If you look at, so I went to clinicaltrials.gov and said, OK, what are the number of clinical trials that are going on? And if you look at heart failure, there are 4,239 trials. And if I looked at active trials and active screening trials, there are 922. So we're going to go over 922 studies in the next 10 minutes. All right. So I took the liberty of actually breaking it up, breaking it up into some of the pharmaceuticals that I think are really important. And I think it's really important for us to realize the importance of how pharmaceuticals are changing the paradigm of heart failure and sudden death because all our future studies need to take those number needed to treat into account rather than the existing ones that we've used in the past. So I broke it up into pharmaceuticals, talked about sensors a little bit, but just a very little bit. AI and phenogrouping, I think that is the future. I think risk stratification and predictive analytics is really going to help us redefine disease subsets. It is going to change the taxonomy of heart failure. We're going to define heart failure by cluster groups and not by an ejection fraction of 35% or less than 35% because that's how it's going to be. And then, obviously, there are a whole host of electroceutical trials out here. They're in random order. I'm going to run through them. You have the slides, and you can read more details about them. But in the next 15 minutes, I'm going to run through all of this very quickly. OK, pharmaceuticals, we know that neprolisin inhibitors, which is the Entresto, seen it in the PARADIGM-HF study, clearly showed that it actually improved outcomes. That was in patients who were fairly stable. We were making the switch. Now it can be used in acutely decompensated patients also, clearly does better than the conventional ACE inhibitors, something really important to realize. SGLT2 inhibitors, there are the DAPA study, the EMPA study, and the CANNA study. All three have looked at three different SGLT2 inhibitors. These are drugs used for diabetes. They work at the renal tubules, distal tubules, excrete the glucose, treat glucosuria. Lo and behold, they have actually reduced mortality, reduced sudden death in all patients with heart failure. Across the board, three different trials have shown that there is a 30% to 40% reduction in sudden death and heart failure outcomes in these patients. So really important to recognize that. What about the other drugs that are being looked at? There are several signaling pathways, and I'm not going to get into the signaling pathways within the heart, but the ones to really pay attention to are the phase 3 studies that are already, that means phase 1 and phase 2 have gone pretty well. And they're looking at phase 3, and they're the direct sarcomere activators. And this is particularly omacantive, which has been studied already for many years, but has been shown to be of use out there. The PD inhibitors are still in class 2, but the important ones, again, are the soluble guanylide cyclase stimulators. This is the only drug that is being developed for HEF-PEF, for the heart failure with preserved ejection fraction, which, again, is disease modifying. So there are a bunch of studies out there which I will encourage you to kind of look at. And there are many studies that are looking at active questions out here. That is, what is the role of infrestrofurther? What is the role of intravenous iron? What are the non-invasive device-based monitoring in heart failure patients? And then where does myosin activation and cyclic GMP signaling stimulation transpire, and how does it affect the outcome? So many questions in many studies, but not getting into the details of those. And then obviously, the one about HEF-PEF, which is a capacity study. Now, when we looked at device therapy, we've always tried to choose the right patient population. But one of the population that was ignored by a lot of folks was patients with chemo-induced cardiomyopathy. Folks said that if you had cancer, and then you developed heart failure, we can write you off. The potential for you doing well is not really high. And this is the MATED-CHIC study. The MATED-CHIC study, which is chemo-induced cardiomyopathy, which looked classically at CRT in these patients and was able to show that even if you had heart failure and you had bad, bad heart failure, if you had a wide QRS and you had a low EF, you could still respond to resynchronization therapy, at least in the short term with reverse remodeling, long-term follow-up study yet to be done. This is a study which was presented at HRS a couple of years ago. It's a year and a half ago, which is now in publication. But it's, again, a study based off the conversation I was telling you before, that there are lots of patients who don't respond well to CRT. And those are non-left bundle branch block patients. And is it because we're not implanting the lead in the best possible way for these particular patients? Is it because we're just using a one-size-fit-all strategy? So we randomized patients to an individualized approach where we targeted the area of electrical delay versus the conventional approach. And lo and behold, we found, and this is why you do randomized study, that there was no difference. There was no difference between the individualized approach versus the conventional approach, as you can see out there. But the important thing that this study actually taught us was that non-left bundle branch block patients, when treated well, usually did pretty well. And 70% of those patients actually improved across the board, both in their response rate at quality of life, but also in terms of ejection fraction out there. So it's suggesting that you can't write out non-left bundles, that if you do target the area which is lateral, which is what we found eventually in these patients, and you have enough separation between the RV and the LV lead, those patients actually go on to do quite well. The next study, which I think everybody's heard of, is the MORE-CRT study. MORE-CRT study was directed towards finding, if you give more of CRT, that is, you pace off more than two electrodes, can you capture more myocardium? Can you resynchronize the heart better? And will those patients do actually better? What did that study find? It found that actually there was no difference. When you gave multipoint pacing versus non-multipoint pacing in patients who are non-responders, so they selected a patient of non-responders, half of them got multipoint pacing, half of them did not, and they found there was no difference in the outcomes. But when they sub-studied those patients, what did they find? They