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VBWG
RAAS Modulation:RAAS Modulation:
Novel Strategies Novel Strategies for Reducing for Reducing
Cardiovascular RiskCardiovascular Risk
VBWG
• The diabetes crisis• CVD and the aging patient
Epidemiology/Guideline Update:
VBWG
CHD risk rises sharply in middle age
0.01.4
3.0
11.6 11.5
16.8
0.3 0.21.6
3.6
6.3
10.3
0
5
10
15
20
Men Women
AHA. Heart Disease and Stroke Statistics—2005 Update.
NHANES 1999–2002
% Population
20–34 35–44 45–54 55–64 65–74 ≥75
Age
VBWG
CV disease: Leading cause of death in Americans
0
100
200
300
400
500
A Total CVD*B Cancer D Chronic lower respiratory diseases
C Accidents
433,825
288,768
69,257 60,71334,301
493,623
268,503
64,10338,94841,877
Deaths(1000s)
*CHD, stroke, HF, hypertension, arterial diseasesData compiled for 2002
Men
Women
F Alzheimer’s Disease E Diabetes
CDC/NCHS and NHLBI.
A B C D E A B C F E
VBWG
Obesity (BMI ≥30 kg/m2)
Population(%)
30
25
2000 2001 2002 2003
*Jan–June
20
15
02004*
8
6
4
2
02000 2001 2002 2003 2004*
Diagnosed diabetes
CDC. 2004 NHIS; www.cdc.gov/nchs/nhis.htm.
21.823.0
23.9 23.724.3 5.9
6.4 6.5 6.6 6.6
Obesity and diabetes among US adults:Growing prevalence
+11.9%
+11.5%
VBWG
ACC/AHA 2002 Guideline Update for Management of Patients with Chronic Stable Angina: Asymptomatic patients
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)
Gibbons RJ et al. J Am Coll Cardiol. 2003;41:159-68.
Based on HOPE
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Based on HOPE and EUROPA
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)
Snow V et al. Ann Intern Med. 2004;141:562-7.
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RAAS: Central Role in the Pathogenesis of
Cardiovascular Disease
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RAAS: Sites of intervention with ACEIs, ARBs
Angiotensinogen
Angiotensin I
Renin
ACEinhibitors
Angiotensin-convertingenzyme (ACE)
Angiotensin II
AT1 receptor
Angiotensin receptorblockers
AT2 receptor
Atherosclerosis, hypertension Vascular protection?
Adapted from Nickenig G. Circulation. 2004;110:1013-20.
VBWG
RAAS: Other potential sites of intervention
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.
Effects
Aldosterone endothelial function, thrombosisvascular compliance,baroreceptor function,fibrosis
Cathepsin G Angiotensinogen Ang IIChymostatin-sensitive system
Chymase Ang I Ang II
ACE2 Ang I Ang (1–9), Ang (1–7)
VBWG
Impaired
NO synthase
Ang II and mechanisms of atherosclerosis
Jacoby DS, Rader DJ. Arch Intern Med. 2003;163:1155-64.
IL-6
MCP-1
PDGF LOX-1
PAI-1
TF
TGF-
VCAM
ICAM
Angiotensin II
Lipid oxidation
Thrombosis
Inflammation
Proliferation fibrosis
Adhesion
Endothelial
dysfunction
Endothelial
dysfunction
VBWG
PERTINENT: ACE inhibition NO via eNOS activity
Ferrari R et al. www.europa-trial.org
0
1
2
3
4
2.5
3.5
2.4
2.93.3
Controlsn = 45
Placebon = 44
Placebon = 44
Perindopriln = 43
Perindopriln = 43
P < 0.01*P < 0.05†
Baseline 1 Year
eNOSactivity in HUVECs
(pmol/min/mg protein)
Controls CAD patients
* vs baseline† perindopril vs placeboPERindopril – Thrombosis, InflammatioN, Endothelial dysfunction and Neurohormonal activation Trial (substudy of EUROPA)HUVEC = human umbilical vein endothelial cell
VBWG
AT1 receptor blockade improves flow-mediated vasodilation122 Hypertensive patients treated for 2 months
*P < 0.05 vs baseline and vs placebo Koh KK et al. Am J Cardiol. 2004;93:1432-5.
