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The Safety of Intravenous Iron Preparations

Systematic Review and Meta-analysis

      Abstract

      Objective

      To amass all available evidence regarding the safety of intravenous (IV) iron preparations to provide a true balance of efficacy and safety.

      Methods

      Systematic review and meta-analysis of all randomized clinical trials comparing IV iron to another comparator. All electronic databases until January 1, 2014, were reviewed. Primary outcome was occurrence of severe adverse events (SAEs). Secondary outcomes included all-cause mortality and other adverse events (AEs). Subgroup analysis was performed on the basis of type of IV iron, comparator, treated condition, and system involved.

      Results

      A total of 103 trials published between 1965 through 2013 were included. A total of 10,390 patients were treated with IV iron compared with 4044 patients treated with oral iron, 1329 with no iron, 3335 with placebo, and 155 with intramuscular iron. There was no increased risk of SAEs with IV iron (relative risk [RR], 1.04; 95% CI, 0.93-1.17; I2=9%). Subgroup analysis revealed a decreased rate of SAEs when IV iron was used to treat heart failure (RR, 0.45; 95% CI, 0.29-0.70; I2=0%). Severe infusion reactions were more common with IV iron (RR, 2.47; 95% CI, 1.43-4.28; I2=0%). There was no increased risk of infections with IV iron. Gastrointestinal AEs were reduced with IV iron.

      Conclusion

      Intravenous iron therapy is not associated with an increased risk of SAEs or infections. Infusion reactions are more pronounced with IV iron.

      Abbreviations and Acronyms:

      AE (adverse event), FCM (ferric carboxymaltose), FG (ferric gluconate), ID (iron dextran), IM (intramuscular), IS (iron sucrose), IV (intravenous), NNH (number needed to harm), NNP (number needed to prevent), RD (risk difference), REM (random-effects model), RR (relative risk), SAE (severe adverse event)
      Iron deficiency anemia is an integral part of many disorders, such as chronic renal failure, chronic heart failure, and cancer. Anemia at presentation is a negative prognostic factor in patients with both solid and hematologic tumors,
      • Clarke H.
      • Pallister C.J.
      The impact of anaemia on outcome in cancer.
      as well as in patients with heart failure.
      • Groenveld H.F.
      • Januzzi J.L.
      • Damman K.
      • et al.
      Anemia and mortality in heart failure patients a systematic review and meta-analysis.
      Iron formulations are among the most prescribed drugs.
      • Auerbach M.
      • Ballard H.
      Clinical use of intravenous iron: administration, efficacy, and safety.
      The efficacy of intravenous (IV) iron was found in dozens of randomized clinical trials and meta-analyses in several fields of medicine.
      • Notebaert E.
      • Chauny J.M.
      • Albert M.
      • Fortier S.
      • Leblanc N.
      • Williamson D.R.
      Short-term benefits and risks of intravenous iron: a systematic review and meta-analysis.
      Intravenous iron is superior to oral iron or no iron in achieving a sustained hemoglobin response, reducing the need for packed red blood cell transfusions and improving quality of life in various clinical settings: chronic heart failure,
      • Avni T.
      • Leibovici L.
      • Gafter-Gvili A.
      Iron supplementation for the treatment of chronic heart failure and iron deficiency: systematic review and meta-analysis.
      inflammatory bowel disease,
      • Avni T.
      • Bieber A.
      • Steinmetz T.
      • Leibovici L.
      • Gafter-Gvili A.
      Treatment of anemia in inflammatory bowel disease- systematic review and meta-analysis.
      chronic kidney diseases and hemodialysis,
      • Rozen-Zvi B.
      • Gafter-Gvili A.
      • Paul M.
      • Leibovici L.
      • Shpilberg O.
      • Gafter U.
      Intravenous versus oral iron supplementation for the treatment of anemia in CKD: systematic review and meta-analysis.
      • Albaramki J.
      • Hodson E.M.
      • Craig J.C.
      • Webster A.C.
      Parenteral versus oral iron therapy for adults and children with chronic kidney disease.
      • Susantitaphong P.
      • Alqahtani F.
      • Jaber B.L.
      Efficacy and safety of intravenous iron therapy for functional iron deficiency anemia in hemodialysis patients: a meta-analysis.
      cancer-related anemia,
      • Gafter-Gvili A.
      • Rozen-Zvi B.
      • Vidal L.
      • et al.
      Intravenous iron supplementation for the treatment of chemotherapy-induced anaemia: systematic review and meta-analysis of randomised controlled trials.
      and pregnancy.
      • Reveiz L.
      • Gyte G.M.
      • Cuervo L.G.
      • Casasbuenas A.
      Treatments for iron-deficiency anaemia in pregnancy.
      A recent meta-analysis revealed a decreased need for transfusions for all indications (relative risk [RR], 0.74; 95% CI, 0.62-0.88; which translates to a number needed to prevent [NNP] of 1 transfusion of 18).
      • Litton E.
      • Xiao J.
      • Ho K.M.
      Safety and efficacy of intravenous iron therapy in reducing requirement for allogeneic blood transfusion: systematic review and meta-analysis of randomised clinical trials.
      However, there is a concern regarding the safety of IV iron. The most feared adverse reaction to IV iron is anaphylaxis. This reaction is rare, much more common with high-molecular-weight iron dextran (ID) than with the more novel preparations.
      • Van Wyck D.B.
      • Cavallo G.
      • Spinowitz B.S.
      • et al.
      Safety and efficacy of iron sucrose in patients sensitive to iron dextran: North American clinical trial.
      • Walters B.A.
      • Van Wyck D.B.
      Benchmarking iron dextran sensitivity: reactions requiring resuscitative medication in incident and prevalent patients.
      According to the Gambro Healthcare US medical database, the incidence of life-threatening adverse events (AEs) to ID was 0.035%, and the overall rate of AEs was 0.5% per year.
      • Walters B.A.
      • Van Wyck D.B.
      Benchmarking iron dextran sensitivity: reactions requiring resuscitative medication in incident and prevalent patients.
      Another concern is that IV iron might cause endothelial damage and promote atherosclerosis by generating oxidative stress.
      • Zager R.A.
      • Johnson A.C.
      • Hanson S.Y.
      • Wasse H.
      Parenteral iron formulations: a comparative toxicologic analysis and mechanisms of cell injury.
      This concern is supported by laboratory studies that found enhanced oxidative stress induced by iron sucrose (IS) and ferric gluconate (FG) in vitro and in vivo. The clinical implications of these observations are still unknown, and in the several trials that evaluated IV iron in patients with chronic heart failure, most patients had a priori coronary heart disease.
      • Anker S.D.
      • Comin Colet J.
      • Filippatos G.
      • et al.
      Ferric carboxymaltose in patients with heart failure and iron deficiency.
      Another concern is that IV iron might promote infection by supplying iron to pathogenic bacteria.
      • Fishbane S.
      Review of issues relating to iron and infection.
      Experimental evidence indicates that iron treatment might decrease chemotaxis, phagocytosis, and intracellular killing ability of polymorphonuclear cells and hence limit the ability to control infection. In addition, the above mentioned meta-analysis
      • Litton E.
      • Xiao J.
      • Ho K.M.
      Safety and efficacy of intravenous iron therapy in reducing requirement for allogeneic blood transfusion: systematic review and meta-analysis of randomised clinical trials.
      found an increase in the rate of infections with IV iron.
      Oral iron is less expensive, easier to administer, and possibly safer than IV preparations. The AEs of oral iron are mainly gastrointestinal (approximately one-third of treated patients). These AEs may limit adherence and the dose that may be administered.
      • Goodnough L.T.
      Iron deficiency syndromes and iron-restricted erythropoiesis (CME).
      Randomized clinical trials are not the best tools for examining the risk of rare and severe adverse events (SAEs). On the other hand AEs are less dependent on the underlying disorder, which is why we have chosen to look at AEs of IV iron in all the trials of IV iron. We conducted a systematic review and meta-analysis assembling data from all randomized clinical trials that evaluated IV iron for any clinical indication.

