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Safety of off-label erythropoiesis stimulating agents in critically ill patients: a meta-analysis

Intensive Care Medicine volume 39, pages 1896–1908 (2013)Cite this article

Abstract

Purpose

Erythropoiesis stimulating agents (ESAs) are used to treat anemia in critically ill patients. This indication is off-label, because it is not licensed by regulatory authorities. Recently ESAs were suspected to harm critically ill patients. Our objective was to assess the safety of ESAs in off-label indications in critically ill patients.

Methods

Eleven databases were searched up to April 2012. We considered randomized controlled trials (RCTs) and controlled observational studies in any language that compared off-label ESAs treatment with other effective interventions, placebo or no treatment in critically ill patients. Two authors independently screened and evaluated retrieved records, extracted data and assessed risk of bias and quality of reporting.

Results

We used frequentist and Bayesian models to combine studies, and performed sensitivity and subgroup analyses. From 12,888 citations, we included 48 studies (34 RCTs; 14 observational), involving 944,856 participants. Harm reporting was of medium to low quality. There was no statistically significant increased risk of adverse events in general, serious adverse events, the most frequently reported adverse events, and death in critically ill patients treated with ESAs. These results were robust against risk of bias and analysis methods. There is evidence that ESAs increase the risk of clinically relevant thrombotic vascular events, and there is some less certain evidence that ESAs might increase the risk for venous thromboembolism.

Conclusions

In critically ill patients, administration of ESAs is associated with a significant increase in clinically relevant thrombotic vascular events but not with other frequently reported adverse events and death.

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Acknowledgments

The review was funded in part by the Medical Scientific Fund of the Mayor of the City of Vienna. We acknowledge Professor Markus Müller (Department of Clinical Pharmacology, Medical University of Vienna, Austria) for his continual support and thoughtful advice throughout this work. We also thank Dr. L. V. Gerasimov (Negovsky Research Institute of General Reanimatology, Russian Academy of Medical Sciences, Moscow, Russia) for providing English translation of his article. We would also like to acknowledge Prof. Gretchen M. Brophy (Department of Pharmacotherapy & Outcomes Science, School of Pharmacy, Virginia Commonwealth University, Richmond, VA), Prof. Farid Zand (Shiraz Anesthesiology and Critical Care Research Center, Shiraz, Iran) and Dr. Farzad Pakdel (Eye Research Center, Rassoul Akram Hospital, Tehran University of Medical Sciences, Tehran, Iran) for providing further details of their studies.

Conflicts of interest

None.

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Authors and Affiliations

  1. Department of Emergency Medicine, General Hospital, Medical University of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria

    Bita Mesgarpour, Benedikt H. Heidinger, Michael Schwameis, Calvin Kienbacher & Harald Herkner

  2. Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria

    Bita Mesgarpour & Michael Schwameis

  3. Department of Statistics, Trinity College Dublin, Dublin, Ireland

    Cathal Walsh

  4. Department of Pharmacology and Therapeutics, Trinity College Dublin, Dublin, Ireland

    Susanne Schmitz

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  1. Bita Mesgarpour
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  2. Benedikt H. Heidinger
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  3. Michael Schwameis
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  4. Calvin Kienbacher
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  5. Cathal Walsh
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  6. Susanne Schmitz
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  7. Harald Herkner
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Correspondence to Harald Herkner.

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Mesgarpour, B., Heidinger, B.H., Schwameis, M. et al. Safety of off-label erythropoiesis stimulating agents in critically ill patients: a meta-analysis. Intensive Care Med 39, 1896–1908 (2013). https://doi.org/10.1007/s00134-013-3030-9

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Keywords

  • Erythropoiesis stimulating agents
  • Epoetin alfa
  • Off-label use
  • Critical illness
  • Drug safety
  • Meta-analysis