Atorvastatin has an important acute anti-inflammatory

effect in patients with acute coronary syndrome:

Results of a randomized, double-blind,
placebo-controlled study
Stella M. Macin, MD,a Eduardo R. Perna, MD,a Eduardo F. Farı́as, MD,a Valeria Franciosi, MD,a
Jorge R. Cialzeta, MD,a Mónica Brizuela, BSc,b Fernanda Medina, BSc,b Carlos Tajer, MD,c Hernan Doval, MD,c
and Reynaldo Badaracco, MDa Corrientes and Buenos Aires, Argentina

Background C-reactive protein (CRP) levels are associated with cardiovascular risk. We assessed the hypothesis that
atorvastatin might have anti-inflammatory effects in acute coronary syndromes (ACS) as shown by CRP reduction.
Methods This study was a prospective, randomized, double-blind, placebo-controlled study of 90 consecutive patients
admitted within 48 hours of onset of ACS with CRP levels z1.4 mg/dL. Patients were assigned to atorvastatin 40 mg daily or
placebo over 30 days. C-reactive protein levels, lipid profiles, serum fibrinogen, white cell count, and erythrocyte
sedimentation rate were measured at entry, hospital discharge, and 1 month later.
Results Baseline clinical characteristics did not differ between atorvastatin and placebo groups (mean age 59.3 F 13.4
vs 61.1 F 11.5, P = ns); myocardial infarction 52.3% versus 67.4% ( P = ns). In both groups, median baseline CRP levels
were comparable (5.97 F 6.2 vs 4.64 F 4.2 mg/dL, P = ns). C-reactive protein levels were lower in the atorvastatin group
versus control group at discharge (1.68 F 1.65 vs 4.12 F 4.18 mg/dL) and at 30 days (0.50 F 0.71 vs 2.91 F 2.68 mg/dL,
both P b .0001). C-reactive protein levels significantly decreased from baseline to discharge and 1 month later in placebo
and atorvastatin groups (both P b .0001); however, the reduction was greater in the atorvastatin group (62% vs 11% at
discharge [ P b .0001]; 84% vs 30% at 1 month [ P b .0001]). In addition, atorvastatin was associated with a reduction in
total and low-density lipoprotein cholesterol and erythrocyte sedimentation rate at discharge and at 30 days ( P b .0001 for
all comparisons). No correlation was found between changes in CRP and cholesterol levels.
Conclusions C-reactive protein levels in ACS were rapidly reduced with atorvastatin. These data provide evidence that
statins have fast and early anti-inflammatory effects in addition to lipid-lowering effects in ACS. (Am Heart J 2005;149:451- 7.)

farction (MI) reduced recurrent ischemic events over a

See related Editorial on page 377.
16-week treatment period and decreased inflammatory
Atherosclerosis is considered an inflammatory dis- markers compared with placebo after 16 weeks of
ease.1,2 C-reactive protein (CRP) is associated with treatment.13 Atorvastatin was associated with an 83%
cardiovascular risk,3 - 6 and several studies have demon- reduction in CRP levels compared with 74% in the
strated that statins decrease CRP levels in primary as placebo group.14 However, the effect of statins on acute
well as secondary prevention.7-12 Recently, the MIRACL inflammatory response during hospitalization has been
trial has demonstrated that the early use of high dose of poorly evaluated.
atorvastatin (80 mg/d) started within 24 to 96 hours of We assessed the hypothesis that atorvastatin might
admission for angina or non–Q-wave myocardial in- have early anti-inflammatory effects in acute coronary
syndromes (ACS). Thus, the primary objective of this
study was to evaluate the effect of atorvastatin admin-
From the aCoronary Intensive Care Unit, bLaboratory, Instituto de Cardiologı́a bJuana F.
istered early after admission in patients with ACS on CRP
Cabral,Q Corrientes, Argentina, and cGEDIC Group, Buenos Aires, Argentina. levels measured at discharge and at 30 days.
Submitted June 15, 2004; accepted July 27, 2004.
Reprint requests: Stella M. Macı́n, MD, Coronary Intensive Care Unit, Instituto de
Cardiologı́a bJuana F. Cabral,Q Bolı́var 1334, Corrientes, 3400, Argentina. Methods
E-mail: macinucic@hotmail.com
0002-8703/$ - see front matter
Study population
n 2005, Elsevier Inc. All rights reserved. This study was a prospective, randomized, double-blind,
doi:10.1016/j.ahj.2004.07.041 placebo-controlled trial carried out in a single institution
 American Heart Journal
452 Macin et al
March 2005

