1. Study rationale and design EUROPA Study Investigators Lancet. 2003;362:782-788.

2. ACE inhibition for secondary prevention of CAD Rationale Anti-atherosclerotic effects Anti-atherosclerotic effects Plaque rupture reduction Plaque rupture reduction Improvement in vascular endothelial function Improvement in vascular endothelial function Enhanced fibrinolysis Enhanced fibrinolysis Modulation of neurohormonally-induced arterial vasoconstriction Modulation of neurohormonally-induced arterial vasoconstriction Blood pressure lowering Blood pressure lowering LV hypertrophy reduction LV hypertrophy reduction Angiotensin II reduction / bradykinin increase

3. Hypothesis In selected patient groups (high CV risk or LV dysfunction), ACE-I results in secondary prevention of coronary disease In selected patient groups (high CV risk or LV dysfunction), ACE-I results in secondary prevention of coronary disease However, the multiple ways by which ACE inhibition affects the atherosclerotic process, suggest that it might occur in all patients with coronary disease However, the multiple ways by which ACE inhibition affects the atherosclerotic process, suggest that it might occur in all patients with coronary disease

4. Aim of the study To investigate whether long-term administration of the ACE inhibitor perindopril, added to standard therapy, leads to a reduction of cardiovascular events in patients with documented coronary disease whatever their risk

5. Study endpoints CV mortality + non fatal MI + cardiac arrest CV mortality + non fatal MI + cardiac arrest Primary endpoint Secondary endpoints Total mortality + non fatal MI + unstable angina + cardiac arrest Total mortality + non fatal MI + unstable angina + cardiac arrest Heart failure Heart failure Revascularisation (PCI/CABG) Revascularisation (PCI/CABG) Stroke Stroke

6. Design Placebo 01224-1/2 Run-in period Randomisation Follow-up Months 3648 4 mg 8 mg Perindopril Perindopril 8 mg once daily 60

7. Selection criteria Male or female > 18 years of age Male or female > 18 years of age Documented coronary disease Documented coronary disease Not scheduled for revascularisation Not scheduled for revascularisation No clinical signs of heart failure No clinical signs of heart failure

8. Selection criteria Male or female > 18 years of age Male or female > 18 years of age Documented coronary disease Documented coronary disease Not scheduled for revascularisation Not scheduled for revascularisation No clinical signs of heart failure No clinical signs of heart failure

9. Documented coronary disease Previous MI > 3 months Previous MI > 3 months PCI / CABG > 6 months PCI / CABG > 6 months Angiographic evidence (  70% stenosis) Angiographic evidence (  70% stenosis) In males with chest pain: positive exercise or stress test In males with chest pain: positive exercise or stress test

10. Baseline characteristics

11. Patient flow Completed 6 107 Completed 6 108 Perindopril 6 110 Placebo 6 108 Randomised 12 218 Not randomised 1 437 Registered 13 655

12. 424 centres : 12 218 patients 102 176141130 57 1251 2176 115 94 300 399 285 511 890 17 22 2068 1772 277 134 209 65 197 830

13. Not randomised Overall: 1 437 of 13 655 pts 10.5 IntoleranceHypotension Creatinine/Potassium rise Poor compliance Major clinical event Non medical reasons Unspecified2.42.11.10.60.50.53.3%

14. Perindopril (mean  SD) Placebo Age (yrs) 60  9 Male (%) 8685 Weight (kg) 81  12 80  12 HR (bpm) 68  10 SBP (mmHg) 137  16 137  15 DBP (mmHg) 82  8 Baseline characteristics

15. Perindopril(%)Placebo (%) (%) Myocardial infarction 64.964.7 Revascularisation54.755.2 Stroke / TIA 3.43.3 Heart failure 1.31.2 Peripheral vascular disease 7.17.4 Medical history

16. Perindopril(%)Placebo (%) (%) Hypertension27.027.2 Diabetes mellitus 11.812.8 Hypercholesterolaemia63.363.3 Current smoker 15.415.1 Risk factors

