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Cardiac Troponin T Elevation AfterCoronary Artery Bypass Grafting Is

Associated With IncreasedOne-Year Mortality

Sekar Kathiresan, MD, Stephen J. Servoss, MD, John B. Newell, AB, Dawn Trani, ANP,Thomas E. MacGillivray, MD, Kent Lewandrowski, MD,

Elizabeth Lee-Lewandrowski, PhD, MPH, and James L. Januzzi, Jr., MD

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he results of the present study extend the value ofssessing troponin T for the prediction of mortality rateyear after coronary artery bypass grafting; this study

upports previous work that demonstrated the value of

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ctmhTIflltpioston, Massachusetts 02114. E-mail: jjanuzzi@partners.org.

2004 by Excerpta Medica, Inc. All rights reserved.he American Journal of Cardiology Vol. 94 October 1, 2004

ostoperative assessment of troponin T for the predictionf in-hospital adverse outcome after coronary arteryypass grafting. �2004 by Excerpta Medica, Inc.

(Am J Cardiol 2004;94:879–881)

yocardial necrosis, as demonstrated by cardiacbiomarker release, occurs almost universally

round the time of coronary artery bypass graftingCABG).1,2 Multiple mechanisms may cause myocar-ial damage during CABG, including direct traumarom surgical manipulation and myocardial ischemiaue to inadequacies in cardioprotection, coronary ar-ery thrombosis, and acute loss of bypass grafts.3ecause some of these causes are unavoidable, it isritical to determine the appropriate threshold of bi-marker release after CABG associated with wors-ned in-hospital and longer-term prognoses. With re-pect to in-hospital adverse events after CABG, wereviously reported that an increased level of troponin

has greater discriminatory ability than the isoen-yme creatine kinase-MB (CK-MB).4 However, theelation between increased concentrations of troponin

after CABG and longer term adverse clinical out-omes remains unknown. We determined whether in-reased levels of troponin T after CABG are associ-ted with increased mortality rates after 1 year.

ETHODSAll study procedures were approved by the hospital

nstitutional review board. One hundred thirty-sixonsecutive patients who underwent CABG withoutoncomitant valve surgery at the Massachusetts Gen-ral Hospital (Boston, Massachusetts) between Octo-er and November 2000 were enrolled. Patients weredentified on admission to the cardiac surgical inten-ive care unit, and a study coordinator blinded to theesults of cardiac markers collected clinical variablesn a prospective manner by chart review. Clinical

rom the Cardiology Division, the Cardiac Surgery Division, and thelinical Chemistry Laboratories, Massachusetts General Hospital, Bos-

on, Massachusetts. This study was supported in part by an unrestrictedrant from Roche Diagnostics Corporation, Indianapolis, Indiana.anuscript received December 9, 2003; revised manuscript received

nd accepted June 18, 2004.Address for reprints: James L. Januzzi, Jr., MD, Cardiology Divi-

ion, Massachusetts General Hospital, Bulfinch 019, 55 Fruit Street,

actors collected included demographics, medical his-ory, previous medication use, cardiac catheterizationesults, presenting cardiac syndrome, and, when avail-ble, preoperative levels of troponin T. Systemic hy-ertension and hypercholesterolemia were defined asreatment with antihypertensive and lipid-loweringedications, respectively. A history of coronary artery

isease was defined as previous stable angina, myo-ardial infarction, or percutaneous coronary interven-ion. Information regarding surgical procedures, in-luding number of bypass grafts, bypass/ischemicimes, and intraoperative complications, was noted.

Blood samples were drawn on arrival to the surgi-al intensive care unit (“postop”) at 6 to 8 hours and8 to 24 hours after surgery and were assayed forK-MB mass and troponin T (Elecsys CK-MB STATnd Troponin T STAT Immunoassays, Roche Diag-ostics Corporation, Indianapolis, Indiana) on anlecsys 1010 platform (Roche Diagnostics Corpora-

ion).The results of troponin T were obtained in a

linded fashion by the study investigators; however,he physicians caring for the patients were not blindedo the CK-MB results because this marker is routinelyeasured at our institution after cardiac surgery. Data

n postoperative outcomes were assessed. In-hospitalnd points are outlined in a previous report.4 Vitaltatus at 1 year from hospital discharge was obtainedy a telephone interview of the referring primary carehysician or cardiologist.

