Is Finding and Fixing Iron Deficiency in Heart Failure Beneficial? IRONMAN in Detail

This transcript has been edited for clarity.

Ileana L. Piña, MD, MPH: Hi. I'm Ileana Piña, heart failure transplant cardiologist and quality chief at Thomas Jefferson in Philadelphia. This is my blog from the American Heart Association meeting in the beautiful town of Chicago.

I've been watching for years my heart failure patients come in with low hemoglobin. I always turn to my heart house staff and ask why the patient is anemic. They'll say, "Oh, that's anemia of chronic disease" but never go beyond that.

Now we know that it does matter and iron deficiency is a problem that is highly prevalent. In the United States, it's highly prevalent, particularly in women and African American women whose iron stores have been depleted and never get replenished. We have conversations about giving IV iron, recognizing that oral iron does not get absorbed.

I am thrilled to have with me here Dr Kalra. Please introduce yourself.

Paul R. Kalra, MD, MB BChir: I'm Paul Kalra from the United Kingdom. I work as a clinical cardiologist and heart failure specialist at Portsmouth Hospitals University NHS Trust in Portsmouth on the South Coast. I also have an honorary contract at the University of Glasgow. That's where we've had this research based. I'm overseeing it from the University of Glasgow.

Piña: We have many friends in the UK who share our experiences here in the US. We talk about them across the pond. You presented IRONMAN.

Kalra: Absolutely.

Piña: Tell us about IRONMAN.

Ferric Carboxymaltose and Ferric Derisomaltose

Kalra: Well, building on the beautiful scene that you've set there about the problem of iron deficiency, we have studies that have shown that it's associated with impaired quality of life, impaired exercise capacity, greater risk of hospitalization for heart failure, and death. That's independent of hemoglobin and anemia. It's very important for people to appreciate.

We've had some data from relatively short-term studies with intravenous ferric carboxymaltose showing that out to 24 weeks, intravenous iron, correcting the deficiency, can help people feel better — very important — and have a better exercise capacity. What we've been missing is longer-term data looking at heart failure. IRONMAN is a trial that's used a different intravenous iron called ferric derisomaltose.

Piña: What's different about that one from the ferric carboxymaltose?

Kalra: Both can be given at a higher dose than some of the other ions that have been available. With ferric derisomaltose, we can give up to 2 g. It depends upon the patient's body weight.

Piña: That's a hefty dose.

Kalra: It is, absolutely. It depends on the body weight and the hemoglobin. For many patients, we can correct iron deficiency in a single infusion.

Piña: Patients hate having to come back two or three times. I agree.

Kalra: Absolutely. We conducted a trial with a primary endpoint of recurrent heart failure hospitalizations and cardiovascular death. This has been funded by the British Heart Foundation, a charity in the UK.

Piña: Good for them for really doing this.

Kalra: We are very grateful. It was a probe design, so open-label, blinded endpoint adjudication. The feedback we had had from research teams and patients was that conducting it double blinded or masked over a prolonged period was going to be very difficult. You would need a blinded and an unblinded team for every patient visit.

Piña: Very costly, too.

Kalra: Very costly. Patients were seen at 4 weeks, 4 months, and every 4 months thereafter.

Entry Criteria and COVID Challenges

Piña: Did they need to be hospitalized to get into the trial?

Kalra: Different to AFFIRM-AHF, we could recruit a broad range of patients who were either hospitalized, had a recent hospitalization within the last 6 months—

Piña: So 6 months.

Kalra: Or if they hadn't had a hospitalization, then an elevated NT-proBNP or BNP.

Piña: What was your cutoff?

Kalra: In sinus rhythm for NT-proBNP, it was 250 ng/L. In atrial fibrillation, it was 1000 ng/L. It was 1-to-1 randomization to intravenous ferric derisomaltose vs usual care. It was an event-driven trial and we had challenges due to COVID-19.

Piña: Everybody has had COVID-19 challenges.

Kalra: I think from an intravenous iron perspective, different to a tablet, where you could get around it, perhaps, by posting it...

Piña: Exactly.

Kalra: ...we needed patients to come up.

Piña: They had to come in.

Kalra: There's no doubt that as the trial went through COVID-19, there's been underdosing in intravenous iron. We had, as most trials have done in COVID-19, a prespecified sensitivity analysis as well. The iron criteria to come in were very similar to the previous studies: transferrin saturation of less than 20% and ferritin less than 100 μg/L.

We were designing the study as far back as 2014 or 2015, so some further data come through, but patients could be randomized up to a ferritin of 400 μg/L if transferrin saturation was less than 20%.

Piña: Did you have a hemoglobin cutoff?

Kalra: Exclusion criteria of less than 9 g/dL. We didn't feel as though people would be comfortable not doing anything below that.

Piña: You'd be surprised how many people will be comfortable not doing anything.

Kalra: We had a higher cutoff of 13 g/dL for women and 14 g/dL for men, not because you don't get iron deficiency above that; it's just less prevalent and we didn't want screen failures.

Piña: It may be harder to randomize them at that point.

Kalra: Ejection fraction less than or equal to 45%.

Piña: A little bit of HFrEF, and a little bit of mrEF. Are you going to look at the separate groups?

Kalra: We've done some initial analysis of subgroups looking at tertiles of ejection fraction.

