Practical Guidance for Diagnosing and Treating Iron Deficiency in Patients with Heart Failure: Why, Who and How?
Abstract
:1. Introduction
2. Why Is Diagnosing and Treating Iron Deficiency in Patients with Heart Failure Important?
2.1. Role of Iron and the Impact of Iron Deficiency
2.2. Iron Deficiency Prevalence in Patients with Heart Failure
2.3. Iron Deficiency Causes in Patients with Heart Failure
3. Who Should Be Assessed for Iron Deficiency?
3.1. Who and When to Screen for Iron Deficiency?
3.2. How to Diagnose Iron Deficiency in Patients with Heart Failure
4. How Should Iron Deficiency in Patients with Heart Failure Be Treated?
4.1. Recommendations for Correcting Iron Deficiency
- Symptomatic patients who have a left ventricular ejection fraction (LVEF) < 45% to alleviate symptoms, improve exercise capacity and QoL (recommendation class IIa, evidence level A)
- Pre- and post-discharge follow-up of patients hospitalised for AHF to improve symptoms and reduce rehospitalisation (recommendation class IIa, evidence level B)
- Symptomatic patients recently hospitalised for HF with LVEF < 50% to lessen the risk of HF hospitalisation (recommendation class IIa, evidence level B) [3].
4.2. Evidence on the Therapeutic Management of Iron Deficiency
4.3. Safety and Tolerability of FCM
4.4. Oral Iron Substitution
4.5. Which Patients with Heart Failure Should Receive IV Iron?
4.6. How to Administer IV Ferric Carboxymaltose and Monitor Patients after Treatment
4.7. Evidence for Erythropoiesis-Stimulating Agent Therapy
4.8. Ongoing Research on IV Irons in HF
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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FAIR-HF [15] | CONFIRM-HF [17] | EFFECT-HF [18] | AFFIRM-AHF [16] | |
---|---|---|---|---|
Design, duration and number of patients who received treatment per arm | Double-blind, placebo-controlled, randomised; 24 weeks FCM: 305 Placebo: 154 | Double-blind, placebo-controlled, randomised; 52 weeks FCM: 152 Placebo: 152 | Open-label, SoC-controlled, randomised; 24 weeks FCM: 88 SoC: 86 | Double-blind, placebo-controlled, randomised; 52 weeks FCM: 559 Placebo: 551 |
Key inclusion criteria | NYHA class II (LVEF ≤ 40%) or III (LVEF ≤45%) Hb 9.5–13.5 g/dL ID (ferritin <100 µg/L or 100–299 µg/L + TSAT <20%) | NYHA class II/III (LVEF ≤ 45%) BNP >100 pg/mL and/or NT-proBNP >400 pg/ml Hb <15 g/dL ID (ferritin <100 µg/L or 100–300 µg/L + TSAT < 20%) | NYHA class II/III (LVEF ≤ 45%) BNP >100 pg/mL and/or NT-proBNP >400 pg/ml Hb <15 g/dL ID (ferritin <100 µg/L or 100–300 µg/L + TSAT < 20%) Peak VO2 10–20 mL/kg/min (reproducible) | Hospitalised for acute HF, treated with at least 40 mg IV furosemide (or equivalent) LVEF < 50% ID (ferritin <100 µg/L or 100–299 µg/L + TSAT <20%) |
Dosing regimen | Dose determined by Ganzoni formula [55] FCM equivalent to 200 mg iron/week for iron repletion then Q4W for maintenance | FCM equivalent to 500–3500 mg iron for iron repletion (baseline and Week 6); 500 mg iron for maintenance (Weeks 12, 24, 36) if iron deficiency still present | FCM equivalent to 500–1000 mg iron for iron repletion (baseline and Week 6) based on screening Hb and weight; only given at Week 6 if <70 kg and Hb <10 g/dL or ≥70 kg and Hb <14 g/dL; 500 mg iron for maintenance (Week 12) if iron deficiency still present | FCM equivalent to 500–1000 mg at baseline and Week 6 for iron repletion; 500 mg iron for maintenance at Weeks 12 and 24 for patients in whom ID persisted and for whom Hb was 8–15 g/dL |
Mean cumulative iron dose/ total number of injections | NA/ Median 6 (3–7) during iron repletion phase | 1500 mg/>75% of patients receiving FCM needed 2 injections maximum to correct and sustain iron parameters during the study | 1204 mg/42% received 1, 55% received 2, and 3.3% received 3 FCM administrations | 1352 mg/80% of patients received 1 or 2 FCM administrations during the treatment phase (i.e., up to Week 24) |
Treatment effect on iron-related parameters | FCM vs. placebo at Week 24 (mean ± SE)
