(Circulation. 1995;92:1758-1764.)
© 1995 American Heart Association, Inc.
Articles |
Kuopio Atherosclerosis Prevention Study (KAPS)
A Population-Based Primary Preventive Trial of the Effect of LDL Lowering on Atherosclerotic Progression in Carotid and Femoral Arteries
From the Research Institute of Public Health, University of Kuopio (Finland) (R.S., K.N., E.P. J.R., J.T.S.), and the Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ (R.B., J.-S.P.).
Correspondence to Prof Jukka T. Salonen, Research Institute of Public Health, University of Kuopio, PO Box 1627, 70211 Kuopio, Finland.
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Abstract |
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 Top Abstract IntroductionMethods Results Discussion References |
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Background The atherosclerotic progression–reducing effect of LDL cholesterol (LDL-C) lowering has been established in subjects with severe atherosclerotic disease but not in persons with elevated LDL cholesterols without severe atherosclerosis. KAPS (Kuopio Atherosclerosis Prevention Study) is the first population-based trial in the primary prevention of carotid and femoral atherosclerosis.
Methods and Results The eligibility requirements were serum LDL-C
4.0 mmol/L and total cholesterol <7.5 mmol/L. Out of a
geographically defined population, 447 men aged 44 to 65 years (mean,
57) were randomized to pravastatin (40 mg/d) or placebo for
3 years. Less than 10% of the subjects had prior myocardial
infarction. Thirty-nine men discontinued study medication; however,
efficacy data were available for 424 men. The primary outcome was the
rate of carotid atherosclerotic progression, measured as the linear
slope over annual ultrasound examinations in the average of the maximum
carotid intima-media thickness (IMT) of the far wall of up to four
arterial segments (the right and left distal common carotid
artery and the right and left carotid bulb). For the carotid arteries,
at the overall mean baseline IMT of 1.66 mm, the rate of progression of
carotid atherosclerosis was 45% (95% CI, 16 to 69%)
less in the pravastatin (0.017 mm/y) than the placebo
(0.031 mm/y) group (P=.005). In the common carotid artery
there was a treatment effect of 66% (95% CI, 30 to 95%;
pravastatin 0.010 mm/y; placebo 0.029 mm/y;
P<.002) at the overall mean baseline IMT of 1.35 mm. A
treatment effect of 30% (95% CI, -1% to 54%) was found for the
carotid bulb (pravastatin, 0.028; placebo, 0.040;
P=.056) at the overall mean baseline IMT of 2.0 mm. The
treatment effect was larger in subjects with higher baseline IMT
values, in smokers and in those with low plasma vitamin E levels. There
was no significant treatment effect on atherosclerotic progression in
the femoral arteries.
Conclusions These data establish the antiatherogenic effect of LDL-C lowering by pravastatin in hypercholesterolemic men in a primary prevention setting and suggest a greater effect in smokers than in nonsmokers.
Key Words: smoking • lipoproteins • clinical trials • atherosclerosis
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Introduction |
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TopAbstractIntroductionMethods Results Discussion References |
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Previous clinical trials based on both angiographic and ultrasonographic imaging of arteries have established the antiatherogenic effect of LDL cholesterol (LDL-C) lowering treatment in persons with advanced atherosclerotic disease.1 Not much is known about the preventive effects of LDL-C lowering in subjects without established atherosclerotic vascular disease and with moderately elevated cholesterol levels. All previous studies to date have selected subjects on the basis of high cholesterol levels and the presence of atherosclerosis at baseline.2 3 4 5 6 7 Ultrasonographic imaging provides a reliable and relatively simple way to noninvasively evaluate the progression of atherosclerosis in carotid and femoral arteries.8 9 10 11 The KAPS study was designed to evaluate the effect of LDL-C lowering by pravastatin on the progression of carotid and femoral atherosclerosis in all eligible men from an observational population-based study, the Kuopio Ischaemic Heart Disease Risk Factor Study (KIHD).12 The subjects were hypercholesterolemic men, not selected on the basis of either their cardiovascular disease history or atherosclerotic findings at entry.13
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Methods |
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TopAbstractIntroductionMethods Results Discussion References |
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Study Design
KAPS was a randomized, double masked, placebo-controlled, single center study to evaluate the effect of LDL-C lowering with a hydroxy methylglutaryl coenzyme A (HMG CoA) reductase inhibitor, pravastatin, on the arterial wall of the carotid and the femoral arteries as evaluated by B-mode ultrasound. Subjects were stratified according to smoking status and presence of atherosclerotic lesions at baseline. The study consisted of a 2
month placebo lead-in period and a 3-year
double masked
placebo controlled treatment period. The primary outcome was the rate
of carotid atherosclerotic progression, measured as the linear slope
over annual ultrasound examinations in the average of maximum carotid
IMT of the far wall of up to four arterial segments (left
and right common carotid artery and left and right carotid bulb).
Secondary outcomes included the rate of atherosclerotic progression in
the far walls of the common carotid artery, bulb and femoral artery
individually, and the combined outcome of the carotid and femoral
arteries. The study protocol was approved by an international policy
advisory board and by the Research Ethical Committee of the University
of Kuopio. The advisory board also acted as the safety committee. Two
independent monitors ascertained that the study was conducted according
to good clinical practice standards.
Subjects
The present study was carried out in subjects drawn
from an
observational population study, KIHD. KIHD is an ongoing study to
investigate and identify risk factors for coronary heart
disease, extracoronary atherosclerosis, and
related outcomes.12 The study sample consisted of a
randomly selected cohort of men, aged either 42, 48, 54, or 60 years at
the entry examination, living in the city of Kuopio and seven
neighboring rural communities. In the baseline examinations, carried
out between 1984 and 1989, a total of 2682 men (82.9% of those invited
and eligible) participated. The details of the examination have been
described earlier.12
All KIHD participants with serum
LDL-C levels of 4.25 mmol/L or more
and body mass index of 32 kg/m2 or less (n=1194) were
invited to LDL-C rescreening in 1989 or 1990. If at rescreening a
subject had serum LDL-C >4.25 mmol/L, serum total
cholesterol <8.0 mmol/L, body mass index <32
kg/m2, and liver enzymes (alanine aminotransferase [ALAT]
and aspartate aminotransferase [ASAT]) not exceeding 1.5-fold the
laboratory upper normal limit, he was eligible for participation in
KAPS. Of the 987 rescreening participants, 606 men were eligible and
invited to participate in KAPS. Of those invited, 21 men refused to
participate, 11 had severe illness, and 17 were already on LDL-C
lowering medication that was considered necessary. Five hundred and
fifty-seven (557) eligible men were enrolled in KAPS, started on
placebo and given dietary advice to lower LDL-C. After the
2-month placebo lead-in/dietary advice period,
447 men
whose serum LDL-C remained >4.0 mmol/L and total serum
cholesterol was <7.5 mmol/L were randomized. Lipid
measurements were repeated at randomization. Before entry, all
participants signed a written informed consent. All subjects were
entered into the double-masked phase between January and September
1990 and they completed the trial during January to September 1993.
