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Balion C, Santaguida PL, Hill S, et al. Testing for BNP and NT-proBNP in the Diagnosis and Prognosis of Heart Failure. Rockville (MD): Agency for Healthcare Research and Quality (US); 2006 Sep. (Evidence Reports/Technology Assessments, No. 142.)

  • This publication is provided for historical reference only and the information may be out of date.

This publication is provided for historical reference only and the information may be out of date.

Cover of Testing for BNP and NT-proBNP in the Diagnosis and Prognosis of Heart Failure

Testing for BNP and NT-proBNP in the Diagnosis and Prognosis of Heart Failure.

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B-type Natriuretic Peptides

B-type natriuretic peptide (BNP) and N-terminal proBNP (NT-proBNP) have emerged as promising markers for heart failure (HF) diagnosis, prognosis, and treatment. BNP is produced from heart muscle cells, mainly in the left ventricular myocardium but also in the atrial myocardium, as a pro-hormone and released into the cardiovascular system in response to ventricular dilation and pressure overload. Regulation of BNP is at the level of gene expression; there is no storage of BNP in cardiomyocytes. The pro-hormone (proBNP1-108) is split inside the myocyte by the protease furin and secreted as the physiologically active C-terminal fragment BNP77-108 (BNP1-32 or BNP) and the inactive NT-proBNP1-76 fragment. BNP exhibits several physiologic functions including vasodilation, promotion of natriuresis and diuresis, inhibition of the sympathetic nervous system and several hormone systems such as the renin-angiotensin-aldosterone system, as well as inhibitory and beneficial effects on the physiological mechanisms associated with the cardiovascular system.151 BNP has a half-life of 22 minutes,152 whereas NT-proBNP has a longer half-life estimated to be 1 to 2 hours.153 The major clearance mechanisms for BNP are endocytosis through the natriuretic peptide receptor C and by enzymatic degradation by neutral endopeptidase, while for NT-proBNP it is through the reticuloendothelial system and renal clearance. For more information on the biochemistry and physiology of B-type natriuretic peptides the reader is referred to recent reviews on this subject.154, 155 In this report BNP and NT-proBNP will be referred to as the B-type natriuretic peptides unless it is pertinent to refer to one of these specifically.

Heart Failure

Heart failure is a complex clinical syndrome that occurs when there is alteration in the function or structure of the heart that reduces its capability to supply adequate blood flow throughout the body. It is an important clinical problem with significant morbidity, mortality, and socioeconomic impact. Approximately 5 million patients in the United States of America have HF, and a first time diagnosis will occur in over 550,000 patients annually.156 The prevalence is 1.8 percent but rises to 10 percent after age 75. Heart failure is the leading cause of hospitalization in people over 65 years. The natural history of HF is poor, and within 5 years of diagnosis 60 percent of men and 49 percent of women will die of the disease.

Given that HF is a complex clinical syndrome, diagnosis relies on clinical judgments with respect to generic symptoms reflecting cardiac problems. The clinical symptoms in the early stages of HF are non-specific and although a key symptom is dyspnea, it may be difficult to identify the cause. Similar symptoms are found in the elderly or obese patients with respiratory disease,157 and syndromes associated with edema and fatigue. Imaging diagnostics such as chest x-rays, echocardiography, radionuclide angiogram (RNA), magnetic resonance imaging (MRI) and computed tomography (CT) are used as objective criteria to diagnosis and monitor patients. Several guidelines for diagnosis and management of HF have been produced including those from the American College of Cardiology/American Heart Association,156 the Canadian Cardiology Society,158 the European Society of Cardiology, 159 and the modified Framingham Clinical Criteria for Heart Failure160. Early diagnosis of HF and prompt treatment (e.g., angiotensin-converting enzyme (ACE) inhibitors, diuretics, and beta blockers) leads to a better prognosis and quality of life.161

Determinants of B-type Natriuretic Peptides

As B-type natriuretic peptides are involved in several physiological processes their concentrations will be influenced by factors that affect these processes. Increasing age is associated with a decline in cardiac function and endocrine diseases such as hyperthyroidism increase blood pressure. Drugs such as ACE inhibitors that affect the renin-angiotensin-aldosterone system, or that reduce the effects of catecholamines such as beta blockers, as well as those like diuretics that increase fluid loss, will alter the level of B-type natriuretic peptides. These are just a few examples of variables that may be important when interpreting B-type natriuretic peptide levels. Analytical factors such as sample collection procedure, test method, interference and sample stability can also falsely alter concentrations.155 Given the potential importance of B-type natriuretic peptides there was interest in gathering the evidence on determinants that are associated with changes in B-type natriuretic peptide levels.162 These determinants have the potential to confound the accurate interpretation related to diagnosis, prognosis and the ability to monitor treatment effectively.151

