From the University of Glasgow and Glasgow Royal Infirmary, Scotland, UK.
Correspondence to Professor Chris J. Packard, FRCPath, DSc, Department of Pathological Biochemistry, Glasgow Royal Infirmary University NHS Trust, Fourth Floor, Queen Elizabeth Building, Glasgow G31 2ER, UK. E-mail chrispackard{at}compuserve.com
Methods and Results—Relationships between baseline lipid
concentrations and incidence of all cardiovascular
events and between on-treatment lipid concentrations and risk reduction
in patients taking pravastatin were examined by use of Cox
regression models and by division of the cohort into quintiles.
Variation in plasma lipids at baseline did not influence the relative
risk reduction generated by pravastatin therapy. Fall in
LDL level in the pravastatin-treated group did not
correlate with CHD risk reduction in multivariate
regression. Furthermore, maximum benefit of an
Conclusions—We conclude that the treatment effect of 40 mg/d of
pravastatin is proportionally the same regardless of
baseline lipid phenotype. There is no CHD risk reduction unless
LDL levels are reduced, but a fall in the range of 24% is sufficient
to produce the full benefit in patients taking this dose of
pravastatin. LDL reduction alone does not appear to account
entirely for the benefits of pravastatin therapy.
Risk reductions in earlier cholestyramine- and gemfibrozil-based
primary prevention studies were linked to the decrease in LDL
cholesterol10 and the rise in HDL,
respectively.11 In the present report,
analysis of the WOSCOPS was undertaken to ascertain to what
extent variations in baseline lipids and in plasma lipid levels during
pravastatin treatment influenced outcome. The hypothesis
was that benefit would be related principally to LDL reduction.
The end point used in this report is all cardiovascular
events, defined as the occurrence of definite or suspected fatal MI,
other cardiovascular death, definite or suspected
nonfatal MI, or CABG or PTCA as a first event. This provided
Baseline Lipids Versus CHD Risk
Change in Plasma Lipids and Treatment Effect
Associations between percent or absolute LDL fall as a
continuous variable and risk reduction for the all-cardiovascular-event
end point in the pravastatin group were sought by use of
Cox regression models with and without adjustment for the baseline
covariates (noted above). Because the hypothesis to be tested was that
reduction in LDL was associated with decrease in risk, only subjects
with a nominal >5% reduction from baseline in mean LDL were included
(n=2642). Similar analyses were performed for absolute change
in HDL cholesterol and plasma triglyceride
levels.
Comparison of CHD Risk in Placebo and Pravastatin
Subjects With the Same LDL Cholesterol Level
Comparison of Observed Event Rates Versus Those Predicted From the
Framingham Risk Model
Pravastatin-Induced Changes in Plasma Lipids and
CHD Risk
CHD risk in each quintile of the pravastatin-treated
patients was then compared with risk in the entire placebo group (Fig 2B
When quintiles of absolute reduction in LDL were examined, the
relationship with risk was found to be similar to that seen for percent
fall. That is, as noted above, RR of any cardiovascular
event was similar to placebo in the quintile of least reduction
(quintile 1), whereas quintiles 2 through 5 had significant risk
reductions, with maximum benefit first present in quintile 3. The
mean change from baseline and the RR compared with the placebo group
was, for quintile 1, 0.0 mmol/L, RR=1.06 (CI, 0.81, 1.38); for
quintile 2, -0.60 mmol/L (-23 mg/dL), RR=0.70 (0.50, 0.96); for
quintile 3, -1.16 mmol/L (-45 mg/dL), RR=0.57 (0.41, 0.81); for
quintile 4, -1.52 mmol/L (-59 mg/dL), RR=0.64 (0.47, 0.89); and
for quintile 5, -2.01 mmol/L (-78 mg/dL), RR=0.57 (0.41, 0.78).
Pravastatin affected both plasma triglyceride
(mean 12% reduction) and HDL cholesterol (mean 7%
increase), but neither of these perturbations was associated with
change in risk (Table
Lipid Values and CHD Risk in Pravastatin- and
Placebo-Treated Groups
There was remarkable agreement between the observed CHD event rate in
the placebo group and the value predicted from the Framingham model
(Fig 4A
It was noteworthy that, in agreement with the 4S
study,22 the benefit of therapy was independent of baseline
LDL cholesterol and was also unaffected by baseline HDL
cholesterol and plasma triglyceride levels.
