Well, thank you very much to the HFSA support staff. You've been wonderful in facilitating this seminar from a technical and logistics standpoint, and welcome to everybody at this Heart Failure Virtual Seminar. This one, the topic is on guideline-directed medical therapy. And I think that the mere fact that we've had over 200 people sign up for this, you're voting with your feet in terms of expressing how important this topic is. So welcome everybody and thank you for joining us. Guideline-directed therapy is, of course, important for any disease state because it essentially guides you on how to manage based on the evidence-based therapy. So welcome everybody and we have a wonderful group of presenters. Essentially, we'll be talking about what to give in guideline-directed therapy, how to give it, which will be the first presentation by Dr. Babak Zian. And then we'll be addressing the issue that really plagues guideline-directed therapy in all disease states, and certainly not different in heart failure, which is that it's paltry the amount of how far we reach in terms of success rate. Perhaps we're doing okay with beta blockers and ACE inhibitors, etc., but it still is very hard to give it. And while it's often said that it's because of inertia from providers, I think there are a lot of clinical barriers. So we'll be having Orly Bardany talk about the clinical barriers and how we circumvent some of the issues that come up in implementing it. And then followed by that will be Nancy Albert. We'll be talking about how we implement it and how we monitor it. So let's get started. But before I do that, in addition to thanking these wonderful speakers that we'll be having, introducing and thanking Megan Pelter, who's one of our heart failure fellows, to be starting off with the initial presentations. And before we do that, let me go along with just acknowledging that this seminar is an independent grant support from Boringer Ingelheim and Eli Lilly. I also, before we start, want to thank very much the course planners, which are part of the education committee. We have Kristen Almeida, who is one of the course planners and pharmacist from Baptist Hospital in Miami. And we also have Louis Farfound, who unfortunately can't be here today, but he's one of the nurse practitioners that's on the education committee. We were all, who helped very much with determining the course and inviting the speakers, et cetera. So the speakers, let me start off by first introducing Megan, who will be giving the case presentations. Megan, thank you very much for joining us. And Megan did her undergraduate degree in biology and astrobiology, which I thought was fascinating at USC. She is part of the resident's honors program and then went on to do her medical school at UC Riverside, and then her residency and chief residency and heart failure fellowship at Scripps University, Scripps Hospital. And then we've been had the fortune of having her be one of the best and kindest fellows that we've had in the heart failure program. So with that, we should probably get started because it's a, put on your seatbelts. It's a lot of stuff that we'll be covering in the one and a half hours that we'll be doing. So Megan, go ahead and start with the case presentation. Yeah. Thank you so much, Dr. Modi for the kind introduction and thank you to the planning committee for the invitation to present this case. Can everybody see my screen? Excellent. So I have no disclosures. So let's dive straight into the case. So the patient is a 70 year old male who presents to the emergency room initially for shortness of breath as well as low extremity edema. The symptoms started about one month prior to his admission and initially occurred only with exertion, but now started to occur at rest over the last week or so, which prompted him to come in. It was associated with a low extremity swelling as well as a 10 pound weight gain. Patient denied any recent illnesses or sick contacts, but did have an episode of chest pain about two months prior for which he did not seek treatment. His past medical history is as follows. He has a history of hypertension, dyslipidemia, as well as coronary artery disease status post PCI to the LAD in 2011. He is currently on aspirin of 81 milligrams daily and a torvastatin of 40 milligrams daily, but hasn't really followed up with the cardiology department in most recent years. He denies any current alcohol or recreational drug use, but does have a 20 pack year smoking history for which he quit 10 years ago. He is a veteran and currently lives alone. And prior to this episode, he was able to do all of his daily chores of life without any difficulty. Upon arrival in the emergency room, his physical exam was as follows, and we'll go through the pertinence. Blood pressure of 110 over 76. His oxygenation was low at 89% on room air, which improved with nasal cannula. And as you can tell from the scope of the seminar, he is volume overloaded. His JVP is elevated. He's got crackles, he's tachycardic, and he's also got two plus pyrimidema up to the thighs. So thankfully he is still warm to the touch. Here are some of his basic labs of note. His B1N-creatinine is 31 and 1.28, which is higher than his prior baseline several years ago. And his NT-proBNP is 2000. Here are some of his sample echocardiogram findings, including a short axis on the left, as well as an apical four. And what it demonstrated was severely reduced LV systolic function with global left ventricular hypokinesis, an LVEF that was approximately 25% to 30%. It was also noted to have moderately enlarged right ventricular size and reduced function. There we go. So patient is admitted up to the floor on one of the house staff services. He undergoes workup for the etiology for his new onset of heart failure, which is beyond the scope of this seminar. And he undergoes aggressive diuresis with removal of greater than 12 liters of fluid. Once euvolemic, the discussion between the house staff as well as the attending moves towards initiation of guideline-directed medical therapy. So the question is, what GDMT should we start and when? And for that, I move to Dr. Zaheian. All right. Thank you. Share my screen. Oops. Babak, I'd love to introduce you before you do that, before you move on. So thank you very much first, Babak, for joining. We really appreciate you joining and you're just the perfect speaker for the topic you're doing. Dr. Zaheian is an assistant professor at the UCLA and is part of the faculty at the VA. One of the best things that has happened to us since we merged with UCLA for our training program and also as a department. He graduated from UC Irvine Medical School, was part of the STAR program in cardiovascular fellowship after finishing his residency at Yale, and has gotten a doctorate degree in the public health department, looking at HNSR, HR S&D work, looking at disparities, utilization of the hospital. So nobody could be more perfect for discussing the impact of GDMT in terms of its effect. And of course, he won't be discussing the disparities aspect today, but welcome and thank you very much for joining us today, Babak. All right. Thanks for the kind introduction and thanks for having me at this wonderful event. So my mini lecture is on the timing and efficacy of GDMT and is polypharmacy justified? So these are my disclosures, research supported by NIMHD and the AHA. Okay. So I have my first poll question before we get started, but over what time frame should we aim to optimize GDMT for patients with a new diagnosis of heart failure with reduced ejection fraction? So you've diagnosed a new patient with symptomatic heart failure, and we're trying to get them optimized on all our classes of GDMT. Over what period of time do we try to make this medically optimized? So great participation in the poll. Looks like the leading answer is within three months. All right. I think that's a good enough time, so I can share the current poll results. I guess there are 33% of the people who are very shy to answer, huh? Yeah. So in the guidelines, it actually says within three to six months. So the correct answer for this one was B, but it's in that window of time that you're trying to do all these titrations and adjustments and figuring out what's the maximally tolerated therapy a patient with heart failure with reduced ejection fraction can tolerate. So why is it important to get our GDMT medications on board? This is from a paper I published with my colleagues at UCLA and one of our residents who's currently a cardiology fellow at UC Davis. And so we wanted to model the sort of cost-effectiveness and benefits of guideline-directed medical therapies when you sort of look at the RCTs and attribute the addition of each therapy. So if you're on the four major classes of medications for heart failure, you're going to want to look at the medications for heart failure with reduced ejection fraction. The projected survival advantage is nearly 11 years over the lifetime for that patient. If you get three of our therapies on board, you gain about 9.26 years. And then if you're just on two cornerstone therapies, you estimate around beta blockers, ACE inhibitors, you get about eight years. So that's the importance. So we have this race to optimize in this three to six-month window. And the very first step in terms of how I approach a patient is first, you want to make sure the patient is at their optimal volume status, that they're decongested, ideally, and before you start aggressively going up on the titration protocol. So in all our studies, patients are usually stable with the outpatient therapies as they get added on. And these are the therapies we're trying to add. We're trying to add our Ras inhibitors, beta blockers, MRAs, SGLT2s, and using our diuretics as needed. And then the guidelines give us the target doses that were achieved within the RCTs that show benefit for heart failure patients in improving outcomes such as mortality, hospitalization risk, and quality of life. Step two is trying to titrate these medications to target dosing. So again, these are the target doses for some of the therapies, our MRAs, SGLT2s. They're pretty easy because they're often started. The starting dose and initiation dose and target dose are the same. And then how do we go about guiding our decisions on what to start, when to start, and why? So just to start off the bat, you want to get a sense for a patient's symptoms. Even before they've started therapies, do they have issues with dizziness and orthostasis? And then as you layer on treatments and decide whether to back off