0.15
1.14
1.66
1.32
0.0
0.5
1.0
1.5
2.0
Placebo(n = 30)
Irbesartan300 mg(n = 30)
Losartan100 mg(n = 31)
Candesartan16 mg
(n = 31)
FMD
inbrachialartery(%)
2.5
*
*
*
VBWG
Inflammation
IL-6
MCP-1
PDGF
Inflammation
Ang II and mechanisms of atherosclerosis
Jacoby DS, Rader DJ. Arch Intern Med. 2003;163:1155-64.
Impaired
NO synthase
LOX-1
PAI-1
TF
TGF-
VCAM
ICAM
Lipid oxidation
Thrombosis
Proliferation fibrosis
Endothelial
dysfunction
Adhesion
Angiotensin II
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ACE inhibition reduces oxidative stress and inflammation20 Patients with type 2 diabetes
Marketou ME et al. J Am Coll Cardiol. 2005;45 (suppl A):396A.
Baseline Perindopril 4 mg x 6 mos
* P < 0.05 vs baseline
TNF- IL-6Lipid peroxides
3.3
2.0
0
1
2
3
4
2.9
1.8
370
264
0
100
200
300
400
mol/L pg/mL
** *
VBWG
LOX-1
VCAM
ICAM
Jacoby DS, Rader DJ. Arch Intern Med. 2003;163:1155-64.
Ang II and mechanisms of atherosclerosis
IL-6
MCP-1
PDGFImpaired
NO synthase
PAI-1
TF
TGF-
Thrombosis
Inflammation
Proliferation fibrosis
Endothelial
dysfunction
Angiotensin II
Lipid oxidationLipid oxidation
AdhesionAdhesion
VBWGAT1, LOX-1 receptor cross-talk promotes adhesion molecule expression: Interaction between RAAS and dyslipidemia
Mehta JL, Li D. J Am Coll Cardiol. 2002;39:1429-35.
OxLDL
Endothelial cell
LOX-1
Endothelin
Shearstress
TNF-
Ang IIAT1 Scavenger
receptors??
ROS
MCP-1
eNOSBadFas
Monocyteattachment andactivation
AtherosclerosisDysfunctionApoptosisInjury
PKs
MAPKsNF-B
Adhesion moleculeexpression
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Ang II upregulates LOX-1 expression via lipoxygenase pathway
* P < 0.0001 vs control† P < 0.0001 vs Ang II‡ P < 0.05 vs Ang IIBai = baicalein (12-lipoxygenase inhibitor)
Human vascular smooth muscle cells
Limor R et al. Am J Hypertens. 2005;18:299-307.
Ang II10-7 mol/L+
losartan 10-5 mol/L
0
100
200
300
Control Ang II10-7 mol/L
Ang II10-7 mol/L+
Bai 10-5 mol/L
LOX-1mRNA
*
†‡
400
VBWG
TGF-
Jacoby DS, Rader DJ. Arch Intern Med. 2003;163:1155-64.
Ang II and mechanisms of atherosclerosis
IL-6
MCP-1
PDGFImpaired
NO synthase
LOX-1
PAI-1
TF
VCAM
ICAM
Angiotensin II
Lipid oxidation
Thrombosis
Inflammation
Endothelial
dysfunction
Adhesion
ProliferationProliferation fibrosis
VBWG
HOPE: Dose-dependent effects of ramipril on LV mass and function
5.31
2.9
–1.9–3
0
2
4
68.21 7.86
–3.53–4
0
5
10
LV end-systolic volumeLV mass
Lonn E et al. J Am Coll Cardiol. 2004;43:2200-6.Mean baseline LVEF 58%, all groups
(mL)
(g)
PTrend = 0.001PTrend = 0.03
N = 446 follow-up, 4 years
Placebo Ramipril 2.5 mg
Ramipril 10 mg
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LIFE: Greater reduction in LV mass with angiotensin receptor blockade vs beta-blockade
Devereux RB et al. Circulation. 2004;110:1456-62.
Patients with hypertension and LVH
Change inLV mass
(g)
–50
–20
Year
–10
0
Losartan 50–100 mg (n = 457)
Atenolol 50–100 mg (n = 459)
–30
–40
1 2 3 4 5Lastvisit
P = 0.009 for all time points
VBWG
PAI-1
TF
Jacoby DS, Rader DJ. Arch Intern Med. 2003;163:1155-64.
