Clinical Investigation and Reports

Clinical Investigation and Reports
Long-Term Effects of Cholesterol Lowering and
Angiotensin-Converting Enzyme Inhibition on
Coronary Atherosclerosis
The Simvastatin/Enalapril Coronary Atherosclerosis Trial (SCAT)
Koon K. Teo, MB, PhD; Jeffrey R. Burton, MD; Christopher E. Buller, MD; Sylvain Plante, MD;
Diane Catellier, MSc, DrPH; Wayne Tymchak, MD; Vladimir Dzavik, MD; Dylan Taylor, MD;
Shinji Yokoyama, MD; Terrence J. Montague, MD; for the SCAT Investigators
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Background—This long-term, multicenter, randomized, double-blind, placebo-controlled, 2⫻2 factorial, angiographic trial
evaluated the effects of cholesterol lowering and angiotensin-converting enzyme inhibition on coronary atherosclerosis
in normocholesterolemic patients.
Methods and Results—There were a total of 460 patients: 230 received simvastatin and 230, a simvastatin placebo, and
229 received enalapril and 231, an enalapril placebo (some subjects received both drugs and some received a double
placebo). Mean baseline measurements were as follows: cholesterol level, 5.20 mmol/L; triglyceride level, 1.82 mmol/L;
HDL, 0.99 mmol/L; and LDL, 3.36 mmol/L. Average follow-up was 47.8 months. Changes in quantitative coronary
angiographic measures between simvastatin and placebo, respectively, were as follows: mean diameters, ⫺0.07 versus
⫺0.14 mm (P⫽0.004); minimum diameters, ⫺0.09 versus ⫺0.16 mm (P⫽0.0001); and percent diameter stenosis,
1.67% versus 3.83% (P⫽0.0003). These benefits were not observed in patients on enalapril when compared with
placebo. No additional benefits were seen in the group receiving both drugs. Simvastatin patients had less need for
percutaneous transluminal coronary angioplasty (8 versus 21 events; P⫽0.020), and fewer enalapril patients experienced
the combined end point of death/myocardial infarction/stroke (16 versus 30; P⫽0.043) than their respective placebo
patients.
Conclusions—This trial extends the observation of the beneficial angiographic effects of lipid-lowering therapy to
normocholesterolemic patients. The implications of the neutral angiographic effects of angiotensin-converting enzyme
inhibition are uncertain, but they deserve further investigation in light of the positive clinical benefits suggested here and
seen elsewhere. (Circulation. 2000;102:1748-1754.)
Key Words: atherosclerosis 䡲 coronary disease 䡲 cholesterol 䡲 angiotensin-converting enzyme inhibitors
T
he clearly demonstrated benefits of cholesterol-lowering
therapy in reducing coronary atherosclerotic disease
(CAD)1–3 are thought to be related, at least in part, to the
slowed progression or enhanced regression of CAD.4 – 8 Although individuals with elevated cholesterol levels are at a
high risk for CAD, most CAD patients have cholesterol levels
that are average or “normal” for the population at large.9,10 It
remains unclear whether, and to what extent, cholesterol
lowering will affect CAD progression or regression in these
patients.11
The biological and pathogenetic complexity of atherosclerotic plaque formation, progression, and rupture suggests that
multiple therapies may have cumulative or synergistic effects.
For example, various mechanisms12,13 have been proposed to
explain the decrease in ischemic events seen with angiotensin-converting enzyme (ACE) inhibition in heart failure
Received March 30, 2000; revision received May 11, 2000; accepted May 11, 2000.
From the University of Alberta Hospitals, Edmonton, Alberta (K.K.T., J.R.B., W.T., V.D., D.T., S.Y., T.J.M.); Vancouver Hospital and Health Sciences
Centre, Vancouver (C.E.B); Hôpital Laval, Ste-Foy, Quebec (S.P.); and the Epidemiology Coordinating and Research (EPICORE) Centre, Division of
Cardiology, Department of Medicine, University of Alberta, Edmonton, Alberta (K.K.T., J.R.B., D.C., W.Y., V.D., D.T., T.J.M.), Canada. Dr Teo is
currently affiliated with the Department of Medicine, McMaster University, Hamilton, Ontario, Canada; Dr Catellier with the Department of Biostatistics,
University of North Carolina, Chapel Hill; Dr Yokoyama with Biochemistry 1, Nagoya City University Medical School, Nagoya, Japan; and Dr Montague
with Merck Frosst Canada & Co, Kirkland, Quebec, Canada.