Figure 1

Study design.

Table I. Baseline characteristics (4) history of systemic inflammatory disease or cancer; (5)
known hypersensitivity to statins; (6) patients judged to be
Variable Atorvastatin Placebo P
unlikely to comply with the study drug regimen or study
process; (7) known infectious disease in the last 30 days; (8)
Age (y) 59.3 F 13.4 61.1 F 11.5 .38
Men 34 (77.3) 33 (71.7) .46
unwilling to provide written informed consent; and (9)
Diabetes mellitus 10 (22.7) 11 (23.9) .22 cardiogenic shock or acute pulmonary edema.
Dyslipidemia 23 (52.3) 24 (52.2) .53 The protocol was approved by the local ethics committee and
Smokers 18 (40.9) 19 (41.3) .53 written informed consent was obtained from all patients. Eligible
Initial diagnosis patients were randomly assigned (1:1) to receive 40 mg of
Unstable angina 21 (47.7) 15 (32.6) .90 atorvastatin daily (44 patients) or placebo (46 patients) in a
MI 23 (52.3) 31 (67.4) double-blind fashion during 30 days (Figure 1). The mean time
from onset of symptoms to first dose of atorvastatin or placebo
Values are given as n (%) or mean F SD.
was 18 hours. In addition, all patients received dietary counsel-
ing to promote compliance with National Cholesterol Education
Program diet. An ambulatory control was planned at 30 days.

between December 1999 and November 2000. Patients were Blood sampling and laboratory determinations
included if they were men or women N21 years old who fulfilled We measured plasma concentrations of CRP, total choles-
both of the following criteria: ACS within 48 hours of onset and terol (T-C), low-density lipoprotein cholesterol (LDL-C), high-
CRP levels z1.4 mg/dL within 24 hours. Acute coronary syn- density lipoprotein cholesterol (HDL-C), white blood cells
drome was diagnosed in the presence of ischemic chest pain at (WBC), erythrocyte sedimentation rate (ESR), triglycerides,
rest lasting z20 minutes and at least one of the following: new or and fibrinogen at baseline, at discharge (mean 4 F 3 days),
presumably new ST-segment deviations on electrocardiogram and after 30 days of therapy.
(electrocardiographic evidence of ST-segment elevation or Plasma concentrations of CRP were determined by means
depression), enzyme abnormalities (creatine kinase–MB above of an immune turbidimetry automatic with Hitachi 202 (Tina
upper limit of reference in z2 samples obtained with an interval Quant (a), Roche Diagnostics, Indianapolis, Ind), with a
of N6 hours), and/or troponin T z 0.02 ng/mL. detection range of 0.3 to 24 mg/dL and a reference interval
An MI was confirmed when 2 of 3 following criteria were of b0.5 mg/dL.
accomplished: (1) new Q-wave development; (2) creatine
kinase–MB 2 times the upper normal level; (3) chest pain Objectives and end points
lasting N30 minutes. According to entry criteria, the remaining The primary objective was to evaluate the effect of
patients were considered a high-risk group for unstable angina. atorvastatin on CRP levels measured at discharge and at 30
Study exclusion criteria were (1) use of 3-hydroxy-3-methyl- days. The secondary objective was to evaluate the effect of
glutaryl coenzyme A reductase inhibitor or another lipid- atorvastatin on the lipid profile and other acute phase reactants
lowering agent at any time during the preceding 1 month; (2) (ESR, WBC, fibrinogen), and their correlation with the
history of active liver disease; (3) untreated endocrine disorder; evolution of CRP plasma levels.
American Heart Journal
Macin et al 453
Volume 149, Number 3

