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(Circulation. 2001;104:2660.)
© 2001 American Heart Association, Inc.

Clinical Investigation and Reports

Effect of an Aggressive Lipid-Lowering Strategy on Progression of Atherosclerosis in the Left Main Coronary Artery From Patients in the Post Coronary Artery Bypass Graft Trial

Carl W. White, MD; Fredarick L. Gobel, MD; Lucien Campeau, MD; Genell L. Knatterud, PhD; Sandra A. Forman, MA; James S. Forrester, MD; Nancy L. Geller, PhD; J. Alan Herd, MD; Ann Hickey, MD; Byron J. Hoogwerf, MD; Donald B. Hunninghake, MD; Yves Rosenberg, MD; Michael L. Terrin, MD; , and the Post Coronary Artery Bypass Graft Trial Investigators^*

From the University of Minnesota, Minneapolis (C.W.W., D.B.H.); Minneapolis Heart Institute Foundation, Minneapolis, Minn (F.L.G.); Montreal Heart Institute, Montreal, Quebec, Canada (L.C.); Maryland Medical Research Institute, Baltimore, Md (G.L.K., S.A.F., M.L.T.); Cedars-Sinai Medical Center, Los Angeles, Calif (J.S.F., A.H.); Baylor College of Medicine, Houston, Tex (J.A.H.); Cleveland Clinic Foundation, Cleveland, Ohio (B.J.H.); Office of Biostatistics Research, National Heart, Lung, and Blood Institute, Bethesda, Md (N.L.G.); and Clinical Trials Group, National Heart, Lung, and Blood Institute, Bethesda, Md (Y.R.).

Correspondence to Genell L. Knatterud, PhD, Post CABG Coordinating Center, Maryland Medical Research Institute, 600 Wyndhurst Ave, Baltimore, MD 21210. E-mail gknatterud{at}mmri.org

	Abstract

Top Abstract Introduction Study Design Patients Angiographic Methods Angiographic Outcomes Statistical Analysis Results Discussion References

 
Background— The Post Coronary Artery Bypass Graft Trial, designed to compare the effects of two lipid-lowering regimens and low-dose anticoagulation versus placebo on progression of atherosclerosis in saphenous vein grafts of patients who had had CABG surgery, demonstrated that aggressive lowering of LDL cholesterol levels to a mean yearly cholesterol level from 93 to 97 mg/dL compared with a moderate reduction to a level of 132 to 136 mg/dL decreased the progression of atherosclerosis in saphenous vein grafts. Low-dose anticoagulation did not affect progression. This secondary analysis tested the hypothesis that a similar decrease in progression of atherosclerosis would also be present in native coronary arteries as measured in the left main coronary artery (LMCA).

Methods and Results— A sample of 402 patients was randomly selected from 1102 patients who had baseline and follow-up views of the LMCA suitable for analysis. Patients treated with the aggressive lipid-lowering strategy had less progression of atherosclerosis in the LMCA as measured by changes in minimum (P=0.0003) lumen diameter or the maximum percent stenosis (P=0.001), or the presence of substantial progression (P=0.008), or vascular occlusion (P=0.005) when compared with the moderate strategy.

Conclusions— A strategy of aggressive lipid lowering results in significantly less atherosclerosis progression than a moderate approach in LMCAs.

Key Words: coronary disease • lipids • cholesterol • angiography

	Introduction

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The Post Coronary Artery Bypass Graft Trial (Post CABG) demonstrated that aggressive as compared with moderate lowering of LDL cholesterol (LDL-C) decreased progression of obstructive changes in saphenous vein coronary bypass grafts (SVGs) regardless of age, sex, or the presence of associated risk factors.^1–3 Low-dose warfarin compared with placebo showed no angiographic benefit. Angiographic studies on progression of atherosclerosis in native coronary arteries have also suggested a favorable outcome following cholesterol lowering.⁴ There is a need for additional information regarding the effect of aggressive LDL-C lowering as compared with moderate lowering on the native coronary arteries in patients with

See p 2635

coronary artery disease of sufficient severity to require SVG surgery. This secondary analysis of the Post CABG study tested the hypothesis that the progression of coronary artery disease in native coronary arteries, as measured in the left main coronary artery (LMCA), would be less after aggressive reduction of the LDL-C to a goal of 60 to 85 mg/dL than moderate reduction to a goal of 130 to 140 mg/dL in patients at increased risk. The LMCA was chosen because its well-defined anatomy is suitable for comparison of angiographic measurements and because of its hemodynamic and clinical importance. Although current trials may be more aggressive and attain lower LDL-C levels than the Post CABG Trial, the terms aggressive and moderate were retained to be consistent with previous publications.^1–3,5–9

