Gennaro Cice

Cattedra di Cardiologia

Seconda Università di Napoli

Terapia Farmacologica della

Insufficienza Cardiaca Cronica: è

in arrivo una rivoluzione?

60° CONGRESSO NAZIONALE SIGGNAPOLI, 25-28 NOVEMBRE 2015

HEMODINAMYC HYPOTHESYOF HEART FAILURE

CHRONICAL ARTERO-VENOUS CONSTRICTION

REDUCED RENAL PERFUSIONSKELETAL MUSCLE

REDUCED PERFUSION

INCREASED PRELOAD

AND AFTERLOAD

LEFT VENTRICULAR

HYPERTROPHY-DILATATION

INCREASED SODIUM AND

WATER RETENCTION

OEDEMA

PULMONARY

CONGESTION

REDUCED TOLERANCE

TO PHISICAL STRESS

G. Cice

NEURO-ENDOCRINE HYPOTHESYOF HEART FAILURE

NEURO-HORMONAL ACTIVATION

LEFT VENTRICULAR REMODELLING/DYSFUNCTION

PERPHERAL ANDPULMONARYCONGESTIONMYOCARDIAL DAMAGE

CARDIAC OUTPUT

BLOOD PRESSUREBLOOD FLOW

INOTROPICAND

CHRONOTROPICACTION

CARDIAC WORK

HYPERTROPHYFIBROSIS

APOPTOSISCONTRACTILEDISFUNTION

AFTERLOAD

LEFT VENTRICULARFILLING PRESSURE

PRELOAD

VENOCONSTRICTION

CIRCULATING VOLUME

IDRO-SALINE RETENTION

RENAL ISCHAEMIA

ARTERO-CONSTRICTION

TISSUTALIPOPERFUSION

G. Cice

RAAS INHIBITORS

Placebo

Enalapril

12111098765

Pro

bab

iili

ty o

f D

eath

Months

0.1

0.8

0

0.2

0.3

0.7

0.4

0.5

0.6p< 0.001

CONSENSUSN Engl J Med 1987

43210

Months

302412 180 6

10

30

20

0

Placebo

Ramipril

p = 0.002Mo

rta

lity

%

AIRE

Lancet 1993

G. Cice

0 1 2 3 years0

10

20

30

40

50

Placebo

Candesartan

%

HR 0.77 (95% CI 0.67-0.89), p=0.0004

Adjusted HR 0.70, p<0.0001

3.5

406 (40.0%)

334 (33.0%)

CHARM-Alternative

Eve

nt-

fre

e s

urv

iva

l

0 3 6 9 12 15 18 21 24 27

Time since randomization (months)

Risk reduction: 33,1%p= 0.0002

1.000

0.914

0.829

0.743

0.657

0.571

0.486

0.400

Valsartan

Placebo

Val-HeFT

1.00

0.90

0.80

0.70

0.60

0.50

0.400 6 12 18 24 30 36

Placebo

Spironolactone

% S

urv

iva

l

Months

RR=30%

p< 0.001

N=1663

EF<35%

F.U. 24 m

0 3 6 9 12 15 18 21 24 27 30 33 36Months since randomization

P = 0.008

RR= 0.85 (95% CI, 0.75-0.96)

Placebo

Eplerenone

40 –

35 –

30 –

25 –

20 –

15 –

10 –

5 –

0 –Cu

mu

lati

ve

In

cid

en

ce

(%

)

death from any

cause

Death

from

An

yC

au

se(%

)

Years since randomization

100

60

30

00 1 2 3

Hazard ratio, 0.76 (95% CI, 0.62–0.93)P=0.008

EPLERENONE

PLACEBO

RALES

EPHESUS

EMPHASIS-HF

Pit

t et

al.

. N

Engl

J M

ed 1

999

B.P

itt

et a

l.:N

EJM

20

03;3

48:1

309

-21

Zannad F

-N

Engl

J M

ed 2

011

;364:1

1-2

1.

