Jay Giri, MD, MPH, speaks on the evolving landscape of pulmonary embolism interventions and the role of pulmonary embolism response teams.
Hello. Thank you for the invitation to speak to you today about evolving landscape of pulmonary embolism interventions and the role of pulmonary embolism response teams in practice today turns out that venus rumble embolism represents the third leading cause of cardiovascular death. Uh and you can see here that there could be up to a half million or more vulnerable I per year in the US, resulting in almost 100,000 vets. For this reason it is a super important disease to focus on in the modern era because much less attention has been paid to systems of care and evolutions in therapy than the first two leading cause of death, stroke and myocardial infarction. one of the key factors that we think about when looking at a patient who comes in with acute pulmonary embolism is the effect of that P. E. On the right ventricle. It turns out that the effect on the right ventricle has close relationships to the short term mortality rates that patients experience. Specifically in those patients whose RVs are so blown out that they're experiencing shock and hypertension. The so called Master High Risk, the efficient mortality rates about the 30% range in hospital. Those who have signs of RV dysfunction but are maintaining blood pressures without developing clinical shock at least by virtue of low BPS Tend to have mortality rates in the 3-10% range and observational studies. Those patients who are lower risk with more normal Rvs have Mortality rates that are less than 1%. So these are key aspects of risk stratify patients with PDF. What's the rationale for utilizing therapy is over and above. Anti coagulation in the PD patients, no doubt that anti coagulation is by far the cornerstone of therapy and the grand majority of patients with the should be treated with that alone and we'll do fairly well both short and long term. However, as we said, those patients are at the higher end of risk or even in the intermediate range of risk. We hope that we can maybe move them down this risk curve uh, and make them look more like those patients who are imminently stable with normal RVs, therefore hopefully decreasing the risk of early mortality. And then secondarily, we wonder if we may be able to prevent long term problems from pulmonary emboli. Specifically the scourge of chronic drama about pulmonary hypertension, the post P syndrome. These are syndromes there are consequences of one or multiple key hits that then leads either frank pulmonary hypertension or different symptoms that impair quality of life without the manifestation of frank pulmonary hypertension. A lot to learn in this area and a lot to prove for us as interventionists who think we're doing interventions for this purpose but important to keep an eye on these type of functional endpoints long term peace studies as you watch them going forward for the next few minutes, we'll talk specifically about therapies for intermediate risk patients. These are patients were human chemically stable but do have clinical evidence of right ventricular dysfunction, usually seeing on echocardiography or perhaps on cT scan. Often cardiac biomarkers that are positive as well if they are drawn. It's frankly said that the problem with advanced therapies, those therapies greater than the coagulation for P is there's very little randomized data to support their use, especially in intermediate risk P fish. And that's largely true except for one advanced therapy. And that systemic Rambo license, it turns out there have been 16 randomized trials for a 42 year period 19 72,012 that randomized patients to anti coagulation alone versus systemic rival license. And eight of those studies shown here were actually an intermediate risk patients. And they're all relatively modern studies that are classifying these patients that we're classifying them now. They're utilizing T. P. A. Or to check the place largely how we utilize it. Now, interestingly, you see that when these studies were met, analyzed by our group Several years ago, we found a greater than 50% relative risk reduction in mortality for these patients are treated with the stomach rumble ISIS. So does that mean we should be taking every patient who comes to E. D. With an intermediate risky And administering them. 100 mg of epa. Well not so fast. And the reason for that is the risk benefit ratio here is complicated. Specifically a We know that we drop mortality in these patients as a whole when we give them stomach rumble isis but their baseline mortality rates, Nancy alone are not that high. There are only about 3% trial patient. We dropped that to about 1.5% number 93 to 65. So only about a 1 to 1.5% drop in absolute mortality. Uh And unfortunately there was a price to pay and the big price was intracranial hemorrhage when the throttle ice group that rate was 1.5% nearly zero and the anticoagulants. So you have a near equal trade off between I ch and all cause mortality. That makes it very difficult to just universally life's pitch. Also you have additional price to pay with systemic global ISIS namely from non ICU major bleeding obviously much higher. And groups are trading with lyrics as well. So this risk benefit calculus is very narrow, it's very difficult to navigate and it did lead to a lot of interest in thinking about, wow this would be a lot easier especially if we could decrease the bleeding risk in these patients. And that led to a lot of interest over the last six or seven years. And Katharine directed rumble ISIS is the placement of two uh multi sized hole catheters into the lungs, generally two into each lung when you have bilateral pE and then a slow drip of TP a respected place into the lungs over several hours. But the concept being that perhaps this would have less off target bleeding effects due to both the local administration, the T. P. A. And the dramatic reduction in dose with this technique, you can see the details of it on the left side. There's no question that from an efficacy standpoint Catherine acted license does reduce piece of solving