Treatment
Ferinject® wealth of evidence
Ferinject® has an established benefit-risk profile based on an extensive clinical trial programme2-33
Ferinject® is supported by over 30 published company-sponsored RCTs2-31*†‡
Over 30 million patient-years of exposure to Ferinject® since launch34
Five large-scale, multicentre RCTs contribute to the wealth of evidence for Ferinject® in treating iron deficiency in HF2-5, 31
FAIR-HF clinical study
Summary3
FAIR-HF was a multicentre, randomised, double-blind, placebo-controlled study designed to assess whether correction of iron deficiency with Ferinject® confers clinical benefits in patients with HF and impaired LVEF.* Patients (n=459) were randomised 2:1 to Ferinject®† or placebo, and followed for 24 weeks.
The primary endpoints were self-reported Patient Global Assessment and NYHA functional class, both at Week 24.
Outcomes3
Improved exercise capacity
- Ferinject® improved NYHA functional class vs placebo, with 47% having NYHA functional class I or II vs 30% in the placebo group (OR for improvement by one class: 2.40; 95% CI: 1.55, 3.71; P<0.001)
Improved symptoms
- Ferinject® improved HF symptoms vs placebo, evaluated with Patient Global Assessment, with 50% of patients reporting that they were much or moderately improved vs 28% of patients in the placebo group (OR for improvement: 2.51; 95% CI: 1.75, 3.61; P<0.001)
- A significant improvement in HF symptoms was seen as early as four weeks after starting treatment with Ferinject®
*Ambulatory patients who had chronic HF of NYHA class II or III, LVEF ≤40% (for patients in NYHA class II) or ≤45% (for patients in NYHA class III), a haemoglobin level 95-135 g/L and iron deficiency.3
†The total iron dose required for iron repletion was calculated according to Ganzoni's formula. Ferinject® (200 mg) or saline was administered weekly until iron repletion was achieved (correction phase) and then every 4 weeks during the maintenance phase.3
CI, confidence interval; HF, heart failure; LVEF, left ventricular ejection fraction; NYHA, New York Heart Association; OR, odds ratio.
CONFIRM-HF clinical study
Summary2
CONFIRM-HF was a multicentre, double-blind, placebo-controlled trial that evaluated the benefits and safety of long-term Ferinject® therapy.* Patients (n=304) with chronic HF, impaired LVEF, elevated natriuretic peptides and iron deficiency were randomised 1:1 to Ferinject® 500 or 1000 mg or placebo,† and followed for 52 weeks.
The primary endpoint was Week 24 change in 6MWT from baseline.
Outcomes2
Improved exercise capacity
- Ferinject® achieved a sustained improvement in exercise capacity vs placebo, evaluated with 6MWT
- 33±11 m difference in 6MWT distance with Ferinject® vs placebo at Week 24 (LSM±SE; P=0.002)
Improved symptoms
- Ferinject® improved HF symptoms vs placebo, evaluated with Patient Global Assessment
- Ferinject® improved HF symptoms vs placebo, evaluated with NYHA functional class
Improved quality of life
- Ferinject® improved HRQoL vs placebo, evaluated with the KCCQ
*In the CONFIRM HF trial, Ferinject® was administered as an undiluted intravenous bolus injection over at least 1 minute, which deviated from the approved posology of the SmPC.2 The SmPC should always be consulted for the approved posology and method of administration.
† Study drug (Ferinject® or placebo) was administered in doses based on subject weight and haemoglobin value at screening, according to the scheduled dosing scheme. This included both therapy dosing (correction phase) and maintenance phase.2
6MWT, six-minute walk test; HF, heart failure; HRQoL, health-related quality of life; KCCQ, Kansas City Cardiomyopathy Questionnaire; LSM, least squares mean; LVEF, left ventricular ejection fraction; NYHA, New York Heart Association; SE, standard error; SmPC, Summary of Product Characteristics.
EFFECT-HF clinical study
Summary4
EFFECT-HF* was a prospective, multicentre, randomised, controlled, open-label trial that compared the effect of Ferinject® vs SoC on exercise capacity in patients with mild-to-moderate systolic HF, impaired LVEF, and iron deficiency. Patients (n=172) were randomised 1:1 to Ferinject® 500 or 1000 mg or SoC,† and followed for 24 weeks.
The primary endpoint was change in peak VO2 from baseline to 24 weeks.
