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DOM Medical Grand Rounds: Contemporary Treatment of Pulmonary Thromboembolism: A Team Based Approach
Drs. Belinda Rivera-Lebron and Catalin Toma each present from the 2016 UPMC Department of Medicine Grand Rounds. Dr. Rivera-Lebron discusses Pulmonary Thromboembolism and the approach to treatment that involves multiple disciplines. Dr. Toma discusses acute PE and the emerging percutaneous options for chronic thromboembolic pulmonary hypertension.
Upon completion of this activity, participants should be able to:
- Recognize the differences between Submassive PE and other types of PE including the appropriate risk stratification work-up.
- Teach the appropriate medical options in treating Submassive PE
- Teach the various interventional options in treating Submassive PE
- Discuss the different clinical classifications of PE and the appropriate risk stratification workup.
- Review medical options available to treat submassive PE
- Recognize the various interventional options in treating submassive PE and chronic thromboembolic pulmonary hypertension.
- Kearon, et al. Antithrombotic Therapy for VTE Disease
- CHEST Guideline and Expert Panel Report. CHEST 2016; 149(2):315-352.
- Konstantinides et al. 2014 ESC Guidelines on the diagnosis and management of acute pulmonary embolism. European Heart Journal
- Kuchcr et al. Randomized Controlled Trial of Ultrasound-Assisted Catheter-Directed Thrombolysis for Acute Intermediate-Risk Pulmonary Embolism. Circulation 2014.
- Aujesky. AM J Respir Crit Care Med 2005.
- Jimenez. Arch Intern Med 2010.
- Zamorano. European Heart J 2014.
- Konstantinides. European Heart J 2014.
- Handoko. AM J Respir Crit Care Med 2014.
- Sharif M et al. AM J Cardiol 2013.
- Zhang Z et al. Thumb Res. 2013
- Armstrong PW et al. AM Heart J 201.
- Klok F. Blood Reviews 2014.
- Sanchez O. J Thromb Haemostatasis 2010.
- Jimenez, et al, Journal of Respiratory and Critical Care Medicine 189 March 15, 2014.
- Meyer et al, N Engl J Med 2014;370:1402-11.
Drs. Rivera-Lebron and Toma have reported no relevant relationships with proprietary entities producing health care goods or services.
All presenters disclosure of relevant financial relationships with any proprietary entity producing, marketing, re-selling, or distributing health care goods or services, used on, or consumed by, patients is listed above. No other planners, members of the planning committee, speakers, presenters, authors, content reviewers and/or anyone else in a position to control the content of this education activity have relevant financial relationships to disclose.
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The University of Pittsburgh School of Medicine designates this enduring material for a maximum of 1 AMA PRA Category 1 Credits™. Each physician should only claim credit commensurate with the extent of their participation in the activity. Other health care professionals are awarded (0.1) continuing education units (CEU) which are equivalent to 1 contact hour.
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We are very glad to be here to talk about PE and our approach that involves multiple disciplines in the treatment of not just acute PE but chronic PE as well. So as you know PE is a very serious problem, it's very common in the United States and just last year this is a quote from the CDC, there are close to a million cases of both PEs and DVTs. Out of that almost 250,000 of them get admitted to the hospital, and out of that maybe 100 to 200,000 of them die from a PE related cause. Out of those who survive 50% of them will have some kind of sequelae whether it is chronic pain from a DVT or chronic shortness of breath or any exercise limitation from a PE. And they could end up developing something called chronic thromboembolic pulmonary hypertension which is an elevated blood pressure in the pulmonary artery caused by chronic blood clots, so in up to about 4% of these patients.
VTE is still increasing, so it's still on the rise as you can see from this slide so in all sorts of flavors. So PE, DVT and the combined both entities in the same person are still on the rise. And ti is the third most common cardiovascular cause of death so it's important to talk about and especially recognize early. So it follows MI and stroke in the incidence of cardiovascular death.
So you know and I think that the PE has - it's natural history, it has a different spectrum, it has different ways of how to develop and progress. Most patients however have a complete resolution, so about 90% of them. They come to the hospital, they get treated and they get resolved. So that's a good majority of them and that's great; however there is about up to about 30% that could recur in the first - after 10 years, and this could be even on anticoagulation appropriately. So it's very important to know that the risk still on goes even as far as 10 years down as far as we know, and probably continues for life.
And some of them are going to go for partial recovery and then again some of them are going to go into developing CTEPH or the Chronic Thromboembolic Pulmonary Hypertension. As you can see here the difference between an acute clot and a chronic clot is very different. The acute clot is very frail, very loose and sort of easily ruptured as opposed to a chronic clot which is mostly a fibrotic tissue clot and is very rubbery and kind of like debilitating.
