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Applicability of Cholesterol-Lowering Primary Prevention Trials to a General Population
The Framingham Heart Study
Donald M. Lloyd-Jones, MD;
Christopher J. O'Donnell, MD, MPH;
Ralph B. D'Agostino, PhD;
Joseph Massaro, PhD;
Halit Silbershatz, PhD;
Peter W. F. Wilson, MD
Arch Intern Med. 2001;161:949-954.
ABSTRACT
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Background Four large trials have shown cholesterol-reduction therapy to be effective
for primary prevention of coronary heart disease (CHD).
Methods To determine the generalizability of these trials to a community-based
sample, we compared the total cholesterol and high-density lipoprotein cholesterol
(HDL-C) distributions of patients in the 4 trials with those of Framingham
Heart Study subjects. Lipid profiles that have not been studied were identified.
Twelve-year rates of incident CHD were compared between subjects who met eligibility
criteria and those who did not.
Results The Framingham sample included 2498 men and 2870 women aged 30 to 74
years. Among Framingham men, 23.4% to 42.0% met eligibility criteria for each
of the 4 trials based on their lipid levels; 60.2% met eligibility criteria
for at least 1 trial. For the 1 trial that included women, 20.2% of Framingham
women met eligibility criteria. In general, subjects with desirable total
cholesterol levels and lower HDL-C levels and subjects with average total
cholesterol levels and average to higher HDL-C levels have not been included
in these trials. Among subjects who developed incident CHD during follow-up,
25.1% of men and 66.2% of women would not have been eligible for any trial.
Most ineligible subjects who developed CHD had isolated hypertriglyceridemia
(>2.25 mmol/L [>200 mg/dL]).
Conclusions In our sample, 40% of men and 80% of women had lipid profiles that have
not been studied in large trials to date. We observed a large number of CHD
events in "ineligible" subjects in whom hypertriglyceridemia was common. Further
studies are needed to define the role of lipid-lowering therapy vs other strategies
for primary prevention in the general population.
INTRODUCTION
DYSLIPIDEMIA is a well-established risk factor for coronary heart disease
(CHD). However, the risk associated with increasing total cholesterol and
decreasing high-density lipoprotein cholesterol (HDL-C) levels is continuous
and graded; there are no clear threshold values to discriminate subjects who
will develop CHD from those who will not. For example, when examining univariate
distributions of lipid parameters, there is considerable overlap between the
total cholesterol distribution of men with and without prevalent CHD.1 Similarly, there is considerable overlap in the distribution
of HDL-C for men with and without CHD.1 A simple
method of graphically depicting the overlap of total cholesterol and HDL-C
distributions to compare those with and without CHD is to plot bivariate ellipsoids
representing the means ± 2 SDs of the 2 parameters simultaneously (Figure 1).
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Figure 1. Bivariate ellipsoids showing the
mean ± 2 SDs of the total and high-density lipoprotein cholesterol
(HDL-C) levels of men with (solid line) and without (broken line) prevalent
coronary heart disease (CHD) in the Framingham Heart Study (data from Wilson
et al1). The center point of each ellipsoid
represents the mean total cholesterol and HDL-C value for that group. The
horizontal axes of the ellipsoids include the mean ± 2 SDs of the total
cholesterol level; the vertical axes of the ellipsoids include the mean ±
2 SDs of the HDL-C value. Note the considerable overlap of the 2 ellipsoids
for those with and without prevalent CHD.
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To date, there have been 4 large randomized placebo-controlled trials
of cholesterol reduction aimed at primary prevention of CHD: the Lipid Research
Clinics Coronary Primary Prevention Trial (LRC-CPPT),2
the Helsinki Heart Study (HHS),3 the West of
Scotland Coronary Prevention Study (WOSCOPS),4
and the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS).5 These trials have demonstrated significant 19% to
37% reductions in the risk of first coronary events and/or mortality with
cholesterol-lowering therapy compared with placebo. Such results provide encouraging
evidence that more widespread use of lipid-lowering therapy for primary prevention
could substantially reduce the extensive mortality and disability associated
with CHD. However, the inclusion criteria for these trials have generally
specified only perceived high-risk lipid profiles, and only AFCAPS/TexCAPS
included women.
