European Heart Journal (1997) 18, 226-234

The effect of simvastatin on progression of coronary

artery disease
The Multicenter Coronary Intervention Study (CIS)
H.-P. Bestehorn*, U. F. E. Rensing*, H. Roskamm*, P. Betz*, L. Beneschf,
K. Schemeitatf, G. BlumchenJ, J. Claus$, P. Mathes§, L. Kappenberger||,
H. WielandU and A. Neiss**
*Herz-Zentrum Bad Krozingen; fFachklinik Rhein-Ruhr, Essen-Kettwig; \Klinik Roderbirken, Klinik fur Herz- und
Kreislauferkrankungen der L VA Rheinprovinz, Leichlingen; §Klinik Hohenried fur Herz- und Kreislaufkrankheiten
der LVA obb., Bernried; \\Centre Hospitalier Universitaire Vaudois (CHUV) Lausanne; ^Universitat Freiburg;
**Technische Universitat Munchen, Germany

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Background In several angiographic trials, HMG-CoA
reductase inhibitors have shown a beneficial effect on the
progression of coronary artery disease. Using 20 mg simva-
statin . day ~', a treatment period of up to 4 years was
necessary to show a significant reduction in coronary artery
disease progression. The question remains however,
whether higher dosages of simvastatin would be more
advantageous in respect to the magnitude of the effect and
the required time interval to demonstrate treatment efficacy.
Methods and results In the Coronary Intervention Study
(CIS), a multicentre randomized double-blind placebo-
controlled study, the effects of lipid-lowering therapy with
simvastatin on progression of coronary artery disease
in 254 men with documented coronary artery disease and
hypercholesterolaemia were investigated. Following a period
of lipid-lowering diet, treatment with 40 mg simvastatin or
placebo was maintained for an average of 2-3 years. Two
primary angiographic endpoints were chosen: the global
change score (visual evaluation according to the method of
Blankenhorn) and the per patient mean change of minimum
lumen diameter (evaluated by the CAAS I system).
The mean simvastatin dose was 34-5 mg . day"'. In the
placebo group, the serum lipids remained unchanged; in com-
parison to the placebo group the simvastatin group showed a
35% LDL-cholesterol decrease. Coronary angiography was
repeated in 205 patients (81%) and 203 film pairs (80%) were
evaluable by quantitative coronary angiography. In the sim-
vastatin and placebo groups, the mean global change scores
were +0-20 and +058 respectively, demonstrating a signifi-
cantly slower progression of coronary artery disease in the
treatment group (P-002). The change in minimum lumen
diameter assessed by computer-assisted quantitative evalu-
ation with the CAAS I system was - 002 mm in the simva-
statin group and - 010 mm in the placebo group (P=0002).
In the simvastatin group, there was a significant correlation
between the LDL cholesterol levels achieved therapeutically
and the per patient mean loss of minimum lumen diameter
(r=0-29; />=0003). During the study period, there was no
significant difference in the incidence of serious cardiac events
(15 of 129 patients in the simvastatin group and 19 of 125
patients in the placebo group, ns).
Conclusion Treatment with 40 mg simvastatin . day" '
reduces serum cholesterol and slows the progression of
coronary artery disease significantly within a short period
of treatment time. In the treatment group, retardation of
progression is inversely correlated to the LDL-cholesterol
levels achieved.
(Eur Heart J 1997; 18: 226-234)
Key Words: Atherosclerosis, simvastatin, hydroxymethyl-
glutaryl-CoA reductase inhibitors, progression, coronary
artery disease, quantitative angiography.

Introduction proven in a number of angiographical trials, and

retardation of progression of the disease was inde-
The beneficial effect of cholesterol-lowering therapy pendent of the method used for lipid lowering11"91.
on the development of coronary artery disease is Before HMG-CoA reductase inhibitors (CSE inhibi-
tors) were available, cholesterol-lowering therapy was
Submitted 26 January 1996. and accepted 29 March 1996. associated either with low drug tolerability (coles-
Correspondence: H.-P. Bestehorn, Herz-Zentrum Bad Krozingen. tyramin, colestipol) or with other considerable limi-
Siidring 15, 79189 Bad Krozingen. Germany. tations of lifestyle or acceptability due to special