Likewise, as reported previously,16 the
proportionate risk reduction during pravastatin treatment
was not influenced by age, smoking status, or the signs or symptoms of
CHD.
The possibility that treatment had an effect beyond that associated
with LDL reduction was investigated by comparing event rates in
subjects receiving pravastatin with those receiving placebo
who had approximately the same on-treatment LDL
cholesterol. In this exploratory analysis it was
observed that, within the range of overlap of the two groups, those
receiving pravastatin had a lower CHD risk than those
receiving placebo. The difference could not be ascribed to a imbalance
in the measured baseline risk factors; to changes in HDL
cholesterol, plasma triglyceride, and VLDL
cholesterol during treatment with pravastatin;
or to differing levels of patient compliance. It is recognized that
other confounding influences may have been present, but taken at
face value, the observation suggests that in WOSCOPS, the influence of
pravastatin on CHD risk could not be completely explained
by the reduction in LDL cholesterol. Further support for
this proposal came from the analysis in which the Framingham
risk equation produced a coincidence between predicted and observed
coronary event rate in the placebo group but underestimated the
benefit of pravastatin therapy by
There are a number of possible explanations for this finding. First,
patients in whom LDL cholesterol is reduced to a certain
level may experience, at least for a time, a lower risk than those who
naturally have an LDL at that concentration. Second, in addition to
lowering LDL, pravastatin has been shown to promote the
removal of triglyceride-rich remnant particles from the
bloodstream.23 These lipoprotein species have
been linked to the progression of atherosclerotic
lesions,24 25 26 and their clearance, which is
known to occur through receptor-mediated
pathways,8 may lead to stabilization of plaques
whose rupture would give rise to clinical events. Third,
pravastatin may, through pathways not involving lipid
lowering, beneficially affect atherosclerosis (eg, by
decreasing a tendency for thrombosis).27 28 The
latter two possibilities could account for the relatively early benefit
seen during pravastatin therapy in WOSCOPS. It is
noteworthy that other lipid-lowering therapies that work by stimulating
receptor-mediated catabolism of LDL (ie, bile acid sequestrant resins
and surgical biliary diversion) did not show an early treatment
effect,2 29 although they did provide long-term
risk reduction. This difference in response may arise because these
therapeutic approaches enhance VLDL production in the liver and
do not have the same impact on the plasma concentration of remnants of
triglyceride-rich lipoproteins as do reductase
inhibitors.30 The results described
here are derived from post hoc analysis and therefore must be
viewed cautiously. Nevertheless, they indicate that the benefit seen
with pravastatin treatment, although obviously linked to a
decrease in LDL, cannot be explained by this alone.
Received September 30, 1997;
revision received December 11, 1997;
accepted January 13, 1998.
© 1998 American Heart Association, Inc.
Clinical Investigation and Reports
Influence of Pravastatin and Plasma Lipids on Clinical Events in the West of Scotland Coronary Prevention Study (WOSCOPS)
Abstract
Top
Abstract
Introduction
Methods
Results
Discussion
Appendix 1
References
Background—The West of Scotland
Coronary Prevention Study was a primary prevention trial that
demonstrated the effectiveness of pravastatin (40 mg/d) in
reducing morbidity and mortality from coronary heart disease
(CHD) in moderately hypercholesterolemic men. The
present analysis examines the extent to which differences
in LDL and other plasma lipids both at baseline and on treatment
influenced CHD risk reduction. 
45% risk reduction
was observed in the middle quintile of LDL reduction (mean 24% fall);
further mean decrements in LDL (up to 39%) were not associated with a
greater decrease in CHD risk. Comparison of event rates between
placebo- and pravastatin-treated subjects with the same LDL
cholesterol level provided evidence for an apparent
treatment effect that was independent of LDL.
Key Words: cholesterol • coronary disease • risk factors
Introduction
Top
Abstract
Introduction
Methods
Results
Discussion
Appendix 1
References
Clinical trials
testing the "lipid hypothesis," that lowering plasma
cholesterol leads to decreased risk of CHD, were first
conducted in the 1970s and 1980s.1 2 3 Results
were generally positive and led with increasing conviction to the
conclusion that MI could be prevented by lipid-lowering therapy.
