Ø Dr. Block is the Director of Clinical Research at Colorado Kidney … · 2019-02-13 · Ø Dr....

KidneyDisease:ImprovingGlobalOutcomes

Geoffrey A. Block MD, CCRI

Ø  Dr.BlockistheDirectorofClinicalResearchatColoradoKidneyCare,adepartmenthecreatedtofurtherenhancethecareandtreatmentofpa;entssufferingfromChronicKidneyDisease(CKD)anditseffects.

Ø  CurrentlyDr.BlockisthePrincipalInves;gatororinves;gatorforseveralinterna;onalandna;onalclinicalstudies.

Ø  Dr.BlockservesasanassociateclinicalprofessorinmedicineattheUniversityofColoradoHealth

SciencesCenter,andasanaFendingphysicianatSt.JosephsHospital.HealsoisthemedicaldirectoroftheDaVita-LowryHemodialysisUnit.

UPDATEONMANAGEMENTOFPTHANDVITAMINDINCKD

GEOFFREYA.BLOCK,MDDENVERNEPHROLOGYDENVER,USA

KDIGO2016ClinicalPracCceGuidelineUpdate


CKD-MBDGUIDELINEUPDATE2016

WorkGroup

•  GeoffreyBlock(USA)•  PieterEvenepoel(Belgium)•  MasafumiFukagawa(Japan)•  CharlesA.Herzog(USA)•  LindaMcCann(USA)

•  SharonM.Moe(USA)•  RukshanaShroff(UK)•  MarcelloA.Tonelli(Canada)•  NigelD.Toussaint(Australia)•  MarcG.Vervloet(TheNetherlands)

GuidelineChairsMarkusKeZeler(Germany)

MaryBLeonard(USA)


EVIDENCEREVIEWTEAMLeader

KarenA.RobinsonDirector,JohnsHopkinsUniversity

AHRQEvidence-BasedPracCceCenter

EvidenceReviewTeamCaseyM.Rebholz,PhD,MPHMS

LisaM.Wilson,ScMErmiasJirru,MD,MPHMarisaChiLiu,MD,MPH

JessicaGayleard,BSAllenZhang,BS


KDIGOCONTROVERSIESCONFERENCEONCKD-MBD,2013(MADRID,SPAIN)

•  74aFendeesfrom5con;nentsand19countries

•  Representedexpertsinadult,pediatricandtransplantnephrology,endocrinology,cardiology,bonehistomorphometry,andepidemiology

•  Dividedinto4BreakoutGroups-12ItemsRec.forReview–  BoneQuality

–  CalciumandPhosphate

–  VitaminDandPTH

–  VascularCalcificaCon


AREWEACHIEVINGOURDESIREDOUTCOMES?

WeshouldcareabouttreaCng

PATIENTS,NOTtheirlabvalues!


EVIDENCEBASED

•  WorkingGroupRecognizedthatmanylargeareaswithevidencegapremain

•  ExisCngGuidelinesforwhichtherewerenonewevidencebasedoutcomeswerenotmodifiedoraddressed(e.g.PTHassay)


CHAPTER4.2:TREATMENTOFABNORMALPTHLEVELSINCKD-MBD


ASSESSMENT

4.2.1:InpaCentswithCKDStages3a-5notondialysis,theopCmalPTHlevelisnotknown.However,wesuggestthatpaCentswithlevelsofintactPTHprogressivelyrisingorpersistentlyabovetheuppernormallimitfortheassaybeevaluatedformodifiablefactors,includinghyperphosphatemia,hypocalcemia,highphosphateintake,andvitaminDdeficiency.(2C)


RATIONALE

•  Sincethe2009KDIGOguidelinetherearesCllnoRCTsthatdefineanopCmalPTHlevelforpaCentswithCKDstages3a-5,orclinicalendpointsofhospitalizaCon,fractureormortality.

•  TheWorkGroupfeltthatmodestincreasesinPTHmayrepresentanappropriateadapCveresponsetodecliningkidneyfuncConandhaverevisedthisstatementtoinclude“persistently”abovetheuppernormalPTHlevelaswellas“progressivelyrising”PTHlevels,ratherthan“abovetheuppernormallimit.”Thatis,treatmentshouldnotbebasedonasingleelevatedvalue.


