Behandlung der systolischen Herzinsuffizienz - Wiesbaden · Behandlung der systolischen Herzinsuffizienz. ... Richardson et al., Lancet 1987;II:709-711 Richards.ppt A 14 Pts. - Captopril

M. BöhmInnere Medizin III (Kardiologie / Angiologie / Internistische Intensivmedizin)

Universitätsklinikum des Saarlandes

Homburg/Saar

[email protected]

Behandlung der systolischen

Herzinsuffizienz

McMurray et al, Eur Heart J (2012) doi:10.1093/eurheartj/ehs104 AS-bb9-0512

Faris et al, Int J Cardiol 82 (2002): 149-158 AS-af2-0616

Withdrawal in Patients on ACE-Inhibitors

(Cross over)

Richards.pptRichardson et al., Lancet 1987;II:709-711

A 14 Pts.

- Captopril (3x25 mg)

- Furosemide (40 mg)

+ Amiloride (5 mg)

10 Pts.

(stable)

3 Months

stableCaptopril

4 Pts.

Pulmonary Edema

(11d, 33d, 8d, 16d)B 14 Pts.

- Furosemide (40 mg)

+ Amiloride (5 mg)14 Pts.

(stable)No Withdrawals

Walma et al, BMJ 315 (1997): 464-468 AS-af-0102

Withdrawal of Diuretic inOlder Individuals without Ouvert CHF

2 4 6 8 10 12 14 16 18 20 22 24 260

0

0.2

0.4

0.6

0.8

1.0

Control group (n=100)

Withdrawal group (n=102)

P<0.001

Pro

po

rtio

n W

ith

ou

t R

ein

itia

tio

n

Weeks after withdrawal of diuretics

Walma et al, BMJ 315 (1997): 464-468 AS-ag-0102

Withdrawal of Diuretics inOlder Individuals without Ouvert CHF

Criterion

All

Heart Failure

Hypertension

Subjective shortness of breath

Non-cardiac ankle oedema

Miscellaneous clinical conditions

Other

Withdrawal group(n=102)

50

25

9

6

4

3

3

Control group(n=100)

13

4

5

0

1

1

2

Risk difference (%)(95% CI)

36 (22 to 50)

21 (11 to 31)

4 (-3 to 11)

6 (1 to 11)

3 ( -1 to 8)

2 (-2 to 6)

1 (-3 to 5)

Not new!

Bisoprolol-first (o.d.)

Enalapril-first (b.i.d.)

Bisoprolol o.d.

Enalapril b.i.d.

Bisoprolol o.d.

Enalapril b.i.d

week Study end

1 - 2.5 years

0 2 4 6 8 10 26 28 30 32 34 36week Study end

1 - 2.5 years

First up-titration

First up-titration

Second up-titration

Second up-titrationMaintenance period

Maintenance period

Second maintenance period

22-100 weeks

Second maintenance period

16-94 weeks

1.252.5

3.755.0

7.5

1.252.5

3.755.0

7.5

2.5 5.0

2.5 5.0

* * * * * * * * * * * * * * * * ……….……. * * * * *

* = visits

10.0 mg

10.0 mg

10.0 mg

10.0 mg

Study design – CIBIS III

Bisoprolol o.d.

Enalapril b.i.d

0 2 4 6 8 10 26 28 30 32 34 36* * * * * * * * * * * * * * * * ……….……. * * * * *

DOI: 10.1161/CIRCULATIONAHA.105.582320

PP-A-0905.9

Intention-to-treat (ITT)

50

60

70

80

90

100

0 6 12 18

Per-protocol (PP)

50

60

70

80

90

100

0 6 12 18

Primary endpoint – CIBIS III

% without

endpoint

% without

endpoint

B/E vs E/B

HR 0.97 (95% CI 0.78-1.21)

non-inferiority P=0.046

B/E vs E/B

HR 0.94 (95% CI 0.77-1.16)

non-inferiority P=0.019

503498

356353

265259

8073

505505

389388

291277

8776

months

months

For non-inferiority

P<0.025 denotes

statistical significance

(unilateral test)

DOI: 10.1161/CIRCULATIONAHA.

