This dispatch was filed by Mark Zucker, a cardiologist and Our Man at the ACC: The Enhance study took center-stage today as four panel members - Drs. Joseph Messer, Patrick O’Gara, Harlan Krumholtz and Rick Nishimura - reviewed the data in which 342 patients were randomized to monotherapy and available for analysis and 328 randomized to combination therapy. Findings: No difference in carotid intimal thickness was seen in the aggregate or in any subgroup, whatsoever. No safety concerns were noted.

Proposed explanations for the lack of a difference between the monotherapy and combination therapy cohorts could be that the technique was not sufficiently sensitive; the compound failed to work; or the population was at too low risk. All of these possibilities were considered. Unfortunately, no definitive explanation was provided, however and the focus turned instead to “how to treat patients given the results.”

All commentors observed that the trial does not question the underlying hypothesis that lowering cholesterol matters, it just suggests that how one lowers cholesterol probably does matter. Krumholtz, however, argued that there is uncertainty about the benefit of the drug and proceeded to argue further that outcomes studies with ezetimibe (Vytorin) are needed. After all, certain hormonal supplements improve LDL levels but probably don’t change atherosclerosis progression. (Read what Krumoltz has to say here).

Krumholtz stated further that the use of ezetimibe was encouraged by aggressive marketing. For example, today, 16 percent of all lipid lowering agents used in the US are ezetimibe based as compared to 3 percent in Canada. Uncertain whether there are detrimental effects (although none were suggested by the study), Krumholtz suggested that the drug should not be used as first or second line therapy. Instead, he stated clearly the prescribers should rely upon evidence-based medicine and remain with statins or other proven medications until further studies are completed. Seemingly, the comments were well received by the audience.

The bottom line: Clearly, the role of ezetimibe and how to interpret the Enhance data, even after the publication of the trial, remains unclear. An objective review of the data, the paper, and the accompanying editorial would serve all prescribers well. This will be the subject of much debate and disagreement over the next few weeks. Likely that the use of Vytorin and Zetia will not increase and will probably decrease further.

Not unexpectedly, the officially released data did not add anything subtantive to that which was already known to us from the earlier reports. Hence, as clinical cardiologists, we remain uncertain as to the role of this agent. From a practical point of view, Krumholtz’s recommendations are as logical and reasonable as any other recommendation - start with statins and then use second-line agents before ezetimibe.

Realistically, however, the second-line agents require more frequent administration and are generally less well tolerated. Hence, I would envision that physicians will still default to ezetimibe as a second line agent for statin intolerant patients. That said, I would also envision that use of fixed combination therapy will fall significantly.