Outcomes4
- After 24 weeks, peak VO2 did not deteriorate in the Ferinject® arm‡
- Ferinject® demonstrated successful repletion of iron stores and correction of iron deficiency
*In the EFFECT-HF trial, when Ferinject® was administered as an undiluted intravenous bolus injection, the minimal administration time was 1 minute, which deviated from the approved posology of the SmPC.4 The SmPC should always be consulted for the approved posology and method of administration.
† Dosing at Day 0 and Week 6 was based on screening haemoglobin and weight and not on ferritin and TSAT results. At Week 12, Ferinject® was administered (at a dose of 500 mg Ferinject®) if patients were still iron-deficient.4
‡After 24 weeks, peak VO2 (primary endpoint; n=161) had decreased by -1.19±0.389 mL/min/kg in the SoC group, whereas it was minimally decreased in the Ferinject® group (-0.16±0.387 mL/kg/min). The difference in LSM±SE: 1.04±0.44 mL/kg/min; P=0.020 between groups.4
HF, heart failure; LSM, least squares mean; LVEF, left ventricular ejection fraction; SE, standard error; SmPC, Summary of Product Characteristics; SoC, standard of care; TSAT, transferrin saturation; VO2, volume of oxygen.
AFFIRM-AHF clinical study
Summary5
AFFIRM-AHF was the first international, multicentre, double-blind RCT designed to compare the effect of Ferinject® vs placebo on HF hospitalisations and CV death in patients with iron deficiency*† stabilised after an episode of acute HF.‡
AFFIRM-AHF was conducted across 121 sites in Europe, South America, and Singapore. A total of 1132 patients were randomised 1:1 to receive Ferinject® or placebo before hospital discharge. Study treatment was started in 1110 patients, and 1108 (558 in the Ferinject® group and 550 in the placebo group) had at least one post-randomisation value.‡ The statistical analysis plan included a pre-COVID-19 sensitivity analysis, censoring patients in each country at the date when its first COVID-19 patient was reported.
The primary endpoint was a composite of total HF hospitalisations and CV death up to 52 weeks after randomisation.
Primary outcome5
- Ferinject® reduced the rate of CV death and HF hospitalisations by 21% vs placebo in iron-deficient patients stabilised after an episode of acute HF (RR: 0.79; 95% CI: 0.62, 1.01; P=0.059)
- This result was driven by a 26% reduction in HF hospitalisations with Ferinject® vs placebo (RR: 0.74; 95% CI: 0.58, 0.94; P=0.013)
- There was no difference between the Ferinject® and placebo groups in rates of CV death (HR: 0.96; 95% CI: 0.70, 1.32; P=0.809)
Secondary outcome5
- Ferinject® reduced total CV hospitalisations and CV death by 20% vs placebo, although this was not statistically significant (RR: 0.80; 95% CI: 0.64, 1.00; P=0.05)
- Ferinject® improved the HR for time to first HF hospitalisation or CV death by 20% vs placebo (HR: 0.80; 95% CI: 0.66, 0.98; P=0.030)
- Ferinject® reduced the number of days lost due to HF hospitalisations and CV death by 33% vs placebo (RR: 0.67; 95% CI: 0.47, 0.97; P=0.035)
*Iron deficiency defined as ferritin <100 μg/L or 100-299 μg/L with TSAT <20%.5
† The baseline and Week 6 doses were based on the screening of haemoglobin and bodyweight values. The subsequent doses of study treatment (maintenance doses) were given at Weeks 12 (visit four) and 24 (visit five), only for patients in whom iron deficiency persisted and for whom haemoglobin was 8-15 g/dL.5
‡AFFIRM-AHF primary endpoint statistical significance was narrowly missed (P=0.059).5
Ferinject® was dosed according to the extent of iron deficiency.5
CI, confidence interval; COVID-19, Coronavirus Disease 2019; CV, cardiovascular; HF, heart failure; HR, hazard ratio; RCT, randomised controlled trial; RR, rate ratio; TSAT, transferrin saturation.
AFFIRM-AHF pre-specified analysis
Summary35
A pre-specified analysis of the AFFIRM-AHF trial* evaluated the effect of Ferinject® vs placebo in iron-deficient patients stabilised after an episode of acute HF on the 12-item KCCQ overall summary score and clinical summary score up to 52 weeks after randomisation.
