Dr. Deol is from the Division of Geriatrics, Dr. Vaitkevicius is from the Division of Cardiology, and Dr. Cardozo is Chief, Division of Geriatrics, Geriatric Center of Excellence, Wayne State University/Detroit Medical Center, MI.
Release Date: June 15, 2008
Expiration Date: June 15, 2009
TARGET AUDIENCE
Internists, family practitioners, geriatricians, cardiologists, and others who care for older patients.
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Successful completion entails participants obtaining a score of at least 70% on the post-test. A certificate of completion will be mailed to the address listed on your post-test/evaluation form within 6-8 weeks of receipt of the documents.
ACCREDITATION
MD/DO:
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In compliance with ACCME Standards for Commercial Support and NACCME’s policy and procedure for resolving conflicts of interest, this continuing medical education activity was reviewed by a member of the Advisory Board in May, 2008 for clinical content validity, to ensure that the activity’s materials are fair, balanced, and free of bias, and that the activity materials represent a standard of practice within the profession in the U.S. and that any studies cited in the materials upon which recommendations are made are scientifically objective and conform to research principles generally accepted by the scientific community.
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Learning Objectives
Upon completion of this educational activity, participants should be able to:
1. Explain the role of BNP in the screening, diagnosis, follow-up, and prognosis of heart failure in older patients.
2. Identify and interpret the variation in BNP levels/values due to age, gender, and renal function.
3. Discuss the atypical presentations of heart failure in older persons and the diagnostic difficulties in this patient population.
4. Identify the factors related to the higher frequency of heart failure in older adults and the comorbid conditions that contribute to heart failure in this patient population.
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Despite advances in management and therapies, heart failure (HF) remains a major health and economic concern in the United States and around the world. Currently, there are approximately 5.3 million people with HF, with approximately 550,000 new cases diagnosed annually. There has been a significant increase of nearly 171% in the number of patients discharged from hospitals with the diagnosis of HF. Additionally, for 2008, the direct and indirect costs of HF in the United States is estimated to be $34.8 billion.1
HF in Older Persons
It is estimated that 80% of the 5 million people with HF are above the age of 65 years.2 More than 79% of the patients hospitalized for HF are older persons.3 The current incidence of HF approaches 10 per 1000 population. Along with the increased incidence and prevalence in older age, HF also carries high levels of morbidity and mortality, the latter accounting for nearly 284,365 total deaths in the United States each year.1 Of note, 88% of these deaths occur in adults over age 65 years.3 The U.S. Census Bureau estimates that there are nearly 35.9 million Americans over age 65 years and has projected that by the year 2030 these numbers will exceed 71.4 million. As a result of these demographic shifts, the incidence of HF will quadruple; moreover, half of these cases will be confined to patients over age 80 years. These statistics make HF in older persons a national public health priority.
Why Are Older Persons More Susceptible to HF?
A number of morphologic and physiologic changes in the cardiovascular system contribute to a higher frequency of HF in the older adult. Age and disease-related stiffening of the vessels throughout the vascular system leads to increased systolic blood pressure, even in patients with no evidence of hypertensive heart disease. As a result, peripheral vascular resistance increases, leading to increased afterload stress and a higher ventricular workload.3 Because of the increase in afterload, the myocytes hypertrophy, resulting in acceleration of the myocyte toward apoptosis. In aged hearts, despite the preserved systolic function, apoptosis, cellular hypertrophy, deposition of intramural calcium, and collagen deposits result in increasing stiffness of the ventricular walls.3 In addition, there are age-related changes that slow the intracellular calcium flux and delay diastolic filling in the ventricles, independent of the afterload pressures. Thus, the intrinsic changes in the heart, along with increased prevalence of atherosclerosis and impairment of diastolic function, lead to a higher propensity for the development of cardiac ischemia in the older adult. These changes continue to progress, leading to a decrease in the chronotropic properties of the heart and resulting in a lower cardiac output reserve. This is compounded by autonomic changes in terms of decreased beta-adrenergic responses that blunt the counterregulatory mechanism.