So the American classification for PE which is the most common one and the oldest one tells us that PEs are classified in three different levels: so a low risk; an intermediate or submassive, which is one of the common names; or high risk or massive. So low risk are people that have a normal blood pressure who have no RV strain or any dysfunction in the RV and have normal biomarkers. And by that I mean a troponin and an BNP. The submassives are people who are still are normotensive but then are now starting to show signs of RV strain and that could be either on a CT scan or an echocardiogram and then therefore it's started developing or could start developing biomarkers that are positive like the BNP and the troponin. The high risks or the massives are people who are now hemodynamically unstable and that's defined by a systolic blood pressure of less than 90 for over 50 minutes, who are in shock or requiring a vasopressor or have a cardiac arrest due to a PE.
Now the Europeans did an updated guideline in 2014 that this is more recent than the American one. And as you can see here it's a little bit more complex, so they not only just did the definitions but they also included in the definitions what kind of a risk assessment does each patient need to know which category or classification of PE are they going to have. And the other thing - but the other thing that you can see here is in the intermediate category they actually subdivided the intermediate category in high intermediate and low intermediate. And as you can see that is primarily the main difference here when you are classifying patients. And in the high intermediate you could see that both RV strain and cardio biomarkers are going to be affected as opposed to intermediate low which one of them is going to be affected. So the patient could halve either the RV dysfunction and/or the biomarkers that are going to be elevated.
And the reason why they did that is because it changes their mortality and I'll show you that in this slide. But first I'd like to know that luckily most of the patients have low risk so over 50% of them are going to have low risk. And the minority of the patients are going to have a high risk, so 5% of the patients are going to have a massive PE. However there is still a good amount of patients in that submassive or intermediate category and that could be up to 40%. So that is a very significant amount of patients that have a PE that are still going to have some kind of RV strain. And that is important to recognize because the mortality jumps are quite some from having a low risk which you have a excellent prognosis of less than 1% mortality to in an intermediate low category you have a 5% mortality and then once your two parameters are abnormal, meaning the RV strain and the biomarkers are positive this jumps from 5 to 15%. So that is not an insignificant jump here. And then as you know the mortality for massives or high risk is quite high.
So our integrated approach to know what exactly do we need to order in patients to know what category do they fall into involves the PESI score, which we'll go over in the next slide, but it's the PE score index imaging that includes cardiac imaging like echocardiogram and a CT scan and the biomarkers like I mentioned, the troponin and the BNP.
So this is PESI score, the PE Severity Index, and like many other calculators it comes in the original one which has a lot more involved and a little bit more complex, and then a simplified version. I like to use the simplified version because it actually is a lot quicker to do and you could memorize it. But if you don't have it memorized this is on your MedCalcs or you know and you could Google it and it will come very easily. So this will basically entail all the different parameters that we know that will put you at a higher risk of not doing well in the hospital, such as older age, having a presence of cancer or a cardiac or a pulmonary chronic comorbidity, having a heart rate of over 110, a blood pressure of less than 100 or oxygen saturation of being of less than 90%. And this includes someone who is over 90% but that requires oxygen supplementation. So the calculation is basically very simple. So you could either have a score of 0 or a score of 1 or more, okay. And if you have a score of 0 your 30 day mortality risk is very low, it's 1%, you do well basically you are a low risk patient. However if you have a point or more that already increases your 30 day mortality to about 10%.
So in the imaging section we have - we use echocardiogram very frequently and for the most part we use the RV to LV diameter ratio or presence of RV dysfunction. And here are the - how sensitive and specific it is. So you now it's probably highly sensitive but not as specific. But more importantly it does entail that if you have presence of RV to LV diameter ratio that is increased your mortality is increased and worse outcomes could happen. So for example you could have a high risk of going on a ventilator or requiring a vasopressor or actually decompensating to the point that you have a cardiac arrest.
For a CT scan same parameter in terms of RV to LV diameter as you can see here. The sensitivity is a little bit higher but the specificity is actually lower but it will tell us the same thing. Basically if you have it present then it increase your mortality risk. One point that I really like to make is that when the radiologist will cull the thrombus load into a massive amount that does not - it's not a synonym for a massive PE okay. So the fact that eh thrombus load could be larger, for example someone that could have a saddle PE, that does not mean that the patient is going to have necessarily RV strain and that does not mean that the patient has a massive PE. and that is a very important distinction because they also do use this radiologic term when they are reading the CT scans. For the last couple of years since the PE started and mostly after Dr. Tolmot spearheaded this now as part of our standard PE rule-outs all the CTAs will have a mention of presence of RV strains or absence of RV strain in every CT scan in the Presbyterian and Shadyside system.
These are the biomarkers, the troponin and BNP. And as you can see here I think where I find it helpful is on the negative predictive value as if it's not present then you can kind of safely sort of rule out that it's not there. And that's pretty much the extent of how I take it. But I think that this is a very important slide. So you could see here that if we just use the PESI score it will give you a 10% like we mentioned earlier, but when you keep adding parameters on top of that like the cardiac biomarkers and especially then if you also add presence of DVT in the same patient you could see that the 30 day complication rate can increase to almost 25%. So it actually is very helpful and it will pay off if you order them because then that way you will be correctly sort of risk stratifying the patient into the different categories of low, intermediate and high risk.