RATIONALE•  AlthoughtheopCmalPTHisnotknown,theWorkGroupfelt

thatrisingPTHlevelsinCKDstages3a-5warrantexaminaConofmodifiablefactors:

o  VitaminDinsufficiency/deficiency

o  Hypocalcemia

o  Hyperphosphatemia

o  Highphosphateintake•  WorkGroupalsoadded‘highphosphateintake,’becauseof

theincreasingrecogniConthatexcessphosphateintakedoesnotalwaysresultinhyperphosphatemia,especiallyinearlystagesofCKD,andthathighphosphatecouldpromoteSHPT.


VITAMIND

4.2.2:InadultpaCentswithCKDStages3a-5notondialysis,wesuggestcalcitriolandvitaminDanalogsnotberouCnelyused.(2C)ItisreasonabletoreservetheuseofcalcitriolandvitaminDanalogsforpaCentswithCKDStages4-5withsevereandprogressivehyperparathyroidism.(NotGraded)

Inchildren,calcitriolandvitaminDanalogsmaybeconsideredtomaintainserumcalciumlevelsintheage-appropriatenormalrange.(NotGraded)


RATIONALE

•  SuppressionofPTHviacalcitriolandothervitaminDanalogshavebeenthetherapeuCcmainstayforthetreatmentofSHPT.MulCpleRCTscitedinthe2009Guidelinereportedbenefitsoftheseagentsonimprovingbiochemicalendpointsandadverseeffectsofhypercalcemiawerealsonoted.

•  Twotrials,PRIMOandOPERA,demonstratedsignificantlyincreasedriskofhypercalcemiainpaCentstreatedwithparicalcitol,comparedwithplacebo,intheabsenceofbeneficialeffectsonsurrogatecardiacendpoints.


THEPRIMOTRIAL

ThadaniRetal.JAMA.2012;307:674-684


PARICALCITOLEFFECTONCALCIUMANDPHOSPHATE

•  Serumcalciumlevelsincreasedameanof0.32mg/dL(95%CI,0.19-0.45mg/dL)intheparicalcitolgroupanddecreased0.25mg/dL(95%CI,−0.37to−0.12mg/dL)intheplacebogroup(between-groupdifference,P<.001).

•  Serumphosphoruslevelsincreased0.23mg/dL(95%CI,0.07-0.39mg/dL)intheparicalcitolgroupandincreased0.04mg/dL(95%CI,−0.12to0.20mg/dL)intheplacebogroup(between-groupdifference,P=.05).

•  Hypercalcemia-paricalcitol22.6%versusplacebo0.9%,p<.001

•  eGFRdecrease(creaCnine)paricalcitol-4.1ml/minversusplacebo-0.1ml/min,p<.001

•  NosignificanteffectonmeasuresofLVsizeorfuncCon


THEOPERATRIAL

WangAetal.JAmSocNephrol.2014;25:175-186

Hypercalcemia>2.55mmol/L:Paricalcitol43.3%Placebo3.3%NosignificanteffectonmeasuresofLVsizeorfuncCon


CONCLUSIONS•  RecentRCTsofvitaminDanalogsfailedtodemonstrate

improvementsinclinicallyrelevantoutcomesbutdiddemonstrateincreasedriskofhypercalcemia.Recentmeta-analyseswerelargelyconfirmatoryandsupportedthehypercalcemiariskassociaConwithcalcitriolandvitaminDanalogs.

•  Theseresults,combinedwiththeopinionthatmoderatePTHelevaConsmayrepresentanappropriateadapCveresponse,ledtheWorkGrouptoconcludethattherisk-benefitraCooftreaCngmoderatePTHelevaConswasnolongerfavorableandthattheuseofcalcitriolorvitaminDanalogsshouldbereservedforonlysevereandprogressiveSHPT.


CONCLUSIONS•  TherearesCllnoRCTsdemonstraCngbeneficialeffectsof

calcitriolorvitaminDanalogsonpaCent-leveloutcomes,suchascardiaceventsormortality,andtheopCmallevelofPTHinCKDstages3a-5isnotknown.

•  TherapywiththeseagentsmayhaveaddiConalharmfuleffectsrelatedtoincreasesinserumphosphateandFGF23levels.

•  IfiniCatedforsevereandprogressiveSHPT,calcitriolorvitaminDanalogsshouldbestartedwithlowdoses,independentoftheiniCalPTHconcentraCon,andthenCtratedbasedonthePTHresponse.

