“Can Neurohormonal Antagonists Help?”               Eleventh International Symposium Heart Failure & Co. Reggia di Caserta 29-30 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

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

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

Electrical Instability in the Failing Heart QT interval dispersion Pye M Br Heart J 1994;71:511-514 Zaidi M European Heart Journal (1997) 18, 1129-1134

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 = 130 130 142 Enalapril n = 128 127 137 Greenberg B et al. Circulation 1995 5

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;96:3294-3299

ACE-I reduce mortality due to SCD by 13% 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 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

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

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;2837-2849

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;346:1357-65 (modified)

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;94:2807-2816.

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 6.25 mg 12.5 mg 25 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;94:2807-2816

Influence of Ejection Fraction on Cardiovascular Outcomes in a Broad Spectrum of Heart Failure Patients Salomon SD Circulation 2005;112:3738-3744

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: 2001-7 15

Neurohormonal Interventions in Heart Failure 1 Pacifico A, Henry P. J Cardiovasc Electrophysiol, Vol. 14, pp. 764-775, 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% (< 0.00009) -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.

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.

treatment interaction EPHESUS Study N Eng J Med 2003; 348:1309-1321 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

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 1605 (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:10.1016/S0140-6736(10)61314-1

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. 6 2003

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