Hi, everyone, and welcome to this HFSA seminar. We're so glad you've joined us. My name is Rob Mentz. I'm a heart failure cardiologist at Duke and the editor of JCF, and we have put together a fantastic program. We're so grateful that you've joined us, and we're gonna jump right in. So thanks to the HFSA for all their support putting this together. To give a little bit of background here, so tonight we'll be focusing on iron deficiency, ironing out iron deficiencies. This will be a one-hour program with plenty of time for questions and discussions with our esteemed panel. We would like to give gratitude to our meeting supporter. This seminar is supported through an independent grant from American Region. With regard to CME, so continuing education credit information, in order to claim credit, learners are required to complete a course evaluation, and this is available in the HFSA Learning Center, and it'll be available at the end of this meeting. I'd like to give a huge thank you to the program planners for this, Drs. D. Almeida and Dr. Grew, who just did tremendous work helping identify the right speakers for this, putting together the content, which I'm sure you're going to enjoy. To introduce our faculty, we have three esteemed panel members. We have Dr. Cordwin, a foreign D from Michigan, Dr. Josephine Harrington, one of the senior fellows here at Duke University, and Dr. Sokos, who is at West Virginia University. And just to give a little bit of an overview, so after these introductory remarks, we'll jump right in. George is going to go through pathophys and an overview of iron deficiency and heart failure, and then we're going to have back-to-back talks about inpatient and outpatient implementation, and this really supplements some of the earlier work that HFSA has supported, giving a context of iron deficiency, the epidemiology, and the clinical outcome studies, after this pathophys and overview, we'll take a deep dive into implementation. At the end of the time together, we'll have a panel discussion that'll bring back to a number of key questions. The learning objectives for today, we'll review the prevalence, pathophys, treatment options, and current guidance on the management of iron metabolism in patients with heart failure. We'll discuss the best practices and protocols for identifying and managing iron deficiency and heart failure in the hospital setting, as well as for outpatient management. So again, thank you so much for joining, and without further ado, I will turn it over to our first speaker to go through some of the key details around pathophys. Thank you, Rob. I think everybody can see my screen now. I appreciate the HFSA inviting me to speak on the pathophysiology of iron deficiency and heart failure. Really, I have to credit one of the pharmacists that works with me, Dr. Akito, who really got me involved with iron deficiency, and really trying to establish that in our heart failure clinic. And I think, I'm sure that after this session, most of you out there will have a better idea of not only what I'm speaking about, about the pathophysiology, but really how you implement the treatment of all of this in your heart failure patients. So thank you to HFSA for having us, and without any further ado, I'll get moving on this. So I have no disclosures. And I thought I'd start with a couple of polling questions. And what is the accepted criteria for defining iron deficiency in patients with heart failure? We have some people still answering, but I think we'll keep moving. Okay, more to come on that. And here's our second question. Oral iron supplementation is recommended as a first line therapy for patients with iron deficiency and heart failure due to its cost effect on this. majority of people have answered. We'll go through these again at the end after my talk, so. Okay, so I'm gonna discuss the pathophysiology of iron deficiency, kind of go over some of the definitions, look at prevalence and outcomes, look at the trials utilizing iron supplementation in heart failure and where that's taken us with respect to the guidelines and where we are today. So I think a lot of exciting recent trials that we'll be able to go over, but hopefully give you a little bit of background, a little backbone to be able to teach some of your colleagues. So I encourage all of you to look at this nice scientific statements, it's a fantastic article led by Dr. Beavers and Dr. Mintz and the rest of the authors here. It's a really good paper, I highly suggest you read it. It's very, very concise. There's a lot of information in here, so I encourage that for all of you. So if you look at iron metabolism and its regulation in heart failure, so in heart failure itself, we know that there's some difficulty with absorption, there's some decreased iron bioavailability, so there's less production of hemoglobin. You also see with the inflammation, the disease state itself, you see a hepcidin can actually cause all these things to happen. And I'll show you in the next slide. There's two really different definitions of iron deficiency. There's absolute iron deficiency and then there's functional iron deficiency. So I think that basically we can see with through blood loss or decreased iron intake, you can have an absolute decrease in iron stores, decrease amount of pieces and true iron deficiency in that respect. But in heart failure, oftentimes we see really just functional iron deficiency. And we're gonna go over how we define both those with respect to labs and things. But hepcidin will decrease the amount of iron absorption like I stated earlier, decreases utilization and really you have decreased iron turnover. And so the body itself, while you don't have any decreased iron stores, it functions as if it's iron deficient. So this can lead to decreased exercise capacity, decreased energetic efficiency with respect to the heart and mitochondrial dysfunction. So really important to understand the two different concepts because when you start to test for things, knowing the difference between the two, it matters. It may not necessarily alter your treatment that much, but I think with respect to how you explain it to not only your patients, but most of us will be describing this and telling people why we're doing this with respect to our team, our PCPs that we interact with on a daily basis. And really it's important in our nursing staff and others. So I think it's important that we understand this and be able to explain this to our colleagues. So what about iron deficiency and functional capacity? So we understand that we have this really functional iron deficiency, but what does that do to really functional capacity? Well, you can see that when we have iron deficiency itself, you can decrease your oxygen delivery, you can decrease your oxygen utilization. And we talked about mitochondria, it decreases respiration within the mitochondria which really decreases our ability to utilize oxygen. And then you can see a decrease in LV function as