SEAS: Prostate, skin cancers common among treatment group

The cancer incidence reported is not likely related to simvastatin and ezetimibe combination.

Although he presented no new data at the European Society of Cardiology’s annual Congress on the SEAS trial, Terje R. Pedersen, MD, released data on specific incidents of cancer that patients developed during the four-year trial.

The trial results, comparing simvastatin and ezetimibe (Vytorin, Merck) in aortic stenosis with placebo, were first announced in July during a press conference.

Pedersen, professor at the Preventive Medicine Clinic, Ulleval University Hospital, Oslo, Norway, said the drug showed no benefit in patients with aortic valve disease in preventing further development and progression of disease.

“None of the aortic valve-specific endpoint components showed even a trend of benefit while there was a significant improvement in the prognosis in regard to ischemic events,” Pedersen said. “Only the bypass surgery reached statistical significance.”

There were a total of 108 cancers that developed in the treatment population and 75 in the placebo population. The most common cancer that patients developed in the treatment group (n=943) was prostate (21 patients), any skin cancer (18) and other/unspecified cancer (12). The most common cancer developed by the control group (n=929) was prostate (13) and lung cancer (10). Fatal cancers occurred in 39 people in the treated group and 23 in the placebo group, which Pedersen said was on the border of statistical significance. – by Judith Rusk

The increase in cancer deaths shown in the patients taking Vytorin is very likely due to chance and not real. ... This study reinforces the need to adhere to our current guidelines that say statins should be used first for patients with coronary artery disease. We await longer-term follow-up data from the other two much larger, ongoing trials in order to completely answer the issue. Our greatest worry is that patients might stop taking cholesterol medications out of fear of any perceived risks that are scientifically inconclusive and very improbable.

– W. Douglas Weaver, MD

President of the American College of Cardiology

In a recent review published by Rajamannan, Bonow and Rahimtoola, the researchers concluded that ‘recent studies have demonstrated that the etiology of aortic valve disease has a similar pathophysiology to that of vascular atherosclerosis and that the treatment of this disease could be similar to that of chronic vascular atherosclerosis. The results of the prospective clinical trials testing the effects of statin therapy could change the paradigm for treating valvular heart disease.’ Well, SEAS was such a trial and the investigators should be congratulated on this well-designed and well-conducted study.

This trial provides a clear, negative answer to this interesting question. In any good research, every answer results in more questions, and the SEAS trial, as we’ve heard, was conducted on patients with moderate to severe aortic stenosis, and it looked at progression in patients with established aortic stenosis. The question now is, were mocked lipid-lowering begun earlier in the process, could that prevent the development of aortic stenosis? Statins are extraordinary drugs but they’re being pushed to the outer limits.

An unexpected finding in the SEAS was the increased number of cancer patients in the treated group.

Within hours of learning of these results, as chairman of the IMPROVE-IT trial [I] asked for an unscheduled meeting of our data safety monitoring board. IMPROVE-IT is an 18,000-patient, clinical outcome trial. After examining the interim results in the first 11,600 patients enrolled in trial, the data safety monitoring board recommended continuation of the trial with increased surveillance. The other large trial in which the combination of ezetimibe and simvastatin is the SHARP trial, a placebo-controlled trial. Their data safety monitoring board also recommended continuation of that trial.

Sir Richard Peto, the senior statistician with the Oxford group and a noted cancer epidemiologist, reviewed the unexpected results of SEAS and since an increased cancer risk was an unexpected event, he considered them to be hypothesis generating. He considered SHARP and IMPROVE-IT to be hypothesis-testing. Professor Peto reported that the two hypothesis-testing trials involved more than 20,000 patients and more than 36,000 patient years of observation. Active treatment that included ezetimibe was associated with 313 cases of new cancer, while the non ezetimibe-treated patients had 326 cases. In neither the SEAS trial nor the two hypothesis-testing trials was there a significant increase in any particular type of cancer. This is not consistent with a drug-related carcinogenic effect. Also, Professor Peto pointed out that if there was a real adverse effect on cancer incidence or cancer mortality, then previous experience with the epidemiology of cancer strongly suggests that the relative risk should grow bigger with time.

Professor Peto concluded that the two hypothesis-testing trials, which contain about four times as many cases as the SEAS trial, do not provide credible evidence of any adverse effect on cancer.

– Eugene Braunwald, MD

Distinguished Hersey Professor of Medicine, Harvard Medical School
Chairman, TIMI Study Group, Brigham and Women's Hospital

For more information:

• Pedersen TR. Hotline III. Presented at: The European Society of Cardiology Congress 2008; Aug. 30-Sept. 3, 2008; Munich.