0195-668X/97/020226+O9 S18.00/0 *c 1997 The European Society of Cardiology


Table 1 CIS inclusion and main exclusion criteria
Inclusion criteria
Men, aged 30-55 years
Total plasma cholesterol 207-350 mg . dl ~ ' and total triglycerides <330 mg . dl ~'
At least three coronary segments with a lumen diameter reduction of >20% (visually estimated)
Main exclusion criteria
Hypertension (diastolic >100mmHg)
Diabetes (medically treated)
Left ventricular ejection fraction <30%
Myocardial infarction within the previous 4 weeks
Percutaneous transluminal coronary angioplasty (PTCA) within the previous 4 months
Previous bypass surgery
Scheduled PTCA or bypass surgery
lipid-lowering methods (POSCH, LIFESTYLE,
HELP [3A1 °]).
Since the introduction of the generally well tol-
erated CSE inhibitors, four angiographically controlled
studies with computerized quantitative evaluation of
the angiograms and CSE inhibitor monotherapy
have been undertaken (MARS, CCAIT, MAAS,
REGRESS' 8911121 ), most of them using intervention
durations of about 2 years. In one study (MARS'81) the
chosen primary quantitative angiographic endpoint (per
patient change in percent diameter stenosis) failed to
provide a significant result. Additionally, the only study
using simvastatin (20 mg . day ~ ') (MAAS[1I]) had to be
continued for another 2 years, as an interim analysis
showed no significant differences between treatment and
placebo. These results led to disagreement about suitable
angiographical endpoints (quantitative or panel evalu-
ation) and uncertainty whether treatment with simva-
statin at higher dosages (aiming at LDL-cholesterol
levels <90 mg . dl" ') would result in an earlier signifi-
cant verifiable retardation of coronary artery disease
progression.
The Coronary Intervention Study (CIS) was
begun in 1989 to investigate the effect of lipid lowering
therapy with simvastatin (up to 40 mg) on progression
of coronary artery disease in comparatively young male
patients with documented coronary artery disease and
hypercholesterolaemia. It was designed with two pri-
mary angiographic endpoints derived from two different
evaluation procedures: the minimum lumen diameter
from quantitative analysis and the global change score
from panel evaluation.
Methods
Trial design and treatment
CIS is a multicentre prospective randomized double-
blind placebo-controlled study. Following the exclusion
The Coronary Intervention Study 227
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and inclusion criteria (Table 1) 254 male patients in five
centres were randomly allocated in equal numbers to
one of the treatments simvastatin and diet or placebo
and diet.
The initial simvastatin (20 mg once a day) and
placebo dose was doubled if, after 6 weeks of medi-
cation, the LDL-cholesterol was above 90 mg . dl ~ '.
After 12 weeks, an ion-exchange resin was added if
LDL-cholesterol levels were > 120 mg . dl ~ ' in the sim-
vastatin group or >250 mg . dl ~ ' in the placebo group.
These intervention thresholds in both groups were
supervised from the central laboratory. In case of nec-
essary dose adjustment or additional therapy the inves-
tigators were informed in writing without knowing lipid
values or to which treatments the patients were assigned,
thus maintaining the study blind. In all centres the
patients received diet counselling and were regularly
seen by a dietician. Lipid lowering diet ('PS-Kost',
recommendations of the 'Deutsche Gesellschaft fur
Ernahrung' 1978) was weight-adapted with a maximal
cholesterol intake limited to 300 mg . day" '.
Lipid measurements
Lipid values for patient selection were measured by the
laboratories of the respective centres; low density lipo-
protein (LDL) cholesterol was calculated by means of
the Friedewald formula'131. For follow-up lipid measure-
ments (necessary for subsequent medication adjust-
ments) frozen plasma and serum samples from 12
follow-up visits were sent to the central laboratory:
triglycerides, total cholesterol, high density lipoprotein
(HDL) cholesterol and apolipoproteins AI and B were
measured by specific methods. VLDL-cholesterol was
determined by ultra-centrifugation. LDL-cholesterol
was calculated by subtraction of HDL-cholesterol con-
centration from the cholesterol concentration of the
VLDL-free serum"4-'71.
Eur Heart J, Vol. 18, February 1997
228 H.-P. Bestehorn et al.
Primary angiographic and secondary
endpoints
Since there was uncertainty about suitable parameters
for verification of coronary progression or regression,
two primary angiographic endpoints were chosen, de-
rived from two different evaluation methods. On the one
hand, focal coronary atherosclerosis was described by
the per patient average change of minimum lumen
diameter derived from quantitative measurements, on
the other, global changes in the total coronary tree were
described by the 'global change score' with a 7-point
scale, ranging from —3 (strong regression) to +3
