Kenilworth and Whitehouse Station, NJ - Merck and Schering-Plough presented interim results of the Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) study today, a randomized, multicenter, placebo-controlled study evaluating the effects of combination ezetimibe/simvastatin (Vytorin) on clinical outcomes in roughly 1800 patients with aortic stenosis, and the results showed that the controversial cholesterol-lowering medication was no better than placebo in reducing the primary composite end point of aortic-valve and cardiovascular events.

The combination was significantly more effective than placebo in reducing the risk of ischemic events, a secondary composite end point of nonfatal MI, coronary artery bypass graft (CABG) surgery, PCI, hospitalization for unstable angina, nonhemorrhagic stroke, and cardiovascular death. Vytorin failed to meet a secondary goal of improving aortic-valve disease events, which included valve-replacement surgery, hospitalization because of heart failure, and cardiovascular mortality.

"The SEAS study has given a clear-cut answer to the question of whether intensive lipid lowering will influence the course of aortic-stenosis disease. I think we can conclude that it does not," announced Dr Terje Pedersen (Ulleval University Hospital, Oslo, Norway), chair of the steering committee, during a conference call today with the media. "We have also shown there is benefit in treating such patients with the study drug combination, as we saw a reduction in the risk of coronary artery disease."

The results, however, raised anxiety among the SEAS researchers after a safety signal grabbed everybody's attention. Despite the 20% reduction in ischemic events, concerns were raised by the significant increase in the risk of cancer, a finding that triggered a quickly performed analysis of ongoing studies with ezetimibe and simvastatin. Overall, Pedersen said there was a significantly higher incidence of cancer—102 patients taking ezetimibe/simvastatin compared with 67 taking placebo—and more patients died of cancer with the combination, a finding of borderline significance.

The cancer findings were concerning enough that an independent analysis of the two large ongoing studies, the IMPROVE-IT and SHARP trials, was performed to determine whether the cancer risk was real or chance. Sir Richard Peto (Clinical Trials Service Unit, Oxford, UK), an expert in clinical-trial meta-analyses and cancer epidemiology, said the data warranted further attention and have been reported to all the proper regulatory agencies.

In an analysis of IMPROVE-IT and SHARP, two studies that allowed for the testing of the hypothesis generated in SEAS, four times the number of cancers were observed than in the SEAS trial, but there was no overall risk of developing cancer with ezetimibe/simvastatin, said Peto. The cancer pattern observed in SEAS, occurring so quickly and without any one dominant type of cancer, as well as not increasing over time, is likely due to chance and should not divert anybody from taking the drug.

"The studies do not confirm the hypothesis that treatment with this combination increases the overall risk of developing cancer," said Peto.

Pedersen said he feels reassured by the Oxford analysis that the combination is well tolerated and safe. Dr Rory Collins (Clinical Trials Service Unit, Oxford, UK), chair of the SHARP steering committee, who was present during the conference call, said the data safety monitoring board (DSMB) endorsed Peto's conclusions, while the IMPROVE-IT DSMB is scheduled to meet in September. Dr Eugene Braunwald (Harvard Medical School, Boston, MA), cochair of the IMPROVE-IT steering committee, who phoned into the media event, said the group had been informed of the SEAS findings, but no changes to the study are planned, a recommendation that was made without Peto's analysis. The DSMB will be given the full results of Peto's investigation as soon as possible, said Braunwald.

There was speculation that the trial could help rehabilitate Vytorin after the Effect of Combination Ezetimibe and High-Dose Simvastatin vs Simvastatin Alone on the Atherosclerotic Process in Patients with Heterozygous Familial Hypercholesterolemia (ENHANCE) trial was published in March, but the placebo-controlled trial design, as well as the patient population, were likely to limit the clinical impact.

The presentation of the SEAS results today came as a surprise to investors, financial analysts, and the media, as the full data were not expected until later this year at the American Heart Association 2008 Scientific Sessions, in New Orleans, LA. Pedersen said he would have preferred to present the findings at an upcoming meeting and then publish them in a major medical journal, but interest in the study and difficulties maintaining secrecy about the findings made that problematic.

The SEAS results are the first clinical results for Vytorin since ENHANCE was published. In that study, investigators tested the effectiveness of combined ezetimibe/simvastatin therapy in patients with familial hypercholesterolemia and found that the combination did no better than simvastatin monotherapy on several surrogate end points. The combination did not result in a significant difference in changes in intima-media thickness compared with simvastatin alone, despite significantly greater reductions in LDL cholesterol and C-reactive protein.

Many experts used the ENHANCE findings to criticize the explosion in prescriptions for Vytorin since its approval, an explosion that occurred without hard clinical end-point results. With the benefit of Vytorin unproven and full results of IMPROVE-IT, the clinical outcomes study, not expected until 2012, nearly a decade after the US Food and Drug Administration approval of ezetimibe as an adjunct to statins for cholesterol lowering, it had been thought the SEAS study could help persuade doctors to use Vytorin and ezetimibe alone (Zetia, Merck/Schering-Plough) again. Since ENHANCE, prescriptions of both drugs are down as much as 40%.

Pedersen said that the results of SEAS are unlikely to change clinical practice, and it was pointed out repeatedly that the trial was designed only to test whether aggressive LDL-cholesterol lowering with Vytorin was effective in treating patients with aortic stenosis. In this study, treatment with ezetimibe and simvastatin reduced LDL-cholesterol levels from 140 mg/dL to 52 mg/dL. Investigators stressed the trial was not designed to test whether the addition of ezetimibe to statin therapy provides additional benefit in reducing clinical events, something that will have to wait to be answered by the IMPROVE-IT trial.

"I'm very pleased with the fact that intense cholesterol lowering reduces coronary events in patients with aortic stenosis, a group of patients in whom I've had a longstanding interest," said Braunwald. "We have a green light to continue the [IMPROVE-IT] trial. We think that's a really important trial, sort of the center of a bull's-eye of coronary disease."

Also speaking on the conference call, IMPROVE-IT cochair Dr Robert Califf (Duke Clinical Research Institute, Durham, NC) said it is important not to overreact, either positively or negatively, to the SEAS findings. He called it an important contribution to the literature, but that a single, isolated study is unable to tell a complete story.