Controversial issues in heart failure Can we change the outcome...

Controversial issues

in heart failure

Can we change the

outcome of patients

with acute heart

failure?

Marco Metra, MD, FESCAssociateprofessor of Cardiology.

University of Brescia

The Burden of Acute HF

• Most frequent cause of hospitalization for

patients aged >65 years

• In-hospital stay

– Duration, mean: 4 days (US) / 8 days

(Europe)

– Mortality, 3% to 9%

• Follow-up (2-3 months)

– Mortality, 9% to 13%

– Rehospitalizations, 24% to 30%

Data from: Cleland et al. Eur Heart J. 2003;24:442; Gheorghiade et al. Circulation. 2005;112:3958. Rudiger A et

al. , Eur J Heart Fail 2005; 7:662; Adams et al. , Am Heart J. 2005;149:209; O'Connor et al. J Card Fail.

2005;11:200; Tavazzi L et al., Eur Heart J 2006; 27:1207; Zannad et al. , Eur J Heart Fail 2006; 8;697; Nieminen

M et al. Eur Heart J 2006; 27, 2725; Fonarow et al. J Am Coll Cardiol 2005;45:345A.

One-year survival in AHF patients discharged alive:

comparison between clinical classes.

Harjola V ... Tavazzi Eur J Heart Fail 2010;12:239-248

Renal dysfunction

↓ CO / ↑ LVEDP

End-organ hypoperfusion

↑ venous pressure

Neurohormonal activation

RAA – SNS - ADH

Inflammatory activation

Na-H2O retention

Congestion↑ LV preload

↑ LV wall stress

↑ LV afterload

Fluid redistribution

to the lungs

Lung congestion

↓ coronary perfusion

pressure

tachycardia

↑ MVO2

Myocardial ischemia

Diuretic use

Diuretic resistance

Cardiac dysfunction

diastolicsystolic

Metra et al.. ESC Intensive Acute Cardiac

Care textbook

Pathophysiologic

mechanisms in acute

heart failure

Change in dyspnoea from sitting to lying supine

Change in dyspnoea in the first 6 hours of treatment

Changes in symptoms (dyspnoea) in the

URGENT Trial

Mebazaa et al. Eur Heart J. 2010 Apr;31(7):832-41.

Hogg KJ, McMurray JJ. Eur Heart J. 2010 Apr;31(7):771-2.

Freedom from congestion predicts good survival

also in patients with advanced HF

146 pts with NYHA IV

4-6 weeks after discharge re-

evaluated for congestion

1. Orthopnoea

2. JVP

3. Oedema

4. Weight gain

5. baseline

diuretics

Criteria:

20

40

60

80

2-year survival

(%)

0 crit(n=80)

1-2 crit(n=40)

3 crit(n=26)

Orth+(n=33)

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

High-risk

group

Patients at risk Patients at risk

NT-ProBNP: NT-prBNP:

< 6078 76 69 69 42 32 <3275 57 46 28 24 19

> 6078 31 29 20 11 6 >3275 50 25 15 11 7

Discharge NT-ProBNP <3275

Discharge NT-ProBNP >3275

P<0.0001Discharge NT-ProBNP <6078

Discharge NT-ProBNP >6078

P<0.0001

Cardiac mortality

0

0.2

0.4

0.6

0.8

1

0 90 180 270 360

Days

Fra

cti

on

of

pati

en

ts

Cardiac mortality or CV Hospitalizations

0

0.2

0.4

0.6

0.8

1

0 90 180 270 360

Days

Fra

cti

on

of

pati

en

ts

Prognostic value of NT-ProBNP at discharge in

patients hospitalised for AHF

Metra et al. Eur J Heart Fail. 2007;9:776-86.

NT-ProBNP

<3000 pg/mL

Dimissione

F-Up clinico

NT-ProBNp

ignotoNT-ProBNp

noto

F-Up clinico

Ospedalizzazione IC acuta / No SCA

Misurazione NT-ProBNP

48-72 ore pre-dimissione & alla dimissione

Rivalutazione terapia:↑dose diuretici / ACEi /

Dig/ARB/AA/IDN /Terapia i.v.

