Technology Assessment Report commissioned by the NHS R&D HTA Programme on behalf of the National Institute for Health and Clinical Excellence Reference No. 05/22 11th Final version: 5th June 2006 1. Title of the project: Ezetimibe for the treatment of hypercholesterolaemia 2. TAR team School of Health and Related Research (ScHARR) Technology Assessment Group, The University of Sheffield. Lead: Roberta Ara, Operational Research Analyst ScHARR, University of Sheffield, 30 Regent Court, Sheffield S1 4DA Tel: 0114 222 0788 Fax: 0114 272 4095 E-mail: [email protected] 3. Plain English Summary The UK population has one of the highest average serum cholesterol levels in the world,[1] with about 27% and 70% of people having a serum cholesterol level ≥ 6.5 mmol/L and ≥ 5.0 mmol/L, respectively.[2] High levels of cholesterol in the blood (hypercholesterolaemia) are associated with an increased risk of coronary heart disease (CHD) and stroke.[3] Serum cholesterol is an important determinant of cardiovascular risk. The increased risk is due mainly to raised low-density lipoprotein cholesterol (LDL-C). Lowering concentration of total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C), and raising high-density lipoprotein cholesterol (HDL-C) can reduce the risk of cardiovascular events, and in high risk patients, the cardiovascular morbidity and mortality. More importantly, the absolute risk for an individual also depends on other cardiovascular risk factors such as smoking, diabetes and hypertension, and treatment decisions are generally based on overall risk. Primary hypercholesterolaemia is associated with an underlying genetic defect; this can be due to a single genetic defect, or, much more commonly, to the interaction of a number of genes with dietary and other factors.[4] Secondary hypercholesterolaemia is caused by another disease state or by drug therapy. The majority of people with hypercholesterolaemia have plasma-cholesterol concentrations that are only mildly or moderately elevated, and they exhibit no clinical symptoms. At the other end of the spectrum, severe hypercholesterolaemia can cause xanthomas (lesions on the skin containing cholesterol and fats) and arcus corneae (cholesterol deposits in the eyes). In people with very severe forms of the condition, such as heterozygous familial hypercholesterolaemia (affects about one in every 500 people.), onset of CHD is not uncommon during the second and third decade of life. Men are at greater risk than women, and if untreated, 50-75% will have a heart attack (myocardial infarction) by the age of 60 years.[1] Factors which influence the degree of disease in people with hypercholesterolaemia include diet, obesity, smoking and lack of physical activity. Dietary and lifestyle changes are therefore important components in the management of the condition. Lipid regulating drugs may also be indicated and statins are the first choice drugs.[5] However, lipid goals are frequently not achieved due to the initiation of low doses of lipid-lowering medications, inadequate response to therapy, non-adherence to drug treatment and adverse effects.[6;7] Ezetimibe is a novel, orally active selective inhibitor of intestinal absorption of cholesterol and related plant sterols. Its mechanism of action differs from that of other classes of cholesterol lowering drugs in that ezetimibe selectively inhibits the absorption of dietary and biliary cholesterol and related plant sterols. It does not affect the absorption of fat soluble vitamins or triglycerides in the intestine.[8] The aim of this review is to systematically evaluate and appraise the clinical and cost effectiveness of ezetimibe (in its licensed indication) as combination therapy or monotherapy for the treatment of primary hypercholesterolaemia in the UK. 4. Decision problem 4.1. Purpose of the assessment The assessment will address the question “What is the clinical and cost effectiveness of ezetimibe (in its licensed indications) as combination therapy or monotherapy for the treatment of primary hypercholesterolaemia in adults”. 