(Circulation. 1999;99:3241-3247.)
© 1999 American Heart Association, Inc.
Clinical Investigation and Reports |
Aggressive Cholesterol Lowering Delays Saphenous Vein Graft Atherosclerosis in Women, the Elderly, and Patients With Associated Risk Factors
NHLBI Post Coronary Artery Bypass Graft Clinical Trial
From the Montreal Heart Institute and University of Montreal (L.C.), Canada; The Maryland Medical Research Institute (G.L.K., S.A.F.), Baltimore, Md; The National Heart, Lung, and Blood Institute (M.D., N.L.G., Y.R.), Bethesda, Md; University of Minnesota (D.B.H., C.W.W.), Minneapolis; Minneapolis Heart Institute Foundation (F.L.G.), Minn; Cleveland Clinic Foundation (B.J.H.), Ohio; Cedars-Sinai Medical Center (J.S.F.), Los Angeles, Calif; and Baylor College of Medicine (J.A.H.), Houston, Tex.
Correspondence to Dr Lucien Campeau, Research Center, Montreal Heart Institute, 5000 Bélanger Street East, Montreal, Quebec H1T 1C8, Canada.
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Abstract |
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Background—The NHLBI Post Coronary Artery Bypass Graft trial (Post CABG) showed that aggressive compared with moderate lowering of low-density lipoprotein-cholesterol (LDL-C) decreased obstructive changes in saphenous vein grafts (SVGs) by 31%.1 Using lovastatin and cholestyramine when necessary, the annually determined mean LDL-C level ranged from 93 to 97 mg/dL in aggressively treated patients and from 132 to 136 mg/dL in the others (P<0.001).
Methods and Results—The present study evaluated the treatment
effect in subgroups defined by age, gender, and selected
coronary heart disease (CHD) risk factors, ie, smoking,
hypertension, diabetes mellitus, high-density lipoprotein
cholesterol (HDL-C) <35 mg/dL, and
triglyceride serum levels 
200 mg/dL at baseline. As
evidenced by similar odds ratio estimates of progression (lumen
diameter decrease 0.6 mm) and lack of interactions with
treatment, a similar beneficial effect of aggressive lowering was
observed in elderly and young patients, in women and men, in patients
with and without smoking, hypertension, or diabetes mellitus, and those
with and without borderline high-risk triglyceride
serum levels. The change in minimum lumen diameter was in the same
direction for all subgroup categories, without significant interactions
with treatment.
Conclusions—Aggressive LDL-C lowering delays progression of atherosclerosis in SVGs irrespective of gender, age, and certain risk factors for CHD.
Key Words: bypass • grafting • atherosclerosis • risk factors
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Introduction |
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The Post Coronary Artery Bypass Graft trial (Post CABG) showed that aggressive lowering of low-density lipoprotein-cholesterol (LDL-C) delayed late obstructive changes in saphenous vein coronary bypass grafts (SVGs).1 The present study aimed to determine whether certain patient subgroups, such as women, elderly patients, and patients with selected coronary heart disease (CHD) risk factors, had a similar benefit from aggressive LDL-C lowering. Two of 3 angiographic studies on progression of atherosclerosis in the native coronary arteries, which have reported on the effect of cholesterol lowering in these subgroups, have suggested a favorable outcome.2 3 4 Recent clinical event trials in much larger cohorts have also shown that cholesterol lowering is equally effective in these subgroups.5 6 7 8 However, angiographic trials that specifically evaluated the role of lipid lowering therapy on late modifications of SVGs did not consider the influence of these baseline characteristics.9 10
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Methods |
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Study Design
