On the relative safety of intravenous iron formulations: New answers, new questions
Authors: Glenn M. Chertow, Wolfgang C. Winkelmayer
Journal: American Journal of Hematology (2010)

In the current issue of the American Journal of Hematology, Wysowski and colleagues [1] from the Office of Surveillance and Epidemiology at the United States Food and Drug Administration (FDA) provide the most comprehensive analysis of serious adverse events associated with the provision of parenteral iron formulations assembled to date. The effort undertaken by the authors and the manuscript that resulted from their work will prove to be of great value to physicians and surgeons in practice, including those who commonly use intravenous iron in the management of anemia associated with chronic kidney disease, cancer, menorrhagia and other serious health conditions, and arguably even more so to providers less familiar with the use of intravenous iron, who have generally overestimated risks associated with its use. The authors highlighted important limitations of previously published analyses examining adverse event rates and the relative safety of alternative intravenous iron formulations [2-5]—two of which used data from the FDA's Adverse Event Reporting System (MedWatch). With the caveat that such events were likely under-ascertained, these earlier studies documented relatively low rates of adverse events for all intravenous iron formulations and suggested that the higher molecular weight iron dextran formulation might exhibit higher adverse event rates than the lower molecular weight formulation or non-dextran-complexed iron preparations. The current authors are correct in that these results could be biased by differential under-reporting and ambiguities in coding, among other factors. The authors confirmed and extended earlier reports by creatively examining the exposure to intravenous iron and outcome metrics other than those characterized by voluntary reporting. First, the authors queried death certificate data from the National Center for Health Statistics during 1979-2005 and the US Consumer Product Safety Commission during 1999 using relevant International Classification of Disease ninth revision (ICD-9) codes. These analyses were unable to compare formulations, but recognizing the limitations of death certificate data, confirmed low rates of deaths in which iron administration was considered a contributing or proximate cause. The number of deaths averaged 2.3 per year (range 0 to 10). To place these numbers in context, in the years 2002-06, during which there were 1 to 4 deaths recognized as related to intravenous iron, roughly 10 to 15 million doses were purchased for use each year. The authors also accessed two national databases to identify visits to Emergency Departments during 2004-08 in which adverse events associated with the provision of intravenous iron might be noted. They identified 35 visits (with a female predominance), including seven requiring hospital admission and no deaths. New answers include the key facts that 1) serious adverse events associated with the provision of intravenous iron are relatively rare; 2) serious (including anaphylactoid) adverse events are observed with all of the commercially available formulations; and 3) post-marketing surveillance using traditional methods of adverse event reporting should continue, arguably with more attention to detail, both in characterizing the exposure (in terms of formulation, dose and clinical indication) and outcome. New questions have also arisen that are now ripe for investigation. Whether driven by true or imagined differential risk, clinical experience, convenience, cost, marketing or other factors, patterns of use of alternative intravenous iron formulations have materially changed over the past several years, with iron sucrose becoming the dominant agent prescribed. While it is likely that iron sucrose will remain widely prescribed (the largest for-profit dialysis provider now licenses its use) [6], one new formulation was recently approved [7] and other parenteral formulations await phase III testing and approval in the coming years. In January 2011, the Centers for Medicare and Medicaid Services (CMS) will implement a case mix-adjusted bundled payment for dialysis and related services, (the "end-stage renal disease prospective payment system"), which will include intravenous iron [8]. It is possible that differential costs of intravenous iron preparations will drive utilization, possibly leading to increased use of iron dextran formulations. In concert, evaluation of the risks of exposure to intravenous iron in general, and to the differential risks among various formulations, should be urgently undertaken. Given that event rates are low, and all formulations appear to be reasonably efficacious, randomized clinical trials (whether superiority or non-inferiority trials) are unlikely to be terribly informative. Rather, pharmacoepidemiological studies using state-of-the-art biostatistical techniques to mitigate confounding by indication [9] have the potential to identify subtle but important differences in risk; similar approaches have been recently highlighted in establishing differential risks of cardiovascular events among commercially available thiazolidinediones [10]. Among patients with anemia associated with chronic kidney disease or cancer, the safety of erythropoiesis stimulating agents (ESAs) has been seriously questioned and remains a high priority issue for FDA [11]. New questions regarding the relative safety of intravenous iron—in general, and formulation-specific—now take on even more importance, as we anticipate more judicious use of ESAs in these conditions. Understanding the relative safety of intravenous iron and ESAs, alone and in combination, should be a high priority topic for comparative effectiveness researchers. The thoughtful, creative and comprehensive analysis by Wysowski et al. has set the stage for this future work.