Ezetimibe for treating primary heterozygous-familial and non-familial hypercholesterolaemia

Evidence-based recommendations on ezetimibe (Ezetrol) for treating primary (heterozygous-familial and non-familial) hypercholesterolaemia in adults.

# Recommendations
This guidance should be used with NICE's guidelines on cardiovascular disease: risk assessment and reduction, including lipid modification and familial hypercholesterolaemia: identification and management.
Ezetimibe monotherapy is recommended as an option for treating primary (heterozygousfamilial or nonfamilial) hypercholesterolaemia in adults in whom initial statin therapy is contraindicated.
Ezetimibe monotherapy is recommended as an option for treating primary (heterozygousfamilial or nonfamilial) hypercholesterolaemia in adults who cannot tolerate statin therapy (as defined in section 1.6).
Ezetimibe, coadministered with initial statin therapy, is recommended as an option for treating primary (heterozygousfamilial or nonfamilial) hypercholesterolaemia in adults who have started statin therapy when:
serum total or lowdensity lipoprotein (LDL) cholesterol concentration is not appropriately controlled (as defined in section 1.7) either after appropriate dose titration of initial statin therapy or because dose titration is limited by intolerance to the initial statin therapy (as defined in section 1.6) and
a change from initial statin therapy to an alternative statin is being considered.
When prescribing ezetimibe coadministered with a statin, ezetimibe should be prescribed on the basis of lowest acquisition cost.
For the purposes of this guidance, intolerance to initial statin therapy is defined as the presence of clinically significant adverse effects that represent an unacceptable risk to the patient or that may reduce compliance with therapy.
For the purposes of this guidance, appropriate control of cholesterol concentrations should be based on individual risk assessment according to national guidance on managing cardiovascular disease in the relevant populations.# The technology
Ezetimibe (Ezetrol, Merck Sharp & Dohme) is a cholesterolabsorption inhibitor that blocks the intestinal absorption of dietary and biliary cholesterol and related plant sterols, without affecting the uptake of triglycerides or fatsoluble vitamins. Because of this mechanism of action, ezetimibe can be combined with a statin to provide either a complementary or an alternative mode of cholesterol reduction.
Ezetimibe, with a statin or as monotherapy, has a marketing authorisation in the UK. It is licensed in combination with an HMGCoA reductase inhibitor (statin) as an adjunctive therapy to diet for primary heterozygousfamilial or nonfamilial hypercholesterolaemia that is not appropriately controlled with a statin alone. Ezetimibe monotherapy has a marketing authorisation as an adjunctive therapy to diet for primary heterozygousfamilial or nonfamilial hypercholesterolaemia when a statin is considered inappropriate or is not tolerated.
Adverse reactions with ezetimibe as monotherapy or with a statin are usually mild and transient. When given as monotherapy, they most commonly include abdominal pain, diarrhoea, flatulence and fatigue. When taken with a statin, the most common additional adverse reactions include increased alanine transaminase, aspartate transaminase or both, headache and myalgia. For full details of adverse effects and contraindications, see the summaries of product characteristics.
Ezetimibe is taken orally at a dose of 10 mg once daily. Ezetimibe is available as 10mg tablets (28tablet pack) at a net price per pack of 26.31 (excluding VAT; 'British national formulary' ; accessed September 2015). A fixeddose combination tablet (Inegy, Merck Sharp & Dohme) containing ezetimibe 10 mg and simvastatin 20 mg (28tablet pack) is available at a net price per pack of 33.42, ezetimibe 10 mg and simvastatin 40 mg (28tablet pack) at a net price per pack of 38.98, and ezetimibe 10 mg and simvastatin 80 mg (28tablet pack) at a net price per pack of 41.21 (excluding VAT; BNF; accessed September 2015). Costs may vary in different settings because of negotiated procurement discounts.# Evidence
The Appraisal Committee considered evidence submitted by consultees, Merck Sharp & Dohme and a review of this submission by the Evidence Review Group (ERG). This appraisal was a review of NICE's technology appraisal guidance on ezetimibe for the treatment of primary (heterozygous-familial and non-familial) hypercholesterolaemia. It focused on the cardiovascular outcome data from IMPROVEIT, a study done since publication of NICE's original technology appraisal guidance on ezetimibe. See the history for full details of the evidence, including the evidence used for NICE's original technology appraisal guidance on ezetimibe.