However, definitive proof that such treatment could reduce
cardiovascular mortality and improve overall survival
was not forthcoming until the recent publication of landmark studies in
primary and secondary prevention.4 5 6 These
trials used a new class of hypolipidemic agents,
3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors
(reductase inhibitors), which reduce plasma LDL by
activating specific lipoprotein receptors in the
liver.7 Effects on other lipoproteins (VLDL, HDL)
are modest, although it is recognized that certain apolipoprotein
B–containing particles such as chylomicron remnants, VLDL remnants,
and IDLs are catabolized by the same receptors and may be influenced by
the therapy.8 9
Methods
Top
Abstract
Introduction
Methods
Results
Discussion
Appendix 1
References
The conduct of WOSCOPS has been described in detail in
publications explaining the design of the study and its clinical
outcomes.4 12 The recruits were moderately
hypercholesterolemic men 45 to 64 years old who had
never had an MI. Their plasma lipid and lipoprotein concentrations
(plasma triglyceride, plasma cholesterol, and
VLDL, LDL, and HDL cholesterol) were measured according to
the Lipid Research Clinics' protocol13 in a
central laboratory that participated in and met the quality criteria of
the Lipid Standardization Program organized by the Centers for Disease
Control and Prevention in Atlanta, Ga. Plasma lipids were measured
twice during screening, and patients were included in the study if they
had an LDL 
4.0 mmol/L (155 mg/dL) on both occasions and
4.5 mmol/L (174 mg/dL) on one. If LDL exceeded 6.0 mmol/L
(232 mg/dL) at both screening visits, the patient was excluded. Men
were randomized to receive placebo or pravastatin 40 mg/d,
and subsequent visits were conducted every 3 months. Fasting lipid
profiles were obtained at 6-month intervals during the follow-up
period. In this analysis, baseline plasma lipid levels were
taken as the mean of the values observed at the two screening visits.
As noted in the publication of baseline
characteristics,14 there was no significant
difference in any lipid variables between these visits. To provide
the most accurate measure of plasma lipid concentration during
follow-up, on-treatment lipid values were calculated as the mean of all
lipid measurements made after randomization until the patient had an
event or reached the end of the study. If a lipid value was missing at
a visit but study medication had been issued at the previous visit (3
months earlier), the most recent measurement that had been preceded by
a medication issue was carried forward. If before the visit no such
on-treatment measurement existed, then the baseline value was imputed.
Baseline value was also imputed if no medication had been issued at the
previous visit and the present lipid level was missing. Plasma
triglyceride concentration was log-transformed. 40%
more events than the primary end point4 and hence
enhanced power to detect associations and differences. CABG and PTCA as
separate end points showed similar risk reduction on
pravastatin to the primary end
point.4 The relationships described below between
plasma lipids and CHD risk based on the
all-cardiovascular-events end point were evident also
for the primary end point (data not shown).
All 6595 randomized patients were used to calculate quintiles of
baseline LDL cholesterol, HDL cholesterol, and
plasma triglyceride. The Kaplan-Meier 5-year risk of any
cardiovascular event was then determined separately for
each quintile of the placebo and pravastatin groups.
Baseline lipids as continuous variables were related to risk of any
cardiovascular event in the two groups separately by
Cox regression15 both univariately
and then multivariately with other baseline covariates
(as described in Reference 1616 ) to test their independence as
predictors. The covariates used in the adjustment were age, smoking,
blood pressure, ECG abnormality, self-reported angina, self-reported
hypertension, diabetes, family history of premature death from CHD, and
nitrate use.
Percent change from baseline in LDL cholesterol
(based on mean values with imputation as described above) was
calculated for the pravastatin group. The Kaplan-Meier
4.4-year risk of any cardiovascular event was
determined for each quintile of percent LDL reduction. Each quintile
was then compared with the whole placebo group in a Cox model. In these
analyses, the first 6 months of follow-up in both groups were
excluded, because no on-treatment lipid values were available for
patients who had an event before this time had elapsed. The difference
between treatments was assessed with adjustment for potential baseline
covariate imbalance (covariates as above) and expressed as risk ratios
relative to placebo with 95% confidence limits. To determine whether
quintiles differed from each other with respect to risk of any
cardiovascular event, quintiles 1 through 4 were
compared with quintile 5 (highest percent change in LDL) in Cox
multivariate models. A similar exercise was undertaken
for absolute fall in LDL cholesterol (ie, mean baseline
level minus mean on-treatment value). To rule out the possibility that
the quintile analysis was biased by the use of imputed values,
a separate evaluation was undertaken in which the mean of measured
lipid values only was calculated and used as the on-treatment
level.
