Following ENHANCE, New Ezetimibe Users Down, Discontinuations Up

August 01, 2014

NEW HAVEN, CT — Three years after the negative results of the ENHANCE trial, a study testing the effects of ezetimibe (Zetia, Merck/Schering-Plough) on measures of subclinical atherosclerosis, nearly 2% of patients enrolled in a large pharmacy plan were still taking the medication[1].

Ezetimibe use peaked in January 2008, right around the time the ENHANCE results were first reported, with 266 244 adults (2.5%) in the pharmacy program prescribed ezetimibe. After three years, there was a slight decline in the percentage of adults taking ezetimibe, down to 1.8% of all continuously enrolled beneficiaries in the program.

In a study published online July 28, 2014 in the Journal of the American Medical Association: Internal Medicine, lead investigator Dr Joseph Ross (Yale University School of Medicine, New Haven, CT) assessed the association between the January 2008 announcement that ENHANCE was negative—the lipid-lowering agent had no effect on measurements of carotid intima-media thickness—and patterns of ezetimibe use. To do so, they looked at a national sample of 10 597 296 adults enrolled in the Express Scripts–managed pharmacy benefit plan taking at least one lipid-lowering medication.

Nearly three years after ENHANCE was announced, the study was associated with 0.16% fewer monthly ezetimibe users, a reduction that was not statistically significant.

After ENHANCE, however, the number of patients starting with a new ezetimibe prescription declined. By 2010, less than 1500 individuals (0.2%) within the pharmacy plan were started with ezetimibe. Overall, the ENHANCE study was associated with 0.44% fewer monthly ezetimibe users. The publication of ENHANCE was associated with significantly fewer new users of ezetimibe as monotherapy but there was only a trend toward fewer monthly initiations with ezetimibe with other lipid-lowering medications (ezetimibe is ezetimibe is commonly paired with simvastatin, in a combination known as Vytorin).

Prior to the publication of ENHANCE, monthly discontinuations of ezetimibe increased slowly, increasing from 3.6% to 8.0% per month. After the results were announced, though, the percentage of monthly discontinuations was as high as 20.6%. Investigators say the ENHANCE trial was associated with 12.5% more monthly discontinuations of ezetimibe as monotherapy, but just 0.86% when used with concomitant therapy. Overall, the study's announcement was associated with 10.4% more monthly discontinuations.

"Because the ENHANCE trial was focused on carotid-intima media thickness, as opposed to a clinical outcome, the results were not expected to be definitive," write Ross and colleagues. "However, they were eagerly awaited by the clinical community, as evidenced by the media attention that the trial received. Our findings suggest that physicians and patients were responsive either to the trial's negative findings and the growing awareness of the absence of evidence related to this drug or to any of several other factors that were concurrent with announcement of the trial's results."

Ross reports support from Medtronic and Johnson and Johnson.

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