1. “Gli ACE inibitori sono superiori” Rozzano, 17 aprile 2009 Luigi Tavazzi GVM Hospitals of Care and Research Cotignola

6. Cardiovascular disease as a sequence of related pathological events Coronary thrombosis Myocardial ischemia Coronary artery disease Atherosclerosis Endothelial dysfunction Myocardial infarction Arrhythmia and loss of muscle Cardiac remodeling Ventricular dilation Congestive heart failure End-stage heart disease Risk factors: Hypertension Dyslipidemia Insulin resistance Smoking Role of RAS From Circulation 2006;114:2850-70.

7. The role of timing in science ACEi vs ARBs

8. ANGIOTENSIN SYSTEM Angiotensinogen renin Ang I Ang II Potentiation of sympathetic activity ACE Kyninase (enzyme) BRADYKININ SYSTEM kallikrein kininogen Bradykinin Endothelium Prostaglandin NO  platelet aggregation  SMC mitogenesis Vasodilation Inactive peptide + FGF PDGF + + Vasoconstriction  aldosterone release Angiotensin / Bradykinin Systems

9. ACE INHIBITION TRIALS SECONDARY PREVENTION TREATMENT AFTER AMI EFFICACY BEFORE   HOPE   EUROPA   ADVANCE   QUIET   PEACE   CONS. 2 GISSI 3   ISIS 4 AFTER   AIRE   SAVE   TRACE   CONSENSUS 1   SOLVD AMI PRIMARY PREV.   ASCOT

10. Cardiovascular disease as a sequence of related pathological events Coronary thrombosis Myocardial ischemia Coronary artery disease Atherosclerosis Endothelial dysfunction Myocardial infarction Arrhythmia and loss of muscle Cardiac remodeling Ventricular dilation Congestive heart failure End-stage heart disease Risk factors: Hypertension Dyslipidemia Insulin resistance Smoking Role of RAS From Circulation 2006;114:2850-70.

11. ACE inhibition reduces the incidence of MI Young JB. Cardiovasc Drugs Ther. 1995;9:89-102. SOLVD combined trials Placebo Enalapril Years P<0.001 % MI 20 15 10 5 0 1 0 23 4 SAVE Placebo Captopril Years P=0.015 % MI 20 15 10 5 0 1 0 23 4

12. MI Occurence in ACE-inh trials

13. Rutherford et al. Circulation 1994;90:1731-1738 SAVE CABG 0.2 0.1 0.0 012345 Event rate Placebo Captopril PTCA Placebo Captopril ACE inhibition reduces the need for revascularisation 012345 Years

14. ACE INHIBITION TRIALS SECONDARY PREVENTION TREATMENT AFTER AMI EFFICACY BEFORE   HOPE   EUROPA   ADVANCE   QUIET   PEACE   CONS. 2 GISSI 3   ISIS 4 AFTER   AIRE   SAVE   TRACE   CONSENSUS 1   SOLVD AMI PRIMARY PREV.   ASCOT

15. HOPE Study Investigators. N Engl J Med. 2000;342:145-53. PEACE Trial Investigators. N Engl J Med. 2004;351:2058-68. EUROPA Investigators. Lancet. 2003;362:782-8. Pitt B et al. Am J Cardiol. 2001;87:1058-63. HOPE 15 5 10 0 20 0 Placebo Ramipril 10 mg % Patients 241 22% Risk reduction RR 0.78 (0.70–0.86) P=0.001 3 PEP: CV death, MI, stroke 12 4 10 0 134 14 0 Placebo Perindopril 8 mg 8 6 2 52 EUROPA 20% Risk reduction RR 0.80 (0.71–0.91) P=0.0003 PEP: CV death, MI, cardiac arrest PEACE Time (years) Trandolapril 4 mg Placebo 30 20 10 15 5 12345 25 0 6 % Patients 4% Risk reduction HR 0.96 (0.88–1.06) P=0.43 PEP: CV death, MI, revascularization QUIET 40 20 30 0 50 0 Placebo Quinapril 20 mg Time (years) 1 4% Risk increase RR 1.04 (0.89–1.22) P=0.6 10 2 3 PEP: CV death, MI, cardiac arrest, revascularization, hospitalization for UA Time (years) Secondary prevention of CAD by ACEIs

16. CV mortality 4.1% 5% MI6.4%7.7% Death & MI8.7%10% Relative risk reduction and 95% CI ACEI Placebo Meta-analysis of 32 000 patients 0.85 0.82 0.83 0.85 0.87 Total mortality 7.5% 8.6% ACE better Placebo better

