ENHANCE 2008.

Methods	Design: prospective, randomised, double‐blind, active‐comparator, multi‐centre study Number of study centres: 18 ambulatory care centres in the USA, Canada, South Africa, Spain, Denmark, Norway, Sweden, and the Netherlands Setting: ambulatory care Patient recruitment: August 2002 to April 2004 Duration of study: 24 months Clinical setting: familial hypercholesterolaemia
Participants	Enrolment (N): 1180 Randomised (N): intervention: 357; control: 363 Withdrawn (N): intervention: 41; control: 64 Lost to follow‐up (N): intervention: 2; control: 2 Completed the study (N): intervention: 316; control: 299 Analysed (N): intervention: 357; control: 363 Age (years) (mean ± SD): intervention: 46.1 ± 9.0; control: 45.7 ± 10.0 Sex (male, N, %): intervention: 191 (53.5%); control: 179 (49.3%) Smoking history (N, %): intervention: 104 (28.7%); control: 102 (28.6%) BMI (kg/m², mean ± SD):): intervention: 27.4 ± 4.6; control: 26.7 ± 4.4 Diabetes (N, %): intervention: 8 (2.2%); control: 5 (1.4%) Hypertension (N, %): intervention: 67 (18.8%); control: 51 (14.0%) History of MI (N, %): intervention: 26 (7.2%); control: 14 (3.9%) Statin pretreatment (N, %): intervention: 286 (80.1%); control: 297 (81.8%) Inclusion criteria: men and women between the ages of 30 and 75 years were eligible to participate in the study if familial hypercholesterolaemia had been diagnosed either by genotyping or by their having met the diagnostic criteria outlined by the World Health Organization; untreated levels of LDL cholesterol had to be 210 mg/dL or more. patients who were receiving lipid‐lowering therapy and who had an LDL cholesterol level of less than 210 mg/dL at the time of screening were permitted to undergo randomisation if their LDL cholesterol level was 210 mg/dL or more after the placebo run‐in period. Exclusion criteria: high‐grade stenosis or occlusion of the carotid artery, a history of carotid endarterectomy or carotid stenting, homozygous familial hypercholesterolaemia, New York Heart Association class III or IV congestive heart failure, cardiac arrhythmia, angina pectoris, or recent cardiovascular events.
Interventions	Intervention: simvastatin 80 mg/day + ezetimibe 10 mg/day Comparison: simvastatin 80 mg/day + ezetimibe placebo Details of any 'run‐in' period: a single‐blind 6‐week placebo run‐in period Concomitant medications: not reported Excluded medications: not reported
Outcomes	Primary: the change from baseline in ultrasonographic measurement of the mean carotid‐artery intima‐media thickness. Secondary: the proportion of patients with regression in the mean carotid‐artery intima‐media thickness from baseline; the proportion of patients with new carotid‐artery plaques of more than 1.3 mm; the change from baseline in the mean maximal carotid‐artery intima‐media thickness; the change from baseline in the average mean intima‐media thickness of the carotid and common femoral arteries; the change from baseline in the mean IMT, separately for the three carotid artery segments (common carotid, carotid bulb, and the internal carotid artery) and the femoral artery; the per cent change from baseline in lipid parameters (LDL‐C, HDL‐C, total cholesterol, apoB, and triglycerides); the per cent change from baseline in lipid indices: total cholesterol, calculated LDL‐C, HDL‐C, triglycerides, apolipoprotein B, apolipoprotein AI, and CRP. Other: adverse event; major adverse cardiovascular events, including death, MI, stroke, resuscitated cardiac arrest, and coronary revascularisation.
Notes	Funding: Supported by Merck and Schering‐Plough. NCT00552097
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote "Randomization which was based on computer‐generated codes provided to the clinical centers by a central randomization service, was stratified according to clinical center."
Allocation concealment (selection bias)	Low risk	Central randomisation
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Double‐blind, using matching placebo
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote "Sonographers are also blinded to treatment assignment"
Incomplete outcome data (attrition bias) All outcomes	Low risk	Quote: "All analyses were performed on an intention‐to‐treat basis. We used the last‐observation‐carried‐forward method for patients who did not complete the study." Number of participants that discontinued were reported and reasons were stated.
Selective reporting (reporting bias)	Low risk	The study protocol was pre‐published and all of the study's prespecified outcomes have been reported.
Other bias	Low risk	Although the study was supported by pharmaceutical companies, the primary outcome were negative.