The principal investigator, Dr Teo, has received unrestricted grants from Merck Frosst Canada & Co, as part of the Medical Research Council of Canada
University-Industry Program, in order to carry out this study. Dr. Montague was a Co-Principal Investigator and contributor to the study while he was
head of Cardiology at the University of Alberta; he is now an employee of Merck Frosst Canada & Co.
A complete list of all SCAT Investigators and contributors has been published previously.17
Correspondence to Dr Koon K. Teo, Rm 3U4, McMaster University Medical Centre, 1200 Main Street West, Hamilton, Ontario, Canada L8N 3Z5.
E-mail [email protected]
© 2000 American Heart Association, Inc.
Circulation is available at http://www.circulationaha.org
1748
Teo et al
patients with or without CAD14,15 or those with preserved left
ventricular function.16 Whether the benefits of ACE inhibition are mediated through slowed progression and/or enhanced regression of CAD is not known. Synergism of ACE
inhibition and cholesterol lowering therapy is possible, but
unproven.
We report the findings of the Simvastatin/Enalapril Coronary Atherosclerosis Trial, a quantitative coronary angiographic study of cholesterol-lowering therapy with simvastatin and ACE inhibition with enalapril, alone or in
combination, on CAD progression and regression in normocholesterolemic patients over a period of 3 to 5 years. This
was a randomized, double-blind, placebo-controlled, multicenter, 2⫻2 factorial, clinical trial.
Methods
Patients
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The study design was previously reported in detail.17 Patient eligibility criteria were wider than for previous angiographic trials and
included individuals with the following: (1) age ⱖ21 years and no
upper age limit; (2) total serum cholesterol levels between 4.1 and
6.2 mmol/L, HDL cholesterol ⬍2.2 mmol/L, and triglycerides
⬍4 mmol/L and lower than total cholesterol; (3) angiographically
detectable coronary atherosclerosis in ⱖ3 major coronary artery
segments; and (4) left ventricular ejection fraction ⬎35%. Patients
were not enrolled within 6 months of coronary angioplasty or bypass
surgery. Exclusion criteria were the following: clear indications for
or contraindications to study drugs, clinical instability, imminent
need for intervention, other significant cardiac or systemic diseases,
potential noncompliance, and inability to give informed consent.17
Each participating center’s Research Ethics Board approved
the protocol.
Quantitative Coronary Angiography
Quantitative coronary angiography (QCA) was obtained at baseline
within 1 week before randomization and at closeout 3 to 5 years
later, except for a few patients whose symptoms led to a diagnostic
QCA, which duplicated baseline procedural conditions, before
scheduled closeout. To duplicate baseline conditions, the enalapril/
placebo was stopped ⱖ1 week before closeout QCA. Sublingual
isosorbide dinitrate (5 to 10 mg; 10 minutes before angiography) or
nitroglycerin (100 to 300 ␮g IV just before angiography of each
vessel) was given to minimize variations in coronary tone between
angiograms. Baseline angiography parameters (distances, angles,
and magnification) were reproduced during subsequent and closeout
angiograms. Nonionic contrast media were used to reduce variability
from contrast-related vasodilation. Multiple angiographic projections
of coronary arteries were obtained. Coronary segments were assigned a number based on the published American Heart Association
classification.18
QCA analysis used the MEDIS Cardiovascular Measurement
System (Medical Imaging Systems by Lijsterbeslaan), which was
developed by Reiber et al.19 Validation studies in our QCA Laboratory have yielded interobserver, intraobserver, and intrastudy variation data17 that are consistent with published reports.19 All analyzable coronary segments in the enrollment and closeout studies were
included. QCA measures included absolute mean segment lumen
diameter, absolute minimum segment lumen diameter, and maximum percent lumen diameter stenosis. The best views and frames
were selected from the initial study. Identical views and frames were
analyzed in closeout angiograms, and changes in QCA measures
were averaged for each patient.
