hyperkalemia in heart failure patients – use of sodium-glucose co transporter 2 ... · 2020. 1....
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UseofSodium-GlucoseCoTransporter2(SGLT2)InhibitorsforCardiovascularRisk
Reduction
UriElkayam,MD
ProfessorofMedicine/CardiologyUniversityofSouthernCalifornia
LosAngeles,California
HyperkalemiainHeartFailurePatients–NewApproachesforTherapy
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CasePresentation
• 65YOCaucasianmale.• Historyofhypertensionforlast10years.• CKDstage3A.• ExtensiveanteriorMI2yearsago.• ICDforprimaryprevention1yearago,EF25%.
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CasePresentation
• VS:HR76bpm,BP122/82mmHg.• FunctionalclassII,nosignsofvolumeoverload.
• Labs:Na140,K5.5,Scr 1.4,GFR52mL/min/1.73m2
• Meds:ASA81mg/d,Carvedilol25mgbid,furosemide40mgbid,lisinopril5mg/d(reducedfrom10mg/dB/Ohyperkalemia).
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2017ACC/AHA/HFSAFocusedUpdateofthe2013ACCF/AHAGuidelinefortheManagementofHeartFailure
4
PARADIGM-HF:PatientswithKlevelof>5.2mEqwereexcludedatscreening
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GuidelinesRecommendSpironolactoneinPatientswithResistantHypertension
AddinganMRAisakeystepintherecommendedalgorithmtomanageresistanthypertension1,2
…theuseofspironolactoneforresistanthypertensionshouldusuallyberestrictedtopatientsatlow-riskforhyperkalemia1,2;
Assuch,theuseofspironolactoneshouldberestrictedtopatientswith:eGFR≥45mL/min1.73m2
AndplasmapotassiumK+ ≤4.5mmol/L2
1.ACC/AHAGuidelines: CareyRM,etal.,Hypertension.2018;72:e53-e90.2.ESCGuidelines:WilliamsB,etal.EurHeartJ.2018;39(33):3021-3104.
5
eGFR=estimatedglomerular filtration rate;K+=potassium;MRA=mineralocorticoid receptor antagonist.
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ses
inClinical
Tri
RAASi=renin-angiotensin-aldosterone systeminhibitor; HF=heartfailure;EF=ejection fraction;ACEI=angiotensin-converting enzymeinhibitor; pts=patients.1.Zannad F,etal.NEngl JMed.2011;364:11-21.2.Vardeny O,etal.JAmCollCardiol.2012;60(20):2082-2089.3.McMurrayJJ,etal.NEngl JMed.2014;371(11):993-1004.4.SOLVDInvestigatorsetal.NEngl JMed.1991;325(5):293-302.5.McMurrayJJetal.Lancet.2003;362(9386):767-71.
Hype
rkalem
iaPrevalence
(%ofp
atients)
ClinicalTrials EMPHASIS-HF1 RALES2 PARADIGM-HF3 SOLVD4 CHARM-Added5
SerumK+Level >5.5mEq/L >5.5mEq/L >5.5mEq/L >5.5mEq/L >6.0mEq/L
PatientPopulation HFwithreducedEF HFwithEFof35%orless HFwithEFof40%orless HFwithEFof35%orless PtswithHFandEFof40%orlessandwere treatedwith
ACEI
7.2 7.2
17
2.51
11.8
20.2
16
6.44
0
5
10
15
20
25
1 2 3 4 5Placebo EplerenonePlaceboSpironolactoneEnalaprilLCZ696PlaceboEnalaprilPlaceboCandesartanPts were also taking spironolactone at baseline
6
PrevalenceofHyperkalemiaIncreasesinClinicalTrialsEmployingRAASi
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HyperkalemiainPatientswithHeartFailure
11.4%
25.8%
10.6%
22.2%
9.6%
24.7%
10.2%
24.4%
0% 5% 10% 15% 20% 25% 30%
K+>5.5mEq/L
K+>5.0mEq/L
Overall
HFrEF
HFmrEF
HFpEF
HFmrEF =heart failurewithmid-rangeejection fraction; HFpEF =heartfailurewithpreservedejection fraction; HFrEF =heartfailure withreduced ejection fraction;K+ =potassium.SavareseG,etal.JACCHeart Fail.2019;7(1):65-76.