or continue titrating, are they developing new symptoms of dizziness or orthostasis? Vital signs are helpful. So if a patient is newly diagnosed heart failure and they're hypertensive or normotensive, you'll know that you have more room to work with in terms of layering on therapies and perhaps starting multiple therapies at once at low doses that you think they'll tolerate. If someone is hypotensive at baseline and they're asymptomatic, it doesn't mean we don't try to optimize them further. We just need to have more caution in layering on the therapies. Is this person in sinus rhythm versus AFib? Can dictate how aggressive you want to be and which beta blockers might be preferred in terms of controlling arrhythmias such as AFib, SVTs, non-sustained VTs, et cetera. You might be more persuaded to use something like metoprolol or bisoprolol over carbadolol for those patients. And then thinking about their comorbidities and what might be more beneficial to them if they have diabetes, poorly controlled diabetes, if they have obesity, thinking about therapies that are coming along like our GLP-1s to help with weight management as well. If they have CKD, end-stage renal disease, which therapies are truly beneficial if they have very advanced kidney disease or if they're in pre-kidney disease, which therapies are going to be renally protective and help extend their renal function as well as improve their heart function. So what are the guidelines today in terms of how often we should be optimizing medications? So for patients who are not at risk for adverse events, who haven't had issues, you have plenty of blood pressure room, you're not really concerned, you're supposed to be titrating every two weeks, thinking about is there an opportunity to layer on another therapy or to go up on a dose to get to that target dose. That can be very difficult based on your clinic availability and the patient's ability to come to appointments regularly in the initial period in the outpatient setting. So thinking about whether you can provide the patient some education and guidance for doing a titration at home themselves, especially with therapies such as beta blockers, you can help do that between visits. And then for those who have had prior symptomatic hypotension or maybe low blood pressures to start with, blood pressures less than 90 systolic or in that 90 to 100 range, you can be more cautious and adjust no more quickly than every six weeks. This has actually been studied. There was a nice sub-study looking at patients who were getting started on Entresto. They looked at whether slower titration, whether doing three versus six weeks. And they found it was more likely that you could achieve the target dose after a slower titration. So there's mixed opinions. Getting therapies at low doses on at baseline is helpful because they're less likely to fall off in the future, especially in the hospital setting. Getting our four quadruple therapy started in the hospital setting is more likely that they'll be continued in the outpatient setting. But often, being more cautious and slower, perhaps on more of like a six week interval, patients are more likely to achieve higher doses of our RAS inhibitors like Entresto. And that was studied in a small RCT showing that. With titrations, we always want to be cautious with our electrolyte disturbances. So the initial enthusiasm with using MRAs, people noticed high rates of hyperkalemia and adverse outcomes in the real world setting where people were not checking lab values as consistently as is done in an RCT. And so there's a performance measure now that if you're initiating an MRA for a heart failure patient, you should be checking electrolytes within a week. And we debated whether adding another one because you really should check again at a month. But we definitely want to emphasize the importance of checking electrolytes within a week because of that hyperkalemia risk that patients can experience. And then for our RAS inhibitors, generally when you're starting them, you want to get repeat labs within two to four weeks, sort of monitor them at least every three to six months with their electrolytes for hyperkalemia. And then it is acceptable to see a decrease in GFR, calculated GFR of 30%. But if you're seeing a big increase in creatinine, you might want to back off or hold the therapy and reevaluate. So yeah, rapid initiation, this is a reasonable approach. And the reason being, getting these therapies online, you get remarkable decreases in cardiovascular death and hospitalization, 42%, 25% reduction in death. That's with ARNIs. With beta blockers, you get a mortality benefit, 25%. MRAs, 37% reduction. And then composite for SGLT2 is really a remarkable effect. And so you can start very low doses of all four therapies. And this has been a strategy that's been advocated for. And then titrating more carefully with something like ARNIs in the either two-week or six-week window, depending on the profile of the patient you're managing. So why is this important to do in a timely fashion? So the highest risk for events is in the initial period after a new diagnosis or after a hospitalization event. GDMT, when added, improves the risk of mortality, reduces the risk of mortality hospitalization, and improves patient's quality of life. We believe that the probability of restoring LV function is higher with more efficient optimization. So getting people to target doses faster might help restore their LV function sooner. And then it also helps with making early decisions regarding ICD and CRT therapies. So the risk of sudden cardiac death is always highest in that first year after diagnosis, first after hospitalization. And to really achieve the maximum benefit beyond five years and beyond, you want to have those therapies available if a patient requires them. So polypharmacy is a concern. Unfortunately, with all these beneficial treatments, it means more pills that patients have to take. And they're often older and require other medical therapies as well. But our class one therapies improve patient-centered outcomes. So if those patient-centered outcomes are important to a patient, often heart failure therapies are a really high priority in terms of other medications a patient may need to manage their risk of adverse outcomes and also improve their quality of life. So it's important to explain, educate patients on what the medication is doing, what is the risk reduction that they're achieving with these therapies, and whether it makes sense for them in a patient-centered way if those are aligned with their priorities. But we would expect with GDMT that it should be a very patient-centered approach to improving patient-centered outcomes. You can try to think about strategies to reduce pill burden for a patient, especially if they have trouble with adherence. Try to find options that are daily dosed that might still get them most of the benefits from each of the therapies. And then you can prioritize the medications for them for what their indication is and what the expected benefit is and see if it's aligned with their goals. But often, it's a discussion with these are the medications you're currently taking and what are the ones we can see that we can eliminate that aren't aligned with your treatment goals or outcome goals that you're trying to achieve. So in summary, before we start adding on all our therapies, ideally, you want to try to get people to be euvolemic. Sometimes certain therapies help with that. So our SGLT2s are always something that are easy to add on, well-tolerated, helps with volume management, can be started on admission almost for patients, and can be easily added on as an outpatient. Look for opportunities to start low doses of our class one therapies early and in combination in patients who can tolerate. Helps minimize the number of visits it takes. And then so usually at a minimum, we want to start some RAS inhibition and a beta blocker. And then SGLT2s are usually well-tolerated and actually can help minimize the risk of hyperkalemia and also help manage volume status. MRIs are also very helpful, help have a remarkable risk reduction, often underutilized. But the main concern there is you need to watch out for hyperkalemia. But it can help in terms of patients who have low potassiums and reducing the need for additional potassium supplementation. If you have an older patient, frail patient, people who've had problems with hypotension in the past, try to be conservative with the layering of therapies. Aim for around a six-week titration. You're more likely to achieve target doses with RAS inhibition, especially ARNIs if you take a little bit of a slower approach. And then, yeah, educate patients on their medications, their goals, and what we're doing with this sprint to get to target doses. I always tell patients it's acceptable to have sort of mild hypotensive symptoms to sort of be cautious the first one or two weeks of a therapy that might be more likely to cause symptomatic hypotension. And then that usually improves at one to two weeks after being on a therapy for some time. All right, so ready for my post-lecture polling and see how we're doing. So when should we reassess ventricular function after target or maximally tolerated GDMT is achieved? Didn't mention it in my talk, but is our poll going live? I think it skipped ahead. We skipped to the next poll, which is this question. So we can do that one. So when should we stop? All right. Went back to poll question number one. All right, people doing well with this question. 