Heart failure (HF) is a major concern for health care systems because of its chronic nature and resource implications. HF affects approximately 5.7 million Americans and about 670,000 new cases are diagnosed annually.7 Based on current population estimates,8 HF is present in 1.8 percent of Americans. The estimated total cost for HF in 2010 was $39.2 billion, or 1 to 2 percent of all healthcare expenditures.7 Health care professionals require sound evidence to provide direction for the diagnosis and management of this disease, as they face an aging population along with the need to be efficient with health care dollars.

B-type natriuretic peptide (BNP) and N-terminal proBNP (NT-proBNP) have emerged as promising markers for HF diagnosis, prognosis, and treatment. These peptides are secreted into the bloodstream by cardiac myocytes in response to increased ventricular wall stress, hypertrophy, and volume overload.

BNP is a 32 amino acid polypeptide whose release is modulated by calcium ions.9 BNP binds to and activates natriuretic peptide receptors A and B. NT-proBNP is a 76 amino acid N-terminal fragment of BNP and is secreted along with BNP.9

The physiologic actions of BNP are similar to A-type natriuretic peptide (ANP) and include decreases in systemic vascular resistance and central venous pressure as well as increases in natriuresis. Thus, the net effect of BNP and ANP is a decrease in blood volume which lowers systemic blood pressure and afterload, yielding an increase in cardiac output, partly due to a higher ejection fraction. Since BNP and NT-proBNP levels are increased in persons with HF, measurement of these two peptides have consequently come to be included in clinical practice guidelines for HF.10 It is interesting to note that the various guidelines weight the evidence related to natriuretic peptides differently.10-12 This suggests that the evidence related to the natriuretic peptides is difficult to evaluate. Currently the guidelines recommend the use of natriuretic peptides to help in the diagnosis of HF at the time of presentation because of their ability to rule out HF (Acute HF, Strong recommendation, moderate quality of evidence; chronic HF, Strong recommendation, High quality of evidence11 and class IIa Level C12). Both these guidelines include a comment with the diagnostic information that suggests prognostic information is obtained from the natriuretic peptide test. The European Society of Cardiology (ESC) guideline13 mentions serial testing of natriuretic peptides but does not weight the evidence and the Canadian Cardiovascular Society guidelines11 suggest the addition of an additional drug if natriuretic peptides remain elevated, suggesting that serial monitoring may be performed.

HF is a syndrome characterized by combinations of symptoms, signs and diagnostic test changes.14 It is further sub-categorized into a number of categories that include terms such as “acute”, “decompensated”, “exacerbation”, “systolic”, “diastolic”, “right”, “left”, “congestive” and “chronic”.11,15-17 The challenge facing any synthesis of evidence in a complex syndrome such as HF is in defining what the individual authors and studies interpret and use as HF. However, it remains true that clinicians in practice continue to use the syndrome of HF as a diagnostic term11,12,15,18 and that this condition results in substantial use of the health care system. The challenge in evaluating a diagnostic test is the comparison against a reference “Gold Standard”. The only available standard in HF is clinical judgment and this is an imperfect reference standard. Thus the evaluation of natriuretic peptides needs to be considered in the context of a condition with a variable definition.19 Due to these factors, synthesis of data should try and contextualize the clinical setting to allow the practicing physician the opportunity to identify the set of data that is applicable to the patients that are being evaluated.

A comprehensive systematic review of BNP and NT-proBNP was completed in 2006 by the McMaster Evidence-based Practice Center (EPC) for the Agency for Healthcare Research and Quality (AHRQ).20 This review included studies published up to January 2005.

Due to the vast amount of literature published after January 2005, the obsolescence of certain assay types used in earlier studies of BNP and NT-pro-BNP, as well as new Key Questions (KQ) that account for the evolution of the field, an entirely new systematic review is required to provide an assessment of the “state of the science” in this field.