Randomization, Blinding, Double-Masked Treatment, and
Follow-up
The participants were randomized either to
pravastatin 40 mg once daily at bedtime or to placebo. The
randomization scheme was generated by a KAPS biostatistician and the
double-masked treatment units were prepared at the Bristol-Myers
Squibb Pharmaceutical Research Institute, Moreton, UK, which also
provided the drug supplies. Placebo and pravastatin tablets
looked identical. Randomization was stratified to obtain equal
distribution over the treatment groups and to enable statistical tests
of effect modification. Regular smokers (at least 10 cigarettes/d) and
nonsmokers (for the purpose of stratified randomization defined as less
than 10 cigarettes/d) and subjects with and without atherosclerotic
lesions at their baseline ultrasound examination were randomized
separately. To assure the masking of the investigators and other staff,
the lipid values were kept in a data register, to which there was no
access for investigators other than the chief lipid chemist (KN). The
subjects visited the study center (Research Institute of Public Health,
University of Kuopio) at 3-month intervals.
Ultrasonographic Assessment of
Atherosclerosis
High-resolution B-mode ultrasonography was used to
image
carotid and femoral arteries. The protocol involved the scanning of the
right and left common carotid artery and the area of the carotid sinus
(bulb) as high up as possible and the right and left common femoral
artery including the femoral bifurcation. Three fixed angles of
interrogation were used: anterolateral, lateral, and posterolateral.
Images were focused on the posterior (far) wall. Ultrasonographic
examinations were performed with the subject in the supine position
after a rest of 15 minutes. The ultrasound system used was the Biosound
Phase 2 scanner equipped with a 10-MHz annular array probe. On the
basis of wedge phantom studies, the precision in the measurement of
distances between interfaces from video recordings was of the
order of 0.03 mm.14 The calibration of distance
measurements was checked every 2 weeks against an RMI 414B tissue
phantom. All scannings were done with a single ultrasound system. Four
ultrasound technicians carried out the scannings. They were trained for
6 to 12 months before the study. The PCVISION Plus Frame Grabber
digitizer board (Imaging Technology Inc), installed in an IBM PC 80386
microcomputer, was used to digitize B-scan frames. Image-Measure
morphometry software (Microscience Inc) was used to measure distances.
The site of the most advanced atherosclerotic lesion in each
arterial segment and the projection showing the
greatest distance between the lumen-intima interface and the
media-adventitia interface IMT at baseline was located on the basis
of real-time IMT measurements. The scannings were recorded by a
single Panasonic AG-7330E super-VHS PAL VCR. The maximal IMT was
measured from digitized frozen longitudinal (sometimes confirmed in
cross-sectional) images from the video recordings. The IMT
of the posterior wall was measured as the distance from the leading
edge of the first echogenic (bright) line to the leading edge of the
second echogenic line, as explained earlier in detail.11
Near wall measurements were not done because of their greater
measurement variability.15
One measurement of IMT was carried out of both the right and left artery, separately in three arterial segments: (1) distal common carotid artery below the carotid bulb (below the locally dilated part), (2) carotid bulb area (the locally dilated part), and (3) common femoral artery, each at the site of the greatest IMT at baseline. All measurements were always done consecutively in the same session for each subject after the subject had completed the study. The "paired" reading procedure of baseline and follow-up scannings was chosen to ensure that the IMT measurements were made in the same location and angle for the baseline and all follow-up studies for each subject. All IMT measurements were carried out by a single observer (A.M.). Data on the intraobserver and interobserver variability of common carotid IMT measurements are presented elsewhere.14 16 For the purpose of the present study, a subsample of 63 baseline videotapes was reread by the same observer (A.M.). The Pearson's correlation coefficient between the original and repeat IMT measurements was .89 for common carotid arteries, .79 for carotid bulbs, and .90 for femoral arteries.
Laboratory Measurements
Serum LDL-C was precipitated using
PVS (polyvinyl sulfate,
Boehringer Mannheim) and calculated as the difference between
total and supernatant cholesterol. Serum HDL
cholesterol (HDL-C) concentrations were measured after
precipitation with magnesium chloride dextran sulphate.17
Serum total cholesterol and triglycerides, and
plasma apolipoprotein B were measured with an autoanalyzer
(Kone Specific, Kone Ltd). Cholesterol concentrations were
determined enzymatically (Kone Diagnostics). The
between-batch coefficient of variation (CV) was below 2.2%. Serum
LDL-C concentration was measured 2 weeks before baseline (the value
determining the eligibility for the study), and at baseline and each
annual follow-up.
For triglycerides an enzymatic colorimetric
method (Boehringer Mannheim) was used and for apolipoprotein B
an immunoturbidimetric method from Kone Ltd. The between-batch CV
was below 2.1% for triglycerides and below 4.5% for
apolipoprotein B. Apolipoprotein(a) [Apo(a)] was measured at
baseline
from frozen EDTA plasma and at 36 months from frozen serum. A
radioimmunoassay with an antibody against Apo(a) in the lipoprotein(a)
particle was used (Pharmacia). The between-batch CV was below
6.5%. Plasma fibrinogen was determined with a clotting method (KC4,
Amelung GmbH).18 The between-batch CV of fibrinogen
measurement was below 5.0%. Plasma 
-tocopherol
concentration was determined by a high-performance liquid
chromatographic method.19 Medical history and
the current number of cigarettes, cigars, and pipefuls of tobacco
smoked daily, the duration of regular smoking in years was assessed in
an interview both at baseline and at each annual follow-up
examination.
