From the Clinical Trials Research Unit and Department of Medicine,
University of Auckland (New Zealand) (S.M., N.S., G.G., J.Scott); the
Department of Medicine, North Shore Hospital, Auckland (H.H.); NH and MRC
Clinical Trials Centre, University of Sydney (Australia) (J.Simes); and
Coronary Care and Cardiovascular Research Units, Greenlane Hospital, Auckland
(H.W.).
Correspondence to Dr Stephen MacMahon, Clinical Trials Research Unit, Department of Medicine, The University of Auckland, Private Bag 92019, Auckland, New Zealand. E-mail macmahon{at}ctru.auckland.ac.nz
Methods and Results—In this study, 522 patients with a history of
myocardial infarction or unstable angina and with baseline levels of
total cholesterol between 4 and 7 mmol/L (mean,
5.7 mmol/L) were randomized to treatment with a low fat diet plus
pravastatin (40 mg daily) or to a low fat diet plus
placebo. Treatment with pravastatin reduced the levels of
total cholesterol by 19%, LDL cholesterol by
27%, apolipoprotein B by 19%, and triglycerides by 13%
(all 2P<.0001) and increased apolipoprotein A1 and HDL
cholesterol levels by 4% (both 2P<.0005),
in comparison with placebo. Carotid atherosclerosis was
assessed from B-mode ultrasound measurements of the common carotid
artery. After 4 years, mean carotid wall thickness had increased by
0.048 mm (SE=0.01) in the placebo group and declined by 0.014
mm in the pravastatin-treated group (SE=0.01)
(2P for difference <.0001). The effect of treatment on
wall thickness was similar in three groups classified by tertiles of
total cholesterol at baseline, with mean levels of 4.8,
5.7, and 6.6 mmol/L, respectively (2P for
interaction >.8).
Conclusions—Treatment with pravastatin reduced the
development of carotid atherosclerosis among patients
with coronary heart disease and a wide range of pretreatment
cholesterol levels. Treatment with this agent prevented any
detectable increase in carotid wall thickening over 4 years of
follow-up.
In randomized controlled trials, cholesterol lowering
has been shown to reduce the progression of
coronary8 9 10 11 12 13 14 and
carotid15 16 17 18 19 20 atherosclerosis in
patient populations with average pretreatment cholesterol
levels >6 mmol/L. Moreover, cholesterol lowering has also been
shown to reduce the risks of initial21 22 and
recurrent CHD21 23 in similar patient populations
with elevated cholesterol levels. However, in Western
populations most deaths from CHD occur among individuals whose
cholesterol level is average or below
average,5 and the effect of
cholesterol lowering on both
atherosclerosis and CHD in these individuals is less
well established. There is some evidence that in patient populations
with average pretreatment cholesterol levels of
The Long-term Intervention with Pravastatin in
Ischemic Disease (LIPID) trial31 was
initiated to determine the effects of lowering cholesterol
with the HMG CoA reductase inhibitor
pravastatin on the risk of death from CHD in individuals
with a history of myocardial infarction or unstable angina but with
cholesterol levels that were average or below average both
for patients with CHD and for the age-specific general populations of
the countries in which the study was conducted (Australia and New
Zealand). This study is, by a factor of 2, larger than any previous
randomized trial of cholesterol lowering in patients with
CHD, and it should therefore be able to provide more definitive
evidence about whether the size of the benefits of
cholesterol reduction are determined by pretreatment levels
of cholesterol. The LIPID Atherosclerosis
Substudy is also, by a factor of 2, larger than any previous randomized
study of the effects of cholesterol lowering on carotid
atherosclerosis in patients with CHD. Its results,
which are reported here, provide new information about the effects of
cholesterol lowering on carotid
atherosclerosis among individuals with a broad range of
pretreatment cholesterol levels.
Study Treatment
Carotid Artery Ultrasound
The images collected at baseline, 2 years, and 4 years were measured by
a single ultrasonographer after completion of the 4-year examinations.
