Impact of Leukocyte Count on Mortality and Bleeding in

Patients With Myocardial Infarction Undergoing Primary

Percutaneous Coronary Interventions
Analysis From the Harmonizing Outcome With Revascularization and
Stent in Acute Myocardial Infarction Trial
Tullio Palmerini, MD; Roxana Mehran, MD; George Dangas, MD; Eugenia Nikolsky, MD;
Bernhard Witzenbichler, MD; Giulio Guagliumi, MD; Darius Dudek, MD; Philippe Genereux, MD;
Adriano Caixeta, MD; LeRoy Rabbani, MD; Giora Weisz, MD; Helen Parise, ScD; Martin Fahy, MSc;
Ke Xu, PhD; Bruce Brodie, MD; Alexandra Lansky, MD; Gregg W. Stone, MD

Background—The relationship between white blood cell count (WBCc) and mortality in patients with ST-segment–
elevation acute myocardial infarction treated with percutaneous coronary intervention is poorly understood. Further-
more, whether there is a relationship between WBCc and risk of noncardiac mortality and bleeding after percutaneous
coronary intervention is unknown.
Methods and Results—The baseline WBCc was available in 3193 of 3345 patients (95.5%) who underwent percutaneous
coronary intervention in the Harmonizing Outcome With Revascularization and Stent in Acute Myocardial Infarction
(HORIZONS-AMI) trial. In a propensity-adjusted multivariable analysis, WBCc was an independent predictor of 1-year
cardiac mortality (hazard ratio, 1.15; 95% confidence interval, 1.09 to 1.22), noncardiac mortality (hazard ratio, 1.19;
95% confidence interval, 1.10 to 1.29), and major bleeding (hazard ratio, 1.08; 95% confidence interval, 1.04 to 1.12).
After adjustment for baseline creatinine phosphokinase levels and left ventricular ejection fraction, WBCc remained an
independent predictor of 1-year all-cause mortality and cardiac mortality. In patients matched for baseline creatinine
phosphokinase levels at hospital admission, the median peak creatinine phosphokinase level was significantly higher in
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patients with high WBCc (⬎11 000 per 1 mm3) compared with low WBCc (1851 U/L [range, 880-3307 U/L] versus
1241 U/L [range, 540 to 2,78], respectively; P⬍0.0001). In this subgroup of patients, WBCc was an independent
correlate of peak creatinine phosphokinase level, and remained an independent predictor of 1-year mortality.
Conclusions—In patients with ST-segment– elevation acute myocardial infarction undergoing percutaneous coronary
intervention, elevated baseline WBCc is an independent predictor of infarct size, as assessed by peak creatinine
phosphokinase level, and of 1-year cardiac mortality, noncardiac mortality, and major bleeding.
Clinical Trial Registration—URL: http://www.ClinicalTrials.gov. Unique identifier: NCT00433966.
(Circulation. 2011;123:2829-2837.)
Key Words: angioplasty 䡲 leukocyte count 䡲 myocardial infarction 䡲 stents

A n association between the admission white blood cell

count (WBCc) and morbidity and mortality in patients
with ST-segment– elevation acute myocardial infarction
studies have found WBCc to be an independent predictor of
1-year mortality after primary PCI,4,5 whereas others have
refuted this association.6,7 Moreover, no previous study has
(STEMI) has been reported for more than half a century.1 investigated the relation between WBCc and bleeding or
Although this association has also been described for patients infarct size in patients undergoing primary PCI. We therefore
with STEMI undergoing lytic therapy,2,3 WBCc studies in sought to investigate the impact of WBCc on 1-year all-cause
STEMI patients undergoing primary percutaneous coronary mortality, cardiac mortality, noncardiac mortality, bleeding,
intervention (PCI) have reported conflicting findings. Some and infarct size in patients enrolled in the large-scale, pro-

Received August 22, 2010; accepted April 4, 2011.

From the Istituto Cardiologia, Policlinico S. Orsola, Bologna, Italy (T.P.); Columbia University Medical Center and the Cardiovascular Research
Foundation, New York, NY (T.P., R.M., G.D., E.N., P.G., A.C., L.R., G.W., H.P., M.F., K.X., A.L., G.W.S.); Charite University Medicine Campus
Benjamin Franklin, Berlin, Germany (B.W.); Ospedali Riuniti Bergamo, Bergamo, Italy (G.G.); Jagiellonian University, Krakow, Poland (D.D.); and
LeBauer CV Research Foundation/Moses Cone Hospital, Greensboro, NC (B.B.).
The online-only Data Supplement is available with this article at http://circ.ahajournals.org/cgi/content/full/CIRCULATIONAHA.110.985564/DC1.
Correspondence to Gregg W. Stone, MD, Columbia University Medical Center, New York–Presbyterian Hospital, The Cardiovascular Research
Foundation, 111 E 59th St, 11th Floor, New York, NY 10022. E-mail gs2184@columbia.edu
© 2011 American Heart Association, Inc.
Circulation is available at http://circ.ahajournals.org DOI: 10.1161/CIRCULATIONAHA.110.985564