NT-ProBNP

>3000 pg/mL

Rivalutazione

NT- ProBNP

↓NT-ProBNP

>25% or <3000 pg/ml

Randomizzazione 1:1

NT-proBNP in

the Optimization

of Treatment in

Acute Heart

Failure (BOT-

AcuteHF) Trial

P = 0.035

0%

20%

40%

60%

80%

100%

0 60 120 180 240 300 360 420 480 540 600 660 720

Su

rviv

alp

rob

ab

ilit

y, %

Days of follow-up

Nt-pro-BNP guidedControl

All-cause mortality

Effects of Nt-proBNP guided therapy on survivavl after an AHF hospitalisation

Weight changes in patients hospitalized with

ADHF. Results from ESCAPE (N=433)

Mehta et al. . Am J Cardiol 2009; 103:76

40%

≈25%

Large RCTs in ADHF

Trial Agent Pts

No.

Effects on

symptoms

Effects on

outcomes

VMAC, 2002 Nesiritide 489Yes vs placebo

@ 3 hn.s.

OPTIME-CHF, 2002 Milrinone 951 No No, ↑ AEs

VERITAS, 2007 Tezosentan 1448 No No

EVEREST, 2007 Tolvaptan 4133 Mild No

REVIVE-II, 2009 Levosim. 600 Mild No, ↑ AEs

PROTECT* Rolofylline 2033 Mild No

VMAC PC JAMA 2002; 287:1531; Cuffe et al. JAMA 2002; 287:1541; McMurray et al., JAMA

2007;298:2009; Gheorghiade et al. JAMA 2007; 297:1332; de Lissovoy et al. Eur J Health Econ 2009;;

Massie et al. to be submitted

* All these changes corresponded to a 6 to 12% difference in the proportion of patients

with dyspnea improvement

Noninvasive Ventilation in Acute Cardiogenic Pulmonary Edema

Gray A et al. N Engl J Med 2008;359:142-151

Large RCTs in ADHF

Trial Agent Pts

No.

Effects on

symptoms

Effects on

outcomes

VMAC, 2002 Nesiritide 489Yes vs placebo

@ 3 hn.s.

OPTIME-CHF, 2002 Milrinone 951 No No, ↑ AEs

VERITAS, 2007 Tezosentan 1448 No No

EVEREST, 2007 Tolvaptan 4133 Mild No

REVIVE-II, 2009 Levosim. 600 Mild No, ↑ AEs

PROTECT* Rolofylline 2033 Mild No

VMAC PC JAMA 2002; 287:1531; Cuffe et al. JAMA 2002; 287:1541; McMurray et al., JAMA

2007;298:2009; Gheorghiade et al. JAMA 2007; 297:1332; de Lissovoy et al. Eur J Health Econ 2009;;

Massie et al. to be submitted

* All these changes corresponded to a 6 to 12% difference in the proportion of patients

with dyspnea improvement

Drug’s efficacy

Drug’s cardiovascular safety

Placebo IV

Rolofylline

30 mg IV

Treatment phase Follow-up

Randomisation

Rolofylline to

placebo, 2:1

All cause mortality

CV/Renal hosp All cause

mortality

PROTECT STUDY DESIGN

Kidney Function

Days 1 2 3 4 5 6 7 14 60 180

Screening

• AHF & fluid

overload, need of

iv loop diuretic

• CrCl, 20-80

ml/min

Symptoms relief and short-term outcomes in ADHF

Components of the primary end-point in PROTECT

2,1

0,6

9,7

11,1

1,7

0,4

9,1

12,7

0

2

4

6

8

10

12

14

Death day 7

HF Rehosp day 7

WHFday 7

WRF, day 7-14

PROTECT EC, PC & investigators. Presented at ESC 2009

44,5

51,2

0

10

20

30

40

50

60

Dyspnea relief

Fra

cti

on

of

pati

en

ts, %

Placebo (n=677)

Rolofylline (n=1356)

Time to Death or CV or Renal Rehospitalization - Day 60

0.4

0.3

0.2

0.1

0.0

0 5 10 15 20 25 30 35 40 45 50 55 60 65

Study Day

Cu

mu

lati

ve R

isk

Hazard Ratio (95% CI) = 0.98 (0.83, 1.17)

P-value = 0.861

Placebo

Rolofylline 30 mg

Study Day

No. of patients at risk

Placebo (N=677)

Rolofylline (N=1356)

7

657

1322

14

633

1263

30

566

1134

55

489

1001

65

74

158

Death: Placebo 9.5% vs rolofylline 8.9%

Re-hospitalization: Placebo 25.6% vs rolofylline 25.7%

Effects of rolofylline on short-term outcomes

Metra et al. Submitted to Eur Heart J

Effects of rolofylline on short-term outcomes

Short Term OutcomeBy Baseline Creatinine (Median)

Hazard Ratio (95% C.I.)

