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ACAD EMERG MED d October 2004, Vol. 11, No. 10 d www.aemj.org 1049

The Association between White Blood Cell Count


and Acute Myocardial Infarction In-hospital Mortality:
Findings from the National Registry of Myocardial
Infarction
Mary Grzybowski, PhD, MPH, Robert D. Welch, MD, Lori Parsons, BS,
Chiadi E. Ndumele, MD, Edmond Chen, MD, Robert Zalenski, MD, Hal V. Barron, MD
Abstract
Objectives: Although cross-sectional and prospective stud- quartile showed strong associations with in-hospital mor-
ies have shown that the white blood cell (WBC) count is tality among the entire population and by gender: 4.09 (95%
associated with long-term mortality for patients with confidence interval [95% CI] = 3.83 to 4.73) for all patients,
ischemic heart disease, the role of the WBC count as an 4.31 (95% CI = 3.93 to 4.73) for men, and 3.65 (95% CI = 3.32
independent predictor of short-term mortality in patients to 4.01) for women. Following adjustment for covariates, the
with acute myocardial infarction (AMI) has not been magnitude of the ORs attenuated, but the ORs remained
examined as extensively. The objective of this study was to highly significant (OR, 2.71 [95% CI = 2.53 to 2.90] for all
determine whether the WBC count is associated with in- patients; OR, 2.87 [95% CI = 2.59 to 3.19] for men; OR, 2.61
hospital mortality for patients with ischemic heart disease [95% CI = 2.36 to 2.99] for women). Reperfused patients had
after controlling for potential confounders. Methods: From consistently lower in-hospital mortality rates for all patients
July 31, 2000, to July 31, 2001, the National Registry of and by gender (p , 0.0001). Conclusions: The WBC count is
Myocardial Infarction 4 enrolled 186,727 AMI patients. A an independent predictor of in-hospital AMI mortality and
total of 115,273 patients were included in the analysis. may be useful in assessing the prognosis of AMI in
Results: WBC counts were subdivided into intervals of conjunction with other early risk-stratification factors.
1,000/mL, and in-hospital mortality rates were determined Whether elevated WBC count is a marker of the inflammatory
for each interval. The distribution revealed a J-shaped curve. process or is a direct risk factor for AMI remains unclear.
Patients with WBC counts .5,000/mL were subdivided into Given the simplicity and availability of the WBC count, the
quartiles, whereas patients with WBC counts ,5,000/mL authors conclude that the WBC count should be used in
were assigned to a separate category labeled ‘‘subquartile’’ conjunction with other ancillary tests to assess the prognosis
and were analyzed separately. A linear increase in in- of a patient with AMI. Key words: WBC count; in-hospital
hospital mortality by WBC count quartile was found. The mortality; epidemiology; myocardial infarction; predictor.
unadjusted odds ratio (OR) for the fourth versus the first ACADEMIC EMERGENCY MEDICINE 2004; 11:1049–1060.

Elevated white blood cell (WBC) counts typically development of an atherosclerotic plaque rupture,
indicate infection and inflammation but also play and thrombosis.2,4–6 This suggests that elevated
a role in vascular injury and atherogenesis,1–3 the WBC counts may both serve as a biomarker for, and
be a risk factor for, cardiac disease.
A number of prospective epidemiologic studies
From the Department of Emergency Medicine, Wayne State Uni- have demonstrated that an elevated WBC count is
versity School of Medicine (MG, RDW, RZ), Detroit, MI; Ovation
Research Group (LP), Seattle, WA; Department of Medical Affairs,
associated with risk factors for coronary heart dis-
Genentech Inc. (EC, HVB), South San Francisco, CA; Brigham ease,7–9 acute myocardial infarction (AMI),9–13 coro-
and Women’s Hospital (CEN), Boston, MA; and Departments nary artery disease and related events,14–16 all-cause
of Epidemiology and Biostatistics and Medicine, University of mortality,11,17,18 and long-term mortality in patients
California (HVB), San Francisco, CA. with known coronary artery disease.14
Received January 16, 2004; revision received April 15, 2004;
accepted June 8, 2004.
While an elevated WBC count has been shown to be
The National Registry of Myocardial Infarction is supported by an independent predictor of long-term cardiac mor-
Genentech. Drs. Zalenski and Barron are paid consultants to tality and all-cause mortality, there have been few
Genentech. studies19–21 examining the association between ele-
Address for correspondence and reprints: Mary Grzybowski, PhD, vated WBC count and early death. The purpose of this
MPH, Wayne State University School of Medicine, 6G University
Health Center, 4201 St. Antoine, Detroit, MI 48201. Fax: 313-993-
study was to determine whether the WBC count at
7703; e-mail: mgrzyb@med.wayne.edu. presentation is associated with in-hospital mortality
doi:10.1197/j.aem.2004.06.005 in AMI patients after controlling for demographics,
1050 Grzybowski et al. d WBC COUNT AND MI MORTALITY

medical history, presenting clinical characteristics as TABLE 1. Distribution of National Registry of


