European Journal of Heart Failure Advance Access originally published online on February 19, 2009
European Journal of Heart Failure 2009 11(4):354-360; doi:10.1093/eurjhf/hfp024
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Cystatin C and NT-proBNP, a powerful combination of biomarkers for predicting cardiovascular mortality in elderly patients with heart failure: results from a 10-year study in primary care
1 Department of Cardiology, Heart Center, Linköping University Hospital SE-581 85 Linkoping, Sweden
2 Department of Clinical Chemistry, Laboratory Medicine Östergötland and Institute of Biomedicine and Surgery, Linköping University Hospital SE-581 85, Sweden
* Corresponding author. Tel: +46 132 22000, Fax: +46 132 22324, Email: urban.alehagen{at}ihs.liu.se
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Abstract |
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Aims: Heart failure (HF) is common among the elderly patients. It is essential to identify those at high risk in order to optimize the use of resources. We aimed to evaluate whether a combination of two biomarkers might give better prognostic information about the risk of cardiovascular (CV) mortality in patients with symptoms associated with HF, compared with only one biomarker.
Methods and results: Four hundred and sixty-four primary health-care patients (mean age 73 years, range 65–87) with symptoms of HF were examined. All patients were evaluated using Doppler echocardiography and blood samples, including measurement of cystatin C and NT-proBNP. The patients were followed over a 10-year period. Patients with serum cystatin C levels within the highest quartile had almost three times the risk (HR: 2.92; 95% CI: 1.23–4.90) of CV mortality compared with those patients who had levels within the first, second, or third quartiles. If, at the same time, the patient had a plasma concentration of NT-proBNP within the highest quartile, the risk increased to >13 times (HR: 13.61; 95% CI: 2.56–72.24) during 10 years of follow-up or >17 times (HR: 17.04; 95% CI: 1.80–163.39) after 5 years of follow-up.
Conclusion: Combined analysis of cystatin C and NT-proBNP could provide important prognostic information among elderly patients in the community with symptoms of HF.
Key Words: Elderly patients • Heart failure • NT-proBNP • Cystatin C • Biomarkers
Received April 14, 2008; Revised November 26, 2008; Accepted December 24, 2008
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Introduction |
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In recent years, awareness of the problems of elderly patients with heart failure (HF) and patients with renal failure has increased.1 The problems are more apparent in patients with both HF and renal insufficiency, which is not unusual among the elderly. Van Kimmenade et al.2 suggested that this condition—combined HF and renal insufficiency— might best be regarded as a separate condition, the ‘cardio-renal syndrome’; however, as yet there is no generally agreed definition for this ‘cardio–renal syndrome’. The effective measurement of BNP or NT-proBNP, even in patients with renal failure, has already been demonstrated in the literature.3,4 However, in patients with both cardiac and renal insufficiency it is not known which biomarker should be used in addition to BNP or NT-proBNP, this issue was discussed by van Kimmenade et al.2 in an editorial published in 2007. This question is particularly relevant where resources are limited and where it is therefore important to identify high-risk patients. In the present study, we evaluated use of the combination of NT-proBNP and cystatin C as biomarkers in elderly patients with HF.
Cystatin C is a small serine protease inhibitor that is secreted from almost all active functional cells in the body. Its molecular mass of 13 kDa allows it to be freely filtered by the renal glomerulus. The secretion of cystatin C by the kidneys is regarded as being independent of the nutritional status of the patient and of the body mass index.5,6 It is also considered to be independent of gender among older patients7 and, according to most reports, is also independent of the age of the patient.6 Cystatin C is increasingly being considered as a better indicator of renal function than creatinine or estimated glomerular filtration rate (GFR).8–11 Therefore, cystatin C is deemed a useful biomarker of renal function.9,12,13 Recent reports have indicated that cystatin C might also be a prognostic indicator of cardiovascular (CV) mortality. Lassus et al.14 reported interesting data concerning the relationships between cystatin C and NT-proBNP in patients with acute HF.
The plasma concentration of the N-terminal fragment of proBNP (NT-proBNP) is a well- known indicator of myocardial wall tension, as it is secreted as wall tension increases.15 Thus, the correlation between plasma concentration of NT-proBNP and the severity of cardiac impairment is well established. Published data show that the peptide has the prognostic power to indicate the risk of CV mortality,16–18 which we have reported earlier.19
The aim of this study was to evaluate whether the combined use of these two potent biomarkers (cystatin C and NT-proBNP) could provide better prognostic information about the risk of CV mortality in elderly patients with symptoms of HF compared with a single biomarker.
