Good afternoon. Thank you everybody for joining. Welcome to the Cardiac Contractility Modulation CCM Therapy. I want to thank the organizers and host of this meeting in Pulse Dynamics. I'm Dr. Brad Knight, Head of EP at Northwestern in Chicago. I'm excited you're all here. I'm joined by my co-moderator and friend, Dr. Debbie Nair, Head of EP in Jonesboro, Arkansas. We have four exciting presentations, three by electrophysiologists and one sole heart failure doctor here. I think we all know that we have patients who we share with devices, without devices, with atrial fibrillation who have congestive heart failure. We have a strong partnership with our heart failure colleagues. So we're going to kind of emphasize that as we go through here. I have a few announcements I want to make before we start. There is a QR code. If we can hook that up. You can scan this if you want to ask online questions for us. At the end there will be a separate QR code for you to scan to make an evaluation of the program. We'd encourage you to provide feedback at the end of the program. If you can turn your cell phones off too, that would be great. And we have plenty of seats up front if you want to come up front. We're going to save questions for the end speakers. So we'll have everybody give a talk for about 10 minutes. That's 40 minutes. And it should give us ample opportunity to have a good discussion at the end. So I'm going to introduce our first speaker, Dr. Murat Fudim from Duke. He is a congestive heart failure specialist. He's also the medical director of the clinical research unit, the heart failure remote monitoring and the heart failure device clinic. He's going to give us a talk on we know what to do, why is it not working from a heart failure perspective. We can pull up his first talk. Thanks for having me. Good afternoon, everybody. I hope the food tastes good. I have to stuff some chips in my face before I start. So I'll be talking about the burden of heart failure and, you know, where this device-based therapy and other device-based therapies really fit in into our clinical practice. You know, my background is I'm a heart failure cardiologist. I do take care of our device clinic and our remote monitoring clinic at our institution. You hearing me? Yeah? Okay, perfect. So the interesting thing is so we have about 7 million people with heart failure in the United States, the number one cause of hospitalization. It is the number one cost item in the United States healthcare system, yet a lot of focus in heart failure is really at the beginning and at the end of the disease stage. The beginning is when we titrate GDMT. That's all about implementation, getting the four or five pillars of drugs on patients. There's a lot of education and trials around that aspect, but also around the end stage of the disease. I mean, advanced heart failure doctors are really trained to identify and treat those patients at the end. But however, in the green zone, when patients are optimized on GDMT, whatever that means, we'll talk about in a second, to the need of transplant or VAD, that is a big, big, big unmet need that we often don't address. In Apple recently, we didn't have many solutions to treat. So 64 million patients with heart failure worldwide, if you do the math, half of them have heart failure with reduced ejection fraction. The other half is heart failure with preserved ejection fraction. The cutoff is usually around 40 or 50% of the ejection fraction that we use. If you look at how many of those actually are eligible for CRT, just because that's, you know, you need to know your audience, that would be about 17% of patients. Only a fraction of them actually gets the CRT devices, as you know, for many, many reasons. But that makes a very large addressable market for those patients that are not transplant VAD candidates, they're optimized on medications, their LVF remains low, and are having a narrow QRS, potentially eligible for device-based therapies such as the CCM, the cardiac contractility device. So now, we drill this down into the heads of all our trainees, nurse practitioners, that once patients are diagnosed with heart failure with reduced ejection fraction, you've got to start them on at least four drugs as soon as possible and titrate at a rapid rate. We actually have dedicated trials, such as the STRONG-HF trial, which was a randomized control trial around 1,000 patients that was aborted early due to the benefit on heart failure hospitalization and mortality in this trial, because in an aggressive titration arm, they saw fewer events at one year than in the standard of care arm. Notably, even in a clinical trial where you had to be seen at week one, two, three, six, in person, which is, of course, not something we can do in clinical practice, we still had a number of patients, but half of the patients actually did not end up being on three out of the four drugs that they wanted patients to be on. This trial is now a couple years old. Not in all countries it was run that access to all four drugs. But that's a landmark trial. You will see in our clinical practice the strong push to get these drugs titrated as soon as possible. My clicker. Here we go. So I would argue that we have one big problem in the clinical space. We do tell our trainees, we do tell our partners in the community that we need to titrate patients on medication as fast as possible, but this is not a battle one can win. GDMT titration is not a one and done, because in clinical practice we titrate up, we maintain, titrate down, titrate up, titrate down for the rest of their lives. So usually that's used as an excuse by our partners to actually never transition them to what might be the next step, and in many cases device-based therapies, including CRT, because we think there's always more room to improve. Unfortunately, that battle cannot be won. And I think that is, you will see over the next few years, while we push for the implementation of GDMT, at the same time we will be trying to identify triggers when to move on. And one of the triggers, by the way, is going to be around time. The guidelines tell you to try it for three to six months to titrate GDMT, but GDMT doesn't stop. GDMT titration doesn't stop. So we just have to become more firm on these timelines. So what is counterconductivity modulation? For those that have not seen or known about it, it's a pacing algorithm. It's a dedicated device. Two leads are placed in an interventricular septum, just a regular pacemaker, that now delivers, however, a very high impulse. It's about the 200 times energy of that or a regular pacemaker impulse that gets delivered to that interventricular wall between those two leads that gets deployed at the end of the QRS. And EPs, please correct me if I say something wrong, okay? We will. Thank you very much. So you deliver a lot of energy at the end of the QRS, so it's a refractory pace. You're not going to induce VTVF in that case. And you do that every beat for hours of the