+7 additional authors

Adamson, J.

Auerbach, M.

Bircher, A.

Breymann, C.

Fishbane, S.

Gafter-Gvili, A.

Gasche, C.

Gilreath, J.

Grazzini, G.

Shander, A.

English

Hofstra Northwell Academic Works (Hofstra Northwell School of Medicine)

Journal Articles 2015 On the safety of intravenous iron, evidence trumps conjecture M. Auerbach J. Adamson A. Bircher C. Breymann S. Fishbane Zucker School of Medicine at Hofstra/Northwell See next page for additional authors Follow this and additional works at: https://academicworks.medicine.hofstra.edu/publications  Part of the Nephrology Commons Recommended Citation Auerbach M, Adamson J, Bircher A, Breymann C, Fishbane S, Gafter-Gvili A, Gasche C, Gilreath J, Grazzini G, Shander A, . On the safety of intravenous iron, evidence trumps conjecture. . 2015 Jan 01; 100(5):Article 2105 [ p.]. Available from: https://academicworks.medicine.hofstra.edu/publications/2105. Free full text article. This Article is brought to you for free and open access by Donald and Barbara Zucker School of Medicine Academic Works. It has been accepted for inclusion in Journal Articles by an authorized administrator of Donald and Barbara Zucker School of Medicine Academic Works. For more information, please contact academicworks@hofstra.edu. Authors M. Auerbach, J. Adamson, A. Bircher, C. Breymann, S. Fishbane, A. Gafter-Gvili, C. Gasche, J. Gilreath, G. Grazzini, A. Shander, and +7 additional authors This article is available at Donald and Barbara Zucker School of Medicine Academic Works: https://academicworks.medicine.hofstra.edu/publications/2105 On the safety of intravenous iron, evidence trumpsconjectureAnemia is one of the world’s most common disorders.  In2010, global anemia prevalence was 32.9%, affecting over2.2 billion people, and iron deficiency the most common ofthe causes.1 Oral iron, while inexpensive and effectivewhen taken and tolerated, is frequently associated withunpleasant gastrointestinal side-effects, resulting in highrates of non-adherence.   Furthermore, in conditions suchas inflammatory bowel disease, end-stage renal disease,heavy uterine bleeding, hereditary hemorrhagic telangiec-tasia, and following major and bariatric surgery, oral ironmay be ineffective due to its inability to keep up with lossesor may be harmful by worsening the underlying pathologyor by causing significant gastrointestinal side-effects. Underthese circumstances, intravenous iron administration is therepletion route of choice. Currently, five formulations areavailable in the United States and six in Europe.  Based onthe overwhelming amount of published evidence, intra-venous iron is nearly universally effective, with seriousadverse events being very rare, estimated to be less than1:200,000 administrations.2 Nonetheless, there is an ongo-ing prejudice against the use of parenteral iron largely basedon experience with earlier preparations that are no longeravailable and which were associated with unacceptablyhigh rates of anaphylactic reactions.  Adding to these con-cerns is the use of spontaneous reporting of serious adverseevents, a proscribed method of determining relative safetyprofiles of different formulations,3 and corroborated by arecent guidance document by the European MedicinesAgency stating post-marketing spontaneous reports "can-not be used to detect any differences in the safety profile ofthe different iron medicines”.4Therefore, the seventeen co-authors of this commentarywish to challenge the conclusions drawn in a recentPrescrire publication, which makes recommendationsbased on inferences that are inaccurate and clinicallyimprudent.5In a recent criticism of the use of intravenous iron and awarning against one product, ostensibly less safe than oth-ers, the authors omitted all prospective and intrainstitution-al observational studies that have come to the oppositeconclusion (see below).6,7 An example  is found in the con-cluding paragraph: “Given the risk of serious hypersensitiv-ity reactions as well as other adverse effects, the use ofintravenous iron-containing products should be limited tosituations in which the benefits clearly outweigh the harm.Iron sucrose is the best choice, as other products do nothave a more favorable harm-benefit balance.  The decisionto keep iron dextran on the market is absurd: it protects themanufacturer while exposing patients to unnecessaryrisks”.  In contradistinction, an examination of publishedevidence suggests the above statements are simply incor-rect.  Below we highlight this evidence.Shortly after recombinant erythropoietin was approvedfor correction of anemia in patients on dialysis, it becameapparent that intravenous iron was necessary for an opti-mal erythropoietic response.  High molecular weight irondextran (HMWID, Imferon®), which is no longer available,was the only formulation used at first. While infrequentserious reactions were observed, safety concerns wereraised. Then, in 1991, Imferon® was removed from market,but serendipitously at the same time, low molecular weightiron dextran (LMWID, INFeD® in the United States andCosmoFer® in Europe) was approved for use.  