Hyperkalemia in Heart Failure Patients – Use of Sodium-Glucose Co Transporter 2 ... · 2020. 1....

©Relypsa 2019 Confidential.ForRelypsa advisoryboarduseonly.NotforexternaluseordistributionMRC-US-MED-00313

UseofSodium-GlucoseCoTransporter2(SGLT2)InhibitorsforCardiovascularRisk

Reduction

UriElkayam,MD

ProfessorofMedicine/CardiologyUniversityofSouthernCalifornia

LosAngeles,California

HyperkalemiainHeartFailurePatients–NewApproachesforTherapy


CasePresentation

• 65YOCaucasianmale.• Historyofhypertensionforlast10years.• CKDstage3A.• ExtensiveanteriorMI2yearsago.• ICDforprimaryprevention1yearago,EF25%.


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).


2017ACC/AHA/HFSAFocusedUpdateofthe2013ACCF/AHAGuidelinefortheManagementofHeartFailure

4

PARADIGM-HF:PatientswithKlevelof>5.2mEqwereexcludedatscreening


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.


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


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


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


ReasonstotreatHyperkalemiainHF

•Topreventcomplications.

•ToallowtheuseofRASSinhibitors.

TwomainreasonstotreatHyperkalemiainHF


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


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


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)




MortalityRateaccordingtoRAASiDosage

12

PercentMortalitybyPriorRAASi Dose:ARetrospectiveAnalysis


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


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


VELTASSA®(patiromer)

IndicationandUsage• BothVELTASSAandLOKELMAareindicatedforthetreatmentofhyperkalemia

• LimitationofUse:o Bothshouldnotbeusedasanemergencytreatmentforlife-threateninghyperkalemiabecauseofitsdelayedonsetofaction

15

VELTASSA(patiromer)PotassiumBinders


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.


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


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


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*


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


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


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.


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.


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.


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


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


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

©Relypsa 2019 Confidential.ForRelypsa advisoryboarduseonly.NotforexternaluseordistributionMRC-US-MED-00313 28

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


DIAMOND- Objective

• Effectofpatiromer treatmentofsubjectswithhyperkalemiawhilereceivingRAASi on:

• 1.ContinueduseofRAASi medicationsinaccordancetoguidelinesand

• 2.Decreasethecombinedendpointofcardiovascular(CV)deathandCVhospitalizations.

29


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)§

*

*

†

†

‡ ‡ ‡


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.

31


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.

32

VELTASSA[packageinsert].RedwoodCity,CA.Relypsa,Inc.May2018.


SodiumZirconiumSodiumZirconiumCyclosilicate(Lokelma)

crystallineinorganiccationexchangecompound

Nonabsorbablecrystalline.WorksinthesmallandlargeGItractresultinginearlycaptureofK.HighlyselectiveforKcaptureinexchangeforhydrogenandsodium.


Lokelma preapprovalprogramsN=1700patients


The HARMONIZE Randomized Clinical Trial JAMA. 2014;312(21):2223-2233.

35


Greaterresponseinseverehyperkalemiaandsustainedeffect


AdverseEffects

ZS-9(Lokelma)

• Edema8%- 11%• Each5gdoseof LOKELMA containsapproximately400mgof sodium.

• Hypokalemia4%.

Patiromer(Veltassa)

• Constipation7%• Diarrhea5%• Nausea2%• Abdominaldiscomfort2%• Hypokalemia5%• Hypomagnesemia9%

AdverseEffects


NewTherapiesForHyperkalemia

• HyperkalemiaiscommoninpatientswithHF,CKDand/ordiabetesandcanbefatal.

• HighlevelsofpotassiummayleadtodosereductionordiscontinuationofRAASinhibitors.

• BothPatiromerandLokelmahavebeenshowntobesafeandeffectiveintreatinghyperkalemia.

• BothdrugsmaybeusedtoallowinitiationorpreventdiscontinuationoflifesavingRAASi duetohyperkalemia.

summary

Hyperkalemia in Heart Failure Patients – Use of Sodium-Glucose Co Transporter 2 ... · 2020. 1....

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