Natriuretic Peptides in Congestive Heart Failure

Updated: Sep 13, 2016
  • Author: Donald Schreiber, MD, CM; Chief Editor: Erik D Schraga, MD  more...
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Overview

Overview

Since its discovery over 15 years ago, brain natriuretic peptide (BNP), also referred to as B-type natriuretic peptide, has emerged as an important biomarker with an established role in the diagnosis of congestive heart failure (CHF). Investigators from several large studies examined the performance characteristics of BNP testing in the acute care setting to assist in diagnosing CHF and in predicting long-term morbidity and mortality. Its utility has also been explored in myocardial ischemia and infarction, in right-sided heart failure (eg, cor pulmonale), and in acute pulmonary embolism (PE).

Furthermore, clinical trials are currently under way to determine if serial BNP measurements have a role in guiding the titration of CHF therapies. Recombinant BNP (nesiritide) has been evaluated and approved for adjunctive therapy for acute CHF, although subsequent evidence of harm dramatically diminished its use for this indication.

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Normal Activity of Natriuretic Peptides

Brain natriuretic peptide (BNP) is a member of a family of four human natriuretic peptides that share a common 17-peptide ring structure. [1] The first was identified in 1983 and named atrial natriuretic peptide (ANP). ANP is a 28-amino acid polypeptide resulting from the C-terminal end of the prohormone proANP. The source is largely in the cardiac atria, and ANP is quickly secreted in response to atrial stretching. Normal hearts secrete extremely small amounts of ANP, but elevated levels are found in patients with left ventricular (LV) hypertrophy and mitral valve disease.

A closely related molecule was first identified in pig brains in 1988 and therefore named BNP. However, BNP was subsequently discovered to be present in high concentrations in cardiac tissues, particularly the ventricles. Two additional natriuretic peptides, designated C-type natriuretic peptide (CNP) and Dendroaspis natriuretic peptide (DNP), have also been described; they are thought to act in the peripheral vasculature and the atria, respectively.

Before its activation, BNP is stored as a 108–amino acid polypeptide precursor, proBNP, in secretory granules in both ventricles and, to a lesser extent, in the atria. After proBNP is secreted in response to volume overload and resulting myocardial stretch, it is cleaved to the 76-peptide, biologically inert N -terminal fragment NT-proBNP and the 32-peptide, biologically active hormone BNP. The 2 fragments are secreted into the plasma in equimolar amounts, and both have been clinically evaluated for use in the management of congestive heart failure (CHF).

High ventricular filling pressures stimulate the release of ANP and BNP. Both peptides have diuretic, natriuretic, and antihypertensive effects, which they exert by inhibiting the renin-angiotensin-aldosterone system. They also have systemic and renal sympathetic activity. In addition, BNP may provide a protective effect against the detrimental fibrosis and remodeling that occurs in progressive heart failure.

Although ANP was identified first, concentrations of BNP in the myocardial tissue were found to be higher than those of ANP. Therefore, BNP has been studied more intensely than ANP as a clinically useful marker of increased ventricular filling pressure. An elevated BNP level is a marker of increased LV filling pressures and LV dysfunction.

Natriuretic peptide receptors and plasma endopeptidases actively clear BNP from the circulation; the plasma half-life is thus short, approximately 20 minutes. No receptor-mediated clearance of NT-proBNP is known to occur, and NT-proBNP has a correspondingly prolonged half-life of 60-120 minutes. As a result, plasma levels of NT-proBNP tend to be 3-5 times higher than BNP levels. Clearance of NT-proBNP is thought to be primarily renal. Therefore, the renal clearance of NT-proBNP confounds its diagnostic utility in patients with renal insufficiency.

As a laboratory specimen, NT-proBNP is more stable during storage than BNP. NT-proBNP samples are stable at room temperature for 72 hours, versus less than 4 hours for BNP samples.

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BNP and NT-proBNP Assay Methods

First-generation assays for brain natriuretic peptide (BNP) were competitive radioimmunoassays that required extraction and purification of the plasma sample. Second-generation assays were based on monoclonal antibodies and radioisotope labels. These assays provided improved sensitivity and precision. Commercial versions of the monoclonal antibody assay first appeared in 1994 and initially required 12-36 hours to complete.

Third-generation assays, which provided results in as little as 15 minutes, became available in 2000. These rapid assays used immunofluorescent methods. All of the assays for BNP and NT-proBNP that are commercially available for clinical use in the United States are rapid immunoassays.

The assay used in the Breathing Not Properly study, which first suggested clinically useful BNP cutoff values for diagnosing acute congestive heart failure (CHF), was the point-of-care Triage BNP Test (Biosite Diagnostics Inc; San Diego, CA). Other manufacturers also market rapid-turnaround BNP assays, including the ADVIA Centaur BNP assay (Bayer HealthCare Diagnostics; Tarrytown, NY) and the AxSYM BNP assay (Abbott Diagnostics; Abbott Park, IL).

Assays for the NT-proBNP fragment became available in late 2002. The Elecsys NT-proBNP assay (Roche Diagnostics; Indianapolis, IN) was evaluated in the ProBNP Investigation of Dyspnea in the Emergency Department (PRIDE) study. Other NT-proBNP assays include the Dimension test and the Stratus CS Acute Care NT-proBNP assays (Dade Behring Inc; Deerfield, IL).

Result considerations

When the literature or laboratory data from other institutions are evaluated, care must be taken not to extrapolate the results of one assay to another. Assay values for NT-proBNP have performance characteristics that are different from those for BNP, and evidence-based, rule-in and rule-out CHF cutoff levels change depending on the type of assay used.

Equally important is that the performance characteristics of these tests vary with the patients to whom they are applied; a negative result in a population with a low pretest probability of CHF has an increased negative predictive value. Finally, assays from various manufacturers differ slightly in their performance characteristics. Physicians must be familiar with the particular assay available at their facility.

