Gerasimos Filippatos, MD, FESC, FHFA

President HFA

Acute Heart Failure: Update 2015

Disclosures

• Principal Investigator or Committee member in trials sponsored by Novartis, Bayer, Cardiorentis, Vifor, European Union

Outcome in acute HF is still poor

Death, Rehospitalization or ER visit

DOSE CARRESS-HF

40% at

60 days

All-cause death or hospitalization 1892 pts with acute HF& 3226 pts with chronic

HF

Chronic HF: 17.2%

Acute HF: 35.1%

Days from enrollment

A. Maggioni, U Dahltrom, G, Filippatos et al EJHF2011

EURObservational Research Program:

The Heart Failure Pilot Survey

1-year all cause mortality:

acute HF – 16.8% chronic HF – 6.8%

Management of acute heart failure:

why so difficult ?

Clinical Factors: Underlying causes: multifactorial, precipitating factor often not identified

Clinical presentation: spectrum of various conditions, heterogeneous

pathophysiology

Cardiovascular and non-cardiovascular comorbidities

Pathophysiological targets: uncertain

End-points selection: not standardized

Courtesy of Piotr Ponikowski

• Terminology

(AHF, ADHF, HHF, WHF, WCHF,

AHFS….)

Filippatos G et al 2015

Goals of Treatment in Acute Heart Failure

Immediate

(ED/ICU/CCU)

Intermediate (in-hospital)

Long-term and pre-

discharge

management

Phases in the

AHF management

• Treat symptoms

• Restore oxygenation

• Improve organ perfusion &

haemodynamics

• Limit cardiac/renal damage

• Prevent thrombo-embolism

• Minimize ICU length of

stay

• Stabilise patient and

optimise treatment strategy

• Initiate and up-titrate

disease-modifying

pharmacological therapy

• Consider device therapy in

appropriate patients

• Identify aetiology and

relevant co-morbidities

• Plan follow-up strategy

• Enrol in disease

management programme,

educate, initiate appropriate

lifestyle adjustments

• Plan to up-titrate/optimize

disease-modifying drugs

• Assess for appropriate

device therapy

• Prevent early readmission

• Improve symptoms, quality

of life and survival

ESC Guidelines for the Diagnosis and Treatment

of Acute and Chronic Heart Failure 2012

ESC Guidelines for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012

Recommendations for the treatment of acute

heart failure in HFA – ESC 2012 guidelines

1. Acute management

Oxygen

Diuretics

Opiates

Vasodilators

Nesiritide

Inotropes

Vasopressors

Acute Heart Failure – in hospital management

Pharmacological therapy

ESC Guidelines for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012

2. After stabilization

ACE inhibitor / ARB

Beta-blocker

Mineralocorticoid receptor

antagonist

Digoxin

Non-pharmacological therapy

1.Sodium and fluid intake

restriction

Ventilation

non-invasive

invasive

Mechanical circulatory

support

IABP

VAD

Ultrafiltration

Important developments

Better use of old drugs

New Drugs

Treatment of co-morbidities

ESC Guidelines for the Diagnosis and Treatment of Acute and Chronic Heart Failure

Decompensated chronic HF

• Consider higher dose of diuretics in

renal dysfunction or with chronic

diuretic use.

Diuretic Optimization Strategies

Evaluation in Acute Heart Failure (DOSE)

To evaluate the safety and efficacy of various initial strategies of furosemide

therapy in patients with ADHF

– Route of administration: • Q12 hours bolus

• Continuous infusion

– Dosing • Low intensification (1 x oral dose)

• High intensification (2.5 x oral dose)

Felker NEJM 2011

JACC 2012

Diuretic Strategies in Patients with Acute

Heart Failure. The DOSE Trial

Diuretics in Hospitalized Patients

If patients are already receiving loop diuretic therapy, the

initial intravenous dose should equal or exceed their

chronic oral daily dose and should be given as either

intermittent boluses or continuous infusion.

