Chicago, IL - The Effect of Combination Ezetimibe and High-Dose Simvastatin vs Simvastatin Alone on the Atherosclerotic Process in Patients with Heterozygous Familial Hypercholesterolemia (ENHANCE) trial will be presented in just over a month at the American College of Cardiology 2008 Scientific Sessions, but there are important lessons to be learned from the past, especially as to how the study was initially presented and discussed in past seven weeks [1].

So says Dr Philip Greenland (Feinberg School of Medicine, Chicago, IL), coauthor of a new commentary, along with Dr Donald Lloyd-Jones (Feinberg School of Medicine, Chicago, IL), in the February 27, 2008 issue of the Journal of the American Medical Association. Reviewing key features of the controversial study, Greenland and Lloyd-Jones call the fallout from ENHANCE "an unfortunate medical research experience" and suggest lessons to be learned by drug companies, researchers, clinicians, health agencies, and the media to avoid repeating the same mistakes with other trials.

Speaking with heartwire, Greenland said the ENHANCE trial, in which results were presented in a press release from Merck and Schering-Plough Pharmaceuticals, the makers of the simvastatin/ezetimibe combination tablet (Vytorin) studied in ENHANCE, was a very difficult trial to interpret.

"The reason that it has been so difficult to provide interpretation is that it has not gone through the usual peer-review process," said Greenland. "Normally, with peer review, there is an effort to put the study in the proper context. Even if the authors are unable to be objective about it, you hope that reviewers and editors will be. That then provides some context for the media to be able to report on it. In this situation, all the information came from the drug companies, and while there were efforts in the media to get both sides of the story, there was not a lot of nuanced interpretation."

Instead, after the release of the data on January 14, 2008, discussion about the ENHANCE trial was dominated by those with opinions at opposing ends of the spectrum. In that regard, said Greenland, the polarizing comments from key opinion leaders, with some flatly against the use of Vytorin and others adopting a more wait-and-see approach, led to confusion.

"There were a lot of us who had patients calling up saying that they were stopping their medication," said Greenland. "And as is usually the case, it's the wrong patient who wants to stop."

There were a lot of us who had patients calling up saying that they were stopping their medication. And as is usually the case, it's the wrong patient who wants to stop.

One of the most important lessons to be learned from ENHANCE is that drug trials should not be conducted for marketing purposes. In the commentary, as well as to heartwire, Greenland, who is also the editor of the Archives of Internal Medicine, asked just what specifically the ENHANCE study was designed to prove. A negative outcome would not have led to any different conclusions drawn than a positive outcome would have, mainly because the study was only a small-scale, surrogate-end-point study.

"If you really take the argument that the drug company is taking, that this result is a nonresult, then the logical interpretation is that a different result would have also been a nonresult," said Greenland. "I firmly believe that the goal of this study was to provide a means of promoting the drug for the next several years until the real study, the outcomes study, comes out. To me, if you're not prepared to publish a result that is disappointing, you shouldn't be doing the study in the first place."

The outcomes study, known as IMPROVE-IT, is comparing simvastatin 40 mg plus ezetimibe 10 mg with simvastatin 40 mg alone in patients with a recent acute coronary syndrome. The trial has recruited about 10 000 patients so far, but the results will not be available until approximately 2011, or, as noted by Greenland, nearly nine years after FDA approval of ezetimibe as an adjunct to statins for cholesterol lowering.

Ezetimibe alone (Zetia) and Vytorin 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. This led to problems, because many in the media got the basic facts wrong about the study, said Greenland.

For one thing, ENHANCE was not a clinical-end-point trial, as was reported in the media, nor were the results "negative," said Greenland. They were not statistically significant, a big difference lost among some in the media. Moreover, the end point was not "fatty plaque," as reported by others, but intima-media thickness. More concerning, however, was the fact that ENHANCE "mushroomed" to the point where almost 50 years of "serious and logical research has been damaged and defamed for no good purpose," write Greenland and Lloyd-Jones.

To heartwire, Greenland was critical of a Business Week article [2] entitled "Do cholesterol drugs do any good?" While the aim of the article was to point out that there are people taking statins who are at low risk, its publication might have actually made things more difficult for doctors and their patients.

Putting something out there like this article in mainstream media as they did runs a risk of doing more harm than good.

"Statins are overused, no doubt about it, but that's not because the drugs are bad," he said. "I think the problem is that there is a lot of oversimplification going on. I'm in favor of looking at the totality of evidence with some nuance. Not every patient with a cholesterol level of 220 [mg/dL] has the same cardiovascular risk. This is not a secret to anybody with expertise in cardiovascular medicine. A 20-year-old with elevated cholesterol but no other risk factors has a very different risk profile than somebody who is older, has elevated cholesterol, and blood pressure of 160/90 mm Hg.

"But for those of us in the field," he continued, "those of us trying to help clinicians understand the right patient to treat, putting something out there like this article in mainstream media as they did runs a risk of doing more harm than good."

Greenland also faulted the New York Times, particularly for an opinion piece by Gary Taubes that questioned the importance of lowering cholesterol [3]. "How is that going to inform the public of what's going on?" asked Greenland.

While ENHANCE was being hashed out in the media, Greenland said he hoped the American Heart Association (AHA) would release a statement explaining the incomplete and confusing results of the trial. This, unfortunately, backfired, as the AHA and the American College of Cardiology (ACC), which also released a statement, were criticized for receiving industry financing, something many believed was a conflict of interest. While the AHA and ACC adamantly denied the statements had anything to do with the funding, the US House Energy and Commerce Committee is investigating their relationship with Merck and Schering-Plough.

Greenland told heartwire that he believes the AHA and ACC are capable of sorting through the data to make evidence-based decisions and recommendations. However, as he and Lloyd-Jones write, these "organizations must distance themselves from industry support to retain their credibility with physicians and health consumers. Without that level of credibility, the marketplace for truth is up for grabs, with no one capable of claiming the high road."

Asked about how he first interpreted the results and sorted through the maelstrom of opinion surrounding ENHANCE, Greenland said, "I might have been swayed by the study at a different time in my own career. As a profession, we need to be a lot more suspicious and to look carefully at where the information is coming from."