The Effect of Combined Iron Protocols on Perioperative Allogeneic Transfusion

Study Overview
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Brief Summary
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Previous studies have shown that perioperative intravenous iron has a beneficial effect on patients with perioperative anaemia. To assess whether a combined iron supplementation regimen can reduce perioperative allogeneic blood transfusions in patients with iron deficiency anaemia undergoing major cardiac surgery under haemodynamic anaesthesia, a multicentre randomised clinical trial (CIPAT study) will be conducted. In the CIPAT study, patients undergoing elective major cardiac surgery under general anaesthesia will be randomly allocated to a control group and a combined iron supplementation group. Patients in the combined iron supplementation group will receive a combination iron supplementation regimen of iron sucrose in combination with Human Erythropoietin and vitamin C three times in the week prior to surgery, while patients in the control group will receive the same dose of placebo three times in the week prior to surgery. The primary endpoint is the volume of allogeneic erythrocyte infusion from the start of surgery to 5 days postoperatively. It is hypothesised that patients in the combined iron supplementation group will have fewer perioperative allogeneic red blood cell transfusions than those in the control group.

Detailed Description
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The objective of this study is to examine the potential of iron sucrose in conjunction with human erythropoietin and vitamin C to mitigate the need for perioperative allo-erythrocyte infusion in patients undergoing their initial elective major cardiac surgery. This will be achieved by assessing outcome measures including the quantity of perioperative allo-erythrocyte transfusion and the alteration in perioperative haemoglobin levels. The sample size calculation for this study involved a randomised controlled trial with a parallel design. The intervention group consisted of individuals receiving combination therapy, while the control group received a placebo. The primary outcome indicator observed in the study population was perioperative blood transfusion. Our centre's pre-trial data survey indicated a perioperative blood transfusion rate of 1.8 U in the control group. It was hypothesized that the combination therapy would result in a reduction of blood transfusion by at least 0.5 U.The blood transfusion in the combination therapy group was 1.3. Setting α=0.05 (bilaterally) with a degree of certainty=0.90. Using the bilaterally Mann-Whitney U or the Wilcoxon Rank-Sum test at the 0.05 level of significance (α ), when the mean difference of the null hypothesis was 0. Based on Poisson distribution, the sample size N1 = 188 for the combination treatment group and N2 = 188 cases for the placebo control group was calculated using PASS 21 software. Assuming a 20% loss-to-follow-up rate of study participants, a sample size of at least N1 = 188 ÷ 0.8 = 235 cases and N2 = 188 ÷ 0.8 = 235 cases would be required. In the end, 240 study subjects were included in the combination treatment group and 240 in the placebo control group, for a total of 480 cases.

Official Title
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Effect of Iron Sucrose Combined With Human Erythropoietin and Vitamin C on Perioperative Allogeneic Red Blood Cell Infusion in Major Cardiac Surgery

Conditions
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Transfusion, Anemia, Iron Deficiency Anemia, Perioperative, Cardiac Surgery

Intervention / Treatment
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* Drug: Iron sucrose, Human Erythropoietin Injection, Vitamin C
* Drug: Saline