well. So all of that combined really decreases our VO2P, our oxygen utilization, our cardiac output is reduced. So when you think about how this makes people feel, they're gonna obviously have decreased functional capacity. So I think there's about three different ways that you can see an effect of iron deficiency itself on functional capacity. Really important to understand that. And you can explain to patients when you're talking about receiving iron therapy as to why that's important, how it's gonna make them feel better. And we'll go over some of the data with respect to that as well. So how do we define iron deficiency? I think it's really important because most of our studies utilize this definition to really include patients in the study. And when we go over later each of the trials, why that's important to define this up front. So typically we use a ferritin less than 100. So that's what we've utilized in most of the trials. If you look at the WHO definition of iron deficiency is less than 15, obviously a ferritin less than 30 is a common abnormal reference range. You see that oftentimes in your labs, but we're looking on how we're gonna define it with respect to iron deficiency and heart failure. That by itself is the definition of iron deficiency and heart failure. When you have this middle zone of 100 to 300, we need to add another diagnostic test to that. And so we will look at your T-SAT less than 20%. And so why is that important? When you add that to your ferritin, we know that ferritin is an acute phase reactant in an inflammatory state such as heart failure, it can be elevated. So you can't utilize ferritin by itself, but when you add trituramine saturation to it as well, less than 20%. When you look at some of the studies, when you utilize these definitions and they go to do bone marrow aspirates to really get the absolute definition of iron deficiency, that's the best way to do that. Obviously, we're not gonna do bone marrow biopsies on every patient with heart failure. I think all our patients would wanna kill us in clinic if we did that to them. So we utilize this as a surrogate and over 87% of the time, this is accurate. So we feel comfortable saying that this is enough to define iron deficiency. So you can see the prevalence of iron deficiency by these guidelines. We maintain this over 70% of the time with utilizing this diagnosis of either ferritin less than 100 or the 100 to 299 and the T-SAT of less than 20. So you can feel good about utilizing this. There's a lot of data behind it to say that we can utilize this that really truly majority of time, it's gonna be accurate to say that the patients are truly iron deficient. There's some debate, but I think for most of us to be able to use it on a day-to-day basis in a simple iron panel that we can order in our clinic, it's important to have this as a definition. So how prevalent is iron deficiency in heart failure? So it's a nice paper in European Journal of Heart Failure looking at, if you looked at just guideline iron, definition, which is the less than 100 or 100 to 300 and T-SAT less than 20, it's very prevalent. You can see just by using an iron level less than 13 or T-SAT less than 20 themselves doesn't get you necessarily as high of a rate of, high of prevalence, excuse me. So if you look at males and females, more common in females. If you look at more functional patients, New York Heart Association class one and two, it's less common than in your more ill patients with functional class three and four. Obviously it's a little higher in our patients who are anemic than the non-anemic patients. So point being, it's very common over 60% of the patients in patients with class three and four heart failure patients. So, you know, that's a lot of our clinic population in advanced heart failure clinic. And if you look in the females alone, it's over 60%. So very common, that's why it's so important to understand how to define it, how to find it and then what to do with it afterwards. What about outcomes? So great, we see it, obviously it goes along with patients who are seem to be sicker, but does it really make a difference? You can see here, the blue line is patients who are deficient with the definition we described earlier with the fair to less than a hundred. And you can see that their outcomes are worse than those who don't. So again, that's just looking at all comers in these. So, you know, I think it's important, okay, this data may be a little bit older. What about in our contemporary heart failure trials? So this data actually comes from DAPA-HF. So they went and looked at all the patients enrolled in DAPA-HF and they could try to find who had iron studies and who we could define as having outcomes with iron deficiency and those who were not. If you look at, so their outcomes are worth higher death, higher heart failure events and higher all-cause mortality in patients with iron deficiency. And the primary composite endpoint was increased as well in patients with iron deficiency. So I think really important to understand that. And then again, if you look at all these, again, separately in the patients with iron deficient who received therapy with DAPA versus those who didn't, you know, it played through throughout this as well. So the reason this is important, there was some concern with utilization of SGLT2 inhibitors that it could actually worsen some things in patients who are iron deficient and they still derive benefit with SGLT2 inhibitors. So we can talk more about that in discussion later, but I think it's really important to know that this is, you know, this trial was published in 2022. And so this plays through with all the therapies that we have, because if you go back and look at some of the earlier trials that we're going to look at, it was before SGLT2 inhibitors. Some of them were just at the onset of use of ARNI as well. So I think this trial is important to note that with all the latest therapies that we have with heart failure with four pillars of GDMT, it still holds true. So let's talk about, this is a nice slide talking about all the overview of our major trials and the treatments of iron deficiency and heart failure. The largest trial was the most recent trial was HEART-FID and FIRM-HF, and we'll talk about that and IRONMAN as well. So let's start with one of the earliest ones. So why don't we just use oral iron therapy? Well, unfortunately, when you looked at the early oral iron trials, they've not been effective. There's no statistical significance between utilizing oral iron supplementation and change in peak VO2. They didn't really impact your ferritin levels after treatment versus when you started using IV iron, this is looking at FIR-HF here, you saw and did see an improvement in ferritin levels after treatment versus placebo. So you don't get the benefit out of oral iron therapy. So we don't recommend utilizing oral iron therapy in patients with heart failure to correct their iron deficiency. And a lot of that I think