105.582320

Bisoprolol-first

Enalapril-first

Patients at risk

Patients at risk

Mean follow-up

1.25 years

PP-A-0905.15

Worsening of CHF throughout study

Bisoprolol-first was associated with a trend

towards increased worsening of CHF in the

early phase of treatment.

Time (months)

70

75

80

85

90

95

100

0 6 12 18

B/EE/B

All cause mortality at end of monotherapy phase

Bisoprolol-first showed a trend towards

improved survival during the early study

phase (which was maintained

during combined therapy).

Time (months)

75

80

85

90

95

100

0 1 2 3 4 5 6

B/EE/B

Bisoprolol-first achieved clinically

comparable survival and all-cause

hospitalization compared with enalapril-first.

Primary endpoint PP

40

50

60

70

80

90

100

0 6 12 18

B/EE/B

Time (months)

% event-free

DOI: 10.1161/CIRCULATIONAHA.105.582320

Food for Thoughts – CIBIS III

PP-A-0905.30

Selye, Proc Soc Exp Biol Med 104 (1960): 109-111 AS-au2-0616

Pitt et al,

N Engl J Med 341 (1999): 709-717

AS-ad-1011

Aldosterone Receptor Blocker in Severe (left) andModerate (right) Heart Failure

Zannad et al,

N Engl J Med 364 (2011): 11-21

Vardeny et al, Circ Heart Fail 7 (2014): 573-579

Cooper et al, JAMA 314 (2015): 1973-1975 AS-ap-1215

AS-ah-0804Juurlink et al, N Engl J Med 351 (2004): 543-551

Hospitalizations due to Hyperkalemia after RALES

0.0

0.5

1994 1995 1996 1997 1998 1999 2000 2001

Study Year

Rate

of

In-H

osp

ital D

eath

fro

m H

yp

erk

ale

mia

(pe

r 1000 p

ati

en

ts)

Online release

of RALES

1.0

1.5

2.0

2.5



Pitt & Bakris, Hypertension 66 (2015): 731-738

Structure of ZS-9. Pore detail with potassium ion (A), sodium ion (B), and calcium ion

(C). Blue spheres indicates oxygen atoms; green spheres, silicon atoms; and red

spheres, zirconium atoms.

Reprinted from Stavros et al, PLoS One 9 (2014) e114686 with permission of the

publisher. Copyright © 2014, the Authors.

AS-aa4-1015

Kosiborod et al, JAMA (2014): [doi: 10.1001/JAMA.2014.15688]

Weir et al, N Engl J Med 372 (2015): 211-221

Time to First Recurrence of Hyperkalemia during the Randomized Withdrawal Phase

AS-aw3-0415

What do we need?

- Randomised, prospektive Study

- GFR 15-45 ml/min

- Spironolactone plus Patiromir vs Standardtherapie

- planned

COR LOE Recommendations

I ARNI: B-RIn patients with chronic symptomatic HFrEF NYHA class II or III who tolerate an ACE inhibitor or ARB,

replacement by an ARNI is recommended to further reduce morbidity and mortality (19).

See Online

Data Supplements

1 and 18.