      Methods

      Data Sources

      We searched MEDLINE (January 1, 1966, through December 31, 2013), CENTRAL (The Cochrane Library up to 2013, March, issue 3), LILACS, KOREAMED, and NLM gateway from inception to December 31, 2013. The conference proceedings of the American Society of Hematology, European Haematology Association, American Society of Nephrology, European Renal Association, European Dialysis and Transplant Association, and American Heart Association from 2008 onward and the clinical trials databases for ongoing and unpublished trials were also searched online for further trials. The references of all identified studies were inspected for more trials. The term iron was searched as a Medical Subject Heading term and as a text word for specific iron preparations. The result was limited to randomized clinical trials using a highly sensitive filter.

      Higgins J, Churchill R, Cumpston M, Chandler J, eds. Cochrane Handbook for Systematic Reviews of Interventions. Version 5.1.0. Oxford, England: Cochrane Collaboration; 2011.

      The search study is reported in the Supplemental Appendix (available online at http://www.mayoclinicproceedings.org).

      Study Selection

      We included randomized clinical trials that compared IV iron with no iron, placebo, oral iron, intramuscular (IM) iron, or other treatment for any indication. Trials were included regardless of publication status (published, conference proceedings, or unpublished), trial years, and language. Trials that compared IV iron preparation, different dosages, and administration schedules and trials that did not report AEs were excluded.

      Quality Assessment

      We assessed trials for method quality and examined the following domains: random sequence generation, allocation concealment, masking of participants and personnel, incomplete outcome data reporting, and selective outcome reporting. We graded each domain as low risk of bias, unclear risk (lack of information or uncertainty over the potential for bias), or high risk of bias according to the criteria specified in the Cochrane Handbook for Systematic Reviews of Interventions, version 5.1.0.

      Higgins J, Churchill R, Cumpston M, Chandler J, eds. Cochrane Handbook for Systematic Reviews of Interventions. Version 5.1.0. Oxford, England: Cochrane Collaboration; 2011.

      • Schulz K.F.
      • Chalmers I.
      • Hayes R.J.
      • Altman D.G.
      Empirical evidence of bias: dimensions of methodological quality associated with estimates of treatment effects in controlled trials.
      We have also assessed quality measures addressed by the CONSORT guidelines for AEs
      • Ioannidis J.P.
      • Evans S.J.
      • Gotzsche P.C.
      • et al.
      Better reporting of harms in randomized trials: an extension of the CONSORT statement.
      and adjusted to the design of the included trials. For each item below, we scored whether the item was present or absent and recorded the data when presented.

      Definitions and Rules

      • The AE and severity grading score definitions (or reference to standardized definitions): We regarded the use of a standardized criteria or a similar form
        US Department of Health and Human Services
        National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE).
        for grading as appropriate
      • Mode of data collection: active or passive, questionnaires, or interviews
      • Timing and frequency of AE assessments
      • Rules for discontinuation

      Attribution and Selective Reporting

      • Reporting of AEs by intention to treat
      • Attribution of AEs to the trial drugs
      • The use of a severity threshold (eg, reporting of AEs only above a certain severity grade)
      • The use of an occurrence threshold (eg, reporting of AEs occurring only above a certain percentage of patients)

      AE-Related Outcomes

      • Treatment discontinuations or modifications due to AEs
      • Deaths due to AEs

      Definition of Outcomes

      The primary outcome we extracted was the occurrence of SAEs. We defined an SAE as a grade 3 through 5 reaction per each AE as defined by the Common Terminology Criteria for Adverse Events grading system.
      US Department of Health and Human Services
      National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE).
      We included infections and infusion, cardiovascular, neurologic, respiratory, gastrointestinal, thromboembolic, and constitutional severe reactions. The SAEs were further divided by indication for IV treatment, type of IV iron preparation, and comparator. Secondary outcomes included AEs by system involved as mentioned above, all-cause mortality, AEs requiring discontinuation, AEs regarded by authors as treatment related, and any AEs.

      Data Collection

      We recorded data from all trials with regard to the type of iron preparation, treatment dosage, cumulative dosages, schedule, length of treatment, and follow-up. Two reviewers (T.A., A.B.) independently extracted data from included trials. In case of disagreement, a third reviewer (A.G.G.) extracted the data, and results were attained by consensus. We contacted the investigators of included trials for missing data.

      Data Synthesis and Statistical Analyses

      To include trials with no occurrence of AEs, we used the value 0.1 instead of 0 in the event counter, thus enabling trials that did not observe AEs in both study arms to be used for calculation of the RR.
      • Friedrich J.O.
      • Adhikari N.K.
      • Beyene J.
      Inclusion of zero total event trials in meta-analyses maintains analytic consistency and incorporates all available data.
      Furthermore, we also calculated commutative risk difference (RD) (which is synonymous to absolute risk reduction) and number needed to harm (NNH) or NNP for all outcomes. Dichotomous data were analyzed by calculating the RR for each trial, with the uncertainty in each result being expressed using 95% CIs. Heterogeneity was assessed by calculating the χ2 and I2 tests of heterogeneity. A fixed-effect model was used throughout the review, except in the event of significant heterogeneity among the trials (P<.10, I2>40%), in which we used a random-effects model (REM). We explored potential sources of heterogeneity: type of IV iron preparation, comparator (placebo, oral, no iron, IM iron, or other), indication for iron therapy, adequacy of collecting and reporting methods of the AEs, and the adequacy of allocation generation, concealment, and masking. We used Review Manager, version 5.2 for Windows (The Cochrane Collaboration) and Comprehensive Meta-Analysis, version 2.2 (BioStat) for statistical calculations.

