From Aker Hospital, Oslo, Norway (T.R.P.); Linköping University
Hospital, Sweden (A.G.O.); Århus Hospital, Denmark (O.F.);
Rikshospitalet, University of Oslo, Norway (J.K., B.C.); Sahlgrenska
University Hospital, Göteborg, Sweden (H.W., L.W.); Institute of Medical
Genetics, University of Oslo, Norway (K.B.); Odense Hospital, Denmark (T.H.);
Landspitalinn University Hospital, Reykjavik, Iceland (G.T.); Kuopio
University Hospital, Finland (K.P., T.M.); and Merck Research Laboratories,
Rahway, NJ (J.A.T., T.A.M., T.J.C.).
Correspondence to Dr Terje R. Pedersen, Cardiology Department, Medical Clinic, Aker Hospital, N 0514, Oslo, Norway.
Methods and Results—The Cox proportional hazards model was used
to assess the relationship between lipid values (baseline, year 1, and
percent change from baseline at year 1) and MCEs. The reduction in MCEs
within the simvastatin group was highly correlated with
on-treatment levels and changes from baseline in total and LDL
cholesterol, apolipoprotein B, and less so with HDL
cholesterol, but there was no clear relationship with
triglycerides. We estimate that each additional 1%
reduction in LDL cholesterol reduces MCE risk by 1.7%
(95% CI, 1.0% to 2.4%; P<.00001).
Conclusions—These analyses suggest that the beneficial
effect of simvastatin in individual patients in 4S was
determined mainly by the magnitude of the change in LDL
cholesterol, and they are consistent with current
guidelines that emphasize aggressive reduction of this lipid in CHD
patients.
Patients were randomized to placebo or simvastatin 20
mg/d, with titration to 40 mg simvastatin at 12 or 24 weeks
in patients who did not reach the study target of a serum total
cholesterol level of 3.0 to 5.2 mmol/L (116 to 201
mg/dL) after 6 or 18 weeks. Clinic visits with lipid determination took
place at 6 and 18 weeks and at 6 months, and thereafter every 6 months.
All patients were accounted for at the end of the study. Median
follow-up time was 5.4 years (range, 4.9 to 6.3 years).
Measurement of Lipoprotein Components
Cholesterol and triglycerides were measured
enzymatically by the method of Boehringer Mannheim. HDL
cholesterol was measured after precipitation of apo
B–containing lipoproteins by heparin-MnCl. Although the accuracy and
precision of the analyses were monitored continuously by daily
analyses of HDL cholesterol in control sera, a
small temporary drift during 1992 in the HDL cholesterol
assay of unknown cause was discovered at the completion of the study.
LDL cholesterol was calculated according to the Friedewald
formula.5 Serum apo A-I and apo B were measured
by immunoturbidimetry by test kits with antisera and standards from
Orion. The lipoprotein measurements were stored in a secure computer at
the central laboratory and were not disclosed outside the laboratory
during the trial.
The baseline values of lipids and apolipoproteins are means of two
measurements from serum collected
End Points
Statistical Methods
Age, sex, smoking at baseline, a history of hypertension, myocardial
infarction, and diabetes were included as covariates in all the
statistical models. Baseline lipid and apolipoprotein values were
included in the statistical models that assessed the relationship
between percent change in lipoprotein components at year 1 (which is
essentially independent of baseline) and MCEs but not in the models
that assessed the relationship between year 1 absolute lipoprotein
value (which is strongly correlated with the baseline value) and MCEs.
Logistic regression was used to estimate the proportion of patients
with MCEs as a function of baseline and year 1 lipoprotein components.
The Cox proportional hazards model was used to assess the relationship
between lipoprotein values (baseline, year 1, and percent change from
baseline) and MCEs. This model was compared with other potential models
and previous studies in a sensitivity analysis.
The relative importance of lipids in a pair was assessed by selecting a
primary and a secondary lipid from all combinations of total, LDL, and
HDL cholesterols and triglycerides. Linear
regression with the primary lipid value as the independent variable
and the secondary lipid value as the dependent variable provided
the residual of the secondary lipid, which was then included with the
primary lipoprotein in a Cox proportional hazards model. The
significance of the residual in this model indicated whether or not it
added predictive information.
