(Circulation. 1997;96:4211-4218.)
© 1997 American Heart Association, Inc.
Articles |
Cholesterol-Lowering Therapy in Women and Elderly Patients With Myocardial Infarction or Angina Pectoris
Findings From the Scandinavian Simvastatin Survival Study (4S)
From the Department of Medicine, University of Helsinki (Finland) (T.A.M.); Department of Medicine, University of Kuopio (Finland) (K.P.); Department of Internal Medicine, Linköping (Sweden) University Hospital (A.G.O.); Merck Research Laboratories, Rahway, NJ (T.A.M., T.J.C.); Århus (Denmark) University Hospital (O.F.); Institute of Medical Genetics, University of Oslo (Norway) (K.B.); Medical Department, Åker Hospital, Oslo, Norway (T.P.); and Department of Medicine, Rikshospitalet, Oslo, Norway (J.K.).
Correspondence to Prof Tatu Miettinen, Department of Medicine, University of Helsinki, 00290 Helsinki 29, Finland.
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Abstract |
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Background The Scandinavian Simvastatin Survival Study (4S) demonstrated pronounced reductions in mortality and major coronary events in a cohort of patients with established coronary heart disease (CHD). The present study provides a detailed, post hoc assessment of the efficacy and safety of simvastatin therapy in the following subgroups of 4S patients: those
65 years of age, those <65 years of age, women,
and men.
Methods and Results The 4S cohort of 4444 CHD patients included
827 women and 1021 patients 65 years of age. Total
cholesterol at baseline was 5.5 to 8.0 mmol/L with
triglycerides 
2.5 mmol/L. Patients were randomized
to therapy with simvastatin 20 to 40 mg daily or placebo
for a median follow-up period of 5.4 years. End points consisted of
all-cause and CHD mortality, major coronary events (primarily
CHD death and nonfatal myocardial infarction), other acute CHD and
atherosclerotic events, hospitalizations for CHD and
cardiovascular events, and coronary
revascularization procedures. Mean changes in serum
lipids were similar in the different subgroups. In patients 65 years
of age in the simvastatin group, relative risks (95%
confidence intervals) for clinical events were as follows: all-cause
mortality, 0.66 (0.48 to 0.90); CHD mortality, 0.57 (0.39 to 0.83);
major coronary events, 0.66 (0.52 to 0.84); any
atherosclerosis-related event, 0.67 (0.56 to 0.81); and
revascularization procedures, 0.59 (0.41 to 0.84).
In women, the corresponding figures were 1.16 (0.68 to 1.99); 0.86
(0.42 to 1.74), 0.66 (0.48 to 0.91), 0.71 (0.56 to 0.91), and 0.51
(0.30 to 0.86), respectively.
Conclusions Cholesterol lowering with
simvastatin produced similar reductions in relative risk
for major coronary events in women compared with men and in
elderly (65 years of age) compared with younger patients. There were
too few female deaths to assess the effects on mortality in women.
Because mortality rates increased substantially with age, the absolute
risk reduction for both all-cause and CHD mortality in
simvastatin-treated subjects was approximately twice as
great in the older patients.
Key Words: hypercholesterolemia • coronary disease • simvastatin • mortality
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Introduction |
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A direct relationship between serum cholesterol levels and risk for developing CHD has been most clearly demonstrated in studies of middle-aged men. Although a similar relationship has been observed in middle-aged women and in some older populations (
65 years of age),
the strength of the relationship is reported to be weaker in the
elderly and is less convincingly established for elderly women compared
with elderly men.1 Women and elderly patients
have been poorly represented in prior
cholesterol-lowering clinical trials. Consequently, the
value of lipid screening and cholesterol-lowering therapy
in these populations has been subject to
question.2
The 4S randomized 4444 moderately
hypercholesterolemic patients with a history of
myocardial infarction or angina pectoris to double-blind treatment with
simvastatin or placebo. Patients 35 to 70 years of age were
entered regardless of sex. Treatment with simvastatin over
a median follow-up period of 5.4 years resulted in a 30% reduction in
risk of death from all causes (P<.0003), attributable to a
42% reduction in risk of CHD death (P<.00001). Of the
total patient population, 19% were female and 23% were 65 years of
age at the start of the study. The initial 4S
publication3 provided limited results for women
and for patients 60 years of age. In the present article, the
efficacy and safety of simvastatin therapy in elderly (age
65) and female 4S patients are reported in depth.