21 responses. Did it get cleared out? All right, I think there was some polling technical issues. But it looks like most people got a vote in, and most people got it right. So within three months, you want to reassess a person's LV if it was previously less than 35%, especially to decide on other therapies, such as ICD for prevention of sudden cardiac death and CRT therapies. Going to my next post question. So when should we stop optimizing GDMT for a patient with heart failure reduced EF? A, when their heart function is returned to normal. B, when blood pressure is 90% to 100% systolic. C, when the patient has symptoms related to higher or additional classes of medications that they cannot tolerate. D is answers A and C. E is all of the above. We've gone to poll question two. Is that activated? All right, so we have a mix of questions, a mix of answers here on the current sample. Correct answer I said would be D, so A and C. So if someone's heart, once someone's recovered their LVEF, we don't need to keep layering on therapies. So if by chance, you know, you just started two therapies, LV function is returned, we don't want to keep adding on therapies onto that patient. In general, the idea is that whatever therapies help restore heart function, we want to continue those indefinitely, because there is a risk when you stop GDMT for a patient who's recovered their LVEF, and there's an RTC to show that, that in TREAD-HF, when you stop the heart failure therapies, you get a risk of recurrence. I think often in practice with with people may not be experienced managing heart failure, may not be a cardiologist, or people will stop titrating medications when they see a blood pressure and an asymptomatic pressure in an asymptomatic patient that's lower. You know, a lot of our really low EF patients live with low systolic pressures, and when you add on our guideline-directed medical therapies, the blood pressure really doesn't budge much, and they actually feel better. They're getting better cardiac output, they're lowering their SVR, and it's actually assisting a weakened heart. So you don't want to stop based on blood pressure alone. You know, heart rate is important in terms of not making someone super bradycardic. You know, with a resting heart rate in the low 50s is acceptable for a heart heart failure patient, but we're not really trying to titrate a lot of our therapies to vital signs. We're going off symptoms and what they're able to tolerate based on their symptoms and also their renal and laboratory functions, their electrolytes. So thank you. That's my portion of the talk, and I'll give it back to Dr. Modi for our next speaker. Thank you. Thank you. So that was very good. We have quite a few questions, but we'll probably discuss them later, I think. What we'll do, I think, just in the interest of time, we'll probably just start off with the case presentation number two, Megan, and then try and, because a lot of the questions were related to also the challenge of putting it in, so maybe we can do that after Orly's had her presentation. Go ahead, Megan. Sounds good. Excellent talk, Dr. Zaheyan. So we're going to move back to our case, which, as a reminder, is a 70-year-old male with a new diagnosis of heart failure with reduced ejection function. So a patient in the hospital underwent diuresis to euvolemia, and while in-house attempts were made to start him on GDMT. Now, due to baseline low blood pressures, he was only able to get on Carvedilol of 6.25 milligrams BID and Secubitril-Valsartan 24-26 milligrams BID before he was ultimately discharged. The patient was discharged, and within one to two weeks, established care with the heart failure clinic, and at his first clinic visit, a rather exuberant fellow initiated the following, the Pagaflozin of 10 milligrams daily, Spironolactone of 25 milligrams daily, as well as increased Secubitril-Valsartan to 49 and 51 milligrams BID. The patient was then recommended to follow up in two weeks for uptitration of medical therapy. Patient then returns to the clinic in two weeks and reports that he's been doing well, except that he's been having these really profound episodes of lightheadedness and dizziness, and whenever he checks his pressures, they seem to be low in the 80s over 50s. Repeat labs obtained demonstrate a BUN and creatinine of 69 and 1.97, as well as an elevated potassium of 5.2. So the question is, what do we do with his GDMT, and how do we overcome some of these barriers of hyperkalemia, as well as hypotension? Thank you for the case, Dr. Pelter. I'd like to introduce our next speaker. Our next speaker is Dr. Orly Vardany. She's an Associate Professor of Medicine at the University of Minnesota in Minneapolis. Her clinical practice is in the outpatient management of patients with chronic heart failure. Dr. Vardany serves as the United States National Lead Investigator and Steering Committee Member for the numerous clinical trials investigating novel therapies in patients with heart failure. She's an Associate Editor for Circulation Heart Failure, and she was on the writing group member for the 2022 AHA, ACC, HFSA Heart Failure Guidelines. And today, she'll be presenting on clinical barriers in implementing guideline-directed medical therapy, the role of the pharmacist. Great. Thank you so much for that introduction. I am very pleased to be here, and thank you to the HFSA for the invitation and the opportunity. So today, we're going to be talking about a topic that's definitely near and dear to my heart, and something that I do frequently is trying to troubleshoot some of these clinical factors that may prevent us from optimizing GDMT. These are my disclosures. We're going to start off with a polling question. Patients with heart failure with reduced ejection fraction and concomitant renal dysfunction have reduced efficacy from saccubitrile valsartan and middle corticoid receptor antagonists. All right. I can see that we're skewed to one answer versus another, and we'll talk about the result at the end of the talk. Okay, moving on to the next question. Polling question number two is, which of the following options can be considered for patients who experience hypotension during GDMT optimization? And we talked about some of this in the previous talk. Switch-loop diuretic to hydrochlorothiazide, reduce dose or frequency of diuretics if appropriate, for hydralazine change from three times a day to twice a day, change the timing to all GDMT doses to bedtime, or all of the above. This is a tricky one. Maybe I can add another one, Orly. How about switching Carvedilol to Metoprolol as option number F? Yes, we can definitely do that as well as an option. Okay. All right. We're split with reducing the dose of loop diuretics and all of the above. All right. So we will continue on and talk about these results or talk about the results of these in just a few minutes. So today, what I should start off with is saying that there are numerous categories of barriers to implementation of GDMT. Today, for this specific talk, we're going to discuss clinician barriers that are related to concerns for adverse events for medications for GDMT. And these include adverse renal effects, blood pressure, hypotension specifically, as well as hypokalemia. So to start off with renal concerns, some of the questions that come up frequently are, are RAS inhibitors, RNA, MRA, SGLT2 inhibitors effective in patients with heart failure and concomitant CKD? Next question is, often when these therapies are initiated, there's an initial dip in GFR. Does the clinical benefit of these agents persist even in the setting of worsening renal function? So to answer the first question, whether there's similar benefit to some of these therapies in the setting of heart failure and chronic kidney disease, which, by the way, occurs in up to 40% of our patients with heart failure. The post-talk or a secondary analysis of the EMPHASIS-HF study with a player known in mildly symptomatic heart failure with reduced ejection factors showed that regardless of baseline EGFR, meaning whether EGFR was greater than or less than 60, there were similar benefits that were observed in terms of efficacy. And the same was shown with sacubitrile valsartan. These are data from the PARADIGM-HF study showing that in patients with CKD or EGFR less than 60 compared to EGFR greater than 60, the sacubitrile valsartan resulted in a similar relative risk reduction in those with CKD as those without. However, interestingly, the absolute risk reduction was even greater for patients with CKD compared to those without. For SGLT2 inhibitors, what we saw from the DAPA-HF and from the DELIVER studies with dapagliflozin was that there was a consistent benefit across the spectrum of EGFR, as you can see both on the left and the right panels, all the way down to when EGFR gets to about 30 for DAPA-HF and down to 25 or so for DELIVER. Again, this is with dapagliflozin. What we should note is that there is a favorable effect of some of these therapies on what's called EGFR slope. And what that means is in patients without heart failure, there's a normal decline in EGFR of approximately 1 mL per minute per year. In patients with heart failure, that number is about 2 to 3 mL per minute. On average per year. But the therapies that we start, namely GADMT, such as ARNI shown in red and SGLT2 inhibitors shown in green, favorably affect or reduce the negative trajectory of EGFR decline. So not only are they beneficial in patients with concomitant chronic kidney disease, they actually in some cases have a protective effect of worsening kidney disease or worsening EGFR. So then the next question is, does the clinical benefit of these agents persist in the setting of worsening renal function that can occur at the very beginning? And we looked at this in the RAL study. And what we found was that even in the setting of worsening renal function of about 20% decline in EGFR, there was a sustained benefit on or consistent benefit in terms of the 30% reduction in all-cause mortality with spironolactone compared to placebo. And that's shown on the left panel. On the right panel, we see the effects of when there is worsening renal function by treatment arm. And if patients had worsening renal function were on placebo, they had an 80% increased risk for mortality. Conversely, with spironolactone, if there was worsening renal function, there was not an increased risk for mortality. So there was still maintained benefit in the setting of worsening renal function. Now, for sacubitril-valsartan, data from Paradigm HF and Paragon showed us that the relative benefit on the primary composite endpoint by occurrence of EGFR decline of at least 15%, that benefit was maintained in both heart failure with reduced ejection fraction as well as heart failure with mildly reduced or preserved ejection fraction. In addition, there were similar rates of safety outcomes, including study drug discontinuation, irrespective of EGFR decline. Now, for SGLT2 inhibitors, data from the DAPA HF and DELIVER studies showed us that dapagliflozin pretended a beneficial effect on the primary composite of cardiovascular death or heart failure hospitalization, even if EGFR dropped to below 25 at least once, as shown on the left panel, or if patients had persistent deterioration of EGFR less than 25. There was still a maintained benefit on the primary outcome with dapagliflozin as compared with placebo. Now, how should we think about worsening renal function in terms of when do we need to intervene? These are adapted from the Heart Failure Association guidelines or position statement showing