The aim of this study was to evaluate the possibility of incorrect assessment of mortality risk factors in a group of patients affected by acute coronary syndrome, due to the lack of hazard proportionality in the Cox regression model. One hundred and fifty consecutive patients with acute coronary syndrome (ACS) and no age limit were enrolled. Univariable and multivariable Cox proportional hazard analyses were performed. The proportional hazard assumptions were verified using Schoenfeld residuals, χ2 test and rank correlation coefficient t between residuals and time. In the total group of 150 patients, 33 (22.0%) deaths from any cause were registered in the follow-up time period of 64 months. The non-survivors were significantly older and had increased prevalence of diabetes and erythrocyturia, longer history of coronary artery disease, higher concentrations of serum creatinine, cystatin C, uric acid, glucose, C-reactive protein (CRP), homocysteine and B-type natriuretic peptide (NT-proBNP), and lower concentrations of serum sodium. No significant differences in echocardiography parameters were observed between groups. The following factors were risk of death factors and fulfilled the proportional hazard assumption in the univariable model: smoking, occurrence of diabetes and anaemia, duration of coronary artery disease, and abnormal serum concentrations of uric acid, sodium, homocysteine, cystatin C and NT-proBNP, while in the multivariable model, the risk of death factors were: smoking and elevated concentrations of homocysteine and NT-proBNP. The study has demonstrated that violation of the proportional hazard assumption in the Cox regression model may lead to creating a false model that does not include only time-independent predictive factors.
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Abeysekera W. W. M. & Sooriyarachchi M. R. (2009). Use of Schoenfeld’s global test to test the proportional hazards assumption in the Cox proportional hazards model: an application to a clinical study. Journal of the Naional Science Foundation of Sri Lanka 37(1) 41–51.
Akerblom A. Wallentin L. Larsson A. Siegbahn A. Becker R. C. Budaj A. Himmelmann A. et al. (2013). Cystatin C- and Creatinine-Based Estimates of Renal Function and Their Value for Risk Prediction in Patients with Acute Coronary Syndrome: Results from the PLATelet Inhibition and Patient Outcomes (PLATO) Study. Clinical Chemistry 59(9) 1369–1375.
Aronson D. Darawsha W. Promyslovsky M. Kaplan M. Abassi Z. Makhoul B. F. Goldberg A. et al. (2014). Hyponatraemia predicts the acute (type 1) cardio-renal syndrome. European Journal of Heart Failure 16(1) 49–55.
Ata N. & Sözer M. T. (2007). Cox Regression Models with nonproportional Hazards applied to Lung Cancer Survival Data. Hacettepe Journal of Mathematics Statistics 36(2) 157–167.
Babińska M. Chudek J. Owczarek A. J. Prochaczek F. & Wiecek A. (2005). Acute coronary syndrome in patients with chronic kidney disease-risk stratification. Polskie Archiwum Medycyny Wewnętrznej 114(6) 1226–1235.
Bellera C. A. MacGrogan G. Debled M. de Lara C. Brouste V. & Mathoulin-Pélissier S. (2010). Variables with time-varying effects and the Cox model: Some statistical concepts illustrated with a prognostic factor study in breast cancer. BMC Medical Research Methodology 10(1) 20–32.
Bellomo G. Lippi G. Saronio P. Reboldi G. Verdura C. Timio F. & Timio M. (2003). Inflammation infection and cardiovascular events in chronic hemodialysis patients: a prospective study. Journal of Nephrology 16(2) 245–251.
Bjorklund E. (2005). Admission N-terminal pro-brain natriuretic peptide and its interaction with admission troponin T and ST segment resolution for early risk stratification in ST elevation myocardial infarction. Heart 92(6) 735–740.
Danaei G. Lawes C. M. Vander Hoorn S. Murray C. J. & Ezzati M. (2006). Global and regional mortality from ischaemic heart disease and stroke attributable to higher-than-optimum blood glucose concentration: comparative risk assessment. The Lancet 368(9548) 1651–1659.
De Sutter J. (2005). Plasma N-terminal pro-brain natriuretic peptide concentration predicts coronary events in men at work: a report from the BELSTRESS study. European Heart Journal 26(24) 2644–2649.
Dickstein K. Vardas P. E. Auricchio A. Daubert J. C. Linde C. McMurray J. Ponikowski P. et al. (2010). 2010 Focused Update of ESC Guidelines on device therapy in heart failure: an update of the 2008 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure and the 2007 ESC Guidelines for cardiac and resynchronization therapy. European Heart Journal 31(21) 2677–2687.
EUROSTAT. (2015). Causes of death. Retrieved from http://ec.europa.eu/eurostat/web/health/causes-death
Ezekowitz J. A. Kaul P. Bakal J. A. Armstrong P. W. Welsh R. C. & McAlister F. A. (2009). Declining In-Hospital Mortality and Increasing Heart Failure Incidence in Elderly Patients With First Myocardial Infarction. Journal of the American College of Cardiology 53(1) 13–20.
Fácila L. Nuñez J. E. G V. B. Sanchis J. Bodi V. Chorro F. J. & Llacer A. (2005). Early determination of homocysteine levels in acute coronary syndromes is it an independent prognostic factor? International Journal of Cardiology 100(2) 275–279.
Filipiak K. J. Kołtowski Ł. Grabowski M. Karpiński G. Główczyńska R. Huczek Z. Kochman J. et al. (2014). Comparison of the seven-year predictive value of six risk scores in acute coronary syndrome patients: GRACE TIMI STEMI TIMI NSTEMI SIMPLE ZWOLLE and BANACH. Kardiologia Polska 72(2) 155–165.
