Relation of an Elevated White Blood Cell Count AfterPercutaneous Coronary Intervention to

Long-Term Mortality

Vivek Rajagopal, MD, Hitinder S. Gurm, MD, Deepak L. Bhatt, MD,A. Michael Lincoff, MD, James E. Tcheng, MD, Dean J. Kereiakes, MD,

Neal S. Kleiman, MD, Gang Jia, MS, and Eric J. Topol, MD

Increased inflammatory markers are associated with apoor prognosis after percutaneous coronary interven-tion. Leukocytes play a key role in inflammation, and anincrease in white blood cell (WBC) counts is a nonspe-cific marker of inflammation. In patients undergoingpercutaneous coronary intervention, baseline WBCcounts independently predict long-term mortality. In apooled cohort of patients from the Evaluation of c7E3 forthe Prevention of Ischemic Complications (EPIC), theEvaluation in PTCA to Improve Long-term Outcome withabciximab Glycoprotein IIb/IIIa blockade (EPILOG), andEvaluation of Platelet IIb/IIIa inhibitor for STENTing(EPISTENT) trials, postprocedural WBC counts were alsofound to be an independent predictor of long-termmortality. �2004 by Excerpta Medica, Inc.

(Am J Cardiol 2004;94:190–192)

Inflammation plays a prominent role in atherosclero-sis.1,2 In addition to promoting plaque development,

inflammation increases plaque instability, leading toplaque rupture and thrombosis.3 Several studies havedemonstrated an association between inflammatory sta-tus and prognosis in coronary artery disease.4–6 Whiteblood cells (WBCs) are important producers of inflam-matory cytokines. Accordingly, studies have shown anassociation between higher WBC counts and worseoutcomes in stable and unstable coronary artery dis-ease.6–10 In patients undergoing percutaneous coro-nary intervention (PCI), the preprocedural WBC countindependently predicts long-term mortality.11,12 Be-cause balloon injury activates leukocytes, the postpro-cedural WBC count may represent the acute inflam-matory response to arterial injury.13 Therefore, wehypothesized that WBC counts after PCI would inde-pendently predict long-term morality.

• • •Patients were pooled from 3 randomized trials of

adjunctive IIb/IIIa inhibition during PCI: Evaluationof c7E3 for the Prevention of Ischemic Complications(EPIC), Evaluation in PTCA to Improve Long-term

Outcome with abciximab Glycoprotein IIb/IIIa block-ade (EPILOG), and Evaluation of Platelet IIb/IIIaInhibitor for STENTing (EPISTENT). In the EPICtrial, 2,099 patients who underwent PCI in high-risksettings—high-risk angiographic characteristics, un-stable angina pectoris, or myocardial infarction—wererandomized to a bolus infusion of abciximab, a bolusof abciximab, or placebo.14 In the EPILOG trial, 2,792patients who underwent elective or urgent PCI wererandomized to placebo with standard-dose heparin,abciximab with low-dose heparin, or abciximab withhigh-dose heparin.15 In the EPISTENT trial, 2,399patients who underwent elective or urgent PCI wererandomized to PCI plus abciximab, stent plus placeboand standard-dose heparin, or stent plus abciximaband low-dose heparin.16

All-cause mortality was determined for all patientsat 3 years. WBC count was measured at baseline andat a mean of 36 hours after PCI. The cohort wasdivided into quintiles of postprocedural WBC counts,and differences in baseline characteristics betweengroups were evaluated using Fisher’s exact and chi-square tests. After spline transformation, the WBCcount was used as a continuous variable for outcomeanalysis. Unadjusted and adjusted hazard ratios for3-year mortality were estimated by Cox proportional-hazards regression analysis. The multivariate modelincluded the following variables: baseline WBCcount, postprocedural WBC count, age, gender, sys-temic hypertension, diabetes, previous myocardial in-farction, congestive heart failure, previous coronaryartery bypass grafting, previous PCI, angina, smokingstatus, weight, body mass index, systolic blood pres-sure, diastolic blood pressure, heart rate, hemoglobin,creatinine, prehospital medications, platelet glycopro-tein IIb/IIIa use, and American College of Cardiology/American Heart Association lesion score. All analyseswere performed using the SAS 8.0 system (SAS Inc.,Cary, North Carolina).

