Media Backgrounder

Media Backgrounder

31 August 2015

Ferinject® (ferric carboxymaltose) in iron deficient heart failure patients: a meta-analysis of individual-patient data from randomised clinical trials shows potential to reduce rate of cardiovascular hospitalisation and cardiovascular death.

Heart Failure

More than 23 million people worldwide suffer from heart failure (HF), a progressively burdensome and debilitating condition1 with an increasing incidence and prevalence especially in the elderly (>10% prevalence).2

Despite advances in HF management, a diagnosis of HF carries a substantial risk of poor outcomes to include, hospitalisation and mortality; half of all patients diagnosed with HF will die with 4 years.3

HF is responsible for high rates of costly hospitalisations4 and around 1-2% of total healthcare expenditure in developed countries, with HF hospitalisations representing nearly 70% of these costs.5 Reducing the risk for cardiovascular hospitalisation and death remain a clinical priority in CHF.6

Iron Deficiency in Heart Failure

Iron deficiency (ID) is a recognised comorbidity in chronic heart failure (CHF)8 and, in Europe, present in up to 50% of patients. ID, even in the absence of anaemia, is associated with high symptom burden, reduced exercise capacity, and impaired quality of life. In addition, ID is an independent risk factor for mortality.

ID therefore represents a modifiable risk factor where therapeutic intervention could provide benefit to patients and since 2012, the European Society of Cardiology Heart Failure has recommended the screening and diagnosis of ID in all patients suspected of having HF, with management a key component of overall patient care.6 ID is defined as ferritin <100 ng/mL, or ferritin 100-300 ng/mL if transferrin saturation (TSAT) <20%.

However, ID remains an under-diagnosed and under-treated co-morbidity of HF.7

Meta-analysis Purpose and Design

Although several individual studies have evaluated intravenous (i.v.) iron therapy for ID in CHF, only studies with i.v. iron as Ferinject® have delivered evidence supporting clinically meaningful improvements on exercise capacity, symptoms and quality of life.8-13 One of these Ferinject® studies, CONFIRM-HF, reported an associated reduction in hospitalisations due to HF across 301 patients when treated with Ferinject® compared to placebo.13

To further characterise Ferinject® benefits on hospitalisation and mortality in ambulatory patients with systolic CHF and ID, a meta-analysis on individual patient data was performed using all the available data from 4 completed trials conducted in systolic CHF patients with ID (FER-CARS-01, FAIR-HF, EFFICACY-HF and CONFIRM-HF) which compared the i.v. iron therapy with Ferinject® with placebo (saline). This analysis represents data from over 800 ambulatory patients with systolic CHF and ID.

All the trials were designed as double-blind, multi-centre, prospective, randomised trials and enrolled ambulatory patients with symptomatic CHF (NYHA class II/III) with left ventricular ejection fraction (LVEF) ≤45% and with the presence of ID (defined as ferritin <100 ng/mL, or ferritin 100-300 ng/mL if transferrin saturation (TSAT) <20%).

A summary of these trials can be found in Table 1.

The primary efficacy outcome was the composite of all cardiovascular (CV) hospitalisations and CV deaths. Secondary outcomes included the composites: HF hospitalisation and CV death, CV hospitalisation and all-cause death and, HF hospitalisation and all-cause death in addition to the individual composite components. For all four studies, hospitalisations and cause of death were independently adjudicated in a blinded manner by an adjudication committee.

Ferinject®

Ferinject® (ferric carboxymaltose) is an innovative non-dextran intravenous (i.v.) iron replacement therapy discovered and developed by Vifor Pharma, a company of the Galenica Group. To date, Ferinject® has gained marketing authorisation in 68 countries worldwide for the treatment of iron deficiency where oral iron is ineffective or cannot be used. In many countries, intravenous iron replacement products are primarily used to treat dialysis patients. However, iron deficiency is also a complication of many other diseases. Vifor Pharma is evaluating new opportunities in the treatment of iron deficiency with Ferinject® in different therapeutic areas. Further clinical trials with Ferinject® in chronic kidney disease (CKD), oncology (anaemia in cancer patients), cardiology (chronic heart failure), patient blood management and women’s health are ongoing.

