1. “Can Neurohormonal Antagonists Help?”
             
Eleventh International Symposium
Heart Failure & Co.
Reggia di Caserta April 2011
Session V
APPROACHES to the PREVENTION of SUDDEN DEATH
“Can Neurohormonal Antagonists Help?”
E. Gronda, MD, FESC
Cardiology Division
Cardiovascular Department
IRCCS, H S. Giuseppe, MultiMedica, Group
S.S. Giovanni - Milano

2. SCD is the leading cause of CV death (mortality by cause in control groups of 39 selected HF trials)
Other CV death
Sudden Cardiac Death 44%
HF progression 38%
P. Kress, PhD
Medtronic 2004

3. Disruption of Myocytes Syncitial Integrity
Why Left Ventricular Remodelling is an Independent Predictor of Malignant Ventricular Arrhythmia?
Activation
of SNS
LV Dilation
Myocardial
stretch
Activation of the RAAS
Aldosterone Synthesis in the Myocardium
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
Fibrosis
Pathologic Remodeling =
Electrical Remodeling

4. Electrical Instability in the Failing Heart
QT interval dispersion
Pye M Br Heart J 1994;71:
Zaidi M European Heart Journal (1997) 18,

5. End-diastolic Volume (cc) End-systolic Volume (cc)
ACE Inhibition Prevents Remodelling: SOLVD – Echocardiographic Substudy
220
210
200
190 4 12
Month
End-diastolic Volume (cc)
P = 0.
025
160
155
150
140
P = 0.019
145
End-systolic Volume (cc)
0.40
0.30
0.20
0.10
Ejection Fraction HG
Placebo n =
Enalapril n =
Greenberg B et al. Circulation 1995 5

6. A CLEAR RELATION WAS PRESENT BETWEEN LV SIZE AND VT
IN SAVE STUDY LV DILATATION IN DIASTOLE (LEFT) AND SYSTOLE (RIGHT) INCREASED SIGNIFICANTLY FROM 1 TO 2 YEARS AFTER MI
A CLEAR RELATION WAS PRESENT
BETWEEN LV SIZE AND VT
Sutton St J Circulation. 1997;96:

7. ACE-I reduce mortality due to SCD by 13%
P. Kress, PhD
Medtronic 2004

8. 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
Systolic
Dysfunction
Remodeling/
Pathological HTY
<
>
b-blockers
 mortality by 32%
(cumulative  by 44%)
ACEIs
 12 month
mortality by 17%
Adapted from Mann DL, Bristow MR Circulation, 2005

9. Patients not on beta-blockers Patients on beta-blockers
Pharmacogenetic Interaction Between the ACE Deletion Polymorphism and Beta-blocker Therapy in CHF
Patients not on beta-blockers
(n=208)
Patients on beta-blockers
(n=120)
1,00
1,00
0,80
0,80
0,60
0,60
Transplant-free survival
0,40
0,40
P=0.005
P=0.073
0,20
0,20
ACE II
ACE ID
ACE DD
ACE II
ACE ID
ACE DD
0,00
0,00 6 12 18 24 30 6 12 18 24 30
Months of follow up
Months of follow up
McNamara et al., Circulation 2001; 103:1644

10. Mann, Bristow Circulation 2005;111;2837-2849
Biological/Physiological Responses Mediated by Postjunctional Adrenergic Receptors in the Human Heart
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
Mann, Bristow Circulation 2005;111;

11. MYOCARDIAL GENE EXPRESSION IN DILATED CARDIOMYOPATHY
TREATED WITH BETA-BLOCKING AGENTS ,
Adult Phenotype
Fetal Phenotype
BRIAN D.L et al. N Engl J Med 2002;346: (modified)

12. Effect of Carvedilol on LVEF
MOCHA* † 1 2 3 4 5 6 7 8
P<.001 † †
LVEF (EF units)
Therefore, the dose of a β-
blocker should be individualized in clinical practice. Although
the low-dose group tended to be older and to have
reduced cardiac function, lower BP, and a higher mortality
rate compared with the high-dose group, there were no significant
predictors differentiating the high-dose and lowdose
groups. Thus there is no value in attempting to draw
conclusions about dose response in a clinical study in which
flexible dosing is allowed. Such conclusions can only be
reached from fixed, forced-titration studies with multipledose
designs.58–60
Placebo
(n=81)
6.25 mg bid
12.5 mg bid
25 mg bid
Carvedilol (n=261)
Patients receiving diuretics, ACE inhibitors, ± digoxin; follow-up 6 months
*Multicenter Oral Carvedilol Heart Failure Assessment.
Adapted from Bristow et al. Circulation. 1996;94:

13. Carvedilol trials: MOCHA
Six-month crude mortality
deaths/randomized pt X 100
16 -
14 -
12 -
10 -
8 -
6 -
4 -
2 -
0 -
* p <.05
** p <.07
*** p <.001
15.5 ** % *
6.7
6.0
***
1.1
Placebo mg mg mg
bid bid bid
Bristow et al. Carvedilol produces dose-related improvements in left ventricular function
and survival in subjects with chronic heart failure. Circulation 1996;94:

14. Influence of Ejection Fraction on Cardiovascular Outcomes in a Broad Spectrum of Heart Failure Patients
Salomon SD Circulation 2005;112:

15. Benefit on SCD of Beta - Adrenergic Blocking Agents
MERIT-HF
37 %
SCD - Treated pts
MERIT-HF 3.6%
CIBIS II 4%
US Carvedilol 1.7%
MOCHA 2.3%
LV EF
28 %
Per il MERIT-HF e gli altri studi sui beta-bloccanti
AVERAGE SD decrease 33%
Lancet 1999; 353: 15

16. Neurohormonal Interventions in Heart Failure
1 Pacifico A, Henry P. J Cardiovasc Electrophysiol, Vol. 14, pp , July 2003.
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
TRACE
2,606
<36%
Trandolapril
100%
-22% (<0.001)
-24% (<0.03)
HOPE
9.297
N11% on ominallly >40%
Ramipril
-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
Metoprolol
-34%
(< )
-41% (<0.0002)
COPERNICUS
2,289
20%
Carvedilol
97%
-35%
(< 0.001)
Not reported
SOLVD-T
2,569
Enalapril
-16% (0.004)
-10% (NS)
SOLVD-P
4,228
-8% (0.3)
-7% (NS)
11% on β Blocker
Total Death Risk Reduction 52%
*Values indicated death incidence rates per 100 person-years during follow-up; enalapril by itself in either SOLVD-T or SOLVD-P did not significantly reduce sudden-cardiac mortality; however, in a reanalysis of SOLVD-P, enalapril with beta-blockers, compared to enalapril along signifcantly reduced total (4.3% vs. 5.6%), P <0.01) and sudden death mortality (1.3% vs. 1.8%l p <0.05).
ACE-I = angiotensin-converting enzyme I; LVEF = left ventricular ejection fraction; SCD-= sudden cardiac death; SOLVD-T and SOLVD-P refers to the treatment and prevention trials of SOLVD.

17. EPHESUS: New subgroup analysis
N = 6632 with post-MI LVSD, mean follow-up 16 months
Eplerenone better
Placebo better P
0.001
0.002
0.022
0.127
0.03
0.641
0.012
0.01
History of hypertension
All-cause mortality
CV mortality/hospitalization
Sudden cardiac death
History of diabetes
LVEF ≤30%
EPHESUS: New subgroup analysis
The Eplerenone Post–Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS) was a placebo-controlled evaluation of the aldosterone blocker eplerenone 50 mg in 6632 patients with acute MI, LVEF ≤40%, and signs of heart failure. All patients also received standard medical therapy. Patients were followed for up to 2.5 years (mean, 16 months).
There was a 15% RRR in the primary outcome of all-cause mortality (P = 0.008). Significant reductions in other end points (ie, CV mortality and/or hospitalization, sudden cardiac death) were also observed.
An analysis of eplerenone effects in high-risk subgroups enrolled in EPHESUS is summarized on the slide. Patients with diabetes appeared to obtain less benefit than those with hypertension or severe LV systolic dysfunction.
0.2
0.4
0.6
0.8
1.0
1.2
1.4
1.6
1.8
Odds ratio (95% Cl)
Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study
Pitt B et al. Am J Cardiol. 2006;97(suppl):26F-33F.

18. treatment interaction
EPHESUS Study
N Eng J Med 2003; 348:
ACE I / ARB and Beta Blockers
None
ACE I /ARB or Beta Blockers
p-value for
treatment interaction
Boths
P=0.04
0.6
0.8
1.0
1.2
1.4
Eplerenone
better
Hazard ratio
placebo better

19. Ivabradine in heart failure: no paradigm SHIFT…yet
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
NYHA Class II 52%: ivabradine (50%) pcb 1618 (50%), mean age 60 y, IHD 67% Mean LVEF% 29
More than 70% of pts were not in optimaized β – blocker therapy
Teerlink JR. Lancet August 29, 2010 DOI: /S (10)

20. Bristow MR et al Journal of Cardiac Failure Vol. 9 No. 6 2003
“… 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

21. Mortality in the placebo arm of Val-HeFT by treatment group: 23-month mean follow-up
Courtesy Prof. JN Cohn