pressure. Is 150 patients prospectively studied that had immediate drops as you can see in their peace. Systolic pressure's. This is consistent with me and pay pressures and changes in their RV function as measured on serial echoes where the RV kind of shrinks down after you. Like patients with Kathy. That's great news and it tends to correlate well with patients having faster resolution and symptoms. Uh it's also true that major bleeding in the perspective Katharine directed license trials um seems to be a little lower than that seen in randomized trials, stomach places specifically. We looked at this in about analysis six observational prospective CDL trials and we found that the major bleeding rates for about 4%. If you remember in the randomized trials, systemic crisis I showed you before that rate was about 9%. These aren't apples to apples comparison because it's not comparing systemic problems for council direct places. This is the best available data we have on patients and studies and the rates of leads they have. This is major bleeding overall. That's non intracranial average about 4% As far as intracranial hemorrhage. We found those rates to be about .7% and six trucks. Again, you might remember me saying that that rate was about 1.5%. The stomach driver license trump. So again this is not perfect data but it suggested the catholic directed license seems to have a better safety profile than systemic crumble license. From an efficacy standpoint. These we know the Catherine reckless as I mentioned. Drop speed pressure, cruise RV dysfunction. It probably does it to a similar degree as typical systemic rumble. IsIS regiments were mainly getting potentially a little safety benefit with systemic drama license. The problem of course is that I told you That major bleeding and I ch still exist and I would argue a clinically significant proportion of patients for 5% major bleeding 1%. I ch that's not trivial. And for that reason there became a lot of interest in thinking it would be great to treat these peas with no letting drugs at all. And that's where all the interests and the count from back to that comes from right now. There are three major platforms the market to which have FDA clearance, the number 12, which we call a small or moderate or you know um electively device that utilizes mechanized aspirations brought back to me to suck out clock. The flow Trevor which is really a 20-24 French system, much larger war and utilized, performed largely aspiration from back to me. But it does have a mechanical from back to the component to mobilize more sub Q where adherent clock the edge of Ac is less studied. Uh, it's not yet FDA cleared specifically for pulmonary embolism work although it is sometimes used in these groups of patients comparing the limited trial data that exists in the FDA clearance. Studies between small boring black Catherine erected license and large ground elected. You can see that the changes in R. V. L. D ratio 48 hours, which is what the FADA looks for. As an f standpoint to clear these devices looks relatively similar. But you see uh vast differences in the safety endpoints where there's a lot less bleeding in the A block in the arms and there is in the cath directly start. Not surprisingly, the trade off does not mention here that seems to come out a little bit the large wearing black to the trials that there may be a slightly higher risk of human dynamic decompensation with large wearing black to me than with a simple placement of two tiny uh catheters to drip politics than when. So these are the tradeoffs that we're thinking about here. We're also thinking about an atomic characteristics which may be variably favorable for the two therapies with more distal clot not being the best for ml ectomy approaches. Probably definitely not large wearing black but being really well addressed off politics and with more proximal cause potentially being utilized by both but really being the wheelhouse especially large where I'm like there is a little bit more recent data that's come out a large more objectivity expert centers, the 18 most experienced centers in the country. And it's pretty provocative data. 230 patients largely intermediate risk. And what's most provocative about it is the safety profile that was seen which is an improvement over the initial FDA clearance study Where there was actually surprisingly 0% mortality and zero economic decompensation seen in these patients. Uh you have taken with a grain of salt because they're 18 experience sites. They may have been select patients as well. Uh there's no control arm but it does kind of show that experience probably matters here with utilization. Is that blackberry devices and the field is evolving rapidly. Um as we as we learn how to use these devices better and apply them to patients their overall. What do we know about these various therapies? We know that Catherine record license more rapidly improves rbl the racial anti coagulation alone, it more rapidly improves pulmonary pressure and limited on black to me. Data show similar results but we don't have direct comparisons either systemic crumble ISIS uh for either of these endpoints and we don't have any direct comparison collectively versus Katherine directed license. So when we weigh lyrics, for example, ectomy, it's important to weigh their safety profiles, increased major bleeding and I ch athletics there is increased to injury. You may precipitate more decompensation especially for an experienced operator with intellect and that goes to learning curve that I mentioned. What about high risk patients? Those who are actually hypertensive in shock or arresting when you see that. Well, the one thing we know about these patients is that current paradigms just don't work With nearly 30% in hospital mortality seen in about analysis that a group of the public recently has submitted for publication. Believe it or not has only been one systemic license massive pe uh randomized controlled trial. So this despite it sometimes getting level one evidence in some consensus guidelines. It's been studied in one trial. Not even to tell you anything about the results of