Heart Failure with Preserved EjectionFraction- What is new?

3rd Dubrovnik Cardiology Highlights

ESC Update Programme, Dubrovnik, 26.-29.9.2013

Prof. Burkert Pieske

Department of Cardiology

Medical University Graz

&

Ludwig-Boltzmann-Institute

Translational HF Research

www.kardiologie-graz.at www.heart.lbg.ac.at

The Relationship Between Pressure and Volume

HFPEF, HFNEF, or Diastolic Heart Failure??

HFpEF – News 2013

• News I: Pathophysiology

• News II: Diagnosis?

• News III: Therapy?

„Heart failure“with

preserved EF

Ventricular Dysfunction• Impaired relaxation• Impaired filling• Systolic Dysfunction

Atrial dysfunction

Autonomic dysfunctionChronotropic incompetence

Elevated blood pressureInadequate BP response to exercisePulmonary hypertension

Vascular dysfunctionVascular stiffeningVentriculo-arterial coupling

Valvular diseaseDynamic mitral regurgitation

„Heart failure“with

preserved EF

Lung DiseaseCOPD

Iron deficiencyand anemia

Renal dysfunctionVolume overload

Aging & Deconditioning

Obesity &Sarcopenia

Psychic DisordersDepression

„Heart failure“with

preserved EF

Lung DiseaseCOPD

Iron deficiencyand anemia

Renal dysfunctionVolume overload

Aging & Deconditioning

Obesity &Sarcopenia

Psychic DisordersDepression

Ventricular Dysfunction• Impaired relaxation• Impaired filling• Systolic Dysfunction

Atrial dysfunction

Autonomic dysfunctionChronotropic incompetence

Elevated blood pressureInadequate BP response to exercisePulmonary hypertension

Vascular dysfunctionVascular stiffeningVentriculo-arterial coupling

Valvular diseaseDynamic mitral regurgitation

HFpEF – News 2013

• News I: Pathophysiology

• News II: Diagnosis?

• News III: Therapy?

EF

40-5

0 %

Mega-Trial Approach: HF + “preserved EF”

Fonarow G et al. JACC. 2007; 50:768-777.

EF

≥ 5

0 %

OPTIMIZE-HF Registry, N=41,267

EF

≤ 4

0 %

I-Preserve Echo Substudy

Structural LV Remodeling

Zile et al.; Circulation 2011; 124

Almost 50%: no structural LV Remodeling!

HFA/ESC Recommendations

Paulus W et al., Eur Heart J 2007; 2539-2550

HFA/ESC Recommendations: Diagnosis

1. Signs and/or Symptoms of Heart Failure

2. Preserved global systolic LV Function (EF>50%)

3. Indices of abnormal LV relaxation, filling, compliance

or stiffness

4. BNP or NTproBNP

Diagnosis: Diastolic Heart Failure

HFA/ESC 2007

Paulus W et al.

Diagnosis: Diastolic Heart Failure

HFA/ESC 2007

Paulus W et al.

E/é and LVEDP

Little et al.; Circulation 2009; 120: 802-809

Diagnosis: Diastolic Heart Failure

Change in Paradigms 2013:

• New Echo Techniques & Parameters

(e.g., strain, torsion)

• Echo Stress test („Diastolic Stress Test“)!

• New Biomarkers: Subgroups, Response

to Therapy (e.g., Galectin-3, ST2)

HFpEF – News 2013

• News I: Pathophysiology

• News II: Diagnosis?

• News III: Therapy?

Systolic Heart Failure: Therapy 2013

NYHA I NYHA II NYHA III NYHA IV

Beta-Blockers

Diuretics

ACE – Inhibitors

Digitalis

MR Antagonists

AT-1-Antagonists/Ivabradine

Diastolic Heart Failure: Therapy 2013

NYHA I NYHA II NYHA III NYHA IV

?

Diuretics ?

?

?

?

?

Redfield M, Circ Heart Fail 2012;5;653-659

Large Trials in HFPEF – no clear benefit

Emerging Therapies

1. Pharmacological management

Ivabradine

PDE-5 Inhibition

Guanylate cyclase stimulation

Neprilysin Inhibition

MR antagonists

2. Interventions and Devices

Renal Denervation

Interatrial Shunting, Vagus/Baroreceptor stimulation..

