EUROPA

1
Study rationale and design
EUROPA Study Investigators Lancet.
2003362782-788.
2
ACE inhibition forsecondary prevention of CAD
Rationale

• Anti-atherosclerotic effects
• Plaque rupture reduction
• Improvement in vascular endothelial function
• Enhanced fibrinolysis
• Modulation of neurohormonally-induced
  arterial vasoconstriction
• Blood pressure lowering
• LV hypertrophy reduction

Angiotensin II reduction / bradykinin increase
3
Hypothesis

• In selected patient groups (high CV risk or LV
  dysfunction), ACE-I results in secondary preventi
  on of coronary disease

• However, the multiple ways by which
  ACE inhibition affects the atherosclerotic
  process, suggest that it might occur in all
  patients with coronary disease

4
Aim of the study

To investigate whether long-term
administrationof the ACE inhibitor perindopril,
added tostandard therapy, leads to a reduction
ofcardiovascular events in patients
withdocumented coronary disease whatever their
risk
5
Study endpoints
Primary endpoint

• CV mortality non fatal MI cardiac arrest

Secondary endpoints

• Total mortality non fatal MI unstable angina
  cardiac arrest
• Heart failure
• Revascularisation (PCI/CABG)
• Stroke

6
Design
Perindopril 8 mg once daily
Perindopril
Placebo
60
0
12
24
-1/2
-1
36
48
Months
Randomisation
Run-in period
Follow-up
7
Selection criteria

• Male or female gt 18 years of age
• Documented coronary disease
• Not scheduled for revascularisation
• No clinical signs of heart failure

8
Selection criteria

• Male or female gt 18 years of age
• Documented coronary disease
• Not scheduled for revascularisation
• No clinical signs of heart failure

9
Documentedcoronary disease

• Previous MI gt 3 months
• PCI / CABG gt 6 months
• Angiographic evidence (? 70 stenosis)
• In males with chest pain positive exercise
  or stress test

10
Baseline characteristics
11
Patient flow
12
424 centres 12 218 patients
13
Not randomised
14
Baseline characteristics
Perindopril (mean ? SD) Placebo (mean ? SD)
Age (yrs) 60 ? 9 60 ? 9
Male () 86 85
Weight (kg) 81 ? 12 80 ? 12
HR (bpm) 68 ? 10 68 ? 10
SBP (mmHg) 137 ? 16 137 ? 15
DBP (mmHg) 82 ? 8 82 ? 8
15
Medical history
Perindopril () Placebo ()
Myocardial infarction 64.9 64.7
Revascularisation 54.7 55.2
Stroke / TIA 3.4 3.3
Heart failure 1.3 1.2
Peripheral vascular disease 7.1 7.4
16
Risk factors
Perindopril () Perindopril () Placebo ()
Hypertension Hypertension 27.0 27.2
Diabetes mellitus Diabetes mellitus 11.8 12.8
Hypercholesterolaemia Hypercholesterolaemia 63.3 63.3
Current smoker Current smoker 15.4 15.1
17
Baseline medication
Perindopril () Placebo ()
Platelet inhibitors 91.9 92.7
?-blockers 62.0 61.3
Lipid lowering drugs 57.8 57.3
Nitrates 42.8 43.0
Ca-blockers 31.7 31.0
Diuretics 9.1 9.4
Oral anticoagulants 4.4 4.2
18
Results
19
Primary endpoint
CV death, MI or cardiac arrest
Placebo
Perindopril
Placebo annual event rate 2.4
20
Primary endpoint
CV death, MI or cardiac arrest
RRR 20 95 CI 9 - 29
21
Primary and firstsecondary endpoint
22
Sub-groups analysis
23
Sub-groups analysis
24
Sub-groups analysis
92 patients on platelet inhibitors
25
Secondary endpoints
26
Fatal and non fatal MI
()
Placebo
Perindopril
27
Heart Failure
Placebo
Perindopril
28
Blood pressure
?SBP 5 mmHg ?DBP 2 mmHg
29
Adherence to treatment
ns
30
Conclusion
31
Summary of results
In EUROPA, the largest and longest trial in
stabledocumented CAD patients, perindopril 8
mg/dsignificantly reduced

