7th Annual
International Diovan
Symposium
Lisbon, 3–5 February 2006
Sponsored by
Novartis Pharma AG
From the Expert’s Files:
Case Presentation
Victor Dzau
Duke University, Durham, USA
Sponsored by
Novartis Pharma AG
Presentation
 52-year-old African-American woman
 Museum curator
 History of
– Type II diabetes (diet controlled)
– Retinopathy and nephropathy
 Referred to specialist due to BP = 160/100 mmHg
despite amlodipine 10 mg, bendrofluazide 2.5 mg and
atenolol 50 mg
Examination
 Not overweight
 Questioning reveals
– ex-smoker for 5 years having smoked 20 cigarettes a day
from age 16 years
– some breathlessness on exertion
 Clinic BP = 164/103 mmHg
 Pulse regular
 Auscultation:
– Abdominal bruit
– AF
Investigations
 Creatinine = 250 μmol/L (2.82 mg/dL)
 Mid-stream urine (MSU) = 2+ protein
 Sugar = 9 mmol/L (162 mg/dL)
 HbA1C = 7% (normal <5%)
 Total cholesterol = 5 mmol/L (193 mg/dL)
 Chest x-ray = normal
 ECG = sinus rhythm, LVH on voltage criteria
 Echo = EF 55%, LVH
7th Annual
International Diovan
Symposium
Lisbon, 3–5 February 2006
VARIABLE 3:
Hypertension and
Microalbuminuria
Sponsored by
Novartis Pharma AG
Pathophysiology of
Microalbuminuria in Hypertension
Michel Burnier
CHUV, Lausanne, Switzerland
Sponsored by
Novartis Pharma AG
Definition of Microalbuminuria
24-hour urines
Urine spot
mg/24
hours
µg/min
mg/L
mg/mmol
creatinine
<30
<20
<20
<2
Microalbuminuria
30–300
20–200
20–200
2–20
Macroalbuminuria
>300
>200
>200
>20
Category
Normal
Natural History of Diabetic Nephropathy
Clinical type 2 diabetes
Functional changes*
Structural changes†
Rising blood pressure
Microalbuminuria
Proteinuria
Rising serum
creatinine levels
End-stage
renal disease
Cardiovascular death
Onset of diabetes
2
5
10
20
Years
*Renal haemodynamics altered, glomerular hyperfiltration
†Glomerular basement membrane thickening , mesangial expansion ,
microvascular changes +/-
30
Pathophysiological Processes Leading to
Albuminuria and Glomerular Lesions
Glucose
Urinary protein
Glycoxidation
(glycation)
AGEs
= angiotensin AT1
receptor
Increased
glomerular
pressure
Ang II
Efferent
arteriolar
constriction
Ang II
Albuminuria and Progression of
Nephropathies
Glomerular permeability for macromolecules
Excessive reabsorption of proteins in the proximal tubule
Intracellular accumulation of protein degradation products
Gene activations
chemokines and cytokines
Proliferation of fibroblasts and extracellular matrix
Development of fibrosis and renal atrophy
Remuzzi et al. Kidney Int 1997;51:2–15
Prevalence of Microalbuminuria in Patients
with Hypertension*
40
38.0
33.7
Prevalence (%)
30.0
30
19.8
20
10
6.7
6.1
4.1
0
Bigazzi
1992
Calvino
1999
Grandi Pontremoli Palatini
2000
1997
1996
Jensen
1997
*Defined as > 140/90 mmHg except Calvino, Palatini (135/85 mmHg)
Jensen (> 140/90 mmHg or on AHY)
Diercks et al. Can J Cardiol 2002;18:525–35
Mean
Microalbuminuria is Associated with Left Ventricular
Hypertrophy and Carotid Hypertrophy in
Hypertensive Patients
Left ventricular mass index
200
Intima/media thickness
*
***
IMT (mm)
LVMI (g/m2)
**
0.8
150
100
50
0
*
****
1
0.6
0.4
0.2
C
Ht AI–
Ht AI+
0
C
C = control; Ht = hypertensive; Al– = no albuminuria; Al+ = with albuminuria
*p<0.001 intergroup comparison; **p<0.001 compared to C;
***p<0.05 compared to Ht Al–; ****p<0.01 compared to Ht Al–
Pontremoli et al. Am J Hypertens 1998;11:430–8
Ht AI–
Ht AI+
Microalbuminuria as a Predictor of Vascular
Disease in Non-diabetic Subjects
Odds ratio for coronary heart disease
Age (10 years)
Male sex
Systolic BP
Diastolic BP
Body mass index (10 kg/m2)
Current or ex-smoker
Treatment of hypertension
Diabetes or insulin resistance
Microalbuminuria
1
5
10
Odds ratio
Yudkin et al. Lancet 1988;2:530–3
15
20
Microalbuminuria and Risk of CV Events,
CHF and Death in the HOPE Trial
4
MI/Stroke/CV death
All-cause mortality
CHF hospitalisation
Relative risk
3
2
1
0
<0.22
0.22–0.57
0.58–1.62
Alb/Crea (mg/mmol)
Adjusted for age, sex, SBP/DBP, waist-hip ratio, diabetes and HbA1c
Gerstein et al. JAMA 2001;286:421–6
>1.62
Renal Insufficiency, Albuminuria and
CV Survival in the HOPE Trial
HR for primary outcome
(CV death, MI, stroke)
2.5
Systolic and diastolic BP NOT significant risk factors
2.0
1.5
1.0
0.5
0
S. creat
>124 µmol/L
Microalbuminuria
Mann et al. Ann Intern Med 2001;134:629–36
Both
Albuminuria and CV Diseases
LIFE study, 8,029 subjects with hypertension
and LV hypertrophy, mean age 66 years
Prevalence (%)
40
Normoalbuminuria
Microalbuminuria (Alb/Crea >3.5 mg/mmol)
Macroalbuminuria (Alb/Crea >35 mg/mmol)
30
20
10
0
Diabetes
Cerebrovascular
disease
Peripheral
vascular
disease
Wachtell et al. J Hypertens 2002;20:405–12
Coronary
vascular
disease
Endpoint rate (%)
Composite Endpoints (CV Death, Non-fatal Stroke
and MI) Stratified by Time-varying Albuminuria in the
LIFE Trial
>3 mg/mmoL (n=2,435, 1,708, 1,760)
1–3 mg/mmoL (n=2,219, 1,827, 1,946)
0.5–1 mg/mmoL (n=1,591, 1,587, 1,814)
0.5 mg/mmoL (n=1,961, 3,385, 2,458)
24
22
20
18
16
14
12
10
8
6
4
2
0
0
6
12
18
24
30
36
42
Month
Ibsen et al. Hypertension 2005;45:198–202
48
54
60
66
Microalbuminuria and Mortality in the General
Population: the PREVEND Study
n=85,421 subjects, age: 28–75 years from the Groningen area
Non-CV death
6.0
5.5
5.0
4.5
4.0
3.5
3.0
2.5
2.0
1.5
1.0
0.5
0
Hazard ratio
Hazard ratio
CV death
1
10
100
1,000
Urinary albumin concentration (mg/L)
6.0
5.5
5.0
4.5
4.0
3.5
3.0
2.5
2.0
1.5
1.0
0.5
0
1
10
1,00
1000
Urinary albumin concentration (mg/L)
Hillege et al. Circulation 2002;106:1777–82
Microalbuminuria and CV Complications in
Hypertension: Is the Threshold Correct?
