Vascular Protection
ACE inhibitor Trials
© Continuing Medical Implementation ®
…...bridging the care gap
Heart Outcomes Prevention
Evaluation Study
A large, simple, randomized trial of
Ramipril and vitamin E in patients
at high risk for cardiovascular
events
Final
Key Inclusion/Exclusion
Criteria
Inclusion Criteria
Patients (age 55) at high risk for
cardiovascular events because of:
• any evidence of vascular disease (CHD,
stroke, PVD)
• diabetes + one other coronary risk factor
Exclusion Criteria
Heart failure or low EF
On ACE-I or Vitamin E
Randomized
Final
Active Placebo SECURE
low dose
Ramipril
4645
4652
Vitamin E
4761
4780
Total No for Ramipril
N=9297
Total No for Vitamin E
N=9451
244
Final
Primary Adjudicated Events Ramipril vs Placebo 1/2
Ramipril Plac
(%)
(%)
RR
No. Rand.
Stroke*
Non-CV Death
p
4645 4652
1°Outcome
MI,Stroke,CVDth 14.1
CV Death*
6.1
MI*
95% CI
9.9
3.4
4.3
10.4
Mortality
*not mutually exclusive
17.7
8.1
12.2
4.9
4.1
12.2
0.78
0.75
0.80
0.69
1.03
0.84
0.70-0.86 0.000002
0.64-0.87 0.0002
0.71-0.91 0.0005
0.56-0.84 0.0003
0.84-1.25 0.78
0.75-0.95 0.0058
Final
Secondary Adjudicated Events
- Ramipril vs Placebo 2/2
Ramipril Placebo
(%)
(%)
Ramipril vs Placebo
RR
No. Rand
2° Outcomes
4645
Unstable Angina 12.2
with ECG
3.9
changes
HF Hosp
3.3
Revascularization 16.0
95% CI
p
4652
12.4 0.98 0.87-1.10 0.68
4.0 0.96 0.79-1.18 0.72
3.8 0.87 0.70-1.08 0.19
18.6 0.84 0.76-0.930.0005
Primary Outcome Ramipril vs Placebo
Kaplan-Meier Rates
Final
0.2
Ramipril
Placebo
0.15
0.1
0.05
0
0
500
1000
1500
Days of Follow-up
RR=0.78 (0.700.86)
P=0.000002
Prespecified Subgroups Ramipril vs Placebo
Final
No. Of Placebo Rate
CVD+
CVD-
Pts.
8160
18.7
10.1
1137
Diabetes
+ 3578
19.8
16.5
Diabetes 5719
-
0.6
0.8
1.0
RR (95% CI)
1.2
Final
Other Subgroups of Prior Stated
Interest: Ramipril vs Placebo (1/2)
Age<65
Age 65+
Male
Female
Hypertension+
HypertensionCAD+
CAD-
No. Of Pts.
4169
5128
Placebo
Rate
14.1
20.7
6817
2480
18.7
14.8
4355
4942
19.4
16.3
7475
1822
18.5
14.2
0.6
0.8
1.0
RR (95% CI)
1.2
Final
Other Subgroups of Prior Stated
Interest: Ramipril vs Placebo (2/2)
No. Of Pts.
CerebroVD+
1013
Placebo
Rate
CerebroVD-
8284
25.9
16.7
PVD+
4046
PVD-
5251
22.0
14.3
MA+
1956
MA-
7341
26.4
0.6
0.8
1.0
RR (95% CI)
1.2 15.3
Final
Ramipril vs Placebo
Patients with Documented normal EF
[N= 4759; mean 0.59 (SD 0.11)]
RamiprilPlacebo RR 95% CI
P
(%)
(%)
2387
2372
14.0
18.9 0.73 (0.63-0.84)0.00001
N
Primary
Outcome
CV death
MI
Stroke
All HF
Revasc.
