the evolution of acute heart failure treatment · a. ularitide had no effect on dyspnea in the...

The Evolution of Acute Heart Failure Treatment: A Review of Current Guidelines and Evidence with

Emerging Therapies

W.H. Wilson Tang, MD, FACC

Professor of Medicine, Cleveland Clinic Lerner College of Medicine

Cleveland, OH

Disclosures

Dr. Tang has no relationships with commercial interests to

disclose. He intends to reference off-label/unapproved

uses for Serelaxin, a Novartis product. He will be

presenting findings from the following commercially

funded research studies: Teerlink et. al. Lancet

2013:381:29, and Metra et. al. JACC 2013:61:196.

.

Objectives

• Describe the pathophysiology and clinical features of acute

heart failure (AHF) in both patients with heart failure with

preserved ejection fraction (HF-PEF) and reduced ejection

fraction (HF-REF)

• Identify the signs, symptoms, and tests that may help in early

diagnosis and treatment of patients with AHF

• Discuss the importance of early diagnosis and intervention to

reduce end-organ damage on long-term outcomes in patients

with AHF

• Outline current guideline recommendations for the treatment of

patients with AHF

• Evaluate recent clinical data with emerging therapies for the

management of AHF

Demographic Questions

How many patients with heart failure do you

see in your practice each week?

A. None

B. 1-10

C. 11-20

D. 21-30

E. >30

Pre-Activity Questions 1 of 4

• Which of the following is not a characteristic

seen in patients with acute heart failure ?

A. About 75% of AHF patients present with a SBP ≥120

mmHg

B. Dyspnea on presentation in 90% of patients

C. About 90% of patients with AHF have LVEF of <40%

D. Fluid redistribution from the periphery to lungs


• Which of the following statements regarding AHF

is incorrect ?

A. Measurement of BNP or NT-proBNP levels is not

useful in the diagnosis of AHF

B. Benefits of vasodilator therapy is increased with

early treatment initiation (≤15.5 hours) in AHF

patients

C. The mortality rate of patients with HF-REF and HF-

PEF are similar following discharge after AHF

D. Worsening renal function in AHF patients is

associated with increase LOS and mortality



therapies in development is true ?

A. Ularitide had no effect on dyspnea in the SIRIUS II

study

B. Serelaxin was shown to significantly reduce dyspnea

and the symptoms of congestion in the RELAX-AHF

study

C. Aliskiren was shown to reduce dyspnea or HF

hospitalizations in the ASTRONAUT study

D. Serelaxin had no effect on the secondary endpoints

of worsening HF or CV death


• A 68-year old female is admitted to the hospital with acute

decompensated heart failure. She was discharged 45 days ago

following a previous admission for acute heart failure. Today she

presents with dyspnea, pulmonary congestion, SBP 150 mmHg,

and LVEF 35%. If you employ current guideline recommendations

for her management, you should:

A. Initiate thromboprophylaxis to prevent thromboembolism

B. Prescribe high-dose furosemide because high dose diuretic

therapy is significantly better than low-dose in reducing

symptoms in AHF

C. Initiate intravenous nesiritide immediately to stabilize AFH

pateints

D. Consider ultrafiltration instead of IV diuretics

Current Burden Heart Failure

Heart Failure (HF)

• 5.1 million people in the United States have heart failure

– 825,000 new HF cases annually

– Projected to increase by 46% from 2012 to 2030 resulting in

>8 million people HF

• One in 9 deaths in 2009 included heart failure as

contributing cause

• About half of people who develop heart failure die within

5 years of diagnosis.

• Heart failure accounts for an estimated $32 billion in

direct and indirect costs each year.

http://www.cdc.gov/dhdsp/data_statistics/fact_sheets/fs_heart_failure.htm. Accessed September 27, 2014. Go AS, et al. Circulation. 2014;129:e28-e292.

Acute Heart Failure (AHF)*

• Defined as the sudden or gradual onset of the

signs or symptoms of heart failure requiring

unplanned office visits, emergency room

visits, or hospitalization

• AHF is primarily a clinical diagnosis

• Measure of BNP or NT-proBNP can be used to

support clinical diagnosis

*Also referred to as acute decompensated heart failure (ADHF) in patients with a pre-existing diagnoses of chronic heart failure (CHF).

BNP = brain natriuretic peptide; NT-proBNP = N-terminal pro-brain natriuretic peptide.

Yancy CW, et al. J Am Coll Cardiol. 2013;62(16):e147-239.

Symptoms of AHF

• Shortness of breath (dyspnea)

– Persistent cough or wheezing with white or pink blood-tinged

phlegm

• Swelling (edema) in legs, ankles and feet; swelling of

abdomen (ascites); sudden weight gain from fluid

retention

• Fatigue and weakness

• Decreased organ perfusion – Reduced ability to exercise;

lack of appetite and nausea; difficulty concentrating or

decreased alertness; reduced urine output

http://www.heart.org/HEARTORG/Conditions/HeartFailure/WarningSignsforHeartFailure/Warning-Signs-for-Heart-Failure_UCM_002045_Article.jsp#. Accessed December 1, 2014. Yancy CW, et al. J Am Coll Cardiol. 2013;62(16):e147-239.

