So, today I'm going to talk a little bit about cangrelor and ACS and cardiogenic shock, and sort of a follow-up to what Dr. Henry has so wisely pointed out to us. I'm an interventional cardiologist at Duke, and an important disclosure for me, I'm the principal investigator for a cangrelor-based study on AMI patients, which I'll describe here. So, I'm going to talk a little bit about the foundation of cangrelor in terms of its indication in PCI. So, why did the FDA give it a certain package dose labeling? We'll talk about that. What's the evidence for it in ACS, and what's the growing evidence for it in cardiogenic shock? We don't have a randomized controlled trial, but we do have observational data. In my mind, what questions remain unanswered? So, I just want to take us back to how we're supposed to be using cangrelor. I think certainly we've seen many instances where we're using it in different practices and in the real world in different ways. So, it's an IV antiplatelet inhibitor, and it's meant to reduce the risk of paraprocedural MI, repeat coronary vascularization, stent thrombosis in patients who have not been treated with a P2Y12 inhibitor. And I'll argue here in a moment that I don't think that that's based on much data for why that was in the indication, and who are not being given a G2B3A inhibitor. So, just back to pharmacology, and again, I realize I'm right in the middle of lunch trying to talk with you about reversible and irreversible binding. That's never a good combination, but just as a reminder, ticagrelor is a reversible binding oral antiplatelet inhibitor. So is cangrelor. As you remember, the half-life of cangrelor is on the order of two to four minutes. The onset of action for ticagrelor, 30 minutes to four hours. Now, look at clopidogrel and prazugrel, who have active metabolites that have to be formed to be able to bind to the receptor. The onset of action, two hours to eight hours, and that's in a normal patient, a patient with normal gut and liver function, okay? So, keep that in mind as I talk over the next couple of slides about why that's important and how we're proceeding and pursuing patients undergoing PCI for ACS or cardiogenic shock. Briefly just touch on this. I think really the champion trials, platform PCI in Phoenix, I'm highlighting Phoenix here, really the call for why we use cangrelor was this synthrombosis signal that was significantly less with cangrelor compared to clopidogrel. Though I wanted to call out, if you look at the subgroup analyses from the initial trial, really the greatest benefit in terms of cangrelor was within stable angina. They did not see this within non-STEMI or STEMI populations. However, I think it's important to note, MI practices were different, I would say. This was published in 2013 based on data from almost 20 years ago now. And they also excluded patients with cardiogenic shock. The label, though, for cangrelor is based on these trials, and so I think that's really important to keep in mind as we talk about our contemporary practices. Just quickly bring up ArcAngelo. It was an Italian study, a prospective study on cangrelor, and it looked at about 1,000 patients with ACS that all got cangrelor. So they came in, and they all were treated with a bolus and then an infusion for two to four hours, and then about 75% of them were transitioned to ticagrelor. This was not meant to be, there was no control arm, it was just meant to look at is cangrelor safe and effective in the ACS population? And I've just highlighted over here 5.2% bark bleeding risk at 30 days and 1.4% mace at 30 days. And it's of note that that bark bleeding, that's not the severe bark bleeding, there weren't any intracranial bleeds. So I think overall, we can say in a contemporary practice, this is about 93% radial access, that cangrelor is demonstrating that it's safe and effective. Now coming to our CAMEO registry here, this is a registry that I and others at Duke and others around the country helped to start pre-pandemic. We've now got about 4,000 patients, and we wanted to be able to answer what are real world uses of cangrelor in the U.S.? I've listed our sites across the country. And we wanted to be able to look at things all from cabbage, sort of the bridge does use in cabbage. We wanted to look at transition patterns. We wanted to look at the outcomes based on opiate usage. And then we wanted to look at sicker patients with cardiogenic shock. This was from some early data we put out, and I think something that was sort of eye-opening to me is that it's a great drug, but we've got to use it right. And so patients that were being transitioned from cangrelor and across these practice patterns across the U.S., largely it was done right when they were started on ticagrelor. They overlapped it nicely. You can see the overlap with cangrelor, negative 49 minutes, where there was good 50-minute overlap with cangrelor and ticagrelor. But look at clopidogrel, two and a half hours median for when they stopped the cangrelor and started the clopidogrel. And certainly we face this at my institution a lot, where patients, unfortunately, because there's not an understanding of the drug, there may be a significant gap. They have been thrombosis, and we have had really a couple of bad outcomes as a result of these gaps. We then looked at the question of, okay, so according to the package dose, we're not supposed to be using it after you get an oral P2Y12 inhibitor, but that's just not the way it's being used. A lot of your patients come in for STEMI or non-STEMI, have had prior PCIs. You take them to the cath lab. They're on a P2Y12 inhibitor at home, but you don't know, did they take it when they're supposed to? When's the last time they took it? Did your non-STEMI patient come in and get a load of ticagrelor? Did your STEMI patient get a load of clopidogrel in your ED, and now 10 minutes later, you've got radial access, and you're wondering about your oral P2Y12 inhibition? So we just looked in an observational manner, and this was a couple thousand patients. We wanted to know what the bleeding risk. So if you got these antiplatelet therapies either within 24 hours from a home perspective or in the hospital, did you have increased bleeding if you got ticagrelor, and we found across the board, no. So no significant difference in bleeding with upstream use, no significant difference in bleeding regardless of time between P2Y12 and ticagrelor, and then it didn't really matter based on the potency of high versus low. And this was based on, I think, some work by one of my colleagues, Dr. Angel