Transcript EUROPA - Landmarktrials

Study rationale and design
EUROPA Study Investigators Lancet. 2003;362:782-788.
ACE inhibition for
secondary 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
Hypothesis

In selected patient groups (high CV risk or
LV dysfunction), ACE-I results in secondary
prevention 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
Aim of the study
To investigate whether long-term administration
of the ACE inhibitor perindopril, added to
standard therapy, leads to a reduction of
cardiovascular events in patients with
documented coronary disease whatever their risk
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
Design
Perindopril 8 mg once daily
Perindopril
4 mg 8 mg
Placebo
-1 -1/2
0
12
24
36
Randomisation
Run-in period
Follow-up
48
60
Months
Selection criteria

Male or female > 18 years of age

Documented coronary disease

Not scheduled for revascularisation

No clinical signs of heart failure
Selection criteria

Male or female > 18 years of age

Documented coronary disease

Not scheduled for revascularisation

No clinical signs of heart failure
Documented
coronary disease

Previous MI > 3 months

PCI / CABG > 6 months

Angiographic evidence ( 70% stenosis)

In males with chest pain: positive exercise or
stress test
Baseline characteristics
Patient flow
Registered
13 655
Not randomised
1 437
Randomised
12 218
Perindopril
Placebo
6 110
6 108
Completed
Completed
6 107
6 108
424 centres : 12 218 patients
141
57
134
2068
130
176
115
94
1772
300
277
1251
197
2176
209
399
65
285
830
22
890
102
17
511
Not randomised
%
Intolerance
2.4
Hypotension
2.1
Creatinine/Potassium rise
1.1
Poor compliance
0.6
Major clinical event
0.5
Non medical reasons
0.5
Unspecified
3.3
Overall: 1 437 of 13 655 pts
10.5
Baseline characteristics
Perindopril
Placebo
(mean  SD)
(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
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
Risk factors
Perindopril
Placebo
(%)
(%)
Hypertension
27.0
27.2
Diabetes mellitus
11.8
12.8
Hypercholesterolaemia
63.3
63.3
Current smoker
15.4
15.1
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
Results
Primary endpoint
% CV death, MI or cardiac arrest
14
Placebo
12
10
Perindopril
8
6
RRR: 20%
p = 0.0003
4
2
0
0
1
2
3
Placebo annual event rate: 2.4%
4
5 Years
Primary endpoint
CV death, MI or cardiac arrest
RRR: 20% [95% CI : 9 - 29]
No events
700
600
9.9%
8.0%
500
400
603
488
300
200
100
0
Perindopril
Placebo
(6 110)
(6 108)
Primary and first
secondary endpoint
Perindopril Placebo
better
better
RRR (%)
20
CV mortality, MI, CA
CV mortality
14
Non fatal MI
22
Cardiac arrest
46
Total mortality, MI, UAP,CA
14
0.5
1.0
2.0
Sub-groups analysis
Perindopril better
Placebo better
RRR (%)
Male
19.3
Female
22.0
Age  56 yrs
27.3
Age 57 - 65
14.3
Age > 65 yrs
18.2
Previous MI
22.4
No previous MI
12.1
0.5
1.0
2.0
Sub-groups analysis
Perindopril
better
Placebo
better
RRR (%)
Hypertension
18.6
No hypertension
19.9
Diabetes mellitus
18.9
No diabetes mellitus
19.0
Stroke/TIA
15.8
No stroke/TIA
19.9
0.5
1.0
2.0
Sub-groups analysis
Perindopril
better
Placebo
better
RRR (%)
Lipid lowering drug
16.3
No lipid lowering drug
22.3
-blockers
26.4
No -blockers
7.0
Calcium blockers
15.8
No calcium blockers
22.2
0.5
92% patients on platelet inhibitors
1.0
2.0
Secondary endpoints
Perindopril better
Placebo better
RRR (%)
Total mortality, MI, UAP,CA
14.0
CV mortality & MI
19.3
CV mortality, MI & stroke
17.4
CV mortality, MI, revascularisation
11.3
CV mortality, MI, unstable angina
15.5
Fatal & non fatal MI, unstable angina
16.5
Non fatal and fatal MI
23.9
Total mortality
11.0
CV mortality
13.9
Unstable angina
7.1
Cardiac arrest
45.6
Stroke
4.3
Revascularisation
4.2
Heart failure
39.2
0.5
1.0
2.0
Fatal and non fatal MI
(%) 10
RRR: 24%
p < 0.001
8
Placebo
Perindopril
6
4
2
0
0
1
2
3
4
5 Years
Heart Failure
Placebo
RRR: 39%
p = 0.002
(%) 2.0
1.5
Perindopril
1.0
0.5
0.0
0
1
2
3
4
5 Years
Blood pressure
Perindopril 8mg
Placebo
mmHg
140
130
120
110
SBP: 5 mmHg
DBP: 2 mmHg
100
90
80
70
-1
-1/2
0
3
6
12
18
24
Months
30
36
42
48
54
60
Adherence to treatment
(%) 120
100
ns
80
60
Placebo
Perindopril 8mg
40
20
0
0
6
12
18
Months
24
30
36
Conclusion
Summary of results
In EUROPA, the largest and longest trial in stable
documented CAD patients, perindopril 8 mg/d
significantly reduced:

CV mortality + non fatal MI + cardiac arrest: 20%

CV mortality and non fatal MI: 19%

Fatal + non fatal MI: 24%

Heart failure: 39%
Absolute benefits
Perindopril 8 mg once a day prevents
one cardiovascular death, nonfatal MI
or cardiac arrest among every
50 patients with coronary disease treated
for 4 years
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
Possible explanations of results
PERTINENT
PERindopril – Thrombosis, InflammatioN, Endothelial dysfunction
and neurohormonal activation Trial
A sub study of
R Ferrari, WJ Remme, M Simoons, M Bertrand, K FOX,
On behalf of the EUROPA investigators.
Cardiovasc Res. 2007 Jan 1;73(1):237-46

The background hypothesis for EUROPA trial
was a possible vascular and anti-atherosclerotic
effect of perindopril (8 mg/day)

The PERindopril - Thrombosis, InflammatioN,
Endothelial dysfunction and Neurohormonal
activation Trial (PERTINENT) is a sub-study of
EUROPA designed to test this hypothesis
Methodology
PERTINENT
Endothelial Function
1. Human Umbilical Vein Endothelial Cells (HUVECs) were
isolated and incubated for 72 h with serum from healthy
age matched volunteers (n=45) or EUROPA patients
at baseline and after 1 year of treatment with either
perindopril (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
Cardiovasc Res. 2007 Jan 1;73(1):237-46
PERTINENT
Methodology
Isolation of human endothelium
Incubated (72 h) with serum from
Healthy subjects
Europa Patients
ecNOS
Apoptosis
To mimic the effects of circulating blood on endothelial function
Cardiovasc Res. 2007 Jan 1;73(1):237-46
PERTINENT
Baseline characteristics
PERTINENT
EUROPA
placebo
perindopril
placebo
perindopril
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
ecNOS expression PERTINENT
Effects of HUVECs incubation with serum from:
Controls
CAD PERTINENT patients
baseline
1 year
p = ns‡
p<0.01#
(arbitrary units/mg protein)
ecNOS expression
10
7.5
5
9.8
7.4
7.1
7.6
8.7
2.5
0
Controls
n = 45
Placebo Perindopril
n = 44
n = 43
Placebo Perindopril
n = 44
n = 43
#
p=controls vs baseline
‡ p=  perindopril vs  placebo
Cardiovasc Res. 2007 Jan 1;73(1):237-46
ecNOS activity
PERTINENT
Effects of HUVECs incubation with serum from:
Controls
CAD PERTINENT patients
baseline
(pmol/min/mg protein)
ecNOS activity
4
p <0.01#
1 year
p < 0.05 ‡
3
2
3.5
2.5
2.4
2.9
3.3
1
0
Controls
n = 45
Placebo Perindopril
n = 44
n = 43
Placebo Perindopril
n = 44
n = 43
#
p=controls vs baseline
