BNP Level in the Emergency Department: Does it Change Management?

Authors: Michael Lamberta, MD (@EMLamberta, EM Senior Resident Physician, Jacobi / Montefiore Medical Center, Bronx, NY) and Andrew Chertoff, MD (@AChertoff, Site Director, EM Attending, Montefiore Medical Center) // Edited by: Jennifer Robertson, MD, MSEd and Alex Koyfman, MD (@EMHighAK, EM Attending Physician, UTSW / Parkland Memorial Hospital)

Background

Evaluating the acutely dyspneic patient conjures a range of differential diagnoses and treatment algorithms.  Often a simple history will suggest the etiology, such as a patient with a 50 pack- year history of smoking, on home oxygen (O₂), with worsening cough and accessory muscle use. Other examples include the nursing home patient who aspirated a day ago and is now febrile, or the patient with a history of heart failure (HF) who ran out of his daily furosemide. On the other hand, patients with multiple comorbidities, overlapping signs and milder symptoms can generate diagnostic uncertainty when evaluating dyspneic patients in the Emergency Department (ED).

What is BNP?

Brain or B-Type Natriuretic Peptide (BNP) is an What is BNP?

Brain or B-Type Natriuretic Peptide (BNP) is an endogenous peptide hormone secreted from ventricles that have elevated end-diastolic pressure or increased ventricular volume.   Release of this peptide into circulation cues systemic effects and mediates the neurohormonal responses of Acute Decompensated Heart Failure (ADHF).

Pearl: Nesiritide is recombinant BNP that has been studied for the treatment of ADHF.

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. [1] Fifteen years after their commercial introduction, these biomarkers are now a routine part of ED dyspnea order sets, but have we seen this translate into a change in patient management?

Pearls:

• The half-life of NT-proBNP is 4-5x longer than BNP contributing to higher diagnostic cut-offs of NT-proBNP.
• NT-proBNP proceeds through renal clearance, whereas BNP is neutralized. Although both are elevated in renal failure NT-proBNP is more sensitive to decrease in GFR.
• Nesiritide will be detected through BNP assay, but will not confound NT-proBNP testing,

Case cont:

Physical Exam

Vital signs: Temperature (T)98.2° Farenheit (F), Pulse (P) 106 beats per minute (bpm),         Blood pressure (BP) 150/100, respiratory rate (RR) 24, Oxygen saturation 93% on     room air (RA)

General: Obese 167 kilograms (kg), sitting up in stretcher in mild distress

Neck: Jugular venous distention (JVD) evaluation limited by body habitus

Pulmonary: Visibly SOB, Decreased breath sounds at bases. No wheezing.

Cardiovascular: tachycardic and irregular

Abdomen:    Obese, non-tender (NT)

Extremities:    Full range of motion at joints, no effusions. 2+ pitting edema up to knees.

Neurological: Alert & Oriented x3, Speech fluent

Do Natriuretic Peptides (NPs) Improve Diagnosis in the ED?

Since 2001, multiple trials have sought to establish the diagnostic accuracy of NPs relative – and in addition – to routine physician evaluation. While these studies do not specifically address the effects of NP testing on patient management, it has been shown that NPs add little value to an Emergency Physician (EP)’s diagnosis of heart failure.  This is best expressed in a review on heart failure that concluded, “For patients with classic signs of ADHF (i.e. prior episodes of ADHF, volume overload, dyspnea, and orthopnea) or those with shortness of breath consistent with other etiologies (i.e. asthma, COPD), BNP is not likely to assist in the diagnostic workup. Checking BNP levels in indeterminate cases may aid in diagnosing or excluding ADHF, but results may leave the EP with additional questions.”[2]  Several derivation trials and associated analyses also support this conclusion [3,4,5,6,7,8]. Still, this is not to say that NPs have no utility in patient evaluation, especially in more equivocal cases.

What are the outcomes?

As emergency physicians, we should recognize how the potential application of a test may change patient management plans and outcomes, and/or contribute to societal costs.

Most conversation about NPs extrapolates on anecdotal evidence. Without a standardized use, it is difficult to study how knowledge of NP biomarkers may influence the outcomes of a patient’s clinical course.  Accordingly, there have only been 7 large randomized controlled trials (RCTs) evaluating how clinician’s knowledge of NP results may have an effect on patient outcomes. [4,9,10,11,12,14,15]  In addition, these RCTs have largely evaluated patient disposition, length of stay, cost of care, 30-day re-admissions, and mortality.

