Introduction
Iron Metabolism
Definitions of ID
Epidemiology of ID in HF
Mechanism of ID in HF
Importance of ID in HF
Iron Treatment in HFrEF
Oral Iron
Intravenous Iron
Trial | Patient group | Design and iron preparation | Outcome |
---|---|---|---|
HFrEF trials | |||
ID patients with Hb < 12.5 g/dL, CrCl < 90 mL/min, and LVEF ≤ 35% | Double-blinded study with 40 patients randomised to placebo or IV iron sucrose complex for 5 weeks. Primary endpoints were changes in renal and haematological parameters, NT-proBNP and CRP levels at 6 months | IV iron showed better haematological values, renal function, ↓NT-proBNP, and ↓CRP. LVEF also improved as did symptoms, measured by 6MWT, and ↓hospitalisations at 6-month, 1-year, and 5-year follow-up. Mortality at 5 years was also significantly lower with IV iron | |
FERRIC-HF [65] | ID and CHF patients with LVEF ≤ 45%, NYHA Class II-III, Hb ≤ 14.5 g/dL, and pVO2 14.0 ± 2.7 mL/kg/min | Randomised 35 patients to receive 16 weeks of either IV iron sucrose or no treatment. The observer-blinded primary end point was the change in absolute pVO2 | IV iron improved NYHA class (p = 0.007) and pVO2/kg (p = 0.01). In anaemic patients, there was an improvement in absolute pVO2 (p = 0.02) and pVO2/kg (p = 0.01) with IV iron. Adverse events were similar between two groups |
FAIR-HF [10] | CHF patients with ID, LVEF ≤ 40% for NYHA II patients, and LVEF ≤ 45% for NYHA III patients, Hb 9.5–13.5 g/dL | 459 patients were randomly assigned, in a 2:1 ratio, to IV FCM or placebo. The primary end points were the self-reported PGA and NYHA functional class at week 24 | 47% of IV FCM vs. 30% placebo patients had NYHA functional class I or II at week 24 (OR 2.40; 95% CI, 1.55 to 3.71). Results similar with and without anaemia. IV FCM ↑distance on 6MWT and QoL assessments. The rates of death, adverse events, and serious adverse events were similar in the two groups |
IRON-HF [52] | Patients with LVEF < 40%, NYHA class II-IV, Hb 9–12 g/dL, Tsat < 20%, and ferritin < 500 μg/L | Double-blinded multicentre trial of 18 patients randomised to IV iron sucrose for 5 weeks, oral ferrous sulphate for 8 weeks or placebo. Primary endpoint was variation of pVO2 over 3-month follow-up | Those treated with IV iron had ↑ functional capacity (increase of 3.5 mL/kg/min in pVO2). ↑Ferritin, ↑TSat, and ↑Hb in both treated groups |
CONFIRM-HF [69] | Iron-deficient patients with stable CHF, LVEF ≤ 45% M NYHA II-III on optimal background therapy for CHF | 304 patients were randomised 1:1 to IV FCM or placebo for 52 weeks. The primary end-point was the change in 6MWT distance from baseline to week 24 | With IV FCM ↑6MWT distance at week 24 (p = 0.002), this was consistent among all subgroups and sustained to week 52. Also, ↑NYHA class, ↑PGA, and ↑QoL in patients treated with IV FCM from week 24 onwards. Treatment with IV FCM ↓hospitalizations for worsening HF (HR 0.39 (0.19–0.82), p = 0.009). Death rate and the incidence of adverse events comparable between both groups |
IRONOUT-HF [47] | Patients with HFrEF (< 40%) and ID | Double-blind trial of 225 patients randomised to receive either oral iron polysaccharide or placebo for 16 weeks. The primary end point was a change in pV̇O2 from baseline | The change in pV̇O2 and 6MWT at 16 weeks did not significantly differ between the oral iron and placebo groups |
EFFECT-HF [70] | ID subjects with stable CHF, LVEF ≤ 45%, NYHA II–III, and on optimal background therapy | 172 patients randomised to treatment with IV FCM for 24 weeks or standard of care. The primary end point was the change in pVO2 from baseline to 24 weeks | IV FCM significantly ↑ serum ferritin and transferrin saturation. At 24 weeks, ↓pVO2 in control group but maintained on IV FCM. ↑PGA and ↑NYHA improved on IV FCM versus standard of care |
