CADTH Health Technology Review

Intravenous Iron Preparations for Patients Undergoing Elective Surgery: A 2022 Update

Rapid Review

Authors: Shannon Hill, Melissa Severn

Key Messages

• For adults who are iron deficient before elective surgery, patients who received IV iron supplementation may have greater increases in hemoglobin and ferritin concentrations, similar or lower lengths of stay in hospital, and similar quality of life measures, functional outcomes, and rates of adverse events, compared to patients who did not receive IV supplementation. The findings were mixed for the rate of blood transfusions.

• For adults who are iron deficient before elective surgery, patients who received IV iron supplementation may experience similar changes in hemoglobin levels, quality of life scores, or number of adverse events when compared to patients who received oral iron supplementation. The findings were mixed regarding the risk of blood transfusions.

• No studies were found on the cost-effectiveness of IV iron preparation therapy for patients who are iron deficient undergoing elective surgery that met the criteria for this review.

• One guideline recommends the use of IV iron supplementation for patients with iron deficient anemia when surgery is less than 8 weeks away, patients are unable to tolerate or absorb oral iron supplementation, or for patient with suboptimal hemoglobin levels.

Context and Policy Issues

Pre-operative anemia is a common problem and can impact as much as 30% to 50% of patients presenting for surgery.^1,2 The WHO defines anemia as a hemoglobin level of less than 130 mg/mL in men and 120 mg/mL in non-pregnant women.¹ It is estimated that approximately 3% of Canadians have anemia and is most prevalent for people age 65 to 79.³ The most common form of anemia is iron deficiency anemia, which can be acute or chronic, but becomes problematic when there are insufficient number of red blood cells to maintain oxygen demand.¹ This can be detrimental during surgery where blood loss may be high and may result in peri-operative blood transfusions and adverse post-operative outcomes such as inpatient complications, delayed hospital discharge, or mortality.^1,2

A 2015 National Institute for Health and Care Excellence (NICE) guideline recommends that oral iron supplementation should be the first-line treatment option for patients with anemia undergoing surgery.^2,4 Oral iron supplementation is common and inexpensive, and can be an effective method of iron supplementation; however, oral iron can be poorly absorbed by the body and compliance with oral iron treatment is often low with only 20% to 40% of patients completing a full course of treatment.² Another common treatment option is peri-operative blood transfusion, but this can be associated with increased patient length of stay, morbidity, and mortality, and may be effected by a limited supply and increase demand of donated blood.¹ IV iron preparation (or supplementation) is an alternative treatment option for patients with iron deficiency undergoing elective surgery. IV iron is a method of iron supplementation administered directly to the patient and is often given to patients to correct anemia before surgery.² IV iron can be administered closer to the time of surgery because iron absorption is often more rapid compared to oral iron supplementation.² There are a number of common IV iron supplementations available to treat pre-operative anemia including ferric carboxymaltose, ferric derisomaltose (also known as iron isomaltoside), ferric gluconate, ferumoxytol, iron dextran, and iron sucrose.⁵ The recommended doses for each type of IV iron supplementation varies, but can range from multiple doses at 125 mg to single doses at 2,000 mg.⁵ IV iron supplementations approved for use in Canada include ferric derisomaltose,⁶ ferric gluconate,⁷ ferumoxytol,⁸ iron dextran,⁹ and iron sucrose.¹⁰

The purpose of this report is to summarize the evidence related to clinical effectiveness, cost-effectiveness, and recommendations regarding IV iron preparations to support decisions involved in the use of this treatment for patients identified as iron deficient undergoing elective surgery. This report is an update to a previous CADTH report from 2019 that evaluated the use of IV iron preparations for the same population.¹¹

Research Questions

1. What is the clinical effectiveness of IV iron preparations for patients identified as iron deficient undergoing elective surgery, including high blood loss surgery?

2. What is the cost-effectiveness of IV iron preparations for patients identified as iron deficient undergoing elective surgery, including high blood loss surgery?

3. What are the evidence-based guidelines regarding the use of IV iron preparations for patients identified as iron deficient undergoing elective surgery, including high blood loss surgery?

Methods

Literature Search Methods

The literature search strategy used in this report is an update of 1 developed for a previous CADTH report.¹¹ For the current report, a limited literature search was conducted by an information specialist on key resources including MEDLINE, the Cochrane Database of Systematic Reviews, the International HTA Database, Canadian and major international health technology agencies, as well as a focused internet search. No filters were applied to limit the retrieval by study type. The initial search was limited to English-language documents published between January 1, 2014 and February 28, 2019. For the current report, database searches were rerun on September 13, 2022 to capture any articles added to the databases since the initial search date. The search of major health technology agencies was also updated to include documents published since February 2019.

Selection Criteria and Methods

One reviewer screened citations and selected studies. In the first level of screening, titles and abstracts were reviewed and potentially relevant articles were retrieved and assessed for inclusion. As an update to a previous CADTH report, articles were reviewed if they were made available since the previous search date and were not included in the 2019 CADTH report.¹¹ The final selection of full-text articles was based on the inclusion criteria presented in Table 1.

The terms IV iron, IV iron preparation, IV iron supplementation are all used in the literature to describe the intervention of interest, but for the purpose of this report the term IV iron supplementation will be used consistently to summarize the findings from the literature.

Exclusion Criteria

Articles were excluded if they did not meet the selection criteria outlined in Table 1, or they were duplicate publications. Economic evaluations and evidence-based guidelines were excluded if they were published before 2019, and health technology assessments, systematic reviews, RCTs, and non-randomized studies were excluded if they were published before 2021. Systematic reviews in which all relevant studies were captured in other more recent or more comprehensive systematic reviews were excluded. Primary studies retrieved by the search were excluded if they were captured in 1 or more included systematic reviews. Guidelines with unclear methodology were also excluded.

Critical Appraisal of Individual Studies

The included publications were critically appraised by 1 reviewer using the following tools as a guide: A MeaSurement Tool to Assess systematic Reviews 2 (AMSTAR 2)¹² for systematic reviews, the Downs and Black checklist¹³ for randomized and non-randomized studies, and the Appraisal of Guidelines for Research and Evaluation (AGREE) II instrument¹⁴ for guidelines. Summary scores were not calculated for the included studies; rather, the strengths and limitations of each included publication were described narratively.

Summary of Evidence

Quantity of Research Available

A total of 465 citations were identified in the literature search. Following screening of titles and abstracts, 384 citations were excluded and 81 potentially relevant reports from the electronic search were retrieved for full-text review. Thirty-nine potentially relevant publications were retrieved from the grey literature search for full-text review. Of these potentially relevant articles, 103 publications were excluded for various reasons, and 17 publications met the inclusion criteria and were included in this report, with 1 additional report included through a bibliographical hand-search. These comprised 6 systematic reviews (SRs), 4 randomized controlled trials (RCTs), 6 non-randomized studies, and 1 evidence-based guideline. Appendix 1 presents the PRISMA¹⁵ flow chart of the study selection.

Summary of Study Characteristics

Six SRs^16-21 including 3 with meta-analysis (MA),^16,17,19 4 RCTs,^22-25 6 non-randomized studies,^26-31 and 1 evidence-based guideline³² was included in this report.

Four SRs^16-18,20 had broader inclusion criteria than this report: 3 SRs^16-18 including 2 with MA^16,17 included a range of interventions related to iron supplementation including the use of oral iron supplementation. One SR included a study with an irrelevant comparator.²⁰ Only studies that fit the inclusion criteria for this report will be reported on.

Additional details regarding the characteristics of included publications are provided in Appendix 2, Tables 2 to 4. There was some overlap of studies included in the SRs, and the degree of overlap is summarized in Appendix 5, Table 15.

