1. Nicolas DANCHIN, HEGP, Paris

2. Collaborations Subventions de recherche : Pfizer, Servier, The MedCo Honoraires pour conférences et/ou consultance: Astra-Zeneca, BMS, Boehringer-Ingelheim, GSK, Lilly, Menarini, MSD-Schering, Novartis, Novo, Pfizer, sanofi-aventis, Servier, The MedCo

3. Endothelial damage Mechanical fatigue Atherosclerosis Central aortic pressures Central aortic pressures Pulse pressure Large arteries Large arteriesstiffening Perindopril disrupts the pathophysiological continuum at multiple points 1. Tropeano AI. Hypertension 2006;48:80-86. 2. Williams B. Circulation 2006;113:1213-1225. 3. Ceconi C. Cardiovasc Res 2007;73:237-246. 4. Bruining N. 2008 ESC. Sept, 3 at 11h00. Zagreb-Zone B3. DAPHNET Large arteries stiffness 1 PERSPECTIVE Non-calcified plaque size 4 PERTINENT Endothelial dysfunction 3 Central aortic pressures 2

4. Morbi-mortality trials of perindopril along the cardiovascular disease continuum (n=50 822) Hypertensive patients n=19 257 Patients with stable CAD n=12 218 Patients with diabetes n=11 140 Post-stroke patients n=6 105 Post-AMI patients n=1 252 Diastolic HF n=850 Hypertensive patients n = 3 845

5. Per+Ind, perindopril+indapamide fixed combination Non-fatal MI or death from coronary heart disease Unstable angina requiring hospitalisation, coronary revascularisation or silent MI Macrovascular events 480520 8% (-4 to 19) Microvascular events 439 477 9% (-4 to 20) Primary endpoint861938 9% (0 to 17) Number of events Per / IndPlacebo (n=5,569) (n=5,571) Relative risk reduction (95% CI) Major coronary heart disease 265 294 11% (-6 to 24) All coronary heart disease 468535 14% (2 to 24) Other coronary heart disease 283324 14% (-1 to 27) New or worsening nephropathy 181 216 18% (-1 to 32) New microalbuminuria10941317 Favours Per / Ind Favours placebo Hazard ratio 0.5 1.0 2.0 21% (14 to 27) Total renal events12431500 21% (15 to 27) 2P 0.04 0.02 <0.01 ADVANCE Collaborative Group. Lancet 2007;370:829-40. Reduction in cardiac and renal events in diabetic patients

6. Reduction in all-cause mortality in diabetic patients ADVANCE Collaborative Group. Lancet 2007;370:829-40. Relative risk reduction 14% p=0.025 Follow-up (months) 0 10 06121824303642485460 Placebo Perindopril+indapamide Cumulative incidence (%) 5 All-cause death

7. amlodipine perindopril better atenolol thiazide better 0.500.701.001.45 Selected end-points Primary Non-fatal MI (incl silent) + fatal CHD Secondary Total coronary end point Total CV event and procedures All-cause mortality Cardiovascular mortality Fatal and non-fatal stroke Tertiary New-onset diabetes mellitus New-onset renal impairment Post hoc Primary end point + revascularization CV death + MI + stroke 2.00 Unadjusted Hazard ratio (95% CI) 0.90 (0.79-1.02) 0.87 (0.79-0.96) 0.84 (0.78-0.90) 0.89 (0.81-0.99) 0.76 (0.65-0.90) 0.77 (0.66-0.89) 0.70 (0.63-.078) 0.85 (0.75-0.97) 0.86 (0.77-0.96) 0.84 (0.76-0.92) Dahlof B et al. Lancet 2005; 366: 895-906. Reduction in cardiovascular events in hypertensive patients at CV risk

8. Number at risk Amlodipine perindopril 96399544 9441 93229167 8078 Atenolol thiazide 96189532 9415 92619085 7975 0.0 1.0 2.0 3.04.05.0 Years 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 amlodipine perindopril (No. of events 263) atenolol thiazide (No. of events 342) HR = 0.76 (0.65­0.90) p = 0.0010 % Dahlof B. Lancet 2005; 366: 895-906. Reduction in cardiovascular mortality in hypertensive patients at CV risk

9. Number at risk Amlodipine perindopril 70746853 6667 65086312 5513 Atenolol thiazide 70466743 6494 62626040 5226 0.0 1.02.0 3.04.05.0 Years 0.0 2.0 4.0 6.0 8.0 10.0 amlodipine perindopril (No. of events = 567) atenolol thiazide (No. of events = 799) HR = 0.69 (0.62­0.77) p < 0.0001 % Prevention of the new onset diabetes mellitus Dahlof B. Lancet 2005;366:895-906.

