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Safety and efficacy of intravenous iron therapy in reducing requirement for allogeneic blood transfusion: systematic review and meta-analysis of randomised clinical trials

BMJ 2013; 347 doi: https://doi.org/10.1136/bmj.f4822 (Published 15 August 2013) Cite this as: BMJ 2013;347:f4822

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Re: Safety and efficacy of intravenous iron therapy in reducing requirement for allogeneic blood transfusion: systematic review and meta-analysis of randomised clinical trials

Bioavailability of iron can be a limiting factor for growth of pathogens in a host.1 Intravenous (IV) iron may promote bacterial growth and impair host defence, but this risk has not been clinically well-defined. To evaluate the efficacy and safety of IV iron, Litton et al performed a systematic review and meta-analysis of 72 randomised controlled trials (RCTs) published between 1966 and 2013 with a total of 10,605 patients.2

Compared with oral iron and no iron, Litton et al found that IV iron effectively increased haemoglobin concentration and reduced red blood cell transfusions in various settings, but it was also associated with increased risk of infection (relative risk [RR] 1.33, 95% confident interval [CI] 1.10-1.64).2 However, the authors acknowledged that since infection was not a predefined endpoint in many pooled studies, there was possibility of unmeasured bias. They could not detect a dose-response association between iron and risk of infection, further undermining the causal relationship. Finally, rates of mortality and other serious adverse events were not statistically significantly higher in patients randomized to IV iron.2

The authors performed heterogeneity and sensitivity analyses, but these measures cannot be fully reassuring when data from studies on different populations (medical and surgical) with various pathologies, receiving different IV iron formulations with different dosing regimens are pooled. As an example, only 2 surgical RCTs were included, neither of which reported any associations between IV iron and infection rates.3;4

Without a reliable measure of infection rates and amidst no difference in serious adverse outcomes, it is impossible to determine the impact of IV iron on clinically significant infections and no inference can be made. Nonetheless, the authors concluded that IV iron was associated with increased risk of infections.2

It appears that the search strategy was incomplete since published relevant trials (some dating back to 2000) were overlooked (Appendix). Additionally, even though the authors indicated that only data from published RCT were used, they asked for and included additional data from the authors of some of the studies. The applied eligibility criteria also excluded a wealth of data from a number of well-designed published studies. In a prospective cross-sectional study of 988 dialysis patients , Hoen et al observed that use of catheters, history of infections, immunosuppression and anaemia were associated with increased risk of bacteraemia, whereas IV iron administration, its dose or durationwere not.5 In a subsequent review of these data no significant association between IV iron administration and the risk of bacteremia was demonstrated, with the exception of a slightly increased risk in patients receiving high-dose IV iron in high frequency.6

Brookhart et al estimated the effects of various iron dosing patterns on risks of mortality and infection-related hospitalizations in 776,203 exposure/follow-up pairs, and reported that while bolus dosing was associated with increased risk, maintenance dosing with IV iron was not associated with increased risk for adverse outcomes including infections, compared with no iron.7

In a study by Muñoz et al, diagnosis of infection was clinically made by a senior member of the clinical team using pre-established criteria and confirmed by laboratory, microbiologic or radiologic evidence. Compared with oral iron or no iron, perioperative IV iron (200-600 mg) - with or without single dose of ESA - reduced rates of transfusion, infection and 30-day mortality in 1,361 hip fracture patients; benefits were observed in transfused and non-transfused patients. Additionally, in 1,186 elective arthroplasty patients, IV iron reduced transfusion rates.8 Similarly, Torres et al found no impact of IV iron on the postoperative infection rate in a cardiac surgery cohort (n=863), using established infection criteria.9

