Intravenous iron for heart failure with evidence of iron deficiency: a meta-analysis of randomised trials

Abstract

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 abstract

Acute heart failure and iron deficiency: a prospective, multicentre, observational study

“…reduced iron availability only) as suggested by the AFFIRM‐AHF as discussed earlier. 11 It could be hypothesized that patients with absolute ID have greater benefit of FCM, probably not only by accomplishing reduction of rehospitalizations as shown in several meta‐analyses of FCM trials, 13 , 14 , 15 but eventually also a reduction in mortality.…”

“…Meta‐analyses of randomized controlled trials with intravenous iron therapy to correct ID in patients with HF with reduced left‐ventricular ejection fraction (LVEF) showed benefits in patient‐related outcomes, such as improvement in New York Heart Association (NYHA) class, 6 minute walking distance, quality of life, and hospitalization rates. 13 , 14 , 15 In the chronic setting, ID is defined as a serum ferritin level <100 μg/L (absolute ID) or a serum ferritin level 100–300 μg/L in combination with a transferrin saturation (TSAT) < 20% (functional ID). However, the assessment in AHF is less well defined.…”

“…Absolute ID persisted from T0 to T2 in 66% of the patients, while functional ID resolved in 56% of the patients. Ferritin (median [interquartile range] 124 μg/L [56-247] to 150 μg/L [73-277]), transferrin saturation (15% [10][11][12][13][14][15][16][17][18][19][20] to 18% [12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27]), and iron levels (9 μmol/L [6-13] to 11 μmol/L [8-16]) increased significantly (all P < 0.001) from T0 to T1. Transferrin saturation (to 21% [15-29]) and iron levels (to 13 μmol/L [9-17]) also increased significantly (both P < 0.01) from T1 to T2 without iron supplementation.…”

Iron Deficiency in Heart Failure: Mechanisms and Pathophysiology

“…These observations underscore the crucial role of iron beyond erythropoiesis [ 26 ]. Additionally, although the recent AFFIRM-AHF study statistically missed its primary endpoint (i.e., combined recurrent hospitalisations or cardiovascular mortality), administering intravenous (IV) iron in patients with acute HF significantly reduced recurrent hospitalisations [ 27 , 28 ]. The evidence on mortality is yet to be ascertained [ 29 ].…”

Safety and Efficacy of Intravenous Ferric Derisomaltose Compared to Iron Sucrose for Iron Deficiency Anemia in Patients with Chronic Kidney Disease With and Without Heart Failure

“…13 Meta-analyses of randomized trials also suggest that, compared to placebo/control arm, IV iron reduces the risk of hospitalizations for HF. 19,20 Furthermore, cardiology guidelines document an improvement in well-being with IV iron. 15 Several other pivotal trials (ClinicalTrials.gov identifiers: NCT02642562 [IRONMAN]; NCT03036462 [FAIR-HF2]; and NCT03037931 [HEART-FID]) are currently evaluating the effect of IV iron on morbidity and mortality in patients with HF.…”