(Circulation. 2000;102:1748.)
© 2000 American Heart Association, Inc.
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)
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.
Correspondence to Dr Koon K. Teo, Rm 3U4, McMaster University Medical Centre, 1200 Main Street West, Hamilton, Ontario, Canada L8N 3Z5. E-mail teok{at}fhs.mcmaster.ca
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Abstract |
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Background—This long-term, multicenter, randomized, double-blind, placebo-controlled, 2x2 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.
Key Words: atherosclerosis • coronary disease • cholesterol • angiotensin-converting enzyme inhibitors
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Introduction |
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The clearly demonstrated benefits of cholesterol-lowering therapy in reducing coronary atherosclerotic disease (CAD)1 2 3 are thought to be related, at least in part, to the slowed progression or enhanced regression of CAD.4 5 6 7 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 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, 2x2 factorial, clinical trial.
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Methods |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Patients
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
21 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 3 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 1 week before closeout
QCA. Sublingual isosorbide dinitrate (5 to 10 mg; 10 minutes before
angiography) or nitroglycerin (100 to 300 µg 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 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 0.4 mm (or by an absolute 15% in
diameter stenosis) in 1 segment while the other segments
remained unchanged. Mixed progressors/regressors had 1 segment
with progression plus 1 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
95% 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).
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Results |
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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.
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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 65
years, smoking status, diabetics, nondiabetics, hypertensives,
normotensives, and degree of baseline lesion severity [50%,
<50%], significant differences (or strong trends)
consistently existed in slowing of disease progression in favor
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 1
coronary artery occurred in 16 simvastatin and 15
placebo patients.
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) 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).
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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.
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Clinical End Points
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).
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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.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Important findings from this trial are that long-term lipid-lowering 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 progression 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 2 3 14 15 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 5 6 7 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 12 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 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 been operative in large trials demonstrating clinical benefits.14 15 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.
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Acknowledgments |
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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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Footnotes |
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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
Received March 30, 2000; revision received May 11, 2000; accepted May 11, 2000.
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References |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. Scandinavian Simvastatin Survival Study Group. Randomized trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet. 1994;344:1383–1389.[Medline] [Order article via Infotrieve]
2.
Sacks FM, Pfeffer MA, Moye LA, et al, for the
Cholesterol and Recurrent Events Trial Investigators. The
effect of pravastatin on coronary events after
myocardial infarction in patients with average cholesterol
levels. N Engl J Med. 1996;335:1001–1009.
3.
Downs JR, Clearfield M, Weis S, et al, for the
AFCAPS/Tex CAPS Research Group. Primary prevention of acute
coronary events with lovastatin in men and women
with average cholesterol levels: results of AFCAPS/TexCAPS.
JAMA. 1998;279:1615–1622.
4.
Kane JP, Malloy MJ, Ports TA, et al. Regression of
coronary atherosclerosis during treatment of
familial hypercholesterolemia with combined
drug regimens. JAMA. 1990;264:3007–3012.
5. Brown BG, 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;323:1289–1298.[Abstract]
6.
Waters D, Higginson L, Gladstone P, et al, for the
CCAIT Study Group. Effects of monotherapy with an HMG-CoA reductase
inhibitor on the progression of coronary
atherosclerosis as assessed by serial quantitative
arteriography: the Canadian Coronary
Atherosclerosis Intervention Trial.
Circulation. 1994;89:959–968.