3. Physical acitvity and Exercise

Reil et al, Eur Heart J, 2012:1-11

Ivabradine – If channel inhibition

Genetic mouse model of HFPEF (db/db)

Invasive hemodynamics with Ivabradine

Ivabradine improved diastolic function

Study CL2-16257-101

Effects of ivabradine versus placebo on cardiac

function, exercise capacity, and neuroendocrine

activation, in patients with Chronic Heart Failure and

Preserved left ventricular Ejection Fraction

An 8-month, randomised double-blind, placebo controlled,

international, multicentre study

Phase II

Ivabradine phase II study in HFPEF

Primary objective

Ivabradine vs placebo on diastolic function, exercise capacity and

neuroendocrine activation over an 8-month treatment period in patients with

chronic HF-PEF

Primary endpoint

Co-primary endpoint based on echocardiography (E/e’),

neuroendocrine activation (NT-proBNP) and six-minute walk test evaluated at

8 months

Secondary objectives

-To evaluate the effects of ivabradine compared to placebo on cardiac

function and structural parameters, quality of life (KCCQ) , NYHA

classification and other biomarkers

-To evaluate the safety and tolerance profile of ivabradine compared to

placebo

Start: May 2013 !

Increasing cyclic GMP in HFPEF ?

Redfield M, Circulation. 2012;5;653-659

Myocardial dysfunction impaired relaxation, diastolic

stiffening, energy wastage

Endothelial dysfunction disturbed endothelium-dependent

vasotone regulation

Insufficient soluble Guanylate Cyclase (sGC): an unmet mechanism in HFPEF

ß-BlockersMRA

ACE-I / ARB

PDE5 Inhibition?

Desai A S, American Heart Journal, December 2011

Redfield M, JAMA, 2013;309(12)

RELAX

216 patients

Randomized, double

blind, placebo-controlled

Sildenafil 3x20mg

(12w), 3x60mg 12w)

EF>50%

Elevated NTproBNP

PEP: peak VO2

Redfield M, JAMA, 2013;309(12)

RELAX

Outcomes after 24 weeks:

Myocardial dysfunction impaired relaxation, diastolic

stiffening, energy wastage

Endothelial dysfunction disturbed endothelium-dependent

vasotone regulation

Insufficient soluble Guanylate Cyclase (sGC): an unmet mechanism in HFPEF

ß-BlockersMRA

ACE-I / ARB sGC stimulators

Desai A S, American Heart Journal, December 2011

55

60

65

70

75

80

Placebo (N=56)

0.5 mg (N=22)

1.0 mg (N=28)

2.0 mg (N=54)

Heart

rate

(b

pm

)

Heart rate

1,8

2

2,2

2,4

2,6

2,8

Placebo (N=56)

0.5 mg (N=22)

1.0 mg (N=27)

2.0 mg (N=54)

Card

iac i

nd

ex (

L·m

in–1·m

–2)

Cardiac index

Changes from baseline in cardiac index, heart rate, and MAP at 16 weeks

Riociguat Riociguat

31

Adjusted placebo-corrected difference:

+0.36 L·min–1·m–2 (95% CI: 0.18 to

0.54)

P=0.0001

Adjusted placebo-corrected difference:

–0.4 bpm (95% CI: –4.0 to 3.2)

P=0.83

0 0 0

SOCRATES Study Program: parallel phase IIb studieswith once daily oral sGC stimulator (coming Fall 2013)

SOCRATES-REDUCED SOCRATES-PRESERVED

Indication HF with reduced EF (HFrEF) HF with preserved EF (HFpEF)

LVEF <45% ≥45%

Medical need

High event rates after hospitalization for HF despitestandard treatment

No specific standard therapy approved

Evidence Well tolerated cardiac index increase at 16 weeks Riociguat added to standard therapy in systolic HF and sec. PH (LEPHT)

