Acute Heart Failure:

New Drugs, New Tools?

G. Michael Felker, MD, MHS, FACC, FAHA

Chief, Heart Failure Section

Duke University School of Medicine

Disclosures

• Grant Support and/or Consulting

– NIH/NHLBI

– Novartis

– Amgen

– Trevena

– Roche Diagnostics

– BMS

– Otsuka

– Celladon

– St Judes

– Singulex

• I will discuss investigational agents that are not currently

approved by the US FDA

Terminology: What’s in a Name?

Acute Heart Failure Acute

Decompensated Heart Failure

Hospitalization for Heart Failure

Acute Heart Failure Hospitalizations

0

100

200

300

400

500

600

700

79 80 85 90 95 00 06

Years

Dis

ch

arg

es

in

Th

ou

sa

nd

s

Male Female

United States: 1979-2006 Source: NHDS/NCHS , NHLBI. Hospital Compare 2007-2010

The majority of patients hospitalized with HF were previously hospitalized

with HF

1.0 Million Hospitalizations a Year and Rising

30-Day

Rehospitalization

Rates in HF

24.8%

(Medicare)

Estimated Direct and Indirect Costs of HF in US

10.5%

9.7% 8.2%

6.4%

11.9%

53.3%

Hospitalization

$20.9

Lost Productivity/

Mortality*

$4.1 Home Healthcare

$3.8

Drugs/Other

Medical Durables

$3.2

Physicians/Other

Professionals

$2.5

Nursing Home

$4.7

Heart Disease and Stroke Statistics—2010 Update: A Report From the AHA

Circulation, Feb 2010; 121: e46 - e215.

Total Cost

$39.2 billion

State of the Art ADHF Therapy

• Diuretics

• Vasodilators

• Oxygen

• Consider inotropic

therapy

Ramirez and Abelmann, New Engl J Med, 1974

0

10

20

30

40

50

60

70

80

90

%

Diuretics Dopamine Dobutamine Milrinone Nesiritide NTG

Fonarow,GC et al. AHJ 2007

2007 1974

History of Phase III Trials in Acute HF

Milrinone

Tezosentan

Rolofylline

Levosmimendan

Nesiritide?

Relaxin

• Naturally-occurring peptide

• Found in men and women

• Normal hormone of pregnancy

• Women “exposed” for 9 months

to increased plasma

concentrations:

0.8-1.6 ng/ml pregnancy*

• Benign safety profile

*Szlachter et al, Obstet & Gynecol 1982;59:167-70;

Stewart et al, J Clin Endocrinol Metab 1990;70:1771-3.

Relaxin

Biologic Effects of Relaxin

• Vascular

– Vasodilation

– Increased arterial compliance

– Decreased SVR

• Renal

– Increased renal blood flow

– Increased GFR

• Fibrosis

– Decreased collagen synthesis

– Increased collagen degradation

0

5

10

15

20

25

30

35

0 1 2 3 4 5

1° Endpoint: Dyspnea Relief (VAS

AUC)

AUC with placebo, 2308 ± 3082

AUC with serelaxin, 2756 ± 2588

*P=0.0075

Change f

rom

baselin

e (

mm

)

19.4% increase in AUC with serelaxin

from baseline through day 5

(Mean difference of 448 mm-hr)

Days 6

Serelaxin

Placebo

12 hrs

Teerlink et al. Lancet 2012

1° Endpoint: Dyspnea Relief (Likert)

0

10

20

30

40

50

60

70

80

6 hr 12 hr 24 hr 6, 12, and 24 hr

Placebo

Serelaxin p=0.086

p=0.051

p=0.113

p=0.702

n=150 n=156 n=205 n=180 n=256 n=288 n=362 n=389

Proportion of subjects with moderately or markedly better dyspnea by Likert by time point

Teerlink et al. Lancet 2012

CV Death through Day 180

0 0

14

12

10

8

6

4

2

K-M estimate CV death (ITT) (%)

14 30 60 90 120 150 180

HR 0.63 (0.41, 0.96); p=0.028

55 (9.5%)

35 (6.0%)

Placebo (N=580)

Serelaxin (N=581)

Number of

Events, n

(%)*

NNT = 29

Days

Teerlink et al. Lancet 2012

0

2

4

6

8

10

12

Index Hospitalization Length of

Stay (Days)

*p=0.039

0

0.5

1

1.5

2

2.5

3

3.5

4

4.5Placebo Serelaxin

*p=0.029

Length of ICU/CCU Stay (Days)

n=578

n=574

n=580

n=581

Index Hospitalization LOS

Teerlink et al. Lancet 2012

Biomarkers and Outcomes in RELAX-AHF

Serelaxin affected multiple biomarkers associated with long term

outcomes: A mechanism for a long term effect?

