efficacy and safety of erythropoietin and intravenous iron in perioperative blood management: a...

Transfusion Medicine Reviews 27 (2013) 221–234

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Transfusion Medicine Reviews

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Efficacy and Safety of Erythropoietin and Intravenous Iron in Perioperative BloodManagement: A Systematic Review

David M. Lin a,⁎, Estelle S. Lin b, Minh-Ha Tran c,d

a Lin Shin Hospital, Department of Medicine, Taichung City, Taiwanb Department of Medicine, University of California, Irvine Medical Center, Orange, CAc Department of Pathology and Laboratory Medicine, University of California Irvine School of Medicine, Orange, CAd Transfusion Medicine Service, Orange, CA

a b s t r a c ta r t i c l e i n f o

Conflict of interest statement: This study was perfo⁎ Corresponding author. David M. Lin, MD, MHA, Vis

Taiwan 40867.E-mail addresses: [email protected] (D.M. Lin), e

0887-7963/$ – see front matter © 2013 Elsevier Inc. Alhttp://dx.doi.org/10.1016/j.tmrv.2013.09.001

Article history:
Available online 15 October 2013
The use of erythropoietin (EPO) and intravenous (IV) iron as bloodless therapeutic modalities is beingexplored in the current era of restrictive transfusion strategies and perioperative blood management. It isunclear, however, whether the evidence in the literature supports their safety and efficacy in reducingperioperative red cell transfusions. Adhering to the Preferred Reporting Items for Systematic Reviews andMeta-Analysis guidelines, we conducted a systematic review to evaluate their use in a variety ofperioperative settings. We performed a literature search of English articles published between July 1997and July 2012 in MEDLINE via PubMed, The Cochrane Library, and CINAHL. Only studies with a comparatorgroup were eligible for inclusion. Twenty-four randomized controlled trials (RCTs) and 15 nonrandomizedstudies were included in the final review. Using the Cochrane risk of bias tool, 8 RCTs were assessed to be atlow risk for methodological bias. Of these, however, only 4 RCTs were adequately powered to detect areduction in transfusion rates. Patients with preoperative iron deficiency anemia may have an earlier andmore robust hemoglobin recovery with preoperative IV iron therapy than with oral iron supplementation. Ashort preoperative regimen of EPO, or a single dose of EPO plus IV iron in the preoperative or intraoperativeperiod, may significantly reduce transfusion rates (number needed to treat to avoid any transfusion rangedfrom 3 to 6). With regard to the safety of erythropoietin-stimulating agent therapy, IV iron appears to be aswell tolerated as oral iron; however, the incidence of severe anaphylactic-type reactions attributable to IViron is difficult to estimate in prospective trials because of its relatively infrequent occurrence. Furthermore,EPO may increase the risk of thromboembolism in spinal surgery patients who receive mechanicalantithrombotic prophylaxis in the perioperative period so pharmacological thromboprophylaxis is advised.Future low risk of bias, adequately powered prospective efficacy, and safety trials in various surgicalsettings that traditionally require red cell transfusions would be required to make evidenced-basedconclusions about the clinical significance of erythropoietin-stimulating agent as a transfusion avoidancestrategy in perioperative blood management.

rmed without external funding.iting Physician, Lin Shin Hospital, Department of Medici

[email protected] (E.S. Lin), [email protected] (M.-H. Tran).

l rights reserved.

© 2013 Elsevier Inc. All rights reserved.

Contents

Methods. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 222Protocol Registration and Eligibility Criteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 222Search Strategy and Information Sources . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 222Study Selection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 222Data Items and Extraction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 222Risk of Bias Assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 222

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222 D.M. Lin et al. / Transfusion Medicine Reviews 27 (2013) 221–234

Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 223Study Selection and Characteristics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 223Cochrane Risk of Bias Assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 223Intravenous Iron . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 223Erythropoietin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 223Erythropoietin Plus IV Iron . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 223

Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 224Efficacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 230Safety . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 231

Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 231Appendix A. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 231References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 233

Red blodd cell (RBC) transfusions are commonly used in theperioperative setting to rapidly optimize oxygen delivery to peripheraltissues. Despite increasingly restrictive donor selection criteria, donorinfectious diseases testing, and adherence to good manufacturingpractices, recipients of blood products remain at risk for transfusion-transmitted diseases, febrile and allergic transfusion reactions, andtransfusion-related immunomodulation, with the latter potentiallyassociated with higher rates of postoperative infections [1]. Althoughsome infectious complications are on the order of 1 in 1000000, non-infectious risks, such as allergic transfusion reactions, transfusion-asso-ciated circulatory overload, and transfusion-related acute lung injury, areorders of magnitudemore common, ranging in prevalence from 1 in 100to 1 in 10,000 products transfused [2]. These and other potential riskshave ledclinicians to seekbloodless strategies inperioperative setting [3].

Erythropoietin (EPO) is approved for patients with preoperativeanemia scheduled for elective, noncardiac, nonvascular surgery [4].A dose-comparison study by Goldberg et al [5] demonstrated thatonce weekly administration of EPO (ie, 600 IU/kg administeredsubcutaneously once a week for 4 doses) had similar efficacy andsafety in correcting preoperative anemia compared with dailydosing regimens. Cheung et al [6] published results showing thata higher dose of EPO (40000 IU) administered once weekly for 4weeks to healthy adults was more likely to be efficacious than alower dose (20000 IU). However, optimal dosing and duration ofEPO therapy remain uncertain as there are potentially importantmodifiers to its efficacy, such as postoperative inflammation and theavailability of iron stores.

It has been suggested that functional iron deficiency develops inpostoperative patients as a result of a surge in circulating inflamma-tory cytokines [7]. In this state of iron-restricted erythropoiesis, ironstores are normal but unavailable for erythropoiesis due to ironsequestration [8]. To overcome this, intravenous (IV) iron therapy hasbeen used to restore levels of accessible transferrin-bound iron [9].The availability of nondextran iron formulations (eg, iron sucrose andsodium ferric gluconate) has renewed interests in the use IV iron asthey have demonstrated an improved safety profile over dextran-containing formulations, albeit the risk of serious anaphylactic-typereactions remains real [10-13].

Several nonsystematic reviews [14-17] have looked at the efficacyand safety of EPO and IV iron in the perioperative setting; however,no systematic reviews have been published in this area. Therefore, weconducted a systematic literature search to evaluate the use theseerythropoietin-stimulating agents (ESA) as a transfusion avoidancestrategy in perioperative blood management.

Methods

Protocol Registration and Eligibility Criteria

We carefully adhered to the Preferred Reporting Items for Sys-tematic Reviews and Meta-Analysis guidelines throughout the

entire process of writing this systematic review and registered aprotocol online in advance (PROSPERO 2012:CRD42012002599).The PICOS approach was used to define the criteria for inclusion(Table 1). Any disagreements between review authors (DL and MT)in the process of study selection and appraisal were resolvedby discussion.

Search Strategy and Information Sources

We conducted a systematic literature search of English articlespublished between July 1997 and July 2012 in MEDLINE via PubMed,The Cochrane Library, and CINAHL (electronic search strategy shownin Table A1 in Appendix A). Additional studies were identified bymanually searching the references of included studies.

Study Selection

Two reviewers (DL and MT) independently screened the titlesand abstracts of retrieved records for potential inclusion thentogether performed a full-text review of the remaining records.Studies that did not fulfill the eligibility criteria were excluded.

Data Items and Extraction

Two reviewers (DL and EL) extracted the data independentlythen together checked for accuracy and relevance. Dataextracted included references, funding, details of study design,patient population, primary and comparator intervention(s), andefficacy and safety outcomes. Perioperative transfusion rate wasthe primary efficacy outcome of interest. For trials demonstrat-ing statistically significant differences between groups, wecalculated the absolute reduction in transfusion rate (%) andthe number needed to treat (NNT) to avoid transfusion.Important safety outcomes included rates of mortality, infection,and thromboembolism.