      Results

      The literature search identified 5326 publications; of them, 164 were potentially eligible publications on IV iron therapy. A total of 103 trials
      • Anker S.D.
      • Comin Colet J.
      • Filippatos G.
      • et al.
      Ferric carboxymaltose in patients with heart failure and iron deficiency.
      • Adhikary L.
      • Acharya S.
      Efficacy of IV iron compared to oral iron for increment of haemoglobin level in anemic chronic kidney disease patients on erythropoietin therapy.
      • Agarwal R.
      • Rizkala A.R.
      • Bastani B.
      • Kaskas M.O.
      • Leehey D.J.
      • Besarab A.
      A randomized controlled trial of oral versus intravenous iron in chronic kidney disease.
      • Aggarwal H.K.
      • Nand N.
      • Singh S.
      • Singh M.
      • Hemant
      • Kaushik G.
      Comparison of oral versus intravenous iron therapy in predialysis patients of chronic renal failure receiving recombinant human erythropoietin.
      • Al R.A.
      • Unlubilgin E.
      • Kandemir O.
      • Yalvac S.
      • Cakir L.
      • Haberal A.
      Intravenous versus oral iron for treatment of anemia in pregnancy: a randomized trial.
      • Allegra V.
      • Mengozzi G.
      • Vasile A.
      Iron deficiency in maintenance hemodialysis patients: assessment of diagnosis criteria and of three different iron treatments.
      • Allen R.P.
      • Adler C.H.
      • Du W.
      • Butcher A.
      • Bregman D.B.
      • Earley C.J.
      Clinical efficacy and safety of IV ferric carboxymaltose (FCM) treatment of RLS: a multi-centred, placebo-controlled preliminary clinical trial.
      • Al-Momen A.
      • Al-Meshari A.
      • Al-Nuaim L.
      • et al.
      Intravenous iron sucrose complex in the treatment of iron deficiency anemia during pregnancy.
      • Arutyunov G.
      • Bylova N.
      • Ivleva A.
      • Kobalava Z.
      The safety of intravenous (IV) ferric carboxymaltose versus IV iron sucrose on patients with chronic heart failure (CHF) and chronic kidney disease (CKD) with iron deficincy (ID).
      • Athibovonsuk P.
      • Manchana T.
      • Sirisabya N.
      Prevention of blood transfusion with intravenous iron in gynecologic cancer patients receiving platinum-based chemotherapy.
      • Auerbach M.
      • Ballard H.
      • Trout J.R.
      • et al.
      Intravenous iron optimizes the response to recombinant human erythropoietin in cancer patients with chemotherapy-related anemia: a multicenter, open-label, randomized trial.
      • Auerbach M.
      • Silberstein P.T.
      • Webb R.T.
      • et al.
      Darbepoetin alfa 300 or 500 mug once every 3 weeks with or without intravenous iron in patients with chemotherapy-induced anemia.
      • Bager P.
      • Dahlerup J.F.
      Randomised clinical trial: oral vs. intravenous iron after upper gastrointestinal haemorrhage: a placebo-controlled study.
      • Bailie G.R.
      • Mason N.A.
      • Valaoras T.G.
      Safety and tolerability of intravenous ferric carboxymaltose in patients with iron deficiency anemia.
      • Bastit L.
      • Vandebroek A.
      • Altintas S.
      • et al.
      Randomized, multicenter, controlled trial comparing the efficacy and safety of darbepoetin alpha administered every 3 weeks with or without intravenous iron in patients with chemotherapy-induced anemia.
      • Bayoumeu F.
      • Subiran-Buisset C.
      • Baka N.E.
      • Legagneur H.
      • Monnier-Barbarino P.
      • Laxenaire M.C.
      Iron therapy in iron deficiency anemia in pregnancy: intravenous route versus oral route.
      • Beck-da-Silva L.
      • Piardi D.
      • Soder S.
      • et al.
      IRON-HF study: a randomized trial to assess the effects of iron in heart failure patients with anemia.
      • Beguin Y.
      • Maertens J.
      • De Prijck B.
      • et al.
      Darbepoetin-alfa and I.V. iron administration after autologous hematopoietic stem cell transplantation: a prospective multicenter randomized trial.
      • Bellet R.
      • Ghazal H.
      • Flam M.
      • et al.
      A phase III randomized controlled study comparing iron sucrose intravenously (IV) to no iron treatment of anemia in cancer patients undergoing chemotherapy and erythropoietin stimulating agent (ESA) therapy.
      • Bencaiova G.
      • von Mandach U.
      • Zimmermann R.
      Iron prophylaxis in pregnancy: intravenous route versus oral route.
      • Bhandal N.
      • Russell R.
      Intravenous versus oral iron therapy for postpartum anaemia.
      • Birgegard G.
      • Schneider K.
      • Ulfberg J.
      High incidence of iron depletion and restless leg syndrome (RLS) in regular blood donors: intravenous iron sucrose substitution more effective than oral iron.
      • Breymann C.
      • Gliga F.
      • Bejenariu C.
      • Strizhova N.
      Comparative efficacy and safety of intravenous ferric carboxymaltose in the treatment of postpartum iron deficiency anemia.
      • Burns D.L.
      • Mascioli E.A.
      • Bistrian B.R.
      Effect of iron-supplemented total parenteral nutrition in patients with iron deficiency anemia.
      • Charytan C.
      • Bernardo M.V.
      • Koch T.A.
      • Butcher A.
      • Morris D.
      • Bregman D.B.
      Intravenous ferric carboxymaltose versus standard medical care in the treatment of iron deficiency anemia in patients with chronic kidney disease: a randomized, active-controlled, multi-center study.
      • Charytan C.
      • Qunibi W.
      • Bailie G.R.
      Venofer Clinical Studies Group
      Comparison of intravenous iron sucrose to oral iron in the treatment of anemic patients with chronic kidney disease not on dialysis.
      • Coyne D.W.
      • Kapoian T.
      • Suki W.
      • et al.
      Ferric gluconate is highly efficacious in anemic hemodialysis patients with high serum ferritin and low transferrin saturation: results of the Dialysis Patients' Response to IV Iron with Elevated Ferritin (DRIVE) Study.
      • Dangsuwan P.
      • Manchana T.
      Blood transfusion reduction with intravenous iron in gynecologic cancer patients receiving chemotherapy.
      • Daniilidis A.
      • Giannoulis C.
      • Pantelis A.
      • Tantanasis T.
      • Dinas K.
      Total infusion of low molecular weight iron-dextran for treating postpartum anemia.
      • Dawson D.W.
      • Goldthorp W.O.
      • Spencer D.
      Parenteral iron therapy in pregnancy.
      • Dhanani J.V.
      • Ganguly B.P.
      • Chauhan L.N.
      Comparison of efficacy and safety of two parenteral iron preparations in pregnant women.
      • Earley C.J.
      • Horska A.
      • Mohamed M.A.
      • Barker P.B.
      • Beard J.L.
      • Allen R.P.
      A randomized, double-blind, placebo-controlled trial of intravenous iron sucrose in restless legs syndrome.
      • Edwards T.J.
      • Noble E.J.
      • Durran A.
      • Mellor N.
      • Hosie K.B.
      Randomized clinical trial of preoperative intravenous iron sucrose to reduce blood transfusion in anaemic patients after colorectal cancer surgery.
      • Erichsen K.
      • Ulvik R.J.
      • Nysaeter G.
      • et al.
      Oral ferrous fumarate or intravenous iron sucrose for patients with inflammatory bowel disease.
      • Evstatiev R.
      • Alexeeva O.
      • Bokemeyer B.
      • et al.
      Ferric carboxymaltose prevents recurrence of anemia in patients with inflammatory bowel disease.
      • Fishbane S.
      • Frei G.L.
      • Maesaka J.
      Reduction in recombinant human erythropoietin doses by the use of chronic intravenous iron supplementation.
      • Froessler B.
      • Cocchiaro C.
      • Saadat-Gilani K.
      • Hodyl N.
      • Dekker G.
      Intravenous iron sucrose versus oral iron ferrous sulfate for antenatal and postpartum iron deficiency anemia: a randomized trial.
      • Garrido-Martin P.
      • Nassar-Mansur M.I.
      • de la Llana-Ducros R.
      • et al.
      The effect of intravenous and oral iron administration on perioperative anaemia and transfusion requirements in patients undergoing elective cardiac surgery: a randomized clinical trial.
      • Giannoulis C.
      • Daniilidis A.
      • Tantanasis T.
      • Dinas K.
      • Tzafettas J.
      Intravenous administration of iron sucrose for treating anemia in postpartum women.
      • Grote L.
      • Leissner L.
      • Hedner J.
      • Ulfberg J.
      A randomized, double-blind, placebo controlled, multi-center study of intravenous iron sucrose and placebo in the treatment of restless legs syndrome.
      • Hedenus M.
      • Birgegard G.
      • Nasman P.
      • et al.
      Addition of intravenous iron to epoetin beta increases hemoglobin response and decreases epoetin dose requirement in anemic patients with lymphoproliferative malignancies: a randomized multicenter study.
      • Henry D.H.
      • Dahl N.V.
      • Auerbach M.
      • Tchekmedyian S.
      • Laufman L.R.
      Intravenous ferric gluconate significantly improves response to epoetin alfa versus oral iron or no iron in anemic patients with cancer receiving chemotherapy.
      • Hussain R.
      • Christi S.
      • Naqvi S.
      Experience of iron saccharate supplementation in haemodialysis patients treated with erythropoietin.

      Kalra P, Thomsen L. Effect of iron isomaltoside 1000 on phosphate levels in patients with non-dialysis dependent chronic kidney disease. American Society of Nephrology, kidney week 2012 abstract supplement, page 687A. https://www.asn-online.org/education/kidneyweek/archives/. Accessed February 19, 2013.

