Study rationale and design

Study rationale and designStudy rationale and design

EUROPA Study Investigators EUROPA Study Investigators Lancet.Lancet. 2003;362:782-788. 2003;362:782-788.

ACE inhibition forACE inhibition forsecondary prevention of secondary prevention of

CADCADRationaleRationale

Anti-atherosclerotic effectsAnti-atherosclerotic effects Plaque rupture reductionPlaque rupture reduction Improvement in vascular endothelial functionImprovement in vascular endothelial function Enhanced fibrinolysisEnhanced fibrinolysis Modulation of neurohormonally-induced arterialModulation of neurohormonally-induced arterial

vasoconstrictionvasoconstriction Blood pressure loweringBlood pressure lowering LV hypertrophy reductionLV hypertrophy reduction

Angiotensin II reduction / bradykinin increaseAngiotensin II reduction / bradykinin increaseAngiotensin II reduction / bradykinin increaseAngiotensin II reduction / bradykinin increase

HypothesiHypothesiss

In selected patient groups In selected patient groups (high CV risk or(high CV risk or

LV dysfunction)LV dysfunction), ACE-I results in secondary, ACE-I results in secondary

prevention of prevention of coronary diseasecoronary disease

However, the multiple ways by which However, the multiple ways by which ACEACE

inhibition affects the atherosclerotic process,inhibition affects the atherosclerotic process,

suggest that it might occur in suggest that it might occur in allall patients patients

with coronary diseasewith coronary disease

Aim of the studyAim of the study

To investigate whether long-term administrationTo investigate whether long-term administration

of the ACE inhibitor perindopril, added toof the ACE inhibitor perindopril, added to

standard therapy, leads to a reduction ofstandard therapy, leads to a reduction of

cardiovascular events in patients withcardiovascular events in patients with

documented coronary disease documented coronary disease whatever their riskwhatever their risk

sticares

sticares

EUROPA is the only study to examine the effect of an ACE inhibitor in all patients with coronary artery disease irrespective of cardiac function and irrespective of the presence or absence of a high risk profile for CADIn this long-term trial of approx 4 years trial the effect of perindopril on cardiovasular mortality and/or non-fatal MI and/or cardiac arrest with successful resuscitation is studied.

Study endpointsStudy endpoints

CV mortality + non fatal MI + cardiac arrestCV mortality + non fatal MI + cardiac arrest

Primary endpointPrimary endpoint

Secondary endpointsSecondary endpoints

Total mortality + non fatal MI + unstable angina +Total mortality + non fatal MI + unstable angina +

cardiac arrestcardiac arrest

Heart failureHeart failure

Revascularisation (PCI/CABG)Revascularisation (PCI/CABG)

StrokeStroke

DesignDesign

PlaceboPlacebo

00 1212 2424-1/2-1/2-1-1

Run-in periodRun-in period

RandomisationRandomisation

Follow-upFollow-up

MonthsMonths3636 4848

4 mg4 mg 8 mg8 mg

PerindoprilPerindopril

Perindopril 8 mg once dailyPerindopril 8 mg once daily

6060

Selection criteriaSelection criteria

Male or female > 18 years of ageMale or female > 18 years of age

Documented coronary diseaseDocumented coronary disease

Not scheduled for revascularisationNot scheduled for revascularisation

No clinical signs of heart failureNo clinical signs of heart failure

DocumentedDocumentedcoronary diseasecoronary disease

Previous MI > 3 monthsPrevious MI > 3 months

PCI / CABG > 6 monthsPCI / CABG > 6 months

Angiographic evidence (Angiographic evidence ( 70% stenosis) 70% stenosis)

In males with chest pain: positive exercise orIn males with chest pain: positive exercise or

stress teststress test

Baseline characteristicsBaseline characteristics

Patient flowPatient flow

CompletedCompleted6 1076 107

CompletedCompleted6 1086 108

PerindoprilPerindopril6 1106 110

PlaceboPlacebo6 1086 108

RandomisedRandomised12 21812 218

Not randomisedNot randomised1 4371 437

RegisteredRegistered13 65513 655

424 centres424 centres : : 12 218 patients12 218 patients

102102

176176141141

130130

5757

12511251

21762176

115115

9494

300300

399399

285285

511511890890

1717

2222

20682068

17721772

277277

134134

209209

6565

197197

830830

Not randomisedNot randomised

Overall: 1 437 of 13 655 ptsOverall: 1 437 of 13 655 pts 10.510.5

IntoleranceIntolerance

HypotensionHypotension

Creatinine/Potassium riseCreatinine/Potassium rise

Poor compliancePoor compliance

Major clinical eventMajor clinical event

Non medical reasonsNon medical reasons

UnspecifiedUnspecified

2.42.4

2.12.1

1.11.1

0.60.6

0.50.5

0.50.5

3.33.3

%%

PerindoprilPerindopril(mean (mean SD) SD)

Placebo Placebo (mean (mean SD) SD)

Age Age (yrs)(yrs) 60 60 9 9 60 60 9 9

Male Male (%)(%) 86 86 8585

Weight Weight (kg)(kg) 81 81 12 12 80 80 12 12

HR HR (bpm)(bpm) 68 68 10 10 68 68 10 10

SBP SBP (mmHg)(mmHg) 137 137 16 16 137 137 15 15

DBP DBP (mmHg)(mmHg) 82 82 8 8 82 82 8 8

Baseline characteristicsBaseline characteristics

PerindoprilPerindopril(%)(%)

