Cardio-Renal Syndrome in Acute Heart Failure:

Target for Therapy

Marvin A. Konstam, M.D.

Research support and/or consulting relevant to this lecture:

Merck, Otsuka, Johnson & Johnson; Amgen; Cardiokine

“Heart” Failure: A Cardio-Renal-Vascular Syndrome

Compliance and Contractilty

HEART

Functional

Incapacity

Systemic

Congestion

Pulmonary

Congestion

GFR and Survival: SOLVD

Al-Ahmad A et al. JACC. 2001;38:955-62.

0.5

0.9

0.9

0.9

0.9

1.0

0 1000 2000

GFR >75

Follow-up (days)

% s

urv

ival

GFR 60-75

GFR <60

Association Between eGFR (CKD-EPI) and All-Cause Mortality in Patients with HF, Grouped by LVEF

McAlister F A et al. Circ Heart Fail 2012;5:309-314

Predictors of Renal Impairment During ARB

Treatment: HEAAL

Kiernan M et al. Eur J HF, 2012

Impact of Incident Adverse Events on Outcomes:

HEAAL

Kidney Impairment Hyperkalemia Hypotension

HR

(95% CI)

p-value HR

(95% CI)

p-

value

HR

(95% CI)

p-value

Death 2.36

(2.07, 2.70)

<0.001 1.77

(1.47, 2.13)

<0.001 2.01

(1.69, 2.38)

<0.001

First

Hospitalization

1.61

(1.40, 1.84)

<0.001 1.77 (1.47,

2.14)

<0.001 1.37

(1.14, 1365)

<0.001

Death or First

Hospitalization

1.63

(1.44, 1.85)

<0.001 1.72 (1.44,

2.05)

<0.001 1.32

(1.11, 1.56)

0.002

*Model includes variables corresponding to age, gender, aldosterone blocker use, associated

baseline laboratory value, and ACEi indicators.

Kiernan M et al. Eur J HF, 2012

ADHERE CART: Predictors of In-Hospital Mortality

SYS BP 115n = 24,933

SYS BP 115n = 7150

6.41%

n = 5102

15.28%

n = 2048

21.94%

n = 62012.42%

n = 1425

5.49%

n = 4099

2.14%

n = 20,834

BUN 43N = 33,324

Greater thanLess than

2.68%

n = 25,122

8.98%

n = 7202

Cr 2.752045

Highest to Lowest Risk Cohort

OR 12.9 (95% CI 10.4-15.9)

Fonarow GC et al. JAMA 2005; 293:572-80.

Baseline Kidney Function as Predictor of CV

Mortality/HF Hospitalization

10

BUN

2nd vs 1st

quartile

3rd vs 1st

quartile

4th vs 1st

quartile

3 months1.15

(0.90-1.46)

1.25

(0.99-1.57)

1.50

(1.19-1.88)

Overall1.08

(0.91-1.27)

1.20

(1.02-1.41)

1.60

(1.36-1.87)

Adjusted for: Age, Race, Region, HF hospitalization, Previous MI, Diabetes, Dyspnea, NYHA

Class, ACE/ARB, Beta Blockers, Systolic BP, EF, Serum Sodium, BNP, Pro-BNP, QRS Duration, and

Atrial Fibrillation on admissionGheorghiade M, et al: ESC, 2008

2nd vs 1st

quartile

3rd vs 1st

quartile

4th vs 1st

quartile

3-months1.32

(1.05-1.65)

1.55

(1.21-1.98)

1.68

(1.32-2.13)

Overall1.10

(0.95-1.28)

1.37

(1.16-1.61)

1.50

(1.28-1.76)

Creatinine

Post-discharge Kidney Function Change and Outcomes

11

BUN < 25% increase

N = 2776 (79.3%)

BUN ≥ 25% increase

N = 725 (20.7%)

Adjusted HR

(95% CI)

Death 542 (19.5%) 195 (26.9%) 1.25 (1.05-1.49)

CV Death/HF Hospitalization 1045 (37.6%) 325 (44.8%) 1.17 (1.02-1.34)

Cr < 25% increase

N = 3159 (90.2%)

Cr ≥ 25% increase

N = 345 (9.8%)

Adjusted HR

(95% CI)

Death 636 (20.1%) 103 (29.9%) 1.37 (1.09-1.73)

CV Death/HF Hospitalization 1203 (38.1%) 168 (48.7%) 1.29 (1.08-1.55)

BUN/ Cr < 25%

increase

N = 2852 (81.5%)

BUN/Cr ≥ 25% increase

N = 648 (18.5%)

Adjusted HR

(95% CI)

Death 563 (19.7%) 174 (26.9%) 1.30 (1.08-1.57)

CV Death/HF Hospitalization 1097 (38.5%) 272 (42.0%) 1.05 (0.91-1.21)

eGFR < 25% decrease

N = 3229 (92.2%)

eGFR ≥ 25% decrease

N = 273 (7.8%)

Adjusted HR

(95% CI)

Death 649 (20.1%) 89 (32.6%) 1.49 (1.16-1.91)

CV Death/HF Hospitalization 1233 (38.2% 137 (50.2%) 1.31 (1.08-1.59)

BUN

Cr

BUN/Cr

eGFR

Gheorghiade M, et al: ESC, 2008

HF

KidneyInjury

↓GFR

Treatment

↓Survival

HF

KidneyInjury

↓GFR

RASInhibition

↓Survival

A B

Possible Mechanisms Linking Renal Function and Survival in Heart Failure

Konstam MA. Circ Heart Fail. 2011 4(6):677-9.

