All right, good afternoon, everybody. I'm impressed there's so many people here today. I think Hawaii's calling a lot of times during the afternoon session. So I'm glad to see you guys come out. I think this will be an entertaining session. We have a pro-con debate. And so there's two questions that are going to be debated. The first one is looking at the new European diagnostic criteria where they drop the PVR from 3 versus 2. And so we have two distinguished faculty looking at that question. Lana Melendez-Groves, who's a professor of medicine at University of New Mexico and runs the pulmonary hypertension program there. And then Chris Mullins from Brown University. He's an assistant professor at Brown. And he's the associate medical director of the pulmonary hypertension programs at both Rhode Island Hospital and Brown. And so they're going to battle it out. And then our heavyweight match, I think, expect a more genteel intellectual conversation for the first pro-con session. But then the heavyweight match comes. It's two legends in the field of pulmonary hypertension. We have Frank Rahaghi from Cleveland Clinic, Florida. And so Frank the Tank is going to take on Harrison Hapthahammer-Farber from Tufts. And so Frank just took a job as the president of the PFF, the Pulmonary Fibrosis Foundation. Congratulations to him. And he's the director of the Advanced Lung Disease Program at the Cleveland Clinic in Florida. And then Hap is a professor of medicine at Tufts University in Boston. He's the director of the PH fellowship there. So you guys didn't come here to hear me talk. I just wanted to get everybody introduced. I think Lana will start out. All right. Well, thank you very much. I think I'll thank you for inviting me to be part of this session. We'll see how that all goes. So first, I just want to tell everybody good afternoon. And to say it is a pleasure, these are my esteemed colleagues. So we're going to do our best to keep it highbrow, maybe. But also, I purposely wore a very vibrant dress because of the vibrant personalities that are going to come after me. And I felt like I could at least try and keep up somehow. So let me see. All right, so as mentioned, we're going to be doing a pro-con debate about the applicability of the ESC-ERS guidelines in the US. And more specifically, I'm going to be taking the pro stance when it comes to patients with a mean pulmonary pressure of 20 to 25 and the PVR of 2 to 3, and that these patients should be treated with pulmonary vasodilators, and that that should be applicable in the United States. I mean, I fit all of the European countries on the US. I feel like I've already got a point there. But as we move forward, I actually do have some learning objectives. I mean, I can't speak to whether Frank and Hop are going to have learning objectives. But for now, we're going to try to at least cover a few things. So I want to definitely remind people of where we were in 2015 in terms of the diagnostic criteria from the ESC and ERS guidelines. And then I'm going to take a few position points to support my pro stance. Now, before I sort of get into the meat of my topic, I do need to give you a little bit of background. I know that Chris gave you some. But in reality, anybody who knows me very well knows that medicine is not really what my family does. And I would say it's suffice to say that is not at all what they do. And at the risk of alienating the entire audience, my family is entirely 100% lawyers. This is from my sister to my brother to my brother to my father to my aunts to my uncles to my sister-in-laws. It goes on and on. And so growing up in my household, if you didn't debate, you did not eat. That was just how it was. So for today's discussion, I know we often have sort of a style to our pro-con debates. But I'm going to take a little turn here. And I'm actually going to do it in a more traditional debating style, which is Lincoln-Douglas debate. And this requires a value to defend your stance. So if I can defend this value, well, I win. And that's just how it goes. So in order to prove my case, first off, I did actually learn how to say this. Epistemological humility. That is going to be the value that I am basing my entire stance on, which is attributed to Immanuel Kant, who is a German philosopher. Again, European. Clearly another point for me. And encompasses the recognition that our knowledge and beliefs are limited and that we should remain open to the possibility of being wrong. And I know that scares us, being wrong. In medicine, it scares us. However, this is an intellectual virtue. It is grounded in the realization that our knowledge is always provisional and incomplete and that it might require revision in light of new evidence. This belief can be traced all the way back to Socrates and Plato. Not Plato, Franck, like you thought last night, but Plato. And I don't know if any of you remember the allegory of the cave. But if we can go back to high school, which I'm not sure how many of you remember that, when we were taught, no? So I'm going to give you the cliff notes on this one. In this situation, what happened was Plato said that when you were placed, whatever was in front of you for long enough became your reality. If that was shadows on the wall of a cave, that was your reality. However, if you stepped into the sunlight, then to comprehend new information as true reality was much more difficult. And then convincing others of that reality was made that much harder. So with that, it brings me to my first position point, that this new criteria is more scientifically accurate to describe normal. So