17. Heart failure 3.8% 5% Revascularization 2.1%2.7% Stroke 10.5% 11.3% Relative risk reduction and 95% CI ACEI Placebo 0.74 0.92 0.74 Meta-analysis of 32 000 patients ACE Placebo better ACE Placebo better

18. MI occurrence in ARB trials

19. Incidence of AMI in ONTARGET No statistical difference between groups, but …

20. Atheroma formation and progression: a struggle between death and regeneration Endothelial cells undergo suicide (apoptosis) and regenerate When a mismatch occurs, the endothelium loses its continuity Endothelial cells undergo suicide (apoptosis) and regenerate When a mismatch occurs, the endothelium loses its continuity Atherosclerosis ACS

22.  90% of ACE is a tissue enzyme present in the heart and vessel ( endothelium and smooth muscle )  CAD up-regulates tissue ACE and alters the balance between:  90% of ACE is a tissue enzyme present in the heart and vessel ( endothelium and smooth muscle )  CAD up-regulates tissue ACE and alters the balance between: Angiotensin II Bradykinin which, in turn, impairs endothelial function ACE activity and endothelial function

23. ENDOTHELIAL FUNCTION eNOS activity % of apoptosis eNOS activity % of apoptosis Biologic end-points: Clinical end-points: Vasomotion to endothelial dependent stimulation (Ach, Bradykinine, etc) von Willebrand factor

24. PERTINENT substudy von Willebrand factor p <0.01 vWf (%/Unit) Normal Range (44-158 ) Placebo Perindopril CAD PERTINENT patients baseline1 year 0 100 200 300 Significant prognostic role Years outcome 0.7 0.8 09 1.002341 Low (  142% / Unit) High (>142% / Unit) p<0.01 (1175 pts) Perindopril

25. Healthy subjects Incubated (72 h) with serum from EUROPA pts ecNOS Apoptosis To mimic the effects of circulating blood on endothelial function Isolation of human endothelium PERTINENT substudy (1175 pts)

26. PERTINENT Analysis in cultured HUVECs P<0.05 Apoptosis Controls CAD PERTINENT patients baseline1 year Placebo n=44 Treated n=43 Controls n=45 0 10 20 P<0.01 Apoptosis Effects of HUVEC incubation with serum from: #P=controls vs baseline *P=perindopril vs placebo Ceconi C et al. Cardiovasc Res. 2006

27. Normal rate of apoptosis: 3% Maintenance of endothelial layer Excess rate of apoptosis Onset of atherosclerotic Protection against atherosclerosis Endothelial apoptosis and atherosclerosis Plaque erosion and rupture Endothelium continuity

28. WHY ? Different tissue affinity Different effects on the bradykinine (anti-apoptoic) angiotensin (pro-apoptoic) Specific effects on typical apoptoic inducer: TNF-  Different tissue affinity Different effects on the bradykinine (anti-apoptoic) angiotensin (pro-apoptoic) Specific effects on typical apoptoic inducer: TNF-  (ANTI) bradykinineangiotensin (PRO)

29. ACE EnzymeACE activity Bradikynin, and not Angiotensin I, is the “natural” substrate for ACE Affinity Km ~1x10 -4 M Catalytic rate k cat ~10 sec Affinity Km ~1x10-6M Catalytic rate kcat ~1 sec Reaction Rate ~ 50 times faster

30. Bradykinin / Angiotensin II Bradykinin (Pg/mL) p <0.01 CAD PERTINENT baseline1 year Placebo (n=44) Perindopril (n=43) 14.812.412.3 18.0 Controls Controls (n=45) 18.3 p<0.01 0 10 20 5 15 Placebo (n=44) Perindopril (n=43) Bradykinin Angiotensin II (Pg/mL) p <0.05 CAD PERTINENT baseline1 year Placebo (n=44) Perindopril (n=43) 17.115.814.412.5 Controls Controls (n=45) 10.8 p<0.01 Placebo (n=44) Perindopril (n=43) Angiotensin II # p=controls vs baseline ‡ p=∆perindopril vs ∆placebo 0 10 20 5 15 #‡ #‡

31. 0 5 10 15 20 25 30 35 40 TNF - a ( pg / mL ) Controls n = 45 18.0 p<0.01 # Controls baseline1 year p <0.05 ‡ Placebo n = 44 Placebo n = 44 Perindopril n = 43 Perindopril n = 43 27.1 27.7 28.9 24.6 CADPERTINENT patients # p=controlsvsbaseline ‡ p=  perindoprilvs  placebo TNF-  PERTINENT

