Transcript European heart survey ACS registry 2009

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)
Patients with stable CAD
n=12 218
Hypertensive patients
n = 3 845
Post-stroke patients
n=6 105
Post-AMI patients
n=1 252
Hypertensive patients
n=19 257
Patients with diabetes
n=11 140
Diastolic HF
n=850
Reduction in cardiac and renal events
in diabetic patients
Number of events
Per / Ind Placebo
(n=5,569) (n=5,571)
Favours Favours
Per / Ind placebo
Relative risk
reduction (95% CI)
2P
Primary endpoint
861
938
9% (0 to 17)
Macrovascular events
Microvascular events
480
439
520
477
8% (-4 to 19)
9% (-4 to 20)
All coronary heart disease
Major coronary heart disease†
Other coronary heart disease‡
468
265
283
535
294
324
14% (2 to 24)
11% (-6 to 24)
14% (-1 to 27)
0.02
Total renal events
1243
New or worsening nephropathy 181
New microalbuminuria
1094
1500
216
1317
21% (15 to 27)
18% (-1 to 32)
21% (14 to 27)
<0.01
0.5
1.0
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
0.04
2.0
ADVANCE Collaborative Group.
Lancet 2007;370:829-40.
Reduction in all-cause mortality
in diabetic patients
All-cause death
10
Placebo
Perindopril+indapamide
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.
Reduction in cardiovascular events
in hypertensive patients at CV risk
Unadjusted Hazard
ratio (95% CI)
Selected end-points
Primary
Non-fatal MI (incl silent) + fatal CHD
0.90 (0.79-1.02)
Secondary
Total coronary end point
Total CV event and procedures
All-cause mortality
Cardiovascular mortality
Fatal and non-fatal stroke
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)
Tertiary
New-onset diabetes mellitus
New-onset renal impairment
0.70 (0.63-.078)
0.85 (0.75-0.97)
Post hoc
Primary end point + revascularization
CV death + MI + stroke
0.86 (0.77-0.96)
0.84 (0.76-0.92)
0.50
0.70
1.00
amlodipine  perindopril better
1.45
2.00
atenolol  thiazide better
Dahlof B et al. Lancet 2005; 366: 895-906.
Reduction in cardiovascular mortality
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
0.0
Number at risk
Amlodipine  perindopril 9639
Atenolol  thiazide
9618
1.0
2.0
3.0
4.0
5.0
9544
9532
9441
9415
9322
9261
9167
9085
8078
7975
Years
Dahlof B. Lancet 2005; 366: 895-906.
Evénements vasculaires majeurs
Tous les participants
Evts
actif placebo
Actif
meilleur
Placebo
meilleur
Réduction de
risque
(IC 95%)
Mort vasculaire
181
198
9% (-12 à 25%)
IDM non-fatal
60
96
38% (14 à 55%)
AVC non-fatal
275
380
29% (17 à 39%)
Total
458
604
26% (16 à 34%)
0.4
1.0
2.0
Risque relatif
Reduction in major cardiac events
in patients with stable CAD
Perindopril Placebo
better
better
RRR (%)
P value
CV mortality, MI, CA
20
0.0003
CV mortality
14
Non fatal MI
22
Resuscitated CA
46
Primary endpoint:
First secondary endpoint:
14
Total mortality, MI, UAP,CA
0.5
CA, cardiac arrest; UAP, unstable angina pectoris
1.0
0.0009
2.0
EUROPA Investigators. Lancet 2003;362:782-88.
Reduction in cardiovascular events
whatever the endpoint definition
CV death, MI,
cardiac arrest
CV death, MI,
stroke
CV death, MI,
stroke, HF hosp
(EUROPA definition)
(HOPE definition)
(ONTARGET definition)
Event
rate, %12
-17%
P<0.001
-20%
P=0.0003
10
11.8
-20%
P<0.001
10.9
9.9
9.5
9.0
8
8.0
6
4
2
0
placebo
Perindopril
placebo
Perindopril
placebo
Perindopril
Adapted from EUROPA Investigators. Lancet 2003;362:782-88.
Prevention of cardiac remodeling in post-AMI patients with
preserved LV function
LVEDV Volumes (ml)
means ± SE
87
83.6±1.2
84
81
83.0±1.2
81.1±1.1
81.8±1.3
81.2±1.2
Placebo
n=619
Perindopril
n=631
79.6±1.1
p<0.01
p<0.01
78
75
Baseline
6-month
12-month
PREAMI Investigators. Arch Intern Med. 2006;166:659-666
Consistent benefit of ACE inhibitors
 17%
 18%
 39%
 13%
20
Placebo
18.1
EUROPA
15.6
Perindopril
15
11.0
9.6
9.7
10
5.9
4.9
5
4.0
4.9
 14%
6.0
0
Quintiles of predicted risk for death/MI
Adapted from Deckers JW et al. Eur Heart J 2006;27:796–801.
