However, the results didn't shed light on whether or not further lowering LDL cholesterol with ezetimibe reduces hard clinical end points, such as MI. ENHANCE, a surrogate-end-point study, showed that combined therapy with ezetimibe and simvastatin in patients with familial hypercholesterolemia failed to bring about significant changes in intima-media thickness (IMT) compared with simvastatin alone, despite significantly greater reductions in LDL cholesterol and C-reactive protein.

Now, the study designed to specifically determine whether or not ezetimibe reduces clinical events, known as the IMPROVE-IT study, is expected to be delayed for an additional year, until 2012, because investigators have added more patients, increasing enrollment from the last target of 12 500 to 18 000. To date, 11 000 patients have been enrolled in IMPROVE-IT, a study chaired by Dr Eugene Braunwald of the TIMI Study Group and cochaired by Dr Robert Califf of the Duke Clinical Research Institute.

Speaking with heartwire, Dr Richard Veltri (Schering-Plough Research Institute, Kenilworth, NJ) said that more patients were added to the trial because blinded aggregate event rates were lower than expected. Investigators needed more patients to ensure that the study had appropriate power to detect a significant reduction in risk. This was first announced in a press release issued by the TIMI study group just two days before the ENHANCE study was presented and published. Investigators say the expansion will allow the study to test definitively whether the additional lowering of LDL cholesterol with ezetimibe plus statin therapy will translate into clinical benefit.

Veltri told heartwire that adding more patients was an option to "improve timing," despite the expected results being pushed back one year. Because it is an event-driven trial, the study is completed when the target number of events is reached and the last subject enrolled is followed for a minimum of 2.5 years. With lower aggregate event rates, an option would have been to extend the trial to detect significant reductions in risk, but the data monitoring board added more patients to get the results in a timely manner, said Veltri.

Although adding more patients will give study investigators sufficient power to detect differences between the two treatment approaches, the delay is hardly good news to Merck & Co and Schering-Plough. Nearly everyone heartwire spoke with saw little positive news in the ENHANCE study for ezetimibe, with experts saying 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.

Increasing the size of the trial, however, with a corresponding delay in the trial completion date, leaves Merck and Schering-Plough open to more criticism. As reported by heartwire, the drug companies marketing ezetimibe came under intense scrutiny for the 18-month delay in reporting the ENHANCE results and for issuing the results in a press release. The harshest criticism emerged when the company announced that it had convened an independent panel to review the images and as a result of that independent panel decided to change the primary end point of the trial, although the change was subsequently abandoned.

Lead investigator Dr John Kastelein (Academic Medical Center, Amsterdam, the Netherlands) said that ENHANCE has prevented him "from doing any real work for the past six months" and that his involvement in the trial has "been a very difficult period in my life."

Kastelein previously stated that he was relieved when the end point of ENHANCE was not changed, leaving some to question whether Merck/Schering-Plough were micromanaging the study. As previously reported, concerns about missing data or implausible IMT data led the companies to convene an independent panel to review select images; Kastelein was not a part of those discussions. Schering-Plough told heartwire that Kastelein endorsed the independent panel, recommended experts, and volunteered not to attend to prevent biasing their views.

Interestingly, as first reported by Forbes [2,3], no recording of the meeting exists and no minutes were taken. Schering-Plough's Veltri said they purposely did not to take minutes so that attendees could speak freely. Dr James Stein (University of Wisconsin, Madison), who was part of the independent panel, confirmed to heartwire that he participated in the panel and that they were told no minutes would be taken. He said the panel, which included Drs Robin Crouse and Gregory Evans (Wake Forest University, Winston-Salem, NC), former FDA division director Dr David Orloff, and Dr Michiel Bots (University Medical Center, Utrecht, the Netherlands), was told that Kastelein had recommended them and recused himself.

Stein said that he was asked to discuss the ENHANCE data and that he never felt that the purpose of the panel was to hide anything or deceive anyone. "Maybe I'm naive," said Stein, "but I never got the sense that anything improper was going on." He admitted, however, that it was "irregular" that the results were delayed, that the panel was convened, and that the results were presented in a press release.

Stein was selective about what he would divulge concerning the meeting because of an ongoing investigation by the House of Representatives' Committee on Energy and Commerce but said he thought it was an "overstatement to suggest that we unanimously recommended changing the primary end point." He added that the idea of changing the end point was considered, and each panel member had the opportunity to discuss the possibility, but enthusiasm varied.

In the end, he said, the panel felt it was a "not-unreasonable option" to change the end point. He stressed that panel members saw only a limited number of images, and without seeing them all they had no real way of commenting on the quality of the images. Schering-Plough has said that image quality is one of the reasons it entertained the idea of changing the primary end point (the change in carotid IMT, an average of the right and left common carotid arteries, carotid bulbs, and internal carotid arteries).

"At the end, though, all of our recommendations were qualified by the fact that we saw only a subset," said Stein. "Rereading them all just wouldn't be possible, given the delays already with this trial. There are over 40 000 images, and if we saw 100 of them, there is no way to make a judgment about it."

Schering-Plough sent a summary of the meeting to the US FDA. The summary was first sent to all those who participated in the meeting, including representatives from Merck and Schering-Plough, and then to the panel members. When they all agreed on the summary of the meeting, it was sent on to the FDA for its review, said Veltri.

During the press conference announcing the results, Kastelein said he would never do a trial like this on his own. "I was the sole PI. There was no steering committee, which is not that abnormal, but I would have loved five of my buddies to be standing next to me having the discussions with the statisticians, and not me alone."