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Low- and High-Density Lipoprotein Cholesterol and Ischemic Cerebrovascular Disease
The Bezafibrate Infarction Prevention Registry
Nira Koren-Morag, PhD;
David Tanne, MD;
Eran Graff, PhD;
Uri Goldbourt, PhD;
for the Bezafibrate Infarction Prevention Study Group
Arch Intern Med. 2002;162:993-999.
ABSTRACT
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Background Despite increasing evidence that  -hydroxy--methyglutaryl
coenzyme A reductase inhibitors reduce the incidence of stroke in patients
with coronary heart disease (CHD), the associations between blood lipid levels
and cerebrovascular disease (CVD) are not clear.
Objective To evaluate whether blood cholesterol level and its fractions are risk
factors for stroke in a large group of patients with CHD.
Methods We followed up 11 177 patients with documented CHD who were screened
for but not included in the Bezafibrate Infarction Prevention study, a secondary
prevention randomized clinical trial of lipid modification, and had no history
of stroke for subsequent CVD. During a 6- to 8-year follow-up period, 941
patients were identified as having nonhemorrhagic CVD, of whom 487 had verified
ischemic stroke or transient ischemic attack (TIA).
Results Increases in age-adjusted rates of both nonhemorrhagic CVD and verified
ischemic stroke or TIA were identified with increasing cholesterol and low-density
lipoprotein cholesterol levels, decreasing high-density lipoprotein cholesterol
levels, and decreasing percentage of total serum cholesterol contained in
the HDL moiety. In logistic regression models, adjusting for clinical covariates,
the following odds ratios (95% confidence intervals) were identified for lipid
values in the upper vs lower tertile for the end point of nonhemorrhagic CVD:
total cholesterol, 1.43 (1.20-1.70); low-density lipoprotein cholesterol,
1.52 (1.27-1.81), high-density lipoprotein cholesterol, 0.84 (0.70-1.00);
and percentage of serum cholesterol contained in HDL, 0.69 (0.58-0.83). Similar
trends appeared for the end point of verified ischemic stroke or TIA.
Conclusion These findings clearly support the role of total cholesterol and its
fractions in prediction of ischemic CVD among patients with established CHD.
INTRODUCTION
CORONARY HEART disease (CHD) and ischemic stroke share multiple risk
factors and a common pathophysiologic antecedent, namely atherosclerosis.1-3 There is overwhelming
evidence for independent positive associations between total cholesterol and
low-density lipoprotein cholesterol (LDL-C) and CHD and an inverse association
between high-density lipoprotein cholesterol (HDL-C) and CHD.
The associations between blood lipid levels and cerebrovascular disease
(CVD) are, however, not as clearly established, as reflected in a recent controversy
on this issue4-5 and a large systematic
review6 of 45 prospective studies, which did
not identify a relationship between total cholesterol levels and stroke. In
contrast, recent randomized clinical trials in patients with CHD7-9
and systematic reviews showed that cholesterol-lowering agents, in the form
of -hydroxy--methyglutaryl coenzyme A (HMG-CoA) reductase inhibitors,
or statins, and recently also gemfibrozil, reduce the incidence of not only
myocardial infarction but also stroke.10-13
The purpose of this study was to evaluate whether blood cholesterol levels
and its fractions are risk factors for subsequent ischemic CVD in a large
group of patients with CHD.