0.2 0.4 0.6 1.0 1.4 2.0

14 Days30 Days

In-hospital

14 Days30 Days

In-hospital

14 Days30 Days

In-hospital

14 Days30 Days

In-hospital

14 Days30 Days

In-hospital

14 Days30 Days

In-hospital

Favors Rolofylline Favors Placebo

Baseline Creatinine< 1.5 mg/dL

>= 1.5 mg/dL

All Cause Mortality

HF Mortality

CV Mortality

All Cause Mortality

HF Mortality

CV Mortality

Metra et al. Submitted to Eur Heart J

Renal dysfunction

↓ CO / ↑ LVEDP


↑ venous pressure


RAA – SNS - ADH


Na-H2O retention


↑ LV wall stress

↑ LV afterload


to the lungs

Lung congestion


pressure

tachycardia

↑ MVO2

Myocardial ischemia

Diuretic use

Diuretic resistance

Cardiac dysfunction

diastolicsystolic

Metra et al. ESC Intensive Acute Cardiac

Care textbook

Acute HF treatment strategy according to SBP

Oxygen /NIV, loop diuretic + vasodilator

Clinical evaluation

SBP >100 mmhg SBP 90-100 mmhg SBP <90 mmhg

Vasodilator (NTG,

nitroprusside,

nesiritide),

levosimendan

Vasodilator

and/or inotrope (dobutamine, PDEI,

levosimendan)

Consider preload

correction with

fluids or inotrope (dopamine)

Good response

stabilize & initiate oral

diuretics, ACEI/ARB,

β-blocker

Poor response

inotrope, vasopressor,

mechanical support,

consider PAC

ESC 2008 guidelines

Significance of SBP in AHFS

• Index of cardiac function &

peripheral perfusion

• Indication for the choice of treatment

• Cause of end-organ damage

Increased symptom-improvement with the novel

vasodilator, relaxin, in AHF patients with

elevated BP. Results from Pre-Relax-AHF

Systolic blood pressure, mmhg

120 130 140 150 160 170 180

Placebo

Relaxin 30 mcg/kg/m

Pre

dic

ted

va

lue

of V

AS

AU

C c

ha

ng

e

Teerlink et al. Eur Heart J 2009 ; 30 ( Abstract Supplement ), 164

Sustained Dyspnea Improvement

through Day 14 (Visual Analog Scale)

Teerlink, Metra, Felker et al. Lancet 2009;373:1429.

RELAX-AHF: Cardiovascular Deaths

to Day 180

0.8

0.85

0.9

0.95

1

0 30 60 90 120 150 180

Kapla

n-M

eie

r E

vent-

free S

urv

ival (%

)

Days

Placebo

Relaxin 10 mcg/kg/d

Relaxin 100 mcg/kg/d

Relaxin 250 mcg/kg/d

Relaxin 30 mcg/kg/d(p<0.05)

Teerlink, Metra, Felker et al. Lancet 2009;373:1429.