Fox K. A. A. Carruthers K. F. Dunbar D. R. Graham C. Manning J. R. De Raedt H. Buysschaert I. et al. (2010). Underestimated and under-recognized: the late consequences of acute coronary syndrome (GRACE UK-Belgian Study). European Heart Journal 31(22) 2755–2764.
Goldberg A. Hammerman H. Petcherski S. Zdorovyak A. Yalonetsky S. Kapeliovich M. Agmon Y. et al. (2004). Prognostic importance of hyponatremia in acute ST-elevation myocardial infarction. The American Journal of Medicine 117(4) 242–248.
Grambsch P. M. & Therenau T. M. (1994). Proportional hazards tests and diagnostic based on weighted residuals. Biometrika 81(3) 515–526.
Gul M. Uyarel H. Ergelen M. Akgul O. Karaca G. Turen S. Ugur M. et al. (2013). Prognostic value of total bilirubin in patients with ST-segment elevation acute myocardial infarction undergoing primary coronary intervention. The American Journal of Cardiology 111(2) 166–171.
National Institutes of Health. (2008). Disease statistics. National Heart Lung and Blood Institute Fiscal Year 2008 Fact Book. Retrieved from https://www.nhlbi.nih.gov/files/docs/factbook/FactBook2008.pdf
Jernberg T. (2004). Cystatin C: A Novel Predictor of Outcome in Suspected or Confirmed Non-ST-Elevation Acute Coronary Syndrome. Circulation 110(16) 2342–2348.
Keele L. (2010). Proportionally Difficult: Testing for Nonproportional Hazards in Cox Models. Political Analysis 18(2) 189–205.
Lawler P. R. Filion K. B. Dourian T. Atallah R. Garfinkle M. & Eisenberg M. J. (2013). Anemia and mortality in acute coronary syndromes: A systematic review and meta-analysis. American Heart Journal 165(2) 143–153.
Lazzeri C. Valente S. Chiostri M. Attanà P. Picariello C. & Gensini G. F. (2012). Usefulness of Hyponatremia in the Acute Phase of ST-Elevation Myocardial Infarction as a Marker of Severity. The American Journal of Cardiology 110(10) 1419–1424.
Levey A. S. Stevens L. A. Schmid C. H. Zhang Y. L. Castro A. F. Feldman H. I. Kusek J. W. et al. (2009). A new equation to estimate glomerular filtration rate. Annals of Internal Medicine 150(9) 604–612.
Minister Zdrowia (2015). Narodowy program wyrównywania dostępności do profilaktyki i leczenia chorób układu sercowo naczyniowego POLKARD na lata 2013–2016. Retrieved from http://www.mz.gov.pl/data/assets/pdf_file/0003/29802/POLKARD-2015-aktualizacja.pdf
Panichi V. Migliori M. De Pietro S. Taccola D. Bianchi A. M. Giovannini L. Norpoth M. et al. (2002). C-reactive protein and interleukin-6 levels are related to renal function in predialytic chronic renal failure. Nephron 91(4) 594–600.
Park H. W. Kim W. H. Kim K.-H. Yang D. J. Kim J. H. Song I. G. Kwon T. G. et al. (2013). Carotid plaque is associated with increased cardiac mortality in patients with coronary artery disease. International Journal of Cardiology 166(3) 658–663.
Plakht Y. Shiyovich A. Weitzman S. Fraser D. Zahger D. & Gilutz H. (2012). A new risk score predicting 1- and 5-year mortality following acute myocardial infarction. International Journal of Cardiology 154(2) 173–179.
Plakht Y. Shiyovich A. Weitzman S. Fraser D. Zahger D. & Gilutz H. (2013). Soroka acute myocardial infarction (SAMI) score predicting 10-year mortality following acute myocardial infarction. International Journal of Cardiology 167(6) 3068–3070.
Rutkowski B. & Rutkowski P. (2005). Serce a nerki. Przegląd Lekarski 62(2) 3–6.
Schoenfeld D. (1982). Partial Residuals for the Proportional Hazards Regression-Model. Biometrika 69(1) 239–241.
Shroff G. R. Frederick P. D. & Herzog C. A. (2012). Renal failure and acute myocardial infarction: clinical characteristics in patients with advanced chronic kidney disease on dialysis and without chronic kidney disease. A collaborative project of the United States Renal Data System/National Institutes National Institutes of Health and the National Registry of Myocardial Infarction. American Heart Journal 163(3) 399–406.
Singla I. Zahid M. Good C. B. Macioce A. & Sonel A. F. (2007). Effect of hyponatremia (<135 mEq/L) on outcome in patients with non-ST-elevation acute coronary syndrome. The American Journal of Cardiology 100(3) 406–408.
Sitkiewicz D. (2007). Biochemia kliniczna i diagnostyka laboratoryjna chorób układu krążenia (I). Warszawa: OINPHARMA.
Walker A. M. Schneider G. Yeaw J. Nordstrom B. Robbins S. & Pettitt D. (2006). Anemia as a predictor of cardiovascular events in patients with elevated serum creatinine. Journal of the American Society of Nephrology 17(8) 2293–2298.
Winett A. & Sasieni P. (2001). A note on scaled Schoenfeld residuals for the proportional hazard model. Biometrika 88(2) 565–571.