PATIENTS AND METHODS
STUDY PARTICIPANTS
The Bezafibrate Infarction Prevention (BIP) study was a placebo-controlled,
secondary prevention randomized clinical trial that assessed the effect of
bezafibrate retard. The design and rationale of the BIP study have been previously
published.14 A total of 15 524 patients
with documented CHD were screened for inclusion in the BIP study between February
1990 and October 1992. Patients 40 to 74 years old, with a diagnosis of CHD,
were eligible for inclusion in the BIP study if they had evidence of myocardial
infarction occurring 6 months or more but 5 years or less before enrollment
or coronary insufficiency observed either at rest or during effort, as manifested
by typical pain and dynamic electrocardiographic changes or both. Coronary
insufficiency episodes must have occurred between 6 months and 2 years before
enrollment. In addition, specific serum lipid ranges were required because
the study examined the efficacy of intervening to reduce serum triglyceride
levels and increase HDL-C levels. The limits to enter an initial 2-month dietary
period were as follows: total cholesterol, 270 mg/dL or less ( 6.98 mmol/L);
HDL-C, 45 mg/dL or less (1.16 mmol/L); and serum triglycerides, 300 mg/dL
or less (3.39 mmol/L). In approximately 7000 patients who fulfilled these
criteria at visit 1, there were duplicate laboratory measures that permitted
the estimation of the regression dilution bias. For randomization into the
study, after the 2-month diet, the following levels were required: serum total
cholesterol, 180 to 250 mg/dL (4.65-6.47 mmol/L); LDL-C, 180 mg/dL or less
(4.65 mmol/L); HDL-C, 45 mg/dL or less (1.16 mmol/L); and triglycerides,
300 mg/dL or less (3.39 mmol/L). Main exclusion criteria other than serum
lipid levels outside the preset limits were current use of lipid-modifying
drugs, severe heart failure, unstable angina pectoris, insulin-dependent or
poorly controlled diabetes mellitus, or refusal to participate.
For the current analysis, we excluded the actual BIP study participants,
since the use of bezafibrate may have modified the association between blood
lipid levels and stroke. We also excluded patients with a history of prior
stroke or transient ischemic attack (TIA) to assess the risk of first-ever
stroke associated with blood lipid levels. The total number of patients in
the present analysis was 11 177.
During the first physician visit, records were obtained on medical history,
conventional risk factors, and medications used, and a complete physical examination
was performed. Mortality data were obtained through January 1999 from the
Israel Population Registry, with cause of death coded according to the International Classification of Diseases, Ninth Revision (ICD-9). The participants in the BIP study (3122 patients) were of similar
age to the other BIP study screenees but were more often men (92%), had a
lower proportion of diabetes mellitus (10%), had a higher proportion of a
prior myocardial infarction (78%), and had a selected lipid profile, as required
for inclusion in this study.
LABORATORY METHODS
Laboratory measurements were all performed at a central study laboratory
(the Physiological and Hygiene Laboratory at the Wolfson Medical Center, Holon,
Israel). All analyses were performed with a random access analyzer (Boehringer-Hitachi
704; Boehringer-Mannheim, Mannheim, Germany) using Boehringer diagnostic kits.
Blood samples were obtained after at least 12 hours of fasting. Precipitation
of LDL and very low-density lipoprotein with phosphotungstate reagent and
determination of cholesterol determined HDLC levels. Cholesterol levels were
determined by the CHOD-PAP (cholesterol oxidase/p-aminophenazone) method (enzymatic
colorimetric test), and LDL-C levels were approximated by the formula of Friedewald
et al.15
ASSESSMENT OF CVD
We obtained computerized data files from hospitals participating in
the BIP study screening process. Hospitalizations with a diagnosis of CVD
(ICD-9 codes 430-438 or code 38.1) were identified.
We also matched the patients (based on national identification number and
name) against a registry of the Clalit Health Services, which insures more
than 60% of Israeli citizens (Israel has an obligatory 100% national health
insurance). This registry contains information on both Clalit-maintained hospitals
participating in the BIP study and several who did not participate. A total
of 1100 patients were identified, and attainable medical records and hospital
discharge summaries were systematically reviewed. Data were collected on history,
findings on neurologic examination, brain computed tomography (CT), and ancillary
examinations as available to verify the diagnosis and determine stroke type
and ischemic stroke subtypes. Two investigators, including a stroke neurologist
(D.T.), reviewed all classifications.
Stroke was defined according to World Health Organization criteria.
Events that resolved completely within less than 24 hours were diagnosed as
TIA. Patients with subarachnoid hemorrhage or subdural hemorrhage and those
not fulfilling the criteria for stroke or TIA after review were excluded.
Ischemic stroke and intracerebral hemorrhage were differentiated by the results
of brain CT performed at the acute stage. Ischemic stroke was diagnosed if
the patient had an appropriate clinical event and had a brain CT that showed
a compatible low-density lesion or was normal or had findings compatible with
hemorrhagic conversion of a cerebral infarct. Ischemic stroke subtypes were
determined based on the TOAST (Trial of Org 10172 in Acute Stroke Treatment)
classification.16 Only 24 cases were identified
with verified intracerebral hemorrhage by clinical findings and brain CT,
and thus associations with intracerebral hemorrhage were not sought.
