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(Circulation. 1999;99:736-743.)
© 1999 American Heart Association, Inc.
Clinical Investigation and Reports |
Influence of Low HDL on Progression of Coronary Artery Disease and Response to Fluvastatin Therapy
From Baylor College of Medicine (C.M.B., J.A.H., L.L.F., J.K.D., J.A.F., P.H.J.), Houston, Tex; Novartis Pharmaceuticals Corporation (J.R.S.), East Hanover, NJ; and Cornell University Medical College (A.M.G.), New York, NY.
Correspondence to Christie M. Ballantyne, MD, Baylor College of Medicine, 6565 Fannin, MS A-601, Houston, TX 77030. E-mail cmb{at}bcm.tmc.edu
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Abstract |
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Background—Patients with coronary artery disease (CAD) commonly have low HDL cholesterol (HDL-C) and mildly elevated LDL cholesterol (LDL-C), leading to uncertainty as to whether the appropriate goal of therapy should be lowering LDL-C or raising HDL-C.
Methods and Results—Patients in the Lipoprotein and
Coronary Atherosclerosis Study (LCAS) had
mildly to moderately elevated LDL-C; many also had low HDL-C, providing
an opportunity to compare angiographic progression and the benefits of
the HMG-CoA reductase inhibitor fluvastatin in
patients with low versus patients with higher HDL-C. Of the 339
patients with biochemical and angiographic data, 68 had baseline HDL-C
<0.91 mmol/L (35 mg/dL), mean 0.82±0.06 mmol/L (31.7±2.2
mg/dL), versus 1.23±0.29 mmol/L (47.4±11.2 mg/dL) in patients
with baseline HDL-C 
0.91 mmol/L. Among patients on placebo,
those with low HDL-C had significantly more angiographic progression
than those with higher HDL-C. Fluvastatin significantly
reduced progression among low–HDL-C patients: 0.065±0.036 mm
versus 0.274±0.045 mm in placebo patients
(P=0.0004); respective minimum lumen diameter decreases
among higher–HDL-C patients were 0.036±0.021 mm and
0.083±0.019 mm (P=0.09). The treatment effect of
fluvastatin on minimum lumen diameter change was
significantly greater among low–HDL-C patients than among
higher–HDL-C patients (P=0.01); among low–HDL-C
patients, fluvastatin patients had improved event-free
survival compared with placebo patients.
Conclusions—Although the predominant lipid-modifying effect of fluvastatin is to decrease LDL-C, patients with low HDL-C received the greatest angiographic and clinical benefit.
Key Words: angiography • cholesterol • coronary disease • drugs • lipoproteins
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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The inverse relation between HDL cholesterol (HDL-C) and coronary artery disease (CAD) events has been established in many epidemiological studies. It is estimated that for each 1-mg/dL increase in HDL-C, risk for a CAD event is reduced by 2% in men and 3% in women.1 Accordingly, the US National Cholesterol Education Program (NCEP) uses HDL-C concentration to stratify patients by CAD risk; HDL-C <0.91 mmol/L (35 mg/dL) is a major positive risk factor in the NCEP treatment algorithm for primary prevention; HDL-C
1.55 mmol/L (60 mg/dL)
is a negative risk factor.2 Most CAD patients do not have substantially elevated total or LDL cholesterol (LDL-C).3 Instead, low HDL-C is frequently the predominant lipid abnormality, which leads to confusion as to the primary treatment goal in patients with low HDL-C: whether to raise HDL-C or lower LDL-C. The Lipoprotein and Coronary Atherosclerosis Study (LCAS)4 enrolled patients whose LDL-C was only mildly to moderately elevated; many also had low HDL-C, similar to patients commonly seen in clinical practice.
In this post hoc analysis, we compared patients with low HDL-C, as defined in the NCEP guidelines, and patients with normal or elevated HDL-C to determine whether low–HDL-C patients have increased angiographic progression, as might be predicted by the increased CAD event rates at lower HDL-C concentrations in epidemiological studies and by the relation between angiographic progression and clinical event rates.5 6 Also, we examined the effect of fluvastatin, an HMG-CoA reductase inhibitor (statin), in each category of baseline HDL-C to see if fluvastatin produced similar angiographic benefits in patients with low or higher HDL-C.