Statistical Methods
Baseline characteristics of treatment
groups were compared by
one-way ANOVA for continuous variables and
2 tests for categorical variables. The
analysis of ultrasound data included all randomized subjects
with any follow-up ultrasound measurements regardless of their
compliance with treatment. The ultrasound data were analyzed by
a two-way ANCOVA of SAS statistical software, version
6. As the slopes of regression of IMT change on baseline IMT were
different in the four groups according to treatment and smoking status,
models allowing for unequal slopes were used to adequately describe
atherosclerotic progression. The dependent variable was the
individual subject's rate of progression obtained by least squares
regression of the mean IMT values on follow-up time. The model
included terms for treatment, smoking, treatment by smoking
interaction, baseline mean IMT as the covariate, and baseline mean IMT
by treatment by smoking interaction. Although subjects were stratified
by smoking status and presence of atherosclerotic lesions at baseline,
less than 5% of all subjects were in the category of having no carotid
atherosclerosis at baseline. Therefore, baseline mean
IMT was included as a covariate in the above model. Ninety-five
percent confidence intervals for a reduction in atherosclerotic
progression rate were estimated using the Fieller's theorem for a
ratio.20 No interim analyses were planned or done
for the primary efficacy variables. The percent changes in lipid
levels from baseline to the mean of annual follow-up visits were
analyzed by a two-way ANCOVA of the logarithms of the mean
posttreatment to pretreatment ratios. Point estimates (and 95%
confidence intervals) for mean percent changes within treatment groups
were obtained by exponentiating the adjusted means (and 95% confidence
limits) obtained from the ANCOVA. All tests were two-sided at .05
level of significance.
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Results |
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TopAbstractIntroductionMethods Results Discussion References |
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Subject Enrollment and Compliance
A total of 447 subjects were randomized in the double-masked phase. During the study 39 subjects discontinued study medication, 16 in the pravastatin group and 23 in the placebo group. Of these discontinuations, 20 were due to adverse events (pravastatin 8, placebo 12); six subjects died, three in each group; five subjects discontinued at their own request (pravastatin 3, placebo 2); two subjects in the placebo group were lost to follow-up; four subjects, two in each group, were discontinued because of poor compliance with the protocol, and two subjects in the placebo group were discontinued because they received prohibited lipid-lowering medication. Of the 39 subjects that discontinued study medication, 16 had at least one follow-up visit with evaluable ultrasound measurements and thus ultrasound examinations from 424 subjects were included in the statistical analyses. On the basis of the count of returned tablets, compliance with study drug was 93% in the placebo group and 92% in the pravastatin group.
Baseline Characteristics
The mean age of the subjects was
57.3 years (SD, 4.3; range, 44 to
65) in the pravastatin group and 57.5 years (SD, 4.4;
range, 44 to 63) in the placebo group. Baseline serum LDL-C levels
(last assessment before randomization) were 4.9 mmol/L in the
pravastatin group and 4.9 mmol/L in the placebo group.
Other baseline characteristics are presented in Table 1
. There
were no statistically significant differences
in any of the baseline characteristics measured between the subjects
who received pravastatin and those receiving placebo.
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Effects on Lipids and Other Laboratory
Analyses
The effects of pravastatin on lipids and other
laboratory parameters are presented in Table 2. For the effects
of pravastatin on lipid
levels, the average levels for the duration of the study were used; for
the effects on apolipoproteins, fibrinogen, and
-tocopherol levels, the baseline and end of study
values were used. Serum total cholesterol and LDL-C levels
declined in the pravastatin treated group by 21.0 (95% CI:
-22.0, -19.6) and 27.4 (95% CI: -29.0, -25.6) percent
from
baseline, whereas there was no significant change in the placebo group
(P<.001 between groups). Pravastatin also
significantly decreased triglycerides by 7.6% (95% CI:
-12.0, -3.1) (between groups, P<.001).
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For HDL-C, although the pravastatin group did not change statistically significantly from baseline, the placebo group showed a significant reduction from baseline and there was a significant between-group difference (P<.001).
In the pravastatin group plasma apolipoprotein B levels decreased by 19.5% (95% CI: -22.0, -17.1), whereas there was no change in the placebo group (between groups, P<.001). There was no statistically significant difference in the effects on fibrinogen levels; in both groups fibrinogen levels increased statistically significantly (P<.001): 10.2% (95% CI: 7.8, 12.6) in the placebo group and 8.2% (95% CI: 5.8, 10.6) in the pravastatin group. No changes in apo(a) were observed in either treatment group.
Plasma -tocopherol, divided by LDL-C, the
major
carrier for -tocopherol, showed a statistically
significantly greater increase in the pravastatin (55.9%,
95% CI: 50.2, 61.8) than in the placebo group (28.0%, 95% CI: 23.3,
32.8; P<.001, between groups).
Effects on Atherosclerotic Progression
In the placebo group
the annual rate of progression was dependent
on the baseline IMT: the higher the baseline IMT the greater the rate
of progression, whereas there was no relationship between baseline IMT
and rate of progression in the pravastatin group. Since the
linear relationship between atherosclerotic progression and baseline
IMT was different for each combination of treatment and smoking status
(P<.007 for baseline by treatment-by-smoking
interaction) estimated rates of progression for smokers and nonsmokers
are presented separately in the pravastatin and
placebo groups as a function of mean IMT at baseline for the primary
outcome of the common carotid artery and bulb combined (Fig 1).
The pravastatin group showed nearly
constant progression rates regardless of baseline IMT and smoking
status. In contrast, the placebo group showed increasing progression
rates with increasing baseline IMTs for both smokers and nonsmokers.
Placebo smokers progressed faster than placebo nonsmokers; the
treatment effect was therefore greater in smokers than in
nonsmokers.
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Fig 2 shows the treatment effect and 95%
confidence
intervals on the estimated annual rate of change at the overall mean
baseline IMTs for the combined outcome of the common carotid artery and
the bulb, and the secondary outcomes: the common carotid artery, bulb
and femoral artery individually, and the combined outcome of all
segments. The results show that compared to placebo, progression of
atherosclerosis was slower in the
pravastatin group for all segments. The treatment effect
was greatest in the common carotid artery.