well as medications given within 24 hours of pre- Myocardial Infarction 4 Final Study Population by
sentation, and diagnostic and therapeutic procedures Geographic Regions (n = 115,273)
administered during hospitalization. U.S. Census Region Percent
East (10.9%)
METHODS New England 3.5
Middle Atlantic 7.4
Study Design. The National Registry of Myocardial South (30.9%)
Infarction (NRMI)22 is an observational study of East South Central 6.4
hospitalized patients with confirmed AMI that com- West South Central 8.2
South Atlantic 16.3
menced in 1990. NRMI collects data in order to
Midwest (30.7%)
describe national AMI presentation, treatment inter- East North Central 20.7
ventions, practice patterns, and patient outcomes. West North Central 10.0
Since its inception, NRMI has launched four multi- West (27.5%)
center observational studies. The study population for Mountain 8.0
Pacific 19.5
the current investigation was from the NRMI 4
database. Data for the current study were collected
from 1,189 hospitals between July 31, 2000, and July
31, 2001, in all 50 states in the United States. All study health care facilities because the outcome results
site coordinators were formally trained and given were not consistently available at nonstudy sites,
a manual of operations to correctly abstract the data 2) patients who presented with cardiogenic shock or
from the medical records, inclusive of electrocardio- had missing heart failure data, 3) patients who did not
gram readings, and transcribe the data onto case have the WBC count documented in the medical chart,
report forms. The case report forms were then and 4) patients who did not have a primary diagnosis
forwarded to StatProbe, Inc. (Lexington, KY), where of AMI. The latter criterion eliminated patients with
the data underwent double data entry or electronic other primary illnesses that may have resulted in
scanning as well as multiple electronic checks for altered WBC counts.
accuracy. Any unrecorded fields or inconsistencies
were flagged and returned to the site for clarification Data Collection and Analysis. Independent varia-
and correction. NRMI collection procedures have bles included WBC count at admission, demograph-
been previously reported.23 Individual sites were ics, medical history, presenting clinical characteristics,
responsible for compliance with institutional review medications administered within 24 hours of pre-
board protocols regarding the collection and use of sentation, diagnostic studies used, and therapeutic
data for research purposes. procedures. Age, systolic blood pressure, heart rate,
and WBC count were analyzed as both continuous
Study Population. Adult AMI patients eligible for and categorical variables. Values for continuous var-
study inclusion (n = 186,727) were obtained from the iables outside the following ranges were set to
NRMI 4 database between July 31, 2000, and July 31, missing: WBC count equal to 0 or .30 (103/mL),
2001. Hospital participation varied by geographic systolic blood pressure ,1 mm Hg or .250 mm Hg,
location, ranging from 10.9% in the East to 30.9% in and heart rate ,1 beat/min or .220 beats/min. For
the South (Table 1). The diagnosis of myocardial the multivariate regression, all independent variables
infarction was based on a patient history suggestive were categorical (yes or no); elder age was defined as
of AMI accompanied by at least one of the following: older than 75 years, systolic hypotension as ,90 mm
1) a total creatine kinase (CK) or CK-MB value greater Hg, and tachycardia as .100 beats/min. Race was
than or equal to twice the upper limit of normal collapsed into a dichotomous variable (white or non-
(normal as defined by an individual hospital’s labo- white). Heart failure was classified as evidence of
ratory definition; 2) electrocardiographic evidence clinical heart failure (yes [Killip classes II and III] or
indicative an AMI, including new Q-wave and ST no [Killip class I]). The dependent variable was in-
elevation; and 3) in the event the CK, CK-MB, or hospital mortality.
electrocardiogram data were unavailable/inconclu- The collected data were first examined to determine
sive, alternative cardiac markers, nuclear medicine differences between patients who did and did not
testing, echocardiographic evidence, or autopsy evi- meet eligibility for inclusion. Chi-square tests were
dence indicative of AMI. Additionally, a discharge used to determine frequency differences in selected
diagnosis of AMI (International Classification of Dis- characteristics between the groups.24
eases, Ninth Revision, Clinical Modification code White blood cell counts were subdivided into
410.X1) must have been present to qualify for entry intervals of 1,000/mL, and in-hospital mortality rates
into the NRMI 4. Exclusion criteria included the were determined for each interval. The distribution
following: 1) patients who were transferred to other revealed a J-shaped curve (Figure 1). In-hospital
ACAD EMERG MED d October 2004, Vol. 11, No. 10 d www.aemj.org 1051

