WC

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University Medical Center Groningen

Behandeling van Hartfalen:

over 5 jaar

Adriaan Voors, cardioloog

UMCG

WC

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University Medical Center Groningen

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University Medical Center Groningen

Over 5 jaar…

WC

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University Medical Center Groningen

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University Medical Center Groningen

• HFrEF: best evidence, biggest pipeline

• Entresto

• Omcamtiv

• LVAD: destination therapy

• HFrEF: no evidence, smallest pipeline

• Entresto

• Septostomy

• Acute Heart Failure: minimal evidence, biggest problem

• Ularitide, Serelaxin

• Preventing early hospital readmission

Heart Failure Treatment in 5 Years

WC

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University Medical Center Groningen

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University Medical Center Groningen

Treatment of HFrEF: getting better!

WC

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University Medical Center Groningen

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University Medical Center Groningen

HFrEF: Unmet Needs?

WC

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University Medical Center Groningen

Beta blocker

Mineralocorticoid receptor

antagonistACE

inhibitor

Angiotensin receptor blocker

Drugs that inhibit the renin-angiotensin system have modest effects on

survival

40%Based on results of SOLVD-Treatment, CHARM-Alternative,

COPERNICUS, MERIT-HF, CIBIS II, RALES and EMPHASIS-HF

0%

10%

20%

30%

%D

ec

rea

se

inM

ort

ality

2011: Drugs Reducing Mortality in HFrEF

WC

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University Medical Center Groningen

X

ARNI have the potential to restore the appropriate

balance of the RAAS and natriuretic peptides in HF

Beneficial physiological response Pathophysiological response

Vasodilation

↓ blood pressure

↓ sympathetic tone

↓ aldosterone level

↓ fibrosis

↓ hypertrophy

Natriuresis/Diuresis

HF

symptoms/

progression

NPs Ang II

NEP

Damage

Inactive

fragmentsAT1 receptor

X

RAASNP system

Vasodilation

↓ blood pressure

↓ sympathetic tone

↓ aldosterone

↓ fibrosis

↓ hypertrophy

NEP/RAAS

inhibition

(LCZ696)

Neurohormonal balance

X

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University Medical Center Groningen

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University Medical Center Groningen

Prospective comparison of ARNI with ACEI to

Determine Impact on Global Mortality and

morbidity in Heart Failure trial (PARADIGM-HF)

LCZ696400 mg daily

Enalapril 20 mg daily

Aim of the PARADIGM-HF Trial

Specifically Designed To Replace Current Use Of Ace

Inhibitors And Angiotensin Receptor Blockers As The

Cornerstone Of The Treatment Of Heart Failure

WC

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University Medical Center Groningen

LCZ696

(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)

0.0000002

Cardiovascular

death

558

(13.3%)

693

(16.5%)

0.80

(0.71-0.89)

0.00004

Hospitalization

for heart failure

537

(12.8%)

658

(15.6%)

0.79

(0.71- 0.89)

0.00004

Effect of LCZ696 vs Enalapril on Primary

Endpoint Components

NEJM 2014

WC

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University Medical Center Groningen

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University Medical Center Groningen

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University Medical Center Groningen

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University Medical Center Groningen

Entresto approved by EMA and FDA

"Entresto is indicated in

adult patients for treatment

of symptomatic chronic

heart failure with reduced

ejection fraction.”