# Clinical effectiveness
IMPROVEIT was a randomised, doubleblind, activecontrolled study in 18,144 patients with stabilised acute coronary syndrome. Patients were randomised in a 1:1 ratio to either ezetimibe 10 mg plus simvastatin 40 mg once daily or simvastatin 40 mg once daily. At a median followup of 6 years, ezetimibe plus simvastatin produced a 6.4% relative risk (RR) reduction in the primary composite efficacy end point of cardiovascular death, major coronary event, or nonfatal stroke compared with simvastatin alone (hazard ratio  0.936, 95% confidence interval  0.89 to 0.99). There was a reduction in lowdensity lipoprotein cholesterol at 1 year of 0.43 mmol/litre with ezetimibe plus simvastatin compared with simvastatin alone (a relative reduction of 24%). The company reported that no new safety concerns related to ezetimibe were raised in IMPROVEIT.
The company submitted evidence suggesting that clinical outcomes from IMPROVEIT were consistent with a large Cholesterol Treatment Trialists' Collaboration (CTTC) metaanalysis of statins. The evidence showed that a 1 mmol/litre reduction in LDL cholesterol from IMPROVEIT had a similar hazard ratio for cardiovascular events (HR 0.80, 95% CI 0.68 to 0.94) to the CTTC analysis (HR 0.78, 95% CI 0.76 to 0.80).

# Cost effectiveness
The company submitted a Markov model based on the modelling approaches previously developed for NICE's technology appraisal guidance on statins for the prevention of cardiovascular events and its original guidance on ezetimibe. NICE's original technology appraisal guidance on ezetimibe presented basecase results for people who could tolerate statins and people in whom statins were contraindicated or not tolerated. But to be consistent with the updated NICE guideline on lipid modification, the company presented basecase results for the primary and secondary prevention of cardiovascular disease instead of the populations as in the original appraisal.
In NICE's original technology appraisal guidance on ezetimibe, the CTTC metaanalysis was used to model treatment effect by linking the absolute reduction in LDL cholesterol to the proportional reduction in cardiovascular events. Although IMPROVEIT subsequently investigated the effect of adding ezetimibe to statin therapy on reducing cardiovascular events, the patient population was narrower than that specified in ezetimibe's marketing authorisation. Therefore, the company decided not to use the IMPROVEIT data in its economic model. Instead, it chose to use the CTTC metaanalysis to model the effect of ezetimibe on cardiovascular outcomes linked to decreased LDL cholesterol.# Committee discussion
The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of ezetimibe, having considered evidence on the nature of primary heterozygousfamilial and nonfamilial hypercholesterolaemia and the value placed on the benefits of ezetimibe by people with the conditions, those who represent them, and clinical experts. It also took into account the effective use of NHS resources.
This appraisal is a review of NICE's technology appraisal guidance on ezetimibe for the treatment of primary (heterozygous-familial and non-familial) hypercholesterolaemia. The Committee noted that ezetimibe monotherapy was recommended as an option for treating primary hypercholesterolaemia in adults who:
are unable to start statin therapy because it is contraindicated
cannot tolerate statin therapy.It noted that ezetimibe, coadministered with initial statin therapy, was recommended as an option for treating primary hypercholesterolaemia in adults when:
they have started statin therapy and lowdensity lipoprotein (LDL) cholesterol is not appropriately controlled either after dose titration of initial statin therapy or because dose titration is limited by intolerance to statin therapy and
changing to an alternative statin is being considered.The Committee was aware that NICE's guideline on lipid modification crossreferred to NICE's technology appraisal guidance on ezetimibe.

