The document summarizes a study that compared the effects of aggressive vs conventional statin therapy on inflammation in atherosclerosis. The ASAP study found that 80mg of atorvastatin reduced hs-CRP levels and progression of carotid intima-media thickness more than 40mg of simvastatin over 2 years in patients with familial hypercholesterolemia. Patients with the largest hs-CRP reductions showed a 2-fold greater reduction in carotid intima-media thickness. The study suggests that more aggressive statin therapy may be more effective at reducing inflammation and atherosclerosis progression compared to conventional therapy.

1. Aggressive vs. Conventional Statin Therapy:
Reduced Inflammation In Atherosclerosis ?
Provided by:
Christoph Bickel, M.D.
Division of Cardiology
Central German Military Hospital, Koblenz, Germany
Editorial Slides
VP Watch – November 6, 2002 - Volume 2, Issue 44

2.  Although atherosclerosis was formerly considered to be
a bland lipid storage disease, the importance of
inflammation in atherosclerosis has been clearly
demonstrated.1,2
 Early in atherosclerosis endothelial cells express
selective adhesion molecules - like vascular cell
adhesion molecule-1 (VCAM-1) - that mediate adhesion
and transmigration of leukocytes to the vascular
endothelial wall and promote plaque growth and
instability. In patients with CAD it has been shown that
VCAM-1 levels predict independently future fatal
cardiovascular events.3
Inflammation and Atherosclerosis

3.  Interleukin (IL-18) plays a central role in orchestrating
the cytokine cascade and accelerates atherosclerosis.
Serum IL-18 levels were identified as a strong
independent predictor of death from cardiovascular
causes in patients with coronary artery disease.4
 High-sensitivity C-reactive protein (hs-CRP) - a
nonspecific marker of low-grade systemic inflammation
- has received attention in atherogenesis. The cytokine
cascade induces expression of hepatic genes
encoding acute-phase reactants found in blood,
including CRP.5
Inflammation and Atherosclerosis

4.  hs-CRP levels have been demonstrated to
identify increased risk of initial cardiovascular
events in coronary heart disease patients and
increased risk of recurrent cardiac events in
patients with stable and unstable angina,
patients with acute myocardial infarction, and
patients undergoing elective coronary
revascularization procedures.2,5-7
.
Inflammation and Atherosclerosis

5.  Nevertheless it has been shown that using a
multimarker strategy (patients are categorized
based on the number of elevated biomarkers
including hs-CRP) seems to improve risk
stratification in Non-ST elevation acute
coronary syndromes to predict short- and long-
term major cardiac events (death, myocardial
infarction, congestive heart failure).8
Inflammation and Atherosclerosis

6.  Beneath its lipid-lowering properties additional
non-lipid effects of statin therapy9
on
atherosclerosis are discussed:
 In statin treated patients significantly lower levels of
coagulation (von Willebrand factor), systemic
inflammation (hs-CRP, interleukin-6) and soluble cell
adhesion markers (p-selectin) were found.10
 It has been shown that statin treatment influences
the prediction of fatal coronary events by hs-CRP.
Hs-CRP, which is a significant predictor of death
from coronary artery disease, loses this prediction in
statin-treated patients.11
Statin Therapy and Inflammation

7.  Compared with patients receiving statin
medication, patients without statins did not
have increased cardiac mortality (even with
elevated LDL-cholesterol levels) when hs-
CRP levels were not elevated. In contrast,
patients without statins and elevated hs-
CRP had a 2.3-fold increase in risk for fatal
coronary events, independent of LDL
levels.11
Statin Therapy and Inflammation

8.  In high-risk patients with coronary disease,
other occlusive arterial disease, or diabetes
it has been demonstrated that statin therapy
is beneficial even when the initial LDL-
cholesterol level is less than 100 mg/dl. The
effect of statin therapy seems to be
independent of the presenting cholesterol
level.12
Statin Therapy and Inflammation

9.  As reported in VP Watch of this week, van
Wissen et al. show the results of the ASAP
study (effects of atorvastatin vs. simvastatin on
atherosclerosis progression) a 2 year,
randomized double blinded study, to assess
whether treatment with atorvastatin 80 mg or
simvastatin 40 mg could retard atheroscleosis
progression in patients with familial
hypercholesterolaemia.13
ASAP-Study: hs-CRP reduction by statin therapy
Study-design

10.  Baseline measurements of lipoprotein
parameters, hs-CRP and carotid intima
media thickness (IMT) were
performed and repeated after 1 and 2
years.13,14
ASAP-Study: hs-CRP reduction by statin therapy
Study-design