Ang II and mechanisms of atherosclerosis
IL-6
MCP-1
PDGFImpaired
NO synthase
LOX-1
TGF-
VCAM
ICAM
Angiotensin II
Lipid oxidation
Inflammation
Proliferation fibrosis
Endothelial
dysfunction
AdhesionThrombosisThrombosis
VBWG
PAI-1 release: Differing effects of ACEinhibition vs AT1 receptor blockade
Ramipril 10 mg
Losartan 100 mg
–20
–15
–10
–5
0
5
10
15
1 3 4 6Weeks
in
PAI-1antigen(ng/mL)
Brown NJ et al. Hypertension 2002;40:859-65.P = 0.043, drug x time interaction
20 insulin-resistant, hypertensive patients treated for 6 weeks
VBWG
Change in PAI-1 antigen levels: Differing effects of ARBs
Koh KK et al. Atherosclerosis. 2004;177:155-60.
%Change
–40
20
40
60
Placebo
80
–20
0
Irbesartan 300 mg
Losartan 100 mg
Candesartan 16 mg
P < 0.01
P = 0.012P = 0.163
126 Patients with hypertension
VBWG
tPA release: Differing effects of ACEinhibition vs AT1 receptor blockade
Matsumoto T et al. J Am Coll Cardiol. 2003;41:1373-9.*P < 0.05 vs baseline
20
10
15
5
0.2
0
0 0.6 2.0
tPA antigenin coronary
sinus (ng/mL)
Bradykinin (g/min)
Perindopril 4 mg(n = 16)
Losartan 50 mg(n = 15)
Control(n = 14)
P < 0.05
*
**
**
* *
25
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.
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ARB blunts MMP expression in human carotid plaques: Potential role in plaque stabilization
25.828.2
25.1
22.4
5.8 6.2 7.25.6
0
10
20
30
MMP-2 MMP-9 COX-2 mPGES-1P < 0.0001 all comparisonsARB = AT1
receptor blockadeMMP = matrix metalloproteinase
% Positive staining
Chlorthalidone Irbesartan
Cipollone F et al. Circulation. 2004;109:1482-8.
Carotid endarterectomy specimens
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Role of RAAS Modulation in CAD Patients
VBWG
ACE inhibition in CAD: Short-term trials in acute MI
Odds ratio (95% CI)
220/3044 (7.23%)
570/9682 (5.89%)
2035/29,028 (7.01%)
676/7460 (9.06%)
CONSENSUS-II*
Test for Heterogeneity: 2 5.8 (2p = 0.1) df = 3
Deaths (n)/Randomized (n)
GISSI-3
ISIS-4
CCS-1
Total
Control O-E Variance
1.0 1.25 1.50.750.5
727/7489 (9.71%)
650/9712(6.69%)
192/3046(6.30%)
2171/29,022(7.48%)
3501/49,214(7.11%)
3740/49,269(7.59%)
14.07
–39.06
–68.22
–24.14
–117.35
96.05
285.83
975.33
317.85
1675.06
ACEI
ACEI better Control better
Odds reduction (± SD)7 ± 2
Treat Eff: 2 (2p = 0.004)
ACE Inhibitor MI Collaborative Group. Circulation. 1998;97:2202-12.*IV infusion followed by oral therapy
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ACE inhibition in CAD: Long-term trials in post-MI LV dysfunction and HF
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.
AIRE
TRACE
SOLVD
(Treatment)
SAVE
0.002
0.001
0.0036
0.019
0 5 10 15 20 25
Risk reduction in total mortality (%)
P
30
SOLVD
(Prevention)
0.30
27%
22%
8%
16%
19%
VBWGAldosterone blockade and AT1 receptor blockade: Trials in post-MI/LV dysfunction or HF
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.
