Transcript Relazione: Beta bloccaanti

9th International Symposium
Heart Failure & Co.
Milano, Istituto Clinico Humanitas
Lettura:
Nell’interpretazione della sindrome
cardio-renale: quale è il ruolo della
funzione renale dal punto di vista del
cardiologo?
Prof. Livio Dei Cas
Cattedra e U.O. di Cardiologia
Dipartimento di Medicina Sperimentale ed Applicata
Dipartimento Cardio-toracico
Università e Spedali Civili di Brescia
The Cardio-renal syndrome
Decreased cardiac
performance
Neurohormonal
activation, inflammation,
oxidative stress
Increased water
and Na+ retention
Hypertension
Decreased
cardiac output /
increased venous
pressure
Neurohormonal
activation,
inflammation,
oxidative stress
↓renal perfusion,
↑ renal venous pressure
Impaired
renal function
L Dei Cas, 1989
Cardio-renal syndrome: a definition
• Presence or development of renal dysfunction in
patients with cardiac dysfunction
– Chronic heart failure
– Acute heart failure
• Patients are volume overloaded and/or with low
cardiac output (dehydration must be excluded)
Cardio-renal syndrome
• Epidemiology
• Prognostic significance
• Mechanisms of renal damage
• Treatment
Cardio-renal syndrome
• Epidemiology
• Prognostic significance
• Mechanisms of renal damage
• Treatment
Prevalence of cardio-renal syndrome
33% of patients
with eCrCl <60
ml/min
GFR, ml/min/1.73 m2
Anavekar et al., New J Med 2004; 351:1285
60% of patients
with eCrCl <60
ml/min
GFR, ml/min/1.73 m2
Heywood et al., J Card Fail 2007; 13:422
Prevalence of worsening function
in acute heart failure
Gottlieb et al., J CardFail 2002; 8:136
Cardio-renal syndrome
• Epidemiology
• Prognostic significance
• Mechanisms of renal damage
• Treatment
Prognostic significance of cardio-renal
syndrome
• Patient at risk of cardiovascular events
• Chronic heart failure
• Acute heart failure
Prognostic significance of cardio-renal
syndrome
• Patient at risk of cardiovascular events
• Chronic heart failure
• Acute heart failure
Renal insufficiency as a predictor of cv
outcomes and the impact of ramipril: the
HOPE randomized trial
Mann et al., Ann Intern Med 2001; 134:629
Renal insufficiency as a predictor of cv
outcomes and the impact of ramipril: the
HOPE randomized trial
Mann et al., Ann Intern Med 2001; 134:629
Relation between Glomerular Filtration Rate and Outcome
after Myocardial Infarction with LV Dysfunction and/or
CHF and Serum Creatinine <2.5 mg/dl: VALIANT Trial
All Cause Mortality
CV Composite End Point
Anavekar, N. S. et al. N Engl J Med 2004;351:1285-1295
Hazard Ratio for Death From Any
Cause, According to eGFR at Baseline
Hazard ratio (95% CI) for
death from any cause
14
12
10
8
6
4
2
0
0
20
40
60
80
100
120
140
Estimated GFR (mL/min/1.73 m2)
Anavekar NS, et al. N Engl J Med. 2004;351:1285-1295.
Prognostic significance of cardio-renal
syndrome
• Patient at risk of cardiovascular events
• Chronic heart failure
• Acute heart failure
Freedom from Death of the Patients Assessed Before
Beta-blocker Treatment. Value of Renal Function
Serum creatinine
Glomerular filtration rate
Fraction of patients
1.0
1.0
86%
81%
0.8
0.8
72%
0.6
70%
0.6
0.4
0.4
P = 0.07
Creatinine < 1.2 mg% (n=99)
0.2
P = 0.003
GFR > 70 ml/hr (n=100)
GFR < 70 ml/hr (n=95)
0.2
Creatinine > 1.2 mg% (n=96)
0.0
0.0
0
6
12
18
Months
24
30
36
0
6
12
18
24
30
36
Months
Dei Cas et al., 2006
Proportional Relationship of eGFR With
Mortality in Cox-Adjusted Survival
Analysis: data from PRIME II
3.5
1.0
GFRc
LVEF
0.9
Proportion survival
Relative risk for mortality
4.0
3.0
2.5
2.0
1.5
1.0
0.8
0.7
59 – 76 mL/min
0.6
44 – 58 mL/min
0.5
0.5
0.4
0.0
GFRc (mL/min)
LVEF (%)
0.3
> 76 59 – 76 44 – 58 < 44
> 30 26 – 30 20 – 25 < 20
> 76 mL/min
< 44 mL/min
0
250
500 750 1,000 1,250
Days
Hillege HL, et al. Circulation. 2000;102:203-210.
