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NT-proBNP: improved standard in CHF diagnosis.

The utility of natriuretic peptides (NPs)--both brain natriuretic peptide (BNP) and N-terminal prohormone brain natriuretic peptide (NT-proBNP)--as an aid in diagnosing congestive heart failure (CHF) is well known. Both markers have been shown in a number of studies to be useful blood tests to rule in and rule out CHF. While numerous studies show these markers to be clinically comparable, NT-proBNP has been deemed superior by many investigators due to its increased half-life in blood. (1), (2) The increased half-life of the NT-proBNP molecule compared to BNP is advantageous in terms of improved prognostic value in both CHF and acute coronary syndrome (ACS) as it "normalizes" individual biologic variation, thereby enhancing the predictive value of the biomarker.

The detection of elevated BNP and NT-proBNP levels in the blood (whole blood or plasma) correlates with severity of CHF when assessed by the New York Heart Association (NYHA) classification of CHF. (3), (4) Low levels of NT-proBNP can be used to rule out CHF with a high negative predictive value.

NP tests are routinely performed in the central laboratory. To improve the turnaround time (TAT) for reporting results to clinicians, however, there is a need for rapid point-of-care tests (POCTs) for use in emergency departments (EDs) and clinics to aid in diagnosis, predict patient outcomes, and monitor the effects of acute and long-term intervention.

Hospital discharges from CHF in the United States rose from 400,000 in 1979 to 1.084.000 in 2005, an increase of 171 % (National Hospital Discharge Survey and National Heart, Lung, and Blood Institute; American Heart Association [AHA] computation). More than 550,000 new cases are diagnosed each year, according to the AHA. (5) Worldwide, more than 22 million people suffer from CHF, and two million new cases are diagnosed each year, according to the World Health Organization. The five-year mortality rate for CHF is as high as 50%, and CHF represents the single largest expense for most developed countries' healthcare costs. Timely diagnoses are critical to reducing the rising costs of healthcare.

Conventional diagnostic methods for heart failure include the use of chest X-rays, pulmonary function, and stress-testing electrocardiograms. Echocardiography (ultrasound) may also be used to image the heart and aid in the determination of left ventricular systolic dysfunction (LVSD), but is time consuming, expensive, and requires a skilled technician and consultation with a radiologist. Additionally, while these methods are valuable diagnostic tools, they are usually not available at the point of treatment to augment standard clinical symptoms of CHF, including dyspnea (shortness of breath), pulmonary, and peripheral edema.

Until recently, there was no approved NT-proBNP POCT in the United States for whole blood. Lab-based tests use plasma, which requires an additional centrifugation step. Typically, a blood sample sent from the ED to a central lab can take 45 minutes to more than an hour to provide a result. TAT is particularly significant for high-risk patients, leading to delays in medical intervention. A whole-blood test in the ED can be conducted in about 15 minutes.

Clinical evidence of the NT-proBNP advantage

BNP and NT-proBNP are two separate pieces of the parent proBNP molecule, a single-chain precursor peptide. In CHF, the ventricle compensates by secreting increased NPs to decrease fluid (diuresis) and sodium load (natriuesis) as well as increasing vasodilation. Upon secretion from the cardiac myocyte, proBNP splits into both inactive N terminal (NT-proBNP) and biologically active C-terminal pieces (BNP). The concentration of either NP in the blood is correlated with an increase in ventricular size and ventricular pressure. (6)

Because BNP is biologically active, it is subject to three forms of degradation and elimination, giving it a circulating half-life of roughly 20 minutes. NT-proBNP, on the other hand, has just one mechanism of clearance--renal filtration--resulting in a half-life of approximately 120 minutes. This greater stability results in the NT-proBNP molecule having better predictive value in CHF and ACS. One paired study found NT-proBNP more accurately determined the odds of an adverse outcome within 30 to 90 days of a second heart attack, the need for urgent care (re-vascularization angioplasty or bypass), or death and was also superior to BNP in predicting mortality and morbidity, and re-hospitalization for heart failure. (7)

A comparison of the automated Roche NT-proBNP assay and Biosite BNP assay found that NT-proBNP had good analytical performance and better precision than Biosite BNP. Unlike BNP, NT-proBNP is stable in EDTA plasma for three days at room temperature or longer at 4[degrees]C. (8) Although a patient's gender, age, and renal function must be taken into account to obtain an accurate NT-proBNP reading, a clinically validated, cost-effective algorithm that accounts for these factors exists. (9)