      • Karkouti K.
      • McCluskey S.A.
      • Ghannam M.
      • Salpeter M.J.
      • Quirt I.
      • Yau T.M.
      Intravenous iron and recombinant erythropoietin for the treatment of postoperative anemia.
      • Khalafallah A.
      • Dennis A.
      • Bates J.
      • et al.
      A prospective randomized, controlled trial of intravenous versus oral iron for moderate iron deficiency anaemia of pregnancy.
      • Kim Y.H.
      • Chung H.H.
      • Kang S.B.
      • Kim S.C.
      • Kim Y.T.
      Safety and usefulness of intravenous iron sucrose in the management of preoperative anemia in patients with menorrhagia: a phase IV, open-label, prospective, randomized study.
      • Kim Y.T.
      • Kim S.W.
      • Yoon B.S.
      • et al.
      Effect of intravenously administered iron sucrose on the prevention of anemia in the cervical cancer patients treated with concurrent chemoradiotherapy.
      • Kochhar P.K.
      • Kaundal A.
      • Ghosh P.
      Intravenous iron sucrose versus oral iron in treatment of iron deficiency anemia in pregnancy: a randomized clinical trial.
      • Kotaki M.
      • Uday K.
      • Henriquez M.
      • Blum S.
      • Dave M.
      Maintenance therapy with intravenous iron in hemodialysis patients receiving erythropoietin.
      • Krayenbuehl P.A.
      • Battegay E.
      • Breymann C.
      • Furrer J.
      • Schulthess G.
      Intravenous iron for the treatment of fatigue in nonanemic, premenopausal women with low serum ferritin concentration.
      • Kulnigg S.
      • Stoinov S.
      • Simanenkov V.
      • et al.
      A novel intravenous iron formulation for treatment of anemia in inflammatory bowel disease: the ferric carboxymaltose (FERINJECT) randomized controlled trial.
      • Kulnigg-Dabsch S.
      • Schmid W.
      • Howaldt S.
      • et al.
      Iron deficiency generates secondary thrombocytosis and platelet activation in IBD: the randomized, controlled thromboVIT trial.
      • Kuo K.L.
      • Hung S.C.
      • Wei Y.H.
      • Tarng D.C.
      Intravenous iron exacerbates oxidative DNA damage in peripheral blood lymphocytes in chronic hemodialysis patients.
      • Li H.
      • Wang S.X.
      Intravenous iron sucrose in peritoneal dialysis patients with renal anemia.
      • Li H.
      • Wang S.X.
      Intravenous iron sucrose in Chinese hemodialysis patients with renal anemia.
      • Li H.
      • Wang S.X.
      Intravenous iron sucrose in maintenance dialysis patients with renal anemia: a clinical study.
      • Lindgren S.
      • Wikman O.
      • Befrits R.
      • et al.
      Intravenous iron sucrose is superior to oral iron sulphate for correcting anaemia and restoring iron stores in IBD patients: a randomized, controlled, evaluator-blind, multicentre study.
      • Macdougall I.C.
      • Tucker B.
      • Thompson J.
      • Tomson C.R.
      • Baker L.R.
      • Raine A.E.
      A randomized controlled study of iron supplementation in patients treated with erythropoietin.
      • Madi-Jebara S.N.
      • Sleilaty G.S.
      • Achouh P.E.
      • et al.
      Postoperative intravenous iron used alone or in combination with low-dose erythropoietin is not effective for correction of anemia after cardiac surgery.
      • McMahon L.P.
      • Kent A.B.
      • Kerr P.G.
      • et al.
      Maintenance of elevated versus physiological iron indices in non-anaemic patients with chronic kidney disease: a randomized controlled trial.
      • Michael B.
      • Coyne D.W.
      • Fishbane S.
      • et al.
      Sodium ferric gluconate complex in hemodialysis patients: adverse reactions compared to placebo and iron dextran.
      • Mudge D.W.
      • Tan K.S.
      • Miles R.
      • et al.
      A randomized controlled trial of intravenous or oral iron for posttransplant anemia in kidney transplantation.
      • Nagaraju S.P.
      • Cohn A.
      • Akbari A.
      • Davis J.L.
      • Zimmerman D.L.
      Heme iron polypeptide for the treatment of iron deficiency anemia in non-dialysis chronic kidney disease patients: a randomized controlled trial.
      • Neeru S.
      • Nair N.S.
      • Rai L.
      Iron sucrose versus oral iron therapy in pregnancy anemia.
      • Okonko D.O.
      • 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.
      • Olijhoek G.
      • Megens J.G.
      • Musto P.
      • et al.
      Role of oral versus IV iron supplementation in the erythropoietic response to rHuEPO: a randomized, placebo-controlled trial.
      • Oluboyede O.A.
      • Ogunbode O.
      • Ayeni O.
      Iron deficiency anaemia during pregnancy a comparative trial of treatment by iron-poly (sorbitol-gluconic acid) complex Ferastral given intramuscularly and iron dextran (Imferon) by total dose infusion.
      • Onken J.E.
      • Bregman D.B.
      • Harrington R.A.
      • et al.
      A multicenter, randomized, active-controlled study to investigate the efficacy and safety of intravenous ferric carboxymaltose in patients with iron deficiency anemia.
      • Pedrazzoli P.
      • Farris A.
      • Del Prete S.
      • et al.
      Randomized trial of intravenous iron supplementation in patients with chemotherapy-related anemia without iron deficiency treated with darbepoetin alpha.
      • Provenzano R.
      • Schiller B.
      • Rao M.
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      • Brenner L.
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      Ferumoxytol as an intravenous iron replacement therapy in hemodialysis patients.
      • Qunibi W.Y.
      • Martinez C.
      • Smith M.
      • Benjamin J.
      • Mangione A.
      • Roger S.D.
      A randomized controlled trial comparing intravenous ferric carboxymaltose with oral iron for treatment of iron deficiency anaemia of non-dialysis-dependent chronic kidney disease patients.
      • Reinisch W.
      • Staun M.
      • Tandon R.K.
      • et al.
      A randomized, open-label, non-inferiority study of intravenous iron isomaltoside 1,000 (Monofer) compared with oral iron for treatment of anemia in IBD (PROCEED).
      • Rohling R.G.
      • Zimmermann A.P.
      • Breymann C.
      Intravenous versus oral iron supplementation for preoperative stimulation of hemoglobin synthesis using recombinant human erythropoietin.
      • Schaller G.
      • Scheiber-Mojdehkar B.
      • Wolzt M.
      • et al.
      Intravenous iron increases labile serum iron but does not impair forearm blood flow reactivity in dialysis patients.
      • Schindler E.
      • Scholz S.
      • Boldt J.
      • et al.
      Effectiveness of oral versus parenteral iron substitution in autologous blood donors.
      • Schroder O.
      • Mickisch O.
      • Seidler U.
      • et al.
      Intravenous iron sucrose versus oral iron supplementation for the treatment of iron deficiency anemia in patients with inflammatory bowel disease: a randomized, controlled, open-label, multicenter study.
      • Seid M.H.
      • Derman R.J.
      • Baker J.B.
      • Banach W.
      • Goldberg C.
      • Rogers R.
      Ferric carboxymaltose injection in the treatment of postpartum iron deficiency anemia: a randomized controlled clinical trial.
      • Serrano-Trenas J.A.
      • Ugalde P.F.
      • Cabello L.M.
      • Chofles L.C.
      • Lazaro P.S.
      • Benitez P.C.
      Role of perioperative intravenous iron therapy in elderly hip fracture patients: a single-center randomized controlled trial.
      • Shafi D.
      • Purandare S.V.
      • Sathe A.V.
      Iron deficiency anemia in pregnancy: intravenous versus oral route.
      • Singh A.
      • Patel T.
      • Hertel J.
      • Bernardo M.
      • Kausz A.
      • Brenner L.
      Safety of ferumoxytol in patients with anemia and CKD.
      • Singh H.
      • Reed J.
      • Noble S.
      • Cangiano J.L.
      • Van Wyck D.B.
      United States Iron Sucrose Clinical Trials Group
      Effect of intravenous iron sucrose in peritoneal dialysis patients who receive erythropoiesis-stimulating agents for anemia: a randomized, controlled trial.
      • Singh K.
      • Fong Y.F.
      • Kuperan P.
      A comparison between intravenous iron polymaltose complex (Ferrum Hausmann) and oral ferrous fumarate in the treatment of iron deficiency anaemia in pregnancy.
      • Sloand J.A.
      • Shelly M.A.
      • Feigin A.
      • Bernstein P.
      • Monk R.D.
      A double-blind, placebo-controlled trial of intravenous iron dextran therapy in patients with ESRD and restless legs syndrome.
      • Sood S.K.
      • Ramachandran K.
      • Rani K.
      • et al.
      WHO sponsored collaborative studies on nutritional anaemia in India. The effect of parenteral iron administration in the control of anaemia of pregnancy.
      • Spinowitz B.S.
      • Kausz A.T.
      • Baptista J.
      • et al.
      Ferumoxytol for treating iron deficiency anemia in CKD.
      • Steensma D.P.
      • Sloan J.A.
      • Dakhil S.R.
      • et al.
      Phase III, randomized study of the effects of parenteral iron, oral iron, or no iron supplementation on the erythropoietic response to darbepoetin alfa for patients with chemotherapy-associated anemia.
      • Stein M.L.
      • Gunston K.D.
      • May R.M.
      Iron dextran in the treatment of iron-deficiency anaemia of pregnancy: haematological response and incidence of side-effects.
      • Stoves J.
      • Inglis H.
      • Newstead C.G.
      A randomized study of oral vs intravenous iron supplementation in patients with progressive renal insufficiency treated with erythropoietin.
      • Strickland I.D.
      • Chaput de Saintonge D.M.
      • Boulton F.E.
      • Francis B.
      • Roubikova J.
      • Waters J.I.
      The therapeutic equivalence of oral and intravenous iron in renal dialysis patients.
      • Svara F.
      • Sulkova S.
      • Kvasnicka J.
      • Polakovic V.
      Iron supplementation during erythropoietin therapy in patients on hemodialysis.
      • Talbot N.P.
      • Smith T.G.
      • Privat C.
      • et al.
      Intravenous iron supplementation may protect against acute mountain sickness: a randomized, double-blinded, placebo-controlled trial.
      • Toblli J.E.
      • 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.
      • Vadhan-Raj S.
      • Strauss W.
      • Ford D.
      • et al.
      Efficacy and safety of IV ferumoxytol for adults with iron deficiency anemia previously unresponsive to or unable to tolerate oral iron.
      • van Iperen C.E.
      • Gaillard C.A.
      • Kraaijenhagen R.J.
      • Braam B.G.
      • Marx J.J.
      • van de Wiel A.
      Response of erythropoiesis and iron metabolism to recombinant human erythropoietin in intensive care unit patients.
      • Van Wyck D.B.
      • Mangione A.
      • Morrison J.
      • Hadley P.E.
      • Jehle J.A.
      • Goodnough L.T.
      Large-dose intravenous ferric carboxymaltose injection for iron deficiency anemia in heavy uterine bleeding: a randomized, controlled trial.
      • Van Wyck D.B.
      • Martens M.G.
      • Seid M.H.
      • Baker J.B.
      • Mangione A.
      Intravenous ferric carboxymaltose compared with oral iron in the treatment of postpartum anemia: a randomized controlled trial.
      • Van Wyck D.B.
      • Roppolo M.
      • Martinez C.O.
      • Mazey R.M.
      • McMurray S.
      United States Iron Sucrose Clinical Trials Group
      A randomized, controlled trial comparing IV iron sucrose to oral iron in anemic patients with nondialysis-dependent CKD.
      • Verma S.
      • Inamdar S.
      • Malhotra N.
      Intravenous iron therapy versus oral iron in postpartum patients in rural area.
      • Wali A.
      • Mushtaq A.
      • Nilofer
      Comparative study: efficacy, safety and compliance of intravenous iron sucrose and intramuscular iron sorbitol in iron deficiency anemia of pregnancy.
      • Weisbach V.
      • Skoda P.
      • Rippel R.
      • et al.
      Oral or intravenous iron as an adjuvant to autologous blood donation in elective surgery: a randomized, controlled study.
      • Westad S.
      • Backe B.
      • Salvesen K.A.
      • et al.
      A 12-week randomised study comparing intravenous iron sucrose versus oral ferrous sulphate for treatment of postpartum anemia.
      • Yin L.
      • Chen X.
      • Chen J.
      • Cheng M.
      • Peng Y.
      • Yang L.
      Multi-frequency low-dose intravenous iron on oxidative stress in maintenance hemodialysis patients.
      published from January 1, 1966, through December 31, 2013, fulfilled the inclusion criteria (Figure). Pooled together, 10,390 patients treated with IV iron were compared with 4044 patients treated with oral iron, 1329 treated with no iron, 3335 treated with placebo, and 155 treated with IM iron. Study characteristics are presented in Supplemental Table 1 (available online at http://www.mayoclinicproceedings.org). Ferric carboxymaltose (FCM) was used in 15, IS in 57 trials, FG in 7, ID in 14, ferumoxytol in 4, iron polymaltose in 3, and iron isomaltoside in 2 (1 trial used both FCM and IS
      • Arutyunov G.
      • Bylova N.
      • Ivleva A.
      • Kobalava Z.
      The safety of intravenous (IV) ferric carboxymaltose versus IV iron sucrose on patients with chronic heart failure (CHF) and chronic kidney disease (CKD) with iron deficincy (ID).
      ). Control arms included 14 trials of no iron, 20 trials of placebo, 56 trials of oral iron, 4 trials of IM iron, 8 trials of oral iron and placebo or no iron, and 1 trial of IM iron and no iron. Among the trials that reported the total amount of IV iron given, the median dosage was 1400 mg (range, 70-3200 mg). Patients were followed up for 1 to 52 weeks (median, 8 weeks); follow-up losses were reported in only a few trials. Other trial characteristics, including inclusion criteria, hematologic data, and treatment schedule, are detailed in Supplemental Table 1.

