ExpandingtheroleofARNIsinHeartFailure

ScottD.Solomon,MD

TheEdwardD.FrohlichDistinguishedChair

ProfessorofMedicine,HarvardMedicalSchool

BrighamandWomen’sHospital

DISCLOSURES

• Dr.SolomonhasreceivedresearchgrantsfromAlnylam,Amgen,AstraZeneca,Bellerophon,Bayer,BMS,Celladon,Cytokinetics,Eidos,Gilead,GSK,Ionis,LoneStarHeart,Mesoblast,MyoKardia,NIH/NHLBI,Neurotronik,Novartis,Respicardia,SanofiPasteur,Theracos,andhasconsultedforAkros,Alnylam,Amgen,Arena,AstraZeneca,Bayer,BMS,Cardior,Cardurion,Corvia,Cytokinetics,Daiichi-Sankyo,Gilead,GSK,Ironwood,Merck,Myokardia,Novartis,Roche,Takeda,Theracos,QuantumGenetics,Cardurion,AoBiome,Janssen,CardiacDimensions,Tenaya,Sanofi-Pasteur,Dinaqor,Tremeau,CellProThera,Moderna,AmericanRegent

TheMostAppropriateTermforHeartFailurewithLVEF>40%is:1. HeartFailurewithPreservedEjectionFraction2. DiastolicHeartFailure3. HeartFailurewithNormalEjectionFraction4. HeartFailurewithmildlyreducedandPreserved

EjectionFraction5. HeartFailurewithMidly ReducedandNormal

EjectionFraction6. Noneoftheabove

The Ejection Fraction “Spectrum” of Heart Failure

HFrEF HFpEF

Similar Signs and Symptoms to HFrEF

HFpEF is increasing in Prevalence

Chang P. Circulation 2018

GlobalVariationInHFpEF:PARAGON.

Tromp,etal.CircHeart Fail2021

• ConsiderAlternativeDiagnoses• SymptomaticTreatmentwithDiuretics• TreatmentofHypertension• TreatmentofotherComorbidities• RatecontrolinAtrialFibrillation(?MaintainSR)• DiagnoseandTreatIschemia

SomepatientswithHFpEFmayhaveother(treatable)diseasesHypertrophiccardiomyopathy,amyloidheartdisease,otherinfiltrativediseases

• HFpEFisheterogeneouswithmultiplecauses

• Prospectivelyscreened consecutivepatients ≥60yearsoldadmittedduetoHFpEFwithLVhypertrophy(≥12mm).

• 120HFpEFpatients(59%women,82+8years).TTRgene,andnomutationswerefound.

• diphosphono-1,2-propanodicarboxylicacid(99mTc-DPD)scintigraphy

HypertrophicCardiomyopathy• Unexplainedventricularhypertrophy

• Myocytedisarray

• Causedpredominantly bysarcomeric mutations

• CanpresentwithHFpEFandwhenhypertrophy isnotovert,canbedifficult todistinguish

FromHeartDisease,11th Edition

DiureticUseinHFpEF

• Ifthereisnoneedfordiuretics,thisisprobablynotheartfailure!

• DiureticuseinHFpEF isempiric– butappearstoworktoreducecongestion.

• Loopandthyazide diureticsarereasonable

TreatmentofHypertensionPREVENTSHeartFailure

Upadhya … Kitzman D. et al. Spring Investigators. Circ Heart Fail 2017

AtrialFibrillationportendsincreasedriskinHFpEF

CVDeathorHFHospitalization

Cikes M.etal.JACC-HF2018

0-90 days 90 days to 1 Year > 1 YearHa

zard

for P

rimar

y Ou

tcom

e

0.00

0.10

0.20

0.30

0.40

0.50

Probability

0 12 24 36 48 60 72Months

HR=0.82 (0.69-0.98)

HR=1.10 (0.79-1.51)

Interaction p=0.122

US, Canada, Argentina, Brazil

Russia, Rep Georgia

Placebo:280/881 (31.8%)

Placebo:71/842 (8.4%)

TOPCAT:ResultsbyRegion

Pfeffer MA et al. Circulation. 2015 Jan 6;131(1):34-42

AT1 receptor

Angiotensinogen(liversecretion)