• cGMP deficiency: causal role in HFPEF

• Myocardial and vascular targets

Design Parallel conduct of two dose finding ph IIb studies, each with 5 parallel arms (2 low doses and 2 with uptitration to higher doses) in patients stabilized after hospitalization for worsening chronic HF

Solomon S D, Lancet 2012;380:1387-95

Neprilysin Inhibition – The PARAMOUNT Trial

LCZ696 – A First-in-Class Angiotensin

Receptor Neprilysin Inhibitor

34

Vasodilation

blood pressure

sympathetic tone

aldosterone levels

fibrosis

hypertrophy

Natriuresis/Diuresis

Inactive

fragments

BNP

pro-BNP

NT-pro BNP

XNeprilysin

Natriuretic Peptide System

AT1 receptorX

Vasoconstriction

blood pressure

sympathetic tone

aldosterone

fibrosis

hypertrophy

Angiotensinogen

(liver secretion)

Angiotensin I

Angiotensin II

Renin Angiotensin System

NH

N

N

N

N

O

OH

O

OH

ONH

O

OH

O

ValsartanAHU377

↓LBQ657

Heart Failure

LCZ696

PARAMOUNT: Study Design

Primaryobjective

NT pro-BNP reduction from baseline at 12 weeks

Secondaryobjectives

Echocardiographic measures of diastolic function, left atrial size, LV size and function, PASP

HF symptoms, Clinical composite assessment and Quality of life (KCCQ)

Safety and tolerability

LCZ696100 mg BID

LCZ696 50 mg BID

Valsartan40 mg BID

1 week 10 weeks2 weeks

Placebo run-in

Discontinue ACEI or ARB therapy one day prior to randomization

LCZ696 200 mg BID

Valsartan80 mg BID Valsartan 160 mg BID

1 week

Prior ACEi/ARB use discontinued

6 month extension

Baseline randomization visit and visit at end of 12 weeks of core study

Week

Visit

-2

1

0

2

21

3 4

12

7

4 8

65 8 9 10 11

18 24 30 36

Clinicaltrials.gov NCT00887588

Weeks Post Randomization

LCZ696

Valsartan

0 5 10200

300

400

500

600

700

800

900

1000

NT

pro

BN

P(p

g/m

l)

LCZ696/Valsartan:

0.77 (0.64, 0.92)

P = 0.005

p = 0.063

12

Primary Endpoint: NT-proBNP at 12 Weeks

783 (670,914)

862 (733,1012) 835 (710, 981)

605 (512, 714)

Changes in Key Echocardiographic Measures

Left Atrial Volume

12 Weeks 36 Weeks

-6

-5

-4

-3

-2

-1

0

1

2

Cha

ng

e in

Le

ft A

tria

l V

olu

me

(m

l)

Valsartan

LCZ696

12 Weeks 36 Weeks

-2.0

-1.8

-1.6

-1.4

-1.2

-1.0

-0.8

-0.6

-0.4

-0.2

0.0

Cha

ng

e in

E/E

'

E/E’

P = 0.18 P = 0.003

P = 0.71 P = 0.42

12 weeks 36 weeks0.0

0.5

1.0

1.5

2.0

Cha

ng

e in

La

tera

l M

itra

l A

nn

ula

r

Rela

xa

tio

n V

elo

city (

E') (

cm

/s)

P = 0.56

P = 0.40

Lateral E’

12 weeks 36 weeks

-0.20

-0.15

-0.10

-0.05

0.00

Cha

ng

e in

LA

Wid

th (cm

)

P = 0.07 P = 0.03

Left Atrial Width

No Significant Changes in LV volumes, Ejection Fraction, or LV mass at 12 or 36 weeks

3. Board Meeting LBI.HF,

21.03.2013

38

MR Receptor Antagonism – Aldo-DHF

Edelmann F,.. Pieske B. JAMA 2013; February 27, 2013-Vol 309, No.8

Placebo (n= 210)

Spironolactone 25 mg daily (n= 210)

Week/

Month

Qualifying

Screen

Initial

Screen

Visit

< - 1w - 1w + 1w0 1w 3mo 6mo + 4w9mo 12mo (18mo)

2 31 4 5 76 8 (9)(8) 9 (10)

Treatment Period

Primary Endpoint

Equally ranked co-primary endpoints: Change in diastolic function (E/é) and maximal exercise capacity (peak VO2) after 12 months for spironolactone compared to placebo.

