(Circulation. 1995;92:2404-2410.)
© 1995 American Heart Association, Inc.
Articles |
Effects of Cholesterol Lowering on the Progression of Coronary Atherosclerosis in Women
A Canadian Coronary Atherosclerosis Intervention Trial (CCAIT) Substudy
Presented in part at the American College of Cardiology 43rd Annual Scientific Session, Atlanta, Georgia, March 13-17, 1994, and published in abstract form (J Am Coll Cardiol. 1994;23:455A).
Correspondence to David Waters, MD, Division of Cardiology, Hartford Hospital, 80 Seymour St, Hartford, CT 06102-5037.
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Abstract |
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Background Although coronary disease is the leading cause of death in women and its clinical features differ from those in men, very few women have been included in angiographic trials of cholesterol lowering.
Methods and Results Sixty-two women with diffuse but
not necessarily severe coronary atherosclerosis
documented on a recent angiogram and with fasting serum
cholesterol between 220 and 300 mg/dL were enrolled in a
double-blind, placebo-controlled trial. More than one half had
a history of hypertension, approximately one quarter were diabetics,
and one third were current smokers. All women received dietary
counseling. Lovastatin or placebo was begun at 20 mg/d and
was titrated if necessary to 40 and then to 80 mg during the first 16
weeks to attain a fasting LDL cholesterol 
130 mg/dL. The
mean lovastatin dose was 34 mg/d. Total and LDL
cholesterol decreased by 24% and 32%, respectively, in
lovastatin-treated women but by <3% in women
receiving placebo. Coronary arteriography was repeated after 2
years in 54 women (87%), and their 394 lesions were measured
"blindly" on pairs of film with an automated computerized
quantitative system. Progression, defined as a worsening in minimum
diameter of one or more stenoses by 
0.4 mm, occurred in 7 of
25 lovastatin-treated women and 17 of 29
placebo-treated women (28% versus 59%, P=.031). New
coronary lesions developed in 1
lovastatin-treated woman and 13 placebo-treated
women (4% versus 45%, P<.001). The outcome for each of
the angiographic end points was not significantly different between the
women and the 245 men who completed the trial.
Conclusions Lovastatin slows the progression of coronary atherosclerosis and prevents the development of new coronary lesions in women.
Key Words: atherosclerosis • women • coronary disease • cholesterol
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Introduction |
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TopAbstractIntroductionMethods Results Discussion References |
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Coronary heart disease is the leading cause of death among women in the United States.1 The mortality rate after myocardial infarction is substantially higher among women than among men,2 as is the in-hospital mortality rate after coronary angioplasty or coronary bypass surgery.3 4 On average, coronary disease becomes manifest in women about a decade later than in men and is much more often associated with comorbid conditions, particularly diabetes and hypertension.
Risk factors for coronary disease differ in women and men in several important aspects. HDL cholesterol levels are higher in women; LDL cholesterol levels are lower for premenopausal women but are higher in postmenopausal women than in men.5 In pooled epidemiological studies,6 the slope of the curve relating overall mortality to total cholesterol is much flatter in women than in men. Total cholesterol is also a poorer predictor of cardiovascular mortality in women,6 yet total cholesterol level does predict coronary mortality in middle-aged women nearly as well as in men.7 These considerations have contributed to the formulation of more conservative recommendations for the treatment of hyperlipidemia in women, even after menopause.8
The treatment of women with coronary disease is hampered by
uncertainty because they have been underrepresented in
the clinical trials that have shaped current recommendations. This is
particularly true for cholesterol-lowering therapy
because the epidemiological evidence suggests that women may react much
differently than men and because few women have been enrolled in the
relevant trials. The two major primary prevention trials of
cholesterol-lowering agents excluded
women.9 10 Among 12 coronary angiographic trials
of cholesterol lowering or multiple risk factor
reduction,11 12 13 14 15 16 17 18 19 20 21 22
2144 men but only 181 women contributed to
the angiographic end points, as listed in Table 1
. Of
the 72 patients completing the trial of Kane et al14 41
were women, and the angiographic outcome of those in the active
treatment group was significantly better than in control subjects.
However, these patients were not typical of the average
coronary patient because all had heterozygous familial
hypercholesterolemia with very high baseline
LDL cholesterol levels.
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In the recently reported Canadian Coronary Atherosclerosis Intervention Trial (CCAIT),17 lovastatin significantly slowed coronary progression and prevented the appearance of new coronary lesions compared with placebo. Treatment allocation in CCAIT was stratified according to sex. Of the 331 patients enrolled in the trial 62 were women, including 54 of the 299 who underwent repeat coronary arteriography after 2 years with computerized quantitative analysis of their pairs of film. The purpose of this report is to describe the clinical features and responses to treatment of the women enrolled in CCAIT.
