Some of the studies referenced above are discussed here in detail:
In 2016, Bernabeu-Wittel et al20 and the investigators of the Spanish PAHFRAC-01 trial (Efficacy of Ferric Carboxymaltose With or Without EPO Reducing Red-cell Transfusion Packs in Hip Fracture Perioperative Period) published the results of their double-blind, placebo-controlled RCT. They randomized 277 elderly, anemic patients with hip fractures into 3 study arms before surgery. Patients received either 40,000 IE Epo subcutaneously (sc) in combination with 1000 mg of IV ferric carboxymaltose (EpoFe group), ferric carboxymaltose plus placebo sc (Fe group), or placebo via IV and sc (placebo group). Compared with the placebo group, the EpoFe group had a statistically significant difference of 0.5 g/dL in Hb levels at discharge from hospital (mean length of stay in the hospital [LOS] 8 days) and 0.6 g/dL Hb 60 days after discharge. In addition, 52% of patients in the EpoFe group recovered from anemia compared with 39% of patients in the placebo group as indicated by Hb increase to Hb ≥12 g/dL. Transfusion requirements were not different in this study.
In 2012, Calleja et al21 and the Spanish Colon Cancer Study Group conducted a prospective, multicenter, observational study of 266 patients undergoing elective colon cancer surgery. Patients were preoperatively administered ferric carboxymaltose or oral iron. Published in 2016, the trial showed a significant reduction in transfusion rates (9.9% vs 38.7%) and LOS (8.4 vs 10.9 days) in the ferric carboxymaltose group. Ferric carboxymaltose was given at a mean of 28.5 ± 16.7 days before surgery. The medication led in 44 of 111 patients to normalized Hb levels 30 days postoperatively (40%). In the control group, 26.7% presented with normalized Hb levels (n = 155). In addition, the response rate (Hb increase >1.5 g/dL) 30 days after surgery was significantly higher in the ferric carboxymaltose group (48.1% vs 20.0%) compared with the control group. There were no serious adverse effects observed.
Rineau et al22 came to similar conclusions in a French 2-phase, prospective, observational study that compared transfusion requirements and Hb courses before (phase 1) and after (phase 2) the implementation of a PBM protocol. In phase 2, there was a significant decrease in the number of transfused patients and a reduction of patients with moderate to severe anemia on discharge from the hospital.
In an Australian retrospective before-and-after study, Kopanidis et al16 demonstrated the effectiveness of preoperative correction of anemia and intraoperative administration of tranexamic acid in total hip and knee replacements. The intervention group showed a significantly lower transfusion rate (6% compared with 20%) and the lowest Hb value observed at postoperative day 1 was significantly higher in the intervention group.
Laso-Morales et al23 published in 2017, that IV iron was able to treat preoperative anemia in patients undergoing colorectal cancer surgery. Hb levels increased to similar levels before surgery as nonanemic patients and remained at similar levels 30 days after surgery.
To conclude, high-quality studies on the use of IV iron in the preoperative setting exist. In 11 of 17 studies, an effect on Hb levels was observed, which was mostly in a range between 0.4 and 1.2 g/dL in ΔHb. The use of RBC transfusions was reduced in 7 of 17 studies. The quality of studies was high. Therefore, the early correction of preoperative anemia before surgery can be recommended.
Perioperative Anemia Treatment With IV Iron
Perioperative treatment of anemia with IV Iron formulations was the goal of 6 RCTs and 1 observational trial (Table 2). The subject groups in these studies were 3 orthopedic cohorts, 1 trauma cohort, 2 cardiac cohorts, and 1 abdominal surgery cohort. Only 1 study used ferric carboxymaltose, 4 studies investigated iron sucrose, and 1 study used iron isomaltoside. In 1 study, the IV iron preparation was not mentioned. More than 50 patients per group were included in 5 studies, 2 studies were performed with <50 patients per group. The Hb levels in patients treated with IV iron were measured in 6 of 7 studies. Nonsignificant data were reported in 3 studies and 2 studies observed an increase in ΔHb of roughly 1 g/dL (Figure 2). Reticulocytes were only measured in 3 studies. In 1 study, no significant difference was observed, while the other 2 studies showed higher reticulocytes 7 days and 4 weeks after IV iron treatment. In 2 trials, a positive effect on RBC transfusions was observed and 1 trial reported a positive effect in a subgroup analysis. The remaining trials observed nonsignificant data or did not analyze parameters regarding RBC transfusions or IV iron treatment.17
Some of the studies are discussed in the following paragraphs in detail. Johansson et al24 conducted the PROTECT trial (A Prospective, Comparative Study of Intravenous Iron Isomaltoside 1000 [Monofer®] Administered by Infusions to Non-Anaemic Patients Undergoing Elective or Sub-Acute Coronary Artery Bypass Graft, Valve Replacement or a Combination Thereof) in 60 preoperative, nonanemic patients undergoing cardiac surgery. This randomized, double-blind, placebo-controlled clinical RCT revealed that a single IV dose of 1000 mg iron isomaltoside significantly increased Hb levels and prevented anemia 4 weeks after surgery. The short-term safety profile of IV iron isomaltosidose was similar to placebo.