(strong progression) as described by Blankenhorn121.
Coronary angiography and evaluation of the
angiograms
Coronary angiographic studies at baseline and at
follow-up were performed strictly according to the
standardized requirements for quantitative analysis, ex-
tensively described elsewhere118191, including the admin-
istration of coronary vasodilators (0-8 mg nitroglycerin
and isosorbide dinitrate 5 mg sublingually) 5 min before
coronary angiography. In a blinded fashion (blinded for
treatment and order), the film pairs of all centres were
simultaneously evaluated visually, and prepared for
quantitative computer-assisted analysis with the Cardio-
vascular Angiographic Analysis System (CAAS'18').
Visual evaluation, performed by two cardiologists with
experience in angiography working independently, in-
cluded the caliper-assisted measurement of percent sten-
osis and an overall assessment of the difference between
the two angiograms expressed by the global change
score. Where different global change score values were
derived from the two independent evaluations, consen-
sus was achieved by reviewing the films in a consensus
session with both evaluators present and without any
information about their prior judgements.
Preparation for quantitative analysis included
the selection of paired end-diastolic frames. Each had
identical projections of all segments suitable for quanti-
tative analysis, with adequate filling of contrast medium,
sufficient film quality and calibration conditions and
without overlapping or foreshortening. The instructions
for analysis with the CAAS system were documented
on forms and on the video-printouts of the selected
enlarged segments, indicating the frame numbers, seg-
ment length, the stenosis site, site of user-reference
and projection data for projection-adapted pincushion
distortion correction.
If a patient underwent percutaneous translumi-
nal coronary angioplasty (PTCA) or coronary artery
bypass grafting (CABG) during the trial period, either
the pre-intervention angiography was taken for com-
parison between baseline and follow-up, or in the case of
PTCA, the dilated vessel was excluded from evaluation
in the post-PTCA follow-up angiography.
Eur Heart J. Vol. 18. Februar> 1997
Quantitative analysis of coronary angiograms
permits absolute measurements in mm1"1. Our long-term
variability data using the CAAS system were found to be
identical with literature data'201 and have been reported
previously12'1. For each available segment the minimum
lumen diameter, the mean width of the segment, the
reference diameters, the stenosis length, and the percent-
age stenosis were measured. Occlusions or subtotal
stenosis, which cannot be evaluated by quantitative
angiography, were scored in the following way: total
occlusion without any distal flow: minimum lumen
diameter 0 0 mm/stenosis 100%; subtotal stenosis with
delayed antegrade flow: minimum lumen diameter
0-1 mm/stenosis 99%; subtotal stenoses with minimal or
not delayed antegrade flow: minimum lumen diameter
0-2 mm/stenosis 95%. Segments distal to a subtotal
stenosis or occlusion were not analysed.
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Statistical analysis
Continuous variables are presented as mean, median
and standard deviation; categorical variables as absolute
and relative frequencies. Lipid changes per patient are
described by the difference between the mean lipid
concentration of five follow-up measurements and the
baseline measurement. Treatment effects are represented
by the differences between the treatment groups in the
mean global change score values and in the within-
patient mean change between baseline and follow-up
quantitative coronary angiography measurements.
Depending on the type and distribution of the
variables considered, the t-test, the Wilcoxon rank sum
test, Fisher's exact test and the chi-square test were used
to compare treatment groups at baseline.
To investigate the relationship between lipid
values and the primary endpoints, Pearson's correlation
coefficients were calculated. For the analysis of the
primary endpoints a linear model with the factors treat-
ment, centre and treatment centre interactions was
usedf22'.
All analyses used the intention-to-treat ap-
proach. The analysis of the primary endpoints was
performed according to the procedure of Bonferroni-
Holm[23'241 adjusting the significance level of the statisti-
cal tests to guarantee a multiple a level of 5%.
Results
Patient randomization and treatment
From September 1989 to December 1992, 254 patients
were randomized (129 simvastatin, 125 placebo). The
last follow-up angiography was performed in September
1994. The baseline data of the two groups showed no
significant differences (Table 2). Additionally, there were
no significant differences between the total study group
(n=254) and the subgroup of patients with a second
angiogram (n = 205).
 The Coronary Intervention Study 229

