Thrombolysis In Myocardial Infarction (TIMI) Risk Score and Mortality in Patients With

Thrombolysis In Myocardial Infarction(TIMI)Risk Score and Mortality in Patients With Advanced Chronic Kidney Disease andon DialysisUsman Baber,MD a,Annapoorna S.Kini,MD a,Samin K.Sharma,MD a,Michael C.Kim,MD a, Michael E.Farkouh,MD,MSc a,and Paul Muntner,PhD a,b,*There are limited data on the validity of the Thrombolysis In Myocardial Infarction(TIMI)risk score for unstable angina pectoris(UAP)/non–ST-elevation myocardial infarction inpatients with moderate to advanced chronic kidney disease(CKD),including patientsusing dialysis.Accordingly,we evaluated the prognostic ability of the TIMI risk score inconsecutive patients across the entire spectrum of CKD who presented with UAP ornon–ST elevation myocardial infarction and underwent percutaneous coronary interven-tion from July1,1999,to June30,2007.Patients were categorized by estimated glomerularfiltration rate(eGFR)>60(n؍4,938),30to59(n؍1,592),and<30ml/min/1.73m2(n؍202)and use of dialysis(n؍208).Hazard ratios of all-cause mortality associated withTIMI risk score levels(0to2,3to4,>5)were calculated within each eGFR category.Overa median follow-up of3.2years,813deaths occurred.For patients with an eGFR>60ml/min/1.73m2,race-and gender-adjusted hazard ratios of mortality associated with TIMIrisk scores of3to4and>5compared with0to2were2.92(95%confidence interval[CI]1.93to4.40)and4.26(95%CI2.82to6.43),respectively.Analogous hazard ratios were1.26(95%CI0.80to1.98)and1.77(95%CI1.13to2.78)for patients with an eGFR of30to59ml/min/1.73m2,2.23(95%CI0.71to6.94)and2.83(95%CI0.89to8.99)for patients withan eGFR<30ml/min/1.73m2,and3.16(1.33to7.48)and3.67(95%CI1.52to8.86),respectively,for patients on dialysis.In conclusion,the TIMI risk score for UAP/non–STelevation myocardial infarction discriminates mortality risk across the full range of CKD,including patients on dialysis.©2009Elsevier Inc.(Am J Cardiol2009;103:1513–1517)Patients with chronic kidney disease(CKD)who present with non–ST elevation acute coronary syndromes are at increased risk for mortality compared with those with pre-served renal function.1,2In addition,the excess mortality risk attributed to CKD in the setting of acute coronary syndrome persists after percutaneous coronary intervention (PCI).3Because negative outcomes occur more frequently in patients with CKD after non–ST elevation acute coronary syndromes,further risk stratification may guide clinicians in choosing and evaluating the efficacy of therapeutic inter-ventions.Among the widely used risk-stratification sche-mes,the Thrombolysis In Myocardial Infarction(TIMI)risk score for unstable angina pectoris(UAP)/non–ST elevation myocardial infarction is particularly attractive because of its simple scoring system and use of variables that are routinely obtained at the time of presentation.4There are limited data evaluating the TIMI risk score in patients with moderate to advanced CKD.Accordingly,we sought to assess the pre-dictive value of the TIMI risk score in a population with non–ST elevation acute coronary syndromes across the en-tire spectrum of CKD including patients on dialysis. MethodsFrom July1,1999,all patients undergoing PCI at the Mount Sinai Hospital(New York,New York)were enrolled in an outcomes registry.The population for the present analysis was limited to adult patientsՆ18years of age presenting with UAP or non–ST elevation myocardial in-farction who underwent PCI from July1,1999,to June30, 2007.For patients presenting with these symptomsϾ1time, the earliest presentation was used as the index event.Pa-tients with terminal illnesses(nϭ27)or without a serum creatinine measurement on hospital admission available in the registry(nϭ125)were excluded from the present analyses.After these exclusions,the present analyses in-cluded6,940consecutive patients.All data were collected using standardized methods and recorded onto forms designed for the PCI registry.Of rel-evance to the present analysis,demographic characteristics and current cigarette smoking were based on patient self-report.The presence of co-morbid conditions was ascer-tained using a standardized chart abstraction form.Medica-tions being taken by patients,on hospital admission,were abstracted from medical charts by research staff.Patients with a previous myocardial infarction or who had under-gone coronary artery bypass graft surgery previously werea Cardiac Catheterization Laboratory,Cardiovascular Institute,MountSinai Hospital,and b Department of Community and Preventive Medicine,Mount Sinai School of Medicine,New York,New York.Manuscriptreceived November30,2008;revised manuscript received and acceptedJanuary31,2009.