Marat Fudim, MD, MHS, discusses devices in chronic heart failure.
the session was more attendant. Little did they know that those diseases don't matter compared to heart failure. Heart failure is by far the most relevant disease. I mean six million people in the United States have heart failure alone and probably another two million with that often diagnosed human disclosures. I'll be talking about. I was asked to talk about device based strategies. So number one cause of hospitalization. The United States is heart failure. There will be nine million heart failure patients by 20 by 2040. And the current state of the art for the management of heart failure. And when we often say heartfelt, we really mean heart failure with reduced ejection fraction is quadruple therapy because we actually have really good therapies for this patient population. The benefit of giving people quadruple therapy is that you actually not only improve quality of life, you actually can reduce morbidity. You can make people stay out of the hospital but also increase the lifespan. Very few therapies in cardiology can increase the lifespan of patients to the degree that heart failure drugs can do. The problem is despite the promised land with the fantastic four as we call them. That patients now live longer. You know, 5678 additional years gained. The problem remains that the residual risk of death is twice as high as that. For C. A. D. So we should next next session you have is hard for the talks are gonna be twice as long as the C. A. D. Talks because the mortality is twice as high. So residual risk remains massive. Okay that's and that's the major burden of healthcare in the United States. But here's the reality in clinical practice. Those six million people, maybe seven million people that we have right now with heart failure. We give them G. D. M. T. And heart failure preserve rejection practice really. Just one drug may be as guilty too. We titrate up. It takes me 234 months to titrate that up then we'll give him an I. C. D. Or C. R. T. When eligible. Guess what, 70% of patients still remain symptomatic with class two or class three heart failure. I don't have time to elaborate this but that is terrible. It means they cannot do activities of daily living in about half of the cases. That's the that's the reality. With advanced heart failure population which applies about 30% of population would not be able even to do activities of daily living. So in total 70% still remain symptomatic. What do we do? We watched the trajectory of heart failure is a decline patients. Heart failure will never I repeat never get better or recover. In most cases that disease will come and bite back if you stop those medications. So the trajectory is downward trajectory. The lifespan is shortened in those patients compared to their neighbors that have no heart failure. But we keep watching those patients, maybe my institution, we consider remote monitoring for them. At that sign point like cardiograms that doesn't often change the trajectory too much patient remains symptomatic. We watch them, we watch them and my institution loves to transport patients. The problem at the sign .5% of the population only is eligible for this, 95% is either dead or in eligible. So that gap for 95% of patients that remain symptomatic but not eligible for advanced therapies. That's why I think device therapies fit very fit in very nicely. So what is the benefit of the vice based therapies compared to pharmacological therapies? Well, first of all, not all path of physiological processes will be targeted with drugs. Its debts due to side effects. First of all, if you have a torn might relief like you wouldn't want to throw medications at it only because probably if you have a mechanical problem you need a mechanical solution. But systemic drug administration also has side effects. There is a very nice study marks. Con trial is one of my favorites if better blockers are good to suppress the sympathetic tone. Then more better blockers. Maybe a central sympathetic such as quantity and proximity. And it's better that was the question the problem that trial that so many side effects actually the population that was getting the drug compared to placebo had more deaths in it. So the trial was stopped. So it just shows you that systemic administration of drugs can have its limitations. The one big benefit of device based therapy is that because there's an upfront cost and that's not just the actual dollar amount but because there is an increased risk of doing things to a patient such as a procedure. In most cases we tend to do better phenotype NG in patients with device based strategies for the disease at hand than we do with drugs. Think of the last time we prescribe, what's the G fro and 30 here is the same thing with are the same thing better blockers with devices. I spent weeks thinking about them doing tests for Towers. We do 500 CT scans to make sure we landed right zone. So that is the benefit of device we do slightly better phenotype NG then compliance and adherence tends to be not a problem. Once the tower valve is in, it stays in once the pacemaker is in it stays in one symmetrical is in it stays in. You don't have to rely on a patient to take the drug And last but not least in heart failure with reduced ejection fraction. We now actually therapies that will go over in the next slides that have been shown to improve quality of life, reduce heart failure, hospitalization beyond standard GMT. So we now have the evidence to support the actual benefit. So they've been to laws enacted by Congress over the last 15 years, no matter which administration you like both of them have been part of it. They that increase the uptake of device-based strategies in the United States. The last loss the breakthrough device designation concept which allows device companies to come to the U. S. Market at a much earlier pace by doing so they can operate and reduce costs and get the device is FDA approved at a faster pace. That was important because what you see on the right side is that the number of devices entering the US market has been dramatic. I mean an exponential increase and the majority of the devices entering under the breakthrough device designation law cardiovascular devices. Okay, so we