      Risk of Bias Assessment

      Allocation generation was adequate in 61 trials (59%), inadequate in 1 trial (1%), and unclear in 41 (40%). Allocation concealment was adequate in 52 trials (50%), inadequate in 3 trials (3%), and unclear in 48 (47%). Double blinding was used in 20 trials. In 29 trials (28%), intent-to-treat analysis of primary outcome was performed. Industrial sponsorship was declared in 44 trials (42.7%), nonindustrial or academic sponsorship in 10 trials (9.7%), and sponsorship was unclear in 49 trials (47.5%).
      A total of 20 trials had valid AE grading (14 trials used the Common Terminology Criteria for Adverse Events grading system
      US Department of Health and Human Services
      National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE).
      or a similar grading system; 6 trials developed an acceptable AE grading system). In 83 trials (80%), the grading system for AEs was not reported or invalid. Thirty-three trials reported AEs by intent to treat, 11 trials reported only treatment-related AEs, and 23 reported both any and treatment-related AEs. In 36 trials, the reporting of the relevance of AEs to the treatment was unclear. Severity threshold for the reporting of AEs was not used, but 6 trials reported AEs only if there was more than a 1% to 5% occurrence rate. Adverse events that required discontinuation of treatment were reported in 80 trials; rules for discontinuation were reported in 2 trials. Other methodologic details are presented in Supplemental Table 2 (available online at http://www.mayoclinicproceedings.org).

