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Intravenous Iron for Treatment of Anemia in the 3 Perisurgical Phases: A Review and Analysis of the Current Literature

Peters, Frank MD*; Ellermann, Ines PHARM; Steinbicker, Andrea U. MD, MPH*

doi: 10.1213/ANE.0000000000002591
Blood Management
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Anemia is a common comorbidity throughout the entire hospital stay. Treatment options include intravenous (IV) iron, oral iron, erythropoietin, and red blood cell (RBC) transfusions. IV iron has gained in popularity with the implementation of patient blood management programs. A variety of studies have been performed to investigate the use of IV iron in preoperative, perioperative, and postoperative settings. An objective review on these studies has yet to be performed. The current narrative review provides an overview of trials investigating IV iron use in the preoperative, perioperative, and postoperative settings. We performed a literature research of English articles published between 1964 and March 2017 in Pubmed including Medline and The Cochrane Library. Only studies with a control group were included. The final review includes 20 randomized controlled trials (RCTs), 7 observational trials, and 5 retrospective studies. Measured outcomes included hemoglobin (Hb) levels, reticulocyte counts, and/or RBC concentrates. Meta-analyses of RCTs using IV iron administration before surgery led to an increase in Hb levels, a reduction of RBC use, and an improvement in patient outcome. Only a few studies investigated the use of IV iron in the perioperative setting. These studies recommended the use of perioperative IV iron in cases of severe anemia in orthopedic surgery but not in all types of surgery. Published RCTs in the postoperative setting have shown positive effects of IV iron on Hb levels, length of hospital stay, and transfusion requirements. Some studies demonstrated an increase of Hb of 0.5–1 g/dL over 4 weeks postoperatively, but the clinical relevance and effect of this increase on an improvement of patient’s long-term outcomes are uncertain. To summarize, the evidence to use IV iron is strongest in the preoperative setting, while it remains an individual treatment decision to administer IV iron perioperatively or postoperatively.

From the Departments of *Anesthesiology, Intensive Care and Pain Medicine

Pharmacy, University Hospital Muenster, Muenster, Germany.

Published ahead of print December 19, 2017.

Accepted for publication September 15, 2017.

Funding: A. U. Steinbicker is supported by a DFG grant (STE-1895-4/1).

The authors declare no conflicts of interest.

Reprints will not be available from the authors.

Address correspondence to Andrea U. Steinbicker, MD, MPH, Department of Anesthesiology, Intensive Care and Pain Medicine, University Hospital Muenster, Albert-Schweitzer Campus 1, Bldg A1, 48149 Muenster, Germany. Address e-mail to andrea.steinbicker@ukmuenster.de.

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PLAIN LANGUAGE SUMMARY

Anemia is a common comorbidity throughout the entire hospital stay. This narrative review on treatment of anemia with intravenous (IV) iron includes 20 randomized controlled trials (RCTs), 7 observational trials, and 5 retrospective studies that focus on IV iron use in the preoperative, perioperative, and postoperative settings. Measured outcomes in these studies included hemoglobin (Hb) levels, reticulocyte counts, and/or red blood cell (RBC) concentrates.

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REVIEW OF THE LITERATURE

Anemia is a frequent condition observed in hospitalized patients. Research has revealed that untreated anemia impacts patients’ health. Treatment options include oral iron, IV iron, erythropoietin (Epo), and RBC transfusions (Figure 1). Iron is required as a substrate for the bone marrow to produce erythrocytes. Epo is produced in the kidney and required for erythropoiesis. Epo production may be reduced in renal disease. The level of Hb determines if patients are categorized as nonanemic (Hb in men ≥13 g/dL, in women ≥12 g/dL), anemic (Hb in men <13 g/dL, in women <12 g/dL), or severely anemic (Hb <8 g/dL). At Hb levels <8 g/dL, transfusions of RBCs may be considered.

Figure 1.

Figure 1.

A variety of factors contribute to development, progression, and persistence of anemia (Figure 1). Iron deficiency (ID) arises mostly due to malnutrition.1 ID anemia is therefore the most frequent form of anemia, closely followed by anemia of inflammation (also called anemia of chronic disease), which is caused by acute or chronic inflammation or cancer. With inflammation, iron availability may be reduced and Epo production and response of the bone marrow to Epo may be diminished, while RBC clearance may be increased. Chemotherapy or radiation therapy may temporarily impair the ability of the bone marrow to produce erythrocytes and thereby contribute to anemia.2 In addition, preoperative, perioperative, or postoperative bleeding and blood withdrawal enhance anemia. Hemolysis can also cause or contribute to anemia.

Systemic iron homeostasis has been well investigated to date. In physiologic conditions, the hepatic hormone hepcidin is induced if sufficient iron is available.1,2 Hepcidin binds to the sole iron exporter ferroportin and causes its internalization and degradation.3 As a consequence, ferroportin expression in the duodenum is decreased, so that less iron is absorbed in the intestine. In cellular sites of iron storage such as macrophages and hepatocytes, ferroportin degradation causes trapping of iron within the iron stores. In inflammation and cancer, hepcidin is upregulated by cytokines. This induction occurs independently of iron-dependent regulation. A relative ID and ultimately the anemia of inflammation develop.