day, not all day, every day. So the result of that is actually very interesting. Initially, it's acutely when you turn the device, so it's actually a positive inotropic therapy. So now I don't want to scare you all by thinking, oh, inotropes, isn't that what you give to NCH heart failure patients? No. I mean, there's many therapies that could be positive inotropes. Unfortunately, a lot of the therapies we give to patients that are inotropic in its concept have also detrimental effect. They leak troponin. They might actually lower blood pressure. That is not the case here. So here, this acute stimulation results in the change in calcium handling. You actually increase the calcium uptake into the cell inside of the cell called the sarcoplasmic reticulum. So through that electronic impulse, you enhance the way calcium travels through the cell. And calcium is vital for the cell's ability to contract. So now, those are the acute effects. It's a rechargeable battery, which is a key differentiator. Every week, you have to charge it for one to two hours to maintain its battery life for up to 20 years, maybe even longer. That's a key advantage to many other device-based therapies where you, of course, have to exchange battery at five to eight years. All right. So what's the evidence behind this implantable tool for patients with class III symptomatic heart failure, Monsa, Tetra, and GDMT? Well, it's interesting. And again, sort of know the crowd you're talking to, I guess. Let's talk about CRTs. When CRT devices came initially to the market and were approved or proven to be beneficial, they used so-called soft endpoints. They looked at quality of life, functional status. And one way to measure functional status is actually to measure your peak VO2. So all of these parameters are measured. And that's what these devices were proven to be beneficial and approved upon, such as the CRT miracle trials. But now, when you put that in contrast to the CCM device, which also was tested on, quote-unquote, soft endpoints initially in a number of studies, which had only a couple hundred patients at best. These are relatively small trials. They were able to demonstrate very comparable benefit of functional capacity, 6-minute walk test, Minnesota living heart failure, which is a quality of life questionnaire, and as it was seen with the CRT devices. So now, to make this actually more interesting, because the CCM has been tested in patients as low as 25% ejection fraction, it's approved with an ejection fraction of 25, all the way up to 45. If you look at the subgroups, that about half of the population that had the higher ejection fraction, so 35 to 45, you had even more benefit. So contrasting the all comers, see in green, versus just the ones that had a particularly high ejection fraction. That's also, by the way, the group that I preferentially implant those patients in, not at least because they actually have sort of out of proportion benefits in that patient population. All right, so that's to contrast to where we stand. Now, indicated with an ejection fraction 25 to 45, you have to have symptomatic class 3 heart failure. I would also argue it's hard to convince patients that are asymptomatic, even sometimes with class 2 symptoms, to do any device-based intervention, even drug-based intervention, by the way. Asymptomatic disease is really, really hard to treat, which is why we're doing such a bad job with treating diabetes and hypertension, because people don't feel it until it's too late. So the way we, at least I advertise this technology to patients, is that it's going to improve your quality of life. Six minute walk distance might actually have some benefit on your ejection fraction, the ability to squeeze. Sometimes we use it as an upfront strategy to then maybe decide whether they need an ICD or not. I have a patient like that right now with an implant. And so those quote-unquote soft endpoints is really what we advertise. So now, is there evidence of benefit beyond quote-unquote those soft endpoints? Yes. Go back to the mechanism. The acute effect is the rapid contractility, sort of the safe inotrope approach. That's the acute effects you can see in a petri dish, in an animal, and in human, if you do PV loops right then and there. And then if you extend the benefit and continue watching those patients over subsequent days to weeks, you actually change, see a change in the protein expression. So now those genes and those proteins that handle that calcium, now not only working harder and faster, actually you can also see that they're overexpressed. You can actually measure the expression of certain genes that are down-regulated in heart failure patients, now being up-regulated compared to control patients. Now extend that out to weeks to months, beyond that, you see that this is no longer a local effect. There's actually studies, one was from Germany, where they biopsied the lateral wall, the lateral wall of the heart, even though that's not where they're paced, and they demonstrated protein expression changes, even the walls that were not originally paced. Okay. So now this is what I refer to if you do, this is a quasi PV loop study. Now I don't want to overwhelm people here, but the bottom is the amount of contractility, sorry, I got to take it easy, it's primarily a Vivek directed comment. Yeah, it's true. So if you measure the amount of contractility generated, so the force generated with an impulse, a regular beat and a paced beat, as demonstrated here with the CCM device, you see that it occurs, you generate more force, the green line goes from left to right, there's more force generated, but not at an additional expense of oxygen. So the cell did not have to work harder to generate that amount of contractility. That is not the case if you look at dobutamine and inotrope, which is the not safe inotrope. It generates more force without doubt, and a lot of it so, but it comes at a greater cost. And then if you see LV pacing, it's sort of relatively neutral as well. As a matter of fact, over time might be more beneficial, but again, applies only of course to left spinal branch block patients. So now does this translate to long-term outcomes? If we improve short-term, you express, you change gene expression locally and globally. As a matter of fact, in the trials they had, they had patients with six months follow-up. It was a secondary endpoint. That's not what the FDA approved it for a label indication, but the data was there. It was pre-identified endpoint to look at, and it did see a reduction in heart failure hospitalization mortality when looking at those patients between the control arm and the treatment arm. That's in a trial. Now in the post-trial era where patients go out and get the devices clinically and have the device followed as part of registries, that was actually reproduced. That was primarily data from Germany where this device was implanted a lot originally. They saw a reduction compared to what you would have expected as