So let's look, I've copied here from the 2018 Clinical Practice Guideline on Management of Ventricular Arrhythmias and Prevention of Sudden Cardiac Death. These are two different recommendations, and I want to walk through them together. So the first one is in patients with an LVEF of 35% or less that is due to ischemic heart disease. Now we're talking about patients with ischemic cardiomyopathy for at least 40 days post-MI and at least 90 days post-revascularization with NYJ class 2 or 3 symptoms. And I've highlighted here, despite GDMT, it is absolutely critical that these patients are assessed after they've been optimized on GDMT. An ICD is recommended if meaningful survival of greater than one year is expected. And then the other recommendation in patients with non-ischemic cardiomyopathy, again, class 2, 3 NYJ symptoms, an EF of 35% or less, again, despite GDMT, an ICD is recommended, again, if we expect meaningful survival of at least one year. So I want to emphasize these are class 1 level of evidence A recommendations. What does that mean? Class 1, this is our strongest recommendation from our Clinical Practice Guidelines. This means that an intervention is useful, it's effective, it's beneficial, it should be performed. Level A, this is the highest quality of evidence. This is not expert opinion. This is at least one randomized clinical trial. In many cases for the medications that I'm going to discuss here this morning, more than one RCT has been conducted, meta-analyses where we're putting together the randomized controlled trial evidence, corroboration by registry studies, oftentimes NCDR studies, studies using NCDR data. So this is absolutely critical. This is the highest quality evidence. This is the highest quality of evidence for GDMT. What does the acronym stand for? I think we generally think of it as guideline-directed medical therapy, sometimes guideline-directed management and therapy is how it's defined in the 2022 Heart Failure Guideline. And again, what we're going to focus on here is for patients who have HFREF, heart failure with reduced ejection fraction. So we'll start with a polling question before diving in. Which of the following is not a guideline-directed medical therapy class of medications for patients with HFREF? So which is not? Option one, beta-blockers. Option two, SGLT-2, sodium glucose co-transporter 2 inhibitors. Three, mineralocorticoid receptor antagonists or MRAs. Four, ACE inhibitors, angiotensin receptor blockers or ARNI, angiotensin receptor neprilysin inhibitor. Five, hydralazine nitrates. Or six, none of the above. So let's take 15 minutes, excuse me, 15 seconds for the poll. All right, great. So we have about, get my cursor here. Okay, so we have about 13% of people said beta blocker, 7% SGLT2, about a third MRAs, nobody ACE-ARB, about a quarter hydralazine nitrates, and 20% none of the above. So definitely by the end of the talk, all of you will be grouped with the 20% here, none of the above. So all of these beta blockers, SGLT2 inhibitors, MRAs, ACE-ARB, ARNI, hydralazine nitrates, all of these are class one level of evidence A. Randomized control trial evidence showing that all of these classes of medications improve outcomes in patients and the most important outcome that is that they help patients to live longer, that they have a mortality benefit. So let's walk through, this is a slide that I took. We're going to walk through each of the classes, but just to get us started, this is a slide, this is an image that I took from the 2022 Heart Failure Guideline. Start at the bottom here. So we're talking about ICDs and cardiac resynchronization therapy and CRT. What the column here represents is the relative reduction in all-cause mortality. This is all causes of death. How much benefit do you get in a patient with heart failure with reduced ejection fraction from these various interventions? ICDs based primarily on clinical trials like MADET-2 and SCUD-HEFT get about a 23% relative reduction in mortality. Cardiac resynchronization therapy, 36%. But now let's go to the top. Let's look at the medications. ACE inhibitors, angiotensin receptor blocker, 17%. An additional benefit of 16% from ARNI. Beta blockers, 34%. 34% reduction in all-cause risk of death for patients with heart failure with reduced ejection fraction from getting a beta blocker. MRA, mineralocortis receptor antagonist, 30%. SGLT-2 inhibitors, these are a new kid on the block relatively for heart failure. 17%. We'll talk about hydralazine or nitrates in individuals who self-identify as African American. We have clinical trials showing a mortality benefit, 43% if they have advanced heart failure. So absolutely we are getting an important benefit from our patients with the implantation of an ICD by placing CRT. But all of these medication classes are absolutely critical to ensuring that our patients are living as long as possible with heart failure with reduced ejection fraction. Again, this is all-cause mortality from randomized controls, from the highest quality evidence that we have. So now we'll walk through the five classes of medications so that we're all up to speed and on the same page. So the first class is ARNI, ACE inhibitors, angiotensin receptor blockers. So these are generally the general class or renin, angiotensin, aldosterone system blockers. I've also listed here the medications and bullet points so that you're familiar. So ARNI stands for