or examining changes in renal function based on increases in serum creatinine on the very left or reduction in EGFR next to it. As you can see, up to 50% of increase in serum creatinine or up to 30% of decline in EGFR, we don't need to make any changes in our RAS inhibitors, ARNIs, or SGLT2 inhibitors. When we get to a 50% to 100% increase in serum creatinine or a reduction that's 30% to 50%, for ARNI, ARB, or ACE inhibitors, we may want to consider reducing the dose in half. For SGLT2 inhibitors, we stay the course. We continue if the EGFR or serum creatinine are at acceptable levels. In the setting of increases in creatinine of 100%, so doubling of serum creatinine or a 50% increase, higher than a 50% increase in EGFR, we do want to consider discontinuing ARNI, ARB, or ARNI. Excuse me, ACE inhibitor, ARB, or ARNI. This is really unexpected usually with SGLT2 inhibitors. We want to think about potentially other causes. If we can't identify anything, we might want to consider discontinuation of this therapy. What about hypotension? We've talked a little bit about hypotension with the previous discussion. What we want to look at first is examine the medication list and discontinue all non-GDMT blood pressure lowering agents if possible. These are things like amlodipine and hydrochlorothiazide. There are other tricks and tips that we can try. We can try to separate out the beta blocker if it's taken once a day from the rest of the GDMT that's usually taken in the morning. We can try taking a once-a-day beta blocker, moving the metoprolol succinate to bedtime. Or if a twice-a-day beta blocker like carbetolol, we can try a smaller dose in the morning and a larger dose at night. We can switch, as Dr. Modi alluded to, from carbetolol to metoprolol, which will have less robust blood pressure lowering effects. We can also, in terms of sacubitril-valsartan, start with a low dose. I have to emphasize this because even though the package insert will tell you that if patients are taking an equivalent daily dose of enalprol 20 mg per day, you can start with sacubitril-valsartan 49-51 mg twice a day, often patients don't tolerate this. Unless they're hypertensive, I always start with the lowest dose of sacubitril-valsartan and titrate up. Sorry, this is my VA computer that's yelling at me. Moving on to if we find low blood pressure readings that are not consistent, so the patient may have a low blood pressure reading sporadically, something we might want to think about is fluid status or fluid intake, especially among older adults and make sure that they are having enough fluids during the day to prevent hypotension as that can be a contributor. Lastly, as we layer on these GDMT therapies, patients will start to get better. As a result, they may not require as high of a dose of a loop diuretic. If weight has been stable for some time or if there's hypotension or both, we may want to think about either reducing the dose or switching to PRN if appropriate. This can be seen in a couple of our clinical trials in Paradigm HF. We looked at loop diuretic dose requirements and at different time points, six months, one year, and two years, loop diuretic doses for sacubitril-valsartan compared to enalapril were more likely to have reductions in doses and less likely to have dose increases of loop diuretics at these different time points. There was an overall reduced decreased diuretic dose requirement that tended to increase over time, excuse me, that tended to become more significant over time. For loop diuretics and SGLT2 inhibitors, and these are data from Deliver, loop diuretic dose increases were less frequent with dapagliflozin compared to placebo as well as sustained dose reductions were more frequent in loop diuretics in the dapagliflozin group. Now over time, the placebo group required more or higher loop diuretic doses over time. However, those taking dapagliflozin, there was not that increased risk or increased dose of loop diuretic. Now it took some time to see these effects, which suggests that it is more likely that improved clinical benefit of SGLT2 inhibitor is to blame here, not so much the immediate proposed diuretic effect that these agents may have. And then what about hyperkalemia? We need to remember that hyperkalemia is defined as potassium greater than or equal to 5.5. Therefore, we shouldn't panic if potassium goes up to 5.1 or 5.2. It is much riskier for a patient to have hypokalemia than to have hyperkalemia. But having said that, when we do encounter hyperkalemia, these are some things we can think about. Don't forget about potassium supplements, and these can be ones that we provide the patient or that patients are taking on their own over the counter. We can ask about salt substitutes and ensure that they don't contain potassium as they often do. We can advise patients to reduce intake of high potassium containing foods. This often doesn't yield us very much potassium change, but we can try to limit intake. Of course, we think of bananas, but there's many other foods. And in my neck of the woods, I have to counsel about baked potatoes or potatoes in general and beans, as well as orange juice and cantaloupe. We want to try to prioritize quadruple GDMT. That means that in order to gain some potassium, we may need to reduce the dose of the Ras inhibitor and RNA so that we can enable addition of the MRA. And then lastly, we could consider potassium binders in the setting of hyperkalemia, such as pteromer or sodium zirconium cyclosilicate, because these can help enable titration or initiation of these therapies. What do the guidelines say about potassium binders? There's a 2B recommendation, and that is because although we see lower potassium with these potassium binders, the effect on clinical outcomes is yet to be determined, but we'll learn that very soon in upcoming trials. So where does the pharmacist sit in or where does the pharmacist role in GDMT optimization? And pharmacists are well positioned to work either independently or as part of a team helping with increasing doses, as well as initiating new heart failure therapies. And this was a study in an academic medical center where providers that were caring for patients with PEPFREF were approached for patients to participate in a protocolized approach to GDMT optimization. This was done by phone with patient navigators and overseen by pharmacists, nurse practitioners, and physicians, and we saw an improvement or significant increases in RNA, ACE inhibitor, and ARBs, as well as beta blockers, but less so for MRAs. Now, Ankit Bhat conducted a study in three hospitals looking at virtual care team guided strategy with a physician and pharmacist versus usual care. This was in the hospital looking at compositive in-hospital GDMT optimization score. What was shown was that the intervention significantly improved these scores versus usual care, and this was also the case for new initiations of therapies. So to summarize, baseline kidney function does not modify the cardiovascular benefit of ACE inhibitors, ARBs, RNA, MRA, or SGLT2 inhibitors in patients with heart failure. The benefit of these therapies is maintained even in the setting of modest decline in renal function shortly after initiation. In the setting of hypotension, consider loop diuretic dose adjustments prior to reducing or discontinuing GDMT. And lastly, as medication experts, pharmacists are well-poised to work on teams to optimize GDMT in patients with heart failure. All right, we're going to go back to our polling question number one. Patients with HFREF and concomitant renal dysfunction have reduced efficacy from saccubitrile valsartan and MRAs. All right, so far looking good with majority of folks saying false, and that is the correct answer. You succeeded. All right, we are going to. That's great. Yes, we're going to move on to the next poll, which was the trickier one. Oops. Which of the following can be considered for patients who experience hypotension during GDMT optimization? Yes, I'm seeing the majority of folks are picking now the right answer, which is B, reduce the dose or frequency of diuretics if appropriate. All right, and with that, I'm going to turn it back over to Dr. Modi for the next speaker. Thank you so much. That was really good and really important, you know, especially the messages on how to optimize. Because I really think that knowing these tips and tricks are probably the bigger reason why we don't meet our GDMT goals, you know, what we see on the data, rather than clinical inertia, which is slamming the providers for saying they're not doing what they're supposed to be doing. So thank you so much for that. And I think there'll be a lot of questions that we'll discuss in the panel discussion later on. But go ahead and start with the last case presentation, Megan, and then I'll introduce Nancy for the last presentation. Sounds good. Excellent presentation, Dr. Vardhani. So we'll now move on back to our patient and to, sorry, there we are, the last section of our case presentation. So again, to recap, this is our 70-year-old gentleman with heart failure with reduced ejection fraction who is going up on GDMT. Adjustments were made to his regimen to help improve hypotension and renal dysfunction. And he was recommended to come back to clinic in one to two weeks for repeat clinic visit and laboratory work in the general heart failure clinic. However, unfortunately, patient was lost to follow up for the next three months. Three months after his last clinic visit, he actually represented to the hospital with worsening lower extremity swelling, orthopnea, and PND. There was concern for medication non-adherence. At that time, he was admitted for acute decompensated heart failure, diaries to euvolemia, and started back on some of his medications. He was then discharged with close follow-up in the heart failure discharge clinic, a specific clinic looking at up titration of GDMT and in close monitoring following discharge. He was also educated significantly on the need for adherence to medication, as well as need for follow-up. Over the next couple of weeks to months, he was able to follow up closely with the heart failure discharge clinic. And over the course of time, he was gradually placed back on GDMT for which he was able to tolerate a lower doses. With the strategy, he was demonstrated continued and improved adherence with medication. And after three months of GDMT, a repeat echocardiogram was performed. His repeat echocardiogram did demonstrate an LVEF of less than 35%, so he was ultimately referred for device therapy. He underwent placement