OPTIMIZE-HF Investigators, Gheorghiade, et al. JAMA. 2006;296(18):2217-2226.

Acute Heart Failure Patient Characteristics

• Vasoconstriction

• Redistribution of fluid

from periphery to lungs

• Presentation:

– Dyspnea

(shortness of breath)

– Normal to elevated BP

SBP <120 mmHg SBP 120-139 mmHg

SBP 140-161 mmHg SBP >161 mmHg

24.9% 25.2%

24.9% 24.9%

~75% patients with

SBP ≥120 mmHg

Distribution of LVEF in Acute HF Patients

Stough W, et al. J Am Coll Cardiol. 2006;47:47A.

Left Ventricular Ejection Fraction (%)

0-

5

6-

10

11-

15

16-

20

21-

25

26-

30

31-

35

36-

40

41-

45

46-

50

51-

55

56-

60

61-

65

66-

70

71-

75

76-

80

81-

85

86-

90

91-

95

96-

100

0

1,000

2,000

3,000

4,000

5,000

44

1,137

2,345

4,183

3,506

3,814

2,924 2,947

2,331

2,812 2,806

3,193

1,833

1,270

553

274 100 32 10 1

Pati

en

ts (

%)

Documented LVEF Measured prior to or during Hospitalization

Distribution of LVEF in Acute HF Patients

HF-REF = heart failure with reduced ejection fraction (EF); HF-PEF = heart failure with preserved EF.

Stough W, et al. J Am Coll Cardiol. 2006;47:47A.

Left Ventricular Ejection Fraction (%)

0-

5

6-

10

11-

15

16-

20

21-

25

26-

30

31-

35

36-

40

41-

45

46-

50

51-

55

56-

60

61-

65

66-

70

71-

75

76-

80

81-

85

86-

90

91-

95

96-

100

0

1,000

2,000

3,000

4,000

5,000

44

1,137

2,345

4,183

3,506

3,814

2,924 2,947

2,331

2,812 2,806

3,193

1,833

1,270

553

274 100 32 10 1

Pati

en

ts (

%)

Documented LVEF Measured prior to or during Hospitalization

HF-REF

HF-PEF

Acute Heart Failure

LV dysfunction

(contractility;

stiffness)

Vascular

dysfunction

(arterial and

venous

stiffness)

Heart Failure Society of America, Lindenfeld J, et al. J Card Fail. 2010;16(6):e1-194. Yancy CW, et al. J Am Coll Cardiol. 2013;62(16):e147-239.

Pulmonary Congestion

COLV Pressure BP & Wedge

http://thumbs.dreamstime.com/z/symbol-yin-yang-20556267.jpg

AHF Is a Syndrome Caused by Different Diseases

• Acute Vascular Failure:

(Elderly, female=male, preserved EF, mild chronic CHF)

– Rapidly evolving pulmonary congestion + blood pressure

– Rapid respiratory failure, multi-organ failure and death

• Acute Cardiac Failure:

(Younger, male, low EF, significant background CHF)

– Slow deterioration in severe chronic HF

– Slowly progressive pulmonary congestion and peripheral hypoperfusion

accompanied by relatively blood pressure, peripheral edema and

weight gain

• Other:

– ACS, arrhythmias (mostly AF), high output failure, RV failure

EF = ejection fraction; AF = atrial fibrillation.

Heart Failure Society of America, Lindenfeld J, et al. J Card Fail. 2010;16(6):e1-194. Yancy CW, et al. J Am Coll Cardiol. 2013;62(16):e147-239.

Why Is It Important?

• Over 1.1 million hospitalizations annually in U.S. and have

tripled in last 3 decades

• High post-discharge re-hospitalization (20-30%) and mortality

(10-20%) within 3-6 months

• Over 75% of patients have normal or elevated blood pressure

on presentation

• Approximately 90% present with shortness of breath

(dyspnea)

• Pathophysiology: Vasoconstriction associated with

neurohormonal activation, inflammation, and myocardial

ischemia

• Need for novel therapies that address these issues

Gheorghiade M, Pang P. J Am Coll Cardiol. 2009;53:557-73.

Acute Heart Failure Have We Made Progress?

The Good News:

• In-hospital mortality 5%

( 40% in 10 years)

• Mean length of stay

5-6 days

( 30% in 10 years)

The Bad News:

• Readmission rates

remain high

– 25% within 30 days

– 50% within 6-12 months

• High mortality rates

persist

– 5-10% at 30 days

– 20-40% at 6-12 months

Gheorghiade M, Pang PS. J Am Coll Cardiol. 2009;53:557-73.

Post-Discharge Outcomes in AHF

*Risk-adjusted rates relative to 1999.

