Role of Preoperative Intravenous Iron Therapy to Correct Anemia before Major Surgery A thesis ...

190 Pages·2017·3.11 MB·English

by  Abdelsalam Elhenawy

Role of Preoperative Intravenous Iron Therapy to Correct Anemia before Major
Surgery

By
Abdelsalam M. Elhenawy

A thesis submitted in partial fulfillment of the requirements for the degree of
Master of Science
in
Clinical Epidemiology

Department of Public Health Sciences
University of Alberta

© Abdelsalam M. Elhenawy, 2018
ABSTRACT
In patients undergoing elective major surgery, preoperative anemia is a common
morbidity that may necessitate allogeneic blood transfusion in a substantial proportion of
patients depending on the degree of anemia. Allogeneic blood transfusion has potential
adverse outcomes. Preoperative intravenous iron (IV) monotherapy has been
recommended as a bloodless therapy to decrease perioperative blood transfusion;
however, class 1A evidence is lacking due to the absence of meta-analysis and
systematic reviews, and high quality randomized controlled trials.
The aim was to evaluate the efficacy and safety of preoperative IV monotherapy
injection versus placebo/oral iron (standard of care) as a strategy to increase the
hemoglobin concentration to minimize the necessity of blood transfusion. Therefore, this
systematic review and meta-analysis of the randomized controlled trials was conducted.
The results of the meta-analysis study in this thesis showed that preoperative IV iron
supplementation was found to be effective in decreasing allogeneic blood transfusion by
17% in patients who received IV iron therapy compared to who did not receive it. This
reduction in transfusion rate was statistically significant (risk ratio [RR]: 0.83, 95%
confidence interval [CI]: 0.70, 0.98, p = 0.03). Concomitantly, pre-operative IV iron therapy
was also associated with increases in the hemoglobin concentrations prior to surgery
compared with not receiving pre-operative IV iron therapy (mean difference [MD] between
the study groups: 6.65, 95% CI: 0.83, 12.47 g/L, p = 0.03). Because some of the trials
started administration of IV iron 3-4 weeks before surgery and some studies started the
IV injection 1-2 days before surgery, the hemoglobin rise showed a bi-phasic pattern with
the first wave appeared before surgery and the second wave existed 4 weeks after
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surgery. Moreover, the blood loss perioperatively interrupted this hemoglobin
concentration growth throughout the hospital stay. As a follow-up > 4 weeks
postoperatively, the second wave existed and the hemoglobin level increased significantly
again in favor of the IV group (6.46, 95% CI: 3.11, 9.80 g/L, p = 0.0002) indicating an
augmented/new effect of the injected IV iron later by the other trials.
Intravenous iron administration was able to restore the depleted iron stores and
increased serum ferritin levels significantly pre-surgery, at hospital discharge, and > 4
weeks postoperatively, (MD between groups: 108.03, 95 % CI: 45.58, 170.49 ng/mL, p =
0.0007), (MD between groups: 547.77, 95 % CI: 36.61, 1058.94 ng/mL, p = 0.04), and
(MD between groups: 391.00, 95 % CI: 271.44, 510.56 ng/mL, p < 0.00001), respectively.
There were no differences in non-serious and serious adverse effects between the two
groups (RR: 1.17, 95% CI: 0.80, 1.71, p = 0.42) and (RR: 0.89, 95% CI: 0.40, 1.99, p =
0.77) respectively.
Similar results were obtained from the case series of the thesis where is IV iron
treatment was capable to increase Hb level significantly from 125.70 ± 11 g/L at baseline
to be 132.30 ± 16 g/L at the time of surgery with p = 0.007, with mean difference of 6.6
g/L (95% confidence interval [CI]: 2.00, 11.11 g/L). Moreover, depleted iron stores were