11.  Plasma levels of lipoprotein parameters and hs-CRP at
baseline and after 2 years with 40mg simvastatin or 80
mg atorvastatin13
ASAP-Study: hs-CRP reduction by statin therapy
Results 1
Statin Baseline (N=268) 2 years (N=268) Change (%)
TC S 10.20 (1.89) 6.45 (1.15) -35.9
A 10.04 (1.87) 5.59 (1.09) -43.5
LDL-c S 8.22 (1.90) 4.53 (1.15) -44.0
A 8.06 (1.83) 3.76 (1.07) -52.6
HDL-c S 1.16 (0.29) 1.32 (0.35) 13.8
A 1.18 (0.33) 1.33 (0.40) 14.3
TG S 1.79 (0.90) 1.37 (0.77) -19.0
A 1.84 (1.07) 1.16 (0.64) -31.1
hs-CRP S 2.0 (0.8 / 3.0) 1.5 (0.6 / 3.0) -19.7
A 2.1 (0.9 / 5.2) 1.1 (0.6 / 2.4) -40.1
Values are means (S.D.), except hs-CRP which is given as median (interquartile range); TC, total cholesterol; LDL-
c, low density lipoprotein;HDL-c, high density lipoprotein; TG, triglcerides (all given in mmol/l); hs-CRP, high
sensitive C-reactive protein (in mg/l); S = Simvastatin 40 mg;A = Atorvastatin 80 mg; % change: percentage
change of median hs-CRP after 2 years of treatment;

12.  In the atorvastatin 80 mg group 71.8% patients
experienced a decrease of hs-CRP after 2 years of
treatment, compared with 59.4 % in the simvastatin 40
mg group.13
 However 1/3 of the patients developed an increase of
hs-CRP after 2 years of treatment: in the atorvastatin
80 mg group 26.7% compared with 36.1 % in the
simvastatin 40 mg group.13
 1.5% of the patients in the atorvastatin and 4.5% of the
patients in the simvastatin group had no change in hs-
CRP level.13
ASAP-Study: hs-CRP reduction by statin therapyASAP-Study: hs-CRP reduction by statin therapy
Results 2

13.  As published before the overall baseline IMT,
combining the measurements of the common
and internal carotid artery and the carotid
bifurcation on both sides, was 0.93 mm (SD
0.22) and 0.92 mm (0.21) in the atorvastatin
and simvastatin groups. 13,14
ASAP-Study: hs-CRP reduction by statin therapy
Results 3

14.  After treatment with atorvastatin for 2 years,
IMT decreased (-0.031 mm [95% CI -0.007 to
-0.055]; p=0.0017), whereas in the simvastatin
group it increased (0.036 [0.014-0.058];
p=0.0005). The change in thickness differed
significantly between the two groups
(p=0.0001).13,14
ASAP-Study: hs-CRP reduction by statin therapyASAP-Study: hs-CRP reduction by statin therapy
Results 3

15.  A significant correlation was found between the
decrease of hs-CRP and the reduction of IMT, as
seen in all patients combined (r = 0.13, P =
0.03).13
 Patients in the highest tertile of CRP change
(median hs-CRP reduction 3.28 mg/l; mean
reduction IMT 0.016 mm/2 years), compared with
the bottom tertile (median hs-CRP increase 0.57
mg/l; mean increase IMT 0.032 mm/2 years),
exhibited a 2-fold greater reduction of mean
carotid IMT.13
ASAP-Study: hs-CRP reduction by statin therapy
Results 4

16. Conclusion:
 Aggressive statin therapy (80 mg
atorvastatin) reduces hs-CRP levels to a
greater extent than conventional statin
therapy (40mg simvastatin) in patients
with familial hypercholesterolaemia.
 Patients with the largest hs-CRP reduction
showed a 2-fold greater reduction in IMT.

17. Conclusion:
 Aggressive statin therapy induces
increased reduction of inflammatory
parameters like hs-CRP and seems to
be associated with a decrease in
progression rate of atherosclerosis
especially in the prevention of
premature atherosclerosis in high-risk
patients with familial hypercholesterol-
aemia

18. Questions:
• Is the difference in hs-CRP reduction
between the both treatment groups a
consequence of the different, non
equivalent statin dosage or caused by
the different agents independently from
dosage ?
an increase in dosage of the same statin does not seem to cause an additional decrease
of hs-CRP [in an randomized intervention study performed among 785 patients with
primary hypercholesterolemia, Ridker observed highly significant reductions in plasma
concentrations of CRP associated with both low-dose (0.4 mg) and high-dose (0.8 mg)
cerivastatin given over an 8-week period. In contrast to LDL-C, he did not observe a
significant dose-response effect for cerivastatin on CRP. Finally, there was no evidence
that the change in LDL-C (or HDL-C) attributable to cerivastatin was related to the change
in CRP that was also observed with the use of this agent]15
.

19. Questions:
• Why does about one third of the
patients show an increase of hs-CRP
under statin treatment in this study ?
• Is this increase in hs-CRP really
causally related to statin therapy or
influenced by other circumstances that
may affect hs-CRP, a non-specific
marker of low-grade systemic
inflammation e.g. infections ?

20. Questions:
• Should coadministration of statins in
postmenopausal women with oral estrogens,
which cause a hs-CRP increase16
with potential
inflammatory and thrombotic consequences,
be controlled by hs-CRP measurement to
exclude an additional hs-CRP elevation and to
verify that the combination of statins with
estrogens may attenuate the potential harmful
effects of estrogen therapy and reduce
cardiovascular risk ?

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