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

Litton E, Xiao J, Ho KM
BMJ 2013;347:f4822.
NATA Rating :
Review by : M. Muñoz
NATA Review

The authors performed a meta-analysis of 72 studies including 10,605 patients, from very different clinical settings (renal failure, cancer, surgery, cardiac, gynecology, inflammatory bowel diseases, preoperative autologous blood donation, etc), receiving different intravenous (IV) iron formulations, doses and durations of treatment, with or without erythropoiesis-stimulating agents (different compounds, doses, durations of treatment, and target hemoglobin levels).

Their main findings were as follows: 1) IV iron therapy can effectively reduce the need for red blood cell transfusion across a range of acute care settings; 2 A benefit of IV iron in increasing hemoglobin concentration was seen when compared with both oral iron and no iron supplementation; 3 IV iron was more effective when used with erythropoiesis-stimulating agents and in patients with lower baseline plasma ferritin concentrations; and 4 IV iron therapy was associated with an increased risk of infection (RR 1.33, 95%CI 1.10-1.64).

However, some criticisms can be raised: 1) The search strategy was incomplete since at least 8 RCTs (some dating back to 2000) were overlooked without explanation; 2) As infection was not a predefined endpoint in many of the pooled studies, there was possibility of unmeasured bias (as recognized by the authors). Without a reliable measure of infection rates it is impossible to determine the impact of IV iron on clinically significant infections and no inference can be made. Notwithstanding, the authors conclude that IV iron is associated with increased infections, based on unreliable data in this reviewer’s opinion; 3) Neither a dose-response association between iron and risk of infection nor an increased rate of mortality and other serious adverse events were detected in patients randomized to IV iron, further undermining the authors’ conclusions.

The conclusions of the meta-analysis are unfortunately weakened by the above-mentioned limitations, and are somewhat contradictory to other published studies. While provocative animal and in vitro studies suggest that iron may be linked to induction of inflammation, oxidative stress, infection and kidney damage, the overwhelming preponderance of clinical studies has reported no clinically meaningful increase in infectious complications when IV iron was adequately dosed according to available guidelines.

Therefore, as the data supporting a possible relationship between IV iron and infection are currently suboptimal and incomplete, this primarily represents a limitation of the currently available evidence. This serious limitation cannot be overcome by a systematic review. IV iron preparations, like any other medication, are not free of risks and are not all equal in their safety profiles. Thus, their purported risks must be viewed in the context of their associated benefits in terms of avoiding the “clear and present dangers” of anemia and allogeneic blood transfusions. This is especially important when considering the use of IV iron as a most valuable tool to face the restrictions posed on the use of erythropoiesis-stimulating agents.

Acknowledgement: The contributions of Prof. Michael Auerbach and Prof. Aryeh Shander are gratefully acknowledged.

– Manuel Muñoz