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BNP and NT-proBNP Levels in LV Dysfunction

Initial studies demonstrated that brain natriuretic peptide (BNP) levels were highly correlated with increasing congestive heart failure (CHF) symptoms. [2, 3, 4, 5, 6] These studies showed that BNP levels were strongly related to impaired left ventricular (LV) function, as measured using the LV ejection fraction (LVEF) during echocardiography and angiography. Studies compared BNP and NT-proBNP assays as well, finding little diagnostic difference between them; however, the studies tended to be underpowered with regard to detecting such a difference.

Seino and colleagues, using BNP and NT-proBNP assays, compared 105 patients having chronic heart failure with 67 healthy control subjects and found that the peptide levels were significantly correlated with CHF symptoms. The levels were measured using the New York Heart Association (NYHA) classification of heart failure. [7]

Furthermore, receiver operating characteristic (ROC) curves were calculated to detect an LVEF of less than 40%, with resulting area under the curve (AUC) values of 0.75 and 0.77 for NT-proBNP and BNP measurements, respectively. (The ideal test has an AUC of 1.0, and a test based on chance alone has an AUC of 0.5.) When adjusted to detect an LVEF of less than 50%, AUC values increased to 0.82 and 0.79 for NT-proBNP and BNP, respectively.

In another study, of 180 inpatients, Mueller et al concluded that BNP and NT-proBNP were equally sensitive for diagnosing an exacerbation of CHF but that NT-proBNP may be most useful for detecting early LV dysfunction without overt clinical CHF. [8] Heart failure was diagnosed in 43 patients, with no difference in the AUC detected (0.92 and 0.93 for BNP and NT-proBNP, respectively). However, among 56 patients with asymptomatic structural heart disease and 81 patients without structural heart disease, NT-proBNP measurements resulted in an AUC of 0.84, a statistically significantly greater value than the AUC of 0.74 found for BNP measurements.

In a small study in which 43 symptomatic patients with echocardiographic abnormalities were compared with 137 asymptomatic control subjects with normal echocardiograms, the AUC to detect significant LV dysfunction was 0.92 for NT-proBNP and 0.93 for BNP. These results were slightly superior to those obtained in 339 hospitalized patients referred for diagnostic coronary angiography. In this patient population, NT-proBNP measurements provided an AUC of 0.83 for identifying severe systolic dysfunction and 0.81 for identifying any LV dysfunction.

The relative performance of BNP and NT-proBNP was also compared, and no significant difference in performance characteristics was detected. However, NT-proBNP measurements tended to improve sensitivity in detecting low levels of LV dysfunction.

In a large study by McDonagh et al in which the authors defined an abnormal NT-proBNP level as one greater than the 95th percentile for patients without LV dysfunction, NT-proBNP levels aided the diagnosis of CHF with a sensitivity of 75% and a negative predictive value of 99%. [9]

In this study, NT-proBNP levels were compared with LV function in 3051 patients pooled from 3 large European data sets. About 10% of these patients had significant LV dysfunction, whereas 3% had acute CHF. Median values for patients with normal LV function, LV dysfunction, and acute CHF were 20, 117, and 270pg/mL, respectively. AUCs for diagnosing clinical CHF and for detecting any LV dysfunction were 0.85 and 0.69, respectively.

Rather than selecting a specific cutoff with optimal performance characteristics, the authors, as stated, defined an abnormal NT-proBNP level as one greater than the 95th percentile for patients without LV dysfunction, corrected for age and sex. By using this cutoff strategy, NT-proBNP levels had the above-mentioned sensitivity of 75% and negative predictive value of 99% in the diagnosis of CHF

These data confirm the correlation between natriuretic peptide levels and degree of LV dysfunction, using either a BNP or the NT-proBNP assay. Furthermore, subjects with echocardiographically determined LV dysfunction or structural LV heart disease (eg, valvular heart disease), but without clinical CHF exacerbation, have natriuretic peptide levels between those of persons with a normal heart and normal LV function and the levels of patients who have been diagnosed with acute clinical CHF.

Although these studies demonstrated moderate discriminatory power of natriuretic peptide testing in detecting LV dysfunction, each study revealed substantial overlap in BNP and NT-proBNP levels between patients with and those without LV dysfunction, symptomatic or not. These results suggest that BNP or NT-proBNP might not be useful in screening for CHF or LV dysfunction.

However, with appropriate cutoffs and in certain high-risk populations, such as patients with dyspnea in the emergency department, BNP and NT-proBNP test characteristics provide sufficient negative predictive value to effectively rule out LV dysfunction.

Recombinant BNP

Recombinant brain natriuretic peptide (BNP), also known as nesiritide, has been studied as a therapeutic adjunct in acute decompensated congestive heart failure (CHF). [10, 11, 12, 13, 14, 15] Nesiritide (Natrecor, Scios Inc; Fremont, Calif) received a US Food and Drug Administration (FDA)–approved indication for the treatment of acute decompensated heart failure with dyspnea in 2001.

The treatment of CHF with recombinant BNP is beyond the scope of this article. However, the clinician must be aware that nesiritide is a BNP measured by the BNP assay. Therefore, the measurement of BNP is not indicated in patients who are receiving nesiritide. If BNP is used as a diagnostic marker to rule in CHF, the level must be determined before nesiritide therapy is started. NT-proBNP is not therapeutically active, and it does not affect the measurement of NT-proBNP levels.

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BNP and NT-proBNP Evaluation in the ED

The utility of brain natriuretic peptide (BNP) testing in the acute care setting is derived from the landmark Breathing Not Properly study and later studies. [16, 17, 18, 19, 20, 21] The initial Breathing Not Properly multicenter prospective study involved 1586 patients presenting to the emergency department (ED) with acute dyspnea.