angiotensin receptor neprolysis inhibitor. We have one on the United States market, Secubitril, Valsartan. ACE inhibitors, we'll again listed them here. I won't read them all out, but you've probably seen patients on these medications, I think most commonly probably Benazepril, Lisinopril, Ramipril. And then ARBs, angiotensin receptor blockers. Again, I've listed them here. Candesartan, Losartan, Valsartan, Telmasartan. So these are the medications that we are looking for all of our patients with HFREF to be prescribed one of these and not all. So what do the guidelines say exactly in terms of the progression? Again, class one, this is the strongest class of recommendation, level of evidence A, randomized trial evidence, the strongest class of, excuse me, strongest level of evidence. So the first recommendation is you start with an ARNI. So if a patient can take an ARNI, if it's feasible, and we'll talk about some of the reasons that it might not be feasible, then the patient should be on an ARNI, should be on Secubitril, Valsartan. Now, some patients for multiple reasons, some of which are structural, for example, related to cost, which we'll talk about, but also for other reasons, for example, lightheadedness, hypotension, might not tolerate ARNI, might not tolerate Secubitril, Valsartan. And in that case, you go to an ACE inhibitor, Lisinopril, Benazepril, etc. So ARNI is number one if you can. If the patient can't, if it's not feasible, you go to an ACE inhibitor. And then some patients are intolerant of ACE inhibitors. For example, ACE inhibitors often induce a cough. It can also lead to ACE inhibitor-induced angioedema, which is certainly quite serious. Then you trial and go to an ARB. So all of our patients, ideally, should be on an ARNI, on Secubitril, Valsartan. If not, an ACE inhibitor. If intolerant to an ACE inhibitor, then we go to the ARB. The mechanism is these medications, as all of the classes of medications that I'll describe, reduce neurohormonal effects of the sympathetic nervous system, including vasoconstrictive effects. The pathophysiologic milieu of heart failure is one of increased sympathetic overdrive, of vasoconstriction, of cardiac remodeling in a negative way, and that leads to adverse cardiovascular outcomes like ventricular tachycardia, like ventricular fibrillation, like heart failure decompensation. So this class of medications, ARNI or an ACE or an ARB, they reduce these neurohormonal effects. They help in reverse cardiac remodeling. So the heart that is failing is getting reversed from that failed state. And so they're helping to improve outcomes through these neurohormonal effects. These medications do require monitoring of renal function, of kidney function, monitoring of electrolytes, in particular potassium, monitoring of blood pressure. Certainly ACE inhibitors and angiotensin receptor blockers are commonly used just for the treatment of essential hypertension. So that's our first class of medications. ARNI, if not feasible, then the ACE inhibitor, if not because of side effects, then the angiotensin receptor blocker. Beta blockers, similarly, we've had these medications for decades. Again, reduce neurohormonal effects of the sympathetic nervous system. They do reduce heart rate and contractility. Now with beta blockers, it's not any beta blocker, but we have three beta blockers that have been studied in rigorous randomized clinical trials. And they're listed here. Again, I've highlighted them. Bisoprolol, carvedilol, and sustained release metoprolol succinate. So all of our patients with heart failure with reduced ejection fraction, again, unless they cannot tolerate one of these medications, should be on either bisoprolol or carvedilol or long-acting metoprolol, metoprolol succinate. This is not the Tartrate, not the twice-daily medication. Now again, these medications are sometimes used for blood pressure, although less commonly over the last decade. They're sometimes used in the post-MI setting as well. So patients may be on these for other reasons. They can reduce heart rate. Some of our patients are bradycardic. But if we are talking about the patient having a CID, having an ICD, having a cardiac resynchronization therapy with pacing or with defibrillator, they already have the backup pacing. They already have a lower rate limit. And so the heart rate is not that much of an issue. It's a non-issue. So beta blockers, again, bisoprolol, carvedilol, sustained release, metoprolol succinate. Next, I want to talk about mineralocorticoid receptor antagonists. Now these medications, generally spironolactone or aplarinone are the ones that are currently on the United States market. We also have some recent data from finarinone and from the Fine Arts trial that was published to coincide with the presentation at the European Society of Cardiology meeting a couple of weeks ago. But MRAs, they've tended to be underappreciated and I think are absolutely a centerpiece. It is critical that patients with heart failure with reduced ejection refraction are on one of these medications, MRAs. It can be a little bit trickier. Some patients may tolerate these medications a bit less often. But let's look again, class one level of evidence. A, let's look at what the guideline says. Class two to four symptoms. Recommended, again, to reduce morbidity. And I want to, again, emphasize all-cause mortality. If a patient has HFREF, they will live longer if they