|Year : 2020 | Volume
| Issue : 4 | Page : 184-190
Intravenous iron versus oral iron in anemia management for perioperative patients: A systemic review and meta-analysis
Ahmed H Alshantti1, Zarour Ahmed2, Sophie Robertson3, Omar M Aboumarzouk2, Alaa Alshantti4
1 Department of Urology, Glasgow Royal Infirmary, Greater Glasgow and Clyde, Glasgow, UK
2 Department of Urology, Hamad General Hospital, Hamad Medical Corporation, Doha, UK
3 Qatar, Queen Elizabeth University Hospital, Glasgow, UK
4 Department of Pediatric, Rotherham General Hospital, UK
|Date of Submission||20-May-2020|
|Date of Decision||01-Aug-2020|
|Date of Acceptance||15-Aug-2020|
|Date of Web Publication||17-Nov-2020|
Dr. Ahmed H Alshantti
Glasgow Royal Infirmary, NHS Greater Glasgow and Clyde, Glasgow
Source of Support: None, Conflict of Interest: None
INTRODUCTION: Perioperative anemia commonly occurs in patients undoing major surgery. We aimed to assess the efficacy and safety of intravenous iron therapy (IVIT) given compared to standard practice of oral iron in the perioperative period.
DESIGN: We conducted a Cochrane style systematic review. The search strategy included common search engines: Medline, Embase, Cochrane, and Google Scholar for only eligible clinical trials (randomized controlled trials) comparing IV over oral iron therapy up to July 2019. The primary outcome was the effect of IVIT on the change of hemoglobin level. The secondary outcomes were the effects of IVIT compared to oral iron on ferritin level, mean corpuscular volume, and adverse side effects. Data were collected from each trial and where applicable meta-analyzed using RevMan.
RESULTS: Six randomized clinical trials that fit our inclusion criteria were included in the study. We found that IVIT increases the level of hemoglobin compared to oral iron (MD: Mean difference 0.90, 95% confidence interval [CI]: 0.44–1.36, P = 0.000). Serum ferritin levels increased significantly in favor of the IV iron group compared to the oral iron group at posttreatment (MD: 106.95, 95% CI: 73.29, 140.62 ng/mL). In addition, marked increases in the pooled mean corpuscular volume (MCV) level were observed in favor of the IVIT (MD: 6.07, 95% CI: −0.88–13.02). There was no significant difference in the rate of adverse effects in both the groups.
CONCLUSION: IV iron therapy is more effective than oral iron on increasing hemoglobin, ferritin, and MCV in the perioperative period and is also as safe with no diffidence in the risk of developing adverse side effects.
Keywords: Anemia, intravenous iron, perioperative
|How to cite this article:|
Alshantti AH, Ahmed Z, Robertson S, Aboumarzouk OM, Alshantti A. Intravenous iron versus oral iron in anemia management for perioperative patients: A systemic review and meta-analysis. J Appl Hematol 2020;11:184-90
|How to cite this URL:|
Alshantti AH, Ahmed Z, Robertson S, Aboumarzouk OM, Alshantti A. Intravenous iron versus oral iron in anemia management for perioperative patients: A systemic review and meta-analysis. J Appl Hematol [serial online] 2020 [cited 2020 Nov 28];11:184-90. Available from: https://www.jahjournal.org/text.asp?2020/11/4/184/300772
| Introduction|| |
Anemia is one of the most common hematological comorbidities encountered among surgical patients.
Perioperative anemia is associated with adverse outcomes such as infections, cardiac complications, and increased postoperative hospital stay.,
Oral iron preparations are the standard for iron-deficiency anemia management, mainly due to their low cost and easily administered. However, the gastrointestinal (GI) adverse effects have limited its use.,, IV iron increases the hemoglobin level quicker and with less reported side effects than oral iron.,,
The aim of this systematic review was to assess the efficacy of IV iron compared to oral iron with regard to the improvement in Hb level, ferritin level, and safety profile among surgical patients.
| Methodology|| |
The search strategy included: The US National Library of Medicine's life science, database (Medline) (1948–July 2019), Embase (1948–July 2019), Cochrane Central Register of Controlled Trials (all issues up to issue up to 2019), ClinicalTrials.gov for unpublished trials, Google Scholar, and searching on the reference list of the included studies.
