1. Program outline
This program highlights the Prevention of Events with Angiotensin Converting Enzyme Inhibition (PEACE) trial—providing an overview of ACE inhibition in patients with preserved left ventricular function, including the following topics:
• The RAAS and its role in atherosclerosis
• The role of ACE inhibition in CV risk reduction
• Update on recent trial data
• ACC/AHA recommendations of the role of ACE inhibition in post-MI patients

2. Deleterious effects of angiotensin II
PAI-1/ thrombosis
Abnormal vasoconstriction
Ang II
Platelet aggregation
Activate SNS
Superoxide production
Vascular smooth muscle growth
Aldosterone
Myocyte growth
Collagen
Vasopressin
Endothelin
Remodeling
Burnier M, Brunner HR. Lancet. 2000;355:
Brown NJ, Vaughn DE. Adv Intern Med. 2000;45:
SNS = Sympathetic nervous system

3. PERTINENT: ACEI improves endothelial function—Effects on cultivated HUVECs
Healthy control
Perindopril 8 mg
Placebo
ecNOS activity (U/mg)
Apoptosis (%)
4.0 9
P < 0.05
3.5 8
7.8
P < 0.05
3.5
3.3
7.0 7
6.8
3.0
2.9
2.5 6
2.5
2.4 5
4.7
2.0 4
1.5 3
1.0 2
1.3
0.5 1
Control
Baseline
1 Year
Control
Baseline
1 Year
HUVECs = human umbilical vein endothelial cells
Ferrari R. ESC 2004; Munich.

4. PERTINENT: Effects of ACEI on bradykinin, Ang II, and TNF — Plasma analysis25 18
17.1
P < 0.05
P < 0.05
15.8 16 20
14.4
18.3
17.7 14
12.5
14.8 12
10.8 15
12.4
pg/mL
12.3
pg/mL 10 10 8 6 5 4 2
Control
Baseline
1 Year
Control
Baseline
1 Year 35
TNF-
P < 0.05 30
28.9
27.1
27.7 25
24.6
Healthy control 20
pg/mL
18.0
Perindopril 8 mg 15
Placebo 10 5
Control
Baseline
1 Year
Ferrari R. ESC 2004; Munich.

5. Major clinical outcome trials of RAAS manipulation
ACE inhibition
GISSI-3
ISIS-4
AIRE
SAVE
SOLVD-Prevention
TRACE
CHARM-Preserved
OPTIMAAL
VALIANT
Angiotensin receptor blockade
HOPE EUROPA
PEACE
QUIET
SOLVD-Treat
CHARM-Added
CHARM-Alternative
ELITE II
Val-HeFT
ALLHAT
ANBP2
INVEST
LIFE
CONSENSUS

6. PEACE: Prevention of Events With Angiotensin Converting Enzyme Inhibition
Objective: To assess the effect of ACE inhibition added to conventional therapy in patients with stable CAD and normal or slightly reduced LV function
Design: 8290 patients randomized to trandolapril 4 mg or placebo
Follow-up: 4.8 years
Primary
Outcome: CV death, nonfatal MI, CABG, PCI
PEACE Trial Investigators. N Engl J Med. 2004;351:

7. PEACE: Treatment effect on primary outcome
Placebo 30 25
Trandolapril 20
Incidence of primary outcome (%) 15 10 5 1 2 3 4 5 6
Years after randomization
No. at risk
Trandolapril
4158
4017
3752
3506
3079
1963
969
Placebo
4132
3990
3719
3486
3027
1929
891
PEACE Trial Investigators. N Engl J Med. 2004;351:

8. PEACE: Treatment effect on components of primary outcome and total deaths
Event rate (%)
Hazard ratio (95% CI)
Trandolapril
Placebo
Primary*
21.9
22.5
0.96 (0.88–1.06)
CV death
3.5
3.7
0.95 (0.76–1.19)
Nonfatal MI
5.3
1.00 (0.83–1.20)
CABG
6.5
7.1
0.91 (0.77–1.07)
PCI
12.4
12.0
1.03 (0.91–1.16)
All-cause death
7.2
8.1
0.83 (0.67–1.03)
Non-CV death
4.4
0.89 (0.76–1.04)
*CV death, nonfatal MI, and coronary revascularization
PEACE Trial Investigators. N Engl J Med. 2004;351:

9. HOPE, EUROPA: Overview HOPE N = 9297 (4.5 years) Ramipril 10 mg
Study (Follow up)
ACE inhibitor
Key inclusion criteria
Primary outcome
HOPE
N = 9297
(4.5 years)
Ramipril 10 mg
Vascular disease* (80% had CAD)
LVEF ≥40%
Age ≥55 years
CV death, MI, stroke
EUROPA
N = 12,218 (4.2 years)
Perindopril 8 mg
CAD
No heart failure
Age ≥18 years
CV death, MI, cardiac arrest
*CV disease, peripheral artery disease, stroke or diabetes + ≥1 CV risk factor
HOPE Investigators. N Engl J Med. 2000;342:
EUROPA Investigators. Lancet. 2003;362:782-8.

10. HOPE, EUROPA: Treatment benefit on primary and selected secondary outcomes
Favors
ACEI
Favors
placebo
Event rate (%)
ACEI Placebo
Composite outcome
CV mortality
Myocardial infarction
Stroke
Cardiac arrest
HOPE
EUROPA
0.5
1.0
1.5
EUROPA = European Trial on Reduction of Cardiac Events with Perindopril in Stable Coronary Artery Disease
HOPE = Heart Outcomes Prevention Evaluation
Hazard ratio
EUROPA Investigators. Lancet. 2003;362:782-8.
HOPE Study Investigators. N Engl J Med. 2000;342:

11. HOPE, EUROPA, PEACE, QUIET: CV event rate in placebo group14
12.3
HOPE 12
EUROPA
PEACE 10
QUIET
8.1
Event rate (%) 8
6.2 6
5.3
4.6
4.1
3.7 4 2
1.5
CV death Nonfatal MI
HOPE Investigators. N Engl J Med. 2000;342:
EUROPA Investigators. Lancet. 2003;362:782-8.
PEACE Investigators. N Engl J Med. 2004;351:
Pitt B. et al. Am J Cardiol. 2001;87:

12. CV therapies at baseline
HOPE, EUROPA, PEACE, QUIET:
CV therapies at baseline
HOPE
EUROPA
PEACE
QUIET
Antiplatelet agents* (%) 76 92 91 73
-Blockers (%) 40 62 60 26
Lipid-lowering agents (%) 29 58 70
Calcium channel
blockers (%) 47 32 36
Diuretics (%) 15 10 13 NA
HOPE Investigators. N Engl J Med. 2000;342:
EUROPA Investigators. Lancet. 2003;362:782-8.
PEACE Investigators. N Engl J Med. 2004;351:
Pitt B. et al. Am J Cardiol. 2001;87:
*Mostly aspirin

13. HOPE, EUROPA: Use of lipid-lowering drugs intensified during studies
Baseline
During study † 69 70 58 60
49* 50 %
Patients 40 29 30 20 10
HOPE
EUROPA
*End of study †3 years
Yusuf S. Symposium at: AHA 2004; New Orleans.
EUROPA Investigators. Lancet. 2003;362:782-8.

14. HOPE, EUROPA: Effect of ACEI plus concomitant CV therapy
ACE inhibitor
Added benefit
No added benefit
EUROPA*
Lipid-lowering drug
No lipid-lowering drug
HOPE†
Lipid-lowering drug
No lipid-lowering drug
EUROPA*
-blockers
No -blockers
HOPE†
-blockers
No -blockers
0.6
0.8
1.0
2.0
*Perindopril 8 mg
†Ramipril 10 mg
EUROPA Investigators. Lancet. 2003;362:782-8
Dagenais GR et al. Circulation. 2001;104:522-6.