is most likely some of the absorption issues that we have. Again, we know that from when we were talking about the pathophysiology of iron deficiency in heart failure itself early. So moving on to some of the initial IV iron studies in reduced ejection fraction and moderate reduced ejection fraction. Again, we go back to FIR-HF, there's 459 patients looked at over 24 weeks. And the primary endpoint was patient global assessment and neurocardioassociation class, looking at confirmed HF over 300 patients. And that primary endpoint was six minute walk distance. And then effect HF was about 170 patients over 24 weeks looking at peak VO2. So really looking at functional status, you saw improvements in functional status, biomarkers and patient global assessment in these trials. And specifically looking at confirm HF, you saw a nice benefit in six minute walk test. And that held true over a full year. So you saw a 33 meter difference in improvement, excuse me, in the patients treated with IV iron versus those who were not. There was a trend, there's a reduction in heart failure hospitalization in this trial as well. Wasn't powerful that necessarily, but you can see that that got everybody thinking, okay, if we see improvement in functional capacity, see a improvement in hospitalization, we should probably take a bigger look at this. Again, this was 300 patients in this trial, over 300 patients. So that led to the 2017 guidelines, putting a class 2B recommendation that in patients with class 2 and 3 heart failure and iron deficiency, IV iron replacement might be reasonable to improve functional status and quality of life. So again, led us to thinking we need more data. And I don't have a slides on this here, but if you think about, I don't know if you, some of us may remember back to like a thing about red HF, looking at erythropoietin and looking at trying to stimulate erythropoiesis directly in these populations. That didn't pan out either. We had increased thrombotic events in those patients. So now we needed more patients, we needed more, so we have two newer trials looking at IV iron supplementation and replacement. So we saw an improvement in patients in the AFIRM acute heart failure trial with a reduction in total heart failure hospitalizations and cardiovascular death. And then you look at IRONMAN, which again, showed a reduction, a combined endpoint of recurrent heart failure and CV death. So it got us all excited. Again, some of these trials were affected by COVID. And so we have to keep that in mind. But again, you start to see, this was incredible news. So we're very happy that we, now we have more data with even a larger patient population. So where do we go next with things? We didn't quite see what we wanted to with respect to the PBI is this, but it got us thinking we need to do more. So that actually, and then we have the meta-analysis looking at all these trials, looking at Bayesian statistics, which I am far from an expert in that, I don't claim to be. But the nice thing that we got out of this was that treatment of iron deficient patients with reduced ejection fraction, appears to reduce a combined endpoint of CV mortality and heart failure hospitalization. But where it wasn't enough, there's still some uncertainty with this. So the where to next led to another study, as it always does, right? We always think we don't get all the answers we want. We see trends in areas we want to get to. Then we start to think more, but we need more data. Always, more data is typically better, right? So to our next trial, which Dr. Mentz and his team led, we're looking at chronic heart failure reduced ejection fraction with an EF less than 40%. I think it's important to look at some of the other studies earlier. We talked about confirmed. Those were had a little bit higher ejection fraction, 45%. Some of them were less than 50% as well. So this trial was less than 40% because we really wanted to get to who do we put on therapy, right? We're not treating HF-PEFs at this point. We're looking at reduced ejection fraction and moderately reduced. So this trial is one of the largest to date, over 3,000 patients. And again, the inclusion criteria was iron deficiency, less with our classic criteria that we discussed earlier. And then either a heart failure hospitalization within the last 12 months or an elevated NT pro BNP, somewhat higher over 1,000 if they had atrial fibrillation. So this was a little bit different than there was a hierarchical composite endpoint with all cause mortality, heart failure hospitalizations and change in six minute walk distance. And then a secondary endpoint of combined cardiovascular death and heart failure hospitalization. So enrollment began in March of 2017. You can see recruitment ended in 2021. We know that the world stopped pretty much in 2020. So affected definitely, that you can't ignore that within this trial. And then follow-up ended in February of 2023. Mean age was 69, 34% women and 11% black race. So what did we see? So again, this is looking at the hierarchical endpoint here. So I'm gonna go over these individually first and then I'll kind of explain how they went through this endpoint. So of the patients, if you look at all cause mortality, it was somewhat higher in the placebo versus iron treated group. And then the total heart failure hospitalizations was somewhat higher. Again, it's placebo versus the treatment group. And there was an increase in six minute walk distance in the treated group. Now, the way the statistics looked, they compared these groups first. And if they took, if this was, if they looked at each individual patient and if this was better, if the treatment group was better, it was considered a win. If the placebo group was not better, it was not considered a win. And then they went to the second endpoint. So the patients who didn't win in this, so if they didn't have an improvement in mortality, if it wasn't, if it weren't basically mortality, this group, you went to the second one, which is, okay, you're treated with IV iron. Did you have a heart failure hospitalization? If you didn't, that was considered a win here. If you did, you went on to the next one, which has changed the six minute walk distance. So there's this, this level of, went down the chain, so to speak. So the most important, obviously, was mortality. Then heart failure hospitalizations, then change in six minute walk distance. So there's these pre-specified endpoints and how they went through this. And it didn't meet statistical significance in this trial for these, for these, for this endpoint. You look over time, as far as time, the cardiovascular disaster, first heart failure hospitalization, did not meet significance here either between the treatment group and the placebo group. I think it's important, though, I mean, that this was a, this, this population was a little different than what we looked at earlier. Again, that's why I spoke to it earlier, because the EF was lower and we were looking at