1674 Mo

Novità in tema di blocco del RAAS

Alberto Morganti

Centro Fisiologia Clinica e Ipertensione

Ospedale Policlinico, Università di Milano

Prendiamoci a Cuore il ReneMilano 2-3 Dicembre 2016

1948 Mo

Different Levels of Pharmacological Blockade of

the Renin-Angiotensin System

AngiotensinogenAsp-Arg-Val-Tyr-Lle-His-Pro-Phe-His-Leu-Val…

Angiotensin IAsp-Arg-Val-Tyr-Lle-His-Pro-Phe-His-Leu

Angiotensin IIAsp-Arg-Val-Tyr-Lle-His-Pro-Phe

Angiotensin(1,9)

Angiotensin(1,7)

Kidney: Na retention, fibrosisHeart: Hypertrophy (?), fibrosisAdrenals: Aldosterone releaseVessels: Constriction, hypertrophyBrain: SNS activation, ADH release, thirst, salt appetite

Liver Kidney, Adrenals,

Retina, Ovaries, Testis

Prorenin

(Pro)renin receptors

Renin

Inactive peptides

Bradykinin

Mas AT2 AT1

ACE

ACE2

ACE2

ACE ACE

- - +

+??

Residual risk: morbidity and mortality remains high,

despite treatment with ACEIs and ARBs

0 0.5 1.0 1.5 2.0 2.5 3.0 3.5

30

25

20

15

10

5

0

Pro

po

rtio

n d

ied

(%

)

Time (years)

12%

relative

risk

reduction

Re

sid

ua

l

Ris

k

CHARM-Overall1: CV death

0 500 1,000 1,500

0.20

0.15

0.10

0.5

0Po

pu

lati

on

of

pati

en

ts

Days of follow-up

22%

relative

risk

reduction

Res

idu

al R

isk

HOPE2: CV death, stroke and MI

0 6 12 18 24 30 36 42 48 54 60 66

16

14

12

10

8

6

4

2

0Pro

po

rtio

n o

f p

ati

en

ts

wit

h f

irs

t e

ve

nt

(%)

Time (months)

14.6%

relative

risk

reduction

Re

sid

ua

l R

isk

LIFE3: CV death, stroke and MI

0 3 6 9 12 15 18 21 24

100

90

80

70

0

Even

t-fr

ee p

rob

ab

ilit

y (

%)

Time post-randomization (months)

13.2%

relative

risk

reduction

Re

sid

ua

l

Ris

k

Val-HeFT4: freedom from combined endpoint

Placebo

Ramipril

Atenolol

Losartan

Valsartan

Placebo

1Pfeffer et al. Lancet 2003;362:759–66; 2Yusuf et al. N Engl J Med 2000;342:145–53; 3Dahlöf et al. Lancet 2002;359:995–1003; 4Cohn et al. N Engl J Med 2001;345:1667–75

Placebo

Candesartan

Time to Primary OutcomeONTARGET:

Years of Follow-up

Cum

ula

tive H

azard

Rate

s0

.00

.05

0.1

00

.15

0.2

00

.25

0 1 2 3 4

Ramipril

Telmi & Ram

# at Risk Yr 1 Yr 2 Yr 3 Yr 4R 8576 8214 7832 7473 7095T&R 8502 8134 7740 7377 7023

3014 Mo

Composite, cardiac and renal outcome in ALTITUDE study

Parving HH et al., NEJM 2012; 367: 2204-2213

Primary

Cardiovascular Renal

Co

mp

osi

te o

utc

om

e (%

) 60

50

40

30

20

10

0

60

50

40

30

20

10

0

60

50

40

30

20

10

0

CV

ou

tco

me

(%)

Ren

al

ou

tcom

e (%

)

0 12 24 36 48Months since randomization

0 12 24 36 48Months since randomization

Aliskiren (n = 4274)

Placebo (n = 4287)

HR 1.08

P = 0.12

HR 1.11

P = 0.09

HR 1.03

P = 0.74

Aliskiren (n = 4274)

Placebo (n = 4287)