17. Perindopril(%)Placebo(%) Platelet inhibitors 91.992.7  -blockers 62.061.3 Lipid lowering drugs 57.857.3 Nitrates42.843.0 Ca-blockers31.731.0 Diuretics9.19.4 Oral anticoagulants 4.44.2 Baseline medication

18. Results

19. Primary endpoint % CV death, MI or cardiac arrest Placebo annual event rate: 2.4% Perindopril Placebo p = 0.0003 RRR: 20% Years 0 2 4 6 8 10 12140 1 2345

20. Primary endpoint RRR: 20% [95% CI : 9 - 29] CV death, MI or cardiac arrest 0 100 200 300 400 500 600 700 No events Perindopril (6 110) 8.0% 488 Placebo (6 108) 9.9% 603

21. Primary and first secondary endpoint 0.51.02.0 20 14 22 46 14 RRR (%) Perindopril better Placebo better CV mortality, MI, CA CV mortality Non fatal MI Cardiac arrest Total mortality, MI, UAP,CA

22. Sub-groups analysis RRR (%) 0.51.02.0 Perindopril better Placebo better Previous MI No previous MI 22.4 12.1 Age  56 yrs Age 57 - 65 Age > 65 yrs 27.3 14.3 18.2 Male Female 19.3 22.0

23. Sub-groups analysis 0.51.0 2.0 Hypertension RRR (%) Perindopril better Placebo better No hypertension Diabetes mellitus No diabetes mellitus Stroke/TIA No stroke/TIA 18.6 19.9 18.9 19.0 15.8 19.9

24. 92% patients on platelet inhibitors Sub-groups analysis RRR (%) Lipid lowering drug Perindopril better Placebo better 0.51.02.0 No lipid lowering drug  -blockers No  -blockers Calcium blockers No calcium blockers 16.3 22.3 26.4 7.0 15.8 22.2

25. Secondary endpoints Fatal & non fatal MI, unstable angina 0.51.02.0 Perindopril better Placebo better Total mortality, MI, UAP,CA CV mortality & MI CV mortality, MI & stroke CV mortality, MI, revascularisation CV mortality, MI, unstable angina Non fatal and fatal MI Total mortality CV mortality Unstable angina Cardiac arrest Stroke Revascularisation Heart failure RRR (%) 14.0 19.3 17.4 11.3 15.5 16.5 23.9 11.0 13.9 7.1 45.6 4.3 4.2 39.2

26. Fatal and non fatal MI Perindopril Placebo 0 2 4 6 810 012345Years(%) p < 0.001 RRR: 24%

27. Heart Failure Perindopril Placebo 501234Years p = 0.002 RRR: 39% 0.0 0.5 1.0 1.5 2.0(%)

28. -1/2036121824303642485460 Months 70 80 90 100 110 120 130 140mmHg Blood pressure  SBP: 5 mmHg  DBP: 2 mmHg Perindopril 8mg Placebo

29. Adherence to treatment 061218243036 Months 0 20 40 60 80 100 120 (%)Placebo Perindopril 8mg ns

30. Conclusion

31. Summary of results In EUROPA, the largest and longest trial in stable documented CAD patients, perindopril 8 mg/d significantly reduced: CV mortality + non fatal MI + cardiac arrest: 20% CV mortality + non fatal MI + cardiac arrest: 20% CV mortality and non fatal MI: 19% CV mortality and non fatal MI: 19% Fatal + non fatal MI: 24% Fatal + non fatal MI: 24% Heart failure: 39% Heart failure: 39%

32. Absolute benefits Perindopril 8 mg once a day prevents one cardiovascular death, nonfatal MI or cardiac arrest among every 50 patients with coronary disease treated for 4 years