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Table 3
presents estimated (based on a regression
model) annual progression rates and the treatment effects for all
outcomes at the overall mean IMTs at baseline and at arbitrarily
selected IMT values above the baseline mean, to show the increasing
treatment effect at higher baseline wall thicknesses.
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For the carotid artery segments (ie, common carotid artery and bulb) the annual rate of progression in the pravastatin group (0.017 mm/y) was significantly different (P=.005) from the placebo group in which there was progression of 0.031 mm/y at the overall mean baseline IMT of 1.66 mm. This represents a 45% (95% CI: 16, 69) reduction in atherosclerotic progression. Similar results were seen for the common carotid and carotid bulb segments examined separately and for the combined outcome of all carotid and femoral arterial segments. In the common carotid artery segment there was a statistically significant treatment effect of 66% (95% CI: 30, 95; P=.002) at the overall mean baseline IMT (1.35 mm). The treatment effect in the carotid bulb was marginally nonsignificant (30%, 95% CI: -1, 54; P=.056) at the overall mean baseline IMT (2.00 mm). The femoral artery segment showed similar progression rates in both groups. However, when all carotid and femoral segments were combined, there was a statistically significant treatment effect of 32% (95% CI: 7, 53; P=.020) at the overall mean baseline IMT (1.81 mm).
For higher baseline IMT values the treatment effect was greater and was highly significant for the common carotid artery and marginally nonsignificant for the bulb. For the femoral artery a similar relationship existed, although the treatment effect did not reach statistical significance for any of the investigated baseline IMT levels.
The effects of baseline plasma -tocopherol levels on
atherosclerotic progression were also investigated for each of the
treatment and smoking combinations by means of regression
analyses. As noted above, in placebo smokers progression was
faster with increasing baseline IMT values (P=.035).
However, at any given baseline IMT value, progression of
atherosclerosis was also faster with decreasing
baseline -tocopherol levels (P=.057).
Consequently, the treatment effect was greater (63%) in the
participants with decreased (below the median, <28 µmol/L) plasma
-tocopherol levels at baseline than in those with
higher -tocopherols (14%), when allowing for
smoking and baseline IMT in two separate models (z=2.08,
P<.05 for difference).
Clinical Events
Table 4 presents the clinical
cardiovascular events that occurred during the trial.
The number of cardiovascular events in the
pravastatin group was lower than in the placebo group,
particularly for myocardial infarctions, although the difference was
not statistically significant. Of the four strokes in the placebo
group, one was fatal. Of the noncardiovascular
deaths, one pravastatin-treated subject died of metastatic
lung cancer. One placebo subject discontinued study medication for a
cholecystectomy and died of a postoperative pancreatitis.
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Eight (4%) of the 224 pravastatin-treated subjects and 12 (5%) of the placebo-treated subjects discontinued study medication due to adverse events, mostly gastrointestinal complaints (pravastatin, 3; placebo, 7). Other reasons for discontinuation were, one of each: elevated liver enzymes, pneumonia, eczema, nerve pain, and stroke in the pravastatin group, and prostate cancer, chest pain, depression, and stroke (two cases) in the placebo group.
The most common adverse events were musculoskeletal pain (pravastatin, 22.8%; placebo, 20.2%), abdominal pain (pravastatin, 11.2%; placebo, 9.4%), and cough (pravastatin, 8.9%; placebo, 8.5%). Four (1.8%) pravastatin-treated and three (1.3%) placebo-treated subjects had elevations of ALAT over three times the upper limit of normal on at least one occasion (one of the pravastatin-treated subjects was discontinued from therapy). Four percent of the pravastatin-treated subjects and 5% of the placebo-treated subjects had elevations of creatine kinase (CK) over 4 times the pretreatment value on at least one occasion. None of these elevations were associated with myopathic syndromes. Analyses of the adverse events showed no statistically significant differences between the treatment groups.
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Discussion |
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TopAbstractIntroductionMethods Results Discussion References |
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The present trial based on all eligible men from an observational population-based study confirms previous observations in selected clinical samples concerning the effects of LDL-C lowering on progression of atherosclerosis. In the pravastatin group, for both smokers and nonsmokers, the rates of progression were nearly constant for all baseline IMT values, indicating that atherosclerotic progression had been attenuated to a lower level that was independent of the amount of atherosclerosis present at baseline or smoking status. Progression of atherosclerosis was faster in placebo smokers compared to placebo nonsmokers. The treatment effect of pravastatin was therefore greater in smokers than in nonsmokers. A greater treatment effect with LDL-C lowering in smokers has not been observed before and remains to be confirmed in further studies. There are at least two possible explanations for the greater atherosclerosis preventive effect of pravastatin treatment in smokers than in nonsmokers. First, in the same study area, in prospective population studies, a synergistic association has been observed of elevated serum cholesterol levels and smoking both for the risk of myocardial infarction21 and for the progression of carotid atherosclerosis.22 If the atherogenic effect of high LDL-C levels is greater in smokers than in nonsmokers, then also the lowering of elevated LDL-C levels should have a greater antiatherogenic effect in smokers. Second, the effect of LDL-C lowering may simply be greater in persons who already have atherosclerotic lesions with lipid deposition. In this trial, the treatment effect on the primary study outcome was very small if the baseline carotid wall thickness (IMT) was below 1.6 mm. In the majority of previous clinical trials concerning the effect of LDL-C lowering on atherosclerotic progression, the treatment effect has been greater in subjects with advanced atherosclerosis in the beginning of the study.1
A novel finding was that especially in smokers, atherosclerotic progression was faster with lower baseline plasma vitamin E levels independent of the baseline IMT value. This might indicate that particularly in smokers the antioxidative effects of vitamin E can attenuate atherosclerotic progression. In nonsmokers, or after LDL-C reduction with pravastatin, the protective effects of vitamin E might be less. Even though based on a post-hoc interaction analysis, the greater antiatherogenic effect of LDL-C lowering in men with low vitamin E status is consistent with the suggestion that the atherogenicity of elevated LDL-C levels is mediated to an important extent through lipid peroxidation.23 24
Few trials have been previously published in which ultrasonographically assessed atherosclerotic progression was the primary outcome.25 26 In a two-by-two factorial trial, Furberg and coworkers gave 10 to 40 mg/d of lovastatin, another HMG-CoA reductase inhibitor, or warfarin (1 mg/d) or both or placebo to 919 men or women, who had mild to moderate hypercholesterolemia and early carotid atherosclerosis. Daily aspirin (81 mg/d) was recommended for all subjects. The average annual change in the mean (over 12 sites) maximum IMT was 0.006 mm (SE, 0.003 mm) in the double placebo group, -0.009 mm (SE, 0.003 mm) in the active lovastatin-warfarin placebo group, and -0.003 mm (SE, 0.003) in the lovastatin-warfarin group, averaging -0.006 mm for both lovastatin-treated groups. Because of aspirin treatment and consequently a very small annual increase in carotid IMT, the absolute changes in treated groups cannot be directly compared with our study. However, the absolute net treatment effect of lovastatin was a reduction of 0.012 mm in the mean maximum carotid IMT. The respective treatment effect in our study was similar, 0.014 mm smaller annual progression for both carotid segments combined and 0.019 mm/y treatment effect in the common carotid arteries.
