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European Journal of Heart Failure 2007 9(3):266-271; doi:10.1016/j.ejheart.2006.07.002
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© 2007 European Society of Cardiology

A change in N-terminal pro-brain natriuretic peptide is predictive of outcome in patients with advanced heart failure

Roy S. Gardnera,*, Kwok S. Chongb, James J. Mortonb and Theresa A. McDonaghc

a Department of Cardiology, Glasgow Royal Infirmary UK, 10 Alexandra Parade, Glasgow, G31 2ER, UK
b Division of Cardiovascular and Medical Sciences Western Infirmary, Glasgow, UK
c Department of Cardiology Royal Brompton Hospital, London, UK

* Corresponding author. Tel.: +44 211 4000; fax: +44 141 211 4950. E-mail address: rsgardner{at}doctors.org.uk


   Abstract
Top
 Abstract
1. Background
 2. Methods
 3. Results
 4. Discussion
 References
 
Background: The prognosis of chronic heart failure has improved with modern medical therapy. However, identifying those patients who fail to respond to such therapy and therefore those who remain at high risk is notoriously difficult. The B-type natriuretic peptides are established independent predictors of prognosis in CHF. However, the relevance of a change in NT-proBNP concentration over time in advanced heart failure is unknown.

Methods: We prospectively studied 133 patients with advanced CHF referred for consideration of cardiac transplantation. Plasma for NT-proBNP analysis was sampled at baseline and a median of 4months later in the 112 patients surviving without cardiac transplantation. Patients were followed up for a median of 1003days.

Results: The primary endpoint of all-cause mortality occurred in 30 (26.8%) patients. Those subjects who had the highest NT-proBNP concentration at 4months were at the greatest risk of death (log rank statistic=10.4, p=0.001). On Cox regression analysis, both a NT-proBNP concentration above the median and an absolute increase in NT-proBNP were independent predictors of mortality ({chi}2=53, p<0.0001 and {chi}2=17.3, p<0.0001, respectively).

Conclusion: A single NT-proBNP concentration above the median and a change in NT-proBNP concentration over a 4-month period were independent predictors of mortality in patients with advanced heart failure.

Key Words: Chronic heart failure • Prognosis • Transplantation • Natriuretic peptides

Received November 8, 2005; Revised June 6, 2006; Accepted July 10, 2006


   1. Background
Top
 Abstract
 1. Background
2. Methods
 3. Results
 4. Discussion
 References
 
Due to advances in medical therapy, the prognosis of advanced chronic heart failure (CHF) due to left ventricular systolic dysfunction (LVSD) is improving, with a one-year mortality of around 17% [1]. However, identifying those patients who fail to respond to disease-modifying medical therapy, and therefore remain at high risk, can be very difficult. It is for these very patients that cardiac transplantation (CTx) remains an option.

Many studies have concentrated on trying to identify markers of adverse outcome in such a population. Until recently, the cardiopulmonary exercise test was the gold-standard method of assessing such risk. Patients with a peak VO2≤14 ml/kg/min have been shown to benefit in terms of prognosis from transplantation [2-4]. However, many centres now apply a composite scoring system-the Heart Failure Survival Score (HFSS)-to predict those who will benefit from transplantation [5].

In addition to the classical methods of predicting survival, we now have the B-type natriuretic peptides. Brain natriuretic peptide and its N-terminal fragment, NT-proBNP, are known to be increased in terms of their circulating concentrations in both asymptomatic and symptomatic LVSD [6,7] and increase in proportion to the severity of chronic heart failure [8]. They independently predict morbidity and mortality in asymptomatic LVSD [9], in mild-moderate [10-12] and severe CHF [1]. In addition, BNP is a strong, independent predictor of sudden death in patients with CHF [13]. More recently, changes in concentrations of the B-type natriuretic peptides have also been shown to be a predictor of outcome in acute coronary syndromes [14], in post-MI heart failure [15], as well as in patients with moderate CHF [16,17].

We have previously demonstrated that a baseline NT-proBNP concentration is superior in terms of its prognostic power to the left ventricular ejection fraction, peak VO2, the HFSS, as well as other neurohormones, in patients with advanced heart failure [1,18]. However, whether a change in NT-proBNP concentration over time is superior to a single measurement at predicting an adverse outcome in patients with advanced heart failure remains unknown.