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Methods |
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The Ethics Committee of the University Hospital of Linköping approved the study protocol. All patients provided written informed consent before inclusion into the study.
Patients
The study population has previously been described in detail.20 All patients aged 65–87 years, with symptoms of and/or signs that might be attributed to HF and who attended primary health care during 1996, were evaluated. A total of 1168 patient records were identified, of these 548 patients in whom HF could not be excluded on the basis of the patients’ records were invited to participate. The symptoms and/or signs that indicated possible HF included shortness of breath and/or peripheral oedema and/or fatigue. Of these 548 patients, 510 agreed to participate in the study, 38 patients refused to participate either due to long-travelling distances or because of severe illness or incapacity. Of the 510 patients, 464 consented to having blood samples drawn and constituted the final study population.
All patients were assessed by the same cardiologist (UA), who recorded patient history, performed a clinical examination and assessed New York Heart Association functional class (NYHA class). Dyspnoea was defined from the patient history, whereas the presence of peripheral oedema was defined from the patient history and/or by clinical examination. Twelve-lead electrocardiography was also performed, as was echocardiographic assessment of systolic and diastolic functions, and blood sampling.
Echocardiography
Doppler echocardiographic examinations (Accuson XP-128c) were performed with the patient in the supine left position. Both M-mode and 2D methodology was used. Values for systolic function,21 expressed as ejection fraction (EF),22,23 were categorized into four classes with interclass limits of 30, 40, and 50%. A semi-quantitative method of assessment was used. Normal systolic function was defined as EF
50%, whereas severely impaired systolic function was defined as EF<30%. For assessment of diastolic function, mitral early wave/atrial contraction ratio and pulmonary venous flow pattern were analysed and compared with age-adjusted decision limits.
Blood sampling
Blood samples were drawn while the patients were fasting and in a sitting position after resting for 30 min. The samples were collected in pre-chilled plastic tubes containing EDTA (Terumo EDTA K-3), placed on ice and centrifuged at 3000 g for 10 min at +4°C. Plasma was then immediately transferred to a freezer with an ambient temperature of –70°C, and stored at this temperature until analysis.
Analysis of cystatin C
Cystatin C was measured by endpoint turbidometry with antibodies from Dako (Glostrup, Denmark) utilizing an Advia 1650 clinical chemistry analyser from Bayer (Gothenburg, Sweden). The between assay variation coefficient was 9.5% for 1.38 mg/L, (n = 98) and 9.5% for 4.93 mg/L. The reference range for age >50 years is 0.63–1.44 mg/L.
Analysis of NT-proBNP
The Elecsys 2010 (Roche Diagnostics, Mannheim, Germany) NT-proBNP assay, first described by Karl et al.,24 was used. This assay utilizes two polyclonal antibodies directed against amino acids, 1–21 and 39–50, and electrochemiluminiscence detection. The analytical range was 0.6–4130 pmol/L (5–35.000 ng/L). The total variation coefficient was 4.8% at the level of 26 pmol/L (217 ng/L) (n = 70) and 2.1% at the level of 503 pmol/L (4261 ng/L) at our laboratory.
Comorbidity
Hypertension was defined as a blood pressure of >140/90 mm Hg measured in the right arm with the patient in the supine position after at least 30 min rest. Patients were defined as hypertensive if they had previously been diagnosed with hypertension and were receiving antihypertensive medication. Ischaemic heart disease was defined as a history of angina pectoris, treatment for angina, and/or a previous myocardial infarction. Diabetes was defined as a fasting blood glucose concentration 7.0 mmol/L or ongoing treatment for diabetes.
Statistical methods
Descriptive data are presented as percentage or mean and standard deviation. In the case of continuous variables, analyses were performed using Student’s unpaired two-sided t-test, whereas the 
2-test was used for discrete variables. In the multivariate analysis of nominal variables the 2-test for trend was used, and in the multivariate analysis of continuous variables ANOVA analysis for trend was used. NT-proBNP was 10log transformed before analysis, as there was a skewed distribution of values.
