HFrEF and Neurohormonal Systems · 2018. 8. 12. · •34% all-cause mortality EMPHASIS- HF6 (2011) 2,737 patients Eplerenone (MRA) vs placebo: 37% CV mortality or HF hospitalization

21/06/2018

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HFrEF and NeurohormonalSystems

Richard Troughton

CSANZ Breakfast Symposium

15 June 2018

Vasoconstrictor

Salt and H2O

retaining

Normal Control of the Circulation:

Neurohumoral Balance

Endothelin

Angiotensin II

Aldosterone

Norepinephrine

BNP

ANP

Urocortin

Adrenomedullin

Vasodilator

Diuretic

Adapted from Shah M et al. Rev Cardiovasc Med. 2001;2(suppl 2):S2–S6.

Neurohormonal Imbalance in Heart Failure

Endothelin

Aldosterone

Vasopressin

Angiotensin II

Norepinephrine

Excess v

asoconstric

tion

Compensation

Excess vasodilation

BNP

ANP

Urocortin

Adrenomedullin

• HF is characterized by heightened sympathetic tone

• Imbalances in baroreceptor reflexes and AngII-dependent SNS activation play an important role in adverse haemodynamic and cardiac responses

• Stimulation of SNS in HF results in

• Heart rate

• Contractility

• Na reabsorption

• Renal and peripheral vascular resistance

• Direct myocardial toxicity

Ach=acetylcholine; AngII= angiotensin II; CV=cardiovascular; E=epinephrine; HF=heart failure; NE=norepinephrine; SNS=sympathetic nervous system

Floras, JACC, 2009, 34: 375-85. Lymperopoulos et al. Circ Res 2013;113:739–53.

Sympathetic Nervous System: Role in the pathophysiology of HF

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*Studies ongoing; not approved for treatment of HFACE=angiotensin-converting enzyme; ACEI=angiotensin-converting-enzyme inhibitor; ADH=antidiuretic hormone; ARB=angiotensin receptor blocker; MRA=mineralocorticoid receptor antagonist; RAAS=renin-angiotensin-aldosterone system

Zaman et al. Nat Rev Drug Discov 2002;1:621–36; Schrier and Abraham. N Engl J Med 1999;341:577–85; Brewster et al. Am J Med Sci 2003;326:15–24; Schmieder. Am J Hypertens 2005;18:720–30; McMurray et al. Eur Heart J 2012;33:1787–847 Francis et al.

Ann Intern Med 1984;101:370–7; Von Lueder et al. Circ Heart Fail 2013;6:594–605.

RAAS: Initially compensatory and subsequently pathological in HF

Angiotensinogen

Ang I

Ang II

ACE

Renin

AT1 receptor

Biological actions

Signalling

cascade

Direct renin

inhibitors*

ACEIs

ARBs

Hypertrophy

Fibrosis

Vasoconstriction

hypertrophy

Aldosterone

secretion

Na+/H2O

retention

ADH

Secretion

Norepinephrine release

Sympathetic tone

Cardiac remodeling

Myocyte necrosis

Blood

Pressure Blood volume Heart rate

Contractility

MRAs

•ACEI=angiotensin-converting enzyme inhibitor; ARB=angiotensin receptor blocker; ARNI=angiotensin receptor neprilysin inhibitor; BB=beta blocker; CV=cardiovascular; HF=heart failure; HFrEF=heart failure with reduced ejection fraction; MRA=mineralocorticoid receptor antagonist. See notes for definitions of study names

•1. SOLVD Investigators. N Engl J Med 1991;325:293–302 2. MERIT-HF study group, Lancet, 1999, 353:2001-7 3. Granger et al. Lancet 2003;362:772−6 4. McMurray et al. Lancet

2003;362:767–771; 5. Swedberg et al. Lancet 2010;376:875–85 6. Zannad et al. N Engl J Med 2011;364:11–21; 7. McMurray et al. N Engl J Med 2014;371:993–1004 8 CIBIS-II

Investigators. Lancet 1999;353:9–13

Landmark trials in HFrEF

MERIT-HF2 (1999)3991 patients

Metoprolol vs placebo:

• 34% all-cause mortality

EMPHASIS-HF6 (2011)2,737 patients

Eplerenone (MRA) vs

placebo:

• 37% CV mortality or HF

hospitalization

SHIFT5 (2010)6,558 patients

Ivabradine (If inhibitor) vs

placebo:

• 18% CV death or HF

hospitalization

SOLVD-T1 (1991)2,569 patients

Enalapril (ACEI) vs placebo:


CHARM-Alternative3 (2003)2,028 patients

Candesartan (ARB) vs

placebo:


hospitalization

CHARM-Added4 (2003)2,548 patients


placebo:


hospitalization

1990s 2000s 2010s

CIBIS-II8 (1999)2,647 patients

Bisoprolol (BB) vs placebo:


Combination ACEI, -Blocker and MRA are now the cornerstone of therapy for HFrEF

ACEI

ARB

BB

ACEI + BB

ACEI + ARB

ARB + BB

ACEI +MRA

ACEI + ARB +BB

ACEI +BB + MRA

0.83 (0.66, 1.01)

0.88 (0.61, 1.26)

0.57 (0.33, 0.94)

0.57 (0.41, 0.72)

0.83 (0.51, 1.24)

0.47 (0.23, 0.86)

0.57 (0.35, 0.91)

0.52 (0.31, 0.80)

0.44 (0.26, 0.66)

HR (95% credible interval) for treatment vs. placebo*

0 0.5 1 1.5

*HR<1 favors treatment

Results are based on random-effects network meta-analysis using Bayesian models2

Studies included: 57 RCTs, Phase II/III (Jan 1987- April 2015) assessing guideline-recommended drug classes for HFrEF

Patient population: Patients (aged ≥18 years) with chronic HFrEF (LVEF <45%) and NYHA class II–IV of varying etiology presenting in the

outpatient department were included

1. McMurray et al. Eur Heart J 2012;33:1787–847;.2. Burnett H et al. Circ Heart Fail. 2017;10:e003529 Adapted from Shah M et al. Rev Cardiovasc Med. 2001;2(suppl 2):S2–S6.

Neurohormonal Imbalance in Heart Failure

Endothelin

Aldosterone

Vasopressin

Angiotensin II

Norepinephrine

Excess v

asoconstric

tion

Compensation

Excess vasodilation

BNP

ANP

Urocortin

Adrenomedullin

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The Natriuretic Peptide Family

H2 N

H2 N

H2 N

HOOCHOOC

HOOC

ANP BNP CNP

Courtesy of Dr Ruskoaho

1. Mangiafico et al. Eur Heart J 2013;34:886–93; 2. Gardner et al. Hypertension 2007;49:419–26; 3. Yamahara et al., PNAS, 2003, 100:3404-09. 4. Yamamoto et al. ,AJP,

1997, 273: H2406-14. 5. Clarkson et al., Clin Science 1995: 88: 159-64. 6. Kasama et al., Eur. Heart. J. 2008: 29:1485-94. 7.Volpe et al., Clin Science, 2016: 130:57-77. 8. Levin et al. N

Engl J Med 1998;339;321–8.

Effects of the Natriuretic Peptides

NPR-A

GTP

ANP and BNP

NPR-C

Internalization

Degradation

of NPs7

Receptor

recycling

Cardiomyocytes1

cGMP

⚫ Vasodilation1,2

⚫ Antihypertrophy1,2

⚫ Antiproliferation2

⚫ Vascular regeneration3

⚫ Myocardial relaxation4,5

⚫ Diuresis, natriuresis1,2

⚫ Antiapoptosis6

⚫ Anti-aldosterone1,2

⚫ Renin secretion inhibition7

⚫ Reduced sympathetic tone8

⚫ Lipolysis7

NPR-B

CNP

Endothelial cells1

GTPcGMP

⚫ Vasodilation1,2




⚫ Venodilation1

⚫ Antifibrosis1

Natriuretic peptide degradation and clearance

Effect of Short Term Augmentation of BNP and Adrenomedullin Levels in HFrEF.

