Rev. Bras. Hematol. Hemoter. vol.36 número6

rev bras hematol hemoter. 2014;36(6):450–453

Revista

Brasileira

de

Hematologia

e

Hemoterapia

Brazilian

Journal

of

Hematology

and

Hemotherapy

w w w . r b h h . o r g

Special

article

Guidelines

on

the

treatment

of

anemia

of

chronic

renal

failure

using

recombinant

human

erythropoietin:

Associac¸ão

Brasileira

de

Hematologia,

Hemoterapia

e

Terapia

Celular

Guidelines

Project:

Associac¸ão

Médica

Brasileira

–

2014

Aderson

da

Silva

Araújo

_,

_Clarisse

_Lopes

_de

_Castro

_Lobo

_,

_Dimas

_Tadeu

_Covas

_,

Fernando

Ferreira

Costa

_,

_Letícia

_Medeiros

_,

_Rodolfo

_Delfini

_Canc¸ado

,

Sandra

Fátima

Menosi

Gualandro

_,

_Sara

_Teresinha

_Olalla

_Saad

b_{InstitutoEstadualdeHematologiaArthurdeSiqueiraCavalcanti(HEMORIO),RiodeJaneiro,RJ,Brazil} c_{FaculdadedeMedicinadeRibeirãoPreto(FMRP),UniversidadedeSãoPaulo(USP),RibeirãoPreto,SP,Brazil} d_{UniversidadedeCampinas(UNICAMP),Campinas,SP,Brazil}

e_{Associac¸ãoMédicaBrasileira(AMB),SãoPaulo,SP,Brazil}

f_{FaculdadedeCiênciasMédicasdaSantaCasadeSãoPaulo(FCMSCSP),SãoPaulo,SP,Brazil} g_{UniversidadedeSãoPaulo(USP),SãoPaulo,SP,Brazil}

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Articlehistory:

Received11August2014 Accepted2September2014 Availableonline1October2014

Introduction

Theguidelines projectisa jointinitiative ofthe Associac¸ão MédicaBrasileiraandtheConselhoFederaldeMedicina.Itaimsto collectinformationtostandardizedecisionsandhelpcreate

∗ _{Correspondingauthorat:HemocentrodaSantaCasadeSãoPaulo,RuaMarquêsdeItu,579,3}◦_{andar,01223-001SãoPaulo,SP,Brazil.} E-mailaddress:[email protected](R.D.Canc¸ado).

strategiesduringdiagnosis andtreatment.Thesedatawere preparedand are recommended bytheAssociac¸ão Brasileira de Hematologia, Hemoterapia e Terapia Celular (ABHH). Even so, allpossibledecisionsshouldbeevaluatedbythe physi-cianresponsiblefordiagnosisandtreatmentaccordingtothe patient’ssettingandclinicalstatus.

http://dx.doi.org/10.1016/j.bjhh.2014.09.009

revbrashematolhemoter.2 0 1 4;36(6):450–453

451

Table1–Checklistusedforcriticalanalysisofthe

evidence.

Studydetails

References,studydesign,

Jadadscore,strengthof

evidence

Samplecalculation

Estimateddifferences,

power,levelofsignificance,

totalpatients

Patientselection

Inclusionandexclusion

criteria

Patients

Recruited,randomized,

prognosticdifferences

Randomization

Descriptionandblinded

allocation

Patientfollowup

Time,losttostudy

Treatmentplan

Intervention,controland

blinding

Analysis

Treatmentintervention,

analyzedandcontrol

Outcomesconsidered

Primary,secondary,

instrumenttomeasurethe

outcomeofinterest

Result

Benefitorharminabsolute

data.Meanbenefitorharm

Descriptionoftheevidencecollectionmethod

ThemembersoftheABHHCommitteeresponsiblefor writ-ingtheguidelinesonthetreatmentofanemiaofchronicrenal failureusingrecombinanthumanerythropoietinpreparedthe mainquestionrelatedtoitstreatment.Theissuewas struc-turedusing the Patient/Problem, Intervention, Comparison andOutcome(PICO)system. Thesearchstrategy(Appendix 1)wasappliedtotheprimaryscientificdatabases(MEDLINE PubMed,Embase,SciELOand,Lilacs)andsecondaryscientific database(CochraneLibrary).