Outcomes35
- Ferinject® improved HRQoL vs placebo, evaluated with KCCQ-12. Ferinject® resulted in significantly greater improvements in KCCQ-12 overall summary score and clinical summary score vs placebo from Week 4 to Week 24
- At Week 4, the mean change difference between treatment arms was +2.9 (95% CI: 0.5, 5.3; P=0.018) for overall summary score and +2.8 (95% CI: 0.3, 5.3; P=0.029) for clinical summary score, in favour of Ferinject®
- At Week 24, the mean change difference between treatment arms was +3.0 (95% CI: 0.3, 5.6; P=0.028) for overall summary score and +2.9 (95% CI: 0.2, 5.6; P=0.035) for clinical summary score in favour of Ferinject®
*AFFIRM-AHF primary endpoint statistical significance was narrowly missed (P=0.059).5
†Ferinject® is indicated for the treatment of iron deficiency when oral iron preparations are ineffective or cannot be used, or there is a clinical need to deliver iron rapidly. The diagnosis of iron deficiency must be based on laboratory tests.1
CI, confidence interval; HF, heart failure; HRQoL, health-related quality of life; KCCQ, Kansas City Cardiomyopathy Questionnaire.
HEART-FID clinical study
Summary31
HEART-FID was a multicentre, randomised, double-blind, placebo-controlled trial designed to assess the efficacy and safety of ferric carboxymaltose (FCM) in the treatment of symptomatic HFrEF patients with iron deficiency. A total of 3065 patients were randomised 1:1 to receive FCM (n=1532) or placebo (n=1533). The primary endpoint was a hierarchical composite of death and HF hospitalisation at 12 months and change from baseline to 6 months in 6MWD.
HEART-FID is the largest study to assess long-term safety and efficacy of FCM in HFrEF patients with iron deficiency. It adds to the totality of evidence from past trials, providing information on the safety profile of IV iron and its effects on clinical outcomes in iron-deficient patients with HF.
Outcomes31
- FCM resulted in modest improvement for the primary hierarchical endpoint of all-cause mortality, HF hospitalisation and 6MWD; however, this missed statistical significance (P=0.02 with a specified level of 0.01)
6MWD, six-minute walk distance; FCM, ferric carboxymaltose; HF, heart failure; HFrEF, heart failure with reduced ejection fraction; IV, intravenous.
2018 meta-analysis
Summary36
A meta-analysis of individual patient data from the FER-CARS-01, FAIR-HF, EFFICACY-HF and CONFIRM-HF* trials compared the rate of HF hospitalisations, among other outcomes, with Ferinject® vs placebo in HF patients with iron deficiency (n=839; 504 who were randomised to Ferinject®). All patients were ambulatory, NYHA class II/III, and had systolic chronic HF with iron deficiency. The main outcome measures were recurrent CV hospitalisations and CV mortality.
Outcomes36
- Ferinject® was associated with a 59% reduction in recurrent HF hospitalisations (RR: 0.41; 95% CI: 0.23, 0.73; P=0.003)
*In the CONFIRM-HF trial, Ferinject® was administered as an undiluted intravenous bolus injection over at least 1 minute, which deviated from the approved posology of the SmPC.2 The SmPC should always be consulted for the approved posology and method of administration.
CI, confidence interval; CV, cardiovascular; HF, heart failure; NYHA, New York Heart Association; RR, rate ratio; SmPC, Summary of Product Characteristics.
2023 meta-analysis
Summary32
A pooled analysis of individual patient data (N=4051) from three randomised, double-blind, placebo-controlled trials evaluating ferric carboxymaltose (FCM) treatment in HF patients with iron deficiency with ≥52 weeks of follow-up: CONFIRM-HF,* AFFIRM-HF, and HEART-FID. The co-primary efficacy endpoints were composite of total/recurrent CV hospitalisations and CV death, and composite of total HF hospitalisations and CV death, through 52 weeks.
This meta-analysis is the largest pooled analysis using individual patient data to examine the effects of FCM on clinical outcomes.
Outcomes32
- FCM was associated with a significant reduction in the rate of the composite of CV death and CV hospitalisation at 1 year in patients with HF and iron deficiency (P=0.029)
- There was a trend toward reduction in the rate of the composite of CV death or total HF hospitalisations during the 12-month follow-up (P=0.076)
*In the CONFIRM-HF trial, Ferinject® was administered as an undiluted intravenous bolus injection over at least 1 minute, which deviated from the approved posology of the SmPC.2 The SmPC should always be consulted for the approved posology and method of administration.
