VBWG
RAAS Modulation:
Novel Strategies
for Reducing
Cardiovascular Risk
VBWG
Epidemiology/Guideline
Update:
•
•
The diabetes crisis
CVD and the aging patient
VBWG
CHD risk rises sharply in middle age
NHANES 1999–2002
20
16.8
15
11.6
11.5
10.3
%
10
Population
6.3
5
3.6
3.0
1.6
1.4
0
0.0 0.3
20–34
0.2
35–44
45–54
55–64
65–74
≥75
Age
Men
Women
AHA. Heart Disease and Stroke Statistics—2005 Update.
VBWG
CV disease: Leading cause of death
in Americans
493,623
500
433,825
400
Deaths
(1000s)
Men
Women
288,768
300
268,503
200
100
69,257 60,713
64,103
34,301
0
A
B
A Total CVD*
B Cancer
C
D
E
A
B
C Accidents
D Chronic lower respiratory diseases
*CHD, stroke, HF, hypertension, arterial diseases
Data compiled for 2002
C
41,877 38,948
F
E
E Diabetes
F Alzheimer’s Disease
CDC/NCHS and NHLBI.
VBWG
Obesity and diabetes among US adults:
Growing prevalence
Obesity (BMI ≥30 kg/m2)
30
Diagnosed diabetes
8
6.4
25
21.8
Population
(%)
23.0
23.9
23.7
24.3
6
20
4
15
2
0
0
2000 2001 2002 2003 2004*
*Jan–June
6.5
6.6
6.6
5.9
2000 2001 2002 2003 2004*
CDC. 2004 NHIS; www.cdc.gov/nchs/nhis.htm.
ACC/AHA 2002 Guideline Update for
Management of Patients with Chronic Stable
Angina: Asymptomatic patients
VBWG
Class I recommendations for pharmacotherapy to prevent MI and death
1. Aspirin in the absence of contraindication in patients with prior MI
(Level of evidence: A)
2. -Blockers as initial therapy in absence of contraindications in
patients with prior MI (Level of evidence: B)
3. Lipid-lowering therapy in patients with documented CAD
and LDL-C >130 mg/dL, with target LDL <100 mg/dL
(Level of evidence: A)
4. ACEI in patients with CAD who have diabetes and/or
systolic dysfunction (Level of evidence: A)
Based on HOPE
Gibbons RJ et al. J Am Coll Cardiol. 2003;41:159-68.
VBWG
ACP recommendations for ACEI in chronic
stable angina or asymptomatic CAD
• To prevent MI or death and reduce symptoms in patients
with chronic stable angina (Level of evidence: A)
• To prevent MI and death in asymptomatic patients with:
– Evidence of CAD and with systolic dysfunction
(Level of evidence: A)
– Diabetes with (Level of evidence: A) or without evidence
of CAD (Level of evidence: B)
Based on HOPE and EUROPA
Snow V et al. Ann Intern Med. 2004;141:562-7.
VBWG
RAAS: Central Role
in the Pathogenesis of
Cardiovascular Disease
RAAS: Sites of intervention with
ACEIs, ARBs
VBWG
Angiotensinogen
Renin
Angiotensin I
ACE
Angiotensin-converting
inhibitors
enzyme (ACE)
Angiotensin II
Angiotensin receptor
blockers
AT1 receptor
AT2 receptor
Atherosclerosis, hypertension
Vascular
protection?
Adapted from Nickenig G. Circulation. 2004;110:1013-20.
RAAS: Other potential sites of intervention
VBWG
Effects
Aldosterone
endothelial function, thrombosis
vascular compliance,
baroreceptor function,
fibrosis
Cathepsin G
Chymostatinsensitive system
Angiotensinogen  Ang II
Chymase
Ang I  Ang II
ACE2
Ang I  Ang (1–9), Ang (1–7)
Struthers AD, MacDonald TM. Cardiovasc Res. 2004;61:663-70.
Jacoby DS, Rader DJ. Arch Intern Med. 2003;163:1155-64.
Zisman LS. Eur Heart J. 2005;26:322-4.
Ang II and mechanisms of atherosclerosis
VBWG
Inflammation
Endothelial
Endothelial
dysfunction
dysfunction
IL-6
MCP-1
PDGF
Impaired
NO synthase
Lipid oxidation
LOX-1
Angiotensin II
Thrombosis
VCAM
ICAM
PAI-1
TF
Adhesion
TGF-
Proliferation fibrosis
Jacoby DS, Rader DJ. Arch Intern Med. 2003;163:1155-64.
VBWG
PERTINENT: ACE inhibition  NO
via  eNOS activity
Controls
4
P < 0.01*
†
1 Year
P < 0.05†
3.3
2.9
2.5
2.4
2
1
0
* vs baseline
Baseline
3.5
3
eNOS
activity in
HUVECs
(pmol/min/
mg protein)
CAD patients
Controls
n = 45
Placebo Perindopril
n = 44
n = 43
Placebo Perindopril
n = 44
n = 43
 perindopril vs  placebo
PERindopril – Thrombosis, InflammatioN, Endothelial dysfunction
and Neurohormonal activation Trial (substudy of EUROPA)
HUVEC = human umbilical vein endothelial cell
Ferrari R et al. www.europa-trial.org
VBWG
AT1 receptor blockade improves
flow-mediated vasodilation
122 Hypertensive patients treated for 2 months
2.5

*
2.0
*
FMD
1.5
in
brachial
artery 1.0
(%)
1.66
*
1.32
1.14
0.5
0.0
0.15
Placebo
(n = 30)
*P < 0.05 vs baseline and vs placebo
Losartan
100 mg
(n = 31)
Irbesartan
300 mg
(n = 30)
Candesartan
16 mg
(n = 31)
Koh KK et al. Am J Cardiol. 2004;93:1432-5.
