So, I'll be pretending I'm a Ph.doc here, so forgive me for that. So, what we're going to talk about is what the longer-term consequences are of acute PE. So, what is the natural history of acute PE? And there's a lot of kind of newer evidence around this in terms of how people may respond to anticoagulation alone, especially over time, and how they may be left with different amounts of residual pulmonary vascular obstruction. But older data can sometimes help us, too. And what you see in older data is actually the majority of patients who have PE have higher PE pressures up front, and then they slowly drop over somewhere in the range of 30 to 90 days. And that's been demonstrated in a lot of different studies. That's in population standpoint. The second issue is that the majority of them seem to have, you know, significant clot reduction, but not clot elimination from their pulmonary vascular trees over time. And this is some older data that shows that, you know, on anticoagulation alone, you kind of had clot reductions around 50 to 60 percent with repeat scans or, in that case, repeat angiograms at 14 days. So the big worry is that patients are going to develop these chronic PE syndromes, and that the worst of those is called CTEF, chronic thromboembolic pulmonary hypertension. It's a very complex disease process. You can see it's not driven just by the fact that the clot is in there. There's a bunch of inflammatory issues and, really, a long-term hyperprothrombotic scarring state that develops in the distal circulation, including the distal microvasculature. And it's about 3 percent of patients with incident PE come into the hospital who will end up in that position. There's a huge other proportion of patients who, at least at rest, don't diagnose that they have PVRs of 3 or above. And those patients, though, a percentage of them may still have clot in their lungs that we might find with CT scans or VQ scans that we call RPVO, or residual pulmonary vascular obstruction. So when we think about the overall annual incidence per million of what we're dealing with here in the U.S., PE, we think, is about this many patients here, 11,000 per million. And CTEF, again, it's only about 3 percent of them are going to end up with CTEF. But close to maybe 30 to 40 percent of them still have functional limitations out at 90 days, 6 months, a year, post-PE. And that's what has been called post-PE syndrome. It's a very all-encompassing term. But when we think about it in terms of Venn diagram, let's think about this a little differently. You've got this whole issue of roughly 40 percent, maybe, of incident PE patients, 30 percent to 40, who have post-PE syndrome. That's that post-PE functional impairment. There's a little small group that's called CTEF that's in there. Those are the ones who actually, at rest, if you do a right heart cath on them, they have PVRs of over 3. And we may be moving that down a little bit, the pH docks, down to 2 to 3 now, as some of you may be aware of. But classically, it's been a PVR of 3. And then you have this other group that has CTED. This is chronic thromboembolic dyspnea, essentially. So they have dyspnea, and they have the residual pulmonary vascular obstruction. So both exist. So if you...now, remember, there's this whole other group who it's not so clear they have residual pulmonary vascular obstruction, but they're still limited after their PE. But you're not picking up anything on BQ scans. And that's actually even a larger group than the CTED group, based on the best available data right now. So this is how you need to think of this. The true incidence is unknown of that portion of the Venn diagram. You know you've got the CTEP I told you about, and you know you've got the RPVO, which we've kind of, you know, sorted out. But what percentage of that RPVO patients, patients who have pulmonary vascular obstruction, truly have dyspnea, hasn't been perfectly figured out. The next question that arises is, what's driving this dyspnea? And there's actually a few different issues that may be driving it. There have been, you know, CPET studies performed on these patients, cardiopulmonary exercise tests, at anywhere from 30 days out to a year, and a couple of different groups have done this. And it has been noted that the CTEP patients, patients that have true CTEP, which is a small group, when you put them on the pulmonary exercise test and you make them work, they've got reduced stroke volumes and worse ventilation. So that's not a surprise compared to controls. And then the CTED, not surprisingly, they're kind of in between. You know, they've got, so they have reduced cardiac outputs, stroke volumes, they have reduced ventilation. So why is the cardiac output reduced? Well, it's because of subclinical RV dysfunction is the best that we've figured out. So even on a resting echo, a lot of our measurements are very qualitative with reporting on the RV. But when you really get into it with the CPET, which is really what the right side shows, and what augmentation of the right ventricular ejection fraction will be under exercise, which is what the left panel shows, you can see that the CTEP patients do horrible with both of these. An increased slope here is bad. You can take my word for it if you don't read CPETs. And then you can see their impairment of augmentation of RVF is very bad. And then once again, the CTED group is in between. It's obviously very rational that this would be the pathophysiology, that there's an intermediate group with intermediate problems. But it's also important to recognize that there's a third factor at play. So I told you you've got BQ problems, ventilation problems, and you've got subclinical RV dysfunction late that really only manifests with exercise in most of these patients who don't have true CPET but have CTED. But then there's a huge bucket of them who you don't