Aliskiren (n = 4274)

Placebo (n = 4287)

0 12 24 36 48

3015 Mo

Most commonly reported adverse events in ALTITUDE study

Parving HH et al., NEJM 2012; 367: 2204-2213

Event

Hyperkalemia

Hypotension

Diarrhea

Renal

impairment

Placebo

(n = 4285)

1244 (29.0)

357 (8.3)

312 (7.3)

371 (8.7)

Aliskiren

(n = 4272)

1670 (39.1)

519 (12.1)

417 (9.8)

418 (9.8)

P value

<0.001

<0.001

<0.001

0.07

no. of patients (%)

Any event reported

615 Mo

Omapatrilat: Pharmacologic Actions

Sodium Excretion

Vasodilation

Cardioprotection Hypertrophy

Vasoconstriction

Sodium retention

Angiotensin I

Bradykinin

Natriuretic peptides

(ANP, BNP, CNP)

Angiotensin II

Inactive products

Inactive products

ACE inhibition

NEP inhibition

3243 Mo Hubers SA et al., Circulation 2016; 133: 1115-1124

Mechanisms of action of ARNI

ARB + NEPi

Valsartan / Sacubitril

AT2R

Ang II

Ang I

Angiotensinogen

Natriuretic

Peptides

(ANP, BNP,

CNP)

Inactive

Peptides

Substance P Metabolites

NEPACE

Metabolites

MetabolitesBradykinin

Renin

Endothelin-1,

ADM,

Glucagon,

Amyloid

Vasoconstriction

Sodium retention

Inflammation

Fibrosis

APP

Vasodilation

Natriuresis

Fibrinolysis

Vasodilation

Natriuresis

3012 Mo

Change in mean systolic and diastolic blood pressure during

treatment with angiotensin-neprilysin inhibitor (LCZ696)

Ruilope LM et al., Lancet 2010; 375: 1255-1266

-16

-12

-8

-4

0

-10

-8

-6

-4

-2

0

Ch

an

ge

in S

BP

(m

mH

g)

Ch

an

ge

in D

BP

(m

mH

g)

200 mg

AHU377

(n = 164)

100 mg

LCZ696

(n = 154)

80 mg

Val

(n = 163)

200 mg

LCZ696

(n = 168)

160 mg

Val

(n = 163)

400 mg

LCZ696

(n = 170)

320 mg

Val

(n = 163)

**

**

3017 Mo

Outcome in angiotensin-neprilysin inhibitor

(PARADIGM-HF) study

McMurray S et al., NEJM 2014; 371: 993-1004

Primary endpoint CV death

Hospitalization for HF All-cause death

Cu

m.

pro

ba

bil

ity

Cu

m.

pro

ba

bil

ity

1.0

0.6

0.4

0.2

0.0

1.0

0.6

0.4

0.2

0.0

1.0

0.6

0.4

0.2

0.0

1.0

0.6

0.4

0.2

0.0

0 180 360 540 720 900 1080 1260

Days since randomization0 180 360 540 720 900 1080 1260

Days since randomization

HR 0.80

P < 0.001

HR 0.80

P < 0.001

HR 0.879

P < 0.001

HR 0.84

P < 0.001

Enalapril

(n = 4212)

LCZ696

(n = 4187)

3249 Mo McMurray JJV et al., New Engl J Med 2014; 371: 993-1004

Effects of ARNI

in patients with HF by prespecified groups

Subgroup

Age< 65 yr≥ 65 y

SexMaleFemale

NYHA classI or IIIII or IV

Estimated GFR< 60 ml/min/1.73m2

≥ 60 ml/min/1.73m2

Hazard Ratio forPrimary endpoint

Subgroup

DiabetesNoYes

Ejection fraction≤ Median> Median

NT-proBNP≤ Median> Median

HypertensionNoYes

Hazard Ratio forPrimary endpoint

0.3 1.0 1.7 0.3 1.0 1.7

LCZ696 better Enalapril better LCZ696 better Enalapril better

3016 Mo

Adverse events in PARADIGM-HF study

McMurray S et al., NEJM 2014; 371: 993-1004

Event

Hypotension

Symptomatic with SBP < 90 mmHg

Elevated serum creatinine

≥ 3.0 mg/dl

Elevated serum potassium

> 6.0 mmol/

Angioedema

Enalapril

(n = 4212)

