Effects of Fluvastatin on Coronary Atherosclerosis in Patients With Mild to Moderate Cholesterol Elevations (Lipoprotein and Coronary Atherosclerosis Study [LCAS])

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Abstract

Despite the potential for reduced morbidity and mortality, aggressive intervention against mild to moderate hypercholesterolemia in patients with coronary heart disease (CHD) remains controversial and infrequently practiced. Eligible patients in the 2.5-year Lipoprotein and Coronary Atherosclerosis Study were men and women aged 35 to 75 years with angiographic CHD and mean low-density lipoprotein (LDL) cholesterol of 115 to 190 mg/dl despite diet. Patients (n = 429; 19% women) were randomized to fluvastatin 20 mg twice daily or placebo. One fourth of patients were also assigned open-label adjunctive cholestyramine up to 12 g/day because prerandomization LDL cholesterol remained ≥160 mg/dl. The primary end point, assessed by quantitative coronary angiography, was within-patient per-lesion change in minimum lumen diameter (MLD) of qualifying lesions. Across 2.5 years, mean LDL cholesterol was reduced by 23.9% in all fluvastatin patients (± cholestyramine) (146 to 111 mg/dl) and by 22.5% in the fluvastatin only subgroup (137 to 106 mg/dl). Primary end point analysis (340 patients) showed significantly less lesion progression in all fluvastatin versus all placebo patients, ΔMLD −0.028 versus −0.100 mm (p <0.01), and for fluvastatin alone versus placebo alone, ΔMLD −0.024 versus −0.094 mm (p <0.02). A consistent angiographic benefit with treatment was seen whether baseline LDL cholesterol was above or below 160 or 130 mg/dl. Beneficial trends with treatment were also consistently seen in clinical event rates but were not statistically significant. Thus, lipid lowering by fluvastatin in patients with mildly to moderately elevated LDL cholesterol significantly slowed CHD progression.

Section snippets

Trial Design

The design of the trial has been described in detail elsewhere.[3] In brief, LCAS was a randomized, double-blind, placebo-controlled trial of fluvastatin, 20 mg bid, conducted at a single center (Baylor College of Medicine) using 2 clinic sites. The trial comprised a 4-week screening and dietary lead-in period, 6-week diet stabilization and placebo washout period, and 2.5-year active treatment period that included diet as background therapy (Fig. 1). Open-label cholestyramine, up to 12 g/day as

Patient Group

Of the 909 patients entered into the dietary lead-in period, 429 were randomized. The major reasons for exclusion were lipid ineligibility (39.8%), lack of cooperation (21.0%), and transaminase elevation (13.5%). Selected baseline characteristics of the randomized patients are shown in Table 1; mean baseline lipid values are included in Table 2. The 2 randomized groups were comparable, although the placebo group included a higher proportion of men and lower proportions of patients with elevated

Discussion

Treatment with fluvastatin in LCAS yielded significant coronary lesion benefit; after 2.5 years, MLD decreased only 0.028 mm in all fluvastatin patients and 0.024 mm in fluvastatin monotherapy patients versus reductions of 0.100 and 0.094 mm in respective placebo patients (p <0.01 and <0.02, respectively). A unique feature of the LCAS population was that 34 of the patients had relatively normal or only mildly elevated baseline LDL cholesterol concentration. One fourth of LCAS patients had

Acknowledgements

Funding for the Lipoprotein and Coronary Atherosclerosis Study was provided by Sandoz Pharmaceuticals Corporation Grant B351, East Hanover, New Jersey; and GCRC Grant 5M0IRR00350 from the National Institutes of Health, Bethesda, Maryland.

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    A list of the LCAS investigators and their affiliations appear in the Appendix.

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