Affect of Associated Comorbidities
Older patients tend to have a number of comorbid conditions that contribute to HF. Other cardiovascular diseases, hypertension, coronary artery disease, cardiac valve disease, and atrial fibrillation may be concomitantly present with HF, leading to acceleration of cardiovascular aging and decompensation of HF. Older patients are in a “homeostenotic state.” They have reduced system reserves as a part of the normal aging process. As a result of these comorbid conditions (eg, renal insufficiency, diabetes, thyroid diseases, metabolic disturbances, depression, anemia, stroke, malignancy), the cardiovascular reserves can become overwhelmed, leading to decompensated HF. Polypharmacy can also contribute to adverse outcomes as a result of drug interactions, toxicity, or reduced compliance. In addition, nonadherence with fluid restriction, consumption of foods with high salt content, lack of exercise, alcohol, and drug abuse can also impair cardiovascular stability in older patients.
Diagnostic Difficulties in Older Persons with HF
Older patients do not always present with typical features of HF, such as dyspnea, orthopnea, and lower-extremity edema. They may have subtle or nonspecific complaints like confusion, somnolence, fatigue, anorexia, depression, and a decreased level of activity. The presence of atypical presentations may be compounded by other comorbid conditions, rendering the diagnosis of HF in the older adult difficult. When older patients present with dyspnea, it is frequently difficult to distinguish between cardiac and non-cardiac causes. After a careful history and examination, echocardiography—which is considered a gold standard—may help to define the cause; however, lack of immediate access might be a problem. In addition, echocardiography has practical limitations, it is time-consuming, expensive, not readily available at the bedside, and requires expertise to interpret the results.4,5 It is also important to recognize that echocardiography has a poor sensitivity for the diagnosis of diastolic dysfunction.6
In the context of typical HF symptomatology, echocardiography is helpful in defining those patients with HF in the setting of a normal ejection fraction, which may comprise as many as 40% of the older patients with HF. The problem arises in patients with atypical symptoms and an echocardiogram demonstrating a preserved contractile function. A retrospective study of 116 older patients (median age, 86 yr) in Europe found that because of atypical presentation, presence of comorbid conditions, and other diagnostic difficulties, they were less likely to be further evaluated with the use of echocardiography.7
Given the prevalence of atypical symptoms, confusion caused by manifestations of associated comorbid conditions, and the lack of access or underutilization of echocardiography, the role of B-type or brain natriuretic peptide (BNP) in the diagnosis and management of HF in the older adult merits review.
The Role of BNP in HF
Because of the dramatic impact HF has on the morbidity, mortality, and cost of care, a rapid, accurate, and reliable tool is needed to differentiate HF from other causes of dyspnea. Based on numerous studies, BNP is increasingly being used for the diagnosis of HF, especially in the emergency room setting. It is estimated that in the United States more than 70% of hospitals utilize BNP testing.8 In addition to the clinical presentation, BNP levels not only help with the diagnosis and monitoring of patients with HF, but also provide information on risk of hospitalization, prognosis, and mortality.
