COMMENTARY

Iron Therapy Improves HF, But Not by Improving Anemia

Ileana Piña, MD, MPH; Darlington O. Okonko, MBBS, MRCP, PhD

Disclosures

May 03, 2018

Ileana L. Piña, MD, MPH: Hello. I'm Ileana Piña from Montefiore Medical Center in the Bronx, New York. This is my blog. I'm here at the 67th meeting of the American College of Cardiology (ACC), where the presentations have been absolutely outstanding.

ACC is moving quickly into the digital age, and their website is full of educational stuff for clinicians and research scientists. The presentations are also on the website, and I think you will really enjoy them.

Anemia in Heart Failure Is Common

I've spoken to you before about how common anemia in heart failure (HF) is. A lot of my patients in the Bronx have anemia. My residents look at it as if it were normal, and I keep telling them, "No, it's not normal. A male with a hemoglobin of 10 g/dL is not normal. A woman with a hemoglobin of 8 g/dL is not normal." We're always looking to see what kind of anemia it is. Is it anemia of chronic disease? We find a lot of iron deficiency. We put them on oral iron, and it's not being absorbed, and the hemoglobin does not change. I can tell you that the heart does not like low hemoglobins.

I want to welcome Dr Darlington Okonko, from King's College in London. He had a very interesting abstract concerning iron in HF. Tell us a little bit about your FERRIC-HF studies.

Background of FERRIC-HF2

Darlington O. Okonko, MBBS, MRCP, PhD: Thank you very much, Dr Pina. The first one was called FERRIC-HF.[1] We demonstrated that if you replete iron levels with intravenous (IV) iron in patients with HF, you produce a dramatic improvement in symptoms and exercise performance as measured with a peak VO2.

This was subsequently corroborated in the larger FAIR-HF study,[2] which was published in the New England Journal of Medicine and showed dramatic improvements in the 6-minute walk test. The surprising thing about both studies was that the hemoglobin response to IV iron was surprisingly small.

The point of the FERRIC-HF II study was to try to work out why IV iron repletion caused dramatic improvements in exercise performance yet a low hemoglobin response.

Piña: Why do you think that is?

Okonko: It's really unclear. The point of the FERRIC-HF II study[3] was to try to work out why IV iron repletion caused dramatic improvements in exercise performance yet a low hemoglobin response. The ability to exercise is based on the ability of muscles to generate adenosine triphosphate (ATP), which is the energy currency used by the cell to do muscle contraction. Because iron is incorporated in many of these mitochondrial enzymes and helps them generate ATP, we hypothesized that IV iron repletion might be augmenting exercise performance via mechanisms unrelated to hemoglobin and may be related to augmentation of mitochondrial enzymes.

Measuring ATP Is Very Difficult

Piña: How do you measure ATP?

Okonko: ATP is very difficult to measure. There are two ways to assess energetics in living humans. One is to take a skeletal muscle biopsy, and the other is a technique called 31 phosphorus magnetic resonance spectroscopy. This is a magnetic resonance-based technique. You get the patient to exercise against resistance; and every 2 seconds, the phosphorus coil measures phosphocreatine and ATP in the muscle. ATP levels in exercising muscle stay relatively constant throughout exercise and recovery; the only thing that changes is the phosphocreatine level. Phosphocreatine is donating phosphate groups to adenosine diphosphate to regenerate ATP. Because ATP levels are relatively constant, you can't really use them to assess energetics.

The best way to assess it is to look at the ability of phosphocreatine to regenerate ATP. Because phosphocreatine levels drop during exercise and recover once you stop exercising, and the rate of recovery is completely dependent on the ability of the mitochondria to generate phosphocreatine in the process of oxidative phosphorylation, you can look at the kinetics (ie, the rate at which phosphocreatine is returning back to baseline after you stop exercising).

Piña: How interesting. I studied exercise post-oxygen consumption for a while, and I never thought of that post-exercise. Patients who have poor peak VO2s and are very sick also recover terribly. Maybe there is something there. How did you do the resistance?

Novel Exercise Technique

Okonko: Everything has to be MRI compatible; that's the real difficulty with this technique. We utilized a customized weight using barium salts. Barium salts are MRI compatible, yet they have sufficient density, so you can put a substantial load on the patient.

This is done in the magnet, so the patient's ankle is in the isocenter of the magnet.

Piña: How do you do that? Do you put a weight on the leg?

Okonko: The barium salts are placed in a customized bag that we made ourselves. The bag is then strapped around the dominant ankle of the patient. The phosphorus coil, which measures phosphocreatine, is then strapped on the patient's dominant quadriceps.

Piña: The exercise is a quadriceps exercise, knee kicking?

Okonko: That's right. This is done in the magnet, so the patient's ankle is in the isocenter of the magnet. They exercise for 1 minute and then rest for 5 minutes. This can be repeated.

Piña: When do you get the final measurement with the phosphorus coil?

Okonko: The phosphorus coil is amazing. It measures phosphocreatine, ATP, and inorganic phosphate every 2 seconds during exercise and recovery. You can draw the curve of the fall in phosphocreatine during exercise and its recovery.

Population Characteristics

Piña: Who were the patients in the study?

Okonko: The patients had symptomatic HF with New York Heart Association (NYHA) Class 2 or 3 and left ventricular ejection fraction ≤45%.