2829
 2830 Circulation June 21, 2011

spective, randomized Harmonizing Outcome With Revascular-

ization and Stent in Acute Myocardial Infarction (HORIZONS-
AMI) trial.8
Clinical Perspective on p 2837

Methods
The study design of the HORIZONS-AMI trial has previously been
reported in detail.9 Briefly, HORIZONS-AMI was a prospective
randomized trial including consecutive patients ⱖ18 years of age
who presented within 12 hours after the onset of symptoms with
ST-segment elevation of ⱖ1 mm in ⱖ2 contiguous leads, new left
bundle-branch block, or true posterior infarction. Patients were
randomized before angiography in a 1:1 ratio to anticoagulation with
unfractionated heparin plus a glycoprotein IIb/IIIa inhibitor or to the
direct thrombin inhibitor bivalirudin alone. After angiography, stent-
eligible patients were randomized in a 3:1 ratio to paclitaxel-eluting Figure 1. Distribution of baseline white blood cell (WBC) count
or bare metal stents. All adverse cardiac and bleeding events were in the study population.
adjudicated by an independent clinical events committee blinded to
treatment assignment. The study was approved by the institutional coronary bypass graft surgery; renal dysfunction; Killip class;
review board or ethics committee at each participating center, and all peripheral vascular disease; anterior myocardial infarction; baseline
patients provided written informed consent. Blood samples were Thrombolysis in Myocardial Infarction flow; ␤-blocker, angioten-
obtained at the time of admission at each participating center and sin-converting enzyme inhibitor, oral hypoglycemic, and aspirin
recorded in the electronic case report form. Total WBCc was therapy at hospital admission; and procedural antithrombotic treat-
measured in an EDTA-anticoagulated whole-blood specimen. ment. The propensity score was then entered into the multivariable
analyses as a linear term in 3 separate multivariable Cox models,
Study Objectives and Definitions with WBCc entered as continuous data, by using the cutoff value of
For the purpose of this study, we included only patients treated with 11 000 per 1 mm3, or stratified by quartiles. Nonlinearity was
primary PCI who had a baseline WBCc obtained. The primary checked with Martingale residuals. Because left ventricular ejection
objective of this study was to evaluate the impact of WBCc on 1-year fraction (LVEF) at hospital admission was not available in 472
mortality. Secondary objectives of the study were to evaluate the patients (and therefore was excluded in determining the propensity
impact of WBCc on reinfarction, target vessel revascularization, score), multivariable analyses of 1-year mortality and cardiac mor-
stent thrombosis defined according to the Academic Research tality were also performed in the subset of patients who had LVEF
Downloaded from http://ahajournals.org by on February 27, 2020

Consortium definition,10 and major bleeding not related to coronary determined. To avoid overfitting, the following variables known to
artery bypass surgery. We also sought to determine the relationship affect prognosis after STEMI were considered in this model: baseline
of WBCc to infarct size as assessed by peak creatinine phosphokinase hemoglobin and CPK level measured at hospital admission (the latter
(CPK) levels. The primary end-point definitions in the HORIZON trial to adjust for the degree of myonecrosis at baseline), age, renal
have previously been reported in detail.9 In addition, cardiac mor- dysfunction, Killip class, baseline Thrombolysis in Myocardial
tality was adjudicated as death caused by any of the following: acute Infarction flow, LVEF, and WBCc (as continuous data). Moreover,
MI, cardiac perforation or pericardial tamponade, arrhythmia or a propensity score including the 23 variables specified above and
conduction abnormality, stroke, or procedural complication. Any LVEF was also determined in this subgroup of patients and entered
death in which a cardiac cause could not be excluded was also into the multivariable analysis as a linear term in addition to WBCc
adjudicated as cardiac. as continuous data. The impact of WBCc on outcomes was also
assessed after matching patients for baseline CPK levels. Indepen-
Statistical Analysis dent predictors of final infarct size, estimated by the peak CPK
Categorical variables were compared by the ␹2 or Fisher exact test. level,12 were then examined by use of a multivariable linear
Continuous data are presented as mean⫾SD or median and inter- regression analysis in the population matched for baseline CPK
quartile range and were compared by use of the Student t test or the levels. The following variables were entered into the model: WBCc
Mann-Whitney rank-sum test as appropriate. All outcomes were (as continuous data), baseline hemoglobin and CPK levels measured
expressed with Kaplan-Meier methodology and compared by use of at hospital admission, age, sex, renal dysfunction, baseline Throm-
the log-rank test. The correlation between WBCc and baseline CPK bolysis in Myocardial Infarction grade 0/1 flow, and anterior MI.
levels was determined by the Pearson correlation coefficient. Anal- This model was tested in patients with and in those without measured
ysis was stratified according to patients with a WBCc ⬎11 000 and LVEF. Statistical analyses were performed with SAS version 9.1.
ⱕ11 000 per 1 mm3 as a cutoff for normal, according to previous Values of P⬍0.05 were considered statistically significant.
studies.11 Receiver-operating characteristic curves were also con- The authors had full access to and take full responsibility for the
structed to assess the accuracy of WBCc to predict 1-year all-cause integrity of the data. All authors have read and agree to the manuscript
mortality, cardiac mortality, noncardiac mortality, and bleeding and as written.
of baseline CPK for 1-year cardiac mortality. The optimal cutoff
values from the receiver-operating characteristic curves were chosen Results
by use of the Youden index. To assess the association between
WBCc and 1-year all cause mortality, cardiac mortality, noncardiac Baseline Characteristics According to White Blood
mortality, and major bleeding, Cox multivariable regression analyses Cell Count
were performed. To adjust for possible confounders, a propensity Among the 3602 patients enrolled in the trial, 3345 (92.9%)
score for high (⬎11 000 per 1 mm3) versus low (ⱕ11 000 per underwent primary PCI, 3193 of whom (95.5%) had a
1 mm3) WBCc was determined by use of a logistic regression model. baseline WBCc available, signifying the present study cohort.
The following variables were considered for the propensity score:
age; sex; diabetes mellitus; smoking; family history of coronary As shown in Figure 1, WBCc was normally distributed.
artery disease; hypertension; hypercholesterolemia; baseline CPK; Clinical characteristics of patients stratified by baseline
hemoglobin levels and platelet count; prior MI; prior PCI; prior WBCc availability are shown in Table I in the online-only
 Palmerini et al WBC Count in STEMI 2831