So I would say that this is, this is increasing by the minute. All the options that we have now are definitely a lot more than they were 10 years ago. And so we have just plain old anticoagulation, we have thrombolytics, so whether it is in systemic form or catheter directed form and sometimes we use ultrasound assisted echoes to that. Then there is the mechanical actual extraction of the clot, whether you can fragment it and aspirate it or also use some medications at the same time; or going to the OR for open embolectomy. And the reality is there are so many options it's sometimes hard to know which is the one that applies best for my patient. So that is why for the - we've created and sort of came together in this acute PE team or PERT team, so PE Response Team. And I think that this is how we are moving into a lot of the different diseases not just for PE but specifically what we really want is we just have the expertise to be able to improve patient care. And that's our main goal.
So what do we do if we facilitate multidisciplinary consultation and quickly we also provide follow-up for patients for acute PE to know what exactly happened to that RV strain, did that resolve? Does this person need to be screened for presence of CTEPH in the future? We meet regularly to discuss cases and our ongoing research. We have a registry to keep track of what we do internally so that we could not just publish it but you know probably contribute to what helps different patients. And we have ongoing clinical trials which Catalin will talk about, not just right now interventional but also we are going to hopefully do some medical trials too. And we are part of the consortium, so there is a National PERT Consortium of different hospitals that have a PE Team and a way to approach this disease. So you could see here that these are all the different players in our PE Team and so it goes from kind of like medical, then interventionalist and then surgery. We you know also take, have hematology definitely most important for the recurrence and the chronic follow-ups and then we have early involvement with the emergency room participating as well.
So prior to having a PE Team this is actually what happened. You had someone with a PE and you didn't really know who to call. So maybe the referring hospital directly called the surgery team or maybe they called medicine or they sent the patine to the ED and then from here you know, so it was very confusing and complicated on how to get to the right person that could help this patient. And now with our new model once yo diagnose or suspect a PE all you need to do is consult the PE Team and then we have a virtual meeting and this is either in person or by phone and then we involve all the people who are key players in making decisions. So that could just be maybe the pulmonary doctor with the interventionalist or it could also involve the surgery team and it will always involve the primary team. So whether that patient is in the ICU or on a floor we definitely would want your input so that you know your patient best. And then we quickly implement the plan, whether that is to start TPA right away or go to the OR or to the cath lab.
So how do you actually get to us is you can either contact us through the operator or through MedCall and just ask for the PE consult on call. Or you could go to MedTrack and then type in PE Team and as you can see here then you'll have the option of just clicking here and paging the person directly.
So this our algorithm and this is an ongoing and ever changing algorithm. And as more data comes on, more literature comes out then this is adjusted. And I think that just to quickly go over the algorithm here. So if you have a pressure of less than 90 then you are automatically going into the high risk or massive category and then what we do then is take into account what's the bleeding risk of the patient right. So if the patient has a low bleeding risk then we go with probably systemic thrombolysis. If the patient has a moderate bleeding risk it's a catheter directed approach for the most part. And if it's high then we could do either a actual thrombectomy which could be in an open surgical way or a mechanical and more interventional approach, or just leave the patient on anticoagulation alone. Another thing that we offer, not often, but when it's absolutely necessary is if you have someone who is in ongoing cardiac arrest then that person is not really going to survive when you push 50 mg of TPA during the arrest right, so this person needs to go on ECMO and stabilize the cardiovascular system so then you can then implement whatever final treatment the patient will require in any of the forms that we'll comment here.
Then this is going to the other side where you say the patient is hemodynamically stable, then we go into taking into account if there is a strain in the CT scan or echocardiogram and if the biomarkers are elevated. If none of them are elevated and there is no strain then we go into a low risk category and start anticoagulation. But if there are abnormal, any of them, then they are automatically in the intermediate or submassive category and then we go on into subdividing that again as per the European classification if they had both the biomarkers and the strain or if they just have one of each. So if they have both we go again into calculating what their bleeding risk is and then we can offer either catheter directed approach or anticoagulation or maybe a catheter intervention to take out the clot. And this is only a recommendation and it's only meant to be as a guideline, this is not an absolute and it doesn't mean that if you consult us we are going to be pushing for any intervention whatsoever. So what we want to have is just a mere strict algorithm so that we have an idea of where to go with each call, but this is not necessary. It's meant to be individualized for each patient.