‡ p=  perindopril vs  placebo
Cardiovasc Res. 2007 Jan 1;73(1):237-46
BAX / Bcl2 Ratio
(pro-)
/ (anti-) apoptosis
PERTINENT
Effects of HUVECs incubation with serum from
Controls
CAD PERTINENT patients
baseline
p<0.05 #
1 year
p < 0.01 ‡
Bax /Bcl-2 ratio
1
0.5
0.3
0.9
0.8
0.7
0.4
0
Controls
n = 45
Placebo Perindopril
n = 44
n = 43
Placebo Perindopril
n = 44
n = 43
#
p=controls vs baseline
‡ p=  perindopril vs  placebo
Cardiovasc Res. 2007 Jan 1;73(1):237-46
Apoptosis
PERTINENT
Effects of HUVECs incubation with serum from
Controls
10.0
p<0.01 #
CAD PERTINENT patients
baseline
1 year
p < 0.05 ‡
(%)
Apoptosis
7.5
5.0
7.8
2.5
6.8
7.0
4.7
1.3
0
Controls
n = 45
Placebo Perindopril
n = 44
= 43
Placebo Perindopril
n = 44
n = 43
#
p=controls vs baseline
‡ p=  perindopril vs  placebo
Cardiovasc Res. 2007 Jan 1;73(1):237-46
Methodology
PERTINENT
To draw further insights on the mechanisms of action of
perindopril we have also measured in the plasma from
the 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 1;73(1):237-46
Angiotensin II
Controls
CAD PERTINENT patients
baseline
25
1 year
p <0.05 ‡
p<0.01 #
20
(pg/mL)
Angiotensin II
PERTINENT
15
10
5
10.8
15.8
17.1
14.4
12.5
0
Controls
n = 45
Placebo Perindopril
n = 44
n = 43
Placebo Perindopril
n = 44
n = 43
#
p=controls vs baseline
‡ p=  perindopril vs  placebo
Cardiovasc Res. 2007 Jan 1;73(1):237-46
Bradykinin
Controls
PERTINENT
CAD PERTINENT patients
baseline
1 year
p <0.05 ‡
p<0.01 #
15
(pg/mL)
Bradykinin
20
10
18.3
12.4
14.8
12.3
17.7
5
0
Controls
n = 45
Placebo Perindopril
n = 44
n = 43
Placebo Perindopril
n = 44
n = 43
#
p=controls vs baseline
‡ p=  perindopril vs  placebo
Cardiovasc Res. 2007 Jan 1;73(1):237-46
PERTINENT
Neurohumoral Activity
Bradykinin/Angiotensin II ratio
2.0
CAD PERTINENT patients
baseline
p<0.01 #
1 year
p = 0.02 ‡
1.5
(pg/mL)
Bradykinin/Angiotensin II
Controls
1.0
1.9
1
1.1
1.2
1.9
0.5
0
Controls
n = 45
Placebo Perindopril
n = 44
n = 43
Placebo Perindopril
n = 44
n = 43
#
p=controls vs baseline
‡ p=  perindopril vs  placebo
Cardiovasc Res. 2007 Jan 1;73(1):237-46
TNF- 
Controls
40
35
PERTINENT
CAD PERTINENT patients
baseline
1 year
p <0.05 ‡
p<0.01 #
TNF-a
(pg/mL)
30
25
20
27.7
15
10
27.1
28.9
24.6
18.0
5
0
Controls
n = 45
Placebo Perindopril
n = 44
n = 43
Placebo Perindopril
n = 44
n = 43
#
p=controls vs baseline
‡ p=  perindopril vs  placebo
Cardiovasc Res. 2007 Jan 1;73(1):237-46
PERTINENT
Correlations

