A serum ferritin level <15 to 20 μg/L historically identified patients who had absent bone marrow iron stores, but serum ferritin levels are distorted by the systemic inflammatory states seen in patients with chronic kidney disease or heart failure. As a result, nearly 25 years ago, the diagnostic ferritin threshold was increased 5- to 20-fold in patients with chronic kidney disease (ie, iron deficiency was identified if the serum ferritin level was <100 μg/L, regardless of transferrin saturation [TSAT], or 100 to 299 μg/L if TSAT was <20%). This guidance was motivated not by the findings of studies of total body or tissue iron depletion, but by a desire to encourage the use of iron supplements to potentiate the response to erythropoiesis-stimulating agents in patients with renal anemia. However, in patients with heart failure, this definition does not reliably identify patients with an absolute or functional iron-deficiency state, and it includes individuals with TSATs (≥20%) and serum ferritin levels in the normal range (20–100 mg/L) who are not iron deficient, have an excellent prognosis, and do not respond favorably to iron therapy. Furthermore, serum ferritin levels may be distorted by the use of both neprilysin and sodium-glucose cotransporter 2 inhibitors, both of which may act to mobilize endogenous iron stores. The most evidence-based and trial-tested definition of iron deficiency is the presence of hypoferremia, as reflected by as a TSAT <20%. These hypoferremic patients are generally iron deficient on bone marrow examination, and after intravenous iron therapy, they exhibit an improvement in exercise tolerance and functional capacity (when meaningfully impaired) and show the most marked reduction (ie, 20%–30%) in the risk of cardiovascular death or total heart failure hospitalizations. Therefore, we propose that the current ferritin-driven definition of iron deficiency in heart failure should be abandoned and that a definition based on hypoferremia (TSAT <20%) should be adopted.

Anemia is a predictor of adverse outcomes in acute myocardial infarction. We studied the relationship of hemoglobin, or its change over time, and outcomes in patients with stable coronary artery disease. The ProspeCtive observational LongitudinAl RegIstry oF patients with stable coronary arterY disease is a prospective, cohort study of outpatients with stable coronary artery disease (32,901 in 45 countries 2009-2010): 21,829 with baseline hemoglobin levels. They were divided into hemoglobin quintiles and anemia status (anemic or normal at baseline/follow-up: normal/normal; anemic/normal; normal/anemic; anemic/anemic. All-cause mortality, cardiovascular events, and major bleeding at 4-year follow-up were assessed. Low baseline hemoglobin was an independent predictor of all-cause, cardiovascular, and noncardiovascular mortality, the composite of cardiovascular death/myocardial infarction or stroke and major bleeds (all P <.001; unadjusted models). Anemia at follow-up was independently associated with all-cause mortality (hazard ratio [HR], 1.90; 95% confidence interval [CI], 1.55-2.33 for anemic/anemic; 1.87; 1.54-2.28 for normal/anemic; both P <.001), noncardiovascular mortality (P <.001), and cardiovascular mortality (P = .001). Patients whose baseline anemia normalized (anemic/normal) were not at increased risk of death (HR, 1.02; 95% CI, 0.77-1.35), although the risk of major bleeding was greater (HR, 2.06; 95% CI, 1.23-3.44; P = .013) than in those with normal hemoglobin throughout. Sensitivity analyses excluding patients with heart failure and chronic kidney disease at baseline yielded qualitatively similar results. In this large population with stable coronary artery disease, low hemoglobin was an independent predictor of mortality, cardiovascular events, and major bleeds. Persisting or new-onset anemia is a powerful predictor of cardiovascular and noncardiovascular mortality.

What is the relationship between blood tests for iron deficiency, including anaemia, and the response to intravenous iron in patients with heart failure? In the IRONMAN trial, 1137 patients with heart failure, ejection fraction ≤ 45%, and either serum ferritin < 100 µg/L or transferrin saturation (TSAT) < 20% were randomized to intravenous ferric derisomaltose (FDI) or usual care. Relationships were investigated between baseline anaemia severity, ferritin and TSAT, to changes in haemoglobin from baseline to 4 months, Minnesota Living with Heart Failure (MLwHF) score and 6-minute walk distance achieved at 4 months, and clinical events, including heart failure hospitalization (recurrent) or cardiovascular death. The rise in haemoglobin after administering FDI, adjusted for usual care, was greater for lower baseline TSAT (P_interaction < .0001) and ferritin (P_interaction = .028) and more severe anaemia (P_interaction = .014). MLwHF scores at 4 months were somewhat lower (better) with FDI for more anaemic patients (overall P_interaction = .14; physical P_interaction = .085; emotional P_interaction = .043) but were not related to baseline TSAT or ferritin. Blood tests did not predict difference in achieved walking distance for those randomized to FDI compared to control. The absence of anaemia or a TSAT ≥ 20% was associated with lower event rates and little evidence of benefit from FDI. More severe anaemia or TSAT < 20%, especially when ferritin was ≥100 µg/L, was associated with higher event rates and greater absolute reductions in events with FDI, albeit not statistically significant. This hypothesis-generating analysis suggests that anaemia or TSAT < 20% with ferritin > 100 µg/L might identify patients with heart failure who obtain greater benefit from intravenous iron. This interpretation requires confirmation. The IRONMAN trial main inclusion criteria, design, and blood markers of iron deficiency, including haemoglobin, transferrin saturation (TSAT), and serum ferritin, used to predict response to intravenous ferric derisomaltose (FDI). Markers of response including increase in haemoglobin, symptoms (Minnesota Living with Heart Failure questionnaire) and 6-minute walk test distance at 4 months and incidence of clinical events, including heart failure hospitalization (HFH) and cardiovascular (CV) death, for the duration of the trial with or without COVID-sensitivity analyses. CI, confidence interval; LVEF, left ventricular ejection fraction; RR, rate ratio. #Serum ferritin < 30 µg/L predicted a marked increase in haemoglobin only when associated with a TSAT < 20%. *Patients with a TSAT < 20% but serum ferritin ≥ 100 µg/L obtained the greatest benefit in terms of improvement in the primary endpoint. ^The benefit of FDI was similar in relative terms for patients with and without anaemia but because those with anaemia were at greater risk, they obtained greater absolute benefit.