Study Design

All 6 SRs were published in 2021^18-21 or 2022.^16,17The authors of 1 SR and MA included 10 RCTs published up to December 2020.¹⁶ The authors of 1 SR and MA included 7 primary studies comprised of 2 RCTs and 5 non-randomized studies published up to February 2021.¹⁷ The authors of 1 SR included 7 RCTs published up to December 2019.¹⁸ The authors of 1 SR and MA included 10 RCTs published up to February 2019.¹⁹ The authors of 1 SR included 10 RCTs published up to January 2021.²⁰ The authors of 1 SR included 9 primary studies comprised of 5 RCTs and 4 non-randomized studies published up to November 2020.²¹ The primary study overlap between these SR is summarized in Appendix 5, Table 15. Eleven of the 30 primary studies were included in 2 or more SRs.

Three RCTs were published in 2022,^22-24 while 1 RCT was published in 2021.²⁵ One non-randomized study was published in 2022,²⁶ while 5 non-randomized studies were published in 2021.^27-31 Five of the non-randomized studies were retrospective cohort studies that used historical patient data in their analysis.^26-30 One non-randomized study was a multicenter prospective cohort study that used prospectively collected patient data.³¹ When reported, patient follow-up time varied across studies depending on the outcome being reported, but ranged from 21 days to 3 months.

One evidence-based guideline³² was identified that presented recommendations that were broader in scope than this report; however, recommendations related to the management of pre-operative anemia were presented. Recommendations were developed by 2 reviewers based on a systematic review of evidence.³² In addition, 1 evidence-based guideline from NICE³³ was identified from the literature search but did not provide any specific recommendations related to the use of IV iron supplementation for patients identified as iron deficient undergoing elective surgery; therefore, no summary of can be provided. This evidence-based guideline did reference a recommendation from an evidence-based guideline from 2015⁴ that was captured in the 2019 CADTH report.¹¹

Country of Origin

The included SRs were conducted in the UK,¹⁶ China,¹⁷ the US,^18,20,21 and Canada.¹⁹

The included RCTs were conducted in Hong Kong,²² Norway,²³ Egypt,²⁴ and Singapore.²⁵ The included non-randomized studies were conducted in Denmark,²⁶ Singapore,²⁷ the UK,^28,30 Canada,²⁹ and Germany.³¹

The included evidence-based guideline was conducted in Canada.³²

Patient Population

Two SRs^16,21 included primary studies of adult patients undergoing elective abdominal surgery receiving pre-operative iron supplementation; however, 1 of these SRs¹⁶ did not restrict on the type of iron supplementation, while the other SR specified including studies that focused on IV iron supplementation.²¹ One SR included primary studies of patients who received iron supplementation undergoing surgery for colorectal cancer.¹⁷ One SR included primary studies of adult patients who receive intra-operative or post-operative iron supplementation for elective total joint arthroplasty surgery.¹⁸ Two SRs^19,20 included primary studies of adult patients who received IV iron supplementation and underwent any elective surgery. One of these SRs focused on pre-operative IV iron supplementation,¹⁹ while the other did not specify.²⁰

One RCT included adults with colorectal cancer undergoing elective curative tumour resection operation and anemia or iron deficiency.²² One RCT included patients who severe aortic stenosis and iron deficiency.²³ One RCT included patients aged 52 to 67 with anemia scheduled for elective coronary artery bypass grafting.²⁴ One RCT included adult patients with iron deficiency or anemia scheduled for elective major abdominal surgery.²⁵

Four non-randomized studies (3 retrospective cohort studies^27-29 and 1 prospective cohort study)³¹ included adult patients undergoing any elective surgery but did specify that patients included in the study were either iron deficient and/or anemic. One non-randomized study included adult patients undergoing colorectal cancer surgery with iron deficiency anemia.²⁶ One non-randomized study included adult elective cardiac and aortic surgical patients with iron deficiency and anemia.³⁰

The target population for the included evidence-based guideline was patients with comorbid condition, specifically anemia, hyperglycemia, and smoking, undergoing major surgery.³² The authors did not specify a type of major surgery for the recommendations.

Interventions and Comparators

Consistent with the inclusion criteria for the current report, the identified SRs included primary studies examined the effectiveness of IV iron supplementation for patients identified as iron deficient undergoing elective surgery.^16-21 The type of IV iron supplementation included IV ferric carboxymaltose,^16-21 IV iron sucrose,^16,17,19,21 IV isomaltoside,^17,18 and unspecified IV iron.^16,19 IV iron supplementation was administered pre-operatively,^16,17,19-21 intra-operatively,¹⁸ and/or post-operatively^17,18,20 at varied doses ranging from 100 mg to 2,000 mg. The comparators for the identified SRs included oral iron supplementation (usual care),^16-21 placebo,^16-21 and no treatment.^17,18,20,21

Similarly, the identified RCTs examined to effectiveness various IV supplementation including IV iron isomaltoside or ferric derisomlatose,^22,23 and IV ferric carboxymaltose.^24,25 IV supplementation for each RCT was given pre-operatively at various doses ranging from 1,000 mg to 2,000 mg.^22-25 The comparators for the identified RCTs included no treatment,²² placebo,^23,24 or oral iron supplementation.²⁵ The non-randomized studies examined the effectiveness of various IV supplementation including IV ferric carboxymaltose,^26,27,31 IV iron isomaltoside,^28,30 and IV iron sucrose.²⁹ Each non-randomized study administer the IV iron supplementation pre-operatively at various doses ranging from 200 mg to 1,000 mg.^26-31 The comparators for the identified non-randomized studies included no treatment^26,28-31 and oral iron supplementation.^27,29

The identified evidence-based guideline presented diagnostic and treatment algorithms for the management of pre-operative anemia which included a recommendation related to IV iron supplementation specifically.³²

Outcomes

The identified SRs reported outcomes related to the clinical effectiveness of IV iron supplementation for patients identified as iron deficient undergoing elective surgery. Each SR reported outcomes related to patient hemoglobin levels, and safety and adverse events including mortality and infection.^16-21 Five SRs reported outcomes related to the incidence of blood transfusion.^16,17,19-21 Three SRs reported on patient quality of life outcomes,^18-20 and 2 of these SRs reported on hospital length of stay.^19,20 Additional clinical effectiveness outcomes were captured in the SRs, which included incidence of anemia,^18,19 measures of ferritin level,^19,20 and various measures of functional outcomes.¹⁸

Similarly, the identified RCTs and non-randomized studies reported outcomes related to the clinical effectiveness of IV supplementation for patients identified as iron deficient undergoing elective surgery. Each RCT^22-25 and 3 non-randomized studies reported outcomes related to patient hemoglobin levels.^26,28,29 Two RCTs^22,25 and 6 non-randomized studies^26-31 reported outcomes related to the incidence of blood transfusion. Each RCT^22-25 and 2 non-randomized studies^26,30 reported various outcomes related to safety and adverse events. In relations to safety and adverse event outcomes, 2 of the RCTs^23,24 and 4 non-randomized studies^26,28,30,31 reported mortality outcomes, while 3 RCTs^22-24 and 2 non-randomized studies reported infection related outcomes.^26,30 Three RCTs^22,23,25 reported outcomes related to quality of life measured by quality of recovery²² and the European Quality of Life – 5 Dimensions questionnaire.^23,25 Three RCTs^22,24,25 and 4 non-randomized studies^26-28,31 reported outcomes related to length of patient recovery measured by length of hospital stay^{22,24,26-28,31} or days alive at home.^22,25,26 Additional clinical effectiveness outcomes were captured from the identified RCTs and non-randomized studies including measures of ferritin level,^22,23,28 and measures of functional outcomes.²³

The identified evidence-based guideline provided recommendations related to the use of IV iron supplementation for the management of pre-operative anemia for patients undergoing surgery.³² The strength of recommendation and quality of evidence supporting the recommendation was assessed using Grading of Recommendations Assessment, Development and Evaluation (GRADE).³²

Summary of Critical Appraisal

An overview of the critical appraisal of the included studies is summarized below. Additional details regarding the strengths and limitations of included publications are provided in Appendix 3, Tables 5 to 7.