To summarize the current body of scientific knowledge, this review examines the diagnostic and prognostic use of BNP and NT-proBNP in several aspects of HF. The review will consider BNP and NT-proBNP test performance, cutpoints, and factors that affect test performance in emergency, urgent care, and primary care settings. As well, the review will investigate whether BNP and NT-proBNP are independent predictors of morbidity and mortality in HF, or whether they add information to other methods used to predict morbidity and mortality. The review will examine whether therapies involving BNP and NT-proBNP improve outcomes in HF patients and whether the biologic variation of BNP and NT-proBNP differs in HF and non-HF populations.

Diagnosis, Prognosis, and Treatment Strategies

Diagnosis of Heart Failure

Congestive HF is a common condition, especially among the elderly, and one of the most common reasons for admission to hospital. The diagnosis of HF remains a difficult clinical challenge. The diagnosis is based on a constellation of symptoms (e.g., breathlessness, fatigue, and ankle swelling) and signs (e.g., tachycardia, tachypnea, rales, increased jugular venous pressure, hepatomegaly, and edema), supported by objective evidence of structural abnormality of the heart shown by abnormalities in the echocardiogram or chest X-ray. Reviews of the role of the natriuretic peptides BNP and NT-proBNP suggest that they have value in ruling out the presence of HF due to the high sensitivity of the test. However, low specificity limits the test's usefulness for ruling in HF.20,21 In addition there are challenges in assessing the diagnostic utility of a test when there is no valid reference standard.19

Clinical guidelines,11,12 including the 2009 update to the American College of Cardiology/American Heart Association (ACC/AHA) 2005 guideline for the diagnosis and management of HF in adults,10 indicate that measuring natriuretic peptides may be a useful addition to the standard set of diagnostic tools used to evaluate suspected HF. These guidelines caution users about poor specificity and the need to account for potential confounders, such as age, ethnicity, and comorbidities (including renal disease and obesity).

Since the publication of the AHRQ review in 2006,20 several primary publications have addressed the diagnostic test accuracy of the natriuretic peptides for patients with HF presenting to the emergency department and to primary care physicians.22-28 Both the emergent population (those with symptoms acute enough to warrant presentation to the emergency department or urgent care facilities) and the primary care population (those with risk factors, signs, and symptoms evaluated by a primary care physician) are areas of research that would benefit from a systematic review of the evidence. Decision cutpoints have been proposed in several publications (most recently in the National Institute for Health and Clinical Excellence (NICE) Clinical Guideline No. 108, 201029), but they have not been optimized for specific populations. Also, the effect of comorbidities on the decision cutpoints has not been systematically reviewed in terms of diagnosis. The value of these tests will be further refined by examining which decision cutpoints maximize the diagnostic criterion of interest and how they perform in specific populations, including patients with comorbidities.

Prognosis of Heart Failure

Prognostic use of BNP and NT-proBNP has been studied in a number of primary studies and has been the subject of at least four systematic reviews.30-33 The most recent of these systematic reviews includes primary studies up to July 2009.30Although these systematic reviews differed in the eligible studies evaluated, they reported consistent evidence that BNP and NT-proBNP were independent predictors of mortality and other cardiac outcomes in patients with HF.30-33 In addition, they suggested that a discharge or post-treatment BNP and NT-proBNP is a better predictor of prognosis.30-33 The reviews also found that BNP and NT-proBNP could add useful information to the standard cardiovascular disease (CVD) risk assessment in certain populations. In fact, the updated NICE guideline29 for CHF notes that higher BNP and NT-proBNP levels are associated with poorer prognosis in HF. NICE recommends high priority research in the area of determining prognostic stratification (page 208) and lists important outcomes in this respect. The most recent update to the Canadian guideline includes reference to the use of natriuretic peptides in a prognostic score.11 The European guideline includes a table of prognostic factors that includes the natriuretic peptides.12 Neither of these guidelines separate out the prognostic use of BNP and NT-proBNP from the diagnostic use.