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Methods |
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Study Design and Conduct
Details of the 4S design, organization, conduct, and baseline characteristics of the entire study cohort have been published previously.3,4 In brief, 4444 patients (827 female) 35 to 70 years of age (1021 were
65 years) were enrolled at
94 clinical sites within the Nordic countries. To qualify for entry,
patients were required to have total serum cholesterol
between 5.5 and 8.0 mmol/L (213 to 309 mg/dL), a
triglyceride level 2.5 mmol/L (220 mg/dL) on a
lipid-lowering diet, and either a documented prior acute myocardial
infarction or active, stable angina pectoris. Premenopausal women of
childbearing potential were excluded. Other exclusions have been
described previously.3,4 Qualifying patients were
randomized to receive simvastatin 20 mg daily or placebo.
The dosage was increased to 40 mg daily in patients whose
cholesterol remained >5.2 mmol/L (201 mg/dL) at the
6- or 18-week measurements. All-cause mortality and major
coronary events (CHD death, nonfatal myocardial infarction, or
resuscitated cardiac arrest) were the primary and secondary end points
of the study, respectively. Any CHD-related event, any
atherosclerosis-related event, and coronary
revascularization procedures were tertiary end
points.
Safety and Tolerability Assessment
Patients were evaluated for adverse events at clinical visits
that were scheduled after the initiation of therapy at 6 weeks, 12
weeks, and 6 months and semiannually thereafter. Measurement of serum
AST, ALT, and creatine kinase were performed at each of these visits;
ECG and routine physical examination were performed annually. An
adverse event is defined as any new or worsening symptom or any
unfavorable change in the structure, function, or chemistry of the body
or the worsening of a preexisting condition. The study investigators at
each of the participating clinics classified each adverse event as to
relationship to study therapy using the categories of definitely,
probably, possibly, probably not, or definitely not drug related. They
also recorded whether the adverse event was "serious," ie, one
that resulted in death, was immediately life threatening, resulted in
permanent or substantial disability, was a malignant neoplasm, resulted
in hospitalization, or prolonged an existing hospitalization.
Statistical Analyses
Treatment group differences were assessed by the log-rank test.
Relative risk and 95% confidence intervals were calculated with the
Cox regression model.5 Mortality, major
coronary events, and revascularization data
were also analyzed with baseline variables that were
significantly related to outcome (two-sided probability values of
P<.05) included in the model. Time to first hospitalization
and time to first revascularization were determined
by use of the Kaplan-Meier procedure. Treatment differences in the rate
of acute CHD hospitalizations, revascularization
procedures, and total acute cardiovascular
hospitalizations were assessed with a Cox regression method for
recurrent events.6 ANOVA was used to test
treatment differences in the average length of stay per hospitalization
and total bed days per patient. All data were analyzed by
intention to treat.
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Results |
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Baseline Characteristics
The distribution of male and female patients by age (5-year intervals) in the simvastatin and placebo treatment groups is shown in Fig 1
. Mean age of the
subgroup of patients 65 years of age was 
67 years compared with 56
years for the <65 subgroup. Baseline characteristics (including
lipids) for the four subpopulations of interest (women, men, patients
65 years of age, and patients <65 years of age) are provided in
Table 1. In general, the two treatment
groups within each age or sex subgroup were well matched at baseline.
However, there were clear differences in baseline characteristics
between women and men and between patients 65 and <65 years of age
(Table 1). Female participants were slightly older at entry (on
average, 2.3 years), and more female patients were entered on the basis
of documented angina pectoris without a history of prior myocardial
infarction. There were fewer prior
revascularization procedures, fewer patients with
major Q waves on baseline ECGs, more nonsmokers, more patients with a
diagnosis of hypertension, and greater use of nitrates and, to a lesser
extent, calcium channel blockers among women compared with men. Women
had higher baseline HDL cholesterol on average compared
with men. The elderly (65 years of age) subgroup included a higher
proportion of women, more patients entered on the basis of prior
myocardial infarction, and more nonsmokers compared with the younger
(<65 years of age) subgroup.
