A comparative study of biomarkers for risk prediction in acute coronary syndrome—Results of the SIESTA (Systemic Inflammation Evaluation in non-ST-elevation Acute coronary syndrome) study



      We compared the 1-year predictive value of several inflammatory and non-inflammatory biomarkers in ACS patients.


      In 610 patients (73.0% male) – 36.0% unstable angina (UA) and 64.0% NSTEMI – we assessed high-sensitivity C-reactive protein (hs-CRP), interleukins 6, 10 and 18, soluble CD40 ligand, P- and E-selectin, NT-proBNP, fibrinogen and cystatin C at hospital admission. Two outcomes at 1-year follow up were selected for analysis: (1) all-cause death, MI, UA, or coronary revascularization, and (2) all-cause death, and non-fatal MI. The effect of biomarker levels on endpoints was examined by the Cox proportional hazards model, and their discrimination ability with the C statistic (AUC).


      Of 549 patients (90.0%) who completed the 1-year follow up, 206 (37.5%) and 54 (8.9%) reached the first and second composite endpoints, respectively. None of the biomarkers studied improved prediction of the first endpoint. However, considered as continuous variables, and in combination, NT-proBNP and fibrinogen, increased the AUC from 0.64 (95% CI 0.55–0.72) to 0.73 (95% CI 0.64–0.81; p = 0.02) for prediction of the second endpoint. Cut-off values for NT-proBNP and fibrinogen, regarding best sensitivity and specificity for prediction of the secondary endpoint were 1043.9 ng/L and 4.47 mg/dL, respectively. For these cut-off points, sensitivity, specificity, positive predictive value and negative predictive value were 40.5% vs 59.5%, 83.3% vs 67.1%, 18.8% vs 14.9% and 93.5% vs 94.4% for NT-proBNP and fibrinogen, respectively.


      In ACS patients, inflammatory biomarkers offer modest incremental information to that provided by clinical risk markers. Fibrinogen and NT-proBNP measurements, however, improve cardiovascular risk prediction.


      ACS (Acute coronary syndrome), AMI (Acute myocardial infarction), UA (Unstable angina), CD (Cardiac death), CAD (Coronary artery disease), PCI (Percutaneous coronary intervention), hs-CRP (High-sensitivity C-reactive protein), TIMI (Thrombolysis in Myocardial Infarction), NSTE-ACS (Non-ST-segment elevation acute coronary syndrome), NSTEMI (Non-ST-segment elevation myocardial infarction), NT-proBNP (N-terminal prohormone brain natriuretic peptide)