K+ >5.0mEq/L
K+ >5.5mEq/L
SwedeHF (SwedishHeartFailure)Registryfrom2006to2011HyperkalemiaEventRatesinPatientswithHeartFailureby
EjectionFraction,1-YearFollow-Up,N=5,848
7
HyperkalemiainPatientswithHeartFailure
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RecurrentHyperkalemia(>5.0mEq/L)inPatientswithHF31,649patientswithHFinprimaryorhospitalcarewereassessedinapopulation-basedcohort1
HF=heart failure;HK=hyperkalemia.1.ThomsenRW,etal.JAmHeartAssoc.2018;7(11):e008912.
Approximatelyhalfoftheremainingpatientsexperienceasecond,third,andfourthHKevent
1,7384th HKEvent(60.1%)
0.38Yrs2,891
3rd HKEvent(54.3%)
0.44Yrs5,326
2nd HKEvent(43.2%)
0.52Yrs12,340
1st HKEvent(39%)
Recurrenteventswerecommonandatsuccessivelyshorterintervals
8
RecurrentHyperkalemia(>5.0mEq/L)inPatientswithHF
Hyperkalemiariskfactors:DM,CKDandspironolactone
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ReasonstotreatHyperkalemiainHF
•Topreventcomplications.
•ToallowtheuseofRASSinhibitors.
TwomainreasonstotreatHyperkalemiainHF
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52
41
2226
16
21
0
10
20
30
40
50
60
Mildhyperkalemia(potassium5.1–5.4mEq/L)
Moderate-to-severehyperkalaemia(potassium≥5.5mEq/L)
Hyperkalem
icevents(%
) Maintaineddose Down-titrated Discontinued
ElevatedK+ IsoneofthePrincipalReasonsforReducingorStoppingRAASi Therapy
PatientswithCKDatStages3–5wereenlistedwithinthestudy.OnlythosepatientswhowereonmaximumRAASidosewereincluded withinthispartofthestudy(whichiswhythetotalnumbersdonotequal100%).EpsteinMetal.AmJManag Care.2015;21:S212-20.
38%47%
(23,556hyperkalemic eventsexperiencedacrossdoses) (11,608hyperkalemic eventsexperiencedacrossdoses)
~50%ofCKDandHFpatients aretreatedatthetargetdose
10
ElevatedK+ IsoneofthePrincipalReasonsforReducingorStoppingRAASi Therapy
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CHAMP-HFRegistry:WhenPrescribed,MajorityofPatientsonSubtargetGDMTDoses
UseandDosingofGuidelineDirectedMedicalTherapyUSPatientswithChronicHFrEF (N=3,518)
11
ACEI=angiotensin-converting enzymeinhibitor; ARB=angiotensinIIreceptor blocker;ARNI=angiotensin receptor neprilysin inhibitor; GDMT=guideline-directed medicaltherapy;HFrEF =heartfailurewithreducesejection fraction; MRA=mineralocorticoid receptor antagonist.GreenSJ,etal.JAmCollCardiol.2018;72(4):351-366.
59.9%
12.8%
72.1% 66.8%
33.1%
39.1%
86.1%
26.2% 32.9%
65.9%
1.1% 1.1% 1.8% 0.2% 1.1%
10.4% 1.8% 12.1% 18.4% 25.2%13.2%
3.8%
16.9%17.9% 7.1%
35.8%
7.2%
42.7% 30.4%
0.6%
0%10%20%30%40%50%60%70%80%90%100%
ACEI/ARB ARNI ACEI/ARB/ARNI β-blocker MRA
Treated WithoutContraindication butNotTreated WithContraindication N/A 100% 50%to100% <50%
Freq
uency(%
)
Documentedpercentageoftargetdoseprescribed
CHAMP-HFRegistry:WhenPrescribed,MajorityofPatientsonSubtarget GDMTDoses
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PercentMortalitybyPriorRAASiDose:ARetrospectiveAnalysis
RAAS=Renin-angiotensin-aldosterone system;CKD=chronic kidneydisease.EpsteinM,etal.AmJManag Care.2015;21:S212-S220.