*Corresponding author:Tel:212-824-7024;fax:212-996-0407.E-mail address:paul.muntner@(P.Muntner).0002-9149/09/$–see front matter©2009Elsevier doi:10.1016/j.amjcard.2009.01.364classified as having significant coronary stenosis.Patients with angina at rest in the week before hospitalization were classified as having severe anginal symptoms.As part of their routine clinical workup,all patients underwent stan-dardized electrocardiography.Electrocardiograms were re-viewed by attending cardiologists and ST deviations were defined as depressions or elevationsՆ0.05mV.Laboratory values including lipid profiles,troponin,cre-atinine kinase-MB fraction,and serum creatinine were mea-sured before patients underwent PCI.Low-density lipo-protein cholesterol was calculated using the Friedewald equation.5Hypercholesterolemia was defined as a low-den-sity lipoprotein cholesterol levelՆ100mg/dl or statin use. Increased serum markers were defined as a serum troponin levelՆ0.1mg/dl.For patients without troponin measure-ments available(nϭ477),increased serum markers was defined as a creatine kinase-MB levelՆ16.4mg/dl.Esti-mated glomerularfiltration rate(eGFR)was determined using serum creatinine and the abbreviated Modification of Diet in Renal Disease study equation.6Assessment of drift in serum creatinine over calendar time showed no changes in mean serum creatinine or the prevalence of GFRϽ60 ml/min/1.73m2(each p valueϾ0.20).Patients were cate-gorized into4levels of eGFR(Ն60,30to59,Ͻ30ml/min/ 1.73m2,or on dialysis).TIMI risk score was derived using7components,namely ageՆ65years,Ն3cardiovascular disease risk factors(cig-arette smoking,hypertension,diabetes mellitus,family his-tory of cardiovascular disease,and hypercholesterolemia), significant coronary stenosis,ST-segment deviation,severe anginal symptoms,aspirin use in the7days before hospital admission,and increased serum cardiac markers.The num-ber of TIMI risk score components present was summed for each participant.Consistent with previous studies,TIMI risk scores were categorized into3levels for analysis(0to 2,3to4,Ն5).7,8The primary outcome for the proposed study was all-cause mortality.Mortality for patients wasascertained Figure1.Mortality rates after PCI by level of eGFR and TIMI risk score.Table1Baseline characteristics of patients with acute coronary syndromes by level of estimated glomerularfiltration rateVariable eGFR(ml/min/1.73m2)p ValueՆ60 (nϭ4,938)30–59(nϭ1,592)Ͻ30(nϭ202)Dialysis(nϭ208)Age(yrs)64.3Ϯ11.771.9Ϯ10.469.2Ϯ11.563.5Ϯ11.3Ͻ0.001 Men67.9%53.5%48.5%61.1%Ͻ0.001 Black11.4%8.0%11.4%23.1%Ͻ0.001 Diabetes mellitus37.5%44.9%66.3%69.7%Ͻ0.001 Current cigarette smoker48.2%41.0%34.7%42.8%Ͻ0.001 Hypertension86.4%92.7%95.1%95.7%Ͻ0.001 LDL cholesterol(mg/dl)92.6Ϯ35.987.1Ϯ32.891.7Ϯ41.373.0Ϯ31.7Ͻ0.001 Statin treatment68.0%68.8%63.9%51.4%Ͻ0.001 Family history of cardiovascular disease32.7%25.1%25.3%20.2%Ͻ0.001 Previous myocardial infarction24.1%26.6%27.2%19.7%0.057 Previous coronary bypass17.8%23.4%29.7%19.7%Ͻ0.001 Values are meansϮSDs or percentages of patients.LDLϭlow-density lipoprotein.Table2Prevalence of Thrombolysis In Myocardial Infarction risk scorecomponents by level of estimated glomerularfiltration rateVariable eGFR(ml/min/1.73m2)p ValueՆ6030–59Ͻ30DialysisAgeՆ65yrs49.8%76.8%67.3%44.7%Ͻ0.001Ն3risk factors forcoronary arterydisease66.0%64.6%73.3%65.4%0.105Significant coronarystenosis*35.5%41.5%46.5%32.7%Ͻ0.001ST deviation48.0%49.8%47.0%53.9%0.261Severe angina pectoris28.3%28.1%36.6%32.7%0.037Aspirin use