All right. I want to welcome everyone. My name is Adam Elsesser. We're webcasting this event. Welcome to the follow-on discussion of Storm- PE. We have members of the steering committee, as well as Dr. Benenati. I'm not going to talk much, but turn it over to Shruthi Narayan, our President, and she will make the proper introductions, and we'll dive into the conversation. Thank you.
Awesome. Thank you, Adam. Thank you all for joining us this afternoon to talk some more about Storm- PE. The data that was just presented a couple of hours ago, needless to say, it's a very exciting time for PE patients, for PE intervention as a whole, and certainly for us here at Penumbra. As you heard from Dr. Lookstein, as well as on the panel today, it is a landmark trial and foundational evidence here. Hopefully, we will all have the opportunity to be involved in treating more and more PE patients. I do want to just introduce the members of the Storm- PE steering committee that are here with us today. We have Dr. Rob Lookstein, who is from Mount Sinai, New York City, the international co-PI of the Storm- PE trial. We have Dr.
Rachel Rosovsky, hematologist from Massachusetts General Hospital, also an international co-PI of the Storm- PE trial. Then we have Dr. Stavros Konstantinides from University of Mainz, who's also on the steering committee and provides, you know, global sort of representation. Along with that, other than Adam and I from Penumbra, we have Dr. Jim Benenati, our CMO, that will also moderate some of the discussion. In terms of format, we're going to actually first have Dr. Lookstein go through just the highlights from the study that were just presented earlier. Then we'll open it up for Q&A with Adam and Dr. B moderating the Q&A session. I do want to reiterate that this event is only going to be discussing Storm- PE results that were presented today. Any questions about the business, we will defer to our third quarter earnings call in early November. With that, I will turn it over to Dr. Lookstein.
Thank you, Shruthi. Thank you, Adam. It's a pleasure to be here in front of all of you. Again, a great day for advancing pulmonary embolism care. Can we go to the next slide, please? Oh, I'm advancing it.
She's advancing the screen. You're doing well here. If you just.
They're not connected. Oh, okay. Thank you. Sorry about that. This idea has been brewing for 10 years. The endovascular era for acute pulmonary embolism started 10 years ago with the Ultima trial. Despite the fact that there have been seven devices that have been approved by the U.S. FDA, there have been no trials since Ultima that have compared any form of endovascular therapy to anticoagulation alone, which is currently the gold standard of care and in the guidelines for intermediate high-risk pulmonary embolism. There have been no randomized trials comparing mechanical thrombectomy versus anticoagulation. This trial that we presented today is the first randomized trial evaluating any endovascular therapy versus anticoagulation in over 10 years. It's the first randomized trial comparing mechanical thrombectomy versus anticoagulation.
Obviously, the mechanical thrombectomy device that was used as part of this trial is the CABT, the Lightning Flash System by Penumbra, who's here today. We chose the RV to LV ratio as the primary endpoint because it's been adjudicated in countless studies in the cardiovascular literature to denote strain on the heart. The higher the RV ratio, the more strain there is from the heart from the acute pulmonary embolism. The idea here was very focused. We set out to demonstrate that the introduction of a CABT procedure on top of the gold standard anticoagulation could reduce the strain on the heart faster and in a more uniform way than just treating the patient with anticoagulation alone. We used multiple safety endpoints, a composite endpoint of clinical deterioration, PE-related mortality, symptomatic recurrent PE, and major bleeding. The primary efficacy endpoint was assessed by an independent blinded core lab.
The secondary outcomes here, the composite safety endpoint, was assessed by an independent clinical events committee. The study schedule and data collection are listed here. There are numerous functional endpoints and quality of life endpoints that will be presented later at a subsequent meeting. We're very excited to share that with you, but that was not presented this afternoon. Suffice it to say, the patients after being assessed were randomized to either, again, continue to receive anticoagulation alone or to undergo the CABT procedure. The patients were followed for a total of 90 days. The baseline assessments of these patients in both arms mapped almost perfectly. They were well-matched groups. There were no significant medical comorbidities between the two groups. When they presented and were assessed, they had similar vital signs. They had similar presenting symptoms. They had similar medical comorbidities.
All the assessments that have been shown to have a poor prognosis for outcomes were well matched between the two groups. The tools that we as physicians use to denote the degree of thrombotic burden or the clot burden in the lungs were also matched between the two groups. We set out to see if there was going to be a treatment effect by adding on the CABT procedure. The endpoint is shown here. It showed that there was a reduction in the RV to LV ratio in both groups, but the reduction in the CABT group was significantly superior to anticoagulation alone. This procedure took the strain off of the right heart in a more reproducible, more uniform, and in a statistically superior way than anticoagulation alone. The FDA has set out that a therapeutic effect is defined as reducing this ratio by 0.2.