The measuring ultrasonographer was blind to treatment allocation but
not to the date of the examination. With the use of a locally developed
program, measurements were made on a 1-cm length of the carotid artery
immediately proximal to the bulb. This area was magnified (x10), and,
at millimeter intervals, 10 consecutive point estimates were made of
the thickness of the near and far walls. Such estimates were made on
each of three representative images from each
examination. The average of these 30 resulting estimates was used to
estimate the thickness of the far wall and the lumen diameter. The
estimates of the thickness of the near wall are affected by both random
and systematic error as a consequence of the juxtaposition of this wall
with the jugular vein, and for these reasons, measurements of near wall
thickness were not used in this study. Hence all references to CWT
hereafter refer to the thickness of the far wall of the common carotid
artery.
The choice of the far wall of the common carotid artery as the primary
end point in this trial was based on experimental studies conducted in
the Cardiovascular Research Laboratory of the
University of Auckland demonstrating the histologic validity of such
ultrasound measurements.32 Additionally, the
choice was influenced by the greater reliability of measurements from
this section of artery compared with that for other sections such as
the carotid bulb or the internal carotid artery and the larger
proportion of patients from whom measurable images can be obtained. In
quality control series conducted before and during the measurement
period, the coefficient of variation for repeat measures of CWT by the
responsible ultrasonographer was between 6% and 7%.
Lipids and Lipoproteins
Study Outcomes
Statistical Issues
Number of Participants With Outcome Data for Carotid Wall
Thickness
Lipid and Lipoprotein Levels
For subgroups of participants defined by tertiles of total
cholesterol at baseline, the mean total (and LDL)
cholesterol levels at baseline were 4.8 (3.2), 5.7 (3.9),
and 6.6 (4.7) mmol/L, respectively. However, the true tertile
averages for usual levels of total and LDL cholesterol will
be less disparate because of regression to the mean; for this reason,
average levels during follow-up for patients assigned placebo provide a
better estimate of average usual levels in the tertiles defined by
baseline measurements. For total cholesterol after 4 years
of follow-up (and for LDL cholesterol after 3 years), the
average values for the three groups were 4.5 (2.8), 5.2 (3.4), and 5.6
(3.8) mmol/L, respectively. The effects of study treatment on
total and LDL cholesterol in each of these three subgroups
defined by tertiles of total cholesterol at entry were
similar (2P for interaction, all >.3).
Similarly, the effects of study treatment on total and LDL
cholesterol in each of the three subgroups defined by
tertiles of CWT at entry were also similar (2P for
interaction, all >.1).
Carotid Artery Wall and Lumen Dimensions
For participants classified by tertiles of total
cholesterol at entry, there were similar differences
between treatment and placebo groups in the change in CWT from baseline
to 2 and 4 years (2P for interaction, .8; Table 3
The results of this study extend those of earlier studies that have
demonstrated that cholesterol lowering reduces the
progression of both carotid and coronary
atherosclerosis in patient populations with average
pretreatment cholesterol levels of
The evidence suggests that cholesterol-lowering treatment
should reduce the risk of clinical sequelae of atherosclerotic disease
in a large proportion of the population at risk of such events and not
only in those with high cholesterol levels. This is
supported by the results of trials such as the Scandinavian
Simvastatin Survival Study (4S),23
which suggest that there are beneficial effects of treatment with
simvastatin on the risk of recurrent CHD among individuals
with pretreatment cholesterol levels of
Carotid atherosclerosis is not only a marker of CHD
risk,33 34 35 36 37 it is also a marker of the risks of
stroke and ischemic cerebrovascular
disease.36 37 Thus the finding here and in
previous studies of a marked effect of cholesterol lowering
on carotid atherosclerosis suggests that such treatment
might be expected to reduce the risk of ischemic stroke. In the
older trials of agents with only modest
cholesterol-lowering properties, there was little evidence
of an effect on overall stroke risk.21 However,
in more recent studies of HMG CoA reductase inhibitors,
reductions in stroke risk have been reported. An overview of results
from 13 trials involving >20 000 individuals among whom 462 strokes
were recorded, observed a reduction in stroke risk of
Received October 22, 1997;
revision received December 29, 1997;
accepted January 12, 1998.
© 1998 American Heart Association, Inc.