The long-term toxicity of IV iron remains a concern. In one of the most comprehensive works on this subject, the time-dependent association between IV iron and all-cause and cardiovascular mortality in 32,566 maintenance haemodialysis patients was studied.10 After extensive adjustment for confounders, the lowest all-cause and cardiovascular death risks were associated with ferritin levels between 200-1200 mg/ml and TSATs between 30 and 50%. Furthermore, compared with those who did not receive IV iron, maintenance doses up to 400 mg per month were associated with improved survival. Supporting higher maintenance doses in a study of 5,833 haemodialysis patients, Feldman et al reported a slightly increased mortality in patients receiving more than one gram of IV iron over a six month period; the association disappeared after controlling for confounding factors.11 More recently, a study of 1,774 dialysis-dependent chronic kidney disease (CKD) patients reported that a relatively high haemoglobin level, moderate IV iron administration (≤455 mg/month), and presence of indicators of iron sufficiency were associated with improved long-term survival.12 IV iron administration decreases hyporesponsiveness to erythropoietin stimulating agents (ESAs) as well as iron depletion-associated thrombocytosis in CKD patients and therefore may also reduce mortality associated with the high ESA doses.10

These results are consistent with the report of the RCT by Anker et al in which patients with heart failure (including ~40% with CKD) had improvements in quality of life and functional status without increased infections.13

The conclusions of the meta-analysis by Litton et al are unfortunately undermined by the limitations of their study, and are somewhat contradictory to the litany of other studies. While provocative animal and in vitro studies suggest that iron may be linked to induction of inflammation, oxidative stress, infection and kidney damage, the overwhelming preponderance of clinical studies has reported no clinically meaningful increase in infectious complications when IV iron was adequately dosed according to available guidelines. In addition, the use of IV iron has emerged as a viable alternative to allogeneic blood transfusions and a valuable tool to face ESA restrictions.14 While IV iron preparations like any other medications are not free of risks and not all are equal in their safety profiles, their purported risks must be viewed in context of the associated benefits of these medications in terms of avoiding other "clear and present dangers"; anaemia and allogeneic blood transfusions.15

Reference List

(1) Parrow NL, Fleming RE, Minnick MF. Sequestration and Scavenging: Iron in Infection. Infect Immun 2013.
(2) Litton E, Xiao J, Ho KM. Safety and efficacy of intravenous iron therapy in reducing requirement for allogeneic blood transfusion: systematic review and meta-analysis of randomised clinical trials. BMJ 2013; 347:f4822.
(3) Schindler E, Scholz S, Boldt J, Zickmann B, Knothe C, Dietrich G et al. [Effectiveness of oral versus parenteral iron substitution in autologous blood donors]. Infusionsther Transfusionsmed 1994; 21(4):236-241.
(4) Serrano-Trenas JA, Ugalde PF, Cabello LM, Chofles LC, Lazaro PS, Benitez PC. Role of perioperative intravenous iron therapy in elderly hip fracture patients: a single-center randomized controlled trial. Transfusion 2011; 51(1):97-104.
(5) Hoen B, Paul-Dauphin A, Hestin D, Kessler M. EPIBACDIAL: a multicenter prospective study of risk factors for bacteremia in chronic hemodialysis patients. J Am Soc Nephrol 1998; 9(5):869-876.
(6) Hoen B, Paul-Dauphin A, Kessler M. Intravenous iron administration does not significantly increase the risk of bacteremia in chronic hemodialysis patients. Clin Nephrol 2002; 57(6):457-461.
(7) Brookhart MA, Freburger JK, Ellis AR, Wang L, Winkelmayer WC, Kshirsagar AV. Infection risk with bolus versus maintenance iron supplementation in hemodialysis patients. J Am Soc Nephrol 2013; 24(7):1151-1158.
(8) Muñoz M, Gómez-Ramírez S, Cuenca J, García-Erce JA, Iglesias-Aparicio D, Haman-Alcober S, et al. Very-short-term perioperative intravenous iron administration and postoperative outcome in major orthopedic surgery: a pooled analysis of observational data from 2547 patients.Transfusion. 2013 Apr 15. doi: 10.1111/trf.12195. [Epub ahead of print]
(9) Torres S, Kuo YH, Morris K, Neibart R, Holtz JB, Davis JM. Intravenous iron following cardiac surgery does not increase the infection rate. Surg Infect (Larchmt ) 2006; 7(4):361-366.
(10) Kalantar-Zadeh K, Streja E, Miller JE, Nissenson AR. Intravenous iron versus erythropoiesis-stimulating agents: friends or foes in treating chronic kidney disease anemia? Adv Chronic Kidney Dis 2009; 16(2):143-151.
(11) Feldman HI, Joffe M, Robinson B, Knauss J, Cizman B, Guo W et al. Administration of parenteral iron and mortality among hemodialysis patients. J Am Soc Nephrol 2004; 15(6):1623-1632.
(12) Pollak VE, Lorch JA, Shukla R, Satwah S. The importance of iron in long-term survival of maintenance hemodialysis patients treated with epoetin-alfa and intravenous iron: analysis of 9.5 years of prospectively collected data. BMC Nephrol 2009; 10:6.
(13) Anker SD, Comin CJ, Filippatos G, Willenheimer R, Dickstein K, Drexler H et al. Ferric carboxymaltose in patients with heart failure and iron deficiency. N Engl J Med 2009; 361(25):2436-2448.
(14) Shander A, Spence RK, Auerbach M. Can intravenous iron therapy meet the unmet needs created by the new restrictions on erythropoietic stimulating agents? Transfusion 2010; 50(3):719-732.
(15) Shander A, Javidroozi M, Ozawa S, Hare GM. What is really dangerous: anaemia or transfusion? Br J Anaesth 2011; 107 Suppl 1:i41-i59.

