e. gronda, md, fesc cardiology division cardiovascular department irccs, h s. giuseppe, multimedica,...
TRANSCRIPT
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E. Gronda, MD, FESC
Cardiology Division
Cardiovascular Department
IRCCS, H S. Giuseppe, MultiMedica, Group
S.S. Giovanni - Milano
“Can Neurohormonal Antagonists Help?”
Session V
APPROACHES to the PREVENTION of SUDDEN DEATH
Eleventh International SymposiumHeart Failure & Co.
Reggia di Caserta 29-30 April 2011
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Sudden CardiacDeath 44%
HF progression38%
Other CV death
SCD is the leading cause of CV death (mortality by cause in control groups of 39 selected HF trials)
P. Kress, PhD Medtronic 2004
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Why Left Ventricular Remodelling is an Independent Predictor of Malignant Ventricular Arrhythmia?
Pathologic Remodeling = Electrical Remodeling
• LV Dilation
• Myocardial stretch
Ionic Channels Function Mutations: Na+ = prolonged depolarization, K+ = QT
dispersion, Ca++ ,Mg++= Increased Authomaticity
Impact on ACTION Potential • Decreased refractoriness time,
Increased vulnerable time
Disruption of Myocytes Syncitial
Integrity
Activation of the RAAS
Activation of SNS
Aldosterone Synthesis in the Myocardium
Fibrosis
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Electrical Instability in the Failing Heart
● QT interval dispersion
Pye M Br Heart J 1994;71:511-514Zaidi M European Heart Journal (1997) 18, 1129-1134
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ACE Inhibition Prevents Remodelling:SOLVD – Echocardiographic Substudy
220
210
200
190
4 120
Month
En
d-d
iasto
lic V
olu
me (
cc)
P = 0.025 160
155
150
140
4 120
Month
P = 0.019
145En
d-s
ysto
lic V
olu
me (
cc) 0.40
0.30
0.20
0.10
4 120
Month
Eje
cti
on
Fra
cti
on
0
Greenberg B et al. Circulation 1995
Placebo n =130 130 142
Enalapril n = 128 127 137
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IN SAVE STUDY LV DILATATION IN DIASTOLE (LEFT) AND SYSTOLE (RIGHT) INCREASED SIGNIFICANTLY FROM 1 TO 2 YEARS AFTER MI
Sutton St J Circulation. 1997;96:3294-3299
A CLEAR RELATION WAS PRESENT
BETWEEN LV SIZE AND VT
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ACE-Ireduce mortality due to SCD by 13%
0.0 0.5 1.0 1.5 2.0
CONSENSUS
SOLVD Treat.
SOLVD Prev.
SAVE
AIRE
TRACE
Pooled
N = 253
N = 2569
N = 4228
N = 2231
N = 2006
N = 1749
RR 0.87 (0.77-0.99)
P. Kress, PhD Medtronic 2004
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The Biomechanical Model of Heart Failure:Therapy that favorably affects the natural history of CHF prevents or
partially reverses either of the two DCM pathophysiological processes
SystolicDysfunction
< > Remodeling/Pathological HTY
ACEIs
12 monthmortality by 17%
b-blockers
mortality by 32% (cumulative by 44%)
Adapted from Mann DL, Bristow MR Circulation, 2005
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Pharmacogenetic Interaction Between the ACE Deletion Polymorphism and Beta-blocker Therapy in CHF
0,00
0,20
0,40
0,60
0,80
1,00
0 6 12 18 24 30
Months of follow up
Tra
nspl
ant-
free
sur
viva
l
0,00
0,20
0,40
0,60
0,80
1,00
0 6 12 18 24 30
Months of follow up
ACE II ACE ID ACE DD ACE II ACE ID ACE DD
P=0.005 P=0.073
Patients not on beta-blockers(n=208)
Patients on beta-blockers(n=120)
McNamara et al., Circulation 2001; 103:1644
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Biological/Physiological Responses Mediated by Postjunctional Adrenergic Receptors in the Human Heart
Mann, Bristow Circulation 2005;111;2837-2849
Biological Response Adrenergic Receptor
Beneficial effects
Positive inotropic response ß1, ß2 >>1C
Positive chronotropic response ß1, ß2
Vasodilation ß1 (epicardial), ß2 (small vessel)
Harmful effects
Cardiac myocyte growth ß1> ß2 >>1C
Fibroblast hyperplasia ß2
Myocyte damage/myopathy ß1> ß2, 1C
Fetal gene induction ß1
Myocyte apoptosis ß1
Proarrhythmia ß1, ß2, 1C
Vasoconstriction ß1C
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MYOCARDIAL GENE EXPRESSION IN DILATED CARDIOMYOPATHYTREATED WITH BETA-BLOCKING AGENTS
,
BRIAN D.L et al. N Engl J Med 2002;346:1357-65 (modified)
-20
-15
-10
-5
0
5
10
15
Ch
ang
e in
Gen
e E
xpre
ssio
n
(mo
lecu
les
mR
NA
x10(
-5)/
mg
to
tal
RN
A
Placebo response (n=9)
B-blocker response (n=26)
Fetal Phenotype
Adult Phenotype
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Carvedilol (n=261)Placebo(n=81)
0
1
2
3
4
5
6
7
8
LV
EF
(EF
un
its)
MOCHA*
P<.001
†
†
†
Patients receiving diuretics, ACE inhibitors, ± digoxin; follow-up 6 months*Multicenter Oral Carvedilol Heart Failure Assessment.