Angiotensin I

AngiotensinII

NH

N

NN

N

O

OH

O

Valsartan

OH

ONH

OOH

O

ReninAngiotensinSystem

VasoactivePeptideSystem

Vasodilation� bloodpressure� sympathetictone�aldosterone levels� fibrosis� hypertrophyNatriuresis/Diuresis

Inactive fragments

XNeprilysin

Vasoconstriction� bloodpressure� sympathetictone� aldosterone� fibrosis� hypertrophy

X

Heart Failure

Sacubitril/Valsartanpro-BNP

NT-proBNP

ANP BNP CNPAdrenomedullinBradykininSubstanceP(angiotensinII)

Sacubitril↓

Sacubitrilat

LCZ696isanovelcrystallinecomplexconsistingofthemolecularmoietiesof

valsartanandsacubitril inanequimolar ratio

Sacubitril/Valsartan– Afirst-in-classAngiotensinReceptorNeprilysin Inhibitor– SimultaneouslyInhibitsNEPandtheRAS

Vardeny O.JACC-HF2014

PARAGON-HFprimaryresultsRecurrenteventanalysisoftotalHFhospitalizations and CVdeath*

*SemiparametricLWYYmethod.

0

5

10

15

20

25

30

35

40

45

50

55

Meancumulativeeven

tsper100patients

0 1 2 3 4Years

TotalHFhospitalizationsandCVdeath

Valsartan(n=2389)1009events,14.6per100pt-years

Sacubitril/valsartan(n=2407)894events,12.8per100pt-years

Rateratio0.87(95%CI0.75,1.01)p=0.059

Solomon etal.NEJM2019

ImprovementinNYHAFunctionalClassandKCCQCSSwithSacubitril/Valsartan

Sac/Val ValsartanEffect Size

(95% CI)P-value(2-sided)

NYHAclassfavorablechangeat8months– n 2316 2302

ImprovedUnchangedWorsened*

15.0%76.3%8.7%

12.6%77.9%9.6%

OR, 1.45 (1.13 – 1.86) 0.004

KCCQ clinical summary score at 8 months – n 2250 2226

LSMofchange frombaseline (SE) -1.5 (0.4) -2.5 (0.4) Difference, 1.0 (0.0 – 2.1) 0.051

≥5 point Improvement 33.0% 29.6% 0.019

≥5 point Deterioration 33.5% 34.5% 0.467

Improvement in Worsening Renal Function with Sacubitril ValsartanSacubitril/Valsartan Reduced the Risk of the Composite Renal Endpoint

Composite

Sacubitril/ValsartanN=2407n (%)

ValsartanN=2389n (%)

Compositerenalendpoint 33(1.4)

64(2.7)

(i)Renal death 1 1

(ii)ReachingESRD 7 12

(iii) ≥50%declineineGFRrelativetobaseline

27 60

0.10

0.00

0.02

0.04

0.06

0.08

0 1 2 3 4

23892407

22732320

21452195

10331049

135129

Number at Risk

valsartansacubitril/valsartan

Prop

ortio

n of

Pat

ient

s

Years

HR0.50(95%Cl0.33– 0.77),p=0.001

valsartansacubritril/valsartan

SignificantHeterogeneityinMultivariateAnalysisbyEjectionFractionandSex

Subgroup

OverallAge (years) Less than 65 years 65 years or olderAge (years) Less than 75 years 75 years or olderGender Male FemaleRace Caucasian Black Asian OtherRegion North America Latin America Western Europe Central Europe Asia/PacificDiabetic Yes NoLVEF at or below median (57%) above median (57%)History of AF Yes NoScreening NT−proBNP at or below median (911pg/mL) above median (911pg/mL)Screening SBP at or below median (137mmHg) above median (137mmHg)MRA use Yes NoBaseline eGFR <60 mL/min/1.73m2 >=60 mL/min/1.73m2NYHA class I/II III/IV

No. ofEvents/Patients

1903/4796

276/8251627/3971

938/2597965/2199

980/2317923/2479

1542/390789/102

237/60735/180

478/55983/370

544/1390466/1715332/762

1041/2069862/2727

1048/2495855/2301

1140/2521763/2275

708/23791183/2378

984/2450919/2344

543/12381360/3558

1115/2341787/2454

1402/3843499/951

Hazard Ratio(95% CI)