Appendix - Randomized controlled trials not included in the meta-analysis:

1. Daniilidis A, Giannoulis C, Pantelis A, Tantanasis T, Dinas K. Total infusion of low molecular weight iron-dextran for treating postpartum anemia. Clin Exp Obstet Gynecol. 2011;38(2):159-61.

2. Dede A, Uygur D, Yilmaz B, Mungan T, Uğur M. Intravenous iron sucrose complex vs. oral ferrous sulfate for postpartum iron deficiency anemia. Int J Gynaecol Obstet. 2005 Sep;90(3):238-9.

3. Giannoulis C, Daniilidis A, Tantanasis T, Dinas K, Tzafettas J. Intravenous administration of iron sucrose for treating anemia in postpartum women. Hippokratia. 2009 Jan;13(1):38-40.

4. Lu M, Cohen MH, Rieves D, Pazdur R. FDA report: Ferumoxytol for intravenous iron therapy in adult patients with chronic kidney disease. Am J Hematol. 2010 May;85(5):315-9. (data on 3 RCT2 in ND CKD and 1 in HD CKD; 2 RCT previously published by Provenzano and Spinowitz).

5. Mudge DW, Tan KS, Miles R, Johnson DW, Badve SV, Campbell SB, Isbel NM, van Eps CL, Hawley CM. A randomized controlled trial of intravenous or oral iron for posttransplant anemia in kidney transplantation. Transplantation. 2012 Apr 27;93(8):822-6.

6. Nagaraju SP, Cohn A, Akbari A, Davis JL, Zimmerman DL. Heme iron polypeptide for the treatment of iron deficiency anemia in non-dialysis chronic kidney disease patients: a randomized controlled trial. BMC Nephrol. 2013 Mar 20;14:64.

7. Rohling RG, Zimmermann AP, Breymann C. Intravenous versus oral iron supplementation for preoperative stimulation of hemoglobin synthesis using recombinant human erythropoietin. J Hematother Stem Cell Res. 2000 Aug; 9(4):497-500.

8. Yoo YC, Shim JK, Kim JC, Jo YY, Lee JH, Kwak YL. Effect of single recombinant human erythropoietin injection on transfusion requirements in preoperatively anemic patients undergoing valvular heart surgery. Anesthesiology. 2011 Nov; 115(5):929-37.

Competing interests: Aryeh Shander has been a consultant or speaker with honorarium for or received research support from Bayer, Luitpold, Masimo, Novartis, Novo Nordisk, OrthoBiotech, Pfizer, Masimo & Zymogenetics; He is a founding member of SABM. Manuel Muñoz has received travel support and/or honoraria for lectures and/or consultancy from Vifor Pharma (Saint Gallen, Switzerland), Vifor Pharma España (Barcelona, Spain), and Pharmacosmos A/S (Olbaek, Denmark), but not for this work. Michael Auerbach has no relevant conflict of interests to declare.

13 September 2013
Manuel Muñoz
Professor, Transfusion Medicine
Michael Auerbach, Aryeh Shander
University of Málaga
Transfusion Medicine, School of Medicine, University of Málaga, 29071 Málaga, Spain