• CV mortality non fatal MI cardiac arrest 20

• CV mortality and non fatal MI 19

• Fatal non fatal MI 24

• Heart failure 39

32
Absolute benefits
Perindopril 8 mg once a day preventsone
cardiovascular death, nonfatal MIor cardiac
arrest among every50 patients with coronary
disease treatedfor 4 years
33
Summary of results

• Benefits occurred on top of recommended therapy
  (92 platelet inhibitors, 58 lipid lowering
  drugs, 62 ?-blockers) and are consistent across
  predefined sub-groups

• Perindopril should be considered for
  chronic therapy in all patients with coronary
  disease

34
Possible explanations of results
35
PERTINENT PERindopril Thrombosis, InflammatioN,
Endothelial dysfunction and neurohormonal
activation Trial
R Ferrari, WJ Remme, M Simoons, M Bertrand, K
FOX, On behalf of the EUROPA investigators.
Cardiovasc Res. 2007 Jan 173(1)237-46
36

• The background hypothesis for EUROPA trialwas a
  possible vascular and anti-atheroscleroticeffect
  of perindopril (8 mg/day)
• The PERindopril - Thrombosis, InflammatioN,Endoth
  elial dysfunction and Neurohormonalactivation
  Trial (PERTINENT) is a sub-study ofEUROPA
  designed to test this hypothesis

37
Methodology
PERTINENT
Endothelial Function
1. Human Umbilical Vein Endothelial Cells
(HUVECs) wereisolated and incubated for 72 h
with serum from healthyage matched volunteers
(n45) or EUROPA patientsat baseline and after 1
year of treatment with eitherperindopril (n43)
or placebo (n44) 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
Cardiovasc Res. 2007 Jan 173(1)237-46
38
Methodology
PERTINENT
Isolation of human endothelium
Incubated (72 h) with serum from
Healthy subjects
Europa Patients
ecNOSApoptosis
To mimic the effects of circulating blood on
endothelial function
Cardiovasc Res. 2007 Jan 173(1)237-46
39
PERTINENT
Baseline characteristics

Age (mean) 61 60 60 60
Male () 93 93 85 85
Previous MI () 77 65 65 65
Diabetes mellitus () 14 7 13 12
SBP (mmHg) 138 139 137 137
DBP (mmHg) 82 81 82 82
Lipid lowering therapy () 32 35 57 58
? Blockers () 61 63 61 62
Calcium channel blockers () 39 44 31 32
PERTINENT
EUROPA
placebo perindopril
placebo perindopril
40
ecNOS expression
PERTINENT
Effects of HUVECs incubation with serum from
Controls
CAD PERTINENT patients
1 year
baseline
plt0.01
p ns
10
7.5
5
7.4
9.8
7.6
8.7
7.1
2.5
0
Controlsn 45
Placebon 44
Perindopril n 43
Placebon 44
Perindopriln 43
pcontrols vs baseline p ? perindopril vs ?
placebo
Cardiovasc Res. 2007 Jan 173(1)237-46
41
ecNOS activity
PERTINENT
Effects of HUVECs incubation with serum from
Controls
CAD PERTINENT patients
baseline
1 year
p lt0.01
p lt 0.05
4
3
2
2.5
3.3
3.5
2.4
2.9
1
0
Controlsn 45
Placebon 44
Perindopril n 43
Placebon 44
Perindopril n 43
pcontrols vs baseline p ? perindopril vs ?
placebo
Cardiovasc Res. 2007 Jan 173(1)237-46
42
BAX / Bcl2 Ratio(pro-) / (anti-) apoptosis
PERTINENT
Effects of HUVECs incubation with serum from
Controls
CAD PERTINENT patients
baseline
1 year
plt0.05
p lt 0.01
Bax /Bcl-2 ratio
0.7
0.8
0.4
0.9
Placebon 44
Placebon 44
Perindopril n 43
Perindopriln 43
Controlsn 45
pcontrols vs baseline p ? perindopril vs ?
placebo
Cardiovasc Res. 2007 Jan 173(1)237-46
43
Apoptosis
PERTINENT
Effects of HUVECs incubation with serum from
Controls
CAD PERTINENT patients
pcontrols vs baseline p ? perindopril vs ?
placebo
Cardiovasc Res. 2007 Jan 173(1)237-46
44
Methodology
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
after HPLC separation bradykinin (BK) by
radioimmunoassay after HPLC separation
tumor necrosis factor (TNF)-alpha by ELISA
as all these substances are known to modulate
ecNOS and the rate of endothelial apoptosis
Cardiovasc Res. 2007 Jan 173(1)237-46
45
Angiotensin II
PERTINENT
pcontrols vs baseline p ? perindopril vs ?
placebo
Cardiovasc Res. 2007 Jan 173(1)237-46
46
Bradykinin
PERTINENT
CAD PERTINENT patients
Controls
baseline
1 year
p lt0.05
plt0.01
20
15
Bradykinin (pg/mL)
10
14.8
12.4
18.3
12.3
17.7
5
0
Placebon 44
Perindopriln 43
Placebon 44
Perindopril n 43
Controlsn 45
pcontrols vs baseline p ? perindopril vs ?
placebo
Cardiovasc Res. 2007 Jan 173(1)237-46
47
PERTINENT Neurohumoral Activity
Bradykinin/Angiotensin II ratio
pcontrols vs baseline p ? perindopril vs ?
placebo
Cardiovasc Res. 2007 Jan 173(1)237-46
48
TNF- ?
PERTINENT
pcontrols vs baseline p ? perindopril vs ?
placebo
Cardiovasc Res. 2007 Jan 173(1)237-46
49
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 (r0.43)
• bradykinin vs. ecNOS activity (r0.45)

