CLINICAL RESEARCH STUDY N-Terminal Pro B-Type Natriuretic Peptide Identifies Patients with Chest Pain at High Long-term Cardiovascular Risk Petrus M. van der Zee, MD, PhD, a Jan Hein Cornel, MD, PhD, b Radha Bholasingh, MD, PhD, c Johan C. Fischer, PhD, d Jan P. van Straalen, d Robbert J. De Winter, MD, PhD a a Department of Cardiology, Academic Medical Center Amsterdam, The Netherlands; b Department of Cardiology, Medical Center Alkmaar, The Netherlands; c Department of Cardiology, Slotervaart Hospital Amsterdam, The Netherlands; d Department of Clinical Chemistry, Academic Medical Center Amsterdam, The Netherlands. ABSTRACT BACKGROUND: Little is known about the long-term prognostic value of N-terminal pro B-type natriuretic peptide (NT-proBNP) and C-reactive protein (CRP) in low-risk patients with chest pain. METHODS: Between June 1997 and January 2000, a standard rule-out protocol was performed in patients presenting to the emergency department within 6 hours of onset of chest pain with a normal or nondiagnostic electrocardiogram (ECG) on admission at the Academic Medical Center Amsterdam, VU University Medical Center Amsterdam and Medical Center Alkmaar, The Netherlands. Patients with acute coronary syndrome were identified by troponin T, recurrent angina, and serial ECGs. CRP and NT-proBNP on admission were measured using standardized methods. RESULTS: A total of 524 patients were included (145 with acute coronary syndrome and 379 with rule-out acute coronary syndrome). Long-term follow-up was successfully carried out in 96% of the study population. Death occurred in 78 patients (15%), 43 (11%) in the rule-out acute coronary syndrome group and 35 (24%) in the acute coronary syndrome group (P  .001). In the rule-out acute coronary syndrome group, 21 patients (42%) died of a cardiovascular cause compared with 24 patients (69%) in the acute coronary syndrome group (P  .001). In multivariate Cox regression analysis, age more than 65 years, previous myocardial infarction, known chronic heart failure, a nondiagnostic ECG on admission, and elevated NT-proBNP levels (87 pg/mL, as derived from the receiver operating characteristic curve) were independent predictors of long-term cardio- vascular mortality in the rule-out acute coronary syndrome group. In the acute coronary syndrome group, these predictors were age more than 65 years, documented coronary artery disease, and elevated NT-proBNP levels. Elevated levels of CRP were an independent predictor for cardiovascular mortality in patients with rule-out acute coronary syndrome at 3-year follow-up only. In patients with rule-out acute coronary syndrome with normal CRP and NT-proBNP levels, the cardiovascular mortality incidence rate was 4.7 per 1000 person-years, compared with a death rate of 20 in patients with both biomarkers elevated, which was comparable to the 17.9 per 1000 person-years incidence rate in patients with acute coronary syndrome. CONCLUSION: A positive biomarker panel discriminates patients with rule-out acute coronary syndrome chest pain with a normal or nondiagnostic ECG who have a high risk for long-term cardiovascular mortality. © 2011 Elsevier Inc. All rights reserved. • The American Journal of Medicine (2011) 124, 961-969 KEYWORDS: Acute coronary syndrome; Chest pain; Coronary artery disease; Natriuretic peptides; Prognosis Optimal risk stratification in patients with chest pain at the emergency department is important. Patients with symptoms suggestive of acute ischemia should undergo early risk strati- fication that focuses on anginal symptoms, electrocardiogram (ECG) abnormalities, and biomarkers of myocardial damage during a brief observation period. 1 High-risk patients require Funding: The Netherlands Heart Foundation (Grant NHS 96.172). Conflict of Interest: None of the authors have any conflicts of interest associated with the work presented in this manuscript. Authorship: All authors had access to the data and played a role in writing this manuscript. Approval from the ethics committees at each of the recruiting sites was obtained, and patients’ consents were received. The authors of this manuscript have certified that they comply with the Prin- ciples of Ethical Publishing in the International Journal of Cardiology. Requests for reprints should be addressed to Petrus M. van der Zee, MD, PhD, Academic Medical Center, Department of Cardiology, Room B2-223, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands. E-mail address: p.m.vanderzee@amc.uva.nl. 0002-9343/$ -see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.amjmed.2011.05.026