The use of erythropoietin plus iron to correct anaemia before surgery to reduce the risk of blood transfusion

Background

Erythropoietin is a hormone produced by the kidneys. It stimulates the bone marrow to produce more red blood cells (RBCs). Erythropoietin is frequently used to correct anaemia caused by a reduced number of red blood cells or low haemoglobin concentration in cases of chronic renal failure. The haemoglobin in red blood cells carries oxygen around the body. 

Adult patients undergoing non-cardiac surgery, such as bone (orthopaedic) surgery, have blood tests before surgery to check their general health. Many individuals are found to be anaemic, which means they may need RBC transfusions with donor blood before, during, or after surgery to increase their haemoglobin concentrations. Giving donor blood can cause an allergic reaction such as a rash, headache, fever, raised blood pressure, temporary loss of kidney function, and blood clotting. If it is possible to diagnose the cause of the anaemia before the operation, then erythropoietin can be used together with iron to treat most of the causes of anaemia.

Review question

We wanted to know whether erythropoietin therapy in combination with iron before surgery is effective in reducing the need for RBC transfusions in the immediate recovery period in anaemic adults undergoing non-cardiac surgery, compared to not giving the treatment.

Erythropoietin therapy can be given by injection below the skin (subcutaneously) or into a vein (intravenously). Iron can be given by mouth (delivered into the gut) or intravenously.

Study characteristics

We identified 12 randomized controlled trials involving a total of 1880 adult participants who were anaemic. The participants were randomly1 assigned to a treatment group receiving erythropoietin and iron or a control group. The control group received either placebo (dummy treatment) or no treatment with or without iron. We looked at the following outcomes: haemoglobin concentrations, need for transfusion, the amount of RBC units transfused per participant, adverse events, and any deaths. Erythropoietin was given either in a low dose (150 to 300 international units (IU)/kg body weight) or high dose (500 to 600 IU/kg body weight).

The evidence is current to August 2019.

Key results

We found that giving erythropoietin with iron supplementation reduces the need for RBC transfusions amongst participants (12 studies; 1880 participants). Higher doses of erythropoietin with iron increased haemoglobin concentrations before surgery (7 studies; 1186 participants), but at lower doses any effect was unclear. The number of units of RBCs required was not changed.

Adverse events did not differ between study groups (10 studies; 1722 participants). Only two studies reported on deaths, with no apparent differences between groups.

We are uncertain whether adults suffering from preoperative anaemia who were treated with erythropoietin and iron had shorter hospital stays than adults with preoperative anaemia who did not receive preoperative treatment before surgery (3 studies; 293 participants).

Quality of the evidence

The quality of the evidence was moderate for the outcome need for RBC transfusion, due to some inconsistency between eligible trials; low for haemoglobin concentration before surgery due to inconsistency between eligible trials and risk of bias; moderate for the amount of RBC units transfused, due to differences in how studies measured the number of units; low for length of hospital stay due to inconsistency in findings and imprecision of the studies; and moderate for mortality and adverse events and death, as only a small number of events were reported.

Authors' conclusions: 

Moderate-quality evidence suggests that preoperative rHuEPO + iron therapy for anaemic adults prior to non-cardiac surgery reduces the need for RBC transfusion and, when given at higher doses, increases the haemoglobin concentration preoperatively. The administration of rHuEPO + iron treatment did not decrease the mean number of units of RBC transfused per patient.

There were no important differences in the risk of adverse events or mortality within 30 days, nor in length of hospital stay. Further, well-designed, adequately powered RCTs are required to estimate the impact of this combined treatment more precisely.

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Background: 

Approximately 30% of adults undergoing non-cardiac surgery suffer from preoperative anaemia. Preoperative anaemia is a risk factor for mortality and adverse outcomes in different surgical specialties and is frequently the reason for blood transfusion. The most common causes are renal, chronic diseases, and iron deficiency. International guidelines recommend that the cause of anaemia guide preoperative anaemia treatment. Recombinant human erythropoietin (rHuEPO) with iron supplementation has frequently been used to increase preoperative haemoglobin concentrations in patients in order to avoid the need for perioperative allogeneic red blood cell (RBC) transfusion.