All analyses were based on the intention-to-treat principle,
and a two-sided value of P<.05 was considered statistically
significant.
Following dietary advice provided at the recruitment visit, patients
fulfilling the entry criteria on average reduced their serum total
cholesterol level by 2.1% and increased their
triglyceride level by 2.9% between the recruitment and
randomization visits (
The study target of a total cholesterol level
A total of 622 patients (28%) in the placebo group had one or more
MCEs, compared with 431 (19%) in the simvastatin group
(P<.0001). This end point included coronary death
(189 versus 111 in the placebo and simvastatin groups,
respectively), definite or probable nonfatal acute myocardial
infarction (418 versus 279), silent myocardial infarction (109 versus
90), resuscitated cardiac arrest (0 versus 1), and myocardial
infarction associated with invasive procedures (mainly CABG) (25 versus
12). During the first year of therapy the difference in MCEs was small
(151 patients in the placebo group and 131 in the
simvastatin group). However, from year 2 through year 6 of
therapy, the risk of MCEs and coronary deaths in the
simvastatin group were reduced by 40% and 47% relative to
the placebo group, respectively.
The relationships between baseline lipoprotein components and MCEs in
the two treatment groups are shown in Table 2
The relationships between 1-year levels of lipoprotein components in
the simvastatin group and the subsequent incidence of MCEs
are shown in Table 3
The relationship between the percent change in serum lipids from
baseline to 1 year in the simvastatin group and the
reduction in risk of MCEs is shown in Table 4
Table 5
Several modifications of the Cox regression analysis were
performed to explore the robustness of the results. Table 6
There is abundant evidence that serum and LDL cholesterol
are major risk factors for CHD,9 10 11 12 13 and current
guidelines emphasize reduction of LDL
cholesterol.9 10 14 Epidemiological
studies have often associated high triglyceride levels and
CHD incidence, but the relationship tends to weaken or disappear with
multivariate
analysis.15 16 This is largely a
consequence of the strong inverse relationship between the levels of
triglycerides and HDL cholesterol and between
HDL cholesterol level and CHD
incidence.13 As a result, there is a range of
opinion on the role of elevated plasma triglycerides in the
pathogenesis of CHD; in North America it has generally not been
considered a major independent risk factor,15
whereas in parts of Europe it is given more
weight.17 Isolated
hypertriglyceridemia may not increase CHD
risk, but there is evidence that it amplifies the risk in patients with
high LDL cholesterol and low HDL
cholesterol,17 who tend to have high
levels of small, dense LDL
cholesterol.18 The HDL
cholesterol level is determined partly by complex exchanges
of triglycerides and cholesterol esters between
chylomicrons and VLDLs and HDL,19 which could
contribute to its strong inverse relationship with CHD.
As shown in Tables 4
Analogous analyses in the Lipid Research Clinics Primary
Prevention Trial (LRC-CPPT)7 and the Helsinki
Heart Study8 produced relationships generally
similar to those observed in 4S, except for the greater effect of
changes in HDL cholesterol in the Helsinki Heart Study. In
both trials, the number of end points were relatively few and the
observed changes in LDL cholesterol were modest. In the
Helsinki Heart Study,8 there was a large
reduction (35%) in serum triglycerides, but as in 4S, it
did not predict CHD events.
