Rationale and design of the IRON-AF study: a double-blind, randomised, placebo-controlled study to assess the effect of intravenous ferric carboxymaltose in patients with atrial fibrillation and iron deficiency

Tu, Samuel J.; Elliott, Adrian D.; Hanna‐Rivero, Nicole; Gallagher, Celine; Mishima, Ricardo S.; Lyrtzis, Ellen; Wlochowicz, Danielle; Clarke, Nicholas; Roberts‐Thomson, Kurt C.; Stokes, Michael B.; Emami, Mehrdad; Lau, Dennis H.; Sanders, Prashanthan; Wong, Christopher X.

doi:10.1136/bmjopen-2020-047642

Cited by 10 publications

(11 citation statements)

References 37 publications

(38 reference statements)

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“… 97 Based on the above-mentioned benefits in terms of improvement in functional status and quality of life which have been linked with FCM use in patients with HF, and being both functional status and quality of life impaired in patients with AF, the IRON-AF iron aims to randomize at least 84 patients with AF and ID to assess the effect of iron repletion with FCM vs. placebo in terms of change in peak VO 2 from baseline to Week 12 as measured by cardiopulmonary exercise test, with quality of life, 6MWD, NYHA class, and AF disease burden scores as secondary outcomes. 98 Currently, there is no indication to treat ID in patients with AF independently of anaemia.…”

Section: Introductionmentioning

confidence: 99%

Iron deficiency and cardiovascular disease

Savarese

Haehling

Butler

et al. 2022

European Heart Journal

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Iron deficiency (ID) is common in patients with cardiovascular disease. Up to 60% of patients with coronary artery disease, and an even higher proportion of those with heart failure (HF) or pulmonary hypertension have ID; the evidence for cerebrovascular disease, aortic stenosis and atrial fibrillation is less robust. The prevalence of ID increases with the severity of cardiac and renal dysfunction and is probably more common amongst women. Insufficient dietary iron, reduced iron absorption due to increases in hepcidin secondary to the low-grade inflammation associated with atherosclerosis and congestion or reduced gastric acidity, and increased blood loss due to anti-thrombotic therapy or gastro-intestinal or renal disease may all cause ID. For older people in the general population and patients with HF with reduced ejection fraction (HFrEF), both anaemia and ID are associated with a poor prognosis; each may confer independent risk. There is growing evidence that ID is an important therapeutic target for patients with HFrEF, even if they do not have anaemia. Whether this is also true for other HF phenotypes or patients with cardiovascular disease in general is currently unknown. Randomized trials showed that intravenous ferric carboxymaltose improved symptoms, health-related quality of life and exercise capacity and reduced hospitalizations for worsening HF in patients with HFrEF and mildly reduced ejection fraction (<50%). Since ID is easy to treat and is effective for patients with HFrEF, such patients should be investigated for possible ID. This recommendation may extend to other populations in the light of evidence from future trials.

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Section: Introductionmentioning

confidence: 99%

Iron deficiency and cardiovascular disease

Savarese

Haehling

Butler

et al. 2022

European Heart Journal

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“…The prevalence of ID is high in patients with HF, 1–3 acute coronary syndromes, 14 atrial fibrillation 15 and valvular heart disease 16 . ID is a well‐established marker of adverse outcomes in the HF population and intravenous iron supplementation improves quality of life and exercise capacity 1–3,17 .…”

Section: Discussionmentioning

confidence: 99%

Prognostic value of three iron deficiency definitions in patients with advanced heart failure

Papadopoulou,

Reinhold,

Grüner‐Hegge

et al. 2023

European J of Heart Fail

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AimsThere is uncertainty about the definition of iron deficiency (ID) and the association between ID and prognosis in patients with advanced heart failure. We evaluated three definitions of ID in patients referred for heart transplantation.Methods and resultsConsecutive patients assessed for heart transplantation at a single UK centre between January 2010 and May 2022 were included. ID was defined as (1) serum ferritin concentration of <100 ng/ml, or 100–299 ng/ml with transferrin saturation <20% (guideline definition), (2) serum iron concentration ≤13 μmol/L, or (3) transferrin saturation <20%. The primary outcome measure was a composite of all‐cause mortality, urgent heart transplantation or need for mechanical circulatory support. Overall, 801 patients were included, and the prevalence of ID was 39–55% depending on the definition used. ID, defined by either serum iron or transferrin saturation, was an independent predictor of the primary outcome measure (hazard ratio [HR] 1.532, 95% confidence interval [CI] 1.264–1.944, and HR 1.595, 95% CI 1.323–2.033, respectively), but the same association was not seen with the guideline definition of ID (HR 1.085, 95% CI 0.8827–1.333). These findings were robust in multivariable Cox regression analysis. ID, by all definitions, was associated with lower 6‐min walk distance, lower peak oxygen consumption, higher intra‐cardiac filling pressures and lower cardiac output.ConclusionsIron deficiency, when defined by serum iron concentration or transferrin saturation, was associated with increased frequency of adverse clinical outcomes in patients with advanced heart failure. The same association was not seen with guideline definition of ID.

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“…In patients with confirmed iron deficiency, iron supplementation seems to be a simple and an efficient way for the prevention of AF. 68 Ferroptosis is a form of oxidative cell death characterized by the accumulation of iron and the generation of ROS. Glutathione peroxidase 4 (GPX4) is the only known antioxidant enzyme that directly reduces lipid peroxidation from ROS.…”

Section: Therapeutic Implicationsmentioning

confidence: 99%

“…Therefore, iron metabolism has been targeted for the development of new AF therapeutic agents. In patients with confirmed iron deficiency, iron supplementation seems to be a simple and an efficient way for the prevention of AF 68 . Contrastingly, iron chelation therapy exerts the antiarrhythmic effects in patients with iron accumulation.…”

Section: Therapeutic Implicationsmentioning

confidence: 99%

Iron and atrial fibrillation: A review

Liu

Yang

et al. 2023

Pacing Clinical Electrophis

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Atrial fibrillation (AF), one of the most common arrhythmias in clinical practice, is classified into paroxysmal, persistent, and permanent AF according to its duration. The development of AF is associated with increased cardiovascular morbidity and mortality. However, the exact etiology of this disease remains poorly understood. Recent studies found disorders of iron metabolism might be involved in the progression of AF. Abnormal iron metabolism in cardiomyocytes provides arrhythmogenic substrates through a variety of mechanisms, including calcium mishandling, ion channel remodeling, and oxidative stress overaction. Interestingly, in AF patients with iron overload, interventions on iron metabolism, such as iron chelators and ferroptosis inhibitors, has been shown to prevent AF via reducing ferroptosis. Herein, we review the possible mechanisms, consequences, and therapeutic implications of altered atrial iron handling for AF pathophysiology.

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Rationale and design of the IRON-AF study: a double-blind, randomised, placebo-controlled study to assess the effect of intravenous ferric carboxymaltose in patients with atrial fibrillation and iron deficiency

Cited by 10 publications

References 37 publications

Iron deficiency and cardiovascular disease

Iron deficiency and cardiovascular disease

Prognostic value of three iron deficiency definitions in patients with advanced heart failure

Iron and atrial fibrillation: A review

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