Right HeartDysfunction

Left HeartDysfunction

Ventricular Shift

+Pericardial Constraint

LVEDP

CVP

Vasopressin

SVCO

RAAS ET-1SNS

Adenosine

NP NOKinninProstacy

clin

Vasoconstriction & Sodium + Water Retention

Vasodilation and Natriureisis

Inflammation

Acute Kidney Injury

NSAIDs RASACE-IARB

Contrast

Renal Vein Pressure

Decreased Renal Perfusion / Ischemia

InterstialEdema

Down Regulation NP Receptors

Intrinsic Renal Disease

RAAS and SNS response overwhelms NP and NO response

Kiernan MS, Udelson JE, Sarnak M, Konstam MA: Cardiorenal syndrome UpToDate, 2011

Cardio-Renal Mechanisms in Acute Heart Failure

Figure 1. Admission-to-discharge percentage change in GFR grouped by presence or absence of hemoconcentration.

Testani J M et al. Circulation 2010;122:265-272

Copyright © American Heart Association

Renal Vein Pressure and Function in Canine Kidney

BUN

1.8

2.1

2.4

2.7

0 7 14 21 28 35 42 49 56 63 70

mg

/dL

Urine output

0

5

10

15

20

0 7 14 21 28 35 42 49 56 63 70

Time (min)

dro

ps

/min

Renal vein pressure

0

10

20

30

0 7 14 21 28 35 42 49 56 63 70

mm

Hg

Adapted from Wencker D, Curr HF Reports 2007;4:134-8;

Winton FR. J Physiol 1931;72:49-61 & 73:151-12

Renal Function Tends to Improve in Patients

with RV Dysfunction

Testani JM et al. Am J Cardiol 2010;105:511–516

Diuretic Resistance in Heart Failure and Kidney Failure

Ellison DH. Cardiology 2001; 96:132–143

All Rights Reserved, Duke Medicine 2007

HF Network 1.0 HF Network 2.0

DOSE TrialPatients' Global Assessment of Symptoms during the 72-Hour Study-Treatment Period.

Felker GM et al. N Engl J Med 2011;364:797-805.

Furosemide Dosing and Renal Function: DOSE Trial

Felker GM et al. N Engl J Med 2011;364:797-805.

Safety End Points: Change in Serum

Creatinine

All Rights Reserved, Duke Medicine 2007

CARRESS-HF

• Randomized trial to evaluate the

effects of ultrafiltration vs. stepped

pharmacologic care in ADHF with

cardiorenal syndrome

• Primary endpoint:

– Change in serum creatinine and

weight assessed at 96 hrs

considered together as a

bivariate outcome

Role of Low-Dose DopaminePatients with AHF(n=60); post 40 mg furosemide bolus

HDF = Furosemide 20mg/hr

LDFD = Furosemide 5mg/hr + Dopamine 5μg·kg-1·min-1

Giamouzis G, et al, J Cardiac Fail 2010;16:922-930

All Rights Reserved, Duke Medicine 2007

ROSE - AHF

• Population: Acute heart failure with renal dysfunction

• Intervention: Three-arm trial comparing low-dose dopamine vs.

placebo and low-dose nesiritide vs. placebo

• Study Design: Randomized, double-blind, placebo-controlled trial

to evaluate 1) low-dose dopamine and 2) low-dose nesiritide for

enhancing renal function in patients with acute heart failure and

renal dysfunction

• Primary endpoints:

– Safety: change in Cystatin C from randomization to 72 hours

– Efficacy: cumulative urinary volume at 72 hours

Distal Tubule

Proximal tubule

Improves

renal

function

Promotes K+

neutral

natriuresis

Afferent Arteriole

3 Renal Sites of Action of A1 Adenosine Antagonists

1

2

3

Effects of Blockade of Renal A1 Adenosine Receptors

-25

-15

-5

5

15

0 500 1000 1500 2000 2500

Renal OutputUrine Volume ( mL) (0-8 hours - chg -base)

Ren

al F

un

cti

on

(%ch

an

ge

in C

rCl) (

1-8

ho

urs

)