5.2
7.5
0.68 (0.54-0.86)0.0009
10.7
14.1
0.75 (0.64-0.88)0.0005
2.9
4.3
0.67 (0.50-0.91)0.0104
8.3
10.5
0.78 (0.65-0.94)0.0082
19.9
24.0
0.80 (0.71-0.91)0.0004
Final
Conclusions:
Ramipril vs Placebo
There is overwhelming evidence that Ramipril
prevents:
– CV death, strokes and MI
– Heart Failure, Revascularization
– Development of diabetes
– Diabetic microvascular complications and
Nephropathy
These benefits are consistently observed in a
very broad range of high risk patients and in
addition to other effective therapies
The only adverse event is a 5% excess of cough
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
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
How does Europa compare with Hope?
A closer look at the Patients….
PATIENT CHARACTERISTICS
HOPE
12 236
9297
Mean age (range)
60 (24-90)
66 (>55)
Previous MI (%)
65
53
Previous revascularization (%)
55
44
7
43
Total patients randomized
Peripheral vascular disease (%)
PATIENT CHARACTERISTICS
HOPE
100
81
27
47
3
11
Diabetes mellitus (%)
12
39
Aspirin or other antiplatelet agents (%)
91
76
Lipid-lowering agent (%)
69
29
-blockers (%)
63
39
Evidence of coronary artery disease (%)
Hypertension (%)
Stroke (%)
Conclusions

The risk level of patients in Europa was lower than
in Hope. This is supported by the patient profile but
also the annual placebo mortality event rates which
were 40% to 80% higher that those in Europa.

The Europa patients were more aggressively
treated as evident by the higher use of anti-platelet
agents, lipid lowering agents and B-blockers.
Results
Primary endpoint
% CV death, MI or cardiac arrest
14
RRR: 20%
p = 0.0003
12
10
Placebo
Perindopril
8
6
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)
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
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 of stable,
low risk 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%
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
The Prevention of Events with
Angiotensin Converting Enzyme
Inhibition (PEACE) Trial
 A double-blind, placebo-controlled, randomized trial
 Sponsored by the National Heart, Lung, and Blood Institute
 Study medication and additional support provided by Abbott
Laboratories/Knoll
Marc Pfeffer, MD, Ph.D
— grants and honorarium: Novartis, AstraZeneca, Bristol-Myers Squibb
— licensing agreement with BWH with Novartis, Abbott, and Merck unrelated to sales or
PEACE patient population
Hypothesis
To test whether ACE inhibitor therapy,
when added to modern conventional
therapy, reduces CV mortality, MI, or
coronary revascularization in lowrisk, stable CAD patients with normal
or mildly reduced LV function.
Inclusion Criteria
 Age  50 years
 Coronary artery disease
—MI, or
—CABG or PCI, or
—Coronary angiogram with obstruction of 50% luminal
diameter in at least one native vessel
 LVEF > 40%
 Tolerated 2 week run-in of 2 mg/day trandolapril
Major Exclusions
 Current use or contraindication to ACE-I or ARB
 CV event in previous 3 months
 Planned elective coronary revasc
 Creatinine > 2.0 mg/dl(177mmol/l)
 Potassium > 5.5 mEq/L
 Limited 5-year survival
 Psychosocial condition precluding long-term
adherence
Comparison of Patients in the