Study End Points
Study end points were QCA measures and prespecified clinical
events (death, myocardial infarction, stroke, hospitalization for
angina, revascularization, and cancer), although the latter were not
Lipid Lowering and ACE Inhibition in CAD
1749
powered to detect conclusive differences. Primary angiographic end
points were average per-patient changes between baseline and
closeout angiograms in mean and minimum absolute diameters and
in maximum percent diameter stenosis of all analyzed coronary
segments. Patients were categorized as progressors or regressors
using the following currently accepted criteria: decreases or increases, respectively, in absolute mean or absolute minimum diameter by ⱖ0.4 mm (or by an absolute 15% in diameter stenosis) in ⱖ1
segment while the other segments remained unchanged. Mixed
progressors/regressors had ⱖ 1 segment with progression plus ⱖ1
segment with regression. Individuals without changes fulfilling these
criteria were classified as “no change.”
Randomization and Follow-up
During a 1-month, single-blind, placebo run-in phase and throughout
the trial, patients were instructed to follow the National Cholesterol
Education Program–Adult Treatment Panel (NCEP-ATP) step I diet
and, when necessary, the step II diet. Randomization followed
baseline QCA and fasting lipid levels obtained at the end of the
run-in phase. At each follow-up visit (1, 2, 3, 4.5, 6, 9, and 12 months
and then every 6 months until closeout), participants underwent a
physical examination and blood tests, including fasting lipid levels.
Other lipid-lowering medications and ACE inhibitors were prohibited. Patients were encouraged to take acetylsalicylic acid (aspirin)
unless contraindicated. Other therapeutic decisions were made by the
patients’ own physicians.
With the 1994 publication of the Scandinavian Simvastatin Survival Study (4S),1 we decided it was unethical to keep patients with
cholesterol levels persistently ⬎5.5 mmol/L on placebo. With
approval of the Data Safety and Advisory Board and the Research
Ethics Boards, the protocol was modified to permit the identification
of these patients and to reallocate them to active simvastatin, instead
of placebo, in a double-blind fashion.
Interventions
Starting medication doses were simvastatin/placebo 10 mg daily and
enalapril/placebo 2.5 mg twice daily. Automatic upward dose titration (done independently for each drug) occurred during the first 3
monthly visits until maximum doses (simvastatin 40 mg daily and
enalapril 10 mg twice daily) or, if side effects occurred, maximally
tolerated doses were achieved and maintained. These doses could be
decreased or discontinued for severe adverse effects.
Statistical Analysis
The sample size of 460 patients, allowing for 15% dropout, had
ⱖ95% power (with a 2-tailed P⬍0.05) for detecting differences in
primary angiographic end points between treatment and control
groups. Primary analyses compared the treatment effects of simvastatin with its placebo and those of enalapril with its placebo.
Secondary analyses compared the effects in patients receiving
simvastatin plus enalapril, simvastatin alone, enalapril alone, and
double placebo, as well as in other specified subgroups. Analyses
followed the intention-to-treat principle.
Comparability of treatment groups with respect to baseline characteristics was assessed using Student’s t tests for continuous
variables and ␹2 tests for categorical variables. Random effects
regression models20 were used to evaluate the effect of treatment on
longitudinal changes in lipid and blood pressure levels after adjusting
for baseline levels. Angiographic outcomes were compared across
treatment groups and subgroups using ANOVA methods. Group
differences in the distribution of patients classified as progressors,
regressors, mixed progressors/regressors, or no change were determined using ␹2 tests. Because of the small number of events,
significance levels for comparisons of clinical end points were
obtained by Fisher’s exact test. Data on continuous variables were
expressed as mean⫾1SD. Statistical significance was set at P⬍0.05
(2-tailed).
1750
Circulation
October 10, 2000
TABLE 1.