Systematic Reviews

All 6 included SRs provided clearly defined research questions and inclusion criteria, included multiple databases in the literature searches, and provided adequate details of the included primary studies.^16-21 Four SRs stated that review methods were established before the review was conducted,^16,19-21 with 3 of the SRs providing PROSPERO registration numbers.^16,19,21 Each SR also indicated that literature search screening and study inclusion was conducted in duplicate,^16-21 but only 4 SRs indicated that additional handsearching of included or relevant studies was done.^16,17,19,20 Two SR indicated that no restrictions were included in the search methods,^17,19 while 3 SRs indicated that no restrictions on search time frame was included in their search.^16,18,20 Two SRs indicated that data extraction of primary studies was performed in duplicate,^17,19 while 1 study indicated that data extraction was performed by 1 author and checked by another author²¹; thus minimizing potential errors in data collection. Each SR assessed the risk of bias of the included primary studies using appropriate techniques,^16-21 while 4 SRs used appropriate techniques for assessing publication bias.^16,17,19,20 SRs with MA included appropriate methods of statistical combination and measurement of heterogeneity (e.g., Cochrane’s Q-test and I² statistics).^16,17,19 Two SRs indicated that risk of bias was accounted for in the analysis,^19,20 while all 3 of the SRs with MA indicated that heterogeneity was accounted for and discussed in their findings.^16,17,19 Three SRs disclosed if any funding was received for the review,^17,20,21 and 5 SRs disclosed any potential conflict of interest implications for the review.^17-21

Overall, none of the SRs provided justification for their exclusion criteria or a list of excluded studies,^16-21 while 5 of the SRs did not adequately justify the included study designs for the review.^16-19,21 SRs that included publication restrictions did not provided adequate details or justifications for restricting publication in their search.^16,18,20,21 This lack of detail may present issues in determining if bias may have impacted the authors selection of primary studies. Two SRs did not indicate if the review protocol was established in advance of conducting the review, presenting challenges in determining if there had been any post hoc deviations to the findings.^17,18 None of the SRs reported sources of funding for the included primary studies.^16-21 Three SRs did not provide adequate information related to the statistical analysis, presenting challenges in determining if appropriate statistical analyses were conducted for primary study outcomes.^18,20,21 Three SRs did not indicate if risk of bias was accounted for in their findings.^16,18,21 Finally, 3 SRs did not report if any funding was received for the review,^16,18,19 while 1 of these SRs did not report if there was any potential conflicts of interest which may impact the ability to determine if these review may have been impacted by any external influence.¹⁶

Randomized Controlled Trials

All 4 RCTs clearly defined the objective, outcomes, inclusion and exclusion criteria, interventions used, and characteristics of included patients.^22-25 Three of the RCTs indicated that the trial protocol had been registered before conducting the trial.^22,24,25 Each RCT clearly described the main findings and included appropriate measures of variability (standard deviation, mean difference, 95% confidence intervals[CI]) and exact P values when needed.^22-25 Each RCT used appropriate statistical tests to assess main outcomes and outcome measures were valid and reliable.^22-25 The patients who were recruited in each RCT and who participated in the trials were likely representative of the entire population from which they were recruited.^22-25 For 2 of the RCTs,^22,24 it is likely that the staff, places, and facilities used in the trial may have been representative of the treatment that majority of patients would likely receive; the level of detail related to staff, places, and facilities was insufficient and therefore unclear for 2 RCTs.^23,25 Three RCTs reported that no patients were lost to follow-up,^22,24,25 and 1 RCT provided characteristics of any patients that were lost to follow-up.²³ Only 1 RCT blinded the patients, investigators, and data collectors to the treatment received,²³ while 2 RCT indicated that only those providing the treatment, the investigators, and data collectors were blinded to the treatment received by the patient.^22,24 One RCT indicated that patients were not blinded to the treatment for safety considerations.²² One RCT did not provide details of patient blinding,²⁴ while another RCT indicated that neither the patients, investigators, or data collectors were blinded to treatment allocation.²⁵ Each RCT clearly described the randomization process,^22-25 while 3 studies clearly described randomization concealment strategies.^22-24 Because of the nature of the intervention, it was assumed that compliance to the intervention was reliable for each RCT.^22-25 Sufficient power calculations were used to determine adequate sample sizes for 3 RCT,^22-24 while 1 RCT did not provide details related to determining adequate sample size.²⁵ Each RCT provided information related to any funding received for the trial, and any potential conflicts of interest implications.^22-25

Non-Randomized Studies

All 6 non-randomized studies clearly defined the objectives, outcomes, inclusion criteria, interventions used, and characteristics of included patients.^26-31 Four of the non-randomized studies received ethical approval,^26,27,29,30 while 1 non-randomized study registered the protocol before conducting their study.³¹ Each non-randomized study clearly described the main findings including appropriate measures of variability (interquartile range, standard deviation, 95% CI) and exact P values when needed.^26-31 Each non-randomized study used appropriate statistical tests to assess main outcomes and outcome measures used were valid and reliable.^26-31 Five non-randomized studies used patient data from the same population over the same period of time for both intervention and comparator groups, and patient data was likely representative of the population from which they were recruited.^26-29,31 One non-randomized study identified principle confounders and accounted for possible confounding factors in the analysis using regression models.²⁹ Five non-randomized studies did not adequately identify principle confounders and it was not clear if confounding factors were accounted for in the analysis.^26-31 One non-randomized study indicated that sufficient power calculations were used to determine adequate sample size.²⁷ It is unclear if all important adverse events were captured in any of the non-randomized studies.^26-31 Due to the retrospective cohort study design of 5 non-randomized studies, it is unlikely that follow-up information was captured.^26-30 One non-randomized study that used a prospective cohort study design did not provide sufficient detail related to patient loss to follow up, and it was unclear if loss to follow-up was accounted for in the analysis.³¹ Three non-randomized studies provided information related to any funding received for the study,^26,27,29 while 5 non-randomized studies declared any potential conflict of interest implications.^27-31

Evidence-Based Guideline

The identified evidence-based guideline clearly described the overall objective and population to which the guideline is meant to apply, its target users, the systematic methods used to collect evidence, and the link between the recommendations and supporting evidence using GRADE.³² The recommendations are easily identifiable, specific and unambiguous, and provide different options for conditions or health issues.³² The evidence-based guideline, however, did not clearly describe the health questions covered in the guideline, did not clearly indicate if relevant professionals or the views and preferences of the target population were included in the guideline development, did not clearly indicate if additional health benefits were considered in the formulation of the recommendations, and did not clearly indicate if the guideline had been externally reviewed before its publication.³² In addition, the evidence-based guideline did not provide criteria for evidence selection, the strengths and limitations of the body of evidence, the methods formulating the evidence, or a procedure for updating the guideline.³² This evidence-based guideline did not provide consideration for external applicability, and it is unclear if the guideline had been influenced by funding of competing interests.³²

Summary of Findings

Clinical Effectiveness of IV Iron Preparations for Patients Identified as Iron Deficient Undergoing Elective Surgery

Six SRs^16-21 (3 with MA),^16,17,19 4 RCTs,^22-25 and 6 non-randomized studies^26-31 were identified regarding the clinical effectiveness of IV iron preparations for patients identified as iron deficient undergoing elective surgery, including high blood loss surgery. Additional details are available in Appendix 4 by outcome: patient hemoglobin level (Table 8), blood transfusion occurrence (Table 9), quality of life (Table 10), days in hospital or recovery (Table 11), safety and adverse events (Table 12), and additional clinical outcomes (Table 13).

Three SRs with MA^16,17,19 were found to have some overlap between studies included in their analysis. A summary table outlining the degree of overlap between the SRs is included in Appendix 5. One SR with MA¹⁶ in which each primary study was captured in another SR was included in this report because the MA presented a combined synthesis of outcomes not captured in other SRs included in this report. Similarly, findings from other SRs are presented for uniquely reported outcomes or primary studies that are not captured in any other included SR. Findings from included SRs with MA^16,17,19 are presented as combined measures of effects, and no attempt was made to present findings from individual studies included in each MA, thus the pooled estimates from separate SRs contain some of the same data. When applicable, findings are presented in relation to comparator as patients who did not receive IV iron supplementation or patients who received oral iron supplementation.