Data Supplement. In general, these 2 groups were well P⫽0.002), cardiac mortality (HR, 1.81; 95% CI, 1.05 to 3.10;
matched, except that patients without baseline WBCc were P⫽0.03), and noncardiac mortality (HR, 2.79; 95% CI, 1.16
more likely to have a lower LVEF and a history of MI and to 6.68; P⫽0.02). When stratified by quartiles, the upper
coronary revascularization. Clinical characteristics of patients quartile of WBCc was associated with an increased risk of
stratified by WBCc are shown in Table 1. Patients with 1-year all-cause mortality (HR, 5.87; 95% CI, 2.90 to 11.88;
WBCc ⬎11 000 compared with ⱕ11 000 per 1 mm3 were P⬍0.0001), cardiac mortality (HR, 5.05; 95% CI, 2.17 to
younger, more likely to be smokers, but less likely to be 11.75; P⫽0.0002), and noncardiac mortality (HR, 7.83; 95%
diabetic, to have renal dysfunction, or to have had prior CI, 2.12 to 28.92; P⫽0.002) compared with the lowest
myocardial infarction, PCI, or coronary artery bypass grafting quartile.
surgery. Moreover, they were less likely to be on aspirin, Receiver-operating characteristic curve analysis demon-
␤-blocker, and angiotensin-converting enzyme inhibitor ther- strated a significant association between WBCc and 1-year
apy on hospital admission, although medication use at dis- all-cause mortality, cardiac mortality, noncardiac mortality,
charge was not significantly different between the groups. and major bleeding, but with slightly different cutoff values.
Anatomic and procedural variables stratified by WBCc are The optimal cutoff values for WBCc with respect to mortal-
shown in Table 2. Patients with WBCc ⬎11 000 per 1 mm3 ity, cardiac mortality, noncardiac mortality, and bleeding
were slightly more likely to present with preprocedural were 12 600 per 1 mm3 (area under the curve, 0.61; 95% CI,
Thrombolysis in Myocardial Infarction grade 0 flow, were 0.56 to 0.67; P⬍0.0001), 12 300 per 1 mm3 (area under the
less likely to have a saphenous vein graft as a culprit vessel, curve, 0.61; 95% CI, 0.54 to 0.67; P⬍0.0001), 13 500 per
and more frequently received bivalirudin. Other baseline 1 mm3 (area under the curve, 0.63; 95% CI, 0.52 to 0.73;
variables were independent of WBCc. P⫽0.001), and 10 700 per 1 mm3 (area under the curve, 0.54;
95% CI, 0.51 to 0.68; P⫽0.008), respectively. After adjust-
Thirty-Day and 1-Year Clinical Outcomes ment for baseline LVEF and baseline CPK, WBCc (per 1000
Follow-up rates in patients with WBCc ⱕ11 000 versus cell per 1 mm3 increase) remained an independent predictor
⬎11 000 per 1 mm3 were 99.4% and 99.7%, respectively, at 30 of 1-year all-cause mortality (HR, 1.14; 95% CI, 1.09 to 1.20;
days (P⫽0.18) and 97.8% versus 98.3% at 1 year (P⫽0.37). The P⬍0.0001) and cardiac mortality (HR, 1.12; 95% CI, 1.06 to
median follow-up durations in patients with WBCc ⱕ11 000 1.18; P⬍0.0001; Table III in the online-only Data Supple-
versus ⬎11 000 per 1 mm3 were 742 days (interquartile range, ment). Moreover, when adjusted for the propensity score
730 to 1094 days) versus 744 days (interquartile range, 731 to including LVEF, WBCc remained an independent predictor
1093 days), respectively (P⫽0.92). Clinical outcomes were of 1-year all-cause mortality (HR, 1.17; 95% CI, 1.11 to 1.23;
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comparable in patients with versus without baseline WBCc P⬍0.0001) and cardiac mortality (HR, 1.16; 95% CI, 1.10 to
available (Table II in the online-only Data Supplement). 1.24; P⬍0.0001).
As shown in Table 3, all-cause mortality during the first 30
days was higher in patients with an elevated baseline WBCc Clinical Outcomes in Patients Matched or
(⬎11 000 per 1 mm3) compared with a lower WBCc, driven Stratified for Baseline Creatinine
by significantly higher cardiac mortality. The rates of rein- Phosphokinase Levels
farction, target vessel revascularization, stent thrombosis, A weak correlation was present between baseline WBCc and
stroke, and bleeding did not vary significantly according to CPK levels (␳⫽0.129; P⬍0.0001). Clinical characteristics of
WBCc at 30 days. At the 1-year follow-up (Table 3), the 2 groups of patients matched for baseline CPK levels are
all-cause mortality remained higher in patients with an shown in Table IV in the online-only Data Supplement. Of
elevated baseline WBCc (Figure 2A), owing to both higher note, the culprit artery, total ischemic time, and door-to-
cardiac (Figure 2B) and noncardiac (Figure 2C) mortality. balloon time were similar between the 2 groups, except for a
Again, no significant differences were apparent in terms of slightly higher prevalence of saphenous vein grafts and left
reinfarction, target vessel revascularization, stent thrombosis, main as culprit arteries in the low-WBCc group. The inci-
stroke, or bleeding, according to WBCc. When stratified by dence of 1-year mortality was 3.0% in patients with low
WBCc quartiles, the higher rates of mortality (Figure 3A), WBCc (ⱕ11 000 per 1 mm3) and 3.8% in patients with high
cardiac mortality (Figure 3B), and noncardiac mortality WBCc (adjusted HR, 1.08; 95% CI, 1.01 to 1.16; P⫽0.03).
(Figure 3C) were confined to patients with the highest Other variables in the model significantly associated with the
quartile of WBCc compared with the other quartiles. risk of 1-year mortality were age (HR, 1.07; 95% CI, 1.05 to
After adjustment for propensity score, WBCc as a contin- 1.10; P⬍0.0001), baseline CPK levels (HR, 1.06; 95% CI,
uous variable was an independent predictor of 1-year all- 1.01 to 1.11; P⫽0.02), baseline hemoglobin levels (HR, 0.84;
cause mortality (hazard ratio [HR] per 1000 cells per 1 mm3 95% CI, 0.72 to 0.98; P⫽0.03), LVEF (HR, 0.93; 95% CI,
increase, 1.16; 95% confidence interval [CI], 1.11 to 1.22; 0.90 to 0.95; P⬍0.0001), and renal insufficiency (HR, 2.38;
P⬍0.0001), 1-year cardiac mortality (HR, 1.15; 95% CI, 1.09 95% CI, 1.09 to 5.18; P⫽0.03). Moreover, the median peak
to 1.22; P⬍0.0001), 1-year noncardiac mortality (HR, 1.19; CPK level (median) was significantly higher in patients with
95% CI, 1.10 to 1.29; P⬍0.0001), and 1-year bleeding (HR, high compared with low WBCc at baseline (1851 U/L [range,
1.08; 95% CI, 1.04 to 1.12; P⬍0.0001). When considered in 880 to 3307 U/L] versus 1241 U/L [range, 540 to 2178 U/L],
the multivariable model as a categorical variable using the respectively; P⬍0.0001). In multivariable analysis, WBCc
cutoff of 11 000 cells per 1 mm3, WBCc was an independent was an independent correlate of peak CPK both in patients
predictor of 1-year mortality (HR, 2.04; 95% CI, 1.30 to 3.23; with measured LVEF (coefficient, 89; 95% CI, 69 to 109;
 2832 Circulation June 21, 2011

