Les bénéfices du perindopril : à propos de 50 000 patients
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Transcript of 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:
Astra-Zeneca, BMS, Boehringer-Ingelheim, GSK, Lilly, Menarini, MSD-Schering, Novartis, Novo, Pfizer, sanofi-aventis, Servier, The MedCo
Morbi-mortality trials of perindopril along the cardiovascular disease continuum (n=50 822)
Hypertensive patientsn=19 257
Patients with stable CAD
n=12 218
Patients with diabetes n=11 140
Post-stroke patientsn=6 105
Post-AMI patientsn=1 252
Diastolic HFn=850
Hypertensive patientsn = 3 845
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 480 520 8% (-4 to 19)Microvascular events 439 477 9% (-4 to 20)
Primary endpoint 861 938 9% (0 to 17)
Number of eventsPer / Ind Placebo
(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 468 535 14% (2 to 24)
Other coronary heart disease‡ 283 324 14% (-1 to 27)
New or worsening nephropathy 181 216 18% (-1 to 32)
New microalbuminuria 1094 1317
FavoursPer / Ind
Favoursplacebo
Hazard ratio0.5 1.0 2.0
21% (14 to 27)
Total renal events 1243 1500 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
Reduction in all-cause mortality in diabetic patients
ADVANCE Collaborative Group.ADVANCE Collaborative Group.Lancet Lancet 2007;370:829-40.2007;370:829-40.
Relative risk reduction 14%
p=0.025
Follow-up (months)
0
10
0 6 12 18 24 30 36 42 48 54 60
Placebo
Perindopril+indapamide
Cu
mu
lati
v e in
c id
e nc e
(%
)
5
All-cause deathAll-cause death
amlodipine amlodipine perindopril better perindopril better atenolol atenolol thiazide better thiazide better
0.500.50 0.700.70 1.001.00 1.451.45
Selected end-pointsSelected end-points
PrimaryPrimary Non-fatal MI (incl silent) + fatal CHDNon-fatal MI (incl silent) + fatal CHD
SecondarySecondaryTotal coronary end pointTotal coronary end pointTotal CV event and proceduresTotal CV event and proceduresAll-cause mortalityAll-cause mortalityCardiovascular mortalityCardiovascular mortalityFatal and non-fatal strokeFatal and non-fatal stroke
Tertiary Tertiary New-onset diabetes mellitusNew-onset diabetes mellitusNew-onset renal impairmentNew-onset renal impairment
Post hoc Post hoc Primary end point + revascularizationPrimary end point + revascularizationCV death + MI + strokeCV death + MI + stroke
2.002.00
Unadjusted Hazard Unadjusted Hazard ratio (95% CI)ratio (95% CI)
0.90 (0.79-1.02)0.90 (0.79-1.02)
0.87 (0.79-0.96)0.87 (0.79-0.96)0.84 (0.78-0.90)0.84 (0.78-0.90)0.89 (0.81-0.99)0.89 (0.81-0.99)0.76 (0.65-0.90)0.76 (0.65-0.90)0.77 (0.66-0.89)0.77 (0.66-0.89)
0.70 (0.63-.078)0.70 (0.63-.078)0.85 (0.75-0.97)0.85 (0.75-0.97)
0.86 (0.77-0.96)0.86 (0.77-0.96)0.84 (0.76-0.92)0.84 (0.76-0.92)
Dahlof B et al.Dahlof B et al. Lancet Lancet 2005; 366: 895-906.2005; 366: 895-906.
Reduction in cardiovascular events in hypertensive patients at CV risk
Number at riskAmlodipine perindopril 9639 9544 9441 9322 9167 8078Atenolol thiazide 9618 9532 9415 9261 9085 7975
0.0 1.0 2.0 3.0 4.0 5.0 Years0.0
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 (0.65 0.90)p = 0.0010
%
Dahlof B.Dahlof B. Lancet Lancet 2005; 366: 895-906.2005; 366: 895-906.
Reduction in cardiovascular mortality in hypertensive patients at CV risk
Evénements vasculaires majeurs Tous les participants
Evts actif placebo
Actifmeilleur
Placebomeilleur
Mort vasculaire
IDM non-fatal
AVC non-fatal
Total
0.4 1.0 2.0Risque 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%)
Reduction in major cardiac events
in patients with stable CAD
0.50.5 1.01.0 2.02.0
2020
1414
2222
4646
1414
RRR (%)RRR (%)PerindoprilPerindoprilbetterbetter
PlaceboPlacebobetterbetter
Primary endpoint:Primary endpoint:
CV mortality, MI, CACV mortality, MI, CA
CV mortalityCV mortality
Non fatal MINon fatal MI
Resuscitated CAResuscitated CA
First secondary endpoint: First secondary endpoint:
Total mortality, MI, UAP,CATotal mortality, MI, UAP,CA
P valueP value
0.00030.0003
0.00090.0009
EUROPA Investigators. EUROPA Investigators. Lancet Lancet 2003;362:782-88.2003;362:782-88.CA, cardiac arrest; UAP, unstable angina pectorisCA, cardiac arrest; UAP, unstable angina pectoris
Adapted from EUROPA Investigators. Adapted from EUROPA Investigators. Lancet Lancet 2003;362:782-88.2003;362:782-88.