Patient Hemoglobin Level

When Compared to No Treatment or Placebo

Two SRs with MA found that patients who received IV iron supplementation showed statistically significantly higher concentrations of hemoglobin compared to those who did not receive IV iron supplementation.^16,17 Similarly, the third SR with MA found that patients who received IV iron supplementation showed a statistically significantly greater increase in hemoglobin concentrations compared to those who did not receive IV iron supplementation at post-treatment and over 4 weeks post-operatively.¹⁹ One SR¹⁸ included 4 primary RCT studies that reported on mean hemoglobin concentrations at various time points between patients who received IV iron supplementation and patients who did not; however, numerical findings and P values were not presented among studies for these outcomes. One included RCT reported that mean post-operative hemoglobin levels significantly favoured those who received IV iron supplementation.¹⁸ One included RCTs reported that the change in pre-operative to post-operative hemoglobin levels was not significant for all patients, but 2 included RCTs reported that change in hemoglobin levels at post-operative day 30 significantly favoured those who received IV iron supplementation.¹⁸ Two included RCTs reported the rate of anemia at post-operative day 30 was significantly lower for those who received IV iron supplementation.¹⁸

One SR²⁰ included 3 primary RCT studies not captured in a SR with MA that reported on measured of hemoglobin concentration at various time points between patients who received IV iron supplementation and patients who did not; however, statistical comparisons were not presented for the studies. Two included RCTs consistently showed higher levels of hemoglobin concentrations for patients who received IV iron supplementation compared to patients who did not, however it is unclear whether these findings are statistically different.²⁰ One SR²¹ included 3 primary studies (3 non-randomized studies) that reported on the mean change in hemoglobin concentration from iron deficiency diagnosis to surgical admission for patients who received IV iron supplementation compared to patients who did not. Three included primary studies showed that the change in hemoglobin concentration was statistically significantly larger for patients who received IV iron supplementation.²¹

Two RCTs reported the mean change in hemoglobin from baseline to before the time of surgery²² or follow-up,²³ and reported that patients who received IV iron supplementation showed a statistically significantly greater change in hemoglobin compared to patients who did not receive IV iron supplementation.^22,23 One RCT reported the comparison of mean hemoglobin concentrations at various time points, including on admission, pre-operatively, post-operatively, 1 week after surgical discharge, and 4 weeks after surgical discharge for patients who received IV iron supplementation compared to placebo.²⁴ The RCT reported that patients who received IV iron supplementation showed statistically significantly higher hemoglobin concentrations pre-operatively and 4 weeks after surgical discharge, while a statistically significantly lower hemoglobin concentration was shown post-operatively.²⁴ The findings should be interpreted with caution because these only give a comparison of hemoglobin level at certain time points rather than comparing a change in hemoglobin levels over time. In addition, the RCT reported that patients who received IV iron supplementation had a statistically significantly lower incidence of anemia 4 weeks after surgical discharge compared to placebo.²⁴

One retrospective cohort study reported that the mean change between baseline and pre-operative hemoglobin concentrations were higher for patients who received IV iron supplementation compared to patients who did not, but this change was not statistically significantly different.²⁶

One retrospective cohort study compared mean hemoglobin levels at various time points across different patients groups, which included patients who were responsive to IV iron supplementation, patients who were unresponsive to IV iron supplementation, patients who did not received treatment, and patients who were not anemic.²⁸ The authors of this retrospective cohort study found that the change in mean hemoglobin concentrations were statistically significantly different from pre-assessment to pre-operative phase, while the change in mean hemoglobin concentrations were lowest among patients who did not received treatment from pre-operative to post-operative phase but the measure of statistical significance was not reported.²⁸

When Compared to Oral Iron

One SR included 1 RCT that reported a lower level of hemoglobin concentration for patients who received IV iron supplementation compared to patients who received oral iron supplementation; however, it is unclear whether these findings are statistically different.²⁰

One RCT reported that the mean rise in hemoglobin levels was not statistically significantly different between patients who received IV iron supplementation and those who received oral iron supplementation.²⁵

One retrospective cohort study reported the change in hemoglobin concentration from referral to pre-operative for patients who received IV iron supplementation at 3 different doses (1 to 300 mg, 301 mg to 600 mg, and > 600 mg), and patients who received oral iron supplementation.²⁹ The authors reported that patients who received IV iron supplementation at more than 600 mg showed a statistically significant increase in hemoglobin concentration from referral to pre-operative, while each other group showed an increase but was reported to be not significant.²⁹

Blood Transfusion Occurrence

When Compared to No Treatment or Placebo

Three SRs with MA with some overlapping primary studies reported findings on the combined total number of blood transfusions received between patients who received IV iron supplementation and patients who did not.^16,17,19 A non-statistically significant finding from 1 SR with MA suggest that for patients who received pre-operative IV iron supplementation there may be little-to-no difference in risk of receiving a pre-operative blood transfusion when compared to patients who received no treatment [i.e., risk ratio (95% CI), 0.57 (0.30 to 1.09); P = 0.09].¹⁶ However, this finding was based on a MA of 4 studies and there was a moderately high level of statistical heterogeneity (i.e., I² = 64%), and it is unclear whether this had an impact on the precision of this effect estimate.

One SR with MA reported that the risk of receiving a blood transfusion was statistically significantly lower for patients who received IV iron supplementation compared to patients who did not [i.e., 35% lower risk (95% CI, 52% to 12%); P = 0.005].¹⁷ One SR with MA reported the risk of receiving a blood transfusion was statistically significantly lower for patients who did not receive IV iron supplementation in both a random and fixed effects model, respectively [i.e., 16% lower risk (95% CI, 29% to 1%); P = 0.04; 17% lower risk (95% CI, 30% to 2%); P = 0.03].¹⁹

One SR²⁰ included 5 primary RCT studies that reported the proportion of patients who received an allogenic blood transfusion for patients who received IV iron supplementation compared to patients who did not; however, statistical comparisons were not presented among studies. The proportion of patients who received an allogenic blood transfusion varied across individual studies, with 3 RCTs reporting a lower proportion of blood transfusions for patients who received IV iron supplementation while 2 RCTs reported higher proportions of blood transfusions for patients who received IV iron supplementation; however, it is unknown whether these difference are statistically significant.²⁰ One SR²¹ included 3 non-randomized studies that reported the proportion of patients who received a blood transfusion and the amount of blood transfused between patients who received IV iron supplementation and those who did not. The proportion of patients who received a blood transfusion was not statistically, significantly different for 2 non-randomized studies, while 1 retrospective cohort study showed that a the proportion of patients who received a blood transfusion was statistically significantly lower for patients who received IV iron supplementation compared to patients who did not.²¹ Similarly, the amount of blood transfused was not statistically significantly different for 1 retrospective cohort study, while 1 retrospective cohort study showed that the amount of blood transfused was statistically, significantly lower for patients who received IV iron supplementation compared to patients who did not.²¹

Two RCTs reported on the number of patients who received a red blood cell transfusion at various time points for patients who received IV iron supplementation compared to patients who did not.^22,25 One RCT found that the proportion of patients who received a red blood cell transfusion pre-operatively and post-operatively was lower for patients who received IV iron supplementation but was not shown to be statistically significant.²²

One retrospective cohort study reported the median number of blood transfusion at various time points, and found that the group of patients who received IV iron supplementation had a higher proportion of blood transfusions at the pre-operative, day of surgery, and post-operative time points compared to the group of patients who did not receive IV iron; however, no statistical comparisons were reported, thus limiting the interpretation of these findings.²⁶ One retrospective cohort study found that the median number of red blood cell units transfused perioperatively was statistically significantly lower for patients who were responsive to IV iron supplementation compared to patients who received IV iron supplementation and were unresponsive or patients who were untreated.²⁸ One retrospective cohort study found that anemic patients who received IV iron supplementation had a statistically significantly higher number of blood transfusion events and median number of blood cell units transfused compared to patients who were not anemic and did not receive treatment; however, no statistically significant difference was found between anemic patients who received IV iron supplementation and anemic patients who did not receive IV iron supplmentation.³⁰ One prospective cohort study found that the mean total blood cell units transfused was highest among patients who are anemic and did not receive treatment compared to patients who are anemic, iron deficient, and received IV iron supplementation or patients who are not anemic and did not receive treatment; however, statistical comparisons were not presented among patient groups, thus limiting the interpretation of these findings.³¹

