[Dr. Peter Eckman]: Welcome any questions from the audience and while people are thinking, I knew I could count on Dr. Boyle to have something to say. I have a quick question for you Farooq. You know, talk a little more about the inclusion of the mid range EF population. And then a second short question is, was there any consideration of a crossover at 24 months? [Dr. Farooq Sheikh]: So thank you so much Peter for the question. Sorry, heard the second one, I forgot. [Dr. Peter Eckman]: The mid range EF. [Dr. Farooq Sheikh]: Yes, so thank you so much for that. For the heart failure with mid range or mildly reduced ejection fraction, which as you all know is EF of 41 percent to 49 percent. It’s really important to recognize that there have been multiple actually large healthcare system publications and multi institutional studies, let alone the control arms of multiple medical therapy trials that demonstrate there’s still significant residual risk for these patients in terms of adverse events. And it is because of the unifying principle that neurohormonal activation sits at the center of the disease state of heart failure with reduced ejection fraction, again defined as an ejection fraction less than 50 percent, it was important to test that hypothesis using Barostim. [Dr. Peter Eckman]: And then crossover? [Dr. Farooq Sheikh]: Yeah, crossover. You know I was not involved in that point in the trial design as to how it relates. But I think it’s really important to understand that you’d say, well this is an open label study, but the reality of doing a sham operation for these patients is not, first of all, we recognize from other studies the adoption rate is very low. Patients do not want to have a surgery and not get the therapy, that’s number one. But number two, the manipulation, and Matt would know this and our surgical team could speak to this better than I can, the sheer act of doing the surgery and manipulating the carotid sinus, the carotid artery in and of itself creates injury and does actually potentially create some signal, which may be hard to ascertain and to be able to study. And so therefore the decision was made to have a open label trial with a true control arm. [Dr. Peter Eckman]: Thank you. Dr. Boyle. [Dr. Boyle]: Well, there’s another Canadian in the room. Nice. Glad to be here. I’m curious because in real life, the sympathetic nervous system overwhelms the parasympathetic nervous system. So have you found, Shelley and Peter, whether people have to be adequately beta blocked in order to get this device to have its effect? In other words, do you see people responding better who are able to tolerate 25 milligrams BID of carvedilol versus the more common patient that I see in clinic, which is three point one two five or six point two five of carvedilol, and they’re not adequately beta blocked and therefore the sympathetic system would still be able to overwhelm the parasympathetic system that you’re trying to stimulate. [Dr. Shelley Hall]: That’s a very interesting question that I had not thought of before. When we implant, we typically drop their diuretics in half and drop their vasodilator in half at the time of implant. That is not a universal approach. That’s just what we have found work because we definitely had some patients that would get significant hypotension. And so our goal is rather than put them through that, drop their vasodilator and then when they come back for their first up titration, we reassess and continue to readvance their GDMT. What I have found is the ability to advance GDMT further after they’ve stabilized on this device. But I’ve not anecdotally noticed a beta blocker dosing relation. Now I want to go back and check all the patients. So, that’s a really good question. [Dr. Peter Eckman]: Yeah, have nothing to add. We haven’t done enough that I could comment on that, but I was actually going to ask you if you’ve also seen some fraction of these patients were able to escalate their other medical therapies. So, I feel like we have seen that, and I think some of it has been that we’ve been able to back off their diuretics, and so it’s easier to push these other meds. [Dr. Shelley Hall]: I would also say just that we’ve missed the boat on some of them. And I think it reflects that all of our abilities to prognosticate where they are aren’t great. We had some patients we were absolutely confident they were in that nice sweet spot and then they just got worse and worse and we ended up moving forward with transplant or VAD on some of them. So I don’t call that a device failure. I call that our ability to evaluate and identify the right patient failure. And what I tell them is it’s identified to me that you are far sicker than I actually thought you were. And I might not have known that for a while if I hadn’t gone through with attempting this device. [Dr. Peter Eckman]: Thank you. We’ll take a question on the back and then the front. [Nancy Liu]: Hi, thank you. Nancy Liu from Sutter in California. So a couple of questions going forward. For the clinical trial, are you at all concerned that you’re including the FDA indicated group and with somebody really is interested in the device and they’re randomized to a control arm that they would just leave the trial? [Dr. Farooq Sheikh]: So I think the purpose of including that group, they wanted that group to be included was to test the portion of outcome that was not tested or was inconclusive, could not be tested with BeAT-HF, which is the idea of mortality and morbidity benefit for that group. It’s a good question in terms of whether patients will commercially want the therapy, but again the way it’s structured, that is only a fraction of the cohort. So we remain confident that we’ll be able to enroll