Search terms used in conjunction with each other included: “Iron,” “dextran,” “Ferrlecit,” “sucrose,” “preparations,” “anemia,” and “randomized controlled trial.”
The Medical Subject Headings (MeSH) phrases included:
- (Iron Anemia [Mesh]) AND (Randomized Controlled Trial)
- (iron Compounds [Mesh]) AND (Randomized Controlled Trial)
- (iron Compounds [Mesh]) AND Perioperative [Mesh] AND (Randomized Controlled Trial).
| Study Selection and Data Extraction|| |
All clinical trials reporting on the use of an intravenous iron therapy (IVIT) compared to oral iron in any patient undergoing major surgery were included. The authors were contacted wherever the data were not available or not clear, to be able to adequately assess inclusion and risk of bias of their study.
The reviewers (AA and AZ) identified studies for inclusion and extracted the data, verified by the senior author independently (OA). Disagreement between the authors was resolved by consensus of all authors.
Data were extracted and documented in a predesigned electronic form by the authors (AA and OA). The following data were retrieved: study characteristics (including the study identifiers, study type, country of origin, setting, and inclusion and exclusion criteria); patient demographics (including a number of patients per group, age, gender, and type of surgery); description of the intervention and the comparator (dose, frequency, course treatment timing, and mode of administration); and primary efficacy outcomes and safety outcomes (Adverse effects (AEs), mortality, and morbidity).
Data tables were used to present a descriptive synthesis of the studies. Where data are comparable, a meta-analysis will be conducted on the outcome measure. The meta-analysis was conducted using the Cochrane Collaboration's Review Manager (RevMan) software. The mean differences and 95% confidence intervals (CIs) were calculated using the inverse-variance method and then apply random effect for continuous data. Statistical heterogeneity was assessed using the I2-statistic and interpretation followed the Cochrane Handbook for Systematic Reviews of Interventions rough guide (chapter 9, 5, and 2).
| Results|| |
The literature search identified a total of 3815 studies [Figure 1]. A total of 194 duplicates studies were removed. Three thousand five hundred and ninety-five records were excluded due to nonrelevance after the title and abstract screening. Of the 26 records assessed in full text, a total of 20 were excluded. Thus, a total of six studies were included in the review.
Study characteristics and description of participants
Of the six trials included in this review, there were 557 participants (277 in the intravenous iron group and 280 in the oral iron group). All participants had major surgery either elective or nonelective; two studies were gynecological surgery, three studies were abdominal surgery,,, and one was orthopedic surgery. The studies included in this review originated from six countries (the UK, Spain, India, Australia, Brazil, and South Korea) [Table 1]. All the studies in this review are published between 2009 and 2019.
Description of intervention and comparison
The included studies involved various preparation of intravenous and oral iron with different treatment dosages, as shown in [Table 1]. With regard to the IV iron group, 114 patients received ferric carboxymaltose IV, 113 patients received iron sucrose, and 50 patients received iron polymaltose, and in the oral iron group, 25 patients received iron succinylate, 28 patients received iron polymaltose, and 227 patients received ferrous sulfate. The mean parenteral iron amount given ranged between 200 and 1000 mg a week. The timing of IVIT and oral therapy administration was in the preoperative period in three studies,, and in the postoperative period in three studies.,,
Most included trials in the review were judged as good quality. All the details regarding the risk of bias for each trial are shown in [Table 2]. In all included studies, there was proper random sequence generation, as all the trials reported details on the way they used to make randomization. With regard to the allocation concealment, two studies had a high risk of bias, the first, the allocation was done by the authors and, in the second, the envelope of the treatment arm was opened by the investigator once a patient was randomized.
|Table 2: Risk of bias and methodological quality of the included studies|
Click here to view
Performance risk was high in three trials and not clear in one,,, and low in two trials.,
With regard to the blinding of outcome assessment, all had a low risk of detection bias, except in, it had an unclear risk of detection bias.
With respect to incomplete outcomes data, three of the studies,, had a low risk of attrition bias, one trial had a medium (unclear) risk of bias, and two studies, had a high risk of bias in this domain. Regarding reporting bias, two trials, had a low risk of bias and others had unclear risk.