reviewed the literature to see how many devices out there that are hitting the market. First of all, they're 3 to 4 devices approved for the heart failure space. This is the tear the trans capital edge to edge repair really. This is another fancy term for mitral clip. So mitra club was one of the first approved but it was not on a breakthrough device designation law. Then you have to contact alien modulation, very reflex activation therapy and you're frantic nerve stimulation which are put here because it actually, while not specifically approved for heart failure purposes. The majority of patients that get this device actually heart failure patients but below on the investigational therapies you have dozens maybe hundreds of devices that are currently under investigation for the treatment of heart failure but have not across the threshold being actually FDA approved. Those are buckets in which they fit such as neuromodulation strategies, structural therapies for the right side for the left side etcetera. Okay Some history. The man in the middle. Most people know that's Braunwald. His lady on the left. I gave it away. It was actually his wife. His first wife. She passed away in the 90s. And for her name is Nina Braunwald. I always joking this time point. I actually gave grand rounds on Monday. I did not do this joke but the joke usually do here. She probably did all the work and he did and he reaped all the benefits. He got famous. But anyway so she was a surgeon and they two together in the 1960s. Actually did what only was approved now three years ago. And that is very flex activation therapy. So device therapies and heart failure date back 50 60 years ago. And the idea here was if you stimulate the barrier reflex via stimulation cuff here they actually put the stimulation right on the barrier reflex. The barrier reflex is located in the crowded pulp. Afrin fibers go to the brain, integrate the input for better reflexes, stretch receptors and then decrease the sympathetic tone and increase the parasympathetic tone as an E front output from the brain. So the idea here was back then in 19 sixties they had when the patient engine shows up. There's only nitrates that I could give you back then and they noted if you stimulate the better reflex for hours to days that the blood pressure fell. The heart rate fell and then they started doing that and repeatedly, more and more patients and then noted what if we give it to people also that have an exercise. Patients are limited by engine and exercise and we have found is that patient had less engine addressed less engine with exercise and it was all at a lower lower blood pressure with exercise and a lower heart rate. So patients were just able to do more at less with less stress to the heart essentially. Okay, So that gave birth to the concept of a reflex activation therapy where this device is now miniaturized, it's implantable. This is all done. Extra vascular has now approved by the FADA since 2019. For the treatment of patients with ejection fraction of less than 35 equal or less. So it's implanted like a regular pacemaker on the opposite side of where you would typically put a pacemaker and then leaders tunneled it's stitched by a vascular surgeon right on top of the carotid artery. Again, it's a purely stimulation that goes to the brain and gets out, put it to the body. If you turn on the stimulator, the effect is actually quite immediate right then and there on the table. The sympathetic tone falls. So does the blood pressure. The patients hypertensive. So that's the heart rate of the heart rate is elevated and in response the bearer of light sensitivity, the ability to sense pressure changes increases. This was started in a couple of randomized controlled studies the last one is to beat HF study. And here they found that if you give it to patients and randomized them for six months compared to optimal medical therapy alone. So drugs alone that patients had a better quality of life in Minnesota living heart fell in the middle. Then they had a long a six minute walk distance. All clinically significant 30 40 m difference in six minute walk differences a lot And then also changing anti Peruvian team. So that was what led to the approval of the therapy so that 35% or less. The other therapy that was approved the same year two months later was cardi conductivity modulation. I don't know if you offered your institution. We are about to participate as part of a trial. And the idea here is that this is not a nerve stimulation is not in your modulation device, it is like a pacemaker. You pace the inter ventricular septum between two leads. The big difference here is first of all this device is implanted like a pacemaker. Use standard pacemaker leads but this device is externally charged. It uses a lot of energy, a lot of juice. Okay. And that and electricity is delivered in the QRS complex. So it paces during the QRS complex where the heart is already polarized. And what happens is that now when you when you stimulate with high current heart muscle it forces the cell to take the calcium out of the side of the free floating calcium. Which is not good. And to put into psychosomatic particularly if you store away free floating calcium. That is a good thing because the cell hates free floating calcium and that free following calcium then gets released in the systolic beat thereafter and binds to myosin, troponin or whatever and then actually leads to the systolic contraction. So this device is really a systolic contraction enhancer and leads to an improved systolic performance, interestingly also leads to a better diastolic performance because it forces the cell to pick up the calcium at a faster pace, release at a faster pace. The cool thing about strategy is has been shown that when you stimulate long enough ak you stimulate this really every day not all day just for hours at a time that you change the protein profiling and the protein expression of the self so you actually stimulate and change the way it expresses proteins over time. So this has also been tested in randomized control. This was a sham controlled study and found to improve the functional performance you really the PQ to improved so that the quality of life. And then they pulled the two studies together and