the trial. There's only one thing you need to know about the truck. There were eight patients in the study. So we don't know anything. I would argue in a randomized fashion about efficacy of systemic crisis for massive PE in a rigorous has been studying a rigorous We also know that overall major bleeding, as I mentioned before with lyrics is relatively high and I ch. Is clinically significant. And all these rates seem higher and observational groups of patients massive P with 10% major bleeding rates and 3% ice plus I. Ch rates and stuff. That's really high. And we also know that probiotics surprisingly don't tend to be used systemic politics and most unstable. Keep patients. This is older data but still bears out today that it's a small minority of patients. About a quarter you can see in 2000 and eight of those patients who are massive p really unstable even had systemic places. Adminis so I argue is systemic license. The ideal therapy. I would say its efficacy is unknown. There are safety concerns, especially relating completing and the utilization is poorer. We need a better way of addressing massive p patients. I argue that of course we have to use it sometimes, but please push it when you only have no other options. So what I mean by no other option? Well, in my opinion, I think that these patients have a very high mortality. So we have to take a very different approach. And the first question I asked is should we institute emergent mechanical circulatory support. I asked three questions are their life threatening comb orbits like stage four cancer risk of dying within a year. Are they reasonable age? We usually use an age around eight. And is the patient have escalating pressers one in hospital rest that's witnessed if these criterias are met. I think strongly about getting patients on mechanical support. First, we generally use vino arterial ECMO for this purpose. Get oxygenation and circulatory benefits from this and give the right ventricle and the lungs arrest, especially the right metric, it's also enables take a deep breath and then make decisions about how we may then adjunctive. We treat the clock birth, there may be uh things going on. You know, dance is coming down the line for increased utilization of isolated rd support. Place for containing some of these patients. The jury is still a little bit out of either way, you're going to use your support as a bridge. The definitive therapies that could include Catherine erected isIS large, more intellectually small bore and elect me or even surgical on black. To be honest, you might even just anti coagulate these patients for three or four days and give them time to rest. I've done that in a patient, for example, whose post find surgery on day one when I didn't have, you know, good and black recaptures available several years ago. So and then and then you hope to do calculate them after that. No question that doing more aggressive therapies probably enables for earlier do calculations what about those patients who are relatively stable? Quote unquote massive patients. There only on a single press for the low dose, I argue. Take those patients the Cath lab have mechanical support on standby and then choose between Catherine, right place the dumbbell ectomy based on your experience and they're an atomic considerations. Last thing I'll talk about for two minutes is what's going on with pulmonary embolism response tapes. Who needs these anyway, where I would say that peas are common. They're leading cause of death. And many sub specialists involved, their care and they show up at different areas in the hospital. They have options of therapies that are all over the bath as we've already talked about and the guideline rex for venus tribalism have almost no evidence. You'll see here that these represent a level of evidence. See guidelines when we looked at this in a recent publication and the Oranges DVT and PE therapies for 75% of recommendations and major guidelines by the HR sec uh come with a level of evidence. The recommendation means it's just based on our opinions, not based on any of the Mhm. Because of that we have very we try to put together groups of experts at local experts to kind of help come together and make decisions on patients. These RPG response to they may do all of these following things that you see here like triaging patients recommending different interventional therapies or even ECMO and then arranging for for quick resource mobilization to the sickest patients. Importantly, I think it's important to have follow ups on these patients to and your ph clinics which can be folded into your current team infrastructure. A lot of theoretical benefits of a part that I just alluded to follow ups rapidly mobilizing resources. Getting a lot of minds together to ask questions to recommend the best therapies. There could be downsides including lack of reimbursement and obviously do we have that much evidence that cruise process and outcomes. The big evident elephant in the room or is part just a fancy excuse to drive procedural box. Well it turns out in the studies that have been done and three have been reported from George Cornell and Cleveland clinic, Only about 20-30, to 35% of patients with intermediate recipe were treated. These perks received advance there, so they weren't just driving all intermediate risk patients to the Cath lab and doing things to them. The grand majority were true that are made with with anticoagulants. So to me this is reassuring that you know, this is really a lot of cognitive expertise was being brought to the table and not just a way to drive procedure even. And the limited data we have out there about parts uh in terms of outcome differences, we're seeing that you know at least a bunch of process outcomes are being improved including time to diagnosis with p time to heparin infusion and keep patients and time from triage patient admission. All shown to be improved with parts in this I think University of Rochester experience. So that's my time and I hope you guys will think carefully about this next phase of interventional care for pulmonary embolism going forward. Thank you
