Thank you so much. That's really helpful. I know when I was a, you know, a general fellow, I don't think I really fully understood the distinction between oral iron and IV iron, but it's helpful to remember because we see difficulty absorbing medications in our heart failure patients with a lot of different things. So thanks for that. I know we've all seen a number of randomized critical trials done in this space, particularly learning about the confirmed HS and FAIR-HF study, which I learned about years ago now at medical school. But more recently the data presented in a firm, AHS and Ironman, and perhaps most recently in Hartfin trial that you and your colleagues have published. So how do you iron out all of this data in terms of who to treat, when to treat, formulation of therapy, and what outcomes we're hoping for with treatment? Yeah,

really good points. And for those may be less familiar with some of the studies so just got quick bullet points here. So the first key trial of IV iron in heart failure with iron deficiency was FAIR-HF. It showed improvements in quality of life and functional status giving IV ferric carboxymaltose, one of the IV iron formulations. Then a follow-up study confirm H.A. confirmed those benefits of giving IV, FCM, or ferric carboxymaltose, with pretty striking benefits around six-minute walk distance. So actually a 30-meter benefit in terms of improvement in six-minute walk, really clinically significant. So it was after those studies that guidelines in the clinical community began to use IV iron improve the function and feel endpoints. So quality of life and functional status for our patients. And then in more recent years, you've now just highlighted three of the key big outcomes trials. I'll rattle these off quickly. A firm AHF really relates to our patients. So that was EF less than 50% in the hospital with heart failure, with iron deficiency, gave ferric proboxymaltose and looked at clinical outcomes. Primary endpoint, cardiovascular death and total heart failure hospitalization in over a thousand patients. It showed a nominal reduction really driven by heart failure hospitalization. It was technically a neutral trial. It was grammatically impacted by the COVID pandemic and in a pre-specified analysis accounting for that, it did meet nominal significance. The kind of key summary from affirm was that a large study showing that IV iron was safe, and it led to likely a reduction in heart failure hospitalizations. But that's the first trial and then subsequent to that was the Ironman trial, a different IV iron formulation, FDI, or ferric duraisomaltose. Again, pretty similar in terms of some of the design features to affirm but formulation. It was reduced ejection fraction, but actually an open label study. So it was not a blinded study like a firm was, but had the same endpoint. It actually interestingly showed a similar numerical reduction in that endpoint of heart failure hospitalizations and cardiovascular death, about 20%. So there's those 18%. Also, totally a neutral study, the P value was 0.7 and also impacted by COVID. And in that case, similar pre-specified analyses. In that case, when you adjust for COVID, suggested about a 24-25 % reduction in that endpoint. So that led to a growing suspicion and belief that IV iron and now multiple different formulations would reduce heart failure hospitalizations. And it was actually right before we presented the heart fed trial that the most recent European cardiology guidelines were updated. And we'll come to the guidelines in a moment, but right after their guideline recommendation now with a class one recommendation for quality of life and functional status, they gave a class two recommendation for heart failure hospitalization reduction. Then the very next day we presented heart FID, which we can talk to in more detail. but a large trial over 3,000 patients have FREF iron deficiency, giving IV iron with ferric carboxy maltose every six months. If patients were still iron deficient in it, similar to the earlier trials, it was technically a neutral trial, but it had a higher bar just based on discussions with the FDA for this one. But in summary, what we found was a numerical reduction actually in mortality, heart failure hospitalizations as well, but a more modest benefit around six minute walk distance. So we can get into more of the nuance, but importantly, as we pool all of the data together, it does look like there's a clinically relevant reduction in heart failure hospitalizations as well. So that's led many of the clinical community and scientific statements now to not only know that IV iron is safe and improves function feel endpoints, but it does appear to have benefits around reduction in heart failure hospitalization. Phew, that was a lot. Hopefully that is helpful to summarize a lot of trials, but I'm looking forward to some of your reflections on this and certainly giving back to our case as well. That

was really great. And a good summary of, you know, all that we've known about IV iron and heart failure thus far. So it sounds like going back to our case that Miss written with her persistent system could benefit from IV iron supplementation to improve her quality of life and even reduce her chance for rehospitalization, but the data isn't as clear on if it will reduce her risk of mortality. So at that time she was treated in the hospital with IV ferric or carboxy maltose and was eventually discharged home. When Ms. Ritten came for her follow-up appointment, she had definitely noted improvement in her symptoms from NYSA Class 3 to NYSA Class 2, and questioned whether she should continue this treatment in the outpatient study. So, with all of the data that we've summarized so far today, what would you say are the most important things to think about for the clinician managing these heart failure patients in the outpatient study?