Hemoglobin concentration change
All the included randomized controlled trials (RCTs) provided data about the change hemoglobin level, which was similar at baseline (MD between the groups: −0.04, 95% CI: −0.22–0.14, P = 0.68), as shown in [Figure 2]. After giving iron treatment, Hb level increased significantly at 4 weeks in favor of the IV iron group compared to the oral group at 4-week follow-up (MD between the groups: 0.90, 95% CI: 0.44–1.36, P = 0.000), as revealed in [Figure 3].
|Figure 2: Forest plot comparison shows the pooled comparison of baseline value of hemoglobin level (g/dL) between intravenous iron therapy versus oral iron (random effects model)|
Click here to view
|Figure 3: Forest plot comparison shows the pooled comparison of post treatment (at week follow-up) value of hemoglobin level (g/dL) between intravenous iron therapy versus oral iron (random effects model)|
Click here to view
Ferritin level change
Three trials, have analyzed the mean ferritin level at baseline [Figure 4]. While the pooled means of trials' participants were 78 ng/mL in the IV iron and ng/mL in 66 the oral iron group, statistically, they had a similar pooled comparison across the groups (MD: −2.91, 95% CI: −48.48, 42.64 ng/mL).
|Figure 4: Forest plot comparison shows the pooled comparison of baseline value of ferritin levels (ng/mL) between intravenous iron therapy versus oral iron (random effects model)|
Click here to view
After giving the iron therapy, [Figure 5], significant improvements in iron stores were observed. As a result, serum ferritin levels increased significantly in favor of the IV iron group compared to the oral iron group at posttreatment (MD: 106.95, 95% CI: 73.29, 140.62 ng/mL).
|Figure 5: Forest plot comparison shows the pooled comparison of posttreatment value of ferritin levels (ng/mL) between intravenous iron therapy versus oral iron (random effects model)|
Click here to view
Mean corpuscular volume or mean cell volume level (fL)
Three studies,, provided data at the baseline level that showed similar mean corpuscular volume (MCV) values for both the trial groups (MD: 1.00, 95% CI: −0.59, 2.52 fL, P = 0.54), as exhibited in [Figure 6]. After administration of IV iron, two trials, described data for MCV, and marked increases in the pooled MCV level were observed in favor of the IV iron group compared to the oral iron group at posttreatment (MD: 6.07, 95% CI: −0.88–13.02), as shown in [Figure 7].
|Figure 6: Forest plot comparison shows the pooled comparison of baseline value of mean corpuscular volume (MCV) between intravenous iron therapy versus oral iron|
(random effects model)
Click here to view
|Figure 7: Forest plot comparison shows the pooled comparison of posttreatment value of Mean corpuscular volume (MCV) between intravenous iron therapy versus oral iron (random effects model)|
Click here to view
Five trials,,,, have reported briefly and narratively about the adverse effect; as a result, it was impossible to include this outcome into a meta-analysis. Most of AEs were mild to moderate and found that there was no difference between the IV iron group and the oral iron group.
| Discussion|| |
Summary of main results
For the primary outcomes, all studies reported hemoglobin change, except for one clinical trial, which had not reported posttreatment Hb. The IV iron treatment versus oral iron therapy showed significantly increase hemoglobin in the IV iron group with (MD: 0.90, 95% CI: 0.44–1.36, P = 0.000).
Allogenic blood transfusion is the standard treatment for perioperative anemia in major surgery;, alternatively, iron therapy can be used due to its safety and better outcome compared to blood transfusions., Oral iron is considered the first line of treatment for iron anemia;, however, it is not effective as IV iron in surgical patients, particularly in functional IDA because of the ineffective GI absorption in the perioperative period. IVIT is more effective in treating iron-deficiency anemia because of the quick delivery of iron to the body without serious side effects in traumatic or surgical patients. This is because the IVIT increases the erythropoietic effect five times more than oral iron and extends to an average of 8 days. Most of the studies in this review have reported mild-to-moderate side effects of both IVIT and oral iron with no difference in both the groups. IV iron has side effects like oral iron such as GI side effects., Patients may be at the risk of anaphylaxis if iron dextran was used.
However, in a systemic review that studies the safety of IVIT, has found that there was no associated serious neurological or cardiovascular side effects, or an increase in the mortality.