Methodological quality was assessed using the Jadad score,1_{butthiswasnotusedasanexclusioncriterion.The} criticalassessmentofthestudiesconsidereditemswithJadad scores<3asinconsistent,and thosewithscores≥3

consis-tent.Thestrengthofevidencewasanalyzedaccordingtothe Oxfordclassification.2

Recommendationdegreeandevidencelevel(Oxford classification)

A:Experimentalor observationalstudiesofbetter consis-tency

B:Experimentalor observationalstudieswithless consis-tency

C:Casereports(uncontrolledstudies)

D:Opinionwithoutcriticalevaluationbasedonconsensus, physiologicalstudiesoranimalmodels

Background

Usually identified when the glomerular filtration rate falls below 30mL/min, normocytic normochromic anemia is present in most patients with chronic kidney disease. Althoughthistypeofanemiahasmanycauses,itismainly relatedtoreducedproductionoferythropoietin,a glycopro-teinhormoneof165aminoacidswithamolecularweightof 30.4kDa,responsiblefortheregulationoferythropoiesisand subsequentmaintenanceofoxygenhomeostasis.3

Erythropoietinisahematopoieticgrowthfactorprimarily producedinthekidneycortex,whichstimulatesthe prolifer-ationanddifferentiationoferythroidprogenitorcellsinthe bonemarrow; whenerythropoietinisabsentthese progen-itorcells arenotprotectedagainstapoptosis.Patientswith chronickidneydiseasegraduallydevelopaninabilityto pro-duceadequateamountsoferythropoietintomaintainnormal hemoglobinlevels.4

Recombinanthumanerythropoietin(epoetinalfaand epo-etinbeta)wasproducedtomeettheneedsofthesepatients byculturingtransformedcellsfromChinesehamsterovaries andthekidneysofyounghamsters.Withahalf-lifeof24h, epoetin carries complementary DNA that encodes human erythropoietin.4

Theshorthalf-lifeofepoetinwiththenecessityoffrequent doses,ledthepharmaceuticalindustrytoinvestigate strate-giestoprolongtheactionofthe molecule.Thisresultedin thedevelopmentofdarbepoetinalfawithahalf-lifeof72h, andcontinuouserythropoietinreceptoractivator(CERA)with ahalf-lifeofaround130h.4

Aims

Toevaluatethebenefitsandadverseeffectsofrecombinant humanerythropoietinandCERAtotreatanemiaindialysis andpredialysiskidneydiseasepatients.

Searchquestion

Whatarethemainbenefitsandadverseeffectsof recombi-nanterythropoietin,darbepoetinalfaandCERAusedtotreat anemiaindialysisandpredialysiskidneydiseasepatients?

Studiesselectioninclusioncriteria

All fulltext clinical randomized controlled trials produced between1981and 2014inPortuguese,Englishand Spanish wereconsideredforthecreationoftheseguidelines.

ThetypeIIerrorwasnotusedintheselectionofstudiesso asnottoimposeanevengreaterlimitationontheselection.

According tothe PICOsystem, all patients withchronic renal failure and anemia in dialysis or pre-dialysis were included without age restriction. Interventions included treatment with erythropoietin, CERA or darbepoetin alfa. Conventional treatment and placebo were compared and outcomes were defined withan assessmentoftherapeutic response,suchasthelevelofhemoglobinandtheneedfor transfusion.

Atotalof411studieswerechosenforanalysis (PubMed-Medline:396;Embase:13andScielo/LilacsandCochranevia theBibliotecaVirtualenSalud:2).Atotalof352articleswere selected after the first analysis,all were from the primary electronicdatabaseswithnootherarticlesbeingfoundina manualsearch.

Evidenceselectedinthecriticalevaluation

452

leavingtenarticlestocomprisetheguidelines.Noarticlewas excludedduetotheunavailabilityofthefulltext.Table1was usedinthecriticalanalysisofthearticles.

Erythropoietin

Stage5renal failure patientsinchronic peritonealdialysis with anemia (hematocrit <30%) who received erythropoi-etin(4000Uthreetimesweeklyifhematocritwas<32%,and twotimesweeklyif hematocritwasbetween32%and38%) haveimprovementsinanemiaaftersixto12weeksof treat-ment(numberneededtotreat[NNT]=2)whencomparedtoa placebo.Thereisnoincreaseintheincidenceortheseverityof adverseeventsrelatedtothedrug.Patientsintreatmentmay haveaworseningofbloodpressurecontrol(numberneeded toharm[NNH]=3)5_(A).

Anemic patients with pre-dialysis chronic renal failure receivingerythropoietin(50–150U/kgthreetimesaweek)have abettertherapeuticresponse(6%increaseinhematocritfrom baseline)comparedtoplacebo(NNT=2).Thereisnoincrease intheincidenceofadverseeventssuchashighblood pres-sure,headache,jointpain, swelling,anddiscontinuationof treatment6_(A).

Anemic patients (hemoglobin <9g/dL) on hemodialysis receiving erythropoietinhavereduced needfortransfusion (NNT=2),andanelevatedriskofincreasesindiastolic pres-surewiththeneedforantihypertensivedrugs(NNH=6)7–9_(A).

