Heart failure is increasingly prevalent and continues to have a high mortality rate, yet the future isn’t bleak. Cardiologist Liviu Klein, MD, MS, director of the UCSF Mechanical Circulatory Support Program, presents cutting-edge therapeutic options, including drugs, surgical implants and advanced monitoring systems.
I'd like to go where? Ah, a few of the therapies for heart failure. And, uh, if you are treating heart failure patients, you gotta admit it's a pretty exciting time. Um, you know, in in treatment for heart failure, we're going to go over a few of the Hartford statistics, which are probably known toe many of you, um, some of the recent pathways for heart failure treatment, especially for heart fitted with reduced ejection fraction, which are just published by the a c C N h a couple of weeks ago. We're going to go over the recent pharmacological trials in hardware with reduced ejection fraction and then some of the unmet needs and exciting new novel device clinical trials that we are offering the UCSF. We all know that hard for, let's, say, one of the cardiovascular diseases that has an increased prevalence. There are 6.5 million patients with symptomatic heart failure in the U. S. And about 10 million in Europe. The incidents is increasing because the older population is increasing. About 1600 patients over age 65 have heart failure. We have about a million new cases every year and lifetime risk of developing heart fair for someone. Their forties is between 20 and 40% depending if they haven't entering my cardio infarction. The mean age of diagnosis has increased in. Many of our patients are actually diagnosed in their mid seventies. So in the older age older age group, despite all the treatments that we have for heart failure, it is very still very symptomatic. Disease patients have a very high symptoms burden. If we quantify that by using tools such as the Kansas City Cardiomyopathy Questionnaire, most of these patients who have a score about 55 meaning that they still very symptomatic, you know, score of 100 someone that you know feels really, really well has no symptoms, no limitations score of zero someone that's, you know, dying. So a lot of these patients still have a significant amount of symptoms. Overall, they have a very high hospitalization rate. We know that 20% of the patients re admitted within 30 days, and about 60% of the patients are readmitted within a year off their diagnosis. And still at five years When I was in medical school, we used to say that you know the survival in heart fits, you know, 50% of five years. 20 years later, we haven't really made a whole lot off difference mortality. It's still about, you know, 40% of five years after diagnosis. So still a lot of work to do to treat this disease. I'm sure that every talking hard fair must have a part physiologic that, you know, diagram. And a lot of us have learned some of these in medical school. When I was in medical school, the only really knew about these things. Sympathetic activation and rusty activation on the treatments. You know, it's inhibitors air B s beta blockers now has you know the part of physiology has exploded, and we have more and more treatment targets for heart failure. Unfortunately, many of them are just for patients who have reduced ejection fraction on then, very few options who have. For patients who have preserved ejection fraction, it's a very busy slide. But if you follow the color code, the blue, the blue labels are medications and the green labels are devices, so we have our classic medications. We have based inhibitors the RBS, Arnie's so security robots, Artan mineral cortical receptor antagonist or M. R. V s diuretics, beta blockers and then some of the newer medications. We have SGL between inhibitors Irrawaddy miles in activators, which was just presented last year in clinical trials. As you see simulators, which again was recently in fact two weeks ago or a week ago was approved by FDA for patients who have a recently compensation for heart failure. When we look at devices for heart failure, we have devices that are targeting the autonomic modulation devices that target the kidneys. Devices that try to improve into can function, either by partitioning the ventricle or by appreciating the ventricle. And we'll talk about some of those in clinical trials. We have devices to repair the mitral valve mitral valve clips that were recently also approved by the idea for treatment of functional monitor regurgitation. Of course, we have the CRTs and I C. D s for patients who meet certain indications. As I mentioned just a couple of weeks ago, the A, C C. H. A have updated their treatment recommendations for patients who have reduced ejection fraction. And really, the update was meant to emphasize that Now we have four main drugs, four class off therapy that can improve survival significantly in hardware. With this ejection fraction and as first line therapy, the guidelines now strongly advocate for use off the Arnie's So security of our soft. And for patients who can afford three armies and beta blockers as first line therapy, followed shortly thereafter by introduction off mineral cortical etcetera antagonisms as guilty to inhibitors. In fact, if we think about the pillars for therapy, we have these quite pillars or the four horses in heart failure again naturalizing inhibition, sympathetic inhibition, all that's run inhibition and, as you'll between divisions so security of our serpent agility to inhibitors memories and beta blockers, which have proven toe improve survival significantly in heart failure. Then we have other medications which have recently bean tested in heart failure, with potential benefit in subgroup of patients. So we have patients who are recently hospitalized for heart failure, and they may benefit from solve all gone like cyclists stimulators for patients who again have had very high