In the Pravastatin, Lipids, and Atherosclerosis in the Carotids ("PLAC-II") trial, 151 coronary patients were randomized either to 20 to 40 mg/d of pravastatin or to placebo for 3 years.26 In this secondary preventive trial the atherosclerotic progression, as measured by the aggregate mean maximum carotid IMT, was reduced by 12% by the treatment (0.068 mm/y in the placebo and 0.059 mm/y in pravastatin group), the absolute treatment effect being 0.009 mm annually. As in our study, the treatment effect was greater in the common carotid arteries (35% or 0.016 mm/y, P=.03) than in the carotid bifurcations (13% or 0.014 mm/y, P=.44). In the internal carotid arteries, there was no treatment effect.
Our findings indicate that the effect of LDL-C lowering is greater in the carotid than in the femoral arteries. The observation is consistent with our earlier finding based on cross-sectional data.11 27 The smaller treatment effect in the carotid bulb than in the common carotid arteries may be explained partly by the larger random measurement variability in the bulb than in the straight part of the common carotid artery. Also, atherosclerotic progression in the carotid bulb and the femoral bifurcation, in which the blood flow is turbulent, may be determined more by hemodynamic, rheologic, and local mechanical factors than by lipids.11 27 On the basis of this trial, we recommend the use of the straight part of the common carotid artery as the site for ultrasonographic imaging in future studies in which atherosclerotic progression will be assessed by B-mode ultrasonography.
It has previously been demonstrated that the wall thickness and the severity of atherosclerosis in the common carotid arteries are strong predictors of the extent of coronary atherosclerosis and coronary events.11 28 29 30 Carotid atherosclerosis also appears to have a similar risk factor profile as coronary atherosclerosis.8 22 31 All these findings suggest that carotid wall thickness is associated with coronary atherosclerosis and can be used as its surrogate in clinical trials and population studies.
In this study a favorable effect of pravastatin was observed on cardiovascular events. Although the differences in events were not statistically significant, the reductions in event rates were similar as those reported with other pravastatin studies in subjects with evidence of atherosclerotic disease or with multiple risk factors for coronary artery disease.32 33
In conclusion, the findings of the present study confirm the preventive effect of LDL-C lowering on the progression of carotid atherosclerosis in persons free of advanced atherosclerotic disease and establish the antiatherogenic effect of pravastatin. They also suggest that the benefit of LDL-C lowering may be greater in smokers and possibly in men with low vitamin E status, hypotheses to be tested in further trials. Finally, our data are inconclusive with regard to the effects of LDL-C lowering on the progression of femoral atherosclerosis.
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Acknowledgments |
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This study was supported by grants from the Academy of Finland and the Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ. The authors thank Margot Mellies, MD, and Mark McGovern, MD, for their contribution to the study protocol, Arja Malkki, registered radiology technician, for carrying out the ultrasonographic measurements, Arto Haapanen, MD, PhD, for consulting in the ultrasound quality control studies, Kimmo Ronkainen, MPh, for data management and analyses, Richard Kronmal, PhD, for advice in statistical analysis, Ulrika Persson and Karin Käll for monitoring the study, public health nurses Anne Airaksinen, Hannele Kastarinen, Annikki Konttinen, Leena Leskinen, and Raili Weeman for subject management, Timo Lakka, MD, PhD, for participating in the clinical work, and Erkki Voutilainen, MD, PhD, lipidologist, for clinical consulting.
Received February 1, 1995; revision received April 19, 1995; accepted May 3, 1995.
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References |
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|
TopAbstractIntroductionMethods Results Discussion References |
|---|
1. Blankenhorn D, Hodis HN. Arterial imaging and atherosclerosis reversal. Arterioscler Thromb. 1994;14:177-192.
2.
Levy RI, Brensike JF, Epstein SE, et al. The
influence of changes in lipid values induced by cholestyramine and diet
on progression of coronary artery disease: results of the NHLBI
Type II Coronary Intervention Study.
Circulation. 1984;69:325-337.
3. 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]
4.
Blankenhorn DH, Nessim SA, Johnson RL, Sanmarco ME,
Azen SP, Cashin-Hemphill L. Beneficial effects of combined
colestipol-niacin therapy on coronary
atherosclerosis and coronary venous bypass
grafts. JAMA. 1987;257:3233-3240.
5. Ornish D, Brown SE, Scherwitz LW, et al. Can lifestyle changes reverse coronary heart disease? The Lifestyle Heart Trial. Lancet. 1990;336:129-133. [Medline] [Order article via Infotrieve]
6.
Kane JP, Malloy MJ, Ports TA, Phillips NR, Diehl JC,
Havel RJ. Regression of coronary
atherosclerosis during treatment of familial
hypercholesterolemia with combined drug
regimens. JAMA. 1990;264:3007-3012.
7. Watts GF, Lewis B, Brunt JN, et al. Effects on coronary artery disease of lipid-lowering diet, or diet plus cholestryramine, in the St Thomas' Atherosclerosis Regression Study (STARS). Lancet. 1992;339:563-569. [Medline] [Order article via Infotrieve]
8.
Salonen R, Seppänen K, Rauramaa R, Salonen JT.
Prevalence of carotid atherosclerosis and serum
cholesterol levels in eastern Finland.
Arteriosclerosis. 1988;8:788-792.
9.
