Kenilworth and Whitehouse Station, NJ - The Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) trial, a randomized, multicenter, placebo-controlled study evaluating the effects of combination ezetimibe and simvastatin (Vytorin, Merck and Schering-Plough) on clinical outcomes in patients with aortic stenosis, was presented this week, and while some experts say the results provide little new information and won't alter clinical practice, some see the results as positive for Vytorin, especially when placed in the context of other LDL-lowering studies.

The study, presented by Dr Terje Pedersen (Ulleval University Hospital, Oslo, Norway) this week during an unusual press conference, showed that the cholesterol-lowering combination was no better than placebo in reducing the primary composite end point of aortic valve and cardiovascular events. Vytorin was significantly more effective than placebo in reducing the risk of ischemic events, a secondary composite end point of nonfatal MI, CABG surgery, PCI, hospitalization for unstable angina, nonhemorrhagic stroke, and cardiovascular death.

This drug does not have sufficient evidence for it to be used as a front-line agent. . . . Right now using it is based on an assumption that you know what IMPROVE-IT will find.

With this 22% reduction in ischemic events, however, concerns were raised when SEAS investigators also showed a significantly increased risk of cancer. A group independent of researchers, however, says this finding is likely due to chance.

Asked about the results and how they fit into the context of existing Vytorin data, Dr Harlan Krumholz (Yale University School of Medicine, New Haven, CT) told heartwire that SEAS reinforces the message from March when 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 presented.

"This drug does not have sufficient evidence for it to be used as a front-line agent," he said. "Statins are the drugs of choice. The evidence is not even strong enough to say that people who cannot tolerate statins should go on it. It is an option. Right now using it is based on an assumption that you know what IMPROVE-IT will find."

IMPROVE-IT is the clinical outcomes study chaired by Dr Eugene Braunwald of the TIMI Study Group and cochaired by Dr Robert Califf (Duke Clinical Research Institute, Durham, NC). The study will compare simvastatin 40 mg plus ezetimibe 10 mg with simvastatin 40 mg alone in 18 000 patients with a recent acute coronary syndrome. Those results will be available in 2012, nearly a decade after the US Food and Drug Administration approval of ezetimibe as an adjunct to statins for cholesterol lowering.

Commenting on the SEAS study, Dr Richard Karas (Tufts University School of Medicine, Boston, MA) took issue with the tone of media coverage surrounding the results, including heartwire's coverage. He said many in the media portrayed the study as another failure for Vytorin, something he did not believe to be the case.

"There are people saying that there is no clinical-trial evidence showing that Vytorin does anything on atherosclerotic events," said Karas. "Now we have a secondary end point, which is important to recognize, but it's a prespecified end point, and the drug has a statistically significant benefit on ischemic events. That's really the story, in my opinion."

Still, despite the statistical significance of benefit in this secondary end point, others are not impressed with the results. Dr Allen Taylor (Walter Reed Army Medical Center, Washington, DC) told heartwire that although there was a dramatic 61% reduction in LDL cholesterol, the relative reduction in ischemic events was just 22% compared with placebo in a high-risk population. "That's actually less relative risk protection than was seen in 4S and the Heart Protection Study, studies using similar doses of simvastatin but with less LDL reduction," said Taylor. "It falls beneath one's expectations."

Now we have a secondary end point . . . a prespecified end point, and the drug has a statistically significant benefit on ischemic events.

There are difficulties making cross-trial comparisons because the populations are not the same and the end points are not uniform, said Taylor, but the overall benefit observed in SEAS does not provide any useful information about the additive benefit of the combination over simvastatin alone.

Dr Rory Collins (Clinical Trials Service Unit, Oxford, UK), the lead investigator of the Study of the Heart and Renal Protection (SHARP) trial, a randomized placebo-controlled study of simvastatin and ezetimibe in 9400 patients with chronic kidney disease, told heartwire, however, that he does see these findings as benefiting a difficult-to-treat patient population.

"Although the study didn't provide evidence of benefit on the aortic valve, I think it does provide good evidence that you get quite a worthwhile absolute reduction in ischemic events—almost 5%—in a population that is currently not being treated with statins," he said.

Speaking with heartwire, Karas said too much emphasis in the media was placed on the motives for designing the trial, including speculation that positive findings could rehabilitate Vytorin in the eyes of cardiologists. The purpose of the study, he said, was to determine whether medical therapy might be successful in the treatment of a condition in which surgery is the only existing option. Karas acknowledged that Merck and Schering-Plough have successfully marketed Vytorin, but many other drugs, including atorvastatin (Lipitor, Pfizer) when it first came on the market, were prescribed because of the LDL-lowering capabilities.