So there are new chest guidelines on anticoagulation that came out February of this year, and one of the very important recommendations that is a new recommendation is that for all VTEs that have patients with PEs and DVTs that don't have active cancer, that don't have malignancy the first line of anticoagulation is not vitamin K antagonists like it used to be, it's actually a NOAC, so one of the new oral anticoagulation agents that I put in here. So it's either Dabigatran, Rivaroxaban, Apixaban or Edoxaban. And I put in some of the asterisks for the ones that require bridging with either Heparin or Lovenox. And the reason why they made this strong recommendation is because when they pulled all those major randomized controlled trials that each of the drugs had there is a significant reduced risk of bleeding with the use of the NOACs. I think that because we are in the hospital we tend to see more of the people who have the complications, right. So in the hospital setting we see the people who bleed. But in reality is that for all comers, for everyone who has gone into one of these therapies they actually tend to not have a complication as opposed to Coumadin. One important thing to mention is that the only agent that has a reversal on the market is the Dabigatran. There is another agent called Dexonet which will be applying for the other 3 drugs that is supposed to be presented to the FDA but it hasn't been approved yet. So it is something that is expected to be in the market and approved in the next year.
Now the recommendation for patients with some kind of VTE with cancer did not change, and that is Lovenox as the first line.
This is another change which is for patients who have a provoked event they get to be treated for 3 months, it used to be 6 to 9 months and it was a little bit more of a range so now this is a strict 3 month treatment with anticoagulation; however this is another major change, if you have an unprovoked event you get to be treated indefinitely. So that means that you are treated until the risk of bleeding exceeds the risk of clotting. So if you have an event then in a few years down the road have some issues with GI bleeding that's the moment to stop the medication.
Another change that the guidelines mention is what exactly do we need to do with a subsegmental PE? It's a question that we've had for years, what do we do about it? Do we need to pay attention to it or not? Sometimes a lot of patients get some screening scans for other reasons and then you found out incidentally that they have this small tiny distal PE, what to do about it. So you don't need anticoagulation if it's only a single PE and subsegmental. If it's a low risk for recurrence, meaning that you don't have any active ongoing risk factors like an active malignancy for example, if you don't have a DVT on Doppler and if you don't have symptoms, or if the symptoms could be explained by any other finding on the CT scan. And this did not change which is the very strong recommendation of not using any IVC filters unless you cannot tolerate anticoagulation.
So out of hospital PE treatment was another thing that was discussed in the guidelines and as yo can see here. So anyone who is low risk who is kind of stable, doesn't have any complications, has a history of being compliant and coming back to appointments and feels well enough to be treated with simplified PESI score of 0 is a candidate to be treated as an outpatient. And that means that they could either get a shot of Lovenox in the emergency room or even the first does of NOAC in the emergency room and then given a script so that they could just fill it out and then see their doctor in the next week or two.
So how about systemic thrombolysis, let's go over the literature of the system thrombolysis in high risk or massive PE patients. So this is one of the initial metaanalysis included in 11 randomized controlled trials that compared lysis versus Heparin. And in all comers with any PE there was a trend toward improvement in mortality but it was not significant. However when they stratified it by massive they did see that there was a decrease in their mortality and that was significant.
This is a more recent study that included a lot more patients that were hemodynamically unstable and by that they defined that by either being in shock or on a vasopressor or being on the ventilator. So we know that this is not necessarily the definition that we go by, but it's close enough and I think it's worth mentioning. So in this study they saw a pretty significant decreased reduction in their mortality when you had systemic thrombolytics.
So how about systemic thrombolytics in the intermediate or submassive PE patients? So this trial that came out in 2014 called the PEITHO Trial, most of you know that, most of you are familiar with it, it randomized patients to either thrombolysis and Heparin or just Heparin alone, included over 1,000 patients that had submassive PE defined by dysfunction either on CT scan or an echo and having a myocardial injury by having an elevated troponin. So if we were to just try to classify this I would say that these were the intermediate high sort of category patients. Their end points were either all cause mortality or hemodynamic collapse in the first 7 days after a diagnosis. And that included either CPR or hypotension or requiring a vasopressor.
So this is the results in the trial. So as you could see here they had a very significant decrease in their mortality when they used the lytics. However when the data was looked at - when you looked at the data a little closely you could see here that death from all cause there is really no difference in the two groups, however the driver for the odds ratio was really the hemodynamic decompensation. So very significant increase, 5% versus 1%, and that was mostly driven by some of these things either requiring a intervention or requiring to go on an open label thrombolytic. So this was the driver for the primary outcome.
And then when they looked at what were the bleeding risks there was a 5 times higher bleeding risk, a 12 times higher stroke risk which included hemorrhagic strokes and this bleeding risk was a lot higher when you divided and looked at the patients that were over 75. So really all in all when we take a look at this trial what we say is and what we can take out of it is lytics really work but at a very high cost. So I don't think that this - this definitely didn't make the guidelines, and the guidelines say that if you have a submassive patient you should not be using system thrombolytics because the bleeding risk is definitely a lot higher than with the benefit that you might get from hemodynamic decompensation.
