HF Prognosis Differs According to Iron Deficiency Definition

Patrice Wendling

January 25, 2022

There's overall agreement that iron deficiency is prevalent and portends a worse prognosis in patients with heart failure (HF), regardless of ejection fraction or anemia. What remains unclear, however, is which of the many definitions of iron deficiency most closely aligns with adverse outcomes.

Iron deficiency (ID) differs in chronic inflammatory conditions, such as chronic HF, and is defined in international guidelines as a ferritin less than 100 ng/mL or ferritin 100 to 299 ng/mL with a transferrin saturation (TSAT) less than 20%.

A new study examining four definitions of ID in more than 4000 patients with HF revealed that TSAT and serum iron — but not guideline criteria — were independently associated with higher 5-year all-cause mortality, regardless of HF phenotype.

"The standard definition, the society guideline definition of iron deficiency, simply isn’t related to outcome at all. The lines for mortality are, more or less, superimposed," senior author Andrew L. Clark, MD, Hull University Teaching Hospital NHS Trust, United Kingdom, told theheart.org | Medscape Cardiology.

"So we do think, therefore, there's a need for a rethink as to what constitutes a definition of iron definition in people with heart failure."

The results were published in the February 1 issue of the Journal of the American College of Cardiology.

Previous studies have shown that guideline-defined ID is an independent predictor of mortality in chronic HF, but others have questioned its diagnostic and prognostic utility. A 2018 study using bone marrow iron staining as the gold standard, showed that a TSAT of 19.8% or less or serum iron 13 µmol/L or less, but not ferritin, identified HF patients at the highest risk for death.

A 2016 report from the Hull LifeLab cohort also showed that the highest quintiles of ferritin had the worst all-cause and cardiovascular (CV) mortality.

Commenting on the new results for theheart.org | Medscape Cardiology, Maria Rosa Costanzo, MD, Midwest Cardiovascular Institute, Naperville, Illinois, said, "the first clinical implication is that we should not use these guidelines to define iron deficiency."

"The fundamental problem with the definition is that ferritin is not a good marker of iron deficiency because ferritin is an inflammatory marker," she said. "So you could have high ferritin and still have iron deficiency because heart failure, like many other diseases, is an inflammatory state."

In the present analysis of 4422 patients referred to the Hull LifeLab clinic between 2001 and 2019, iron deficiency was defined using international guideline criteria, ferritin less than 100 ng/mL, TSAT less than 20%, and serum iron 13 µmol/L or less.

In line with previous studies, the prevalence of ID was high, ranging from 44% to 68%, depending on the definition. ID was more common in women and in those with more severe symptoms, anemia, or preserved ejection fraction.

Overall, 5-year mortality was 34.5% (median follow-up, 49 months). Unadjusted mortality was lowest for patients with a serum ferritin less than 100 ng/mL and a TSAT greater than 20% and was highest for those with serum ferritin above 100 ng/mL with a TSAT less than 20%.

Serum iron levels and TSAT were highly correlated with each other (r = 0.92; P < .001). "Serum iron is almost entirely transferrin bound, and therefore a close association between serum iron and TSAT is not surprising," note the authors, led by Gabriele Masini, MD, University of Brescia, Italy.

After multivariate adjustment, TSAT less than 20% (hazard ratio [HR], 1.27; P < .001) and serum iron 13 µmol/L or less (HR, 1.37; P < .001) were associated with greater all-cause mortality but not with CV mortality.

Serum ferritin less than 100 ng/mL tended to be associated with lower adjusted all-cause mortality (HR, 0.91; P = .09), whereas ferritin greater than 300 ng/mL was associated with lower all-cause (HR, 0.69, P < .001) and CV (HR, 0.78; P = .048).

No association was found for guideline ID criteria and all-cause or CV mortality. Among patients fulfilling guideline ID criteria with a TSAT less than 20% and a ferritin 100 to 299 ng/mL, the adjusted hazard ratio for 5-year mortality was 1.82.

A "New Iron Age"

Although 3011 (68%) patients met the guideline definition of ID, 32% of these patients had a TSAT of 20% or greater and serum iron above 13 µmol/L, noted Costanzo.

"In other words, 30% of the patients do not have true iron deficiency," she said. "If these patients are enrolled in trials of treatment for iron deficiency, they may spuriously reduce the efficacy of treatment."

Intravenous iron has been shown to improve exercise capacity and quality of life in iron-deficient patients with HF in a series of trials, including FAIR-HF, CONFIRM-HF, and EFFECT-HF, and to reduce HF hospitalizations by 21% in the recent AFFIRM-AF trial.

Although from a single center, Clark said their findings are robust and hoped they spur a reanalysis of the data from older IV iron trials, as well as the IRONMAN trial expected later this year in patients with TSAT less than 20% or ferritin less than 100 ng/L.

"I would very much like to encourage industry to take our study and run with it a little bit and see if we can actually persuade them to rerun studies, maybe even very small-scale studies with a couple hundred patients, to see what the signal is using our definition of iron deficiency and seeing if we get a more striking immediate consequence from IV iron treatment as a result," he said. "Because we think that we’ve now been able to define a group of patients whose iron deficiency is giving them a very poor prognosis and they, therefore, have much more to gain."

In an accompanying editorial, Costanzo and coauthor James Januzzi, MD, Massachusetts General Hospital, Harvard University, Boston, also call for further research into better ID definitions and treatments.

"Diagnostically, soluble transferrin receptor levels may have the strongest correlation with the gold standard of bone marrow iron deficit, whereas new treatments, such as blockade of hepcidin, a key modulator of iron absorption and distribution, may emerge as an effective treatment for both absolute and functional ID."

"Ultimately, the study by Masini et al places us squarely in a new iron age and underscores the great need for more investigation of the pathophysiology, clinical consequences, and treatment of iron deficiency in all patients with HF," she concludes.

Masini reports having no relevant financial relationships. Coauthor disclosures are listed in the paper. Januzzi is supported by the Hutter Family Professorship; is a trustee of the American College of Cardiology; is a board member of Imbria Pharmaceuticals; has received grant support from Abbott Diagnostics, Applied Therapeutics, Innolife, and Novartis; has received consulting income from Abbott Diagnostics, Boehringer Ingelheim, Janssen, Novartis, and Roche Diagnostics; and participates in clinical endpoint committees/data safety monitoring boards for AbbVie, Siemens, Takeda, and Vifor. Costanzo is a member of the board of directors for Nuwellis; is a consultant for Boehringer Ingelheim, V-Wave, and Nuwellis; and has received grant support from Novartis, Bayer, V-Wave, Nuwellis, and Abbott.

J Am Coll Cardiol. 2022;79:341-351, 352-354. Full text, Editorial

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