risk, are fair with hospitalizations or very low ejection. Fraction may benefit from miles in activates or my captive. We have patients who have increased heart rate in Sinus rhythm and hurried above 70 who might benefit from Barbara Dean and then patients that are self identified as African Americans who may benefit from hydrology and has a sore by. And lastly, we have patients who have iron deficiency that may benefit from intravenous iron. And in fact, if we put together all these recent clinic trials in heart failure, we can see the results in terms of improvement in primary end points. Paradigm HF very familiar trial that tested Asarco beatable started in patients who had an injection of factionalized and 40%. The trial was actually stopped early in the trial compares a cubicle about certain within our appeal for heart failure to use ejection fraction. And it showed that 20% decrease in mortality in hardware hospitalization because I mentioned the trial was stopped early for benefit, and the medication has been a for the last almost five years to be used in these patients. More recently, I'm sure you're familiar with the trial and hardly with preserved ejection fraction and inside. The advisory panel to the FDA has recently recommended approval off track a bit of Osaka for certain subgroups of patients who have reserved ejection fraction more recently in the last year or so to new trials that are testing that have tested as you're doing inhibitors that CHF and Emperor reduced. So this sort medications so inhibited sodium glucose transporter and were initially used for diabetes and certain that initially were discovered to improve heart failure symptoms and cardiovascular mortality. So these two drugs have now been tested in patients with and without diabetes, with low ejection fraction and they both showing the same thing about a 25% reduction. Immortality and more beauty from heart failure and the drugs have now been approved for treatment off heart failure, even in patients without diabetes. More recently, we had two other trials testing two different medications from different, uh, part of physiologic pathways. So Victoria tested Sobel Guan like cycling stimulator. So medications to enhance basal dilation, if you will, in 5000 patients with reduced ejection fraction below 45%. And it did show a significant but you know, modest decrease in cardiovascular death or hospitalization, mainly driven by about 15% relative reduction hospitalization in this very high risk patient population. In fact, the FDA had has just approved this drug in the last week or so for patients who have been recently hospitalized for heart figure. It remains to be seen where we find AH place for for these drug in our armamentarium, especially that basal dilation. It's also enhanced by armies by security. Robots are can, and it is unclear if the benefit off very cigar will apply in patients to take security about Sarka. Lastly, the last trial that we have seen coming out last year the American Heart Association, meeting a new molecule, a cardiac Miles and activated on the captive, which is testing about 8000 patients with an injection fraction below 35%. Again, very high risk patients. A lot of those patients, about half of those patients or hospitalized recently had very high, not ready peptide levels. And in that patient population, there was an 8% reduction in cardiovascular death and hospitalization, again mainly given by a reduction in hospitalization and finally to ongoing trials for patients who have iron deficiency unnecessarily anemia. But just iron deficiency on ejection fraction that below 35 or 45% to different preparation off iron, intravenous iron and we're still waiting Thio see the results of these trials in terms of improvement in outcomes. Going back to our very busy scheme, I would like to focus on devices for heart failure. We think about autonomic modulation, something that beta blockers do currently pharmacologically. There have been several devices tested for heart failure, table nerve stimulation, spinal cord stimulation, corrected artery stimulation. Uh, you know, our third innovation. So all these trials, with the exception of the corrected artery, our stimulation have been negative. And there's no FDA approved product for that indication. The battery sector stimulator has recently been approved last year by Theo FDA to improve symptoms in patients who have a metal cure s and an injection fraction below 35%. We're still waiting to see effect on mortality and hospitalization for these device. Finally, frantic nerve stimulation improves central sleep apnea, which is president. About half of the patients who have heart failure or in patients who have atrial tribulation so friend in their stimulation is another option for these patients who have central sleep apnea. Michael Regurgitation. Very prevalent function, mitral regurgitation, very prevalent in patients who have systolic heart failure and, as we know, the cooperative trial has put the micro clip on the map for appropriate patients on optimal gala injecting medical therapy Improvement. In my regurgitation, using micro clip can decrease the mortality and hospitalization in the suburb of patients going now to clinical trials. So there's a lot off data that is unknown. There's a lot off unmet need in this patient population and again focusing on mental Barre modeling the chronic model the patient of patients who have low ejection fraction leads to chronic them through very modeling. And we have tried using medications or biological pathways to reshape toe, really model the left ventricle and again using medications on, you know, in the extreme cases you using ventricular assist devices. However, there is a new era in interventional cardiology looking at testing minimally invasive capital. Deliver devices to improve particular shape mechanically in these patients and two of