New definition for iron deficiency in CV disease proposed – Medscape

A cohort study of patients with pulmonary hypertension (PH) has questioned the guideline definition of iron deficiency and the criteria used to identify and potentially treat it, with implications that could extend to cardiovascular disease in general.

In the study involving more than 900 patients with PH, researchers at seven U.S. centers determined the prevalence of iron deficiency using two separate definitions and assessed its association with functional measures and quality of life (QoL) scores.

A definition of iron deficiency conventionally used in heart failure (HF) – ferritin <100 g/ml or 100-299 ng/ml with transferrin saturation (TSAT) <20% - failed to distinguish between patients with reduced peak oxygen consumption (peakVO2), 6-minute walk test (6MWT) results and QoL scores on the 36-item Short Form Survey (SF-36).

But an alternative definition for iron deficiency, simply a TSAT <21%, predicted such patients with reduced peak VO2, 6MWT and QoL. It was also associated with an increased risk of mortality. The study was published in the June 7 issue of the European heart journal.

“A low TSAT, less than 21%, is key in the pathophysiology of iron deficiency in pulmonary hypertension” and is associated with those important clinical and functional features, lead author Pieter Martens MD, PhD, told | Medscape Cardiology. The study “underscores the importance of these criteria in future intervention studies in testing iron therapies for pulmonary hypertension.”

A broader implication is that “we need to review how we define iron deficiency in heart failure and cardiovascular disease in general, and how we select patients for iron therapies,” said Martens of the Cleveland Clinic’s Heart, Vascular & Thoracic Institute, Cleveland. , Ohio.

The role of iron in pulmonary vascular disease

“Iron deficiency is associated with an energetic deficit, especially in energy-demanding tissue, leading to early skeletal muscle acidification and reduced contractile reserve of the left and right ventricle (RV) during exercise,” the published report states. It can lead to “maladaptive RV remodeling,” which is a “characteristic feature” that predicts morbidity and mortality in patients with pulmonary vascular disease (PVD).

Some studies have suggested that iron deficiency is a common comorbidity in patients with PVD, their prevalence estimates vary widely, due in part to the “absence of a uniform definition,” the authors write.

Martens said the current study was conducted in part in response to the increasingly common observation that the HF-associated definition of iron deficiency “has limitations.” However, “without validation in the field of pulmonary hypertension, the 2022 pulmonary hypertension guidelines endorse this definition.”

Since iron deficiency is a causative risk factor for HF progression, Martens added, the HF field “has taught us the importance of using validated definitions for iron deficiency when selecting patients for iron treatment in randomized controlled trials.”

In addition, some evidence suggests that iron deficiency may be associated with reduced exercise capacity and quality of life in patients with PVD by some definitions, associations that have not been confirmed in large studies, the report notes.

Therefore, it continues, the study sought to “determine and validate” the optimal definition of iron deficiency in patients with PVD; document its prevalence; and examine associations between iron deficiency and exercise capacity, QoL, and cardiac and pulmonary vascular remodeling.

Evaluating definitions of iron deficiency

The prospective study, called PVDOMICS, included 1195 subjects with available iron levels. After excluding 38 patients with sarcoidosis, myeloproliferative disease, or hemoglobinopathy, 693 patients remained with “overt” PH, 225 with milder PH serving as PVD comparators, and 90 by age, gender, race/ethnicity. “healthy” adults who served as controls.

According to the conventional HF definition of iron deficiency, i.e. ferritin 100-299 ng/ml and TSAT <20%, prevalences were 74% in patients with overt PH and 72% in patients "across the PVD spectrum".

But by that definition, iron-deficient and non-iron-deficient patients did not differ significantly in peak VO2, 6MWT distance, or SF-36 physical component scores.

In contrast, patients meeting the alternative iron deficiency definition of TSAT <21% showed significantly lower functional and QoL measures compared to those with TSAT ≥21%.

Table. Functional and quality of life findings in patients with TSAT <21% vs. ≥21%


Absolute average difference

P value

PeakVO2 (ml/kg/min)


< .001

6MWT (metres)


< .001

SF-36 physical component score


< .001

The group with TSAT <21% also showed significantly more RV remodeling on cardiac MRI compared to those with TSAT ≥21%, but their invasively measured pulmonary vascular resistance was similar.

