Natriuretic Peptide Levels in Heart Failure Therapy
Despite several advances in heart failure (HF) therapies over the past two decades, morbidity and mortality relating to HF remains high.1 In addition, the relative number of patients that are prescribed or currently utilize these evidence-based therapies remains low.2-3 Natriuretic peptide markers, such as B-type natriuretic peptide (BNP), or its amino-terminal fragment (NT-proBNP), have emerged as important tools for the diagnosis and risk stratification of patients with HF. However, there exists significant controversy surrounding their potential role for helping to guide outpatient management in individuals with HF.
Physiology of Natriuretic Peptides
Although BNP and NT-proBNP levels are closely correlated, these hormones exhibit several key differences in terms of their physiological effects, ranges and proposed cutpoints.4 Cardiac myocytes release and cleave proBNP into its BNP and NT-proBNP fragments in response to myocardial ventricular wall stress.5-6 Whereas NT-proBNP is a biologically inert substance, BNP has a diversity of biological targets and effects, including inhibition of the renin-angiotensin system and reduced secretion of aldosterone. BNP has a half life of 5-10 minutes before being degraded by endopeptidases, while NT-proBNP is cleared passively primarily by the kidneys and has a longer half life of 25-120 minutes.7 Despite these differences, these two hormones have shown similar diagnostic and prognostic utility.8-10
Importantly, it has known that there exists significant inter- and intra-individual variability in natriuretic peptide concentrations. In the absence of physiological perturbations, natriuretic peptide levels may fluctuate in a given individual if measured sequentially over hours to days. In addition, natriuretic peptide concentration has been shown to correlate with a variety of variables including age, sex, BMI, and renal function.11-14 These observations carry important implications if natriuretic peptides are to be used to help guide outpatient HF therapy. In particular, they raise questions regarding the reliability of following sequential natriuretic peptide levels over time and the appropriateness of universal natriuretic peptide targets for all individuals.
Natriuretic Peptides and Management of HF
As clinicians have become more familiar with natriuretic peptides, there has been growing interest in a role for natriuretic peptide levels to help guide outpatient HF therapy. In clinical practice, physicians have become accustomed to using targets to help guide the titration of medication. For example, medications for blood pressure, cholesterol and diabetes, are all titrated in response to objective measurements and laboratory values. In addition, natriuretic peptide may provide more objective data for clinicians than symptoms or physical exam alone.
To date, what evidence do we have to support the use of natriuretic peptides in the outpatient management of HF? Several studies have repeatedly demonstrated that higher levels of natriuretic peptides are associated with an increased risk of adverse outcomes, including a higher incidence of death and hospitalizations for patients with HF. A recent systematic review of 19 studies showed that each 100 ng/L rise in BNP concentration was accompanied by a 35% increase in the relative risk of death.15 Moreover, growing evidence suggests that a reduction in natriuretic peptide concentration is associated with a lower risk of recurrent cardiovascular (CV) events.16-18 Importantly, natriuretic peptides are not believed to play a pathological role in HF, so a reduction in natriuretic peptide concentration is believed to reflect a reduction in hemodynamic wall stress.10 To that end, several therapies with established benefit in HF, including angiotensin-converting enzyme inhibitor19 or angiotensin-receptor blockers20, spironolactone21 and cardiac resychronization therapy22, have been shown to reduce BNP and NT-proBNP levels in patients with reduced ejection fractions.
However, some opponents of a natriuretic peptide-guided approach believe that its apparent benefit is unrelated to natriuretic peptide concentration, but rather that natriuretic peptides simply encourage clinicians to uptitrate established HF therapies more frequently. To that end, prior studies have demonstrated improved outcomes for patients who are able to tolerate higher doses of HF medication such as ACE-I’s.23 Dose selection for many HF therapies is intended to be based on maximum tolerability rather than physical function or volume status. Moreover, there is no clear evidence to date to suggest that patients with higher levels of natriuretic peptides derive a greater benefit from evidence-based therapies.24-26 As such, one could argue that the majority of HF patients would benefit from more intensive escalation of evidence-based therapies regardless of their BNP or NT-proBNP levels.10
Existing Trial Data
Much of the early interest in the use of natriuretic peptides to guide outpatient HF management arose after the publication of a pilot study in New Zealand that enrolled patients with symptomatic HF and a reduced ejection fraction.27 The study demonstrated that patients whose therapy was guided by NT-proBNP levels had a significant reduction in CV death, hospital admission or HF decompensation as compared with patients whose care was guided by a clinical HF score. More frequent intensification of therapy was observed in the NT-proBNP group.