Survival by Baseline GFR in SOLVD
(6630 patients)
Al-Ahmad et al., JACC 2001; 38:955
Renal Function as a Predictor of Outcome
in a Broad Spectrum of Patients With Heart
Failure. Results from CHARM
Low LVEF
Preserved LVEF
Hillege et al., Circulation. 2006;113:671-678
Prognostic significance of cardio-renal
syndrome
• Patient at risk of cardiovascular events
• Chronic heart failure
• Acute heart failure
Serum Creatinine at Discharge and Outcome in patients
discharged after an AHF Hospitalization
P=0.040
S-Creatinine ≤ 1.3 mg/dl
S-Creatinine >1.3 mg/dl
P=0.008
S-Creatinine ≤ 1.3 mg/dl
S-Creatinine >1.3 mg/dl
Dei Cas et al. in press
Variables Selected by Multivariable Analysis
for the Prediction of Mortality
HFSS
Age
v
Heart rate
v
SBP
v
Resp. Rate
v
LVEF
v
pVO2
v
BUN
v
v
v
v
s-Sodium
v
CAD
v
NYHA class
v
v
v
v
v
v
LBBB
Comorbidities
EFFECT ADHERE OPTIME-CHF
v
v
v
v
ADHERE: Risk Stratification for Inhospital
Mortality in the Validation Cohort
32,229 hospitalizations
BUN < 43 mg/dL
Mortality, 2.8%
BUN ≥ 43 mg/dL
Mortality, 8.3%
24,702 hospitalizations
6,697 hospitalizations
SBP
≥ 115 mmHg
Low risk
2.3% mortality
SBP
< 115 mmHg
Intermediate risk
5.7% mortality
SBP
≥ 115 mmHg
Intermediate risk
5.6% mortality
SBP
< 115 mmHg
15.3% mortality
1,862 hospitalizations
S-creatinine
< 2.75 mg/dL
Intermediate risk
13.2% mortality
S-creatinine
≥ 2.75 mg/dL
High risk
19.8% mortality
Fonarow GC, et al. JAMA. 2005;293:572-580.
Prognostic Significance of Worsening
Renal Function in Patients With ADHF
HF hospitalizations and
CV-mortality–free survival
CV-mortality–free survival
1.0
1.0
86%
0.8
55%
0.6
0.4
P < 0.001
Patients (%)
Patients (%)
0.8
28%
0.2
0.6
59%
0.4
P < 0.001
0.2
Δ creatinine < 25% and/or < 0.3 mg/dL
Δ creatinine ≥ 25% and ≥ 0.3 mg/dL
Δ creatinine < 25% and/or < 0.3 mg/dL
Δ creatinine ≥ 25% and ≥ 0.3 mg/dL
0.0
0.0
0
0
90 180 270 360 450 540 630 720
Days
Patients at risk
Absolute and percent s-Cr change:
< 0.3 or 25%
≥ 0.3 & 25%
211
107
143
64
92
36
90 180 270 360 450 540 630 720
Days
Patients at risk
Absolute s-Cr change:
55
19
36
14
< 0.3
≥ 0.3
184
134
125
82
79
49
46
27
33
21
Metra M, … Dei Cas Eur J Heart Fail. 2008;10:188-195.
Worsening Renal Function and outcome
Study
Inhospital patients
Krumholz (2000), n=1681
Smith (2003), n=412
Akhter (2004), n=480
Cowie (2006), n=299
Owan (2006), n=6052
Subtotal
Odds ratio (95% CI)
1.41 ( 1.10, 1.82)
1.73 ( 1.00, 2.98)
2.62 ( 1.66, 4.13)
1.71 ( 0.96, 3.05)
1.49 ( 1.30, 1.71)
1.61 ( 1.35, 1.93)
Outhospital patients
De Silva (2005), n=1216
Jose (2006), n=1854
Khan (2006), n=6535
Subtotal
1.44 ( 0.98, 2.09)
1.46 ( 1.06, 2.02)
1.79 ( 1.59, 2.02)
1.69 ( 1.48, 1.94)
Overall
1.62 ( 1.45, 1.82)
.1
.2
.5
lower risk for WRF
1
2
4
8
higher risk for WRF
Damman et al. J Card Fail 2007
Why is renal dysfunction an independent
prognostic factor in heart failure
• Need of higher diuretics doses
• Lower tolerance of life saving therapies (RAA
inhibitors)
• Anemia
• Neurohormonal & inflammatory activation
• Oxidative stress, endothelial dysfunction
• ???...
