European Heart Journal Advance Access published online on November 23, 2008
European Heart Journal, doi:10.1093/eurheartj/ehn525
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Prognostic threshold levels of NT-proBNP testing in primary care
1 Department of Cardiology, Frederiksberg University Hospital, Nordre Fasanvej 57, 2000 Frederiksberg, Denmark
2 Department of Cardiology, Rigshospitalet, Blegdamsvej 9, 2100 København Ø, Denmark
3 Københavns Praktiserende Lægers Laboratorium, Pilestræde 65, 1112 København K, Denmark
4 Department of Cardiology, Glostrup University Hospital, Nordre Ringvej 57, 2600 Glostrup, Denmark
Received 4 August 2008; revised 22 September 2008; accepted 31 October 2008.
* Corresponding author. Tel: +45 38 16 43 78, Fax: +45 38 16 43 59, Email: cor{at}dadlnet.dk
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Abstract |
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Aims: Chronic heart failure (HF) is a common condition with a poor prognosis. As delayed diagnosis and treatment of HF patients in primary care can be detrimental, risk-stratified waiting lists for echocardiography might optimize resource utilization. We investigated whether a prognostic threshold level of the cardiac peptide, NT-proBNP, could be identified.
Methods and results: From 2003–2005, 5875 primary care patients with suspected HF (median age 73 years) had NT-proBNP analysed in the Copenhagen area. Eighteen percent died and 20% had a cardiovascular (CV) hospitalization (median follow-up time: 1127 and 1038 days, respectively). In Cox proportional hazards regression models regarding NT-proBNP levels, the fourth decile (range: 83–118 pg/mL) was associated with a 90% (95% CI: 30–190, P < 0.01) increased risk for CV hospitalization and the seventh decile (range: 229–363 pg/mL) was associated with an 80% (95% CI: 20–190, P = 0.01) increased mortality risk after adjustment for age, sex, previous hospitalization, CV diseases, and chronic diseases.
Conclusion: We identified prognostic threshold levels for mortality and CV hospitalization for NT-proBNP in primary care patients suspected of HF. Our results have the potential to be used to risk-stratify waiting lists for echocardiography.
Key Words: Brain natriuretic peptide • Prognosis • Congestive heart failure • Primary care
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Introduction |
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Chronic heart failure (HF) is a common condition with a poor prognosis.1 Well-documented treatment options such as ACE-inhibitors, beta-blockers, and implantable devices are known to improve symptoms and prognosis.2–4 Early treatment of HF or left ventricular systolic dysfunction improves outcome, and consequently rapid identification and treatment of HF patients are important.5 Echocardiography is an essential part of the diagnostic work-up for HF, but rapid access to echocardiography in primary care is limited in many countries, and patients may wait months for the needed diagnostic work-up.1 Risk-stratified waiting lists for primary care referrals for echocardiography might serve as a reasonable solution to reduce the risks of increased morbidity and mortality associated with waiting for a diagnostic echocardiogram.
B-type natriuretic peptides are released from the heart owing to increased wall stress as in congestive HF.6 Other conditions such as ischaemic heart disease, atrial fibrillation, and valvular heart disease along with cardiovascular (CV) medications such as ACE inhibitors, angiotensin receptor blockers, and spironolactone are known to modulate the plasma level of B-type natriuretic peptides.7–11 Elevated plasma levels are associated with a poor outcome in the general population as well as in HF patients.12–14
Prior studies suggest that primary care patients with symptoms suggestive of HF who have low levels of B-type natriuretic peptides in fact are very unlikely to suffer from HF and echocardiography may not even be necessary.15–17
We hypothesized that the N-terminal part of pro-brain natriuretic peptide (NT-proBNP) exhibits a prognostic threshold level by which it is possible to identify primary care patients with possible HF who have an increased risk of death or CV hospitalization.
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Methods |
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NT-proBNP
The NT-proBNP test was introduced by 2 April 2003 in Copenhagen in primary care to be used only on the suspicion of HF. Regarding NT-proBNP, general practitioners in the counties of Copenhagen and Frederiksberg (catchment area of 969.735 adult inhabitants) were exclusively served by two laboratories, namely Copenhagen General Practitioners' Laboratory and Frederiksberg University Hospital's Biochemical Laboratory. NT-proBNP was measured by a second generation commercial kit: the Elecsys proBNP Immunoassay (Roche Diagnostics Corporation, Indianapolis, Indiana) on an Elecsys 2010 platform. Blood samples were analysed as part of the laboratories' routine programmes. The test results were retrieved electronically from the laboratories' databases. All NT-proBNP samples from the two laboratories in the period 2 April 2003 to 15 December 2005 from primary care were included. General practitioners were not obliged to refer patients suspected of HF to an NT-proBNP test.