Reduction in cardiovascular events whatever the endpoint
definitionCV death, MI, CV death, MI, cardiac arrestcardiac arrest
(EUROPA definition)(EUROPA definition)
CV death, MI, CV death, MI, strokestroke
(HOPE definition)(HOPE definition)
CV death, MI, CV death, MI, stroke, HF hospstroke, HF hosp
(ONTARGET definition)(ONTARGET definition)
0
2
4
6
8
10
12Event Event rate, %rate, %
9.99.9
8.08.0
10.910.9
9.09.0 9.59.5
11.811.8
placeboplacebo placeboplacebo placeboplaceboPerindoprilPerindopril PerindoprilPerindopril PerindoprilPerindopril
-20%-20%PP=0.0003=0.0003
-17%-17%PP<0.001<0.001
-20%-20%PP<0.001<0.001
79.6±1.1
83.0±1.283.6±1.2
Perindopril
Placebo
75
78
81
84
87
LVEDV Volumes (ml)means ± SE
Baseline 6-month 12-month
p<0.01 p<0.01
81.1±1.181.2±1.2
81.8±1.3
n=631
n=619
PREAMI Investigators. PREAMI Investigators. Arch Intern MedArch Intern Med. . 2006;166:659-6662006;166:659-666
Prevention of cardiac remodeling in post-AMI patients with Prevention of cardiac remodeling in post-AMI patients with preserved LV functionpreserved LV function
20
15
10
5
0
17% 18% 39% 13% 14%
4.94.0
5.94.9
9.7
6.0
11.09.6
18.1
15.6
Quintiles of predicted risk for death/MI
Placebo
Perindopril
EUROPA
Consistent benefit of ACE inhibitorsConsistent benefit of ACE inhibitors
Adapted from Deckers JW et al. Adapted from Deckers JW et al. Eur Heart J Eur Heart J 2006;27:796–801.2006;27:796–801.
Prevention of heart failure occurrence Prevention of heart failure occurrence and/or hospitalisation with perindopriland/or hospitalisation with perindopril
-40
-35
-30
-25
-20
-15
-10
-5
0
-39%P=0.002
-37%P=0.033
-26%P=0.02
-28%NS
Stable CADStable CAD Diastolic HFDiastolic HF Post-MIPost-MI Post-strokePost-stroke
EUROPA Investigators. EUROPA Investigators. Lancet Lancet 2003;362:782-88.2003;362:782-88.Cleland JGF. Cleland JGF. Eur Heart JEur Heart J 2006;27:2338-2345. 2006;27:2338-2345.PROGRESS Collaborative Group. PROGRESS Collaborative Group. Eur Heart JEur Heart J
2003;24:475-484.2003;24:475-484.PREAMI Investigators. PREAMI Investigators. Arch Intern MedArch Intern Med. .
2006;166:659-6662006;166:659-666
Consistent effect of perindopril in patients with and without hypertension
Overall study populationOverall study population
Subpopulation Subpopulation withwith hypertension hypertension
Subpopulation Subpopulation withoutwithout hypertension hypertension
PROGRESS Collaborative Group. PROGRESS Collaborative Group. Lancet Lancet 2001;358:1033-41.2001;358:1033-41.
EUROPA Investigators. EUROPA Investigators. Lancet Lancet 2003;362:782-2003;362:782-88.88.
ADVANCE Collaborative Group. ADVANCE Collaborative Group. Lancet Lancet 2007;370:829-40.2007;370:829-40.
Post-stroke patientsPost-stroke patients
Recurrent strokeRecurrent stroke
-20-20
-10-10
00
-30-30
RRRRRR (%)(%)
-32%
-27%-28%
CV death, MI, cardiac arrestCV death, MI, cardiac arrest
-15-15
-10-10
-5-5
00
-20-20
RRRRRR (%)(%)
-20%-18%
-20%
Patients with CADPatients with CAD
Macro and microvascular eventsMacro and microvascular events
-5-5
00
-10-10
RRRRRR (%)(%)
-9%-10%-9%
Diabetic patientsDiabetic patients
Consistent effect of perindopril in patients with and without diabetes mellitus
Overall study populationOverall study population
Subpopulation Subpopulation withwith diabetes diabetes
Subpopulation Subpopulation withoutwithout diabetes diabetes
Berthet K. Berthet K. Blood PressureBlood Pressure 2004; 2004;EUROPA Investigators. EUROPA Investigators. Lancet Lancet 2003;362:782-88.2003;362:782-88.
