CHARLES BURGER: So in terms of disclosures, we've participated over the years in multiple industry-sponsored, multi-center interventional trials for drugs-- primarily for pulmonary arterial hypertension. And as such, the various pharmaceutical companies that make the agents have sponsored the trials. I haven't received any direct monies from these folks for that research. And I won't be discussing anything off-label.
The objectives this morning are to get a better sense for the various diagnostic groups. It's always a little confusing with PH because there's functional class, which is a symptom categorization of severity of the symptoms. And then there's a functional diagnostic classification that originally was designed by the World Health Organization and has been taken over by the Pulmonary Hypertension Community to be used to help pigeonhole patients into a proper designation so that treatment decisions can be made.
And that's really their diagnostic group even though it's entitled a classification. So sometimes, that gets confusing for folks. We'll talk a little bit about that. The World Symposium on Pulmonary Hypertension generally meets every three to five years. Last met in 2018, February. And so there were some updates out of that that we'll bring to your attention. I'd like you to focus on the guideline-based recommendations, understanding that individual decisions have to be made for each patient.
But to get you to be as accurate and as timely in your diagnosis as possible, a little bit of a sense of how to choose the best initial therapy. And then talk a little bit about diagnostic group for, which is chronic thromboembolic disease pulmonary hypertension. So when you talk about pulmonary hypertension, it's really a condition where the pressures and the pulmonary circulation are high.
Multiple cause of pulmonary hypertension-- per se-- isn't a diagnosis any more than tachycardia is a diagnosis. You want to know the underlying reasons for the pulmonary hypertension in order to understand and develop a true diagnostic classification so that you can make the right decision for treatment recommendations for the patient. So on the front end, we always think about those things that tighten up the blood vessels and increase resistance to flow.
Therefore, upstream, the right heart has to generate higher pressure. So, reversible vasoconstriction can occur, obstruction with CTE-- for example-- the vessels can be obliterated with scarring. So there are a variety of ways that the vessel caliber can decrease. And that's really where one pulmonary hypertension falls.
On the downstream side of the equation with which you're most familiar, anything that would elevate pulmonary venous pressure from pulmonary veno-occlusive disease, all the way to issues with the left heart can, of course, ultimately increase the pressure that right heart has to generate to overcome that downstream pressure. And one that many people forget about is that if you distend the pulmonary circulation with more cardiac output, the pressures will increase.
So with exercise, if you take your cardiac output from 5 to 15, you distended the pulmonary circulation. And although it has an amazing capacity to accept that, the overall mean pulmonary arterial pressure will increase. So high-flow states that are pathologic, large, arterial, venous, connections, fistulas, malformations-- particularly in our chronic renal disease patients, liver disease that has high cardiac output state can all increase the mean pulmonary arterial pressures with the pulmonary circulation being absolutely normal.
So that's important to bear in mind. What's going on behind the scenes? Well, we know that there can be some genetic predisposition. The one that I will allude to momentarily that's widest known is biomorphic genetic protein receptor 2, which is a disruption and transform and growth factor pathway. Many of the pulmonary vascular changes that occur really mimic what you would see with benign neoplasia.
The cells grow out of control. They don't respond to normal cellular signaling mechanisms. They have abnormal life cycles. And they produce a total disarray in the microcirculation of the pulmonary vasculature. Metabolic derangements can contribute to this. There's a lot of interest in the endotype and phenotype of metabolic syndrome and its impact on the primary circulation. And then some growth or inflammatory injury.
So this is just one of the many pathologic, pathobiologic pathways that you can call from the literature. A lot of these slides look overwhelming. And really, a lot of overlap with a lot of other conditions. But I would just call your attention to a couple of things. So that bone morphogenetic protein receptor 2 mutation, as I said, is the one that really fits with heritable pulmonary arterial hypertension-- for the most part.