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Methods |
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Trial Design
The design of LCAS has been described in detail previously.7 In brief, LCAS was a randomized, double-blind, placebo-controlled trial of fluvastatin 20 mg BID. Open-label adjunctive cholestyramine, up to 12 g/d as tolerated (mean 8 g/d), was assigned in addition to the randomized treatment in all patients with mean prerandomization LDL-C
4.14 mmol/L (160
mg/dL) despite diet therapy (25% of all randomly selected patients);
in the present study, unless otherwise indicated, patients were
analyzed by randomized treatment, ie, fluvastatin
or placebo. The primary endpoint was within-patient per-lesion change
in minimum lumen diameter (MLD) of qualifying lesions as assessed by
quantitative coronary angiography at baseline and 2.5-year
follow-up.
Patients
Men and postmenopausal women aged 35 to 75 years with
angiographic evidence of CAD and LDL-C of 2.97 to 4.91 mmol/L (115
to 190 mg/dL) on the NCEP Step I diet2 were
eligible. Angiographic criteria included 1 atherosclerotic lesion
causing 30% to 75% diameter stenosis by caliper measurement
in a coronary artery untreated by PTCA and not 100% occluded
and at least 2 of the 3 major coronary arteries untreated by
PTCA, not 100% occluded, and evaluable by angiography. Patients were
not excluded for prior myocardial infarction (MI) at least 6 months
before randomization. Exclusion criteria included mean fasting plasma
triglyceride >2.82 mmol/L (250 mg/dL) in patients
assigned cholestyramine or >3.39 mmol/L (300 mg/dL) in any
patient, diabetes mellitus requiring insulin or an oral hypoglycemic
agent, fasting blood glucose >9.4 mmol/L (170 mg/dL),
uncontrolled hypertension, prior CABG, atherectomy, and coronary
stent.
Lipids, Apolipoproteins, and Coagulation Factors
Lipid, apolipoprotein, and coagulation factor concentrations
were assessed in fasting blood samples drawn at weeks –2, 0, 54, and
130 by a laboratory certified by the US National Heart, Lung, and Blood
Institute/Centers for Disease Control and Prevention Part III Program
(Medical Research Laboratories) as previously
described.8
Quantitative Coronary Angiography
The Cardiovascular Angiography Analysis
System was used for angiographic assessment at baseline (1 to 16 weeks
before randomization) and at final follow-up (as close to week 130 as
possible; angiography required for clinical reasons could be
substituted if evaluable for analysis and performed 1 year
after randomization). All patients received 0.4 mg sublingual
nitroglycerin unless medically contraindicated. Lesions
qualifying for the primary analysis had MLD 25% of the
reference lumen diameter at baseline and MLD at least 0.8 mm less
than the reference lumen diameter at either baseline or follow-up.
Lesions were excluded from the analysis if they were poorly
visualized at baseline or follow-up, had reference lumen diameter
<1.5 mm at baseline, or were in arteries treated by PTCA or with
total occlusion at baseline.
Clinical Events
Clinical events were defined as PTCA, CABG, definite or probable
MI, unstable angina pectoris requiring hospitalization, and death of
any cause.
Statistical Analysis
Baseline lipid values were the average of values at weeks –2
and 0. Final lipid values were those assessed closest to the date of
the final angiogram. For patients with final angiography before 2.5
years because of a clinical event, measurements at week 54 were
substituted.
To compare baseline characteristics between HDL-C categories, 1-way
ANOVA (for continuous variables) or the 
2
test (for categorical variables) was used. If the assumptions
underlying these tests were not satisfied, Mann–Whitney rank-sum test
and Fisher's exact test, respectively, were used.