Objectives: 

To evaluate the efficacy of preoperative rHuEPO therapy (subcutaneous or parenteral) with iron (enteral or parenteral) in reducing the need for allogeneic RBC transfusions in preoperatively anaemic adults undergoing non-cardiac surgery.

Search strategy: 

We searched CENTRAL, Ovid MEDLINE(R), Ovid Embase, ISI Web of Science: SCI-EXPANDED and CPCI-S, and clinical trial registries WHO ICTRP and ClinicalTrials.gov on 29 August 2019.

Selection criteria: 

We included all randomized controlled trials (RCTs) that compared preoperative rHuEPO + iron therapy to control treatment (placebo, no treatment, or standard of care with or without iron) for preoperatively anaemic adults undergoing non-cardiac surgery.

We used the World Health Organization (WHO) definition of anaemia: haemoglobin concentration (g/dL) less than 13 g/dL for males, and 12 g/dL for non-pregnant females (decision of inclusion based on mean haemoglobin concentration). We defined two subgroups of rHuEPO dosage: 'low' for 150 to 300 international units (IU)/kg body weight, and 'high' for 500 to 600 IU/kg body weight.

Data collection and analysis: 

Two review authors collected data from the included studies. Our primary outcome was the need for RBC transfusion (no autologous transfusion, fresh frozen plasma or platelets), measured in transfused participants during surgery (intraoperative) and up to five days after surgery. Secondary outcomes of interest were: haemoglobin concentration (directly before surgery), number of RBC units (where one unit contains 250 to 450 mL) transfused per participant (intraoperative and up to five days after surgery), mortality (within 30 days after surgery), length of hospital stay, and adverse events (e.g. renal dysfunction, thromboembolism, hypertension, allergic reaction, headache, fever, constipation).

Main results: 

Most of the included trials were in orthopaedic, gastrointestinal, and gynaecological surgery and included participants with mild and moderate preoperative anaemia (haemoglobin from 10 to 12 g/dL). The duration of preoperative rHuEPO treatment varied across the trials, ranging from once a week to daily or a 5-to-10-day period, and in one trial preoperative rHuEPO was given on the morning of surgery and for five days postoperatively.

We included 12 trials (participants = 1880) in the quantitative analysis of the need for RBC transfusion following preoperative treatment with rHuEPO + iron to correct preoperative anaemia in non-cardiac surgery; two studies were multiarmed trials with two different dose regimens.

Preoperative rHuEPO + iron given to anaemic adults reduced the need RBC transfusion (risk ratio (RR) 0.55, 95% confidence interval (CI) 0.38 to 0.80; participants = 1880; studies = 12; I2 = 84%; moderate-quality evidence due to inconsistency). This analysis suggests that on average, the combined administration of rHuEPO + iron will mean 231 fewer individuals will need transfusion for every 1000 individuals compared to the control group.

Preoperative high-dose rHuEPO + iron given to anaemic adults increased the haemoglobin concentration (mean difference (MD) 1.87 g/dL, 95% CI 1.26 to 2.49; participants = 852; studies = 3; I2 = 89%; low-quality evidence due to inconsistency and risk of bias) but not low-dose rHuEPO + iron (MD 0.11 g/dL, 95% CI −0.46 to 0.69; participants = 334; studies = 4; I2 = 69%; low-quality evidence due to inconsistency and risk of bias).

There was probably little or no difference in the number of RBC units when rHuEPO + iron was given preoperatively (MD −0.09, 95% CI −0.23 to 0.05; participants = 1420; studies = 6; I2 = 2%; moderate-quality evidence due to imprecision). 

There was probably little or no difference in the risk of mortality within 30 days of surgery (RR 1.19, 95% CI 0.39 to 3.63; participants = 230; studies = 2; I2 = 0%; moderate-quality evidence due to imprecision) or of adverse events including local rash, fever, constipation, or transient hypertension (RR 0.93, 95% CI 0.68 to 1.28; participants = 1722; studies = 10; I2 = 0%; moderate-quality evidence due to imprecision).

The administration of rHuEPO + iron before non-cardiac surgery did not clearly reduce the length of hospital stay of preoperative anaemic adults (MD −1.07, 95% CI −4.12 to 1.98; participants = 293; studies = 3; I2 = 87%; low-quality evidence due to inconsistency and imprecision).

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