Piña: You did the HFrEF (HF with reduced ejection fraction) group with a little bit of midrange HF in there.

Okonko: They had to be iron deficient as defined by the FERRIC-HF criteria of ferritin <100 ng/mL or 100-300 ng/mL with transferrin saturations <20%. Obviously, they had to have no contraindications to MRI scanning.

They had to be on optimal medical therapy for at least 4 weeks with no dose changes. On average, 86% of patients were on an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB), 87% were on a beta blocker, and I think 65% were on aldosterone blockade.

Piña: That is incredibly good. Were these your patients from clinic?

Okonko: These were patients from my HF clinic and some from Professor McDonald's clinic. They are amazing because the study was extremely taxing for the patients with two muscle biopsies, the 31-phosphorus, cardiopulmonary exercise testing (treadmill exercise testing), and 6-minute walk test.

Piña: What was the peak VO2 of the group on average?

Okonko: On average, it was 15.3 mL/kg/min.

Piña: In HF-ACTION, it was about 14.9 mL/kg/min.[4] Your group was maybe a little less sick. How many patients?

Okonko: There were 40 patients in total.

Iron Isomaltoside 1000

Piña: Tell us about the iron administration.

Okonko: We utilize a relatively newer formulation called iron isomaltoside 1000. This is marketed as Monofer®, and the 1000 essentially refers to the size of the sugar molecule that is used to conjugate iron. In the old days, IV iron always had a bad name because it was associated with anaphylactic reactions.

Piña: Patients would say it was painful.

Okonko: This infusion is comfortable for patients. We had three adverse events in the IV iron-treated group, and they were relatively mild reactions. The control group, which received normal saline, had one reaction. The key thing about this study was that we gave the total repletion dose at a single sitting over 30- to 60-minute infusions depending on the mL/kg dose involved.

Then we did the testing 2 weeks after giving the infusion. We deliberately went for a short reassessment time, largely because we wanted to minimize attribution of the study results to skeletal muscle adaptation to exercise. We wanted to get that out of the equation and just see that results were truly driven from the iron and not from exercising more.

Piña: What did you find?

This magnitude of benefit is comparable to what is seen with 3-6 months of exercise training in heart failure.

Why No Increase in Hemoglobin?

Okonko: Of note, we found that iron isomaltoside improved phosphocreatine recovery half time, which implies that it improves skeletal muscle mitochondrial function by about 7 seconds. This magnitude of benefit is comparable to what is seen with 3-6 months of exercise training in HF.

Again, we compared it with studies done previously by Professor Coats[5] looking at exercise training on 31-phosphorus.

Piña: Donna Mancini[6] did some work on that years ago. What happened to the hemoglobin?

Okonko: The hemoglobin was no different.

Piña: Where is this iron going? I keep thinking it should be binding.

Okonko: I think, conventionally, people have always thought that iron equates with hemoglobin—that is, iron is the same thing as hemoglobin. A lot of animal studies have clearly shown that iron has important beneficial effects beyond the hemoglobin. This is what we targeted to show that actually iron had effects on energetics irrespective of what was happening to the hemoglobin changes.

Piña: Are you going to follow these patients longer term to see what does happen?

Okonko: Because they are in my clinic, I see most of them now. Some of them I have seen a year down the line. Still, the hemoglobin has not changed.

Piña: Have you given them any more iron?

Okonko: Those who were randomly assigned to placebo got IV iron after the placebo. Patients who got IV iron are part of our routine workup, so we check on their status every 3 months. If they meet the criteria for IV iron, they will get it again.

Piña: I wonder how much better my patients would feel if their hemoglobins were better?

Okonko: This is interesting because I think that the target should not be the hemoglobin. This is where all of the studies point.

[D]espite the fact that there was no change in hemoglobin, skeletal muscle energetics were improved, and patients felt better.

Piña: That's the way we think.

Okonko: That's the problem. The point of this trial was to show that despite the fact that there was no change in hemoglobin, skeletal muscle energetics were improved, and patients felt better. The surprising thing was that NYHA class was significantly improved even at 2 weeks.

Piña: That is an early improvement that we often don't accomplish with the drugs. This is fascinating.

Future Directions

Piña: Where is it going to be published?

Okonko: There are lots of discussions, and we are trying to come up with the best strategy. There are a lot of data. We still have not presented the skeletal muscle molecular dataset, and I think there will be too much to try to put them all together.

Piña: You have a lot more analysis to do yet. I would look at the drugs too. ACE inhibitors do draw up hemoglobin, which a lot of people do not know. It would be interesting to see who is on an ARB and who is on an ACE inhibitor.

This is a fascinating study, and it gives us a lot to think about. There are large iron trials going on right now, so it's going to be very interesting.

Okonko: I believe that there are [four] survival trials in iron: IRONMAN in the United Kingdom; FAIR-HF2, which is run by Professor Anker; HEART-FID in the United States; [and Affirm-AHF in acute HF].

Piña: Fascinating. We need to have you back again so that you can tell us more about your work.

Okonko: Thank you; I'd love to come back.

Piña: I want to thank our audience. I hope that these points will help you take care of your patients—that is what we want to do. We want to raise interest and educate. Thank you for joining me today. From Orlando, Florida, have a great day.

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