aspects of CTEF? Can't hear me? Okay, let me see if I can turn up the volume. Is it better now? Weird. Okay. If it gets quiet again, let me know. I have a tendency to get quiet when I'm talking about important stuff. I've been doing it since I was a kid. So, all right. I'm going to talk about medical therapies for chronic thromboembolic pulmonary hypertension. My name is Dr. Jean Elwing, and my focus is pulmonary vascular disease, and I see these people in my pulmonary hypertension workup, and then I send them to our experts to help me manage them. So, I do have some disclosures listed here. What I want to leave you with is talking about just some basic risk factors for CTEF you may not be aware of. Talk about medications and their indications, and a little bit about things on the horizon. Okay. We never start without a case at CTEF. We want to be real life interactive. This is Nancy. She's 63-year-old. She has a history of breast cancer. She had it resected. She got chemotherapy, no recurrence. She had a port put in, and then she never got it removed. I see this more than you know. Never got it taken care of either. She had a DVT remotely five years ago after a motor vehicle accident, had three months of Coumadin, done. She now comes to you and says, I'm short of breath, six months, some chest pain, it's kind of weird. I went to my cardiologist. He did a stress test and an echo, and he said, stress test was okay. She didn't really remember much about that echo, and she had some mild lower extremity edema, left more than right. Vital-wise, not too bad, but she's 92% for a woman who doesn't have any other cardiopulmonary disease, not absolutely reassuring. She was alert, interactive. She had some bad jagular reflux, but no JVD. Then when you listen to her heart, you're like, something is going on. A little bit of loud P2, a 2 out of 6 and 2, you also noted some lower extremity edema. You do some labs, pretty good, other than BNP is higher than it should be, and we have to be very sensitive to BNP. BNP, you know, when we see our left heart failure patients, maybe it's 5,000, but 150 is not normal for the average person, and it is abnormal for a pulmonary hypertension patient. So you're like, okay, you said you got that echo, let me actually find it. So you pull it up, and what do you guys think? RV's big, RA's big, she has septal flattening on the parasternal short axis, she has good TRJ there, and you can estimate her pulmonary pressure's at 50, and you're like, mm-mm, it's not normal. So we're going to go down this route of the pulmonary hypertension workup, and that's how I encounter chronic PE. So I get my VQ scan, and as Horaci says, it's either normal or abnormal. I love that. I've adopted that now. And this is, you know, we're not talking about, we're not trying to interpret more than it's not normal. So then I'm really worried. Do you see that? The ventilation is good. It looks like lungs. If I'd superimpose my perfusion on top of my ventilation, it would not match, right? It's unmatched defects. So it's an abnormal scan. So I do my CTPA, and I'm like, ooh, no central stuff. But I'm still really worried about that. I get my right heart catheterization, and she has real pulmonary vascular disease, pre-capillary. And remember, that's a diagnosis as greater than 20 PA pressure, mean pressure, and that wedge is normal, and our PBR, pulmonary vascular resistance is high at 4. So I'm going to call a friend. I'm going to send her to my near and dear folks here for an evaluation for her chronic thromboembolic disease, because I'm worried about that because her VQ is abnormal. Even though my people said my CTPA is normal, I need help. So she underwent a further evaluation. She had a pulmonary angiogram. She had no central disease, and they felt that she most likely had very distal disease, not an operable candidate and not a BPA candidate at that point either. So you're going to ask yourself, what do I do next? Do I remove her port? Do I anticoagulate her? You probably already did that. Do I do an IBC filter, or do I do medical management? Which do you not recommend? Which are you guys not going to do? You're not going to put a filter in her? Thank you. We don't need more problems. And she's like, but why did I get this? All right, she had a DBT. She didn't have a PE in the past. She could be hypercoagulable, but you did all those labs and nothing was abnormal. She has her spleen. She doesn't have any shunts. She doesn't have a pacemaker. She doesn't have any cancers that are recent, but she does have that remote history of breast cancer, and her thyroid's okay. But you're really worried. She has that port in place, so it's like flicking off little things, little tiny clots and causing her problems. All right, so what's false? Do you recommend lifelong anticoagulation? Do you say, after about three years, we're good. We can go down to low-dose anticoagulation? Do you say, I don't really know for sure what the right anticoagulation strategy is, but most experts tell me probably it's Warfarin. I checked with my experts and they're still telling me that. And there's no randomized controlled trials to really guide me. So which is false? Have you ever heard of going down to half-dose anticoagulation? I bet you have, because patients ask for it. They ask for lower-dose anticoagulation all the time, but definitely not the answer. Okay, so what do we know about anticoagulation? I will have to tell you, expert recommendation is still Warfarin, but many of us know that if we had to take Warfarin, it would be very difficult. Okay, the expert study was an international multi-center perspective, uncontrolled, non-interventional cohort study. Whenever there's so many words, you start to worry. 