Elsevier

Atherosclerosis

Volume 146, Issue 2, October 1999, Pages 369-379
Atherosclerosis

The effect of aggressive and moderate lowering of LDL-cholesterol and low dose anticoagulation on plasma lipids, apolipoproteins and lipoprotein families in post coronary artery bypass graft trial

https://doi.org/10.1016/S0021-9150(99)00151-3Get rights and content

Abstract

The reported results (The Post Coronary Artery Bypass Graft Trial Investigators. The effect of aggressive lowering of low-density lipoprotein cholesterol levels and low-dose anticoagulation on obstructive changes in saphenous-vein coronary-artery bypass grafts. New Engl J Med 1997;336:153–162) of the Post Coronary Artery Bypass Graft (Post CABG) trial have shown that aggressive lowering was more effective than moderate lowering of low density lipoprotein (LDL) cholesterol in reducing the progression of atherosclerosis in saphenous-vein grafts (27 vs. 39%; P<0.001); low dose warfarin had no effect on the progression of atherosclerosis. The present report describes the effect of long-term (an average of 4.3 years) aggressive treatment with high (40–80 mg/day) and moderate treatment with low (2.5–5 mg/day) doses of lovastatin on lipids, apolipoproteins (apo) and apoA- and apoB-containing lipoprotein families. To achieve the target LDL-cholesterol levels (60–85 mg/dl for aggressive group and 134–140 mg/dl for moderate group), cholestyramine (8 g/day) was given to 25% of subjects on aggressive and 5% of subjects on moderate treatment. Although with both treatment strategies there were significant decreases (P<0.001) in the levels of total cholesterol, LDL-cholesterol, apoB, LDL-apoB and cholesterol-rich Lp-B family, percent changes in the levels of these variables were greater in the aggressive- than in the moderate-treatment groups. These treatments had only marginal effects in increasing the levels of high density lipoprotein cholesterol, apoA-I and Lp-A-I and Lp-A-I:A-II families. The long-term aggressive treatment exerted no effect on the concentrations of triglycerides, apoC-III, apoC-III in VLDL+LDL and triglyceride-rich Lp-Bc families. Neither treatment affected the levels of Lp(a). The potentially modifying influence of warfarin and apoE phenotypes on lovastatin-induced changes in lipoprotein variables was found to be of little significance. It is likely that the beneficial effect of lovastatin in reducing the progression of atherosclerosis in grafts is mediated through its specific lowering effect on cholesterol-rich Lp-B particles.

Introduction

The purpose of the Post Coronary Artery Bypass Graft (Post CABG) trial [1] was to determine whether an aggressive lowering of low density lipoprotein (LDL) cholesterol levels is more effective than a moderate lipid-lowering regimen in reducing the progression of atherosclerotic lesions in vein grafts; an equally important goal was to assess the effects of low-dose anti-coagulation on the progression of graft obstruction.

Post CABG was a multicenter, double-blind, randomized, angiographic trial of 1351 subjects who had saphenous vein coronary bypass graft surgery 1–11 years prior to study entry [1]. Study subjects were assigned in a 2×2 factorial design to aggressive or moderate treatment to lower LDL-cholesterol levels with lovastatin and, if needed, cholestyramine, and to treatment with warfarin or placebo. Angiography was repeated on average of 4.3 years after baseline. The primary end point was the percentage per patient of grafts with a decrease of 0.6 mm or more in lumen diameter.

In Post CABG the aggressive lowering of LDL-cholesterol resulted in levels below 100 mg/dl, as compared with moderate lowering which resulted in levels in the range of 130–140 mg/dl, and showed a significant reduction in the progression of atherosclerotic lesions in vein grafts (27 vs. 39%; P<0.001) as reported previously [1]. A low dose of warfarin had no effect on the progression of atherosclerosis in the vein grafts.

The present report describes the effect of aggressive and moderate lowering of LDL-cholesterol and the effect of warfarin and warfarin-placebo on plasma concentrations of lipids, apolipoproteins (apo) and apoA- and apoB-containing lipoprotein families of particles in three subgroups of Post CABG participants.

Section snippets

Subjects

The Post CABG study design, including eligibility, has been described in detail [1]. In brief, the study cohort consisted of 1351 men (92%) and women (8%) with a mean age of 61.5 years. Subjects had undergone bypass surgery 1–11 years before entering the study with men having at least two and women at least one patent SVG. The LDL-cholesterol levels were between 130 and 175 mg/dl and triglyceride levels less than 300 mg/dl at baseline after the initiation of a Step 1 diet [2].

Study design

Study subjects

Lipids and apolipoproteins

The clinical characteristics and plasma lipid profiles at baseline were similar to the total Post CABG study population [1]. Furthermore, all four treatment subgroups were well matched at the baseline in the subsets of 492 (Table 1, Table 2), 296 (Table 3), and 200 (Table 4) subjects included in the analysis of specified lipid, apolipoprotein or lipoprotein family variables.

Both the aggressive and moderate strategies with lovastatin and, when necessary, with lovastatin and cholestyramine

Discussion

In addition to demonstrating the beneficial effect of aggressive lowering of LDL-cholesterol levels on the progression of atherosclerosis in grafts, the Post CABG study offered the opportunity to determine the long-term effect of an aggressive vs. moderate LDL-lowering strategy with lovastatin and cholestyramine, if necessary, and warfarin on plasma lipids, apolipoproteins and lipoprotein families defined by apolipoprotein composition.

High (aggressive strategy) and low (moderate strategy) doses

Acknowledgements

The Post CABG study was supported by research contracts with the National Heart, Lung, and Blood Institute, Merck & Company and by Dupont Pharma. 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; aspirin was donated by Bayer. We thank Ms. Kathy Hampton for assistance in the preparation of the manuscript.

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