This secondary analysis of the Post CABG trial tested whether aggressive compared with moderate LDL-C lowering and low-dose anticoagulation versus placebo delayed the progression of atherosclerosis in SVGs in certain patient subgroups. In brief, Post CABG included 102 women and 1249 men in whom SVGs were placed 1 to 11 years previously. Using a 2x2 factorial design, patients were randomly assigned to aggressive or moderate LDL-C lowering and warfarin (DuPont Pharma, Wilmington, Del) or placebo therapy. The goal for the aggressive LDL-C lowering was 60 to 85 mg/dL (1.6 to 2.2 mmol/L) and between 130 to 140 mg/dL (3.4 to 3.6 mmol/L) for the moderate lowering strategy. In this double-blind study, lovastatin (Merck & Co, West Point, Pa), an inhibitor of HMG-CoA reductase, in doses of 40 to 80 mg/d, was prescribed to patients assigned to the aggressive group and in doses of 2.5 to 5 mg/d to the others. Eight grams per day of the bile sequestrant cholestyramine (Bristol-Myers Squibb, Evansville, Ind) were added when the LDL-C level remained >95 mg/dL (2.5 mmol/L) in the aggressively-treated patients and >160 mg/dL (4.1 mmol/L) in the others. Low-dose anticoagulation with warfarin aimed to maintain an International Normalized Ratio (INR) below 2, as measured by a modified Biotrack (Mountain View, Calif) machine. All patients were encouraged to take 81 mg of aspirin (Bayer, Elkhart, Ind) per day. Patient follow-up ranged from 4 to 5 years, with a mean of 4.3 years.
Patients
The patients were enrolled in 7 clinical centers; they were
between 21 and 74 years of age and were required to have patent SVGs
without narrowing 75% (at least 2 in men and at least 1 in women).
An LDL-C between 130 and 175 mg/dL (3.4 and 4.6 mmol/L) at
least once at the prerandomization visits and triglycerides
<300 mg/dL (3.4 mmol/L) at any one visit after initiation of the
American Heart Step 1 low-fat diet were required. Included in this
study are 1192 patients with follow-up angiographic data and 64
deceased patients for whom it was assumed that all their grafts were
occluded (worst case scenario), for a total of 1256, or 93% of
enrolled subjects. Surviving patients (n=95) who had neither an interim
nor a scheduled follow-up angiogram were excluded.
Outcome Measures
Two outcomes were selected for the present study: the
primary main trial outcome and a secondary angiographic
outcome.1 11 The primary trial outcome was the percentage
of patent major SVGs per patient that developed substantial progression
of atherosclerosis. Substantial progression was defined
as a decrease of 0.6 mm of the lumen diameter as determined by
quantitative (computer-assisted) angiography. It included worsening of
preexisting lesions, new lesions in previously intact grafts, and
occlusion.
The secondary outcome was the mean change per patient of the minimum lumen diameter (MLD) of each graft. Symptom-motivated interim angiograms were used to define these end points when the scheduled follow-up angiogram was not obtained. All grafts were considered occluded in patients who died without having a follow-up angiogram.
Baseline Variables
Subgroup categories and their prevalence are shown in Table 1
. Smokers included patients who reported
currently smoking cigarettes. Hypertension was defined as
systolic blood pressure 140 mm Hg or
diastolic pressure 90 mm Hg without considering the
use of antihypertensive drugs. Only patients taking oral glucose
lowering drugs or insulin were considered to have diabetes mellitus.
High-density lipoprotein cholesterol (HDL-C) and
triglycerides were included as high CHD risk factors being
only slightly influenced by the LDL-C lowering in this
trial.1 Except for the triglyceride values at
year 1 that were lower in the aggressive strategy group (138±75 versus
165±93, P<0.0001), no other significant differences were
observed at the 4 yearly determinations for both variables. Serum
HDL-C levels <35 mg/dL (1.03 mmol/L) and
triglycerides 200 mg/dL (1.64 mmol/L) were
identified as borderline high-risk, (Guidelines of The National
Cholesterol Education Program12 ). The
treatment effect was also evaluated in patients having 0 to 1 or
more risk factors which could include smoking, hypertension,
diabetes mellitus, HDL-C <35 mg/dL, and triglycerides
200 mg/dL.