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Methods |
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TopAbstractIntroductionMethods Results Discussion References |
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Patient Selection
The design features of this trial, including the criteria for patient selection, were described in detail in a previous report.23 Men or women without childbearing potential were recruited if their fasting total serum cholesterol was
220 and 300 mg/dL. Coronary arteriography must have been
performed within 12 weeks of study entry. Patients aged 21 to 50 years
with an extent score 4, 51 to 60 years with a score 5, or 61 to 65
years with a score 6 met the angiographic eligibility criteria.
Extent score was calculated by counting by visual assessment the number
of segments containing coronary lesions between 5% and 75%.
The age limit was increased from 65 to 70 years after enrollment had
begun. The main exclusion criteria were (1) coronary angioplasty within the 6 months preceding the qualifying coronary arteriogram, or previous coronary bypass surgery; (2) coronary angioplasty or bypass surgery planned within the 24-month study period; (3) ejection fraction <40%; (4) left main coronary artery stenosis >50%; (5) triple-vessel disease with preseptal left anterior descending coronary artery stenosis >70%; (6) any coexisting severe illness that would make repeat arteriography ethically unjustifiable; (7) myocardial infarction or unstable angina within 6 weeks before study entry or after the entry coronary arteriogram; (8) a technically suboptimal coronary arteriogram; (9) plasma triglycerides >500 mg/dL; (10) concurrent use of lipid-lowering drugs, cyclosporine, anticoagulants, corticosteroids, or cimetidine; (11) elevated hepatic enzymes or impaired renal function; and (12) patients living too far away from the clinic, or any potential condition or problem that might hinder follow-up or compliance or present an unacceptable risk to the patient. Written informed consent was obtained from each patient. The trial was approved by the ethics committees of each of the participating institutions.
Enrollment Procedures
All patients undergoing coronary
arteriography in each
of the clinical centers were tracked by the study nurses until they
were either enrolled in the trial or declared ineligible. The most
common reasons for exclusion were failure to meet the age-extent
score criteria, a fasting total serum cholesterol level
outside the required range, previous coronary bypass surgery,
ejection fraction <40%, and planned coronary
revascularization. Between October 1988 and June
1990, 21 395 consecutive arteriograms were screened to identify 488
patients who met the study entry criteria; 331 of them (68%) were
enrolled. Patients were randomized and began treatment a mean±SD of
31±16 days (range, 0 to 79 days) after their baseline coronary
arteriogram. Treatment allocation was stratified according to sex.
Patients, study personnel, and other clinic staff were blinded as to
treatment allocation and lipid levels throughout the trial.
Drug Treatment
Patients began double-blind treatment with
either placebo or
20 mg lovastatin taken immediately after the evening meal.
In each center, a physician otherwise uninvolved in the trial monitored
serum lipid levels and recommended dose changes based on a
predetermined algorithm. Drug doses were increased over the first 16
weeks of the trial in a stepwise manner to a maximum of 40 mg twice per
day, in an attempt to attain a target LDL cholesterol level
130 mg/dL. To preserve blinding, placebo-treated patients had
their doses modified in a pattern similar to patients receiving
lovastatin. All patients received counseling from a
dietitian at study entry with the goal of adhering to the American
Heart Association phase I diet. With the exception of those who had
contraindications or who developed side effects, all patients were
treated with 325 mg enteric-coated aspirin on alternate days to
reduce the risk of thrombotic coronary events.
Follow-up Procedures During the Study
After the randomization
visit when treatment was initiated, 20
visits were planned over the ensuing 24 months of the study. Compliance
was verified by tablet counts at each visit and averaged >90% for all
participants. The use of concomitant medication to control angina was
left to the discretion of the referring physician. All
cardiovascular intercurrent events were categorized
according to predetermined standard definitions23 by one
investigator who was blinded to treatment assignment. Repeat
coronary arteriography was scheduled for 24 months after study
entry but was performed earlier in 21 patients. The reason for early
arteriography was myocardial infarction in 5 patients, documented or
suspected unstable angina in 10 patients, and a persistent,
unacceptable level of stable angina in 6 patients. At the visit 1 week
before coronary arteriography, antianginal medication was
adjusted to be identical to that taken at the time of the first
arteriogram, especially with respect to coronary vasodilators.
