gms | German Medical Science

50. Jahrestagung der Deutschen Gesellschaft für Medizinische Informatik, Biometrie und Epidemiologie (gmds)
12. Jahrestagung der Deutschen Arbeitsgemeinschaft für Epidemiologie (dae)

Deutsche Gesellschaft für Medizinische Informatik, Biometrie und Epidemiologie
Deutsche Arbeitsgemeinschaft für Epidemiologie

12. bis 15.09.2005, Freiburg im Breisgau

Prognostic Value of N-Terminal-Pro-B-Natriuretic Peptide Levels in Patients with Stable Coronary Heart Disease: Results of the KAROLA-Study

Meeting Abstract

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  • Dietrich Rothenbacher - Deutsches Zentrum für Alternsforschung, Heidelberg
  • W. Koenig - Dept. of Internal Medicine II-Cardiology, University of Ulm, Ulm
  • H. Brenner - Deutsches Zentrum für Alternsforschung, Heidelberg

Deutsche Gesellschaft für Medizinische Informatik, Biometrie und Epidemiologie. Deutsche Arbeitsgemeinschaft für Epidemiologie. 50. Jahrestagung der Deutschen Gesellschaft für Medizinische Informatik, Biometrie und Epidemiologie (gmds), 12. Jahrestagung der Deutschen Arbeitsgemeinschaft für Epidemiologie. Freiburg im Breisgau, 12.-15.09.2005. Düsseldorf, Köln: German Medical Science; 2005. Doc05gmds085

The electronic version of this article is the complete one and can be found online at:

Published: September 8, 2005

© 2005 Rothenbacher et al.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( You are free: to Share – to copy, distribute and transmit the work, provided the original author and source are credited.



Introduction and Aims

Because we are currently witnessing a dramatic change of the age composition in our society with an increase of the elderly population in addition to an increasing life expectancy, the prevalence of coronary heart diseases (CHD) will increase within the next years. Therefore, beside new avenues and concepts of primary prevention, secondary preventive strategies of CHD will be needed to reduce the burden of recurrent complications for the individual as well as to compensate the burden of the disease for the society.

The use of biologic markers for diagnostic purposes and risk stratification represents one promising area in cardiology. Especially B-type natriuretic peptide (BNP) and the amino-terminal (NT)-proBNP (the latter with a much longer half life than BNP [1]) have been introduced as markers to aid in the diagnosis of heart failure [2], [3], [4]. Also, raised BNP and NT-proBNP serum levels are of prognostic value as they are independently associated with adverse prognosis in several cardiac disorders, including chronic heart failure (CHF) and acute coronary heart disease [2], [5]. However, so far only limited information is available on the prognostic information associated with elevated NT-proBNP in patients with stable CHD.

In this study we investigated the prognostic role of NT-proBNP serum levels for the subsequent risk of cardiovascular events in a large cohort of patients with stable CHD weeks after the first clinical manifestation or diagnosis after controlling for potential confounders, including markers of chronic inflammation and renal impairment.


All patients with CHD ((International Classification of Diseases, 9th Rev. codes 410-414) aged 30-70 years and participating in an in-hospital rehabilitation program between January 1999 and May 2000 in two co-operating clinics (Schwabenland-Klinik, Isny and Klinik am Südpark, Bad Nauheim, Germany) were enrolled in the KAROLA-study (Langzeiterfolge der KARdiOLogischen Anschlussheil-behandlung) [6]. At the beginning of the in-hospital rehabilitation program all participants filled out a standardized questionnaire containing sociodemographic information and medical history. In addition, information was taken from the patients’ hospital charts which included also information from the acute hospital. In all patients active follow-up was conducted one and three years after discharge from the rehabilitation center. Information was obtained from the patients using a mailed standardized questionnaire. Information regarding secondary cardiovascular events and treatment since discharge from the in-hospital rehabilitation clinic was obtained from the primary care physician also by means of a standardized questionnaire. If a patient had died during follow-up, the death certificate was obtained from the local Public Health Department and the main cause of death was coded according to the International Classification of Diseases (9th Revision). Secondary cardiovascular events were defined either as cardiovascular diseases (CVD) as the main cause of death (as stated in the death certificate), non-fatal myocardial infarction (MI), or ischemic cerebrovascular event (stroke or transitory ischemic attack, TIA). All non-fatal secondary events were reported by the primary care physicians.

NT-proBNP at baseline was measured from fasting serum samples (Elecsys, Roche Diagnostics, Mannheim, Germany).


Overall, 1206 patients with a diagnosis of CHD within the past three months were included in the study at baseline during the in-hospital rehabilitation program. Three year follow-up information was complete for 1033 patients (85.7%).

During a mean follow-up of 33 months 71 patients (6.9%) experienced a secondary CVD-event. Increased NT-proBNP levels were strongly and independently associated with secondary CVD events (p=0.0004).

Compared to patients in the bottom quartile of the NT-proBNP distribution at baseline, patients in the top quartile had a hazard ratio (HR) of 3.05 (95% confidence interval (CI) 1.46-6.38) for a CVD event during follow-up after adjustment for age and gender (p for trend = 0.0005). The HR was slightly attenuated after further adjustment for body mass index, smoking status, duration of school education, history of myocardial infarction, history of diabetes mellitus, severity of cardiovascular disease (number of affected vessels at baseline), and rehab clinic (HR 2.87, 95% CI, 1.33-6.18); it was 2.73 (95% CI, 1.26-5.91) after further adjustment HDL-cholesterol and treatment with lipid-lowering drugs (which were other factors contributing significantly (p<0.1) to the model). Adjustment for C-reactive protein and creatinine clearance at baseline did not alter the results.

Results were similar if the population was restricted to patients with no or only minor impairment of the left ventricular function.


This prospective cohort study including 1033 patients aged 30 to 70 years with stable CHD at baseline demonstrates that increased NT-proBNP levels measured several weeks after the acute manifestation of a CHD or coronary artery revascularization were strongly and independently associated with secondary CVD events. Patients in the top quartile of the NT-proBNP distribution had an 2.8-fold increased risk for subsequent secondary CVD events compared to those in the bottom quartile, even after controlling for a large variety of potential confounders, including markers of inflammation and renal impairment. Notably, the relationship persisted after restriction of the analysis to patients with no or only minor impairment of the left ventricular function. Therefore, NT-proBNP seems to be a clinically useful marker which may provide complementary prognostic information to the established risk determinants in patients with stable CHD.

Financial support

German Federal Ministry of Education and Research, grant number 01GD9820/0 and Association of German Pension Fund Agencies, grant number 02 7 08


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