Efficacy and safety of iron chelators in thalassemia and sickle cell disease: a multiple treatment comparison network meta-analysis and trial sequential analysis

ABSTRACT

Background: To compare the efficacy and safety of desferrioxamine (DFO), deferiprone (DFP), deferasirox (DFX) and silymarin in patients with either thalassemia or sickle cell disorder through network meta-analysis.

Methods: Electronic databases were searched for appropriate randomized clinical trials comparing iron chelators in patients with iron overload. Random effects model was used to generate direct, indirect and mixed treatment comparison pooled estimates for the following outcomes: serum ferritin, liver iron concentration (LIC), changes in serum ferritin, mortality, urine iron excretion, adverse events, neutropenia, agranulocytosis and number of patients withdrawing the chelating therapy.

Results: Thirty-two clinical trials were included in the meta-analysis. DFX/DFO was associated with better serum ferritin levels compared to DFO, DFX, DFO/Silymarin and DFP/DFO. DFX/DFO also lower LIC significantly compared to DFO. DFP/DFO was associated with higher LVEF, low risk of adverse events and reduced end of serum ferritin compared to DFO. Combination of silymarin with either DFP or DFX was observed with reduced end of treatment serum ferritin compared to using either of the drugs alone. DFP was observed with better effects in sickle cell disease. The strength of evidence was very low for most of the comparisons.

Conclusion: Relative estimates between the individual iron chelators have been established. However, this evidence should be considered preliminary and may change with the results of future head-to-head clinical trials.

KEYWORDS:

• Deferasirox
• deferiprone
• desferrioxamine
• Silymarin
• thalassemia
• sickle cell disease

Description about authors

Dr. Kannan Sridharan is a Clinical Pharmacologist with interest and experience in the conduct of randomized clinical trials and meta-analysis for the past 8 years. He has published around 80 papers in various reputed national and international journals. Dr. Gowri Sivaramakrishnan is a Prosthodontist interested in Evidence-based medicine. She has authored over 50 articles.

Acknowledgments

We thank PROSPERO for registering the protocol of this review. We thank Cochrane reviews for utilizing RevMan software for generating risk of bias graph and to EpiGear for using MetaXL in generating mixed treatment comparison results for secondary outcomes. We are also grateful to Erasmus Institute of Research Management for utilizing Meta-Essentials for assessing publication bias.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper is not funded.