heart failure, active malignancy, current smoking


status, chronic obstructive pulmonary disease, diabe-
tes, stroke, and prior coronary artery bypass graft
[CABG] surgery and percutaneous coronary interven-
tion [PCI]), presenting clinical characteristics (evi-
dence of clinical heart failure, systolic hypotension,
tachycardia, ST elevation or left bundle branch block;
infarct location [anterior/septal or neither]), transfer
status (having been transferred from a different in-
stitution), medications administered within 24 hours
of arrival (aspirin, beta-blockers, angiotensin-convert-
Figure 1. In-hospital mortality by white blood cell count ing enzyme inhibitors, calcium channel blockers, and
(1,000/mL). glycoprotein IIa/IIIb inhibitors), initial hospital di-
agnostic test (cardiac catheterization), and hospital
mortality was 28.6% in the lowest interval (0.1–1.0 3 therapeutic procedures (initial reperfusion and non-
103/mL), decreased to 3.7% when the WBC count was primary CABG surgery and PCI). The c statistics for
.5–6 3 103/mL, and peaked at 34.8% when the WBC covariate-specific fitted models were computed to
count was .25–26 3 103/mL. Patients with WBC indicate the ability to discriminate between in-hospi-
counts .5,000/mL were subdivided into quartiles, tal death and survival. Because of reports of gender-
whereas patients with WBC counts ,5,000/mL were specific differences regarding demographics, medical
assigned to a separate category labeled ‘‘subquartile.’’ history, and treatment in AMI patients, adjusted in-
Classifying patients in this manner ensured that the hospital mortality rates were calculated for all
first quartile, which had the least mortality, would patients and then by gender using logistic regres-
serve as the appropriate reference group for compar- sion.27–33 Logistic regression is appropriate in esti-
ing the odds of death. Four indicator variables were mating the association between a binary dependent
created to assess comparisons for the subquartile and variable and a primary independent variable while
quartiles 2, 3, and 4 relative to quartile 1. Baseline adjusting for at least one potential confounder. Logis-
differences between quartiles were compared using tic regression requires only minimal assumptions
analysis of variance and chi-square tests for continu- of the distribution properties of the independent
ous variables and categorical variables, respectively.24 variables and allows for estimation of the OR via
The Cochran–Mantel–Haenszel test was used to de- exponentiation of the b coefficient.34 Appropriate
termine proportional trends for selected independent regression diagnostics were performed to confirm
variables and in-hospital mortality by WBC count the validity of the multivariate models and included
quartile. Chi-square and trend tests excluded patients testing for outliers and assessing the predicted out-
with WBC counts in the subquartile group because comes by actual outcomes via classification tables.34,35
they may have represented a special subpopulation All reported p-values are two-tailed. An a of 0.05
(e.g., patients in the subquartile group had the highest was considered significant. Due to the extremely large
proportion of active malignancy history). We also number of patients in this investigation, care must
evaluated the association between reperfusion status be used in interpreting the clinical importance of all
and in-hospital mortality by WBC count quartile p-values. All statistical analyses were performed
before and after adjusting for age, gender, and race. using SAS version 8.2 (SAS Institute, Inc., Cary,
Maximum likelihood estimates of the unadjusted NC).36
and adjusted odds ratios (ORs) were calculated using
simple and multivariate logistic regression, respec-
tively, to estimate the association between in-hospital
RESULTS
mortality and WBC count quartile indicator variables. Of 186,727 eligible study patients, a total of 71,454
Variables considered for entry in the multivariate patients (38.3%) were excluded from analysis for
models were based on the significance of bivariate several reasons. We excluded 38,479 patients who
associations and empirical knowledge. Although geo- were transferred from NRMI-participating hospitals
graphic variations in the treatment of AMI have been to other health care facilities, 4,967 patients who
demonstrated in the literature,25,26 we a priori chose presented with cardiogenic shock or had missing
not to adjust for geographic region because we heart failure data, 6,204 patients who did not have
suspected that region would be highly correlated WBC count data, and 21,804 patients who did not
with several of the predictor variables. Variables were have a primary diagnosis of AMI. Therefore, 115,273
entered into the models in successive covariate- patients were included in this analysis.
specific blocks: demographics (age, gender, and race), Mean WBC counts, gender distributions, or race
medical history (chronic renal failure, previous AMI, distributions did not differ between patients who
hypertension, cerebrovascular disease, congestive were and were not included in the final study
1052 Grzybowski et al. d WBC COUNT AND MI MORTALITY

population. Patients included were more likely to be among women than men (10.8% vs. 7.3%; OR, 1.55;
elders than those excluded (35.9% vs. 38.4%; OR, 1.11; 95% CI = 1.49 to 1.61). Overall significant differences
95% confidence interval [95% CI] = 1.09 to 1.13) and were found for all characteristics by WBC count
more likely to have been transferred to an NRMI- quartile (Tables 2 and 3).
participating hospital than those excluded (14.3% vs. Trend tests showed that the proportion of patients
26.7%; OR, 2.18; 95% CI = 1.13 to 2.24). Those included increased by WBC count quartile for patients with the
were also more likely to have a medical history of following demographic and medical history charac-
myocardial infarction (25.1% vs. 22.7%; OR, 1.14; 95% teristics (Table 2): white race, smoking, and history of
CI = 1.11 to 1.16). Fewer systolic hypotensive patients chronic illnesses, including congestive heart failure,
were included in the analysis (3.4% vs. 4.8%; OR, 0.70; chronic obstructive pulmonary disease, chronic renal
95% CI = 0.66 to 0.73). insufficiency, diabetes, peripheral vascular disease,
The mean (6SD) age of the final study population and stroke. Inverse associations were found between
was 68.8 (614.3) years, and the mean (6SD) WBC the following characteristics and WBC count quartile:
count was 10.4 (64.0) 3 103/mL. The mean (6SD) male gender and history of chronic illnesses, includ-
heart rate was 86.3 (623.7) beats/min, and the mean ing angina, hypercholesterolemia, hypertension, myo-
(6SD) systolic blood pressure was 144.1 (632.0) mm cardial infarction, and history of CABG surgery and
Hg. Most patients included in the study were white PCI.
(84%), and almost 60% were men. The overall in- Mean heart rate increased from the first to the
hospital mortality rate was 8.7% (95% CI = 8.53% to fourth WBC count quartile (82.3 to 92.8 beats/min;
8.86%). The in-hospital mortality rate was higher p , 0.0001), whereas mean systolic blood pressure