# Current practice and treatment
The Committee considered current NHS practice for treating primary hypercholesterolaemia. The Committee observed that the patient population in the company's submission was different to the population covered by the marketing authorisation and the final NICE scope for ezetimibe (see section 2.2). This was because the company's submission considered a primary prevention population (people with a 10year risk of developing cardiovascular disease of 1030%) and a secondary prevention population (people with established cardiovascular disease) with primary heterozygousfamilial or nonfamilial hypercholesterolaemia. It noted that this was because the updated NICE guideline on lipid modification made recommendations according to primary and secondary prevention of cardiovascular risk. The Committee heard from the clinical experts and noted the comments received at consultation that suggested the way cardiovascular risk is assessed and managed may have changed since NICE's original technology appraisal guidance on ezetimibe was published. It further heard that despite the recommendations in NICE's guideline on lipid modification, which are largely based on assessing 10year cardiovascular risk using the cardiovascular disease risk calculator QRISK2, meeting target cholesterol levels to prevent cardiovascular disease remained an important part of clinical practice in England. The Committee concluded that, in clinical practice in the NHS in England, treating hypercholesterolaemia to prevent cardiovascular disease starts either because of a person's 10year risk of developing cardiovascular disease or to meet a specific target cholesterol level. The Committee further concluded that this remained consistent with the approach taken in NICE's original technology appraisal guidance on ezetimibe.
The Committee considered the current treatment pathway for people with primary hypercholesterolaemia. The Committee heard from the clinical experts that statins are the main treatment for familial and nonfamilial hypercholesterolaemia (as described in NICE's guidelines on familial hypercholesterolaemia and on lipid modification). It further heard from the clinical experts that fibrates, nicotinic acid and bile acid sequestrants (anion exchange resins) are not routinely used to treat nonfamilial hypercholesterolaemia. The Committee then heard that, although recommended in NICE's guideline on familial hypercholesterolaemia, these treatments are not commonly used to treat familial hypercholesterolaemia because they are poorly tolerated. It heard from the clinical experts that ezetimibe monotherapy is used to treat primary hypercholesterolaemia when a statin is considered inappropriate or is not tolerated; ezetimibe with a statin is used in people when cholesterol levels are not low enough, despite increasing the dose of the statin, or if a person is unable to have higher doses of the statin because it is likely to cause side effects. The Committee concluded that statins are the main option for treating primary hypercholesterolaemia (when a statin is considered appropriate), and that no treatments apart from ezetimibe monotherapy are established NHS practice in England for treating familial and nonfamilial hypercholesterolaemia in adults who are unable to take a statin.

# Clinical effectiveness
The Committee discussed the clinical effectiveness of ezetimibe, focusing on the relevance of the new evidence from IMPROVEIT in reducing cardiovascular events in people with primary hypercholesterolaemia. The Committee heard from the clinical experts and noted consultation comments that stated the IMPROVEIT population represented only part of the eligible population who could have statins or ezetimibe. This was because the patients in IMPROVEIT had acute coronary syndrome (that is, they were having treatment for secondary prevention, and not primary prevention, of cardiovascular disease). It noted the comments made by consultees that although IMPROVEIT's lower baseline LDL cholesterol level resulted in a smaller absolute reduction in LDL cholesterol with ezetimibe compared with the wider secondary prevention population, it considered this to be consistent with the trend predicted by the Cholesterol Treatment Trialists' Collaboration (CTTC) metaanalysis (see section 3.2). The Committee considered that ezetimibe plus a statin was more clinically effective than a statin alone in IMPROVEIT, as shown by lower LDL cholesterol and reduced cardiovascular events, but agreed that the trial population was not wholly representative of the population receiving ezetimibe in current NHS practice in England. The Committee recalled that NICE's original technology appraisal guidance on ezetimibe concluded that ezetimibe coadministered with a statin was clinically effective in adults in whom primary hypercholesterolaemia was not appropriately controlled with statin therapy compared with statins. It also recalled that ezetimibe monotherapy was clinically effective compared with placebo in people for whom statins were contraindicated or who cannot tolerate them. The Committee therefore decided that the clinical effectiveness of ezetimibe using the updated evidence base was consistent with that in NICE's original technology appraisal guidance on ezetimibe, and that the conclusions it had previously made were still appropriate.