Strengths and limitations
One of the strengths of this review is the comprehensive search which was performed in the three dominant databases (Medline, Cochrane, and Embase) and other information resources.
Furthermore, all necessary and supporting documents were given in the appendix, to allow replication the review to ensure transparency and decrease the bias risk of this review.
This systemic review and meta-analysis has included only RCTs and provided a statistically and clinically significant result of the effects of IV iron over PO iron in hemoglobin and ferritin level. This adds to the existing evidence base of the use of IV in surgical patients and as such will have implication for clinical practice.
Limitations of the review were the lack of generalizability, in that we could not apply the findings across all ages as the average age of participants in the included studies was more than 40 years, and therefore, our findings are more valid for the middle and old aged population.
Another limitation of the meta-analysis is the small sample size of most of the studies which make it difficult to estimate and interpret the reported side effect. Reporting any but most common side effect requires large sample size studies to better ensure reliability.
Finally, according to The Cochrane Handbook for Systematic Reviews, “Publication bias” was not assessed because we could not draw a funnel plot as the number of trials included is only six trials.
Implication for research
No study in this review has given a clear and comprehensive understanding of IV iron and PO iron response in surgical patients. Hence, multicenter clinical trials with low risk of bias and powered sample size to provide a definitive understating on the effectiveness, recovery profile, cost-benefit, and quality of life of patients for IV iron therapy in the perioperative period.
Any trial in the future that compares IV iron to PO iron should have strict guidelines of blood transfusion and definition of iron-deficiency anemia. In addition, they should include new preparations of IV iron which contains more iron concentration to decrease the risk of having a blood transfusion in the perioperative period.
The implication for practice
In light of the above, IV iron should be recommended rather than oral iron to be used in the perioperative period to increase the hemoglobin levels and avoid giving a blood transfusion. However, the available information that compares oral iron to IV iron is limited.
| Conclusion|| |
This is the first meta-analysis looking at the difference between oral and IV iron. We found that IV iron significantly increases the hemoglobin level more so than the oral preparations, in addition to having a good safety profile with minimal side effects. Therefore, we recommend the use of IV iron in the preoperative setting in patients undergoing major surgery who have iron-deficiency anemia.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Mundy GM, Birtwistle SJ, Power RA. The effect of iron supplementation on the level of haemoglobin after lower limb arthroplasty. J Bone Joint Surg Br 2005;87:213-7.
Nissenson AR, Goodnough LT, Dubois RW. Anemia: Not just an innocent bystander? Arch Intern Med 2003;163:1400-4.
Kansagra AJ, Stefan MS. Preoperative anemia: Evaluation and treatment. Anesthesiol Clin 2016;34:127-41.
Muñoz M, Laso-Morales MJ, Gómez-Ramírez S, Cadellas M, Núñez-Matas MJ, García-Erce JA. Pre-operative haemoglobin levels and iron status in a large multicentre cohort of patients undergoing major elective surgery. Anaesthesia 2017;72:826-34.4.
Gupta PK, Sundaram A, Mactaggart JN, Johanning JM, Gupta H, Fang X, et al
. Preoperative anemia is an independent predictor of postoperative mortality and adverse cardiac events in elderly patients undergoing elective vascular operations. Ann Surg 2013;258:1096-102.
Pizzi LT, Weston CM, Goldfarb NI, Moretti D, Cobb N, Howell JB, et al
. Impact of chronic conditions on quality of life in patients with inflammatory bowel disease. Inflamm Bowel Dis 2006;12:47-52.
Jans Ø, Jørgensen C, Kehlet H, Johansson PI; Lundbeck Foundation Centre for Fast-track Hip and Knee Replacement Collaborative Group. Role of preoperative anemia for risk of transfusion and postoperative morbidity in fast-track hip and knee arthroplasty. Transfusion 2014;54:717-26.
Muñoz M, García-Erce JA, Villar I, Thomas D. Blood conservation strategies in major orthopaedic surgery: Efficacy, safety and European regulations. Vox Sang 2009;96:1-3.
Parker MJ. Iron supplementation for anemia after hip fracture surgery: a randomized trial of 300 patients. J Bone Joint Surg Am 2010;92:265-9.