a mortality for those patients. Now of course with the caveat is a single arm open label registries, the device seems to outperform what we would expect for this relatively sick patients. So now maybe to make the last few slides, because I have only 40 seconds left, is that heart failure is the number one cause of hospitalization. There's only one disease state that has actually more hospitalizations. It's childbirth. I have two sons. Sometimes it's a disease state, sometimes it's not a disease state. It depends on their behavior that day. But it is number one cost item we need to focus on. We obsess. I know you have kids. I've seen your kids. You understand. People with kids understand. For every patient with cancer, you have many more patients with heart failure running around, costing us more mortality associated with the disease. You can make the argument of AFib. I know the crowd I'm talking to. I'm trying not to trash talk too much. But you love AFib. But don't forget, those patients have heart failure. In most cases, they have heart failure first, AFib second. So there's a big unmet need. Thank you for your attention. And I'll very much look forward to the next talk that will dive deep into the data and what's to come. Thank you. Thank you. I look forward to our discussion, maybe to talk more about the issue you raised of you just can't beat that battle and some of the other stuff. But we'll wait for the discussion for some questions. Our next speaker, Dr. Vivek Reddy at Mount Sinai. He's going to talk to us about what's new in CCM therapy. Vivek. Okay. Thank you very much, Brad. That was a great talk. So it's time to take a little bit of a break. So touch your legs a little bit. Okay. I want to thank Impulse Dynamics for that very kind invitation. So my charge is to discuss some of the new aspects of CCM therapy. And there's, again, disclosures. There are five aspects that I want to speak to. First is the efficacy of CCM in sort of what we call the intermediate QRS patients. Some real-world survival data with CCM therapy. Let's talk a little bit about what is the right time to institute device therapy. And something for the future, CCM potentially for the 50% of patients that Murat spoke of who have heart failure with preserved ejection fraction. And finally, an interesting case. So again, intermediate QRS. So we know, for example, of course, that CCM is designated for patients with heart failure with reduced ejection fraction who do not receive CRT devices. But we also know that patients with a QRS – this clicker doesn't work very well – patients with a QRS less than 150 don't derive as much benefit with CRT therapy. So the question is, what is the impact of CCM in this intermediate QRS population? The patients with QRS greater than 120, less than 150. And we have some data. This is a European registry. And from this European registry, there's a recent publication where the investigators looked at these patients with intermediate QRS on the left and normal QRS on the right. So mean of 130 milliseconds versus 99 milliseconds. If we look at the population, they're very similar. Age in the 60s, pretty high percent of males, both about 80% males. Mean ejection fraction was matched around 30%. Mostly class III heart failure patients. And mostly, well, two-thirds were ischemic cardiomyopathy. And here's what was seen. If you look at the patients who have QRS less than 120, let's say the standard CCM population, you have what you expect, which is a significant reduction in heart failure hospitalization if you compare to the previous year before they received the device. But if you look at those patients who had a QRS that's between 120 and 150, there was, again, a significant reduction in heart failure hospitalization, a 72% reduction. An ejection fraction improved by 6.9% versus baseline, as well as improvements in quality of life. So in this difference, this effect in the normal QRS versus the intermediate QRS was not specifically significant. So these patients with the intermediate QRS do derive benefit. That's the first point. The second, let's talk about real-world survival with CCM therapy. This is a study that was recently presented as a late-breaking clinical trial at THT. The study was looking, it was a retrospective analysis using the Truvada real-world database. And the question was, what is the survival in patients receiving CCM therapy, and how does this compare with CRT therapy? So they looked at patients who had a class 3 heart failure and compared all-cause mortality in patients who received CCM versus patients who received CRT. So the inclusion criteria, again, were these populations from the Truvada database between 2016 and 2024. So first, what is the Truvada database? It aggregates EMR data and claims data from a number of different healthcare networks in the United States, including 100 million patients. That's almost one in three patients in the United States. It takes de-identified data and it provides basically a database to conduct some of these retrospective analyses. And here's what we're seeing. So CCM is going to be in blue, CRT is in green. And if you look at the full population, what you see is survival is not statistically significantly different. So the benefit with CCM, again, in this retrospective analysis, seems to be similar to what we see with CRT therapy. Now you can say, okay, that's fine and dandy, but we know that CCM is really implemented in those patients with ejection fraction between 25 and 45, versus CRT we implement in patients with even lower ejection fractions. Well, if you look at only that subset who had an EF between 25 and 45, again, statistically not significantly different results. You can see CCM survival of 1,000 days was 78% compared to the CRT patients, 71%. Again, suggestive that the benefit in terms of mortality is very similar with CCM compared to CRT. What about the timing of initiating device therapy? We know that there are a number of very good GDMT agents, and every day there seems to be another one, but we have at least five now, and depending on the patients, more. So when do you initiate this? And Murata actually started talking about this. And I think he was one of the authors on this position statement from the Heart Fair Association, from ERA, from ESC. And I'll just cut to the chase. What they note is devices and drugs work synergistically. It's not a surprise. And we can have improved disease control with devices, which allows further optimization of drug therapy, devices to optimize drug therapy. So the point is that device therapy should be integrated in these heart fair programs, perhaps a little bit earlier. Unfortunately, that's not the case. Let's just talk about timing of device therapy. This is a really interesting study that was published a few years ago, looking at CRT and timing of CRT therapy. So looking at a very large UK database, almost 50,000 patients who received CRT devices. And they were followed for about five years. And they looked