JohnMcMurrayBHFCardiovascularResearchCentre

UniversityofGlasgowScotland

UK

Angiotensinreceptor-neprilysininhibition(ARNI):Thenewfronteir?

HF-REF:Thebuildingblocksoftherapy

Tx

VAD

CRT

ICD

Beta-blocker MRAACEI/ARB

Digoxin Ivabradine

H-ISDNCABG

Canwechangetheparadigm?

Harnessendogenousprotectivesystemsaswellasinhibittheharmfulones?

Replacinganexistingtreatmentandnotaddinganewone?

Heartfailure:astateofneurohumoralimbalance

Vasoconstrictor/anti-natriuretic/pro-mitoticmediators

Vasodilator/natriuretic/anti-mitoticmediators

Aparadigmshift:fromneuro-humoralinhibitiontoneuro-humoralmodulation

Vasoconstrictor/anti-natriuretic/pro-mitoticmediators

Vasodilator/natriuretic/anti-mitoticmediators

Natriureticpeptides:Howtheheartprotectsitself

Theheartisanendocrineorgan

ItsecretesAandBtypenatriureticpeptidesintothecirculationwheretheyactonthebloodvessels,kidneys,adrenalglands,brainetc

Thesepeptidesprotecttheheartfromvolumeandpressureoverolad

NatriureticpeptidesBK,ADM

Subs-P,VIP,CGRPAngiotensinII

Vasoconstriction Sodium/waterretention Fibrosis/hypertrophyDegradationproducts

Neprilysin AT1Receptor

AngiotensinReceptorNeprilysinInhibition(ARNI):LCZ696

Vasodilation Natriuresis Diuresis Inhibitionofpathologicgrowth/fibrosis

LCZ696

sacubitril valsartan

PARADIGM-HFProspectivecomparisonofARNIwithACEItoDetermineImpacton

GlobalMortalityandmorbidityinHeartFailuretrial

LCZ696 200 mg BID (n=4187)

Enalapril 10 mg BID (n=4212)

Outcome driven (CV death): Stopped early for benefitMedianfollow-up=27months

1-2 weeks

Enalapril 5-10 mg bid LCZ 100 mg bid LCZ 200 mg bid

1-2 weeks 2 weeks

PriorACEi/ARBusediscontinued

Single-blindperiod Double-blindperiod

N = 8442 (1:1 randomization)

PARADIGM-HFProspectivecomparisonofARNIwithACEItoDetermineImpacton

GlobalMortalityandmorbidityinHeartFailuretrial

Age 18 years. NYHA class II-IV. LVEF 0.40 (amended to 0.35). BNP 150 pg/ml (NTpro-BNP 600 pg/ml) or if HF hosp. within12 mo. BNP

100 pg/ml (NTpro-BNP 400 pg/ml) Background RAS blocker therapy equivalent to enalapril 10 mg/d Beta-blocker and MRA as recommended by guidelines SBP 100 mmHg run-in/ 95 mmHg at randomization eGFR 30 ml/min/1.73m2 /no decrease >25% (amended to 35%) Potassium 5.2 mmol/l run-in/ 5.2 mmol/l at randomization

LCZ696(n=4187)

Enalapril(n=4212)

Age(years) 63.811.5 63.811.3Women(%) 21.0% 22.6%Ischemiccardiomyopathy(%) 59.9% 60.1%LVejectionfraction(%) 29.66.1 29.46.3NYHAfunctionalclassII/III(%) 71.6%/23.1% 69.4%/24.9%Systolicbloodpressure(mmHg) 12215 12115Heartrate(beats/min) 7212 7312N-terminalpro-BNP(pg/ml) 1631(885-3154) 1594(886-3305)B-typenatriureticpeptide(pg/ml) 255(155-474) 251(153-465)Historyofdiabetes 35% 35%Digitalis 29.3% 31.2%Beta-adrenergicblockers 93.1% 92.9%Mineralocorticoidantagonists 54.2% 57.0%CRT 7.0% 6.7%ICD 15% 15%