Ang II and mechanisms of atherosclerosis
VBWG
Inflammation
IL-6
MCP-1
PDGF
Endothelial
dysfunction
Impaired
NO synthase
Lipid oxidation
LOX-1
Angiotensin II
Thrombosis
VCAM
ICAM
PAI-1
TF
Adhesion
TGF-
Proliferation fibrosis
Jacoby DS, Rader DJ. Arch Intern Med. 2003;163:1155-64.
ACE inhibition reduces oxidative stress
and inflammation
VBWG
20 Patients with type 2 diabetes
Lipid peroxides
400
TNF-
IL-6
4
370
3.3
300
200
mol/L
*
264
2.9
3
*
2
2.0
*
1.8
pg/mL
100
1
0
0
Baseline
* P < 0.05 vs baseline
Perindopril 4 mg x 6 mos
Marketou ME et al. J Am Coll Cardiol. 2005;45 (suppl A):396A.
Ang II and mechanisms of atherosclerosis
VBWG
Inflammation
IL-6
MCP-1
PDGF
Endothelial
dysfunction
Impaired
NO synthase
Lipid
oxidation
Lipid
oxidation
LOX-1
Angiotensin II
Thrombosis
VCAM
ICAM
PAI-1
TF
Adhesion
Adhesion
TGF-
Proliferation fibrosis
Jacoby DS, Rader DJ. Arch Intern Med. 2003;163:1155-64.
AT1, LOX-1 receptor cross-talk promotes
adhesion molecule expression: Interaction
between RAAS and dyslipidemia
VBWG
Endothelial cell
Ang II
LOX-1
AT1
ROS
MAPKs
OxLDL
PKs
TNF-
Scavenger
receptors??
Adhesion molecule
expression
MCP-1
NF-B
Endothelin
Shear
stress
eNOS
Bad
Fas
Monocyte
attachment and
activation
Dysfunction
Apoptosis
Injury
Atherosclerosis
Mehta JL, Li D. J Am Coll Cardiol. 2002;39:1429-35.
Ang II upregulates LOX-1 expression
via lipoxygenase pathway
VBWG
Human vascular smooth muscle cells
400
*
300
LOX-1
mRNA
†
‡
200
100
0
Control
* P < 0.0001 vs control
† P < 0.0001 vs Ang II
‡ P < 0.05 vs Ang II
Bai = baicalein (12-lipoxygenase inhibitor)
Ang II
10-7 mol/L
Ang II
10-7 mol/L+
Bai 10-5 mol/L
Ang II
10-7 mol/L+
losartan 10-5
mol/L
Limor R et al. Am J Hypertens. 2005;18:299-307.
Ang II and mechanisms of atherosclerosis
VBWG
Inflammation
IL-6
MCP-1
PDGF
Endothelial
dysfunction
Impaired
NO synthase
Lipid oxidation
LOX-1
Angiotensin II
Thrombosis
VCAM
ICAM
PAI-1
TF
Adhesion
TGF-
Proliferation
Proliferation
fibrosis
Jacoby DS, Rader DJ. Arch Intern Med. 2003;163:1155-64.
VBWG
HOPE: Dose-dependent effects of
ramipril on LV mass and function
N = 446 follow-up, 4 years
LV mass
10

(g)
8.21
LV end-systolic volume
5.31
6
7.86
4
5
2.9
 2
(mL)
0
0
–4
PTrend = 0.03
–3.53
Placebo
Mean baseline LVEF 58%, all groups
–3
PTrend = 0.001
Ramipril
2.5 mg
–1.9
Ramipril
10 mg
Lonn E et al. J Am Coll Cardiol. 2004;43:2200-6.
LIFE: Greater reduction in LV mass
with angiotensin receptor blockade
vs beta-blockade
VBWG
Patients with hypertension and LVH
Year
0
–10
Change in
LV mass
(g)
–20
1
2
3
4
5
Last
visit
Losartan 50–100 mg
(n = 457)
Atenolol 50–100 mg
(n = 459)
–30
–40
P = 0.009 for all time points
–50
Devereux RB et al. Circulation. 2004;110:1456-62.
Ang II and mechanisms of atherosclerosis
VBWG
Inflammation
IL-6
MCP-1
PDGF
Endothelial
dysfunction
Impaired
NO synthase
Lipid oxidation
LOX-1
Angiotensin II
Thrombosis
Thrombosis
VCAM
ICAM
PAI-1
TF
Adhesion
TGF-
Proliferation fibrosis
Jacoby DS, Rader DJ. Arch Intern Med. 2003;163:1155-64.
PAI-1 release: Differing effects of ACE
inhibition vs AT1 receptor blockade
VBWG
20 insulin-resistant, hypertensive patients treated for 6 weeks
15
10

Ramipril 10 mg
5
Losartan 100 mg
in
0
PAI-1
antigen
–5
(ng/mL)
–10
–15
–20
1
3
4
6
Weeks
P = 0.043, drug x time interaction
Brown NJ et al. Hypertension 2002;40:859-65.
VBWG
Change in PAI-1 antigen levels:
Differing effects of ARBs
126 Patients with hypertension
80
P < 0.01
60
40
%
Change 20
0
–20
–40
Irbesartan
300 mg
Placebo
Candesartan
16 mg
Losartan
100 mg
P = 0.012
P = 0.163
Koh KK et al. Atherosclerosis. 2004;177:155-60.
tPA release: Differing effects of ACE
inhibition vs AT1 receptor blockade
VBWG
25
*
20
tPA antigen
in coronary
sinus (ng/mL)
*
15
10
*
*
*
*
*
0.6
2.0
P < 0.05
5
0
0
0.2
Bradykinin (g/min)
Perindopril 4 mg
(n = 16)
*P < 0.05 vs baseline
Losartan 50 mg
(n = 15)
Control
(n = 14)
Matsumoto T et al. J Am Coll Cardiol. 2003;41:1373-9.