in previous7days91.2%91.0%89.6%83.2%0.001Increased serum cardiacmarkers33.0%39.3%48.5%54.8%Ͻ0.001TIMI risk scoregrouping0–221.8%13.2%8.4%20.2%Ͻ0.0013–456.1%55.0%56.4%53.9%0.812Ն522.1%31.9%35.1%26.0%Ͻ0.001*Previous myocardial infarction or coronary bypass.1514The American Journal of Cardiology()through the New York State interventional database and Social Security Death Index.In a secondary analysis,oc-currence of target lesion revascularization was analyzed.Patients undergoing target lesion revascularization were identified through patient interviews conducted 1year after PCI and review of hospital records through July 1,2007.All aspects of the proposed study including data collec-tion and participant follow-up were approved by the insti-tutional review board of Mount Sinai School of Medicine.Patient consent for collection and analysis of procedural data and outcomes was obtained.Baseline characteristics and prevalence of TIMI risk score components and categories were calculated,overall and by level of eGFR (Ն60,30to 59,Ͻ30ml/min/1.73m 2,or on dialysis),as means for continuous variables and preva-lences for dichotomous variables.The statistical signifi-cance of differences across eGFR categories was tested by analysis of variance.For mortality analysis,follow-up for each patient was calculated as the time between the pro-cedure and the date of death or July 1,2007,whichever occurred first.Initially,the age-,race-,and gender-adjusted hazard ratio of mortality associated with eGFR level and dialysis was calculated.Next,mortality rates were calcu-lated by TIMI risk score and eGFR category.The race-and gender-adjusted hazard ratio of mortality associated with TIMI risk score level was calculated overall and within each level of eGFR using Cox proportional hazards regression models.Adjustment for age was not performed because it was included as a component of the TIMI risk score.Secondary analyses were performed by calculating haz-ard ratios of target lesion revascularization associated with TIMI risk score for each level of eGFR.For these analyses,follow-up was calculated as the time between a patient’s PCI and the first target lesion revascularization procedure,date of death,or July 1,2007,whichever occurred first.Patients who died before target lesion revascularization were censored on their date of death.The proportionality assumption of Cox regression models was confirmed using Schoenfeld residuals.9All data management and analysis were conducted using SAS 8.1(SAS Institute,Cary,North Carolina).ResultsBaseline characteristics of the study population are listed in Table 1by eGFR category.Age,gender,race,prevalence of diabetes mellitus,cigarette smoking,hypertension,use of statins,family history of cardiovascular disease,coronary artery bypass grafting,and low-density lipoprotein choles-terol levels differed across eGFR categories.Among the 7TIMI risk score components,age Ն65years,significant coronary stenosis,severe anginal symp-toms,aspirin before presentation with non–ST elevation acute coronary syndromes,increased serum cardiac mark-ers,and prevalence of TIMI risk scores of 0to 2and Ն5differed across eGFR categories and across levels of eGFR (Table 2).Patients were followed for a median of 3.2years (max-imum 8)during which time there were -pared with patients with an eGFR Ն60ml/min/1.73m 2,the age-,race-,and gender-adjusted hazard ratios of mortality were 1.62(95%confidence interval [CI]1.39to 1.90),3.29(95%CI 2.45to 4.42),and 7.57(95%CI 5.88to 9.74)for patients with an eGFR of 30to 59ml/min/1.73m 2,Ͻ30ml/min/1.73m 2,and on dialysis,respectively.Within each eGFR category,including patients on dial-ysis,there was a stepwise increase in mortality rates across TIMI risk score levels (Figure 1).Specifically,in patients with an eGFR Ն60ml/min/1.73m 2,mortality rates per 100person-years were 0.8for patients with TIMI risk scores of 0to 2and 2.2and 3.2for their counterparts with TIMI risk scores of 3to 4and Ն5,respectively.Analogous mortality rates were 3.6,4.6,and 6.4for patients with an eGFR of 30to 59ml/min/1.73m 2,4.6,10.7,and 14.5for