So how about low dose thrombolytics? There have been smaller studies that were pulled together in this metaanalysis that looked at either 50 mg versus 100 mg of systemic TPA. No change, no improvement in the all cause mortality or recurrent PE; however there is definitely less bleeding when using lower dose.
So again just to reiterate, systemic thrombolysis in the most recent guidelines it will say yes to use it with hypotension, so for massives; yes to use it when you have deteriorated even after starting any kind of anticoagulation; and in patients without hypotension that have severe symptoms or marked cardiopulmonary impairment may benefit from lytics. So this is a very sort of wishy-washy I would say kind of statement and I am not sure what kind of patient would fit this criteria because it's so loosely mentioned. And that's why here we only use systemic thrombolysis in patients who have a clear massive or high risk PE.
So how about catheter directed interventions or catheter directed thrombolytics, especially in the intermediate risk patients? So I would say sit tight for that because Catalin will talk about that.
And we are now going to move on to talk about life after a PE. So what happens after a PE? So a lot of patients as you could see have different complications and that includes anything from trouble breathing, decreased exercise tolerance, having chronic perfusion defects or chronic blood clots and then definitely true exercise limitations and again something called CTEPH, chronic thromboembolic pulmonary hypertension.
So the natural history of the clots, it's very rare, it's very odd I would say because ti's something that you think that everyone that has a PE again it will go away. However when we do VQ scans as an outpatient we see that about 66% of the patients are going to have an abnormal VQ scan, meaning they are going to have some kind of perfusion abnormality at 3 months out. And still 12 months out there is still a good amount, a third of the patients are going to have that abnormal finding.
And what we know is that having a VQ scan abnormality or having a perfusion defect means that you are going to be more short of breath, that you are not going to be able to walk as far and that your pressures estimated on an echo are going to be higher. So these are patients that we need to not just screen for but we have to actually serially follow them because what is - what we don't know is what is the incidence of developing CTEPH with having some of these chronic blood clots.
And what we know is the risk factors for having incomplete resolutions are so this is where size matters. So before size didn't really matter in terms of saddle and all those things, here definitely it does matter. So the larger the clot the more likely you have that it will not completely resolute and the longer the time between your first symptoms and your treatment and older age. So those three things definitely will put you at a higher risk of developing a chronic blood clot. But then not everyone that develops a chronic blood clot has chronic thromboembolic pulmonary hypertension, and we'll go over what exactly the criteria is and the diagnosis. But again this is pulmonary hypertension caused by chronic blood clots and by chronic we mean after 3 months from your acute event.
We mentioned earlier that there were about 4% of the patients that develop acute PE that go on to developing CTEPH, so that's still about 20,000 patients a year if we go by the 900,000 originally diagnosed with a VTE, so it's a very significant patient amount. And a lot of things - one interesting factor is that a lot of these patients do not have that initial acute PE or acute DVT that is clearly identified. So about a quarter of them to almost 40% of them could have CTEPH without even ever having an acute event, so what we call the silent PE.
So what we know is that from this recently published trial called INFORM Trial that was based on retrospectively going through the claims of each patient 87% of the patients that have an acute PE will have a complaint to their doctor about a PE related symptom, whether it is shortness of breath, lightheadedness, chest pain, edema. But then only 61% of them had a diagnostic test to say - to actually confirm any of these findings. So I think that this is telling us that we need to be - have a higher surveillance for these patients and to be able to follow them and ask them for the symptoms but then also act upon them. So whether that patient will need to develop - will need any of the specific testing to diagnose pulmonary hypertension.
So in general for the screening of CTEPH we start with an echo, like with any other pulmonary hypertension. And when pressures are elevated there or there is changes in the RV that are suggestive of it then we go into ordering a VQ scan. And note here how a CTA is not included in the screening because VQ scans have a higher sensitivity and actual specificity to identifying a chronic blood clot more so than the CT scan. And the reason that is is because CTAs might not show those distal smaller chronic occlusions and it might - it also, the VQ scan will allow you to recognize not just like where the clot is but if they have a perfusion defect associated with it, okay. Then if those are abnormal then we move onto a diagnostic right heart cath to confirm that the pressures are elevated. And then we obtain - how we obtain a CTA and/or a PA gram to know where those clots are and if they are a surgical candidate. And the reason why we obviously are interested in it is because if we left a CTEPH untreated this 5 year survival is very high. So the higher your pressure the worse your survival. But even with a modestly elevated mean pulmonary artery pressure of over 40 the survival is 30%, which is quite low.
So the preferred treatment is actually surgery. So it's called pulmonary thromboendarterectomy, and this can be curative. So 70% of patients that go through a PTE that have their clot removed could actually be cured and then after that they don't need to be on any pulmonary vasodilators and they don't have any pulmonary hypertension. So there is definitely a surgical selection process to it that will be based on not just where the clot is or are but the comorbidities that the patient might have and how high the hemodynamics of the patient is. So you know it's quite an involved surgery that I won't go through but it does involve circulatory arrest and a prolonged period of time.