pick up on the CPET either one of those two things. You don't pick up that they have inefficient ventilation. And their RV and their cardiac output augmentation seems to be actually reasonably appropriate, but they're still super winded compared to before they had their PE. And that's who you put into this deconditioning bucket. So there's this huge group of patients that it looks like their impairments are driven by deconditioning. So the relative contributions of those three factors, deconditioning versus subclinical RV dysfunction versus ventilation issues late, we haven't perfectly teased that out. And there's also a colinearity there. What I mean by that is that if you are deconditioned, you might start being deconditioned because initially in your first 30 to 60 days, you've got some of those other problems. And then now those resolve with continuing anticoagulation on scans and even on CPETs, but your deconditioning remains because you never got going again. And that's something that also has not been teased out. So this is complex, and it's something we have to put a lot more work into, a lot more data around that, and more data around that the deconditioning is a big issue. So the key things I want to get through to folks is that there's these three different issues, which is post-PE dyspnea, which is a lot of patients, some of whom have residual pulmonary vascular obstruction. Number two is the dyspnea with the residual pulmonary vascular obstruction, but without resting pulmonary hypertension, and finally, have resting pulmonary hypertension, which is on the right side. And the issue here is that what do we know? Well, we know a few things. We know that surgery or balloon pulmonary angioplasty may improve symptoms and hemodynamics in both of these groups, both the true CTEP patients and the CTED patients. We do argue that you need a multidisciplinary team to sort this out. So we try to funnel our acute PE patients into an outpatient follow-up clinic that's run by our Ph. Doc. Then we have all these dedicated imaging protocols and, additionally, cardiopulmonary exercise testing to tease out what we're really dealing with here, because it's quite complex. Then we have multidisciplinary team meetings to decide which of the groups they should go into. Medical management, which if it's kind of very distal disease, we'll end up in. Balloon pulmonary angioplasty for distal segmental disease. Surgery or BPA at this intermediate area, which is for the segmental areas. And then surgery for the more proximal disease if they don't have horrible comorbidities. And as I mentioned, PT surgery certainly improves quality of life both in CTEP and CTED. And it looks like balloon pulmonary angioplasty probably does as well, although it's a fair amount of work to get it done. So that gives you a layout of where we are right now and what we need to know about what's happening down the line. Jay, great talk, and thank you for keeping us on time. You know, this is such an important part that gets overlooked. We are so focused on acute outcomes in PE patients, just getting them to survive the index hospitalization, but we need to do a better job at looking beyond that at three- to six-month outcomes, because a lot of these patients still continue to have residual deficits and problems, and it can really affect their quality of life. So it's nice to see that the trials now are starting to recognize and focus on that. We're no longer just looking at 48-hour outcomes or in-hospital outcomes. We are now focusing on three- to six-month outcomes, functional outcomes, quality of life outcomes, both with HiPytho. With tomorrow, we're going to present the FLASH 800 outcomes data and with the ongoing clinical trials. So it's an important part that also needs to have a significant focus and recognition of. Jay, just a question for you. Great talk, and I think this is going to be a nice transition to our next section on CTEF. Are you guys doing – CPE is very hard, it's a very technical test, and it's very challenging to do, depending upon which institution you're at. Are you doing any exercise to ride hard cats? I mean, we have something we call the Piedmont Peloton, where we put a ride hard cat in and they're on the bike while they're in the calf lab, and the stuff can be a little bit challenging, but I think it's important that if you're going to do BPA, if you're going to take this next step and be a center for that, that you have a multidisciplinary team. What are you guys doing at your institution? Is it all CPE? Is it exercise ride hard cat? What is it? Yeah, we're lucky in that we have a really high-quality CPET lab, actually, at Smears Hospital that runs all our CPETs when we end up in these difficult situations when we can't tease out what's going on. Exercise ride hard cats we've used in other clinical arenas, like for some of the randomized trials of intrauterine shunting devices and other things, where it's part of the protocols, but we, as of yet, have not applied it to the PE population. I think certainly it would be an area to write about. Just a quick question. I know we're out of time, but this is something I observed in your presentation compared to the first two. So in Tamam and Yolanka's presentation, you notice in their last slide, their patients within two days of mechanical treatment had restoration of their RV function, okay? What's interesting is what you're telling us here is that these patients have all these syndromes, and a lot of it is attributed either to pulmonary vascular obstruction, which there was very little in both of their cases, and RV dysfunction. So it's hard for me to reconcile that, so that we somehow think that heparinizing these patients and putting them on an OAC and we can't prove the benefit when they just showed, in all of these cases, we see this all the time. When you remove all the thrombus and