(Circulation. 2000;102:21.)
© 2000 American Heart Association, Inc.
Clinical Investigation and Reports |
Secondary Prevention by Raising HDL Cholesterol and Reducing Triglycerides in Patients With Coronary Artery Disease
The Bezafibrate Infarction Prevention (BIP) Study
From the Israeli Society for Prevention of Heart Attacks, Tel-Hashomer, Israel.
Correspondence to the BIP Study Group, Coordinating Center/S. Behar, MD, Neufeld Cardiac Research Institute, Sheba Medical Center, Tel-Hashomer 52621, Israel. E-mail behar{at}post.tau.ac.il
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Abstract |
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Background—Coronary heart disease patients with low high-density lipoprotein cholesterol (HDL-C) levels, high triglyceride levels, or both are at an increased risk of cardiovascular events, but the clinical impact of raising HDL-C or decreasing triglycerides remains to be confirmed.
Methods and Results—In a double-blind trial, 3090 patients with a
previous myocardial infarction or stable angina, total
cholesterol of 180 to 250 mg/dL, HDL-C 
45 mg/dL,
triglycerides 300 mg/dL, and low-density lipoprotein
cholesterol 180 mg/dL were randomized to receive either
400 mg of bezafibrate per day or a placebo; they were followed for a
mean of 6.2 years. The primary end point was fatal or nonfatal
myocardial infarction or sudden death. Bezafibrate increased HDL-C by
18% and reduced triglycerides by 21%. The frequency of
the primary end point was 13.6% on bezafibrate versus 15.0% on
placebo (P=0.26). After 6.2 years, the reduction in the
cumulative probability of the primary end point was 7.3%,
(P=0.24). In a post hoc analysis in the subgroup
with high baseline triglycerides (
200 mg/dL), the
reduction in the cumulative probability of the primary end point by
bezafibrate was 39.5% (P=0.02). Total and noncardiac
mortality rates were similar, and adverse events and cancer were
equally distributed.
Conclusions—Bezafibrate was safe and effective in elevating HDL-C
levels and lowering triglycerides. An overall trend in a
reduction of the incidence of primary end points was observed. The
reduction in the primary end point in patients with high baseline
triglycerides (200 mg/dL) requires further confirmation.
Key Words: lipids • prevention • cardiovascular diseases • triglycerides • lipoproteins, HDL • bezafibrate
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Introduction |
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Epidemiological evidence has suggested that high-density lipoprotein cholesterol (HDL-C) levels are inversely correlated with coronary artery disease (CAD) and are independently predictive of cardiovascular morbidity and mortality.1 2 3 4 In many prospective studies, triglyceride levels were predictive of CAD in univariate and multivariate analyses controlling for total cholesterol or low-density lipoprotein cholesterol (LDL-C) levels.5 6 7 Although in some analyses this association did not persist after adjustment for HDL-C,8 the predictive value of high triglycerides has been confirmed in a meta-analysis.9 Nevertheless, direct evidence for the clinical benefit of elevating HDL-C or reducing blood triglyceride levels is scarce because the efficacy of lipid-modifying drugs that lower triglyceride levels and raise HDL-C levels had not been directly assessed in large-scale clinical trials in CAD patients. In the Coronary Drug Project,10 nicotinic acid, which elevates HDL-C and lowers LDL-C, decreased coronary morbidity; however, HDL-C measurement was not part of the study protocol. An analysis of the joint effects of baseline triglyceride and lipoprotein cholesterol levels, conducted in the framework of the primary prevention Helsinki Heart Study, demonstrated a strong interdependence of LDL-C, HDL-C, and triglycerides as predictors of CAD risk and a beneficial effect of treatment with gemfibrozil.11
The relation of serum total cholesterol and LDL-C with
the development and progress of atherosclerosis and CAD
has been demonstrated in numerous clinical and epidemiological studies.
Moreover, the benefit of LDL-C reduction has now been strongly
supported by the significant decrease in cardiovascular
events, including cardiovascular mortality, achieved by
reducing LDL-C with hepatic hydroxymethylglutaryl coenzyme
A reductase inhibitors (statins).12 13 14 15 16
However, in the Cholesterol and Recurrent
Events14 study, this benefit was not observed in the
subgroup of patients with baseline LDL-C concentrations <125 mg/dL.