VBWG
Antiatherosclerotic effect of RAAS
modulation: Clinical and experimental evidence
• Studies in several animal models of atherosclerosis
demonstrated reduced lesion progression with ACE
inhibitor or AT1 receptor blocker1
• Regression of human carotid plaque demonstrated
with ramipril (SECURE2), losartan (LAARS3), and
fosinopril (PHYLLIS4)
1Jacoby
DS, Rader DJ. Arch Intern Med. 2003;163:1155-64.
2Lonn E et al. Circulation. 2001:103;919-25.
3Ludwig M et al. Clin Ther. 2002;24:1175-93.
4Zanchetti A et al. Stroke. 2004;35:2807-12.
VBWG
ARB blunts MMP expression in human
carotid plaques: Potential role in
plaque stabilization
Carotid endarterectomy specimens
30
28.2
25.8
25.1
22.4
20
%
Positive
staining
10
5.8
6.2
7.2
5.6
0
MMP-2
P < 0.0001 all comparisons
ARB = AT1 receptor blockade
MMP = matrix metalloproteinase
MMP-9
Chlorthalidone
COX-2
mPGES-1
Irbesartan
Cipollone F et al. Circulation. 2004;109:1482-8.
VBWG
Role of RAAS
Modulation in
CAD Patients
VBWG
ACE inhibition in CAD: Short-term
trials in acute MI
Deaths (n)/Randomized (n)
ACEI
ACEI better
Control
O-E
CONSENSUS-II* 220/3044
(7.23%)
192/3046
(6.30%)
14.07
96.05
570/9682
(5.89%)
650/9712
(6.69%)
–39.06
285.83
ISIS-4
2035/29,028
(7.01%)
2171/29,022
(7.48%)
–68.22
975.33
CCS-1
676/7460
(9.06%)
727/7489
(9.71%)
–24.14
317.85
3501/49,214
(7.11%)
3740/49,269
(7.59%)
–117.35
1675.06
GISSI-3
Total
Control better
Variance
Odds reduction (± SD)
7±2
0.5
0.75
1.0
1.25
1.5
Odds ratio (95% CI)
Test for Heterogeneity: 2 5.8 (2p = 0.1) df = 3
*IV infusion followed by oral therapy
Treat Eff: 2 (2p = 0.004)
ACE Inhibitor MI Collaborative Group. Circulation. 1998;97:2202-12.
VBWG
ACE inhibition in CAD: Long-term
trials in post-MI LV dysfunction and HF
P
AIRE
27%
TRACE
0.001
22%
SOLVD
(Treatment)
0.0036
16%
SOLVD
(Prevention)
8%
0.30
0.019
19%
SAVE
0
5
10
0.002
15
20
25
30
Risk reduction in total mortality (%)
AIRE Study Investigators. Lancet. 1993;342:821-8.
Køber L et al. N Engl J Med. 1995;333:1670-6.
SOLVD Investigators. N Engl J Med. 1991;325:293-302.
SOLVD Investigators. N Engl J Med. 1992;327:685-91.
Pfeffer MA et al. N Engl J Med. 1992;327:669-77.
VBWG
Aldosterone blockade and AT1 receptor blockade: Trials
in post-MI/LV dysfunction or HF
RALES
EPHESUS
1.00
30% Risk reduction
RR 0.70 (0.60–0.82)
P < 0.001
0.90
Probability
of survival
0.75
Spironolactone
0.60
Placebo
0.45
0.00
15% Risk reduction
RR 0.85 (0.75–0.96)
P = 0.008
22
18
Placebo
Eplerenone
Cumulative 14
incidence 10
(%)
6
2
0
0
6
12
18
24
30
36
Months
0
6
12
18
24
30
36
Months
VALIANT
0.4
2% RR V/C vs C
HR 0.98 (0.89–1.09)
P = 0.73)
0% RR V vs C
HR 1.00 (0.90–1.11)
P = 0.98
0.3
Valsartan
Captopril
Probability
0.2
of event
Valsartan/captopril
0.1
0.0
0
6
12
18
24
Months
30
36
Pitt B et al. N Eng J Med. 1999;341:709-17.
Pitt B et al. N Eng J Med. 2003;348:1309-21.
Pitt B et al. N Eng J Med. 2003;349:1893-906.
VBWG
HOPE, QUIET, EUROPA, PEACE: Primary outcomes
HOPE
20
22% Risk reduction
RR 0.78 (0.70–0.86)
P = 0.001
15
Placebo
Ramipril
10 mg
%
Patients 10
5
0
1
0
2
3
Time (years)
25
Placebo
2
3
4
Time (years)
5
4% Risk increase
RR 1.04 (0.89–1.22)
P = 0.6
30
Quinapril
20 mg
Placebo
20
10
0
5
0
1
QUIET
40
Trandolapril
4 mg
Placebo
Perindopril
8 mg
50
4% Risk reduction
HR 0.96 (0.88–1.06)
P = 0.43
20
%
Patients 15
10
20% Risk reduction
RR 0.80 (0.71–0.91)
P = 0.0003
0
4
PEACE
30
EUROPA
14
12
10
8
6
4
2
0
0
1
2
3
4
Time (years)
5
6
1
2
Time (years)
3
HOPE Study Investigators. N Engl J Med. 2000;342:145-53.
EUROPA Investigators. Lancet. 2003;362:782-8.
PEACE Trial Investigators. N Engl J Med. 2004;351:2058-68.
Pitt B et al. Am J Cardiol. 2001;87:1058-63.
VBWG
HOPE, EUROPA: Consistency of
treatment benefit
Event rate (%)
ACEI
Favors
Favors
ACE inhibitor Placebo
Placebo
14.0
17.8
8.0
9.9
HOPE
(ramipril 10 mg)
CV mortality
6.1
3.5
8.1
4.1
EUROPA
(perindopril 8 mg)
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
Composite outcome
Cardiac arrest
0.5
1.0
Hazard ratio
1.5
HOPE Study Investigators. N Engl J Med. 2000;342:145-53.