In a head-to-head comparison of NT-proBNP and BNP in patients with/without LVSD, NT-proBNP was found to aid in identifying LVSD. The authors concluded that although both assays are reliable and have good analytical performance, the slightly wider detection range and the more stable structure of NT-proBNP are an improvement in the evaluation of patients with LVSD. (10) Omland, et al, concluded that the NT-proBNP is a "particularly strong predictor of heart failure or death. This risk is independent of all other variables, including renal function or troponin, and is proportional to the magnitude of NT-proBNP release, with higher risk observed among those with a more marked elevation of the marker."(11)

Similarly, Januzzi, et al, found that "[i]n addition to assisting in emergency diagnosis and triage, NT-proBNP concentrations at presentation are strongly predictive of one-year mortality in dyspneic patients." (12) The authors recommend additional measurements at 24 to 72 hours and again at three- to six-month intervals to improve long-term prognostic capability. In patients with stable coronary-artery disease, these intervals may be extended to six to 18 months. NT-proBNP is beneficial in the early detection of CHF because it is more accurate than BNP in differentiating patients with mild CHF from those without CHF, and it may enable the prognosis in patients with mild cardiac dysfunction. (13), (14)

There is a common misconception that renal disease reduces the reliability of NT-proBNP measurements. But it has been found that while both BNP and NT-proBNP are useful in predicting CHF across a wide range of renal function levels, NT-proBNP was the superior predictor of one-year mortality, particularly in patients with chronic kidney disease. (15)

Cost benefits of the NT-proBNP testing

In addition to its diagnostic benefits, when compared to the usual care for patients with symptoms of heart failure, an NT-proBNP test can reduce medical costs by nearly $1,000 per patient. These savings result from less time spent in the emergency department and a significant reduction in the number of patients that are re-admitted within 60 days. (16) And the IMPROVE-CHF study concluded that inclusion of NT-proBNP testing improves the management of patients presenting to EDs with dyspnea through improved diagnosis, cost savings, and improvement in selected outcomes. (17) Similarly, the "BATTLESCARRED" trial compared the usual care of CHF patients with NT-proBNP-guided care and found there were fewer outpatient diagnostic tests, including echocardiography, radionuclide ventriculography, and computed tomography scan in the NT-proBNP group. (18)

Test availability

In the United States, BNP tests dominate the market, with automated platforms for the lab from major manufacturers including Siemens, Beckman, and Abbott Labs. BNP POCTs include Biosite Triage and Abbott i-Stat. In Europe, however, NT-proBNP assays dominate and their use within U.S. labs is growing, including such prominent medical institutes as the Massachusetts General Hospital and the Mayo Clinic. NT-proBNP tests for automated platforms are now manufactured by Roche, Siemens Mitsubishi, and Ortho-Clinical Diagnostics. NT-proBNP POCTs include the Roche Cardiac Reader and cobas h 232 system, neither of which are currently available in the United States.

An NT-proBNP POCT for whole blood has recently been approved for use in the United States (Response Biomedical-RAMP NT-proBNP). A second test--Nanogen's Vyent NT-proBNP--is standardized to the Roche Elecsys 2010 assay, CE Marked for sale in Europe, and expected to receive 510(k) clearance in early 2009. (19) Vyent NT-proCHF is a fully quantitative, 15-minute test performed on an instrument the size of a small laptop computer.

The improved standard

The literature and widespread use of BNP and NT-proBNP biomarkers demonstrate the value of these tests in the diagnosis and prognosis of CHF. NT-proBNP has been shown to be superior to BNP in several aspects when age-related cut-offs are used. The South West London Cardiac Network Project for Optimising the use of NT-proBNP Testing in Primary Care concluded that ''NT-proBNP is the test of choice in the diagnostic pathway for heart failure. It facilitates equivalent measurements in both the hospital and community without inconvenience to patients or carers and is, therefore, adopted as the gold standard" (20) and is highly sensitive for cost-effective exclusion of CHF in symptomatic patients in a primary-care practice. (21) With its greater predictive value, cost savings, and high correlation to central lab NT-proBNP testing, an NT-proBNP rapid POCT is an invaluable diagnostic aid to emergency and clinical practitioners alike.

References

(1.) Ander D, et al. Society of Chest Pain Centers Recommendations for the Evaluation and Management of the Observation Stay Acute Heart Failure Patient Diagnosis. Crit Pathways in Cardiol. 2008;7:91-95.

