Intravenous Iron Therapy in Heart Failure With Iron Deficiency: An Umbrella Review of Systematic Reviews and Meta-Analyses

Iron deficiency is a distinct comorbidity in patients with heart failure (HF), independent of anemia, and is associated with reduced functional capacity and increased hospitalization and mortality. Randomized trials of intravenous (IV) iron repletion have yielded directionally consistent but incompletely aligned results, prompting numerous systematic reviews and meta-analyses that largely draw on the same underlying trials. We performed an umbrella review to consolidate this evidence base and clarify the strength and consistency of treatment effects across outcomes. Across the pooled reviews, IV iron, predominantly ferric carboxymaltose (FCM), reduced the composite risk of HF hospitalization and cardiovascular death in patients with heart failure with reduced ejection fraction (HFrEF), an effect attributable chiefly to fewer hospitalizations rather than a survival benefit, which remained non-significant throughout. Functional capacity, symptom class, and quality of life improved consistently. Safety appeared favorable among the outcomes formally assessed, though fewer than half of the included reviews performed a dedicated statistical safety analysis, and known formulation-specific risks such as hypophosphatemia were not evaluated in this literature. The treatment effect appeared attenuated in the one review restricted to acute heart failure, and possible differences in benefit by sex and by baseline iron-transport capacity emerged as hypothesis-generating candidate explanations for residual heterogeneity, warranting prospective confirmation rather than immediate clinical application. Evidence was drawn predominantly from FCM trials, with more limited supporting data for ferric derisomaltose and minimal data for other formulations; findings should not be extrapolated beyond HFrEF, as HF with preserved ejection fraction populations were not separately represented in this literature. Because the available reviews draw heavily on a shared and aging set of trials (corrected covered area of 31.9%, indicating very high primary-study overlap), this synthesis should be regarded as clarifying rather than expanding the evidence base. Taken together, IV iron repletion, particularly with FCM, in iron-deficient HFrEF reduces hospitalizations and improves quality of life, but a mortality benefit has not been established, underscoring the need for adequately powered trials designed specifically to resolve this question.