Erythropoietin with iron supplementation for preoperative anaemia in non‐cardiac surgery
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
We aim to evaluate the efficacy and safety of preoperative erythropoietin (rHuEPO) with supplemental iron (parenteral or oral) in reducing perioperative allogeneic red blood cell transfusions in preoperatively anaemic people undergoing non‐cardiac surgery.
Background
Description of the condition
Anaemia is defined by the World Health Organization (WHO) as a haemoglobin concentration less than 12 g/dL in non‐pregnant adult women and less than 13 g/dL in adult men. Anaemia before surgery (preoperative anaemia) is common among people undergoing non‐cardiac surgery with a prevalence from 27% reported in Baron 2014, to 39% reported in Musallam 2011. Preoperative anaemia is associated with an increased requirement for allogenic red blood cell transfusion and postoperative morbidity and mortality (Jans 2014; Munoz 2008; Munoz 2012; Musallam 2011), as well as a prolonged postoperative hospital stay and increasing perioperative costs (Shander 2010). Haemoglobin levels of 10 g/dL were considered to be standard threshold levels for transfusion (Blair 1986; McIntyre 2004). Allogeneic red blood cell transfusion per se is an important risk factor for mortality, infection, pneumonia, and sepsis (Jans 2014; Morton 2010). In addition, red blood cell resources due to demographic changes are contemporaneously decreasing (Greinacher 2011).
Description of the intervention
Pre‐ and intraoperative strategies to avoid transfusion in general and in the case of preoperative anaemia are recommended in the guidelines of the Network for the Advancement of Transfusion Alternatives (NATA) (Goodnough 2011), and as a part of the guidelines of the European Society of Anaesthesiology for the management of severe perioperative bleeding (Kozek‐Langenecker 2013). The guidelines recommend the use of supplemental iron ‐ oral or intravenous ‐ (grade of recommendations ‐ European Society of Anaesthesiology: 1B; NATA: 1C) in preoperative iron deficiency; and treatment with erythropoiesis‐stimulating agents (ESA) when iron deficiency has been ruled out (grade of recommendations ‐ European Society of Anaesthesiology: 2A); or corrected or both (grade of recommendations ‐ NATA: 2A) (Goodnough 2011).
ESA are recombinant erythropoietin preparations with an amino acid sequence comparable to endogenous human erythropoietin (Jelkmann 2013). Recombinant human erythropoietin (rHuEPO) is the most often used substance of the ESA group. After publications of both guidelines, several studies were conducted addressing the application of rHuEPO in combination with intravenous or oral iron in people with preoperative anaemia in non‐cardiac surgery (David 2013; Feagan 2000; Weber 2005). These studies were mainly focused on the haemoglobin concentration and the proportion of participants with need for allogenic red blood cell transfusion receiving the intervention of interest.
rHuEPO acts as a growth factor on progenitor cells and stimulates the proliferation and differentiation of red cell precursors in the bone narrow and can increase erythropoiesis, resulting in increased haemoglobin levels and haematocrit in anaemic people. After parenteral application of rHuEPO in clinically relevant single doses of 50 IU/kg body weight, the drug is eliminated at a first‐order kinetic rate followed by a rapid distribution phase (Jelkmann 2013). After subcutaneous administration, peak plasma concentrations of rHuEPO are achieved after 12 to18 hours, but the slow absorption allows for about 30% lower drug requirements compared to intravenous application (Jelkmann 2013).
One of the first investigations examined the safety and efficacy of rHuEPO in reducing the need for allogeneic blood transfusion in non‐cardiac surgery (Laupacis 1993). They proved rHuEPO reduced the need for perioperative allogeneic transfusion without any increased risk of deep venous thrombosis, high blood pressure, or other adverse experiences (Laupacis 1993). When preoperative anaemic participants scheduled for primary hip arthroplasty received rHuEPO with oral iron application starting four weeks before surgery, rHuEPO significantly reduced the overall need for perioperative allogeneic transfusion as well as increased the haemoglobin concentration. The incidence of thromboembolic events did not differ among the different regimens. ESA treatment supplemented with oral or intravenous iron in preoperative anaemic participants undergoing major orthopaedic surgery led to increased haemoglobin values in the postoperative period and reduced the transfusion rates (Weber 2005). Concomitantly, ESA treatment delivered no significant effect on postoperative recovery (time to ambulation, time to discharge, and infection rate). However, postoperative recovery was significantly impaired when participants were transfused.