The Copenhagen City Heart Study
Cox-estimated age-adjusted curves of cumulative incidence of coronary
heart disease for a 60-year-old person based on 1,734 hypertensive
subjects with microalbuminuria and normoalbuminuria
RR of CHD
UAE 4.8 µg/min
UAE <4.8 µg/min
30
3
2
1
0
20
<2.5 2.5–5 5–10
>10
4
10
0
0
2
4
6
8
Years from entry
10
12
Klausen et al. Hypertension 2005;46:33–7
RR of death
Cumulative mortality (%)
4
3
2
1
0
<2.5 2.5–5 5–10 >10
UAE (µg/min)
Microalbuminuria and Incidence of CV
Events: The Framingham Study
Survival free of CVD
According to sex-specific median UACR
Percentage
100
95
< Median
 Median
90
0
1
2
3
4
Years
Arnlov et al. Circulation 2005;112:969–75
5
6
7
8
What Links Microalbuminuria to CV Risk ?
Microalbuminuria
24-hour Blood Pressure Profile in Clinically Healthy
Subjects With or Without Microalbuminuria
Microalbuminuria (n=26)
Normoalbuminuria (n=45)
Blood pressure (mmHg)
165
140
115
90
65
40
0
0
4
8
12
Clock time
Clausen et al. Hypertension 1998;32:71–7
16
20
24
Expression of Endothelial Dysfunction in
Humans
Endothelial dysfunction
Impaired endothelium-dependent vasodilation
Reduces vasodilation
Increased endothelin
Favours vasoconstriction
Increased transcapillary escape rate of albumin
Increases permeability (microalbuminaria)
Increased von Willebrand factor
Increases prothrombotic activity
Increased tPA and PAI-1
Reduces profibrinolytic activity
Increased E-selectin and VCAM-1
Leucocytes adhesion and permeability
Increased ICAM-1
Induces inflammation
Increased fibronectin and type IV collagen fragments
Alters matrix synthesis
Flow-associated Vasodilation of Brachial Artery in
Clinically Healthy Subjects According to Microalbuminuria
Flow-associated dilatation (%)
p<0.05
105
104
103
102
101
100
0
Normoalbuminuria
Elevated UAE
Clausen et al. Circulation 2001;103:1869–74
Pathobiological Processes Potentially Involved in the
Development and Progression of Vascular Diseases
Dyslipidaemia
Hypertension
Diabetes
Smoking
Oxidative stress
Endothelial dysfunction
NO, local mediators, RAAS (Ang II)
Vasoconstriction
Thrombosis
Inflammation Plaque rupture
Adapted from Dzau. Hypertension 2001;37:1047–52
Vascular lesion
and remodelling
Chronic Kidney Disease and CV Risk
Traditional risk factors
Non-traditional risk factors
Age
Albuminuria
Sex
Homocysteine
Hypertension
LP(a) and apolipoproteins
HDL and LDL cholesterol
Anaemia
Diabetes
Ca/phosphate metabolism
Smoking
Salt and water overload
Physical activity
Oxidative stress
Family history of CVD
Inflammation
LVH
Malnutrition
Thrombogenic factors
Sleep disturbance
NO/endothelin balance…
Vascular Effects of Angiotensin II
Vasoconstriction
Stimulation of Ang II type 1 receptors
Release of endothelin and norepinephrine
Reduction of NO bioactivity and production of peroxynitrite
Inflammation
Activation NADH/NADPH oxidase and production of
superoxide anion
Induction of MCP-1, VCAM, TNF-a, IL-6 expression
Activation of monocytes and macrophages
Remodelling
Stimulation of SMC migration, hypertrophy and replication
Induction of PDGF, bFGF, IGF-1, TGF-b expression
Stimulation of matrix glycoproteins and metalloproteinase
expression
Thrombosis
Stimulation of PAI-1 synthesis and change in tPA/PAI-1 ratio
Activation of platelet with increased aggregation and adhesion
Angiotensin II Inhibition Retards the
Progression of Renal Diseases
Prevention
Benedict
Study
Normoalbuminuria
Protection
IRMA 2
IDNT
MARVAL
RENAAL
Microalbuminuria
Macroalbuminuria
ESRD
CV morbidity and mortality
Early stage
Late stage
Terminal stage
Severity of renal disease
Reduction in Albuminuria Translates Into a Decrease
in CV Events in Hypertensive Patients: LIFE Study
Fraction suffering
composite endpoint
0.20
High baseline/high year 1
High baseline/low year 1
Low baseline/high year 1
Low baseline/low year 1
0.15
0.10
0.05
0
0
10
20
30
40
50
Follow-up (months)
Ibsen et al. Hypertension 2005;45:198–202
60
70
Effect of Fosinopril on CV Event Rates
in Patients with Microalbuminuria
1.00
Event-free survival
0.98
0.96
0.94
0.92
HR 0.60 [0.33–1.10], p=0.098 (Log-rank)
0.90
Placebo
Fosinopril
0.10
0
0
10
20
30
Follow-up (months)
Asselbergs et al. Circulation 2004;110:2809–16
40
Event-free Survival According to
the Level of Microalbuminuria
1.00
Event-free survival
0.95
0.90
0.85
p=0.008
UAE
UAE
UAE
UAE
0.80
0.10
<50 mg/24 hours, placebo
>50 mg/24 hours, placebo
<50 mg/24 hours, fosinopril
>50 mg/24 hours, fosinopril
0
0
10
20
30
Follow-up (months)
Asselbergs et al. Circulation 2004;110:2809–16
40
Conclusions
 Microalbuminuria is frequent in hypertension and is
associated with target organ damage and the incidence
of CV complications
 The pathophysiological link between microalbuminuria
and CV risk is not completely understood but it may be
due to endothelial dysfunction with an impaired NO
balance, activation of local mediators and increased
activity of the RAAS system
 Blockade of the RAAS with ACE inhibitors or AT1
receptor blockers is an important therapeutic approach
to reduce microalbuminuria and to prevent the
development of CV and renal complications in
hypertension
7th Annual
International Diovan
Symposium
Lisbon, 3–5 February 2006
Sponsored by
Novartis Pharma AG
Point-Counterpoint
Are Benefits Beyond Blood Pressure
Lowering Clinically Relevant?
Sponsored by
Novartis Pharma AG
Albuminuria-associated Disease:
Are Benefits Beyond BP Lowering
Clinically Relevant?