FAIR-HF / FER-CARS-01 / EFFICACY-HF / CONFIRM-HF
Patient population / Ambulatory, optimally treated, systolic CHF with ID, NYHA class II/III / Ambulatory, optimally treated, systolic CHF with ID, NYHA class II/III, renal dysfunction (eGFR< 60ml/min per 1·73m2) / Ambulatory, optimally treated, systolic CHF with ID, NYHA class II/III / Ambulatory, optimally treated, systolic CHF with ID, NYHA class II/III
Randomisation / 2:1 (FCM:placebo) / 1:1 (FCM:placebo) / 1:1 (FCM:placebo) / 1:1 (FCM:placebo)
Number of patients (FAS) FCM/Placebo / 304/155 / 30/15 / 20/14* / 150/151
Comparator / i.v. FCM vs. placebo / i.v. FCM vs. placebo§ / i.v. FCM vs. placebo / i.v. FCM vs placebo
Study duration / 24 weeks / 12 weeks / 24 weeks / 52 weeks
Calculation of iron repletion dose / Ganzoni formula using the mean of two baseline Hb values / Ganzoni formula using the mean of two baseline Hb values / Ganzoni formula using the mean of two baseline Hb values / Determined by baseline Hb values and screening body weight
Correction phase
(i.e. until iron repletion) / Over three to maximally nine weeks: weekly i.v. injections (200mg/100mg iron) of FCM/placebo / For maximally four weeks: weekly i.v. injections (200mg/100mg iron) of FCM/placebo / Over three to maximally nine weeks: weekly i.v. injections (200mg/100mg iron) of FCM/placebo / Over a six week period, maximally two i.v. injections (500mg/1000mg iron) of FCM/placebo
Maintenance phase / 4-weekly 200mg iron i.v. injection (FCM/placebo) up to 24 weeks after randomisation / 4-weekly 200mg iron i.v. injection (FCM/placebo) up to 12 weeks after randomisation / 4-weekly 200mg iron i.v. injection (FCM/placebo) up to 24 weeks after randomisation / 3-monthly 500mg iron i.v. injection (FCM/placebo) up to 36 weeks after randomisation, if ID still present
Primary endpoint(s) / PGA at Week 24 and NHYA class from baseline to Week 24 / PGA at Week 24 and NHYA class from baseline to Week 24 / Change in 6MWT and NHYHA class from baseline to Week 24 / Change in 6MWT from baseline to Week 24

Table 1 – Design features of the RCTs included in this meta-analysis

CHF=chronic heart failure. ID= iron deficiency . NYHA=New York Heart Association. eGFR=estimated glomerular filtration rate. FCM=ferric carboxymaltose., IS=iron sucrose. FAS=Full Analysis Set. i.v.=intravenous. Hb=haemoglobin. PGA=Patient Global Assessment. 6MWT=six-minute walk test. RCT=randomised clinical trial. Ganzoni formula of total iron deficit [mg] = body weight (b.w.) [kg] x (150 - actual Hb [g/L]) x 0.24 + 500 [mg]. Iron repletion dose=correction of iron deficiency. * EFFICACY-HF was discontinued due to recruitment issues. § Placebo = i.v. normal saline.

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References

1.  McMurray JJ, Petrie MC, Murdoch DR, Davie AP. Clinical epidemiology of heart failure: public and private health burden. Eur Heart J 1998;19 (Suppl P):P9–P16.

2.  Lloyd-Jones D, et al. Heart disease and stroke statistics—2010 update: a report from the American Heart Association. Circulation 2010;121:e46–e215.

3.  Bleumink GS, et al. Quantifying the heart failure epidemic: prevalence, incidence rate, lifetime risk and prognosis of heart failure. The Rotterdam Study. Eur Heart J 2004;25:1614–1619.

4.  Goldberg RJ, Ciampa J, Lessard D, et al. Long-term survival after heart failure: a contemporary population-based perspective. Arch Intern Med 2007;167:490–496.

5.  Stewart S, et al. The current cost of heart failure to the National Health Service in the UK. Eur J Heart Fail 2002;4:361–371.

6.  McMurray JJ, Adamopoulos S, Anker SD, et al. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2012. Eur Heart J 2012; 33:1787–1847.

7.  Silverberg DS, Schwartz D, Schwartz I, Ben Assa E. The missed opportunities to diagnose and treat iron deficiency in patients hospitalized with heart failure.Int J Cardiol. 2013 Oct 3;168(3):2164-6.

8.  Toblli JE, Lombrana A, Duarte P, Di Gennaro F. Intravenous iron reduces NT-pro-brain natriuretic peptide in anemic patients with chronic heart failure and renal insufficiency. J Am Coll Cardiol 2007;50:1657–1665.

9.  Bolger AP, Bartlett FR, Penston HS, et al. Intravenous iron alone for the treatment of anemia in patients with chronic heart failure. J Am Coll Cardiol 2006;48:1225–1227.

10.  Okonko DO, Grzeslo A, Witkowski T, et al. Effect of intravenous iron sucrose on exercise tolerance in anemic and nonanemic patients with symptomatic chronic heart failure and iron deficiency FERRIC-HF: a randomized, controlled, observer blinded trial. J Am Coll Cardiol 2008;51:103–112.

11.  Usmanov RI, Zueva EB, Silverberg DS, Shaked M. Intravenous iron without erythropoietin for the treatment of iron deficiency anemia in patients with moderate to severe congestive heart failure and chronic kidney insufficiency. J Nephrol 2008;21:236–242.

12.  Anker SD, Comin Colet J, Filippatos G, et al. Ferric carboxymaltose in patients with heart failure and iron deficiency. N Engl J Med 2009;361:2436-2448.

13.  Ponikowski P, van Veldhuisen DJ, Comin Colet J, et al. Beneficial effects of long term intravenous iron therapy with ferric carboxymaltose in patients with symptomatic heart failure and iron deficiency. European Heart Journal 2015;36:657–668.