Locat (lopid coronary angiography trial) is a large regression trial of 400 men from Finland who had undergone prior coronary bypass grafting (CABG), had relatively low HDL cholesterol levels, and were randomized to gemfibrozil or placebo for 2-3 years. Patients with an HDL-C of more than 42.5 mg/dL, LDL-C of more than 174 mg/dL, or triglycerides more than 354 mg/dl were excluded, as were those with significant hypertension, obesity, low ejection fraction, or a fasting glucose of more than 140. Subjects were advised to eat a low-fat, low-cholesterol diet. All had a baseline coronary angiogram and a follow-up study after a mean of 32 months. Coronary arteries and bypass grafts were carefully imaged in the same projection and cardiac cycle following sublingual nitroglycerin. Computer-assisted, quantitative blind analyses were carried out, with assessment of average segment diameter (ADS) and minimum lumen diameter (MLD) in all vessels. The primary endpoints were angiographic, assessing the differences between gemfibrozil and placebo in change from baseline in the follow-up angiograms in both the ADS and MLD of stenoses, as well as assessment of new lesions. Changes of all variables were measured, and coronary lesions were categorized as to whether they were in ungrafted arteries, proximal-to-graft insertion (graft-affected), or distal to graft insertion (graft-dependent). More than 200 men were randomized in each group, 94% of whom had a follow-up angiogram. Approximately four vessels per individual were bypassed.
The results indicate that gemfibrozil lowered baseline triglycerides (TG) by 36%; HDL-C increased by 21%. Total and LDL-C were essentially unchanged. Placebo patients demonstrated a small increase in all lipid levels at the end of 2.5 years. Baseline LDL-C was 140 mg/dL, TG 143, and HDL was 31 mg/dL. Treatment lipid levels in the gemfibrozil group were: TC 186 mg/dL; LDL-C 130 mg/dL; HDL 38 mg/dL; and TG 92 mg/dL. Group differences between placebo and gemfibrozil therapy were highly significant.
Serial angiography was performed at 32 months in all subjects. There was less progression in the active treatment cohort in both coronary arteries and graft segments. Specifically, the decrease in ADS was less in the gemfibrozil group, most marked in the unaffected coronary segments and less so in the graft-affected arteries. However, there was no difference in the graft-dependent segments (i.e., lesions distal to the graft anastomosis). When all segments were analyzed, there was significantly less progression in the gemfibrozil group vs. placebo group. Progression of focal coronary atherosclerosis was less in treated patients (P = ns), and lesion progression was milder (P = ns). New lesions were not altered by active therapy, but in graft-affected segments, there were significantly less new lesions in gemfibrozil patients. With respect to the venous bypass grafts, there was a trend toward a greater mean diameter stenosis in the placebo group than gemfibrozil. Approximately half of the grafts had stenotic lesions at baseline. There was a substantial reduction in new lesions in bypass grafts in the treatment cohort. Clinical outcomes were comparable. There were no deaths during the trial. Nine gemfibrozil patients and no placebo patients had liver enzyme elevations. Frick and associates conclude that, in this cohort of CABG patients with a low HDL-C and relatively low LDL-C, gemfibrozil was beneficial in slowing the progression of native vessel stenosis as well as slowing graft atherosclerosis.
In the discussion, Frick et al also discuss the BECAIT trial using bezafibrate in young male survivors of myocardial infarction. This study was positive with respect to angiographic endpoints as well as clinical events. They point out that in the CLAS trial, it was also shown that the major benefit was in coronary artery segments proximal to graft insertion. In that trial, disease progression in the proximal segments was concordant with clinical endpoints. CLAS also showed no treatment effect in the graft-dependent vessels, with a positive benefit in arteries proximal to graft insertion and non-bypassed arteries. Frick et al conclude "our data support that the conclusions of CLAS that active treatment of hyperlipidemia after bypass surgery retards the progression of atherosclerosis both in native coronary arteries and in bypass grafts." Thus, the message is that different lipid lowering agents achieve comparable benefits. (Frick MH, et al. Circulation 1997;96:2137-2143.)
COMMENT BY JONATHAN ABRAMS, MD
This trial, as well as BECAIT, supports a beneficial effect of fibrates in patients with low HDL-C and elevated TG. In neither study was LDL cholesterol particularly high, nor was it lowered appreciably. In the LOCAT cohort, the depressed HDL-C was out of proportion to the TG levels. Frick et al discuss other lipoprotein particles and point out that subgroup analyses in prior regression trials have suggested that decreases in VLDL cholesterol and triglyceride-rich lipoproteins may be beneficial in the presence of relatively normal LDL-C levels. They suggest that other lipoprotein particles in addition to LDL-C may be atherogenic.
This study is strongly supported by the recently published Post-CABG Trial (N Engl J Med 1997;336:153-162) indicating that progression of bypass graft disease may be slowed by treatment of hypercholesterolemia. The Post-CABG Trial dramatically lowered LDL-C to well below 100/dL and resulted in a clear-cut decrease in graft disease as well as total occlusions in the statin-treated group. Together, LOCAT and the Post-CABG Trial are convincing evidence that treatment of dyslipidemia in coronary bypass population has a real payoff and should be undertaken by clinicians. The baseline lipid levels in LOCAT were unremarkable and quite familiar to anyone caring for coronary artery disease patients. Frick et al point out that other regression trials, usually using a statin, have shown comparable angiographic outcomes. They suggest, as does an accompanying editorial (Havel RJ. Circulation 1997;96:2113-2114), that there may not be a particular lipoprotein particle that must be altered in order to achieve a reduction in native vessel or graft disease. Instead, a multiplicity of lipid factors may affect individuals with various types of dyslipidemia. Clinical events were not lowered in the Post-CABG Trial (high-dose lovastatin) or in LOCAT (gemfibrozil), probably because of the stable nature of the post-CABG patient. One must rely on the favorable changes in native vessel and grafts as being surrogates for long-term clinical outcomes. This is a valid conclusion when one examines the large number of published coronary regression trials, almost all of which have shown favorable effects on atherosclerosis and a cumulative suggestion that clinical endpoints are reduced in the active treatment groups. These studies predict the 4S, CARE, and the Coronary Bypass trial results. It is unclear whether the elevation in HDL-C, the reduction in TG, or the improvement in the TCDL ratio was responsible for the benefits seen in LOCAT. Whatever the lipid fraction responsible for these beneficial results, it is a mandate for physicians to aggressively treat post-CABG patients with lipid lowering, tailoring pharmacologic therapy to the lipid profile.
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