Clinical Investigation and Reports
Effects of Lowering Average or Below-Average Cholesterol Levels on the Progression of Carotid Atherosclerosis
Results of the LIPID Atherosclerosis Substudy
Abstract
Top
Abstract
Introduction
Methods
Results
Discussion
References
Background—Cholesterol
lowering in patients with above-average cholesterol levels
has been shown to reduce the progression of
atherosclerosis and lower the risk of coronary
heart disease events. However, there has been uncertainty about the
effects of cholesterol lowering in patients with average or
below-average cholesterol levels.
Key Words: cholesterol • atherosclerosis • carotid arteries • coronary disease
Introduction
Top
Abstract
Introduction
Methods
Results
Discussion
References
Continuous
associations of total and LDL cholesterol levels with the
extent of atherosclerosis have been reported in several
cross-sectional studies using coronary
angiography1 2 or carotid artery B-mode
ultrasound.3 4 In longitudinal studies of Western
populations, the association between cholesterol levels and
the risk of myocardial infarction or death from CHD also appears to be
continuous, with no lower level of cholesterol identified
below which the risks of CHD do not continue to
decline.5 6 Indeed, even in Eastern populations
in which average cholesterol levels are much lower than in
the West, there still appears to be a continuous association of
cholesterol levels with CHD risk.7
Overall among individuals of middle age, each 0.6 mmol/L lower
total cholesterol confers 
30% less risk of CHD across a
wide range of cholesterol
levels.6 6
mmol/L, cholesterol-lowering treatment with HMG CoA
reductase inhibitors reduces the development of
atherosclerosis in the
coronary24 25 26 27 and
carotid28 arteries. A recent study has also
reported a reduction in coronary
atherosclerosis is patients with an average
pretreatment cholesterol level of 5.7
mmol/L.29 The Cholesterol And
Recurrent Events (CARE) trial reported a significant reduction in the
risk of recurrent myocardial infarction in a patient population with an
average pretreatment cholesterol level of 5.5
mmol/L.30 However, in that study it was reported
that the proportional effects of treatment on CHD risk declined in
direct proportion to the initial level of LDL cholesterol
such that there were no detectable benefits of treatment in those
patients whose pretreatment LDL cholesterol levels were
<125 mg/dL (3.2 mmol/L). There remains, therefore, uncertainty as
to how widely the benefits of cholesterol lowering extend
to those with lower pretreatment cholesterol levels.
Methods
Top
Abstract
Introduction
Methods
Results
Discussion
References
Participants
The participant selection criteria for entry to the LIPID trial
have been described in detail elsewhere.31
Briefly, individuals were eligible for inclusion if they had a history
of myocardial infarction or hospitalization for unstable angina 3
months to 5 years before enrollment and if they had a total serum
cholesterol level between 4 and 7 mmol/L (155 to 271
mg/dL) after 2 months on a low fat diet (target <30% kJ from fat).
Individuals were not eligible if they were already receiving
cholesterol-lowering drug therapy or had serum
triglyceride levels >5.0 mmol/L, serum alanine amino
transferase or aspartate amino transferase levels >1.5 times the upper
limit of normal, serum bilirubin levels 
30 µmol/L, serum
albumin levels <3 g/dL, or serum creatinine levels
160 µmol/L. Participants in the LIPID
Atherosclerosis Substudy were recruited from the four
LIPID trial clinical centers in Auckland, New Zealand: the Auckland,
Green Lane, Middlemore, and North Shore hospitals.
After a 2-month run-in period during which potentially eligible
patients received placebo tablets and dietary instruction for
cholesterol lowering, eligible patients who provided
written consent to participate were randomized, double-blind, to
receive either pravastatin 40 mg daily (at night) or
placebo. After randomization, individuals in both groups continued to
receive dietary instruction. The study treatment was scheduled to
continue for at least 5 years; during this period, all study
participants were free to receive whatever other medical treatment they
required, including active cholesterol lowering therapy if
this was deemed to be definitely indicated.