BNP is a 32-amino acid protein, first isolated in porcine brain.9 It is secreted specifically from the ventricles of the normal heart as well as a failing heart.9 Its secretion is in proportion to many triggers resulting from volume overload, including stretching of the ventricular wall, ventricular dilation, and increased pressures.8 Many studies have shown that BNP has a superior correlation to other parameters that reflect ventricular systolic dysfunction.8,9 Diastolic dysfunction resulting from impairment of ventricular relaxation is a common cause of HF in patients presenting with dyspnea, and is also associated with high BNP levels, though the mechanism by which this occurs is poorly understood. A study was conducted by Lubien et al10 to assess the utility of BNP in detecting diastolic dysfunction in patients referred for echocardiography. Patients diagnosed with abnormal diastolic function had an elevated BNP concentration as compared to the normal left ventricular (LV) function group. Moreover, these levels were elevated with all diastolic filling patterns.10
BNP Assay
The measurement of BNP is done by blood sample assay. Currently available BNP assays are rapid and accurate. The most widely used assay is the Triage® BNP test, which is a point-of-care assay that uses whole blood or plasma, produces results in approximately 15 minutes, and uses a cutoff level of 100 pg/mL.8 In a study by Maisel and colleagues,5 the BNP cutoff value of 100 pg/mL had a sensitivity of 90%, a specificity of 76%, and an accuracy of 83% for differentiating HF from other causes of dyspnea. Lower values were associated with more accurate negative predictive values (for a BNP value of 50 pg/mL, the negative predictive value was 96%). A BNP value of 100 pg/mL or more was the strongest predictor of HF.5 As per the BNP Consensus Panel 2004 (statement 2), if the BNP level is less than 100 pg/mL, HF is unlikely; if the BNP level is greater than 500 pg/mL, HF is very likely. For BNP levels of 100-500 pg/mL, one must consider baseline elevation of the BNP secondary to stable cardiac dysfunction, cor pulmonale, acute pulmonary embolism, and renal insufficiency.8
Are BNP Levels Reliable in All Patient Groups?
Variation in the predictive value of BNP has been noted due to age, gender, and renal function. This necessitates adjusting the BNP level when interpreting the results.
Effect of Age
BNP levels increase with age in normal populations free of ventricular dysfunction.11,12 Age and LV hypertrophy independently contribute to elevation of BNP. Some contribution to these elevated levels may be attributed to reduction in glomerular filteration rate and mild diastolic dysfunction.11 Each of these changes is likely to alter BNP production and turnover. A study was done in Paris by Ray et al4 to evaluate the usefulness of BNP in older persons (> 65 yr) presenting to the emergency department with acute dyspnea of less than two weeks duration. Data were analyzed from 308 patients, with a mean age of 80 ± 8 years and a creatinine clearance of 54 ± 35 mL/min. The median BNP level was 575 pg/mL in the group with cardiogenic pulmonary edema and 75 pg/mL in those without. The best threshold value of BNP was greater than 250 pg/mL. Previous studies have demonstrated similar findings; however, the study populations mostly involved patients younger than age 65 years where the cutoff level of BNP was 100 pg/mL. This study suggests that the threshold value of BNP is higher in older patients. A cutoff value of 250 pg/mL had good sensitivity, specificity, and accuracy for the diagnosis of cardiogenic pulmonary edema in an emergency department. In the multiple regression model, a BNP level of 250 pg/mL or more was not only the strongest independent predictor of cardiogenic pulmonary edema, but was also associated with greater inhospital mortality.4
Sayama and colleagues11 compared echocardiographic measures of LV function with BNP levels in 117 older adult patients undergoing physical rehabilitation due to stroke or frailty related to dementia. Six percent had history of coronary artery disease, 8% had HF with all being New York Heart Association Class II or less, the mean ejection fraction was 59% and was similar by gender. The average BNP was 3.5 times higher than the normal range and was greater for those with renal dysfunction. In this study, LV hypertrophy, LV systolic and diastolic dysfunction and renal failure contributed to elevation in BNP levels in this patient cohort without overt HF symptoms.11
Effect of Gender 
The relationship of BNP levels with gender is less well defined, demonstrating variability between studies. One trial has shown that females have higher levels of BNP than males, and female gender is an independent predictor of BNP levels in the older adult even without cardiac dysfunction.13 Other studies did not find any significant interaction between age and BNP, or between gender and BNP with regard to accuracy of diagnosing HF.11,14,15 The discrepancy among the findings in these studies is likely explained in part by the differences in the study designs and study populations.