I'm going to just wager to say that since we're all here at this conference, we believe in science and that our adherence to statistical analysis for the purpose of moving our field forward is essential. In this instance, the use of standard deviation and confidence intervals is crucial. We must adhere to epistemological humility that our original criteria to define PAH did not meet the two standard deviations above normal to classify individuals with PAH. So as a reminder, in 2015, we were looking at these guidelines that indicated that a mean pulmonary pressure of 25 or more and a normal left side of the heart were added in that PVR of greater than 3 defined PAH. Well, now we've come to show, based off the more recent guidelines from 2022, that actually a lower mean pulmonary pressure and a lower PVR was actually more appropriate. So this has been shown all the way going back to 2009 with some of our reviews to today that a normal mean pulmonary pressure is actually realistically in healthy adults should be less than 20 and that a PVR is less than two wood units. And these were shown through 20,000 plus veterans that when that pulmonary pressure was less than or equal to 18, that they did better than those with a higher mean pulmonary pressure. So I don't think that's a lot of what we're debating today. I think that we probably have agreed that, yes, maybe the lower pulmonary pressure was appropriate and that we needed to do that. And that was at least from our 2018 World Symposium PAH update in terms of recommendations. But additionally, when you actually look at patients in terms of their mortality hazard, these patients that had not only the mean pulmonary pressure of 19 but a PVR of 2.2 worsened. So for our patients, now we're saying, all right, so they do worse if their pressure is anything above 19 and their PVR is at least 2.2 or higher. So from that, we can then start moving into position 0.2. So from the criteria, we know that this allows us to potentially identify pulmonary hypertension patients that are at-risk patients. I mean, we've been saying it for decades. It takes us too long to diagnose. It takes us too long to find them. Let's try to do this earlier. Well, now we're given the opportunity to try to identify these patients and then from there, be able to move forward with their care. So in BMJ, Zantholi showed in 2020 that after that change of classification from 2018 with the lower mean pulmonary pressure, that realistically, it didn't reclassify our patients very much. There was a small cohort of patients that maybe now we say have pulmonary hypertension. But it wasn't until we looked at decreasing the PVR that some of the reclassification actually occurred. And so when looking at 284 patients, we found that there was about 15% of patients that would not have been classified previously under the old recommendations were now being classified as potentially these patients with pulmonary arterial hypertension. And this is concerning because about half of those patients that would have been reclassified actually had a mean pulmonary pressure of 25 or more. I don't think anyone in the room would say that that isn't significant. And those patients had not only worsening six-minute walk distances, worsening pulmonary arterial compliance, but they also had increasing mortality. So from my perspective, I think that you have to start to say when we know that the mortality is 8% for our systemic sclerosis patients with a PVR of less than 2, and that jumps to greater than 18 when you're just looking at two to three wood units, all of a sudden we're saying, this is one of our most concerning groups. And now we have the ability to not only capture them, classify them, but actually do research on them, understand them, be able to move forward with the potential of treating them. So that then moves us into, again, I'm bringing back the lawyer thing, the letter of the law versus the spirit of the law. So from my perspective, if any of us in here were told you cannot use your clinical judgment to care for your patient, that would be our last day on the job. We love guidelines. We love recommendations. But at the end of the day, it is a patient sitting in front of us at that time, at that moment, that you make decisions. I think that my colleague recently made a decision like that for one of his patients, where maybe just reportedly I've heard that the PVR on her was 2.2, and all of a sudden therapy was being initiated. Because for that patient in that moment with those potential opportunities to improve outcomes, we would stand by that. So I know that everything we've ever done in terms of our clinical trials was based on what we used to classify PAHs. So I'm not trying to say I have lots of data to treat these patients. Not at all. But I think the moment that we start to say, I only treat based on the evidence that I have in front of me, we lose opportunity. And how can we ever move our field forward if we don't take opportunity to do that? The other point I would say is that the actual supplement in the ESC ERS 2022 guidelines indicated, refer to a pH center for individual decision making. They are not telling you you have to treat, but they are telling you we are giving you the opportunity to treat if that is appropriate for your patient. And we're already looking at this through multiple trials simply because we changed things so now we can look at it. And this was not only for ambrosentin, but for sildenafil. And I did just find out, I didn't realize that Dr. Mattai was my con person's mentor. So I feel like, again, he's helping to give me a