Article

An Update on N-terminal Pro-Brain-type Natriuretic Peptide for Risk Stratification in Chronic Heart Failure

Register or Login to View PDF Permissions
Permissions× For commercial reprint enquiries please contact Springer Healthcare: ReprintsWarehouse@springernature.com.

For permissions and non-commercial reprint enquiries, please visit Copyright.com to start a request.

For author reprints, please email rob.barclay@radcliffe-group.com.
Average (ratings)
No ratings
Your rating
Copyright Statement:

The copyright in this work belongs to Radcliffe Medical Media. Only articles clearly marked with the CC BY-NC logo are published with the Creative Commons by Attribution Licence. The CC BY-NC option was not available for Radcliffe journals before 1 January 2019. Articles marked ‘Open Access’ but not marked ‘CC BY-NC’ are made freely accessible at the time of publication but are subject to standard copyright law regarding reproduction and distribution. Permission is required for reuse of this content.

Chronic heart failure (HF) is a major cause of death and disability. Predicting patients at risk of death or further cardiovascular events that require more intense monitoring and therapy is clinically challenging. Several factors are associated with increased mortality and morbidity in patients with HF, including age, a history of diabetes mellitus or renal dysfunction, advanced functional disability, reduced left ventricular ejection fraction, lower sodium concentrations, lower body mass index, lower blood pressure, the presence of ankle oedema and lower quality of life scores.1 Accordingly, multivariable risk scores that differently combine these clinical variables have been derived from well-characterised populations of patients with HF, but they may be of limited practical use.

There is currently a great interest in developing simple and economical circulating biomarkers that would be of incremental value to conventional clinical risk factors and establish rapid and accurate risk stratification of patients with HF or help in guiding therapy.2,3 To date, markers of the natriuretic peptides family are the most promising tools. Atrial natriuretic peptide (ANP) and brain natriuretic peptides (BNP) are of cardiac origin and are therefore more relevant to the pathophysiology of HF. These two hormones are secreted mainly by stretched atrial and ventricular myocytes (increased myocardial tension and intravascular volume), but also during ischaemia, and act on specific receptors and exhibit a wide range of physiological effects including natriuresis, diuresis, vasodilatation and opposition to fibrosis, cellular hypertrophy and neurohormonal activation.

ANP and BNP are secreted as inactive circulating prohormones (proANP and proBNP) that are successively processed in the respective mature C-terminal hormones and N-terminal peptides of presently unknown function.4 There are convincing data, briefly reviewed here, that the determination of the physiologically inactive N-terminal proBNP (NT-proBNP 1–76) provides powerful and independent prognostic information in patients with chronic HF in different clinical settings and at all stages of the disease.

Prognostic Value in Multicentre Controlled Clinical Trials

The strongest evidence of the prognostic value of NT-proBNP in HF arose from large-scale multicentre controlled clinical trials and robust statistical interpretation. In the Valsartan Heart Failure Trial (Val-HeFT), 5,010 patients with mild to moderate chronic HF were randomised to an angiotensin II type 1 receptor blocker or placebo.5 Blood was collected at study entry for the measurement of different biomarkers.

Mortality and the combined end-point of mortality and morbidity (mainly hospitalisation for HF), the two centrally adjudicated end-points, increased progressively with increasing plasma concentrations of NT-proBNP, starting from levels well below the diagnostic value for chronic HF (see Figure 1). An increment of 500pg/ml of NT-proBNP was associated with an increased adjusted risk of 3.8% for mortality and 3.0% for hospitalisation for HF.6 Moreover, NT-proBNP ranked as the first independent prognostic factor in these patients, ahead of traditional clinical risk factors such as functional disability by New York Heart Association (NYHA) class, age, left ventricular dilation or renal dysfunction.

