Right here. Let’s listen in — on “efficacy” first, then cancer — shall we? Yes, let’s:
. . . .There was little uncertainty, however, that the primary end point was null, since the hazard ratio for treatment relative to placebo was 0.96, with a 95% confidence interval (CI) of 0.83 to 1.12.
There was, however, an unexpected finding in the trial. An excess of incident cancers was observed in the simvastatin–ezetimibe group, with 105 in that group as compared with 70 in the placebo group (P=0.01). There was an increase in the incidence of a variety of cancers, including prostate, gastrointestinal, and skin cancers. Also, deaths from cancer were more frequent in the active-treatment group (39 deaths, vs. 23 in the placebo group), although the difference achieved only borderline statistical significance (P=0.05).
The SEAS investigators suggested that the difference in incident cancers could have occurred by chance but acknowledged that the unanticipated findings should be pursued through additional studies. Using existing data, the Clinical Trial Service Unit and Epidemiological Studies Unit at Oxford University were able to undertake such a study. The researchers had access to interim cancer data in two large ongoing clinical trials, the Study of Heart and Renal Protection (SHARP) (NCT00125593 [ClinicalTrials.gov] ) and the Improved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT) (NCT00202878 [ClinicalTrials.gov] ), which were unblinded only for cancer outcomes but provided relatively short follow-up (a mean of 2.7 years and 1.0 year, respectively, as compared with 4.1 years in the SEAS trial). Because of the large size of these trials, however, they provided more cancer data than the SEAS trial, even in patients with 3 or more years of follow-up. The Oxford researchers examined the data to determine whether the imbalance in incident cancers and cancer deaths observed in the SEAS trial was replicated in the ongoing trials. They asked whether the increased risk of cancer in the SEAS trial reflected a previously unobserved true signal or was simply the play of chance. It should be noted that the Oxford group is also conducting the SHARP trial and received research funding from Merck and Schering-Plough for the work. The authors note, however, that their analyses were performed independently of the companies.
The analysis by the Oxford group, reported in this issue of the Journal failed to confirm the increase in cancer incidence noted in the SEAS trial (P=0.61 for the incidence of all cancers in the combined IMPROVE-IT and SHARP active-treatment groups as compared with the placebo groups). However, as in the SEAS trial, a nonsignificant increase in cancer mortality was observed (P=0.07). It is important to note that none of the three trials were designed primarily to address cancer risk. However, cancer mortality is an end point that would be expected to be reliable.
. . . .Although the Oxford group may ultimately prove to be correct, it is appropriate to raise a note of caution. Whether the increased mortality risk is due solely to the play of chance is uncertain. Ezetimibe interferes with the gastrointestinal absorption not only of cholesterol, but also of other molecular entities that could conceivably affect the growth of cancer cells. The fact that the combined data from all three trials showed an increase in cancer mortality with ezetimibe should not be assumed to be a chance finding until further data are in. It is appropriate that SHARP and IMPROVE-IT continue. Careful follow-up of the patients in these trials will be essential, and other existing data sets on ezetimibe-treated patients should be analyzed for cancer end points. The Food and Drug Administration has already announced that during the next few months it will conduct its own analysis of the potential cancer hazard of ezetimibe. . . .
I think it is high-time to listen to these independent experts’ voices — voices that stand to make no money from the companies involved. Voices that want science, not just commerce, to be advanced.