Cox proportional hazard regression analyses as well as a Kaplan–Meier analysis were used to analyse the risk of mortality during the follow-up period. In the analysis clinically well-known variables that were found to be significant in an elderly population were used.25
A P-value <0.05 was considered statistically significant.
All data were analysed using generally available statistical analysis software packages (Statistica v. 8.0, Statsoft Inc., Tulsa, OK, USA; Analyse-it v. 2.04, Analyse-it Software Ltd, Leeds, UK).
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Follow-up period
Of the 464 patients, 294 were still alive after 3650 days (10 years).Of those who died during the follow-up period (n = 170) 113 deaths were due to CV mortality. In the non-survivor group, the median follow-up period was 6.2 years (range 242–3852 days). No patient dropped out of the study during follow-up. All mortality data were registered during the follow-up period and were collected from the National Board of Health and Welfare, Stockholm, Sweden or from autopsy records.
Relation of cystatin C to clinical variables
The clinical characteristics of the study population according to quartiles of cystatin C are presented in Table 1. Patients in the fourth quartile of cystatin C were older than those in the first quartile and had greater impairment of functional capacity (NYHA functional class III). The patients in the higher quartiles of cystatin C also received more intensive pharmacological treatment. The proportion of patients with impaired systolic function increased as the quartile concentration of cystatin C increased. The median serum concentration of cystatin C in patients who survived to 10 years of follow-up was 1.39 mg/L (range 0.72–3.31), compared with 1.53 mg/L (range 0.88–3.61) in those who suffered CV mortality at some time during the 10-year follow-up period. The difference in serum concentration of cystatin C between survivors and non-survivors was significant (t = 6.00; P < 0.0001).
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Relation of cystatin C to renal function
Cystatin C was evaluated against creatinine levels and the estimated GFR according to the MDRD formula.26 The correlation was significant both between serum cystatin C and plasma creatinine (r = 0.63) and between cystatin C and estimated GFR (r = – 0.70). To analyse these two alternative markers for renal function (creatinine and estimated GFR) as indicators of the risk of CV mortality, a Cox proportional hazard regression analysis was performed to analyse the first quartile of the biomarker against second, third, and fourth quartiles (Table 2). From the analysis, it was found that cystatin C was a better indicator than creatinine or eGFR of an increased risk of CV mortality. There was a higher hazard ratio in all three quartiles than in the first quartile, which was used as reference compared with creatinine or estimated GFR.
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We also analysed the risk of CV mortality in those with the lowest quartile of serum cystatin C (n = 107; CV mortality n = 10) compared with those with the highest quartile (n = 69; CV mortality n = 23), but with normal renal function (defined as serum creatinine <115 µmol/L). The univariate Cox proportional hazard regression indicated that in this group the risk of CV mortality among those within the fourth quartile of serum cystatin C was four times higher during 10 years of follow-up (HR: 3.61; 95% CI: 1.81–7.14) than those in the first quartile.
Prognostic information from cystatin C
A multivariate Cox proportional hazard regression was performed, in which some well-known risk factors for CV mortality were added to the second, third, and fourth quartiles of cystatin C and analysed against the first quartile with respect to risk of CV death during 10 years of follow-up (Table 3). It was found that patients with a serum concentration of cystatin C in the fourth quartile had a three times greater risk of CV mortality than those in the first quartile even when combined with well-known variables that influence the risk of CV mortality and together with the second, third, and fourth quartiles of NT-proBNP in a multivariate analysis.
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Prognostic information from NT-proBNP
The prognostic information from NT-proBNP concerning risk of CV mortality was analysed in a multivariate Cox proportional hazard regression over a follow-up period of 10 years (Table 3). We found that those patients with serum concentrations of NT-proBNP in the third and fourth quartiles had an increased risk of CV mortality even when other well-known risk factors were taken into account.
Prognostic information from cystatin C and NT-proBNP combined
Both cystatin C and NT-proBNP provided significant, independent prognostic information concerning the risk of CV mortality when analysed as continuous variables in a multivariate analysis and when they were adjusted for each other as well as for the other background variables (cystatin C: P = 0.0085; NT-proBNP: P < 0.0001). The two biomarkers were then classified into quartiles and the fourth and first quartiles were evaluated in different combinations. This is illustrated in a Kaplan–Meier analysis over the 10 years of follow-up (Figure 1). Of those patients with a plasma concentration in the first quartile for both biomarkers, >90% were still alive after 10 years, when compared with only 30% of those with a plasma concentration in the fourth quartile for both biomarkers combined.
