First of all, thank you so much for having me here today. We'll be doing a deep dive into the CHAMPION trials. My learning objectives today are really threefold. First, to really look into clinical considerations for antiplatelet strategies in PCI, to review the current evidence, and then to talk about how I use Kangalore in my practice. Platelet inhibition during and after PCI is critical to reducing periprocedural thrombotic events. We know that endothelial injury from spontaneous or iatrogenic plaque rupture can result in activation of platelets and initiation of clotting mechanisms. But there's also several downstream complications we have to consider, and this is stem thrombosis, MI, ischemia-driven revascularization, and death. We've all been using heparin in the cath lab now for about 107 years is how old heparin is now. But there are pitfalls. Yeah, I've been using it for 107 years, and it works well a lot of the time, but there are some pitfalls—narrow therapeutic window, procoagulant effect with heparin-induced thrombocytopenia, reduced activity when platelet-rich thrombi are present, and an unpredictable coagulant response. But we also need to think about the oral platelet inhibitors that we use. So in an acute setting, achieving the expected antiplatelet effect with oral administration sometimes just isn't feasible, and this can be due to delayed bioavailability, morphine use, mechanical ventilation, active vomiting, cardiogenic shock, heavy sedation, and therapeutic hypothermia. And in the current cath labs, we're seeing a lot of patients with this, especially shock and higher-risk patients. The PACIFI trial showed us that there was delayed and reduced absorption of oral P2Y12 inhibitors with fentanyl, and this led to some very important fine print. Multiple studies have been published on morphine and fentanyl interactions with oral P2Y12 inhibitors, and they're labeled for clopidogrel, prasugrel, and ticagrelor, to update on these interactions that are important to consider. So that's really where cangrelor comes in. This is an IVP2Y12 inhibitor that's indicated as an adjunct to PCI to reduce the risk of periprocedural MI, repeat coronary revascularization, and stent thrombosis. And what we know about the pharmacology of cangrelor is that it allows rapid and potent platelet inhibition with basically greater than 98% inhibition of platelet aggregation. When we compare this to ticagrelor, prasugrel, and clopidogrel, we see that it has a much shorter onset, only 2 minutes as opposed to 30 minutes and 2 hours. Its time to maximal effect is only 2 minutes as opposed to 2 hours and 3 to 7 days for clopidogrel, and its maximum platelet inhibition is greater than 98% as opposed to 88% for ticagrelor, 80% for prasugrel, and 40% to 60% for clopidogrel. So CHAMPION-PCI was one of the first studies that randomized patients to IV cangrelor versus clopidogrel 30 minutes prior to PCI. These were 60% MI patients, but it was prematurely interrupted due to futility. Primary endpoint they looked at was death, MI, or ischemia-driven revascularization. And it's important to remember the definition of MI here was a new Q wave lasting longer than 0.03 seconds in 2 contiguous leads and CK and B elevation greater than 3 times the upper limit of normal or greater than 50% the upper limit of normal. There was no significant reduction in the primary endpoint with an increase in minor bleeding from this study. We then moved to the CHAMPION-Platform trial, which randomized patients to cangrelor versus placebo and patients undergoing PCI. These patients were 5% stable angina, 95% ACS. Primary endpoint, again, of composite of death, MI, ischemia-driven revascularization at 48 hours. But they also, this time, looked at a secondary endpoint of stent thrombosis and death. Again, there was no significant difference in the primary endpoint, but there was reduced stent thrombosis and death at 48 hours, as you can see in panels B and C here, and this was an important signal. So at this point, you may tell me, but these trials failed to meet their primary endpoint and were interrupted due to futility, so I still don't use cangrelor in my practice. Well, you're right. They were interrupted and they didn't meet their primary endpoint, but it's important to consider why, and that's because the definition of periprocedural MI in these studies did not allow discrimination of reinfarction in patients presenting for PCI soon after admission for biomarker-positive ACS, and this really complicated adjudicating MI in these studies. That led to the design of the CHAMPION-Phoenix study, which addressed baseline biomarker status carefully and had an angiographic core lab that examined for interprocedural events. CHAMPION-Phoenix randomized to IV cangrelor versus Plavix in an all-comers population and looked at death, MI, ischemia-driven revascularization, or stent thrombosis at 48 hours. And what this found was a 22 percent relative risk reduction in the primary composite endpoint and a 38 percent relative risk reduction in the secondary endpoint. It's important to note that 63 percent of these events occurred in the first two hours, and with cangrelor, there was a 51 percent reduction in events in the first two hours. And so, really, what we ask ourselves is, what are we doing in those first two hours, which is when we're with the patients, to reduce these events? CHAMPION-Phoenix also looked at, in this sub-analysis, the MACE events by time point, and you can see that there was almost a 300-fold increase in the number of MACE