To assess the frequency of chronic kidney disease (CKD), define the associated demographics, and evaluate its association with use of evidence-based drug therapy in a contemporary global study of patients with stable coronary artery disease. 22,272 patients from the ProspeCtive observational LongitudinAl RegIstry oF patients with stable coronary arterY disease (CLARIFY) were included. Baseline estimated glomerular filtration rate (eGFR) was calculated (CKD-Epidemiology Collaboration formula) and patients categorised according to CKD stage: >89, 60–89, 45–59 and <45 mL/min/1.73 m². Mean (SD) age was 63.9±10.4 years, 77.3% were male, 61.8% had a history of myocardial infarction, 71.9% hypertension, 30.4% diabetes and 75.4% dyslipidaemia. Chronic kidney disease (eGFR<60 mL/min/1.73 m²) was seen in 22.1% of the cohort (6.9% with eGFR<45 mL/min/1.73 m²); lower eGFR was associated with increasing age, female sex, cardiovascular risk factors, overt vascular disease, other comorbidities and higher systolic but lower diastolic blood pressure. High use of secondary prevention was seen across all CKD stages (overall 93.4% lipid-lowering drugs, 95.3% antiplatelets, 75.9% beta-blockers). The proportion of patients taking statins was lower in patients with CKD. Antiplatelet use was significantly lower in patients with CKD whereas oral anticoagulant use was higher. Angiotensin-converting enzyme inhibitor use was lower (52.0% overall) and inversely related to declining eGFR, whereas angiotensin-receptor blockers were more frequently prescribed in patients with reduced eGFR. Chronic kidney disease is common in patients with stable coronary artery disease and is associated with comorbidities. Whilst use of individual evidence-based medications for secondary prevention was high across all CKD categories, there remains an opportunity to improve the proportion who take all three classes of preventive therapies. Angiotensin-converting enzyme inhibitors were used less frequently in lower eGRF categories. Surprisingly the reverse was seen for angiotensin-receptor blockers. Further evaluation is required to fully understand these associations. The CLARIFY (ProspeCtive observational LongitudinAl RegIstry oF patients with stable coronary arterY disease) Registry is registered in the ISRCTN registry of clinical trials with the number ISRCTN43070564. http://www.controlled-trials.com/ISRCTN43070564.

Objective Explore the interaction between patient experienced symptoms and burden of treatment (BoT) theory in chronic heart failure (CHF). BoT explains how dynamic patient workload (self-care) and their capacity (elements influencing capability), impacts on patients’ experience of illness. Design Review of qualitative research studies. Data sources CINAHL, EMBASE, MEDLINE, PsycINFO, Scopus and Web of Science were searched between January 2007 and 2020. Eligibility Criteria Journal articles in English, reporting qualitative studies on lived experience of CHF. Results 35 articles identified related to the lived experience of 720 patients with CHF. Symptoms with physical and emotional characteristics were identified with breathlessness, weakness, despair and anxiety most prevalent. Identifying symptoms’ interaction with BoT framework identified three themes: (1) Symptoms appear to infrequently drive patients to engage in self-care (9.2% of codes), (2) symptoms appear to impede (70.5% of codes) and (3) symptoms form barriers to self-care engagement (20.3% of codes). Symptoms increase illness workload, making completing tasks more difficult; simultaneously, symptoms alter a patient’s capacity, through a reduction in their individual capabilities and willingness to access external resources (ie, hospitals) often with devasting impact on patients’ lives. Conclusions Symptoms appear to be integral in the patient experience of CHF and BoT, predominately acting to impede patients’ efforts to engage in self-care. Symptoms alter illness workload, increasing complexity and hardship. Patients’ capacity is reduced by symptoms, in what they can do and their willingness to ask for help. Symptoms can lower their perceived self-value and roles within society. Symptoms appear to erode a patient’s agency, decreasing self-value and generalised physical deconditioning leading to affective paralysis towards self-care regimens. Together describing a state of overwhelming BoT which is thought to be a contributor to poor engagement in self-care and may provide new insights into the perceived poor adherence to self-care in the CHF population. PROSPERO registration number CRD42017077487.

For patients with heart failure and reduced or mildly reduced left ventricular ejection fraction, iron deficiency is common and associated with more severe symptoms, worse quality of life and an increased risk of hospitalisations and death. Iron deficiency can be swiftly, effectively and safely treated by administering intravenous iron, either as ferric carboxymaltose or ferric derisomaltose, which improves patient well-being and reduces the risk of hospitalisations including those for heart failure. However, the current definition of iron deficiency in heart failure has serious flaws. A serum ferritin <100 µg/L does not identify patients more likely to respond to intravenous iron. In contrast, patients with transferrin saturations <20%, most of whom are also anaemic, are more likely to have a beneficial response to intravenous iron. In this review, we summarise the available evidence for use of intravenous iron in heart failure and provide recommendations for targeted future research and practical considerations for the general cardiologist.