	Study Design

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The Post CABG Trial included 102 women and 1249 men in whom SVGs were placed 1 to 11 years before study entry.¹ With the use of a 2x2 factorial design, patients were randomly assigned to aggressive or moderate LDL-C lowering and warfarin or placebo therapy.¹ 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. Lovastatin in doses of 40 to 80 mg daily was prescribed for patients assigned to the aggressively treated group and in doses of 2.5 to 5 mg daily to those assigned to the moderately treated group. Cholestyramine (8 grams daily) was prescribed for patients in the aggressively treated group when the LDL-C level remained >95 mg/dL and for patients in the moderately treated group when the LDL-C level remained >160 mg/dL. Low-dose anticoagulation with warfarin aimed to maintain an International Normalized Ratio (INR) <2 in patients assigned this therapy. All patients were encouraged to take 81 mg of aspirin.

This secondary analysis included 402 randomly selected patients from 1102 patients who had a patent LMCA at baseline and had LMCA views suitable for analysis at baseline and routine follow-up angiography. No patients were excluded for other reasons. A sample of available paired angiograms was selected for reading because of limited resources. Samples were selected to include 37% of patients with available studies from each of the clinical sites.

	Patients

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In the Post CABG Trial, 1351 patients were enrolled and were required to have patent SVGs without narrowing (at least 2 in men and at least 1 in women). An LDL-C level between 130 and 175 mg/dL (3.4 and 4.6 mmol/L) at least once at a prerandomization visit and triglyceride level <300 mg/dL (3.4 mmol/L) at any one visit after initiation of the American Heart Step 1 low-fat diet were required. As measured annually during the study period, the mean LDL-C level of patients who received aggressive treatment ranged from 93 to 97 mg/dL yearly; with moderate treatment, the range was from 132 to 136 mg/dL (P<0.001).¹ The mean INR at the end of the dose-adjustment period was 1.4 in the warfarin group and 1.05 in the placebo group. Approximately 93% of patients took aspirin; 86% took 81 mg/d.¹

	Angiographic Methods

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Baseline angiograms and follow-up angiograms (performed 4 to 5 years after enrollment) were obtained with catheterization techniques that permitted computer-assisted quantitative measurement (CAAS System, PIE Medical Maastrecht).^7,10 All native coronary arteries and coronary artery bypass grafts were injected, usually through 7F catheters, in a suggested standardized sequence of views.⁸ LMCA segments were oriented in the image plane and clearly seen in at least two different views. Additional studies performed to assess the reproducibility of readings and the repeatability of imaging indicated that the magnitude of variability was small and had negligible impact on the angiographic measurements.⁷ Nitroglycerin was given to patients, with the same route of administration used during both baseline and follow-up angiography.⁸ Quantitative assessments of the angiograms were performed at the angiography core laboratory by individuals blinded to other patient information. The following information was obtained: the minimal lumen diameter of the LMCA segment, the percentage of stenosis at the site of any lesion, and the diameter of the lumen at the lesion site showing the greatest change from baseline. Totally occluded LMCA segments at follow-up angiography were assigned a value of 0 (for minimum lumen diameter) or 100% for percent diameter stenosis.

	Angiographic Outcomes

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The primary end point of this study was the extent of progression of luminal narrowing in the LMCA segment as measured by the change in minimum lumen diameter. Secondary end points included the mean change in percent maximal stenosis, occurrence of new lesions, and percent of patients with substantial lesion change. In the Post CABG Trial, a 0.6-mm change (progression or regression) was prospectively chosen as a substantial lesion change for SVGs rather than the more frequently used 0.4-mm change in native coronary arteries because SVGs are much larger and 0.6 mm exceeded 3 SD of repeatability measurements.⁷ For evaluation of the LMCA segment, however, the more widely utilized change of 0.4 mm (progression or regression) was chosen.⁴

	Statistical Analysis

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The change in minimum diameter from baseline to follow-up observed in SVGs was -0.197 mm for patients assigned to aggressive strategy and -0.379 mm for patients assigned to the moderate strategy with standard deviation of 0.50.¹ Since it was expected that native vessels would show less change than SVGs, the expected change in the LMCA was assumed to be -0.16 mm for the aggressive strategy and -0.32 mm for the moderate strategy with a proportionately lower standard deviation of 0.42 mm. On the basis of the latter assumptions and to have power of 90% with a 2-sided level of 0.01, the number of films to be graded was determined to be 410 (205 in each lipid group as well as 205 in warfarin and placebo groups). The baseline characteristics of patients in the two groups (patients with films graded for LMCA and all other patients with baseline and follow-up films) were compared by ² tests for categorical variables and t tests for continuous variables. All analyses were performed on an intention-to-treat basis. A test for the homogeneity of the effects of lipid-lowering treatment in the warfarin and placebo groups was performed for each angiographic end point. The results were pooled to provide single comparisons of treatment effects, since no interactions between the two factors of treatment were detected. For secondary analysis of the Post CABG Trial data, such as this, the protocol specified that comparisons between subgroups were considered to show some evidence of differences if P was 0.01 and strong evidence if P was 0.001.

