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Guideline 2.3 – Treatment of Anaemia with Iron Therapy – Route of Administration

Guideline 2.3 – Treatment of Anaemia with Iron Therapy – Route of Administration

We suggest that for people with CKD not requiring HD, or people currently receiving PD who are being considered for ESA therapy, intravenous iron should be considered to reduce ESA dose requirements. (2B)

Guideline 2.3.1

We suggest for people with NDD-CKD or maintained on PD (i.e. not requiring HD), the choice between oral vs. parenteral iron depends on a shared decision and should include the impact of the severity of iron deficiency, the previous response and side effects, the availability of venous access and the need to initiate ESA or HIF-PHI therapy. (2A)

Guideline 2.3.2

We recommend that most people on haemodialysis will require IV iron. (1A)

Guideline 2.3.3

We suggest when offering IV iron therapy to people not receiving in-centre HD, to consider high dose, low frequency (HiD/LF) IV iron as the treatment of choice for adults and young people when trying to achieve iron repletion, considering all of the following (2B):

  • Availability of venous access
  • Preferences of the person with anaemia of CKD or, where appropriate, their family or carers
  • Nursing and administration costs
  • Cost of local drug supply
  • Provision of resuscitation facilities

Guideline 2.3.4

We suggest the frequency of administration of HiD/LF IV iron for people with CKD not requiring HD and for people receiving PD needs to be tailored for each person as there is no clear data. (not graded)

Rationale

The evidence base for IV iron over oral iron in people with CKD who are pre-dialysis or maintained on PD is limited. Oral iron, if tolerated, appears to be adequate in most people particularly in combination with ESA therapy. In people who appear resistant to ESA therapy on oral iron, or are intolerant of oral iron, a therapeutic trial of IV iron trial seems reasonable.

  • One randomised study in 188 participants with IV iron (1000 mg iron sucrose in divided doses over 14 days) versus oral iron (ferrous sulphate 325 mg TDS) in pre-dialysis participants demonstrated a greater improvement in Hb outcome in those on IV iron (more participants achieved a Hb increased of >10 g/L) but no difference in the proportion of participants who had to commence ESA after the start of the study (1).
  • Two studies in pre-dialysis populations not on ESA (one without oral iron and the other after oral iron therapy) demonstrated improvements in Hb outcome after IV iron (2, 3).

Oral iron is easy and cheap to prescribe. However, it seems reasonable to treat people with CKD who have not responded to, or have been intolerant of, oral iron with IV iron.

Two randomised controlled trials of oral versus IV iron supplementation in participants with advanced NDD-CKD receiving concomitant ESAs agree. In the first study of 45 participants with Hb <110 g/L given either ferrous sulphate 200 mg TDS versus 300 mg iron sucrose IV monthly, there was no difference in Hb or ESA dose between the oral and IV group receiving ESA over a mean 5.2 months follow-up (4). Iron stores were greater in the IV than oral group. Five participants (55%) in the oral iron group had diabetes, compared to none on the IV iron group and this may have confounded the results on iron stores. In addition, more participants in the oral iron group were exposed to ACEi/ARBs.

Similar findings were reported in another study of 96 people with NDD-CKD comparing 5 weeks of IV iron sucrose (200 mg every 7 days for a total of 5 doses) versus 29 days of thrice daily oral iron (ferrous sulphate 325 mg TDS). There was no difference in Hb or ESA dose but greater increase in ferritin in the IV group (5). In this study the frequency of gastrointestinal symptoms was greater in the oral iron group than the IV iron group (constipation 34.5% vs. 12.5%; nausea 10.4% vs. 4.2%).

High dose, low frequency (HiD/LF) is considered to be a maximum of 2 infusions. For adults this is considered to be a minimum of 500 mg of iron in each infusion. Low dose, high frequency (LD/HF) is considered to be more than 2 infusions. For adults, there would typically be 100–200 mg of iron in each infusion.

At the time of publication intravenous iron products available in the UK did not have a UK marketing authorisation for all ages of children and young people for this indication.

