Abstract
Interview with Professor Chris Packard, MD, PhD by Tanya Stezhka (Commissioning Editor)
The IMPROVE-IT trial, launched 9 years ago, has finally provided physicians with long-term efficacy and safety evidence for ezetimibe. The large-scale study in acute-coronary-syndrome patients showed a clear benefit in reducing cardiovascular events when added to simvastatin in this population. The size of the benefit was proportionate to the reduction in LDL cholesterol.
We spoke to Professor Chris Packard (University of Glasgow, UK) about his interest in the trial, and the importance of lowering LDL and research in the wider clinical context.
| • | Could you tell us about your background and your involvement with the IMPROVE-IT trial? | ||||
Colleagues from across Europe, including myself, were concerned that there would be misinterpretation of IMPROVE-IT results, so we published some articles ahead of the trial to try and set the scene as to what people should and shouldn’t expect and interpret from the trial results, especially if they were not used to analysing big data. I have a background in placebo–statin trials and was one of the main investigators on two major studies, WOSCOPS, which was the first primary prevention statin trial, and PROSPER, which looked at pravastatin in the at-risk elderly. Although conducted a while ago, we are still producing data that helps build the evidence base and illuminate how best to undertake LDL lowering in practice.
| • | What does IMPROVE-IT tell us and why is lowering LDL-C important? | ||||
The most important result from the IMPROVE-IT trial was the finding that a non-statin based LDL-lowering treatment (ezetimibe) was able to lower LDLc and reduce clinical events. The decrease in major cardiovascular events in the ezetimibe group for a given drop in LDLc was the same as that seen with statins. There was consensus in the community that the IMPROVE-IT trial result completely validated the LDL story, which suggests that for every 1.0 mmol/l you lower LDLc, you reduce risk by 22%. The results also tell us that LDL is one of the major, if not the primary, atherogenic factor in blood.
How low should we reduce LDLc is a question that follows from the IMPROVE-IT results. Of course, we cannot drop it to zero since people with the inherited disease, abetalipoproteinemia, (complete lack of LDL) have neurological problems linked to an inability to transport fat-soluble vitamins around your blood stream. So the ideal value is somewhere in the very low range. There is another inherited condition called hypobetalipoproteinemia where people have very low levels of LDLc and low heart disease rates but are otherwise completely healthy.
| • | Which patients should be targeted for treatment? | ||||
LDL appears to be highly toxic to vessel walls and is the primary cause of atherosclerosis, so we should treat those at most risk. Statins are still the first line of therapy and, for those that can tolerate it or have high LDLc, more intensive statin therapy is still the sensible next step. For those that cannot take high-dose statin due to side effects, the addition of ezetimibe to a low-dose of a statin could be a solution which gives good patient compliance and maximum therapeutic effect. Where it may be used most often is in people who have familial hypercholesterolemia, other forms of severe hypercholesterolemia or those with a troubling history of coronary disease in whom you want to get LDL down as far as you can. The average UK general practitioner would not prescribe ezetimibe to somebody whose LDL is already 1.8mmol/l; unless they were very worried about somebody’s risk, the average person with a well-controlled LDL level has lots of other things to attend to about before driving their LDL down further as the additional benefit would only be reduction of 6-7% relative risk.
| • | Current guidelines do not include ezetimibe – may that change after IMPROVE-IT? | ||||
US guidelines have been revised recently to have a reduced emphasis on LDL targets. This may need to be revisited on the basis of the new information that IMPROVE-IT provides. I think certainly the EU guidelines, and to some extent the UK guidelines, will be relatively easily revised to include this new data.
| • | Which other current or future trials look most promising in this field and what are your expectations of the field in the next 5 years? | ||||
The PCSK9 inhibitor trials are looking promising, and because they are focused on LDL lowering in the same kind of range as IMPROVE-IT, we anticipate that we’ll see a clear clinical benefit from more aggressive LDL lowering of the order of 50–60% on top of the statins.
In the next 5 years ezetimibe will become generic, which may prompt the wider use of combination therapy rather than mono-, or step-wise titration-, monotherapy. We are also beginning to understand from genetic studies the need to start treatment earlier – instead of the average age of intervention being 60–65, it may decrease to 30–45. I also think there may be more aggressive intervention in asymptomatic individuals where a gene or biomarker score identifies them as being at high risk.
| • | What else are you working on that may be of interest to our readers? | ||||
We are currently working on the use of data from long-term follow-up of WOSCOPS and PROSPER to evaluate life-long statin efficacy and safety. This will hopefully significantly improve our risk–benefit calculations where we take into account the fact that people have multiple cardiovascular events, whereas most short-term trials focus only on the first event.
We are also looking at biomarkers of cardiac damage using some of our stored samples and patient cohorts to try and determine whether there are profiles of molecules in the bloodstream that signal the state of the myocardium. We hope to produce novel biomarkers and high-sensitivity assays that show what fluctuations in these biomarkers may mean in these patients.
Disclaimer
The opinions expressed in this interview are those of the interviewee and do not necessarily reflect the views of Expert Reviews.
Financial & competing interests disclosure
The interviewee has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.