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Study rationale and design

Study rationale and design. EUROPA Study Investigators Lancet. 2003;362:782-788. ACE inhibition for secondary prevention of CAD. Rationale. Anti-atherosclerotic effects Plaque rupture reduction Improvement in vascular endothelial function Enhanced fibrinolysis

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Study rationale and design

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

  2. ACE inhibition forsecondary prevention of CAD Rationale • Anti-atherosclerotic effects • Plaque rupture reduction • Improvement in vascular endothelial function • Enhanced fibrinolysis • Modulation of neurohormonally-induced arterial vasoconstriction • Blood pressure lowering • 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 • 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 administrationof the ACE inhibitor perindopril, added tostandard therapy, leads to a reduction ofcardiovascular events in patients withdocumented coronary disease whatever their risk

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

  6. 4 mg 8 mg Design Perindopril 8 mg once daily Perindopril Placebo 60 -1 -1/2 0 12 24 36 48 Months Randomisation Run-in period Follow-up

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

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

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

  10. Baseline characteristics

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

  12. 141 176 57 115 134 130 2068 94 1772 300 277 1251 197 2176 209 399 65 285 830 22 890 102 17 511 424 centres : 12 218 patients

  13. % Intolerance Hypotension Creatinine/Potassium rise Poor compliance Major clinical event Non medical reasons Unspecified 2.4 2.1 1.1 0.6 0.5 0.5 3.3 Overall: 1 437 of 13 655 pts 10.5 Not randomised

  14. Baseline characteristics

  15. Medical history

  16. Risk factors

  17. Baseline medication

  18. Results

  19. 14 12 10 8 6 RRR: 20% 4 p = 0.0003 2 0 1 0 2 3 4 5 Years Primary endpoint % CV death, MI or cardiac arrest Placebo Perindopril Placebo annual event rate: 2.4%

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

  21. Placebobetter Perindoprilbetter RRR (%) 20 CV mortality, MI, CA CV mortality 14 Non fatal MI 22 Cardiac arrest 46 Total mortality, MI, UAP,CA 14 0.5 1.0 2.0 Primary and firstsecondary endpoint

  22. RRR (%) Perindopril better Placebo better Male 19.3 Female 22.0 Age  56 yrs 27.3 Age 57 - 65 14.3 Age > 65 yrs 18.2 Previous MI 22.4 No previous MI 12.1 0.5 1.0 2.0 Sub-groups analysis

  23. RRR (%) Perindoprilbetter Placebobetter Hypertension 18.6 No hypertension 19.9 Diabetes mellitus 18.9 No diabetes mellitus 19.0 Stroke/TIA 15.8 No stroke/TIA 19.9 2.0 0.5 1.0 Sub-groups analysis

  24. RRR (%) Perindoprilbetter Placebobetter Lipid lowering drug 16.3 No lipid lowering drug 22.3 -blockers 26.4 No -blockers 7.0 Calcium blockers 15.8 No calcium blockers 22.2 0.5 1.0 2.0 Sub-groups analysis 92% patients on platelet inhibitors

  25. RRR (%) Perindopril better Placebo better 14.0 Total mortality, MI, UAP,CA 19.3 CV mortality & MI 17.4 CV mortality, MI & stroke 11.3 CV mortality, MI, revascularisation 15.5 CV mortality, MI, unstable angina 16.5 Fatal & non fatal MI, unstable angina 23.9 Non fatal and fatal MI 11.0 Total mortality 13.9 CV mortality 7.1 Unstable angina 45.6 Cardiac arrest 4.3 Stroke 4.2 Revascularisation 39.2 Heart failure 0.5 1.0 2.0 Secondary endpoints

  26. RRR: 24% 10 p < 0.001 8 6 4 2 0 Years 0 1 2 3 4 5 Fatal and non fatal MI (%) Placebo Perindopril

  27. RRR: 39% (%) 2.0 p = 0.002 1.5 1.0 0.5 0.0 Years 0 1 2 3 4 5 Heart Failure Placebo Perindopril

  28. Perindopril 8mg Placebo 140 mmHg 130 120 110 100 90 80 70 -1 -1/2 0 3 6 12 18 24 30 36 42 48 54 60 Months Blood pressure SBP: 5 mmHg DBP: 2 mmHg

  29. (%) 120 100 80 60 Placebo 40 Perindopril 8mg 20 0 0 6 12 18 24 30 36 Months Adherence to treatment ns

  30. Conclusion

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

  32. Absolute benefits Perindopril 8 mg once a day preventsonecardiovascular death, nonfatal MIor cardiac arrest among every50patients with coronary disease treatedfor 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 • Perindopril should be considered for chronic therapy in all patients with coronary disease

  34. Possible explanations of results

  35. A sub study of PERTINENT PERindopril – Thrombosis,InflammatioN,Endothelial dysfunction andneurohormonal activation Trial R Ferrari, WJ Remme, M Simoons, M Bertrand, K FOX, On behalf of the EUROPA investigators. Cardiovasc Res. 2007 Jan 1;73(1):237-46

  36. The background hypothesis for EUROPA trialwas a possible vascular and anti-atheroscleroticeffect of perindopril (8 mg/day) • The PERindopril - Thrombosis, InflammatioN,Endothelial dysfunction and Neurohormonalactivation Trial (PERTINENT) is a sub-study ofEUROPAdesigned to test this hypothesis

  37. Methodology PERTINENT Endothelial Function 1.Human Umbilical Vein Endothelial Cells(HUVECs) wereisolated and incubated for 72 h with serum from healthyage matched volunteers (n=45) or EUROPA patientsat baseline and after 1 year of treatment with eitherperindopril (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 Cardiovasc Res. 2007 Jan 1;73(1):237-46

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

  39. PERTINENT Baseline characteristics PERTINENT EUROPA placebo perindopril placebo perindopril

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

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

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

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

  44. Methodology PERTINENT To draw further insights on the mechanisms of action ofperindopril we have also measured in the plasma fromthe 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 Cardiovasc Res. 2007 Jan 1;73(1):237-46

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

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

  47. Controls CAD PERTINENT patients baseline 1 year p<0.01 # p = 0.02 ‡ 2.0 1.5 Bradykinin/Angiotensin II (pg/mL) 1.9 1.0 1 1.1 1.2 1.9 0.5 Controlsn = 45 Placebon = 44 Perindopriln = 43 Placebon = 44 Perindopril n = 43 0 PERTINENTNeurohumoral Activity Bradykinin/Angiotensin II ratio # p=controls vs baseline ‡p=  perindopril vs  placebo Cardiovasc Res. 2007 Jan 1;73(1):237-46

  48. Controls CAD PERTINENT patients baseline 1 year 40 p<0.01 # p <0.05 ‡ 35 30 25 TNF-a(pg/mL) 20 27.7 27.1 28.9 24.6 15 18.0 10 5 0 Controlsn = 45 Placebon = 44 Perindopriln = 43 Placebon = 44 Perindopriln = 43 TNF-  PERTINENT # p=controls vs baseline ‡p=  perindopril vs  placebo Cardiovasc Res. 2007 Jan 1;73(1):237-46

  49. PERTINENT Correlations • There was no correlation of any parameter withSBP, DBPnor with any concomitant medications • The only significant correlations observed are: • bradykinin vs. ecNOS expression (r=0.43) • bradykinin vs. ecNOS activity (r=0.45) Cardiovasc Res. 2007 Jan 1;73(1):237-46

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

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