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Emilio Vanoli Università di Pavia IRCCS Fondazione Policlinico S. Matteo, Pavia

“Trattamento nello scompenso cardiaco: bloccare prima il sistema RAA o il sistema simpatico?". Emilio Vanoli Università di Pavia IRCCS Fondazione Policlinico S. Matteo, Pavia Policlinico di Monza, Italy. Practical guidance on using ACE-I in heart failure. Who should receive ACE-I

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Emilio Vanoli Università di Pavia IRCCS Fondazione Policlinico S. Matteo, Pavia

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  1. “Trattamento nello scompenso cardiaco: bloccare prima il sistema RAA o il sistema simpatico?" Emilio Vanoli Università di Pavia IRCCS Fondazione Policlinico S. Matteo, Pavia Policlinico di Monza, Italy

  2. Practical guidance on using ACE-I in heart failure Who should receive ACE-I • All patients with heart failure or symptomatic left ventricular dysfunction. When to start • As soon as possible after diagnosis and exclusion of contraindications. The Task Force on ACE-inhibitors of the European Society of Cardiology. Eur Heart J 2004;25:1454

  3. Pratical guidance on using -adrenergic blockers in heart failure The Task Force on Beta-Blockers of the European Society of Cardiology. Eur Heart J 2004;25:1341

  4. Hospital Discharges for Congestive Heart Failure by Sex United States: 1970-2002 Note: Hospital discharges include people living and dead. Source: CDC/NCHS.

  5. Beta-Blockers, ACE-Inhibitors, Angiotensin Receptor Blockers, Aldosterone Antagonists, CRT, ICD, LVAD, Ultrafiltration, BNP, Monitoring Devices, Digoxin, Diuretics, Transplant 2006 1984-1994 ACE-Inhibitors, Digoxin, Diuretics, Transplant Digoxin, Diuretics, Transplant Palliation, Disease Exchange 1967-1984 Reversal of Disease, “Remission”, Palliation, Disease Exchange

  6. Who Administers Care to Heart Failure Patients? Internist General Cardiologist CV Family Medicine EP or CHF

  7. Updated from S. Nisam 280 250 250 Annual ICD implants per million inhabitants 208 200 180 154 USA 150 132 105 100 84 63 60 56 54 50 44 44 38 37 31 31 27 Europe 24 22 18 14 10 8 6 4 2,5 0 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 The Gap in ICDs

  8. CARDIAC DEATHS – INCIDENCE AND TOTAL EVENTS Convalescent phase VT/VF after MI Non-Sudden Sudden Out-of-Hospital cardiac arrest survivors EF < 30% heart failure Any prior coronary event High coronary risk sub-group Non-Sudden Sudden Overall incidence in adult population 250.000 250.000 25 50 50 25 5 0 5 0 Events/year Percent/year Modified from Myerburg

  9. Linee Guida ACC/AHA per la valutazione e la gestione della CHF nell’adulto (Modificata da Hunt et al. ACC/AHA 2001)

  10. The IMPROVEMENT International Survey • Physicians practises, 15 countries, • 11062 CHF pts Eligible Patients Treated % 60 34 20 12 ACEIs B-Block ACEI + B-Block Aldosterone Antagonist GC Fonarow Rev Cardiovacs Med 2005; 6: S32-S42

  11. Dispensed ACE Inhibitors or ARB Prescriptions Dispensed -Adrenoreceptor Antagonists Low-Risk Average-Risk High-Risk Risk-Treatment Mismatch in the Heart Failure Lee DS et al JAMA. 2005;294:1240-1247

  12. British Heart Journal, 1975,37:1022-1036 Effect of chronic beta-adrenergic receptor blockade in congestive cardiomyopathy F. Waagstein, A. Hjalmarson, E. Varnauskas, and I. Wallentin From the Department of Medicine I, Division of Cardiology and Department of Clinical Physiology, Sahlgren’s Hospital, University of Göteborg, Sweden

  13. Clinical Trials with Beta-Blockers APSI LIT Simpaticetomia cardiaca sx e oxprenololo in pz. con IMA ISIS-1 • BEST • COPERNICUS • CAPRICORN • CARMEN • COMET • BELFAST metoprolol trial • MIAMI • ESVEM • CASH • MDC PREMIS • SOTALOL trial • BHAT • The effect of pindolol.. CIBIS • GMT • NORVEGIAN timolol multicenter study US-CHFP • CIBIS II • MERIT-HF Effect of chronic beta… 1982/1983 1975 1981 1984 1985 1986 1987 1990 1992 1993 1994 1996 1999 200…. POST-MI TRIALS HF TRIALS