In the patient with dyspnea, overlapping or even conflicting historical, physical, and radiographic findings often hinder the differentiation between cardiac and noncardiac etiology. Initial misdiagnosis occurs in approximately 15-20% of patients presenting to the emergency department (ED) with dyspnea secondary to an acute exacerbation of congestive heart failure (CHF). This misdiagnosis may incur clinically significant morbidity and mortality.

The primary value of BNP and NT-proBNP testing in the ED is its diagnostic value in the differential diagnosis of acute dyspnea and possible CHF. levels of the natriuretic peptides may also assist the emergency physician in appropriately triaging the patient with CHF.

Studies have shown that measurements of BNP or NT-proBNP in the ED can be used to establish the diagnosis of CHF when the clinical presentation is ambiguous or when confounding comorbidities are present. Given that BNP and NT-proBNP assays have different cutoff values for ruling in and ruling out CHF, these values are specified separately below where appropriate.

Factors affecting BNP/NT-proBNP assays

Given the renal clearance of NT-proBNP and, to a lesser degree, BNP, several studies have been completed to examine the effects of renal insufficiency on the performance characteristics of natriuretic peptide testing.

The authors of the Breathing Not Properly study suggested an increased rule-out CHF cutoff of less than 200pg/mL for patients with an estimated glomerular filtration rate (GFR) of less than 60mL/min. The investigators examined a subset of their 1452 patients for whom baseline BNP and estimated GFR were available. (Patients receiving dialysis were excluded from the original study.) BNP levels were inversely correlated with estimated GFRs. [22]

In a similar study, the effect of renal function on NT-proBNP and BNP levels was evaluated in 381 ED patients presenting with dyspnea. [23] Acute decompensated CHF was diagnosed in only 30%, but a similar inverse relationship was found between estimated GFR and NT-proBNP and BNP levels. The authors suggested rule-out CHF cutoffs of 290 and 515pg/mL for patients with estimated GFR of 60-89 and 15-29mL/min, respectively. For NT-proBNP assays, optimal cutoffs were 1360 and 6550pg/mL, respectively.

However, large studies are needed to validate these estimated GFR-dependent cutoff values. Furthermore, it is unknown if adjustment of NT-proBNP cutoffs beyond those recommended for age are needed to correct for impaired estimated GFR or if an estimated GFR–based stratification of NT-proBNP cutoffs is superior to the currently recommended age-dependent thresholds.

In contrast to renal impairment, the inverse relationship between obesity and BNP levels may adversely affect the utility of BNP levels to exclude CHF in obese patients. [24, 25] In the Breathing Not Properly study, body mass indexes (BMIs) were calculated from self-reported heights and weights in 86% of participants. Mean BNP values were 3 times higher for lean patients with CHF than for obese patients with CHF (517 vs 176mg/mL), and BNP was significantly and inversely correlated with BMI. [24]

In addition, in a study of 316 patients with CHF, those with BMIs of less than 25, 25-29.9, or 30kg/m2 or greater had median BNP levels of 747, 380, and 332pg/mL, respectively. [26] Obese patients with BMIs greater than 25 kg/m2 had median BNP levels below the recommended rule-in threshold of 500pg/mL. Additional study is required to further evaluate the cut-off values for BNP and NT-proBNP in obese patients.

Atrial fibrillation (AF) confounds the utility of BNP assay for diagnosing acute CHF exacerbation. [27, 28] A study found that in acute CHF, AF had no detectible effect on BNP levels, while in patients without CHF, AF was correlated with increased BNP levels. In this investigation, 1431 patients presenting with acute dyspnea, BNP levels were drawn, and patients were prospectively classified as those without AF and those with a history of paroxysmal or permanent AF (and, therefore, 1139 without).

Areas under the curve (AUCs) for CHF diagnosis were 0.84 and 0.91 for patients with and those without AF, respectively. With the previously established rule-out CHF cutoff of 100pg/mL, specificity was only 40% in patients with AF, compared with 79% in the others. The authors concluded that AF was associated with increased BNP levels in the absence of acute CHF. A high cutoff value to exclude CHF is required, but further study is needed to establish accurate thresholds.

Overall, the confounding variables of age, obesity, and AF may affect the clinical utility of BNP assessment in certain subsets of patients. Additional studies are needed to further evaluate these variables and their effect on the clinical performance of BNP and NT-proBNP tests. After the effects of these variables are elucidated, the accuracy of the natriuretic peptide assays will improve, but the complexity of their performance characteristics may also increase.

BNP versus NT-proBNP assays

In addition to the studies described above, head-to-head comparisons of BNP and NT-proBNP assays have been performed. [7, 29, 30, 31, 32, 33, 34]

In a study by Richards et al, BNP and NT-proBNP had nearly identical performance characteristics in detecting a left ventricular ejection fraction (LVEF) of less than 30% and in predicting hospital admission and cardiac mortality rates. Similar confounding effects of age, sex, and renal insufficiency were discovered. [30]

The study, one of the largest comparisons of BNP and NT-proBNP assays, was conducted in New Zealand in more than 1000 patients with stable heart failure. The goal was to compare BNP and NT-proBNP test results with several clinical variables. Age, sex, BMI, LVEF (measured on radionuclide scanning), and estimated creatinine clearance were determined, in addition to BNP and NT-proBNP levels. Endpoints were hospital admission and all-cause mortality over 12 months. Because the study patients had stable heart failure, it is unclear if the results can be extrapolated to ED patients with acute dyspnea and acute CHF.

NT-proBNP is most sensitive for the detection of mild left ventricular (LV) dysfunction and structural heart disease identified during echocardiography. The clinical significance of this performance characteristic is unclear because most of the patients had no symptoms of acute CHF. BNP was less sensitive to the effects of renal insufficiency than NT-proBNP, and the clinical utility of having only single cutoff thresholds for ruling in acute CHF may be an advantage in some settings.

