IRONMAN

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Intravenous iron or placebo for anaemia in intensive care: the IRONMAN multicentre randomized blinded trial

Litton. Intensive Care Medicine 2016; First online September 30th, 2016. doi:10.1007/s00134-016-4465-6

Clinical Question

  • In critically ill patients who are anaemic, does early administration of intravenous iron compared to placebo reduce the requirement for blood transfusion?

Design

  • Randomised, placebo-controlled trial
  • Double-blinded design with opaque sleeve covering study drug
    • Adequacy of blinding assessed with sub-study
  • Online software produced 1:1 randomisation sequence stratified by study centre
  • Sealed, opaque, numbered envelopes maintained allocation concealment
  • Power calculation was based upon observational data suggesting a mean of 4 red blood cell (RBC) units transfused with a standard deviation (SD) or 2 units
    • 140 patients allowed a detection of a clinically meaningful 1 unit difference with a false negative chance of 20% (80% Power) and a false positive chance of 5% (alpha significiance 0.05)
  • The primary outcome was not normally distributed and therefore the analysis was changed from parametric testing (as published a priori) to non-parametric testing with reporting of median rather than mean units transfused

Setting

  • 4 Intensive Care Units in Perth, Western Australia
  • June 2013 to June 2015

Population

  • Inclusion: age 18 or older; within 48 hours of ICU admision; anticipated to require ICU care beyond next day; anaemic with Hb < 100 g/l within preceeding 24 hours
  • Exclusion: suspected or confirmed severe sepsis; ferritin > 1,200 ng/ml; transferrin saturation greater than 50%
  • 140 patients randomised

Intervention

  • Intravenous (IV) Iron
    • 500 mg ferric carboxymaltose
    • Made in 100 ml 0.9% NaCl
    • Given as two consecutive 50 ml syringes

Control

  • Placebo
    • 100 ml 0.9% NaCl
    • Given as two consecutive 50 ml syringes

Common management of both groups

  • On day 4, patients still in ICU were assessed for a repeat dose of iron or placebo as per randomisation group
    • This was given if they fulfilled the inclusion / exclusion criteria
    • Repeat dosing assessment was made daily until four doses had been give, the patient died, or the patient was discharged from ICU
  • Patient management was otherwise at the blinded treating physicians’ discretion
    • This included the administration of red blood cell (RBC) transfusions (primary outcome)
  • Open-label  IV iron or erythropoiesis-stimulating drugs were considered protocol violations

Outcome

  • Primary outcome: there was no significant difference in the median number of RBC units transfused between the IV iron group and the placebo group (from randomisation until hospital discharge)
    • IV iron group: median RBC units was 1 [IQR 0-2]
    • Placebo group: median RBC units was 1 [IQR 0-3]
    • P-value = 0.53
    • Incident rate ratio (IRR): 0.71 (95% CI 0.43 to 1.18; p-value 0.19)
  • Secondary outcome:
    • Median Hb was significantly higher in the IV iron group at discharge from hospital: 107 g/l vs 100 g/l (p = 0.02)
    • Median lengths of stay were not significantly different
    • Mortality rates were not significantly different
    • Adverse event rates were not significantly different

tbl-ironman-data-table

Authors’ Conclusions

  • In anaemic patients who are admitted to ICU, IV iron did not result in a reduction in red blood cell transfusion compared to placebo, however they did leave hospital with a higher haemoglobin level.

Strengths

  • Multi-centre randomised trial
  • Robust blinding of patient and treating clinicians
  • Adequate randomisation and concealment of allocation
  • Minimal cross-over

Weaknesses

  • Despite attempting to represent all ICU patients, a large proportion were cardiothoracic surgical (35%) or trauma (32%) patients
    • Medical patients only made up 14%
    • This reduces the generalisability of the study to other units and populations
  • The mean units transfused was 1.9, which is much less than the expected 4.0
    • This reduces the effective power of the study
    • It is possible that a false negative conclusion (type 2 error) has been drawn
  • The distribution of the primary outcome was not as anticipated, leading to a post-hoc change in the analysis
    • Whilst the statistical methods are appropriate, this potentially reduces the strength of the internal validity and the study’s conclusion

The Bottom Line

  • This study is inconclusive due to the impact of the unanticipated low rate of transfusion
  • The point estimate favours IV iron, but the confidence intervals are wide
  • Further studies are needed before the widespread use of IV iron can be rejected or implemented

External Links

Metadata

Summary author: Duncan Chambler
Summary date: 8 December 2016
Peer-review editor: Celia Bradford

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