Baseline Characteristics
Simvastatin
n
Male
Female
Enalapril
Overall
Active
Placebo
Active
Placebo
460
230
230
229
231
410 (89)
201 (87%)
209 (91)
204 (89)
206 (89)
50 (11)
29 (13%)
21 (9)
25 (11)
25 (11)
61⫾9
61⫾10
61⫾9
60⫾10
62⫾9
Age
Average, y
Age 30–59 y
194 (42)
95 (43)
99 (41)
104 (45)
90 (39)
60–75 y
244 (53)
121 (53)
123 (53)
114 (50)
130 (56)
22 (5)
14 (3)
8 (6)
11 (5)
11 (5)
⬎75 y
History
Angina
249 (54)
129 (56)
120 (52)
118 (52)
131 (57)
Myocardial infarction
324 (70)
159 (69)
165 (72)
161 (70)
163 (71)
50 (11)
31 (14)
19 (8)
25 (11)
25 (11)
162 (36)
80 (35)
82 (36)
89 (39)
73 (32)
Diabetes
Hypertension
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Smoking
Current
69 (15)
35 (15)
34 (15)
34 (15)
35 (15)
Previous
306 (67)
148 (64)
158 (69)
157 (69)
149 (65)
85 (18)
47 (20)
38 (16)
38 (17)
47 (20)
ASA
413 (90)
205 (90)
208 (90)
208 (91)
205 (89)
␤-Blockers
217 (47)
110 (48)
107 (47)
110 (49)
105 (46)
Nitrates
295 (64)
151 (66)
144 (63)
143 (62)
152 (66)
65 (14)
27 (12)
38 (17)
36 (16)
29 (13)
Never
Concomitant medications
Calcium blockers
Values are n (%), except for average age, which is mean⫾SD.
Results
Screening ⬎16 500 charts and 4000 coronary angiograms led
to the enrollment of 460 patients between June 1991 and July
1995 in 4 Canadian centers. One third of patients entering the
run-in phase were not randomized. This may have reduced
subsequent dropouts. Patients had closeout angiograms on a
first-in, first-out basis between July 1996 and July 31, 1998,
when the first and last patients had been followed for 5 and 3
years, respectively.
Baseline characteristics are summarized in Tables 1 and 2.
The average daily simvastatin dose was 28.5⫾13.0 mg and
that of its placebo, 32.2⫾11.6 mg; for enalapril, the average
daily dose was 7.4⫾3.3 mg twice a day and that for its
placebo, 8.3⫾2.9 mg twice a day. Average compliance for
both drugs and placebos, assessed by pill counts at each visit,
was ⬇95% throughout the trial.
Average follow-up was 47.8 months. Closeout angiograms
were not obtained in 19 patients who died and in 47 others
because of refusal or intercurrent disease; 394 patients had
paired angiograms for analysis. Baseline characteristics and
responses to the treatments were not different between these
394 patients and the overall study population.
Lipid Levels and Blood Pressure
No differences existed in baseline lipid levels between
simvastatin and placebo groups. Substantial and highly significant changes in lipid levels were found in patients
receiving simvastatin but not placebo. Baseline systolic and
diastolic blood pressures did not differ between enalapril and
placebo patients. Systolic and diastolic blood pressures decreased significantly in patients on enalapril but not placebo
(Table 2).
Angiographic End Points
Effects of Simvastatin
Of the 394 patients with paired angiograms, 194 (2117
segments) were on simvastatin, and 200 patients (2101
segments) were on placebo. No baseline differences existed
in mean (2.75 versus 2.72 mm) and minimum (2.03 versus
2.01 mm) absolute diameters or percent diameter stenosis
(28.5% versus 27.9%) between simvastatin and placebo
patients. During treatment, the average per-patient mean
absolute diameter decreased by 0.07⫾0.20 mm with simvastatin and by 0.14⫾0.25 mm with placebo (P⫽0.004). The
respective average decreases in minimum absolute diameters
were 0.09⫾0.17 mm and 0.16⫾0.20 mm (P⫽0.0001). The
average increase in maximum percent diameter stenosis with
simvastatin was 1.67⫾5.01% and with placebo, 3.83⫾6.58%
(P⫽0.0003) (Figure 1). When the changes were examined by
prespecified subgroups (men, women, age⬍65 years, age
ⱖ65 years, smoking status, diabetics, nondiabetics, hypertensives, normotensives, and degree of baseline lesion severity
[ⱖ50%, ⬍50%], significant differences (or strong trends)
consistently existed in slowing of disease progression in favor
Teo et al
TABLE 2.