33. Summary of results Benefits occurred on top of recommended therapy (92% platelet inhibitors, 58% lipid lowering drugs, 62%  -blockers) and are consistent across predefined sub-groups Benefits occurred on top of recommended therapy (92% platelet inhibitors, 58% lipid lowering drugs, 62%  -blockers) and are consistent across predefined sub-groups Perindopril should be considered for chronic therapy in all patients with coronary disease Perindopril should be considered for chronic therapy in all patients with coronary disease

34. Possible explanations of results

35. R Ferrari, WJ Remme, M Simoons, M Bertrand, K FOX, On behalf of the EUROPA investigators. A sub study of PERTINENT PER indopril – T hrombosis, I nflammatio N, E ndothelial dysfunction and neurohormonal activation T rial Cardiovasc Res. 2007 Jan 1;73(1):237-46

36. The background hypothesis for EUROPA trial was a possible vascular and anti-atherosclerotic effect of perindopril (8 mg/day) The PERindopril - Thrombosis, InflammatioN, Endothelial dysfunction and Neurohormonal activation Trial (PERTINENT) is a sub-study of EUROPA designed to test this hypothesis

37. 1. Human Umbilical Vein Endothelial Cells (HUVECs) were isolated and incubated for 72 h with serum from healthy age matched volunteers (n=45) or EUROPA patients at baseline and after 1 year of treatment with either perindopril (n=43) or placebo (n=44) 2. Measurements: protein expression and activity of endothelial nitric oxide synthase (ecNOS) ratio between 2 cytosolic proteins: Bcl2 (anti-apoptotic) and Bax (pro-apoptotic) rate of HUVECs apoptosis Endothelial Function PERTINENT Methodology Cardiovasc Res. 2007 Jan 1;73(1):237-46

38. PERTINENT Healthy subjects Incubated (72 h) with serum from Europa Patients ecNOS Apoptosis To mimic the effects of circulating blood on endothelial function Isolation of human endothelium Methodology Cardiovasc Res. 2007 Jan 1;73(1):237-46

39. Age (mean) 61606060 Male (%) 93938585 Previous MI (%) 77656565 Diabetes mellitus (%) 1471312 SBP (mmHg) 138139137137 DBP (mmHg) 82818282 Lipid lowering therapy (%) 32355758  Blockers (%) 61636162 Calcium channel blockers (%) 39443132 Baseline characteristics PERTINENTEUROPA placebo perindopril PERTINENT

40. Effects of HUVECs incubation with serum from: 0 10 2.5 7.5 ecNOS expression (arbitrary units/mg protein) Controls p<0.01 # Controls n = 45 9.8 CAD PERTINENT patients 1 year p = ns ‡ Placebo n = 44 Perindopril n = 43 7.6 8.7 baseline Placebo n = 44 Perindopril n = 43 7.4 7.1 # p=controls vs baseline ‡ p=  perindopril vs  placebo ecNOS expression 5 PERTINENT Cardiovasc Res. 2007 Jan 1;73(1):237-46

41. Controls n = 45 3.5 p <0.01 # p < 0.05 ‡ Placebo n = 44 2.5 Perindopril n = 43 2.4 Placebo n = 44 2.9 Perindopril n = 43 3.3 1 year baseline # p=controls vs baseline ‡ p=  perindopril vs  placebo 0 4 1 3 ecNOS activity (pmol/min/mg protein) Effects of HUVECs incubation with serum from: ControlsCAD PERTINENT patients 2 PERTINENT ecNOS activity Cardiovasc Res. 2007 Jan 1;73(1):237-46

42. p < 0.01 ‡ CAD PERTINENT patients baseline1 year 0.7 Placebo n = 44 0.9 Placebo n = 44 0.8 Perindopril n = 43 0.4 Perindopril n = 43 0.3 Controls Controls n = 45 p<0.05 # Bax /Bcl-2 ratio 0 1 0.5 # p=controls vs baseline ‡ p=  perindopril vs  placebo BAX / Bcl2 Ratio (pro-) / (anti-) apoptosis Effects of HUVECs incubation with serum from PERTINENT Cardiovasc Res. 2007 Jan 1;73(1):237-46

