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Relation Between Previous Lipid-Lowering Therapy and Infarct
Size (Creatine Kinase-MB Level) in Patients Presenting With Acute
Myocardial Infarction
Herbert D. Aronow, MD, MPHa,*, A. Michael Lincoff, MDb, Martin J. Quinn, MD, PhDc,
A. Thomas McRae, MDd, Hitinder S. Gurm, MDe, Penny L. Houghtaling, MSb,
Christopher B. Granger, MDf, Robert A. Harrington, MDf, Franz Van de Werf, MD, PhDg,
Eric J. Topol, MDh, and Michael S. Lauer, MDi, on behalf of the GUSTO IIb and PURSUIT
Trial Investigators
Animal experimental data have shown that lipid-lowering agents reduce myocardial
infarct size. This association has not been well studied in humans. We compared infarct
size in 10,548 patients in the GUSTO IIb and PURSUIT trials who were (n ⴝ 1,028) or
were not (n ⴝ 9,520) on lipid-lowering therapy before an enrolling myocardial infarction (MI). Patients using lipid-lowering agents before their index MI had smaller
infarcts than those who were not using these agents (median peak creatine kinase
[CK]-MB 4.2 vs 5.2 times the upper limit of normal [ULN]; p <0.0001). Similarly, in
an unadjusted model, patients on previous lipid-lowering therapy were less likely to
have a peak CK-MB >3 times the ULN (620 of 1,028 [60.3%] vs 6,486 of 9,520 patients
[68.1%]; p <0.001; relative risk 0.88, 95% confidence interval 0.84 to 0.93, p <0.0001).
In a covariate- and propensity-adjusted multivariable model, the association between
pretreatment with lipid-lowering agents and smaller infarct size persisted (relative risk
for CK-MB >3 times the ULN 0.94, 95% confidence interval 0.88 to 0.99, p ⴝ 0.04). In
conclusion, patients on lipid-lowering agents before an MI had significantly smaller
infarcts. These findings suggest that lipid-lowering therapy may exert additional salutary effects in the setting of acute coronary syndromes. © 2008 Elsevier Inc. All
rights reserved. (Am J Cardiol 2008;102:1119 –1124)
We sought to determine whether the use of lipid-lowering
therapy before the development of an acute myocardial
infarction (MI) was associated with less myocardial cell
necrosis in patients in the Global Use of Streptokinase or
t-PA for Occluded Coronary Arteries (GUSTO) IIb1 and
Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor
a
Clinical Scholars Program, Michigan Heart and Vascular Institute at
St. Joseph Mercy Hospital, Ann Arbor, Michigan; bCardiovascular Medicine, Cleveland Clinic, Cleveland, Ohio; cSt. Vincents University Hospital,
Dublin, Ireland; dCentennial Heart Cardiovascular Consultants, Nashville,
Tennessee; eDivision of Cardiovascular Medicine, University of Michigan
Medical School, Ann Arbor, Michigan; fDuke Clinical Research Institute,
Durham, North Carolina; gDepartment of Cardiology, University Hospital
Gasthuisberg, Leuven, Belgium; hDivision of Cardiovascular Diseases,
Scripps Clinic, La Jolla, California; and iDivision of Prevention and Population Sciences, National Heart, Lung, and Blood Institute, National
Institutes of Health, Bethesda, Maryland. Manuscript received February
27, 2008; revised manuscript received and accepted June 17, 2008.
Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy (PURSUIT) was supported by COR Therapeutics, Inc., San Francisco, California, and Schering-Plough Research
Institute, Kenilworth, New Jersey; and Global Use of Streptokinase or t-PA
for Occluded Coronary Arteries IIb (GUSTO IIb) was supported by CibaGeigy, Inc., Summit, New Jersey; Boehringer-Mannheim, Indianapolis,
Indiana; and Guidant Corp., Redwood City, California.
*Corresponding author: Tel: 734-712-8000; Fax: 734-712-8010.
E-mail address: [email protected] (H. Aronow).
0002-9149/08/$ – see front matter © 2008 Elsevier Inc. All rights reserved.
doi:10.1016/j.amjcard.2008.06.032
Suppression Using Integrilin Therapy (PURSUIT)2 studies.
Both randomized controlled trials included patients with
acute MI; GUSTO IIb enrolled patients with both ST-elevation and non–ST-elevation MI, whereas only those with
non–ST-elevation MI were eligible for participation in
PURSUIT.
Methods
Patients: GUSTO IIb enrolled 12,142 patients with STor non–ST-elevation acute coronary syndromes from 373
hospitals in 13 countries from May 1994 to October 1995.