Effect of Renal Dysfunction
The Breathing Not Properly Multinational Study is a large prospective study using BNP as diagnostic test to evaluate the independent relationship between renal function, HF, and BNP.16 It concluded that the BNP levels are affected by renal function. Patients with renal insufficiency may need to have different cutoff values. The influence is primarily seen in those with an estimated glomerular filtration rate of less that 60 mL/min, where a 200 pg/mL level would be a clinically reasonable cutoff.16
Thus, BNP values should be interpreted while taking into consideration comorbid conditions, such as renal insufficiency, as well as the influence of other factors such as age and gender.
Cost-Effectiveness of BNP Measurement 
Many studies have shown that measurement of BNP for diagnosis of HF in the emergency department is cost-effective. It is associated with a decrease in hospital admission rate, length of stay, and readmission rates. The total cost of treatment is also reduced by more efficient use of hospital resources, by eliminating the need for expensive cardiac tests, and by focusing on alternative diagnosis when applicable.8,16-18
The Prognostic Value of BNP (Inpatient and Outpatient)
A study done by Koglin et al18 examined the role of BNP in risk stratification of patients with HF. Individual patients were assigned to a prognostic score risk group (low, medium, high), based on individual heart failure survival score (HFSS). Study results showed that plasma BNP concentrations and HFSS showed a significant inverse correlation. A high HFSS with low BNP levels was associated with better outcomes, while the low HFSS with high BNP had worse outcomes. Increased plasma BNP levels were also strongly associated with deterioration of physical activity. Thus, elevated level of BNP is significantly associated with clinical events (deterioration of physical activity or patient death). A cutoff of beyond 107 pg/mL was 88% sensitive and 75% specific for differentiating patients with adverse clinical outcomes.
Harrison and colleagues19 followed a convenient sample of 325 patients for six months after they presented to the emergency department with dyspnea. They found that increasing BNP levels predicted worse outcomes. BNP levels greater than 480 pg/mL showed worse prognosis as compared to BNP levels below 230 pg/mL, where the prognosis was excellent.19
Data from the Valsartan Heart Failure Trial (Val-HeFT) examined the role of BNP on mortality and morbidity.20 Plasma BNP levels were measured before randomization and during follow-up (4, 12, and 24 mo) in approximately 4300 patients. Data showed that the incidence of all-cause mortality and first morbid events was significantly higher for patients with elevated baseline BNP. While the absolute change from baseline did not show change in mortality, the percentage change from baseline demonstrated a direct relationship with mortality. The highest mortality was seen in patients with the largest percentage increase in BNP, while the lowest mortality was observed in patients with the largest percentage decrease in BNP.
In patients hospitalized for decompensated HF, predischarge BNP levels can help identify patients who are at high risk of readmission.21 Logeart et al21 showed that the predischarge BNP levels are a strong predictor of short-term death or readmission after acute hospital care for decompensated HF. The risk of death or readmission increased in a step-wise fashion for those with increasing BNP levels. There was a significant increase in the events at levels 350 ng/L and higher. BNP levels greater that 700 ng/L were associated with a major risk (31% of death or readmission for HF at 1 month and 93% at 6 months). Bettencourt and colleagues22 followed 84 patients with systolic dysfunction, measuring the baseline BNP on recruitment and at intervals of 8 to 12 months. Increasing levels of BNP were found to be associated with shorter survival. This indicates that serial measurements of BNP provide important prognostic information in HF. It is known that patients with HF are at risk for sudden cardiac death. Berger et al23 studied 452 ambulatory patients with ejection fraction of less that 35%. BNP levels of less than 130 pg/mL showed higher survival than those at higher values. Using this level as a cutoff, only 1% below this level experienced sudden death as compared to 19% above this level.23 This indicates that BNP levels are a strong independent predictor of sudden death in patients with HF, and it can be a guide to determine which patients may benefit from implantable cardioverter defibrillator placement.