some different things. So you did see an improvement in distance. If you look at, if you improve 10 meters or you improve 20 meters in the treatment group versus placebo, again, these didn't meet statistical significance, but it did suggest, you know, both at six months and 12 months that there was a trend towards improvement. So, you know, I think it's important to understand that while the trial overall was, didn't meet statistical significance, there were some still trends in things that we saw. So things that we saw in earlier trials were evident here as well. And, you know, that's led us to our most recent guideline changes. So, the ACCHA and HFSA joint guidelines suggest as a 2A recommendation, patients with reduced ejection fraction and iron deficiency with or without anemia, the IV iron replacement is reasonable to improve functional status and quality of life. And then the European guidelines from last year, there's a class one level of evidence to use our IV iron supplementation on patients with reduced ejection fraction and moderately reduced EF and iron deficiency to alleviate heart failure symptoms and improve quality of life. And then it's a 2A to reduce, to treat with IV iron to reduce the risk of heart failure hospitalization. So, I think, you know, we have a lot of trials suggesting benefit, enough so that we've made it to the guidelines. And I think it's important that you understand that in those trials, what we saw to really get that into the guidelines. So, I know this is in some of our other slides later with some of our treatments in both the inpatient and outpatient. But when do we really want to think about treating? So, we have symptomatic heart failure with EF less than 45% and a hemoglobin less than 15. Do they have life-threatening anemia? If yes, you're going to treat those, evaluate those etiologies and transfuse. If not, we're going to obtain iron studies. Do they meet our definition? No. Then we continue to survey annually. If they do, then we're going to treat and go and hopefully see an improvement. If they're inpatient, we're going to administer IV iron to replete their deficit. If they're outpatient, we're going to coordinate a plan for outpatient IV iron therapy. And that's what our next two speakers are going to go into in a lot more detail than me. So, I hope you really got the definition of iron deficiency and why we, how we came up with that and why that's the case. Again, remembering there's functional iron deficiency as well as absolute. And understanding that iron deficiency is prevalent in our heart failure population. We talk about over 60% in some of those populations, particularly in women. In our sicker population, class three and four heart failure, which pretends worse outcomes in heart failure even in our contemporary trials. We know that IV iron improves functional status and potentially reduces heart failure hospitalizations. But we don't have a mortality benefit at this point in time. So, I thank you for allowing me the opportunity to talk about this. I'm going to transition to our other speakers and we'll have more time for questions after their talks. So, thank you very much. Great. Thank you so much. We're going to hand it over now to Dr. Corwin to talk through inpatient implementation and keep the questions coming. We're going to make sure to get through all of these during the discussion period together. Dr. Corwin? Thank you. Just unmute myself and turn my camera on. I appreciate the invitation from the HFSA panel. My portion of the talk is really going to cover the inpatient implementation. So, after Dr. Sokos summarized all the data of why we should be thinking about doing it, now it's kind of answering the question of how we do it and kind of reviewing how us ourselves at Michigan Medicine or University of Michigan Health have implemented this on the inpatient side. I have no disclosures to note for this presentation. The first thing that I kind of want to go to is since Dr. Sokos kind of reviewed when to do it. So, looking at the guideline approved definitions of iron deficiency and, you know, who to target with this. The next question is how much do we give? There's a few different equations that we can look at for it. The first one is the Ganzoni equation, which is an equation that was developed to kind of estimate what dose we should give of iron to kind of replete their stores. So, that's based off of their weight and the target hemoglobin of where we're trying to get to and where they're currently at with their hemoglobin status. And then looking at kind of replenishing their iron stores, which is an estimation, but a lot of times the studies will use like 500 milligrams for that iron store repletion to add on to what we get with their weight and hemoglobin-based calculation. That was used in the FAIR-HF trial, and I know some institutions also use this to kind of calculate how much iron to give patients when they are in the inpatient setting. There's also the iron dextran labeling, which is a different equation, which, again, kind of uses their lean body weight and their target hemoglobin to calculate it. The calculation ends up in milliliters, or sorry, in mils that you need to kind of replete, and then you just have to multiply that by 50 because the vials are 50 milligrams per ml to calculate how much they need in milligrams. This is actually what we use at Michigan Medicine, since the majority of our use is iron dextran. So this is the equation that we follow to calculate how much iron to give. And then there's also the various trial dosing. So a lot of the trials use different dosing when they're repleting their iron. So a lot of the ferric carboxymaltose trials used different calculations based on where they're at baseline with their hemoglobin and where they're at baseline with their weight. So there's various different dosing information you can use, and I would just encourage you to kind of find a standard to implement in your own patient population so that there can be some consistency, especially when going back and looking at quality improvement and things along those lines. My whole question is basically just trying to get an assessment of the audience of what your institution uses for IV iron in patients that are admitted for heart failure that have been identified as having iron deficiency. I'm going to let this kind of roll into my next slide, so feel free to keep answering that poll. And I kind of review the answers at the end of my next slide. There's a handful of different agents that we can look at for iron repletion in an inpatient setting. And there's different advantages and disadvantages to each one. I kind of have reviewed them in a chart here. I think the main thing that a lot of us think about is how quickly can we get it in? What's the biggest single dose that we can give? With sodium ferric gluconates, 250 in some studies. There's been some publishing about even using that twice a day to kind of speed up the amount of time it