43. 1.3 Controls n = 45 p<0.01 # # p=controls vs baseline ‡ p=  perindopril vs  placebo p < 0.05 ‡ baseline 1 year Placebo n = 44 7.0 Perindopril n = 43 4.7 Perindopril = 43 6.8 Placebo n = 44 7.8 Apoptosis (%) 0 2.5 5.0 10.0 7.5 CAD PERTINENT patients Controls Effects of HUVECs incubation with serum from Apoptosis PERTINENT Cardiovasc Res. 2007 Jan 1;73(1):237-46

44. To draw further insights on the mechanisms of action of perindopril we have also measured in the plasma from the same population: angiotensin II (Ang II) by radioimmunoassay after HPLC separation bradykinin (BK) by radioimmunoassay after HPLC separation tumor necrosis factor (TNF)-alpha by ELISA as all these substances are known to modulate ecNOS and the rate of endothelial apoptosis Methodology PERTINENT Cardiovasc Res. 2007 Jan 1;73(1):237-46

45. p <0.05 ‡ CAD PERTINENT patients baseline1 year Perindopril n = 43 17.1 Placebo n = 44 15.8 Placebo n = 44 14.4 Perindopril n = 43 12.5 Controls Controls n = 45 10.8 p<0.01 # # p=controls vs baseline ‡ p=  perindopril vs  placebo 0 5 10 15 20 25 Angiotensin II (pg/mL) Angiotensin II PERTINENT Cardiovasc Res. 2007 Jan 1;73(1):237-46

46. 0 10 20 Bradykinin (pg/mL) p <0.05 ‡ CAD PERTINENT patients baseline1 year Placebo n = 44 Perindopril n = 43 14.8 12.4 Placebo n = 44 Perindopril n = 43 12.3 17.7 Controls Controls n = 45 18.3 p<0.01 # # p=controls vs baseline ‡ p=  perindopril vs  placebo Bradykinin 5 15 PERTINENT Cardiovasc Res. 2007 Jan 1;73(1):237-46

47. Bradykinin/Angiotensin II ratio Controls Controls n = 45 1.9 p<0.01 # PERTINENT Neurohumoral Activity 0 0.5 1.0 1.5 2.0 Bradykinin/Angiotensin II (pg/mL) CAD PERTINENT patients Placebo n = 44 Perindopril n = 43 Perindopril n = 43 1.111.21.9 p = 0.02 ‡ baseline1 year # p=controls vs baseline ‡ p=  perindopril vs  placebo Cardiovasc Res. 2007 Jan 1;73(1):237-46

48. 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 Perindopril n = 43 27.127.728.924.6 CAD PERTINENT patients # p=controls vs baseline ‡ p=  perindopril vs  placebo TNF-  PERTINENT Cardiovasc Res. 2007 Jan 1;73(1):237-46

49. Correlations There was no correlation of any parameter with SBP, DBP nor with any concomitant medications The only significant correlations observed are: bradykinin vs. ecNOS expression (r=0.43) bradykinin vs. ecNOS activity (r=0.45) PERTINENT Cardiovasc Res. 2007 Jan 1;73(1):237-46

50. ecNOS activity and expression in HUVECs incubated for 72 h with serum of EUROPA patients receiving perindopril with or without ICATIBANT in the incubation medium n = 87 7.4 Baseline ICATIBANT Without Perindopril n = 43 8.7 Perindopril n = 20 7.0 With ecNOS EXPRESSIONecNOS ACTIVITY (arbitrary units/mg protein) 0 2.5 5.0 10.0 7.5 0 2.5 5.0 10.0 7.5 (pmol/min/mg protein) n = 87 Baseline 2.5 ICATIBANT 2.1 Perindopril n = 20 With Perindopril n = 43 Without 3.3 PERTINENT Cardiovasc Res. 2007 Jan 1;73(1):237-46