Diagnosis of Heart Failure Using B-type Natriuretic Peptides

Evaluation of the diagnostic properties of the B-type natriuretic peptides are important if they are to be fully understand both in terms of both strengths and weaknesses for use in HF. The quality of any biochemical test is dependent upon the biological properties of the analyte, the test method used, the diagnostic threshold chosen and the skill and knowledge of those interpreting the test result. The characteristics of the population that presents for testing, including the prevalence and severity of the disease, are also important. This is particularly true in situations where the severity of the disease affects the magnitude of the test response, such as in HF. The diagnostic characteristics of a test, including sensitivity, specificity, negative and positive likelihood ratio, are likely to vary by the setting where patients present for care. The acuity of symptoms in patients who are evaluated in an emergency department setting, for instance, are likely to be quite different than those who are seen in primary care settings or in a specialized clinic. Furthermore, when interpreting the results of a diagnostic test, it is important to know whether or not the information obtained is independent from, and of added value to, information obtained by other tests.

Prognostic Utility of B-type Natriuretic Peptides

There are high rates of mortality and acute decomposition events requiring hospitalization in HF patients. This demonstrates the need for a good prognostic indicator so that treatments can be optimized. Identification of patients who may be at higher risk for readmission could result in these patients being treated more aggressively. B-type natriuretic peptides could be used to more quickly identify patients who are at higher risk for developing cardiovascular events. Again, as for HF patients, these at risk patients may benefit from accelerated therapy. It is not clear, however, whether or not B-type natriuretic peptides measurements provide an added benefit to current methods of assessment of patients who may be at high risk for cardiovascular events.

Several studies have reported that elevated B-type natriuretic peptide levels are inversely related to the prognosis in patients with coronary artery disease (CAD), HF and possibly other subgroups. Higher levels of B-type natriuretic peptides, or levels that do not decrease despite an intervention, suggest a poorer prognosis overall.163 The ability of the B-type natriuretic peptides tests to function as a prognostic marker for subsequent cardiac events is important to consider. As a prognostic marker B-type natriuretic peptides could have great value in identifying subjects by level of risk for subsequent cardiac events and in identifying those most amenable to interventions for arresting further progression to more serious disease.

The use of B-type natriuretic peptides as a screening test could assist in reducing morbidity associated with subsequent heart dysfunction development. However, its use would also have to take into consideration the efficacy and acceptability of the current therapies for HF, and the degree to which the natural history of the disease is understood.

Treatment Monitoring Using B-type Natriuretic Peptides

Therapeutic strategies range from drugs to invasive and costly methods such as cardioverter-defibrillators and heart transplantation. The pace and type of therapy given is, for the most part, clinically guided. It would be of benefit to have more objective guides to monitor therapy. B-type natriuretic peptides may be helpful in this regard as they have been shown to predict morbidity and mortality in HF patients.

There has been some evidence that suggests the potential usefulness of sequential BNP or NT-proBNP measurements in monitoring patients with HF.148, 149 B-type natriuretic concentrations decrease when patients with HF are treated, and lower BNP concentrations are associated with fewer cardiovascular events. It remains unclear, however, both if monitoring BNP levels can reduce those levels more quickly by prompting the use of more aggressive therapy and, what the target levels should be. It might be possible to improve current drug therapy by tailoring it to the patient if clearer measures of the effect of the therapy were known. Some patients may benefit from dosages higher than the guidelines indicate, or conversely, lower doses may be sufficient in other patients thereby reducing the risk of side effects. Moreover, it is not clear if the utility of the B-type natriuretic peptides measurement varies with the type of intervention used to manage HF. It was therefore of interest to search the literature for information on the utility of sequential BNP or NT-proBNP measurements in monitoring treatment in stable HF patients.

Scope and Purposes of the Systematic Review

This systematic review addresses 4 main questions as follows:


What are the determinants of both BNP and NT-proBNP measurement?


With respect to the diagnosis of heart failure:


What are the clinical performance characteristics of both BNP and NT-proBNP measurement in patients with symptoms suggestive of heart failure (HF) or with known HF


presenting to the emergency department (ED)


in a specialized clinic or outpatient setting


presenting to a primary care setting


presenting in long term care setting


all settings combined


Does measurement of BNP or NT-proBNP add independent diagnostic information to the traditional diagnostic measures of HF in patients with symptoms suggestive of HF?


Do BNP or NT-proBNP levels predict cardiac events in populations:


Specific populations


at risk for coronary artery disease (CAD)


with diagnosed CAD


with diagnosed HF


What are the screening characteristics of BNP or NT-proBNP in general asymptomatic populations?


Can BNP or NT-proBNP measurement be used to monitor response to therapy?

This systematic review will serve to identify both the strength of the evidence and gaps in existing research to facilitate future research priorities.

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