takes to get the total dose infusion in. Iron sucrose, there's data in our CKD population up to 500 milligrams at a time. Ferric carboxymaltose, some of the studies use up to 1,000 milligrams at a time. Ferrimoxitol up to 1,020, but we do see some more increased side effects when we get to these higher doses with ferrimoxitol. Characterized amaltose up to 20 mg per kg per the body weight. And then iron dextran, also that 20 mg per kg per body weight has been evaluated. They also differ in their infusion time. So for some of them, you can give a little bit quicker. So like iron sucrose, if you're doing the smaller amounts, you can give them over a relatively quick period of time. So over 15 minutes per the package insert. However, we see once you start increasing that dose, you kind of have to spread out that infusion time to where you can't just do, you know, 200 milligrams over 30 minutes. You might get some more side effects that we see with it. And then just some of the comments on some of these agents. Dextran, as we all are probably aware, requires that test dose. Due to the older data with some of the high molecular weight iron dextran is causing some anaphylactic-like reactions to where we always want to test dose. There's even been some, you know, meta-analyses looking at the low molecular weight iron dextran still showing some of that anaphylactic-like reaction. So always good to kind of require that test dose. We even require a test dose if they've had it before in the past. We'll still give that 25 milligrams just to make sure that we're safe to give the full infusion. Ferrimoxytol is kind of unique to where the package insert mentions the MRI interference up to three months following the injection. There's different types of imaging techniques with MR that you can utilize to kind of bypass that. But it's just something to note if a patient, if your institution does use that, that's something that your residence lab should probably be aware of just in case they need to change what type of technique they use if imaging is required. I'm sure we've all been a part of P&T discussions of, you know, what agent to add to formulary. And I think a lot of time, cost is a big talking point associated with that. So I just kind of calculated based on their average wholesale costs that I grabbed from Lexicomp. So obviously, this will be different depending on each institution and the type of negotiations you're able to get with your drug suppliers. However, this is just average wholesale costs for, you know, a thousand milligrams of each of these agents. And as you'll see, some of the newer agents, so ferric carboxymaltose, ferric derisomaltose, ferrimoxytol tend to be on the upper end of the cost range, which is why a lot of times you won't see these approved for inpatient use. And you might see them more in the outpatient setting, even though, you know, ferric carboxymaltose is the only one that has package insert approved indication for heart failure. So even though that one does have that indication, you might not see it a ton in the inpatient setting just due to the cost of it. At Michigan Medicine, iron dextran is our go-to agent for a few reasons. As I kind of mentioned in the last slide, it is the cheapest option for us to use. We also really prefer to do the total dose infusion, where you can just get the whole iron deficiency caught up with just one dose. So if you're running into, you know, the patient needing to get discharged, you can fill the tank up before they go home in just one fell swoop. We really like that side of things. We also have a lot of experience with it. We've been using it for many years. And we've done a few studies that are published and unpublished, looking at it and have internal validity of safety with this agent. And we're quite comfortable using it. Iron sucrose is our alternative. We've had to turn to it when we run into shortages. And some of our, you know, our end-stage renal disease, we also use it for a lot of our dialysis patients. So we still have it on formulary for those purposes. But we have had to turn and use it when iron dextran is on shortage. And we do typically use the 500 milligram daily infusions, although we do tend to see a little bit more hypotension with it, just anecdotally, when we use those higher infusions, especially when we give them on back-to-back days. So something just to kind of watch out for if you do end up having to utilize iron sucrose is you could consider lower doses to kind of avoid some of those reactions. I did just kind of want to review at least the published data that we have with our use of iron dextran. This is a paper published back in 2016 from some of our group. The median dose that we use, and most of these were iron dextran, was around 1,000 milligrams. But we have doses all the way up to 1,925 milligrams in this patient population. And I've given infusions up to 2,000 milligrams. So we do like to, again, use that total dose infusion. And we feel like this data kind of supports it. The main outcome in this was the change in hemoglobin, which we did see was better in our iron group than our control group. And readmissions we looked at, although they weren't the most balanced groups with our controls because a lot of our patients that were more iron deficient were going to get IV iron. So our control patients weren't as iron deficient as some of our IV iron patient groups. But readmissions, we saw 30% with the IV iron, 22% with control. We just think that this wasn't a randomized control trial. We've seen from some of our larger randomized control trials that there's some benefit there. Adverse events, we only had two patients that had adverse events, even with our higher dosing of iron dextran. And those were headache, back pain, nausea, and vomiting. And those were all self-limiting. We just basically either slowed down or stopped the infusion and those went away. We didn't really run into any of the anaphylactic-like reactions that you might worry about with iron dextran. When we looked at iron indices, these were up to 90 days after the TSAT increased from 6.2 to 17.7. In the iron group, showing that even though iron dextran doesn't have a lot of randomized control trial data, we feel like it is improving their iron indices and improving their iron deficiency from our internal data, which is why we felt comfortable continuing to use it. At Michigan Medicine, since we use a lot of it and we try to target a lot of our heart failure patients on admission to get baseline iron panel and ferritin numbers to kind of determine who needs it, we end up using it a lot. Since we use the iron dextran package insert equation to calculate how much they need, a lot of times it fell on the pharmacist to kind of, you know, after rounds go and calculate it. Enough to where we were using it so much that we decided to kind of build a panel in Epic to kind of help us calculate that. So the teams are more comfortable ordering it on them by themselves. So just