The ENHANCE trial: Simvastatin and ezetimibe in familial hypercholesterolemia [Classics Series]

1. In patients with familial hypercholesterolemia, simvastatin and ezetimibe combination therapy does not result in significant differences in carotid artery thickness when compared to treatment with simvastatin alone.

2. Treatment with simvastatin and ezetimibe led to significantly greater reductions in LDL cholesterol, triglyceride, and C-reactive protein levels as compared to treatment with simvastatin alone.

3. There were no significant differences between the two groups in the rates of adverse events or drug discontinuation.

Original Date of Publication: April 3, 2008

Study Rundown: Ezetimibe is a cholesterol-absorption inhibitor that lowers plasma cholesterol by decreasing the amount of cholesterol absorption in the small intestine. This drug is sometimes used in combination with statins, and this combination has been shown to further reduce levels of low-density lipoprotein (LDL) when compared to statins alone. No prior large-scale randomized clinical trial had been conducted to assess the effect of adding ezetimibe to statins on atherosclerosis progression. In the ENHANCE trial, 720 patients with familial hypercholesterolemia were randomized to receive simvastatin with placebo or simvastatin with ezetimibe. After 24 months of therapy, there was no significant difference between the two groups in mean change in intima-media thickness of the carotid arteries (P=0.29). Nevertheless, patients that took combination therapy rather than simvastatin alone experienced greater reductions in LDL cholesterol, triglyceride, and C-reactive protein levels.

Click to read the study in NEJM

In-Depth [randomized controlled trial]: This double-blinded randomized control trial was originally published in the NEJM in 2008. It was conducted at 18 centres in the United States, Canada, South Africa, Spain, Denmark, Norway, Sweden, and the Netherlands. Patients were eligible for the study if they were between 30-75 years of age and had been diagnosed with familial hypercholesterolemia by genotyping or World Health Organization diagnostic criteria. Exclusion criteria included having high-grade stenosis/occlusion of the carotid artery, a history of carotid endarterectomy/stenting, homozygous familial hypercholesterolemia, New York Heart Association class III or IV congestive heart failure, and cardiac arrhythmia. All patients underwent a screening phase, a single-blind 6-week placebo run-in period, and a double-blind study period lasting 24 months. The primary outcome was the mean change in intima-media thickness of the carotid arteries, as measured by ultrasonography of the carotid arteries.

A total of 720 patients with familial hypercholesteremia were randomized into two treatment groups: 1) simvastatin 80 mg daily with placebo or 2) simvastatin 80 mg daily and ezetimibe 10 mg daily. In the simvastain-only group, the mean change in thickness was 0.0058±0.0037 mm, while it was 0.0111±0.0038 mm in the simvastatin-ezetimibe group, an insignificant difference (P=0.29). Patients in the simvastatin-ezetimibe group experienced a 16.5% greater reduction in LDL levels compared with the simvastatin-only group (P<0.01). Patients in the combination group also experienced significantly greater reductions in triglyceride and C-reactive protein levels, when compared with simvastatin alone (P<0.01). There were no significant differences between the two groups in the rates of adverse events and medication discontinuation.

Image: PD

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