To determine whether there was a differential impact of treatment in
the 2 HDL-C categories, the relation of fluvastatin
patients to placebo patients in the low–HDL-C category was compared
with the relation of fluvastatin to placebo in the
higher–HDL-C category for both baseline and posttreatment
characteristics. This potential treatment group–by–HDL-C category
interaction was analyzed using ANOVA for continuous outcome
variables (except MLD and percent diameter stenosis) and
logistic regression for categorical outcome variables. Multinomial
logistic regression analysis was used to compare the
distribution of patients categorized as progressors (MLD decrease
0.4 mm in any qualifying lesion), regressors (MLD increase
0.4 mm in any qualifying lesion and no MLD decrease 0.4
mm), and stable (no MLD change 0.4 mm in any qualifying lesion).
Hierarchical mixed-model regression analysis of MLD and percent
diameter stenosis was performed on a per-lesion basis to
account for the variability of lesions within patients. The log-rank
test was used to analyze time to first clinical event.
MLD and percent diameter stenosis are reported as least square
mean±SE. All other variables are reported as mean±SD. All tests
of significance were 2-sided with an overall P
0.05
indicating statistical significance. The Bonferroni procedure was
applied to control the error rate associated with the number of tests
for a given set of variables. All calculations were performed with
Stata (Stata Corporation) or the Statistical Analysis System
(SAS Institute).
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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The primary results of LCAS have been published previously.4 Of the 429 patients randomized, 339 had extensive lipoprotein and coagulation profiles at >1 time point during the trial and evaluable baseline and follow-up angiography. Lipoprotein and coagulation values at week 54 were substituted for week 130 values in 11 patients because final angiography was performed before 2.5 years (because of a clinical event).
Comparison of Patients with Low Versus Higher Baseline
HDL-C
Baseline Characteristics
One fifth of patients (n=68) had HDL-C <0.91 mmol/L
(35 mg/dL) (mean 0.82±0.06 mmol/L [31.7±2.2 mg/dL], versus
mean 1.23±0.29 mmol/L [47.4±11.2 mg/dL] in the 271 patients
with HDL-C 0.91 mmol/L). In a comparison of baseline
characteristics (Table 1
),
low–HDL-C patients were significantly more likely to be male and had
significantly increased body-mass index, triglyceride
levels (2.18±0.65 mmol/L [193.5±58.0 mg/dL] versus
1.71±0.61 mmol/L [151.7±53.9 mg/dL]; P<0.001), and
apo B-100/apo A-I ratio (1.30±0.23 versus 1.00±0.24;
P<0.001); they also had significantly decreased total
cholesterol (5.50±0.55 mmol/L [212.8±21.2
mg/dL] versus 5.77±0.64 mmol/L [223.3±24.6 mg/dL];
P=0.01), apo A-I (106.9±10.6 mg/dL versus 139.9±28.0
mg/dL; P<0.001), and lipoproteins containing only apo A-I
(37.6±6.1 mg/dL versus 47.6±11.9 mg/dL; P<0.001). In
addition, they were somewhat more likely (nonsignificant) to smoke and
to have prior MI, increased apo C-III in apo B–containing particles
(23.3±13.4 mg/dL versus 19.4±11.0 mg/dL), and decreased apo C-III in
non–apo B–containing particles (14.8±9.4 mg/dL versus 18.0±8.7
mg/dL). Blood pressure (Table 1), coagulation factors, and diet
(not shown) were not different between HDL-C categories.
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Quantitative Coronary Angiography and Clinical
Events
To examine the influence of baseline HDL-C on CAD progression, MLD
change was compared in placebo-only patients (ie, excluding patients
assigned to receive adjunctive cholestyramine) in each HDL-C category
(Figure 1). Placebo-only patients with
low HDL-C (n=21) had significantly more progression than placebo-only
patients with higher baseline HDL-C (n=111): MLD decreased
0.250±0.047 mm versus 0.083±0.020 mm
(P=0.001).
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Among all patients, time to first clinical event was not significantly different between low–HDL-C patients (10 of 68 patients with events) and higher–HDL-C patients (33 of 271).