There was no correlation of any parameter with
SBP, 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)
Cardiovasc Res. 2007 Jan 1;73(1):237-46
PERTINENT
ecNOS activity and expression in HUVECs incubated for 72 h with serum of EUROPA
patients receiving perindopril with or without ICATIBANT in the incubation medium
ecNOS EXPRESSION
Baseline
ecNOS ACTIVITY
ICATIBANT
Without
With
Baseline
10.0
7.5
5.0
7.4
8.7
7.0
2.5
(pmol/min/mg protein)
(arbitrary units/mg protein)
10.0
ICATIBANT
Without
With
7.5
5.0
2.5
2.5
0
n = 87
Perindopril Perindopril
n = 43
n = 20
3.3
0
n = 87
2.1
Perindopril Perindopril
n = 43
n = 20
Cardiovasc Res. 2007 Jan 1;73(1):237-46
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 1;73(1):237-46
Methodology
PERTINENT
To further investigate the role of perindopril on
endothelial function we have measured plasma
levels of von Willebrand factor (vWf), a marker of
endothelial cell damage, both at baseline and after
1 year of treatment with either perindopril (n=591)
or placebo (n=566)
Cardiovasc Res. 2007 Jan 1;73(1):237-46
von Willebrand factor PERTINENT
CAD PERTINENT patients
baseline
1 year
200
p <0.05 #
180
160
vWf (%/Unit)
140
120
100
80
145
142
135
128
Placebo
n =566
Perindopril
n = 591
Placebo
n = 566
Perindopril
n = 591
60
40
20
0
#
P =  perindopril vs  placebo
Cardiovasc Res. 2007 Jan 1;73(1):237-46
PERTINENT
Significant Prognostic Role for vWf
1.0
Low (142% / Unit)
outcome
09
High (>142% / Unit)
p<0.01
0.8
0.7
0
1
2
Years
3
4
Cardiovasc Res. 2007 Jan 1;73(1):237-46
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 1;73(1):237-46
Conclusions
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
Cardiovasc Res. 2007 Jan 1;73(1):237-46
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),
Cardiovasc Res. 2007 Jan 1;73(1):237-46
ML Simoons (The Netherlands)
Verbetering coronaire
endotheelfunctie
HT patients
Verbetering structuur
coronaire arteriën
CAD patients
Vermindering LVH
HT patients
Eenmaal daags,
24 uurs werking
US DATA sheet
COVERSYL
Benazepril
T/P ratios as stated by FDA
75% to 100%
 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 twicedaily 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.
Verbetert endotheelfunctie
HT patiënten
Ghiadoni L, Magagna A, Versan D, et al. Hypertension. 2003;41:1281-1286
Verbetering vaatwandstructuur
HT patiënten
Verbetering vaatwandstructuur
HT patients
Verbetering vaatwandstructuur,
onafhankelijk van bloeddrukverlaging
HT patients
Mulvany MJ. Hypertension. 1995;25:474-481
Vermindert linkerventrikelhypertrofie
onafhankelijk van bloeddruk verlaging
HT patients
Kuperstein R, Sasson Z. Circulation. 2000;102:1802-1806
Verbetert functie grote arterieen
onafhankelijk van bloeddrukverlaging
carotid artery elasticity
(% improvement)
20