TABLE 2. Demographic and Medical History Characteristics by White Blood Cell Count Quartile
Subquartile Quartile 1 Quartile 2 Quartile 3 Quartile 4
All Quartiles ,5.0 3 103/ 5.0–7.7 3 103/ 7.8–9.7 3 103/ 9.8–12.4 3 103/ $12.5 3 103/ p-
Characteristic (n = 115,273) mL (n = 3,544) mL (n = 27,268) mL (n = 28,446) mL (n = 28,217) mL (n = 27,798) value
Demographics
Mean age,
yr (SD) 68.8 (14.3) 70.6 (13.5) 69.6 (13.6) 68.5 (14.0) 67.8 (14.5) 69.0 (15.1) ,0.0001
Age 75 years
or older 44,244 (38.4) 1,508 (42.6) 10,799 (39.6) 10,479 (36.8) 10,071 (35.7) 11,387 (41.0) ,0.0001
Male gender 68,813 (59.7) 2,154 (60.8) 17,091 (62.7) 17,395 (61.2) 16,951 (60.1) 15,222 (54.8) ,0.0001
White race 96,797 (84.0) 2,628 (74.2) 22,258 (81.7) 23,949 (84.3) 24,043 (85.3) 23,919 (86.1) ,0.0001
Medical history
Cigarette
smoker 29,848 (25.9) 497 (14.0) 4,801 (17.6) 7,111 (25.0) 8,758 (31.0) 8,681 (31.2) ,0.0001
Active
malignancy 2,545 (2.2) 248 (7.0) 564 (2.1) 514 (1.8) 514 (1.8) 705 (2.5) ,0.0001
Angina 14,633 (12.7) 521 (14.7) 4,020 (14.7) 3,812 (13.4) 3,391 (12.0) 2,889 (10.4) ,0.0001
Congestive
heart failure 19,399 (16.8) 595 (16.8) 3,949 (14.5) 4,322 (15.2) 4,662 (16.5) 5,871 (21.1) ,0.0001
Chronic obstructive
pulmonary disease 17,633 (15.3) 453 (12.8) 3,417 (12.5) 3,936 (13.8) 4,320 (15.3) 5,507 (19.8) ,0.0001
Cerebrovascular
disease 5,922 (5.1) 177 (5.0) 1,353 (5.0) 1,397 (4.9) 1,410 (5.0) 1,585 (5.7) ,0.0001
Chronic renal
insufficiency 11,279 (9.8) 369 (10.4) 2,372 (8.7) 2,503 (8.8) 2,632 (9.3) 3,403 (12.2) ,0.0001
Diabetes 34,242 (29.7) 953 (26.9) 7,443 (27.3) 8,142 (28.6) 8,502 (30.1) 9,202 (33.1) ,0.0001
Hypercholesterolemia 40,497 (35.1) 1,148 (32.4) 10,399 (38.1) 10,428 (36.7) 10,086 (35.7) 8,436 (30.3) ,0.0001
Hypertension 69,449 (60.2) 2,178 (61.5) 16,670 (61.1) 17,194 (60.4) 16,867 (59.8) 16,540 (59.5) ,0.001
Myocardial infarction 28,903 (25.1) 986 (27.8) 7,392 (27.1) 7,173 (25.2) 6,845 (24.3) 6,507 (23.4) ,0.0001
Peripheral vascular
disease 9,963 (8.6) 297 (8.4) 2,092 (7.7) 2,326 (8.2) 2,433 (8.6) 2,815 (10.1) ,0.0001
Stroke 11,319 (9.8) 329 (9.3) 2,385 (8.7) 2,624 (9.2) 2,693 (9.5) 3,289 (11.8) ,0.0001
History of therapeutic
procedures
Coronary artery
bypass graft surgery 16,571 (14.4) 611 (17.2) 4,896 (18.0) 4,339 (15.3) 3,597 (12.7) 3,128 (11.3) ,0.0001
Percutaneous
coronary
intervention 13,938 (12.1) 499 (14.1) 3,922 (14.4) 3,631 (12.8) 3,239 (11.5) 2,647 (9.5) ,0.0001
Data are presented as the number (percent) unless otherwise indicated. p-value for overall difference represents differences by
quartiles only (excludes subquartile). All tests for trend were highly significant (p , 0.0001) except age 75 years or older, active
malignancy, and cerebrovascular disease.
ACAD EMERG MED d October 2004, Vol. 11, No. 10 d www.aemj.org 1053

