Hello, everyone. We have a very interesting panel here today. We're going to talk about iron deficiency and give you maybe some practical points with some of our patients who are really sick, and we hear a lot of talk about iron deficiency. I have two of my good friends here today with me, and I'm going to let them introduce themselves. Dr. Butler, would you like to start? Yeah, absolutely delighted to be here. Javed Butler. I'm a cardiologist, heart failure cardiologist and clinical trialist at Baylor Scott & White in Dallas. I also run the research institute here, and I serve as a professor of medicine at University of Mississippi. Vanessa, would you like to start? Thank you so much for having me. I'm one of the advanced heart failure and transplant cardiology fellows at the Cleveland Clinic, and before being here, I did my cardiology training at Duke and a year of research at the DCRI. Very happy to join this crew today. A blue demo with us in the flesh. And I'm Ileana Pina. I'm the chief quality officer for the cardiovascular division at Thomas Jefferson University Hospital in Philadelphia. And so it's obvious that we see these patients as part of our practices. So I'm going to give a little history first. We're going to be talking about iron deficiency, and we have a paper that will probably be coming out through the Heart Failure Society about iron deficiency, really taking it apart into the bits and pieces. But this is very interesting. Iron deficiency is probably one of the most common nutritional deficiencies worldwide. We're talking about billions of people with iron deficiency. And we know that in prehistoric times, the skeletal remains had already iron deficiency, but it was in the late 20s that I think she was a nurse, Helen McKay, actually observed that infants who had a limited nutrition and were given supplemental iron had less postnatal hyperchromic anemia and looked healthier by that description. And so if we take that further through time, we recognize that socioeconomic changes may in fact lower the iron intake in populations, in staple foods, and that patients with symptomatic heart failure may have concomitant anemia and or concomitant iron deficiency, have iron deficiency without anemia necessarily. So iron deficiency really is a public health issue that spans time. And I've been around long enough in heart failure that we weren't doing anything about it. I mean, we saw patients all the time who were iron deficient and we put them on oral iron and we kind of expected it to work, but not necessarily. So with that introduction, I want to talk about a patient of mine who just got out of the hospital recently, but I think it illustrates how iron deficiency can really affect heart failure. This is a patient of mine with half breath, definitely ischemic, who in whom I've been working with him now since last summer, because he got sent home on IV milrinone and nothing and hydralazine and nitrate. And that was it. Because everybody said, oh, his renal function is too marginal. You know, the usual story. We can't start any brass inhibition. So I started very small doses of enalopril to see how he felt. And he started feeling better. By then his hemoglobin was roughly 11.5, 12. I gradually up titrated him up to 20 BID. I had him on a beta blocker. He's been on an SGLT2 inhibitor and I had him on odactone. So he was like all four therapies on there really feeling well. And I stopped the milrinone. He's been off it. Then he comes into clinic and he says, I'm feeling fine. You know, I'm taking it history. He has a lot of MR and I've been considering him for a MitraClip. And he says, oh, by the way, my stools are dark. Oh, great. Well, we sent some labs because he had been on milrinone. He was still getting labs at home. And his hemoglobin was six. And the hemoglobin that I had just before that was 12. And we got to admit that because we can't leave him like that. And what does the house staff do? They remove the RAS inhibition. Totally. And he say, don't stop that because it made me feel better. So now I've had to re-up titrate him, which has been rather difficult because now his blood pressure is around 90. You know, and I'm fighting this hypotension right now. Actually, I have him up to five. So here's a common problem that we see. And my question to you both is in a situation like this, you transfuse and then add iron supplement. And how do you give the iron supplement? Or do you give IV iron for several periods of time? And maybe we can discuss that IV iron. So Javed, why don't you start? Yeah, so this case is interesting, right? So one, for a male patient, you have a hemoglobin of 12. So there was some degree of anemia to begin with. But then there was this acute drop from 12 to six. So this is not really part of iron deficiency or the so-called anemia of chronic disease or heart failure or anything like that. I mean, you know, so the question is, why did he drop the hemoglobin to this level? So evaluation of that, now I assume he got upper-lower endoscopy and