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
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
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
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
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
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
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
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
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
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
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
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
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
**
Influence of Ejection Fraction on Cardiovascular Outcomesin a Broad Spectrum of Heart Failure Patients
Salomon SD Circulation 2005;112:3738-3744
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 %
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%
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)
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
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
“… 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
Mortality in the placebo arm of Val-HeFT by treatment group: 23-month mean follow-up
Courtesy Prof. JN Cohn