found that if you place them from two electrodes that were really far away, and you were capturing more myocardium, so there was a greater separation between the two electrodes, the apical and the proximal, you actually translated into making non-responders into responders. So this was not a part of the phase one study, but because they did a sub-study analysis, they found that there was a signal out there, and they now have embarked on the phase two study. And the phase two study is selectively now looking at multipoint pacing, but using a prescribed strategy of pacing with greater separation. Now, we know multipoint pacing can capture more myocardium, and there are many individualized cases, and some that I've seen myself, where actually it does a whole lot of good. Patients who have used salvage CRT, and if I've paced from really distant electrodes, they actually have done well. But there are many other studies, which I'm not going to go through, that are actually looking at multipoint pacing. Multipoint pacing in narrow QRS patients, multipoint pacing where you adjust the RVLV times and the electrical delay out there, multipoint pacing with hemodynamic assessments. There's a bunch of these studies out here, which I would recommend, if you're interested in, is actually look at those particular studies. This is really interesting technology, and I think it's, again, disruptive technology. This is looking at a leadless LV electrode, as you can see out there next to the penny. That's the leadless electrode. That's how small it is. It is about a centimeter and three millimeters in width. This is implanted trans-femorally, retrograde across the aortic valve into the LV endocardium. It can also be implanted transeptally. That lead, after it's put in, there's an ultrasound transmitter, which is battery-powered, which then sends the ultrasound signal to that electrode. That is converted to electrical energy, and it can actually resynchronize hearts. This is based off a study called the SelectLV study, which actually looked at a small cohort of patients and found that patients who failed CRT, patients who were non-responders to CRT, or in patients that could not get CRT, this technology actually helped those patients do better, and it's now being investigated, and Conflict of Interest, I'm the global PI on this, it's being investigated in Europe, Australia, and the US. There are 350 patients transatlantic at this point in time, and it's recruiting well. Having said that, what are the alternatives to conventional CRT? We talked about this already, and I'm not gonna belabor this. There's His Bundle pacing. There is transventricular pacing. The UK group has actually put a lead right across. They have RF ablated through the interventricular septum, and then put a little lead inside the interventricular septum out there, based on LV endocardium, and then obviously there are a bunch of other strategies, but the main two are transventricular pacing and His Bundle pacing. How many studies are going on in the His Bundle space? Just six, and all of them are really small studies. Couple of them are randomized. Others are registry and follow-up studies, and if you look at this study, this was presented at the last Heart Rhythm Society meeting. It is called the HIS-SYNC study, and the HIS-SYNC study basically randomized, how many patients? 20 patients to CRT versus His Bundle pacing, but they were all candidates for CRT, and what did they find? They found that His Bundle pacing actually did pretty well. It improved the echocardiographic response and the ejection fraction response, but there was no significant difference between the two arms, because it was a really small study, but the important thing out here also is that the study was significantly compromised because of crossover between both the arms. There were a lot of patients with HIS-SYNC who didn't get the HIS Bundle, and with CRT who failed, and there was a lot of crossover, so really, even though it was one of, one of the two randomized studies, so these are the different studies of HIS Bundle that have transpired over the course of the last many years, okay, and I want to point out, there are just two studies that are randomized, and of those two studies, one was an 18-patient study, and the other was a 20-patient study. Go figure. So as much as we're interested in HIS Bundle, as David said, that you really need long-term data out there to really justify how to use this technology. It's great technology as a bailout at this point in time, but there's not enough evidence out there to use that as a first-line therapy in many patients. Many programming studies are there. There's the SYNC-AV CRT study. There's the SMART-AV CRT study. The SYNC-AV CRT basically, again, looks at programming the vectors between the LV and the RV in such a way to get the narrowest QRS. That has been able to show that it translates into better short-term outcomes. Long-term studies are still needed to kind of determine this. There's the adaptive CRT, which again uses a technology which preserves intrinsic conduction down the right bundle and then triggers LV pacing so that there's fused pacing, but using the physiological pacing, intrinsic conduction on the RV side. And this has been shown that by programming the AV and the V-to-V delays, you can get the best out of patients in this particular algorithm. And this is just published in JCE, a large registry in 1,800 patients, which showed that using this algorithm in patients with a short PR interval, you can actually reduce the AF burden and actually improve long-term outcome and mortality. Now, we always forget about sleep apnea. And we know that almost 30% of patients with heart failure have central sleep apnea. And we also know that central sleep apnea, when treated by positive pressure ventilation, actually translates into poor outcomes with the CERV study that most of you know about. This is new technology, which looks at pacing the phrenic nerve in conjunction with the sensing electrode down the azagus and keeps patients up awake. No, it doesn't keep them awake, but it actually stimulates them when they go into an apneic spell and has been clearly shown to reduce the central apnea index as well as the apnea-hypopnea index. And this again, whether it translates into better outcomes really needs to be shown, but clearly physiologically, it seems to be something that works. Another area of interest is cardiac contractility modulation and I think all of us recognize this requires putting two leads inside the ventricle. One senses, one paces. Paces during the absolute refractory period of the QRS, causes sarcolemal calcium release. This