Patients were eligible for participation if they had experienced chest discomfort and ischemic electrocardiographic
changes during the previous 12 hours. PURSUIT enrolled
10,948 patients with non–ST-elevation acute coronary syndromes from 726 centers in 28 countries from November
1995 to January 1997. Eligible patients had chest pain
within the previous 24 hours and ischemic electrocardiographic changes within 12 hours of chest pain. Those who
experienced an MI as their enrolling event, had available
creatine kinase (CK)-MB data, and survived to hospital
discharge (GUSTO IIb, n ⫽ 6,414; PURSUIT, n ⫽ 4,134)
were included in this analysis.
Treatment: In GUSTO IIb, patients were randomly assigned to an intravenous bolus and infusion of recombinant
hirudin or unfractionated heparin for 3 to 5 days. Use of
fibrinolytic therapy was left to the discretion of the treating
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Table 1
Patient characteristics in the overall cohort (n ⫽ 10,548)
Variable
Median age (yrs)
Median body mass index (kg/m2)
Women
Hypertension
Hyperlipidemia
Diabetes mellitus
Current smoker
Peripheral vascular disease
Heart failure
Previous MI
Previous percutaneous coronary intervention
Previous coronary artery bypass
Previous angina pectoris
Enrolling ST-elevation MI
Enrolling non–ST-elevation MI
Median systolic blood pressure (mm Hg)
Rales
Previous aspirin
Previous angiotensin-converting enzyme inhibitor
Previous ␤ blocker
Thrombolytic therapy
GUSTO IIb trial
PURSUIT trial
Median propensity score
Previous Lipid-Lowering Therapy
No (n ⫽ 9,520)
Yes (n ⫽ 1,028)
p Value
64 (54–72)
26.6 (24.2–29.4)
2,502 (26%)
4,281 (45%)
3,138 (33%)
1,689 (18%)
3,440 (36%)
692 (7%)
587 (6%)
2,146 (23%)
567 (6%)
607 (6%)
5,894 (62%)
3,105 (33%)
6,415 (67%)
130 (118–148)
1,136 (12%)
5,996 (63%)
1,339 (14%)
2,283 (24%)
2,727 (29%)
5,917 (62%)
3,603 (38%)
0.012 (0.003–0.110)
63 (55–70)
27.5 (24.9–30.4)
300 (29%)
606 (59%)
955 (93%)
296 (29%)
273 (27%)
124 (12%)
94 (9%)
477 (46%)
213 (21%)
245 (24%)
795 (78%)
201 (20%)
827 (80%)
130 (116–146)
137 (13%)
794 (77%)
249 (24%)
464 (45%)
205 (20%)
497 (48%)
531 (52%)
0.287 (0.154–0.451)
0.034
⬍0.001
0.045
⬍0.001
⬍0.001
⬍0.001
⬍0.001
⬍0.001
⬍0.001
⬍0.001
⬍0.001
⬍0.001
⬍0.001
⬍0.001
—
0.34
0.19
⬍0.001
⬍0.001
⬍0.001
⬍0.001
⬍0.001
—
⬍0.001
Values expressed as median (interquartile range) or number (percent).
physician, except for patients randomly assigned to tissue
plasminogen activator or primary angioplasty in the GUSTO
IIb angioplasty substudy (n ⫽ 1,012). In PURSUIT, patients
were randomly allocated to an intravenous bolus and infusion of either eptifibatide or placebo for up to 96 hours. In
both studies, medications used before admission, including
lipid-lowering agents, were captured on the trial case report
form; lipid levels were not captured. Hyperlipidemia was
defined as total cholesterol ⬎240 mg/dl in PURSUIT, but
not strictly defined in GUSTO IIb.
Outcomes: The primary end point in our study was
infarct size, gauged by peak CK-MB. Peak CK-MB is
highly correlated with anatomic infarct size3 irrespective of
reperfusion therapy4 and appeared to more accurately reflect
infarct size than CK alone.5 In PURSUIT, CK-MB was
collected within 12 and 18 hours of enrollment for enrolling
MI, within 24 hours of percutaneous coronary intervention
for periprocedure MI, within 24 hours of coronary artery
bypass grafting for perioperative MI, and within 18 hours
for other MIs. In GUSTO IIb, CK-MB was collected at
enrollment and hours 6 to 8 and 12 to 16. Peak CK-MB
indicated the maximum CK-MB ratio (to the upper limit of
normal) available for each patient at the listed times. CK
assays were performed at respective institutions and institutional upper limits of normal (ULNs) were used for determination of abnormal values. CK-MB data were available for all except 323 patients in GUSTO IIb and 8 patients
in PURSUIT. In a secondary analysis of all patients, including those who did not survive until hospital discharge (n ⫽
11,038), we examined the incidence of in-hospital adverse
clinical outcomes, including death, reinfarction, and devel-
opment of heart failure according to previous use of lipidlowering therapy.