Postprocedural WBC counts were available for2,982 of the 7,290 patients enrolled in the 3 trials:1,809 (61%) from EPIC, 765 (23%) from EPILOG,and 497 (17%) from EPISTENT. Patients with post-procedural WBC counts differed significantly frompatients with only preprocedural WBC counts. Morepatients with postprocedural WBC counts had a pre-vious myocardial infarction (58% vs 47%, p �0.001),previous coronary artery bypass grafting (14% vs11%, p � 0.001), and congestive heart failure (8% vs5%, p �0.001), but fewer previous PCIs (19% vs

From The Cleveland Clinic Foundation, Cleveland, Ohio; Duke Uni-versity Medical Center, Durham, North Carolina; The Lindner Centerand Ohio Heart Health Center, Cincinnati, Ohio; and Methodist-DeBakey Heart Center and Baylor College of Medicine, Houston,Texas. Dr. Bhatt’s address is: Department of Cardiovascular Medicine,Desk F25, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleve-land, Ohio 44195. E-mail: bhattd@ccf.org. Manuscript receivedFebruary 20, 2004; revised manuscript received and acceptedMarch 30, 2004.

190 ©2004 by Excerpta Medica, Inc. All rights reserved. 0002-9149/04/$–see front matterThe American Journal of Cardiology Vol. 94 July 15, 2004 doi:10.1016/j.amjcard.2004.03.060

22%, p � 0.005). Baseline characteristics of patientsaccording to postprocedural WBC count quintile arelisted in Table 1. Patients with higher WBC countswere more likely to have diabetes, a higher body massindex, previous myocardial infarction, congestiveheart failure, hypertension, or a history of recentsmoking.

Over the 3-year period, 219 of 2,982 patients died.Postprocedural WBC counts correlated strongly withmortality at 3 years (hazard ratio for every 1,000/�Lincrease 1.11, 95% confidence interval 1.08 to 1.15)(Figure 1). This relation remained in multiple pre-specified subgroups (Figure 2). As previously reportedfor preprocedural WBC counts, the association be-tween postprocedural WBC counts and long-termmortality was somewhat diminished in current or re-cent smokers (�1 year), indicating an interaction be-tween smoking and WBC counts.11 In multivariateanalysis (Table 2), the postprocedural WBC countremained predictive of 3-year mortality. The globalchi-square for the model with only preproceduralWBC counts was 175, with a C-index of 0.747; in-

clusion of postprocedural WBC counts increased thechi-square to 185 (p �0.001), with a C-index of 0.753.

• • •Thus, we found that the postprocedural WBC

count was strongly and independently associated withlong-term mortality, even after correcting for baselinecharacteristics and preprocedural WBC counts. Thesefindings add to our knowledge that inflammation be-fore PCI correlates with the hazard of long-term mor-tality. Several studies have demonstrated this correla-tion; e.g, WBC counts and other markers ofinflammation, such as C-reactive protein, fibrinogen,and interleukin-6 measured before PCI were corre-lated with adverse cardiac events.6,17 In previous stud-ies, it was shown that baseline WBC counts were astrong predictor of 3-year mortality (adjusted hazardratio for 1,000/�L increase in WBC counts 1.10, 95%confidence interval 1.07 to 1.13, p �0.001).11 Simi-larly, Chew and colleagues6 found that the highestquartile of C-reactive protein was associated with anodds ratio for 30-day myocardial infarction or deathafter PCI of 3.68 (95% confidence interval 1.51 to8.99, p � 0.004).

