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Vytorin Risks Debated in Medical Journal

The cholesterol drug, produced by Schering-Plough and Merck, produced a higher rate of cancer vs. a control group in a recent study, but a larger analysis said the results are statistically insignificant.

Uncertainty lingers for cholesterol drug Vytorin, as experts gave mixed opinions about the cancer risks for the






joint venture in a prestigious medical journal.


New England Journal of Medicine

on Tuesday published results from one study that showed an increased incidence of cancer, but another, larger number-crunching effort showed that the number of cancer cases coming up in Vytorin studies vs. control groups was not statistically significant.

The SEAS (Simvastatin and Ezetimibe in Aortic Stenosis) trial compared Vytorin -- a melding of a cholesterol lowering statin and Zetia -- with a placebo with respect to the incidence of cardiovascular events in older people with aortic-valve stenosis. The drug didn't have an effect on the narrowing of the aortic valve, and the trial didn't meet its primary endpoint, a reduction in major cardiovascular events.

On the plus side, it did lower "bad" cholesterol and meet some secondary endpoints, such as a reduction in "atherosclerotic events", like nonfatal heart attacks and cardiovascular deaths in high-risk patients.

But a statistically significant -- but unexpected -- increase in the incidence of cancer in the Vytorin group vs. the placebo group

sparked alarm

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. The group using Vytorin produced 105 patients with cancer, compared to 70 in the control group. There also were also more deaths from cancer in the Vytorin group, 39 vs. 23, which just made statistical significance with a p-value of 0.05.

To get a firmer grip on any possible risk, the Clinical Trial Service Unit and Epidemiological Studies Unit at Oxford University looked at cancer mortality data from the SEAS and interim data from two ongoing trials, dubbed SHARP and IMPROVE-IT. When combined, there were 134 patient deaths in the Vytorin arms of the studies, vs. 92 in the control groups, but the result was not statistically significant, according to the results which also were reported in the current issue of the

New England Journal of Medicine


"The Oxford researchers believe that this finding is due entirely to the play of chance rather than to a true increase in cancer mortality," write the authors of an editorial titled "Ezetimibe and Cancer -- An Uncertain Association," appearing in the same issue. "They argue that an increase in the risk of cancer death, if real, should be paralleled by an increase in the risk of cancer incidence, which was not found in the combined analysis, and that there is no plausible mechanism for such an effect."

But, the editorial's authors say it is still appropriate to raise a note of caution. They note that Zetia interferes with the gastrointestinal absorption not only of cholesterol, but also of other molecular entities that could conceivably affect the growth of cancer cells. Thus, we shouldn't assume the increase in cancer deaths with Zetia to be a chance finding until we have more data, they say.

Schering Plough and Merck have been reeling since the ENHANCE study showed that Vytorin lowered "bad" cholesterol, did no more to reduce the plaque that leads to heart attacks than a statin alone.

The full data for that trial were presented at the annual meeting of the American College of Cardiology in late March. An expert panel at the meeting recommended doctors avoid prescribing Vytorin and revert patients to statins, traditional cholesterol lowering drugs.

Per the recent concern over incidence of cancer, Credit Suisse analyst Catherine J. Arnold called the

New England Journal of Medicine

Editorial on Tuesday -- the most critical published perspective -- an important barometer to the reaction.

"This article takes the position that although the cancer analysis by the Oxford epidemiologist is credible, you still don't conclusively know whether Vytorin truly poses any cancer risk and is a variable that will have to be monitored," writes Aronld. "The tone and arguments of the article were balanced and we see that as a positive vs. investor fears."

In their editorial, the group of M.D.s and Ph.D.s -- Jeffrey Drazen, Ralph Agostino, James Ware, Stephen Morrissey and Gregory Curfman -- conclude that "Physicians and patients are unfortunately left for now with uncertainty about the efficacy and safety of the drug,"

Shares of Merck were down 2.5%, while Schering-Plough stock was up 1.9% in recent trading Tuesday.