Statistical analysis: Continuous data appear as mean ⫾
SD when normally distributed and median with interquartile
range when non-Gaussian in distribution. Unpaired t tests
and Mann-Whitney rank sum tests were used for bivariate
analyses of normally and non-normally distributed continuous data, respectively. Categorical data were given as
frequencies and percentages, and bivariate analyses of these
data were performed using chi-square or Fisher’s exact
tests, when appropriate. Prespecified subgroup analyses
were performed in patients with and without age ⬎65 years,
female gender, diabetes, hyperlipidemia, current smoking,
ST elevation at presentation, and use of fibrinolytic therapy
and by clinical trial.
In observational studies, unlike in randomized controlled
trials, treatment allocation is often biased by external factors. Before standard multivariable modeling of our primary
outcome to adjust for measurable confounding, a propensity
analysis was performed6 to minimize bias associated with
the decision to initiate lipid-lowering therapy before hospital admission. The intent of propensity analyses is to mimic
the conditions of a randomized trial such that patients are
similar in every measurable respect except for treatment
allocation.7 Propensity analysis was conducted as follows.
First, the probability that each patient would be using lipidlowering therapy before hospital admission was predicted
using a multivariable logistic regression model that included
available demographic, clinical, and treatment characteristics (this probability is the propensity score). The ability of
the regression model to discriminate between patients who
Coronary Artery Disease/Lipid-Lowering Therapy and Infarct Size
1121
Figure 1. Relation between lipid-lowering therapy and myocardial infarct
size (n ⫽ 10,548). LLA ⫽ lipid-lowering agent.
were and were not receiving lipid-lowering therapy before
admission was estimated using the c statistic.
Second, the entire cohort was divided into propensity
score deciles, and within each decile, patients were stratified
according to whether they were or were not receiving lipidlowering therapy before admission. There are a number of
available propensity score methods for reducing imbalances
in measured characteristics between treatment groups, including matching and stratification. Whereas matching may
result in greater variance, stratification can culminate in
more bias.8 Stratification by decile was used to minimize
loss of patients from the much smaller lipid-lowering therapy group. Propensity scores and clinical characteristics
were then compared across treatment groups by propensity
score decile. There were too few patients in propensity score
deciles 1 to 4 to permit statistical comparisons of measured
characteristics across treatment groups. Consequently, patients in these deciles were excluded from the propensityrestricted analysis. In deciles 5 to 10, differences in patient
characteristics across treatment groups observed in the overall cohort were no longer statistically significant. Analyses
were subsequently performed in the overall (i.e., all deciles
included) and propensity-restricted (i.e., only the most
closely matched deciles included) cohorts.
Third, propensity scores were entered along with other
potential confounders into multivariable logistic regression
models predicting the independent effect of previous lipidlowering agent use on infarct size (defined as peak CK-MB
⬎3 vs ⱕ3 times the ULN). Statistical analyses were performed using the SAS system, version 8.02 (SAS Inc., Cary,
North Carolina).
Results
Baseline characteristics: There were 10,548 patients
with an enrolling MI and available CK-MB data in the
GUSTO IIb and PURSUIT trials (6,414 and 4,134 patients,
respectively). Baseline characteristics according to treatment group are listed in Table 1.
Lipid-lowering therapy and infarct size: Patients using lipid-lowering therapy before their index MI had smaller
infarcts (median peak CK-MB 4.2 vs 5.2 times the ULN;
p ⬍0.0001) and were more likely to be enrolled with non–
ST- than ST-elevation MI in GUSTO IIb (PURSUIT included only patients with non–ST-elevation MI). When
infarct size was categorized according to the range of
Figure 2. Subgroup analysis: Previous lipid-lowering therapy and risk of
CK-MB ⬎3 times the ULN (n ⫽ 10,548). Abbreviation as in Figure 1.
