Thank you. Thank you very much, Creighton. That was excellent. I look forward to discussing that a little later during our panel discussion. Our next speaker is Dr. Roxana Mehran, who's going to talk with us about antiplatelet therapy, including choices of agents and duration of therapy. Thank you for that nice introduction, Dr. Riley, and it really is my pleasure to be here with you to discuss the antiplatelet choices duration from the guidelines. Important for you to note all of my disclosures that are here, the relevant ones, of course, down here, which has already been disclosed to all of you. We've evolved in the duration of antiplatelet therapy over the last three decades or so. We've evolved from the era of thrombosis, where we just cared about making sure we protected our patients after stenting for thrombotic complications such as stent thrombosis. And as we push the envelope in terms of duration of dual antiplatelet therapy from an earlier shorter duration to the longer duration, because we cared so much about thrombosis, bleeding became much, much more prevalent, especially with the potent agents that came about and the fact that at the same time, we had an improvement in our second generation DES. And over time, we began thinking about how important bleeding was in terms of its association with mortality. And Dr. Sunil Rao was one of the very first people who really recognized this and brought this to our attention. And hence, the whole idea of a bleeding avoidance strategy like radial approach that he's championed. And of course, rethinking about the antiplatelet therapies. And I think where we are today is an area of ACOPO is we have safer stent platforms, much better understanding of dapt cessation. And now we are thinking about novel approaches such as shorter duration of dapt and even switching our long-term therapy going from our single antiplatelet therapy of aspirin forever, maybe to a P2Y12 monotherapy, and of course, then de-escalation. Now, where are we in the evolution of the guidelines in terms of everything else that's been going on in all of these trials here? We've come a long way from 2011, 2016, we had adapt guideline oversight sort of to complement what we had published in 2011. And in 2021, with the revascularization guidelines and all of this data behind us, we came to some other newer conclusions. And I'm going to take you through some of this ride, but I want to begin with one of the biggest dilemmas that we all face as interventionalists and how we came to the P2Y12 monotherapy maybe through this platform of patients who are undergoing PCI with atrial fibrillation, where the antiplatelet therapy in combination with oral anticoagulants as a triple threat could have an important implication in the bleeding complications. And it was really through this group with all of these trials that I've listed here, where the dropping of the aspirin, which came first from the very first trial, which was the WUST trial, a smaller 600 patient or so study where they dared to drop aspirin in AFib patients undergoing PCI receiving drug eluding stents, brought us to where we are today with the novel oral anticoagulants and the ability to now show without a doubt that by dropping aspirin and going to a dual therapy versus triple therapy, you can reduce bleeding without increasing ischemic complications. And I think in over 12,000 patients now with the updated meta-analyses that we have, that without a doubt with switching to a novel oral anticoagulant and taking away the aspirin shortly after PCI, there is definitely a reduction in bleeding as well as intracranial hemorrhage, which is tremendous. And very important that the major adverse cardiovascular events, although they're still underpowered for some of these different variables, do not seem to show a signal of harm, although those confidence intervals are still quite wide in there. So when we came from the guidelines in 2016, when there was no recommendation around antiplatelet therapy after PCI in patients who required oral anticoagulation for atrial fibrillation, back then in 2016, we did not have all of these trials that I just showed you, but there was a very important message in the written portion of that guideline to keep that triple therapy duration as short as possible, that the dual therapy with an oral anticoagulant clopidogrel may be considered in select patients, and that we were really saying that clopidogrel is the P2Y12 inhibitor of choice. And at the same time, around the same time, the ESC guidelines had given a class three recommendation around combining the potent agents with an oral anticoagulant when it was needed. But in 2021, after everything that we just showed you with the clinical trials, there was a clear cut class one recommendation to stop aspirin within one to four weeks after PCI and maintaining the P2Y12 inhibitor with non-vitamin K oral anticoagulant or warfarin to reduce the risk of bleeding, and with a 2A recommendation that perhaps the novel oral anticoagulants could be better than warfarin in terms of reducing bleeding. And I think those are really, really good recommendations based on the true evidence that was in front of us at the time. Now, coming back to the 2016 DAPT guidelines regarding antiplatelet therapies for stable ischemic heart disease and acute coronary syndromes, here's what you're seeing. At that time, we were very much still on the fact that ACS patients would have to receive aspirin plus clopidogrel or Prasugrel or Ticagrelor, that dual antiplatelet therapy, for at least 12 months. Some of them could have a 2B recommendation for six months of dual antiplatelet therapy and going to aspirin monotherapy, and those had to do with high bleeding risk patients. And in the stable ischemic heart disease, it was aspirin clopidogrel now down to six months from the previous 12 months with a out at three months monotherapy. That's where we were in 2016. But so much has happened since