Meet the Expert: Dr Abdullahi Mohamed on Iron Deficiency in Patients with HF

Dr Abdullahi Mohamed (Herlev-Gentofte Hospital, Denmark) discusses his research on iron deficiency in patients with heart failure (HF), particularly focusing on the varying prevalence of iron deficiency and its impact on patient outcomes based on different diagnostic criteria. His study, which analysed data from over 9,000 patients with new-onset HF in the Danish Heart Failure Registry, found that iron deficiency defined by transferrin saturation (TSAT) <20% or serum iron ≤13 μmol/L is strongly associated with increased mortality and first hospitalisation in patients with chronic heart failure, regardless of anaemia status [1]. In contrast, the current European Society of Cardiology (ESC) Guidelines for iron deficiency were found to be less predictive of adverse outcomes, highlighting the need to reassess these criteria in clinical practice. Dr Mohamed's research aims to redefine iron deficiency to improve the management and prognosis of HF.

“For the last year and a half, I have been researching iron deficiency in patients with HF. At the time, iron deficiency in HF was a relatively new and hyped topic, seen as a possible new treatment on top of the already established, evidence-based medical therapies for HF. We started by looking at the definition of iron deficiency and found it somewhat arbitrary. The definition was primarily based on criteria used for patients with chronic kidney disease, who were thought to be a similar patient group due to shared characteristics, like systemic inflammation. This definition was then used in several trials, even though it hadn’t been validated in the way you would typically expect—for instance, through bone marrow staining to confirm iron deficiency. Instead, they used surrogate biomarkers in the blood to infer low iron levels in the bone marrow.”

And biomarkers in the blood are not reliable surrogates?

“Exactly, it’s not a good surrogate. The gold standard would be to check bone marrow for every patient, but that’s not feasible, so we use biomarkers. But before spending so much money on these trials, you’d expect that they would have ensured the definition was accurate. That’s why we examined it further.”

Why are patients with HF at increased risk for iron deficiency?

“There are several reasons. One of them is that these patients are often on blood thinners, which can cause small, unnoticed bleeding in the gut. Over time, this can lead to iron deficiency. Another major reason found in the literature is low-grade inflammation, which increases levels of a protein called hepcidin. Hepcidin rises with inflammation and traps iron in enterocytes and hepatocytes, making it unavailable for the body to use.”

Why is it important to treat comorbidities like iron deficiency in comprehensive HF therapy?

“HF patients usually present with a bundle of comorbidities, and iron deficiency is just one of many. We know that patients with iron deficiency who receive treatment often have a better quality of life—they can do more, walk longer distances, and generally have more energy. Treating iron deficiency also reduces hospitalisations for HF. It’s primarily about improving quality of life.”

What are the proposed new definitions for iron deficiency?

“We looked at 4 different definitions, including the ESC Guidelines. One study tried to validate these definitions using bone marrow staining, which is the gold standard. They found that patients with transferrin saturation under 20% or serum iron levels of 13 micromoles per litre or less were more likely to have low iron in the bone marrow. These patients also had a higher risk of all-cause mortality, whereas the ESC Guidelines didn’t show this association. However, the ESC Guidelines haven’t changed, possibly because the study I mentioned had a small sample size and larger trials like IRONMAN still use the old criteria.”

Is there a difference across the ejection fraction spectrum in how patients respond or should be defined?

“The guidelines don’t specify different criteria for the 3 HF types; they use the same definition across the board. However, they only recommend treatment for patients with reduced or mildly reduced ejection fraction because these were the groups included in the trials.”

So, patients with HFpEF don’t have any specific recommendations at this point?

“Correct, they don’t have their own treatment guidelines yet.”

In your research, you found that the previous ESC Guidelines might not be sufficient for defining the at-risk patient population. If you applied more accurate criteria, like in the IRONMAN trial, do you think the results would have been different?

“I believe so. In the IRONMAN trial, a sub-analysis showed that patients with transferrin saturation (TSAT) below 20% had a higher risk reduction of their primary endpoint (hospitalisation for HF or cardiovascular death) compared with patients with TSAT above 20% and ferritin <100 ng/ml. This suggests that using different criteria might lead to better results. Many trials only show a reduction in hospitalisations, not mortality, and I think that might be because the wrong criteria are being used, excluding patients who could benefit.”

So, there might be an underestimation?

“Yes, I believe there are underestimations. In our study, we found that 26% of patients with serum iron levels at or below 13 micromoles per litre didn’t meet the ESC criteria for iron deficiency. Additionally, 15.5% of patients with TSAT under 20% also didn’t meet the diagnostic criteria.

This means many patients who could potentially benefit from IV iron are being left out of these trials. The big trials like IRONMAN used the ESC Guidelines, which means that in our population, over a quarter of patients would have been excluded from the trials. So, there’s significant potential for improvement.

We believe that serum iron levels at or below 13 micromoles per litre might be the best definition because it’s not affected by inflammation, unlike the other parameters, including TSAT.”

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   1. Mohamed AA, et al. Impact of various iron deficiency definitions on mortality risk in chronic heart failure across the spectrum of left ventricular ejection fraction spectrum. Session “Collateral damage in heart failure: comorbidities and their treatment”, ESC Congress 2024, 30 Aug–02 Sept, London, UK.

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Posted on 9 September 202425 September 2024