•  Hypercalcemiashouldbeavoided.


VITAMIND

4.2.2:InadultpaCentswithCKDStages3a-5notondialysis,wesuggestcalcitriolandvitaminDanalogsnotberouCnelyused.(2C)ItisreasonabletoreservetheuseofcalcitriolandvitaminDanalogsforpaCentswithCKDStages4-5withsevereandprogressivehyperparathyroidism.(NotGraded)

Inchildren,calcitriolandvitaminDanalogsmaybeconsideredtomaintainserumcalciumlevelsintheage-appropriatenormalrange.(NotGraded)


RATIONALE

•  ArecentCochranereviewexaminedvitaminDtherapyforbonediseaseinchildrenwithCKDstages2–5andondialysis.Bonedisease,asassessedbychangesinPTHlevels,wasimprovedbyallvitaminDpreparaConsregardlessofpreparaConorrouteorfrequencyofadministraCon.TheCochranereviewhasnotshownanysignificantdifferenceinhypercalcemiariskwithvitaminDpreparaConscomparedwithplacebo,butonestudyshowedasignificantlygreaterriskofhypercalcemiawithintravenouscalcitrioladministraCon.


CONCLUSIONS

•  NodifferenceingrowthrateswasdetectedbetweendifferentvitaminDanalogsoruseoforalorintravenousvitaminDtreatments.

•  TheWorkGrouprecommendedthatserumcalciumshouldbemaintainedwithinage-appropriatereferencerangeinchildren,andgiventheassociaConofhighPTHlevelswithreducedbonemineralizaConandincreasedvascularcalcificaCon,childrenarelikelytorequirecalcitriolorotheracCvevitaminDanalogtherapy.


LOWERINGPTH

4.2.4:InpaCentswithCKDStage5DrequiringPTH-loweringtherapy,wesuggestcalcimimeCcs,calcitriol,orvitaminDanalogs,oracombinaConofcalcimimeCcsandcalcitriol,orvitaminDanalogs.(2B)


RATIONALE

•  ThisrecommendaConoriginallyhadnotbeenidenCfiedforanupdate.However,duetoasubsequentseriesofsecondaryandpost-hocpublicaConsoftheEVOLVEtrial,theWorkGroupdecidedtore-evaluateRec.4.2.4aswell.


EVOLVE:LOWERINGPTH

Chertow GM, et al. N Engl J Med. 2012;367:2482-2494


EVOLVESTUDY:CINACALCET

Chertow GM, et al. N Engl J Med. 2012;367:2482-2494


530475

489425

452374

415326

383293

345261

319239

291203

254182

233167

210155

194136

180119

11672

6746

1615

Age<65years

CinacalcetPlacebo

HazardraCo,0.99(95%CI,0.88,1.11)Log-rank,p=0.824

Prop

or;o

nEven

t-free

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Time(months)0 4 8 12 1620 24 2832 364044 4852 5660

Subjectsatrisk:

0.2

0

0.3

TIMETOPRIMARYCOMPOSITEENDPOINT

CinacalcetPlacebo

HazardraCo,0.74(95%CI,0.63,0.86)Log-rank,p<0.001

Prop

or;o

nEven

t-free

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Time(months)0 4 8 12 1620 24 2832 364044 4852 5660

Subjectsatrisk:

0.2

0

0.3

Age≥65years

14181460

13531379

12871319

12231253

11731183

11271123

10651073

10121021

976978

944942

905898

857860

809821

563578

332358

9799

Parfreyetal,CJASN,2015


TIMETOFIRSTEPISODEOFSEVEREUNREMITTINGHPT(INTENT-TO-TREATANALYSIS)

CinacalcetPlacebo

Prop

or;o

nEven

t-free

Time(months)

HazardraCo,0.43(95%CI,0.37,0.50)Log-rank,p<0.001

0.0

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60

Severe,unremi]ngHPT• Pre-specifiedanddefinedas–  PTH>1000pg/mL(106.0pmol/L)withserumcalcium>10.5mg/dL(2.6mmol/L)on2consecuCveoccasionsOR

–  PTH>1000pg/mLwithserumcalcium>10.5mg/dLonasingleoccasionandsubsequentcommercialcinacalcetusewithin2monthsofthelaboratoryassessmentOR