VALIANT
Months
CaptoprilValsartan
0.4
0.1
0.2
6 12 24 30 36
0.3
0.0
Probability of event
0% RR V vs CHR 1.00 (0.90–1.11)
P = 0.98
RALES
0.75
0.60
1.00
0
Placebo
Spironolactone
Months
Probability of survival
24 366
30% Risk reductionRR 0.70 (0.60–0.82)
P < 0.001
300.00
12 18
0.90
0.45
180
Valsartan/captopril
22
10
2
6 24 300
Eplerenone
Months
18
14
6
3612
EPHESUS15% Risk reductionRR 0.85 (0.75–0.96)
P = 0.008
Cumulativeincidence
(%)
Placebo
018
2% RR V/C vs CHR 0.98 (0.89–1.09)
P = 0.73)
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HOPE, QUIET, EUROPA, PEACE: Primary outcomes
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.
PEACE
HOPE
15
5
10
0
20
0
Placebo
Ramipril 10 mg
Time (years)
%Patients
2 41
22% Risk reductionRR 0.78 (0.70–0.86)
P = 0.001
3
40
20
30
0
50
0
12
4
10
0
1 3 4
14
0
Placebo
Perindopril 8 mg
Time (years)
86
2
52
EUROPA20% Risk reductionRR 0.80 (0.71–0.91)
P = 0.0003
Placebo
Quinapril 20 mg
Time (years)1
4% Risk increaseRR 1.04 (0.89–1.22)
P = 0.6
10
2 3
QUIET
Time (years)
Trandolapril4 mgPlacebo
30
20
10
15
5
1 2 3 4 5
25
06
%Patients
4% Risk reductionHR 0.96 (0.88–1.06)
P = 0.43
VBWG
HOPE, EUROPA: Consistency of treatment benefit
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
FavorsACE inhibitor
FavorsPlacebo
HOPE(ramipril 10 mg)
EUROPA(perindopril 8 mg)
HOPE Study Investigators. N Engl J Med. 2000;342:145-53.EUROPA Investigators. Lancet. 2003;362:782-8.
Hazard ratio 0.5 1.0 1.5
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HOPE, EUROPA: Concomitant CV therapy
2.01.0
Added benefit No added benefit
0.6 0.8
Lipid-lowering drugNo lipid-lowering drug
-BlockersNo -blockers
HOPE
EUROPA
EUROPA Investigators. Lancet. 2003;362:782-8. Dagenais GR et al. Circulation. 2001;104:522-6.
EUROPA: perindopril 8 mg
HOPE: ramipril 10 mg
Lipid-lowering drugNo lipid-lowering drug
HOPE
EUROPA
-BlockersNo -blockers
Hazard ratio
VBWG
PEACE: Prevention of Events with Angiotensin Converting Enzyme inhibition
PEACE Trial Investigators. N Engl J Med. 2004;351:2058-68.
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
Primaryoutcome: CV death, nonfatal MI, CABG, PCI
VBWG
PEACE Trial Investigators. N Engl J Med. 2004;351:2058-68.
PEACE: Primary outcome
Trandolapril4 mg
Placebo30
20
10
15
5
1 2 3 4 5
25
0
6
%Patients
Time (years)
CV death, MI, CABG/PCI; N = 8290
4% Risk reductionHR 0.96 (0.88–1.06)
P = 0.43
VBWG
ACE inhibitor Key inclusion criteria Primary outcome
EUROPA
N = 12,218 (4.2 years)
Perindopril 8 mg CAD
No heart failure
Age ≥18 years
CV death, MI, cardiac arrest
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
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
VBWG
N 9,297 12,218 8,290 1,750
Follow-up (yrs) 4.5 4.2 4.8 2.3
ACEI/dose (mg) R-10 P-8 T-4 Q-20
Age (yrs) 66 60 64 58
Men (%) 73 85 82 82
CAD/Cor rev (%) 80/44 100/55 100/72 100/100
Diabetes (%) 39 12 17 16
HTN (%) 47 27 46 47
Prior MI (%) 53 65 55 49
EF NA NA 58 59
PVD (%) 43 7 NA NA
ACEI outcome trials in CAD patientswithout HF: Key baseline characteristics
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.
HOPE EUROPA PEACE QUIET
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HOPE EUROPA PEACE QUIET
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
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.
*at study end†at 3 yrs
ACEI outcome trials in CAD patients without HF: CV therapies 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.
ACEI outcome trials in CAD patients without HF: BP at entry/during study
VBWG
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.