About 40% of patients with CAD have LDL-C levels <130 mg/dL, and most
of these patients also have low levels of HDL-C, with or without
increased triglyceride levels. In a previous publication
from the large Bezafibrate Infarction Prevention (BIP) Registry
population, we found that 25% of CAD patients had
cholesterol levels <200 mg/dL (mean LDL-C, 117 mg/dL);
among these patients, more than half had HDL-C levels <35 mg/dL. In
addition, 17% of patients with CAD in the BIP Registry had combined
low HDL-C (<35 mg/dL) and high triglyceride levels (200
mg/dL).17
The BIP study18 was designed and initiated in 1990. The primary question of the trial was whether bezafibrate, which raises HDL-C and reduces triglycerides, would reduce CAD mortality and nonfatal myocardial infarction (MI) in patients with established CAD, HDL-C <45 mg/dL, and moderately elevated cholesterol. Recent studies on the mode of action of fibrates indicate that some of these effects are mediated via the peroxisome proliferator-activated receptor pathway,19 which alters the transcription rate of genes encoding for proteins that control lipoprotein metabolism. The triglyceride-lowering effect is thus linked to an induction of lipoprotein lipase–mediated lipolysis and to lowered apoC-III production, and the HDL-increasing effect is due to an induction in the synthesis of apoAI and apoAII.20 21 22
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Methods |
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Study Design and Patients
Between February 1990 and October 1992, 15 524 male and female patients with CAD aged 45 to 74 years were screened for inclusion in the BIP study in 18 of the 25 cardiology departments in Israel. After an initial 2 months on a lipid-lowering diet, 3122 patients who fulfilled the inclusion criteria were randomized to the study between May 1990 and January 1993. A total of 32 of the randomized patients, who were equally distributed between the placebo and bezafibrate treatment groups, never began study medication and were excluded from analysis. Inclusion criteria for men and women comprised the following: age of 45 to 74 years, history of MI
6
months but <5 years before enrollment into the study and/or stable
angina pectoris confirmed by coronary angiography, and/or
radionuclear studies or standard exercise tests. In addition, a lipid
profile of serum total cholesterol between 180 to 250
mg/dL, LDL-C 180 mg/dL (160 mg/dL for patients <50 years), HDL-C
45 mg/dL, and triglycerides 300 mg/dL was required. The main exclusion criteria were insulin-dependent diabetes mellitus, severe heart failure, unstable angina pectoris, hepatic or renal failure, known sensitivity to bezafibrate, or current use of lipid-modifying drugs.18
Patients were assigned consecutive randomization numbers within each recruiting center after giving written informed consent. They were allocated to receive either 400 mg of bezafibrate retard or placebo once a day, in addition to dietary advice. Patients were allowed to take prescribed medications for cardiac and other conditions except for lipid-lowering drugs. Lipid profiles, fibrinogen levels, and safety parameters were measured in the Central Laboratory at randomization, at 4 months, and annually thereafter until the end of the study. Additional details of the study design and the patients’ baseline characteristics have been described elsewhere.18 23
Routine visits to the clinics were scheduled bimonthly for study medication distribution and compliance assessment by tablet count and every 4 months for clinical evaluation. Compliance was further assessed by annual measurements of alkaline phosphatase. During the 4-month visit, data on any adverse events (as defined in the study protocol), hospitalizations, and study outcomes were obtained. Study medication was withdrawn after the following: (1) a primary end point, (2) an adverse event deemed to be intolerable, (3) an increase in LDL-C to >210 mg/dL (or >190 mg/dL for patients aged <50 years) or triglycerides >500 mg/dL, or (4) safety variables exceeded predefined critical limits. All study participants, regardless of whether they continued to take the trial medication, were followed-up until the last patient had completed 5 years of follow-up.
In July 1994, after the publication of the Scandinavian Simvastatin Survival Study results,15 the International Review and Advisory Board approved the recommendation of the Steering Committee to add colestipol for patients on study medication if their LDL-C exceeded 180 mg/dL in 2 separate laboratory examinations after reinforcement of dietary advice. Colestipol was given concomitantly with the study medication to 165 patients (57 patients in the bezafibrate and 107 in the placebo group) during the study.
The trial was conducted independently of the sponsor (Boehringer Mannheim GmbH, which is now part of F. Hoffmann-La Roche, Ltd), and it was approved by the Helsinki Committees of each center and the central national Helsinki Committee.