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The potential importance of chance differences in baseline characteristics between the two treatment groups for any of these four subpopulations was evaluated by assessment of the relationship of all of the listed baseline variables to total mortality and to major coronary events, as described in "Methods." The inclusion of those baseline characteristics that were significantly related to outcome in the Cox regression model for the analysis of treatment group differences had virtually no impact on the results. Consequently, only results from analyses unadjusted for baseline variables are reported in the following sections.
Use of estrogens was very low among women participating in 4S and was equally distributed between the two treatment groups (31 patients at baseline: 15 of 407 (3.7%) in the simvastatin group and 16 of 420 (3.8%) in the placebo group).
Serum Lipids During Treatment
Table 2 lists the
(intention-to-treat) mean between-treatment group differences for
percent change from baseline in total cholesterol, LDL
cholesterol, HDL cholesterol, and
triglycerides. Values are presented from
measurements taken 6 weeks after initiation of therapy with the study
drug (at which point all patients allocated to simvastatin
were still taking 20 mg/d), and values representing the
mean between-group differences over the full duration of the trial are
given. In general, the observed changes in each of the four
subpopulations of interest were similar, and the changes measured at 6
weeks were remarkably stable over the entire 5- to 6-year study
period.
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Among patients in the simvastatin group, the proportion of
women whose dose required titration from 20 to 40 mg was 39% compared
with 37% for men. Corresponding figures for patients 65 and <65
years of age were 31% and 39%, respectively. The percentages of
patients achieving total cholesterol levels <5.2
mmol/L (201 mg/dL) at the 1-year time point were 68.6% for women,
73.1% for men, 75.8% for patients 65 years of age, and 71.2% for
patients <65 years of age.
Total and CHD Mortality
Total and CHD mortality for the four subpopulations of interest
are provided in Table 3. There were 53
deaths among the 827 female patients (6.4%), 28 in the
simvastatin group, and 25 in the placebo group. (This
includes one female CHD death in the simvastatin group that
had been incorrectly reported as a male death in the first 4S
publication, an error discovered after publication.) There were 17
deaths attributed to CHD among the female patients in the placebo group
(a rate of 4.0%, less than half the 9.5% CHD mortality rate observed
in men) compared with 14 CHD deaths in the simvastatin
group. Thus, the overall numbers of deaths were too low to permit
meaningful assessment of either total or CHD mortality. There were no
meaningful differences between the treatment groups in the individual
categories of non-CHD death classified by the blinded End Point
Classification Committee; the non-CHD deaths for women in the
simvastatin:placebo groups were distributed in the
following categories: other cardiac, 1:1; nonembolic cerebral
infarction, 1:0; intracerebral hemorrhage, 2:0;
other arteriosclerotic, 1:0, cancer, 6:6;
suicide/violence/accident, 1:1; and other
noncardiovascular, 2:1.
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All-cause mortality was significantly reduced in patients 65 years of
age in the simvastatin group compared with the group
receiving placebo (relative risk, 0.66; P=.009). The
reduction in relative risk was slightly greater than that observed for
patients <65 years of age (0.72, P=.007), with overlapping
95% confidence intervals. Relative risk for CHD mortality in the
simvastatin group was similarly reduced in the two age
groups, by 43% and 42% for patients 65 and <65 years of age,
respectively, and these results were highly statistically significant
for both groups (Table 3
). All-cause and CHD mortality rates in the
placebo group over the duration of the study were more than twice as
high for patients 65 years of age (19.1% and 14.5%, respectively)
compared with patients <65 years of age (9.3% and 6.7%,
respectively). Consequently, the absolute risk reduction in the 65
years of age group was more than twice that in the <65 years of age
group for both total and CHD mortality (ie, the numbers of deaths
prevented by simvastatin therapy in the 65- and
<65-year-old 4S subpopulations were 61.5 versus 25.5 per 1000 patients
[all cause] and 60.2 versus 28.1 [CHD], respectively; see Table 3).