EUROPA Investigators. Lancet. 2003;362:782-8.
HOPE, EUROPA: Concomitant CV therapy
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
VBWG
No added benefit
1.0
2.0
Hazard ratio
EUROPA: perindopril 8 mg
HOPE: ramipril 10 mg
EUROPA Investigators. Lancet. 2003;362:782-8.
Dagenais GR et al. Circulation. 2001;104:522-6.
VBWG
PEACE: Prevention of Events with
Angiotensin Converting Enzyme inhibition
Objective:
Assess effect of ACEI in patients
with stable CAD and normal/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: Primary outcome
CV death, MI, CABG/PCI; N = 8290
30
4% Risk reduction
HR 0.96 (0.88–1.06)
P = 0.43
25
Placebo
Trandolapril
4 mg
20
%
Patients
15
10
5
0
1
2
3
4
5
6
Time (years)
PEACE Trial Investigators. N Engl J Med. 2004;351:2058-68.
ACEI outcome trials in CAD patients
without HF
ACE inhibitor
Key inclusion criteria
VBWG
Primary
outcome
EUROPA
N = 12,218
(4.2 years)
Perindopril 8 mg
CAD
No heart failure
Age ≥18 years
CV death, MI,
cardiac arrest
HOPE
N = 9297
(4.5 years)
Ramipril 10 mg
Vascular disease
(80% had CAD)
LVEF ≥40%, or
No heart failure
Age ≥55 years
CV death,
MI, stroke
PEACE
N = 8290
(4.8 years)
Trandolapril 4 mg
CAD
LVEF ≥40%
Age ≥50 years
CV death, MI,
coronary
revascularization
QUIET
N = 1750
(2.25 years)
Quinapril 20 mg
PTCA, atherectomy
Normal LVEF
CV death, MI,
coronary revasc,
cardiac arrest, hosp
for angina
EUROPA Investigators. Lancet. 2003;362:782-8.
HOPE Study Investigators. N Engl J Med. 2000;342:145-53.
PEACE Trial Investigators. N Engl J Med. 2004;351:2058-68.
Pitt B et al. Am J Cardiol. 2001;87:1058-63.
ACEI outcome trials in CAD patients
without HF: Key baseline characteristics
N
Follow-up (yrs)
ACEI/dose (mg)
Age (yrs)
Men (%)
CAD/Cor rev (%)
Diabetes (%)
HTN (%)
Prior MI (%)
EF
PVD (%)
HOPE
EUROPA
PEACE
9,297
4.5
R-10
66
73
80/44
39
47
53
NA
43
12,218
4.2
P-8
60
85
100/55
12
27
65
NA
7
8,290
4.8
T-4
64
82
100/72
17
46
55
58
NA
VBWG
QUIET
1,750
2.3
Q-20
58
82
100/100
16
47
49
59
NA
EUROPA Investigators. Lancet. 2003;362:782-8.
HOPE Study Investigators. N Engl J Med. 2000;342:145-53.
PEACE Trial Investigators. N Engl J Med. 2004;351:2058-68.
Pitt B et al. Am J Cardiol. 2001;87:1058-63.
VBWG
ACEI outcome trials in CAD patients
without HF: CV therapies at entry/during study
HOPE
EUROPA
Antiplatelet agents (%)
76
92
91
73
-Blockers (%)
40
62
60
26
Lipid-lowering agents (%)
29/49*
58/68†
70
0/14*
Calcium antagonists (%)
47
32
36
0/7*
Diuretics (%)
15
10
13
NA
*at
†at
study end
3 yrs
PEACE QUIET
EUROPA Investigators. Lancet. 2003;362:782-8.
HOPE Study Investigators. N Engl J Med. 2000;342:145-53.
PEACE Trial Investigators. N Engl J Med. 2004;351:2058-68.
Pitt B et al. Am J Cardiol. 2001;87:1058-63.
ACEI outcome trials in CAD patients
without HF: BP at entry/during study
VBWG
BP (mm Hg)
HOPE
EUROPA
PEACE QUIET
At entry
139/79
137/82
133/78
123/74
Average ∆ BP during
follow-up (active
vs placebo)
3.3/1.2
5/2
3/1.2
NA
EUROPA Investigators. Lancet. 2003;362:782-8.
HOPE Study Investigators. N Engl J Med. 2000;342:145-53.
PEACE Trial Investigators. N Engl J Med. 2004;351:2058-68.
Pitt B et al. Am J Cardiol. 2001;87:1058-63.
Sleight P et al. Lancet 2001;358:2130-1.
VBWG
ACEI outcome trials in CAD patients
without HF: Differences in baseline CV risk
3.0
2.0
Annualized
event rate in
placebo group
(%/yr)
1.0
2.7
2.0
1.8
1.5
1.1
1.0
0.8
0.7
0.0
CV death
HOPE
Nonfatal MI
EUROPA
PEACE
QUIET
HOPE Study Investigators. N Engl J Med. 2000;342:145-53.
EUROPA Investigators. Lancet. 2003;362:782-8.
PEACE Trial Investigators. N Engl J Med. 2004;351:2058-68.
Pitt B et al. Am J Cardiol. 2001;87:1058-63.
VBWG
ACEI outcome trials in CAD patients
without HF: Annualized all-cause mortality—
placebo vs general population
3.0
65–74 years
2.7
2.4
All-cause 2.0
mortality
rate
(%/yr) 1.0
0.0
*Mean age in years
Age group
55–64 years
1.7
1.6
1.4
1.0
General
population
HOPE
(66*)
General
population
PEACE
(64*)
EUROPA
(60*)
QUIET
(58*)
HOPE Study Investigators. N Engl J Med. 2000;342:145-53.
EUROPA Investigators. Lancet. 2003;362:782-8.
PEACE Trial Investigators. N Engl J Med. 2004;351:2058-68.