CV, cardiovascular; FCM, ferric carboxymaltose; HF, heart failure; SmPC, Summary of Product Characteristics.
References & footnotes
Footnotes
*Over 30 RCTs with a comparator group. Studies with heterogenous design with limitations as disclosed in the individual publication. Includes all patients administered at least 1 dose of Ferinject® during clinical trials completed and published by September 2023. Control subjects in all mentioned studies received either placebo, oral iron or another IV iron treatment.2-31
†Includes Van Wyck DB et al. 2009, a single publication combining data from two studies.28 IV iron products should not be used during pregnancy unless clearly necessary. Ferinject® treatment should be confined to the 2nd and 3rd trimester if the benefit is judged to outweigh the potential risk to mother and the foetus.1
‡Includes Barish CF et al. 2012, a single publication combining data from two studies.7
Abbreviations
HF, heart failure; ID, iron deficiency; IV, intravenous; RCT, randomised controlled trial.
References
- Ferinject UAE SmPC. Ferinject KSA SmPC.
- Ponikowski P et al. Beneficial effects of long-term intravenous iron therapy with ferric carboxymaltose in patients with symptomatic heart failure and iron deficiency. Eur Heart J 2015;36(11):657–68.
- Anker SD et al. Ferric carboxymaltose in patients with heart failure and iron deficiency. N Engl J Med 2009;361(25):2436–48.
- van Veldhuisen DJ et al. Effect of ferric carboxymaltose on exercise capacity in patients with chronic heart failure and iron deficiency. Circulation 2017;136(15):1374–83.
- Ponikowski P et al. Ferric carboxymaltose for iron deficiency at discharge after acute heart failure: a multicentre, double-blind, randomised, controlled trial. Lancet 2020;396(10266):1895–904.
- Bailie GR et al. Safety and tolerability of intravenous ferric carboxymaltose in patients with iron deficiency anaemia. Hemodialysis Int 2010;14(1):47–54.
- Barish CF et al. Safety and efficacy of intravenous ferric carboxymaltose (750 mg) in the treatment of iron deficiency anaemia: two randomised, controlled trials. Anemia 2012;2012:172104.
- Boomershine CS et al. A blinded, randomised, placebo-controlled study to investigate the efficacy and safety of ferric carboxymaltose in iron-deficient patients with fibromyalgia. Rheumatol Ther 2018;5(1):271–81.
- Breymann C et al. Comparative efficacy and safety of intravenous ferric carboxymaltose in the treatment of postpartum iron deficiency anaemia. Int J Gynecol Obstet 2008;101(1):67–73.
- Breymann C et al. Ferric carboxymaltose vs. oral iron in the treatment of pregnant women with iron deficiency anaemia: an international, open-label, randomised controlled trial (FER-ASAP). J Perinat Med 2017;45(4):443–53.
- Charytan C et al. Intravenous ferric carboxymaltose versus standard medical care in the treatment of iron deficiency anaemia in patients with chronic kidney disease: a randomised, active-controlled, multi-centre study. Nephrol Dial Transplant 2013;28(4):953–64.
- Evstatiev R et al. Ferric carboxymaltose prevents recurrence of anaemia in patients with inflammatory bowel disease. Clin Gastroenterol Hepatol 2013;11(3):269–77.
- Evstatiev R et al. FERGIcor, a randomised controlled trial on ferric carboxymaltose for iron deficiency anaemia in inflammatory bowel disease. Gastroenterology 2011;141(3):846–53.
- Favrat B et al. Evaluation of a single dose of ferric carboxymaltose in fatigued, iron-deficient women—PREFER a randomised, placebo-controlled study. PLoS ONE 2014;9(4):e94217.
- Geisser P, Bank-Bochita J. Pharmacokinetics, safety and tolerability of intravenous ferric carboxymaltose: a dose-escalation study in volunteers with mild iron-deficiency anaemia. Arzneimittelforsch 2010;60(6a):362–72.
- Hedenus M et al. Intravenous iron alone resolves anaemia in patients with functional iron deficiency and lymphoid malignancies undergoing chemotherapy. Med Oncol 2014;31(12):302.
- Hussain I et al. Direct comparison of the safety and efficacy of ferric carboxymaltose versus iron dextran in patients with iron deficiency anaemia. Anemia 2013;2013:169107.