CK-MB increase, patients on lipid-lowering therapy were
significantly more likely to have infarcts of smaller size (1
to 3 times the ULN), significantly less likely to have larger
infarcts (⬎10 times the ULN), and equally likely to have
infarcts of moderate size (3 to 5 and 5 to 10 times the ULN;
Figure 1). When the population was dichotomized into
those with CK-MB increases ⱕ3 vs ⬎3 times the ULN,
bivariate predictors of larger infarcts included younger age,
male gender, current smoking, absence of diabetes, and
ST-elevation MI. Patients with larger infarcts were also less
likely to have a history of previous angina, MI, or coronary
revascularization (percutaneous transluminal coronary angioplasty or coronary artery bypass grafting surgery) or be
using angiotensin-converting enzyme inhibitors, ␤ blockers,
or calcium channel blockers before admission. Patients who
received lipid-lowering agents before their index MI were
less likely to have infarcts with a peak CK-MB ⬎3 times the
ULN (620 of 1,028 [60.3%] vs 6,486 of 9,520 patients
[68.1%]; p ⬍0.001; relative risk 0.88, 95% confidence interval 0.84 to 0.93, p ⬍0.0001). The association between
previous lipid-lowering therapy and infarct size persisted
across nearly all predefined subgroups, although it appeared
to be more robust in the GUSTO IIb than PURSUIT population (Figure 2). In the 41% of patients with information
available for left ventricular function, average left ventricular ejection fraction was not statistically different between
those on and not on lipid-lowering therapy before admission
(53% vs 52%, p ⫽ 0.13).
Propensity analysis: The multivariable logistic regression model of lipid-lowering therapy use before admission
included the significant positive independent predictors of
older age; white race/ethnicity; hyperlipidemia; diabetes;
absence of current smoking; family history of premature
coronary disease; previous MI; previous percutaneous transluminal coronary angioplasty or coronary artery bypass
graft surgery; concomitant use of ␤ blockers, angiotensinconverting enzyme inhibitors, or calcium channel blockers;
enrollment in the PURSUIT trial; and enrollment in North
America, Western Europe, or Australia/New Zealand (compared with Eastern Europe or Latin America). The c statistic
was 0.89, indicating that the propensity model discriminated
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Table 2
Infarct size models
Patients
All
All (with propensity score only)
All (with propensity score and
covariates)
Deciles 5–10
Deciles 5–10 (with propensity
score only)
Deciles 5–10 (with propensity
score and covariates)
RR
(95% confidence interval)
p Value
0.88 (0.84–0.93)
0.93 (0.88–0.98)
0.94 (0.88–0.99)
⬍0.0001
0.0095
0.0145
0.93 (0.88–0.98)
0.93 (0.87–0.99)
0.0067
0.0145
0.93 (0.87–0.99)
0.0153
RR comparing infarct size (CK-MB ⬎3 times the ULN) in patients using
versus not using lipid-lowering therapy before admission.
Figure 3. Select independent predictors of myocardial infarct size from
propensity- and covariate-adjusted models (n ⫽ 10,548). SBP ⫽ systolic
blood pressure.
well between patients who did and did not receive lipidlowering therapy before admission.
Multivariable analysis of lipid-lowering therapy and
infarct size: Multivariable models of the association between previous lipid-lowering therapy and infarct size in
overall and propensity-restricted cohorts are listed in Table
2. When propensity score was added to the unadjusted
model described, the resulting RR estimate was larger, suggesting that the propensity score method avoided potential
overestimation of the true relative risk reduction. RR estimates from a model adjusted for both propensity score and
covariates in this cohort were similar. When the cohort was
restricted to propensity score deciles in which patients were
most closely matched (propensity score deciles 5 to 10, n ⫽
6,371), RR estimates were similar in unadjusted, propensity-adjusted, or covariate- and propensity-adjusted models.
Select independent predictors of infarct size from the propensity- and covariate-adjusted model in the overall cohort
are shown in Figure 3.
Lipid-lowering therapy and in-hospital clinical events:
In-hospital adverse clinical event rates were analyzed for all
patients, including those who did not survive their index
hospitalization (n ⫽ 11,038). Comparing patients who did
and did not receive lipid-lowering therapy before hospitalization, there were no statistically significant differences in
incidences of in-hospital death (56 of 1,084 [5.2%] vs 434
of 9,954 patients [4.4%], p ⫽ 0.22), nonfatal reinfarction
(63 of 1,084 [6.1%] vs 503 of 9,954 patients [5.4%], p ⫽
0.31), or heart failure (62 of 1,084 [5.7%] vs 650 of 9,954
patients [6.5%], p ⫽ 0.30), respectively.