Pitt B et al. Am J Cardiol. 2001;87:1058-63.
Anderson RN, Smith BL. Natl Vital Stat Rep. 2005;53:1-90.
VBWG
ACEI outcome trials in CAD patients
without HF: Annualized CV mortality—
placebo vs general population
Age group
65–74 years
2.0
55–64 years
1.8
1.5
CV
1.0
mortality
rate
0.5
(%/yr)
0.0
*Mean age in years
1.0
0.8
0.7
0.7
0.3
General
population
HOPE
(66*)
General
population
PEACE
(64*)
EUROPA
(60*)
QUIET
(58*)
HOPE Study Investigators. N Engl J Med. 2000;342:145-53.
EUROPA Investigators. Lancet. 2003;362:782-8.
PEACE Trial Investigators. N Engl J Med. 2004;351:2058-68.
Pitt B et al. Am J Cardiol. 2001;87:1058-63.
Anderson RN, Smith BL. Natl Vital Stat Rep. 2005;53:1-90.
VBWG
ACEI outcome trials in CAD patients
without HF: Cumulative evidence
Pooled all-cause mortality results
No. of deaths/no. of patients (%)
ACEI
Control
ACEI
Control
P
HOPE
482/4645
(10.4)
569/4652
(12.2)
0.005
EUROPA
375/6110
(6.1)
420/6108
(6.9)
0.098
PEACE
299/4158
(7.2)
334/4132
(8.1)
0.126
1156/14,913
(7.8)
1323/14,892
(8.9)
< 0.001
Total
0.6
0.8
1.0
3.0
5.0
Odds ratio
Yusuf S, Pogue J. N Engl J Med. 2005;352:937-9.
ACEI outcome trials in CAD patients
without HF: Totality of trial evidence
VBWG
HOPE, EUROPA, PEACE, QUIET
Event rate (%)
ACEI
All-cause death
7.5
Placebo
Favors ACEI Favors placebo
P
0.0004
8.9
0.86
MI
6.4
7.7
0.0004
0.86
Stroke
2.1
2.7
0.0004
0.77
Revascularization
15.5
16.3
0.025
0.93
0.5
0.75
1
1.25
Odds ratio
Pepine CJ, Probstfield JL. Vasc Bio Clin Pract.
CME Monograph; UF College of Medicine. 2004;6(3).
VBWG
CAMELOT: Trial of BP reduction with
ACEI or CCB in CAD patients without HF
Study design:
Randomized, double-blind, multicenter,
24-month trial in patients with angiographically
documented CAD, LVEF ≥40%, and no HF
(N = 1991)
Treatment:
Amlodipine (10 mg), enalapril (20 mg),
or placebo added to background therapy
with -blockers and/or diuretics
Primary
outcome:
Incidence of CV events for amlodipine
vs placebo
IVUS substudy:
Measurement of atherosclerosis progression
using IVUS (n = 274)
Outcome:
Change in percent atheroma volume
Nissen SE et al. JAMA. 2004;292:2217-26.
VBWG
CAMELOT: Reduction in primary outcome
with amlodipine and enalapril
0.25
HR (95% CI)
A vs P: 0.69 (0.54–0.88)
E vs P: 0.85 (0.67–1.07)
A vs E: 0.81 (0.63–1.04)
0.20
Cumulative
CV events
(proportion)
P = 0.16
P = 0.003
P = 0.1
0.15
Placebo
0.10
Enalapril
Amlodipine
0.05
0
0
6
12
Months
18
24
Placebo
655
588
558
525
488
Enalapril
673
608
572
553
529
Amlodipine
663
623
599
574
535
No. at risk
Primary outcome = incidence of CV events
Nissen et al. JAMA. 2004;292:2217-26.
CAMELOT: Clinical implications
VBWG
• Optimal BP levels in CAD patients may be
~120 mm Hg systolic
• Regression of CAD suggested with systolic
BP reduction >10 mm Hg
• Hemodynamic effects may also modulate
clinical outcome
• Increasing evidence to support the following strategies:
– Combinations of drugs with differing modes of action
– Lower BP targets in special populations
Pepine CJ. JAMA. 2004;292:2271-3.
VBWG
ACEI outcome trials in CAD patients
without HF: Clinical implications
• Cumulative evidence supports ACE inhibitors for stable
CAD patients with/without clinical signs of HF
• Not all ACE inhibitors can be assumed to have
comparable effects for all indications
– Dose and individual properties of ACEIs
are important
• Benefit may depend on risk level
– Benefit may be less in patients with well
controlled risk factors
• Randomized clinical trial evidence and guidelines should
guide selection of effective ACE inhibitor and dose for
CAD patients without HF
Pitt B. N Engl J Med. 2004;351:2115-7.
Factors that may lead to divergent
results in ACEI trials
VBWG
• Underdosing
– Dose-related effects on vascular and myocardial tissue
– Dose for CAD patients can’t be predicted from studies
in HF or hypertension
• Differences may exist among ACEIs
• Differences in baseline risk (age, diabetes, HTN, PAD)
• Inclusion of revascularization in primary outcome
• Lack of power
• Poor adherence to assigned treatment
Pitt B et al. Am J Cardiol. 2004;87:1058-63.
Yusuf S, Pogue J. N Engl J Med. 2005;352:937-8.
Pitt B. N Engl J Med. 2004;351:2115-7.
Pepine CJ, Probstfield JL. Vasc Bio Clin Pract.
CME Monograph; UF College of Medicine. 2004;6(3).
VBWG
Are all ACEIs the same:
Survival post-MI by ACEI at discharge
N = 7512
100
90
Unadjusted
cumulative
survival
(%)
Ramipril
n = 905
Perindopril n = 243
80
Lisinopril
n = 2201
Enalapril
n = 2577
Quinapril
n = 276
Fosinopril
n = 889
Captopril
n = 421
2
4
P < 0.001 log-rank
70
0
6
Months
8
10
12
Pilote L et al. Ann Intern Med. 2004;141:102-12.