1. Dharmarajan K, et al. JAMA. 2013;309:355-363. 2. Chen J, et al. JAMA. 2011;306:1669-1678.

30

0

5

25

10

20

15

Pati

en

ts R

ead

mit

ted

(%

)

Days Following

Hospital Discharge

20 10 0 30 40

100

0

10

90

20

50

30 Ris

k-A

dju

ste

d

Mo

rtality

Rate

* (%

)

Year

2003 2002 1999 2001 2005 2000 2008 2007

70

40

Nearly 1 in 4 AHF Patients

Readmitted

within 30 Days1

1-year Mortality Rates

Haven’t Changed

over the Last Decade2

2006 2004

80

60

60- to 90-Day Survival Post-Discharge

*P value (40%≤ EF ≤50% vs EF >50%).

Fonarow GC, et al. J Am Coll Cardiol. 2007;50:768777.

0 20 40

0.75

Su

rviv

al

Fu

nc

tio

n

1.00

0.80

0.95

10 80 90 30

0.85

0.90

60

Survival Time in Days since Discharge

HF-PEF

HF-REF

2294 2188 469 1994 LVSD

2604 2471 441 2195 No LVSD

*p = 0.459

50 70

Gheorghiade M, et al. Am J Cardiol. 2005;96(6A).

Myocardial Injury in Acute Heart Failure: “The Perfect Storm”

• Decreases coronary perfusion due to:

– High LV and RV diastolic pressure +/-decreased

blood pressure

– Inotropic stimulation

• Further activation of neurohormones

• Ischemic/hibernating myocardium

Worsening Renal Function in ADHF Patients

Outcome RF Not Worse RF Worse OR (95% CI)

In-hospital mortality 3% 7% 2.7 (1.6–4.6)

30-day mortality 6% 10% 1.9 (1.3–2.8)

6-month mortality 19% 25% 1.6 (1.2–2.1)

LOS (days) 6.93 9.14

ADHF = acute decompensated heart failure.

Krumholz H, et al. Am J Cardiol. 2000;85:1110.

• 70% of patients admitted with ADHF have worsening Cr

• 20-30% increase Cr >0.3 mg/dL

• Worsening Cr tends to occur early in the hospitalization

• Associated with longer stay, increased cost and worse long and short term

mortality

Common Denominator in Worsening Renal Function – Volume Overload

Chaudhary SI, et al. Circulation. 2007;116:1549-1554.

45 35 20

-5

Dail

y W

eig

ht

Ch

an

ge (

Mean

) 5

-3

3

40 0 30

-1

1

Days

Controls

Cases

10

4

-4

2

-2

0

25 15

HR: 2-5 lbs=2.77, 5-10 lbs=4.66, >10 lbs=7.65

5

Risk Assessment for Patients with Acute Heart Failure

Prognostic Factors in ADHF

• Hyponatremia

• Incomplete treatment of congestion

• Blood pressure

• Renal function

• Biomarkers (e.g. BNP, troponins)

• Early worsening heart failure

ADHF = acute decompensated heart failure; BNP = brain natriuretic peptide.

Gheorghiade M, Pang PS. J Am Coll Cardiol. 2009;53(7):557-73.

Impact of Tn Release on Survival in Acute Heart Failure

Tn = troponin.

Kociol RD, et al. JACC. 2010;56:1071-8.

Troponin / Quartile

In-h

osp

ital M

ort

ality

(%

) p<0.001

2.0

2.7

3.4

5.3

0

8

2

4

6

1

7

3

5

≤0.04 >0.10-0.2 >0.04-0.10 >0.2

11,090 9,323 10,367 9,534 No. of Patients:

PCWP = pulmonary capillary wedge pressure; CI = cardiac index.

Fonarow GC, et al. Circulation. 1994;90:1-488.

High PCWP at Hospital Discharge Is Associated with Higher Long-Term Mortality

60

0

10

50

20

40

30

Mo

rtality

(%

)

Time (months)

12 6 0 18 24

60

0

10

50

20

40

30

Mo

rtality

(%

)

Time (months)

12 6 0 18 24

N=199

PCWP >16 mmHg

N=257

PCWP ≤16 mmHg

p=.001

Atrial

CI >2.6 L/min/m2

N=236

CI ≤2.6 L/min/m2

N=220

Lucas C, et al. Am Heart J. 2000;140:840.

Post-Discharge Freedom of Congestion Is Associated with Better Prognosis

Symptoms of congestion: orthopnea, jugular venous distention,

weight gain ≥2 lbs in a week, need to increase diuretic dose, leg edema

100

0

80

20

60

40

Su

rviv

al

(%)

Months after Reassessment

12 6 0 18 24

p<.0001

No residual symptoms

of congestion (N=80)

1–2 residual symptoms


3–5 residual symptoms


7% 6%

13%

24%

33%

15%

3% 2%

0

5

10

15

20

25

30

35

<-20 -20 to -15 -15 to -10 -10 to -5 -5 to 0 0 to 5 5 to 10 >10

Pati

en

ts (

%)

Change in Weight (lbs)

Most Patients Have Little or No Weight Loss During Hospitalization

Fonarow GC. Rev Cardiovasc Med. 2003;4(suppl 7):S21-S30.