The literatureis rife with safety and efficacy reports, and serious adverseevents with LMWID are extremely rare. It was not until1996, when a HMWID (Dexferrum®), which is also nolonger available, was released, that serious adverse eventsbecame frequent; numerous publications support thisview.8 With HMWID now withdrawn from the market,there is no credible evidence supporting either increasedefficacy or decreased safety with any of the remainingavailable formulations compared to any other.  As a result,the US FDA wrote a letter to the American distributors ofiron sucrose, which is now in the public domain, orderingthem to remove all advertising claiming any safety advan-tage with iron sucrose.Three prospective studies, a meta-analysis and an intra-institutional observational study at the Harvard MedicalSchool hospitals6,7 report no significant efficacy or safetydifferences. A comparison of ferric carboxymaltose andLMWID in second and third trimester gravidas reportedsafety and efficacy without serious adverse events in eithergroup.9 Supporting their conclusions in a single institutionobservational study using a prospective model for the inte-grated safety analysis, 1266 total dose infusions (1000 mgin 1 h) of low molecular weight iron dextran were given to888 patients, 162 of whom were pregnant, intolerant oforal iron, or in whom oral iron was ineffective or con-traindicated.10 No serious adverse events were observed.Low molecular weight iron dextran is the formulation cur-rently being used for the first prospective study of intra-venous iron in the second or third trimester of pregnancy inthe US under an FDA IND (#114696). In a preliminaryanalysis of 57 of 60 planned subjects having completedstudy treatment to date, no serious adverse events havebeen observed.  It should be noted that the total number ofsubjects included in these studies is small, and importantadverse effects and relative differences in adverse eventscould be present that are not reflected in the studies. In a prospective, controlled, randomized trial of 162patients, comparing iron sucrose and ferumoxytol inpatients with chronic kidney disease, the authors reportedno difference in safety or efficacy.11 The only prospectivetrial to report a significant safety difference between any ofthe formulations compared the now unavailable HMWIDto ferric carboxymaltose and erroneously concluded, with-out differentiating the high and low molecular weight for-mulations, that ferric carboxymaltose had a safety advan-tage over iron dextran.12 Corroborating data were recentlypublished in a large meta-analysis of studies carried out inthousands of subjects who received intravenous iron.13In an editorial accompanying the article, Prescrire report-ed that “there is no advantage to the use of iron dextranover iron sucrose and the risks of using iron dextran far out-weigh the benefits”.  Not only is the statement without evi-dence to support it, but a replacement dose of intravenousiron sucrose requires four or five clinical visits compared toone visit with an infusion of 1000 mg of LMWID  (a com-monly used method approved in Europe but still off label inthe US). The same advantage can be achieved with ferriccarboxymaltose (approved as 1000 mg in 15 min in Europeand 750 mg in the US), iron isomaltoside (Europe only),and ferumoxytol (approval limited to 510 mg per visit).Pre-medication with antihistamines is frequently admin-istered without any data supporting their use. There areeven published data suggesting that the majority of adverseevents seen with intravenous iron, when intravenousdiphenhydramine is used as pre-medication, are due to thepre-medication and mistakenly attributed to the intra-haematologica 2015; 100:e214LETTERS TO THE EDITORvenous iron.14 Antihistamines can cause flushing, hypoten-sion, somnolence, and supraventricular tachycardia,prompting inappropriate intervention and the conversionof a minor reaction to a severe one.  In contrast, there is asyndrome occurring in approximately 1:200 patients, con-sisting of arthralgias, myalgias or flushing, without associ-ated hypotension, tachycardia, tachypnea, wheezing, stri-dor or periorbital edema. No intervention is necessary.15After symptoms abate, re-challenge is appropriate.  In therare patient who reacts twice, the iron formulation shouldbe changed. Antihistamines are inappropriate since meas-ured tryptase levels after these reactions have always beennormal.16 While post-marketing, spontaneous adverseevent reporting can provide useful and important informa-tion, one simply cannot determine relative safety amongformulations. Without head-to-head trials, such conclu-sions lack validity.   