Age per 10.52 years

Systolic BP per 19.17 mmhg

BUN per 11.34 mg/dl

Creatinine increase >0.3 mg/dl at day 5

BNP>500 or NTproBNP >2000 pg/mL

Sodium per 3.93 mEq/L

Relaxin 10 & 30 mcg vs Placebo

Relaxin 100 & 250 mcg vs Placebo

0.01 0.1 1 10 100

Hazard ratios and 95% CIs

Dyspnea AUC at 5 days per 2692.4 mm*h

WHF vs none

Prediction of CV death or HF/RF

rehospitalisations at 60 days: Multivariable

regression model

Metra et al. Presented at HFA 2009 LBCTs

Predictors of WRFin Pre-RELAX AHF:

Role of SBP

change in SBP (mmHg)

-100 -80 -60 -40 -20 0 20 40 60P

robabili

ty o

f pers

iste

nt W

RF

0,0

0,2

0,4

0,6

0,8

1,0

234 AHF patients (SBP≥125mmHg) from the Pre-RELAX-AHF study

Voors et al, Eur Heart J 2009 ; 30 ( Abstract Supplement ), 1020

• Persistent WRF was associated >5 times higher day 60 (p<0.001) mortality

• Adjusted for potential confounders, a higher baseline SBP (p<0.001) and a greater SBP drop

<48 hours of admission (p=0.008) were the strongest predictors of persistent WRF

Baseline SBP (mmHg)

100 120 140 160 180 200 220

Pro

babili

ty o

f pers

iste

nt W

RF

0,0

0,2

0,4

0,6

0,8

1,0

Renal dysfunction

↓ CO / ↑ LVEDP


↑ venous pressure


RAA – SNS - ADH


Na-H2O retention


↑ LV wall stress

↑ LV afterload


to the lungs

Lung congestion


pressure

tachycardia

↑ MVO2

Myocardial ischemia

Diuretic use

Diuretic resistance

Cardiac dysfunction

diastolicsystolic


Care textbook

AHF & myocardial ischaemia

• Acute coronary syndromes– Myocardial infarction/unstable angina with large

extent of ischemia and ischemic dysfunction– Mechanical complication of acute myocardial

infarction– Right ventricular infarction

• Chronic coronary artery disease– Ischaemia / necrosis precipitated by AHF

• Non-ischaemic cardiomyopathy– Ischaemia / necrosis precipitated by AHF ?

Prevalence of Detectable (>0.01 pg/ml)Troponin T

in patients with AHF with daily blood sampling

26%

28%

46%

Coronary artery disease

TnT (1 sample)

TnT (>1 sample)

No TnT

26%

14%

60%

Idiopathic dilated cardiomyopathy

TnT (1 sample) TnT (>1 sample)

No TnT

Metra et al., Eur J Heart Fail. 2007;9:776-86

Patients at risk Patients at risk:

No cTnt 56 55 44 35 33 No cTnt 56 44 30 26 21

cTnT 51 34 21 15 11 cTnt 51 23 11 9 4

No cTnT detectable

cTnT detectable

P<0.0001

No cTnT detectable

cTnT detectable

P<0.01

Cardiac mortality

0

0.2

0.4

0.6

0.8

1

0 90 180 270 360

Days

Fra

cti

on

of

pati

en

ts

Cardiac mortality or

CV hospitalizations

0

0.2

0.4

0.6

0.8

1

0 90 180 270 360

Days

Fra

cti

on

of

pati

en

ts

Freedom from Death or CV Hospitalization and

cTnT plasma levels in Acute Heart Failure

Metra et al., Eur J Heart Fail. 2007;9:776-86

Giorni

Rilascio TnT

(n=39)

Non Rilascio

TnT (n=141)

p=0.0372

Significato del rilascio di tropinina durnate l’ospedalizzazione per IC acuta:

Incidenza di morti o riospedalizzazioni

Renal dysfunction

↓ CO / ↑ LVEDP


↑ venous pressure


RAA – SNS - ADH


Na-H2O retention


↑ LV wall stress

↑ LV afterload


to the lungs

Lung congestion


pressure

tachycardia

↑ MVO2

Myocardial ischemia

Diuretic use

Diuretic resistance

Cardiac dysfunction

diastolicsystolic


Care textbook

Worsening Renal Function and outcome

lower risk for WRF higher risk for WRF

.1 .2 .5 1 2 4 8

Study Odds ratio (95% CI)

Inhospital patientsKrumholz (2000), n=1681 1.41 ( 1.10, 1.82)Smith (2003), n=412 1.73 ( 1.00, 2.98)Akhter (2004), n=480 2.62 ( 1.66, 4.13)Cowie (2006), n=299

Jose (2006), n=1854Khan (2006), n=6535

Owan (2006), n=6052

Outhospital patients

Subtotal

De Silva (2005), n=1216

Subtotal

Overall

1.44 ( 0.98, 2.09)

