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SEATTLE, Sept. 4 -- Simvastatin/ezetimibe (Vytorin) may increase the risk of cancer after all, concluded a leading American biostatistician who dismissed as prematurely reassuring an analysis by Richard Peto, Ph.D., F.R.S., that found the link with excess malignancy to be overblown.

"Additional data are needed to adequately address the signal that simvastatin/ezetimibe is associated with an increased risk of death from cancer," wrote Thomas R. Fleming, Ph.D., of the University of Washington, in an editorial published online in the New England Journal of Medicine -- the same journal that published the Peto analysis online.

He said such data are needed from "completed prospective trials than have been designed and conducted to meet the performance standards for safety trials."

Dr. Fleming wrote that the excess cancer deaths observed in interim data from the ongoing IMPROVE-IT and SHARP trials suggest that the risk of cancer mortality could be from 34% to 84% greater among patients taking simvastatin/ezetimibe. (See: ESC: SEAS Data Fail to Quiet Ezetimibe/Simvastatin Controversy)

Dr. Fleming argued in his editorial that it was biologically plausible that ezetimibe could be associated with excess cancers or cancer deaths because it "blocks the absorption of phytosterols and other phytonutrients that are linked to protection against cancer."

In the two trials, there were 97 cancer deaths in the simvastatin/ezetimibe groups versus 72 in the control group for a hazard ratio of 1.34 (95% CI 0.98 to 1.84).

Dr. Fleming wrote that "given this confidence interval, investigators cannot exclude a relative increase of as much as 84% in the risk of cancer-related death associated with the use of simvastatin/ezetimibe. Hence there are clinically important increases in the risk of cancer-related death that are not ruled out by these data."

He wrote that the Peto analysis did not prove that ezetimibe does not increase cancer mortality. The Peto data are only sufficient to rule out the hypothesis that simvastatin/ezetimibe increased the relative risk of cancer by 12% because there were 313 new cancers in the simvastatin/ezetimibe arms versus 326 in controls (HR 0.96, 95% CI 0.82 to 1.12).

In the Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) trial, there were 105 cancers in the ezetimibe/simvastatin group versus 70 in the placebo arm (P=0.01). It was this observation that led to the Peto analysis of the cancer risk in the two ongoing trials -- IMPROVE-IT and SHARP.

There were 39 fatal cancers in the SEAS ezetimibe/simvastatin arm, versus 23 in the control arm for a hazard ratio of 1.67 (P=0.05). Eugene Braunwald, M.D., of Harvard Medical School, one of the principal investigators of IMPROVE-IT, called Dr. Peto "the best biostatistician in the universe."

Dr. Fleming was also critical of the method used by Peto et al because they conducted a meta-analysis using interim data from two ongoing trials.

Doing so, he wrote, was problematic because it raised the "serious risk of misinterpreting interim data as well as disturbing the integrity of ongoing trials through the release of interim data."

Moreover, Dr. Fleming wrote, "without full access to the peer-reviewed summaries of these data, it is not possible to determine the extent to which the two trials meet the list of performance standards for safety trials."

The SEAS, IMPROVE-IT, and SHARP trials were funded by Merck/Schering-Plough, the developers of simvastatin/ezetimibe. Dr. Fleming said he had no financial disclosures.

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