Metra, M et al. JACC 2013

Omecamtiv Mecarbil

A Cardiac Myosin Activator

• Preclinical

– Selective activator of cardiac myosin

– Prolongs duration of systole by

o Increasing entry rate of myosin into force-producing state

o Thus increasing overall number of active cross-bridges

– No increase in myocyte calcium

– No change in dP/dtmax

– No increase in MVO2

– Increases stroke volume

NO2

NH

O

ON

F

NH

NNH

ONN CH3

O

H3CO

F

Malik FI, et al. Science 2011

Increases in Systolic Ejection Time

Underlie Increases in Cardiac Function

Δ Stroke Volume

(mL)

Δ Fractional

Shortening

(% points)

Δ Ejection Fraction

(% points)

Δ = placebo corrected

change from baseline

Mean ± SEM

300 600 900 1200

-80

-40

0

40

80

120

160

Healthy Volunteers vs. Heart Failure Patients

SET Heart Failure

SET Healthy Volunteers

[Omecamtiv mecarbil] (ng/mL)

SE

T (

msec)

Ch

an

ge f

rom

Baselin

e

Δ SET (msec)

Cleland JGF, et al. Lancet 2011; 378: 676–83.

Teerlink JR, et al. Lancet 2011; 378: 667–75.

Healthy Volunteers

-5

0

5

1 0

1 5

2 0

0

4

8

1 2

1 6

0 2 0 4 0 6 0 8 0 1 0 0

-4

0

4

8

1 2

Pharmacodynamic Effects of Omecamtiv in HF

Primary Efficacy Endpoint: Dyspnoea Response (Likert Scale)

Pooled Placebo

Response Rate Ratio*

1.03 1.15 1.23

95% CI (0.79, 1.35) (0.90, 1.47) (0.97, 1.55)

*Ratio of response rate to Pooled Placebo

p-value of a CMH test among all 3 Placebo arms = 0.32

Overall p-value = 0.33

Pooled

Placebo

OM

Cohort 1

OM

Cohort 2

OM

Cohort 3

Dyspnoea R

esponse R

ate

(% R

esp

on

de

rs)

0

5

10

15

20

25

30

35

40

45

50

55

42%

47% 51%

41%

Within 7 days of IP initiation

Pooled Placebo

(N = 303)

Cohort 1 OM

(N = 103)

Cohort 2 OM

(N = 99)

Cohort 3 OM

(N = 101)

Death or WHF*

Yes - n(%) 52 (17) 13 (13) 9 (9) 9 (9)

Relative risk 0.67 0.54 0.54

(95% CI) (0.38, 1.18) (0.28, 1.04) (0.27, 1.08)

p-value 0.151 0.054 0.067

WHF*

Yes - n(%) 51 (17) 13 (13) 8 (8) 9 (9)

Relative risk 0.68 0.49 0.55

(95% CI) (0.38, 1.21) (0.24, 0.98) (0.28, 1.09)

p-value 0.179 0.034 0.075

Secondary Efficacy Endpoint: Worsening Heart Failure (WHF)

*Worsening heart failure is defined as clinical evidence of persistent or deteriorating heart failure requiring at least one of the following treatments: • Initiation, reinstitution or intensification of IV vasodilator • Initiation of IV positive inotropes, or IV vasopressors • Initiation of ultrafiltration, hemofiltration, or dialysis • Initiation of mechanical ventilatory or circulatory support

-0.05

-0.04

-0.03

-0.02

-0.01

-1E-16

0.01

0.02

0.03

HR4 HR15 HR24 HR48 Day 4 Day 6

Troponin-I Change from Baseline (ng/mL) Compared with Pooled Placebo

Baseline TnI (ng/mL) Pooled Placebo Cohort 1 Cohort 2 Cohort 3

Median 0.044 0.060 0.044 0.056

(Q1, Q3) 0.023, 0.080 0.028, 0.141 0.030, 0.084 0.026, 0.092

4 hours 15 hours 24 hours 48 hours Day 4 Day 6

Time

Tro

po

nin

Ch

ange

fro

m B

ase

line

(n

g/m

L)

Q3

Median

Q1

0.03

0.02

0.01

0.00

–0.01

–0.02

–0.03

–0.04

–0.05

New Tools:

Can We Do a Better Job With Therapies We Have?

Definition of Biomarker

“If it costs less than 20 bucks, it’s a lab test. If it costs more

than 20 bucks, it’s a biomarker.”

