E. Gronda, MD, FESC Cardiology Division Cardiovascular Department

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

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e E

xpre

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NA

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tal

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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