Clinical Status at Time of Discharge

No Mention

11%

Asymptomatic

44%

<1%

4%

<1%

Improved

(but still symptomatic)

40%

Evidence of Incomplete Relief from Congestion

All Enrolled Discharges (n=150,745) October 2001 to December 2004.

No Change

Not Applicable

Worse

Fonarow GC. Rev Cardiovasc Med. 2003;4(suppl 7):S21-S30.

Lack of Dyspnea Improvement Predicts Adverse Outcome – PROTECT Study

PROTECT study. Metra M, et al. Eur Heart J. 2011;32(12):1519-34.

Association between Dyspnea Relief and Mortality at Days 14 and 30

Variable HR 95% CI p-Value

14-day Mortality

Dyspnea relief at Days 2 and 3 0.34 0.18, 0.62 <0.0001

Age, per 1 year increase 1.04 1.01, 1.07 0.021

NYHA class before admission IV vs. I/II/II 0.92 0.52, 1.63 0.78

Systolic blood pressure at screening, per 1 mmHg

increase 0.99 0.98, 1.01 0.426

Screening BNP >750 or NT-proBNP >300 pg/mL 1.32 0.77, 2.26 0.306

Day 1 serum sodium, per 1 mEq/L increase 0.90 0.85, 0.95 <0.001

Baseline creatinine clearance, per 1 mL/min increase 0.99 0.97, 1.01 0.295

30-day Mortality

Dyspnea relief at Days 2 and 3 0.42 0.26, 0.67 <0.0001

Age, per 1 year increase 1.03 1.00, 1.05 0.025

NYHA class before admission IV vs. I/II/II 0.79 0.49, 1.28 0.332

Systolic blood pressure at screening, per 1 mmHg

increase 0.98 0.97, 0.99 0.004

Screening BNP >750 or NT-proBNP >300 pg/mL 1.17 0.75, 1.82 0.492

Day 1 serum sodium, per 1 mEq/L increase 0.90 0.86, 0.94 <0.001

Baseline creatinine clearance, per 1 mL/min increase 0.99 0.98, 1.01 0.252

Cong = congestion.

Metra M, et al. Circ Heart Fail. 2012;5:54-62.

WRF together with Congestion

has the worst survival

The Role of Congestion and Its Interaction with Worsened Renal Function (WRF)

0 60 120

0

Su

rviv

al

1.0

0.2

0.8

30 330 390 90

0.4

0.6

210

Days

WRF/Cong

No WRF/Cong

150 270

WRF/No Cong

45

31

253

266 No WRF/No Cong

300 360 180 240

40

31

247

259

32

29

243

249

29

27

235

244

28

26

218

237

26

26

216

229

26

24

204

227

24

22

196

223

23

20

189

217

23

19

188

214

23

19

186

208

22

19

178

202

20

18

170

197

0.9

0.1

0.7

0.3

0.5

No WRF / No Cong

WRF / No Cong

No WRF / Cong

WRF / Cong

Metra M, et al. J Am Coll Cardiol. 2013;61(2):196-206.

Impact of Worsening Biomarkers and Worsening HF on Survival

0.20

0.15

0.10

0.05

0

Study Day

120 160 0 40

<30% Decrease

≥30% Decrease

80

NT-proBNP E

140 180 20 60 100

0.20

0.15

0.10

0.05

0

120 160 0 40

<22 nmo/L Increase (0.3 mg/L)

≥22 nmo/L Increase (0.3 mg/L)

80

Cystatin C B

140 180 20 60 100

0.20

0.15

0.10

0.05

0

Cu

mu

lati

ve

Ris

k

Study Day

120 160 0 40

<20% Increase

≥20% Increase

80

ALT D

140 180 20 60 100

0.20

0.15

0.10

0.05

0

Cu

mu

lati

ve

Ris

k

120 160 0 40

<20% Increase

≥20% Increase

80

Troponin T A

140 180 20 60 100

0.20

0.15

0.10

0.05

0

Study Day

120 160 0 40

No WHF to Day 5

WHF to Day 5

80

Worsening Heart Failure F

140 180 20 60 100

0.20

0.15

0.10

0.05

0

120 160 0 40

<20% Increase

≥20% Increase

80

AST C

140 180 20 60 100

0.47 (0.31, 0.69)

p=0.0001

2.10 (1.38, 3.20)

p=0.0004

1.96 (1.13, 3.40)

p=0.0152

1.80 (1.16, 2.78)

p=0.0076

1.66 (0.92, 3.00)

p=0.0987

1.90 (1.11, 3.22)