at the outcomes as a function of when the CRT was implemented compared to when the patients developed heart failure. What you're going to see here is the mortality or heart failure hospitalization events. What you see, if the patients didn't have a previous hospitalization, that is what you see in terms of the mortality, very, very low mortality or heart failure hospitalization. If it's during the first hospitalization or if you implement it within one year of the first heart failure hospitalization, things are a little bit worse. And you see the trend. Basically, the longer you wait before you implement CRT therapy, the higher the mortality or heart failure hospitalization. OK, now that's with CRT. What about with CCM therapy? Well, recently, Jurgen presented these data. I'm sorry, forget the references wrong there. Jurgen just recently presented this at IHRA. And he asked the same question, early CCM therapy versus late CCM therapy. And what are the results? Well, if you look at the early CCM shown in blue, the improvement in ejection fraction is higher than with late implementation of therapy. Same thing when you look at diastolic parameters. And if you look at clinical outcomes, again, heart failure hospitalization, that's EC. You have fewer events compared to later implementation of CCM therapy. Also true with other hospitalizations, as well as it turns out with ventricular arrhythmias. So there's significantly higher of these heart outcomes in the later CCM cohort. Finally, let's talk about the potential future, which is CCM in HFF patients. One of the things we know is that there's a relative dearth of therapies that are effective in HFF patients. So CCM might play a role. Now, this is a point that actually Mehran also brought up earlier, which is as the ejection fraction improves, or when you implement the therapy in patients with higher ejection fractions, you actually see greater improvements. Here, change in VO2 max. So this raised the question, well, maybe if you look at even higher ejection fraction patients, you'll see further improvements. In a single arm study, this was a study conducted in Australia in 17 centers, 47 HFF patients. So they had preserved ejection fraction. And they assessed a number of parameters, including quality of life. The first thing they did, or first, let's look at the patients. Mean age of 74. You can see 70% of the patients are women. Again, we do tend to see more HFF in women. The BMI is 31, and the ejection fraction, of course, is preserved at a mean of 59%. You see that these patients, 2 3rds were class 3, and the remaining were class 2 heart failure. And you can see the KCCQ score, it's hard to say that fast, is about 49, which is pretty low. And then the antiprobing P, by the way, is over 1,000. My clicker is getting tired. I'm getting tired. OK, and here's the result. So we're looking from baseline to 24 weeks. And what you see, the primary endpoint, which is a change in KCCQ, was 18 points. I mean, that's pretty dramatic. Now again, this is not a randomized trial. This is not sham control. So those are important caveats. But an 18 point improvement in KCCQ, you don't see that very often. If you look at the secondary endpoints, including left atrial volume index, it actually got reduced in these patients who received CCM, as well as E over E prime also improved. And if you look at clinical parameters, and again, this is looking at heart failure hospitalization in the year before CCM therapy versus the year after. So the year before, it was 32%. The year after, it was 11%, 67% reduction. Again, this is a single arm trial, and there's some limitations that we're well aware of. But certainly, it's interesting. Interesting enough that the company has actually initiated a trial, which I will tell you about, if I can make this clicker work. Feel bad for you guys. You're going to have to go after me. It really is crazy now. OK. So let's just talk about, and this is important. There's a trial that we're going to talk about. But before that, I just want to caution. The indications in the United States are as follows, class 3 heart failure patients, EF between 24 and 45, who are symptomatic despite GDMT. But based on these data, in Europe, the therapy is approved for both systolic or diastolic obedisfunction patients with heart failure. This is a trial called the AIM-HIRE trial. The study objective is to look at the effect of CCM therapy in patients who have symptomatic heart failure and preserved ejection fraction, going from ejection fraction 40% or higher. It is a randomized, sham-controlled, blinded trial with 1,500 subjects. The primary endpoint is going to be change in functional parameters, in six-minute walk and KCCQ, between baseline and six months, compared between groups who have CCM on versus off. And of course, there's also a clinical endpoint, which will include the full cohort of 1,500 patients, looking at a hierarchical composite endpoint that includes cardiovascular mortality, heart failure hospitalizations, et cetera. And of course, there's a safety endpoint. And this is an ongoing study. So finally, an interesting case, which I'll go through very quickly. Basically, a 65-year-old patient with dilated cardiomyopathy, mechanical valve, who had VT, treated with amiodarone, and had escalating frequency of ICD shocks, was not a candidate for CRT. They received a CCM device and a six-month follow-up, basically complete disappearance of ICD interventions. And I think the point here is, when you improve heart failure, you improve everything. And I think we know this from other therapies also, including improving ventricular arrhythmias and the potential for sudden death. So thank you very much. And I think we're going to move on. And we're going to hear some exciting new data on CCM therapy. Thank you, Vivek. That was great. It's only Saturday. You can't be too tired yet. You've got another day. Yeah. Dr. Niraj Varma from the Cleveland Clinic, who just spent some time in London at the Cleveland Clinic, London-based program, generating an EP program. He's going to be talking about how CCM fills an unmet need for today and the future directions for tomorrow. Niraj. Thank you very much, Brad, Davey. Good afternoon, ladies and gentlemen. So CCM, future directions for tomorrow, but also what can we do today? This is a disclaimer from Impulse Dynamics, saying they won't support anything that I say. You're on your own. Dr. Fudim has shown you that GDMT is very powerful. And we know this. Current era GDMT is very powerful in reducing risk of heart failure hospitalizations and survival. This has been consistently shown. But I would suggest that GDMT doesn't guarantee immunity from heart failure. There's a significant residual risk with contemporary GDMT. That is best GDMT under trial conditions. That doesn't represent real world conditions where many patients cannot be maintained on four pillar GDMT. And that is because of comorbidities largely. So what are the other options? We've