Prevention of heart failure occurrence
and/or hospitalisation with perindopril
Stable CAD
Diastolic HF
Post-MI
Post-stroke
0
-5
-10
-15
-20
-28%
NS
-25
-30
-35
-39%
P=0.002
-26%
P=0.02
-37%
P=0.033
-40
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
Consistent effect of perindopril in patients
with and without hypertension
Patients with CAD
Post-stroke patients
Recurrent stroke
CV death, MI, cardiac arrest
RRR 0
(%)
RRR 0
(%)
Diabetic patients
Macro and microvascular events
RRR 0
(%)
-5
-10
-10
-5
-15
-20
-20
-20%
-18%
-27%
-28%
-20%
-9%
-10
-30
-9%
-10%
-32%
Overall study population
Subpopulation with hypertension
Subpopulation without hypertension
PROGRESS Collaborative Group. Lancet 2001;358:1033-41.
EUROPA Investigators. Lancet 2003;362:782-88.
ADVANCE Collaborative Group. Lancet 2007;370:829-40.
Consistent effect of perindopril in patients
with and without diabetes mellitus
Patients with CAD
Post-stroke patients
Recurrent stroke
CV death, MI, cardiac arrest
Hypertensive patients
Total CV events and procedures
RRR 0
(%)
RRR 0
(%)
RRR 0
(%)
-5
-10
-5
-10
-20
-10
-28%
-15
-20
-28%
-30
-20%
-19%
-19%
-13%
-15
-18%
-38%
-40
-16%
-20
Overall study population
Subpopulation with diabetes
Subpopulation without diabetes
Berthet K. Blood Pressure 2004;
EUROPA Investigators. Lancet 2003;362:782-88.
Dahlof B. Lancet 2005;366:895-906.
Summary of evidence from large-scale clinical
trials with perindopril
Year
Trial
Patients
Number
Main results
2001
PROGRESS
Post-stroke
6 105
Recurrent stroke: -28%
12 218
CV death/MI/cardiac arrest: -20%
Stable CAD
2003
EUROPA
Preserved LV
2005
ASCOT
Hypertension
19 257
CV 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
11 140
Macro and microvascular events: -9%;
Total mortality: -14%
CV-DEATH, MI or STROKE
ADVANCE EUROPA PROGRESS
HR 0.82 (0.76-0.87) P < 0.001
11.8
%
10
9.0
9.7
Placebo 6.3
7.4
5
3.3
5.3
Perindopril-based
2.8
0
0
1
2
3
years
Brugts JJ, et al. Eur Heart J. 2009;30:1385-1394.
4
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
1.5
2.8
4.5
Perindopril-based
1.2
0
0
1
2
3
years
Brugts JJ, et al. Eur Heart J. 2009;30:1385-1394.
4
Les questions
 Associer IEC et autres traitements ?
 Equivalence de tous les IEC ?
 Equivalence IEC-ARA 2 ?
Consistent benefit of ACE inhibitors
EUROPA
Lipid lowering
Previous Revasc.
yes
yes
no
12.2
no
11.9
9.6
8.0
9.3
8.3
7.0
6.6
Plac. Perin.
6709
5509
EUROPA Investigators. Lancet 2003;362:782-788.
6831
5387
ACE inhibitors
Calcium channel blockers
CHD
CHD
Verdecchia P, et al. Hypertension. 2005;46:386-392.
ACE inhibitors
Calcium channel blockers
CHD
- 15% risk of CHD
Verdecchia P, et al. Hypertension. 2005;46:386-392.
ACE inhibitors
Calcium channel blockers
STROKE
STROKE
Verdecchia P, et al. Hypertension. 2005;46:386-392.
ACE inhibitors
Calcium channel blockers
STROKE
STROKE
- 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 ?
Death, MI, or Stroke
Patients with or without LV dysfunction
Odds Ratio (95% CI)
ACE-I Placebo
7.9
9.8
9.5
10.2
EUROPA
PEACE
14.0
17.8
0.81 (0.75-0.87) 10.3
12.4
SOLVD-P
20.0
22.8
AIRE
22.9
29.6
39.1
43.8
29.2
28.2
34.3
45.6
51.0
34.1
HOPE
Overall
SAVE
SOLVD-T
TRACE
Overall
0.79 (0.73-0.85)
0.5
Dagenais G et al. Lancet 2006; 368:581-588
1
2
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)
BP-independent reduction in CHD by ACE-I
BPLTTC Regression Meta-analysis
Additional RRR of CHD
at zero BP reduction
ACE inhibitors
BP-independent effect
ACE inhibitors vs ARBs
RRR 9% (14% to 3%), P=0.004
P=0.002
RRR -8% (17% to -39%), NS
ARBs
30% 20% 10% 0% 10% 20% 30%
Risk Decrease
Risk Increase
« For ACEI, but not for ARB, there is evidence of blood pressureindependent effects on the risk of major coronary disease events. »
J Hypertens 2007;25:951-958.
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.