More clinical studies have addressed BNP than NT-proBNP. However, the present authors know of no specific study data that clearly establishes a diagnostic advantage of one natriuretic peptide over the other.

Current licensing and patent rules limit the BNP and NT-proBNP assays to specific laboratory instrumentation platforms. One company may not have the required licensing permits to perform BNP (or NT-proBNP) testing. The laboratory instrumentation platform already in place at that institution, and not necessarily any objective evaluation of the assay, determines the particular assay available at any one hospital.

The table below summarizes the evidence-based cutoff values proposed for the diagnosis of CHF in the patient with dyspnea who presents to an acute-care facility. The corresponding likelihood ratios and predictive values are also summarized.

BNP cutoff values

The utility of BNP testing in the acute care setting is derived from the landmark Breathing Not Properly study and later studies. The initial Breathing Not Properly multicenter prospective study involved 1586 patients presenting to the ED with acute dyspnea. See Table 1, below.

Table 1. Evidence-Based BNP and NT-proBNP Cutoff Values for Diagnosing Heart Failure (Open Table in a new window)

Criterion BNP, pg/mL NT-proBNP, pg/mL
HF Unlikely



(LR-Negative)



HF Likely



(LR-Positive)



HF Unlikely



(LR-Negative)



HF Likely



(LR-Positive)



Age, y >17 < 100 (0.13)* >500 (8.1)* - -
>21 - - < 300 (0.02) -
21-50 - - - >450 (14)
50-75 - - - >900 (5.0)
>75 - - - >1800 (3.1)
Estimated GFR, < 60 mL/min < 200 (0.13) >500 (9.3) - -
BNP = B-type natriuretic peptide; GRF = glomerular filtration rate; HF = heart failure; LR = likelihood ratio; NPV = negative predictive value; NT-pro-BNP = N-terminal proBNP; PPV = positive predictive value; – = not specifically defined.



* Derived from Breathing Not Properly data (1586 emergency department [ED] patients, prevalence of HF = 47%). [4]



Derived from PRIDE data (1256 ED patients, prevalence of HF = 57%). [18, 19]



Derived from subset of Breathing Not Properly data (452 ED patients, prevalence of HF = 49%). [5]



Likelihood ratios

BNP levels in several pilot studies had a strong correlation with the severity of illness and were very reliable in differentiating heart failure from pulmonary disease. The recommended thresholds of less than 100pg/mL to rule out heart failure and more than 500pg/mL to rule in heart failure have been estimated to have the following likelihood ratios (LRs): LR-negative = 0.13 and LR-positive = 8.1. These different cutoffs create an intermediate range of 100-500pg/mL with LR-positive of only 1.9. Therefore, an intermediate BNP result alone cannot be used to rule in or rule out heart failure.

To explore the effect of clinical variables on intermediate BNP values, the Breathing Not Properly group calculated LR, accounting for a history of heart failure and/or coronary artery disease (CAD), lower-extremity edema, pulmonary edema, cephalization of the pulmonary vasculature, or cardiomegaly. In all patients, the LR-positive for a history of heart failure alone was 4.6. [35] As expected, the cumulative LR-negative was 0.02 for BNP < 100 pg/mL, no history of heart failure, and 0 or 1 clinical feature. [4, 5]

At the opposite extreme, a BNP level of greater than 500 pg/mL, a history of heart failure, and 2 or more clinical features had an LR-positive of 37. Other LRs were as follows:

  • A midrange BNP level with a history of heart failure - Had a modest cumulative LR of 4.3, which was not significantly different from the LR of heart failure alone [4, 5]
  • Any 2 or more clinical features, a heart failure history, and a mid-range BNP level - Had a cumulative LR-positive of 10
  • A mid-range BNP level, no history of heart failure, and 0 or 1 clinical criterion - Had an intermediate cumulative LR-negative of 0.7, which was not clinically useful

These data emphasize that an intermediate BNP result that is in conjunction with 2 or more clinical features and a history of heart failure is reasonably predictive of an ultimate diagnosis of an exacerbation of heart failure. However, an intermediate BNP result without these criteria (ie, no history of heart failure and 0 or 1 clinical variable) does not help to rule in or rule out heart failure as the etiology of the patient's dyspnea. Care must be taken in interpreting these intermediate results. The use of serial BNP measurements for monitoring the treatment of heart failure is not well established. [36, 37, 38]

A study by Alehagen et al found that among elderly patients with symptoms of heart failure, elevated concentrations of copeptin and the combination of elevated concentrations of copeptin and NT-proBNP were associated with an increased risk of all-cause mortality. [39]

Steinhart et al derived and validated a diagnostic prediction model for acute heart failure that incorporates clinical assessment and NT-proBNP. Variables used to predict acute heart failure were age, pretest probability, and log NT-proBNP. Validation of the model in 1073 patients showed that LRs for acute heart failure with NT-proBNP were 0.11 for cut-point values of less than 300pg/mL, increasing to 3.43 for values 2700-8099pg/mL and to 12.80 for values 8100pg/mL or higher.

When the model was applied to external data, 44% of patients who had been clinically classified as having intermediate probability of acute heart failure were appropriately reclassified to either low- or high-probability categories, with negligible (< 2%) inappropriate redirection. [40]

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Risk Stratification and Outcome Prediction

Many groups have evaluated the utility of brain natriuretic peptide (BNP) and NT-proBNP levels for risk stratification and as predictors of adverse clinical outcomes. [41, 42, 43] The studies differ in patient populations, definition of clinical endpoints, and durations of follow-up. However, most studies have consistently demonstrated a direct correlation between BNP and NT-proBNP levels and clinical outcomes in patients with congestive heart failure (CHF). The natriuretic peptides may also be useful as triage instruments to help guide the emergency physician.