Adapted from Bristow et al. Circulation. 1996;94:2807-2816.
Effect of Carvedilol on LVEF
25 mg bid6.25 mg bid
12.5 mg bid
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Carvedilol trials: MOCHA
Six-month crude mortality deaths/randomized pt X 100
16 -
14 -
12 -
10 -
8 -
6 -
4 -
2 -
0 -
Placebo 6.25 mg 12.5 mg 25 mg bid bid bid
15.5
6.06.7
1.1
****
* p <.05 ** p <.07*** p <.001
%
Bristow et al. Carvedilol produces dose-related improvements in left ventricular functionand survival in subjects with chronic heart failure. Circulation 1996;94:2807-2816
**
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Influence of Ejection Fraction on Cardiovascular Outcomesin a Broad Spectrum of Heart Failure Patients
Salomon SD Circulation 2005;112:3738-3744
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Benefit on SCD of Beta - Adrenergic Blocking Agents
SCD - Treated pts
MERIT-HF 3.6%CIBIS II 4%US Carvedilol 1.7%MOCHA 2.3%
MERIT-HF
Lancet 1999; 353: 2001-7
• AVERAGE SD decrease 33%
LV EF
28 %
37 %
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Drug Effects on Total and Sudden Cardiac Death Risks1
Patients Randomized
LVEF Drug Tested
ACE-I (% of Pts)
Total Death Risk
Reduction (p-value)
SCD Risk Reduction
(p-value)
TRACE 2,606 <36% Trandolapril 100% -22% (<0.001) -24% (<0.03)
HOPE 9.297 N11% on ominallly
>40%
Ramipril 100% -26% (<0.005)
-38% (<0.02)
RALES 1,663 25% Spironolactone 95% -30% (<0.001) -29% (<0.02)
CIBIS-II 2,647 28% Bisoprolol 96% -34% (<0.0001)
-44% (<0.001)
MERIT-HF 3,991 28% Metoprolol 96% -34% (< 0.00009)
-41% (<0.0002)
COPERNICUS 2,289 20% Carvedilol 97% -35% (< 0.001)
Not reported
SOLVD-T 2,569 25% Enalapril 100% -16% (0.004) -10% (NS)
SOLVD-P 4,228 28% Enalapril 100% -8% (0.3) -7% (NS)
1 Pacifico A, Henry P. J Cardiovasc Electrophysiol, Vol. 14, pp. 764-775, July 2003.
Neurohormonal Interventions in Heart Failure
11% on β Blocker
Total Death Risk Reduction 52%
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EPHESUS: New subgroup analysis
Pitt B et al. Am J Cardiol. 2006;97(suppl):26F-33F.
N = 6632 with post-MI LVSD, mean follow-up 16 months
Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study
History of hypertensionAll-cause mortalityCV mortality/hospitalizationSudden cardiac death
History of diabetesAll-cause mortalityCV mortality/hospitalizationSudden cardiac death
LVEF ≤30%All-cause mortalityCV mortality/hospitalizationSudden cardiac death
P
0.0010.0020.022
0.1270.03
0.641
0.0120.001
0.01
0.2 1.0 1.2 1.8
Eplerenone better Placebo better
1.4 1.60.4 0.6 0.8Odds ratio (95% Cl)
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Eplerenonebetter
Hazard ratio
placebo better
0.6 0.8 1.0 1.2 1.4
p-value fortreatment interaction
P=0.04
N Eng J Med 2003; 348:1309-1321
ACE I / ARB and Beta Blockers
• None
• ACE I /ARB or Beta Blockers
• Boths
EPHESUS Study
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Ivabradine in heart failure: no paradigm SHIFT…yet
Teerlink JR. Lancet August 29, 2010 DOI:10.1016/S0140-6736(10)61314-1
NYHA Class II 52%: ivabradine 1605 (50%) pcb 1618 (50%), mean age 60 y, IHD 67% Mean LVEF% 29More than 70% of pts were not in optimaized β – blocker therapy
NYHA Class III 95%: bisoprolol 304 (95%) pcb 305 (95%) mean age 68 y, IHD 56%, Mean LVEF% 25
17.3% of pts received 1.25 mg/d, 29.5% received 2.5 mg, 2% received 3.75 mg, and 51% received 5 mg
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“… the dose of a β-blocker should be individualized in clinical practice.”
“ in MERIT II study.. there were no significant predictors differentiating the high-dose and low dose groups. ….
…An uptitration schedule for β-blocker dosing is therefore essential, as tolerated, to achieve the positive β-blocker mortality benefits observed in the completed mortality trials in patients with HF.”
Bristow MR et al Journal of Cardiac Failure Vol. 9 No. 6 2003
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Mortality in the placebo arm of Val-HeFT by treatment group: 23-month mean follow-up
Courtesy Prof. JN Cohn