ACEI outcome trials in CAD patients without HF: Differences in baseline CV risk
HOPE EUROPA PEACE
Annualizedevent rate in placebo group
(%/yr)
CV death Nonfatal MIQUIET
1.8
1.00.8 0.7
2.7
1.5
1.1
2.0
0.0
1.0
2.0
3.0
VBWG
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.
ACEI outcome trials in CAD patients without HF: Annualized all-cause mortality— placebo vs general population
*Mean age in years
HOPE(66*)
EUROPA(60*)
PEACE(64*)
All-causemortality
rate(%/yr)
QUIET(58*)
2.42.7
1.0
1.7 1.61.4
0.0
1.0
2.0
3.0
Age group
55–64 years65–74 years
Generalpopulation
Generalpopulation
VBWG
ACEI outcome trials in CAD patients without HF: Annualized CV mortality— placebo vs general population
*Mean age in years
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.
CV mortality
rate(%/yr)
0.0
0.5
1.0
1.5
2.0
HOPE(66*)
EUROPA(60*)
PEACE(64*)
QUIET(58*)
Age group55–64 years65–74 years
0.7
1.8
0.3
0.81.0
0.7
Generalpopulation
Generalpopulation
VBWG
ACEI outcome trials in CAD patients without HF: Cumulative evidence
Yusuf S, Pogue J. N Engl J Med. 2005;352:937-9.
Pooled all-cause mortality results
482/4645 (10.4)
375/6110 (6.1)
299/4158 (7.2)
1156/14,913 (7.8)
HOPE
EUROPA
PEACE
Total
Control P
1.0 3.0 5.00.80.6
1323/14,892 (8.9)
420/6108(6.9)
569/4652(12.2)
334/4132(8.1)
0.005
0.098
0.126
< 0.001
ACEI
ACEI Control
Odds ratio
No. of deaths/no. of patients (%)
VBWG
ACEI outcome trials in CAD patients without HF: Totality of trial evidence
MI
Stroke
All-cause death
Event rate (%)
Favors ACEIACEI
Revascularization
Favors placeboPlacebo
7.5
6.4
2.1
15.5
8.9
7.7
2.7
16.3
0.86
0.86
0.77
0.93
0.0004
0.0004
0.0004
0.025
0.5 0.75 1.251Odds ratio
P
Pepine CJ, Probstfield JL. Vasc Bio Clin Pract. CME Monograph; UF College of Medicine. 2004;6(3).
HOPE, EUROPA, PEACE, QUIET
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
Primaryoutcome: 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
No. at risk
Placebo 655 588 558 525 488
Enalapril 673 608 572 553 529
Amlodipine 663 623 599 574 535
Nissen et al. JAMA. 2004;292:2217-26.Primary outcome = incidence of CV events
Cumulative CV events(proportion)
0
0.25
0.20
0.10
0.05
6 12 18 24Months
0.15
0
Placebo
Amlodipine
Enalapril
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)
P = 0.16
P = 0.1P = 0.003
VBWG
CAMELOT: Clinical implications
• 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.
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• 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.
ACEI outcome trials in CAD patients without HF: Clinical implications
VBWG
Factors that may lead to divergent results in ACEI trials
• 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 treatmentPitt 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
P < 0.001 log-rank
100
90
80
70121086420
Months
Captopril
Ramipril
Quinapril
Fosinopril
Lisinopril
Enalapril
Perindopril
Unadjusted cumulative
survival(%)
N = 7512
Pilote L et al. Ann Intern Med. 2004;141:102-12.
n = 421
n = 905
n = 276
n = 889
n = 2201
n = 2577
n = 243
VBWG
Ongoing major outcomes trials of RAAS modulation
Patients Treatment
Follow-up (years)
Primary outcome
ONTARGET* 55 years with CAD, stroke, PAD, or diabetes + end-organ 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 + end-organ damage
(N = 5776)
Telmisartan 80 mg
Placebo
5.5 CV death, MI, stroke, hosp for heart failure
ONTARGET/TRANSCEND Investigators. Am Heart J. 2004;148:52-61.
*Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial†Telmisartan Randomized Assessment Study in ACE Intolerant Subjects with Cardiovascular Disease
VBWG
RAAS Modulation in Patients With Diabetes
VBWG
HOPE Study Investigators. Lancet. 2000;355:253-9.Daly CA et al. Eur Heart J. 2005. epub;April 28.