Table 2 Baseline variables for all patients (n=254) and for patients with follow up angiography (n—205)

All patients randomized (n = 254) Patients with follow-up angiography (n = 205)

- P values
Parameter Simvastatin Placebo Simvastatin Placebo (n = 254)
(n=129) (n=125) (n=104) (n = 101)

Age (years ± SEM) 49-8 ± 0-45 48-8 ± 0-49 49-9 ±0-51 49-2 ±0-52 015
Height (cm ± SEM) 175-2 ±0-59 1750 ±0-59 175-4 ±0-66 175-2 ±0-65 0-82
Weight (kg ± SEM) 80-5 ± 0-80 80-3 ±0-76 801 ±0-90 801 ±0-85 0-80
Family historyt (n/%) 60/46-5 57/45-6 49/47-1 49/48-5 0-88
Smoking (n/%) 108/83-7 106/84-8 87/83-6 87/86-1 016
RR syst (mmHg ± SEM) 123-8 ± 1-32 122-7 ± 1-47 123-5 ±1-51 123-2 ± 1-69 0-58
RR diast (mmHg ± SEM) 80-2 ± 0-86 78-5 ±0-87 79-8 ± 0-93 78-6 ± 0-95 018
Fasting serum glucose (mg . dl ~ ' ± SEM) 89-8 ± 202 91-1 ± 1-88 890 ± 1-78 90-6 ±1-98 0-64
Total cholesterol (mg . d l " ' ± SEM) 240-3 ± 3-78 243-4 ± 3-50 236-5 ±4-03 241-5 ±3-79 0-55
LDL-cholesterol (mg . dl ~ ' ± SEM) 164-5 ±3-25 167-4 ±3-20 163-8 ±3-80 166-7 ±3-54 0-53
HDL-cholesterol (mg . d l " ' ± SEM) 44-3 ±0-91 43-6 ± 0-89 44-1 ± 103 43-3 ±0-99 0-59
Coronary score (1,2,3-VD* ± SEM) 213 ±0-08 1-98 ± 0 0 8 212 ± 0 0 9 1-93 ± 0 09 0-40
Ventricular score (LV 0,l,2,3,)t ( ± SEM) 102 ± 0 0 6 0-90 ± 0-06 1 03 ± 0 0 7 0-89 ± 007 0-34

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T h e mean value of 1-, 2-, and 3-vessel disease ;|mean extent of impairment of left ventricular (LV) function, 0 = none, l=some,
2 = moderately severe, 3 = severe impairment of LV function.

.200 101 placebo group) at a mean interval of 2-3 years

(28-4 months simvastatin group; 27-7 months placebo
-o Control group). Of the 49 patients without a second angiogram
(25 simvastatin 24 placebo) five patients had died; the
- 150
2 P = 0.0000 remaining 44 patients did not continue the study or
-2 A = 59 mg.dr 1 = 35% refused follow-up angiography usually due to lack of
i Simvastatin symptoms.
100 All 205 follow up angiographies were evaluated
0 visually; 203 were suitable for quantitative analysis (one
I I I I I
follow-up angiogram was performed in a non-study
12 18 24 30
centre without regard to quantitative coronary angiog-
Months raphy, one follow-up film did not allow for calibration).
Figure 1 LDL-cholesterol values (mg. dl ') ± 3 x Initially 1616 segment pairs were identified for quanti-
SEM at baseline and at five follow-up visits (3, 6 12, 18, tative analysis. Prior to unblinding, 35 (2%) of them
30 months) in both treatment groups. The average differ- were eliminated during the analysis process because of
ence (A) of 35% between simvastatin and control-group is an obvious false contour detection. Additional error-
calculated from five follow-up values. checking of the measurements based on the visual
impression (regression/progression/unchanged) and ref-
erence diameter comparisons led to the elimination of a
Mean simvastatin treatment dose was further 112 segment-pairs (7%) from the final evalu-
34-5 mg . day" '. Simvastatin treatment resulted in the ation. A total of 1469 segments were used for the final
following lipid changes: compared with placebo, in the quantitative result, corresponding to 7-2 segments/film.
simvastatin group there was an LDL-cholesterol reduc-
tion of 35% (P=00000) (Fig. 1). Total cholesterol
decreased by 28-5% (i>=00000), triglycerides by 28% Global change score results
(P=002) and HDL-cholesterol increased by 6 1 %
(P=0-22). The mean global change score (±SEM) was +0-20
CSE inhibitor medication was well tolerated. In ( ± 008) in the simvastatin group and +058 ( ± 010) in
15 of the 254 patients (six placebo, nine treatment, the placebo group indicating significantly less progres-
chi-square=0-54, ns) the study medication was discon- sion in the simvastatin group (P=002). The frequency
tinued for various reasons; in no case of treatment- distributions of the global change score values show a
medication discontinuation was the underlying reason notable shift to the left by the simvastatin group with
considered drug related. lower global change score values (Fig. 2). In the sim-
vastatin group, patients with progression were found
less frequently than in the placebo group: based on the
Angiographic analysis global change score, 34-6% of the patients in the sim-
vastatin group and 53-5% of the patients in the placebo
Follow-up angiography was performed in 205 (81%) group had progression (global change scores +1, +2,
of the 254 randomized patients (104 simvastatin group, + 3); 18-3% of the patients in the simvastatin group

Eur Heart J, Vol. 18, February 1997

230 H.-P. Bestehorn et al.

-2 - 1 0 1

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Global change score
Figure 2 The frequency distribution of the global change score values in the simvastatin (D) and
placebo (B) groups. The simvastatin group shows a notable shift to the left to the lower global change
score values. *The mean global change score values in the simvastatin and the **placebo groups.

Simvastatin Placebo

-0.02
(b)
Ij-0.02
-0.04
s e
-0.06

-0.08
1=3 -0.1
P = 0.002
a
-0.10
-0.12

Simvastatin Placebo -0.14 !

