Rob, great job as always. I'm just going to narrate the conversation. We have about 20 minutes left. The questions have been great. Keith, thank you for a comment on peerless. We're going to make sure to address that in our Q&A session. But what we wanted to do for the next 10 minutes or so is try to cover all the ongoing randomized trials that are going to fill out the rest of our evidence base for PE intervention in the next few years. So we are again blessed that many companies have gone forward and committed to randomized trials even though their devices are already in the market and these aren't required. And we've talked a lot about this publicly at different meetings. And we've lost this opportunity in atherectomy and some of the other device states where only single-arm trials are required. And this is unique where in the post-market space, we have commitments to running large randomized trials. On top of that, however, most of these are run by device companies making these devices. And we need some independent studies. And so we're also very fortunate that we have Akeith Sista, who has persistently put forward applications to run a publicly funded trial, which is now underway called PE Track. And we'll have an opportunity to cover all of these. So I'm going to go around the horn. I'm going to try to match people with trials that I know they are at least familiar with or involved with. So starting at the top, I'm going to talk about HiPytho. I'm going to take this one myself as I run the CEC, and then I'm going to send off the rest of them to our teammates here on the call. So this is a trial from Boston Scientific looking at a comparison of patients who are randomized to either ECOS plus anticoagulation or anticoagulation alone. You can see on the slide, there's up to 544 patients who will be enrolled. And this is at more than 60 centers, both in the U.S. and in Europe. And I think what's unique about this trial is these are not intermediate low risk. These are really truly intermediate high risk PE populations. So not only do they have to have the typical acute PE, elevated RV to LV ratio, as well as an elevated troponin, they also need to have criteria that predicts some sort of in-hospital event, whether it's hemodynamics, looking at the systolic blood pressure, respiratory rate, heart rate, or oxygen requirements, as well as other concerns that are not due to conditions that can cause some neurohemodynamic compromise like sepsis. The primary endpoint is really a clinical endpoint, PE-related mortality, PE recurrence, and cardiorespiratory decompensation. I think this trial, which is now over half enrolled, will be next up in terms of results, is my understanding. And I think this is really going to be a foundational trial for demonstrating that us bringing patients to the cath lab or IR suite or OR for a catheter-based intervention is the right decision making for this population that is at higher risk, but do not meet massive or high-risk criteria. I'm going to leave it to the panel. If anybody has any comments about this trial, we again have a lot of promise that this trial will be resulted in 2025, and I think will be an important talking point for how we move forward. Any comments from the panel before we move to the next trial? Very good. Well, we've talked a lot about catheter-directed thrombolysis, so let's move to the next slide. There's no one better, literally no one better, who can discuss this trial than Dr. Sista. Aki, I'm going to hand this over to you to talk a little bit about PE-TRACT. Yeah, thanks, Eric. It's a pleasure to talk about the trial, and for those of you who are not familiar with it, this is a long-designed, long-awaited trial that we got started finally with our first enrollment in July 2023. Basically, this is a randomized controlled trial against anticoagulants alone. The comparators are CDT plus anticoagulation and anticoagulation alone. CDT is comprised of both mechanical thrombectomy and catheter-directed thrombolysis. We're comparing up to 500 patients, and our primary endpoint is actually not... I'm sorry, maybe there's another slide here, but is there just one slide on this, Eric? Okay. Oh, I see. I'm sorry. I didn't realize that. What we're really looking at as a primary endpoint is the medium to long-term. Looking at cardiopulmonary exercise testing, and specifically the peak oxygen consumption at three months, and then the NYHA classification at 12 months. There are two primary outcomes, and they're linked together through what we call a gatekeeping mechanism. We are collecting many secondary outcomes, including short-term outcomes that we've heard of from the other trials. At the end of the day, we want to know if catheter-directed therapy, which is what we're referring to as CDT, offers better cardiopulmonary health in the year following PE than anticoagulants alone, with a bunch of other secondary outcome measures that will hopefully round out the discussion and be a comprehensive assessment of the two therapies. Great. Akeem, any update on the enrollment right now to date? To date, at about 49 clinical centers across the United States, we have had 258 to 259 enrollments. We just passed through our first interim analysis. We have those every 50 patients, and the trial is continuing. That's the most up-to-date numbers. Wow. Congratulations. That's quite a short timeline, and again, knowing the funding line on NIH trials and getting that many sites active is quite a feat. Congratulations, Akeem, on seeing that forward. Our next trial we're going to discuss is DORM-PE, and I'm going to ask Dr. Lookstein to walk us through that trial. Sure. Thanks, Eric. Very, very, very briefly, this is the first of its kind randomized trial for anticoagulation versus, in this case, penumbra medium-bore thrombectomy in the intermediate high-risk population. The primary endpoint is solely the RV to LB ratio, and it was really just designed to determine whether or not you could offload or stabilize the