Classification and Review of Study End Points
The primary end point of the study was fatal MI, nonfatal MI, or
sudden death (occurring within 24 hours of onset of
symptoms).18
Secondary end points, for patients free of primary end points, included hospitalization for unstable angina, percutaneous transluminal coronary angioplasty, and coronary artery bypass grafting. Stroke and death from any cause were also monitored. An independent Critical Event Committee, whose members were blinded to the treatment assignment, reviewed primary end points and all-cause mortality.
An independent International Review and Advisory Board regularly monitored the progress of the study and the incidence of adverse events. Two scheduled interim analyses were performed 4 and 5.5 years after the randomization of the first patient.
Laboratory Methods
Blood samples, which were collected in the 18 participating
medical centers using standardized equipment and procedures, were
transferred in cooled containers to the Central Laboratory at the
Institute of Physiological Hygiene Laboratory at
the E. Wolfson Medical Center, Holon. Blood samples were drawn after
12 hours of fasting to determine serum levels of
cholesterol, HDL-C, triglycerides, and plasma
fibrinogen. Laboratory measurements were performed using standard
automated procedures with commercially available kits (Roche
Diagnostics). HDL-C was measured by precipitation, and LDL
was estimated using Friedewald et al’s equation.24
Fibrinogen was measured by an automated kinetic method. Accuracy and
precision of lipid and lipoprotein determinations were under periodic
surveillance by the Centers for Disease Control/National Heart, Lung,
and Blood Institute’s Lipids Standardization Program; other
determinations, including the safety variables, were under
surveillance by the Wellcome-Murex Diagnostic Clinical
Chemistry Quality Assessment Program.
Statistical Analysis
The study design a priori assumed a cumulative event rate
of 16% to 24% in the placebo arm of the study over 6 years and an
expected reduction of the event rate of between 20% and 25%. Under
these assumptions and using a 1-sided test, as originally planned, a
sample size of between 2100 and 3300 would have provided a power of
80% to detect the expected reduction. However, during the course of
the study, a decision was made to perform 2-sided rather than 1-sided
statistical tests in light of the results of the Helsinki Heart Study
II. Furthermore, the cumulative incidence of the primary end point
under placebo turned out to be lower than expected. Under these
circumstances, the randomization of 3000 patients provides a power
between 62% and 85% to detect a 20% to 25% reduction in incidence
rate with bezafibrate (
=0.05, 2-sided) when the cumulative incidence
of the primary end point is 15%, as was observed in the placebo
group.
Data were analyzed using SAS software.25 All
patients who took the study medication at least once (n=3090) were
included in the intent-to-treat analysis. Baseline
characteristics in the 2 study groups were compared using the
2 test for dichotomous parameters
and the t test for continuous variables. Changes in
laboratory parameters were calculated as the difference
between the baseline value (measured before administration of the study
medication) and the mean of the values measured in the annual
laboratory examinations before the occurrence of a primary end point or
during the entire follow-up period for patients free of a primary end
point.
The cumulative probability of events was computed using the Kaplan-Meier life-table method. The curves of cumulative probability of event for patients in the placebo and the bezafibrate groups were compared using the log-rank test.
To determine which factors affected primary end points in subgroups of patients by high and low baseline triglyceride and HDL-C levels and by using the cut points recommended by the expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (National Cholesterol Education Program),26 multivariate analyses were performed using Cox’s proportional hazard stepwise regression modeling.
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionAppendix 1References |
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Although 3122 patients were randomized to the study, 32 patients were excluded from analysis because they never started the study medication. Patients in the placebo (n=1542) and bezafibrate (n=1548) groups were well balanced in terms of clinical and laboratory baseline characteristics and concomitant medications (Table 1
). The number of patients with
prior MI (62% in the bezafibrate group and 61% in the placebo group)
or angina (38% and 39% in the bezafibrate and placebo groups,
respectively) as inclusion criteria was similar in both groups.
