Comparative Risk of Anaphylactic Reactions Associated With Intravenous Iron Products

Wang, Cunlin; Graham, David J.; Kane, Robert C.; Xie, Diqiong; Wernecke, Michael; Levenson, Mark; MaCurdy, Thomas; Houstoun, Monica; Ryan, Qin; Wong, Sarah Anne; Mott, Katrina; Sheu, Ting-Chang; Limb, Susan L.; Worrall, Chris; Kelman, Jeffrey A.; Reichman, Marsha E.

doi:10.1001/jama.2015.15572

Cited by 183 publications

(179 citation statements)

References 26 publications

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“…A 3 times higher rate of adverse events was found for iron dextran compared to other IV iron. Also, more anaphylactic reactions were seen after the first administration of IV iron compared to repeated administration [23]. This phenomenon is in line with our results and the description of CARPA [24].…”

Section: Discussionsupporting

confidence: 91%

Distinct in vitro Complement Activation by Various Intravenous Iron Preparations

Hempel

Poppelaars²,

Costa

et al. 2016

Am J Nephrol

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Background: Intravenous (IV) iron preparations are widely used in the treatment of anemia in patients undergoing hemodialysis (HD). All IV iron preparations carry a risk of causing hypersensitivity reactions. However, the pathophysiological mechanism is poorly understood. We hypothesize that a relevant number of these reactions are mediated by complement activation, resulting in a pseudo-anaphylactic clinical picture known as complement activation-related pseudo allergy (CARPA). Methods: First, the in-vitro complement-activating capacity was determined for 5 commonly used IV iron preparations using functional complement assays for the 3 pathways. Additionally, the preparations were tested in an ex-vivo model using the whole blood of healthy volunteers and HD patients. Lastly, in-vivo complement activation was tested for one preparation in HD patients. Results: In the in-vitro assays, iron dextran, and ferric carboxymaltose caused complement activation, which was only possible under alternative pathway conditions. Iron sucrose may interact with complement proteins, but did not activate complement in-vitro. In the ex-vivo assay, iron dextran significantly induced complement activation in the blood of healthy volunteers and HD patients. Furthermore, in the ex-vivo assay, ferric carboxymaltose and iron sucrose only caused significant complement activation in the blood of HD patients. No in-vitro or ex-vivo complement activation was found for ferumoxytol and iron isomaltoside. IV iron therapy with ferric carboxymaltose in HD patients did not lead to significant in-vivo complement activation. Conclusion: This study provides evidence that iron dextran and ferric carboxymaltose have complement-activating capacities in-vitro, and hypersensitivity reactions to these drugs could be CARPA-mediated.

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Section: Discussionsupporting

confidence: 91%

Distinct in vitro Complement Activation by Various Intravenous Iron Preparations

Hempel

Poppelaars²,

Costa

et al. 2016

Am J Nephrol

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“…8 A very recent cohort of 688,183 new users of IV iron found anaphylaxis risk for nondextran products to be as low as 24 events/100,000 persons. 40 The true anaphylaxis rate might have been even lower because the positive predictive value of the algorithm used to identify anaphylaxis was only 63%. 40 Furthermore, newer IV iron formulations enable restoration of iron stores quickly and efficiently and are much more convenient for administration compared with older preparations.…”

Section: Discussionmentioning

confidence: 99%

Intravenous Versus Oral Iron Supplementation for the Treatment of Anemia in CKD: An Updated Systematic Review and Meta-analysis

Shepshelovich

Rozen‐Zvi

Avni

et al. 2016

American Journal of Kidney Diseases

196

118

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“…Despite a relatively high prevalence of anemia, relatively few patients with stages 4-5 CKD are treated with intravenous (IV) iron, 10 owing to associated risks including anaphylactoid reactions, concerns regarding the need for multiple venous cannulations in patients who may require creation of arteriovenous fistula for hemodialysis, and a variety of logistic hurdles. 11,12 Ferric citrate functions as an intestinal phosphate binder, and has been approved by the US Food and Drug Administration and other major regulatory agencies for the treatment of hyperphosphatemia in patients on dialysis. 13,14 Prior studies in patients receiving dialysis and a phase 2 study in patients with NDD-CKD found ferric citrate to increase transferrin saturation, serum ferritin, and hemoglobin.…”

mentioning

confidence: 99%

Effects of Ferric Citrate in Patients with Nondialysis-Dependent CKD and Iron Deficiency Anemia

Fishbane

Block

Loram

et al. 2017

JASN

131

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Iron deficiency anemia is common and consequential in nondialysis-dependent CKD (NDD-CKD). Efficacy and tolerability of conventional oral iron supplements are mixed; intravenous iron administration associates with finite but important risks. We conducted a randomized double-blind clinical trial in adults with NDD-CKD and iron deficiency anemia to compare the safety and efficacy of oral ferric citrate (n=117) and placebo (n=115). The primary end point was the proportion of patients who achieved a $1.0 g/dl increase in hemoglobin at any time during a 16-week randomized period. Patients who completed the 16-week period could also participate in an 8-week open-label extension period. Significantly more patients randomized to ferric citrate achieved the primary end point (61 [52.1%] versus 22 [19.1%] with placebo; P,0.001). All secondary end points reached statistical significance in the ferric citrate group, including the mean relative change in hemoglobin (0.84 g/dl; 95% confidence interval, 0.58 to 1.10 g/dl; P,0.001) and the proportion of patients who achieved a sustained increase in hemoglobin ($0.75 g/dl over any 4-week period during the randomized trial; 57 [48.7%] versus 17 [14.8%] with placebo; P,0.001). Rates of serious adverse events were similar in the ferric citrate (12.0%) and placebo groups (11.2%). Gastrointestinal disorders were the most common adverse events, with diarrhea reported in 24 (20.5%) and 19 (16.4%) and constipation in 22 (18.8%) and 15 (12.9%) patients treated with ferric citrate and placebo, respectively. Overall, in patients with NDD-CKD, we found oral ferric citrate to be a safe and efficacious treatment for iron deficiency anemia.

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Comparative Risk of Anaphylactic Reactions Associated With Intravenous Iron Products

Abstract: Among patients in the US Medicare nondialysis population with first exposure to IV iron, the risk of anaphylaxis was highest for iron dextran and lowest for iron sucrose.

Cited by 183 publications

References 26 publications

Distinct in vitro Complement Activation by Various Intravenous Iron Preparations

Distinct in vitro Complement Activation by Various Intravenous Iron Preparations

Intravenous Versus Oral Iron Supplementation for the Treatment of Anemia in CKD: An Updated Systematic Review and Meta-analysis

Effects of Ferric Citrate in Patients with Nondialysis-Dependent CKD and Iron Deficiency Anemia

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