Intravenous iron supplementation in heart failure and iron deficiency: an umbrella review of systematic reviews and meta-analyses

Background Iron deficiency is frequently encountered in patients with heart failure. It is related not only to anemia, but also to exercise intolerance, impaired health status, and repeated hospitalization. Intravenous iron has been evaluated in randomized trials and in many systematic reviews, but the review conclusions are not completely aligned, particularly for mortality and functional outcomes. We therefore reviewed the existing review-level evidence, with particular attention to methodological quality and repeated use of the same primary trials. Methods PubMed, Embase, Web of Science, the Cochrane Library, CNKI, and Wanfang were searched from January 2016 to 31 March 2026. Eligible studies were systematic reviews and meta-analyses evaluating iron supplementation in patients with heart failure and iron deficiency. Reviews including mixed iron formulations were considered only when intravenous iron outcomes were separately reported or intravenous iron represented the predominant intervention of interest. AMSTAR2 was used to assess review quality. Trial overlap was examined using the corrected covered area (CCA), and GRADE was used to judge certainty of evidence. Results Forty-five eligible reviews were identified, and 18 representative reviews were included in the detailed synthesis. Across the available evidence, intravenous iron showed the most consistent association with reduced heart failure hospitalization, including recurrent hospitalization and composite endpoints combining heart failure hospitalization with cardiovascular death. The randomized evidence was derived predominantly from populations with reduced left ventricular ejection fraction (LVEF), with some trials extending eligibility into the mildly reduced ejection fraction range. Evidence for cardiovascular mortality and all-cause mortality remained inconsistent. Findings for functional capacity and health status were generally favorable but remained uncertain because of heterogeneity and very low certainty evidence, whereas effects on cardiac function were uncertain. No clear increase in serious adverse events was identified with intravenous iron therapy, although the certainty of safety evidence remained limited. According to AMSTAR2, methodological confidence was low in seven reviews and critically low in eleven reviews. The evidence base comprised 23 unique randomized controlled trials with 163 trial occurrences, yielding a CCA of 35.81%, indicating substantial redundancy among representative reviews included in the quantitative synthesis. GRADE certainty was moderate for overall heart failure hospitalization, low for total/recurrent hospitalization, composite hospitalization–cardiovascular death outcomes, all-cause mortality, and serious adverse events, and very low for first hospitalization, cardiovascular mortality, functional outcomes, and cardiac function. Conclusions Current review-level evidence, derived predominantly from populations with reduced or mildly reduced LVEF, suggests a potential reduction in heart failure hospitalization. This potential benefit should be interpreted in relation to the patient populations, clinical settings, and iron formulations studied in major randomized trials. The clinical certainty of these findings remains constrained by substantial trial overlap, prominent methodological limitations of the published reviews, and inconsistent outcome definitions. Evidence regarding mortality reduction, functional status, and structural cardiac remodeling remains uncertain and requires cautious interpretation.