little bit of backing here, saying what do we do for these patients that have their mean pressure between 21 and 24? Is sildenafil appropriate in our systemic sclerosis patients? Maybe ambrosentin didn't meet lowering the mean pulmonary pressure in terms of the baseline to six months, but they had other portions to their trial that indicated improvements in hemodynamics. Now it helps us shape further clinical trials. All right. So my last position point here is going to be the applicability in the US of this criteria for treatment with vasodilators. Well, I guess what I need to say is that we base all our guidelines, European, US, essentially off the same information. The same clinical trials, registries across the world. And so to try to pick and choose when we're going to use this, I don't think is a sound argument. But I can also say that I definitively know that those patients in those same registries, take just the US ones, let's say, do not reflect my population in New Mexico. So do I have no guidelines? So I have to take what we have. So therefore, absolutely, that would be applicable in terms of our patients in the United States. So in conclusion, I have clearly supported the value of epistemological humility and that we stop remaining open to the possibility that we are wrong. We stop making progress. Lest we forget that we once believed the sun revolved around the Earth. I stand in the affirmative that patients with a mean pressure between 20 and 25 and a PVR between two and three wood units should be treated with pulmonary vasodilators in the right circumstance. And that this is applicable to our patients in the United States. Thank you. Thank you. I'm certainly glad Lana took it easy on him, which is what she had told me, that she didn't take the gloves off. That was very thorough, I thought, very convincing. So without further ado. I'm really kind, Chris, so I feel like you need to go easy on me. And if not, I wore tennis shoes so I can run out. I'm not going to be easy. I'm just going to be correct. Fair enough, fair enough. Bring it. Bring it. All right, so I'm taking the con side against Lana here. The only disclosure I have, I'm actually on the DSMB for this updated study, which we talked about. It's relevant here. So I'm going to convince you that the use of pulmonary vasodilators for the treatment of patients with these borderline PA pressures and PVR lacks sufficient evidence. It's not necessarily going to make anybody better. And it has the potential for really detrimental effects on the pH community at large and every single person in this room. So that's pretty hyperbolic, but I'm really all in on this take, so just bear with me. So there are a few points that I'm willing to concede about this con side. That one is that a mean PA pressure of 20 to 25 and a PVR of 2 to 3 would units are really above the upper limit of normal for health and control subjects. I think we're not really debating this anymore. I think I'm also willing to concede that borderline hemodynamics are associated with increased mortality in retrospective studies. And in at-risk cohorts, particularly that with people with systemic sclerosis, there is a rationale for treating borderline or mild or exercise pH or whatever you want to call it, but there's really no good data for it. So let's walk through it. So I think Lon alluded to this earlier, but what I did is I looked through some of the more recent studies that I've looked at reclassification of patients with systemic sclerosis that had mean PA pressures of 21 to 24. And you're exactly right that lowering the PVR threshold from 3 to 2 reclassifies, at least by my math, about 45% of those of having PAH based on the lower PVR. And so this is a pretty significant amount of patients within this population, and it's important. And while the PVR more than two would units is associated with hemodynamic progression and worse survival in some studies, it's not in all. And so this is actually a Kaplan-Meier curve here from the paper that was published in 2022 out of France that showed that people with scleroderma and a PVR of 2 to 3 had similar survival as people who had PVR from 0 to 2, and that was both better than PVRs that were higher. So what data do we have to sort of say that these patients with borderline hemodynamics are going to get better with pulmonary vasodilators? So the ADIDAS study was 38 patients, and these patients either had, with scleroderma, who either had mild or exercised pH, and their PVR was about 2.2 on average, plus or minus 0.8. This was a negative study. There was no change in mean PAH pressure at six months. And although PVR and cardiac index improved, and there were statistically significant improvements in functional class and walk distance, there was a pretty significant dropout, 16%. And sort of importantly, in that study, 17 patients that got inbrosentin actually later came back and were diagnosed with post-capillary pH. And so this was really sort of unmasked post-capillary pH, which we'll come back to in a second. And so this is an area which we don't know of its benefits, and there's enough equipoise, which is why this ADIDAS study is ongoing. I thought potentially Lana was going to talk a little bit about this study that came out in 2020. It was a retrospective analysis of data from the Australia and New Zealand registry, 82 patients that had diagnosis of PAH but had PVRs of less than three that were treated, and they looked at outcomes and follow-up. And so this was largely a cohort of patients that had connective tissue disease, a little over half, and walk distance improved and