Simvastatin does not inhibit intimal hyperplasia andrestenosis but promotes plaque regression innormocholesterolemic patients undergoingcoronary stenting: A randomized study withintravascular ultrasoundAnna Sonia Petronio, MD, Giovanni Amoroso, MD, PhD, Ugo Limbruno, MD, PhD, Barbara Papini, RT,Marco De Carlo, MD, Andrea Micheli, MD, Nicola Ciabatti, MD, and Mario Mariani, MD Pisa, Italy

Background Restenosis after coronary stenting is mainly caused by intimal hyperplasia. Both experimental andclinical studies suggest that statins may be able to inhibit intimal hyperplasia and, therefore, in-stent restenosis (ISR), bymechanisms beyond lipid lowering.

Methods In a 12-month study, we randomized 71 normocholesterolemic patients to 20 mg simvastatin or no treatment,2 weeks before elective coronary stenting. Patients were evaluated by quantitative coronary angiography and intravascularultrasound, immediately after the index procedure and at the 12-month catheterization.

Results Binary ISR was present in 15% and in 18% of simvastatin-treated patients and controls, respectively ( P = NS).Intimal hyperplasia did not differ significantly between the 2 groups (3.6 F 1.8 vs 3.8 F 2.3 mm3/mm, 34% F 15% vs35% F 23% for simvastatin vs controls, P = NS). However, peristent plaque decreased with simvastatin but increased incontrols (�4.0 F 4.0 vs +1.6 F 3.8 mm3/mm, �14% F 10% vs +6% F 12%, P b .05). The same behavior was shownby intermediate plaques at nonstented sites (�2.5 F 3.0 vs +1.0 F 3.0 mm3/mm, �10% F 8% vs +9% F 9%, P b .05).Major adverse events at 12 months were present in 11% and 24% of simvastatin-treated patients and controls, respectively( P = .20).

Conclusions In normocholesterolemic patients undergoing coronary stenting, simvastatin does not prevent intimalhyperplasia or ISR, but it promotes atherosclerotic regression both at stented and at nonstented sites. (Am Heart J2005;149:520-6.)

See related Editorial on page 384.

Bare metal stents have been a breakthrough in

interventional cardiology because they have been prov-

en to reduce restenosis in comparison with balloon

angioplasty.1,2 However, they still carry a risk of

restenosis, accounting for 20% to 40% of all procedures.

Restenosis after coronary stenting is mainly caused by an

exaggerated hyperplasia of the intimal layer because of

smooth muscle cell proliferation and extracellular

From the Cardiothoracic Department, University of Pisa, Italy.

Submitted August 5, 2004; accepted October 9, 2004.

Reprint requests: Giovanni Amoroso, MD, PhD, Dipartimento Cardiotoracico, Ospedale

di Cisanello, via Paradisa 2, 56124 Pisa, Italy.

E-mail: gioamor@hotmail.com

0002-8703/$ - see front matter

n 2005, Published by Elsevier Inc.

doi:10.1016/j.ahj.2004.10.032

matrix deposition.3 Very recently, stents, which are

capable of reducing the incidence of in-stent restenosis

(ISR) by eluting antiproliferative drugs (sirolimus and

taxol), have been developed.4,5 Yet, the effect of drug-

eluting stents (DES) onto the underlying atherosclerotic

disease seems minimal.6

The 3-hydroxy-3-methylglutaryl coenzyme A inhibitors

(statins) have been clearly shown to reduce mortality

after coronary stenting.7 The beneficial effects of statins,

beyond their lipid-lowering action, mostly rely on their

anti-inflammatory properties.8 Simvastatin, but not other

molecules, has also proven to inhibit smooth muscle

cells proliferation.9

When previously tested to prevent restenosis after

balloon angioplasty, statins have given conflicting

results.10 Recently, Walter et al11 have suggested that

statins can reduce the incidence of angiographic ISR.