Giancarlo Viberti, MD
Professor of Diabetes and Metabolic Medicine
Cardiovascular Division
KCL School of Medicine
Guy’s Hospital
King’s College London
London, UK
Age-specific Relation of Usual BP to Vascular Mortality
In Individuals With No Previous Vascular Disease
Prospective Studies Collaboration. Lancet 2002;360:1903–13
Annual Transition Rates Through
Stages of Diabetic Nephropathy
No nephropathy
2.0%
(1.9% to 2.2%)
1.4%
(1.3% to 1.5%)
Microalbuminuria
2.8%
(2.5% to 3.2%)
3.0%
(2.6% to 3.4%)
Macroalbuminuria
2.3%
(1.5% to 3.0%)
Elevated plasma creatinine or
renal replacement therapy
4.6%
(3.6% to 5.7%)
19.2%
(14.0% to 24.4%)
Adler et al. Kidney Int 2003;63:225–32
Relationship Between SBP and ACR in T2DM
Patients with Different Degrees of AER
ACR mg/mmol
100
10
1
0.1
80
100
120
140
160
180
200
220
240
SBP mmHg
Smith et al. JASN 2005;16:1069–75
Risk factors for
microalbuminuria in type 1
diabetic patients with
baseline normoalbuminuria
(7 yr follow-up)
Excess Mortality With Hypertension
and Proteinuria In Type 2 Diabetes
Status of hypertension (H) and proteinuria (P) in type 2 diabetes
1000
Standardised
mortality ratio
500
0
P-H- P-H+ P+H- P+H+
P-H- P-H+ P+H- P+H+
Men
Women
Wang et al. Diabetes Care 1996;19:305–12
Epidemiology
Relative Risk of Cardiovascular Disease
and Mortality in Diabetes Mellitus By
Quartile of Albuminuria (ACR)
ACR (mg/mmol) quartiles RR (95% CI)
1st
2nd
3rd
4th
<0.22
0.22–0.57
0.58–1.62
>1.62
p for trend
MI, stroke
and CV death
1
0.85
1.11
1.89
<0.001
(0.63–1.14)
(0.86–1.43)
(1.52–2.63)
All-cause
mortality
1
0.86
1.41
2.38
(0.58–1.28)
(1.01–1.95)
(1.80–3.20)
CHF
1
0.72
1.83
3.65
(0.32–1.63)
(0.98–3.43)
(2.06–6.46)
Variable
<0.001
<0.001
n=3,498
Gerstein et al. JAMA 2001;286:421–6
Rate of eGFR Decline
in Type 2 DM With Normoalbuminuria
AER categories:
I = ≤10 mg/24h
II = 10.1 to 20 mg/24h
III = 20.1 to 30 mg/24h
Rachmani et al. Diabetes Res Clin Pract 2000;49:187–94
Survival Curves in Type 2 DM
According To Baseline AER Category
AER categories:
I = ≤10 mg/24h
II = 10.1 to 20 mg/24h
III = 20.1 to 30 mg/24h
Rachmani et al. Diabetes Res Clin Pract 2000;49:187–94
Albuminuria and CVD risk in hypertensive
patients with LVH
The LIFE Study
ACR (mg/mmol)
<0.25
≥0.25 to
<0.82
≥0.82
to<1.62
≥1.67
to<4.32
≥4.32 to
<9.45
P value
for trend
HR
1
1.3
1.8
2.3
2.7
<0.001
Adjusted
HR
1
1.3
1.5
1.9
2
<0.001
Composite
endpoint
Composite endpoint = CVD death, fatal or non-fatal stroke, fatal or non-fatal MI
Relative Risk of CVD and Mortality in
5,545 High-risk Patients Without Diabetes by
Quartile of Albuminuria (ACR)
ACR (mg/mmol) quartiles RR (95% CI)
Variable
1st
2nd
3rd
4th
<0.22
0.22–0.57
0.58–1.62
>1.62
p for trend
MI, stroke
and CV
death
1
1.24
1.54
1.83
(1.03–1.49) (1.29–1.85) (1.52–2.20)
<0.001
All-cause
mortality
1
1.17
1.49
2.27
(0.93–1.47) (1.19–1.87) (1.82–2.82)
<0.001
CHF
1
1.45
1.86
2.93
(0.87–2.44) (1.12–3.10) (1.79–4.81)
<0.001
Gerstein et al. JAMA 2001;286:421–26
Albuminuria and Incidence of CVD Events
in Non-hypertensive and Non-diabetic Subjects
The Framingham Heart Study
Survival free of CVD
According to sex-specific median UACR
Median UAER:
M: 3.9 μg/mg
F: 7.5 μg/mg
Arnlov et al. Circulation 2005;112:969–75
Albuminuria and Risk of CHD and Death
In The General Population
Third Copenhagen City Heart Study
25%-ile: 2.1 μg/min
50%-ile: 3.0 μg/min
75%-ile: 4.8 μg/min
Klausen et al. Circulation 2004;110:32–35
Albuminuria and CVD/Non-CVD Mortality
in The General Population
PREVEND Study
Hillege et al. Circulation 2002;106:1777–82
The Clinical Trial Evidence
Change in AER Predicts Loss of GFR
Rossing et al. Diabetologia 1994;37:511–16
RENAAL: Change From Baseline
in Proteinuria*
40
Placebo
20
Median
percent
change
0
p=0.0001
35% overall reduction
-20
-40
Losartan
-60
0
P (+CT) 762
L (+CT) 751
12
24
Months
36
48
632
661
529
558
390
438
130
167
*Proteinuria measured as the urine albumin:
creatinine ratio from a first morning void
Brenner et al. N Engl J Med 2001;345:861–9
RENAAL: Baseline Proteinuria As A
Determinant of Renal Events In T2DM
Composite Endpoint
100
3.0 g/24h
100
80
60
<1.5 g/24h
40
20
0
% with ESRD endpoint
% with renal endpoint
80
ESRD
3.0 g/24h
60
40
20
<1.5 g/24h
0
0
12
24
Month
36
48
0
12
24
36
48
Month
De Zeeuw et al. Kidney Int 2004;65:2309–20
RENAAL: Baseline Proteinuria As A
Determinant For Cardiac Events In T2DM
CV Endpoint
≥3.0g/24h
% with CV endpoint
Heart Failure
60
40
<1.5 g/24h
20
0
% with heart failure endpoint
60
40
3.0 g/24h

20
<1.5 g/24h
0
0
12
24
Month
36
48
0
12
24
36
48
Month
De Zeeuw et al. Circulation 2004;110:921–7
RENAAL: Initial Antiproteinuric
Response vs Renal Risk
ESRD
Hazard ratio
Renal Endpoint
2.5
2.5
2.0
2.0
1.5
1.5
1.0
1.0
0.5
0.5
0.0
0.0
-90
-25 0
25 50 72
Albuminuria reduction (%)
-90
-25
0
25 50 72
Albuminuria reduction (%)
De Zeeuw et al. Kidney Int 2004;65:2309–20
RENAAL: Proteinuria Reduction
(<0% versus >30%) Determines the
Cardiovascular Outcome
% with CV endpoint
<0%
>30%
30
20
10
Heart Failure
40
% with heart failure
CV Endpoint
40
30
20
<0%
10
>30%
0
0
0
12
24
Month
36
48
0
12
24
36
48
Month
De Zeeuw et al. Circulation 2004;110:921–7
Changes In BP and AER By Valsartan
and Amlodipine in T2DM Patients With
Microalbuminuria
The MARVAL Study
UAER (µg/min)
Mean BP change (mmHg)
SBP
DBP
70
0
2
60
4
40
6
30
50
8
-6.6
10
12
p <0.001
-6.5
20
10
-11.2 -11.6
0
Valsartan
Amlodipine
Baseline
Valsartan 24 Wks
Amlodipine 24 Wks
Viberti et al. Circulation 2002;106:672–8
Arterial blood pressure (mmHg)
Blood Pressure According To
Treatment Group
160
Systolic
150
140
130
120
Trandolapril
Verapamil
Trandolapril plus Verapamil
Placebo
110
100
90
Diastolic
80
70
0
3
6
9
12
15
18
21
24
27
30
33
36
39
42
45
48
Follow-up (months)
Ruggenenti et al. N Engl J Med 2004
20
No ACE inhibitor
Cumulative incidence of
microalbuminuria (%)
(66 events)
15
10
5
ACE inhibitor
(35 events)
A.F. (95 % C.I.) = 0.44 (0.27 – 0.70) p=0.001
0
0
6
12
18
24
30
36
42
48
Follow-up (months)
No. at risk
ACE inhibitor
601
503
469
441
417
399
380
311
220
No ACE inhibitor
603
463
424
405
376
357
338
270
188
Ruggenenti et al. N Engl J Med 2004
Rate of CVD Events By Time-varying Albuminuria
In Subjects With Essential Hypertension and LVH
The LIFE Study
Composite endpoint
CV death, fatal or non-fatal stroke,
fatal or non-fatal MI
Ibsen et al. Hypertension 2005;45:198–202
Risk of ESRD vs Initial Change( 6–0 months) in
Proteinuria in African Americans with Hypertension
and Non-diabetic Kidney Disease
AASK
Lea et al. Arch Intern Med 2005;165:947–953
How do we obtain better
evidence?