  14. HEART FAILURE + + Myocardial cell death Myocardial cell death CARDIAC OUTPUT Myocardial energy expenditure Myocardial energy expenditure + - - Inotropy Lusitropy Afterload NEUROHUMORAL ACTIVATION Renin-angiotensin Sympathetic-adrenergic Cytosolic Ca++ Vasoconstriction Arrhythmias, Sudden death

  15. Effects of angiotensin-II Sympathetic outflow • Enhancement of peripheral noradrenergic neurotransmission • Cathecolamine release from the adrenal medulla Inflammation • Activation and migration of macrophages • Increased expression of adhesion molecules (VCAM-1, ICAM-1, P-selectin), chemotactic proteins (MCP-1) and cytokines (IL-6) Trophic effects • Hypertrophy of cardiac myocytes • Stimulation of vascular smooth muscle migration, proliferation and hypertrophy • Stimulates proto-oncogenes (fos, myc, jun) and MAPKs (ERKs, JNK) • Increased production of growth factors (PDGF, bFGF, IGF-1, TGF1) • Increased synthesis of extracellular matrix proteins (fibronectin, collagen type-I and III, laminin- 1 and 2) and metalloproteinases The Task Force on ACE-inhibitors of the European Society of Cardiology. Eur Heart J 2004;25:1454

  16. LV stroke work (top) fell significantly with chronic rapid pacing and was significantly improved with either concomitant ACEI, AT1 Ang II receptor blockade (AT1 block), or combination treatment (ACEI/AT1 block) LV stroke work fell significantly with chronic rapid pacing and was significantly improved with either concomitant ACEI, AT1 Ang II receptor blockade (AT1 block), or combination treatment (ACEI/AT1 block) Spinale, F. G. et al. Circulation 1997;96:2385

  17. A sympatethic reflex Elicited by experimental Coronary occlusion Malliani A, Schwartz PJ and Zanchetti A. Am J Physiol 1969

  18. NGF expression in acute myocardial ischemia Hiltunen et al. J of Pathology 2001;194:247

  19. Cao J et al, Circulation 2000;101:1960

  20. Cao J et al, Circulation 2000;101:1960

  21. 1,02 1 0,98 0,96 0,94 BRS >3, LVEF <35 (120) 0,92 0,9 Proportion Surviving 0,88 0,86 Log Rank = 47.97 (p<0.0001) 0,84 BRS <3, LVEF <35 ( 59) 0,82 0,8 0 0,5 1 1,5 2 Autonomic Tone and Reflexes After Myocardial Infarction Years N° at Risk BRS >3, LVEF >35 879 851 761 598 373 BRS <3, LVEF >35 124 116 104 81 47 BRS >3, LVEF <35 120 110 94 71 52 BRS <3, LVEF <35 59 53 46 35 19

  22. Beta-blockers and ACEIs should be used in all patientswith a recent or remote history of MI regardless of EF orpresence of HF (Level of Evidence: A)

  23. Trials Number of pts Annuals rates in placebo groups OR (95% CI) p PEACE 8290 2.13 7 (-8 to 19) 0.328 HOPE total 9297 3.95 25 (16 to 32) 0.0001 HOPE lower risk 3083 2.17 18 (-4 to 35) HOPE medium risk 3100 3.58 20 (3 to 33) HOPE high risk 3114 5.98 24 (12 to 34) 19 (8 to 28) EUROPA total 12218 2.60 0.0007 EUROPA lower risk 3976 1.40 19 (-5 to 38) 10 25 35 40 30 5 20 15 0 -5 EUROPA medium risk 3975 2.41 28 (11 to 41) EUROPA high risk 3975 4.00 10 (-4 to 22) Percentage reduction in odds of cardiovascular death, non-fatal MI, or stroke for PEACE, HOPE and EUROPA Dagenais et al. Lancet 2006;368:581

  24. Use of ACE-I in myocardial infarction: guidelines AMI, first 24 h • High risk (heart failure, LVD, no reperfusion, large infarcts) IA • All patients IIaA Evolving AMI (> 24 h), Post MI • Clinical heart failure, Asymptomatic LVD (LVEF<45%) IA • Diabetes or other high risk patients IA The Task Force on ACE-inhibitors of the European Society of Cardiology. Eur Heart J 2004;25:1454

  25. Use of ACE-I in hypertension: guidelines • To control blood pressure • Patients with heart failure, systolic left ventricular dysfunction, diabetics, previuos MI or stroke, high coronary disease risk The Task Force on ACE-inhibitors of the European Society of Cardiology. Eur Heart J 2004;25:1454

  26. Pratical guidance on using -adrenergic blockers in heart failure The Task Force on Beta-Blockers of the European Society of Cardiology. Eur Heart J 2004;25:1341