Their studies were, however, not randomized and

included only hypercholesterolemic patients. Moreover,

Table I. Characteristics of the study population

VariableSimvastatin

(n = 36)Controls(n = 35) P

Age (y) 63 F 10 60 F 9 .15Men 26 (72%) 27 (77%) .78Previous MI 4 (11%) 5 (14%) .73Systemic hypertension 24 (67%) 26 (74%) .60Smokers 18 (50%) 15 (43%) .63Total cholesterol (mg/dL) 183 F 25 188 F 26 .34LDL-cholesterol (mg/dL) 114 F 21 117 F 20 .47Use of ACE inhibitors 18 (50%) 21 (58%) .47

American Heart Journal

Volume 149, Number 3Petronio et al 521

coronary angiography is a poorly sensitive tool for

measuring intimal hyperplasia. In this setting, intravas-

cular ultrasound (IVUS) appears clearly superior, and it

presents the adjunctive capability of investigating the

behavior of the atherosclerotic plaque and the vessel

wall beyond the stent.12

In this study, we aimed at evaluating, through IVUS,

the efficacy of simvastatin in preventing intimal hyper-

plasia after coronary stenting. We also intended to assess

vessel and plaque volume changes, at both stented and

nonstented sites after simvastatin treatment.

Vessel treatedLAD 18 (50%) 22 (63%) .34CxA 6 (19%) 7 (20%) .76RCA 10 (28%) 6 (17%) .39

Stent length (mm) 16 F 8 15 F 9 .59MLD before stenting (mm) 0.72 F 0.51 0.81 F 0.50 .40RLD (mm) 3.21 F 0.40 3.33 F 0.38 .17

MI, Myocardial infarction; ACE, angiotensin-converting enzyme; LAD, left anteriordescending artery; CxA, circumflex artery; RCA, right coronary artery; MLD,minimal lumen diameter; RLD, reference lumen diameter.

MethodsPatient population and study design

This was an open-label, randomized, single-center study in

which simvastatin was compared with no treatment. Primary

end points were angiographic ISR and ultrasound-assessed in-

stent intimal hyperplasia. Secondary end points were ultra-

sound-assessed vessel wall changes and plaque progression/

regression, and major adverse events.

Normocholesterolemic patients aged 18 to 75 years with

angiographic findings of a significant de novo stenosis (N50%

on quantitative coronary angiography [QCA]) on a native

coronary artery and a clinical indication for elective revascu-

larization were included in the study. Excluded from the study

were patients with acute coronary syndromes, diabetes, left

ventricular ejection fraction b30%, ongoing statin or other

lipid-lowering treatment, intolerance to statins, more lesions

requiring revascularization, vessels b2.75 mm, lesions N20

mm, and chronic total occlusions dating N1 month. Results

from a recent cholesterol level examination had to show levels

b210 mg/dL for total cholesterol and b130 mg/dL for low-

density lipoprotein (LDL)–cholesterol.

Patients were randomized by means of sealed envelopes to

20 mg/d of simvastatin or no treatment, 2 weeks before the

index procedure. The modalities of coronary stenting were

left to the choice of the operator, who was kept unaware of

randomization arm: in any case, no other device than balloon

was allowed before stent deployment, and only bare metal

stents were implanted. At the end of the procedure, a baseline

coronary angiography and an IVUS pullback were acquired.

Patients received 100 mg/d acetylsalicylic acid and standard

dosages of ticlopidine or clopidogrel for 1 month. Antihyper-

tensive and anti-ischemic agents and all other drugs were

freely prescribed as clinically indicated.

Upon successful coronary stenting (QCA residual stenosis

b30% and no adverse events during index hospitalization),

study therapy was continued until follow-up catheterization.

When any clinically driven cardiac catheterization occurred N6

months after stenting and/or any subsequent revascularization

at any time, IVUS was also performed, and both coronary

angiography and IVUS pullback were at that time considered as

the follow-up examination. In all other cases, follow-up

catheterization (with coronary angiography and IVUS pullback)

was performed at 12 months.

Clinical follow-up visits were also performed at 1, 6, and 12

months to record major cardiovascular adverse events (MACEs)

and any drug-related event. Total cholesterol and LDL-choles-

terol levels were also measured at 12 months. Patients’

compliance to therapy was verified by collection of blisters.

Compliance b80% was considered a reason for dropout.

Patients gave full informed consent to the study, and the

protocol was approved by the local ethics committee.

Intravascular ultrasound imagingIntravascular ultrasound imaging examinations at baseline and

follow-up were performed with a CVIS system (Atlantis SR Plus

40 MHz; Boston Scientific, Maple Grove, Minn). Before insertion

of the catheter, 1 mg isosorbide dinitrate was injected into the

coronary artery. The ultrasound catheter was then positioned

into the distal part of the treated vessel. Pullback was performed

automatically at a speed of 0.5 mm/s up to the ostium.