So what if you can't go through surgery? Then medical treatment would be the next step. There is a drug approved about a year, 2 years ago now called Riociguat, the brand name is Adempas, and it's the only pulmonary hypertension drug that it's approved for CTEPH. It is sort of like a cousin of a PDE5, it's similar to Sildenafil or Tetanophil; but it's actually stimulator of cyclic GMP as opposed to an inhibitor. And the indications are for either patients who are nonoperable or who have residual pH after they had surgery. And the approval was based on an improvement in their 6 minute walk test by 39 meters and decreased PVR by 2.8.
In addition to that you are always going to be on anticoagulation, so that's once you are diagnosed with chronic blood clots or CTEPH you are just going to stay on anticoagulation. But one important point is that you know refer early, this is not a moment to try drugs to see if you are going to do well because surgery definitely works better than just medical approach. And we'll talk about these emerging catheter based interventions right now.
So my take home points are that PE, really the third most common cardiovascular cause of death with high mortality especially in massives and submassives; systemic thrombolysis research for massives because they have a higher increased risk of bleeding and especially intracranial bleeds. The first line of anticoagulation for all PEs in general or DVTs are NOACs and that's a new guideline. PEs can be associated with not just acute but also long term sort of negative cardiovascular outcomes including CTEPH and we have both a PE Acute Team and a Chronic Team that is multidisciplinary that we are happy to help for any questions that you might have.
So I'm going to talk a little bit about the two sides of the coin, the acute PE side and then we'll talk about emerging percutaneous options for chronic thromboembolic pulmonary hypertension. So first of all the question is do we really need something else other than Heparin for the submassive PEs? And as you've seen in the prior talk there is clearly a group of patients with submassive PEs who are at higher risk to develop complications. And not only that but based on the data that we have available we developed tools that allow us to identify this patient. So again just to recapitulate these are patients who have elevated cardiac markers or patients who have an RV to LV ratio more than 1 and are patients that have a simplified PESI score more than 1 basically, if it's to remember only a few things.
And more current data do again confirm the fact that if you have a multitude of these factors together you are at risk of having adverse events, this includes mortalities pretty high, it's in the 25% range. So it's interesting that this is a completely different group than what Belinda was referring to and they came up with almost exactly the same number. There is a group of patients in the submassive category that we are currently treating with Heparin alone that do poorly in the hospital, which emphasizes the need perhaps to try to do something better for them.
And what do they look like? Well this is a patient that we treated a while back. This is a relatively young guy, has a history of cardiomyopathy. This is his CT scan and you can see very easily that his RV is more dilated, it's larger than the LV. This is fairly easy to determine. Has a troponin of .5 that's rising, his PESI score is high. He has main central PE in the main PA and the lobar arteries.
So this represents a subgroup of patients that we know that do poorly with anticoagulation so what else can we offer them? And as Belinda alluded to, people have looked at lysis for this. I'm not gong to go again over this whole thing, this is the PEITHO Trial again for lysis in submassive PEs, and the primary end point was met but when you are looking at mortality there is no difference. So when you are looking at this depth right these are the causes of death for patients in this trial.
And if you are looking at the patients in the TNK group they don't die of hemodynamic decompensation or recurrent PE, so this is PE attributable death, while the Heparin patients do have all of these problems, 3 of them died of hemodynamic decompensation, 3 of recurrent PE and so forth. /So if you are looking at the PE attributable death there is definite difference between Tenecteplase and Heparin in the favor of the lytic. Now if you are looking at the bleeding related death that goes the other way. So as you'd expect the patients who have received Tenecteplase are more likely to die from a bleeding related cause and that's usually a stroke or a hemorrhagic stroke relative to the Heparin. So when you add it all together it washes out but again the PE attributable death is in the favor of Tenecteplase. This is what we are talking about, this is what you know we in cardiology have feared, you know we used to see this before when we used to give lytics to the ST elevation MIs and we really don't want to see this again.
So the question is can we achieve the hemodynamic benefit of systemic lysis without the bleeding? And this is probably where the catheter based PE treatment comes into play, and I'm going to talk about - I use the term contemporary because I don't want to go over some of the technologies that we used in the past that perhaps weren't that effective. And within this group there are two main categories. There is something called catheter directed lysis where this ultrasound assisted lysis falls into. We can do catheter directed lysis without the ultrasound using a Craig McNamara catheter for instance. And the other subgroup is that of thrombectomy, so we are talking about percutaneous thrombectomy here where you go in with a device that you can remove the clot and/or aspirate the clot. And these are some of the devices that are in that subgroup.