One retrospective cohort study showed that patients who received IV iron supplementation at the lowest dose (1 mg to 300 mg) had statistically significantly greater odds of receiving a blood transfusion compared to no treatment.²⁹ Patients who received IV supplementation at larger doses (301 mg to 600 mg, and > 600 mg) and oral iron supplementation reported that the odds of receiving a blood transfusion compared to no treatment was not statistically significantly different.²⁹

When Compared to Oral Iron

One SR with MA also reported that the risk of blood transfusion between patients who received IV iron supplementation and patients who received oral iron supplementation was not statistically significantly different [i.e., risk ratio (95% CI), 0.88 (0.51 to 1.51); P = 0.63].¹⁹

One RCT that compared patients who received IV iron supplementation to oral iron supplementation found no statistically significant difference in the number of patients who received a blood transfusion from recruitment to discharge, pre-operatively, or post-operatively.²⁵ The RCT found a statistically significantly larger number of patients who received IV iron supplementation had blood transfusions intra-operative [i.e., 6 (46.2%) versus 1 (7.7%) respectively; P = 0.03].²⁵

One retrospective cohort study reported the number of blood transfusions at various time points for patients who received IV iron supplementation compared to oral supplementation, and found that patients who received IV iron supplementation had a significantly lower number of intra-operative blood transfusions.²⁷ The authors found that number of transfusions received over the entire peri-operative period was not statistically significantly different between IV iron and oral iron supplementation.²⁷

Quality of Life

When Compared to No Treatment or Placebo

One SR included 1 primary RCTs that reported quality of life outcomes using the European Quality of Life – 5 Dimension Questionnaire (EQ-5D).¹⁸ The SR authors reported that for the included RCT that the difference in EQ-5D scores between patients who receive IV iron supplementation and patients who did not was not significant, however, no numerical or statistical values were reported.¹⁸ One SR with MA reported quality of life outcomes from 2 included RCTs, and the SR authors reported that the changes in quality of life outcomes were not statistically significant at 60-days post-hospital discharge and 4 weeks post-surgery for patients who received IV supplementation and patients who did not; however, the measurements were not reported.¹⁹

One SR included 3 primary RCTs that reported on various quality of life outcomes for patients who received IV iron supplementation compared to patients who did not; however, statistical significance findings were not presented among studies.²⁰ One included RCT reported that quality of life, physical, and mental scores from post-operative day 1 to week 12 were higher for patients who received IV iron supplementation compared to patients who did not.²⁰ One included RCT reported that mean fatigue and dyspnea scores were lower for patients who received IV iron supplementation compared to placebo.²⁰ One included RCT reported similar mean EQ-5D 5 level utility and health scores at 10 days, 8 weeks, and 6 months post-operative and similar multi-dimensional fatigue inventory scores for patients who receive IV iron supplementation compared to placebo.²⁰

One RCT reported a lower median quality of recover score for patients who received IV iron supplementation compared to patients who did not; however, this was not statistically significantly different.²² One RCT reported EQ-5D 3 level index and visual analogue scale scores at baseline and follow up and found no statistically, significant difference between patients who received IV iron supplementation and placebo.²³

When Compared to Oral Iron

One SR included 1 RCT that reported quality of life outcomes using the EQ-5D and independence index score outcomes.¹⁸ The SR authors reported that the difference in EQ-5D scores and independence index scores between patients who received IV iron supplementation and oral iron supplementation was not significant; however, no numerical or statistical values were reported.

One RCT reported no statistically significant difference in EQ-5D 3 level scores at baseline, 1 month, and 3-month follow-up for patients who received IV iron supplementation compared to oral iron supplementation.²⁵

Days in Hospital or Recovery

When Compared to No Treatment or Placebo

One SR included 8 primary RCTs that reported mean or median length of stay in hospital for patients who received IV iron supplementation compared to patients who did not; however, statistical comparisons were not presented for the studies.²⁰ Each included RCT reported the same or a lower number of days spent in hospital for patients who received IV iron supplementation compared to patients who did not, but the lack of statistical comparisons limits the certainty in these findings.²⁰ One SR included 3 non-randomized studies (1 retrospective cohort studies, 1 retrospective and prospective cohort study, and 1 prospective cohort study) that reported the mean length of hospital stay for patients who receive IV iron supplementation compared to patients who did not.²¹ Two included non-randomized studies reported no statistically significant difference in mean length of hospital stay between groups, while 1 retrospective and prospective cohort study reported a statistically significant lower number of days spent in hospital for patients who received IV iron supplementation.²¹

One RCT reported no statistically significant difference in median post-operative length of stay days and days at home within 30 days of surgery for patients who received IV iron supplementation compared to patients who did not.²² One RCT reported that patients who received IV iron supplementation showed a statistically significantly lower length of hospital and ICU stay compared to placebo.²⁴

One retrospective cohort study reported no statistically significant difference in median length of hospital stay days and days alive and out of hospital at 30 days and 90 days between patients who receive IV iron supplementation and those who did not.²⁶ One retrospective cohort study reported that the mean length of stay in days was statistically significantly higher among patients who received IV iron supplementation but were unresponsive to treatment compared to patients who were not anemic and did not receive treatment.²⁸ One prospective cohort study found that the mean length of hospital stay in days was lowest among patients who were not anemic and received no treatment compared to patients who were anemic, iron deficient and received IV iron supplementation, patients who were just iron deficient and received IV iron supplementation, and patients who were anemic and did not receive treatment; however, statistical comparisons were not presented among patient groups, thus limiting the interpretation of these findings.³¹

When Compared to Oral Iron

One RCT reported that patients who received IV iron supplementation compared to oral supplementation showed no statistically significant difference in mean days alive and out of hospital at 30 days, 3 months, and 6 months.²⁵

One retrospective cohort study reported a statistically significantly lower mean length of hospital stay for patients who received IV iron supplementation compared to oral supplementation.²⁷

Safety and Adverse Events

When Compared to No Treatment or Placebo

One SR included 2 primary RCTs that reported the rates of adverse events for patients who received IV iron supplementation compared to patients who did not; however, no statistical comparisons were presented among studies.¹⁸ The rates of adverse events was similar for patients who received IV iron supplementation compared to patients who did not for both included RCTs, with 1 RCT reporting no adverse events for both groups.¹⁸

One SR with MA reported on the occurrence of serious adverse effects based on findings from 2 included primary studies, and the occurrence non-serious adverse effects based on the findings from 7 included primary studies.¹⁹ The findings suggest that patients who received IV iron supplementation had no difference in risk of serious adverse effects compared to patients who did not receive IV iron supplementation [i.e., risk ratio (95% CI), 0.96 (0.44 to 2.10); P = 0.92].¹⁹ The findings also suggested that patients who received IV iron supplementation had little-to-no difference in risk of non-serious adverse effects compared to patients who did not receive IV iron supplementation [i.e., risk ratio (95% CI), 1.13 (0.78 to 1.65); P = 0.52].¹⁹

One SR included 4 primary RCTs that reported the proportion of patients who experienced adverse events for patients who receive IV iron supplementation and patients who did not; however, no statistical comparisons were presented among studies.²⁰ Two included RCTs reported that a higher proportion of patients who received IV iron supplementation experienced adverse events compared to placebo, while 2 included RCT reported that 0 patients who received IV iron supplementation experience adverse events.²⁰