Recordings were automatically fed into the digital system.

Intravascular ultrasound analysisIntravascular ultrasound imaging images for each patient

were analyzed by 2 experienced operators (G.A. and B.P.)

unaware of randomization arm, by means of EchoPlaque 2.5

software (INDEC Systems Inc, Mountain View, Calif), at

baseline and follow-up. Longitudinal reconstruction was per-

formed, and the stenting site was properly identified. From

baseline images, a coronary segment with the following

features was also sought: presence of a nonobstructive

(lumen area N4.0 mm2) atherosclerotic plaque, at least 1 cm

in length, at least 1 cm far from edges of stent (either distally

or proximally), and absence of calcifications covering N908.With the aid of several anatomic references (stent edges,

side branches, and coronary ostium), the same segment was

also identified on follow-up images. Vessel, lumen, and stent

contours of the stented and target segments were deter-

mined, both at baseline and follow-up, for every 0.5-mm

slice by semiautomatic detection contour mode. Intra-

observer and interobserver agreements were r = 0.98 and

r = 0.92, respectively.

The following measures were calculated: minimal in-stent

lumen area (MLA) at baseline and follow-up, intimal hyperplasia

Table II. Intravascular ultrasound findings at baseline and follow-up

Simvastatin Controls

Baseline Follow-up Baseline Follow-up

MLA (mm2) 8.7 F 1.6 5.7 F 1.4* 9.4 F 2.4 6.1 F 2.2*IHV (mm3/mm) – 3.6 F 1.8 – 3.8 F 2.3IH% – 34 F 15 – 35 F 23PSPV (mm3/mm) 11.9 F 4.2 7.9 F 3.3y 10.9 F 4.0 11.6 F 3.5yPSP% 53 F 10 39 F 9y 51 F 12 57 F 11yNSPV (mm3/mm) 9.8 F 3.6 7.3 F 2.5y 8.8F2.9 9.8 F 3.1yNSP% 49 F 8 39 F 7y 47 F 8 56 F 10y

*P b .01 follow-up versus baseline.yP b .01 simvastatin versus controls.

American Heart Journal

March 2005522 Petronio et al

volume (IHV) (corrected for stent length) at follow up =

[stent � lumen volume]/stent length, intimal hyperplasia

percent (IH%) at follow up = [stent � lumen volume]/stent

volume percent, peristent plaque volume (PSPV) (corrected for

stent length) at baseline and follow-up = [vessel � stent

volume]/stent length, peristent plaque percent (PSP%) at

baseline and follow-up = [vessel � stent volume]/vessel

volume percent, nonstented plaque volume (NSPV) (corrected

for segment length) = [vessel � lumen volume]/segment

length, and nonstented plaque percent (NSP%) at baseline and

follow-up = [vessel � lumen volume]/vessel volume percent.

Quantitative coronary angiographyCoronary angiography images were acquired in at least 2

orthogonal views after intracoronary injections of 1 mg

isosorbide dinitrate. Care was taken to avoid vessel overlapping

and to obtain the same views at baseline and follow-up. In-stent

stenosis percent at baseline and follow-up were measured by

means of Quantcor Siemens System (Siemens AG, Erlangen,

Germany). Binary ISR was allocated when in-stent stenosis

percent at follow-up was N50%.

The analysis was performed by 2 operators (A.S.P. and

A.M.) blinded to the IVUS findings and unaware of random-

ization arm.

Statistical analysisFor the sample size determination, we assumed a 20% and a

40% binary restenosis rate at 1 year, respectively, in the

simvastatin-treated and control groups, which would imply a

relative decrease in the restenosis rate of 50%. To have an 80%

power with an a error of .05, a total of 75 patients seemed

appropriate. Continuous variables are summarized by time

point and treatment with mean F SD, after verification of

normal distribution. Dichotomous variables are summarized

with absolute and relative frequencies (percentages).

Dichotomous baseline characteristics and the incidences of

MACE and ISR at follow-up between the 2 study groups were

compared by using m2 or Fisher exact test, when appropriate.