restored, and serum ferritin level increased significantly from 25.43 ± 18.47 ng/mL at
baseline to be 239.80 ± 18.47 ng/ml at surgery (p = 0.004). Allogeneic perioperative red
blood cell transfusion occurred in 9 (29%) patients, which is lower than a recent Canadian
report.
Preoperative intravenous iron monotherapy is a safe and efficacious intervention. It
successfully lowers the transfusion rate and increases hemoglobin concentration pre-
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surgery and at four weeks postoperatively. However, further randomized controlled trials
are required to establish its effectiveness, potential adverse effects, and to show which
intravenous iron preparation has better cost-effectiveness than the other preparations to
reduce blood transfusion.
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PREFACE
This Master’s Degree thesis is an original work by Abdelsalam Elhenawy. All data in
Chapters III and VI were collected and synthesized by Dr. Elhenawy, with Dr. Meyer
serving as an independent second reviewer. Abdelsalam Elhenawy wrote the thesis
chapters and conducted the statistical analyses. This thesis is based on three papers
written as Chapters II, III, and IV.
A version of the first paper (Chapter II) has been published as Elhenawy AM, Meyer
SR, Bagshaw SM, MacArthur RG, Carroll LJ. Role of preoperative intravenous iron
therapy to correct anemia before major surgery: study protocol for systematic review and
meta-analysis. Syst Rev. 2015 Mar 15; 4:29. doi: 10.1186/ s13643-015-0016-4.
To achieve chapter IV (Optimizing preoperative hemoglobin in adult cardiac surgery
using intravenous iron sucrose (Venofer): a case series study), on June 5, 2014, we
obtained approval from my institutional review ethical board (REB #: Pro00045780) to
waive the need for patient consent. A copy of this approval is the Appendix 6 of the thesis.
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ACKNOWLEDGEMENT
The present work was carried out in the Clinical Epidemiology Program at the School
of Public Health, University of Alberta. We as a group do not have any relevant/similar
publications.
My first appreciation goes to my supervisory committee members, Dr. Steven Meyer,
Dr. Linda Carroll, Dr. Sean Bagshaw, and Dr. Roderick MacArthur for their excellent
mentorship, kindness, guidance, and valuable suggestions.
I wish to express my sincere thanks for Mrs. Trish Chatterley who is a Collections
Manager at John W. Scott Health Sciences Library at the University of Alberta for her
support in developing a search strategy for the planned systematic review and updating
the search twice during my working on the systematic review and meta-analysis chapter
of the thesis.
I would like to thank Mr. Ben Vandermeer; he is a biostatistician at the Alberta
Research Centre for Health Evidence (ARCHE), located within the Department of
Pediatrics at the University of Alberta for his guidance in using the RevMan statistical
software.
My next appreciation goes to Mr. Imran Hassan, he is a statistician at the
Epidemiology Coordinating Research (EPICOR) Centre, the University of Alberta for his
assistance to estimate the mean and the standard deviation using the confidence interval,
p-value, standard error, Z-score and the sample size when the included trials did not
report these.
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I am deeply thankful and indebted to my wife Omnia who had compromised a lot to
support me every day of our married life and especially for being my rock through the
worst financial situation I have been through when I was working on my Master Degree.
My gratitude also goes out to my daughter Laila Elhenawy who is a Bachelor Degree
student in Psychology Department at the University of Alberta, and my son Mohamed. I
