (≥100 pg/mL).
In the later 2000s, large RCTs would similarly establish the accuracy of NT-proBNP in ADHF. The PRIDE (N-Terminal Pro-BNP Investigation of Dyspnea in the Emergency Department) constructed ROC curves to conclude that adding NT-proBNP to the evaluation of patients with dyspnea was superior to clinician-estimated likelihood of CHF alone with area under the curve (AUC) measuring 0.90 for clinician alone versus 0.94 for clinician+NT-proBNP, (p = 0.006). The Canadian IMPROVE-CHF study affirmed similarly that adding NT-proBNP to clinical judgment alone increased the AUC from 0.83 to 0.90. 
Despite showing statistical differences in diagnostic accuracy through Receiver-Operator Characteristic Curves, the application of natriuretic peptides did not appear to add much to clinical judgement at the extremes of pre-test probability, so many began to apply it to patients who were considered intermediate pretest probability (21% to 79%) or under circumstances of competing diagnoses ie COPD vs PNA vs CHF. Steinhart et al. attempted to better stratify these “intermediate probability” patients by deriving an algebraic model that capitalized on increased positive likelihood ratios at higher absolute levels of NT-proBNP. In a validation study, this model appeared to correctly reclassify 44% of the “intermediate” patients to either low risk or high risk. The strength of this approach is that it provides for practical application of NT-proBNP as a continuous variable rather than just relying on discrete cut-offs, it accounts for age-adjusted variability, and it prompts the clinician to appropriately consider pre-test probability before interpreting the test result. The weakness lies in the fact that it requires math (yet, an excel model is available for download here), and it does not appear to approve diagnostic accuracy in a majority of cases. In this study, the model helped to correctly reclassify 10% of the study participants. [8,9]
When NPs came to the scene 15 years ago the hope was that it would be the “super-hero” for the bewildered clinician in the diagnosis of dyspnea, but subsequent trials and meta-analyses gave BNP the persona of more of a “yes-man” supporting what the clinician already knew and equivocating just as much for cases of “intermediate probability.” The literature of the last 15 years has elucidated NP test characteristics, confounding variables (Tables 1 and 2), and interpretation, but application of the test still appears rather heterogeneous by anecdote as either a rule-in, rule-out, adjudicator, or prognosticator.
- Ruling-in low-probability: BNP as a rule-in test to diagnose patients who are being treated erroneously for other conditions ie a 65-year-old patient with a history of COPD but no current diagnosis of HF. Rosen even suggests “we abandon the routine obtaining of a BNP level for patients deemed to be having a CHF flare-up, and instead consider it in all dyspnea patients that we don’t believe are having CHF.”  This implies a sentiment of screening. In an older population, where prevalence is higher, it may be a good consideration.
- Ruling-out high-probability: As expenditures for heart failure continue to soar, the use of BNP, in concert with other clinical signs and adjunct studies, may have significant application for ruling-out ADHF in known HF patients. This may lead to scoring protocol or institutional decision rules to help identify ED patients who are safe for outpatient management.
- Adjudicating intermediate risk: Likely BNP will continue to find application case-by-case by the ED clinician who is interested in detecting the presence of heart strain whether it will change management or not. Interpretation of BNP should be considered after establishing pre-test probability for the patient, with the knowledge of confounding variables, and can employ tools to interpret the test like that proposed by Steinhart et al. (available for download here). That said, the same cases of intermediate probability will more likely represent the complex and sicker patients requiring longer hospital stays and extended work-ups and more than half the time the knowledge of BNP will unlikely help to narrow the diagnosis. 
- Prognosticating: Elevated BNP almost always suggests a poor prognosis whether it is used to stratify ADHF, NSTEMI, or PE, but prognosis is often more accurately reflected—and more easily assessed—by patient hemodynamics and renal perfusion. [11,12,13] There is no strong evidence that BNP will consistently help an admitting team in their management, but there is still ongoing research discerning how BNP may help in response-guided therapy and discharge planning.
- Outcomes: Only a handful of randomized controlled trials have measured changes in outcomes for clinicians who use natriuretic peptide assays in the ED. Meta-analyses of these trials have shows trends towards decreased cost and length of stay, but no reproducible significant difference in these outcomes or in regards to therapy or mortality. [14,15]
- 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;347:161-167.