1.61 ( 1.35, 1.93)

1.71 ( 0.96, 3.05)

1.46 ( 1.06, 2.02)

1.49 ( 1.30, 1.71)

1.69 ( 1.48, 1.94)1.79 ( 1.59, 2.02)

1.62 ( 1.45, 1.82)

Damman et al. J Card Fail 2007

Patients at risk Patients at risk

Absolute and percent s-Cr change: Absolute s-Cr change:

< 0.3 or 25% 211 143 92 55 36 < 0.3 184 125 79 46 33

≥ 0.3 & 25% 107 64 36 19 14 ≥ 0.3 134 82 49 27 21

HF hospitalizations and

CV-mortality–free survival

55%

28%

0.0

0.2

0.4

0.6

0.8

1.0

0 90 180 270 360 450 540 630 720

Days

Pati

en

ts (

%)

CV-mortality–free survival

P < 0.001

Δ creatinine < 25% and/or < 0.3 mg/dL

Δ creatinine ≥ 25% and ≥ 0.3 mg/dL

86%

59%

0.0

0.2

0.4

0.6

0.8

1.0

0 90 180 270 360 450 540 630 720

Days

Prognostic Significance of Worsening Renal Function in Patients With ADHF

P < 0.001

Δ creatinine < 25% and/or < 0.3 mg/dL

Δ creatinine ≥ 25% and ≥ 0.3 mg/dL

Pati

en

ts (

%)

Metra M, … Dei Cas Eur J Heart Fail. 2008;10:188-195.

Adenosine type 1 receptor antagonists initial trials

Agent Author, year Model/ patients Effects

BG-9719 Lucas, JCP 2001 Pacing HF model ↓PWP, ↑CrCl, ↑uNa

BG-9719 Jackson, JPET

2001

CMP model ↑diuresis, ↑RBF, ↑GFR

BG-9719 Gottlieb,

Circulation 2002

63 CHF patients ↑diuresis, ↑uNa,

inhibition furosemide-

induced ↓GFR

BG-9928 Greenberg,

JACC 2007

50 CHF patients ↑uNa, ↓BW, =GFR

Rolofylline

(KW-3902)

Givertz, JACC

2007

146+35 CHF

patients

↑diuresis, ↑GFR,

↓s-Creat, ↓Fur dose,

sustained at 7 days

Rolofylline

(KW-3902)

Dittrich, JCF

2007

32 CHF patients 32%↑GFR, 45% ↑RBF

Rolofylline Cotter, JCF 2008 301 hospitalised

AHF patients

↑symptoms,↓BW,

↓s-Creat, …

Symptoms relief and short-term outcomes in ADHF

Components of the primary end-point in PROTECT

2,1

0,6

9,7

11,1

1,7

0,4

9,1

12,7

0

2

4

6

8

10

12

14

Death day 7

HF Rehosp day 7

WHFday 7

WRF, day 7-14

PROTECT EC, PC & investigators. Presented at ESC 2009

44,5

51,2

0

10

20

30

40

50

60

Dyspnea relief

Fra

cti

on

of

pati

en

ts, %

Placebo (n=677)

Rolofylline (n=1356)

Secondary Endpoint: Persistent Renal Impairment*P

erc

en

t o

f P

atie

nts

Odds ratio (95% CI) vs Pbo: 1.11 (0.85, 1.46); p = 0.441

0

2

4

6

8

10

12

14

1613.7

Ro 30 mg

15.0

Placebo

*Persistent renal impairment SCr ↑ >0.3 mg/dL at both Day 7 and Day 14 or

initiation of hemofiltration or dialysis through Day 7, or death by Day 7

Damman, K. et al. J Am Coll Cardiol 2009;53:582-588

Curvilinear Relationship Between CVP and eGFR According to Different Cardiac Index Values

Central venous pressure, mmHg

Cardiac index

>3.2 L/min/m2

2.5- 3.2 L/min/m2

<2.5 L/min/m2

50%

60%

70%

80%

90%

100%

0 60 120 180 240 300 360

Days

Su

rviv

al (

%)

No Congestion / No WRF (n=267)

