Ironing Out Heart Failure: Clarifying the Role of Intravenous Iron Therapy

In recent years, intravenous iron therapy has taken its place on the ever-expanding mantel of therapies available for patients with heart failure (HF). Both the European Society of Cardiology (ESC) and the American Heart Association (AHA)/American College of Cardiology (ACC)/Heart Failure Society of America (HFSA) guidelines recommend intravenous iron supplementation for patients with a left ventricular ejection fraction (LVEF) less than 45% to alleviate HF symptoms and improve both exercise capacity and quality of life.^{1, 2}  Might intravenous iron do even more for patients with HF? The recently published results of two large randomized controlled trials, AFFIRM-AHF and IRONMAN, have enticed clinicians with the prospect of a reduction in the rate of recurrent hospitalization and cardiovascular death in patients with HF, although both trials fell just short of reaching statistical significance for this composite primary outcome.^{3, 4} 

Pursuing this lead, Fraser J. Graham, MD, and colleagues conducted a meta-analysis of randomized clinical trials assessing the effect of intravenous iron therapy versus either placebo or the standard of care in patients with HF and iron deficiency.⁵  Both AFFIRM-AHF and IRONMAN were included in the analysis, alongside eight other trials comprising 3,373 total participants. The primary outcome — a composite of recurrent hospitalizations for HF and cardiovascular mortality — was the same as that used in AFFIRM-AHF and IRONMAN. Overall, intravenous iron therapy reduced the composite primary outcome with a risk ratio of 0.75 (95% CI 0.61-0.93, p<0.01). This reduction was primarily driven by a reduction in hospitalizations for HF; results for the impact on mortality were inconclusive (Figure).

In the wake of these encouraging findings, the results of the HEART-FID trial published later in the year proved a disappointment.⁶  This double-blind, randomized trial enrolled 3,065 patients with HF and reduced ejection fraction who had either been hospitalized in the past 12 months or had an elevated natriuretic peptide level. Iron deficiency was defined as a ferritin level less than 100 ng/ml or ranging from 100 to 300 ng/ml with a transferrin saturation less than 20%. Patients were randomized 1:1 to receive intravenous ferric carboxymaltose or placebo. The primary outcome was a hierarchical composite of death within 12 months, hospitalization for HF, or a change in 6-minute walk distance from baseline. The study was negative, both for the primary outcome and the composite secondary outcome of cardiovascular death or hospitalization for HF.

What is the practicing clinician to make of these apparently contradictory results? The HEART-FID investigators point out that their trial studied a lower-risk population than those covered by the AFFIRM-AHF (all enrolled patients were hospitalized) and IRONMAN trials (15% of patients were enrolled while hospitalized), with a much higher rate of first hospitalization for HF or cardiovascular death in AFFIRM-AHF than in HEART-FID.⁶  Additionally, the mean baseline transferrin saturation among patients enrolled in HEART-FID was higher than that in previous trials.⁶  It is plausible that the less sick and less iron-deficient population examined in HEART-FID simply had less room for clinical improvement with intravenous iron therapy.

Reviewing the discourse on intravenous iron therapy for patients with HF brings to mind the Gartner hype cycle, in which initial enthusiasm reaches a peak of (inflated) expectations, followed by a trough of disillusionment, slope of enlightenment, and finally a plateau of productivity.⁷  The results of HEART-FID, which by itself enrolled nearly as many patients as the 10 trials included in the updated meta-analysis combined, cannot be ignored: Intravenous iron therapy is not a panacea for patients with HF and iron deficiency. The way out of this trough of disillusionment may well be thoughtful patient selection — intravenous iron therapy appears most impactful when given to patients with functional iron deficiency (perhaps best defined as a transferrin saturation <20%) who are at high risk of recurrent hospitalization for HF.⁸  However, it bears remembering that we already know intravenous iron makes patients feel better and is already guideline-recommended for this reason.^{1, 2, 8}  Intravenous iron therapy is also safe; in HEART-FID, only five hypersensitivity and two angioedema events were observed among the 1,532 patients in the intravenous iron group.⁶  I, for one, will continue to provide intravenous iron liberally to my patients with HF exhibiting iron deficiency, especially those who are symptomatic or who have been recently hospitalized with HF exacerbation.