Similar to the findings for non‐cardiac surgery, the use of rHuEPO with intravenous iron in anaemic participants before off‐pump coronary bypass surgery confirmed an increase of the haemoglobin concentration and a decrease of allogenic blood transfusion in the rHuEPO‐treated group (Weltert 2010). On the other hand a systematic Cochrane Review evaluated the efficacy of rHuEPO, pre‐ and perioperatively, in reducing allogeneic blood transfusions and improving haemoglobin, quality of life, recurrence rate, mortality, and survival, following colorectal surgery, but concluded that the occurrence of thrombotic events did not increase (Devon 2009). The authors concluded that there was no sufficient evidence supporting a recommendation for pre‐ and perioperative rHuEPO for any mentioned outcome, apart from haemoglobin levels (Devon 2009).
Iron deficiency and anaemia mediated by chronic diseases are common causes of preoperative anaemia. Early preoperative oral iron supplementation may be suitable to refill iron stores (Casalduero 2008). Due to gastrointestinal side effects and poor intestinal absorption parenteral iron application can be indicated. In the case of persisting iron deficiency, despite adequate iron application, or in the case of severe preoperative anaemia, the use of rHuEPO should be considered. In most of the investigations and in clinical practice, rHuEPO application is mostly supplemented by oral or parenteral iron (Laupacis 1993; Na 2011; Weber 2005). It has been suggested that people may develop a functional iron deficiency postoperatively due to a surge in circulating inflammatory cytokines (Lin 2013). In this state of iron‐restricted erythropoiesis, iron stores are normal but unavailable for erythropoiesis, and intravenous iron is required to restore levels of accessible transferrin‐bound iron (Lin 2013). The role of iron therapy without rHuEPO in people with preoperative anaemia will be addressed in an upcoming Cochrane Review (Ng 2015).
How the intervention might work
Depending on the degree and the cause of preoperative anaemia, a weekly administration over four weeks prior to operation in preoperative anaemic participants was normally used in the clinical trials (Weber 2005). rHuEPO has a half‐life of one day, but its effect is evident only five days later, when the induced red cell proliferation is mature enough for release into the circulation (Fisher 2003). People should receive iron supplementation throughout the course of rHuEPO therapy, to optimize the dose‐response relationship for rHuEPO therapy and red blood cell production in the presurgical setting (Goodnough 2011).
An internal turnover of 20 mg of iron per day is required for erythropoiesis in the bone marrow (Munoz 2008), which is available by iron recycling from aging erythrocytes and by daily exchange within iron‐containing enzymes and iron stores (Steinbicker 2013). An amount of 1 mg to 2 mg is compensated by iron absorption from the diet. Oral iron supplementation may be less effective due to an insufficient absorption of iron and increased gastrointestinal side effects. Nevertheless, in terms of a supportive iron therapy in preoperative anaemic people undergoing ESA treatment, iron is still administrated orally in a daily dose of 200 mg (Feagan 2000). To bypass the reduced absorption of oral iron, recent investigations recommended the parenteral application of iron in case of rHuEPO treatment in preoperative anaemic people (Ralley 2014). People diagnosed with preoperative anaemia due to iron deficiency or chronic disease may better respond to preoperative treatment with intravenous iron, depending on the timescale before surgery, tolerance of iron, and iron status (Goodnough 2011). In case of an insufficient increase in haemoglobin, an additional treatment with rHuEPO may be indicated.
Why it is important to do this review
One of the main therapeutic strategies to avoid red blood cell transfusion in preoperative anaemic people is preoperative treatment with ESAs and iron, aiming to normalise the haemoglobin concentration and red cell mass.
Preoperative anaemia seems to be affected by gender. Females suffer from a higher risk of preoperative anaemia and higher rates of red blood cell transfusion compared to males (Khanna 2003; Musallam 2011).
The recommendations of ESAs and iron in the NATA guidelines, as well as partly in the European Society of Anaesthesiology guidelines, are based on a limited number of randomized controlled trials (RCTs) in participants with preoperative anaemia. The major clinical impact of preoperative anaemia on outcome, and the associated social economic burden, suggest that a contemporary update of the evidence for or against the use of rHuEPO in combination with iron would be appropriate. This Cochrane Review should add systematic evidence on the use of rHuEPO therapy with supplemented iron in people with preoperative anaemia, as well as safety data, and the influence of both gender and age on the treatment of preoperative anaemia. Furthermore, this Cochrane Review will update and strengthen existing recommendations.