found that between the two studies but both were randomized controlled studies that also reduce heart failure hospitalization. This was a secondary endpoint. So this also FDA approved. I think this is utilized the United States more common because it's easier to be implanted by cardiologist done by an Ep as opposed to a vascular surgeon. Okay, so I like to talk about comorbidities because in heart failure very well known fact is that all our heart failure patients have multiple comorbidities. And if we simply as cardiologists focus on the heart itself, it's a losing proposition. A duke. I call myself as a doctor below the belly. I couldn't care less about the heart. Very few things we can do to the heart that's failing in front of us to actually improve morbidity, mortality going forward. Think of particularly in patients with path patients are predominantly defined by the co morbid disease. The only therapies that work in half of patients. Weight loss surgery, SCL T two is and probably GLP one R. S. This weight loss drugs, it's all below the diaphragm. It's all metabolic. That's how we're going to help the majority of heart failure patients. But sleep hypertension, diabetes and chronic kidney disease are the other disease forms that now getting target by device strategies. I talk about sleep because often neglected but very prevalent in heart failure obstructive sleep apnea. Everybody knows or has a family member or a wife or husband, that we kick at night. So they stop snoring. Everybody knows obstructive sleep apnea. I will deny that my wife snores. But the central sleep apnea is the component where your brain just stops breathing, breath, breath, breath and you stop breathing because there's no signal coming down from the brain to the diaphragm. A lot harder to diagnose because that's often mixed in with obstructive sleep apnea and sleep labs love to call out obstructive but not central sleep apnea. That's something to pay attention to the problem. Senator sleep apnea is that 30 to 40% of all half of patients have a degree of center sleep apnea. 20% of patients have central sleep apnea, but you cannot treat central sleep apnea with pap therapies. Positive airway pressure CPAP or bi pap has never been proven to be beneficial. As a matter of fact in the survey HF. Trial was in Union General 200,015 paper, They stopped the trial early because positive airway pressure killed patients with central sleep apnea and have at a greater rate than not treating them for central sleep apnea. So it just shows you that we really need dedicated therapies and surprise surprise. There is a dedicated therapy which is the sole approved dedicated therapy for central sleep apnea. That's very nervous simulation. This is a neuro stimulator here. Whether you believe in mother nature or God. They placed the creator place the vein right next to the left, frantic nerve and electro physiologists are praying to that God all day every day. Why? Because they can tunnel a lead right into that vein. So it can stimulate that nerve. So it's quite fortuitous otherwise it's done like a pacemaker. It turns on only at night and simulates patients at night. And you know when the diaphragm is not breathing because there's no neuro impulse coming down the nerve it turns on and stimulates them. Very simple concept and works like a charm. Okay, I move on to my little bit self advertisement here. So that's the pipeline. So what's going to come? Those therapists? I just showed you this is it? I just skip the mitral valves and the towers. I don't like talking about valves. I don't do those procedures myself leading up to the structural guys. But when we think about heart failure decompensation, we often think. We talked about gray haired professors. The ecology compensation is driven by salt and water. Overload. Salt and water overload. That chick fil a is what kicked our patient's heart filet. Right? We learned that what if I tell you that the majority of heart failure patients actually do not have any significant weight gain preceding hospitalization. 50, of patients presenting to the hospital have no significant weight gain compared to the longitudinal control. If you look back at their weight, they have not gained any weight, even though the neck veins, understand it. So here's a nice experiment which shows you that congestion is a complex concept. So these are cardiac patients. We implanted a duke in Memphis. And when we implant cardamom? We also injected radio tracer to measure how much blood volume they have? Why do I care about blood volume? We're going to give diuretics. Are patients? We diaries them primarily by focusing on the central blood volume component. We make them dry. So here to what you see here is that on the right side the X axis is the pressure. P. A. D. Is equal to wedge. Diastolic pressure equals to wedge. If you are above 15 it's high wedge pressure and on the Y axis you have T. B. V. For total blood volume deviation. What that means is that if you're outside of the green box above 8% or below 8% you're either wet or dry. Very simple. So you wanted to be in the green box? Well I had only one patient in the green box. Either as a provider or it's because we implant cardamom patients and patients that are struggling and usually are not olymic. Right? So these patients had no normal volumes, no normal pressures. But the key thing is I would have expected the majority of my patients to land in the yellow box. High pressures on the X axis and high volumes. Right? But it wasn't the case. The majority of patients 60% were in the high pressures blue box but were at the same time low and normal volumes. So I repeat myself when you see a page clinic and they have high pressure's 60% chance. If you believe the small sample size have actually normal to low volumes. What is our number one? Number two. Number three action at Duke before the patient gets seen by provider Lasix. Lasix. Lasix to everything. LASIK solution to everything in the problem is I argued many patients we overdid erasing them that sample size of 20 patients that has been done in hundreds of patients in historic studies. The reason emphasizing it here with the modern sample sizes that these patients are getting committed to a pressure guided management strategy for the rest of their life called condoms. So obviously I'm no longer a consultant to Abbott because I walked up to them and said well you know what? We keep diaries in them. But 50% of them probably don't need it. So they fired me Right. How do you explain the fact that you can have high pressures despite a normal or even low volume? And I told you it's at least 50% of population. Very simple. You can increase the filling pressures. Think of the stress blood volume is what you see by the neck veins. That's a pre load that's seen by the heart. Well, I can elevate your veins by pushing down your gut and squeezing all the fluid from the abdominal cavity into your chest. Why the gut? The gut is the largest reservoir for inter basket blood volume. 