We use that to demonstrate a therapeutic effect. We saw this in 78% of the patients treated with CABT and only 52% of patients treated with anticoagulation. We also denote a normal RV to LV ratio, showing that there is no strain on the heart, as defined as the ratio being 1 or less. This was observed in 39% of patients in the CABT group and only 13% of patients in the anticoagulation group. Just to paraphrase this, just by introducing the CABT procedure, almost 40% of the patients returned to a normal level with no evidence of right heart strain on their follow-up CAT scan. The safety endpoints are listed here. There were two major adverse events in the CABT group and four in the anticoagulation group. These were not statistically significant whatsoever. This is a foundational trial. It's a game changer.
It's the first of its kind trial that demonstrates the efficacy and superiority of mechanical thrombectomy, obviously in this trial, the CABT procedure, over anticoagulation alone in the treatment of intermediate high-risk patients. The CABT procedure dropped the pressure on the right heart uniformly across the cohort. This led to a statistically superior reduction in the RV to LV ratio compared to anticoagulation alone. The safety profile was comparable between the two groups. This, once and for all, establishes on a foundation level the role of mechanical thrombectomy to treat and rescue patients with intermediate high-risk pulmonary embolism. I'll say this again, our entire trial leadership is excited and looking forward to sharing our functional data and our quality of life data at future meetings in the next weeks and months to come.
Thank you, Rob. I appreciate that. We're going to open it up to questions in just a moment. We're going to have mics, so we have to wait only because it's webcast and we got to hear the question appropriately. We're raising hands again. Oh, come on. You guys are going to make me pick. Let's see. Hold on. No. Why don't you pick, Jim?
OK. To be fair, the first hand I saw go up was yours. Second row. Okay.
Thanks for sharing that and congratulations on the study.
Thank you.
I just want to understand, or at least help me understand, how do you think the physicians will look at the fact that there were like 767 patients that were randomized and only 100 patients treated? How do we think about that as just the opportunity? What's the true TAM? Like, I mean, if you're only treating one out of seven patients or less, just any colored helpful thing.
If I could correct that, 767 patients were screened to participate in a randomized interventional trial comparing a medical therapy with an interventional therapy, right? Of those 767, a very significant percentage were not eligible to participate because they were either too sick or too healthy. The points I made before that we wanted very well matched, very symptomatic, but well matched patients in this trial was intentional. We had a high threshold in order to allow patients into this study. The patients had to understand and agree to be randomized between a medical therapy and an interventional therapy. We screened 767 patients in order to randomize only 100, all right? 100 patients didn't get treated with CABT. Only 43 patients were treated with CABT. This is actually a very, very good screening ratio for a large cardiovascular trial, especially a trial that randomizes medical therapy to interventional therapy. I think Dr. Benenati and I have both participated in interventional or endovascular trials where the ratio of screened patients to randomized is 10 to 1 or 20 to 1. We were very happy with these results that we only had to screen 767 patients to randomize 100.
Yeah. I'd just tell you that from 30 years' experience participating in trials, a 1 to 7 screening ratio is outstanding. As Rob said, a 1 to 15 ratio we've seen in many trials. Part of that is because when you randomize someone, you have to look at a patient and say, you have to agree to a coin flip. In a single-arm study, you could say, I have a new device, w ould you like to try that? That's a much easier question for a patient to answer than for them to have to say, I'm willing to.
Can I? There's another part of his question if I can play the role of follow-up here. That is, what is your perception? It's unrelated to the number of patients screening, which is where that got sort of onto a different topic. What's your perception of the opportunity? How many more patients given this trial can we help in terms of like a percentage more?
The prevalence of intermediate high-risk pulmonary embolism across the United States is estimated somewhere between 15% and 25% of all pulmonary embolism. The incidence of pulmonary embolism with screening with CT pulmonary angiography can be as high as 900,000 in the U.S. I'm not going to do the arithmetic, but you're talking about tens of thousands, if not hundreds of thousands of patients just in the U.S. Obviously, you have the opportunity to expand the reach of this disruptive therapeutic option to the entire globe. It's a huge opportunity to really improve the care that we're providing just to this subset of acute pulmonary embolism.
I just wanted to add, up until today, if you look at the guidelines, the American Heart Association guidelines, the European guidelines, CHEST guidelines, PERT guidelines, when you look at the intermediate high risk and how to treat those, it's all anticoagulate and then monitor and consider rescue reperfusion if the person deteriorates. There's been no guidance up until today to help us think about, is there a better way to treat those patients? This is the first trial, which is really a game changer because we now have evidence. We have evidence that you don't actually have to wait until these people deteriorate, that you can actually do it up front. I think this is the trial we've all been waiting for literally for a decade. When you think about those patients, it's the intermediate high risk.