Cardiac marker levels were log-transformed, andomparisons of mean levels of cardiac marker be-ween patients alive and those dead at 1 year wereade by multivariate analysis of variance with post

oc Bonferroni’s corrected pairwise comparisons.hese tests were conducted with SYSTAT 10 (SPSS,

nc. Chicago, Illinois). To analyze the prognostic in-uence of an increased level of troponin T, marker

evels were log-transformed and divided into quin-iles. Multivariable analysis using stepwise Cox’s pro-ortional hazards regression was performed to identify

ndependent covariates of event-free survival rate at 1

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ear. The primary dependent variable was 1-year mor-ality rate. The primary independent variable was anncreased level of troponin T in any of the 3 postop-rative samples. Other independent variables includedhe results of CK-MB testing, demographics, present-ng syndrome, cardiovascular risk factors, medicationse, extent of CAD, ejection fraction, repeat CABG,ype of cardioplegia, and other clinical factors, asescribed previously.4 Cox’s regression analysis usedorward stepwise regression. An independent variableas removed from the model only when its corre-

ponding regression parameter was not significantlyifferent from 0 at p �0.1. Cox’s regression analysisas conducted with BMDP 7 (BMDP Statistical Soft-are, Inc., Saugus, Massachusetts). For all significant

ovariates of event-free survival rate, 95% confidencentervals were computed. All p values were 2-sided,nd a p value �0.05 was considered statistically sig-ificant.

ESULTSOf 136 patients, 2 (1.5%) were lost to follow-up.

he 2 patients lost to follow-up were imputed to belive and free of complications. Baseline demograph-cs of the study patients are listed in Table 1 and areomparable to those in previous studies on outcomesfter CABG. Seven patients (5%) died during the

TABLE 1 Baseline Characteristics of the Subjects (n � 136)

Age (yrs) 67 � 12Men 77%Medical history

Diabetes 34%Systemic hypertension 75%Hypercholesterolemia 86%Tobacco use 42%Coronary artery disease 67%Previous acute myocardial infarction 35%Valve disease 5%Congestive heart failure 15%Percutaneous coronary intervention 18%

Extent of coronary artery disease, vessels 2.6 � 0.7Extent of coronary artery disease

1 vessel 10%2 vessels 17%3 vessels or left main artery 73%

Ejection fraction (%) 42 � 23Presenting syndrome

Congestive heart failure 13%Unstable angina pectoris 39%Stable angina pectoris 18%Non–ST-segment elevation myocardial infarction 20%ST-segment elevation myocardial infarction 9%Cardiac arrest 2%

Previous medication useAspirin 94%� blocker 83%Statins 76%Nitrates 69%Heparin 39%

Surgical detailsRepeat surgery 8%No. of vessels grafted 3.4 � 1.3

Data are presented as mean � SD or number (percentage).

-year follow-up. The mean levels of cardiac markers s

80 THE AMERICAN JOURNAL OF CARDIOLOGY� VOL. 94

n patients stratified by vital status are presented inable 2.

In the patients who died during the 1-year follow-p, the immediate postop, 6- to 12-hour, and 18- to4-hour median (and interquartile ranges) levels ofroponin T were 6.4 ng/ml (1.3 to 10.7), 7.4 ng/ml (2.0o 9.8), and 7.8 ng/ml (3.6 to 16.1), respectively,hich were significantly higher than comparably

imed levels of troponin T in patients who survived:.0 ng/ml (0.6 to 1.5), 1.3 ng/ml (0.76 to 1.9), and 0.76g/ml (0.42 to 1.26), respectively. The differences inevels of troponin T between patients who were alivend those who were dead at 1 year were significant forhe 6- to 12- and 18- to 24-hour specimens (each p

0.05). Identically timed CK-MB values did not dif-er significantly between patients who were alive andhose who were dead at 1 year.

Multivariable analysis suggested that an 18- to4-hour postoperative level of troponin T in the high-st log quintile (�1.58 ng/ml) was the strongest pre-ictor of a 1-year mortality rate (odds ratio 5.45, 95%onfidence interval 4.5 to 232.5, p �0.0001), whereasK-MB results added no independent information.

