Role of raas inhibition in management of hypertension

Role of RAAS inhibition Role of RAAS inhibition
in the Management of in the Management of
HypertensionHypertension
Dr KyawSoe Win
MBBS, M Med Sc (Int Med), MRCPUK, FRCPE, FAsCC, FAPSIC
Asso: Prof / Senoir Consultant Cardiologist
Department of Cardiovascular Medicine
Mandalay General Hospital
Hot Topic In Hypertension
2013
12th
January 2013

RAAS:
Central Role in the Pathogenesis
of Cardiovascular Disease

Ang II effect in target organ damage
McFarlane SI et al. Am J Cardiol. 2003;91(suppl):30H-7.
Angiotensinogen
Angiotensin I
Angiotensin II
Renin
ACE
Aldosterone
(Adrenal/CV tissues)
Stroke HF
Kidney
failure
↑BP
VSMC
Fat cells
Reduced
baroreceptor
sensitivity

RAAS: Sites of intervention with
RAAS modulators
Angiotensinogen
Angiotensin I
Renin
ACE
inhibitors
Angiotensin-converting
enzyme (ACE)
Angiotensin II
AT1 receptor
Angiotensin receptor
blockers
AT2 receptor
Atherosclerosis, hypertension Vascular
protection?
Adapted from Nickenig G. Circulation. 2004;110:1013-20.
Direct renin
inhibitor
Aldosterone
Aldo antagonist

Atherosclerosis-promoting actions of
Ang II and protective effects of bradykinin
↑↑ VasodilationVasodilation
↑↑ ProstacyclinProstacyclin
↑↑ Nitric oxideNitric oxide
↑↑ tPAtPA
↑↑ VasoconstrictionVasoconstriction
↑↑ ICAM-1, VCAM-1ICAM-1, VCAM-1
↑↑ Growth factorsGrowth factors
↑ Oxyradical formationOxyradical formation
↑ PAI-1PAI-1
↑ Smooth muscle cellSmooth muscle cell
proliferationproliferation
↑ Matrix degradationMatrix degradation
Protection againstProtection against
the effectsthe effects
of Ang IIof Ang II
↑ Endothelial dysfunctionEndothelial dysfunction
↑ InflammationInflammation
↑ CoagulationCoagulation
↑ AtherogenesisAtherogenesis
BradykininBradykinin
Ang IIAng II
Inactive peptidesInactive peptides
Ang IAng I
--
--
ACE
inhibitor
Ferrari R. Expert Rev Cardiovasc Ther. 2005;3:15-29.

AT1R blockade upregulates both
Ang II levels and AT2R expression
Ang I
Strauss MH, Hall AS. Circulation. 2006;114:838-54.
Ang II
AT2
ACE
ARB
AT1 AT4
Ang I
Ang II
AT2
ACE
ARB
AT1 AT4
+
Both physiologic and pathologic effects have been proposed
for AT2R stimulation
Vasodilation Hypertrophy
Inflammation

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-β
VCAM
ICAM
Angiotensin II
Lipid oxidation
Thrombosis
Inflammation
Proliferation fibrosis
Adhesion
Endothelial
dysfunction
Endothelial
dysfunction

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
2.9
3.3
Controls
n = 45
Placebo
n = 44
Placebo
n = 44
Perindopril
n = 43
Perindopril
n = 43
P < 0.01*
P < 0.05†
Baseline 1 Year
eNOS
activity in
HUVECs
(pmol/min/
mg protein)
Controls CAD patients
* vs baseline
†
∆ perindopril vs ∆ placebo
PERindopril – Thrombosis, InflammatioN, Endothelial dysfunction
and Neurohormonal activation Trial (substudy of EUROPA)
HUVEC = human umbilical vein endothelial cell

Schwartzkopff B et al. Hypertension. 2000;36:220-5.
0
200
400
600
800
Periarteriolar collagen
P = 0.04
53%
558 ± 270
260 ± 173
µm2
0
2
4
6
8
Total
interstitial collagen
P = 0.04
22%
5.5 ± 3.8
4.3 ± 3.2Vv%
Pretreatment
(n = 14)
Post-treatment*
(n = 14)
Coronary reserve
+67%
P = 0.001
Baseline 2.1
3.5Perindopril
*Perindopril 4–8 mg for 12 months
ACEI normalizes structure of resistance
arteries in CAD patients
At treatment end (12 mo)

AT1 receptor blockade improves
flow-mediated vasodilation
122 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)
Irbesartan
300 mg
(n = 30)
Losartan
100 mg
(n = 31)
Candesartan
16 mg
(n = 31)
∆
FMD
in
brachial
artery
(%)
2.5
*
*
*

Inflammation
IL-6
MCP-1
PDGF
Inflammation
Impaired
NO synthase
LOX-1
PAI-1
TF
TGF-β
VCAM
ICAM
Lipid oxidation
Thrombosis
Endothelial
dysfunction
Adhesion
Angiotensin II

ACE inhibition reduces oxidative
stress and inflammation
20 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-α IL-6Lipid peroxides
3.3
2.0
0
1
2
3
4
2.9
1.8
370
264
0
100
200
300
400
µmol/L pg/mL
*
* *

LOX-1
VCAM
ICAM
IL-6
MCP-1
PDGF
Impaired
NO synthase
PAI-1
TF
TGF-β
Thrombosis
Inflammation
Endothelial
dysfunction
Angiotensin II
Lipid oxidationLipid oxidation
AdhesionAdhesion

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 II
Bai = baicalein (12-lipoxygenase inhibitor)
Human vascular smooth muscle cells
Limor R et al. Am J Hypertens. 2005;18:299-307.
Ang II
10-7
mol/L+
losartan 10-5
mol/L
0
100
200
300
Control Ang II
10-7
mol/L
Ang II
10-7
mol/L+
Bai 10-5
mol/L
LOX-1
mRNA
*
†
‡
400

TGF-β
IL-6
MCP-1
PDGF
Impaired
NO synthase
LOX-1
PAI-1
TF
VCAM
ICAM
Angiotensin II
Lipid oxidation
Thrombosis
Inflammation
Endothelial
dysfunction
Adhesion
ProliferationProliferation fibrosis

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 = 0.001
PTrend = 0.03
N = 446 follow-up, 4 years
Placebo Ramipril
2.5 mg
Ramipril
10 mg

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 in
LV 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 5
Last
visit
P = 0.009 for all time points

PAI-1
TF
IL-6
MCP-1
PDGF
Impaired
NO synthase
LOX-1
TGF-β
VCAM
ICAM
Angiotensin II
Lipid oxidation
Inflammation
Endothelial
dysfunction
AdhesionThrombosisThrombosis