Continuous baseline characteristics and differences in IHV and

IH% at follow-up between the 2 study groups were compared

by using unpaired Student t test. Changes in total cholesterol

and LDL-cholesterol levels, MLA, PSPV, PSP%, NSPV, and NSP%

from baseline to follow-up were analyzed by means of

repeated-measures analysis of variance, with treatment as an

effect. Correlations between changes in PSPV and NSPV and

between changes in PSP% and NSP%, from baseline to follow-

up in the overall study group were performed by linear

regression analysis. Differences were considered significant

with a 2-tailed P b .05. Statistical analysis was performed with

NCSS 2001 (NCSS, Kaysville, Utah).

ResultsBetween January and June 2001, 85 patients who

underwent coronary angiography at our Center satisfied

the inclusion criteria; 72 of them agreed to be enrolled

and underwent randomization and subsequent coronary

stenting. Immediate angiographic success was achieved

in all: however, 1 patient had myocardial infarction (as a

result of subacute stent thrombosis) during the index

hospitalization. Thus, the final study population was

represented by 71 patients (36 simvastatin, 35 controls);

the characteristics of whom are reported in Table I. There

were no significant differences in clinical and procedural

variables between the 2 groups. However, patients in the

simvastatin group were slightly older ( P = .15), had less

left anterior descending artery treated ( P = .34), and

smaller reference diameters ( P = .17). Patients in the

simvastatin group had also slightly but not significantly

lower total cholesterol levels ( P = .34).

Clinical and angiographic follow-upA 12-month clinical follow-up was available for 69

patients (98% of total). One patient was lost at follow-up,

and 1 voluntarily discontinued the study. Both patients

were in the control group. No relevant side effect

because of the study drug was reported at any time.

Total cholesterol and LDL-cholesterol levels in the

simvastatin-treated patients at the 12-month follow-up

were significantly reduced in comparison with controls

(�15% F 7% vs�1%F 9%, and�17%F 8% vs�2%F 9%,

respectively; P b .01 for both). Major cardiovascular

adverse events occurred in 4 (11%) of 36 in the

simvastatin group: 3 repeat target vessel revasculariza-

Figure 1

Intimal hyperplasia at follow-up in simvastatin-treated patients (graycolumns: S) and controls (black columns: N) patients. No differencewas found either in volume (IHV, mm3/mm; left panel) or inobstruction percent (IH%, %; right panel).

Figure 2

Plaque changes between baseline and follow-up in simvastatin-treated patients (gray dots: S) and controls (black dots: N), at bothstented (round dots) and nonstented sites (square dots). Unlikecontrols, simvastatin-treated patients exhibited a significant reductionin both plaque volume (upper panel) and percent (lower panel).

Figure 3

Linear regression curves between plaque changes at stented andnonstented sites in the overall study population. A significantcorrelation was present in both volume (upper panel) and percent(lower panel) changes. DPSPV(%): change in peristent plaque volume(%); DNSPV (%): change in nonstented plaque volume (%).

American Heart Journal

Volume 149, Number 3Petronio et al 523

tions (TVRs) and 1 acute myocardial infarction, and in

8 (24%) of 33 in the control group ( P = .20): 4 re-TVR,

2 acute myocardial infarctions, 1 non-TVR, and 1 death.

Follow-up catheterizationSixty-one patients (85%) had repeat catheterization at

11 F 7 months. Binary angiographic ISR rates were 5

(15%) of 33 and 5 (18%) of 28 in the simvastatin-treated

and control groups, respectively ( P = NS).

Fifty-six (30 simvastatin, 26 controls) patients had

good-quality IVUS recordings of the stented segment at

baseline and follow-up. Among the 5 patients discarded

from analysis, 1 had a totally occlusive ISR, and an IVUS

had not been performed at follow-up. In 43 of the 56

patients, a nonstented segment, fulfilling our criteria for

evaluation, was also selected for analysis.

Intravascular ultrasound findingsComplete IVUS findings are reported in Table II. No

significant difference in MLA, peristent plaque (PSPV

and PSP%), and nonstented plaque (NSPV and NSP%)

between simvastatin-treated patients and controls was

present at baseline.

Minimal in-stent lumen area at follow-up showed a

significant decrease versus baseline in both simvastatin-

treated patients and controls ( P b .01), with no

significant difference between the 2 study groups.

Intimal hyperplasia, measured in both IHV and IH%, was

not significantly different (Figure 1).

Instead, peristent plaque decreased from baseline to

follow-up in simvastatin-treated patients, whereas it

increased in controls (DPSPV: �4.0 F 4.0 vs +1.6 F 3.8

mm3/mm, P b .001; DPSP%: �14% F 10% vs +6% F12%, P b .001, for simvastatin vs controls, respectively)

(Figure 2).