# Cost effectiveness
The Committee considered the cost effectiveness of ezetimibe following the comments received at consultation. The Committee noted that some consultees preferred the original costeffectiveness analyses and recommendations for ezetimibe, which did not differentiate between primary and secondary prevention of cardiovascular disease when treating hypercholesterolaemia or use results from IMPROVEIT. The Committee decided that the company's current incremental costeffectiveness ratios (ICERs) according to primary and secondary prevention of cardiovascular disease and the Evidence Review Group's (ERG's) estimates using IMPROVEIT were not suitable for decisionmaking. The Committee considered the estimated ICERs from the original appraisal of ezetimibe to be more plausible than the current estimates from the company and ERG because the population in the original appraisal was better aligned with the final NICE scope, current practice and ezetimibe's marketing authorisation. The Committee concluded that current practice, treatment (see sections 4.3 and 4.4) and the clinical effectiveness of ezetimibe using the updated evidence base (see section 4.5) are consistent with NICE's original technology appraisal guidance. Therefore, the cost effectiveness of ezetimibe was likely to be more plausible in NICE's original technology appraisal guidance compared with the current estimates from the company and the ERG. It decided not to use the company and ERG's current costeffectiveness estimates for ezetimibe for its decisionmaking. It further concluded that the recommendations in NICE's original technology appraisal guidance on ezetimibe were still appropriate (see section 4.2). The Committee agreed to amend the recommendations so that they no longer referred to superseded NICE guidance.
The Committee was aware of NICE's position statement on the Pharmaceutical Price Regulation Scheme (PPRS) 2014, and in particular the PPRS payment mechanism. It accepted the conclusion 'that the 2014 PPRS payment mechanism should not, as a matter of course, be regarded as a relevant consideration in its assessment of the cost effectiveness of branded medicines'. The Committee heard nothing to suggest that there is any basis for taking a different view about the relevance of the PPRS to this appraisal. It therefore concluded that the PPRS payment mechanism was not relevant in considering the cost effectiveness of ezetimibe in this appraisal.

# Summary of Appraisal Committee's key conclusions
TA385
Appraisal title: Ezetimibe for treating primary heterozygousfamilial and nonfamilial hypercholesterolaemia
Section
Key conclusion
Ezetimibe monotherapy is recommended as an option for treating primary (heterozygousfamilial or nonfamilial) hypercholesterolaemia in adults in whom initial statin therapy is contraindicated.
Ezetimibe monotherapy is recommended as an option for treating primary (heterozygousfamilial or nonfamilial) hypercholesterolaemia in adults who cannot tolerate statin therapy.
Ezetimibe, coadministered with initial statin therapy, is recommended as an option for treating primary (heterozygousfamilial or nonfamilial) hypercholesterolaemia in adults who have started statin therapy when:
serum total or lowdensity lipoprotein (LDL) cholesterol concentration is not appropriately controlled either after appropriate dose titration of initial statin therapy or because dose titration is limited by intolerance to the initial statin therapy and
a change from initial statin therapy to an alternative statin is being considered.
The Committee decided not to use the company and Evidence Review Group's (ERG) current costeffectiveness estimates for ezetimibe for its decision-making. It further concluded that the recommendations in NICE's original technology appraisal guidance on ezetimibe were still appropriate. The Committee agreed to amend the recommendations so that they no longer referred to superseded NICE guidance.
Current practice
Clinical need of patients, including the availability of alternative treatments
The Committee concluded that statins are the main option for treating primary hypercholesterolaemia (when a statin is considered appropriate), and that no treatments apart from ezetimibe monotherapy are established NHS practice in England for treating familial and nonfamilial hypercholesterolaemia in adults who are unable to take a statin.
The technology
Proposed benefits of the technology
Ezetimibe is a cholesterolabsorption inhibitor that blocks the intestinal absorption of dietary and biliary cholesterol and related plant sterols, without affecting the uptake of triglycerides or fatsoluble vitamins.
What is the position of the treatment in the pathway of care for the condition?