VBWG
Ongoing major outcomes trials
of RAAS modulation
Patients
Treatment
Follow-up
(years)
Primary
outcome
ONTARGET*
55 years with
CAD, stroke, PAD,
or diabetes + endorgan damage
(N = 25,620)
Ramipril 10 mg
Telmisartan 80 mg
Ramipril 10 mg +
telmisartan 80 mg
5.5
CV death, MI,
stroke, hosp for
heart failure
TRANSCEND†
55 years, ACEI
intolerant, with
CAD, stroke, PAD,
or diabetes + endorgan damage
(N = 5776)
Telmisartan 80 mg
Placebo
5.5
CV death, MI,
stroke, hosp for
heart failure
*Ongoing Telmisartan Alone and in Combination
with Ramipril Global Endpoint Trial
†Telmisartan Randomized Assessment Study in
ACE Intolerant Subjects with Cardiovascular Disease
ONTARGET/TRANSCEND Investigators.
Am Heart J. 2004;148:52-61.
VBWG
RAAS Modulation in
Patients With Diabetes
MICRO-HOPE, PERSUADE:
ACEI in high-risk patients with diabetes
MICRO-HOPE
Patients:
ACE inhibitor:
PERSUADE
Diabetes + CVD
or ≥1 CV risk factor
Normal LV function
N = 3577
Diabetes + CAD
No heart failure
Ramipril 10 mg
Perindopril 8 mg
Follow-up (years):
Primary
outcome:
VBWG
N = 1502
4.5
4.2
CV death/MI/
stroke
CV death/MI/
cardiac arrest
PERindopril SUbstudy in coronary Artery disease
and DiabEtes (substudy of EUROPA)
HOPE Study Investigators. Lancet. 2000;355:253-9.
Daly CA et al. Eur Heart J. 2005. epub;April 28.
VBWG
MICRO-HOPE, PERSUADE:
Primary outcome
25
PERSUADE
(N = 3577)
CV death/MI/stroke
(N = 1502)
CV death/MI/cardiac arrest
15
25
Placebo
25% Risk reduction
RR 0.75 (0.64–0.88)
P = 0.0004
20
%
MICRO-HOPE
20
15
Ramipril
10 mg
10
5
0
0
1
2
3
Follow-up (years)
4
5
Perindopril
8 mg
10
5
0
Placebo
19% Risk reduction
P = 0.131
0
1
2
3
4
5
Follow-up (years)
HOPE Study Investigators. Lancet. 2000;355:253-9.
Daly CA et al. Eur Heart J. 2005. In press.
VBWG
MICRO-HOPE, PERSUADE:
Consistency of benefit
Favors ACEI
Favors placebo
Primary outcome
Total mortality
MICRO-HOPE
(N = 3577)
CV mortality
PERSUADE
(N = 1502)
All MI
Stroke
0.2
0.4
0.6
0.8
1.0
1.2
1.4
1.6
1.8
Relative risk (95% CI)
HOPE Study Investigators. Lancet. 2000;355:253-9.
Daly CA et al. Eur Heart J. 2005. In press.
VBWG
MICRO-HOPE: ACEI improves renal
and CV outcomes in type 2 diabetes
N = 3577 (32% with microalbuminuria)
MI
Overt
CV nephroStroke death pathy
0
3.0
Placebo
2.5
10
Risk
reduction 20
(%)
Mean albumincreatinine ratio
P = 0.02
2.0
1.5
22
24
P = 0.01
Ramipril 10 mg
P = 0.001
1.0
P = 0.027
30
P = 0.007
40
0.5
33
37
P = 0.0001
0
1
2
3
4.5
Years
HOPE Study Investigators. Lancet. 2000;355:253-9.
LIFE: Comparison of treatment effects in
overall population vs with diabetes
VBWG
Patients with hypertension and LVH
Favors losartan Favors atenolol
50–100 mg
50–100 mg
P
Overall (n = 9193)
0.206
CV death
Diabetes (n = 1195)
0.028
0.001
Stroke
0.204
0.491
MI
0.373
0.5
1.0
1.5
Hazard ratio
Dahlöf B et al. Lancet. 2002;359:995-1003.
Lindholm LH et al. Lancet. 2002;359:1004-10.
Effects of ARBs in type 2 diabetes:
Renal and CV outcomes
Study
(N)
ARB
Primary outcome:
Renal disease
progression*
VBWG
Secondary
outcomes
(CV)
Average
duration
(years)
IDNT
(N = 1715)
Irbesartan
300 mg/d vs
amlodipine
10 mg
20% vs placebo,
(P = 0.02) and 23%
vs amlodipine
(P = 0.006)
Combined CV
outcomes: NS
2.6
RENAAL
(N = 1514)
Losartan
100 mg/d
vs placebo†
16% (P = 0.02)
CV morbidity
and mortality:
NS HF
hospitalization
32%
3.4
IRMA-2
(N = 590)
Irbesartan 150–
300 mg
vs placebo
39% with
150 mg (P = 0.08)
70% with
300 mg (P < 0.001)
Nonfatal CV
events: NS
*Doubling of baseline serum creatinine, end-stage
renal disease (IDNT, RENAAL): progression to
diabetic nephropathy (IRMA-2)
2
Lewis EJ et al. N Engl J Med. 2001;345:851-60.
Brenner BM et al. N Engl J Med. 2001;345:861-9.
Parving HH et al. N Engl J Med. 2001;345:870-8.
VBWG
Impact of Lifestyle Change
and Pharmacologic Therapy
on Diabetes/CV
Prevention Strategies
VBWG
INTERHEART: Positive impact of
lifestyle factors on acute MI
Risk factor
Current smoking
Diabetes
Hypertension
Women
Men
Abdominal obesity
Psychosocial factors
Fruits/Vegetables
Exercise
Alcohol
ApoB/ApoA1 ratio
0.25
0.5
1.0
2
4
8
16
Odds ratio (99% CI)
Yusuf S et al. Lancet. 2004;364:937-52.
