Thank you so much for the opportunity to talk to you a little bit about real-world and ongoing studies of IV platelet inhibition. There's a little bit of platelet humor just to start off with because I am a Vassar biologist and I think that Vassar biology is really funny and cool. So, sorry, I know thrombus is not funny, but platelets can be funny. So, okay. So, overview. I know we already talked a little bit about the champion trials, so basically we're going to just talk about some of the other studies beyond that, and cangrelor for bridging, real-world observational studies, as well as some ongoing randomized and observational studies. And there's actually a lot going on, probably more than you would realize. So here are some additional randomized trials to talk about. I know Megha already commented on CANTIC, which is platelet inhibition with cangrelor and crushed ticagrelor in STEMI patients undergoing primary PCI. This is a prospective randomized, double-blind, placebo-controlled investigation, so high-quality study of the pharmacodynamic effects of cangrelor versus placebo in patients who were undergoing primary PCI treated with crushed 180-milligram loading dose of ticagrelor. And as we've already seen this particular figure, we found that cangrelor reduced platelet inhibition after less than five minutes. There were no drug interactions with ticagrelor given at the same time as cangrelor at the start of PCI, and then this has some very practical implications, especially for patients who may be in shock and may have decreased gastrointestinal mobility and poor absorption. Subsequent to that, we had this very recently published study, the SWAP-5 study published in Jack Interventions just this year, which looked at this question of actually preloading patients with ticagrelor before they would receive cangrelor. So these patients were loaded one hour before receiving cangrelor, and then actually after several weeks, these patients sort of went into a crossover study so that actually the patients who had received placebo before actually received the cangrelor in the next go-around. And essentially what was found was that when patients were preloaded with ticagrelor, they still had an over-and-above additional benefit in terms of reduced platelet reactivity when they received cangrelor, and the patients did not have any increased platelet reactivity when they were coming off of cangrelor, and that we don't have to be concerned that cangrelor somehow has been taking up receptor space that ticagrelor can't get to, and that somehow we're actually doing a disservice to our patients. So you don't have to worry about that based off of the SWAP-5 study. As I mentioned before, the SWAP-6 study hopefully will be published sometime soon, and that will give us some more information about preloading and sort of the switchover with prazegrel and cangrelor. I did want to acknowledge this other study that was published a couple of years ago, Facilitation Through Agristat or Cangrelor Bolus in Infusion over Prazegrel, which was a multicenter randomized open-label trial in patients with STEMI referred for primary PCI, and the question was about platelet inhibition with tyrophoban versus cangrelor, and this was a little bit of a surprising result that cangrelor actually had lower platelet inhibition compared to tyrophoban but was more than prazegrel, and so the likely explanation for this, which were very counterintuitive findings, probably has to do with the suboptimal method of assessing platelet inhibition in this particular study. It was done by agrometry, which actually requires several steps in terms of assessing platelet inhibition. It probably took long enough for that to be assessed that essentially the cangrelor had probably worn off, is my interpretation of this, and it was also not powered for clinical endpoints. We also talked a little bit about bridging as an indication for using cangrelor. It's a very attractive agent because it's very quick on and off, and we have patients sometimes who need to undergo surgery, and we are reluctant to discontinue their P2Y12 inhibitor. So in the bridge study, the Bridging Antiplatelet Therapy with Cangrelor in Patients Undergoing Cardiac Surgery study, there were 210 patients who were taking ethanolpurity and awaiting cardiac surgery, and they, in a previous study, had identified the optimal bridging regimen of cangrelor at this particular dose, and this was a placebo-controlled infusion for at least 48 hours and up to 7 days. And ultimately, the results from this demonstrated that although there was a minor increase in minor bleeding, there was no significant differences in major bleeding around the time of CABG, and more patients treated with cangrelor had low levels of platelet reactivity throughout the entire treatment period. So again, sort of reinforcing this idea that cangrelor is very consistent in terms of its platelet inhibition and has a very quick offset, and this data was integrated into this very helpful expert consensus document that was published in Circulation a few years ago and I still refer to often in terms of giving us advice for the ideal timing of starting and stopping cangrelor around the time of surgery. I also wanted to comment