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The study lasted for a mean of 6.2 years (range, 4.7 to 7.6 years). Vital status at the end of the study was ascertained for all patients except one. A total of 76% of the patients alive at the end of the study were on study medication (74% in the placebo group and 77% in the bezafibrate group). For 511 patients (17%), the study medication was withdrawn for reasons other than the occurrence of a primary end point or death. Of them, 373 patients (237 on placebo and 136 on bezafibrate) received open-label lipid-modifying treatment either before the occurrence of a primary end point or before the end of the study. Reasons for discontinuation of study medication were as follows: lipid levels exceeded predefined limits and necessitated treatment with a lipid-lowering drug (1.5% and 1.0% in the placebo and bezafibrate groups, respectively), adverse event (5.8% and 6.5%, respectively), patient’s request to discontinue study medication (7.0% and 7.2%), and other miscellaneous reasons (2.6% and 1.5%).
Compliance, according to the tablet count, exceeded 90% in 74% of
patients in both groups; it was between 75% and 90% for 17% of
patients and <75% for the remaining 9% of patients. These data were
confirmed in the bezafibrate group, in which alkaline phosphatase
decreased by 10 U/L in 84% of patients, did not change in 10%, and
increased by 10 U/L in 7% of patients.
Effect of Treatment on Lipid and Fibrinogen Levels
Average changes in lipid and fibrinogen levels are shown in Figure 1. The most marked changes were an
increase of 18% in HDL-C and a reduction of 21% in
triglycerides in the bezafibrate group. In the placebo
group, values of total cholesterol and LDL-C remained
stable for 3 years; thereafter, they declined (Figure 2).
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Clinical Outcome
The effect of treatment on the primary end point (nonfatal and
fatal MI and sudden death) is shown in Table 2. Among patients treated with
bezafibrate, the crude rate of primary end points was 13.6% versus
15.0% in the placebo group (9.4% reduction; P=0.26).
Figure 3 depicts Kaplan-Meier curves of
the primary end point for the bezafibrate and placebo groups throughout
the mean study period (6.2 years). The 2 curves started to separate
after 2 years, but in the last 2 years of the study, a change in the
slope of the placebo group becomes evident. The reduction in the
cumulative probability of the primary end point at 6.2 years was 7.3%
(P=0.24). Beyond 6.2 years, the number of patients at risk
and the number of events were small and rather unstable (at 7 years,
the reduction in the cumulative probability of the primary end point
was 5.3%, but the standard error was 8.8% because only 10 events in
the treatment group and 9 events in the placebo group had
occurred).
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Mortality rates were similar in both groups (Table 2
). Among the
161 deaths in the bezafibrate group, 95 were due to cardiac causes,
whereas in the placebo group, 88 of 152 deaths were attributed to
cardiac causes (P=0.61). The distribution of all-cause and
cardiac mortality was not different between the 2 study groups.
Kaplan-Meier curves for all-cause mortality are shown in Figure 4. The incidence of secondary end points
and stroke were comparable between the 2 groups (Table 2).
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The study hypothesis was based on the effect of bezafibrate on baseline
triglyceride and HDL-C levels. Therefore, we performed a
post hoc analysis of the study primary end point by baseline
HDL-C and triglyceride levels (Table 3). In patients with
triglycerides <150 mg/dL, no clear benefit of bezafibrate
treatment was observed. Among patients with baseline
triglycerides 150 mg/dL, bezafibrate reduced the crude
primary end point rate in direct relationship with the level of
baseline triglycerides. Among patients with baseline
triglycerides 200 mg/dL (225 patients in the placebo
group and 234 in the bezafibrate group), bezafibrate reduced the
cumulative probability of a primary end point by 39.5%
(P=0.02), whereas among patients with
triglycerides <200 mg/dL (1317 patients in the placebo
group and 1314 in the bezafibrate group), the reduction in the
cumulative probability of an end point was insignificant (Figure 5).
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After adjustment for age, sex, prior MI, New York Heart Association
class, angina class, and bezafibrate use, the relative risk for primary
end points associated with bezafibrate treatment in the subgroup of
patients with high baseline triglycerides (200 mg/dL) was
0.57 (95% confidence interval, 0.35 to 0.93). When the interaction
between study treatment and different baseline triglyceride
levels was further examined by low (<35 mg/dL) and high (35 mg/dL)
HDL-C (Table 3), the effect of bezafibrate in patients with
baseline triglycerides 200 mg/dL was of similar
magnitude.