PARADIGM-HF and PARAMOUNT trials

In July 2015, the FDA approved the combination tablet sacubitril/valsartan (Ernesto) to reduce the risk of cardiovascular death and hospitalization for heart failure in patients with CHF (NYHA class II-IV) and reduced ejection fraction. [44] The combination drug is the first approved agent in the angiotensin receptor-neprilysin inhibitor (ARNI) class and consists of the angiotensin-receptor blocker valsartan affixed to the neprilysin inhibitor sacubitril. The cardiovascular and renal effects of sacubitril’s active metabolite (LBQ657) in heart failure are attributed to the increased levels of peptides that are degraded by neprilysin (eg, natriuretic peptide). Administration results in increased natriuresis, increased urine cGMP, and decreased plasma mid-regional proatrial natriuretic peptide (MR-proANP) and NT-proBNP.

The approval was based on the Prospective Comparison of ARNI with ACE-I to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) trial. [45] PARADIGM-HF studied 8442 patients with CHF treated with either valsartan/sacubitril or enalapril. The combination significantly reduced cardiovascular death or heart-failure hospitalizations (the study's primary end point) by 20% compared with treatment with enalapril alone. All-cause mortality, a secondary end point, was also significantly reduced with the ARNI when compared with enalapril.

The Prospective Comparison of ARNI with ARB on Management of Heart Failure with Preserved Ejection Fraction (PARAMOUNT) trial compared reduction of NP-proBNP levels with sacubitril plus valsartan and valsartan alone over 12 weeks in 149 patients with LVEF of 45% or greater. Sacubitril/valsartan reduced NT-proBNP levels to a significantly greater extent (783 pg/mL at baseline and 605 pg/mL at 12 weeks) compared with valsartan alone (862 pg/mL at baseline and 835 pg/mL at 12 weeks). [46]

Framingham Heart Study

In a prospective study, researchers evaluated 3346 patients without heart failure from the Framingham Heart Study to determine the usefulness of BNP in predicting the risks for all-cause mortality, CHF, acute coronary syndrome (ACS), atrial fibrillation (AF), and stroke or transient ischemic attack (TIA). [6] Patients were followed up for a mean period of 5.2 years.

After adjustment for known cardiovascular risk factors, high levels of BNP were associated with a 27% increase in risk of all-cause mortality, a 28% increase in risk for a first cardiovascular event, a 77% increase in the risk of CHF, a 66% increase in the risk of AF, and a 50% increase in the risk of stroke or TIA.

A surprising finding was that BNP levels were not predictive of coronary heart disease. BNP levels greater than the 80th percentile (20pg/mL for men, 23pg/mL for women) were significantly associated with multivariable-adjusted hazard ratios of 1.6 for death, 1.8 for a first major cardiovascular event, 1.9 for atrial fibrillation, 2.0 for stroke or TIA, and 3.1 for heart failure.

These values were well below the proposed cutoff of 100pg/mL to rule out CHF in emergency department (ED) patients with dyspnea. However, they raise the issue of whether BNP testing has a role in risk stratification and screening for cardiovascular and cerebrovascular disease in asymptomatic populations.

REDHOT study

This investigation indicated that BNP level is a strong predictor of 90-day patient outcome with regard to cardiac mortality and subsequent ED visits and/or rehospitalization for acute CHF.

The Breathing Not Properly investigators undertook the multicenter Rapid Emergency Department Heart Failure Outpatient Trial (REDHOT) to examine the prognostic role of BNP in the ED. [47] They examined baseline BNP levels in 464 patients with dyspnea when they presented to the ED and evaluated its relationship with clinical decision making and with clinical outcomes. Treating physicians were blinded to the BNP levels throughout the study.

The primary outcome measure was the decision to admit or discharge the patient from the ED. A secondary composite 90-day outcome was based on cardiac mortality and subsequent ED visits and/or rehospitalization for acute CHF.

About 90% of patients were admitted. Of interest, baseline BNP levels did not significantly differ between patients who were discharged and those who were admitted. On logistic regression analysis, the decision to admit or discharge a patient and the initial severity of CHF based on the New York Heart Association (NYHA) classification score had no influence on 90-day outcomes. The BNP level was a strong predictor of the 90-day outcome.

Of admitted patients, 11% had BNP levels lower than 200pg/mL; however, the treating ED physician determined that 66% of these patients had disease of NYHA functional class III or IV and that they were at risk for adverse outcomes. The 90-day composite adverse event rate in admitted patients with a BNP level of less than 200pg/mL was 9%, significantly lower than the 29% rate of those admitted with a BNP level of greater than 200pg/mL.

Overall, 26% of all admitted patients had an adverse outcome at 90 days, versus 42% of patients who were discharged. Mortality rates at 90 days between the admitted and discharged groups were not significantly different.

This study highlighted the lack of correlation between the physician’s clinical impression and the BNP level as an objective measure of disease severity. With the high cost of hospitalization and prolonged lengths of stay for CHF patients, the utility of BNP as a triage tool to guide admission decisions merits further study.

BASEL study

Swiss investigators examined this hypothesis. In a randomized, controlled study of 452 ED patients with acute dyspnea, Mueller et al found that, although mortality rates were not significantly lowered with BNP measurement, the data suggested that equivalent outcomes can be achieved with lowered hospital and intensive care unit (ICU) admission rates and shortened hospital stays when BNP testing is incorporated into the decision-making process for patient admissions. [8]

In the B-Type Natriuretic Peptide for Acute Shortness of Breath Evaluation (BASEL) study, patients were randomly assigned to undergo standard evaluation or evaluation aided with rapid bedside BNP measurement.

