The worrisome cancer data come from a clinical trial called SEAS, reported today at a major European cardiology conference and simultaneously published online by The New England Journal of Medicine. But these findings come as no surprise.
That's because of a highly unusual news conference held last July. SEAS study leader Terje Pedersen, MD, PhD, announced the unexpected finding of a possible Vytorin cancer link. Then he turned the podium over to Oxford University's Richard Peto, FRS, who said his independent analysis of two ongoing Vytorin studies revealed no credible evidence linking Vytorin to cancer risk.
Not so fast, says an editorial by Jeffrey M. Drazen, MD, editor-in-chief of The New England Journal of Medicine, and colleagues. The editorial says we simply can't assume -- as Peto asserts -- that the Vytorin cancer link is simply a chance finding.
"What these data show is there is a potential for a small risk for increased cancer and cancer deaths from Vytorin," Drazen tells WebMD. "Until clinical trials are completed, no one can say this drug is cleared -- and no one can say it causes cancer. We have to live with this uncertainty."
Assessing Cancer Risks
If there is a risk, it isn't very large, says Richard H. Karas, MD, PhD, director of preventive cardiology at Tufts Medical Center in Boston. Karas was not involved in the Pedersen or Peto studies, but he reviewed the published reports for WebMD.
In the SEAS trial, patients on placebo had a 0.5% annual risk of getting cancer. This risk doubled in patients on Vytorin -- but only to 0.9% a year. This risk was even lower in the two ongoing trials: 0.4% per year in control patients, and 0.5% per year in patients taking Vytorin.
But Peto tells WebMD that this risk -- if it were real -- would be frighteningly large. That's because it appeared in a very short time, in just the first years after patients began taking Vytorin. A real doubling of cancer risk in such a short time, he says, would make Vytorin one of the most dangerous carcinogens ever known.
But that, Peto says, is preposterous. When his team looked at the data from the IMPROVE-IT and SHARP trial, they found no increase in cancer over time -- which one would expect from a potent cancer-causing agent. Moreover, they found no increase in any specific kind of cancer.
"If this stuff was 100 times as dangerous as cigarette smoke, as the SEAS finding suggests, you would expect to see an increase over time in the hazard. And we don't," Peto tells WebMD. "And if you had no effect, you would expect the excess cases to be distributed evenly over time, and they are. So we do not get any increase over time in risk, either in cancer incidence or in death from cancer."
Yet Drazen and Steven Nissen, MD, chairman of the Cleveland Clinic's department of cardiovascular medicine, point to a disturbing statistical anomaly. If all the cancer deaths in the SEAS, IMPROVE-IT, and SHARP trials are added together, there were 134 cancer deaths in patients taking Vytorin and 92 deaths in patients taking inactive placebo or the cholesterol-lowering drug Zocor.
That suggests a 45% increase in cancer deaths with Vytorin -- with a statistical probability of 0.007, meaning the odds of it being a chance finding are seven in 1,000.
Peto, a professor of medical statistics, says this isn't a fair analysis. First of all, with all the thousands of clinical trials being done all over the world, every year there will be false findings that have only a one in 1,000 chance of happening.
More specifically, he says, the reason for looking at the IMPROVE-IT and SHARP results was to see whether the unexpected SEAS finding was true. Adding the SEAS data to the other data pollutes the analysis.
"Suppose I have a freak result. To test whether it is true, I will check out other data independently," Peto says. "What you cannot do is add up the independent test with the test that got you alarmed in the first place. If you include the test that got you freaky results in the first place, you will have a freaky result in the end."
Waiting for More Data
Pedersen agrees with Peto that the Vytorin cancer link is likely a chance finding. He notes that the SEAS trial looked at 1,250 disease categories and saw "quite amazing single differences between the Vytorin and placebo groups clearly arising by chance."
Nevertheless, Pedersen agrees with Drazen that the jury is still out until more data become available.
"We should not just dismiss this and say it is just a chance finding," Pedersen tells WebMD. "We should carefully collect data in the IMPROVE-IT and SHARP trials to get more information."
There is an ongoing FDA investigation of Vytorin data to see whether a safety warning is appropriate. Meanwhile, Pedersen agrees with the American Heart Association and the FDA advice not to stop taking any cholesterol medication without a doctor's advice.
"My brother has been on Vytorin for three years," Pedersen says. "I told him I would not be concerned about cancer risk, and that it is better to have your cholesterol down."