The results of an analysis of the proportion of patient deaths
(CHD and all cause) as a function of age with a logistic regression
model (with treatment group, age, and treatment by age interaction in
the model) are shown in Fig 2. The curves
estimate the proportion of patients who died in each group as a
function of patient age at entry into the study from the 5th to 95th
age percentiles. Total and CHD mortality increased with age in both
groups, with a beneficial simvastatin treatment effect seen
across the full range of patient ages shown in the figures.
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Kaplan-Meier curves for all-cause mortality in patients 65 and <65
years of age are shown in Fig 3. The
curves begin to separate at <1 to 2 years, as was the case for the
entire study population,4 and continue to diverge
for the duration of follow-up in the study.
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Major Coronary Events and Other Event Categories
Analysis of major coronary events in female 4S
patients provides considerably greater statistical power compared with
CHD mortality because there were approximately five times the number of
such events observed. The relative risk for major coronary
events for women in the simvastatin group (Table 3) was
0.66 (P=.012), identical to the relative risk observed in
men. The related event category of nonfatal myocardial infarctions
showed a similar degree of risk reduction and statistical significance.
Significant risk reductions in women were seen in all the other
prespecified tertiary end-point categories for which significant
results were observed in the entire study cohort, including any acute
CHD-related event, any acute atherosclerosis-related
event, and need for coronary
revascularization procedure. The magnitude of risk
reductions in these categories was quantitatively similar to that
observed in men (Table 3) and in the entire study
population.3
Highly significant risk reductions were also observed for these
secondary and tertiary end-point categories in patients 65 years of
age in the simvastatin group (Table 3), with 95%
confidence intervals overlapping those observed for the patients <65
years of age and the entire 4S study cohort.3 The
magnitude of the relative risk reductions in each case was as great as
or greater for patients 65 years of age compared with patients <65
years of age.
Kaplan-Meier curves for major coronary events and for
revascularization procedures are shown for the
subpopulations of interest in Fig 4. The
curves are similar to those previously published for the entire study
population,3 separating at <1 to 2 years and
continuing to diverge during the remainder of the follow-up period.
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Hospitalizations
The numbers of hospitalizations and total hospital bed days for
acute CHD and acute cardiovascular events in patients
in the simvastatin and placebo groups within each of the
four subpopulations are shown in Table 4.
Statistically significant reductions in both numbers of
hospitalizations and total hospital bed days for both categories were
observed in each subgroup. There were no consistent differences
in the magnitude of these reductions in the different subgroups. The
frequency of all coronary artery
revascularization procedures (as opposed to only
the first procedure, captured as a tertiary end point) is also listed
Table 4. Significant reductions were seen in simvastatin-
compared with placebo-treated patients in both age subgroups and for
men as well as women.
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Safety and Tolerability
A detailed analysis of adverse experiences, safety, and
tolerability for the entire study cohort has been published
separately,7 including an assessment of cancers,
which were approximately equally distributed between
simvastatin and placebo patients. There was no evidence for
increased prevalence of any sex-specific cancer in patients treated
with simvastatin (breast, 3 simvastatin and 6
placebo; ovary, 2 simvastatin and 1 placebo; penis, 1
simvastatin and 0 placebo; prostate, 17
simvastatin and 20 placebo; and uterus, 1
simvastatin and 3 placebo).
The numbers of patients within each of the age and sex subpopulations
who permanently discontinued study drug for any reason other than death
are listed in Table 5. Discontinuations
were 20% lower for simvastatin-treated patients
compared with placebo-treated patients in each subpopulation.
Discontinuation rates were similar for patients 65 and <65 years of
age. Adverse clinical experiences were the reason for discontinuation
in similar proportions of patients in the simvastatin and
placebo groups within each of the age and sex subpopulations.
Discontinuations because of adverse laboratory experiences were
uncommon (none at all in the age 65 subgroup) and were distributed
nearly equally between simvastatin- and placebo-treated
patients in each subpopulation. They consisted primarily of elevations
in liver enzymes.