are prescribed and taking an MRA. Now these cannot be used in patients with compromised renal function. The traditional cutoff has been an estimated glomerular filtration rate of at least 30. And these medications can also cause hyperkalemia. So you want the patient's baseline potassium to be less than five. Obviously most patients are less than five, but it is very important to monitor, as I have down here, the patient's kidney function, the patient's electrolytes, especially the potassium within a week or a week to 10 days of starting the medication. Again, just as with the ACE-ARB-ARNI, as with beta blockers, the MRAs reduce neurohormonal effects of the sympathetic nervous system. They help with reverse cardiac remodeling. They help to keep patients living longer. So they are a centerpiece of GDMT for patients with HFREF. Just needing to be careful to monitor the kidney function to ensure the patient's coming in for a lab, making sure that their potassium is okay, that they haven't developed renal insufficiency. The relative new kid on the block, SGLT2 inhibitors. So I have some sugar here in the corner. These medications initially were developed for the treatment of diabetes and they've been used by endocrinologists and in diabetes treatment for a longer period of time. But over the last half decade, we have developed, again, class one level of evidence A, evidence that SGLT2 inhibitors in HFREF, as well as heart failure with preserved ejection fraction, again, reduce hospitalization and keep people living longer. Irrespective of the presence of type two diabetes. So this is the fourth arm of GDMT. The medications most commonly prescribed are empagliflozin, dipagliflozin, sotagliflozin. We have ertugliflozin on the market. The mechanism is not completely elucidated. There is some diuretic effect. There is some reduced arterial stiffness. And again, I want to emphasize that the benefit here is irrespective of glucose reductions. So patients, again, with HFREF should absolutely be prescribed an SGLT2 inhibitor. These medications are rigorously studied. They are newer to the cardiovascular medicine arena, but it is absolutely essential that patients are prescribed these medications. And finally, the last class one level of evidence A recommendation is hydralazine isosorbidinitrate. So here's, again, copied from the 2022 heart failure guideline. For patients self-identified as African American with New York Heart Association class three or four, heart failure with reduced ejection fraction, receiving optimal medical therapy, the combination of hydralazine isosorbidinitrate is recommended to improve symptoms and reduce morbidity and reduce mortality. So again, we have two RCTs that were conducted roughly about 20 years ago that showed among patients who self-identified as African American and had advanced heart failure, class three, four. Now we're getting into class four heart failure. So rest symptoms, lived longer if they were treated with hydralazine isosorbidinitrate, getting the afterload reduction from these medications. So in summary, key take home points, class one level of evidence A, GDMT. This cocktail is what all patients should be on unless they cannot tolerate or for other reasons related to feasibility. And we'll talk about that in the next few minutes. ACE, ARB, ARNI, a beta blocker, an MRA, an SGLT2 inhibitor, and for individuals who identify as African American, hydralazine or isosorb, excuse me, hydralazine and isosorbidinitrate. So I'm not going to go through all of these things. So it's not unfortunately enough to just prescribe a medication to a patient. It's not enough to have a patient on lisinopril two and a half milligrams a day or metoprolol succinate 25 milligrams once daily. In addition to being on these medications, the patient should be up titrated. They should have their medications optimized to target doses. It's not just the starting dose that we might start a patient on, but it's critical that the patient is on a target dose. And the 2024 ACC expert consensus recommends that once a patient's been diagnosed with HFRAF, we have up to three months to get patients as optimized as possible. Now, obviously we want to do it more quickly. If we can get them optimized as I'll show you even in a few weeks, that's ideal. But we want to be getting the patients optimized on their medications. And again, we're supported by RCT data. This is the strong HF trial. This was conducted mostly in Europe. And the goal here was that among patients who were hospitalized with heart failure with reduced ejection fraction, so they were hospitalized, acute heart failure, decompensation in the hospital. By the time the patient was at discharge, the researchers tried to get people initiated on all of the right medications and at least at half of the target dose. And then within two weeks of hospital discharge, patients discharged today, within two weeks, they're optimized. They're at the full target doses. So really rapid up titration of these medications. And what do they find? You can see in the in the bottom bullet here, a lower rate of death or heart failure readmission. So not only is it critical to get patients on GDMT, it's critical to get patients on GDMT as quickly as possible and to get patients on target doses as quickly as possible. But unfortunately, we're not doing a great job. We can see the flag. We know where we need to go, but we're not there. And why