Table 1. Baseline Clinical Characteristics According to Admission White Blood Cell Count
WBCc ⬎11 000 per WBCc ⱕ11 000 per
1 mm3 (n⫽1559) 1 mm3 (n⫽1634) P
Age, y 57.6 (50.3– 66.8) 63.1 (55.0 –72.0) ⬍0.0001
Male, % (n/N) 76.7 (1196/1559) 78.0 (1275/1634) 0.38
Premature family history of CAD, % (n/N) 29.7 (462/1558) 29.4 (481/1634) 0.89
Hypertension, % (n/N) 48.7 (758/1558) 56.7 (926/1634) ⬍0.0001
Diabetes mellitus, % (n/N) 14.8 (231/1558) 17.8 (291/1634) 0.03
Hypercholesterolemia, % (n/N) 41.3 (643/1558) 44.9 (734/1634) 0.04
Smoking, % (n/N) 73.4 (1137/1549) 55.8 (909/1630) ⬍0.0001
Prior myocardial infarction, % (n/N) 9.4 (146/1558) 11.2 (183/1634) 0.08
Prior PCI, % (n/N) 9.0 (140/1557) 11.7 (191/1634) 0.01
Prior CABG, % (n/N) 1.4 (22/1558) 3.5 (57/1634) 0.0002
Peripheral vascular disease, % (n/N) 4.0 (62/1557) 4.7 (77/1634) 0.31
Renal dysfunction, % (n/N) 2.1 (33/1557) 3.4 (56/1634) 0.02
Left ventricular ejection fraction, % (n/N) 50 (41–58) 50 (45–60) 0.003
Killip class, % (n/N)
I 89.8 (1399/1557) 92.4 (1509/1632) 0.009
II 8.2 (128/1557) 6.3 (102/1632) 0.03
III 1.2 (18/1557) 0.6 (9/1632) 0.06
IV 0.8 (12/1557) 0.7 (12/1632) 0.91
Access site, % (n/N)
Femoral 93.5 (1457/1558) 93.5 (1527/1634) 0.94
Radial 6.2 (96/1558) 6.2 (102/1634) 0.92
Brachial 0.3 (5/1558) 0.3 (5/1634) 1
Total ischemic time, min* 225 (162–333) 219 (159–334) 0.44
Symptom onset to first hospital, min 115 (64–206) 115 (64–197) 0.67
Door to balloon, min† 95 (75–35) 98 (72–134) 0.26
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CPK at hospital admission, U/L 157 (95–337) 139 (87–251) ⬍0.0001