The angiographic procedures followed in the trial have been described
previously.23
The pair of arteriograms for each patient
were interpreted together in
the core quantitative angiographic laboratory by a radiologist and
technicians blinded to treatment allocation, the order of the films,
and the identity of the patient. For each lesion and segment, an
end-diastolic frame was chosen from each arteriogram
with identical angulation that best showed the stenosis at its
most severe. The Cardiovascular Measurement System
developed by Reiber et al24 was used in this trial to
measure coronary segments and lesions, as previously described
in detail.17 23 25 A change in minimum
lumen diameter
0.4 mm was taken to represent a true change, either
progression or regression.
End Points of the Trial
The angiographic definitions and end
points of this trial were
established before the study was unblinded and any of the arteriograms
were interpreted and have been described in detail
elsewhere.23 The primary end point of the trial is a
comparison between the lovastatin and placebo groups for
coronary change score, defined as the per-patient mean of
the minimum lumen diameter changes (follow-up minus baseline
angiogram) for all lesions measured, excluding those <25% on both
films. The treatment groups were compared for five secondary end
points: (1) proportion of patients classified as progressors, (2)
proportion of patients classified as regressors, (3) proportion of
patients with one or more new lesions, (4) proportion of patients with
one or more new total occlusions, and (5) coronary change
score, including only lesions 50% in diameter stenosis at
baseline.
A progressor and a regressor were defined as a patient with
one or more
lesions narrowing or widening, respectively, by 0.4 mm. A new lesion
was defined as a stenosis that was not apparent on the first
film or that was <25% in diameter stenosis but that narrowed
by 0.4 mm in minimum lumen diameter at the second angiogram. An
all-patients-treated approach was used for the analyses
reported here.
Statistical Analyses
Baseline characteristics of the
treatment groups were compared
using the 
2 test, the Fisher's exact test, or a
two-sample t test as appropriate. All randomized
patients with interpretable follow-up arteriograms were included in
the end-point analyses regardless of their compliance
status or the timing of their follow-up arteriograms.
Coronary change score was compared between treatment groups
using an ANOVA model. The model included terms for center and
"center by treatment" interaction; no significant interaction was
found. ANCOVA was also performed, with the number of lesions and
baseline mean minimum lumen diameter as covariates; again, no
significant interaction was found. The categorical secondary end points
were analyzed using the Mantel-Haenszel test, with treatment
and sex as blocking factors. Coronary change score was compared
between treatments for women and men. A multivariable
regression analysis that included clinical and angiographic
descriptors, concomitant medication, and baseline lipid values was
performed to determine which factors correlated with coronary
change score. A probability value of .05 was considered significant,
and tests were two sided.
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Results |
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TopAbstractIntroductionMethods Results Discussion References |
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Baseline Features of the Study Population
The baseline clinical and angiographic characteristics of the women involved in our study are listed in Table 2
.
Compared with the 269 men enrolled in the trial, the 62 women were on
average 5 years older (P<.001) and nearly twice as likely
to have hypertension (P<.001) or diabetes
(P=.04). Previous infarction was more common in men
(P=.007), and previous angina was more common in women
(P=.016). Only 6 of the 62 women received hormone
replacement therapy during the trial. Overall, the treatment groups
were well balanced for baseline characteristics; among the women, the
only factor that was significantly different was age, with the
lovastatin-treated group being older
(P=.033).
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Effect of Treatment on Plasma Cholesterol
Levels
The plasma lipid levels for women and men in the two treatment
groups are listed in Table 3. Women had higher HDL
cholesterol levels (P<.002), higher
apolipoprotein A1 levels (P<.001), and lower
triglyceride levels (P=.029) compared with men.
Total cholesterol levels were slightly higher in women
(P=.063). None of the baseline differences in lipid levels
between lovastatin-treated and placebo-treated
women were statistically significant.
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The mean prescribed dose of
lovastatin per day was 34.3 mg
for women and 35.9 mg for men (P=NS). Lovastatin
lowered total and LDL cholesterol levels in both men and
women (P<.001). The decreases in women, 23.9% for total
cholesterol and 31.9% for LDL cholesterol,
were slightly greater than the corresponding decreases in men, 19.9%
(P=.073) and 27.5%, respectively (P=.065).
These
values have been averaged over the 24 months of the study and include
results for the 9 lovastatin patients who stopped taking
lovastatin. Plasma lipid levels in placebo-treated
women and men remained relatively stable during the trial and are shown
in Table 3
.