p=0.0164

Current Guideline Recommended Treatment for

Acute Heart Failure

Current Treatment of ADHF

Diuretics

Reduce

Fluid

Volume

Vasodilators

Decrease

Preload

and

Afterload

Inotropes

Augment

Contractility


Therapies in the Hospitalized HF Patient

Recommendation COR LOE

HF patients hospitalized with fluid overload should be treated with

IV diuretics I B

HF patients receiving loop diuretic therapy, should receive an initial

parenteral dose greater than or equal to their chronic oral daily dose,

then should be serially adjusted

I B

HF-REF patients requiring HF hospitalization on GDMT should continue

GDMT unless hemodynamic instability or contraindications I B

Initiation of beta-blocker therapy at a low dose is recommended

after optimization of volume status and discontinuation of IV agents I B

Thrombosis/thromboembolism prophylaxis is recommended for

patients hospitalized with HF I B

Serum electrolytes, urea nitrogen, and creatinine should be measured

during the titration of HF medications, including diuretics I C

COR = class of recommendation; LOE = level of evidence; IV = intravenous; GDMT = guideline-directed medical therapy.


Therapies in the Hospitalized HF Patient (cont)

Recommendation COR LOE

When diuresis is inadequate, it is reasonable to

a) Give higher doses of IV loop diuretics; or

b) add a second diuretic (e.g., thiazide)

IIa

B

B

Low-dose dopamine infusion may be considered with loop

diuretics to improve diuresis IIb B

Ultrafiltration may be considered for patients with obvious

volume overload IIb B

Ultrafiltration may be considered for patients with refractory congestion IIb C

IV nitroglycerin, nitroprusside or nesiritide may be considered an

adjuvant to diuretic therapy for stable patients with HF IIb B

In patients hospitalized with volume overload and severe

hyponatremia, vasopressin antagonists may be considered IIb B

COR = class of recommendation; LOE = level of evidence.


Clinical Value of Current Recommended Therapies in ADHF

• Diuretics

– Symptomatic relieve

• Vasodilators

– Symptomatic relieve as adjunct to diuretics

• Intravenous inotropes

– Improve cardiac output in patients shock or

impending shock


Effects of Diuretic Regimens on Symptoms In ADHF Patients

ADHF = acute decompensated heart failure; AUC = area under the curve.

Felker GM, et al; NHLBI Heart Failure Clinical Research Network. N Engl J Med. 2011;364:797–805.

Low-Dose vs High-Dose Strategy

0

Hours

20 10 0 40 70 50 30 60

80

10

20

50

30

Glo

bal

VA

S S

co

re

40

60

100

70

90

0.00

Low

Dose

High

Dose

0.05

Ch

an

ge in

Cre

ati

nin

e (

mg

/dl)

0.15

0.10

0.04

0.08

p=0.21

High Dose

Low Dose

AUC with low-dose strategy, 4171±1436

AUC with high-dose strategy, 4430±1401

p=0.06

IV Vasodilators for the Treatment of AHF

Parameter Nitroprusside Nesiritide Nitroglycerin Serelaxin*

Prospective

studies in HF - +++ + ++

Hemodynamic

effect +++ +++ +++ +++

Need for dose

titration Yes No Yes No

Effect on

symptoms NA +/- NA +

Long term

mortality NA - NA +?

*Not FDA approved; ? = to be confirm in further studies.

Metra M, et al. Heart Fail Rev. 2009;14:299-307. Yancy CW, et al. J Am Coll Cardiol. 2013;62(16):e147-239. Teerlink JR, et al. Lancet. 2013;381:29-39.

Vasodilators in AHF: Should Be Used Early

• ASCEND HF Trial

– Patients receiving nesiritide early (≤15.5 hrs) had

significantly less dyspnea within 6 hrs (p≤0.001)

compared to patients receiving it >15.5 hrs

O’Connor CM, Starling RC, Hernandez AF, et al. N Engl J Med. 2011;365:32–43.

http://www.medscape.com/viewarticle/743415. Accessed December 15, 2014.

Early Initiation of Therapy Improves the Likelihood of Benefit

0 8 20

0 Rela

tive O

dd

s f

or

Bett

er

Sta

tus

Dysp

nea (

Hig

her

Is B

ett

er)

1.8

0.4

1.6

4 36 12

0.8

1.2

Time to Drug (hours)

Placebo

Nesiritide

28

0.2

1.4

0.6

1.0

16 24

Chi-square for treatment = 9.66 for 2 df, p=0.0080

Estimate of Effect of Nesiritide on 6 Hour Dyspnea Relief

Based on Time from Presentation to Study Drug

32

Placebo Mean (pts)

Nesiritide Mean (pts)

df = degrees of freedom.

https://my.americanheart.org/idc/groups/ahamah.../ucm_426740.pdf. Accessed January 5, 2015.

Drugs to Treat AHF That Are Positive Inotropes or Vasopressors or Both

*Available outside USA, not FDA approved.

McMurray JJV, et al. Eur Heart J. 2012;33:1787-1847.