I IIa IIb III

Vasopressin Receptor Antagonists in Different Stages of Development

V1a V1b V2 V1a/V2

Relcovaptan

OPC-21268 SSR-149415

Lixivaptan

Mozavaptan*

Satavaptan

Tolvaptan

RWJ-351647

Conivaptan*

RWJ-676070

Filippatos G et al. Journal of Cardiac Failure 2008

If symptomatic hypotension is absent, intravenous

nitroglycerin, nitroprusside or nesiritide may be considered

an adjuvant to diuretic therapy for relief of dyspnea in

patients admitted with acutely decompensated HF.

I IIa IIb III

ESC Guidelines for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012

Members of the Natriuretic Peptide Family

S S

Ser

Pro

Lys

Met

Val Gln

Gly

Cys Gly Ser Phe

His Arg

Arg Leu

Val

Lys Cys

Gly

Leu Gly Ser

Gly Arg Lys

Met Asp

IIe

Ser

Ser

Ser

Arg

COOH-

NH2

BNP

CNP

S S

Gly

Leu

Ser

Lys Gly

Cys

Phe

Cys

Gly

Leu Gly Ser

Met

Ser

Gly

IIe

Arg

Asp Leu

Lys Leu Gly

COOH-

NH2

NH2

COOH-

Ser Leu

Arg

Arg

Ser

Ser Cys

Phe

Gly

Gly Arg

Cys

Gly

Arg Tyr

Asn

Phe Ser

Gly

Leu Ser

Gin

Ala

Gly

IIe

Arg

Asp Met

S S

ANP

Urodilatin

Thr

Ala Pro

Arg Ser

Leu Arg

Arg

Tyr

Arg

Phe Ser

Asn

Cys

Gly

Leu Gly Ser Gin

Ala

Gly

IIe

Arg

Asp

Met Arg Gly

Gly Phe

Cys

Ser Ser

S S

COOH-

NH2

Ularitide/urodilatin

mod. Forssmann Cardiovasc Res 2006

Urodilatin

• Synthesized in distal tubular cells

• Binds downstream in IMC duct to NPR-A

• Increases Renal Plasma Flow (via cGMP)

• Increases GFR:

• Dilates Vas afferens

• Constricts Vas efferens

• Relaxes mesangials cells

• Decreases sodium reabsorption in PCT and CD

via cGMP dependent phosphorylation of ENaC

• Inhibits renin, aldosterone, and vasopressin secretion

• NOT degraded by NEP inhibition

SIRIUS II: Ularitide Reduces PCWP

Placebo 7.5 ng /kg/min 15 ng /kg/min 30 ng /kg/min

* p<0.01 vs Placebo

*

*

*

*

*

* *

* *

*

*

*

†

† p<0.05 vs Placebo

- 12

- 10

- 8

- 6

- 4

- 2

0

0 2 4 6 8 10 12 14 16 18 20 22 24 26

Time (Hours) Time (Hours)

D

PC

WP

(m

mH

g)

† †

†

Mitrovic Eur Heart J 2006

TRUE-AHF

TRial of Ularitide's Efficacy and safety in patients

with Acute Heart Failure

Study aim

• efficacy and safety of ularitide on clinical status and mortality in AHF

• build on the growing body of evidence to treat AHF patients as early as

possible

The first-ever acute heart failure (AHF) Phase III trial to be specifically designed to assess the effect of early

treatment on cardiovascular mortality as a co-primary endpoint.

Relaxin: Mechanisms of Action

• Found in men and women

• Increased in pregnancy

• Vasodilation

– Upregulation of ETB receptor

• Preferential dilation of constricted vessels

• Anti-inflammatory

• Anti-apoptotic

• Anti-fibrotic

Relaxin Receptor LGR7

Teichman, SL, et al. Heart Fail Rev 2009

Dschietzig, T, et al. Pharmacol Therap 2006

Published online 06.November, 2012

Effect of Serelaxin on Cardiac, Renal and Hepatic

Biomarkers in the RELAX-AHF Development Program:

Correlation with Outcome Marco Metra, MD; Gad Cotter, MD; Beth A. Davison, PhD; G. Michael Felker, MD, MHS; Gerasimos Filippatos, MD; Barry H.