One RCT reported the number of patients who experienced any surgical complications, the grade of surgical complication, and hospital readmissions within 30 days and found no statistically significant difference in each outcome for patients who received IV iron supplementation compared to patients who did not.²² One RCT reported that patients who received IV iron supplementation had a lower number of serious and non-serious adverse events compared to patients who received placebo.²³ One RCT reported the incidence of adverse cardiovascular events, prolonged ventilation, heart failure, and stroke for patient who receive IV iron supplementation compared to placebo.²⁴ Patients who received IV iron supplementation reported lower numbers for each outcome compared to placebo; however, the incidence for each outcomes was not significantly different.²⁴

One retrospective cohort study reported the proportion of patients experiencing any complication, surgical complications, and medical complications for patient who received IV iron supplementation compared to patients who did not.²⁶ The authors found that the number of all complications and surgical complications was significantly higher for patients who received IV iron supplementation, and that the number of medical complications was higher for patients who received IV iron supplementation but was shown to be not statistically significant.²⁶

One retrospective cohort study reported the number of cerebrovascular accidents, renal replacement procedures, and re-operations for patients who are anemic and received IV iron supplementation, patients who are anemic and did not receive IV supplementation, and patient who are not anemic.³⁰ Overall, patients who are anemic and received IV iron supplementation reported the highest relative proportion for each outcome across groups.³⁰

One SR with MA,¹⁹ and 1 SR²⁰ with 2 included primary RCTs not captured in a SR with MA reported the difference in risk and proportion of patients who died for patients who received IV iron supplementation compared to those who did not. The authors of the SR and MA reported little-to-no difference in the risk of mortality at 30-days post-operatively and more than 2 months post-hospital discharge.¹⁹ The SR reported similar proportions of post-operative mortality across both included RCT for patients who received IV iron supplementation compared to patients who did not.²⁰ In addition, 2 RCTs,^23,24 3 retrospective cohort studies,^26,28,30 and 1 prospective cohort study reported the number of deaths or mortality rate for patients who received IV iron supplementation compared to patients who did not. Generally, the number or rate of mortality was similar for each included primary study^{23,24,26,28,30,31}; however, 1 retrospective cohort study found that the number of in-hospital mortality was statistically significantly lower for patient who were anemic and received IV iron supplementation compared to patients who were anemic and did not receive IV iron supplementation.³⁰

One SR with MA¹⁹ reported little-to-no difference in the risk of post-operative infection for patients who received IV iron supplementation compared to patients who did not.¹⁹ Three RCTs^22-24 and 2 retrospective cohort studies^26,30 reported number or incidence of infections between patients who received IV iron supplementation and patients who did not. Generally, the number or incidence of infections were similar between groups and no statistically significant difference was found in any of the included primary studies.^22-24,26,30

When Compared to Oral Iron

One RCT reported the number patients readmitted to hospital for 6 months follow-up was not statistically significantly different between patients who received IV iron supplementation and oral iron supplementation.²⁵

Additional Clinical Outcomes

Functional Outcomes

One SR included 2 primary RCTs that reported functional outcomes for 6-Minute Walk Test scores and Functional Assessment of Cancer Therapy for patients with Anemia/Fatigue scores and the SR authors reported that the difference in both functional outcomes was not significant for patients who received IV iron supplementation and patients who did not, however, numerical findings were not reported.¹⁸ One RCT reported the mean 6-Minute Walk Test distance between patients who received IV iron supplementation and placebo at baseline and follow-up and found the mean difference in distance between the groups was not statistically significantly different.²³

Ferritin Levels

One SR and MA reported mean ferritin level differences at various time points.¹⁹ The authors found that mean ferritin levels were significantly higher at post-treatment and pre-surgery, hospital discharge, and at 4 or more weeks post-operative for patients who received IV iron supplementation compared to patients who did not.¹⁹ Two RCTs reported a significantly greater mean change in ferritin concentration from baseline to before surgery or follow-up for patients who received IV iron supplementation compared to patients who did not.^22,23,28

Cost-Effectiveness of IV Iron Preparations for Patients Identified as Iron Deficient Undergoing Elective Surgery

No evidence was identified regarding the cost-effectiveness of IV iron preparations for patients identified as iron deficient undergoing elective surgery; therefore, no summary can be provided.

Guidelines Regarding the Use of IV Iron Preparations for Patients Identified as Iron Deficient Undergoing Elective Surgery

One evidence-based guideline was identified regarding the use of IV iron preparations for patients identified as iron deficient undergoing elective surgery, including high blood loss surgery.³² Additional details are available in Appendix 4, Table 14.

The guideline recommends that IV iron supplementation may be appropriate for patients with iron deficient anemia in certain circumstances which includes less than 8 weeks until surgery, unable to tolerate or absorb oral iron supplementation, or hemoglobin levels under 100 g/L.³² Evidence supporting this recommendation was from 1 SR, 4 RCTS, 1 prospective cohort study, and 2 retrospective cohort studies.³² The strength of recommendation was considered strong and the quality of evidence was considered high.³²

Limitations

The primary studies summarized in the 6 included SRs were of variable quality.^16-21 Three of the 4 RCTs included in 1 SR with MA were shown to have high risk of bias.¹⁶ One SR with MA reported that each primary study (2 RCTs and 5 non-randomized studies) had low risk of bias.¹⁷ The risk of bias for the 7 RCTs included in 1 SR were reported to be varied, with 4 RCTs having low risk of bias, 1 RCT having high risk of bias, and 2 RCTs having unclear risk of bias.¹⁸ Six of the 10 included RCTs for 1 SR with MA were reported to have unclear of high risk of bias.¹⁹ One SR reported that each of the 10 included RCTs were considered to have high risk of bias largely due to a lack of blinding.²⁰ All 9 included studies for 1 SR were reported to have low risk of bias due to blinding and randomization in the RCTs and good comparability of cohorts in the non-randomized studies.²¹ In addition, 3 included SR with MA reported a large degree of heterogeneity across primary studies for major outcomes related to hemoglobin concentration^16,17,19 and risk of blood transfusion.¹⁶ There was also a large degree of overlap in primary studies included in the SRs, and this overlap should be considered when interpreting findings from SRs with MA.^16,17,19

The evidence in this report may be limited by the clinical heterogeneity of the included publications. The type of IV iron supplementation, the time of administration, and the dose of supplementation varied across each included SR and primary study included in this report. In addition, the type of comparator varied across each study and some included studies described the comparator as a control, which may include more than 1 relevant comparator. The populations varied across each study, specifically in relation to the type of surgery that was provided which can be challenging to compare outcomes between surgery type. Because of the heterogeneity across each study in terms of intervention used and comparator, it may be challenging to determine the generalizability of the overall findings for outcomes related to clinical effectiveness of IV iron use in patients identified as iron deficient. The recommendation from the included evidence-based guideline did not specify the type, administration, or dose of IV iron supplementation; however, this may be dependent on the patient and type of surgery.

No evidence was identified regarding the cost-effectiveness of IV iron preparations for patients identified as iron deficient undergoing elective surgery, and no conclusion can be drawn related to funding considerations for this treatment.

One non-randomized study²⁹ and the included evidence-based guideline³² was conducted in Canada. One SR and MA was conducted in Canada but included primary studies from a variety of countries.¹⁹ Majority of the included evidence related to the clinical effectiveness of IV iron use for patients identified as iron deficient undergoing elective surgery were conducted in a variety of countries. Thus, it is unclear how generalizable the findings are to the Canadian context. This should be considered because the prevalence of iron deficiency, access to elective surgeries, and availability or type of IV iron supplementation may vary between countries, and therefore may have different implications depending on the population and cultural context.

Conclusions and Implications for Decision- or Policy-Making

This report included 6 SRs (3 with MA),^16-21 4 RCTs,^22-25 6 non-randomized studies,^26-31 and 1 evidence-based guideline related to the use of IV iron preparations for patients identified with iron deficiency undergoing elective surgery, including high blood loss surgery. No evidence was identified regarding the cost-effectiveness of IV iron preparations for patients identified as iron deficient undergoing elective surgery.