PlaceboPlacebo (%)(%)

Myocardial infarctionMyocardial infarction 64.964.9 64.764.7

RevascularisationRevascularisation 54.754.7 55.255.2

Stroke / TIAStroke / TIA 3.43.4 3.33.3

Heart failureHeart failure 1.31.3 1.21.2

Peripheral vascular Peripheral vascular diseasedisease 7.17.1 7.47.4

Medical historyMedical history

PerindoprilPerindopril(%)(%)

PlaceboPlacebo

(%)(%)

HypertensionHypertension 27.027.0 27.227.2

Diabetes mellitusDiabetes mellitus 11.811.8 12.812.8

HypercholesterolaemiaHypercholesterolaemia 63.363.3 63.363.3

Current smokerCurrent smoker 15.415.4 15.115.1

Risk factorsRisk factors

Perindopril Perindopril (%)(%)

PlaceboPlacebo(%)(%)

Platelet inhibitorsPlatelet inhibitors 91.991.9 92.792.7

-blockers-blockers 62.062.0 61.361.3

Lipid lowering drugsLipid lowering drugs 57.857.8 57.357.3

NitratesNitrates 42.842.8 43.043.0

Ca-blockersCa-blockers 31.731.7 31.031.0

DiureticsDiuretics 9.19.1 9.49.4

Oral anticoagulantsOral anticoagulants 4.44.4 4.24.2

Baseline medicationBaseline medication

ResultsResults


% CV death, MI or cardiac arrest% CV death, MI or cardiac arrest

Placebo annual event rate: 2.4%Placebo annual event rate: 2.4%

Perindopril Perindopril

PlaceboPlacebo

p = 0.0003p = 0.0003RRR: 20%RRR: 20%

YearsYears00

22

44

66

88

1010

1212

1414

00 11 22 33 44 55


RRR: 20% [95% CI : 9 - 29]RRR: 20% [95% CI : 9 - 29]CV death, MI or cardiac arrestCV death, MI or cardiac arrest

00

100100

200200

300300

400400

500500

600600

700700

No eventsNo events

PerindoprilPerindopril(6 110)(6 110)

8.0%8.0%

488488

PlaceboPlacebo(6 108)(6 108)

9.9%9.9%

603603

Primary and firstPrimary and firstsecondary secondary

endpointendpoint

0.50.5 1.01.0 2.02.0

2020

1414

2222

4646

1414

RRR RRR (%)(%)PerindoprilPerindoprilbetterbetter

PlaceboPlacebobetterbetter

CV mortality, MI, CACV mortality, MI, CA

CV mortalityCV mortality

Non fatal MINon fatal MI

Cardiac arrestCardiac arrest

Total mortality, MI, UAP,CATotal mortality, MI, UAP,CA

Sub-groups analysisSub-groups analysis

RRR RRR (%)(%)

0.50.5 1.01.0 2.02.0

Perindopril betterPerindopril better Placebo betterPlacebo better

Previous MIPrevious MI

No previous MINo previous MI

22.422.4

12.112.1

Age Age 56 yrs 56 yrs

Age 57 - 65Age 57 - 65

Age > 65 yrsAge > 65 yrs

27.327.3

14.314.3

18.218.2

MaleMale

FemaleFemale

19.319.3

22.022.0


0.50.5 1.01.0 2.02.0

HypertensionHypertension

RRR RRR (%)(%)PerindoprilPerindoprilbetterbetter


No hypertensionNo hypertension

Diabetes mellitusDiabetes mellitus

No diabetes mellitusNo diabetes mellitus

Stroke/TIAStroke/TIA

No stroke/TIANo stroke/TIA

18.618.6

19.919.9

18.918.9

19.019.0

15.815.8

19.919.9

92% patients on platelet inhibitors92% patients on platelet inhibitors


RRR RRR (%)(%)

Lipid lowering drugLipid lowering drug

PerindoprilPerindoprilbetterbetter


0.50.5 1.01.0 2.02.0

No lipid lowering drugNo lipid lowering drug

-blockers-blockers

No No -blockers-blockers

Calcium blockersCalcium blockers

No calcium blockersNo calcium blockers

16.316.3

22.322.3

26.426.4

7.07.0

15.815.8

22.222.2

Secondary endpointsSecondary endpoints

Fatal & non fatal MI, unstable anginaFatal & non fatal MI, unstable angina

0.50.5 1.01.0 2.02.0

Perindopril betterPerindopril better Placebo betterPlacebo better

Total mortality, MI, UAP,CATotal mortality, MI, UAP,CA

CV mortality & MICV mortality & MI

CV mortality, MI & strokeCV mortality, MI & stroke

CV mortality, MI, revascularisationCV mortality, MI, revascularisation

CV mortality, MI, unstable anginaCV mortality, MI, unstable angina

Non fatal and fatal MINon fatal and fatal MI

Total mortalityTotal mortality

CV mortalityCV mortality

Unstable anginaUnstable angina

Cardiac arrest Cardiac arrest

StrokeStroke

RevascularisationRevascularisation

Heart failureHeart failure

RRR RRR (%)(%)