of an AICD without complications. Long term, however, patient continues to do well. His device ultimately got upgraded to a CRTD, but symptomatic-wise has demonstrated significant improvement on GDMT as well as improved exercise capacity. But the strategy with the heart failure discharge clinic and closer monitoring raises the question, what are some strategies that we can improve GDMT utilization? So to that, I turn to Dr. Halberg. Sorry, I have myself on mute. So with that, thank you very much, Megan. And that is a good introduction to our last speaker before we get to the panel discussion. And Nancy, thank you very much again for joining us. I kept my fingers crossed that you'd be able to join us with your busy schedule. We're so fortunate to have you because you're so experienced in this area and we'll be able to lend a lot of tips and tricks to how to implement and monitor it. So Nancy Albert is a PhD and she is currently working at, I think, one of the probably the best premier cardiac institutes in America, which is at the Cleveland Clinic. She is a PhD and the chief nursing officer in research and innovation at Cleveland Clinic, which is a multi-center system. Nancy has a really long history of doing outstanding research in evidence-based outcomes and looking at conduct in biobehavioral aspects of adherence to GDMT and treatment of heart failure. She serves as a clinical nurse specialist at the Kauffman Center for Heart Failure Treatment and Recovery and the Heart Vascular Thoracic Institute. She's also an adjunct professor in Denmark, in Aalborg, Denmark, just demonstrating her very wide national and international presence in terms of management of heart failure and overseeing research there. She's also the professor at Case Western University School of Nursing. She's very well-published with her large experience, over 385 peer-reviewed publications, book chapters, and very much building off a good nursing research program where she's at and has, of course, received a lot of acknowledgement and awards at the Heart Failure Society in distinguished nursing leadership and also from the AHA in critical care nursing. Welcome, Nancy, and thank you again for joining us. We look forward to your talk. Thanks so much for having me. I'm thrilled to be here, and I'm just going to get it set up here for us to share. All right, so hopefully everybody can see my screen now. I was asked to talk about implementation science and strategies to improve guideline-directed medication therapy utilization. You can see my disclosures here, and I'm going to share two polling questions with you. I'm not going to discuss the answers now because we'll talk about them at the end, but you could see the first polling question here. The Heart Failure Collaboratory Medical Therapy score provides a score for which of the following, A, B, C, or D? I'll let you guys tell me what you think. All right, I see the numbers are changing a little bit, but it looks like there's a mix here. So hopefully at the end, we'll have more of a single line of blue coming up. So I will again, share that now. It means you have a lot to learn. Yeah, yeah, that's okay. It's all good, right? That's the whole point of it. All right, so let me go to the next question. All right, the rationale for optimizing core heart failure medications in a short timeframe is to, and we have four options here, and you may have gotten a clue from this answer from Orly's talk as well as our first speaker's talk, Dr. Zariot. All right, it looks like C and D are trying to fight for each other a little bit with the answer. So again, I'll stop here now so we can jump into the talk, and we'll be happy to talk about these more at the end. So thanks for sharing your ideas and thoughts in the polling questions. So I was asked to talk about implementation science, and I didn't want to make the assumption everybody knew what implementation science meant. So again, it's a type of science, it's a research methodology that investigates methods and strategies to facilitate the adoption of evidence-based practices, interventions, or policies. And the whole goal is to get it into regular use by us, practitioners. And there's three important steps. One is that you need to, let's see if I can get it to go, oh, so how do we adhere to guideline-directed medical therapies? Well, first we have to know what they are, then we have to mine the gap, and then finally we have to actually do it. And so I'm just going to go over in my 20 minutes here, these three themes, know, mine the gap, and do. So let's start with know. We all know that there's lots of guidelines out there, and you can see they've been changing very rapidly. We went through a period of a desert, it felt like, between 2013 and, or maybe like 2003 almost, and 2015, between a plurinome coming on board in 2003 and Secubitrol-Valsartan in 2015, and then everything is really accentuated more recently. So you can see there are five different recommendations, and they keep changing as we get more and more feedback coming in. And I saw the question earlier about strong heart failure, and I will be talking about that, so hang in there for that one. So the bottom line is, is if, in order for us to know guideline-directed medication therapies, we really need to get familiar. And for those of you that aren't in the know, you're learning in this webinar today, but you feel like you just don't understand all the nuances, there's different ways that you can get more knowledge. One is to go ahead, and for the Heart Failure Society of America, they have an optimized medical therapy certification course. It's a self-study course. You could take it 24-7 on your own time, and do it over days, weeks, or months to get the information you need. You could study for the Heart Failure Certification, or the American Association of Heart Failure Nurses Certification. In both of those certifications, you do need to read up on medications and have that knowledge, so that's one way to become more knowledgeable. You could attend grand rounds, scientific sessions at different meetings, and you could pay attention by mentoring from experts. I occasionally get students who want to come into my heart failure clinic when I see patients, just to spend time with me, so that they could kind of see in real life how to get familiar. Because even if you've got book knowledge, if you're not familiar with the nuances of heart failure, you may be timid, or a little bit shy about getting started. Now, I do want to talk about strong heart failure, because this was a wonderful study in which NT-ProBNP, which again, is a biomarker that tells us about the stress of the ventricular wall, and how it was used to deliver guideline-directed medication therapies in acute heart failure. So first of all, at screening, when they were thinking a patient would meet the criteria for being in the study, patients had to have an N-terminal ProBNP greater than 2,500 micrograms per milliliter. So they definitely had wall stress. We believe their symptoms were due to heart failure and not some other problem. And then, right when they were screening the patient, they had to still have an elevated N-terminal ProBNP. Again, to reflect that, the wall stress was still up, but that they had early treatment with diuretics and other drugs that were given early after admission helped to reduce that N-terminal ProBNP. And then you can see the other guidelines here. Is the systolic blood pressure greater than 100 early on? Is the heart rate equal to or greater than 60? And is the serum potassium equal to or less than 5 within the 24 hours of starting medications? And what they suggested was to prescribe the RASI, the beta blocker, and the MRA at one half of optimal doses. Now you're not going to see an SGLT2 in this study because the SGLT2 was not available in 2019 when they published this methods paper. So they started the study before SGLT2 inhibitors became part of our standard of care. But keep in mind, we have two very well-known SGLT2 inhibitors and one SGLT1 and 2 inhibitor that we can now add and call it quadruple therapy instead of just triple therapy. And so we need to be thinking about all four drugs. And if hemodynamically stable, we want to increase the doses of what they did in this study. All three drugs and SGLT2 inhibitors or SGLT1 or 2 inhibitors do not need to be up titrated. So we look at up titrating the doses of the other three classes if the MRA is not started at the optimal dose. And they did it within the same day over a few days pre-discharge and one day post-discharge. So get the patients on the drug at least half the dose and then think about up titration. Now in strong heart failure, patients were followed post-discharge at week one, two, three, and six. And at each one of those visits, they got an N-terminal ProBNP. Because if the N-terminal ProBNP went up by greater than 10%, then they actually put in their protocol, their algorithm to hold the beta blocker and increase diuretics. So the thought was patients were still a little bit too wet. They were still putting burden on their heart. Their heart was under more duress, not less duress. And so instead of up titrating the other drugs, they wanted to hold off on up titrating beta blocker and again, give more diuretics. If the systolic blood pressure is less than 95, the potassium greater than five or the EGFR less than 30 to hold titration of BRASI and MRA. And if the EGFR was again, less than 30 milliliters per minute alone, even if the other values or hemodynamics were normal to decrease the diuretic dose. So this was the methodology of the strong heart failure study. And what you see on this slide here is the blue lines represent the high intensity group, the patients who got that protocol or the algorithm I just discussed. The red lines are the usual care group, people who maybe went home on none of the right drugs, some of the right drugs, maybe they were never up titrated. And what we're looking at here is the probability of all cause mortality or heart failure hospitalization over six months. The dotted lines reflect heart failure and mildly reduced ejection fraction, or even heart failure and preserved ejection fraction. These solid lines represent heart failure and reduced ejection fraction. And you could see that the group that did the best was actually the group with preserved or mildly reduced ejection fraction, the blue dotted lines. They had the greatest reduction in all cause mortality and heart failure hospitalization. In fact, they had a 56% reduction. And then you could see how the blue lines