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In a multivariate Cox proportional hazard regression analysis, the group with a serum concentration of cystatin C in the fourth quartile and a plasma concentration of NT-proBNP in the fourth quartile (n = 61; CV mort: n = 28) was compared with those in the first quartile of cystatin C and the first quartile of NT-proBNP (n = 65; CV mort n = 3). During a follow-up period of 5 years, use of the combined variable of cystatin C and NT-proBNP in the fourth quartile showed that the risk of CV mortality for these patients was >16 times higher (HR: 16.39; 95% CI: 1.77–66.70; P = 0.01) than for patients in the first quartiles of NT-proBNP and cystatin C combined. Use of this combined variable in estimating the risk of CV mortality showed that the hazard ratio decreased to almost 13 times increased risk of CV mortality for the combined variable, if the study population was followed for 10 years (HR: 12.98; 95% CI: 2.48–67.36; P = 0.002). The patients with a serum concentration of cystatin C in the first quartile and a plasma concentration of NT-proBNP in the first quartile had a CV mortality of 5% during 10 years of follow-up, whereas those having both biomarker concentrations in the fourth quartile had a CV mortality of 60% (Table 4).
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Discussion |
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Cystatin C provides important prognostic information about the risk of HF and CV mortality.27,28 However, we now report the possible benefits of the combined use of two biomarkers, NT-proBNP and cystatin C, to evaluate the risk of CV mortality in elderly patients with chronic HF.
In the present study, a high cystatin C concentration indicated a highly significant increase in CV mortality. This result concurs with findings in the literature.14,29 In addition, the follow-up period of 10 years was longer than that used in previous studies. During the follow-up period, the probability that a patient might change from one cystatin C quartile to another increases with time. However, if a shorter follow-up period such as 5 years is used, the hazard ratio obtained in multivariate analysis is almost the same (HR: 3.38; 95% CI: 1.23–9.30; P = 0.02) as in the 10-year follow-up (HR: 2.63; 95% CI: 1.38–5.02; P = 0.004). This illustrates the robustness of the prognostic information.
NT-proBNP, another well-known biomarker related to the risk of CV mortality, has provided similar results, as reported in the literature.30,31 This biomarker is robust and has a documented ability to indicate the risk of CV mortality both for patients with HF and for those with acute coronary syndrome.
The two biomarkers chosen for evaluation in this study, cystatin C and NT-proBNP, were both independent predictors of CV mortality when analysed as continuous variables. This provides the basis for an extended analysis of the two biomarkers.
By combining these two biomarkers in the risk evaluation of CV mortality, we obtained results that indicate a highly increased risk for those with a high concentration of both biomarkers. This was found in both the univariate and the multivariate analyses, analyses in which other well-known risk factors for CV death were included.
The combined analysis of two biomarkers for evaluating the risk of CV mortality has been previously reported in the literature.4 It has also been shown that a combination of two biomarkers can give a better risk prediction than a single biomarker. However, in the present study, we chose a biomarker of renal function, i.e. cystatin C, which is more sensitive in patients with slightly impaired renal function. We applied it in an elderly outpatient population, the majority of whom did not have severe impairment of either cardiac or renal function. Despite this important prerequisite, the risk of CV mortality was increased in the subgroup of patients with increased plasma concentrations of both biomarkers. The group of patients with a serum concentration of cystatin C in the fourth quartile and a plasma concentration of NT-proBNP in the fourth quartile had a risk of CV mortality that was 16 and 13 times higher, respectively, than for those in the first quartiles of both cystatin C and NT-proBNP during 5 and 10 years of follow-up, respectively. Thus, in patients with less impaired cardiac and renal functions, the combined used of the two biomarkers still gave important prognostic information. In the multivariate analyses, where the second, third, and fourth quartiles of the two biomarkers were analysed in addition to well-known risk factors for CV death, the third and fourth quartiles of NT-proBNP and the second, third, and fourth quartiles of cystatin C were found to be independent predictors of CV mortality (Table 3). Thus, this combined biomarker analysis could be an alternative for identifying patients at increased risk, even though they only have slightly impaired cardiac or renal function, but may be said to have cardio–renal syndrome.