Plaque at nonstented sites also decreased from

baseline to follow-up in simvastatin-treated patients,

whereas it increased in controls (DNSPV: �2.5 F 3.0 vs

+1.0 F 3.0 mm3/mm, P b .001; DNSP%: �10% F 8% vs

+9% F 9%, P b .001, for simvastatin vs controls, res-

pectively) (Figure 2). Changes in peristent versus non-

stented plaque from baseline to follow-up in the same

patient for the whole study group were significantly

American Heart Journal

March 2005524 Petronio et al

correlated (DPSPV vs DNSPV: R2 = 0.35, P b .001;

DPSP% vs DNSP%: R2 = 0.30, P b .001) (Figure 3).

DiscussionTo our knowledge, this is the first randomized study in

which the effect of simvastatin on ISR and intimal

hyperplasia after coronary stenting has been investigated

in normocholesterolemic patients.

The main findings of our study are (1) a similar

incidence of angiographic ISR and intimal hyperplasia in

simvastatin-treated patients and controls and (2) a

significant atherosclerotic regression both at stented and

nonstented sites with simvastatin.

Statins and in-stent restenosisPrevious studies have suggested that statins may have

a beneficial effect in preventing restenosis after coronary

stenting. Walter et al11 have found that patients

receiving prolonged statin therapy developed lower ISR

rates in comparison with nonreceivers (25% vs 38%).

The same authors also demonstrated that this beneficial

effect of statins was particularly evident in patients

carrying the PlA2 allele of the platelet GpIIIa receptor

(28.6% vs 50.9%).13

Unlike the findings of Walter et al, our study failed to

demonstrate a significant difference in angiographic

ISR (15% vs 18%) and intimal hyperplasia (3.6 F 1.8 vs

3.8 F 2.3 mm3/mm, 34% F 15% vs 35% F 23%)

between simvastatin-treated patients and controls. The

reasons for this discrepancy may be found in that the

study of Walter et al was indeed retrospective, enrolled

only hypercholesterolemic patients, and included a

high rate (22%) of patients with acute symptoms,

already known to respond at best to statin treatment.

Yet, the remarkably low rate of ISR in our overall

population, likely caused by the restrictive inclusion

criteria, may have hindered the potential effect of

statins, which may surface only among populations at a

higher risk of restenosis.

Indeed, the issue of pharmacological prevention of ISR

could soon become outmoded, when the favorable

evidences on DES provided by clinical trials will be

confirmed in daily practice. Yet, the RESEARCH study,

the first registry on the extensive use of DES in real-life

patients, reports a 65% reduction in 12-month clinically

driven TVRs (4.1% vs 10.9%).14

Statins and plaque progression/regressionSeminal studies on coronary disease regression sug-

gested the sole capability of statins of inhibiting the

progression of atherosclerotic disease and not of

promoting plaque regression.15 Because the usage of

IVUS proved otherwise,16 this apparent failure has

probably to be ascribed to the inability of coronary

angiography to assess atherosclerotic plaque changes

beyond vessel lumen. Yet, the REVERSAL trial,17 dem-

onstrated either a bzero progressionQ or a progression of

intermediate atherosclerotic plaques after 18-month

treatment with atorvastatin or with pravastatin, respec-

tively. In our study instead, we reported a significant

volumetric reduction of intermediate plaques not sub-

jected to invasive treatment with simvastatin in com-

parison with controls (�10% vs +9%). These results are

in agreement with those of Jensen et al,18 who found a

plaque regression of the same entity (�6.3%, as assessed

by IVUS) after 12-month treatment with simvastatin.

Cholesterol lowering reduces the accumulation of

macrophages into the atherosclerotic plaque and the

subsequent degradation of collagen, thus conferring

stability to the coronary lesion.8 -19

However, the plaque regression induced by simvas-

tatin cannot be explained by lipid lowering alone. In

fact, our study group was constituted only by

normocholesterolemic patients, who showed no ex-

treme reduction in total and LDL cholesterol by

treatment. Apparently, pleiotropic effects are mole-

cule-specific rather than class-specific. Simvastatin,

because of its lipophylic features, is entitled to many

pleiotropic effects, such as to preserve endothelial

function, to exert an anti-inflammatory and antiproli-

ferative action, to maintain the fibrinolytic imbal-

ance.8,20 Qualitatively, it appears that statin treatment

turns coronary plaques toward a hyperechogenic

appearance21 which, in term, is caused by a conver-

sion from a lipidic to a fibrotic pattern.22

The fate of atherosclerotic plaques beyond the stentIs there still a role for adjunctive antiproliferative after

invasive treatment in the DES era?