2014, 2018, almost 1,000 patients. The majority of them were on Coumadin. Hemorrhagic events were similar, but there was a bit of a signal, just as there was in a previous study for more embolic and thrombotic events. But I circled those numbers. They're pretty darn small, 1% on the Warfarin group and 2% on the DOAC group. So really, I would have to say that we have to think about this really closely. Now, the people that can't be on DOACs are people with triple positive antiphospholipid antibody syndrome or people who clot through these drugs. So there are people that you choose based on those things, but at least right now, my experts tell us, Warfarin's still the way to go. Another study looking at 500 patients, observational, 10 years, 8% were inoperable. This showed us that the Coumadin folks had more serious bleeding, but otherwise were relatively equal. Again, this is all observational information. Okay, so I'm not a lot smarter now, but at least I can say that, for the most part, I'll try to keep people on Coumadin. So that was the anticoagulation. That is the most important thing we can do. We can't collect more clots. I tell people who have CTEP that they're hoarders. You don't want to go buy another clot because you're not going to get rid of it, so we cannot have more clots. People get that stuff. They understand that they really have to prevent the problem because that will keep them well as long as possible. Okay, now we're going to talk about medical therapy. We're not erasing clots. We're not doing anything. We are treating the microvascular disease, and what do we have? We have one FDA-approved therapy, which is wonderful because we used to have none, Rio Ciguat, a soluble guanylate cyclase stimulator, increasing the synthesis of cyclic GMP and increasing that calcium sequestration and causing basal relaxation. So yes, we do have an FDA-approved therapy. So how did this get approved? This was in the patent study. More than 250 patients meeting the primary endpoint of improving walk distance, and this is significant. Also improved other endpoints, hemodynamics, BMP, and punctual class. So this is the drug we go to in our patients who are inoperable or have pulmonary hypertension after surgery. This does not replace anything these folks are going to tell you. This is our little Band-Aid that helps our patients get through, but it is not the ultimate intervention we want. Okay, what has failed? What is not FDA-approved? Well, they tried Sildenafil with 19 patients. It didn't meet its endpoint, and we never studied again in any meaningful way, so that is not FDA-approved. Bosentin, they looked at that in 157 patients. That didn't meet its endpoint of six-minute walk distance, but there were some hints about improving hemodynamics, pulmonary vascular resistance, and it was well-tolerated. So thought-provoking, right? That's an endothelin receptor antagonist we used in the past more frequently for our pulmonary arterial hypertension patients. So let's go on to a more modern version of Bosentin. Massetentin, which is an endothelin receptor antagonist. Phase 2 study looking at 80 patients, and that had a positive impact on PBR, but this did not get this drug approved, right? We need to study it more. So they are studying it again in an additional study at higher dose, 75 milligrams. So more to come on that. So there could be a second drug that could be approved, but nothing right now. They went to the prostacyclin pathway. We have a lot of little case reports about using prostacyclins in chronic PE patients. So in Japan, they studied Celexapeg, which is a prostacyclin agonist, and they had a positive signal in terms of the PBR. So we studied it further, the Janssen product, in the CELEX study, and that study was actually just terminated because it did not meet its primary endpoint at its planned interim analysis. So I'm sad to say we have one FDA-approved drug, but we're going to get another one, don't you think? So this lady wants to be in a study. So we look on the clinicaltrials.gov, and we try to find an option for her. So this is what comes up when you look. There's some registries which are very important, telling us about outcomes and follow-up, but we found the one study with the high-dose massetentin that we searched for a location for her. So what happens with Nancy? She does remain on her anticoagulation. We took out her port so we wouldn't have this nidus for more clots, and she was absolutely very good about taking her medication, started her ReaSigWatt, up titrated it. You know, it's not an easy drug because it can cause some hypotension, but she did fine. She had some acid reflux and some GI distress, but she got up to her dose of 2.5, now tolerating it, and she did reach her functional class 2 status, and she's doing quite well and able to go back to work. So this is a nice story, but not always so lucky. If our patients could be operable or could have an intervention, we would always go with that rather than this. So with this, I'm going to let Dr. Horaci take the stage. All right, good afternoon, everybody. That was great, Jean, and thank you for inviting me to give this talk. So now it's time to talk about balloon pulmonary angioplasty as a treatment option for CTEPH. These are my disclosures, and first I want to start by talking about why do we need a percutaneous mechanical approach to this disease when we know that, as you will hear later, that pulmonary trauma endarterectomy, surgical extraction of chronic thrombofibrotic disease, is the treatment of choice and should be thought of as the first thing that you think about in terms of treating patients with CTEPH. It turns out that a lot of patients cannot get operated or don't get operated. I'm showing you here data from the International CTEPH Registry showing that 40% of patients don't get operated. And when you look at the numbers, most of them, the reason is what we would consider technically an operable disease. So basically, there's a large proportion of patients with CTEPH that cannot get operated or don't get operated. The second reason is that many patients who get operated are left with residual pulmonary hypertension. And in many cases, this is associated with significant morbidity and mortality. Yet we do a really poor job at looking for that. So these are data that we just published recently showing that only 4% or 5% of patients after surgery in that two-year period get a right heart catheterization, even if they report symptoms related to pulmonary hypertension. And even though the guidelines recommend that patients after endarterectomy should get right heart catheterization. So there are two groups of patients with CTEPH, those who cannot get operated or don't get operated, and those who are operated but are left with a residual pulmonary hypertension. Two large cohorts there that could benefit from additional mechanical treatments for their disease. And so in that context, our colleagues in congenital heart disease, who are used to putting balloons and dilating pulmonary arteries that are occluded, even stenting some of those pulmonary arteries to restore pulmonary flow, came up