Study investigators, led by Dr John Kastelein (Academic Medical Center, Amsterdam, the Netherlands), tested the effectiveness of combined therapy with ezetimibe and simvastatin in patients with familial hypercholesterolemia (FH) and found that the combination did no better than simvastatin monotherapy on several surrogate end points. The combination, known as Vytorin, did not result in a significant difference in changes in intima-media thickness (IMT) compared with simvastatin alone, despite significantly greater reductions in LDL cholesterol and C-reactive protein.

The final results of the study, presented today during a unique opening session at the American College of Cardiology (ACC) 2008 Scientific Sessions and published simultaneously in the New England Journal of Medicine [1], have been the subject of much discussion, rumor, and innuendo, mainly because of the 18-month delay between trial completion and the presentation of the results in a press release January 14, 2008. With the full data now in the public domain, experts say the results contradict expectations, although what should happen next isn't exactly clear.

There is little in ENHANCE that is in the drug's favor, and I don't know if there's anything.

"There is little in ENHANCE that is in the drug's favor, and I don't know if there's anything," Dr Harlan Krumholz (Yale University School of Medicine, New Haven, CT), who was not affiliated with the study but is part of an ACC panel discussing the trial, told heartwire. "There isn't much new in the study either, but it does give us a chance to take a deep breath and recognize how little we know about the real effect of this drug on people. However, I think to say we should keep doing what we're doing until the clinical trials come out is a problem."

During the opening session, Krumholz spoke passionately on behalf of panel members Drs Joseph Messer (Rush University, Chicago, IL), Rick Nishimura (Mayo Clinic, Rochester, MN), and Patrick O'Gara (Brigham and Women's Hospital, Boston, MA), and the overall panel consensus was a "return to first principles, optimizing the doses of statin medications," rather than adding ezetimibe to a low-dose statin.

In an editorial accompanying the published study [2], Drs Greg Brown (University of Washington School of Medicine, Seattle) and Allen Taylor (Walter Reed Army Medical Center, Washington, DC) write that the possibility that ezetimibe provides no clinical benefit when added to statin therapy is the "elephant in the parlor" and deserves serious consideration in a discussion of the study results.

"Although a reduction in intima-media thickness does not guarantee a reduction in the rate of events, it seems unlikely that a reduction in events can be expected without a reduction in the progression of intima-media thickness," write Brown and Taylor.

Dr Steven Nissen (Cleveland Clinic, OH), who was not part of the ENHANCE study, said the ability of ezetimibe to reduce hard clinical end points is questionable, which causes problems for clinicians. "Everyone would have to agree that ENHANCE is not a clinical-outcomes trial and is not the final word, but it's certainly not looking very good for the drug," Nissen told heartwire. "The really interesting question is what to do when you have no evidence of clinical benefit, where the numbers are actually going in the wrong direction for most of the end points. What do you do in the meantime?"

Ezetimibe alone (Zetia) and Vytorin, both marketed by Merck & Co and Schering-Plough Corporation, have combined sales of about $5 billion. Because of these enormous numbers, the ENHANCE trial was closely watched by financial analysts and the media. However, with no outcomes data yet, clinicians also eagerly anticipated the results of this surrogate end-point study.

ENHANCE investigators sought to determine whether 20 mg of ezetimibe in combination with 80 mg of simvastatin would reduce the progression of atherosclerosis, as measured by B-mode ultrasonography in 720 patients with FH. The rationale for studying these patients, according to investigators, was that they have a greatly increased risk of developing premature coronary artery disease and have an increased rate of progression of IMT. The primary end point of the study was change in the carotid IMT, an average of the right and left common carotid arteries, carotid bulbs, and internal carotid arteries.

As expected and as has been previously reported by heartwire, ezetimibe/simvastatin combination therapy significantly reduced LDL cholesterol more than simvastatin alone—a between-group difference of 16.5%. New data show that C-reactive protein and triglyceride levels were also reduced to a significantly greater extent with the combination therapy.

In terms of the primary outcome, however, treatment with ezetimibe/simvastatin did not have an effect on the progression of IMT, with no significant differences in the change in carotid IMT between ezetimibe/simvastatin and simvastatin alone. Regarding secondary end points, including the regression in mean carotid IMT, new plaque formation, and various individual measurements of the carotid artery, there was no significant difference between the two therapies.

Speaking with the media during a hastily convened press conference, Kastelein said that his clinic takes care of approximately 10 000 patients with FH, the most in the world. For this special population, ezetimibe has been extremely useful in reducing LDL-cholesterol levels. Despite the lack of effect on carotid IMT, he is planning to keep his patients on the drug until more evidence is available.

"For them, the addition of ezetimibe to statin therapy, the highest-dose statin therapy, is the only way to get normal LDL cholesterol," he said. "So what will I do? I'll wait until I get the results of the IMPROVE-IT trial. . . . I can't go back to Amsterdam and tell them, 'Listen, we've done a 700-person trial and now I'm going to stop ezetimibe.' "

Discussing the results with heartwire, however, Krumholz was critical, saying he is not so quick to dismiss the statistically nonsignificant finding that atherosclerosis progression was nearly doubled with the ezetimibe/simvastatin combination. Although this could be due to chance, doctors still have no assurances that the drug is safe. Patients aren't having reactions to the drug, and there are no apparent adverse effects with ezetimibe, but the safety data aren't in yet and won't be until large clinical trials are done, he said.

"We don't know what this drug does for people, and that means we should be very cautious with how we use it," said Krumholz. Although ezetimibe might prove to be effective in reducing clinical events and lowering LDL cholesterol through the drug's mechanisms—ezetimibe inhibits cholesterol absorption in the gut—might prove to be beneficial, the ENHANCE findings make this unlikely, he said.