C$ 22.10

C$ 22.10

Pharmacologic Actions of hBNP

Hemodynamic

(balanced vasodilation)

veins

arteries

coronary arteries

Neurohumoral

aldosterone

endothelin

norepinephrine

Renal

diuresis

natriuresis

GFR

D R I

M K R G

S S S

S G L G

F C C S S

G S G Q V M

K V L R R

H

K P S

Cardiac

lusitropic

antifibrotic

anti-remodeling

BNP Reflects Ventricular Wall Stress

Iwananga, JACC 2006

Natriuretic Peptides and Prognosis in Chronic HF:

Data from Val-HeFT

Anand, I. et al, Circ 2003

Critical Question

Can we use biomarkers for

something besides risk prediction?

Significance of Estimating Prognosis for the

Individual Patient is Limited

Great news!

I can predict you will

live 4.5 months with a

p value of 0.03

#&@(!

Rationale for Natriuretic Peptide Guided

Therapy

• Decreases in NP levels over time associated with

favorable outcomes

• Proven effective HF therapies decrease NP levels

Will a strategy of titrating therapy to specific NP targets improve outcomes?

How Should we Apply our Current Therapies in

Chronic HF?

Current guidelines:

Therapy should be up-titrated to targets from clinical

trials or the maximally tolerated dose

An alternate hypothesis:

Therapy should be up-titrated based upon the

personalized physiologic response of each individual

patient

Does

everyone

need the

same doses

of HF

medications?

Examples from other Areas of Medicine

• HIV/Hepatitis Viral load

• Diabetes mellitus HbA1C

• Hypertension Blood pressure

• Hyperlipidemia LDL

• Anticoagulation INR

• Heart failure ?

40

50

60

70

80

90

100

0 30 60 90 120 150 180

NT-proBNP

Clinical

Heart failure or death

P = 0.049

Time after randomisation (days)

40

50

60

70

80

90

100

0 30 60 90 120 150 180

NT-proBNP

Clinical

Time after randomisation (days)

Cardiovascular events

Even

t fr

ee (

%)

P = 0.034

Chronic HF Therapy Guided by BNP

Troughton, R. Lancet 2000

N = 69

PROTECT: Primary Endpoint

0

20

40

60

80

100

120

Total CV Events

Nu

mb

er

of

eve

nts

100 events

58 events

P =.009

SOC

NT-proBNP

*Logistic OddsNT-proBNP= 0.44

(95% CI= .22-.84; P =.019)

Januzzi, JACC 2011

Biomarker Guided Therapy and All-Cause Mortality:

Meta-Analysis

Combined

BATTLESCARRED

STARS-BNP

STARBRITE

Troughton

TIME-CHF

PRIMA

Felker GM. Am Heart J 2009

N = 1627

Adjusted HR = 0.69 (0.55-0.86)

BGT works

PROTECT

STARS-BNP

Troughton pilot

Berger

BGT doesn’t work

PRIMA

Northstar

STARBRITE

BGT might work

TIME-CHF

BATTLESCARRED

Equipoise?

Biomarker Guided Therapy for HF

• A biologic hypothesis:

– Titrating HF therapy to minimize total LV wall stress over time

will slow/halt LV remodeling and HF progression, resulting in

improved outcomes

• A process of care hypothesis:

– Providing a quantitative target will improve intensification of

evidence based therapy compared to usual care and improve

outcomes

Risk-Treatment Mismatch in HF:

Canadian EFFECT Study

Lee D. JAMA. 2005;294:1240-1247

At Hospital Discharge 90-Day Follow-Up 1-Year Follow-Up

0

10

20

30

40

50

60

70

80

90

Low Risk Average Risk High Risk

ACEI ACEI or

ARB

-

Blocker 1-Year

Mortality Rate

Pati

en

ts,

%

ACEI ACEI or

ARB

-

Blocker

Use rates in absence of contraindications. For all drug classes, P < .001 for trend.

GUIDE-IT

GUIDing Evidence Based Therapy Using

Biomarker Intensified Treatment in Heart

Failure Study

GUIDE-IT Study Design

Multicenter, prospective, randomized, parallel

control group clinical trial sponsored by NIH

Randomized Trial of NTproBNP guided therapy

vs usual care in high risk systolic heart failure

patients

~45 sites in US and Canada

1100 subjects

12-24 months of follow-up (last patient enrolled

followed for 12 months)

Does Having a Target Makes Things Easier?

Titrate medicines as high as

patient can stand

Titrate medicines to “safe” NTproBNP

level

Biomarkers Always Augment Clinical Judgment