WC

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University Medical Center Groningen

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University Medical Center GroningenHasenfuss and Teerlink; Eur Heart J 2011;32:1838-45

University Medical Center Groningen

COSMIC-HF

Chronic Oral Study of Myosin Activation

to Increase Contractility in Heart Failure

• Primary objectives

• To select an oral modified release formulation and dose for chronic

twice daily dosing in patients with symptomatic HFrEF (NYHA II/III,

LVEF ≤ 40%, NT-proBNP ≥ 200 pg/mL/≥ 1200 pg/mL if AF)

• Secondary objectives

• Safety and tolerability

• Changes in SET, SV, LVESD, LVEDD, heart rate and NT-pro BNP

levels

JR Teerlink, Late-Breaking Clinical Trial Session at the American Heart Association (AHA) Scientific Sessions 2015

University Medical Center Groningen

Efficacy of Omecamtiv Mecarbil

JR Teerlink, Late-Breaking Clinical Trial Session at the American Heart Association (AHA) Scientific Sessions 2015

University Medical Center Groningen

Efficacy of Omecamtiv Mecarbil, Cardiac

troponin I levels

JR Teerlink, Late-Breaking Clinical Trial Session at the American Heart Association (AHA) Scientific Sessions 2015

WC

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University Medical Center Groningen

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University Medical Center Groningen

Left Ventricular Assist Device

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University Medical Center Groningen

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University Medical Center Groningen

HFrEF versus HFpEF

HFrEF: LVEF <40%

HFpEF: LVEF >50%

Between 40-50%: grey-area

ESC Heart Failure Guidelines 2012

WC

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University Medical Center Groningen

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University Medical Center Groningen

Treatment of Diastolic Heart Failure

No treatment has yet been shown, convincingly, to reduce morbidity and mortality in patients with HFPEF. Diuretics are used to control sodium and water retention and relieve breathlessness and oedema. Adequate treatment of hypertension and myocardial ischaemia is also considered to be important, as is control of the ventricular rate in patients with AF.

ESC Heart Failure Guidelines EJHF 2008 +2012

WC

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University Medical Center Groningen

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University Medical Center Groningen

HFpEF: Unmet Needs?

WC

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University Medical Center Groningen

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University Medical Center Groningen

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University Medical Center Groningen

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University Medical Center Groningen

PARAMOUNT: main results

Solomon et al. Lancet 2012

301 HFpEF patients; LVEF≥45%; NT-proBNP>400 pg/mL

LCZ696 2 dd 200 mg or Valsartan 2 dd 160 mg

WC

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University Medical Center Groningen

• Target patient population: 4,300 patients with symptomatic HF

(NYHA Class II–IV) and LVEF 45%

PARAGON-HFPEF: study design

*Valsartan 40 mg BID (up to 2 weeks) followed by

valsartan 80 mg BID as an optional starting run-in dose for

those patients being treated with less than the minimum

dose of ACEI or ARB at Visit 1

up to 2 weeks ~240 weeks

Valsartan 160 mg BID

LCZ696 200 mg BIDLCZ696

100 mg BID

On top of optimal background medications for

co-morbidities (excluding ACEIs and ARBs)

Primary outcome: CV death and total (first and recurrent)

HF hospitalizations (anticipated ~1,721 primary events)

Valsartan

80 mg BID*Screening

3–8 weeks

Active run-in period

Double-blind treatment period

Randomization 1:1

Solomon SD, et al. Poster presentation at ESC-HF Congress, 25 May 2013;

Clinicaltrials.gov NCT01920711;accessed March 2014

WC

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University Medical Center Groningen

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University Medical Center Groningen

Interatrial Shunt Device:

Novel therapy for HFpEF?

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University Medical Center Groningen

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University Medical Center Groningen

• Prospective, nonrandomized, open-label trial

• A minimum of 60 patients: LVEF>40% and NYHA III-IV

• PCWP >15 mm Hg at rest or >25 mm Hg during exercise

• All patients receive IASD System II

• Primary outcome measures for safety are periprocedural

and 6-month major adverse cardiac and cerebrovascular

events (MACCE) and systemic embolic events (excluding

pulmonary thromboembolism).