Survival curves for patients with high levels (topuintile in the 18- to 24-hour specimen) and low levelsquintiles 2 through 5 in the 18- to 24-hour specimen) ofroponin T are displayed in Figure 1. Most patients whoied were in the highest log quintile of troponin T.

ISCUSSIONIn the present study, we describe for the first time a

orrelation between levels of troponin T after CABG andonger term adverse outcomes. In univariate and multi-ariable modeling, the level of troponin T after CABGas the single best predictor of mortality rate at 1 year

nd was superior to CK-MB for this indication.The clinical significance of release of cardiac bi-

markers after cardiac procedures has been a subjectf controversy and has generally been defined byelating marker levels to clinical outcomes.5–8 Twoecent studies have established a relation betweenK-MB after CABG and worsened medium-term out-omes.9,10 However, the sensitivity and specificity ofK-MB in the 2 analyses were limited. In previous

TABLE 2 Cardiac Marker Levels at Different Time Points AfterCABG, Expressed as a Function of Mortality (n � 7) VersusNo Mortality (n � 129)

Marker and TimingDeath

(n � 7)No Death(n � 129) p Value

Troponin TPostop 6.4 (1.3–10.7) 1.0 (0.60–1.5) 0.076–12 h 7.4 (2.0–9.8) 1.3 (0.76–1.9) 0.0218–24 h 7.8 (3.6–16.1) 0.76 (0.42–1.26) 0.02

CK-MBPostop 79.6 (35–109) 42.2 (29–85) 0.506–12 h 77.9 (33–97) 47.2 (28–80) 0.4018–24 h 46.0 (21–117) 21.6 (13–42) 0.12

Data are presented as median (interquartile range) (in nanograms permilliliter).

tudies, troponin I was found to be superior to CK-MB

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or prediction of in-hospital complications after car-iac surgery.11,12 Fellahi et al13 studied the value ofesting troponin I to predict long-term outcomesmong 202 patients who underwent elective CABGnd reported that a troponin I level �13 ng/ml on therst day after surgery was associated with a 7.3-fold

ncreased risk of death within 2 years after CABG.ur results are remarkably similar for testing of tro-onin T and suggest a superiority of troponin T overK-MB for predicting longer term risk, in addition to

hort-term prognostication of impending complica-ions after surgery.

Our results suggest that routine biomarker screen-ng with troponin T after CABG is justified. Patientsith increased levels of troponin T after CABG mayerit more intensive monitoring during the index hos-

italization and increased scrutiny for ischemic com-lications after discharge. Further, strategies to pre-ent perioperative myocardial necrosis may beptimally tested with the evaluation of troponin Tevels after surgery. For example, we previously re-orted that off-pump CABG may offer greater cardio-rotection as shown by the smaller amount of troponinelease with off-pump compared with conventionalABG.14 If these long-term outcome results are con-rmed in additional prospective studies, the biochem-

cal definition of myocardial infarction after CABGhould moved to the troponin standard.

Our study has limitations. First, the 1-year fol-ow-up by telephone interview of referring physiciansay have missed clinical outcomes. However, vital

tatus was confirmed in all but 2 patients, and theddition of additional clinical events would mostikely have improved the prognostic value of testingor serum troponin T. Second, although our study is

IGURE 1. Kaplan-Meier survival curves show that patients withow levels of troponin T (solid line) have a lower risk of mortalityuring the first year after CABG than do those with troponin T

evels >1.58 ng/ml at 18 to 24 hours after CABG (dashed line).

he first to assess results of troponin T and 1-year A

ortality rates after CABG, a larger sample wouldncourage greater confidence in the specific troponinprognostic threshold that identifies patients as being

t high risk for impending complications. A recenttudy that examined troponin T in relation to in-ospital myocardial infarction after CABG found aroponin T level �3.4 ng/ml to have the greatestiagnostic accuracy for the prediction of early com-lications.15 Third, not all patients in the study had anssessment of preoperative levels of troponin T.