with patients with heart failure and reduced ejection fraction had a 30% rejection. And this is why the study was stopped early because starting drugs early and getting them to a higher dose quicker and not waiting months and months and maybe never getting there really can help our patients in terms of mortality reduction and rehospitalization reduction. So how do we mine the gap? We know it's important. So what are we going to do? Well, we need to assess for team and global gaps. So do a little assessment of your own sites. How well are you doing on getting patients on the right therapies prior to discharge? Or if you're in an outpatient clinic, how well are you doing in general? We have a study at my center, I'm getting ready to publish it. And on the main campus where we have a lot of heart failure cardiology specialists, we are doing pretty good. But when we look at some of the outlying sites, maybe we're not doing so well. So look at your own sites. I had the pleasure of participating in CHAMP heart failure. And we had over 150 cardiology practices in that study. And yet we did not see patients on guideline directed medication therapies as discussed in our guidelines. And so we need to find out what's going on. We need to share the findings internally with our own colleagues and discuss what the expectations are. We really need to understand provider barriers. And when you read the literature, we do hear a lot about inertia, provider inertia. So I realized the comment that Dr. Modi was making. But when we look and break it down, it seems like the two biggest barriers are time, time to do it. Maybe somebody's got too busy of a schedule, and they're seeing patients every 10 to 15 minutes. They don't have time to introduce new drugs. They don't have time to teach patients about what to expect, and even why they want to change a drug that maybe somebody's been taking for years. And then familiarity. And so the familiarity is that knowledge piece. Again, Orly did a really nice job of talking about hypotension or kidney dysfunction. And there's other side effects people may be worried about. Everybody needs to develop a feasible plan and then develop a quality monitoring program. So I'm going to talk a little bit about some of these. So the heart failure collaboratory, this was the first of the two questions I asked you. This is the conceptual approach. This collaboratory was a group of heart failure experts, including PharmDs and physicians, who got together and said, look, how can we tell if our patients are getting the right therapies? Maybe we could have a systematic approach. And so this is something you could think about using in your own centers to determine are your patients on the right medications at the right doses. So it looks at what the patient's taking and has it been up titrated to the right dose. And if your patients have a score of five or less, it means that they either are not on the right drugs or they're probably not on the right doses of the right drugs. Here's a study over here that was just published last year in CERC Heart Failure. This was a retrospective review from over 26,000 Danish patients. And at baseline, you could see ACE and ARBs were used 77% of the time, beta blockers 81% of the time, MRA 30% of the time, Ernie only 2% of the time. And so their median heart failure collaboratory score was only four. We want to see a score of about nine. That tells us that patients are really on the right drugs at the right doses, unless, of course, they have contraindications. And there's always, if we document why, then that is a good rationale. And when they did multivariable adjustment on the results, it turned out that a higher heart failure collaboratory score was associated with a decrease in mortality. And it was a 28% reduction, very similar to what we saw in the strong heart failure for the patients with reduced ejection fraction. And they also, again, saw a graded inverse association between the heart failure collaboratory score overall and death. And that was highly statistically significant. So we know it's important, again, to get our patients on the right drugs at the right dose. Now, we know that our patients are, when they're in the hospital, they're a captive audience. They're there. They're not going anywhere unless we discharge them, most likely. And we should try really hard to get patients on therapy. Well, why is it so important? Well, if you look at the left side of the side with beta blocker, the blue bars and the red bars, the blue bars are showing the patients who were on the drug pre-discharge and who remained on the drug 60 to 90 days after follow-up. So blue bars are people that were on the drug at hospital discharge. The red bars, they were not on at hospital discharge. And you could see at 90 days, only 30% were prescribed. So when people tell patients, oh, I'm going to order this for you in the outpatient department. When you see me next, we'll take care of it. It doesn't happen. And if you look at ARNI and MRA, and now this is 12-month follow-up, again, if you were ordered it or prescribed it at hospital discharge at 12 months, 80% were on an ARNI and 85.5% were on MRA. If you did not order it in the hospital, only 7.7% were on ARNI and 22% were on MRA 12 months later. So again, you can't consider prescribing it. You got to just do it. Think about the Nike commercial of just do it. And in fact, our 2022 heart failure guidelines, the Heidenreich LL guidelines that are published also really push us pre-discharge to start one plus new therapy before discharge. So unless patients have really low cardiac output, they have severe volume overload, they're in advanced AP block, or they've got angioedema and cannot tolerate a RASI, we should be really considering making sure we get one new drug therapy on if indeed our patients are not on the quadruple therapy regimen. So how do we want to think about it? Well, the first study on the left, Orly did a nice job of showing you the figures. So this is what she presented earlier. This was a pharmacist-physician guideline-directed medication therapy team. And in the hospital, this was started and you could see that they had an increase in guideline-directed medication therapy optimization score. And it was statistically significantly higher and they had no adverse events. So keep that in mind. Most of the time, patients were able to tolerate it. You could see the exclusions here, critical illness, de novo heart failure, and systolic low blood pressure less than 90 within the preceding 24 hours. On the right side, you see a study by Dr. Rao and others that was published late last year in circulation. This was an interesting study. It was an in-hospital virtual peer-to-peer consultation. So patients who were admitted to non-cardiology service, the providers peered up with a cardiologist and did a virtual consult. So they didn't get together in person. They had one virtual consult, discussed the patient, discussed the medications. You could see the exclusions here. end-stage renal disease, hemodynamic instability, concurrent COVID-19, or hospice care. Otherwise, they tried really hard to get the patients on optimized medical therapy at discharge. And it turned out it was higher in the treatment group versus the usual care group. So when we develop programs, whether it's a peer-to-peer virtual consultation, whether it's a pharmacy physician program or other programs, we can actually make a big difference to our patients. And then this slide just shows you a bunch of different bullets for a lot of other programs that have been discussed in the literature. Some have been beneficial, some maybe not, but it depends on how much push the providers make in actually following through. So you could see EMR alarms, reminders, or critical alerts, shared decision-making with patients and family. I particularly find that to be very satisfying in getting patients on drugs. Meds to beds when patients are in the hospital, so they go home with their meds and don't have to wait to go to a pharmacist. Medications in little packets in the outpatient department, so they open the packet and gobble everything that's in there at lunchtime or the packet at dinnertime or at breakfast time so patients don't forget certain medications. Multidisciplinary team-based approaches, even including external coaches, virtual care teams, home care, facilitated home cardiac rehab. And again, we've got so many virtual options available for us now. There's patient messaging via their telephone, engagements, encounters, remote patient monitoring. So there's lots of different ways we can think about how to get to the right end point. So again, when we think of how, this is an editorial from Beacon Bozkirk in Jack Heart Failure. And if you look at the left side, she says, first line, quadruprotherapy. It doesn't matter what order, just get them started. So this is really my message here to say, don't pay attention that I have to do this drug first and this drug second. You could use any of the drugs, get them started. And then of course we could add on other drugs based on symptoms our patients are still having. And then on this slide, I really don't want you to pay attention to the top two rows. That just says that we could start in the outpatient or start in the hospital setting and then use our clinics or telehealth programs to up titrate. So if you ignore those two, I thought this was a provocative editorial by Dr. Beacon Bozkirk again. And she's saying, whether you start them in the hospital or the outpatient department, maybe we ought to consider for some of our patients who we know can follow instructions and are very awake and alert, they're not frail, they don't have cognitive decline, that we can have self up titration. We expect patients with chronic other medical diseases to take care of themselves. Diabetics are wearing continuous glucose monitors so they can take care of themselves. If we can do this for our patients, it's going to decrease our long appointment wait times. It's going to help us with our staffing shortages. It's going to get rid of patient transportation issues as the rationale for missing their appointments. And for patients without an internet or a computer or a smartphone, they can't use one of those devices anyway. So maybe thinking about how we can get patients to self up titrate can really be beneficial to us down the road. So I'm going to leave you with this little thought that, you know, we need to understand how patients and families experience heart failure. We need to understand their quality of life