Antihypertensive and Antiproteinuric
Responses To Increasing ACE-I Dose
Lisinopril dose (mg)
5 mg
10 mg
15 mg
20 mg
0
-10
-20
-30
% reduction
vs control
-40
-50
-60
-70
BP
Urinary protein
-80
Adapted from Palla et al. Int J Clin Pharmacol Res 1994;14:35–43
Conclusions
Albuminuria is a powerful and independent risk
factor for renal and cardiovascular disease. The
relationship is linear across a range which includes
normalcy
Correction of albuminuria per se appears to be
related to reduction of risk of renal and
cardiovascular events
To acquire direct clinical evidence a trial is required
that compares different doses of the same
compound with similar BP-lowering effects but
different albuminuria reduction potency
Are Benefits Beyond BP
Lowering Clinically Relevant? No
Giuseppe Mancia
University of Milan-Bicocca, Italy
Sponsored by
Novartis Pharma AG
The Question
 Does BP reduction per se substantially contribute to CV
protection (i.e. reduction in CV morbidity and mortality)
in hypertension?
Effects of Antihypertensive Drugs
on CVD in Controlled Trials
CVD (%)
Comparator
Diuretics
–16
Placebo
Beta-blockers
–21
Placebo
Calcium antagonists
–28
Placebo
ACE inhibitors
–24
Placebo
Ang II antagonists
–10
Active therapy*
* BP –2/–1 mmHg
Metanalysis of Trials Comparing Different Treatments
or Treatment Versus Placebo in Hypertension
1.50
Stroke
1.50
Major CVD
1.25
1.25
1.25
1.00
1.00
1.00
0.75
0.75
0.75
0.50
0.50
0.50
0.25
–10 –8 –6 –4 –2 0
1.50
Relative risk of
outcome event
Relative risk of
outcome event
1.50
2
0.25
4
–10 –8 –6 –4 –2 0
1.50
CVD death
2
CHD
0.25
4
–10 –8 –6 –4 –2 0
Total mortality
1.25
1.25
1.00
1.00
0.75
0.75
0.50
0.50
0.25
–10 –8 –6 –4 –2 0
0.25
–10 –8 –6 –4 –2 0
2
4
SBP difference between randomised groups (mmHg)
Turnbull et al. Lancet 2003;362:1527–35
2
4
2
4
VALUE: Analysis of Results
Based on BP Control at 6 Months
Patients treated with valsartan
Patients treated with amlodipine
Odds ratio
Fatal/non-fatal cardiac
events
Fatal/non-fatal
stroke
*
*
All-cause death
*
0.50
(0.39–0.64)
*
*
0.79
(0.69–0.91)
0.62
(0.50–0.77)
0.4 0.6 0.8 1.0 1.2
Controlled
Non-controlled
patients†
patients
(n=5,253)
(n=2,396)
Hazard ratio 95% CI
*p<0.01; †SBP <140 mmHg at 6 months
Weber et al. Lancet 2004;363:2047–49
0.73
(0.63–0.85)
*
0.79
(0.69–0.92)
0.91
(0.71–1.17)
0.83
(0.66–1.03)
Myocardial infarction
Heart failure
hospitalisations
0.76
(0.66–0.88)
0.60
(0.48–0.74)
*
Odds ratio
*
0.64
(0.52–0.79)
0.4 0.6 0.8 1.0 1.2
Controlled
Non-controlled
patients†
patients
(n=5,502)
(n=2,094)
Hazard ratio 95% CI
FEVER: Endpoint Analysis (First Time
Occurrence in Each Category)
Per 1,000 patient-years
Felodipine
Placebo
Hazard ratio (95% CI)
(138.1/82.3 mmHg) (141.6/83.9 mmHg)
Stroke
11.2
Fatal
2.1
Non-fatal
9.1
All CV events
15.2
All cardiac events 4.6
All-cause death
7.1
CV death
4.6
Coronary events
4.5
Heart failure
1.1
New-onset diabetes 3.1
Cancer
2.6
15.9
3.1
12.7
21.2
6.6
9.6
6.4
6.2
1.7
2.7
3.9
0.72
0.70
0.72
0.72
0.66
0.70
0.68
0.68
0.76
1.03
0.60
0.4
0.6 0.81.0 1.5 2.0
Felodipine better
Liu Lisheng et al. J Hypertens 2005
Placebo better
More Versus Less Intensive Treatment
in DM +
DM + (n=3,599)
 BP –6.0/–4.6 mmHg
0
Stroke
CHD
CHF
CVD
Total
CV death mortality
Risk ratio
–10
–16
–20
–25*
–30
–40
–31
–36*
*Statistically significant
Turnbull et al. Arch Intern Med 2005;165:1410–19
–27*
–33
Clinical Outcomes – Unadjusted
BP control by visit
Percent of visits with BP
control (<140/90 mmHg)
HR
Primary outcome
<25%
1.00
25%–<50%
0.67
50%–<75%
0.60
75%
0.54
Reduced risk
(0.59–0.76)
(0.53–0.67)
(0.48–0.61)
MI (fatal + non-fatal)
<25%
25%–<50%
50%–<75%
75%
1.00
0.70
0.63
0.55
(0.57–0.86)
(0.53–0.76)
(0.46–0.65)
Stroke (fatal + non-fatal)
<25%
25%–<50%
50%–<75%
75%
1.00
0.88
0.62
0.43
(0.66–1.18)
(0.47–0.82)
(0.32–0.58)
Increased risk
(95% CI)
0.40
0.60
0.80
HR (95% CI)
1.00
Group with <25% of visits with BP control used as reference
Primary Outcome = first occurrence of death (all cause), non-fatal MI, or non-fatal stroke
1.20
 Does CV protection (reduction in CV morbidity
and mortality) exclusively depend on BP
reduction per se?
 Are there specific protective effects of different
drugs or drug classes?