TABLE 3. Clinical Presenting Characteristics, Medications Administered within 24 Hours, Initial Diagnostic
Tests Administered, and Therapeutic Procedures by White Blood Cell Count Quartile
Subquartile Quartile 1 Quartile 2 Quartile 3 Quartile 4
All Quartiles ,5.0 3 103/ 5.0–7.7 3 103/ 7.8–9.7 3 103/ 9.8–12.4 3 103/ $12.5 3 103/
Characteristic (n = 115,273) mL (n = 3,544) mL (n = 27,268) mL (n = 28,446) mL (n = 28,217) mL (n = 27,798) p-value
Clinical presentation
Heart rate
.100 beats/min 26,486 (23.3) 643 (18.3) 4,366 (16.2) 5,311 (18.9) 6,513 (23.4) 9,653 (35.3) ,0.0001
Systolic blood
pressure
,90 mm Hg 3,843 (3.4) 126 (3.6) 583 (2.2) 733 (2.6) 876 (3.1) 1,525 (5.6) ,0.0001
Killip class II/III 27,109 (23.5) 648 (18.3) 4,629 (17.0) 5,542 (19.5) 6,578 (23.3) 9,712 (34.9) ,0.0001
ECG reading
Normal 8,463 (7.4) 390 (11.1) 2,632 (9.7) 2,249 (7.9) 1,901 (6.8) 1,291 (4.7) ,0.0001
ST elevation 37,625 (32.8) 734 (20.8) 6,837 (25.2) 8,949 (31.6) 10,333 (36.8) 10,772 (38.9) ,0.0001
ST depression 33,705 (29.4) 833 (23.6) 6,983 (25.7) 8,102 (28.6) 8,773 (31.2) 9,014 (32.6) ,0.0001
T-wave inversion 16,318 (14.2) 517 (14.7) 4,145 (15.3) 4,194 (14.8) 3,925 (14.0) 3,537 (12.8) ,0.0001
Nonspecific ST/
T waves 36,549 (31.9) 1,316 (37.3) 9,715 (35.8) 9,255 (32.7) 8,456 (30.1) 7,807 (28.2) ,0.0001
Q wave 10,041 (8.8) 181 (5.1) 1,764 (6.5) 2,330 (8.2) 2,753 (9.8) 3,013 (10.9) ,0.0001
LBBB (new/unknown) 4,491 (3.9) 121 (3.4) 840 (3.1) 1,001 (3.5) 1,042 (3.7) 1,487 (5.4) ,0.0001
LBBB (old) 2,622 (2.3) 76 (2.2) 629 (2.3) 593 (2.1) 632 (2.2) 692 (2.5) ,0.05
RBBB 7,145 (6.2) 234 (6.6) 1,772 (6.5) 1,685 (6.0) 1,683 (6.0) 1,771 (6.4) ,0.01
Other ECG reading 22,153 (19.3) 818 (23.2) 5,298 (19.5) 5,256 (18.6) 5,153 (18.3) 5,628 (20.3) ,0.0001
Anterior/septal
infarct 24,483 (21.2) 621 (17.5) 4,866 (17.9) 5,721 (20.1) 6,398 (22.7) 6,877 (24.7) ,0.0001
Transferred in 30,775 (26.7) 855 (24.1) 7,231 (26.5) 7,888 (27.7) 7,817 (27.7) 6,984 (25.1) ,0.0001
Medications
administered
Aspirin 97,654 (84.7) 2,911 (82.1) 23,551 (86.4) 24,652 (86.7) 24,190 (85.7) 22,350 (80.4) ,0.0001
Angiotensin-
converting enzyme
inhibitors 39,632 (34.4) 1,179 (33.3) 9,253 (33.9) 9,888 (34.8) 9,884 (35.0) 9,428 (33.9) ,0.01
Antiarrhythmics 10,160 (8.8) 216 (6.1) 1,796 (6.6) 2,302 (8.1) 2,711 (9.6) 3,135 (11.3) ,0.0001
Beta-blockers 77,451 (67.2) 2,343 (66.1) 18,868 (69.2) 19,952 (70.1) 19,270 (68.3) 17,018 (61.2) ,0.0001
Calcium channel
blockers 16,196 (14.1) 549 (15.5) 4,084 (15.0) 3,912 (13.8) 3,811 (13.5) 3,840 (13.8) ,0.0001
Digoxin 12,536 (10.9) 372 (10.5) 2,538 (9.3) 2,803 (9.9) 3,035 (10.8) 3,788 (13.6) ,0.0001
Diuretics 35,868 (31.1) 1,091 (28.8) 7,176 (26.3) 7,859 (27.6) 8,762 (31.1) 11,052 (39.8) ,0.0001
Glycoprotein
IIa/IIIb inhibitors 28,217 (24.5) 640 (18.1) 6,553 (24.0) 7,267 (25.5) 7,536 (26.7) 6,221 (22.4) ,0.0001
Lipid-lowering
agent 5,286 (4.6) 183 (5.2) 1,441 (5.3) 1,371 (4.8) 1,241 (4.4) 1,050 (3.8) ,0.0001
Statins 26,802 (23.3) 777 (21.9) 6,914 (25.4) 6,961 (24.5) 6,764 (24.0) 5,386 (19.4) ,0.0001
Initial diagnostics
Cardiac
catheterization 42,105 (36.5) 1,252 (35.3) 10,927 (40.1) 11,036 (38.8) 10,386 (36.8) 8,504 (30.6) ,0.0001
Initial reperfusion
therapy* 30,954 (27.0) 573 (16.3) 5,928 (21.8) 7,704 (27.2) 8,694 (30.9) 8,055 (29.1) ,0.0001
Thrombolytics 17,752 (15.4) 321 (9.1) 4,195 (15.5) 4,338 (15.3) 5,006 (18.1) 17,752 (15.5)
PCI (with/without
stent) 12,596 (10.9) 245 (7.0) 2,516 (9.3) 3,217 (11.4) 3,526 (12.6) 3,092 (11.2)
Immediate CABG
surgery 592 (0.5) 7 (0.2) 127 (0.5) 146 (0.5) 160 (0.6) 152 (0.5)
Nonprimary therapeutic
procedures
PCI 28,939 (25.1) 819 (23.1) 7,386 (27.1) 7,699 (27.1) 7,375 (26.1) 5,660 (20.4) ,0.0001
CABG surgery 12,641 (11.0) 302 (8.5) 3,267 (12.0) 3,478 (12.2) 3,098 (11.0) 2,496 (9.0) ,0.0001
Data are presented as number (percent). p-value for overall difference represents differences by quartiles only (excludes
subquartile). All tests for trend were highly significant (p , 0.0001) except old LBBB, RBBB, other ECG reading, angiotensin-converting
enzyme inhibitors, beta-blockers, calcium channel blockers, and glycoprotein IIa/IIIb inhibitors.
CABG = coronary artery bypass graft; ECG = electrocardiogram; LBBB = left bundle branch block; PCI = percutaneous coronary
intervention; RBBB = right bundle branch block.
*Includes at least one reperfusion strategy: thrombolytics, PCI, and immediate CABG.
1054 Grzybowski et al. d WBC COUNT AND MI MORTALITY