nothing was found? Nothing was found. We did upper endoscopy. We even gave him a capsule to swallow. The capsule showed nothing and nothing in the stools. He had some blood in the stools when he first came in. He tested positive. But you're right, 12.5 is already low for a male. But he'd been sick for a while. And he wasn't eating as well. The hydralazine and the nitrates just didn't agree with him, especially the hydralazine. Stomach was always upset. So I gradually got rid of all of that. And I've had him on the guideline-directed medical therapy. And he was doing extremely well, so well that I stopped the Vilronone. And he came off it. So I am really jogging my memory way back when to the chief residency year. And this looks like the Dullafoy syndrome, those subcutaneous AV malformations that on endoscopy you don't see at the surface. And these people bleed because you definitely have a diagnosis of bleeding. But this is a person who may have sort of an acute issue on top of a chronic issue. Now you have sort of transfused him. So whether or not to give him IV iron replacement is a little bit of a gray zone thing. But if you have transfused him, he does not have enough, you know, any more GI bleeding and continues to have some degree of anemia. And you recheck the iron levels, and they are low. And you can tie it to his heart failure. Then I think he will definitely be a candidate for iron replacement. So Vanessa, what do you think? I totally agree with Dr. Butler. I think this is not the most common case, I would say, that we would talk about when we're talking about iron deficiency. And it's not clearly the case that is addressed in the guideline, right, because he's having an active bleed. So I think in this case, obviously, he warrants a transfusion with a hemoglobin of six. I think obviously once he's a little bit more stable, I think we can check for iron deficiency. But I do think that this case allows several other teaching points. And you kind of brought it up in some way. You brought up, do we correct it with oral iron? And I think this is a good, you know, teaching point to say, if we really prove that this patient is iron deficiency in the future, you know, oral iron is not the way to go. And we learned that with Iron Out in 2017, published in JAMA, that if we really want to improve outcomes, oral iron is not the way to go. And I can let you guys talk a little bit more about that. And I think the other thing that we should discuss is, you know, are we only going to check iron and correct iron in the case of anemia? Or do we actually replete iron in cases of patients without anemia? And I'm going to leave it there. And I'm seeing Dr. Butler nod, so I'll give it back to him. How would you do? I'm going to actually maybe pose a case. So if you have an inpatient that you are seeing who has had several readmissions for acutely decompensated heart failure, and now you're seeing this patient in the ICU, I'm going to say it's a woman of 56 years old. Hemoglobin is 14.1. Should you be checking for iron deficiency in this patient? And if you do, how would you, if you prove that this patient is iron deficiency, should you correct it and how? So, Vanessa, what are her symptoms? What are her symptoms? Does she have dyspnea? Yeah, yeah, she's symptomatic, gets admitted to the ICU, volume overloaded with some signs of hypoperfusion. Yeah, so, you know, so this is sort of a typical case that you're describing. So there's a lot of misconception about iron deficiency out there. So first of all, iron deficiency is not something rare. If you look at the heart failure patients, there's a pretty direct correlation with the NYHA class. So the more sick you are, the more prevalent it is. And then the sickest patient, like the one that you're describing who is hospitalized, we're talking about in hospitalized patients, some of the studies would suggest that almost 70% of the people will have iron deficiency if you check for it. If you look at outpatient, you know, sort of NYHA 2, 2, 3 sort of a population, even then it's 45, 50%. So it's very common. The second issue that you raised is if, you know, this person does not meet the definition of anemia, so do we really worry about iron deficiency? And the answer is sort of absolutely yes. And, you know, these are sort of, again, two separate concepts. So there are multiple ways by which you can get iron deficient, right? So one is you are not taking in enough iron, so nutrition, or you're taking in enough iron and you're not absorbing it. So you have gut edema or something like that. So that's on one extreme. And the other extreme is that you're taking it, it's getting absorbed, but you are now bleeding. So whether it is heavy menstrual losses or GI bleeding like this patient or something like that, chronic peptic ulcer disease. But the third thing that we tend to forget is this whole issue of inflammatory condition and how your, you know, hepcidin levels, when it goes up as part of the pro-inflammatory process, iron itself is very toxic. So