For the purpose of this study, we assessed 2 end points. The first end
point was cases considered to have any nonhemorrhagic CVD, which totaled 941
cases. This end point included cases with ICD-9 codes
of CVD other than hemorrhage, excluding cases considered to have had a nonvascular
cause after medical record review. The second end point was patients with
verified ischemic stroke (350 cases) or TIA (137 cases) after review of medical
records, which totaled 487 cases. For the remaining patients, brain CT was
not performed or medical records were not available for review so that stroke
type could not be determined.
STATISTICAL ANALYSIS
Age-adjusted rates of nonhemorrhagic CVD per 10 000 person-years
were calculated using an SAS statistical software macro (SAS Institute Inc,
Cary, NC).17 Multivariate analyses were performed
using the logistic regression models.18 Levels
of lipids were introduced into the model once as continuous variables and
once as tertiles. Each model included one lipid fraction and was adjusted
for clinical confounders. A final model for prediction of nonhemorrhagic CVD
included both total cholesterol and HDL-C. The significance levels for entering
and removing an independent variable were set at .05 and .10, respectively.
The Hosmer-Lemeshow goodness-of-fit test was conducted for assessing overall
model fit for each of the models.19
Odds ratios (ORs) were also computed to apply correction for regression
dilution, using the repeated measurements for 7000 patients 2 months after
the first visit. The regression dilution factors were calculated by dividing
the difference in mean lipid levels between the lowest and highest quintiles
computed from the first measurement by the difference in mean lipid level
at the second measurement in similarly defined lowest and highest quintiles.20
Nonhemorrhagic CVD-free survival of patients in the first, mid, and
top tertile of cholesterol and HDL-C was assessed through December 1998. Survival
curves were adjusted for sex, age, lipid-lowering medications, previous myocardial
infarction, diabetes mellitus, New York Heart Association class, hypertension,
chronic obstructive pulmonary disease, peripheral vascular disease, angina
pectoris, current smoking, and body mass index.
RESULTS
BASELINE CHARACTERISTICS
At baseline, 518 (5%) of the 11 177 patients were treated with
lipid-lowering drugs. Of these, 203 were treated with lovastatin, 294 with
bezafibrate, and 37 with colestipol hydrochloride. The percentages of use
of lipid-lowering drugs were 4% for the patients who developed nonhemorrhagic
CVD vs 5% for counterparts remaining free of CVD.
During the follow-up period, 941 cases of nonhemorrhagic CVD were identified.
Patients who subsequently developed a nonhemorrhagic CVD were, as expected,
older (62 vs 60 years) and had a higher frequency of diabetes mellitus (35%
vs 20%), hypertension (42% vs 32%), peripheral vascular disease (8% vs 4%),
anginal syndrome (66% vs 59%), and current smoking (12% vs 10%; P<.05 for all). They had higher serum levels of total cholesterol
and LDL-C, lower levels of HDL-C, and a smaller percentage of total serum
cholesterol contained in the HDL moiety (%HDL) (Table 1). Patients identified as having the large vessel atherothrombosis
subtype had significantly higher antecedent levels of LDL-C than patients
developing ischemic stroke related to cardioembolism or small vessel occlusive
disease (Table 1).
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Table 1. Baseline Cholesterol and Its Fractions in Patients With and
Without Nonhemorrhagic CVD and Within Identified CVD Subtypes*
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Age-adjusted rates of nonhemorrhagic CVD increased with increasing quintiles
of total cholesterol and LDL-C (Figure 1A-B).
Rates per 10 000 person-years increased for total cholesterol and LDL-C
from 103 to 141 and 104 to 142, respectively. Age-adjusted rates of nonhemorrhagic
CVD per 10 000 person-years decreased stepwise with increasing HDL-C
and %HDL quintiles from 151 to 90 and 176 to 91, respectively (Figure 1C-D). Similar trends appeared with all lipid fractions for
the end point of ischemic stroke or TIA.