relieve the pressure on the RV, they recover very quickly. So just interesting. How do you reconcile that? Yeah, well, the big issue is, I don't think there will be a lot of argument there from the folks in the room, but the question is, at what cost, and I'm not talking about financial cost, that should hopefully be irrelevant with the patient at the bedside, but at what cost to the patient in terms of complications of the procedure? Because there's a proportion of them, a large proportion, that don't end up in any of these buckets, and some who might even end up in a bucket but have no clear clinical consequences of it, because it doesn't impair their livelihoods. So the big issue becomes, what price are we paying up front? You know, with lytic therapies, bleeding issues, with large boron melectomy, hemolytic decompensation, other vascular complications, that's something we have to demonstrate, and that's the biggest issue. Yeah, and to add to his point, so just that the RV function was normal two days after, you know, CDT or thrombectomy, so it doesn't mean it's going to stay normal and follow up. But we know the right ventricle is very dynamic, and, you know, it can change over days. So one other comment on Drew's point about cardiopulmonary exercise testing being complicated, if you go ask a bunch of pulmonologists who do this for a living, they would say nuclear medicine stress testing is complicated, or reading an EKG is complicated, like, you know, it's not something that we can learn, like, so we have a room full of cardiologists there. Call to action. Set up CPET labs. Yeah. It'll make Aki's trial better, too. Aki, do you have a comment? I saw you standing up over there, and then we'll wrap up. Well, good morning, everybody. It's great to be here. I think I'm the only non-interventional cardiologist here, which is great, which is great. It's lovely to be here, actually. The debate's been great. The cases have been awesome. These are the real issues we're dealing with. So as most of you know, PE tract is on its way. We're going to enroll our first patient probably in July. But to the question of, like, shouldn't we just be doing this for these patients if you've got clear pulmonary arteries and no RV dysfunction two days after an embolectomy? Why randomize this patient, right? Well, so that's the hypothesis of PE tract, is that, you know, it's like the open vein hypothesis of the pulmonary arteries, is that if you can clear out clot, you're going to result in better cardiopulmonary health in the next year. But that just hasn't been proved now. And if you look at the ATTRACT trial, not to say this is the exact same thing, but the presumption was that if you remove as much thrombus as possible, you're going to reduce post-thrombotic syndrome two years later. And it turns out in most patients, that wasn't true. So I think the A equals B equals C hypothesis is just that at this point. So who knows what factors we're going to uncover with this study? I mean, as interventionalists, we all hope that this is going to be another arrow in our quiver for why we should be doing this. But that is really the essential question that PE tract is looking to answer. And it's going to be complementary to high-Pi. I've got to talk on this later, so I won't belabor the point. But that, I think, was that what you wanted me to comment on? Yeah. While you're here, do you want to give a quick just what PE tract is in the timeframe? Yeah, sure. So it's a catheter-directed therapy versus anticoagulation alone in intermediate-risk PE patients, all comers, up to 500 patients enrolled. The primary endpoint is a dual primary outcome, peak oxygen uptake at three months via cardiopulmonary exercise testing, and NYHA class at 12 months. They're linked by a gatekeeper approach. Those are the primary assessments. Of course, we're going to look at all of the secondary short-term assessments, but we're not actually enriching the intermediate-risk population, because that is not the primary question we're asking. I think high-Pi, though, is complementary that way. And I mean, there will be other parts to this in the upcoming talk, but that's the general framework. No, perfect. Such an important trial. I think he's worked years to get it to fruition. So… Yeah. So, right now, catheter-directed therapy encompasses any FDA-cleared device for PE-specific use—thrombectomy and catheter-directed lysis, yeah. So basically, we're making the argument that we yet do not know which one of these is best. You know, there might be compelling evidence that comes out in the next five, seven years, but for the snapshot for where we are, for modern PE practices, we would have to include both. And importantly, the trial can adapt to that in the sense that if it turns out that you clearly have some evidence that is very convincing in the community that a certain device is more optimal, there is the opportunity, I think, for a steering committee to, you know, adapt to that within the confines of a trial that's going to roll for several years, correct? Yeah, we have to be careful with that. I mean, you know, given the small numbers, you know, we'd also have to take in safety into account very, very clearly, you know, but the evidence would have to be very compelling to remove or even add additional devices, you know, and you'll see there are about nine coming out, so it'll be upon us to try to figure out which one of those devices makes sense for the trial going forward, and, you know, it's going to be—and there are certainly criticisms of this approach, but there are also benefits, and I don't think there's a right answer there. All right. Well, I'd like to thank all of the presenters today and the fellow panelists.

acute pulmonary embolism

natural history

anticoagulation treatment

residual pulmonary vascular obstruction

chronic thromboembolic pulmonary hypertension