Subsequently, the STARS-BNP trial was the first large-scale clinical trial to again demonstrate improved CV outcomes using the peptide-guided approach.28 In STARS-BNP, therapy guided by BNP led to a 50% reduction in the incidence of HF-related death or hospitalization for HF, as compared with standard care, in patients with a reduced ejection fraction and NYHA class II or III HF. This benefit was driven primarily by a significant reduction in hospitalizations for HF. Of note, the BNP-guided group was seen by their physicians more than twice as frequently and had more frequent medication intensification (including ACE-I and beta blockers) than the standard care group.
Subsequent studies have since yielded mixed results. The STARBRITE trial enrolled subjects with symptomatic HF and reduced ejection fractions at the time of hospital discharge.29 There was no significant difference in hospitalization-free survival for those subjects whose therapy was guided by BNP levels, as compared with a standardized congestion score. However, the study may have been relatively underpowered to detect a significant difference.
The TIME-CHF trial enrolled subjects ≥ 60 years of age with symptomatic HF and a reduced ejection fraction and randomized them to therapy guided by age-specific NT-proBNP target levels versus symptom management alone.30 Overall, the study found no difference in quality of life or all-cause hospitalization between the two groups. However, the frequency of HF-free hospitalization was reduced with an NT-proBNP-guided approach. Notably, a significant interaction was observed; only individuals younger than 75 years appeared to benefit from a natriuretic-peptide guided approach to HF therapy. As with other trials, individuals in the NT-proBNP guided arm were more likely to receive higher doses of ACE inhibitors and β-blockers, or be treated with spironolactone or eplerenone. These findings raised the question as to whether older subjects may be less tolerant or have more adverse effects in the setting of more intensive therapy uptitration.
A similar interaction between age and the benefit of a natriuretic-peptide guided approach to HF was observed in the BATTLESCARRED trial.31 Subjects in the trial had a preserved or reduced ejection fraction and were randomized to one of three treatment arms: usual care, intensive clinical management, or NT-proBNP-guided therapy. Overall, there was no clear advantage for an NT-proBNP-guided approach as compared with intensive care. However, subjects younger than 75 years randomized to NT-proBNP-guided therapy had a lower incidence of mortality than subjects managed by usual care alone. In contrast, there was no clear benefit from either an NT-proBNP guided or intensive approach in those subjects over 75 years. These findings were supported by a recent meta-analysis of 8 trials that showed that the benefit of a natriuretic-peptide-guided approach to HF management was restricted to individuals younger than 75 years.32
In BATTLESCARRED, although there was a trend toward a lower event rate for patients managed by NT-proBNP levels or intensive management, this difference did not achieve statistical significance.31 In contrast, a recent Viennese pilot study did demonstrate a benefit for an early intensive NT-proBNP-guided management strategy led by a HF specialist, as compared with a nurse-led multidisciplinary team.33 However, the NT-proBNP guided arm again demonstrated more frequent use and escalation of established HF therapies, including neurohormonal agents. These findings help to emphasize the fact that natriuretic peptides may be useful for helping even well trained clinicians to prescribe and escalate HF therapies more frequently.
In recent years, natriuretic peptides have moved from the emergency department to outpatient clinician offices. However, studies on the use of these peptides to guide therapy for HF have yielded conflicting and inconsistent results. The available evidence suggests that a natriuretic peptide-guided approach may reduce HF hospitalizations and HF-related mortality in patients under the age of 75 years, as compared with usual therapy. To date, there is no clear evidence that it reduces all-cause mortality or all-cause hospitalization. Much of the benefit of this approach is likely due to improved administration of evidence-based therapies and more aggressive uptitration.