Effect of Fluvastatin in Patients with Low Versus
Higher Baseline HDL-C
Baseline Characteristics
After confirmation that patients with low HDL-C had the
greatest CAD progression, we examined the effects of
fluvastatin in low–HDL-C patients compared with
higher–HDL-C patients. Within each HDL-C category, baseline
characteristics were comparable between treatment groups except for men
(P<0.002) and glucose (P=0.04) (Table 2).
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Quantitative Coronary Angiography
Among low–HDL-C patients, fluvastatin
significantly reduced CAD progression measured by MLD
de- crease: 0.065±0.036 mm versus 0.274±0.045 mm with
placebo (P=0.0004); respective MLD decreases among
higher–HDL-C patients were 0.036±0.021 mm versus
0.083±0.019 mm (P=0.09) (Figure 2). The treatment effect of
fluvastatin on MLD change, calculated as the difference
between MLD change in fluvastatin and placebo patients, was
significantly greater among low–HDL-C patients than among
higher–HDL-C patients (P=0.01).
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Increase in percent diameter stenosis was also
significantly reduced with fluvastatin among low–HDL-C
patients: 1.4±1.2% versus 8.4±1.6% with placebo
(P=0.0005). Respective increases in higher–HDL-C patients
were 1.0±0.7% versus 2.5±0.7% (P=0.1). The treatment
effect of fluvastatin on change in percent diameter
stenosis was significantly greater in low–HDL-C patients
(P=0.01). In both HDL-C categories, fluvastatin
significantly improved the categorization of patients as progressors,
regressors, or stable (Table 3), with
low–HDL-C placebo patients having the highest frequency of progression
(60%).
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Sex, age, and glucose were assessed as potential influences on the relation of MLD change to treatment, HDL-C category, and the treatment–by–HDL-C interaction. Only sex had a significant effect (P<0.05), but because no placebo-treated women had low HDL-C, the 3-way interaction of sex by treatment by HDL-C category could not be evaluated. The 2-way interactions of sex by treatment and sex by HDL-C category were not significant.
Lipids
The effects of fluvastatin on lipids and
apolipoproteins were similar in patients with low or higher HDL-C
(Table 3
). A comparison of baseline and final values showed that
the major effect of fluvastatin in both HDL-C categories
was to lower LDL-C and apo B-100: respective reductions with
fluvastatin were 24.6% and 11.6% in low–HDL-C patients
and 26.1% and 17.6% in higher–HDL-C patients. Favorable but modest
increases in HDL-C (15.9% and 7.4% in the respective HDL-C
categories) and apo A-I (8.9% and 6.6%) and decreases in
triglyceride (1.2% and 2.2%) and apo B-100/apo A-I ratio
(17.3% and 20.5%) occurred, but the other parameters
measured, including coagulation factors (not reported), were not
affected.
LDL-C achieved with fluvastatin was the same in low–HDL-C
and higher–HDL-C patients; therefore, LDL-C level alone cannot explain
the difference in angiographic benefit between HDL-C categories.
Treatment effects on all lipids and lipoproteins were similar in
patients with low or higher HDL-C (Table 3); no significant
interactions between HDL-C category and treatment were detected for
lipid and apolipoprotein changes.
Clinical Events
Event-free survival was significantly improved with
fluvastatin in low–HDL-C patients (P=0.002),
with events in 2 of 43 fluvastatin and 8 of 25 placebo
patients (Figure 3). Event-free survival
did not differ among higher–HDL-C patients: 19 of 128
fluvastatin and 14 of 143 placebo patients had events.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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In LCAS, which studied patients with mildly to moderately elevated LDL-C, patients who also had low HDL-C at baseline had more CAD progression than patients with higher HDL-C.