To your point, it's those people that had strain of their heart, not just on their echo or their CAT scan, but also in the biomarkers. It's those high risk. If you look at the mortality rate, we know patients that have high risk, those are the people that are hypotensive, their mortality rate can be in the 40%, 50% at three months. We also know the people that are in the intermediate risk, their mortality rate can be up to 15%. This is a real important issue because when you think about the RV, LV, that strain on the heart, when you look at those patients and you wait until they deteriorate, you wait until they become hypotensive, if you look at that curve of who dies from mortality, it shoots way up. You want to prevent people from getting to that point where they're straining their heart so much that they're becoming hypotensive because their risk of mortality goes way up.
Stavros, any comments about the screening, the number of patients, the randomization process?
No, I only want to fully agree that a screening ratio of 7 to 1 is a good ratio. There are two things to that. Trials, as you all know, are highly regulated, right? We have very strict rules on whom to include, particularly on whom to exclude from trials. Sometimes it could be that the patients do not meet the criteria of the protocol of the trial, or sometimes there are other issues, some other diseases that prevent us from randomizing these patients. This is a good ratio. Another part and another mark of the quality of this trial is the fact that the screening ratio was very well and consistently documented. This is not something that happens always. Sometimes some centers do not document all the patients that they screen. They say, oh, we had a very high randomization ratio. It has to be done in a diligent and honest manner. This is what was done in this trial. We have a representative and I would say objective screening ratio of 7 to 1. I also agree that this is a good one.
Jim?
NextJust a question.
Yeah, Cecilia, please pass the mic to the next person.
Thanks. Robbie Marcus from JPMorgan. Congrats on the nice trial. Two questions from me. First, how important will the secondary endpoints be? I believe mortality is one of them. Do you think the RV, LV unloading alone is enough to drive adoption? Do you think you'll need the secondary endpoints? The second one, I'll ask up top. How do you think about guideline changes? You talked about the need for more data evidence. We have, I believe, three more trials coming, looking at this. The trial's great, but it's still fairly small in size. Do you think you'll need, along with the other three, assume they all read out positively? Will that be enough to change guidelines?
I'll answer the first part, and then I'll defer the guidelines question to my colleague down the row, Stavros, who I think has a little bit more insight to that. We had to demonstrate the RV to LV ratio as the primary endpoint because it had never been done before. Again, just to reemphasize this issue, there's not been an endovascular trial in 10 years. There had never been one for mechanical thrombectomy, not the least of which CABT. We had to demonstrate efficacy. I'll say this again. We are very excited to share the functional outpoints with you in the near future. We obviously can't go into details about that for obvious reasons. We do think that the wealth of evidence that's going to be shared over the next weeks and months will be very, very exciting for the entire field. Stavros, do you want to talk about what's going to go into the guidelines and how the other trials will frame into that?
Yes. What the guidelines need for recommending some sort of therapy is randomized controlled trials. I must say it was thought for a long time, actually, until now, that such trials are not possible for devices in PE . People thought there will never be state-of-the-art trials. This is why there was all this discussion because there were believers and non-believers, but there was no one to judge. I mean, can this now really be formally recommended? The criteria for recommending some device or a drug are quite the same amongst guidelines. You need a state-of-the-art randomized controlled trial. There's no number of patients that the trial has to have in, right? It's not the number of patients. It's the effect, how relevant the effect is. This is what Dr. Lookstein alluded to. RV to LV ratio is something that has been established for years, actually since the early 1990s.
By coincidence, I didn't know it back then. I was quite young. It was first proposed in Mainz, actually, at the university by my later supervisor. Then it was taken up also by the team of Professor Goldhaber here in Harvard Medical School. One is that the guideline says there is superiority based on these criteria. If this is also a clinically relevant endpoint, and this is the case for RV to LV, the guidelines will say, yes, we recommend this type of treatment versus the standard of care until now with a level of evidence. Now, when more trials come, what changes is not the recommendation, provided that the results are consistent, of course. If one trial says one and the other, then it's a different story. If the results are consistent, then what changes is not the recommendation. It's the level of evidence. If you have more than one randomized controlled trial, then you move up from level of evidence B to level of evidence A. The recommendation can be based, a strong recommendation can be based on a single state-of-the-art randomized controlled trial.
OK. Let's grab another question.
Thanks. Chris Pasquale in Nephron. I wanted to ask along a similar vein about translating these data into actual clinical adoption. I'm curious about the audience that needs to really be convinced for this to become, to move that needle on what's considered standard of care. You're in front of a very interventionalist audience today. The additional data is going to be a different audience. Again, lots of folks that do procedures. With pulmonary embolism, how broad is the audience you really need to get to? Are there a lot of physicians who are not going to be reading this manuscript, not going to be seeing these slides that need to be convinced before patients can get consistent therapy?
Rachel, do you want to take that and comment about the publication? I think there's a lot of people who aren't interventionalists that this is targeted to.