ARA: ALL-CAUSE MORTALITY

-BLOCKERS ALL-CAUSE MORTALITY

0 200 400 600 800

1.0

0.8

0.6

0

Bisoprolol

Placebo

Time after inclusion (days)

p<0.0001

Su

rviv

al

Risk reduction

34%

CIBIS-IILancet 1999

Months of follow-up

Mo

rtali

ty (

%)

0 3 6 9 12 15 18 21

20

15

10

5

0

Placebo

Metoprolol CR/XL

p=0.0062

Risk reduction

34%

MERIT-HFLancet 1999

Su

rviv

al

Carvedilol

Placebo

Days

0 50 100 150 200 250 300 350 400

1.0

0.9

0.8

0.7

0.6

0.5

Risk reduction

65%

p<0.001

US CarvedilolNEJM 1996

G. Cice

ACC/AHA NYHA

STAGE A Asymptomatic with no heart damage but have risk factors for heart failure

STAGE B Asymptomatic left ventricular dysfunction

STAGE C Have symptoms and heart damage

STAGE D End-stage disease

NYHA I No symptoms and no limitation in ordinary physical activity

NYHA II Mild symptoms (mild shortness of breath and/or angina) and slight limitation during ordinary activity

NYHA III Marked limitation in activity due to symptoms, even during less-than-ordinary activity. Comfortable only at rest.

NYHA IV Severe limitations. Experiences symptoms even while at rest. Mostly bedbound patients.

HF CLASSIFICATION

ACC/AHA guidelines, 2005

SUMMARY OF DRUG TREATMENT FOR CHF

AsymptomaticLV Dysfunction

Mild toModerate CHF

Moderate toSevere CHF

ESC - CHF guidelines - update 2012

ACE inhibitorBeta blocker

ACE inhibitor and/or ARBBeta blocker+ivabradineDiureticsDigoxin (?)

ACE inhibitor and/or ARBBeta blocker+ivabradineDiureticsDigoxinSpironolactone

SOLD REGISTRY DATA

0 2 4 6 8 10 12

months

12

10

8

6

4

2

0All c

ause m

ort

ality

(%

)

PROGNOSIC VALUE OF LVEF<35%

<35%

>35%

LV EF RESPONSE IMPACTS ON MORTALITY AND HOSPITALISATIONS

Freedom from cardiac

death or hospitalisation

0.00

0.20

0.40

0.60

0.80

1.00

0 6 12 18 24

Time (months)

Fra

cti

on

of

pati

en

ts

P < 0.001

LV EF > 15

LV EF < 15

79%

59%

Freedom from cardiac death

0

0.20

0.40

0.60

0.80

1.00

0 6 12 18 24

Time (months)

Fra

cti

on

of

pati

en

ts

P < 0.001

LV EF > 15

LV EF < 15

95%

77%

Metra M et al. Am Heart J 2003

ACE Inhibition Prevents Remodelling:SOLVD – Echocardiographic Substudy

Greenberg B et al. Circulation 1995

220

210

200

190

4 120

Month

En

d-d

iasto

lic V

olu

me (

cc)

P = 0.025 160

155

150

140

4 120

Month

P = 0.019

145

En

d-s

ysto

lic V

olu

me (

cc)

0.40

0.30

0.20

0.10

4 120

Month

Eje

cti

on

Fra

cti

on

0

Placebo n = 130 130 142

Enalapril n = 128 127 137

LV

ES

VI (b

ipla

ne

) [m

l/m

2]

P values for BL to M6, M12, M18

Primary Endpoint: LVESVI Comparison Between Treatments

Carvedilol & Enalapril

Carvedilol

Enalapril

-7

Month 6 Month 12 Month 18Baseline

NSP < 0.002

-6

-5

-4

-3

-2

-1

0

P < 0.05

Poole-Wilson PA et al. Lancet 2003;362:7-13

LVEF: Change From BaselineWithin Treatment-arm Comparison

* P < 0.05; ** P < 0.01; *** P < 0.001

EnalaprilCarvedilol &

Enalapril

Carvedilol

-1

0

1

2

3

4

5

LV

EF

(%

)

