Munich, Germany - Full data from the Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) study were presented here today at the European Society of Cardiology (ESC) Congress 2008 and showed that the cholesterol-lowering combination (Vytorin, Merck/Schering-Plough Pharmaceuticals) was no better than placebo in reducing the primary composite end point of aortic-valve and cardiovascular events in patients with mild to moderate asymptomatic aortic stenosis, a finding that was first presented by the SEAS investigators earlier this summer [1].

The combination was significantly more effective than placebo in reducing the risk of ischemic events, a secondary composite end point that was driven primarily by reductions in coronary artery bypass graft (CABG) surgery. The findings did not yet kill the lipid-lowering hypothesis for halting the progression of aortic stenosis—the ASTRONOMER aortic-stenosis trial with rosuvastatin (Crestor, AstraZeneca) is ongoing, and those findings will likely be presented next year at the American College of Cardiology (ACC) Scientific Sessions—but there were concerns raised over the significantly increased risk of cancer observed in SEAS.

Among those treated with the ezetimibe/simvastatin combination, there were significantly more cases of fatal or nonfatal cancer compared with those treated with placebo. The new cancers, however, were not specific to one site, and an analysis of ongoing ezetimibe/simvastatin studies by Sir Richard Peto (Clinical Trials Service Unit, Oxford, UK) revealed no increased risk [2]. The cancer association, conclude the SEAS investigators, as well as Peto and colleagues, is likely the play of chance rather than a real finding.

"I'm not aware of any data that would support [the hypothesis] that ezetimibe causes fatal cancer within three years after the onset of treatment," SEAS steering committee chair Dr Terje Pedersen (Ulleval University Hospital, Oslo, Norway) told the media during a crowded ESC press conference. "I don't know of anything that can do that, except maybe a Chernobyl catastrophe."

In an editorial accompanying the SEAS trial paper and the subsequent meta-analysis, the New England Journal of Medicine editorialists, including Drs Jeffrey Drazen, Ralph D'Agostino, James Ware, Stephen Morrissey, and Gregory Curfman, were not swayed by the Oxford investigators and expressed uncertainty about the safety and efficacy of ezetimibe [3]. They even point out a possible mechanism in which the cholesterol-lowering medication could increase the risk of cancer and urge further study.

"Although the Oxford group may ultimately prove to be correct, it is appropriate to raise a note of caution," write the editorialists. "Whether the increased risk is due solely to the play of chance is uncertain. Ezetimibe interferes with the gastrointestinal absorption not only of cholesterol but also of other molecular entities that could conceivably affect the growth of cancer cells. The fact that all three trials showed an increase in cancer mortality with ezetimibe should not be assumed to be a chance finding until further data are in."

The SEAS trial, the editorial, and the interim analysis of cancer data in the Improved Reduction in High-Risk Subjects Presenting with Acute Coronary Syndrome (IMPROVE-IT) and Study of the Heart and Renal Protection (SHARP) trials are published online today in the New England Journal of Medicineto coincide with the ESC presentation.

The SEAS study is a randomized, double-blind, clinical trial involving 1873 patients with aortic stenosis who were treated with 40 mg of simvastatin and 10 mg of ezetimibe or placebo daily. There was hope that significantly reducing LDL-cholesterol levels could prevent the progression of aortic-valve stenosis and reduce the need for valve-replacement surgery, according to investigators.

Despite reducing LDL-cholesterol levels by 61%, down to a mean of 53 mg/dL, treatment with ezetimibe/simvastatin failed to reduce the risk of the primary end point, a composite of major cardiovascular and aortic-valve events. There was a significant 22% reduction in the risk of ischemic events, a finding that was driven primarily by a 32% reduction in the need for CABG surgery.

The cancer data, however, were what captured the attention of many in the medical community. In SEAS, there was a significantly increased risk in the onset of fatal and nonfatal cancer, as well as a significantly increased risk of death from cancer. The site of cancer was nonspecific, but there were numeric increases in the risk of skin, stomach, and prostate cancer.

The analyses have been submitted to the Food and Drug Administration (FDA) for its review. Ten days ago, the agency issued a statement informing clinicians about its investigation into the possible link between Vytorin and an increased risk of cancer. The FDA review stated patients should not stop taking Vytorin or any other cholesterol-lowering drug. A full safety report from the FDA is expected sometime in 2009.

Speaking with heartwire, Pedersen said the SEAS findings, including the cancer signal, do nothing to alter his opinion of the drug or how he plans to use it. "Like most of my European colleagues, I don't use ezetimibe as a first choice," he said. "It's an add-on drug, which is used in patients who don't get to target or those who don't tolerate high doses of statins, although there are very few of those. For us, ezetimibe is a second or third choice, and we relegate it to higher-risk patients who can't get their LDL-cholesterol levels down."

Moderating the morning press conference, Dr Eugene Braunwald (Harvard Medical School, Boston, MA), who is also the cochair of the IMPROVE-IT study, along with Dr Robert Califf (Duke Clinical Research Institute, Durham, NC), answered numerous questions from the media, and in doing so, reiterated his support of the analysis by the Oxford investigators and their conclusions that the data do not provide credible evidence of an increased risk of cancer with the drug. He told reporters that he still uses it in his patients and continues to take it himself, because ultra-low cholesterol levels are the best way to prevent atherosclerotic disease.

Asked whether the available data are concerning enough for clinicians to begin a conversation with their patients about a possible cancer risk, Braunwald said, "People should be made aware, in a general sense, of the most important things that are known about a drug," and the most important finding today is that the statistical analysis has shown no support for an increased cancer risk with Vytorin.

Dr Douglas Weaver (Henry Ford Health System, Detroit, MI), the president of ACC, told heartwire that the increased cancer incidence and mortality observed in SEAS is likely a play of chance, although longer exposure to the drug in IMPROVE-IT and SHARP will help definitively answer the question about risk. "My biggest concern with the drug is that patients, in general, are always concerned about cholesterol-lowering therapies. They're concerned about liver side effects, myopathies, and if we throw this information out there, will they all stop taking their drugs? It would be terrible if that were to occur."

Also commenting to heartwire on the findings, Dr Sanjay Kaul (Cedars-Sinai Medical Center, Los Angeles, CA) said cancer death is "arguably a more reliable end point than incident cancer, and it is consistently going in the wrong direction in all three trials." This signal is reinforced when data from all three trials are combined. Kaul said it is possible that by blocking the absorption of phytosterols, ezetimibe may interfere with tumor immunosurveillance and alter or accelerate the clinical course of preexisting subclinical cancers. Like the journal editorialists, Kaul pointed out that other epidemiologic studies demonstrate an association between phytosterols and cancer, but definitive evidence of a causal relationship is lacking at the current time.

"Even though the cancer findings are inconclusive, they do adversely impact the benefit/risk equation of ezetimibe, especially given the lack of clinical benefits," Kaul told heartwire. "Thus, one has to be even more circumspect not to consider these as first- or second-line treatment options for lipid lowering. As far as ongoing clinical trials are concerned, I think they should continue with careful scrutiny and more frequent monitoring."

Vytorin has been in the news for some time, with Schering-Plough and Merck first coming under scrutiny for a delay in presenting the Effect of Combination Ezetimibe and High-Dose Simvastatin vs Simvastatin Alone on the Atherosclerotic Process in Patients with Heterozygous Familial Hypercholesterolemia (ENHANCE) study. When those results were presented this past March at the ACC meeting, it showed that combined therapy with ezetimibe and simvastatin in patients with familial hypercholesterolemia 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.