–  parathyroidectomy


PRIMARYCOMPOSITEENDPOINT:SENSITIVITYANALYSES

AnalysisType Placebo(N=1935)

Cinacalcet(N=1948) HR(95%CI) p-value

ITT 952(49.2) 938(48.2) 0.93(0.85,1.02) 0.112

CensoratPTX 911(47.1) 916(47.0) 0.90(0.82,0.99) 0.031

CensoratKTX 907(46.9) 891(45.7) 0.90(0.82,0.99) 0.029

CensoratCommercialCinacalcetUse 818(42.3) 870(44.7) 0.90(0.82,0.99) 0.032

CensoratPTXorCommercialCinacalcetUse 786(40.6) 854(43.8) 0.87(0.79,0.96) 0.006

CensoratPTX,CommercialCinacalcet,orKTX 748(38.7) 812(41.7) 0.84(0.76,0.93) <0.001


RATIONALE•  AlthoughEVOLVEdidnotmeetitsprimaryendpoint,the

majorityoftheWorkGroupwerereluctanttoexcludepotenCalbenefitsofcalcimimeCcsforStage5DpaCents,basedonsubsequentprespecifiedanalyses.

•  NoPTH-loweringtreatmentwasprioriCzedatthisCme,sincecalcimimeCcs,calcitriol,orvitaminDanalogsareallacceptablefirst-lineopConsinCKDStage5DpaCents.

•  TheWorkGroupexplicitlyendorsesthepresenceofclinicalequipoiseandtheneedtoconductplacebocontrolledtrialswithcalcimimeCcsversusstandardtherapyforthetreatmentofSHPTinpaCentswithCKDstage5Dwithemphasisonthoseatgreatestrisk(e.g.,older,presenceofcardiovasculardisease).


PEDIATRICPERSPECTIVE

•  Studiesofcinacalcetinchildrenarelimitedtocasereports,caseseries,asinglecenterexperience(with4to28paCents),andanopenlabelstudyofasingledosein12childrenondialysis.InrecogniConoftheuniquecalciumdemandsofthegrowingskeleton,PTH-loweringtherapiesshouldbeusedwithcauConinchildrentoavoidhypocalcemia.FuturestudiesareneededinchildrenbeforemakingpediatricspecificrecommendaCons.


KEYMESSAGES

•  ItisimportanttoemphasizetheinterdependencyofserumCa,P,andPTHforclinicaltherapeuCcdecision-making.

•  ThePRIMOandOPERAstudiesfailedtodemonstrateimprovementsinclinicallyrelevantoutcomesbutdiddemonstrateincreasedriskofhypercalcemia.Accordingly,rouCneuseofcalcitrioloritsanalogsinCKDstages3a–5isnolongerrecommended.


KEYMESSAGES

•  Noconsensuswasreachedtorecommendcinacalcetasfirst-linetherapyforloweringPTHinallpaCentswithSHPTandCKDStage5D.TheWorkGroupdecidedtomodifythe2009recommendaContolistcalcimimeCctherapynowfirst,inalphabeCcalorder,amongacceptabletreatmentopConswhilesCllrecognizingtheuClityandefficacyofacCvevitaminDcompounds.


COMPARISONOF2016VS2009RECOMMENDATIONS

NEW4.2.1.InpaCentswithCKDStages3a-5notondialysis,theopCmalPTHlevelisnotknown.However,wesuggestthatpaCentswithlevelsofintactPTHprogressivelyrisingorpersistentlyabovetheuppernormallimitfortheassaybeevaluatedformodifiablefactors,includinghyperphosphatemia,hypocalcemia,highphosphateintake,andvitaminDdeficiency.(2C)

OLD4.2.1.InpaCentswithCKDstages3–5notondialysis,theopCmalPTHlevelisnotknown.However,wesuggestthatpaCentswithlevelsofintactPTHabovetheuppernormallimitoftheassayarefirstevaluatedforhyperphosphatemia,hypocalcemia,andvitaminDdeficiency(2C).

ItisreasonabletocorrecttheseabnormaliCeswithanyorallofthefollowing:reducingdietaryphosphateintakeandadministeringphosphatebinders,calciumsupplements,and/ornaCvevitaminD(notgraded).



