From the Department of Medicine, Brigham and Women's Hospital and
Harvard Medical School, Boston, Mass (F.M.S., M.A.P., E.B.); University of
Texas School of Public Health, Houston (L.A.M., B.R.D.); Washington
University, St Louis, Mo (T.G.C.); Montreal Heart Institute, Montreal, Quebec,
Canada (J.L.R.); and State University of New York Health Sciences Center,
Syracuse (D.T.N.).
Methods and Results—The Cholesterol and Recurrent
Events (CARE) trial compared pravastatin and placebo in
patients who had experienced myocardial infarction (MI) who had average
concentrations of total cholesterol <240 mg/dL (baseline
mean, 209 mg/dL) and LDL cholesterol (LDL) 115 to 174 mg/dL
(mean, 139 mg/dL). Pravastatin reduced coronary
death or recurrent MI by 24%. In multivariate
analysis, the LDL concentration achieved during follow-up was a
significant, although nonlinear, predictor of the coronary
event rate (P=.007), whereas the extent of LDL reduction was
not significant, whether expressed as an absolute amount
(P=.97) or a percentage (P=.76). The
coronary event rate declined as LDL decreased during follow-up
from 174 to
Conclusions—The LDL concentrations achieved during treatment with
pravastatin or placebo were associated with reduction in
coronary events down to an LDL concentration of
The CARE trial5 provides the opportunity to study the
effect of lowering LDL to levels not previously achieved in large-scale
clinical trials on coronary events. The combination of a
pretreatment range of LDL concentrations of 115 to 175 mg/dL,
encompassing approximately the 20th to 80th percentiles of the North
American population of patients with CHD, and an average reduction of
LDL of 32% in the pravastatin group produced LDL
concentrations during the trial ranging from 71 to 136 mg/dL.
Pravastatin treatment significantly reduced the incidence
of the primary end point of the trial, fatal CHD or nonfatal MI, by
24%, and of coronary revascularization
procedures by 27%. In this report, the relations between several
measures of the effect of pravastatin on the risk of
coronary events were investigated: the LDL concentration
achieved during therapy, the absolute reduction of LDL, and the
percentage lowering of LDL. In addition to lowering LDL,
pravastatin raises HDL and lowers
triglycerides. A secondary goal was to investigate the
relationship of HDL and triglyceride concentrations during
follow-up to the reduction in coronary events with
pravastatin.
Blood was collected into evacuated tubes containing edetic acid after
at least an 8-hour fast. Plasma was separated at the clinics by
centrifugation, packaged with coolant, and sent by
overnight courier to the core laboratory (Washington University, St
Louis, Mo). Plasma lipid analyses were performed within 3 days
of receipt. Total and HDL cholesterol and glycerol-blanked
total triglycerides were measured by commercially available
automated enzymatic methods (Miles-Technicon). LDL
cholesterol was calculated by subtracting from the total
cholesterol the sum of HDL cholesterol and the
triglyceride concentration divided by 5.12 We
validated this commonly used formula by direct LDL measurements with
ultracentrifugation. The mean LDL
cholesterol concentrations by calculation and direct
determination were 136.3 and 139.3 mg/dL, respectively, and the
regression equation had a slope of 0.974, an intercept of 0.6 mg/dL,
and a correlation coefficient of .963 (n=6778). The core laboratory was
standardized by the Lipid Standardization Program of the Centers for
Disease Control, and it was a member of the Cholesterol
Reference Method Laboratory Network of the Centers for Disease Control,
which verifies performance of clinical laboratories and
manufacturers in the measurement of total and HDL
cholesterol.
Statistical Methods
The influence of follow-up LDL cholesterol, HDL
cholesterol, and triglycerides on
coronary events was investigated in time-dependent Cox
analyses separately and then together. Lipid concentrations
during treatment, the percentage reduction from baseline, and the
absolute reduction in concentration from baseline were studied. To
determine which of these three variables most highly predicted the
coronary event rate, the follow-up lipid concentration and
either the percentage or absolute change in lipid concentration were
included simultaneously as time-dependent covariates in the
Cox analyses. The corresponding baseline lipid concentrations
were included in analyses as appropriate. In other
analyses, treatment group was added as a covariate to
investigate to what extent the lipid concentrations during treatment
explained the reduction in coronary events. Relative risks were
computed for the treatment group before and after adjustment for LDL,
HDL, and triglycerides during treatment. For this purpose,
other covariates, baseline lipids, and the risk factors were not
added.