Therefore, the applicability of the results of these trials to a general
population remains unknown. Furthermore, the unstudied lipid profiles that
merit further examination in clinical trials have not been fully elucidated.
In our current study, we determine the proportion of subjects from a community-based
sample who met or did not meet eligibility criteria for the 4 trials based
on their lipid levels. Using bivariate ellipsoids, we depict graphically the
lipid profiles that have not yet been studied in these trials. To identify
subgroups of patients who may be at high risk for CHD but whose lipid profiles
have not been included in the trials to date, we also determined the proportion
of incident CHD events that occurred in subjects who did not meet eligibility
criteria.
PARTICIPANTS AND METHODS
STUDY SAMPLE
The Framingham Heart Study was established in 1948 when 5209 residents
of Framingham, Mass, aged 28 to 62 years, were enrolled to evaluate potential
risk factors for CHD.6-7 Members
of this cohort have received follow-up evaluations every 2 years with medical
history reviews and physical examinations as well as selected laboratory tests.
In 1971, 5124 additional subjects (offspring of original cohort subjects and
their spouses) were enrolled in the Framingham Offspring Study.8-9
These participants have received follow-up evaluations approximately every
4 years. All examinations and procedures have been approved by the institutional
review board of Boston University School of Medicine, Boston, Mass.
The current study sample included original cohort participants in examination
cycle 12 (1971-1974), and offspring cohort participants in examination cycle
1 (1971-1975). To determine the applicability of the 4 cholesterol-lowering
primary prevention trials to a primary prevention population, we restricted
our analyses to members of the original and offspring cohorts who were between
ages 30 and 74 years and had fasting lipids measured at the index examination.
Further, we excluded subjects with prevalent CHD (defined as history of definite
angina pectoris, coronary insufficiency, or myocardial infarction).
FASTING LIPID MEASUREMENTS
Blood was drawn at the index examination after an overnight fast, and
ethylenediaminetetraacetic acid plasma was used for all cholesterol and triglyceride
measurements. Cholesterol levels were determined according to the Abell-Kendall
technique,10 and HDL-C levels were measured
after precipitation of very low-density lipoproteins and low-density lipoproteins
(LDLs) with heparin magnesium following the Lipid Research Clinics Program
protocol.11 When triglyceride levels were lower
than 4.52 mmol/L (400 mg/dL), the concentration of LDL cholesterol (LDL-C)
was estimated indirectly using the Friedewald formula12;
for triglyceride levels at 4.52 mmol/L (400 mg/dL) or higher, the concentration
of LDL-C was estimated directly after ultracentrifugation of plasma and measurement
of cholesterol in the bottom fraction when plasma density was less than 1.006.13 For the purposes of this study, hypertriglyceridemia
was defined as a triglyceride level higher than 2.25 mmol/L (200 mg/dL), and
low HDL-C was defined as an HDL-C level lower than 0.90 mmol/L (35 mg/dL).
STATISTICAL ANALYSIS
We compared the lipid levels of the Framingham Heart Study sample with
the published entry lipid ranges of participants in each of the 4 trials to
determine the number and proportion of Framingham subjects who met eligibility
criteria for each study. Bivariate ellipsoids were constructed separately
for men and women using the mean ± 2 SDs to represent the total cholesterol
and HDL-C distributions of the study sample. The entry lipid ranges of the
trials were overlaid on the bivariate ellipsoids of the Framingham sample
(Figure 2) to graphically display
the relative proportions of eligible Framingham subjects.