And when you get disruption there, ultimately, you end up with hyperproliferation of the pulmonary artery endothelium, vascular smooth muscle, hypertrophy, and avascular wall. All of which narrow the pulmonary vascular lumen and increased pulmonary vascular resistance. We know that there can be various things externally that can trigger this disruption from high-flow states with cardiac shunts, to drug and toxins-- fen-phen being at the top of the list.
And these can increase a lot of abnormalities in signaling this. Bromodomain. Extra-terminal motif has been one that's received a lot of attention. BRD4 which is seen in other cardiovascular disease, so you may have some familiarity with it. But certainly can lead to all three of these things at the bottom of the slide, which can ultimately lead to vascular occlusion fibrosis.
And then a big one on our list, which we'll talk about is systemic sclerosis, which has about a 12% chance of ultimately evolving into group one for arterial hypertension. At a physiologic level, as the pulmonary vessels begin to move from normal state into this vascular smooth muscle hypertrophy and pulmonary endothelium-- a disruption that PVR obviously continues to rise as the vascular limit narrows.
Upstream pressure has to increase to parallel that and overcome this higher resistance. Cardiac output is able to keep up with this initially with right ventricular hypertrophy. But over time, you get dilatation, of course, to the right heart and you begin to get systolic cytokinesis as the pulmonary vasculopathy. Gets more and more severe. And ultimately, if you die of pulmonary arterial hypertension, you die because the right heart fails.
And I would just show you that at the end stage, these pulmonary pressures may fall off. So you could be reading an echo where pulmonary arterial pressure appear to improve. Yet, the condition has worsened because contractility has really dropped off of the starling curve. And PVR is still sky high. Right ventricular afterload is still sky high. And you're basically at right heart failure. So cardiac output goes down to a critical level.
What are the symptom presentations? If you look at about 3,000 patients in the REVEAL Registry-- which is 54 US-based pulmonary hypertension centers-- fairly non-specific, most have dyspnea. Particularly with exertion. You certainly can have fatigue and chest pain in about a quarter of patients. The one that probably signals pulmonary hypertension as a potential cause of the dyspnea-- particularly in a young woman-- as up to 4/5 of these patients are female-- is exertional syncope or exertional near syncope.
Asthma tends to be a misdiagnosis in this group of patients. But if this is occurring, it's not asthma. And certainly, this would indicate significant right ventricular afterload. So that with exercise, the right heart pressures increase. They displace the septum into the left side of the heart, decreasing left heart filling. And therefore, decreasing perfusion to the cortex. And therefore, near syncope or syncope. So this really equates to a functional class four symptomatology.
So the functional class, which is, again, different than the diagnostic grouping is very similar to what I use every day with New York Heart Association Functional Class. The only thing that's really somewhat a modification is the addition of exertional syncope to functional class four. Telling you that the right heart is in significant duress and that aggressive treatments are warranted.
Most patients fall within the group three, which tends to be a rather broad category. And we even subdivided into group 3A and 3B to sort of help us in the clinic. 3A being that they can handle most activities of daily limiting, but with heavy exertion, they certainly had the symptoms. Whereas 3B, they can't do much of anything, including ADLs. But they're not symptomatic at rest.
So this is the breakdown in the REVEAL Registry. As I said, most patients fall into group three, followed by functional class two. And folks who present with right heart failure, fortunately, is the least common presentation. Subgroups of group one, pulmonary arterial hypertension, as modified recently by the 6th World Symposium on Pulmonary Hypertension are as in this slide.
Group 1.1, which is idiopathic, no secondary cause. Heritable would primarily be BMPR2. Certainly, drug and toxin. And the one that's on the rise in the US is exposure to methamphetamine. Group 1.4 has various subgroups. Connective tissue disease, HIV, portal hypertension, et cetera. But those are the three that we see the most of with an increasing population of congenital heart disease due to a growing practice, Dr. Phillips.
Changes that have been made is there was in addition to separate out pulmonary arterial hypertension that has both an acute and a long-term response to calcium channel blockers. This is a small percentage of patients, but it is important to call them out because they have an excellent prognosis and don't need the newer, more expensive agents that have been developed over the last 15 years. And then a combination in 1.6, pulmonary arterial hypertension that occurs because the pulmonary being inside of the equation is obstructed either with PVOD or pulmonary capillary hemangiomatosis.
