The main finding of this meta-analysis showed that IV iron for the treatment of anemia before cardiac surgery was not associated with a reduced transfusion rate when compared with the control group. In addition, IV iron decreased the incidence of all-cause mortality. However, units transfused per patient, ICU stay, hospital LOS and adverse events did not differ between the IV iron group and the control group.
There was actually one review [
14] and one meta-analysis [
13] reporting intravenous (IV) iron therapy for patients undergoing cardiac surgery. And these two studies were different in both population and outcomes from this meta-analysis. First, 2 of 6 studies included non-anemic participants in Tankard et al.’s study [
14] and 6 of 7 observational studies had no clear participants inclusion criteria in Gupta et al.’s study [
13]. Second, the primary outcome was different. Tankard et al. just overviewed the findings of included studies in transfusion rate without concrete data processing and Gupta et al. set transfusion rate as a secondary outcome.
Because more than half of anemic patients undergoing cardiac surgery have iron deficiency, IV iron therapy preoperatively is recommended [
2,
28,
29]. However, the evidence regarding the effect of IV iron on reducing the transfusion rate for cardiac surgery patients with preoperative anemia is limited and unclear [
2,
13,
14,
30].This systematic review and meta-analysis suggested that IV iron did not decrease transfusion rates compared with the control group, which was not consistent with Gupta et al. [
13] or Elhenawy et al. [
31] as they found a significant association of IV iron treatment with a reduced transfusion rate in cardiac surgery patients (RR 0.81, 95% CI 0.70–0.94, P = 0.005) or other major surgery patients (RR 0.84, 95% CI 0.70 to 0.99, P = 0.04). However, their meta-analysis [
13,
31] included studies exploring the efficacy of IV iron in nonanemic patients. Nonanemic patients were less likely to receive blood transfusion than anemic patients [
32,
33], resulting in overall transfusion rates in these studies [
13,
31] decreasing. However, this positive change may be caused by participants’ characteristics or IV iron therapy, and thus the benefits of IV iron on reducing the transfusion requirement for patients with anemia may be obfuscated. In addition, the application of TSA indicated that the merits of IV iron therapy in anemic cardiac surgery patients require further trials.
Furthermore, subgroup analyses (Fig.
3) for the primary outcome were performed. The subgroup analyses by the presence of other agents and by the time interval between iron therapy administration and surgery suggested that the application of other agents (mainly EPO) and IV iron therapy < 1 week before surgery were beneficial for decreasing transfusion rates. Although the dosage of EPO varied in five studies and influenced the externality of this practice, some meta-analyses [
34,
35] suggested that preoperative iron (enteral or IV) plus EPO therapy decreased the need for erythrocyte transfusion in anemic surgical patients, which was concordant with our study. The results of subgroup analysis by the time interval of IV iron administration were contradictory to those of other studies [
36,
37], probably due to limited studies and sample sizes. However, from a practical perspective, initiating IV iron therapy the week prior to surgery is also suggested [
38]. Taken together, future studies with a sufficiently large sample size are needed to focus on patients undergoing cardiac surgery. Further data are also required to examine the role of IV iron in three aspects: [
1] applying IV iron with or without other agents (mainly EPO); [
2] dosage of IV iron; and [
3] time of IV iron administration preoperatively [
33].
Meanwhile, IV iron was associated with a reduction in mortality, which was concordant with Gupta et al. [
13]. In addition, there were no significant differences in units transfused per patient, ICU stay, hospital LOS or adverse events between the two groups. These secondary outcomes were consistent with other meta-analyses [
31,
39,
40]. Nonetheless, we cannot conclude that there was no association between IV iron and these secondary outcomes in cardiac surgery. The different follow-up times and limited trials exploring these secondary outcomes potentially introduced heterogeneity.
Therefore, the ongoing trials, the Evaluating the Efficacy of Erythropoietin and Intravenous Iron on Transfusion Requirements in Patients Undergoing Cardiac Surgery (IRCT20190121042447N1) and the Intravenous Iron for Treatment of Anemia Before Cardiac Surgery (NCT02632760) [
1] are anticipated to elucidate the impact of preoperative IV iron for anemic patients undergoing cardiac surgery.
Several limitations should be considered in our study. First, the conclusion on the internal and external validity of the finding of primary outcome was drawn with caution due to a limited high-quality RCTs and sample size. Second, the certainty of our findings ranked very low to moderate because of the inclusion of trials with a high risk of bias and observational studies. Third, the dosage of IV iron and the time of IV iron administration varied among studies. Although we performed subgroup analyses to control some confounding factors, it is difficult to obtain high-quality conclusions from the pooled studies. Fourth, transfusion triggers were not confirmed in the included studies, which may have influenced the transfusion rate. However, we deemed that patient blood management in diverse hospitals was similar and guided by the international guidelines. In addition, we did not extract data that might help elucidate a potential cause for the decreased mortality, given that were no differences in the other outcomes measured. Finally, the result that IV iron therapy was not associated with reduced transfusion rates is not yet conclusive and requires further trials to affirm as indicated in TSA.