Recommendations for Renin-Angiotensin System

Inhibition With ACE Inhibitor or ARB or ARNI

Yancy et al, Circulation 134 (2016) AS-bi6-0516

Regulation of Natriuretic Peptides, Bradykinin and Angiotensin II

Kidney

Blood vessels

Heart

Angiotensin II

Inactive products

Inactive products

Angiotensin I

Bradykinin

Natriuretic peptides

(ANP, BNP, CNP)

ACE

NEP

Cardioprotection

Vasodilation

Sodium

excretion

Hypertrophy

Vasoconstriction

Sodium Retention

{

Bayés-Genis et al, J Am Coll Cardiol 65 (2015): 657-665 AS-ag4-0415




Concept of ARNIs : Pharmacologic Actions

Kidney

Blood vessels

Heart

Angiotensin II

Inactive products

Inactive products

Angiotensin I

Bradykinin

Natriuretic peptides

(ANP, BNP, CNP)

ACE Inhibition

NEP Inhibition

Cardioprotection

Vasodilation

Sodium

excretion

Hypertrophy

Vasoconstriction

Sodium Retention

{

LCZ696 comprises the anionic

forms of sacubitril and valsartan,

sodium cations and water2

Its smallest crystal structure unit

consists of:2

• 6 sacubitril and 6 valsartan

molecules in anionic form

• 18 sodium cations

• 15 water molecules

• LCZ696 is available in three doses:3– 50 mg (24 mg sacubitril / 26 mg valsartan)

– 100 mg (49 mg sacubitril / 51 mg valsartan)

– 200 mg (97 mg sacubitril / 103 mg valsartan)

2D LCZ696 structure1

6

Sacubitril Valsartan

LCZ696 is a salt complex

H2O=water; Na=sodium

1. Novartis Data on File: LCZ696 Investigator’s Brochure Edition 16, 25 March 2015;

2. Feng et al. Tetrahedron Lett 2012;53:275–6;3. Highlights of prescribing information (ENTRESTO);

http://www.pharma.us.novartis.com/product/pi/pdf/entresto.pdf Accessed 21 August 2015

AS-ab7-0116

1. Novartis Data on File: LCZ696 Investigator’s Brochure Edition 16, 25 March 2015;

2. Feng et al. Tetrahedron Lett 2012;53:275–6;3. Highlights of prescribing information (ENTRESTO); http://www.pharma.us.novartis.com/product/pi/pdf/entresto.pdf Accessed 21 August 2015

http://www.pharma.us.novartis.com/product/pi/pdf/entresto.pdf

http://www.pharma.us.novartis.com/product/pi/pdf/entresto.pdf

At risk

Enalapril: 4212 3883 3579 2922 2123 1488 853 236

Cu

mu

lati

ve

Pro

po

rtio

n o

f P

ati

en

ts

wit

h P

rim

ary

En

d P

oin

t (%

)

Days after Randomization

0

10

20

30

40

0 180 360 540 720 900 1080 1260

HR: 0.80 (0.73, 0.87)

p < 0.001 1117Enalapril

(n=4212)

LCZ696

(n=4187)

914

PARADIGM-HF: Primary outcomeProspective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure trial

LCZ696: 4187 3922 3663 3018 2257 1544 896 249

Death from CV causes20% risk reduction

HF hospitalization21% risk reduction

693

558

658

537

McMurray, Packer et al NEJM 2014

P = 0.00004 P = 0.00004

PARADIGM-HFProspective comparison of ARNI with ACEI to Determine Impact on

Global Mortality and morbidity in Heart Failure trial

Death from CV causes20% risk reduction

HF hospitalization21% risk reduction

693

558

658

537

McMurray, Packer et al NEJM 2014

P = 0.00004 P = 0.00004

PARADIGM-HFProspective comparison of ARNI with ACEI to Determine Impact on

Global Mortality and morbidity in Heart Failure trial

Simpson et al., JACC 66: 2059-71, 2015

Cardiomyocyte

Blood

What to do with Markers:NT pro BNP and BNP

0 2 4 6 8

0

100

200

300

400

500

600

700

800

900

1000

1100

1200

1300

1400

0

50

100

150

200

250

300

350

400

450

500

NT

-pro

BN

P p

g/m

l

Months

BN

P p

g/m

l

LCZ696

Enalapril

NT-proBNP

BNP

PARADIGM-HF: NT-proBNP and BNP

Packer et al, Circulation (2014): [doi:10.1161/CIRCULATIONAHA.114.013748]

Pro BNP/

NT proBNP

Pre- Post- Pre- Post-

BNP

Hemmung

des BNP

Abbaues

Reduzierte

Wandspannung

LCZ696 LCZ696

NT pro BNP and BNP Änderungenwith LCZ696 (schematisch)

Packer et al, Circulation (2014): [doi:10.1161/CIRCULATIONAHA.114.013748]

How to Switch from an ACE

Inhibitor?