0.87 (0.75−1.01)

0.99 (0.64−1.53)0.85 (0.73−0.99)

0.82 (0.66−1.02)0.92 (0.76−1.11)

1.03 (0.85−1.25)0.73 (0.59−0.90)

0.83 (0.71−0.97)0.69 (0.24−1.99)1.25 (0.87−1.79)1.03 (0.47−2.28)

0.80 (0.57−1.14)1.33 (0.75−2.36)0.69 (0.53−0.89)0.97 (0.76−1.24)1.10 (0.79−1.52)

0.89 (0.74−1.09)0.84 (0.68−1.04)

0.78 (0.64−0.95)1.00 (0.81−1.23)

0.83 (0.69−1.00)0.94 (0.75−1.18)

0.85 (0.67−1.08)0.87 (0.73−1.05)

0.88 (0.72−1.07)0.86 (0.69−1.06)

0.73 (0.56−0.94)0.94 (0.79−1.12)

0.79 (0.66−0.95)1.01 (0.80−1.27)

0.90 (0.76−1.06)0.79 (0.59−1.06)

0.4 0.6 0.8 1.0 2.0

Rate Ratio (95% CI)

Subgroup

OverallAge (years) Less than 65 years 65 years or olderAge (years) Less than 75 years 75 years or olderGender Male FemaleRace Caucasian Black Asian OtherRegion North America Latin America Western Europe Central Europe Asia/PacificDiabetic Yes NoLVEF at or below median (57%) above median (57%)History of AF Yes NoScreening NT−proBNP at or below median (911pg/mL) above median (911pg/mL)Screening SBP at or below median (137mmHg) above median (137mmHg)MRA use Yes NoBaseline eGFR <60 mL/min/1.73m2 >=60 mL/min/1.73m2NYHA class I/II III/IV

No. ofEvents/Patients

1903/4796

276/8251627/3971

938/2597965/2199

980/2317923/2479

1542/390789/102

237/60735/180

478/55983/370

544/1390466/1715332/762

1041/2069862/2727

1048/2495855/2301

1140/2521763/2275

708/23791183/2378

984/2450919/2344

543/12381360/3558

1115/2341787/2454

1402/3843499/951

Hazard Ratio(95% CI)

0.87 (0.75−1.01)

0.99 (0.64−1.53)0.85 (0.73−0.99)

0.82 (0.66−1.02)0.92 (0.76−1.11)

1.03 (0.85−1.25)0.73 (0.59−0.90)

0.83 (0.71−0.97)0.69 (0.24−1.99)1.25 (0.87−1.79)1.03 (0.47−2.28)

0.80 (0.57−1.14)1.33 (0.75−2.36)0.69 (0.53−0.89)0.97 (0.76−1.24)1.10 (0.79−1.52)

0.89 (0.74−1.09)0.84 (0.68−1.04)

0.78 (0.64−0.95)1.00 (0.81−1.23)

0.83 (0.69−1.00)0.94 (0.75−1.18)

0.85 (0.67−1.08)0.87 (0.73−1.05)

0.88 (0.72−1.07)0.86 (0.69−1.06)

0.73 (0.56−0.94)0.94 (0.79−1.12)

0.79 (0.66−0.95)1.01 (0.80−1.27)

0.90 (0.76−1.06)0.79 (0.59−1.06)

0.4 0.6 0.8 1.0 2.0

Rate Ratio (95% CI)

Subgroup

OverallAge (years) Less than 65 years 65 years or olderAge (years) Less than 75 years 75 years or olderGender Male FemaleRace Caucasian Black Asian OtherRegion North America Latin America Western Europe Central Europe Asia/PacificDiabetic Yes NoLVEF at or below median (57%) above median (57%)History of AF Yes NoScreening NT−proBNP at or below median (911pg/mL) above median (911pg/mL)Screening SBP at or below median (137mmHg) above median (137mmHg)MRA use Yes NoBaseline eGFR <60 mL/min/1.73m2 >=60 mL/min/1.73m2NYHA class I/II III/IV

