Therapie der

diastolischen Herzinsuffizienz

Prof. Burkert Pieske

Department of Cardiology

Med.University of Graz

Kardiologie UpdateMünchen, 15.-16.12.2012

physical

acvity ↓

CVD risk

factors &

biomarkers

environmental

determinants

genetic

determinants

Diastolische

Herzinsuffizienz

Systolische

Herzinsuffizienz

Vaskuläres Remodeling

LVH

KHK / Infarkt

Mikrozirkulations-

störung

Myokardiales Remodeling

Diastolische

Dysfunktion

Systolische

Dysfunktion

Das kardiovaskuläre Kontinuum

Stadium A B C/D

Diastolische Herzinsuffizienz

• Pathophysiologie

• Diagnose & Epidemiologie

• Therapie

The Relationship Between Pressure and Volume

HFPEF, HFNEF, oder Diastolische Herzinsuffizienz?

Pathophysiologie HFPEF

Kardiale Dysfunktion & Remodeling

Diastolische DysfunktionSystolische Dysfunktion

VorhofdysfunktionEnergiestoffwechsel

Mikrozirkulation

Autonome DysfunktionChronotrope Inkompetenz

Frequenzstarre

Vaskuläre VeränderungenEndotheldysfunktionCompliancestörung

Ventrikulo-arterielle Kopplung

NierenfunktionsstörungVerminderte GFR

(Latente) ÜberwässerungGestörte Na-Homöostase

(renale) Anämie

Pulmonale FunktionPostkapilläre/präkapilläre

HypertoniePulmonale

Begleiterkrankungen (COPD)

Alter/LebensstilAdipositas

Dekonditionierung

Diastolische Herzinsuffizienz

• Pathophysiologie

• Diagnose & Epidemiologie

• Therapie

Diagnose diastol. Herzinsuffizienz

1. Zeichen oder Symptome der Herzinsuffizienz

2. Normale globale systolische LV-Funktion (EF>50%)

3. Hinweise auf abnorme linksventrikuläre Relaxation, Füllung, Dehnbarkeit oder Steifigkeit

4. BNP oder NTproBNP

Diagnose diastolische Herzinsuffizienz

HFA/ESC 2007

Paulus W et al.

Baseline plasma NT-proBNP and clinical characteristics: results from the irbesartan

in heart failure with preserved ejection fraction trial.

McKelvie RS, Komajda M, McMurray J, Zile M, Ptaszynska A, Donovan M, Carson P,

Massie BM; I-Preserve Investigators.

Majority in NYHA III

Median NTproBNP: 341 (135-974) pg/ml

No Atrial fibrillation: around 250 pg/ml (ca. 75%)

With atrial fibrillation: >900 pg/ml (ca. 25%)

NTproBNP in I-Preserve

Diagnose diastolische Herzinsuffizienz

Paradigmenwechsel 2011:

• Neue Echo-Techniken & Parameter

• Belastungstests („Diastolic Stress Test“)!

• Neue Biomarker: Subgruppen, Response to Therapy

Epidemiology of DDys

Kuznetsova et al.; Circ Heart Fail 2009; 2_105-112

Belgien (539 Teilnehmer, 52 Jahre):

Ddys stage 1: 9.8%Ddys stage 2: 14.1%Ddys stage 3: 3.4%

Overall prevalence of LV diastolic dysfunction in a

middle-aged general population: 27.3%

Zunahme der diastol. Herzinsuffizienz

Owan et al., N Engl J 2006; 355

6076 CHF patients, EF >50% vs. EF <50%

Relative proportion of EF>50%

DHF – Can we predict therapy?

• Problems:

• DHF is no single disease entity

• Pathophysiology is multifacetted

• Prevalence of diastolic dysfunction high

• 2012: >50% of HF cases are HFPEF

Diastolische Herzinsuffizienz

• Pathophysiologie

• Diagnose & Epidemiologie

• Therapie

Systolische Herzinsuff.: Therapie 2012

NYHA I NYHA II NYHA III NYHA IV

Beta-Blocker

Diuretika

ACE – Hemmer

Digitalis

Spironolacton

AT-1-Antagonisten

Diastolische Herzinsuff.: Therapie 2012

NYHA I NYHA II NYHA III NYHA IV

?

