Debate About Ezetimibe Not Over Yet: Experts Again Weigh in on Cancer Risk

January 08, 2009

January 8, 2009 (Boston, Massachusetts) — In its January 1, 2009 issue, the New England Journal of Medicine rings in the New Year with a few high-profile cardiologists once again debating the safety of ezetimibe (Zetia, Merck/Schering-Plough), the controversial cholesterol-lowering medication featured so prominently in the news last year [1,2].

At the heart of an exchange of letters between Dr Steven Nissen (Cleveland Clinic, OH) and Dr Rory Collins and Sir Richard Peto (Clinical Trials Service Unit, Oxford Unit) is whether or not a conclusion can be made that there is "no credible evidence" regarding a cancer risk associated with ezetimibe.

"Provided an appropriate distinction is made between hypothesis-generating and hypothesis-testing findings (as in our article), the trial results provide no credible evidence of an adverse effect of ezetimibe," state Collins and Peto.

Nissen, on the other hand, is not convinced, pointing to an analysis of cancer mortality data that only rules out a risk of death from cancer of 84% or more. "The conclusion that there is no 'credible evidence' for a cancer risk associated with ezetimibe is simply not supported by the data," argues Nissen.

From SEAS To IMPROVE-IT and SHARP

The cancer signal first arose in the Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) study, a trial presented at the European Society of Cardiology (ESC) in Munich, Germany last year and reported by heartwire at that time. Among those treated with the ezetimibe/simvastatin (Vytorin, Merck/Schering-Plough Pharmaceuticals) combination, there were significantly more cases of fatal or nonfatal cancer compared with those treated with placebo.

When the cancer findings became known, it led to an independent analysis of two ongoing ezetimibe studies, the IMPROVE-IT and SHARP trials, by the Oxford investigators, to determine whether the cancer risk was real or chance.

In IMPROVE-IT and SHARP, which provided more cancer data than the SEAS trial alone, including more data in patients with at least three years of follow-up, there was no increased risk of incident cancer or cancer mortality. When all three trials were combined, there remained an increased risk of death from cancer in the active-treatment arm.

As he also pointed out in his letter to the editor, Nissen, in speaking with heartwire , said the decision to analyze data from IMPROVE-IT and SHARP before those studies were completed sets a dangerous precedent, raises scientific and ethical issues, and is not reliable for the evaluation of drug safety.

"A decision to unblind a clinical trial is something that should be done under only the most extreme circumstances," said Nissen. "Once you unblind a trial, you forever alter the conduct of that study. Most individuals who think very hard about clinical trials will tell you that you better have an extremely good reason for unblinding an ongoing clinical trial, and I don't think there was a good reason here."

Moreover, Nissen said these two incomplete trials represent an incomplete experiment and notes that the mean exposure time to the drug in some patients is insufficient, and this dilutes the signal of risk.

Collins, on the other hand, told heartwire , that unblinding the ongoing studies was appropriate because it is not in the interest of public health to label ezetimibe unsafe without credible evidence that it causes cancer, something that might have occurred if only data from the SEAS trial were available. He said it would have been more shocking not to present the analysis from IMPROVE-IT and SHARP than to present it.

"A dangerous precedent is having this drug being withdrawn from the market, and already we're seeing substantial reductions in its use, when it has been shown to be effective at reducing LDL-cholesterol levels," Collins told heartwire . "Unblinding the study helped us rule out the risk of cancer, and we will continue to study its safety and efficacy in these patients."

In their response to Nissen's letter, Peto and Collins point out that the ongoing studies involve more than four times as many cancers as SEAS but do not suggest an increase in cancer incidence, either in the overall patient population or among those receiving the drug for at least three years. Death from cancer was nonsignificant, although numerically higher and given to rise to the confidence interval highlighted in Nissen's letter.

Cancer Deaths and Incident Cancer

Commenting on the issue for heartwire , Dr Richard Karas (Tufts University School of Medicine, Boston, MA), who has studied cholesterol levels, cholesterol drugs, and cancer risks, pointed out that the cancer risk observed in SEAS occurred primarily in the first year of exposure to the medication. Assessing the hypothesis-testing cancer findings from the IMPROVE-IT and SHARP studies, even though they were incomplete, is justified given that the cancer signal in SEAS occurred so early.

Regarding the unblinding issue, Karas said he is not particularly troubled by the analysis performed by the Oxford investigators. While reporting adverse events before the study is complete is unusual, these studies are not about cancer.

"They didn't spoil anything about the studies," said Karas. "I agree with the Oxford group in that it is unfair to wrongly suggest that a drug is unsafe if it is safe. It is equally important to figure out if those accusations are correct or incorrect in both directions."

Speaking with heartwire , Nissen said he disagreed with the approach and that the medical community would have to live with uncertainty regarding ezetimibe based on the SEAS trial. In the face of such uncertainty, rather than unblind two ongoing studies, "the right approach is to go back to what we know works and go back to what we know is safe, and that is statin therapy, until those trials are done," said Nissen.

Sales of the ezetimibe/simvastatin combination and ezetimibe alone have been on the decline since January 2008, when the results of the ENHANCE carotid intima-media thickness study were made known. In March, at the American College of Cardiology Scientific Sessions in Chicago, IL, where the full results were presented, a panel of experts, including Dr Harlan Krumholz (Yale University School of Medicine, New Haven, CT), called for a "return to first principles, optimizing the doses of statin medications," rather than adding ezetimibe to a low-dose statin.

According to a recent report in the Associated Press, the total number of US prescriptions for the two drugs was 3.23 million in January 2008, but was down 39% to around two million at the end of November 2008 [3].

  1. Nissen SE. Analyses of cancer data from three ezetimibe trials: to the editor. N Engl J Med 2009; 360:86-87. Abstract

  2. Collins R, Peto R. Analyses of cancer data from three ezetimibe trials: the authors reply. N Engl J Med 2009; 360:86-87.

  3. Johnson L. Schering says cholesterol drug sales falling again. Associated Press, December 18, 2008. Available at www.ap.org

 

face="Verdana" size="1">The complete contents of Heartwire , a professional news service of WebMD, can be found at www.theheart.org, a Web site for cardiovascular healthcare professionals.

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