4.2. Clear definition of the interventions Ezetimibe is a unique cholesterol absorption inhibitor that blocks the intestinal absorption of dietary and biliary cholesterol and related plant sterols without affecting the uptake of triglycerides or fat soluble vitamins. Ezetimibe monotherapy (Ezetrol, MSD-Schering-Plough Ltd) is licensed as an adjunctive therapy to diet for: Primary (heterozygous familial and non-familial) hypercholesterolaemia in patients in whom a statin is considered inappropriate or is not tolerated Primary (heterozygous familial and non-familial) hypercholesterolaemia, co- administered with a statin, in patients who are not appropriately controlled with a statin alone Homozygous familial hypercholesterolaemia, co-administered with a statin. Patients may also receive adjunctive treatments such as LDL-C apheresis) Homozygous familial sitosterolaemia A fixed dose combination tablet containing ezetimibe and simvastatin (Inegy, MSD- Schering-Plough Ltd) is also licensed as an adjunctive therapy to diet for use in: Primary (heterozygous familial and non-familial) hypercholesterolaemia or mixed hyperlipidaemia where use of a combination product is appropriate: patients not appropriately controlled with a statin alone or patients already treated with a statin and ezetimibe Homozygous familial hypercholesterolaemia. Patients may also receive adjunctive treatments such as LDL-C apheresis 4.3. Place of intervention in the treatment pathway The review will focus on the use of ezetimibe (in its licensed indication) as combination therapy or monotherapy in adults for the treatment of primary hypercholesterolaemia in the UK. The National Service Framework for CHD[9] recommends that patients with clinical evidence of CHD or those with a 10 year risk greater than 30% should be prescribed lipid lowering therapy (combined with advice on diet and lifestyle) with the aim of reducing serum TC to less than 5 mmol/L (or a reduction of 20-25% if that produces a lower concentration) and LDL-C to below 3 mmol/L (or a reduction of about 30% if that produces a lower concentration). More recent guidance from six joint British Societies[3] advocate lower treatment thresholds (e.g. TC less than 4.0 mmol/L and LDL-C below 2.0 mmol/L in all people with CVD or at high risk of CVD, defined as a total CVD risk ≥ 20% over 10 years). The recent technology appraisal on statins for the prevention of cardiovascular events recommends initiation of statin treatment in patients with 20% or greater 10 year CVD risk.[10] Statins are the most effective drug for lowering LDL-C, in comparison to other classes of drugs, and reduce coronary events, all cardiovascular events and total mortality.[5] However, lipid goals are frequently not achieved due to the initiation of low doses of lipid-lowering medications, inadequate response to therapy, non- adherence to drug therapy and adverse effects.[6;7] The current review will not consider the use of ezetimibe in people with homozygous familial hypercholesterolaemia or homozygous sitosterolaemia. 4.4. Relevant comparators For patients whose condition is not adequately controlled with a statin alone (defined as failure to achieve a target lipid level) the relevant comparator is: Optimal statin therapy Treatment with a statin in combination with other lipid regulating drugs, such as nicotinic acid/acipimox, bile acid resins and fibrates For patients in whom a statin is considered inappropriate, or is not tolerated, the relevant comparators are: Other lipid regulating drugs, such as nicotinic acid/acipimox, bile acid resins and fibrates 4.5. Population and relevant subgroups The population for the assessment will include adults (aged 18 years and over) with primary (heterozygous familial and non-familial) hypercholesterolaemia who are candidates for treatment with statins on the basis of their CVD status or risk and whose condition is not appropriately controlled with a statin alone, or in whom a statin is considered inappropriate or is not tolerated. The identification of subgroups of patients for whom ezetimibe is particularly appropriate or inappropriate will be governed by the available evidence. However, on a priori grounds, information will be sought for people with or without existing ischaemic heart disease or other vascular disease, people with or without diabetes and different ethnic groups. 4.6. Key factors to be addressed The review will aim to evaluate the following objectives: Evaluate the clinical effectiveness of ezetimibe as combination therapy or monotherapy in terms of mortality and cardiovascular morbidity. Surrogate end-points (such as total, LDL and HDL cholesterol) will be utilised where information on clinical endpoints is unavailable Evaluate the adverse effect profile and toxicity Evaluate the cost-effectiveness of ezetimibe in terms of incremental cost per quality-adjusted life years Advise on the patient groups for whom ezetimibe might be particularly appropriate Estimate the possible overall cost in England and Wales 5. Report methods for synthesis of evidence of clinical effectiveness A review of the evidence for clinical effectiveness will be undertaken systematically following the general principles recommended in the QUOROM statement.[11] 5.1. Population 5.1.1. Inclusion criteria Adults (defined as > 18 years of age) with primary (heterozygous familial and non- familial) hypercholesterolaemia 5.1.2. Exclusion criteria Adults with homozygous