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Figure 2. Bivariate ellipsoid representing
the mean ± 2 SDs of the total cholesterol and high-density lipoprotein
cholesterol (HDL-C) levels of the 2498 Framingham men in the study sample,
with rectangular overlays representing the entry lipid levels of the 4 large
randomized cholesterol-lowering primary prevention trials.
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Subjects were observed for 12 years for incident CHD events (defined
as coronary insufficiency, myocardial infarction, or coronary death) using
previously published criteria.14 Surveillance
for CHD consisted of regular examinations at the Framingham Heart Study clinic,
Framingham, Mass, and review of medical records from outside physician office
visits and hospitalizations. We calculated the rates of incident CHD over
12 years for all Framingham Heart Study subjects, subjects who met eligibility
criteria for each of the trials, and subjects who did not meet eligibility
criteria for any of the trials. To characterize the lipid profiles that merit
further study, we also examined the trial eligibility and lipid levels of
subjects who had incident CHD events during follow-up.
RESULTS
The Framingham sample included 2498 men and 2870 women (aged 30-74 years)
from Framingham who were free of prevalent CHD and had fasting lipid levels
drawn at the index examination. The baseline characteristics of the Framingham
sample and the participants in each of the 4 trials are given in Table 1. Three of the trials studied participants
with mean pretreatment total cholesterol levels substantially higher than
those observed in the Framingham sample. The AFCAPS/TexCAPS participants had
similar total cholesterol levels but lower HDL-C levels compared with the
Framingham sample. The prevalences of nonlipid CHD risk factors varied markedly
across the 4 trial populations.
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Table 1. Baseline Characteristics of Framingham Heart Study Participants
and Patients in the 4 Large Randomized Cholesterol-Lowering Primary Prevention
Trials*
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ELIGIBILITY FOR TRIALS
The bivariate ellipsoids for the total cholesterol and HDL-C distributions
in the Framingham sample are shown in Figure
2 and
Figure 3 for men and women, respectively. The overlaid rectangles
represent the entry lipid levels for each of the 4 trials. Framingham subjects
whose lipid levels met eligibility criteria for a given study would fall within
the area covered by the rectangle for that study. As defined by their entry
criteria, the trials have tended to include subjects with high total cholesterol
levels and generally those with low HDL-C levels. As shown in Figure 2, men with desirable total cholesterol levels and lower
HDL-C levels (lower left quadrant of the bivariate ellipsoid), and men with
average total cholesterol levels and average to higher HDL-C levels (upper
left quadrant of the bivariate ellipsoid) have not been included in these
trials.
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Figure 3. Bivariate ellipsoid representing
the mean ± 2 SDs of the total and high-density lipoprotein cholesterol
(HDL-C) levels of the 2870 Framingham women in the study sample, with the
rectangular overlay representing the entry lipid levels of Air Force/Texas
Coronary Atherosclerosis Prevention Study (the only trial to include women).
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Table 2 gives the number
and percentage of Framingham men and women who fell into the area covered
by each of the studies. In men, the percentages ranged from a low of 23.4%
who had lipid levels eligible for LRC-CPPT, to a high of 42.0% who had levels
eligible for AFCAPS/TexCAPS. In the aggregate, 60.2% of the men fell into
an area covered by at least 1 of the studies, leaving 39.8% who would not
have been eligible for any of the studies. Using AFCAPS/TexCAPS criteria,
only 20.2% of Framingham women had lipid levels that met eligibility criteria
for this trial, whereas 79.8% had lipid levels that did not.
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Table 2. Framingham Subjects With Lipid Profiles Eligible for the 4
Large Randomized Cholesterol-Lowering Primary Prevention Trials*
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OUTCOMES
During 12 years of follow-up, 275 men (11.0%) and 136 women (4.7%) developed
CHD. The rates of incident CHD were 17.1%, 14.9%, 15.9%, and 12.9% in men
eligible for LRC-CPPT, HHS, WOSCOPS, and AFCAPS/TexCAPS, respectively. Among
the men eligible for at least 1 of the trials, the rate of 12-year incident
CHD was 13.7%; in women eligible for AFCAPS/TexCAPS it was 7.9%. The rates
of 12-year incident CHD among men or women ineligible for all trials were
half the rates observed in subjects eligible for at least 1 trial (Figure 4).
