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Low-Dose Combined Therapy with Fluvastatin and Cholestyramine in Hyperlipidemic Patients

Dennis L. Sprecher, MD; Jonathan Abrams, MD; John W. Allen, MD; William F. Keane, MD; Steven G. Chrysant, MD; Henry Ginsberg, MD; Jerome J. Fischer, MD; Brian F. Johnson, MD; Pierre Theroux, MD; and Leonard Jokubaitis, MD
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From the Center for Cholesterol Research, University of Cincinnati Medical Center, Cincinnati, Ohio; University of New Mexico Hospital, Albuquerque, New Mexico; Heart Inc., The Hospital of the Good Samaritan, Los Angeles, California; Hennepin County Medical Center, Minneapolis, Minnesota; Oklahoma Cardiovascular and Hypertension Center and the University of Oklahoma, Oklahoma City, Oklahoma; Columbia University College of Physicians and Surgeons, New York, New York; Diabetes and Glandular Disease Research Center, San Antonio, Texas; University of Massachusetts Medical School, Worcester, Massachusetts; Institut de Cardiologie de Montreal, Montreal, Quebec; Sandoz Research Institute, East Hanover, New Jersey. Requests for Reprints: Dennis L. Sprecher, MD, Center for Cholesterol Research, University of Cincinnati Medical Center, University Hospital, 231 Bethesda Avenue, Mail Location 540, Cincinnati, OH 45267. Acknowledgments: The authors thank Joan Heggland, RN, for data collection, Rachel Neuwirth for analysis, and Martha Hoffmann for manuscript preparation. Grant Support: By Sandoz Pharmaceuticals Corporation, and Sandoz Canada, Inc.

Copyright ©2004 by the American College of Physicians

Ann Intern Med. 1994;120(7):537-543. doi:10.7326/0003-4819-120-7-199404010-00002
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Objective: To compare the low-density lipoprotein (LDL) cholesterol-lowering efficacy of low-dose combinations of cholestyramine and fluvastatin.

Design: Randomized, double-blind, parallel group, placebo-controlled trial with a 24-week double-blind treatment period divided into three phases.

Setting: Office-based clinics.

Patients: Hypercholesterolemic, with LDL cholesterol of 4.14 mmol/L or greater (≥ 160 mg/dL) and plasma triglycerides of 3.39 mmol/L or less (≤ 300 mg/dL). Four hundred sixty patients were screened; 224 patients were randomized into a double-blind treatment period; 203 completed the study; 6 dropped out because of adverse events.

Intervention: Patients were treated with 10 mg or 20 mg of fluvastatin alone, 8 g or 16 g of cholestyramine alone, or combinations of these fluvastatin and cholestyramine dosages (six treatment groups).

Measurements: Changes in lipid variables, particularly LDL cholesterol.

Results: The 10-mg and 20-mg fluvastatin monotherapy groups showed considerable reductions in LDL cholesterol initially (−20.1% [SD, 8.8%] and −20.2% [SD, 10.1%], respectively); these reductions were maintained. Reductions in LDL cholesterol that resulted from the addition of cholestyramine, 8 g/d, to 10 mg of fluvastatin and 20 mg of fluvastatin were greater than those observed with monotherapy (10-mg fluvastatin − [10-mg fluvastatin plus cholestyramine], 9.1%; 95% CI, 3.8% to 14.4%) and 20-mg fluvastatin − [20-mg fluvastatin plus cholestyramine], 11.6%; CI, 6.5% to 16.8%). The increase in cholestyramine dose to 16 g/d in the three combination groups provided only a modest additional response.

Conclusions: Low-density lipoprotein cholesterol reductions of about 25% to 30% can be achieved with low-dose combination therapy with fluvastatin and cholestyramine. The addition of low-dose resin appears to produce greater overall cholesterol reduction than does a simple doubling of the fluvastatin dosage. The low-dose combination treatment was highly successful in achieving the goals of the National Cholesterol Education Program guidelines.


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Figure 1.
Study design and numbers of patients initially assigned to each treatment group.

Monotherapy groups received either placebo, fluvastatin, 10 mg/d, or fluvastatin, 20 mg/d, throughout the study. In the combined therapy groups, cholestyramine, 8 mg/d, was added in phase 2 and the dose increased to 16 mg/d in phase 3. CME = cholestyramine; FL = fluvastatin.

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Figure 2.
Mean low-density lipoprotein cholesterol values in the combination therapy groups during the course of the study.

In phase 1 (weeks 1 to 8), each group showed reductions in mean low-density lipoprotein (LDL) cholesterol similar to those seen in the monotherapy group receiving the same treatment. Increased LDL cholesterol reductions were seen with the addition of cholestyramine, 8 g/d, in phase 2 (weeks 9 to 16), and modest additional reductions occurred when the dose was increased to 16 g/d in phase 3 (weeks 17 to 24).

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Figure 3.
Percentage of patients in each treatment group achieving low-density lipoprotein cholesterol levels less than 4.

14 mmol/L (<160 mg/dL) at study end point. End-point analysis includes last available lipid measurements for patients who did not complete the study. The highest proportions of patients achieving National Cholesterol Education Program guidelines (low-density lipoprotein cholesterol < 4.41 mmol/L [<160 mg/dL]) were in the combination therapy groups.

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