Does BNP change disposition?

The B-type Natriuretic Peptide for Acute Shortness of Breath EvaLuation (BASEL) was one of the earliest RCTs to evaluate outcomes.  The study found a reduction in percentage of admissions 85% vs 75% in the BNP group, and similar reduction in ICU admission 24% vs 15%.  The authors did not provide data about baseline history of heart failure between groups, but found similar final diagnoses of heart failure (45% BNP group, 51% Control group).  There was, however, a significant difference in the number of patients ultimately diagnosed with chronic obstructive pulmonary disease (COPD) in the test group (23% vs 11%), which raises the issue of potential selection bias.  One would think with proper randomization, the discharge diagnoses between groups would be similar, but that knowledge of BNP may decrease time to make the diagnosis.  Yet, this significant difference in final diagnosis between groups may have contributed to the length of stay, especially if COPD patients recovered faster. [9] Another study in the Netherlands found that the ED clinician’s knowledge of NT-proBNP showed a similar trend, although not statistically significant, toward decreased admission rates in the BNP group (62% vs 67%).  However, this sample represented a younger cohort (mean age 58.2 years), and the admission rates of 62 and 67% were, overall, comparatively lower than other studies. [10] Several other studies recruited patients with mean ages of (65-74) and reported higher overall admission rates of 85-90%.  These older populations consistently showed no statistical difference in admission rates between the BNP and non-BNP groups. [4,11,12,14,15] These results likely reflect the reality that when older patients present to the ED with acute dyspnea, they are often sicker. Thus, the majority will require admission regardless of cause and the outcomes of BNP testing.

Does BNP testing decrease length of stay?

The provocative BASEL study further demonstrated a significant decrease in time to discharge for patients who received BNP testing (8 vs 11 days). [9]  A cohort in the Netherlands yielded somewhat equivocal results with a 2-day decrease (1.9 vs 3.9) in “time to discharge” from entry to the ED, but this study did not find a significant difference in the length of stay for admitted patients.  Three subsequent studies and a meta-analysis of available data could not find any significant difference in length of stay for patients evaluated by NT-proBNP. [4,11,12,13,14,16]

Does it Save Money?

It is not surprising that the 2 RCTs that found decreased time until discharge also found a decrease in the cost per patient (Rutten et al. and BASEL).  As shorter hospital stays will lower the bill, the trials that showed decreased time in hospital in the BNP group also found an average savings just above $1,000. [9,10]  Moe et al. also measured a savings of approximately $1,000 despite no difference in length of stay (LOS), but perhaps accounted for by the decreased number of readmissions (35%) over 60 days.  It should be noted, however, that the lead author received significant funding from Roche Diagnostics, which is the biomarker manufacturer. [4] Still, there were no significant cost differences reflected in un-biased RCTs evaluating populations in heterogeneous healthcare systems. [11,12,15]

Does it Change Therapy?

Anecdotally, BNP has been promoted for its strength to discriminate between COPD, pneumonia, and heart failure, but so far, no studies have clearly demonstrated that it has helped reduce the use of “inappropriate therapy”. Schneider et al. was the only trial to comment “Knowledge of BNP levels did not change the use of bronchodilators, diuretics, vasodilators, antibiotics, steroids, angiotensin-converting enzyme inhibitors, and noninvasive ventilation, and use of appropriate heart failure medication was not increased in patients with heart failure in the BNP group versus the control group.”[11] The authors did not provide data on this finding, but in the case of dyspneic patients in the ED, most clinicians will broadly cover the patient for multiple conditions based on more specific evaluations such as chest x-ray findings, volume status, or hypercarbia.

Does it Decrease Mortality? 

