Aggregate Clinical and Biomarker-Based Model Predicts Adverse Outcomes in Patients With Coronary Artery Disease

Abstract

Despite guideline-based therapy, patients with coronary artery disease (CAD) are at widely variable risk for cardiovascular events. This variability demands a more individualized risk assessment. Herein, we evaluate the prognostic value of 6 biomarkers: high-sensitivity C-reactive protein, heat shock protein-70, fibrin degradation products, soluble urokinase plasminogen activator receptor, high-sensitivity troponin I, and B-type natriuretic peptide. We then develop a multi-biomarker-based cardiovascular event prediction model for patients with stable CAD. In total, 3,115 subjects with stable CAD who underwent cardiac catheterization at Emory (mean age 62.8 years, 17% Black, 35% female, 57% obstructive CAD, 31% diabetes mellitus) were randomized into a training cohort to identify biomarker cutoff values and a validation cohort for prediction assessment. Main outcomes included (1) all-cause death and (2) a composite of cardiovascular death and nonfatal myocardial infarction (MI) within 5 years. Elevation of each biomarker level was associated with higher event rates in the training cohort. A biomarker risk score was created using optimal cutoffs, ranging from 0 to 6 for each biomarker exceeding its cutoff. In the validation cohort, each unit increase in the biomarker risk score was independently associated with all-cause death (hazard ratio 1.62, 95% confidence interval [CI] 1.45 to 1.80) and cardiovascular death/MI (hazard ratio 1.52, 95% CI 1.35 to 1.71). A biomarker risk prediction model for cardiovascular death/MI improved the c-statistic (∆ 6.4%, 95% CI 3.9 to 8.8) and net reclassification index by 31.1% (95% CI 24 to 37), compared with clinical risk factors alone. Integrating multiple biomarkers with clinical variables refines cardiovascular risk assessment in patients with CAD. Despite guideline-based therapy, patients with coronary artery disease (CAD) are at widely variable risk for cardiovascular events. This variability demands a more individualized risk assessment. Herein, we evaluate the prognostic value of 6 biomarkers: high-sensitivity C-reactive protein, heat shock protein-70, fibrin degradation products, soluble urokinase plasminogen activator receptor, high-sensitivity troponin I, and B-type natriuretic peptide. We then develop a multi-biomarker-based cardiovascular event prediction model for patients with stable CAD. In total, 3,115 subjects with stable CAD who underwent cardiac catheterization at Emory (mean age 62.8 years, 17% Black, 35% female, 57% obstructive CAD, 31% diabetes mellitus) were randomized into a training cohort to identify biomarker cutoff values and a validation cohort for prediction assessment. Main outcomes included (1) all-cause death and (2) a composite of cardiovascular death and nonfatal myocardial infarction (MI) within 5 years. Elevation of each biomarker level was associated with higher event rates in the training cohort. A biomarker risk score was created using optimal cutoffs, ranging from 0 to 6 for each biomarker exceeding its cutoff. In the validation cohort, each unit increase in the biomarker risk score was independently associated with all-cause death (hazard ratio 1.62, 95% confidence interval [CI] 1.45 to 1.80) and cardiovascular death/MI (hazard ratio 1.52, 95% CI 1.35 to 1.71). A biomarker risk prediction model for cardiovascular death/MI improved the c-statistic (∆ 6.4%, 95% CI 3.9 to 8.8) and net reclassification index by 31.1% (95% CI 24 to 37), compared with clinical risk factors alone. Integrating multiple biomarkers with clinical variables refines cardiovascular risk assessment in patients with CAD. Patients with established coronary artery disease (CAD) are at high risk for recurrent cardiovascular events. Despite standardization of secondary prevention, a heterogeneous risk of recurrent events exists that demands a more individualized approach to risk assessment and management.1Bhatt DL Eagle KA Ohman EM Hirsch AT Goto S Mahoney EM Wilson PW Alberts MJ D'Agostino R Liau CS Mas JL Röther J Smith Jr, SC Salette G Contant CF Massaro JM Steg PG REACH Registry InvestigatorsComparative determinants of 4-year cardiovascular event rates in stable outpatients at risk of or with atherothrombosis.JAMA. 2010; 304: 1350-1357Crossref PubMed Scopus (595) Google Scholar Traditional risk factors and measures such as left ventricular ejection fraction (LVEF) are commonly used to assess risk but fail to reliably estimate the residual risk of recurrent events.2Sabatine MS Morrow DA de Lemos JA Gibson CM Murphy SA Rifai N McCabe C Antman EM Cannon CP Braunwald E. Multimarker approach to risk stratification in non-ST elevation acute coronary syndromes: simultaneous assessment of troponin I, C-reactive protein, and B-type natriuretic peptide.Circulation. 