“Gli ACE inibitori sono superiori”

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

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

6. ACEi vs ARBs The role of timing in science

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

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

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

10. SOLVD combined trials % MI 20 Placebo 15 Enalapril 10 5 P<0.001 0 0 Years 2 3 1 4 SAVE Placebo 20 % MI Captopril 15 10 5 P=0.015 0 0 Years 2 3 1 4 ACE inhibition reduces the incidence of MI Young JB. Cardiovasc Drugs Ther. 1995;9:89-102.

11. MI Occurence in ACE-inh trials

12. ACE inhibition reduces the need for revascularisation SAVE CABG PTCA 0.2 Placebo Placebo 0.1 Event rate Captopril Captopril 0.0 0 1 2 3 4 5 0 1 2 3 4 5 Years Rutherford et al. Circulation 1994;90:1731-1738

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

14. Secondary prevention of CAD by ACEIs QUIET HOPE 50 4% Risk increase RR 1.04 (0.89–1.22) P=0.6 Placebo 20 % Patients Quinapril 20 mg 22% Risk reduction RR 0.78 (0.70–0.86) P=0.001 40 15 30 Ramipril 10 mg 20 Placebo 10 10 PEP: CV death, MI, cardiac arrest, revascularization, hospitalization for UA 5 PEP: CV death, MI, stroke 0 Time(years) Time(years) 0 1 2 0 3 1 2 3 4 0 EUROPA PEACE 30 Placebo 4% Risk reduction HR 0.96 (0.88–1.06) P=0.43 14 20% Risk reduction RR 0.80 (0.71–0.91) P=0.0003 % Patients 12 25 10 Trandolapril 4 mg 20 8 Placebo 15 Perindopril 8 mg 6 10 4 PEP: CV death, MI, cardiac arrest 2 5 PEP: CV death, MI, revascularization 0 Time(years) Time (years) 0 0 1 2 3 4 5 1 2 3 4 5 6 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.

15. Meta-analysis of 32 000 patients Relative risk reduction and 95% CI ACEI Placebo 0.87 Total mortality 7.5% 8.6% 0.82 CV mortality 4.1% 5% 0.83 MI 6.4% 7.7% 0.85 0.85 Death & MI 8.7% 10% ACE better Placebo better

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

17. MI occurrence in ARB trials

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

19. 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 ACS Atherosclerosis

21. ACE activity and endothelial function • 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

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

23. 1.0 09 0.8 0.7 PERTINENT substudy (1175 pts) von Willebrand factor Significant prognostic role CAD PERTINENT patients Low (142% / Unit) baseline 1 year 300 p <0.01 200 High (>142% / Unit) outcome Normal Range (44-158) vWf(%/Unit) p<0.01 100 0 0 1 2 3 4 Placebo Perindopril Placebo Perindopril Years

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

25. ApoptosisEffects of HUVEC incubation with serum from: PERTINENTAnalysis in cultured HUVECs Controls CAD PERTINENT patients baseline 1 year P<0.01 20 Apoptosis P<0.05 10 0 Treatedn=43 Treatedn=43 Controlsn=45 Placebon=44 Placebon=44 #P=controls vs baseline *P=perindopril vs placebo Ceconi C et al. Cardiovasc Res. 2006

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

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

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

29. 20 20 15 15 10 10 5 5 0 0 Bradykinin / Angiotensin II Bradykinin Angiotensin II Controls CAD PERTINENT Controls CAD PERTINENT # p=controls vs baseline ‡ p=∆perindopril vs ∆placebo baseline 1 year baseline 1 year # ‡ # ‡ p <0.01 p <0.05 p<0.01 p<0.01 Angiotensin II (Pg/mL) Bradykinin (Pg/mL) 18.0 18.3 12.4 14.8 12.3 10.8 15.8 17.1 14.4 12.5 Placebo (n=44) Placebo (n=44) Controls (n=45) Controls (n=45) Placebo (n=44) Placebo (n=44) Perindopril (n=43) Perindopril (n=43) Perindopril (n=43) Perindopril (n=43)

30. 40 35 30 ) mL / 25 pg ( a 20 - TNF 27.7 28.9 15 18.0 10 5 0 a TNF - PERTINENT Controls CAD PERTINENT patients baseline 1 year p<0.01 p <0.05 # ‡ 27.1 24.6 Controls Placebo Perindopril Placebo Perindopril Controls Placebo Perindopril Placebo Perindopril n = 45 n = 44 n = 43 n = 44 n = 43 n = 45 n = 44 n = 43 n = 44 n = 43 p= controls vs baseline # D D p= perindopril vs placebo ‡

31. ANGIO II TNF α Oxygen free radicals

32. RAS Blockade reduces the incidence of cerebrovascular events Trial HOPE PROGRESS MOSES Drug Ramipril Perindopril Eprosartan

33. RAS Blockade reduces the incidence of diabetes

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

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

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

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

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

40. Time to first recurrence of AF (n. 1442) GIS GISSI-AF 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

41. RAS Blockade improves renal function

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

43. Evidence-based recommendations for the blockers of the RAAS Hypertension ACE-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 events ACE-I or ARBs Combination not recommended Atrial fibrillationPrimary prevention: ??? Secondary prevention: not recommended Prevention of diabetes ACE-I? ARBs? Both ?

44. 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 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.

45. END

46. Ratio of means (95% CI)* forchange in proteinuria, by randomized therapy, over two follow-up intervals Kunz R et al. Ann Intern Med 2008; 148:30-48

47. 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

48. 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