patients with an eGFR Ͻ30ml/min/1.73m 2,and 6.7,19.6,and 25.0for patients on dialysis.In the overall population,compared with patients with TIMI risk scores of 0to 2,race-and gender-adjusted hazard ratios of mortality associated with TIMI risk scores of 3to 4and Ն5were 2.36(95%CI 2.10to 2.66)and 3.53(95%CI 2.63to 4.73),respectively (Table 3).Patterns of increas-ing race-and gender-adjusted hazard ratios of mortality associated with progressively higher TIMI risk score cate-Table 3Hazard ratios of all-cause mortality and target lesion revascularization associated with Thrombolysis In Myocardial Infarction risk score overall and by level of estimated glomerular filtration rate eGFR (ml/min/1.73m 2)TIMI Risk Scorep Value for Trend0,1,23,45,6,7All-cause mortality Overall 1(reference) 2.36(2.10–2.66) 3.53(2.63–4.73)Ͻ0.001Ն601(reference) 2.92(1.93–4.40) 4.26(2.82–6.43)Ͻ0.00130–591(reference) 1.26(0.80–1.98) 1.77(1.13–2.78)0.002Ͻ301(reference) 2.23(0.71–6.94) 2.83(0.89–8.99)0.078Dialysis1(reference) 3.16(1.33–7.48) 3.67(1.52–8.86)0.007Target lesion revascularization Overall 1(reference) 1.20(0.94–1.54) 1.57(1.20–2.05)Ͻ0.001Ն601(reference) 1.22(0.92–1.62) 1.37(1.01–1.90)0.05730–591(reference)0.97(0.54–1.75) 1.68(0.94–3.02)0.008Ͻ301(reference) 1.33(0.16–10.9) 2.29(0.28–19.1)0.277Dialysis1(reference)1.88(0.22–3.62)3.62(0.39–33.8)0.050Values are hazard ratios (95%CIs).Hazard ratios are adjusted for race and gender.1515Coronary Artery Disease/TIMI Risk Score and CKDgories were present within each eGFR category and forpatients on dialysis.Overall,550patients required target lesion revascular-ization during follow-up.Rates of target lesion revascular-ization per100person-years were2.4,2.9,2.6,and3.6forpatients with eGFRsՆ60,30to59,andϽ30ml/min/1.73m2and on dialysis,respectively(pϭ0.76).In patients witheGFRՆ60ml/min/1.73m2,the race-and gender-adjustedhazard ratio of target lesion revascularization associatedwith TIMI risk scoresՆ5was significantly higher com-pared with those with TIMI risk scores of0to2(Table3).Within each eGFR category,higher hazard ratios of targetlesion revascularization were present at TIMI risk scores of3to4andՆ5compared with their counterparts with scoresof0to2.These trends were statistically significant forpatients with eGFRsՆ60and30to59ml/min/1.73m2andon dialysis.DiscussionPrevious studies have demonstrated an association ofTIMI risk score for UAP/non–ST elevation myocardialinfarction with mortality in unselected populations.Thepresent study extends these previous studies and demon-strates a strong,graded association between TIMI risk scoreand risk for long-term mortality in patients with advancedCKD,including those on dialysis.In the present study,graded associations were present between higher TIMI riskscores and increased mortality in patients with eGFRs of30to59andϽ30ml/min/1.73m2and on dialysis.Two previous investigations have presented an associa-tion between TIMI risk score and mortality in patients withmoderate CKD(eGFRϽ60ml/min/1.73m2).2,10In thesestudies,a stepwise increase in30-day and6-month mortalityrates across TIMI risk score levels(0to2,3to4,Ն5)waspresent within the eGFR categories studied(Ն90,60to89,Ͻ60ml/min/1.73m2).Neither study,however,reported the mortality risk in patients with an eGFRϽ30ml/min/1.73m2or on dialysis.Our results extend these previous inves-tigations by demonstrating a strong,graded,statisticallysignificant association between TIMI risk score and mortal-ity for these patient populations.Important differences between the present analysis andprevious studies are that the main outcome measurement inthe present study included mortality up to8years after PCIand a population composed entirely of patients who under-went PCI.Although the TIMI risk score was originallyderived in the context of a randomized controlled trial topredict short-term cardiovascular outcomes after non–STelevation acute coronary syndromes,its prognostic value indetecting outcomes up to1year has also been shown inunselected populations.8,11Risk stratification with conventional algorithms has beendemonstrated in some studies to be