Diuretika ?

?

?

?

?

Therapie der diastolischen HI

1. Prävention ?

2. Allgemeinmassnahmen

3. Spezifische Behandlungsansätze

4. Neue therapeutische Optionen

Age-dependent decline in diast. Fct.

Redfield et al., Circulation 2005;112:2254

Population-based, >45Jahre

Filling pressure (E/É)LV-Relaxation

Diastolic LV stiffness

Physical activity & Heart FailureFramingham Heart Study, 1142 Teilnehmer

Elisabeth Kraigher-Krainer et al., Circulation 2010; 122: A15104 (Abstract)

Therapie DHF

1. Prävention ?

2. Allgemeinmassnahmen

3. Spezifische Behandlungsansätze

4. Neue therapeutische Optionen

1. Sind alle Risikofaktoren optimal kontrolliert?

BP < 130/80 mmHg? (v.a. durch RAS-Blocker)

HbA1c < 7.0 mg% ?

Statin-Therapie, wenn indiziert

2. Liegt ein inadäquater RR-Anstieg unter Belastung vor?

Belastungstest - Therapieren!

3. Wie ist die Herzfrequenz unter Belastung?

Tachykard – Antitachykarde Therapie

Chronotrope Inkompetenz? – Bradykardisierende Substanzen ab

4. Vorhofflimmern? – SR wieder herstellen?

5. Zeichen der Überwässerung?

Diuretika beginnen/steigern, Salz-Restriktion

6. Gewichtsreduktion, regelmässige körperliche Aktivität

Therapie der diastolischen HI

RCT’s in Diastolic Heart Failure

Charm-Preserved PEP-CHF I-PRESERVE

Drug Candesartan 32

mg vs. Placebo

Perindopril 4 mg

vs. Placebo

Irbesartan 300

mg vs. Placebo

Number 3023 850 4128

Age 67 years 75 years 72 years

% Female 40 55 60

LVEF >40% (54) >40% (64) >45% (60)

Primary Outcome CV-death or HF-

hosp

Death or HF-hosp Death or CV-hosp

Follow-up 37 months 25 months 50 months

I-Preserve: Irbesartan in HFNEF

Massie BM et al., N Engl J Med 2008; 359

Primary endpoint: All-cause mortality or cardiovascular hospitalisation

At 49 months:

742 (Irbesartan) vs. 763 (Placebo)

I-Preserve: Echo-Substudie

Zile et al.; Circulation 2011; 124

1/3 ohne LA-Remodeling! 1/3 normale diastol. Funktion!

Therapy of diastolic Heart Failure

1. Prevention ?

2. General recommendations

3. Specific therapeutical modalities

4. Neue Therapieoptionen

202 Studien zu DHF/HFPEFwww.clinicaltrials.gov

Diastolic dysfunction

Sosalla and Maier; Pharmacololgy&Therapeutics 2011; doi: 10.1016/j.pharmathera.2011.11.003

Ranolazine in human HF

Jakobshagen et al.; Clin Cardiol 2011; 34; 7: 426-432

Ranolazine – Ongoing trials

RAZE: The Effects of Ranolazine on Exercise Capacity in Patients With Heart Failure With Preserved Ejection Fraction (NCT01505179)

Prospective, randomised efficacy study, n=40Ranolazine 500-1000 mg bid vs PlaceboPrimary endpoint: Exercise capacity (treadmill)

RALI-HF: Ranolazine in Diastolic Heart Failure (NCT01163734)Randomised, double-blind, placebo-controlled Phase II trialRanolazine i.v., followd by 13 days oral applicationn=20 (12 vs. 8)Primary endpoint: Invasive hemodynamics after 30 min