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Figure 1. Age-adjusted nonhemorrhagic cerebrovascular
disease rates (per 10 000 person-years) by quintiles of total cholesterol
(A), low-density lipoprotein cholesterol (LDL-C) (B), high-density lipoprotein
cholesterol (HDL-C) (C), and percentage of total serum cholesterol contained
in the HDL moiety (%HDL) (D).
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MULTIVARIATE ANALYSIS
The ORs associated with total cholesterol level or its fractions, adjusted
for clinical covariates for incident nonhemorrhagic CVD, verified ischemic
stroke or TIA, and the subgroup of patients with the large vessel atherothrombosis
subtype, are presented in Table 2.
Total cholesterol level and its fractions were independent predictors of nonhemorrhagic
CVD and verified ischemic stroke or TIA, after adjusting for clinical covariates.
For the large vessel atherothrombosis subtype, LDL-C, but not HDL-C, emerged
as a strong predictor.
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Table 2. Odds Ratios Associated With Levels of Lipids for All Incident
Nonhemorrhagic CVD, Ischemic Stroke or TIA, and Large Vessel Atherothrombosis
Subtype*
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The ORs of incident nonhemorrhagic CVD associated with total cholesterol
or LDL-C (per 40 mg/dL [1.03 mmol/L]), HDL-C (per 10 mg/dL [0.26 mmol/L]),
and %HDL (per 5%) were 1.14, 1.19, 0.93, and 0.86, respectively (Table 2). The ORs were similar when patients
taking lipid-lowering drugs at baseline were excluded from analyses, with
ORs of 1.14, 1.19, 0.92, and 0.89, respectively.
The regression dilution correction factors for total cholesterol, LDL-C,
HDL-C, and %HDL were 1.31, 1.32, 1.15, and 1.39, respectively. Correcting
for the regression dilution bias modified the adjusted ORs for prediction
of all nonhemorrhagic CVD associated with total cholesterol, LDL-C, HDL-C,
and %HDL to 1.17, 1.25, 0.92, and 0.81, respectively, and for incident ischemic
stroke or TIA to 1.16, 1.19. 0.87, and 0.77, respectively.
We ran a final model for prediction of incident nonhemorrhagic CVD,
including both total cholesterol and HDL-C and adjusting for clinical covariates.
The emerging ORs were 1.14 for total cholesterol and 0.90 for HDL-C. The Hosmer-Lemeshow
goodness-of-fit test (P = .65) did not exhibit a
meaningful departure of the models from the observed data. Comparing the predicted
numbers of nonhemorrhagic CVD by deciles of probability to the actual number
of events observed, we found that rates increased more than 6-fold from subjects
in the lower to the upper decile of probabilities.
The odds for incident nonhemorrhagic CVD associated with serum levels
in the upper relative to the lower tertile were 1.43 for total cholesterol,
1.52 for LDL-C, 0.84 for HDL-C, and 0.69 for %HDL (Table 3). Similar trends appeared for the end point of verified
ischemic stroke or TIA.
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Table 3. Odds Ratios Associated With Tertiles of Lipids for All Incident
Nonhemorrhagic CVD and Ischemic Stroke or TIA*
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NONHEMORRHAGIC CVD-FREE SURVIVAL FUNCTIONS
Figure 2 shows the curve divergence
of the nonhemorrhagic CVD-free survival functions (at mean of covariates)
by tertiles of lipids. Longer survival time free of nonhemorrhagic CVD was
evident in the lowest tertiles of total cholesterol and LDL-C and in the highest
tertiles of HDL-C and %HDL (P<.01 for all).
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Figure 2. Nonhemorrhagic cerebrovascular
disease–free survival curves by tertiles of total cholesterol (A), low-density
lipoprotein cholesterol (LDL-C) (B), high-density lipoprotein cholesterol
(HDL-C) (C), and percentage of total serum cholesterol contained in the HDL
moiety (%HDL) (D).
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COMMENT
Epidemiologic findings have indicated little or no association between
cholesterol and its fractions and incident stroke in persons free of CHD.