Risk of Bias Assessment

Two reviewers (DL and EL) independently assessed the risk ofbias using the Cochrane risk of bias tool; the criteria used forpotential high risk of bias are summarized in Table 2. We criticallyappraised each study by the method of randomization, allocationconcealment, whether blinding to intervention was likely toinfluence efficacy and safety outcomes, whether hematologicalparameters (ie, reticulocyte response and iron stores) werereported, completeness of outcomes data reporting, selectiveoutcomes reporting, and potential conflict(s) of interest. We

Table 2Cochrane risk of bias assessment high-risk criteria

Randomization generation Describes nonrandom sequence generation,such as odd or even. Nonrandomized studieshave a high risk of selection bias that isinherent to the design.

Allocation concealment Participants and/or investigators couldpossibly foresee assignment to treatmentarms.

Relevant laboratory data Authors do not report reticulocyte responseand baseline iron stores.

Blinding to intervention(s) Outcomes potentially influenced by knowingthe allocated intervention ahead of time.

Incomplete outcome data The reasons or number of missing data arenot addressed or not balanced acrossintervention groups. For randomized studies,results are not analyzed based on ITTpopulation; instead, a modified ITT populationwas used to analyze treatment efficacy.

Selective outcomes reporting Reports efficacy outcomes clearly specifiedin the methods section that preservesrandomization (if applicable)

Potential conflict(s) of interest Funding source or authors receive fees orhonoraria from the manufacturer ofhemostatic therapies used in the study.

Abbreviation: ITT, intention to treat.

Table 1Inclusion criteria using the PICOS approach

Population Adults with anemia scheduled for surgery, excludingpregnancy and the use of IV hematinic to augmentautologous blood donation

Intervention Use of erythropoietin and IV iron in management ofperioperative anemia

Comparator Autologous blood donation, oral iron, or placeboEfficacy Outcomes • Allogeneic blood transfusion

requirement• Hematologic parameters,such as Hb, reticulocyte,iron profile

Safety Outcomes • Thromboembolic events• Other adverse events relatedto the allocated intervention

Study design RCTs and nonrandomized studieswith a comparator group

Abbreviation: Hb, hemoglobin.

223D.M. Lin et al. / Transfusion Medicine Reviews 27 (2013) 221–234

further defined that a low risk of bias study had to be arandomized controlled trial (RCT) with at least 8 low risk of biascategories; studies that do not meet these criteria are considered atleast at moderate risk of bias.

Results

Study Selection and Characteristics

The study selection process is depicted in Fig. Most identifiedrecords were easily excluded by the title or abstract alone. After thisinitial screening, records that potentially fulfilled the inclusioncriteria were selected for full-text review. Thirty-nine articles wereeligible for inclusion, of which 8 studies were identified throughmanual search of references. In the end, 24 RCTs and 15nonrandomized studies with a comparator group were included inthe final review. In Tables 3A, 3B, and 3C, study characteristics aresummarized using the PICOS format (population, intervention,comparator, outcomes, and study design) and organized accordingto the allocated therapy.

Cochrane Risk of Bias Assessment

The Cochrane risk of bias tool was applied across all studies (TableA2 in Appendix A). Most studies were assessed to be at least atmoderate risk of bias (defined in the “Methods” section) with theexception of 1 IV iron study [24], 4 EPO studies [35,37,44,51], and 3EPO plus IV iron trials [53,54,62].

Intravenous Iron

The RCT by Serrano-Trenas et al [24] was assessed to be of low riskof methodological bias; authors reported that perioperative IV ironsucrose did not reduce transfusion rates when compared with astandard transfusion protocol (42.3% vs 33.3%, P N .05) in mildlyanemic patients with normal iron stores under going hip fracturesurgery (Table 4A). In contrast, administering IV iron sucrose afterdelivery towomenwith iron deficiency anemia improved hemoglobinlevels by approximately 2 g/dL when compared with oral ironsupplementation [29].

There were no observed severe anaphylactic-type reactionsattributed to IV iron therapy (Table 5A). Although Cuenca et al[25] reported lower rates of infection (IV iron 16.4% vs control33.3%, P b .05) and mortality (IV iron 0% vs control 19.3%, P b

.05) [26] in the IV iron arms when compared with historical

controls, both studies were at least at moderate risk of bias, withmultiple design flaws.

Erythropoietin

In an RCT by Feagan et al [35] of anemic patients with normal ironstores undergoing total hip arthroplasty, the absolute reduction intransfusion rate was 33.5% (NNT, 3) and 22.1% (NNT, 5) for patientswho had received high or low doses of EPO, respectively, whencompared with placebo (Table 4B). Dousias et al [44] randomizedwomen with iron deficiency anemia due to uterine leiomyoma toreceive a preoperative EPO regimen or placebo and reported an 18.5%absolute reduction in transfusion rate (NNT, 6); however, prestudypower analysis was not performed, and the sample size was small(n = 50). In another RCT, Yazicioglu et al [51] did not report peri-operative transfusion rates; instead, authors studied whether preop-erative EPO reduces the volume of RBC transfused in mildly anemicpatients who had predonated 400 mL of whole blood and werescheduled for on-pump coronary artery bypass graft surgery. Com-pared with the control group, preoperative EPO reduced the meanRBC volume transfused (330 ± 43 mL vs 680 ± 75 mL, P b .05).

In a multicenter, randomized controlled safety trial, Stowell etal [37] studied the incidence of deep vein thrombosis (DVTs) inspinal surgery patients randomized to receive preoperative EPOor standard blood conservation when only mechanical thrombo-prophylaxis was used. The between-group difference in theincidence of any DVT was 2.6% with an upper 97.5% confidencelimit of 5.4%. Because the predefined criterion for noninferioritywas set to be confidence limit less than 4%, EPO therapy wasassociated with an increased risk of DVTs (Table 5B).

Erythropoietin Plus IV Iron

Yoo et al [62] was the most methodologically sound RCT in theliterature, scoring the maximum number of low risk of bias categories(Table A2 in Appendix A) (Table 4C). Adequately powered to dem-onstrate superiority, authors reported that a single preoperative doseof EPO plus IV iron sucrose given to anemic patients with normalbaseline iron stores, who were scheduled for elective on-pump valvesurgery, reduced the absolute transfusion rate by 27% (NNT, 4) when

Fig. Prisma flow diagram depicting the study selection process.


compared with placebo. Similarly, Na et al [53] administered a singleintraoperative dose of EPO plus IV iron sucrose to women with irondeficiency anemia scheduled for bilateral total knee replacementand found 33.3% absolute reduction in transfusion rate (NNT, 4)when compared with the controls. In another RCT, Olijhoek et al[54] did not report perioperative transfusion rates; instead, authorsstudied whether preoperative EPO plus IV iron enhances RBCproduction in anemic patients with normal baseline iron stores.Compared with IV iron monotherapy, preoperative EPO plus IV ironincreased mean RBC production (219 mL vs 18.4 mL, P b .05);however, prestudy power analysis was not performed. The safety ofcoadministering EPO and IV iron is unclear as 5 of 10 includedstudies did not report any adverse events (Table 5C).

Discussion

The strength of this systematic review lies in our careful adherenceto the Preferred Reporting Items for Systematic Reviews and Meta-Analysis, including a rigorous appraisal process using the Cochranerisk of bias tool. This systematic review is limited by a search strategyrestricted to English publications and exclusion criteria for autologousblood donation, children, and pregnantwomen.Most included studieswere assessed to be at least at moderate risk of bias; therefore, thefollowing discussion is mainly focused on low risk of bias studies thatreport perioperative transfusion rates, an outcome that is moreclinically meaningful than surrogate markers of clinical efficacy, suchas hemoglobin recovery.