kind of a recommendation to utilize the EMR and the resources you have. As you can see in this little window here on the order instructions, it basically tells them the equation and it also tells them if you would scroll down in this, it would calculate it out based on their most recent hemoglobin with a target hemoglobin of 13, how much to give for these patients to replete their stores. So it's an easier way for the team to kind of feel comfortable ordering that. There are some inpatient considerations to kind of think about. Adverse reactions are usually the first thing that come up. So hypersensitivity based on this JAMA meta-analysis is that it still seems like iron dextran is the most likely to cause some of these anaphylactic-like reactions. I've personally never ran into that. I have ran into some infusion reactions, but overall the risk is relatively low and it still requires some monitoring with that test dose like I mentioned. Hypotension is something that's relatively common with especially higher dose IV iron infusions. It can either be part of the hypersensitivity-like reaction or just a vascular reaction from the iron hitting the vasculature. Pretty low rates reported in the trials and it's usually related to the rate of administration. So a lot of times if they are getting hypotensive or having some of this infusion-like reaction just slowing down the infusion sometimes takes care of that pretty well. Infection is a topic that comes up relatively frequently just because iron is an essential growth factor for most pathogens. So just theoretically if you're providing the pathogens more food to grow there's a risk that the infection can kind of take over. It's mostly extrapolated from some animal models and some in vitro data. JAMA also put out an open paper that looked at this from a lot of different randomized trials or studies. So 64 trials and showed an increased incidence in infection rate. However, this wasn't a randomized control trial itself. In the randomized control trials that we've seen in our heart failure patient population so that we didn't see this increased risk of infection. However, based on our practice in Michigan Medicine we basically just wait till we finish antibiotics before giving the administration. And if that needs to continue into the outpatient world we just kind of send a note to the outpatient team to consider IV iron infusions once their course of antibiotics is finished up just to kind of remove this theoretical risk of either worsening the infection or starting it getting worse. Volume considerations. Of course, a lot of these patients are going to be admitted for, sorry, I've drawn a pen on there. There's going to be admitted for acute decompensated heart failure. So a lot of them are going to have extra fluid. So just something to kind of consider. At Michigan Medicine we compound the iron dextran. So a thousand milligrams will come out to roughly 350 mils being administered with our iron sucrose of being closer to the 300 mils per 500 milligrams. So we usually wait till they're a little bit closer to uvulemia before we consider administering our IV iron just to make sure that we're not worsening that problem at all. And sometimes you can even use it to your benefit. If you end up potentially over diuresing a patient you can use this to kind of give them some fluid back instead of just giving them 250 mls of normal saline. Blood products are always something to consider. One unit of Packard blood cells usually contains roughly 200 to 250 milligrams of iron. So just kind of considering that if you did end up giving some blood products earlier in the mission to subtract that from your total iron dose you can even include that in your order panel as you kind of saw from ours earlier. We'll kind of pull to see if there was any infusions previously. Discharge planning, infusion times can be up to four hours. So if somebody's leaving imminently you're probably not going to be able to get the IV iron in. So it's good to kind of plan for this earlier on in the stay. So we'll usually just kind of mark it on our progress notes of patient will require IV iron before discharge. And then once we're considering, you know switching them to oral diuretics just kind of use that as the time to pull the trigger to start the iron infusion or iron repletion. And then you can always coordinate with your outpatient team that the infusion cannot be completed on the inpatient side. So whether that be due to infection, to their volume status or to the infusion time complications of the patient wanting to leave right now those are always things that we can kind of pass off to the outpatient side. Speaking of passing to the outpatient side I will turn it over to Dr. Harrington to kind of talk about our outpatient considerations. Wonderful. Thank you so much, Dr. Corwin. That was a tour de force. We'll hand it over to Dr. Harrington to bring us home with the outpatient management. And maybe as you're going, I just want to make sure we touch on some of the questions that came in the chat box. If you want to maybe talk about the SGLT2 inhibitor piece that that came up and then any data in HFPEF. Dr. Corwin, I can stay paused if you want to address those quickly. Oh, no, I was just saying, Dr. Harrington if you wanted to comment on those go through but you're all set. Happy to. All right. Can everybody hear me okay? Looks good. All right. Well, my name's Dr. My name's Josephine Harrington. I'm one of the heart failure fellows at Duke. So I'm delighted for this opportunity to talk to you about using IV iron for patients with heart failure in the outpatient setting and thinking about when that's the right time and when there may be other opportunities too. So thank you very much to the HFSA for this chance. I have no disclosures. So when we think about the outpatient implementation of IV iron for patients with heart failure I think one of the first really important considerations that we'll discuss is what the best setting is and whether that might be inpatient or outpatient. I'm going to talk a little bit about the importance of creating a protocol and standardizing this process for your patients, both in terms of monitoring to decide which patients are the right patients for IV iron therapy. And then also to help protocolize the actual administration process to help maintain your sanity and to make sure that things are efficient. We'll talk a little bit about some of the IV iron formulation options. And then more broadly about some of the barriers that we've observed here at Duke in terms of prescribing IV iron and some of, I think, the opportunities to streamline this process and make it a little bit more efficient for our patients and for ourselves. So first we're going to go ahead and have a polling question. Do you prescribe IV iron to outpatients? So option one is never. And as far as I know it's not common practice where I work. Two, I haven't personally but I think that my colleagues do. Three, I have