Ranolazine in cardiomyopathy patients with persistent chest pain (NCT01345188)Randomised, double-blind, crossover design, 12 weeksIschemic or non-ischemic cardiomyoathy without treatable CADPrimary endpoint: Improvement in Angina symptoms (Questionnaire)

AVAST: Adjunctive ventricular arrhythmia suppression trial (NCT01480336)Randomised, double-blind, in ICD patients with vent. ArrhythmiasAmiodarone vs. Amiodarone + Ranolazine; EP: Pharmacokinetics

PDE-5 Hemmung (Sildenafil)

44 Patienten, EF>50% + PA systol. Druck >40 mmHgSildenafil 3x50mg vs. Placebo, FU 12 Monate

Rechtsherzkatheter

Sildenafil

Guazzi et al.; Circulation 2011; 124: 164-174

RELAX• Study Design: Randomized (1:1), double-blind, placebo

controlled treatment study• Intervention: PDE-5 inhibition with sildenafil (20 mg tid for 12

weeks followed by 60 mg tid for 12 weeks) or placebo for 24 weeks

• Study population: 190 patients with a clinical diagnosis of HF and normal EF ( 50%) enrolled over a planned 3.25 year enrollment period.

• Primary outcome: The primary endpoint will be exercise capacity as assessed by the change in peak peak VO2 at 24 weeks of double blinded therapy compared to the baseline peak VO2 .

• Secondary outcomes:• 1. Change in a composite score reflective of clinical status after

24 weeks of double-blinded treatment with PDE-5 inhibitor or placebo.

• 2. Change in submaximal exercise capacity at 12 and 24 weeks as assessed by 6 minute walk test

• 3. Change in peak VO2 at 12 weeks

Scott D. Solomon, MD, Michael Zile, MD, Burkert Pieske, MD,

Adriaan Voors, MD, Amil Shah, MD, Elisabeth Kraigher-Krainer, MD,

Victor Shi, MD, Toni Bransford, MD, Madoka Takeuchi, MS,

Jianjian Gong, PhD, Martin Lefkowitz, MD, Milton Packer, MD,

John J.V. McMurray, MD for the PARAMOUNT Investigators

The Angiotensin Receptor Neprilysin Inhibitor LCZ696 in Heart Failure with

Preserved Ejection FractionThe Prospective comparison of ARNI with ARB on

Management Of heart failUre with preserved ejectioN fraction (PARAMOUNT) Trial

Objectives and Hypothesis

• The PARAMOUNT trial was designed to test the safety and efficacy of LCZ696 in patients with HFpEF.

• We hypothesized that LCZ696 would reduce NT-proBNP to a greater extent than the ARB valsartan at 12 weeks, and would be associated with favorable changes in cardiac structure and function at 36 weeks

Weeks Post Randomization

LCZ696

Valsartan

0 5 10200

300

400

500

600

700

800

900

1000N

Tpr

oBN

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)

Lancet. 2012 Aug 24 [Epub]

Aldosterone Receptor Blockade

in Diastolic Heart Failure

The Aldo-DHF Trial

Frank Edelmann, M.D., Rolf Wachter, M.D., Albrecht Schmidt, M.D., Elisabeth Kraigher-

Krainer,M.D., Caterina Colantonio, M.D., Wolfram Kamke, M.D., André Duvinage, M.D.,

Raoul Stahrenberg, M.D., Kathleen Dustewitz, M.D., Markus Löffler, M.D., Hans-Dirk

Düngen, M.D., Carsten Tschöpe, M.D., Christoph Herrmann-Lingen, M.D., Martin Halle,

M.D., Gerd Hasenfuss, M.D., Götz Gelbrich,Ph.D., and Burkert Pieske, M.D.

For the Aldo-DHF Investigators

Registered at www.controlled-trials.com: ISCRTN94726526; Eudra-CT no. 2006-002605-31

ESC Munich, Aug 26, 2012

Hot Line I

Objective and Hypothesis

Aldo-DHF was designed to test the efficacy and

safety of the aldosterone receptor antagonist

spironolactone in patients with diastolic heart

failure.