(2.) Januzzi JL, Richards AM, eds. An International Consensus Statement Regarding Amino Terminal Pro-B-Type Natriuretic PeptideTesting: The International NT-proBNP Consensus Panel. Am J Cardiol. 2008;101(3A).

(3.) Mueller C, et al. The integration of BNP and NT-proBNP into clinical medicine. Swiss Med Wkly 2007; 137:4-12.

(4.) Januzzi J, et al. NT-proBNP testing for diagnosis and short-term prognosis in acute destabilized heart failure: an international pooled analysis of 1256 patients: the International Collaborative of NT-proBNP study. Eur Heart J. 2006;27:330337.

(5.) American Heart Association, Heart Disease and Stroke Statistics-2008 update. Dallas, Texas: American Heart Association; 2008. www.americanheart.org/presenter.jhtml?identifier = 3000090. Accessed November 5, 2008.

(6.) Bluestein B, et al. BNP and NT-proBNP testing--what you don't know about your laboratory's test could hurt you. Business Briefing: Emergency Medicine Review. June 2005

(7.) Masson S, et al. Direct comparison of B-Type natriuretic peptide (BNP) and amino-terminal proBNP in a large population of patients with chronic and symptomatic heart failure: the Valsartan Heart Failure (Val-HeFT) data. Clin Chem. 2006;52:1528-1538.

(8.) Yeo, K, et al. Multicenter evaluation of the Roche NT-proBNP assay and comparison to the Biosite Triage BNP assay. Clin Chim Acta. 2003;338:107-115.

(9.) Januzzi J, et al. Amino-terminal pro-B-type natriuretic peptide testing for the diagnosis or exclusion of heart failure in patients with acute symptoms. Am J Cardiol. 2008;l01[Suppl]:29A38A.

(10.) Vanderheyden M, et al. Head to head comparison of N-terminal pro-B-type natriuretic peptide and B-type natriuretic peptide in patients with/ without left ventricular systolic dysfunction. Clin Biochem. 2006;39:640-645.

(11.) Omland T, deLemos J. Amino-terminal pro-B-type natriuretic peptides in stable and unstable ischemic heart disease. Am J Cardiol 2008;101 [Suppl]:61A-66A.

(12.) Januzzi JL, et al. Utility of amino-terminal probrain natriuretic peptide testing for prediction of 1-year mortality in patients with dyspnea treated in the emergency department. Arch Intern Med. 2006;166:315-320.

(13.) Emdin M, et al. Comparison of brain natriuretic peptide (BNP) and amino-terminal proBNP for early diagnosis of heart failure. Clin Chem. 2007;53:1289-1297.

(14.) Omland T, et al. Prognostic value of B-type natriuretic peptides in patients with stable coronary artery disease, the PEACE trial. J Am Coll Cardiol. 2007;50:205-214.

(15.) DeFilippi C, et al. Impact of renal disease on natriuretic peptide testing for diagnosing decompensated heart failure and predicting mortality. Clin Chem. 2007;53:1511-1519.

(16.) Januzzi J, et al. NT-proBNP levels, echocardiographic findings, and outcomes in breathless patients: results from the ProBNP Investigation of Dyspnoea in the Emergency Department (PRIDE) echocardiographic substudy. Bur Heart J. 2006;27:839-845.

(17.) Moe G, et al. 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. 2007:115:3103-3110.

(18.) Lainchbury J, et al. NT proBNP-guided drug treatment for chronic heart failure: design and methods in the "BATTLESCARRED" trial. Eur J Heart. 2006;8:532-538.

(19.) Vyent [TM] NT-proBNP Package Insert, Part No, 141090, RevA, Nanogen, Inc., San Diego, CA. Data on file.

(20.) Optimising the use of NTproBNP Testing in Primary Care. www.heart.nhs.uk/BNP/south_west_london/optimising_NTproBNP_in_PC.ppt Accessed November 13, 2008

(21.) Hildebrandt P, Collinson P. Amino-terminal proB-type natriuretic peptide testing to assist the diagnostic evaluation of heart failure in symptomatic primary care patients. Am J Cardio. 2008; 101[suppl]:25A-28A. www.mlo-online.com

By Barry Bluestein, PhD, and Alexander Belenky, PhD

Barry Bluestein, PhD, is senior director and Alexander Belenky, PhD, principal scientist for Cardiac Product Development for Nanogen Inc. in San Diego, CA.
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Title Annotation:LAB MANAGEMENT
Author:Bluestein, Barry; Belenky, Alexander
Publication:Medical Laboratory Observer
Geographic Code:1CANA
Date:Dec 1, 2008
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