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Efficacy and Safety of Ezetimibe Co-Administered With Simvastatin Compared With Atorvastatin in Adults With Hypercholesterolemia

Background: Current therapeutic guidelines for hypercholesterolemia recommend statin drugs or combination products of statins and other lipid lowering therapies such as ezetimibe, niacin, and cholestipol to decrease cholesterol levels and lower the risk of heart attack, stroke, and atherosclerotic heart disease in patients at risk. Medications with different mechanisms of action such as inhibiting absorption with ezetimibe and blocking the biosynthesis of cholesterol with a statin could have a proposed benefit of decreasing cholesterol levels.

Objective: The purpose of this study was to evaluate the efficacy and safety of the combination of simvastatin and ezetimibe compared to atorvastatin monotherapy in treating patients with hypercholesterolemia.

Methods: This was a multi-center, active-controlled, double-blinded study. Patients were included over the age of 18 with an LDL cholesterol level at or above the drug treatment threshold established by the National Cholesterol Education Program Adult Treatment Panel III guidelines bases on the patients LDL levels and associated risk factors. There was no exclusion criteria stated, although patients could drop out of the study at any time. The study used a modified intention to treat analysis for all of the subjects with valid baseline and at least 1 on treatment measurement. 788 Patients were centrally stratified based on their LDL cholesterol level to receive 1 of 3 treatments in a 1:1:1 ratio; atorvastatin 10mg monotherapy, ezetimibe plus simvastatin 10mg/10mg, ezetimibe plus simvastatin 10mg/20mg. Each of the treatment groups was titrated every 4 weeks of this 24-week study to a maximum of 80 mg atorvastatin or 10/80 of ezetimibe plus simvastatin. The primary efficacy measure was the mean percent change in LDL cholesterol from baseline to the end of the initial 6-week treatment period. Secondary measures were percent change in LDL levels from baseline to the ends of the second and fourth (final) 6-week treatment period, and the percent change in high-density lipoprotein (HDL) cholesterol from baseline to the end of the final 6-week treatment period. The safety measures consisted of the incidence of any clinical or laboratory adverse event, serious adverse event, and drug-related events. The power of the study was 90% to detect a 5% difference in mean percent change from baseline in LDL after initial 6-week treatment period. The power of the study was 86% to detect a 3.5% treatment difference in mean percent change from baseline in HDL cholesterol.

Results: Of 788 study subjects, 83% of the patients finished the study with roughly 28.5% of subjects in the atorvastain treatment group and 27.5% in simvastatin & ezetimibe treatment groups. For the primary outcome, the mean decrease in LDL at the end of the 1st treatment period was 46.1% for the 10/10mg combination group and 37.2% for the atorvastatin group with a difference of –8.9% (95% CI –11.1 to –6.7, p< 0.001). The 10/20mg combination groups mean decrease in LDL was 50.3% with a difference of –13.1% (95% CI –15.2 to –10.9) p < 0.001) compared to the atorvastatin group. At the end of treatment period 4, mean HDL levels increases by 12.3% in the combination groups and 6.5% in the atorvastatin group with a difference of 5.9% (95% CI 3.5 to 8.2, p< 0.001). Overall, when averaged across the entire dose range, the mean % decrease in LDL from baseline was 52.4% for the combination group and 45.1% for the atorvastatin group resulting in a difference of -7.3%, (95% CI -9.3 to -5.3, p < 0.001). Other lipid parameters except for triglycerides also significantly improved in the combination groups compared to the atorvastatin group. There was no significant difference in changes in triglycerides between the groups. There were no significant differences in the safety parameters observed between the three treatment groups. The authors concluded that combination therapy of simvastatin and ezetimibe shows greater efficacy and similar safety than that of mono-therapy with atorvastatin across a vast majority of outcome measures.

Strengths: This study was a fairly large study that was done in multiple centers. This study also used guidelines that have already been established for the inclusion criteria of their study population. This study also ensured that the three separate study groups were very similar in baseline characteristics and laboratory values.

Weaknesses: The study did not clearly define the pre-washout period of other medications the subjects could have been taking. This study did also not take into account the lifestyles, weights, or co-morbid disease states that these subjects could have had. This study was sponsored by Merck, which could result in bias. The measure of variability used was standard error of the mean, which makes the variability of the results appear smaller than the standard measure of variability of standard deviation. The study did not mention if adverse effects based on the discretion of the investigators was standardized and followed predetermined criteria.

Conclusion: The results of this study show that for many outcome parameters, the combination therapy did prove to be statistically significant in lipid lowering effects. When looking at the data to see the relevance of being clinically significant, it may not be clinically significant to see a LDL cholesterol difference of only 3.5%. Due to the weaknesses of the study, it is hard to conclude that by just looking at the statistics, the combination therapy is superior. The safety profile did prove to be as good when compared in combination as opposed to mono-therapy. Overall, more studies need to be done, especially with possible head to head studies, comparing the efficacies of other combination therapies.

Ballantyne CM, Blazing MA, King TR, Brady WE, Palisano J. Efficacy and Safety of Ezetimibe Co-Administered With Simvastatin Compared With Atorvastatin in Adults With Hypercholesterolemia. The American Journal of Cardiology. Jun 2004; (93), p1487-94.

Chanda Saucerman, Pharm D. Candidate