2002; 105: 1760-1763Crossref PubMed Scopus (654) Google Scholar,3Vittinghoff E Shlipak MG Varosy PD Furberg CD Ireland CC Khan SS Blumenthal R Barrett-Connor E Hulley S Heart and Estrogen/progestin Replacement Study Research Group. Risk factors and secondary prevention in women with heart disease: the Heart and estrogen/progestin Replacement Study.Ann Intern Med. 2003; 138: 81-89Crossref PubMed Google Scholar The transition from stable disease to acute plaque disruption is complex and involves activation of multiple pathophysiologic pathways including inflammation, immune activation, cellular stress, coagulation, myocardial stretch, and ischemia.4Eapen DJ Manocha P Ghasemzadeh N Patel RS Al Kassem H Hammadah M Veledar E Le NA Pielak T Thorball CW Velegraki A Kremastinos DT Lerakis S Sperling L Quyyumi AA Soluble urokinase plasminogen activator receptor level is an independent predictor of the presence and severity of coronary artery disease and of future adverse events.J Am Heart Assoc. 2014; 3e001118Crossref Google Scholar, 5Eapen DJ Manocha P Patel RS Hammadah M Veledar E Wassel C Nanjundappa RA Sikora S Malayter D Wilson PW Sperling L Quyyumi AA Epstein SE. Aggregate risk score based on markers of inflammation, cell stress, and coagulation is an independent predictor of adverse cardiovascular outcomes.J Am Coll Cardiol. 2013; 62: 329-337Crossref PubMed Scopus (69) Google Scholar, 6Ghasemzedah N Hayek SS Ko YA Eapen DJ Patel RS Manocha P Al Kassem H Khayata M Veledar E Kremastinos D Thorball CW Pielak T Sikora S Zafari AM Lerakis S Sperling L Vaccarino V Epstein SE Quyyumi AA Pathway-specific aggregate biomarker risk score is associated with burden of coronary artery disease and predicts near-term risk of myocardial infarction and death.Circ Cardiovasc Qual Outcomes. 2017; 10e001493Crossref PubMed Scopus (20) Google Scholar Circulating biomarkers representing dysregulation of these pathways may help identify the patients who are at greatest risk and thus aid individualization of preventive treatment. High-sensitivity C-reactive protein (hs-CRP) representing inflammation,7Sabatine MS Morrow DA Jablonski KA Rice MM Warnica JW Domanski MJ Hsia J Gersh BJ Rifai N Ridker PM Pfeffer MA Braunwald E Investigators PEACE Prognostic significance of the Centers for Disease Control/American Heart Association high-sensitivity C-reactive protein cut points for cardiovascular and other outcomes in patients with stable coronary artery disease.Circulation. 2007; 115: 1528-1536Crossref PubMed Scopus (305) Google Scholar soluble urokinase plasminogen activator receptor (suPAR) also representing immune activation,4Eapen DJ Manocha P Ghasemzadeh N Patel RS Al Kassem H Hammadah M Veledar E Le NA Pielak T Thorball CW Velegraki A Kremastinos DT Lerakis S Sperling L Quyyumi AA Soluble urokinase plasminogen activator receptor level is an independent predictor of the presence and severity of coronary artery disease and of future adverse events.J Am Heart Assoc. 2014; 3e001118Crossref Google Scholar,8Hayek SS Sever S Ko YA Trachtman H Awad M Wadhwani S Altintas MM Wei C Hotton AL French AL Sperling LS Lerakis S Quyyumi AA Reiser J. Soluble urokinase receptor and chronic kidney disease.N Engl J Med. 2015; 373: 1916-1925Crossref PubMed Scopus (284) Google Scholar heat shock proteins (HSPs) representing cellular stress,9Pockley AG Frostegård J. Heat shock proteins in cardiovascular disease and the prognostic value of heat shock protein related measurements.Heart. 2005; 91: 1124-1126Crossref PubMed Scopus (15) Google Scholar fibrin degradation products (FDPs) representing coagulation,5Eapen DJ Manocha P Patel RS Hammadah M Veledar E Wassel C Nanjundappa RA Sikora S Malayter D Wilson PW Sperling L Quyyumi AA Epstein SE. Aggregate risk score based on markers of inflammation, cell stress, and coagulation is an independent predictor of adverse cardiovascular outcomes.J Am Coll Cardiol. 