is that? What's the evidence that we're not there? And how can we do better? This is research using NCDR data showing that we're not reaching GDMT goals published in JAK about eight years ago. So what I've highlighted with the red box here, our patients, before they received an ICD, the researchers used NCDR data to see, well, how many of these patients were, and all they looked at was just ACE inhibitor or ARB, or HFBB is a heart failure beta blocker, essentially, carvatalol, metopsoxenate, bisoprolol. Did the patient fill a prescription the last 90 days for an ACE or an ARB or one of the beta blockers? Just 61% of patients had filled a prescription. And what's worse is at least 80 days of those last 90 were covered by prescriptions for only 28% of patients. So what is this telling us? Using NCDR data, national, the most rigorous data, we're seeing that fewer than two-thirds of our patients were on an ACE or ARB. And this is just an ACE or ARB. We're not even talking about an MRA. We're not even talking about an SGLT2 inhibitor. And patients were either not filling their prescriptions, had incomplete prescription before they're coming in to the EP lab for the device. So we could certainly have an entire summit, unfortunately, on the reasons at the healthcare system, at the clinician, at the patient level for inadequate GDMT. I'm going to walk through some of them so that we're thinking about them. I know so many of you, I enjoyed seeing some of the posters, the e-posters as well. I know many of you are working on this topic. It's critically important getting patients on GDMT. But I do want to lay out what this really nice review article in Jack a couple of years ago laid out in terms of barriers to GDMT. We have a healthcare system, unfortunately, that has restrictive pharmacotherapy pricing and policy, inadequate health IT to support us in prescribing GDMT when patients are diagnosed with HFREF. Unfortunately, many patients can't come to see a cardiologist, to see clinicians in cardiovascular care. They're not receiving multidisciplinary care. There are clinician-related barriers as well, knowledge and communication gaps, uncertainty about trial generalizability, concerns about contraindications about medication safety, biased decision-making, unfortunately, older adults, women, racial and ethnic minorities, individuals with lower socioeconomic status less likely to be prescribed these medications. Therapeutic inertia is just hard to make a change. We just oftentimes don't make a change. We're not doing what the investigators did in strong HF. We're not bringing the patients in every week, every couple of weeks, and up titrating their medications as much as we should be. Patient-level factors as well can impede getting patients on GDMT. Preference against initiating or changing medications, suboptimal health literacy, lack of insurance coverage or affordability, lack of adherence. Our patients oftentimes are frail, older adults. They have complex comorbidities. They may suffer from side effects that are not tolerable. So it's certainly not easy. It takes a village. It takes incredible multidisciplinary care to get patients on GDMT. We can do it, but we know that it's hard. But it is critical if we want patients for whom we care to live longer, to stay out of the hospital, to live better, which is why we're all here. The next poll question I want to think about with all of you costs. So what is the estimated annual out-of-pocket costs of GDMT consisting of an evidence-based beta blocker, ARNI, an SGLT2 inhibitor and an MRA? $20 a year, $200 a year, $2,000 a year, $20,000 a year. Medicare beneficiary. Let's take 15 seconds. Great. So about two-thirds of you said $2,000 a year, and you're absolutely right. But let's just take a minute and think about that. So this is a Medicare beneficiary, so generally an older adult who has, again, generally other chronic conditions, might be COPD, hypertension, diabetes, may be on a limited income, $2,000 a year just for these four medications. So this is a research study that our team published in JAC a couple of years ago. $2,217 for a patient annually, Medicare beneficiary, take a beta blocker, ARNI, an MRA, and SGLT2. And the cost of these, the dramatic nature of these costs, driven primarily by the fact that the SGLT2 inhibitor and the MRA, excuse me, the SGLT2 inhibitor and ARNI are currently brand name, so they're not available for generic. So if you take just one of those away, you get to about $1,300. And if you go to just generic medications, the evidence-based beta blocker, an ACE inhibitor, so not ARNI, even though that has the strongest recommendation, or an MRA, it's just $160 a year, which obviously is an order of magnitude less. So I think this is to emphasize that certainly costs, there are many, many reasons I think costs are certainly an important one, but there are multifactorial reasons why we need to help support our patients getting on GDMT. So in summary, we have unfortunately underuse of GDMT. Even when GDMT is prescribed, it's often at inadequate, insufficient doses. Many factors explain lack of GDMT and certainly cost is an important one. So for the next couple segments of the talk, which are shorter, we'll talk about how GDMT affects left ventricular ejection fraction next. And then we'll get to generator changes, generator replacements, again, thinking about patients with ICD. So again, just to emphasize the 