PARADIGM-HF:BaselineCharacteristics

Trial NTargetdose,

mgMeandailydose,mg

CONSENSUS(1987)* 127 20bid 18.4

SOLVD-T(1991) 1284 10bid 16.6

SOLVD-P(1992) 2111 10bid 16.7

V-HeFTII(1991) 403 10bid 15.0

OVERTURE(2002) 2884 10bid 17.7

CARMEN(2004) 190Eonly191E+Carv

10bid10bid

16.814.9

CIBIS-3(2005) 190Efirst191Bisopfirst

10bid10bid

17.215.8

DoseofACEInhibitor(enalapril)achievedinrandomizedoutcometrialsusingforcedtitration

N.B. active run-in; 49% reached target dose.*22% reached target dose

PARADIGM-HF 4212 10bid 18.9

NTproBNPandBNP

Cardiomyocyte

Blood

PARADIGM-HF:NT-proBNPandBNP

0 2 4 6 80

100200300400500600700800900

10001100120013001400

0

50

100

150

200

250

300

350

400

450

500N

T-pr

oBN

P p

g/m

l

Months

BN

P p

g/m

l

LCZ696Enalapril

NT-proBNP

BNP

ExplainingtheNTproBNPandBNPchangeswithLCZ696(schematic)ProBNP/NTproBNP

Pre- Post- Pre- Post-

BNP

InhibitionofBNPbreakdown

ReducedLVwallstress

LCZ696 LCZ696

PARADIGM-HF:PARADIGM-HF:GeometricmeanurinaryGeometricmeanurinarycyclicGMPconcentrationcyclicGMPconcentrationbyvisitbyvisit

CyclicGMPistheintracellularsecondmessengerstimulatedbynatriureticpeptidesandothervasoactive

substancesincludingnitricoxide

PARADIGM-HF:Pre-specifiedendpoints

Primary:Cardiovasculardeathorheartfailurehospitalization

Cardiovascular death

Heart failure hospitalization

Secondary:

Deathfromanycause

KCCQ(CSS-symptomsandphysicallimitations)

New onset atrial fibrillation

Decline in renal function

PARADIGM-HF:PrimaryoutcomeProspectivecomparisonofARNIwithACEItoDetermineImpacton

GlobalMortalityandmorbidityinHeartFailuretrial

At riskEnalapril: 4212 3883 3579 2922 2123 1488 853 236

LCZ696: 4187 3922 3663 3018 2257 1544 896 249

Cum

ulat

ive

Pro

porti

on o

f Pat

ient

s w

ith P

rimar

y E

nd P

oint

(%)

Days after Randomization

0

10

20

30

40

0 180 360 540 720 900 1080 1260

HR: 0.80 (0.73, 0.87)p=0.0000004 1117Enalapril

(n=4212)

LCZ696(n=4187)

914

PARADIGM-HF:Pre-specifiedendpoints

Primary:Cardiovasculardeathorheartfailurehospitalization

Cardiovasculardeath

Heart failure hospitalization

Secondary:

Deathfromanycause

KCCQ(CSS-symptomsandphysicallimitations)

New onset atrial fibrillation

Decline in renal function

PARADIGM-HFProspectivecomparisonofARNIwithACEItoDetermineImpacton

GlobalMortalityandmorbidityinHeartFailuretrial

DeathfromCVcauses20%riskreduction

HFhospitalization21%riskreduction

693

558

658

537

McMurray, Packer et al NEJM 2014

P=0.00008 P=0.00008

PARADIGM-HF:Pre-specifiedendpoints

Primary:Cardiovasculardeathorheartfailurehospitalization

Cardiovasculardeath

Heart failure hospitalization

Secondary:

Deathfromanycause

KCCQ(CSS-symptomsandphysicallimitations)

New onset atrial fibrillation

Decline in renal function