Now all of this is very new, all of this technology has come of age - is coming of age as we speak. There is very little clinical data in this space, but perhaps the one that has more data behind it is this ultrasound assisted lysis, the company is called EKOS. The concept is that the ultrasound facilitates the penetrance of small amounts of lytic in the clot and these catheters are placed in the pulmonary arteries and left there overnight or for 12 hours. And this is what this looks like. You see the two catheters, one going to the right and one going to the left. These dark elements are the ultrasound elements.
What is the evidence behind this? As I said the studies are small and we are learning. This is one of the few studies that looked at EKOS versus Heparin alone and as you can see it's a relatively small study looking at 25 versus 25 patients. Both groups were anticoagulated and the primary end point because it's such a small trial you end up with a surrogate end point of the RV to LV ratio. And the gist of this, and this is proven and accepted now, is that these patients have a large RV to LV ratio and with EKOS and Heparin they respond very quickly. So within 12 hours they normalize basically in terms of RV to LV ratio. And they obviously stay relatively normal at 90 days. With Heparin that takes time, at 90 days you end up in the same spot. So basically what you get out of this is a more rapid improvement in the RV to LV ratio, a more rapid improvement in hemodynamics. And when looking at the RV function and this is a semiquantitative way of looking at RV function you can also see that perhaps with EKOS and Heparin at 90 days you get better RV improvement than at 90 days with Heparin. So you see more of the green in this column, more normal RVs at 90 days compared to Heparin alone.
When you go and look at critical data however there is no difference and these patients were relatively low risk. Remember this is - there is still a dose of lytics that's administered here so this excluded a lot of patients that were perceived to be high bleeding risk, which is a large chunk of the patients that we see with PEs. They had zero recurrent DVT, there was one death that was cancer related in the Heparin group and minor bleeding was slightly higher as you'd expect on the interventional arm. So the clinical data is not there yet, but again the hemodynamic improvement with these therapies is certainly there and it's certainly impressive and this has been our experience as well. I'm going to show you some of that.
This is another study looking at this same technology, it's a single arm registry essentially looking at 150 patients that included massive PEs here as well. And you can see mean - the PA systolic pressure dropped significantly overnight basically with the therapy with a mean of 50 to 37 and then it's maintained at 48 hours. So this is the catheter directed lysis right, so we place these catheters in the clot, we drip them with low dose lytics and we are getting these hemodynamic results
How about patients who have high risk of bleeding? There are new technologies coming out that utilize thrombectomy based, different forms of thrombectomy or aspiration which are helpful perhaps in this patient population postop, patients who are at high risk of bleeding that may not get lytics. This is one of the devices that we've used a number of times, it's called Flowtriever, basically has these wire forms that are deployed across the clot and retract it and aspirate it at the same time. And again the potential advantage of this are no need for lytics and more rapid hemodynamic improvement.
And this is kind of an interesting case that we put together. We were happy that you know we got very good images. These our digital subtraction angiograms of the lungs and you can easily appreciate that the right lung is only perfused in the middle portion, the top and bottom don't get any blood flow. On the left side the inferior lobe is completely underperfused and you can actually see the clot. This is a patient who had an intracerebral procedure a few days before and we thought she might be high risk for bleeding so we treated her with the Flowtriever and we were able to aspirate clot from the interlobar artery on the left as well as from the trunk ascent here on the right and the interlobar on the right. And you can see marked improved perfusion on the follow-up angiograms. And this is a patient that left the lab on no oxygen basically after this.
There are a couple of other devices out there, a little less well characterized in this space. There is this Penumbra aspiration system, it's an 8F catheter that aspirates really hard and it's used for peripheral applications. Our vascular colleagues have more experience with that. And the Angiovac catheter which actually goes on the other side is very large. This was initially designed as a PE device but because of its bulkiness it's used only primarily for IVC or clots in transit, clots in the right atrium and such.
So basically the data that we have available to us now indicate that with catheter based treatments in the PE setting and for PE we can get rapid improvement in hemodynamics and more rapid recovery in the RV function. And another thing that you see clinically when you do these patients is how much better they feel the following day. And this is something that is not yet quantified very well but a lot of these patients come very tachycardic, very hypoxic and 2 days later they go home on a NOAC. So it's pretty impressive how quickly they respond to this.
But again the question remains is there a clinical benefit here? We all are driven by hard clinical end points, mortality and hemodynamic decompensation and we don't have the answer to that. And what are the risks of this therapy? So are we - is this the same story as we saw with the TNK, are we getting a benefit at the risk of bleeding? And what we know so far is this is pool data we are using again, ultrasound assisted lysis is that none of these patients gets a hemorrhagic stroke. So as far the biggest fear that we have of having a hemorrhagic stroke in our patients that does not seem to happen with catheter directed lysis. The dose of lytics is very low and it's over a long period of time and it's administered in the clot and my sense is that the systemic lytic effect here is pretty low.
So potentially we have a therapy that's equivalent in clinical benefit to systemic lysis without the associated bleeding related mortality. So if that pans out to be true this would definitely be something that can be considered. Again this is for higher risk submassive PEs, it's not for everybody.