14.014.0

19.319.3

17.417.4

11.311.3

15.515.5

16.516.5

23.923.9

11.011.0

13.913.9

7.17.1

45.645.6

4.34.3

4.24.2

39.239.2

Fatal and non fatal MIFatal and non fatal MI

PerindoprilPerindopril

PlaceboPlacebo

00

22

44

66

88

1010

00 11 22 33 44 55 YearsYears

(%)(%)

p < 0.001p < 0.001RRR: 24%RRR: 24%

Heart FailureHeart Failure

Perindopril Perindopril

PlaceboPlacebo

5500 11 22 33 44 YearsYears

p = 0.002p = 0.002RRR: 39%RRR: 39%

0.00.0

0.50.5

1.01.0

1.51.5

2.02.0(%)(%)

-1-1 -1/2-1/2 00 33 66 1212 1818 2424 3030 3636 4242 4848 5454 6060

MonthsMonths

7070

8080

9090

100100

110110

120120

130130

140140

mmHgmmHg

Blood pressureBlood pressure

SBP: 5 mmHgSBP: 5 mmHgDBP: 2 mmHgDBP: 2 mmHg

Perindopril Perindopril 8mg8mg PlaceboPlacebo

Adherence to treatmentAdherence to treatment

0 6 12 18 24 30 36

MonthsMonths

0

20

40

60

80

100

120(%)

PlaceboPlacebo

Perindopril Perindopril 8mg8mg

nsns

ConclusionConclusion

Summary of resultsSummary of results

In EUROPA, the largest and longest trial in stableIn EUROPA, the largest and longest trial in stable

documented CAD patients, perindopril 8 mg/ddocumented CAD patients, perindopril 8 mg/d

significantly reduced:significantly reduced:

CV mortality + non fatal MI + cardiac arrest:CV mortality + non fatal MI + cardiac arrest: 20%20% CV mortality and non fatal MI:CV mortality and non fatal MI: 19%19% Fatal + non fatal MI:Fatal + non fatal MI: 24%24% Heart failure:Heart failure: 39%39%

Absolute benefitsAbsolute benefits

Perindopril 8 mg once a day Perindopril 8 mg once a day preventsprevents

oneone cardiovascular death, nonfatal MIcardiovascular death, nonfatal MI

or cardiac arrest among everyor cardiac arrest among every

5050 patients with coronary disease treatedpatients with coronary disease treated

for 4 yearsfor 4 years

Summary of resultsSummary of results

Benefits occurred on top of recommendedBenefits occurred on top of recommended

therapy therapy (92% platelet inhibitors, 58% lipid(92% platelet inhibitors, 58% lipid

lowering drugs, 62% lowering drugs, 62% -blockers)-blockers) and are and are

consistent across predefined sub-groupsconsistent across predefined sub-groups

Perindopril should be considered for chronicPerindopril should be considered for chronic

therapy in all patients with coronary diseasetherapy in all patients with coronary disease

Possible explanations of resultsPossible explanations of results

R Ferrari, WJ Remme, M Simoons, M Bertrand, K FOX, R Ferrari, WJ Remme, M Simoons, M Bertrand, K FOX,

On behalf of the EUROPA investigators.On behalf of the EUROPA investigators.

A sub study ofA sub study of

PERTINENTPERTINENTPERPERindopril indopril – – TThrombosishrombosis,, IInflammationflammatioNN,, EEndothelial dysfunction ndothelial dysfunction

andand neurohormonal activation neurohormonal activation TTrialrial

Cardiovasc Res. 2007 Jan 1;73(1):237-46Cardiovasc Res. 2007 Jan 1;73(1):237-46

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 ofEUROPA designed to test this hypothesis

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

Endothelial Function

PERTINENT Methodology


PERTINENT

Healthy subjectsHealthy subjects

IncubatedIncubated (72 h)(72 h) with serum from with serum from

Europa PatientsEuropa Patients

ecNOSecNOSApoptosisApoptosis

To mimic the effects of circulating blood on endothelial functionTo mimic the effects of circulating blood on endothelial function

Isolation of human endotheliumIsolation of human endothelium

Methodology


Age (mean)Age (mean) 6161 6060 6060 6060

Male (%)Male (%) 9393 9393 8585 8585

Previous MI (%)Previous MI (%) 7777 6565 6565 6565

Diabetes mellitus (%)Diabetes mellitus (%) 1414 77 1313 1212

SBP (mmHg)SBP (mmHg) 138138 139139 137137 137137

DBP (mmHg)DBP (mmHg) 8282 8181 8282 8282

Lipid lowering therapy (%)Lipid lowering therapy (%) 3232 3535 5757 5858

Blockers (%)Blockers (%) 6161 6363 6161 6262

Calcium channel blockers (%)Calcium channel blockers (%) 3939 4444 3131 3232

Baseline characteristicsPERTINENT EUROPA

placebo perindopril placebo perindopril

PERTINENT

Effects of HUVECs incubation with serum from:Effects of HUVECs incubation with serum from:

0

10

2.5

7.5

ecN

OS

exp

ress

ion

(arb

itra

ry u

nit

s/m

g p

rote

in)