2013; 62: 329-337Crossref PubMed Scopus (69) Google Scholar,10Kannel WB Wolf PA Castelli WP D'Agostino RB Fibrinogen and risk of cardiovascular disease. The Framingham study.JAMA. 1987; 258: 1183-1186Crossref PubMed Google Scholar high-sensitivity troponins (hs-TnIs) representing myocardial stress/injury,11Westermann D Neumann JT Sörensen NA Blankenberg S. High-sensitivity assays for troponin in patients with cardiac disease.Nat Rev Cardiol. 2017; 14: 472-483Crossref PubMed Scopus (117) Google Scholar and natriuretic peptides as a marker of myocardial stretch12Wang TJ Larson MG Levy D Benjamin EJ Leip EP Omland T Wolf PA Vasan RS. Plasma natriuretic peptide levels and the risk of cardiovascular events and death.N Engl J Med. 2004; 350: 655-663Crossref PubMed Scopus (1275) Google Scholar, 13European Association for the Study of the Liver (EASL), European Association for the Study of Diabetes (EASD), European Association for the Study of Obesity (EASO)EASL-EASD-EASO clinical practice guidelines for the management of non-alcoholic fatty liver disease.J Hepatol. 2016; 64: 1388-1402Abstract Full Text Full Text PDF PubMed Scopus (2811) Google Scholar, 14Berger R Huelsman M Strecker A P B-type natriuretic peptide predicts death in patients with chronic heart 2002; 105: PubMed Scopus Google Scholar, JM J peptides as of and cardiac death acute myocardial infarction in the Am Coll Cardiol. 2004; PubMed Scopus Google Scholar prognostic significance in patients at risk of or with established CAD. we (1) evaluate the prognostic value of these and (2) develop and a model for prediction of adverse events in patients with stable CAD. were from the Emory a of subjects who underwent cardiac catheterization for the of CAD at Emory and of the DJ Manocha P Patel RS Hammadah M Veledar E Wassel C Nanjundappa RA Sikora S Malayter D Wilson PW Sperling L Quyyumi AA Epstein SE. Aggregate risk score based on markers of inflammation, cell stress, and coagulation is an independent predictor of adverse cardiovascular outcomes.J Am Coll Cardiol. 2013; 62: 329-337Crossref PubMed Scopus (69) Google Scholar subjects and who underwent cardiac catheterization for the of or CAD were to risk and as DJ Manocha P Patel RS Hammadah M Veledar E Wassel C Nanjundappa RA Sikora S Malayter D Wilson PW Sperling L Quyyumi AA Epstein SE. Aggregate risk score based on markers of inflammation, cell stress, and coagulation is an independent predictor of adverse cardiovascular outcomes.J Am Coll Cardiol. 2013; 62: 329-337Crossref PubMed Scopus (69) Google Scholar with acute coronary heart cardiac heart a and biomarker were The was by the Emory subjects and were were using the The presence of diabetes and was by in the was as or and were on the index was as in by in at cardiac catheterization were using from or within the Emory The was using the chronic kidney disease JW P T J Disease A to estimate Intern Med. PubMed Scopus Google Scholar was as was and were by and by of The were included in receptor and of coronary was using a Heart of of the coronary and using the LS Murphy A on patients for coronary artery disease. of the for of on cardiovascular Heart PubMed Google C L S T R E A T T C Blankenberg S. score assessment cardiovascular risk the clinical value of and Cardiol. 2013; PubMed Scopus Google Scholar outcomes were from for and were catheterization and at of the biomarker assays DJ Manocha P Ghasemzadeh N Patel RS Al Kassem H Hammadah M Veledar E Le NA Pielak T Thorball CW Velegraki A Kremastinos DT Lerakis S Sperling L Quyyumi AA Soluble urokinase plasminogen activator receptor level is an independent predictor of the presence and severity of coronary artery disease and of future adverse events.J Am Heart Assoc. 2014; 3e001118Crossref Google DJ Manocha P Patel RS Hammadah M Veledar E Wassel C Nanjundappa RA Sikora S Malayter D Wilson PW Sperling L Quyyumi AA Epstein SE. Aggregate risk score based on markers of inflammation, cell stress, and coagulation is an independent predictor of adverse cardiovascular outcomes.J Am Coll Cardiol. 2013; 62: 329-337Crossref PubMed Scopus (69) Google Scholar and were using a was with a and by Plasma levels were using Plasma was using the Plasma B-type natriuretic peptide was also on the in The of of is and an of of at and were and points of all-cause death and the composite of cardiovascular death and nonfatal myocardial infarction (MI) within 5 of were adverse cardiovascular events were as a composite of cardiovascular for heart nonfatal or nonfatal within 5 years. 