VBWG
Randomized controlled trials of
Mediterranean-style diets in CAD patients:
 Fatal/nonfatal CV events
1989
1997
1999
Diet and Reinfarction Trial
(N = 2000)
 29% all-cause mortality
 27% MI
Indian Experiment of Infarct
Survival Trial
(N = 360)
 50% cardiac death
 48% MI
GISSI-Prevenzione
(N = 11,324)
 20% all-cause mortality
 30% CV mortality
1999
2002
Lyon Diet Heart Study
(N = 605)
 68% cardiac death, MI
Indo-Mediterranean Diet
Heart Study
(N = 1000)
 33% fatal MI
Parikh P et al. J Am Coll Cardiol. 2005;45:1379-87.
VBWG
Prospective cohort studies of Mediterraneanstyle diets:  Mortality
2002
2002
2003
Physician’s Health Study
(N = 20,551)*
Nurses’ Health Study
(N = 84,688)
45% fatal CHD
Cardiovascular Health Study
(N = 5,201)*
2003
2005
European Prospective
Investigation into Cancer
and Nutrition–Greek cohort
(N = 22,043)†
European Prospective
Investigation into Cancer
and Nutrition–elderly cohort
(N = 74,607)†
2004
The Healthy Aging:
A Longitudinal Study in Europe
(N = 2339)
23% all-cause mortality
*Blood levels of n-3 fatty acids inversely
related to death
†Greater adherence associated with lower mortality
Parikh P et al. J Am Coll Cardiol. 2005;45:1379-87.
Trichopoulou A et al. BMJ. 2005;330:991-7.
Knoops KTB et al. JAMA. 2004;292:1433-9.
VBWG
Decrease in mortality with Mediterranean
diet: EPIC–elderly prospective cohort study
Objective:
Assess effect on mortality of modified
Mediterranean diet in subjects free
from CHD, stroke, or cancer
Design:
N = 74,607, age ≥60 years, from
9 European countries
Dietary adherence estimated on scale
of 0 (low) to 9 (high)
Follow-up:
Median 89 months
Result:
Each 2-unit  in adherence =
8%  all-cause mortality
(95% CI, 3%–12%)
Trichopoulou A et al. BMJ. 2005;330:991-7.
VBWG
Mediterranean diet reduces the
metabolic syndrome
Mediterranean diet
90
Control diet
84
82
75
66
60
%
Patients 45
34
30
20
18
11
15
9
13
9
8
1
0
3
4
5
3
4
Metabolic syndrome components (N)
Baseline
P < 0.001 for effect of
Mediterranean vs control diet
5
2 years
Esposito K et al. JAMA. 2004;292:1440-6.
Diabetes Prevention Program: Impact of
lifestyle intervention or metformin
40
N = 3234, no diabetes
Age 50 years
207 lbs
Glucose 107
30
Cumulative
incidence of 20
diabetes
(%)
VBWG
Placebo
P
Metformin
31%
< 0.001
Lifestyle
58%
< 0.001
• Lose 5–10 lbs
10
• Exercise 2.5 hrs/wk
0
0
0.5 1.0 1.5 2.0 2.5 3.2 3.5 4.0
Year
Diabetes Prevention Program Research Group. N Engl J Med. 2002;346:393-403.
VBWG
Diabetes Prevention Program:
Impact of PPAR agonist
15
Placebo
Metformin
Cumulative 10
incidence
(%)
5
Lifestyle
Troglitazone*
75% vs placebo
P <0.001
0
0.0
(2343)
0.5
(1568)
1.0
(739)
1.5
(237)
Years (n)
*Terminated early after 1.5 years
Diabetes Prevention Program Research Group.
Diabetes. 2005;54:1150-6.
VBWG
Diabetes Prevention Program: Impact of
lifestyle intervention or metformin on development
of metabolic syndrome
N = 3234 with impaired glucose tolerance (FG ≥95 mg/dL);
47% without metabolic syndrome at baseline
P*
0.75
Placebo group
(n = 490)
17% Metformin group
(n = 503)
0.60
Cumulative
incidence of
metabolic
syndrome
0.45
51%
Lifestyle group
(n = 530)
0.03
<0.001
0.30
0.15
0.00
0
*vs placebo
1
2
3
4
Time since randomization (year)
Orchard TJ et al. Ann Intern Med. 2005;142:611-9.
VBWG
HOPE/HOPE-TOO: Prevention of diabetes
New diabetes, all patients
HOPE study
termination
0.12
0.10
0.08
Hazard
ratio
Placebo
0.06
0.04
0.02
Ramipril
RR 0.70 (CI, 0.57–0.86)
0.00
1
2
3
4
Years
5
6
7
Bosch J. Circulation. 2005; in press.
CV pharmacotherapy: Impact on newly
diagnosed diabetes
VBWG
0
10
20
% Reduction
of new diabetes
30
100
Randomized active treatment vs control
(e.g. placebo, diuretic, or β-blocker  diuretic)
ACEI or ARB
CA + ACEI or ARB
CA
Pepine CJ, Cooper-Dehoff RM.
J Am Coll Cardiol. 2004;44:509-12.
Sever PS et al. Lancet. 2003;361:1149-58.
VBWG
Ongoing trials of diabetes prevention
with RAAS modulation
Patients
DREAM*
NAVIGATOR†
Treatment
Impaired glucose
tolerance or impaired
fasting glucose
(N = 5269)
Ramipril 15 mg
Impaired glucose
tolerance
(N = 9518)
Valsartan 160 mg
Follow-up
Anticipated
completion
3 yrs
2006
Until
accrual of
1000 CV
events
2007
Rosiglitazone 8 mg
Placebo
Nateglinide 60 mg
Valsartan 160 mg +
nateglinide 60 mg
Placebo
* Diabetes Reduction Approaches with
Ramipril and Rosiglitazone Medications
†Nateglinide and Valsartan in Impaired
Glucose Tolerance Outcomes Research
Gerstein HC et al. Diabetologia. 2004;47:1519-27.
