title: Iron deficiency in heart failure: the importance of a definition
Creators: name: Graham, Fraser John
Publisher: name: University of Glasgow
Year: 2023

description: Iron deficiency (ID) is present in around half of patients with heart failure, is associated with more advanced symptoms, worse quality of life and poorer outcomes and may be a risk factor for the development and progression of heart failure. However, how ID is defined by blood markers in heart failure remains a debate. Treatment of ID with intravenous iron in those with heart failure improves symptoms and quality of life, but it remains unclear if benefits extend to reducing hospitalisations for heart failure and cardiovascular death. These gaps in research will form the focus of my thesis. Through a detailed literature review, chapter one provides an overview of ID in heart failure including prevalence, diagnosis, associations with outcomes and effects of iron therapy in each phenotype of heart failure. Chapters three, four and five present results from retrospective analysis of a large prospective cohort of ambulatory patients with heart failure from the Hull LifeLab. Chapter six reports pooled data from available randomised clinical trials of patients with heart failure and serum iron deficiency assessing the efficacy of intravenous iron to reduce cardiovascular deaths and hospitalisations for heart failure. Chapter seven reports data obtained from the comprehensive Glasgow-wide SafeHaven, comprising primary and secondary care data of patients with and at risk of heart failure within Greater Glasgow and Clyde. Data from patients with heart failure of different phenotypes enrolled in the Hull LifeLab was analysed to determine how varying definitions of ID affected clinical characteristics, prevalence of ID and associations with mortality. Irrespective of how it is defined, ID is more common in women, in those with anaemia and in those with heart failure with preserved ejection fraction. A low serum iron (≤13μmol/L) and a low transferrin saturation (TSAT) (&lt;20%) were independently associated with higher mortality whereas definitions of ID using ferritin, including the current guideline directed definition of ID, were not. From the Hull LifeLab, 906 patients with heart failure who had two available blood results one year apart were investigated for incidence and recovery of ID and anaemia according to various definitions. Most patients with heart failure have or will develop ID over the course of one year, and a large proportion of these will also have anaemia. Those with persistent ID have a worse outcome compared to those in whom it resolves but anaemia is associated with higher mortality irrespective of whether it resolves or persists. Iron deficiency when defined by a low transferrin saturation (TSAT &lt;20%), or a low serum iron (≤13μmol/L), is more strongly associated with prognosis than the current guideline definition of ID. Transferrin saturation reflects both serum iron and serum transferrin. Further analysis of patients from the Hull LifeLab with confirmed heart failure was undertaken to analyse the relation between serum transferrin concentrations and other markers of serum iron status and mortality. Patient characteristics were also assessed according to quartiles of serum transferrin. Over one third of patients with low transferrin (Quartile 1; ≤2.3 g/L) and evidence of ID (low serum iron, low haemoglobin) had a normal TSAT (&gt;20%) meaning they would be falsely classified as being iron replete. Similarly, if transferrin is high (Quartile 4; ≥3.0g/L), TSAT is often &lt;20% even if serum iron is normal. Having a low transferrin is associated with higher mortality, particularly if accompanied by a low serum iron. A low serum iron is associated with higher mortality irrespective of serum transferrin or TSAT. From a meta-analysis comprising data from seven randomized trials, in 2,166 patients with heart failure and evidence of serum ID treated with intravenous (IV) iron or usual care, IV iron reduced the primary composite endpoint of cardiovascular deaths or hospitalisations for heart failure. This result was driven primarily by the reduction in hospitalisations for heart failure. From the Glasgow wide SafeHaven, 197,152 patients with, or at increased risk of heart failure, were investigated for trends and results of testing for ID and anaemia according to whether heart failure was prevalent, newly incident, or not present. Haemoglobin was widely tested but iron indices were not. Testing of iron indices was more common in those with lower haemoglobin concentrations and testing was related more closely to haemoglobin result than the presence or absence of heart failure. Very high, but particularly, very low levels of haemoglobin were associated with higher mortality and incident heart failure. Low serum iron and TSAT but not low ferritin was associated with higher mortality. These analyses emphasize the clinical importance, both locally and more widespread, of ID and anaemia in patients with heart failure. Improving awareness of the high incidence and prevalence, and the negative consequences of ID may change clinician behaviour in favour of testing for ID in those with heart failure. This is particularly pertinent as when treated with IV iron, hospitalisations for heart failure fall. However, current diagnostic criteria for both ID and anaemia are outdated and require revision. The research presented here suggests that a low serum iron (≤13μmol/L) may be the simplest, most prognostically important marker of ID in patients with heart failure. Current guideline definitions of ID may result in many patients who stand to gain from IV iron therapy missing out on its potential benefits. Future targeted prospective research and sub-group analysis of outcomes according to various definitions of ID in ongoing large clinical trials of iron repletion in patients with heart failure will help corroborate these findings.