Double-blind randomized study

N = 41 hypertensive patients

T = 6 months
p < 0.05
15
16*
10
5
HCTZ 25 mg + amiloride 2,5 mg
Perindopril 4 mg
0
1
*p<0.05 versus baseline
Kool M.J. Van Bortel L.M. et al. J Hypertens 1995 ; 13 :839 - 848
Clinical implications
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
Natural history of coronary
atherosclerosis
Plaque rupture
CV Risk factors
Clinical expression
of coronary disease
Unstable
angina
Stable
Angina
MI
Coronary
Disease
Silent
ischemia
Heart
failure
Sudden
death
Efficacy whatever their level of
risk
Relative risk reduction in the primary end point is consistent across
all groups of cardiovascular risk
Low risk
RRR 17%
Medium risk
High risk
RRR 32%
RRR 12%
5.3%
5.4
5.2
5.0
4.8
4.6
4.4%
4.4
4.2
4.0
3.8
Placebo
Coversyl 8 mg
10
9
8
7
6
5
4
3
2
1
0
9%
15.5
6.1%
15.4%
15.0
14.5
14.0
13.5%
13.5
13.0
12.5
Placebo
Coversyl 8 mg
Placebo
Coversyl 8 mg
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 Apr;27(7):796-801.
Efficacy whatever their
concomitant preventive therapy
Favors
Coversyl 8 mg
Favors
placebo
RRR %
Previous
revascularization
17
Lipid-lowering drug
16.3
-blockers
26.4
0.5
EUROPA Study Investigators Lancet. 2003;362:782-788.
1.0
2.0
Efficacy in patients with normal
LVEF
Relative risk reduction in the primary end point is consistent in patients with
normal left ventricular function
Overall EUROPA population
EUROPA patients LVEF 40%
N=12 218
N=6 878
RRR 20%
RRR 16%
P=0.0003
P=0.03
9.8%
9.9%
8.0%
Placebo
Coversyl 8 mg
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.
8.3%
Placebo
Coversyl 8 mg
Mean EF 57 + 10.4%.
Only 3.2% of patients had an EF < 40%
Efficacy in CAD patients whether
they are hypertensive or not
No interaction between treatment and SBP: P=0.464
Primary end point-risk
reduction
Coversyl 8 mg
20%
Placebo
15%
RRR 39%
RRR 17%
RRR 18%
2 745
10%
2 722
2 788
666
2 722
575
5%
0%
<120 mm Hg
>120 - <140 mm Hg
>140 mm Hg
SBP
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
with/without previous revascularization
Number of
patients
Primary events (%)
Coversyl 8 mg Placebo
7 910
4 299
8.9
6.4
11.3
7.3
Previous revasc.
6 709
No previous revasc. 5 509
6.6
9.6
8.0
12.2
Previous M.I.
No previous M.I.
0.5
1.0
Favors
Coversyl 8 mg
EUROPA Study Investigators.Lancet.2003;362:782-788.
2.0
Favors
placebo
New therapeutic option
for CAD patients
In perspective of other trials
 Statins
 Other ACEI or BP lowering drugs
Cardiovascular protection of ACE-I
(and CA channel blockers)
 Post MI
 LVSD + EF<40%
 HF
High CV risk, no HF
SOLVD
SAVE
AIRE
TRACE
SOLVD
(prev)
HOPE
PROGRESS
Stroke, no HF
Stable CAD,
No HF
EUROPA
PEACE,
no CV
protection
ACTION,
no CV protection
Placebo MI rate per 100 subjects per 5 years
Major Statin Trials
22.6
15.9/13.2
7.9
2.8
4S
n=4,444
TC 6.8 mmol/l
LIPID
n=9,014
TC 5.6 mmol/l
With CHD +
high cholesterol
CARE
n=4,159
TC 5.4 mmol/l
WOS
n=6,595 TC 7.0 mmol/l
TexCAPS
n=6,605 TC 5.7 mmol/l
WOS : NEJM 1995
CARE : NEJM 1996
LIPID : NEJM 1998
4S : Lancet 1994
TexCAPS: JAMA 1998
With CHD +
normal cholesterol
Without CHD +
high cholesterol
Without CHD +
low HDL
Similar benefits of statins and
ACE inhibition
EUROPA
CARE
Patiënten inclusie
Leeftijd
Vrouw
CVL
