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Program outline
VBWG
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
Deleterious effects of angiotensin II
Abnormal
vasoconstriction
PAI-1/
thrombosis
Ang II
Platelet
aggregation
Activate
SNS
Aldosterone
Vasopressin
Endothelin
SNS = Sympathetic nervous system
VBWG
Superoxide
production
Vascular
Myocyte
smooth muscle Collagen
growth
growth
Remodeling
Burnier M, Brunner HR. Lancet. 2000;355:637-45.
Brown NJ, Vaughn DE. Adv Intern Med. 2000;45:419-29.
PERTINENT: ACEI improves endothelial
function—Effects on cultivated HUVECs
Healthy control
Perindopril 8 mg
Placebo
ecNOS activity (U/mg)
Apoptosis (%)
9
4.0
3.5
VBWG
P < 0.05
3.3
3.5
2.9
3.0
2.4
2.5
7.8
8
6.8
7
P < 0.05
7.0
6
2.5
5
2.0
4.7
4
1.5
3
1.0
2
0.5
1
0
0
Control
Baseline
1 Year
HUVECs = human umbilical vein endothelial cells
1.3
Control
Baseline
1 Year
Ferrari R. ESC 2004; Munich.
VBWG
PERTINENT: Effects of ACEI on bradykinin,
Ang II, and TNF — Plasma analysis
Bradykinin
25
20
Ang II
P < 0.05
18.3
17.7
14.8
15
12.4
pg/mL
12.3
10
5
0
Control
Baseline
1 Year
35
18
16
14
12
pg/mL 10
8
6
4
2
0
TNF-
30
27.1 27.7
25
Healthy control
Perindopril 8 mg
Placebo
pg/mL
20
17.1
15.8
14.4
12.5
10.8
Control
P < 0.05
Baseline
1 Year
P < 0.05
28.9
24.6
18.0
15
10
5
0
Control
Baseline
1 Year
Ferrari R. ESC 2004; Munich.
VBWG
Major clinical outcome trials
of RAAS manipulation
ACE inhibition
Angiotensin receptor blockade
HOPE
EUROPA
PEACE
QUIET
GISSI-3
ISIS-4
AIRE
SAVE
SOLVD-Prevention
TRACE
CHARM-Preserved
OPTIMAAL
VALIANT
SOLVD-Treat
CHARM-Added
CHARM-Alternative
ELITE II
Val-HeFT
ALLHAT
ANBP2
INVEST
LIFE
CONSENSUS
VBWG
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;351:2058-68.
VBWG
PEACE: Treatment effect on primary outcome
Placebo
30
25
Incidence
of primary
outcome (%)
Trandolapril
20
15
10
5
0
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;351:2058-68.
PEACE: Treatment effect on components
of primary outcome and total deaths
Outcome
Event rate (%)
VBWG
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
5.3
1.00 (0.83–1.20)
CABG
6.5
7.1
0.91 (0.77–1.07)
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
3.7
4.4
0.89 (0.76–1.04)
PCI
*CV death, nonfatal MI,
and coronary revascularization
PEACE Trial Investigators. N Engl J Med. 2004;351:2058-68.
HOPE, EUROPA: Overview
VBWG
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;342:145-53.
EUROPA Investigators. Lancet. 2003;362:782-8.
HOPE, EUROPA: Treatment benefit on
primary and selected secondary outcomes
Favors
ACEI
Event rate (%)
ACEI
17.8
8.0
9.9
CV mortality
6.1
3.5
8.1
4.1
Myocardial infarction
9.9
4.8
12.3
6.2
Stroke
3.4
1.6
4.9
1.7
0.8
1.3
0.1
0.2
Cardiac arrest
Favors
placebo
Placebo
14.0
Composite outcome
VBWG
HOPE
EUROPA
0.5
EUROPA = European Trial on Reduction of Cardiac Events
with Perindopril in Stable Coronary Artery Disease
HOPE = Heart Outcomes Prevention Evaluation
1.0
Hazard ratio
1.5
EUROPA Investigators. Lancet. 2003;362:782-8.
HOPE Study Investigators. N Engl J Med. 2000;342:145-53.
VBWG
HOPE, EUROPA, PEACE, QUIET:
CV event rate in placebo group
14
12.3
HOPE
EUROPA
PEACE
QUIET
12
10
Event rate
(%)
8.1
8
6.2
6
4.1
4
4.6
3.7
1.5
2
0
5.3
CV death
Nonfatal MI
HOPE Investigators. N Engl J Med. 2000;342:145-53.
EUROPA Investigators. Lancet. 2003;362:782-8.
PEACE Investigators. N Engl J Med. 2004;351:2058-68.
Pitt B. et al. Am J Cardiol. 2001;87:1058-63.