We have previously reported that the relative risk reduction
produced by simvastatin is independent of the baseline LDL
cholesterol level.3 There is also no
evidence in 4S for any percent reduction or on-treatment threshold
level below which further lipid lowering is futile. In the Post
Coronary Artery Bypass Graft Trial, reducing mean LDL
cholesterol levels to <100 mg/dL (2.6 mmol/L)
retarded the progression of atherosclerosis in grafts
more than less aggressive lipid lowering. Current US guidelines
recommend a reduction of LDL cholesterol in CHD patients to
<100 mg/dL (2.6 mmol/L).10 14 This level
was reached (at 1 year) by 23% of the patients in 4S (a low percentage
reflecting the study goal of total cholesterol <5.2
mmol/L [201 mg/dL], the submaximal average dose of 27 mg/d, and the
high baseline LDL cholesterol). Our results are
consistent with the continuous relationship between serum
cholesterol and CHD mortality11 and
the rarity of coronary disease in populations with very low
serum cholesterol levels, even when other risk factors are
prevalent.20 21 In contrast, the authors of the
Cholesterol and Recurrent Events (CARE) study concluded
that there was no effect of pravastatin therapy in patients
with baseline LDL cholesterol <125 mg/dL (3.2
mmol/L).22 However, the 95% CI in this subgroup
included a risk reduction of up to 23%. The risk of misinterpretation
of results in small subgroups that appear to be different from those of
the study as a whole is well known.23
Because 4S was designed to test the hypothesis that lowering serum
cholesterol reduces mortality and not to provide answers to
the questions addressed in this report, the rigorous methods used for
the original analysis could not be applied. Although our data
are drawn from a randomized, placebo-controlled trial, the conclusions
in this paper derive from within-group analyses, as opposed to
comparison of randomized groups. Although we attempted to correct for
factors associated with risk (age, sex, smoking history, hypertension,
and diabetes), our analyses could have been influenced by other
unknown factors (as is typically the case in observational studies). In
addition, even though there were 1053 patients with MCEs (774 with the
first MCE in years 2 through 6), these may still have been insufficient
to detect all meaningful correlations.
The analyses presented in this report were not
predefined; rather, they were selected from a large number of
exploratory analyses of the relationship between lipoprotein
levels and risk. We tried to identify methods that were simple,
conservative, and least likely to be confounded, but ultimately our
choices were a matter of judgment. As shown in Table 6
Despite the limitations discussed above, our conclusions are generally
consistent with epidemiological
data,11 21 24 other intervention
studies,7 8 and
meta-analyses.25 26 27 However, randomized
trials are needed to confirm them. For example, our main conclusion
that greater reduction in LDL cholesterol should further
reduce coronary risk will be tested in a new trial in the
United Kingdom. This study (SEARCH) will randomize post-MI patients to
simvastatin 20 or 80 mg/d, the larger dose producing an
average reduction in LDL cholesterol of
47%.28
Received February 4, 1998;
accepted February 5, 1998.
© 1998 American Heart Association, Inc.
Clinical Investigation and Reports
Lipoprotein Changes and Reduction in the Incidence of Major Coronary Heart Disease Events in the Scandinavian Simvastatin Survival Study (4S)
Abstract
Top
Abstract
Introduction
Methods
Results
Discussion
References
Background—The Scandinavian
Simvastatin Survival Study (4S) randomized 4444 patients
with coronary heart disease (CHD) and serum
cholesterol 5.5 to 8.0 mmol/L (213 to 310 mg/dL) with
triglycerides 
2.5 mmol/L (220 mg/dL) to
simvastatin 20 to 40 mg or placebo once daily. Over the
median follow-up period of 5.4 years, one or more major
coronary events (MCEs) occurred in 622 (28%) of the 2223
patients in the placebo group and 431 (19%) of the 2221 patients in
the simvastatin group (34% risk reduction,
P<.00001). Simvastatin produced substantial
changes in several lipoprotein components, which we have attempted to
relate to the beneficial effects observed.
Key Words: coronary disease • lipoproteins • cholesterol • simvastatin
Introduction
Top
Abstract
Introduction
Methods
Results
Discussion
References
The
4S1 2 randomly allocated 4444 patients with CHD
and total cholesterol 5.5 to 8.0 mmol/L (213 to 310
mg/dL) to double-blind therapy with placebo or simvastatin
for 4.9 to 6.3 years. Simvastatin reduced coronary
mortality by 42% (P<.00001), thus reducing all-cause
mortality by 30% (P=.0003), and reduced the incidence of
MCEs (CHD death and nonfatal myocardial infarction) by 34%
(P<.00001). The relative reduction in the risk of MCEs was
independent of the baseline levels of total, LDL, and HDL
cholesterol.3 One or more MCEs were
observed in 622 (28%) of the 2223 patients in the placebo group and
431(19%) of the 2221 patients in the simvastatin group
(P<.00001). The large number of patients with clinical end
points in 4S and the substantial changes in serum lipoprotein levels in
the simvastatin group offered the opportunity to study the
relationship between outcome and baseline lipoprotein levels and
changes from baseline in the simvastatin group. Our
objective was to determine which baseline lipoproteins predict
coronary events and which lipoprotein changes produced by
therapy could best account for the observed clinical benefits.