Dr Antonio Gotto (Weill-Cornell Medical School, NY) told heartwire that he is concerned about the panel recommendations, mainly out of fear that patients will stop taking their medications. Moreover, he thinks that the panel overplayed the safety issue, saying he believes the drug is extremely safe and that there is no reason to expect that taking it won't reduce hard clinical end points, such as MI and death, because of the significant 16% further reduction in LDL cholesterol. While patients should always be started on statins, he sees as many as 10% to 15% of patients who are statin intolerant.

With the data out there, the big question then becomes: What happened with ezetimibe, a drug that produced reductions in LDL cholesterol beyond high-dose statin therapy but did not affect atherosclerosis disease as measured by IMT? As pointed out by Kastelein and colleagues, IMT is a validated surrogate marker for atherosclerotic vascular disease.

The group suggests that the reason ezetimibe failed to show a benefit is because the treatment of patients with FH has changed, with most, including those in this study, having been treated with high-dose statin therapy from an early age. This intensive therapy attenuates the progression of IMT, as was shown in the Atorvastatin vs Simvastatin on Atherosclerosis Progression (ASAP) trial and as was observed in the finding that FH patients in ENHANCE had lower baseline carotid IMT than was observed in earlier trials, with the exception of the Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol 1 (ARBITER-1).

"These data raise the possibility that there may be limits to the extent to which the lowering of LDL-cholesterol levels can result in a further decrease in the progression of intima-media thickness in the context of previous statin therapy and a modest baseline intima-media thickness," suggest the ENHANCE investigators.

The results show what they show, and the results are very disappointing.

Nearly everyone heartwire spoke with saw little positive news in the ENHANCE study for ezetimibe, but Dr Roger Blumenthal (Johns Hopkins University Medical Center, Baltimore, MD) told heartwire that he is cautiously optimistic that the upcoming clinical-outcomes trial, known as IMPROVE-IT, will be positive. He noted that the ORION study showed that rosuvastatin altered the composition of the plaque, something that is still a possibility with ezetimibe and that could result in favorable clinical outcomes.

Although he echoed many concerns raised by other investigators, including the lack of benefit in statin-naive patients and new plaque formation going in the wrong direction with ezetimibe, Blumenthal said two limitations "bias ENHANCE toward the null." He pointed out that investigators did not perform EKG gating, meaning that they did not take measurements of the carotid IMT during the heart's contraction, a commonly used means of controlling image variability. They also used single-frame technology instead of putting the images on a cine loop, a method that would have also improved quality.

"Nevertheless," said Blumenthal, "the results show what they show, and the results are very disappointing."

Commenting to heartwire, Dr Sanjay Kaul (Cedars Sinai Medical Center, Los Angeles, CA) said that although several mechanisms have been suggested, "the bottom line is that we simply don't know the reasons for the lack of an effect on IMT." Although laboratory investigations might be suggestive of the lipid-independent effects of statins—the so-called "pleiotropic effects," which might contribute to vascular protection—trial data so far do not provide supportive evidence. "Thus, this is unlikely to explain Zetia's null effect on IMT," he said.

In their editorial, Brown and Taylor agree that that the mean baseline carotid IMT is much thinner than in the ASAP study and that long-term statin therapy could affect the ability of ezetimibe to have a treatment benefit. The argument against this hypothesis, as pointed out by Blumenthal and Nissen, is that the 19% of patients not receiving statins at the time of study enrollment did not fare any better than those who were on previous statin therapy.

You should use statins first, statins second, and statins third.

Nissen agreed with the editorialists, emphasizing the importance of the subgroup analyses. He disputed the notion that patient arteries were too healthy and noted that even those with carotid IMT above the median at baseline did not benefit from the addition of ezetimibe. In the meantime, Nissen, Blumenthal, Kaul, Brown, and Taylor advise that clinicians should prescribe ezetimibe only in patients who fail to achieve LDL- and HDL-cholesterol treatment targets with statins and other drugs that have shown clinical benefit when added to statins, such as nicotinic acid, fibrates, and bile acid sequestrants.

"You should use statins first, statins second, and statins third," said Nissen. "You should consider every other alternative, reserving ezetimibe only for patients who do not respond to or cannot tolerate other agents."

Krumholz told heartwire that although this is good theory, the reality is more difficult. "The hard part here is saying you should use niacin, resins, and fibrates, but we know that those aren't really going to get people to target," he said. "Patients have a hard time tolerating those drugs. The one thing we all agree on is that there are a lot of people who were not maximized on a statin before getting started on ezetimibe. Every single one of those individuals should be taken off ezetimibe and maximized on statins. That's something there shouldn't be any controversy about."

He added that there might be a group of patients who do not tolerate statins and these other agents, and ezetimibe might be an option for them, although he wasn't sure if this would be the right decision. Fortunately, said Krumholz, the number of patients who can't tolerate high doses of statins is not that large.

Although experts finally have the ENHANCE study to hash over and clinicians will digest the findings and their implications, the waiting game begins again. The clinical-outcomes study, IMPROVE-IT, was originally set to compare simvastatin 40 mg plus ezetimibe 10 mg with simvastatin 40 mg alone in 10 000 patients with a recent acute coronary syndrome and is set to clarify the ENHANCE findings. However, Dr Richard Veltri (Schering-Plough Research Institute, Kenilworth, NJ) told heartwire that event rates reported so far are lower than expected, and for that reason the study will now enroll 18 000 patients. Those results will be available in 2012, nearly a decade after the US Food and Drug Administration approval of ezetimibe as an adjunct to statins for cholesterol lowering.

In the meantime, the ENHANCE findings are a "red flag but not a black box," conclude Brown and Taylor.