*** *** ***

*** *** **

*

M6 M12 M18 M6 M18M12 M6 M12 M18

Poole-Wilson PA et al. Lancet 2003;362:7-13

SURVIVAL RATES IN CHF PATIENTSSOLVD-PREVENTION

BBENALAPRILNOTHING

ACE-i+BB

100

90

80

0 365 730 1095 1460

days of follow-up

Surv

ival (%

)

J Am Coll Cardiol, 1999; 33:916-23

SURVIVAL RATES IN CHF PATIENTSSOLVD-TREATMENT

BBENALAPRILNOTHING

ACE-i+BB

100

90

80

70

60

0 365 730 1095 1460

days of follow-up

Surv

ival (%

)

J Am Coll Cardiol, 1999; 33:916-23

LANDMARK TRIALS IN CHF

ELITE II

CHARM

Val-HeFT

OPTIMAAL

VALIANT

losartan

CONSENSUS

captopril

Potential benefit:vasodilatation

SOLVD V-HeFT II

Hy-C

AIRE, TRACE

SAVE, ISIS-4

Heart Ratetherapeutictarget in HF

SHIFT

Recognition ofneurohormonal

activation

1960 1970 1980 1990 2000 2011courtesy of P.Ponikowski

EPHESUS

spironolactoneRALES

EMPHASIS - HF

SENIORS

propranolol

Beta-blockers contra-indicated

CIBIS MDC

USCP

MERIT-HFCIBIS II

COPERNICUS

COMET

CIBIS III

US-CARVEDILOL

RENEWAL ETANERCEPT

anti TNF-a2002

OVERTUREOMAPATRILAT

vasopeptidase-i2002

ENABLEBOSENTAN

endothelin-blk2002

COMPOSECINACIGUAT

Guanliat cyclase act

2012

EARTHDARUSENTANEndothelin-i

2004

PROTECTROLOFILLIN

Adenosine-ago2011

FLOSEQUINANvasodilator

2000

PRIME IIIBOPAMINEIno-dilator

1997

DIG-TRIALDIGITALISInotrope

1997

MILRINONE MONOXIDINEFUSIONNESIRITIDE

2006

SURVIVELEVOSIMWENDAN

2007

G. Cice

NECTAR-HFVAGAL-STIM

2014

G. Cice

Combination drug of valsartan and sacubitril, in a 1:1 mixture

Dual-acting angiotensin receptor-neprilysin inhibitor (ARNi)although the two effects are achieved by two different molecules

Valsartan blocks the angiotensin II receptor type 1 (AT1)

Sacubitril is a progrug activated to LBQ657 by de-ethylation via esterases

LBQ657 inhibits the enzyme neprilysin,which is responsible for the degradation of atrial and brain natriuretic peptide

LCZ696Valsartan/Sacubitril

G. Cice

Vasodilationnatriuresis/diuresis

Cardiac stressRemodelling

NatriureticPeptides

VasoconstrictionSodium/fluid retentionChronic cardiac stress

Tissue remodelling/fibrosis

OPPOSITE FORCES IN HEART FAILURE

Renin-Angiotensin-AldosteroneEndothelin

Catecholamines

G. Cice

Ferro Circulation 1998;97:2323–30; Levin N Engl J Med 1998;339:321–8; Nathisuwan & Talbert. Pharmacotherapy 2002;22:27–42; Schrier Kidney Int 2000;57:1418–25; Schrier & Abraham. N Engl J Med 1999;341:577–85; Stephenson Biochem J. 1987;241:237–47; Langenickel , Dole. Drug Discov Today: Ther Strategies 2014

NP system

Ang II

AT1 receptor

RAS

HFsymptoms

progression

Vasodilation

BP

Sympathetic tone

Aldosterone

Fibrosis

Hypertrophy

Natriuresis/diuresis

Vasoconstriction

BP

Sympathetic tone

Aldosterone

Fibrosis

Hypertrophy

HEART FAILURE

NPs

G. C

ice

Ferro Circulation 1998;97:2323–30; Levin N Engl J Med 1998;339:321–8; Nathisuwan & Talbert. Pharmacotherapy 2002;22:27–42; Schrier Kidney Int 2000;57:1418–25; Schrier & Abraham. N Engl J Med 1999;341:577–85; Stephenson Biochem J. 1987;241:237–47; Langenickel , Dole. Drug Discov Today: Ther Strategies 2014