Chronic diuretic use and increase in mortality: a
retrospective analysis with propensity score methods
from DIG trial
All cause mortality
Heart failure mortality
Ahmed, A. et al. Eur Heart J 2006 27:1431-1439
Predictors of Worsening Renal Failure
Among 318 Patients Hospitalized for AHF
Results of Multivariable Analysis
Predictor
Odds ratio (95% CI)
P
History of chronic kidney disease
1.84 (1.04 – 3.27)
< 0.0001
IV furosemide dose > 100 mg/d
2.18 (1.27 – 3.73)
0.004
NYHA class (IV vs. III)
2.07 (1.24 – 3.45)
0.005
LV ejection fraction < 30%
1.66 (1.01 – 2.75)
0.047
Metra M, … Dei Cas Eur J Heart Fail. 2008;10:188-195.
Prognostic significance of intolerance to ACE
inhibitors for Circulatory-Renal limitations
(CRLimit)
1.0 –
0.9 –
149
Event-free survival
0.8 –
120
90
0.7 –
0.6 –
46
30
0.5 –
22
32
31
10
CR Limit, no inotropes, n=45
16
0.4 –
12
7
5
3
1
CR Limit, on inotropes, n=14
0.3 –
3
0.2 –
CRLimit vs. on ACE: HR, 2.8 (1.8 to 4.4; p<0.0001)
adjusted for age, SBP, creatinine…
Inotropes vs. no inotropes: p=0.0002
0.1 –
0.0 –I
0
On ACEi, n=173
66
I
2
I
4
I
6
I
I
I
I
I
I
8
10
12
14
16
18
Months from hospitalization
I
20
I
22
I
24
I
26
Kittleson, M. et al. J Am Coll Cardiol 2003;41:2029-2035
Impact of congestive heart failure, chronic kidney
disease, and anemia on survival in the Medicare
population. An analysis of 1,136,201 patients
Herzog et al. J Cardiac Fail 2004
Cardio-renal syndrome
• Epidemiology
• Prognostic significance
• Mechanisms of renal damage
• Treatment
Increased Central Venous Pressure Is Associated With
Impaired Renal Function in Patients With CV Disease:
Curvilinear Relationship Between CVP and eGFR According to Different
Cardiac Index Values
P=0.0217
Solid line = cardiac index <2.5 l/min/m2;
dashed line = cardiac index 2.5 to 3.2 l/min/m2;
dotted line = cardiac index >3.2 l/min/m2.
Central venous pressure
Damman, K. et al. J Am Coll Cardiol 2009;53:582-588
Determinants of Glomerular filtration rate in
patients with heart failure
Variable
Univariate analysis
Partial R P value
Multivariate analysis
Partial R
P value
Age
-0.338
0.001
Gender
-0.312
0.003
Renal blood flow
0.888
<0.001
0.938
<0.001
Filtration fraction
0.573
<0.001
0.786
<0.001
Urinary albumin excretion
-0.306
0.005
Mean BP
0.306
0.005
Hemoglobin
0.312
0.004
-0.520
<0.001
NT-proBNP
-0.533
<0.001
Plasma renin activity
-0.501
<0.001
sVCAM-1
-0.279
0.010
Nox
-0.276
0.011
ADMA
-0.168
0.126
CRP
-0.016
0.88
Damman et al. Clin Res Cardiol 2009; 98:121
Regulation of Intraglomerular
Pressure
Role of Angiotensin II in the
Pathogenesis of Renal Disease
TGF-
Ang II
Hypertension
PG, NO
Afferent
dilation
Efferent
constriction
Glomerular hypertension
Proteinuria
 Extracellular matrix
Interstitial fibrosis
Focal segmental glomerulosclerosis
PG = prostaglandin; NO = nitric oxide.
High Prevalence of Microalbuminuria in
Chronic Heart Failure Patients
Van de Wall et al., J Card Fail 2005; 11:602
Neurohormonal markers in patients with
heart failure with and without
microalbuminuria
Van de Wall et al., J Card Fail 2005; 11:602
Relation between Renal Blood Flow and
Urinary Albumin Excretion in patients with
Heart Failure
Damman et al. Clin Res Cardiol 2009; 98:121
Cardio-renal interactions in heart failure
Heart failure
↓renal blood flow
Albuminuria
↓Glomerular filtration rate
↑venous
congestion
↑diuretics
Worsening
renal function
Salt water
retention
anemia
Treatment and cardio-renal
syndrome
 Inotropic agents
 Vasodilators
 Vasopressin antagonists
 Adenosine antagonists
 Ultrafiltration
 RAA inhibitors
A Meta-Analysis of the Use of
Dopamine in Acute Renal Failure
Holmes CL, et al. Chest. 2003;123:1266-1275.