Low–HDL-C patients had increased triglyceride levels and body-mass index values and were almost exclusively male. Consistent with having low HDL-C, they also had reduced apo A-I and lipoprotein A-I. Although total cholesterol was also lower in these patients, LDL-C and apo B-100 were similar, with a more unfavorable apo B-100/apo A-I ratio. Although not statistically significant, low–HDL-C patients tended to have a higher incidence of cigarette smoking, increased plasma glucose and apo C-III in apo B–containing particles, and decreased apo C-III in non–apo B–containing particles, which may be a marker for delayed clearance of triglyceride-rich lipoproteins. Low HDL-C is associated with the metabolic syndrome consisting of impaired glucose metabolism; postprandial lipemia; small, dense LDL; and LDL that is more susceptible to oxidation.8 Because of the clustering of risk factors, low HDL-C may be a marker rather than a mechanism for increased progression. Using methods such as ultracentrifugation to measure IDL and VLDL,9 LDL density,10 apolipoprotein and lipoprotein particle assessment,11 and LDL-C cutpoints in patients with hyperapo B-100,12 several studies have identified high-risk subgroups that may benefit the most from therapy. Despite the different methods used, the high-risk group had lower HDL-C in all cases.
Unlike methods such as ultracentrifugation and apolipoprotein measurement, which are not routinely used, HDL-C is routinely measured and therefore may frequently play a role in decisions regarding risk assessment and treatment. The increased CAD progression seen in low–HDL-C patients is consistent with numerous studies that have shown that these patients are at increased risk for CAD events.1 Yet despite their known risk for CAD events, low–HDL-C patients in LCAS were less frequently treated with a statin before the study (14.7% versus 20.3%), perhaps reflecting confusion as to whether the treatment of low–HDL-C patients should focus on raising HDL-C or lowering LDL-C.
The treatment effect of fluvastatin on MLD change, calculated as the difference between MLD change in fluvastatin patients and placebo patients, was significantly greater among low–HDL-C patients than higher–HDL-C patients (P=0.01). Event-free survival was also significantly improved with fluvastatin in low–HDL-C but not higher–HDL-C patients. As would be expected with a statin, the primary impact of fluvastatin was to lower LDL-C and apo B-100. Significant but more modest changes were seen in HDL-C, apo A-I, and triglyceride, and no significant changes were seen in Lp(a), apo C-III in apo B–containing lipoproteins, apo C-III in non–apo B–containing lipoproteins, fibrinogen, and factor VIII-c compared with placebo.
The results from LCAS showing the greatest angiographic and
clinical benefit with treatment in low–HDL-C patients are in contrast
to an earlier trial of cholestyramine monotherapy. In the Lipid
Research Clinics Coronary Primary Prevention Trial, patients
with HDL-C 1.29 mmol/L (50 mg/dL) had the greatest benefit on
CAD death or MI, whereas patients with HDL-C <1.03 mmol/L (40
mg/dL) had no benefit (adjusted incidence ratios of 0.75 versus
1.13).13 However, increased benefit in lower–HDL-C
patients has been reported in statin trials with clinical events as the
primary endpoint (Figure 4). In the
Scandinavian Simvastatin Survival Study
(4S),14 West of Scotland Coronary Prevention Study
(WOSCOPS),15 and Air Force/Texas Coronary
Atherosclerosis Prevention Study
(AFCAPS/TexCAPS),16 statin therapy reduced the
risk for coronary events in lower–HDL-C patients to
approximately that of placebo patients with higher HDL-C (22.5% versus
24.4% in 4S; 6.7% versus 6.2% in WOSCOPS; 3.8% versus 4.1% in
AFCAPS/TexCAPS).
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Similar results were reported for disease progression in saphenous vein grafts in the Post Coronary Artery Bypass Graft Trial, in which lovastatin produced the greatest reduction in progression in patients with baseline HDL-C <0.91 mmol/L (35 mg/dL).17 The percent of grafts with progression was identical in aggressively treated low–HDL-C patients and in moderately treated (control) patients with higher HDL-C.