Table 3APerioperative IV iron study characteristics

Study Funding Design Population Intervention Comparator Outcomes

Serrano-Trenas et al [24] Spanish Ministry ofHealth & ConsumerAffairs

Single centerRandomizedOpen labelFull ITT

Adult age N65 y ± preoperativeanemia scheduled for hipfracture surgery

Perioperative IV iron sucrose 200 mg q48 h × 3 doses (n = 100)

Transfusion protocol withoutIV iron (n = 100)

Transfusion rates

Cuenca et al [25] Not disclosed Single centerNonrandomizedCompared a prospective armwith historical control

Adults age N65 y scheduledfor pertrochanteric hipfracture surgery

Preoperative IV iron sucrose 100 mg × 2 doses.A third preoperative dose given if Hbremains b12 (n = 55)

Historical controls did notreceive IV iron (n = 102)

Transfusion rates

Cuenca et al [26] Not disclosed Single centerNonrandomizedCompared a prospective cohortwith historical control

Adults age N65 y scheduled fordisplaced subcapital hip fracture

Preoperative IV iron sucrose 100 mg × 2 doses.A third preoperative dose given if Hb remainsb12 (n = 20)


Transfusion rates

Munoz et al [27] Grant from Institutode Salud Carlos

Single centerNonrandomizedCompared a prospective armwith historical control

THR ± preoperative anemia Postoperative IV iron sucrose 100 mg givenonce daily × 3 doses (n = 24)


Transfusion rates

Bhandal et al [28] Not disclosed Single centerRandomizedOpen labelFull ITT

Postpartum women with irondeficiency anemia Hb b9 afterelective C section. Excludedperipartum transfusion

Postpartum IV iron sucrose 200 mg givenon days 2 and 4 after delivery (n = 22)

Postpartum oral iron 200 mgtwice a day × 6 wk (n = 22)

Hematologicalparameters

Kim et al [29] Not disclosed MulticenterRandomizedOpen labelModified ITT

Women with menorrhagia andpreoperative iron deficiencyanemia Hb b9

Total preoperative IV iron sucrose calculatedby weight and target Hb of 10 given individed doses 3 times per week for 3 wk(n = 39)

Preoperative oral iron 80 mggiven daily (n = 37)


Diez-Lobo et al [30] Not disclosed Single centerNonrandomizedCompared 2 prospectivecohorts

Women with iron deficiency ±anemia an Hb b12 scheduledfor abdominal hysterectomy

Preoperative IV iron sucrose max 600 mgper week in divided doses for 2-4 wk toreplenish calculated total iron deficit(n = 31)

Preoperative oral iron of variabledoses and duration (n = 44)

Transfusion rates

Armand-Ugon et al [31] Authors receive honorariafrom Vifor

Single centerNon-randomizedCompared two prospectivecohorts

Women with anemia aftersurgery for complicated pregnancyor childbirth

If Hb b10 on POD 1, given IV iron sucrose200 mg × 3 d then discharged on oral irontherapy 256 mg/d (n = 14)

If Hb N10 on POD 1, oral iron256 mg/d (n = 14)

Transfusion rates

Edwards et al [32] Syner-Med Pharmaceuticalprovided Venofer

Single centerRandomizedDouble blindModified ITT

Bowel resection for colorectalcancer ± preoperative anemia

Preoperative IV iron sucrose 300 mg onceweekly × 2 doses (n = 35)

IV saline 250 mL × 2 doses(n = 27)

Transfusion rates

Titos-Arcos et al [33] No reported conflictof interest

Single centerNonrandomizedCompared 2 retrospectivecohorts

Colorectal cancer surgery ±postoperative anemia

If postoperative Hb b11, postoperative IViron therapy 100 to 200 mg up to max3 doses per week (n = 52)

No postoperative IV iron(n = 52)

Transfusion rates

Abbreviations: POD, postoperative day, THR, total hip replacement.

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Table 3BPerioperative EPO study characteristics


Deutsch et al [34] Ortho BiotechClinical Affairs


Preoperative Hb 10-13 scheduled forTKR. Excluded iron deficiency.

Preoperative SQ EPO 40000 IUgiven once weekly × 2 doses plusoral iron (n = 26)

If preoperative Hb 11-13, PAD up to2 U, otherwise no predonation. Allgot oral iron (n = 26)

Transfusion rates

Feagan et al [35] Janssen-Ortho, Inc MulticenterRandomized3:5:5 ratioDouble blindModified ITT

Preoperative Hb 9.8-13.7 scheduledfor THR

Preoperative SQ EPO 40000 IU(high dose) or 20000 IU (lowdose) given once weekly × 4doses plus oral iron (n = 46;n = 86)

SQ placebo injections once weekly × 4doses plus oral iron (n = 82)

Transfusion rates

Stowell et al [36] RW JohnsonPharmaceuticResearch Institute,NJ

MulticenterRandomizedOpen labelModified ITT

Preoperative Hb 11-13 scheduledfor THR or TKR

Preoperative SQ EPO 600 IU/kggiven once weekly × 4 doses plusoral iron (n = 241)

PAD in accordance with AABB standardsplus oral iron (n = 249)

Transfusion rates

Stowell et al [37] Centocor OrthoBiotech ServicesLLC

MulticenterRandomizedOpen labelFull ITT

Preoperative Hb 10-13 scheduledfor spinal surgery only withmechanical DVT prophylaxis

Preoperative SQ EPO 600 IU/kggiven once weekly × 4 doses plusoral iron (n = 340)

Standard blood conservation plusoral iron. No EPO administered(n = 340)

Safety study; postoperativeDVT by screening US oflower limbs

Weber et al [38] Ortho BiotechEurope

MulticenterRandomized2:1 ratioOpen labelModified ITT

Preoperative Hb 10-13 scheduledfor major orthopedic surgery(spine, hip, or knee)

Preoperative SQ EPO 40000 IUonce weekly × 4 doses plus oraliron (n = 467)

PO or IV iron therapy based on standardof care at various centers (n = 237)

Transfusion rates

Cushner et al [39] Not disclosed MulticenterNonrandomizedCompared aprospectivecohort withhistorical control

Preoperative Hb b13 scheduled forsecond stage re-do TKR s/p removalof infected prosthesis and 6-8 wkof IV antibiotics

SQ EPO 40000 IU × 1 dose beforesecond stage surgery plus oraliron. Single postoperative EPOdose was given as needed(n = 41)

No SQ EPO given before secondstage surgery (n = 83)

Transfusion rates

Laffosse et al [40] Not disclosed Single centerNonrandomizedCompared 2prospectivecohorts

Preoperative Hb b13 scheduledfor THR

Preoperative SQ EPO 30000 IUonce weekly × 4 doses (n = 28)

Hb b13 (n = 42) and Hb N13 controls(ie, no EPO) (n = 101)

Transfusion rates

Cushner et al [41] Ortho BiotechProducts

Single centerNonrandomizedCompared 2retrospectivecohorts

Preoperative Hb 10-13 scheduledfor TKR

Preoperative SQ EPO 40000 IUonce weekly × 3 doses (n = 56)

One unit of PAD without SQ EPO.Automatic postoperative reinfusion(n = 48)

Transfusion rates

Kourtzis et al [42] Not disclosed Single centerRetrospectiveCompared 2retrospectivecohorts

TKR ± preoperative anemia Perioperative blood savingprotocol and techniques, includinglower Hct transfusion trigger 21 to22 SQ EPO 150 IU/kg given oncedaily × 5 preoperative doses and3 postoperative doses plus oraliron (n = 61)

Higher Hct transfusion trigger 26 to 27;no perioperative blood saving protocol(n = 58)

Transfusion rates

Sesti et al [43] Not disclosed Single centerProspectiveNonrandomizedCompared 2prospectivecohorts

Women scheduled for hysterectomyfor benign gynecologic issues. Thosewith preoperative Hb b12 receivedEPO

If Hb 11-12 (n = 24), totalpreoperative dose of 80000 IUEPO given over 8 d. If Hb 10-11(n = 17), total preoperative dose120000 IU given over 12 d. If Hb6-10 (n = 19), total preoperativedose 160000 IU over 16 d

Hb N12 did not received EPO or oraliron supplementation (n = 60)

Hematological parameters

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Dousias et al [44] Not disclosed Single centerRandomizedDouble blindFull ITT

Women with uterine leiomyomasand preoperative Hb 9-12 scheduledfor total hysterectomy

Preoperative SQ EPO 600 IU/kgonce weekly × 3 doses plus oraliron 200 mg once daily (n = 23)

Normal saline SQ injection plus oraliron 200 mg once daily (n = 27)