No. ofEvents/Patients

1903/4796

276/8251627/3971

938/2597965/2199

980/2317923/2479

1542/390789/102

237/60735/180

478/55983/370

544/1390466/1715332/762

1041/2069862/2727

1048/2495855/2301

1140/2521763/2275

708/23791183/2378

984/2450919/2344

543/12381360/3558

1115/2341787/2454

1402/3843499/951

Hazard Ratio(95% CI)

0.87 (0.75−1.01)

0.99 (0.64−1.53)0.85 (0.73−0.99)

0.82 (0.66−1.02)0.92 (0.76−1.11)

1.03 (0.85−1.25)0.73 (0.59−0.90)

0.83 (0.71−0.97)0.69 (0.24−1.99)1.25 (0.87−1.79)1.03 (0.47−2.28)

0.80 (0.57−1.14)1.33 (0.75−2.36)0.69 (0.53−0.89)0.97 (0.76−1.24)1.10 (0.79−1.52)

0.89 (0.74−1.09)0.84 (0.68−1.04)

0.78 (0.64−0.95)1.00 (0.81−1.23)

0.83 (0.69−1.00)0.94 (0.75−1.18)

0.85 (0.67−1.08)0.87 (0.73−1.05)

0.88 (0.72−1.07)0.86 (0.69−1.06)

0.73 (0.56−0.94)0.94 (0.79−1.12)

0.79 (0.66−0.95)1.01 (0.80−1.27)

0.90 (0.76−1.06)0.79 (0.59−1.06)

0.4 0.6 0.8 1.0 2.0

Rate Ratio (95% CI)

Primaryendpoint

Male 980/2317 1.03(0.85–1.25)

0.73(0.59–0.90)

Sex

Female 923/2479

atorbelowmedian(57%) 1048/2495 0.78(0.64–0.95)

1.00(0.81–1.23)

LVEF

abovemedian(57%) 855/2301

Rateratio(95%CI)0.4 0.6 0.8 1.0 2.0

P=0.002(continuous)

P=0.03(categorical)

P<0.006

Multivariableinteractionp-value

Rateratio(95%CI)

No.ofevents/patients

Subgroup

Onlyinteractionsforsexandejectionfractionremainednominallysignificant

Solomon etal.NEJM2019

SubgroupNo.of

Events/PatientsRateRatio(95%CI)

OverallEF 1903/4796 0.87(0.75–1.01)

≤50 512/1208 0.82(0.63–1.06)

>50–57 536/1287 0.77(0.57–1.03)>57–63 467/1202 0.91(0.68–1.22)>63 388/1099 1.09(0.80–1.47)

Treatment Effect by Ejection Fraction QuartilesPrimary Composite Total HF Hospitalizations and CV Death

Subgroup estimates are based on re-running the primary analysis model for each of the four subgroups defined by the by LVEF quartiles.

0.4 1.610.6 0.8 1.2 1.4

Sacubitril/Valsartan Compared to RAS inhibitorPre-specified Pooling of PARAGON-HF and PARADIGM-HF (N=13,195)

0.003

P-value

< 0.001

< 0.001

<<Solomon et al. Circulation. 2020;141:352–361>><<Solomon et al. AHA 2019>>

(hazard ratio)

(rate ratio)

(rate ratio)

P-value

(hazard ratio)

<0.001

<0.001

<0.001

(hazard ratio)

(hazard ratio)

Treatment Effect by Continuous Ejection FractionTotal HF Hospitalizations and CV Death (PARAGON-HF Primary Endpoint)

Rate ratio = 1 (unity)

95% CI

Sac/val better

RASi better

95% CI

P-interaction=0.02

Solomon etal.AHA2019;Circulation2019

Treatment Effect by LVEF and SexBenefit extends to higher LVEF in Women

Total HF Hospitalizations and CV Death

Men

Women

Solomon etal.AHA2019;Circulation2019

7,599 patients with NYHA class II-IV heart failure and no LVEF exclusion

FemaleMale

LVEFinMenandWomenwithHeartFailureLVEF distribution in CHARM

<<McMurray JJV, Jackson AM et al Circulation. 2020;141:338–351>>

WeCANtreatthemid-rangeofheartfailure!