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Statistical Analyses
The generalized estimating equations (GEE) model, a robust
regression model, was used to obtain estimates of odds ratios of
aggressive versus moderate LDL-C lowering of the percentage of SVGs per
patient with substantial progression for each category of selected
subgroups.13 14 This statistical procedure takes into
account the correlation among grafts within each individual. The
advantage of using the GEE model instead of the modified ratio estimate
statistic used to assess treatment differences in the main study is
that covariates can be added to the model to estimate the treatment
differences, and thus it is possible to take into account any possible
imbalances in important covariates that may exist between the 2
treatment groups. Also, interaction terms can be included in the model
to determine if the treatment effects observed in the trial are
consistent across different patient groups. The covariates in
the GEE model used to evaluate specific graft outcomes can be either
specific to the individual patient or specific to the graft being
evaluated.
Because this was a secondary analysis, only comparisons of
progression rate between the 2 treatment groups that yielded
P
0.01 were accepted as showing a significant difference.
The 99% CI for the odds ratio estimates falling below unity were
considered statistical evidence of a significantly greater treatment
effect of the aggressive compared with the moderate LDL-C lowering
strategy. The GEE model also estimated the interaction between the
treatment effect and subgroup categories of baseline characteristics.
An interaction P0.01 provided the best estimate of whether
there was a true difference among the subgroup categories with respect
to treatment effects. All analyses were performed on an
intent-to-treat basis.
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Results |
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Main Study
As previously published, the annually determined mean LDL-C level ranged from 93 to 97 mg/dL (2.4 to 2.5 mmol/L) for patients assigned to aggressive treatment and from 132 to 136 mg/dL (3.4 to 3.5 mmol/L) for patients allocated to moderate therapy1 (P<0.001). The mean percentage of grafts per patient that showed substantial change was 27% for patients assigned to aggressive LDL-C lowering and 39% for those allocated to the moderate group (P<0.001). The INR at the end of the dose-adjustment period (year 1) was 1.4 in the warfarin group and 1.05 in the placebo group. The INR in the range of 1.5 to 2 was achieved in only 38% of patients assigned to the active anticoagulation therapy. This very low intensity anticoagulation showed no benefit with regard to angiographic and clinical outcomes. There was no significant interaction between the lipid lowering and anticoagulation interventions.
Subgroup Study
The baseline characteristics of the patients who had follow-up
angiographic data and the deceased patients for whom it was assumed
that all their grafts were occluded in each of the lipid-lowering
groups are shown in Table 1
.
The probability of substantial progression (progression rate) of
atherosclerosis in the 1360 SVGs of patients assigned
to aggressive LDL-C lowering and in the 1318 SVGs of patients in the
moderate LDL-C lowering strategy is displayed in Table 2. The treatment effect of aggressive
compared with moderate LDL-C lowering did not differ significantly
among categories of all subgroups, as evidenced by the absence of
significant interaction (P>0.01). Interaction was of
borderline significance only for HDL-C serum levels
(P=0.04). The odds ratio estimates of progression with
aggressive compared with moderate LDL-C lowering were also similar for
all subgroup categories except for HDL-C.
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Aggressive LDL-C lowering appeared most beneficial, showing
significantly less progression of graft atherosclerosis
compared with moderate lowering in categories having a relatively
higher risk potential, such as an HDL-C <40 mg/dL (1.03 mmol/L),
triglycerides 145 mg/dL (1.64 mmol/L) and associated
risk factors. As illustrated in Figures 1 and 2, the progression rates associated
with aggressive LDL-C lowering were quite similar irrespective of the
risk potential, contrasting with the progressively greater progression
rates in patients of the moderate lowering group as the risk potential
increased.
