2. ACE INHIBITION TRIALS IN CAD SECONDARY PREVENTION TREATMENT AFTER AMI EFFICACY BEFORE   EUROPA   HOPE   PEACE   QUIET   CONSENSUS 2   GISSI 3   ISIS 4 TIMING OF ADMINISTRATION FROM AMI   AIRE   SAVE   TRACE   CONSENSUS 1   SOLVD

3. ACE INHIBITION AND CAD FROM TREATMENT TO PREVENTION WHY ?   Unexpected data from clinical trials   Shifting from pharmacological (blood pressure reduction) to biological (antiatherosclerosis) effects of ACE inhibitors

4. Vascularsmoothmusclecell Mode of action of ACE inhibition ANGIOTENSINOGENKININOGEN Renin Angiotensin I Angiotensin II Kallikrein ACE Inactivated Vasoconstriction Vasoconstriction Cell proliferation Vasodilation Vasodilation Growth inhibition + + + Receptors Receptors Endothelial cell Endothelial cell B2B2B2B2 Receptor Receptor + Bradykinin AT CMF Learning Systems in 2000, “Courtesy CM Ferrario, MD”

5.  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

6. Enhanced Angiotensin II favours atherosclerosis  Increased uptake and oxydation of LDL by macrophages and endothelial cells  Vascular inflammation: - production of pro-inflammatory genes (IL6, TNF , MCP1) - adhesion molecules (ICAM-1, VCAM-1) - recruitment macrophages, monocytes (VEGF)  Matrix degradation (increased matrix-metalloproteinases)  Fibrinolytic imbalance  Oxyradical production (NADH/NADPH oxidase activity, cNOS) leading to endothelial dysfunction  Increased uptake and oxydation of LDL by macrophages and endothelial cells  Vascular inflammation: - production of pro-inflammatory genes (IL6, TNF , MCP1) - adhesion molecules (ICAM-1, VCAM-1) - recruitment macrophages, monocytes (VEGF)  Matrix degradation (increased matrix-metalloproteinases)  Fibrinolytic imbalance  Oxyradical production (NADH/NADPH oxidase activity, cNOS) leading to endothelial dysfunction

7. Enhanced Bradykinin Protects against Atherosclerosis by:  Counteracting the negative effects of angiotensin II  Increasing cNOS expression and preserving endothelial function  Exerting indirect antioxidant effect  Increasing t-PA and fibrinolysis  Exerting a cardiovascular anti-remodelling effect  Counteracting the negative effects of angiotensin II  Increasing cNOS expression and preserving endothelial function  Exerting indirect antioxidant effect  Increasing t-PA and fibrinolysis  Exerting a cardiovascular anti-remodelling effect

8. 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

9. Reliable 24-hour blood pressure control High tissue ACE affinity Specifically increase in bradykinin Anti-ischemic properties : 3 Normalisation of the fibrinolytic balance 3 Normalization of structure of resistance arteries 3 Correction of coronary endothelial dysfunction Anti-atherosclerotic effect Good tolerance even in fragile patients (heart failure, stroke) Reliable 24-hour blood pressure control High tissue ACE affinity Specifically increase in bradykinin Anti-ischemic properties : 3 Normalisation of the fibrinolytic balance 3 Normalization of structure of resistance arteries 3 Correction of coronary endothelial dysfunction Anti-atherosclerotic effect Good tolerance even in fragile patients (heart failure, stroke) Why perindopril for EUROPA?

10. The multiple ways ACE inhibition affects the atherosclerotic process suggest that significant secondary prevention of ischemic events should occur in all patients with coronary artery disease, irrespective of cardiac function or further high-risk profile Hypothesis Hypothesis

11. Perindopril: a reliable 24-h blood pressure control Myers MG. Can J Cardiol 1996; 12: 1191-1996 SBP DBP

12. Perindopril specifically Increases the cNOS Expression in patients with CAD Perindopril specifically Increases the cNOS Expression in patients with CAD Zhuo JL et al. Hypertension 2002;39[part 2]:634-638. Model: stained human coronary artery bypass graft

13. Specifically increase of bradykinin perindopril perindopril Morishita T, Tsutsui M, Shimokawa H et al.Jpn J. Pharmacol. 2002 ;88 :101- 107.

14. Anti-ischemic effects in CAD patients Morishita T et al. Jpn J Pharmacol. 2002;88:100-107. - 42% - 39% EXERCISE-INDUCED LEFT VENTRICULAR SYSTOLIC DYSFUNCTION ST-SEGMENT DEPRESSION 0 1 2 3 4 5 6 P < 0.05 42% Before 3 months perindopril ST-segment changes (mm) 0 0.5 1 1.5 2 2.5 P < 0.05 39 % Before 3 months perindopril Left ventricular motion score

15. tPA release in the coronary circulation Hypertensive patients (n=34) Minai K et al. Japanese Circulation Journal. 2001;65(suppl I-A) * P<0.05 vs control * P<0.05 vs control ** P<0.05 vs losartan Losartan 50 mg/d Control perindopril 4 mg/d Bradykinin (µg/min) tPA release (ng/min/100 mL) -100 100 300 500 700 00.20.62.0 * ** Enhancement of fibrinolysis

16. Normalization of structure of resistance arteries in CAD patients Schwartzkopff B, et al. Hypertension 2000;36:220-225 0 200 400 600 800 0,0 2,0 4,0 6,0 8,0 Pre-Treatment Post-Treatment (m2)(m2) (Vv%) 558  270 Periarteriolar Collagen Area Total Interstitial Collagen 260  173 5.5  3.8 4.3  3.2 p=0.04 53% 22% n=14 patients Perindopril 4-8 mg/qd for 12 months Coronary reserve

17. * P<0.01 6 months versus baseline ** P<0.01 versus other treatments Improvement in endothelial dysfunction Ghiadoni L. et al. Hypertension 2003;41:1281-1286 FMD (%) 7.1 6.4 4.8 5.1 5.7 5.6 5.2 Normotensive patients Hypertensive patients Perindopril 4mg Nifedipine 30-60 mg Amlodipine 5-10 mg Atenolol 50-100mg Nebivolol 5-10mg Telmisartan 80-160mg *** 8 6 4 2

18. Anti-atherosclerotic effect (A) Control Candido R et al. Circulation. 2002;106:246-253. (B) Diabetic apoE-deficient mice (C) Diabetic apoE-deficient mice perindopril 4 mg-treated ControlPathologic status Treated by perindopril during 5 months

19. Good tolerance even in fragile patients MacFadyen RJ, et al. Br Heart J 1991; 66: 206-211 Compared to enalapril and captopril, perindopril produces no more first-dose hypotension than placebo Change in mean arterial pressure (mmHg ) Placebo perindopril 2 mg Captopril 6.25 mg Enalapril 2.5 mg 5 0 -5 -10 -15 -20 -25 -30 01234567891024 Time (hours) * * * * * * * * * * * * * * * * * n = 48 * P< 0.05 versus placebo

20. 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 all patients with documented coronary disease

21. 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

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

23. 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

24. 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