WC

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University Medical Center Groningen

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University Medical Center Groningen

Group Medication

Class recommendation,

Level of evidence

Diuretics Indication I, B

Vasodilators Nitrates IIa, B

Sodium Nitroprusside IIb, B

Morphine Indication IIa, C

Inotropics Dopamine IIb, C

Dobutamine IIa, C

Acute Heart Failure: Recommendations and levels of evidence

McMurray et al. Eur J Heart Fail 2012; 33:1787–847

WC

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University Medical Center Groningen

PDE inhibitors: milrinone: OPTIME-CHF

Endothelin antagonists: tezosentan: VERITAS

Calcium sensitizers: levosimendan; SURVIVE/REVIVE

AVP antagonists: tolvaptan; EVEREST

Adenosine A1-receptor antagonist: rolofylline; PROTECT

Natriuretic peptides: nesiritide: ASCEND-HF

Wrongconcept?

Wrong study

design?

Wrong drugs?

Several Drugs in AHF Not Successful

AVP = arginine vasopressin;PDE = phosphodiesterase

WC

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University Medical Center Groningen Mitrovic V, et al. Eur Heart J. 2006;27(23):2823-2832.

Ularitide: Sirius II

WC

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University Medical Center Groningen

Ularitide: TRUE-AHF

• A phase 3, double-blind, randomized, placebo-controlled,

multicenter study

• 48-hour IV infusion with ularitide, 15 ng/kg body

weight/min

• 2152 patients hospitalized for acute heart failure

• Study treatment within 12 hours after ED admission

• Co-Primary endpoint:

• hierarchical clinical composite including dyspnea relief,

worsening of heart failure, and all-cause mortality

• CV-mortality

ClinicalTrials.gov NCT01661634

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University Medical Center Groningen

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University Medical Center Groningen

Relaxin

Hsu et al. Science 2002;295:671–674; Jeyabalan et al. Adv Exp Med Biol 2007;612:65–87;

Dschietzig et al. Circ Res 2003;92:32–40

• Naturally occurring hormone, discovered in 1929

• Elevated in circulation in first trimester of

pregnancy and throughout 9 months

• Relaxin receptors, identified in 2002, localized in

blood vessels

• Mechanism of action involves activation of the

endothelial endothelin type B receptor

• Contributes to maternal hemodynamic

adjustments to pregnancy

Relaxin

WC

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University Medical Center GroningenTeichman SL, et al. Curr Heart Fail Rep. 2010;7(2):75-82.

Relaxin

↓ Inflammation ↓ Fibrosis ↑ Vasodilation Renal effects Angiogenesis

↓ TNF-

↓ TGF-

↑ MMP

↓ Collagendeposition

↑ EndothelialETB receptor

ET-1

ET1-32 NOS ↑ VEGF

NO

Relaxin receptor

ETB receptor = endothelin receptor type B; ET-1= endothelin-1; MMP = matrix metalloproteinase; NO = nitric oxide; NOS = nitric oxide synthase; TGF = transforming growth factor; TNF = tumor necrosis factor; VEGF = vascular endothelial growth factor

Serelaxin Is NOT Just Another Vasodilator

WC

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University Medical Center Groningen

First primary endpoint: change in dyspnea with VAS

Teerlink JR, et al. Lancet. 2013;381(9860):29-39.

35

30

25

20

15

10

5

0

Ch

ange

Fro

m B

ase

line

(mm

)

0 6h Day 1 Day 2 Day 3 Day 4 Day 5Follow-up

12h

Serelaxin (n=581)

Placebo (n=580)

Placebo: mean AUC (SD) = 2308 (3082) mm/h

Serelaxin: mean AUC (SD) = 2756 (2588) mm/h

P = .007

Randomized, Double-Blind, Placebo-Controlled Trial in 1161 ADHF Patients

…but no significant effects on second primary endpoint and secondary endpoints

RELAX-AHF

AUC = area under the curve; SD = standard deviation; VAS = visual analogue scale

WC

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University Medical Center Groningen

OrthopneaP = .002

EdemaP = .01

RalesP = .008

JVPP = .06

Pat

ien

ts (

%)

100

80

60

40

20

0

None

Mild

Moderate

Severe

NoneNone

None

<6 cm

6–10 cm

>10 cm

<1/3

1/3–2/3

>2/3

1+

2+

3+

1 Pillow

2 Pillows

>30°

DOEP = .02

DOE = dyspnea on exertion; JVP = jugular venous pressure

Signs and Symptoms at Day 2

Teerlink JR, et al. Lancet. 2013;381(9860):29-39.