with balloon pulmonary angioplasty for CTEPH. And indeed, in 2001, Feinstein and colleagues reported the first major BPA series, showing indeed some improvements in hemodynamics and even symptoms. However, this was met with a large complication rate. And this really lowered the enthusiasm for further attempts at BPA, particularly in the US and in Europe. However, the Japanese teams took this concept further, refined the technique. And then in the early 2010s, we started seeing reports from Japanese centers telling us that with advancements and refinements in BPA techniques, you could actually lead to good outcomes with a much better safety profile. And so over the last decade, you see now growing experience in centers outside of Japan, longer-term data, and to the point that now the latest pH guidelines from Europe have given BPA for CTEPH a Class 1 recommendation. So this is how it basically works. You normally have a guide catheter through which a guide wire is inserted that gets through the lesion. And then you get a balloon through that lesion. The balloon gets inflated. It pushes away the chronic thrombophybrotic material that gets incorporated into the pulmonary artery wall, and you restore pulmonary flow. That's the basic concept of angioplasty in any vascular breath, for that matter. I think the key here is patient selection. As you will hear again, operability assessment is key. Patients with CTEPH that can be operated should get operated. That remains the treatment of choice. But again, as I showed you, a large proportion of patients are not operable. The problem, though, is how you define that, right? And so you do need precise and detailed imaging to map out the thrombotic burden, and that usually includes VQ scans, CT scans, and pulmonary angiography. And if you have findings like this with disease really in the sort of distal, segmental, sub-segmental level with a pattern on the perfusion imaging that really is a small perfusion defects, subplural hypoperfusion, and with a degree of hemodynamics that I'm showing you in this real case, that would be, you consider for most centers, a technically inoperable case. But there is a large subjective component to the operability assessment. What might be operable in one center, what might be inoperable in one center, might be operable in another. And that depends largely on the experience and expertise of the CTEPH team. So I think patient selection for BPA remains a critical issue. Centers use sort of specialized, advanced imaging techniques. Our team has resorted to comb beam CT. You do this at the time of the pulmonary angiogram with a rotational C-arm tomography. And on your right, you can see that that allows you to appreciate webs in this example that are appreciated much more easily than in other imaging techniques. There are other imaging tools that other teams use, but this is what our team has resorted to. Now what's the efficacy in terms of hemodynamics? This is data from a nice meta-analysis that was published in 2019, reporting the results from the studies from 2012 all the way down to 2018. And indeed, what you can see there is a significant effect in mean pulmonary artery pressure, with a mean decrease of about 14 millimeters of mercury. Similarly, PBR improved significantly with a mean effect of about 300 dynes. The effects on cardiac output and cardiac index are a bit less striking in this particular study, showing significant improvement, but only 0.16 liters per minute. There's some more recent BPA experience. Most of this is not captured in the meta-analysis that I just showed you that allows you also to take a deeper dive into the experience. The largest experience comes again from Japan, multi-center registry, looking at 1,400 sessions in more than 300 patients. And what you can see there is a pretty striking hemodynamic benefit, right? Patients start with PBRs in the 850 dyne range, and they go all the way down to just under 300. This has not been replicated in Western series, as you can see there. The hemodynamic benefits are not that striking, while still there and significant, are just not as good as Japan. There are many potential reasons for that. One of them is that the Japanese teams are just better, more experienced. They've been doing this for longer. But also, if you look at their patient population, you start seeing some interesting differences. You can see there 80% of their cohort are women. And this is not what you usually see in CTEF cohorts, where usually it's an even split between men and women. They're obviously not obese, as some of our cohorts. In addition, they tend to have a much lower rate of associated conditions, such as splenectomy, thrombophilias. And also, they have a much lower rate of prior history of DVT or PE, compared to Western cohorts. So perhaps the Japanese population represents a specific cohort that tends to benefit more from BPA. Perhaps they identify a particularly inoperable BPA beneficial cohort. We just don't know. But there's definitely significant differences in terms of the clinical phenotype of the patients. There were some early concerns, also, about the durability of the BPA benefits, in terms of restenosis, or whether or not pulmonary hypertension would come back. Luckily, longer term data are emerging. And this is just one example showing that the hemodynamic benefits, as well as the BMP improvements, are sustained after a median follow-up of almost three years in this particular example. And there are other series that are showing this already. So it seems like the beneficial effects on hemodynamics are sustained. And finally, in retrospective observational data, it does seem that BPA is having a favorable impact in long-term survival. Again, in cohorts of patients with CTEF that are not operated, shown here from the French registry. This is just an example that I'm showing you to sort of illustrate what BPA can do. A 67-year-old woman has a splenectomy. This is a left lung pulmonary angiogram, showing that after several sessions of BPA, you really get nice reperfusion associated with hemodynamic benefits, but also symptomatic benefits. Functional class, six-minute walk distance, oxygenation, all these things improve. And this has been documented in many series, as well. However, a bit lost in all of these series is the impact of medical therapy. So if you look carefully at all these series that I've shown you, a large majority of patients are on