Patient selection
Patients eligible for this study were >17 years without known history of HF referred from primary care to an NT-proBNP test in the period 2 April 2003 to 15 December 2005. In case of repeated measurements, only the first sample was included in the analysis (Figure 1). The blood sampling date is considered as the index date.
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Diagnoses, deaths, and hospitalizations
Information about deaths was obtained from the Danish Civil Registration System on 14 February 2008. All diagnoses and related dates in the period 1 January 1995 to 14 February 2008 as well as CV procedures as percutaneous coronary intervention (PCI), coronary by-pass surgery (CABG), and pacemaker implantation were collected from The National Patient Registry on 14 February 2008. In Denmark, the attending physician assigns a WHO International Statistical Classification of Diseases and Related Health Problems 10th Revision (ICD-10) code diagnosis as the main reason for the hospital stay at discharge. These diagnoses are reported systematically to The National Patient Registry as part of the Danish health care system.
Known disease
We identified diseases in our protocol known to affect either the plasma level of NT-proBNP or the prognosis. Definitions of diseases are detailed in Table 1 by WHO International Statistical Classification of Diseases and Related Health Problems 10th Revision (ICD-10) codes. Diagnoses registered in The National Patient Registry prior to the index date were defined as known disease. Patients with PCI or CABG prior to the index date were also registered as having ischaemic heart disease.
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End points
Two end points were prespecified in our protocol: all-cause mortality and CV hospitalization. A CV hospitalization was defined as an acute hospital admission after the index date with a primary discharge WHO ICD-10 diagnosis in The National Patient Registry defined as CV as detailed in Table 1.
Background population
The age distribution in the background population above 17 years in the counties of Frederiksberg and Copenhagen per 1 January 2006 were obtained from Statistics Denmark. CV hospitalization rate and death rate for 2005 were collected from the same source.
The study complies with the Declaration of Helsinki. The Ethics Committee of Copenhagen and Frederiksberg has approved the research protocol. As the study was a database study only, it was not necessary to obtain informed consent from the patients in compliance with Danish law.
Statistical methods
Data analysis was performed with SAS software, version 9.1.3, Cary, NC, USA. Continuous baseline variables are given as medians (fifth–95th percentile), whereas calculated estimates are presented with 95% confidence intervals. A significance level of 0.05 is used and all statistical tests were two-sided.
When calculating the CV hospitalization rate, only the first CV admission per patient was used. CV hospitalization rates and death rates were directly age-adjusted with the age distribution from the background population. The patients were divided into quintiles according to their NT-proBNP level instead of deciles to avoid unstable estimates of the adjusted rates.
Cumulative survival curves were constructed by the Kaplan–Meier method for each end point stratified by NT-proBNP quintile.
The covariate of primary interest was NT-proBNP. Four Cox proportional-hazards regression models are presented in this paper. To identify the prognostic threshold levels, two exploratory models used all prespecified factors along with NT-proBNP divided into deciles. The end points were all-cause mortality and CV hospitalization, respectively. The lowest decile served as reference. The overall effect of NT-proBNP was evaluated by a Wald Chi-square test in the two full models. With parallel end points, two other models with log-transformed NT-proBNP values as a continuous covariate and all prespecified factors were tested. Knowing that all logarithms are proportinal, a log-base of 1.3 was chosen, making it possible to interpret the estimated hazard ratios as the ratios in risk of death or CV hospitalization in two patients with the same covariate structure, but a 30% difference in NT-proBNP. Biological variation in NT-proBNP has been shown to be 30% in stable HF patients, making 30% a clinically relevant difference.18
The functional form of NT-proBNP and age was formally tested by cumulative sums of martingale residuals (1000 iterations). No readily available transformation of age as a continuous covariate was satisfactory. Age was subsequently included as a categorical covariate with four levels as a trade-off between quartiles and meaningful categories: 18–60 years, 60–69 years, 70–79 years, and 80+ years, each category including more than 1000 patients. All other covariates, gender and prior diseases, were entered as dichotomous factors. All Cox proportional-hazards models met the assumption of proportional hazards. The assumption of proportional hazards was tested by a Kolmogorov-type supremum test.