Brown NJ et al. Hypertension. 2002;40:859-65.P = 0.043, drug × time interaction
ACE inhibition (ramipril) AT1 receptor blockade (losartan)
10
0
–10
20
Week 1
–20
∆
PAI-1
antigen
(ng/mL)
30
Week 3 Week 4
Sustained decrease in PAI-1
antigen over time with ACEI vs ARB
Week 6

Greater decrease in PAI-1
over time with ACEI vs ARB
85 Hypertensive diabetic patients treated for 12 weeks
Fogari R et al. Am J Hypertens. 2002;15:316-20.
10
–10
5
0
–5
Losartan 50 mg
4
Perindopril 4 mg
–10
P < 0.01
*P = 0.028 perindopril vs placebo
∆
PAI-1
ng/dL
*

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 = 0.012
P = 0.163
126 Patients with hypertension

Pretorius M et al. Circulation. 2003;107:579-85.
*P < 0.05 vs baseline
†P < 0.05 vs vehicle or baseline
‡P < 0.05 vs enalaprilat + vehicle
HOE 140 = bradykinin B2 receptor antagonist
Greater effect in women vs men
Women (n = 7) Men (n = 5)
Baseline
‡
HOE 140 +
Enalaprilat
HOE
140
2
1
0
3
Net tPA
release
(ng/min/
100 mL)
2
1
0
Baseline
*†
Vehicle +
Enalaprilat
Vehicle
3
ACEI increases tPA release
through endogenous bradykinin

tPA release: Differing effects of ACE
inhibition 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 antigen
in coronary
sinus (ng/mL)
Bradykinin (µg/min)
Perindopril 4 mg
(n = 16)
Losartan 50 mg
(n = 15)
Control
(n = 14)
P < 0.05
*
*
*
*
*
* *
25

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
)
1
2
Lonn E et al. Circulation. 2001:103;919-25.
3
Ludwig M et al. Clin Ther. 2002;24:1175-93.
4
Zanchetti A et al. Stroke. 2004;35:2807-12.

Lonn EM et al. Circulation. 2001;103:919-25.
0
0.005
0.010
0.015
0.020
0.025
Ramipril
10 mg
Ramipril
2.5 mg
Placebo
0.022
0.018
0.014
NS
37% Reduction
P = 0.028
Mean
maximum
IMT slope
(mm/y)
SECURE
ACEI reduces atherosclerosis
progression

ARB blunts MMP expression in human
carotid plaques: Potential role in
plaque stabilization
25.8
28.2
25.1
22.4
5.8 6.2
7.2
5.6
0
10
20
30
MMP-2 MMP-9 COX-2 mPGES-1
P < 0.0001 all comparisons
ARB = AT1 receptor blockade
MMP = matrix metalloproteinase
%
Positive
staining
Chlorthalidone Irbesartan
Cipollone F et al. Circulation. 2004;109:1482-8.
Carotid endarterectomy specimens

Role of RAAS Modulation:
Evidence from Clinical Trials
• CAD
• Heart Failure

ACEIs: Evolution of benefits
BP reduction
Cardioprotection
Improved glycemic control (?)
Vascular protection
Lonn E et al. Eur Heart J Suppl. 2003;5(suppl A):A43-8.
DREAM Trial Investigators. N Engl J Med. 2006;355:1551-62.
Renal protection

Benefit of ACE inhibition in CADBenefit of ACE inhibition in CAD
EUROPA
HOPE
All CAD patientsAll CAD patients
Post-MI, HF, LVEF <40%
SOLVD
SAVE
AIRE
TRACE
SOLVD
(prev)
High risk
Bertrand ME. Curr Med Res Opin. 2004;20:1559-69.

ACEI trials in CAD without HF: Primary outcomes
HOPE Study Investigators. N Engl J Med. 2000;342:145-53.
Pitt B et al. Am J Cardiol. 2001;87:1058-63.
PEACE
CV death/MI/CABG/PCI
HOPE
CV death/MI/stroke
15
5
10
0
20
0
Placebo
Ramipril
10 mg
Time (years)
%
2 41
22% Risk reduction
HR 0.78 (0.70–0.86)
P < 0.001
3
Time (years)
12
4
10
0
1 3 4
14
0
Placebo
Perindopril
8 mg
8
6
2
52
EUROPA
CV death/MI/cardiac arrest
20% Risk reduction
HR 0.80 (0.71–0.91)
P = 0.0003
40
20
30
0
50
0
Placebo
Quinapril
20 mg
Time (years)
1
4% Risk increase
HR 1.04 (0.89–1.22)
P = 0.6
10
2 3
QUIET
All CV events
Time (years)
Trandolapril
4 mg
Placebo
30
20
10
15
5
1 2 3 4 5
25
0
6
4% Risk reduction
HR 0.96 (0.88–1.06)
P = 0.43
EUROPA Investigators. Lancet. 2003;362:782-8.
PEACE Trial Investigators. N Engl J Med. 2004;351:2058-68.
%
%
%

HOPE EUROPA PEACE QUIET
Antiplatelet agents (%) 76 92 91 73
β-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 study end
†
at 3 yrs
ACEI outcome trials in CAD patients
without HF: CV therapies at entry/during study

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
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

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 1.251
Odds ratio
P
Pepine CJ, Probstfield JL. Vasc Bio Clin Pract.
CME Monograph; UF College of Medicine. 2004;6(3).
HOPE, EUROPA, PEACE, QUIET

HOPE, EUROPA, PEACE: Benefit of
ACEIs across broad spectrum of risk
Dagenais GR et al. Lancet. 2006;368:581-8.
Trial
Patients
(n)
Annual rates in
placebo groups
OR
(95% CI) P
-5 20 405 3015 35
Odds reduction (%)
25100
PEACE 8290 2.13 7 (-8 to 19) 0.328
HOPE total 9297 3.95 25 (16 to 32) 0.0001
HOPE lower risk 3083 2.17 18 (-4 to 35)
HOPE med risk 3100 3.58 20 (3 to 33)
HOPE high risk 3114 5.98 24 (12 to 34)
EUROPA total 12,218 2.60 19 (8 to 28) 0.0007
EUROPA lower risk 3976 1.40 19 (-5 to 38)
EUROPA med risk 3975 2.41 28 (11 to 41)
EUROPA high risk 3975 4.00 10 (-4 to 22)
AIRE 1986 22.6 24 (7 to 38) 0.0068
TRACE 1749 17.0 25 (9 to 33) 0.0028
SOLVD-P 4228 7.4 15 (2 to 27) 0.0252
SOLVD-T 2569 13.1 23 (10 to 33) 0.0009
SAVE 2231 9.8 20 (4 to 33) 0.0168
CV death,* nonfatal MI or stroke
ACEI
worse
ACEI
better
*Or total mortality in AIRE,
TRACE, SOLVD, SAVE trials

without HF: Differences in baseline CV risk
HOPE EUROPA PEACE
Annualized
event rate in
placebo group
(%/yr)
CV death Nonfatal MI
QUIET
1.8
1.0
0.8
0.7
2.7
1.5
1.1
2.0
0.0
1.0
2.0
3.0