51. Treatment with perindopril for 1 year results in: Restoration of Angiotensin II/Bradykinin balance Improvement of ecNOS Activity Reduction of TNF  activation Reduction of the rate of endothelium apoptosis Messages PERTINENT Cardiovasc Res. 2007 Jan 1;73(1):237-46

52. To further investigate the role of perindopril on endothelial function we have measured plasma levels of von Willebrand factor (vWf), a marker of endothelial cell damage, both at baseline and after 1 year of treatment with either perindopril (n=591) or placebo (n=566) Methodology PERTINENT Cardiovasc Res. 2007 Jan 1;73(1):237-46

53. von Willebrand factor vWf (%/Unit) 0 20 40 60 80 100 120 140 160 180 200 CAD PERTINENT patients baseline Placebo n =566 145 Perindopril n = 591 142 1 year p <0.05 # Perindopril n = 591 Placebo n = 566 135 128 # P =  perindopril vs  placebo PERTINENT Cardiovasc Res. 2007 Jan 1;73(1):237-46

54. Years Significant Prognostic Role for vWf outcome 0.7 0.8 09 1.002 3 41 Low (  142% / Unit) High (>142% / Unit) p<0.01 PERTINENT Cardiovasc Res. 2007 Jan 1;73(1):237-46

55. Conclusions In CAD patients, treatment with perindopril: 1) increases bradykinin which in turn up-regulates ecNOS activity 2) reduces angiotensin II and TNF  levels 3) reduces rate of apoptosis 4)reduces von Willebrand factor levels which are predictive for outcomes This results in improvement of endothelial dysfunction PERTINENT Cardiovasc Res. 2007 Jan 1;73(1):237-46

56. These data show that the vascular and anti-atherosclerotic effects of perindopril may be important at least in part explaining the results of EUROPA PERTINENT Conclusions Cardiovasc Res. 2007 Jan 1;73(1):237-46

57. Acknowledgements The PERTINENT patients and Investigators The PERTINENT corelabs for the investigations Gussago (Italy) and Birmingham (UK) The PERTINENT Steering Committee: F Arbustini (Italy), A Blann (UK), D Cokkinos (Greece), C Kluft ( The Netherlands), MPM de Maat (The Netherlands), J Tavazzi (Italy) The PERTINENT Statistical Committee: A de Carli (Italy), G Parinello (Italy) The EUROPA Executive Committee: KM FOX (UK), M Bertrand (France), WJ Remme (The Netherlands), ML Simoons (The Netherlands) Cardiovasc Res. 2007 Jan 1;73(1):237-46

58. Verbetering coronaire endotheelfunctie HT patients

59. Verbetering structuur coronaire arteriën CAD patients

60. Vermindering LVH HT patients

61. US DATA sheetT/P ratios as stated by FDA CaptoprilNot stated (twice or 3 times daily) Benazepril   50% Quinapril50% Ramipril50% to 60% Lisinopril "At all doses studied mean antihypertensive effect was substantially smaller 24h after dosing than 6h after dosing" Enalapril Not stated but once- or twice- daily dosage FosinoprilDBP = 50% to 60%; SBP = 80% COVERSYL75% to 100% Trandolapril50% to 90% Physician's Desk Reference. 58 th ed. Montvale, NJ: Thomson PDR; 2004. Eenmaal daags, 24 uurs werking

62. Verbetert endotheelfunctie Ghiadoni L, Magagna A, Versan D, et al. Hypertension. 2003;41:1281-1286 HT patiënten

63. Verbetering vaatwandstructuur HT patiënten

64. Verbetering vaatwandstructuur HT patients

65. Mulvany MJ. Hypertension. 1995;25:474-481 Verbetering vaatwandstructuur, onafhankelijk van bloeddrukverlaging

66. HT patients Kuperstein R, Sasson Z. Circulation. 2000;102:1802-1806 Vermindert linkerventrikelhypertrofie onafhankelijk van bloeddruk verlaging