Lillo at the University of Florida, looking at the SWOP-5 and SWOP-6 studies, which many of you may be familiar with, about 20 patients got pretreated with 180 of ticagrelor, then got a bolus and infusion of cangrelor, and then they wanted to look at the platelet reactivity units. They found that about the 30, the one-hour mark, significant difference in the platelet reactivity units if you got both versus just placebo. By about two hours after the cangrelor infusion stopped, they're equal, so there's no lasting effects, there's no drug-drug interactions, and so I think there's increasing evidence that it's okay to use it downstream. Now what about cardiogenic shock and cangrelor? So Dr. Henry's gone over an overview of why we might not want to stick crushed ticagrelor down internal access in a patient with cardiogenic shock, poor gut perfusion, mechanical ventilation, obviously concomitant opiate usage for sedation, and unclear gut absorption. This is some early work by colleagues at the Brigham, looking at 147 patients that received cangrelor, 26% with clinical cardiogenic shock, and they just wanted to understand what's the bleeding rates in these patients. And they found that, actually, the patients with cardiogenic shock from a MACE perspective, far worse than the hemodynamically stable cohort, but in general, they found that the majority of these patients, they're having bleeding events, but they're mild to moderate gusto bleeding events and not severe. So I think just sort of some early data about using cangrelor and cardiogenic shock. Now from our CAMEO registry, and this is unpublished, just kind of came out about a month ago, we had 2,400 cangrelor-treated AMI patients, 243 of those patients with cardiogenic shock. You can see the patients are relatively diverse, 32% female, 20% African-American, 36% diabetes, and then about a quarter had multivessel PCI. Little surprising to me, based on the institutions that we're working with, but only about 32% radial. 60% of them had some form of MCS for their cardiogenic shock, with about 60% balloon pump, 45% impella, and then 20% underwent thrombectomy, with about also a fifth having a duration of MCS after cath greater than five days. So I think a relatively thick population of patients. We looked at the median duration of infusion, obviously longer, as you might expect for patients with cardiogenic shock, versus just our overall cohort that were mixed in with hemodynamically stable patients. Increasing age was associated with shorter infusion, and MCS associated with longer infusion. The rates of MACE were 42% and bleeding, 25% among the cangrelor-treated cardiogenic shock patients. We're gonna do more work, obviously, to tease out how this may differ from our other cohorts, but I think some work coming out, obviously, in the registry for cardiogenic shock. This just briefly shows the bridge dose associated with increased bleeding and cardiogenic shock. I think that's probably because you're on a longer infusion, or it's already a marker for a clinician is concerned about your bleeding risk. And then, obviously, if you're on the infusion for a longer period of time, a greater risk of bleeding. You get MCS or have diabetes, a greater risk of bleeding as well. Just briefly touch on another trial that's coming down the pike for cardiogenic shock and cangrelor. So this is DAP-SHOCK-AMI. It's gonna be complete in enrollment at the end of this year, and then a one-year follow-up period of time. These patients are being randomized to upfront cangrelor until resolution of shock, then followed by ticagrelor immediately at the end of PCI. The cangrelor can't be run for longer than four hours after the PCI, and then the control arm is just a control infusion when they get ticagrelor, either oral or via their NG tube when they get to the ICU. So we'll see what that data shows. I would say criticism of that, and again, clinical trials are difficult to design. A lot of shock patients don't go out of shock at four hours. So I think it would be helpful to know longer infusions and sort of some of the data from that as well. The cangrelor out-of-hospital cardiac arrest trial, just briefly I'll talk about this. So this was out-of-hospital cardiac arrest patients randomized to cangrelor versus placebo with ticagrelor given at the end. And I think, again, this sort of mirrors what Dr. Angelillo has shown, but when the cangrelor infusion is stopped, as you can see, at that five-hour and eight-hour mark, really there's no significant difference in your PRU levels according to the Verify Now assay. So I'll just briefly end up with some questions I think are still left to be answered. I think we still need to know a lot about outcomes of patients with cardiogenic shock in the use of this drug. I think it would be difficult to do a clinical trial with it, but I think we need that level of data to better understand the bleeding risk. And I think the other great thing about cangrelor is that it doesn't have to go through the kidneys. And so in comparison to a G2B3A inhibitor, when you're using MCS and have a high bleeding risk, I do think cangrelor is better for a lot of those patients that have some form of AKI or CKD. And then when prolonged infusion is needed, what is the timing of the bridge dose? There's a lot of controversy at my institution and others about bridge dosing. If you go to the 7 West, which is our cardiac intensive care unit, the bridge dose is used all the time there at various dosing levels. And so I think we need to know a little bit more about how it's being used across the country. And then in contemporary MI practice, how much do opiates impact absorption? So I think we still need to know a little bit more about that. I think there is going to be some work coming down the road looking at PRU and high platelet reactivity in a cardiogenic shock population. And then I would like to know more about CKD and AKI and how those patients fare in terms of bleeding risk. So I'll go ahead and conclude up here. So we have highly variable practice in cangrelor use in the United States. I do think it can be a safe and effective drug in treating AMI patients, particularly in our contemporary practice of heavy radial use and heavy ultrasound use. And then growing evidence that the use of cangrelor after home use or in-hospital use is not associated with significantly higher bleeding. And then I think there's going to be increasing data in the coming years for cangrelor and cardiogenic shock.

cangrelor

acute coronary syndrome

cardiogenic shock

PCI

observational data