Lainchbury et al. Hypertension. 1999;34:70-75

Short term NP infusion not associated with

improvements in mortality or hospitalisation

Longer term infusion or S/C treatment not feasible

Inhibition of Clearance a potential therapeutic target

ANP=atrial natriuretic peptide; BNP=B-type natriuretic peptide; CNP=C-type natriuretic peptide; cGMP=cyclic guanosine monophosphate; GTP=guanosine triphosphate; NPR=neprilysin receptor

1. Mangiafico et al. Eur Heart J 2013;34:886–93; 2. Gardner et al. Hypertension 2007;49:419–26; 3. Yamahara et al., PNAS, 2003, 100:3404-09. 4. Yamamoto et al. ,AJP, 1997, 273: H2406-

14. 5. Clarkson et al., Clin Science 1995: 88: 159-64. 6. Kasama et al., Eur. Heart. J. 2008: 29:1485-94. 7.Volpe et al., Clin Science, 2016: 130:57-77. 8. Levin et al. N Engl J Med

1998;339;321–8;.

Natriuretic peptides are cleared via NPR-C and degraded by the protease, neprilysin

NPR-A

GTP

ANP and BNP

NPR-C

Endocytosis

Inactivation

of NPs7

Receptor

recycling

Cardiomyocytes1

cGMP

NPR-B

Endothelial cells1

GTPcGMP

⚫ Vasodilation1,2




⚫ Venodilation1

⚫ Antifibrosis1

ANP

BNP

CNP Inactive

cleavage

productsCNP

Natriuretic peptide degradation and clearance

NEPNeprilysin

Natriuretic peptide signaling and effects

⚫ Vasodilation1,2




⚫ Myocardial relaxation4,5

⚫ Diuresis, natriuresis1,2

⚫ Antiapoptosis6

⚫ Anti-aldosterone1,2

⚫ Renin secretion inhibition7

⚫ Reduced sympathetic tone8

⚫ Lipolysis7

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Antoni Bayes-Genis et al. JACC 2016;68:639-653

Neprilysin / Neutral Endopeptidase

NEP is 749-AA, membrane-bound, zinc-dependent endopeptidase

Found in epithelia, fibroblasts and neutrophils and in soluble form

in the circulation, urine and CSF

Widely present in kidneys, heart, brain, gut and lungs

Neprilysin Cleavage Sites

• ANP and CNP are degraded by neprilysin with similar levels of enzymatic efficiency

• BNP is also degraded by neprilysin, but at a slower rate than ANP and CNP

Antoni Bayes-Genis et al. JACC 2016;68:639-653

Lainchbury et al, J Clin Endocrinol Metab. 1999;84(2):

Short-term NEP Inhibition in HFrEFOral NEP inhibition elevates NP levels in patients with HF

Single oral doses of candoxatril increase ANP and BNP levels in seven patients with chronic HF1#

Dose of candoxatril

Before treatment

Pla

sm

a B

NP

(p

mol/L)

Pla

sm

a A

NP

(p

mol/L)

50

40

30

20

10

0

100

80

60

40

20

00 mg 10 mg 50 mg 200 mg

Dose of candoxatril

*

*

**

**

After treatment

0 mg 10 mg 50 mg 200 mg

#Seven patients (mean age 65) with chronic HF NYHA II–III were given candoxatril 10, 50, 200 mg or placebo as a

single dose in a four-way crossover study. Values as mean and SEM; *p<0 05 vs 0 mg (placebo) (ANOVA);

Candoxatril - an orally active inhibitor of neprilysin

1. Lang et al. Lancet 1991;338:255

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• Candoxatril showed minimal hemodynamic effects compared with placebo in patients with HFrEF1-3

•Westheim et al. J Am Coll Cardiol 1999;34:1794–801; 2. Cleland and Swedberg. Lancet 1998; 351:1657–83 3. MaDowell and

Nicholls, Cardiovasscular drug reviews, 2000; 18: 259-70

Oral NEP inhibitor monotherapy failed to demonstrate clinical efficacy in HFrEF1

Left and right

atrial pressures

(reduced)

Arterial pressures

(no change)Heart rate

(no change)

Cardiac index

(no change after

exercise)

Systemic or

pulmonary

vascular

resistance

(no change)