The aim of this study was therefore to evaluate the prognostic ability of a change in NT-proBNP concentration over a median of 4 months in patients with advanced heart failure referred for consideration of cardiac transplantation.


   2. Methods
Top
 Abstract
 1. Background
 2. Methods
3. Results
 4. Discussion
 References
 
2.1. Patient selection
We prospectively recruited 133 consecutive patients with advanced heart failure referred to the Scottish Cardiopulmonary Transplant Unit for cardiac transplant assessment between April 2001 and April 2004. Patients with chronic heart failure secondary to left ventricular systolic dysfunction (LVEF≤35% by radionuclide ventriculography) in New York Heart Association functional classes II-IV were included. No patients fulfilled the exclusion criteria of age less than 16 years, pregnancy or known concurrent malignancy. The local research ethics committee approved the study protocol and all patients gave written informed consent. The study complies with the Declaration of Helsinki.

At baseline screening, patients had a full medical history taken, clinical examination performed and NYHA class assigned. All patients had an LVEF measured by RNVG and, where possible, a cardiopulmonary exercise test to quantify their peak VO2. A baseline HFSS was calculated for each patient [5].

Of the initial 133 patients, 10 patients died and 11 patients were transplanted (1 urgently) before 4 months of follow-up. These 21 patients were excluded from further analysis, as a baseline NT-proBNP concentration has already been shown to be a powerful predictor of prognosis. Thus, 112 patients survived, or were free from transplantation, and had a follow-up sample taken for NT-proBNP analysis.

2.2. Measurement of NT-proBNP plasma levels
Blood samples were collected in ethylenediamine-tetraacetic acid-containing tubes at baseline. The samples were then centrifuged at 3000 rpm for 10 min at 0 °C. The plasma was then removed and frozen in aliquots at – 70 °C until analysis. As patients were followed up every 2 to 4 months, a further sample was taken 4 months after recruitment (day 0 of follow-up) to ensure all applicable patients had a follow-up sample taken. NT-proBNP was measured using a chemiluminescent immunoassay kit (Roche Diagnostics) on an Elecsys 2010 analyser. The clinicians involved with the patients' care were blinded to the NT-proBNP values obtained.

2.3. Follow-up
The primary endpoint was all-cause mortality. The secondary endpoint was all-cause mortality or urgent transplantation. Urgent transplantation is considered in suitable inotrope dependent patients with end-stage heart failure who have an anticipated life expectancy of less than 1 week. Patients were followed up until the endpoints were reached or 1st April 2005. The median follow-up after the second NT-proBNP sample was 1003 days (range=8 to 1378).

2.4. Statistical analysis
All data analysis was performed using the Statistical Package for Social Sciences (SPSS 11.5) software (SPSS Inc., Chicago, Illinois). Normally distributed, continuous data, unless otherwise stated, are expressed as mean values (±S.D.). Non-normally distributed continuous data are expressed as medians [25th and 75th percentile].

Kaplan-Meier survival curves were calculated with the data dichotomised at the mean or median values for each parameter as appropriate. To identify predictors of death, Cox proportional hazards analysis was used and variables achieving p<0.10 on univariate analysis (NT-proBNP, absolute change in NT-proBNP, serum sodium, creatinine, peak VO2 and HFSS) were then tested in a stepwise (forward) multiple Cox regression survival model to determine the independent predictors of both the primary and secondary endpoints. A p<0.05 was considered statistically significant.


   3. Results
Top
 Abstract
 1. Background
 2. Methods
 3. Results
4. Discussion
 References
 
Of the 133 patients initially recruited, 10 patients died and 11 patients were transplanted (1 urgently) before having a follow-up sample taken for NT-proBNP analysis. The baseline clinical and demographic features of the remaining 112 patients are described in Table 1. The population was predominantly male (84.8%). 83% of patients were in NYHA classes III and IV, the mean LVEF was 15.1% and the mean peak VO2 was 11.6 ml/kg/min. The median HFSS was 7.63 [7.15-8.20] and the NT-proBNP concentrations were skewed with a median of 1283 [510-3918] pg/ml.