background medical therapy. So while they report the effects of BPA right before BPA and after, I think the fact that these patients are pre-treated with medical therapy tells us that this is not just BPA leading to these improvements. And so we really didn't know a lot about that until the publication of the RACE trial just recently. This is a study done in France in multiple centers, about 100 people, half of them randomized to BPA, the other to Riociwa, the only approved medical therapy. Followed for six months, primary endpoint was PBR. And indeed, BPA actually did better in terms of improving PBR, as shown there, but also did better in terms of improving symptoms as measured as functional class, and also decreasing the BMP levels. Six-minute walk distance, there was a trend, but that wasn't significant. So BPA did better. Mechanical approach to the disease did better than medical therapy alone, which makes sense. I think we've always believed that you need to address the mechanical component, even when it's beyond the reach of the surgeons. However, this came at a cost of way more serious adverse events in the BPA group compared to the medical therapy group. And then what the investigators did was very smart, and they had this crossover design where people who were initially treated with BPA could get then medical therapy, and vice versa. People initially treated with Riociwa could then be treated with BPA if they had a residual pH defined basically as a PBR greater than four wood units. And what that sort of long extension phase show was that no matter how you started, you ended up with a similar benefit in terms of PBR reduction. However, in that journey, if you started with medical therapy followed by BPA, you got there with much less severe side effects. And so I think that this sort of puts together the story where you really need to address the microscopic vasculopathy with medical therapy and treat the mechanical component with balloon pulmonary angioplasty to achieve the best outcomes. And so I also think that that means that in terms of reporting future BPA series, we need to acknowledge that. And this is what we're trying to do in our work that is not published yet. But I think that showing data in terms of the baseline diagnostic evaluation, then looking at data right before BPA, which includes at least three months of medical therapy, and then the effects of BPA, I think it allows us to understand and see the effects of this hybrid multimodality approach. All right. So based on that experience and all that data, as I told you, the European guidelines have given a class one recommendation for BPA for people who are deemed inoperable by an experienced multidisciplinary CTEF team usually follow in medical therapy. And also in patients with persistent or residual symptomatic pH after endarterectomy, again, usually medical therapy first and then BPA. But clearly now, it's really, again, it's medical therapy plus balloon pulmonary angioplasty. However, all of this doesn't come free. The complication rate is not trivial. So this is not a trivial proposition. In that meta-analysis that I showed you, reperfusion lung injury was observed in 25% of sessions and reperfusion EDM in 16%. Nomenclature here is a bit tricky. Again, this is data expanding a decade. The complications were not easily understood at the beginning. Now we think that most of the complications are due to wire injury leading to extravasation and bleeding into the lungs. And now lung injury is sort of what we tried to report as a complication defined as opacities on chest x-ray or CT scan associated with hypoxemia with or without clinical hemoptysis. So with that in mind, you see in most recent series a rate of significant complications around 10% of sessions. The other thing that you need to pay attention to, though, is because this is a journey, right? This is not one and done. In fact, the median number of sessions in this series is about four or five per patient. And so during that BPA journey, if about 10% of the sessions are complicated, if the patient gets several sessions during that lifespan, it's very likely they're going to get a complication. And for example, in the French registry, if you see in the French report, you see 46% of patients experience a complication at some point. So clearly this is not a trivial proposition. Mortality is in the low single digits. And then when you look at this and compare it to sort of the complications of surgery, the numbers are roughly equivalent, which I think that it's why I think most people in the community feel that BPA is certainly a valid treatment strategy for these patients. But you need to be prepared to deal with complications. If you do BPA, complications will happen. And this is at least how we think about this. Luckily, we haven't had to do the things to the bottom of the slide. But you have to have a plan to deal with complications if you do a procedure in patients with pulmonary pressures that are very high, and you're opening up balloons and putting wires there. It's not a trivial procedure. And it's best done, of course, in a center that has CTF expertise and all these things that are available to support the patient if something goes wrong. BPA after PTE is increasingly being done. Most of the series that I show you included just a tiny fraction of patients after PTE, 4% for the Japanese registry, 8% for the French report. In our hands, it's about 16% of the cohort that went BPA after surgery. The results are good. In this example that I'm showing you there in orange, you see the people after PTE, the hemodynamics improve. But if you touch them up further with BPA, things get even better, as well as symptoms and six-minute walk distance. However, again, at a cost of perhaps a higher rate of complication, in this initial report of 10 people, the rate of injury was 33%, which is higher than what I've shown you. And in a more recent report, the same signal, right? So lung injury with severe hemoptysis requiring embolization, colon embolization, was much higher in the post-PTE BPA population than in the inaugural one. So there's a number of unanswered questions still and lots to learn. There's some ongoing registries. There's an international BPA registry that just got completed. That is being analyzed. So there's really much more to learn. And these are some of the things that we think about. As I mentioned, patient selection remains key. I