Two definitions of follow-up lipid concentrations (LDL, HDL,
triglycerides) were used. The average follow-up lipid
concentration refers to a weighted average of postrandomization
follow-up concentrations. Because more measurements were obtained in
the first year than in later years of follow-up, the average was
computed so that each year had the same weight. The most recent lipid
concentration refers to the most recent lipid measurement before a
patient had a coronary event or the final lipid measurement in
the trial for patients who did not experience an event during
follow-up.
Pravastatin lowered LDL cholesterol by an
average of 32% in the first year, and this reduction was maintained
for the duration of the study (Fig 1
In the total cohort, the average LDL concentrations during treatment,
when modeled as a linear variable and adjusted for baseline risk
factors, correlated significantly with the risk of a primary or
expanded coronary end point (Table 1
The relationship between average LDL during treatment and the expanded
coronary end point in the pravastatin group,
considered separately, was also significant overall (P=.02)
but nonlinear (Fig 4
We considered the possibility that this analysis could not have
detected reductions in coronary rates below an LDL
concentration of 125 mg/dL. First, we calculated that the relative risk
of an expanded coronary event in patients in the
pravastatin group whose average follow-up LDL was
The LDL concentration during follow-up, the absolute change in LDL
concentration, and the percentage change were examined in
multivariate analyses to determine which had
the strongest relationship to the coronary event rate. When LDL
concentration was considered with either the absolute change or the
percentage change, only the concentration significantly predicted the
expanded coronary end point (P=.007 to .008 for LDL
concentration, P=.97 for absolute change, P=.76
for percentage change) (Table 2
The HDL level during follow-up was not significantly associated with
the coronary event rate after adjustment for baseline nonlipid
risk factors (Table 1
We investigated whether there was an effect of pravastatin
treatment on coronary incidence after the LDL, HDL, and
triglyceride levels achieved during treatment had been
taken into consideration. We did this by adding "treatment group"
as an independent variable to the multiple regression model used
previously (Table 1
The CARE trial was able to investigate the relationship between LDL
concentration and coronary events in patients with a much lower
range than previous trials did. The average LDL concentrations during
follow-up in the active treatment groups in previous trials ranged from
125 to 175 mg/dL,2 3 9 10 whereas in the CARE trial, the
LDL concentrations during treatment across deciles ranged from 71 to
136 mg/dL because of the substantial effects of the study drug,
pravastatin, and the relatively low pretreatment
concentrations (115 to 174 mg/dL). In CARE, the nonlinear relationship
that was found between LDL during treatment and coronary
events, with a cutpoint of 125 mg/dL, is consistent with the
previously reported finding in CARE that a baseline LDL of >125 mg/dL
identified the portion of the population that subsequently experienced
a reduction in coronary events.5 Approximately
80% of the patients in the pravastatin group had
pretreatment LDL levels >125 mg/dL. These findings from
analysis of LDL concentrations before and during treatment
suggest that LDL concentrations >125 mg/dL, present in most
post-MI patients, have a clinically important influence on subsequent
coronary events and that pravastatin is effective
in reducing both the LDL concentration and the coronary event
rate in this group.
The results in CARE on follow-up LDL concentrations and
coronary events are supported by a recently reported
meta-analysis21 that included all published lipid
trials. Coronary event rates among the trials were closely
correlated with the average achieved total cholesterol
level, as we found within the CARE trial for LDL
cholesterol. The meta-analysis also found that the
relationship between achieved total cholesterol
concentration and coronary events was curvilinear, with no
further decrease in events expected below
In a multivariate analysis that included LDL
concentration during follow-up, the change in LDL from baseline,
expressed either as a percentage or absolute change in concentration,
was not found to be significantly related to coronary events.
If atherosclerosis and the occurrence of
coronary events are influenced by the absolute concentration of
LDL, as suggested by epidemiological observations,14 then
it is not surprising that the change in LDL is an imperfect indicator
of atherogenic influence of LDL.