seen this downward spiral history of natural history of heart failure patients. And the objective is really to keep them on a plateau and prevent those dips. So even on best GDMT, they are vulnerable to this. So in the middle section, we have NYHA class two and three patients on GDMT, but at risk of deterioration. So what can we do? We've looked to device therapies here. ICDs and CRTDs protect from sudden death, but they don't treat heart failure. They usually don't treat heart failure. So we use ICDs and CRTs in patients with HFREF. They don't treat accompanying heart failure. So what I'd like to suggest is that ICD therapy in heart failure patients is indicated as works very well for patients at risk of sudden cardiac death. But most implanted ICDs do not treat accompanying heart failure apart from the CRT indicated patients. Now, most HFREF patients, those that meet class 1A indications for CRT, left bundle branch block with a QRS of more than 150, only account for 15% or less, perhaps 10% of HFREF patients. We know CRT is a very effective therapy. Multiple trials have shown this. It improves heart failure hospitalization and survival. But only a fraction, a minority of HFREF patients are eligible for it. So what do we do with the remaining 85%? Well, many of those are eligible for CCM. They are eligible for CCM. And CCM, as we've heard earlier, employs a high energy pulse. It's a biphasic pulse that's delivered into the refractory period of the QRS. It's delivered intermittently. That is for one hour periods, five times a day. It's delivered by a pulse generator that delivers the impulse through two leads that are implanted in the right ventricular septum. The generator is rechargeable. The generator is rechargeable. This is a very important factor. And the clinical data for these two groups, CRT-eligible patients and CCM-eligible patients, the clinical data for outcomes are very similar. Now, these are from two entirely different patient populations. And this trial has not been done. But if you draw the results out from the CRT trials and from CCM trials, you see that peak VO2, Minnesota score, six minute hall walk, and NYHA class improve similarly. That peak VO2 level of 0.84 is significant. That is what was observed in the first CRT trial, which was Miracle. And it was a very sick group of patients. So the clinical outcomes are very similar between CRT and CCM. So how does this fit into our workflow for device implantation? So again, the indication is for NYHA-3 symptomatic patients, regardless of QRS duration, if not receiving CRT. That is the July 2024 FDA labeling, patients not receiving CRT. They may have a CRT device, but if they're non-responders and you've switched it off, then they're not receiving CRT. So this is the July 2024 FDA statement. So let's look on the right. NYHA class 3, EF less than 45%, GDMT. If they have left bundle branch block and a QRS of more than 150 and HFREF, that is EF less than 35, they meet class 1A recommendations for a CRTD. So that is not disputable, CRTD. If the EF is 35 to 45, then CRTP. These are standard indications, standard indications that we've been practicing for a decade or so. What happens if they don't meet class 1A recommendations for CRT? Then the EF could be in these different bandwidths, less than 25, 25 to 35, 35 to 45. Then they do meet indications for CCM. 25 to 45%, left bundle branch block, QRS of greater than 150, these are eligible patients for CCM. Let's go back to the right, patients who have received CRT but still have ongoing NYHA 3 symptoms. So essentially, non-responders to CRT. And they account for about 30% of patients receiving CRT. It's a significant fraction of patients receiving CRT. Well, then they become eligible for CCM. Switch CRT off, and you can implant a CCM device. So that could be a workflow that follows the recent FDA labeling. So actually, this is the first patient in whom I implanted a CCM device. The patient did have CRT, not for class 1A indications, but class 2A indications. Right bundle branch block and QRS of more than 150. He had a CRT device. Unfortunately, he was a worsener, not even a non-responder, but a worsener. Increased diuretic dose, more congestive symptoms. We actually switched that LV lead off. Fortunately, about six months later, CCM was approved. This is in 2019. So we implanted a concurrent CCM device. And he improved significantly. So a CRT worsener, but a CCM responder. But we have implanted two devices, so we were very careful about potential interactions. So we tested it. And on the left, you see CCM being delivered appropriately. The high voltage pulse being delivered into the QRS complex. Then we induced VT, standard T wave shock. You see, CCM is withdrawn immediately. We induce VF. And despite fine VF, CCM is not delivered inappropriately into that VF. So there's no interaction between the two devices. And then the ICD appropriately defibrillates. And you can see with resumption of normal rhythm, CCM reinstitutes itself immediately. So completely synergistic device function. So this is not a danger between these devices. And similarly, there are data to show that there's no interaction with extracardiac ICDs. So there's no CCM versus ICD interaction. OK, we have two therapies. It would be ideal to have one device that delivers both. So this reduces procedural risk. Nobody wants to implant two devices and multiple leads. So that minimizes implanted hardware if you have only one device. If you have a rechargeable system, like a standard CCM device, it reduces the need for downstream generator replacements. Significant, because that carries risk. Patient risk, infections, lead fracture, extractions, and also costs for the health care system. So you want to reduce these complications. So from this scenario, can we progress to this scenario? One single device, two leads that defibrillates and also delivers CCM, investigational device. The answer is yes. So exactly two years ago, I was privileged to implant the first such device with my colleague, Bruce Wilcoff, the first Integra-D defibrillator, two leads implanted to the RV septum, standard commercially available leads, a DF4 lead and an IS1 lead to the septum. We implanted the first one. Again, we tested for interaction. And you see CCM being delivered on the left-hand side. We induced VF. CCM was withdrawn immediately. The device detected and defibrillated with a 26 joule shock in 14 seconds. And subsequently, there was some post-shock RV pacing, backup pacing. And then CCM was reinstated several hours later, which is according to device specifications. So no interaction between hybridized circuits in one device. So that, in fact, was the number one implant for the Integra-D trial. This patient was followed up one year later. Battery charging noncompliance was zero. CCM-D is rechargeable. It's a defibrillator that has rechargeable circuits. Not completely. ICD functions are autonomous. And that's a separate ICD battery. And high voltage therapies are delivered