Before randomization and after 2 and 4 years, ultrasound scans
of the right common carotid artery were performed in the
Cardiovascular Research Laboratory of the University of
Auckland Department of Medicine. B-mode ultrasound images of the common
carotid artery were captured with an ATL UM-8 ultrasound machine
(10-MHz mechanical sector transducer at minimum power) gated by ECG to
200 ms past the peak of the R wave; these images were digitized and
stored for off-line analysis. For each patient, three views of
the right distal common carotid artery were collected, maximizing the
lumen diameter to ensure that the plane of interrogation was orthogonal
to the artery wall. Using a standardized protocol, one ultrasonographer
performed all baseline examinations and a second ultrasonographer
performed the examinations at years 2 and 4. Both ultrasonographers
were blind to treatment allocation.
Total cholesterol was measured at the randomization
visit and at annual visits thereafter. Additionally
triglycerides, LDL cholesterol, HDL
cholesterol, apolipoprotein A1 and apolipoprotein B were
measured at randomization and at visits 1 and 3 years after
randomization. All lipid and lipoprotein measurements were made at a
central laboratory (Flinders Medical Center, Adelaide) certified by the
Lipid Standardization Program of the Centers for Disease Control,
Atlanta, Ga. Total cholesterol was measured enzymatically
with standard methods (Boehringer Mannheim) and total
triglyceride was measured by standard spectrophotometric
techniques (Boehringer Mannheim). After precipitation of LDL
and VLDL particles with phosphotungstic acid, HDL
cholesterol was measured enzymatically in the supernatant
by a modification of the method for total cholesterol.
Apolipoproteins A1 and B were measured with immunonephelometric assays
(Behring Diagnostics).
The primary study outcome was the change from baseline in CWT
after 2 and 4 years of follow-up. Secondary outcomes included changes
in lumen diameter; the ratio of CWT to lumen diameter; CWT within
subsets of participants defined by tertiles of total
cholesterol at baseline; and CWT within subsets defined by
tertiles of CWT at baseline.
The study sample size was chosen to provide 90% power (with
2P=.05) to detect a 0.06-mm difference between groups in
mean CWT. All outcome analyses were conducted according to the
intention-to-treat principle. Differences between randomized groups in
changes in CWT, lumen, and CWT-to-lumen ratio during follow-up were
tested with the Student's t test for independent groups. A
multivariate approach to the analysis of
repeated measures was also used to estimate main and interaction
effects, with maximum likelihood imputation of missing values performed
using the MIXED procedures of SAS. The same methods were used to
estimate differences between randomized groups in lipid and lipoprotein
levels during follow-up. Interaction effects were prespecified for
differences in treatment effects on CWT between groups of participants
classified by tertiles of total cholesterol and by tertiles
of CWT at baseline. All probability values were calculated from
two-tailed tests of statistical significance (2P). A 5%
significance level was maintained throughout these
analyses.
Results
Top
Abstract
Introduction
Methods
Results
Discussion
References
Characteristics of Study Participants at Baseline
A total of 522 individuals were randomized,
representing 88% of the 592 potentially eligible patients
who entered in the prerandomization run-in period. At randomization,
the average age of participants was 61 years, 88% were men, 75% had a
history of myocardial infarction, and 5% were diabetic. The mean
total, LDL, and HDL cholesterol concentrations were 5.7,
4.0, and 0.9 mmol/L, respectively, and the mean CWT, lumen
diameter, and CWT-to-lumen ratio were 0.79 mm, 7.04 mm, and
0.11, respectively. A total of 273 subjects were assigned treatment
with pravastatin and 249 were assigned placebo; the slight
imbalance in the number of patients in the two groups arose because
randomization was not stratified within this substudy. The study groups
were well matched for most characteristics at randomization.
Outcome data were sought from all participants irrespective of
whether or not they continued to take the randomized study treatment.
Data were available from all 522 participants at baseline, from 459
participants (88%) after 2 years, and from 404 participants (77%)
after 4 years. One third of the losses to follow-up were due to death
and one third were due to relocation outside the Auckland region. The
proportion of patients with follow-up data was almost identical in the
pravastatin and placebo groups (77% and 78%,
respectively, at 4 years), and for this reason it seems unlikely that
the loss to follow-up would have introduced any large bias in the
comparison of outcome between the two groups. However, it is possible
in this study, as in all studies of atherosclerosis,
that modest biases could be introduced by a reduction in mortality if
the likelihood of death was associated with the degree of
atherosclerotic progression. In such circumstances, loss to follow-up
through death of control group patients with more rapidly progressing
disease would reduce the size of any observed beneficial effects of
treatment on disease progression.