HOPE, EUROPA, and PEACE Trials
Characteristic
HOPE
EUROPA
PEACE
Mean age
Prior MI
n=9297
66
53
n=12218
60
65
n=8290
64
55
Diabetes mellitus
Prior CABG or PCI
Mean LV EF
Mean SBP/DBP
38
40
NA
139/79
12
55
NA
137/82
17
72
58
133/78
Aspirin/antiplatelet
Lipid lowering
Beta blocker
76
29
40
92
58
62
91
70
60
% (unless otherwise specified)
Statistical Considerations
 1º outcome: CV death, MI, or coronary revasc
 Sample size and assumptions
— n = 8,100
— 90% power,  = 0.05
— 18% relative reduction in incidence of primary outcome
— 19% cumulative incidence in placebo
— 15% discontinuation of study drug in active treatment
— 15% crossover to open-label ACE-I in placebo group
 Statistical analysis
— Intention-to-treat
— Time to event log-rank test
— Proportional-hazards regression
Baseline Demographics
Characteristic
Trandolapril
Placebo
(n=4158)
64+8
(n=4132)
64+8
Women
19
17
Caucasian
92
93
US (incl. Puerto Rico)
58
58
Canada
30
30
Italy
12
12
% (unless otherwise specified)
Age (mean+SD)
Region
Baseline Medical History
Characteristic, %
Trandolapril
Placebo
Documented MI
54
56
CABG or PCI
72
72
Diabetes
18
16
Hypertension
46
45
Stroke or TIA
7
6
Current cigarette use
14
15
Baseline Measurements
Characteristic
Trandolapril
Placebo
LVEF (%)
58+10
58+9
Systolic BP (mm Hg)
134+17
133+17
Diastolic BP (mm Hg)
78+10
78+10
Creatinine (mg/dl)
1.0+0.2
1.0+0.2
Cholesterol (mg/dl)
192+39 (4.9)
192+40
Mean +SD
Baseline Medications
Characteristic,%
Trandolapril
Placebo
Aspirin or antiplatelets
90
91
Lipid lowering drug
70
70
Beta blocker
60
60
Diuretic
13
13
Anticoagulant
5
5
Insulin
4
4
Digitalis
4
4
Antiarrhythmic
2
2
Compliance
100
Percent taking trandolapril or
90 an open label ACE inhibitor
81.9
80
78.5
74.5
Percent
70
60
50
40
30
Percent taking an open
label ACE inhibitor
20
10
1.5
4.6
8.3
0
1
2
Trandolapril
3
Years
1
2
Placebo
3
Side Effects*
%
Trandolapril
Placebo
P-value
Dizziness
32.9
31.1
N.S.
Cough
39.1
27.5
0.01
Skin rash
11.7
11.9
N.S.
Headache
18.1
19.5
N.S.
Syncope
4.8
3.9
0.04
Fatigue
35.4
36.5
N.S.
Angioedema
0.1
0.2
N.S
*A patient may be in more than one category
Pressure Change (mm Hg)
Change in Systolic
Blood Pressure
0
=-1.4
-1
-2
-3
-4
-5
=-4.4, p<0.001
-6
0
Baseline=
13317
1
2
3
4
Time Since Randomization (Years)
Placebo
Trandolapril
5
6
Pressure Change (mm Hg)
Change in Diastolic
Blood Pressure
0
-1
-2
-3
-4
-5
-6
-7
=-2.3
=-3.6, p<0.001
0
Baseline=
7810
1
2
3
4
Time Since Randomization (Years)
Placebo
Trandolapril
5
6
Incidence of Primary Outcome
1º Outcome
CV Death, MI, CABG, or
0.35
PCI
0.30
HR=0.96 (95% CI, 0.88-1.06) P=0.43
0.25
0.20
0.15
0.10
Placebo
Trandolapril
0.05
0.00
0
1
2
3
4
5
6
Years from Randomization
Number of Patients
Placebo 4132
3992
3722
3491
3034
1941
906
Active
4019
3758
3515
3093
1981
985
4158
1º Outcome and its
Components
Outcome
Trandolapril
n=4158
Placebo
n=4132
Hazard Ratio
(95% CI)
Pvalue
%
%
CV death, MI,
CABG or PCI
21.9
22.5
0.96 (0.88-1.06)
NS
CV death
3.5
3.7
0.95 (0.76-1.19)
NS
Non-fatal MI
5.3
5.3
1.00 (0.83-1.20)
NS
Revasc
17.8
18.0
0.98 (0.88-1.08)
NS
Onset of New Diabetes1
12
Patients (%)
10
11.5%
9.8%
Risk
Reduction
17%
8
6
4
2
p=0.01
0
Trandolapril
Placebo