Each of the included studies and evidence-based guideline specified that the population of interest included adult patients identified as anemic and/or iron deficient undergoing elective surgery.^16-32 Most of the included studies specified that IV iron treatment was administer pre-operatively,^{16,19,21,22,24-30} while some studies indicated that IV iron was administered intra-operatively, post-operatively, or did not specify.^{17,18,20,23,31,32} Each study indicated the specific type and dose of IV iron supplementation used, but this varied among studies. The type of IV iron supplementation included IV ferric carboxymaltose, iron sucrose, iron isomaltoside, or unspecified IV iron and doses ranged from 100 mg to 2,000 mg.

Based on the evidence summarized within this report, patients who received IV iron supplementation were reported to generally have greater increases in the change of hemoglobin levels at various time points of the surgical care compared to patients who did not receive IV iron supplementation.^16-24,26,28 Similar findings were present for patient ferritin levels.^19,22,23 The evidence also showed that patients who received IV iron supplementation had similar or lower lengths of hospital stay or days in recovery compared to patients who did not receive IV iron supplementation.^{20-22,24,26,28,31} The evidence related to the number of patients who received a blood transfusion was mixed, with some studies reporting fewer blood transfusion occurrences while some studies reported no difference or more blood transfusion occurrences for patient who received IV iron supplementation compared to patients who did not.^{16,17,19-22,26,28,30,31} Findings related to blood transfusion occurrences should be interpreted with caution due to measurements of imprecision and heterogeneity within studies, and a lack of statistical tests reported for some results. Because of these variations in findings, it is challenging to accurately draw conclusion on the impact of IV iron supplementation for blood transfusion occurrences. The evidence related to patient quality of life generally found outcomes for patients who received IV iron supplementation and patients who did not were similar for various quality of life measures.^18-20,22,23 Similarly, the evidence that reported on outcomes related to adverse events and safety was mixed but generally found no differences between patients who received IV iron supplementation and patients who did not for various outcomes.^{18-20,22-24,26,30} In addition, evidence related to the number or rate of mortality^{19,20,23,24,26,28,30,31} and the number or incidence of infection^{19,22-24,26,30} generally found similar or no difference in patients who received IV iron supplementation compared to patients who did not. Outcomes related to patient function also showed no difference in patients who receive IV iron supplementation and patients who did not.^18,23

In general, the studies summarized in this report suggest that when compared to oral iron supplementation, those who were treated with IV iron supplementation had no difference in hemoglobin levels,^20,25,29 quality of life scores,^18,25 or the number of adverse events.²⁵ The findings related to mean length of stay were mixed with 1 study reporting no difference,²⁵ or lower lengths of stay when comparing IV iron to oral iron supplementation.²⁷ The findings were mixed regarding the risk of blood transfusions at various time points, with studies reporting no differences,^19,25,27 increases,²⁵ and decreases²⁷ when comparing IV iron to oral iron supplementation,

The evidence-based guideline was conducted in Canada for patients with comorbid condition, specifically anemia, hyperglycemia, and smoking, undergoing major surgery.³² This guideline provided a strong recommendation for the use of IV iron supplementation for patients with iron deficient anemia in circumstances where surgery is less than 8 weeks away, patients are unable to tolerate or absorb oral iron supplementation, or for patient with hemoglobin levels under 100 g/L.³²

The previous 2019 CADTH report reported on similar outcomes related to hemoglobin concentration, blood transfusion occurrences, and adverse events including infections and mortality.¹¹ The findings from this report are generally consistent with those outlined in the previous CADTH report, with IV iron supplementation being favoured for hemoglobin concentration control and mixed results found for the need for blood transfusion and mortality between IV iron supplementation compared to no treatment.¹¹ These clinical findings may be challenging to compare between reports due to the volume and level of evidence that informed the findings in the 2019 CADTH report, which included 1 SR and 3 non-randomized studies, while the clinical evidence in this report is informed by 6 SRs (3 with MA), 4 RCTs and 6 non-randomized studies. The 2019 CADTH report also included 1 economic evaluation and an evidence-based guideline, which was used to inform an updated guideline identified (but not included) in this report.¹¹

The limitations for the included literature (e.g., variable quality of primary studies included in the SRs, clinical heterogeneity of the included studies, the overall quality of the included studies, lack of cost-effectiveness literature, and limited Canadian context) should be considered when interpreting the findings of this report. The evidence from this report is meant to build from the literature that was identified in the 2019 CADTH report,¹¹ and provide decision-makers with the updated and relevant evidence related to the use of IV iron preparations for patients identified as iron deficient undergoing elective surgery. Further research that is specific to the Canadian context is needed to adequately assess the clinical effectiveness and cost-effectiveness of IV iron preparation and inform recommendations that are relevant to Canadian users.

References

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2.Richards T, Baikady RR, Clevenger B, et al. Preoperative intravenous iron for anaemia in elective major open abdominal surgery: the PREVENTT RCT. Health Technology Assessment (Winchester, England). 2021;25(11):1-58. PubMed

3.Statistics Canada. Iron Sufficiency of Canadians. 2015; https://www150.statcan.gc.ca/n1/pub/82-003-x/2012004/article/11742-eng.htm#:~:text=2009%20to%202011-,Anemia,iron%2C%20but%20by%20other%20factors. Accessed October 7, 2022.

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5.Intravenous (IV) iron products (use in adults). Waltham (MA): UpToDate; 2022: https://www.uptodate.com/contents/image?imageKey=HEME%2F106130. Accessed October 11, 2022.

6.Monoferric. Monoferric: Ferric Derisomaltose for Injection [product monograph]. Kirkland (QC): Pfizer Canada ULC; 2021: https://pdf.hres.ca/dpd_pm/00062976.PDF. Accessed October 11, 2022.

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8.Feraheme: ferumoxytol for injection [product monograph]. Waltham (MA): AMAG Pharmaceuticals, Inc; 2015: https://pdf.hres.ca/dpd_pm/00031146.PDF. Accessed October 11, 2022.

9.Dexiron: Iron Dextran Injection, USP [product monograph]. Richmond Hill (ON): Fresenius Medical Care Canada Inc.; 2019: https://pdf.hres.ca/dpd_pm/00049568.PDF. Accessed October 11, 2022.

10.Venofer: Iron Sucrose Injection, USP [product monograph]. Richmond Hill (ON): Fresenius Medical Care Canada Inc.; 2019: https://pdf.hres.ca/dpd_pm/00049389.PDF. Accessed October 11, 2022.

11.Banerjee S, McCormack S. Intravenous Iron Preparations for Patients Undergoing Elective Surgery: A Review of Clinical Effectiveness, Cost-Effectiveness, and Guidelines CADTH Rapid Response Report: Summary with Critical Appraisal. Ottawa: CADTH; 2019: https://www.ncbi.nlm.nih.gov/books/NBK545893/.

12.Shea BJ, Reeves BC, Wells G, et al. AMSTAR 2: a critical appraisal tool for systematic reviews that include randomised or non-randomised studies of healthcare interventions, or both. BMJ. 2017;358:j4008. PubMed

13.Downs SH, Black N. The feasibility of creating a checklist for the assessment of the methodological quality both of randomised and non-randomised studies of health care interventions. J Epidemiol Community Health. 1998;52(6):377-384. PubMed

14.Agree Next Steps C. The AGREE II Instrument. [Hamilton, ON]: AGREE Enterprise; 2017: https://www.agreetrust.org/wp-content/uploads/2017/12/AGREE-II-Users-Manual-and-23-item-Instrument-2009-Update-2017.pdf.

