Comparative Efficacy and Safety of Iron Chelators in Sickle Cell Disease: A Meta-Analysis

Introduction

Patients with sickle cell disease (SCD) may receive repeated red blood cell transfusions for managing acute complications and preventing end-organ damage. However, significant iron overload inevitably develops after more than 20 simple lifetime transfusions. The standard of care for transfusional iron overload involves iron chelation using agents such as deferoxamine (DFO), deferiprone (DFP), and deferasirox (DFX).

Few trials have exclusively evaluated the effectiveness and safety of iron chelators in patients with SCD, and even fewer studies have compared their efficacy and safety profiles, yielding conflicting results. Pooled results of these studies could improve our understanding of optimal iron chelation management in patients with SCD; however, no previous meta-analyses have been performed in this population. This meta-analysis aimed to examine the comparative efficacy and safety of DFO against DFP and DFX, as well as compliance rates, in patients with SCD who require iron chelation.

Methods

We performed a systematic search on PubMed, Medline, OVID, Embase, and Cochrane in June 2024 to identify randomized clinical trials comparing the efficacy and/or adverse effects of DFO, DFP, and DFX in chronically transfused patients with SCD. Studies with a subpopulation of SCD patients were included if data were reported separately. Two independent reviewers screened the articles, with discrepancies resolved by consensus or a third reviewer. Data analysis was conducted using a random-effects model. The standardized mean difference (SMD) and mean difference (MD) were used for continuous outcomes, while risk ratios (RR) were employed for categorical outcomes. Subgroup analyses were performed based on the type of iron chelator. Heterogeneity was assessed using the Chi-squared test and the I² statistic.

Results

From 534 studies initially identified, four studies met our inclusion criteria, encompassing a total population of 815 patients. The serum ferritin reduction analysis showed that the SMD comparing DFO and DFX was similar among interventions (SMD = -0.09, 95% CI: [-0.41, 0.23], p = 0.57). However, when comparing DFO to DFP, DFO showed a significant reduction in serum ferritin over DFP (SMD = -2.23, 95% CI: [-2.61, -1.85], p < 0.00001). The analysis of liver iron concentration (LIC) reduction revealed no significant difference between DFO and DFX (MD = 0.20, 95% CI: [-2.58, 2.98], p = 0.89) or between DFO and DFP (MD = -0.75, 95% CI: [-2.13, 0.63], p = 0.29).

The analysis of adverse events included fever, vomiting, nausea, arthralgia, and SCD crises. For vomiting, the pooled RR from comparing DFO to DFP significantly favored DFO (RR = 0.11, 95% CI: [0.02, 0.56], p = 0.008). When comparing DFO versus DFX, the RR was comparable among drugs (RR = 0.75, 95% CI: [0.39, 1.44], p = 0.39). For arthralgia, the pooled RR comparing DFO versus DFP was similar (RR = 0.70, 95% CI: [0.30, 1.66], p = 0.42). However, when we compared DFO to DFX, DFO carried a significantly greater arthralgia risk (RR = 4.02, 95% CI: [2.14, 7.54], p < 0.0001). No statistically significant differences were identified for fever, nausea, and SCD crises (p > 0.05).

The compliance analysis revealed comparable rates between DFO and DFP (RR = 1.00, 95% CI: [0.74, 1.34], p = 0.99), as well as between DFO and DFX (RR = 0.96, 95% CI: [0.92, 1.01], p = 0.16).

Conclusions

Our analysis demonstrates that, in terms of reducing serum ferritin levels, DFO and DFX exhibit comparable efficacy, while DFO shows significantly better efficacy compared to DFP. When it comes to reducing LIC, both DFO vs. DFX and DFO vs. DFP show comparable efficacy. Regarding safety profiles, DFO is associated with a significantly lower risk of vomiting compared to DFP, but a higher risk of arthralgia compared to DFX. In terms of compliance, despite the varying administration burdens, compliance rates are similar across medications. These findings suggest that while DFO and DFX achieve similar efficacy in reducing serum ferritin and LIC, DFX may offer a better safety profile for SCD patients, with no significant differences in patient compliance. Further studies and multicenter collaborations are warranted to enhance the evidence base for optimizing chelation strategies in this unique patient population and to confirm these findings.