through that. But housekeeping functions are executed by rechargeable circuits hybridized with the CCM. So this projects device longevity to decades. The real change here. Battery charging noncompliance, zero. Total CCM delivered 96%. The energy and endurance of the patient was doubled, at least. He's walking hills all day. He couldn't walk from the prep recovery room to the implant room on that implant day, on the procedural day. So an excellent result. He was number one of the Integra-D trial. Inclusion criteria, LVF less than 40%. Functional class two to four on GDMT. Best GDMT for more than three months. Class one indication for ICD. And not indicated for CRT-D. Primary efficacy endpoint, successful defibrillation efficacy. And also safety endpoints. Device rated comprehension and inappropriate shocks. So the primary efficacy endpoint will be presented tomorrow morning in the late breaking trial session. So please attend if you can. I think this is a game changer in the world of ICDs that treat heart failure therapy. Trial update, HRSL-BCT being presented tomorrow. 200 patients have been implanted so far. The trial enrollment should complete this summer. Six month follow up with the last enrolled patient, probably late this year. And then, subsequently, commercial availability of CCM-D. So a very, very attractive device. But I would also say that our patients don't have time to wait. We've learned that they don't have time to wait with GDMT. A strong HF trial said that you have to accelerate GDMT. Initial data for CRT also say don't wait. Don't wait at all, because those patients in whom you wait to implement CRTD have a poorer prognosis. Exactly the same principle applies to CCM-eligible patients. Our patients don't have time to wait. They don't have time to wait for the CCMD device becoming commercially available. But this, for patients who need it, this two-generator solution is very effective, as I've shown to you. It's very, very effective. Thank you very much. Thank you. Thank you, that was great. The timer didn't go off, but I'll bet it was a perfectly timed presentation. So, yeah, I look forward to the late breaker tomorrow. Our next speaker is Dr. Ambrose Panico. He's in Mesa, Arizona. He did his training at Loyola in Chicago, where I am, and wisely decided to go somewhere warmer, and has been there for about five years. He's going to share some of his personal experiences and patient stories with CCM therapy. That's not the right slide. All right, well, we'll go with it. So there's a list of disclosures. I got the easiest job to come up and talk about a patient. So, 52-year-old female, pretty standard for who we see, coronary disease, remote MI, ischemic cardiomyopathy with class three heart failure, hypertension, tobacco use, COPD, depression. Interestingly, if you really dive into it, her depression symptoms were all related to her heart failure symptoms, which I think we often glance over and don't ask those questions. Medications, reasonable medications. She's on beta blocker at a reasonable dose, high dose of lisinopril, aldosterone antagonist, and PRN Lasix and potassium. So she comes to our practice from outside. She's got this history of cardiomyopathy. It dates back almost two decades with an ejection fraction reported 30 to 35%. Historically, she was never offered an ICD for no reason I can find in the documentation. Establishes with our group. She's one of my partners, gets some baseline testing. She has an ejection fraction of 20 to 25% with some mild valvular heart disease. She's got scar on a nuclear stress test, but no active ischemia. So they put her in a wearable defibrillator and they send her to me. So I see her in September, early in my tenure as an attending, and I say, well, we should probably optimize her GDMT. We gotta get her in Tresto. Well, prior Roth required. We gotta get her on an SGL2. Well, prior Roth required. So none of that's gonna happen fast. And since she's got this longstanding cardiomyopathy, I doubt she's gonna recover. Let's just go ahead and move forward with an ICD. So what about CRT or CCM at this point? So looking at this patient, kind of falls into that intermediate QRS range. She's got a right bundle morphology with 136 millisecond QRS. So I do not recommend CRT. If that box was shrunk down like it was supposed to be, the last indication, it's a 2B indication, right? We don't anticipate that this patient's gonna have a really robust response to CRT. So why go down that road? But what about CCM? Now, I'm gonna go through this quickly because some of it's already been touched by some of our other speakers. We have the comparison here looking at your CRT versus CCM as far as FDA indication. They're on par with each other. When it comes to the workflow, this is something we do every day. And it's really not a stretch to add this extra thought to the way that you think about patients. Clearly left bundle patients, if they have an EF less than 35, they get a CRTD. 35 to 45, they would qualify for CRTP and benefit from resynchronization. But that's the vast minority of the patients we take care of. Everyone else, we look at less than 25%, not indicated for CCM in this country, but it is a primary prevention ICD indication. And those folks who have an EF of 25 to 35% would benefit from not only a primary prevention ICD, but from CCM. And that class of 35 to 45 that Murat pointed out was kind of that super responder class would benefit from CCM alone. Interestingly, as Dr. Farmer also pointed out, the folks who have CRT who are not either responding, have a suboptimal resynchronization, or have just persistent symptoms despite resynchronization, you can turn off CRT and you have something else to offer them to help them get through. Okay, back to the patient. She gets an implantation. And I'd like to just point out that I did that within a month because I was so not busy as a young attending at that time. But we get her now, as we get prior authorizations, we get her on Entresto, she remains class three. We get her on increased dose of Entresto and titrate of her beta blotter, she remains class three. We get her on GL2, she remains class three. We finally repeat an echocardiogram. Her echo actually went down to 25%. And surprise, surprise, she remains class three. So I see her and I say, well now, I've got no other choice. I've gotta do something, let's offer CCM. So we did that. And I'm gonna stand here and tell you that I no longer do that. And it's the exact opposite way to think about it because as everybody up here has pointed out, time is of the essence and we don't have it in these patients. So what I would challenge everybody to do is to make sure they're not symptomatic. Make your patients convince you they don't have symptoms. I do this with my kids all the time. When they tell me I'm wrong, I say convince me and I'll reconsider. And yes, it has bit me in the you know what multiple times. But they're all gonna be great lawyers one day. So look for clues. Have