If you look at REVEAL and the breakdown, about 45% or so are idiopathic with another 50% in that associated category. And of that associated category, half of those are connective tissue disease. And if you took a pie graph of this side, 3/4 would be scleroderma. If you compare that to what we see here in Florida, looking at a group of over 400, pretty similar breakdown with a big percentage of idiopathic.
And of the associated condition, scleroderma in liver disease because we're a big transplant center certainly have that starkly our two big subgroups associated pulmonary arterial hypertension. And then we see a fair amount of chronic thromboembolic disease-- PH. So just a question to kind of wake you up with your coffee. Which of the following have been validated in screening for group 1 pulmonary arterial hypertension associated conditions? HIV serology, ANA, overnight oximetry, or ACE level.
Five seconds to think about it. And we actually looked at it with one of our current hospitals actually, Dr. Pagan. And a positive ANA is one of all of those that's really been validated. You'll see many of those listed on the guidelines with a good area under the curve as an excellent screening test for connective tissue disease. If you make the diagnosis of potential hypertension first and then you're looking for secondary causes in ANA, certainly should be done.
We looked at HIV in over 400 patients, only one of which was positive. We knew she was positive, she just didn't bring the test with her so we repeated it. So in certain populations, you really just need to quest for exposures. If you work in an urban setting, that might be a little different. But HIV has not been validated as a screening test, even though it appears on the guidelines just as if you were wondering about that choice as a distractor on the question.
How about the other way-- patients in a busy rheumatology practice-- should they be screened for pulmonary hypertension? Certainly if a patient's dyspneic, you want to work that out. It's clear there were predisposes not only pulmonary arterial hypertension, but interstitial lung disease. There have been a variety of screening algorithms that have been designed and tested worldwide, actually. One of which is DETECT, which was spearheaded out of Ann Arbor, looking at a couple of steps.
So patients with scleroderma often had telangiectasias. But if they tell you that they're increasing or increasing in size-- number or size-- that's worrisome that there's an accelerated pulmonary vascular process ongoing is one clinical clue for you to take home from today. Certainly, that anti-centromere antibody with what appears to be limited scleroderma crest syndrome. And then you see other diagnostics that point this way. Right axis deviation on ECG.
If you've done pulmonary function tests to screen for ILD and the DLCO is quite low, but the lung volumes are well-preserved, that makes you think a little bit more about pulmonary vascular disease. And then certainly, if there's of stress on the right heart as indicated by an elevated brain natriuretic peptide, then you would move to echocardiography. And if that's abnormal, rate heart catheterization. And if you compare a lot of these various screening algorithms that have been tested worldwide, they are all quite sensitive.
No matter which one, I emphasize DETECT today in the lecture. But there's others if you're inquisitive in this area that you could look at. So good sensitivity. Obviously not to greatest specificity, but this is how you want to proceed with screening. Ultimately, if the echocardiography suggests PH, then absolutely right heart catheterization is paramount and critical to not only confirm the diagnosis, but look for other causes that can only be measured by heart catheterization-- such as left-to-right shunting with an oxygen saturation run as an example.
So, full complement in hemodynamics are required, as well as that saturation run. And then testing with acute basal dilators which is typically inhaled nitric oxide in our practice. If you look at echocardiography and its role, we developed a methodology by which you can measure mean pulmonary arterial pressure on echo years ago and published it.
It's been incorporated into Mayo's Standard Pulmonary Hypertension Echocardiography Report across the enterprise, showing good bland [INAUDIBLE] correlation with the mean by echo compared to the mean by right heart cath. 117 consecutive patients with the stent simultaneously. So excellent performance. And it outperformed right ventricular systolic pressure. It's important for two reasons. One is it's better. And two, it's mean pulmonary pressure that defines pulmonary hypertension. Not pulmonary artery systolic pressure.