Statins inhibit HMG-CoA reductase, with subsequent increase in LDL receptor number and enhanced clearance of apo B-100–containing lipoproteins. Fluvastatin, like all statins, reduces not only LDL but also IDL and VLDL remnant particles (thought to be atherogenic). These triglyceride-rich particles are frequently increased in low–HDL-C patients. Because HDL plays a role in reverse cholesterol transport,18 may prevent LDL oxidation,19 and may have direct protective effects on the vessel wall,20 the atherogenic effects of LDL-C and apo B-100–containing lipoproteins may have been more pronounced in low–HDL-C patients and thus reductions in LDL-C with fluvastatin gave greater benefit. In addition, HDL-C was also significantly improved. Unfortunately, one of the limitations of this study was the lack of women with low HDL-C; consequently, we were unable to examine the potential influence of sex on the treatment effect of fluvastatin in low–HDL-C patients.
Two recent angiographic trials have examined the effects of
fibrate therapy on CAD progression in low–HDL-C patients (Table 4). In the Bezafibrate Coronary
Atherosclerosis Intervention Trial,21
median MLD decrease was 0.06 mm with bezafibrate and 0.17 mm
with placebo; estimation of a treatment effect on the basis of this
difference indicated 0.13 mm less progression with bezafibrate
(P=0.049). In the Lopid Coronary Angiography
Trial,22 gemfibrozil patients had significantly less
CAD progression as measured by MLD decrease in all native
coronary segments, 0.04 mm versus 0.09 mm in placebo
patients. A comparison of these studies with LCAS (Table 4)
suggests that statin therapy is at least as beneficial as fibrate
therapy in low–HDL-C patients. In addition, the safety, effectiveness,
and morbidity and mortality benefits of statins have been clearly
documented in numerous clinical trials, whereas the data on fibrates
remain incomplete.
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The combined results of the statin and fibrate trials raise the question of whether combination therapy to lower LDL-C and raise HDL-C might provide greater benefit. Several studies have shown that combinations of a statin plus either nicotinic acid23 or gemfibrozil24 provide additional benefits of reduced triglyceride levels, increased HDL-C, and improved LDL particle size; combination therapy has been shown to produce greater angiographic benefit than monotherapy.25 Adding low-dose nicotinic acid (1 to 2 g/d) to a statin is particularly appealing because of the low cost and additional benefit of reducing Lp(a).26 Future studies should address the question of whether a statin in conjunction with an agent to increase HDL-C, such as nicotinic acid or a fibrate, produces greater clinical benefit than a statin alone.
In the NCEP guidelines, the primary focus of therapy is reduction
of LDL-C, to 2.59 mmol/L (100 mg/dL) in CAD patients. In CAD
patients with low HDL-C who require drug therapy to reduce elevated
LDL-C, the drug selected should increase HDL-C as well as lower LDL-C.
The guidelines also provide for the consideration of nicotinic acid in
CAD patients with low HDL-C even if LDL-C is below the initiation level
for drug therapy.
Our findings support the NCEP guidelines: the first goal of treatment should be to lower LDL-C, even in patients whose LDL-C is only mildly to moderately elevated. Although low–HDL-C patients in LCAS had more CAD progression than patients with normal or elevated HDL-C, low–HDL-C patients also had the greatest angiographic benefit with fluvastatin treatment, even though the predominant lipid-regulating effect of fluvastatin is to lower LDL-C. In summary, statin therapy provides substantial benefits to patients with CAD, low HDL-C, and mild to moderate elevations of LDL-C.
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Acknowledgments |
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Funding for LCAS was provided by Novartis Pharmaceuticals Corporation Grant No. B351 (A.M.G.), NIH GCRC Grant No. 5 M01RR00350 (J.A.H.), and an AHA Established Investigator Award (C.M.B.). The authors appreciate the contribution of M. Stewart West, PhD, to the statistical analysis and the editorial assistance of Kerrie Jara.
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Footnotes |
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Guest Editor for this article was Dr Charles J. Glueck, Cincinnati, Ohio.
Received June 26, 1998; revision received October 18, 1998; accepted October 26, 1998.
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