Table II. C-reactive protein plasma levels in both groups at admission, discharge, and 30 days
Atorvastatin Placebo
Median Median
Mean ± SD (IQ interval) Mean ± SD (IQ interval) P

Baseline (mg/dL) 5.97 (6.2) 3.6 (2.2-6.3) 4.64 (4.2) 2.35 (1.8-5.6) .24
Discharge (mg/dL) 1.68 (1.65) 1.2 (0.6-2.1) 4.12 (4.18) 2.1 (1.75-4.81) b.0001
1 m (mg/dL) 0.50 (0.71) 0.2 (0.1-0.5) 2.91 (2.68) 1.8 (1.3-3.8) b.0001
P (Friedman test) b.0001 b.0001

Clinical outcomes are also described, but the trial is

underpowered to detect a difference in clinical evolution.
Figure 2

Statistical analysis
To detect a 30% difference in CRP plasma levels between
atorvastatin versus placebo group at 1 month after recruitment,
with and a error of .05 and a power 1 b = .8, the sample size
was calculated to be 44 patients per group. Cholesterol levels
and changes were normally distributed and are described as
mean F SD, and the significance of changes was evaluated with
paired t test. Because the distribution of CRP is skewed
rightward, median concentrations were computed, and the
significance of any differences between groups was assessed by
the Mann-Whitney U test or the Wilcoxon signed rank test. We
also computed the absolute and percent change in CRP
observed over time for each study subject, a process that
resulted in a nonnormal distribution of values. Thus, Wilcoxon
signed rank tests were applied to evaluate the significance of
any difference in CRP changes over time, both overall and Percent CRP level reduction in both groups at discharge and at 30
within each group. Correlation coefficients were computed to days.
assess any evidence of association between the change in CRP
observed over time and the change observed for LDL-C or T-C.
When the CRP levels or changes were skewed rightward, log-
normalized values were used to assess any correlation between significantly decreased from baseline to discharge and
CRP levels and absolute and percent changes and baseline- 1 month later in the placebo ( P b .0001) as well as in
evolutionary levels or changes of either LDL-C or T-C. When
the atorvastatin group ( P b .0001). However, the
the distribution was not log-normal or normal, Spearman
quantitative and proportional reduction was signifi-
correlation was calculated. For comparison of categorical
variables, a m2 test with Fisher exact test was used. Statistical cantly higher in the atorvastatin group than the pla-
analysis was performed using SPSS version 10.0 for Windows. cebo group (62% vs 11% at discharge [ P b .0001],
84% vs 30% at 1 month [ P b .0001]) (Table II)
(Figure 2).
Results In addition, the influence of the size of myocardial
Between December 1999 and November 2000, 430 damage on the effect of atorvastatin was evaluated
patients were admitted to the Coronary Intensive Care through the modifications in CRP levels according to the
Unit with the diagnosis of ACS. From these, 90 consec- index event. The 30-day CRP change in patients diag-
utive patients with unstable angina or acute MI who nosed as unstable angina was 32.5% F 22.7% in
fulfilled the inclusion criteria were prospectively in- placebo group compared with 81.6% F 37.8% in
cluded in the randomized protocol, and 44 patients atorvastatin group ( P b .0001). In those with acute MI,
received atorvastatin 40 mg daily and 46 patients the 30-day CRP change in patients randomized to place-
placebo. Baseline clinical characteristics did not differ bo and atorvastatin was 28.5% F 29.4% and 86.2% F
between the atorvastatin and placebo groups (Table I). 59.2%, respectively ( P b .0001). In subjects on placebo
and atorvastatin, these changes on CRP levels at 30 days
Effects of atorvastatin on CRP levels were similar in those with unstable angina ( P = .76) as
In atorvastatin and placebo groups, the baseline CRP well as acute MI ( P = .99), suggesting that the effect of
levels were comparable (5.97 F 6.2 vs 4.64 F 4.2 active treatment is independent of the magnitude of
mg/dL, P = ns) (Table II). C-reactive protein levels myocardial injury.
 American Heart Journal
454 Macin et al
March 2005