30 to 40% of all blood sits in the abdominal cavity. Why delivering spleen and nothing else and sponges full of blood. So the hypothesis here is that you could distribute blood volume from the periphery and cause cottage in compensation by shifting the blood from the abdominal cavity into the chest. Okay, so one strategy to tackle that is intellectual shunting. You heard a lot about it maybe or maybe not. But the idea here is if that blood volume shifts into the heart, that actually elevates the filling pressures and the heart does not like high filling pressures. So why don't we just shut off blood from the left side of the heart? But shunting at least temporarily back to the right side, really just recirculating the blood. It doesn't get rid of the volume that's shifting towards the heart. Which could explain to some degree the lack of the benefits were seen. But the study has been studied and a large chairman controlled study was the largest study done with devices ever. The study was neutral, but the subgroup of patients with normal pulmonary vascular resistance resistance less than two seem to have benefits. So that now more studies coming on to test the concept of just shifting the blood away from the left atrium temporarily. But I would argue the way you want to get rid of the volume is actually by preventing the shift of blood into the abdomen into the chest to begin with, by getting rid of the splanchnic nerves and the splanchnic nerves of the nerves. That on that bottle trick was the thumb, the thumb that was pushing the blood from the abdominal cavity into the chest. Those are sympathetic nerve fibers, stress, stress, fight or flight numbers fibers, and those are the ones that are located in the so called splanchnic nerve. So we propose that what if we get rid of those nerves to try to prevent compensation? But before we a bladed those nerves, we stimulated them to demonstrate to ourselves what happens if you push the fluid into the chest by stimulating just those nerves. We stimulate those nerves and healthy adults that actually had the abdomen exposed long story but we increased the output to pre loaded double we double the pressures within seconds of stimulation you turn off the stimulator. The pressures came down, we repeated an experiment in heart failure patients when we stimulated pressures went up but actually didn't come down. So that told us that in patients with heart failure, once you shift the blood centrally they'll say no thank you. My heart will not tolerate any any volume shifts and decompensate that way. So then we went on we cut those nerves temporarily by blocking them. With anesthetics were able to show that heart failure patients acutely. We're lowering the pressures on the right and on the left side here are a pressure pressure pressure in reverse the mean pressures also dropped as well. So we affected central arterial pressure as well. But the index increased temporarily. So we did like to decongest the heart, the cardiac output increased. So that was hospitalized patients. Then we went on to block the nerves and ambulatory heart failure. Patients undergoing transplant, evil sick puppies but underwent this procedure and in black is what happens when you exercise when you have or have ref your wedge pressure on the right side is in the high twenties, just legs down, legs up. The pressure goes up more when we exercise the pressure rises and only when we tell them to stop exercise. The pressure comes down when we block the people and repeated the exercise on a supine bike. We found the gray line that the arresting pressures and exertion pressures were dampened. They all came down. So the idea here is if you prevent the shift of blood into the chest, you might prevent some of that decompensation process whether it's acute or sub acute And then things I cannot do at my institution would have fired me. I could have gone and just cut the nerve. I had enough confidence but I couldn't do it. My institutions went to Europe actually cut the nerve on the right side with Janikowski in Poland and there we follow patients for 12 months, all single arm. Open label studies here for 12 months were able to demonstrate that the pressures in the heart with exercise were lower than compared to baseline people had a better functional capacity and improvement of as well as a class. Okay. That was reassuring. So now there's a dedicated strategy so now there's a catheter that was built. You can go through the right groin I. V. C. As focus down the vein. Usually only let physiologists play in that area and then they go into the intercostal vein and just burn the nerve. Why? Because the splanchnic nerve starts in the chest, goes into the belly and cross intercostal vein always in the same spot at the level of T 10 T 11. So we burn that nerve with a dedicated system. So now there have been two studies on the left is a single arm study from eastern europe where we went and actually burned that nerve in 11 patients and here without human just following up for 12 months. No safety events, patients did not get off the static but they had an improvement in 600 walk distance and shortness of breath last month at least on the right side. We then went on and actually did that in 12 centers in the United States and showed that we were able to reproduce what we showed the Duke in eastern europe. Were able to lower the pressures. Final side, there remains to be an unmet needs unmet need for Hartfield is massive. I argue device based therapies will be able to fill that void. Thank you very much