7. MAAS Investigators. Effect of simvastatin on coronary atheroma: the Multicentre Anti-Atheroma Study (MAAS). Lancet. 1994;344:633–638.[Medline] [Order article via Infotrieve]
8. Herd JA, Ballantyne CM, Farmer JA, et al, for the LCAS Investigators. Effects of fluvastatin on coronary atherosclerosis in patients with mild to moderate cholesterol elevations (Lipoprotein and Coronary Atherosclerosis Study [LCAS]). Am J Cardiol. 1997;80:278–286.[Medline] [Order article via Infotrieve]
9. Rubins HB, Robins SJ, Collins D, et al, for the Department of Veterans Affairs HDL Intervention Trial Study Group. Distribution of lipids in 8500 men with coronary artery disease. Am J Cardiol. 1995;75:1196–1201.[Medline] [Order article via Infotrieve]
10. Kannel WB. Range of serum cholesterol values in the population developing coronary artery disease. Am J Cardiol. 1995;76:69C–77C.[Medline] [Order article via Infotrieve]
11. Sacks FM, Pasternak RC, Gibson CM, et al, for the Harvard Atherosclerosis Reversibility Project (HARP) Group. Effect of coronary atherosclerosis of decrease in plasma cholesterol concentrations in normocholesterolemic patients. Lancet. 1994;344:1182–1186.[Medline] [Order article via Infotrieve]
12.
Lonn EM, Yusuf S, Jha P, et al. Emerging role of
angiotensin-converting enzyme inhibitors in
cardiac and vascular protection. Circulation. 1994;90:2056–2069.
13. Dzau VJ. Mechanism of protective effects of ACE inhibition on coronary artery disease. Eur Heart J. 1998;19(suppl J):J2–J6.
14. Yusuf S, Pepine CJ, Garces C, et al. Effect of enalapril on myocardial infarction and unstable angina in patients with low ejection fractions. Lancet. 1992;340:1173–1178.[Medline] [Order article via Infotrieve]
15. Pfeffer MA, Braunwald E, Moye LA, et al. Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med. 1992;327:669–677.[Abstract]
16.
The Heart Outcomes Prevention Evaluation (HOPE) Study
Investigators. Effects of an angiotensin-converting-enzyme
inhibitor, ramipril, on cardiovascular
events in high risk patients. N Engl J Med. 2000;342:145–153.
17. Teo KK, Burton JR, Buller C, et al, on behalf of the SCAT Investigators. Rationale and design features of a clinical trial examining the effects of cholesterol lowering and angiotensin-converting enzyme inhibition on coronary atherosclerosis: Simvastatin/Enalapril Coronary Atherosclerosis Trial (SCAT). Can J Cardiol. 1997;13:591–599.[Medline] [Order article via Infotrieve]
18. Austen WG, Edwards JE, Frye RL, et al. A reporting system on patients evaluated for coronary artery disease: report of the Ad Hoc committee for Grading of Coronary Artery Disease, Council of Cardiovascular Surgery, American Heart Association. Circulation. 1975;51:5–40.[Medline] [Order article via Infotrieve]
19.
Reiber JHC, Serruys PW, Kooijman CJ, et al. Assessment
of short-, medium- and long-term variations in arterial
dimensions from computer-assisted quantitation of coronary
cineangiograms. Circulation. 1985;71:280–288.
20. Laird NM, Ware JH. Random effects models for longitudinal data. Biometrics. 1984;38:963–974.
21.
Brown BG, Zhao XQ, Sacco DE, et al. Lipid lowering and
plaque regression: new insights into prevention of plaque disruption
and clinical events in coronary disease.
Circulation. 1993;87:1781–1791.
22.
Mancini GBJ, Henry GC, Macaya C, et al.
Angiotensin-converting enzyme inhibition with quinapril
improves endothelial vasomotor dysfunction in patients
with coronary artery disease: the TREND (Trial on Reversing
Endothelial Dysfunction) study. Circulation. 1996;94:258–265.
23. Pitt B, Yusuf S, for the SOLVD Investigators. Studies of left ventricular dysfunction (SOLVD) sugbroup results. J Am Coll Cardiol. 1992;19:215A.