Yeah. I'm not an interventionalist. I'm a hematologist. The fact that on their steering committee and actually the co-global PI was a non-interventionalist was intentional and very important. I think the question you ask is also very important. I think this is the first place that we've announced this. We will be having a publication come out once we get all of our data, the secondary endpoints as well. That will be our goal, to get that in a very high-end journal, which will then be able to reach not just interventionalists. There are also various other conferences over the next year or two that we will be targeting. The other thing is this was in partnership with the primary embolism responce team consortium. We've recently launched something with Penumbra called PRISM.
The goal of PRISM is actually to do exactly what you're saying, to get this information out to all of the people. As Rob alluded to, the majority of patients that were put in this trial had PERT teams already. If you think about a PERT team, that's multidisciplinary. That's not just the interventionalists. It's the critical care, the pulmonologists, the emergency room physicians, the hematologists, the pharmacists, the nurses, all of those people. We need to think about educating all of those people about this trial so that it can be adopted. We recently did also, this was sponsored by Penumbra, called Get Out the Clot, which kind of looked at what's people's understanding right now of how these devices are used. We were shocked to find that actually the majority of people might not have the best understanding of where these should be used.
I think this is a huge opportunity, the fact that this trial has shown this. When we get secondary outcomes, we'll be able to share those as well. I think that's going to launch this and allow us to really educate everybody that's taking care of PE. I think that's so important. I think your question actually speaks to just raising awareness about PE in general. If you look at World Thrombosis stated, a survey that looked at just participants who knew what a PE was. They looked at MI. About 90% of people knew what an MI was. 90% of people knew what a stroke was. Only 50% of people that they surveyed knew what a PE was. Our work has cut out for us. I think this is opening the door to allow us to really share this.
Wouldn't you say that in the PERT Consortium membership, the majority of people are non-interventionalists?
Yes.
This trial is done in conjunction with PERT. As this gets through the PERT, as this is disseminated through PERT, the majority of people this is going to are non-interventionalists. That was a specific target in the design of this trial. It's the reason we collaborated with a non-interventional group primarily. Your point, again, well taken. It's something that we targeted and executed on completely. Next question.
From Citi Bank. Thank you for presenting this data. It's impressive. I think the question I have is to take off of everyone else's question. What has to be done? It's the additional data. We hit upon that. It's the publication. We hit upon that. Do you need changes in guidelines? Do you need changes in reimbursement? Do you need more than 100 patients? I'm trying to go from today's wonderful data presentation to adoption and what steps have to come from here to there. Thank you.
I'll take a stab at that. I think that this trial, to quote my dear colleague, opens the door. There are countless providers across the United States and around the globe that have a little bit of skepticism, don't necessarily understand that this is a safe and effective therapy. I think this trial allows us to embrace this technology as a safe and effective therapy to rescue patients that are presenting to our emergency rooms with right heart strain. We have to start somewhere. I believe this is a foundational trial that allows the majority of the medical community that are treating patients with acute pulmonary embolism to recognize, again, this is an effective therapeutic option in our armamentarium. Our hope is that more and more patients in the next weeks, months, and years to come will be offered this therapy. This is the first step in the right direction to allow more and more patients to be rescued with this therapy.
Can I , add a couple of comments to address what's next? We at Penumbra were obviously very, very involved over a decade ago in what happened after the trials in stroke. It's a similar moment. It was amazing to have that data. To address your question, that's when the real work started in terms of what to do. We're in a very different spot now than we were in stroke. I say that just about structurally what the field looks like. There, we had to deal with where the patient showed up, potentially moving them to other centers. We don't really have that issue here. We're years ahead because of the work that PERT has already done, building cross-functional teams where there is an awareness and a desire to treat the group of patients with pulmonary embolism differently. We're not looking at the same type of roadblocks.
It doesn't mean we don't have to educate, get out, and get that information. We were thrilled to see the announcement that PERT made about their very ambitious program around education, training at centers, many more members coming in. The level of that engagement that PERT is going to do gives me hope that we're going to see a very different arc around the ability to treat more and more PE patients and get the treatment they deserve. I'm incredibly optimistic. It is just groundwork. It is just the hard work of now the trial's done. How do we educate everyone? How do we get that out there? I can tell you, we scheduled this at 4:00 P.M. because for the last hour and a half before 4:00 P.M., since the presentation, we were on many, many different calls laying out. Now that we can publicly talk about it, that work that I've just alluded to. We didn't do this one first. We did that one first because it matters. No offense, please. We're just going to do the work. We haven't stopped.
OK. Let's see. Other questions? You've been waiting a long time.
I guess just a couple of follow-ups. How quickly do you think guidelines could evolve here for this to be practice changing? It seems like awareness is the gating factor. Should we think about it being more gradual, or are there a subset of people kind of waiting out there to get data like this? You could switch them. Lastly, how do you think about a class effect here? Thank you.