Transfusion rates

Larson et al [45] Not disclosed Single centerRandomizedOpen labelFull ITT

Women with uterine myoma andpreoperative iron deficiency Hbb12 scheduled for hysterectomy

Preoperative SQ EPO 5000 IUtwice per week × 4 wk plus oral100 mg twice a day (n = 15)

Oral iron 100 mg twice a day(n = 16)

Transfusion rates

Christodoul-akiset al [46]

Not disclosed MulticenterRandomizedOpen labelModified ITT

Preoperative Hb 9-12 with resectablecolorectal cancer

Preoperative SQ EPO 150 or 300IU/kg once daily 10 d until POD1plus oral iron therapy 200 mgonce daily (n = 69, 67)

Preoperative oral iron therapy200 mg daily (n = 68)

Transfusion volume

Qvist et al [47] Janssen-Cilag,Denmark


Preoperative Hb b8.5 scheduled forcolorectal cancer surgery

Preoperative SQ EPO 300 IU/kgonce daily × 4 doses plus oraliron, then postoperative SQ EPO150 IU/kg once daily × 7 doses(n = 49)

SQ injections of placebo plus oral irondaily (n = 51)

Transfusion rates

Scott et al [48] Grant fromOrtho BiotechProducts


Preoperative Hb 10-13.5 scheduledfor head and neck cancer surgery

Preoperative SQ EPO 600 IU/kgonce weekly × 3 doses plus oraliron 150 mg twice a day(n = 30)

SQ placebo plus oral iron sulfate 150 mgtwice a day (n = 30)

Transfusion rates

Nieder et al [49] Not disclosed Single centerNonrandomizedCompared twoprospectivecohorts

Preoperative Hct b48 scheduled forprostatectomy for localized prostatecancer

Preoperative SQ EPO 600 IU/kgonce weekly × 2 doses(n = 100)

Preoperative SQ EPO 300 IU/kg givenonce weekly × 2 doses (n = 100)

Transfusion rates

Weltert et al [50] No reportedconflict ofinterest


Preoperative Hb b14.5 scheduled forurgent off-pump CABG

Preoperative SQ EPO 14000 IUgiven once daily × 2 doses thenpostoperative SQ EPO 8000 IUgiven once daily × 3 doses(n = 158)

No treatment (n = 162) Transfusion rates

Yazicioglu et al [51] Not disclosed Single centerRandomizedBlinded providerFull ITT

Elective on-pump CABG predonated400 mL of whole blood beforesurgery

Preoperative IV EPO 100 IU/kggiven once daily × 4 dosesplus retransfusion ofpredonated whole blood(n = 25)

No preoperative EPO (n = 28) Transfusion volume

Abbreviations: TKR, total knee replacement; SQ, subcutaneous; PAD, preoperative autologous donation; AABB, American Association of Blood Banks; PO, oral; US, ultrasound; Hct, hematocrit; CABG, coronary artery bypass graft.

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Table 3CPerioperative EPO plus IV iron study characteristics


Kateros et al [52] Not disclosed Single centerRandomizedOpen labelUnclear if ITT

Preoperative Hb 9.6-12.7 scheduledfor intertrochanteric fracture surgery

Preoperative and postoperative SQ EPO 20000 IUonce daily × 10 doses plus IV iron 100 mg oncedaily × 10 doses (n = 38)

Preoperative and postoperative SQ placeboonce daily plus IV iron 100 mg oncedaily × 10 doses (n = 41)

Transfusion volume

Na et al [53] Authors report noconflict of interest

Single centerRandomizedOpen labelModified ITT

Women with preoperative Hb N10and iron deficiency scheduled forbilateral TKR

Intraoperative single dose of IV iron sucrose200 mg plus SQ EPO 3000 IU. Max of 2 additionaldoses given postoperative if Hb remained7-8 (n = 56)

No IV hematinics were givento controls group (n = 57)

Transfusion rates

Olijhoek et al [54] Not disclosed MulticenterRandomized1:1:1:1 ratioEPO double blindIron open labelFull ITT

Preoperative Hb 10-13 with relativeiron deficiency (ferritin N50 g/dL)scheduled for elective orthopedicsurgery

Preoperative SQ EPO 600 IU/kg given once weekly× 2 doses on day 1 and 8 of 14-d study plus IV ironsaccharate 200 mg (n = 29) or oral iron 200 mgdaily × 14 d (n = 29)

Preoperative SQ placebo given onceweekly × 2 doses on day 1 and day 8of 14-d study plus IV iron 200 mg(n = 25) or oral iron 200 mg × 14 d(n = 27)

RBC production

Garcia-Erce et al [55] Grant from Instituto deSalud Carlos, Spain, andEuropean Union

Single centerNonrandomizedCompared 2prospectivecohorts

Adults age N65 y ± preoperativeanemia scheduled for osteoporotichip fracture surgery

Blood saving protocol of preoperative IV ironsucrose 200 mg once every 48 h × 3 doses plusSQ EPO 40000 IU × 1 dose if baseline Hb b13(n = 83)

No parenteral hematinics were given(n = 41)

Transfusion rates

Gonzalez-Porras et al [56]

Authors report noconflict of interest

Single centerNonrandomizedCompared aprospective armwith historicalcontrol

Preoperative Hb N10 and various ironstatus scheduled for THR or TKR

Preoperative blood saving protocol (n = 303)including no preoperative therapy (n = 80), oraliron (n = 145), preoperative IV iron sucrose 200 mgonce weekly × 4 wk (n = 49), preoperative SQEPO 10000 IU once weekly plus IV iron (n = 9)× 4 wk, PAD 2 U plus oral iron (n = 20)

Historical control matched by age, sex,type of arthroplasty not on individualizedpreoperative blood saving protocol(n = 305)

Transfusion rates

Garce-Erce et al [57] Grant from InstitutoAragones de Cienciasde la Salud, Spain

Single centerNonrandomizedCompared 2retrospectivecohorts

Adults age N65 y with preoperativeHb 10-13 scheduled for osteoporotichip fracture surgery

Preoperative SQ EPO 40000 U × 1 dose plus bloodconservation protocol, ie, restrictive trigger plus 3perioperative doses of IV iron sucrose 200 mg onceevery 48 h (n = 81)

Intended preoperative SQ EPO doseswere missed but same blood conservationprotocol was followed (n = 115)

Transfusion rates

Braga et al [58] Not disclosed Single centerRandomizedBlinded providerModified ITT

Preoperative iron deficiency Hb ≤11,serum iron b600 g/L scheduled forsurgical resection of GI tractadenocarcinoma

Preoperative SQ EPO 100 IU/kg given once every4 days × 4 doses plus IV iron gluconate 125 mgonce daily × 15 doses (n = 12)

Preoperative SQ EPO 50 IU/kg given onceevery 4 d × 4 doses plus IV iron gluconate125 mg once daily × 15 doses (n = 12)

Transfusion rates

Kettelhack et al [59] Not disclosed MulticenterRandomizedDouble blindModified ITT

Preoperative Hb 8.5-13.5 scheduledfor elective right hemicolectomy forcolon cancer

Perioperative SQ EPO 20000 IU once daily × 5-10doses until postoperative day 4 (min 10 doses,max 15 doses). Single postoperative dose of IViron sulfate 40 mg (n = 52)

Single postoperative doseof IV iron 40 mg (n = 57)

Transfusion rates

Karkouti et al [60] Authors receivedresearch fundsand speakers' fees fromOrtho Biotech


POD 1 Hb 7-9 after major surgery(open heart, total hip, or spinalfusion); preoperative anemiawas an exclusion criteria

Postoperative IV iron sucrose 200 mg given oncedaily × 3 doses plus EPO given on POD 1 (IV 300 +SQ 300) and POD 3 (SQ 600 IU/kg) (n = 12)

Postoperative IV iron sucrose 200 mggiven once daily × 3 doses (n = 13)or IV normal saline 200 mL as placebo(n = 13)


Madi-Jebara et al [61] Not disclosed Single centerRandomizedDouble blindModified ITT

Post-pump Hb 7-10 after electiveon-pump cardiac surgery excludingintraoperative transfusion

Postoperative IV iron sucrose 200 mg given oncedaily to replete calculated total iron deficit plus SQEPO 300 IU/Kg × 1 dose (n = 40)

IV iron sucrose only arm (n = 40) orplacebo arm (n = 40)

Transfusion rates

Yoo et al [62] Institution anddepartmentfunding

Single centerRandomizedBlinded providerFull ITT

Preoperative anemia (men Hb b13,women Hb b12) without irondeficiency scheduled for electiveon-pump valvular surgery

16-24 h preoperative IV EPO 500 IU/kg × 1 doseplus IV iron sucrose 200 mg × 1 dose (ns = 37)

Equivalent volume of normal salinewithout iron (n = 37)

Transfusion rates

Abbreviation: GI, gastrointestinal.

