Independent Analyses of the SEAS, SHARP and IMPROVE-IT Studies of Ezetimibe

Tuesday, July 22, 2008 General News
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LONDON, July 21 The University of Oxford Clinical TrialService Unit and Epidemiological Studies Unit (CTSU) proposed that thehypothesis-generating results of the SEAS trial of ezetimibe should be testedby reviewing the combined cancer results from the SHARP and IMPROVE-IT trialsof ezetimibe, and reporting on the overall findings to the relevantregulatory authorities, independently of the drug manufacturers.

The two hypothesis-testing trials (SHARP and IMPROVE-IT) contain aboutfour times as many cancers as the SEAS trial. They do not confirm thehypothesis raised by the SEAS trial that treatment increases the overall riskof developing cancer. In addition, there is no increase with time in therelative risk (active vs placebo) suggested by the cancer incidence andmortality from all 3 trials together (or just from the pair ofhypothesis-testing trials). Consequently, the SEAS, SHARP and IMPROVE-ITtrials do not provide credible evidence of any adverse effect on cancer.

Allocation to 5 years of substantial LDL-cholesterol lowering by a statinhas been shown previously to have no apparent effect on cancer. TheCholesterol Treatment Trialists' collaboration has published results (Lancet2005;366: 1267-78) based on 90,000 patients randomised evenly between statinand control. Based on 5530 patients with cancer onset after randomisation,the statin vs control relative risk was 0.997 (with 95% confidence interval0.95-1.05; not significant). Of these patients, 2163 died of their cancerduring the scheduled follow-up period; the relative risk for cancer death was1.01 (with 95% confidence interval 0.91-1.12; not significant).

In the final results from the SEAS trial, there appears to be a smallincrease in total cancer incidence in the group allocated ezetimibe + statin,but this is based on only 102 vs 67 cancer cases (including 39 vs 23 fatalcases) and there is no significant increase in any particular type of cancer.

Two other large trials of ezetimibe + statin are still in progress: (i)SHARP (ezetimibe + simvastatin vs placebo in 9,000 patients; recruitmentcompleted, but treatment and follow-up continuing) and (ii) IMPROVE-IT(ezetimibe + simvastatin vs placebo + simvastatin in 11,000 patients;recruitment continues towards an eventual target of 18,000 patients).Together, they have already accumulated about four times as many cancers asSEAS (see table). If treatment really did increase total cancer by 50% thenthis would have been clearly apparent in the hypothesis testing SHARP &IMPROVE-IT trials. Instead, there was no evidence of any increase in cancer(see table).

If there were a real adverse effect on cancer incidence or cancermortality then previous experience with the epidemiology of cancer (ie, withother causes of the disease in humans) strongly suggests that the relativerisk (active versus control) should grow bigger with time, but it does not,whether the hypothesis-testing trials are considered separately or all 3trials are considered together.

Note: The University of Oxford Clinical Trial Service Unit andEpidemiological Studies Unit (CTSU) has decades of experience in cancerepidemiology, in vascular and other trials, and in collaborativemeta-analyses of trials. Although CTSU is conducting the SHARP trial, it isdoing so independently of the source of funding, and has a policy of notaccepting honoraria or consultancy fees. This report to regulatoryauthorities on the analyses of SEAS, SHARP and IMPROVE-IT was initiated,conducted and interpreted by the CTSU independently of any source of funding.

For more information, please, refer to the press release issued by theSEAS investigators today.

Contact: Andrew Trehearne, CTSU, +44(0)1865-743960, +44(0)789-404-2600

Co-directors: Rory Collins FMed Sci FRCP BHF Professor of Medicine andEpidemiology Sir Richard Peto FRS Hon FRCP Professor of Medical Statisticsand Epi

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