32. ANGIO II TNF α Oxygen free radicals

33. RAS Blockade reduces the incidence of cerebrovascular events TrialHOPEPROGRESSMOSESDrugRamiprilPerindoprilEprosartan

34. RAS Blockade reduces the incidence of diabetes

35. GISSI-3 Study Effect of Lisinopril in pts with AMI

36. HOPE and PEACE: new onset diabetes 3.6% 5.4% 9.8% 11.5% HR 0.66 95% CI 0.51-0.85 p <0.001 HR 0.83 95% CI 0.72-0.96 p =0.014

38. Incident diabetes in clinical trials of antihypertensive drugs: a network meta-analysis Elliott WJ, et al. Lancet 2007;369(9557):201-7

39. RAS blockade reduces the incidence of atrial fibrillation (?)

40. Healey JS et al. JACC 2005; 45:1832-39

41. Valsartan: 371/722 (51.4%) Placebo: 375/720 (52.1%) Adjusted* HR 0.99 96%CI 0.85-1.15 P value 0.84 * The 96%CI was calculated by Cox proportional hazards model adjusted for ACE-I, amiodarone use, cardioversion, PAD, CAD Time to first recurrence of AF (n. 1442) GISGISGISGIS GISSI-AF

42. RAS Blockade improves renal function

43. Modulatori RAS a confronto ACE-I hanno avuto spazi di applicazioneACE-I hanno avuto spazi di applicazione più aperti e successi più consolitati più aperti e successi più consolitati efficacia simile (bradichinina può essere un plus)efficacia simile (bradichinina può essere un plus) Tollerabilità simile (in qualche trial ARB in vantaggio)Tollerabilità simile (in qualche trial ARB in vantaggio) Associazione ACE-I + ARB non vantaggiosaAssociazione ACE-I + ARB non vantaggiosa (occasionalmente dannosa) (occasionalmente dannosa)

44. Evidence-based recommendations for the blockers of the RAAS HypertensionACE-I or ARBs Heart failure ACE-I ARBs if ACE-I not tolerated ACE-I plus ARBs Myocardial infarction ACE-I or ARBs Combination not recommended Renal dysfunction ACE-I or ARBs Combination??? Prevention of CV eventsACE-I or ARBs Combination not recommended Atrial fibrillation Primary prevention: ??? Secondary prevention: not recommended Prevention of diabetesACE-I? ARBs? Both ?

45. The fallacy of surrogate end-point: Albuminuria In ONTARGET albuminuria was reduced by a combination of telmisartan and ramipril, but serum creatinine and dialysis rate doubled.In ONTARGET albuminuria was reduced by a combination of telmisartan and ramipril, but serum creatinine and dialysis rate doubled. In a diabetic subgroup (~ 700 pts) with overt (≥ 300 mg/g creatinine) proteinuria and fast loss of GFR, dual RAS blockade had no significant effect on renal outcome.In a diabetic subgroup (~ 700 pts) with overt (≥ 300 mg/g creatinine) proteinuria and fast loss of GFR, dual RAS blockade had no significant effect on renal outcome.

46. END

47. Kunz R et al. Ann Intern Med 2008; 148:30-48 Ratio of means (95% CI)* for change in proteinuria, by randomized therapy, over two follow-up intervals Randomized therapyOver 1-4 moOver 5-12 mo ARBs vs placebo0.57 (0.47–0.68) 0.66 (0.63– 0.69) ARBs vs ACE-I0.99 (0.92–1.05) 1.08 (0.96– 1.22) ARBs vs CCBs0.69 (0.62–0.77) 0.62 (0.55– 0.70) ARB+ACE-I vs ARBs0.76 (0.68–0.85) 0.75 (0.61– 0.92) ARB+ACE-I vs ACE-I0.78 (0.72–0.84) 0.82 (0.67– 1.01) ACE-I=angiotensin-converting-enzyme inhibitor ARB=angiotensin-receptor blocker CCB=calcium-channel blocker *Ratio of means=ratio of the average treatment effect in the intervention group (either ARBs alone or in combination with ACE-I) relative to the control group (placebo or single-drug comparator), with 95% CI

48. ARBs in Secondary Prevention Superior to placebo? YES / NO More effective than ACEi? NO Less effective than ACEi? NO Equal than ACEi? YES Should be used with ACE? NO Superior to placebo? YES / NO More effective than ACEi? NO Less effective than ACEi? NO Equal than ACEi? YES Should be used with ACE? NO

49. ARBs in Heart Failure Superior to placebo? YES More effective than ACEi? NO Less effective than ACEi? NO Equal than ACEi? YES Should be used with ACE? NO / YES but only to reduce hospitalisation Superior to placebo? YES More effective than ACEi? NO Less effective than ACEi? NO Equal than ACEi? YES Should be used with ACE? NO / YES but only to reduce hospitalisation