An apparent conflict arose when strong evidence was forwarded that HMG-CoA
reductase inhibitors (statins) and more recently the fibrate gemfibrozil reduced
the risk of both myocardial infarction and ischemic stroke in patients with
CHD.7-13
However, statins also have important nonlipid effects that may reduce the
risk of stroke.21
Because atherosclerosis is a main underlying process for both myocardial
and atherothrombotic ischemic stroke, it is not unreasonable to expect a similar
pattern of lipid abnormalities in both diseases. Yet, a review of 45 prospective
cohorts6 found no association between total
cholesterol and the risk of stroke. Furthermore, in the Framingham Study,
no clear association was found between cholesterol and vascular disease of
the brain,22 and most case-control studies
were consistent with an absence of an association.23
In this context, our study found clear evidence for the role of cholesterol
and its fractions in prediction of subsequent ischemic stroke or TIA among
a large group of patients with established CHD. How could our findings be
explained in light of the substantial amount of older negative studies? First,
our study patients had established CHD, similar to the randomized clinical
trials showing the benefit of statins and fibrates in stroke prevention. Second,
most of the older studies did not record nonfatal strokes and types of strokes
were not assessed. Lack of any overall relationship might conceal a positive
association with ischemic stroke together with a negative association with
hemorrhagic stroke, as shown in the Multiple Risk Factor Intervention Trial
for stroke mortality and in several other studies.24-25
When patients in the Honolulu Heart Study were followed up for 15 or more
years, increases in both CHD and thromboembolic stroke rates were seen with
higher levels of serum cholesterol.26 In the
Copenhagen City Heart Study,27 an increased
risk of ischemic stroke was found for total cholesterol, but only for levels
above 309 mg/dL (8 mmol/L).
In the current study, we assessed specifically incident ischemic stroke
or TIA during a relatively long follow-up in an especially large group of
patients. All lipid measurements have been performed at one central study
laboratory and assessed before the event. Because of additional lipid measurements
in a large proportion of patients, we were able to estimate and correct for
the regression dilution bias, thus providing a more accurate estimate of ORs.20
Although myocardial infarction is typically caused by in situ thrombosis
associated with a coronary artery plaque, the pathogenesis of ischemic stroke
is more complex with multiple potential mechanisms that often coexist, complicating
the assessment of the role of lipids. In a population-based study28 from Rochester, Minn, the main identifiable subtype
of ischemic stroke was cardioembolic, whereas large vessel cervical and intracranial
atherosclerosis with stenosis together constituted about 16% of cases and
small vessel occlusive disease a similar proportion. Furthermore, about 40%
of ischemic strokes are of undetermined cause.28-29
High-resolution ultrasonography has clearly established that thickening
of the carotid artery intima and media is a predictor for strokes.30 An association between carotid atherosclerosis and
LDL-C has been found in several studies,23
and randomized clinical trials with statins have demonstrated plaque regression
or reduced progression of the carotid arteries.31-32
Furthermore, the Scandinavian Simvastatin Survival Study trial showed that
the relative risk of cerebrovascular events was reduced by 37%, similar to
the reduction in subsequent coronary events, but the benefit was confined
to nonembolic stroke and TIA.7 This finding
emphasizes that strokes with a basis of large vessel atheroma are most likely
to be reduced by statins. In the current observational study, we have identified
strong associations between LDL-C levels and a selected group of patients
with cerebral large vessel atherosclerosis, supporting these results from
randomized interventional trials.
We have previously found an independent inverse association between
serum HDL-C levels and ischemic stroke mortality in a 21-year observational
study of nearly 10 000 apparently healthy men included in the Israeli
Ischemic Heart Disease study.33 In the current
study, we have found similar inverse associations with HDL-C level and %HDL
for incident ischemic stroke or TIA. Although HDL-C was an independent predictor
for ischemic stroke or TIA, it did not emerge as a predictor for the large
vessel atherothrombosis subtype. Recently, Sacco and colleagues34
have shown in a population-based, incident case-control study that increased
HDL-C levels are associated with reduced risk of ischemic stroke in elderly
patients and among different racial or ethnic groups.