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  		Table 1 Baseline general patient characteristics in 112 patients with advanced heart failure

 
At 4 months, the median change in NT-proBNP was –47.5 pg/ml [–491.5, 268]. The median percentage change in NT-proBNP concentration was –6.8% [–47.7%, 19.1%]. During this period, the mean dose of furosemide fell from 117 mg to 99 mg, and the mean percentage of optimal dose of ACE inhibition increased from 61% to 70% and beta-blockade from 41% to 81%. Of the 112 patients, 30 (26.8%) reached the primary endpoint of death (14.3% 1-year mortality). 33 patients reached the secondary endpoint of all-cause mortality or urgent transplantation (29.5%). A further 19 patients (17.0%) were transplanted during the study, but these subjects were considered survivors.

Fig. 1 depicts a Kaplan-Meier survival curve for NT-proBNP dichotomised above and below the median concentration at 4 months follow-up against all-cause mortality and urgent transplantation. A NT-proBNP concentration greater than the median was predictive of all-cause mortality (log rank statistic=7.1, p=0.008 at baseline and 10.4, p=0.001 at 4 months—data not shown) and the secondary endpoint (log rank statistic=9.5, p=0.002 and 10.7, p=0.001, respectively). Fig. 2 shows the combined effect of baseline and 4-month NT-proBNP concentrations on outcome. Patients who had a NT-proBNP concentration above the median at baseline and at 4 months were at the highest risk of death or urgent transplantation, compared to those consistently below the median who had a lower risk of death (log rank statistic=12.8, p=0.005). This was also true of the primary endpoint (log rank statistic=10.0, p=0.01—data not shown).


Figure 01
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  		Fig. 1 Kaplan-Meier survival curve for NT-proBNP at 4 months stratified above (solid line) and below (broken line) the median concentrations, against all-cause mortality and urgent transplantation, in 112 patients with advanced heart failure.

 


Figure 02
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  		Fig. 2 Kaplan-Meier survival curve—NT-proBNP concentrations grouped according to NT-proBNP at baseline and at 4 months split in 112 patients with advanced heart failure against all-cause mortality and urgent cardiac transplantation.

 
Fig. 3 depicts Kaplan-Meier survival curves for absolute change in NT-proBNP concentration where patients with a greater than 268 pg/ml increase in concentration were at the highest risk of death (log rank statistic=16.4, p=0.004). Fig. 4 shows the hazard ratios for all-cause mortality. In particular, there is a significant difference in risk between quartile 1 and quartile 4 (significant falls compared to significant increase in NT-proBNP concentration)—HR=3.8 (95% confidence interval 1.2-12.1). On Cox regression analysis, both a NT-proBNP concentration above the median at 4 months and absolute increase in NT-proBNP were independent predictors of mortality ({chi}2=53, p<0.0001 and {chi}2=17.3, p<0.0001, respectively).


Figure 03
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  		Fig. 3 Kaplan-Meier survival curves split into quartiles of absolute change in NT-proBNP concentration from baseline to 4 months, in 112 patients with advanced heart failure against all-cause mortality (log rank statistic=16.4, p=0.004).

 


Figure 04
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  		Fig. 4 Hazard ratio plots (versus first quartile) for percentage change in NT-proBNP concentrations between baseline and 4 months in 112 patients with advanced heart failure for all-cause mortality.

 

   4. Discussion
Top
 Abstract
 1. Background
 2. Methods
 3. Results
 4. Discussion
References
 
This study follows on from our previous research which identified that NT-proBNP was a powerful and independent marker of mortality in patients with advanced CHF [1,18,19]. The truly advanced nature of the LVSD in this transplant referral population is highlighted by the fact that 83% of patients were either in NYHA class III or IV, the mean LVEF was 15.1% and the mean peak VO2 was 11.6 ml/kg/min. However, it should also be highlighted that this was a relatively well-treated population, with over 70% of patients on a beta-blocker and 60% on spironolactone at baseline.

Of the neurohormones activated in patients with chronic heart failure, the B-type natriuretic peptides are thought to be beneficial counter-regulatory hormones inducing natriuresis and vasodilatation. They are known to be increased in proportion to the severity of disease, and have been shown to be predictive of mortality in mild, moderate and severe CHF. It would seem logical, therefore, that a reduction in NT-proBNP concentration should be associated with an improved prognosis in patients with advanced heart failure.

Some studies have now been published suggesting that this may be the case. Cheng et al. demonstrated that the adverse outcomes of death or readmission to hospital with heart failure occurred in those patients whose BNP concentrations failed to fall during an emergency admission with decompensated heart failure [20]. This differs from our study of younger out-patients who have heart failure of a more advanced nature. Indeed, in the former study, the mean ejection fraction was 37%, compared to 15% in this study.