59 (1.4)

83 (2.0)

236 (5.6)

5 (0.1)

LCZ696

(n = 4187)

112 (2.7)

63 (1.5)

181 (4.3)

10 (0.2)

P value

<0.001

0.10

0.007

0.19

no. of patients (%)

3244 Mo Voors AA et al., Eur J Heart Fail 2015; 17: 510-517

Changes in eGFR and urinary ACR induced by ARNI treatment

in patients with HF and preserved EF (Paramount Study)

Change in eGFR Change in UACR

Ch

an

ge

in e

GF

R (

ml/

min

.1.7

3m

2)

Weeks after randomization

Valsartan (n = 120)

LCZ696 (n = 121)

P = 0.008

-8

-6

-4

-2

0

2

0 12 24 36

-4

-2

0

2

4

6

8

0 12 24 36

Ch

an

ge

in l

og

-UA

CR

(m

g/m

mo

l)Weeks after randomization

P = 0.016

Valsartan (n = 120)

LCZ696 (n = 121)

3246 Mo Ruilope L et al., Lancet 2010; 375: 1255-1266

Effects of ARNI on plasma renin and aldosterone in HT patients

Renin

Aldosterone

n

Baseline (mU/l)

Mean change (%)

P <

n

Baseline (pmol/l)

Mean change (%)

P <

100

21

11

+72

0.01

43

238

+14

n.s.

LCZ696 dose (mg/day)

200

46

10.2

+94

0.01

58

231

+4

n.s.

400

56

11.3

+157

0.01

67

227

+8

n.s.

2514 Mo

Incidence of aldosterone “escape” phenomenon

during treatment with RAS inhibitors

Definition

Any increase from baseline

Aldosterone above levels

in healthy subjects

In patients with CHF

In patients without CHF

Bomback AS et al., Nat Clin Prac Nephrol 2007; 3: 486-492

6 months

40%

10%

10%

40%

12 months

53%

38%

38%

53%

556 patients from 8 studies

Duration of treatment

3232 Mo Ferrario CM, Schiffrin EL, Circ Res 2015; 116:206-213

Pleiotropic aldosterone actions contributing to

the pathogenesis of cardiovascular diseases

Inflammation

Dyslipidemia

Cardiac & Vascular

Fibrosis Gluconeogenesis

HypertensionObesity &

Type 2 Diabetes

Vascular Endothelial

Dysfunction

Renal Na+/K +

Regulation

ALDOSTERONE

3136 Mo

Associations between aldosterone and different comorbidities

in the general community

Buglioni A et al., Hypertension 2015; 65: 45-53

Comorbidity

Hypertension (n = 478)

Obesity (n = 535)

CKD (n = 243)

Central obesity (n =554)

Metabolic syndrome (n = 352)

Concentric LVH (n = 251)

OR

Top tertile of aldosterone

2.45

1.69

1.75

1.61

1.53

1.31

2744 Mo

Anti-aldosterone medications

Aldosterone receptor

antagonist (ARA)

Non-steroids

Aldosterone biosynthesis

inhibitor (ASI)

Denomination

Spironolactone

Canrenone

Eplerenone

Some DHP CCBs

(nimodipine, felodipine,

nitredipine, finerenone)

BR-4628, FAD 286,

LCI 1699

Development

Early 1960s

1980s

2000s

2000s

2010s

3227 Mo Bianchi S et al., Kidney Int 2006; 70: 2116-2123

Percent decline of proteinuria and eGFR in patients with CKD treated with

spironolactone in addition to conventional therapy including RAS inhibitors%

red

uct

ion

of

pro

tein

uri

a

% r

edu

ctio

n o

f eG

FR

-80

-60

-40

-20

0

-12

-10

-8

-6

-4

-2

0

Conventional therapy(n=82)