Baseline hemoglobin levels, mg/dL 14.7 (13.8–15.7) 14.4 (13.5–15.4) ⬍0.0001
Baseline platelet count, ⫻103/mm3 264 (224–310) 231 (194–272) ⬍0.0001
Medication at hospital admission, % (n/N)
Aspirin 21.3 (331/1557) 24.5 (399/1631) 0.03
Clopidogrel 2.3 (36/1557) 2.2 (36/1630) 0.84
Ticlopidine 0.3 (4/1557) 0.3 (5/1631) 1
␤-blocker 18.9 (295/1557) 23.2 (378/1630) 0.003
Calcium channel blocker 9.8 (152/1557) 10.6 (172/1630) 0.46
ACE inhibitors/ARB 21.0 (327/1557) 25.9 (422/1630) 0.001
Insulin 4.1 (64/1557) 4.4 (71/1631) 0.73
Oral antidiabetic medication 8.4 (131/1556) 10.8 (176/1630) 0.02
Diuretics 10.5 (164/1557) 11.1 (181/1631) 0.61
Digoxin 0.8 (13/1557) 0.9 (14/1631) 0.94
Amiodarone 0.3 (4/1557) 0.4 (6/1631) 0.75
Discharge medications, % (n/N)
Aspirin 98.8 (1501/1519) 98.6 (1581/1603) 0.64
Clopidogrel 96.4 (1465/1520) 95.6 (1531/1602) 0.25
␤-blockers 89.8 (1394/1552) 91.6 (1490/1627) 0.09
ACE inhibitors 77.8 (1183/1520) 77.2 (1238/1604) 0.67
ARB 6.4 (98/1520) 7.3 (117/1604) 0.35
Diuretics 21.6 (328/1520) 21.4 (343/1604) 0.89
Statins 95.7 (1454/1520) 95.7 (1535/1604) 0.96
Warfarin 3.8 (58/1520) 3.6 (58/1604) 0.77
WBCc indicates white blood cell count; CAD, coronary artery disease; PCI, percutaneous coronary intervention; CABG,
coronary artery bypass grafting; CPK, creatinine phosphokinase; ACE, angiotensin-converting enzyme; and ARB, angiotensin
receptor blockers. Continuous data are presented as median (interquartile range).
*Total ischemic time is the time from symptom onset to balloon dilatation in minutes.
†Arrival from first outside hospital or study hospital to first balloon inflation.
 Palmerini et al WBC Count in STEMI 2833

Table 2. Anatomic and Procedural Characteristics According to Admission White Blood

Cell Count
WBCc ⬎11 000 per WBCc ⱕ11 000 per
1 mm3 1 mm3 P
Vessels treated, mean⫾SD, n 1⫾0.2 1⫾0.2 0.75
Multiple vessel treated, % (n/N) 3.9 (59/1518) 4.1 (66/1598) 0.73
Culprit artery, % (n/N)
Left main 0.4 (7/1667) 0.7 (12/1748) 0.30
LAD 40.9 (68/1667) 40.2 (703/1748) 0.71
Cx 15.8 (264/1667) 15.6 (272/1748) 0.82
RCA 42.6 (710/1667) 41.9 (732/1748) 0.67
RIMA 0.1 (1/1667) 0.0 (0/1748) 0.49
SVG 0.2 (4/1667) 1.6 (28/1748) ⬍0.0001
Initial TIMI flow, % (n/N)
0 60.9 (1011/1661) 52.6 (919/1747) ⬍0.0001
I 8.1 (134/1661) 9.5 (1661/1747) 0.14
II 13.6 (226/1661) 18.0 (314/1747) 0.0005
III 17.5 (290/1661) 19.9 (348/1747) 0.07
Final TIMI flow, % (n/N)
0 1.4 (23/1662) 1.8 (32/1747) 0.30
I 0.5 (8/1662) 0.7 (13/1747) 0.33
II 6.3 (104/1662) 6.1 (106/1747) 0.82
III 91.9 (1527/1662) 91.4 (1596/1747) 0.58
POBA only, % (n/N) 3.5 (53/1528) 4.1 (66/1609) 0.35
ⱖ1 Stent implanted, % (n/N) 93.8 (1462/1559) 93.6 (1530/1634) 0.87
Stents implanted, n 1.5⫾0.8 1.5⫾0.9 0.19
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Total stent length, median (interquartile 24 (20–36) 24 (18–36) 0.78