Piña: It might be interesting to see that. What were your results?

Kalra: For the overall trial, we found that the rate ratio was 0.82, so an 18% relative risk reduction.

Piña: Of the combined endpoint?

Kalra: Of the combined endpoint, yes, with a P value of.07.

Piña: You almost squeezed by.

Kalra: When we look at the COVID-19 data, by which we think the trial was markedly influenced, then the rate ratio is stronger. It's 0.76, so 24% relative risk reduction.

Piña: That's much more significant.

Kalra: The P value was.0447. There were numerically fewer heart failure hospitalizations and cardiovascular deaths, but neither of those, when you look at those individual endpoints, reached statistical significance.

Piña: How many patients got the whole thing? How many patients got only one visit? How did you divide that up?

Underdosing and the Body of Evidence

Kalra: We still have some data analysis to do. This was an intention-to-treat study, so very important and slightly different from AHF. Overall, 98% of people in the intravenous iron arm received at least one dose. Just below 80% of patients, over the trial duration — median follow-up, 2.7 years — had one or two doses.

What we're uncertain on is how many people have missed redosing. To know that, we needed them to have attended to have a blood test. We haven't got those tests.

Piña: When would redosing have happened?

Kalra: At 4 weeks, 4 months, and every 4 months thereafter, we rechecked the iron indices. If the ferritin was less than 100 μg/L or the transferrin saturation was less than 25%, we redosed.

Piña: You redosed.

Kalra: We chose a higher cutoff for the transferrin saturation on entry, given that our goal here was to try to maintain iron repletion. To me, it's counterintuitive; it's bad for you to wait for that to reoccur for substantial periods of time.

Piña: Exactly. Wow, this must have been a very tough trial to do during COVID-19.

Kalra: Absolutely. There were times in the UK when we had national lockdowns, where patients weren't permitted to come up. We had a superb vaccination development program and all of the research staff were pulled.

Piña: This was all going on at the same time.

Kalra: When we started the trial, we were anticipating that over a longer duration, patients' status might change and that some patients might not be able to attend hospital. Actually, we asked patients to consent to record linkage for hospitalizations and death.

Piña: You could at least check and see.

Kalra: To see what had happened, so 97% there.

Piña: That was really smart to do that. What would you tell our clinical audience that listens to this?

Kalra: I think the important thing here is how this builds on other data. This isn't a standalone trial. It's building on the data demonstrating well-being; certainly, we need double-blind trials to demonstrate that. I do believe that. AFFIRM-AHF, which was a study presented at AHA 2 years ago, looked at a specific group of people hospitalized, predischarged with ferric carboxymaltose, treated out to 24 weeks if required, and followed for a year. It showed very similar magnitudes of benefit with and without the COVID-19 sensitivity analysis.

I think that the totality of data now — I am very comfortable speaking to patients to say that iron deficiency, correcting it, there's a good chance it can make you feel better.

Piña: You'll feel better.

Kalra: Actually, we have increasing data demonstrating that it can reduce heart failure hospitalizations. For patients, they hate hospitalization.

Piña: They hate to be in the hospital — that's for sure.

Kalra: For healthcare providers, it's an expensive service.

Piña: Yes. For the system, it's expensive. Now, the US has been doing their own trials, including people at Duke.

Kalra: Absolutely.

Piña: How do you see that combining?

Kalra: The Duke team is doing a really important study called HEART-FID, hoping to present that next year. It will be numerically the largest number of patients with heart failure with reduced ejection fraction again. We still have missing data for the HFpEF group. Hopefully, we'll cement this even further in clinical practice. Perhaps pooling the data, looking at cardiovascular death, we may well get a—

Piña: You could pool it, but maybe even some kind of meta-analysis. I'm not a big fan of meta-analysis, but it will give you an idea where the points sit.

Kalra: There have been some questions raised after AFFIRM about whether patients with ischemic etiology have the most to gain.

Piña: It makes logical sense, but we still need to get after it and prove it.

Kalra: We do. I think my final message is that we've got to look for it to start with. If we don't look for it, we aren't going to do anything.

Piña: Yes, if you don't get those lab tests, you'll never find it.

Kalra: These are simple lab tests. They're available to everyone.

Piña: All the labs have them.

Kalra: Absolutely. I think patients will find this attractive as a different option to another tablet.

Piña: Yes. It says to them, "I can make you feel better if we can do this."

I want to congratulate you because that was a large amount of work. It's just amazing how in clinical trials, we just keep pushing along. Next time you do another analysis, come back and talk to us again. Thank you for being here.

I want to thank my audience. I hope you're taking some really good clinical points here, that if you don't measure it, you won't see it. Think about it when you have that patient in front of you.

I know I keep telling you all these other things you have to think about. This is a definite one while the work continues to accumulate, but they're all pointing in the right direction.

I'm Ileana Piña, signing off from the American Heart Association meeting.

Ileana L. Piña, MD, MPH, is a heart failure and cardiac transplantation expert. She serves as an advisor/consultant to the FDA's Center for Devices and Radiological Health and has been a volunteer for the American Heart Association since 1982. Originally from Havana, Cuba, she is passionate about enrolling more women and minorities in clinical trials. She also enjoys cooking and taking spin classes.

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