© 2003 European Society of Cardiology
Pre-discharge, but not admission, levels of NT-proBNP predict adverse prognosis following acute LVF
Department of Medicine and Therapeutics, University of Leicester Clinical Sciences Building, Leicester Royal Infirmary, Leicester LE2 7LX, UK
* Corresponding author. Tel.: +44-116-252-3125; fax: +44-116-252-3108 E-mail address: is11{at}le.ac.uk
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Abstract |
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 Top Abstract 1. Introduction2. Methods3. Results4. DiscussionReferences |
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Background: Circulating natriuretic peptide levels provide prognostic information following acute coronary syndromes and in chronic heart failure. Little evidence exists of their utility following hospitalisation with acute left ventricular failure (LVF).
Aims: To examine the relative prognostic value of admission and pre-discharge plasma N-terminal pro B-type natriuretic peptide (NT-proBNP) following hospitalisation with acute heart failure.
Methods: NT-proBNP was measured at admission in 96 patients hospitalised with acute LVF. In a subset of 34 patients, NT-proBNP was also measured prior to discharge. Multivariate analysis was performed of the clinical and serological predictors of a combined primary endpoint of death or heart failure (hospitalisation or as an outpatient).
Results: During follow up (median 350 days, range 2–762), 37 (38.5%) patients died (n=16, 16.7%), or experienced at least 1 heart failure event (n=21, 21.9%). For the entire cohort of 96 patients, only a prior history of heart failure was associated with the primary endpoint (OR 3.5 [1.10–11.08], P=0.034). Admission plasma NT-proBNP was not predictive (OR 1.84 [0.75–4.51], P=0.185). In the 34 patients for whom both admission and pre-discharge NT-proBNP was available, 19 (55.9%) died (n=8, 23.5%) or experienced heart failure (n=11, 32.4%). Only pre-discharge plasma NT-proBNP (OR 15.30 [95% CI: 1.4–168.9], P=0.026) was independently predictive of the composite endpoint. The area under the receiver–operator-characteristic (AUC ROC) curve for pre-discharge NT-proBNP was superior to that for admission NT-proBNP for prediction of death or heart failure (AUC ROC 0.87 cf 0.70), for death (0.79 cf 0.66), LVF hospitalisation (0.78 cf 0.70) or heart failure as an outpatient (0.71 cf 0.61).
Conclusions: Plasma NT-proBNP measured pre-discharge provides useful prognostic information following hospitalisation with acute LVF.
Key Words: Heart failure • Natriuretic peptides • Prognosis
Received November 20, 2002; Revised February 18, 2003; Accepted May 11, 2003
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1. Introduction |
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TopAbstract1. Introduction2. Methods3. Results4. DiscussionReferences |
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Acute left ventricular failure (LVF) and decompensated chronic heart failure together represent a major burden on medical services in industrialised nations. While numbers of hospital admissions associated with heart failure increased over the latter part of the 20th century, the prevalence of heart failure is also increasing. This is due in part to the general ageing of the population but also to improved survival from many of the precipitants of heart failure, most notably ischemic heart disease [1]. Heart failure accounts for nearly 2% of NHS expenditure and for 4% of all UK hospital admissions, the average duration of each being 8–9 days [2,3].
The prognosis for patients newly hospitalised with heart failure is poor. Even in the modern treatment era, 1-year mortality exceeds 40%. Moreover as many as one third of patients admitted with heart failure will experience further hospitalisation within 1 year [4,5]. While factors such as age, NYHA and Killip class are useful in identifying individuals at high risk of adverse outcome, these are crude and relatively insensitive [6]. For the identification of those patients at highest risk physicians tend to rely on assessment of the severity of left ventricular dysfunction as a surrogate marker of prognosis. Echocardiography provides a non-invasive and convenient method of assessing cardiac structure and function and has come to be the ‘gold standard’ in the assessment of left ventricular systolic function. Ejection fraction and wall motion index scores, for example, are now accepted measures of cardiac function, which provide prognostic information in heart failure [7]. However, these measures are to some extent operator dependent and interpretation of the severity of dysfunction may vary widely. Furthermore, echocardiographic estimate of ejection fraction may be normal in patients with a clinical diagnosis of heart failure, especially women and the elderly [8,9].