Levosimendan Improves Renal Function in
Patients With ACHF Awaiting HTx
2.4
Levosimendan
2.4
2.2
Creatinine (mg/dL)
Creatinine (mg/dL)
2.2
Controls
2.0
1.8
1.6
1.4
1.2
2.0
1.8
1.6
1.4
1.2
1.92  1.60
1.0
1.91  1.90
1.0
Baseline
3 months
Baseline
3 months
Zemljic G, et al. J Card Fail. 2007;13:417-421.
Risk of Worsening Renal Function with Nesiritide in
Patients with ADHF
Nesiritide better
Nesiritide worse
A
B
C
D
E
F
0
0.5
1
1.5
2
2.5
Risk ratio (95% CI)
A, nesiritide <0.03 μg/kg/min vs non-inotrope based controls; B, nesiritide <0.03 μg/kg/min vs all controls;
nesiritide <0.015 μg/kg/min vs non-inotrope based controls; C,nesiritide <0.015 μg/kg/min vs non-inotrope
based controls; D, nesiritide <0.015 μg/kg/min vs all controls; E, nesiritide <0.06 μg/kg/min vs non-inotrope
based controls; F, nesiritide <0.06 μg/kg/min vs all controls
Sackner-Bernstein et al., Circulation 2005; 111:1487
EVEREST: Changes in Renal Function
with Tolvaptan
8
6
BUN
(mg/dL)
Inpatie
nt
Outpatient
4
2
0
-2
-4
1980
1987
Day
1
1940
1951
Day 7 or
Discharge
1828
1820
14
1687
1674
1433
1434
1220
1247
1001
1014
851
853
713
706
558 TLV
559 PLC
8
16
24
32
40
48
56
0.6
Tolvaptan
Placebo
0.4
Serum Cr
(mg/dL)
0.2
0.0
-0.2
-0.4
1912
1925
Day
1
1864
1886
Day 7 or
Discharge
Inpatient
1755 1620
1761 1614
1381
1382
1168
1203
955
978
813
821
675
677
525 TLV
537 PLC
14
16
24
32
40
48
56
8
After Discharge (wk)
EVEREST: Tolvaptan in ADHF
1.0
All-cause mortality
Proportion surviving
0.9
Tolvaptan
Placebo
0.8
0.7
0.6
0.5
Est. 1-year mortality, 25 vs. 26%; HR 0.98
0.4
0.3
Log-rank test: P = 0.76
Peto–Peto–Wilcoxon Test: P = 0.68
Stratified Peto–Peto–Wilcoxon Test: P = 0.68
0.2
0.1
0.0
0
3
6
9
12
15
18
21
24
Months in study
Konstam MA, et al. JAMA. 2007;297:1319-1331.
Effects of adenosine on renal haemodynamics
Renal blood flow
Renal vascular resistance
Elkayam, U. et al. J Am Coll Cardiol 1998;32:211-215
Change in Urine Volume and
renal function with Furosemide and Adenosine
antagonist (BG9719)
20
BG9719
Δ GFR1 – 8 hours (%)
15
10
BG9719 +
Furosemide
5
0
−5
Placebo
−10
−15
Furosemide
alone
−20
−25
0
500
1000
1500
2000
2500
Urine output0 – 8 hours (mL)
Day 1 – Baseline
Gottlieb SS, et al. Circulation. 2002;105:1348-1353.
PROTECT Pilot
Mean change in serum creatinine (mg/dL)
Change in Serum Creatinine
0.35
0.3
Placebo (n = 78)
10 mg (n = 74)
20 mg (n = 75)
30 mg (n = 74)
0.25
0.2
0.15
0.1
0.05
0
−0.05
Day 2
Day 3
Day 7
Day 14
*Nominal P < 0.05 for dose-related trend at Day 14
Cotter G, et al. J Card Fail. 2008;14:631-640.
Ultrafiltration in Advanced HF
Clinical benefits:
 ↓ peripheral and pulmonary
edema
 ↓ PA pressures
 ↓ neurohormonal activation
 ↑ subsequent diuretic efficacy
 Persistent effects for several
months
Freedom From Heart Failure
Rehospitalization in UNLOAD
Patients free from
rehospitalization (%)
100
Ultrafiltration arm (16 events)
80
60
Standard care arm (28 events)
40
P = 0.037
20
0
0
10
20
30
40
50
Days
60
70
80
90
Number of patients at risk
Ultrafiltration
88
85
Standard care
86
83
80
77
77
74
75
66
70
59
66
58
64
52
45
41
72
63
Costanzo MR, et al. J Am Coll Cardiol. 2007;49:675-683.