BNP measurement significantly decreased rates of admission (75% vs 85%) and admission to the intensive care unit (ICU) (15% vs 24%). [8] Length of hospitalization was also significantly shortened with BNP measurement, with a median of 8 versus 11 days for the control group. The clinical endpoint of 30-day all-cause mortality occurred in 10% of the BNP group, with 12% mortality in the control group.

Copenhagen Hospital Heart Failure study

In the Copenhagen Hospital Heart Failure study, on multivariate analysis, NT-proBNP level was predictive of 1-year mortality in patients with heart failure, but left ventricular ejection fraction (LVEF) and NYHA class were not.

In the study, 1-year mortality was evaluated in 2230 consecutively hospitalized patients. [48] Study patients underwent an assessment of cardiac status on admission, with clinical examination, echocardiography, and measurement of NT-proBNP values.

Heart failure was diagnosed in only 161 patients, but their 1-year mortality rate was 30%. On univariate analysis, LVEF, NYHA class, and NT-proBNP level were independently highly predictive of 1-year mortality. However, on multivariate analysis, only the NT-proBNP level was statistically significant. LVEF provided no additional prognostic value over NT-proBNP values in this small subset of patients with heart failure.

Rothenburger et al study

German researchers evaluated NT-proBNP levels in 550 extremely ill patients with severe dilated cardiomyopathy in whom cardiac transplantation was being considered. [49] All patients underwent extensive cardiac evaluation, including echocardiography and right heart catheterization.

The annual mortality rate was predicted by using the NT-proBNP level. At 1 year, patients with levels less than 1000pg/mL had a less than 1% mortality rate, patients with levels of 1000-5000 pg/mL had a 2% mortality rate, and patients with levels greater than 5000 pg/mL had a 28% mortality rate.

O’Brien et al study

In contrast to previous studies, this report, which looked at 96 patients who were hospitalized for exacerbation of CHF, did not reveal a statistically significant relationship between the admission NT-proBNP level and outcome. However, the discharge NT-proBNP level was a statistically significant predictor of adverse outcome.

In the study, a group from the United Kingdom assessed the predictive value of admission NT-proBNP levels compared with discharge levels in predicting adverse outcomes. [50] NT-proBNP values were measured in all patients on admission and in 34 patients at discharge. Outcome measures were death and/or recurrent CHF presentation over a median follow-up period of 1 year.

Bettencourt et al study

In this study, change in NT-proBNP level was the strongest predictor of death and/or hospital readmission in hospitalized patients with CHF.

In the report, Portuguese investigators evaluated 182 hospitalized patients with CHF who were followed up for 6 months for a primary endpoint defined as death or hospital readmission for CHF. [51] Levels of NT-proBNP were measured on admission and again at hospital discharge. Patients were stratified as those whose NT-proBNP levels decreased 30% or more between admission and discharge, those with any change less than 30%, and those with an increase of 30% or greater.

At 6 months, 43% of patients died or were readmitted with an exacerbation of CHF. As stated, the change in NT-proBNP level was the strongest predictor of death and/or hospital readmission. However, therapy for CHF was not controlled and was left to the discretion of the attending physician.

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NT-proBNP for Monitoring Therapeutic Response

Monitoring the therapeutic response in patients with acute decompensated congestive heart failure (CHF) is based on several clinical factors, including symptomatic relief of dyspnea, weight change, fluid balance, and resolution of S3 cardiac sounds, jugular venous distention, and lower-extremity edema. Researchers have explored the use of serial natriuretic peptide measurements to objectively follow up therapeutic responses. [52]

Data from a Spanish study suggested that serial NT-proBNP—or brain natriuretic peptide (BNP)—levels may be useful adjuncts in monitoring therapeutic responses in patients admitted to the hospital with acute CHF. However, the sample size in the study was small.

In the study, NT-proBNP levels were measured in 100 patients with acute dyspnea when they presented in the emergency department (ED), at 24 hours, and at 7 days. [53] CHF was echocardiographically diagnosed. Patients were classified as those with acute CHF exacerbations, those with underlying heart failure and superimposed acute pulmonary disease, and those with a noncardiac etiology of dyspnea.

NT-proBNP levels were highly predictive of LV dysfunction, and patients with complete symptom resolution had mean decreases in NT-proBNP values of 56%. Patients whose conditions were stabilized but still symptomatic had intermediate mean decreases of 37%. Patients whose decompensation persisted at 7 days had decreases of 21%.

Some investigators have suggested that the absolute change between the baseline, or dry, natriuretic peptide level and the ED admission level might be the best predictor of the patient’s outcome and the most useful triage tool. [31, 32]

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BNP and NT-proBNP Testing in Other Diseases

Acute coronary syndrome

Researchers examined the role of brain natriuretic peptide (BNP) levels as a marker of left ventricular (LV) dysfunction associated with myocardial ischemia in acute coronary syndrome (ACS). In animal studies, the induction of transient hypoxia provoked BNP release without troponin release. Transient BNP elevations are detected during coronary angiography, presumably due to the transient effects of contrast material inhibiting blood flow in the coronary arteries.

A more important finding is that BNP levels are correlated with the extent of ischemic myocardium on stress thallium testing and with the number of diseased vessels detected on coronary angiography. However, BNP levels considerably overlap across study subjects and do not enable sufficient discrimination on their own to rule ACS in or out.

In patients with confirmed ACS, the natriuretic peptides may have a role in risk stratification. NT-proBNP levels were measured in 1791 patients with non–ST-elevation ACS at presentation and were measured again 48 and 72 hours later. [54] The measurements were related to adverse outcome measures of death and/or myocardial infarction (MI) within 7 and 30 days. After adjustment for other risk factors, a baseline NT-proBNP level of greater than 250pg/mL was associated with an adverse cardiac event.

Furthermore, in patients without troponin elevation (ie, those with unstable angina without MI), a high NT-proBNP level portended the same cardiac risk as it did in patients with MI and elevated troponin levels. In addition, patients with persistently elevated NT-proBNP levels over 72 hours had a worsened 30-day prognosis.