Over the 48 months of follow-up, total cholesterol was
reduced by an average of 1.0 mmol/L (SE=0.01) in the
pravastatin group compared with the placebo group (18%;
2P=.0001) (Table 1
).
Additionally, over the first 36 months of follow-up, LDL
cholesterol, apolipoprotein B, and total
triglyceride levels were reduced by an average of 0.9
mmol/L (SE=0.04), 0.05 mmol/L (SE=0.01), and 0.29 mmol/L
(SE=0.05), respectively, in the pravastatin group compared
with the placebo group (all 2P<.0006). Over the same
period, apolipoprotein A1 and HDL cholesterol levels
increased by 0.06 mmol/L (SE=0.01) and 0.05 mmol/L (SE=0.01)
in the pravastatin group compared with the placebo group
(both 2P<.0005). After 48 months of follow-up, 15% of
patients discontinued treatment with pravastatin and 12%
of control patients began nonstudy cholesterol-lowering
treatment. However, this did not result in any detectable convergence
of levels of lipids and lipoproteins between groups over the duration
of follow-up (2P for interaction, all >.05).
View this table:
[in a new window]
Table 1. Effects of Study Treatment on Lipids and Lipoprotein
Levels During Follow-up
After 2 years of follow-up, the mean CWT increased by 0.039
mm in the placebo group and was essentially unchanged in the
pravastatin group (Table 2
and Fig 1). After 4 years of follow-up,
the mean CWT had increased by a total of 0.048 mm in the placebo
group and had declined by 0.014 mm in the pravastatin
group. Thus after 2 years there was a 0.049-mm (SE=0.01) difference
between groups in the mean change in CWT from baseline
(2P=.003), and after 4 years there was a 0.062-mm (SE=0.01)
difference between groups (2P<.0001). There was no
detectable difference in lumen diameter between groups after either 2
or 4 years, and, as a consequence, the ratio of lumen to wall thickness
increased by 5% after 2 years (2P=.03) and by 8% after 4
years (2P=.0015) in the pravastatin group
compared with the placebo group.
View this table:
[in a new window]
Table 2. Effects of Study Treatment on CWT, Lumen, and
CWT-to-Lumen Ratio
View larger version (12K):
[in a new window]
Figure 1. Carotid artery wall thickness in
pravastatin and placebo groups at baseline, year 2 and year
4. and Fig 2). In other analyses, there were
no significant effects of levels of total or LDL
cholesterol at baseline on the size of the effect of
treatment on CWT (both 2P>.8). For participants classified
by tertiles of CWT at entry there were no significant differences
between subgroups in the size of the effects of treatment on CWT
(2P for interaction, .5). Additionally, there were no
significant differences in the size of the effects of treatment in
smokers and nonsmokers, diabetic and nondiabetic subjects, and
hypertensive and nonhypertensive subjects (2P for
interaction, all >.5).
View this table:
[in a new window]
Table 3. Effects of Study Treatment on CWT in Groups Defined
by Tertiles of Pretreatment
Cholesterol
View larger version (26K):
[in a new window]
Figure 2. Change in carotid artery wall thickness in
pravastatin and placebo groups after 4 years by tertiles of
baseline cholesterol.
Discussion
Top
Abstract
Introduction
Methods
Results
Discussion
References
The results of this study demonstrate that treatment with the HMG
CoA reductase inhibitor pravastatin reduced the
development of carotid atherosclerosis among
individuals with a history of CHD with average or below-average
cholesterol levels for Western populations. In this study
population, with a mean pretreatment cholesterol level of
5.7 mmol/L (range, 4 to 7 mmol/L), treatment with
pravastatin reduced total cholesterol levels by
19%, LDL cholesterol levels by 27%, apolipoprotein B
levels by 19%, and total triglyceride levels by 13%.