less accurate in patientswith versus without CKD.12,13One proposed reason is thatnontraditional risk factors,such as increased C-reactiveprotein and anemia,14are more prevalent in adults withCKD and may mediate excess cardiac risk in these patients.Moreover,nontraditional risk factors appear to play a moreimportant role in patients with advanced CKD.For exam-ple,among dialysis cohorts,increased calcium-by-phospho-rus product and vascular calcification are robust predictors of all-cause and cardiac mortality.15,16Our study,however, demonstrates that the TIMI risk score,a conventional algo-rithm that does not include nontraditional risk factors,also discriminates mortality risk in patients with advanced CKD and on dialysis.As a secondary analysis,we evaluated the capability of the TIMI risk score to predict target lesion revascularization after PCI.Similar tofindings from previous analyses,target lesion revascularization rates after coronary stenting were not increased in patients with CKD.3,17,18Severe angio-graphic restenosis,however,may be increased in patients with renal dysfunction after PCI in the setting of acute coronary syndromes.18The discrepancy between angio-graphic restenosis and symptom-driven target lesion revas-cularization may be due to silent ischemia in patients with CKD.19We were unable to further explore this issue be-cause follow-up angiography was not mandated in our co-hort.Although a graded association between TIMI risk score and target lesion revascularization was present in patients regardless of degree of CKD,the results were not statistically significant for patients with an eGFRϽ30ml/ min/1.73m2not on dialysis.Despite the lack of signifi-cance,the association was strong;the hazard ratio of target lesion revascularization comparing TIMI risk scores ofՆ5 versus0to2wasϾ2for patients with advanced CKD and on dialysis.A limitation to the present analysis is the evaluation of only patients after PCI.The clinical decision to refer pa-tients to the cardiac catheterization laboratory translates into a cohort with many high-risk features compared with pa-tients in other non–ST elevation acute coronary syndromes studies.Unfortunately,full data on all patients presenting with non–ST elevation acute coronary syndromes,in par-ticular those treated conservatively,were not available over the period under study.Although all patients in our study underwent PCI,the optimal treatment of non–ST elevation acute coronary syndromes(conservative vs early invasive) in patients with CKD remains unknown due to limited and conflicting literature.20,21Other limitations include reliance on a single measurement of serum creatinine for determin-ing eGFR and lack of data on recurrent myocardial infarc-tion and cause of death.In addition,patients without base-line renal dysfunction may have been misclassified as having CKD in the setting of prerenal azotemia due to hemodynamic instability or pump failure at the time of presentation.We were also unable to determine the propor-tion of patients in whom renal function may have deterio-rated or recovered after the non–ST elevation acute coro-nary syndrome episode because serum creatinine was not measured serially in all patients during the study period.A strength of our study is the inclusion of a large number of patients who had advanced CKD or were on dialysis.In addition,we analyzed consecutive patients,making the findings generalizable to real-world patients with non–ST elevation acute coronary syndromes treated with PCI.We were also able to ascertain outcomes up to8years after presentation,whereas most previous studies have reported on short-term outcomes or events within thefirst year after presentation.1516The American Journal of Cardiology()1.Al Suwaidi J,Reddan DN,Williams K,Pieper KS,Harrington RA,Califf RM,Granger CB,Ohman EM,Holmes DR Jr.Prognostic implications of abnormalities in renal function in patients with acute coronary syndromes.Circulation2002;106:974–980.2.Gibson CM,Dumaine RL,Gelfand EV,Murphy SA,Morrow DA,Wiviott SD,Giugliano 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