The significance of inflammation after PCI hasbeen less well defined, although it is well known thatPCI evokes systemic inflammation early after ballooninjury. Aggarwal and associates18 demonstrated that

TABLE 1 Baseline Characteristics According to Postprocedural White Cell Count (WBC)

DemographicsFirst Quintile(n � 616)

Second Quintile(n � 597)

Third Quintile(n � 587)

Fourth Quintile(n � 589)

Fifth Quintile(n � 593)

Post-white cell count median � SD (k/�l) 5.7 � 0.8 7.3 � 0.3 8.4 � 0.3 9.7 � 0.5 13.2 � 2.8Age (yrs) 61 � 10 61 � 11 60 � 11 59 � 11 60 � 11Body mass index (kg/m2) 28 � 5 28 � 5 28 � 5 29 � 5 29 � 6Women 194 (31%) 166 (28%) 164 (28%) 148 (25%) 189 (37%)Angina pectoris 530 (86%) 508 (85%) 499 (85%) 491 (84%) 490 (83%)Diabetes mellitus 113 (18%) 131 (22%) 129 (22%) 136 (23%) 180 (30%)Previous myocardial infarction 334 (55%) 328 (56%) 331 (56%) 355 (60%) 372 (63%)Congestive heart failure 37 (6%) 34 (6%) 47 (8%) 57 (10%) 72 (12%)Systemic hypertension 322 (52%) 327 (55%) 321 (55%) 338 (58%) 371 (63%)Previous coronary artery bypass grafting 100 (16%) 90 (15%) 67 (11%) 70 (12%) 77 (13%)Previous percutaneous coronary intervention 165 (27%) 136 (23%) 103 (18%) 92 (16%) 78 (13%)Smoking within 1 yr 140 (23%) 180 (30%) 213 (36%) 230 (39%) 250 (42%)

FIGURE 1. Relation between post-PCI WBC count and 3-yearmortality (Cox proportional-hazards model with spline transfor-mation. CI � confidence interval.

FIGURE 2. Hazards ratio for 3-year mortality in subgroups.

BRIEF REPORTS 191

interleukin-6 levels increased as early as 1 hour afterangioplasty. Similarly, Almagor and colleagues19

showed that C-reactive protein levels increased afterangioplasty, even in patients with stable coronary ar-tery disease. It is unclear whether this inflammatoryresponse is merely a surrogate of the inflammatorystate before PCI or a marker of myonecrosis after PCI.

Our findings help to clarify these uncertainties. Ina multivariate analysis, the WBC count after PCI wasan independent predictor, even with preproceduralWBC counts in the model. This indicates that post-PCI WBC count is not just tracking the baselineinflammatory state, but suggests a secondary inflam-matory response to injury that carries additional prog-nostic importance. Similarly, the WBC count was asignificant predictor of mortality in the subgroup ofpatients with an increase in postprocedural creatinekinase-MB values, and was an independent predictorin multivariate modeling that included creatine kinase-MB.

Our findings are tempered by several limitations.Like any retrospective analyses, it is not possible tocorrect for all confounders, and any association cannotbe interpreted as causal. As noted in a previous anal-ysis,11 patients in the EPIC, EPILOG, and EPISTENTtrials did not have other markers of inflammationmeasured, such as interleukin-6, C-reactive protein,fibrinogen, or myeloperoxidase. Therefore, it is un-known whether inclusion of these markers woulddiminish the predictive value of the WBC count.Also, selection biases may limit the applicability ofthese findings in other populations. Not only didpatients with postprocedural WBC counts comepredominantly from the EPIC trial, which hadhigher risk patients, but more patients with postpro-

cedural WBC counts had higherrisk features than patients with onlypreprocedural WBC counts.