Evidence from various types of studies has been cited to support
a continuous relationship between plasma cholesterol and
coronary events that has no threshold. Most arteriographic
trials have demonstrated slowing of progression of coronary
disease with diet or drug therapy.22 23 However,
quantitative reviews and meta-analyses of all arteriographic
studies have not found a relationship between lower LDL concentrations
achieved during therapy and improvement in coronary
lesions.22 23 Epidemiological studies relating
cholesterol to coronary events have demonstrated a
continuous relationship from average to elevated
concentrations.6 14 15 16 17 19 20 However, the relationship
has not been clearly demonstrated within the lower range of total or
LDL cholesterol concentrations that are readily achievable
by treatment of patients with average cholesterol levels,
who make up the majority of patients with coronary artery
disease (such as those in CARE), with HMG-CoA reductase
inhibitors. In the largest single prospective
epidemiological study with 361 662 US men15 and in a
meta-analysis of 18 other populations that totaled 172 760
men,16 the results show little or no relationship between
serum total cholesterol and CHD death in the lowest 20% to
25% of cholesterol concentrations, ie, up to 170 to 180
mg/dL. In a meta-analysis of 11 populations with 124 814
women, the incidence of CHD death did not increase until serum total
cholesterol reached 200 mg/dL.16 In a 25-year
follow-up of Mediterranean populations, in whom the usual
cholesterol range is lower than in North American or
northern European populations, no relationship was found between serum
total cholesterol concentrations and coronary
events in the lower half of the range (<196 mg/dL).17 In
Shanghai, China, in contrast, the relationship with coronary
events appears to be stronger in the lowest half of the total
cholesterol range, <160 mg/dL, and is attenuated in the upper
half.18 The paradoxical shape of the curve in the Shanghai
population is not consistent with other epidemiological studies
of US and European populations14 15 16 17 19 20 or of a rural
Japanese cohort17 and could be a chance finding due to the
small number of coronary events, 13 in the lower half of the
cholesterol range, or due to confounding by unmeasured risk factors
such as obesity, diabetes, and physical inactivity, or by other less
well-understood mechanisms.
Limitations of the analysis described here should be
considered. In particular, this type of analysis is not based
on randomized groups, and the possibility always remains of confounding
by unidentified variables. However, the
multivariate analysis did not find evidence for
important confounding by the known nonlipid variables that affect
outcomes in patients with coronary artery disease, such as age,
sex, smoking, hypertension, diabetes, and left ventricular
ejection fraction. The identification of a nonlinear relationship
between follow-up LDL concentrations and coronary events with a
cutpoint of 125 mg/dL is derived from an exploratory analysis
and should be examined prospectively in future trials. Although there
were 2450 patients whose average follow-up LDL was <125 mg/dL and 518
of them experienced an expanded coronary end point, a small
reduction in coronary events within this range might not have
been detected because of a type II error. However, we determined that
the probability was high, 90%, that even a modest reduction in
coronary events of 15% would have been detected. Finally, the
relationship between LDL concentration and coronary events was
investigated within the structure of a 5-year clinical trial in a
population that had had many decades to develop clinical manifestations
of atherosclerosis. The influence of LDL may be
different in younger individuals and over a lifetime of exposure.
There are several strengths of this investigation in the population in
the CARE trial. Adherence to the therapy was excellent for the entire
duration of the trial, so that variation in compliance is unlikely to
have affected the results. Multiple lipid measurements were obtained to
characterize concentrations during treatment, and coronary
events were exhaustively searched for and validated. For these reasons,
misclassification of LDL concentrations and end points would be
minimal. In view of the strict double-blind conditions of the trial, it
is difficult to imagine selective overreporting of coronary
events in patients whose LDL concentrations were in the lower range of
the population, which could have caused a nonlinear relationship of
coronary events with LDL concentrations. The principal findings
are robust, because several different approaches to defining the LDL
concentration during treatment and both primary and expanded end points
gave similar results. The findings are applicable to common clinical
practice in which treatment is ordinarily begun in middle age or
later.
In conclusion, the CARE trial established that the majority of patients
with CHD, those with average cholesterol concentrations,
should receive lipid treatment to reduce the risk of recurrent events.