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Results |
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In the period 2 April 2003 to 15 December 2005, 7779 NT-proBNP blood samples were analysed. A total of 1175 blood samples were excluded owing to repeated measurements. Three patients were younger than 18 years. Even though the test was introduced by the laboratories to be used in patients suspected of HF, 726 patients already had a diagnosis of HF at the time of blood sampling, and these patients were excluded from further analysis. The remaining 5875 patients are our sample of interest (Figure 1). Owing to the completeness of the Danish national databases, no patients were lost to follow-up.
Baseline characteristics are given in Table 2. The population is characterized by a median age of 73 (47–88) years and 57.7% females. Less than 0.5% had acute or chronic nephropathy or was on dialysis. A total of 1057 deaths (18.0%, 59 per 1000 patient-years) and 1165 CV hospitalizations (19.8%, 73 per 1000 patient-years) were observed during follow-up. The proportion of patients who had a CV hospitalization before they died in the follow-up period was 35%. Admission owing to HF was observed in 144 cases (nine per 1000 patient-years). Median follow-up time related to CV hospitalization was 1038 (79–1658) days and 1127 (278–1698) days for all-cause mortality.
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Mortality and admission rates
Median age in the background adult population of 969.735 was 43 (21–80) years by 1 January 2006. The crude mortality rate in the adult background population in 2005 was 13.1 deaths per 1000 patient-years. The corresponding CV hospitalization rate was 18.6 admissions per 1000 patient-years.
Directly age-adjusted CV hospitalization and mortality rates are presented by quintiles of NT-proBNP in Figures 2 and 3, respectively. The age-adjusted mortality rate in the lowest quintile was 13.7 (12.5–14.8) deaths per 1000 patient-years and the age-adjusted CV hospitalization rate was 22.4 (21.2–23.6) admissions per 1000 patient-years. The risk of death and CV hospitalization increased with increasing NT-proBNP quintile.
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Cumulative survival curves of death and probability of no CV hospitalization stratified by NT-proBNP quintile are presented in Figure 4A and B, respectively.
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Prognostic threshold levels
Hazard ratios per NT-proBNP decile from the two full exploratory models are illustrated in Figures 5 and 6, respectively. The overall effect of NT-proBNP in both models were highly significant (P < 0.001). The included covariates were NT-proBNP, age, sex, atrial fibrillation, hypertension, valvular heart disease, ischaemic heart disease, stroke and transient cerebral ischaemic attack, diabetes, chronic nephropathy, acute nephropathy, dialysis, chronic obstructive pulmonary disease, hyperlipidaemia, liver cirrhosis, schizophrenia and affective disorders, dementia, and cancer. An NT-proBNP level of 229–363 pg/mL was, in this model, associated with a factor 1.8 (1.2–2.9, P = 0.01) increase in risk of death as compared with a peptide level <34 pg/mL. From Figure 6 it seems as if the CV hospitalization rate starts to increase at a lower level of NT-proBNP, an NT-proBNP level of 83–118 pg/mL being associated with a factor 1.9 (1.3–2.9, P < 0.01) increase in risk of CV hospitalization compared with the lowest decile. Modelling NT-proBNP as a continuous variable with all other covariates included, demonstrated a 30% increase in NT-proBNP was associated with 1.08 (1.06–1.10, P < 0.001) and 1.12 (1.11–1.14, P < 0.001) increases in all-cause mortality in males and females, respectively (covariates: NT-proBNP, age, sex, atrial fibrillation, hypertension, valvular heart disease, ischaemic heart disease, stroke and transient cerebral ischaemic attack, diabetes, chronic nephropathy, acute nephropathy, dialysis, chronic obstructive pulmonary disease, hyperlipidaemia, liver cirrhosis, schizophrenia and affective disorders, dementia and cancer plus the interaction term: NT-proBNP and sex). Corresponding increases in risk of CV hospitalization were 1.09 (1.07–1.11, P < 0.001) in males and 1.11 (1.10–1.13, P < 0.001) in females (covariates: NT-proBNP, age, sex, atrial fibrillation, hypertension, valvular heart disease, ischaemic heart disease, stroke and transient cerebral ischaemic attack, diabetes, chronic nephropathy, acute nephropathy, dialysis, chronic obstructive pulmonary disease, hyperlipidaemia, liver cirrhosis, schizophrenia and affective disorders, dementia, and cancer plus the interaction term: NT-proBNP and sex).