Lipid Lowering and ACE Inhibition in CAD
1751
Lipid Levels and Blood Pressures
Active
Placebo
Baseline
5.23⫾0.61
5.13⫾0.59
During trial
4.13⫾0.59
5.29⫾0.69
⫺1.09 (⫺20.6)
0.15 (3.3)
P*
Simvastatin
Average lipid levels, mmol/L
Total cholesterol
⌬ (%⌬) during trial
⬍0.001
HDL cholesterol
Baseline
0.99⫾0.24
0.97⫾0.25
During trial
1.07⫾0.24
1.01⫾0.25
⌬ (%⌬) during trial
0.07 (8.4)
0.02 (3.4)
⬍0.006
LDL cholesterol
Baseline
3.39⫾0.56
3.33⫾0.56
During trial
2.33⫾0.49
3.43⫾0.54
⫺1.06 (⫺30.5)
0.08 (3.5)
⌬ (%⌬) during trial
⬍0.001
Triglycerides
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Baseline
1.85⫾0.75
1.77⫾0.72
During trial
1.62⫾0.70
1.92⫾0.89
⫺0.23 (⫺9.7)
0.13 (8.6)
⌬ (%⌬) during trial
⬍0.001
Enalapril
Average blood pressures, mm Hg
Systolic
Baseline
128⫾19
132⫾20
During trial
122⫾14
130⫾14
⌬ (%⌬) during trial
⫺5.2 (⫺3.1)
⫺1.3 (⫺0.1) ⬍0.001
Diastolic
Clinical End Points
Baseline
77⫾11
78⫾10
During trial
74⫾7
77⫾8
⌬ (%⌬) during trial
Figure 1. Changes (⌬) between baseline and closeout angiographic mean absolute diameter, minimum absolute diameter,
and percent diameter stenosis in patients randomized to simvastatin or placebo and to enalapril or placebo. Patients randomized to active drug (solid bars) were compared with those on
placebo (open bars).
⫺3.3 (⫺3.3) ⫺0.35 (⫺0.5) ⬍0.001
*Comparing active with placebo.
Values are mean⫾SD or n (%).
of patients on simvastatin versus placebo. No relationship
existed between angiographic changes and baseline lipid
levels, but a clear relationship existed between angiographic
changes and changes in lipid levels during the study. Simvastatin treatment resulted in fewer progressors, more regressors, and more patients with no changes, compared with
placebo, for all 3 QCA end points (Figure 2). Total occlusion
of ⱖ1 coronary artery occurred in 16 simvastatin and 15
placebo patients.
Effects of Enalapril
Paired angiograms in 199 enalapril patients (2146 segments)
and 195 placebo patients (2072 segments) showed no differences in QCA end points (Figure 1).
Effects of Combination Therapy
Figure 3 compares QCA end points in the 4 treatment
subgroups: both simvastatin and enalapril (n⫽112), simvastatin plus enalapril placebo (n⫽118), enalapril plus simvastatin placebo (n⫽117), and double placebo (n⫽113). The
effects of simvastatin plus enalapril did not differ from those
of simvastatin alone, and the effects of enalapril and double
placebo were not different.
As summarized in Table 3, no differences existed between
simvastatin and placebo or enalapril and placebo in all-cause
mortality, in cardiovascular events (myocardial infarction,
stroke, or hospitalization for angina), or incidence of cancer.
Fewer revascularization procedures (6% versus 12%,
P⫽0.021) and angioplasties (3% versus 9%, P⫽0.020) were
required in simvastatin patients compared with placebo.
Compared with placebo, enalapril was associated with a
decrease in the combined end point of death/myocardial
infarction/stroke (7% versus 13%; P⫽0.043) (Table 3). Clinical events did not differ significantly among patients treated
with simvastatin and enalapril, simvastatin alone, enalapril
alone, and double placebo (Table 4).
Both agents were well tolerated. Serial biochemical monitoring showed no differences in the frequency of elevated
creatine kinase and liver enzyme abnormalities between
patients on simvastatin and those on placebo and no differences in the frequency of elevated serum potassium and
creatinine levels between patients on enalapril and those on
placebo.
Discussion
Important findings from this trial are that long-term lipidlowering therapy with simvastatin resulted in significant
slowing of CAD progression in normocholesterolemic patients that was independent of baseline lipid levels but related
to changes in lipid levels during treatment. Long-term ACE
inhibition with enalapril had a neutral effect on CAD pro-
1752
Circulation
October 10, 2000
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Figure 3. Changes (⌬) between baseline and closeout angiographic mean absolute diameter, minimum absolute diameter,
and percent diameter stenosis in patients randomized to simvastatin alone (Simva), simvastatin plus enalapril (Simva⫹Enal),
enalapril alone (Enal), or double placebo (Placebo).