WC

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University Medical Center Groningen

12

10

8

6

4

2

0

CV

De

ath

(%

)

0 14 30 60 90 120 150 180

Time Since Randomization (days)

Placebo: 55 CV deaths (9.6%)

Serelaxin: 35 CV deaths (6.1%)

HR, 0.63 (95% CI, 0.41-0.96)

P = .028

n=580

n=581

RELAX-AHF: CV Mortality

Teerlink JR, et al. Lancet. 2013;381(9860):29-39.

CI = confidence interval; HR = hazard ratio

WC

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University Medical Center Groningen

RELAX-AHF-2: study designPlease note that the study design information for RELAX-AHF-2 is subject to change

Discharge#

Placebo i.v.

Serelaxin 30 µg/kg/d i.v.*

0 6 12 24 48 72 96 120 h 14 60 120 180 d

48 h study drug infusion (i.v.) period

*Same weight range-adjusted dosing as in RELAX-AHF; ‡Standard HF therapy permitted at physician’s discretion; #If discharge visit coincides with a scheduled visit, only the discharge visit will be performed.AHF=acute heart failure; CV=cardiovascular; d=day; h=hour; i.v.=intravenous; SBP=systolic blood pressure

Clinicaltrials.gov: NCT01870778; Novartis, data on file 2013

In addition to standard HF therapy‡

Screening

Double-blind randomized treatment period

Screening occurred after ≥40 mg i.v. furosemide

Presentation <16 h

Randomization 1:1

Target patient population: 6,375 patients hospitalized with AHF, presenting with dyspnea, normal to

elevated SBP (125 mmHg) and mild-to-moderate renal impairment

Primary outcome: time to CV death

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University Medical Center Groningen

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University Medical Center Groningen

• Better understanding of the disease

• Prevention

• Personalized medicine

General unmet needs

Acute

Heart

Failu

re

University Medical Center Groningen

periods of highest risk for readmission

unavoidable readmissions

AHF early post-discharge vulnerable phase

Desai AS and Stevenson LW .Circulation. 2012;126:501-506.

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University Medical Center Groningen

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University Medical Center Groningen

• Appropriate discharge therapy

• Training and education before discharge

• Length of hospital stay

• Adequate decongestion during hospital admission

• Discharge planning and disease management programs

How to prevent early re-admission?

WC

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University Medical Center Groningen

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University Medical Center GroningenValente, et al. EHJ 2014

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University Medical Center Groningen

Diuretic response in AHF related to

re-hospital admission up to day 60

PROTECT: 2033 AHF patients;

Diuretic response = kg weight loss/40 mg furosemide

Valente, et al. EHJ 2014

% r

e-a

dm

issio

n

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University Medical Center Groningen

Diuretic response: death or HF/RF

readmission through day 60

P<0.0001

Voors et al. Eur J Heart Fail 2014

RELAX-AHF: 1161 AHF patients;

Diuretic response = kg weight loss/40 mg furosemide

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University Medical Center Groningen

• Better understanding of the disease

• Prevention

• Personalized medicine

General unmet needs

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University Medical Center Groningen

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University Medical Center Groningen

Differential response to therapy

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University Medical Center Groningen

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University Medical Center Groningen

Over 5 jaar…

• HFrEF: best evidence, biggest pipeline

• Better drugs in severe HFrEF?

• HFrEF: no evidence, smallest pipeline

• Better understanding, better therapies

• Acute Heart Failure: minimal evidence, biggest problem

• First proven thersapies upcoming?

• Preventing early hospital readmission

• General aims: prevention and personalized medicine