2022 heart failure guideline says you should reevaluate a patient's EF at least 40 days after an MI, at least 90 days after revascularization, at least 90 days after GDMT. To determine if the patient meets criteria, is their ejection fraction still reduced in less than 35%? And so we should, the patient still meets criteria for an ICD or CRT. So this is a registry study showing that GDMT oftentimes improves EF, improve HF registry. So they took patients who had a reduced ejection fraction, less than 35%, they initiated them on ARNI, and they followed them up with echocardiograms over a year. And so the red bar is where patients started. And you can see that the overwhelming majority of patients had a substantial improvement in their EF. Everyone starts less than 35%, 35 or less. And the median is that a patient improves their EF by about 10%, from 35 to 45, which is pretty dramatic. Some patients even going up by 20 points, 25%. And only a small minority of patients had an even worse ejection fraction. And very few had the same ejection fraction. The EF is going up with GDMT. This is another study to demonstrate the same, took 231 patients who had a reduced ejection fraction after a myocardial infarction, got them on GDMT, followed them for 90 days. Only 43%, fewer than half, still had a reduced ejection fraction. 31% of patients were between 36 and 49. And a quarter of patients had an EF that was near the normal range, greater than or equal to 50%. So GDMT is absolutely critical, both in the post-MI setting, as well as for all patients. And here they predicted, predictors of near normal EF, patients who had a higher EF at presentation. Female patients, if they had a lower troponin, didn't have a prior MI, and if they were under arrests from VF, VT at the time of presentation, generally have a stunned myocardium. So we can get a quarter of our patients back to, into the normal range. So in summary, GDMT is critical. We talked in the first sector of the talk about improving mortality, but it's also improving patients' left ventricular ejection fraction. And this is really important because it helps to inform, think about candidacy for ICD placement. So in the last segment here, let's now fast forward. We have a patient who's optimized on GDMT, received a primary prevention ICD because the patient met criteria, and now it's 10, 12, 13 years later, 14 years later, and the time has come to consider a gen change, to consider a generator change, a generator replacement, because the generator has reached elective replacement indicator, ERI. So what's the milieu? How should we think about GDMT and how should we think about generator replacements? So again, as we all know, the ICD generator battery has a fixed life. It depletes over time, depending on how much it's been used, how much therapy a patient has received, how much they're getting paced, et cetera, and then it reaches ERI, an elective replacement indicator that gives you at least about six months to replace the generator. The generator is nearly always replaced in clinical practice. About 30,000 generator replacements occur annually. But a generator replacement, it's not without risk, right? These are patients who received an ICD, and now they're a decade older. So they have more comorbidities, probably more frailty. The risk-benefit calculus may not quite be the same as when they were 65, now that they're 75. There is also periprocedural risk, such as bleeding, pocket hematomas, infections, and these risks are higher with the generator change because there's a pocket that we're going back into as compared with a new implant. And these certainly, again, in general, these are older adults, can result in hospitalization and other downstream sequelae, need for intravenous antibiotics, sometimes antibiotics at home, an adverse event from an antibiotic like C. diff, other complications. So it's not without risk that a generator replacement is performed. So again, as I mentioned, in terms of considerations for ICD replacement, the patients are older, they have more comorbidities. They've also had the device in for many years, and they may or may not even have ever received ICD therapy. They may not have received a shock. They may not have received appropriate anti-tachycardia pacing, ATP. They may not have needed to be paced because they became bradycardic. And also what's really important is the patients may or may not have had LVEF improvement, and those are the data that we're going to look at in the next few slides. Approximately 30 to 40% of patients actually will have had an improvement in their EF from the time that they received their initial ICD to the time when it's time to consider a generator replacement. And of course patients, as you probably know by now, who are taking GDMT are more likely to have that improvement in their ejection fraction. So here's our last question for the morning. Among patients who receive a primary prevention ICD, approximately what portion have an EF that is higher, at least 40%, greater than or equal to 40% at the time of elective generator replacement? So we know their EF was less than 35 at the time of the initial placement, a decade ago, 8, 10, 12 years ago. Now what is it at the time of generator replacement, 5%, 15%, 25%, 50%? What percent of patients have an EF that's greater than 40% that's improved by at least 5%? That's a lot of percents. Excellent. Great. We have a bit of a spread. The