Controls

pp<0.01<0.01##

ControlsControlsn = 45n = 45

9.8

CAD PERTINENT patients1 year

p = nsp = ns‡‡

PlaceboPlacebon = 44n = 44

PerindoprilPerindopriln = 43n = 43

7.6 8.7

baseline



7.4 7.1

## p=controls vs baseline p=controls vs baseline‡‡ p= p= perindopril vs perindopril vs placebo placebo

ecNOS expression

5

PERTINENT


Controlsn = 45

3.5

p <0.01# p < 0.05 ‡

Placebon = 44

2.5

Perindopriln = 43

2.4

Placebon = 44

2.9

Perindopriln = 43

3.3

1 yearbaseline

# p=controls vs baseline‡ p= perindopril vs placebo

0

4

1

3

ecN

OS

act

ivit

y(p

mo

l/min

/mg

pro

tein

)

Effects of HUVECs incubation with serum from:Effects of HUVECs incubation with serum from:Controls CAD PERTINENT patients

2

PERTINENT ecNOS activity


p < 0.01 p < 0.01 ‡‡

CAD PERTINENT patients

baseline 1 year

0.7


0.9


0.8


0.4


0.3

Controls


p<0.05 p<0.05 ##

Bax

/Bcl

-2 r

atio

0

1

0.5


BAX / Bcl2 Ratio(pro-) / (anti-) apoptosis

Effects of HUVECs incubation with serum fromEffects of HUVECs incubation with serum from

PERTINENT


1.3

Controlsn = 45

p<0.01 #


p < 0.05 ‡

baseline 1 year

Placebon = 44

7.0

Perindopriln = 43

4.7

Perindopril = 43

6.8

Placebon = 44

7.8

Ap

op

tosi

s(%

)

0

2.5

5.0

10.0

7.5

CAD PERTINENT patientsControlsEffects of HUVECs incubation with serum fromEffects of HUVECs incubation with serum from

Apoptosis 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 afterHPLC separation

• bradykinin (BK) by radioimmunoassay after HPLCseparation

• tumor necrosis factor (TNF)-alpha by ELISA

as all these substances are known to modulate ecNOS and the rate of endothelial apoptosis

Methodology PERTINENT


p <0.05 p <0.05 ‡‡


baseline 1 year

Perindopriln = 43

17.1

Placebon = 44

15.8

Placebon = 44

14.4

Perindopriln = 43

12.5

Controls

Controlsn = 45

10.8

p<0.01 p<0.01 ##


0

5

10

15

20

25

An

gio

ten

sin

II

(pg

/mL

)Angiotensin II PERTINENT


0

10

20

Bra

dyk

inin

(p

g/m

L)

p <0.05 ‡


baseline 1 year

Placebon = 44

Perindopriln = 43

14.812.4

Placebon = 44

Perindopriln = 43

12.3 17.7

Controls

Controlsn = 45

18.3

p<0.01 #


Bradykinin

5

15

PERTINENT


Bradykinin/Angiotensin II ratioBradykinin/Angiotensin II ratio

Controls


1.9

p<0.01 p<0.01 ##

PERTINENTPERTINENT Neurohumoral ActivityNeurohumoral Activity

0

0.5

1.0

1.5

2.0

Bra

dyk

inin

/An

gio

ten

sin

II

(pg

/mL

)






1.11 1.2 1.9

p = 0.02 p = 0.02 ‡‡

baseline 1 year



0

5

10

15

20

25

30

35

40

TN

F-a

(pg

/mL

)


18.0

p<0.01 p<0.01 ##

Controls

baseline 1 year

p <0.05 p <0.05 ‡‡





27.127.7 28.9 24.6



TNF- PERTINENT


Correlations

There was no correlation of any parameter withSBP, DBP nor with any concomitant medications

The only significant correlations observed are:

bradykinin vs. ecNOS expression (r=0.43)

bradykinin vs. ecNOS activity (r=0.45)

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

n = 87

7.4

BaselineICATIBANT

Without

Perindopriln = 43

8.7

Perindopriln = 20

7.0

With

ecNOS EXPRESSION ecNOS ACTIVITY

(arb

itra

ry u

nits

/mg

pro

tein

)

0

2.5

5.0

10.0

7.5

0

2.5

5.0

10.0

7.5

(pm

ol/m

in/m

g p

rote

in)

n = 87

Baseline

2.5

ICATIBANT

2.1

Perindopriln = 20

With

Perindopriln = 43

Without

3.3

PERTINENT


Treatment with perindopril for 1 year results in:

Restoration of Angiotensin II/Bradykinin balance

Improvement of ecNOS Activity

Reduction of TNF activation

Reduction of the rate of endothelium apoptosis

Messages PERTINENT


To further investigate the role of perindopril onendothelial function we have measured plasmalevels of von Willebrand factor (vWf), a marker ofendothelial cell damage, both at baseline and after1 year of treatment with either perindopril (n=591)

or placebo (n=566)

Methodology PERTINENT


von Willebrand factor v

Wf

(%/U

nit)