No Congestion / WRF (n=178)

Congestion & WRF (n=183)

Congestion / No WRF (n= 101)

Survival in AHFS: Role of Congestion and

Worsening Renal Function

Clinical significance of high blood

pressure in AHF

• Cause of AHF– Afterload mismatch

• Consequence of AHF– ↑neurohormonal activation

– ↑cardiac function

SBP in AHF Registries

• ADHERE, AHJ 2005

– 107 362 patients from 282 hospitals

• Mean SBP, 144 mmhg

• SBP >140: 50% of pts

• OPTIMIZE-HF, JAMA 2006

– 48 612 patients from 259 hospitals

• Mean SBP, 143+33 mmhg

• SBP >140: 50% of pts

• Italian Survey, EHJ 2006

– 2807 patients from 206 cardiology centers

• Mean SBP, 141+37 mmhg, 138+36 WHF, 146+36 de novo

• SBP >140: 43%; 38% WHF, 49% de novo

• EFICA, EJHF 2006

– 599 patients from 60 centers

• Mean SBP, 126+39 mmhg; 139 without CS pts

Cause of AHF According to SBP: OPTIMIZE-HF Study48 612 patients FROM 259 us HOSPITALS

1318

25

35

0

20

40

< 120 120-139

140-161

>161

% o

f p

ati

en

ts

SBP quartiles, mmhg

Hypertensive

Gheorghiade et al., JAMA 2006; 296:2217

51 4944

39

0

20

40

60

< 120 120-139

140-161

>161%

of

pati

en

ts

SBP quartiles, mmhg

Ischemic



LV Systolic dysfunction

63

5244

35

0

20

40

60

80

< 120 120-

139

140-

161

>161

SBP quartiles, mmhg

% o

f p

ati

en

ts

LV Ejection fraction

33.337.8

40.944.4

0

20

40

60

80

SBP quartiles, mmhg

LV

EF

un

its

< 120 120-

139

140-

161

>161


7,2

3,62,5

1,7

0123456789

10

< 120 120-139

140-161

>161

% o

f p

ati

en

ts

SBP quartiles, mmhg

In-hospital mortality


14

8,4

6 5,4

0

4

8

12

16

< 120 120-139

140-161

>161%

of

pati

en

ts

SBP quartiles, mmhg

Postdischarge mortality


30,6 29,9 30,327,6

05

101520253035404550

< 120 120-139

140-161

>161

% o

f p

ati

en

ts

SBP quartiles, mmhg

60-90 d rehospitalisations


Clinical signs & ECHO in the

management of AHFS

AHF with SBP < 100

mmHg

Assess volume status:

signs of dehydration

ECHO: Treatable cause

ECHO: LV systolic

dysfunction

ECHO: persistent

↑intracardiac pressure

IVC congestion

Fluid administration

Coronary angiography,

PCI, surgery, etc.

Inoropic agent

↑ diuretic dose / trial of

vasodilator

Yes

Yes

Yes

Yes

Risk of Worsening Renal Function With Nesiritide in Patients With ADHF

Nesiritide ≤ 0.03 μg/kg/min vs.non–inotrope-based controls

Nesiritide ≤ 0.03 μg/kg/min vs. all controls; nesiritide ≤ 0.015 μg/kg/min vs. non–inotrope-based controls


Nesiritide ≤ 0.015 μg/kg/min vs.all controls


Nesiritide ≤ 0.06 μg/kg/min vs.all controls

0 0.5 1 1.5 2 2.5

Risk ratio (95% CI)

Nesiritide better Nesiritide worse

Sackner-Bernstein JD, et al. Circulation. 2005;111:1487-1491.

