• R Ara, I Tumur, A Pandor, A Duenas, R Williams, A Wilkinson, S Paisley, and J Chilcott.
• School of Health and Related Research (ScHARR), University of Sheffield, UK.
• Health Technol Assess. 2008 May 1;12(21):iii, xi-xiii, 1-212.

ObjectivesTo review the clinical and cost-effectiveness of ezetimibe as a combination therapy or monotherapy for the treatment of primary hypercholesterolaemia in the UK.Data SourcesTwelve electronic databases were searched from inception to June 2006. Searches were supplemented by hand-searching relevant articles, sponsor and other submissions of evidence to the National Institute of Health and Clinical Excellence and conference proceedings.Review MethodsA systematic review and meta-analysis (where appropriate) of the clinical efficacy evidence was undertaken following recommended guidelines. A Markov model was developed to explore the costs and health outcomes associated with ezetimibe treatment.ResultsNo published clinical outcome trials (> 12 weeks) were identified. In the absence of clinical end-point data from trials, 13 (of which five were multi-arm) phase III multi-centre randomised controlled trials (RCTs) (of varying methodological quality) of short-term duration (12-48 weeks) with surrogate end-point data were included. For patients not adequately controlled with a statin alone, a meta-analysis of six studies showed that a fixed-dose combination of ezetimibe and statin treatment was associated with a statistically significant reduction in low-density lipoprotein cholesterol (LDL-c) and total cholesterol (Total-c) compared with statin alone (p < 0.00001). Four studies (not eligible for meta-analysis) that titrated (either forced or stepwise) the statin doses to LDL-c targets generally showed that the co-administration of ezetimibe and statin was significantly more effective in reducing plasma LDL-c concentrations than statin monotherapy (p < 0.05 for all studies). For patients where a statin is not considered appropriate, a meta-analysis of seven studies demonstrated that ezetimibe monotherapy significantly reduced LDL-c levels compared with placebo (p < 0.00001). There were no statistically significant differences in LDL-c-lowering effects across different subgroups. Ezetimibe therapy (either in combination with a statin or monotherapy) appeared to be well tolerated compared to statin monotherapy or placebo, respectively. No ezetimibe studies reported data on health-related quality of life (HRQoL). There was a wide range in the economic results depending on the treatment strategies evaluated. When comparing ezetimibe monotherapy with no treatment in individuals with baseline LDL-c values of 3.0-4.0 mmol/l, the results range from 21,000 pounds to 50,000 pounds per quality-adjusted life-year (QALY). Results for individuals with baseline LDL-c values over 5.0 mmol/l are below 30,000 pounds per QALY. When comparing the costs and benefits of adding ezetimibe to ongoing statin treatment compared with maintaining statin treatment at the current dose, the majority of results are above values generally considered to be cost-effective (range 19,000 pounds to 48,000 pounds per QALY). Based on the evidence available, when comparing the costs and benefits associated with adding ezetimibe to ongoing statin treatment compared with a switch to a more potent statin, the results are governed by the difference in the cost of the treatment regimens compared and results range from 1500 pounds to 116,000 pounds per QALY.ConclusionsThe short-term RCT clinical evidence demonstrated that ezetimibe was effective in reducing LDL-c when administered as monotherapy or in combination with a statin. However, when used as a monotherapy, ezetimibe is less effective than statins in lowering LDL-c. Given the limitations in the effectiveness data, there is great uncertainty in the economic results. These suggest that ezetimibe could be a cost-effective treatment for individuals with high baseline LDL-c values, for patients with diabetes and for individuals with heterozygous familial hypercholesterolaemia. Long-term clinical outcome studies are needed to allow more precise cost-effectiveness estimates to be calculated.

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