correct answer is 3, number 3, 25%. So let's just step back. So again, the patient had an EF of 35 or less, received an ICD. We now follow that patient and we see that 25% of patients, their EF has improved. They may have suffered another MI. They may have had other adverse consequences. They may have continued to suffer from uncontrolled hypertension. But still, a quarter of patients now actually don't meet that primary prevention ICD criteria. So this is a study, again, published in JAC. You can tell I'm biased towards the journal, about a decade ago. This used actually data from the Veterans Health Administration, from VA, and looked at ICD indications at the time of elective generator replacement. And what they did was, so all these patients received a generator replacement. And then they looked to see, well, how many patients still had an EF less than 35%? How many patients were greater than 40% and had not received appropriate therapy? I should also mention, so if a patient has had a primary prevention ICD and received appropriate therapy, that's incredibly important information because obviously they're at risk for future therapy and almost always is an indication to continue with the ICD in place. Or unclear, they didn't have their EF assessed. And this is where we get the 26% number from. So about 26% now had an EF that was above 40%. So if we looked at the patient today, their EF is greater than 40%. They haven't received any appropriate therapy. They generally would not meet criteria for a primary prevention ICD. Of course, hindsight is 20-20. We can't go back in time, but this is still helpful information to consider. And then the researchers looked at how many patients, so this is the time of the generator change at time zero. And they followed patients for several years after, and they looked to see how many patients actually received appropriate ICD therapy. And again, this is why we put ICDs in, so that when patients develop ventricular tachycardia, ventricular fibrillation, that they get ATP, anti-tachycardia pacing, that they get a shock, and that breaks their tachyarrhythmia. If the ICD was indicated, if their EF was still down, if they received prior therapy, within about five years, about half of patients got appropriate ICD therapy. So a pretty high number. But if the ICD was not indicated, meaning that their EF was 40% or higher and they had not previously received therapy, they had a much lower risk of appropriate ICD therapy. That is, again, of developing VTVF. Another study, just to emphasize the same, this is a meta-analysis of 15 studies, 30,000 patients. Again, showed that about 25% of patients had an EF improvement. About that 25% is about the number that we see in multiple studies. And we ask, what is the risk of appropriate ICD therapy in patients who have improved versus ongoing low ejection fraction? And again, it's the same. I'll draw your attention to the orange bar here. If your EF improved in follow-up, you had only about a 5% rate of downstream appropriate therapy. If your EF was still down, was still less than 35%, you had more than double the risk of appropriate ICD therapy. So really important that we're reducing the risk of patients getting appropriate ICD therapy. That means that we're reducing the risk of getting shocks for ventricular tachycardia for ventricular fibrillation. We're improving their EF with GDMT. Last couple of slides here. So just thinking about ICD generator replacement, research again using NCDR data showed that the risks of mortality after an ICD generator replacement are higher with non-cardiac comorbidities. This is again not surprising if patients have chronic lung disease, if patients have cerebrovascular disease, if they've suffered a stroke, if they have renal disease, renal insufficiency, they're going to be at higher risk. And so it's important that we consider the role of these comorbidities in that decision making at the time of a generator change. So in summary, a substantial proportion of patients will have improved EF at the time of ERI, the need for a generator change, and patients with improved EF have a lower risk of appropriate therapy. So that's what I have for you this morning. Looking forward to the Q&A, talking about GDMT, talking about therapy, talking about generators. Thanks so much for your attention and thanks for joining. All right, we've had a number of great questions come in from the audience throughout the presentation. Let's begin with one specific to the medications. Are these for life or do they get decreased if the ejection fraction improves? Yeah, so for life. The ejection fraction fortunately will improve, but there's a large body of research that I haven't shown here suggesting that patients continue to be at risk in a couple of ways. So if you have, we call it heart failure with recovered ejection fraction, that's the kind of HFREF that you want to have if you have a diagnosis of HFREF. But there are a couple of things. So first, if you have developed a reduced ejection fraction, then you are at risk of, again, redeveloping that reduced ejection fraction. So maybe it was from a myocardial infraction. Maybe it was from uncontrolled hypertension. Certainly the number one predictor of developing another MI of having, again, decompensation in your EF is that you had previous reduced ejection fraction. The other important factor is that these patients with heart failure