The findings in this report suggest that the effect of
pravastatin to lower LDL cholesterol to <125
mg/dL was responsible for most of the reduction in coronary
events. Realistically, coronary risk is unlikely to change
abruptly at any specific cutpoint, and the LDL concentration of 125
mg/dL may represent an approximate rather than an exact
boundary for clinical effectiveness. A conservative clinical
application of these findings is to suggest a range for optimal LDL
concentrations during lipid therapy, eg, 100 to 125 mg/dL. This is
consistent with results of a recent meta-analysis that
used the overall results of published lipid trials.21
Ultimately, combining evidence from major lipid trials, as is planned
in a prospective pooling project,24 should give the
most precise estimate for treatment goals for prevention of
coronary heart disease.
Received February 2, 1998;
accepted February 5, 1998.
© 1998 American Heart Association, Inc.
Clinical Investigation and Reports
Relationship Between Plasma LDL Concentrations During Treatment With Pravastatin and Recurrent Coronary Events in the Cholesterol and Recurrent Events Trial
Abstract
Top
Abstract
Introduction
Methods
Results
Discussion
References
Background—Although LDL lowering has
been shown to reduce recurrent coronary events in patients with
coronary heart disease, little direct information is available
on the extent of LDL lowering required to achieve this
outcome. 
125 mg/dL, but no further decline was seen in the LDL
range from 125 to 71 mg/dL. In multivariate
analysis, triglyceride but not HDL concentrations
during follow-up were weakly but significantly associated with the
coronary event rate. 125 mg/dL.
LDL concentrations <125 mg/dL during treatment were not associated
with further benefit. Absolute or percentage reduction in LDL had
little relationship to coronary events.
Key Words: lipoproteins • cholesterol • coronary disease • drugs
Introduction
Top
Abstract
Introduction
Methods
Results
Discussion
References
The beneficial effects of
cholesterol-lowering therapy for the primary and secondary
prevention of CHD have been conclusively demonstrated in large-scale
clinical trials.1 2 3 4 5 Meta-analysis of trials in
hypercholesterolemic patients suggested that the
reduction in cardiovascular events and in total
mortality is directly proportional to the mean percentage reduction of
elevated plasma cholesterol concentrations.1
However, there are limitations to such a conclusion. First, the
predominantly high pretreatment LDL concentrations of patients in these
trials are not representative of the LDL concentrations of
the majority of contemporary CHD patients.6 7 8 Second, the
mean LDL cholesterol concentration during therapy was also
relatively high, 125 to 175 mg/dL,2 3 9 10 corresponding
to the average pretreatment range for North American and European
populations with CHD.6 7 8 There is no information on the
relationship between LDL during treatment and coronary events
with LDL concentrations <125 mg/dL that can now be regularly achieved
in the majority of patients with CHD using inhibitors of
HMG-CoA reductase. For these reasons, the relationship between LDL
concentrations and their reduction during treatment and the incidence
of recurrent coronary events requires further
definition.
Methods
Top
Abstract
Introduction
Methods
Results
Discussion
References
The design11 and major results5 of the
CARE trial have been published. In summary, 4159 patients, 576 women
and 3583 men, were assigned at random to either pravastatin
40 mg/d or placebo and remained on therapy for a median duration of 5
years (range, 4 to 6 years). The major eligibility criteria were MI
between 3 and 20 months before randomization, age 21 to 75 years, total
cholesterol <240 mg/dL, LDL cholesterol 115 to
174 mg/dL, triglycerides <350 mg/dL, and left
ventricular ejection fraction >25%. Lipid levels were
measured on two occasions during screening to determine eligibility and
after 6 weeks, 3 months, 6 months, and every 6 months afterward for the
duration of the trial. The primary end point was coronary death
or nonfatal MI confirmed by a clinical events committee. The trial was
conducted at 80 clinical centers in Canada and in the United States.
The sites and investigators are listed elsewhere.5 11 The
study was approved by the Institutional Review Boards of the centers,
all patients gave informed consent, and the procedures were in
accordance with institutional guidelines.