0

20

40

60

80

100

120

140

160

180

200


baseline

Placebon =566

145

Perindopriln = 591

142

1 year

p <0.05 #

Perindopriln = 591

Placebon = 566

135 128

# P = perindopril vs placebo

PERTINENT


Years

Significant Prognostic Role for vWf

outc

ome

outc

ome

0.7

0.8

09

1.0

00 22 33 4411

Low (Low (142% / Unit)142% / Unit)

High (>142% / Unit)High (>142% / Unit)

p<0.01p<0.01

PERTINENT


Conclusions

In CAD patients, treatment with perindopril:

1) increases bradykinin which in turn up-regulates ecNOS activity

2) reduces angiotensin II and TNF levels

3) reduces rate of apoptosis

4) reduces von Willebrand factor levels which are predictive for outcomes

This results in improvement of endothelial dysfunction

PERTINENT


These data show that the vascular and

anti-atherosclerotic effects of perindopril may be

important at least in part

explaining the results of EUROPA

PERTINENT Conclusions


Acknowledgements

The PERTINENT patients and Investigators

The PERTINENT corelabs for the investigationsGussago (Italy) and Birmingham (UK)

The PERTINENT Steering Committee:F Arbustini (Italy), A Blann (UK), D Cokkinos (Greece), C Kluft ( The Netherlands), MPM de Maat (The Netherlands),J Tavazzi (Italy)

The PERTINENT Statistical Committee:A de Carli (Italy), G Parinello (Italy)

The EUROPA Executive Committee:KM FOX (UK), M Bertrand (France), WJ Remme (The Netherlands), ML Simoons (The Netherlands) Cardiovasc Res. 2007 Jan 1;73(1):237-46Cardiovasc Res. 2007 Jan 1;73(1):237-46

Verbetering coronaire Verbetering coronaire endotheelfunctieendotheelfunctie

HT patientsHT patients

Verbetering structuur Verbetering structuur coronaire arteriëncoronaire arteriën

CAD patientsCAD patients

Vermindering Vermindering LVHLVH

HT patients

US DATA sheet T/P ratios as stated by FDA

Captopril Not stated (twice or 3 times daily)

Benazepril 50%

Quinapril 50%

Ramipril 50% to 60%

Lisinopril "At all doses studied mean antihypertensive effect wassubstantially smaller 24h after dosing than 6h after dosing"

EnalaprilNot stated but once- or twice-

daily dosage

Fosinopril DBP = 50% to 60%; SBP = 80%

COVERSYL 75% to 100%

Trandolapril 50% to 90%

Physician's Desk ReferencePhysician's Desk Reference. 58. 58thth ed. Montvale, NJ: Thomson PDR; 2004. ed. Montvale, NJ: Thomson PDR; 2004.

Eenmaal daags, Eenmaal daags, 24 uurs werking24 uurs werking

Verbetert endotheelfunctie Verbetert endotheelfunctie

Ghiadoni L, Magagna A, Versan D, et al. Hypertension. 2003;41:1281-1286

HT patiënten

Verbetering vaatwandstructuurVerbetering vaatwandstructuur

HT patiëntenHT patiënten

Verbetering vaatwandstructuurVerbetering vaatwandstructuur

HT patientsHT patients

HT patientsMulvany MJ. Hypertension. 1995;25:474-481

Verbetering vaatwandstructuur, Verbetering vaatwandstructuur, onafhankelijk van bloeddrukverlagingonafhankelijk van bloeddrukverlaging

HT patientsKuperstein R, Sasson Z. Circulation. 2000;102:1802-1806

Vermindert linkerventrikelhypertrofie Vermindert linkerventrikelhypertrofie onafhankelijk van bloeddruk verlagingonafhankelijk van bloeddruk verlaging

HCTZ 25 mg + amiloride 2,5 mg

Perindopril 4 mg

carotid artery elasticity(% improvement)

0

5

10

15

20

1

16*

p < 0.05

*p<0.05 versus baseline

Double-blind randomized studyDouble-blind randomized study

N = 41 hypertensive patientsN = 41 hypertensive patients

T = 6 months T = 6 months

Kool M.J. Van Bortel L.M. et al. J Hypertens 1995 ; 13 :839 - 848

Verbetert functie grote arterieen Verbetert functie grote arterieen onafhankelijk van bloeddrukverlagingonafhankelijk van bloeddrukverlaging

Clinical implicationsClinical implications

Burden of coronary Burden of coronary diseasedisease

56 millions deaths worldwide in 200156 millions deaths worldwide in 2001

29% due to CV disease (~ 16 millions)29% due to CV disease (~ 16 millions)

(37% are foreseen in 2020)(37% are foreseen in 2020)

20 millions of people in the EU have 20 millions of people in the EU have coronary diseasecoronary disease

56 millions deaths worldwide in 200156 millions deaths worldwide in 2001

29% due to CV disease (~ 16 millions)29% due to CV disease (~ 16 millions)

(37% are foreseen in 2020)(37% are foreseen in 2020)

20 millions of people in the EU have 20 millions of people in the EU have coronary diseasecoronary disease

Plaque rupturePlaque rupture

Natural history of coronary Natural history of coronary atherosclerosisatherosclerosis

