3 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 IMPROVE‑IT, 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

3.1 IMPROVE‑IT was a randomised, double‑blind, active‑controlled 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 follow‑up 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 non‑fatal stroke compared with simvastatin alone (hazard ratio [HR] 0.936, 95% confidence interval [CI] 0.89 to 0.99). There was a reduction in low‑density 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 IMPROVE‑IT.

3.2 The company submitted evidence suggesting that clinical outcomes from IMPROVE‑IT were consistent with a large Cholesterol Treatment Trialists' Collaboration (CTTC) meta‑analysis of statins. The evidence showed that a 1 mmol/litre reduction in LDL cholesterol from IMPROVE‑IT 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

3.3 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 base‑case 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 base‑case results for the primary and secondary prevention of cardiovascular disease instead of the populations as in the original appraisal.

3.4 In NICE's original technology appraisal guidance on ezetimibe, the CTTC meta‑analysis was used to model treatment effect by linking the absolute reduction in LDL cholesterol to the proportional reduction in cardiovascular events. Although IMPROVE‑IT 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 IMPROVE‑IT data in its economic model. Instead, it chose to use the CTTC meta‑analysis to model the effect of ezetimibe on cardiovascular outcomes linked to decreased LDL cholesterol.

  • National Institute for Health and Care Excellence (NICE)