Cox proportional hazards analyses with time-dependent
covariates were used.13 In these Cox analyses, the
follow-up lipid measurement (LDL cholesterol, HDL
cholesterol, or triglycerides) was the
time-dependent covariate. The lipid concentrations were updated for
each patient as the analysis progressed through patients'
follow-up periods. The primary end point (fatal CHD or nonfatal MI) and
an expanded end point (fatal CHD, nonfatal MI, CABG, or PTCA) were used
as the outcome variables. The primary analysis of lipid
levels during treatment combined patients in the
pravastatin and placebo groups together into a single group
called the "total cohort." Additional analyses examined the
pravastatin and placebo groups separately. Unless otherwise
stated, multivariate models adjusted for the baseline
variables of age, sex, smoking history, diabetes, hypertension, and
left ventricular ejection fraction. The initial Cox
proportional hazards models evaluated the assumption of a linear
relationship between follow-up lipid concentrations and
coronary event rates. However, to explore the possibility of
nonlinearity, the lipid concentrations were divided into deciles, with
indicator variables to identify these deciles in a time-dependent
manner, with the decile of highest lipid concentration or least
reduction in lipid concentration being the referent.
Results
Top
Abstract
Introduction
Methods
Results
Discussion
References
The principal baseline characteristics of the enrolled patients
were summarized as follows5 : mean age, 59 years; women,
14%; diabetes, 14%; current smoking, 21%; history of hypertension,
43%; and mean left ventricular ejection fraction, 53%.
Aspirin was taken by 83% of the patients, and a
revascularization procedure had been performed
before enrollment in 54%. Mean baseline lipid levels (mg/dL) were
total cholesterol, 209; LDL cholesterol, 139;
HDL cholesterol, 39; and triglycerides, 155. At
the end of the trial, the percentages of patients taking assigned study
medication were 94% and 86% in the pravastatin and
placebo groups, respectively. 
).
The difference in LDL concentrations between the
pravastatin and placebo groups was 31% in the first year
and 27% at the end of the trial. The small reduction in the difference
between the pravastatin and placebo groups in follow-up LDL
concentrations resulted from a decrease in LDL of the placebo group
caused by 8% of the placebo patients going on lipid-lowering treatment
(dropouts), most of which occurred late in the trial. Compared with the
placebo group, HDL levels increased by an average of 5% and
triglycerides decreased by an average of 10% in the
pravastatin group.
View larger version (13K):
[in a new window]
Figure 1. Percent change from baseline in LDL
cholesterol and LDL cholesterol concentration
during follow-up in pravastatin and placebo groups. ). The results were very similar when
the LDL value used in the analysis was the average or the most
recent value. Adjustment for the baseline risk factors had little
effect on the results. However, the relationship between follow-up
average LDL and coronary events in the total cohort was
determined to be nonlinear by use of time-dependent decile
analysis (Fig 2). The relative
risks for both the primary end point and expanded end point declined
progressively from the 10th decile (median LDL, 162 mg/dL) to the sixth
decile (median, 121 mg/dL), after which there was no further reduction.
Time-dependent decile analysis that used the most recent LDL
concentration showed a similar result (not shown). In the placebo
group, the relationship between follow-up LDL and coronary
events was similar to the relationship in the total cohort in the upper
range which was composed primarily of placebo patients (Fig 3). To evaluate this nonlinear phenomenon
more closely, a sequence of Cox proportional hazards models were
evaluated for the total cohort. These models used a dichotomization of
the follow-up LDL concentration and evaluated various cutpoints. When
the maximum-likelihood criterion was used, the best model had a
cutpoint of 125 mg/dL. The relative risk of a primary end point for
patients who had follow-up LDL 
125 mg/dL (mean, 145 mg/dL), whether
in the pravastatin or placebo group, was 43% greater than
for those with follow-up LDL <125 mg/dL (P<.01).
View this table:
[in a new window]
Table 1. Relationship Between Average Lipid Levels During
Treatment and Coronary Events
View larger version (28K):
[in a new window]
Figure 2. LDL cholesterol concentration
during follow-up and coronary events. Placebo and
pravastatin groups combined, n=4159 patients. A, Primary
end point: coronary death or nonfatal MI (n=486 patients with
end point, 55 in the 10th decile); B, expanded end point:
coronary death, nonfatal MI, CABG, or PTCA (n=979 patients with
end point, 111 in 10th decile). Relative risk determined by Cox
proportional hazards analysis with time-dependent covariates
(see text). Data points show relative risks with 95% CIs for
coronary events for deciles of follow-up LDL concentration.