decreased (from 147.8 to 139.1 mm Hg; p , 0.0001). those not receiving reperfusion were more likely to
Table 3 includes the associations between presenting die while hospitalized (1.84 [95% CI = 1.74 to 1.94] for
clinical characteristics, medications administered all patients, 2.24 [95% CI = 2.08 to 2.24] for men, and
within 24 hours of arrival, and diagnostic tests and 1.27 [95% CI = 1.8 to 3.7] for women). Men, compared
therapeutic procedures used during hospitalization. with women, were 1.8 times more likely to undergo
There were positive linear trends in the proportion of initial reperfusion (95% CI of OR = 1.76 to 1.86).
patients and WBC count quartiles for the following Among reperfused patients, men were more likely
presenting clinical characteristics: tachycardia, systolic to survive to discharge (OR, 2.33; 95% CI = 2.13 to
hypotension, clinical signs of heart failure, and elec- 2.58). Because NRMI results have shown that out-
trocardiogram readings including ST depression, Q comes of reperfusion,37 coronary angiography,37 and
wave, new/unknown left bundle branch block, and immediate mechanical reperfusion38 differ by age and
evidence of an anterior/septal myocardial infarction. gender, and given our findings of significant differ-
Inverse linear trends were found among patients ences in age, gender, and race by WBC count quartile,
presenting with normal electrocardiogram readings, we calculated the ORs for in-hospital mortality and
T-wave inversions, and nonspecific ST/T waves. With reperfusion status before and after controlling for age,
regard to medications administered, positive linear gender, and race for all quartiles and the subquartile.
trends were noted in patients given antiarrhythmics, Figure 2 clearly illustrates that, compared with pa-
digoxin, and diuretics, whereas inverse trends were tients receiving initial reperfusion, patients not re-
observed in those given aspirin, lipid-lowering agents, ceiving reperfusion were significantly more likely to
and statins. Initial reperfusion was positively associ- die, except for those in the subquartile group (OR,
ated with WBC count quartile. Inverse linear trends 1.22; 95% CI = 0.88 to 1.8). Although the strength of
were also found between WBC count quartile and the associations decreased following adjustment, the
patients having had a diagnostic cardiac catheteriza- ORs retained their statistical significance, except for
tion and nonprimary therapeutic procedures, includ- patients in quartile 1. Both unadjusted and adjusted
ing CABG surgery and PCI during hospitalization. analyses showed that the ORs increased in magnitude
In-hospital mortality increased as WBC count quar- from WBC count quartile 1 to 4.
tile increased among all patients, by gender, and by To investigate the independent association of high
initial reperfusion status (Table 4). Lower prevalences WBC count and in-hospital mortality after controlling
of in-hospital mortality were consistently found in for potential confounding factors, multivariate mod-
male patients for all quartiles and the subquartile. els were developed for WBC count quartile (4 vs. 1)
In-hospital mortality in the subquartile group gener- alone, for WBC count adjusting for covariate-specific
ally was in the midrange between quartiles 2 and 3. blocks, and for WBC count adjusting for therapeutic
Compared with patients receiving initial reperfusion, procedures. Results are presented for the entire data

TABLE 4. In-hospital Mortality among All Patients and by Gender, Initial Reperfusion Status, and White
Blood Cell Count Quartile
All Subquartile Quartile 1 Quartile 2 Quartile 3 Quartile 4
Characteristic Quartiles ,5.0 3 103/mL 5.0–7.7 3 103/mL 7.8–9.7 3 103/mL 9.8–12.4 3 103/mL $12.5 3 103/mL p-value
In-hospital mortality
(n = 115,273) 8.7 7.1 4.4 6.2 8.4 15.9 ,0.0001
Gender
Male
(n = 68,813) 7.3 6.3 3.6 5.2 7.3 13.9 ,0.0001
Female
(n = 46,460) 10.8 8.4 5.8 7.7 10.2 18.4 ,0.0001
Initial reperfusion
status
No (n = 83,775) 9.9 7.4 4.7 7.0 10.0 18.6 ,0.0001
Male
(n = 46,920) 8.7 7.0 4.0 6.3 9.2 17.6 ,0.0001
Female
(n = 36,855) 11.3 8.0 5.8 8.0 10.9 19.6 ,0.0001
Yes
(n = 30,954) 5.6 5.9 3.5 4.0 5.0 9.3 ,0.0001
Male
(n = 21,561) 4.1 3.6 2.4 2.9 3.8 7.0 ,0.0001
Female
(n = 9,393) 9.1 12.3 6.2 6.6 8.0 14.0 ,0.0001
All p-values for trend chi-square are ,0.0001.
ACAD EMERG MED d October 2004, Vol. 11, No. 10 d www.aemj.org 1055

Figure 2. Unadjusted (filled circle) and adjusted (open diamond) odds ratios representing the relationship between reperfusion
status and in-hospital mortality (n = 115,273).

set and by gender (Table 5). As expected, the strength those in the highest quartile relative to the lowest
of the association attenuated as covariates were added quartile (33.7%, 33.4%, and 28.5%, respectively) fol-
to the models. For all patients, male patients, and lowed by patients in the WBC count subquartile
female patients, the greatest reductions in the ORs group (19.3%, 9.9%, and 8.7%, respectively). The
occurred after adding presenting clinical character- magnitudes of association remained higher in male
istics (22.9%, 26.6%, and 18.3%, respectively). Relative patients, with the exception of the OR assessing the
to those in the first quartile, there was a 2.7-fold subquartile effect on in-hospital mortality relative to
increase in the odds of death during hospitalization the first quartile.
for all patients in the fourth quartile. Men had
a slightly higher OR (9.1% higher) for in-hospital
mortality than women (ORs of 2.87 and 2.61, re-
DISCUSSION
spectively) after controlling for covariates. In this study, we evaluated the association between
Table 6 presents the unadjusted and adjusted ORs WBC count at admission and in-hospital mortality
for in-hospital mortality for each quartile and sub- following AMI in 115,273 patients at 1,189 hospitals in
quartile relative to the first quartile. Covariates from the United States. We observed a strong association
the final population-specific multivariate model (de- between WBC count and in-hospital mortality of AMI
scribed in Table 5) were used in adjusting in-hospital patients. After adjustment for patient demographics,
mortality for each population. For example, covariates medical history, presenting clinical characteristics,
from the final model for men in Table 5 were used to and treatment factors, patients in the higher WBC
adjust in-hospital mortality ORs in Table 6. Again, count quartile remained with significantly increased
after adjustment, the greatest reductions in OR among odds of death. This association was independent of
all patients, male patients, and female patients were in age, gender, and reperfusion status, with increasing
1056 Grzybowski et al. d WBC COUNT AND MI MORTALITY