MICRO-HOPE PERSUADE
Patients: Diabetes + CVD Diabetes + CAD
or ≥1 CV risk factor No heart failure
Normal LV functionN = 3577 N = 1502
ACE inhibitor: Ramipril 10 mg Perindopril 8 mg
Follow-up (years): 4.5 4.2
Primary CV death/MI/ CV death/MI/outcome: stroke cardiac arrest
MICRO-HOPE, PERSUADE: ACEI in high-risk patients with diabetes
PERindopril SUbstudy in coronary Artery disease and DiabEtes (substudy of EUROPA)
VBWG
HOPE Study Investigators. Lancet. 2000;355:253-9.Daly CA et al. Eur Heart J. 2005. In press.
PERSUADE(N = 1502)
CV death/MI/cardiac arrest
MICRO-HOPE(N = 3577)
CV death/MI/stroke
MICRO-HOPE, PERSUADE: Primary outcome
Placebo
Ramipril10 mg
25
20
15
10
5
0
%
Follow-up (years)
0 1 2 3 4 5
25% Risk reductionRR 0.75 (0.64–0.88)
P = 0.000420
15
10
5
00 1 2 3 4 5
Follow-up (years)
Placebo
Perindopril8 mg
19% Risk reductionP = 0.131
25
VBWG
MICRO-HOPE, PERSUADE: Consistency of benefit
HOPE Study Investigators. Lancet. 2000;355:253-9.Daly CA et al. Eur Heart J. 2005. In press.
Primary outcome
Total mortality
CV mortality
All MI
Stroke
0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8
Favors ACEI Favors placebo
Relative risk (95% CI)
MICRO-HOPE(N = 3577)
PERSUADE(N = 1502)
VBWG
HOPE Study Investigators. Lancet. 2000;355:253-9.
3.0
2.5
2.0
1.5
1.0
0.5
0 1 2 3 4.5
Placebo
Ramipril 10 mg
Mean albumin-creatinine ratio
Years
P = 0.001
P = 0.02
0
10
20
30
40
Overtnephro-pathy
CV deathStrokeMI
Riskreduction
(%)P = 0.027
P = 0.0001
P = 0.007
P = 0.01
22
3337
24
N = 3577 (32% with microalbuminuria)
MICRO-HOPE: ACEI improves renal and CV outcomes in type 2 diabetes
VBWG
LIFE: Comparison of treatment effects in overall population vs with diabetesPatients with hypertension and LVH
Dahlöf B et al. Lancet. 2002;359:995-1003. Lindholm LH et al. Lancet. 2002;359:1004-10.
0.5 1.0 1.5
Overall (n = 9193)
Diabetes (n = 1195)0.206
0.028
0.001
0.204
0.491
0.373
Favors losartan50–100 mg
Favors atenolol50–100 mg
P
CV death
Stroke
MI
Hazard ratio
VBWG
Effects of ARBs in type 2 diabetes: Renal and CV outcomes
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.
*Doubling of baseline serum creatinine, end-stage renal disease (IDNT, RENAAL): progression todiabetic nephropathy (IRMA-2)
Study(N) ARB
Primary outcome: Renal disease progression*
Secondaryoutcomes
(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
2
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Impact of Lifestyle Changeand Pharmacologic Therapy
on Diabetes/CVPrevention Strategies
VBWG
INTERHEART: Positive impact of lifestyle factors on acute MI
Yusuf S et al. Lancet. 2004;364:937-52.
Risk factor
Current smoking
Diabetes
Hypertension
Abdominal obesity
Psychosocial factors
0.25 0.5 1.0 2 4 8 16
Odds ratio (99% CI)
Fruits/Vegetables
Exercise
Alcohol
ApoB/ApoA1 ratio
Women
Men
VBWG
Randomized controlled trials of Mediterranean-style diets in CAD patients: Fatal/nonfatal CV events
Parikh P et al. J Am Coll Cardiol. 2005;45:1379-87.
1989Diet and Reinfarction Trial(N = 2000) 29% all-cause mortality 27% MI
1999Lyon Diet Heart Study(N = 605) 68% cardiac death, MI
1999GISSI-Prevenzione(N = 11,324) 20% all-cause mortality 30% CV mortality
2002Indo-Mediterranean Diet Heart Study(N = 1000) 33% fatal MI
1997Indian Experiment of InfarctSurvival Trial(N = 360) 50% cardiac death 48% MI
VBWG
Prospective cohort studies of Mediterranean-style diets: 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.