then, and we've got so much more data now that we can really shorten the duration of antiplatelet therapy. One of them being the TWILIGHT trial where after an open label of enrollment of three months of high-risk PCI patients, 7,119 patients who were free of ischemic and major bleeding events were randomized to Ticagrelor plus aspirin versus Ticagrelor plus a matching placebo where aspirin was withdrawn in these patients with a very close follow-up. And we showed effectively that there was a major reduction in bleeding complications of BARK2, 3, and 5, but also in major bleeding of BARK3 and 5, but this was the primary endpoint. Numbers needed to treat of 33, absolute risk reduction of 3.1% without any change in ischemic harm in over 7,100 patients. So a good feeling that this was absolutely non-inferior in terms of death, MI, and stroke, but a very good platform to go to in reducing bleeding complications. And at the same time, there were several other trials that had, in an open label fashion, undergone looking at an important endpoint in looking at P2Y12 monotherapy with really a look at Ticagrelor alone or Clopidogrel alone. And most of these showed very similarly that there was a definitely no signal of harm in terms of death, MI, stroke, and that for most of them, except for global leaders, there was a major reduction in bleeding. And so together, these data really led to the thought and the idea that high bleeding risk is an important, and so much data was being presented with the shorter duration of DAPT, with EVOLVE, with the Zions programs, and all of the different programs, and Onyx programs with the current generation drug eluding stance, that now there was a, in this 2021 guidelines, that in addition to what we had seen before, there was a 2A recommendation for a shorter duration of DAPT in those patients who are at high bleeding risk, as short as one month and as high as three months for those patients who are at high bleeding risk. And I think the other very important issue was that you could get a, go to a P2Y12 monotherapy as well in select patients with a 2A recommendation. And furthermore now, we have novel approaches and perspectives in terms of de-escalation. We talked about the aspirin-free P2Y12 inhibitor monotherapy, and then really interesting, the idea of chronic maintenance in terms of P2Y12 inhibitor monotherapy versus aspirin. And the meta-analyses are all looking pretty good in terms of de-escalation, in terms of reducing bleeding. Not a single one of these trials are powered for these endpoints to show you effectively that you actually are having an important impact because they are quite small. But as you could see from these meta-analyses that de-escalation, whether guided or unguided, could have an important effect in reducing bleeding and no change in major adverse cardiovascular events. And in fact, maybe even towards in a, in a right direction. And I think what you're seeing from this paper in Jack Intervention of much recently is that a short duration of DAPT or a de-escalation can show you this important comparison of whether or not, what, in which way can we go? And it seems that in major bleeding, you can definitely favor shorter duration of DAPT, but in most of the other endpoints, you're really seeing a very similar effect with either reducing the duration or de-escalation. And it really is kind of something for us, and these are acute coronary syndrome patients with a very, very interesting way of looking at this three node or five node network meta-analyses that has been performed by a very, very interesting statistical methodology where we are seeing an important effect of where we could be perhaps in terms of reducing bleeding and even major adverse cardiovascular events when we are shortening duration of DAPT or de-escalating, especially in the right patient population. Finally, in terms of preseveral data on P2Y12 monotherapy, the data is scarce. We have 200 patients with no real power to really say anything about this particular agent. And then lastly, I think it's important to note of the ongoing trials that are looking at P2Y12 monotherapy, which we would hope to be seeing in May of 2025 and May of 2024, and very important multitudes of de-escalations, genotype guiding, DAPT duration, data that's going to come over the next few months that I think we're, or few years that we're looking forward to. Finally, I want to talk to you about the chronic maintenance. There's only one trial that has been looked at in looking at aspirin versus clopidogrel in chronic maintenance for patients post-PCI after six to 18 months. Here, these investigators randomized 5,500 patients to aspirin versus clopidogrel for chronic maintenance. As you know, there's class 1A indication for aspirin indefinitely post-PCI. And this is really sort of questioning whether we could switch that over to clopidogrel. And these investigators showed that over a 24-month period after this randomization, that there was a reduction in the primary outcome of all-cause death, non-fatal MI, stroke, readmission for ACS, and major bleeding of BARK3 to 5. And the numbers needed to treat are small at 51. And it really questions the dogma of our aspirin indefinitely question, but it's only one trial and it certainly did not make it to our 2021 guidelines. And especially with chronic maintenance after PCI, there are four trials that are ongoing right now, which we hope to see in the next few years. And I would just say that I think we're going to see a lot more and perhaps updates to our guidelines as we go forward with all of these new studies coming forth, pending their results and their power to actually make an important change in the current guidelines. So I want to thank you for your attention, and I tried to stay within the time in covering a very, very difficult topic for all of you. Thank you.

antiplatelet therapy

bleeding complications

atrial fibrillation

dual therapy

guidelines