Furosemide

Placebo

BG9719 +Furosemide

BG9719 Alone

BG9719 prevents reduction of renal function caused by diuretic therapy via

interruption of TGFand augments natriuresis via effect on tubules

A1 Adenosine Antagonists in CHF

(Gottlieb et al, Circulation 2002)

N = 31

BG9719 dose 0.75 ugm/ml

All patients on ACEi

INVESTIGATIONAL

51,2

12,7

44,5

11,1

0

15

30

45

60

PROTECT

• Moderate or marked dyspnea improvement at 24

and 48 hours: 51.2% with rolofylline vs. 44.5% with

placebo

• Death by 7 days: 1.7% vs. 2.1%

• HF readmission by 7 days: 0.4% vs. 0.6%

• Persistent renal impairment: 12.7% vs. 11.1%

Trial design: Patients with AHF were randomized in a double-blind manner to rolofylline 30 mg/day (n =

1,356) or placebo (n = 677). Treatment was administered as a 4-hour daily infusion and repeated for 3

days.

Results

Conclusions

• Among patients with acute heart failure, composite

outcomes were similar with rolofylline vs. placebo

• Due to lack of efficacy, research on rolofylline has

been discontinued by the study sponsor

Presented by Dr. Marco Metra at ESC 2009

(p = NS)

(p = NS)

Rolofylline Placebo

%

Dyspnea

improvement at 24 &

48 hours

Persistent renal

impairment

INVESTIGATIONAL

Arginine Vasopressin

V1a Blood vessels

Myocardium

V2 Renal tubules

Tolvaptan

0

1

2

3

4

Median Plasma AVP (pg/mL) in

SOLVD Trial1

Control Prevention Treatment

(1.4-2.3) (1.7-3.0) (2.3-4.4)

Francis et al. Circulation 1990;82:1724-1729.

Effects of Tolvaptan and Furosemide on

GFR, ERPF, and RBF

-15

-10

-5

0

5

10

GFR (mL/min) ERPF (mL/min) RBF (mL/min)

TLV

FURO

% C

ha

ng

e v

s P

lac

eb

o

*

*

*

**

* P < 0.05 vs. Placebo; **P < 0.001 vs. PlaceboBurnett et al, 2003

Secondary Endpoints: 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

INVESTIGATIONAL

All-Cause Mortality

TLV

PLC

Peto-Peto Wilcoxon Test: P=0.68

TLV 30 mg

PLACEBO

Pro

po

rtio

n A

live

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Months In Study

0 3 6 9 12 15 18 21 24

2072 1812 1446 1112 859 589 404 239 97

2061 1781 1440 1109 840 580 400 233 95

HR 0.98; 95%CI (.87-1.11)

Meets criteria for non-inferiority

CV Mortality or HF

Hospitalization

Peto-Peto Wilcoxon Test: P=0.55

TLV

PLC

Pro

po

rtio

n W

ith

ou

t E

ve

nt

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 3 6 9 12 15 18 21 24

2072 1562 1146 834 607 396 271 149 58

2061 1532 1137 819 597 385 255 143 55

HR 1.04; 95%CI (.95-1.14)

TLV 30 mg

PLACEBO

Months In Study

Primary End Points

Median follow-up: 9.9 mos

OutpatientInpatient

Changes in Renal Function

BUN

(mg/dL)

Serum Cr

(mg/dL)

-0.4

-0.2

0.0

0.2

0.4

0.6

Day1

Day 7 orDischarge

1 4 8 16 24 32 40 48 56

19121925

18641886

17551761

16201614

13811382

11681203

955978

813821

675677

525537

TLVPLC

-4

-2

0

2

4

6

8

Day1

Day 7 orDischarge

1 4 8 16 24 32 40 48 56

TLVPLC

19801987

18281820

16871674

14331434

12201247

10011014

851853

713706

558559

19401951

Tolvaptan

Placebo

After Discharge (wk)Inpatient

INVESTIGATIONAL

SECRET of CHF TRIALThe Study to Evaluate Challenging

REsponders to Therapies for

deCongestion in Heart Failure Trial

Multi-center, randomized, double-blind, placebo-controlled

trial to assess the effects of vasopressin receptor

antagonism (30 mg q.d. of tolvaptan) on dyspnea in

patients hospitalized for worsening HF, who have any of:

– Hyponatremia

– Renal insufficiency

– Inadequate initial diuretic response

The Cardio-Renal Syndrome in Acute Heart Failure:

Conclusions

• Abnormal and worsening renal function are adverse prognostic markers.

• Nevertheless, WRF should not unduly deter use of evidence-based Rx.

• Complex mechanisms contribute to renal impairment in HF

– Reduced cardiac output and renal hypoperfusion

– Elevated CVP and renal venous congestion

– Neurohormonal activation

• CRS contributes to diuretic resistance.

• Conversely, volume correction impacts renal function in complex ways

• Pharmacologic approaches to renal impairment have promise, but have

not yet yielded clear benefit.

• Renal injury and dysfunction remain important treatment targets.