Of note, those with TSAT <21% also showed significantly increased all-cause mortality (hazard ratio [HR], 1.63; 95% CI, 1.13 - 2.34; P = .009) after adjustment for age, sex, hemoglobin and natriuretic peptide.

“Proper validation of the definition of iron deficiency is important for prognosis,” states the published report, “but also for providing a working definition that can be used to identify suitable patients for inclusion in randomized controlled trials” of iron deficiency drugs .

In addition, the finding that TSAT <21% indicates patients with reduced functional and exercise capacity is "consistent with more recent heart failure studies" suggesting that "functional abnormalities and adverse cardiac remodeling are worse in patients with low TSAT." The report indeed states that such treatment effects were "most compelling" in HF trials.

Broader implications

An accompanying editorial agrees that the study’s implications go far beyond PH. It highlights that iron deficiency is common in PH, when such PH “is not substantially different from the problem in patients with heart failure, chronic kidney disease and cardiovascular disease in general,” Editor in Chief John GF Cleland, MD, PhD, University of Glasgow, United Kingdom, said | Medscape Cardiology. “It’s also common as people get older, even in people without these diseases.”

Cleland said the anemia definition currently used in cardiovascular research and practice is based on a hemoglobin concentration below the 5th percentile of age and sex in mostly young, healthy people, and not on its association with clinical outcomes.

“We recently analyzed data from a large population in the UK with a wide range of cardiovascular disease and found that unless the anemia is severe, [other] markers of iron deficiency are usually not measured,” he said. Low hemoglobin and TSAT, but not low ferritin levels, are associated with a worse prognosis.

Cleland agreed that the HF-oriented definition is “bad,” with profound implications for conducting clinical trials. may be harmed by IV iron. Inclusion of such patients may also “weaken” any benefit that emerges and render the outcome inaccurate.

But if the definition of iron deficiency lacks sensitivity, “then in clinical practice many patients with iron deficiency may be denied simple and effective treatment.”

Measuring serum iron can potentially be useful, but it’s not usually done in randomized trials “mainly because taking an iron tablet can give a temporary ‘blip’ in serum iron,” Cleland said. “So TSAT is a reasonable compromise.” He said he “looks forward” to any further data on serum iron as a way to assess iron deficiency and anemia.

Half full versus half empty

Cleland likened the question of who to treat with iron supplementation as a “glass half full versus half empty” clinical dilemma. is to withhold iron from everyone unless there is evidence that they are iron deficient.

Recent evidence from the IRONMAN trial suggested that the patients with HF who received intravenous iron were less likely to be hospitalized for infections, particularly COVID-19, than a usual care group. The treatment can also help reduce frailty.

“So should we offer IV iron specifically to people who are considered iron deficient, or should we make sure everyone over age 70 gets iron supplements?” Cleland mused rhetorically. Warning, he added, iron supplements might be harmful if not needed.

Cleland suggested “focusing on iron-deficient people for now, but exploring the possibility that we are being overly restrictive and should be giving iron to a much wider population.” However, that course would require large population-based studies.

“We need more experience,” Cleland said, “to make sure the benefits outweigh the risks before we can just give everyone iron.”

Martens has received consultancy fees from AstraZeneca, Abbott, Bayer, Boehringer Ingelheim, Daiichi Sankyo, Novartis, Novo Nordisk and Vifor Pharma. Cleland declares subsidy support, travel support and personal fees from Pharmacosmos and Vifor. Disclosures for other authors are in the published report and editorial.

Eur Hart J, 2023. Published June 7. Full text, editor

Batya Swift Yasgur, MA, LSW is a freelance writer with a consulting practice in Teaneck, New Jersey. She is a regular contributor to numerous medical publications, including Medscape and WebMD, and is the author of several consumer-focused health books andBehind the Burqa: Our Life in Afghanistan and How We Escaped to Freedom(the memoirs of two brave Afghan sisters who told her their story).

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