With an excellent area under the curve using our methodology. So you should just be aware that we developed that on this site. Then more recent work with our cardiology division looking at ways to use the echo to determine if you need to move to right heart cath if all indications are that this is left heart disease. And obviously, the clinical setting in which this is most common is heart failure with preserved ejection fraction.
So with a lot of work with a validation cohort of well over 300 patients looked at a transpulmonary ratio using our methodology for the mean pulmonary arterial pressure and then dividing into that, that e to e prime ratio from the medial mitral valve inflow velocity to get a ratio that would suggest that this is left heart disease versus pulmonary arterial hypertension with pulmonary vascular obstruction.
So a ratio of 2.7 really fit more with this being left heart disease versus a ratio for higher pulmonary vascular disease. And if you looked at the performance just of that ratio of the area under the curve was about 0.7. If you added in a couple other echocardiography measures-- such as ejection fraction and stroke volume-- as well as whether or not the patient has systemic hypertension, then this area under the curve gets up to 0.8 range.
And that played out in a validation sample as well. So hopefully, this looks like it's well on its way to being published in print. And once that happens, we can have more widespread use of it. As you know, the focus oftentimes on the echo is what is the pressure? And that's based on what you see with the tricuspid regurgitant jet velocity. But there's so many more clues.
I sort of kid the pulmonary fellows. Look at page two, three, four, five of that echo report because you really want to look at what's going on with multiple other measures that are available to you. Not the least of which are measures of right ventricular systolic contractility, such as FAC, [INAUDIBLE], lateral velocity of the mitral valve, the Tei index or the RIMP, or the right ventricle strain. So all of those are useful.
But if you're not as familiar with those, certainly looking to see if there are other signs that this might be pulmonary hypertension, such as what's going on with the right ventricle-- is it dilated? Is the septum shifted over toward the left, which really tells you there's quite a bit of pressure overload on the right side. And you can look at some of these other more technical terms. Obviously, the cardiology and cardiac transplant fellows would be doing that. You might not be doing as much of this as a critical care fellow.
But all of you would be looking at right atrial pressure, as estimated by what goes on with the inferior vena cava. Both in terms of baseline size and its response during negative intrathoracic pressure inspiration to help estimate RAP. And I'll show you that is a very powerful prognostic measure parameter if it's elevated.
Ultimately, you go to right heart catheterization. Now historically, mean pulmonary pressure 25 or higher had been used for the definition. This has changed. I'll show you the reasoning behind that by the World Symposium on Pulmonary Hypertension. But it's now 21 or higher, so they introduced what we had been calling borderline elevation and pulmonary arterial pressures.
But very importantly, for purposes of pulmonary arterial hypertension, you must have elevated pulmonary vascular resistance. So if it's downstream, you're not likely to have that. If it's just a high flow state, this is going to be normal. So you can't just do it off of the pressure. You have to have the full complement of hemodynamics to get the pulmonary vascular resistance. I see this all the time on outside right heart catheterizations where no cardiac output is measured and we don't have this value.
So it becomes worthless and we have to repeat it for the patients, which is a shame for them. So the old definition from 2013 was that mean day pressure, 25 or higher. Again, requiring that high pulmonary vascular resistance. And a newer definition brings it down to greater than 20. So 21 or higher. But still requiring high TVR.
So what are the pros and cons behind this? Perhaps, we're able to pick up pulmonary arterial hypertension a little earlier. And of course, particularly, in high risk groups such as scleroderma. But there's also more potential. If you lower that threshold for putting folks in a category of having a potentially deadly disease when they don't quite meet the historical definition where we understand the course more completely, there's going to be overtreatment.
I think HFpEF patients who will have pressures in this range but just have diastolic left ventricular dysfunction and the increase left heart filling pressures. And then there's no recommendation with lowering that diagnostic threshold pressure between 21 to 24 per treatment recommendation. So they really left it quite open-ended. And there was a lot of debate over this and some dissension expressed certainly at the conference to say, well, why would you lower the diagnostic threshold and not change the treatment recommendation?