Methods
Top
Abstract
Introduction
Methods
Results
Discussion
References
Study Design and Patients
4S was a double-blind, randomized, placebo-controlled,
multicenter clinical trial of long-term simvastatin therapy
in patients with CHD. The design of the trial and the main findings on
mortality, morbidity, and long-term safety have been described
previously.1 2 3 4 In brief, the patients were men
and women 35 to 70 years old (mean, 58.7 years) with a history of acute
myocardial infarction or angina pectoris. For them to qualify for
randomization, their serum total cholesterol had to be
between 5.5 and 8.0 mmol/L (213 and 310 mg/dL) and serum
triglyceride levels 2.5 mmol/L (220 mg/dL), after
dietary advice 2 months previously.
Blood samples were collected after 12 to 14 hours of fasting and
left to coagulate for 1 to 2 hours at room temperature. Serum was
separated by centrifugation and divided into three
aliquots. One tube was shipped unfrozen to the central laboratory the
same day to be analyzed for total cholesterol, and
the two other tubes were frozen immediately at -20°C. The frozen
serum was shipped batchwise in insulated containers with dry ice to the
central laboratory to be analyzed within 3 months. 
2 months after dietary advice, the
first at the beginning of the single-blind placebo period and the
second 2 weeks later on the day of randomization, except for apo A-I
and apo B, which were measured only at randomization.
End-point definition has been described
previously.1 In brief, all end-point events were
classified by an independent end-point classification committee. The
primary study end point was death from any cause. The secondary end
point was MCEs, defined as fatal or nonfatal definite or probable acute
myocardial infarction, including silent myocardial infarction; sudden
cardiac death; or resuscitated cardiac arrest. Although there were 438
deaths (the primary end point), the secondary end point, MCEs, is more
appropriate for correlation analyses because it is not diluted
by noncoronary events and because >1000 patients had one or
more MCEs, providing greater statistical power. Only the first
end-point event was included in the analysis.
Because the 1-year measurements were the first to be performed
after completion of the dose titration procedure, only baseline and
year 1 values were used in the principal analyses, avoiding the
problem of "using the future to predict the
future."6 Patients with MCEs in the first year
of the study were excluded from the analyses relating year 1 or
percent change at year 1 values to subsequent MCEs.
Results
Top
Abstract
Introduction
Methods
Results
Discussion
References
The frequency distribution of serum lipoprotein components in the
simvastatin group at baseline and at 1 year is shown in Fig 1
. There were no important differences in
baseline values between the two treatment groups. There were negative
correlations at baseline between HDL cholesterol and
triglycerides (r=-.40) and between LDL
cholesterol and HDL cholesterol
(r=-.22).
View larger version (21K):
[in a new window]
Figure 1. Frequency distribution of baseline ( 
) and
1-year (
) lipoprotein component levels in the
simvastatin group. To convert mmol/L to mg/dL, multiply by
38.7 for cholesterol and 88 for
triglycerides.2 months apart). Fig 2 shows the mean concentrations of serum
lipoprotein components in the placebo and simvastatin
groups during the trial. At 6 weeks, at which point all patients
randomized to simvastatin were taking 20 mg/d, there was a
28% reduction in serum total cholesterol, a 38% reduction
in LDL cholesterol, an 8% increase in HDL
cholesterol, and a 15% decrease in
triglycerides. The corresponding changes in the placebo
group were -1%, -1%, 0%, and 3%. Over the median 5.4-year
follow-up period, the mean reductions in the placebo and
simvastatin groups were serum total
cholesterol, +1%, -25%; LDL cholesterol,
+1%, -34%; HDL cholesterol, +1%, + 8%;
triglycerides, +7%, -9%; apo A-I, -3%, -3%; apo B,
-3%, -27%; and total/HDL cholesterol ratio, 0%,
-39%, respectively. Three quarters of the
simvastatin-treated patients had mean LDL
cholesterol levels reduced 30% or more, and a quarter of
the patients achieved reductions of >45%. Because the
analyses are based on the intention-to-treat principle,
patients who discontinued study therapy but continued to provide blood
samples are included. This contributes to the slight increases in serum
total and LDL cholesterol and in triglyceride
levels in the simvastatin group over the course of the
study.