Angioedema?

LCZ696 actively inhibits Neprilysin and the AT1 receptor, thus

enabling alternative degradation pathways for bradykinin

Active

bradykinin

Inactive

bradykinin

ACE APP NEP DPP-4

Bradykinin breakdown

Omapatrilat inhibits ACE, APP and NEP2

LCZ696 inhibitsonly NEP1,4,5

Active

bradykinin

Inactive

bradykinin

Bradykinin is a substrate of Neprilysin and other vasopeptidases (ACE,

APP, DPP-4) – its elevation has been associated with cough and

angioedema2,3

Omapatrilat inhibits three enzymes (ACE, APP, NEP) involved in the

breakdown of bradykinin, which is likely to be responsible for the

development of angioedema2

LCZ696 actively inhibits Neprilysin and the AT1 receptor, thus

enabling alternative degradation pathways for bradykinin

Active

bradykinin

Inactive

bradykinin

ACE APP NEP DPP-4

Bradykinin breakdown

Omapatrilat inhibits ACE, APP and NEP2

LCZ696 inhibitsonly NEP1,4,5

Active

bradykinin

Inactive

bradykinin

Bradykinin is a substrate of Neprilysin and other vasopeptidases (ACE,

APP, DPP-4) – its elevation has been associated with cough and

angioedema2,3

Omapatrilat inhibits three enzymes (ACE, APP, NEP) involved in the

breakdown of bradykinin, which is likely to be responsible for the

development of angioedema2

Take Care of Wash Out, ie at least 36 hours!

OMAPATRILAT

Natriureticpeptides Bradykinin

Angiotensin I

Angiotensin II

NEP ACE

ACE-NEP Inhibition: Omapatrilat

AS-cs8-0409

AS-bb-0511

Quincke-Ödem

What do we need?

- PARAGON: LCZ in HFPEF

- Single application

- Resistent hypertension. Impaired renal function

McMurray JJV | Session 412-08

McMurray et al. NEJM 2016: http://www.nejm.org/doi/pdf/10.1056/NEJMoa1514859

In reducing the risk of the primary composite outcome of

cardiovascular death or heart failure hospitalization …

• Aliskiren added to enalapril is superior to enalapril

• Aliskiren monotherapy is superior to enalapril

• Aliskiren monotherapy is non-inferior to enalapril

Superiority

hyptheses

Non-inferiority

hyptheses

Primary outcome: CV death or heart failure hospitalization(event driven: target 2318 patients, 2369 occurred)

Enalapril 5-10mg bid* (N=2336)

Aliskiren 300mg qd# (N=2340)

Enalapril 5-10mg bid + Aliskiren 300mg qd (N=2340)

Enalapril

5-10mg bid

Aliskiren

300mg qd

Open-label run-in

4-12 weeks

Double-blind

median FU 36.6 months

Prior ACEi use dicontinued

*89% 10 mg#target dose (titrated from 150mg qd)

R

ATMOSPHERE

Methods

AS-ap48-0416

McMurray JJV | Session 412-08

McMurray et al. NEJM 2016: http://www.nejm.org/doi/pdf/10.1056/NEJMoa1514859

Cu

mu

lati

ve

eve

nt

rate

(%

of

pa

tie

nts

)