they been seen more than usual? Have you had to titrate medications? Have there been heart failure hospitalization follow-ups? Are there abnormal indicators from their devices that they do have implanted that are telling us that they're struggling? Use them. Ask them questions. Do they enjoy, can they still enjoy their normal hobbies? Do they play golf? Can they still play 18 or can they only make it through three holes? Ask them about simple things like can they go for a walk with their family? Can they walk their dog? And I love this one. Ask them about what like normal things like grocery shopping. We say, oh, can you do the normal things you do? And everybody's like, yeah, sure, okay. Well, can you grocery shop? Can you go to 7-Eleven? Can you make it around a regular grocery store? Or can you do six laps around a Costco which I myself struggle with at times? Okay, so ask specific questions. You'll get specific answers and make sure you document it so that you have it to refer back to. All right, back to the patient. So she undergoes her CCM implant with the Optimizer smart device. Her post-op follow-up's uncomplicated. She has a six-month post-op follow-up where her repeat echo shows that her EF has improved 50 to 55%. So a woman with a depressed ejection fraction for nearly 20 years whose ejection fraction improved. Oh, and she's class one heart failure now. Happy as can be, right? So this is where I like to use the term why not CCM and why not now? I think fundamentally we all have to decide are we gonna be the guy that Phil Collins sung about who stands there and watched somebody drown or are you gonna throw him a life preserver, right? And I'm gonna say that you think of this as a life preserver. So who? We've been over this a few times already. It improves functional status, improves six-minute walk, improves quality of life in our patients who are EF of 25 to 45, symptomatic despite GDMT, and who are not receiving CRT. This is a wonderful option for those patients. So I'm gonna kind of get towards the closure here by talking about my approach to patients now. So I recommend CCM early and I consider it in everybody at primary ICD implantation and recommendation. Number two, whoops, yep, this is the wrong slide. Dang it, my jokes aren't gonna work. I have a conversation with everybody about this. Don't forget these orphans of heart failure as I've grown to call them with the EF less than 45 and indeterminate QRS, right? They're too narrow for CRT. They're too symptomatic for GDMT alone and they do not qualify or aren't sick enough for advanced therapy. But we have an option when we didn't before. Again, remember with the indication for CCM that the weaker CRT indications, they benefit more from a CCM. It's never too late to take a shot, throw them that life preserver. But I'd actually like to challenge you, give it to them while they're still treading water. And device therapy should be considered equally as important as GDMT and maintenance of sinus rhythm. This is an EP conference after all, I have to give a plug. Okay, don't forget to spread the love. There's a few people up here who you might recognize from their work on social media, but it's a great way to spread the message, show the successes, right? Get the message out there and get more people involved. Please do not forget to come and see Dr. Varma at the Late Breaker tomorrow. And if you do miss it, we will cover it on HRSTV because I get to interview him tomorrow for that. All right, and the last thing, if I haven't said it, if we haven't said it enough, don't wait, right? You don't have the luxury of time. So here's a list of some really terrible diseases and illnesses. And here's their associated mortality rates, okay? Heart failure, in recent studies, over 54,000 patients showing a five-year, 51% mortality, okay? That's worse than all of those cancers. So don't wait, your patients need this and they need it now. That's all I got. Did I go fast enough? Yes. Excellent, thank you. Thank you, everyone. That was a great, great session. We do have a QR code that's up there. Please do send us questions. But let me start off asking a few questions. So I'm gonna ask Dr. Fadim first. So you talked about, we see in heart failure trials with GDMT therapy that we value quality of life, we value the morbidity, mortality data. But when we look at the ARNI trials and SGLT trials, we don't talk a lot about quality of life improvement. We don't, you know, we are focused so much in this heart failure population about mortality and not really what their day-to-day life is. Do you think it's time for us to shift gear? Because, I mean, that's the data, right? That's what we're going after. So do you think it's time for us to change our perspectives on our heart failure patients? Well, so it comes up, a very interesting question coming. First of all, you know, the patient might value quality of life, certainly more so than heart failure hospitalization than death. Having said that, the payers and the guidelines do value heart outcomes more so than those quote-unquote soft outcomes. So this is the reason pharma has pushed for those, you know, big trials to look at those interesting endpoints, I mean, the mortality and morbidity. The interesting thing is that those things don't have to always correlate. You might actually improve by living longer, and resto, and might have very little to no KCQ benefits. Same with the SGLTs. SGLTs have only a two-point KCQ benefit. It's marginal to actually not clinically or statistically significant. So I think that this therapy, which is why the guidelines don't give this a class one indication at this time point, because it does not have mortality, morbidity benefit, but our patients don't care about that to the same degree. So our duty is to offer it to them as the next line of therapy. And, you know, patients usually say not no to let's do something for your quality of life. Can I just, I just want to ask you a follow-up question, Murat, on the same issue. I mean, this concept of valuing quality of life as much as, or at least on the same scale of mortality, this is something that's been talked about a lot over the past couple of years. And I'm curious, amongst your colleagues, amongst the Hartford colleagues, has this been internalized, do you think? Like what percent of people really actually have taken that and said, yeah, that is as important? I think it has not been internalized. We have been spoiled as a cast of characters because we have those 8,000 patient trials that occasionally deliver us mortality and morbidity benefit. So I think it has not been internalized. I do think we do our patients a disservice by not discussing quality of life of patients. We don't test the functional capacity. A six-minute walk, this is not done in Hartford clinics across the country. So we actually don't know how they're doing. We just want to get them on the drugs and we just teeter and teeter and teeter. That's why the hamster wheel of like, you've