Ø dr. block is the director of clinical research at colorado kidney … · 2019-02-13 · Ø dr....
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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
KidneyDisease:ImprovingGlobalOutcomes
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)
KidneyDisease:ImprovingGlobalOutcomes
EVIDENCEREVIEWTEAMLeader
KarenA.RobinsonDirector,JohnsHopkinsUniversity
AHRQEvidence-BasedPracCceCenter
EvidenceReviewTeamCaseyM.Rebholz,PhD,MPHMS
LisaM.Wilson,ScMErmiasJirru,MD,MPHMarisaChiLiu,MD,MPH
JessicaGayleard,BSAllenZhang,BS
KidneyDisease:ImprovingGlobalOutcomes
KDIGOCONTROVERSIESCONFERENCEONCKD-MBD,2013(MADRID,SPAIN)
• 74aFendeesfrom5con;nentsand19countries
• Representedexpertsinadult,pediatricandtransplantnephrology,endocrinology,cardiology,bonehistomorphometry,andepidemiology
• Dividedinto4BreakoutGroups-12ItemsRec.forReview– BoneQuality
– CalciumandPhosphate
– VitaminDandPTH
– VascularCalcificaCon
KidneyDisease:ImprovingGlobalOutcomes
AREWEACHIEVINGOURDESIREDOUTCOMES?
WeshouldcareabouttreaCng
PATIENTS,NOTtheirlabvalues!
KidneyDisease:ImprovingGlobalOutcomes
EVIDENCEBASED
• WorkingGroupRecognizedthatmanylargeareaswithevidencegapremain
• ExisCngGuidelinesforwhichtherewerenonewevidencebasedoutcomeswerenotmodifiedoraddressed(e.g.PTHassay)
KidneyDisease:ImprovingGlobalOutcomes
CHAPTER4.2:TREATMENTOFABNORMALPTHLEVELSINCKD-MBD
KidneyDisease:ImprovingGlobalOutcomes
ASSESSMENT
4.2.1:InpaCentswithCKDStages3a-5notondialysis,theopCmalPTHlevelisnotknown.However,wesuggestthatpaCentswithlevelsofintactPTHprogressivelyrisingorpersistentlyabovetheuppernormallimitfortheassaybeevaluatedformodifiablefactors,includinghyperphosphatemia,hypocalcemia,highphosphateintake,andvitaminDdeficiency.(2C)
KidneyDisease:ImprovingGlobalOutcomes
RATIONALE
• Sincethe2009KDIGOguidelinetherearesCllnoRCTsthatdefineanopCmalPTHlevelforpaCentswithCKDstages3a-5,orclinicalendpointsofhospitalizaCon,fractureormortality.
• TheWorkGroupfeltthatmodestincreasesinPTHmayrepresentanappropriateadapCveresponsetodecliningkidneyfuncConandhaverevisedthisstatementtoinclude“persistently”abovetheuppernormalPTHlevelaswellas“progressivelyrising”PTHlevels,ratherthan“abovetheuppernormallimit.”Thatis,treatmentshouldnotbebasedonasingleelevatedvalue.
KidneyDisease:ImprovingGlobalOutcomes
RATIONALE• AlthoughtheopCmalPTHisnotknown,theWorkGroupfelt
thatrisingPTHlevelsinCKDstages3a-5warrantexaminaConofmodifiablefactors:
o VitaminDinsufficiency/deficiency
o Hypocalcemia
o Hyperphosphatemia
o Highphosphateintake• WorkGroupalsoadded‘highphosphateintake,’becauseof
theincreasingrecogniConthatexcessphosphateintakedoesnotalwaysresultinhyperphosphatemia,especiallyinearlystagesofCKD,andthathighphosphatecouldpromoteSHPT.
