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COMPARE CRUSH: A Randomized Trial of Prehospital Crushed vs Uncrushed Prasugrel in STEMI

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C. Michael Gibson and Georgios Vlachojannis discuss the randomized trial of Prehospital Crushed vs Uncrushed Prasugrel in STEMI.

Hi mike gibson coming to you virtually from tct 2020 and i’m joined by my colleague georgios lacoyanas welcome georgio hello mike well i you know i’m very excited about what you’re going to talk about you know with prasa grove back when we first conducted the triton trial uh we found that pressure was superior to pedigree largely because what i call the three

Ps is more potent it’s more prompt and more predictable in its pk than clopidogrel you did a study where you crushed prasa grill and to make it even more prompt than swallowing it and that was the crush trial talk to us a little bit about it i mean getting the drug on board as quickly as possible and achieving high levels of a drug in the setting of stemi is

Absolutely critical so seems like a great idea what did you find so thank you mike indeed so the um the reason for this study was as you said to have the to to see the maximum effect of all anti-platelet therapy with prussogral as we know this is delayed in stemi patients and by crushing the tablets it has been shown to get the best pharmacodynamic profile out

Of this tablet on the other side here in the netherlands we use a pre-treatment scheme in the ambulance so we gave also this medication at the earliest possible time point um just to kind of underscore that georgios you know in stemi um you have a lot of people getting uh narcotic analgesia and that delays transit into the stomach and you also have some edema

Possibly in the liver you know prasa grove does require some metabolism just like clopidogrel so a lot of things working against it to get it acting quickly absolutely i think with all p2x12 inhibitors and even with the potent ones it is an uphill battle right in the acute phase of stemming so we were optimistic because of this impressive pharmacokinetic and

Pharmacodynamic data to achieve even maybe better reperfusion earlier perfusion in stemite patients these were our primary endpoints timi3 flow at first on geography nst segment resolution at one hour after pci we had secondary endpoints we looked obviously at platelet reactivity and clinical outcomes and we had the safety endpoint bleeding at 48 hours timmy

Major or bark three to five so we did not see any difference regarding the primary endpoint however we saw that crushed tablets work they work good but not good enough it seems we had at prime at the beginning of pci a significant reduction in platelet reactivity by one third sixty two patients of p of uh who were uh treated with the integral tablets had high

Platelet reactivity this was defined as pier u over 208 and this was reduced by crushing to 43 so by one third however this did not have influence to the primary endpoint so let me ask you georgios you know um did you have enough patients look at other outcomes like uh stem thrombosis you know uh general montelesco in his study similar study but with titagal or

Pre-treatment saw something similar but did see a reduction in stem thrombosis any hints of that we didn’t we didn’t see uh any uh signal towards reduced ten thrombosis but we have to clearly say that our study was not powered for this we had similar stand from those rates yes you know i have to say looking back backwards uh gosh that couple decades ago frankly

When we combined or added in clopidogrel versus placebo and in a large number of patients 2 800 patients looked at st segment resolution early on we didn’t see any improvement so you know this is kind of really three strikes against the thymo pyridines were an early effect what we did see in clarity is a reduction in reocclusion you saw was your study reduction

In stem thrombosis it seems as though these drugs are what you might expect i mean they block platelet activation and they tend to block re-occlusion re-thrombosis but you know it doesn’t look like they’re doing a whole lot as best we can see for disaggregating existing plot and um you know it’s an interesting distinction versus the 2b3 inhibitors which do

Disaggregate and break apart those existing clouds yeah i am absolutely agree with what you said it’s uh it was a very high bar this end point absolutely on the other side as i said if we go back to the atlantic trial which you uh just mentioned we have uh obviously the atlantic trial the primary uh endpoints were pre-pcr by both st resolution and team e3 flow

But if we look at in the atlantic trial at st resolution at one hour we see a borderline p-value of 0.05 and once you exclude the patients who received morphine you have the significance so this this actually gave us a base to believe that at least the st resolution endpoint we had a good shot at it and that’s one hour after uh the pci exactly so again after

The procedure starting just starting to see some benefits you know that’s fascinating yeah well you know it’s not you know i’m so disappointed these days when i look at the sd segments and i look at the fellow and i say why do you think the person says t segments are still up they say oh the stent is undersized and i just shank my head you know it’s really

Micro thrombosis and downstream embolization and not all the clot not all the clot is in the artery a lot of it has moved down into the microvasculature so you know it’s interesting perhaps we are inhibiting some of that microvascular thrombosis with this more even more prompt uh impotent inhibition as you did here absolutely absolutely i think uh this study

Adds to to other studies that it seems that we can’t get the job done we can’t bridge the gap with all antiplatelets in the acute face of stemi and that we have to look for alternatives and this next step seems to be currentero we’re going to go back i guess to glico protein inhibitors now a subcutaneous one is going to come in a phase three trial selector rail

Um this is going to be also interesting to see how to apply this so we’re moving i guess uh back to parenteral and we’re gonna see what this is gonna bring yeah yeah i’m a little more optimistic about the potential for the 2b3 inhibitors upstream given subcutaneously we saw good results for intravenous upstream use in a time-dependent disaggregation of cloud

I’m not optimistic about uh solata grow in the p2y12s upstream it just doesn’t seem like uh upstream therapy with that class of drugs is really going to do much well georgios congratulations on a great study very well conducted very important question i’m very excited to hear the twist you talked about there at the end about morphine it really does underscore

The importance of considering a more aggressive parental approach when you’ve given someone analgesics by the way in the label in the fda label for every one of these drugs prospero tychargo or particular it says if you have administered a parental analgesic you should consider a parental anti-platelet agent and i think this your study actually uh cements that

Uh kind of understanding thanks for joining us georgios thank you mike and thanks to all of you for joining us here virtually from tct 2020 you

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COMPARE CRUSH: A Randomized Trial of Prehospital Crushed vs Uncrushed Prasugrel in STEMI By TCTMD