There has been considerable recent research interest in the role of the natriuretic peptides as potential markers of prognosis in patients with cardiovascular disease. Focus has centred on atrial (ANP) and B-type (BNP) natriuretic peptides, and the N-terminal fragments of the prohormones, N-terminal proANP and N-terminal pro B-type natriuretic peptide (NT-proBNP). Despite the plethora of data suggesting a strong prognostic role for the natriuretic peptides in symptomatic and asymptomatic chronic heart failure [10,11], following acute myocardial infarction [12,13], and in acute coronary syndromes as a whole [14], surprisingly little information exists on their utility as markers of prognosis after hospitalisation with acute LVF. The small studies to date show that BNP measured after recovery from acute heart failure has at least short-term independent prognostic utility [15] and a convalescent BNP level correlates with cardiovascular morbidity and mortality in elderly patients with heart failure [16].
NT-proBNP has a slower clearance from plasma than BNP and shows a correspondingly greater rise in disease [17,18]. Thus, the prohormone may be the better marker of ventricular dysfunction and by implication, of prognosis. This study was designed to assess the prognostic value of NT-proBNP following hospital admission in a cohort of unselected patients with acute LVF. We investigated whether plasma levels measured during the acute admission phase or prior to discharge is the superior marker of prognosis.
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2. Methods |
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TopAbstract1. Introduction2. Methods3. Results4. DiscussionReferences |
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2.1. Study population
We studied 96 consecutive patients admitted to the Coronary Care Unit of Leicester Royal Infirmary. Patients were enrolled into the study based on a clinical diagnosis of acute LVF, the severity meriting coronary care management, as determined by the attending physician. To reflect normal clinical practice, no particular exclusion criteria were made with regard to age, gender, the perceived need for inotropic support, or prior medical history. None of the recruited patients had a second life threatening condition that might have been expected to affect prognosis. Patients with acute myocardial infarction (diagnosed by the criteria of any two of typical history, ECG changes and creatine kinase rise to greater than twice the upper limit of normal) were excluded from the study.
Relevant clinical information was collected, including prior medical history, pharmacological therapy, Killip class, cardiac enzymes, renal function, haemoglobin, glucose, and lipid profile. All patients gave informed consent to participation in the study, which was approved by the local Ethics Committee. This study conforms to the principles of the Declaration of Helsinki.
2.2. Blood sampling
In all 96 patients, blood was sampled for measurement of plasma NT-proBNP immediately on arrival on the coronary care unit. In a subset (n=34) a second sample was taken once the patient was deemed clinically stable, and ready for discharge home. To avoid any influence of diurnal variation in NT-proBNP, these samples were taken in the morning after 30 min supine rest. Each sample consisted of 20 ml of peripheral venous blood drawn into pre-chilled sodium-EDTA (1.5 mg/ml blood) tubes containing 500 IU/ml aprotinin. After centrifugation at 3000 rpm at 4 °C for 15 min, plasma was separated and stored at –70 °C until assay.
2.3. Assay of NT-proBNP
Our assay for NT-proBNP is based on the non-competitive technique described by Karl [19]. Peptides corresponding to the N-terminal (amino acids 1–12) and C-terminal (amino acids 65–76) of the human NT-proBNP sequence were synthesized in the MRC Toxicology Unit, University of Leicester and polyclonal antibodies to these amino acid sequences were raised in rabbits injected with the respective peptides conjugated to keyhole limpet hemocyanin [20]. IgG from the sera was purified on protein A sepharose columns. The C-terminal directed antibody (0.5 mg in 100 ml for each well) was immobilized onto ELISA plates. The N-terminal antibody was affinity purified and biotinylated using biotin-X-N-hydroxysuccinimide ester (Calbiochem, Nottingham, UK). Aliquots (20 ml) of samples or NT-proBNP standards were incubated in the wells for 24 h at 4 °C. ELISA plates were washed with 0.1% Tween in PBS, and streptavidin (Chemicon International Ltd, Harrow, UK) labeled with methyl-acridinium ester (streptavidin-MAE, 5x106 relative light units/ml) [21] added to each well. Plates were read on a Dynatech MLX Luminometer, with sequential injections of 100 ml of 0.1 M nitric acid (with H2O2) and then 100 ml of sodium hydroxide (with cetyl ammonium bromide) [20]. The lower limit of detection was 14.4 fmol/ml. Within and between assay coefficients of variation were 2.3 and 4.8%, respectively. There was no cross-reactivity with ANP, BNP or C-type natriuretic peptide.
2.4. Endpoints
The primary endpoint was defined as a composite of death, heart failure readmission and worsening heart failure in an outpatient clinic setting. Secondary endpoints were each of these endpoints individually, admission with an acute coronary syndrome or a revascularisation procedure. Patients could contribute more than one endpoint if they suffered different discrete endpoints. If more than one endpoint occurred during a single episode (e.g. acute LVF followed by death, or outpatient heart failure leading to hospital admission) then the more severe endpoint only was counted.
