angiotensin receptor-neprilysin inhibition(arni):the new fronteir ?
TRANSCRIPT
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JohnMcMurrayBHFCardiovascularResearchCentre
UniversityofGlasgowScotland
UK
Angiotensinreceptor-neprilysininhibition(ARNI):Thenewfronteir?
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HF-REF:Thebuildingblocksoftherapy
Tx
VAD
CRT
ICD
Beta-blocker MRAACEI/ARB
Digoxin Ivabradine
H-ISDNCABG
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Canwechangetheparadigm?
Harnessendogenousprotectivesystemsaswellasinhibittheharmfulones?
Replacinganexistingtreatmentandnotaddinganewone?
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Heartfailure:astateofneurohumoralimbalance
Vasoconstrictor/anti-natriuretic/pro-mitoticmediators
Vasodilator/natriuretic/anti-mitoticmediators
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Aparadigmshift:fromneuro-humoralinhibitiontoneuro-humoralmodulation
Vasoconstrictor/anti-natriuretic/pro-mitoticmediators
Vasodilator/natriuretic/anti-mitoticmediators
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Natriureticpeptides:Howtheheartprotectsitself
Theheartisanendocrineorgan
ItsecretesAandBtypenatriureticpeptidesintothecirculationwheretheyactonthebloodvessels,kidneys,adrenalglands,brainetc
Thesepeptidesprotecttheheartfromvolumeandpressureoverolad
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NatriureticpeptidesBK,ADM
Subs-P,VIP,CGRPAngiotensinII
Vasoconstriction Sodium/waterretention Fibrosis/hypertrophyDegradationproducts
Neprilysin AT1Receptor
AngiotensinReceptorNeprilysinInhibition(ARNI):LCZ696
Vasodilation Natriuresis Diuresis Inhibitionofpathologicgrowth/fibrosis
LCZ696
sacubitril valsartan
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PARADIGM-HFProspectivecomparisonofARNIwithACEItoDetermineImpacton
GlobalMortalityandmorbidityinHeartFailuretrial
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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
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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
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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
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NTproBNPandBNP
Cardiomyocyte
Blood
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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
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ExplainingtheNTproBNPandBNPchangeswithLCZ696(schematic)ProBNP/NTproBNP
Pre- Post- Pre- Post-
BNP
InhibitionofBNPbreakdown
ReducedLVwallstress
LCZ696 LCZ696
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PARADIGM-HF:PARADIGM-HF:GeometricmeanurinaryGeometricmeanurinarycyclicGMPconcentrationcyclicGMPconcentrationbyvisitbyvisit
CyclicGMPistheintracellularsecondmessengerstimulatedbynatriureticpeptidesandothervasoactive
substancesincludingnitricoxide
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PARADIGM-HF:Pre-specifiedendpoints
Primary:Cardiovasculardeathorheartfailurehospitalization
Cardiovascular death
Heart failure hospitalization
Secondary:
Deathfromanycause
KCCQ(CSS-symptomsandphysicallimitations)
New onset atrial fibrillation
Decline in renal function
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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
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PARADIGM-HF:Pre-specifiedendpoints
Primary:Cardiovasculardeathorheartfailurehospitalization
Cardiovasculardeath
Heart failure hospitalization
Secondary:
Deathfromanycause
KCCQ(CSS-symptomsandphysicallimitations)
New onset atrial fibrillation
Decline in renal function
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PARADIGM-HFProspectivecomparisonofARNIwithACEItoDetermineImpacton
GlobalMortalityandmorbidityinHeartFailuretrial
DeathfromCVcauses20%riskreduction
HFhospitalization21%riskreduction
693
558
658
537
McMurray, Packer et al NEJM 2014
P=0.00008 P=0.00008
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PARADIGM-HF:Pre-specifiedendpoints
Primary:Cardiovasculardeathorheartfailurehospitalization
Cardiovasculardeath
Heart failure hospitalization
Secondary:
Deathfromanycause
KCCQ(CSS-symptomsandphysicallimitations)
New onset atrial fibrillation
Decline in renal function