Myocardial-IRON [68] | Patients with ID, LVEF < 50%, NYHA II–III symptoms and Hb < 15 g/dL | Multicentre double-blinded study. 53 patients randomised to IV FCM or placebo. Primary objective was to assess myocardial iron repletion estimated by T2* and T1 mapping CMR sequences 7 and 30 days after treatment | Baseline T2* and T1 mapping values did not significantly differ across treatment arms. On day 7, both T2* and T1 mappings were significantly lower in the FCM arm (p = 0.025) indicating repletion. At 30 days, there was a similar reduction on T2* mapping (p = 0.003) but not T1 |
AFFIRM-AHF [71••] | Patients with ID and admitted with acute HF with LVEF < 50% | 1108 participants randomised to IV FCM or placebo for up to 24 weeks, dosed according to the extent of iron deficiency. The primary outcome was a composite of total hospitalisations for heart failure and CV death up to 52 weeks | 370 total CV hospitalisations and deaths occurred in IV FCM group and 451 in placebo group (RR 0.80, 95% CI 0.64–1.00, p = 0.050). No difference in CV death between groups. 217 HF hospitalisations occurred in FCM group and 294 in placebo group (RR 0.74; 95% CI 0.58–0.94, p = 0.013) |
IRONMAN [72••] | ID patients with new or established HFrEF (LVEF ≤ 45%) and current or recent (within 6 months) hospitalisation for HF | Prospective, randomised open-label, blinded endpoint (PROBE) event-driven. Iron preparation is IV ferric derisomaltose. Primary endpoint was combined rate of recurrent hospitalisations for HF and CV death | 336 primary endpoints in the IV ferric derisomaltose group and 441 in the usual care group (RR 0.82, 95% CI 0.66–1.02, p = 0.070). In the prespecified COVID-19 sensitivity analysis, 210 primary endpoints in the IV ferric derisomaltose group and 280 in the usual care group (RR 0.76, 95% CI 0.58–1.00, p = 0.047), mainly driven by a reduction in HF admissions |
HEART-FID [73] NCT03037931 | Stable CHF patients with ID, Hb 9–13 g/dL (females) or < 15 g/dL (males) and LVEF ≤ 40% on optimal therapy | Multi-centre and double-blinded study with patients randomised to IV FCM or placebo. Assessing 12-month rate of death, hospitalisation for worsening HF, and the 6-month change in 6MWT distance | Estimated to end June 2023 |
FAIR-HF2 [74] NCT03036462 | HFrEF patients for at least 12 months, iron deficiency, Hb 9.5–14 g/dL. Estimated enrolment of 1200 patients | Multi-centre and double blinded study with patients randomised to IV FCM or placebo. Primary endpoint of combined rate of recurrent HF hospitalisations and CV death in 12 months | Estimated to end May 2024 |
IVOFER-HF [53] 2017–005,053-37 | HFrEF (LVEF ≤ 45%) patients on optimal medical therapy with NYHA II-IV class symptoms and ID | Patients randomised to IV FCM, oral iron (ferrous sulphate or liposomal iron) or placebo. Primary endpoint is a change in 6MWT distance from baseline to week 24 | Unknown end date |
HFpEF trials | |||
FAIR-HFpEF [75] NCT03074591 | Patients with HFpEF (LVEF ≥ 45%) and ID, with or without anaemia, Hb 9.0–14.0 g/dL and recent HF hospitalisation | Patients will be randomised to IV FCM or placebo. Primary outcome is difference in 6MWT from baseline to end of study between two groups | Unknown end date |
PREFER-HF [76] NCT03833336 | Stable CHF patients on optimal medical therapy with ID and LVEF > 45% | Randomised trial with quadruple masking. Patients randomised to placebo, IV FCM, oral ferroglycine sulphate, or oral Sucrosomial iron. Primary outcome is change in 6MWT from baseline to week 24 | Unknown end date |