Review: In HF with iron deficiency, iron supplementation reduces HF admissions and improves cardiac function

Question

In patients with systolic heart failure (HF) and iron deficiency, does iron supplementation improve clinical outcomes?

Review scope

Included studies compared iron supplementation with placebo in patients with systolic HF and iron deficiency (ferritin < 100 ng/mL or 100 to 300 ng/mL plus transferrin saturation < 20%) and reported ≥ 1 outcome of interest. Outcomes included all-cause mortality, hospitalization for worsening HF, 6-minute walk distance, New York Heart Association class, Kansas City Cardiomyopathy Questionnaire score, and N-terminal pro-B-type natriuretic peptide and C-reactive protein levels.

Review methods

PubMed, EMBASE/Excerpta Medica, and Cochrane databases to Mar 2018 were searched for English-language randomized controlled trials (RCTs). 10 RCTs (n = 1404, mean age 62 to 76 y across 8 trials, follow-up 2 to 52 wk) met inclusion criteria. 8 used IV iron (200 to 1000 mg/wk), and 3 used oral iron (300 to 600 mg/d); 1 trial used both forms of iron. 2 RCTs had adequate allocation concealment, 8 blinded patients and study staff and 7 blinded outcome assessors, and 7 had adequate completeness of outcome data.

Main results

The main results are in the Table.

Iron supplementation vs placebo in patients with systolic heart failure and iron deficiency^*

Outcomes	Number of trials (n)	Weighted event rates		At 2 to 52 wk
		Iron supplementation	Placebo	RRR (95% CI)	NNT (CI)
All-cause mortality	6 (1217)	3.5%	4.6%	23% (−35 to 56)	Not significant
Hospitalization for worsening heart failure	5 (1009)	6.2%	14%	57% (18 to 78)	13 (9 to 40)
				Weighted mean difference (CI)
6-minute walk distance, m	5 (NR)			33 (4.5 to 61)†
NYHA class	5 (NR)			−0.68 (−1.13 to −0.24)‡
KCCQ score	4 (NR)			4.1 (0.61 to 7.6)†
NT-proBNP, pg/mL	5 (NR)			−333 (−497 to −167)‡
C-reactive protein, mg/L	3 (NR)			−4.6 (−6.1 to −3.2)‡

^*KCCQ = Kansas City Cardiomyopathy Questionnaire; NR = not reported; NT-proBNP = N-terminal pro-B-type natriuretic peptide; NYHA = New York Heart Association; other abbreviations defined in Glossary. Weighted event rates, RRR, NNT, and CI calculated from placebo event rates and odds ratios in article.

^†Positive values = better outcomes with iron supplementation.

^‡Negative values = better outcomes with iron supplementation.

Conclusion

In patients with systolic heart failure and iron deficiency, iron supplementation reduces heart failure hospitalizations and improves cardiac function.

Commentary

The meta-analysis by Zhou and colleagues provides aggregate evidence supporting IV iron therapy to improve health-related quality of life and functional capacity in patients with systolic HF and iron deficiency. However, a class I guideline recommendation for IV iron therapy will require RCTs powered for clinical outcomes (e.g., HF hospitalization and mortality). An ongoing RCT is comparing IV iron (ferric carboxymaltose [FCM]) with placebo for its effect on a composite outcome of death, HF hospitalization, or change in 6-minute walk distance in patients with systolic HF and iron deficiency (Randomized Placebo-controlled Trial of FCM as Treatment for Heart Failure with Iron Deficiency [HEART-FID], NCT03037931).

Despite the mounting clinical evidence and published guidance for use in clinical practice (1), routine IV iron therapy in patients with systolic HF has challenges, particularly in outpatient settings. Facilities must be equipped and have space and trained personnel to administer IV injections or infusions. No more than 1000 mg of IV iron should be administered per week; thus, patients with severe deficits will require multiple clinic visits. Although a 1000-mg infusion requires only 15 minutes, patients must be monitored for rare (> 0.1% to < 1%) hypersensitivity reactions for 30 minutes after infusion (1). Without evidence of improvement in clinical outcomes or cost-effectiveness, patients may be reluctant to attend extra outpatient visits and health care systems may be unwilling to incur additional costs. The primary results from the HEART-FID trial should help to address these concerns.