There are currently several studies which are partly summarized in systematic reviews investigating the use of rHuEPO and iron in people with different causes of anaemia, or in people scheduled for autologous blood donation, but there are a limited number of studies investigating rHuEPO with iron supplementation in the case of preoperative anaemia. Therefore, recommendations for rHuEPO in preoperative anaemia are mainly based on studies of rHuEPO augmented with preoperative autologous blood donation (Goodnough 2011; Kozek‐Langenecker 2013). This existing gap between current recommendations based on a limited body of evidence, and clinical practice, requires a current evaluation of the body of evidence of rHuEPO in conjunction with iron supplementation in preoperative anaemic people.
Objectives
We aim to evaluate the efficacy and safety of preoperative erythropoietin (rHuEPO) with supplemental iron (parenteral or oral) in reducing perioperative allogeneic red blood cell transfusions in preoperatively anaemic people undergoing non‐cardiac surgery.
Methods
Criteria for considering studies for this review
Types of studies
We will include randomized controlled trials (RCTs) and cluster‐randomized trials. We will include trials which are only published in abstract form, even if sufficient information is not available. We will place the abstract in the section, 'Awaiting classification'.
Types of participants
We will include all adult participants (older than 18 years of age), irrespective of gender and type of non‐cardiac surgery, with mild or severe preoperative anaemia (WHO criteria on haemoglobin levels: m < 13 g/dL, f < 12 g/dL).
We will exclude studies which focus on perioperative anaemia in pregnant women undergoing, for example, a caesarean section.
Types of interventions
We will include all RCTs with preoperatively (day of decision for surgery or day of surgery) started rHuEPO administration (subcutaneous or parenteral) and parenteral or oral iron supplementation of any dose and duration. The types of interventions will be:
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erythropoietin (rHuEPO) (subcutaneous or parenteral) in combination with iron (oral or parenteral).
Participants will receive different doses of rHuEPO and iron supplementation, depending on the type and severity of anaemia.
We will compare the outcomes between the intervention and placebo or no treatment/standard of care group (as per each trial protocol). Where the effect of rHuEPO was combined with another co‐intervention (except iron), we will exclude the trial.
Types of outcome measures
Primary outcomes
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Need for allogeneic red blood cell transfusion (no autologous transfusion or other transfusions like haemostatic blood products in the form of fresh frozen plasma or thrombocytes), measured in transfused participants during surgery (intraoperative and postoperative (up to five days after operation, depending on operating procedure)).
Secondary outcomes
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Haemoglobin level preoperatively (directly before surgery).
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Amount of blood transfused per participant, measured in units (where one unit contains approximately 450 mL of blood) during surgery (intraoperative and postoperative (up to three to five days after operation, depending on operating procedure)).
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Mortality (within 30 days after surgery).
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Length of hospital stay.
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Adverse events (e.g. thromboembolism, hypertension, allergic reaction, headache), measured in numbers of participants with adverse events between day of surgery and discharge from hospital.
Search methods for identification of studies
Electronic searches
We will search the following databases.
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Cochrane Central Register of Controlled Trials (CENTRAL) (latest Issue).
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Ovid MEDLINE(R), Ovid MEDLINE(R) In‐Process & Other Non‐Indexed Citations, Ovid MEDLINE(R) Daily and Ovid OLDMEDLINE(R) (1946 to most recent date available).
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Embase Classic + Embase (OvidSP) (1947 to most recent date available).
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ISI Web of Science: Science Citation Index Expanded (SCI‐EXPANDED) (1970 to most recent date available).
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ISI Web of Science: Conference Proceedings Citation Index Science (CPCI‐S) (1990 to most recent date available).
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ClinicalTrials.gov (clinicaltrials.gov).
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WHO International Clinical Trials Registry Platform (ICTRP) Search Portal (apps.who.int/trialsearch).
For detailed search strategies, see Appendix 1.
If we detect additional relevant key words during any of the electronic or other searches, we will modify and document revised electronic search strategies.
We will not impose any language restriction.
Searching other resources
We will search the following conference proceedings electronically and manually for the years not included in CENTRAL.
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American Society of Anesthesiology (ASA) (last four years).
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European Society of Anaesthesiology (last four years).
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German Society of Anaesthesiology and intensive Care (DGAI) (last 4 years).
When necessary, we will contact authors of studies containing unclear information in order to ensure the accuracy of the review.