|
Mean treatment effect (baseline-adjusted) difference for FCM vs. placebo at Week 52:
|
FCM vs. control (SoC) at Week 24:
| Compared with placebo, serum ferritin and TSAT both rose with FCM by week 6 and continued to be significantly higher at week 52 |
Primary endpoint results |
Changes in PGA and NYHA functional class at Week 24 for FCM vs. placebo
|
LS means ± SE 6 MWT distance at Week 24 for FCM vs. placebo
| Primary analysis LS means change from baseline in peak VO2 at Week 24 for FCM vs. control (SoC)
| Composite of total HF hospitalisations and CV deaths up to 52 weeks after randomisation for FCM vs. placebo:
|
Key secondary endpoint results | Significant improvement (p < 0.001) with FCM vs. placebo in:
| Significant improvements in PGA, NYHA class and 6 MWT with FCM vs. placebo:
|
Significant improvements in NYHA class and PGA with FCM vs. control:
| Total CV hospitalisations and CV deaths with FCM vs. placebo
|
Safety endpoint results | FCM vs. placebo (incidence per 100 patient-years at risk)
| FCM vs. placebo (incidence per 100 patient-years at risk)
| FCM vs. control (SoC)
| FCM vs. placebo
|
Study Name | Study Design and Duration | Patient Population/Key Inclusion Criteria | IV Iron Intervention/Dose | Primary Endpoint |
---|---|---|---|---|
FAIR-HF2 (NCT03036462) [65] | Double-blind, parallel-group, randomised, placebo-controlled trial |
1200 patients with HFrEF Key inclusion criteria:
| 1000 mg FCM followed by optional 500–1000 mg within the first 4 weeks (up to 2000 mg), followed by administration of 500 mg FCM Q4M, unless Hb >16.0 g/dL or ferritin >800 µg/L | Combined rate of HF hospitalisations and CV deaths after ≥12 months of follow-up |
FAIR-HFpEF (NCT03074591) [62] | Single-blind, parallel-group, randomised, placebo-controlled trial | 200 patients with HFpEF Key inclusion criteria:
| 750 mg FCM given as an infusion over 15 min in 100 mL NaCl | The change in 6-min walking distance measured in meters from baseline to end of study |
HEART-FID (NCT03037931) [66] | Double-blind, parallel-group, randomised (1:1), placebo-controlled trial | 3068 patients with stable HFrEF Key inclusion criteria:
| FCM two undiluted bolus doses (15 mg/kg bw) seven days apart to a maximum 750 mg single dose of and a maximum 1500 mg combined dose Q6M as required by iron indices | Composite of:
|
IRONMAN (NCT02642562) [67] | Open-label, randomised, standard of care-controlled trial | 1300 patients Key inclusion criteria:
| Iron (III) isomaltoside 1000 | CV mortality or hospitalisation for worsening HF |
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Sindone, A.; Doehner, W.; Manito, N.; McDonagh, T.; Cohen-Solal, A.; Damy, T.; Núñez, J.; Pfister, O.; van der Meer, P.; Comin-Colet, J. Practical Guidance for Diagnosing and Treating Iron Deficiency in Patients with Heart Failure: Why, Who and How? J. Clin. Med. 2022, 11, 2976. https://doi.org/10.3390/jcm11112976
Sindone A, Doehner W, Manito N, McDonagh T, Cohen-Solal A, Damy T, Núñez J, Pfister O, van der Meer P, Comin-Colet J. Practical Guidance for Diagnosing and Treating Iron Deficiency in Patients with Heart Failure: Why, Who and How? Journal of Clinical Medicine. 2022; 11(11):2976. https://doi.org/10.3390/jcm11112976
Chicago/Turabian StyleSindone, Andrew, Wolfram Doehner, Nicolas Manito, Theresa McDonagh, Alain Cohen-Solal, Thibaud Damy, Julio Núñez, Otmar Pfister, Peter van der Meer, and Josep Comin-Colet. 2022. "Practical Guidance for Diagnosing and Treating Iron Deficiency in Patients with Heart Failure: Why, Who and How?" Journal of Clinical Medicine 11, no. 11: 2976. https://doi.org/10.3390/jcm11112976
APA StyleSindone, A., Doehner, W., Manito, N., McDonagh, T., Cohen-Solal, A., Damy, T., Núñez, J., Pfister, O., van der Meer, P., & Comin-Colet, J. (2022). Practical Guidance for Diagnosing and Treating Iron Deficiency in Patients with Heart Failure: Why, Who and How? Journal of Clinical Medicine, 11(11), 2976. https://doi.org/10.3390/jcm11112976