0 360 1800

Primary composite endpoint

Combination vs. enalaprilHR 0.93 (95% CI 0.85-1.03), P=0.17

Aliskiren vs. enalaprilHR 0.99 (95% CI 0.90-1.10), P=0.91

Days since Randomization

720 1080 1440

0 360 1800720 1080 1440 0 360 1800720 1080 1440

0 360 1800720 1080 1440

100

90

80

70

60

50

40

30

20

10

0

100

90

80

70

60

50

40

30

20

10

0

100

90

80

70

60

50

40

30

20

10

0

100

90

80

70

60

50

40

30

20

10

0

Cu

mu

lati

ve

eve

nt

rate

(%

of

pa

tie

nts

)

Cu

mu

lati

ve

eve

nt

rate

(%

of

pa

tie

nts

)C

um

ula

tive

eve

nt

rate

(%

of

pa

tie

nts

)


Aliskiren vs. enalaprilHR 1.06 (95% CI, 0.94–1.19) P=0.34


Death from CV causes

Death from any cause


Aliskiren vs. enalapril

HR 1.04 (95% CI 0.93-1.16), P=0.46


First heart failure–related hospitalization


Aliskiren vs. enalaprilHR 0.99 (95% CI 0.87-1.13), P=0.91


Combination

Aliskiren

Enalapril

Combination

Aliskiren

Enalapril

Combination

Aliskiren

Enalapril

Combination

Aliskiren

Enalapril

ATMOSPHERE

Results – superiority hypothesis

AS-ap50-0416

Cleland et al, Eur Heart J 34 (2013): 3547-3556 AS-al3-0616

Cleland et al, Eur Heart J 34 (2013): 3547-3556 AS-al2-0616

Baseline heart rate is a predictor of endpoints on placebo

Primary composite endpoint: risk increases by 2.9% per 1-bpm increase, and by 15.6% per 5-bpm increase

50

40

30

20

10

0

0 6 12 18 24 30Months

≥87 bpm

80 to <87 bpm

75 to <80 bpm

72 to <75 bpm

70 to <72 bpm

P<0.001

Patients with primary composite endpoint (%)

Böhm et al, Lancet 2010; 376: 886-894.

Stable CHF, SR > 70 bpm

Ivabradine n=793 (14.5%PY) Placebo n=937 (17.7%PY)

HR = 0.82 p<0.0001

0 6 12 18 24 30

Months

40

30

20

10

0

Ivabradine

Placebo

- 18%

Cumulative frequency (%)

Primary composite endpoint

Swedberg et al, Lancet 376 (2010): 875-885

NNT=26 (annualized)

NYHA II-IV, SR > 70 bpm

Endpoints Hazard ratio 95% CI p value

Primary composite endpoint 0.82 [0.75;0.90] p<0.0001

CV death 0.91 [0.80;1.03] p=0.128

Hospitalization for HF 0.74 [0.66;0.83] p<0.0001

All-cause death 0.90 [0.80;1.02] p=0.092

Death from HF 0.74 [0.58;0.94] p=0.014

Hospitalization for any cause 0.89 [0.82;0.96] p=0.003

Hospitalization for CV reason 0.85 [0.78;0.92] p=0.0002

Effect of ivabradine on outcomes

Swedberg et al. Lancet 2010; 376: 875-885.

Primary composite endpoint according to heart rate achieved at D28* in the ivabradine group

≥75 bpm

70-<75 bpm

60-<65 bpm

65-<70 bpm

<60 bpm

Patients with

primary

endpoint (%)

Months0 6 12 18 24 30Day 28

50

40

30

20

10

0

Böhm et al, Lancet 2010; 376: 886-894.

