Ferric Carboxymaltose in Heart Failure with Iron Deficiency (HEART-FID)

Authors, Journal, Affiliations, Type, DOI

• Authors: Robert J. Mentz, Jyotsna Garg, Frank W. Rockhold, Javed Butler, Carmine G. De Pasquale, Justin A. Ezekowitz, Gregory D. Lewis, Eileen O'Meara, Piotr Ponikowski, Richard W. Troughton, Yee Weng Wong, Lilin She, Josephine Harrington, Robert Adamczyk, Nicole Blackman, Adrian F. Hernandez — for the HEART-FID Investigators
• Journal: New England Journal of Medicine 2023;389:975–986 (September 14, 2023)
• Affiliations: Duke University School of Medicine / Duke Clinical Research Institute; Baylor Scott and White; Flinders Medical Centre (Australia); University of Alberta (Canada); Massachusetts General Hospital; Wroclaw Medical University (Poland); Christchurch Heart Institute (New Zealand); American Regent (sponsor)
• Type: Double-blind, randomised, placebo-controlled, event-driven, multicentre RCT (sponsored by American Regent/Daiichi Sankyo; coordinated by DCRI independent of sponsor)
• DOI: https://doi.org/10.1056/NEJMoa2304968

Overview

HEART-FID is the largest RCT of IV ferric carboxymaltose (FCM) in ambulatory HFrEF patients with iron deficiency (n=3,065; LVEF ≤40%; median follow-up 1.9 years). The hierarchical composite primary outcome — death at 12 months, HF hospitalizations at 12 months, or change in 6-minute walk distance (6MWT) at 6 months — yielded a win ratio of 1.10 (99% CI 0.99–1.23) which was numerically favorable but failed to meet the pre-specified significance threshold of p<0.01 (Wilcoxon-Mann-Whitney P=0.02). The main secondary composite (CV death or first HF hospitalisation) was also non-significant (HR 0.93; 96% CI 0.81–1.06). Repeated FCM dosing was well tolerated with an acceptable safety profile.

Keywords

Ferric carboxymaltose · Heart failure · Iron deficiency · Intravenous iron · 6-minute walk distance · Win ratio · Hierarchical composite · Randomised controlled trial

Key Takeaways

Trial Design

• Double-blind, 1:1 randomisation of ambulatory patients with LVEF ≤40%, iron deficiency (ferritin <100 ng/mL or ferritin 100–300 ng/mL with TSAT <20%), and hemoglobin >9.0 g/dL to either IV FCM or placebo, added to standard therapy.
• Enrolled March 2017 – November 2021 (n=3,065); 1,532 FCM, 1,533 placebo.
• FCM or placebo administered every 6 months as needed based on iron indexes and hemoglobin; weight-based dosing (two doses 7 days apart).
• Significance threshold pre-specified at p<0.01 (primary) and p<0.0399 (main secondary) to satisfy FDA special protocol agreement.
• Median follow-up 1.9 years (IQR 1.3–3.0); majority enrolled during COVID-19 pandemic.

Primary Outcome

• Hierarchical composite (death at 12mo → HF hospitalizations at 12mo → 6MWT change at 6mo): overall Wilcoxon-Mann-Whitney P=0.02 (did NOT reach pre-specified threshold of p<0.01).
• Unmatched win ratio 1.10 (99% CI 0.99–1.23) — numerically favoring FCM but confidence interval crosses 1.0.
• Component win ratios (first imputed dataset): death 1.20 (18.0% of decisions), HF hospitalizations 1.00 (18.0%), 6MWT 1.11 (63.9%).
• Death at 12 months: 8.6% vs 10.3%; total HF hospitalizations by 12 months: 297 vs 332.
• Mean 6MWT change from baseline to 6 months: +8 ±60 m (FCM) vs +4 ±59 m (placebo).

Secondary Outcomes

• Main secondary (CV death or first HF hospitalisation during follow-up): 31.0% vs 32.2%; HR 0.93 (96% CI 0.81–1.06) — non-significant (16.0 vs 17.3 events per 100 patient-years).
• All-cause death during follow-up: 23.6% vs 24.5%; HR 0.90 (95% CI 0.78–1.05) — NS.
• All-cause death through 12 months: HR 0.82 (95% CI 0.65–1.05) — NS (exploratory).
• 6MWT change at 12 months: +5 ±71 m vs +4 ±72 m — minimal difference.
• Prespecified analyses: odds of ≥10 m and ≥20 m 6MWT improvement both significantly higher with FCM (>20% higher odds).
• Subgroup heterogeneity signals (prespecified): age, sex, renal insufficiency, and ischaemic vs non-ischaemic aetiology.

Safety

• Serious adverse events during treatment period: 27.0% FCM vs 26.2% placebo — similar.
• Hypersensitivity events (probably drug-related): 3 events (one severe, all resolved).
• Angioedema: 1 probable drug-related event (moderate facial edema, resolved with oral therapy).
• Hypophosphatemia: 1 event (unrelated per investigator, resolved).
• No long-term hypophosphatemia signal despite known short-term FCM effect from prior trials.

Contextual Comparison with Other IV Iron Trials

• HEART-FID placebo arm: 17.3 events/100pt-yr vs 47.1/100pt-yr in AFFIRM-AHF — much lower-risk population.
• AFFIRM-AHF used ferric carboxymaltose at discharge from acute HF hospitalisation (higher-risk, higher-benefit window).
• Higher baseline TSAT in HEART-FID vs AFFIRM-AHF suggests possible less severe iron deficiency enrolled.
• Meta-analysis of IV iron in HF (Graham et al., EHJ 2023; n=3,773): IV iron reduces HF hospitalizations without mortality effect.

Limitations of the Document

• Pre-specified significance level of p<0.01 was stringent (required by FDA special protocol agreement); the P=0.02 result would be considered significant in most standard RCTs — the trial is a "statistical near-miss."
• COVID-19 pandemic affected hospitalization rates: majority of patients enrolled during pandemic; lower background hospitalization rates would attenuate between-group differences.
• Iron deficiency definition debate: TSAT <20% is now considered the more clinically relevant criterion; HEART-FID used ferritin <100 ng/mL OR ferritin 100–300 ng/mL + TSAT <20%, which may have enrolled patients with functional (rather than absolute) iron deficiency.
• Missing 6MWT data: some data missing at follow-up (imputation required), though proportions similar between groups and sensitivity analyses consistent.
• Low SGLT2 inhibitor use at baseline (8%): incremental iron benefit on top of modern quadruple GDMT is not established.
• Single composite primary outcome design: hierarchical endpoint dilutes individual component signal (63.9% of decisions driven by 6MWT, a heterogeneous endpoint).
• Dose timing difference vs AFFIRM-AHF: dosing initiated in stable ambulatory patients (vs post-acute discharge) may represent a fundamentally different physiological state with less iron-responsive signaling.

Key Concepts Mentioned

• concepts/Iron-Deficiency-in-HF — central concept; FCM as treatment; trial evidence
• concepts/Cardiac-Rehabilitation — 6-minute walk distance as functional endpoint

Key Entities Mentioned

• entities/HFrEF — trial population; iron deficiency management section

Wiki Pages Updated

• Created wiki/sources/fe-hf-heartfid-nejm-2023.md
• Created wiki/concepts/Iron-Deficiency-in-HF.md
• Updated wiki/entities/HFrEF.md — added HEART-FID trial detail to iron section; updated contradictions
• Updated wiki/sourceindex.md
• Updated wiki/wikiindex.md