EUROPA: EUropean trial on Reduction
Of cardiac events with Perindopril in
stable coronary Artery disease
Objective: Assess effects of the ACEI perindopril on CV risk
in a broad-spectrum population with stable CAD
and without HF
Design: N = 12,218, age ≥18 years, with
CAD/without HF at randomization
Treatment: Perindopril 8 mg or placebo
Follow-up: 4.2 years
Primary
outcome: CV death, nonfatal MI, cardiac arrest

EUROPA: Baseline characteristics
Female
History of CAD
– MI
– PCI
– CABG
Documented CAD
– Angiographic evidence
(stenosis >70% )
14.5
100
64.9
29.0
29.3
60.4
14.7
100
64.7
29.5
29.4
60.5
– Positive stress test
(in men w/chest pain)
History of stroke/TIA
PVD
Hypertension
Diabetes
Hypercholesterolemia
22.6
3.4
7.1
27.0
11.8
63.3
23.3
3.3
7.4
27.2
12.8
63.3
Placebo (%)
(n = 6108)
Perindopril (%)
(n = 6110)

EUROPA: Concomitant medications
Platelet inhibitors
Beta-blockers
Lipid-lowering agents
Nitrates
Calcium channel blockers
Diuretics
92
62
58
43
32
9
91
63
69
NA
NA
NA
Baseline (%) 3 Years (%)*
*Concomitant medications
recorded in 11,547 patients

Fox KM. Br J Cardiol. 2004;11:195-204.
EUROPA: Primary outcome
12
4
10
0
1 3 4
14
0
Placebo
Perindopril
8 mg8
6
2
52
Primary
outcome
(%)
Time (years)
10%
11%
14%
20%
CV death, MI, cardiac arrest
RRR 20% (95% CI: 9%–29%)
AR 8.0% vs 9.9%
P = 0.0003
P < 0.05
P = 0.35
AR = absolute risk (perindopril vs placebo)

RRR 24%
AR 5.2% vs 6.8%
P < 0.001
EUROPA Investigators. Lancet. 2003;362:782–8.
Fatal and nonfatal MI
RRR 39%
AR 1.0% vs 1.7%
P = 0.002
2
4
Events
(%)
0
10
6
8
0 1 2 3 4 5
Years
Placebo
Perindopril
8 mg
0.5
1.0
0.0
2.0
1.5
0 1 2 3 4 5
Years
Placebo
Perindopril
8 mg
HF hospitalization
EUROPA: Effect of ACEI on
fatal/nonfatal MI and HF hospitalizations
AR = absolute risk (perindopril vs placebo)

8.0
14.8
7.9
6.1
3.5
5.2
CV mortality, MI, cardiac arrest
Total mortality, MI, UA, cardiac arrest
CV mortality, MI
Total mortality
CV mortality
Fatal/nonfatal MI
Favors
perindopril
Favors
placebo
Perindopril (%)
(n = 6110)
Placebo (%)
(n = 6108)
9.9
17.1
9.8
6.9
4.1
6.8
0.5 1.0 2.0
EUROPA: Benefit of ACEI on primary
and secondary outcomes
N = 12,218

5.6
0.1
1.6
9.4
1.0
Unstable angina
Cardiac arrest
Stroke
Revascularization
HF w/hospital admission
Favors
perindopril
Favors
placebo
Perindopril (%)
(n = 6110)
Placebo (%)
(n = 6108)
6.0
0.2
1.7
9.8
1.7
0.5 1.0 2.0
EUROPA: Benefit of ACEI on
selected secondary outcomes
N = 12,218

EUROPA: Benefit of perindopril was
on top of recommended medications
7.0
9.3
7.6
8.7
9.9
7.1
0.5 1.0 2.0
8.3
11.9
10.2
9.4
11.7
9.0
Lipid-lowering drug
No lipid-lowering drug
β-blockers
No β-blockers
Calcium channel blockers
No calcium channel blockers
Favors
perindopril
Favors
placeboPerindopril
(n = 6110)
Placebo
(n = 6108)
Primary events (%)

EUROPA HOPE
Age, mean (yrs) 60 66
BP (mm Hg) 137/82 139/79
Known CAD (%)
MI (%)
PVD (%)
Stroke/TIA (%)
Revascularization (%)
Diabetes (%)
Hypertension (%)
Hypercholesterolemia (%)
100
65
7
3
58
12
27
63
80
53
43
11
44
39
47
66
EUROPA vs HOPE:
Study populations

EUROPA vs HOPE: Inclusion criteria
HOPE
• Age ≥55 years
• Females: 27%
• No HF or LV dysfunction
• High-risk of CV events
with history of
– CAD, stroke, or peripheral
vascular disease
– Diabetes + ≥1 CV risk factor
(hypertension, dyslipidemia,
smoking, microalbuminuria)
EUROPA
• Age ≥18 years
• Females: 15%
• No clinical HF
• Documented CAD including
– Previous MI, PCI/CABG
– Angiographic evidence of
CAD with/without previous
coronary event
– Positive stress test (men)
HOPE patients were at higher risk than EUROPAHOPE patients were at higher risk than EUROPA

EUROPA vs HOPE: Event rates in
placebo groups reflect differences
in baseline risk
80% higher annual rate of CV and total mortality in HOPE80% higher annual rate of CV and total mortality in HOPE
CV mortality Total mortality
Annualized
event rate
in placebo
groups
(%)
HOPEEUROPA
1.8
2.7
1.0
1.5
0.0
0.5
1.0
1.5
2.0
2.5
3.0

Are all ACEIs the same:
Survival post-MI by ACEI
at discharge
P < 0.001 log-rank
100
90
80
70
121086420
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

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 treatment
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).