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Figure 4. Rates of 12-year incident coronary
heart disease (CHD) among men and women from the Framingham sample who met
eligibility criteria for at least 1 trial compared with those who did not
meet criteria for any of the trials.
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Of the 275 men with incident CHD, 69 (25.1%) would not have been eligible
for any of the trials. Of these 69, most (n = 62) had hypertriglyceridemia,
representing 22.5% of all men with incident CHD. Among the 62 men with hypertriglyceridemia,
43 had isolated hypertriglyceridemia, and 19 had hypertriglyceridemia with
associated low levels of HDL-C, representing 15.6% and 6.9%, respectively,
of all men with incident CHD. Only 33.8% of the 136 women with incident CHD
met eligibility criteria for AFCAPS/TexCAPS, whereas most (n = 90 [66.2%])
did not. Of these 90 women, 83 (61.0% of women with incident CHD) had hypertriglyceridemia,
and only 6 (4.4%) had associated low levels of HDL-C.
Since diabetes may have confounded the relationship between hypertriglyceridemia
and incident CHD, we examined whether the prevalence of diabetes was higher
among subjects who developed CHD and were ineligible for the trials compared
with those who met eligibility criteria. Among men who developed CHD, the
prevalence of diabetes was 15.9% for those who were ineligible compared with
10.2% for those who were eligible (P = .20). Among
women who developed CHD, the prevalence of diabetes was 20.0% for those who
were ineligible compared with 10.8% for those who were eligible (P = .23).
COMMENT
In our community-based population of adults without CHD aged 30 to 74
years, 40% of men and 80% of women had lipid profiles that did not meet eligibility
criteria for inclusion in the large primary prevention trials published to
date. Men who have not been included in trials include those with desirable
total cholesterol and low HDL-C levels, and those with average total cholesterol
and average to higher HDL-C levels. Randomized trial data remain sparse for
women across a wide range of lipid profiles (other than those in AFCAPS/TexCAPS).
IMPLICATIONS FOR CLINICAL PRACTICE AND RESEARCH
Rates of incident CHD during follow-up were half as great among subjects
who did not meet eligibility criteria for the trials compared with those who
were eligible. This finding validates the inclusion criteria of the trials
in that higher-risk individuals were selected for cholesterol-lowering intervention.
Nonetheless, a substantial proportion of first CHD events (25% in men and
66% in women) occurred among subjects with lipid profiles that have not been
studied. Most ineligible subjects with incident CHD had hypertriglyceridemia
with or without low HDL-C levels. Therefore, further primary prevention trials
targeting hypertriglyceridemia and low HDL-C levels seem warranted. In addition,
further epidemiologic studies examining the population-attributable risk associated
with hypertriglyceridemia would be useful.
With the current paucity of clinical trial data for primary prevention
in women, clinicians may be using the published primary prevention trial results
for men to inform treatment decisions for their female patients. However,
because of the different endocrinologic and cardiovascular milieu present
in women, extrapolation of results from male trial participants may be misleading.
This may be true particularly for premenopausal women, who generally have
a very low risk of incident CHD and may be much less likely to benefit from
primary prevention than higher-risk subgroups. Women may currently be receiving
drug therapy with little chance of benefit but some risk of adverse toxic
effects. Further trials of the efficacy and safety of lipid-lowering therapy
for primary prevention of CHD in women are therefore warranted.