2002Nurses’ Health Study(N = 84,688)45% fatal CHD
2004The Healthy Aging: A Longitudinal Study in Europe (N = 2339)23% all-cause mortality
2002Physician’s Health Study(N = 20,551)*
2005European Prospective Investigation into Cancer and Nutrition–elderly cohort (N = 74,607)†
2003Cardiovascular Health Study(N = 5,201)*
2003European Prospective Investigation into Cancer and Nutrition–Greek cohort (N = 22,043)†
*Blood levels of n-3 fatty acids inversely related to death†Greater adherence associated with lower mortality
VBWG
Decrease in mortality with Mediterranean diet: EPIC–elderly prospective cohort study
Trichopoulou A et al. BMJ. 2005;330:991-7.
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%)
VBWG
Mediterranean diet reduces the metabolic syndrome
Esposito K et al. JAMA. 2004;292:1440-6.
82
20
9
84
18
9
34
11
1
66
138
0
15
30
45
60
75
90
Mediterranean diet Control diet
Baseline 2 years
% Patients
Metabolic syndrome components (N)
53 4 53 4
P < 0.001 for effect of Mediterranean vs control diet
VBWG
Diabetes Prevention Program: Impact of lifestyle intervention or metformin
Diabetes Prevention Program Research Group. N Engl J Med. 2002;346:393-403.
0
0
10
20
30
40
0.5 1.0 1.5 2.0 2.5 3.2 3.5 4.0
Year
N = 3234, no diabetesAge 50 years207 lbsGlucose 107
• Lose 5–10 lbs
• Exercise 2.5 hrs/wk
Placebo
Metformin
LifestyleCumulativeincidence of
diabetes(%)
31%
58%
P
< 0.001
< 0.001
VBWG
Diabetes Prevention Program: Impact of PPAR agonist
Diabetes Prevention Program Research Group. Diabetes. 2005;54:1150-6.
10
15
5
0
1.5(237)
Cumulativeincidence
(%)
Years (n)
1.0(739)
0.5(1568)
0.0(2343)
75% vs placebo P <0.001
*Terminated early after 1.5 years
Placebo
Metformin
Lifestyle
Troglitazone*
VBWG
Diabetes Prevention Program: Impact of lifestyle intervention or metformin on development of metabolic syndrome
Orchard TJ et al. Ann Intern Med. 2005;142:611-9.
N = 3234 with impaired glucose tolerance (FG ≥95 mg/dL);47% without metabolic syndrome at baseline
0.75
0.45
0.15
0.30
0.00
1 2 3 4
0.60
Placebo group(n = 490)
Metformin group(n = 503)
Lifestyle group(n = 530)
Cumulativeincidence ofmetabolicsyndrome
0Time since randomization (year)
*vs placebo
17%
51%
P*
0.03
<0.001
VBWG
HOPE/HOPE-TOO: Prevention of diabetesNew diabetes, all patients
Bosch J. Circulation. 2005; in press.
0.12
0.06
0.02
0.04
0.00
1 2 3 4
0.08
0.10
Hazardratio
HOPE studytermination
RR 0.70 (CI, 0.57–0.86)
5 6 7
Placebo
Ramipril
Years
VBWG
100
30
20
10
0STOP-2
INSIG
HT
ALLHAT
% Reduction of new diabetes
INVEST
ALPINE
SCOPE
CHARM
ANBP2
LIFE
HOPE
ALLHAT
CAPPP
STOP-2
VALUE
PEACE
ASCOT
Pepine CJ, Cooper-Dehoff RM. J Am Coll Cardiol. 2004;44:509-12.
Sever PS et al. Lancet. 2003;361:1149-58.Randomized active treatment vs control (e.g. placebo, diuretic, or β-blocker diuretic)
CV pharmacotherapy: Impact on newly diagnosed diabetes
ACEI or ARBCA + ACEI or ARBCA
VBWG
Ongoing trials of diabetes prevention with RAAS modulation
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.