CV Risk factorsCV Risk factors

Silent ischemia

Stable Angina

Unstable angina

MI

Heart failure

Suddendeath

Coronary Disease

Clinical expressionClinical expressionof coronary diseaseof coronary disease

Relative risk reduction in the primary end point is consistent acrossRelative risk reduction in the primary end point is consistent across

all groups of cardiovascular riskall groups of cardiovascular risk

Low riskLow risk

RRR 17%

PlaceboPlacebo

5.3%5.3%

3.8

4.0

4.2

4.4

4.6

4.8

5.0

5.2

Coversyl 8 mgCoversyl 8 mg

4.4%4.4%

Medium riskMedium risk

RRR 32%

9%9%

PlaceboPlacebo

6.1%6.1%

Coversyl 8 mgCoversyl 8 mg0123456789

10

High riskHigh risk

RRR 12%

15.4%15.4%

PlaceboPlacebo

13.5%13.5%


12.5

13.0

13.5

14.0

14.5

15.0

15.5

No heterogeneity between groups (P =0.15)

Efficacy whatever their level of Efficacy whatever their level of risk risk

Deckers JW, Goedhart DM, Boersma E, et al. Treatment benefit by perindopril in patients with stable coronary artery disease at different levels of risk. Eur Heart J. 2006 Apr;27(7):796-801.

5.4

Efficacy whatever their Efficacy whatever their concomitant preventive therapyconcomitant preventive therapy

Lipid-lowering drug

-blockers

Previous revascularization

FavorsCoversyl 8 mg

Favorsplacebo

0.5 1.0 2.0

RRR %

17

26.4

16.3

EUROPA Study Investigators Lancet. 2003;362:782-788.

Mean EF 57 Mean EF 57 ++ 10.4%. 10.4%.

Only 3.2% of patients had an EF < 40% Only 3.2% of patients had an EF < 40%

Overall Overall EUROPA populationEUROPA populationN=12 218N=12 218

RRR 20%PP=0.0003=0.0003

8.0%

Coversyl 8 mg

9.9%

Placebo

EUROPA patients EUROPA patients LVEF LVEF 40%40%N=6 878N=6 878

RRR 16%RRR 16%PP=0.03=0.03

8.3%

Coversyl 8 mg

9.8%

Placebo

Relative risk reduction in the primary end point is consistent in patients Relative risk reduction in the primary end point is consistent in patients with with

normal left ventricular functionnormal left ventricular function

Efficacy in patients with normal Efficacy in patients with normal LVEFLVEF

Bertrand ME. Effects of perindopril on long term clinical outcome of patients with coronary artery disease and preserved left ventricular function.The EUROPA study.Eur Heart J.2005;26(Abst Suppl):578.

No interaction between treatment and SBP: No interaction between treatment and SBP: PP=0.464=0.464

Efficacy in CAD patients whether Efficacy in CAD patients whether they are hypertensive or notthey are hypertensive or not

RRR 39%RRR 39% RRR 17%RRR 17% RRR 18%RRR 18%

0%0%

5%5%

10%10%

15%15%

20%20%

<120 mm Hg<120 mm Hg >120 - <140 mm Hg>120 - <140 mm Hg >140 mm Hg>140 mm Hg

575575

6666662 7222 722

2 7882 788 2 7222 722

2 7452 745

SBPSBP

Primary end point-risk reduction


PlaceboPlacebo

Remme WJ. Prevention of cardiovascular events by perindopril in patients with stable coronary artery disease does not depend on blood pressure and its reduction.Results from the EUROPA study. Circulation 2004;110:III-638. Abstract 2919.

Efficacy in CAD patients Efficacy in CAD patients with/without previous revascularizationwith/without previous revascularization

Previous M.I.No previous M.I.

Previous revasc.No previous revasc.

Number ofpatients Coversyl 8 mg Placebo

Primary events (%)

7 910 8.9 11.3 4 299 6.4 7.3

6 709 6.6 8.05 509 9.6 12.2

0.5 1.0 2.0

Favors Coversyl 8 mg

Favorsplacebo

EUROPA Study Investigators.Lancet.2003;362:782-788.

New therapeutic optionNew therapeutic optionfor CAD patientsfor CAD patients

In perspective of other trialsIn perspective of other trials

StatinsStatins

Other ACEI or BP lowering drugs Other ACEI or BP lowering drugs

In perspective of other trialsIn perspective of other trials

StatinsStatins

Other ACEI or BP lowering drugs Other ACEI or BP lowering drugs

PROGRESS

SOLVDSAVEAIRE

TRACE

HOPE

SOLVD(prev)

EUROPA

Cardiovascular protection of ACE-ICardiovascular protection of ACE-I(and CA channel blockers)(and CA channel blockers)