Refer to the Summary of Product Characteristics for the prescription of individual iron preparations.

There is increasing evidence that using IV iron in CKD-PD is safe, improves Hb levels and reduces ESA dose requirements (6):

  • A cross-over study of oral and IV iron demonstrated higher Hb and lower ESA doses with IV iron after 4 months oral (7).
  • A retrospective study evaluating ferric carboxymaltose (FCM) in a population of 91 people with CKD-PD over 12 months found no SAEs including hypersensitivity. More than 60% of participants achieved ferritin 200–800 mcg/L and TSAT >20% and a reduced ESA dose was necessary to maintain Hb levels (8).
  • A study demonstrated that abnormal iron status, is associated with an increased risk of mortality in people treated with PD. Functional Iron Deficiency (FID) had the greatest all-cause and cardiovascular mortality (9).

The relative safety of parenteral iron compared with oral iron was assessed in a study involving participants with stage 3 and 4 NDD-CKD and iron deficiency anaemia. Study participants were randomly assigned to either oral ferrous sulphate (n=69 to 325 mg three times daily for 8 weeks) or IV iron sucrose (n=67 to 200 mg every 2 weeks, total 1 g). The trial was terminated early based of a higher risk of serious adverse events in the IV iron treatment group. There were 36 serious cardiovascular events among 19 participants assigned to the oral iron treatment group and 55 events among 17 participants of the intravenous iron group (adjusted incidence rate ratio 2.51 (1.56–4.04)). Infections resulting in hospitalisation had a significantly increased adjusted incidence rate ratio of 2.12 (1.24–3.64). The authors concluded that among people with NDD-CKD and anaemia, IV iron therapy could be associated with an increased risk of serious adverse events, including those from cardiovascular causes and infectious diseases (10).

Conversely, the above finding was not reproduced in another larger trial that involved 626 people with NDD-CKD with anaemia and iron deficiency not on ESAs (11). In this trial, participants were randomised (1:1:2) to intravenous (IV) ferric carboxymaltose (FCM), targeting a higher (400–600 microgram/L) or lower (100–200 microgram/L) ferritin range or oral iron therapy. The primary end point was time to initiation of other anaemia management (ESA, other iron therapy or blood transfusion) or Hb trigger of two consecutive values <100 g/L during Weeks 8–52. Achieving a higher ferritin target range led to a delay in the need to initiate ESA therapy and also a reduction in ESA dosage. The increase in Hb was greater with high-ferritin FCM versus oral iron (P = 0.014) and a greater proportion of participants achieved an Hb increase ≥10 g/L with high-ferritin FCM versus oral iron (HR: 2.04; 95% CI: 1.52–2.72; P < 0.001). Rates of adverse events and serious adverse events were similar in all groups (11).

Similarly, no safety signal could be detected in another trial comparing intravenous iron isomaltoside versus oral iron in stage G5 NDD-CKD. In this trial 351 iron-deficient participants were randomised 2:1 to either iron isomaltoside 1000 or iron sulphate administered as 100 mg elemental oral iron twice daily (200 mg daily) for 8 weeks. Hb response, serum-ferritin and TSAT were significantly increased with IV iron compared with those treated with oral iron. Incidence of adverse drug reactions was not different between both groups. More participants treated with oral iron sulphate withdrew from the study due to adverse events (4.3 versus 0.9%, P = 0.2) (12).

At present oral iron should remain first line treatment among people with NDD-CKD and IV iron used if recipients are intolerant of oral iron or remain with absolute or FID despite oral iron therapy. The further interpretation of these results is limited by several factors including the relative short duration of follow-up and limited data on potential long term adverse effects such as the impact of oxidative stress. However, as indicated by NICE, therapy should be individualised, or perhaps tailored and a high dose low frequency intravenous regime should be employed.