There was no difference in 30-day mortality in any of the RCTs that measured this outcome including the BASEL trials. [4,9,10,12]  The Rapid Emergency Department Heart Failure Outpatients Trial (REDHOT) took another approach by evaluating prognostic value of BNP.  The study found that patients with BNP values >200pg/mL had worse 90-day outcomes including mortality, cardiac readmissions, and cardiac ED visits concluding that severe elevation in BNP can help to better stratify those who are at risk for adverse outcomes. [14]  The REDHOT II trial attempted to bare these results out by studying the use of serial BNPs in admitted patients.  This trial did not prove to show significant improvement in mortality, readmission rate, or length of stay. Alternatively, authors found renal function and hemodynamics to be more closely associated with in-hospital 30-day mortality than serial measurements of BNP. [15]

Take-Aways:

The BASEL and the IMPROVE-CHF trials showed significant reduction in costs and admissions, but had questionable conflicts of interest, generalizability and/or sample imbalance. Later RCTs showed no difference in relevant outcomes. RCTs are inconclusive for the routine use of BNP in the evaluation of dyspnea in the ED.Take-Aways:

• BNP is promoted in cases of uncertainty. Despite the potential use of BNP to reduce costs by decreasing admissions, it is uncertainty alone that often dictates whether a dyspneic patient is admitted, irrespective of heart failure or BNP level.
• Up to 90% of patients in older study cohorts were admitted, which likely reflects that most patients with ADHF are older, sicker and likely chronically ill patients who will require admission regardless of the etiology of the dyspnea.
• Prognosticating: Elevated BNP almost always suggests a poor prognosis whether it is used to stratify ADHF, non-ST elevation myocardial infarction (MI), or PE, but prognosis is often more accurately reflected – and more easily assessed – by patient hemodynamics and renal perfusion. [14,17,18] There is no strong evidence that BNP will consistently help an admitting team in their management, but there is still ongoing research that is attempting to discern how BNP may help in response-guided therapy and discharge planning.
• Ruling-in: Some suggest BNP as a rule-in test to diagnose patients who are being treated erroneously for other conditions, such as a 65-year-old patient with a history of COPD. 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 do not believe have CHF.” [19] This method of screening for heart failure is not a common application, and has not been systematically studied, but could drastically change treatment course.
• Ruling-out: 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 help identify patients who are safe for outpatient management.  Some studies have attempted to derive scoring methods for this purpose.

• The “gray zone”: Likely BNP will continue to find application on a   case-by-case basis by the ED clinician who is interested in detecting the presence of heart strain or not. Interpretation of BNP should be considered after establishing pre-test probability for the patient, with the knowledge of confounding variables (Table 2). Clinicians can also employ tools to interpret the test like that proposed by Steinhart et al. (available for download here). [21]  That said, some cases of intermediate probability may represent the complex and sicker patients who requiring longer hospital stays and extended work-ups. In these cases, more than half the time, the knowledge of BNP will unlikely help narrow the diagnosis. [21]
• Although anecdote may support BNP in certain cases, based on the current trials, there is little evidence to show that this biomarker has the potential to change management that will lead to clinically significant outcomes.

References / Further Reading

1. 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.
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
3. 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.
4. 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
5. 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.
6. 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.
7. 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
8. 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.
9. 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;350:647–54
10. Rutten JH, Steyerberg EW, Boomsma F, van Saase JL, Deckers JW, Hoogsteden HC, et al. N-terminal pro-brain natriuretic peptide testing in the emergency department: beneficial effects on hospitalization, costs, and outcome. Am Heart J 2008;156(1):71-7
11. Schneider HG, Lam L, Lokuge A, et al. B-type natriuretic peptide testing, clinical outcomes, and health services use in emergency department patients with dyspnea: a randomized trial. Ann Intern Med 2009;150:365–71.
12. Meisel SR, Januzzi JL, Medvedowski M, et al. Pre-admission NT-proBNP improves diagnostic yield and risk stratification – the NT-proBNP for Evaluation of dyspneic patients in the Emergency Room and hospital [BNP4EVER] study. Acute Cardiovas Care 2012
13. 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.
14. 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 Sep 15. 44(6):1328-33.
15. 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
16. 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.
17. 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.
18. 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.
19. 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.
20. Emergency Medicine Journal Club. Does BNP Augment Acute Decompensated CHF ED Management? WUSM-St. Louis. Journal Club November, 2009. http://emed.wustl.edu/education/EmergencyMedicineJournalClub/Archive/November2009.aspx
21. 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.

Figures

1. LB Daniels, AS Maisel. Natriuretic Peptides. J Am Coll Cardiol. 2007 Dec 18. 50(25): 2357-68. (Tables 1-2)

2. 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