"In this area, the evidence is so strong that successfully altering lipids produces benefit," said Karas. "My perspective is not so black and white, but medicine is an art, and we have to practice medicine on the basis of the best evidence we have. Would you rather leave a patient's LDL cholesterol above the national guideline targets because there aren't clinical end-point data?"

Collins added there is always a need to be cautious interpreting secondary end points. However, placing the SEAS findings in the context of other LDL-cholesterol-lowering studies makes the reduction in ischemic events a strong finding of benefit in this population. To make this point, Collins notes that the Incremental Decrease in Events through Aggressive Lipid Lowering (IDEAL) study wasn't statistically significant, but in the context of other aggressive vs conventional LDL-lowering studies, it was very consistent with efficacy.

"LDL lowering decreases the risk of cardiovascular events, and that has been shown consistently when you look at the totality of evidence," said Collins. "It is important not to look at trials in isolation."

We truly do not know the effect of this drug on patient outcomes, and the only way to find out is to monitor risk and benefit in a trial.

Speaking last March at the American College of Cardiology (ACC) 2008 Scientific Sessions, Krumholz urged clinicians to return to first principles: maximizing statins to the highest tolerated dose before adding other agents. He said the ENHANCE trial gave pause to many assumptions and reminded researchers how many lipid-lowering drugs have not come to fruition when subjected to the scrutiny of a clinical trial.

"The fact that some of the leading cardiologists are involved in IMPROVE-IT tells you that they are comfortable in saying that we truly do not know the effect of this drug on patient outcomes, and the only way to find out is to monitor risk and benefit in a trial," Krumholz told heartwire this week. "Any patient using the drug should understand where we stand with respect to the evidence and the uncertainty about the drug."

Taylor stressed the results should not alter clinical practice and that the community must still wait for the findings from IMPROVE-IT. Nothing changed this week, he said, except there is now a little more uncertainty about the drug, with the unexpected adverse-event signal. "It might be due to chance, but it still needs due consideration," he added.

The SEAS study was designed to answer the question about whether or not lipid-altering therapy altered the course of aortic valve disease. Its failure to yield a significant effect on the primary outcome—a large composite end point that included aortic and cardiovascular events—should not be interpreted as a failure of the drug, Karas told heartwire.

"This is a whole different kettle of fish than what are the effects of lipid lowering on atherosclerosis," said Karas. "Investigators came up with the question asking whether there might be a relationship between lipid-altering interventions and slowing the progression of aortic valve disease, and the answer to that is no."

As a general rule, when primary outcomes fail to meet statistical verdicts, analyses of secondary outcomes should be interpreted with caution.

Dr Sanjay Kaul (Cedars-Sinai Medical Center, Los Angeles, CA) told heartwire that initial hopes for statins to halt the progression of calcified aortic valve disease were based on retrospective data and open-label studies, but SEAS and an investigation of atorvastatin 80 mg in SALTIRE have now failed to show any benefit of LDL lowering for this condition. Although the ASTRONOMER trial with rosuvastatin (Crestor, AstraZeneca) is ongoing, "the time is ripe for the lipid-lowering hypothesis for [halting] progression of calcific aortic valve stenoses to be abandoned," said Kaul.

Regarding the reduction in ischemic events, Kaul was careful in his interpretation.

"As a general rule, when primary outcomes fail to meet statistical verdicts, analyses of secondary outcomes should be interpreted with caution," said Kaul. "This applies equally to the ischemic composite end point, which showed a 20% reduction with Vytorin, and to the 50% increased cancer risk associated with Vytorin. Nonetheless, the signal for increased cancer rate is 'concerning' and merits careful scrutiny. Interim analyses of ongoing studies to refute or corroborate findings observed in other clinical trials are a slippery slope."

The cancer findings were concerning enough for investigators that an independent analysis of the two large ongoing studies, the IMPROVE-IT and SHARP trials, was performed 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. His analysis showed "no credible evidence" that Vytorin posed a cancer risk and should not be a reason to divert patients from the drug.

Regarding the cancer findings, Krumholz said he was surprised by it, and while "it is never good to see a drug associated with a 50% increased risk of cancer," he has doubts about whether it truly represents an adverse effect. Although he has not had time to fully read the analysis by Peto and colleagues, he said he was glad to hear the analysis did not show similar findings.

Karas, who also conducts research on cancer risks, lipid-lowering interventions, and LDL-cholesterol levels, as well as Collins, told heartwire they believe the safety conclusions reached by Peto are correct. PROSPER and CARE also turned up a statistically significant increased risk of cancer, but two large meta-analyses later showed that statins do not increase the risk. In SEAS, the timing and the type of cancers involved make little sense and are likely a chance finding, they both said.