Yeah, really a nice case that I think brings us all together. So in the hospital with heart failure, iron deficiency received IV iron. And now you're seeing her in follow-up symptoms of it prove she's on otherwise good GDMT, then you say, well, when do we need to think about rechecking her iron stores and there's still evolving data in this space, but in HeartFit, we did it at a six month interval. And if patients were still ironed efficiently, gave more iron. So typically what I'll do is whether in the in-hospital setting or out of hospital, we'll repeat those labs. It's six months, see if they need more IV iron. Make sure we're doing this on a good background therapy of their other GDMT as well. I might underscore some other kind of key pearls. There were some concerns recently. Is there any interaction with SGLT2 inhibitors? We know that SGLT2 inhibitors improve clinical outcomes in heart failure across the EF spectrum, but there was a concern given some of the changes on hemoglobin. Everything we've seen thus far suggests that really the treatment benefits of IV iron are consistent regardless of SGLT2 inhibitors. But stay tuned because I know there has been some conversation in the space around that. And we are hopeful for additional trials that help better tease out the optimal definition of iron deficiency. I alluded to this a little bit earlier as well. And some of the data from heart fit that have been recently presented at meetings as well as from Ironman suggests that it really is probably that T-SAT less than 20% group that have the largest clinical outcome benefit. So stay tuned. Hopefully we'll get more data in that space. But as of right now, we're really still looking at all of those iron indices and really using IV iron to improve. quality of life, functional status, and potentially even heart failure hospitalization endpoints. So

do you foresee any role for IV iron supplementation in patients with HEPPEP and is there any ongoing research in this space?

Yeah, this is a really exciting space certainly with the evolution in half-path pharmacotherapy is now with SGLT2 thinking about GOP1s. Interestingly, a trial was just presented at the Heart Failure Association in Lisbon. Just this past May, a small study, Fair Half-path, initially designed to be larger, but for a number of challenging reasons, it was just around 40 patients and did show with IV ferric carboxymaltose some potential benefits around functional status as well. So under power, but was technically a positive trial, so we'll hopefully see more data in that space. And then I'd be remiss if I didn't also highlight the ongoing FAIR-HF2 trial, a HEF-REF study, it's actually testing a little bit of a different hypothesis. The earlier studies looked at giving depletion or getting iron stores back in this range and this trial is actually looking at more of a supplementation. So as long as ferritin levels are less than 800, it's actually giving additional iron if follow-up. So I think that'll be a key study that should report out in the next year or so as well. So still important trials ongoing in this space to help better clarify how we can help our patients with heart cell area across the EF spectrum. Yeah, sounds like a lot of great data to look forward to. Now, we've covered a lot of ground in terms of iron deficiency in heart failure, who to test, how to test, when to treat, how to treat, appropriate follow-up. Rob, what are some key takeaways we should walk away with to hopefully help improve the lives and outcomes in patients with heart failure? Thanks, Ahmed. So my top pearls would be again, that when you see heart failure, think about iron deficiency, don't wait for anemia. Remembering that definition, ferritin less than a hundred or 100 to 300, the T-SAT less than 20, some evolving data, maybe we can focus on just a T-SAT, but we still need to prove that in randomized trials. And really that oral iron is not going to be effective. We need to be giving IV iron and that we have important data that this will help our patients feel and function better. And now in the European guidelines, actually a class two recommendation to reduce heart failure hospitalizations as well. So lots of different trials have reported out, and I think really an exciting time to think about the diagnosis and management of iron deficiency as a important comorbidity in heart failure. That's

really great, Dr. Mendes. We've covered a lot today. And so just to close, I have to ask you, what makes your heart flutter about iron deficiency and heart failure?

That's a great question. So for me, you know, I think it's so exciting to help take care of patients and get them on their routine quad therapy. And you see this amazing benefits around clinical outcomes and LV remodeling. But the idea of the pill burden, and what's really nice about diagnosing and treating iron is it's not another pill they have to take every day. It's pretty easy whether in the hospital setting to give IV iron. There's a little more complexity in the out of hospital setting, but it's this nice concept of they can come in, get their iron infusion and hopefully feel and function and maybe have better outcomes as well. So I guess it would be the idea of it's another tool in our toolkit to really help our patients.

Dr. Munn, thank you so much. And Shodley, it was so wonderful to get to record with you. It's always a blast. Dr. Munn, we really appreciate your time and insights. You're a, you're a leader in this space. And so all of the cardio nerds I'm sure are grateful to hear. Thank you all for joining us. And we hope that you guys have a lot of great insights about iron and heart failure going out of this podcast.