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Discussion |
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Our data suggest that primary care patients with symptoms of HF and an NT-proBNP value above the prognostic threshold level require rapid diagnostic evaluation including an echocardiographic evaluation compared with patients below the prognostic threshold level.
NT-proBNP has been investigated as a screening tool for HF in primary care. In patients with symptoms suggestive of HF, the sensitivity of 0.92–0.99 and a high negative predictive value makes the test valuable for ruling out HF; only doing echocardiography in patients with NT-proBNP above a certain cut-off level, and in patients with low levels of NT-proBNP but a very high suspicion of HF.16,17,19 In asymptomatic patients from the general population, the pretest probability of HF is so low that it can be concluded that NT-proBNP is not suitable as a screening test for HF.20–22 The present knowledge suggests that the natriuretic peptides can be used as screening tests for HF in asymptomatic patients with high risk (e.g. known ischaemic heart disease, diabetes), but more data are needed for a recommended use for this population.20,23 Even though it has been difficult to establish a normal range for NT-proBNP, values below 34 pg/mL are generally considered well within the normal range. A value of 125 pg/mL has been suggested as a cut point to rule out left ventricular systolic dysfunction in primary care.17 Extrapolating from this cut point, we have identified a low-mortality group of patients (n = 1031, 17%) with a need of an echocardiography on the suspicion of HF owing to NT-proBNP levels above 125 pg/mL and below 229 pg/mL. It seems reasonable to prioritize patients with NT-proBNP levels above 200–300 pg/mL for rapid echocardiographic assessment, as they have an increased long-term mortality risk. Patients with NT-proBNP levels below the rule-out cut point of 125 pg/mL have low risk of HF and other diseases are more likely.15 They should preferably be referred to other examinations such as lung spirometry or chest X-ray. Persistent symptoms without other explanation, cardiac murmurs, or abnormal ECG should lead to review of the indication for echocardiography.
The age-adjusted event-rates in the lowest NT-proBNP quintile of the study population were not very different from the crude event rates in the background population. Using the lowest decile as reference in the Cox proportional hazards models therefore seems reasonable.
Surprisingly, only 144 admissions were owing to HF in the follow-up period. One explanation might be the relatively low NT-proBNP median of 161 pg/mL in the study population. In Denmark, the attending physician codes an ICD-10 diagnosis as the main reason for the hospital stay at discharge. These diagnoses are reported systematically to The National Patient Registry as part of the Danish health care system. One might speculate, if HF is considered a secondary diagnosis triggered by another disease, i.e. acute coronary syndrome.
Being able to identify patients with 80–90% increase in risk of death or CV hospitalization is indeed of clinical importance. This is especially true in HF patients, where well-documented treatment options are available to improve patient symptoms and prognosis.
In the Framingham Heart Study, the average age was 70 years with 51% males at the time of HF diagnosis which is reasonable comparable to the median age and sex distribution in our study population.24 Not surprisingly, 36–43% died within 1 year of the HF diagnosis in the historical cohort of Framingham patients underlining the severity of established HF. Hypertension and diabetes were present 74 and 19% in the Framingham HF patients, respectively.
No standardized form was used by the general practitioners to grade patient symptoms. General practitioners did not systematically request ECG, chest X-ray, or further blood samples, i.e. creatinine at the time of NT-proBNP measurement. It was not possible to report data on patient care by the general practitioner after the NT-proBNP test, as we did not have access to patient files from primary care. Cause of death was unobtainable from The National Patient Registry making it impossible to use CV death as an end point, as would have been preferred over total mortality. Selection bias cannot be excluded, as patients from primary care could bypass the NT-proBNP test at the discretion of the general practitioners.
Conclusions and perspective
Measurement of NT-proBNP in patients suspected of HF in primary care can identify patients with substantial increases in risks of CV hospitalization and death. Our results might have the potential to improve the prognosis of high-risk patients from primary care suspected of HF, if risk-stratified waiting lists for echocardiography, using NT-proBNP, are implemented, but prospective intervention trials are needed to establish this strategy. Finally, it is still unknown whether or not screening of high-risk patients in primary care with NT-proBNP would improve patient outcome. A prospective, randomized trial, where patients are randomized so only half of the general practitioners receive the NT-proBNP test result to act upon, is needed.
Conflict of interest: P.H. reports receiving significant funds in the form of research support, speaker honoraria, and consulting fees from Roche Diagnostics.
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Funding |
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The Danish Heart Foundation (06-10-B425-A1202-22349) to J.R. and (07-10-R60-A1762-B425-22408) to J.R.
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