Serrano-Trenas et al25 investigated in a single-center, RCT the effect of preoperative IV iron therapy in elderly patients with hip fractures. There was no difference in the rate of transfusion, number of RBCs transfused, or morbidity, mortality, or LOS. Only the subgroup of intracapsular fractures showed a benefit and reduction in RBC transfusions compared with controls.
The Prevalence of Perioperative Anaemia and need for patient blood management in elective orthopaedic surgery (PREPARE) study revealed a prevalence of anemia in 1534 orthopedic patients of 14.1% before surgery.17 RBC transfusion was given in 14.8% of the preoperatively anemic patients and in only 2.8% of the preoperatively nonanemic patients. As stated above, this trial focused on anemia prevalence and the retrospective evaluation of anemia treatment. Lasocki et al17 came to the conclusion that there is a high use of RBC transfusions to treat anemia. IV iron, as well as Epo, was in the authors point of view underused in Europe, even in PBM centers. Only 201 of 1534 patients received iron: 127 (24.1%) oral and 74 (14.1%) intravenously.
Muñoz et al26 stressed the need to perform large prospective RCTs in 2008. They stated that recovery from anemia, caused by perioperative blood loss and aggravated by inflammation-induced inhibition of erythropoiesis and functional ID, might be hastened by IV iron administration.26
In 2017, we draw the same conclusion: To date, the level of evidence for the use of perioperative IV iron still remains low. Only a few of the available studies indicate effectiveness, mainly in orthopedic patient cohorts. The majority of the publications indicate ineffectiveness of perioperatively administered iron to increase Hb or reduce transfusion requirements. Therefore, IV iron supplementation should be carefully considered in individual settings but cannot be recommended in general.
Postoperative Anemia Treatment With IV Iron
Postoperative treatment of anemia with IV iron formulations was the goal of 6 RCTs and 2 retrospective trials (Table 3). In 4 studies, ferric carboxymaltose was used, 3 studies used iron sucrose, and 1 study used ferric carboxymaltose and iron sucrose. Six studies were performed with more than 50 patients per group, 2 with <50 per group. In 6 of these 8 studies, an effect of IV iron was observed, which was measured most frequently by Hb increase, reticulocytes, or RBC transfusions. Only 2 studies observed a positive effect on RBC transfusion. Reticulocytes were only measured in 2 studies. In 1 study, higher reticulocytes until day 5 and a decrease in all groups after day 15 were observed. The other study showed a significant increase in reticulocytes after IV iron treatment only in combination with Epo.27
Why were these studies performed in the postoperative setting? First, effective means to treat postoperative anemia have yet to be established. In 2014, the Journal of Patients Safety published a statement that anemia at discharge was associated with a severity-dependent increased risk for 30-day readmission. A strategy that focused on anemia treatment care paths during index hospitalization offered an opportunity to influence subsequent readmissions.28 Second, postoperative anemia is very common: the PREPARE study, mentioned above, revealed a prevalence of postoperative anemia of 83.8% in 1534 orthopedic patients, who were preoperatively nonanemic. Patients with preoperative anemia were also postoperatively anemic in 97.7%.17 Therefore, the studies investigating IV iron in the postoperative setting were performed in various patient cohorts. In 2016, Litton et al29 presented the findings of the Intravenous Iron or Placebo for Anaemia in Intensive Care (IRONMAN) trial, a blinded, randomized, placebo-controlled multicenter trial. The authors primarily compared the need for RBCs in 70 patients receiving IV ferric carboxymaltose with 70 patients assigned to placebo in the course of their ICU stay. Of secondary interest was the between-group difference in Hb values at hospital discharge. All patients were recruited out of a collective of critically ill patients in 4 Australian ICUs, admitted either postoperatively or for other medical reasons. The results did not show a significant difference in the RBC transfusion rate between both groups (IV iron 54% vs 56% in the control), whereas a significantly higher Hb level at hospital discharge by 0.38 (CI, 0.14–0.89) g/dL in favor of the IV iron group was observed. The mean duration from study-drug supplementation to hospital discharge was 11 days in the IV iron group and 15 days in the control group. The trial revealed no statistically significant between-group difference in the infection rate or frequency of serious adverse events.