10. Evénements vasculaires majeurs Tous les participants Evts actif placebo Actif meilleur Placebo meilleur Mort vasculaire IDM non-fatal AVC non-fatal Total 0.41.02.0 Risque relatif 181 60 275 458 198 96 380 604 9% (-12 à 25%) 38% (14 à 55%) 29% (17 à 39%) 26% (16 à 34%) Réduction de risque (IC 95%)

12. Reduction in major cardiac events in patients with stable CAD 0.51.02.0 20 14 22 46 14 RRR (%) Perindopril better Placebo better Primary endpoint: CV mortality, MI, CA CV mortality Non fatal MI Resuscitated CA First secondary endpoint: Total mortality, MI, UAP,CA P value 0.0003 0.0009 EUROPA Investigators. Lancet 2003;362:782-88. CA, cardiac arrest; UAP, unstable angina pectoris

13. Adapted from EUROPA Investigators. Lancet 2003;362:782-88. Reduction in cardiovascular events whatever the endpoint definition CV death, MI, cardiac arrest (EUROPA definition) CV death, MI, stroke (HOPE definition) CV death, MI, stroke, HF hosp (ONTARGET definition) Event rate, % 9.9 8.0 10.9 9.0 9.5 11.8 placeboplaceboplaceboPerindoprilPerindoprilPerindopril -20% P=0.0003 -17% P<0.001 -20%

14. 79.6±1.1 83.0±1.2 83.6±1.2 Perindopril Placebo 75 78 81 84 87 LVEDV Volumes (ml) means ± SE Baseline6-month 12-month p<0.01 81.1±1.1 81.2±1.2 81.8±1.3 n=631 n=619 PREAMI Investigators. Arch Intern Med. 2006;166:659-666 Prevention of cardiac remodeling in post-AMI patients with preserved LV function

15. 20 15 10 5 0 17% 18% 39% 13% 14% 4.9 4.0 5.9 4.9 9.7 6.0 11.0 9.6 18.1 15.6 Quintiles of predicted risk for death/MI Placebo Perindopril EUROPA Consistent benefit of ACE inhibitors Adapted from Deckers JW et al. Eur Heart J 2006;27:796–801.

16. Deckers JW et al. Eur Heart J 2006;27:796–801. Low risk RRR -17% placebo 5.3% 3.8 4.0 4.2 4.4 4.6 4.8 5.0 5.2 Perindopril 4.4% Medium risk RRR -32% 9.0% placebo 6.1% Perindopril 0 1 2 3 4 5 6 7 8 9 10 High risk RRR -12% 15.4% placebo 13.5% Perindopril 12.5 13.0 13.5 14.0 14.5 15.0 15.5 No heterogeneity between groups (P =0.15) Reduction in primary endpoint* across groups of CV risk level *Primary endpoint: CV death, nonfatal MI, resuscitated cardiac arrest - 0.9% -2.9% -1.9%

17. Prevention of heart failure occurrence and/or hospitalisation with perindopril -39% P=0.002 -37% P=0.033 -26% P=0.02 -28% NS Stable CAD Diastolic HF Post-MI Post-stroke EUROPA Investigators. Lancet 2003;362:782-88. Cleland JGF. Eur Heart J 2006;27:2338-2345. PROGRESS Collaborative Group. Eur Heart J 2003;24:475-484. PREAMI Investigators. Arch Intern Med. 2006;166:659-666

18. Consistent effect of perindopril in patients with and without hypertension Overall study population Subpopulation with hypertension Subpopulation without hypertension PROGRESS Collaborative Group. Lancet 2001;358:1033-41. EUROPA Investigators. Lancet 2003;362:782-88. ADVANCE Collaborative Group. Lancet 2007;370:829-40. Post-stroke patients Recurrent stroke -20 -10 0 -30 RRR (%) (%) -32% -27% -28% CV death, MI, cardiac arrest -15 -10 -5 0 -20 RRR (%) (%) -20% -18% -20% Patients with CAD Macro and microvascular events -5 0 -10 RRR (%) (%) -9% -10% -9% Diabetic patients

19. Consistent effect of perindopril in patients with and without diabetes mellitus Overall study population Subpopulation with diabetes Subpopulation without diabetes Berthet K. Blood Pressure 2004; EUROPA Investigators. Lancet 2003;362:782-88. Dahlof B. Lancet 2005;366:895-906. Total CV events and procedures -15 -10 -5 0 -20 RRR (%) (%) -13% -18% -16% Hypertensive patients CV death, MI, cardiac arrest -15 -10 -5 0 -20 RRR (%) (%) -20% -19% Patients with CAD Recurrent stroke -30 -20 -10 0 -40 RRR (%) (%) -38% -28% Post-stroke patients

20. Summary of evidence from large-scale clinical trials with perindopril YearTrialPatientsNumberMain results 2001PROGRESSPost-stroke6 105Recurrent stroke: -28% 2003EUROPA Stable CAD Preserved LV 12 218CV death/MI/cardiac arrest: -20% 2005ASCOTHypertension19 257 CV mortality: -24%; CV events and procedures: - 16% 2006PREAMIPost-AMI1 252Death/HF/cardiac remodelling: -38% 2006PEP-CHFDiastolic HF850Death/HF hospitalisation: -31% 2007ADVANCEDiabetes11 140 Macro and microvascular events: -9%; Total mortality: -14%

