Program outline

1
Program outline
This program highlights the Prevention of Events
with Angiotensin Converting Enzyme Inhibition
(PEACE) trialproviding 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
Ang II
Abnormalvasoconstriction
Plateletaggregation
ActivateSNS
Superoxideproduction
Vascularsmooth musclegrowth
?Aldosterone
Myocytegrowth
?Collagen
?Vasopressin
?Endothelin
Remodeling
Burnier M, Brunner HR. Lancet. 2000355637-45. Br
own NJ, Vaughn DE. Adv Intern Med. 200045419-29.
SNS Sympathetic nervous system
3
PERTINENT ACEI improves endothelial
functionEffects on cultivated HUVECs
Healthy control
Perindopril 8 mg
Placebo
Apoptosis ()
ecNOS activity (U/mg)
9
4.0
P lt 0.05
3.5
P lt 0.05
7.8
8
3.5
3.3
7.0
6.8
7
2.9
3.0
6
2.5
2.4
2.5
5
4.7
2.0
4
1.5
3
1.0
2
1.3
1
0.5
0
0
Baseline
1 Year
Control
Baseline
1 Year
Control
HUVECs human umbilical vein endothelial cells
Ferrari R. ESC 2004 Munich.
4
PERTINENT Effects of ACEI on bradykinin, Ang
II, and TNF Plasma analysis
Bradykinin
Ang II
25
17.1
18
P lt 0.05
15.8
P lt 0.05
16
14.4
20
18.3
17.7
14
12.5
14.8
10.8
12
15
12.4
12.3
pg/mL
pg/mL
10
8
10
6
4
5
2
0
0
Baseline
1 Year
Control
Baseline
1 Year
Control
35
TNF-?
P lt 0.05
28.9
30
27.7
27.1
24.6
25
Healthy control
20
18.0
pg/mL
Perindopril 8 mg
15
Placebo
10
5
0
Ferrari R. ESC 2004 Munich.
Baseline
1 Year
Control
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
HOPEEUROPA 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.
20043512058-68.
7
PEACE Treatment effect on primary outcome
Placebo
30
25
Trandolapril
20
Incidence of primary outcome ()
15
10
5
0
1
2
3
4
5
6
Years after randomization
PEACE Trial Investigators. N Engl J Med.
20043512058-68.
8
PEACE Treatment effect on components of primary
outcome and total deaths
CV death, nonfatal MI, and coronary
revascularization
PEACE Trial Investigators. N Engl J Med.
20043512058-68.
9
HOPE, EUROPA Overview
HOPE Investigators. N Engl J Med.
2000342145-53. EUROPA Investigators. Lancet.
2003362782-8.
CV disease, peripheral artery disease, stroke or
diabetes 1 CV risk factor
10
HOPE, EUROPA Treatment benefit on primary and
selected secondary outcomes
Favors ACEI
Favors placebo
Event rate () ACEI Placebo 14.0 17.8
8.0 9.9 6.1 8.1 3.5 4.1 9.9
12.3 4.8 6.2 3.4 4.9 1.6 1.7
0.8 1.3 0.1 0.2
Composite outcome CV mortality Myocardial
infarction Stroke Cardiac arrest
HOPE
EUROPA
0.5
1.0
1.5
Hazard ratio
EUROPA European Trial on Reduction of Cardiac
Events with Perindopril in Stable Coronary
Artery Disease HOPE Heart Outcomes Prevention
Evaluation
EUROPA Investigators. Lancet. 2003362782-8. HOPE
Study Investigators. N Engl J Med.
2000342145-53.
11
HOPE, EUROPA, PEACE, QUIET CV event rate in
placebo group
14
12.3
HOPE
12
EUROPA
PEACE
10
QUIET
8.1
Event rate()
8
6.2
5.3
6
4.6
4.1
3.7
4
1.5
2
0
CV death
Nonfatal MI
HOPE Investigators. N Engl J Med.
2000342145-53. EUROPA Investigators. Lancet.
2003362782-8. PEACE Investigators. N Engl J
Med. 20043512058-68. Pitt B. et al. Am J
Cardiol. 2001871058-63.
12
HOPE, EUROPA, PEACE, QUIET CV therapies at
baseline
HOPE Investigators. N Engl J Med.
2000342145-53. EUROPA Investigators. Lancet.
2003362782-8. PEACE Investigators. N Engl J
Med. 20043512058-68. Pitt B. et al. Am J
Cardiol. 2001871058-63.
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
0
HOPE
EUROPA
End of study 3 years
Yusuf S. Symposium at AHA 2004 New
Orleans. EUROPA Investigators. Lancet.
2003362782-8.
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
2.0
1.0
0.6
0.8
Perindopril 8 mg Ramipril 10 mg
EUROPA Investigators. Lancet. 2003362782-8
Dagenais GR et al. Circulation. 2001104522-6.
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
5
8
8.21
7.86
? LV end systolic volume (mL)
4
6
? LV mass (g)
2.9
3
4
2
2
1
0
0
2
1
2
4
3.53
1.9
3
6
P Trend 0.03
P Trend 0.001
Lonn E et al. J Am Coll Cardiol. 2004432200-6.
16
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
37 Reduction
0.015
0.014
0.010
0.005
0
Placebo
Ramipril 10 mg
Ramipril 2.5 mg
Lonn E et al. Circulation. 2001103919-925.
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. 20043512115-7.
18
1-Year survival in post-MI patients according to
ACEI Rx at discharge
N 7512
100
90
Cumulativesurvival()
Ramipril
Perindopril
Lisinopril
80
Enalapril
Quinapril
Fosinopril
P lt 0.001 for log-rank test
Captopril
70
12
10
8
6
4
2
0
No. of patients
Time (months)
Ramipril
817
905
Perindopril
215
243
Lisinopril
1894
2201
Enalapril
2118
2577
Quinapril
224
276
Fosinopril
713
889
Captopril
325
421
Unadjusted
Pilote L et al. Ann Intern Med. 2004141102-12.
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 25
20
6.7
7
18.3
Event rate ()
15
5
12.4

10
3
7.0
6.7
5.8
5.7
1.7
5
2.3
1.5
1
1.6
1.3
0
Target-lesion event
Nontarget- lesion event
1
2
3
4
5
Year
Cutlip DE et al. Circulation. 20041101226-30.
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
65? P 0.042
10
5
at 6.9 yrs
35? P 0.27
0
6
5
4
3
2
1
7
0
Years
APRES Angiotensin-Converting Enzyme Inhibitor
Post-Revascularization Study
KjØller-Hansen L et al. Am Heart J.
2004148475-80.
21
ACC/AHA recommendations on role of ACEIs in
post-MI patients at discharge
Based on HOPE Based on HOPE and EUROPA NSTEMI
nonST-elevation MI STEMI ST-elevation MI UA
unstable angina
Braunwald E et al.www.acc.org/clinical/guidelines
/unstable.pdf Antman EM et al. J Am Coll Cardiol.
200444671-719.
22
Cumulative impact of 4 CV-protective medication
classes in post-MI patients

• Cumulative risk reduction if all 4 medication
  classes are used 70
• NNT to prevent 1 major CV event in 5 years 7

Fonarow GC. Rev Cardiovasc Med. 20034(suppl
3)537-46.
RRR relative risk reduction