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Effect of Combination Therapy with Lipid-Reducing Drugs in Patients with Coronary Heart Disease and “Normal” Cholesterol Levels: A Randomized, Placebo-Controlled Trial

Richard C. Pasternak, MD; Lisa E. Brown, MPH; Peter H. Stone, MD; David I. Silverman, MD; C. Michael Gibson, MD; and Frank M. Sacks, MD
[+] Article and Author Information

for the Harvard Atherosclerosis Reversibility Project (HARP) Study Group; From Massachusetts General Hospital, Beth Israel Hospital, Brigham and Women's Hospital, and Harvard Medical School, Boston, Massachusetts. Grant Support: In part by grants from the National Heart, Lung, and Blood Institute (HL34980) and the National Center for Research Resources (NCRR GCRC MO1 RR02635) and by the National Institutes of Health and Bristol-Myers Squibb (Princeton, New Jersey). Requests for Reprints: Richard C. Pasternak, MD, Cardiac Unit, Jackson 1402, Massachusetts General Hospital, Fruit Street, Boston, MA 02114. Current Author Addresses: Dr. Pasternak: Cardiac Unit, Jackson 1402, Massachusetts General Hospital, 5 Fruit Street, Boston, MA 02114.


Copyright ©2004 by the American College of Physicians


Ann Intern Med. 1996;125(7):529-540. doi:10.7326/0003-4819-125-7-199610010-00001
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Background: Combination drug therapy has been shown to decrease cholesterol levels in hyperlipidemic patients. However, its efficacy has not been well studied in patients previously considered to be normolipidemic, many of whom are now candidates for this therapy.

Objective: To determine the efficacy and tolerability of multidrug therapy designed to improve low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol levels in patients with coronary heart disease and average lipid levels.

Design: Randomized, placebo-controlled, 2.5-year trial comparing patients receiving usual care with patients receiving stepped-care drug therapy.

Intervention: Stepped-care therapy (pravastatin, nicotinic acid, cholestyramine, and gemfibrozil) to decrease total cholesterol levels to less than 4.1 mmol/L (160 mg/dL) and the ratio of LDL cholesterol to HDL cholesterol to less than 2.0.

Setting: 2 academic, urban, tertiary care hospitals.

Patients: 91 patients (80 men and 11 women) with coronary heart disease, a mean age of 60 years, total cholesterol levels less than 6.4 mmol/L (250 mg/dL) at baseline, and ratios of total cholesterol to HDL cholesterol greater than 4.0 at baseline.

Measurements: Fasting serum lipoprotein profile, fasting apolipoprotein levels, and frequency of adverse effects. Patients were assessed every 6 weeks during drug titration and every 3 months thereafter.

Results: Mean lipid levels at baseline were as follows: total cholesterol, 5.5 mmol/L (214 mg/dL); LDL cholesterol, 3.6 mmol/L (140 mg/dL); HDL cholesterol, 1.1 mmol/L (42 mg/dL); and triglycerides, 1.8 mmol/L (159 mg/dL). With pravastatin, changes in levels from baseline were −22% for total cholesterol, −32% for LDL cholesterol, +8% for HDL cholesterol, and −15% for triglycerides (P < 0.001 for all comparisons). With the addition of 1.5 g of nicotinic acid, additional changes were −6% for total cholesterol (P < 0.002), −11% for LDL cholesterol, +8% for HDL cholesterol, and −10% for triglycerides (P < 0.001 for all comparisons). With 2.25 to 3 g of nicotinic acid, these changes were −7% for total cholesterol (P = 0.007), −14% for LDL cholesterol (P < 0.001), +6% for HDL cholesterol (P = 0.02), and −13% for triglycerides (P = 0.03). With cholestyramine, total cholesterol and LDL cholesterol levels were unchanged compared with the previous step; the change in HDL cholesterol level was −8%(P = 0.03); and the change in triglyceride level was +46% (P < 0.001). With gemfibrozil, total cholesterol level was unchanged; the additional change in LDL cholesterol level was +12% (P = 0.09); the change in HDL cholesterol level was +12% (P = 0.03); and the change in triglyceride level was −37%(P < 0.001). Apolipoprotein B levels decreased by 25% overall (P < 0.001); lipoprotein(a) levels did not change significantly. Adverse effects were primarily attributable to nicotinic acid or cholestyramine. In 18 of the 35 patients (50%) whose baseline LDL cholesterol levels were greater than 3.35 mmol/L (130 mg/dL), pravastatin decreased LDL cholesterol levels to 2.6 mmol/L (100 mg/dL) or less by 6 weeks; 70% of patients needed combination therapy to reach this National Cholesterol Education Program goal during the 2.5 years of the study. Adding nicotinic acid to pravastatin produced LDL cholesterol levels of 2.6 mmol/L or less in 15 more of these 35 patients, so that 94% (n = 33) of the patients receiving these two drugs reached this goal.

Conclusions: To reach current goals for LDL cholesterol levels, most normolipidemic patients with coronary heart disease in this study needed combination therapy. Pravastatin with nicotinic acid and pravastatin with gemfibrozil are well-tolerated combinations that can maintain target LDL cholesterol levels, decrease triglyceride levels, and increase HDL cholesterol levels. Adding resin to these combinations produced no further benefit.

Figures

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Figure 1. A. Total cholesterol levels. B. High-density lipoprotein (HDL) cholesterol levels. C. Low-density lipoprotein (LDL) cholesterol levels. D. Triglyceride levels. E. Apolipoprotein B levels. F. Lipoprotein(a) levels. Data given for the treatment group are the average effects at each measurement. Thus, the treatment curves show the effect of the stepped-care program during the course of therapy. Thin line = control group; thick line = treatment group.
Average changes in plasma lipid levels over time.
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Figure 2. Nicotinic acid. Cholestyramine. Gemfibrozil. Horizontal bars represent the 95% Cls. Numbers given in boxes are numbers of patients who received the medication. HDL = high-density lipoprotein; LDL = low-density lipoprotein.
The incremental effect of each drug added in the sequence specified by the stepped-care algorithm. Top.Middle.Bottom.
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