Coronary Change Score
Of the 62 women enrolled in the study,
54 (87%) underwent
follow-up angiography; 180 qualifying lesions from 25
lovastatin-treated women and 214 lesions from 29
placebo-treated women are included in the end-point
analysis. The mean minimum lumen diameter at baseline was
similar in women and men, 1.46 versus 1.53 mm, respectively
(P=NS), as was the mean diameter stenosis, 38.9%
versus 40.2%, respectively (P=NS).
Coronary change score, defined as the per-patient mean of the minimum lumen diameter changes (follow-up minus baseline angiogram) for all lesions measured, excluding those <25% on both films, was -0.05±0.10 mm in lovastatin-treated women and -0.09±0.13 mm in placebo-treated women (P=.40). These results were almost identical to those of the men, -0.05±0.14 and -0.10±0.17 mm, respectively (P=.018); however, the difference in men attained statistical significance because of the larger group size.
Categorical Analyses
The angiographic results on a
per-patient basis for women and
men are shown in Table 4. One or more coronary
lesions progressed in 7 of 25 lovastatin-treated women
and 17 of 29 placebo-treated women (28% versus 59%,
P=.031). One or more new lesions developed during the trial
in 1 of the 25 lovastatin-treated women compared
with 13 of the 29 placebo-treated women (4% versus 45%,
P<.001). Regression, new occlusions, and
recanalizations were less common findings and were
not significantly influenced by treatment. None of the differences
between women and men for categorical end points approached statistical
significance.
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Clinical Events
Coronary events during the trial were
classified according
to standard, predefined criteria24 by an investigator
blinded as to treatment allocation. None of the women died during the
study, and only three in each treatment group experienced a
coronary event, as listed in Table 5. The trend
toward fewer events in lovastatin-treated men was not
statistically significant.
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Multivariable Analysis
A multiple regression analysis that
included all of the
study patients was performed on coronary change score by use of
the following factors: sex; treatment group; history of hypertension,
diabetes, or angina; treatment with ß-blockers, calcium channel
blockers, or angiotensin-converting enzyme
inhibitors; history of smoking; current smoking; number of
coronary lesions; baseline minimum lumen diameter; and baseline
lipid values. Sex was not a predictor of coronary change score.
Better scores were associated with higher baseline HDL
cholesterol levels (P=.001), wider baseline
minimum lumen diameters (P=.002), the lovastatin
treatment group (P=.002), a history of hypertension
(P=.02), and more lesions that were 25% at baseline
(P=.028). Current smoking was associated with a worsening
coronary change score (P=.006), and none of the
other factors were significant at the P<.1 level.
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Discussion |
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TopAbstractIntroductionMethods Results Discussion References |
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The results of this study indicate that in women with coronary disease, cholesterol lowering slows the progression of coronary atherosclerosis and prevents the development of new lesions. This outcome was attained with lovastatin, which at a mean dose of 34 mg per day lowered total cholesterol by an average of 24% and LDL cholesterol by 32%. As is commonly seen in clinical practice, the women in this trial were older than the men and carried a heavy load of risk factors: More than one half had hypertension, one third were current smokers, and one quarter had diabetes. Although clinical features and baseline lipid profiles in these women differed from those of the men, their angiographic outcomes did not.
Previous Studies
Twelve randomized, controlled clinical
trials11 12 13 14 15 16 17 21 22 26 27 28
have demonstrated that
cholesterol lowering has a beneficial effect on the
evolution of coronary atherosclerosis as
assessed by angiography. The longest and largest of these studies, the
Program on the Surgical Control of the Hyperlipidemias
(POSCH),26 included 78 women and reported that their
outcome for the primary end point of the trial, total mortality, was
similar to that of the men; however, the angiographic results of the
women were not reported separately. In the trial of Kane et
al,14 41 of the 72 patients were women, and the
angiographic outcomes of those in the active treatment group were
significantly better than in the control group. These patients all had
heterozygous familial hypercholesterolemia with
very high baseline LDL cholesterol levels, and they
differed considerably from most coronary patients: Only 2 of
the 72 had ever had coronary symptoms, none had diabetes, and
only a few smoked or had hypertension. Active therapy consisted of
colestipol plus niacin and in less than one half of the patients,
lovastatin when it became available. Thus, the clinical
features of the women and the treatment used to lower
cholesterol differed between our study and the trial of
Kane et al. Yet the outcomes were similar, indicating that
cholesterol lowering with the use of different approaches
produces angiographic benefit to a broad spectrum of women with
coronary disease.