and what their goals are for care and understand their willingness to start on new medications. And again, that's where that shared decision making could really be very important. We need to provide accurate information to them, explain not just what, but also how and when. We need to understand their habits in taking medications. It may be that giving them some meds at nighttime or at dinnertime are better than having them gobble too many drugs in the morning. And then we need to have a sensitive communication style. So a tailored approach is really important. And again, we need to think about our patients' habits. So I'm going to go back to the two polling questions real quickly here. This is polling question number one. And let's see how you guys do with it now that you heard a little bit about the Heart Failure Collaboratory. Right. So we're running a little behind in time. So we'll give a little less time for these polling questions now. Okay. All right. Well, I'm seeing 70%, 67% saying number two. So let me just go on to the next one. Which is the right answer, right? Yeah. That was the right answer. Correct. And post polling question number two, the rationale for optimizing core medications. And again, excellent. It was to really push the mortality and rehospitalization. So thank you very much. So you were effective in getting the message across, Nancy. Thank you. Okay. So that was excellent. Three wonderful presentations. And Megan, thank you very much for the very germane evolving of the patient case. So this leaves us some time for questions. We have about 10 minutes instead of the 15 minutes. Let me, while Megan is putting together, maybe consolidating some of the questions into a few questions, let me ask a question to each of you that I think is important. Let me start off with you, Babak. Your mentor, Greg Fonro, is perhaps more aggressive than you in terms of initiating heart failure therapy. And I guess in light of the STRONG-HF trial, do you think maybe we should push back optimization to within a month rather than three to six months, as your polling question answered? I think there's more and more data that we probably can start all four, or at least three out of four before discharge. And based on the STRONG-HF, they were on a little bit of everything almost before discharge. Given the work that you did that shows, you know, the widening of the benefit very early, much before 30 days, do you think we should push this back to say that people should be optimized by one month or titrated and start before and everything before they start, before they leave the hospital? Yes, I think the challenge is how our health services are organized. So, you know, with our, with an RVA hospital, it's very hard. People want, you know, hospital beds full, clinic grids full. And so how are you going to make sure to streamline these patients into your clinics and make sure it's being done safely? You know, after each titration, making sure how often do we have systems in place to make sure that patients got their labs drawn to follow up those issues with safety. And then the idea of, I think, starting all these meds at once, the benefit of an RCT is they're often an enriched population. So if you look at the ARNI studies, there was a big run-in phase, right? You take these heart failure patients and you have them all on ACE inhibitors at baseline with some criteria, and then you switched them all to low dose of Entresta to make sure they could tolerate it before they even got randomized. And then you start ramping them up. So those selected populations in a study that helps give us a good estimate of the treatment effects. So how effective is it in achieving the primary outcome? But in the real world, you're not going to be faced with those patients. You're going to be seeing the patients that are more frail, have had more issues, who have more PVD and more likely to become orthostatic. And so, yeah, in the inpatient setting, it's great to start all of them if they can tolerate early, but we have patients who have CKD at baseline or already have a K towards five. And are you really going to hit them with Entresta and an MRA right at the beginning? And then when their K does go too high, are you going to be able to decide what was the main cause of that? So I think you have to tailor it to your patient. Definitely if someone who's younger has blood pressure room or hypertensive, you want to get those four therapies on early. Someone who's got hypokalemia and you're not worried about the MRA dosing, you can start that stuff all at once. But you really have to tailor to the profile and then figure out, you know, my next titration, start planning for your next titration. What really bugs me is if people are, you know, I think notes are important. It's a way for us to communicate to other providers what we're doing and what our thought process is. But when you're writing your plan for your heart failure patient, you need to tell me what you're doing now for that patient in terms of optimization and what do you envision is next for that patient? Or why didn't you add a certain therapy? Is this patient someone who's got incontinence and SGLT2 is going to be a relative contraindication and put them at risk for adverse events? And so give me some idea of your thinking around each of our, you know, five main classes and what are the plans going forward? I think the resources, you know, in a strong HF trial, they were actually less, they didn't exclude, they didn't cherry pick as much as other randomized control trials did. But I think the resources you have in terms of follow-up for fast titration is a big limitation. Yeah, thank you. So Orly, you know, that was really an excellent talk and I think so important, you know, in terms of reaching these goals. I'm really glad that you emphasize, you know, the part about decreasing diuretics when people's blood pressure is low. Because I think this is something that's overlooked a lot in clinical medicine. You know, when the blood pressure comes down, people forget that one is, you start off with a higher dose of diuretics because you're taking off those 12 liters like you had, but maintenance dose is always a lot less and people leave them on the maintenance dose, you know, on the diuretic dose instead of lowering it to the maintenance dose. And so I think this is one thing that people often forget. So when people are dizzy and orthostatic, it is something to look at all the time. But I think one of the other problems is that when you see that increase in creatinine, you know, I'm glad that you refer to it as worsening renal failure. I think what needs to be emphasized is at the end of all these studies, the creatinine actually came down. You know, it's starting off with the SAVE trial, with CAPTOPRIL, and down to the PARADIGM trial, that these agents are nephroprotective. And often, that worsening renal failure is just transient, right? While you have that ACE, you know, sort of like the afferent arteriole and the efferent, you know, that change in dynamics that comes when you start with this, but ultimately they do better. And I know a lot of house staff, when they think that there's a CKD to a higher extent, they often don't give these ACE and ARBs. And, you know, initially I used to get apoplectic and, you know, was fit to be tied when I heard this, because really those are the people that should be on it, right? Because all these drugs are nephroprotective too. They're not just cardioprotective. So the people with CKD needed even more. You just have to be more careful about it. And I think that because we refer to it sometimes as AKI, acute kidney injury, rather than worsening renal failure, as you did, I think because they hear that word injury, they think that they're actually doing harm to a patient. And so they often stop the drug and, you know, they cut back on it instead of sitting on their hands, you know, knowing that there's a transient worsening renal failure. So I think that's a very important point that you brought up and something that people should take away in terms of, you know, optimizing GDMT and not holding it or not preventing the titration. Any comments about that, Orly? Yeah. So I think in general, people get nervous when they see worsening renal function. And so it's important to know that for RAS inhibitors, for maybe to a lesser extent for ARNI, but for SGLT2 inhibitors, that just becomes the new baseline of what their new normal is for renal function. Because you might see it improve back to their old baseline, but a lot of times you don't. And so that just becomes their baseline to follow. And over time, the chronic protective effect will reduce the need for hemodialysis or 50% decline in renal function. So while initially you might see that little bit of decline, that's not indicative of renal injury, just as you said. Right. Go ahead, Nancy. I was going to say, Dr. Costanzo, whenever she's giving talks on chronic renal dysfunction in patients with heart failure and medications, she likes to remind the audience that you know your drugs are working if you see a decline in renal function. Exactly. And instead of us worrying that it's an adverse event, we should expect it as an event. Right. And know that means the drugs are doing what they're supposed to do because they change some of the renal function to help to carry out the reaction. And so we should be not happy about it, but we shouldn't be upset about it and we shouldn't stop medication because of that. Which is unfortunately what happens. That's right. That's right. Yeah. And go ahead. Anything else to comment on that? Nancy, let me ask you a question before we go on to the other questions. So we'll have to go over a little bit. One of the things that you talked about in terms of implementing is how about the feedback to the providers? Do you think that's a very important element of monitoring of giving feedback when people don't meet the guidelines? I think it's really important when guidelines are not being followed. A lot of our patients have multiple providers these days, not just one. So they have a cardiologist, an internal medicine doc, an endocrinologist, a nephrologist. And so because of the complexity of care and the many different hands looking out for the patient, I think it's up to the cardiology partner, whoever's really managing the heart failure to do a really good job of taking notes and providing a sense of what's next. Because the patient may only see the cardiologist once a year and it turns out it's the internal medicine provider that the