Apolipoprotein A 1 and HDL cholesterol were both increased
by 5%. These changes in lipid and lipoprotein levels appeared to
attenuate the progression of atherosclerotic progression such that
there was no detectable carotid wall thickening over 4 years of
follow-up among the patients assigned pravastatin.
Moreover, the effects of treatment appeared to be similar in three
groups defined by tertiles of entry cholesterol (with
average baseline cholesterol levels of 4.8, 5.7, and
6.6 mmol/L, respectively). These results suggest that
cholesterol lowering is likely to reduce atherosclerotic
progression in most patients with CHD, across a broad range of
pretreatment cholesterol levels. 6 mmol/L. They
are also consistent with the results of the one study that has
investigated the effects of cholesterol lowering on
coronary atherosclerosis in patients with an
average entry level of 5.7 mmol/L.29 The
observation within this study of similarly reduced atherosclerotic
progression among individuals with a broad range of pretreatment
cholesterol levels (4.8 to 6.6 mmol/L) is
consistent with other evidence about the effects of
cholesterol lowering on coronary
atherosclerosis from the REGRESS
trial.25 In that study, the average pretreatment
cholesterol level was somewhat higher (6.0 mmol/L)
than that in our study, but beneficial effects of
pravastatin were observed across a similar range of
pretreatment cholesterol levels to those studied here. As a
consequence, there is now consistent evidence of beneficial
effects of cholesterol lowering on the progression of both
carotid and coronary atherosclerosis at above
average, average, and below average pretreatment levels of total (and
LDL) cholesterol in Western populations. 6.5 mmol as
well as among those with higher levels.23 The
results of the Cholesterol and Recurrent Events (CARE)
trial suggest beneficial effects of treatment with
pravastatin in a patient population with even lower levels
of cholesterol. However, the conclusion from that study
that the benefits of treatment decline in direct proportion to the
pretreatment level of LDL cholesterol appears
inconsistent with the results of the present study and of
REGRESS,25 in which the effects of the same
treatment on carotid and coronary atherosclerotic progression
appeared to be largely independent of initial total and LDL
cholesterol values across a similar range to those of
patients included in CARE.30 This
inconsistency could reflect limitations of change in
atherosclerosis as a surrogate for changes in CHD risk.
However, it could also reflect the low statistical power of CARE to
detect a modest effect of treatment on CHD risk in the subgroup of 851
patients with pretreatment LDL cholesterol levels <125
mg/dL (3.2 mmol/L), among whom a total of only 182 CHD events were
observed. This uncertainty may be resolved by the results of the other
ongoing or recently completed studies (including the LIPID trial),
among which there may be, at least collectively, sufficient patients
with LDL cholesterol levels <125 mg/dL to determine
reliably any true effects of cholesterol on CHD risk. 30% among
patients assigned treatment with an HMG CoA reductase
inhibitor.38 Data from several of
these trials indicate that these effects primarily reflect a reduction
in strokes of ischemic origin, as might be expected. It
therefore appears that the reduction in ischemic stroke risk
produced by cholesterol lowering may be of similar relative
magnitude to the reduction in CHD risk. This hypothesis will be tested
by the LIPID trial in which 350 strokes (of definite or suspected
ischemic origin) and 1250 major CHD events were documented
by the end of follow-up.
Selected Abbreviations and Acronyms
CHD
=
coronary heart disease
CWT
=
carotid wall thickness
HMG CoA
=
3-hydroxy-3-methylglutaryl-coenzyme A
Acknowledgments
The LIPID trial was conducted under the auspices of the National
Heart Foundation of Australia with a grant from Bristol-Myers Squibb.