2.5. Statistics
Data are presented as mean±S.D. or median (range) for data with non-normal distribution, which were log transformed prior to analysis. Correlation analysis of continuous variables was performed using the Pearson product moment correlation coefficient. For continuous variables, mean levels in those suffering or being spared each clinical event were compared by one-way analysis of variance (ANOVA). The value of individual categorical variables for the prediction of clinical endpoints was assessed using the 
2-test. Clinical variables included as potential predictors of outcome included age, Killip class, renal function (plasma creatinine), and history of prior myocardial infarction, heart failure, hypertension or diabetes. Factors with univariate significance of P<0.1 were included in multivariate analyses. The independent predictive power of clinical factors and admission levels of plasma NT-proBNP was tested using binary logistic regression analysis. For the subset of patients for whom both admission and pre-discharge NT-proBNP levels were available, both were entered into the analysis.
Kaplan–Meier survival curves were constructed for groups with admission and discharge NT-proBNP levels above and below the respective median value. For multivariate analyses, significance was declared at P<0.05. The relative sensitivity, specificity and predictive value of NT-proBNP for clinical endpoints were assessed by construction of receiver operating characteristic (ROC) curves. Analyses were performed using both the MINITAB (Minitab Inc.) and SPSS (SPSS Corp.) statistical applications.
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3. Results |
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TopAbstract1. Introduction2. Methods3. Results4. DiscussionReferences |
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3.1. Patient characteristics
Demographic and clinical characteristics of the 96 patients are summarised in Table 1. Aetiology of heart failure was often multifactorial, but a majority of the patients had a history of ischaemic heart disease (n=56, 58.3%). During the acute phase, 46 patients were treated with intravenous vasodilator therapy in the form of either sodium nitroprusside (n=20 (20.8%)) or glyceryl trinitrate (n=26 (27.1%)). Three patients (3.1%) received intravenous inotropic support. At discharge, 67 (69.8%) were established on ACE inhibition, 41 (42.7%) were receiving beta-blocker, 37 (38.5%) oral nitrate, and 92 (95.8%) were receiving diuretic.
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3.2. Primary and secondary endpoints
During the median follow up period of 350 days (range 2–762), a total of 37 (38.5%) patients reached the composite primary endpoint. Of these, 16 died, 9 as their first event. Seven patients died after one or more non-fatal heart failure events. One patient had a non-fatal heart failure admission before death, 2 developed worsening heart failure as an outpatient, and 4 experienced both outpatient and in-patient heart failure episodes. A further 21 patients experienced heart failure events but were alive at the end of the observation period. Of these, 10 patients had a heart failure admission alone; 5 had outpatient heart failure alone; and 11 experienced both endpoints during the follow up period. No episode of non-fatal myocardial infarction occurred during follow up. Fifteen patients (15.6%) were admitted with an acute coronary syndrome. Fourteen patients (14.6%) underwent coronary angiography and of these 8 (8.3%) went on to have a revascularisation procedure.
In the subset of 34 patients for whom both admission and pre-discharge levels of NT-proBNP were assessed, 19 (55.9%) reached the composite primary endpoint. Amongst this number, 8 (23.5%) died, 6 as their first endpoint and 2 following a heart failure event. Eleven (32.4%) more had one or more non-fatal heart failure events: 2 suffered a hospital readmission alone, 5 developed worsening heart failure in an outpatient setting, and 4 suffered both these secondary endpoints.
3.3. Plasma NT-proBNP
In this group of 96 patients hospitalised with acute LVF, plasma NT-proBNP levels were higher (median 2944 fmol/ml, range 14–29 368) than in 210 samples drawn from an ongoing study of the value of natriuretic peptides in community screening for LVSD (median age 64, median NT-proBNP 64 fmol/ml, range 14–933 P<0.0005). These controls had normal left ventricular systolic function on echocardiography, and none had any history of cardiovascular disease or was receiving any cardiovascular medication. In the 34 patients for whom paired blood samples were available, admission levels (median 5395 fmol/ml, range 14–29 368) were significantly higher than those prior to discharge (median 1944 fmol/ml, range 14–8155 P=0.009) (Fig. 1). Admission and discharge levels of NT-proBNP were correlated with each other (r=0.54, P=0.001), with age (r=0.43, P=0.011 and r=0.47, P=0.006, respectively), 1/creatinine (r=–0.50, P=0.003 and r=–0.44, P=0.01). Admission NT-proBNP correlated with plasma glucose level (r=0.27, P=0.011). NT-proBNP also increased with the severity of heart failure assessed by either Killip class or with echocardiographic evaluation of left ventricular systolic dysfunction (Fig. 2).