It was purely to help follow some of these patients more closely. So it's a debatable move, but it has happened. So what are those changes? I just want to summarize. New pressure level to define pre-capillary PH to try to simplify the core clinical classification. I called out having a separate designation for those that are acutely and long-term responsive to calcium channel blockers.
Here. And also the PVOD and PCH category. And then most importantly, that pressure threshold, but still requiring a high pulmonary resistance. Key diagnostic tools. Once you get to the point where you're honing in on pulmonary hypertension is to make sure it's not due to lung disease. Really important to screen for CTPH. I'll talk about that.
And heart catheterization we talked about. Numerous other biomarkers are being studied. But the one that we rely the most on at this point is the NP. Although there's a fair amount of evidence with D. Dimer and others that they do have predictive roles in prognostication.
So the diagnostic algorithm from the 6th World Symposium is if you're headed this way and you've screened and you have a high probability for PH, then you really want to get a VQ scan early in the course of events. VQ has fallen by the wayside for acute PE. That's diagnosed by CT with contrast PE protocol. But for chronic CTE, really VQ outperforms more conventional CT angiography.
Although advancements are being made and that may not always be the case, you do need a VQ to screen for CTPH. And if it's abnormal, the recommendation is that you would refer to a PH center because CTPH has a different treatment algorithm.
I emphasize this, VQ not CTA for screening. The reason you refer to a center is that, if the patients are eligible for a pulmonary thromboendarterectomy, it's curative. So the acute clot has been replaced by a fibrotic obstruction that adheres to the pulmonary artery intima. And this can be removed surgically. It's a very complex surgery performed at our center by Dr. Kevin Landolfo that can result in complete resolution of the pulmonary hypertension. Therefore if the patient is eligible you want to go that route.
We're looking more and more into balloon pulmonary angioplasty. Experience worldwide has grown over the last several years. Dr. Peter Pollack is heading up our practice with Dr. Charles Ricci in radiology. We have two patients that we've done so far, but several others that, in fact, we're going to talk about in our CTE selection meeting this Wednesday, along with a couple of patients that may be eligible for a PTE.
For those patients that aren't eligible for these interventions or have had them and have persistent PH riociguat, which is a soluble guanylate cyclase stimulator, has been approved, again, for inoperable disease not as a primary treatment. So you make the diagnosis. If they're vasoreactive, we talked about the potential to treat with calcium channel blockers. If they're not vasoreactive and they're on the lower side of risk by functional class BNP, RB performance, six minute walk distance, then you can begin with monotherapy with close follow up with low threshold to add a second drug, or there's significant evidence of starting two drugs up front. If they present right heart failure, then you need to proceed with more aggressive therapy. Generally infusion, epoprostenol, or treprostinil.
And at that point, you might think about odds of them responding and engage lung transplant early in the course of events if you think that may be problematic, or certainly if they don't respond to therapy. What are the pathways, i.e. the targets for the current FDA approved armamentarium pharmacologic intervention or group one, arterial hypertension? Prostacyclin pathway is the one in which we've had the longest experience.
These prostacyclin derivatives work through cyclic AMP and ultimately to counteract the proliferation that I talked about at the pulmonary micro circulatory level and produce some basil dilatation. Intravenous drugs, oral drugs, inhaled drugs, are all available in this pathway. More recently a IP receptor agonist has been developed, also an oral drug. In the endothelin pathway, the idea is working on blocking endothelin-1, which is the most potent endogenous vasoconstrictor produced by the human species.
And the available drugs are all oral, and they block the receptor A and B on pulmonary vascular smooth muscle and pulmonary artery endothelin. Again, leading to counteracting the vasoconstriction and the proliferation produced by endothelin, so blocking these actions. In the nitric oxide pathway, you can give inhaled nitric oxide. That's problematic to do as an outpatient, although there are some ways of doing that, novel ways that are being studied.