Data collection and analysis for this substudy were funded by
grants from the National Heart Foundation of New Zealand. The
project was also supported in part by a Program Grant from the
Health Research Council of New Zealand. Dr Stephen MacMahon is the
recipient of a Principal Research Fellowship from the Health Research
Council of New Zealand. Colleen Ciobo and Julia Zorn performed the
ultrasound examinations and Jenny Baker provided data from the LIPID
database. Julie Yallop, Mary-Jean Mackie, and Alison Clague provided
local study coordination, and Janet Brown, Renee Coxon, Mary Denton,
Jacqui Elliot, Alison Hall, Lynette Pearce, Pam Reid, and Philippa
Wright managed the study clinics. Members of the LIPID Management
Committee are Michael Ablett, Phillip Aylward, David Colquhoun, Paul
Glasziou, Phillip Harris, David Hunt, Anthony Keech, Maynard MacAskill,
Stephen MacMahon, Paul Magnus, Norman Sharpe, John Simes,
Peter Thompson, Andrew Tonkin (Chair), Peter Wallace, Malcolm West, and
Harvey White. John Shaw (deceased) was Chair of the LIPID Management
Committee from 1989 to 1994.
References
Top
Abstract
Introduction
Methods
Results
Discussion
References
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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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A. Zanchetti, G. Crepaldi, M. G. Bond, G. Gallus, F. Veglia, G. Mancia, A. Ventura, G. Baggio, L. Sampieri, P. Rubba, et al. Different Effects of Antihypertensive Regimens Based on Fosinopril or Hydrochlorothiazide With or Without Lipid Lowering by Pravastatin on Progression of Asymptomatic Carotid Atherosclerosis: Principal Results of PHYLLIS--A Randomized Double-Blind Trial Stroke, December 1, 2004; 35(12): 2807 - 2812. [Abstract] [Full Text] [PDF]
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 G. B. J. Mancini, B. Dahlof, and J. Diez Surrogate Markers for Cardiovascular Disease: Structural Markers Circulation, June 29, 2004; 109(25_suppl_1): IV-22 - IV-30. [Full Text] [PDF]
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P. Amarenco and A. M. Tonkin Statins for Stroke Prevention: Disappointment and Hope Circulation, June 15, 2004; 109(23_suppl_1): III-44 - III-49. [Abstract] [Full Text] [PDF]
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A. G. Thrift Cholesterol Is Associated With Stroke, but Is Not a Risk Factor Stroke, June 1, 2004; 35(6): 1524 - 1525. [Full Text] [PDF]
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J. P.J. Halcox and J. E. Deanfield Beyond the Laboratory: Clinical Implications for Statin Pleiotropy Circulation, June 1, 2004; 109(21_suppl_1): II-42 - II-48. [Abstract] [Full Text] [PDF]
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M. L. Bots, G. W. Evans, W. A. Riley, and D. E. Grobbee Carotid Intima-Media Thickness Measurements in Intervention Studies: Design Options, Progression Rates, and Sample Size Considerations: A Point of View Stroke, December 1, 2003; 34(12): 2985 - 2994. [Abstract] [Full Text] [PDF]
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 E. M. Tuzcu and P. Schoenhagen Acute coronary syndromes, plaque vulnerability,and carotid artery disease: The changing role ofatherosclerosis imaging J. Am. Coll. Cardiol., September 17, 2003; 42(6): 1033 - 1036. [Full Text] [PDF]
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M. K. Duggirala, D. A. Cook, K. F. Mauck, Y. F. Tai, P. Prandoni, A. W.A. Lensing, and M. H. Prins An Association between Atherosclerosis and Venous Thrombosis N. Engl. J. Med., July 24, 2003; 349(4): 401 - 402. [Full Text] [PDF]
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A. T Hirsch and A. M Gotto Jr Undertreatment of dyslipidemia in peripheral arterial disease and other high-risk populations: an opportunity for cardiovascular disease reduction Vascular Medicine, November 1, 2002; 7(4): 323 - 331. [Abstract] [PDF]
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 R. P. Byington, C. D. Furberg, D. M. Herrington, J. A. Herd, D. Hunninghake, M. Lowery, W. Riley, T. Craven, L. Chaput, C. C. Ireland, et al. Effect of Estrogen Plus Progestin on Progression of Carotid Atherosclerosis in Postmenopausal Women With Heart Disease: HERS B-Mode Substudy Arterioscler. Thromb. Vasc. Biol., October 1, 2002; 22(10): 1692 - 1697. [Abstract] [Full Text] [PDF]
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