IMPLICATIONS FOR PUBLIC HEALTH
The findings of this study have implications in terms of the cost-effectiveness
of primary prevention with lipid-lowering agents. Currently, medical therapy
of dyslipidemia has been firmly established as cost-effective for secondary
prevention of CHD. Data from the Scandinavian Simvastatin Survival Study (4S)
indicate that 13 patients with CHD would need to be treated for 5 years to
prevent 1 recurrent major coronary event.15
In considering the cost-effectiveness of an intervention, the concept of "cost
per year of life gained" is typically used. Interventions that cost less than
$20 000 per year of life gained are generally considered to be very cost-effective,
and those that cost less than $40 000 have been recommended by some authors,
whereas those that cost more than $75 000 are generally considered not
cost-effective.16 From 4S, the direct costs
per year of life gained using simvastatin for secondary prevention ranged
from $3800 for 70-year-old men with a total cholesterol level of 8.0 mmol/L
(309 mg/dL) to $27 400 for 35-year-old women with a total cholesterol
level of 5.5 mmol/L (213 mg/dL). When indirect costs were included, the costs
per year of life gained ranged from a net savings in 35-year-old patients
to a cost of $13 300 for 70-year-old women with a cholesterol level of
5.5 mmol/L (213 mg/dL).17 Such data have led
to the widespread acceptance of medical therapy for secondary prevention of
CHD in patients with hypercholesterolemia.
In contrast, the role of medical therapy of dyslipidemia for the primary
prevention of CHD remains controversial because of the potential costs involved
in treating large segments of the population. From the 4 primary prevention
trials, a range of approximately 40 to 75 patients would need to be treated
for 5 years to prevent a single coronary event. As previously noted, these
studies have selected patients with relatively high-risk lipid profiles that
reflect a fairly small proportion of the general population. The study sample
in AFCAPS/TexCAPS was most representative of the general population in that
it was a healthy group of men and women with average total cholesterol and
LDL-C values but below average HDL-C levels. In AFCAPS/TexCAPS, it was estimated
that 53 patients would need to be treated with lovastatin for 5 years to prevent
a single acute coronary event (including unstable angina and myocardial infarction).
In the past decade, the introduction and widespread use of the 3-hydroxy-3-methylglutaryl
coenzyme A reductase inhibitors (the "statin" compounds) have clearly provided
a major therapeutic advance in the treatment of hypercholesterolemia. Indeed,
WOSCOPS and AFCAPS/TexCAPS observed greater relative reductions in coronary
events with statins than did LRC-CPPT or HHS with cholestyramine and gemfibrozil,
respectively, despite the fact that the latter 2 trials had higher baseline
total cholesterol levels. However, statins are also significantly more costly
than the older medications. The cost-effectiveness of cholesterol-lowering
therapy for primary prevention has therefore been questioned.
Estimates of the cost-effectiveness of medical therapy for primary prevention
vary widely, depending on the risk profile of the population studied.16, 18 In one study by Goldman et al,19 therapy with statins was not cost-effective for any
subgroup of women, and only men with multiple risk factors (eg, combined obesity,
smoking, and hypertension) had costs per year less than $40 000. In another
analysis using Framingham risk equations, Hamilton and colleagues20 adjusted for the additional benefit of HDL level
elevation seen with lovastatin therapy. They calculated costs of $28 000
to $44 000 per year of life gained for low-risk men aged 40 to 60 years
and low-risk women aged 50 to 70 years. For higher-risk men, the costs ranged
from $13 000 to $33 000.18
Thus, the challenge for clinicians and policy makers is to identify
higher-risk patients for whom medical therapy will be more cost-effective.
Selection of high-risk patients using multivariate risk score21
or global risk assessment strategies22-23
is likely to improve the clinical effectiveness and cost-effectiveness of
antihyperlipidemia drugs.
As CHD incidence was approximately half as great among those who did
not meet eligibility criteria compared with those who were eligible, the cost-effectiveness
of treating dyslipidemia in the large subgroup of ineligible patients may
be poor. Similarly, the number of subjects who need to be treated to prevent
1 CHD event in this subgroup likely exceeds the value of 53 observed in AFCAPS/TexCAPS.
Nonetheless, the high proportion of incident CHD events that occurred in the
ineligible subgroup should be of concern to policy makers and clinicians alike.
