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Deepak Bhatt, MD: Time to Benefit in REDUCE-IT

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Deepak Bhatt, MD, MPH, discusses the results of a REDUCE-IT REVASC analysis assessing the time to benefit seen with icosapent ethyl in the REDUCE-IT trial.

So the first question i have for you would be related to the most recent reduce analyses we’ve seen which is actually analysis of reduce it reevas now could you just sort of take me through the purpose of this analysis and what it adds to our understanding of total events and the reduction of that caused by reducing or caused by echo safe and ethical absolutely

So coronary revascularization was part of the primary composite endpoint and as we reported in the new in the journal of medicine it was significantly reduced so that was actually the new material medicine paper as part of a five-point major adverse cardiovascular event composite and that was the time the first event what we have reported now or actually i should

Say what one of my interventional cardiology fellows ben peterson had reported as a late breaker at sky was a deeper dive into the coronary revascularization endpoint showing overall a reduction of 34 percent in relative terms percent or so in absolute terms in coronary revascularization over the duration of the trial so that was the overall finding in addition

To that which i think was pretty important what he had reported there was a significant reduction in elective emergent and urgent revascularization as discrete categories and furthermore showed data that as far as coronary revascularization goes the time to percutaneous coronary intervention as an end point was significantly reduced that was 32 percent lower

But also that the time to coronary artery bypass grafting was significantly reduced to 39 relative risk reduction there so that in particular struck us as very important the novel that even in a blinded trial with independent adjudication of endpoints the need for coronary artery bypass graft surgery was significantly reduced pointing to the profound reductions in

Atherosclerotic burden that must be occurring with use of the drug so that was at sky or the society of cardiovascular angiography as a late breaking clinical trial now what i’ve presented as a non-correlate breaker at the american society of preventive cardiology was a recap of that but then some additional data taking things even further in terms of evaluating

The timing of benefit and what we demonstrated was that there’s a very early benefit we’re seeing here in coronary revascularization again in this blinded trial with independent adjudication of endpoints done by mike gibson’s group as a matter of fact and what we’re seeing is a significant reduction in coronary revascularization by 11 months so that’s probably

Much earlier than people were thinking icosapent ethyl is working in a stable cardiovascular population and in fact the hazard ratios even before the 11 months were close to statistically significant but achieved sustained statistical significance by 11 months in fact the benefits seemed even earlier occurring relatively soon after randomization so unlike what i

Think most people were assuming was the case with icosapent ethyl where it just takes years to work in fact the benefits do seem to be kicking in pretty early and this is in line with what was noted in the interim analysis the pre-specified interim analysis from evaporate which has now been published in cardiovascular research where that showed in that coronary

Ct imaging study that there was a significant effect on plaque progression with icosapent ethyl versus placebo by nine months so that’s very similar to what we’re seeing here by 11 months is significant reduction and as i said there’s even evidence before that 11-month time point of the hazard ratio for coronary revascularization being well below one that is

Suggesting that there’s very early benefit i’ll point out to your viewers that in reducing these were stable outpatients that we enrolled and we excluded by protocol patients with planned coronary revascularizations so the patients who would have been at highest risk of repeat revascularizations or bonovo revascularizations were excluded by protocol from the

Study so the effect sizes we’re seeing here both in relative and absolute terms are large and are early but are probably still an underestimate of the actual potential benefit if we were to use the drug say in patients who had just undergone coronary revascularization or who were at very high risk of it so i think that these results especially when viewed in a

Historical context are really quite important because if you think back to trials in the past like historic trials the 4s trial of statins for example you know there there was a significant reduction in revascularization as well but now what we’re seeing is a risk reduction that really in terms of magnitude of effect is quite uh in that ballpark of 4s but in a

Statin treated population so this is an incremental reduction beyond say statin versus placebo just to put that in the proper context and indeed the reduction of revascularization we’re seeing here exceeds what other therapies beyond those initial stanton trials have shown so i think that the effects are really quite clinically relevant and could have a major

Impact on the way we treat patients who are at risk for coronary revascularization which is a lot of patients all right thank you for that now when we’re talking about the clinical relevance of these results i know in the past when we’ve discussed reduce it you suggested that maybe total events is the way that most patients like to look at the impacts of these

Studies in this world of people wanting effects immediately and to see results of the medications that they take what kind of added tool is this that clinicians can tell their patients they’ll see benefit that in comparison to other drugs is pretty immediate given the 11 months that you guys found in the study sure well you mentioned total events i guess i

Should complete the picture i was so far just referring to first events if we look at total revascularization events in this data set and reduce it we see a 36 reduction in total revascularization and even when we put it in a multi-variable model we see that the only thing that emerges as a predictor of lower risk of revascularization is the icosapent death

Will get a 36 relative risk reduction there uh whereas predictors of revascularization are the usual culprits things like a history of prior pci being male versus female having diabetes versus not having diabetes having elevated triglycerides or elevated crp were all predictors independent predictors of revascularization but those were predictors of having

It the only predictor in our multi-variable model of not having it was treatment with icosapent methyl randomization that cost the pentathyl so you know that’s the overall sort of impact clinically obviously there are cost effectiveness implications of this we didn’t examine that in this particular analysis but dr bill weintraub has already presented reduce it

Cost effectiveness analyses at the last american heart association is a late breaker showing that the drug is highly cost effective and most of the scenario analysis is in fact a dominant strategy meaning not only cost effective but actually cost saving so i think revascularization is an important part of that story because obviously let’s talk about the us

Healthcare system revascularization is a very expensive event whether it’s pci and in particular one it is cabbage so you know those are implications at a societal level now from an individual patient level as you asked certainly what we’ve seen in the overall trial is that the longer patients are on therapy the more the curves separate that is the greater the

Degree of benefit on first ischemic events and in particular on recurrent or repeat events so that totality of the after thrombotic burden is very significantly reduced about a 32 reduction there with significant reductions in first second third and even fourth or more events we published that in the journal of the american college of cardiology so i think that

These data really helped complete that picture with the added insight and perhaps this is a particularly important point for patients that the benefits do also kick in early it’s not just a matter of if you’re on it for a long time you get benefits that’s true of course as with statins or other effective therapies but here and there’s a benefit that’s kicking in

Pretty early and uh this as i also alluded to uh dovetails quite nicely with the evaporate interim analysis results of course we have to see what the final results of evaporate are but even at the entering point a variety of different measures of plaque volume were significantly favorably influenced by icosapentethyl versus placebo so now we’ve got mechanistic

Data showing benefits occurring on the order of months with icosapent ethyl versus placebo from evaporate we have large cardiovascular upcoming trial data from reduce it showing a relatively early benefit on this end point of revascularization again within months of randomization so i think it really paints a cohesive picture of how this drug is working not only

In terms of preventing later cardiovascular events but even earlier ones and again from a patient’s perspective as you asked that might be useful information for them to know

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Deepak Bhatt, MD: Time to Benefit in REDUCE-IT By Practical Cardiology