think operability assessment remains critical. And we probably need to provide some objectivity to that, which currently lacks. These hybrid approaches are becoming more and more frequent. And also, the role of BPA in patients with symptoms from chronic thromboembolic disease without resting pulmonary hypertension, so-called symptomatic CTED. Another thing that's tricky is when do you stop, right? What are the treatment goals? Many of these series in some centers currently target a mean pulmonary pressure less than 30, but with an ongoing new definition, should be less than 25, should be less than 20, should be complete normalization, symptomatic improvement, biomarkers, oxygenation, withdrawal of pH meds, all of the above. That's something that the literature has not fleshed out yet. And also how to execute it, right? I mentioned we use cone beam CT, but others use aerial detector CT, others use OCT, although much less frequently. IVUS, I believe, has fallen out of favor. I think everybody doing angioplasty are doing supraselective pulmonary angiography. Many centers use, or some centers use, the pressure wire to measure that gradient, not only to find hemodynamically significant lesions, but also to target the dilation, make sure that you don't get a gush of blood. And there's some data that suggests that that actually is associated with lung injury. So lots of variability in all of these reports. And also, I think we need to still understand more about the nature of the complications. But all that said, I think BPH certainly is a welcome addition to the treatment armamentarium. I think it has a really defined role in that sort of distal segmental, subsegmental population in conjunction with medical therapy, because everybody who has that with significant pH will have a significant amount of microscopic vasculopathy. So I think we're in a really exciting era where we have a lot of different tools to offer our patients. And with that, I thank you for your attention. Thank my team for the support. And I think we're taking questions later. So thank you so much. Thank you. Thank you for watching! Thanks. Hi. What? I talk louder than these guys do, so is that better? They were so quiet. I hate following Gustavo. It's so frustrating. How come that's not working? We said you could do it without the slides. It doesn't matter. So as I'm sitting here listening to the lovely, both of their presentations, really wonderful, lovely, I'm saying, oh damn, now I'm going to have to change what I was going to say. But I'm not here to debate Gustavo, okay? And I'm reminding Bill, you're not here to debate Gustavo, okay? This is not a which is better between BPA versus BTE, okay? I'm here to talk to you about surgical intervention. And I'm going to pull a senior card on these guys because I'm way older than all of them. I got a lot more data. But this is an ex—and also, in full disclosure, I'm also very pro-BPA. I do head the BPA CTEF alliance that currently exists in the United States. So I'm very pro-BPA. It's been a wonderful, exciting time in managing CTEF patients over the last decade. This has been a brilliant advancement in our ability to take care of more patients with chronic thromboembolic pulmonary hypertension. With medical therapy now available in addition to BPA. Because in the old days, which really wasn't that long ago, you were either a surgical candidate or you, you know, if you weren't a surgical candidate, then you ended up in a situation where all we had was some medical therapy that may or may not be really effective in improving your pulmonary hypertension and prolonging your life. That's where we were in 2010. Okay? But now, the last 10 years have been really, really exciting. I forgot to do my disclosures. Hang on. So I'm going to talk to you about—why do you advance this? Why am I having such a hard time here? You think this is my first talk. Okay. My name is Bill Ogier, for those of you who don't know. I don't know. It is late. And I have a consultancy contract with Janssen PH and NEPU Medical currently. And I found myself increasingly over the last 10 years being invited to give this talk about surgical intervention for patients with CTEF. Okay? And I'm sort of defending what we have claimed for years was the procedure of choice to deal with the obstructive component of chronic thromboembolic disease. Okay? And it's like I'm defending it. Now we have something else. Look at all the improvement in their hemodynamics. Is BPA going to be better, or is surgery going to go away? And I'm here to say, no way, baby. Okay? That's not going to happen. It's not the best thing for your patients. Okay? So let's talk about surgery. And that's the end of my debate with Gustavo. What did you say? He lost. I lost. Stop. So we're going to talk about surgical option for patients with CTEF, some of the important outcomes following PTE surgery. And in that, I'm going to really present, which hasn't been really talked about in the CTEF community very much, particularly in the United States, about the results of the United States CTEF registry. Here we go. Okay? Old days. If you had patients with chronic thromboembolic disease, you know, the best option you had in order to improve or cure their pulmonary hypertension was pulmonary thromboendodrectomy surgery. And obviously, if you're going to undergo surgery, you have to have operable disease. Doesn't make sense. If you're not a surgical candidate, why would you have an operation? But since 2012, really, now we have FDA-approved medical therapy for patients who are deemed inoperable, as well as now balloon pulmonary angioplasty. And this led to the most recently published and approved by the experts. This is the treatment algorithm. They made it as simple as possible. Some people in the group just kind of wanted to go, CTEF diagnosis, refer to patient. That was their treatment algorithm. But that's a little impractical, right? But again, what we found here, and this has been a consistent algorithm for how to approach these patients. The decision that all of us as diagnosticians need to make, does this patient have CTEF? And if they have CTEF, the next important decision we need to make, is it operable or is it inoperable? Okay? If it's operable, the treatment of choice is an operation. If it's inoperable, everything that Gustavo said, do that. Okay? And everything Gene said, do that. But it's critically important we make that distinction. What