(absolute incidence 399/3472) (absolute incidence 336/3432)
The PEACE trial investigators. Angiotensin-Converting-Enzyme Inhibition in Stable Coronary Artery Disease (the PEACE trial). N Engl J Med
2004;351:2-58-68
†The analysis included 3432 patients in the trandolapril group and 3472 patients in the placebo group and excluded
CHF as a primary cause of
1
hospitalization or death
4.0
Patients (%)
3.5
3.0
3.7%
2.8%
2.5
Risk
Reduction
25%
2.0
1.5
1.0
p=0.02
0.5
0.0
Trandolapril
Placebo
(absolute incidence 1529/4132) (absolute incidence 115/4158)
The PEACE trial investigators. Angiotensin-Converting-Enzyme Inhibition in Stable Coronary Artery Disease (the PEACE trial). N Engl J Med 2004;351:2-58-68
PEACE Compared with
EUROPA, HOPE studies
PEACE
EUROPA
HOPE
Trandolapril
Perindopril
Ramipril
Quantitative LVEF Yes
assessment
No
No
Inclusion criteria Age > 50 and:
• Documented CAD (> 3
months post-MI, PTCA or
CABG, > 50% stenosis)
• LVEF > 40 % (< 18 months
before randomisation)
Age > 18 and:
• Documented CAD (> 3
months post-MI, > 6
months post-PTCA or
CABG, > 70% stenosis)
Age > 55 with one of the
following:
• Documented CAD (> 1 month
post-MI, CABG or PTCA, > 50%
stenosis on > 2 arteries or
positive stress)
• Peripheral vascular disease
• Stroke
• Diabetes associated with one
other cardioascular risk factor
Exclusion criteria LVEF < 40 %
Clinical heart failure
Primary endpoint Combined: MI, cardiovascular
death,
need for PTCA or CABG
Combined: CV death, nonfatal MI or, cardiac arrest
No. of patients
12,218
ACE Inhibitor
8,290
Mean follow-up
Industry sponsored
5.2
years
N
LVEF known to be < 40%
Combined: MI, stroke,
cardiovascular death
4.2 years
9,297
Yes
Ye
4.5 years
PEACE vs. HOPE and EUROPA:
Baseline Characteristics
PEACE1
HOPE2
EUROPA3
(n = 8290)
64
(n = 9297)
66
(12,218)
60
Male (%)
83
73
85
Mean ejection fraction (%)
58
NA
NA
133/78
139/79
137/82
28
28
NA
MI
56
52
65
Diabetes
17
38
12
PTCA/CABG
72
NA
59
CABG
39
26
29
PTCA
42
18
29
Characteristic
Age (y)
Mean BP (mmHg)
Mean BMI
History of (%)
1. Pfeffer MA, et al: Am Heart J 2001; 142(3):375-7. 2. Yusuf S, et al: N Engl J Med 2000;
342(3):145-53. 3. EUROPA Investigators: Lancet 2003; 362:782–8.
Cumulative Failure Rate (%)
HOPE and PEACE Comparison
CV death, MI, or Stroke
0.2
0.15
0.1
0.05
0
0
1
2
3
4
5
Years from Randomization
HOPE Placebo
HOPE Active
Cumulative Failure Rate (%)
HOPE and PEACE Comparison
CV death, MI, or Stroke
0.2
0.15
0.1
0.05
0
0
1
2
3
4
5
Years from Randomization
HOPE Placebo
HOPE Active
PEACE Placebo
Cumulative Failure Rate (%)
EUROPA and PEACE Comparison
CV death, MI, or Cardiac Arrest
0.1
0.08
0.06
0.04
0.02
0
0
1
2
3
4
Years from Randomization
EUROPA Placebo
EUROPA Active
Cumulative Failure Rate (%)
EUROPA and PEACE Comparison
CV death, MI, or Cardiac Arrest
0.1
0.08
0.06
0.04
0.02
0
0
1
2
3
4
Years from Randomization
EUROPA Placebo
EUROPA Active
PEACE Placebo
Annualized CV Mortality in the
Placebo Arms of HOPE,
EUROPA, & PEACE
Annualized CV Mortality (%)
1.8
1.6
1.62
1.4
1.2
1
0.8
0.97
0.77
HOPE
EUROPA
PEACE
0.6
0.4
0.2
0
The annualized all-cause mortality in the PEACE population was only
1.6%, similar to that of an age and gender matched general population.