iron needs some sort of a detoxifier. So when we give iron, IV iron, it is combined with something so that there is this detoxification. But in the body, it is also combined with something. It is not just free-floating iron because then it gets converted into reactive oxygen species and increases oxidative stress. So in the blood, it's the transferrin with which it is bound and gets from one place to another. And in the storage cells, whether it's liver, whether it's reticular endothelial system, it is stored with ferritin. So the question is, how does it come in and out of the cell? How does it come in and out of the pool from ferritin to transferrin and back? There are cell membrane receptors called ferroportin, and that's the receptor through which it goes. So in pro-inflammatory conditions, hepcidin binds to ferroportin and basically inactivates it. So you could have plenty of iron sitting in your liver, in your reticular endothelial system. It is just not coming out of the cell, not binding to transferrin. Your transferrin saturation is down. So that is called functional iron deficiency. So A, you can have an absolute iron deficiency, in which case your ferritin levels are low, your storage is low. Or you can have a relative or a functional iron deficiency where your storage is fine, your ferritin levels are fine, but your transferrin saturation is low. So depending on how low your iron is, the initial problem is that iron is a cofactor of a lot of enzymatic function in the body. We always think about iron and hemoglobin synthesis, and that's fair. But iron is also a cofactor in mitochondrial function and ATP generation. It's a cofactor on soluble gonadalate cyclase and much of the cardiovascular function requires CGMP, soluble gonadalate cyclase activity. So even if iron deficiency is not severe, even if you haven't developed iron deficiency anemia, these other enzymatic function gets affected, ATP production gets affected, and your heart failure gets worse. So iron deficiency anemia and iron deficiency are two separate things. This person with their current admissions definitely needs to be checked for iron deficiency. That's such a good explanation of it. And yet, we often see patients running around with hemoglobin sub-8 and 10 that they've had for years. Nobody has done anything. And if I tell the health staff, what is this from? They'll say, oh, it's anemia of chronic disease. And that's a really learning point because what we are calling anemia of chronic disease is anemia of chronic inflammatory disease, but that is functional iron deficiency. That's exactly right. That was actually a brilliant explanation and one of the best ones that I've heard. So thank you so much. I think another interesting point to maybe discuss is comparing the guidelines, the heart failure guidelines, the European and the American guidelines, there are mild differences. And I think one of them, if we continue with this case, is how do we correct iron if we were to now replete iron stores? So the European guidelines are very specific that we would do this with varic carboxymaltose while the American guidelines just basically say IV iron. So if we were to do this here, and I'll open it up to both of you, whoever wants to answer, what would be your preference on how we would give IV iron to patients, both in the inpatient setting and the outpatient setting? Has to do with what's on your formulary. Very often, you only get one choice. In my formulary, it's the carboxymaltose. So that's what we offer the patients. It's interesting, my patient that bled, one of the, he was on a resident service. One of the residents who was going to be an intensivist gave him iron because he felt that, you know, the decrease in iron in him had been so precipitous that after we transfused him, I think he got maybe two units that we needed to keep it up. So he went for that. So very often, it's decided on what you have available. Not always fair, but that's very often. Javed, I don't know if you want to comment on that. Yeah, so I mean, this is where sort of there's a little bit of a clash between sort of, you know, evidence-based medicine versus what's really sort of available. So the vast majority of the data that we have so far is with ferric carboxymaltose. There's now one trial out with ferric dirizomaltose as well. So at least there are outcomes data with two of the iron preparations, although they don't exactly show the same result, but at least there are studies out there. Now, remember when I was talking about that iron by itself is toxic, so it needs a detoxifier. So in the body, it's transferrin and ferritin, but when we give IV iron, that also is then in sort of a shell, and it's sort of covered around, and it's that cell that determines your tolerability. So all of those earlier sort of, you know, worries that we have that, you know, you get anaphylactic reaction, that's actually not related to iron itself, but it's related to what it is, what's the shell it is covered in, and dextran and iron dextrose