Post MI LVSD + EF<40% HF

High CV risk, no HF

Stable CAD,No HF

Stroke, no HF

PEACE,no CV protectionACTION,no CV protection

22.622.6

15.9/13.215.9/13.2

7.97.9

2.82.8

Pla

ceb

o M

I ra

te p

er 1

00

sub

ject

s p

er

5 ye

ars

Pla

ceb

o M

I ra

te p

er 1

00

sub

ject

s p

er

5 ye

ars

WOS : NEJM 1995CARE : NEJM 1996LIPID : NEJM 19984S : Lancet 1994TexCAPS: JAMA 1998

Major Statin TrialsMajor Statin Trials

CAREn=4,159

TC 5.4 mmol/l

LIPIDn=9,014

TC 5.6 mmol/l

WOSn=6,595 TC 7.0 mmol/l

4Sn=4,444

TC 6.8 mmol/l

With CHD +With CHD +high cholesterolhigh cholesterol

With CHD +With CHD +normal cholesterolnormal cholesterol

Without CHD +Without CHD +high cholesterolhigh cholesterol

TexCAPSn=6,605 TC 5.7 mmol/l

Without CHD +Without CHD +

low HDLlow HDL

EUROPAEUROPA CARECAREPatiënten inclusiePatiënten inclusieLeeftijdLeeftijd 60jr60jr 59jr59jrVrouwVrouw 15%15% 14%14%CVLCVL 100%100% 100%100%Hartinfarct in het verledenHartinfarct in het verleden 65%65% 100%100%Revascularisatie in het verledenRevascularisatie in het verleden 55%55% 54%54%DiabetesDiabetes 12%12% 15%15%SBPSBP 137 mmHg137 mmHg 129 mmHg129 mmHgCholesterolCholesterol 5,6 mmol/l5,6 mmol/l 5,2 mmol/l5,2 mmol/l Actieve behandelingActieve behandelingAntiplatelet therapieAntiplatelet therapie 92%92% 83%83%BetablokkerBetablokker 62%62% 39%39%CalciumblokkerCalciumblokker 31%31% 38% 38% LipidenverlagingLipidenverlaging 58%58% 50%50%ACE-remmerACE-remmer 50%50% 14%14% Behandeleffecten (RR)Behandeleffecten (RR)CV / CHZ sterfte, niet fataal MICV / CHZ sterfte, niet fataal MI 20%20% 24%24%HartinfarctHartinfarct 24%24% 25%25%RevascularisatieRevascularisatie 5%5% 27%27%HartfalenHartfalen 39%39% nana

EUROPAEUROPA CARECAREPatiënten inclusiePatiënten inclusieLeeftijdLeeftijd 60jr60jr 59jr59jrVrouwVrouw 15%15% 14%14%CVLCVL 100%100% 100%100%Hartinfarct in het verledenHartinfarct in het verleden 65%65% 100%100%Revascularisatie in het verledenRevascularisatie in het verleden 55%55% 54%54%DiabetesDiabetes 12%12% 15%15%SBPSBP 137 mmHg137 mmHg 129 mmHg129 mmHgCholesterolCholesterol 5,6 mmol/l5,6 mmol/l 5,2 mmol/l5,2 mmol/l Actieve behandelingActieve behandelingAntiplatelet therapieAntiplatelet therapie 92%92% 83%83%BetablokkerBetablokker 62%62% 39%39%CalciumblokkerCalciumblokker 31%31% 38% 38% LipidenverlagingLipidenverlaging 58%58% 50%50%ACE-remmerACE-remmer 50%50% 14%14% Behandeleffecten (RR)Behandeleffecten (RR)CV / CHZ sterfte, niet fataal MICV / CHZ sterfte, niet fataal MI 20%20% 24%24%HartinfarctHartinfarct 24%24% 25%25%RevascularisatieRevascularisatie 5%5% 27%27%HartfalenHartfalen 39%39% nana

Similar benefits of statins and Similar benefits of statins and ACE inhibitionACE inhibition

HOPE

RRR=22%P <0.001

PEACE

RRR=4%P=0.43

AC TIO NAC TIO N

AC TIO N

17

0.0

0.2

0.4

0.6

0.8

1.0

0 2 4 6

years

Proportion event-free

A C TIO NA C TIO N

nifedip ineplacebo

All-cause death (p=0.4)

RA = refractory anginaPREV = peripheral revascularisation

Prim ary endpoint for efficacy(death, M I, RA, HF, CVA, PR EV)

p=0.5

Prim ary endpoint for safety (death, M I, CVA, p=0.9)

EUROPA

4 mg/d4 mg/d 2 mg/d2 mg/d30 mg/d30 mg/d2.5 mg/d2.5 mg/dRun-inRun-in

Dose titration and acceptabilityDose titration and acceptability

4 mg/d4 mg/d8 mg/d8 mg/d60 mg/d60 mg/d10 mg/d10 mg/dTarget doseTarget dose

8.2908.290

PEACEPEACE

12.21812.2187.6657.6659.2979.297NN

EUROPAEUROPAACTIONACTIONHOPEHOPEStudy Study populationpopulation

6969939384847171Achieved target Achieved target dose (%)dose (%)

PerindoprilPerindoprilRamiprilRamiprilDrugDrug TrandolaprilTrandolaprilNifidepine GITSNifidepine GITS

7575818179797474Compliance (%)Compliance (%)

NN 8.2908.29012.21812.2187.6657.6659.2979.297

Study Study populationspopulations

4545

134134

6464

PEACEPEACE

606063636666AgeAge

27*/4527*/45525247*47*Hypertensive (%)Hypertensive (%)

137137137137139139SBP (mm Hg)SBP (mm Hg)

858580807373Men (%)Men (%)

EUROPAEUROPAACTIONACTIONHOPEHOPEStudyStudy

* > 160/95 mm Hg, or antihypertensive treatment. All other BP value´s % patients with < 140/90 mmHg.