67. HCTZ 25 mg + amiloride 2,5 mg Perindopril 4 mg carotid artery elasticity (% improvement) 0 5 10 15 20 1 16* p < 0.05 *p<0.05 versus baseline  Double-blind randomized study  N = 41 hypertensive patients  T = 6 months Kool M.J. Van Bortel L.M. et al. J Hypertens 1995 ; 13 :839 - 848 Verbetert functie grote arterieen onafhankelijk van bloeddrukverlaging

68. Clinical implications

69. Burden of coronary disease 56 millions deaths worldwide in 2001 56 millions deaths worldwide in 2001 29% due to CV disease (~ 16 millions) 29% due to CV disease (~ 16 millions) (37% are foreseen in 2020) (37% are foreseen in 2020) 20 millions of people in the EU have coronary disease 20 millions of people in the EU have coronary disease 56 millions deaths worldwide in 2001 56 millions deaths worldwide in 2001 29% due to CV disease (~ 16 millions) 29% due to CV disease (~ 16 millions) (37% are foreseen in 2020) (37% are foreseen in 2020) 20 millions of people in the EU have coronary disease 20 millions of people in the EU have coronary disease

70. Plaque rupture Natural history of coronary atherosclerosis CV Risk factors

71. Silent ischemia Stable Angina Unstable angina MI Heart failure Sudden death Coronary Disease Clinical expression of coronary disease

72. Relative risk reduction in the primary end point is consistent across all groups of cardiovascular risk Low risk RRR 17% Placebo5.3% 3.8 4.0 4.2 4.4 4.6 4.8 5.0 5.2 Coversyl 8 mg 4.4% Medium risk RRR 32% 9% Placebo 6.1% Coversyl 8 mg 0 1 2 3 4 5 6 7 8 9 10 High risk RRR 12%15.4%Placebo 13.5% Coversyl 8 mg 12.5 13.0 13.5 14.0 14.5 15.0 15.5 No heterogeneity between groups (P =0.15) Efficacy whatever their level of risk Deckers JW, Goedhart DM, Boersma E, et al.Deckers JW, Goedhart DM, Boersma E, et al. Treatment benefit by perindopril in patients with stable coronary artery disease at different levels of risk. Eur Heart J. 2006 Apr;27(7):796-801. 5.4

73. Efficacy whatever their concomitant preventive therapy Lipid-lowering drug  -blockers Previous revascularization Favors Coversyl 8 mg Favors placebo 0.5 1.02.0 RRR % 17 26.4 16.3 EUROPA Study Investigators Lancet. 2003;362:782-788.

74. Mean EF 57 + 10.4%. Only 3.2% of patients had an EF < 40% Overall EUROPA population N=12 218 RRR 20% P=0.0003 8.0% Coversyl 8 mg 9.9% Placebo EUROPA patients LVEF  40% N=6 878 RRR 16% P=0.03 8.3% Coversyl 8 mg 9.8% Placebo Relative risk reduction in the primary end point is consistent in patients with normal left ventricular function Efficacy in patients with normal LVEF Bertrand ME. Effects of perindopril on long term clinical outcome of patients with coronary artery disease and preserved left ventricular function.The EUROPA study. Eur Heart J.2005;26(Abst Suppl):578.

75. No interaction between treatment and SBP: P=0.464 Efficacy in CAD patients whether they are hypertensive or not Efficacy in CAD patients whether they are hypertensive or not RRR 39% RRR 17% RRR 18% 0% 5% 10% 15% 20% <120 mm Hg >120 - 120 - <140 mm Hg >140 mm Hg 575 666 2 722 2 788 2 722 2 745 SBP Primary end point-risk reduction Coversyl 8 mg Coversyl 8 mg Placebo Remme WJ. Prevention of cardiovascular events by perindopril in patients with stable coronary artery disease does not depend on blood pressure and its reduction.Results from the EUROPA study. Circulation 2004;110:III-638. Abstract 2919.

