Cardio-Renal Syndrome in Acute Heart...
Transcript of Cardio-Renal Syndrome in Acute Heart...
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.