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        • Murray C.J.
        • Lopez A.D.
        Alternative projections of mortality and disability by cause 1990–2020: Global Burden of Disease Study.
        Lancet. 1997; 349: 1498-1504
        • Yeghiazarians Y.
        • Braunstein J.B.
        • Askari A.
        • Stone P.H.
        Unstable angina pectoris.
        N Engl J Med. 2000; 342: 101-114
        • Antmann E.M.
        • Cohen M.
        • Bernink P.J.L.M.
        • et al.
        The TIMI risk score for unstable angina/non-ST elevation MI: a method for prognostication and therapeutic decision making.
        JAMA. 2000; 284: 835-842
        • Mulvihill N.T.
        • Foley J.B.
        Inflammation in acute coronary syndromes.
        Heart. 2002; 87: 201-204
        • Ross R.
        Atherosclerosis—an inflammatory disease.
        N Engl J Med. 1999; 340: 115-126
        • Danesh J.
        • Wheeler J.G.
        • Hirschfield G.M.
        • et al.
        V. C-reactive protein and other circulating markers of inflammation in the prediction of coronary heart disease.
        N Engl J Med. 2004; 350: 1387-1397
        • Lindalh B.
        • Toss H.
        • Siegbahn A.
        • Venge P.
        • Wallentin L.
        Markers of myocardial damage and inflammation in relation to long-term mortality in unstable coronary artery disease. FRISC Study Group. Fragmin during Instability in Coronary Artery Disease.
        N Engl J Med. 2000; 343: 1139-1147
        • Blankenberg S.
        • Mc Queen M.J.
        • Smieja M.
        • et al.
        Comparative impact of multiple biomarkers and N-terminal pro brain natriuretic peptide in the context of conventional risk factors for the prediction of recurrent cardiovascular events in the Heart Outcomes Prevention Evaluation (HOPE) study.
        Circulation. 2006; 114: 201-208
        • De Lemos J.A.
        • Morrow D.A.
        • Bentley J.H.
        • et al.
        The prognostic value of B-type natriuretic peptide in patients with acute coronary syndromes.
        N Engl J Med. 2001; 345: 1014-1021
        • Jernberg T.
        • Lindahl B.
        • James S.
        • Larsson A.
        • Hansson L.O.
        • Wallentin L.
        Cystatin C—a novel predictor of outcome in suspected or confirmed non-ST-elevation acute coronary syndrome.
        Circulation. 2004; 110: 2342-2348
        • Braunwald E.
        • Antman E.M.
        • Beasley J.W.
        • et al.
        ACC/AHA guidelines for the management of patients with unstable angina and non ST segment elevation myocardial infarction. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients With Unstable Angina).
        J Am Coll Cardiol. 2000; 36: 970-1062
        • Bertrand M.E.
        • Simoons M.L.
        • Fox K.A.
        • et al.
        Task Force on the Management of Acute Coronary Syndromes of the European Society of Cardiology. Management of acute coronary syndromes in patients presenting without persistent ST-segment elevation.
        Eur Heart J. 2002; 23: 1809-1840
        • Cannon C.P.
        • Battler A.
        • Brindis R.G.
        • et al.
        American College of Cardiology key data elements and definitions for measuring the clinical management and outcomes of patients with acute coronary syndromes. A report of the American College of Cardiology Task Force on Clinical Data Standards (Acute Coronary Syndromes Writing Committee).
        J Am Coll Cardiol. 2001; 38: 2114-2130
        • Terkelsen C.J.
        • Lassen J.F.
        • Norgaard B.L.
        • et al.
        Mortality rates in patients with ST-elevation vs. non-ST-elevation acute myocardial infarction: observations from an unselected cohort.
        Eur Heart J. 2005; 26: 18-26
        • Hasdai D.
        • Behar S.
        • Wallentin L.
        • et al.
        A prospective survey of the characteristics, treatments and outcomes of patients with acute coronary syndromes in Europe and the Mediterranean basin; the Euro Heart Survey of Acute Coronary Syndromes (Euro Heart Survey ACS).
        Eur Heart J. 2002; 23: 1190-1201
        • Mueller C.
        • Buettner H.J.
        • Hodgson J.M.
        • et al.
        Inflammation and long-term mortality after non-ST elevation acute coronary syndrome treated with a very early invasive strategy in 1042 consecutive patients.
        Circulation. 2002; 105: 1412-1415
        • Morrow D.A.
        • Rifai N.
        • Antman E.M.
        • et al.
        C-reactive protein is a potent predictor of mortality independently of and in combination with troponin T in acute coronary syndromes: a TIMI 11 A substudy. Thrombolysis in Myocardial Infarction.
        J Am Coll Cardiol. 1998; 31: 1460-1465
        • Ferreiros E.R.
        • Boissonnet C.P.
        • Pizarro R.
        • et al.
        Independent prognostic value of elevated C-reactive protein in unstable angina.
        Circulation. 1999; 100: 1958-1963
        • Pai J.K.
        • Pischon T.
        • Ma J.
        • et al.
        Inflammatory markers and the risk of coronary heart disease in men and women.
        N Engl J Med. 2004; 351: 2599-2610
        • Ridker P.M.
        • Cannon C.P.
        • Morrow D.
        • et al.
        Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction 22 (PROVE IT-TIMI 22) Investigators, C-reactive protein levels and outcomes after statin therapy.
        N Engl J Med. 2005; 352: 20-28
        • Blankenberg S.
        • Yusuf S.