constitutes operability? What constitutes inoperability? All right? This is, you've already seen this slide like twice already, because we all use it. Right? And operability, I wanted to remind everybody, operability is a technical distinction. It's not the same thing as not surgical. And you saw on Gustavo's slide, see I changed my talk, as you know, I see more as my prior speakers. In the recent international registry, they labeled a number of patients as inoperable. Underneath, they said anatomically couldn't get the clot and as well as the clot burden was not enough to explain the level of pulmonary hypertension. But that was only like 50% of that group, right? That was labeled as inoperable. The rest of the group had comorbidities that prevented them from, you know, pretty much from inpatient refusal. It doesn't mean that they didn't have operable disease. Okay? They may have had operable disease, but it was nonsurgical. There were good reasons why that person could not proceed with surgery. And are those two patient groups different? And that's what this is all about. Because as we try to decide, oh, goodness, sorry. As we try to decide where the level of operability is, Dr. Areci was saying, well, okay, there's some subjectivity in what's operable in one center may be operable in another center. Okay? And that's what that's all about. At UCSD, after a tremendous amount of surgical experience, they're able to go further and further out in the pulmonary vascular bed. So operability has a different definition there than it does in someplace else. And that's that zone here that you see. At what level can chronic thrombovolocollusions be removed? And of course, the important question is, if you can operate more distally, are they going to get better? Right? Or are you wasting the patient's time and placing them at risk? I'm not doing very well by trying to get out the more distal disease. And BPA was the most appropriate approach in that particular patient. But that's the decision-making process that we have here. So a more logical algorithm, treatment algorithm, actually expands on that decision point of operability versus non-operability. Are they technically operable? Or, I'm sorry, technically inoperable? Are they technically operable with acceptable risk? Or the third group is that we deal with. This is real world stuff. As Dr. Varasi did explain to you, there are those patients who are left with residual disease. Okay? And aren't candidates for, let's say, a second operation that you can deal with medical therapy and BPA. This is an amazing operation. And look at this picture. This is for real, man. This stuff comes out of patients' pulmonary vascular bed. With angioplasty, you're not taking any of this stuff out. Okay? So you have to keep that in mind. You're dealing with the obstructive component with pulmonary angioplasty. In the distal vascular bed, you're pushing the lesions aside. You ain't taking anything out. With endarterectomy surgery, you are removing this material from the pulmonary vascular bed. It's a very complicated surgery. It requires a lot of technical expertise on the part of your surgeons, your anesthesiologists, your perfusionists, and post-operative care, as you're about to hear, can be complicated. But it leads to this. Okay? Marked reperfusion of the pulmonary vascular bed. And by echo, considerable and immediate. This is an intraoperative phenomenon where you're markedly reducing RV afterload and improving RV function and their level of pulmonary hypertension immediately, post-endarterectomy. These are pre- and post-echocardiogram. On the left that you see here, you see RV and RA enlargement. Post-operatively, you're seeing the echo on the right, where the RV is much smaller. The right atrium is much smaller. Okay? The time difference between those two is seven days. And I present hemodynamic data like this for patients. Doing it for years. This comes out of San Diego. It was published in 2012. I highlight here the change in PVR in the early experience at UCSD versus later experience in both instances showing a marked reduction, perioperative reduction, in PVR with improvement in cardiac output. Pretty impressive, right? Okay? Patients feel this. But what we don't talk about, and this study does not come from UCSD, although the data, unpublished data from UCSD is really quite similar. This is in segmental more distal endarterectomies in which you see a substantial improvement in PVR in those patients even in the same group. This comes from Italy. Compared to those patients with more proximal disease. So if you are able to do segmental or more distal endarterectomy, okay, you can achieve significant improvement in their hemodynamics. Okay? This is an option for your patients if you end up with a diagnosis of more distal endarterectomy and your surgical team feels comfortable with that particular operation. Because you can achieve, potentially can achieve, an immediate marked improvement in their RV afterload and their pulmonary hypertension. And again, I've spent years presenting this data. Patients who undergo endarterectomy surgery experience a marked improvement in their functional capacities that persist over time. This is also data that says if you have CTEF and you can do an operation, they survive. Their survival curve is much better than those who can't undergo surgery. But full disclosure, much of this data, this is all pre-BPA information. So we're still learning. Okay? I wanted to present to you some of the data that was published last year in CHEST coming out of the United States CTEF registry. And what we did, we said, okay, instead of saying this is a multi-center registry in which patients with newly diagnosed CTEF, okay, 750 patients were followed over a number of years in their intervention. Some were surgical, some were not surgical. What happened to them? But I also need to say that this also, data accumulation occurred during a time in which BPA really wasn't very available in the United States. Okay? But we divided into the three groups that I just explored to you. They were operable. They were operable but didn't undergo surgery. They were nonsurgical for legitimate reasons. To a large extent, patient refusal or associated with comorbidities that the surgical group felt surgery was precluded. And those patients that were inoperable. And I show you this data because, first of all, it's kind of interesting. And again, the