Califf RM. Eur Heart J Suppl. 2003;5 (suppl C):C13-18.
Leiter LA, Lewanczuk RZ. Am J Hypertens. 2005;18:121-8.
VBWG
Peri-Interventional Care
of CAD Patients:
Optimal Discharge Strategies
ACC/AHA recommendations:
Discharge medical therapy after STEMI
VBWG
Class 1
RAAS modulation
ACEI for all patients (Level of evidence: A)
ARB for ACEI-intolerant patients with HF
or LVEF <0.40 (Level of evidence: B)
Aldosterone blocker for patients on ACEI with
LVEF <0.40 and HF or diabetes (Level of evidence: A)
Lipid lowering
Statins in patients with LDL-C >100 mg/dL (Level of
evidence: A) or with LDL-C <100 mg/dL (Level of evidence:
B)
Beta-blockade
Beta-blockers for all patients except those with
normal/near-normal ventricular function, successful
reperfusion, absence of ventricular arrhythmias
(Level of evidence: A)
Antiplatelet therapy
Aspirin 75-162 mg for all patients (Level of evidence: A)
Antman EM et al. J Am Coll Cardiol. 2004;44:671-719.
ACC/AHA recommendations: Discharge
therapy after unstable angina/NSTEMI
VBWG
Class 1
RAAS modulation
ACEI for patients with CHF, LV dysfunction
(EF <0.40), hypertension, or diabetes
(Level of evidence: A)
Lipid lowering
Lipid-lowering agents + diet in patients
with LDL >130 mg/dL, including after revascularization
(Level of evidence: A)
Lipid-lowering agents if LDL-C after diet is
>100 mg/dL (Level of evidence: C)
Beta-blockade
All patients (Level of evidence: B)
Antiplatelet therapy
Aspirin 75-325 mg/d (Level of evidence: A)
Clopidogrel 75 mg/d if aspirin is contraindicated (Level
of evidence: B)
Braunwald E et al. J Am Coll Cardiol. 2002;40:1366-74.
Available at www.acc.org
VBWG
Opportunity for optimizing discharge care
1600
1400
1200
1000
Procedures
in thousands
800
600
400
200
0
79
80
85
90
95
00
01
02
Year
Catheterizations
PTCA
Open heart
Endarterectomy
Bypass
Pacemakers
AHA. Heart Disease and Stroke Statistics–2005 Update.
VBWG
Nontarget-lesion events drive adverse
outcomes 5 years after PCI
1228 patients in 2nd generation coronary stent trials*
50
46.3%
Composite
40
Event rate
(%)
Nontarget
lesion
30
37.9%
20.3%
20
Target lesion
10
0
0
1
2
3
4
5
Years
*non-drug eluting stents
Cutlip DE et al. Circulation. 2004;110:1226-30.
Improving long-term outcomes in
patients with coronary stents
VBWG
• With 2nd-generation stents, the stented lesion is
relatively stable after the first 12 months
• Greatest opportunity for improvement in
long-term outcomes is prevention of disease
progression at other sites through aggressive
risk-factor intervention
Cutlip DE et al. Circulation. 2004;110:1226-30.
CRUSADE: Variations among hospitals
in discharge care
VBWG
65,426 UA/NSTEMI patients from participating hospital registries
100
94
89
82
80
Patients
receiving
correct
treatment
(%)
81
72
68
65
59
60
50
42
40
20
0
Aspirin
-Blocker
ACEI
Lagging centers
(lowest quartile)
Statin
Clopidogrel
Leading centers
(highest quartile)
Ohman EM et al. Am Heart J. 2004;148 (suppl 5):S34-9.
VBWG
CRUSADE: Discharge care in men
and women
21,323 men and 14,552 woman with UA/NSTEMI
100
90.4
87.5
80
82.7 80.5
63.4
60
%
Patients
55.5 55.3
55.9
53.2
48.0
40
20
0
Aspirin
-Blocker
ACEI
Men
Statin
Clopidogrel
Women
Blomkalns AL et al. J Am Coll Cardiol. 2005;45:832-7.
VBWG
Evidence-based medications in ACS
patients: Effect on 6-month mortality
N = 1358
Appropriateness
level*
Lower mortality
Higher mortality
n
IV
630
0.10 (0.03–0.42)
III
314
0.17 (0.04–0.75)
II
302
0.18 (0.04–0.77)
I
91
0.36 (0.08–1.75)
0.0
0.5
1.0
1.5
2.0
3.0
Odds ratio (95% CI)
* Number of evidence-based medications used
(aspirin, ACE inhibitor, -blocker, statin) vs number indicated
Mukherjee D et al. Circulation.
2004;109:745-9.
VBWG
Guideline adherence reduces
in-hospital mortality
NRMI-4; quality of care defined by ACC/AHA class I indications
20
100
Lowest quartile (n = 271)
15
Highest quartile (n = 271)
% 10
5
0
80
In-hospital mortality
Lowest
quartile
Highest
quartile
60
Performance
quartiles*
40
(%)
20
0
Aspirin -Blocker Acute GP llb/IIIa ACE
Lipid Smoking
<24 h
<24 h inhibitor therapy advice
reper<24 h
fusion
*Proportion correct care out of
Peterson ED et al. Circulation. 2002;106(suppl):II-722.
total opportunities
Potential impact of CV-protective
medication class in post-MI patients
VBWG
Improving quality of care, quality of life
Medication class
None
Aspirin
-Blocker
ACE inhibitor
Lipid lowering
RRR (%)
0
25
25
25
30
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
Fonarow GC. Rev Cardiovasc Med. 2003;4(suppl 3):S37-46.