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3.4. Predictors of outcome—univariate analyses
Within the entire cohort of 96 patients, univariate predictors of death or any heart failure episode were age (77.6 vs. 70.7 years P<0.002), higher serum creatinine (131 vs. 100 µmol/l P<0.0005) prior history of heart failure (17/37 vs. 9/59 P<0.001), and higher Killip class (3 or 4 vs. 2, P<0.001).
Findings for the individual components of the primary endpoint were similar. Patients dying were older (78.6 vs. 73.1 years P=0.035), had higher plasma creatinine (194 vs. 117 µmol/l, P=0.001), higher Killip class (P=0.001), and more often had prior history of heart failure (P=0.024) than those surviving to the end of follow up. Observations were similar for those experiencing, compared to those being spared, re-admission with heart failure (age 77.6 vs. 73.0 years P=0.048; creatinine 167 vs. 119 µmol/l, P=0.004; Killip class P=0.032, prior history of heart failure P=0.017). Only higher Killip class (P=0.01) and prior history of heart failure (P=0.008) were associated with outpatient heart failure. There were no significant associations between peptide levels and the other secondary endpoints of acute coronary syndrome or revascularisation procedure.
Median peptide levels on admission and prior to discharge for those patients suffering or being spared the primary and secondary endpoints are summarised in Table 2. Admission levels of NT-proBNP were higher in those suffering compared to those being spared the composite endpoint of death or any heart failure episode (5559 vs. 1287 fmol/ml P<0.001). Similarly, for the individual components of this composite endpoint, admission levels of NT-proBNP were higher in patients dying, in those readmitted with heart failure and in those developing worsening heart failure in clinic.
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For the 34 patients for whom both admission and pre-discharge NT-proBNP levels were available, pre-discharge levels were higher in those dying compared to those surviving (4546 vs. 2336 fmol/ml, P=0.013) and in those suffering heart failure hospitalisation compared to those not (6038 vs. 1839 fmol/ml, P=0.047).
3.5. Predictors of outcome—multivariate analyses
In the full cohort of 96 patients, only a previous history of heart failure was associated with the composite primary endpoint (odds ratio 3.5 [1.10–11.08], P=0.034). Admission plasma level of NT-proBNP was not predictive (odds ratio 1.84 [0.75–4.51], P=0.185).
In the cohort for whom both admission and pre-discharge peptide levels were available, only the pre-discharge plasma level of NT-proBNP (odds ratio 15.30 [95% CI: 1.4–168.9], P=0.026) remained independently predictive of the composite primary endpoint in multivariate analysis. The admission level of NT-proBNP was not associated with occurrence of the primary endpoint (P=0.082).
Fig. 3 shows Kaplan–Meier survival curves for admission and pre-discharge NT-proBNP concentrations above and below the median level. Only pre-discharge NT-proBNP above the median was significantly associated with poorer survival (log rank score 8.6, P=0.034). Indeed no patient with pre-discharge levels of NT-proBNP below the median value of 1944 fmol/ml died during follow up. The superiority of pre-discharge peptide levels is further illustrated by the areas under the receiver–operator-characteristic curves for each peptide and endpoint (Table 3).
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There was no association between the magnitude or direction of the change in peptide and the occurrence of the primary endpoint.
3.6. Influence of treatment
Neither admission nor pre-discharge level was significantly associated with (subsequent or previous) use of ACE inhibitors (P=0.062 and P=0.807, respectively) or beta-blockers (P=0.393 and P=0.092, respectively). Patients prescribed ACE inhibitor/Angiotensin II receptor antagonist were more likely (49%) to experience the composite primary endpoint than those patients not prescribed (21.6%, 2=7.276, P=0.007) either of these treatments. However, this latter factor did not retain predictive value on multivariate analysis. There was no association of the prescription or non-prescription of beta-blocker (2=2.598, P=0.107) or either beta-blocker or ACE inhibitor/Angiotensin II receptor antagonist (2=0.425, P=0.514) with the likelihood of experiencing the composite primary endpoint.