BNP is largely produced by the left ventricle and changes in this neurohormone may be considered a biological marker for changes in cardiac structure and function. Our study adds further promise to the ongoing research in the use of the B-type natriuretic peptides to guide treatment, targeted to reduce BNP to a predefined level compared to a clinically guided approach. In the only randomised controlled trial to date of such titration of therapy guided by NT-proBNP concentration or current best practice by Troughton et al., NT-proBNP appeared to fall further in the NT-proBNP driven group compared to those receiving usual care (79 pmol/l vs. 3 pmol/l, p=0.16) [21]. The NT-proBNP group also had a better outcome in terms of subsequent death or readmission to hospital with heart failure (19 vs. 54 events, p=0.02). This study however was in a small group of 69 patients with more moderate heart failure (mean LVEF=27%) attending a heart failure clinic.

The effect of a change in BNP concentration was also addressed in a large sub-study of the Val-HeFT trial. Anand et al. found that a change in BNP, as well as norepinephrine, over time was associated in corresponding changes in morbidity and mortality [17]. The Val-HeFT study, however, was in a population of patients with stable heart failure, where around two-thirds were in NYHA class II [22], compared to the present study where 83% of patients were in NYHA classes III and IV. Our study could also be said to be more contemporary, as only about a third of patients in the Val-HeFT trial were receiving beta-blocker therapy, compared to 71% in our cohort.

Recently, Logeart et al. demonstrated that it was the pre-discharge BNP concentration which best determined the outcome of the patients with regard to death or readmission for heart failure in both derivation and validation cohorts made up of patients admitted with decompensated heart failure (HR=15.2 [8.5-27], p=0.0001) [23]. Although patients who had the greatest fall in their BNP concentration during admission had a much more favourable outcome than those with a more modest reduction (HR=0.18 [0.07-0.48], p=0.001), ROC analysis revealed that a pre-discharge BNP was the most predictive parameter.

In this study, the mortality rate at the median follow-up of 1003 days was 14.3% in those who had a >491 pg/ml reduction in NT-proBNP concentration over 4 months (quartile 1), compared to 48.3% in those who had an increase in their NT-proBNP concentration by more than 268 pg/ml (quartile 4, p=0.001). Like Logeart et al., however, we too found that a recent single measurement of NT-proBNP is a more powerful predictor of death than either an absolute or relative change in NT-proBNP concentration.

This study provides further important prognostic information on NT-proBNP concentration in patients with advanced heart failure. Whilst a single assay of this natriuretic peptide is a powerful predictor of outcome, an absolute change in NT-proBNP concentration has also been shown to be an independent predictor of mortality in this study. This therefore adds further to the information that NT-proBNP can provide in the risk stratification of such patients. Indeed, a patient with a rising NT-proBNP concentration despite optimisation of medical therapy could be regarded at higher risk and therefore a potential candidate for expensive device therapy or the rare resource of a transplant.

Larger studies will obviously be needed to extend this work on how to use the B-type natriuretic peptides for prognostication. Whether we should take a value which fails to fall or integrate BNP into simple scoring systems such as the heart failure survival score to predict outcome is not known at this time. It is also not clear whether NT-proBNP or BNP is superior in terms of their prognostic potential in this patient group, and this also requires clarification.

As the natriuretic peptides and in particular BNP and NT-proBNP are now in clinical use for the diagnosis of heart failure, we are now only beginning to unravel how to best use their enormous prognostic potential. This study suggests that, in seeking to use them to help our selection of patients with advanced heart failure for expensive and limited treatments such as device therapy and cardiac transplantation, the failure of B-type natriuretic peptide to fall with therapy may be more useful that relying on a single baseline concentration.

4.1. Study limitations
Whilst both single measurement of NT-proBNP and an absolute change in NT-proBNP concentration have been shown to be independent risk factors for all-cause mortality in this study, the relatively small study population makes it difficult to discern which marker is truly more predictive of outcome.


   Acknowledgements
 
We would like to acknowledge the help and support of the patients and staff of the Scottish Cardiopulmonary Transplant Unit. We would also like to acknowledge the financial assistance of the British Heart Foundation.


   References
Top
 Abstract
 1. Background
 2. Methods
 3. Results
 4. Discussion
 References
 

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