	Results

Top Abstract Introduction Study Design Patients Angiographic Methods Angiographic Outcomes Statistical Analysis Results Discussion References

 
There were no significant baseline differences in clinical characteristics or lipid levels between the 402 patients in the LMCA study and the other patients in the Post CABG Trial who had baseline and follow-up angiography (Table 1). Among these 402 patients, 203 were assigned to the aggressive strategy and 199 to the moderate strategy; 203 received warfarin and 199 received a placebo. The response to therapy in these patients was similar to all patients in the trial in that LDL-C was lowered to a mean range of 92 to 97 mg/dL in the aggressively treated group and 131 to 135 mg/dL in the moderately treated group as measured annually. At baseline, the mean INR was 1.0 for both the warfarin group and the placebo group. The range of the mean INR during the trial is indicated in Table 2. There were no differences between values for the patients in the LMCA study and the other patients in the trial at baseline and at yearly intervals.

View this table: [in this window] [in a new window]   Table 1. Comparison of Patients Included in the LMCA Study and Other Patients in the Post CABG Trial

View this table: [in this window] [in a new window]   Table 2. Mean Values at Baseline and During Trial in LMCA Study Patients by Treatment Assignment

There was a tendency toward less atherosclerosis on baseline angiography in the aggressively treated group, but the angiographic end points evaluating change from baseline take account of baseline status. Most patients (61.4%) had at least one lesion in the LMCA, whereas 27 patients (6.7%) had lesions obstructing 50% of the lumen (Table 3).

View this table: [in this window] [in a new window]   Table 3. Baseline LMCA Angiographic Data by Treatment Assignment

Patients treated with the aggressive lipid-lowering strategy had less progression of atherosclerosis in the LMCA as measured by changes in the minimum lumen diameter (P=0.0003) or the mean change in the maximum stenosis (P=0.001) (Table 4). Warfarin had no beneficial effect on the progression of atherosclerosis in the LMCA.

View this table: [in this window] [in a new window]   Table 4. LMCA Follow-Up Angiographic Data: Angiographic Outcomes According to Treatment Assignment

Substantial lesion progression (0.4 mm reduction in lumen diameter at the site of the lesion with greatest change from baseline to follow-up angiography) in the LMCA was present in 24.1% of patients treated with moderate therapy but in only 13.8% of patients treated with aggressive therapy (P=0.008). Warfarin offered no protection, with substantial progression being noted in 19.7% of the warfarin group and 18.1% of the placebo group (P=0.68). Results were similar when 0.6-mm change was defined as substantial progression as compared with 0.4-mm change (data not shown).

Of the 11 patients in whom occlusion of the LMCA developed, 1 patient had been assigned to the aggressive strategy and 10 patients to the moderate strategy (P=0.005); 9 were in the warfarin group and 2 were in the warfarin-placebo group (P=0.04). Among those patients who had occlusion of the LMCA segment were 6 (58%) who had >50% obstruction and 1 without stenosis at baseline. Analysis excluding occlusions resulted in lesser differences between groups (Table 4).

	Discussion

Top Abstract Introduction Study Design Patients Angiographic Methods Angiographic Outcomes Statistical Analysis Results Discussion References

 
This study indicates that lowering LDL-C to 92 to 97 mg/dL reduced the progression of atherosclerosis in the LMCA as compared with a program of moderate reduction to 131 to 135 mg/dL. The Post CABG Trial is the only large randomized trial that compared the effect of two LDL-C–lowering goals as its primary objective. It concluded that lowering of the mean LDL-C to levels ranging from 93 to 97 mg/dL reduced the progression of atherosclerosis and occurrence of total occlusion in SVGs as compared with treatment to levels ranging from 132 to 136 mg/dL. Low-dose warfarin did not reduce the progression of atherosclerosis. These benefits persist irrespective of sex, age, and other risk factors for coronary heart disease such as smoking, hypertension, diabetes, and low HDL-C levels.^1–3 In the Post CABG study, the beneficial effect of aggressive LDL-C lowering was demonstrated in SVGs, and this analysis extends these findings to the LMCA.

