Executive Summary of HTA journal title
Health Technol Assess 2008;12(21):1–232
Ezetimibe for the treatment of hypercholesterolaemia: a systematic review and economic evaluation
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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
* Corresponding author
To review the evidence for the clinical and cost-effectiveness of ezetimibe (in its licensed indication) as combination therapy or monotherapy for the treatment of primary (heterozygous familial and non-familial) hypercholesterolaemia in the UK.
In all, twelve electronic bibliographic databases covering the biomedical, scientific, and grey literature were searched from inception to June 2006 (supplemented by contact with experts in the field). Data relating to study design, baseline patient characteristics, clinical or surrogate outcomes, and adverse events were abstracted and methodological quality was assessed. In addition, results of eligible randomised controlled trials (RCTs) were statistically synthesised (meta-analysed) where appropriate.
A new Markov model was developed, to assess the costs and health outcomes associated with ezetimibe treatment. Several treatment regimens were explored including: ezetimibe monotherapy versus no treatment for individuals in whom statin therapy is contraindicated or those who do not tolerate statins; ezetimibe plus a statin compared with the same statin; ezetimibe plus a statin compared with a switch to a more potent statin. The model utilised the established relationship linking changes in low-density lipoprotein cholesterol (LDL-c) and cardiovascular events to estimate the cardiovascular events avoided through lipid lowering therapies.
Clinical effectiveness results
No published clinical outcome trials (>12 weeks) examining the cardiovascular benefit of ezetimibe were identified. In the absence of clinical end-point data from trials, 13 (of which five were multi-arm) Phase III multi-centre RCTs (of varying methodological quality) of short-term duration (12–48 weeks) with surrogate end-point data [such as LDL-c and total cholesterol (Total-c)] were included. Although all the included studies involved patients with primary hypercholesterolaemia (mean baseline LDL-c levels ranging from 3.36 to 6.50 mmol/l), the populations were not fully representative of the population specified in the inclusion criteria, that is, individuals whose lipids were not adequately controlled with current statin treatment or those who are intolerant of statins. The clinical evidence is derived from a population that required a washout or discontinuation of all ongoing lipid regulating drug therapy prior to randomisation and initiation of study treatments.
For patients whose condition is not adequately controlled with a statin alone
A meta-analysis of six studies showed that the combination of ezetimibe and statin treatment was associated with a statistically significant reduction in LDL-c and Total-c compared with statin alone (p < 0.00001). No RCTs were identified that compared ezetimibe plus statin with statin plus other lipid lowering therapy (nicotinic acid, bile acid resins or fibrates).
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). No RCTs were identified that compared ezetimibe plus statin with statin plus bile acid resins or fibrates. One study reported that low–moderate doses of atorvastatin/rosuvastatin plus niacin achieved similar marked LDL-c reductions compared with the highest doses of rosuvastatin monotherapy or ezetimibe/simvastatin.
For patients in whom a statin is considered inappropriate, or is not tolerated
A meta-analysis of seven studies demonstrated that ezetimibe monotherapy significantly reduced LDL-c levels compared with placebo (p < 0.00001). This effect was generally consistent across all trials. No RCTs were identified that directly compared ezetimibe with other lipid-regulating drug (nicotinic acid, bile acid resins or fibrates) therapy.
There were no statistically significant differences in LDL-c-lowering effects across different subgroups such as people with or without existing coronary heart disease (CHD) or other vascular disease, people with or without diabetes, different ethnic groups and patients with or without heterozygous familial hypercholesterolaemia (HeFH).
Safety and tolerability
Ezetimibe therapy (either in combination with a statin or monotherapy) appeared to be well tolerated compared to statin monotherapy or placebo, respectively. The low frequency of adverse events may be attributed to the relatively short periods of the included studies (the majority were 12 weeks). Long-term adverse events are unknown.
Quality of life
No ezetimibe studies reported data on health related quality of life (HRQoL).
Two full studies and one abstract were identified in the systematic review for economic evaluations. The studies described country-specific adaptations of a core model. The results ranged from £7700 per life year when comparing ezetimibe co-administered with current statin with current statin in adults with a history of CHD in Germany, to £50,700 per life year when comparing ezetimibe co-administered with current statin treatment with current statin treatment titrated by one dose for adults with diabetes and no history of CHD in Spain. The abstract, which provided insufficient detail for review, reported results to be £8000 per QALY (Quality Adjusted Life Year) for patients aged 65 years with a history of CVD when comparing ezetimibe plus current statin with titration of current statin treatment in Scotland.