patient thinks is managing the heart failure. The internal medicine provider thinks somebody else is doing it and then nothing ends up happening. So I really do think it's important to communicate. I could tell you years ago, Cleveland Clinic participated in Improve Heart Failure, which was a quality improvement initiative or a research study, but an initiative. And at first our chair did not want us to be in it because we're the Cleveland Clinic, we do everything right. And we started noticing that we weren't giving one of the drugs, it was the MRA at the rate we thought we were. And so the assumption is, of course, everybody's doing it. Well, once we started monitoring, we saw that that wasn't happening. And it didn't take long, we just shared with each individual provider their own stats, we didn't, you know, make a big deal about it broadly. And those providers started coming up, or they started documenting the contraindications. So patient has angioedema or patient's blood pressure keeps dropping down to symptomatic 85 or something. So then we would know why they can't be on the medication. Right, right. So I think that is part of the problem is that the feedback should be given to people who are not, you know, the heart failure experts, we're sort of preaching to the... And one of the things I want to do as part of the Education Committee is to take this kind of information to the internist who will probably stop, or, you know, the... will probably stop the ARNI because the creatinine's gone up a little bit, or the ER doctor who says, oh, you know, the blood pressure is too low, even though the asymptomatic and may stop the beta blocker. So I think that this information, the feedback needs to be given to the multiple providers too, and the education, right? I agree. And you know, one thing just to keep in mind is that when patients are fluid overloaded, their blood pressure actually can drop. And so once we diurese them and normalize them, and they're more euvolemic, their blood pressure will go up. And there's at least two studies out. One's an SGLT2 inhibitor study. And when patients were hypotensive, blood pressure, I think it was less than 100 was the cut point. They found out for the hypotensive patients, their blood pressure went up an average of six millimeters of mercury once they started the SGLT2 inhibitor. Probably a little bit of extra fluid on board that was coming off. Patients that were hypertensive, their blood pressure came down. So yes, it will reduce blood pressure and hypertension, but it doesn't reduce it in all. So we don't have to assume that because the blood pressure is low, we should not start a medication. Right, right. Well, the stroke volume may go up. You know, that's probably the mechanism of how the blood pressure comes up. So Megan, do we, can we consolidate some of the questions that we have? I know that there were some logistic questions like, is the HF-SIRT of the HF-SA pertinent to physicians? And is it being updated? And those, yes, they are. They're for physicians, nurse practitioners, pharmacists, everybody, the HF-SIRT, and they are constantly being updated. So go ahead with the other questions, Megan. Yeah, I think a couple of questions have come in surrounding the SGLT2 inhibitors, in particular their effect on glycemic control. So one of them is, what is the substitution for SGLT2 inhibitors when the patient has severe nocturnal hypoglycemia in a diabetic patient? And kind of the inverse of that, is there a typical cutoff not to start SGLT2 inhibitors if the A1c is greater than 10 or 12? So if we could maybe speak a little bit more to that. Go ahead, Orne. Why don't you, because I can if you are not comfortable with that. Nancy, go ahead. All right. So there's been quite a few studies now looking at hemoglobin A1c in patients who are type 1 or type 2 diabetics or patients without diabetes. And in patients who do not have a lot of extra glucose on board, they're not hyperglycemic, we can see that they stay at baseline over time. They don't have a huge drop in their hemoglobin A1c, which I found very fascinating when we first started using it, because that was the number one worry many of our physicians had. Besides DKA, the big worry was that the hemoglobin A1c was going to drop, people were going to become hypoglycemic and get into trouble. So if your patient does not have type 2 diabetes, you should not expect a huge decrease in glucose coming out in the urine, which also means those patients are going to have a little bit less natriuresis effect as well, and a little bit less sodium coming out at the same time. So if the patient has nocturnal hypoglycemia, I think that was the question that Megan posed, from type 1 diabetes, again, I haven't seen that personally for myself, but I can tell you that all the patients that we put SGLT2 inhibitors on, I'd say over half of my patients are diabetic, they're on anti-diabetic drugs and the SGLT2 inhibitor for heart failure, and we have not seen a big problem with nocturnal hypoglycemia. We should mention that SGLT2 inhibitors should not be used in patients with type 1 diabetes. Right, and for the type 2, they're not very potent anti-diabetic, they only reduce the hemoglobin A1c by 0.5, kind of like the DPP-4s, so that's why they're probably safe in the non-diabetics too, they're not very potent things. I think there was another question on using ACE and ARBs in people on hemodialysis, and just to make a comment on that, our nephrologists use both ACE, ARBs on people who are on dialysis, as well as ARNIs as well. We do use that off-label. I know that the FDA, you know, they weren't included in the paradigm trial, but we are using it off-label for both in hemodialysis patients. Remember, you know, the thing we're concerned about in patients with severe CKD and ACE, ARB, and ARNIs is that if they have renal artery stenosis, bilateral renal artery stenosis, those are the only people who really get harmed a lot with ACE and ARBs and ARNIs because of the afferent-efferent vasomotor modulation is not the same in people with bilateral renal artery stenosis. So those are the people where it's really just contraindicated in giving ACE and ARBs when they have CKD as much as end-stage renal disease. Any other comments on that, Babak, Orly, or Nancy, referring to that question from the audience? No? Okay. Anything else, Megan, that was covered? I know somebody asked about LVADs and GDMT. That's a very different question. Maybe you could answer that, Megan? Yes, I was actually about to respond to that in the chat as well. So, you know, for heart failure, heart transplant patients, it also depends on what status they are. So there are six statuses. One through three are the ones that are in-house. Typically, they're in shock on inotropic support as well as temporary mechanical support as well. So in those particular patients, oftentimes the beta blockers, Barney, ACEs, all that good stuff, are often held given the acute shock and that kind of phase. For the LVAD patients, we do attempt to place them on GDMT once they receive their LVAD and upon stabilization and titration of pressors and outside the acute phase. But that's kind of the short answer to that particular question. Thank you. We need short answers right now since we're already 10 minutes over. There was another question on why in the guidelines, hydralazine and isordyl is only used in African Americans. And the reason is because the study, the AHEF trial, was in people who were self-identified as African Americans. And so the VA cooperative study, the VHAF study, also was in people who were self-identified. There's actually a biological reason for that. People think that African Americans have more, the ENOS or the endothelial nitric oxide synthesis may play a bigger role in heart failure treatments as opposed to the European population or the Caucasian population where RAS might be playing a bigger role. And so I think that's the sort of, I guess, molecular reasons why they had these different therapies based on the African American and race related. But the data is only in African Americans and that's why the guidelines have to state it that way. Hope that answers the question. Any other comments? If there are other questions that weren't answered, please feel free to send them to the HFSA coordinators and I'll be happy to answer them on email and also send it to the faculty to answer questions that didn't get answered. Any other final wrap-up comments from Orly, Nancy or Babak or the course planner, Kristen? I'll just make a comment about the one question that's in there about heart failure and preserved ejection fraction in the future of guideline-directed medication therapies. The European guidelines and the ACC, I think it was Michelle Kittleson was the first author of a paper in Jack and they talk about, it was a consensus guideline and SGLT2 inhibitor in both the European guidelines and in this consensus document was moved up to a class 1 drug and the diuretics being a class 2 and then some of the ACE and ARP being lower down. And beta blockers is not even indicated any longer for heart failure and preserved ejection fraction, maybe for some other comorbidities but not specifically for the HFPAF. Yeah, they didn't have it in the European guidelines at all. I know John McMurray made a big point of that, that that was the big difference between the European and the American guidelines for HFPAF, right? Yeah. Okay. Well, thank you very much to everybody involved in the presentation and the cases today. I thought it was very helpful clinically and we hope that there were many tips and tricks and clinical nuances that you picked up in augmenting the guideline-directed therapy, accelerating its implementation, because it, you know, as it's very important because it impacts on our patients' survival and their quality of life. So there's lots of motivation for doing it and we hope that this seminar has provided some more clinical options for you to manage. I think that Orly, your slides on what to do when the blood pressure is low and what to do when the renal function should probably be magnified and posted everywhere in the heart failure clinics, what options they need to take. Okay. Thank you so much. Thank you, everybody. Thank you all. Take care. Bye-bye. Thank you.

medication adherence

heart failure management

close follow-up

left ventricular function

symptom improvement

disease prevention

reduced hospitalizations

non-adherence

case study

guideline-directed therapy

medication dosing

communication

SGLT2 inhibitors

patient care