▪ Another neprilysin inhibitor, ecadotril, led to numerically more deaths, as well as no evidence of clinical efficacy compared with placebo in patients with HF2

▪ Consequently, the development of both candoxatril and ecadotril for HF was discontinued2

⚫opposing actions of multiple neprilysin substrates

⚫increased Ang II levels offsetting beneficial effects of enhancing the NP system

⚫systemic vasoconstrictor rather than vasodilator effects (in part due to increased levels of the potent vasconstrictor ET-1)

•1. Westheim et al. J Am Coll Cardiol 1999;34:1794–801; 2. Kimmelstiel et al. Cardiology 1996;87:46–53; 3. Kentsch et al. Eur J Clin Pharmacol 1996;51:269–72; •4. McDowell et al. Br J Clin Pharmacol 1997;43:329–32; 5. Ando et al. Hypertension 1995;26:1160–6; 6. Von Lueder et al. Pharmacol Ther 2014;144: 41–9;

•7. Langenickel and Dole. Drug Discov Today:Ther Strateg 2012;9:e131–9.

Rationale for lack of efficacy with NEP inhibitor monotherapy in HFrEF1

Natriuretic peptides

Endothelin

Substance P

Bradykinin

Angiotensin II

Adrenomedullin

Angiotensin I

NEP

Inactive

fragments

or metabolites

⚫ Neprilysin metabolizes Ang I and Ang II 1,2

⚫ Inhibition of neprilysin alone is associated with an increase in Ang II levels, counteracting the potential benefits of neprilysin inhibition2

⚫ Neprilysin inhibition must be accompanied by simultaneous RAAS blockade

•1. Von Lueder et al. Circ Heart Fail 2013;6:594–605;

•2. Langenickel and Dole. Drug Discov Today: Ther Strateg 2012;9:e131–9.

Neprilysin inhibition must be accompanied by simultaneous RAAS blockade

Angiotensinogen

Ang I

Ang II

AT1 receptor

Biological actions


↑ Sympathetic tone

Vasoconstriction

Hypertrophy

Na+/H2O retention

Aldosterone release

Hypertrophy

Fibrosis

Signaling

cascade

Ang-(1–7)

Renin

ACE

Inactive

fragments

Neprilysininhibitor

Neprilysin

Neprilysin

Neprilysininhibitor • The IMPRESS study, tested the efficacy and safety of omapatrilat compared with the

ACEi lisinopril in 573 patients with HFrEF over 24 weeks*

•1. Rouleau et al. Lancet 2000;356:615–20

Vasopeptidase inhibitors (dual NEP and ACE inhibition) showed promise in HFrEF

Pro

port

ion w

ith e

vent

0.15

0.10

0.05

01801501209060300

Death or admission for heart failure

Lisinopril

Omapatrilat

p=0.052

0.15

Death, admission for heart failure, or

discontinuation of treatment

p=0.035

0.10

0.05

01801501209060300

Lisinopril

Omapatrilat

Pro

port

ion w

ith e

vent

Time from randomization (days)Time from randomization (days)

*A randomized, double-blind, parallel trial in patients with chronic HF NYHA class II–IV, LVEF ≤40%, and receiving an ACEI. Omapatrilat 40 mg (n=289) or lisinopril

20 mg (n=284)

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• Omapatrilat was compared with enalapril in 5,770 patients with HFrEF

•Packer et al.Circulation 2002;106:920–6

OVERTURE study showed trends towards efficacy with dual NEPi/ACEi but raised significant safety concerns

Event-

free s

urv

ival (%

)

1.0

0.8

0.6

0211815630

Time to death or HF hospitalization

Omapatrilat

Enalapril

p=0.187

Months

0.4

0.2

249 12

▪ Omapatrilat discontinued due to:

• Lack of efficacyattributed to sub-optimal neprilysin and ACE inhibition over 24 hours due to the once-daily dosing regimen

• Safety concernunacceptable risk of angioedema (24 patients [0.8%] vs 14 patients [0.5%] for omapatrilat and enalapril, respectively)., attributed to dual neprilysin and ACE inhibition leading to elevated bradykinin levels,

