Sophia Antipolis, France - Early next month at the upcoming European Society of Cardiology (ESC) 2008 Congress, in Munich, Germany, investigators will present study results from the Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) trial, a study that generated yet more controversy for the cholesterol-lowering combination when the results were presented a few weeks ago. The presentation should give clinicians a better look at the data, investigators told the ESC, and provide more information about the end points and the incidence of clinical events in patients, as well as information on the incidence and types of cancer observed in the study.

The ESC 2008 Congress is scheduled to begin August 30, 2008 and run until September 3, 2008, with the SEAS results presented by Dr Terje Pedersen (Ulleval University Hospital, Oslo, Norway) during a morning press conference scheduled for Tuesday, September 2, 2008. The results of the study—SEAS is a randomized, multicenter, placebo-controlled study evaluating the effects of combination Vytorin (Merck/Schering Plough Pharmaceuticals) on clinical outcomes in roughly 1800 patients with aortic stenosis—will be presented in full that same day during the ESC hotline sessions.

Interim findings were previously presented July 21, 2008 during a press conference in London, UK and reported by heartwire at that time. The results showed the 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. This reduction, noted investigators, was driven largely by a reduction in CABG surgery.

In an interview with the ESC, Pedersen said there is a need to be cautious when interpreting the secondary end point but that the ischemic-event end point in SEAS was prespecified and therefore valid. "My approach is to take the results of other trials into consideration—there are now 25 randomized trials showing that ischemic events related to atherosclerosis will be reduced with lipid-lowering therapy," said Pedersen. "So it seems valid when we find a reduction in coronary bypass surgery in our treated patients. The evidence from other trials gives plausibility to our secondary-end-point findings."

Although the combination reduced ischemic events, what really grabbed everybody's attention was the statistically significant increase in the risk of cancer. The cancer findings triggered an independent analysis of two other large ongoing studies, the IMPROVE-IT and SHARP trials, by Sir Richard Peto (Clinical Trials Service Unit, Oxford, UK), an expert in clinical-trial meta-analyses and cancer epidemiology, to determine whether the cancer risk was real or chance. Peto said his meta-analysis of the studies did not confirm the hypothesis that treatment with the combination increases the overall risk of developing cancer. Pedersen told the ESC that he accepts the analysis and doesn't believe there is any increased cancer risk with Vytorin.

In speaking with the ESC, Pedersen stressed that the SEAS trial was an investigation testing the hypothesis of using lipid-lowering agents in the treatment of aortic stenosis. "They were people who today are not normally considered candidates for LDL-cholesterol-lowering therapy," he said. "But the finding we made was that a large proportion of these patients actually did have a high risk of developing atherosclerotic disease. The patients who received the cholesterol-lowering treatment benefited—from less complicated surgery and less atherosclerotic disease. So what we learned is to focus more on atherosclerosis in a patient population with aortic disease."

As previously reported by heartwire, many experts do not see a likely role for lipid-lowering agents in aortic stenosis, although, hypothetically, Pedersen said the drugs might need to be introduced earlier if they are to modify aortic-stenosis progression. Many of the patients may have been "at a stage of aortic disease where they had passed the limit of no return, so to speak," he said. The trial did show, however, that patients at an earlier stage of disease, who would not normally be candidates for lipid-modification therapy, might consider lipid-lowering therapy to a greater extent than before, said Pedersen.

During the hotline session, Pedersen will have 13 minutes for his presentation, followed by a five-minute commentary from an independent expert. The results of the SEAS trial, although a study in patients with aortic stenosis, are anticipated because of the disappointment of Vytorin in the Effect of Combination Ezetimibe and High-Dose Simvastatin vs Simvastatin Alone on the Atherosclerotic Process in Patients with Heterozygous Familial Hypercholesterolemia (ENHANCE) trial.

Pedersen did not comment on the ENHANCE study, nor did he address the benefit of Vytorin over generic simvastatin, telling the ESC he does not believe it is possible to compare the two trials because of the different patient populations and different clinical end points. Future studies, such as IMPROVE-IT, will need to be completed before it is known whether or not reducing LDL cholesterol with Vytorin has any therapeutic benefit over simvastatin alone, he said.