Achiewed Heart Rate at Day 28

Relevance

Comorbidities in Chronic Heart Failure

Dickstein et al, Eur Heart J 29 (2008): 2388-2442

Detect Co-morbidities and

Precipitating Factors

Non-cardiovascular

Anaemia

Pulmonary disease

Renal dysfunction

Thyroid dysfunction

Diabetes

Cardiovascular

Ischemia / CAD

Hypertension

Valvular dysfunction

Diastolic dysfunction

Atrial fibrillation

Ventricular dysrhythmias

Bradycardia

Diabetes

Silverman M, Turner RJ. In: Windhager EE, ed. Handbook of Physiology, Vol. II. New York, NY: Oxford University Press; 1992:2017-2038.

0

200

400

600

0 200 400 600 800

Plasmaglukose (mg/dL)

Glu

ko

se

(m

g/m

in)

11070

Normale

Plasma-

glukose

Fast die gesamte filtrierte Glukose wird

beim Gesunden reabsorbiert

Bei normaler Plasmaglukose (70-110 mg/dL), wird Glukose fast komplett reab-sorbiert

Bei hoher Plasma-glukose, wie bei Diabetes, wird Glukose weiter tubulär reabsor-biert

Tubuläre Reab-sorption unterhält Hyperglykämie

Wenn TmG über-schritten wird (~180–200 mg/dL), kommt es zur Glukosurie


0

200

400

600

0 200 400 600 800

Plasmaglukose (mg/dL)

Tubuläre

Reabsorption

TmGGlu

ko

se

(m

g/m

in)

11070

Normale

Plasma-

glukoseUrin

Glukose

Schwelle

kaum

Glukose

im Urin

Glukose im

Urin

Erhöhte Plasmaglukose

Fast die gesamte filtrierte Glukose wird

beim Gesunden reabsorbiert

Distales S3 Segment des

proximalen Tubulus

~10% Glukose reabsorbiert

Transport durch SGLT1

S1 Segment des proximalen

Tubulus

~90% Glukose reabsorbiert

Transport durch SGLT2

Keine Glukoseim Filtrat

Sammelrohr

Glomerulus filtriert

Proximaler Tubulus reabsorbiert


Bakris GL, et al. Kidney Int. 2009;75:1272-1277.

Glukose

Glukose- Reabsorption findet im

proximalen Tubulus statt

SGLT: sodium glucose transporter

EMPA-REG OUTCOME®: Trial design

67

• Study medication was given in addition to standard of care

• The trial was to continue until at least 691 patients experienced an

adjudicated primary outcome event

• 97.0% of patients completed the study and final vital status was available for

99.2% of patients

Randomized and

treated

(n=7020)

Empagliflozin 10 mg

(n=2345)

Empagliflozin 25 mg

(n=2342)

Placebo

(n=2333)

Screening

(n=11531)

Zinman B et al. N Engl J Med 2015 DOI: 10.1056/NEJMoa1504720.

Zinman et al., New Engl J Med (2015): [doi:10.1056/NEJMoa1504720]

Zinman et al., New Engl J Med (2015): [doi:10.1056/NEJMoa1504720]

Patients

hospitalized

for

heart failure

(%)

HR 0.75

(95% CI 0.48, 1.19)

HR 0.59

(95% CI 0.43, 0.82)

Cox regression analysis.

HR, hazard ratio; CI, confidence interval.

Hospitalization for heart failure

in patients with vs without heart failure at baseline

Zinman et al, N Engl J Med (Suppl.) [doi: 10.1056/NEJMoa1504720]

AS-bn-0709Home et al, Lancet 373 (2009): 2125-2135

Leitlinien Sind lesenswert!

… sollten nur auch gelesen werden!

Guide-

lines

M. Böhm

Klinik für Innere Medizin III

Universitätsklinikum des Saarlandes

Homburg/Saar, Germany

Tel. 06841-16-23372

Fax. 06841-16-23369

[email protected]

Thank you

for your attention!

Documents

Behandlung der systolischen Herzinsuffizienz - Wiesbaden · Behandlung der systolischen Herzinsuffizienz. ... Richardson et al., Lancet 1987;II:709-711 Richards.ppt A 14 Pts. - Captopril