KidneyDisease:ImprovingGlobalOutcomes
VITAMIND
4.2.2:InadultpaCentswithCKDStages3a-5notondialysis,wesuggestcalcitriolandvitaminDanalogsnotberouCnelyused.(2C)ItisreasonabletoreservetheuseofcalcitriolandvitaminDanalogsforpaCentswithCKDStages4-5withsevereandprogressivehyperparathyroidism.(NotGraded)
Inchildren,calcitriolandvitaminDanalogsmaybeconsideredtomaintainserumcalciumlevelsintheage-appropriatenormalrange.(NotGraded)
KidneyDisease:ImprovingGlobalOutcomes
RATIONALE
• SuppressionofPTHviacalcitriolandothervitaminDanalogshavebeenthetherapeuCcmainstayforthetreatmentofSHPT.MulCpleRCTscitedinthe2009Guidelinereportedbenefitsoftheseagentsonimprovingbiochemicalendpointsandadverseeffectsofhypercalcemiawerealsonoted.
• Twotrials,PRIMOandOPERA,demonstratedsignificantlyincreasedriskofhypercalcemiainpaCentstreatedwithparicalcitol,comparedwithplacebo,intheabsenceofbeneficialeffectsonsurrogatecardiacendpoints.
KidneyDisease:ImprovingGlobalOutcomes
THEPRIMOTRIAL
ThadaniRetal.JAMA.2012;307:674-684
KidneyDisease:ImprovingGlobalOutcomes
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
KidneyDisease:ImprovingGlobalOutcomes
THEOPERATRIAL
WangAetal.JAmSocNephrol.2014;25:175-186
Hypercalcemia>2.55mmol/L:Paricalcitol43.3%Placebo3.3%NosignificanteffectonmeasuresofLVsizeorfuncCon
KidneyDisease:ImprovingGlobalOutcomes
CONCLUSIONS• RecentRCTsofvitaminDanalogsfailedtodemonstrate
improvementsinclinicallyrelevantoutcomesbutdiddemonstrateincreasedriskofhypercalcemia.Recentmeta-analyseswerelargelyconfirmatoryandsupportedthehypercalcemiariskassociaConwithcalcitriolandvitaminDanalogs.
• Theseresults,combinedwiththeopinionthatmoderatePTHelevaConsmayrepresentanappropriateadapCveresponse,ledtheWorkGrouptoconcludethattherisk-benefitraCooftreaCngmoderatePTHelevaConswasnolongerfavorableandthattheuseofcalcitriolorvitaminDanalogsshouldbereservedforonlysevereandprogressiveSHPT.
KidneyDisease:ImprovingGlobalOutcomes
CONCLUSIONS• TherearesCllnoRCTsdemonstraCngbeneficialeffectsof
calcitriolorvitaminDanalogsonpaCent-leveloutcomes,suchascardiaceventsormortality,andtheopCmallevelofPTHinCKDstages3a-5isnotknown.
• TherapywiththeseagentsmayhaveaddiConalharmfuleffectsrelatedtoincreasesinserumphosphateandFGF23levels.
• IfiniCatedforsevereandprogressiveSHPT,calcitriolorvitaminDanalogsshouldbestartedwithlowdoses,independentoftheiniCalPTHconcentraCon,andthenCtratedbasedonthePTHresponse.
• Hypercalcemiashouldbeavoided.
KidneyDisease:ImprovingGlobalOutcomes
VITAMIND
4.2.2:InadultpaCentswithCKDStages3a-5notondialysis,wesuggestcalcitriolandvitaminDanalogsnotberouCnelyused.(2C)ItisreasonabletoreservetheuseofcalcitriolandvitaminDanalogsforpaCentswithCKDStages4-5withsevereandprogressivehyperparathyroidism.(NotGraded)
Inchildren,calcitriolandvitaminDanalogsmaybeconsideredtomaintainserumcalciumlevelsintheage-appropriatenormalrange.(NotGraded)
KidneyDisease:ImprovingGlobalOutcomes
RATIONALE
• ArecentCochranereviewexaminedvitaminDtherapyforbonediseaseinchildrenwithCKDstages2–5andondialysis.Bonedisease,asassessedbychangesinPTHlevels,wasimprovedbyallvitaminDpreparaConsregardlessofpreparaConorrouteorfrequencyofadministraCon.TheCochranereviewhasnotshownanysignificantdifferenceinhypercalcemiariskwithvitaminDpreparaConscomparedwithplacebo,butonestudyshowedasignificantlygreaterriskofhypercalcemiawithintravenouscalcitrioladministraCon.