24. Nguyen KN, Aursnes I, Kjekshus J. Interaction between enalapril and aspirin on mortality after acute myocardial infarction: subgroup analysis of the Cooperative New Scandinavian Enalapril Survival Study II (CONSENSUS II). Am J Cardiol. 1997;79:115–119.[Medline] [Order article via Infotrieve]
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S. Heeneman, J. C. Sluimer, and M. J.A.P. Daemen Angiotensin-Converting Enzyme and Vascular Remodeling Circ. Res., August 31, 2007; 101(5): 441 - 454. [Abstract] [Full Text] [PDF]
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 C. G. P. Roberts, E. Guallar, and A. Rodriguez Efficacy and Safety of Statin Monotherapy in Older Adults: A Meta-Analysis J. Gerontol. A Biol. Sci. Med. Sci., August 1, 2007; 62(8): 879 - 887. [Abstract] [Full Text] [PDF]
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 V. J. Dzau, E. M. Antman, H. R. Black, D. L. Hayes, J. E. Manson, J. Plutzky, J. J. Popma, and W. Stevenson The Cardiovascular Disease Continuum Validated: Clinical Evidence of Improved Patient Outcomes: Part I: Pathophysiology and Clinical Trial Evidence (Risk Factors Through Stable Coronary Artery Disease) Circulation, December 19, 2006; 114(25): 2850 - 2870. [Full Text] [PDF]
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 S. Bonovas, K. Filioussi, N. Tsavaris, and N. M. Sitaras Statins and Cancer Risk: A Literature-Based Meta-Analysis and Meta-Regression Analysis of 35 Randomized Controlled Trials J. Clin. Oncol., October 20, 2006; 24(30): 4808 - 4817. [Abstract] [Full Text] [PDF]
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 T.-M. Lee, M.-S. Lin, T.-F. Chou, and N.-C. Chang Additive effects of combined blockade of AT1 receptor and HMG-CoA reductase on left ventricular remodeling in infarcted rats Am J Physiol Heart Circ Physiol, September 1, 2006; 291(3): H1281 - H1289. [Abstract] [Full Text] [PDF]
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 N. Danchin, M. Cucherat, C. Thuillez, E. Durand, Z. Kadri, and P. G. Steg Angiotensin-Converting Enzyme Inhibitors in Patients With Coronary Artery Disease and Absence of Heart Failure or Left Ventricular Systolic Dysfunction: An Overview of Long-term Randomized Controlled Trials. Arch Intern Med, April 10, 2006; 166(7): 787 - 796. [Abstract] [Full Text] [PDF]
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 Additional Information JAMA, March 15, 2006; 295(11): E1 - E6. [Full Text] [PDF]
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W. Rief, J. Avorn, and A. J. Barsky Medication-Attributed Adverse Effects in Placebo Groups: Implications for Assessment of Adverse Effects Arch Intern Med, January 23, 2006; 166(2): 155 - 160. [Abstract] [Full Text] [PDF]
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K. M. Dale, C. I. Coleman, N. N. Henyan, J. Kluger, and C. M. White Statins and Cancer Risk: A Meta-analysis JAMA, January 4, 2006; 295(1): 74 - 80. [Abstract] [Full Text] [PDF]
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J. G. Robinson, B. Smith, N. Maheshwari, and H. Schrott Pleiotropic Effects of Statins: Benefit Beyond Cholesterol Reduction?: A Meta-Regression Analysis J. Am. Coll. Cardiol., November 15, 2005; 46(10): 1855 - 1862. [Abstract] [Full Text] [PDF]
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 P. Verdecchia, G. Reboldi, F. Angeli, R. Gattobigio, M. Bentivoglio, L. Thijs, J. A. Staessen, and C. Porcellati Angiotensin-Converting Enzyme Inhibitors and Calcium Channel Blockers for Coronary Heart Disease and Stroke Prevention Hypertension, August 1, 2005; 46(2): 386 - 392. [Abstract] [Full Text] [PDF]
