Gagné Study Design¹: An 8-week, double-blind study in which 769 patients with primary hypercholesterolemia, known CHD, or multiple CV risk factors—and already receiving statin monotherapy—were randomized to receive either ZETIA or placebo in addition to their ongoing, stable statin dose. Total patients on statins: atorvastatin 40% (weighted mean baseline dose 34 mg); simvastatin 31% (37 mg); and others 29% combined (including pravastatin 29 mg, fluvastatin 35 mg, and lovastatin 26 mg).⁸

Mean baseline LDL-C on statin monotherapy: placebo + statin=139 mg/dL; ZETIA + statin=138 mg/dL.

Mean LDL-C after adding ZETIA or placebo: placebo + statin=133 mg/dL; ZETIA + statin=102 mg/dL.

Mean additional LDL-C reduction when ZETIA was added to any available statin was 25% vs 4% with adding placebo, P<0.001.

Stein Study Design²: A 14-week, double-blind study (N=621) of patients with heterozygous familial hypercholesterolemia, coronary heart disease, or ≥2 cardiovascular risk factors and LDL-C ≥130 mg/dL on atorvastatin 10 mg. This study compared LDL-C efficacy with response-based titration of atorvastatin 10 mg to 80 mg vs adding ZETIA followed by response-based titration of atorvastatin 10 mg to 40 mg. Mean treated baselines were 186 mg/dL (ZETIA + atorvastatin 10 mg) and 187 mg/dL (atorvastatin monotherapy). Percent changes in LDL-C correspond to mean additional LDL-C reductions of 43 mg/dL with ZETIA + atorvastatin 10 mg and 16 mg/dL with atorvastatin titrated from 10 mg to 20 mg. Evaluating the primary end point over the 14-week study duration, 22% reached protocol-specified LDL-C goal (≤100 mg/dL) with ZETIA + titrated atorvastatin (up to 40 mg) vs 7% with titrated atorvastatin monotherapy (up to 80 mg).

Mean additional LDL-C reduction when ZETIA was added to atorvastatin 10 mg was 23% vs 9% with titration to atorvastatin 20 mg, P<0.01.

EASE Study Design³: A 6-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group, community-based study (N=3,030) evaluating the efficacy of ezetimibe in reducing LDL-C levels as well as in NCEP ATP III goal attainment. Mean baseline LDL-C was 129 mg/dL. Patients were randomized 2:1 to receive either 10 mg/day of ezetimibe or placebo plus their current statin therapy and dose.

Mean additional LDL-C reduction when ZETIA was added to any available statin at time of study was 26% vs 3% with adding placebo, P<0.001.

Adding ZETIA in patients on pravastatin (n=412, mean baseline LDL-C=132 mg/dL) resulted in a 23% reduction in LDL-C vs a 1% reduction with adding placebo, P<0.001. Adding ZETIA in patients on other statins (lovastatin or fluvastatin, mean baseline LDL-C=132 mg/dL, n=192) resulted in a 24% reduction in LDL-C vs a 1% reduction with adding placebo, P<0.001.^3,4

Mean additional LDL-C reduction when ZETIA was added to atorvastatin was 27% vs 4% with adding placebo, P<0.001.

Mean additional LDL-C reduction when ZETIA was added to simvastatin was 27% vs 3% with adding placebo, P<0.001.

TEMPO Study Design⁵: A 6-week, double-blind, randomized, parallel-group study (N=184) in patients on atorvastatin 20 mg at moderately high risk for CHD who have not reached goal on atorvastatin 20 mg alone. This study compared attainment of NCEP ATP III LDL-C goal of <100 mg/dL with titrating atorvastatin 20 mg to 40 mg vs adding ZETIA to atorvastatin 20 mg. Mean baseline LDL-C was 120 mg/dL for the group receiving ZETIA and 118 mg/dL for the group in which atorvastatin was titrated.

Mean additional LDL-C reduction when ZETIA was added to atorvastatin 20 mg was 31% vs 11% with titration to atorvastatin 40 mg, P<0.001.

EZ-PATH Study Design⁶: A 6-week, double-blind, randomized, parallel-group study (N=556) in patients on atorvastatin 40 mg at high risk for CHD who have not reached goal on atorvastatin 40 mg alone. This study compared attainment of NCEP ATP III LDL-C goal of <70 mg/dL with titrating atorvastatin 40 mg to 80 mg vs adding ZETIA to atorvastatin 40 mg. Mean baseline LDL-C was 89 mg/dL for the group receiving ZETIA and 90 mg/dL for the group in which atorvastatin was titrated. Mean additional LDL-C reduction when ZETIA was added to atorvastatin 40 mg was 27% vs 11% with titration to atorvastatin 80 mg, P<0.001.

ZETELD Study Design⁷: A 12-week, double-blind, multicenter, randomized, parallel-group study (N=1,025) in patients aged ≥65 years at high risk of CHD, with or without atherosclerotic vascular disease, who have not reached LDL-C <70 mg/dL or <100 mg/dL, respectively, on atorvastatin 10 mg/day. The primary end point was the percent change from baseline in LDL-C levels after 6 weeks of treatment. Mean baseline LDL-C was 103 mg/dL for the group receiving ZETIA + atorvastatin 10 mg. Mean baseline LDL-C was 101 mg/dL for the group receiving atorvastatin 20 mg. Additional mean LDL-C reduction when ZETIA was added to atorvastatin 10 mg was 27% vs 13% with titration from atorvastatin 10 mg to atorvastatin 20 mg; P<0.001.

References:
1. Gagné C, Bays HE, Weiss SR, et al. Efficacy and safety of ezetimibe added to ongoing statin therapy for treatment of patients with primary hypercholesterolemia. Am J Cardiol. 2002;90:1084–1091.

2. Stein E, Stender S, Mata P, et al. Achieving lipoprotein goals in patients at high risk with severe hypercholesterolemia: efficacy and safety of ezetimibe co-administered with atorvastatin. Am Heart J. 2004;148:447–455.

3. Pearson TA, Denke MA, McBride PE, et al. A community-based, randomized trial of ezetimibe added to statin therapy to attain NCEP ATP III goals for LDL cholesterol in hypercholesterolemic patients: the Ezetimibe Add-On to Statin for Effectiveness (EASE) trial. Mayo Clin Proc. 2005;80:587–595.

4. Data available on request from Merck & Co., Inc., Professional Services-DAP, WP1-27, PO Box 4, West Point, PA 19486-0004. Please specify information package 20502459(5)-ZET.

5. Conard SE, Bays HE, Leiter LA, et al. Efficacy and safety of ezetimibe added on to atorvastatin (20 mg) versus uptitration of atorvastatin (to 40 mg) in hypercholesterolemic patients at moderately high risk for coronary heart disease. Am J Cardiol. 2008;102:1489–1494.

6. Leiter LA, Bays H, Conard S, et al. Efficacy and safety of ezetimibe added on to atorvastatin (40 mg) compared with uptitration of atorvastatin (to 80 mg) in hypercholesterolemic patients at high risk of coronary heart disease. Am J Cardiol. 2008;102:1495–1501.

7. Zieve F, Wenger NK, Ben-Yehuda O, et al. Safety and efficacy of ezetimibe added to atorvastatin versus up titration of atorvastatin to 40 mg in patients ≥65 years of age (from the ZETia in the ELDerly [ZETELD] Study). Am J Cardiol. 2010;105:656–663.

8. Data available on request from Merck & Co., Inc., Professional Services-DAP, WP1-27, PO Box 4, West Point, PA 19486-0004. Please specify information package 20350055(4)-ZET.