Crouse JR, Harpold GH, Kahl FR, Toole JF, McKinney WM.
Evaluation of a scoring system for extracranial carotid
atherosclerosis extend with B-mode ultrasound.
Stroke. 1986;17:270-275.
10. Salonen R, Haapanen A, Salonen JT. Measurement of intima-media thickness of common carotid arteries with high-resolution B-mode ultrasonography: inter and intra-observer variability. Ultrasound Med Biol. 1991;17:225-230. [Medline] [Order article via Infotrieve]
11. Salonen JT, Salonen R. Ultrasound B-mode imaging in observational studies of atherosclerotic progression. Circulation. 1993;87(suppl II):II-56-II-65.
12. Salonen JT. Is there a continuing need for longitudinal epidemiologic research: the Kuopio Ischaemic Heart Disease Risk Factor Study. Ann Clin Res. 1988;20:46-50. [Medline] [Order article via Infotrieve]
13. Salonen JT, Salonen R, Nyyssönen K, Korpela H, Voutilainen E, Ylitalo P. Kuopio Atherosclerosis Prevention Study. CVD Epidemiology Newsletter. American Heart Association 1992, Winter 1991/1992, No. 47:6.
14. Salonen JT, Korpela H, Nyyssönen K, Salonen R. Precision and reproducibility of ultrasonographic measurement of progression of common carotid artery atherosclerosis. Lancet. 1993;341:1158-1159.
15. Wickstrand J, Wendelhag L. Methodological considerations of ultrasound investigation of intima-media thickness and lumen diameter. J Int Med. 1994;236:555-559. [Medline] [Order article via Infotrieve]
16. Salonen R, Salonen JT. Intima-media changes in a population study: KIHD. In: Boccalon H, ed. Vascular Medicine. New York, NY: Elsevier Science Publishers BV; 1993.
17. Finley PR, Schifman RB, Williams RJ, Lichti DA. Cholesterol in high-density lipoprotein: use of Mg2+/dextran sulfate in its enzymic measurement. Clin Chem. 1978:24:931-933.
18. Clauss A. Geringungsphysiologische Schnellmethode zur Bestimmung des Fibrinogens. Acta Haematol. 1957;17:237-246. [Medline] [Order article via Infotrieve]
19. Nyyssönen K, Porkkala E, Salonen R, Korpela H, Salonen JT. Increase in oxidation resistance of atherogenic serum lipoproteins following antioxidant supplementation: a randomized double-blind placebo-controlled clinical trial. Eur J Clin Nutr. 1994;48:633-642. [Medline] [Order article via Infotrieve]
20. Finney DJ. Statistical Method in Biological Assay. London, England: Griffin; 1978:80-82.
21.
Salonen JT, Puska P, Kottke TE. Smoking, blood
pressure and serum cholesterol as risk factors of acute
myocardial infarction and death among men in Eastern Finland.
Eur Heart J. 1981;2:365-373.
22. Salonen R, Salonen JT. Progression of carotid atherosclerosis and its determinants: a population-based ultrasonography study. Atherosclerosis. 1990;81:33-40. [Medline] [Order article via Infotrieve]
23. Steinberg D, Parthasarathy S, Carew TE, Khoo JC, Witztum JL. Beyond cholesterol: modifications of low-density lipoprotein that increase its atherogenicity. N Engl J Med. 1989;320:915-924. [Medline] [Order article via Infotrieve]
24. Salonen JT, Ylä-Herttuala S, Yamamoto R, et al. Autoantibody against oxidised LDL and progression of carotid atherosclerosis. Lancet. 1992;339:883-887. [Medline] [Order article via Infotrieve]
25.
Furberg CD, Adams HP, Applegate WB, et al.
Effect of lovastatin on early carotid
atherosclerosis and cardiovascular
events. Circulation. 1994;90:1679-1687.
26. Crouse JR III, Byington RP, Bond MG, Espeland MA, Craven TE, Sprinkle JW, McGovern ME, Furberg CD. Pravastatin, Lipids, and Atherosclerosis in the Carotid Arteries (PLAC-II). Am J Cardiol. 1995;75:455-459. [Medline] [Order article via Infotrieve]
27. Salonen JT, Salonen R. Risk factors for carotid and femoral atherosclerosis in hypercholesterolemic men. J Int Med. 1994;236:561-566. [Medline] [Order article via Infotrieve]
28.
Salonen JT, Salonen R. Ultrasonographically
assessed carotid morphology and the risk of coronary heart
disease. Arterioscler Thromb. 1991;11:1245-1249.
29.
Solberg LA, Strong JP. Risk factors and
atherosclerotic lesions: a review of autopsy studies.
Arteriosclerosis. 1983;3:187-198.
30.
Craven TE, Ryu JE, Espeland MA, et al.
Evaluation of the associations between carotid artery
atherosclerosis and coronary artery
stenosis: a case control study.
Circulation. 1990;82:1230-1242.