patients using this therapy. [Dr. Peter Eckman]: And if I can add one thing to that, because we’ve been excited about that in the sense that we’re still having some challenges with some payers don’t want to cover this. And so to go from a zero percent chance of getting the device to if you’re in a trial, you get a two out of three chance of getting the device. So I think it may help give access to some of these patients in a way that they don’t otherwise have and I think that’s why I would be interested in, and it’s maybe not too late to introduce, say, once you’ve hit your two year endpoint, can you then cross over so that some of these patients that have insurance that still won’t pay for it, they may still be able to get access to it through the trial. That would be another at least idea, but we’ve looked at that as a positive. [Nancy Liu]: And then as come somewhat of a two part question, so will there be blood pressure parameters for the trial and or in your clinical practice, do you use a certain blood pressure parameter in terms of so that the patients can, are able to not only tolerate the device but still be on their GDMT? [Dr. Farooq Sheikh]: I’ll start just because my answer will be brief. The rationale of design paper has been accepted in The Journal of Cardiac Failure should be online very shortly, you’ll be able to review it. In the exclusion criteria, symptomatic hypotension, there’s no cutoff that provides that, is an exclusion criteria as defined by the investigator. But there is no concern in that regard. There are some other disease states that are exclusions, cardiac amyloidosis, diseases historically associated with dysautonomia or peripheral nerve abnormalities. But in a trial that will not in and of itself be a measure by which you would exclude patients. [Dr. Shelley Hall]: Yeah, I would say practically, obviously not trial wise, we usually want a systolic blood pressure greater than 90. [Nancy Liu]: And then for patients who are able to go forward then to VAD therapy, have you seen any sort of differences in how they respond to VAD hemodynamics continuous? [Dr. Shelley Hall]: Usually once they’re on a VAD, we turn it off. [Dr. Peter Eckman]: Same here. Though fascinating question because obviously the RV doesn’t have the mechanical benefits of the LVAD and neurohormonal activation remains an issue. Remember, LVAD patients, heart failure hospitalizations are one of the two major reasons why they still engage with healthcare systems. I think it’s actually a hypothesis generating aspect. And yes, I believe we’ve had four patients with the Barostim and we have been turning them off, but I don’t think we have the definitive answer. [Nancy Liu]: Thank you very much. [Dr. Peter Eckman]: Thank you, and then in the front. [Dr. Ahmed Khan]: Hi, I’m Ahmed Khan with MedStar in DC. Thanks for your talks. Kind of a similar question. For the patients, you presented data to Dr. Ekman about blood pressure kind of remaining stable for patients who are receiving Barostim therapy. Do you have anecdotal evidence or experience of patients who are presenting perhaps an extremist with vasoplegic shock or also patients who are progressing to advanced therapies in the perioperative period. How are you managing the Baristin? [Dr. Shelley Hall]: So one of my longtime patients that I tried to get to do this therapy two years ago and she’s very, very resistant. Our son was one of my transplant patients. He had died. She was really struggling with it all. And finally when she was getting worse, she agreed to proceed. And I was away and my partner talked to her and she’s like, yes, yes. And I probably wouldn’t have done it at this stage, but I wasn’t around to kind of give them all that historical background. They did end up doing it and she did not do well. She ended up needing inotropes and she went home on inotropes. So I think that knowing these patients longitudinally helps a lot for identifying and avoiding that kind of scenario because you know, I feel like I wasted the device on her. And but what we are doing is we are slowly uptitrating it now that she’s on inotrope support to see if that will over time facilitate weaning her off because she’s not an advanced therapies candidate. [Dr. Farooq Sheikh]: Amit, I would add that unfortunately patients have sepsis, have infection, have other reasons to be hypotensive, the device reps have been wonderful advocates helping us titrate down. At our center, Richa Gupta leads the effort and so we’ve had a few of those patients who’ve had that UTI, urosepsis, and then we’ve had to down modulate the therapy. Then eventually, I actually just saw a patient last week who went through that and is now back at 8 milliamps and doing very well with her therapy. It had actually a significant symptomatic benefit, but because of infectious complication, we had to avoid any more further hypotension, bring it down. It was very easy to get CVRx to help us. It was not a problem. [Dr. Ahmed Khan]: Don’t have anything Temporary MCS also. Have you been [Dr. Farooq Sheikh]: Oh, I apologize. I do not recall we must have, but I don’t recall what we did in that setting. We probably did down I hear from other investigators and clinicians that they’ve done it, but I apologize, I don’t remember the history of that. [Dr. Shelley Hall]: We haven’t had that peri op, but we’ve certainly had patients that eventually their disease progressed and they ended up hospitalized for advanced therapies and had been on temporary support. And we have typically down titrated the settings and sometimes turn it off because, you know, the EKG, it freaks all the ICU nurses out and can’t, you know, you have to get sleep too. So, we will often down titrate or turn off once they reach