Because this analysis involved both treatment arms of
the study, compliance (rather than any LDL change) was the criterion
used to identify adherence to the protocol. To be included in the
overlap analysis, patients in both groups had to be >75%
compliant (based on visit attendance and issue of study medication) and
not have had an event in the first 6 months of follow-up. Investigation
of the LDL cholesterol distribution in the placebo and
pravastatin cohorts revealed that the region of 3.62 to
4.65 mmol/L (140 to 180 mg/dL) included substantial numbers of
subjects in each treatment group who had overlapping LDL values (1071
receiving pravastatin and 1120 receiving placebo)
throughout the treatment phase of the study. Risk of any
cardiovascular event in these two groups was compared
first by a log-rank test and then by a hierarchy of three Cox models.
In the first, on-treatment LDL cholesterol was forced into
a model even though it was not a significant predictor of risk (model
A). In the second (model B), in addition to on-treatment LDL, baseline
covariates were entered if they were significant at the
P=.05 level and remained so during stepwise regression.
Covariates were as stated before but excluded diabetes because an
insufficient number of patients in this group suffered from the
disorder and included a composite variable of self-reported angina
or nitrate consumption as well as baseline lipid levels. In the third
(model C), on-treatment values for plasma triglyceride and
VLDL and HDL cholesterol levels were forced into model B.
The effect of narrowing the overlap region to 3.88 to 4.39 mmol/L
(150 to 170 mg/dL) was also tested. In this range, mean LDL
cholesterol was virtually the same in the two treatment
groups.
The equation published by the Framingham
investigators17 18 19 permits calculation of the
risk of a CHD event on the basis of sex, age, plasma
cholesterol, HDL cholesterol, smoking habit,
systolic blood pressure, and presence of diabetes. This model
was used as a further approach to test the hypothesis that the event
reduction seen in patients taking pravastatin could not be
explained entirely by changes in plasma lipid levels. To generate
compatibility with the Framingham coronary event
definition,17 18 19 the end point was taken as
definite nonfatal MI or CHD death plus
revascularization (PTCA and CABG). Again, patients
were omitted from the analysis if they had experienced a
coronary event, had cancer, or had undergone angiography within
6 months of randomization. Men with preexisting vascular disease
(self-reported angina, claudication, stroke, transient ischemic
attack, or use of nitrates) were excluded. To be included, patients had
to fall into the ranges of plasma cholesterol (4.13 to
7.23 mmol/L; 160 to 280 mg/dL) and blood pressure
(diastolic, 70 to 105 mm Hg; systolic,
110 to 170 mm Hg) that characterized the Framingham
population from which the risk equation was derived. They also had to
comply with the treatment regimen (as described above). Risk was
estimated from the point at which on-treatment lipid levels were
available (6 months after randomization) over the remaining period of
the trial (4.4 years, because the mean total length of follow-up was
4.9 years). Predicted event rates were derived for each patient by use
of the mean (with imputation when necessary) on-treatment level for
plasma cholesterol and HDL cholesterol. After
patients were grouped into quintiles of predicted risk, a Kaplan-Meier
4.4-year risk of an event was determined from the observed outcomes for
each quintile. The numbers of predicted and observed events across the
quintiles were compared for placebo and pravastatin groups
by a z-score test. A total of 1251 patients in the placebo
group and 1803 patients in the pravastatin group met the
inclusion criteria for this analysis. The comparison of
predicted versus observed risk was repeated without the restrictions on
plasma lipids and blood pressure, the compliance threshold, or
preexisting vascular disease but with a requirement that subjects
taking pravastatin had a >5% reduction in LDL during treatment. In
this instance, 3293 men taking placebo and 2605 men taking pravastatin
were included in the analysis.