range), mm
Any drug-eluting stent, % (n/N) 72.0 (1056/1466) 71.9 (1103/1534) 0.94
Any bare metal stent, % (n/N) 29.3 (430/1466) 29.2 (448/1534) 0.94
Aspiration device, % (n/N) 11.7 (179/1536) 11.1 (179/1616) 0.61
Thrombectomy device, % (n/N) 1.2 (18/1532) 0.9 (14/1610) 0.39
Glycoprotein IIb/IIIa inhibitors, % (n/N) 54.3 (845/1557) 57.6 (939/1631) 0.06
Bivalirudin, % (n/N) 52.4 (813/1551) 47.8 (779/1631) 0.009
Loading dose of clopidogrel given 98.7 (1537/1558) 97.8 (1598/1634) 0.07
during hospitalization, % (n/N)
300 mg 33.9 (520/1534) 35.2 (562/1597) 0.45
600 mg 64.7 (993/1554) 63.9 (102/1597) 0.64
Other 1.2 (19/1534) 0.2 (14/1597) 0.32
WBCc indicates white blood cell count; LAD, left anterior descending artery; Cx, circumflex artery; RCA, right
coronary artery; RIMA, right mammary artery; SVG, saphenous vein graft; TIMI, Thrombolysis in Myocardial Infarction;
and POBA, plain balloon angioplasty.

P⬍0.0001) and in those without measured LVEF (coeffi- tients with high baseline CPK levels (adjusted HR, 1.14;
cient, 100; 95% CI, 80 to 119; P⬍0.0001). Other independent 95% CI, 1.07 to 1.22; P⬍0.0001). In patients with low
correlates of peak CPK are shown in Table 4. baseline CPK, age was the only independent predictor of
In the receiver-operating characteristic analysis, base- 1-year cardiac mortality (adjusted HR, 1.05; 95% CI, 1.02
line CPK level was strongly related to 1-year cardiac to 1.09; P⫽0.0008). In patients with low CPK, WBCc
mortality (area under the curve, 0.64; 95% CI, 0.59 to 0.69; (adjusted HR, 1.1; 95% CI, 1.03 to 1.18; P⫽0.006), age
P⫽0.0002); the value of baseline CPK with the best (HR, 1.07; 95% CI, 1.04 to 1.10; P⬍0.0001), and renal
sensitivity and specificity was 195 U/L. With this cutoff insufficiency (HR, 3.57; 95% CI, 1.46 to 8.76; P⫽0.005)
value, patients were grouped into those with low baseline were the only independent predictors of 1-year all-cause
CPK (ⱕ195 U/L) and those with high baseline CPK (⬎195 death. The risk of 1-year cardiac mortality in patients with
U/L). As shown in Figure 4, high WBCc remained an high baseline CPK and low WBCc was similar to that of
independent predictor of 1-year cardiac mortality in pa- patients with low baseline CPK and a high WBCc.
 2834 Circulation June 21, 2011

Table 3. Thirty-Day and 1-Year Clinical Outcomes According

to Baseline White Blood Cell Count
WBCc ⬎11 000 WBCc ⱕ11 000
per 1 mm3 per 1 mm3
(n⫽1559), % (n) (n⫽1634), % (n) P
30-d Clinical outcomes
Death 3.0 (47) 1.7 (28) 0.02
Cardiac 2.8 (43) 1.7 (27) 0.03
Noncardiac 0.3 (4) 0.1 (1) 0.16
Reinfarction 2.3 (35) 1.7 (28) 0.28
Q wave 1.8 (27) 1.2 (20) 0.23
Non–Q wave 0.7 (10) 0.5 (8) 0.56
Death or reinfarction 4.9 (77) 3.1 (51) 0.009
Stroke 0.5 (7) 0.6 (9) 0.69
Major bleeding, non–CABG 7.4 (115) 7.2 (117) 0.84
related
Major bleeding, including 8.2 (127) 8.7 (141) 0.61
CABG related
Target vessel 2.8 (43) 2.2 (36) 0.32
revascularization
Any stent thrombosis 2.8 (41) 2.2 (34) 0.33
Definite 2.3 (35) 1.7 (27) 0.24
Probable 0.4 (6) 0.5 (7) 0.84
1-y Clinical outcomes
Death 5.0 (77) 3.1 (50) 0.007
Cardiac 3.5 (54) 2.3 (37) 0.04
Noncardiac 1.5 (23) 0.8 (13) 0.06
Downloaded from http://ahajournals.org by on February 27, 2020