Can I address guidelines for a second and then open it up for you to disagree with what I'm going to say? Again, living through what we saw in stroke, there is no central body in the world that issues guidelines. There are lots and lots of different organizations that have guidelines, suggestions. They call them different things. There is no, when you all ask the question about guidelines, that is not a thing that we think about in quite the same way because there are so many different organizations. Some do it every couple of years. You miss their cycle, they're not going to do it. It doesn't mean people don't get treated. Guidelines matter. The most important thing here in the short- term, for the next period of time, is getting hospitals to be aware at the treatment level of what this trial says and what they could do differently. There are different things, and we understand that difference. We are not waiting for the other. It doesn't mean we're not more than happy when organizations change their recommendations or guidelines. I think I'm stating that right. I wanted to say that out there.
Stavros, who’s written guidelines and has been lead author on many guidelines, could you comment?
Yes. That's how it is. I mean, each guideline is each society that issues guidelines has its own cycle. It could be three, four, five years. There's always guidelines that are coming, right, that will appear, let's say, in a year from now or within a year from now. This is also the case here. Actually, let's say from the European point of view, this is a very good moment because the guidelines are being finalized now. They should be final early next year and appear a little bit a couple of months later. This is a moment which is a good one. The American Heart Association is going on with guidelines. There are many, many societies all over the world. You always can have the evidence needed to provide to the next guidelines that will come.
Generally, although there are many guidelines in many countries or continents, generally, when the guidelines issue a recommendation, they are in agreement. It is extremely rare that you will find, let's say, guidelines in North America saying that and guidelines in Europe saying the opposite or disagreeing. This is something when usually when the evidence is here, the process of evaluating this evidence, of issuing a recommendation is quite similar. We think this will not be an issue in this case.
If I may, about the class effect, Okay. I think there will be a slight class effect. This is a very important concept. I alluded to this in the presentation. The safety profile that we witnessed during this trial, where completely naive operators did two cases and had no device-related complications, no access site complications, no device-related transfusions, I would argue potentially sets a new gold standard for safety. I think that as more and more interventional operators, not only in the U.S. but around the world, think about how they're going to incorporate mechanical thrombectomy into their treatment algorithm, they're going to look at this data and look at previously published data. They're going to question whether or not perhaps a device that they've used historically can offer them that degree of safety. I think it's a testament to the operators that we had participate in this trial. It's also a testament to how uniformly they all said, this is an easy device to learn how to use. It's incredibly safe in my hands. I think the data bears that out.
Rob, may I mention that one of the things that distinguishes a device used in this trial from everything else is this computer algorithm, the FLASH. That algorithm, which helps regulate and modulate blood flow, is only present in one device. Whether this data could be reproduced by others is something we'll have to see. I think that when you look at the things that Rob mentioned and when you look at the technology that differentiates this device, I believe this device is its own class. I do not believe that we can generalize that every device that's out there that works very differently would all function the same. We'll have to see on that.
Can I add one thing? There was also this very interesting aspect of the question on the proof of cost effectiveness. I'm not an economist, but we have been also working on a little bit health economic evaluations. It is very interesting to see, especially with any medical intervention, but in this case, with a catheter intervention, of course, the upfront costs. The question is, first of all, how many life years you potentially save and how many quality-adjusted life years you potentially save and how many indirect costs you reduce by having someone live better, live longer, and not seek medical help again and again because they have a lot of rest thrombus. This causes them to go into the hospital again and again after the acute PE . The data that we already have is really very promising.
What we were waiting for was also the direct comparison of medical outcomes to strengthen this data. I am very optimistic. This is being done by many specialized academic institutions, and we're also collaborating with some of those. The cost effectiveness data that will follow after the medical data will also be very, very positive because there are many ways in which you can affect long-term costs also by relieving the patient from the acute clot overload.
I think that goes into your question about the functional outcomes. I think that's why the functional outcomes are critically important because we want these people to get back to the life that they had, get back to their jobs, get back to their families. Those will be critically important.
Yes, Cecilia, go ahead.
Hey there. [Peter Tickering] at Deutsche Bank. Every center in this trial had a PERT team. Is that a limitation for adoption going forward? How do you see expanding CABT into hospitals that don't have PERT teams?
Go ahead.
Do you want to go first?
First of all, not every center did. The majority of centers did have a PERT team. I think that with the new PRISM program with PERT, we will be expanding the number of centers really around the world. PERT started in the United States. We now have PERT International. We already have 12 countries, and I think 50 more are waiting to sign up. When you think about PERT teams, even if somebody does not have a formalized PERT team, I think the way that people think about treating PE is very different because most places it's not one person making that decision. It's more than one. It's the ER doctor that sees the patient and calls the interventionalist, ER the doctor sees the patient, calls the ICU person. Even though they might not call it a formal PERT, it's not one person. I do think that this can be adopted whether centers are calling themselves PERT or not. I do think this opens the opportunity to allow people to think about adopting PERTs and actually formalizing those. It's very easy to do. Again, the PRISM program is really going to help us with that.