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C. A. Daly, K. M. Fox, W. J. Remme, M. E. Bertrand, R. Ferrari, M. L. Simoons, and on behalf of the EUROPA investigators The effect of perindopril on cardiovascular morbidity and mortality in patients with diabetes in the EUROPA study: results from the PERSUADE substudy Eur. Heart J., July 2, 2005; 26(14): 1369 - 1378. [Abstract] [Full Text] [PDF]
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P. K. Whelton, J. Barzilay, W. C. Cushman, B. R. Davis, E. IIamathi, J. B. Kostis, F. H. H. Leenen, G. T. Louis, K. L. Margolis, D. E. Mathis, et al. Clinical Outcomes in Antihypertensive Treatment of Type 2 Diabetes, Impaired Fasting Glucose Concentration, and Normoglycemia: Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) Arch Intern Med, June 27, 2005; 165(12): 1401 - 1409. [Abstract] [Full Text] [PDF]
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Blood Pressure Lowering Treatment Trialists' Colla Effects of Different Blood Pressure-Lowering Regimens on Major Cardiovascular Events in Individuals With and Without Diabetes Mellitus: Results of Prospectively Designed Overviews of Randomized Trials Arch Intern Med, June 27, 2005; 165(12): 1410 - 1419. [Abstract] [Full Text] [PDF]
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E. Shinoda, Y. Yui, K. Kodama, A. Hirayama, H. Nonogi, K. Haze, T. Sumiyoshi, S. Hosoda, C. Kawai, and for the Japan Multicenter Investigation for Cardio Quantitative Coronary Angiogram Analysis: Nifedipine Retard Versus Angiotensin-Converting Enzyme Inhibitors (JMIC-B Side Arm Study) Hypertension, June 1, 2005; 45(6): 1153 - 1158. [Abstract] [Full Text] [PDF]
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 J. A. Papadakis, D. P. Mikhailidis, G. E. Vrentzos, A. Kalikaki, I. Kazakou, and E. S. Ganotakis Effect of Antihypertensive Treatment on PlasmaFibrinogen and Serum HDL Levelsin Patients with Essential Hypertension Clinical and Applied Thrombosis/Hemostasis, April 1, 2005; 11(2): 139 - 146. [Abstract] [PDF]
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 P. Amarenco, J. Labreuche, P. Lavallee, and P.-J. Touboul Statins in Stroke Prevention and Carotid Atherosclerosis: Systematic Review and Up-to-Date Meta-Analysis Stroke, December 1, 2004; 35(12): 2902 - 2909. [Abstract] [Full Text] [PDF]
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Task Force Members, J. Lopez-Sendon, K. Swedberg, J. McMurray, J. Tamargo, A. P. Maggioni, H. Dargie, M. Tendera, F. Waagstein, J. Kjekshus, et al. Expert consensus document on angiotensin converting enzyme inhibitors in cardiovascular disease: The Task Force on ACE-inhibitors of the European Society of Cardiology Eur. Heart J., August 2, 2004; 25(16): 1454 - 1470. [Full Text] [PDF]
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K. K. Koh, J. W. Son, J. Y. Ahn, D. S. Kim, D. K. Jin, H. S. Kim, S. H. Han, Y.-H. Seo, W.-J. Chung, W. C. Kang, et al. Simvastatin Combined With Ramipril Treatment in Hypercholesterolemic Patients Hypertension, August 1, 2004; 44(2): 180 - 185. [Abstract] [Full Text] [PDF]
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T. J. Wilt, H. E. Bloomfield, R. MacDonald, D. Nelson, I. Rutks, M. Ho, G. Larsen, A. McCall, S. Pineros, and A. Sales Effectiveness of Statin Therapy in Adults With Coronary Heart Disease Arch Intern Med, July 12, 2004; 164(13): 1427 - 1436. [Abstract] [Full Text] [PDF]
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J. M. E. Walsh and M. Pignone Drug Treatment of Hyperlipidemia in Women JAMA, May 12, 2004; 291(18): 2243 - 2252. [Abstract] [Full Text] [PDF]