. Bonnefoy E, Filley S, Kirkorian G, Guidollet J, Roriz R, Robin J, Touboul P.roponin I, troponin T, or creatine kinase-MB to detect perioperative myocardialamage after coronary artery bypass surgery. Chest 1998;114:482–486.. Jacquet L, Noirhomme P, El Khoury G, Goenen M, Philippe M, Col J, Dion. Cardiac troponin I as an early marker of myocardial damage after coronaryypass surgery. Eur J Cardiothorac Surg 1998;13:378–384.. Alpert JS, Thygesen K, Antman E, Bassand JP. Myocardial infarction rede-ned—a consensus document of the Joint European Society of Cardiology/merican College of Cardiology Committee for the redefinition of myocardial

nfarction. J Am Coll Cardiol 2000;36:959–969.. Januzzi JL, Lewandrowski K, MacGillivray TE, Newell JB, Kathiresan S,ervoss SJ, Lee-Lewandrowski E. A comparison of cardiac troponin T andreatine kinase-MB for patient evaluation after cardiac surgery. J Am Collardiol 2002;39:1518–1523.. Califf RM, Abdelmeguid AE, Kuntz RE, Popma JJ, Davidson CJ, Cohen EA,leiman NS, Mahaffey KW, Topol EJ, Pepine CJ, et al. Myonecrosis after

evascularization procedures. J Am Coll Cardiol 1998;31:241–251.. Harrington RA, Lincoff AM, Califf RM, Holmes DR Jr, Berdan LG,’Hanesian MA, Keeler GP, Garratt KN, Ohman EM, Mark DB, et al. Charac-

eristics and consequences of myocardial infarction after percutaneous coronaryntervention: insights from the Coronary Angioplasty Versus Excisional Atherec-omy Trial (CAVEAT). J Am Coll Cardiol 1995;25:1693–1699.. Tardiff BE, Califf RM, Tcheng JE, Lincoff AM, Sigmon KN, Harrington RA,ahaffey KW, Ohman EM, Teirstein PS, Blankenship JC, et al. Clinical out-

omes after detection of elevated cardiac enzymes in patients undergoing percu-aneous intervention. IMPACT-II Investigators. Integrilin (eptifibatide) to Mini-ize Platelet Aggregation and Coronary Thrombosis-II. J Am Coll Cardiol

999;33:88–96.. Kugelmass AD, Cohen DJ, Moscucci M, Piana RN, Senerchia C, Kuntz RE,aim DS. Elevation of the creatine kinase myocardial isoform following other-ise successful directional coronary atherectomy and stenting. Am J Cardiol994;74:748–754.. Klatte K, Chaitman BR, Theroux P, Gavard JA, Stocke K, Boyce S, Bartels C,eller B, Jessel A. Increased mortality after coronary artery bypass graft surgery

s associated with increased levels of postoperative creatine kinase-myocardialand isoenzyme release: results from the GUARDIAN trial. J Am Coll Cardiol001;38:1070–1077.0. Costa MA, Carere RG, Lichtenstein SV, Foley DP, de Valk V, Lindenboom, Roose PC, van Geldorp TR, Macaya C, Castanon JL, et al. Incidence,

redictors, and significance of abnormal cardiac enzyme rise in patients treatedith bypass surgery in the arterial revascularization therapies study (ARTS).irculation 2001;104:2689–2693.1. Benoit MO, Paris M, Silleran J, Fiemeyer A, Moatti N. Cardiac troponin I: itsontribution to the diagnosis of perioperative myocardial infarction and variousomplications of cardiac surgery. Crit Care Med 2001;29:1880–1886.2. Eigel P, van Ingen G, Wagenpfeil S. Predictive value of perioperative cardiac

roponin I for adverse outcome in coronary artery bypass surgery. Eur J Cardio-horac Surg 2001;20:544–549.3. Fellahi JL, Gue X, Richomme X, Monier E, Guillou L, Riou B. Short- and

ong-term prognostic value of postoperative cardiac troponin I concentration inatients undergoing coronary artery bypass grafting. Anesthesiology 2003;99:70–274.4. Kathiresan S, MacGillivray TE, Lewandrowski K, Servoss SJ, Lewandrowski, Januzzi JL Jr. Off-pump coronary bypass grafting is associated with lessyocardial injury than coronary bypass surgery with cardiopulmonary bypass.eart Surg Forum 2003;6:E174–E178.5. Carrier M, Pellerin M, Perrault LP, Solymoss BC, Pelletier LC. Troponin

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