Figure 3 (a) Average minimum lumen diameters in mm ± SEM at baseline (D) and follow-up ( • ) in both treat-
ment groups, (b) Average changes in minimum lumen diameters in mm ± SEM from baseline to follow-up in both
treatment groups.

and 12-9% of the patients in the placebo group had Relationship of angiographic changes to
regression (global change scores — 1, - 2 , - 3 ; LDL-cholesterol
chi-square = 7-39, />=0025).
Looking at the angiographic outcome in relation to lipid
levels achieved, a significant correlation was found in the
Quantitative angiographic results
simvastatin group between the LDL-cholesterol levels
The results from the quantitative evaluation are summar- achieved therapeutically and the loss in minimum lumen
ized in Fig. 3(a and b): the average minimum lumen diameter (without occlusions and subtotal stenosis;
diameters ( ± SEM) at baseline and follow-up angiogra- r=0-29, /"=0003): the per patient average loss of
phy were, respectively, 204 mm (± 0-037), and 202 mm minimum lumen diameter increased with increasing
( ± 0038) in the simvastatin group, and 203 mm LDL-cholesterol values (Fig. 4).
( ± 0032) and 1 -93 mm ( ± 0034) in the placebo group. The number of patients with at least one serious
The mean change in minimum lumen diameter was cardiac event such as cardiac death, non-fatal myo-
- 0 0 2 m m ( ± 0 0 1 4 ) in the simvastatin group and cardial infarction, cardiovascular interventions (PTCA,
- 010 mm ( ± 0017) in the placebo group (P=0002). CABG) and hospitalization because of angina showed

Eur Heart J, Vol. 18, February 1997


220
200
180
^ 160
^ 140 ^ ^
g (PTCA, bypass)
120 r = 0.29
P = 0.003
100
80
• >:V
60
I J_
0.3 0.4
-0.3 -0.2 -0.1 0 0.1 0.2
MLD loss (mm)
Figure 4 Correlation between LDL-cholesterol achieved
therapeutically and per patient mean loss in minimum
lumen diameter (MLD) from baseline to follow-up in the
verum group. The higher the LDL-cholesterol levels, the
bigger the mean MDL loss.
no significant difference (n=15 simvastatin group; n=19
placebo group, ns; Table 3).
Discussion
This study demonstrates, that reduction of serum LDL-
cholesterol using simvastatin results in a significant
retardation of coronary artery disease progression.
While similar to the recently reported trials using like
endpoints there are several features of the CIS trial
which make this study unique.
The CIS patients had a mean age of 49-6 years
and represented a young study population in compari-
son to CCAIT[9] with 53 years, MAAS1"1 with 55 years
and REGRESS1121 with 56 years. These patients had a
more severe coronary artery disease reflected by the
higher percentages of patients with 2- and 3-vessel
disease (69-3%). The corresponding percentages were
33% in CCAIT[9] and 23% in MAAS1"1.
Compared with the prior study published using
simvastatin (MAAS1"1), the CIS results demonstrate
significant retardation of coronary artery disease after a
mean treatment period of only 2-3 years. This may be
due to the CIS design requiring a dosage adjustment for
LDL-cholesterol levels above 90 mg . dl~', thus leading
The Coronary Intervention Study 231
Table 3 Number of patients with at least one serious
cardiovascular event during the study period in the sim-
vastatin and placebo groups. For each patient the most
severe event was taken, and the severity is listed hier-
archically. The difference between the event rates is
statistically not significant
The most severe Simvastatin Placebo
cardiovascular event (n=129) (n=125)
Cardiac death 1 2
Non-fatal MI 1 5
• Intervention 5 4
Angina -»hospitalization 8 8
Total 15 19
Other deaths 0 2*
(non-cardiovascular)
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*Bronchial cancer and stomach/pleura cancer.
to a more pronounced LDL-cholesterol decrease
( — 35% vs —31-4%) and especially a lower absolute
LDL-cholesterol level than in MAAS1"1 (109 vs
nemg.dr1).
0.5
In CIS, two primary endpoints based on two
different evaluation methods were chosen. One reason
for this was the uncertainty about the 'best' angiographi-
cal endpoint at the time the study was initially planned.
While the parameter reflecting 'focal atherosclerosis'
(minimum lumen diameter) was identical with other
studies, the parameter representing 'diffuse atheroscler-
osis' in CIS was the global change score based on visual
panel evaluation. The more recently applied 'mean
lumen diameter' from quantitative coronary angiogra-
phy may have the advantage of improved accuracy and
precision, but represents only a small part of the whole
coronary tree evaluable by quantitative coronary angi-
ography, especially excluding new occlusions, for which
mean lumen diameters are not evaluable. Furthermore,
it is conceivable that in spite of standardized use of
nitrates prior to angiography, mean lumen diameter is
additionally influenced by factors other than progression
or regression of atherosclerosis. Recently, in patients
with coronary atherosclerosis and lovastatin-induced
lipid lowering, improved local regulation of coronary
arterial tone was found'25'261. Panel evaluation with a
global change score, while unlikely to be influenced by
small changes in vasomotor tone, will be influenced
by changes in the morphology of the atheromatous
coronary arteries, including the possibility of new occlu-
sions. Additionally, the panel reader is not limited by a
reduced number of evaluable segments fulfilling the
requirements for quantitation. This can be seen in the
difference between the number of evaluable segments by
quantitative coronary angiography (7-2 segments/film)
and visual evaluation (18-7 segments/film).
The mean global change score values found in
CIS, (+0-20 in the simvastatin group and +0-58 in the
placebo group) are comparable with the findings in
Eur Heart J, Vol. 18, February 1997
232 H.-P. Bestehorn et al.