Greenberg, MD; Piotr Ponikowski, MD, PhD; Elaine Unemori, PhD; Adriaan A. Voors, MD, PhD; Kirkwood F. Adams, Jr., MD;

Maria Dorobantu, MD; Liliana Grinfeld, MD; Guillaume Jondeau, MD; Alon Marmor, MD; Josep Masip, MD; Peter S. Pang,

MD; Karl Werdan, MD; Margaret F. Prescott, PhD; Christopher Edwards; Samuel L. Teichman, MD; Angelo Trapani, PhD;

Christopher A. Bush, PhD; Rajnish Saini, MD; Christoph Schumacher, PhD; Thomas Severin, MD; John R. Teerlink, MD; for

the RELAXin in Acute Heart Failure (RELAX-AHF) Investigators

J Am Coll Cardiol 2013

Relaxin in AHF RELAX-AHF

Teerlink et al, Lancet 2012

• 1161 AHF pts, • SBP >125 mmHg • Serelaxin, recombinant human relaxin 2,

• 48-hour iv or placebo • Early treatment

0

14

12

2

4

6

8

10

60

Composite event components (%) K-M estimate for time to first

CV Death or HF/RF re-hosp (%)

CV death:

(% subjects)

HR=0.7

p=0.23

HF/RF re-hospitalization

(% subjects)

HR=1.2

p=0.32

n=27 n=19 n=50 n=60

0 45 30 14

HR 1.02 ( 0.74, 1.41)

p=0.89

Placebo

Serelaxin

580 559 539 522 501 581 563 531 514 498

p value by log rank test

HR estimate by Cox model

2°Endpoint: CV Death or HF/RF

Re-hospitalization through Day 60

Days

RELAX-AHF:

Cardiovascular and All-Cause Death

Teerlink Lancet 2012

Placebo,

K-M%

Serelaxin,

K-M%

HR (95%CI) p value for

interaction

CV death or hospitalization for heart/renal failure

through Day 60 (secondary endpoint)

Overall population1 13.0 13.2 1.02 (0.74, 1.41)

LVEF <50% 12.6 13.7 1.10 (0.75, 1.61)

0.97 LVEF ≥50% 12.8 13.9 1.08 (0.57, 2.06)

CV death through Day 180 (efficacy endpoint)

Overall population1 9.6 6.1 0.63 (0.41, 0.96)

LVEF <50% 9.4 6.1 0.64 (0.39, 1.07)

0.87 LVEF ≥50% 8.5 5.1 0.59 (0.23, 1.50)

All-cause mortality through Day 180 (safety endpoint)

Overall population1 11.3 7.3 0.63 (0.43, 0.93)

LVEF <50% 11.1 7.1 0.63 (0.39, 1.00) 0.82

LVEF ≥50% 11.3 8.1 0.70 (0.32, 1.50)

Hazard ratio (vs placebo)

0 1 10

Relaxin in AHF: pEF vs rEF RELAX-AHF

Filippatos et al, ESC HFA 2013, Late Breaking Clinical Trials Eur Heart J 2014

2 weeks

Randomization

Placebo

Aliskiren 300 mg

Conventional therapy‡

Aliskiren

150 mg Acute HF LVEF<40%

BNP >400pg/mL

SBP≥110mmHg

~1,800 patients

‡Except concomitant use of an ACEI and ARB *Follow-up at Week 2, Month 1, 2 and 3, with on-going

assessments every 3 months thereafter

~15 months (event-driven)* In-hospital

entry and

initiation

design overview

Primary outcome: CV death or HF hospitalization

at 6 months (381 events)

HR: 0.80 (95% CI: 0.61-1.04)

p = 0.11

10

5

0

25

20

15

Ka

pla

n-M

eie

r e

stim

ate

of

cu

mu

lative

eve

nt ra

te (

%)