• Bradykinin is a substrate of neprilysin, ACE and other vasopeptidases

• Simultaneous inhibition of ACE and neprilysin results in elevated levels of bradykinin leading to higher risk of cough and angioedema1,2

• A selective neprilysin inhibitor coupled with an ARB can enhance beneficial effects of NP system while inhibiting RAAS with minimal effect on bradykinin degradation1

•1. McMurray et al. Eur J Heart Fail 2014;16:817–25; 2. Gu et al. J Clin Pharmacol 2010;50: 401–14;

Co-inhibition of neprilysin and AT1-receptor: better efficacy with lower angioedema risk?

Active

bradykinin

Inactive

bradykinin

Omapatrilat inhibits

ACE, APP and NEP2

Bradykinin breakdown

Active

bradykinin

Inactive

bradykinin

Selective NEP and

ARB inhibition

ACE APP NEP DPP-4

• Sacubitril/Valsartan is a salt complex comprised of two active components in a 1:1 molar ratio

•sacubitril (AHU377) – a pro-drug metabolised to the neprilysin inhibitor sacubitrilat

•valsartan – an AT1 receptor blocker

Sacubitril/Valsartan a first in class dual neprilysin inhibitor and AT1 receptor blocker

1. Bloch and Basile. J Clin Hypertens 2010;12:809–12; 2. Gu et al. J Clin Pharmacol 2010;50:401–14; 3. Langenickel and Dole. Drug Discov Today: Ther Strateg 2012;9:e131–9.

3D sacubitril/valsartan structure2

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•ACEI=angiotensin-converting enzyme inhibitor; ARB=angiotensin receptor blocker; ARNI=angiotensin receptor neprilysin inhibitor; BB=beta blocker; CV=cardiovascular; HF=heart failure; HFrEF=heart failure with reduced ejection fraction; MRA=mineralocorticoid receptor antagonist. See notes for definitions of study names

•1. SOLVD Investigators. N Engl J Med 1991;325:293–302 2. MERIT-HF study group, Lancet, 1999, 353:2001-7 3. Granger et al. Lancet 2003;362:772−6 4. McMurray et al. Lancet

2003;362:767–771; 5. Swedberg et al. Lancet 2010;376:875–85 6. Zannad et al. N Engl J Med 2011;364:11–21; 7. McMurray et al. N Engl J Med 2014;371:993–1004 8 CIBIS-II

Investigators. Lancet 1999;353:9–13

Landmark trials in HFrEF

MERIT-HF2 (1999)3991 patients

Metorprolol vs placebo:


EMPHASIS-HF6 (2011)2,737 patients

Eplerenone (MRA) vs

placebo:


hospitalization

SHIFT5 (2010)6,558 patients

Isvabradine (If inhibitor) vs

placebo:

• 18% CV death or HF

hospitalization

PARADIGM-HF7

(2014)

8,442 patients

Sacubitril/valsartan

(ARNI) vs enalapril:

SOLVD-T1 (1991)2,569 patients

Enalapril (ACEI) vs placebo:


CHARM-Alternative3 (2003)2,028 patients


placebo:


hospitalization

CHARM-Added4 (2003)2,548 patients


placebo:


hospitalization

1990s 2000s 2010s

CIBIS-II8 (1999)2,647 patients

Bisoprolol (BB) vs placebo:


Sacubitril/valsartan development timelines in HFrEF

1. de Bold AJ et al. Life Sci 1981;28:89–94; 2. Brauwald E et al, J Am Coll Cardiol

2015;65:1029–41

1998-2000:

Omapatrilat

and

Angioedema

1981-1983:

ANP is

discovered

1988-1992:

NEP

inhibitor

research

2005-2006:

Sacubitril/

valsartan

is born

2008-2014:

PARADIGM-HF

study. Trial

stopped early

2015: Sacubitril/

valsartan

approval in US

and EU

The future

Through its action of ANP

hydrolysis, NEP inhibition

leads to natriuresis and diuresis

First in class oral dual NEP and

ACE inhibitors discovered but

discontinued due to significant angioedema cases

Largest HF trial in history

compares sacubitril/valsartan

to ACEi enalapril in HFrEF patients

ANP released by

heart under

stress conditions lowers the blood

pressure

Both ESC-HF and US guidelines

give a recommendation of class IB

and replacement of ACEi/ARB with sacubitril/valsartan in all

symptomatic HFrEF patients

Novartis develops a unique, well-defined crystalline

salt complex comprising valsartan and sacubitrilat

along with sodium ions and water. A proof of concept human study of sacubitril/valsartan in

hypertension gives positive results

20 Jan 2016

TGA Approval


(Entresto®) receives

Australian TGA approval and is listed on the ARTG

Sacubitril/

valsartan is

available on the PBS

1 June 2017

PBS Listing

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•ACEI=angiotensin-converting enzyme inhibitor; Ang=angiotensin; ARB=angiotensin receptor blocker; AT1R=angiotensin II type 1 receptor; HF=heart failure; HFrEF=heart failure with reduced ejection fraction; MRA=mineralocorticoid receptor antagonist; NP=natriuretic peptide; NPRs=natriuretic peptide receptors; RAAS=renin-angiotensin-aldosterone system; SNS=sympathetic nervous system

•1. McMurray et al. Eur J Heart Fail 2013;15:1062–73; 2. Minguet et al., Exp. Opin.Pharamacother, 2015, 16:435-46;,

•Figure references: Levin et al. N Engl J Med 1998;339:321–8

Sacubitril/valsartan: Neprilysin inhibition combined with RAAS blockade is an alternative to an ACEI or ARB in patients with HFrEF1

SNS

RAAS

VasoconstrictionBlood pressure

Sympathetic toneAldosteroneHypertrophy

Fibrosis

Ang II AT1R

HF SYMPTOMS &

PROGRESSION

INACTIVE

FRAGMENTS

NP system

VasodilationBlood pressureSympathetic toneNatriuresis/diuresisVasopressinAldosteroneFibrosisHypertrophy

NPRs NPs

Epinephrine

Norepinephrineα1, β1, β2

receptors

VasoconstrictionRAAS activity

VasopressinHeart rate

Contractility

Neprilysin

inhibitors

RAAS inhibitors

(ACEI, ARB, MRA)

β-blockers


Neprilysin degrades other vasoactive peptides substrates including

Ang II

AT1 receptor

Signaling

cascades

NPR-A NPR-B

GTP GTP

cGMP

ANP

BNP CNP

Vasodilation

Cardiac fibrosis/hypertrophy

Natriuresis/diuresis

Ang II

Vasoconstriction

Cardiac fibrosis/hypertrophy

Sodium/water retention

NPR-C

Receptor

recyclingEndocytosis

ANP

BNP

CNP

ANP

BNP

CNP

Inactive

cleavage

products

Neprilysin

Ang II

Ang I

AdrenomedullinBradykinin

ET-1

Substance P

Inactivation

of NPs1,2,5

⚫ Neprilysin metabolizes Ang I and Ang II 1,2

⚫ Inhibition of neprilysin alone is associated with an increase in AngII levels, counteracting the potential benefits of neprilysininhibition2

⚫ Neprilysin inhibition must be accompanied by simultaneous RAAS blockade

•1. Von Lueder et al. Circ Heart Fail 2013;6:594–605;

•2. Langenickel and Dole. Drug Discov Today: Ther Strateg 2012;9:e131–9.

Neprilysin inhibition must be accompanied by simultaneous RAAS blockade

Angiotensinogen

Ang I

Ang II

AT1 receptor

Biological actions


↑ Sympathetic tone

Vasoconstriction

Hypertrophy

Na+/H2O retention

Aldosterone release

Hypertrophy

Fibrosis

Signaling

cascade

Ang-(1–7)

Renin

ACE

Inactive

fragments

Neprilysininhibitor

Neprilysin

Neprilysin

Neprilysininhibitor

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9

Documents

HFrEF and Neurohormonal Systems · 2018. 8. 12. · •34% all-cause mortality EMPHASIS- HF6 (2011) 2,737 patients Eplerenone (MRA) vs placebo: 37% CV mortality or HF hospitalization