The results showed that the iron group had faster Hb recovery at POD 14 and significantly higher rate of functional IDA during the study period and that the rate of transfusion and EQ-5D index were not different between the iron and non-iron groups. To the best of our knowledge, this is the first clinical study to analyze postoperative anemia recovery and rate of functional iron deficiency following IV iron administration one day before TKA.
Conventionally, oral iron has been used to treat IDA [21]. However, the efficacy of oral iron is compromised due to poor absorption, poor compliance, and gastrointestinal side effects [7, 22, 23]. Das et al. [7] found that IV iron sucrose administration had a better safety profile and efficacy in the treatment of IDA than conventional oral iron supplements. In addition, Macdougall et al. [8] found that among the oral, intramuscular, and IV iron administration methods, IV was the most reliable method for reducing adverse risks and optimizing erythropoietin response. Deloughery et al. [24]found that oral iron administration was often poorly tolerated and that up to 70% of patients in their study complained of gastrointestinal issues. According to a recent meta-analysis of 20,000 patients from 103 studies, IV iron administration can effectively treat anemia without increasing adverse events or the incidence of infection when compared to oral or intramuscular iron administration [25]. Therefore, IV administration is considered more effective than oral or intramuscular administration.
Currently, three IV iron formulations (iron sucrose, ferric carboxymaltose, and iron isomaltoside) are most commonly used because they do not have serious side effects [26]. Many studies have compared the efficacy and safety of different IV iron formulations [27–30]. Derman et al. [28] analyzed IV iron isomaltoside and IV iron sucrose administration and found that iron isomaltoside required fewer administrations and showed a higher and faster Hb response than iron sucrose administration. Wolf et al. [29] compared IV iron carboxymaltose and IV iron isomaltoside and found that IV iron isomaltoside administration led to a lower incidence of hypophosphatemia over 35 days and that it was a safer treatment for anemia than IV iron carboxymaltose administration. In addition, Pollock et al. [30] found that IV iron isomaltoside was more effective even when used less frequently than IV iron carboxymaltose and thus was more cost-effective. Therefore, when comparing several studies, IV iron isomaltoside has been regarded as the most effective and safest of the currently utilized IV formulations.
The current protocol states that IV iron should be administered to IDA patients four weeks before surgery; although this is the ideal treatment, it is not always possible in the field of orthopedic surgery [16, 31]. Jeong et al. [16] indicated that this lack of feasibility was due to time constraints, requiring frequent outpatient visits and multiple blood sampling tests. Moreover, several reports indicate that IV iron administration used in the perioperative period was effective for treating postoperative anemia after TKA [10, 32, 33]. Yoo et al. [10] found that intraoperative IV iron isomaltoside administration was an effective method to recover from postoperative anemia after TKA. Similarly, Park et al. [11] found that intraoperative IV iron carboxymaltose administration was effective in the treatment of postoperative anemia in patients who had undergone TKA. However, to date, no study has analyzed the effect of preoperative administration of IV iron one day before TKA. IV iron administration one day before TKA may have several advantages when compared to intraoperative administration, considering that it can be administered in a hemodynamically stable state and since there is no contraindication with other drugs [34–36].
In this study, serum ferritin and TSAT were higher and the rate of functional IDA was lower during the study period in the iron group when compared to those in the non-iron group, which resulted in faster Hb recovery of patients in the iron group. Serum ferritin levels reflect the total amount of iron stored in the body, and TSAT reflects the amount of circulating iron which can be directly used in erythropoiesis [37–39]. Several studies have shown that circulating iron levels were more crucial to postoperative anemia recovery than total iron levels [40–42]. Functional IDA can be caused by the TKA-induced inflammatory response in which the available quantities of total iron are sufficient but iron mobilization is decreased due to an increase in hepcidin synthesis. Hepcidin inhibits ferroportin (an iron transporter), which regulates iron excretion from the body’s storage reserves to the bloodstream for erythropoiesis. Considering that the circulating iron is insufficient for anemia recovery, owing to acute blood loss during TKA and decreased iron mobilization due to TKA-induced inflammation, IV iron administration quickly restores iron utilization to prevent the development of functional iron deficiency and promotes the erythropoietic response to quickly recover from anemia [23, 43–45].
In our study, despite faster Hb recovery in the iron group, transfusion rate and EQ-5D index were not different between the two groups. Regarding QOL, several studies have shown that postoperative anemia was associated with patient function and postoperative recovery, which consequently affects QOL [46–51]. Foss et al. [50] found that the degree of anemia was associated with functional mobility in the early postoperative period. Moreover, Lawrence et al. [51] found that patients with higher postoperative Hb levels had higher functional recovery. However, in this study, the EQ-5D index was only evaluated for 2 weeks after TKA. During this postoperative period, the EQ-5D index is greatly influenced by other factors such as various comorbidities [52–54]. We assumed that the recovery from anemia may be related to both functional recovery and improvement in patients’ quality of life—from a long-term perspective—and subsequent investigations focusing on long-term outcomes are warranted. Regarding transfusion rate, several reports state that IV iron administration could lower the risk of transfusion [55–57]. However, postoperative transfusion is determined by the amount of acute blood loss that occurs during surgery; therefore, most transfusions occur within 1–2 days (hyper-acute phase) after surgery. We assumed that the effect of IV iron administration one day before surgery has not been demonstrated yet within the hyper-acute phase. In addition, it is possible that our IV iron dose and administration timing was not optimal to obtain a low transfusion rate. Considering that several authors have reported that the transfusion rate was different according to IV iron dose and administration timing [58–60], the optimal dose and timing of iron supplementation to reduce transfusion rates in TKA should also be investigated in the future.
Our study has several limitations. First, this study had a relatively short-term follow-up period. Further study is warranted to evaluate the changes in Hb, ferritin and TSAT levels through long-term follow-up, and to identify whether the difference in Hb and iron profile levels between the two groups can lead to differences in patient-reported outcomes in the long term. Second, due to the retrospective study design, there may be concern of possible selection bias. To overcome this limitation, special efforts were made by deciding to administer IV iron based only on the date of surgery. Furthermore, patients in both groups were treated with the same surgical procedure with identical perioperative management. Moreover, propensity score matching was also performed to appropriately set the usage of IV iron as the only independent variable. Lastly, the number of subjects used in this study was determined by the number of eligible patients by retrospective review. Prospective studies with a sufficient power analysis are warranted to confirm our findings.
In conclusion, intravenous iron administered one day before TKA improved postoperative anemia recovery but did not lower the postoperative transfusion rate. Because approximately half of the patients undergoing TKA experience postoperative functional IDA, clinicians should consider the use of IV iron to improve iron availability.