Reinfarction 4.2 (64) 3.9 (63) 0.67

Q wave 2.4 (37) 1.9 (31) 0.34
Non–Q wave 2.0 (30) 2.2 (34) 0.79
Death or reinfarction 8.6 (133) 6.5 (105) 0.02
Stroke 1.1 (17) 0.7 (12) 0.28
Major bleeding, non–CABG 7.9 (122) 7.7 (125) 0.87
related
Major bleeding, including 8.9 (137) 9.3 (150) 0.69
CABG related
Target vessel 7.1 (106) 7.0 (112) 0.96
revascularization
Any stent thrombosis 4.0 (59) 3.4 (53) 0.42
Definite 3.3 (48) 2.7 (41) 0.34
Probable 0.5 (7) 0.5 (8) 0.86
Possible 0.3 (4) 0.3 (4) 0.94
WBCc indicates white blood cell count; CABG, coronary artery bypass graft
surgery. Event rates are presented as Kaplan-Meier survival estimates.
Figure 2. Time-to-event curves showing the rates of (A) all-
cause mortality, (B) cardiac mortality, and (C) noncardiac mor-
Discussion tality through the 1-year follow-up in patients with white blood
The principal findings of our study are the following: (1) The cell (WBC) count ⬎11 000 vs ⱕ11 000 per 1 mm3.
baseline WBCc drawn at the time of presentation with
STEMI was an independent predictor of infarct size as STEMI undergoing primary PCI,4 –7 possibly because of their
assessed by peak CPK level, as well as the 1-year rates of heterogeneity in terms of sample size, patient selection
all-cause mortality, cardiac mortality, noncardiac mortality, criteria, cutoff values for WBCc, and statistical methodolo-
and major bleeding after primary PCI; and (2) the correlation gies. The present analysis represents the largest study to date
between WBCc and subsequent mortality was independent of addressing the relation between WBCc and mortality, cardiac
baseline CPK and LVEF. mortality, noncardiac mortality, and major bleeding in pa-
Prior studies have reported discrepant results regarding the tients after primary PCI and strongly supports significant
association between WBCc and mortality in patients with prognostic utility for this measure.
 Palmerini et al WBC Count in STEMI 2835

Table 4. Independent Correlates of Peak Creatinine

Phosphokinase Levels in Patients Matched for Baseline
Creatinine Phosphokinase Levels
Model A Model B
Coefficient Coefficient
(95% CI) P (95% CI) P
WBCc 100 (80 –119) ⬍0.0001 89 (69 –109) ⬍0.0001
Baseline 111 (61–161) ⬍0.0001 91 (39–143) 0.0006
hemoglobin
level
Baseline CPK 74 (48–101) ⬍0.0001 68 (40–90) ⬍0.0001
Anterior MI 568 (427–709) ⬍0.0001 296 (141–451) 0.0002
Age 3 (⫺3–9) 0.36 2 (⫺4–8) 0.52
Male gender 266 (83–448) 0.004 236 (48–423) 0.01
Renal 132 (⫺292–557) 0.54 152 (⫺309–614) 0.52
insufficiency
TIMI grade 1231 (1088–1374) ⬍0.0001 1110 (961–1259) ⬍0.0001
0/1 flow
LVEF ⫺33 (⫺40–⫺26) ⬍0.0001
CI indicates confidence interval; WBCc, white blood cell count; CPK,
creatinine phosphokinase; MI, myocardial infarction; TIMI, Thrombolysis in
Myocardial Infarction; and LVEF, left ventricular ejection fraction. Model A was
formed from the entire cohort of matched patients; model B was formed from
the cohort of matched patients who had a baseline LVEF measured. WBCc was
used as continuous data.

baseline CPK), WBCc remained an independent predictor of

1-year cardiac mortality. Even after patients were stratified
for baseline CPK levels, those with high CPK and high
Downloaded from http://ahajournals.org by on February 27, 2020

WBCc had a significantly higher mortality than those with

high CPK and low WBCc. Patients with a high baseline CPK
and low WBCc had a rate of 1-year cardiac mortality similar
to that of patients with low baseline CPK and high WBCc.
The relationship between the baseline WBCc and subsequent
cardiac mortality was also independent of baseline LVEF, an
important prognostic determinant in patients with STEMI
undergoing primary PCI.15 These data collectively suggest
that a high level of systemic inflammation in the early phase

Figure 3. Time-to-event curves showing the rates of (A) all-

cause mortality, (B) cardiac mortality, and (C) noncardiac mor-
tality through 1-year follow-up in patients stratified by quartiles
of white blood cell (WBC) count.