these devices, which are in clinical trials in the idea clinical trials United States are relevant, and the accuse each president. It's a very interesting device. It's essentially meant to exclude scar in patients who had a very, uh, severe car ischemic cardiomyopathy with a very large and peers car, and essentially by excluding the scar implicating it away, making the ventricle smaller and more efficient in contraction. Mhm in the divided, implanted, minimal, invasive. So there is a I J approach. And then there's a lateral approach through a minute thoracotomy, going thio the apex of the left ventricle individual scar. And I'll play a video briefly Thio to show you how exactly, works so under for a Skopje access of pain through the internal jugular vein and then through the scar transept. Early, there's a placement off a synching device, another synching device on the outside of the heart. And essentially it's pushing away the scar into it into itself and then placated this abnormal part off the ventricle, excluding the scar on, then making the ventricle smaller and more efficient. And this is tied. Looks on an X ray Post op playing in the data from the European studies are very encouraging and currently, where FDA has approved the i d trialing 20 sites in the United States. UCSF. It's actually the only site in California, and it enrolls patients who have a ninja action fraction less than 45% somewhat dilated ventricle, more than 50 amongst the meter square patients who have a history of my cardio infarction and have, ah, scarring the interior water Antrel entre septal region off the off the left ventricle. And, uh, you know, the primary endpoint of trials, essentially seeing if the procedure improved. The outcome compared to a cohort that's there will be in parallel medically managed. So patients are randomized to medical management versus the life procedure. Obviously, it is not a blinded trial because the patients will know if they have a procedure or not. The adjudicators will be blinded, and the end points will be thio. Look at the number of hospitalizations for heart failure, improvement in quality off life, six minutes walking distance and the New York Art Association class. So again, if you have a patient who has a previous semi and they're struggling with Class three symptoms or even, you know, kind of late class two or early class sport, um, they may be a good patient for this trial. The other device that it's being tested in reshaping the ventricle, it's theocracy change, which is used in patients to have either ischemic or dilated cardiomyopathy. The difference off these devices actually implanted completely. Trans catheter and there is a synching portion that goes right under the mitral apparatus. And then by cinching the device, you're decreasing the radios, making the ventricle smaller at the base in a more physiologically very similar to what you might think about cardiac risk Equalization therapy. So essentially you obtain access. Trans aortic with the guide wire goes under the motto Apparatus finished the court day, and then the Catholics then deliver the delivery system delivers thes anchoring system, and then you have anchors that go into the left ventricular wall to cinch the base off the heart. And then there's a cooling mechanism but makes the heart smaller for this trial. In the course in VHF trial, three patients have to have an injection fraction below between 2040%. Have thio have a dilated ventricle. Eso the end that's our dimension has to be more than 55 millimeters. They can be anywhere between class two and four, and they have to be on garland direct medical therapy that includes at least an army. So trust off beta blockers and Maria. A lot of these patients will be presented Thio Eligibility Committee and a lot of these patients will be, um, actually asked to be on SGL due to inhibitors as well. Asai mentioned the primary endpoint. It's similar to the live trial, essentially looking at hospitalizations for heart failure, mortality, transplantation, need for ventricular assist device and then improvement in quality of life using the cases. If the questionnaire and we are the only site in, uh in California and in fact, we're having our first patient being implanted in a couple of weeks, eso very, very exciting for these patients moving on from reshaping the ventricle to try to control the fluid status. So we all know that high pressures in the left atrium and in the left ventricle need to ponder oedema and lead to these patients being short of breath and being admitted to the hospital. What if there's a way to passively decrease the pressures on the left side? And that is exactly what the idea behind the atrial shanties there's various atrial Sean devices through the first two here, the Weather and Korea are now in clinical trials. In fact, core via has completed their clinical trials in hefty, so just patients would preserve ejection fraction. The wave so being used in patients who have reduced and preserved ejection fraction on then the other. You know, shots are still in development, but interesting. You know, both of these devices are made off 19 all, and then they have a self anchoring component. The diameter of the shan't differs between five and eight millimeters, and there is the idea behind the passive flow from a high to a low pressure level. So kind of like a tour effect, if you will. In the view action on Ben, they're implanted trans transsexual. It's similar to a micro clip procedure. Um, and the the implant is, you know, it's very easy. This is the shank can see under the tea or ice. You contend the fossil valleys and then you puncture it. We have the guard who are going through going through the septum. Then you have the delivery system coming across. They haven't violator over the guide wire, and then the delivery system coming through the violator with the shank, the shanties