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tal prognostic value of elevated baseline C-reactive protein among establishedmarkers of risk in percutaneous coronary intervention. Circulation 2001;104:992–997.7. Bhatt DL, Chew DP, Lincoff AM, Simoons ML, Harrington RA, Ommen SR,Jia G, Topol EJ. Effect of revascularization on mortality associated with anelevated white blood cell count in acute coronary syndromes. Am J Cardiol2003;92:136–140.8. Yen MH, Bhatt DL, Chew DP, Harrington RA, Newby LK, Ardissino D, Vande Werf F, White JA, Moliterno DJ, Topol EJ. Association between admissionwhite blood cell count and one-year mortality in patients with acute coronarysyndromes. Am J Med 2003;115:318–321.9. Blake GJ, Ridker PM. C-reactive protein and other inflammatory risk markersin acute coronary syndromes. J Am Coll Cardiol 2003;41:37S–42S.10. Brown DW, Giles WH, Croft JB. White blood cell count: an independentpredictor of coronary heart disease mortality among a national cohort. J ClinEpidemiol 2001;54:316–322.11. Gurm HS, Bhatt DL, Lincoff AM, Tcheng JE, Kereiakes DJ, Kleiman NS, JiaG, Topol EJ. Impact of preprocedural white blood cell count on long termmortality after percutaneous coronary intervention: insights from EPIC, EPILOG,and EPISTENT trials. Heart 2003;89:1200–1204.12. Gurm HS, Bhatt DL, Gupta R, Ellis SG, Topol EJ, Lauer MS. Preproceduralwhite blood cell count and death after percutaneous coronary intervention. AmHeart J 2003;146:692–698.13. Serrano CV Jr, Ramires JA, Venturinelli M, Arie S, D’Amico E, Zweier JL,Pileggi F, da Luz PL. Coronary angioplasty results in leukocyte and plateletactivation with adhesion molecule expression. Evidence of inflammatory re-sponses in coronary angioplasty. J Am Coll Cardiol 1997;29:1276–1283.14. The EPIC Investigators. Use of a monoclonal antibody directed against theplatelet glycoprotein IIb/IIIa receptor in high-risk coronary angioplasty. TheEPIC Investigation. N Engl J Med 1994;330:956–961.15. The EPILOG Investigators. Platelet glycoprotein IIb/IIIa receptor blockadeand low-dose heparin during percutaneous coronary revascularization. The EPI-LOG Investigators. N Engl J Med 1997;336:1689–1696.16. The EPISTENT Investigators. Randomised placebo-controlled and balloon-angioplasty-controlled trial to assess safety of coronary stenting with use ofplatelet glycoprotein-IIb/IIIa blockade. The EPISTENT Investigators. Evaluationof Platelet IIb/IIIa Inhibitor for Stenting. Lancet 1998;352:87–92.17. Rahel BM, Visseren FL, Suttorp MJ, Plokker TH, Kelder JC, de Jongh BM,Bouter KP, Diepersloot RJ. Preprocedural serum levels of acute-phase reactantsand prognosis after percutaneous coronary intervention. Cardiovasc Res 2003;60:136–140.18. Aggarwal A, Schneider DJ, Terrien EF, Gilbert KE, Dauerman HL. Increasein interleukin-6 in the first hour after coronary stenting: an early marker of theinflammatory response. J Thromb Thrombolysis 2003;15:25–31.19. Almagor M, Keren A, Banai S. Increased C-reactive protein level aftercoronary stent implantation in patients with stable coronary artery disease. AmHeart J 2003;145:248–253.

TABLE 2 Significant Predictors from Multivariate Analysis

Variable Hazard Ratio 95% CI p Value

Congestive heart failure 2.90 2.08–4.03 �0.001Systemic hypertension 1.51 1.09–2.08 0.01Coronary artery bypass grafting 1.42 1.01–1.20 �0.001Post-PCI WBC count* 1.08 1.03–1.12 0.001Baseline WBC count* 1.05 1.01–1.10 0.03Age 1.05 1.03–1.06 �0.001Heart rate 1.01 1.00–1.02 0.04Systolic blood pressure �114 mm Hg 1.01 1.00–1.02 0.01Body mass index �26 (kg/m2) 0.91 0.84–0.99 0.02Hemoglobin 0.90 0.81–0.98 0.01Women 0.54 0.39–0.76 �0.001

*Adjusted hazard ratio for each 1,000/�l increase in WBC.CI � confidence interval.

192 THE AMERICAN JOURNAL OF CARDIOLOGY� VOL. 94 JULY 15, 2004