Study rationale and design EUROPA Study Investigators Lancet. 2003;362:782-788.
Transcript of Study rationale and design EUROPA Study Investigators Lancet. 2003;362:782-788.
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
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
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
Primary endpointPrimary endpoint
% 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
Primary endpointPrimary endpoint
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
Sub-groups analysisSub-groups analysis
0.50.5 1.01.0 2.02.0
HypertensionHypertension
RRR RRR (%)(%)PerindoprilPerindoprilbetterbetter
PlaceboPlacebobetterbetter
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
Sub-groups analysisSub-groups analysis
RRR RRR (%)(%)
Lipid lowering drugLipid lowering drug
PerindoprilPerindoprilbetterbetter
PlaceboPlacebobetterbetter
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
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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
Cardiovasc Res. 2007 Jan 1;73(1):237-46Cardiovasc Res. 2007 Jan 1;73(1):237-46
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
PlaceboPlacebon = 44n = 44
PerindoprilPerindopriln = 43n = 43
7.4 7.1
## p=controls vs baseline p=controls vs baseline‡‡ p= p= perindopril vs perindopril vs placebo placebo
ecNOS expression
5
PERTINENT
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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
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p < 0.01 p < 0.01 ‡‡
CAD PERTINENT patients
baseline 1 year
0.7
PlaceboPlacebon = 44n = 44
0.9
PlaceboPlacebon = 44n = 44
0.8
PerindoprilPerindopriln = 43n = 43
0.4
PerindoprilPerindopriln = 43n = 43
0.3
Controls
ControlsControlsn = 45n = 45
p<0.05 p<0.05 ##
Bax
/Bcl
-2 r
atio
0
1
0.5
# p=controls vs baseline‡ p= perindopril vs placebo
BAX / Bcl2 Ratio(pro-) / (anti-) apoptosis
Effects of HUVECs incubation with serum fromEffects of HUVECs incubation with serum from
PERTINENT
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1.3
Controlsn = 45
p<0.01 #
# p=controls vs baseline‡ p= perindopril vs placebo
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
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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
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p <0.05 p <0.05 ‡‡
CAD PERTINENT patients
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 ##
# p=controls vs baseline‡ p= perindopril vs placebo
0
5
10
15
20
25
An
gio
ten
sin
II
(pg
/mL
)Angiotensin II PERTINENT
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0
10
20
Bra
dyk
inin
(p
g/m
L)
p <0.05 ‡
CAD PERTINENT patients
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 #
# p=controls vs baseline‡ p= perindopril vs placebo
Bradykinin
5
15
PERTINENT
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Bradykinin/Angiotensin II ratioBradykinin/Angiotensin II ratio
Controls
ControlsControlsn = 45n = 45
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
)
CAD PERTINENT patients
PlaceboPlacebon = 44n = 44
PlaceboPlacebon = 44n = 44
PerindoprilPerindopriln = 43n = 43
PerindoprilPerindopriln = 43n = 43
1.11 1.2 1.9
p = 0.02 p = 0.02 ‡‡
baseline 1 year
# p=controls vs baseline‡ p= perindopril vs placebo
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0
5
10
15
20
25
30
35
40
TN
F-a
(pg
/mL
)
ControlsControlsn = 45n = 45
18.0
p<0.01 p<0.01 ##
Controls
baseline 1 year
p <0.05 p <0.05 ‡‡
PlaceboPlacebon = 44n = 44
PlaceboPlacebon = 44n = 44
PerindoprilPerindopriln = 43n = 43
PerindoprilPerindopriln = 43n = 43
27.127.7 28.9 24.6
CAD PERTINENT patients
# p=controls vs baseline‡ p= perindopril vs placebo
TNF- PERTINENT
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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
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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
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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
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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
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von Willebrand factor v
Wf
(%/U
nit)
0
20
40
60
80
100
120
140
160
180
200
CAD PERTINENT patients
baseline
Placebon =566
145
Perindopriln = 591
142
1 year
p <0.05 #
Perindopriln = 591
Placebon = 566
135 128
# P = perindopril vs placebo
PERTINENT
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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
Cardiovasc Res. 2007 Jan 1;73(1):237-46Cardiovasc Res. 2007 Jan 1;73(1):237-46
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
Cardiovasc Res. 2007 Jan 1;73(1):237-46Cardiovasc Res. 2007 Jan 1;73(1):237-46
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
Cardiovasc Res. 2007 Jan 1;73(1):237-46Cardiovasc Res. 2007 Jan 1;73(1):237-46
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%
Coversyl 8 mgCoversyl 8 mg
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
Coversyl 8 mgCoversyl 8 mg
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
EUROPAEUROPAACTIONACTIONHOPEHOPEStudy populationStudy population
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
EUROPAEUROPAACTIONACTIONHOPEHOPEStudy populationStudy population
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