and recovered ejection fraction are still at much higher risk of hospitalization, of cardiovascular death, of other downstream adverse cardiovascular outcomes compared to people who just have a normal EF and never had that reduced ejection fraction. So the medications, I almost always tell my patients, once we're starting them, these are lifelong medications. Again, unless you develop intolerance, unless you develop some untoward side effect, these are a part of the cocktail going forward. Excellent. Being a physician yourself, how do you encourage physicians to document GDMT appropriately for the registry? Boy. It's really tricky. There is no good answer here. Definitely, obviously, to the extent that it's possible to have a template, those are the most ideal, that this is what we know that a patient with HF-REF, this is the cocktail, this is what they're on, and this is why they're not. I'm sorry. I know you all work really hard. I know that takes a lot of effort to assess, and it's critically important that we assess if the patients are on those medications or not. I'm hoping that some of the solutions that Dr. Bott talked about earlier today will help. I know that in our healthcare system and documentation, it's tricky, but it is a centerpiece of what we need to be doing better. Great. Today, the EP registry looks primarily at use of beta blockers, ACE-ARBs, and ARNIs. Are there plans to include nitrates in these metrics, or I would extend the question to the other classes of medications you brought up as well. Yeah, that's a good question. I'm actually not sure where we are in terms of updates. I suspect that it will be soon. These are absolutely essential. The hydralazine isorbidin nitrate for African American patients, we've had those data for a while, and since we have a more limited ... I don't think it's a part of the current quality metrics as it is, but definitely what we frame as quadruple therapy, that is the ARNI, ACE-ARB, beta blocker, MRA, and I'm sure SGLT2, sort of the quadruple therapy I'm expecting will probably be a part of quality metrics. And again, absolutely for African American individuals, the hydralazine isorbidin should 100% be a part of that, and ideally be checked based on what race is captured in the registry. I don't know. Christina, if you're able to talk more to that, or we can get back. Yeah, I would just say it's definitely an item that should be brought to the steering committee to make the recommendation to add the new measures that are now part of expected guideline treatment. That sounds great. I'll add it to my list after the talk. Thank you. Next question. Are the cardiovascular benefits of SGLT2 inhibitors directly related to weight loss associated with this class of medication? No. So the weight loss associated with SGLT2, there's not much, not like the GLP-1 receptor agonists that we're certainly hearing a lot about in the news over the last year or two. So we don't have a great understanding of why the SGLT2 inhibitors are working. There are various researchers looking into it. Some people sort of joke, it does cause a diuresis, so it prevents the uptake of glucose from the kidneys, and so there's more glucose urea, which means that people essentially are urinating more. So some people have jokingly said, well, hey, this is like a really expensive diuretic. This is a really expensive furosemide or bumetanide. So that may actually be a part of the mechanism of action. There also appear to be neurohormonal effects. It appears that the benefits are driven primarily by the kidney, but we don't have a great understanding of why the medications are working, except I will say we have very clear evidence that they are working, that they are working very well. Multiple of the medications have been studied in RCTs. These medications are always studied in their own RCTs. So dipagliflozin was studied in the DAPA HF RCT, and pagliflozin was studied in its own RCT. So we do know that this is a class effect. It's not kind of one specific medication. And I would also, we didn't talk about heart failure with preserved ejection fracture and HEF-PEF here this morning, but SGLT2 inhibitors again have been shown in HEF-PEF to have substantial benefits and are a critical part of the cocktail for HEF-PEF, in which unfortunately we haven't had many therapies that have worked. There is some evidence for MRAs from spironolactone. There is some evidence for secubitrylvalsartan. Actually secubitrylvalsartan has an FDA indication for HEF-PEF, but the data are a bit shakier. But definitely SGLT2 inhibitors universally, if a patient has heart failure, patients should be trialed on these medications again, unless they have one of a few number of, very small number of contraindications. Okay. A couple more about access. So if the goal is to achieve GDMT within two weeks of a hospital discharge or, you know, as promptly as possible, how can sites achieve that up titration with a one or two month backlog most cardiologist offices have? Yeah. Can I, I'm just going to add on to that because I had that question as well, just kind of elaborating a little bit more, because you indicated that you are hoping to achieve 50% of the target dose. If you already know the target dose and given the barriers to patient compliance, patients, you know, getting back along, you know, with the backup, but even patients getting there or the approach or changes in the medication