VBWG
HOPE, EUROPA, PEACE, QUIET:
CV therapies at baseline
HOPE
EUROPA
Antiplatelet agents* (%)
76
92
91
73
-Blockers (%)
40
62
60
26
Lipid-lowering agents (%)
29
58
70
0
Calcium channel
blockers (%)
47
32
36
0
Diuretics (%)
15
10
13
NA
*Mostly aspirin
PEACE QUIET
HOPE Investigators. N Engl J Med. 2000;342:145-53.
EUROPA Investigators. Lancet. 2003;362:782-8.
PEACE Investigators. N Engl J Med. 2004;351:2058-68.
Pitt B. et al. Am J Cardiol. 2001;87:1058-63.
HOPE, EUROPA: Use of lipid-lowering
drugs intensified during studies
70
Baseline
†
During study
69
58
60
49*
50
%
40
Patients
30
VBWG
29
20
10
0
HOPE
*End of study
†3 years
EUROPA
Yusuf S. Symposium at: AHA 2004; New Orleans.
EUROPA Investigators. Lancet. 2003;362:782-8.
HOPE, EUROPA: Effect of ACEI plus
concomitant CV therapy
VBWG
ACE inhibitor
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
*Perindopril 8 mg
†Ramipril 10 mg
0.8
No added benefit
1.0
2.0
EUROPA Investigators. Lancet. 2003;362:782-8
Dagenais GR et al. Circulation. 2001;104:522-6.
VBWG
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)
10
8
6
∆ LV
mass 4
(g) 2
8.21
6
5
∆ LV 4
end
3
systolic 2
volume
1
(mL)
7.86
0
–2
5.31
2.9
0
–4
–6
Ramipril 10 mg (n = 146)
–3.53
P Trend = 0.03
–1
–2
–3
–1.9
P Trend = 0.001
Lonn E et al. J Am Coll Cardiol. 2004;43:2200-6.
SECURE: Dose-dependent effect of
ramipril on carotid atherosclerosis
0.025
0.020
VBWG
P = 0.028
0.022
Slope
of the
0.015
mean
maximum
carotid-intima 0.010
thickness
(mm/y)
NS
0.018
37% Reduction
0.014
0.005
0
Placebo
Ramipril
2.5 mg
Ramipril
10 mg
Lonn E et al. Circulation. 2001;103:919-925.
HOPE, EUROPA, PEACE, QUIET:
Clinical implications
VBWG
• 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;351:2115-7.
VBWG
1-Year survival in post-MI patients
according to ACEI Rx at discharge
N = 7512
100
Cumulative
survival*
(%)
90
Ramipril
Perindopril
Lisinopril
Enalapril
Quinapril
Fosinopril
Captopril
80
P < 0.001 for log-rank test
70
0
No. of patients
Ramipril
Perindopril
Lisinopril
Enalapril
Quinapril
Fosinopril
Captopril
*Unadjusted
905
243
2201
2577
276
889
421
2
4
6
8
Time (months)
10
12
817
215
1894
2118
224
713
325
Pilote L et al. Ann Intern Med. 2004;141:102-12.
5-Year outcomes after PCI show major
impact of disease progression
VBWG
1228 patients in second-generation coronary stent trials
Target-lesion event
25
20
Event
rate 15
(%)
Nontarget-lesion event
Average event rate, years 2–5
18.3
7
12.4
5
6.7
%
10
7.0
5.8
3
6.7
5.7
1.7
5
2.3
1.5
1.3
1.6
1
0
1
2
3
Year
4
5
Target-lesion
event
Nontargetlesion event
Cutlip DE et al. Circulation. 2004;110:1226-30.
APRES: Long-term benefit of ACEI
started early after PTCA/CABG
VBWG
N = 159, ramipril 10 mg or placebo 1 to 7 days post-revascularization
25
APRES ends
Cardiac death/HF
20
72%
Placebo
Event rate 15
in cardiac
death/HF
10
(%)
P = 0.018
at 4.3 yrs
Ramipril
65%
at 5.5 yrs
P = 0.042
5
35%
0
0
1
2
3
4
5
6
7
Years
No. at
Ramipril
at 6.9 yrs
P = 0.27
80
78
78
77
74
55
30
Placebo
79
71
68
67
*APRES = Angiotensin-Converting Enzyme
Inhibitor Post-Revascularization Study
65
47
23
KjØller-Hansen L et al. Am Heart J. 2004;148:475-80.
ACC/AHA recommendations on role of
ACEIs in post-MI patients at discharge
VBWG
STEMI (2004)†
UA/NSTEMI (1999)*
Class I
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.
www.acc.org/clinical/guidelines/unstable.pdf
Antman EM et al. J Am Coll Cardiol. 2004;44:671-719.
Cumulative impact of 4 CV-protective
medication classes in post-MI patients
Medication class
None
Aspirin
-Blocker
ACE inhibitor
Lipid lowering
RRR (%)
0
25
25
25
30
VBWG
5-Year
CV-event risk (%)
20.0
15.0
11.3
8.4
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):537-46.