The prognostic performance of NT-proBNP has been evaluated in several other clinical trials. NT-proBNP predicted one-year mortality in a sub-study of the Prospective Randomised Amlodipine Survival Evaluation (PRAISE) 2 trial that enrolled 181 patients with severe congestive HF (NYHA III-IV and left ventricular ejection fraction less than 30%) of a presumed non-ischaemic aetiology.7

NT-proBNP also predicted death and hospitalisation for HF in a subgroup of 1,011 patients with a left ventricular ejection fraction less than 25% and severe HF in the Carvedilol Prospective Randomized Cumulative Survival (COPERNICUS) trial.8 In this trial, NT-proBNP above the median concentration was a powerful predictor of one-year all-cause mortality (relative risk (RR), 2.7; 95% confidence interval (CI), 1.7–4.3; p=0.0001) and of all-cause mortality or hospitalisation for heart failure (RR, 2.4; 95% CI, 1.8–3.4; p=0.0001). There was no significant interaction between NT-proBNP and study treatment.8 The prognostic value of NT-proBNP in patients with severe HF has also been observed in smaller single-centre studies9,10 or in patients referred for consideration of, or after cardiac transplantation.11–14

Incremental Prognostic Value of Repeated Measurements of NT-proBNP

A single determination of NT-proBNP, at any time during the progression of chronic HF, provides a clinically useful tool for risk stratification. Repeated measurements of the same biomarker over time convey incremental prognostic information beyond that of a single one, as shown in different settings, and may help in monitoring the progression of disease and the clinical effect of medical therapy.2 For instance, relative changes in NT-proBNP concentrations during hospitalisation were good predictors of subsequent hospital readmission and death within six months of discharge in 182 patients admitted to hospital due to decompensated HF.15

Thus, changes in NT-proBNP may be potentially useful in assisting clinicians in making the decision to discharge HF patients. In another study16 patients with a reduction of NT-proBNP greater than 50% after cardiac resynchronisation therapy had a more favourable outcome than the rest of the population and this was associated with positive changes in left ventricular remodelling and exercise capacity. Absolute changes in NT-proBNP concentration across a given value (for instance median concentration) can also predict mortality in patients with advanced HF referred for consideration of cardiac transplantation,17 as already shown in Val-HeFT for BNP in patients with mild to moderate chronic HF.18 Likewise, absolute changes in NT-proBNP concentration across the median over four months were related to outcome in 3,488 patients with chronic HF enrolled in Val-HeFT (see Figure 2).

The intra-individual biological variation of NT-proBNP should be considered for a correct understanding of the clinical significance of repeated determinations of this biomarker, even in patients deemed clinically stable. Estimates of biological variation are not easily interpretable since they vary with the clinical criteria used for the selection of the population examined, the definition of clinical stability, the severity of disease in the population examined, the interval of time considered and the statistical methods used to calculate them. Reference change values for week-to-week variations of NT-proBNP are relatively high, in the range of 50–100%.19,20

However, at longer intervals, recent findings indicate that the biological variability could be smaller (reference range values of 23%).21,22 For instance, the year-to-year co-efficient of variation (standard deviation of repeated measurement/mean concentration) of NT-proBNP amounted to 30% in patients with chronic HF (5% when NT-proBNP was expressed on a logarithmic scale), but these data were observed in a highly selected population of patients with stable chronic HF, not necessarily representative of everyday ambulatory patients.21 Importantly, changes in NT-proBNP concentrations below the estimated biological variation have clinical relevance.

NT-proBNP and the Multimarker Approach

Head-to-head comparative studies of circulating factors generally show the superiority of NT-proBNP in terms of prognostic performance over other currently measured biomarkers (aldosterone, endothelin peptides, adrenomedullin, tumour necrosis factor-alpha, C-reactive protein, norepinephrine, erythropoietin).6,13,23

However, the various fragments of the natriuretic peptide family (NT-proANP, mid-regional proANP, BNP, NT-proBNP) seem roughly equivalent for risk stratification in HF.6,24–28 Markers of cardiac injury (cardiac troponin T,29 or troponin I30) or imaging techniques (echocardiography31,32) may be combined with NT-proBNP to further improve the prognostic performance and accuracy compared with the natriuretic peptide alone.

