ENHANCE Finds No Slowing of Plaque Burden With Ezetimibe/Simvastatin (Vytorin)

By Peggy Peck
The combination of ezetimibe/simvastatin (Vytorin) did not appear to slow progression of atherosclerosis among patients with heterozygous familial hypercholesterolemia, according to the drug makers.But in the face of unverified reports that the trial data had been delayed for marketing reasons, congressional leaders said they planned to pursue an investigation into the circumstances surrounding the reporting. There was no significant difference in the randomized ENHANCE study's primary endpoint -- mean change in carotid intima-media thickness -- between a change of 0.0111 mm for 356 ezetimibe/simvastatin patients versus 0.0058 mm for 360 control patients (P=0.29) taking simvastatin alone.
The combination achieved a significantly greater decrease in LDLs, a 58% reduction in LDLs for the ezetimibe/simvastatin group versus 42% for simvastatin controls after 24 months (P<0.01), according to a joint announcement today from Merck here and Schering-Plough in Kenilworth, N.J.
But that LDL drop was not significantly greater than declines reported with aggressive doses of more potent statins such as atorvastatin (Lipitor) and rosuvastatin (Crestor). And high-dose atorvastatin has been associated with a slowing of plaque progression in several randomized trials.
That suggested to Steven Nissen, M.D., director of cardiovascular medicine at the Cleveland Clinic, that mechanistic differences between ezetimibe and statins might affect atherosclerosis progression.
The pleiotrophic effects of statins -- lower LDL, increased HDL, and decreased C-reactive protein -- may be more potent than simply lowering LDL, he said.
Dr. Nissen said the ENHANCE results, issued today as a press release, were stunning, adding that on the basis on this evidence there was no good reason to prescribe ezetimibe, because "if it doesn't work in [heterozygous familial hypercholesterolemia], why use it?"
As a result, Dr. Nissen called for a moratorium on the use of both ezetimibe/simvastatin and ezetimibe (Zetia) monotherapy.
He said, "every endpoint [in ENHANCE] is going in the wrong direction."
The primary endpoint of ENHANCE was the mean change in intima-media thickness measured at the left and right common carotids, the internal carotids, and the carotid bulb between patients randomized to ezetimibe/simvastatin (10 mg/80mg) versus patients randomized to 80 mg of simvastatin.
At baseline, the mean carotid intima-media thickness measurement for ezetimibe/simvastatin was 0.68 mm and for simvastatin 80 mg was 0.69 mm. There was also no statistically significant difference between the treatment groups for each of the components of the primary endpoint, including the common carotid artery. The key secondary imaging endpoints showed no statistical difference between treatment groups.
The overall occurrence rates of treatment-related adverse events, serious adverse events, or adverse events leading to discontinuation were generally similar between treatment groups.
The occurrence rates of consecutive elevations of serum transaminases (≥3xULN) was 10 of 356 for ezetimibe/simvastatin (2.8 %) compared with eight of 360 for simvastatin (2.2%).
The occurrence rate of elevated creatine phosphokinase (≥10xULN) was four of 356 (1.1%) in the ezetimibe/simvastatin group and eight of 360 (2.2%) in the simvastatin group. There were two cases (0.6%) of CPK≥10xULN associated with muscle symptoms in the ezetimibe/simvastatin group and one case (0.3%) in the simvastatin group.
There were two cardiovascular deaths, three nonfatal MIs, and one nonfatal stroke in the ezetimibe/simvastatin group versus one cardiovascular death, two nonfatal MIs, and one nonfatal stroke in the simvastatin arm. Six patients who received the combination and five patients in the simvastatin arm required revascularization.
There were no cases of rhabdomyolysis in the ENHANCE trial.
The release of data by Merck and Schering-Plough followed a letter sent to the drug makers by Rep. John Dingell (D-Mich.) in December. That letter alleged that the companies were intentionally withholding the results of the ENHANCE study, which had originally been slated to be reported almost two years ago.
In the letter, Dingell, who chairs the House Energy and Commerce Committee, said that withholding data significantly affected medical management of hypercholesterolemia.
Dingell also asked the company to respond to rumors that it attempted to "change the endpoints" of the trial. In the months that researchers have been waiting for results of ENHANCE, there have been a number of rumors of post hoc changes in trial design, including a report that a "committee of experts" was recommending such a change.
Dingell has asked that Enrico Veltri, M.D. of Schering-Plough, and John Kastelein, M.D. of the Academic Medical Center in Amsterdam in Holland, who is principal investigator of ENHANCE, meet with his committee to discuss ENHANCE.
Late today, Dingell and Rep. Bart Stupak (D-Mich.), who chairs an Energy and Commerce subcommittee on oversight and investigations, said they are continuing the investigation they started on Dec. 11.
Dr. Kastelein will present the full results of ENHANCE at the American College of Cardiology meeting in late March and it is likely that the study will be simultaneously published in a major journal