View larger version (15K):
[in a new window]
Figure 2. Mean levels of lipids in the placebo ( 
) and
simvastatin () groups over the course of study. To
convert mmol/L to mg/dL, multiply by 38.7 for
cholesterol and 88 for triglycerides.5.2
mmol/L (201 mg/dL) at 6 and 18 weeks on 20 mg simvastatin
therapy was reached in 1398 patients (63%) in the
simvastatin group. In the remainder, who tended to be less
responsive to 20 mg and have higher baseline LDL and total
cholesterol levels (Table 1),
the dosage of simvastatin was increased to 40 mg/d. At 1
year, 77% of patients had total cholesterol 5.2
mmol/L.
View this table:
[in a new window]
Table 1. Mean Lipid Changes in Patients Taking 20 mg
Simvastatin Throughout and in Patients Titrated to 40 mg
After 12 Weeks or 6 Months of Therapy . In the placebo group, all lipids and
ratios except apo A-I were significantly related to MCE risk,
especially non-HDL cholesterol (P=.002),
triglycerides (P=.007), and total
cholesterol/HDL cholesterol
ratio(P=.008). In the simvastatin group, the
only significant relationships were with HDL cholesterol
(P=.026), apo B (P=.039), and the total
cholesterol/HDL cholesterol ratio
(P=.009). The association of baseline
triglycerides with MCEs in the placebo group but not the
simvastatin group is illustrated in the logistic regression
plot shown in Fig 3.
View this table:
[in a new window]
Table 2. Relationship of Serum Lipoprotein Components at
Baseline and Risk Reduction of MCEs According to Cox Proportional
Hazards Regression Models1
View larger version (15K):
[in a new window]
Figure 3. Relationship between baseline
triglyceride levels and MCEs with 95% CIs in the placebo
and simvastatin groups, adjusted for sex, age, history of
myocardial infarction, smoking, hypertension, and diabetes. Points
represent the mean value for each quintile. To convert
mmol/L to mg/dL, multiply by 88. . Significant
correlations were observed for all lipoproteins except for
triglycerides, HDL cholesterol, and apo A-I.
For example, a 1-mmol/L (38.7-mg/dL) reduction of serum total
cholesterol is associated with a 22.5% reduction in MCE
risk (P=.0001). Fig 4 shows
the relationship between the 1-year levels of LDL
cholesterol in the placebo and simvastatin
groups and the subsequent incidence of MCEs.
View this table:
[in a new window]
Table 3. Relationship of Serum Lipoprotein Components in the
Simvastatin Group Measured After 1 Year of Therapy and the
Subsequent Risk of MCEs According to the Cox Proportional Hazards
Regression Model1
View larger version (17K):
[in a new window]
Figure 4. Relationship between LDL cholesterol
levels at year 1 and subsequent risk of MCEs in the placebo and
simvastatin groups, with 95% CIs. Points represent
the mean value for each quintile. To convert mmol/L to mg/dL,
multiply by 38.7. . For each additional percentage point
reduction in total cholesterol, the MCE risk was reduced by
1.9% (P=.00005). Changes in LDL and HDL
cholesterol both contributed to the reduction in risk, but
LDL cholesterol changes appear more important, as is
evident in the larger absolute regression coefficient and lower
P value. Fig 5 shows the
modeled curvilinear relationship between reduction in LDL
cholesterol and reduction in risk. According to the model,
the incremental benefit became progressively less as the LDL
cholesterol reduction increased. Reduction in
triglycerides did not contribute to risk reduction.
