Is ezetimibe/simvastatin no better than simvastatin alone? Lessons learned and clinical implications

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The last participant completed the trial in April 2006. Reading of the almost 30,000 scans was not started until the last participant was finished, so that all scans for each participant could be read in a blinded, randomized order by five separate readers. A significant proportion of the images that the protocol called for could not be obtained or analyzed, particularly in the internal carotid artery and the carotid bulb, which are often difficult to visualize. As a result, 17% of the internal carotid or carotid bulb measurements were discarded.

To change the end point post hoc, or not to change the end point?

The sponsor of the trial was concerned about the missing data points and convened a special advisory board to review the blinded data. This group suggested a solution: changing the primary end point from the six-site composite value to the mean value in just the common carotid arteries. They based this suggestion on the greater success rate in measuring the common carotids (97%) than in measuring all six sites (88%), as well as on recent trials that indicated that the common carotid artery measurement correlates better with clinical outcomes (because the internal carotid and the bulb measurements vary more). On November 26, 2007, Merck/Schering-Plough announced the primary end point would be changed to the mean change in the common carotid arteries.

However, during a separate meeting on November 30, 2007, some members of the Merck/Schering-Plough advisory board objected to the change. On December 11, 2007, the company announced that the original primary end point would not be changed.

Neutral results, negative publicity

On December 31, 2007, the ENHANCE study was unblinded, and on January 14, 2008, Merck/Schering-Plough issued a press release announcing the results. The press release stated that there were no statistically significant differences between the treatment groups in the primary end point or in any of the secondary end points, despite a 16.5% greater reduction in LDL-C (about 50 mg/dL) in the group receiving the ezetimibe/simvastatin combination. The composite intima-media thickness had increased by an average of 0.0111 mm in the combined-therapy group vs 0.0058 mm in the simvastatin-only group ( P = .29) over the 24-month treatment period. 5

The press release received unprecedented international media attention. One leading cardiologist commented to the media that ENHANCE showed “millions of patients may be taking a drug [ezetimibe] that does not benefit them, raising their risk of heart attacks and exposing them to potential side effects.” 6 The perceived message that ezetimibe/simvastatin is harmful resulted in thousands of phone calls from concerned patients to their physicians throughout the United States. The American Heart Association (AHA) and the American College of Cardiology (ACC) issued a joint statement the next day saying that ezetimibe/simvastatin does not appear to be unsafe and that patients should not stop taking the drug on their own. In the following days, Merck/Schering-Plough placed advertisements in newspapers reaffirming the safety of ezetimibe and quoting the AHA/ACC statement.

But the full results of the study were not available at that point. In fact, Senator Charles Grassley (R-Iowa) had launched a congressional investigation into the delays in releasing the results of the ENHANCE trial in December 2007. A focus of the investigation was whether the sponsor was delaying the release either because the data reflected negatively on its product or because it was legitimately concerned about the quality of the measurements of the carotid intima-media thickness. After Merck/Schering-Plough placed the advertisements quoting the AHA/ACC statement, these organizations were criticized for touting the safety of ezetimibe while receiving educational grants and other funds from Merck/Schering-Plough. Senator Grassley sent a letter to the ACC in late March requesting information about the amount of funds the ACC had received.

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