Safety
The overall incidence of any adverse event was 69% in both
groups, and the frequency of each type of adverse event was similar in
both groups. There were 85 cases (5.5%) of newly diagnosed fatal and
nonfatal cancers in the bezafibrate group versus 91 cases (5.9%) in
the placebo group, with no significant differences between the groups
at any site. Seven patients in the placebo group and 5 patients in the
bezafibrate group complained of muscular pains during follow-up.
Creatine phosphokinase levels exceeding twice the upper normal limit
(390 U/L for men and 260 U/L for women) were recorded in 5 patients
(4 in the bezafibrate group). For the other safety laboratory
parameters, small differences were observed between the
study groups; these differences had no clinical significance.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionAppendix 1References |
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Although bezafibrate therapy led to a substantial increase in HDL-C and a reduction in triglycerides, the observed reduction in the primary end point was not as expected. In this respect, the time course of the Kaplan-Meier curves of the combined primary end point are intriguing. In the first 5 years of follow-up, the 2 curves diverged; at 5 years, they displayed a cumulative reduction in primary end points of 16.3% (P=0.09) between the bezafibrate and placebo groups. By the end of the study, the overall difference of the cumulative probability of primary end points was markedly reduced (Figure 3
), reflecting an unexpected
flattening of the placebo curve toward the end of the study. In
previous lipid trials with statins and
fibrates,14 15 27 a continuous separation of the
Kaplan-Meier curves was observed beginning at 12 to 24 months of
follow-up and resulting in the desired effect of the active medication
on the incidence of end points.
The convergence of the 2 curves of the primary end point could also be
due to greater variation of the primary end point incidence rate toward
the end of the study, which was caused by the relatively few events
occurring in smaller groups of patients at risk in the last months of
follow-up. The time course of the primary event curve of the placebo
group was consistent with the decline in LDL-C levels in this
group toward the end of the study (Figure 2). Of note, 373
patients, two-thirds of whom were randomized to placebo, received
open-label lipid-modifying drugs before the occurrence of a primary end
point or the end of the study. In addition, 164 patients (two thirds of
whom were in the placebo group) with high LDL-C levels (>180 mg/dL)
were given colestipol as adjuvant therapy to the study medication
before the occurrence of a primary end point or the end of the study.
It is to be expected that adding lipid-modifying therapy to patients in
the placebo group would have a greater effect on outcome compared with
patients in the bezafibrate group, where one effective therapy was
added to or substituted for another.
A beneficial effect of fibric acid derivatives has been reported in the Helsinki Heart Study and in small angiographic secondary prevention trials in patients with isolated low HDL-C28 and in young men after MI.29 Recently, the results of the Veterans Affairs HDL Intervention Trial (VA-HIT), a secondary prevention study with the fibrate gemfibrozil, were published.27 Comparison of mean lipid levels at baseline of patients recruited to VA-HIT and BIP shows that VA-HIT patients had lower HDL (32 mg/dL versus 34.6 mg/dL), lower LDL (111 mg/dL versus 148 mg/dL), and higher triglyceride levels (161 mg/dL versus 149 mg/dL) than BIP participants. After a mean follow-up of 5 years, a 22% reduction in the primary end point (defined as in our study) was observed in the VA-HIT study. By the end of 5 years of follow-up in the BIP study, the cumulative probability of primary end points was reduced by 16.3% with bezafibrate (P=0.09). It is noteworthy that although the placebo primary end point incidence rate in the VA-HIT study was 22%, this rate was 15% in the BIP study.
The low event rate in the BIP study may be partially explained by different patient characteristics and medical practice in the 2 study cohorts. The VA-HIT population was older and included more diabetic patients. Also, 2% of the placebo group and 1% of the gemfibrozil group were given open-label lipid medication in the VA-HIT study, whereas in the BIP study, 15% and 11% of patients in the placebo and bezafibrate groups, respectively, received such therapy. In addition, differences existed in the lipid responses of the 2 studies. In VA-HIT, HDL-C rose by 8%, in comparison to 18% in BIP, and triglycerides declined by 31%, as compared with 21% in BIP. We cannot rule out the possibility that reducing triglycerides may be more important than elevating HDL-C for secondary prevention in CAD patients with relatively low LDL-C levels and high triglycerides. Our data on patients with triglycerides >200 mg/dL may support this possibility.
The rates of adverse events, cancer, and mortality from any cause during follow-up were equally distributed between the 2 study groups. We can conclude from these data that long-term treatment with bezafibrate is safe.