events between zero and two hours when you compare to three to 720, and so we really need to do more and to target patients in this zero to two-hour mark. And that's when 60 percent of CHAMPION-Phoenix patients had stable angina. Imagine if this was 100 percent ACS population. In this post-hoc analysis, you can see that these results held across the board in all patients, but also in stable angina and ACS, where cangrelor fared better, reducing net clinical adverse events. So, at this point, you may say, but I don't really have an issue with events post-PCI, especially stent thrombosis, and is this really clinically relevant? First, when people say this to me, I say, ignorance is bliss, which you don't know can't hurt you, right? But ignorance is bliss until it isn't. This is a patient that presented with acute stent thrombosis 18 hours after their stent was placed. This was an OCT-placed stent, beautifully expanded. The patient had received a load of ticagrelor in the ED and, for whatever reason, ended up coming in with this back from the floor at 18 hours. And you can see that the stent's well-expanded, but there's clearly acute stent thrombosis approximately. And what we know from this sub-analysis of the CHAMPION-Phoenix study is that CoreLab-adjudicated intraprocedural stent thrombosis is associated with increased mortality. So not only do these events happen, they're important. They're associated with adverse events, and what we're trying to do is reduce those events in those first two hours if we can. So to this, people may say, but I don't use clopidogrel anymore. The initial studies were all with clopidogrel and ticagrelor is better. Well, CANTIC was designed to assess comparative pharmacodynamics effects of cangler plus crushed ticagrelor versus crushed ticagrelor alone and found that cangler was associated with more rapid and potent P2Y12 inhibition with less variability when compared to crushed ticagrelor. And we know from the PLATO study that subacute stent thrombosis and late stent thrombosis is improved with ticagrelor, but the patient I showed you had stent thrombosis at 18 hours, and we don't really have anything that's reducing those events at 18 hours. And so that's really where cangleror comes into play. Some people say, well, I just use GP2B3 inhibitors when I have slow flow during a case or when I have stent thrombosis, and we know from the 2021 guidelines that this is no longer recommended. 2B3 inhibitors have not been associated with improved clinical outcomes and actually increased bleeding complications. This subanalysis from Champion Phoenix looked at use of GP2B3 inhibitors in the trial and found that there was reduced use of this as a bailout when cangleror was on board. And this is important because this really tells us that there's a need to prevent events, not treat them once they happen, because once you're pulling for the GP2B3 inhibitors, these patients are younger, more often male, more likely to present with the STEMIs, and have higher ischemic and bleeding rates, and so we need to focus on prevention as opposed to treating once the events happen. Then others will often say, I worry about the increased bleeding risk with cangleror, and I don't know. The groins blow up, and I am not really interested in using them. Well, let's look back at the data. First of all, you're correct to be concerned about it. There is an adverse impact of bleeding on prognosis in patients with acute coronary syndrome, and we know from the sub-analysis that severe or major bleeding is associated with increased 30-day and one-year mortality. We also know from the CHAMPIONS-PHOENIX study that there was no significant difference in the rates of gustosevere bleeding, moderate bleeding, or the need for transfusion. The increase was only in minor bleeding, which didn't translate to adverse long-term events. Lastly, we'll go over what about the CHIP population? Are these patients that we're seeing more and more often in the lab? What role does cangleror have for these patients? And what we'll see here is that 24.8% of patients in the study had greater than three high-risk features angiographically, and there are increased events with increased number of high-risk features. So when you get to greater than three, your adverse event rate is significantly increased, and this seemed to be mitigated by cangleror, as you can see in green here. So the MACE event seems to be less, as well as the stent thrombosis event rate. And so with that, then, I would say how and why do I use cangleror in my practice? I use it in all my ACS patients, and the goal there is I'm really striving for optimal platelet inhibition. I use it in all my elective cases where I think they have a high-risk stress test and I may want an immediate CABG consult. I strongly consider it in my CTO population, as well as my other left main cases, because of the goal of reducing events from those analyses. And in no reflow or high thrombus burden, I use it as well because of the better risk profile and the new guidelines that suggest not using 2b3 inhibitors. So some key take-home points. Adequate platelet inhibition is important. Cangleror allows rapid and potent platelet inhibition with reduced variability. It's not associated with increased major or life-threatening bleeding, and it's been associated with reduced stent thrombosis and death, and high-risk patients may benefit from cangleror based on the subanalyses. Thank you.

CHAMPION trials

cangrelor

antiplatelet strategy

percutaneous coronary intervention

platelet inhibition