Two systematic reviews, published in 200531 and 2006,20 have evaluated the evidence that BNP and NT-proBNP are predictive of mortality and other cardiac events in patients with HF. Doust et al.31 evaluated studies in patients with HF and also in persons with no overt disease. Based on this review, BNP was shown to be consistently associated with an increased relative risk (RR) of death, even among asymptomatic subjects. The second systematic review20 employed broader eligibility criteria and included almost double the number of eligible studies. This review showed similar results to the review by Doust et al. and indicated that baseline BNP or NT-proBNP levels were independent predictors of mortality across various cutpoints.

The prognostic value of these tests requires further evaluation in the different clinical settings (acute care and physician office or out-patient clinic) and type of HF (decompensated and chronic) in which the tests are proposed for use as a prognostic factor.


Optimization of therapy for patients with HF remains challenging due to the difficulty in perceiving signs and symptoms associated with HF unless they are overt. Current practice guidelines are based on target doses used in clinical trials, but are not individualized for patients. Up-titrations of these medications may take into consideration factors such as age, disease severity, and other comorbidities, but do not include any biological parameter of HF. That is, a biomarker that reflects the functioning of the heart, similar to other biomarkers used in disease therapy such as thyroid stimulating hormone for hypothyroidism or hemoglobin A1c for diabetes monitoring. The measurements of BNP and NT-proBNP have been advocated as biomarkers to guide treatment because the peptides are independently associated with prognosis32 and their concentrations decrease with effective therapy.34 It is unclear whether biomarker-assisted therapy to achieve a concentration below a target value, or intensified therapy (the adjustment of therapy based on a change in biomarker concentration) reduces mortality, rehospitalization, or increases quality of life, compared with usual care.

When the AHRQ report on BNP was produced in 2006, the large interventional trials to address this question had just begun, so minimal data were available. Since then, nine randomized controlled trials (RCTs) have been completed and several more RCTs are currently underway. The design of the RCTs are such that one arm receives usual care for HF and the other arm receives management based on a target BNP or NT-proBNP goal. In the most recent systematic review,35 eight RCTs were reviewed and BNP-guided therapy was found to be beneficial: the RR for all-cause mortality was lower in the guided therapy group compared with the usual care group (RR=0.76; 95% CI, 0.63 to 0.91; p=0.03). However, this review has been critiqued for having an absence of information on the included studies and a discussion that does not thoroughly explain the findings.36 Pooling of different studies with different populations and different management algorithms limits the robustness of the effect estimate.

Furthermore, knowledge of the variation of a test measure is important when treatment is based on a difference between serial measurements. It is not currently known how much of a difference in BNP or NT-proBNP concentrations is clinically important. Variation in a test measure is a function of the analytical variation of the assay method (bias and precision) and the inherent biologic variation of the molecule tested. The biologic variation may also be a function of disease severity, sex, medications, and comorbidity.

Several studies have collected data in an attempt to understand the magnitude of the variation of BNP and NT-proBNP.37-39 These studies have looked at the within-day, day-to-day, and week-to-week variations of BNP and NT-proBNP in healthy individuals and in patients with stable chronic HF. The biologic variation for individuals (CVI) was found to increase with time between measurements for both BNP and NT-proBNP. However, there is inconsistency among studies, method types, and statistical analysis methods.

Key Questions

The EPC convened a group of experts in the fields of BNP, NT-proBNP, HF, and systematic review methods to form the Technical Expert Panel (TEP). Members of the TEP provided clinical and methodological expertise and input to help interpret the KQs guiding this review, identify important issues, and define parameters for the review of evidence. Discussions among the EPC, Task Order Officer (TOO), and the TEP occurred during a series of teleconferences and via email.

The KQs listed in the Introduction were provided by the American Association for Clinical Chemistry (AACC). We revised the KQs for scope and clarity in conjunction with the AACC, TEP, and TOO.

Key Question 1: In patients presenting to the emergency department or urgent care facilities with signs or symptoms suggestive of heart failure (HF):

  1. What is the test performance of BNP and NT-proBNP for HF?
  2. What are the optimal decision cutpoints for BNP and NT-proBNP to diagnose and exclude HF?
  3. What determinants affect the test performance of BNP and NT-proBNP (e.g., age, gender, comorbidity)?

