Comparison of the lipid-modifying efficacy and safety profiles of ezetimibe coadministered with simvastatin in older versus younger patients with primary hypercholesterolemia: a post Hoc analysis of subpopulations from three pooled clinical trials

Theodore Feldman, Michael Davidson, Arvind Shah, Darbie Maccubbin, Alan Meehan, Michelle Zakson, Diane Tribble, Enrico Veltri, Yale Mitchel
Clinical Therapeutics 2006, 28 (6): 849-59

BACKGROUND: Despite the need for effective and well-tolerated lipid-lowering therapies for primary hypercholesterolemia in older patients, there is a relative paucity of published data on such treatments in this population.

OBJECTIVE: We conducted a post hoc analysis to examine the lipid-modifying efficacy and safety profile of simvastatin (SIMVA) monotherapy, and the coadministration of ezetimibe (EZE) and SIMVA (EZE/SIMVA) in older (ie, aged>or=65 years) versus younger (ie, aged<65 years) patients with primary hypercholesterolemia.

METHODS: We analyzed pooled data from 3 previously published, similarly designed, randomized, double-blind, placebo-controlled studies in patients with primary hypercholesterolemia. After a 6- to 8-week washout, a 4-week dietary stabilization period, and a 4-week placebo run-in period, patients with low-density lipoprotein cholesterol (LDL-C) of 145 to 250 mg/dL were randomized to EZE/SIMVA 10/10, 10/20, 10/40, or 10/80 mg; SIMVA 10, 20, 40, or 80 mg; EZE 10 mg; or placebo for 12 weeks. In this post hoc analysis, the percent change from baseline to week 12 in LDL-C, high-density lipoprotein cholesterol (HDL-C), non-HDL-C, apolipoprotein B (apo B), triglycerides (TG), and high-sensitivity C-reactive protein (hs-CRP) for EZE/SIMVA (pooled across doses) versus SIMVA alone (pooled across doses) was compared between older and younger patients with primary hypercholesterolemia. Tolerability was assessed by adverse event reports and laboratory and vital signs assessments throughout the study.

RESULTS: A total of 3083 patients aged 20 to 87 years were included in the 3 studies (2320 were aged<65 years and 763 were aged>or=65 years). Baseline lipid values and patient characteristics were similar among all treatment groups for patients aged<65 years versus those aged>or=65 years except that there was a higher percentage of females (62% vs 50%) and patients with hypertension (46% vs 29%) in the older versus younger subgroup (both, P<0.001). EZE/SIMVA was associated with greater improvements than SIMVA alone in LDL-C, non-HDL-C, apo B, TG, and hs-CRP (all, P<0.001); these effects did not appear to differ between the older and younger sub-groups (all, P=NS). Changes in HDL-C did not differ significantly between the EZE/SIMVA and SIMVA groups. More patients receiving EZE/SIMVA than SIMVA monotherapy achieved the target LDL-C level<100 mg/dL (P<0.001), regardless of age subgroup (77% vs 41% for patients aged<65 years and 85% vs 48% for patients aged>or=65 years). In the younger sub-group, the incidence of creatinine phosphokinase (CK) elevations>or=10x the upper limit of normal (ULN) was <I% in the placebo, SIMVA, and EZE/SIMVA groups and 0% in the EZE group; in the older subgroup, no CK elevations>or=10x ULN were reported. In younger patients, the incidence of consecutive alanine amino-transferase or aspartate aminotransferase levels>or=3x ULN was 0% for placebo and EZE, <1% for SIMVA, and 2% for EZE/SIMVA; in older patients, it was 1% for placebo and EZE, <1% for SIMVA, and 0% for EZE/SIMVA.

CONCLUSION: This post hoc analysis of pooled data from 3 previously published large clinical trials suggests that EZE/SIMVA was well tolerated and associated with improved lipid profiles in both older and younger patients with primary hypercholesterolemia.

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