• 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.
without HF: Clinical implications

• Totality of clinical trial evidence supports ACEI for treatment of
stable CAD patients with/without HF
• Benefits have been shown in patients at all levels of risk
• All ACEIs may not have comparable effects for all indications
• Consider evidence and guidelines in selection of an ACEI
and dose.
• Both ramipril and perindopril reduce risk of CV events in
stable CAD patients without HF
– Ramipril 10 mg has proven efficacy in CAD patients ≥55 yrs
– Perindopril 8 mg has proven efficacy in CAD patients ≥18 yrs
Pitt B. N Engl J Med. 2004;351:2115-7.
Should all patients with stable CAD
without HF receive an ACEI?
Interpreting evidence

Evidence-based medicine:
Updated guide-lines for ACEI
in CAD patients without HF
“ACE inhibitors should be used as routine secondary
prevention for patients with known CAD, particularly in
diabetics without severe renal disease.” . . . R.J. Gibbons et
al.
“The HOPE trial…confirms that the ACE inhibitor ramipril
reduced CV death, MI, and stroke in patients who were at
high risk for, or had, vascular disease in the absence of
heart failure.” . . . R.J. Gibbons et al.
EUROPA “showed that an ACE inhibitor can have a
vasculoprotective effect in patients at lower risk than those
enrolled in the HOPE study.” . . . V. Snow et al.
Gibbons RJ et al. 2002 ACC/AHA Practice Guidelines. www.acc.org; July 2005.
Snow V et al. Ann Intern Med. 2004;141:562-7.

Role of RAAS Modulation
in
CAD Patients with heart failure

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: χ2
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: χ2
(2p = 0.004)
ACE Inhibitor MI Collaborative Group. Circulation. 1998;97:2202-12.*IV infusion followed by oral therapy

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%

Aldosterone 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.
VALIANT
Months
Captopril
Valsartan
0.4
0.1
0.2
6 12 24 30 36
0.3
0.0
Probability
of event
0% RR V vs C
HR 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 reduction
RR 0.70 (0.60–0.82)
P < 0.001
30
0.00
12 18
0.90
0.45
180
Valsartan/captopril
22
10
2
6 24 300
Eplerenone
Months
18
14
6
3612
EPHESUS
15% Risk reduction
RR 0.85 (0.75–0.96)
P = 0.008
Cumulative
incidence
(%)
Placebo
0
18
2% RR V/C vs C
HR 0.98 (0.89–1.09)
P = 0.73)

EPHESUS: New subgroup analysis
Pitt B et al. Am J Cardiol. 2006;97(suppl):26F-33F.
N = 6632 with post-MI LVSD, mean follow-up 16 months
Eplerenone Post-Acute Myocardial Infarction
Heart Failure Efficacy and Survival Study
History of hypertension
All-cause mortality
CV mortality/hospitalization
Sudden cardiac death
History of diabetes
All-cause mortality
LVEF ≤30%
All-cause mortality
P
0.001
0.002
0.022
0.127
0.03
0.641
0.012
0.001
0.01
0.2 1.0 1.2 1.8
Eplerenone better Placebo better
1.4 1.60.4 0.6 0.8
Odds ratio (95% Cl)

Greenberg B et al. Am J Cardiol. 2006;97(suppl):34F-40F.
EMPHASIS-HF: Study design
Eplerenone
+ standard therapy
N = 2584 with NYHA class II chronic systolic HF
Results in 2010
Placebo
+ standard therapy
Primary end point:
CV death, hosp for HF
Follow-up: 4 years
Effect of Eplerenone in Chronic Systolic Heart Failure

EMPHASIS-HF: Major results
EMPHASIS-HF
Outcome Eplerenone (%) Placebo (%) Adjusted hazard ratio (95%
CI)
p
Cardiovascular death/heart-failure
hospitalization
18.3 25.9 0.63 (0.54–0.74) <0.001
Cardiovascular death 10.8 13.5 0.76 (0.61–0.94) 0.01
Heart-failure hospitalization 12.0 18.4 0.58 (0.47–0.70) <0.001
Hospitalization for hyperkalemia 0.3 0.2 1.15 (0.25–5.31) 0.85
NYHA Class II HF (N=2737)
LV EF < 30%
Eplerenone 25-50mg QD vs. Placebo

Greenberg B et al. Am J Cardiol. 2006;97(suppl):34F-40F.
TOPCAT: Study design
Spironolactone
N ≅ 4500 with HF and LVEF >45%
Results anticipated 2011
Placebo
Primary end point:
CV death, hosp for HF
Follow-up: ≥2 years
Treatment of Preserved Cardiac Function Heart Failure with an
Aldosterone Antagonist
Enrollment: 3445
Study Start Date: August 2006
Estimated Study Completion Date: June 2013
Estimated Primary Completion Date: June 2013

RAAS Modulation in
Patients With Diabetes

Potential role of RAAS activation in
metabolic syndrome and diabetes
Adapted from Henriksen EJ, Jacob S. J Cell Physiol. 2003;196:171-9.
Paul M et al. Physiol Rev. 2006;86:747-803.
RAAS activation
Skeletal muscle Pancreatic β cells
↑MetS ↑T2DM
MetS = metabolic syndrome
T2DM = type 2 diabetes
Obesity

RAAS activation in obesity
Engeli S et al. Hypertension. 2005;45:356-62.
Circulating RAAS, N = 38 menopausal women
*P < 0.05
Renin
(ng/l)
ACE
(U/l)
Aldosterone
(ng/l)
Ang II
(nmol/l)
Lean Obese
0
3
6
12
9
0
15
30
60
45
0
90
0.00
0.05
0.10
30
60
Lean Obese
Lean Obese Lean Obese
* *
*

Obesity
Volume expansion
Arterial hypertension
Sharma AM. Hypertension. 2004;44:12-19.
↑LeptinRenal medullary
compression
↑RAAS activation
Sodium
reabsorption
Renal vasodilation ↑SNS activation
SNS = sympathetic nervous system
RAAS activation contributes to
obesity-related hypertension

Adipocyte and vasculature interactionsAdipocyte and vasculature interactions
Courtesy of W. Hseuh; 2005.
IL-6
PAI-1
TNF-α
Adiponectin
Leptin
Insulin sensitivity Insulin resistance
Vascular inflammation Endothelial dysfunction
Angiotensinogen
FFA
Visfatin

Furuhashi M et al. Hypertension. 2003;42:76-81.
• Insulin sensitivity, BMI, and
HDL-C independent
determinants of
adiponectin concentrations
• ACEI and ARB increased
insulin sensitivity and
adiponectin (P < 0.05)
• Changes in insulin sensitivity
correlated with changes in
adiponectin
(r = 0.59, P < 0.05)
*P < 0.05
N = 16 with essential hypertension and insulin resistance
RAAS blockade increases adiponectin
6
4
10
Adiponectin
(µg/mL)
0
8
2
Before After Before After
6
4
10
0
8
2
Temocapril 4 mg
(n = 9)
Candesartan 8 mg
(n = 7)
*
*