CV Events in Patient Subgroups
 2.9/1.7 mmHg
Amlodipine/perindopril
(BP 164.1/94.8  135.5/79.1 mmHg)
Atenolol/thiazide
(BP 163.9/94.5  136.3/78.4 mmHg)
Diabetes
No diabetes
Current smoker
Non-current smoker
Obese
Non-obese
LVH
No LVH
Older (>60 years)
Younger (≤60 years)
Female
Male
Previous vascular disease
No previous vascular disease
Renal dysfunction
No renal dysfunction
With metabolic syndrome
Without metabolic syndrome
0.70
0.80
0.90
1.00
1.50
Major CVD with ACE-I Versus D/BB
CA
Favours
first
 BP (mmHg)
Favours
second
Versus
RR (95% CI)
I2 (%)
ACE-I versus D/BB
Diabetes
–0.5/0.1
No diabetes
0.6/0.1
Overall
0.90 (0.74–1.11) 55
1.04 (0.98–1.10) 0
p homog = 0.19
CA versus D/BB
Diabetes
0.7/–0.6
No diabetes 1.4/–0.2
Overall
0.95 (0.82–1.10)
1.04 (0.98–1.10)
p homog = 0.82
0
0
ACE-I versus CA
Diabetes
0.4/1.2
No diabetes 0.4/0.8
Overall
0.92 (0.79–1.07)
0.99 (0.92–1.07)
p homog = 0.37
0
0
0.25
0.5
1
Risk ratio
Turnbull et al. Arch Intern Med 2005;165:1410–19
2
Meta-analysis of Trials Comparing ACE-I-based with
ARB-based Regimens for the Outcomes of Stroke,
CHD and Heart Failure
Outcome
Trial
Favours ARB
Stroke
ELITE II
OPTIMAAL
VALIANT
Overall
1.63 (0.77–3.44)
1.06 (0.84–1.33)
0.95 (0.76–1.17)
1.02 (0.87–1.19)
Major CHD
ELITE II
OPTIMAAL
VALIANT
Overall
1.24 (1.00–1.55)
1.01 (0.88–1.15)
0.97 (0.89–1.05)
1.03 (0.92–1.16)
Heart failure ELITE II
OPTIMAAL
VALIANT
Overall
0.87 (0.59–1.28)
1.14 (0.99–1.31)
1.01 (0.93–1.11)
1.05 (0.95–1.15)
0.5
Favours ACE-I
1.0
Relative risk
Relative risk (95% CI)
1.5
Blood Pressure Lowering Treatment Trialists’ Collaboration
Relative Risk of MI for ARBs and ACE-Is Versus
Active Drugs and Placebo
ARBs versus ACE-I
ARBs versus placebo and active drug
ARBs versus active drug
ARBs versus placebo
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Favours ARB
Volpe et al. J Hypertens 2005;23:2113–18
1.1
1.2
1.3
Favours other drug
1.4
Should Guidelines Convey the Message that What
Matters for CV Protection is Only BP Control?
 CVD  by many drugs (and drug combinations),
provided BP 
 For a given BP  little/no  CVD between treatments
 Benefit proportional to degree of BP 
 BP control versus lack of control associated with large
 CVD
 Tighter BP control (well below 140/90 mmHg) associated
with greater CV protection (high-risk patients)
Short-term Protection
BP
reduction
Drug
Mancia, 2004
May Event-based Trials Underestimate
Potential Differences Between Drugs?
 Trial limitations
– High-risk patients
– Patients’ drop-out/cross-over (dilution factor)
– Short-term duration
Pseudoequivalence?
 Prevention of events not superimposable to prevention
of disease
Differences Between Drugs on Factors
Responsible for Progression of Disease
 BP lowering
Probably not
 Lipid profile
Yes, minor
 Insulin resistance
Yes
 New-onset diabetes
Yes
 Metabolic syndrome
Yes
 LVH progression/regression
Yes
 Small vessel remodelling
Yes
 Large artery structure/function/atherosclerosis
Yes
 Renal protection
Yes
Role of Drug-specific Properties Versus BP
Reduction per se in CV Protection of Hypertensive
Patients
Short-term
protection
BP
reduction
Drug
Mancia, 2004
Long-term
protection
Drug
BP
reduction
?
Effect of Antihypertensive Treatment (n=10)
GFR
(ml/min/1.73 m2)
MAP
(mmHg)
125
115
Start of treatment
105
95
105
95
85
75
65
Albuminuria
(g/min)
1,250
750
250
–30 –24 –18 –12
–6
0
6
Months
Parving et al. Lancet 1983;2:1175–9
12
18
24
30
36
7th Annual
International Diovan
Symposium
Lisbon, 3–5 February 2006
Sponsored by
Novartis Pharma AG
From the Expert’s Files:
Case Presentation
Marc Pfeffer
Harvard Medical School, USA
Sponsored by
Novartis Pharma AG
Presentation
 60-year-old Turkish male lawyer presents for routine
check-up
 History of ischaemic heart disease and hypertension
 Myocardial infarction 3 years previously, uncomplicated
recovery
 Progressive shortness of breath on exertion for past 3
weeks
 Current meds
–
–
–
–
ASA
statin
beta-blocker
ACE-I
Examination
 BP = 110/70 mmHg
 Height = 1.85
 Weight = 93 kg
– BMI = 27
 Heart rate = 76
 No peripheral oedema
 JVP elevated at 30°
 Carotid upstrokes normal, no bruit
 Lungs: basal crepitations
 Systolic murmur, no S3
Investigations
 Dipstick protein –ve
 Creatinine = 141 mmol/L (1.5 mg/dL)
 eGFR = 52
 ECG = Evidence of old anterior MI
I
aVR
V1
V4
II
aVL
V2
V5
III
aVF
V3
V6
IV
II
V5
 Echo = Ejection fraction 35%; dilated left ventricle
The Multiplicative Effect of Global
Risk Factors in Post-MI HF Patients:
The Root Cause
Peter Liu
University of Toronto, Canada
Sponsored by
Novartis Pharma AG
Incidence of Post-MI HF
Based on the 44-year follow-up of the NHLBI’s
Framingham Heart Study…
 The incidence of HF approaches 10 per 1,000 population
after age 65
 Approximately 22% of male and 46% of female MI
patients will experience HF within 6 years
NHLBI = National Heart, Lung, and Blood Institute
Hurst. The Heart, Arteries and Veins. 10th ed. New York,
NY: McGraw-Hill, 2001; American Heart Association. Heart Disease and
Stroke Statistics – 2005 Update. Dallas, Texas: American Heart
Association, 2004
VALIANT Registry: In-hospital Clinical Events Among
Post-MI Patients With and Without HF/LVSD
25
HF/LVSD (n=2,347)
No HF/LVSD (n=3,219)
Patients (%)
20
16
15
13
10
8
7.1
5
2.3
2.5
6
2.2
1.4
0.9
0
Death
Reinfarction
AF
Stroke
LOS (days)
LVSD = left ventricular systolic dysfunction; AF = atrial fibrillation