31. Salonen R, Salonen JT. Determinants of carotid intima-media thickness: a population-based ultrasonography study in Eastern Finnish men. J Int Med. 1991;229:225-231. [Medline] [Order article via Infotrieve]
32. The Pravastatin Multinational Study Group for Cardiac Risk Patients. Effects of pravastatin in patients with serum total cholesterol levels from 5.2 to 7.8 mmol/liter (200 to 300 mg/dl) plus two additional atherosclerotic risk factors. Am J Cardiol. 1993;72:1031-1037. [Medline] [Order article via Infotrieve]
33. Furberg CD, Byington RP, Crouse JR, Espeland MA. Pravastatin, lipids and major coronary events. Am J Cardiol. 1994;73:1133.[Medline] [Order article via Infotrieve]
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|
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|
|
|
|
|
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|
|
|
|
|
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|
|
|
|
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|
|
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|
|
|
|
 |
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
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 |
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|
|
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 |
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|
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P. Angerer, S. Stork, W. Kothny, P. Schmitt, and C. von Schacky Effect of Oral Postmenopausal Hormone Replacement on Progression of Atherosclerosis : A Randomized, Controlled Trial Arterioscler Thromb Vasc Biol, February 1, 2001; 21(2): 262 - 268. [Abstract] [Full Text] [PDF]
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R. P. Byington, B. R. Davis, J. F. Plehn, H. D. White, J. Baker, S. M. Cobbe, and J. Shepherd Reduction of Stroke Events With Pravastatin : The Prospective Pravastatin Pooling (PPP) Project Circulation, January 23, 2001; 103(3): 387 - 392. [Abstract] [Full Text] [PDF]
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T. A. Lakka, J. A. Laukkanen, R. Rauramaa, R. Salonen, H.-M. Lakka, G. A. Kaplan, and J. T. Salonen Cardiorespiratory Fitness and the Progression of Carotid Atherosclerosis in Middle-Aged Men Ann Intern Med, January 2, 2001; 134(1): 12 - 20. [Abstract] [Full Text] [PDF]
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 C. Held, P. Hjemdahl, S.V. Eriksson, I. Bjorkander, L. Forslund, and N. Rehnqvist Prognostic implications of intima-media thickness and plaques in the carotid and femoral arteries in patients with stable angina pectoris Eur. Heart J., January 1, 2001; 22(1): 62 - 72. [Abstract] [PDF]
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J. Hsia, J. A. Simon, F. Lin, W. B. Applegate, M. T. Vogt, D. Hunninghake, and M. Carr Peripheral Arterial Disease in Randomized Trial of Estrogen With Progestin in Women With Coronary Heart Disease : The Heart and Estrogen/Progestin Replacement Study Circulation, October 31, 2000; 102(18): 2228 - 2232. [Abstract] [Full Text] [PDF]
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M. Pignone, C. Phillips, and C. Mulrow Use of lipid lowering drugs for primary prevention of coronary heart disease: meta-analysis of randomised trials BMJ, October 21, 2000; 321(7267): 983 - 986. [Abstract] [Full Text]
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D. Sander, C. Kukla, J. Klingelhofer, K. Winbeck, and B. Conrad Relationship Between Circadian Blood Pressure Patterns and Progression of Early Carotid Atherosclerosis : A 3-Year Follow-Up Study Circulation, September 26, 2000; 102(13): 1536 - 1541. [Abstract] [Full Text] [PDF]
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 H. D. White, R. J. Simes, N. E. Anderson, G. J. Hankey, J. D.G. Watson, D. Hunt, D. M. Colquhoun, P. Glasziou, S. MacMahon, A. C. Kirby, et al. Pravastatin Therapy and the Risk of Stroke N. Engl. J. Med., August 3, 2000; 343(5): 317 - 326. [Abstract] [Full Text] [PDF]
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H. Koshiyama, Y. Nakamura, S. Tanaka, and J. Minamikawa Decrease in Carotid Intima-Media Thickness after 1-Year Therapy with Etidronate for Osteopenia Associated with Type 2 Diabetes J. Clin. Endocrinol. Metab., August 1, 2000; 85(8): 2793 - 2796. [Abstract] [Full Text]
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P. Sun, K. M. Dwyer, C. N. B. Merz, W. Sun, C. A. Johnson, A. M. Shircore, and J. H. Dwyer Blood Pressure, LDL Cholesterol, and Intima-Media Thickness : A Test of the "Response to Injury" Hypothesis of Atherosclerosis Arterioscler Thromb Vasc Biol, August 1, 2000; 20(8): 2005 - 2010. [Abstract] [Full Text] [PDF]
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M. Zureik, P. Ducimetiere, P.-J. Touboul, D. Courbon, C. Bonithon-Kopp, C. Berr, and C. Magne Common Carotid Intima-Media Thickness Predicts Occurrence of Carotid Atherosclerotic Plaques : Longitudinal Results From the Aging Vascular Study (EVA) Study Arterioscler Thromb Vasc Biol, June 1, 2000; 20(6): 1622 - 1629. [Abstract] [Full Text] [PDF]
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L. A. Prosser, A. A. Stinnett, P. A. Goldman, L. W. Williams, M. G.M. Hunink, L. Goldman, and M. C. Weinstein Cost-Effectiveness of Cholesterol-Lowering Therapies according to Selected Patient Characteristics Ann Intern Med, May 16, 2000; 132(10): 769 - 779. [Abstract] [Full Text] [PDF]
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D. Baldassarre, E. Tremoli, M. Amato, F. Veglia, A. Bondioli, and C. R. Sirtori Reproducibility Validation Study Comparing Analog and Digital Imaging Technologies for the Measurement of Intima-Media Thickness Stroke, May 1, 2000; 31(5): 1104 - 1110. [Abstract] [Full Text] [PDF]
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J. C. LaRosa, J. He, and S. Vupputuri Effect of Statins on Risk of Coronary Disease: A Meta-analysis of Randomized Controlled Trials JAMA, December 22, 1999; 282(24): 2340 - 2346. [Abstract] [Full Text] [PDF]
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E. R Mohler III, N. Delanty, D. J Rader, and E. C Raps Statins and cerebrovascular disease: plaque attack to prevent brain attack Vascular Medicine, November 1, 1999; 4(4): 269 - 272. [Abstract] [PDF]
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C. Skoglund-Andersson, R. Tang, M. G. Bond, U. de Faire, A. Hamsten, and F. Karpe LDL Particle Size Distribution Is Associated With Carotid Intima-Media Thickness in Healthy 50-Year-Old Men Arterioscler Thromb Vasc Biol, October 1, 1999; 19(10): 2422 - 2430. [Abstract] [Full Text] [PDF]