Hartinfarct in het verleden
Revascularisatie in het verleden
Diabetes
SBP
Cholesterol
60jr
15%
100%
65%
55%
12%
137 mmHg
5,6 mmol/l
59jr
14%
100%
100%
54%
15%
129 mmHg
5,2 mmol/l
Actieve behandeling
Antiplatelet therapie
Betablokker
Calciumblokker
Lipidenverlaging
ACE-remmer
92%
62%
31%
58%
50%
83%
39%
38%
50%
14%
Behandeleffecten (RR)
CV / CHZ sterfte, niet fataal MI
Hartinfarct
Revascularisatie
Hartfalen
20%
24%
5%
39%
24%
25%
27%
na
EUROPA
14
HOPE
12
10
Placebo
Perindopril
8
6
14%
4
RRR=22%
P <0.001
RRR: 20%
p = 0.0003
12%
2
10%
0
0
1
2
3
4
5 Years
Placebo annual event rate: 2.4%
EUROPA Study Investigators Lancet 2003;362:7822003;362:782-788
ACTION
ACTION
ACTION
ACTION
Proportion event-free
All-cause death (p=0.4)
1.0
0.8
Primary endpoint
for efficacy
0.6
Primary endpoint for
safety (death, MI,
CVA, p=0.9)
(death, MI, RA, HF, CVA, PREV)
p=0.5
0.4
nifedipine
placebo
0.2
RA
= refractory angina
PREV = peripheral revascularisation
0.0
0
2
PEACE
years
4
6
17
RRR=4%
P=0.43
Dose titration and acceptability
Study
population
HOPE
ACTION
EUROPA
PEACE
N
9.297
7.665
12.218
8.290
Drug
Ramipril
Nifidepine GITS
Perindopril
Trandolapril
Run-in
2.5 mg/d
30 mg/d
4 mg/d
2 mg/d
Target dose
10 mg/d
60 mg/d
8 mg/d
4 mg/d
Achieved target
dose (%)
71
84
93
69
Compliance (%)
74
79
81
75
Study populations
Study
HOPE
ACTION
EUROPA
PEACE
N
9.297
7.665
12.218
8.290
Age
66
63
60
64
Men (%)
73
80
85
82
SBP (mm Hg)
139
137
137
134
DBP (mm Hg)
79
80
82
78
Hypertensive (%)
47*
52
27*/45
45
BP reduction (mmHg)
3/2
6/3
5/2
3/1
Hyperchol (%)
66
62
63
?
* > 160/95 mm Hg, or antihypertensive treatment. All other BP value´s % patients with < 140/90 mmHg.
Concomitant treatments
Study population
HOPE
ACTION
EUROPA
PEACE
N
9.297
7.665
12.218
8.290
Antiplatelet drugs (%)
76
86
92
91
Beta blockers (%)
39
76
62
60
Lipid lowering drugs (%)
29
63
58/69
70
at 3 yrs
Study populations
Study population
HOPE
ACTION
EUROPA
PEACE
N
9.297
7.665
12.218
8.290
History of MI (%)
53
51
65
55
Heart failure (%)
0
0
0
0
CVA / TIA (%)
11
na
3
7
Revascularisation (%)
44
45
55
72
PAD (%)
43
13
7
na
DIABETES (%)
38
15
12
17
Risk factors
Univariate Hazard Ratios
Age decades > 65 yrs
PVD/CVD
Diabetes
Previous MI
Smoking
Male
SBP / 10 mmHg
Previous Revasc.
0
0,5
1
1,5
2
2,5
3
Study populations
Study population
HOPE
ACTION
EUROPA
PEACE
N
9.297
7.665
12.218
8.290
History of MI (%)
53
51
65
55
Heart failure (%)
0
0
0
0
CVD (%)
11
na
3
7
Revascularisation (%)
44
45
55
72
PVD (%)
43
13
7
na
DIABETES (%)
38
15
12
17
4,2 year event rate in the
placebo group
HOPE
ACTION
CV death (%)
7,7
4,9
4,1
3,2
Non-fatal MI (%)
11,8
7,1
6,2
4,6
CV Death & MI (%)
19,5
12,0
10,3
7,8
4,2 years is the duration of the mean follow up in EUROPA
EUROPA
PEACE
Results HOPE, EUROPA, PEACE
and ACTION
CV Death and MI
Bloeddruk
verschillen
OR
95% CI
HOPE
0.81
[0.71-0.92]
p=0.0008
3/2
EUROPA
0.79
[0.70-0.90]
p=0.0003
5/2
PEACE
0.96
[0.83-1.12]
p=0.62
4/4
ACTION
1.00
[0.85-1.18]
p=0.54
6/3
0.5
Treatment better
1
Placebo better
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.
1.5
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
>1 not adequately controlled risk factor(s):





Myocardial infarction
Hypertension
Diabetes
Dyslipidemia
Smoking