NP system

Ang II

AT1 receptor

RAS

HFsymptoms

progression

Vasodilation

BP

Sympathetic tone

Aldosterone

Fibrosis

Hypertrophy

Natriuresis/diuresis

Vasoconstriction

BP

Sympathetic tone

Aldosterone

Fibrosis

Hypertrophy

Inactive fragments

HEART FAILURE

Neprilysin

NPs

LCZ696

G. C

ice

PARADIGM-HF: Study Design

NYHA class II-IV heart failure with LV ejection fraction ≤ 40%

BNP ≥ 150 (or NT-proBNP ≥ 600), or 400 if hospitalized for heart failure within 12

months

Beta-blockers and mineralocorticoid receptor antagonists and use of ACE inhibitor

or ARB

able to tolerate dose equivalent to enalapril 10 mg daily for at least 4 weeks

Systolic BP ≥ 95 mm Hg, eGFR ≥ 30 ml/min/1.73 m2 and serum K≤5.4 mEq/L

Primary endpoint was cardiovascular death or hospitalization for

heart failure, but sample-size of the PARADIGM-HF was defined on

the basis of cardiovascular mortality alone

G. Cice

2 weeks 1-2 weeks 2-4 weeks

Single-blind run-in period Double-blind period

(1:1 randomization)

Enalapril

10 mgBID

Enalapril 10 mg BID

LCZ696 200 mg BID

PARADIGM-HF: Study Design

Randomization

100 mgBID

200 mgBID

LCZ696

G. Cice

8399 patients randomized for ITT analysis

LCZ696

(n=4187)

Enalapril

(n=4212)

Age (years) 63.8 ± 11.5 63.8 ± 11.3

Women (%) 21.0% 22.6%

Ischemic cardiomyopathy (%) 59.9% 60.1%

LV ejection fraction (%) 29.6 ± 6.1 29.4 ± 6.3

NYHA functional class II / III (%) 71.6% / 23.1% 69.4% / 24.9%

Systolic blood pressure (mm Hg) 122 ± 15 121 ± 15

Heart rate (beats/min) 72 ± 12 73 ± 12

N-terminal pro-BNP (pg/ml) 1631 (885-3154) 1594 (886-3305)

B-type natriuretic peptide (pg/ml) 255 (155-474) 251 (153-465)

History of diabetes 35% 35%

Digitalis 29.3% 31.2%

Beta-adrenergic blockers 93.1% 92.9%

Mineralocorticoid antagonists 54.2% 57.0%

ICD and/or CRT 16.5% 16.3%

PARADIGM-HF: Study Population

G. Cice

0

16

32

40

24

8

Enalapril(n=4212)

360 720 10800 180 540 900 1260

Days After Randomization

4187

4212

3922

3883

3663

3579

3018

2922

2257

2123

1544

1488

896

853

249

236

LCZ696

Enalapril

Patients at Risk

1117

Kap

lan

-Meie

r E

sti

mate

of

Cu

mu

lati

ve R

ate

s (

%)

914

LCZ696(n=4187)

PARADIGM-HF: PRIMARY ENDPOINT

CARDIOVASCULAR DEATH OR HF HOSPITALIZATION

HR = 0.80 (0.73-0.87)P = 0.0000002

NNT=21

McMurray, et al. N Engl J Med 2014

HR = 0.80 (0.71-0.89)P = 0.00004

Enalapril(n=4212)

LCZ696(n=4187)

Kap

lan

-Meie

r E

sti

mate

of

Cu

mu

lati

ve R

ate

s (

%)

Days After Randomization

4187

4212

4056

4051

3891

3860

3282

3231

2478

2410

1716

1726

1005

994

280

279

LCZ696

Enalapril

Patients at Risk

360 720 10800 180 540 900 12600

16

32

24

8

693

558

PARADIGM-HF: CARDIOVASCULAR DEATH

NNT=32

McMurray, et al. N Engl J Med 2014

PARADIGM-HF: ALL-CAUSE MORTALITY

4187

4212

4056

4051

3891

3860

3282

3231

2478

2410

1716

1726

1005

994

280

279

LCZ696

Enalapril

Enalapril(n=4212)