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A summary of the numbers/percentages of patients in the different
subgroups who experienced adverse clinical or laboratory events is also
provided in Table 5. The lower occurrence of adverse clinical events
within the simvastatin subgroups in each of the four
subpopulations (particularly those rated as serious) was a consequence
of the larger numbers of cardiovascular adverse events
in placebo-treated patients, consistent with the end-point
findings. Review of specific clinical adverse event categories did not
reveal any significant age- or sex-specific toxicities of
simvastatin within the subpopulations. Among women, the
only adverse clinical experience category not related to end point with
a statistically significant (P<.05) difference between the
treatment groups was new or increased hypertension
(simvastatin, 18; placebo, 38, P=.009). The
latter difference was also seen in the entire 4S cohort
(simvastatin, 133; placebo, 168; P=.042) but not
in men (simvastatin, 115; placebo, 130; P=.32).
In patients 65 years of age, laboratory adverse experiences of
increases in ALT or AST occurred significantly more frequently in
simvastatin- versus placebo-treated patients (for ALT, 40
patients (7.7%) versus 22 patients (4.4%), P=.026; for
AST, 26 patients (5.0%) versus 10 patients (2.0%), P=.01).
The minor and generally transient nature of these elevations in the
elderly is reflected both by the fact that no patient 65 years of age
discontinued the study drug permanently because of liver enzyme
elevations and by the fact that elevations to levels three times the
upper limit of normal among these patients were infrequent and
comparably distributed between the treatment groups (for ALT, 5
simvastatin and 3 placebo; for AST, 3
simvastatin and 5 placebo).
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Discussion |
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Patients in 4S were randomized regardless of sex provided that they met the entry criteria specified in the protocol.4 The percentage of women in 4S (19%) was similar to percentages randomized in smaller secondary prevention trials that entered CHD patients of both sexes within a similar age range.8–10
Differences in baseline characteristics for women compared with men in 4S included a lower proportion of prior myocardial infarction, more nonsmokers, more baseline diagnoses of hypertension, greater use of nitrates and calcium antagonists, and fewer prior coronary revascularization procedures. Female participants were slightly older than male participants and had higher HDL cholesterol levels with comparable LDL cholesterol levels. Some of these differences undoubtedly contributed to the lower incidence of CHD mortality and nonfatal CHD events in women compared with men. Estrogen use among women was very low and was equally distributed between treatment groups; it is unlikely, therefore, to have had any impact on results other than possibly contributing slightly to the lower mortality and morbidity seen in women. The most notable baseline differences between the age subgroups were fewer smokers and greater numbers of patients entered on the basis of myocardial infarction in older versus younger patients. Because of the randomization process, however, between-treatment group differences for the age subpopulations were minor and did not significantly affect the results.
The mean changes in serum lipids produced by simvastatin
were similar in each of the examined subpopulations and were similar to
the changes observed in the entire study cohort.3
For the subjects 65 versus <60 years of age, lipid changes of a
similar magnitude were achieved despite titration of fewer patients
from 20 to 40 mg (31% compared with 39%). This is consistent
with other data suggesting that increasing age enhances
cholesterol-lowering responsiveness to HMG CoA reductase
inhibitors.11 Baseline total, LDL,
and HDL cholesterol levels showed no significant
relationship to treatment outcome (reduction in relative risk) for any
of the examined subpopulations (data not shown), as was also the case
for the entire study cohort.12
The 4S is the first clinical trial to convincingly demonstrate that
cholesterol-lowering therapy reduces the risk of major
coronary events in women with preexisting CHD. The magnitude of
the reduction (34%) was similar to that observed in men, as were the
magnitudes of risk reductions for the tertiary end points of any CHD
event, any atherosclerotic event, and need for coronary
revascularization. Decreased rates of
cardiovascular hospitalizations and hospital bed days
further support the benefit of treatment. Small numbers of CHD and
total deaths in women precluded meaningful assessment of
simvastatin effects on all-cause or CHD mortality in women.