Mehta MN, Kongnathi SA. Safety and Effectiveness of Intravenous Iron Sucrose versus Oral Iron: A Study among Preoperative Anemic Women with Menorrhagia. Ntl J Community Med 2015; 7(1):60--63.
Mudge DW, Tan KS, Miles R, Johnson DW, Badve SV, Campbell SB, et al. A randomized controlled trial of intravenous or oral iron for posttransplant anemia in kidney transplantation. Transplantation 2012;93:822-6.
Kim YH, Chung HH, Kang SB, Kim SC, Kim YT. Safety and usefulness of intravenous iron sucrose in the management of preoperative anemia in patients with menorrhagia: a phase IV, open-label, prospective, randomized study. Acta Haematol 2009;121:37-41.
Keeler BD, Simpson JA, Ng O, Padmanabhan H, Brookes MJ, Acheson AG, et al
. Randomized clinical trial of preoperative oral versus intravenous iron in anaemic patients with colorectal cancer. Br J Surg 2017;104:214-21.
Montano--Pedroso JC, Bueno Garcia E, Alcântara Rodrigues de Moraes M, Francescato Veiga D, Masako Ferreira L. Intravenous iron sucrose versus oral iron administration for the postoperative treatment of post-bariatric abdominoplasty anaemia: an open-label, randomised, superiority trial in Brazil. Lancet Haematol 2018;5:e310-e320.
Shander A, Javidroozi M, Ozawa S, Hare GM. What is really dangerous: anaemia or transfusion? Br J Anaesth 2011;107 Suppl 1:i41-59.
Cuenca J, García-Erce JA, Martínez AA, Solano VM, Molina J, Muñoz M. Role of parenteral iron in the management of anaemia in the elderly patient undergoing displaced subcapital hip fracture repair: preliminary data. Arch Orthop Trauma Surg 2005;125:342-7.
Hill GE, Frawley WH, Griffith KE, Forestner JE, Minei JP. Allogeneic blood transfusion increases the risk of postoperative bacterial infection: A meta-analysis. J Trauma 2003;54:908-14.
Muñoz M, Breymann C, García-Erce JA, Gómez-Ramírez S, Comin J, Bisbe E. Efficacy and safety of intravenous iron therapy as an alternative/adjunct to allogeneic blood transfusion. Vox Sang 2008;94:172-83.
Litton E, Xiao J, Ho KM. Safety and efficacy of intravenous iron therapy in reducing requirement for allogeneic blood transfusion: systematic review and meta-analysis of randomised clinical trials. BMJ 2013;347:f4822.
Beris P, Muñoz M, García-Erce JA, Thomas D, Maniatis A, Van der Linden P. Perioperative anaemia management: Consensus statement on the role of intravenous iron. Br J Anaesth 2008;100:599-604.
Bisbe E, Moltó L, Arroyo R, Muniesa JM, Tejero M. Randomized trial comparing ferric carboxymaltose vs oral ferrous glycine sulphate for postoperative anaemia after total knee arthroplasty. Br J Anaesth 2014;113:402-9.
Muñoz M, Gómez-Ramírez S, Bhandari S. The safety of available treatment options for iron-deficiency anemia. Expert Opin Drug Saf 2018;17:149-59.
Goodnough LT, Maniatis A, Earnshaw P, Benoni G, Beris P, Bisbe E, et al
. Detection, evaluation, and management of preoperative anaemia in the elective orthopaedic surgical patient: NATA guidelines. Br J Anaesth 2011;106:13-22.
Avni T, Bieber A, Grossman A, Green H, Leibovici L, Gafter-Gvili A. The safety of intravenous iron preparations: systematic review and meta-analysis. Mayo Clin Proc 2015;90:12-23.
Lasocki S, Krauspe R, von Heymann C, Mezzacasa A, Chainey S, Spahn DR. PREPARE: the prevalence of perioperative anaemia and need for patient blood management in elective orthopaedic surgery: a multicentre, observational study. Eur J Anaesthesiol 2015;32:160-7.
Muñoz M, Naveira E, Seara J, Palmer JH, Cuenca J, García-Erce JA. Role of parenteral iron in transfusion requirements after total hip replacement. A pilot study. Transfus Med 2006;16:137-42.
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7]
[Table 1], [Table 2]