I would say that we are a little more advanced than what the current guidelines are. The current guidelines are somewhat conservative as far as catheter directed lysis go. They always recommend systemic over catheter directed lysis and again the evidence for this is as poor as the evidence the other way. And PEs with hypotension with high bleeding risk or failed systemic thrombolytics may be somebody who would benefit from catheter directed lysis according to the guidelines. As you saw in our PE response team algorithm we are a little more aggressive than this and we actually treat with a catheter based approach our high risk submassive PEs.
And just to show you we are learning right, we are collecting our data. As Belinda was mentioning we have an internal registry. This is our hemodynamic data, I tortured the Fellows to get hemodynamics after we do this lysis even it's at 4:00 o'clock in the morning. And as you can see again the PA systolic pressure drops fairly dramatically. It doesn't normalize but it's significantly better after lytics. The PA Sat improves significantly so it goes from 50 to 60, 65 so that's a significant improvement in cardiac output, it's a significant improvement in pulmonary vascular resistance.
There are some trials ongoing and I just listed here a few of the trials that we are involved. FLAIR Trial is looking at the Flowtriever device. TAPE, I didn't even know this actually had an acronym, this is our own homebrewed trial of Ekos versus standard catheter directed therapy for submassive PE. That Dr. Avgerinos from Vascular Surgery is leading and put together. And OPTALYZE PE is a trial looking at different ways of using the Ekos technology that Dr. Maholic at Hamot is involved with. And probably the most important trial that we need to have is a trial of catheter directed lytics versus Heparin for submassive PE, and this is work done at NYU with NIH support to get this trial going.
So moving onto something that's very exciting and is very new, the field of percutaneous interventions for chronic thromboembolic pulmonary hypertension, for CTEPH. As you saw in the prior slides we talked about this sequelae of pulmonary embolism, if these patients are operable they should get pulmonary endarterectomy. This is a lifesaving procedure. A large number of patients are inoperable and they could be inoperable because they have comorbidities or they could be inoperable because they have very peripheral disease. So think about this as this is the spectrum, the more central emboli are likely to be candidates for surgery while the more peripheral ones might be candidates for this new approach of angioplasty.
There is a lot of work in Japan done for this. There are 5 centers in Japan that do a very large volume of these procedures and in fact one of the guys that we interacted with he basically that's all he does, he's an interventional cardiologist and all he does is BPA for CTEPH. And this is what we are talking about, this is the disease that's amenable to angioplasty. For surgery you have a clot here that can't be removed, for angioplasty you are talking about segmental arteries. So this is the A10, this is a technology called cold beam CT that can be done in the cath lab and you see this type of disease, it's very different than atherosclerosis, it's not you know central narrowing of the lumen. We did it more with webs and with slits in these vessels and this is exactly why angioplasty works so well in this scenario because all you need to do is cross this and disrupt this web or disrupt the slit, you don't need to do high pressure angioplasty and affect the vessel wall which could lead to restenosis.
So does this work? Again this is data from the Cardiovascular Center in Osaka, and as you can see there is significant improvement in the PA pressure, mean PA pressures before and after angioplasty. I should mention here that this is not a onetime procedure, this is usually a 4 to 5 different procedures, you do this stage, you never do this all at once because there is a risk of pulmonary edema if you open too much. Even post-PA cases, so patients who are operated before have residual hypertension that responds to this.
Again if you look at the combined experience across the world all of this are Japanese groups with the exception of this group from Norway. You are getting a 30 to 60% decrease in pulmonary vascular resistance And I'm gong to go back to this for a second because the important thing here is the fact that at 1 year the effect is maintained, and at 2 years the effect is maintained. So this is something that people were worried about that you do this and the disease comes back and you have to angioplasty kind of the same we did in the corners. But because of different pathology, because of it's a completely different disease these patients actually respond very well with durable response to angioplasty.
The 6 minute walk distance improved significantly. This is a 60 meter improvement. If you are paying attention to the medical therapy for CTEPH that only gives you about 30 so meters of improvement in 6 minute walk.
The RV gets better in time. There is massive RV dilatation before and significant RV improvement afterwards. And at the same time the complications if it's done right, and a lot of the Japanese colleagues have figured this out how to do it right, the complication rate remains relatively low. The procedural mortality remains in some groups as low as zero basically. Reperfusion edema which was something that people were worried about in the past again has come down to zero. So this is a very exciting field. We are about to start our own program for treating CTEPH with BPA and we'll keep you posted.
So in conclusion catheter directed lysis and thrombectomy options are available now for PE. We know that in selected groups of patients with submassive high risk PEs this technology has led to significant and rapid hemodynamic improvement. Balloon angioplasty is emerging as a very promising field for distal inoperable CTEPH patients. We have favorable initial clinical experience, we are learning about this and we are hoping to acquire some clinical data as we move forward. So thank you for your time.