Results
Top
Abstract
Introduction
Methods
Results
Discussion
Appendix 1
References
Baseline Lipids and CHD Risk
Patients were divided into quintiles of baseline lipid level (LDL
cholesterol, HDL cholesterol, and
triglyceride), each of which was related separately to the
event rates observed in the placebo and pravastatin groups
(Fig 1
). Baseline LDL
cholesterol was a weak predictor of risk in both groups
(Table). Individuals in the top quintile
of the placebo group experienced a rate for the
all-cardiovascular-event end point of 12% per 5 years
compared with 9% in the bottom quintile (Fig 1A). The proportionate
reduction in risk of an event was similar across all quintiles in
patients taking pravastatin. Baseline HDL
cholesterol exhibited a clear negative association with
event rate (Fig 1B) and was a major predictor of CHD risk in both
treatment arms of the study. Again, the RR reduction was similar for
all quintiles of this lipid fraction. The plasma
triglyceride level at baseline was positively related to
the risk of CHD (Fig 1C). Patients receiving placebo who had a baseline
triglyceride level of 2.3 mmol/L (204 mg/dL) had
almost twice the event rate of patients with an initial
triglyceride level of <1.2 mmol/L (106 mg/dL) despite
having similar baseline LDL levels (mean of 5.0 mmol/L [194
mg/dL] in all quintiles of plasma triglyceride). On the
basis of univariate analysis, the starting
triglyceride value was a highly significant predictor of
risk in both groups (Table). In line with previous
observations,20 inclusion of baseline HDL in
multivariate models led to a loss of significance of
baseline plasma triglyceride as a predictor.
View larger version (24K):
[in a new window]
Figure 1. Baseline lipids and CHD risk. Patients in
placebo- and pravastatin-treated groups were divided into
quintiles according to mean baseline levels of LDL
cholesterol, HDL cholesterol, and plasma
triglyceride levels. Kaplan-Meier 5-year estimated event
rates were derived for each quintile. Significance of associations for
each treatment group are revealed in univariate risk ratios
(Table 
). Solid columns indicate placebo; open columns,
pravastatin. To convert mmol/L cholesterol
to mg/dL, multiply by 38.7; to convert mmol/L
triglyceride to mg/dL, multiply by 88.5.
View this table:
[in a new window]
Table 1. Plasma Lipids as Univariate Predictors of CHD Risk
in WOSCOPS
The percentage fall in LDL cholesterol during
treatment varied (Fig 2) even in patients
who complied with the treatment regimen (ie, they attended and had
study medication issued on 75% of the scheduled visits, data not
shown). When the pravastatin group was divided into
quintiles of percentage LDL reduction (based on measured plus imputed
values), it was observed that the mean change varied from 0% to -39%
(Fig 2A) and the absolute change from 0.0 to -2.01 mmol/L (-78
mg/dL) (data not shown). We expected that a decrease in LDL would be
the major determinant of risk reduction and that a strong, graded
association would be present between these two variables.
However, Fig 2A illustrates that in quintiles 2 through 5, there was no
obvious correlation between percent LDL reduction and event rate. To
test for an association, risk of any cardiovascular
event in quintiles 1 through to 4 was compared with risk in the
quintile of greatest LDL reduction (quintile 5). When adjustment was
made for baseline covariates, the RR in quintile 4 versus 5 was 1.39
(P=.14); in quintile 3 versus 5, 1.09 (P=.72); in
quintile 2 versus 5, 1.43 (P=.11); and in quintile 1 versus
5, 2.24 (P=.0001). Thus, quintiles 2 through 4 did not
differ significantly from quintile 5 in terms of
cardiovascular risk reduction achieved. When the
percentage decrease in LDL was examined as a continuous variable in
univariate (Table) or multivariate (data
not shown) analysis, it was not a significant predictor of risk
in the pravastatin group. Virtually identical results were
obtained in a repeat analysis in which imputed values were
omitted and only measured LDL levels were used to calculate percent LDL
reduction (data not shown).
View larger version (11K):
[in a new window]
Figure 2. Relationship between LDL decrease and risk
reduction. A, Patients receiving pravastatin were divided
into quintiles of percentage decrease in LDL on treatment (with imputed
values used where necessary). First 6 months of follow-up were
excluded. Kaplan-Meier 4.4-year risks were calculated for each
quintile. Bounds for each quintile of LDL change were 1 (+20% to
-4%); 2 (-4% to -19%); 3 (-19% to -28%); 4 (-28% to
-34%); and 5 (-34% to -57%). Similar results were seen without
imputed values. B, Each quintile in A was compared with entire placebo
group by a Cox proportional hazards model with adjustment for baseline
covariates. RR and 95% CI are shown by horizontal bar. Wald
P values for difference between each quintile and
placebo group after adjustment for baseline covariates were quintile 1,
P=.54; 2, P=.030; 3,
P=.0007; 4, P=.018; and 5,
P=.0001. ). This revealed that individuals in quintile 1 who achieved no LDL
reduction gained no risk reduction. The full benefit in terms of
reduction in risk of a cardiovascular event was seen in
patients in quintile 3, who had a mean 24% decrease in LDL. No further
significant decrement in risk was apparent in those in quintile 5, who
experienced a mean 39% LDL decrease (range, 34% to 57%
decrease). ).