ACEIs: Potential mechanisms
of improved glucose metabolism
Henriksen EJ, Jacob S. J Cell Physiol. 2003;196:171-9.
Angiotensin I
ACE/Kininase II
Degradation
products
↑Nitric oxide
Angiotensin II
↓Angiotensin II
ACE inhibitors
Bradykinin
↑Bradykinin
↑Skeletal muscle
blood flow
↑Glucose metabolism

Effect of ACEIs and ARBs on
new-onset diabetes
Abuissa H et al. J Am Coll Cardiol. 2005;46:821-6.
Meta-analysis of 12 randomized controlled trials
CAPPP
STOP-2
HOPE
LIFE
ALLHAT
ANBP2
SCOPE
ALPINE
CHARM
SOLVD
VALUE
PEACE
All pooled
ACEI pooled
ARB pooled
0.79 (0.67–0.94)
0.96 (0.72–1.27)
0.66 (0.51–0.85)
0.75 (0.63–0.88)
0.70 (0.56–0.86)
0.66 (0.54–0.85)
0.81 (0.61–1.02)
0.13 (0.03–0.99)
0.78 (0.64–0.96)
0.26 (0.13–0.53)
0.77 (0.69–0.86)
0.83 (0.72–0.96)
0.75 (0.69–0.82)
0.73 (0.63–0.84)
0.77 (0.71–0.83)
0.125 0.25 0.5 1 2 4 8
Less likely to develop T2DM
Relative risk (95% CI)
More likely to develop T2DM

HOPE, EUROPA, PEACE: Reduction in new-
onset diabetes (placebo-controlled trials)
0
2
4
6
8
10
12
14
HOPE EUROPA PEACE Pooled data
New-onset
diabetes
(%)
Placebo ACEI
Dagenais GR et al. Lancet. 2006;368:581-8.
n = 23,340 free from diabetes* at baseline
Ramipril
10 mg
Perindopril
8 mg
Trandolapril
4 mg
Overall
14% RRR
RR 0.86 (0.78–0.95)
P = 0.0023
(all trials)
*Not a prespecified end point

PERSUADE: PERindorpil SUbstudy
of coronary Artery disease and DiabEtes:
The diabetic substudy of EUROPA
Objective: Investigate the effect of long-term treatment with
perindopril added to standard therapy on CV
events in diabetic patients with CAD and without heart
failure
Population: N = 1502 with known diabetes
at randomization
Treatment: Perindopril 8 mg (n = 721) or placebo (n = 781)
Follow-up: 4.2 years
Daly CA et al. Eur Heart J. 2005;26:1369-78.

PERSUADE: Primary outcome
Cumulative
frequency
(%)
Perindopril
8 mg
Placebo
2 3 4 510
Years from randomization
0
4
8
12
16
20
RRR: 19%
95% CI: –7% to 38%
P = 0.13
CV death, MI, cardiac arrest

PERSUADE: Clinical implications
• Perindopril 8 mg once daily reduced CV events in
patients with CAD and diabetes
• Relative risk reduction in primary and secondary
outcomes with perindopril was similar to EUROPA
• Results extend the benefit of ACEI shown in MICRO-
HOPE to a lower-risk population with diabetes and
CAD

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
Overt
nephro-
pathy
CV
deathStrokeMI
Risk
reduction
(%)
P = 0.027
P = 0.0001
P = 0.007
P = 0.01
22
33
37
24
N = 3577 (32% with microalbuminuria)
MICRO-HOPE: ACEI improves renal
and CV outcomes in type 2 diabetes

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
Ramipril
10 mg
25
20
15
10
5
0
%
Follow-up (years)
0 1 2 3 4 5
25% Risk reduction
RR 0.75 (0.64–0.88)
P = 0.0004
20
15
10
5
0
0 1 2 3 4 5
Follow-up (years)
Placebo
Perindopril
8 mg
19% Risk reduction
P = 0.131
25

MICRO-HOPE, PERSUADE:
Consistency of benefit
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)

Effects of ACEI on endothelial function:
EUROPA substudies
• PERTINENT: PERindopril Thrombosis, InflammatioN,
Endothelial dysfunction and Neurohormonal
activation Trial
– Determined the mechanisms by which the ACEI
perindopril improved outcomes in patients with
stable coronary
artery disease
• PERFECT: PERindopril-Function of the Endothelium
in Coronary artery disease Trial
– Evaluated whether long-term administration of
perindopril improves endothelial dysfunction
Ferrari R. ESC 2004; Munich.
Bots ML et al. Cardiovasc Drugs Ther. 2002;16:227-36.

PERTINENT: Study design
Endothelial cell (EC) studiesEndothelial cell (EC) studies
ECs incubated with serum from CADECs incubated with serum from CAD
patients at baseline and at 1 year*patients at baseline and at 1 year*
Plasma studiesPlasma studies
Measure substances in plasma thatMeasure substances in plasma that
modulate ecNOS and apoptosismodulate ecNOS and apoptosis
Ang IIAng II
BradykininBradykinin
TNF-TNF-αα
von Willebrand factorvon Willebrand factor
ecNOSecNOS
EC apoptosis rateEC apoptosis rate
*Human umbilical vein ECs
ecNOS = EC nitric oxide synthase Ferrari R. ESC 2004; Munich.
Levels measured at baseline vs 1 year
Objective:Objective:
Evaluate effects of perindopril on endothelial function and markers ofEvaluate effects of perindopril on endothelial function and markers of
inflammation and thrombosis in EUROPA subgroup of CAD patientsinflammation and thrombosis in EUROPA subgroup of CAD patients
EUROPA substudy

↑ ecNOS activity
↓ Endothelial cell apoptosis
↓ Ang II
↑ Bradykinin
↓ TNF-α
↓ von Willebrand factor
Ferrari R. ESC 2004; Munich.*Incubated with patients’ serum
Endothelial cells* Patients’ plasma
EUROPA substudy
• The only significant correlation was between bradykinin and ecNOS
• Results suggest perindopril modifies inflammation and
thrombosis and endothelial function through bradykinin-
dependent mechanisms
PERTINENT: Effects of treatment
with perindopril for 1 year

PERFECT: Study design
Objective: Determine effect of perindopril on brachial
artery endothelial function in patients with
stable CAD and without clinical HF
Design: Double-blind randomized controlled trial
Population: N = 333 at 20 centers
Treatment: Perindopril 8 mg or placebo
Follow-up: 3 years
Primary
outcome: Change in flow-mediated vasodilation of
brachial artery assessed over 36 months
EUROPA substudy
Bots ML et al. J Am Coll Cardiol. 2005;45A(suppl):409A.
Bots ML et al. Cardiovasc Drugs Ther. 2002;16:227-36.