TABLE 5. Adjusted Odds Ratio for In-hospital Mortality (Fourth WBC Quartile vs. First WBC Quartile)
All patients* Meny Womenz
(n = 115,169) (n = 68,742) (n = 46,427)
Mode OR (95% CI) OR (95% CI) OR (95% CI)
Unadjusted 4.09 (3.83, 4.37) 4.31 (3.93, 4.73) 3.65 (3.32, 4.01)
Adjusted for demographics 4.17 (3.90, 4.46) 4.62 (4.20, 5.07) 3.75 (3.41, 4.12)
Adjusted for above and medical history 3.98 (3.72, 4.26) 4.39 (3.99, 4.84) 3.60 (3.27, 4.00)
Adjusted for above and presenting clinical characteristics 3.07 (2.86, 3.29) 3.22 (2.91, 3.56) 2.94 (2.66, 3.25)
Adjusted for above and medications administered within 24 hours 2.85 (2.65, 3.07) 3.02 (2.72, 3.34) 2.71 (2.45, 3.00)
Adjusted for above and diagnostic procedures 2.78 (2.58, 2.99) 2.94 (2.65, 3.25) 2.65 (2.39, 2.93)
Adjusted for above and therapeutic procedures 2.71 (2.53, 2.90) 2.87 (2.59, 3.19) 2.61 (2.36, 2.99)
Only patients with complete data were included in multivariate logistic regression models.
*The model adjusted for demographics included WBC, age 75 years or older, and gender (c statistic = 0.72). The model adjusted for
medical history included smoking, chronic renal failure, cerebrovascular disease, active malignancy, percutaneous coronary
intervention, chronic obstructive pulmonary disease, stroke, diabetes, and congestive heart failure (c statistic = 0.75). The model
adjusted for presenting clinical characteristics included systolic blood pressure ,90 mm Hg, heart rate .100 beats/min, ST elevation
or left bundle branch block, and anterior/septal myocardial infarction location (c statistic = 0.78). The model adjusted for
medications administered within 24 hours included angiotensin-converting enzyme inhibitors, aspirin, beta-blockers, calcium
channel blockers, and GP IIa/IIIb inhibitors (c statistic = 0.81). The model adjusted for diagnostic procedures included cardiac
catheterization (c statistic = 0.81). The model adjusted for therapeutic procedures included initial reperfusion, nonprimary
percutaneous coronary intervention, and nonprimary coronary artery bypass graft surgery (c statistic = 0.82).
yThe model adjusted for demographics included WBC, age 75 years or older, and gender (c statistic = 0.73). The model adjusted for
medical history included smoking, myocardial infarction, chronic renal failure, cerebrovascular disease, active malignancy,
percutaneous coronary intervention, chronic obstructive pulmonary disease, stroke, and congestive heart failure (c statistic = 0.77).
The model adjusted for presenting clinical characteristics included systolic blood pressure ,90 mm Hg, heart rate .100 beats/min, ST
elevation or left bundle branch block, and anterior/septal myocardial infarction location (c statistic = 0.81). The model adjusted for
medications administered within 24 hours included angiotensin-converting enzyme inhibitors, aspirin, beta-blockers, calcium
channel blockers, and GP IIa/IIIb inhibitors (c statistic = 0.83). The model adjusted for diagnostic procedures included cardiac
catheterization (c statistic = 0.84). The model adjusted for therapeutic procedures included initial reperfusion, nonprimary cardiac
catheterization, nonprimary percutaneous coronary intervention, and nonprimary coronary artery bypass graft surgery (c
statistic = 0.89).
zThe model adjusted for demographics included WBC, age 75 years or older, and gender (c statistic = 0.69). The model adjusted for
medical history included smoking, myocardial infarction, chronic renal failure, cerebrovascular disease, active malignancy, stroke,
and congestive heart failure (c statistic = 0.71). The model adjusted for presenting clinical characteristics included systolic blood
pressure ,90 mm Hg, heart rate .100 beats/min, ST elevation or left bundle branch block, and anterior/septal myocardial infarction
location (c statistic = 0.75). The model adjusted for medications administered within 24 hours included angiotensin-converting
enzyme inhibitors, aspirin, beta-blockers, calcium channel blockers, and GP IIa/IIIb inhibitors (c statistic = 0.78). The model adjusted
for diagnostic procedures included cardiac catheterization (c statistic = 0.79). The model adjusted for therapeutic procedures
included nonprimary cardiac catheterization and nonprimary percutaneous coronary intervention (c statistic = 0.80).
WBC = white blood cell.

WBC count associated with progressively higher The WBC count has long been appreciated as a risk
mortality. Although the magnitudes of association factor for subsequent development of coronary events
were slightly greater among men, gender-specific in patients with or without known ischemic heart
associations between WBC count and in-hospital disease.12,14–17,41–49 Friedman et al. first observed a re-
mortality remained strong and significant. Our gen- lationship between leukocyte count and subsequent
der-specific analyses agree with results from NRMI development of myocardial infarction in stable pa-
2,37 the Monitoring Trends and Determinants in tients.12 The correlation between WBC count at ad-
Cardiovascular Disease investigation,39 the Myocar- mission and in-hospital death in patients with
dial Infarction Triage and Intervention study,29 and unstable acute coronary physiology was later noted
the trial registry entitled ‘‘Should We Emergently in the Worcester Heart Attack Study, with patients
Revascularize Occluded Coronaries for Cardiogenic whose WBC counts were .11.4 3 103/mL6 having
Shock?’’40 a significantly increased risk of in-hospital death.19
An important strength of this analysis is that, to our More recently, this observation was extended to
knowledge, it is the first to detect a J-curve distribu- patients with ST-elevated myocardial infarction who
tion when in-hospital mortality was evaluated by were undergoing fibrinolytic treatment in the Throm-
small WBC count intervals. We also created a sub- bosis in Myocardial Infarction (TIMI)-10B study, pa-
quartile group to eliminate the possibility of including tients with unstable angina who were receiving oral
patients with possibly different chronic diseases that glycoprotein IIb/IIIa antagonists in TIMI-OPUS 16,
affect WBC count. Therefore, we were able to estimate and Medicare beneficiaries with AMI in the Cooper-
the odds of death by ensuring that the reference group ative Cardiovascular Project.21,50,51 The WBC count
is truly the group with the lowest in-hospital mortal- consistently predicted increased adverse in-hospital
ity and WBC counts. events and increased risk of death. The present study
ACAD EMERG MED d October 2004, Vol. 11, No. 10 d www.aemj.org 1057

