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Simvastatin With or Without Ezetimibe in Familial Hypercholesterolemia - ENHANCE — Presented at SCAI-ACC i2 Summit/ACC 2008
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.
Study Design
Study Design:
Patients Screened: 1,180
Patients Enrolled: 720
NYHA Class: I or II
Mean Follow Up: 24 months
Mean Patient Age: 45.9 years
Female: 49
Patient Populations:
• 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
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
Drug/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 ezetimibe/simvastatin 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 ezetimibe/simvastatin 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 ezetimibe/simvastatin 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 ezetimibe/simvastatin 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 ezetimibe/simvastatin 10/80 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 ezetimibe/simvastatin 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 ezetimibe/simvastatin 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 ezetimibe/simvastatin 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 ezetimibe/simvastatin in improving cardiovascular outcomes in high-risk patients, compared with simvastatin alone.
References:
Kastelein JJ, Akdim F, Stroes ES, et al. Simvastatin with or without ezetimibe in familial hypercholesterolemia. N Engl J Med 2008;358:1431-43.
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.
Keywords: Myocardial Infarction, Stroke, Creatine Kinase, Atherosclerosis, Carotid Intima-Media Thickness, Hyperlipoproteinemia Type II, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Carotid Arteries, Hypercholesterolemia, Simvastatin, Peripheral Vascular Diseases, Rhabdomyolysis, Cholesterol, Azetidines, Transaminases, Genotype
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