Efficacy and Safety of Ezetimibe Co- Administered With Simvastatin Compared With Atorvastatin in Adults With Hypercholesterolemia Christie M. Ballantyne, MD, Michael A. Blazing, MD, Thomas R. King, MPH, William E. Brady, MS, and Joanne Palmisano, MD This study compared the efficacy and safety of co-admin- istered ezetimibe  simvastatin with atorvastatin mono- therapy in adults with hypercholesterolemia. Seven hun- dred eighty-eight patients were randomized 1:1:1 to 3 treatment groups; each group was force-titrated over four 6-week treatment periods: (1) 10 mg of atorvastatin as the initial dose was titrated to 20, 40, and 80 mg; (2) co- administration of 10 mg of ezetimibe and 10 mg of sim- vastatin (10/10 mg) was titrated to 10/20, 10/40, and 10/80 mg of ezetimibe  simvastatin; and (3) co-admin- istration of 10/20 mg of ezetimibe  simvastatin was titrated to 10/40 mg (for 2 treatment periods) and 10/80 mg of ezetimibe  simvastatin. Key efficacy measures included percent changes in low-density lipoprotein cho- lesterol (LDL) and high-density lipoprotein cholesterol (HDL) from baseline to the ends of (1) treatment periods 1 and 2 (for LDL cholesterol) comparing co-administration of 10/20 mg and 10/10 mg of ezetimibe  simvastatin with 10 mg of atorvastatin and (2) treatment period 4 (for LDL choles- terol and HDL cholesterol) comparing co-administration of 10/80 mg of ezetimibe  simvastatin with 80 mg of atorvastatin. Baseline LDL and HDL cholesterol levels were comparable between treatment groups. At the end of treat- ment period 1, the mean decrease of LDL cholesterol was significantly (p <0.001) greater for co-administration of 10/10 mg and 10/20 mg of ezetimibe  simvastatin than for 10 mg of atorvastatin. At the end of treatment period 4 and after comparing maximum doses, co-administration of 10/80 mg of ezetimibe  simvastatin was superior to 80 mg of atorvastatin in the percent LDL cholesterol decrease (59.4% vs 52.5%, p <0.001) and HDL cholesterol in- crease (12.3% vs 6.5%; p <0.001). All treatments were well tolerated. Thus, a greater LDL cholesterol decrease and HDL cholesterol increase were attained by treating patients with co-administration of ezetimibe and simvastatin than with atorvastatin. 2004 by Excerpta Medica, Inc. (Am J Cardiol 2004;93:1487–1494) T he present study compared the efficacy of decreas- ing low-density lipoprotein (LDL) cholesterol with statin monotherapy with the co-administration of ezetimibe and simvastatin, a treatment strategy that decreases cholesterol through dual inhibition of intes- tinal cholesterol absorption and cholesterol biosynthe- sis. A single tablet containing ezetimibe in combina- tion with simvastatin is currently under development. Atorvastatin was chosen as the comparator because it is the most widely prescribed statin in the United States and thus is an appropriate benchmark for statin monotherapy with maximal titration. METHODS Study design: This was a 28-week (4-week placebo/ diet run-in period and 24-week active treatment period) multicenter, active-controlled, double-blind study. The protocol was approved by appropriate institutional re- view boards, and all patients provided written informed consent before initiation of any study procedure. Patients discontinued fibrate therapy 9 weeks before and all other lipid-lowering therapies 7 weeks before the start of the study. After the placebo/diet run-in period, eligible pa- tients were randomized to 1 of 3 treatment groups in a 1:1:1 allocation. Force titration occurred over a four 6-week treatment periods as follows for each of the 3 treatment groups: (1) 10 mg of atorvastatin as the initial dose was titrated to 20, 40, and 80 mg; (2) co-adminis- tration of 10/10 mg of ezetimibe + simvastatin was titrated to 10/20, 10/40, and 10/80 mg; and (3) co- administration of 10/20 mg of ezetimibe + simvastatin was titrated to 10/40 mg (for 2 treatment periods) and to 10/80 mg in the last treatment period (Table 1). To decrease the number of daily tablets, a partial-blinding scheme was used. Patients took 4 tablets (1 active and 3 placebo) each evening during the placebo/run-in phase and periods 1 and 2 and 3 tablets (1 active and 2 placebo) during periods 3 and 4. The mix of placebo tablets was changed to maintain the blind. Randomization was cen- trally stratified by baseline LDL cholesterol level (130 and 160 mg/dl, 160 and 190 mg/dl, and 190 mg/dl) to provide balance across treatment groups. Study population: Patients 18 years with a LDL cholesterol level at or above drug treatment threshold established by National Cholesterol Education Pro- From the Baylor College of Medicine, Houston, Texas; Duke University Medical Center, Durham, North Carolina; and Merck & Co., Inc., West Point, Pennsylvania. This study was sponsored by Merck/Scher- ing Plough Pharmaceuticals, North Wales, Pennsylvania. Manuscript received December 18, 2003; revised manuscript received and ac- cepted February 24, 2004. Address for reprints: Joanne Palmisano, MD, Merck & Co., Inc., HM-218, PO Box 4, West Point, Pennsylvania 19486. E-mail: joanne_palmisano@merck.com. 1487 ©2004 by Excerpta Medica, Inc. All rights reserved. 0002-9149/04/$–see front matter The American Journal of Cardiology Vol. 93 June 15, 2004 doi:10.1016/j.amjcard.2004.02.060