Cardiovasc Res. 2007 Jan 173(1)237-46
50
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
ecNOS EXPRESSION
ecNOS ACTIVITY
Cardiovasc Res. 2007 Jan 173(1)237-46
51
Messages
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
Cardiovasc Res. 2007 Jan 173(1)237-46
52
Methodology
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 (n591)or placebo (n566)
Cardiovasc Res. 2007 Jan 173(1)237-46
53
von Willebrand factor
PERTINENT
P ? perindopril vs ? placebo
Cardiovasc Res. 2007 Jan 173(1)237-46
54
PERTINENT
Significant Prognostic Role for vWf
Low (?142 / Unit)
High (gt142 / Unit)
outcome
plt0.01
0
2
3
4
1
Years
Cardiovasc Res. 2007 Jan 173(1)237-46
55
Conclusions
PERTINENT
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
Cardiovasc Res. 2007 Jan 173(1)237-46
56
PERTINENT
Conclusions
These data show that the vascular
andanti-atherosclerotic effects of perindopril
may beimportant at least in partexplaining the
results of EUROPA
Cardiovasc Res. 2007 Jan 173(1)237-46
57
Acknowledgements
The PERTINENT patients and Investigators The
PERTINENT corelabs for the investigations Gussago
(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 173(1)237-46
58
Verbetering coronaire endotheelfunctie
HT patients
59
Verbetering structuur coronaire arteriën
CAD patients
60
Vermindering LVH
HT patients
61
Eenmaal daags, 24 uurs werking
US DATA sheet
T/P ratios as stated by FDA
COVERSYL
75 to 100
Benazepril

• 50

Quinapril
50
Ramipril
50 to 60
Lisinopril
"At all doses studied mean antihypertensive
effect was substantially smaller 24h after dosing
than 6h after dosing"
Enalapril
Not stated but once- or twice-daily dosage
Fosinopril
DBP 50 to 60 SBP 80
Captopril
Not stated (twice or 3 times daily)
Trandolapril
50 to 90
Physician's Desk Reference. 58th ed. Montvale,
NJ Thomson PDR 2004.
62
Verbetert endotheelfunctie
HT patiënten
Ghiadoni L, Magagna A, Versan D, et al.
Hypertension. 2003411281-1286
63
Verbetering vaatwandstructuur
HT patiënten
64
Verbetering vaatwandstructuur
HT patients
65
Verbetering vaatwandstructuur, onafhankelijk van
bloeddrukverlaging
HT patients
Mulvany MJ. Hypertension. 199525474-481
66
Vermindert linkerventrikelhypertrofie
onafhankelijk van bloeddruk verlaging
HT patients
Kuperstein R, Sasson Z. Circulation.
20001021802-1806
67
Verbetert functie grote arterieen onafhankelijk
van bloeddrukverlaging

• Double-blind randomized study
• N 41 hypertensive patients
• T 6 months

• carotid artery elasticity
• ( improvement)