Patients Treatment Follow-up
DREAM* Impaired glucose tolerance or impaired fasting glucose
(N = 5269)
Ramipril 15 mg
Rosiglitazone 8 mg
Placebo
3 yrs 2006
NAVIGATOR† Impaired glucose tolerance
(N = 9518)
Valsartan 160 mg
Nateglinide 60 mg
Valsartan 160 mg +nateglinide 60 mg
Placebo
Until accrual of 1000 CV events
2007
* Diabetes Reduction Approaches with Ramipril and Rosiglitazone Medications†Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research
Anticipated completion
VBWG
Peri-Interventional Careof CAD Patients:
Optimal Discharge Strategies
VBWG
ACC/AHA recommendations: Discharge medical therapy after STEMI
Antman EM et al. J Am Coll Cardiol. 2004;44:671-719.
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)
Class 1
VBWG
ACC/AHA recommendations: Dischargetherapy after unstable angina/NSTEMI
Braunwald E et al. J Am Coll Cardiol. 2002;40:1366-74.Available at www.acc.org
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)
Class 1
VBWG
Opportunity for optimizing discharge care
AHA. Heart Disease and Stroke Statistics–2005 Update.
0
200
400
600
800
1600
79 80 85 90 00 01
Year
Proceduresin thousands
0295
1000
1200
1400
Catheterizations Open heart BypassPTCA Endarterectomy Pacemakers
VBWG
Cutlip DE et al. Circulation. 2004;110:1226-30.
46.3%
37.9%
20.3%
0
10
20
30
40
50
0 1 2 3 4 5
Composite
Nontarget lesionEvent rate
(%)
Years
Target lesion
Nontarget-lesion events drive adverse outcomes 5 years after PCI1228 patients in 2nd generation coronary stent trials*
*non-drug eluting stents
VBWG
Improving long-term outcomes in patients with coronary stents
• 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.
VBWG
0
20
40
60
80
100
ACEI ClopidogrelStatinAspirin -Blocker
Patientsreceiving
correcttreatment
(%)
82
94
72
89
50
68 65
81
42
59
Lagging centers(lowest quartile)
Leading centers(highest quartile)
Ohman EM et al. Am Heart J. 2004;148 (suppl 5):S34-9.
CRUSADE: Variations among hospitals in discharge care65,426 UA/NSTEMI patients from participating hospital registries
VBWG
CRUSADE: Discharge care in men and women21,323 men and 14,552 woman with UA/NSTEMI
90.482.7
55.563.4
53.2
87.580.5
55.3 55.948.0
0
20
40
60
80
100
Aspirin -Blocker ACEI Statin Clopidogrel
Men Women
Blomkalns AL et al. J Am Coll Cardiol. 2005;45:832-7.
%Patients
VBWG
Mukherjee D et al. Circulation. 2004;109:745-9.
N = 1358
* Number of evidence-based medications used (aspirin, ACE inhibitor, -blocker, statin) vs number indicated
0.5 1.0 1.5 3.0
Lower mortality Higher mortality
2.00.0
IV
III
II
I
0.10 (0.03–0.42)
0.17 (0.04–0.75)
0.18 (0.04–0.77)
0.36 (0.08–1.75)
Appropriateness level*
Odds ratio (95% CI)
630
314
302
91
Evidence-based medications in ACS patients: Effect on 6-month mortality
n
VBWG
Guideline adherence reduces in-hospital mortality
Peterson ED et al. Circulation. 2002;106(suppl):II-722.*Proportion correct care out oftotal opportunities
NRMI-4; quality of care defined by ACC/AHA class I indications
0
20
40
60
80
100
-Blocker<24 h
Aspirin<24 h
Acutereper-fusion
GP llb/IIIa<24 h
ACEinhibitor
Lipidtherapy
Smokingadvice
Performancequartiles*
(%)
Lowest quartile (n = 271)
Highest quartile (n = 271)
0
5
10
15
20
%
In-hospital mortality
Lowestquartile
Highestquartile
VBWG
Medication class RRR (%)5-Year
CV-event risk (%)
None 0 20.0
Aspirin 25 15.0
-Blocker 25 11.3
ACE inhibitor 25 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
Fonarow GC. Rev Cardiovasc Med. 2003;4(suppl 3):S37-46.
Potential impact of CV-protective medication class in post-MI patientsImproving quality of care, quality of life