LOS = length of stay
Velazquez et al. Eur Heart J 2004;25:1911–9
Beta-blocker: Carvedilol Post-MI
Reduces Cardiovascular Mortality
Proportion Event-free
1.00
0.90
Carvedilol n=975
0.80
Placebo n=984
Risk reduction:
25% (4%, 42%)
p=0.024
0.70
0.60
Cardiovascular mortality rates:
placebo 14%; carvedilol 11%
0
0
0.5
1.0
1.5
2.0
Time (years)
Adapted from The CAPRICORN Investigators. Lancet 2001;357:1385–90
Antiplatelet Therapy: Clopidogrel and Aspirin
Reduce Risk of Death, MI or Stroke at One Year
Aspirin/clopidogrel
Placebo
Death, MI, or stroke (%)
12
10
8
RRR 26.9%
p=0.02
11.5
RRR
19.7%
p=NS
6.9
6
5.5
RRR
37.4%
p=0.04
4
8.5
4.6
2.9
2
0
Day 28
Day 29 to 1 year
Composite
RRR = Relative risk reduction; NS = non significant
Adapted from Steinhubl et al. for the CREDO Investigators. JAMA 2002;288:2411–20
Statin: Fluvastatin Significantly Reduces the Risk of
Cardiac Events After A First Successful PCI
In patients with average cholesterol levels, fluvastatin significantly reduced the
risk of MACE by 22% (p=0.0127)
Patients free from MACE (%)
100
90
Fluvastatin (80 mg/d, n=844)
80
Risk
reduction
= 22%
Placebo
(n=833)
70
0
0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
4.0
Time post-randomisation (years)
PCI = percutaneous coronary intervention; MACE = Major Adverse Cardiac Events
Serruys et al. JAMA 2002;287:3215–19
Remodelling Post MI: Renin–Angiotensin
Activation
Initial infarct
Infarct expansion
(hours to days)
Global remodelling
(days to months)
Modified from Jessup and Brozena. New Engl J Med 2003;348:2007–18
Acute Ischemia
Chronic Repair
Mechanical stress
Oxydative stress
Hypoxia
ECM
Initial cytokine release
Osteopontin
TIMPs, MMPs
Ischemic
Myocytes
Cytokine
AII, OFR
Cytokine  Angiotensin
Apoptotic
Myocytes
Hypertrophied
Myocytes
Angiogenesis
VEGF, Angiopoietins
Intergin b3
Necrotic
Myocytes
= Neutrophils
= Monocyte
= Macrophages
= Mast Cells
= Collagen
= Angiogenesis
Nian et al. Circ Res 2004;94:1543–53
Myocyte Stretch and AII Production
Angiotensin II
Myocyte Transillum’n
Leri. J Clin Invest 1998;101:1326–42
Inflammatory Cytokine Levels in Post-MI
Patients With and Without HF/Death
TNF- a
Inflammatory cytokine levels
p<0.01
IL- 6
p<0.01
80
p<0.0001
p<0.0001
70
60
50
40
30
20
10
0
Group 1
(n=140)
Group 2
(n=44)
Group 1
(n=141)
Intrahospital
Group 2
(n=30)
Follow-up
Group 1: made up of patients free from death and HF;
Group 2: patients with HF and/or death
Valgimigli et al. Circulation 2005;111:863–70
Apoptosis in the Failing Human Heart
Propidium Iodide
Number of labelled myocyte
Nuclei/106 Nuclei
Deoxyuridine triphosphate labelling
5,000
4,000
3,000
Deoxyuridine Triphosphate
2,000
20
10
0
Control
Ischaemic Idiopathic
CM
DCM
CM = cardiomyopathy; DCM = dilated cardiomyopathy
Olivetti et al. N Engl J Med 1997;336:1131–41
Matrix Metalloproteinase (MMP) post MI
MTMMP/ADAMs
uPA/Plasmin
IL-1, CD40
Zn
TNF, EMPRINN
TIMP3
OFR, Chymase
ACE / AII
Sun et al. Circulation 2004;110:3221–8;
Kassiri et al. Circulation Research 2005;97:380–90
MMP Inhibitors
ACEi/ARBs
Pathophysiology of Ventricular Remodelling
in Post-MI HF
 Increased levels of inflammatory cytokines
 Changes in the extracellular matrix: increased
fibroblast and myocardial matrix
metalloproteinase (collagenase) activity
 Myocyte apoptosis or necrosis
 Hypertrophy of remaining myocytes
Localised ACE/Chymase Presence Post MI
Control
3 days
7 days
28 days
Renin–Angiotensin Aldosterone System
(RAAS)




Non-ACE pathways
(e.g. chymase)
Vasoconstriction
Cell growth
Na/H2O retention
Sympathetic activation
Angiotensinogen
Renin
Angiotensin I
AT1 receptor
Angiotensin II
ACE
Cough,
angio-oedema
benefits?
 Bradykinin
Aldosterone AT2 receptor
Inactive
fragments
ACE = angiotensin-converting enzyme;
AT1 = angiotensin II type 1; AT2 = angiotensin II type 2
 Vasodilation
 Antiproliferation
(kinins)
Post-MI Remodelling: Ang II Modulation
by RAAS Blockade
Control
Ang II modulation
Effects of ACE Inhibitor Treatment on
All-Cause Mortality Post-MI
AIRE
SAVE
Radionuclide
EF ≤ 40%
Probability of event
0.40
TRACE
Clinical and/or
radiographic
signs of HF
Echocardiographic
EF ≤ 35%
Placebo
0.35
ACE inhibitor
0.30
0.25
0.20
Placebo: 866/2971 (29.1%)
0.15
ACE inhibitor: 702/2995 (23.4%)
0.10
OR: 0.74 (0.66–0.83)
0.05
0.0
0
Years
ACE inhibitor 2,995
Placebo 2,971
1
2,250
2,184
2
1,617
1,521
EF = ejection fraction; OR = odds ratio
Flather et al. Lancet 2000;355:1575–81
3
892
853
4
223
138
VALIANT: Valsartan Shows Non-inferiority to
ACE Inhibitors
Hazard ratio for death from any cause
SAVE
TRACE
Valsartan
preserves
99.6% of the
mortality
benefit of
captopril
AIRE
SAVE, TRACE and
AIRE combined
VALIANT
(Imputed placebo)
0.5
1
Favours
active drug
Pfeffer et al. N Engl J Med 2003;349:1893–906
2
Favours
placebo
Summary
 Patient post-MI with LV dysfunction is at very high risk for deaths,
arrhythmias and recurrent events
 Pathophysiology of ventricular remodelling in post-MI HF
– Inflammatory cytokines
– Myocyte apoptosis
– Hypertrophy of remaining myocytes and hyperplasia of
fibroblasts
 RAAS activation post-MI contributes to adverse ventricular
remodelling and mortality
 Deleterious effects of angiotensin II mediated via AT1 receptor
 Standard post-MI therapy should include a platelet inhibitor,
beta-blocker, statin, and an ACE-I/ARB
RAAS Blockade in Post-MI HF and
Chronic HF: What’s the Evidence for
This Treatment Strategy?