functional class improved. But it's really important to note that probably only a quarter of these patients actually had PAH pressures of less than 25. The mean was 27, and the IQR was from 25 to 30, right? And this is a really small minority of the patients that were in this PAH registry. So who are the patients that led to the data that Lana showed us already that a mildly elevated PAH pressure is associated with worse survival? So these are patients that have lots and lots of medical comorbidities. So this is the graph, that's sort of the mortality hazard ratio by mean PAH pressure. And if you looked at the patients that had the pressures in Brad Merrin's first paper of 19 to 24 milliliters of mercury were more likely to be obese, had more diabetes, had more heart failure, had more COPD. Sort of similarly, the sort of follow-up study looking at a PVR more than 2.2 would units, those patients had increased mortality, increased heart failure exacerbations, but they had more CHF, more COPD, and more ILD. So these are not the patients that are included in our clinical trials. So this was a table and a slide that I borrowed from my colleague, Corey Ventuolo, who took a look at sort of all the data and sort of individualized from 18 RCTs and PAH from 98 to 2014, right? So the average mean PAH pressure in all these patients is 51, PVR of 10, diabetes 5%. These are not the patients that are included in our trials. And sort of furthermore, if you think about some of the recently sort of completed trials or ongoing trials, we're actually increasing our PVR threshold, right? Stellar's PVR was more than five would units. The Procera study's PVR is more than five. The perfect study, which was, you know, inhaled triprosanol and COPD was a PVR of four, right? There's a reason why the pharmaceutical companies and the studies that are being designed are including people with higher PVRs because the drugs probably aren't gonna work in those with lower PVRs. So how is this like detrimental to the community? So I think that, right, the vast majority of what I've hopefully shown you is the vast majority of people that are patients that have mean PAH pressures of 20 to 25 and a PVR of two to three, they have left heart disease and they have lung disease, right, and so we've never been able to show with the exception of patients that have ILD and pre-capillary PAH with high PVRs, we've never been able to show that pulmonary vasodilators work for people that have left heart disease or have other lung disease. And even in the cohort and the data of scleroderma patients, some of the patients that are the highest risk of developing pulmonary vascular disease, those were treated with ambrescent and had a serious fair number of them had unmasked post-capillary PAH. So I think we're setting ourselves up for potentially harming patients, but also sort of harming ourselves and falling into some psychological fallacies. So I think sometimes that gets thrown about in these debates is that when we say, well, you know, other people can't identify these borderline patients that are gonna benefit, but I can, and that's a psychological fallacy known as the better than average effect. I don't know if anyone's ever heard of this, but it was sort of really sort of publicized back in the early 80s when they surveyed people in Sweden and the United States about their perception of their own driving abilities and 93% of the drivers ranked their skill as above average. Okay, so this was a meta-analysis from a couple years ago that sort of said there's a robust tendency for people to perceive themselves as superior compared to their peers. And this effect is more pronounced when examining personality traits than abilities, right? So associated with people thinking that they have higher self-esteem, not that they're better at their skill. And I don't know about you, but when I look around this room, when I look in the mirror, I see a lot of people with high self-esteem in our field. And so I think the knowledge of saying, well, yeah, not all these patients benefit, but I'm better at identifying the ones that can is sort of really sort of falling into a psychological fallacy here. And so we already prescribe too many pulmonary vasodilators for areas where there's no good data for efficacy. So the study that I often cite for this is out of Ontario, Canada, where there are more PDE5 inhibitors prescribed for group two pH instead of group one pH. So just sort of marinate on that for a little bit. But this also can hurt our patients because if we're thinking about treating these borderline hemodynamic patients with pulmonary vasodilators, that's cost, that's time, that's energy that takes away the patients, us, their other doctors from managing their other comorbidities. And frankly, we may sort of overwhelm our pH centers not by seeing sort of patients that have true pH who really benefit from our expertise, but by sifting through mildly elevated pressures in people that have occult HEF-HEF or mild lung disease. So in conclusion, even in scleroderma patients with borderline hemodynamics, it's still unknown if treatment with pulmonary vasodilators improves outcomes. And the vast majority of people that have these borderline hemodynamics are patients with cardiovascular comorbidities. And there are downsides to sort of uniformly treating these and sort of detrimental to our field, to our patients and to ourselves. So I wanted to wrap this up. And I thought, ugh, how do I win this debate? So I started to Google like who is sort of some of the best debaters of all time. And one of the first people that comes