Patients with ACS and clinical signs of congestive heart failure (CHF) at presentation are well known to have an increased risk of adverse cardiac events. Therefore, the finding that patients with ACS and elevated natriuretic peptide levels as markers of CHF on admission also have a high risk for adverse cardiac events was not surprising.

In another study, researchers examined the utility of such risk stratification in 1676 patients with non–ST-elevation ACS. [55] Patients were randomly assigned to receive early invasive or conservative management. BNP levels greater than 80pg/mL were predictive of adverse cardiac outcomes beyond those predicted on the basis of troponin levels alone (even after as long as 6 months). However, treatment strategies did not significantly differ when retrospectively stratified by BNP level.

The same researchers found that a BNP cutoff of greater than 80pg/mL at presentation in patients with ST-elevation and non–ST-elevation ACS was predictive of an increased cardiac mortality risk or the onset of CHF at 4 and 12 months. In this study, part of the A to Z trial, the investigators analyzed serial BNP levels in more than 3000 patients presenting with ST-elevation and non–ST-elevation ACS. [56]

Another group evaluated a single baseline NT-proBNP level on admission in 755 patients with non–ST-elevation ACS. [57] Elevated levels predicted a heightened risk of cardiac mortality at 40 months, even after adjustment for clinical background factors, electrocardiographic (ECG) findings, and elevated troponin levels. Compared with the lowest NT-proBNP quartile, patients in the 2nd, 3rd, and 4th quartiles had relative risks of death of 4, 11, and 27, respectively. Although the data were clearly predictive, the role of such information in patient care remains to be determined.

Jernberg et al determined whether NT-proBNP values, in combination with troponin T and interleukin (IL)-6 levels, were predictive of 2-year outcomes in patients randomly selected to receive an early invasive strategy or conservative treatment. [58] Although NT-proBNP was again predictive of long-term outcome, only patients with both elevated NT-proBNP and elevated IL-6 concentrations had a survival benefit with the early invasive strategy. Furthermore, only elevated troponin levels were independently associated with recurrent MI and death from MI.

Similar prognostic value was found in 1034 patients with CAD symptoms who were referred for coronary angiography. [59] Compared with patients with NT-proBNP levels in the lowest quartile, those patients with levels in the highest quartile were older; they had lower left ventricular ejection fractions (LVEFs) and estimated creatinine clearances; and they were more likely to have a history of MI, clinically significant coronary artery disease (CAD), and diabetes.

In the group of study subjects, the NT-proBNP level added prognostic information beyond conventional risk factors, (age, sex, personal history of CAD, family history of CAD, hypertension, diabetes, smoking status), creatinine clearance, BMI, lipid levels, LVEF, and clinically significant CAD on angiography. Similar findings were uncovered in a substudy analysis of the Fragmin and Fast Revascularisation During Instability in Coronary Artery Disease (FRISC)–II data. [60]

RV dysfunction and pulmonary disease

Danish researchers extrapolated the relationship between BNP and left ventricular (LV) dysfunction and the relationship between BNP and right ventricular (RV) dysfunction. [61] In 50 patients with normal LV function and normal coronary arteries who were referred for lung transplantation, NT-proBNP levels were determined before they underwent right heart catheterization. Patients with primary pulmonary hypertension had NT-proBNP concentrations 40 times higher than those of patients with terminal parenchymal lung disease.

Levels of NT-proBNP have also been useful in predicting uncomplicated clinical courses of patients with a diagnosis of acute pulmonary embolism (PE). [62, 63, 64, 65] Swiss investigators measured the NT-proBNP levels in 73 patients with confirmed PE within 4 hours of diagnosis. [62] Twenty patients had adverse outcomes, which was defined as death or the need for any of cardiopulmonary resuscitation, thrombolysis, embolectomy, vasoactive medications, or mechanical ventilation.

In this small study, a NT-proBNP level less than 500pg/mL had a negative predictive value (NPV) of 97% for complications due to PE. The NT-proBNP level remained an independent predictor for adverse outcome even after the analysis was adjusted for age, sex, history of CHF, and severity of PE.

A group in Poland performed a similar study in 79 patients with acute PE and concluded that NT-proBNP values were elevated in most cases of PE that caused RV dysfunction. They further suggested that plasma levels reflected the degree of RV overload and may help in predicting short-term outcomes. [66]

In the study, the investigators measured NT-proBNP and performed RV echocardiography to measure the extent of RV dysfunction. NT-proBNP levels were significantly higher in patients with RV dysfunction. The NPV of a normal NT-proBNP level in avoiding adverse events was 100%. Fifteen in-hospital deaths occurred, all in patients with levels greater than 600pg/mL, which were also observed in 24 patients with adverse events. However, because most NT-proBNP elevations were still less than 1000pg/mL, the positive predictive value (PPV) for adverse events with an elevated NT-proBNP level was only 36%.

The same group went on to develop a risk-stratification strategy using NT-proBNP. [67] In their validation study, both echocardiograms and NT-proBNP levels were recorded in 100 consecutive patients with acute PE. An NT-proBNP level of less than 600pg/mL was predictive of a benign course, with a mortality rate of only 4%, compared with a 33% mortality rate for patients with levels greater than 600pg/mL.

Of interest, on multivariate analysis, echocardiographic results were not independent predictors of adverse events, but NT-proBNP levels were. However, this effect may simply have been due to small sample size.

Another group examined 124 consecutive patients with proven PE who also underwent echocardiography to detect RV dysfunction and baseline measurement of NT-proBNP values. [68] Results were compared with the endpoint of death or major in-hospital adverse events. A baseline NT-proBNP cutoff of less than 1000 pg/mL had NPVs of 95% for a complicated course and 100% for death. However, an NT-proBNP level higher than this had little predictive power.