But historically, it's been blocking the breakdown of the nitric oxide with phosphodiesterase-5 inhibitors. So if block this enzyme, then whatever nitric oxide is in the system becomes more available to produce vasodilation and antiproliferation. More recently, the drug that I referred to earlier, riociguat, the soluble guanylate cyclase stimulator works for cyclic GMP to generate nitric oxide. So low may be effective when there's endogenous low levels of nitrous oxide, not just by blocking its metabolism.
So this is just a table sort of breaking it down by route of administration. All of the ERAs are oral that are listed here. The two phosphodiesterase-5 inhibitors, all of you are very familiar with them I'm sure, are both oral. Riociguat, again, oral. And then the newer prostacyclin receptor agonist, oral. The prostocyclin analogs are where it ranges from either oral option to inhale to fusion, with treprostinil giving you the option of either continuous intravenous infusion through an indwelling intravenous catheter, versus subcutaneously.
So another question, your probably eyes are glazing over by this point. I have to wake you up again. I can't see all of you with working off of the PowerPoint, but I'm sure you're all well dressed with your hair combed. 32-year-old woman with Raynaud's, telangiectasias, GERD, and symptoms consistent with New York Heart Association Functional Class III. BNP is elevated. Six minute walk for a 32-year-old is reduced 350 meters. And the [INAUDIBLE] dynamics by right heart catheterization including a right atrial pressure of 12, PA pressure 84 over 28 with a mean of 47, wedge pressure is 12, millimeter and mercury respectively. Cardiac output five liters per minute, calculated pulmonary vascular resistance seven Wood units. And then in response to inhaled nitric oxide, the mean pressure drops slightly to 40 with a cardiac output that increases to 6 liters per minute.
So what's the best treatment? Calcium blocker since the mean PA pressure dropped with inhaled NO endothelin receptor antagonists. Adding phosphodiesterase-5 inhibitor plus an endothelin receptor antagonist are going with that newer agent that I showed you, the oral IP receptor agonists selexipag. So I'll give you 10 seconds to think about that.
And really the evidence would support in a patient functional class III with a lot of the prognostic indicators, BNP, walk, right heart cath, indicating a fairly severe disease to start with initial upfront combination therapy with a PD-5 inhibitor and ERA. Ambition was a trial that showed that. Multicenter, placebo controlled, prospective, of course, randomized that studied tadalafil and ambrisentan up front versus each of those as monotherapy with significant clinical reduction and important events, such as worsening of the PH, hospitalization, need to go in to infusion therapy, need for transplant, and death, hazard ratio of 0.5, in yellow bottom right corner.
And over three years the event ratio is 68% in combination upfront therapy, versus in the pooled monotherapy, which was about 56%. If you look at this same sort of impact in other efficacy studies, not in upfront therapy, but in add on therapy-- I'll bring to your attention one study, SERAPHIN, where macitentan was studied at two different doses 10 in 3 milligrams versus placebo. Again, looking at the percentage of having these important clinical events, that macitentan-10 had the best curb with less of these clinical events, but it's important to note that 61% of these patients were on combination therapy, typically with a PD-5.
So this is really sequential therapy showing that two drugs are better than one drug, but it wasn't an upfront start study as was ambition. We looked at the impact of hospitalization, and I'll bring to your attention how I think that should be incorporated and how we follow these patients as well. Looking at that REVEAL population, newly diagnosed 960. There were some exclusions that didn't meet hemodynamic criteria. And we looked for hospitalizations among that 860 patients.
And 490 out of that 860, or 57%, had hospitalization within the first year, often multiple hospitalizations. And over one half were directly attributable to the PAH. And that had implications in terms of survival. So if you did have a hospitalization for PAH, your survival 57% versus 68% if you did not have a hospitalization per PAH. So it really should be rolled into how we think about our goals for treating pulmonary hypertension.
Certainly we want to reduce symptom burden. I think all the patients would agree they want to stay out of the hospital. We would certainly agree with that as well, I would hope. We want to do this with minimal treatment burden. That's not always possible, but that's part of the balancing of the equation. And of course, we want to improve survival and avoid transplant if at all possible.
