Seas study

Ezetimibe inhibits the intestinal absorption of cholesterol by binding to the Niemann–Pick CI-like 1 protein. The combination of ezetimibe and an HMG CoA reductase inhibitor (“statin”) is logical. This is because statins lower low-density lipoprotein (LDL) cholesterol by inhibition of cholesterol synthesis and upregulation of the hepatic LDL receptor which clears cholesterol from the vascular compartment, but at the same time, they increase the intestinal absorption of cholesterol.

In the double-blind controlled SEAS trial, 1873 patients with asymptomatic mild-moderate aortic stenosis and no indication for statin therapy were randomised to receive the coformulation of simvastatin 40 mg and ezetimibe 10 mg daily or matching placebo. The study was based on previous observational data relating cholesterol and cholesterol lowering to progression of aortic stenosis and the known associated pathology of the aortic valve in this condition, which resembles atherosclerosis.

Despite a large reduction in LDL cholesterol of 61% to a mean of 53 mg/dl (1.3 mmol/l) at 8 weeks, and a 54% reduction over total follow-up (of a mean of 4.1 years), treatment with simvastatin and ezetimibe failed to reduce the primary end-point, a composite of aortic valve disease events and ischaemic cardiovascular events (hazard ratio 0.96; 95% CI 0.83 to 1.12; p=0.59). Results concerning secondary endpoints were mixed, with a significant reduction in ischaemic cardiovascular events, but not aortic valve disease events alone.

Why the controversy? In the group assigned simvastatin and ezetimibe, incident cancer was diagnosed in 105 patients (11.1%) compared with 70 patients (7.5%) among those assigned placebo (p=0.01). The excess cancers in those randomised to simvastatin and ezetimibe were not clustered at any particular site. Further analysis showed that the risk of incident cancer was not associated with the degree of LDL-cholesterol lowering. Fatal cancers occurred in 39 patients (4.1%) of those randomised to simvastatin and ezetimibe, and 23 (2.5%) of those randomised to placebo. The hazard ratio for cancer-related mortality was 1.67; 97% CI 1.00 to 2.79; p=0.05 using the prespecified Cox proportional hazards model (p=0.06 with Yates' logrank continuity correction). Notably, neither cancer incidence nor mortality was designated as a primary or secondary endpoint in SEAS, and these results arose from analyses of possibly a large set of safety endpoints and thereby are at greater risk of being merely a chance finding.

These unexpected results in an unplanned endpoint could only be considered as hypothesis generating, rather than being definitive. Realising this, the pooled interim analysis of cancer data from two ongoing placebo-controlled trials of simvastatin and ezetimibe2 accompanied the SEAS publication, along with two editorials.3 4

The two trials in the pooled interim analysis were the Study of Heart and Renal Protection (SHARP) study5 and the Improved Reduction of Outcomes: Vytorin Efficacy Intervention Trial (IMPROVE-IT).6 These trials are ongoing in patients with chronic kidney disease and following acute coronary syndromes, respectively. The SHARP study is a placebo-controlled trial of simvastatin 20 mg and ezetimibe 10 mg, and 9264 patients with a mean follow-up of 2.7 years and IMPROVE-IT (testing simvastain 40 mg and ezetimibe 10 mg) including 11 353 patients with a mean follow-up of 1.0 year at the time of the pooled analysis of cancer data. In the combined analysis of SHARP and IMPROVE-IT, there was no increase in either all incident cancers (313 on simvastatin and ezetimibe vs 326 on placebo, risk ratio 0.96; 95% CI 0.82 to 1.12; p=0.61) or cancer at any organ-specific site.2 There was a non-significant excess in cancer deaths (97 vs 72; p=0.07) in those randomised to receive simvastatin/ezetimibe but fewer non-fatal cancers (216 vs 254; p=0.08).

There was also no evidence of a trend in the risk of incident or fatal cancer with increasing duration of follow-up in this pooled analyses of the SHARP study and IMPROVE-IT.2 This might be expected if the treatment were related to cancer risk. Together, these point towards the increased cancer incidence and mortality in SEAS being merely a chance finding. The authors concluded that “the available results … do not provide credible evidence of any adverse effect of ezetimibe on rates of cancer.”2

Scientific evidence base

In general, the evidence related to benefit or harm of specific interventions is derived from multiple sources. These include: basic science which can elucidate putative mechanisms; epidemiological observational studies which identify associations; clinical research and large-scale randomised clinical trials to establish efficacy, net benefit and inform cost-effectiveness analyses; randomised clinical trials to establish safety4 and outcomes research and long-term surveillance data, to allow an estimate of outcomes and effectiveness in usual clinical practice.

Each of these sources of evidence is important but also has some limitations.

