Heart Drug's Safety Scrutinized

July 25, 2008— -- A study that unexpectedly linked the heart drug Vytorin to excess cancer deaths has provoked controversy among heart specialists worried that the drug's risks may outweigh its benefits.

The study, called SEAS, was designed to test whether Vytorin could prevent severe, age-related heart valve problems by sharply reducing cholesterol. But lead investigator Terje Pedersen of Ulleval University Hospital in Oslo reported Monday that the study turned up a "disturbing" link to cancer.

At that same session, Oxford University experts released a separate analysis comparing SEAS data with two other ongoing studies and concluded that the cancer link wasn't "credible."

The debate rages on, with prominent heart specialists reluctant to discount the cancer risk. "Evidence like this should raise concerns," says cardiologist Harlan Krumholz of Yale University. "Patients should be aware that there's some uncertainty about the safety of Vytorin that will not be resolved until we get more definitive trial evidence."

Vytorin and its chemical cousin, Zetia, are widely prescribed. Sales for both drugs, made by Merck and Schering-Plough, total more than $4 billion a year. Both are made with the cholesterol-blocker ezetimibe; Vytorin also contains simvastatin, now a generic cholesterol-lowering drug.

The 2,000-patient SEAS study found a roughly 70 percent increase in the risk of dying from cancer. But the Oxford analysis of the two ongoing studies, called IMPROVE-IT and SHARP, found about a 33% increase in the risk of dying from cancer, considered borderline in statistical significance.

Oxford's Sir Richard Peto says he could find no pattern that could plausibly link the cancer deaths to Vytorin, such as a rise in the number of cancer deaths as exposure to the drug increases.

The evidence leaves many doctors uncertain. "Obviously, if you see it in one study, even if it's not statistically significant, you've got to be worried," says oncologist Ezekiel Emanuel of the National Institutes of Health. "Maybe this has a biological mechanism we don't know anything about."

Federal regulators also wrestle with how to respond, says former FDA commissioner David Kessler, now of the University of California-San Francisco. "The hard part is if you're a patient before all the data come in, when you have scientists waging these (debates) about the level of risk."

Robert Califf of Duke University, a co-leader of IMPROVE-IT, says that until the evidence is in, patients should take the standard cholesterol-lowering drugs called statins, rather than Vytorin, if they can. "Vytorin should be used for patients who can't hit their target with a statin," he says.

Vytorin was approved in 2004 based on its power to reduce cholesterol. Yet researchers still don't know whether that potency translates into lives saved. The answers won't be available until 2012, when the 18,000-patient IMPROVE-IT trial ends.

A statement by Merck and Schering-Plough acknowledged a higher incidence of cancer and "a non-significant increase" in cancer deaths in study patients. It adds: The finding is "an anomaly that, taken in light of all the available data, doesn't support an association with Vytorin."

"Your first reaction is, 'Is it just a chance finding?' Then you see it in a second trial, and say, 'Whoa, can this be true? What's the science here?' " says Allen Taylor, chief of cardiology at Walter Reed Army Medical Center.