Two cost-effectiveness models were presented by the industry submission. The first (referred to as the Cook model) is an adaptation of the model used in the studies identified in the literature search. The second (referred to as the Basic model) was built and submitted to lend credence to the results generated by the more complex model. The Cook model uses the Framingham equations to predict annual changes in coronary risk based on changes in Total-c and HDL-c. The Basic model utilises published evidence on the link between chemically induced reductions in LDL-c and reductions in CV events. Effectiveness rates are derived from meta-analyses of published data. Several treatment regimens are used and the base case evaluates the cost-effectiveness of ezetimibe plus current weighted statin therapy compared with current weighted statin therapy titrated by one dose. The results range from £8800 per QALY for South Asian males aged 60 years at high risk of a CHD event to £122,000 per QALY for females aged 80 years with no history of CVD. However, several key errors were identified and the results are not considered to be robust.
ScHARR economic evaluation
There is a wide range in the results depending on the treatment strategies compared. 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 to £50,000 per QALY. Results for individuals with baseline LDL-c values over 5.0 mmol/l are below £30,000 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 to £48,000 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 £1,500 to £116,000 per QALY.
Limitations of the cost-effectiveness estimates
There are several major limitations associated with the economic evaluation:
- A lack of robust long-term data on clinical effectiveness evidence derived from patients who fail to achieve lipid goals on statin treatment or patients who are intolerant of statins.
- The need to translate changes in surrogate outcomes to reductions in cardiovascular events and the need to extrapolate well beyond the RCT evidence underpin all analyses and increase the uncertainty in the results generated.
- It is uncertain if the proportional reduction in event rates per mmol/L in LDL-c derived from patients receiving statin treatment is generalisable to patients receiving either ezetimibe monotherapy or ezetimibe in combination with a statin.
- The lack of direct evidence of ezetimibe plus a low-dose statin versus a more potent-dose statin increases the uncertainty associated with the effectiveness of the treatments.
- Although the short-term safety profile appears to be good, long-term adverse event data associated with ezetimibe treatment are not available.
The 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, the ability of ezetimibe to lower LDL-c is less effective than that of statins. Given the lack of detailed effectiveness data, there is a great deal of uncertainty in the cost-effectiveness of ezetimibe. The results suggest that depending on the comparator, ezetimibe could be a cost-effective treatment for individuals with high baseline LDL-c values, for patients with diabetes and for individuals with HeFH. Further research is urgently required to allow more precise estimates of cost-effectiveness to be calculated.
Generalisability of findings
There is a major concern regarding the generalisability of the results of the short-term RCT effectiveness evidence into routine clinical practice. The current evaluation explores the costs and benefits associated with adding ezetimibe treatment to ongoing treatment for individuals not achieving adequate lipid control. Due to inclusion and exclusion criteria and the washout periods, the populations in the RCTs may not be representative of the target population.
Recommendations for future research
Further research is required in the following areas:
- Long-term clinical outcome trials involving patients who are intolerant of statins, patients in whom statins are contraindicated and patients who fail to achieve lipid control on statin monotherapy. Studies exploring the long-term effectiveness and safety profile of ezetimibe using combinations of lipid-lowering treatments are also required.
- Lifetime adherence to combination therapies in the relatively healthy younger and asymptomatic patients with no history of CVD.
- To establish if reductions in lipids to predetermined targets provide additional reductions in cardiovascular events.
- Research on short- and long-term changes in HRQoL associated with primary or subsequent cardiovascular events is also required to reduce uncertainty in cost-effectiveness estimates for cardiovascular interventions.
Ara R, Tumur I, Pandor A, Duenas A, Williams R, Wilkinson A, et al. Ezetimibe for the treatment of hypercholesterolaemia: a systematic review and economic evaluation. Health Technol Assess 2008;12(21).
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The research reported in this issue of the journal was commissioned and funded by the HTA Programme on behalf of NICE as project number 05/22/01. The protocol was agreed in June 2006. The assessment report began editorial review in December 2006 and was accepted for publication in January 2008. The authors have been wholly responsible for all data collection, analysis and interpretation, and for writing up their work. The HTA editors and publisher have tried to ensure the accuracy of the authors' report and would like to thank the referees for their constructive comments on the draft document. However, they do not accept liability for damages or losses arising from material published in this report.
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