Conventional therapy +

Spironolactone (25 mg/day)n=83

All patients(n=165)

GFR < 60 ml/min

GFR > 60 ml/min

Months of treatment

1 3 6 9 12

Months of treatment

1 3 6 9 12

3145 Mo

Home blood pressure during treatment with spironolactone,

doxazosin and bisoprolol in patients with resistant hypertension

Williams B et al., Lancet 2015; 386: 2059-2068

134

136

138

140

142

144

146

148

150

76

78

80

82

84

86

Sy

sotl

icD

iaso

tlicH

om

e B

P (

mm

Hg)

Baseline

(n =314)

Placebo

(n =274)

Spironolactone

25-50 mg

(n =285)

Doxazosin

4-8 mg

(n =282)

Bisoprolol

5-10 mg

(n =285)

P < 0.0001

P < 0.0001

3214 Mo

Pharmacological characteristics of finerenone

Non-steroidal compound

Dihydropyridine derivative devoid of action on L-type CC

High affinity for MR

Long lasting binding to MR (protrusion of receptor domain

critical for binding)

Changes of MR co-activators and co-repressors

Equal distribution in heart and kidney

At low dose lower binding to kidney MR

3222 Mo Bakris GL et al., JAMA 2015; 314: 884-894

Change in UACR in patients with diabetic nephropathy

treated with finerenone

1.5

1.0

0.5

Placebo 1.25 2.5 5 7.5 10 15 20

Finerenone, mg/d

Ra

tio

of

Da

y 9

0 U

AC

R t

o b

ase

lin

e U

AC

R

F.U. 90 days

3221 Mo Bakris GL et al., JAMA 2015; 314: 884-894

Changes in GFR, serum potassium, SBP and DBP induced by

increasing doses of finerenone in patients with diabetic nephropathy

120

130

140

150

50

60

70

80

90

3.5

4.0

4.5

5.0

65

70

75

80

85

Placebo

Finerenone

1.25 mg/d

2.5 mg/d

5 mg/d

7.5 mg/d

10 mg/d

15 mg/d

20 mg/d

eGFR

Days

1 90

Days

1 90

Serum K+

SBP DBP

mm

ol/

lm

mH

g

mm

Hg

ml/

min

.1.7

3m

2

3225 Mo

Changes in serum potassium and eGFR in patients with CHF and

moderate CKD receiving finerenone or spironolactone

15 days treatment (n = 61)

29 days treatment (n = 57)

-8

-7

-6

-5

-4

-3

-2

-1

0

1

2

-0.1

0

0.1

0.2

0.3

0.4

0.5

0.6

eGFR

Ch

an

ge

in e

GF

R (

ml/

min

/1.7

3m

2)

Placebo2.5 mg qd 5 mg qd 10 mg qd

Spironolactone(25-50 mg)

Finerenone

Ch

an

ge

in K

(m

mo

l/l)

Placebo2.5 mg qd 5 mg qd 10 mg qd

Spironolactone(25-50 mg)

Finerenone

Serum potassium

2525 Mo

Il nuovo antagonista del RAS agisce con un effetto combinato

di blocco dei recettori dell’angiotensina II e di inibizione

della neprelisina , una endopeptidasi neutra ( ARNI),con

conseguente aumento dei fattori natruretici con azione

vasodilatante Questo farmaco ha dimostrato di ridurre

efficacemente la pressione arteriosa e gli end point

cardiovascolari nei pazienti con HF.

Anche ARNI, a somiglianza degli altri antagonisti del RAS,

non riduce significativamente l’aldosterone nei pazienti

ipertesi. L’aldosterone , anche a livelli moderatamente elevati,

può causare danni cardiovascolari e renali.

Gli antialdosteronici convenzionali ( spironolattone,

eplerenone) sono efficaci antipertensivi, di prima scelta nelle

ipertensioni resistenti e, come il nuovo finerenone, si sono

dimostrati efficaci nella ridurre la microalbuminuria nella

nefropatia diabetica.

Conclusioni