BNP as a Marker of Prognosis in the Very Old 
A longitudinal population study of 541 patients age 85 years was performed in Sweden. BNP was measured in this cohort and followed for five years. Results showed that the BNP was predictive of the five-year mortality in the total population. The total mortality in the very old was significantly predicted by BNP in both patients with cardiovascular disease as well as those without.24 Another study enrolled 111 very old patients who had no history of cardiac disease. Each 50 pg/mL increase in the plasma BNP concentration increased the risk of cardiac events by 1.6-fold and total mortality by 1.4-fold, making BNP a useful biomarker for predicting cardiac morbidity and mortality in the older adult.25
Use of BNP for Management of HF in Long-Term Care
The role of BNP in diagnosis and management of HF in long-term care facilities is less well studied. Two studies indicate that despite HF being common in this population it remains undertreated, with many receiving suboptimal inpatient care when compared to others with the same diagnosis.26,27 It is likely that this population may benefit most from use of BNP as a diagnostic and a prognostic tool for HF, especially when echocardiography is not readily available, though studies are needed to understand appropriate cutoffs, indications, and cost-benefit effects.
BNP and NT-proBNP 
NT-proBNP also circulates in human plasma and has been shown to be useful in the diagnosis of HF. A commercial assay is available now and is FDA-approved.8 It has a longer half-life than BNP, and levels increase with normal aging. The cutoff values for age under 75 years is 125 pg/mL and for age 75 years and over is 450 pg/mL.8,28 It is less well studied than BNP and is not available at point of care. It is influenced by renal function and age.28 Studies have shown that both BNP and NT-proBNP accurately reflect HF, but BNP is more accurate in identifying reduced LV function.28
A recent study conducted in patients age 65 years and older by Ray and colleagues29 compared BNP and proBNP in the diagnosis of cardiogenic pulmonary edema. In this study, 202 patients age 65 years and older admitted to the emergency department for acute dyspnea were included, and both BNP and proBNP were measured. There was a strong correlation between BNP and proBNP values. Both values were significantly higher in patients with cardiogenic pulmonary edema. The best threshold for BNP was 250 pg/mL and for proBNP was 1500 pg/mL. The authors found that proBNP was as sensitive as BNP but less specific. They concluded that proBNP is less accurate than BNP in diagnosing cardiogenic pulmonary edema, although both are good markers of this condition, and higher values of both were associated with increased inpatient mortality.
A recent study comparing BNP and NT-proBNP assays examined their role in differentiating cardiac and respiratory causes of acute dyspnea in the emergency room.30 Values with the highest sensitivity and specificity for BNP were 116 pg/mL for access BNP assay, 79 pg/mL for Bayer ADVIA Centaur® BNP assay, and 817 pg/mL in Elecsys® NT-proBNP assay. The accuracy of diagnosing etiology for dyspnea was similar. The study population had a mean age of 75 ± 14.77 years. There was no distinct relationship between age and gender and the natriuretic peptides (P < 0.001).
Conclusion  
BNP is an effective tool in screening, diagnoses, and follow-up of older patients with HF and is a useful marker of future prognosis. It becomes even more important in the frail elderly, where the diagnosis of HF may be masked by the presence of other comorbid conditions. Further studies in nursing home residents may shed more light on the reliability and cost-effectiveness of this important tool in diagnosis and management of HF in this subgroup, where the trials are lacking and the utility may be great.
References
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8. Silver MA, Maisel A, Yancy CW, et al; BNP Consensus Panel. BNP Consensus Panel 2004: A clinical approach for the diagnostic, prognostic, screening, treatment monitoring, and therapeutic roles in natriuretic petptides in cardiovascular diseases [published correction appears in Congest Heart Fail 2005;11(2):102]. Congest Heart Fail 2004;10(5 Suppl 3):1-30.
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12. Maisel AS, Clopton P, Krishnaswamy P, et al; BNP Multinational Study Investigators. Impact of age, race, and sex on the ability of B-type natriuretic peptide to aid in the emergency diagnosis of heart failure: Results from the Breathing Not Properly (BNP) Multinational Study. Am Heart J 2004;147(6):1078-1084.