Eric J Velazquez
Duke University, Durham, USA
Sponsored by
Novartis Pharma AG
The Cardiovascular Continuum
Oxidative stress/
endothelial
dysfunction
Target organ
damage
Tissue injury
(MI, stroke)
Atherosclerosis and LVH
Pathologic
remodelling
Target organ
dysfunction (HF, renal)
Vascular
dysfunction
Risk factors:
diabetes,
hypertension
AT1 receptor
Endstage
organ failure
Death
LVH = left ventricular hypertrophy
MI = myocardial infarction; HF = heart failure
Adapted from Dzau and Braunwald. Am Heart J 1991;121:1244–63
The Scope of CHD and MI
 Worldwide, 17 million people die of CVD every year1
 More than 60% of the global burden of CHD occurs in
developing countries1
 It is estimated that in 2005, 1.2 million Americans will
have a new or recurrent coronary attack*2
 In 2002, nearly 180,000 people died of an MI2
*Coronary attack=definite or probable MI, or fatal CHD
CHD=coronary heart disease
1http//www.who.int/cardiovascular_diseases
2American
Heart Association. 2005 Heart and Stroke Statistical Update. 2004
MI and CAD: Secondary Prevention
Treatment objectives
Prevent
reinfarction
Prevent LV
remodelling
Prevent
progression to
HF
Reduce risk of
arrhythmias
Improve survival
How can we help these
high-risk patients?
Treatment of Post-MI
Patients with LVSD/Acute HF
LVSD or
Acute HF
Severity of LV damage
Antiplatelet
+
Statin
LVSD and
Acute HF
Death and Major CV Events
SAVE
AIRE
TRACE
Radionuclide
EF 40%
Clinical and/or
radiographic
signs of HF
Echocardiographic
EF 35%
0.75*
(0.67–0.83)
Events (%)
40
ACE-I (n=2,995)
Placebo (n=2,971)
30
0.73*
20
(0.63 – 0.85)
0.80*
(0.69 – 0.95)
10
0
n=
355
n=
460
Readmission for HF
n=
324
n=
391
Reinfarction
*Odds ratio (95% CI)
Flather et al. Lancet 2000;355:1575–81
n=
1,049
n=
1244
Death/MI or
Readmission for HF
Early Treatment of Post-MI
Patients with LVSD/Acute HF
LVSD or
Acute HF
Severity of LV damage
Proven ACE-I
Antiplatelet
+
+
Statin
SAVE/AIRE/TRACE
LVSD and
Acute HF
Potential Pharmacological Benefits of
AT1-receptor Blockade Versus ACE Inhibition
AT1-R antagonists
ACE inhibitors
Chymase
Ang II
Plasma Ang II
(–)
(–)
Plasma Ang II
(+)
(–)
Bradykinin
(–)
Prostagladins
AT2
NO



AT1
AT1
AT2
Cardioprotection
Vasodilation
Negative chronotropism
Anti-fibrosis
Anti-growth
NO
Cardioprotection
Vasodilation
Cardioprotective effects via angiotensin II binding to AT2 receptor
1,2
Angiotensin II generated by non-ACE dependent pathways also blocked from binding to the
AT1 receptor
Reduced side-effect profile (ACE inhibition: increased bradykinin = cough)
Adapted from Matsubara. Circ Res 1998;83:1182–91
1Unger. JRAAS 2001;2(suppl 2):S4–S7
2Petrie et al. J Am Coll Cardiol 2001;37:1056–61
HF Patients Not Receiving an ACE-I
Data from the SPICE registry; N=9,580
9% Intolerant
2% High risk
3% New diagnosis
80%
On ACE-I
5% Unable to determine
1% Data missing
“Despite the proven benefits of ACE inhibitors, the
reported prevalence of ACE inhibitor use among
heart failure patients varies from 17% to 86%.”
Bart BA et al. Eur Heart J 1999
OPTIMAAL:
All-cause Mortality
25
Losartan (n=499 events)
Captopril (n=447 events)
Event rate (%)
20
15
10
5
Relative risk = 1.13 (0.99–1.28); p=0.069
0
Month
Losartan
Captopril
0
2,744
2,733
6
2,504
2,534
12
2,432
2,463
Dickstein et al. Lancet 2002
18
2,390
2,423
24
2,344
2,374
30
2,301
2,329
36
1,285
1,309
Early Treatment of Post-MI
Patients with LVSD/Acute HF
LVSD or
Acute HF
Severity of LV damage
Antiplatelet
+
Statin
+
Proven ACE-I
or
Losartan
50 mg qd
SAVE/AIRE/TRACE
OPTIMAAL
LVSD and
Acute HF
VALIANT
Acute MI (0.5–10 days)—SAVE, AIRE, or TRACE eligible
(either clinical/radiological signs of HF or LV systolic dysfunction)
Major exclusion criteria
– Serum creatinine >2.5 mg/dL
– BP <100 mmHg
– Prior intolerance of an ARB or ACE-I
– Non-consent
Double-blind, active-controlled
Captopril 50 mg tid
(n=4,909)
Valsartan 160 mg bid
(n=4,909)
Captopril 50 mg tid +
Valsartan 80 mg bid
(n=4,885)
Median duration: 24.7 months
Event-driven
Primary endpoint:
Secondary endpoints:
Other endpoints:
All-cause mortality
CV Death, MI, or HF
Safety and tolerability
Pfeffer et al. Am Heart J 2000;140:727–50
VALIANT: All-cause Mortality
Probability of event
0.30
Captopril
Valsartan
Valsartan + captopril
0.25
0.20
0.15
0.10
0.05
Valsartan vs captopril: HR=1.00; p=0.982
Valsartan + captopril vs captopril: HR=0.98; p=0.726
0
0
6
12
18
Time (months)
24
30
36
No. at risk
Captopril
4,909
4,428
4,241
4,018
2,635
1,432
364
Valsartan
4,909
4,464
4,272
4,007
2,648
1,437
357
Valsartan+Captopril 4,885
4,414
4,265
3,994
2,648
1,435
382
HR = hazard ratio
Pfeffer et al. N Engl J Med 2003;349:1893–906
VALIANT: Valsartan is Effective at Reducing
Cardiovascular Morbidity and Mortality
Hazard ratio
(97.5% CI)
p value
CV death
(1,657 events)
0.62
CV death or MI
(2,234 events)
0.25
CV death or HF
(2,661 events)
0.51
CV death,
MI, or HF
(3,096 events)
0.20
0.8
1
Favours valsartan
1.2
Favours captopril
Pfeffer et al. N Engl J Med 2003;349:1893–906
The Effect of Valsartan, Captopril or Both on
Atherosclerotic Events After Acute MI:
An Analysis of VALIANT
Patients with at least one event (%)
25
Captopril (n=4,909)
Valsartan (n=4,909)
20
Valsartan + captopril (n=4,885)
15
10
5
0
Myocardial
infraction
Angina
Revascularisation
Adapted from McMurray et al. Presented at ESC 2005
Stroke
Study Drug Discontinuation
0.4
Captopril
Probability of event
Valsartan
Valsartan + Captopril
0.3
All
0.2
Due
to
*
Adverse
*
Events
0.1
0
0
6
12
18
Months
*p<0.05 vs captopril
24
30
36
Early Treatment of AMI
Patients with LVSD/Acute HF