21. 3.3 6.3 9.0 11.8 2.8 5.3 7.4 9.7 Placebo Perindopril-based ADVANCE EUROPA PROGRESS HR 0.82 (0.76-0.87) P < 0.001 % 10 5 0 CV-DEATH, MI or STROKE 01234 years Brugts JJ, et al. Eur Heart J. 2009;30:1385-1394. Placebo ADVANCE EUROPA PROGRESS HR 0.82 (0.76-0.87) P < 0.001

22. 1.5 3.2 5.2 7.5 1.2 2.8 4.5 6.7 Placebo Perindopril-based ADVANCE EUROPA PROGRESS HR 0.89 (0.82-0.96) P = 0.006 % 10 5 0 01234 years ALL CAUSE MORTALITY Brugts JJ, et al. Eur Heart J. 2009;30:1385-1394.

23. Les questions Associer IEC et autres traitements ? Equivalence de tous les IEC ? Equivalence IEC-ARA 2 ?

24. Patients11 14012 2186 105 Revasc. (%)9553 Antiplatelet479272 Beta blockers256217 Calcium blockers313140 Lipid lowering355614 Brugts JJ, et al. Eur Heart J. 2009;30:1385-1394. ADVANCE EUROPA PROGRESS Role of concomitant therapy DiabetesCADStroke

25. 8.0 Plac.Perin. 6709 5509 6831 5387 Previous Revasc. Lipid lowering yes no yes no 6.6 12.2 9.6 8.3 7.0 11.9 9.3 EUROPA Consistent benefit of ACE inhibitors EUROPA Investigators. Lancet 2003;362:782-788.

26. ACE inhibitorsCalcium channel blockers CHD CHD Verdecchia P, et al. Hypertension. 2005;46:386-392.

27. - 15% risk of CHD CHD ACE inhibitorsCalcium channel blockers Verdecchia P, et al. Hypertension. 2005;46:386-392.

28. ACE inhibitors Calcium channel blockers STROKE Verdecchia P, et al. Hypertension. 2005;46:386-392.

29. STROKE ACE inhibitorsCalcium channel blockers - 8% stroke Verdecchia P, et al. Hypertension. 2005;46:386-392.

30. Les questions Associer IEC et autres traitements ? Equivalence de tous les IEC ? Equivalence IEC-ARA 2 ?

31. Effects of ACE-I on AMI in patients without LV dysfunction Danchin et al. Arch Intern Med 2006 Q 20 R 10 R 5/10 E 20 P 8 T 2/4 E 20

32. 1 Odds Ratio (95% CI) EUROPA PEACE HOPE Overall SOLVD-P AIRE SAVE SOLVD-T TRACE Overall 20.5 ACE-i Placebo 5.2 6.8 5.3 5.3 9.912.3 8.1 9.0 0.81 (0.75-0.89) 11.915.2 8.210.7 12.615.2 6.7 8.1 6.7 8.3 0.79 (0.70-0.89) 8.911.0 Myocardial Infarction Patients with or without LV dysfunction Dagenais G et al. Lancet 2006; 368:581-588

33. 1 Odds Ratio (95% CI) EUROPA PEACE HOPE Overall SOLVD-P AIRE SAVE SOLVD-T TRACE Overall 20.5 ACE-I Placebo 7.9 9.8 9.5 10.2 14.0 17.8 22.928.2 0.81 (0.75-0.87) 29.634.3 39.145.6 43.851.0 10.3 12.4 20.0 22.8 0.79 (0.73-0.85) 29.234.1 Dagenais G et al. Lancet 2006; 368:581-588 Death, MI, or Stroke Patients with or without LV dysfunction

34. Les questions Associer IEC et autres traitements ? Equivalence de tous les IEC ? Equivalence IEC-ARA 2 ?

35. Are ARBs the cause of more AMIs? BMJ 27 November 2004 Etudes retenues : VALUE, CHARM alternative, CHARM preserved, SCOPE, LIFE, RENAAL, tantôt vs contrôle (VALUE), tantôt vs placebo

36. ARBs vs PCB: AMI

37. ARBs vs control: AMI ONTARGET Risk of AMI (telmisartan vs ramipril) OR=1.07 (0.94-1.22)

38. J Hypertens 2007;25:951-958. BP-independent reduction in CHD by ACE-I BPLTTC Regression Meta-analysis ARBs Risk DecreaseRisk Increase RRR 9% (14% to 3%), P=0.004 RRR -8% (17% to -39%), NS 30%20%10% 0% 10%20%30% ACE inhibitors BP-independent effectACE inhibitors vs ARBs Additional RRR of CHD at zero BP reduction P=0.002 « For ACEI, but not for ARB, there is evidence of blood pressure- independent effects on the risk of major coronary disease events. »

39. Conclusion Le perindopril, seul ou en association s'est avéré bénéfique dans la prise en charge de la maladie athéroscléreuse, en réduisant les événements coronaires, cérébro-vasculaires, et la mortalité. Ces effets sont retrouvés quel que soit le niveau de risque des patients, y compris dans de populations recevant les autres traitements recommandés.