Bolus Infusion Rate

Dobutamine No 2-20 µg/kg/min: (b+)

Dopamine No

<3 µg/kg/min: renal effect (d+)

3-5 µg/kg/min: inotropic (b+)

>5 µg/kg/min: (b+), vasopressor (a+)

Milrinone 25-75 µg/kg over 10-20 min 0.375-0.75 µg/kg/min

Enoximone* 0.5-1.0 mg/kg over 5-10 min 5-20 µg/kg/min

Levosimedan* 12 µg/kg over 10 min (optional) 0.1 µg/kg/min, which can be decreased

to 0.05 or increased to 0.2 µg/kg/min

Norepinephrine No 0.2-1.0 µg/kg/min

Epinephrine

Bolus: 1 mg can be given i.v.

during resuscitation, repeated

every 3-5 min

0.05-0.5 µg/kg/min

ROSE Study Design

Co-Primary Endpoints:

1) Cumulative urinary volume from randomization through 72 hours 2)

Change in serum cystatin-C from randomization to 72 hours

Chen HH, et al. JAMA. 2013;310(23):2533-2543.

ROSE Study: Results 72 Hour Urine Volume Change in Cystatin-C

8.3 8.6

0

5

10

15

72-h

ou

r u

rin

e v

olu

me

(L

)

Placebo Nesiritide

P=0.25

0.11

0.07

0.00

0.05

0.10

0.15

0.20

Ch

an

ge

in

Cys

tati

nC

(m

g/L

)

Placebo Nesiritide

P=0.35

Chen HH, et al. JAMA. 2013;310(23):2533-2543.

Yes

PCW = pulmonary wedge pressure; CI = cardiac index; SVR = systemic vascular resistance.

Stevenson LW. Eur J Heart Failure. 1999;1:251-257.

No

Warm and Dry

PCW and CI

normal

Warm and Wet

PCW elevated

CI normal

Cold and Wet

PCW elevated

CI decreased

Cold and Dry

PCW low/normal

CI decreased

Vasodilators

Nitroprusside

Nitroglycerine

Nesiritide

Inotropic Drugs

Dobutamine

Milrinone

Normal SVR High SVR

Congestion at Rest

Low

Perfusion

at Rest

No

Yes

Profiles and Therapies of ADHF

Hospital Discharge: Transitions of Care Recommendation or Indication COR LOE

Performance improvement systems in the hospital and early postdischarge outpatient setting to identify HF for GDMT

I B

Before hospital discharge, at the first postdischarge visit, and in subsequent follow-up visits, the following should be addressed:

a) initiation of GDMT if not done or contraindicated;

b) causes of HF, barriers to care, and limitations in support;

c) assessment of volume status and blood pressure with adjustment of HF therapy;

d) optimization of chronic oral HF therapy;

e) renal function and electrolytes;

f) management of comorbid conditions;

g) HF education, self-care, emergency plans, and adherence; and

h) palliative or hospice care.

I B

Multidisciplinary HF disease-management programs for patients at high risk for hospital readmission are recommended

I B

Effective systems of care coordination with special attention to care transitions should be deployed for every patient with chronic HF that facilitate and ensure effective care that is designed to achieve GDMT and prevent hospitalization.

I B

A follow-up visit within 7 to 14 days and/or a telephone follow-up within 3 days of hospital discharge is reasonable

IIa B

Use of clinical risk-prediction tools and/or biomarkers to identify higher-risk patients is reasonable

IIa B


Novel Therapies

Selected Investigational Agents for AHF

Drug* Mechanism Ongoing Trials Phase

Omecamtiv

mecarbil Cardiac myosin activator ATOMIC-AHF II

CXL-1427 Nitroxyl donor Dose ranging study I & II

ANX-042 Natriuretic peptide None Listed I

Ularitide Synthetic urodilatin TRUE-AHF III

Serelaxin Recombinant relaxin RELAX-AHF-2 III

TRV027 β-arrestin biased ligand

of the AT1R BLAST-AHF II

*Not FDA approved; AT1R = angiotensin II type 1 receptor; ST = standard therapy.

Hasenfuss G, et al. Eur Heart J. 2011;32(15):1838-1845. Gheorghiade M, et al. Eur J Heart Fail. 2011;13:100-106.

Presentation by JR Teerlink. ESC 2013, Amsterdam, Netherlands. http://www.drugdevelopment-

technology.com/search/?q[]=cxl-1427. Accessed January 10, 2015. Clinicaltrials.gov: NCT02157506;

NCT01661634; NCT02064868; NCT01966601.

Investigational Agents that Failed to Show a Benefit in AHF

Drug Mechanism Study Results

Tezosentan* Endothelin receptor

antagonist VERITAS Studies1 No difference in outcomes

Milrinone Phosphodiesterase 3

inhibitor OPTIME-HF2 No significant benefit

Rolofylline* Adenosine A1 receptor

antagonist PROTECT3 No significant benefit

Aliskiren† Direct renin inhibitor ASTRONAUT4 No significant benefit

Nesiritide Recombinant human B-

type natriuretic peptide ASCEND-HF5 No significant benefit

Cinaciguat* Soluble guanylate

cyclase stimulator

COMPOSE

Program6

No difference in dyspnea or

cardiac index

*Not FDA approved; †Not FDA approved for acute heart failure.