228D.M

.Linet

al./Transfusion

Medicine

Reviews27

(2013)221

–234

Table 4AEfficacy outcomes for IV iron therapy

Ref

[24]

[25]

[26]

[27]

[28]

[29]

[30]

[31]

[32]

[33]

Study

Serrano-Trenas

Cuenca

Cuenca

Munoz

Bhandal

Kim

Diez-Lobo

Armand-Ugon

Edwards

Titos-Arcos

Surgery Cochrane risk of bias

1 9

6

6

6

3

3

1

1

4

2 7 1

3 6 1

4 5

7 3

4 6

5 5

1

Hip fracture

Hip fracture

Hip fracture

THR

C-section

Menorrhagia

Hysterectomy

Pregnancy

Colorectal cancer

Colorectal cancer

RCT

Yes

No

No

No

Yes

Yes

No

No

Yes

No

ITT / size (n)

196 / 200

157 / 157

77 / 77

46 / 46

43 / 44

56 / 76

75 / 75

28 / 28

60 / 62

104 / 104

NNT

-

-

-

-

?

?

4

-

-

-

9

12.3

21.8

26.9

?

?

31.8

28.6

4.5

2

P < .05

No

NO

P = .06

P = .07

Yes

?

No

No

Comparator vs Intervention

Transfusion rate (%)

transfusion rate (%)

Absolute reduction in

41 / 97 (42.3)

57 / 102 (55.9)

21 / 57 (36.8)

16 / 22 (72.7)

Hematologic parameters


14 / 44 (31.8)

0 / 14 (0)

5 / 26 (19.2)

16 / 52 (30.8)

33 / 99 (33.3)

24 / 55 (43.6)

3 / 20 (15)

11 / 24 (45.8)

0 / 31 (0)

4 / 14 (28.6)

5 / 34 (14.7)

16 / 52 (28.8)

high risk of bias low risk of bias unclear risk of bias; [28] Baseline, postpartum, day 5, day 14 mean Hb (g/gdL) trend for IV iron arm (11, 7.3, 9.9, 11.1) vs oral iron arm (11.9, 7.5, 7.9, 9);P b .05 for days 5 and 14 [29]. Preoperative, postoperative mean Hb trend in IV iron arm (7.5, 10.5) vs oral iron arm (7.8, 8.6); P b .05 for postoperative Hb.

Table 4BEfficacy outcomes for EPO therapy

Ref

[34]

[35]

[36]

[35]

[37]

[38]

[39]

[40]

[41]

[42]

[43]

[44]

[45]

[46]

[47]

[48]

[49]

[50]

[51]

Study

Deutsch

Feagan

Feagan

Stowell

Stowell

Weber

Cushner

Laffosse

Cushner

Kourtzis

Sesti

Dousias

Larson

Christodoulakis

Qvist

Scott

Nieder

Weltert

Yazicioglu

Surgery Cochrane risk of bias

4 4

2 8

5 2

2 8

4 6

6 2 2

6 3

6 4

4 5

8 1

9 1

2 5 3

3 4 3

2 6 2

2 6 2

5 4

3 7

9 1

1

1

1

1

3

2TKR

THR

THR

THR or TKR

Spinal

Major orthopedic

Re-do TKR

THR

TKR

TKR

Hysterctomy

Hysterctomy

Hysterctomy

Colorectal cancer

Colorectal cancer

Head-neck cancer

Prostate cancer

off-pump CABG

on-pump CABG

RCT

Yes

Yes

Yes

Yes

Yes

Yes

No

No

No

No

No

Yes

Yes

Yes

Yes

Yes

No

Yes

Yes

NNT

-

3

5

-

?

4

3

7

-

2

?

6

-

?

-

-

-

5

?

ITT / size (n)

52 / 52

122 / 128

157 / 168

428 / 490

680 / 680

695 / 704

124 / 124

171 / 171

104 / 104

119 / 119

120 / 120

50 / 50

31 / 31

204 / 223

81 / 100

58 / 60

200 / 200

320 / 320

53 / 53

P < .05

No 20

33.5

22.1

6.3

?

28

45

15.3

0.5

78.1

?

18.5

6.3

?

19

17.3

1

21.4

?

Yes

Yes

P = .08

Yes

Yes

Yes

No

Yes

Yes

No

No

No

No

Yes

Comparator vs intervention

Transfusion rate (%)

transfusion rate (%)

Absolute reduction in

2 / 25 (8)

35 / 78 (44.9)

35 / 78 (44.9)

42 / 219 (19.2)

Safety Study

87 / 235 (37.0)

74 / 83 (89.2)

27 / 143 (18.9)

2 / 48 (4.1)

50 / 58 (86.2)


5 / 27 (18.5)

1 / 16 (6.3)

Trasfusion volume

23 / 43 (53)

24 / 29 (82.8)

7 / 100 (7)

60 / 162 (37.2)

7 / 25 (28)

5 / 44 (11.4)

18 / 79 (22.8)

27 / 209 (12.9)

41 / 460 (8.9)

18 / 41 (43.9)

1 / 28 (3.6)

2 / 56 (3.6)

5 / 61 (8.1)

0 / 23 (0)

0 / 15 (0)

13 / 38 (34)

19 / 29 (65.5)

6 / 100 (6)

25 / 158 (15.8)

Transfusion volume

high risk of bias low risk of bias unclear risk of bias; [37]. See Table 5B Safety outcomes for EPO therapy [43] Baseline, preoperative, discharge mean Hb trend in high dose (8.5, 12, 11),medium dose (10.6, 13.2, 11.7), low dose (11.4, 13.7, 12.3), no EPO (13.2, ?, 9.9); P N 0.05 [46] Perioperative, postopeartive mean transfusion (units/patient) in higher dose(0.8 ± 1.2, 0.8 ± 1.2), lower dose (1.2 ± 1.5, 1.1 ± 1.4), no EPO (1.3 ± 1.6, 1.4 ± 1.6); P b .05 for higher vs. no EPO [51] Perioperative mean transfusion volume (mL) in EPO (330 ± 43)vs. no EPO (680 ± 75); P b .05.

Table 4CEfficacy outcomes for EPO plus IV iron therapy

Ref

[52]

[53]

[54]

[55]

[56]

[57]

[58]

[59]

[60]

[61]

[62]

Study

Kateros

Na

Olijhoek

Garcia-Erce

Gonzalez-Porras

Garcia-Erce

Braga

Kettelhack

Karlouti

Madi-Jebara

Yoo

Surgery Cochrane risk of bias4 3 3

1 8

8 2

2 7 1

3 6 1

4 5 1

2 5 3

1 6

3 7

2

10

7 1

3

1

Hip fracture

Bilateral TKR

Major orthopedic

Hip fracture

THR or TKR

Hip fracture

Gl cancer

Colorectal cancer

Cardiac, orthopedic

on-pump cardiac

on-pump valve

RCT

Yes

Yes

Yes

No

No

No

Yes

Yes

Yes

Yes

Yes

NNT

?

4

?

3

8

6

-

-

?

-

4

ITT / size (n)

79 / 79

108 / 113

102 / 110

124 / 124

89 / 89

196 / 196

14 / 24

102 / 109

20 / 20

80 / 80

74 / 74

P < .05

Yes

?

?

33.3

46.6

13.7

18

0

5

?

5

27

Yes

?