The distribution of mean LDL cholesterol during
treatment was found to overlap substantially between the placebo and
pravastatin groups (Fig 3),
with 2191 patients lying in the interval of 3.62 to 4.65 mmol/L
(140 to 180 mg/dL) LDL cholesterol. This provided an
opportunity to explore further the relationship between LDL
cholesterol and CHD risk in the two treatment arms of the
study. Mean LDL cholesterol levels in this interval were
4.38 mmol/L (170 mg/dL) for placebo-treated patients and 4.10
mmol/L (159 mg/dL) for pravastatin-treated patients. Event
rates for the two subgroups differed markedly. Pravastatin
treatment was associated with a 36% (CI, 9% to 56%) lower risk
(P=.014, Fig 3), a finding that did not appear to be due to
an imbalance in baseline risk factors or to differences in on-treatment
LDL (or on-treatment plasma triglyceride, VLDL
cholesterol, or HDL cholesterol). Similar
differences were obtained on examination of a narrower 3.88 to
4.39 mmol/L (150 to 170 mg/dL) overlap, a region in which the
on-treatment LDL values were virtually equal in the two groups (4.23
versus 4.15 mmol/L [164 versus 161 mg/dL] for placebo- and
pravastatin-treated subjects, respectively).
View larger version (32K):
[in a new window]
Figure 3. Overlap analysis. Frequency
distribution for LDL cholesterol levels on treatment is
given as separate histograms for placebo- and
pravastatin-treated groups. Values represent mean
of two visits in first year of follow-up. Overlap region of 3.62 to
4.65 mmol/L (140 to 180 mg/dL) was chosen to represent
values occurring with a sufficiently high frequency in both groups.
Relative CHD risk was determined for subgroups with overlapping LDL
cholesterol values and existence of a treatment effect
independent of on-treatment LDL level tested in models A, B, and C.
P values are derived from Cox models after adjustment
for factors that independently influenced CHD risk. To
convert mmol/L cholesterol to mg/dL, multiply by
38.7. ). The predicted overall rate of
7.6 per 100 subjects was close to that observed (7.0 per 100).
Treatment with pravastatin reduced total plasma
cholesterol values and, as expected, diminished the risk of
coronary events over the duration of the study (Fig 4B).
However, in contrast to the placebo-treated cohort, those receiving
pravastatin exhibited an observed reduction in events that,
overall, was significantly (P=.026) greater than that
predicted from the Framingham risk equation. According to the
Framingham model, the cholesterol reduction that was
achieved should have lowered the RR of a coronary event by
24%. In fact, the observed reduction was 35%. A similar result was
obtained when the strict criteria for compatibility with the Framingham
data set were relaxed, ie, an observed rate of 8.3/100 versus a
predicted rate of 8.5/100 in patients receiving placebo
(P=.86) and an observed rate of 5.1/100 versus a predicted
rate of 6.1/100 in patients receiving pravastatin
(P=.029). The elevated event rates in this second
analysis reflect the inclusion of patients with higher lipid
levels and blood pressure and those with preexisting vascular
disease.
View larger version (17K):
[in a new window]
Figure 4. Framingham analysis. Predicted risk over
4.4 years for each subject was derived from Framingham risk
equation.17 Subjects were then ranked into quintiles of
predicted risk (continuous line), separately for placebo and
pravastatin groups, and data were plotted against 4.4-year
Kaplan-Meier estimate of an event obtained from observed rates in each
quintile (circles). Only patients who fell into range of plasma lipid
levels and blood pressure readings seen in Framingham population used
to generate risk equation were included in analysis
presented here. Overall predicted (pred) and observed (obs)
rates were calculated for subjects in each group.
Discussion
Top
Abstract
Introduction
Methods
Results
Discussion
Appendix 1
References
Analysis of the relationship in WOSCOPS between the
pravastatin-induced fall in LDL cholesterol and
reduction in CHD risk did not yield the predicted result. On the basis
of the earlier findings of the Lipid Research Clinic Coronary
Primary Prevention Trial,10 we hypothesized that
larger decreases in LDL would be associated with greater benefit.