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4. Discussion |
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TopAbstract1. Introduction2. Methods3. Results4. DiscussionReferences |
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This work establishes the value of NT-proBNP in the prognostic assessment of patients admitted with acute heart failure. The study shows that pre-discharge, rather than admission, concentration is the better predictor of death or readmission with heart failure. Given the broad range of patients included, it also indicates the value of measuring this natriuretic peptide irrespective of age, disease onset, echocardiographic findings or presumed aetiology.
Plasma levels of the natriuretic peptides are elevated in many of the conditions which may be associated with acute and chronic heart failure, such as myocardial infarction [12], hypertension [22], valvular disease [23] and atrial fibrillation [24]. The syndrome of acute heart failure is the end result of a variety of pathological processes, and may present in a variety of clinical situations: in acute myocardial infarction, other acute coronary syndromes, decompensated chronic heart failure, renal artery stenosis or arrhythmia. With this heterogeneity of presentation and aetiology, a single, reliable marker of prognosis would be of potential value in clinical practice. Irrespective of the cause of left ventricular systolic dysfunction, the end result is increased end-diastolic pressures and wall stretch, the primary stimulus to augmented natriuretic peptide expression. Thus, the natriuretic peptides represent a common response mechanism to the renin–angiotensin–aldosterone and adrenergic system activation, which occurs both acutely and chronically in heart failure. It is, therefore, unsurprising that the natriuretic peptides should reflect prognosis in many settings. This study demonstrates the predictive value of plasma NT-proBNP measured during admission in patients with acute LVF and that the risk of death and recurrent heart failure increases significantly with rising admission levels of NT-proBNP. This is very much in keeping with data from previous study of the prognostic value of natriuretic peptides in other conditions [12,14,25].
Perhaps the most important finding in the current study is that the pre-discharge level of NT-proBNP, measured at a time when clinical stability has been attained, has better predictive value than that measured at the point of admission. Levels of natriuretic peptides have been shown to change following treatment for both acute [26] and chronic heart failure [27], a fact supported by our observations. Furthermore, this drop with therapy is also associated with improved symptoms and prognosis [11]. Thus, by the time of discharge, many patients will have received therapy sufficient to allow their clinical condition to be deemed stable. It is likely that pre-discharge natriuretic peptide levels correspond more closely to the underlying level of left ventricular systolic dysfunction than do levels during the acute decompensation. Patients with acute LVF will of course present to hospital at greatly different points in the natural history of left ventricular dysfunction. Similarly, the amount and adequacy of treatment will vary widely and be influenced by a variety of factors. Our observation of the pre-discharge level of NT-proBNP as the better marker of prognosis suggests that this may represent a potential marker for the adequacy and effectiveness of pharmacological therapy in this setting, as has been suggested previously [11]. However, it is of note that patients receiving ‘optimal’ pharmacological therapy, i.e. rennin–angiotensin system antagonist plus beta blocker, were no less likely to reach a clinical endpoint than patients not prescribed these therapy.
4.1. Limitations of the study
There are a number of limitations to this study. The size of the cohort and the numbers of clinical events upon which we base our conclusions are, by comparison to the data accumulated in AMI and chronic heart failure, very small. The discriminatory power of NT-proBNP in this group of patients is perhaps less impressive than in patients after an acute coronary syndrome [14] or with chronic heart failure [12]. Once again, this may be explained by the small numbers of patients in the current study. However, the heterogeneity of the patient population may contribute to the weaker association observed in this study. Further to this the lack of thorough echocardiographic information in the study may be perceived as a weakness.
However, we would suggest that in these two points lies the strength of the study. Our cohort was unselected, in terms of aetiology of heart failure, age, and treatment and is thus very representative of the population seen in standard clinical practice. We did not formally assess LV ejection fraction for this study. The availability of echocardiography is less than optimal in many areas, and the independent prognostic value of the natriuretic peptides over and above echocardiographic measures of left ventricular function in patients with chronic heart failure [7] and acute myocardial infarction [28] is well established. This small study has shown that NT-proBNP's prognostic utility can cautiously be extended to patients hospitalised with decompensated left ventricular dysfunction.
4.2. Summary
Our study illustrates that even amongst a uniformly high-risk group of patients with acute LVF, NT-proBNP is able to identify those at particularly high risk of death or recurrent heart failure admission. In this regard pre-discharge levels are superior to levels on admission to hospital, possibly because of a closer association with residual LV function compared to natriuretic peptide levels during acute decompensation. Larger studies are required to further determine the clinical utility of this observation.
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Acknowledgements |
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RO'B was supported by a grant from the British Heart Foundation. The authors would like to extend their sincerest gratitude to Paulene Quinn and Sonja Jennings for their excellent technical assistance.
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References |
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