KidneyDisease:ImprovingGlobalOutcomes
CONCLUSIONS
• NodifferenceingrowthrateswasdetectedbetweendifferentvitaminDanalogsoruseoforalorintravenousvitaminDtreatments.
• TheWorkGrouprecommendedthatserumcalciumshouldbemaintainedwithinage-appropriatereferencerangeinchildren,andgiventheassociaConofhighPTHlevelswithreducedbonemineralizaConandincreasedvascularcalcificaCon,childrenarelikelytorequirecalcitriolorotheracCvevitaminDanalogtherapy.
KidneyDisease:ImprovingGlobalOutcomes
LOWERINGPTH
4.2.4:InpaCentswithCKDStage5DrequiringPTH-loweringtherapy,wesuggestcalcimimeCcs,calcitriol,orvitaminDanalogs,oracombinaConofcalcimimeCcsandcalcitriol,orvitaminDanalogs.(2B)
KidneyDisease:ImprovingGlobalOutcomes
RATIONALE
• ThisrecommendaConoriginallyhadnotbeenidenCfiedforanupdate.However,duetoasubsequentseriesofsecondaryandpost-hocpublicaConsoftheEVOLVEtrial,theWorkGroupdecidedtore-evaluateRec.4.2.4aswell.
KidneyDisease:ImprovingGlobalOutcomes
EVOLVE:LOWERINGPTH
Chertow GM, et al. N Engl J Med. 2012;367:2482-2494
KidneyDisease:ImprovingGlobalOutcomes
EVOLVESTUDY:CINACALCET
Chertow GM, et al. N Engl J Med. 2012;367:2482-2494
KidneyDisease:ImprovingGlobalOutcomes
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
KidneyDisease:ImprovingGlobalOutcomes
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
KidneyDisease:ImprovingGlobalOutcomes
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
KidneyDisease:ImprovingGlobalOutcomes
RATIONALE• AlthoughEVOLVEdidnotmeetitsprimaryendpoint,the
majorityoftheWorkGroupwerereluctanttoexcludepotenCalbenefitsofcalcimimeCcsforStage5DpaCents,basedonsubsequentprespecifiedanalyses.
• NoPTH-loweringtreatmentwasprioriCzedatthisCme,sincecalcimimeCcs,calcitriol,orvitaminDanalogsareallacceptablefirst-lineopConsinCKDStage5DpaCents.
• TheWorkGroupexplicitlyendorsesthepresenceofclinicalequipoiseandtheneedtoconductplacebocontrolledtrialswithcalcimimeCcsversusstandardtherapyforthetreatmentofSHPTinpaCentswithCKDstage5Dwithemphasisonthoseatgreatestrisk(e.g.,older,presenceofcardiovasculardisease).
KidneyDisease:ImprovingGlobalOutcomes
PEDIATRICPERSPECTIVE
• Studiesofcinacalcetinchildrenarelimitedtocasereports,caseseries,asinglecenterexperience(with4to28paCents),andanopenlabelstudyofasingledosein12childrenondialysis.InrecogniConoftheuniquecalciumdemandsofthegrowingskeleton,PTH-loweringtherapiesshouldbeusedwithcauConinchildrentoavoidhypocalcemia.FuturestudiesareneededinchildrenbeforemakingpediatricspecificrecommendaCons.