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants must be at least 18 years of age. The initial elective major cardiac surgery should encompass procedures such as coronary artery bypass grafting (CABG), valve surgery, or a combination of both. Iron deficiency anemia is defined as having a ferritin level below 100 μg/L or a ferritin level below 300 μg/L accompanied by a transferrin saturation below 25%. Additionally, hemoglobin levels should range between 90 and 130 g/L for men or between 90 and 120 g/L for women. The American Society of Anesthesiologists (ASA) classification should fall within Grade 1-3. Prior to participation, the patient or their legal representative must provide informed consent. Exclusion Criteria: Contraindications for the administration of iron sucrose, ascorbic acid, or rHuEPO. Presence of a temperature exceeding 37.5 °C or the utilization of non-prophylactic antibiotics. Individuals with a weight equal to or less than 50kg. Individuals with a family history of haemochromatosis or thalassaemia, or those with a transferrin saturation level exceeding 50% or a documented history of iron overload. Presence of other known haematological disorders such as folic acid or vitamin B12 deficiency, haemolytic anaemia, haemoglobinopathies, iron granulocytic anaemia, G6PD deficiency, etc. Requirement for emergency surgical intervention. Severe hepatic or renal impairment, ALT >3 times the upper limit of normal value or AST >3 times the upper limit of normal value, creatinine >1.5 times the upper limit of normal value Pregnant or lactating women history of blood transfusion, intravenous iron or ascorbic acid use within 12 weeks prior to surgery Acute blood loss, gastrointestinal bleeding, etc. in the preoperative period.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Intervention group<br>Preoperative randomization was conducted, followed by a three-day regimen in the week preceding surgery, involving the administration of intravenous iron sucrose at a dosage of 200 mg per day, vitamin C at a dosage of 2 g per day, and subcutaneous administration of Human Erythropoietin Injection at a dosage of 150 IU per kilogram. | Drug: Iron sucrose, Human Erythropoietin Injection, Vitamin C<br>* The participants were administered a combined iron supplementation regimen consisting of iron sucrose,Human Erythropoietin Injection, and vitamin C, three times throughout the preoperative week.<br>|
| Placebo Comparator: Control group<br>Preoperative randomization was conducted, followed by the administration of 200 ml of saline via intravenous infusion and 1 ml of saline via subcutaneous injection for three consecutive days in the week preceding the surgery. | Drug: Saline<br>* The participants were administered a placebo regimen consisting of saline three times in the week preceding the surgical procedure.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Perioperative allogeneic red blood cell transfusion volume | The volume of allogeneic red blood cell transfusions during the perioperative period. | From the initiation of the surgical procedure until five days post-surgery. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The quantity and percentage of allogeneic blood products utilized during the perioperative period. | This encompasses blood components such as plasma and platelets, erythrocytes. | From the initiation of the surgical procedure until the patient's release from the hospital or the 30th day following the operation, whichever occurs earlier. | 
| The alterations in perioperative haemoglobin levels. | Haemoglobin levels were assessed at various time intervals. | From the point of randomisation until 90± 7 days following the surgical procedure. | 
| The alterations in ferritin levels and serum total iron binding capacity during the perioperative period. | Ferritin and serum total iron binding capacity values were assessed at various time intervals. | From the point of randomisation until 90± 7 days following the surgical procedure. | 
| The alterations in reticulocyte levels during the perioperative period. | Reticulocyte levels were measured at various time intervals. | From the point of randomisation until 90± 7 days following the surgical procedure. | 
| NYHA classification of cardiac function | NYHA classification of cardiac function values were assessed at various time intervals. | From the point of randomisation until 90± 7 days following the surgical procedure. | 
| The score measuring the quality of life after surgery. | The findings are presented based on the EQ VAS score (0-100), which reflects the overall self-assessed health status. A higher score indicates a better health status. Additionally, the results are reported using the EQ-5D-3L Effectiveness Index (EQ-5D-3L) values (5-15), where a lower EQ-5D-3L value signifies a better state of health. | The time intervals of 30±7 days and 90±7 days were observed following the surgical procedure. | 
| Incidence of perioperative complication within 90 days after major cardiac surgery | The potential postoperative complications within a 90-day timeframe encompass myocardial injury after noncardiac surgery (MINS), acute kidney injury (AKI), serious adverse events (SAE), congestive heart failure, respiratory failure, and various infections. | Within 90 days after surgery | 
| The mortality rate within a 90-day postoperative period. | The mortality rate within a 90-day postoperative period. | Within 90 days after surgery | 
| length of stay in hospital | he time period from admission to the hospital to discharge | through study completion, an average of 14 days | 
| Length of stay in ICU | The time period from admission to ICU after surgery to move out from ICU to normal ward | through study completion, an average of 4 days |