got to get off that wheel. I mean, you just got to, at some point, you have to call it quits, not stop titrating. You just have to escalate based on the next line of therapies. Can I say something controversial? Yes. Always. Always. That's why we're here. Again. So we've been obsessed in CRT trials with LVEF or LVESV changes, so structural remodeling changes, as a surrogate for improved survival. There's no doubt that it works. There is some correlation there. And it's an easier endpoint to measure than, say, wait for survival benefit. So that's been our world as an electrophysiologist and planting devices. That's been our world. But there are some data to suggest that even in CRT patients, prediction of long-term survival is stronger with quality of life changes, how the patient is feeling, than with EF changes. So maybe we've been too engrossed with using EF as the absolute endpoint in these trials, and we've ignored quality of life, which may impart even more information. So something that should be looked at, I think, more intensively. Dr. Panico, let me ask you a question. You shared a great patient story. You're talking about two devices in patients many times. And how often do you get pushback from patients about two devices? Sometimes, obviously, your patient waited many years before they even were considered for one. I would say I get pushback never. And to be honest, I gave myself more pushback at the beginning because I had that mental hurdle to get over until I started seeing patients doing better, happier, better quality of life. And that's what it comes down to. When you talk to a patient, you say, hey, this one's just there to keep you alive if it happens. This one's going to potentially improve your life. I often get asked, well, can't I just have that one? And so that has been a consideration that we've done in some patients. But I get pushback never. When they hear the quality of life improvement, and I go over those numbers with them, what the trial showed, and this is what we would anticipate. And I don't think I've had a single patient turn me down based on the fact that it's a second procedure, second surgery, anything. Neeraj, let me ask you about NYHA class. And especially with payers and such, we have to be careful about these therapies. And we know that NYHA class varies in patients. I mean, they come to clinic. They might be three, but they might be two at home. And so how do you address this NYHA class? Because it's always challenging. They look good in the office, but they are probably miserable at home or the other way around. So how do you address this for device referral? So a very important question. I think patients often underestimate the NYHA class because they've accommodated their limited exercise tolerance. And so I'm feeling fine, but they might not be doing very much. In direct answer to your question, I walk up the stairs with them and see how they do. And often that declares an NYHA 3 patient as opposed to a 2 patient. So they might be misled. I could put them on the treadmill and assess that more formally. And I think patients who have had congestive symptoms at one stage, from my point of view, are always vulnerable to another event under NYHA 3, even if they've stabilized to 2. And in the world of CRT trials, the distinction between 2 and 3 has always been very blurred. Ultimately, that group should probably be coalesced. Vivek, you were talking about the strong HF trial and the earlier implantation now waiting for progression. I mean, we worry about progression of disease. What do you consider as a good timing to, number one, maybe start offering the therapy? Number two, when do you implant? Do you wait for, you know, strong HF should say two weeks. I mean, it's hard to convince sometimes, I would say at least in our institution, our heart failure colleagues to get heart failure therapy in two weeks. I mean, we get pushback and I'm going to go back and give them Murat's number. That's what I'm going to do. But having said that, what do you think is the right time? I was going to ask Murat that question actually, but look, just to be clear, remember strong HF was looking at- Murat, you should answer too after. Yeah, strong HF specifically was looking at institution of heart failure therapy, drug therapy, okay? So just to be clear, an early institution, aggressive institution actually had improved mortality and they had to stop the trial early. We don't have a randomized trial with device therapy that's looked at this, whether it's CRT or CCM. But as you've seen, the retrospective data highly suggest that earlier institution of therapy is associated with improved outcomes. So I think that, but to your very specific question, you know, I don't really know. I mean, I get the feeling though, that right as soon as the patients get instituted on some of their therapies, I mean, the SGLT inhibitor is easy to institute, no hemodynamic effects. Entresto is oftentimes one of the first, Entresto and a beta blocker. And you know, of course the mineral corticoids. But I get the impression that we should be doing it probably within the first couple of months. Is that too aggressive? Is that not aggressive enough, Murat? I think three months is the minimum viable time for them. The same way we'd reassess LVF after initiation of GMT prior to consideration of ICD, I mean, it's the same timeline. I think the most important thing comes in is the actually setting expectation with patients. When we meet them and say, I'm so sorry you have heart failure, here's what we have. It's a great area to have heart failure right now because we have a lot of drugs for you. These are the things we're gonna do. We're gonna reassess at three, four, five months. But I'm telling you that there will be options beyond if we can't improve you. So I'm setting expectations right from the get-go. I'm not telling about plan B. Plan B is gonna be LVF to transplant if things go the wrong way. But things will likely, with GMT era these days, go the right way, just not all the way. And I think making the patients understand that GMT will not cure them. It's just a step towards that direction. And more work will have to be done. They can never stop the drugs. Around three to four months is when I have that discussion about. And now are the things I told you about that are coming because GMT is not the cure. I like that number, three to four months. Well, great. I think we're gonna have to wrap this up. I wanna thank the audience for being here and encourage you to scan that QR code to provide feedback. I wanna thank Impulse Dynamics for providing support for this educational event. Thank you to all the faculty. I think the take home is that GDMT should stand for Give Device Therapy with Medical Therapy. Thank you for coming. Thank you.

Cardiac Contractility Modulation

CCM Therapy

heart failure

ejection fraction

patient selection

quality of life

real-world efficacy

clinical experience

Guideline-Directed Medical Therapy