However, the finding that all CHD end-point categories other than
mortality were similarly positive for men and women (Table 3) makes it
highly likely that a study with adequate statistical power to address
mortality in women (such as the ongoing Heart Protection Study in the
United Kingdom) will yield a positive outcome, particularly because
there is no suggestion in the 4S data of any adverse influence of
simvastatin on non-CHD mortality in women or in the general
4S population.3,7
The 4S is also the first clinical trial to clearly demonstrate that
cholesterol-lowering therapy reduces the risk of all-cause
mortality and major coronary events in CHD patients 65 years
of age. Simvastatin treatment produced a highly significant
34% reduction in risk for all-cause mortality (P=.009),
attributable to a 43% reduction in risk for CHD mortality
(P=.003). The observed relative risk reductions in both
mortality categories, as well as for other secondary and tertiary CHD
end points (Table 3), were as great as or greater than those seen in
younger patients. Because mortality and CHD event rates increased with
age (Fig 2), the absolute reductions in deaths and events were
substantially greater for patients 65 compared with those <65 years
of age. It should be remembered that at the conclusion of the study,
those patients who were 65 years old at entry ranged from 70 to 76
years of age.
Because the strength of the relationship between serum cholesterol and development of CHD observed in some epidemiological studies is reported to weaken in elderly compared with middle-aged subjects,1,13–16 the above findings may at first appear surprising. However, data on the predictive importance of cholesterol in elderly patients with established CHD are limited. Moreover, the mechanisms underlying the relationship between cholesterol and the development of CHD may differ from the mechanisms contributing to therapeutic benefit from cholesterol lowering in the setting of advanced atherosclerosis. There is evidence that "lipid-rich" atherosclerotic plaques are particularly susceptible to rupture, leading to clinical events of myocardial infarction or unstable angina. Lipid depletion of rupture-prone plaques may stabilize such lesions, resulting in fewer clinical events.17 A mechanism of this nature would be expected to reduce risk in patients having vulnerable plaques, regardless of age.
In the CARE trial, 4159 patients with prior myocardial infarction
and total cholesterol level <6.2 mmol/L (240
mg/dL) were randomized to treatment with pravastatin 40
mg/d or placebo for 5 years.18 Women (n=576)
and patients 60 years of age (n=2129) had statistically significant
reductions in major coronary events. It is difficult to compare
specific event rates meaningfully in 4S and CARE because there were
major differences in the definitions of end points and baseline
characteristics of the patients in the two studies. For example, the
end-point category of major coronary events in CARE, unlike 4S,
included revascularization procedures but excluded
silent myocardial infarctions. All women studied in CARE were entered
on the basis of a prior myocardial infarction, while only 63% of 4S
women had a history of prior definite infarction. Pertinent
characteristics of the female cohort in CARE included significantly
more current smokers and higher prevalences at baseline of diabetes,
hypertension, family history of CHD, and multiple risk factors compared
with the male CARE cohort.19 Larger risk
reductions for major coronary events were observed in women
compared with men with pravastatin treatment in CARE (46%
versus 20%, respectively). In contrast, the observed relative risk
reductions for major coronary events in 4S were identical for
the two sexes. Whether the apparent male-female treatment effect
difference in CARE reflects a chance finding (the reported 95%
confidence intervals for men and women overlapped), a consequence of
differences in patient baseline characteristics, or some other
explanation cannot be determined from the available data. Neither 4S
nor CARE had sufficient power to address total or CHD mortality in
women. Total and CHD mortality data for women and for patients 65
have not yet been reported for CARE.
In summary, cholesterol lowering with
simvastatin in 4S produced statistically significant risk
reductions in women, men, and patients 65 or <65 years of age for
major coronary events and all tertiary CHD and
atherosclerosis-related study end points that were
positive for the entire 4S cohort. The magnitudes of the observed risk
reductions in these subgroups were remarkably similar to those reported
for the entire study cohort and for other clinically relevant subgroups
that have been analyzed.3,12,20 Although
4S was not specifically designed to address mortality benefit in the
elderly, high event rates combined with the substantial portion of
patients who fell into this subgroup provided the power to demonstrate
highly significant risk reductions for both all-cause and CHD
mortality. Safety and tolerability findings for the age and sex
subpopulations showed no important differences and were generally
consistent with the findings for the entire study
cohort.7 We conclude that beneficial effects of
cholesterol lowering with simvastatin in CHD
populations such as that studied in 4S occur independent of age and
sex.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This study was supported by a grant from Merck Research Laboratories, Rahway, NJ.
Received July 11, 1997; revision received September 15, 1997; accepted September 23, 1997.
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