4 Committee discussion

4.1 The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of ezetimibe, having considered evidence on the nature of primary heterozygous‑familial and non‑familial 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.

4.2 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, co‑administered with initial statin therapy, was recommended as an option for treating primary hypercholesterolaemia in adults when:

  • they have started statin therapy and low‑density 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 cross‑referred to NICE's technology appraisal guidance on ezetimibe.

Current practice and treatment

4.3 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 10‑year risk of developing cardiovascular disease of 10–30%) and a secondary prevention population (people with established cardiovascular disease) with primary heterozygous‑familial or non‑familial 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 10‑year 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 10‑year 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.

4.4 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 non‑familial 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 non‑familial 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 non‑familial hypercholesterolaemia in adults who are unable to take a statin.

Clinical effectiveness

4.5 The Committee discussed the clinical effectiveness of ezetimibe, focusing on the relevance of the new evidence from IMPROVE‑IT in reducing cardiovascular events in people with primary hypercholesterolaemia. The Committee heard from the clinical experts and noted consultation comments that stated the IMPROVE‑IT population represented only part of the eligible population who could have statins or ezetimibe. This was because the patients in IMPROVE‑IT 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 IMPROVE‑IT'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) meta‑analysis (see section 3.2). The Committee considered that ezetimibe plus a statin was more clinically effective than a statin alone in IMPROVE‑IT, 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 co‑administered 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

4.6 The Committee considered the cost effectiveness of ezetimibe following the comments received at consultation. The Committee noted that some consultees preferred the original cost‑effectiveness analyses and recommendations for ezetimibe, which did not differentiate between primary and secondary prevention of cardiovascular disease when treating hypercholesterolaemia or use results from IMPROVE‑IT. The Committee decided that the company's current incremental cost‑effectiveness ratios (ICERs) according to primary and secondary prevention of cardiovascular disease and the Evidence Review Group's (ERG's) estimates using IMPROVE‑IT were not suitable for decision‑making. 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 cost‑effectiveness 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 (see section 4.2). The Committee agreed to amend the recommendations so that they no longer referred to superseded NICE guidance.

4.7 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 heterozygous‑familial and non‑familial hypercholesterolaemia

Section

Key conclusion

Ezetimibe monotherapy is recommended as an option for treating primary (heterozygous‑familial or non‑familial) hypercholesterolaemia in adults in whom initial statin therapy is contraindicated.

Ezetimibe monotherapy is recommended as an option for treating primary (heterozygous‑familial or non‑familial) hypercholesterolaemia in adults who cannot tolerate statin therapy.

Ezetimibe, co‑administered with initial statin therapy, is recommended as an option for treating primary (heterozygous‑familial or non‑familial) hypercholesterolaemia in adults who have started statin therapy when:

  • serum total or low‑density 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 cost‑effectiveness 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.

1.1–1.4, 4.6

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 non‑familial hypercholesterolaemia in adults who are unable to take a statin.

4.4

The technology

Proposed benefits of the technology

Ezetimibe is a 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.

2.1

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, co‑administered with initial statin therapy, was recommended for people who start statin therapy and their low‑density 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.

4.3, 4.4

Adverse reactions

Ezetimibe's summary of product characteristics lists abdominal pain, diarrhoea, flatulence and fatigue as adverse reactions for ezetimibe.

2.3

Evidence for clinical effectiveness

Availability, nature and quality of evidence

The Committee noted that the company's submission included a clinical trial, IMPROVE‑IT, 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) meta‑analysis of statins.

4.5

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 10‑year 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.

4.3

Uncertainties generated by the evidence

The Committee agreed that although the lower LDL cholesterol and reduced cardiovascular events from IMPROVE‑IT were consistent with the CTTC analysis, the trial population in IMPROVE‑IT was not wholly representative of the population treated in current practice in England.

4.5

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 IMPROVE‑IT 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.

3.2, 4.5

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 cost‑effectiveness estimates according to primary and secondary prevention of cardiovascular disease using IMPROVE‑IT were not suitable for decision‑making.

4.6

How has the new cost‑effectiveness evidence that has emerged since the original appraisal (TA132) influenced the current recommendations?

The Committee considered the incremental cost‑effectiveness 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 cost‑effectiveness 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.

4.6

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.

4.7

End‑of‑life 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.

  • National Institute for Health and Care Excellence (NICE)