People treated with HD have additional iron losses from GI bleeding, blood tests and losses in the dialysis circuit that result in iron supplementation requirements that outstrip the capacity of the gut to absorb iron effectively. Maintenance IV iron in HD greatly reduces ESA requirements and costs (1,4,13-18). Maintaining iron stores at steady state in a HD population requires 50-60 mg/week of intravenous iron (14-16). How this is repleted remains a subject under study. A recent open label, randomised, multicentre, non-inferiority trial conducted in 351 people on HD randomised 2 : 1 to either iron isomaltoside 1000 (Group A) or iron sucrose (Group B) (19). Subjects in Group A were equally divided into A1 (500 mg single bolus injection) and A2 (500 mg split dose). Group B were also treated with 500 mg split dose. All treatments showed similar efficacy and safety (19).

The FERWON Trial of 1538 people with NDD-CKD and iron deficiency anaemia (Hb <110 g/L, SF <100 mcg/L or <300 mcg/L and TSAT<30% and stable dose of ESA, was a randomised, open label study. 1027 participants were randomised to 1g iron isomaltoside and 511 to iron sucrose (200 mg given in in total up to five time) (20). The co-primary endpoints were serious or severe hypersensitivity reactions and change in Hb from baseline to week 8. There were additional key safety endpoints: the incidence of composite cardiovascular adverse events and frequency of hypophosphatemia (<0.65 mmol/L]). The results showed a faster and greater early response with iron isomaltoside for Hb, SF and TSAT compared to iron sucrose. There was no statistically significant difference in the frequency of serious or severe hypersensitivity reactions between the treatment groups. The incidence of composite cardiovascular AEs was statistically significantly lower in the isomaltoside group compared to the sucrose group (4.1% vs 6.9%; p=0.25).

A prospective case control study from rural India comparing oral (ferrous sulfate) vs IV iron (iron sucrose found that serum iron, ferritin and TSAT increased in the IV iron compared to the oral group (21). There were significant increases in Hb in all stages of kidney disease with IV iron in contrast to not being achieved with oral iron (21).

A trial of 60 people with pre-dialysis CKD (NDD-CKD) oral ferric citrate (2 g three times daily) versus oral ferrous sulfate (325 mg TDS) showed greater increases in TSAT and ferritin but no difference in Hb or in incidence of adverse events at 12 weeks (22).

References

  1. Van Wyck DB, Roppolo M, Martinez CO et al. A randomized, controlled trial comparing IV iron sucrose to oral iron in anaemic patients with non-dialysis dependent CKD. Kidney Int 2005; 68: 2846-2856.
  2. Anuradha S, Singh NP, Agarwal SK. Total dose infusion iron dextran therapy in pre-dialysis chronic renal failure patients. Renal Failure 2002; 24: 307-313.

  3. Silverberg DS, Iaina A, Peer G et al. Intravenous iron supplementation for the treatment of the anaemia of moderate to severe chronic renal failure patients not receiving dialysis. Am.J.Kidney Dis 1996; 27: 234-238.

  4. Stoves J, Inglis H, Newstead CG. A randomized study of oral vs. intravenous iron supplementation in patients with progressive renal insufficiency treated with erythropoietin. Nephrol.Dial.Transplant 2001; 16: 967-974.

  5. Charytan C, Qunibi W, Bailie GR. Comparison of intravenous iron sucrose to oral iron in the treatment of anaemic patients with chronic kidney disease not on dialysis. Nephron Clin.Pract 2005; 100: c55-c62.

  6. England E, Sheffield M, Poyah P, Clark D, Wilson J-A. Ferric derisomaltose evaluation in patients with non–dialysis-dependent chronic kidney disease or peritoneal dialysis. Canadian Journal of Hospital Pharmacy. 2023;76(2):94–101. doi:10.4212/cjhp.3310

  7. Ahsan N. Infusion of total dose iron versus oral iron supplementation in ambulatory peritoneal dialysis patients: a prospective, cross-over trial. Adv Perit Dial 2000; 16:80-84.