Table 4 The mean global change score values in four lipid intervention studies

Mean global change Mean global Study size

Study score in the change in the A Significance (number of
treatment group placebo group subjects included)

CLAS [21 0-30 0-80 0-50 /><0001 162

POSCH*131 0-30 0-54 0-24 />=00008 696
MARS' 81 0-40 0-90 0-50 P=0-002 270
CIS 0-20 0-58 0-38 />=00205 205
Mean values 0-30 0-71 0-41

CLAS = Cholesterol Lowering Atherosclerosis Study; POSCH = Program on the Surgical Control
of the Hyperlipidemias; ("the mean values from the POSCH study were calculated from the
reported frequency distribution of the global change score values after three years; +0 and - 0
were taken as zero [unchanged]); MARS = Monitored Atherosclerosis Regression Study;
C1S = Coronary Intervention Study.

Table 5 Minimum lumen diameter changes in four lipid intervention studies

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Mean change of
Mean change of Study size
minimum lumen
minimum lumen (number of
Study diameter (mm) Significance
diameter (mm) in subjects
in the treatment
the placebo group included)
group

CCAIT' 9 ' -005 -009 004 P=00\ 299

MAAS1"1 -0-04 -013 0-09 />=0-007 345
REGRESS' 121 -003 -009 006 P=0-00\ 653
CIS -0-02 -0-10 0-08 />=0002 203
Mean values -0-035 -0-125 0068

CCAIT = Canadian Coronary Atherosclerosis Intervention Trial; MAAS=Multicenter Anti-

Atheroma Study; REGRESS = Regression Growth Evaluation Study; CIS=Coronary Intervention
Study.

the literature (Table 4). In all studies, the percentage
of patients classified as 'no change' was relatively high.
In the treatment group there were still a majority of
patients with progression, indicating that on average
lipid lowering, to the extent achieved in this study, only
retards but does not prevent progression.
The average changes in minimum lumen diam-
eter of — 0-10 mm in the placebo group and — 0-02 mm
in the simvastatin group, as well as the difference of
0-08 mm, reflecting the reduction of atherosclerosis pro-
gression, are consistent with other trials using the same
primary endpoint (Table 5).
In CIS the changes in minimum lumen diameter
appear to be rather small too, because considerable
progression or regression in single segments appear
rarely and their influence to the per patient mean change
is diminished by the 'diluting effect' of averaging the
results of several segments.
In spite of these highly significant angiographic
results, doubts about the clinical importance of these
findings have been raised because of the lack of statisti-
cally significant differences in cardiovascular events in
many of these studies. This is easily explained by the fact
that these studies were not primarily designed to answer
this question and the time interval and the sample sizes
were far too small. However, the impressive results of
the 4S Study, showing a 42% reduction of coronary
deaths and a 34% reduction of major coronary events
in the simvastatin group have definitely answered the
question of the clinical importance of lipid lowering in
secondary prevention of coronary artery disease'27'.
Possible underlying mechanisms for these improvements
caused by lipid lowering with CSE inhibitors are plaque
stabilization'28', improvements in endothelial-mediated
responses with better local regulation of the coronary
arterial tone in patients with coronary artery dis-
ease'25'261 and an immunosuppressive effect of CSE in-
hibitors influencing the inflammatory component in the
process of arteriosclerosis'291.
CIS is the first study showing a significant corre-
lation between the therapeutically achieved LDL levels
and the extent of change in minimum lumen diameter in
the verum group. In spite of similar wide ranges of lipid
concentrations in the placebo group during follow-up,
no correlation could be found here. This evidence seems
to indicate that the remarkable progression-inhibiting
effects of LDL-cholesterol lowering can only be expected
beyond a certain threshold value.
The recently published additional 4S data
showed similar relative treatment effects (reduction of

