Biomarkers in the Age of Sacubitril/Valsarten

AlanS.MaiselMDFACC

ProfessorofMedicine,Emeritus

UniversityofCalifornia,San

Diego,

Myocardial injury to the heart (CAD, HTN, CMP, valvular disease)Initial fall in LV performance, ↑ wall stress

Morbidity and mortalityArrhythmiasPump failure

Peripheral vasoconstrictionHemodynamic alterations

Remodeling and progressiveworsening of LV function

Fibrosis, apoptosis,hypertrophy, cellular/molecular alterations,

myotoxicity

Heart failure symptomsFatigue

Activity altered Chest congestion

EdemaShortness of breath

Activation of RAAS and SNS

Neurohormonal Activation inHeart Failure

RAAS = renin-angiotensin-aldosterone system; SNS = sympathetic nervous system;CMP = cardiomyopathy. Fonarow GC. Rev Cardiovasc Med. 2001;2:7-12.

ACC/AHA HF Guidelines 2013:Management of HFrEF (Stage C)

Life-ProlongingMedicalTherapy• ACEinhibitorsorARB(ClassI,evidenceA)inallpatientswithoutcontraindicationsorintolerance.

• Evidence-basedbeta-blockers(ClassI,evidenceA)inallpatientswithoutcontraindicationsorintolerance. Thiswouldincludecarvedilol(immediateorextendedrelease),metoprololsuccinate,orbisoprolol.

• Aldosteroneantagonists(ClassI,evidenceA)inallpatientswithClassII–IVHFwithoutcontraindicationsorintolerancewhenclosemonitoringcanbeensured.

Yancy CW, et al. J Am Coll Cardiol. 2013;62:1495-1539.

Residual Risk for HFrEF Despite Conventional GDMT

In PARADIGM-HF, study patients were followed over a median of 27 months.2,*

*Adult patients with NYHA class II–IV symptoms and an ejection fraction of 40% or less were required to take a stable dose of a beta blocker and an ACE inhibitor (or ARB) equivalent to at least 10 mg of enalapril daily, with most also receiving MRA.

McMurray J, et al. N Engl J Med. 2014;371:993-1004.

Of all patients randomized to enalapril, the absolute risk of CV death as a first event was 10.9% (n=459/4212)1

Sacubitril /ValsartanMechanismofAction

AlanS.MaiselMD,FACC(1) SherylL.Chow,PharmD,FCCP,FAHA,(2)NicholasWettersten,MD (1)NicholasVoldovarPhD(3),Danielle

GualandroMDFACC(4)OlgaBarnettMDPhD(5),MarinNishimuraMD(1),DamienLogeart MD,(6)MicheleSenni,MD,FESC(7)

AlexandreMebazza MD(8)

Biomarkers in the era Era of Sacubiatril/Valsartaen: Diagnosis, Patient Patient Phenotyping and the

prospect of Personalized Therapy

PRE NT-PRO BNP PreproBNP1-134

PRE

NT-PRO BNP proBNP1-108

Cleavage in sarcoplasmic reticulum

Threonine71 Glycosylation

Predominant binding of BNP assay to proBNP

NT-PRO NT-PRO

Current NT-proBNP assays can only bind non-glycosylated fragments, leaving glycosylated fragment, which are higher in chronic heart failure, unmeasured

Cleavage by corinand furin

BNP BNP1-32

NT-proBNP1-76

PARADIGM-HF:NT-proBNP andBNP

0 2 4 6 80

100

200

300

400

500

600

700

800

900

1000

1100

1200

1300

1400

0

50

100

150

200

250

300

350

400

450

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NT-proB

NPpg

/ml

Months

BNPpg

/ml

LCZ696Enalapril

NT-proBNP

BNP

WhichpeptidewithSacubitril/Valsartan? NT-proBNP?BNP?

BNP

ADD-00056845

Prospective comparison of ARNI with ACEI toDetermine Impact on Global Mortality and

morbidity in Heart Failure trial (PARADIGM-HF)

Sacubitril/Valsartan 97/103 mg twice daily

Enalapril10 mg twice daily

Aim of the PARADIGM-HF Trial

SPECIFICALLY DESIGNED TO REPLACE CURRENT USEOF ACE INHIBITORS AND ANGIOTENSIN RECEPTOR

BLOCKERS AS THE CORNERSTONE OF THETREATMENT OF HEART FAILURE

PARADIGM-HF Trial: DesignEntryCriteria:• NYHAClassII-IVHF,LVEF≤40%→amendedto≤35%• BNP≥150pg/mL(orNT-proBNP≥600pg/mL)or1/3lowerifhospitalizedforHFwithin12mos• OnastabledoseofACEIorARBequivalentto≥10mgofenalaprildailyfor≥4weeks• Unlesscontraindicated,onstabledoseofbeta-blockerfor≥4weeks• SBP≥95mmHg,eGFR≥30mL/min/1.73m2andserumK≤5.4mmol/Latrandomization

Sac/Val = Sacubitril/Valsartan.McMurray JJV, et al. N Engl J Med. 2014;371:993-1004.