up is Thomas Henry Huxley. He was referred to as Darwin's pitbull because he would sort of go to the streets and sort of debate for Darwin's views. And this quote resonated with me. And it says that, science has taught me carefully how I adopt a view which jumps with my preconceptions and to require stronger evidence for such belief than to one that I was previously hostile. And so I thought this was a really kind of good quote because I think treating these patients in these hemodynamic definitions are things that a lot of us have a lot of passion and sort of thoughts about. And so we have to sort of make sure we understand that as we sort of get further data. And then I said, that is way too centrist of a take to end a pro-con debate on and I need to be more aggressive. So then I thought, who is the best debater of my lifetime or who is the best person that I can recall at dropping the mic? And that's B-Rabbit, Eminem's character from the movie Eight Mile. If you are too young or too old to have seen this, I would encourage you to watch it, it is quite entertaining. If you have seen it, you also are probably wondering, how is he going to have a quote from this movie that doesn't have the profanities to get away with a chest? So bear with me on this one. Everybody who treats PDR of less than three, put your PAH meds down and follow me. All right. Well, great, great job, both of you guys. I think both very convincing arguments. I thought I was going to learn about PH. I learned a lot about myself, the better than average theory, actually. And so I think, I don't know that we're going to have a formal vote. We'll just let you guys sort of decide amongst yourselves in your mind who you thought swayed you at that argument. And we'll bring up our next round of debaters. So again, Dr. Rahagi and Dr. Farber are going to talk to us about the European guidelines and whether they apply to the US population. There's a lot of controversial things that came out in the guidelines, in particular, some information about using monotherapy, like in some of their algorithms for patients with comorbidities, which I think would be difficult to apply and so without further ado, I think we'll turn it over and get the debate started. Let's rock. All right. How do we do this? Okay. Okay. So what I'm going to talk about is the European PH guidelines cannot be applied to US populations. Sorry, Lana, but I'm going to prove to you that you're full of it. And actually, even before I prove, he's full of it. Okay. So this is me. Those are my disclosures. Okay. So we're going to talk about the objectives, the hemodynamic criteria, which have already been talked about, and whether they actually are relevant not only worldwide, but in the US. And then what do you do with the information? Okay. This has sort of been looked at, but what we're really interested in are the first two lines of the guidelines, the PH and pre-capillary PH. Okay. Now, how does this pertain to what we're going to talk about? Well, if we have a case here of a 40-year-old woman with a history of hypertension, hyperlipidemia, diabetes, and obesity, who has a BMI of 34, who's short of breath with most activities, gets referred because she has the usual things on an echo, right, a mean, a guess at an RVSP or a PASP of 43, and mild RVE. So she gets cath, okay, outside somewhere, and those are her numbers. Her mean PA is 24. Her wedge is 13. She did not get volume loaded during her cath. She had been diuresed and NPO'd the whole bit, and her cardiac output is 5.3, so it gives her a PVR of 2.1. Okay. So what's she got? Okay. Does she have PH? Does she have PAH? Okay. So first, does she have PH? Yeah. By the new guidelines, yeah. Does she have PAH? By the new guidelines, she does. Okay. And we're all going to jump in there and treat this woman, my ass. Okay. Even you wouldn't treat this. Oh, you might. Okay. So the real question is, are these changes that they have proposed, are the criteria valid? Okay. And of course, you get me up here as the biggest cynic in the world, and I'm going to show to you why some are and some may not be valid. So the change in the value of the mean PA is likely valid. Okay. The studies that you can find, granted there are not a lot, that the mean PA in an average person is 14, but it's measured directly. It's an important point. The change in PVR is less valid and may not be valid at all because it's a derived metric. It is not measured directly. Okay. And what does it take to derive it? Okay. So the PVR depends on the value of the wedge, okay, which also is measured directly. Better by some than others, but still measured directly. So I mean, we're all aware of the formula there. The key number is the wedge because your PVR basically changes or not depending on what your wedge is. Okay. So what is a normal wedge? It's fascinating to me that in all those criteria, this was never discussed. Okay. Which to me, you sort of go, wait a minute, guys. Okay. So according to the National Library of Medicine, a normal wedge is somewhere between 4 and 12. Yeah. Okay. 15. No, 4 and 12. And even in the paper where they change or propose to change the criteria, they cite a normal wedge of 8.6. Yeah. How does 15 show up? So interestingly, what is considered by us as a normal wedge has crept up over the years. It used to be 8. Anybody here old enough to remember when it was 8? It was. Then it was 10. Then it was 12. Now it's 15. And now there are even proposals to raise it to 18. And I'm going to explain to you why, actually. So then if all this is true, why do we use 15 as a normal wedge? And why was there