versus, you know, the target dose, is there a risk benefit to just saying, okay, you know, we're going to get you there early because of the struggles, you know, to get back and the titration and all the follow up? Yeah. Yeah. Absolutely. So I think, again, in our, this is more about our healthcare system. So we have a healthcare system in which when a patient is hospitalized, we're generally trying to minimize the number of days of the patient in the hospital. So absolutely, you know, we could in some cases have the patient, let's say the patient is optimized uvolemic in a couple of days, you know, we could keep them there for a week and keep going up on a daily basis. But obviously our healthcare system is not set up for that. And obviously there are other consequences, you know, patients may not want to be in the hospital for this type of titration. So that's why the investigators, you know, they tried 50% target doses for that reason. I think that there are a couple of approaches, one that's a little bit more pie in the sky and the one that I think is more reasonable. So some people are even suggesting that, well, maybe we'll give patients instructions about, well, hey, you know, you're here tomorrow, unless you're feeling lightheaded, dizzy, double this medication, do that. But this is tough. These are four different medications. Not just that our patients have HFREF, they have diabetes, they have COPD, they may have had a stroke. They may just have had PCI a couple of months ago. They're oftentimes older adults. They may be a caregiver for their partner or spouse who has Alzheimer's dementia. This is not easy. So I think that it's something that we think about, but I don't think that, I think that it may be feasible for some people, but I think is oftentimes difficult. I think the other aspect is multidisciplinary care. There's no reason that the patient needs to come into the cardiologist's office and to see the physician. They don't need to see me. They need to have a care plan and the whole team needs to be bought in as, hey, we're going to have this protocol and we're going to try to up titrate. We're going to identify, we're going to make sure the potassium is checked here around day five. If it looks okay, we're going to go from spironolactone 12 and a half to spironolactone 25. We're going to make sure that someone's checking in with the patient, make sure they didn't get lightheaded, that they didn't get dizzy. If they're checking their blood pressure at home, that they're not 80 over 50. So I think that's really the need and for so many of you here in the room, in the VA we have a pharmacist-led clinic where we determine new diagnosis of HFRAF. These are our goals. Let's see if you can get there. And then consult us, call us and say, hey, the potassium went to 5.0. Is it still okay to go up on this medication? Or the patient felt lightheaded, but maybe it was orthostatic. Should we still increase the sucubitril valsartan? That type of thing. So I think that's what's needed. I think, Christine, to your question, we do sometimes think about going on to higher doses, but there are risks. Patients can, I've certainly seen patients have syncope from going too quickly on the RNA. And again, the last thing we want is for our patient who also has AFib and is on a pixaban to now have a syncope event and hit their head. So I think there are opportunities to go faster in the hospital setting. I think we tend to be a little bit more ginger. And part of that is therapeutic inertia that we need to overcome for GDMT. Great. And you were just speaking to this a little bit, but you might want to elaborate. How would you recommend mitigating some of the barriers patients encounter adhering to the medications because of their social determinants of health risks? Absolutely. Thanks for the question. I think this is certainly the number one thing, the social determinants of health, the structural determinants of health that unfortunately our healthcare system and even our larger society is not set up well to address. I think it requires us to assess what the specific structural barriers are and how we can address those. And again, I think it really takes multidisciplinary care. I think it really takes a village in order to help people. But I think there's much more of a need for assessment of SDOH. I think fortunately Medicare CMS is going in that direction. There are now billing codes for SDOH so you can code for them. Unfortunately, they're coded much less often. But we need to be assessing them and then we need to have tailored strategies as to why our patients are not taking. Is this an individual who's unhoused? Is this an individual who has distrust of the medical system? Is this an individual in whom we have a language barrier? Whatever those might be. But it's a huge ball of wax. I'm glad we're starting to tackle them. Is this a patient who's suffered from structural racism and has mistrust of us because they've been mistreated by our system? So we have a long way to go. Yeah. Thank you for that. And that's all the time we have for questions. If we didn't get to yours, please feel free to follow up with NCDR after the conference. Come take my business card at the end of the session and join me in thanking Dr. Druva for an excellent presentation. Thank you.

ventricular arrhythmias

sudden cardiac death

ICDs

cardiomyopathy

GDMT

HFrEF

ejection fraction

ARNI

ICD replacement