Aliskiren (102/489 patients with events; 20.9%)

Placebo (114/464 patients with events; 24.6%)

0 30 60 90 190

Number of subjects

Aliskiren 489 466 444 427 383

Placebo 464 440 410 393 343

Time in study (days)

Primary Endpoint in non-DM Patients CV Death or HF Re-hospitalization Within 6 Months

Aliskiren n (%)

Placebo n (%)

HR (95% CI)

p-value (two-sided)

CV death 42 (8.6) 49 (10.6) 0.73 (0.48-1.12) 0.14

HF re-hospitalization 74 (15.1) 86 (18.5) 0.77 (0.56-1.05) 0.10

30

Hasenfuss and Teerlink, EHJ 2011

Inotropic Therapies

ISTAROXIME

• Inotropic and lusitropic agent

• Calcium cycling modulator through the

inhibition of Na/K ATPase and

activation of SERCA ATPase.

• Improves systolic and diastolic

function without arrhythmias or ↑ in

MVO2. (1, 2)

.J Am Coll Cardiol 2008

AHJ 2009

Omecamtiv Mecarbil (OM) is a Novel

Selective Cardiac Myosin Activator

Malik FI, et al. Science 2011; 331:1439-43.

Mechanochemical Cycle of Myosin

Force production

Omecamtiv mecarbil increases the entry rate of myosin into the

tightly-bound, force-producing state with actin

“More hands pulling on the rope”

Increases duration of systole

Increases stroke volume

No increase in myocyte calcium

No change in dP/dtmax

No increase in MVO2

Teerlink JR, et al. Lancet 2011; 378: 667–75; Cleland JGF, et al. Lancet 2011; 378: 676–83.

p-value = 0.331

Pooled Placebo

OM Cohort 1

OM Cohort 2

OM Cohort 3

Dys

pn

oea

Res

po

nse

Rat

e

(% R

esp

on

der

s)

0 5

10 15 20 25 30 35 40 45 50 55

42% 47%

51%

41%

A Phase 2 Study of Intravenous Omecamtiv Mecarbil, A Novel Cardiac Myosin Activator, In Patients With AHF

Primary Efficacy Endpoint: Dyspnoea Response (Likert Scale)

Teerlink J, et al

• Efficacy

– OM did not meet the 1° endpoint of dyspnoea relief

• Safety

– Overall SAE profile and tolerability similar to placebo

– Increase in troponin; no clear relationship to OM concentration

Non-steroidal MRAs: more selective for cardiac/vascular than renal tissue?

ARTS

ARTS-HF Safety and efficacy study of

BAY 94-8862 in patients with WCHF and left ventricular systolic dysfunction

and either type 2 diabetes mellitus with or without CKD or moderate CKD alone

ARTS-DN Safety and efficacy study of BAY 94-8862 in patients with type 2 diabetes mellitus

and the clinical diagnosis of diabetic nephropathy

Primary aim Investigate efficacy [percentage of patients with a

relative decrease in NT-proBNP of more than 30% from baseline to visit 8 (day 90±2)] and safety of BAY 94-

8862

Secondary aims •Analyse the composite endpoint of death from any cause, cardiovascular hospitalizations, or emergency

presentations for WCHF until visit 8 (day 90±2)

• Monitor changes in health-related quality of life as assessed by the KCCQ and EQ-5D-3L

• CoChairs: B. Pitt & G Filippatos

Primary aim Investigate change in UACR after treatment with BAY 94-8862 once daily over 90 days versus placebo

Secondary aims •Investigate the safety and tolerability by assessing effects of different doses of BAY 94-8862 on serum potassium and renal function

•Analyse changes in health-related quality of life as assessed by the KDQOL-SF and EQ-5D-3L

37

Conclusions

The therapeutic approach to acute HF has not

changed much in the last few decades

• only one drug in the USA and one drug in Europe have

been approved in the last 15 years

There is a need to identify treatment strategies

and regimens that reduce mortality and the

incidence of HF rehospitalization in patients post-

acute HF1

38