13. Roongsritong C, Qaddour A, Cox SL, et al. Brain natriuretic peptide and diastolic dysfunction in the elderly: Influence of gender. Congest Heart Fail 2005;11(2):65-67.
14. Knudsen CW, Riis JS, Finsen AV, et al. Diagnostic value of rapid test for B-type natriuretic peptide in patients presenting with acute dyspnoe: Effect of age and gender. Eur J Heart Fail 2004;6:55-62.
15. Loke I, Squire IB, Davies JE, Ng LL. Reference ranges for natriuretic peptides for diagnostic use are dependent on age, gender and heart rate. Eur J Heart Fail 2003;5:599-606.
16. McCullough PA, Duc P, Omland T, et al; Breathing Not Properly Multinational Study Investigators. B-type natriuretic peptide and renal function in the diagnosis of heart failure: An analysis from the Breathing Not Properly Multinational Study. Am J Kidney Dis 2003;41(3):571-579.
17. Mueller C, Scholer A, Laule-Kilian K, et al. Use of B-type natriuretic peptide in the evaluation and management of acute dyspnea. N Engl J Med 2004;350: 647-654.
18. Koglin J, Pehlivanli S, Schwaiblmair M, et al. Role of brain natriuretic peptide in risk stratification of patients with congestive heart failure. J Am Coll Cardiol 2001;38:1934-1941.
19. Harrison A, Morrison LK, Krishnaswamy P, et al. B-type natriuretic peptide predicts future cardiac events in patients presenting to the emergency department with dyspnea. Ann Emerg Med 2002;39:131-138.
20. Anand IS, Fisher LD, Chiang YT, et al; Val-HeFT Investigators. Changes in brain natriuretic peptide and norepinephrine over time and mortality and morbidity in Valsartan Heart Failure Trial (Val-HeFT). Circulation 2003;107:1278-1283.
21. Logeart D, Thabut G, Jourdain P, et al. Predischarge B-type natriuretic peptide assay for identifying patients at high risk of re-admission after decompensated heart failure. J Am Coll Cardiol 2004;43(4):635-641.
22. Bettencourt P, Frioes F, Azevedo A, et al. Prognostic information provided by serial measurements of brain natriuretic peptide in heart failure. Int J Cardiol 2004;93:45-48.
23. Berger R, Huelsman M, Strecker K, et al. B-type natriuretic petide predicts sudden death in patients with chronic heart failure. Circulation 2002;105:2392-2397.
24. Wallen T, Landahl S, Hedner T, et al. Brain natriuretic peptide predicts mortality in the elderly. Heart 1997;77:264-267.
25. Ueda R, Yokouchi M, Suzuki T, et al. Prognostic value of high plasma brain natriuretic peptide concentrations in very elderly persons. Am J Med 2003;114:266-270.
26. Heckman GA, Misiaszek B, Merali F, et al. Management of heart failure in Canadian long-term care facilities. Can L Cardiol 2004;20(10):963-969.
27. Ahmed A, Weaver MT, Allman RM, et al. Quality of care of nursing home residents hospitalized with heart failure. J Am Geriatr Soc 2002;50:1831-1836.
28. McCullough PA, Omland T, Maisel AS. B-type natriuretic peptides: A diagnostic breakthrough for clinicians. Rev Cardiovasc Med 2003;4(2):72-80.
29. Ray P, Arthaud M, Birolleau S, et al. Comparison of brain natriuretic peptide and probrain natriuretic peptide in the diagnosis of cardiogenic pulmonary edema in patients aged 65 and older. J Am Geriatr Soc 2005;53:643-648.
30. Sanz MP, Borque L, Rus A, et al. Comparison of BNP and NT-proBNP assays in the approach to the emergency diagnosis of acute dyspnea. J Clin Lab Anal 2006;20:227-232.
Figure. Assessment and Management of an Older Patient with a Possible Diagnosis of HF.