      Primary Outcome: Occurrence of SAEs

      Serious adverse events were reported by 97 trials (95%). Overall, there was no increase in the risk of SAEs with IV iron compared with control (RR, 1.04; 95% CI, 0.93-1.17; I2=9%; Supplemental Figure 1; available online at http://www.mayoclinicproceedings.org). Further classification (Table 1) revealed a statistically nonsignificant lower risk of SAEs when IV iron was compared with placebo in double-blind trials (RR, 0.83; 95% CI, 0.64-1.03; I2=41%). Sensitivity analysis restricted to studies that reported SAEs with adequate allocation concealment (n=49) and studies with adequate AE definitions (n=19) did not alter the results (RR, 1.02; 95% CI, 0.93-1.18; I2=9%; and RR, 0.94; 95% CI, 0.74-1.20; I2=48% [REM]; respectively).
      Table 1Primary Outcomes
      FCM = ferric carboxymaltose; FG = ferric gluconate; FML = ferumoxytol; ID = iron dextran; IPM = iron polymaltose; IS = iron sucrose; ISM = iron isomaltoside; NA = not applicable; NNH = number needed to harm; NNP = number needed to prevent; RR = relative risk; SAE = severe adverse event.
      SAERR (95% CI)NNH or NNP (95% CI)
      All studies1.04 (0.93-1.17)NA
      By indication
       Chronic heart failure0.45 (0.29-0.70)
      Indicates statistically significant results.
      NNP, 10 (6-25)
      Indicates statistically significant results.
       Obstetrics and gynecology2.0 (1.15-3.62)
      Indicates statistically significant results.
      NNH, 119 (61-1725)
      Indicates statistically significant results.
      By comparator
       Placebo0.83 (0.64-1.08)NA
       No iron1.06 (0.90-1.25)NA
       Oral iron1.13 (0.95-1.35)NA
       Intramuscular iron1.36 (0.22-8.49)NA
      By compound
       IS1.33 (0.96-1.83)NA
       FCM0.82 (0.64-1.06)NA
       FML1.04 (0.71-1.53)NA
       ISM or IPM1.09 (0.43-2.80)NA
       ID1.05 (0.77-1.45)NA
       FG1.12 (0.96-1.30)NA
      By system involved
       Infections0.96 (0.63-1.46)NA
       Gastrointestinal1.03 (0.64-1.66)NA
       Cardiovascular0.94 (0.60-1.46)NA
       Thromboembolic0.99 (0.52-1.86)NA
       Respiratory0.91 (0.27-3.86)NA
       Neurologic1.05 (0.47-2.36)NA
      By infusion reaction
       All2.47 (1.43-4.28)
      Indicates statistically significant results.
      NNH, 292 (164-1316)
      Indicates statistically significant results.
       IS1.75 (0.69-4.43)NA
       FCM1.47 (0.40-5.39)NA
       FML2.26 (0.19-26.22)NA
       ISM or IPM1.00 (0.99-1.01)NA
       ID3.10 (0.86-11.22)NA
       FG5.32 (1.49-18.99)
      Indicates statistically significant results.
      NNH, 118 (68-423)
      Indicates statistically significant results.
      Placebo comparator2.96 (1.16-7.51)
      Indicates statistically significant results.
      NNH, 255 (136-1910)
      Indicates statistically significant results.
      a FCM = ferric carboxymaltose; FG = ferric gluconate; FML = ferumoxytol; ID = iron dextran; IPM = iron polymaltose; IS = iron sucrose; ISM = iron isomaltoside; NA = not applicable; NNH = number needed to harm; NNP = number needed to prevent; RR = relative risk; SAE = severe adverse event.
      b Indicates statistically significant results.

      Indication for Therapy

      A subgroup analysis performed on the basis of the indication for therapy revealed that the use of IV iron in patients with chronic heart failure was associated with a decreased rate of SAEs compared with controls (RR, 0.45; 95% CI, 0.29-0.70; I2=0%; NNP, 10; 95% CI, 6-25). In trials in gynecology and obstetrics, the use of IV iron was associated with an increased rate of SAEs (RR, 2.00; 95% CI, 1.15-3.62; I2=0%; NNH, 119; 95% CI, 61-1725). Subdividing the trials by indication for therapy (pregnancy, peripartum, and other) or compound revealed a trend toward increased rate of SAEs with IV iron that was statistically nonsignificant in all subgroups. In trials of chronic kidney disease, inflammatory bowel disease, and cancer-induced anemia, perioperative trials, and other trials of mixed causes, there was no increased risk of SAEs with IV iron therapy.

      SAEs by System Involved

      There was no increased risk of serious infections with IV iron (RR, 0.96; 95% CI, 0.63-1.46; I2=8.2%). Serious infusion reactions were increased with IV iron (RR, 2.47; 95% CI, 1.43-4.28; I2=0%; NNH, 292; 95% CI, 164-1316) and particularly with FG (RR, 5.32; 95% CI, 1.49-18.99; I2=0%; NNH, 118; 95% CI, 68-423). The other iron preparations were not associated with a statistically significant increased risk of severe infusion reactions (IS: RR, 1.75; 95% CI, 0.69-4.43; FCM: RR, 1.47; 95% CI, 0.40-5.39; ferumoxytol: RR, 2.26; 95% CI, 0.19-26.22; ID: RR, 3.1; 95% CI, 0.86-11.22). A subgroup analysis restricted to trials that used placebo as the comparator revealed an increased risk of a severe infusion reaction (RR, 2.96; 95% CI, 1.16-7.51; I2=0%; NNH, 255; 95% CI, 136-1910). The risk of cardiovascular, neurologic, thromboembolic, or gastrointestinal SAEs was not increased with IV iron. Sensitivity analysis was performed on the basis of quality measures did not alter the reported results. Subgroup analysis was performed on the basis of indication for treatment, type of comparator, and type of IV iron formula did not alter the results. No deaths related to SAEs were reported.