Lund…Solomon.CHARMInvest.EurJHeartFail

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SolomonSDetal.EurHeartJ.2015

CHARM

TOPCAT

PARADIGM-PARAGON

CV death or HF hospitalizations (time-to-first)

Treatment Effect by LVEF: 3 Different Therapies

<<Dewan P et al Eur J Heart Fail 2020;22: 898-901>>

CV death or HF hospitalizations (time-to-first)

Treatment Effect by LVEF and SexBenefit Extends to Higher LVEF in Women

<<Dewan et al. Eur J Heart Fail 2020; 22:898-901>>

Estimated Absolute Benefit: Potential Events Prevented by Treating 1000 Patients for 3 Years

*Calculations are based on the between treatment group differences in exposure-adjusted event rates

Primary composite events

Prevented*

HF hospitalizations

prevented*

PARADIGM-HF 122 76

PARAGON-HF: Overall 54 49

PARAGON-HF: LVEF ≤median 108 106

If there really is an effect in patients with a LVEF≤57%, it may be substantial

FDAAdvisoryCommitteeandApprovalofExpandedIndicationforSacubitril/valsartan• OnDecember15,2020anFDAadvisorycommitteevoted12-1toapproveanexpandedindicationforsacubitril/valsartanbasedonthePARAGON-HFResults,andonFebruary16,2021FDAapprovedanexpandedindicationforsacubitril/valsartan:

Sacubitril/valsartanisindicatedtoreducetheriskofcardiovasculardeathandhospitalizationforheartfailureinadultpatientswithchronicheartfailure.Benefitsaremostclearlyevidentinpatientswithleftventricularejectionfraction(LVEF)belownormal.LVEFisavariablemeasure,souseclinicaljudgmentindecidingwhomtotreat[seeClinicalStudies(14)].

EstimatingAbsoluteRiskReductionsandNNTinPARAGON-HFwith3YearsofTreatment

1)IdentifyPotentiallyEligiblePatientswith

HFintheUS

2)ApplyVariousLVEFCriteria toDefine“BelowNormal”

3)EstimateNNTwith3YearsofTreatment

ForecastPotential ImpactonWorseningHFEventswithFull

Implementation

LVEF≤60%(n=3,371)

LVEF≤57%(n=2,495)

LVEF≤55%(n=2,206)

LVEF≤50%(n=1,208)

TotalHFHosp 12 9 8 10CVDeath+TotalHF

Hosp 10 9 8 10

CVDeath+TotalHFEvents(Hosp+UrgentVisits)

10 9 7 9

ApplyingSex-SpecificLVEFRangestoPARAGON-HF:MenNNTRange:27-34WomenNNT:5

Vaduganathan M….Solomon SDESC-HF2021;JAMACardiol InPress

84

Filtered glucose load >180 g/day

SGLT1compensate

SGLT2~90%

SGLT2 inhibitors reduce glucose reabsorption

in the proximal tubule, leading to

urinary glucose excretion* and

osmotic diuresis

SGLT2inhibitor

DM: ~70-80 g glucose/dayNon-DM: ~50 g glucose/day

SodiumExcretion

Volume Loss

Glucose Excretion

SGLT: sodium glucose cotransporter, DM: diabetes mellitus*Loss of ~80 g of glucose per day = 240 cal/day1. Bakris GL, et al. Kidney Int. 2009;75;1272–1277.

Slide courtesy of Faiez Zannad

05

1015

2025

3035

Cum

ulat

ive

Perc

enta

ge(%

)

2371 2258 2163 2075 1917 1478 1096 593 210Placebo2373 2305 2221 2147 2002 1560 1146 612 210Dapagliflozin

Number at Risk

0 3 6 9 12 15 18 21 24Months since Randomization

Placebo

DAPA-HFHR 0.74 (0.65, 0.85)p=0.00001

Reduction in CV Death/HF hospitalization/Urgent HF visit in Heart Failure with Reduced Ejection Fraction

NNT=21

Dapagliflozin

SGLT-2inhibitors:DevelopedfordiabetesbutprovingbeneficialinHeartFailure

Improved Outcomes in Patients with Diabetes and HFpEF in two SGLT-2 Trials

0 6 12Months Since Randomization

18 24

20

0

40

60

80

100Ev

ents

Per

100

Patie

nts

HR 0.63 (95% CI 0.45-0.89), P=0.009 ARR: 11.6 Events Per 100 Patient-Years Treatment Patient-Years to Avoid 1 Event: 9

Placebo

Sotagliflozin

59.0

37.5

Bhatt DL, Szarek M, Pitt B, et al., and Steg PG. N Engl J Med. 2020. Bhatt DL. AHA 2020, virtual.