Prognostic Value in Patients with Chronic Heart Failure and Preserved Systolic Function

NT-proBNP increases with the severity of ventricular systolic as well as diastolic dysfunction.33–37 However, whereas the prognostic value of NT-proBNP in patients with reduced systolic function is well documented, there are few data in patients with chronic HF and preserved systolic function even though they may account for as much as 50% of the patients with symptomatic HF, particularly in the elderly. NT-proBNP was a strong predictor of one-year mortality in 161 consecutively hospitalised patients with heart failure with preserved as well as reduced systolic function.38 Similarly, NT-proBNP is useful to identify patients at risk of adverse outcome regardless of systolic function, as seen in 244 patients admitted for decompensated HF and followed for six months.39

In conclusion, NT-proBNP is a robust prognostic marker for all relevant clinical outcomes in chronic HF. Repeated determinations of this biomarker may convey additional prognostic value. More studies are needed to assess the performance of NT-proBNP in patients with chronic HF and preserved left ventricular systolic function or in clinical subgroups of patients with HF and co-morbidities (diabetes, atrial fibrillation, chronic obstructive pulmonary disease).

References

  1. Pocock SJ, Wang D, Pfeffer MA, et al., Predictors of mortality and morbidity in patients with chronic heart failure, Eur Heart J, 2006;27:65–75.
    Crossref | PubMed
  2. Troughton RW, Frampton CF, Yandle TG, et al., Treatment of heart failure guided by plasma aminoterminal brain natriuretic peptide(N-BNP) concentrations, Lancet, 2000;355:1126–30.
    Crossref | PubMed
  3. Jourdain P, Jondeau G, Funck F, et al., Plasma brain natriuretic peptide-guided therapy to improve outcome in heart failure, J Am Coll Cardiol, 2007;49: in press.
  4. Hall C, NT-ProBNP: the mechanism behind the marker, J Card Fail, 2005;11:S81–S83.
    Crossref | PubMed
  5. Cohn JN, Tognoni G, Valsartan Heart Failure Trial Investigators. A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure, N Engl J Med, 2001;345:1667–75.
    Crossref | PubMed
  6. Masson S, Latini R, Anand IS, et al., Val-HeFT Investigators. Direct comparison of B-type natriuretic peptide (BNP) and amino-terminal proBNP in a large population of patients with chronic and symptomatic heart failure: the Valsartan Heart Failure (Val-HeFT) data, Clin Chem, 2006;52:1528–38.
    Crossref | PubMed
  7. Stanton E, Hansen M, Wijeysundera HC, et al., PRAISE-2 study investigators. A direct comparison of the natriuretic peptides and their relationship to survival in chronic heart failure of a presumed non-ischaemic origin, Eur J Heart Fail, 2005;7:557–65.
    Crossref | PubMed
  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;110:1780–86.
    Crossref | PubMed
  9. Gardner RS, Ozalp F, Murday AJ, et al., N-terminal pro-brain natriuretic peptide. A new gold standard in predicting mortality in patients with advanced heart failure, Eur Heart J, 2003;24: 1735–43.
    Crossref | PubMed
  10. Rienstra M, Van Gelder IC, Van den Berg MP, Boomsma F, Van Veldhuisen DJ, Natriuretic peptides in patients with atrial fibrillation and advanced chronic heart failure: determinants and prognostic value of (NT-)ANP and (NT-pro)BNP, Europace, 2006;8:482–7.
    Crossref | PubMed
  11. Rothenburger M, Wichter T, Schmid C, et al., Aminoterminal pro type B natriuretic peptide as a predictive and prognostic marker in patients with chronic heart failure, J Heart Lung Transplant, 2004;23:1189–97.
    Crossref | PubMed