• Mean FMD* increased (baseline vs 36 months)
Perindopril 2.7% to 3.3% (+37%)
Placebo 2.8% to 3.0% (+7%)
• Endothelial function (rate of change per 6 months)
Perindopril 0.14% (P < 0.05 vs baseline)
Placebo 0.02% (P = 0.74 vs baseline)
(P = 0.07 for perindopril vs placebo)
• Conclusion: Part of the beneficial effect of perindopril on CV
morbidity and mortality in the EUROPA study may be explained by
improvement in endothelial function
*Brachial artery vasodilation in response
to reactive hyperemia Bots ML et al. J Am Coll Cardiol. 2005;45A(suppl A):409A.
PERFECT: ACEI and endothelial
function
EUROPA substudy

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 to
diabetic nephropathy (IRMA-2)
Study
(N) ARB
Primary outcome:
Renal disease
progression*
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
2

Clinical trials of ARBs: CV outcomes
Similar ↓
Greater ↓ with
amlodipine
(2.0/1.6 mm Hg)
Losartan vs
atenolol
Valsartan vs
amlodipine
Essential HTN
N = 9193
(4.8 years)
Essential HTN,
high CV risk
N = 15,245
(4.3 years)
LIFE (2002)
VALUE (2004)
BPTreatment
Patients
(Follow-up)Trial (year)
HTN = hypertension
13% ↓ in primary outcome
(CV death, MI, stroke) with
ARB (P = 0.021) driven by
25% ↓ in stroke (P = 0.001)
No difference in CV death/MI
CV outcomes
Primary outcome similar
at study end
Trend favors amlodipine
at 3 and 6 months
Difficult to interpret due
to BP difference
Dahlöf B et al. Lancet. 2002;359:995-1003.
Julius S et al. Lancet. 2004;363:2022-31.

LIFE: Effects of ARB vs β-blockade
on primary outcome and components
N = 9193 with hypertension and ECG-LVH
LIFE = Losartan Intervention for Endpoint Reduction
in Hypertension
16
Proportion
of patients
with first
event (%)
12
8
4
0
60 18 30 5442 66
Atenolol
Losartan
Primary composite endpoint
(CV death/MI/stroke)
Adjusted RR 13.0%
P = 0.021
(losartan vs atenolol)
Time (months)
5
10
Risk
increase
(%)
0
5
10
15
20
25
Primary outcome
components
(Losartan vs atenolol)
Risk
reduction
(%)
P = 0.206
CV death
P = 0.491
Stroke
MI
P = 0.001

LIFE: Comparison of treatment effects
in overall population vs with diabetes
Patients with hypertension and LVH
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 losartan
50–100 mg
Favors atenolol
50–100 mg
P
CV death
Stroke
MI
Hazard ratio

VALUE: Similar treatment effects
on primary outcome at study end
14
4
2
0
Proportion
of patients
with first
event (%)
0 12 3018 24 54 60 66
Time (months)
6
8
10
12
6 36 42 48
HR = 1.03; 95% CI 0.94–1.14; P = 0.49
Valsartan-based regimen
Amlodipine-based regimen
Julius S et al. Lancet. 2004;363:2049-51

Time
interval
(mos)
∆ SBP
(mm Hg)
Odds ratio Odds ratio
Favors
valsartan
Favors
amlodipine
Favors
valsartan
Favors
amlodipine
Primary outcome Myocardial infarction
0.5 1.0 2.0 4.0 0.5 1.0 2.0 4.0
All study 2.2
0–3 3.8
3–6 2.3
6–12 2.0
12–24 1.8
24–36 1.6
Study end 1.7
36–48 1.4
Julius S et al. Lancet. 2004;363:2022-31.
VALUE: SBP and outcome differences
during consecutive time periods
VALUE = Valsartan Antihypertensive
Long-Term Use Evaluation

Direct Renin Inhibitor
Aliskerin
pre-clinical data

Aliskerin preclinical data
Summary
• Aliskerin demonstrates organ protective
effects in animal models
• Renoprotection comparable with ACEIs and
ARBs
• LVH reductions comparable with ARBs
• Suppresses markers of renal damage in
diabetic nephropathy
• Atherogenesis prevention

Aliskerin
Clinical data

Aliskerin
Outcome data

EFFECT OF THE DIRECT RENIN INHIBITOR
ALISKIREN ON LEFT VENTRICULAR
REMODELING FOLLOWING MYOCARDIAL
INFARCTION WITH LEFT VENTRICULAR
DYSFUNCTION
ASPIRE Trial
Scott D. Solomon, MD, FACC, Sung Hee Shin, MD, Amil Shah, MD, Lars Kober, MD, Aldo P.
Maggioni, MD, Jean Rouleau, MD, FACC, John J. V. McMurray, MD, FACC, Roxzana Kelly, Allen
Hester, Marc A. Pfeffer, MD, PhD, FACC for the Aliskiren Study in Post-MI Patients to Reduce
Remodeling (ASPIRE) investigators
Brigham and Women’s Hospital, Boston, MA; Rigshospitalet Copenhagen University Hospital,
Copenhagen, Denmark; ANMCO Research Center, Firenze, Italy; University of Montreal, Montreal,
Canada; Western Infirmary, Glasgow, Scotland; Novartis Pharmaceuticals, East Hanover, NJ

Cardiovascular Outcomes
ASPIRE Trial
Endpoint
Placebo
n=397
n (%)
Aliskiren
n=423
n (%)
CV Death 6 (1.5) 13 (3.1)
Resuscitated Sudden Death 4 (1.0) 1 (0.2)
HF Hospitalization 17 (4.3) 12 (2.8)
Myocardial Infarction 16 (4.0) 11 (2.6)
Stroke 2 (0.5) 7 (1.7)
Any of the above 34 (8.6) 39 (9.2)
No Significant between group differences

Conclusions ASPIRE Trial
• In high risk post-MI patients with LV systolic dysfunction,
the addition of aliskiren to a standard optimal medical
regimen, including an ACE-I or an ARB, did not result in
benefit with respect to ventricular remodeling compared to
placebo and was associated with more adverse events
• Although ASPIRE utilized a surrogate endpoint, and was not
powered to assess hard clinical outcomes, these results do
not provide support for testing the use of aliskiren in a
morbidity and mortality trial in the high-risk post-MI
population
• Ongoing outcomes trials with aliskiren in patients with heart
failure and diabetic kidney disease are well underway and
will further assess the role for direct renin inhibition in these
populations

Evidence of Dual RAA inhibition

RAAS: Pathways of ACE inhibition
and angiotensin receptor blockade
Dzau V. J Hypertens. 2005;23(suppl 1):S9-S17.
ACE inhibitor
Bradykinin/NO
Inactive
fragments
Chymase,
tPA,
cathepsin
‘Angiotensin II
escape’
ARB
AT1 receptor AT2 receptor
Angiotensin I
Angiotensin II