If I can add, having a PERT program was not a requirement for this trial. It wasn't really even a consideration. It's just this data we collected. The second thing I'd mention is that when we talk about the PERT Consortium, that's a formal consortium and this formal recognition of programs. The term PERT is a vernacular term that everybody that does PE uses now. If there's just two doctors in a hospital working together, they call themselves PERT. That doesn't even mean that they're registered with the consortium. We look at it. It's a vernacular term that's used widespread. I just, again, to emphasize, we did not seek anybody out that had PERT teams. It's just the way they define themselves.
It stands for, I think everybody knows this, Pulmonary Embolism Response Team. As long as there's a team at the institution to take this on, they should be able to sort of triage patients and determine the appropriate course of treatment. Just to reiterate, you didn't have to have a PERT. If you think about it, when PEs are identified, they're not identified, no offense, by the interventionalists, right? They're identified on the wards, the internal medicine, hospitalist, pulmonary. Automatically, it's more than one person. Even though it's technically not called a PERT team, that is what they're doing.
Next question. Do you want to? Yes. After this, we have to go to the back a little bit too.
[True Securities]. Thanks and congrats on the data. Just one, were you surprised by anything positively or negatively in the data relative to what your expectations were? Let me let you ask that. I have one that I wanted to ask about.
I think I mentioned this on the podium earlier today. I was really impressed with the safety profile. I think that was something that we were obviously all optimistic about. The fact that this was a new technology, the fact that we all on the trial leadership believed in the technology, and the fact that we were able to get it into the operator's hands with almost no experience and it had such a high safety profile, that was the most impressive data. We were all optimistic that we were going to show that removing the clot out of the heart was going to offload or take the strain off of the right heart. The safety profile was just so impressive and so uniform that it was very pleasing to see with a novel technology.
I want to, for those of you who weren't in the room watching the presentation, that was actually highlighted not even by people in the trial, but by Dr. Sysemski, who wasn't in the trial but was one of the moderators of the session. He commented on that safety profile and the fact that with very little experience, the operators could have these results. He then asked the question, does that mean that this can democratize the procedure at a pace that's much faster? Somebody who's not associated with the trial has a desire for it to be successful, if you will, had that observation in real time. That was great and a pleasant surprise because I think that's how we have felt about this technology. That was the point of developing this technology, to make it not only faster but safer. To see that obvious in the presented data, I think, meant a lot to us. Thank you.
Control arm, the anticoagulation arm. Were you surprised at all by the amount of benefit in RV to LV ratio in that arm of the trial? How does that stack up to kind of real-world experience?
Yeah. We know that anticoagulation works very well. That's why it's the mainstay of therapy. There was a trial that we did a few years ago where we looked at the thrombus burden decrease from when they got the anticoagulation plus this TAFI inhibitor. We found that that was a negative trial, a different trial. In that trial, at 24 hours, there was a 40% decreased risk in thrombus burden in the anticoagulation arm and the other arm. We were not surprised to see that there was going to be a decrease. We were hoping that there would be. It's just the dramatic difference between the CABT arm plus anticoagulation versus anticoagulation alone. We know anticoagulation doesn't cause the thrombus to decrease. It's your own body resorbing that clot. The anticoagulation is preventing you from getting new clots. Over time, we do expect that to happen. We often see anticoagulation making relief, but not to the degree that that combination did. I wasn't surprised to see that. In fact, I'd be shocked if there was no change with anticoagulation arm. We were looking to see if there was a significant decrease. There was by over 2.3%.
Rachel, can you comment because we've spoken offline about this, about the quality of the anticoagulation delivered as part of this trial and how it compares to other anticoagulation trials, and then how it compares to your practice as a hematologist of whether or not this level of quality of anticoagulation is representative of real-world patient care, and then how you can impute the results of it.
If you were at the presentation, you saw that Rob put up a slide of where 80% of patients had full-dose anticoagulation at 48 hours. That is pretty remarkable because in general, the way this country and world treats PE, a lot of people use unfractionated heparin versus low-molecular heparin. Unfractionated heparin is through the IV. You have to follow levels. We've done studies in our own institution where we found that at 48 hours, less than 50% of people were fully anticoagulated. If you can't even get these people with pretty high-risk PEs fully anticoagulated, we're in trouble. We are not the only ones that have done that. The fact that this trial was able to make sure that people were fully anticoagulated, we've moved away from unfractionated heparin. We're now doing low-molecular heparin. We're getting more and more people therapeutic. I think this is one of the strengths of this trial, that there was no difference in that quality of getting people fully anticoagulated. If there was, that would have been a real confounder. We would not have been able to say, this is what we found and this is the reason. We've taken that off the table.