In summary, bezafibrate was found to be safe and was effective in
elevating HDL-C and lowering triglycerides. Although the
overall effect of bezafibrate on the incidence of primary end points
was moderate (P=0.24), the reduction in the primary end
point was impressive in the subgroup of patients with high baseline
triglycerides (200 mg/dL). The latter finding requires
confirmation in a controlled, randomized trial designed to test this
hypothesis because it was identified in post hoc analysis.
Thus, bezafibrate may have a prominent role in the management of
dyslipidemia and CAD when targeted to the subgroup of
patients with high triglycerides.
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Acknowledgments |
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Supported by a grant from Boehringer Mannheim GmbH, Mannheim, Germany, which is now part of F. Hoffmann-La Roche Ltd, Basel, Switzerland.
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Footnotes |
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1 Boehringer Mannheim GmbH, Mannheim, Germany.
2 PRA Europe, Mannheim, Germany.
A complete list of BIP study participants is given in the Appendix.
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Appendix 1 |
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TopAbstractIntroductionMethodsResultsDiscussionAppendix 1References |
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BIP Study Group: Participating Centers and Committee Membership
Participating Centers, Responsible Investigators and Physicians
Assaf Harofe Hospital, Zrifin: Zwi Schlesinger, MD; Zvi Vered, MD; Aharon Friedenson, MD. Barzilai Medical Center, Ashkelon: Leonardo Reisin, MD; Jamal Jafari, MD; Tatiana Flieb, MD. Beilinson Medical Center, Petach Tikva: Samuel Sclarovsky, MD; Yaakov Friedman, MD; Bruno Ostfeld, MD; Alejandro Solodky, MD. Bnei-Zion Hospital, Haifa: Edward Abinader, MD; Shmuel Rochfleish, MD. Carmel Hospital, Haifa: Abraham Palant, MD; Hanan Schneider, MD. Central Haemek Hospital, Afula: Tiberio Rosenfeld, MD; Suleiman Khalid MD. Edith Wolfson Medical Center, Holon: Yehezekiel Kishon, MD; Ron Narinsky,3 MD; Rene Rotzak, MD; Anatoly Davidov, MD; Gregg Levine, MD. Hasharon Hospital, Petach Tikva: Izhar Zahavi, MD; Janash Vitrai, MD; Dror Diker, MD. Hillel-Yaffe Hospital, Hadera: Benyamin Pelled, MD; Joseph Pardu, MD; Jacob Galamidi, MD; Rasmi Majadla, MD. Ichilov Hospital, Sorasky Medical Center, Tel-Aviv: Shlomo Laniado, MD; Libi Sherf, MD; Shimon Braun, MD; Yemima Eschar, MD. Kaplan Hospital, Rehovot: Avraham Caspi, MD; Alexander Arditi, MD; Shulamit Botwin, MD; Lydia Arkavi, MD; Moshe Ziv, MD. Meir Hospital, Sapir Medical Center, Kfar-Saba: Daniel David, MD; Daniel Weisenberg, MD; Mira Kohanovski, MD; Simcha Meisel, MD. Naharia Hospital, Naharia: Nathan Rougin, MD; Malka Yahalom, MD; Alicia Glusman-Vazan, MD. Rambam Medical Center, Haifa: Walter Markiewitz, MD; Diav Motlak, MD; Jonathan Lessick, MD; Guenady Kagan, MD. Rivka Ziv Hospital, Tzfat: Alon Marmour, MD; Michael Flich, MD; Rachel Solomon, MD. Shaare Zedek Medical Center, Jerusalem: Dan Tzivoni, MD; Monty Zion, MD; Jonathan Balkin, MD. Sheba Medical Center, Tel Hashomer: Babeth Rabinowitz, MD; Eddy Barasch, MD; Zohar Brill, MD; Leon Aharon, MD; Aric Asman, MD. Soroka Medical Center, Be’er Sheba: Alexander Battler, MD; Moshe Gueron, MD; Natalio Cristal, MD; Noa Liel, MD; Bronislav Tsatskis, MD; Jacob Henkin, MD.
Review and Advisory Board
Gerd Assmann, MD; Peter Bauer, PhD; Shlomo Eisenberg,3 MD;
Lewis H. Kuller, MD; Baruch Modan, MD, Chairman; James Schoenberger,
MD.
