Concerns raised on delay of ezetimibe data

November 22, 2007

Amsterdam, the Netherlands - There have been concerns raised in multiple press reports this week about delays in reporting the results of the first key study with the cholesterol drug ezetimibe.

The results of the carotid ultrasound trial, ENHANCE, are indeed late, which has led to much speculation that the results are negative and the companies are therefore delaying their release, but lead investigator of the study, Dr John Kastelein (Academic Medical Center, Amsterdam, the Netherlands), says this is not the case. He commented to heart wire : "Yes, there have been delays with this trial, but that does not mean the results are negative. In fact, the data are still blinded, so we do not know the outcome yet. This whole media interest has been a lot of excitement about not much."

Ezetimibe has a complementary action to the statins, preventing the intestinal absorption of cholesterol, and generally adds an extra 20% LDL reduction to that seen with statins alone. It is available as a standalone treatment under the name Zetia and as a combination tablet with si mvastatin under the name Vytorin and is marketed by Merck and Schering-Plough. Ezetimibe is a relative newcomer to the cholesterol market but is already generating blockbuster sales, said to be in the region of $5 billion. That is despite the fact there are no outcome data available on the drug.

High stakes riding on ENHANCE

The ENHANCE trial is the first major study to be conducted with ezetimibe, which is why the results are so eagerly anticipated. Although it is not a clinical-outcome study, carotid ultrasound studies monitoring the effects of drug therapy on atherosclerotic plaque are seen as a reliable surrogate and normally predict whether a drug will be effective in lowering cardiac events. ENHANCE, which was started in 2002, randomized almost 800 patients with familial hypercholesterolemia to treatment with simvastatin alone or simvastatin plus ezetimibe. It was hoped that results, focusing on the progression of atherosclerosis in the carotid artery, would be available this year, but they have not been presented yet.

Kastelein explained that the study was late in reporting because of technical difficulties with the large amount of data generated. He commented to heart wire : "This is the largest study of carotid IMT that we have conducted, involving 19 different centers, and this is also the first trial in which all the [intima media thickness] IMT data have been recorded digitally rather than on videotape. We have assessed atherosclerosis at three sites in each of the two carotid arteries and in two femoral arteries. And we have to assess each image with two different ultrasound waves—B mode to assess the size of the plaque and M mode to assess the elasticity of the artery. We have almost 40 000 images to process. That is an incredible amount of data to deal with. Maybe we were a little ambitious on the timeframe required to process so much data. That is why there has been some delay. The suggestion that the results are being suppressed because they are negative is simply wrong. People are assuming that anyone can take a peek at the data, but how can they do that if it hasn't even been unblinded and there are 40 000 images to analyze?"

Primary end point changed

Kastelein said the current bout of media reports were generated by a press release issued last week by Schering-Plough announcing that the primary end point of the study was being changed. This was the result of a meeting of an outside expert panel, convened by the company, to discuss how to proceed with the analysis of the data. Kastelein explained: "The company was insecure about a few things—the fact that there were some images missing and some outliers (patients who have odd results). But these things are completely normal in this type of trial. I told them that, but they wanted to consult some other experts on this. And they all said the same thing—that it was normal and they should just get on with the analysis."

One other thing that was discussed at that meeting was which site in the carotid artery would be the best for the primary end point. Kastelein said that when the study began it was believed that a combination of three different measurements from different sites in the carotid artery was the best indication of atherosclerosis progression, and that is what the primary end point was set as. But since then, several other studies have suggested that the one measurement in the common carotid artery was the most sensitive to lipid changes and is easier to measure and so would be subject to less variation, giving greater statistical power. "Slowly a picture is emerging that this one measurement in the common carotid artery may be better, and this was discussed at the expert panel meeting. It was then agreed to switch the primary end point to this measurement, which was a secondary end point before, and the original three-site measurements will now be a secondary end point."

Asked why an independent panel was brought in to make these decisions, which is a rather unusual occurrence, Kastelein said it was because the company was nervous, given the high stakes riding on this study. "These are very important data for the company. The drug has huge sales, and this study will be the first real indication as to whether it is working. Everybody is understandably nervous. My opinion was that everything was fine the way it was and we should just continue, but they wanted some additional reassurance from outside experts and they got it. I didn't like it very much, but it was necessary to settle their minds," he said.

Results at ACC

Kastelein says the results will now likely be presented at the American College of Cardiology (ACC) meeting next March. He says the current media attention will probably mean that the data will be scrutinized more closely than ever. "You can be sure that when I'm standing up there at the ACC announcing the results, one of my first slides will show data to convince people that this trial is not different from other IMT trials."

He says the whole debacle has highlighted the tensions that exist between the lead investigator of a study and the sponsor. "The other experts supported me, but maybe we have had more difficulties with this study because the sponsor has control over the database. If the investigators have control, then we get to do the analysis our way. In future, I will try very hard to get this," he added.

Three clinical-outcome trials under way

Although ENHANCE will give the first indication of whether ezetimibe is working or not, it still won't provide definite information on whether clinical events will be reduced with the drug. But three clinical end point trials are under way. These are the SEAS trial in patients with aortic stenosis, being coordinated by Dr Terje Pedersen (Ulleval University Hospital, Norway) of 4S fame; the IMPROVE-IT trial in 10 000 ACS patients, being run by the Duke and TIMI clinical trial groups; and the SHARP trial in 9000 patients with chronic kidney disease, conducted by the Oxford, UK group.

Media swoop on delays

The lay press were quick to highlight the delays with the ENHANCE study and to drum up speculation that this was not good news. Forbes ran a story quoting another expert in the field, Dr Allen J Taylor (Walter Reed Army Medical Center, Washington, DC), as saying the delay "starts to raise suspicion. The more time it takes, the more you start to naturally wonder what is wrong," and quoting Dr Robert Califf (Duke University, Durham, NC) as saying: "We'd all agree that having this long a delay after a study's over is bad thing," but adding: "I sure hope Zetia works. I'm taking it myself."

The Forbes article also quotes Dr Paul Thompson (Hartford Hospital, Connecticut), highlighting the high stakes of the study: "A bad result would cause Pfizer and AstraZeneca sales reps to turn up at every hospital in the country 'within milliseconds,' " he said. Dr Prediman Shah (Cedars-Sinai Medical Center, Los Angeles, CA) is reported as saying that it would not make "an iota of sense" for Zetia not to work, given it lowers LDL, a view contradicted by Dr Richard Lange (Johns Hopkins University, Baltimore, MD), who notes that so far there is no evidence that patients get extra benefit by adding Zetia. "They're going to have to explain exactly what the delay was," Lange says. "At that point we'll have enough information to know it passes the sniff test." The article also quotes Kastelein as saying: "I certainly want it finished. There are all sorts of conspiracy theories that are not good for my reputation."

The New York Times has Dr Bruce Psaty (University of Washington, Seattle) questioning the change in end point. "This sounds highly unusual to me. You need to live with your primary end point," he comments. The article also quotes Dr John Crouse (Wake Forest University, Winston-Salem, NC), who conducted a similar trial with rosuvastatin, who points out that measuring plaque can be complicated and that Merck and Schering might simply have run into delays in analyzing their data. "It's easy for things not to go the way you would hope they would go," he said.



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