changes the myocardial contractility, improves NYHA class, quality of life, has been shown to show some improvement in ejection fraction and some improvement in outcomes in the long-term, but a lot of data is still required. This study specifically showed that it improved patients who had an ejection fraction between 25 and 45%, specifically those between 35 and 45 and who were class two and early class three patients, indicating that it's a niche area out there, but that then has promoted this new study which is underway, I believe, which is looking at cardiac contractility modulation in HFPEF patients, that is who have preserved ejection fraction, whether by changing the calcium properties, you can actually change the relaxation properties of the heart and actually help patients with HFPEF. This is the sensor approach. We've heard of many sensor approaches. I think the MultiSense is one of the only ones that actually has an integrated sensor strategy where it uses six different sensors. It uses respiratory rate, ventilation, physical activity, trans-thoracic impedance, S3 index. It puts all of those together, creates an index called the heart logic index. That heart logic index can predict which patients actually go into heart failure at least 30 days prior to them going into heart failure and this has been shown to be of value over and above a high BNP in patients through the Sensor AF study. There are many emerging neuromodulation studies and these studies, as we talked about, can involve stimulation or denervation of all these different areas and I'm not gonna go into the details, but I will touch on a couple of the newer technologies that are of interest. One is vagal nerve stimulation. I think we all know that vagal nerve stimulation was tried and tested through three studies which were either neutral or lukewarm. There were the Nectar HF study, the Anthem HF study and the Inovade HF study. The Anthem was positive, but it was only in 30 patients in a study that was conducted in India. The Inovade was a 650 patient study which was negative to neutral that showed that vagal nerve stimulation didn't really translate into significant benefits in terms of remodeling or clinical outcomes. We have now the Anthem RF study, that is the Anthem study in heart failure with reduced ejection fraction. It's a 800 patient study that is looking at vagal nerve stimulation. One of the problems with vagal nerve stimulation studies were that there was variability in the lead design, variability in the stimulation protocol. There was no surrogate of autonomic tone manifestation or changes with vagal nerve stimulation as a result of which people really didn't know what exactly was transpiring. Many other nerves of interest. And I told you that you can stimulate the aortic baroreceptors and there's a study going on and looking at a stent that can be implanted in the aorta that can actually stimulate the baroreceptors with the handheld, change the sympatho-vagal balance, change the diastolic compliance, eventually help patients with heart failure. There is a tragus nerve stimulation. We know the tragus nerve is connected to the vagus nerve. There was a very nice study presented at the Heart Rhythm Society this year called the TREAT-AF study, which by stimulating the tragus nerve, they were actually able to reduce AF burden. And now there's the TREAT-HF study, which again is being looked at from that particular angle that by pacing the tragus nerve for six hours a day or one hour a day, I forget, you can actually change the sympatho-vagal balance and that change in the sympatho-vagal balance can help heart remodeling. And then obviously there are cardiac plexi of interest and the one that is of main interest is the pulmonary artery cardiac plexi. There's the TROPHY trial, which you may have heard of, which is actually aimed at pulmonary artery denervation in patients with heart failure. It's something like renal denervation. They're actually using apparatus quite similar to renal denervation out there. Carotid baroreceptor stimulation. How am I doing for time? Doing all right? Okay, okay. So there's carotid baroreceptor stimulation. We know that stimulating the baroreceptors, you can change the sympatho-vagal balance. That, again, changes the diastolic tone, can, again, improve outcomes in patients. There's the feasibility study, the barostim and HF study, and the BEAT HF study, which was presented at Heart Rhythm Society, again, which showed that by stimulating the baroreceptors, you could actually reduce antiproBNP, you could actually improve the six-minute walk test as well as quality of life, so suggesting that there was a signal out there. I think there are many opportunities in the neuromodulation space that need to be looked at, selecting the right patient with the appropriate sympatho-vagal balance, point-of-care assessment, to know that you're actually making a difference and measure what you're doing, which none of the other studies have done, and then being able to individualize and dose the autonomic stimulation on an individualized basis and then looking at long-term outcomes. And last but not the least, and this is what I'm going to close off with, and this is what I told you is really important, is machine learning strategies. And this is from the MATED-CRT study where they looked at machine learning strategies for classifying echocardiograms in conjunction with demographics and clinical covariates and actually created phenogroups out here, what I call as clusters, not patient with an EF less than 35, more than 35, but putting in a cluster of clinical covariates together. And what did they find? They found that you could actually create clusters even if they had an EF of greater than 35% or they had characteristics that were overlapping, but when you put clinical covariates together, you separated out which patients actually were going to do poorly with CRT as compared to those which were not. So there is something beyond just a single EF that we have to look at, and I think that's where I think all these AI-based strategies and machine learning strategies are going to change the curve of how we approach these patients. So much is going on in the world of heart failure. There's a lot going on in pharmaceuticals, electroceuticals, sensors. I did not talk about biomarkers and predictive analytics. I think we will need to revisit our indication for devices in the background of these advances in biologics and AI-based risk stratifications, and the future, obviously, clearly, is multidisciplinary care and strategy trials. Thank you.

pharmaceuticals

sensors

AI

electroceuticals

heart failure treatment