None of the other coronary angiographic trials have reported outcomes specifically for women. Secondary prevention trials have not provided data for women, with one exception. In the Scandinavian Simvastatin Survival Study, 4444 patients with coronary disease and total cholesterol levels between 212 and 309 mg/dL on diet were randomized to simvastatin or placebo and followed for 5.4 years, with total mortality the primary end point of the trial.29 The relative risk of death in the simvastatin-treated group was 0.70 (95% CI, 0.58 to 0.85; P=.0003), and the relative risk of a major coronary event, defined as coronary death, non-fatal myocardial infarction, or resuscitated cardiac arrest, was 0.66 (95% CI, 0.59 to 0.75; P<.00001). The trial enrolled 827 women; 25 placebo-treated women and 27 in the simvastatin-treated group died. However, with cholesterol lowering, major coronary events were reduced to the same extent as in men, with a relative risk of 0.65 (95% CI, 0.47 to 0.90; P=.01).
Clinical Relevance of Angiographic End Points
Progression of
coronary atherosclerosis,
usually by the mechanism of plaque rupture and overlying thrombosis,
causes unstable angina and myocardial
infarction.30 31 32 Yet
most progression occurs without associated symptoms. However, three
recent reports have demonstrated that progression is a strong predictor
of subsequent coronary events.33 34 35 In
the POSCH
study, patients with progression during the first 3 years were more
than twice as likely to experience cardiac death or myocardial
infarction as nonprogressors were over the next 7 years.33
In patients followed for nearly 4 years after another angiographic
trial, those who had had progression between the angiograms had a
relative risk for subsequent cardiac death of 7.3 (95% CI, 2.2 to
24.7; P<.0001) and for cardiac death or myocardial
infarction of 2.3 (95% CI, 1.3 to 4.2; P=.009). By
multivariable analysis, progression was as strong a
predictor of future coronary events as ejection fraction or
number of diseased vessels. Similar findings have been reported for the
participants in the Cholesterol Lowering
Atherosclerosis Study.35
The most striking effect of treatment for the women in our trial was prevention of new lesion formation. Although new lesions are rarely severe enough to cause myocardial ischemia, they are clinically relevant because the risk of a coronary event increases with the number of coronary lesions seen at angiography,36 37 and the lesion responsible for a coronary event is usually mild until it undergoes plaque rupture.38 39 Lesions at highest risk for plaque rupture are not large but have a high lipid content and a thin fibrous cap.40
Among all placebo-treated patients in our study, new lesions were associated by stepwise logistic regression analysis with current smoking (P<.001), diabetes (P=.037), and female sex (P=.049).41 Most of the women were postmenopasal and not receiving hormone replacement therapy. Among lovastatin-treated patients, only lower baseline HDL cholesterol levels (P<.001) correlated with the appearance of new lesions. Smoking,42 diabetes,43 the postmenopausal state,44 and hypercholesterolemia45 have each been linked to endothelial dysfunction. It is tempting to speculate that in the presence of hypercholesterolemia and additional risk factors, endothelial damage promotes the development of new lesions. The lowering of LDL cholesterol levels might reduce the potential for damage from the other risk factors, since they were no longer predictive of new lesion formation in the active treatment group.
Limitations of the Study
The trial did not have the power to
detect a treatment effect in
only 54 patients, the number of women with angiographic follow-up;
indeed, for the primary end point, coronary change score, the
difference between the treatment groups of women was not statistically
significant. But the difference was the same as for the entire
population, and for the secondary, predefined, per-patient end
points, progression and the development of new lesions,
cholesterol lowering demonstrated statistically significant
benefit. For none of the end points was the treatment effect different
in women than in men; a much larger population with a higher proportion
of women would be required to detect such differences, if they
exist.
Only 6 of the 62 women were receiving hormone replacement therapy. Thus, our trial provides no information as to whether estrogen used with additional cholesterol-lowering therapy provides additive benefit. The mean age of the women in our trial was 58 years, and women older than 70 were excluded. Most women with symptomatic coronary disease are elderly, and whether the results in this somewhat younger age group can be extrapolated to them is uncertain.
Clinical Implications
Nevertheless, the results of this trial
suggest that women with
coronary disease should be treated as aggressively as men with
respect to cholesterol lowering. Such treatment will slow
coronary progression, prevent new lesion formation, and based
on extrapolation from angiographic follow-up
studies,33 34 35 will reduce future
coronary events.
The large burden of other risk factors in the women in this study did
not appear to detract from the benefit of cholesterol
lowering.
The ability of cholesterol lowering to prevent the appearance of new lesions may have implications with respect to primary prevention in high-risk women. This treatment also may block new lesion formation in women without as well as in women with coronary disease.
Received January 16, 1995; accepted March 6, 1995.
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