It was exactly a benefit of this study that for the first time, there was a direct comparison to optimal anticoagulation because until now, studies said, you know, with the catheter, the thrombus was effectively removed. That was great. No one knew how things would have happened if there was also an arm that was a control arm. This shows that optimal anticoagulation also works, I mean, in some patients. The difference was of a factor between 2.3 and 3 to 1, depending on which parameter you were looking at, which is quite remarkable. That means as many as 3x more patients can benefit from this, or in as many as 3x more patients, you can prevent decompensation or you prevent death. 48 hours later, you know i n the beginning, you don't know who of those patients who will be treated with anticoagulation alone.
Again, we're talking about severe PE here, right? We're not talking about all pulmonary embolism. Who of them will survive? Who of them will decompensate? The difference itself is something which is now shown for the first time directly. Until now, there were comparisons to historical controls, which are not correct, or comparisons to what many people thought that anticoagulation would achieve. In real life, that's also the problem as was highlighted. Anticoagulation is bad. All those of us who have been in ICUs, we know that achieving therapeutic anticoagulation within six hours approximately, as was in this trial, is totally utopic. In most cases, you achieve it within 24 - 48 hours. That's unfortunately real life. Anticoagulation is difficult. Even with low-micro heparins, it's getting a little better.
Next question.
Over there.
Brandon in the back.
Hi everyone. Brandon Vasquez from William Blair. Thanks for the look in the back. I wanted to go back to a question from the start of the conversations on kind of the enrollment criteria. You'd made a comment that some patients were either too healthy or too sick. Can you spend a minute on rough proportions of how many were healthy, too healthy, too sick, and then where those patients are going after? Are they getting maybe the sick patients are getting mechanical thrombectomy anyway? We've talked a lot about this being a foundation. Outside of commercial execution, I assume there's more clinical data to build on this foundation. What are the clinical data sets to expect next? What are kind of the timelines for those?
I'll take a stab at that. Patients who were more symptomatic or more ill than the patients that we enrolled in this trial would be widely considered to be high risk or of the highest risk. Those mortality rates are as high as 25% in that cohort. There are guidelines that say those patients need to be reperfused immediately. There is a multitude of different options available to that. It's not necessarily ethical to randomize those patients to anticoagulation alone, all right? We were looking for a very uniform cohort because we were trying to really demonstrate this treatment effect. As Rachel clearly stated, these patients got best-in-class anticoagulation strategy, all right? We showed that we were superior to best-in-class anticoagulation strategy. To do that, we needed a very uniform cohort in terms of symptoms in order to demonstrate that. The more that we allowed a very heterogeneous patient population in, it would question the durability of the results or the applicability of these results here. The fact that it took screening seven patients to enroll one, we were enrolling the right patient to demonstrate the treatment effect in a specific risk categorization against best medical therapy. I hope that answers your question.
Yeah, on the other end of the spectrum, healthy patients.
We did not study the minimally symptomatic patients. These patients were very sick, as demonstrated not only by a very abnormal size of their right ventricle on the CAT scan, but also that their blood work showed that their heart was under significant strain. These are the patients that are right under that high-risk category. Still to this day, in 2025, the guidelines say they should be treated first with anticoagulation alone. That's the cohort that we wanted to study here. Obviously, future trials can and will randomize patients that are much less symptomatic to try and demonstrate benefit for that. We were studying a very specific cohort of patients in this trial.
Mostly because this has not been looked at. If you look at the guidelines, it was a huge gap in care that we have now filled.
Just to clarify for everybody, that is the group of patients that we've been talking about, which is the acute, intermediate high-risk PE patients that were matched up in both arms to then determine the treatment effect of both therapies.
Sure. Right.
Thanks very much. [Mike Krake from Lyrinc]. Lots been asked about the different new physicians and centers using mechanical thrombectomy versus the existing ones. As we think about the near-term additional impact from a commercial standpoint, where do you expect to see that come from between the two, between new physicians versus existing ones that are now more comfortable using this in that intermediate high-risk bucket?
I think we have to talk about what physician groups we're talking about. We're not so much talking about interventionalists at that level. I want to make sure that I heard the question right. I think most interventionalists would treat any of these patients that are referred to them. I'm not aware of interventionalists who would say a doctor or pulmonologist referred a patient to be treated and they said, you know what? I'm not going to treat them. I could be wrong. What we're really talking about is the group of physicians who are seeing them on the front line. I don't think one can judge sort of their reaction. We just have to educate them what the data says. I could be wrong.
Yeah, no, I would agree with that. I mean, I think when you think about who the first person is seeing these, are you asking in general providers? Are you asking interventionalists specifically, and how we're going to get this message out to interventionalists or how we're getting it out to non-interventionalists? Yeah. Yeah, we're not using them for that. Yeah, I think an earlier question was asked very similarly where it's about education, right? If you go back to the stroke data and where we've come with stroke, if you look at the first even MI and stroke, how many years it took to get the first person thinking about something to do interventional, it was like 20, 30 years. Ultima trial was what?
30 is about right.