Dahlof B. Lancet 2005;366:895-906.Dahlof B. Lancet 2005;366:895-906.
Total CV events and proceduresTotal CV events and procedures
-15-15
-10-10
-5-5
00
-20-20
RRRRRR (%)(%)
-13%
-18%
-16%
Hypertensive patientsHypertensive patients
CV death, MI, cardiac arrestCV death, MI, cardiac arrest
-15-15
-10-10
-5-5
00
-20-20
RRRRRR (%)(%)
-20%-19% -19%
Patients with CADPatients with CAD
Recurrent strokeRecurrent stroke
-30-30
-20-20
-10-10
00
-40-40
RRRRRR (%)(%)
-38%
-28%-28%
Post-stroke patientsPost-stroke patients
Summary of evidence from large-scale clinical Summary of evidence from large-scale clinical trials with perindopriltrials with perindopril
Year Trial Patients Number Main results
2001 PROGRESS Post-stroke 6 105 Recurrent stroke: -28%
2003 EUROPAStable CAD
Preserved LV12 218 CV death/MI/cardiac arrest: -20%
2005 ASCOT Hypertension 19 257CV mortality: -24%;
CV events and procedures: - 16%
2006 PREAMI Post-AMI 1 252 Death/HF/cardiac remodelling: -38%
2006 PEP-CHF Diastolic HF 850 Death/HF hospitalisation: -31%
2007 ADVANCE Diabetes 11 140Macro and microvascular events: -9%;
Total mortality: -14%
3.3
6.3
9.0
11.8
2.8
5.3
7.4
9.7Placebo
Perindopril-based
ADVANCE EUROPA PROGRESSHR 0.82 (0.76-0.87) P < 0.001%
10
5
0
CV-DEATH, MI or STROKECV-DEATH, MI or STROKE
0 1 2 3 4years
Brugts JJ, et al. Eur Heart J. 2009;30:1385-1394.
Placebo
ADVANCE EUROPA PROGRESSHR 0.82 (0.76-0.87) P < 0.001
1.5
3.2
5.2
7.5
1.22.8
4.5
6.7
Placebo
Perindopril-based
ADVANCE EUROPA PROGRESS
HR 0.89 (0.82-0.96) P = 0.006%
10
5
00 1 2 3 4
years
ALL CAUSE MORTALITYALL CAUSE MORTALITY
Brugts JJ, et al. Eur Heart J. 2009;30:1385-1394.
Les questions
Associer IEC et autres traitements ?
Equivalence de tous les IEC ?
Equivalence IEC-ARA 2 ?
8.0
Plac. Perin.
6709 5509 6831 5387
Previous Revasc. Lipid loweringyes no yes no
6.6
12.2
9.68.3
7.0
11.9
9.3
EUROPA
Consistent benefit of ACE inhibitorsConsistent benefit of ACE inhibitors
EUROPA Investigators. Lancet 2003;362:782-788.
ACE inhibitorsCalcium channel blockers
CHDCHDCHD
Verdecchia P, et al. Hypertension. 2005;46:386-392.
- 15% risk of CHD
CHDCHD
ACE inhibitorsCalcium channel blockers
Verdecchia P, et al. Hypertension. 2005;46:386-392.
ACE inhibitors Calcium channel blockers
STROKESTROKE
Verdecchia P, et al. Hypertension. 2005;46:386-392.
STROKESTROKE
ACE inhibitors Calcium channel blockers
- 8% stroke
Verdecchia P, et al. Hypertension. 2005;46:386-392.
Les questions
Associer IEC et autres traitements ?
Equivalence de tous les IEC ?
Equivalence IEC-ARA 2 ?
1
Odds Ratio (95% CI)EUROPA
PEACE
HOPE
Overall
SOLVD-P
AIRE
SAVE
SOLVD-T
TRACEOverall
20.5
ACE-I Placebo
7.9 9.8
9.5 10.2
14.0 17.8
22.9 28.2
0.81 (0.75-0.87)
29.6 34.3
39.1 45.6
43.8 51.0
10.3 12.4
20.0 22.8
0.79 (0.73-0.85) 29.2 34.1
Dagenais G et al. Lancet 2006; 368:581-588
Death, MI, or StrokePatients with or without LV dysfunction
Les questions
Associer IEC et autres traitements ?
Equivalence de tous les IEC ?
Equivalence IEC-ARA 2 ?
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
ARBs vs PCB: AMI
ARBs vs control: AMI
ONTARGET
Risk of AMI (telmisartan vs ramipril) OR=1.07 (0.94-1.22)
J Hypertens 2007;25:951-958.
BP-independent reduction in CHD by ACE-IBPLTTC Regression Meta-analysis
ARBs
Risk Decrease Risk 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 effect ACE inhibitors vs ARBsAdditional RRR of CHDat 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. »
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.