and whatnot. So the only thing that I would recommend is that it's not the iron part that worries me as much as it's the side effect and the tolerability part. So if you don't have ferric carboxymaltose, and if you have some other preparation, you might want to check what is the risk profile, because I think if you look at the risk profile based on the clinical trial data, that is specific to that drug per se, and if there is a different preparation, it might have a different safety profile, and you might want to discuss that with the patient, the risk-benefit ratio, and if anything, if you can get one of the iron preparations for which we have the clinical trial data, you're better off giving that. Now, you mentioned something really important, and that is what about inpatient versus outpatient replacement, right? So this is a really tricky issue for us, because inpatient is easier. The patient is there, they have an IV line, and you can sort of order it. In the outpatient setting, you need to get to a place where you can place an IV and give it. So one thing is that you can give it and let the patient go in the next hour. I mean, this is not something that they have to wait there for eight hours or overnight or anything like that. Having said that, many of the cancer infusion centers and other infusion centers are really busy with inflammatory diseases and rheumatologic diseases and cancer. So finding a bed in an infusion center, even if you have an infusion center, is not that easy. But remember, I mean, in cardiology practice, we have IV line facilities everywhere, cath lab, EP lab, echo lab, stress test, you know? So it can be done in a lot of the places, and it's a rapid infusion, and then the person can go after that. So it takes a little bit of arrangement, but I think in cardiology practice, giving it in the outpatient setting would be very feasible. Yeah, oh, I agree totally. But for example, for us at Jefferson, we can only give IV in certain places, and you can't give it like in the stress lab, for example, where there's nursing there or technicians that can actually watch patients. So I think important for our audience to hear that you need to work this through your own institution and what are the settings that will allow you to do that. I have seen personally, particularly with the older women who have lived with this anemia for years and years, because it's still taking iron every day, and it's just not getting absorbed, it's not getting incorporated, and how much better they feel that they say, why didn't anybody do this to me before? And so I find that a lot of the women are becoming those patients who have been iron deficient for a long time, maybe during menopause or before menopause, or maybe during childbirth, and then never really truly replaced. So Vanessa, what is your status here in the Cleveland Clinic? What are you guys doing? Yeah, so that's a great question. And I think that's where it's also important to know what you have in the formulary. And like Dr. Butler was so brilliantly stating, the safety profile of what you have, because that also limits how much what's the maximal dose that you can give. So if you don't have in your formulary carboxymaltose or dextrin, which are the ones that you can give a maximal dose of 1000 milligrams, then you have to have more recurring visits to actually complete or totally replenish the deficit that you have. So if you do have, for example, iron sucrose, or what you have is ferric gluconate, then that limits, I think sucrose limits to 300 milligrams, and I think ferric gluconate limits, I think maximum 250. So this makes, and that's, gluconate is per day, and I think sucrose is three times a week that you can do it. So patients then have to be coming more often in the outpatient setting. And I agree with both of you that that is very hard sometimes in the outpatient settings to coordinate. If anything, that's the ones that have it easier here are patients with CKD, that they can get them during dialysis sessions. That's a great point you're making about giving it during dialysis, as these patients, or many of them, are chronically iron depleted. Well, I'll make a couple of other sort of quick points. So iron depletion is, obviously, we are all sort of proponents for that. But one thing to keep in mind before supplement and one thing to keep in mind after. So before part is that, obviously, we are all sort of clinician and we just want to make sure that the routine screening has been done and there is no other reason for iron deficiency. And this is truly related to heart failure. So you just don't want to miss a colonic mass or something like that. So just screening people for a peptic ulcer disease or other GI losses in cases of absolute iron deficiency would be important. And then the second thing is whether it's functional iron deficiency or absolute iron deficiency, whatever it is, the phenotype that caused you to become iron deficient by iron depletion, that phenotype has not changed, right? So iron