1. McMurray JJ, et al. JAMA. 2007;298(17):2009-19. 2. Cuffe MS, et al. JAMA. 2002;287(12):1541-7. 3. Massie BM, et

al. N Engl J Med. 2010;363:1419-28. 4. Gheorghiade M, et al. JAMA. 2013;309(11):1125-35. 5. O’Connor CM, et al. N

Engl J Med. 2011;365:32-43. 6. Gheorghiade M, et al. Eur J Heart Fail. 2012;14(9):1056-66.

SIRIUS II Study: Results

PCWP = pulmonary capillary wedge pressure; BP = blood pressure.

Mitrovic V, et al. Eur Heart J. 2006;27(23):2823-32.

Most common adverse events were dose dependent BP decrease and hypotension

with no deleterious effects on renal function

70

0

10

20

50

30

Pati

en

ts (

%)

7.5 ng/kg/min

15 ng/kg/min

Placebo 30 ng/kg/min

40

Patient-Assessed Dyspnea:

Moderately or Markedly Better

60

0

-12

-10

-2

-8

-4

-6

Mm

Hg

PCWP

Time (hours) 4 2 24 26 8 6

30’

0.016

<0.001

0.003

0.014

<0.001

0.003

<0.001

<0.001

<0.001 <0.001

<0.001

<0.001

0.017

0.042

0.015

0.131

Ularitide 15 ng/kg/min (n=53) Placebo (n=53)

Ularitide 7.5 ng/kg/min (n=60) Ularitide 30 ng/kg/min (n=55)

0.0026

0.0010

0.0013

0.0058

0.0026

0.0020 6 Hours

24 Hours

Phase III Study

Trial of Ularitide’s Efficacy in Patients with

Acute Heart Failure (TRUE-AHF)

2200 Patients

Co-Primary endpoints:

7-point scale of symptomatic improvement,

lack of improvement, or worsening;

persistent or worsening HF requiring an intervention; and

all-cause mortality

Relaxin and Receptors

*Not FDA approved.

Hernandez-Montfort JA, et al. Curr Heart Fail Rep. 2013;10(3):198-203. Miyares MA, et al. P T. 2013;38(10):606-11.

Structure of relaxin-2

and serelaxin*

Relaxin receptors:

RXFP-1, -2

COO -

COO-

NH3+

pE L Y

S A L

A

N K

C

H V G

C T

K R S

L A

R

D S W

M

V E

E

I K

L C

S

R G

E L V R A Q I A I C G

M S

T W C F

A1

A5

A10

A15

C

A20

A24

B29

B1

B5

B10

B15 B20

B25

RXFP-1 localization in

rat artery

• Naturally occurring, vascular modulating hormone discovered in 1929

• G-protein coupled relaxin receptors (relaxin family receptors, RXFP1 and 2),

identified in 2002, localized in blood vessels

• Recombinant human protein under development (serelaxin) identical to

naturally occurring hormone

• Associated with maternal hemodynamic improvements seen during

pregnancy including increased CO and increased renal blood flow

RELAX-AHF Study

*Not FDA approved; CrCl = creatinine clearance; VAS AUC = visual analogue scale area under the curve.

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

• Hospitalized for AHF

• Dyspnea at rest/minimum

exertion

• Congestion (chest x-ray and

BNP ≥350 ng/L/NT-proBNP

≥1400 ng/L)

• SBP >125 mm Hg

• CrCl = 30-75 mL/min/1.73 m2

• Received 40 mg IV

furosemide

• Randomized within 16 hours

Screening

R

1:1

Placebo

(n=580)

Serelaxin

(n=581)

Treatment

Period

Follow-up

Day 1 4 3 2 5 14 60 180

Assessments

All-cause mortality

CV/renal hospitalization

All-cause

mortality

Primary endpoints:

Dyspnea relief using VAS AUC to day

5 and dyspnea improvement by Likert

scale in 1st 24 hrs.

0

5

10

15

20

25

30

35

0.00 1.00 2.00 3.00 4.00 5.00

Ch

an

ge f

rom

Baseli

ne (

mm

)

19.4% increase in AUC with serelaxin

from baseline through day 5

(Mean difference of 448 mm-hr), p=0.0075

Days 6 12 hrs

*Not FDA approved.


RELAX-AHF: 1° Endpoint of Dyspnea Relief (VAS AUC)

All Patients Treated within 16 Hours of Admission

Placebo

Serelaxin*

RELAX-AHF: Signs and Symptoms of Congestion

p value by 2-sided Wilcoxon rank sum test of change from baseline; *Not FDA approved. Teerlink JR, et al. Lancet. 2013;381:29-39.

