Title: Simvastatin With or Without Ezetimibe in Familial Hypercholesterolemia (ENHANCE)
Trial Sponsor: Merck and Schering-Plough
Year Presented: 2008
Year Published 2008
Topic(s): General Cardiology, Prevention/Vascular
Summary Posted: 3/30/2008
Writer: Dharam J Kumbhani, M.D., S.M.
Author Disclosure: This author has nothing to disclose.
Reviewer: Deepak L. Bhatt, M.D., F.A.C.C.
Author Disclosure: Research Grants: Eisai, Significant (>= $10,000); Research Grants: Sanofi Aventis, Significant (>= $10,000); Research Grants: Bristol Myers Squibb, Significant (>= $10,000); Research Grants: Ethicon, Significant (>= $10,000); Research Grants: The Medicines Company, Significant (>= $10,000); Research Grants: Heartscape, Significant (>= $10,000)

Description
The goal of this trial was to compare the mean change in the intima-media thickness (IMT) measured at three sites in the carotid arteries between patients with heterozygous familial hypercholesterolemia (HeFH) treated with ezetimibe/simvastatin 10/80 mg versus patients treated with high-dose simvastatin 80 mg alone, over a 2-year period.
Hypothesis
Ezetimibe 10 mg in combination with simvastatin 80 mg daily would reduce the progression of atherosclerosis in patients with familial hypercholesterolemia (FH) compared with simvastatin 80 mg daily alone.
Drugs/Procedures Used
Patients with HeFH were randomly assigned to receive simvastatin 80 mg plus placebo or simvastatin 80 mg plus ezetimibe 10 mg.
Principal Findings
A total of 720 patients were randomized: 363 were assigned to the simvastatin arm and 357 to the simvastatin-ezetimibe arm. The baseline low-density lipoprotein (LDL) cholesterol levels between the two arms were comparable (317.8 vs. 319 mg/dl; p = 0.85). Approximately 81% of patients enrolled in the trial had been on statins previously. The baseline mean carotid IMT measurements were similar between the two arms.

The primary outcome measure, change from baseline to study endpoint for mean carotid IMT, was 0.0058 ± 0.0037 mm in the simvastatin arm versus 0.0111 ± 0.0038 mm in the simvastatin-ezetimibe arm (p = 0.29). New plaque formation defined as IMT >1.3 mm was seen in 9/320 (2.8%) of the patients in the simvastatin arm versus 15/322 (4.7%) in the simvastatin-ezetimibe arm, respectively (p = 0.20). No significant changes were observed between treatment groups for the IMT means of the common carotid, carotid bulb, internal carotid, femoral, or the average of the mean carotid and femoral IMT values.

There was no difference in the incidence of cardiovascular clinical events between the simvastatin alone and simvastatin-ezetimibe arms: cardiovascular deaths (0.3 vs. 0.6%), nonfatal myocardial infarction (0.6% vs. 0.8%), nonfatal stroke (0.3% vs. 0.3%), and need for revascularization (1.4% vs. 1.7%) (p = not significant [NS] for all). At the end of 24 months, mean LDL levels decreased to 192.7 mg/dl (39% reduction) in the simvastatin arm, and to 141.3 mg/dl in the simvastatin-ezetimibe arm (56% reduction), a 17% difference (p < 0.01).

The overall incidence of treatment-related adverse events was similar between the two groups: consecutive elevations of serum transaminases =3x upper limit of normal (ULN) (2.2% vs. 2.8%), elevated creatine phosphokinase (CPK) =10 ULN (2.2% vs. 1.1%), and elevated CPK =10 ULN with muscle symptoms (0.3% vs. 0.6%) (p = NS for all). No cases of rhabdomyolysis were reported in either arm.
Interpretation
The results of the multicenter, randomized ENHANCE trial seem to suggest that in patients with very high baseline LDL levels, such as those with HeFH, the combination of simvastatin-ezetimibe 80/10 mg does not result in significant changes in the mean carotid IMT at 2 years when compared with high-dose simvastatin 80 mg alone. There was also no difference in the incidence of cardiovascular mortality, nonfatal myocardial infarction, nonfatal stroke, and need for revascularization, although this study was not powered to study clinical outcomes. The incidence of adverse events was similar. The LDL-lowering effect of simvastatin-ezetimibe was greater than that achieved with high-dose simvastatin alone.

Carotid IMT has been demonstrated to accurately predict the risk of incident cardiovascular events in several studies, as has LDL lowering. Hence, although this was a surrogate endpoint study, the results seem paradoxical: There was no significant reduction in carotid IMT with simvastatin-ezetimibe compared with simvastatin, despite a significant reduction in LDL cholesterol. One possible explanation is that the LDL reduction, though significant, was not adequate. Mean LDL levels even in the simvastatin-ezetimibe arm were 141 mg/dl. Thus, while setting an inclusion criterion for LDL >210 mg/dl helped to reduce their sample size, it may be the reason for their failure as well.

It will be interesting to see if larger ongoing trials will be able to demonstrate any relative benefit of the combination of simvastatin-ezetimibe in improving cardiovascular outcomes in high-risk patients, compared with simvastatin alone.
Conditions
• Hypercholesterolemia / Hyperlipidemia
• Peripheral vascular disease

Therapies
• Lipid-lowering agent/ezetimibe
• Lipid-lowering agent / HMG CoA Reductase Inhibitor / Simvastatin

Study Design
Randomized. Blinded. Parallel.

Patients Screened: 1,180
Patients Enrolled: 720
NYHA Class (% I, II, II, IV): I or II
Mean Follow-Up: 24 months
Mean Patient Age: 45.9 years
% Female: 49

Primary Endpoints
Change from baseline to end of follow-up (24 months) of ultrasound-determined mean carotid IMT
Secondary Endpoints
• Percent of subjects manifesting regression in mean carotid IMT between baseline and study endpoint
• Proportion of subjects developing new carotid artery plaques at study endpoint (lesion thickness >1.3 mm)
• Change from baseline in ultrasound-determined maximum carotid IMT
• Change from baseline in mean carotid IMT plus common femoral artery IMT
• Treatment-related adverse events, defined as consecutive elevations of serum transaminases =3x ULN, elevated CPK =10 ULN, elevated CPK =10 ULN with muscle symptoms, and rhabdomyolysis
• Incidence of major adverse cardiovascular events, including cardiovascular deaths, nonfatal stroke, nonfatal myocardial infarction, and need for revascularization
Patient Population
• Age of 30-75 years
• Diagnosis of FH either by genotyping or by having met the diagnostic criteria outlined by the World Health Organization
• Untreated LDL cholesterol =210 mg/dl
Exclusions:
• High-grade stenosis or occlusion of the carotid artery
• History of carotid endarterectomy or carotid stenting
• Homozygous FH
• Congestive heart failure (New York Heart Association class III-IV)
• Cardiac arrhythmias
• Angina
• Recent cardiovascular events
References: Simvastatin With or Without Ezetimibe in Familial Hypercholesterolemia: The ENHANCE trial. Presented by Dr. John Kastelein at the SCAI-ACC i2 Summit/American College of Cardiology Annual Scientific Session, Chicago, IL, March/April 2008.

Kastelein JJ, Akdim F, Stroes ES, et al. Simvastatin with or without ezetimibe in familial hypercholesterolemia. N Engl J Med 2008;358:1431-43.

Source
Content provided by the American College of Cardiology Foundation