- Kulnigg S et al. A novel intravenous iron formulation for treatment of anaemia in inflammatory bowel disease: the ferric carboxymaltose (FERINJECT) randomised controlled trial. Am J Gastroenterol 2008;103(5):1182–92.
- Kulnigg-Dabsch S et al. Iron deficiency generates secondary thrombocytosis and platelet activation in IBD: the randomised, controlled thromboVIT trial. Inflamm Bowel Dis 2013;19(8):1609–16.
- Macdougall IC et al. FIND-CKD: a randomised trial of intravenous ferric carboxymaltose versus oral iron in patients with chronic kidney disease and iron deficiency anaemia. Nephrol Dial Transplant 2014;29(11):2075–84.
- Onken JE et al. Ferric carboxymaltose in patients with iron-deficiency anaemia and impaired renal function: the REPAIR-IDA trial. Nephrol Dial Transplant 2014;29(4):833–42.
- Onken JE et al. A multicentre, randomised, active-controlled study to investigate the efficacy and safety of intravenous ferric carboxymaltose in patients with iron deficiency anaemia. Transfusion 2014;54(2):306–15.
- Qunibi WY et al. A randomised controlled trial comparing intravenous ferric carboxymaltose with oral iron for treatment of iron deficiency anaemia of non-dialysis-dependent chronic kidney disease patients. Nephrol Dial Transplant 2011;26(5):1599–607.
- Seid MH et al. Ferric carboxymaltose injection in the treatment of postpartum iron deficiency anaemia: a randomised controlled clinical trial. Am J Obstet Gynecol 2008;199(4):435.e1–e7.
- Seid MH et al. Ferric carboxymaltose as treatment in women with iron-deficiency anaemia. Anemia 2017;2017:9642027.
- Trenkwalder C et al. Ferric carboxymaltose in patients with restless legs syndrome and nonanaemic iron deficiency: a randomised trial. Mov Disord 2017;32(10):1478–82.
- Van Wyck DB et al. Intravenous ferric carboxymaltose compared with oral iron in the treatment of postpartum anaemia: a randomised controlled trial. Obstet Gynecol 2007;110(2 Pt 1):267–78.
- Van Wyck DB et al. Large-dose intravenous ferric carboxymaltose injection for iron deficiency anaemia in heavy uterine bleeding: a randomised, controlled trial. Transfusion 2009;49(12):2719–28.
- Allen RP et al. Clinical efficacy and safety of IV ferric carboxymaltose (FCM) treatment of RLS: a multi-centred, placebo-controlled preliminary clinical trial. Sleep Med 2011;12(9):906–13.
- Ikuta K et al. Comparison of efficacy and safety between intravenous ferric carboxymaltose and saccharated ferric oxide in Japanese patients with iron-deficiency anaemia due to hypermenorrhoea: a multi-center, randomised, open-label noninferiority study. Int J Hematol 2019;109(1):41–9.
- Mentz RJ et al. Ferric carboxymaltose in heart failure with iron deficiency. N Engl J Med 2023;389(11):975–86.
- Ponikowski P et al. Efficacy of ferric carboxymaltose in heart failure with iron deficiency: an individual patient data meta-analysis. Eur Heart J 2023;44(48):5077–91.
- CSL Annual Report, February 2022.
- CSL Data on File (REF-12503).
- Jankowska EA et al. The effect of intravenous ferric carboxymaltose on health-related quality of life in iron-deficient patients with acute heart failure: the results of the AFFIRM-AHF study. Eur Heart J 2021;42(31):3011–20.
- Anker SD et al. Effects of ferric carboxymaltose on hospitalisations and mortality rates in iron-deficient heart failure patients: an individual patient data meta-analysis. Eur J Heart Fail 2018;20(1):125–33.
- McDonagh TA et al. 2023 Focused Update of the 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J 2023;44(37):3627–39.
- McDonagh TA et al. 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J 2021;42(36):3599–726.
A complete copy of the cited publications may be requested from CSL in your country.
CSL is a global partner of choice for pharmaceuticals and innovative, leading therapies in iron deficiency and nephrology. We specialize in strategic global partnering, in-licensing and developing, manufacturing and marketing pharmaceutical products for precision healthcare, aiming to help patients around the world lead better, healthier lives. Headquartered in St. Gallen, Switzerland, CSL also includes the joint company Vifor Fresenius Medical Care Renal Pharma (with Fresenius Medical Care).
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