Percentages of patients in each decile of LDL concentration who are in
pravastatin group are indicated by the solid line,
corresponding to right vertical axis.
View larger version (18K):
[in a new window]
Figure 3. LDL cholesterol concentration during
follow-up and coronary events. Placebo group, n=2078 patients.
Expanded end point: coronary death, nonfatal MI, CABG, or PTCA
(430 patients with end point, 67 in 10th decile). Relative risk
determined by Cox proportional hazards analysis with
time-dependent covariates (see text). Data points show medians with
95% CIs for coronary events for deciles of follow-up LDL
concentration. ). In the
pravastatin group, the highest event rate was in the
highest decile, median LDL was 136 mg/dL, and the event rates were
similar across all the other 9 deciles, which had medians of 117 to 71
mg/dL. The results were similar for the primary end point and when the
most recent LDL concentration was used. Adherence, defined as taking
study medication for at least 3 of the 5 years of follow-up, was 92%
in the highest decile of LDL during treatment, 94% to 95% in the 8th
and 9th deciles, and 98% to 99% in the remaining deciles. The average
decrease in LDL concentration that resulted in the median LDL
concentration during follow-up of 125 mg/dL was 25 mg/dL, or 17% of
the pretreatment concentration. Lower LDL concentrations that were
produced by larger decreases in LDL by up to 53 mg/dL, or by 43%, from
baseline were not associated with reductions in the coronary
event rate below that associated with an LDL concentration of 125
mg/dL.
View larger version (26K):
[in a new window]
Figure 4. LDL cholesterol concentration during
follow-up and coronary events. Pravastatin group,
n=2081 patients. Expanded end point: coronary death, nonfatal
MI, CABG, or PTCA (430 patients with end point, 52 in 10th decile).
Relative risk determined by Cox proportional hazards analysis
with time-dependent covariates (see text). Data points show medians
with 95% CIs for coronary events for deciles of follow-up LDL
concentration. Adherence, defined as taking study medication for at
least 3 of the 5 years of follow-up, was 92% in highest decile of
follow-up, 94% to 95% in 8th and 9th deciles, and 98% to 99% in
remaining deciles. 
100
mg/dL was 0.97 compared with those with LDL 101 to 125 mg/dL, thereby
demonstrating that the risks were nearly identical in both ranges of
follow-up LDL. We then used CIs around this relative risk to calculate
that the probability was 10% for a 15% reduction in end points in the
LDL range 100 mg/dL compared with the range 101 to 125 mg/dL. This
suggests that a clinically important reduction in events was unlikely
to have been missed. ). The
findings were similar for the primary end point (Table 2) and when most
recent LDL was used.
View this table:
[in a new window]
Table 2. Multivariate Analysis of LDL
Concentration and Absolute Decrease and Percentage Decrease in LDL
Concentration During Pravastatin Therapy: Relationship to
Coronary Events 
). The change in HDL also did not correlate
significantly with the event rate. In contrast, the
triglyceride level during follow-up was a significant
predictor of coronary events, although less strongly than LDL
(Table 1). The relative risk of a coronary event decreased from
1.0 in the highest triglyceride quintile (median, 260
mg/dL) to 0.90 in the middle quintile (median, 142 mg/dL) to 0.87 in
the lowest quintile (median, 84 mg/dL). When the three lipids were
considered together in the Cox model, LDL and triglycerides
were the independent predictors. Adding the three baseline lipid
concentrations to the models produced little change in these
results. ). This analysis requires that both
treatment groups be represented in a substantial part of
the LDL distribution of the total cohort. The percentage of patients in
each LDL decile who were in the pravastatin group is shown
in Fig 2 (right vertical axis). Pravastatin-treated
patients composed 45% of the middle 4 deciles, 100 to 134 mg/dL. Thus,
there was substantial representation from both treatment groups
in the middle 40% of the follow-up LDL distribution in the total
cohort. In this analysis, the unadjusted relative risk of an
expanded coronary end point in the pravastatin
compared with the placebo group was 0.76 (95% CI, 0.67 to 0.86). If
LDL lowering was entirely responsible for the effect of
pravastatin, the adjusted relative risk for treatment would
be 1.0 when the LDL concentration was included with the treatment
variable. The results showed that the relative risk of an expanded
coronary end point in the pravastatin group was
0.92 (0.77 to 1.10) after adjustment for LDL levels during treatment,
0.95 (0.79 to 1.14) after adjustment for LDL and
triglycerides, and 0.96 (0.80 to 1.15) after adjustment for
LDL, triglycerides, and HDL. This left 33% of the total
effect ([1-0.92]/[1-0.76]) unaccounted for by the LDL
concentration and only 17% ([1-0.96]/[1-0.76]) unaccounted for
by the concentrations of LDL, HDL, and triglycerides.