Our study demonstrated that, mirroring the behavior

of intermediate plaques not subjected to invasive

treatment, in simvastatin-treated patients, also peristent

plaques showed a volumetric reduction in both

absolute (�4.0 F 4.0 vs +1.6 F 3.8 mm3/mm) and

percent values (�14% F 10% vs +6% F 12%). Both

plaque fibrosis and shrinkage, and inhibition of out-

growing intimal hyperplasia can be possibly advocated

as the reasons for our findings.

As recently demonstrated by Degertekin et al6 by

means of IVUS, DES almost abolishes 8-month intimal

hyperplasia in comparison with bare metal stents (0.7 vs

33 mm3). On the other hand, they have no significant

impact on the regression/progression of the preexisting

atherosclerotic plaque surrounding the stent (+3.4% vs

+2.5%). Some authors have speculated that, because of a

slower healing response in human beings than in animal

models, DES may only postpone the occurrence of

restenosis,23,24 a fact which has not been fully excluded

by follow-up data available until now.25

Theoretically, a huge plaque burden surrounding the

stent could contribute to a late catch-up of ISR, thus

American Heart Journal

Volume 149, Number 3Petronio et al 525

jeopardizing the long-term efficacy of DES implantation.

At least for bare metal stents, a significant correlation

has been proven by Alfonso et al26 between external

plaque burden and late restenosis: when plaque exceeds

50% of the lumen area, a 4.4-fold increase in ISR

can be predicted.

Clinical implications for simvastatin therapy aftercoronary stenting

When considered globally, our data suggest that the

effect of simvastatin on coronary disease is substantially

untied from the implantation of stents but relies on a

direct action on the atherosclerotic plaque, which takes

place at both stented and nonstented sites, with

mechanisms which go beyond lipid lowering.

Indeed, the clinical potentials for the use of statins in

normocholesterolemic patients undergoing coronary

stenting are several. First, the bpharmacological

debulkingQ which, as we proved, can be obtained with

simvastatin at stented sites could help improving the

long-term efficacy of coronary stenting, even if DES

would be implanted. Yet, simvastatin-eluting stents are

currently under investigation.27 Second, it must not be

underestimated the adjunctive benefit of plaque regres-

sion at nonstented sites that can be achieved with

simvastatin in patients undergoing invasive procedures,

regardless of their baseline cholesterol levels.

Finally, simvastatin can prevent plaque instabilization,

being it related or not to the invasive procedure, and its

sequelae.28,29 Our study was not sized for clinical end

points: nevertheless, we reported a complete safety in

treatment and, although not statistically significant, a

reduction in adverse events by treatment (11% vs 24%).

These findings go along with those of Chan et al30 and

Schomig et al,7 who proved that statins are responsible

for a significant reduction in mortality after either

coronary intervention (2.4% vs 3.6%) or coronary

stenting (2.6% vs 5.6%).

Study limitationsAfter the Heart Protection Study stated that 40 mg

simvastatin is safe and efficacious in a broad popula-

tion,31 20 mg simvastatin can be considered at present a

low-dose regimen, and its pleiotropic effects on intimal

hyperplasia may have been hindered by so in our study.

However, when it was designed, concerns were raised

by our ethics committee about the safety of a more

aggressive statin regimen.32

Because an automated software for gray-scale analysis

is not implemented in our IVUS equipment, we were

unable to perform a qualitative analysis of the athero-

sclerotic plaque, so we can only speculate about the

reason for its volumetric reduction after treatment with

simvastatin (fibrosis, lipid pool reduction, and cell

growth inhibition), both at stented and nonstented sites.

ConclusionsPreventive treatment with 20 mg simvastatin does not

inhibit intimal hyperplasia and ISR, but it does induce a

volumetric reduction of both the atherosclerotic plaque

surrounding the stent and the intermediate atheroscle-

rotic plaques not otherwise treated, in normocholester-

olemic patients undergoing coronary stenting.

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