Figure 2. Proportions of patients randomized to simvastatin
(solid bars) or placebo (open bars) who were regressors, progressors, mixed progressors/regressors, or had no change by
QCA end points of mean absolute diameter, minimum absolute
diameter, and percent diameter stenosis.
gression as determined by QCA. Adding enalapril to simvastatin did not result in an incremental angiographic effect.
Simvastatin was associated with less revascularization and
enalapril with fewer events (combined end point of death/
myocardial infarction/stroke). Patients receiving both drugs
had no fewer clinical events than those on either drug alone
or on placebo, although events were so few that conclusions
are subject to chance. The effects of individual drugs on
clinical events may be due to chance, but they are consistent
with other large trials of lipid-lowering therapy and ACE
inhibition.1–3,14 –16
The impact of simvastatin on CAD progression in normocholesterolemic patients was similar to that in earlier studies which
enrolled patients with higher cholesterol levels.4 – 8 The magnitude of changes in lumen diameters may be too small to be
clinically relevant.21 However, this may be because the changes
in lumen diameters reported in this and other studies are, for the
purpose of group comparisons, “statistical measures” derived
from averaging effects observed in a large number of segments
instead of “actual measures” in one individual. On a per-patient
basis, lipid lowering in this group of normocholesterolemic
CAD patients resulted in more patients having regression or no
change in their CAD and fewer having progression. The magnitude of these changes on the arterial wall is consistent with the
proposed mechanism of plaque shrinkage due to reduction in
and stabilization of the lipid-rich plaque.21
The smaller sample size and shorter follow-up of normocholesterolemic patients in the Harvard Atherosclerosis Reversibility Project (HARP) trial may explain the reported
neutral effect on angiographic end points, unlike our conclusively positive results. This observation was supported by the
findings of the Multicentre Anti-Atheroma Study (MAAS),
which examined follow-up data at 2 and 4 years. Benefits
became clear and significant at 4 years.7
It had been anticipated a priori that ACE inhibition would
have a beneficial effect on CAD and that adding ACE inhibition
to cholesterol lowering would have a synergistic effect. Our
angiographic results failed to substantiate these expectations.
Reasons for these outcomes are unclear. One important difference between this trial and others that have shown the angiographic benefits of ACE inhibition is the different procedural
conditions. For example, the Trial on Reversing Endothelial
Dysfunction (TREND) study, which examined coronary vasomotor dysfunction using acetylcholine-provoked constriction of
target segments, avoided vasoactive drugs for ⱖ12 hours before
the procedure.22 Because we were interested in changes in
anatomic atherosclerosis, we gave nitrates before and during the
procedure to minimize variability in coronary lumen diameter
due to vasomotor tone. This pretreatment likely abolished any
differences in lumen diameters mediated by differing vasomotor
tone between treatment groups. Preliminary data from a trial of
ACE inhibition suggested benefits when ultrasound measurement of the carotid artery intima-media thickness was used.
Changes in ultrasonic measures of wall thickness, detected with
intravascular ultrasound, would precede QCA lumen diameter
Teo et al
TABLE 3.
Lipid Lowering and ACE Inhibition in CAD
1753
Clinical Events by Treatment
Simvastatin
Enalapril
Placebo
P
13 (6)
6 (2)
0.159
Cardiac
7 (3)
Noncardiac
6 (3)
11 (5)
10 (4)
Active
Death
Myocardial infarction
Fatal
Nonfatal
1 (0.4)
Active
Placebo
8 (3)
11 (5)
4 (2)
4 (2)
7 (3)
2 (1)
4 (2)
4 (2)
8 (3)
13 (6)
1.000
1 (0.4)
1 (0.4)
0.372
1 (0.4)
10 (4)
9 (4)
4 (2)
7 (3)
0.544
2 (1)
9 (4)
0.063
Combined end point
25 (11)
21 (9)
0.642
16 (7)
30 (13)
0.043
Hospitalization for angina
30 (13)
39 (17)
0.297
40 (17)
29 (13)
0.153
Any revascularization
13 (6)
28 (12)
0.021
16 (7)
25 (11)
0.191
8 (3)
21 (9)
0.020
11 (5)
18 (8)
0.250
Stroke
PTCA
CABG
7 (3)
P
0.641
12 (5)
7 (3)
9 (4)
0.801
8 (3)
8 (3)
1.000
14 (6)
18 (8)
0.584
18 (8)
14 (6)
0.470
Cancer
23 (10)
13 (6)
0.117
19 (8)
17 (7)
0.731
Other*
74 (32)
65 (28)
0.417
68 (29)
71 (31)
0.840
Other cardiovascular events
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Noncardiovascular events
Values are n (%). Abbreviations as in Table 3.
changes. In the absence of intravascular ultrasound data, it
cannot be concluded that enalapril had no effect.