9.8
13.7
5 4.1
20.3
27.7
10.18.2
22.4
30.1
13.111
0
20
40
CKDStage3-4 HeartFailure Diabetes TotalPopulation
MaxiumDose SubmaximumDose Discontinued
Percen
tofp
atients(%)
(N=43,288totalpatientsacrossdosecategories)
(N=20,529totalpatientsacrossdosecategories)
(N=79,087totalpatientsacrossdosecategories)
(N=201,655totalpatientsacrossdosecategories)
MortalityRateaccordingtoRAASiDosage
12
PercentMortalitybyPriorRAASi Dose:ARetrospectiveAnalysis
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CharacteristicsofNewPotassiumBindingAgents
Characteristic Patiromer-Veltassa ZS-9(ZirconiumCyclosilicate)-Lokelma
GIAbsorption Non-reabsorbable Non-absorbable
Molecular structure Organic polymer
MechanismofAction Ca-Kexchange Na-Kexchange
RelativeKAffinity - 25-fold>Na
SiteofAction Colon Upper/LowerGItract
KselectivityrelativetoSPSS - 120-fold
Onsetof [K]plowering 7hours 2hours
crystalline inorganic cation exchange compound
NewPotassiumBinders
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2018ExpertConsensusontheManagementofHKinPatientswithCVDTreatedwithRAASi– EuropeanSocietyofCardiology
CVD:cardiovascular disease;HK:hyperkalemia;K+:potassium;RAASi:renin-angiotensin-aldosterone systeminhibitors.1.Rosano GMCetal.EurHeartJCardiovasc Pharmacother.2018;4(3):180-188.
14
2018ExpertConsensusontheManagementofHKinPatientswithCVDTreatedwithRAASi – EuropeanSocietyofCardiology
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VELTASSA®(patiromer)
IndicationandUsage• BothVELTASSAandLOKELMAareindicatedforthetreatmentofhyperkalemia
• LimitationofUse:o Bothshouldnotbeusedasanemergencytreatmentforlife-threateninghyperkalemiabecauseofitsdelayedonsetofaction
15
VELTASSA(patiromer)PotassiumBinders
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Patiromer ClinicalDevelopmentProg
16
P.o.C. Prevention Treatment Post-USApproval
2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018StartYear
AMBER207(rHTN)HKwithCKD
TOURMALINE401(foodeffect)HKwithCKD
104-116(DDI)Healthyvolunteers
AMETHYST205(52-weeksafety&efficacy)HK,CKD,T2DM,HTN
OPAL-HK301(Phase3pivotal)HKwithCKD
103(onset)HKwithCKD
PEARL-HF202HFwith/withoutCKD
204CKDwithHF
2019
201Hemodialysissubjects
101Healthyvolunteers
102Healthyvolunteers
EMERALD206p(Age2-17)HKwithCKD
DIAMOND(RAASi)HKwithHF
Phase3Phase2 Phase4Phase1CKD:chronic kidneydisease;DDI:drug-druginteraction; HTN:hypertension; HF:heartfailure;HK:hyperkalemia;rHTN:resistanthypertension; T2DM:type2diabetesmellitus.
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Patiromer 12-weekStudyOPAL-HK(301):TrialDesign
*Estimatedglomerular filtration rate15to<60perminuteper1.73m2ofbody-surfacearea.†Patiromer dosagewasadjusted asneededbytreating physician.BID:twicedaily;CKD:chronic kidneydisease;K+:potassium;RAASi:renin-angiotensin-adolsterone systeminhibitor.WeirMR,etal.NEnglJMed.2015;372(3):211-221.