  12. Ambrosi P, Oddoze C, Riberi A, et al., Usefulness of N-terminalpro- brain natriuretic peptide levels in predicting survival in heart transplant recipients, Am J Cardiol, 2004;94:1585–7.
    Crossref | PubMed
  13. Gardner RS, Chong KS, Morton JJ, McDonagh TA, N-terminal brain natriuretic peptide, but not anemia, is a powerful predictor of mortality in advanced heart failure, J Card Fail, 2005;11:S47–53.
    Crossref | PubMed
  14. Gardner RS, Chong KS, Murday AJ, et al., N-terminal brain natriuretic peptide is predictive of death after cardiac transplantation, Heart, 2006;92:121–3.
    Crossref | PubMed
  15. Bettencourt P, Azevedo A, Pimenta J, et al., N-terminal-probrain natriuretic peptide predicts outcome after hospital discharge in heart failure patients, Circulation, 2004;110:2168–74.
    Crossref | PubMed
  16. Yu CM, Fung JW, Zhang Q, et al., Improvement of serum NTProBNP predicts improvement in cardiac function and favorable prognosis after cardiac resynchronization therapy for heart failure, J Card Fail, 2005;11:S42–S46.
    Crossref | PubMed
  17. Gardner RS, Chong KS, Morton JJ, McDonagh TA, A change in N-terminal pro-brain natriuretic peptide is predictive of outcome in patients with advanced heart failure, Eur J Heart Fail, 2007;9:266–71.
    Crossref | PubMed
  18. Latini R, Masson S, Wong M, et al., Val-HeFT Investigators. Incremental prognostic value of changes in B-type natriuretic peptide in heart failure, Am J Med, 2006;119:e23–e30.
    Crossref | PubMed
  19. Bruins S, Fokkema MR, Romer JW, et al., High intraindividual variation of B-type natriuretic peptide (BNP) and amino-terminal proBNP in patients with stable chronic heart failure, Clin Chem, 2004;50:2052–8.
    Crossref | PubMed
  20. O’Hanlon R, O’Shea P, Ledwidge M, et al., The biologic variability of B-type natriuretic peptide and N-terminal pro-Btype natriuretic peptide in stable heart failure patients, J Card Fail, 2007;13:50–55.
    Crossref | PubMed
  21. Schou M, Gustafsson F, Kjaer A, Hildebrandt PR, Long-term clinical variation of NT-proBNP in stable chronic heart failure patients, Eur Heart J, 2007;28:177–82.
    Crossref | PubMed
  22. Araujo JP, Azevedo A, Lourenco P, et al., Intraindividual variation of amino-terminal pro-B-type natriuretic peptide levels in patients with stable heart failure, Am J Cardiol, 2006;98:1248–50.
    Crossref | PubMed
  23. George J, Patal S, Wexler D, et al., Circulating erythropoietin levels and prognosis in patients with congestive heart failure: comparison with neurohormonal and inflammatory markers, Arch Intern Med, 2005;165:1304–9.
    Crossref | PubMed
  24. Hulsmann M, Berger R, Mortl D, et al., Incidence of normal values of natriuretic peptides in patients with chronic heart failure and impact on survival: a direct comparison of Nterminal atrial natriuretic peptide, N-terminal brain natriuretic peptide and brain natriuretic peptide, Eur J Heart Fail, 2005;7:552–6.
    Crossref | PubMed
  25. Stanton E, Hansen M, Wijeysundera HC, et al., PRAISE-2 study investigators. A direct comparison of the natriuretic peptides and their relationship to survival in chronic heart failure of a presumed non-ischaemic origin, Eur J Heart Fail, 2005;7:557–65.
    Crossref | PubMed
  26. Alehagen U, Lindstedt G, Levin LA, Dahlstrom U, Risk of cardiovascular death in elderly patients with possible heart failure. B-type natriuretic peptide (BNP) and the aminoterminal fragment of ProBNP (N-terminal proBNP) as prognostic indicators in a 6-year follow-up of a primary care population, Int J Cardiol, 2005;100:125–33.
    Crossref | PubMed