If, as has been suggested, aspirin has a large negative interaction
with enalapril, concomitant aspirin use might confound the results
and negate the effects of ACE inhibition in this study. Secondary
analysis of data from heart failure trials suggests that such an effect
is possible, although its magnitude is probably small. This effect has
not been consistently reported.23,24 The Heart Outcomes Prevention
Evaluation (HOPE) trial reported clear clinical benefits with ACE
inhibition in the same type of patients, most of whom were on
aspirin,16 as those enrolled in the Simvastatin/Enalapril Coronary
Atherosclerosis Trial.
Potential mechanisms of the benefit of ACE inhibition
include normalization of endothelial dysfunction and
plaque formation and stabilization.12,13 These effects,
which are not easily detected by QCA analysis, may have
TABLE 4. Clinical Events by Treatment (Singly, in Combination, or
Double Placebo)
Death
Simvastatin
Simvastatin and
Enalapril
Enalapril
Double
Placebo
7 (6)
6 (5)
2 (2)
4 (4)
Cardiac
4 (3)
3 (3)
1 (1)
3 (3)
Noncardiac
3 (3)
3 (3)
1 (1)
1 (1)
5 (4)
6 (5)
2 (2)
8 (7)
Fatal
0 (0)
1 (1)
0 (0)
1 (1)
Nonfatal
5 (4)
5 (4)
2 (2)
7 (6)
4 (3)
0 (0)
2 (2)
5 (4)
14 (12)
11 (10)
5 (4)
15 (13)
Hospitalization for angina
14 (12)
16 (14)
24 (21)
15 (13)
Any revascularization
10 (8)
3 (3)
13 (11)
15 (13)
PTCA
6 (5)
2 (2)
9 (8)
12 (11)
CABG
5 (4)
2 (2)
6 (5)
3 (3)
8 (7)
6 (5)
12 (10)
6 (5)
Cancer
11 (9)
12 (11)
7 (6)
6 (5)
Other
38 (32)
36 (32)
32 (27)
33 (29)
Myocardial infarction
Stroke
Combined end point
Other cardiovascular events
Noncardiovascular events
Values are n (%). The combined end point was death, myocardial infarction, and/or stroke. PTCA
indicates percutaneous transluminal coronary angioplasty; CABG, coronary artery bypass grafting; and
other, hospitalization for other, noncardiovascular events.
1754
Circulation
October 10, 2000
been operative in large trials demonstrating clinical
benefits.14 –16
Conclusions
The angiographic and clinical results from this long-term
lipid-lowering trial confirm the beneficial effects of therapy
and extend the observation of positive angiographic effects to
normocholesterolemic CAD patients. In other words, these
results support the concept that nearly all CAD patients may
benefit from treatment with simvastatin.
The implications of the neutral angiographic effects of
ACE inhibition are uncertain, but they deserve further investigation in light of the positive clinical benefits suggested
here and seen elsewhere. Although no definitive conclusions
can be drawn from the clinical effects of combination
therapy, this important issue may be further resolved with the
pending results of other large randomized trials.
Acknowledgments
Downloaded from http://circ.ahajournals.org/ by guest on March 2, 2017
The late Dr N.J. Davies contributed substantially to the planning and
implementation of this study. The committed participation of the
patients in this study and the cooperation of their physicians are
gratefully acknowledged. We gratefully acknowledge the financial
and in-kind support of the Medical Research Council of Canada,
Merck Frosst Canada & Co, the Alberta Heritage Foundation for
Medical Research, University of Alberta Hospitals, and
Safeway Canada.
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Long-Term Effects of Cholesterol Lowering and Angiotensin-Converting Enzyme
Inhibition on Coronary Atherosclerosis: The Simvastatin/Enalapril Coronary
Atherosclerosis Trial (SCAT)
Koon K. Teo, Jeffrey R. Burton, Christopher E. Buller, Sylvain Plante, Diane Catellier, Wayne
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for the SCAT Investigators
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Circulation. 2000;102:1748-1754
doi: 10.1161/01.CIR.102.15.1748
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