To date, there is no clear evidence to suggest that patients over the age of 75 years benefit from this more aggressive natriuretic-peptide-guided approach. This may be due to a higher incidence of complications in older patients in the setting of frequent therapy intensification. There is also limited evidence to suggest that a natriuretic-peptide guided approach benefits patients with HF and a preserved ejection fraction. These findings may reflect the limited number of therapies that have been shown to improve outcomes for patients with HF in the absence of systolic dysfunction.
Ongoing or recently completed studies may continue to provide further insight on the potential role of natriuretic peptides in the outpatient management of HF. Trials are also ongoing to evaluate the clinical utility of natriuretic peptides for helping to guide inpatient HF care.
- Bonow RO, Bennett S, Casey DE, Jr., et al. ACC/AHA clinical performance measures for adults with chronic heart failure: a report of the American College of Cardiology/American Heart Association Task Force on Performance Measures (Writing Committee to Develop Heart Failure Clinical Performance Measures) endorsed by the Heart Failure Society of America. J Am Coll Cardiol 2005;46:1144-78.
- Krantz MJ, Tanner J, Horwich TB, et al. Influence of hospital length of stay for heart failure on quality of care. Am J Cardiol 2008;102:1693-7.
- Albert NM, Yancy CW, Liang L, et al. Use of aldosterone antagonists in heart failure. JAMA 2009;302:1658-65.
- Tang WH, Francis GS, Morrow DA, et al. National Academy of Clinical Biochemistry Laboratory Medicine Practice Guidelines: clinical utilization of cardiac biomarker testing in heart failure. Clin Biochem 2008;41:210-21.
- Richards AM, Crozier IG, Yandle TG, Espiner EA, Ikram H, Nicholls MG. Brain natriuretic factor: regional plasma concentrations and correlations with haemodynamic state in cardiac disease. Br Heart J 1993;69:414-7.
- Yasue H, Yoshimura M, Sumida H, et al. Localization and mechanism of secretion of B-type natriuretic peptide in comparison with those of A-type natriuretic peptide in normal subjects and patients with heart failure. Circulation 1994;90:195-203.
- Kroll MH, Twomey PJ, Srisawasdi P. Using the single-compartment ratio model to calculate half-life, NT-proBNP as an example. Clin Chim Acta 2007;380:197-202.
- Januzzi JL, Jr., Camargo CA, Anwaruddin S, et al. The N-terminal Pro-BNP investigation of dyspnea in the emergency department (PRIDE) study. Am J Cardiol 2005;95:948-54.
- Maisel AS, Krishnaswamy P, Nowak RM, et al. Rapid measurement of B-type natriuretic peptide in the emergency diagnosis of heart failure. N Engl J Med 2002;347:161-7.
- O'Donoghue M, Braunwald E. Natriuretic peptides in heart failure: should therapy be guided by BNP levels? Nat Rev Cardiol 2010;7:13-20.
- Redfield MM, Rodeheffer RJ, Jacobsen SJ, Mahoney DW, Bailey KR, Burnett JC, Jr. Plasma brain natriuretic peptide concentration: impact of age and gender. J Am Coll Cardiol 2002;40:976-82.
- Wang TJ, Larson MG, Levy D, et al. Impact of obesity on plasma natriuretic peptide levels. Circulation 2004;109:594-600.
- Wang TJ, Larson MG, Levy D, et al. Impact of age and sex on plasma natriuretic peptide levels in healthy adults. Am J Cardiol 2002;90:254-8.
- Anwaruddin S, Lloyd-Jones DM, Baggish A, et al. Renal function, congestive heart failure, and amino-terminal pro-brain natriuretic peptide measurement: results from the ProBNP Investigation of Dyspnea in the Emergency Department (PRIDE) Study. J Am Coll Cardiol 2006;47:91-7.
- Doust JA, Pietrzak E, Dobson A, Glasziou P. How well does B-type natriuretic peptide predict death and cardiac events in patients with heart failure: systematic review. BMJ 2005;330:625.
- Anand IS, Fisher LD, Chiang YT, et al. Changes in brain natriuretic peptide and norepinephrine over time and mortality and morbidity in the Valsartan Heart Failure Trial (Val-HeFT). Circulation 2003;107:1278-83.<
- Bettencourt P, Azevedo A, Pimenta J, Frioes F, Ferreira S, Ferreira A. N-terminal-pro-brain natriuretic peptide predicts outcome after hospital discharge in heart failure patients. Circulation 2004;110:2168-74.