34-month follow-up

Single-blind run-in period

HFPatients

(n=8,442)R

Enalapril 10 mg BID(n=4,212)

Sac/Val 97/103 mg BID(n=4,187)

Enalapril 10 mg BID(n=10,513)

Sac/Val49/51 mg to

97/103 mg BID(n=9,419)

2 Weeks 4–6 Weeks

Study stopped early after median follow-up of 27 mos

Primary endpoint: Death from CV causes or hospitalization for HF

Sac/Val(n=4187)

Enalapril(n=4212)

Hazard Ratio(95% CI)

p-Value

Primary endpoint

914(21.8%)

1117(26.5%)

0.80(0.73–0.87) <0.001

Cardiovascular death

558(13.3%)

693(16.5%)

0.80(0.71–0.89) <0.001

Hospitalization for heart failure

537(12.8%)

658(15.6%)

0.79(0.71–0.89) <0.001

Sac/Val = Sacubitril/Valsartan. McMurray JJV, et al. N Engl J Med. 2014;371:993-1004.

PARADIGM-HF: Effect of Sac/Val vs. Enalapril on the Primary Endpoint and Its Components

BNP NTproBNP

TimeAcuteHF AcuteHFSacubitril/

valsartan

100 300

?

IL-33

ST2L

sST2

Decoy Receptor

Cardiomyocyte

• Increased Fibrosis• Inflammation• Adverse Remodeling• Hypertrophy• Pro-apoptosis • Anti-fibrotic

• Anti-hypetrophy• Reduced apoptosis

19

Figure2.RelationshipsbetweenbaselinesST2concentrationsandclinicaloutcomes

WhyST-2levelsmightbebetterthanNPlevelstofollowpatients

• MuchdaytodayvariabilityofBNP-diureticuse,saltloadfrommeals,timeofblooddraw.

• “wetbnp”changesrapidly- whichmayjustrepresentvolumeandnotremodeling

• DifficulttousewithCKD-• GUIDEITnegative

• Littlevariability• Doesnotseemtobeaffectedbyvolumeasmuch

• NoteffectedbyCKD• ST-2especiallyresponsivetoantifibroticdrugslikeMRAandSacubitril/Valsarten– Dowereallyneeda“GUIDEitlikestudy?

NP sST2

ENTREST2UsingST2levelstostartEntrestoinhighriskpatientscurrentlynoton

thedrug

PatientswithHReEF qualifiedforSacubitril/Valsartenbutnottaking:Feelwellonace/arb,etc

1000Patients

ST-2levelsmeasured

ST2<35ng/mlREGISTRYARM

N=400

Standardcare

Day90&180Patientscontacted

forevents

ST2≥35ng/mlRANDOMIZATIONARM

N=600

UsualCare(N=300)

Day30SafetyLabMonitoring

Day90&180Patientscontacted

forevents

UsualCare+Entresto(N=300)

Day7SafetyLabMonitoring

Day30SafetyLabMonitoring

Day90&180Patientscontacted

forevents

Astartingdoseof24/26mgtwicedailyisrecommendedforpatientsnotcurrentlytakinganACEinhibitororanangiotensinIIreceptorblocker(ARB)andforpatientspreviously takinglowdosesoftheseagents.DoublethedoseofSacubitril/Valsartenevery2to4weekstothetargetmaintenancedoseof97/103mgtwicedaily,astoleratedby thepatient.

SafetyLabMonitoringwithin3-7daysofanydosetitration

orwhenclinicallyindicated

ENTREST2

NatriureticPeptides RecommendationPredischargeBNP/NTproBNP canhelppredictprognosisprognosticate inpatientshospitalizedwithHF.

Inpatientswithhighriskforreadmissions ormortality,uptitration ofGDMTmaybereasonableusingcurrentHF guideline recommendations aswellasincorporatingotherrecommendations fortransitions ofcare.Otherconsiderations includeimplantablehemodynamicmonitoring orreferralforadvancedtherapies.

BNP/NT-proBNPcanbecollectedathospitaladmissionandbeforedischargetodeterminefutureprognosisandstratifyrisk.

Relativechangesinnatriureticpeptidesduringhospitalization canhelptodetermineresponse totherapy(wettoeuvolemic) andprovideimportantprognosticinformation.Furtheradjustmentsinmedications should bebasedoncurrentHFguidelinerecommendations.Inabilitytoreducenatriureticpeptidesmayidentify ahigh-risk populationapproachingend-stageheartfailure.

DifferentialeffectsonfnatriureticpeptideslevelsshouldberecognizedwhenstartinganARNI.

1.BothBNPandNT-ProBNPcanprovide usefulinformationwheninitiatingARNItherapy.A.NT-proBNPisnotdirectlyaffectedbyBNPorNT-NT-proBNP assaysandcanbeusedasamarkertodetectimprovementoffillingpressures andLVstretchovertimewithARNIs.B.BNPcanbemonitoredupto1monthaslevelsriseasaresultofneprilysieninhibition. Levelsareexpectedtodeclineafter1monthasfillingpressure andLVstretchimprovewiththerapyovertime .

ST-2SerialsST-2concentrationsinCHFpatientsmayidentifypatientswhoarehigh-riskfordeathandreadmissionandmaybenefitfromrequireadditionalanti-fibroticintervention.

BasedonGDMT,itisreasonabletoaddorintensify antifibroticmedicationssuchasMRAsorARNIstoreducesST-2< 35ng/mLaccordingtocurrent US HFguidelines .Especially highrisk populations arethosewithrisingsST2levels onrepeatassessment andmaybenefitmostfromintensificationoftherapy.*Atpresent,therearenoprospective datasupporting biomarker-guidedtherapywithsST2.