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C. M.M. Lawes, D. A. Bennett, V. L. Feigin, and A. Rodgers Blood Pressure and Stroke: An Overview of Published Reviews Stroke, April 1, 2004; 35(4): 1024 - 1033. [Abstract] [Full Text] [PDF]
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S. E. Lipshultz and S. D. Colan Cardiovascular Trials in Long-Term Survivors of Childhood Cancer J. Clin. Oncol., March 1, 2004; 22(5): 769 - 773. [Full Text] [PDF]
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|
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C. M.M. Lawes, D. A. Bennett, V. L. Feigin, and A. Rodgers Blood Pressure and Stroke: An Overview of Published Reviews Stroke, March 1, 2004; 35(3): 776 - 785. [Abstract] [Full Text] [PDF]
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F. H. Messerli Vascular Protection of ACE Inhibitors Arch Intern Med, December 8, 2003; 163(22): 2791 - 2792. [Full Text] [PDF]
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 A. T Hirsch and D. Duprez The potential role of angiotensin-converting enzyme inhibition in peripheral arterial disease Vascular Medicine, November 1, 2003; 8(4): 273 - 278. [Abstract] [PDF]
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D. S. Jacoby and D. J. Rader Renin-Angiotensin System and Atherothrombotic Disease: From Genes to Treatment Arch Intern Med, May 26, 2003; 163(10): 1155 - 1164. [Abstract] [Full Text] [PDF]
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F. A. McAlister, S. E. Straus, D. L. Sackett, and D. G. Altman Analysis and Reporting of Factorial Trials: A Systematic Review JAMA, May 21, 2003; 289(19): 2545 - 2553. [Abstract] [Full Text] [PDF]
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J.-C. Corvol, A. Bouzamondo, M. Sirol, J.-S. Hulot, P. Sanchez, and P. Lechat Differential Effects of Lipid-Lowering Therapies on Stroke Prevention: A Meta-analysis of Randomized Trials Arch Intern Med, March 24, 2003; 163(6): 669 - 676. [Abstract] [Full Text] [PDF]
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J. A Staessen, J.-G. Wang, and W. H Birkenhager Outcome beyond blood pressure control? Eur. Heart J., March 2, 2003; 24(6): 504 - 514. [Full Text] [PDF]
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E. Lonn, H.C. Gerstein, M. Smieja, J.F.E. Mann, and S. Yusuf Mechanisms of cardiovascular risk reduction with ramipril: insights from HOPE and HOPE substudies Eur. Heart J. Suppl., January 1, 2003; 5(suppl_A): A43 - A48. [Abstract] [PDF]
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 J.-G. Wang and J. A. Staessen Conventional Therapy and Newer Drug Classes for Cardiovascular Protection in Hypertension J. Am. Soc. Nephrol., November 1, 2002; 13(90003): S208 - 215. [Abstract] [Full Text]
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E. M. Lonn, S. Yusuf, V. Dzavik, C. I. Doris, Q. Yi, S. Smith, A. Moore-Cox, J. Bosch, W. A. Riley, and K. K. Teo Effects of Ramipril and Vitamin E on Atherosclerosis : The Study to Evaluate Carotid Ultrasound Changes in Patients Treated With Ramipril and Vitamin E (SECURE) Circulation, February 20, 2001; 103(7): 919 - 925. [Abstract] [Full Text] [PDF]
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 Cholesterol Lowering and ACE Inhibition in Normocholesterolemic Patients Journal Watch Cardiology, January 5, 2001; 2001(105): 4 - 4. [Full Text]
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J. H. O'Keefe, M. Wetzel, R. R. Moe, K. Brosnahan, and C. J. Lavie Should an angiotensin-converting enzyme inhibitor be standard therapy for patients with atherosclerotic disease? J. Am. Coll. Cardiol., January 1, 2001; 37(1): 1 - 8. [Abstract] [Full Text] [PDF]
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