15. HOPE: Dose-dependent effects of ramipril on LV mass and function
Mean baseline LVEF 58% in all groups
Placebo (n = 151)
Ramipril 2.5 mg (n = 149)
Ramipril 10 mg (n = 146) 10 6
5.31 8 5
8.21
7.86
∆ LV end systolic
volume
(mL) 4 6
∆ LV mass (g) 3
2.9 4 2 2 1 –2 –1 –4 –2
–3.53
–1.9 –6 –3
P Trend = 0.03
P Trend = 0.001
Lonn E et al. J Am Coll Cardiol. 2004;43:

16. Slope of the mean maximum carotid-intima thickness (mm/y)
SECURE: Dose-dependent effect of ramipril on carotid atherosclerosis
0.025
P = 0.028
0.022 NS
0.020
Slope of the mean maximum carotid-intima thickness (mm/y)
0.018
0.015
37% Reduction
0.014
0.010
0.005
Placebo
Ramipril 2.5 mg
Ramipril
10 mg
Lonn E et al. Circulation. 2001;103:

17. HOPE, EUROPA, PEACE, QUIET: Clinical implications
Cumulative evidence supports ACE inhibitors for a broad range of CAD patients
Not all ACE inhibitors can be assumed to have comparable effects on vascular protection
– Medication adherence and dosage are important
Evidence-based medicine should guide use
– Ramipril 10 mg (HOPE)
– Perindopril 8 mg (EUROPA)
Pitt B. N Engl J Med. 2004;351:

18. Cumulative survival* (%)
1-Year survival in post-MI patients according to ACEI Rx at discharge
N = 7512
100 90
Cumulative survival* (%)
Ramipril
Perindopril 80
Lisinopril
Enalapril
Quinapril
Fosinopril
P < for log-rank test
Captopril 70 2 4 6 8 10 12
No. of patients
Time (months)
Ramipril
905
817
Perindopril
243
215
Lisinopril
2201
1894
Enalapril
2577
2118
Quinapril
276
224
Fosinopril
889
713
Captopril
421
325
*Unadjusted
Pilote L et al. Ann Intern Med. 2004;141:

19. 5-Year outcomes after PCI show major impact of disease progression
1228 patients in second-generation coronary stent trials
Target-lesion event 25
Nontarget-lesion event
Average event rate, years 2–5 20 7
6.7
18.3
Event
rate
(%) 15 5
12.4 % 10
7.0 3
6.7
5.8
5.7
1.7 5
2.3
1.3
1.5
1.6 1 1 2 3 4 5
Target-lesion
event
Nontarget-
lesion event
Year
Cutlip DE et al. Circulation. 2004;110:

20. APRES: Long-term benefit of ACEI started early after PTCA/CABG
N = 159, ramipril 10 mg or placebo 1 to 7 days post-revascularization 25
APRES ends
Cardiac death/HF 20
72%
P = 0.018
at 4.3 yrs
Placebo
Event rate
in cardiac
death/HF (%) 15
Ramipril
at 5.5 yrs 10
65%
P = 0.042 5
at 6.9 yrs
35%
P = 0.27 1 2 3 4 5 6 7
Years
No. at risk
Ramipril 80 78 77 74 55 30
Placebo 79 71 68 67 65 47 23
*APRES = Angiotensin-Converting Enzyme Inhibitor Post-Revascularization Study
KjØller-Hansen L et al. Am Heart J. 2004;148:

21. ACC/AHA recommendations on role of ACEIs in post-MI patients at discharge
UA/NSTEMI (1999)*
STEMI (2004)†
Class I
ACEIs for patients with CHF, LV dysfunction (EF <0.40), hypertension, or diabetes (Level of evidence: A)
ACEI should be prescribed at discharge for all patients without contraindications after STEMI (Level of evidence: A)
*Based on HOPE
†Based on HOPE and EUROPA
NSTEMI = non–ST-elevation MI
STEMI = ST-elevation MI
UA = unstable angina
Braunwald E et al.
Antman EM et al. J Am Coll Cardiol. 2004;44:

22. 5-Year CV-event risk (%)
Cumulative impact of 4 CV-protective medication classes in post-MI patients
Medication class
RRR (%)
5-Year CV-event risk (%)
None
20.0
Aspirin 25
15.0
-Blocker
11.3
ACE inhibitor
8.4
Lipid lowering 30
5.9
Cumulative risk reduction if all 4 medication classes are used: 70%
NNT to prevent 1 major CV event in 5 years: 7
RRR = relative risk reduction
Fonarow GC. Rev Cardiovasc Med. 2003;4(suppl 3):