So did any of these studies show an impact on hospitalization? And indeed, they did. That's what really sort of reinforced the work we had done with the REVEAL registry. In TIME, the first hospitalization hazard ratio is just under 0.4. And if you look at this with connective tissue disease related PAH, it had the same sort of impact. So that upfront dual therapy helped avoid hospitalizations as well.
That macitentan study that I showed you, the SERAPHIN trial, again, a dose related comparison to placebo reduction in hospitalization. So the drugs certainly work on this, and make it a reasonable goal of therapy. The 2015 European Society of Cardiology European Respiratory Society guidelines are listed here. In terms of the therapy as I showed you earlier, the 2016 World Symposium on PH differ a little bit from this, but in general, it's the same philosophically.
And that is if the patient is low risk, strong consideration for that initial oral combination therapy makes the most sense, and it's a higher risk moving to more aggressive therapy, typically infusion. Regardless, close follow up to see what the clinical response is is paramount. You can't just start these drugs and see the patient in a year. They need to see you back in a month or two after initial start and probably every three months thereafter.
And then you may need to add therapy. If you started with two drugs, you may need to add a third. Or if they're really failing, engage our transplant colleagues. One of the ways to monitor clinical response and prognosis in a more detailed way is REVEAL 2.0 published last year in Chest. We helped design and develop this with the REVEAL Investigator Group. It's available online. But it's basically points that would be added if your markers, such as functional class and BNP show worsening or high levels, then you start with a base of six, and as you get higher and higher, obviously with that numerical score, the risk of death at one year increases significantly.
So you really want to keep patients in six, seven, or lower because you can subtract points. So for example, if your functional class is one, you subtract one. Or if your BNP is less than 50, subtract should two. Keeping it at a six or seven, or lower is part of how we track our patients. Done a fair amount of work in conjunction with our cardiology department looking at ways of prognosticating, one of which is cardiac MR.
This is work by Jordan Ray and Bryan Shapiro that they were kind enough to include me on. That shows if you look at the pulmonary artery pulsatility-- somebody needs to mute their mic, please. Getting a lot of feedback. If you look at pulmonary artery pulsatility, which is change in pulmonary artery diameter with cardiac asystole, if that pulmonary artery is compliant and can receive the cardiac output without much in the way of diameter distention, then obviously that's what you want. You want a pulmonary circulation that's recruitable, whereas if this doesn't distend and the pulsatility is low, then that does correlate almost quasi sort of dose dependent or diagnostic parameter dependent way between mild and moderate to severe.
Chris Austin and Bryan Shapiro looked at a simplified echo score to help predict mortality, which looked with the driving parameter being right atrial pressure, but also including peak tricuspid with regards to jet velocity as an example with four or five parameters to each of which would gain a point. And if you had a very high right atrial pressure, or a very high TR jet velocity, you would get a couple points as an example. And it did break down quite nicely with the very simplified point score to show that you can help prognosticate with what you get out of the echocardiographic lab. So we use that extensively in our practice.
Let's switch gears just a little bit to where we are with clinical research. I'll focus on those things in which we're most active here at Mayo Clinic Florida. TRITON study looked at triple upfront therapy versus two drugs up front, looking at macitentan, tadalafil, and selexipag. So all three pathway targets, versus just macitanten and tadalafil, which are the two pathways that were shown in combination in the AMBITION study to impact clinical events. And both groups did remarkably well.
So two drugs in, three drugs, the patients did very well. And so well that there really was a difference between starting the third drug up front. So I think we start with two drugs, and we can add the third drug as needed would be the implications of that study. SOUTHPAW was looking at group 2 pulmonary venous hypertension with heart failure preserved ejection correction looking at oral treprostinil, otherwise known as orenitram. Very difficult study to enroll.
We got a couple of patients, but ultimately, the study was stopped due to limited enrollment. We had one patient who felt significantly better on it. I don't know. That's anecdotal. But it really was not able to get to a point where it could show benefit versus not. Certainly there's a lot of negative studies using these drugs in group 2, and I would caution you against empiric trials in these patients if you produce a lot of upstream vasodilatation and your problem is downstream, you will congest the pulmonary circulation, worsen symptoms, worsen fluid retention, and even in some cases put patients into flash pulmonary edema, which can be life threatening.