Okay, 30. Ultima was 10 years ago. In 10 years, we have closed that gap. It is all about education. One of the things that I mentioned is the PRISM education initiative, which is being run by the PERT Consortium. Penumbra is one of the sponsors of that program. I really think it is about education and thinking of where are the front lines. The front lines are the doctors. The front lines are the hospitalists, internal medicine folks, pulmonary critical care. It is targeting those people and really educating them. It is about educating on PE in general, right? There are so many missed PEs in the hospital a lot. I think it all goes down to education and figuring out all these different venues where that is going to happen. We have already done that through the PERT Consortium. We have already expanded that.
I think we already have kind of a platform for that. The only final point I want to add to that is that these non-interventionalists are not going to now start doing mechanical thrombectomy, right? What this will then do is have them now refer the patient to the interventionalist at their institution to now treat the patient with CAVT. That is the education and the awareness that is being done through this initiative. Feel free to add any additional.
I'll just add it, Troy, just slightly as an interventionalist. I think that interventionalists that have not previously treated acute pulmonary embolism will look at this trial data and look at the efficacy and the safety and the ease of use and think, maybe I can participate. Maybe I can get involved. Maybe I should reconsider whether I'm going to participate in the care of these patients. I'm already getting contacts from my peer group around the United States saying that data is pretty impressive. Let's talk when you get back to New York. I think that the safety and the efficacy are going to resonate with a lot of interventionalists that previously had not considered getting involved with this work.
Okay.
Thank you, [Mike Sourkoh and Jeff Reason]. Thanks for the presentation. Just a follow-up here on the interplay between this kind of cross-functional collaboration and, like, call it an official PERT team. I think the example was used you could just have two doctors collaborating. I wonder if you could unpack how meaningful can adoption be if it is just kind of a loose collaboration versus do you really need more protocolized, kind of systemic, from-the-top-down implementation of this?
I'll try that. The statistics, the epidemiologic studies show that somewhere between 15% - 25% of all PE patients in the United States fall into this category, all right? I think this trial, from a foundational point of view, demonstrates that there's a therapy that is better than anticoagulation alone. I think you're going to see more frontline providers start to consider this as a therapeutic option. Interventionalists are going to be increasingly warming up to this. I think you're going to see organically more and more partnerships form between non-interventionalists and interventionalists. This is going to be organic. The same thing happened with stroke. I think Adam spoke to that very eloquently. I think you're going to see increasing adoption, increasing growth in the months and years to come. Obviously, Stavros mentioned that there's three other randomized trials underway. This is one giant step in the right direction to allow this technology to be offered in more and more patients around the globe.
I think we have time for one more question.
[Dave Raska with Bear]. Thanks for taking the questions. I wanted to ask about the technology itself, right? We've heard some feedback from physicians around having potential to do thrombectomy in some more of the tertiary centers. They're referring those patients to maybe some centers that have higher volumes that are out there. What we've heard even just post the data is that the potential to have more, I guess, tertiary is the word I'm going to use, centers doing this does fall back on maybe the ease of use of the technology and the understanding that they have in using this type of technology in other vascular states, which potentially means that the Penumbra technology itself, the size of the catheter, is going to be the catheter driving that category adoption. Can you help us think about maybe the benefit that Penumbra has in driving this, or the Penumbra catheter has in driving this expansion out there versus the broader kind of thrombectomy category?
I'll just start and let Rob and others formulate their opinion. Your point is correct. We have products that work obviously in stroke and coronary for DVT and for arterial. Fundamentally, the CABT process is identical. The experience that you can gain from one vascular bed can translate to the other. I think that that's a huge factor. In fact, we have a lot of doctors who start because pulmonary embolism therapy, in most people's minds, holds a higher risk. A lot of people like to start in other areas, in DVT, for example. They get their experience and their confidence. The good news is in our other trials, we see similar complication rates and adverse events rates, which are very low. We do think that this is a very positive factor for us to be able to help democratize this procedure. The use in other vascular beds is definitely a learning, a confidence-building level for people when they get into pulmonary embolism.
I'll expand on that a little bit. I think that the most common pattern right now in the U.S. is a more centralized approach to refer the patient to a tertiary center. It's all predicated on, I would say, a moderate safety profile with a first-generation technology, which objectively was pretty crude. Now that we have this, what I would say is a very sophisticated or advanced technology, and you have the safety data that we've shown today, you have the opportunity to explore expanding the footprint for patient access. Again, I'll say this a dozen times. This is one giant step in the right direction to allow more and more patients to have access to this rescue therapy that is clearly showing to be superior to anticoagulation alone. We have to generate more data and educate more and more patients and more and more providers across the country about it.
All right. We're at time. Thank you all for coming. Of course, thank the amazing PIs and steering committee for the work of designing and really executing on this trial. It's a great day for patients as we move forward. Thank you very much.
Thank you.
Thank you.