Yes

No

No

No

Yes

Comparator vs interventionTransfusion rate (%)

transfusion rate (%)Absolute reduction

Transfusion volume

29 / 54 (53.7)

RBC production

29 / 41 (70.7)

11 / 80 (13.7)

69 / 115 (60)

2 / 7 (28.6)

15 / 54 (28)


9 / 40 (22.5)

32 / 37 (86.5)

11 / 54 (20.4)

23 / 83 (24.1)

0 / 9 (0)

34 / 81 (42.0)

2 / 7 (28.6)

16 / 48 (33)

7 / 40 (17.5)

22 / 37 (59.5)

high risk of bias low risk of bias unclear risk of bias; [52] - Mean perioperative transfusion volume (units, range) in EPO plus IV iron (1.5, 0-3) vs. placebo plus IV iron (2.5, 1-4); P b .05.[53] - Mean preoperative red cell producesd (mL) in EPO plus IV iron (219) vs. placebo plus IV iron (18.4); P b .05. [60] - Mean baseline, postoperative day 1, 7, and 42 Hb (g/dL) trend inEPO plus IV iron (14, 8.3, 9.8, 12.8) vs. placebo (14.2, 8.3, 9.6, 12); P N .05.


Unlabelled image

Unlabelled image

Unlabelled image

Table 5ASafety outcomes for IV iron therapy

Ref Study Safety outcome

[24] Serrano-Trenas Mortality (control 10 vs IV iron 11)14.8% overall infections rate (control 13 vs IV iron 16)

[25] Cuenca Mortality (IV iron 8.9% vs control 16.7%)Infection rate (IV iron 16.4% vs control 33.3%) (P b .05)

[26] Cuenca Mortality (IV iron 0% vs control 19.3%) (P b .05)Infection rate (IV iron 15% vs control 33%)

[27] Munoz None observed[28] Bhandal IV iron (5 transient metallic taste, 4 facial flushing)

Oral iron (7 dyspepsia, nausea, or constipation)[29] Kim IV iron (2 myalgia)

Oral iron (1 nausea, 1 dyspepsia)[30] Diez-Lobo None observed[31] Armand-Ugon None observed[32] Edwards 2 transient, mild hypotensive events in IV iron[33] Titos-Arcos Not reported

Table 5CSafety outcomes for EPO plus IV iron therapy


[52] Kateros None observed[53] Na Not reported[54] Olijhoek No mortality or VTE[55] Garcia-Erce Infection (protocol 12.5% vs control 31.4%)

(P b .05)[56] Gonzalez-Porras Not reported[57] Garce-Erce VTE (EPO 1 vs control 4)

Infection (EPO 4 vs control 13)[58] Braga Not reported[59] Kettelhack EPO (1 arterial thrombosis, 3 died of heart failure,

1 died of sudden cardiac death)Placebo group (2 died of heart failure,1 fungal sepsis).

[60] Karkouti Not reported[61] Madi-Jebara Not reported[62] Yoo Postoperative AKI: EPO 9/37 (24.3%) vs placebo 19/35

(54.3%) (P b .05)No difference between groups with respect to otherpostoperative complications, ie, death, atrial fibrillation,or duration of ventilator, ICU stay, hospital stay

Abbreviations: AKI, acute kidney injury; ICU, intensive care unit.


Efficacy

Understanding the pathophysiology of functional iron deficiencymay be important when choosing to use EPO and IV iron as abloodless therapeutic modality in the management of perioperativeanemia [8]. Up-regulated by inflammatory cytokines, such as inter-leukin 6, hepcidin degrades the iron exporter ferroportin and, as aresult, promotes iron sequestration in macrophages and enterocytes[13]. The resultant state of hypoferremia and iron-restricted erythro-

Table 5BSafety outcomes for EPO therapy


[34] Deutsch Stroke (EPO 1 vs PAD 2)[35] Feagan No difference in rate of VTE (92% screened)

VTE (high EPO 2, low EPO 5, placebo 6)[36] Stowell EPO 6 VTE (0 PE, 3 DVT, 2 stroke, 1 acute MI)

PAD 5 VTE (3 PE, 2 DVT)[37] Stowell EPO (all 340)

Mechanical DVT prophylaxis, 263 (77.4%)US Doppler performed, 291 (85.6%)Total thrombotic events, 28 (8.2%)Doppler (+) DVT, 14 (3.2%)Acute DVT by Doppler, 8/14Chronic DVT by Doppler, 6/14Other thrombovascular events, 12 (3.5%)

Control (all 340)275 (80.9%)304 (89.4%)14 (4.1%)7 (2.1%)6 of 71 of 77 (2.1%)

[38] Weber VTE (EPO 2 vs control 1)No difference in rate of infections(EPO 9.4% vs control 10.6%)

[39] Cushner Not reported[40] Laffosse None observed[41] Cushner None observed[42] Kourtzis None observed[43] Sesti None observed[44] Dousias Each arm had 2 transient febrile episodes[45] Larson EPO 1 superficial wound infection

Control 1 severe septicemia, 1 UTI[46] Christodoulakis High EPO (3 fatal postoperative cardiac arrests)

Low EPO (1 fatal postoperative cardiac arrest;1 fatal postoperative embolism)Control (no postoperative events)

[47] Qvist EPO 1 DVT[48] Scott None observed[49] Nieder Not reported[50] Weltert Postoperative DVT (EPO 0% vs control

0.63%) (P b .05)[51] Yazicioglu None observed

Abbreviations: VTE, venous thromboembolism; PE, pulmonary embolism; MI, myocardialinfarction; UTI, urinary tract infection.

poiesis may cause a delay in the recovery of hemoglobin postopera-tively [18]. Interestingly, a single dose of EPO in humans has beenshown to significantly decrease serum levels of hepcidin [19]. Agrowing body number of trials have explored the use of EPO and IViron as a tool to hasten perioperative hemoglobin recovery and reduceRBC transfusion requirements [20].

Maintaining adequate transferrin saturation in the periopera-tive period is crucial for effective erythropoiesis. In the RCT byBhandal et al [28], postoperative IV iron supplementation inwomen with iron deficiency anemia led to a significant rise inhemoglobin that became evident on day 5 and persisted for 2weeks. However, in the absence of iron deficiency, IV ironmonotherapy may be inadequate to induce a robust marrowresponse even in the presence of anemia. Simply restoring ironsubstrate in the absence of exogenous EPO would merely augmentwhatever endogenous erythropoietic drive was already underway,the degree of which is dependent upon both the severity ofanemia and the underlying physiologic status of the surgicalpatient [21]. As an example, Serrano-Trenas et al [24] reportedthat perioperative IV iron monotherapy—when compared with astandard transfusion protocol—did not reduce transfusion rates iniron-replete anemic patients undergoing hip fracture surgery. Wespeculate that the authors' observations may be explained by a statein which the endogenous erythropoietic drive had not yet signifi-cantly increased at the time of IV iron supplementation; however, bythe time such therapy would be expected to have had an effect onRBC mass recovery, patients in both arms had already beentransfused. As a pathophysiologic consequence, the transfused RBCmay have blunted further escalation in the erythropoietic responseby the marrow and masked any potential benefit of IV iron. Furtherconfounding the study's finding is the reported noncompliance withthe prespecified 3-dose IV iron protocol: 20%, 63%, and 16% ofpatients received 1, 2, and all 3 doses, respectively.

Several well-designed RCTs showed that a short preoperativecourse of EPO [35], or a single dose of EPO plus IV iron in thepreoperative [62] or intraoperative [53] period, reduced transfu-sion rates. In an RCT by Feagan et al [35] of iron-replete anemicpatients scheduled for total hip arthroplasty, a 4-week preopera-tive EPO regimen lowered overall transfusion rates, mostly in thepostoperative period (high-dose EPO 9.1%, low-dose EPO 15.2%,placebo 39.7%). Interestingly, the degree of iron utilization in thepreoperative period closely paralleled the degree of erythropoietic


drive induced by a single dose of exogenous EPO; however, bypostoperative day 3, nadir levels of serum iron and peak levels offerritin—reflecting a state of iron sequestration—were observedacross all 3 study groups, suggesting the emergence of functionaliron deficiency and iron-restricted erythropoiesis. Similarly, in anadequately powered RCT to demonstrate superiority, Yoo et al [62]reported that the greatest transfusion rate reduction benefit of asingle dose of preoperative EPO and IV iron occurred duringpostoperative day 2 through 4. Taken together, the number ofpatients needed to treat to completely avoid RBC transfusions inthe perioperative period was clinically significant, ranging from 3to 6.