Elective cardiac surgery patients and cardiac plus orthopedic surgery were investigated by Madi-Jebara et al30 and Karkouti et al,27 respectively. Madi-Jebara et al30 performed a RCT in patients after elective cardiac surgery with Hb levels between 7 and 10 g/dL. Patients were randomized into 3 groups (control, iron sucrose alone postoperatively, or iron sucrose plus Epo postoperatively). There was no difference between the 3 groups. IV iron alone or in combination with Epo was ineffective in correcting anemia after cardiac surgery.30 Karkouti et al27 performed a randomized, double blinded, placebo-controlled trial in 2009 in patients undergoing cardiac or orthopedic surgery to determine if early recovery from postoperative anemia was accelerated by IVI alone or in combination with Epo. Patients, whose Hb was 7–9 g/dL on the first postoperative day, were randomized into 3 groups (control, postoperatively 200 mg of iron sucrose, or IV iron plus Epo) with interventions taking place on postoperative days 1–3. There were no differences in Hb increase on postoperative days 1–7 or 6 weeks after surgery (mean ΔHb 0.3 g/dL [CI, 0.7–1.3]).27 Bisbe Vives and Moltó31 summarized the need for further RCTs to evaluate the role of IVI therapy in the recovery from postoperative anemia after they had performed a single-blinded RCT in patients with total knee replacement. The study compared ferric carboxymaltose to oral iron, and the results did not show differences in Hb levels (mean ΔHb 0.4 g/dL [CI, 0.0–0.8]) or RBC transfusion rates.
Only a few studies indicate a positive, but obviously mild effect of postoperative IV iron supplementation. Kim et al32 reported that 92.2% of patients with IV iron presented a ΔHb > 2 g/dL at week 12 compared with 54% of controls. Khalafallah et al33 presented a prospective RCT in 2016 comparing 103 postoperatively anemic patients supplemented with ferric carboxymaltose, to 98 postoperatively anemic patients receiving standard care. Patients were recruited out of 381 eligible patients undergoing elective, mainly orthopedic surgery. The IV iron and control groups had improved mean Hb levels of 2.4 and 1.6 g/dL at 4 weeks, respectively, a significant difference of 0.8 g/dL (CI, 0.38–1.19) in favor of the iron-supplemented group. At 12 weeks, there was no significant difference between the groups. There was a significantly lower RBC transfusion rate in the IV iron group, in which only 1 patient received RBCs, whereas there were 5 transfused patients in the control group. Also, the IV iron group demonstrated a decrease in the mean length of hospital stay by 3.8 days.33
Jeong and Park34 demonstrated a significant increase in Hb levels among patients after gastric surgery. Hb levels increased by 3.2 g/dL in the IV supplementation group and by 2.5 g/dL in the control group within 6 months after surgery, a small but significant difference of 0.7 g/dL in favor of the IV iron group.
In 2014 Muñoz et al35 presented a study with postoperative IV iron supplementation of 600 mg IV iron after lower limb surgery. IV iron supplementation led to a reduction in frequency of RBC transfusions, especially in anemic patients. When RBCs had to be given, the duration of in-hospital stay was prolonged.
As indicated in Tables 1–3, the majority of data on IV iron and infection is either not significant or was not determined (missing values). Only a few trials presented a lower infection rate in the group treated with IV iron. No trial found a higher infection rate in the IV iron group compared with controls. Therefore, to date, no definite answer can be given to the effect of IV iron on infection rate.
Altogether the number of trials for IV iron in the postoperative setting is still low and further research is needed to give a distinct recommendation for postoperative IV iron treatment.
To conclude, the evidence for the use of IV iron to treat anemia in the preoperative, perioperative, or postoperative setting is low. The evidence for preoperative IV iron therapy is the highest. Therefore, correction of preoperative anemia is recommended, with emphasis on early correction before surgery. To date, evidence for perioperative IV iron is low and as such perioperative IV iron can only be recommended for orthopedic patient cohorts. In the postoperative setting, IV iron has shown a positive effect on Hb levels, length of hospitalization, and transfusion requirements, but the number of trials is still very low. In addition, while significant, the increases in Hb levels after IV iron treatment have to be checked for clinical relevance. Further multicenter RCTs with special focus on effects in different patient cohorts have to be performed.
The authors thank Maria Eveslage, Institute of Biostatistics and Clinical Research, Muenster University Hospital, Muenster, Germany, for statistical advice. We would like to acknowledge Dr Thomas Bartnikas for critical review of the manuscript.
Name: Frank Peters, MD
Contribution: This author helped perform the literature research, analyze the data, design the figures, and write the manuscript.
Name: Ines Ellermann, PHARM
Contribution: This author helped perform the literature research, analyze the data, design the figures, and write the manuscript.
Name: Andrea U. Steinbicker, MD, MPH.
Contribution: This author helped analyze the data, design the figures, write the manuscript, and design the review.
This manuscript was handled by: Marisa B. Marques, MD.
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