a few times. And four, I regularly prescribe IV iron to my outpatient heart failure population. And we'll give you a few seconds here to answer this. I think answering has tapered off. I'm going to go ahead and share these results so that everybody can see them. And in case you can't, I'll say it looks like in general about 40% of you regularly replete with IV iron in the outpatient setting, which is wonderful. And then it's fairly evenly split between people who sort of don't commonly replete or maybe have colleagues who do and those who have done it maybe a few times for special cases. We'll go ahead and ask the next question which is, do you have a protocol to prescribe IV iron specifically to your heart failure patients in the outpatient setting? No, maybe, but it's not used regularly. Yes, and we're actively working to improve it. Or four, yes, we have it. It's really dialed in, it's highly efficient and we regularly leave on it. All right, I'm gonna go ahead and share results. But again, it seems like a third of people don't have a protocol or if they do, they're not aware of it. And then really a very even split between all of the other ones. So a lot of variation in terms of whether there's an outpatient protocol available. Excellent. So the first thing I wanna talk about is inpatient or outpatient. Where are you gonna prescribe your IV iron to your patients with heart failure once you decide that you think that they would benefit from it? And Dr. Cordman did a wonderful job talking about this already. I would say, in my mind, once they're inpatient, you have them, you have them in a highly monitored setting, you have the nurses and the staff available. And so I think that's actually a wonderful opportunity to pursue IV iron. You do still have to sort of address the inpatient formulary and what options are available there. But that can be a really fantastic chance to address opportunities for repletion. In the outpatient setting, I think that there are a few more issues that you have to sort of deal with. There is still the outpatient formulary issue. So what medications are readily available to you? And you have to deal with insurance coverage. It's a different beast in the outpatient setting. It can be really difficult and burdensome to address candidly. There are scheduling issues. Patients are not already hospitalized and you have to coordinate what makes sense for them, whether or not you can fit it in amongst other appointments. You need to develop a reaction protocol in case patients respond to it. You have to look for chair availability because you often cannot give these infusions in your clinic setting. And at least at Duke, we use actual infusion centers. So you need to make sure that you can find a chair for them. And then there are always staffing issues. So making sure that you have special infusion nurses available to monitor them, which again is necessary in the outpatient setting. So I will say inpatient is almost always easier to navigate in my experience and talking to other people. And so if you have inpatients, I would really urge you to protocolize making screening for that process of IV iron repletion a very standard part of your early decision tree. And if you can identify patients early in the process, it can be a really a good time to pursue IV iron repletion. Seems like we have good data that patients who are acutely hospitalized with heart failure seem to benefit nicely from IV iron repletion. And then just from a practical standpoint, it tends to go more smoothly. And then we'll talk about what patient, we've talked about this before, symptomatic patients with HF-REF or HF-MREF. I did see the question about what about patients with HF? We don't have great data for that population yet. The absence of evidence doesn't mean that they wouldn't benefit, but that's an area that really deserves future research. So it's a great question. You're looking generally for patients with a hemoglobin of less than 15. And as we've discussed, either a ferritin of less than 100 or a ferritin of 100 to 300 and a T-SAT of less than 20%. And I've seen a lot of questions in the chat about infection, both in the outpatient and inpatient setting. If you think that someone is severely infected, this is probably not the right time to give it to them. I think if they have a little bit of a stuffy nose, it's probably okay. Similarly on the inpatient side, if they were admitted and it was heart failure versus pneumonia, and it seems very clear that this is actually a heart failure admission, not a pneumonia admission, I think that's fine. T-SAT is a negative acute phase reactant. So the same way that ferritin goes up, T-SAT does tend to go down in inflammatory conditions. I think that that really means that if you think that they're acutely very, very sick from an infection, I wouldn't check it. But otherwise, these are still the markers that we use to identify patients who might benefit from IV iron repletion. And so again, these are the exact definitions that were used in the trials that we're referencing when we think about who would benefit and what data we have to show benefit. So if you want to give IV iron, now what? I would say this is your chance to use and really make your protocol. And I think standardization, both on the inpatient and outpatient setting is such a huge and important part of IV iron. We're not used to checking for this. We're not used to giving it. And you can see that it's, you can see that when people don't have a protocol in place, when it's not standardized, that's really when we miss opportunities to give IV iron to patients. So I'd encourage you to standardize, one, the process to identify the patients who might benefit from IV iron repletion, but then also to create consistent standardized dosing plans so that you don't have to reinvent the wheel every time you identify those patients. And then also really just to facilitate scheduling these appointments for IV iron if they have to happen in the outpatient setting and to address that insurance process because that can be burdensome. And so making sure that you and your team don't need to re-navigate issues that you've maybe already solved for other patients can be really important. So when you think about standardizing, identifying the right patients, that's very easy. You can get a CBC, you can check Faraday and iron labs. Typically we check them every three to six months. You replete if they're iron deficient, and then you again recheck three to six months later. So if you're seeing your patients regularly because they're symptomatic patients with HF-REF or HF-MREF, those regular visits are wonderful opportunities to also just check those labs. It is really important in the outpatient setting to document, this is not the most glamorous part of this talk, but when you want insurance approval, documenting your indications for giving IV iron, especially instead of oral iron is very important. So you need to document that they have systolic