An important question is whether the increased serum concentration of cystatin C is merely an indicator of impaired renal function or something else as well. This discussion is still ongoing in the literature.32 In a study of patients with chronic renal disease, and with cystatin C as prognostic indicator, Menon et al.33 reported that cystatin C might provide prognostic information beyond information about renal function. Therefore, an interesting aspect of the prognostic information concerning CV mortality is the use of dual biomarkers in patients with normal renal function according to serum creatinine, but with increased serum concentration of cystatin C. Arimoto et al.8 found an increased risk of CV mortality in this group. The present study confirms this result. Francis34 reports that almost two thirds of the patients admitted for acute HF at the Cleveland Clinic had normal levels of serum creatinine despite reduced creatinine clearance, indicating that serum creatinine might be insufficiently sensitive for detecting decreased renal function, compared with other markers of renal function, such as cystatin C.35
We used 115 µmol/L as a cut-off value for serum creatinine, which was the upper reference value for men (for women, 100 µmol/L) at the Department of Clinical Chemistry at Linköping University, Sweden, at the time of the study. This was only slightly lower than the value (120 µmol/L) used by the Finnish group in the FINN-AKVA study. Lassus et al.14 reported that 18% of the study population in FINN-AKVA had normal serum creatinine but elevated serum cystatin C; they found an increase in mortality in this group, which is similar to our findings.
Limitations
This study was conducted in elderly patients with symptoms of HF. One limitation is the size of the study population. A larger sample of patients would have made the results from the subgroup analyses more robust. However, we believe that the results obtained are accurate and informative and that the conclusions drawn are correct.
A second limitation is the restricted age range (70–80 years) of the study population. Inclusion of younger patients would have increased the information provided by the study and thus the possibility to extrapolate the findings to the HF population in general.
A third limitation is that only some patients had impaired systolic function according to Doppler echocardiography. However, recent guidelines from the European Society of Cardiology state that increased plasma concentrations of natriuretic peptides may be regarded as an objective sign of impaired cardiac function.36 In accordance with this definition, the study population was examined using increased natriuretic peptide levels as an objective assessment of cardiac function. Using the fourth quartile of NT-proBNP (>400 pg/mL) as a cut-off for possible HF in patients with signs/symptoms of HF, 31% of the study population had increased plasma concentrations of NT-proBNP. It would have been preferable, if all patients included in the study had HF. However, in this study, we used a primary health-care population that was well known to the clinician and included patients with different plasma concentrations of NT-proBNP, who were evaluated according to these specific plasma concentrations.
If, as an alternative, we used a definition of HF based on plasma concentrations of NT-proBNP above the median concentration from a reference population of a corresponding age and in the same geographical area, we found that 372 patients out of 474 (78%) had a plasma concentration above the cut-off level. The reference population appeared free from heart disease and was not being treated with substances that influenced the plasma concentration of NT-proBNP.37
The choice of reference values in an elderly population is certainly controversial, but as the chosen population was interviewed, underwent a clinical examination and Doppler echocardiography, and had blood samples drawn, we were able to exclude all known potential factors that influence NT-proBNP levels in this unselected elderly population. For this reason, we argue that the reference population is representative as a reference population and that the findings can be extrapolated to elderly HF patients in the community.
Conclusion
The use of biomarkers for identifying those at risk of CV mortality is central to the management of patients with HF. In the present study, the combination of cystatin C and NT-proBNP has been used to identify those at risk of CV mortality. A multivariate analysis showed that the risk of CV mortality in patients with serum concentrations of both cystatin C and NT-proBNP in the fourth quartile was 16 times that of a plasma concentration in the first quartile of both biomarkers combined during the first 5 years of follow-up and was almost 13 times that of the first quartile of both biomarkers combined during the full 10 years of follow-up.
The size of the study group is limited and there is therefore a need for additional evaluations of the biomarkers used. However, we suggest that use of the combined analysis among elderly patients with symptoms of HF is indeed useful for identifying those at high risk.
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The study was supported by grants from The County Council of Östergötland, The Swedish Heart and Lung Foundation, and the strategic research area ‘Inflammation, atherosclerosis and ischaemic heart disease—new strategies for prevention, diagnosis and treatment’, which is sponsored by the County Council of Östergötland and the University of Linköping.
Conflict of interest: none declared.
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Acknowledgements |
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We would like to thank Mrs Kerstin Gustavsson, heart failure nurse, for her invaluable help. The principal investigator (UA) had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
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