      Secondary Outcomes: Mortality, AEs Requiring Discontinuation, and Any AEs

      Results are presented in Table 2. All-cause mortality was reported in 57 trials, and of these trials, no deaths occurred during the follow-up period in 29 trails. Overall, there was no increased risk of mortality with IV iron (RR, 1.06; 95% CI, 0.81-1.39; I2=0%). There was no increased risk of AEs that required discontinuation of treatment with IV iron (RR, 0.92; 95% CI, 0.76-1.12; I2=11%). There was a trend toward decreased risk of AEs requiring discontinuation with FCM (RR, 0.69; 95% CI, 0.46-1.00; I2=8%). The occurrence of any AEs was reported by 38 trials. There was no increased risk of any AEs with IV iron (RR, 1.04; 95% CI, 0.99-1.08; I2=74% [REM]). Among the trials that defined AEs as treatment related (n=43), there was no increased risk of treatment-related AEs (RR, 1.08; 95% CI, 0.96-1.21; I2=78% [REM]). Subgroup analysis was performed on the basis of indication for treatment and comparator did not change these results.
      Table 2Secondary Outcomes
      AE = adverse event; FCM = ferric carboxymaltose; FG = ferric gluconate; ID = iron dextran; IS = iron sucrose; NA = not applicable; NNH = number needed to harm; NNP = number needed to prevent; RR = relative risk.
      AERR (95% CI)NNH or NNP (95% CI)
      Mortality1.06 (0.81-1.39)NA
      Any1.04 (0.99-1.08)NA
      Treatment related1.08 (0.96-1.21)NA
      Requiring discontinuation
       Total0.92 (0.76-1.12)NA
       FCM0.69 (0.46-1.00)
      Indicate statistically significant results.
      NNP, 127 (60-1377)
      Indicate statistically significant results.
      Infections1.17 (0.83-1.65)NA
      Gastrointestinal
       Total0.55 (0.51-0.61)
      Indicate statistically significant results.
      NNP, 10 (8-14)
      Indicate statistically significant results.
       ID0.28 (0.14-0.53)
      Indicate statistically significant results.
      NNP, 15 (6-32)
      Indicate statistically significant results.
       FCM0.57 (0.48-0.68)
      Indicate statistically significant results.
      NNP, 15 (8-173)
      Indicate statistically significant results.
       IS0.38 (0.32-0.45)
      Indicate statistically significant results.
      NNP, 7 (5-12)
      Indicate statistically significant results.
       Placebo1.39 (1.13-1.71)
      Indicate statistically significant results.
      NNH, 54 (34-128)
      Indicate statistically significant results.
       No iron0.84 (0.72-0.92)
      Indicate statistically significant results.
      NNP, 24 (12-738)
      Indicate statistically significant results.
       Oral iron0.33 (0.29-0.38)
      Indicate statistically significant results.
      NNP, 6 (5-7)
      Indicate statistically significant results.
      Infusion reaction
       Total2.74 (2.13-3.53)
      Indicate statistically significant results.
      NNH, 64 (44-115)
      Indicate statistically significant results.
       IS3.59 (2.30-5.61)
      Indicate statistically significant results.
      NNH, 44 (25-183)
      Indicate statistically significant results.
       FCM3.36 (2.08-5.44)
      Indicate statistically significant results.
      NNH, 46 (29-110)
      Indicate statistically significant results.
       FG5.85 (1.53-22.30)
      Indicate statistically significant results.
      NNH, 141 (79-627)
      Indicate statistically significant results.
       Placebo2.42 (1.50-3.91)
      Indicate statistically significant results.
      NNH, 92 (52-422)
      Indicate statistically significant results.
       Oral iron3.49 (2.22-5.49)
      Indicate statistically significant results.
      NNH, 50 (32-113)
      Indicate statistically significant results.
       No iron2.19 (1.05-4.56)
      Indicate statistically significant results.
      NNH, 92 (52-422)
      Indicate statistically significant results.
      Cardiovascular
       Total0.99 (0.83-1.17)NA
       FCM0.57 (0.42-0.79)
      Indicate statistically significant results.
      NNP, 28 (17-71)
      Indicate statistically significant results.
       FG1.33 (1.05-1.69)
      Indicate statistically significant results.
      NNH, 39 (21-235)
      Indicate statistically significant results.
      Respiratory1.14 (0.72-1.81)NA
      Neurologic
       Total1.35 (1.13-1.61)
      Indicate statistically significant results.
      NNH, 78 (44-336)
      Indicate statistically significant results.
       IS1.63 (1.10-2.42)
      Indicate statistically significant results.
      NNH, 71 (30-237)
      Indicate statistically significant results.
       Oral iron2.14 (1.54-2.98)
      Indicate statistically significant results.
      NNH, 50 (33-100)
      Indicate statistically significant results.
       Intramuscular iron0.09 (0.03-0.26)
      Indicate statistically significant results.
      NNP, 14 (4-42)
      Indicate statistically significant results.
      Thromboembolic0.92 (0.62-1.38)NA
      Hypotension
       Total1.39 (1.09-1.77)
      Indicate statistically significant results.
      NNH, 97 (58-305)
      Indicate statistically significant results.
       IS3.01 (1.12-8.11)
      Indicate statistically significant results.
      NNH, 68 (37-364)
      Indicate statistically significant results.
       No iron3.83 (1.33-11.02)
      Indicate statistically significant results.
      NNH, 50 (25-100)
      Indicate statistically significant results.
      Skin1.60 (1.05-2.45)
      Indicate statistically significant results.
      NNH, 99 (59-304)
      Indicate statistically significant results.
      Muscle or skeletal
       Total1.58 (1.15-2.17)
      Indicate statistically significant results.
      NNH, 36 (28-53)
      Indicate statistically significant results.
       FCM3.42 (2.02-5.79)
      Indicate statistically significant results.
      NNH, 32 (23-49)
      Indicate statistically significant results.
      Hypertension2.25 (1.00-5.08)
      Indicate statistically significant results.
      NNH, 36 (28-51)
      Indicate statistically significant results.
      Constitutional1.35 (0.97-1.87)NA
      Electrolytes2.45 (1.84-3.26)
      Indicate statistically significant results.
      NNH, 19 (11-67)
      Indicate statistically significant results.
      Abnormal laboratory results1.57 (0.91-2.71)NA
      Iron overload1.40 (0.95-2.07)NA
      a AE = adverse event; FCM = ferric carboxymaltose; FG = ferric gluconate; ID = iron dextran; IS = iron sucrose; NA = not applicable; NNH = number needed to harm; NNP = number needed to prevent; RR = relative risk.
      b Indicate statistically significant results.

      Secondary Outcomes: Infections and Cardiovascular, Gastrointestinal, and Infusion Reactions

      The occurrence of infections was not increased with IV iron regardless of compound, comparator, and indication (RR, 1.17; 95% CI, 0.83-1.65; I2=0%; Supplemental Figure 2; available online at http://www.mayoclinicproceedings.org). There was no increased risk of cardiovascular AEs; however, FCM was associated with a decreased risk of cardiovascular AEs (RR, 0.57; 95% CI, 0.42-0.79; I2=0%; NNP, 28; 95% CI, 17-71), and FG was associated with an increased risk of cardiovascular AEs (RR, 1.33; 95% CI, 1.05-1.69; I2=0%; NNH, 39; 95% CI, 21-235). The use of IV iron was associated with a decreased risk of gastrointestinal AEs (RR, 0.55; 95% CI, 0.51-0.61; I2=84% [REM]; NNP, 10; 95% CI, 8-14), particularly with IS, ID, and FCM and when the comparator was oral iron or no iron (Table 2). Infusion reactions were increased with IV iron (RR, 2.74; 95% CI, 2.13-3.53; I2=26%; NNH, 64; 95% CI, 44-115) and further increased when compared with oral iron (RR, 3.49; 95% CI, 2.22-5.49; I2=0%; NNH, 50; 95% CI, 32-113), placebo (RR, 2.42; 95% CI, 1.50-3.91; I2=0%; NNH, 92; 95% CI, 52-422), and no iron (RR, 2.19; 95% CI, 1.05-4.56; I2=0%, NNH, 86; 95% CI, 41-133). Infusion reactions were further increased when IS, FG, and FCM were used (Table 2).

      Secondary Outcomes: Other AEs

      There was an increase in neurologic AEs (RR, 1.35; 95% CI, 1.13-1.61; I2=35%; NNH, 78; 95% CI, 44-336), which was more pronounced when IS was used (RR, 1.63; 95% CI, 1.10-2.42; I2=0%; NNH, 71; 95% CI, 30-237). Hypotension was increased with IV iron (RR, 1.39; 95% CI, 1.09-1.77; I2=39%; NNH, 97; 95% CI, 58-305). This effect was more pronounced when IS was used (RR, 3.01; 95% CI, 1.12-8.11; I2= 0%; NNH, 68; 95% CI, 37-364) and when compared with no iron (RR, 3.83; 95% CI, 1.33-11.02; I2=38%; NNH, 50; 95% CI, 25-100). The use of IV iron was associated with an increased risk of electrolyte disorder (most trials reported on the occurrence of hypophosphatemia) (RR, 2.45; 95% CI, 1.84-3.26; I2=49% [REM]; NNH, 19; 95% CI, 11-67). Adverse events related to skin (excluding urticaria) were increased with IV iron (RR, 1.60; 95% CI, 1.05-2.45; I2=35%; NNH, 99; 95% CI, 59-304). Finally, muscle and skeletal AEs were increased with IV iron and particularly FCM (RR, 3.42; 95% CI, 2.02-5.79; I2=40%; NNH, 32; 95% CI, 23-49). There was a trend toward hypertension responses with IV iron (RR, 2.25; 95% CI, 1.00-5.08; I2=0%). No statistically significant increase in the occurrence of abnormal laboratory results, constitutional symptoms, or thromboembolic and respiratory AEs was found with any IV iron preparation, comparator, or indication of use. Sensitivity analysis restricted to studies with adequate allocation concealment and studies with adequate AEs definitions did not alter any result.