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MLD Change
As shown in Table 3, differences in
the mean MLD change per patient were significantly smaller
(consistent with a beneficial effect) in patients of the
aggressive lowering strategy in most subgroup categories except in
those having a small n, such as in women and patients with diabetes,
where they were nonetheless in the same direction and most commonly of
similar magnitude. There were no interactions between treatment effect
and all the subgroup categories.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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The objective of the Post CABG trial was to compare the effect on late saphenous vein graft changes of 2 predefined goals of LDL-C lowering using lovastatin and cholestyramine when necessary. The outcome may have been influenced by factors other than the LDL-C lowering, but it is most likely that these potential mechanisms were equally distributed in both LDL-C lowering groups in this randomized trial. The Friedwald formula based on triglyceride and HDL-C serum levels that served to estimate the LDL-C serum levels appears reliable in patients having triglycerides at baseline <300 mg/dL and slight variation during the trial.
Few angiographic trials have documented the influence of age, gender, and risk factors for CHD on the effect of lipid lowering therapy2 3 4 A trial (SCOR) that assigned 41 women and 31 men with heterozygous familial hypercholesterolemia (mean baseline LDL-C 283 mg/dL; 7.32 mmol/L) to a combination drug regimen or to placebo showed a benefit only in women (P=0.05 by 2-tailed t test).2 In the Canadian Coronary Atherosclerosis Intervention Trial (CCAIT), progression of atherosclerosis in women, smokers, and patients with hypertension or diabetes mellitus did not differ from the total study cohort assigned to lovastatin therapy, but the difference between treated and control patients was not significant for these subgroups.3 In the Program On Surgical Control of the Hyperlipidemias by partial ileal bypass (POSCH), no statistically significant changes in clinical event rates were observed among the 32 women assigned to the surgical intervention and the 46 allocated to the diet-control group.4 Many trials enrolled only men9 10 15 16 17 ; and in other studies, female patients represented <15% of the total study population.18 19 20 21 22 Several trials excluded patients older than 67 years.15 16 18 20 22 Furthermore, these studies did not have the statistical power for subgroup analyses because of the small study population which varied between 48 and 395 subjects, except possibly for REGRESS, which included 885 men17 and POSCH with 838 participants, including 78 women.18
However, much larger clinical trials based on clinical outcomes have recently shown that lipid lowering therapy is equally effective in women and men, in the elderly and younger patients, in patients with and without certain risk factors for CHD, hypertension, diabetes mellitus, and smoking.5 6 7 8 Nonetheless, Post CABG remains the only trial that has documented delayed progression of atherosclerosis in SVGs in these subgroups.
It appears that the relative risk of CHD in women is lower for any given level of risk factors. In the Renfrew and Paisley survey, women (both pre- and postmenopause) in the highest quintile of cholesterol (>7.2 mmol/L; 278 mg/dL) had lower CHD death rates compared with men in the lowest quintile (<5.0 mmol/L; 193 mg/dL).23 In the Cholesterol and Recurrent Events Trial (CARE), the rate of major coronary events in patients treated with the HMG CoA reductase inhibitor, pravastatin, as compared with patients given placebo, was lower in women than in men (46% lower versus 20% lower, P=0.05 for the interaction between gender and treatment).7 A similar 34% risk reduction was reported for men and women in the Scandinavian Simvastatin Survival Study (4S).6 The risk reduction did not differ in women compared with men in the present study, despite a greater number of CHD risk factors in women.24
In clinical practice, lipid lowering therapy has frequently been neglected in the elderly, on the basis of epidemiological studies that have reported a weaker relation between serum cholesterol and the risk of CHD in the elderly compared with middle-aged subjects.25 26 27 Kannel et al stated that total cholesterol has little predictive value in persons >50 years.27 On the other hand, it appears that increased age may enhance cholesterol lowering responsiveness to HMG CoA reductase inhibitors.28 The present study shows that patients >60 years have a risk reduction following lipid lowering therapy comparable to that of younger patients.