Factors influencing clinical

presentations & prognosis of AHF

• Blood pressure (peripheral perfusion)

• Fluid overload

• Myocardial ischemia

• Kidney dysfunction

– Each may or may not be present, with

different relative importance, in each patient

0,0

0,1

0,2

0,3

0,4

0,5

0,6

0,7

0,8

0,9

1,0

Seru

m c

rea

tin

ine c

han

ge (

mg

/dL

)

Ultrafiltration arm

Standard care arm

UF n = 72 90 69 47 86 71 75 66

SC n = 84 91 75 52 90 75 67 62

Ultrafiltration vs. IV Diuretics in

Patients Hospitalized for ADHF

Dys

pn

ea

sc

ore

7

6

5

4

3

2

1Ultrafiltration Standard care

m = 6.4, CI ± 0.11(n = 80)

m = 6.1, CI ± 0.15(n = 83)

P = 0.35

Ultrafiltration Standard care

We

igh

t lo

ss

(k

g)

6

5

4

3

2

1

0

m = 5.0, CI ± 0.68

kg(n = 83)

m = 3.1, CI ± 0.75 kg

(n = 84)

P = 0.001

1° efficacy endpoints 1° safety end points

P > 0.05 at all times

Costanzo MR, et al. J Am Coll Cardiol. 2007;49:675-683.

Freedom From Heart Failure Rehospitalization in UNLOAD

100

80

60

40

20

0

0 10 20 30 40 50 60 70 80 90

Ultrafiltration arm (16 events)

Standard care arm (28 events)

P = 0.037

Number of patients at risk

Ultrafiltration 88 85 80 77 75 72 70 66 64 45

Standard care 86 83 77 74 66 63 59 58 52 41

Pati

ents

fre

e fr

om

reh

osp

ita

liza

tio

n (

%)

Days

Costanzo MR, et al. J Am Coll Cardiol. 2007;49:675-683.

Gheorghiade, M. et al. Arch Intern Med 2007;167:1998-2005.

Predicted probability of freedom from death and death or heart failure (HF) rehospitalization across levels of sodium after adjusting for

important covariates

• Prognostic marker

– Peripheral hypoperfusion / Kidney dysfunction

– Neurohormonal activation (RAA, NE)

– Poor prognosis

• Treatment problem: loop diuretics

– Intolerance to neurohormonal antagonists

– Resistance to loop diuretics

– Exacerbation of hyponatremia

– ↑ free water clearance further ↓ s[Na]

• Cause of symptoms & poor prognosis (?)

Hyponatraemia in ADHF

Symptoms of Hyponatremia

Depend on– Severity

– Onset (acute vs chronic - < or >48 hours)

– Susceptibility• Age (young and old)

• CNS insult

• Respiratory reserve

• Female gender and hormonal milieu

– Volume status

140

110

120

130

s[Na+] mmol/L

•Normal

•…

•…

•Lethargy, Apathy

•Confusion

•Muscle Cramps

•Agitation

•Anorexia and nausea

•Hallucinations

•Seizures

•Coma

•Depressed reflexes

•Pseudobulbar palsy

•Hypothermia

•Death

135

Vasopressin antagonists

Antagonist Conivaptan Tolvaptan Lixivaptan Sitavaptan Mozavaptan

Receptors V1/V2 V2 V2 V2 V1/V2

V1/V2

selectivity

10:1 29:1 100:1 112:1 10:1

Route Iv, oral Oral Oral Oral Iv, oral

Half-life, hs 14-17 6-8 7-10 14-17 1-8

Indications HypoNa,

ADHF

HypoNa,

ADHF, PKD

HypoNa,

ADHF with

hypoNa

HypoNa,

ADHF,

cirrhosis

SIADH

Modified from Finley, Konstam, Udelson. Circulation 2008;118:410-421

Schrier RW et al. N Engl J Med 2006;355:2099-2112

EVEREST: Secondary Endpoints at Day 1

– 1.7

± 1.8

– 1.0

± 1.8

– 1.8

± 2.0

– 0.9

± 1.9

Both trials

P<0.001

Difference 0.7 kg 0.9 kg

Δ in

Dyspnea (% of pts with

baseline

dyspnea)

Trial A Trial B

Δ in BW (kg)

Tolvaptan Placebo Tolvaptan Placebo

Both trials

P<0.001

37 35 33 31

24 24 2523

1611 14

11

–2 –3 –2 –3

–20

0

20

40

60

80

Tolvaptan Placebo Tolvaptan Placebo(n=894) (n=915) (n=941) (n=914)

Improved

worsened

Markedly better

Moderately better

Minimally better

Worse

Gheorghiade et al. JAMA 2007;297:1332– 43

Controversial issues in heart failure Can we change the outcome...

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