17
PartA:4-weekTreatmentPhase(Single-Blind)
Patiromer†,continuedRAASi
(n=55)
Week4PartB1oEndpoint
BaselinePartA
SubjectswithCKD*onRAASi(n=243)
• Patiromer4.2gBIDstarting dose(n=92)
• Baseline serumK+5.1to<5.5mEq/L
• Patiromer8.4gBIDstarting dose(n=151)
• Baseline serumK+5.5to<6.5mEq/L
PartB:8-weekRandomizedWithdrawalPhase(Single-Blind)
SubjectswithPartAbaselineK+ 5.5to<6.5andwhocompletedPartAand:
§ SerumK+ 3.8to<5.1mEq/LatPartAWeek4
§ StillonRAASi
(n=107)
Placebo,continuedRAASi
(n=52)
R
Week8PartB2oEndpoint
BaselinePartBWeek4PartA1oEndpoint
R Randomization
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OPAL-HK(301)PartA:PrimaryandSecondaryEfficacyEndpoints
WeirMR,etal.NEnglJMed.2015;372(3):211-221.
18
Base-line
MeanSerumK
+(m
Eq/L)
SecondaryEfficacyEndpoint:76%ofsubjectshadserumK+ inthetargetrange
(3.8to<5.1mEq/L)atweek4
SerumPotassiumLevelsoverTimeDuringtheInitialTreatmentPhase
HK:Hyperkalemia;K+:potassium.
• 4.2gBIDstartingdose(n=92)
• 8.4gBIDstartingdose(n=151) 76%ofsubjects had
serumK+ inthetargetrange(3.8to<5.1mEq/L)atweek4
OPAL-HK(301)PartA:PrimaryandSecondaryEfficacyEndpoints
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PrimaryEndpoint:
• MedianchangeinserumpotassiumfromPartBbaseline*
OPAL-HK(301)PartB:Effect of Discontinuing Patiromer
RAAS:renin-angiotensin-aldosterone system.WeirMR,etal.NEnglJMed.2015;372(3):211-221.
19
*ThePartBprimaryoutcome wasthechangeinserumpotassiumfromPart Bbaselinetotheearliest visitatwhich thepatient’s serumpotassium wasfirstoutsideoftherangeof3.8to5.5mEq/LortoPart BWeek4ifthepatient’s serumpotassiumremained intherange.
ExploratoryEndpoints:
16%
44%
94%
RequiringanyadjustmentofRAASinhibitor(i.e.,down-titrationordiscontinuation) orpatiromertitrationduetohyperkalemia
Receiving anydoseofaRAASinhibitorattheendof
PartB*
%ofP
atients
Placebo Patiromer
00.10.20.30.40.50.60.70.80.91
Placebo Patiromer
SerumPotassiu
m(m
Eq/L) ∆=0.72mEq/L
p<0.001
PrimaryEndpoint:MedianchangeinserumpotassiumfromPartBbaseline*
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Opal-HKPre-SpecifiedSubgroupAnalysisinPatientswithandWithoutHeartFailureonRAASInhibitors
4.0
4.4
4.8
5.2
5.6
6.0
0 1 2 3 4 5 6
MeanSerumChangefromBaselineK+ Levels
HeartFailure Non-heartFailure
HF -0.5±0.05 -0.8±0.05 -0.9±0.05 -1.1±0.05 -1.1±0.05
Non-HF -0.5±0.04 -0.7±0.04 -0.9±0.04 -1.0±0.04 -1.0±0.04
n=102 n=141
SerumK
+(m
Eq/L) Thisanalysisalsofound thattherewasno
differenceintheefficacyofpatiromerbetweenheartfailureandnon-heartfailurepatients.Inbothpopulations, patiromerwasabletolowerserumpotassiumby-1.1and-1.0mEq/Lafter4weeks
BaselineDay3Week1Week2Week3Week4
Pre-specifiedsubgroupanalysisoftheprimaryendpointofOPAL-HKPartA
HF=heart failure;K+ =potassium;RAAS=renin-angiotensin-aldosterone system.PittB, etal.EurJHeartFail.2015;17(10):1057-1065.
