Ezetimibe’s Saga Continues

The ENHANCE study, showing no difference between simvastatin plus ezetimibe (Zetia/Vytorin, Merck and Schering-Plough) compared with simvastatin alone on the progression of carotid atherosclerosis in patients with familial hypercholesterolemia, has been a major talking point over the past few days.

The study results have attracted intense media coverage, which was inevitable given the controversy surrounding the study in the past few weeks. However, many experts are urging that not too much weight be attached to this one imaging study, a view echoed by the American College of Cardiology (ACC). But Dr Steven Nissen (Cleveland Clinic, OH) is sticking to his guns and insists that, in the absence of any evidence of health benefits, the drug should not be used.

Dr Robert Califf (Duke Clinical Research Institute, Durham, NC), who is coordinating one of the large clinical outcome trials with ezetimibe (IMPROVE-IT), is also taking the drug himself and says that while it is disappointing that no benefit was seen in ENHANCE, he is not going to stop taking ezetimibe based on this one study. He says he cannot take high doses of statins because of side effects but can obtain the same degree of LDL lowering with ezetimibe and a low-dose statin, without the adverse affects. "I don’t see any signal of toxicity from this trial, so that is reassuring. There’s no indication that it’s working, either, but that was also the case before ENHANCE came out. Dr. Califf stated that, “for me, the fact it lowers LDL and does not appear to have side effects is enough until definitive outcome data become available,"

Califf said he thought ENHANCE was a "botched" trial. "They took 18 months to get the results out after the trial was completed. I am not aware of any reason why it could take that long unless the database had been messed up. We will find out more about that with the Congressional investigation, but these things sometimes happen. We all have screwed up trials–it happens."

But Califf believes that at the end of the day, the neutral result of ENHANCE is definitely not the end of the world. "This is just an imaging trial, and imaging is just another biomarker. They are by no means proof of anything. There are lots of problems with imaging trials, such as missing data, and we don’t know how many of these studies are actually published. HRT was actually shown beneficial in [intima media thickness] IMT studies. No biomarker can be 100% predictive of clinical outcome. In my book, LDL reduction is a much more solid biomarker than an IMT study, but I wouldn’t want to depend on either of them," he commented.

Dr Harvey White (Green Lane Hospital, Auckland, New Zealand), who is also an investigator in IMPROVE-IT, pointed out that the changes in carotid IMT in the ENHANCE trial were minimal, so that the study had no statistical power to detect differences between the two groups. "This will not change my practice; I think we need to treat to guideline goals with statins, and if that fails we should lower the LDL further with ezetimibe. Large clinical-outcome trials such as IMPROVE IT will help define lower treatment goals with ezetimibe added to simvastatin, as well as safety and efficacy."

And the ACC issued a statement saying that patients should not panic about the ENHANCE results and that major clinical decisions should not be made on the basis of this study alone. "Conclusions should not be made until the three large clinical-outcome trials are presented within the next two to three years. The ACC recommends that Zetia remain a reasonable option for patients who are currently on a high-dose statin but have not reached their goal. The ACC also notes that Zetia is a reasonable option for patients who cannot tolerate statins or can tolerate only a low-dose statin," the statement says.

Smilde TJ, van Wissen S, Wollersheim H, et al. Effect of aggressive versus conventional lipid lowering on atherosclerosis progression in familial hypercholesterolaemia (ASAP): a prospective, randomised, double-blind trial. Lancet 2001; 357:577-81. Abstract