20
p lt 0.05
15
16
10
5
HCTZ 25 mg amiloride 2,5 mg
Perindopril 4 mg
1
0
plt0.05 versus baseline
Kool M.J. Van Bortel L.M. et al. J Hypertens 1995
13 839 - 848
68
Clinical implications
69
Burden of coronary disease

• 56 millions deaths worldwide in 2001
• 29 due to CV disease ( 16 millions)
• (37 are foreseen in 2020)
• 20 millions of people in the EU have coronary
  disease

70
Natural history of coronary atherosclerosis
Plaque rupture
71
Clinical expressionof coronary disease
Unstable angina
MI
Coronary Disease
Stable Angina
Heart failure
Sudden death
Silent ischemia
72
Efficacy whatever their level of risk
Relative risk reduction in the primary end point
is consistent across all groups of cardiovascular
risk
Low risk
High risk
RRR 17
RRR 12
5.4
5.2
5.0
4.8
4.6
4.4
4.2
4.0
3.8
No heterogeneity between groups (P 0.15)
  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
Apr27(7)796-801.
73
Efficacy whatever their concomitant preventive
therapy
Favors Coversyl 8 mg
Favors placebo
RRR
17
Previous revascularization
Lipid-lowering drug
16.3
?-blockers
26.4
0.5
1.0
2.0
EUROPA Study Investigators Lancet.
2003362782-788.
74
Efficacy in patients with normal LVEF
Relative risk reduction in the primary end point
is consistent in patients with normal left
ventricular function
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.200526(Abst Suppl)578.
Mean EF 57 10.4. Only 3.2 of patients had an
EF lt 40
75
Efficacy in CAD patients whether
they are hypertensive or not
No interaction between treatment and SBP P0.464
Primary end point-risk reduction
20
RRR 39
RRR 17
RRR 18
15
2 745
2 722
2 788
10
666
2 722
575
5
0
SBP
lt120 mm Hg
gt120 - lt140 mm Hg
gt140 mm Hg
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 2004110III-638. Abstract 2919.
76
Efficacy in CAD patients with/without
previous revascularization
Primary events ()
Number of patients
Coversyl 8 mg Placebo
7 910 8.9 11.3 4 299
6.4 7.3

Previous M.I. No previous M.I. Previous
revasc. No previous revasc.
6 709 6.6 8.0 5 509
9.6 12.2
0.5 1.0
2.0
Favors Coversyl 8 mg
Favors placebo
EUROPA Study Investigators.Lancet.2003362782-788
.
77
New therapeutic optionfor CAD patients

• In perspective of other trials
• ? Statins
• ? Other ACEI or BP lowering drugs

78
Cardiovascular protection of ACE-I (and CA
channel blockers)

• Post MI
• LVSD EFlt40
• HF

SOLVD SAVE AIRE TRACE
SOLVD (prev)
High CV risk, no HF
HOPE
Stroke, no HF
Stable CAD, No HF
EUROPA
PEACE, no CV protection
ACTION, no CV protection
79
Major Statin Trials
With CHD high cholesterol
4S n4,444 TC 6.8 mmol/l
With CHD normal cholesterol
CARE n4,159 TC 5.4 mmol/l
LIPID n9,014 TC 5.6 mmol/l
Without CHD high cholesterol
WOS n6,595 TC 7.0 mmol/l
Without CHD low HDL
TexCAPS n6,605 TC 5.7 mmol/l
WOS NEJM 1995 CARE NEJM 1996 LIPID NEJM
1998 4S Lancet 1994 TexCAPS JAMA 1998
80
Similar benefits of statins and ACE inhibition

• EUROPA CARE
• Patiënten inclusie
• Leeftijd 60jr 59jr
• Vrouw 15 14
• CVL 100 100
• Hartinfarct in het verleden 65 100
• Revascularisatie in het verleden 55 54
• Diabetes 12 15
• SBP 137 mmHg 129 mmHg
• Cholesterol 5,6 mmol/l 5,2 mmol/l
•  
• Actieve behandeling
• Antiplatelet therapie 92 83
• Betablokker 62 39
• Calciumblokker 31 38 
• Lipidenverlaging 58 50
• ACE-remmer 50 14
•  
• Behandeleffecten (RR)