Electronic search strategy for MEDLINE via PubMed

1. Intravenous iron2. Hematinic3. Erythropoiesis-stimulating agent4. Preoperative OR perioperative OR postoperative5. (1 OR 2 OR 3) AND 4 Filters: Publication date from 1997/07/03 to 2012/07/03;English

Safety

Stowell et al [37] was the only randomized controlled safetytrial evaluating the thromboembolic risk associated with EPOtherapy as a primary end point. Uniquely, this study explored theincidence of DVTs in spinal surgery patients, excluding pulmonaryembolism, when only mechanical thromboprophylaxis wasallowed. Adequately powered to demonstrate noninferiority,authors reported higher DVT rate associated with preoperativeEPO therapy when compared with standard blood conservation.However, the lack of preintervention screening ultrasound con-founds the study's observations. In addition, a significant numberof patients (EPO 22.6% vs standard 19.1%) did not even receive theintended mechanical thromboprophylaxis. An earlier integratedsafety analysis by de Andrade et al [22]—which allowed pharma-cologic antithrombotic prophylaxis—reported that EPO was not anadditional thrombotic risk factor when compared with placebo.The caveat, however, was that if the hemoglobin level was drivento a target that exceeds 11 g/dL, more deaths, serious adversecardiovascular reactions, and strokes were observed. Antithrombo-tic prophylaxis—both mechanical and pharmacological—is thecurrently accepted standard of care in the perioperative period[23]; thus, it remains unclear whether EPO represents a realadditional thrombotic risk factor in this current era of widespreadthromboprophylaxis.

No RCTs studying the safety of IV iron as a primary end pointwere identified. Based on the literature reviewed here, IV ironappears to be as well tolerated as oral iron; however, the incidenceof severe anaphylactic-type reactions due to IV iron is difficult toestimate in prospective trials because of its relatively frequencyof occurrence.

Table A2Cochrane risk of bias assessment of individual studies: 1. Randomization generation; 2. Allocto intervention; 6. Blinding of providers to intervention; 7. Blinding of assessors to interconflict(s) of interest.

Ref Study 1 2 3 4 5 6 7 8 9 10 Appraisal Comments

[24] Serrano-Trenas L L H L L L L L L L Prestudy power analysis (samwith 80% power). Reports bawas not different b/w groupsdoses = 16 (16.2%).

[25] Cuenca H H H H L H L L H ? The following comments refeiron stores. Mean transfusion[26] Cuenca H H H H L H L L H ?

[27] Munoz H H H H L H L L H L[28] Bhandal L L H L L L L L H ? Prestudy power analysis (sa

power). Reports baseline irointroduce bias as transfusion

[29] Kim L L H L L H L H L ? Prestudy power analysis (samwith 80% power). Report basITT population (included onl

[30] Diez-Lobo H H H L L H L L L ? No power analysis. Report btransfusion decisions withou

Conclusion

In recent years, an effort to reduce perioperative RBC trans-fusions has led to a growing number of trials studying EPO and IViron as a bloodless therapeutic modality [3]. Perioperative bloodmanagement strategies might benefit from targeting the underly-ing pathophysiology of functional iron deficiency by choosingpharmacological therapies that would enhance the marrow'serythropoietic drive, particularly in cases of preoperative irondeficiency anemia. Taken together, the 8 low risk of bias RCTsreviewed here support the following general conclusions about theefficacy and safety of EPO and IV iron:

• Patients with preoperative iron deficiency anemia may have anearlier and more robust hemoglobin recovery with preoperativeIV iron therapy than with oral iron supplementation.

• A short preoperative regimen of EPO, or a single dose of EPO plusIV iron in the preoperative or intraoperative period, maysignificantly reduce transfusion requirements (NNT to complete-ly avoid RBC transfusions ranged from 3 to 6).

• Intravenous iron appears to be as well tolerated as oral iron;however, the incidence of severe anaphylactic-type reactionsattributable to IV iron is difficult to estimate in prospective trialsbecause of its relatively infrequent occurrence.

• Erythropoietin may increase the risk of thromboembolism inspinal surgery patients who receive mechanical antithromboticprophylaxis in the perioperative period so pharmacologicalthromboprophylaxis is advised.

Future low risk of bias, adequately powered prospectiveefficacy, and safety trials in various surgical settings thattraditionally require RBC transfusions would be required to makeevidenced-based conclusions about the clinical significance of EPOand IV iron as a transfusion avoidance strategy in perioperativeblood management.

Appendix A

Table A1

ation concealment; 3. Reticulocyte count; 4. Baseline iron profile; 5. Blinding of patientsvention; 8. Incomplete outcome data; 9. Selective outcomes reporting; 10. Potential

ple size 100 per groupwould be sufficient to detect 20% difference in transfusion rateseline iron stores but not reticulocyte response. Compliance to transfusion protocol; however, IV dosing rate was variable: 1 dose = 20 (20.2%), 2 doses = 63 (63.6%), 3

r to F2, F3, and F4: No power analysis. Do not report Reticulocyte response, or baselinetrigger was not reported.

mple size 20 per group would be sufficient to detect 25% increase in Hb with 90%n stores, but not reticulocyte response. Unblinded providers were unlikely torate was not an endpoint.ple size 36 per group would be sufficient to detect 1 g/dL difference in hemoglobin

eline iron stores, but not reticulocyte response. Efficacy was analyzed using modifiedy those with ≥80% compliance).aseline iron stores, but not reticulocyte response. Unblinded providers madet protocol guidance.

(continued on next page)

Table A2 (continued)


[31] Armand-Ugon H H H H L H L L H H No power analysis. Do not report reticulocyte response or baseline iron stores. Unblinded providers madetransfusion decisions without protocol guidance. No real comparator group as postoperative Hb level is a criticalcovariate. Do not clearly report or discuss primary outcomes.

[32] Edwards L L H L L H L L H H Randomization was stratified according to baseline Hb to ensure equal number of anemic and nonanemic patients.Prestudy power analysis (sample size 30 per group would be sufficient to detect 0.5 g/dL difference in Hb with 80%power). Reports baseline iron stores but not reticulocyte response. Unblinded providers made transfusiondecisions. Efficacy was analyzed using modified ITT population (2 patients did not undergo surgery). Anemicpatients only make up n = 18 so underpowered even to detect small difference in Hb.

[33] Titos-Arcos H H H H L H L L L L No power analysis. Do not report reticulocyte response, or baseline iron stores. Excluded preoperative transfusions.Unblinded providers made transfusion decisions.

[34] Deutsch ? ? L L L H L H H H Method of randomization is not clear. Prestudy power analysis performed (sample size 23 per group would besufficient to detect difference of 1.1 g/dL in mean Hb with 80% power). Reports reticulocyte response and excludesiron deficiency anemia. Transfusions decisions made by unblinded attending surgeons. PAD arm may be biasedtoward more transfusions as timing of donation is close to the date of surgery; 7 autologous units (18%) were notused.

[35] Feagan L L L L L L L H L H Prestudy power analysis (total sample size of 216 would be sufficient to detect 20% reduction in transfusion rate).Reports reticulocyte response and excluded iron deficiency. Transfusion trigger was similar b/w groups (P= .165).Efficacy was analyzed using modified ITT population (ie, received at least 1 dose of EPO, underwent surgery).