LVSD or
Acute HF
Severity of LV damage
Antiplatelet
+
Statin
+
Proven ACE-I
(Captopril)
or
Valsartan
160 mg bid
or
Captopril +
Valsartan
SAVE/AIRE/TRACE
VALIANT
LVSD and
Acute HF
CAPRICORN
Survival
1.00
Proportion Event-Free
Carvedilol
Placebo
0.95
0.90
0.85
0.80
0.75
p=0.031
OR 0.77 (0.60–0.98)
0.70
0
0.5
1
1.5
Years
The CAPRICORN Investigators. Lancet. 2001
2
2.5
EPHESUS
All-cause Mortality
10
Cumulative incidence (%)
9
8
7
6
5
4
3
Placebo
2
Eplerenone
RR = 0.79 (95% CI, 0.64–0.97)
p=0.03
1
0
0
3
6
9
12 15 18 21 24 27
Months since randomisation
30
33
36
Eplerenone
3,319
3,044
2,463
1,260
336
0
0
Placebo
3,313
2,983
2,418
1,213
323
2
0
Pitt et al. for EPHESUS Investigators. N Engl J Med 2003;348:1309–21
Early Treatment of AMI
Patients with LVSD/Acute HF
LVSD or
Acute HF
LVSD and
Acute HF
Severity of LV damage
Antiplatelet
+
Statin
+
Proven ACE-I
or
valsartan
160 mg bid
+
Eplerenone
25–50 mg qd
Carvedilol
SAVE/AIRE/TRACE
VALIANT
CAPRICORN
EPHESUS
Cardiac Events Following High-risk MI:
The VALIANT Experience
Cumulative incidence
0.50
Any CV event
0.40
0.30
Death
Heart failure
0.20
Recurrent MI
Sudden death or
cardiac arrest
0.10
0.00
0 YEAR 1
YEAR 2
YEAR 3
YEAR 4
The Framingham Heart Study: 1987
Cumulative probability of event
Risk of heart failure after MI
(Age 35 to 94 at diagnosis)
0.5
MI male
MI female
Matched male
Matched female
0.4
0.3
0.2
0.1
0
0
2
4
6
8
10
12
14
16
18
20
Years following MI
Cupples et al. The Framingham Study, NIH Publication No. 87–2703. 1987
Baseline BNP and NE and All-cause Mortality
BNP
NE
Survival probability
1.0
1.0
%
BNP
Mortality (pg/mL)
0.9
9.7
<41
0.8
14.3
41–97
0.7
20.7
98–238
0.6
%
NE
Mortality (pg/mL)
0.9
0.8
13.8
0.7
16.5 274–394
23.0 395–572
>572
24.2
0.6
32.4
0.5
>238
0.5
0
10
20
30
40
0
Time Since Randomization,
months
Anand IS. Circulation 2003;107:1278−83
10
20
30
40
Time Since Randomization,
months
<274
Kaplan-Meier Analysis of Cumulative Rates of Survival in Patients with
Heart Failure Chronically Treated With ACE Inhibitor Stratified By
Plasma Angiotensin II Levels
1.0
Normal Ang II
0.8
Ang II >16 pg.mL–1
0.6
0.4
0.2
p=0.0002
0
0
2
4
6
Months
Roig et al. Eur Heart J 2000;21:53–7
8
10
12
Val-HeFT: Study Design
5,010 heart failure patients
≥ 18 years old; NYHA II–IV; EF <40 %; LVIDd >2.9 cm/m2 of BSA
Receiving standard therapy
ACE inhibitors (93%), diuretics (86%),
digoxin (67%), beta-blockers (35%)
Randomized to
Valsartan 40 mg bid
titrated to 160 mg bid
Placebo
906 deaths (events recorded)
Primary endpoint was all-cause mortality and the combined
endpoint of all-cause mortality and heart failure morbidity
LVIDd = left ventricular internal diastolic diameter; BSA = body surface area
Cohn J et al. Eur J Heart Fail 2000;2:439–46
Probability of event-free survival
Val-HeFT: Valsartan Significantly Reduces Combined
Endpoint of Mortality and Morbidity in Overall Population
100
95
90
85
80
Valsartan (n=2,511)
13.2%
75
Risk
reduction**
70
Placebo (n=2,499)
65
0
0
3
6
9
12
15
18
Time (months)
21
24
27
Combined endpoint of mortality and morbidity: All-cause mortality, cardiac arrest
with resuscitation, hospitalisation for worsening heart failure, or therapy with IV
inotropes or vasodilators; **p=0.009
Cohn et al. N Engl J Med 2001;345:1667–75
Probability of event-free survival
Val-HeFT: Valsartan Significantly Reduces
Heart Failure-related Hospitalisations
100
95
90
85
Valsartan (n=2,511)
80
27.5%
75
Risk
reduction**
70
Placebo (n=2,499)
65
0
0
3
6
9
12
15
18
Time (months)
First hospitalisation
**p<0.001
Cohn et al. N Engl J Med 2001;345:1667–75
21
24
27
Val-HeFT: Reduction in Combined Morbidity/Mortality*
and Mortality With Valsartan (No ACE-I Subgroup)
Mortality
Combined morbidity/mortality
Placebo (n=181)
100
100
90
80
70
60
44.0% risk reduction
50
Proportion survived (%)
Probability of event-free survival
Valsartan (n=185)
90
80
70
33.1% risk reduction
60
p=0.0171
p=0.0002
40
50
0
3
6
9 12 15 18 21 24 27 30
Time since randomisation (month)
0
3
6
9 12 15 18 21 24 27 30
Time since randomisation (month)
*First morbid event, including death or hospitalisation
Adapted from Maggioni et al. J Am Coll Cardiol 2002;40:1414–21
CHARM-Added: CV Death or CHF
Hospitalization
50
538 (42%)
40
Placebo
483 (38%)
%
30
Candesartan
20
HR 0.85 (95% CI 0.75–0.96), p=0.011
Adjusted HR 0.85, p=0.010
10
0
0
Number at risk
Candesartan 1,276
Placebo
1,272
1
1,176
1,136
2
Years
1,063
1,013
3
3.5
948 457
906 422
McMurray et al. Lancet 2003;362:767–71
NNT = 14
Val-HeFT: Change in Plasma BNP and NE
Over Time
Valsartan
Placebo
n=844
40
n=1,710
0
p<0.001
n=1,886
n=1,696
n=829
30
n=1,890
p<0.001
p<0.001
n=823
–20
 NE* (pg/mL)
 Plasma BNP * (pg/mL)
20
p=0.005
p=0.001
p<0.001
n=1,835
n=1,605
n=800
20
10
n=1,633
0
n=1,850
–40
0
4
12
Time (months)
–10
24
0
4
12
Time (months)
*Mean ± SEM
Latini et al. J Card Fail 2001;7(Suppl 2):Abstract 198l
Anand et al. Circulation 2001;104(suppl II):Abstract 2813
24
Conclusions
 RAAS activation contributes to the chain of events
(atherosclerosis, LVH) leading to coronary artery disease
 Elevated RAAS activity is observed in post-MI HF and chronic HF
 Potential pharmacological benefits of AT1-receptor blockade versus
ACE inhibition
 In high-risk post-MI patients, valsartan is as effective as captopril in
reducing the risk of all-cause mortality, CV death, non-fatal MI or
hospitalisation for HF
 Valsartan reduces combined morbidity and mortality in patients
receiving prescribed therapy for chronic HF, predominantly
because of a reduction in HF hospitalisations