TABLE 6. In-hospital Mortality Rates by Quartile and Odds Ratio for In-hospital Mortality and White Blood
Cell Count Quartile with Quartile 1 Serving as the Reference Group in All Patients, in Male Patients,
and in Female Patients
Quartile 1 Quartile 2 Quartile 3 Quartile 4 Subquartile
5.0–7.7 3 103/mL 7.8–9.7 3 103/mL 9.8–12.4 3 103/mL $12.5 3 103/mL ,5.0 3 103/mL
Patient Population (n = 27,268) (n = 28,446) (n = 28,217) (n = 27,798) (n = 3,544)
All patients (n = 115,273)
Mortality rate, n (%) 1,208 (4.4) 1,756 (6.2) 2,379 (8.4) 4,427 (15.9) 253 (7.1)
Unadjusted OR (95% CI) — 1.42 (1.32, 1.53) 1.99 (1.85, 2.13) 4.09 (3.83, 4.37) 1.66 (1.44, 1.91)
Adjusted OR (95% CI) — 1.42 (1.31, 1.54) 1.87 (1.74, 2.02) 2.71 (2.53, 2.92) 1.34 (1.52, 1.56)
Male patients (n = 68,813)
Mortality rate, n (%) 615 (3.6) 906 (5.2) 1,233 (7.3) 2,109 (13.9) 136 (6.3)
Unadjusted OR (95% CI) — 1.47 (1.33, 1.63) 2.10 (1.90, 2.32) 4.31 (3.93, 4.73) 1.45 (1.21, 1.75)
Adjusted OR (95% CI) — 1.47 (1.33, 1.66) 2.00 (1.80, 2.24) 2.87 (2.59, 3.19) 1.32 (1.07, 1.63)
Female patients (n = 46,460)
Mortality rate, n (%) 593(5.8) 850 (7.7) 1,146 (10.2) 2,318 (18.4) 117 (8.4)
Unadjusted OR (95% CI) — 1.35 (1.21, 1.50) 1.83 (1.65, 2.03) 3.65 (3.32, 4.01) 1.49 (1.21, 1.83)
Adjusted OR (95% CI) — 1.37 (1.22, 1.54) 1.72 (1.56, 1.94) 2.61 (2.36, 2.90) 1.36 (1.10, 1.70)

extended this observation to an even broader patient a crude marker of sympathetic activation requires
population in a contemporary ongoing registry, in- further investigation.
cluding patients of all age groups in a significant As observed in this and prior studies, the WBC count
number of hospitals across the United States. appears to be a simple, inexpensive, and powerful
The role of the WBC count as a significant prog- prognostic tool in the assessment of patients present-
nostic factor in AMI patients is now emerging. In the ing with AMI. A number of biochemical markers have
Cooperative Cardiovascular Project, WBC count was now emerged to be potentially useful in early risk
one of the seven most important predictors of out- assessment, such as C-reactive protein, b-type natri-
come following AMI among 73 clinical variables. The uretic peptide, and troponin.55–60 In particular, in 2002
risk model integrating WBC count on admission early risk assessment based on a validated multi-
demonstrated a predictive value similar to that of an marker approach was advocated.61 Other inflamma-
existing, more complex model.20 Higher leukocyte tory markers and cytokines such as interleukin 6 and
count clearly identifies AMI patients at increased risk tumor necrosis factor-a have emerged to have certain
for adverse outcomes. Higher WBC count at admis- prognostic values as well.57,62–65 Despite the potential
sion appears to identify AMI patients with more prognostic importance of these novel biochemical
baseline cardiac risk factors such as medical history markers, many of them are not routinely available.
of myocardial infarction, congestive heart failure, On the other hand, the WBC count is a simple test that
diabetes, and stroke.21,50–52 is available universally and is one of the most com-
In addition, the WBC count appears to be associ- monly obtained tests in the emergency department. It
ated with a greater ischemic burden, higher angio- can be applied immediately at the bedside, with no
graphic thrombus load, and worse TIMI flow and investment in new infrastructure or tests. In addition,
TIMI myocardial perfusion grades.51 Higher WBC every provider is familiar with its use and its in-
count is also associated with cardiogenic shock, terpretation in routine clinical practice. Given that the
suggesting an association with more significant in- WBC count is a simple yet potent risk factor for
farcts.19,21 This was confirmed by observations that adverse events, as evident in this and prior studies,
the WBC count may identify patients with lower left its role in early triage and risk assessment for AMI
ventricular function after AMI.53,54 In the present patients is clear. Further research is needed, however,
study, increasing WBC count was associated with to assess the comparative roles of the WBC count with
significant cardiac risk factors such as diabetes and other biochemical markers such as C-reactive protein.
congestive heart failure and was associated with It remains unclear whether the WBC count is a risk
higher Killip class and anterior myocardial infarction, factor or a marker for AMI mortality. Nonetheless, there
consistent with the prior published observations. is increasing evidence to support a pathophysiologic
However, even after adjusting for these factors, higher link between WBC count and adverse outcomes fol-
WBC count remained a strong independent predictor lowing AMI. Among patients with ST-elevation myo-
of in-hospital death. The elevated WBC counts may be cardial infarction who were treated with fibrinolytics,
indicative of demargination related to sympathetic increased WBC count was associated with reduced
nervous system activation and catecholamine excess. epicardial patency and an increased ischemic burden.51
Through demargination, neutrophils shift from the This resistance to thrombolytic therapy may reflect
marginal to circulating pool. The WBC count as a hypercoagulable state induced by inflammatory
1058 Grzybowski et al. d WBC COUNT AND MI MORTALITY

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