I’m peggy peck medpage today in light of the controversy surrounding enhance including the unanticipated and according to some biologically implausible finding that ldl reduction had no effect on atherosclerosis it is not surprising that there was little agreement between study investigator dr. evan stein and enhanced critic dr. alan taylor in this series of
Interviews we examine three key areas of disagreement mechanism of action trial design and clinical implications part 2 trial design the enhanced trial both sides agree had its roots in an earlier trial asap done in the late 1990s 1997 in holland in a predominantly dutch population of patients with familial hypercholesterolemia and that understanding that trial
Is critical to understanding what went wrong in enhance when we used asap as a prediction for what would happen in enhance and for determining the control group simvastatin alone was selected and in asap in simvastatin group they continued to progress in terms of carotid thickness in eset they found that the atorvastatin dose did appear to slow progression of
Atherosclerosis by imt compared to the control arm which was in was done it appeared to slow in the first year and in the second year appear to cause some slight regression of disease why where’s in the simvastatin group over the two years it was continued progression thus using the asap model enhance you simvastatin as the control which in enhance also produced
The identical ldl reduction of forty percent that we’ve seen in asap however in order to have a successful outcome to the study one would have to see continued progression of your simvastatin group as was found in asap or one would have to see regression associated with the more aggressive treatment the acetamide + symbol patent on we now don’t have a control group
That is progressing we appear to have thin arteries that have no a thoroughness of virtually no chance of regression so this was a failed trial not a failed drug dr. taylor who co-authored a new england journal of medicine editorial that accompanied publication of the enhanced results had a different take the defenders again have said that the problem is not with
The drug but with the trial with the trial this was the trial i shouldn’t have used a surrogate endpoint they shouldn’t know that they shouldn’t have looked at imt it’s not a good endpoint doesn’t tell us anything we’re not even really sure that it connects with the clinical events every single effective therapy that we have in cardiovascular prevention has been
Shown to act positively through im t let me give you two examples of when the imt trials were negative 1 is toward satrapy the second one is estrogen estrogen failed in qca trials and failed in an im t trial a substudy of hers and those were pretty good bellwethers for the outcomes trials key evidence he said may have been overlooked and one has to go to the new
England journal in the supplementary information to find this but it’s a key figure and what it shows us is that in 25 subgroups the drug was neutral or trended to more progression in the ezetimibe group in 22 of 25 subgroups didn’t work where didn’t it work it didn’t work if patients had never been treated with a statin had been treated with low dose statin or
Hydro statin and so the statement that these patients were really well treated and thus a benefit couldn’t be seen really doesn’t hold water they said the imt was too thin well in those subgroups whether the imt was above average or below average the results were the same they said the ldls were so well treated it didn’t matter whether the ldl was above average
Or below average prior to prior to the initiation is the results were consistent this trial did not test the wrong population fh patients have been a testing ground for lipid drugs this population is enriched with the exact problem this drug is supposed to treat the imt at baseline in this trial is in fact not an outlier it in fact is typical of ifs fh patients at
This age with few other risk factors which this population have in fact the trial that this is contra contrasted against the asap trial etc is the outlier okay this population is not the outlier in imt asap is an outlier they were selected for higher imt and they had five times more prior myocardial infarction more enriched with other risk factors like smoking and
Hypertension so asap is the outlier this is mainstream fh this is a perfect population to test this drug in it is not an outlier population it was not excessively well treated and you cannot make easily cross trial imt comparisons different measurement technique different measurement techniques different technologies different patients themselves the bottom line is
This trial was designed in the right population was acted was was was completed faithfully and did exactly what they wanted was they created an over 50 milligram per deciliter difference in ldl and despite that on 6 of 7 progression measures and on 22 of 25 subgroups it went in the wrong direction let’s look at this issue of pretreatment in the new england journal
Editorial dr. taylor wrote the argument against this hypothesis is that among the nineteen percent of patients who were not receiving statins at the time of study enrollment those who were treated with the combined regimen of simvastatin plus ezetimibe didn’t have a better response than those receiving simvastatin alone how do you answer that well that actually is
An incorrect statement it is a post-hoc analysis and i can show you these and i noticed you can show you the slide which shows the twenty percent of patients roughly sixty patients per group were not treated with statins prior oh and not being treated with lipid-lowering therapy prior to entry and there is a clear separation between the simba staten alone and
The simvastatin pluses aramide group it’s small it’s in it supports the hypothesis of pretreatment if you look at those that were treated at high doses of statins there’s total overlap between the two groups those that were treated with lower there’s a looks like a little eclipse of the moon as they start separating but when you do look at the patients who did not
Receive prior therapy there is a separation obviously it’s a post-hoc analysis it’s not statistically significant it’s a small number the post-hoc analysis is not obvious not connect it’s not included in the supplemental information i don’t know because it was not an a priori analysis so there really doesn’t as post-hoc it can be it can only be hypothesis-generating
I can’t really tell us for perhaps let me get you see here’s what we’re talking about in the changes that one can you see that side this is the group to 20 patients mm-hmm okay who were not on stanton right and there’s those that were high dose you can see both he’s overlap that is like a slight movement down and mississippi so um they commented on what was published
On the data that were published correct but then you caught then i’m not sure how he could have commented yesterday on the fact that he’s no he commented on the subgroups he commented on not based on the imt thickness right yes on the second pretreatment and and in one of the subgroups is low treatment no treatment but in that subgroup analysis and this again this
This is just the image and you can see the change but this isn’t showing actually hey the difference between the two groups this is just showing your p-value treatment differences in pre specified groups so it seems a weak argument to go to a post-hoc analysis rather than than an a priori analysis well it that actually is the same the same analysis in showing the
Data differently yeah it’s showing it what you’re seeing in there is only the mean differences with confidence limits okay i think that that but this showing the day-to-day lately i think it is it something that that’s of concern to clinicians it confuses the practicing physician but again i think going to looking at twenty percent of the patients in a 60 patient
Trial per group is not really what this study was about all right i think overall the study was a failed study this was not a negative result ran will be distributed around benefit and no harm this is a negative result skewed to harm so again just as there was no common ground on mechanism of action dr. stein and dr. taylor had widely divergent views on the trial
Design in the third part of this exclusive report we confront the elephant in the room what are the clinical implications of enhance i’m peggy peck medpage today
Transcribed from video
Researchers Debate Ezetimibe (Vytorin) ENHANCE Trial -Part 2 By MedPage Today