deficiency can come back. So at some frequency over the life journey of the patient, it's not just one and done and then you never check iron again. You have to check it again and some patients may require repeat depletion as well. And it requires good patient education because everybody hears about, well, I have tired blood, which is what the public calls it. Iron deficiency, tired blood. And they think that if you give it once, that that's it. You don't have to worry about it anymore. And I think your point that it does need to be followed up. It does need to be checked. But I can tell you, and you know this, when their fatigue is due to the fact that they have iron depletion and are anemic, when you do give them the iron and they start to incorporate it into their red cells, they really feel better. And most of them will come back and say, why the heck didn't anybody do this to me before? Because if it's changed my energy levels, I can do more, I'm less tired, I'm less fatigued. So I think an important message here for the audience is that there are physical consequences to being low in iron and the patients feel it. And I think the women very often never get repleted because it's seen as, oh, they went through menopause without realizing that during menopause, they may have lost a significant amount of blood as just, oh, it's part of menopause. You have perimenopausal pain, perimenopausal bleed, and that iron never gets replenished. Then they come in now and they have, for example, half-peft, which is also common in women, older women. Now you double their symptoms because it's half-peft with now iron deficiency anemia and that it needs to be replenished. So I was actually going to ask you this question, which obviously is sort of an unanswerable question, so it's entirely in the opinion zone. So if you look at the epidemiology of iron deficiency, that pretty much mirrors in HFREF and HFPEF. If you look at the consequences in terms of functional capacity impairment with iron deficiency, you see that in HFPEF as well. But the replacement trials have been exclusively in HFREF thus far. So, you know, there are some initial studies have started up in Europe in HFPEF patients, but we don't have any data for repletion and the impact of repletion. So what do you do today in HFPEF patients? Do you still screen them for iron deficiency as well? And if you do find it, do you treat it? Or are you waiting for data? Like, I mean, what's your general approach? Vanessa, I'll let you start answering. That's an excellent question. And it's funny that it was going to be my next comment as well, because also- I asked first. I don't have to answer. Because also that's another of the differences between the European guidelines and the American guidelines, right? Because, you know, here our guidelines refer to HFPRESS, but, you know, the European guidelines actually make the difference between acute heart failure and actually repleting iron when it's less than 50%, and then less than 45% in kind of symptomatic patients or in general outpatients. So, I mean, personally, and I don't know if there's a right or wrong answer for this, but if it's a HFPEF patient, unless it's overtly symptomatic, I'm not checking. But I do go with less than 50% for acutely decompensated heart failure. So I guess that that is kind of a little bit in between and applying a little bit more of European guidelines in that sense. Yeah, that makes absolute sense. And you have to think about when you're giving the iron, particularly to the HFPEF patients, don't need a lot of volume replacement because of their shift in their curve of pressure volume. So how much volume are you giving them when you're giving the iron becomes really important because you could precipitate an acute heart failure event. So you have to be very, very careful how you do that. And you may want to increase the number of infusions based on the patient feeling better without having severe symptoms because you're giving them a volume that they perhaps don't need. So there's still a lot of work to be done in this area because this is so common and the patients can be so symptomatic and they've been symptomatic perhaps for years because nobody there to do anything. Oh, I have them on iron, I have them on iron, that iron that never gets absorbed. Well, I'm going to wrap this up for us. I want to thank both of you for taking the time. I think we've had a good discussion and I hope that what our audience takes home is think about iron deficiency. Don't just say, oh, the patient, oh, the hemoglobin's fine, that's it. Or the hemoglobin's been low all the time, this is anemia of chronic disease. Don't make the anemia of chronic disease diagnosis so easy because you have to rule out other things and iron deficiency is obviously one of them. So I want to thank both of you for taking the time to be here with us today and I hope you enjoy the panel.

iron deficiency

heart failure

prevalence

hemoglobin levels

iron replacement therapy

intravenous iron supplementation