20
Opal-HKPre-SpecifiedSubgroupAnalysisinPatientswithandWithoutHeartFailureonRAASInhibitors
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OPAL-HK:Pre-specifiedExploratoryAnalysisintheHeartFailureSubpopulation
TimetorecurrenceofhyperkalemiaProportionofpatientsdiscontinuing
RAASi
21
:
RAASi=renin-angiotensin-aldosterone systeminhibitor.1.PittB, etal.Eur JHeartFail.2015;17(10):1057-1065.2.VELTASSA[packageinsert].RedwoodCity, CA.Relypsa,Inc.2016.
OPAL-HK:Withdrawl PhasePre-specifiedExploratoryAnalysisintheHFSubpopulation
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PEARL-HFStudyDesign (202)
22
SubjectswithahistoryofchronicHF,aged18orolder,clinicallyindicatedtoreceivespironolactonewithaserumK+ atscreeningbetween4.3– 5.1mEq/Land:1. CKD(eGFR<60mL/min)
andon≥1ACEIorARBorβB;OR
2. DocumentedHxhyperK+<6mo*thatledtodiscontinuationofAA,ACEIorARBorβB
Spiro50mgSpiro25mg
Patiromer12.6gBID(n≈50)NoPatiromer DoseTitration inPEARL-HF
Placebo (n≈50) Day28
Endpoints
1°:MeanchangeinserumK+fromBLatDay28
2°:%ofpatientswithserumK+>5.5mEq/Latanytime%ofpatientseligiblefordosetitrationtoSpiro50mg
*Leadingtod/cofRAASiorβB. Day15Spiroto50mgifK+
>3.5to≤5.1ACEI:angiotensin-converting enzymeinhibitor; ARB:angiotensin receptor blocker;βB:betablocker;AA:aldosterone antagonist;Hx:history;Spiro:spironolactone.Note:Inthepublication, 15gBID(30gtotal) isreported which referstodosingcalculation thatincorporates theweightoftheexchangeionandsorbitol complex;Current dosingreflects theactivemoietyonlywhere15gBID=12.6gBID(25.2gtotal)PittB, etal.EurHeartJ.2011;32(7):820-828.
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PEARL-HF(202):PreventionStudyinHeartFailureWith/WithoutCKD
23
• PittB.EurHeartJ.2011Apr;32(7):820-8BaselineDemographicandClinicalCharacteristics
Patiromer(n=55)
Placebo(n=49)
Age (years) 68± 9 68± 11
Male,n(%) 29(53%) 34(69%)
HFduration(years) 5± 5 4± 3
NT-proBNP(pg/ml) 1,395± 1,955 2,339± 5,432
MedianNT-proBNP(pg/ml) 824 756
Leftventricularejectionfraction(%) 40± 12 41± 12
NYHAClass,n(%)IIIIIIIV
2(4%)29(53%)24(44%)0(0%)
1(2%)28 (57%)20(41%)0(0%)
CKDwitheGFR<60mL/min 27(50%) 30(63%)
Historyofhyperkalemia 22(41%) 15(31%)CKD:chronic kidneydisease;eGFR:estimatedglomerular filtration rate;HF:heartfailure;NYHA:NewYorkHeartAssociation.PittB, etal.EurHeartJ.2011;32(7):820-828.
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PEARL-HF(202):MeasurementofSerumK+ DuringTreatmentCourse
24
4.1
4.3
4.5
4.7
4.9
5.1
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30
LSmeanserumK
+(m
Eq/L)
StudyDay
Placebo (n=49)
Patiromer (n=55)
Spironolactoneinitiatedat25mg/dayonday1
Spironolactoneincreasedto50mg/dayonday15
03714172128
*******
** **
||||| |
*P<0.01**P<0.001
K+:potassium.
PittB.EurHeartJ.2011Apr;32(7):820-828.