Table III. Lipid profile on admission, discharge, and 30 days

Baseline mean (SD) Discharge mean (SD) 30-d mean (SD) ANOVA

T-C (mg/dL) Placebo 194.3 (33.6) 202.4 (39.6) 217.0 (41.7) 0.08
Atorvastatin 194.3 (36.2) 166.4 (33.6) 137.6 (24.1) 0.001
P .71 b.0001 .0001
LDL-C (mg/dL) Placebo 119.6 (26.2) 135.2 (48.5) 139.0 (36.3) 0.09
Atorvastatin 127.7 (28.9) 98.35 (29.0) 73.8 (23.7) b0.0001
P .26 b.0001 b.0001
HDL-C (mg/dL) Placebo 37.1 (5) 34.1 (11) 37.2 (9.1) 0.64
Atorvastatin 36.6 (5) 37.6 (14) 35.9 (7.7) 0.79
P .74 .09 .53
Triglycerides (mg/dL) Placebo 184.3 (33.6) 188.8 (76.5) 208.5 (91.7) 0.07
Atorvastatin 194.3 (33.6) 200.4 (56.8) 149.8 (67.7) 0.06
P .76 .50 .07
ESR (mm) Placebo 17.7 (9.6) 20.8 (5.8) 16.2 (13.5) 0.10
Atorvastatin 17.3 (11.2) 11.1 (6.4) 8.2 (5.1) b.0001
P .83 b.0001 b.0001
Fibrinogen (mg/dL) Placebo 312.1 (70.5) 329.2 (68.5) 338.5 (74.2) 0.88
Atorvastatin 340.3 (87.4) 326 (62.1) 346.2 (64.4) 0.80
P .06 .60 .46
WBC Placebo 7400 (1800) 8020 (2013) 8150 (1978) 0.46
Atorvastatin 8172 (2031) 8620 (1920) 8210 (2036) 0.28
P .48 .08 .06

ANOVA, Analysis of variance.

Table IV. Correlations between the evolution of CRP levels and Table V. Events at 30 days in the atorvastatin versus placebo
cholesterol levels in the atorvastatin-treated group groups
At discharge 30 d Atorvastatin Placebo P
Spearman Pearson Spearman Pearson
Death 1 (2.3) 3 (6.5) .34
CRP and T-C MI/reinfarction 1 (2.3) 1 (2.2) .96
Absolute change 0.27 0.23 0.03 0.12 Heart failure 4 (9.3) 10 (21.7) .14
% Change 0.04 0.03 0.24 0.14 Combined end point 6 (14) 13 (28.3) .12
CRP and LDL-C Recurrent ischemia 7 (16.3) 8 (17.4) .88
Absolute change 0.15 0.13 0.18 0.13
Values are given as n (%).
% Change 0.11 0.18 0.22 0.16