no proposal to change it? Okay. We moved everything else down based on normals. Why did we leave a wedge at 15? Ask the Europeans. Ask Mark. Which I have asked multiple times. But anyway, they never discussed it. All right. So the case of the increasing wedge. All right. So if you do this, the math, in order to have a PVR of greater than 2 with a marginal increase in mean pulmonary artery pressure, you have to have, by definition, a low cardiac output. You have to have a cardiac output that is not normal. Okay. So already you look at the people who have something wrong with them, but it may not be their PH or their PAH. Okay. And as was pointed out, most of these people are either from group 2 or group 3 or some combination. And it's funny because if you go back and you, which just data that I pulled out, if you look at PV domics, okay, in the PAH group, if you go back and you apply this criteria, there's less than a handful. Okay. And if you look through a bunch of registries, it's about 1 in 1,000 that would actually really look like they have PH. And it was pointed out that most of them actually do have connective tissue disease. Okay. So, but even without, if you have no cardiopulmonary disease at all, your wedge increases over time because of left heart disease, diastolic dysfunction. Okay. And in all of this stuff, nobody takes into account that the fact that the numbers change over time. We glump all these people together no matter how old they are, whether you're 30 or 90, the same numbers apply. My ass again. We're going to run out of my ass, but that's okay. So, I think this was brought up. The drug companies that are doing the clinical trials are so scared of this, basically, that a lot of the trials now you have to have a wedge of 12 or less, and you have to have a PBR of somewhere around four or five woods units to avoid getting these patients with left heart disease. Okay. Who, if you treat, are likely to end up with left heart disease and get better miraculously when you take them off their meds. So, what factors increase your wedge pressure, aside from age? And this is where we're going to get the Europeans and the U.S. separate. Obesity, hypertension, hyperlipidemia, diabetes. We don't have any of that in the U.S. compared to the rest of the world, right? So, how do we really stack up against the Europeans? So, first off, just to show you that if you're just overweight, if you're fat, okay, and you have epicardial fat, you can see that it actually changes your hemodynamics. Your right atrial pressure is higher. Your wedge pressure is higher automatically, whether you have anything or not. And your mean PA goes up because your wedge goes up. But the key one is the one in the middle. Your wedge goes up just because you have an elevated BMI. Okay. All right? And this is a map of the world and obesity. And the worst, or the most obese, are those dark sort of violet ones. And you'll notice that there's really only one major place where that lights up. Okay? I was surprised about Alaska. No, actually I wasn't. But Europe, you can see they're much less obese than we are. So, automatically, they probably have a different wedge pressure than we do. Okay? So, automatically, now you're starting to think, well, if they have a different wedge pressure than their PVR that matters, it's going to be different. Okay? And that's just to show, I'll give you a second one. This one, we're blue. But we're the darkest blue. It is amazing how very few places are the darkest colors except us. Okay? And I can show you the same thing for hypertension. The red there is, or sort of the reddish orange, are the people who have most hypertension in the world. Not surprisingly, we're up there. USA. USA. Okay? We're good at something. Anyway, and I can show you, I can show you the same sort of graphs for both diabetes and hyperlipidemia, but it gets, there's no point in doing it. So, if you believe all this stuff, then you're basing a PVR on a wedge pressure that's automatically different, that you have not taken into account at all. Okay? So, back to the case. What do I do with this person? Move her to Europe? Leave her here? Okay? So, the trials that have investigated the response of these patients to PH meds are zero. Zero. Okay? So, I would argue that, you know, it's hard to treat people when you have no data. Okay? And the likelihood of large future trials examining these patients is also zero. You will get small, probably connective tissue studies that may or may not show a benefit, but you're never going to get a large PAH trial again that's going to do this. It makes no sense either financially or whatever. It's never going to happen. Okay? So, the bottom line there is, even the guidelines don't recommend that you treat these people, so they wouldn't treat this lady. And it basically says, the cutoff values better reflect the limits of normal range, but I would argue I'm not so sure about the PVR because nobody took into account the wedge pressure. And, but they don't translate into new therapeutic recommendations since the efficacy of PH therapy in these patients is unknown. Okay. That's true. But then, as Lana sort of alluded to, you're stuck because Mrs. whoever this case was waltzes into your office, okay, and she's symptomatic. And she's been referred to you because you're going to save her whatever. Bacon, basically, which you probably had too much of in the first place. But, okay, so you're going to, you're stuck because you want to treat her. You want to make her feel better. And yet the likelihood is you're going to make her not. You're going to actually