on this other recently published randomized clinical trial that looked at patients who were survivors of out-of-hospital cardiac arrest, which is a very difficult patient population to study. As you can see, the numbers were rather small, 30 patients overall, but again, you know, this being a very difficult patient population to study, they did look at platelet inhibition and safety, and they did not see any difference in their safety endpoint but found a very significant reduction in platelet inhibition in patients receiving cangrelor. So we can find that in these patients that are undergoing PCI that we don't think that they're going to absorb their medications, that we can be assured that cangrelor is going to reduce their platelet reactivity, and that in this study they did not see any difference in bleeding. Then I wanted to move on to talking a little bit about real-world observational studies of IV platelet inhibition with cangrelor. There have been several studies looking at this, the first in 2017 from a single center here in the United States, a very high-quality center, that looked at practice patterns, indications for use in clinical events. They found that for their individual institution that 16% of their patients had cardiogenic shock, 13% required mechanical circulatory support, and half of them had STEMI, 80% of them received tetangrelor. So kind of going along with this idea that when people are reaching for this, it does seem, at least in this institution, that it tends to be patients who are very sick, who are at high risk for having complications, but yet in this study they had zero deaths within 48 hours. They did have some deaths within the hospitalization, but when you consider the overall cohort and the risk, ultimately, we got the sense that essentially the adverse events are sort of to be expected for this particularly sick population and probably less so than what you would expect for patients who had received an additional agent that might be considered to increase their predisposition to bleeding. So also in the same center, they looked at a series of 38 patients with cardiogenic shock and looked at their bleeding and mortality, and it was higher than in stable patients, which we would expect, but they did not see any stent thrombosis or severe or life-threatening bleeding within 48 hours, which is the time period you would expect to see any adverse events from cangrelor if you were going to see them. And then in another study looking at real-world use of cangrelor, this was the CAMEO study that was published by Jen Reimer and Jaha just last year. This was a multicenter retrospective observational study of platelet inhibition strategies, and they found that use did vary across hospitals, but then similar to the last observational study that more than 80% of these patients were transitioned to ticagrelor, and the one thing to mention is about 16% of the patients actually did have a one-hour gap between the infusion stopping and receiving their oral P2Y12 inhibitor. I think that's something that we have to be cognizant of is that when we, you know, kind of give instructions about things to make sure that the patient actually has received their antiplatelet medication and the timing that you want them to and sort of making sure that that is lined up well with the stopping of the cangrelor infusion. And then in a real-world study from Sweden that looked at 915 patients, again, 98% of these patients had SEMI, and a third of them had cardiac arrest, again, sort of reinforcing this idea that this is tending to be used in the real world in very sick patients, and oftentimes these patients are being transitioned to ticagrelor, and they found a very low risk of cangrelor and non-cangrelor-treated patients. Stent thrombosis rates at 30 days, overall the numbers were very low in rather both groups, but again, with the non-cangrelor-treated patients not having the same risk profile as the patients who were actually treated with cangrelor. And lastly, the real-world use of cangrelor study from Italy, Arcangelo, again, many STEMI patients oftentimes treated with ticagrelor, and this was the interim results, and it looked like they had very few adverse events as well. Just to comment a little bit on a few ongoing trials or studies that are not published yet, there are several that are looking at transitioning between antiplatelet agents during surgical procedures or before surgical procedures, that is, also looking at patients with acute shock, and then also the SWAP6 study, which I mentioned, which involves switching from prazegrel to cangrelor, and then there are several different other registries going on in Europe to be aware of. I was particularly interested in the fact that there is a cangrelor neonatal study for neonates that have congenital heart disease, and it sounds like there is a definite need for improved and safe drugs in that patient population, so I appreciate the interest in that. And then lastly, there's another observational cohort study in patients at high risk of bleeding undergoing PCI, also in Italy. So I'll end with another joke, and I appreciate your attention. Thank you so much.

IV platelet inhibition

cangrelor

platelet reactivity

safety

PCI