All of the coefficients were not significant. Spearman, Spearman nonparametric

correlation coefficient; Pearson, Pearson linear regression correlation coefficient (r)
(between cholesterol levels and the log transformation of CRP levels or changes).
LDL-C at baseline, discharge, and 30 days in the
placebo group. A significant reduction in LDL-C levels
at discharge and at 30 days was observed in the
atorvastatin group.
There were no differences in triglycerides and HDL-C
Effects of atorvastatin on lipid levels levels between placebo and atorvastatin group on ad-
Baseline T-C levels were comparable in both mission, at discharge, and at 30 days (Table III).
groups (194.3 F 36.2 vs 194.3 F 33.6 mg/dL).
Atorvastatin therapy showed an early effect, decreas- Correlations between CRP, LDL-C, and T-C levels
ing T-C at discharge (166.4 F 33.6 mg/dL) as well as No significant correlation was observed between
at 30 days (137.6 F 24.1 mg/dL). No differences in baseline T-C and CRP levels, as was expected. We per-
cholesterol levels were observed in the placebo formed several additional analyses designed to address
group (Table III). whether the change in CRP observed over time might be
Low-density lipoprotein cholesterol levels were com- related to changes in lipid levels associated with
parable at baseline in both groups. However, at atorvastatin. No substantial correlation was observed
discharge and at 1 month, LDL-C levels were signifi- between the magnitude of change in CRP and the
cantly lower in the atorvastatin group compared with magnitude of change in LDL-C or between the magnitude
placebo (Table III). There were no differences in the of change in CRP and the magnitude of change in T-C
American Heart Journal
Macin et al 455
Volume 149, Number 3

(Table IV). This lack of correlation was observed when unfavorable short- and long-term prognosis.5-7,17,18
considering both the quantitative (absolute change) and C-reactive protein is a 206-amino-acid pentameric poly-
the relative reduction in cholesterol levels, or the log of peptide; synthesis by the liver can be detected as early as
CRP changes and cholesterol levels. 4 hours after injury and peaks between 24 and 72 hours
An additional analysis was carried out, according to after injury.3 Previous works reported an increase in
median LDL-C reduction. Population was classified in events using a cut-off point for CRP of N1.5 mg/dL19,20;
group A if the reduction was b16% and group B if it was therefore, a CRP value of 1.4 mg/dL or higher was
N16%. The 30-day CRP change was 31.6% F 30% and chosen as an inclusion criteria in our study.
79.7% F 32% in groups A and B ( P = .001). In those Statins reduced CRP levels in stable patients.9-11
patients assigned to placebo, 41 in group A and 5 in Recently, MIRACL study in ACS demonstrated that the
group B, the 30-day CRP change was 26.8% F 25.4% early use of high dose of atorvastatin (80 mg/d) started
compared with 52.8% F 30.2% ( P = .049). In patients within 24 to 96 hours of admission decreased inflam-
assigned to atorvastatin, 4 in group A and 40 in group B, matory markers compared with placebo at 4 months.14
the 30-day CRP change was 92.1% F 1.9% compared The present work confirms these findings by showing
with 83.4% F 30.3% ( P = .29). These findings showed a decrease in CRP levels and supports the anti-
that the reduction of CRP levels was significantly higher inflammatory effect of statins,21 which contributes to
in individuals with more reduction in LDL-C in placebo attenuate plaque inflammation and influence plaque
group, but atorvastatin obtained higher effect on CRP stability,16,22 as it was already confirmed by histologic
levels at 30 days, independently of LDL-C reduction. and immunohistochemical analysis.16,23,24 Our study
showed a rapid effect at discharge and at 30 days.
Effects of atorvastatin on other acute phase reactants Another coincident observation in both trials was the
In the placebo group, ESR at discharge and at 30 days spontaneous CRP level reduction in placebo groups.21,24
did not differ from the baseline level. On the other hand, Nevertheless, the CRP fall in the placebo group in
patients randomized to the atorvastatin group showed a MIRACL trial was higher than in this trial, probably
significant reduction of ESR at both discharge and 30 days. because the time evolution was done at 4 months in the
There were no changes in WBC and fibrinogen levels MIRACL trial but at 30 days in the present study.14
over time and no differences between the atorvastatin or
placebo groups (Table III). Statins in lipid profile
Although after the first 24 hours postinfarction, T-C
Effects of atorvastatin on events at 30 days
and LDL-C are reduced because of an acute phase
There was a nonsignificant 2-fold increase of events in reaction, lipid levels do not begin to return to baseline
the placebo group after 30 days (Table V).
levels until several days later.25,26 Previous assays
showed that high atorvastatin doses, 80 mg/d, decreased
Discussion LDL-C levels during the first days of treatment in patients
with ACS.13,27 This work showed that 40 mg/d atorvas-
In this randomized double-blind intervention study
tatin administered on the 48 hours after symptoms onset
performed among 90 patients with ACS, we observed
reduced significantly T-C and LDL-C levels at discharge
early and highly significant reductions in plasma con-
and at 30 days. A decrease in the lipid pool and an
centrations of CRP levels associated with 40 mg/d of
increase in fibrosis of human plaques after 3 months of
atorvastatin given for a month and also an early
statins therapy have been demonstrated.22 However,
significant reduction in T-C and LDL-C. There was a
this study showed no association between the decrease
nonsignificant 2-fold increase of events in the placebo
in CRP levels and T-C and LDL-C at discharge and at 30
group after 30 days.
days, suggesting the independent nature of these 2
Statins-mediated effects on inflammation effects.4,15,28 These data are consistent with similar
findings of previous clinical trials,9,14,22,27,29 confirming
It is well known that in ACS many patients have an
the pleiotropic effects of statins,30 independently of
intense inflammatory process.15,16 Activated T cells may
their effects on cholesterol decrease, such as the
stimulate metalloproteinase production by macrophages
influence on inflammatory response, thrombus forma-
in the lesions, which promote plaque instability and an
tion, endothelial function, and plaque stability.15,16,31
acute immune response, with rises in CRP, fibrinogen,
and other acute phase reactant levels.16
Elevated plasma CRP levels detected in the first days of Statins and other acute phase reactants
ACS may reflect not only a high prevalence of myocar- Other inflammatory markers such as ESR, fibrinogen,
dial necrosis, ischemia-reperfusion damage, or severe and WBC have been considered as independent pre-
coronary atherosclerosis,2 but also an increased systemic dictors of hospital mortality in patients with ACS.32,33
inflammatory response, and have been associated with The present work showed a significant decrease in ESR,
 American Heart Journal
456 Macin et al
March 2005