am thankful for their help conducting the evidence table from the included trials as double
checkers for the numbers to eliminate the human being errors in the meta-analysis
section of my thesis. Mohamed had provided great assistance when it came to
technology.
My last thanks goes to the statisticians who contributed to numerous videos on
YouTube on conducting meta-analyses. These were very helpful in this work.
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TABLE OF CONTENTS
1. CHAPTER I: INTRODUCTION 1
1.1.EPIDEMIOLOGY OF ANEMIA 1
1.2.ANEMIA BASICS 1
1.3.CAUSES OF IRON DEFICIENCY ANEMIA 2
1.3.1. Blood loss 3
1.3.2. Deficient diet 3
1.4.EPIDEMIOLOGY AND MAGNITUDE OF IDA 4
1.5.IRON SUPPLY AND DISTRIBUTION 4
1.5.1. Iron Recycling 5
1.5.2. Heme, Iron Toxicity, and Iron Storage 5
1.5.3. Iron Excretion 6
1.5.4. Systemic Iron Homeostasis 6
1.5.5. Disorders of Iron Homeostasis 6
1.6.RECOGNIZING IDA ANEMIA 7
1.6.1. Clinical Diagnosis 7
1.6.2. Laboratory Diagnosis 8
1.7.PREOPERATIVE ANEMIA 10
1.7.1. Identifying the problem 10
1.7.2. Epidemiology of Blood Transfusion and Outcomes 11
1.7.3. Strategies for perioperative blood conservation 12
1.7.4. Solving the preoperative anemia problem 14
2. CHAPTER II: INTRAVENOUS IRON THERAPY TO CORRECT ANEMIA BEFORE
MAJOR SURGERY: STUDY PROTOCOL FOR SYSTEMATIC REVIEW AND META-
ANALYSIS 15
2.1.ABSTRACT 15
2.1.1. Background 15
2.1.2. Methods/design 15
2.1.3. Discussion 16
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2.2.BACKGROUND 17
2.2.1. Epidemiology of preoperative anemia 17
2.2.2. Epidemiology of blood transfusion and outcomes 17
2.2.3. Strategies for perioperative blood conservation 19
2.2.4. Preoperative intervention: prophylactic iron therapy 20
2.3.METHODS/DESIGN 23
2.3.1. Search strategy 23
2.3.2. Inclusion criteria 23
2.3.3. Exclusion criteria 24
2.3.4. Primary outcomes 24
2.3.5. Secondary outcomes 25
2.3.6. Study screening 25
2.3.7. Data abstraction 26
2.3.8 Assessment of methodological quality 27
2.4.STUDY SYNTHESIS PLAN 27
2.4.1. Analysis plan 27
2.4.2. Meta-analysis 28
2.4.3. Sensitivity analysis, subgroup analysis, and meta-regression analysis 29
2.4.4. Assessment of publication biases 30
2.4.5. Grading the strength of the evidence 30
2.5.DISCUSSION 31
2.5.1. Strengths of our meta-analysis 32
2.5.2. Limitations 33
2.5.3. Future research and policy implications of our meta-analysis 33
3. CHAPTER III (PAPER-II): ROLE OF PREOPERATIVE INTRAVENOUS IRON
THERAPY TO CORRECT ANEMIA BEFORE MAJOR SURGERY: A SYSTEMATIC REVIEW
AND META-ANALYSIS 34
3.1.ABSTRACT 34
3.1.1. Background 34
3.1.2. Objective 34
3.1.3. Methods/Design 35
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3.1.4. Results 36
3.1.5. Conclusions 37
3.2.BACKGROUND 43
3.3.OBJECTIVES 45
3.4.PATIENTS AND METHODS 45
3.4.1. Protocol and Registration 45
3.4.2. Study Screening 47
3.4.3. Modified Article Selection Criteria 47
3.4.4. Data Extraction 49
3.4.5. Assessment of the Risk of Bias 49
3.4.6. Data Synthesis and Analysis: 50
3.5.RESULTS 53
3.5.1. Risk of Bias Assessment 58
3.5.2. Exposure for allogeneic blood transfusion 61
3.5.3. Hemoglobin concentration change 66
3.5.4. Hematocrit value % 69
3.5.5. Ferritin levels 70
3.5.6. Transferrin saturation values (TSAT %) 73
3.5.7. Reticulocyte percentage or counts 74
3.5.8. Mean corpuscular hemoglobin (MCH) level (pg/cell) 76
3.5.9. Mean corpuscular hemoglobin concentration (MCHC) level (g/L) 77
3.5.10. Mean corpuscular volume or mean cell volume (MCV) level (fL). 78
3.5.11. Serum iron (mol/l) 79
3.5.12. Adverse events 80
3.5.13. Mortality 82
3.5.14. Infection 83
3.5.15. Hospital length of stay 84
3.5.16. Quality of life 85
3.6.DISCUSSION 85
3.7.CONCLUSION 96
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