Aims: For patients with heart failure (HF) and iron deficiency (ID), randomized trials suggest that intravenous (IV) iron reduces hospitalizations for heart failure (HHF), but uncertainty exists about the effects in subgroups and the impact on mortality. We conducted a meta-analysis of randomized trials investigating the effect of IV iron on clinical outcomes in patients with HF. Methods and results: We identified randomized trials published between 1 January 2000 and 5 November 2022 investigating the effect of IV iron versus standard care/placebo in patients with HF and ID in any clinical setting, regardless of HF phenotype. Trials of oral iron or not in English were not included. The main outcomes of interest were a composite of HHF and cardiovascular death (CVD), on HHF alone and on cardiovascular and all-cause mortality. Ten trials were identified with 3373 participants, of whom 1759 were assigned to IV iron. IV iron reduced the composite of recurrent HHF and CVD (rate ratio 0.75, 95% confidence interval [CI] 0.61–0.93; p < 0.01) and first HHF or CVD (odds ratio [OR] 0.72, 95% CI 0.53–0.99; p = 0.04). Effects on cardiovascular (OR 0.86, 95% CI 0.70–1.05; p = 0.14) and all-cause mortality (OR 0.93, 95% CI 0.78–1.12; p = 0.47) were inconclusive. Results were similar in analyses confined to the first year of follow-up, which was less disrupted by the COVID-19 pandemic. Subgroup analyses found little evidence of heterogeneity for the effect on the primary endpoint, although patients with transferrin saturation <20% (OR 0.67, 95% CI 0.49–0.92) may have benefited more than those with values ≥20% (OR 0.99, 95% CI 0.74–1.30) (heterogeneity p = 0.07). Conclusion: In patients with HF and ID, this meta-analysis suggests that IV iron reduces the risk of HHF but whether this is associated with a reduction in cardiovascular or all-cause mortality remains inconclusive.

Aims: Iron deficiency (ID) and anaemia are common in heart failure; less is known about changes over time. Methods and results: We investigated prevalence, incidence and resolution of ID and anaemia in 906 patients with chronic heart failure (median age 73 (65–79) years, 70% men, 51% with heart failure with reduced ejection fraction) 1 year apart. ID was defined as serum iron ≤13 µmol/L and anaemia as haemoglobin <13.0 g/dL for men or 13 µmol/L), mortality was higher in those with persistent or incident ID at 1 year [hazard ratio (HR) 1.81 (1.23–2.67), and HR 1.40 (0.91–2.14), respectively] in multivariable models ( P = 0.02). Compared to persistent ID, resolution of ID was associated with a lower mortality [HR 0.61 (0.44–0.86); P = 0.004]. Changes in ID defined by FAIR‐HF criteria were not similarly associated with mortality. Anaemia was associated with a poor outcome even if it resolved. Conclusions: The prevalence and incidence of ID and anaemia are high in chronic heart failure but so is the rate of resolution. Persistent or incident ID, defined by a serum iron ≤13 µmol/L, is associated with higher mortality and resolution of ID with lower mortality.

Background: The recent AFFIRM-AHF trial assessing the effect of intravenous (IV) iron on outcomes in patients hospitalised with worsening heart failure who had iron deficiency (ID) narrowly missed its primary efficacy endpoint of recurrent hospitalisations for heart failure (HHF) or cardiovascular (CV) death. We conducted a meta-analysis to determine whether these results were consistent with previous trials.Methods: We searched for randomised trials of patients with heart failure investigating the effect of IV iron vs placebo/control groups that reported HHF and CV mortality from 1st January 2000 to 5th December 2020. Seven trials were identified and included in this analysis. A fixed effect model was applied to assess the effects of IV iron on the composite of first HHF or CV mortality and individual components of these.Results: Altogether, 2,166 patients were included (n = 1168 assigned to IV iron;n = 998 assigned to control). IV iron reduced the composite of HHF or CV mortality substantially [OR 0.73; (95% confidence interval 0.59–0.90);p = 0.003]. Outcomes were consistent for the pooled trials prior to AFFIRM-AHF. Whereas first HHF were reduced substantially [OR 0.67; (0.54–0.85);p = 0.0007], the effect on CV mortality was uncertain but appeared smaller [OR 0.89; (0.66–1.21);p = 0.47].Conclusion: Administration of IV iron to patients with heart failure and ID reduces the risk of the composite outcome of first heart failure hospitalisation or cardiovascular mortality, but this outcome may be driven predominantly by an effect on HHF. At least three more substantial trials of intravenous iron are underway.Graphic

Background and Aims: Many patients are prescribed loop diuretics without a diagnostic record of heart failure. Little is known about their characteristics and prognosis. Methods: Glasgow regional health records (2009–16) were obtained for adults with cardiovascular disease or taking loop diuretics. Outcomes were investigated using Cox models with hazard ratios adjusted for age, sex, socioeconomic deprivation, and comorbid disease (adjHR). Results: Of 198 898 patients (median age 65 years; 55% women), 161 935 (81%) neither took loop diuretics nor had a diagnostic record of heart failure (reference group), 23 963 (12%) were taking loop diuretics but had no heart failure recorded, 7844 (4%) had heart failure recorded and took loop diuretics, and 5156 (3%) had heart failure recorded but were not receiving loop diuretics. Compared to the reference group, five-year mortality was only slightly higher for heart failure in the absence of loop diuretics [22%; adjHR 1.2 (95% CI 1.1–1.3)], substantially higher for those taking loop diuretics with no record of heart failure [40%; adjHR 1.8 (95% CI 1.7–1.8)], and highest for heart failure treated with loop diuretics [52%; adjHR 2.2 (95% CI 2.0–2.2)]. Conclusions: For patients with cardiovascular disease, many are prescribed loop diuretics without a recorded diagnosis of heart failure. Mortality is more strongly associated with loop diuretic use than with a record of heart failure. The diagnosis of heart failure may be often missed, or loop diuretic use is associated with other conditions with a prognosis similar to heart failure, or inappropriate loop diuretic use increases mortality; all might be true.

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.

Background The prevalence of anaemia and iron deficiency and their prognostic association with cardiovascular disease have rarely been explored at population level. Methods National Health Service records of the Greater Glasgow region for patients aged ≥50 years with a broad range of cardiovascular diagnoses were obtained. During 2013/14, prevalent disease was identified and results of investigations collated. Anaemia was defined as haemoglobin <13 g/dL for men or <12 g/dL for women. Incident heart failure, cancer and death between 2015 and 2018 were identified. Results The 2013/14 dataset comprised 197 152 patients, including 14 335 (7%) with heart failure. Most (78%) patients had haemoglobin measured, especially those with heart failure (90%). Of those tested, anaemia was common both in patients without (29%) and with heart failure (prevalent cases in 2013/14: 46%; incident cases during 2013/14: 57%). Ferritin was usually measured only when haemoglobin was markedly depressed; transferrin saturation (TSAT) even less often. Incidence rates for heart failure and cancer during 2015–18 were inversely related to nadir haemoglobin in 2013/14. A haemoglobin of 13–15 g/dL for women and 14–16 g/dL for men was associated with the lowest mortality. Low ferritin was associated with a better prognosis and low TSAT with a worse prognosis. Conclusion In patients with a broad range of cardiovascular disorders, haemoglobin is often measured but, unless anaemia is severe, markers of iron deficiency are usually not. Low haemoglobin and TSAT, but not low ferritin, are associated with a worse prognosis. The nadir of risk occurs at haemoglobin 1–3 g/dL above the WHO definition of anaemia.