View this table:
[in a new window]
Table 4. Relationship of 1% Decrease in Serum Lipoprotein
Components (Increase for HDL Cholesterol and for Apo A-I)
From Baseline to 1 Year in the Simvastatin Group and
Incidence of MCEs According to a Cox Proportional Hazards Regression
Model1
View larger version (21K):
[in a new window]
Figure 5. Modeled relationship between MCE risk reduction
after year 1 and (A) LDL cholesterol percent reduction at
year 1 and (B) absolute change in LDL cholesterol at year
1. The lighter curves define the 95% CI. To convert mmol/L to
mg/dL, multiply by 38.7. presents the results of the
pairwise analysis of the predictive value of lipids and
apolipoproteins measured after 1 year for the risk of MCEs in the
simvastatin group. All lipids and apolipoproteins with the
exception of triglycerides and HDL cholesterol
had statistically significant correlations to risk when
analyzed as a primary variable in pairs with other lipids
and apolipoproteins. Of the primary single lipids in the model, LDL
cholesterol had the regression coefficients with the
highest statistical significance. The contribution of the secondary
lipid to the prediction of risk was variable. For example, with
total cholesterol as the primary lipid, HDL
cholesterol provided additional predictive information
(P=.022). Conversely, with LDL cholesterol as
the primary lipoprotein component, none of the other lipids or
apolipoproteins provided significant additional predictive information,
indicating that the LDL level at 1 year carries most of the prognostic
information. With LDL cholesterol level as a primary
variable, percent change in LDL cholesterol did not
provide significant residual information, but neither did LDL
cholesterol level when paired as a secondary variable
with percent change of LDL cholesterol. Therefore, it was
not possible to determine which of these highly correlated measures of
efficacy is more important.
View this table:
[in a new window]
Table 5. Residual Risk Information of Secondary Lipids to
MCEs in the Simvastatin Group: Cox Proportional Hazards
Model Using 1-Year Values contains results of the most commonly
used alternative analyses together with results from the Lipid
Research Clinics Study7 and Helsinki Heart
Study8 for comparison. The estimates of the
relationship between reduction in LDL and reduction in MCEs was quite
similar for all methods and highly statistically significant. The HDL
cholesterol–MCE relationship was marginally significant
for most analyses. The 4S time-dependent analyses
indicated a significant relationship between triglycerides
and MCEs that was not seen in the analyses based on year 1 data
or in the other two studies. However, this effect was only about one
third that of LDL cholesterol in the time-dependent
analyses.
View this table:
[in a new window]
Table 6. Sensitivity Analysis: Relationship Using
Various Statistical Techniques Between a 1% Change in Lipoproteins in
the Simvastatin Group in 4S, the Cholestyramine Group in
LRC-CPPT,7 and the Gemfibrozil Group in the Helsinki Heart
Study,8 and the Reduction in the Risk of MCEs
Discussion
Top
Abstract
Introduction
Methods
Results
Discussion
References
At baseline, 95% of patients had LDL cholesterol
levels of 3.0 to 6.0 mmol/L (116 to 232 mg/dL), a range spanning
so-called normal as well as very high levels. In the placebo group, all
baseline lipoprotein components were clearly related to the risk of
subsequent MCEs, except for apo A-I (Table 2
). In the
simvastatin group, the relationships between baseline
lipoproteins and MCEs were relatively weak, as we have previously noted
using a quartile analysis.3 This can be
attributed to the drug effect, which varies from patient to patient,
producing a redistribution of baseline lipid values within a few
weeks. and 5, in the simvastatin group the
reductions in total, LDL, and non-HDL cholesterol and apo B
were all strongly related to risk reduction. Not only LDL but also the
denser fraction of VLDL (IDL) is atherogenic,15
consistent with the strong relationship between non-HDL
cholesterol (essentially LDL cholesterol plus
VLDL cholesterol) and risk in our study. The modeled
relationships are not linear (Figs 5A and 5B). The model estimates a
45% reduction in MCEs for a 35% reduction in LDL, which is close to
the 40% reduction in MCEs observed in years 2 through 6 of the study.
