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ENHANCE: Imaging study did not show clinical benefit
Despite lowering cholesterol, ezetimibe plus simvastatin did not affect intima-media thickness.
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Initial results from the ENHANCE trial suggest that taking ezetimibe along with simvastatin may not affect intima-media thickness or cardiovascular events.
The results of the Effect of Combination Ezetimibe and High-Dose Simvastatin versus Simvastatin Alone on Patients with Heterozygous Familial Hypercholesterolemia (ENHANCE) trial indicated that ezetimibe (Zetia, Schering-Plough, Merck) failed to reduce risk for MI, non-fatal stroke and fatty plaque aggregation. Ezetimibe is often prescribed together with simvastatin (Zocor, Schering-Plough, Merck), and study participants receiving both medications took them in the form of ezetimibe-simvastatin (Vytorin, Schering-Plough, Merck) pills.
Ezetimibe fails to impress
Researchers assigned 720 participants to receive either ezetimibe/simvastatin 10mg/80 mg (baseline LDL 319 mg/dL) or simvastatin 80 mg (baseline LDL 318 mg/dL). The primary endpoint assessed the mean change in intima-media thickness, which was measured at three sites along the carotid arteries.
There was a significant difference in LDL lowering seen between the two groups; a 58% LDL reduction at 24 months on the combination compared with 41% at 24 months with simvastatin. The change in mean intima-media thickness from baseline was 0.0111 mm in the ezetimibe/simvastatin group vs. 0.0058 mm in the simvastatin alone group (P=.29). Incidence rates of cardiovascular adverse events like MI, non-fatal stroke and revascularization were slightly higher in the ezetimibe/simvastatin group, but these differences were not statistically significant.
Although both drugs were well-tolerated and their safety profiles were similar, there was a statistically insignificant rise in mean intima-media thickness in the ezetimibe/simvastatin group compared with the simvastatin group.
The American College of Cardiology recommended that “major clinical decisions not be made on the basis of the ENHANCE study alone.
“Furthermore, the ACC notes that this trial is an imaging study and not a clinical-outcome study,” the ACC said in the statement. “Final conclusions should not be made until the clinical outcome trials are presented. The ACC recommends that Zetia remain a reasonable option for patients who are currently on a high-dose statin but have not reached their lipid goals … Zetia remains a reasonable option for patients who cannot tolerate statins or can only tolerate a low-dose statin.”
These trial results come after Merck and Schering Plough received criticism for delaying the release of ENHANCE results. Since the trial ended in April of 2006, both Merck and Schering-Plough failed to meet several of their deadlines for the release of the information. The companies have submitted an abstract to present the full results next month in Chicago at the ACC Scientific Sessions. The pharmaceutical companies are also currently conducting three large outcome trials involving more than 20,000 high-risk patients. — by Eric Raible
Editor’s note: This is, quite frankly, a stunner. Everyone basically assumed that incremental cholesterol-lowering by adding ezetimibe to simvastatin would produce an incremental benefit. It produced no benefit and, if anything, the trends were going in the wrong direction. It raises the question as to whether or not this is in fact an effective strategy. We know statins work. We know potent statins work better than less potent statins. What we do not know is whether ezetimibe works at all. The study raises a lot of questions about this. And of course, there has been a lot of concern about the delays in reporting the results of the trial, which frankly is raising additional concerns.
— Steven Nissen, MD
For more information:
- Kastelein J, Sager P, de Groot E, et al. Comparison of ezetimibe plus simvastatin monotherapy on atherosclerosis progression in familial hypercholesterolemia: Design and rationale of the ezetimibe and simvastatin in hypercholesterolemia enhances atherosclerosis regression (ENHANCE) trial. Am Heart J. 2005;149:234-239.