Simvastatin with or without Ezetimibe in Familial Hypercholesterolemia

Background: Patients diagnosed with familial hypercholesterolemia are at an increased risk of premature coronary artery disease and display an increased rate of progression of intima-media thickness (IMT). The drug therapy studied is frequently prescribed in the treatment of hypercholesterolemia and in this patient population.

Objective: The objective of this study was to determine whether the daily administration of 10 mg of ezetimibe in combination with 80 mg of simvastatin could reduce the progression of atherosclerosis in patients with familial hypercholesterolemia.

Methods: This study was a prospective, randomized, double-blind clinical trial. To be included in the study, patients were required to be between the ages of 30 and 75 years with familial hypercholesterolemia with a LDL cholesterol > 210 mg/dL after a placebo run-in period. Patients were excluded from the trial if there was a presence of high-grade stenosis or occlusion of the carotid artery, a history of carotid endarterectomy or carotid stenting, homozygous familial hypercholesterolemia, NYHA class III or IV congestive heart failure, cardiac arrhythmia, angina pectoris, or recent cardiovascular events. Patients were enrolled from 18 ambulatory care centers in the eight countries between 2002 and 2006. A total of 720 patients were randomized to one of two groups: 357 patients were assigned to receive simvastatin 80 mg plus ezetimibe 10 mg and 363 were assigned to receive simvastatin 80 mg plus placebo. Each group was treated for a period of 24 months.

Results: The results for the change from baseline in the mean IMT of the carotid artery were 0.0058±0.0037 mm in the simvastatin group and 0.011±0.0038 mm in the combined-therapy group, with a difference of 0.0053 that was not statistically significant (P=0.29). The results of the longitudinal, repeated measures model were in line with the primary outcome measure. The change in the average IMT over time did not differ significantly between the two groups (P=0.17). For the secondary outcome measures, regression in the mean carotid artery IMT was seen in 142 (44.4%) patients in the simvastatin-only group and 146 (45.3%) patients in the combined-therapy group (P=0.92), new plaque formation (new IMT <1.3 mm) was seen in 9 (2.8%) patients in the simvastatin-only group and in 15 (4.7%) patients in the combined-therapy group (P=0.20), no significant change was observed in the mean maximum carotid-artery IMT, an increase of 0.0103±0.0049 mm in the simvastatin-only group and 0.0175±0.0049 mm in the combined-therapy group (P=0.27), no significant changes were observed between study groups regarding mean measures of IMT of the common carotid artery (P=0.93), the carotid bulb (P=0.21) and the femoral artery (P=0.16), nor in the average of the mean values for IMT in the carotid and femoral arteries (P=0.15). The authors concluded that LDL reduction with the addition of ezetimibe to simvastatin did not reduce IMT of the carotid artery wall in patients with familial hypercholesterolemia.

Strengths: The use of a prospective, randomized, double-blind design conducted over a period of 24 months, using multi-center testing sites were strengths of this study. Hiring independent investigators to analyze sonographic imaging and data decreased both bias and variability. The use of an active control commonly used in this specific patient population was appropriate. A power of 90% for the primary outcome measure allowed for statistical significance and reduced the likelihood of a Type II error. Utilizing two statistical tests that analyzed data using the last observation carried forward or only observations strengthened the results by demonstrating there was no difference between those that completed the study and those that dropped out.  

Weaknesses: No power was reported for the secondary outcome measures. A vague compliance rate and measuring the change in IMT, as opposed to clinical endpoints, were weaknesses. Variance between subjects’ medication regimens (antihypertensive, glucose-lowering agents, etc), diet, and physical activity were not accounted for. Also, there is some question as to the duration of drug therapy with ezetimibe corresponding with changes in IMT and, ultimately, cardiovascular outcomes.

Conclusion: The lack of standardization throughout the study and the use of a rare, difficult to treat patient population limit wide-spread clinical applicability at this time. The results of the study’s findings do discourage use of ezetimibe in this patient population, but further research into the effects of ezetimibe and simvastatin in combination on morbidity, mortality, and cardiovascular events.

Kastelein JJ, Akdim F, Stroes ES, et al. Simvastatin with or without Ezetimibe n Familial Hypercholesterolemia. N eng J med. 2008;358(14):1431-1443.

Kate Priddy, Doctor of Pharmacy Candidate

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