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PEARL-HF(202)SecondaryEfficacyEndpoint:ProportionofSubjectsWithSerumK+>5.5mEq/LbyBaselineeGFR
25
n=104
P=0.017
%ofS
ubjects P=0.015
P=0.125
P=0.041
PlaceboPatiromer
n=76 n=28 n=16
1 1 1 2
1.PittB, etal.EurHeartJ.2011;32(7):820-828.2.BuysseJM,etal.FutureCardiol. 2012;8(1):17-28.
25%
19%
39%
56%
7% 8% 7%
0%0%
10%
20%
30%
40%
50%
60%
meaneGFR=81mL/min
meaneGFR≥60mL/min
meaneGFR<60mL/min
meaneGFR<45mL/min=81±33mL/min
eGFR:estimatedglomerular filtration rate;K+:potassium.
PEARL-HF(202)SecondaryEfficacyEndpoint:ProportionofSubjectsWithSerumK+>5.5mEq/LbyBaselineeGFR
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PatrolmenLong-TermEfficacyStudy:AMETHYST-DN(205)StudyDesign
*eGFR15-60ml/min/1.73m2
ACE:angiotensin-converting enzyme;ARBs:angiotensinIIreceptor blockers;BID:twicedaily;CKD:chronic kidneydisease;HK:hyperkalemia;K+:potassium;RAAS:renin-angiotensin-aldosterone system;T2DM:type2diabetesmellitus.Bakris GL,etal.JAMA.2015;314(2):151-161.
26
Screening≤10days
Run-in≤4week Week52Week8Week4†Baseline
1Year,Open-LabelStudy
SubjectswithCKD*andT2DMonstableRAASidose
(enrolledn=324)
79normokalemic patientswhohaduncontrolledbloodpressurewereenteredintotherun-inperiod (usedtoidentifypatientswithouthyperkalemiawhocouldpotentiallybenefitfrominitiationoroptimizationof
RAAStherapy).
245patientswithserumpotassiumlevelsgreaterthan5.0tolessthan6.0mEq/LatscreeningcontinueduseofprescribedACEinhibitor,ARBs,orboth, skipped therun-in,andwererandomizeddirectlyintotreatmentphase. D
MildHK(K+ >5.0–5.5)
n=220
ModerateHK(K+ >5.5–<6.0)
n=84
4.2,8.4,or12.6gpatiromer,givenBID
R Randomization DiscontinuationD Subjectsrandomizedto1of3startingdosegroupsineachstratumandtitratedtothe
targetserumK+ goal:
8.4,12.6,or16.8gpatiromer,givenBID
R
R
Long-TermEfficacyStudy:AMETHYST-DN(205)StudyDesign
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AMETHYST-DN(205):52-WeekStudy:Long-termControlofHyperkalemiainPatientswithCKDandT2DonRAASi
27BakrisGL,etal.JAMA.2015;314(2):151-161.
Mean(95%Cl)SerumPotassiumOverTime
Significant(p<.001)reductionsinmeanserumK+ level48hoursafterpatiromer initiation
Upto95%ofpatientswhohadmoderatehyperkalemiaobtainedserumK+withintargetrange
CKD:chronic kidneydisease;K+:potassium;RAASi =renin angiotensinaldosterone inhibitors; T2D:type2diabetes.
Mild5.0-5.5mEq N=218
Moderate5.6-6.0mEq N=83
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A Multicenter, Double-blind, Placebo-controlled, Randomized Withdrawal, Parallel Group Study of Patiromer for
the Management of Hyperkalemia in Subjects Receiving Renin-Angiotensin-Aldosterone System Inhibitor (RAASi) Medications for
the Treatment of Heart FailurePhase 3b study
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DIAMOND- Objective
• Effectofpatiromer treatmentofsubjectswithhyperkalemiawhilereceivingRAASi on:
• 1.ContinueduseofRAASi medicationsinaccordancetoguidelinesand
• 2.Decreasethecombinedendpointofcardiovascular(CV)deathandCVhospitalizations.