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P. H. Davis, J. D. Dawson, L. T. Mahoney, and R. M. Lauer Increased Carotid Intimal-Medial Thickness and Coronary Calcification Are Related in Young and Middle-Aged Adults : The Muscatine Study Circulation, August 24, 1999; 100(8): 838 - 842. [Abstract] [Full Text] [PDF]
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S. D. Ross, I. E. Allen, J. E. Connelly, B. M. Korenblat, M. E. Smith, D. Bishop, and D. Luo Clinical Outcomes in Statin Treatment Trials: A Meta-analysis Arch Intern Med, August 9, 1999; 159(15): 1793 - 1802. [Abstract] [Full Text] [PDF]
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T. A. Lakka, R. Salonen, G. A. Kaplan, and J. T. Salonen Blood Pressure and the Progression of Carotid Atherosclerosis in Middle-Aged Men Hypertension, July 1, 1999; 34(1): 51 - 56. [Abstract] [Full Text] [PDF]
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S. Ebrahim, O. Papacosta, P. Whincup, G. Wannamethee, M. Walker, A. N. Nicolaides, S. Dhanjil, M. Griffin, G. Belcaro, A. Rumley, et al. Carotid Plaque, Intima Media Thickness, Cardiovascular Risk Factors, and Prevalent Cardiovascular Disease in Men and Women : The British Regional Heart Study Stroke, April 1, 1999; 30(4): 841 - 850. [Abstract] [Full Text] [PDF]
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H. C. Bucher, L. E. Griffith, and G. H. Guyatt Systematic Review on the Risk and Benefit of Different Cholesterol-Lowering Interventions Arterioscler Thromb Vasc Biol, February 1, 1999; 19(2): 187 - 195. [Abstract] [Full Text] [PDF]
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R. Rabbani and E. J. Topol Strategies to achieve coronary arterial plaque stabilization Cardiovasc Res, February 1, 1999; 41(2): 402 - 417. [Abstract] [Full Text] [PDF]
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J. F. Plehn, B. R. Davis, F. M. Sacks, J. L. Rouleau, M. A. Pfeffer, V. Bernstein, T. E. Cuddy, L. A. Moye, L. B. Piller, J. Rutherford, et al. Reduction of Stroke Incidence After Myocardial Infarction With Pravastatin : The Cholesterol and Recurrent Events (CARE) Study Circulation, January 19, 1999; 99(2): 216 - 223. [Abstract] [Full Text] [PDF]
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M.-L. M. Gronholdt Ultrasound and Lipoproteins as Predictors of Lipid-Rich, Rupture-Prone Plaques in the Carotid Artery Arterioscler Thromb Vasc Biol, January 1, 1999; 19(1): 2 - 13. [Abstract] [Full Text] [PDF]
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J. A Papadakis, D. P Mikhailidis, and A. F Winder Lipids and stroke: neglect of a useful preventive measure? Cardiovasc Res, November 1, 1998; 40(2): 265 - 271. [Abstract] [Full Text] [PDF]
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T. A. Jacobson, J. R. Schein, A. Williamson, and C. M. Ballantyne Maximizing the Cost-effectiveness of Lipid-Lowering Therapy Arch Intern Med, October 12, 1998; 158(18): 1977 - 1989. [Abstract] [Full Text] [PDF]
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R. S. Rosenson and C. C. Tangney Antiatherothrombotic Properties of Statins: Implications for Cardiovascular Event Reduction JAMA, May 27, 1998; 279(20): 1643 - 1650. [Abstract] [Full Text] [PDF]
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T. A. Pearson Lipid-Lowering Therapy in Low-Risk Patients JAMA, May 27, 1998; 279(20): 1659 - 1661. [Full Text] [PDF]
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S. MacMahon, N. Sharpe, G. Gamble, H. Hart, J. Scott, J. Simes, and H. White Effects of Lowering Average or Below-Average Cholesterol Levels on the Progression of Carotid Atherosclerosis : Results of the LIPID Atherosclerosis Substudy Circulation, May 19, 1998; 97(18): 1784 - 1790. [Abstract] [Full Text] [PDF]
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R. M. Werner and T. A. Pearson What's So Passive About Passive Smoking?: Secondhand Smoke as a Cause of Atherosclerotic Disease JAMA, January 14, 1998; 279(2): 157 - 158. [Full Text] [PDF]
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T. J. Wilt, H. B. Rubins, S. J. Robins, W. A. Riley, D. Collins, M. Elam, G. Rutan, and J. W. Anderson Carotid Atherosclerosis in Men With Low Levels of HDL Cholesterol Stroke, October 1, 1997; 28(10): 1919 - 1925. [Abstract] [Full Text]
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S. A. Everson, G. A. Kaplan, D. E. Goldberg, R. Salonen, and J. T. Salonen Hopelessness and 4-Year Progression of Carotid Atherosclerosis : The Kuopio Ischemic Heart Disease Risk Factor Study Arterioscler Thromb Vasc Biol, August 1, 1997; 17(8): 1490 - 1495. [Abstract] [Full Text]
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P. R. Hebert, J. M. Gaziano, K. S. Chan, and C. H. Hennekens Cholesterol Lowering With Statin Drugs, Risk of Stroke, and Total Mortality: An Overview of Randomized Trials JAMA, July 23, 1997; 278(4): 313 - 321. [Abstract] [PDF]
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J. Lynch, N. Krause, G. A. Kaplan, R. Salonen, and J. T. Salonen Workplace Demands, Economic Reward, and Progression of Carotid Atherosclerosis Circulation, July 1, 1997; 96(1): 302 - 307. [Abstract] [Full Text]
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A. M. Gotto Jr Statin Therapy and Reduced Incidence of Stroke: Implications of Cholesterol-Lowering Therapy for Cerebrovascular Disease Arch Intern Med, June 23, 1997; 157(12): 1283 - 1284. [Abstract] [PDF]
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J. R. Crouse III, R. P. Byington, H. M. Hoen, and C. D. Furberg Reductase Inhibitor Monotherapy and Stroke Prevention Arch Intern Med, June 23, 1997; 157(12): 1305 - 1310. [Abstract] [PDF]
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G. J. Blauw, A. M. Lagaay, A. H. M. Smelt, and R. G. J. Westendorp Stroke, Statins, and Cholesterol : A Meta-Analysis of Randomized, Placebo-Controlled, Double-Blind Trials With HMG-CoA Reductase Inhibitors Stroke, May 1, 1997; 28(5): 946 - 950. [Abstract] [Full Text]
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J. Lynch, G. A. Kaplan, R. Salonen, and J. T. Salonen Socioeconomic Status and Progression of Carotid Atherosclerosis : Prospective Evidence From the Kuopio Ischemic Heart Disease Risk Factor Study Arterioscler Thromb Vasc Biol, March 1, 1997; 17(3): 513 - 519. [Abstract] [Full Text]
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J. T. Salonen, K. Nyyssonen, R. Salonen, E. Porkkala-Sarataho, T.-P. Tuomainen, U. Diczfalusy, and I. Bjorkhem Lipoprotein Oxidation and Progression of Carotid Atherosclerosis Circulation, February 18, 1997; 95(4): 840 - 845. [Abstract] [Full Text]
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