Principal Investigators
Daniel Brunner, MD; Jacob Agmon, MD; Elieser Kaplinsky,
MD.
Steering Committee
Members of the Scientific Committee and Directors of
Participating Centers.
Scientific Committee
Jacob Agmon, MD; Israel Bar Yehuda; Solomon Behar, MD; Daniel
Brunner, MD, Chairman; Avraham Caspi, MD; Uri Goldbourt, PhD; Eran
Graff, PhD; Elieser Kaplinsky, MD; Yehezekiel Kishon, MD; P.
Dieter Lang,1 MD; Henrietta Reicher-Reiss, MD; Avraham Shotan, MD;
Joachim Vollmar,2 MSc; Joshua Waysbort, MD.
Coordinating Center
Jacob Agmon, MD; Yisrael Bar-Yehuda; Solomon Behar, MD,
Medical Director; Daniel Brunner, MD; Uri Goldbourt, PhD; Elieser
Kaplinsky, MD; Henrietta Reicher-Reiss, MD; Avraham Shotan, MD.
Central Laboratory
Daniel Brunner, MD; Eran Graff, PhD, Director; Sara Schwartz,
MSc; Joshua Waysbort, MD; Shoshana Schwartz, BSc; Tova Haimi, BSc;
Rachel Lingel; Frima Nir; Ruth Sticlaru.
Critical Events and End Point Committee
Chaim Almog, MD; Alexander Battler, MD; Monty Zion, MD.
Stroke Monitoring
David Tanne, MD
Safety Evaluation
Siegfrid Hiemstra, MD; Eugene Heyman, PhD.**
Drug Supply Center
Klaus Kehne, Dr rer nat*
Epidemiology, Statistics, Computing, and
Scientific Programming
Michal Benderly, MSc; Miriam Cohen; Mark Goldberg, BA; Uri
Goldbourt, PhD; Lori Mandelzweig, MPH; Mitchell Snyder, PhD.
Data Entry
Dalia Ben-David; Yafit Makmal; Clara Shalom; Rachel Taub.
Study Monitors
Tzila Halevi, RN; Yemima Nahum, RN.
Secretarial Staff
Lynn Goodman; Leah Hirshkovitz; Tzila Pollak; Rachel Sinay.
Data Validation**
R. Flora, MD; Siegfrid Hiemstra, MD; Doris Kolb; Martin Scott,
MSc; Joachim Vollmar, MSc.
Writing Group
Solomon Behar, MD; Daniel Brunner, MD; Elieser Kaplinsky, MD;
Lori Mandelzweig, MPH; Michal Benderly, MSc.
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References |
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TopAbstractIntroductionMethodsResultsDiscussionAppendix 1References |
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H. Drexel, S. Aczel, T. Marte, W. Benzer, P. Langer, W. Moll, and C. H. Saely Is Atherosclerosis in Diabetes and Impaired Fasting Glucose Driven by Elevated LDL Cholesterol or by Decreased HDL Cholesterol? Diabetes Care, January 1, 2005; 28(1): 101 - 107. [Abstract] [Full Text] [PDF]
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J. Shepherd Raising HDL-C and lowering triglycerides: benefits beyond LDL-C modification The British Journal of Diabetes & Vascular Disease, January 1, 2005; 5(1_suppl): S12 - S16. [Abstract] [PDF]
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 E. A. Meagher Addressing Cardiovascular Disease in Women: Focus on Dyslipidemia J Am Board Fam Med, November 1, 2004; 17(6): 424 - 437. [Abstract] [Full Text] [PDF]
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 S. S. Daskalopoulou, D. P. Mikhailidis, and M. Elisaf Prevention and Treatment of the Metabolic Syndrome Angiology, November 1, 2004; 55(6): 589 - 612. [Abstract] [PDF]
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D. Tanne, N. Koren-Morag, and U. Goldbourt Fasting Plasma Glucose and Risk of Incident Ischemic Stroke or Transient Ischemic Attacks: A Prospective Cohort Study Stroke, October 1, 2004; 35(10): 2351 - 2355. [Abstract] [Full Text] [PDF]
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D.J. Betteridge Treating dyslipidaemia in the patient with type 2 diabetes Eur. Heart J. Suppl., July 1, 2004; 6(suppl_C): C28 - C33. [Abstract] [Full Text] [PDF]
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P. M Ridker, N. J. Brown, D. E. Vaughan, D. G. Harrison, and J. L. Mehta Established and Emerging Plasma Biomarkers in the Prediction of First Atherothrombotic Events Circulation, June 29, 2004; 109(25_suppl_1): IV-6 - IV-19. [Full Text] [PDF]