- 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;43:635-41.
- Motwani JG, McAlpine H, Kennedy N, Struthers AD. Plasma brain natriuretic peptide as an indicator for angiotensin-converting-enzyme inhibition after myocardial infarction. Lancet 1993;341:1109-13.
- Latini R, Masson S, Anand I, et al. Effects of valsartan on circulating brain natriuretic peptide and norepinephrine in symptomatic chronic heart failure: the Valsartan Heart Failure Trial (Val-HeFT). Circulation 2002;106:2454-8.
- Tsutamoto T, Wada A, Maeda K, et al. Effect of spironolactone on plasma brain natriuretic peptide and left ventricular remodeling in patients with congestive heart failure. J Am Coll Cardiol 2001;37:1228-33.
- Cleland JG, Daubert JC, Erdmann E, et al. The effect of cardiac resynchronization on morbidity and mortality in heart failure. N Engl J Med 2005;352:1539-49.
- Packer M, Poole-Wilson PA, Armstrong PW, et al. Comparative effects of low and high doses of the angiotensin-converting enzyme inhibitor, lisinopril, on morbidity and mortality in chronic heart failure. ATLAS Study Group. Circulation 1999;100:2312-8.
- Hartmann F, Packer M, Coats AJ, et al. Prognostic impact of plasma N-terminal pro-brain natriuretic peptide in severe chronic congestive heart failure: a substudy of the Carvedilol Prospective Randomized Cumulative Survival (COPERNICUS) trial. Circulation 2004;110:1780-6.
- Omland T, Sabatine MS, Jablonski KA, et al. Prognostic value of B-Type natriuretic peptides in patients with stable coronary artery disease: the PEACE Trial. J Am Coll Cardiol 2007;50:205-14.
- Cleland J, Freemantle N, Ghio S, et al. Predicting the long-term effects of cardiac resynchronization therapy on mortality from baseline variables and the early response a report from the CARE-HF (Cardiac Resynchronization in Heart Failure) Trial. J Am Coll Cardiol 2008;52:438-45.
- Troughton RW, Frampton CM, Yandle TG, Espiner EA, Nicholls MG, Richards AM. Treatment of heart failure guided by plasma aminoterminal brain natriuretic peptide (N-BNP) concentrations. Lancet 2000;355:1126-30.
- Jourdain P, Jondeau G, Funck F, et al. Plasma brain natriuretic peptide-guided therapy to improve outcome in heart failure: the STARS-BNP Multicenter Study. J Am Coll Cardiol 2007;49:1733-9.
- Shah MR, Claise KA, Bowers MT, et al. Testing new targets of therapy in advanced heart failure: the design and rationale of the Strategies for Tailoring Advanced Heart Failure Regimens in the Outpatient Setting: BRain NatrIuretic Peptide Versus the Clinical CongesTion ScorE (STARBRITE) trial. Am Heart J 2005;150:893-8.
- Pfisterer M, Buser P, Rickli H, et al. BNP-guided vs symptom-guided heart failure therapy: the Trial of Intensified vs Standard Medical Therapy in Elderly Patients With Congestive Heart Failure (TIME-CHF) randomized trial. JAMA 2009;301:383-92.
- Lainchbury JG, Troughton RW, Strangman KM, et al. N-terminal pro-B-type natriuretic peptide-guided treatment for chronic heart failure: results from the BATTLESCARRED (NT-proBNP-Assisted Treatment To Lessen Serial Cardiac Readmissions and Death) trial. J Am Coll Cardiol 2009;55:53-60.
- Porapakkham P, Zimmet H, Billah B, Krum H. B-type natriuretic peptide-guided heart failure therapy: A meta-analysis. Arch Intern Med 2010;170:507-14.
- Berger R, Moertl D, Peter S, et al. N-terminal pro-B-type natriuretic peptide-guided, intensive patient management in addition to multidisciplinary care in chronic heart failure a 3-arm, prospective, randomized pilot study. J Am Coll Cardiol 2010;55:645-53.
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