Discussion
Experimental data from animal models have shown that
statins, when given at least several hours before the induction of ischemia and reperfusion injury, limit myocardial
infarct size.9,10 However, very limited clinical data have
addressed this issue. In 1 single-center study (n ⫽ 264),
patients who received statins before or shortly after admission for acute MI had smaller infarcts, gauged by median
peak CK (416 vs 699 U/L; p ⫽ 0.02), an effect that was
reportedly more pronounced in patients using these agents
before admission.11 In another single-center study (n ⫽
253) of consecutive patients presenting for primary percutaneous coronary intervention, those using statins for ⱖ1
week before the MI had better myocardial perfusion, gauged
by greater angiographic myocardial blush grade than control
patients.12 The present study extends this observation to a
much larger cohort of patients with both ST- and non–STelevation MI hospitalized in hundreds of medical centers
worldwide. In contrast to a study from the National Registry
of Myocardial Infarction,13 we did not observe a significant
decrease in in-hospital clinical events in patients on lipidlowering therapy before admission. Reasons for this disparity are unclear, but may relate to the smaller number of
events in our study or the use of nonstatin lipid-lowering
agents by some of our patients. Nevertheless, the early,
intermediate, and late benefits of lipid-lowering therapy
after MI have borne out in numerous randomized controlled14,15 and observational16 studies.
There are both cholesterol-independent and -dependent
mechanisms that might account for statin-mediated reductions in infarct size. Statins ameliorate reperfusion injury by
improving endothelial function independent of their lipidlowering capacity. They appear to do so in part by increasing myocardial endothelial nitric oxide synthase messenger
RNA expression and endothelial nitric oxide synthase activity, and their infarct size–limiting effect was abolished
when they were co-administered with the nitric oxide synthase inhibitor nitro L-arginine methyl ester (L-NAME) 10 or
administered to nitric oxide synthase– deficient mice.9 Furthermore, in normocholesterolemic mice, statin withdrawal
led to suppression of endothelial nitric oxide production.17
Statins may also improve endogenous fibrinolysis.18
Whether statins can effect smaller infarcts by modifying
lipid levels is unclear. Hyperlipidemia (both acute and
chronic) is associated with larger myocardial infarcts in
animal experimental models.19,20 However, some animal
data suggest that the myocardial infarct–sparing effect of
statin therapy is exerted independently of lipid lowering.21
Although speculative, it is possible that any or all of these
mechanisms might account for some of the reductions in
myocardial infarct size observed in patients on lipid-lowering therapy.
Irrespective of the responsible mechanism(s), if antecedent lipid-lowering therapy were associated with smaller
infarcts, this finding would have important clinical implica-
Coronary Artery Disease/Lipid-Lowering Therapy and Infarct Size
tions. First, although we did not observe such a relation in
our study, lipid-lowering therapy might positively influence
the clinical course after MI. Data from the National Registry of Myocardial Infarction support this premise13; National Registry of Myocardial Infarction investigators observed that compared with discontinuation, continuation of
statin therapy led to fewer in-hospital complications and
deaths. In a study of statin users who presented within 24
hours of an acute ischemic stroke, those randomly assigned
to statin therapy withdrawal had larger infarct volume and
greater risk of death or dependency at 3 months.22
Our findings also may have implications regarding the
underuse23 and cessation13 of lipid-lowering therapy in eligible patients with established atherosclerotic vascular disease. Patient24 and physician25 perceptions of lipid-lowering agent efficacy are important determinants of drug
adherence. Nearly 1 in 5 patients who discontinued lipidlowering therapy did so because of a perceived lack of
efficacy.25 Our findings suggest that even when lipid-lowering agents fail to prevent nonfatal adverse cardiovascular
events, they may still confer important clinical benefits.
These data add to the growing body of evidence supporting
the role of lipid-lowering therapy in the setting of acute
coronary syndromes.14-16,26
A number of important limitations warranted mention.
First, our study was observational. Accordingly, our multivariable models may have incompletely accounted for confounding; some potential confounders (e.g., renal function)
were not captured. Second, “healthy-user bias,” whereby
patients using preventative therapies have better outcomes
because of unmeasured variables that relate to a generally
improved state of health, may in part explain the improved
outcomes associated with a particular therapy (e.g., estrogen
replacement therapy and vitamin E) in observational studies. Propensity scoring may not have completely eliminated
this bias from our observed associations. Third, we were
unable to discriminate between statin and nonstatin lipidlowering agent use on the trial case report forms and did not
have information about statin type, dose, or duration of
therapy. Nevertheless, most patients on ”lipid-lowering
therapy” during trial enrollment likely were receiving statins,27,28 and nonstatin lipid-lowering agents have also
been associated with decreases in MI.29 Finally, patients
who did not survive the index hospitalization were excluded
from the primary analysis (we did so because peak CK-MB
data were not available in many of these patients). Nevertheless, it is unlikely that this exclusion influenced our
results because in-hospital death rates in patients receiving
lipid-lowering agents were similar to those in patients not
receiving these agents before hospital admission.
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