Ra;onale:TheWorkGroupfeltthatmodestincreasesinPTHmayrepresentanappropriateadapCveresponsetodecliningkidneyfuncConandhaverevisedthisstatementtoinclude‘persistently’abovetheuppernormalPTHlevelaswellas‘progressivelyrising’PTHlevels,ratherthan‘abovetheuppernormallimit.’Thatis,treatmentshouldnotbebasedonasingleelevatedvalue.



NEW4.2.2.InadultpaCentswithCKDStages3a-5notondialysis,wesuggestcalcitriolandvitaminDanalogsnotberouCnelyused(2C).ItisreasonabletoreservetheuseofcalcitriolandvitaminDanalogsforpaCentswithCKDStages4-5withsevereandprogressivehyperparathyroidism(NotGraded).

Inchildren,calcitriolandvitaminDanalogsmaybeconsideredtomaintainserumcalciumlevelsintheage-appropriatenormalrange(NotGraded).

OLD4.2.2.InpaCentswithCKDstages3–5notondialysis,inwhomserumPTHisprogressivelyrisingandremainspersistentlyabovetheupperlimitofnormalfortheassaydespitecorrecConofmodifiablefactors,wesuggesttreatmentwithcalcitriolorvitaminDanalogs(2C).

Ra;onale:RecentRCTsofvitaminDanalogsfailedtodemonstrateimprovementsinclinicallyrelevantoutcomesbutdiddemonstrateincreasedriskofhypercalcemia.



NEW4.2.4.InpaCentswithCKDStage5DrequiringPTH-loweringtherapy,wesuggestcalcimimeCcs,calcitriol,orvitaminDanalogs,oracombinaConofcalcimimeCcsandcalcitriol,orvitaminDanalogs.(2B)

OLD4.2.4.InpaCentswithCKDstage5DandelevatedorrisingPTH,wesuggestcalcitriol,orvitaminDanalogs,orcalcimimeCcs,oracombinaConofcalcimimeCcsandcalcitriolorvitaminDanalogsbeusedtolowerPTH(2B).

•  ItisreasonablethattheiniCaldrugselecConforthetreatmentofelevatedPTHbebasedonserumcalciumandphosphoruslevelsandotheraspectsofCKD–MBD(notgraded).



•  Itisreasonablethatcalciumornon-calcium-basedphosphatebinderdosagebeadjustedsothattreatmentstocontrolPTHdonotcompromiselevelsofphosphorusandcalcium(notgraded).

•  Werecommendthat,inpaCentswithhypercalcemia,calcitrioloranothervitaminDsterolbereducedorstopped(1B).

•  Wesuggestthat,inpaCentswithhyperphosphatemia,calcitrioloranothervitaminDsterolbereducedorstopped(2D).

•  Wesuggestthat,inpaCentswithhypocalcemia,calcimimeCcsbereducedorstoppeddependingonseverity,concomitantmedicaCons,andclinicalsignsandsymptoms(2D).

•  Wesuggestthat,iftheintactPTHlevelsfallbelowtwoCmestheupperlimitofnormalfortheassay,calcitriol,vitaminDanalogs,and/orcalcimimeCcsbereducedorstopped(2C).

Old4.2.4(cont’d)



Ra;onalefornew4.2.4:ThisrecommendaConoriginallyhadnotbeenforupdaCngbytheKDIGOControversiesConferencein2013.However,duetoasubsequentseriesofsecondaryandpost-hocpublicaConsoftheEVOLVEtrial,theWorkGroupdecidedtore-evaluateRecommendaCon4.2.4aswell.AlthoughEVOLVEdidnotmeetitsprimaryendpoint,themajorityoftheWorkGroupwerereluctanttoexcludepotenCalbenefitsofcalcimimeCcsforStage5DpaCentsbasedonsubsequentpre-specifiedanalyses.Itwas,however,decidednottoprioriCzeanyPTH-loweringtreatmentatthisCmesincecalcimimeCcs,calcitriol,orvitaminDanalogsareallacceptablefirst-lineopConsinStage5DpaCents.


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TotheKDIGOstaffforallofthemeCculoushelptheyhaveprovidedincreaCngthedrazGuidelinesandwiththedisseminaConofknowledge

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Ø Dr. Block is the Director of Clinical Research at Colorado Kidney … · 2019-02-13 · Ø Dr....

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