failing right ventricle faster than anticoagulation alone. There's a number of functional and quality of life endpoints out to three-month follow-up, which will hopefully be very, very insightful and be able to guide the next set of randomized trials for thrombectomy and the evaluation of intermediate high-risk patients, but it's one-to-one. We're just about halfway enrolled. We've been enrolling for just about a year now, and so we're cautiously optimistic that we'll be able to present this data towards the end of 2025 as well. Wonderful, Rob. That's a great update. I think this will add a lot to the current understanding of the role of these devices versus anticoagulation, so thank you. Next, I'm going to move to Dr. Geary, who's going to walk us through the PIRLIS-2 trial, which will potentially be the largest PE trial in the group that we discussed today. PIRLIS-2, the goal here is to randomize up to 1,200 patients to mechanical thrombectomy versus anticoagulation alone in the intermediate-risk cohort, similar to the other trials. You can see that the primary endpoint, again, is one of these wind ratios, and you can see the little difference in the wind ratio here where we've disaggregated bailout from clinical deterioration and said its protocol defined bailout has moved down in the hierarchy. Additionally, the protocols are more rigorously defined in PIRLIS-2 than they were for PIRLIS-1 with regard to bailout therapy. It's necessary to have that option, it turns out, to get these trials performed at this point, because these trials are being run after these devices are already FDA-cleared, so if we're going to have any hope of enrolling a broadly representative population, I think investigators have to feel like their hands aren't tied when they're enrolling patients into the trial. Importantly, the randomization is up to 1,200, but their interim analysis is planned at 500, 800, and 1,000 patients. The trial's powered to be able to facilitate those analyses, so we'll see if it needs to make it there. Naturally, at each interim analysis, the steering committee will be able to make a judgment on whether to continue the trial or not, and I appreciate everybody who's participating in this trial. The plan is for 100 sites between the U.S. and Europe. Almost all U.S. sites are activated. A little less than half of European sites are activated right now. The trial isn't rolling ahead of schedule. Awesome. Thank you, Jay. I always love that push-pull. We all want to see a large 1,200-person trial, but obviously, if it's powered and hits its endpoints, we'd like to see data early as well, and I think this will complement peerless nicely. If we can move to the next slide, I'm going to ask Dr. Bowman to make a comment on PYTHO3. Yeah, so PYTHO3 is a randomized controlled trial, placebo-controlled, double-blind. It's multi-center, multinational. The goal is to evaluate a reduced-dose thrombolytic therapy. It's acute, intermediate, high-risk PE patients. The goal is around 650 patients, and the reduced dose is no more than 50 milligrams of alteplase versus placebo. Primary endpoints is actually a composite, all-cause mortality, hemodynamic decompensation, or recurrent PE within 30 days. These patients are going to be followed up to two years, so there will be evaluation for CTEF at six months and two years as well. All right. Thank you, Julie. Yeah. My comment is that thrombolysis is still underutilized, as we know, from our large claims databases, and so this will be an interesting addition to our data. Yeah. It's a funny time for a lytics trial in the context of all the U.S.-based trials that are really catheter-based, but the reality is not every institution outside the U.S., even in the U.S., has the ability to do a catheter-based intervention or has access to it in a timely manner, so this will answer some questions from older trials that didn't complete and let us know what this regimen has a role in in terms of PE care. So our last trial before we get into Q&A is the PRESERVE trial. This is a really unique trial, and I'm going to ask Dr. Li to walk us through a high-risk PE trial. Thank you. Actually, Dr. Geary is one of the PIs on this trial. So PRESERVE is a trial enrolling a high-risk PE, 200 patients randomized one-to-one with a flow-treater, a large-bore thrombectomy versus standard of care, and it's really designed to understand the primary endpoints, including all-cause mortality, cardiac arrest, requiring CPR, bailout, major bleeding, as well as persistent need for ECMO. The trial is actually ongoing recruitment right now for very early phases currently, so we do look forward to guiding our management of these very sick patients. Wonderful, and really, oh, sorry, Jay, please. Sorry, I'm just going to make two additional comments just to give a little flavor to PRESERVE. One is that the high-risk population is slightly expanded compared to what folks are used to seeing with regard to ESC criteria, and the specific thing that'll get you in, in addition to what the classic criteria are, is a lactate over four, of course, that's deemed to be coming from cardiogenic shock associated with PE. So you technically could be maintaining your blood pressure with a lactate of five, although we know how sick those patients are, and we're willing to call those patients high-risk PE there here. The second issue is, as June mentioned, the first site was activated in the trial two weeks ago, so we look forward to further sites coming online. This is going to be a particularly complex trial to enroll, as we can imagine in this very sick patient. Yeah, I just wanted to say I was going to comment that, Jay, kudos to you. I know you've put a lot of effort to push in this trial forward, and also to NARA to taking a leap to fund a really high-risk trial that can change patient care for a long, long time. This trial probably can't be done again, potentially.

pulmonary embolism

randomized trials

catheter-based interventions

anticoagulation

PE management