Basic science in laboratory animals suffers from potential different mechanisms of action to that in humans, so that results in animals need not necessarily apply to humans. Observational epidemiological studies suffer from a myriad of selection and confounding biases, in which persons being treated may differ systematically in important but unmeasured (or unmeasurable) prognostic factors from those not being treated. Unless the mechanisms underlying the prescription of treatment are well defined and measurable, these biases are difficult, if not impossible, to remove analytically. Randomised and blinded clinical trials, with no loss to follow-up and analysed using the intention-to-treat principle, provide the gold standard for evaluation of the benefits of assignment to treatment. However, in the face of treatment non-compliance, assessment of efficacy of treatment received must take into account selection biases akin to those of observational studies. In addition, assessment of rare and long-term adverse events is not reliable in randomised trials designed to assess relative short-term efficacy due to the paucity of such events observed during the trial's duration.

Case of cholesterol lowering and cancer

Broader implications and the need for pharmacovigilance studies

Conclusions regarding these aspects may be informed in a variety of ways, but ultimately, infrequent events such as cancer require preplanned longer periods of data collection. Randomised controlled trials are the most reliable way to minimise confounding and bias, and to estimate treatment effects. However, as mentioned earlier, they are much less effective in establishing whether or not an intervention is associated with a serious adverse event.

The placebo-controlled trials of statins and published longer-term follow-up of such trials provide some reassurance regarding the safety of statins with respect to any association with cancer. However, the placebo-controlled data are limited by the relatively short period of exposure and also because analysis is made on an intention-to-treat basis. For example, the usual time for induction of lung cancer by smoking is many years longer.47 Longer-term follow-up of trial cohorts is also somewhat flawed because subjects were/must be offered proven therapies (such as statins) at the end of the controlled trials phase, minimising the differential in exposure to the treatment. For example, in the WOSCOPS, during extended follow-up of the cohort, the percentages of participants being treated with a statin among those initially assigned to pravastatin and placebo were, respectively, 28.6% and 24.3% at 1 year, 33.6% and 29.4% at 3 years, and 38.7% and 35.2% at 5 years.35

New analytical approaches are needed to address problems such as this. Progress has been made recently with statistical methods to assess efficacy associated with full compliance to treatment48 and assessment of dynamic treatment regimens;49 however, these methods are necessarily based on strong assumptions.

Many countries have cancer registries and the potential for linkage of administrative datasets utilised in extended follow-up of patients in clinical trials.33 It is prudent to establish and enhance systems that can link large databases. In the case of statins, one example is provided by the VISN16 database in the USA. Interrogation and case-control analysis in 40 421 women in this database, which contains clinical and demographic information about all veterans (>1.4 million patients) cared for in the fourth Central VA Health Care Network between 1998 and 2004, showed that after appropriate adjustment for age, smoking, alcohol use and diabetes, which were all significant covariates, women using statins were less likely to develop breast cancer (odds ratio 0.49; 95% CI 0.38 to 0.62).50 Internal consistency was suggested by the fact that increased breast cancer risk was also shown for documented risk factors.

Specifically, pharmacovigilance data during malignancy in patients on long-term cholesterol lowering therapy could be compared with national age-specific incidence and mortality data. Such monitoring could also help ascertain whether any drug-class effect or organ-specific effects exist (deleterious or beneficial). These data-linkage systems should include a variety of stakeholders, including regulatory authorities from different countries and the pharmaceutical industry, all cooperating in the provision of more robust information in this and other important areas of pharmacovigilance. Recent issues surrounding the long-term uncertainty of rosiglitazone, cyclo-oxygenase-2 inhibitors and hormone replacement therapy have further highlighted that medication safety must be proven rather than assumed, especially for very widely used medications utilised for long-term therapy.

At this time, it is considered unlikely that cholesterol-lowering generally is associated with cancer. Since the excess cancer mortality in the SEAS trials was not replicated in the interim data in the SHARP and IMPROVE-IT trials, this conclusion will probably extend to simvastatin/ezetimibe as further data are obtained in the ongoing trials.5 6

What should we now do with patients taking simvastatin and ezetimibe (“vytorin”)?

The Data and Safety Monitoring Committees of both IMPROVE-IT and SHARP have reviewed the cancer data, and have discussed and recommended that both trials continue as planned, with particular surveillance concerning future data in this area. Similarly, the Food and Drug Administration in the USA decided that no action was necessary after SEAS was published.51 Ezetimibe and its coformulation with a statin are important additions to cholesterol-lowering therapies. It appears inappropriate to withdraw them from patients in whom their indication is clear and to await the results of ongoing clinical trials5 6 and further information concerning cancer which should be derived from these trials and other sources, including long-term surveillance data, which are required because of the typically very long latency period before cancer is diagnosed.