76. Efficacy in CAD patients with/without previous revascularization Efficacy in CAD patients with/without previous revascularization Previous M.I. No previous M.I. Previous revasc. No previous revasc. Number of patients Coversyl 8 mg Placebo Primary events (%) 7 910 8.9 11.3 4 299 6.4 7.3 6 709 6.6 8.0 5 509 9.6 12.2 0.5 1.0 2.0 Favors Coversyl 8 mg Favors placebo EUROPA Study Investigators.Lancet.2003;362:782-788.

77. New therapeutic option for CAD patients In perspective of other trials  Statins  Other ACEI or BP lowering drugs In perspective of other trials  Statins  Other ACEI or BP lowering drugs

78. PROGRESS SOLVD SAVE AIRE TRACE HOPE SOLVD (prev) EUROPA Cardiovascular protection of ACE-I (and CA channel blockers)   Post MI   LVSD + EF<40%   HF High CV risk, no HF Stable CAD, No HF Stroke, no HF PEACE, no CV protection ACTION, no CV protection

79. 22.6 15.9/13.2 7.9 2.8 Placebo MI rate per 100 subjects per 5 years WOS : NEJM 1995 CARE : NEJM 1996 LIPID : NEJM 1998 4S : Lancet 1994 TexCAPS: JAMA 1998 Major Statin Trials CARE n=4,159 TC 5.4 mmol/l LIPID n=9,014 TC 5.6 mmol/l WOS n=6,595 TC 7.0 mmol/l 4S n=4,444 TC 6.8 mmol/l With CHD + high cholesterol With CHD + normal cholesterol Without CHD + high cholesterol TexCAPS n=6,605 TC 5.7 mmol/l Without CHD + low HDL

80. EUROPACARE Patiënten inclusie Leeftijd60jr59jr Vrouw15%14% CVL100%100% Hartinfarct in het verleden65%100% Revascularisatie in het verleden55%54% Diabetes12%15% SBP137 mmHg129 mmHg Cholesterol5,6 mmol/l5,2 mmol/l Actieve behandeling Antiplatelet therapie92%83% Betablokker62%39% Calciumblokker31%38% Calciumblokker31%38% Lipidenverlaging58%50% ACE-remmer50%14% Behandeleffecten (RR) CV / CHZ sterfte, niet fataal MI20%24% Hartinfarct24%25% Revascularisatie5%27% Hartfalen39%na EUROPACARE Patiënten inclusie Leeftijd60jr59jr Vrouw15%14% CVL100%100% Hartinfarct in het verleden65%100% Revascularisatie in het verleden55%54% Diabetes12%15% SBP137 mmHg129 mmHg Cholesterol5,6 mmol/l5,2 mmol/l Actieve behandeling Antiplatelet therapie92%83% Betablokker62%39% Calciumblokker31%38% Calciumblokker31%38% Lipidenverlaging58%50% ACE-remmer50%14% Behandeleffecten (RR) CV / CHZ sterfte, niet fataal MI20%24% Hartinfarct24%25% Revascularisatie5%27% Hartfalen39%na Similar benefits of statins and ACE inhibition

81. HOPE RRR=22% P <0.001 PEACE RRR=4% P=0.43 EUROPA

82. 4 mg/d 2 mg/d 30 mg/d 2.5 mg/d Run-in Dose titration and acceptability 4 mg/d 8 mg/d 60 mg/d 10 mg/d Target dose 8.290 PEACE 12.2187.6659.297N EUROPAACTIONHOPE Study population 69938471 Achieved target dose (%) PerindoprilRamiprilDrugTrandolapril Nifidepine GITS 75817974 Compliance (%)

83. N8.29012.2187.6659.297 Study populations 45 134 64 PEACE 606366Age 27*/455247* Hypertensive (%) 137137139 SBP (mm Hg) 858073 Men (%) EUROPAACTIONHOPEStudy * > 160/95 mm Hg, or antihypertensive treatment. All other BP value´s % patients with < 140/90 mmHg. 78828079 DBP (mm Hg) 3/15/26/33/2 BP reduction (mmHg) 82 ?636266 Hyperchol (%)