that stage. [Dr. Matthew Danter]: Yeah, the, you know, when you say perioperatively, do you mean around the time of the implant procedure for the Barostim or the time of their VAD or other MCS? [Dr. Ahmed Khan]: Yeah, the latter kind of leading up to [Dr. Matthew Danter]: Yeah, because that’s a different question, obviously. Perioperatively for the implant, I mean, it’s at a very low setting. They haven’t ramped it up. They just tested that they actually get a reasonable response with the device and it’s set on at a very low impulse rate. And then that will be titrated when they’re out in the community and anesthesia is off and all this kind I have no experience with them going to VAD or deteriorating MCS yet because our we’ve only done sort of seven, right? So they’re not progressing, but so. [Dr. Shelley Hall]: I missed didn’t understand that was your question. So we’ve had several go to VAD or transplant with Barostim. We turn them off and we leave them in. Now we thought that was a good idea. So sorry, the device gets removed, but the lead gets cut. So, you know, kind of the way they do with your ICDs and that part that’s stuck on the in the vein. So we thought that was fine. But the problem is many of these patients need MRIs later, and they won’t do an MRI if it’s cut, if you leave it intact you’re fine. But cut not. So now we’re contemplating do we remove the whole device at the time or do we leave it in? Because if it’s all intact and left in, you can do an MRI of head or lower body. But if you cut it, then it’s no longer allowed. So we’re refining our approach with that knowledge. [Dr. Matthew Danter]: I would think it would be relatively challenging with how much is left in subcutaneously, that it’s going to be stuck kind of like, you know, poop to a wool blanket when you try and get in there. So, I would say leave it in if you can. That’s what I would say. Because just if it’s not bugging anybody, because if it’s trying to take that out around the I mean but basically it could be very stuck because you leave a you have the it’s fixed in two places, you have a redundant loop, all of that will be pro inflammatory. And so, I would leave it, if we had encountered something where it wasn’t infected and it was just for purposes of decommissioning it, I would leave it in. But that’s based only on my fear of, yeah, screwing it up. [Dr. Peter Eckman]: That’s timely advice. We have somebody waiting for a transplant right now with a Barostim. She just asked me the other day, ‘Do you take it out at the time of surgery?’ And I said, ‘Probably not.’ And now I’m going to tell her we should probably leave it all together. [Dr. Matthew Danter]: Yeah. Yeah, can take the generator. I’d take the generator out just for…[Dr. Peter Eckman]: Then to Shelly’s point, then you might trash the ability to get MRIs. So medicine is hard. Thank you for your question. Thank you. In the back. Thank you for the visual. [Dr. Will Grandin]: Will Grandin, heart failure transplant cardiology at Beth Israel in Boston. Great session. You guys just answered my second question, was about what we do at the time of transplant. My first question for the panel is just based on the implants you’ve done to date and cases that you’ve seen, are we developing? Do you have a sense of factors that predict response or failure to respond to this therapy akin to what we think around for like for CRT responders, are there things that you think help identify people that are particularly likely to respond or perhaps not respond? [Dr. Peter Eckman]: I’ll go first. From my standpoint, I think sticking to the BNP criteria, at least for the purpose of the trial well, outside the trial. For clinical implants, we had done one or two that had a little higher BNP, and they were too sick. They just didn’t do well. So that’s the only thing that I would reinforce. But I think Shelley and Farooq probably have more experience than I do. [Dr. Shelley Hall]: Yeah, I think that one of the dangers as a heart failure cardiologist is EFs of, you know, 35 look normal to us, right? And we tend to downplay how sick a patient is. I mean until they’re in the ICU on two drips and an Impella, we’re like, oh, they’re fine. And so I think that our biggest danger is that we probably end up being too conservative on the early side and too aggressive on the late side. So, to me, I think it’s really getting to the cardiologist and trusting your general cardiologist history about the patient. If they are struggling, that we should not poo poo that because they’re not like our really sick ones. So, I think that that’s the target area to be focused on. But as far as particular parameters, blood pressure, BNP, all that, have not noticed some single factor that says, yeah, this person’s going to respond. [Dr. Peter Eckman]: I think a challenge with that approach though is that what I found is that the patients, if they’re not pretty symptomatic, they don’t want another device. So you got to get them when they’re symptomatic enough, but not so sick that it’s too late and I don’t know that that’s a well defined window, even, you know, you look at CRT, and we have some factors, but we’re still not great at it. [Dr. Shelley Hall]: And I think that’s why a good history is so important. Really asking them pointed questions. Not how are you doing? Not an open ended teenage question. But very specific questions. What do you do for a living? What kind of, you know, what were you able to do a few months ago? Oh, really? You gave that up? Why’d you give that up? It takes some time to really find out how limited they are because they usually don’t share that unless you pull it out of them. [Dr. Farooq Sheikh]: I would add Dr. Adamson is in the back, knows much more about this