There was a weaker relationship between HDL cholesterol
increase and risk reduction and no significant relationship for
triglycerides and apo A-I. There was a small effect of
triglycerides in the time-dependent analyses, which
may be attributable to the reduced variability of serum
triglycerides when averaged over time, compared with the
single measurement at year 1 in the principal analysis. Also,
triglyceride-rich lipoproteins could affect short-term risk
(for example, through an effect on thrombogenesis) rather than the
long-term atherosclerotic process per se. However,
triglyceride reduction is at most a minor contributor to
MCE reduction in the 4S population. Whether larger and more
consistent effects occur in patients with serum
triglycerides higher than the 2.5 mmol/L (220 mg/dL)
4S cutoff remains to be demonstrated. , there are
several alternative methods that could have been used, but none
improved the robustness of the results. In some alternative
analyses, even minor modification of the methods used
introduced marked changes in coefficients and significance levels. On
the other hand, LDL cholesterol percent change and year 1
value in the simvastatin group correlated
consistently with MCE risk reduction by several different
analytic methods.
Selected Abbreviations and Acronyms
apo
=
apolipoprotein
CHD
=
coronary heart disease
MCE
=
major coronary event
4S
=
Scandinavian Simvastatin Survival Study
Acknowledgments
4S was supported by a grant from Merck Research
Laboratories.
Footnotes
1 Collaborators and participating centers are listed in the Appendix of Reference 1. 
References
Top
Abstract
Introduction
Methods
Results
Discussion
References
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Z. T. Bloomgarden Dyslipidemia and the Metabolic Syndrome Diabetes Care, December 1, 2004; 27(12): 3009 - 3016. [Full Text] [PDF]
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K. Pyorala, C. M. Ballantyne, B. Gumbiner, M. W. Lee, A. Shah, M. J. Davies, Y. B. Mitchel, T. R. Pedersen, and J. Kjekshus Reduction of Cardiovascular Events by Simvastatin in Nondiabetic Coronary Heart Disease Patients With and Without the Metabolic Syndrome: Subgroup analyses of the Scandinavian Simvastatin Survival Study (4S) Diabetes Care, July 1, 2004; 27(7): 1735 - 1740. [Abstract] [Full Text] [PDF]
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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]
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P Barter Is high-density lipoprotein the protector of the cardiovascular system? Eur. Heart J. Suppl., March 1, 2004; 6(suppl_A): A19 - A22. [Abstract] [Full Text] [PDF]
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M. Rauchhaus, A. L. Clark, W. Doehner, C. Davos, A. Bolger, R. Sharma, A. J. S. Coats, and S. D. Anker The relationship between cholesterol and survival in patients with chronic heart failure J. Am. Coll. Cardiol., December 3, 2003; 42(11): 1933 - 1940. [Abstract] [Full Text] [PDF]
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K. O. Akosah, A. Schaper, C. Cogbill, and P. Schoenfeld Preventing myocardial infarction in the young adult in the first place: how do the national cholesterol education panel iii guidelines perform? J. Am. Coll. Cardiol., May 7, 2003; 41(9): 1475 - 1479. [Abstract] [Full Text] [PDF]
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 M. A. W. Umans-Eckenhausen, J. C. Defesche, M. J. van Dam, and J. J. P. Kastelein Long-term Compliance With Lipid-Lowering Medication After Genetic Screening for Familial Hypercholesterolemia Arch Intern Med, January 13, 2003; 163(1): 65 - 68. [Abstract] [Full Text] [PDF]
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W. Lu, H. E. Resnick, K. A. Jablonski, K. L. Jones, A. K. Jain, Wm. J. Howard, D. C. Robbins, and B. V. Howard Non-HDL Cholesterol as a Predictor of Cardiovascular Disease in Type 2 Diabetes: The Strong Heart Study Diabetes Care, January 1, 2003; 26(1): 16 - 23. [Abstract] [Full Text] [PDF]
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