Secondary endpoints: Changes in other echocardiographic measures of cardiac function and structure; Changes in other measures of exercise capacity; Neuroendocrine activation; HF symptoms; Quality of life; Safety and tolerability of study medication.

Multicenter, randomised, placebo-controlled double-blind, two-armed parallel-group study

Aldo-DHF Study Design

Ch

ange

in E

/e‘

1

0

-1

Baseline 6 months 12 months

p < 0.001 p < 0.001

Placebo

Spironolactone

Time since randomisation

Spironolactone: 12.73.6 to 12.1±3.7 Placebo: 12.84.4 to 13.6±4.3

(P<0.001 for difference between groups)

Primary endpoint - E/é

Ch

ange

in p

eak

VO

2

Baseline 6 months 12 months

0.5

0

-0.5

p = 0.57 p = 0.81

Placebo

Spironolactone

1

Primary endpoint - peak VO2

Time since randomisation

Spironolactone: 16.33.6 to 16.8±4.6mL/min/kg Placebo: 16.43.5 to 16.9±4.4mL/min/kg

(P=0.67 for difference between groups)

Edelmann F,.. Pieske B. JAMA 2013; February 27, 2013-Vol 309, No.8

Blood Pressure (BP)

Results for functional and structural reverse remodelling remained significant after adjusting for blood pressure effects

Change in systolic BP Change in diastolic BP

Ch

ange

in

blo

od

pre

ssu

re f

rom

bas

elin

e (

mm

Hg)

Placebo Spironolactone

0

-10

2

-2

-4

-6

-8

0

-2

-4

Placebo Spironolactone

3 months

6 months

12 months

**

*

** *

* p < 0.05 vs. Placebo

2

TOPCAT: Trial Design

• AGE 50 YRS

• EF 45% WITHIN 6 MONTHS

• HEART FAILURE SYMPTOMS AND SIGNS

• CONTROLLED SYSTOLIC BP (< 140 mm Hg)*

• SERUM K+ 5.0 MMOL/L

PLUS ONE OF THE FOLLOWING:

• HF HOSPITALIZATION WITHIN 12 MONTHS

• BNP 100 PG/ML

• N-TERMINAL PRO-BNP 360 PG/ML

RANDOMIZE

SPIRONOLACTONE

15 MG

PLACEBO

15 MG

DOSE TITRATION (TARGET 30 MG)

* Optional Titration to 45 mg at 4 mos

COMPOSITE PRIMARY ENDPOINT

CV death, Aborted cardiac arrest, Hospitalization for

management of HF

Week 4

Week 0

~ 3.25 yrs

N=3500

Desai A S, American Heart Journal, 2011

Emerging Therapies

1. Pharmacological management

Ivabradine

PDE-5 Inhibition

Guanylate cyclase stimulation

Neprilysin Inhibition

MR antagonists

2. Interventions and Devices

Renal Denervation

Interatrial Shunting

3. Physical acitvity and Exercise

Results: Exercise Capacity

Primary Endpoint:

peak VO2

Maximum Workload

Edelmann F & Pieske B, JACC 2011;

Diastolic Function & LA remodeling

Change in E/é Ratio Change in LA Volume Index

Summary I

1. 50% of HF patients have HFPEF

1. Pathophysiology/Etiology is complex and multifactorial, comorbidities can contribute

2. Diagnosis?: EF>50% + objective evidence of diastolicdysfunction. Biomarkers? Stress test?

1. General management: Loop diuretics, risk factor control

Summary II

1. No established targeted therapy for HFPEF

2. New pharmacological approaches under investigation:

Ivabradine (Phase II: Start 2013)

Soluble Guanlyte cyclase stimulation (Phase II: Start

2013 )

Neprilysin inhibition (Phase III: Start 2013)

MR Antagonists (Phase III: Ongoing)

3. New devices and interventions

4. Physical acivity and exercise training (Phase II: Ongoing)