Preoperatively, ID, anemia of chronic disease, or a combination of both forms can be present. Postoperatively, especially in critically ill patients in the intensive care unit (ICU), the anemia of inflammation may be predominant and anemia correction is challenging due to multiple factors that impair erythropoiesis. Systemic inflammation response after major surgery or critical illness may induce hepcidin expression.4 Treatment with Epo is challenging due to cardiovascular side effects. The transfusion of RBCs has common, known side effects, and may lead to an increase in inflammation.5 Treatment with oral iron is possible but only reasonable at least 4 weeks before elective surgery. If surgery has to be performed within a shorter period, IV iron is an impetus and should be used. In patients with inflammation or cancer, ID can also be present and should be treated.6

To find alternatives to the use of RBCs, IV iron pharmaceuticals and their effect on infection rates are questions of current interest. With the implementation of Patient Blood Management Programs (PBMs), IV iron treatment has become more and more popular. Warnings about adverse effects such as anaphylactic reactions versus publications that state the safe use of IV iron have been published.7,8 An international consensus statement on preoperative anemia treatment has been recently published.9 The use of perioperative or postoperative IV iron is still under investigation.

The goal of the current narrative review was therefore to research and summarize the evidence for the use of IV iron in hospitalized patients. The evidence grade was defined as described by the Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) Working Group.10 The studies were graded according the levels of “Evidence for Therapeutic Studies” from the Center for Evidence-Based Medicine.11 We considered trials that were performed using IV iron in the preoperative, perioperative, and postoperative settings (Tables 1–3). The studies are listed according to their study design and quality (RCTs, prospective observational, and retrospective), iron formulations, and effect of IV iron on Hb levels, reticulocytes, and/or use of RBCs, respectively. Only data that indicated significance are listed, otherwise not significant was stated.

Table 1.

Table 1.

Table 2.

Table 2.

Table 3.

Table 3.

Table 4.

Table 4.

Iron formulations that are currently available are summarized in Table 4. The name of the iron preparation is stated, and for each compound, the manufacturer, trade name, the carbohydrate included in the compound, the molecular weight in kilodaltons, the iron content in mg/mL, half-life/ferritin peak, the maximal dose approved, the interval between 2 applications, allowance for a total dose infusion, the requirement for a test dose, and inclusion of preservatives in the formulation are listed as well.

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Preoperative Anemia Treatment With IV Iron

Prevalence of preoperative anemia is high. Preoperative treatment of anemia with IV iron formulations was the goal of 8 RCTs, 6 observational trials, and 3 retrospective studies (Table 1). In 5 studies, ferric carboxymaltose was used, 9 studies investigated iron sucrose, 1 study iron saccharate, 1 study iron polymaltose, and 1 study used iron sucrose and ferric carboxymaltose. In 10 studies, more than 50 patients were included per group, in 7 studies <50 per group. An effect of IV iron was observed in 11 of these 17 studies, in most measured by Hb increase, reticulocytes, or RBC transfusions. In 5 studies, IV iron had no or an insignificant effect on Hb levels. In the studies that observed an effect, there was less than a 2.3 g/dL change in Hb (ΔHb) between the IV iron and control groups (Figure 2). Figure 2 depicts the ΔHb levels that were observed in the studies listed in Tables 1–3, in IV iron study groups before and after IV iron treatment compared with controls before and after the observational time point. A ΔHb level higher than 1 g/dL was reported in 4 studies. To calculate the ΔHb plus confidence interval, first authors were contacted to obtain mean Hb levels plus standard deviation for each study. The data were added to Figure 2.

Figure 2.

Figure 2.

Reticulocyte counts were measured in 4 studies. The effect of IV iron on reticulocyte counts was significant in 2 studies. One of these studies showed higher reticulocytes 7 days after surgery when IV iron was substituted 1 day before or on the day of surgery.18 In the other trial, 200 mg IV iron was given twice a week for 3 weeks before surgery in addition to Epo and compared with oral iron and Epo. Erythrocytes increased in both groups but were higher on day 15 after surgery in the intravenous iron (IVI) and Epo group.19 Reticulocytes were not frequently measured in studies investigating the effect of IV iron, although reticulocytes are a known marker to determine responsiveness of the bone narrow to IV iron.

The use of “RBC transfusions” was analyzed in 15 of 17 studies. The definition of use of RBC transfusions differed between studies. Table 5 gives an overview of parameters analyzed and measured in patients given RBC transfusions. There was no consistent approach to evaluate the effectiveness of IV iron formulations to treat preoperative anemia. Figure 3 indicates the studies that reported a positive effect (reduction in the use of RBCs), those that showed a positive effect in subgroup analysis only, those that failed to demonstrate an effect, and those that did not report data on transfusions. In the preoperative setting, 6 studies reported a positive effect of RBC transfusions. A positive effect in subgroup analysis was reported in 2 studies. No effect on RBC transfusion rates was observed in 5 studies and 4 studies did not report data on the use of RBC transfusions.

Table 5.

Table 5.

Figure 3.

Figure 3.

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.

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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.

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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.

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ACKNOWLEDGMENTS

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.

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DISCLOSURES

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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