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Les bénéfices du perindopril : à propos de 50 000 patients

Les bénéfices du perindopril : à propos de 50 000 patients. Nicolas DANCHIN, HEGP, Paris. Collaborations. Subventions de recherche : Pfizer, Servier , The MedCo Honoraires pour conférences et/ou consultance:

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Les bénéfices du perindopril : à propos de 50 000 patients

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  1. Les bénéfices du perindopril :à propos de 50 000 patients 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. Morbi-mortality trials of perindoprilalong the cardiovasculardisease continuum (n=50 822) Post-stroke patients n=6 105 Patients with stable CAD n=12 218 Hypertensive patients n = 3 845 Post-AMI patients n=1 252 Hypertensive patients n=19 257 Diastolic HF n=850 Patients with diabetes n=11 140

  4. Reduction in cardiac and renalevents in diabetic patients Number of events Per / Ind Placebo Favours Relative risk 2P Favours (n=5,569) (n=5,571) Per / Ind placebo reduction (95% CI) Primary endpoint 861 938 9% (0 to 17) 0.04 Macrovascular events 8% (-4 to 19) 480 520 Microvascular events 9% (-4 to 20) 477 439 All coronary heart disease 14% (2 to 24) 0.02 468 535 Major coronary heart disease† 294 11% (-6 to 24) 265 Other coronary heart disease‡ 14% (-1 to 27) 283 324 <0.01 Total renal events 1243 1500 21% (15 to 27) 18% (-1 to 32) New or worsening nephropathy 216 181 New microalbuminuria 1094 1317 21% (14 to 27) 2.0 1.0 0.5 Hazard ratio Per+Ind, perindopril+indapamide fixed combination †Non-fatal MI or death from coronary heart disease ‡Unstable angina requiring hospitalisation, coronary revascularisation or silent MI ADVANCE Collaborative Group. Lancet 2007;370:829-40.

  5. Reduction in all-cause mortality in diabetic patients All-cause death 10 Placebo Perindopril+indapamide Cumulative incidence (%) 5 Relative risk reduction 14% p=0.025 0 0 6 12 18 24 30 36 42 48 54 60 Follow-up (months) ADVANCE Collaborative Group. Lancet 2007;370:829-40.

  6. Reduction in cardiovascularevents in hypertensive patients at CV risk 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) Selected end-points PrimaryNon-fatal MI (incl silent) + fatal CHD SecondaryTotal coronary end pointTotal CV event and proceduresAll-cause mortalityCardiovascular mortalityFatal and non-fatal stroke Tertiary New-onset diabetes mellitusNew-onset renal impairment Post hoc Primary end point + revascularization CV death + MI + stroke 0.50 0.70 1.00 1.45 2.00 amlodipine  perindopril better atenolol  thiazide better Dahlof B et al. Lancet 2005; 366: 895-906.

  7. Reduction in cardiovascularmortality in hypertensive patients at CV risk % 3.5 atenolol  thiazide (No. of events 342) 3.0 2.5 2.0 amlodipine  perindopril (No. of events 263) 1.5 1.0 HR = 0.76 (0.65­0.90) p = 0.0010 0.5 0.0 Years 3.0 4.0 5.0 2.0 1.0 0.0 Number at risk Amlodipine  perindopril 9639 9544 9441 9322 9167 8078 Atenolol  thiazide9618 9532 9415 9261 9085 7975 Dahlof B. Lancet 2005; 366: 895-906.

  8. Evénements vasculaires majeursTous les participants Réduction de risque (IC 95%) Mort vasculaire IDM non-fatal AVC non-fatal Total Actif meilleur Placebo meilleur Evts actif placebo 181 60 275 458 198 96 380 604 9% (-12 à 25%) 38% (14 à 55%) 29% (17 à 39%) 26% (16 à 34%) 0.4 1.0 2.0 Risque relatif

  9. Reduction in major cardiaceventsin patients with stable CAD Placebobetter Perindoprilbetter RRR (%) P value Primary endpoint: CV mortality, MI, CA 20 0.0003 CV mortality 14 Non fatal MI 22 Resuscitated CA 46 First secondary endpoint: Total mortality, MI, UAP,CA 0.0009 14 0.5 1.0 2.0 CA, cardiac arrest; UAP, unstable angina pectoris EUROPA Investigators. Lancet 2003;362:782-88.

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

  11. LVEDV Volumes (ml) means ± SE 87 84 83.6±1.2 83.0±1.2 Placebo n=619 Perindopril 81.1±1.1 81.8±1.3 81 81.2±1.2 n=631 79.6±1.1 p<0.01 p<0.01 78 75 Baseline 6-month 12-month Prevention of cardiac remodeling in post-AMI patients with preserved LV function PREAMI Investigators. Arch Intern Med. 2006;166:659-666

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

  13. Stable CAD Post-MI Post-stroke Diastolic HF -26% P=0.02 -28% NS -37% P=0.033 -39% P=0.002 Prevention of heart failure occurrence and/or hospitalisation with perindopril 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

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

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

  16. Summary of evidence from large-scale clinical trials with perindopril

  17. CV-DEATH, MI orSTROKE ADVANCE EUROPA PROGRESS HR 0.82 (0.76-0.87) P < 0.001 ADVANCE EUROPA PROGRESS HR 0.82 (0.76-0.87) P < 0.001 % 11.8 10 9.0 9.7 Placebo Placebo 6.3 7.4 5 3.3 5.3 Perindopril-based 2.8 0 0 1 2 3 4 years Brugts JJ, et al. EurHeart J. 2009;30:1385-1394.

  18. ALL CAUSE MORTALITY ADVANCE EUROPA PROGRESS HR 0.89 (0.82-0.96) P = 0.006 % 10 7.5 Placebo 5.2 6.7 5 3.2 4.5 1.5 2.8 Perindopril-based 1.2 0 0 1 2 3 4 years Brugts JJ, et al. Eur Heart J. 2009;30:1385-1394.

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

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

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

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

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

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

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

  26. Death, MI, orStroke Patientswithor without LV dysfunction Odds Ratio (95% CI) ACE-I Placebo 7.9 9.8 EUROPA 9.5 10.2 PEACE 14.0 17.8 HOPE 10.3 12.4 0.81 (0.75-0.87) Overall 20.0 22.8 SOLVD-P 22.9 28.2 AIRE 29.6 34.3 SAVE 39.1 45.6 SOLVD-T 43.8 51.0 TRACE 29.2 34.1 Overall 0.79 (0.73-0.85) 0.5 2 1 Dagenais G et al. Lancet 2006; 368:581-588

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

  28. 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

  29. ARBs vs PCB: AMI

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

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

  32. 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.

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