We hypothesized that spironolactone would improve

diastolic function and exercise capacity as compared

to placebo after 12 months of treatment .

Aldo-DHF Study protocol published:

Edelmann et al., Eur J Heart Fail 2010;12:874-882

Placebo (n= 210)

Spironolactone 25 mg daily (n= 210)

Week/Month

QualifyingScreen

InitialScreen

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

Placebo (n=209) Spironolactone (n=213)

Age (years) 67±8 67±8

Female sex (%) 53 52

Heart failure hospitalisation

(past 12 months; %)36 38

Coronary heart disease (%) 37 43

Hypertension (%) 91 92

Diabetes mellitus (%) 16 17

NYHA class (%)

Class II 88 85

Class III 12 15

BMI - kg/m2 28·9±3·6 28·9±3·6

BP systolic - mmHg 135±18 135±18

BP diastolic - mmHg 80±12 79±10

eGFR - mL/min/1·73m2 78±18 79±19

NT-proBNP (ng/L; median) 148 (80-276) 179 (81-276)

Baseline characteristics

Ch

an

ge

in

E/e

‘

1

0

-1

Baseline 6 months 12 months

p < 0.001 p < 0.001

Placebo

Spironolactone

Time since randomisation

Spironolactone: 12.7±3.6 to 12.1±3.7

Placebo: 12.8±4.4 to 13.6±4.3

(P<0.001 for difference between groups)

Primary endpoint - E/é

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 ENDPOINTCV death, Aborted cardiac arrest, Hospitalization for

management of HF

Week 4

Week 0

~ 3.25 yrs

N=3500

Edelmann F1, Gelbrich G2, Düngen H-D3, Fröhling S1, Wachter R1, Binder L1, Töpper A3, Jahandar Lashki D3, Schwarz S4, Löffler M2, Herrmann-

Lingen C1, Hasenfuß G1, Halle M4, Pieske B5

1 University of Göttingen, Germany; 2 Coordination Centre of Clinical Trails Leipzig,Germany; 3 Charité University Medicine Berlin, Germany; 4 Technical UniversityMunich, Germany; 5 Medical University, Graz, Austria

Exercise training in heart failure with preserved ejection fraction (Ex-DHF)

ISRCTN 42524037

Baseline Visit

n= 71

Randomisation

n= 67

n= 46 n= 21

3 months follow up

n= 20

3 months follow up

n= 44

Training Controls

Return of consent, n= 2

Fulfilled any of the exclusion criteria, n= 2; clinically eligible, rejected participation; n= 2

Violation of protocol, n=1

Patients Follow up

Results: Exercise Capacity

Primary Endpoint: peak VO2

Maximum Workload

Diastolic Function & LA remodeling

Change in E/é Ratio Change in LA Volume Index

New: Ex-DHF: Exercise traininig in DHF

n= 320, combined clinical endpoint (mod. Cleland-Score)

Multicenter, prospective, controlled trial to assess the effects of exercise in DHF

Pieske B, Edelmann F, Gelbrich G, Halle M, BMBF Förderprogramm „Klinische Studien“

Modulation of Autonomic Nervous System

• Renal nerve ablation

• Vagal stimulation

• Spinal cord stimulation

• Baroreceptor stimulation

Zusammenfassung1. Diastolische Herzinsuffizienz wird zu wenig erkannt und zu

wenig therapiert

2. Dies liegt an unzureichendem pathophysiologischem Verständnis, dem Fehlen einheitlicher diagnostischer Kriterien, und der noch unzulänglichen Therapieoptionen

3. Die bisherigen Studien mit ARBs, ACE-Hemmern und Beta-Blocker nicht überzeugend

4. Neue Therapieoptionen in klinischer Prüfung: MR-Antagonisten, PDE-5-Hemmer, Neprilysin-Blockade, Körperliches Trainingsprogramm

5. „On the Edge“: Ranolazin, Ivabradin, sGuanylatzyklase-Stimulation, Devices (CRT, Autonome Modulation, intraatrialer Shunt)