LCZ696(n=4187)

HR = 0.84 (0.76-0.93)P<0.0001

Kap

lan

-Meie

r E

sti

mate

of

Cu

mu

lati

ve R

ate

s (

%)

Days After RandomizationPatients at Risk

360 720 10800 180 540 900 12600

16

32

24

8

835

711

McMurray, et al. N Engl J Med 2014

0

100

200

300

400

500

600

700

Symptomatichypotension

Serum potassium>6.0 mmol/l

Serum creatinine ≥2.5 mg/dl

Cough Angioedema

LCZ-696 ENALAPRIL

PARADIGM-HF: ADVERSE EVENTS

McMurray, et al. N Engl J Med 2014

Patients

No

0

200

400

600

800

1000

1200

intensification ofmedical treatment

hospitalizations forworsening heart failure

intensive care needs

LCZ-696 Enalapril

Patients

No

-5

-4,5

-4

-3,5

-3

-2,5

-2

-1,5

-1

-0,5

0

*KCCQ

PARADIGM-HF:

PROGRESSION, SEVERITY AND QUALITY OF LIFE

Mod. *McMurray, et al. N Engl J Med 2014Packer M, et al. Circulation 2015

McMurray et al. Eur J Heart Fail 2015;17(Suppl 1):143 (Abstract 689)

PARADIGM-HF: PRIMARY OUTCOME BY AGE

Hazard ratio (95% CI)

All patients (n=8,399) 0.80 (0.73–0.87)

Age category (year)

<55 (n=1,624) 0.78 (0.64–0.96)

55–64 (n=2,655) 0.76 (0.65–0.90)

65–74 (n=2,557) 0.80 (0.68–0.93)

75–84 (n=1,442) 0.84 (0.69–1.03)

>85 (n=121) 0.96 (0.54–1.70)

1.000.80Favors LCZ696 Favors enalaprilHazard ratio

p for interaction=0.94 for treatment by age

McMurray, et al. N Engl J Med 2014; ePub ahead of print: DOI: 10.1056/NEJMoa1409077.

Sympathetic nervous system

Renin angiotensinaldosterone system

Ang II AT1R

NatriureticPeptide System

NPRs NPs

Epinephrine

Norepinephrine

α1, β1, β2

receptors

β-blockers

RAAS inhibitors

(ACEI, ARB, MRA)

Neprilysin

inhibitorsVasodilationBlood pressureSympathetic toneNatriuresis/diuresisVasopressinAldosteroneFibrosisHypertrophy

LCZ696

EVOLUTION OF PHARMACOLOGIC THERAPY IN HF

Thanks…for not having left the conference hall!

1. Bohm et al. Eur J Heart Fail 2015;17(Suppl 1):393 (Abstract P1794);

2. McMurray et al. N Engl J Med 2014;371:993–1004;

3. McMurray et al. Eur J Heart Fail 2013;15:1062–73

PARADIGM-HF: DISCONTINUATION FOR HYPOTENSION

Following randomization1,2During run-in1*

LCZ696

Enalapril

0

1

2

p=0.38

0.9 %0.7 %

1.7 %

1.4 %

Pa

tie

nts

wh

o d

isco

ntinu

ed

stu

dy d

rug

fo

r h

yp

ote

nsio

n (

%)

1.5

0.5

Enalapril period 2 weeks 10 mg b.i.d.

LCZ696 period1–2 weeks 100 mg b.i.d.; 2–4 weeks 200 mg b.i.d.

n=10,513 n=9,419 n=4,212 n=4,187

Median 27 months’ follow-up

“…angiotensin receptor–neprilysin inhibition with LCZ696 was superior to ACEinhibition alone in reducing the risks of death and of hospitalization for HF”

“The magnitude of the beneficial effect of LCZ696, as compared with enalapril,on CV mortality was at least as large as that of long-term treatment withenalapril, as compared with placebo.”

