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
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.
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
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 2×2 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.
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.
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.
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.
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 P≤0.01 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.
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.
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.
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.
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.
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.
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.
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.
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.
- Copyright © 1999 by American Heart Association
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