81
EUROPA
HOPE
RRR22 P lt0.001
82
Dose titration and acceptability
PEACE
EUROPA
ACTION
HOPE
Study population
8.290
12.218
7.665
9.297
N
Perindopril
Ramipril
Drug
Trandolapril
Nifidepine GITS
4 mg/d
2 mg/d
30 mg/d
2.5 mg/d
Run-in
4 mg/d
8 mg/d
60 mg/d
10 mg/d
Target dose
69
93
84
71
Achieved target dose ()
75
81
79
74
Compliance ()
83
Study populations
PEACE
EUROPA
ACTION
HOPE
Study
N
8.290
12.218
7.665
9.297
64
60
63
66
Age
85
80
73
Men ()
82
134
137
137
139
SBP (mm Hg)
78
82
80
79
DBP (mm Hg)
45
27/45
52
47
Hypertensive ()
3/1
5/2
6/3
3/2
BP reduction (mmHg)
?
63
62
66
Hyperchol ()
gt 160/95 mm Hg, or antihypertensive treatment.
All other BP values patients with lt 140/90
mmHg.
84
Concomitant treatments
PEACE
EUROPA
ACTION
HOPE
Study population
8.290
12.218
7.665
9.297
N
91
92
86
76
Antiplatelet drugs ()
60
62
76
39
Beta blockers ()
70
58/69 at 3 yrs
63
29
Lipid lowering drugs ()
85
Study populations
PEACE
EUROPA
ACTION
HOPE
Study population
8.290
12.218
7.665
9.297
N
55
65
51
53
History of MI ()
0
0
0
0
Heart failure ()
7
3
na
11
CVA / TIA ()
72
55
45
44
Revascularisation ()
na
7
13
43
PAD ()
17
12
15
38
DIABETES ()
86
Risk factors
Univariate Hazard Ratios
Age decades gt 65 yrs
PVD/CVD
Diabetes
Previous MI
Smoking
Male
SBP / 10 mmHg
Previous Revasc.
0,5
1
1,5
2
2,5
3
0
87
Study populations
PEACE
EUROPA
ACTION
HOPE
Study population
8.290
12.218
7.665
9.297
N
55
65
51
53
History of MI ()
0
0
0
0
Heart failure ()
7
3
na
11
CVD ()
72
55
45
44
Revascularisation ()
na
7
13
43
PVD ()
17
12
15
38
DIABETES ()
88
4,2 year event rate in the placebo group
ACTION
HOPE
EUROPA
PEACE
4,9
7,7
CV death ()
4,1
3,2
7,1
11,8
Non-fatal MI ()
6,2
4,6
12,0
19,5
CV Death MI ()
10,3
7,8
4,2 years is the duration of the mean follow up
in EUROPA
89
1 year event rate in the placebo group
ACTION
HOPE
EUROPA
PEACE
1,2
1,8
CV death ()
1,0
0,8
1,7
2,8
Non-fatal MI ()
1,5
1,1
2,9
4,6
CV Death MI ()
2,5
1,9
90
Results HOPE, EUROPA, PEACE and ACTION
Bloeddruk verschillen
CV Death and MI
OR
95 CI
3/2
HOPE
0.81
0.71-0.92
p0.0008
5/2
EUROPA
0.79
0.70-0.90
p0.0003
4/4
PEACE
0.96
0.83-1.12
p0.62
ACTION
1.00
0.85-1.18
6/3
p0.54
Placebo better
Treatment better
1
0.5
1.5
The HOPE Study Investigators. N Engl J Med
2000342145-53. EUROPA Study Investigators
Lancet. 2003362782-788.The PEACE Trial
Investigators. N Engl J Med 20043512058-6 The
ACTION Investigators. Lancet 2004 364 84957. .
91
Cardiovascular risk management in stable CAD
patients

• Standard preventive therapy
• Aspirin
• Statine
• ACE-inhibitor
• Beta-blocker (post MI)
• Evidence based ACE-inhibitor
• Only perindopril 8mg/d and ramipril 10mg/d
• Only perindopril 8mg/d
• irrespective of risk level
• on top of adequate other preventive therapy
• Beneficial in stable CAD patients with
• gt1 not adequately controlled risk factor(s)
• Myocardial infarction
• Hypertension
• Diabetes
• Dyslipidemia
• Smoking

Without heart failure