84. Concomitant treatments 70 60 91 8.290 PEACE 928676 Antiplatelet drugs (%) 58/69 at 3 yrs 6329 Lipid lowering drugs (%) 627639 Beta blockers (%) 12.2187.6659.297N EUROPAACTIONHOPE Study population

85. Study populations 72 7 55 8.290 PEACE 655153 History of MI (%) 554544 Revascularisation (%) 3na11 CVA / TIA (%) 12.2187.6659.297N EUROPAACTIONHOPE Study population 17121538 DIABETES (%) 0000 Heart failure (%) na71343 PAD (%)

86. Univariate Hazard Ratios Age decades > 65 yrs Male Smoking Diabetes SBP / 10 mmHg PVD/CVD Previous MI Previous Revasc. 0 0,511,522,53 Risk factors

87. Study populations 72 7 55 8.290 PEACE 655153 History of MI (%) 554544 Revascularisation (%) 3na11 CVD (%) 12.2187.6659.297N EUROPAACTIONHOPE Study population 17121538 DIABETES (%) 0000 Heart failure (%) na71343 PVD (%)

88. 4,2 year event rate in the placebo group 4,2 year event rate in the placebo group 12,019,5 CV Death & MI (%) 7,111,8 Non-fatal MI (%) 4,97,7 CV death (%) ACTIONHOPE 7,8 10,3 4,6 6,2 3,2 4,1 PEACE EUROPA 4,2 years is the duration of the mean follow up in EUROPA

89. 1 year event rate in the placebo group 2,94,6 CV Death & MI (%) 1,72,8 Non-fatal MI (%) 1,21,8 CV death (%) ACTIONHOPE 1,9 2,5 1,1 1,5 0,8 1,0 PEACE EUROPA

90. 10.51.5 HOPE EUROPA PEACE 0.81 0.79 0.96 [0.71-0.92] [0.70-0.90] [0.83-1.12] p=0.0008 p=0.0003 p=0.62 OR95% CI The HOPE Study Investigators. N Engl J Med 2000;342:145-53. EUROPA Study Investigators Lancet. 2003;362:782-788. The PEACE Trial Investigators. N Engl J Med 2004;351:2058-6 The ACTION Investigators. Lancet 2004; 364: 849–57.. Results HOPE, EUROPA, PEACE and ACTION ACTION1.00[0.85-1.18] p=0.54 Bloeddruk verschillen 3/2 5/2 4/4 6/3 CV Death and MI Placebo betterTreatment better

91. Standard preventive therapy Aspirin Aspirin Statine Statine ACE-inhibitor ACE-inhibitor Beta-blocker (post MI) Beta-blocker (post MI) Evidence based ACE-inhibitor: Only perindopril 8mg/d and ramipril 10mg/d Only perindopril 8mg/d and ramipril 10mg/d Only perindopril 8mg/d Only perindopril 8mg/d è irrespective of risk level è on top of adequate other preventive therapy Beneficial in stable CAD patients with >1 not adequately controlled risk factor(s): Myocardial infarction Myocardial infarction Hypertension Hypertension Diabetes Diabetes Dyslipidemia Dyslipidemia Smoking Smoking Standard preventive therapy Aspirin Aspirin Statine Statine ACE-inhibitor ACE-inhibitor Beta-blocker (post MI) Beta-blocker (post MI) Evidence based ACE-inhibitor: Only perindopril 8mg/d and ramipril 10mg/d Only perindopril 8mg/d and ramipril 10mg/d Only perindopril 8mg/d Only perindopril 8mg/d è irrespective of risk level è on top of adequate other preventive therapy Beneficial in stable CAD patients with >1 not adequately controlled risk factor(s): Myocardial infarction Myocardial infarction Hypertension Hypertension Diabetes Diabetes Dyslipidemia Dyslipidemia Smoking Smoking Cardiovascular risk management in stable CAD patients Without heart failure