Signs and Symptoms of Congestion at Day 2

100

80

60

40

20

0

Pati

en

ts %

DOE p=0.02

Orthopnea p=0.002

Edema p=0.01

Rales p=0.008

JVP p=0.06

None

Mild

Moderate

Severe

None

1 pillow

2 pillows

>30

None

1+

2+

3+

None

<1/3

1/3-2/3

>2/3

<6 cm

6-10 cm

>10 cm

*

18

0

4

10

14

(%)

0

6

12

2

8

16

RELAX-AHF: Worsening of Heart Failure

*Not FDA approved.


(Numbers of Subjects with WHF shown for each time point)

Day 1 Day 3 Day 5 Day 5

Kaplan-Meier Estimate D14

for Time to WHF (%)

Cumulative Proportion of Worsening

Heart Failure to Day 5 (%)

12 Hr Day 2 Day 4 Day 14

p<0.001 through Day 5

18

0

4

10

14

(%)

6

12

2

8

16

Worsening Heart Failure (WHF) was defined as worsening signs and/or symptoms of HF that

required an intensification of IV therapy for HF or mechanical ventilatory or circulatory support

6 Hr

Placebo (N=573)

Serelaxin* (N=570)

n= 11 3

HR 0.7 (0.51, 0.96); p=0.024

573 570 69 37 16 4 31 10 44 17 57 25 64 36 573 570

RELAX-AHF: CV Death through Day 180

*Not FDA approved.


0 30

0

K-M

Esti

mate

CV

Death

(IT

T)

(%)

14

2

12

14 150 180

4

8

90

Days

Placebo (N=580)

Serelaxin* (N=581)

580 547 444 523 Placebo

581 555 463 542 Serelaxin

HR 0.63 (0.41, 0.96); p=0.028

NNT=29

60 120

10

6

Number of

Events, n (%)

55 (9.6%)

35 (6.1%)

567

573

559

563

535

546

514

536

Incidence of AEs/SAEs to Day 14

Placebo

(N=570)

n (%)

Serelaxin*

(N=568)

n (%)

Subjects with any adverse event (AE) 320 (56.1) 305 (53.7)

Subjects with any drug-related AE[1] 46 (8.1) 47 (8.3)

Subjects with AE leading to study drug d/c 22 (3.9) 26 (4.6)

Hypotension-related AE (through day 5) 25 (4.4) 28 (4.9)

Renal Impairment-related AE (through day 5) 49 (8.6) 26 (4.6)*

Subjects with any serious adverse event (SAE) 78 (13.7) 86 (15.1)

Subjects with any drug-related SAEs 2 (0.4) 3 (0.5)

Subjects with SAE leading to drug d/c 3 (0.5) 5 (0.9)

Serious AE with an outcome of death 15 (2.6) 10 (1.8)

The number of subjects with any AE includes all AEs and SAEs reported through Day 14. Non-serious AEs were collected through Day 5, SAEs through Day 14. *Not FDA approved.


Summary

• ADHF is associated with high risk of morbidity

and mortality, particularly post-discharge

• Current treatment options are limited

• Strategies aimed at decongesting patients and

protecting vulnerable organs (e.g. heart and

kidney) are likely to improve outcomes in ADHF

• Early diagnosis and treatment may improve

outcomes

• The results of RELAX-AHF suggest that serelaxin

is a promising agent for treating ADHF

Post-Activity Questions 1 of 4

• Which of the following is not a characteristic

seen in patients with acute heart failure ?

A. About 75% of AHF patients present with a SBP ≥120

mmHg

B. Dyspnea on presentation in 90% of patients

C. About 90% of patients with AHF have LVEF of <40%

D. Fluid redistribution from the periphery to lungs



is incorrect ?

A. Measurement of BNP or NT-proBNP levels is not

useful in the diagnosis of AHF

B. Benefits of vasodilator therapy is increased with

early treatment initiation (≤15.5 hours) in AHF

patients

C. The mortality rate of patients with HF-REF and HF-

PEF are similar following discharge after AHF

D. Worsening renal function in AHF patients is

associated with increase LOS and mortality



therapies in development is true ?

A. Ularitide had no effect on dyspnea in the SIRIUS II

study

B. Serelaxin was shown to significantly reduce dyspnea

and the symptoms of congestion in the RELAX-AHF

study

C. Aliskiren was shown to reduce dyspnea or HF

hospitalizations in the ASTRONAUT study

D. Serelaxin had no effect on the secondary endpoints

of worsening HF or CV death


• A 68-year old female is admitted to the hospital with acute

decompensated heart failure. She was discharged 45 days ago

following a previous admission for acute heart failure. Today she

presents with dyspnea, pulmonary congestion, SBP 150 mmHg,

and LVEF 35%. If you employ current guideline recommendations

for her management, you should:

A. Initiate thromboprophylaxis to prevent thromboembolism

B. Prescribe high-dose furosemide because high dose diuretic

therapy is significantly better than low-dose in reducing

symptoms in AHF

C. Initiate intravenous nesiritide immediately to stabilize AFH

pateints

D. Consider ultrafiltration instead of IV diuretics

Q and A

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