ONTARGET/TRANSCEND Investigators. Am Heart J. 2004;148:52-61.
ONTARGET: Study design
Ramipril 10 mg Telmisartan 80 mg
N = 25,620
≥55 years with coronary, cerebrovascular, or peripheral vascular disease,
or diabetes + end-organ damage
Results in 2007
Ramipril 10 mg +
telmisartan 80 mg
Primary end point:
CV death, MI, stroke, hosp for HF
Secondary end point:
Newly diagnosed diabetes
ONgoing Telmisartan Alone and in combination with Ramipril Global
Endpoint Trial

ONTARGET/TRANSCEND Investigators. Am Heart J. 2004;148:52-61.
TRANSCEND: Study design
Telmisartan 80 mg
N = 5776 ACEI-intolerant
≥55 years with coronary, cerebrovascular, or peripheral vascular disease,
or diabetes + end-organ damage
Results in 2007
Placebo
Primary end point:
CV death, MI, stroke, hosp for HF
Secondary end point:
Newly diagnosed diabetes
Telmisartan Randomized AssessmeNt Study in aCE iNtolerant
subjects with cardiovascular Disease

Yusuf S et al. N Engl J Med 2008: 358:1547-1559.
ONTARGET: Key results
Outcome Ramipril,
n=8576 (%)
Telmisartan,
n=8542 (%)
Combination,
n=8502 (%)
CV death/MI/
stroke/ CHF
hospitalizationa
16.5 16.7 16.3
CV death/MI/strokeb
14.1 13.9 14.1
MI 4.8 5.2 5.2
Stroke 4.7 4.3 4.4
CHF hospitalization 4.1 4.6 3.9
CV death 7.0 7.0 7.3
Any death 11.8 11.6 12.5
Renal impairment 10.2 10.6 13.5
a. Primary end point
b. Primary end point in the HOPE trial

ONTARGET: Key results
Outcome Risk ratio (95% CI),
telmisartan vs ramipril
Risk ratio (95% CI),
combination therapy vs
ramipril
CV death/MI/
stroke/ CHF
hospitalizationa
1.01 (0.94–1.09) 0.99 (0.92–1.07)
CV death/MI/strokeb
0.99 (0.91–1.07) 1.00 (0.93–1.09)
MI 1.07 (0.94–1.22) 1.08 (0.94–1.23)
Stroke 0.91 (0.79–1.05) 0.93 (0.81–1.07)
CHF hospitalization 1.12 (0.97–1.29) 0.95 (0.82–1.10)
CV death 1.00 (0.89–1.12) 1.04 (0.93–1.17)
Any death 0.98 (0.90–1.07) 1.07 (0.98–1.16)
Renal impairment 1.04 (0.96–1.14) 1.33 (1.22–1.44)
a. Primary end point
b. Primary end point in the HOPE trial

ONTARGET: Reasons for
permanent discontinuations
Outcome Ramipril
(%)
Telmisartan
(%)
Combination
(%)
p, telmisartan vs
ramipril
p, combination
therapy vs
ramipril
Hypotensive
symptoms
1.7 2.7 4.8 <0.001 <0.001
Syncope 0.2 0.2 0.3 0.49 0.03
Cough 4.2 1.1 4.6 <0.001 0.19
Diarrhea 0.1 0.2 0.5 0.20 <0.001
Angioedema 0.3 0.1 0.2 0.01 0.30
Renal
impairment
0.7 0.8 1.1 0.46 <0.001

Conclusions: Telmisartan vs. Ramipril
1. Telmisartan is clearly “non-inferior” to ramipril,with
most ( 95-100%) of the benefits preserved
2. Consistent results on a range of:
• Secondary outcomes
• Subgroups
3. Telmisartan exhibits slightly superior overall
tolerability:
• Less cough and angioneurotic edema
• More mild hypotensive symptoms, but no
difference in severe hypotensive symptoms,
such as syncope

Conclusions: Telmisartan plus Ramipril vs.
Ramipril
1. Combination therapy does not reduce the primary
outcome to a greater extent compared to ramipril alone
and has higher adverse events.
Implications
• Telmisartan is as effective as ramipril, with a slightly
better tolerability.
• Combination therapy is not superior to ramipril, and
has increased side effects.

•The combination of aliskiren (Rasilez) with angiotensin-converting enzyme (ACE)
inhibitors or angiotensin receptor blockers (ARBs) has been associated with serious
adverse cardiovascular and renal outcomes in a recent large clinical trial (ALTITUDE).
•This combination is now contraindicated in: diabetic patients (type I or type II); and
non-diabetic patients with an estimated glomerular filtration rate (eGFR) <60 mL/min
per 1•73 m2
•In all other patient groups, aliskiren in combination with an ACE inhibitor or an ARB is
not recommended
•Any use of aliskiren (either as monotherapy or in combination with other medicines) is
no longer recommended in any patient with severe renal impairment: eGFR <30 mL/min
per 1•73 m2

RAA inhibition
? ACEI
? ARB
? DRI
Evidences from Recent Analysis

Aliskiren in Hypertension
Clinical summary
•Aliskerin provides long- term suppression of PRA
•Aliskerin effectively reduces PRA from baseline as
monotherapy, and blocks the rise in PRA seen during
treatment with other antihypertensives such as ARB
•Aliskerin monotherapy provides dose-dependent
reductions in DBP and SBP
•Additional BP lowering when combined with other
antihypertensives but more side effects

Meta-analyses show consistency of
ACEI benefit in preventing CV events
No. of trials N
Relative risk reduction (%)
CV death MI
Danchin, 2006 7 33,960 19 18
Al-Mallah, 2006 6 33,500 17 16
Dagenais, 2006 3 29,805 18 18
Danchin N et al. Arch Intern Med. 2006.
Al-Mallah MH et al. J Am Coll Cardiol. 2006.
Dagenais GR et al. Lancet. 2006.
Randomized, placebo-controlled trials in patients with CAD without
HF or LV dysfunction

Meta-analysis of trials comparing ARB vs
placebo, non-ACEI comparators, or ACEI
Strauss MH, Hall AS. Circulation. 2006;114:838-54.
9 of 11 trials show excess MI for ARB
Trial
ARB
n/N (MI)
Control
n/N (MI)
ELITE 3/352 4/370
DETAIL 9/120 6/130
ELITE II 31/1578 28/1574
IDNT 39/579 66/1136
CHARM-Alt 75/1013 48/1015
SCOPE 70/2477 63/2460
RENAAL 50/751 68/762
LIFE 198/4605 188/4588
VALUE 369/7649 313/7596
OPTIMAAL 384/2744 379/2733
VALIANT 587/4909 559/4909
Total 26,777 27,273
0.5 1.0 1.5 2.0
Odds ratio (95% Cl)
Favors
ARB
Favors
control
1.08 (1.01–1.16)