  8. Portolés-Pérez J, Durá-Gúrpide B, Merino-Rivas JL, Martín-Rodriguez L, Hevia-Ojanguren C, Burguera-Vion V, et al. Effectiveness and safety of ferric carboxymaltose therapy in peritoneal dialysis patients: An observational study. Clinical Kidney Journal. 2019;14(1):174–80. doi:10.1093/ckj/sfz153

  9. Luo D, Zhong Z, Qiu Y, Wang Y, Li H, Lin J, et al. Abnormal iron status is associated with an increased risk of mortality in patients on peritoneal dialysis. Nutrition, Metabolism and Cardiovascular Diseases. 2021;31(4):1148–55. doi:10.1016/j.numecd.2020.12.018

  10. Agarwal R, Kusek JW, Pappas MK. A randomized trial of intravenous and oral iron in chronic kidney disease. Kidney Int. 2015 Oct;88(4):905-14.

  11. Macdougall IC, Bock AH, Carrera F, et al.; for the FIND-CKD Study Investigators. FIND-CKD: a randomized trial of intravenous ferric carboxymaltose versus oral iron in patients with chronic kidney disease and iron deficiency anaemia. Nephrol Dial Transplant 2014; 29:2075- 2084.

  12. Kalra PA, Bhandari S, Saxena S, et al. A randomized trial of iron isomaltoside 1000 versus oral iron in non-dialysis-dependent chronic kidney disease patients with anaemia. Nephrol Dial Transplant 2016 31: 646– 655.

  13. Besarab A, Kaiser JW, Frinak S. A study of parenteral iron regimens in haemodialysis patients. Am J Kidney Dis 1999; 34: 21-28.

  14. Macdougall IC, Chandler G, Elston O et al. Beneficial effects of adopting an aggressive intravenous iron policy in a haemodialysis unit. Am J Kidney Dis 1999; 34:S40-S46.

  15. Besarab A, Amin N, Ahsan M et al. Optimization of epoetin therapy with intravenous iron therapy in haemodialysis patients. J Am Soc Nephrol 2000; 11: 530-538.

  16. Richardson D, Bartlett C, Will EJ. Optimizing erythropoietin therapy in haemodialysis patients. Am J Kidney Dis 2001; 38: 109-117.

  17. Fishbane S, Frei GL, Maesaka J. Reduction in recombinant human erythropoietin doses by the use of chronic intravenous iron supplementation. Am J Kidney Dis 1995; 26: 41-46.

  18. Macdougall IC, Tucker B, Thompson J et al. A randomized controlled study of iron supplementation in patients treated with erythropoietin. Kidney Int 1996; 50: 1694-1699.

  19. Bhandari S, Kalra PA, Kothari J et al A randomized, open-label trial of iron isomaltoside1000 (Monofer®) compared with iron sucrose (Venofer®) as maintenance therapy in haemodialysis patients. Nephrol Dial Transplant 2015 0: 1–13, doi: 10.1093/ndt/gfv096

  20. Bhandari, S. et al. Safety and efficacy of iron isomaltoside 1000/ferric derisomaltose versus iron sucrose in patients with chronic kidney disease: The FERWON-NEPHRO randomized, open-label, comparative trial. Nephrol. Dial. Transplant. 2021, 36, 1: 111-120 https://doi.org/10.1093/ndt/gfaa011(2020).

  21. Agrawal S, Sonawane S, Kumar S, Acharya S, Gaidhane SA, Wanjari A, et al. Efficacy of Oral Versus Injectable Iron in Patients with Chronic Kidney Disease: A Two-Year Cross-Sectional Study Conducted at a Rural Teaching Hospital. Cureus. 14(7):e27529.

  22. Womack R, Berru F, Panwar B, Gutiérrez OM. Effect of Ferric Citrate versus Ferrous Sulfate on Iron and Phosphate Parameters in Patients with Iron Deficiency and CKD: A Randomized Trial. Clin J Am Soc Nephrol CJASN [Internet]. 2020 Sep 7 [cited 2023 Jul 18];15(9). Available from: https://pubmed.ncbi.nlm.nih.gov/32694162/