An echocardiogram demonstrating RV dysfunction was associated with a 12-fold elevation in the complication risk, whereas NT-proBNP elevation without RV dysfunction on echocardiography did not significantly increase the risk of an adverse outcome. The authors proposed NT-proBNP assay as an initial screening test in acute PE, with echocardiography reserved for patients with elevated NT-proBNP levels.

The utility of BNP and NT-proBNP testing in identifying low-risk patients with acute PE who may be eligible for outpatient therapy requires further evaluation in large studies. Furthermore, the use of the natriuretic peptides in patients with RV failure associated with other pulmonary disorders, such as obstructive sleep apnea, pulmonary hypertension, and severe chronic obstructive pulmonary disease, with cor pulmonale also requires further study.

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Clinical Uses of BNP and NT-proBNP Testing

General recommendations

The following are summary recommendations regarding the use of brain natriuretic peptide (BNP) and NT-proBNP in clinical practice. [31, 32, 69, 70]

Care must be taken to interpret results in the context of the assay being used (BNP vs NT-proBNP), the performance characteristics of the particular manufacturer’s assay, and the patient’s confounding factors and comorbidities (including obesity and renal insufficiency).

BNP levels of less than 100pg/mL and of more than 500pg/mL have a 90% negative predictive value (NPV) and positive predictive value (PPV), respectively, for the diagnosis of congestive heart failure (CHF) in patients presenting with acute dyspnea. For intermediate levels between 100 and 500pg/mL, clinicians must also consider underlying left ventricular (LV) dysfunction, effects of renal insufficiency, or right ventricular (RV) dysfunction secondary to cor pulmonale or acute pulmonary embolism (PE).

In addition, if clinical suspicion is high for CHF but the natriuretic peptide levels are lower than expected, obesity or flash pulmonary edema should be considered. The information BNP testing provides should always be considered an adjunct in decision making about the patient’s treatment and disposition.

BNP and NT-proBNP levels are increased in the presence of renal insufficiency, NT-proBNP levels more so than BNP. NT-proBNP levels can be elevated simply on the basis of the normal age-related decline in estimated glomerular filtration rate (GFR). When the calculated GFR is less than 60mL/min, NT-proBNP levels can be extremely elevated, and their utility in diagnosing CHF in this situation is unclear. For BNP, increasing the rule-out cutoff value to 200pg/mL is recommended when the GFR is less than 60mL/min.

Natriuretic peptide levels may be elevated in the intermediate range in chronic pulmonary disease when RV overload occurs. NT-proBNP and BNP levels may also be elevated in acute PE. Although elevations are not diagnostic for PE, high levels are predictive of a worsened prognosis, particularly when in conjunction with elevated troponin levels. In about 20% of patients with pulmonary disease, natriuretic peptide levels are elevated. Elevations in this context imply CHF, combined CHF and lung disease, cor pulmonale, or acute PE.

BNP and NT-proBNP may be used to identify patients with diastolic dysfunction, but cutoff points remain to be age adjusted and subsequently related to diastolic filling abnormalities.

Patients with a body mass index (BMI) greater than 30kg/m2 have low levels of BNP and NT-proBNP. Although serial determinations are likely to be useful, a diagnosis of CHF must be carefully considered in the appropriate context, even when levels are below cutoff levels.

Natriuretic peptides are independent predictors of mortality in CHF. Increased or persistent elevation in natriuretic peptide levels despite treatment suggests progression of disease or resistance to treatment. In the acute setting, failure of BNP or NT-proBNP levels to decrease with treatment is a poor prognostic factor that requires intensification of treatment.

Natriuretic peptide levels should not be measured daily. One suggested algorithm is to measure levels on admission, after 24 hours of treatment, and at discharge. Decreased natriuretic peptide levels are predictive of excellent outcomes.

BNP levels should not be measured while patients are receiving recombinant infusions of BNP (eg, nesiritide). However, NT-proBNP levels are not affected by nesiritide.

In acute coronary syndrome (ACS), troponin, creatine kinase–MB isoenzyme (CK-MB), and myoglobin are markers of myocardial necrosis and are highly predictive of adverse cardiac events. As a marker of LV dysfunction, natriuretic peptides are not helpful in diagnosing myocardial ischemia and ACS. However, BNP and NT-proBNP levels may be useful for risk stratification in patients with ACS, and they may predict clinical CHF. A multimarker approach may improve risk stratification.

BNP or NT-proBNP screening is not appropriate for low-risk, asymptomatic patients. Screening may have some value in populations with certain risk factors (eg, previous myocardial infarction, diabetes, long-standing uncontrolled hypertension); however, echocardiography is likely to remain the study of choice for assessing LV function.

ACCF/AHA recommendations

Guidelines from the American College of Cardiology Foundation (ACCF) and the American Heart Association (AHA) list as a class I recommendation the use of BNP or NT-proBNP values in the diagnosis of heart failure in ambulatory patients with dyspnea, especially when the diagnosis is uncertain, as well as their use in establishing the prognosis or disease severity in ambulatory patients with chronic heart failure. The guidelines assign a class IIa recommendation to the use of BNP or NT-proBNP in determining optimal dosing for select ambulatory patients who are clinically euvolemic and are undergoing medical therapy in a well-structured heart-failure management program. [38]

For hospitalized/acute patients, the ACCF/AHA guidelines list as a class I recommendation the use of BNP or NT-proBNP in the diagnosis of acutely decompensated heart failure, especially when the diagnosis is uncertain, as well as the use of BNP or NT-proBNP and/or cardiac troponin in establishing the prognosis or disease severity of acutely decompensated heart failure in such patients. However, the guidelines state that the usefulness of BNP or NT-proBNP in guiding therapy in hospitalized/acute patients with acutely decompensated heart failure has not been well established. [38]

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