We plan to contact experts in the field of anaesthesiology, non‐cardiac surgery, and perioperative medicine to identify any potentially eligible but unpublished studies or ongoing studies which have not yet been published.
We will also search the reference lists of retrieved studies.
Data collection and analysis
Selection of studies
Two review authors (LK, AH) will independently scan the retrieved titles and abstracts of all studies for their eligibility for inclusion and apply predefined selection criteria to identify all potentially eligible studies. If a decision on inclusion cannot be made on the basis of a review of the title and abstract, we will obtain a full‐text of the manuscript to assess eligibility. We will resolve disagreements in the selection process through consensus with all review authors. We will document the overall number of studies identified, excluded, or included, with reasons at every stage of searching and screening in sufficient detail to complete a PRISMA flow diagram (Moher 2009).
Data extraction and management
Two review authors (CvH, LK) will extract data relevant to each study using a predefined standardized data extraction form. We will list all necessary information, including general information, study characteristics, participant characteristics, type of intervention or control, and outcome in the table of 'Characteristics of included studies'. We will resolve disagreements by discussion between all review authors. When information is unclear, we will attempt to contact the study investigators for further details. We will enter data into Review Manager 5 software (RevMan 2014), and check for accuracy (AH).
Assessment of risk of bias in included studies
Two review authors (LK and CvH) will independently assess all eligible studies for their risk of bias (assessment of methodological quality) using the methods suggested in Chapter 8.5 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011).
We will consider the following domains:
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Random sequence generation (selection bias)
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Allocation concealment (selection bias)
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Blinding of participants, personnel and outcomes assessors (performance bias)
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Blinding of outcome assessment (detection bias)
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Incomplete outcome data (attrition bias)
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Selective outcome reporting (reporting bias)
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Other sources of bias
We will make judgements using three measures ‐ high, low and unclear risk of bias. We will record this judgement in "Risk of bias" tables and will present a summary "Risk of bias" figure. To improve the transparency of the judgements, we will include quotations from the full‐ text article or from supplemental information from the trial author in the "notes" section of the "Risk of bias" table.
Measures of treatment effect
We will carry‐out statistical analysis using Cochrane's statistical software, Review Manager 5 (RevMan 2014).
For dichotomous data, e.g. red blood cell transfusion, we will use the risk ratio (RR), obtained from the intervention and control event rates.
For continuous outcomes, e.g. preoperative haemoglobin level, we will use the mean difference (MD) or the standardized mean difference (SMD) estimated from means and standard deviations (SDs) of the intervention and control groups.
For time‐to‐event outcomes, we will use hazard ratios (HRs).
Unit of analysis issues
The unit of analysis is the participant.
Cluster‐randomized trials
We will include cluster‐randomized trials in the analyses along with individually‐randomized trials. We will adjust their standard errors using the methods described in the Cochrane Handbook for Systematic Reviews of Interventions using an estimate of the intracluster correlation coefficient (ICC) derived from the trial (if possible), from a similar trial, or from a study of a similar population (Higgins 2011). If we use ICCs from other sources, we will report this and conduct sensitivity analyses to investigate the effect of variation in the ICC. If we identify both cluster‐randomized trials and individually‐randomized trials, we plan to synthesize the relevant information. We will consider it reasonable to combine the results from both if there is little heterogeneity between the study designs and the interaction between the effect of intervention and the choice of randomization unit is considered to be unlikely. We will also acknowledge heterogeneity in the randomization unit and perform a sensitivity analysis to investigate the effects of the randomization unit.
Multi‐armed studies
We will overcome a unit‐of‐analysis error for studies that could contribute multiple comparisons, by either combining groups to create a single pair‐wise comparison or split the shared group into two or more groups with smaller sample size, and include two or more reasonably independent comparisons if the presented data in the trials allow us to do so. The degrees of freedom will be adjusted appropriately.
Dealing with missing data
If there are missing data, we will contact the relevant trial authors to obtain further information. If we do not receive the information required, we will attempt to calculate or estimate the SD from other values and information in the paper using methods described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). If it is not possible to impute values, we will not include such data in the meta‐analysis.
Assessment of heterogeneity
In the case of trials being sufficiently similar in clinical and methodological design, we will include them in a meta‐analysis.
We will evaluate the extent of heterogeneity by visually examining the forest plots and we will use the I2 statistic to quantify it. We will use the I2 statistic to assess
substantial heterogeneity. The I2 statistic describes the percentage of total variation across trials that is due to heterogeneity rather than sampling error.