  27. Richards M, Nicholls MG, Espiner EA, et al., Christchurch Cardioendocrine Research Group; Australia-New Zealand Heart Failure Group. Comparison of B-type natriuretic peptides for assessment of cardiac function and prognosis in stable ischemic heart disease, J Am Coll Cardiol, 2006;47:52–60.
    Crossref | PubMed
  28. Gegenhuber A, Struck J, Dieplinger B, et al., Comparative evaluation of B-type natriuretic peptide, mid-regional pro-Atype natriuretic peptide, mid-regional pro-adrenomedullin, and Copeptin to predict 1-year mortality in patients with acute destabilized heart failure, J Card Fail, 2007;13:42–9.
    Crossref | PubMed
  29. Taniguchi R, Sato Y, Yamada T, et al., Combined measurements of cardiac troponin T and N-terminal pro-brain natriuretic peptide in patients with heart failure, Circ J, 2004;68:1160–64.
    Crossref | PubMed
  30. Perna ER, Macin SM, Cimbaro Canella JP, et al., Importance of early combined N-terminal pro-brain natriuretic peptide and cardiac troponin T measurements for long-term risk stratification of patients with decompensated heart failure, J Heart Lung Transplant, 2006;25:1230–40.
    Crossref | PubMed
  31. Kirk V, Bay M, Parner J, et al., N-terminal proBNP and mortality in hospitalised patients with heart failure and preserved vs. reduced systolic function: data from the prospective Copenhagen Hospital Heart Failure Study (CHHF), Eur J Heart Fail, 2004;6:335–41.
    Crossref | PubMed
  32. Bruch C, Rothenburger M, Gotzmann M, et al., Risk stratification in chronic heart failure: independent and incremental prognostic value of echocardiography and brain natriuretic peptide and its N-terminal fragment, J Am Soc Echocardiogr, 2006;19:522–8.
    Crossref | PubMed
  33. Troughton RW, Prior DL, Pereira JJ, et al., Plasma B-type natriuretic peptide levels in systolic heart failure: importance of left ventricular diastolic function and right ventricular systolic function, J Am Coll Cardiol, 2004;43:416–22.
    Crossref | PubMed
  34. Tschope C, Kasner M, Westermann D, et al., The role of NTproBNP in the diagnostics of isolated diastolic dysfunction: correlation with echocardiographic and invasive measurements, Eur Heart J, 2005;26:2277–84.
    Crossref | PubMed
  35. Dong SJ, de las Fuentes L, Brown AL, et al., N-terminal pro B-type natriuretic peptide levels: correlation with echocardiographically determined left ventricular diastolic function in an ambulatory cohort, J Am Soc Echocardiogr, 2006;19:1017–25.
    Crossref | PubMed
  36. Lim TK, Ashrafian H, Dwivedi G, et al., Increased left atrial volume index is an independent predictor of raised serum natriuretic peptide in patients with suspected heart failure but normal left ventricular ejection fraction: Implication for diagnosis of diastolic heart failure, Eur J Heart Fail, 2006;8:38–45.
    Crossref | PubMed
  37. Talens-Visconti R, Rivera Otero M, Sancho-Tello MJ, et al., Left ventricular cavity area reflects N-terminal pro-brain natriuretic peptide plasma levels in heart failure, Eur J Echocardiogr, 2006;7:45–52.
    Crossref | PubMed
  38. Kirk V, Bay M, Parner J, et al., N-terminal proBNP and mortality in hospitalised patients with heart failure and preserved vs. reduced systolic function: data from the prospective Copenhagen Hospital Heart Failure Study (CHHF), Eur J Heart Fail, 2004;6:335–41.
    Crossref | PubMed
  39. Bettencourt P, Azevedo A, Fonseca L, et al., Prognosis of decompensated heart failure patients with preserved systolic function is predicted by NT-proBNP variations during hospitalization, Int J Cardiol, 2007;117:75–9.
    Crossref | PubMed