15.Liberati A, Altman DG, Tetzlaff J, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. J Clin Epidemiol. 2009;62(10):e1-e34. PubMed

16.Meyer J, Cirocchi R, Di Saverio S, Ris F, Wheeler J, Davies RJ. Pre-operative iron increases haemoglobin concentration before abdominal surgery: a systematic review and meta-analysis of randomized controlled trials. Sci Rep. 2022;12(1):2158. PubMed

17.Tang G, Zhang L, Huang W, Wei Z. Iron Supplementation Effectively Ameliorates Anemia and Reduces the Need for Blood Transfusion in Patients Undergoing Colorectal Cancer Surgery: A Meta-Analysis. Nutr Cancer. 2022;74(7):2303-2312. PubMed

18.Chaudhry YP, MacMahon A, Hasan SA, et al. Intraoperative and Postoperative Iron Supplementation in Elective Total Joint Arthroplasty: A Systematic Review. J Am Acad Orthop Surg. 2021;29(23):e1200-e1207. PubMed

19.Elhenawy AM, Meyer SR, Bagshaw SM, MacArthur RG, Carroll LJ. Role of preoperative intravenous iron therapy to correct anemia before major surgery: a systematic review and meta-analysis. Syst Rev. 2021;10(1):36. PubMed

20.Jones JJ, Mundy LM, Blackman N, Shwarz M. Ferric Carboxymaltose for Anemic Perioperative Populations: A Systematic Literature Review of Randomized Controlled Trials. J Blood Med. 2021;12:337-359. PubMed

21.Moon T, Smith A, Pak T, et al. Preoperative Anemia Treatment with Intravenous Iron Therapy in Patients Undergoing Abdominal Surgery: A Systematic Review. Adv Ther. 2021;38(3):1447-1469. PubMed

22.Fung PLP, Lau VNM, Ng FF, Leung WW, Mak TWC, Lee A. Perioperative changes in haemoglobin and ferritin concentrations from preoperative intravenous iron isomaltoside for iron deficiency anaemia in patients with colorectal cancer: A pilot randomised controlled trial. PLoS One. 2022;17(6):e0270640. PubMed

23.Kvaslerud AB, Bardan S, Andresen K, et al. Intravenous iron supplement for iron deficiency in patients with severe aortic stenosis scheduled for transcatheter aortic valve implantation: results of the IIISAS randomised trial. Eur J Heart Fail. 2022;24(7):1269-1279. PubMed

24.Shokri H, Ali I. Intravenous iron supplementation treats anemia and reduces blood transfusion requirements in patients undergoing coronary artery bypass grafting-A prospective randomized trial. Ann Card Anaesth. 2022;25(2):141-147. PubMed

25.Thin TN, Tan BPY, Sim EY, Shum KL, Chan HSP, Abdullah HR. Preoperative Single-Dose Intravenous Iron Formulation to Reduce Postsurgical Complications in Patients Undergoing Major Abdominal Surgery: A Randomized Control Trial Feasibility Study (PIRCAS Trial Pilot). Cureus. 2021;13(8):e17357. PubMed

26.Ploug M, Kroijer R, Qvist N, Knudsen T. Preoperative Intravenous Iron Treatment in Colorectal Cancer: Experience From Clinical Practice. J Surg Res. 2022;277:37-43. PubMed

27.Abdullah HR, Thamnachit T, Hao Y, Lim WY, Teo LM, Sim YE. Real-world results of the implementation of preoperative anaemia clinic with intravenous iron therapy for treating iron-deficiency anaemia: a propensity-matched case-control study. Ann Transl Med. 2021;9(1):6. PubMed

28.Evans CR, Jones R, Phillips G, Greene G, Phillips M, Morris-Clarke R. Observational study of pre-operative intravenous iron given to anaemic patients before elective cardiac surgery. Anaesthesia. 2021;76(5):639-646. PubMed

29.Peel JK, Trudeau J, Tano R, et al. Determining Optimal Treatment to Correct Preoperative Anemia and Reduce Perioperative Allogeneic Blood Transfusions in Cardiac Surgery: A Retrospective Cohort Study. J Cardiothorac Vasc Anesth. 2021;35(9):2631-2639. PubMed

30.Quarterman C, Shaw M, Hughes S, Wallace V, Agarwal S. Anaemia in cardiac surgery - a retrospective review of a centre's experience with a pre-operative intravenous iron clinic. Anaesthesia. 2021;76(5):629-638. PubMed

31.Triphaus C, Judd L, Glaser P, et al. Effectiveness of Preoperative Iron Supplementation in Major Surgical Patients With Iron Deficiency: A Prospective Observational Study. Ann Surg. 2021;274(3):e212-e219. PubMed

32.Greenberg JA, Zwiep TM, Sadek J, et al. Clinical practice guideline: evidence, recommendations and algorithm for the preoperative optimization of anemia, hyperglycemia and smoking. Can J Surg. 2021;64(5):E491-E509. PubMed

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Appendix 1: Selection of Included Studies

Figure 1: Selection of Included Studies

Appendix 3: Critical Appraisal of Included Publications

Note that this table has not been copy-edited.

Table 5: Strengths and Limitations of Systematic Reviews Using AMSTAR 2¹²

AMSTAR 2 = A MeaSurement Tool to Assess systematic Reviews 2; GRADE = Grading of Recommendations Assessment, Development, and Evaluation; RCT = randomized controlled trial; RoB = risk of bias.

Table 6: Strengths and Limitations of Clinical Studies Using the Downs and Black Checklist¹³

Table 7: Strengths and Limitations of Guidelines Using AGREE II¹⁴

AGREE II = Appraisal of Guidelines for Research and Evaluation II.

Appendix 4: Main Study Findings

Note that this table has not been copy-edited.

Table 8: Summary of Findings by Outcome — Patient Hemoglobin Level

CI = confidence interval; dl = deciliter; EPO = erythropoietin; g = grams; L = liter; MA = meta-analysis; mg = milligram; NR = not reported; POD = postoperative day; SD = standard deviation; SR = systematic review; vs = versus.

^aStatistical significance between groups was not provided by Jones et al. (2021)

Table 9: Summary of Findings by Outcome — Blood Transfusion Occurrence

CI = confidence interval; EPO = erythropoietin; IV = intravenous; MA = meta-analysis; N = number; NR = not reported; NS = not significant; OR = odds ratio; SEM = standard error mean; SR = systematic review; vs = versus.

^aStatistical significance between groups was not provided by Jones et al. (2021)

^bCount ratio represents how many times more red blood cell units are transfused for each variable group.

Table 10: Summary of Findings by Outcome — Quality of Life

CI = confidence interval; EQ-5D = European Quality of Life – 5 Dimensions Questionnaire; EQ-5D-3L = European Quality of Life – 5 Dimension – 3 Levels; EQ-5D-5L = European Quality of Life – 5 Dimension – 5 Levels; IV = intravenous; MA = meta-analysis; MFI = Multidimensional Fatigue Inventory; NR = not reported; QOR-15 = 15-iten Quality of Recovery; RCT = randomized controlled trial; SD = standard deviation; SF36 = short form-36; SR = systematic review; VAS = visual analogue scale.

^aStatistical significance between groups was not provided by Jones et al. (2021)

Table 11: Summary of Findings by Outcome — Days in Hospital or Recovery

DAOH = days alive and out of hospital; EPO = erythropoietin; ICU = intensive care unit; IV = intravenous; MA = meta-analysis; NS = not significant; RCT = randomized controlled trial; SD = standard deviation; SR = systematic review.

^aStatistical significance between groups was not provided by Jones et al. (2021)

Table 12: Summary of Findings by Outcome — Safety and Adverse Events

CI = confidence interval; EPO = erythropoietin; IV = intravenous; MA = meta-analysis; N = number; NR = not reported; RCT = randomized controlled trial; SR = systematic review; vs = versus.

^aStatistical significance between groups was not provided by Jones et al. (2021)

^bMortality in this population was due to unrelated causes.

Table 13: Summary of Findings by Outcome — Additional Clinical Outcomes

6MWT = 6-minute walk test; CI = confidence interval; FACT-An = Functional Assessment of Cancer Therapy for patients with Anemia/Fatigue; IV = intravenous; l = liter; m = meters; MA = meta-analysis; ml = milliliter; μg = microgram; ng = nanogram; NR = not reported; RCT = randomized controlled trial; SR = systematic review.

Table 14: Summary of Recommendations in Included Guidelines

IDA = iron deficient anemia; RCT = randomized controlled trial; SR = systematic review.

Appendix 5: Overlap Between Included Systematic Reviews

Note that this table has not been copy-edited.

Table 15: Overlap in Relevant Primary Studies Between Included Systematic Reviews