- McCullough PA, Nowak RM, McCord J, et al. B-type natriuretic peptide and clinical judgment in emergency diagnosis of heart failure: analysis from Breathing Not Properly (BNP) Multinational Study. Circulation 2002;106:416–22
- Schwam E. B-type natriuretic peptide for diagnosis of heart failure in emergency department patients: a critical appraisal. Acad Emerg Med. 2004;11:(6)686-91.
- Silvers SM, Howell JM, Kosowsky JM, Rokos IC, Jagoda AS. Clinical policy: critical issues in the evaluation and management of adult patients presenting to the emergency department with acute heart failure syndromes. Ann Emerg Med 2007;49:627–69. (BNP Clinical Policy) http://www.acep.org/workarea/DownloadAsset.aspx?id=8778
- Wang CS, FitzGerald JM, Schulzer M, Mak E, Ayas NT. Does this dyspneic patient in the emergency department have congestive heart failure? JAMA 2005;294:1944–56
- Januzzi JL Jr, Camargo CA, Anwaruddin S, et al. The N-terminal Pro-BNP Investigation of Dyspnea in the Emergency Department (PRIDE) study. Am J Cardiol. 2005;95:948-954.
- Moe GW, Howlett J, Januzzi JL, Zowall H, for the Canadian Multicenter Improved Management of Patients With Congestive Heart Failure (IMPROVE-CHF) Study Investigators. N-terminal pro-B-type natriuretic peptide testing improves the management of patients with suspected acute heart failure: primary results of the Canadian prospective randomized multicenter IMPROVE-CHF study. Circulation 2007;115:3103–10
- Emergency Medicine Journal Club. Does BNP Augment Acue Decompensated CHF ED Management. WUSM-St. Louis. Journal Club November, 2009. http://emed.wustl.edu/education/EmergencyMedicineJournalClub/Archive/November2009.aspx
- Steinhart B, Thorpe KE, Bayoumi AM, Moe G, Januzzi JL, Mazer CD. Improving the diagnosis of acute heart failure using a validated prediction model. J Am Coll Cardiol 2009;54:1515–21.
- Carpenter CR, Keim SM, Worster A, Rosen P, BEEM (Best Evidence in Emergency Medicine). BRAIN NATRIURETIC PEPTIDE IN THE EVALUATION OF EMERGENCY DEPARTMENT DYSPNEA: IS THERE A ROLE? The Journal of Emergency Medicine. 2012;42(2):197-205.
- Heeschen C, Hamm CW, Mitrovic V, et al. N-terminal pro-B-type natriuretic peptide levels for dynamic risk stratification of patients with acute coronary syndromes. Circulation. 2004 Nov 16. 110(20):3206-12.
- Binder L, Pieske B, Olschewski M, et al. N-terminal pro-brain natriuretic peptide or troponin testing followed by echocardiography for risk stratification of acute pulmonary embolism. Circulation. 2005 Sep 13.
- Singer AJ, Birkhahn RH, Guss D, et al. Rapid Emergency Department Heart Failure Outpatients Trial (REDHOT II): a randomized controlled trial of the effect of serial B-type natriuretic peptide testing on patient management. Circ Heart Fail 2009;2:287–93.
- Trinquart L, Ray P, Riou B, Teixeira A. Natriuretic peptide testing in EDs for managing acute dyspnea: a meta-analysis. Am J Emerg Med. 2011;29:(7)757-67
- Lam LL, Cameron PA, Schneider HG, et al. Meta-analysis: effect of B-type natriuretic peptide testing on clinical outcomes in patients with acute dyspnea in the emergency setting. Ann Intern Med 2010; 153: 728−735.
LB Daniels, AS Maisel. Natriuretic Peptides. J Am Coll Cardiol. 2007 Dec 18. 50(25): 2357-68. (Tables 1-2)
JM Kosowsky, JL Chan. Acutely Decompensated Heart Failure: Diagnostic and Therapeutic Strategies. EB Medicine Review (2006). https://www.ebmedicine.net/topics.php?paction=showTopic&topic_id=87
Mueller TT. Head-to-head comparison of the diagnostic utility of BNP and NT-proBNP in symptomatic and asymptomatic structural heart disease.. Clinica chimica acta. 2004-03;341:41-48.