  27. Lindholm LH et al. Lancet 2005

  28. Cholest Glucose Insulin HDL-Ch Heart Rate Blood Pressure Triglycer Hematoc B.M.I. Interrelationship of heart rate with various risk factors for atherosclerosis Palatini et al. J of Hypertension 1997

  29. Rapporto fra frequenza cardiaca e mortalità in soggetti ipertesi giovani Benetos A. et al. Hypertension 1999

  30. Rapporto fra frequenza cardiaca e mortalità in soggetti ipertesi anziani Palatini P. et al. Arch Intern Med 2002

  31. Effects of angiotensin-II Sympathetic outflow • Enhancement of peripheral noradrenergic neurotransmission • Cathecolamine release from the adrenal medulla Inflammation • Activation and migration of macrophages • Increased expression of adhesion molecules (VCAM-1, ICAM-1, P-selectin), chemotactic proteins (MCP-1) and cytokines (IL-6) Trophic effects • Hypertrophy of cardiac myocytes • Stimulation of vascular smooth muscle migration, proliferation and hypertrophy • Stimulates proto-oncogenes (fos, myc, jun) and MAPKs (ERKs, JNK) • Increased production of growth factors (PDGF, bFGF, IGF-1, TGF1) • Increased synthesis of extracellular matrix proteins (fibronectin, collagen type-I and III, laminin- 1 and 2) and metalloproteinases The Task Force on ACE-inhibitors of the European Society of Cardiology. Eur Heart J 2004;25:1454

  32. 14 of 19 100 4 of 5 80 60 40 1 of 5 20 0 of 19 0 RAS activation and Sudden Death Incidence of VF (%) Low sodium diet Low sodium diet + lisinopril Low sodium diet + atenolol Control

  33. Early Autonomic and RepolarizationAbnormalities Contribute to LethalArrhythmias in Chronic Ischemic Heart Failure:Characteristics of a Novel Heart Failure Model in DogsWith Postmyocardial Infarction Left Ventricular Dysfunction Philip B. Adamson, MD, FACC,* Emilio Vanoli, MD*† Oklahoma City, Oklahoma and Pavia, Italy JACC 2001

  34. Anterior Myocardial Infarction 30% Dead Exercise and Ischemia Test 60% Resistant Microembolization 3-5 Injections 40% Susceptible Microembolization 1-2 Injections LVEF 35% LVEF 35%

  35. EF 60%, 1 month post-MI EF 35%, 1 Month EF 35%, 2 Months 1 sec Adamson and Vanoli, JACC 2001

  36. EF 65%, 1 month post-MI EF 35%, 6 months 1 sec

  37. Heart rate response to acute ischemia and to left ventricular dysfunction Susceptible Resistant 50 40 30 Heart rate changes (b/min) 20 10 0 LVEF 35% Ex and Ischemia

  38. 7 6 5 4 HF/LF 3 2 1 0 High Risk Low Risk

  39. Per-protocol (PP) 100 90 80 70 B/E vs E/B HR 0.97 (95% CI 0.78-1.21) non-inferiority P=0.046 60 50 503 498 356 353 265 259 80 73 mesi 0 6 12 18 Intention-to-treat (ITT) 100 90 80 70 B/E vs E/B HR 0.94 (95% CI 0.77-1.16) non-inferiority P=0.019 60 50 87 76 389 388 291 277 505 505 Pazienti a rischio mesi 0 6 12 18 Endpoint primario % senza endpoint follow-up medio 1.25 anni Bisoprololo-prima Enalapril-primat DOI: 10.1161/CIRCULATIONAHA. 105.582320 % senza endpoint Per non-inferiorità P<0.025 denota Significavità statistica (unilateral test) Pazienti a rischio

  40. Use of ACE-I to prevent sudden death: guidelines • Patients with heart failure IA • Patients with previous MI IA • Patients with dilated cardiomyopathy IB The Task Force on ACE-inhibitors of the European Society of Cardiology. Eur Heart J 2004;25:1454

  41. CIBIS III – sudden death • Prespecified time points of analysis: • End of monotherapy phase • (157-230 days post randomization, mean 162 days) • After the first year (minimum time of follow-up for all patients) • Study end

  42. 493 476 460 450 444 232 505 Sudden death - monotherapy phase % sudden death 5 Bisoprolol-first vs enalapril-first: 8 versus 16 sudden deaths; HR 0.50; 95% CI 0.21-1.16; P=0.107 1.6% ARR 4 3 Enalapril-first Bisoprolol-first 2 1 0 Time (months) 0 1 2 3 4 5 6 N at risk 488 467 454 444 430 251 505

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