Note from the National Guideline Clearinghouse (NGC): The National Institute for Health and Clinical Excellence (NICE) commissioned an independent academic centre to perform a systematic literature review on the technology considered in this appraisal and prepare an assessment report. The assessment report for this technology appraisal was prepared by the University of Sheffield School of Health and Related Research (ScHARR) (see the "Availability of Companion Documents" field).
Clinical Effectiveness
Identification of Studies
Sources Searched
Eleven electronic databases were searched providing coverage of the biomedical and grey literature and current research. The publications lists and current research registers of seven health services research related organisations were consulted via the World Wide Web (WWW). Keyword searching of the WWW was undertaken using the Google search engine. The submissions of evidence to NICE by sponsors were hand-searched as well as references of retrieved papers. A list of the sources searched is provided in Appendix 1 of the Assessment Report (see the "Availability of Companion Documents" field).
Keyword Strategies
Sensitive keyword strategies using free-text and, where available, thesaurus terms were developed to search the electronic databases. Synonyms relating to the intervention (e.g., ezetimibe, ezetrol, zetia, vytorin, inegy and Chemical Abstracts Service [CAS] Registry number or Enzyme Commission [EC] number: 163222-33-1) were combined with synonyms relating to the condition (e.g., hypercholesterolemia, hypercholesterolaemia). Keyword strategies for all electronic databases are provided in Appendix 1 of the Assessment Report (see the "Availability of Companion Documents" field).
Search Restrictions
A methodological filter aimed at restricting search results to randomised controlled trials (RCTs) was used in the searches of Medline and Embase. The search of pre-MEDLINE was restricted to the last 180 days to capture recent and unindexed Medline references. Date limits were not used on any other database. Language restrictions were not used on any database. All searches were undertaken between April to June 2006.
Inclusion and Exclusion Criteria
Two reviewers independently screened all titles and abstracts. Full paper manuscripts of any titles/abstracts that were considered relevant by either reviewer were obtained where possible. The relevance of each paper was assessed according to the criteria set out below. Trial flow chart is presented in Appendix 2 of the Assessment Report (see the "Availability of Companion Documents" field). Any disagreements were resolved by discussion.
Population
Adult patients (defined as >18 years of age) with primary (heterozygous familial and non-familial) hypercholesterolaemia were included in the review whereas adults with homozygous familial hypercholesterolaemia or homozygous sitosterolaemia were excluded.
Interventions
- For patients whose condition is not adequately controlled with a statin alone the intervention was ezetimibe (Ezetrol®, Merck Sharp and Dohme Limited/Schering-Plough Limited [MSD/SP]) co-administered with a statin or a fixed dose combination tablet containing ezetimibe and simvastatin (Inegy®, MSD/SP)
- For patients in whom a statin is considered inappropriate, or is not tolerated, the intervention is ezetimibe monotherapy (Ezetrol®, MSD/SP)
Comparators
The comparator treatment included the following:
- For patients whose condition is not adequately controlled with a statin alone the relevant comparator was optimal statin monotherapy or treatment with a statin in combination with other lipid regulating drugs (e.g., nicotinic acid, bile acid resins, or fibrates).
- For patients in whom a statin is considered inappropriate, or is not tolerated, the relevant comparator was an alternative lipid regulating agent (e.g., nicotinic acid, bile acid resins, or fibrates) or no treatment.
Outcomes
Data on the following outcomes were included: survival, fatal and non-fatal cardiovascular events, adverse effects of treatment and health-related quality of life (HRQoL). Where information on clinical end-points is unavailable, consideration were given to surrogate endpoints, such as low-density lipoprotein-cholesterol (LDL-c), total cholesterol (Total-c), and high-density lipoprotein-cholesterol (HDL-c).
Study Design
Phase III randomised controlled trials of at least 12 weeks duration were included on the ground that trials of less than 12 weeks duration are unlikely to inform on survival, cardiovascular disease (CVD) events, adverse events, or HRQoL due to lipid lowering treatments. In the absence of clinical endpoint data from trials, the Assessment Group identified and included data from RCTs of sufficient duration (i.e. at least 12 weeks) for surrogate endpoints. This decision was then validated by clinical experts' opinion and meta-analysis.
Reviews of primary studies were not included in the analysis, but retained for discussion and identification of additional trials. The following publication types were excluded from the review: non-randomised studies (except for adverse events); animal models; preclinical and biological studies; narrative reviews, editorials, opinions; non-English language papers and reports where insufficient methodological details are reported to allow critical appraisal of the study quality.
Handling of the Company Submission
Company submissions were screened for data additional to that identified in published studies retrieved from the literature search.
Cost-Effectiveness
Systematic Review of Existing Cost Effectiveness Evidence
Search Strategy
Studies were identified through searches of the following databases: Medline, Embase, Cochrane Library, National Health Service Economic Evaluation Database (NHSEED), NHS Centre for Review and Dissemination Database of Abstracts Reviews of Effectiveness (NSH CRD DARE), NHS CRD Health Technology Assessment (NHC CRD HTA), CINAHL, OHE HEED and Web of Science. Publications lists and current research registers of HTA organisations were consulted via the WWW. Hand-searching and citation searches of included studies and of the company submission were undertaken. All searches were undertaken between April and June 2006. A list of the sources consulted and the keyword strategies used are given in Appendix 22 of the Assessment Report (see the "Availability of Companion Documents" field).
Inclusion Criteria
- Cost effectiveness/cost-utility analyses
- Ezetimibe monotherapy
- Ezetimibe co-administered with statins
- The benefits in terms of life-years saved (LYS) or quality adjusted life-years (QALYs)
- Adult population (aged 18 years and over)
Exclusion Criteria
- Studies that do not report results in terms of incremental cost utility ratios (ICERs)