A Systematic Review and Indirect Treatment Comparison of Ferric Carboxymaltose Versus Iron Isomaltoside in Correcting Iron Deficiency Anemia

Background: Iron deficiency anemia (IDA) is a global public health concern. It is estimated 1.24 billion people with IDA and responsible for about 800,000 deaths per year. Intravenous iron therapy is one of the treatment options and in recent years has been promoted for first-line use in correcting IDA. Currently in the literature, there is a lack of direct evidence of comparative effectiveness between ferric carboxymaltose (FCM) and iron isomaltoside (IIM) in correcting IDA. Available indirect evidence is far from conclusive. With more evidence emerging from the literature, the aim of the current study was to conduct an indirect treatment comparison (ITC) of FCM versus IIM in correcting IDA.

Method: To address potential heterogeneity, two separate ITC analyses were proposed: one via iron sucrose (IS) and the other via oral iron (OI) and focused on non-chronic-kidney-disease (non-CKD) patients. A systematic literature review, searching PubMed, EMBASE, and Cochrane Library, was conducted to identify relevant randomized controlled trials (RCTs). The data cut-off date was 2022.03.31. The risk of bias for each involved study was assessed based on the Cochrane review criteria. Bucher's ITC method and random-effects model for meta-analysis were applied to compare outcomes. The efficacy outcomes included the response rate, mostly defined as 2 g/dL increase from baseline or hemoglobin (Hb) level normalized, and hemoglobin level change from baseline. The safety outcome was adverse drug reactions (DARs) and drug-related serious adverse events (SAEs). When feasible, subgroup analyses by underlying disease were also conducted.

Results: For ITC via IS, 8 RCTs (7 FCM vs IS and 1 IIM vs IS) were included. Most of the studies presented with the low risk of bias. The total number of patients in FCM and IIM RCTs were 1471 and 1512, respectively. The distribution of baseline characteristics between two groups were: the proportion of female (84.8 vs 89.2%), age (35.7 vs 44.0), baseline Hb level (8.7 vs 9.2 g/dL) and serum ferritin level (10.3 vs 13.6 ug/mL) . The ITC result indicated that FCM had a statistically significant better response rate with a risk ratio (RR) of 1.34 (95% CI: 1.03 - 1.75), compared to IIM. FCM also resulted in a significantly larger increase from baseline Hb level in comparison to IIM, with a mean difference of +0.87 g/dL (95% CI: 0.40 - 1.34). For safety as measured by DARs, FCM showed no significant difference with IIM (RR of 0.80, 95% CI: 0.40 - 1.57). Due to a high number of zero event reported in the studies and different SAE definitions, indirect comparison of SAE was not conducted.

For ITC via OI, 17 RCTs (15 FCM vs OI and 2 IIM vs OI) were included. The total number of patients in FCM and IIM RCTs were 3428 and 677, respectively. Between the two groups, the average age (38.1 vs 45.5 years), proportion of female (88.0 vs 65.9 %) and baseline Hb level (9.8 vs 9.9 g/dL) were similar. In the IIM group, half of patients were cancer patients with chemotherapy. The results of the ITC via OI were similar to those via IS. FCM had a non-significant better response rate (RR 1.18, 95% CI: 0.96 - 1.45) and a statistically significant larger increase from baseline Hb level (+0.81 g/dL, 95% CI: 0.37 - 1.25) in comparison to IIM. For safety, there was no significant difference between the two (RR of 1.23, 0.27 - 5.57). Subgroup analysis was conducted in IBD patients (3 FCM and 1 IIM RCT, 486 vs. 327 patients). The result also indicated that FCM had a significantly larger increase from baseline hemoglobin (+0.99 g/dL, 0.86 - 1.13) in comparison to IIM.

Conclusion: Based on the current evidence, both indirect treatment comparison analyses indicated that in non-chronic-kidney-disease patients ferric carboxymaltose has better efficacy outcomes than iron isomaltoside and no difference in terms of adverse drug reactions. Future head-to-head trials might be needed to confirm the current findings.

Chuang:GongJing Healthcare Consultancy: Consultancy. Sun:Vifor Fresenius Kabi (Beijing) Pharmaceutical Consulting Co. Ltd: Current Employment. Sun:Vifor Fresenius Kabi (Beijing) Pharmaceutical Consulting Co. Ltd: Current Employment.