      Discussion

      Our systematic review assesses safety of IV iron by compiling data from all randomized clinical trials evaluating IV iron treatment. We found that IV iron is not associated with an increase in SAEs (RR, 1.04; 95% CI, 0.93-1.14; I2=9%). Moreover, certain IV formulations were associated with a decreased risk of SAEs. Gastrointestinal AEs were decreased, and the risk of discontinuation of therapy was lower with IV iron. There was no increase in the risk of infections.
      Although the efficacy of IV iron was found in many settings,
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      Iron supplementation for the treatment of chronic heart failure and iron deficiency: systematic review and meta-analysis.
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      Treatment of anemia in inflammatory bowel disease- systematic review and meta-analysis.
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      • Gafter-Gvili A.
      • Paul M.
      • Leibovici L.
      • Shpilberg O.
      • Gafter U.
      Intravenous versus oral iron supplementation for the treatment of anemia in CKD: systematic review and meta-analysis.
      • Gafter-Gvili A.
      • Rozen-Zvi B.
      • Vidal L.
      • et al.
      Intravenous iron supplementation for the treatment of chemotherapy-induced anaemia: systematic review and meta-analysis of randomised controlled trials.
      there are still concerns regarding safety. The most important finding of our systematic review is the lack of increase in all SAEs with iron. In addition, there was no increase in AEs that required discontinuation and no increase in mortality. Moreover, there was no increased risk of cardiovascular, respiratory, neurologic, thromboembolic, constitutional, or gastrointestinal SAEs with IV iron.
      Another interesting finding is the decrease in cardiovascular AEs and risk of discontinuation of therapy with FCM. However, 86% of all patients in trials of chronic heart failure were treated with FCM, thus outweighing other formulations and potentially creating reporting bias. This is a promising new formulation of a non–dextran-containing iron complex that allows administration of a large dose of iron (up to 1000 mg) in a single infusion. Our review included 16 trials with FCM. A previous systematic review of the efficacy and safety of FCM for various indications
      • Moore R.A.
      • Gaskell H.
      • Rose P.
      • Allan J.
      Meta-analysis of efficacy and safety of intravenous ferric carboxymaltose (Ferinject) from clinical trial reports and published trial data.
      suggested that FCM is largely effective in achieving a superior hemoglobin response than oral iron treatment. The safety profile of FCM in that review was similar to our results, including infusion reactions (regarded as general and administration site reaction).
      Another significant finding is the lack of increase in any infections (RR, 1.17; 95% CI, 0.83-1.65) and serious infections (RR, 0.96; 95% CI, 0.63-1.46). Experimental data have suggested that IV iron might promote infection by supplying iron to pathogenic bacteria.
      • Fishbane S.
      Review of issues relating to iron and infection.
      In our review, this did not translate into an increase in infection. A prospective study of 988 patients undergoing hemodialysis in 19 European centers followed up for 6 months with 51 episodes of bacteremia found on multivariate analysis that there was no association between IV iron and risk of infection.
      • Hoen B.
      • Paul-Dauphin A.
      • Hestin D.
      • Kessler M.
      EPIBACDIAL: a multicenter prospective study of risk factors for bacteremia in chronic hemodialysis patients.
      • Hoen B.
      • Paul-Dauphin A.
      • Kessler M.
      Intravenous iron administration does not significantly increase the risk of bacteremia in chronic hemodialysis patients.
      The lack of increase in infection may possibly be related to the fact that low free iron concentrations are associated with the newer IV iron preparations. In contrast to our findings, a recent systematic review and meta-analysis by Litton et al
      • Litton E.
      • Xiao J.
      • Ho K.M.
      Safety and efficacy of intravenous iron therapy in reducing requirement for allogeneic blood transfusion: systematic review and meta-analysis of randomised clinical trials.
      found a statistically significant increase in the rate of infection (RR, 1.33; 95% CI, 1.1-1.64) with IV iron. This review included a total of 75 trials, and data regarding infections were derived from only 24 trials, whereas our study compiled the data from 103 trials and the infection data from 32 trials. Moreover, in the study by Litton et al, trials that did not report any events in the intervention and comparison groups were excluded, whereas we were able to use the data from these studies for calculation of the RR. Thus, the comprehensiveness of our meta-analysis may explain the difference. Of note, although the study by Litton et al found an increase in infections, it did not find a dose response association with iron and infection risk, and there was no difference in mortality and other SAEs in the IV iron groups (as shown in our meta-analysis).
      The fact that no increase in infections in the IV iron arm is revealed in our meta-analysis is important, although the other therapeutic option for treatment of anemia, red blood cell transfusion, needs to be taken into account. A large meta-analysis,
      • Rohde J.M.
      • Dimcheff D.E.
      • Blumberg N.
      • et al.
      Health care-associated infection after red blood cell transfusion: a systematic review and meta-analysis.
      including 21 randomized clinical trials with 8735 patients that compared a restrictive and a permissive red blood cell transfusion strategy, found that a restrictive transfusion strategy was associated with a reduced risk of health care–associated infection compared with a liberal transfusion strategy. Therefore, implementing restrictive strategies may have the potential to lower the incidence of health care–associated infection. Intravenous iron administration may possibly help facilitate this.
      Of note, an increase in any and serious infusion reactions was demonstrated (RR, 2.47; 95% CI, 1.43-4.28). However, the NNH was 200 for serious infusion reactions, and no death or anaphylaxis was reported by any trial. The feared anaphylactic reaction is extremely rare and occurs mainly with the high-molecular-weight ID. When assessing each of the formulations separately, there was no statistically significant increase for any of the formulations except FG, and overall, 35 severe infusion reactions were reported for 9223 patients (1:263; range, 101-481), none of which resulted in death. Thus, it seems that the newer formulations are safer to administer and no test dose is required.
      There might be still a reluctance to incorporate IV iron as a standard in the treatment of iron deficiency and other settings of iron restricted erythropoiesis. For many of the examined conditions, 1 or 2 infusions ease care, and the incorporation of IV iron into chemotherapy and dialysis regimens may increase adherence. Therefore, it may be the safety issue rather than convenience that is responsible for the failure of patients to use IV iron. Another explanation may lie in the fear of minor infusion reactions and the addition of antihistamines as premedication before IV iron infusion.
      • Auerbach M.
      • Ballard H.
      • Glaspy J.
      Clinical update: intravenous iron for anaemia.
      This practice may result in an apparently severe anaphylactic reaction with IV iron therapy and should probably be abandoned because these reactions usually resolve without therapy and rarely recur with rechallenge.
      • Baribeault D.
      • Auerbach M.
      Iron replacement therapy in cancer-related anemia.
      The strength of our systematic review stems primarily from the large volume of trials and patients (103 trials that included 10,390 patients). Several limitations merit consideration. The included trials were heterogeneous regarding the type of patients, different iron preparations, schedule, and total dose of IV iron administered. Of note, tests for heterogeneity were low (<40% and most often 0% for SAEs), Although most trials were of good methodologic design and reporting, 80% of the trials did not report quality measures addressed by the CONSORT guidelines for AEs.
      • Ioannidis J.P.
      • Evans S.J.
      • Gotzsche P.C.
      • et al.
      Better reporting of harms in randomized trials: an extension of the CONSORT statement.
      Another possible concern comes from including trials that were diverse in follow-up time and methods. Trials of chronic heart failure, for instance, had relatively long follow-up and concentrated on cardiovascular AEs in contrast to trials of obstetric or perioperative iron administration, which had short follow-up and concentrated on administration and general AEs.
      We found that IV iron formulations are safe. They should be considered as an alternative to red blood cell transfusions. Red blood cell transfusions are associated with events that cause major morbidity in 1 in 21,413 components issued according to the Serious Hazards of Transfusion 2012 data.
      • Bolton-Maggs P.H.
      • Cohen H.
      Serious Hazards of Transfusion (SHOT) haemovigilance and progress is improving transfusion safety.
      Intravenous iron, on the other hand, is associated with an estimated SAE incidence of less than 1 in 200,000 (when high-molecular-weight ID is avoided).
      • Chertow G.M.
      • Mason P.D.
      • Vaage-Nilsen O.
      • Ahlmen J.
      Update on adverse drug events associated with parenteral iron.

      Conclusion

      Intravenous iron formulations are safe and may be given to iron deficient individuals without fear of infection or cardiovascular events. Newer preparations may have the highest safety threshold and may be given safely in 1 or 2 doses. Further research should focus on head-to-head comparisons of IV iron formulations for specific conditions.

      Supplemental Online Material

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      • Continued Caution Recommended in Use of Intravenous Iron Preparations
        Mayo Clinic ProceedingsVol. 90Issue 5
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          We read with interest the report of the well-performed study of Avni et al1 on the safety of intravenous (IV) iron administration published in the January 2015 issue of Mayo Clinic Proceedings. After carefully analyzing more than 100 published randomized, controlled trials (RCTs) that included more than 10,000 patients, the authors concluded that there is no increased risk of serious adverse effects (SAEs) with IV iron preparations compared with other oral iron preparations or placebo and that IV iron formulations are safe and may be given to iron-deficient individuals without fear of infection or cardiovascular events.
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