So, thanks for inviting me here today. I do want an additional tab on my badge next year if I'm lucky enough to be invited back for the longest assigned title talk, but I'll try and put this all in a short period of time here. So, a lot of these things that I'm going to talk about we've heard already that I'm just going to summarize a little bit differently to really get into how do we incorporate these things into our daily clinical practice. So, just to reiterate some of the things we heard already about antiplatelet concerns. You heard a lot about the pharmacology, and I'm not going to go through it in too much detail, but I do just want to remind everybody that clopidogrel and prasugrel are pro-drugs which require absorption intestinally, requires hepatic metabolism to work, and ticagrelor is not. And intestinal absorption, we know, is compromised in the setting of shock from splenic basal constriction and intestinal edema, and we know that hepatic injury slows down hepatic metabolism and therefore can lead to less available pro-drug like prasugrel or clopidogrel. As you also heard, platelet inhibition is iatrogenically impaired by the things that we do. CPR itself leads to platelet inhibition, therapeutic hypothermia, opioids which slow gut transit, and then proton-trump inhibitors as well. So again, like I said, what I want to focus on is how do we incorporate these theoretical issues into our practice, and I think the best summary comes from part of a slide you already saw, which was an article that was published in 2019 in Jack, which talks about bridging the gap. If the gap between the time that we give an oral antiplatelet drug and then we see its downstream effects, which is really what we're trying to achieve. And there's three things that clearly don't work or don't work very well, which is extra loading doses of very high doses, giving methanolaltrexone to reverse opioids to increase gut transit, and upstream is a plus-minus. We talked about that already. And then I'm also going to cross off cangrelor from this list here because it's something that you heard a great talk about just now, and we know that that drug really has the potential to get rid of a lot of these issues. But the two I want to focus on is the evidence-based practices that we know work right now that at least at our institution I can say the use of is low, and those two things are the concurrent use of IV metoclopramide and crushing the antiplatelet agent. And I'm going to start with the IV metoclopramide, and even in preparing this talk I was surprised to see that the evidence is actually relatively strong for this. And there was a major trial called Metamorphosis, which looked at if you were to deliver ticagrelor plus spenoclopramide versus ticagrelor alone, when do you see platelet reactivity drop? And there was a significant reduction in platelet reactivity in the first 60 minutes if you co-administer with Reglan. So something we don't do very much, I'm not sure how often it's done at your institutions, but something that clearly works and can help bridge this gap. The other is the crushing of the P2Y12, and I think that this is something that we all theoretically know works. It's a little bit annoying to do, and I think in the moment we question is it really worth all of that effort. And I think if you go back through the data, the answer to that question is it is worth the effort. And there's two separate studies, one that was done for Berlinta, which is the Mojito study. So this looked at STEMI patients that got ticagrelor and whether it was crushed or not crushed. And crushed here clearly provided earlier platelet inhibition as compared to the non-crushed. And the same thing was proven with Prasugrel. This is a trial called the Compare Crush trial, which looked at STEMI patients who were receiving Prasugrel as a primary antiplatelet. And this was actually given pre-hospital, which is less important for the concept that we're trying to prove, which is crushed versus not crushed. And the primary endpoint was, the point was that significant earlier platelet inhibition was found when the Prasugrel was crushed, just like when the Berlinta was crushed. So crushing works, and it's something that we should do more often probably than we do right now. And I'll also say in terms of incorporating into our practice, we all know antiplatelets carry risk, and they also lead to bleeding. As much as we like in the cath lab having no platelet activity, we really like them to turn back on when we need them. And there's a lot of reasons for this, and one is that patients may require mechanical circulatory support and large bore axis, which may or may not require a surgical cut down. They can bleed for other reasons that would require a cessation of antiplatelet therapy. And I think most importantly for our patient population is the unweanable MCS patient who then needs surgical therapy of some kind, whether it's an LVAD transplant, et cetera. And right now, I think that all of these theoretical barriers are another problem with ticagrelor use. So aside from the fact that it takes some time to act and all of the pathophysiology of shock slows its absorption and effectiveness, also on the back end, there's a problem where if we want to turn platelets back on, it's really hard to do that when you've given ticagrelor already. But there is a reversal agent coming. I'm not going to say it just so I don't make a fool of myself up here and pronounce it incorrectly. I'll just let you read it. But it is a monoclonal antibody that's capable of reversing ticagrelor, and theoretically, it's been proven in some clinical trials already to restore platelet effectiveness within as soon as 10 minutes. In the trials that have been done, it was really to facilitate surgery. When this drug is given, almost all patients had equal hemostasis at the end of the case if they got Berlinta plus the reversal agent as if they had not gotten any platelet at all. So in conclusion, I think we know already, and you've heard from this great panel here, that patients in AMI cardiogenic shock, they do require aggressive platelet inhibition, especially while in the cath lab. And we know that the pathophysiology of this disease process can make these drugs less effective. And let's all remember as a community that direct acting, crushed, oral, any platelet drug, especially when given with Reglan, may be helpful in overcoming some of the barriers that we have currently, that when these reversal agents come, we'll need to, you know, re-evaluate our practice on who gets Cangrelor versus who gets Ticagrelor with the reversal agent on backup. And, of course, we know already that IV antiplatelet agents like Cangrelor can potentially address many of these issues. And like I said, I think last year I went in the reverse order and I set up the talk for you, but this time I'll just remind you that you've already heard a great talk about how IV antiplatelets can potentially address this issue. So thanks again for having me back to the course organizers and to everybody here. So thank you.

antiplatelet therapy

pharmacology

iatrogenic factors

evidence-based practices

IV antiplatelet agents