another inflammatory marker, confirming the anti- by CRP values, but also the T-C and LDL-C levels as fast
inflammatory effects of atorvastatin. as at hospital discharge and at 30 days and may con-
tribute to improve clinical evolution.13,36,42,43
Statins and bacuteQ cardiac risk Our data support the use of atorvastatin given 40 mg
In the 3 classic secondary prevention trials with to achieve early and sustained reduction in LDL and CRP.
statins, treatment did not start until at least 3 months in
the CARE9 study and the Cholesterol And Recurrent Conclusions
Events LIPID34 trial and at 6 months in the 4S35 after the In conclusion, in this prospective trial, atorvastatin
index event. treatment significantly reduced inflammatory markers in
Three trials assessed an earlier effect: the MIRACL ACS, independently to cholesterol reduction. These data
study on patients with ACS with 80 mg/dL of atorvas- provide evidence that statins have fast and early anti-
tatin showed a 16% reduction ( P = 0.048) in the primary inflammatory effects in addition to their lipid-lowering
end points, nonfatal MI, resuscitated cardiac arrest, effects in ACS.
worsening angina, or death at 16 weeks.13 Recently
published, the PROVE IT–TIMI 22 study demonstrated a
16% reduction in the primary end points of death from We thank the medical residents, nurses, and labo-
any cause, MI, unstable angina requiring rehospitaliza- ratory staff of the Coronary Intensive Care Unit of the
tion, revascularization, and stroke at 2 years, with high Instituto de Cardiologı́a, Corrientes, for their collabo-
doses of atorvastatin (80 mg daily) compared with rations in this trial, to Laboratorio ELEA SACIFyA for
pravastatin (40 mg daily) in 4162 patients with ACS.36 providing the active drug and placebo, and Thomas
The FLORIDA study with fluvastatin 40 mg twice daily Buckingham, MD, for his translation and editing of the
within 24 hours of MI symptom onset in 540 patients manuscript.
reduced the incidence of residual myocardial ischemia
and clinical events at 1 year.37
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