1st July 2009
An analysis of post-marketing adverse event reports did not find any increased risk of cancer with ezetimibe▼ compared with statins, either alone or when taken in combination with simvastatin.
Level of evidence:
Level 3 according to the SORT criteria.
Although these data are reassuring, it would seem sensible to use ezetimibe▼ only with caution because there is no published evidence of its benefit on clinically important outcomes such as cardiovascular (CV) events and its long-term safety is unknown. Prescribers should continue to use evidence-based statins (e.g. simvastatin 40mg/day) first-line in most patients who require a lipid-lowering agent.
What is the background to this?
As we blogged in September 2008, the SEAS trial unexpectedly raised concerns about the safety of ezetimibe because there was an increased incidence of cancer in the active treatment group. However, this increase was not seen in other large, ongoing trials of ezetimibe. A large, high-quality meta-analysis has suggested that statins do not increase the risk of cancer. More details are available in MeReC Monthly No. 8.
In the November 2008 edition of Drug Safety Update, the MHRA reported that no conclusions about the possible effect on cancer could be drawn from current data and that further assessment would be made when results of the two large, ongoing randomised trials become available.
This study analysed the rates of cancer in adverse event reports filed with the US FDA in people taking ezetimibe, either alone or in combination with simvastatin and compared them with those taking simvastatin, atorvastatin or rosuvastatin.
What does this study claim?
It found that, from July 2004 to March 2008, there were 559 million prescriptions for all the cholesterol lowering drugs studied. Of these, approximately 52 and 55 million were for ezetimibe, and ezetimibe plus simvastatin, respectively. There were 2,334 reports of cancer-related adverse events for all drugs, with 151 and 73 associated with ezetimibe, alone and in combination, respectively.
Rates of cancer adverse event reports were similar between the groups (rates per million prescriptions: ezetimibe 2.9, simvastatin plus ezetimibe 1.3, simvastatin 5.1, atorvastatin 4.7 and rosuvastatin 3.1; P<0.01 for each pair-wise comparison of ezetimibe or the combination vs. the other drugs, except ezetimibe vs. rosuvastatin).
These findings persisted whether the analysis was limited to reports where the drug was believed to be related to the adverse event, or not; when rates of cancer as a proportion of all adverse events were examined; and when other time periods were considered.
Post-marketing surveillance data have many limitations and should be interpreted cautiously. Adverse events are often under-reported, so the number of reports for a particular medicine cannot be used to determine the frequency of an adverse reaction. In addition, a reported adverse reaction may not necessarily have been caused by the drug. Many factors have to be taken into account in assessing the likelihood that a drug has caused a reaction including the possible contribution of other medication that the patient may be taking and any underlying disease that the patient may have.
The study authors point out that, when using such data, small absolute differences in rates between drugs are not likely to be clinically meaningful. This seems to be the case here where the rates of cancer adverse event reports with ezetimibe and ezetimibe plus simvastatin, , appear significantly lower than for the statins studied.
In spite of the limitations, post-marketing surveillance is a useful source of information about adverse effects and the findings from this large-scale analysis are consistent with the interim evidence from two large trials of ezetimibe plus simvastatin. The MHRA will reassess the evidence around ezetimibe and cancer when the final results of these studies are available.
These data provide some reassurance around any possible increased cancer risk seen in the SEAS study. However, the long-term safety of ezetimibe is still unclear and, importantly, there is no good evidence that ezetimibe, either alone or added to a statin, reduces the risk of CV events compared to a statin alone. Adding ezetimibe to statin therapy also substantially increases the cost to the NHS. NICE guidance on ezetimibe seems sensible — use ezetimibe monotherapy only if statins are contraindicated or not tolerated, and ezetimibe in combination with a statin in some limited circumstances where statins have not appropriately controlled cholesterol levels, despite appropriate dose titration and consideration of switching statins.
Design: Post-marketing analysis of cancer adverse event reports filed with the US FDA
Patients, intervention and comparison: Reports in patients taking ezetimibe or ezetimibe plus simvastatin were compared to reports in patients taking simvastatin, atorvastatin and rosuvastatin.
Outcomes and results: Adverse event reports listing ‘cancer’ or ‘malignancy’, which were filed between July 2004 and March 2008, were analysed. Rates were calculated for reports per million prescriptions. A secondary analysis examined cancer reports as a proportion of all reported adverse events for each medication.
Prescriptions for all the drugs studied totalled 559 million (approximately 52 and 55 million prescriptions of ezetimibe and ezetimibe plus simvastatin, respectively), and cancer adverse event reports totaled 2,334. There were 2.9 and 1.3 cancer-associated adverse event reports per million ezetimibe or ezetimibe plus simvastatin prescriptions, respectively, compared to a range of 3.1 to 5.1 per million prescriptions for the other drugs. Findings were similar when only reports listing the drug as ‘suspect’ were considered. The proportions of reports listing cancer relative to all adverse event reports were 2.0% and 1.9% for ezetimibe, alone and in combination, respectively, compared to a range of 1.3% to 3.9% for the other drugs.
Sponsorship: No specific funding was obtained for this analysis.
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