7878828280807979DBP (mm Hg)DBP (mm Hg)

3/13/15/25/26/36/33/23/2BP reduction (mmHg)BP reduction (mmHg)

8282

??636362626666Hyperchol (%)Hyperchol (%)

Concomitant Concomitant treatmentstreatments

7070

6060

9191

8.2908.290

PEACEPEACE

929286867676Antiplatelet drugs (%)Antiplatelet drugs (%)

58/6958/69

at 3 yrsat 3 yrs63632929Lipid lowering drugs (%)Lipid lowering drugs (%)

626276763939Beta blockers (%)Beta blockers (%)

12.21812.2187.6657.6659.2979.297NN

EUROPAEUROPAACTIONACTIONHOPEHOPEStudy populationStudy population

Study populationsStudy populations

7272

77

5555

8.2908.290

PEACEPEACE

656551515353History of MI (%)History of MI (%)

555545454444Revascularisation (%)Revascularisation (%)

33nana1111CVA / TIA (%)CVA / TIA (%)

12.21812.2187.6657.6659.2979.297NN


1717121215153838DIABETES (%)DIABETES (%)

00000000Heart failure (%)Heart failure (%)

nana7713134343PAD (%)PAD (%)

Univariate Hazard Ratios

Age decades > 65 yrs

Male

Smoking

Diabetes

SBP / 10 mmHg

PVD/CVD

Previous MI

Previous Revasc.

00 0,50,5 11 1,51,5 22 2,52,5 33

Risk Risk factorsfactors

Study populationsStudy populations

7272

77

5555

8.2908.290

PEACEPEACE

656551515353History of MI (%)History of MI (%)

555545454444Revascularisation (%)Revascularisation (%)

33nana1111CVD (%)CVD (%)

12.21812.2187.6657.6659.2979.297NN


1717121215153838DIABETES (%)DIABETES (%)

00000000Heart failure (%)Heart failure (%)

nana7713134343PVD (%)PVD (%)

4,2 year event rate in the 4,2 year event rate in the placebo groupplacebo group

12,012,019,519,5CV Death & MI (%)CV Death & MI (%)

7,17,111,811,8Non-fatal MI (%)Non-fatal MI (%)

4,94,97,77,7CV death (%)CV death (%)

ACTIONACTIONHOPEHOPE

7,87,810,310,3

4,64,66,26,2

3,23,24,14,1

PEACEPEACEEUROPAEUROPA

4,2 years is the duration of the mean follow up in EUROPA

10.5 1.5

HOPE

EUROPA

PEACE

0.81

0.79

0.96

[0.71-0.92]

[0.70-0.90]

[0.83-1.12]

p=0.0008

p=0.0003

p=0.62

OR 95% CI

The HOPE Study Investigators. N Engl J Med 2000;342:145-53. EUROPA Study Investigators Lancet. 2003;362:782-788.The PEACE Trial Investigators. N Engl J Med 2004;351:2058-6 The ACTION Investigators. Lancet 2004; 364: 849–57..

Results HOPE, EUROPA, PEACE Results HOPE, EUROPA, PEACE and ACTIONand ACTION

ACTION 1.00 [0.85-1.18] p=0.54

Bloeddruk verschillen

3/2

5/2

4/4

6/3

CV Death and MI

Placebo betterTreatment better

Standard preventive therapyStandard preventive therapy AspirinAspirin StatineStatine ACE-inhibitorACE-inhibitor Beta-blocker (post MI)Beta-blocker (post MI)

Evidence based ACE-inhibitor:Evidence based ACE-inhibitor: Only perindopril 8mg/d and ramipril 10mg/dOnly perindopril 8mg/d and ramipril 10mg/d Only perindopril 8mg/dOnly perindopril 8mg/d

irrespective of risk levelirrespective of risk level on top of adequate other preventive therapyon top of adequate other preventive therapy

Beneficial in stable CAD patients withBeneficial in stable CAD patients with>1 not adequately controlled risk factor(s):>1 not adequately controlled risk factor(s):

Myocardial infarctionMyocardial infarction HypertensionHypertension DiabetesDiabetes DyslipidemiaDyslipidemia SmokingSmoking

Standard preventive therapyStandard preventive therapy AspirinAspirin StatineStatine ACE-inhibitorACE-inhibitor Beta-blocker (post MI)Beta-blocker (post MI)

Evidence based ACE-inhibitor:Evidence based ACE-inhibitor: Only perindopril 8mg/d and ramipril 10mg/dOnly perindopril 8mg/d and ramipril 10mg/d Only perindopril 8mg/dOnly perindopril 8mg/d

irrespective of risk levelirrespective of risk level on top of adequate other preventive therapyon top of adequate other preventive therapy

Beneficial in stable CAD patients withBeneficial in stable CAD patients with>1 not adequately controlled risk factor(s):>1 not adequately controlled risk factor(s):

Myocardial infarctionMyocardial infarction HypertensionHypertension DiabetesDiabetes DyslipidemiaDyslipidemia SmokingSmoking

Cardiovascular risk management inCardiovascular risk management instable CAD patientsstable CAD patients

Without heart failure

Without heart failure

Study rationale and design

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