KidneyDisease:ImprovingGlobalOutcomes
KEYMESSAGES
• ItisimportanttoemphasizetheinterdependencyofserumCa,P,andPTHforclinicaltherapeuCcdecision-making.
• ThePRIMOandOPERAstudiesfailedtodemonstrateimprovementsinclinicallyrelevantoutcomesbutdiddemonstrateincreasedriskofhypercalcemia.Accordingly,rouCneuseofcalcitrioloritsanalogsinCKDstages3a–5isnolongerrecommended.
KidneyDisease:ImprovingGlobalOutcomes
KEYMESSAGES
• Noconsensuswasreachedtorecommendcinacalcetasfirst-linetherapyforloweringPTHinallpaCentswithSHPTandCKDStage5D.TheWorkGroupdecidedtomodifythe2009recommendaContolistcalcimimeCctherapynowfirst,inalphabeCcalorder,amongacceptabletreatmentopConswhilesCllrecognizingtheuClityandefficacyofacCvevitaminDcompounds.
KidneyDisease:ImprovingGlobalOutcomes
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).
KidneyDisease:ImprovingGlobalOutcomes
COMPARISONOF2016VS2009RECOMMENDATIONS
Ra;onale:TheWorkGroupfeltthatmodestincreasesinPTHmayrepresentanappropriateadapCveresponsetodecliningkidneyfuncConandhaverevisedthisstatementtoinclude‘persistently’abovetheuppernormalPTHlevelaswellas‘progressivelyrising’PTHlevels,ratherthan‘abovetheuppernormallimit.’Thatis,treatmentshouldnotbebasedonasingleelevatedvalue.
KidneyDisease:ImprovingGlobalOutcomes
COMPARISONOF2016VS2009RECOMMENDATIONS
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.
KidneyDisease:ImprovingGlobalOutcomes
COMPARISONOF2016VS2009RECOMMENDATIONS
NEW4.2.4.InpaCentswithCKDStage5DrequiringPTH-loweringtherapy,wesuggestcalcimimeCcs,calcitriol,orvitaminDanalogs,oracombinaConofcalcimimeCcsandcalcitriol,orvitaminDanalogs.(2B)
OLD4.2.4.InpaCentswithCKDstage5DandelevatedorrisingPTH,wesuggestcalcitriol,orvitaminDanalogs,orcalcimimeCcs,oracombinaConofcalcimimeCcsandcalcitriolorvitaminDanalogsbeusedtolowerPTH(2B).
• ItisreasonablethattheiniCaldrugselecConforthetreatmentofelevatedPTHbebasedonserumcalciumandphosphoruslevelsandotheraspectsofCKD–MBD(notgraded).
KidneyDisease:ImprovingGlobalOutcomes
COMPARISONOF2016VS2009RECOMMENDATIONS
• 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)
KidneyDisease:ImprovingGlobalOutcomes
COMPARISONOF2016VS2009RECOMMENDATIONS
Ra;onalefornew4.2.4:ThisrecommendaConoriginallyhadnotbeenforupdaCngbytheKDIGOControversiesConferencein2013.However,duetoasubsequentseriesofsecondaryandpost-hocpublicaConsoftheEVOLVEtrial,theWorkGroupdecidedtore-evaluateRecommendaCon4.2.4aswell.AlthoughEVOLVEdidnotmeetitsprimaryendpoint,themajorityoftheWorkGroupwerereluctanttoexcludepotenCalbenefitsofcalcimimeCcsforStage5DpaCentsbasedonsubsequentpre-specifiedanalyses.Itwas,however,decidednottoprioriCzeanyPTH-loweringtreatmentatthisCmesincecalcimimeCcs,calcitriol,orvitaminDanalogsareallacceptablefirst-lineopConsinStage5DpaCents.
KidneyDisease:ImprovingGlobalOutcomes
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KidneyDisease:ImprovingGlobalOutcomes
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