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coronary artery J Cardiol. Full Text Full Text PDF PubMed Scopus Google Scholar the Emory cohort, higher levels are associated with the burden of CAD, more of CAD, and higher risk of and cardiovascular A P Hayek SS Hammadah M A M Ghasemzadeh N Ko YA MM N Patel A G J Wilson P L Vaccarino V Epstein SE Sperling L Quyyumi AA High-sensitivity troponin levels and coronary artery disease and outcomes.J Am Heart Assoc. Scopus Google Scholar and other natriuretic peptides are from cardiac and levels are associated with higher event rates in the H and risk of cardiac death and coronary heart disease in from the Am Coll Cardiol. PubMed Scopus Google Scholar in with heart and in of acute R Huelsman M Strecker A P B-type natriuretic peptide predicts death in patients with chronic heart 2002; 105: PubMed Scopus Google Scholar in the to Heart the of for heart M J C E E C R M A G V L M L and for heart the randomized 2013; PubMed Scopus Google Scholar levels independently cardiovascular disease and adverse cardiovascular PM C-reactive protein to the value of and in risk of myocardial PubMed Google H P R J M S S the of into a prognostic a and of of C-reactive protein in stable coronary artery Med. 2010; Scopus Google Scholar levels are with and other and its is independently with the of plaque and PM T C J P D J R A T L M H H M P with for disease.N Engl J Med. 2017; PubMed Scopus Google Scholar are proteins that aid in the cellular to acute and are in protein and of heat shock proteins in 2002; PubMed Scopus (305) Google Scholar is of the more DJ Manocha P Patel RS Hammadah M Veledar E Wassel C Nanjundappa RA Sikora S Malayter D Wilson PW Sperling L Quyyumi AA Epstein SE. Aggregate risk score based on markers of inflammation, cell stress, and coagulation is an independent predictor of adverse cardiovascular outcomes.J Am Coll Cardiol. 2013; 62: 329-337Crossref PubMed Scopus (69) Google J Quyyumi AA H G D A J J Epstein SE. levels of heat shock protein are associated with risk of coronary artery 2003; PubMed Scopus Google Scholar are measures of degradation including and D and E and products from fibrin and levels cardiovascular S MM DJ R A and of an in patients in the Diabetes PubMed Scopus Google Scholar is an marker of coronary and disease. The urokinase plasminogen activator is a by and and to its receptor to the of The urokinase in the of Full Text Full Text PDF PubMed Scopus Google Scholar is in including and cell Plasma cellular of is to of and is stable of acute levels independently in M G H Soluble urokinase plasminogen activator receptor in is associated with of from the and Full Text Full Text PDF PubMed Scopus Google Scholar and the severity of CAD and risk of events in patients with DJ Manocha P Ghasemzadeh N Patel RS Al Kassem H Hammadah M Veledar E Le NA Pielak T Thorball CW Velegraki A Kremastinos DT Lerakis S Sperling L Quyyumi AA Soluble urokinase plasminogen activator receptor level is an independent predictor of the presence and severity of coronary artery disease and of future adverse events.J Am Heart Assoc. 2014; 3e001118Crossref Google Scholar levels are of acute kidney SS A M S SS Sever S A Altintas MM Wei C D Jr, JL Quyyumi AA Reiser J Soluble urokinase receptor and acute kidney Engl J Med. PubMed Scopus Google Scholar and and SS Sever S Ko YA Trachtman H Awad M Wadhwani S Altintas MM Wei C Hotton AL French AL Sperling LS Lerakis S Quyyumi AA Reiser J. Soluble urokinase receptor and chronic kidney disease.N Engl J Med. 2015; 373: 1916-1925Crossref PubMed Scopus (284) Google Scholar In to in as in the of biomarkers and with In the of patients with higher levels of and a risk in biomarker levels with therapy, that a a of patients with a high from CP MA A JA P H JW P C AM Braunwald E to acute coronary Engl J Med. 2015; PubMed Scopus Google Scholar in and levels in the Diabetes cohort a of was independently associated with improved N MM H R Sikora S Sperling L Quyyumi AA Epstein SE. aggregate biomarker risk score predicts high risk of near-term myocardial infarction and from Am Heart Assoc. 2017; PubMed Scopus Google Scholar of biomarkers for risk as we of clinical The biomarkers pathways in the of and heart and activation a for of The of in the heart and for the cell PubMed Scopus (284) Google Scholar into or clinical the score was more the clinical risk factors of residual risk in patients with CAD and clinical risk factors who to at risk for secondary events. 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