We will consider substantial statistical heterogeneity if I2 > 50% (Higgins 2011). We will investigate possible causes of heterogeneity via prespecified subgroup analyses. If prespecified subgroup analyses do not explain the statistical heterogeneity, we plan to perform a sensitivity analysis.
Assessment of reporting biases
If there are 10 or more studies in the meta‐analysis, we will investigate reporting biases (such as publication bias) using funnel plots. We will assess funnel plot asymmetry visually. If asymmetry is suggested by a visual assessment, we will perform exploratory analyses to investigate it.
Data synthesis
We will estimate summary statistics by random‐effects meta‐analysis using inverse variance estimators for RR, MD, and SMD. For HRs, we will summarize log HRs with standard errors (SEs) using generic inverse variance methods.
We will present results as summary RRs, MDs, SMDs, or HRs with the z statistic, P value and 95% confidence interval (CI) in tables and forest plots. Statistical
significance will be declared if P < 0.05 or the 95% CI of the summary statistic does not cross the identity value.
When I2 > 50% among trials, and the trial estimates are in different directions, we will evaluate heterogeneity. We will not present orphan studies (comparisons with only a single included study) in an analysis with forest plots, but will place them in an additional table.
Subgroup analysis and investigation of heterogeneity
If we identify heterogeneity (I2 > 50%), we will investigate it using subgroup analysis and sensitivity analysis. We plan to carry‐out the following subgroup analyses.
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Different participant populations.
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Different dosages of rHuEPO: 2.1 high dose (500 IU to 600 IU subcutaneous/kg body weight); 2.2 low dose (150 IU to 300 IU subcutaneous/kg body weight)
We will compare subgroups for qualitative interaction (direction of effect reversed) and quantitative interaction (magnitude of effect differs). We will assess the Review Manager 5 calculated interaction z statistic with P value to declare a difference between subgroups (RevMan 2014).
Sensitivity analysis
We will conduct sensitivity analyses based on the overall 'Risk of bias' judgement (low risk of bias versus unclear or high risk of bias).
If we identify sufficient trials, we plan to conduct a sensitivity analysis comparing the results using all trials as follows.
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Using only those RCTs with high methodological quality (studies that are classified as having a 'low risk of bias' (Higgins 2011). It is unlikely that we will find many trials at low risk of bias in all items. To manage this, we plan to choose three core domains instead of all: generation of allocation sequence, incomplete outcome data, and selective reporting bias.
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For dichotomous outcomes in studies with possible attrition bias, we plan to conduct 'best‐case' and 'worst‐case' scenarios. The 'best‐case' scenario will be that all participants with missing outcomes in the experimental intervention group have good outcomes, and all those with missing outcomes in the control intervention group have poor outcomes; the 'worst‐case' scenario is the converse (Higgins 2011).
We will also evaluate the risk of attrition bias, as estimated by the percentage of participants lost.
'Summary of findings' table and GRADE
We will use the principles of the GRADE system to assess the quality of the body of evidence associated with the following outcomes (Guyatt 2008; Guyatt 2011; Schuenemann 2009).
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Need for allogeneic red blood cell transfusion (no autologous transfusion or other transfusions like haemostatic blood products in the form of fresh frozen plasma or thrombocytes), measured in transfused participants during surgery (intraoperative and postoperative (up to three to five days after operation, depending on operating procedure)).
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Haemoglobin level preoperatively (directly before surgery).
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Amount of blood transfused per participant, measured in units (where one unit contains approximately 450 mL of blood) during surgery (intraoperative and postoperative (up to three to five days after operation, depending on operating procedure)).
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Mortality (within 30 days after surgery).
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Length of hospital stay.
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Adverse events (e.g. thromboembolism, hypertension, allergic reaction, headache), measured in numbers of participants with adverse events between day of surgery and discharge from hospital.
We will produce a 'Summary of findings' table using the GRADEpro software (GRADEpro GDT 2014). The GRADE approach appraises the quality of a body of evidence based on the extent to which one can be confident that an estimate of effect or association reflects the item being assessed (Guyatt 2008; Guyatt 2011;
Schuenemann 2009). The quality of a body of evidence takes into consideration within‐study risk of bias (methodological quality), the directness of the evidence, heterogeneity of the data, precision of effect estimates, and risk of publication bias.
