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.