Therefore, other strategies including public health and individual measures
aimed at aggressive dietary management and control of other coronary risk
factors should also be considered in the treatment of patients with these
unstudied lipid abnormalities. Such an approach may be preferable given that
hypertriglyceridemia and low HDL-C levels are often markers of other metabolic
risk factors for CHD, including hyperinsulinemia, central obesity, and hypertension.
It should be noted that none of the groups of Framingham subjects who
met eligibility criteria for any of the trials had 10-year rates of CHD that
exceeded the level of 20%, which has recently been recommended as a threshold
for screening and treatment of coronary risk factors by the joint task force
from the european societies of cardiology, atherosclerosis, and hypertension.23 Therefore, further study is needed of risk-stratification
techniques designed to identify higher-risk patients among the ineligible
subgroup. Such techniques might involve the routine incorporation of triglyceride
and HDL-C data into risk assessment and might indicate further strategies
to provide optimal risk reduction.
POTENTIAL LIMITATIONS
This study has several potential limitations. First, the original and
offspring cohorts of the Framingham Heart Study are composed almost exclusively
of white individuals. However, data from the NHANES (National Health and Nutrition
Examination Study) surveys from the 1970s through the 1990s indicate that
in the United States, mean cholesterol values vary by less than 5 points across
different ethnic groups for men and women,24(p191)
and the proportions of individuals with hypercholesterolemia are remarkably
similar across ethnicities.25 Therefore, our
findings would likely apply to other ethnicities as well. Second, the Framingham
sample represents the experience of a single municipality. There are known
regional variations in both lipid values and rates of incident CHD within
the United States. However, the risk profile of the Framingham subjects used
in this report is quite similar to concurrent national profiles with regard
to prevalence of smoking, diabetes, and hypertension, as well as hypercholesterolemia.24 It should be noted that the mean HDL-C level for
women in our Framingham sample was 1.50 mmol/L (58 mg/dL), slightly higher
than the mean HDL-C level of 1.40 mmol/L (54 mg/dL) for white women in this
age range from the NHANES II sample.26 Finally,
to allow examination of follow-up events, we used data from Framingham subjects
seen in the 1970s and observed into the 1980s, so incident rates of CHD from
the Framingham sample may not be representative of a current sample. These
data are likely to be more accurate than NHANES follow-up data, however, because
national data must rely on death certificates, which can be unreliable when
used to diagnose CHD.27
CONCLUSIONS
In conclusion, a substantial proportion of CHD events occurs in individuals
with lipid profiles that have not been included in large primary prevention
trials to date. Further research seems warranted in men with hypertriglyceridemia
and in women with all lipid profiles. Given that the perceived high-risk lipid
profiles have been studied, the role of lipid-lowering therapy vs other strategies
to reduce risk in the unstudied groups is unclear.
AUTHOR INFORMATION
Accepted for publication September 9, 2000.
This research was supported by the National Institutes of Health National
Heart, Lung, and Blood Institute, Bethesda Md, contract N01-HC-38038 (Drs
Lloyd-Jones, O'Donnell, and Wilson).
Reprints: Peter W. F. Wilson, MD, Framingham Heart Study, 5 Thurber
St, Framingham, MA 01702 (e-mail: peter{at}fram.nhlbi.nih.gov).
From the Framingham Heart Study, National Heart, Lung and Blood Institute,
the National Institutes of Health, Bethesda, Md (Drs Lloyd-Jones, O'Donnell,
and Wilson); the Cardiology Division, Department of Medicine, Massachusetts
General Hospital and Harvard Medical School (Drs Lloyd-Jones and O'Donnell),
the Departments of Mathematics and Statistics, Boston University (Drs D'Agostino
and Silbershatz), and Epidemiology and Biostatistics, Boston University School
of Public Health (Dr Massaro), Boston, Mass.
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