Choosing the LMCA for evaluation offered several important advantages. It is a large vessel that is easily visualized, has a clearly defined length, and therefore can be readily measured. It is anatomically important, being the pathway to two major coronary arteries, the left anterior descending and the circumflex. It is also clinically important since narrowing 50% has a poor prognosis and may require bypass graft surgery. Being at some distance from SVG insertion sites, disease progression in the LMCA is less likely to be influenced by flow stagnation from the dominant, competitive flow in the SVG, an effect that usually disappears after the first year following surgery.^11,12

Results of the outcome measurements for most of the study variables were concordant. Changes were noted in minimum lumen diameter, the mean change in maximum percent stenosis, substantial progression, and vascular occlusion. The change in substantial progression was similar when either the more commonly used 0.4-mm change for native arteries or the 0.6-mm change used in the Post CABG Trial was chosen. The magnitude of change after LDL-C lowering was similar to other angiographic studies of native coronary arteries.¹³

LDL-C lowering has an important impact on vascular occlusion, as noted by other investigators.⁴ In the Post CABG Trial, occlusion of the SVG was more common in the moderately treated (11%) than in the aggressively treated group of patients (6%, P<0.001).¹ Although the number of occlusions in this study is small (n=11), results were concordant.

Regression of atherosclerosis occurred in only two patients. This is less regression than noted in some studies but similar to others.⁴ Regression was infrequently observed in SVGs.¹

Warfarin did not protect patients from either disease progression or occlusion of the LMCA. The mean INR achieved in this LMCA study was low, and we cannot exclude the possibility that more aggressive anticoagulation would be beneficial. Nearly all patients were receiving aspirin during this study, which might have mitigated the benefits from low-dose anticoagulation Although some studies of native coronary arteries have suggested a benefit for low-dose warfarin anticoagulation, others have not.^9,14–16 It is possible that a follow-up period of >4.3 years would be necessary to demonstrate benefit from low-dose warfarin.^9,14,15

The findings of this LMCA study are also clinically relevant. A follow-up of the Post CABG Trial patients demonstrated a 21% reduction in the composite clinical end point of death, nonfatal myocardial infarction, stroke, and revascularization procedures in the aggressively treated group versus the moderately treated group (P<0.001).⁹ The life-table curves for revascularization procedures (bypass surgery or angioplasty) diverge progressively after 2.5 years, indicating a trend in favor of aggressive therapy.¹ This divergence continued in the Extended Post CABG study, and at 7.5 years of follow-up there was a 29% reduction in revascularization procedures in the aggressively treated group (P<0.001).⁹ A subsequent analysis suggested that progressive changes in saphenous vein grafts are predictors of clinical outcomes.¹⁷ In native coronary arteries, angiographic changes have been shown to predict clinical outcomes.^18–20 Several angiographic studies of native coronary arteries have indicated that regression or a reduction in the progression of atherosclerosis with LDL-C lowering is associated with a reduction in future clinical cardiovascular events.⁴ Finally, several large-scale, prospective, randomized clinical (not angiographic) trials have demonstrated that lowering of LDL-C reduces clinical events both for secondary^21–23 and for primary prevention.^24–26 The benefit in reducing progression of atherosclerosis in the LMCA and possibly other native vessels may have contributed to the decrease in clinical events noted in the Post CABG Trial.

These findings indicate that a strategy of aggressive lipid lowering results in significantly less atherosclerosis progression than a moderate approach for LMCAs. It would seem reasonable to expect similar results for native coronary arteries overall. The reduction in occlusions of the LMCA segments in the aggressive treatment group appeared to be related to a reduction in progression of atherosclerosis. These findings support the National Cholesterol Education Program’s recommendation that LDL-C levels should be reduced to <100 mg/dL in patients who have coronary artery disease.²⁷

	Acknowledgments

 
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. Lovastatin was donated by Merck & Company; warfarin and placebo were donated by Dupont Pharma; cholestyramine and placebo were donated by Bristol-Myers Squibb; modified Biotrack machines were provided by Biotrack; and aspirin was donated by Bayer.

	Footnotes

 
The Coordinating Center for the Post-CABG trial at the Maryland Medical Institute received funds in 1999 from Merck-Frostt in Canada for analytical analyses (G.A.K., S.A.F., M.L.T.); Dr Hunninghake receives grant/research support from and serves on the Speakers Bureau of Merck.

*Investigators and centers participating in the trial are listed in Reference 1.

Received July 23, 2001; revision received September 24, 2001; accepted September 25, 2001.

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