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G. Assmann and A. M. Gotto Jr HDL Cholesterol and Protective Factors in Atherosclerosis Circulation, June 15, 2004; 109(23_suppl_1): III-8 - III-14. [Abstract] [Full Text]
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 K. Kuwabara, K. Murakami, M. Todo, T. Aoki, T. Asaki, M. Murai, and J. Yano A Novel Selective Peroxisome Proliferator-Activated Receptor {alpha} Agonist, 2-Methyl-c-5-[4-[5-methyl-2-(4-methylphenyl)-4-oxazolyl]butyl]-1,3-dioxane-r-2-carboxylic acid (NS-220), Potently Decreases Plasma Triglyceride and Glucose Levels and Modifies Lipoprotein Profiles in KK-Ay Mice J. Pharmacol. Exp. Ther., June 1, 2004; 309(3): 970 - 977. [Abstract] [Full Text] [PDF]
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A. Tenenbaum, M. Motro, E. Z. Fisman, E. Schwammenthal, Y. Adler, I. Goldenberg, J. Leor, V. Boyko, L. Mandelzweig, and S. Behar Peroxisome Proliferator-Activated Receptor Ligand Bezafibrate for Prevention of Type 2 Diabetes Mellitus in Patients With Coronary Artery Disease Circulation, May 11, 2004; 109(18): 2197 - 2202. [Abstract] [Full Text] [PDF]
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D. Colquhoun, A. Keech, D. Hunt, I. Marschner, J. Simes, P. Glasziou, H. White, P. Barter, A. Tonkin, and for the LIPID Study Investigators Effects of pravastatin on coronary events in 2073 patients with low levels of both low-density lipoprotein cholesterol and high-density lipoprotein cholesterol: results from the LIPID study Eur. Heart J., May 1, 2004; 25(9): 771 - 777. [Abstract] [Full Text] [PDF]
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J. McKenney New Perspectives on the Use of Niacin in the Treatment of Lipid Disorders Arch Intern Med, April 12, 2004; 164(7): 697 - 705. [Abstract] [Full Text] [PDF]
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 G. Desideri and C. Ferri Authors' Response: Bezafibrate and Simvastatin: Different Beneficial Effects for Different Therapeutic Aims J. Clin. Endocrinol. Metab., April 1, 2004; 89(4): 1978 - 1979. [Full Text] [PDF]
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M. Haim, V. Boyko, U. Goldbourt, A. Battler, and S. Behar Predictive Value of Elevated White Blood Cell Count in Patients With Preexisting Coronary Heart Disease: The Bezafibrate Infarction Prevention Study Arch Intern Med, February 23, 2004; 164(4): 433 - 439. [Abstract] [Full Text] [PDF]
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 S. Fazio and M. F. Linton Apolipoprotein AI as Therapy for Atherosclerosis: Does the Future of Preventive Cardiology Include Weekly Injections of the HDL Protein? Mol. Interv., December 1, 2003; 3(8): 436 - 440. [Abstract] [Full Text] [PDF]
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I. Goldenberg, M. Jonas, A. Tenenbaum, V. Boyko, S. Matetzky, A. Shotan, S. Behar, and H. Reicher-Reiss Current Smoking, Smoking Cessation, and the Risk of Sudden Cardiac Death in Patients With Coronary Artery Disease Arch Intern Med, October 27, 2003; 163(19): 2301 - 2305. [Abstract] [Full Text] [PDF]
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 W. H Reinhart Fibrinogen - marker or mediator of vascular disease? Vascular Medicine, August 1, 2003; 8(3): 211 - 216. [Abstract] [PDF]
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C.M. Ballantyne Raising high-density lipoprotein cholesterol: where are we now? Eur. Heart J. Suppl., June 1, 2003; 5(suppl_D): D17 - D25. [Abstract] [PDF]
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P. Barter Review: Reconsidering the value of fibrates: lessons from the trials The British Journal of Diabetes & Vascular Disease, May 1, 2003; 3(3): 162 - 167. [Abstract] [PDF]
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