However, no clear, graded relationship was observed between LDL fall
and risk reduction with pravastatin. Rather, the full
benefit of an 45% risk reduction was seen in subjects who had a
mean LDL fall in the range of 24%; further decreases in LDL were not
associated with larger reduction in CHD risk. The findings of the
quintile analysis were confirmed in regression models in which
fall in LDL cholesterol failed to be a significant
predictor of risk reduction. Attenuation of risk reduction as plasma
cholesterol levels fall is to be expected from the
curvilinear nature of the relationship between plasma
cholesterol and coronary
risk.21 Whether this fully explains our current
observation is yet to be determined. 31%.
Selected Abbreviations and Acronyms
CABG
=
coronary artery bypass graft surgery
CHD
=
coronary heart disease
MI
=
myocardial infarction
PTCA
=
percutaneous transluminal coronary angioplasty
RR
=
relative risk
WOSCOPS
=
West of Scotland Coronary Prevention Study
Appendix 1
Top
Abstract
Introduction
Methods
Results
Discussion
Appendix 1
References
This report was prepared by the publication committee of the
West of Scotland Coronary Prevention Study: Christopher J.
Packard, DSc, Department of Pathological Biochemistry, Glasgow Royal
Infirmary; James Shepherd, FRCP, Department of Pathological
Biochemistry, Glasgow Royal Infirmary; Stuart M. Cobbe, FRCP,
Department of Medical Cardiology, Glasgow Royal
Infirmary; Ian Ford, PhD, Robertson Center for Biostatistics, Database
Unit, University of Glasgow; Christopher G. Isles, FRCP, Department of
Medicine, Dumfries and Galloway Royal Infirmary; James H. McKillop,
FRCP, University Department of Medicine, Glasgow Royal Infirmary; Peter
W. Macfarlane, FRSE, Department of Medical Cardiology,
Glasgow Royal Infirmary; A. Ross Lorimer, FRCP, Department of Medical
Cardiology, Glasgow Royal Infirmary; in collaboration
with John Norrie, MSc, Robertson Center for Biostatistics, University
of Glasgow. A full list of Study Group members is given in
Reference 8.
Acknowledgments
Bristol-Myers Squibb Co Pharmaceutical Research Institute
provided a research grant to support this work. The authors are
grateful to Nancy Thomson for her excellent secretarial assistance in
the preparation of the manuscript.
References
Top
Abstract
Introduction
Methods
Results
Discussion
Appendix 1
References
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 N. Haramaki, H. Ikeda, K. Takenaka, A. Katoh, R. Sugano, S.-i. Yamagishi, H. Matsuoka, and T. Imaizumi Fluvastatin Alters Platelet Aggregability in Patients With Hypercholesterolemia: Possible Improvement of Intraplatelet Redox Imbalance via HMG-CoA Reductase Arterioscler. Thromb. Vasc. Biol., June 1, 2007; 27(6): 1471 - 1477. [Abstract] [Full Text] [PDF]
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 S. C. Fagan, H. F. Elewa, and D. J. Rychly Statin Therapy for Secondary Stroke Prevention: Evidence Catches Up to Practice Journal of Pharmacy Practice, April 1, 2007; 20(2): 117 - 122. [Abstract] [PDF]
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 P. J. Barter and K.-A. Rye The Argument Against the Appropriateness of Over-the-Counter Statins Circulation, September 19, 2006; 114(12): 1315 - 1320. [Full Text] [PDF]
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 J. A. Vogt, K. B. Ishii-Schrade, P. B. Pencharz, P. J. H. Jones, and T. M. S. Wolever L-Rhamnose and Lactulose Decrease Serum Triacylglycerols and Their Rates of Synthesis, but Do Not Affect Serum Cholesterol Concentrations in Men J. Nutr., August 1, 2006; 136(8): 2160 - 2166. [Abstract] [Full Text] [PDF]
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C. J. Packard, I. Ford, M. Robertson, J. Shepherd, G. J. Blauw, M. B. Murphy, E. L.E.M. Bollen, B. M. Buckley, S. M. Cobbe, A. Gaw, et al. Plasma Lipoproteins and Apolipoproteins as Predictors of Cardiovascular Risk and Treatment Benefit in the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER) Circulation, November 15, 2005; 112(20): 3058 - 3065. [Abstract] [Full Text] [PDF]