OngoingHFpEF TrialsDELIVER Study Design Overview

35

Dapagliflozin 10 mgSoC

PlaceboSoC

E R

Visit 1 2 3 4 5 6 7

Day 240 48030 1201-21 360

PACD SCV

≤6 weeks

E=Enrolment; R=Randomization; SoC= Standard of Care; PACD=Primary Analysis Censoring Date; SCV=Study Closure Visit; LVH= Left Ventricular Hypertrophy; LAE= Left Atrial Enlargement

Months 8 161 4 12

8

600

20

ü Heart failure (NYHA class II-IV)

ü Typical symptoms/signs for HF for ≥6 weeks

ü Requiring treatment with diuretic(s) for HF

ü LVEF >40% AND evidence of structural heart disease (LVH or LAE)

ü Elevated NT-pro BNP

ü Ambulatory OR Hospitalized (off intravenous heart failure therapy)

ü No iv diuretics within 24 hours prior to randomization

Primary endpointTime to first adjudicated event of either:• CV death • Hospitalization for HF• urgent HF visit

4700 randomized patients

ClinicalTrials.gov NCT03619213

8"mmLA

RA8 mm

Feldman T…Shah SJ. Circ Heart Fail 2016

8"mmLA

RA

IASD proposed mode of action: dynamic decompression of overloaded LA chamber by shunting blood from LA à RA

47

Potassium > 5.0 mmol/L; eGFR <25 mL/min/1.73 m²

Continuous MRA use (>3 months) in the 12m prior to enrollment; MRA use in the 30d prior to randomization

MI or PCI 30d prior to randomization

Cardiogenic shock at randomization, prior to first intake of study drug

History of dilated cardiomyopathy, peripartum cardiomyopathy, chemotherapy induced cardiomyopathy, or infiltrative cardiomyopathy. Amyloidosis.

Alternative causes for symptoms: severe lung disease, anemia with hemoglobin < 10g/dL, valve disease, primary PH, BMI >50 kg/m2K

ey E

xclu

sion

Crit

eria

Symptomatic HF (NYHA II-IV) with documented EF ≥ 40% within the last 12 months, ambulatory or with prior heart failure hospitalization < 3m (enrollment prior to hospital discharge is encouraged)

NT-proBNP ≥ 300 pg/mL in sinus rhythm (or ≥ 900 pg/mL in atrial fibrillation) at following timepoints:

within 90 days prior to randomization if patient had been hospitalized for HF requiring initiation or change in HF therapy OR if patient had an urgent visit for HF requiring IV diuretic therapy

within 30 days prior to randomization if patient has not been hospitalized for HF in the past 3m

Structural heart disease associated with HFpEF: left atrial enlargement or left ventricular hypertrophy on any local measurement within the last 12 months

Treatment with diuretics in the 30d prior to randomization

Key

Incl

usio

n C

riter

ia

Visits: Month 1, then 3-monthly for first 12 months, 4-monthly visits thereafter with telephone contact in between

1:1Randomization

Finerenone 10, 20 and 40 mg based on eGFR: ≤60 max dose 20 mg, >60, max. 40 mg

Matching Placebo

• N = 5,500 randomized; Recruitment period 24 months, treatment up to 42 months

Primary EndpointComposite of CV death and total / recurrent HF events (hospitalization/urgent visit)

Secondary EndpointsChange in TSS of KCCQTime to first renal composite endpointTime to all-cause mortality

Exploratory Endpoints

Stud

y En

dpoi

nts

Steering Committee: S. Solomon (Chair), J. McMurray (Co-Chair), Carolyn Lam, Sanjiv Shah, Faiez Zannad, Bertram Pitt, Adriaan Voors

Summary

Therapyforheartfailurewithmildlyreducedandpreservedejectionfractionhasbeenempiric

Importanttoruleoutother,targetable,causesofdisease

Therapiesthathavebeenbeneficialinpatientswithheartfailureandreducedejectionfractionarelikelybeneficialinpatientswithheartfailureandmildlyreducedejectionfraction

Severaladditionaltherapiesarebeingtested…staytuned!