29
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DIAMONDStudyDesign
30
*=Startat8.4g/dayandup-titrate asnecessaryupto25.2g/day.Subjectmustreturn within 1week(± 3days)afterpatiromer initiation ordoseadjustment toassesspotassiumlevels.†=InitiateselectedMRA;up-titrate to50mg/day.‡=IftherearechangestoACEI,ARB, ARNi and/orMRAdoseorserumpotassiumvariesoutside theintendedrange,unscheduled weeklyormonthlyvisitsshouldoccur untilstability returns. § =IfthepotassiumAssessmentVisitisat2weeksaftertheEOSVisit,thenfollow-up Phonecall isnotrequired.
Hyperkalemia(HK)
HistoryofHK
PotassiumAssessmentVisit(within2weeksofpatiromer/placebodiscontinuation)
and/orFollow-upPhoneCall(atleast2weeksafterthe
EOSvisit)§
*
*
†
†
‡ ‡ ‡
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ADVERSEREACTIONSinUSPI6.1ClinicalTrialsExperience
• Table1providesasummaryofthemostcommonadversereactions(occurringin≥2%ofpatients)inpatientstreatedwithVeltassaintheseclinicaltrials.Mostadversereactionsweremildtomoderate.Constipationgenerallyresolvedduringthecourseoftreatment.
Adverse Reactions Patients treated with Veltassa(N=666)
Constipation 7.2%
Hypomagnesemia 5.3%
Diarrhea 4.8%
Nausea 2.3%
Abdominaldiscomfort 2.0%
Flatulence 2.0%
Table1.AdverseReactionsReportedin≥2%ofPatients
VELTASSA[packageinsert].RedwoodCity,CA.Relypsa,Inc.May2018.
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ADVERSEREACTIONSinUSPI6.1ClinicalTrialsExperience(cont’d)
• Duringtheclinicalstudies,themostcommonlyreportedadversereactionsleadingtodiscontinuationofVeltassaweregastrointestinaladversereactions(2.7%),includingvomiting (0.8%),diarrhea (0.6%),constipation (0.5%)andflatulence (0.5%).
• Mildtomoderatehypersensitivityreactionswerereportedin0.3%ofpatientstreatedwithVeltassa inclinicaltrials.Reactionshaveincludededemaofthelips.
LaboratoryAbnormalities
• Approximately4.7%ofpatientsinclinicaltrialsdevelopedhypokalemiawithaserumpotassiumvalue<3.5mEq/L.
• Approximately9%ofpatientsinclinicaltrialsdevelopedhypomagnesemia withaserummagnesiumvalue<1.4mg/dL.
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VELTASSA[packageinsert].RedwoodCity,CA.Relypsa,Inc.May2018.
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SodiumZirconiumSodiumZirconiumCyclosilicate(Lokelma)
crystallineinorganiccationexchangecompound
Nonabsorbablecrystalline.WorksinthesmallandlargeGItractresultinginearlycaptureofK.HighlyselectiveforKcaptureinexchangeforhydrogenandsodium.
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Lokelma preapprovalprogramsN=1700patients
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The HARMONIZE Randomized Clinical Trial JAMA. 2014;312(21):2223-2233.
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Greaterresponseinseverehyperkalemiaandsustainedeffect
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AdverseEffects
ZS-9(Lokelma)
• Edema8%- 11%• Each5gdoseof LOKELMA containsapproximately400mgof sodium.
• Hypokalemia4%.
Patiromer(Veltassa)
• Constipation7%• Diarrhea5%• Nausea2%• Abdominaldiscomfort2%• Hypokalemia5%• Hypomagnesemia9%
AdverseEffects
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NewTherapiesForHyperkalemia
• HyperkalemiaiscommoninpatientswithHF,CKDand/ordiabetesandcanbefatal.
• HighlevelsofpotassiummayleadtodosereductionordiscontinuationofRAASinhibitors.
• BothPatiromerandLokelmahavebeenshowntobesafeandeffectiveintreatinghyperkalemia.
• BothdrugsmaybeusedtoallowinitiationorpreventdiscontinuationoflifesavingRAASi duetohyperkalemia.
summary