[36] Stowell ? ? H H L ? L H H H Method of randomization is not clear. Prestudy power analysis performed (sample size 500 per group would besufficient to detect 8% difference in allogeneic transfusion rate with 80% power); however, study was terminatedearly due to unexplained administrative reasons so only 490 of the planned 1110 participants were enrolled. Donot report reticulocyte response or baseline iron stores. Providers not blinded but mean transfusion trigger similarb/w groups (EPO 8.4 ± 1.05 vs PAD 8.3 ± 0.84). Efficacy was analyzed using modified ITT population (ie,randomized to a treatment group and who underwent surgery as planned). Sixty-two patients withdrew beforesurgery (32 EPO arm vs 30 PAD arm).

[37] Stowell L L L L L L L H L H Interim power analysis (total sample size 674 would be sufficient to show noninferiority with 80% power of EPOcompared with standard blood conservation with respect to incidence of DVT). No prestudy screening US for DVTwas performed; thus, without this key baseline clinical data, attributing DVTs to EPO treatment may beconfounded. Furthermore, Doppler images were only obtained in EPO arm, which was 291 (85.6%) and comparatorarm was 304 (89.4%). EPO arm included 2 DVTs despite normal US.

[38] Weber L L H H L L L L H H No power analysis. Do not report reticulocyte response or baseline iron stores. Transfusion trigger is similar b/w groups. Efficacy was analyzed using modified ITT population; however, only a few patients were excluded so it isconsidered at low risk. Compared time to ambulation and discharge b/w nonrandomized groups (transfused vs nottransfused); this subgroup analysis is at high risk for systematic selection bias.

[39] Cushner H H H H L H L ? H ? No power analysis. All patients had active infection; however, do not report reticulocyte response or iron stores.Transfusion decisions made by unblinded providers; lower transfusion rates during stage 1 and poststage 2 in theEPO arm and historical cohort suggest that transfusion bias exists. Timing of single EPO administration during 6-8 weeks of IV antibiotics is unclear. Furthermore, it is unclear how many received poststage 2 EPO.

[40] Laffosse H H H H L H L H L ? No power analysis. Do not report reticulocyte response or baseline iron stores. Do not report mean transfusiontrigger. It is unclear how many patients predonated autologous blood in the low Hb arm; this may represent animportant explanatory covariate.

[41] Cushner H H H H L H L L L H No power analysis. Do not report reticulocyte response or baseline iron stores. Mean transfusion trigger isunknown. Inconsistencies in reported overall vs stage 2 transfusion rates b/w the main text and associated figures.

[42] Kourtzis H H L H L H L L L ? No power analysis. Reticulocyte response reported; however, does not report iron stores. Lowering transfusiontrigger from Hct 26-27 to Hct 21-22 may potentially explain differences in transfusion rates. Intention of bloodsaving techniques was not to normalize preoperative Hct but to increase postoperative RBC production (seereticulocyte peak).

[43] Sesti H H H H H H L H H ? No power analysis. Do report reticulocyte response or baseline iron stores. Do not address compliance to self-administered EPO therapy. Do no report transfusion rates. No comparisons b/w groups were reported; inferentialstatistics were not performed.

[44] Dousias L L L L L L L L L ? No power analysis (small sample size 23 vs 27). Included only women with ferritin N50; reported reticulocyteresponse.

[45] Larson ? ? H L L H L L L ? Method of randomization is not clear. Prestudy power analysis (sample size 15 per group would be sufficient todetect 1 g/dL difference in Hb with 80% power). Report baseline iron stores; however, does not report reticulocyteresponse. Transfusion decisions were made by unblinded providers.

[46] Christodoulakis ? ? H L L H L H L ? Method of randomization is not clear. No power analysis. Reports baseline iron stores but not reticulocyteresponse. Unblinded providers made transfusion decisions. Modified ITT population (91.5%); do not report thenumber of patient randomly allocated to treatment arms.

[47] Qvist ? ? L L L L L H L H Method of randomization is not clear. No power analysis. Report reticulocyte response and baseline iron stores.Efficacy was analyzed using amodified ITT population since 11 (EPO) and 8 (placebo) excluded for various reasons.

[48] Scott ? ? L L L L L H L H Method of randomization is not clear. No power analysis. Report reticulocyte response and baseline iron stores.Modified ITT population (incomplete hematologic data).

[49] Nieder H H H H L H L L L ? No power analysis. Do not report reticulocyte response, or baseline iron stores. Transfusion decisions made by asingle unblinded surgeon.

[50] Weltert L L H H L H L L L L Prestudy power analysis (sample size 160 per group would be sufficient to detect 15% reduction in transfusion ratewith 90% power). Do not report reticulocyte response, or baseline iron stores. Unblinded providers madetransfusion decisions.

[51] Yazicioglu L L L L L L L L L ? No power analysis. Report reticulocyte response and baseline iron stores. Transfusion decisions were made byblinded providers.

[52] Kateros H ? H H L H L ? L ? Method of randomization is not clear. No power analysis. Do not report reticulocyte response or iron stores.Unblinded providers made transfusion decisions.

[53] Na ? L H L L L L L L L Method of randomization is not clear. Performed prestudy power analysis (sample size 54 per group would besufficient to detect 25% reduction in transfusion rate with 80% power). All patients were iron deficient; do notreport reticulocyte response. Efficacy was analyzed using a modified ITT population; however, small and balancednumber of patients withdrew from the study. Transfusion trigger guidelines were followed. Subgroup analysis(transfused vs not transfused) broke randomization and introduced systematic selection bias (iron profile).


[54] Olijhoek ? L L L L L L L L ? Method of randomization is not clear. No power analysis. Reported reticulocyte response; excluded absolute irondeficiency. Did not plan to report perioperative efficacy or safety outcomes.

[55] Garcia-Erce H H L L L ? L L L L Prestudy power analysis (sample size of 73 in treatment arm, 36 in control group would be sufficient to detect 30%difference in transfusion rate with 80% power). Reported reticulocyte response, iron stores (including serumtransferrin receptor), and CRP. Postoperative transfusion decided by unblinded physician; however, no between-group differences in transfusion trigger (P = .87).

[56] Gonzalez-Porras

H H H L L ? L L L L No power analysis. Do no report reticulocyte response. Although providers were not blinded, 2 independentreviewers evaluated and reported transfusion appropriateness.

[57] Garce-Erce H ? H H L H L L L L No power analysis. EPO dose was unintentionally missed so risk of systematic selection bias is unclear. Do notreport reticulocyte response or iron stores. Transfusion decisions were unblinded; do not report transfusiontrigger.

[58] Braga ? ? L L L L L H H ? Method of randomization is not clear. No power analysis. Report reticulocyte response and baseline iron stores.Efficacy was analyzed using a modified ITT population as 4 withdrew presurgery due to GI bleed. Providers wereblinded. Details about transfusion provided only for 14 out of 20 patients who underwent curative surgery; left outtransfusion data for 6 patients who underwent palliative surgery.

[59] Kettelhack ? ? L L L L L H L ? Method of randomization is not clear. Prestudy power analysis (sample size 90 per group would be sufficient todetect 25% reduction in ABT with 90% power). Report reticulocyte response and baseline iron stores. Providerswere blinded. Study terminated early after interim analysis at 50% recruitment (n = 109) because EPO was noteffective. Efficacy analyzed using a modified ITT population (4 and 3 excluded from EPO and placebo, respectively).

[60] Karkouti L L L L L L L H H H Interim power analysis (sample size 20 per group would be sufficient to detect 0.8 ± 0.9 increase in Hb with 80%power). Report reticulocyte response and baseline iron stores. Study terminated early due to results of interimpower analysis. Reports Hb levels during the second postoperative week when the expected effect of EPO therapywas most likely to be observed. Efficacy analyzed using a modified ITT population as 7 patients were excluded.

[61] Madi-Jebara L L L L L L L H H ? No power analysis. Report reticulocyte response and baseline iron stores. Efficacy was analyzed using a modifiedITT population as those requiring postoperative transfusion for Hb b7 were excluded.

[62] Yoo L L L L L L L L L L Study designed to validate the superiority of EPO treatment. Interim power analysis (sample size 32 per groupwould be sufficient to detect reduction from 44% to 13% with 80% power). Reports reticulocyte response andexcludes iron deficiency anemia. Blinded providers made transfusion decisions. Full ITT population analyzed.Complete data set reported.

Table A2 (continued)



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