Darbepoetinalfa

In adult patients with chronic renal failure (creatinine >4mg/dLand creatinine clearance<30mL/minper 1.73m2₎ and anemia (hematocrit <30%), treatment with darbepo-etinalfaatadoseof0.45mg/kgsubcutaneously,onceevery twoweeks,ortreatment witherythropoietinalfaatadose 90IU/kgsubcutaneously,onceperweek,comparedto treat-ment without drugs that modify the biological course of diseaseresultsinanaverage30%increaseintheconcentration ofhemoglobinandimprovementsinleftventricularejection fraction,althoughthereisnoimprovementinrenalfunction10 (B).

Oncomparingadultpatientsonperitonealdialysisforat leastthree monthswith hemoglobinlevels between 8and 12g/dLundertreatmentwithrecombinanterythropoietinto thosetreatedwithdarbepoetinalfaatadoseof0.45mg/kg sub-cutaneouslyonceeverytwoweeks,thelattergrouprequired fewerdosestoachievethesameincreasesinhemoglobinat 24weeksoffollow-up.Themostcommonadverseeventsare edemaandirondeficiency11_(B).

Treatmentofdiabeticpatientswithchronicrenal insuffi-ciency(glomerular filtrationrate 20–60mL/minper 1.73m2₎ and anemia (hemoglobin level<11g/dL) using darbepoetin alfa,resultsinsignificantincreasesinhemoglobinlevels(20% onaverage)within24months.There wasa9.7%reduction inthenumberoftransfusions(NNT=10),buta2.4%increase intheoccurrenceofstrokes(NNH=40).Therewere no sig-nificantdifferencesinmortalityorworseningrenalfunction amongpatients undergoing and not undergoingtreatment withdarbepoetinalfa.Thetreatmentincreasesarterialand venousthromboemboliceventsby0.9%(NNH=100)and1.8%

(NNH=55),respectively.Inpatientswithahistoryofcancer, thereisanincreaseindisease-relatedmortality12_(A).

Moreover,thereisa4%increaseincardiovascularevents (NNH=25) and 2.4% increase in mortality (NNH=40) in patients withminorresponses(increaseofless than2%in hemoglobinlevelsinthefirstmonthoftreatment)13_(A).

Continuouserythropoietinreceptoractivator(CERA)

In adultpatients withchronicrenal failureand anemiaon hemodialysis or peritoneal dialysis, the use ofCERA (dose between 60 and 180mgfortwo weeks) comparedto treat-mentwithdarbepoetin,producesnodifferenceinbenefitsor adverseevents14_(A).

Closingremarks

Recombinant humanerythropoietinhasbeen producedfor alongtimetoimproveerythropoiesis,orredbloodcell pro-ductioninpatientswithchronicrenalfailure.Syntheticforms withlongerhalf-liveshavebeendevelopedsuccessfullywith resultingimprovementsinanemia,qualityoflifeandneed fortransfusion,andtimebetweenapplications.Hemoglobin levels shouldbekeptbetween11 and12g/dLtoavoid pos-sibleincreasesincardiovasculareventsandthromboembolic phenomena15_(A).

Summary

of

the

evidence

Theuseoferythropoietintotreatanemiaassociatedto chronicrenalfailure

Benefit

Treatment with erythropoietinincreaseshemoglobin levels andreducesthenumberoftransfusionsneeded.

Adverseeffects

Treatment with erythropoietinincreasesblood pressure,in particulardiastolicpressure,andtheneedofantihypertensive drugs.

Theuseofdarbepoetinalfatotreatanemiaassociatedto chronicrenalfailure

Benefit

Treatmentwithdarbepoetinalfaincreaseshemoglobinlevels, andreducesthenumberofdosesofmedicationtoobtainthe samelevelofhemoglobincomparedtoerythropoietin,thereby reducingthenumberoftransfusions.Itimprovestheleft ven-tricularejectionfraction.

Adverseeffects

revbrashematolhemoter.2 0 1 4;36(6):450–453

453

Theuseofcontinuouserythropoietinreceptoractivatorto treatanemiaassociatedtochronicrenalfailure

Inpatientswithchronicrenalinsufficiencyandanemia,there are nosignificant differences inbenefitsor adverseeffects comparingtheuseofcontinuouserythropoietinreceptor acti-vatortotreatmentwithdarbepoetin.

Conflicts

of

interest

Theauthorsdeclarenoconflictsofinterest.

Appendix

A.

Supplementary

data

Supplementarydataassociatedwiththisarticlecanbefound, intheonlineversion,atdoi:10.1016/j.bjhh.2014.09.009.

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