Eur Heart J, Vol. 18. February 1997


major coronary events) in all four quartiles of baseline
cholesterol in the treatment group'301. However, looking
at the absolute number of major coronary events, there
was a clear decrease with decreasing baseline cholesterol.
Assuming a relationship between baseline and thera-
peutically achieved lipid values, the 4S data confirm
our findings regarding the correlation between thera-
peutically achieved LDL-cholesterol and the extent of
progression inhibition. Nevertheless, it has to be empha-
sized that cardiac events and changes in coronary lumen
dimensions are two different endpoints, which could be
influenced at different levels of lipid lowering and after
different time intervals of therapy.
The conclusion and therapeutic implication is,
that in secondary prevention, lipid lowering is beneficial
in all patients with elevated lipid levels. While the
relative benefit in relation to major cardiac events seems
to be independent from the baseline situation, an opti-
mal absolute benefit of lipid lowering therapy requires
the achievement of the lowest possible levels.
Participating Centers
Herz-Zentrum Bad Krozingen; Fachklinik Rhein-Ruhr,
Essen-Kettwig; Klinik Roderbirken, Klinik fur Herz-
und Kreislauferkrankungen der LVA Rheinprovinz,
Leichlingen; Klinik Hohenried fur Herz- und
Kreislaufkrankheiten, Bernried; Centre Hospitalier
Universitaire Vaudois (CHUV) Lausanne, Universitat
Freiburg (Lipid-Analysis); Technische Universitat
Miinchen (Statistics).
Advisory Committee
Prof. Dr med F. Follath, Universitatsspital Zurich, Prof.
Dr med D. Seidel, Maximilians Universitat Miinchen,
Prof. Dr med W. Rutishauser, Centre de Cardiologie
Hopital Cantonal Universitee Geneve.
The Coronary Intervention Study was sponsored by Merck
Sharp & Dohme, Munich.
References
[1] Levy RI, Brensike J, Epstein SE el al. The influence on lipid
values induced by colestyramin and diet on progression of
coronary artery disease: results of the NHLBI type II cor-
onary intervention study. Circulation 1984; 69: 325-37.
[2] Blankenhorn DH, Nessim SA, Johnson RL et al. Beneficial
effects of combined colestipol-niacin therapy on coronary
atherosclerosis and coronary venous bypass grafts. JAMA
1987; 257: 3233^0.
[3] Buchwald H, Varco RL, Matts JP et al. Effect of partial ileal
bypass surgery on mortality and morbidity from coronary
heart disease in patients with hypercholesterolemia: report
of the program on the surgical control of hyperlipidemia
(POSCH). N Engl J Med 1990: 323: 946-55.
[4] Ornish D, Brown SE, Scherwitz LW et al. Can lifestyle
changes reverse coronary heart disease? Lancet 1990; 336:
129-33.
The Coronary Intervention Study 233
[5] Brown G, Albers JJ. Fisher LD et al. Regression of coronary
artery disease as a result of intensive lipid-lowering therapy in
men with high levels of apolipoprotein-B. N Engl J Med 1990:
323: 1289-98.
[6] Kane JP. Malloy MJ. Ports TA et al. Regression of coron-
ary atherosclerosis during treatment of familial hyper-
cholesterolemia with combined drug regimens. JAMA 1990;
264: 3007-12.
[7] Watts GF, Lewis B, Brunt JNH et al. Effects on coronary
artery disease of lipid lowering diet, or diet plus colestyramin.
in the St Thomas Atherosclerosis Regression Study (STARS).
Lancet 1992; 339: 563-9.
[8] Blankenhorn DH, Azen SP, Kramsch DM et al. Coronary
angiographic changes with lovastatin therapy: the monitored
atherosclerosis regression study (MARS). Ann Intern Med
1993; 119: 969-76.
[9] Waters D, Higginson L, Gladstone P et al. Effects of mono-
therapy with an HMG CoA reductase inhibitor on the pro-
gression of coronary atherosclerosis as assessed by serial
quantitative arteriography: the Canadian Coronary Athero-
sclerosis Intervention Trial. Circulation 1994; 89: 959-68.
[10] Schuff-Werner P, Gohlke H. Bartmann U el al. The HELP-
Downloaded from http://eurheartj.oxfordjournals.org/ by guest on December 7, 2013
LDL-apheresis multicentre study, an angiographically as-
sessed trial on the role of LDL-apheresis in the secondary
prevention of coronary heart disease. II. Final evaluation of