heart failure you want to document that they have iron deficiency and you want to reference their need for IV iron supplementation. You can again, standardize and protocolize this. So we have two different dot phrases available through our EMR that can help make this a little bit easier. We have a not very pithy dot phrase dot referral heart failure form iron, which really just shows what their diagnosis is, what their need for it is, and then to facilitate our scheduling, what IV infusion center the patient might prefer. And we have a much pithier dot phrase dot IV iron that very clearly for both your personal documentation and then also for insurance approval, lays out very clearly that they have an indication for IV iron. It pulls in automatically all the relevant laboratory information. It explicitly states that oral iron is not recommended in this population, that it doesn't seem to work. And then it specifically calls out the fact that ferric carboxymaltose is the only FDA approved treatment for iron deficiency in this population. And that we think it's really the most data-driven practice. So this is what we have available in our dot phrase. It saves a lot of time. And I think it also helps to prevent those downstream issues when you're looking for things like prior auths with insurance companies. This is our algorithm again laid out, I think visually nicely on one page. It's steps one and two are really identifying the right population of patients who you think might benefit from IV iron. We are very lucky. We have a dedicated heart failure pharmacist who really supports us and a pharma tech. So once you've identified the right patient, you can put in these orders and you let the heart failure pharmacist know. And they really do help with ordering the IV iron and completing things like prior authorization and scheduling. And then importantly, they circle back and they close the loop and they let us know what the IV iron plan is. And then we can develop a plan for further monitoring because patients do often need repeat dosing with IV iron. So our heart failure pharmacist orders the IV iron therapy plan. They schedule the IV iron therapy with the patient to make sure that it's a time that works for them and where the infusion center is available and has a chair. And then a pharma tech conducts a prior auth review and submits it to the insurance. As I said, we prefer ferric carboxymaltose. It doesn't always work out that way. They don't always get approval. Otherwise we use iron dextrose or iron sucrose, especially as Dr. Cordwin said in our patients who have end stage renal disease. This is our dosing outpatient for patients with ferric carboxymaltose. You can see it's based on both hemoglobin and body weight. And again, when we talk about protocolizing and standardizing, we have order sets for all of these. Now, ferric carboxymaltose, we do premedicate with loratadine. And so we give very explicit dosing directions here. And you can see that it's tied to things like emergency medications for some sort of a hypersensitivity reaction and making sure that they get scheduled and then scheduled for repeat dosing. So iron sucrose, very similar, a little bit more premedication dosing and patients come back for three different visits. So again, it can be extra burden because you need to now find a chair availability that links with your patient's availability on three separate occasions. And then dextran where you, again, do a test dose the same way that they do for inpatients. And then you dose to address their IV iron deficiency. Again, you can see that they get pre-dosed with many more medications to address those infusion, those anaphylactic reactions. And then you have to have emergency medications available if they do have some sort of a reaction. I won't belabor this part because I think we've seen it before. The cost is widely variable on these medications. The number of visits that patients have to have to complete the therapy. And again, this is every three to six months for some patients. And then the volume load can vary very widely for these. So just being aware of what those look like can be helpful. And when we think about barriers and opportunities, IV ferricoboxymaltose has the best data. It is the easiest to give. It may not be on formulary yet. It's not on formulary at the Duke outpatient infusion clinics. It may not be available at your institution. I think trying to figure out if it is available and if it is wonderful, and then advocating and sort of championing for your patients to try to get it on formulary can be helpful. Insurance hurdles can be significant. And so figuring out what your resources are, whether you have access to a pharm tech or a pharmacist who can help to standardize the process for you and taking advantage of those documentation efforts to try to preempt and pre-address some of those issues is really smart. And then remembering that patients may require redosing. So making this a really standard part of your every three month or every six month visit that you have with some of your symptomatic patients. And then I'll say again, identifying those patients inpatient too to try to prevent some of these outpatient infusions can be really helpful. So in conclusion, I'd say all patients with heart failure and either reduced or sort of mid-range reduced EF should be evaluated regularly for iron deficiency. IV iron repletion is almost always easier for inpatient. So if you have an opportunity to replete your patients in that setting, take it. If they're not able to receive IV inpatient iron repletion, perhaps because they don't get hospitalized, that's okay. But protocolization is really essential to ensure that you're efficient, that your patients get good care and also to maintain your own sanity. And then ideally, I think you'd link those iron repletion efforts to things like GDMT protocols to help ensure standardization and just make things more efficient. So thank you so much. I think we're gonna roll into our panel discussion. So I look forward to talking with people a little bit more. I think we are right at the top of the hour, but a huge thank you to all of our speakers. This was a phenomenal session. So thanks to each of you. Just in summary, we went through the pathophysiology of iron deficiency in patients with heart failure, talked through the trial data, and then importantly, really got into the details, the nuts and bolts around inpatient and outpatient implementation. So lots of good discussion this evening. We hope you found this session valuable. Thank you to our independent sponsor, American Regent, a huge thank you to the HFSA for getting the word out there and thanks to all of our attendees for listening. Everyone have a great rest of the day and we look forward to the next seminar with you. Take care now.

iron deficiency

heart failure

pathophysiology

prevalence

functional capacity

diagnosis

clinical trials

IV iron supplementation

quality of life

management