        The inflammatory hypothesis. Any progress in risk stratification and therapeutic targets?.
        Circulation. 2006; 114: 1557-1560
        • Folsom A.R.
        • Wu K.K.
        • Rosamond W.D.
        • Sharrett A.R.
        • Chambless L.E.
        Prospective study of hemostatic factors and incidence of coronary heart disease: the Atherosclerosis Risk in Communities (ARIC) study.
        Circulation. 1997; 96: 1102-1108
        • Wang T.J.
        • Gona P.
        • Larson M.G.
        • et al.
        Multiple biomarkers for the prediction of first major cardiovascular events and death.
        N Engl J Med. 2006; 355: 2631-2639
        • Folsom A.R.
        • Chambless L.E.
        • Ballantyne C.M.
        • et al.
        An assessment of incremental coronary risk prediction using C-reactive protein and other novel risk markers: the atherosclerosis risk in communities study.
        Arch Intern Med. 2006; 166: 1368-1373
        • Tateishi J.
        • Masutani M.
        • Ohyanagi M.
        • Iwasaki T.
        Transient increase in plasma brain (B-Type) natriuretic peptide after percutaneous transluminal coronary angioplasty.
        Clin Cardiol. 2000; 23: 776-780
        • Heeschen C.
        • Hamm C.W.
        • Mitrovic V.
        • Lantelme N.H.
        White HD for the Platelet Receptor Inhibition in Ischemic Syndrome Management (PRISM) Investigators. N-terminal pro-B-type natriuretic peptide levels for dynamic risk stratification of patients with acute coronary syndromes.
        Circulation. 2004; 110: 3206-3212
        • Bazzino O.
        • Fuselli J.J.
        • Botto F.
        • et al.
        Relative value of N-terminal probrain natriuretic peptide, TIMI risk score, ACC/AHA prognostic classification and other risk markers in patients with non-ST-elevation acute coronary syndromes.
        Eur Heart J. 2004; 25: 859-866
        • Steen H.
        • Futterer S.
        • Merten C.
        • Jünger C.
        • Katus H.A.
        • Giannitsis E.
        Relative role of Nt-pro BNP and cardiac troponin T at 96 hours for estimation of infarction size and left ventricular function after acute myocardial infarction.
        J Cardiovasc Magn Reson. 2007; 9: 749-758
        • Vanzetto G.
        • Jacon P.
        • Calizzano A.
        • et al.
        N-terminal pro-brain natriuretic peptide predicts myocardial ischemia and is related to postischemic left ventricular dysfunction in patients with stable coronary artery disease.
        J Nucl Cardiol. 2007; 14: 83642
        • Toss H.
        • Lindahl B.
        • Siegbahn A.
        • Wallentin L.
        Prognostic influence of increased fibrinogen and C-reactive protein levels in unstable coronary artery disease. FRISC Study Group. Fragmin during Instability in Coronary Artery Disease.
        Circulation. 1997; 96: 4204-4210
        • Arnau Vives M.A.
        • Rueda Soriano J.
        • Martinez Dolz L.V.
        • et al.
        Prognostic value of fibrinogen in patients admitted with suspected unstable angina and non-Q-wave myocardial infarction.
        Rev Esp Cardiol. 2002; 55: 622-630
        • Eggers K.M.
        • Lagerqvist B.
        • Vengue P.
        • Wallentin L.
        • Lindahl B.
        Prognostic value of biomarkers during and after non-ST-segment elevation acute coronary syndrome.
        J Am Coll Cardiol. 2009; 54: 365-367
        • Shemesh T.
        • Rowley K.G.
        • Jenkins A.J.
        • Best J.D.
        • O’Dea K.
        C-reactive protein concentrations are very high and more stable over time than the traditional vascular risk factors total cholesterol and systolic blood pressure in an Australian Aboriginal Cohort.
        Clin Chem. 2009; 55: 336-341
        • Aziz N.
        • Fahey J.L.
        • Detels R.
        • Butch A.W.
        Analytical performance of a highly sensitive C-reactive protein-based immunoassay and the effects of laboratory variables on levels of protein in blood.
        Clin Diag Lab Immunol. 2003; 10: 652-657
        • Ledue T.B.
        • Rifai N.
        Preanalytic and analytic sources of variations in C-reactive protein measurement: implications for cardiovascular disease risk assessment.
        Clin Chem. 2003; 49: 1258-1271
        • Cauliez B.
        • Guignery J.
        • Marinier S.
        • Mariau I.
        • Lavoinne A.
        Two-year stability of NT-proBNP in frozen samples using the Roche Elecsys system.
        Ann Clin Biochem. 2008; 45: 318-319
        • Kenis G.
        • Teunissen C.
        • De Jongh R.
        • Bosmans E.
        • Steinbusch H.
        • Maes M.
        Stability of interleukin 6, soluble interleukin 6 receptor, interleukin 10 and CC16 in human serum.
        Cytokine. 2002; 19: 228-235
        • Aziz N.
        • Nishanian P.
        • Mitsuyasu R.
        • Detels R.
        • Fahey J.L.
        Variables that affect assays for plasma cytokines and soluble activation markers.
        Clin Diagn Lab Immunol. 1999; 6: 89-95
        • Tworoger S.S.
        • Hankinson S.E.
        Use of biomarkers in epidemiologic studies: minimizing the influence of measurement error in the study design and analysis.
        Cancer Causes Control. 2006; 17: 889-899
        • Tworoger S.S.
        • Hankinson S.E.
        Collection, processing and storage of biological samples in epidemiological studies: sex hormones, carotenoids, inflammatory markers, and proteomics as examples.
        Cancer Epidemiol Biomarkers Prev. 2006; 15: 1578-1581