the effect of regular treatment on LDL-cholesterol plasma
concentrations and the course of coronary heart disease. Eur J
Clin Invest 1994; 24: 724-32.
[11] MAAS Investigators. Effect of simvastatin on coronary
atheroma: the Multicentre Anti-Atheroma Study (MAAS).
Lancet 1994; 344: 633-8.
[12] Joukema JW, Bruschke AVG, Van Bowen AJ et al. Effects of
lipid lowering by Pravastatin on progression and regression of
coronary artery disease in symptomatic men with normal to
elevated serum cholesterol levels. The Regression Growth
Evaluation Study (REGRESS). Circulation 1995; 91 2528^0.
[13] Friedewald WT, Levey RI, Fredrickson DS. Estimation of
plasma low-density lipoprotein cholesterol without the use of
the preparative ultracentrifuge. Clin Chem 1972; 18: 499-502.
[14] Manual of Laboratory Operations. Lipid Research Clinics
Program. DHEW No (NIH) 75-628. Bethesda. National
Heart und Lung Insitut, 1971: 1-74.
[15] Wanner C, Hod WH, Luley C, Wieland H. Effect of HMG-
CoA reductase inhibitors in hypercholesterolemic patients on
hemodialysis. Kidney Int 1991; 31: 754-9.
[16] Nauck M, Winkler K, Marz W, Wieland H. Quantitative
determination of high-, low- and very-low-density lipoproteins
and lipoprotein (a) by agarose gel electrophoresis and enzy-
matic cholesterol staining. Clin Chem 1995; 41: 1761-7.
[17] Nauck M, Winkler K, Wittmann Cet al. Direct determination
of lipoprotein (a) cholesterol: ultracentrifugation and agarose
gel electrophoresis with enzymatic staining. Clin Chem 1995:
41: 731-8.
[18] Reiber JHC, Serruys PW, Slager CJ. Quantitative coronary
and left ventricular cineangiography: Methodology and
clinical applications. Boston Dordrecht Lancaster: Martinus
NijhofT Publishers, 1986.
[19] De Feyter PJ, Serruys PW, Davies MJ, Richardson P, Lubsen
J, Oliver MF. Quantitative coronary angiography to meaure
progession and regression of coronary atherosclerosis: value,
limitations, and implications for clinical trials. Circulation
1991; 84: 412-23.
[20] Reiber JHC, Serruys PW, Kooijman JC et al. Assessment of
short-, medium- and longterm variations in arterial dimen-
sions from computer assisted quantitation of coronary cine-
angiograms. Circulation 1985: 71: 280-8.
[21] Barthold A. Ein Beitrag aus der quantitativen Koronarangi-
ographie: Biologische Variabilitaten und pathologische
Veranderungen vor dem Hintergrund methodologischer
Schwankungen. (Inaug Diss) Albert Ludwigs Universitat
Freiburg 1993.
[22] SAS-Release 6.10 [computer program]. SAS Institut Inc. Cary
NC, USA 1993.
Eur Heart J, Vol. 18, February 1997
234 H.-P. Bestehom et al.
[23] Holm S. A simple sequentially rejective multiple test pro-
cedure. Scand J Statistics 1979; 6: 65-70.
[24] Hochberg Y, Tamhane AC. Multiple comparison procedures.
New York: Winley, 1987.
[25] Treasure CB, Klein JL, Weintraub WS et al. Beneficial effects
of cholesterol-lowering therapy on the coronary endothelium
in patients with coronary artery disease. N Engl J Med 1995;
332: 481-7.
[26] Anderson TJ, Meredith IT, Yeung AC, Frei B, Selwyn AP,
Ganz P. The effect of cholesterol lowering and antioxidant
therapy on endothehum-dependent coronary vasomotion.
N Engl J Med 1995; 332: 488-93.
[27] Pedersen TR, Kjekshus J, Berg K et al. (Scandinavian
Simvastatin Survival Study Group) Randomized trial of
Eur Heart J, Vol. 18. February 1997
cholesterol lowering in 4444 patients with coronary heart
disease: the Scandinavian Simvastatin Survival Study (4S).
Lancet 1994; 344- 1383-9.
[28] Brown BG, Zhao XQ, Sacco DE, Albers JJ. Atherosclerosis
regression, plaque disruption and cardiovascular events: a
rationale for lipid lowering in coronary artery disease. Ann
Rev Med 1993; 44 365-76.
[29] Kobashigawa JA, Katznelson S, Laks H et al. Effect of
pravastatin on outcomes after cardiac transplantation N Engl
J Med 1995; 333: 621-7.
[30] Pedersen TR, Kjekshus J, Berg K et al. (Scandinavian Sim-
vastatin Survival Study Group) Baseline serum cholesterol
and treatment effect in the Scandinavian Simvastatin Survival
Study (4S). Lancet 1995; 345: 1274-5.
Downloaded from http://eurheartj.oxfordjournals.org/ by guest on December 7, 2013