“This robust finding provides strong evidence that combined inhibition of theangiotensin receptor and neprilysin is superior to inhibition of the RAS alone inpatients with chronic HF.”

“…results are applicable to a broad spectrum of patients with HF, including those who are currently taking an ACE inhibitor or ARB or who are likely to be able to take such an agent without having unacceptable side effects.”

McMurray, et al. N Engl J Med 2014; ePub ahead of print: DOI: 10.1056/NEJMoa1409077.

PARADIGM-HF: TAKE HOME MESSAGES

CONCLUSIONS FROM PUBLICATION

G. Cice

DRUGS THAT IMPROVE PROGNOSYS IN HF

Drugs that inhibit the

renin-angiotensin system

have modest effects on

survival

Based on results of SOLVD-Treatment, CHARM-Alternative,COPERNICUS, MERIT-HF, CIBIS II, RALES EMPHASIS-HF SHIFT

10%

20%

30%

40%

0%

% D

ecrease i

n M

orta

lity

Betablocker

Mineralocorticoidreceptor

antagonist

Angiotensinreceptorblocker

ACEinhibitor

Ivabradine

In heart failure with reduced ejection fraction, when compared with recommended doses of enalapril on top of

B-Blocker and ARA:

PARADIGM-HF: TAKE HOME MESSAGES

LCZ696 was more effective than enalapril inReducing the risk of CV death and HF hospitalizationReducing the risk of CV death by incremental 20%Reducing the risk of HF hospitalization by incremental 21%Reducing all-cause mortality by incremental 16%Incrementally improving symptoms and physical limitations

LCZ696 was better tolerated than enalaprilLess likely to cause cough, hyperkalemia or renal impairmentLess likely to be discontinued due to an adverse eventMore hypotension, but no increase in discontinuationsNot more likely to cause serious angioedema

G. Cice

Increase in Life Expectancy by Enalapril in Combined SOLVD Trials

Years after Randomization

Mo

rtality

0 1 2 3 4 5 6 7 8 9 10 11 12

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

Enalapril (n=472)*Placebo (n=448)*

Median Life ExpectancyDifference of9.4 months

p=0.004

http://www.phri.ca/x-solvd/ * Number of patients alive at 12 years

“PARADIGM-HF may well represent a new threshold of hopefor patients with HF”

“Now, a novel drug, LCZ696, a dual inhibitor of angiotensin IIreceptor and neprilysin, may prove to be the first disruptiveagent to the heart-failure treatment algorithm, which hasremained essentially unchanged for a decade”

“The beneficial results seen in PARADIGM-HF may apply to awide spectrum of patients, even those who are currentlyreceiving the best possible therapy”

Jessup. N Engl J Med 2014; ePub ahead of print: DOI: 10.1056/NEJMe1409898G. Cice

Sympathetic nervous system

Renin angiotensinaldosterone system

VasoconstrictionBlood pressure

Sympathetic toneAldosteroneHypertrophy

Fibrosis

Ang II AT1R

NatriureticPeptide System

VasodilationBlood pressureSympathetic toneNatriuresis/diuresisVasopressinAldosteroneFibrosisHypertrophy

NPRs NPs

Epinephrine

Norepinephrine

α1, β1, β2

receptors

VasoconstrictionRAAS activity

VasopressinHeart rate

Contractility

NEURO-ENDOCRINE EFFECTS OF HF

PARADIGM-HF: ADVERSE EVENTS

LCZ696(n=4187)

Enalapril(n=4212)

PValue

Prospectively identified adverse events

Symptomatic hypotension 588 388 < 0.001

Serum potassium > 6.0 mmol/l 181 236 0.007

Serum creatinine ≥ 2.5 mg/dl 139 188 0.007

Cough 474 601 < 0.001

Discontinuation for adverse event 449 516 0.02

Discontinuation for hypotension 36 29 NS

Discontinuation for hyperkalemia 11 15 NS

Discontinuation for renal impairment 29 59 0.001

Angioedema (adjudicated)

Medications, no hospitalization 16 9 NS

Hospitalized; no airway compromise 3 1 NS

Airway compromise 0 0 ----

McMurray, et al. N Engl J Med 2014