Parenteral iron is not just ‘superior’, it is a necessity sinceoral iron is ineffective in a number of clinical settings.Overstating the avoidance of intravenous iron is not onlycounterproductive but potentially harmful. Limiting its usewill dramatically increase erythropoietin usage as well astransfusions and their associated complications. Essentially,all interpretable evidence supports the equivalent efficacyand safety of all of the current intravenous iron formula-tions. If minor infusion reactions occur with one formula-tion, switching to another is appropriate and safe.Michael Auerbach,1 John Adamson,2 Andreas Bircher,3Christian Breymann,4 Steven Fishbane,5 Anat Gafter-Gvili,6Christoph Gasche,7 Jeffrey Gilreath,8 Giuliano Grazzini,9David Henry,10 Giancarlo Liumbruno,11 Francesco Locatelli,12Iain Macdougall,13 Manuel Munoz,14 David Rampton,15 GeorgeRodgers,16and Aryeh Shander171Georgetown University, Washington DC, WA, USA; 2University ofCalifornia San Diego, San Diego, CA, USA; 3University HospitalBasel, Basel, Switzerland; 4Zurich University Hospital, Switzerland;5Long Island Jewish-Northshore Medical Center, Manhasset, NY,USA; 6Rabin Medical Center, Petah-Tikva, Israel; 7Medical Universityof Vienna, Austria; 8University of Utah School of Medicine, Salt LakeCity, UT, USA; 9Italian National Blood Center, National Institute ofHealth, Rome, Italy; 10University of Pennsylvania, Philadelphia,Pennsylvania, USA; 11Italian National Blood Center, National Instituteof Health, Rome, Italy; 12Alessandro Manzoni Hospital, Lecco, Italy;13Kings College, London, UK; 14Perioperative Transfusion Medicine,School of Medicine, University of Málaga, Spain; 15Barts and LondonSchool of Medicine, London, UK; 16University of Utah, Salt Lake City,UT, USA; and 17Mt. Sinai School of Medicine, New York, NY, USACorrespondence: mauerbachmd@abhemonc.comdoi:10.3324/haematol.2014.121004Key words: current, intravenous iron formulations, efficacy, safety,studies, evidence.Information on authorship, contributions, and financial & other disclo-sures was provided by the authors and is available with the online versionof this article at www.haematologica.org.References1. Kassebaum N, Jasasaria R, Naghavi N, et al.  A systemic analysis ofglobal anemia burden from 1990 to 2010. Blood. 2014;123(5):615-624.2. Chertow G, Mason P, Vaage-Nilsen O, et al. Update on adverse drugevents associated with parenteral iron. Nephrol Dial Transplant.2006;21(2):378-382.3. Wysowski D, Swartz L, Borders-Hemphill V, et al.  Use of parenteraliron products and serious anaphylactic-type reactions. Am JHematol. 2010;85(9):650-654.4. European Medicines Agency. New recommendations to manage riskof allergic reactions with intravenous iron-containing medicines. 28 June 2013. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/Press_release/2013/06/WC500144874.pdf5. Prescrire International Translated from Rev Prescrire. 2014;34(365):182-183.6. Critchley J, Dundar Y. Adverse events associated with intravenousiron infusion (low-molecular-weight iron dextran and iron sucrose):a systematic review. Transfus Alternat Transfus Med. 2007;9(1):8-36.7. Okam M, Mandell E, Hevelone N, et al. Comparative rates ofadverse events with different formulations of intravenous iron. Am JHematol. 2012;87:E123-E124.8. Rodgers G, Auerbach M, Cell D, et al. High-molecular weight irondextran: a wolf in sheep’s clothing? J Am Soc Nephrol.2008;19(5):833-834.9. Myers B, Myers O, Moore J. Comparative efficacy and safety ofintravenous ferric carboxymaltose (Ferinject) and iron(III) hydroxidedextran (Cosmofer) in pregnancy. Obstet Med. 2012;5(3):105-107.10. Auerbach M, Pappadakis J, Bahrain H, et al. Safety and efficacy ofrapidly administered (one hour) one gram of low molecular weightiron dextran (INFeD) for the treatment of iron deficient anemia. AmJ Hematol. 2011;86(10):860-862.11. Macdougall I, Strauss W, McLaughlin J, et al. A randomized compar-ison of ferumoxytol and iron sucrose for treating iron deficiency ane-mia in patients with CKD. Clin J Am Soc Nephrol. 2014;9(4):705-712.12. Hussain I, Bhoyroo J, Butcher A, et al. Direct comparison of the safe-ty and efficacy of ferric carboxymaltose versus iron dextran inpatients with iron deficiency anemia. Anemia. 2013 Aug 29. [Epubahead of print]13. Avni T, Bierber A, Grossman A, et al. The safety of intravenous ironpreparations: systematic review and meta-analysis. Mayo ClinicProc. 2015;90(1):12-23.14. Barton J, Barton E, Bertoli L, et al. Intravenous iron dextran therapyin patients with iron deficiency and normal renal function who failedto respond to or did not tolerate oral iron supplementation. Am JMed. 2000;109(1):27-32.15. Fishbane S, Ungureanu V, Maesaka J, et al. The safety of intravenousiron dextran in hemodialysis patients. Am J Kidney Dis.1996;28(4):529-534.16. Bircher A, Auerbach M. Hypersensitivity from intravenous ironproducts. Immunol Allergy Clin N Am. 2014;34(3):707-723.haematologica 2015; 100:e215LETTERS TO THE EDITOR

On the safety of intravenous iron, evidence trumps conjecture

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On the safety of intravenous iron, evidence trumps conjecture

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