ENHANCE Saga Continues: Experts Dispute Ezetimibe's Future and "Weight" of Imaging Studies

January 18, 2008

January 18, 2008 (Whitehouse Station/Kenilworth NJ) - 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. It was the lead item on many US television news programs on Monday, and sales of ezetimibe--which have been running at around $5 billion worldwide--are now bound to fall. Indeed, in a poll on theheart.org, 60% of respondents said they would now be less likely to prescribe the drug.

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.

Califf: "I'm still taking it"

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. For me, the fact it lowers LDL and does not appear to have side effects is enough until definitive outcome data become available," he told heartwire .

Califf gave similar comments to the Wall Street Journal when the ENHANCE results were first released, adding: "Until that point, I'm only losing money." The newspaper reports that a 30-day supply of ezetimibe 10 mg costs around $93 and Vytorin (10 mg ezetimibe and 80 mg simvastatin) $100, vs just $32 for generic simvastatin 80 mg.

Contributors to the Wall Street Journal Health Blog did not seem to take too kindly to Califf's comments, pointing out that as a prominent cardiologist, he can probably afford ezetimibe, but many others can't, and that Schering-Plough contributes heavily to the Duke Clinical Research Institute. Califf told heartwire that this was a "fair comment."

"People need to interpret my comments any way they will. Yes, we do a lot of work with Schering-Plough, but we also work with about 80 other companies, and unfortunately you can't conduct large trials without involvement with the industry. But I don't think I would actually be taking a drug just because I am doing a trial for the company that makes it."

A "botched" trial?

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.

Several other experts contacted by heartwire took a view similar to Califf's. Dr Sanjay Kaul (Cedar Sinai Medical Center, Los Angeles, CA) commented: "Embracing a therapeutic intervention as a resounding success or rejecting it as a disappointing failure simply on the basis of an imaging outcome study is rather short-sighted and betrays a higher confidence in surrogacy than is otherwise warranted by the existing body of evidence. Bottom line, surrogate end points are a slippery slope. We need to await the results of clinical-outcome studies before drawing any firm conclusions."

Power limited

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.

Nissen not reassured

But Nissen is still not convinced by all these reassurances. "If the ENHANCE trial had shown regression of atherosclerosis or slowed progression, both the company and advocates of ezetimibe would be trumpeting the results as a landmark study. Now that the trial has failed, they describe ENHANCE as a small and unimportant imaging study. You can't have it both ways," he commented to heartwire . Contrary to Califf's assertion that it was "botched," Nissen says ENHANCE was well designed and well executed, and the sponsors had an understanding with the FDA that a positive result would potentially yield a label claim.

"The main problem is that after six years on the market, there are no data for ezetimibe demonstrating any health outcome benefit. Statins do much more than lower LDL. They increase HDL, lower triglycerides, and reduce inflammation. In the absence of any demonstrable effect beyond LDL lowering, nearly one million prescriptions per week are written for ezetimibe. Is this rational?" Nissen asked.

He cited another imaging study, ASAP, which was published in the Lancet in 2001 by the same lead investigator as ENHANCE (Dr John Kastelein [Academic Medical Center, Amsterdam, the Netherlands]) and studied simvastatin and atorvastatin in the same familial-hypercholesterolemia population as ENHANCE [1]. "ASAP showed a 9% additional lowering of LDL with atorvastatin, which resulted in a highly significant difference in CIMT progression. In fact, the intensive-statin group actually regressed. In contrast, ENHANCE had a 17% lower LDL in the ezetimibe-simvastatin group, but the progression rates showed no benefit and actually trended in the wrong direction," Nissen added.

  1. 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

The complete contents of Heartwire , a professional news service of WebMD, can be found at www.theheart.org, a Web site for cardiovascular healthcare professionals.

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