ACC: ENHANCE Data on Ezetimibe/ Simvastatin (Vytorin) Reveal Wavy Bottom Line

By Peggy Peck
CHICAGO, March 30 -- A full-airing here today of findings of the ENHANCE trial did nothing to blunt the null finding for the combination of ezetimibe/simvastatin (Vytorin) that were prefaced in a press release in January.
That press release, issued by Merck and Schering Plough, described a significant reduction in LDL cholesterol with ezetimibe/simvastatin (Vytorin) without a significant slowing of atherosclerosis progression.
But today's "showcase" scientific presentation of the results at the American College of Cardiology meeting, along with an analysis of ezetimibe (Zetia) and ezetimibe/simvastatin (Vytorin) use in the United States and Canada, may help calm concerns that ENHANCE suggested cholesterol-lowering does not correlate with clinical outcomes.
A clear clinical message from the ACC presentation, plus a simultaneous online release of the ENHANCE results by the New England Journal of Medicine, as well as a marketing analysis and two editorials, however, left the issue clearly open to interpretation. Advocates on both sides of the ezetimibe issue offered conflicting views.
To recap the ENHANCE story, the trial found no significant difference in the primary endpoint -- mean change in carotid intima-media thickness -- between patients randomized to ezetimibe/simvastatin versus 360 control patients who received simvastatin alone (P=0.29).
The combination therapy led to a significantly greater decrease in LDLs, a 58% reduction in LDLs for the ezetimibe/simvastatin group versus 42% for simvastatin controls after 24 months (P<0.01), said principal investigator John Kastelein, M.D., of the Academic Medical Center in Amsterdam in Holland.
There were also significant reductions in triglycerides (6%) and C-reactive protein (25.7%) between the two groups and those were significant (P<0.01), he said.
Nonetheless, those reductions did not result in significant reductions in the surrogate endpoint of carotid intima-media thickness, which begs two questions. First, is LDL reduction an invalid clinical goal? Second, what is the clinical evidence to support the use of ezetimibe?
The second question becomes especially crucial in light of data reported online today in the NEJM by Cynthia A. Jackevicius, Pharm.D., of the Western University of Health Sciences in Pomona, Calif., and colleagues. They found that ezetimibe had captured more than 15% of the market for lipid-lowering medications by 2006. This translates in to 3.1 million prescriptions for ezetimibe or ezetimibe/simvastatin in December 2006.
Moreover, the increased use of ezetimibe appears to have gained market share by cutting into statin prescriptions, which declined by 6.5% since ezetimibe was introduced in 2006.
Ezetimibe use also increased in Canada but the rise was markedly less, from 0.2% of prescriptions for lipid-lowering drugs in 2003 to 3.4% in 2006.
Two factors, Dr. Jackevicius and colleagues said, may explain the difference between U.S. and Canadian use. The combination of ezetimibe and simvastatin is not approved in Canada, and Canada does not permit direct-to-consumer advertising of prescription drugs.
In the U.S., Merck and Schering Plough spent $200 million on marketing ezetimibe and the combination product and sales here have "eclipsed $5 billion," Dr. Jackevicius and colleagues said.
Addressing the issue of the clinical value of LDL cholesterol lowering, two editorials concluded that the ENHANCE data should not be taken as evidence that cholesterol doesn't really matter.
Rather, the editorials hinted, there is a need to broaden the message so that it encompasses both lower is better and how you get there counts.