same thing that we see here. If you undergo surgery, you experience a marked improvement in your functional status. Okay? But so do the other groups. And the other groups did that as a result of, frankly, medical therapies. Okay? There was an improvement in their functional capabilities within that first year. Okay? But it was better with surgery. But I also present this to say, hey, you know what? It wasn't perfect. Surgery wasn't perfect. Okay? There were patients left with pulmonary hypertension. Patients still requiring oxygen therapy at a year. Patients still, okay, requiring pH-directed medical therapy. All right? It wasn't a cure. A lot of folks say surgery leads to a cure. Well, that's true in a lot of patients. Okay? But let's get real here. All right? It doesn't happen in all patients. And that's why it's so exciting that we have other modalities to help treat these patients. The survival statistics were much better in those patients who were operated on. Okay? And the most notable thing here is the second bar here, or the third bar, I'm sorry, in which the patients were truly operable but didn't undergo surgery. Again, it emphasizes that if it's possible, a lot of patients, you know, presented with, oh, you know, you have operable disease, but, you know, it's a tough operation. You know, you've got to go to, you know, Cleveland or something or San Diego to get your operation on. I don't want to do that. But, again, this provides the, you know, you're not going to do as good. You have operable disease, so you really want to, you know, perhaps present this information. This is for real. They just don't do as well if you don't operate on them long-term. And what was presented at this particular meeting a couple of days ago, again, coming from the registry, is the first registry that actually accumulated patient-reported outcomes, showing that, you know, it's, you know, survival statistics are improving in the operated patients. Hemodynamics are better. Functional status is better. But this is the first study that using SF-36 surveys and a more pH-specific or a disease-specific emphasis tent information, showing that over time quality-of-life measures are better in the operated group, more so in those patients who were in those other two categories. Very exciting information. So, in summary, surgical thromboendarterectomy is still considered, and it's not just my opinion, the primary treatment of choice for those patients, select patients, operable patients who have CTEF. And it's really key. The key to success in either instance is a multidisciplinary decision-making team to achieve optimal outcomes in this patient population. And, yes, successful PT leads to improvement at point. Hemodynamics, functional status, survival and quality-of-life outcomes. And segmental PTE is possible in the right hands and with experienced groups. Make the right decisions for your patients. Just don't accept without expert assessment that just because it's segmental, that doesn't mean it's inoperable. Okay? And residual pulmonary hypertension after endarterectomy. Now there are treatment options for this group of patients. And so this is a really important and very interesting time and wonderful time for patients with CTEF. So I'm going to close with those comments and get off the stage. All right. Thank you. Wow. Thanks for sticking until the end. I think that maybe the proposal next year should be that talks after four should have a little bit of like a happy hour situation. But the good news is these excellent speakers have already presented everything that I was going to present. So I am going to go quick in those slides that are repetitive. I come from the University of Pittsburgh. My name is Belinda Rivera. And we're going to talk about, okay, now your patient's had surgery. So what's next? How do you manage them? What's really happening after they get surgery? Here are my disclosures. And, you know, quick presentation, 54-year-old female. She has hypothyroidism. She had a blood clot in her lungs two years ago. She comes to clinic and she's short of breath. She can't walk. Her echo has signs of pulmonary hypertension, really high RV systolic pressure, as you can see here. RV is dilated. It still has a normal function. Here's her VQ scan. I think the more and more you see this, the better you're going to get at it. But basically you're comparing kind of like top to bottom in every, you know, all the views and just looking in the perfusion areas that are not there. So what's kind of not there compared to the ventilation. So I marked them for you, as you can see. And here are the hemodynamics, you know, obviously as expected. She has pulmonary hypertension secondary to chronic thromboembolic disease. So surgery was performed. This is a beautiful picture. We love getting those pictures. So what happens next? So now the postoperative care is kind of divided between the acute, immediately acute after surgery, and then sort of like the chronic follow-up. So the acute focus is really on oxygenation, optimizing, RV preload, and then inotropic support. The patient is usually extubated within the first day or two after surgery. And they're weaned after the inotropes with maybe second day or third day usually. And then shortly after that, then you can, you know, take all the lines and the swan and the pacer wires out. And then they're transitioned over from IV, usually IV heparin, to an oral anticoagulation, which as we've heard, it's usually Coumadin, although there's no prospective data. And if no complications, they're transferred out of the ICU shortly after, maybe post-op day three to four. And they can be sent home within a week, maybe a week and a half after surgery. So some of the complications that we see are similar to other cardiothoracic surgeries. But you can see here mortality in this publication was around 5%. But 3% need for ECMO, pericardial effusion is not that uncommon. And some pulmonary edema, bleeding, neurological complications like delirium, for example. I guess stroke can also be there. Persistent pulmonary hypertension and infection. Two important sort of post-op complications that are related to, that are kind of unique about CTEP surgeries can be both presented with hypoxia after surgery. So reperfusion pulmonary edema and pulmonary arterial steel syndrome. You can see here that the reperfusion pulmonary edema is less common. And it also occurs earlier, usually in the