Key Question 2: In patients presenting to a primary care physician with risk factors, signs, or symptoms suggestive of HF:

  1. What is the test performance of BNP and NT-proBNP for HF?
  2. What are the optimal decision cutpoints for BNP and NT-proBNP to diagnose and exclude HF?
  3. What determinants affect the test performance of BNP and NT-proBNP (e.g., age, gender, comorbidity)?

Key Question 3: In HF populations, is BNP or NT-proBNP measured at admission, discharge, or change between admission and discharge, an independent predictor of morbidity and mortality outcomes?

Key Question 4: In HF populations, does BNP measured at admission, discharge, or change between admission and discharge, add incremental predictive information to established risk factors for morbidity and mortality outcomes?

Key Question 5: Is BNP or NT-proBNP measured in the community setting an independent predictor of morbidity and mortality outcomes in general populations?

Key Question 6: In patients with HF, does BNP-assisted therapy or intensified therapy improve outcomes compared with usual care?

Key Question 7: What is the biological variation of BNP and NT-proBNP in patients with HF and without HF?

Analytic Framework

To guide this systematic review and facilitate the interpretation of the KQs, an analytic framework (Figure 1) that depicts the logical progression and interconnection of all seven KQs was developed.

Figure 1 is the analytic framework integrating the seven Key Questions addressed in this review. Acute care (signs or symptoms of heart failure) and primary care (risk factor[s], signs or symptoms of heart failure) are written at the extreme left of the figure. An arrow leads to the right of acute care and this arrow represents KQ 1. An arrow leads leads to the right of KQ 2 and this arrow represents KQ 2. Both arrows lead to a box labelled ‘heart failure’. Emanating from this box are arrows representing KQs 3, 4, and 6. At the extreme bottom left of the figure are the words ‘general population’ and an arrow representing KQ 5 runs from this text to the right of the figure. The arrows for KQs 3, 4, 5, and 6 lead to a box at the right-hand side of the figure. This box contains the following text: Mortality (all cause, heart failure), Hospitalization (heart failure, all cause, planned, unplanned), Change in NYHA class, and Quality of life. Arrows connect KQ 1 and 2 with KQ 5. An arrow for KQ 7 is separate from the other arrows and at the top of the figure. This arrow connects to KQ 1 and 2 on the left and leads to a box on the right side of the figure labelled ‘Biological variation’. The arrow for KQ 7 is labelled ‘BNP and NT-proBNP’. Arrows involving KQ 6 are labelled ‘BNP or NT-proBNP guided or assisted therapy’ and ‘Usual care’. KQ 3 arrow is labelled ‘BNP or NT-proBNP value’ and KQ 4 arrow is labelled ‘Other progostic factor’.

Figure 1

Analytic framework. Note: BNP = B-type natriuretic peptide; ED = emergency department; KQ = Key Question; NT-proBNP = N-terminal proBNP; NYHA = New York Heart Association.

The analytic framework describes the interconnection between the study questions examining diagnosis, prognosis, therapy and screening. For diagnosis of patients with signs and symptoms compatible with HF, the two settings are acute care (KQ1) and primary care (KQ2). A third setting is the general, undifferentiated, population without overt signs or symptoms of HF (KQ5). KQ5 examines the ability of BNP/NT-proBNP to predict mortality and morbidity outcomes in this population. Prognosis of patients with established HF is addressed in KQ3 and 4. Prognosis, where the outcome is associated with the concentration of BNP/NT-proBNP is addressed in KQ3, whereas other prognostic measures are dealt with in KQ4. Once a diagnosis of HF has been made, patients are treated. KQ6 will examine RCTs comparing usual care with BNP/NT-proBNP guided therapy to assess outcome measures. The outcomes to be examined, if reported, include mortality, hospitalization, change in New York Heart Association (NYHA) class and quality of life. In addition, information on the biological variation of BNP and NT-proBNP will be gathered (KQ7).