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T. Murata, K. Kinoshita, M. Hori, M. Kuwahara, H. Tsubone, H. Karaki, and H. Ozaki Statin Protects Endothelial Nitric Oxide Synthase Activity in Hypoxia-Induced Pulmonary Hypertension Arterioscler. Thromb. Vasc. Biol., November 1, 2005; 25(11): 2335 - 2342. [Abstract] [Full Text] [PDF]
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 S. D. Wiviott, C. P. Cannon, D. A. Morrow, K. K. Ray, M. A. Pfeffer, E. Braunwald, and for the PROVE IT-TIMI 22 Investigators Can Low-Density Lipoprotein Be Too Low? The Safety and Efficacy of Achieving Very Low Low-Density Lipoprotein With Intensive Statin Therapy: A PROVE IT-TIMI 22 Substudy J. Am. Coll. Cardiol., October 18, 2005; 46(8): 1411 - 1416. [Abstract] [Full Text] [PDF]
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K. K. Ray and C. P. Cannon The Potential Relevance of the Multiple Lipid-Independent (Pleiotropic) Effects of Statins in the Management of Acute Coronary Syndromes J. Am. Coll. Cardiol., October 18, 2005; 46(8): 1425 - 1433. [Abstract] [Full Text] [PDF]
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 J. Crespo, J. Martinez-Gonzalez, J. Rius, and L. Badimon Simvastatin inhibits NOR-1 expression induced by hyperlipemia by interfering with CREB activation Cardiovasc Res, August 1, 2005; 67(2): 333 - 341. [Abstract] [Full Text] [PDF]
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M. Ii, H. Nishimura, K. F. Kusano, G. Qin, Y.-s. Yoon, A. Wecker, T. Asahara, and D. W. Losordo Neuronal Nitric Oxide Synthase Mediates Statin-Induced Restoration of Vasa Nervorum and Reversal of Diabetic Neuropathy Circulation, July 5, 2005; 112(1): 93 - 102. [Abstract] [Full Text] [PDF]
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 J. Shepherd Raising HDL-cholesterol and lowering CHD risk: does intervention work? Eur. Heart J. Suppl., July 1, 2005; 7(suppl_F): F15 - F22. [Abstract] [Full Text] [PDF]
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 W. Li, T. Asagami, H. Matsushita, K.-H. Lee, and P. S. Tsao Rosuvastatin Attenuates Monocyte-Endothelial Cell Interactions and Vascular Free Radical Production in Hypercholesterolemic Mice J. Pharmacol. Exp. Ther., May 1, 2005; 313(2): 557 - 562. [Abstract] [Full Text] [PDF]
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A. Kawakami, M. Tani, T. Chiba, K. Yui, S. Shinozaki, K. Nakajima, A. Tanaka, K. Shimokado, and M. Yoshida Pitavastatin Inhibits Remnant Lipoprotein-Induced Macrophage Foam Cell Formation Through ApoB48 Receptor-Dependent Mechanism Arterioscler. Thromb. Vasc. Biol., February 1, 2005; 25(2): 424 - 429. [Abstract] [Full Text] [PDF]
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L. Verschuren, R. Kleemann, E. H. Offerman, A. J. Szalai, S. J. Emeis, H. M. G. Princen, and T. Kooistra Effect of Low Dose Atorvastatin Versus Diet-Induced Cholesterol Lowering on Atherosclerotic Lesion Progression and Inflammation in Apolipoprotein E*3-Leiden Transgenic Mice Arterioscler. Thromb. Vasc. Biol., January 1, 2005; 25(1): 161 - 167. [Abstract] [Full Text] [PDF]
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 P. van der Harst, A. A. Voors, D. J. van Veldhuisen, M. Miller, A. M. Gotto Jr., J.-M. Paradis, J. LeLorier, J. Auer, T. Weber, B. Eber, et al. Intensive versus Moderate Lipid Lowering with Statins after Acute Coronary Syndromes N. Engl. J. Med., August 12, 2004; 351(7): 714 - 717. [Full Text] [PDF]
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S. Kitamoto, K. Nakano, Y. Hirouchi, Y. Kohjimoto, S. Kitajima, M. Usui, S. Inoue, and K. Egashira Cholesterol-Lowering Independent Regression and Stabilization of Atherosclerotic Lesions by Pravastatin and by Antimonocyte Chemoattractant Protein-1 Therapy in Nonhuman Primates Arterioscler. Thromb. Vasc. Biol., August 1, 2004; 24(8): 1522 - 1528. [Abstract] [Full Text] [PDF]
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