Discussion
Top
Abstract
Introduction
Methods
Results
Discussion
References
The CARE trial demonstrated that the HMG-CoA reductase
inhibitor pravastatin significantly prevented
recurrent coronary events in patients with average
cholesterol levels who had experienced an MI.5
We now report that the rate of coronary events was associated
strongly with the plasma LDL cholesterol concentrations
during treatment in the total cohort consisting of the patients treated
with pravastatin or placebo. This is not an unexpected
finding, considering that the HMG-CoAs were developed primarily to
reduce LDL concentrations and that a close relationship between plasma
total or LDL cholesterol and coronary events is
well established.14 15 16 17 18 19 20 A central finding of this study is
that the relationship between LDL during treatment and coronary
events is not a linear one but rather appears not to decline further
below a concentration of 125 mg/dL. Pravastatin also has
beneficial effects on plasma HDL cholesterol and
triglycerides, and the reduction in
triglyceride with pravastatin also appears to
contribute to the reduction in coronary events. 150 mg/dL (corresponding
to an LDL concentration of 110 mg/dL), a result that is very similar
to that found within the CARE trial. This suggests that the findings in
CARE are compatible with the totality of available evidence from
clinical end-point trials.
Selected Abbreviations and Acronyms
CABG
=
coronary artery bypass graft surgery
CARE
=
Cholesterol and Recurrent Events trial
CHD
=
coronary heart disease
HMG-CoA
=
hydroxymethylglutaryl coenzyme A
MI
=
myocardial infarction
PTCA
=
percutaneous transluminal coronary angioplasty
Acknowledgments
This study was supported by an investigator-initiated grant from
Bristol-Myers Squibb Pharmaceutical Research Institute.
Footnotes
Reprint requests to F.M. Sacks, Nutrition Department, Harvard School of Public Health, 677 Huntington Ave, Boston, MA 02115.
References
Top
Abstract
Introduction
Methods
Results
Discussion
References
This article has been cited by other articles:
 |
|
 |
|
  M. W. Medina, F. Gao, W. Ruan, J. I. Rotter, and R. M. Krauss Alternative Splicing of 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Is Associated With Plasma Low-Density Lipoprotein Cholesterol Response to Simvastatin Circulation, July 22, 2008; 118(4): 355 - 362. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Settergren, F. Bohm, L. Ryden, and J. Pernow Cholesterol lowering is more important than pleiotropic effects of statins for endothelial function in patients with dysglycaemia and coronary artery disease Eur. Heart J., July 2, 2008; 29(14): 1753 - 1760. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 U. Ravnskov Lack of Evidence for Recommended Low-Density Lipoprotein Cholesterol Treatment Targets Ann Intern Med, April 17, 2007; 146(8): 614 - 614. [Full Text] [PDF]
|
|
|
|
 |
|
 S. J. Nicholls and S. L. Hazen Myeloperoxidase and Cardiovascular Disease Arterioscler. Thromb. Vasc. Biol., June 1, 2005; 25(6): 1102 - 1111. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Z. Zhou, E. Rahme, M. Abrahamowicz, J. V. Tu, M. J. Eisenberg, K. Humphries, P. C. Austin, and L. Pilote Effectiveness of statins for secondary prevention in elderly patients after acute myocardial infarction: an evaluation of class effect Can. Med. Assoc. J., April 26, 2005; 172(9): 1187 - 1194. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Tunon, L. M. Blanco-Colio, J. L. Martin-Ventura, and J. Egido Intensive treatment with statins and the progression of cardiovascular diseases: the beginning of a new era? Nephrol. Dial. Transplant., November 1, 2004; 19(11): 2696 - 2699. [Full Text] [PDF]
|
|
|
|
|
|