High LDL-C levels had, however, a major predictive role in particular
for large vessel atherothrombosis. The diagnosis of large vessel atherothrombosis
was derived from medical records of patients undergoing evaluation for their
cause of stroke or screening for carotid endarterectomy. Large vessel atherothrombosis
was therefore probably underdiagnosed, and our findings on this issue should
be regarded as hypothesis generating. They demonstrate, however, that in a
disease with a pathogenesis as heterogeneous as in ischemic CVD, the role
of lipids may differ between subtypes. In the Atherosclerosis Risk in Communities
study, Sharrett and colleagues35 recently reported
that LDL-C was a major predictor for both carotid atherosclerosis and CHD,
whereas HDL-C was strongly associated with CHD incidence but only weakly with
carotid atherosclerosis.
Several potential sources of bias have been considered in our study.
First, a common limitation to many observational studies is the absence of
information concerning potential spontaneous or therapy-induced changes in
cholesterol level and its fractions during the follow-up period. At baseline,
only a small fraction of patients were treated with lipid-lowering medications
and exclusion of these patients did not affect our results. Statins were introduced
in increasing percentage toward the latter period of our follow-up period
that started in 1990, following the results of the pivotal clinical trials.
Despite the compelling evidence from these trials, recent CHD prevention surveys
between 1994 and 1998 have unveiled a wide therapeutic gap between scientific
evidence and practice in the secondary prevention of CHD.36
Second, CHD tends to occur at a substantially higher rate and earlier age
than ischemic stroke. Because of shared risks between these conditions, total
cholesterol and its fractions, which are powerful risk factors for CHD, may
be underestimated as predictors of ischemic stroke. These shortcomings may
have diluted the reported associations between blood lipid levels and ischemic
CVD.
The screening process for the BIP study took place in most hospitals
in Israel (18 of the 25 cardiology departments). In identifying incidence
cases, we may have missed a few patients admitted to hospitals outside the
BIP collaboration. This would occur only if the latter hospital did not belong
to the comprehensive Clalit Health Services. We assumed that only a few cases
were missed in this way. In addition, patients with minor stroke events who
were not admitted to a hospital may have been missed.
Finally, the predictive role of cholesterol and its fractions for ischemic
CVD in this study was found in a group of patients with established CHD. These
findings are in agreement with the recent data on the beneficial role of statins
for stroke prevention, specifically in patients with CHD. When primary and
secondary prevention statin trials have been analytically segregated, a nonsignificant
15% to 20% reduction in stroke events has been observed in the former studies,
compared with a 31% to 32% reduction in the latter.10-13
The nonsignificant 11% stroke reduction observed in the West of Scotland Coronary
Prevention Study,37 an investigation of the
effects of pravastatin on cardiovascular outcome in patients with moderate
hypercholesterolemia without prior myocardial infarction, would also seem
to underscore this difference. Thus, generalization of our results to broader
populations at lower risk of stroke, such as those without clinically manifest
CHD, is unwarranted.
In conclusion, this large observational study of patients with CHD demonstrates
for the first time to our knowledge strong evidence for the role of total
cholesterol, LDL-C, and HDL-C in prediction of incident ischemic CVD. These
findings corroborate the results of clinical trials with statins and fibrates
and emphasize the role of serum cholesterol and its fractions as important
risk factors for ischemic stroke.
AUTHOR INFORMATION
Accepted for publication September 5, 2001.
Corresponding author and reprints: Uri Goldbourt, PhD, Division of
Epidemiology and Preventive Medicine, Sackler School of Medicine, Tel Aviv
University, Ramat Aviv, Tel Aviv 69978, Israel (e-mail: Goldbu1{at}ccsg.tau.ac.il).
From the Division of Epidemiology and Preventive Medicine, Sackler
School of Medicine, Tel-Aviv University (Drs Koren-Morag and Goldbourt), Stroke
Unit, Department of Neurology, Sheba Medical Center, Tel Hashomer (Dr Tanne),
Biochemical Laboratory, Ichilov Hospital, Tel Aviv Medical Center, and Institute
for Physiological Hygiene, Wolfson Medical Center (Dr Graff), and Neufeld
Cardiac Research Institute, Sheba Medical Center, Tel Hashomer (Dr Goldbourt),
Israel. A complete list of the members, participating centers, and committee
membership of the Bezafibrate Infarction Prevention Study Group was published
previously (Circulation. 2000;102:21-27).
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