Percent of Deaths due to CV Causes
in the Placebo Arms of HOPE,
EUROPA, & PEACE and in the
General Population
% of Deaths due to CV Causes
70
63
60
50
40
59
47
35
HOPE
EUROPA
PEACE
General Population*
30
20
10
0
* Age
and gender
matched to PEACE
cohort
Baseline Concomitant Medications in
Major ACE Inhibitor Studies
PEACE
EUROPA
HOPE
% of patients at baseline
100
91
80
60
40
76
70
60
62
92
58
47
35
40
32
29
20
0
CCB
Beta-blocker
Pfeffer MA, et al: Am Heart J 2001; 142(3):375-7.
Fox KM, et al: Lancet 2003; 362(9386):782-8.
Yusuf S, et al: N Engl J Med 2000; 342(3):145-53.
Lipid-low ering
Antiplatelet
% Death, MI, Cardiac
12.7
arrest
%
15.2
8.1
5.2
6.2
Low
6.2
Medium
High risk
Age, gender, previous MI, previous CABG/PCI,
PVD or stroke, hypertension, diabetes,
smoking, hyperchol., lipid lowering, -blockers.
Conclusions
 PEACE was conducted in a population with CAD
and preserved LV function who received intensive
contemporary management.
— This usually included coronary revascularization, lipid
lowering and blood pressure control.
— The CV event rate was lower than in HOPE and
EUROPA.
 In this population, which represents the majority
of patients with CAD, the addition of an ACE
inhibitor did not reduce further clinical
atherosclerotic events.
So What Can We Say About
the Role of ACEi in CAD?
 After PEACE, the AHA-ACC secondary prevention guidelines
recommending that ACE inhibitors be considered for all
patients with vascular disease remains unchanged.
 Patients with vascular disease that are at low to moderate or
high risk, or with LV dysfunction should routinely have an
ACE inhibitor.
 PEACE demonstrates that, as the absolute risk of a patient
decreases, if LV function is preserved and intensive
contemporary management given, with good control of all risk
factors, the absolute benefits of an ACE inhibitor decrease
and their routine use in these patients may not be warranted.
 The role of ACE inhibitors started early post-CABG in patients
with preserved LV function and intensive contemporary
management remains to be determined and should get
answered by the IMAGINE study.
The IMAGINE Study
Ischemia Management with Accupril
post bypass Graft via Inhibition of
the coNverting Enzyme
Comparison with Other Trials
Study
PostCABG
CV
Event
Rate
(%)
BP
Reading at
Baseline
% Diabetic
% Lipidlowering
Therapy
%
Betablocker
Use
% ASA∕
Antiplatelet
Use
HOPE
> 4 yrs
1.62
139/79
mmHg
38
29
40
76
EUROPA
>6
months
0.92
137/82
mmHg
12
56
63
92
PEACE
>3
months
0.77
133/78
mmHg
17
70
60
90
IMAGINE
≤ 7 days
0.46
122/70
mmHg
<10
90*
80*
98*
*average use during study
Annualized All Cause Mortality (%)
All Cause Mortality in Placebo Arms
2.5
2.4
HOPE
EUROPA
PEACE
IMAGINE
2
1.6
1.7
1.5
1
0.5
0
0.86
CV Mortality in Placebo Arms
Annualized CV Mortality (%)
1.8
1.6
1.62
HOPE
EUROPA
PEACE
IMAGINE
1.4
1.2
1
0.8
0.6
0.4
0.2
0
0.97
0.77
0.46
CV Mortality in Placebo Arms
Annualized CV Mortality (%)
1.8
1.6
1.62
HOPE
EUROPA
PEACE
IMAGINE
1.4
1.2
1
0.8
0.6
0.4
0.2
0
0.97
IMAGINE After 3 months
0.77
0.46
0.38
Role of ACE inhibitors in
Vascular Health Management &
Prevention
© Continuing Medical Implementation ®
…...bridging the care gap
© Continuing Medical Implementation ®
…...bridging the care gap
© Continuing Medical Implementation ®
…...bridging the care gap
© Continuing Medical Implementation ®
…...bridging the care gap