than me. There is a CVRx sponsored registry of commercially implanted devices which has matured and is, you know, there’ll be data that’ll come out of that. And I certainly know some of the investigators are looking to assess what those predictors may be. Of single or maybe most institutional data, I’m not familiar. I don’t recall anything recently demonstrating those predictors, but if anyone will know, Phil will. He’s in the back. [Dr. Peter Eckman]: Otherwise, it’s a great idea for a poster session next year. Sarah. [Sarah Shettle, PA]: Hi, I’m Sarah Shettle, Mayo Clinic, Rochester. Thank you all for these talks. I just had a question if any of you have experience as to whether the central nervous system has any sort of acclimation or adaptation to chronic stimulation over time? And do you need to adjust or titrate therapies as a result? [Dr. Shelley Hall]: I mean we’ve had to up obviously our goal is to up titrate to maximally tolerate it. And we’ve certainly seen some down titration as well. I’m not sure that I am sophisticated enough to know if it’s due to the central nervous system or not. But clinically we have had scenarios that point us to go up or down. [Dr. Peter Eckman]: Yeah, I don’t know anything either. I don’t know, Phil, if you have any comments on that. We also turn it up as high as we can and then we leave it alone. It’s very plausible that over years there’ll be differential regulations so benefit may change. [Dr. Philip Adamson]: Yeah, question, Sarah. I think we don’t see a diminution of clinical effect over a long period of time so there doesn’t appear to be an acclimation to it, there’s constant stimulation. Remember, it’s unilateral so there is input to that central system from both sides. There is no evidence at this point that there’s central acclimation nor is there evidence that there’s depletion of neurotransmitters with continuous stimulation as well. [Dr. Peter Eckman]: Thank you. Thanks, Phil. Question in front. [Dr. Stephen Waller]: Yeah. Hi. Stephen Waller, University of Kansas. I’ve got one simple question. Because the infraclavicular placement of the generator, if you had a pacemaker on one side that was infected or something, needed to move it. Would the presence of that preclude your ability to put a pacemaker there? [Dr. Matthew Danter]: The answer is it depends. I mean, that would be a very challenging thing to do. Because typically what happens is these people already have an ICD, at least the ones we have, they’ve already got an ICD, and you’re putting it over there because this area is. But you’re right, they’re going to get generator changes. They’re going to get you know, potentially need lead extraction or something like that from that side. Where we traditionally put the pocket on the right under the right clavicle is right where you would typically put a right sided ICD if somebody wanted it over there for the you know, it didn’t have a Barostim with it. So I think it would be very challenging. I mean, have lots of different sites where we can put pockets for pacemakers and things like that. But it would it is in the traditional place where you would put a right sided system if you needed to put it there. So it’s a good question. Because the longer these people have this in, they were just starting to pick up things. Now post transplant we’ve got an immunocompromised person with a bunch of equipment in forever. And I really think it’s going to be stuck to the carotid, and in that the carotid sheath. Taking all of these things out is something to consider surgically. [Dr. Peter Eckman]: Thank you. I think we have time for one more question. [Caitlin]: Okay, I’ll be super fast. My name is Caitlin. I’m with Baylor Dallas. I’m a clinical exercise physiologist. I was really excited to see the changes in functional capacity with this. I was wondering if with the central influence of the therapy, would that restore a more physiologic or normal response to exercise that we see go away with advanced heart failure or a lot of heart failure therapies? [Dr. Peter Eckman]: I don’t know the data on specifics of physiologic improvements. Best I can comment on is sort of the aggregate data of their six minute walk times or better, but whether they’re, you know, heart rate response or variability or some of those parameters, I’m not aware of. I’m very lucky to have Dr. Adamson here to bail me out again. [Dr. Philip Adamson]: Absolutely fantastic question, and this is I think one of the contributors to the improvement in exercise tolerance is the restoration of parasympathetic control. If you think about normal parasympathetic control during exercise, the early cardio acceleration is not sympathetic activation, it’s parasympathetic withdrawal. If a patient starts exercising with no parasympathetic control, they’re already starting at an advanced exercise physiology and so restoring the parasympathetic control, which we see clearly with heart rate variability measurements repeated over time that we do restore that. So the idea is by restoring that, that allows patients to have that early phase of acceleration where they wouldn’t otherwise. [Caitlin]: I don’t know if you can hear me. Thank you so much. If anybody wants an idea for a poster looking at VO two uptake kinetics with this device would be an interesting one too. [Dr. Farooq Sheikh]: It’s definitely an area that I was going to say. I actually was going to bring that up that CPET is an area of interest for a lot of number of investigators. Yes, it’s definitely worth start looking at that. [Dr. Peter Eckman]: All right, well we’re going to have to close our session, but again I’d like to thank you for joining us and thank our panelists as well. I hope you enjoy the rest of the conference.