The Committee noted that NICE's original technology appraisal guidance on ezetimibe for the treatment of primary (heterozygous-familial and non-familial) hypercholesterolaemia recommended ezetimibe monotherapy for treating primary hypercholesterolaemia in adults for whom initial statin therapy was contraindicated or who cannot tolerate statin therapy. It noted that ezetimibe, coadministered with initial statin therapy, was recommended for people who start statin therapy and their lowdensity lipoprotein (LDL) cholesterol is not appropriately controlled either after dose titration of initial statin therapy or because dose titration is limited by intolerance to statin therapy.
The Committee noted that using statins, the main treatment for hypercholesterolaemia, is based on NICE's guidelines on familial hypercholesterolaemia and on lipid modification. It heard from the clinical experts that ezetimibe monotherapy is used to treat primary hypercholesterolaemia when a statin is considered inappropriate or is not tolerated; ezetimibe with a statin is used in people when cholesterol levels are not low enough, despite increasing the dose of the statin, or if a person is unable to have higher doses of the statin because it is likely to cause side effects.
Adverse reactions
Ezetimibe's summary of product characteristics lists abdominal pain, diarrhoea, flatulence and fatigue as adverse reactions for ezetimibe.
Evidence for clinical effectiveness
Availability, nature and quality of evidence
The Committee noted that the company's submission included a clinical trial, IMPROVEIT, which presented evidence on cardiovascular outcomes. The lower LDL cholesterol and reduced cardiovascular events were considered to be consistent with a large Cholesterol Treatment Trialists' Collaboration (CTTC) metaanalysis of statins.
Relevance to general clinical practice in the NHS
The Committee was aware that, in clinical practice in the NHS in England, treating hypercholesterolaemia to prevent cardiovascular disease starts either because of a person's 10year risk of developing cardiovascular disease or to meet a specific target cholesterol level. The Committee concluded that this remained consistent with the approach taken in NICE's original technology appraisal guidance on ezetimibe.
The Committee observed that the patient population in the company's submission was different to the population covered by the marketing authorisation and the final NICE scope for ezetimibe because it considered the primary and secondary prevention of cardiovascular disease.
Uncertainties generated by the evidence
The Committee agreed that although the lower LDL cholesterol and reduced cardiovascular events from IMPROVEIT were consistent with the CTTC analysis, the trial population in IMPROVEIT was not wholly representative of the population treated in current practice in England.
Estimate of the size of the clinical effectiveness including strength of supporting evidence
How has the new clinical evidence that has emerged since the original appraisal (TA132) influenced the current recommendations?
The Committee considered the new clinical outcome evidence from IMPROVEIT in reducing cardiovascular events for people with primary hypercholesterolaemia.
It decided that the clinical effectiveness of ezetimibe using the updated evidence base was consistent with that in NICE's original technology appraisal guidance on ezetimibe, and that the conclusions the Committee had previously made were still appropriate.
Evidence for cost effectiveness
Availability and nature of evidence
Uncertainties around and plausibility of assumptions and inputs in the economic model
The Committee decided that the company's costeffectiveness estimates according to primary and secondary prevention of cardiovascular disease using IMPROVEIT were not suitable for decisionmaking.
How has the new costeffectiveness evidence that has emerged since the original appraisal (TA132) influenced the current recommendations?
The Committee considered the incremental costeffectiveness ratios (ICERs) from the original appraisal of ezetimibe to be more plausible than the current estimates from the company and ERG because the population in the original appraisal was better aligned with the final NICE scope, current practice and ezetimibe's marketing authorisation.
It decided not to use the company and ERG's current costeffectiveness estimates for ezetimibe for its decisionmaking. It further concluded that the recommendations in NICE's original technology appraisal guidance on ezetimibe were still appropriate. The Committee agreed to amend the recommendations so that they no longer referred to superseded NICE guidance.
Additional factors taken into account
Patient access schemes (PPRS)
The Committee concluded that the PPRS payment mechanism was not relevant in considering the cost effectiveness of ezetimibe.
Endoflife considerations
Not applicable.
Equalities considerations and social value judgements
No potential equality issues were identified during the scoping process, in any of the submissions, during consultation or during the Committee meetings. None had been previously identified in NICE's technology appraisal guidance on ezetimibe.
# Review of guidance
The guidance on this technology will be considered for review 3 years after publication of the guidance. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators.Andrew DillonChief ExecutiveFebruary 2016