deployed into the left, a human. Then it's pulled back. You can see the our shape essentially being deployed there, and you can see it very nicely on the ice or a p and then pulling back on the right side. We're pulling back the delivery system, and then the shank essentially cinches on the right side as well in the Agua shape. And then you have flow across the Grady in can see the shank here. It's very hard to see on a regular X ray. You can see it in the cath lab, you know, with see me or high density floor, and then obviously can see it with a P or even with the transfer Asik echocardiogram. You can see that, Sean. The idea behind this is again Thio, shown from a high to a low pressure radiant and therefore, theoretically, the risk off shunting from right to left. It's abolished because in Heart Fair, both have rap and half bath. You always have higher pressures on the left side. So the really VHF trial, which were part off it's essentially a sham controlled people. Try a where the patient is brought to the cath lab. It's, uh, patient has a ice or tea and the right heart cath. And then the random ization occurs in the cattle, so the patient does not know if they're being randomized or not to have the procedure. The shot itself. The deployment of the Shan takes about half an hour. So for patients in the control group that they're just kind of kept in the cat lab. And you know they have year mop so they cannot hear the physicians talking on Ben. They're they're just treated the same way as the patients who have got the Sean. Um, Initially, there are about 100 patients in the role in arm Way had three patients in the role in arm and we a za p I. I knew that they had the shot and two of those patients actually had cardinals devices in so we could see over time the peer pressure decreasing in these patients. And interesting enough, both patients who have cardio mum's were able thio cut their diuretics in half eso very, very interesting physiology since then. Now we're down to the randomized portion where I'm blinded Thio. Which patient has received the Shang, although I can tell you that even being blinded, I think I know which patients have the shot because we had a few patients that had a marked improvement in in their six minute walkers There is a season in tow test done at one month and six months. And, you know, a few patients have literally walked more than 100 m after their initial procedure at one month. So Theus assumptions that they probably have the shot. The trial is Mento last for about a year on again. The end point of the trial is hospitalization for heart failure. Three end of the year or mortality. Patients enrolled have to be class three or ambulatory class for if they have a reduced ejection fraction. Again, they have to be on this guideline directed medical therapy. If they have preserved ejection fraction, there's obviously no God and directed medical therapy for that group on to ensure that the patients are properly treated, there's an eligibility committee where we have to present every single patients. And if the committee feels that the patients are not optimally treated, then we're asked to optimize the treatment and then come back when the patients are optimally optimally managed. Mm. Lastly, we're talking about against Louis status and mine during devices for for heart failure. We all know that when patients present to the hospital represent because they're short of breath. They have clinical congestion in in most of our patients. The way we try to the technical congestion is very rudimentary by asking the patient weigh themselves every day. And then, if they do see a way, way to increase toe, take more diuretics or call us a lot of hospitals. Ours included have, you know, hardly a program. Stella Monitoring programs trying to, you know, decreased patients being hospitalized and creates the admissions for patients who recently hospitalized. And they do work with some degree off variability, depending on the patient population and the intensity off mine during in randomized clinical trials, they actually showed no benefit in many, many clinical trials. Then you do have Thea implantable devices. So defibrillators, pacemakers, CRT devices who was a byproduct have the ability to test some markers off hard for the compensation, either through ASIc, impedance or heart sounds or Harvard viability respiratory rate. So using those you know, modalities such as hard logic, for instance, or triage, HF were able to somehow managed these patients on an outpatient basis. Most of these physiologic markers tend to change 23 weeks prior to a patient developing symptoms, so if you have a monitoring program set up, you could detect thes patients before they end up in the hospital. However, even better than that, even more, you know, proximal or earlier. We know that the pressures in the heart increase. So if we're able to detect lifted the pressure increases or pommy arctic pressure increases, then we're able to make small adjustments in their medications and again prevent this whole three compensation toe occur five or six weeks prior to the patient becoming symptomatic. We all know that there is a approved device called arguments, which has recently Bean, um expanded in in clinical trials, now enrolling patients class to four in the Guide HF trial on Ben, we have another device called Cordell, another family Arctic pressure sensor. And then I left data pressure sensors to monitor demonstrations. And the whole idea is that we're trying not to wait until clinical congestion is manifest, but rather to detect humor, dynamic or subclinical congestion to prevent this patients from coming to the hospital. So the three devices that are available as I mentioned the left date of pressure device victorious, which has started I D trials in United States, Uh, current Mints, which is a currently approved for Class three patients