A novel finding from our study is that the association

between WBCc and cardiac mortality was independent of
baseline CPK levels, an indicator of the extent of myonecro-
Figure 4. Time-to-event curves showing the rates of 1-year car-
sis at hospital admission (before reperfusion therapy).13,14 diac mortality according to baseline creatinine phosphokinase
The correlation between WBCc and baseline CPK was poor, (CPK) levels (⬎195 and ⱕ195 U/L) and white blood cell (WBC)
and after correction for measured confounders (including count (⬎11 000 and ⱕ11 000 per 1 mm3).
 2836 Circulation June 21, 2011

of STEMI (as reflected by the WBCc) is strongly associated coronary syndromes undergoing PCI reported that WBCc and
with 1-year cardiac mortality. not C-reactive protein was an independent predictor of 1-year
Whether an elevated WBCc is directly responsible for the mortality.4 Baseline data on corticosteroid and statin usage,
poor prognosis of patients with STEMI after primary PCI is which may affect WBCc, were not collected. Finally, the
unknown. Leukocytes may have a prothrombotic effect by present study demonstrates a strong association between an
producing tissue factor,16,17 by providing a catalytic surface elevated baseline WBCc, final infarct size, and subsequent
for thrombin generation,18 and/or by forming platelet- mortality, but it does not prove causality. This issue might be
leukocyte aggregates.19 An elevated WBCc may also result in addressed in future studies investigating the effect of thera-
diminished microcirculatory perfusion by adhesion, aggrega- pies that decrease WBCc on final infarct size and clinical
tion, platelet recruitment,20 and release of proinflammatory outcomes. Coller29 reviewed the potential risks and benefits
and vasculotoxic factors.21 These effects may contribute to of WBCc-lowering drugs in this context.
reperfusion injury22 and subsequent extension of myocardial
necrosis. The present study is consistent with this mechanism Sources of Funding
in that a high WBCc was an independent determinant of peak This trial was sponsored by the Cardiovascular Research Foundation
CPK, a direct indicator of final infarct size.12 Moreover, with unrestricted grant support from Boston Scientific Corp and The
leukocyte-depleting filters may attenuate myocardial injury Medicines Company.
during elective coronary artery bypass surgery,23 and several
experimental studies have suggested a beneficial effect of
Disclosures
Dr Mehran has received research grant from Bristol Myers Squibb/
antiinflammatory therapies in reducing reperfusion injury,24 Sanofi; has received honoraria from AstraZeneca, Cordis, and The
although clinical evidence remains to be demonstrated. How- Medicines Company; and has been a consultant for Abbott Vascular,
ever, causality cannot be proven from the present study, and Cardiva, and Regado Biosciences. Dr Dangas has received honoraria
it is unknown whether an elevated baseline WBCc is simply from The Medicine Company. Dr Nikolsky has received lecture fees
from Abbott. Dr Witzenbichler is on the speakers’ bureau of The
a marker for unmeasured confounders also correlated with
Medicines Company. Dr Guagliumi has been a consultant from
subsequent mortality in STEMI. In this regard, a novel Boston Scientific and Volcano and received research grant support
finding of the present study is the observation that a high from LightLab, Medtronic Vascular, and Boston Scientific. Dr
WBCc was an independent predictor of 1-year noncardiac Dudek is on the speakers’ bureau and is consultant for Nycomed. H.
mortality. To the best of our knowledge, this has not Parise is employed by the Cardiovascular Research Foundation. Dr
Brodie is on the speakers’ bureau for The Medicine Company and
previously been reported. The mechanisms underlying this MEDRAD/Possis. Dr Lansky has received research grants from The
association are unclear and require further study. Medicines Company, Cordis, Boston Scientific, Medtronic, and
Downloaded from http://ahajournals.org by on February 27, 2020

Another noteworthy finding from the present study was the Abbott. Dr Stone has served on the scientific advisory boards for and
independent association between WBCc and major bleeding. has received honoraria from Abbott Vascular and Boston Scientific
Ndrepepa et al4 have recently reported an association between and is a consultant to The Medicines Company, Merck, Bristol-
Meyers-Squibb, AstraZeneca, and Eli Lilly. The other authors report
high WBCc and bleeding in patients presenting with acute no conflicts.
coronary syndromes. We have previously reported this asso-
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CLINICAL PERSPECTIVE
The relationship between the baseline white blood cell count and mortality in patients with ST-segment– elevation acute
myocardial infarction treated with percutaneous coronary intervention is poorly understood. Furthermore, whether there is
a relationship between white blood cell count and the risk of noncardiac mortality, bleeding, and infarct size after
percutaneous coronary intervention is unknown. From the large-scale Harmonizing Outcome With Revascularization and
Stent in Acute Myocardial Infarction (HORIZONS-AMI) trial, we have demonstrated that (1) the baseline white blood cell
count drawn at the time of presentation with ST-segment– elevation acute myocardial infarction was an independent
predictor of the 1-year rates of all-cause mortality, cardiac mortality, noncardiac mortality, and major bleeding after
primary percutaneous coronary intervention and (2) elevated white blood cell count at baseline was also an independent
determinant of peak creatinine phosphokinase (a direct indicator of infarct size) after primary percutaneous coronary
intervention for ST-segment– elevation acute myocardial infarction. Therefore, the baseline white blood cell count, which
is routinely obtained at the time of admission in patients with ST-segment– elevation acute myocardial infarction, is an
important prognostic predictor of infarct size, major bleeding, and cardiac and noncardiac mortality after primary
percutaneous coronary intervention. Further studies are required to determine whether these associations are causal.