harm her. So, do we treat this person? Unfortunately, they are getting treated. Even, we can argue here all we want, but they're getting treated. Okay? And they will be treated in the future. And we'll have no idea. We'll have no data at all about whether they're actually doing better or not, whatever. So, until you have data, I mean, you know, I think Lana alluded to the fact that we believe everybody in this room believes in science. So, ugh, let's believe in science, actually, and figure out what the right PVR actually is. I mean, it really did surprise me when I was making this up that nobody ever looked at the wedge pressure, which totally controls your PVR. And I'm out. Wait, wait, hold on. It broke. It broke the pointer. Wow. It's tough, tough arguments that come back from my ass. That's, yeah, it's a, I don't know what the rebuttal to that is. I didn't have a mic. You were strong. You were strong. Huh? Thank you. Huh? You were powerful. It worked. All right. So, got it. So, first, I want to say that I think one point for me, but really one point for the field of pulmonary hypertension is the victory that we're all witnessing of Dr. Farber actually donning a jacket for any reason. Well, I thought you had a jacket, so I had to wear one. But wait, but wait, as long as we're talking jackets, that jacket and that shirt, even I know that sucks. Even I wouldn't wear that. Okay. And it begins. All right. So, first, thanks a lot for inviting us. But, Chris, why did you pick a negative? It really took us like six or seven. It took us that day to figure out what we were arguing about. And I was still saying there's a 50-50% chance that Hap's doing the other side. And me too. We really, really had to think about this, that what is a con of European guidelines cannot be applied. So, full disclosure, I grew up in France, so I'm apparently taking the European side. Okay. This is me. Why are Europeans so good examining the reasons for our similarities? They are people, so are we. And why should we follow their recommendations at the end of the day? Some disclosures, although I'm going to lose a lot of these coming up. I'm sorry. Sadly. Live in abject poverty. So, one of the advantages Europeans have, and let's accept this, the government subsidized everything. We had reveal and we milked it, present company included, so much. And it gave us so much data. But, unfortunately, the likelihood of it happening again is very low. And yet the Europeans, every government subsidizes, pushes patients to the center, and they have this wealth of data. So, unfortunately, they have something over us. And this could be one of the reasons why we may have to listen to them. Silence. Speaking of activity. So, we should use their guidelines because we have the same level of activity. Not really. But this is where we have to think about different areas in the United States. I know that Lana put all different bits of United States. First of all, have you noticed that our country, when they say where are you from, they say France. When they say where are you from, people say United States. What is that? That's not even a name. That just means we're a bunch of states together. We make sure everybody knows, and I know some of you have that feeling about Florida right now, that everybody knows that we are not the same and every state is different. So, there are some states that are very close to European in their lifestyle. If you go to Portland and, you know, Portlandia and other places, you know, people behave differently. Like, they may be very close to Swedish people. And in Alabama, we may be very close to, well, not Swedish people. Speaking of. So, we said we're skinnier. But, hey, you know, our original, I guess it's really bad. Today is a day to recognize indigenous people. But if you look at Britain that, you know, apparently we had to secede from, they ain't skinny. That's where the English breakfast comes from. As opposed to the continental one, which is cheaper and cleaner and doesn't involve fat and eggs and sausage and blinks and all of that. And so, you have, you know, the purple states that are obese. So, you know, some states you can follow European guidelines. So, I know he called us fat, but, you know, and we are. And, you know, my BMI is 30. And every time we go on a meeting, it goes above 30. And then I go home, exercise, it goes below 30. And, you know, my Vigobi prescription is not getting filled because Cleveland Clinic doesn't want to pay it. And so, I'm stuck. So, basically, the idea that Europeans are too skinny to tell us what to do doesn't work. Because they have multiple states. We have multiple states. And we could basically use their guidelines. They have the same life expectancy. Yeah, that's not even true. But it's a small percentage. So, once you are 77 and you die, you wished you were European and you lived an extra three years. But it's only 3.75%. What's that amongst friends? So, same life expectancy, let's say. And they have the same healthcare system. Yeah, no. You know, the only civilized country that doesn't have universal healthcare is us. Saudi Arabia has universal healthcare. I'm just saying. All right. So, maybe that wasn't a good reason. You know, we should listen to them because they achieve better outcomes, better life expectancy, spending half as much. So, we should really follow their lead. Look at how much we're spending. Twice as much. By the way, 45% of American healthcare goes to intermediaries and is not spent neither on pharma nor on doctors. That 45% is the difference between the two and represents insurance companies and big