The Framingham Heart study has shown a very potent influence of other
risk factors when associated with
hypercholesterolemia.27 Adding
glucose intolerance, systolic hypertension, and cigarette
smoking to hypercholesterolemia increases the
8-year probability of cardiovascular disease by 8-fold
(from 3.9 to 34.6 per 1000). This observation suggests that the
atherogenic potential of these associated risk factors are such that
lowering cholesterol may be less beneficial in patients
having multiple risk factors compared with patients with only
hypercholesterolemia, or that they may require
more intensive lowering. The present study shows instead that the
treatment effect of aggressive LDL-C lowering was quite similar in
patients with or without hypertension, with or without diabetes, and in
smokers compared with nonsmokers. Similar findings concerning the
effect of cholesterol lowering on major coronary
events in patients with CHD were also noted in recent clinical
trials.6 7 Progression of SVG
atherosclerosis in patients of the aggressive LDL-C
lowering group was similar despite incremental risk potential of
baseline HDL-C and triglyceride serum levels (Figure 1). Thus, aggressive LDL-C lowering appeared to suppress the
atherogenic potential of these risk factors. In contrast, in moderate
LDL-C lowering progression of atherosclerosis in SVGs
increased progressively with higher levels of risk, suggesting that
there was less suppression of the atherogenic potential. The difference
in progression rates between aggressive and moderate LDL-C lowering
increased progressively as the risk potential of these associated risk
factors became greater. This finding suggests a greater
cholesterol lowering requirement when certain associated
risk factors are present, consistent with the Framingham
Heart Study that showed an increasingly greater risk when multiple risk
factors were added to hypercholesterolemia.
Conversely, less intensive lipid lowering appears sufficient when
hypercholesterolemia is the only risk factor,
as suggested by the absence of significant difference in treatment
effects of aggressive and moderate LDL-C lowering when the risk
potential is very low, (baseline HDL 45 mg/dL,
triglyceride serum level 145 mg/dL or without other risk
factors), as shown in Figures 1 and 2. In the West of Scotland
primary prevention study,29 a significant benefit was
associated with a mean during-trial LDL-C serum level of 143 mg/dL in
the subgroup of 5401 patients without associated risk factors. In
contrast, no significant benefit was observed in the 1194 patients
having multiple CHD risk factors in this a posteriori analysis,
suggesting perhaps that this LDL-C therapeutic level was not
sufficiently low. The National Cholesterol Education
Program (NCEP) recommends for primary prevention the lowering goals:
<160 mg/dL for patients having fewer than 2 CHD risk factors and <130
mg/dL when multiple risk factors are present.12 As
shown in Figures 1 and 2, it appears that aggressive LDL-C
lowering below 100 mg/dL is definitely required in patients with CHD
risk factors other than hypercholesterolemia in this secondary
prevention trial but that moderate lowering may be sufficient in
patients without other CHD risk factors.
Clinical Relevance
Elderly patients and women benefited from aggressive lipid
lowering as much as young patients and men. These results also
emphasize that aggressive LDL-C lowering retards
atherosclerosis in saphenous vein coronary
bypass grafts in patients despite associated coronary heart
disease risk factors such as smoking, hypertension, and diabetes. They
also show that aggressive LDL-C lowering is most beneficial in higher
risk patients, such as patients with HDL-C levels <35 mg/dL or
triglycerides serum levels 200 mg/dL, or patients having
other associated CHD risk factors. We conclude, therefore, that
aggressive LDL-C lowering below 100 mg/dL, as recommended by the
NCEP adult treatment panel II for secondary prevention of
atherosclerosis,12 is indicated after CABG
surgery in women as in men, in the elderly as in young patients, and in
patients with other CHD risk factors.
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Acknowledgments |
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This study was supported by Contracts N01-HC-75071, 75072, 75073, 75074, 75075, and 75076 from the National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Md; and was partially supported by Merck & Company.
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Footnotes |
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Reprint requests to Dr Genell L. Knatterud, Post CABG Coordinating Center, Maryland Medical Research Institute, 600 Wyndhurst Ave, Baltimore, MD, 21210.
1 A list of Post CABG investigators appears in a prior publication.1 
Received October 16, 1998; revision received March 29, 1999; accepted April 9, 1999.
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