Meta-analyses of ACEI and ARB trials
StraussStrauss TsuyukiTsuyuki VolpeVolpe VerdecchiaVerdecchia
N
ACEIACEI
150,943150,943
ARBARB
55,05055,050
ARBARB
68,71168,711
ARBARB
56,25456,254
ARBARB
64,38164,381
MIMI ↓↓14%14%
(P < 0.00001)(P < 0.00001)
Event Rate 5.8%Event Rate 5.8%
↑8%
(P = 0.03)(P = 0.03)
↑3%
(P = ns)
↑4%
(P = ns)
↑2%
(P = ns)
CV deathCV death ↓↓12%12%
(P < 0.0005)(P < 0.0005)
↑↑1%
(P = ns)
NA NA ↓1%
Strauss MH, Hall AS. Circulation. 2006.
Tsuyuki RT, McDonald MA. Circulation. 2006.
Volpe M et al. J Hypertension. 2005.
Verdecchia P et al. Eur Heart J. 2005.
Relative risk

ACEIs vs ARBs: Comparative effect
on stroke, HF, and CHD
Turnbull F. 15th European Meeting on Hypertension. 2005.
Adapted by Strauss MH, Hall AS. Circulation. 2006;114:838-54.CHD = MI and CV death
Blood Pressure Lowering Treatment Trialists’ Collaboration meta-analysis
N = 137,356; 21 randomized clinical trials
ACEI
ARB
Stroke -1% (9% to -10%)
HF 10% (10% to 0%)
CHD 9% (14% to 3%)
Stroke 2% (33% to -3%)
HF 16% (36% to -5%)
CHD -7% (7% to -24%)
30% 0 30%
Decrease Increase
Stroke
P = 0.6
HF
P = 0.4
CHD
P = 0.001
Risk
RRR (95%)

Eur Heart J 2012
Van Vark LC, Bertrand M, Fox K, Mourad JJ, Boersma E, et al. Eur Heart J 2012; published online April 17.

All-cause mortality: effect of ACE inhibitors
ASCOT-BPLA
ADVANCE
HYVET
Overall
1.03 (0.90-1.15)
0.90 (0.75-1.09)
0.99 (0.62-1.58)
1.32 (0.61-2.86)
0.89 (0.81-0.99)
0.86 (0.75-0.98)
0.79 (0.65-0.95)
0.90 (0.84-0.97)
ACE inhibitor better Control better
Random effects model HR (95% CI) P
N= 76 6150.50 0.75 1.33 2.01
HR (log scale)
0.03
0.03
0.02
0.87(0.81-0.93)
0.004
<0.001
ALLHAT (lisinopril)
ANBP-2 (enalapril)
pilot HYVET (lisinopril)
JMIC-B (lisinopril, enalapril)
(perindopril)

All-cause mortality: effect of ARBs
RENAAL (losartan)
IDNT (irbesartan)
LIFE (losartan)
SCOPE (candesartan)
VALUE (valsartan)
MOSES (eprosartan)
JIKEI HEART (valsartan)
PRoFESS (telmisartan)
TRANSCEND (telmisartan)
CASE-J (candesartan)
HIJ-CREATE (candesartan)
KYOTO HEART (valsartan)
NAVIGATOR (valsartan)
Overall
HR (log scale) Control betterARB better
0.50 0.75 1.33 2.01
1.03 (0.83-1.29)
0.92 (0.69-1.23)
0.88 (0.77-1.01)
0.96 (0.81-1.14)
1.04 (0.94-1.14)
1.07 (0.73-1.57)
1.09 (0.64-1.85)
1.03 (0.93-1.14)
1.05 (0.91-1.22)
0.85 (0.62-1.16)
1.18 (0.83-1.67)
0.76 (0.40-1.30)
0.90 (0.77-1.05)
0.99 (0.94-1.04)
Random effects model HR (95% CI) P
N=82 383
0.683

 Among RAAS inhibitors, only ACE inhibitors have demonstrated
a significant 10% mortality reduction in hypertensive patients
(P=0.004).
 No significant reduction in all-cause mortality could be
demonstrated with ARBs (HR, 0.99 (0.95-1.04); P=0.683).
 The difference in treatment effect between ACE inhibitors and
ARBs was statistically significant (P-value for interaction 0.036).
 The largest mortality reductions were observed in ASCOT-BPLA,
ADVANCE, and HYVET, which studied the ACE inhibitor
perindopril (pooled HR, 0.87 [0.81-0.93]; P<0.001).
 Because of the high prevalence of hypertension, the widespread
use of ACE inhibitors may result in an important gain in lives
saved.

Savarese G,et al.J Am Coll Cardiol.In press.doi:10.1016/i.iacc.2012.10.011

Savarese G,et al.J Am Coll Cardiol.In press.doi:10.1016/i.iacc.2012.10.011
Conclusion From Saverese G,et alConclusion From Saverese G,et al
Meta-analysisMeta-analysis
End Points ACEI ARB
Composite
outcome
-14.9%
p=0.001
-7%
p=0.005
CV death -10%
p=0.112
No benefit
MI -17.7%
p<0.001
-9.5%
NS
Stroke -19.6%
p=0.004
-9.1%
p=0.011
All cause death -8.3%
p=0.008
No benefit
New-onset HF -20.5%
p=0.001
No benefit
New-onset DM -13.7%
p=0.012
-10.6%
P<0.001

RAAS modulation in high-risk patients: Summary
• Opportunity for greater use of RAAS modulation in
patients at high risk for CV events
• ACEIs reduce CV death, MI, HF, and stroke across a
broad range of patients with vascular disease
– With/without LVSD or HF
– With/without other proven CV therapies
– Annual event rates of 1.4%–22.6% in untreated
groups
• ARBs reduce HF and stroke
• ACEIs may be considered in all patients with
vascular disease
• ARBs are an alternative in ACEI-intolerant patients
• Dual RAAS inhibition is not better than single
therapy and causes more side effects

AHA/ACC secondary-prevention
guidelines: ACEIs and ARBs
ACEIs
• All patients with LVEF ≤40%, hypertension, diabetes,
or chronic kidney disease (IA)
• Consider for all other patients (IB)
• Optional: Lower-risk, post-revascularization patients
with normal LVEF and well-controlled risk factors
(IIaB)
ARBs
• ACEI-intolerant patients with HF or post-MI LVEF
≤40% (IA)
• Consider in DM and other ACEI-intolerant patients
(IB)
• Consider use in combination with ACEIs in systolic

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