health. Which, by the way, I don't know if you guys know, but Affordable Care Act forced them to cap their profits at 20%. Which means that all the healthcare companies are now interested in buying up stuff. So, if you have any healthcare idea, they're going to fund it. So, get out there and do some stuff. Do they have a better initial risk stratification? I don't think so. Actually, I'm with the Ray Group. The reveal used a much more rigorous statistical analysis to come up with its. So, they started with statistics and came up with those dimensions. As opposed to, you know, Marius, Mark, and others getting together and writing things that make sense and then backwards provide the fact that it actually separates. So, maybe we have better initial risk stratifier, but they have a better subsequent one, or at least we don't have anything to offer right now. We did a, actually some of the people in this group did a Delphi with us, and we actually came up with the idea of low-intermediate and high-intermediate naturally, because we said, well, if you are not in low-risk, but you're in intermediate risk, and you're in heart failure, you're kind of like a high-risk patient and you should go on prostacyclines. But if you're in the lower, you have some options like oral and maybe using replace data. So, yeah, but maybe they have a better follow-up model. This idea of dividing people in low-risk, intermediate risk, and low-intermediate, high-intermediate is a good one. And they have the same medications, well, sort of, right? I mean, they don't have IV, Ilopros, what's that? Does that even work? It apparently does. Don't we believe in Flolan, but apparently not quite, and they still haven't managed to get the inhaled troprosinol going, and they don't have oral troprosinol. So, you know, are we really good to follow their guidelines? But, again, this is where you have to think about guidelines. And there was a time when we had leeches, and, you know, we didn't tell patients that they were dying of cancer. And then we started really organizing ourselves and really taking everything seriously, and we started following evidence. But we practice medicine. We don't, we're not oppressed by evidence. We use it. And I suggest that the European guidelines are good enough for smart people to use. They don't have to be exactly right. When I follow a recipe, I don't do exact numbers. If I like mushrooms, I add a little bit more mushrooms. And I, you know, and, you know, I do the same thing when I treat patients, for better or for worse, with mushrooms. Okay, we've been too busy writing guidelines. We're doing the trials, or we're doing consulting, or we're speaking. So there's nobody left without conflict of interest to do anything. Yours truly included. Maybe. But these guys have been, you know, like, when was the last time? The chest? That was a long time ago. And then it got updated. Updated after 14 years? How about doing it again, guys? Let's do it again. Let's, where is the U.S. team? And actually, if you don't use European guidelines, are you going to use the World Symposium? Are we, you know, then we're represented, but like we're one-tenth of it, of the world? Maybe a little bit more. So we really should sort of up our game and start actually writing guidelines. So if you say, well, the European guidelines do not match our expectations of everything, then what do you have? At the end of the day, underneath it all, we're the same humans at the end. Like I said, some fat people, some skinny people, some exercise, some don't. But United States is diverse enough that we can fit Europe in the U.S. somewhere in there. And as the Bard said, if you prick us, do we not bleed? If you tickle us, do we not laugh? If you poison us, do we not die? And if you wrong us, shall we not revenge? And, you know, if your PVR is kind of lowish, shouldn't you treat us? So at the end of the day, we better listen to them. Not necessarily, and I agree with Hap that everything they said is right, but yeah, I do actually. The access, they have access to more and better data, sadly. They have a cohesive approach because everybody gets funneled to their centers, which I'm extremely envious of. They have more or less the same meds in generality. So when they say use IV prostacycline, we understand what that means. The more fundamental and important aspects of guidelines are probably above regional sensitivities. You can say it, but it's like polishing a cannonball. At the end of the day, they sort of do the same thing. They have a simpler, maybe not better risk calculator, but at least it's simpler. And they keep updating their guidelines. And believe it or not, I kind of read that guideline. It has really good English. You know, for a bunch of French and German people to get together, that's pretty good. And Hap, you know, I don't know if you know, but Dr. Farber had an accident. He's very athletic. I know you guys know this. He's always out there skiing, you know. He goes to the south, goes against the gravity to find where's the best biking, skiing, whatever. And unfortunately, he actually had an accident with a deer. I don't know if you know this. And he's recovered quite well. But we have discovered that this was no accident. And it was a result of Dr. Farber's apparent opposition to the importation of the European guidelines. Yeah, don't mess with the Europeans. Okay, that's it. Thank you, guys. Thank you.

pro-con debate

European diagnostic criteria

pulmonary hypertension

PVR threshold

scientifically accurate definition

at-risk patients

pulmonary vasodilators

sufficient evidence

harm

PH