first 24 hours after surgery, as opposed to pulmonary arterial steel, which is a little bit later. So the reperfusion pulmonary edema kind of looks like ARDS. It's like acute lung injury, non-cardiogenic. And in the imaging, you're going to have bilateral pulmonary infiltrate, as is typical from an ARDS acute lung injury. Patients that have higher pressures, it increases the risk of developing it. And the way to treat it is really like acute lung injury. So low tidal volume ventilation, protective lung ventilation, diuresis if it's needed. You may be using INO or Flolan. And usually not proning, given the, you know, surgery, sternotomy. But I guess it's not super, you know, if it's really needed, it can be done. And then from a pulmonary arterial steel syndrome, it's kind of like the redistribution of the pulmonary artery that is kind of taken away from areas that were well perfused into new areas. The imaging is usually don't, it doesn't present with infiltrates. And the treatment is essentially supportive. And it's kind of self-resolves. It takes a little bit longer, but it goes away. So immediately after testing, these are the studies that are done. We usually get closing hemodynamics, right? So before taking the swan out, everyone gets numbers. Most people get an echo and a few days before going home. The VQ scan may be done as an inpatient, or it can be done after they get seen in clinic. And then ambulation for oxygen, if they need ambulation, they walk in the hallway. Here are the outcomes. So the 70% of patients are going to have improvement in their hemodynamics, as you've seen. About 20%, they're going to have some residual pulmonary hypertension. And then 10% or less get RV failure. Mortality, as you've heard, 5% or less. It can be as low as 1% to 2% in really expert centers. And the predictors of mortality are higher pressures, age, and distal disease, although none of which are going to be a contraindication to have surgery. They just need to be cautious that complications may occur. Mortality can happen. And when it does, it's usually related to the RV failing. Pulmonary edema, the aforementioned pulmonary edema. Massive bleeding, although it's very rare, but it can happen. Multi-organ failure kind of picture as well. So then now we moved on to the chronic phase, right? So now what happens, kind of transitioning into the long-term follow-up. And what we know is that those immediate hemodynamics that I told you about, when the swan comes out and we take those numbers, they really have a moderate correlation with what hemodynamics are later on. So it's really recommended that three to six months after, then you reassess. And how do you reassess? So echo, the VQ scan, if you haven't done it at the time of discharge. A six-minute walk. And then a right heart cardiac catheterization, which is usually done if the echo does have signs that are suggestive of pulmonary hypertension. So your pressure is still elevated. It can be, like, maybe about 25 or 30 or more, or if you have RV dilation or dysfunction for sure. You've seen images like this. So 30% may still have some persistent pulmonary hypertension after surgery. But the good news is, right, so that means 70% are going to be cured. And that's what you're going to use to sell it to the patient, right? So and that means that a lot of these patients may come off therapy, may come off, you know, medications if that's the case. So these are the predictors of persistent pulmonary hypertension after surgery. Usually a higher preoperative PBR and the presence of central disease. You've seen this image. So what happens next? Then you decide on if you're going to do medical therapy or angioplasty. Again, seeing this image again and seeing some of these therapies, I think the only one that Gene did not mention was that there was this study using Triprostanil that did have as a primary outcome using a six-minute walk test. But most of these medications are going to have hemodynamic and functional class and six-minute walk improvement. You've heard about the Select trial, which was on CelexaPag, which was terminated early, and we're all very sad about that. But the Massy-TEF is ongoing. It's currently recruiting, and we're just, you know, hopeful. Just to highlight on the Rio Ciguat trial, the 28 percent, so a third of the patients in this trial had residual pulmonary hypertension, and so it really worked. And those who did have residual pulmonary hypertension, you can see their hemodynamics were still quite high after surgery. So if that's the case, then, you know, put them on medical therapy. You've seen this. It's a two-phase trial, so comparing angioplasty versus medical therapy. And now, more and more, we're moving towards hybrid therapy. And what this shows is that there's still benefit. You have your surgery, and then you move on to angioplasty. You can see from all three graphs that there's definitely an improvement, a very dramatic improvement with surgery, but that there could still be even a better, you know, hemodynamic and functional class if you do a procedure like angioplasty. And same as this, so medical therapy and then followed by angioplasty. I think the only scenario which you didn't mention was the other way around, right? So using angioplasty and then going towards surgery. You know, maybe we can talk about those in the Q&A. But some of the surgeons feel like using angioplasty can sort of distort the plane field for their dissection, right? And then will prefer not to be done beforehand. Again, anticoagulation was discussed already. No prospective data. There is some signal on the increased risk of recurring VTEs on DOACs, but the same rate of bleeding. So back to my patient, and I'm really almost ready to wrap this up. You can see how this CT angiogram shows improvement in the vasculature and the circulation. And she felt better. She was able to walk further. Her pressure on her echo came down from 100 to close to 40. And she underwent a repeat cardiac cath, and her pressures were much better. But there still had signs of pulmonary hypertension, so we elected to start her on RioCeguat. And we're just considering whether or not angioplasty is the next step for her. So, yeah, I'm done. I'm done. I'm done. It's a... Thank you.

CTEPH

surgical intervention

acute phase

post-operative care

chronic phase

medical therapy

balloon pulmonary angioplasty

BPA

multidisciplinary decision-making

ongoing monitoring