Topline results from the SEAS trial, which were first disclosed publicly at a press conference in London on 21st July, have since then caused heated reaction. The results showed that reducing levels of LDL-cholesterol with a proprietary combination of simvastatin and ezetimibe in patients with aortic stenosis had no more effect on major cardiovascular events (the study's primary endpoint) than with placebo. However, concentrations of LDL-cholesterol fell by 61% in the simvastatin/ezetimibe treatment group when compared with the placebo group.
The results - as well as their manner of disclosure - have raised many questions among cardiologists, patients, politicians and the press. Some press reports in the past two weeks have concentrated on the incidence of cancers found in both arms of the trial - even though this seemed to have been adequately explained - while others have questioned the efficacy of simvastatin/ezetimibe in the prevention of certain major cardiovascular conditions.
As a prelude to the ESC press conference, the ESC has interviewed Professor Pedersen and raised some of the issues to emerge in the past few weeks. His responses, as recorded below, are available for quotation.
Questions and answers
ESC: You presented the results from the SEAS trial at a press conference in London on 21st July. Why then, and why to the press?
T. Pedersen: There are two reasons, and both relate to the trial's sponsors. First, the sponsors of the trial had a legal responsibility to inform the regulatory agencies about any potential health concerns raised by the study and they had to do that within a certain specified time limit. In this case the concern was cancer. Because the regulatory agencies had to be informed, it was deemed impossible to keep the information secret. Rumours could be damaging for the study and to the sponsors. In addition, the sponsoring company had agreed to report its projected earnings to the New York stock market on 21 July. Giving information to the stock market is regulated by law, and we felt the information could not be disclosed after that date.
ESC: Next month (2 September) you will be presenting the SEAS results to a large audience of cardiologists at the ESC Congress in Munich. Will you be saying anything more than you said in London?
TP: I'll only have 13 minutes for presentation and five minutes for commentary in Munich, so I'll only have around 20 slides. But the audience will be much different from our press conference in London, where I focused on just the main findings. I'll give more details about the endpoints and the incidence of clinical events in patients - how many myocardial infarctions were there, how many coronary artery bypass procedures, the echocardiographic data, and so on.
ESC: So what message would you take from the results for an audience of cardiologists?
TP: The patients in the SEAS study were selected. They were people who today are not normally considered candidates for LDL-cholesterol-lowering therapy. But the finding we made was that a large proportion of these patients actually did have a high risk of developing atherosclerotic disease. The patients who received the cholesterol-lowering treatment benefited - from less complicated surgery and less atherosclerotic disease. So what we learnt is to focus more on atherosclerosis in a patient population with aortic disease. However, in aortic stenosis itself, we will probably need modalities other than cholesterol-lowering to modify disease progression. If there is a role for lipid-lowering in the prevention or modification of aortic stenosis, it should probably be introduced much earlier in the disease's progression. But that's a hypothetical answer. It will depend on finding which patients are inclined to develop atherosclerosis in aortic stenosis. That's something we have to look for in the trial data.
ESC: The trial failed to find any beneficial effect of simvastatin/ezetimibe in its primary endpoint of major cardiac events in the treatment group, despite a 61% reduction in LDL cholesterol. How would you interpret that finding?
TP: That's true, but only in the primary endpoint. It may be that we met the patients at a stage of aortic disease where they had passed the limit of no-return, so to speak. However, if we accept the fact that reduction in LDL cholesterol has no effect on aortic disease, we have to move to the secondary endpoint of atherosclerosis. And then it becomes difficult to interpret because much of the effect was dependent on bypass surgery. This was a low-risk population in terms of ischaemic disease and the major component of the ischaemic secondary endpoint was bypass surgery. We found that the treated patients having surgical valve repair had less atherosclerosis - and less need for bypass surgery - than the placebo patients. This means that the course of the ischaemic development, the progress of atherosclerotic changes in the coronary arteries, must have been affected.
ESC: This statistically significant reduction in one of the two secondary endpoints of the trial (atherosclerotic events) was found in the simvastatin/ezetimibe group. Is it reasonable to draw evidential conclusions from secondary endpoints?
TP: Well, when the primary endpoint of a trial is not significant, we have to be cautious about secondary endpoints. I know that some statisticians would not allow that. But the secondary endpoints were pre-specified and my approach is to take the results of other trials into consideration - there are now 25 randomised trials showing that ischaemic events related to atherosclerosis will be reduced with lipid-lowering therapy. So it seems valid when we find a reduction in coronary bypass surgery in our treated patients. The evidence from other trials gives plausibility to our secondary endpoint findings. However, without the evidence from other trials, our secondary endpoint information would only be hypothesis-generating.
ESC: Press reports following your press conference have mainly focused on safety concerns with respect to cancers found in the treatment group of the study. Are these concerns justified?
TP: I have to rely on the work done by Sir Richard Peto on our data and data from the two other simvastatin/ezetimibe trials. They found no credible evidence of any adverse effect on cancer. I accept that and don't believe there is any increased risk of cancer.
ESC: We should not forget that the SEAS trial was a study in patients with aortic stenosis. Are there implications in its results for primary prevention or lipid lowering in other cardiovascular conditions?
TP: In terms of preventing atherosclerosis, this was a primary prevention trial, because no patients had signs or symptoms of disease. However, aortic stenosis and aortic sclerosis are also very common conditions. I think we have shown that, even in these patients not normally considered for lipid-lowering therapies, that there is an increased risk of atherosclerotic disease. And therefore I think that decisions about patients with aortic sclerosis - which is the early stage of the disease - might consider lipid-lowering therapy to a greater extent than before. But this is based only on our secondary endpoint findings.
ESC: Both this and the ENHANCE trial failed to translate the benefit of reduced LDL with simvastatin/ezetimibe into primary endpoint benefit. Could you explain this?
TP: I don't think it's possible to consider the two trials together. The ENHANCE trial used a surrogate endpoint in a healthy, well treated population. We used a completely different population with a different clinical endpoint. So it's impossible to compare the two studies. There are so many studies in the history of statins showing the benefits of lowering LDL cholesterol, and what we're doing now is looking at different patient populations who might benefit from this. Our study was based on epidemiological evidence that cholesterol was a risk factor for aortic stenosis, in much the same way that cholesterol is a risk factor for heart attacks. We have shown that that assumption was not correct - at least in a patient population where there is already calcification of the valve.
ESC: Finally, as raised by an expert panel following presentation of the ENHANCE trial results and in the light of your own results, do you think the simvastatin/ezetimibe combination has any therapeutic benefit over generic simvastatin?
TP: We did not design the SEAS study to answer that question. We only had patients who received simvastatin/ezetimibe and placebo. It's a very important question, of course, but only properly designed trials will answer it.