and is being the testing, the guided chef trial for Class 23 and four patients, and the Cordell A device from Under Trying, which is being tested in the proactive HF trial. We are actually part of this trial, and the reason for this is that the sensor it's it's a, uh if you will a second generation formulated pressure sensor so you can see the shape of the sensor is quite interesting. And as opposed to the government, which goes into the left bombing artery, this goes into the right family artery. It's fairly easy to implant both from a internal jugular approach or from a a similar approach, and the thing that really, really made us a very interesting the trial is the ability to test the pressures with a handheld device. Um, for people who use condiments, you know that they have the patients have to lie on a pillow, so we're getting supine pressures and treating supplying pressures, not truly ambulatory pressures. With the cord ella device, we're able to treat ambulatory pressures and seated pressures, not just supplying, and we actually can have patients walk and then measure their precious at the end of the walk. So we're able to see the dynamic human dynamic changes during during exertion. In addition, the Cordell A system comes with a whole package off things that patients can be monitored. It comes with an iPad weighing scale of blood pressure Conference on. So all this information now comes a za package. Thio caregivers the physicians on the patients, uh, and able to, you know, we reviewed remotely and improve outcomes because I mentioned the the package with the regular tools. Let's say it's available for clinical use. And the sensor is currently being tested in I. D. Charles, both in Western Europe, in in Syriana for a CMR trial and then in the United States with Proactiv HF trial We are the first site that in all the patients a year ago, so our first patient is now a year out Onda. The trial itself will know all about 1000 patients of class three symptoms and again randomized thio, placebo treated or controlled treatment versus peer pressure, mind and treatment. So all the patients get the sensor. But in half the patients, a physician eyes blinded to the pressure readings, so they will have too much to monitor and treat the patients according to sign symptoms. You know, weight changes and so on. Sort of standard of care on then in the other half, the physicians has access to the pulmonary artery pressures, and there's a whole treatment algorithm that way. Used to lower department right, precious three endpoint The trial Be essentially hospitalizations for heart failure or mortality. 12 months. Eso very, very exciting, you know, trial for monitoring patients with heart failure. What will happen the next five years? I think we'll see more and more pharmacological therapies targeting other pathways in heart failure with reduced ejection fraction. Obviously, the limitation is that the patients have to take so many pills, and at some point they will not be able to either afford or, you know, you know, want to take so many pills. Eso We'll probably see patients now being targeted in in smaller groups. Morphine. A typical personalized group of patients you know, using either image ING or clinical tools or bio markets or genetics. There is a plethora of structural devices being developed both for half red and half and you know, there's probably at least 10 other devices in very early stages. First in man Andi were part of some of those are very, very exciting therapies for heart failure. Ah, lot off interesting long term monitoring devices to use current existing treatment but better treating or better targeting human dynamics in these patients. And some of these devices are implantable. Some are wearables. So again very interesting and very exciting for for these trials. And finally, for the very end stage patients for patients who are not candidates for heart transplantation, for instance, we have trials with antique proces devices and the full implantable device are coming in the next five years, which will eliminate the need for external drive lines and batteries and so on. So patients will be completely, you know, mobile Andi, then by you know, doing that and minimizing the adverse events of these patients have we'll be able to offer these small, upstream analyst sick patients and may be used them as a platform to enhance medical therapy. Um, there's also, you know, coming down action. The next six months, a communication and build. Your patients can send data from their remote remotely from their L. That's to us as physicians, and we can treat these patients remotely without having to come to the office, which we all have seen the past year since Kobe Telehealth has really grown tremendously and very, very fast. So what about our clinical trial in heart failure? I just showed you a few of them that were part off. We lead. Actually, enrollment in the nation's for many of those were either the first or second highest in all in the country, where the only sent in Northern California and sometimes on the West Coast. For many of these device trials in heart failure and former hypertension, I might add, we have a very streamlined, easy access process for patients to be extremely any role. We have, uh, you know, negotiated with sponsors to help patients come to UCSF and, you know, pay for transportation and parking and so on. To make it easy, we partner with the treating cardiologists and keep them in the loop with, you know, the patient. They screen for procedure for trialing. They've been enrolled, and you know what? How are they progressing to the trial in many of these trials? Obviously patients are able to be offered three testing, right? So they get echocardiograms catheterization so on, and they get another layer of ice in their care in the form of our coordinators.
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