So that should not be something that's done on a routine basis without referral to a pulmonary hypertension center or enrollment in a clinical trial, in my opinion. INCREASE looked at group 3. So we know that group 2, pulmonary venous hypertension with heart failure, and group 3 with lung disease. Statistically and quantitatively the two largest groups of patients who have pulmonary hypertension and may far outnumber group 1 PAH. So we're continuing to explore ways of treating these patients.
So a recent trial that's been presented at American Thoracic Society not yet been published in print looked at inhaled treprostinil in patients with interstitial lung disease. We had three patients in the trial. Overall, there was improvement in six minute walk distance of 21 meters, which was statistically significant. You could argue back and forth about what that means clinically, but for these patients they certainly felt that improvement because they were so limited otherwise. So it may be that inhaled treprostinil will develop a role in treating PH associated with parenchymal lung disease and hypoxemia. We'll see how all that plays out.
And then REVEAL 2.0 I pointed out as being a very useful tool that's been now well validated and published and available for use in the clinical practice for following clinical response and prognosticating. PERFECT now builds on what we saw with the INCREASE trial, but it's focusing on COPD associated pulmonary hypertension. So same concept, an inhaled drug versus placebo to see if there's improvement in six minute walk and other parameters of PH. It got put on hold with COVID 19, and an Amendment to allow it to reopen that's going through the processes of review for approval.
SELECT is a trial that we do have open. Selexipag for inoperable chronic thromboembolic disease pulmonary hypertension, building on the idea that if riociguat showed benefit, perhaps selexipag will too. There was a trial with masitentan called MERIT that showed benefit. They're is not FDA approval for that drug, however. GB002 is an inhaled platelet derived growth factor inhibitor in the tyrosine kinase pathway that we're participating in a trial. We've had one patient go through, another they recently consented. And it's an early phase trial looking primarily at safety and tolerability with an opportunity to go into an open label extension.
But the reason I bring it up is we need other targeted pathways, and this would be a fourth pathway if we can show benefit. It would be very exciting. Then we continue to look at different ways of delivering the same drugs. Inhaled treprostinil requires a proprietary dispenser and nebulizer, which is fairly large. I mean, you can take it with you, but certainly wouldn't fit in your pocket, or whatever side bag you would carry around. And so powdered formulations have been studied by a company called Liquidia, which was recently purchased, and also by United Therapeutics. So we've been participating in those trials, and they look quite favorable.
And then Dr. Shapiro continues to actively recruit looking at the respiratory biome in patients with PAH. So in summary, I wanted to call your attention to the updates from the Sixth World Symposium on Pulmonary Hypertension, particularly the change in hemodynamic diagnostic criteria, lowering the threshold of [INAUDIBLE] or internal pressure to 21, but still emphasizing that you need elevated pulmonary vasoresistance in order to meet this criteria. There was a change in treatment in this 21 to 24 range, while the treatment diagnostic algorithms apply to 25 or higher.
Screening for CTEPH is done with VQ scan, and is recommended because there are interventions, particularly pulmonary thromboendarterectomy that can be curative, and a growing role for pulmonary balloon angioplasty. Up front therapy for functional class III I believe has been well demonstrated now to be the approach for these patients if at all possible, particularly with combining PD-5 and an ERA. And hospitalization, with its impact on general quality of life as well as mortality, now to me should be firmly embedded as a goal of therapy to reduce hospitalization that's transparently discussed with patients and incorporated in future studies.
And so for those of you who joined late, I suppose you can still get your CME if you text. I will stop there. And if there's any questions, I'll just put up some of the references that I used if you have any interest in jotting those down, or you can send me an email, and I can send those to you.
MODERATOR: Thank you very much. You're a great lecturer. Great update on many things that have been advanced in the past few years. So we'll open this for some questions from the audience.