J. Dernellis and M. Panaretou Relationship between C-reactive protein concentrations during glucocorticoid therapy and recurrent atrial fibrillation Eur. Heart J., July 1, 2004; 25(13): 1100 - 1107. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Lamarche and S. Desroches Metabolic syndrome and effects of conjugated linoleic acid in obesity and lipoprotein disorders: the Quebec experience Am. J. Clinical Nutrition, June 1, 2004; 79(6): 1149S - 1152S. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
U. Schonbeck and P. Libby Inflammation, Immunity, and HMG-CoA Reductase Inhibitors: Statins as Antiinflammatory Agents? Circulation, June 1, 2004; 109(21_suppl_1): II-18 - II-26. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Corti, J. I. Osende, J. T. Fallon, V. Fuster, G. Mizsei, H. Jneid, S. D. Wright, W. F. Chaplin, and J. J. Badimon The selective peroxisomal proliferator-activated receptor-gamma agonist has an additive effect on plaque regression in combination with simvastatin in experimental atherosclerosis: in vivo study by high-resolution magnetic resonance imaging J. Am. Coll. Cardiol., February 4, 2004; 43(3): 464 - 473. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Shepherd Statins for primary prevention: strategic options to save lives and money J R Soc Med, February 1, 2004; 97(2): 66 - 71. [Full Text] [PDF]
|
|
|
|
 |
|
 U. Ravnskov High cholesterol may protect against infections and atherosclerosis QJM, December 1, 2003; 96(12): 927 - 934. [Full Text] [PDF]
|
|
|
|
|
|
C. D. Williams Clinical decision making on statin drug interactions J. Am. Coll. Cardiol., July 16, 2003; 42(2): 396 - 397. [Full Text] [PDF]
|
|
|
|
|
|
P. K. Shah Low-Density Lipoprotein Lowering and Atherosclerosis Progression: Does More Mean Less? Circulation, October 15, 2002; 106(16): 2039 - 2040. [Full Text] [PDF]
|
|
|
|
 |
|
 H.-J. Park, D. Kong, L. Iruela-Arispe, U. Begley, D. Tang, and J. B. Galper 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Inhibitors Interfere With Angiogenesis by Inhibiting the Geranylgeranylation of RhoA Circ. Res., July 26, 2002; 91(2): 143 - 150. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
U. Ravnskov Is atherosclerosis caused by high cholesterol? QJM, June 1, 2002; 95(6): 397 - 403. [Full Text] [PDF]
|
|
|
|
|
|
E. J Schaefer Lipoproteins, nutrition, and heart disease Am. J. Clinical Nutrition, February 1, 2002; 75(2): 191 - 212. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. K. Ito, G. M. Delucca, and M. A. Aldridge The Relationship Between Low-Density Lipoprotein Cholesterol Goal Attainment and Prevention of Coronary Heart Disease-Related Events Journal of Cardiovascular Pharmacology and Therapeutics, June 1, 2001; 6(2): 129 - 135. [Abstract] [PDF]
|
|
|
|
 |
|
 E. Leitersdorf Cholesterol absorption inhibition: filling an unmet need in lipid-lowering management Eur. Heart J. Suppl., June 1, 2001; 3(suppl_E): E17 - E23. [Abstract] [PDF]
|
|
|
|
 |
|
 A. S. Kamigaki, D. S. Siscovick, S. M. Schwartz, B. M. Psaty, K. L. Edwards, T. E. Raghunathan, and M. A. Austin Low Density Lipoprotein Particle Size and Risk of Early-Onset Myocardial Infarction in Women Am. J. Epidemiol., May 15, 2001; 153(10): 939 - 945. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. M. Sacks Lipid-Lowering Therapy in Acute Coronary Syndromes JAMA, April 4, 2001; 285(13): 1758 - 1760. [Full Text] [PDF]
|
|
|
|
 |
|
 W. S. Aronow Treatment of Older Persons With Hypercholesterolemia With and Without Cardiovascular Disease J. Gerontol. A Biol. Sci. Med. Sci., March 1, 2001; 56(3): 138M - 145. [Abstract] [Full Text]
|
|
|
|
 |
|
 J Shepherd The statin era: in search of the ideal lipid regulating agent Heart, March 1, 2001; 85(3): 259 - 264. [Full Text]
|
|
|
|
</ |