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Sponsored by Novartis Pharma AG
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
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
Sponsored by Novartis Pharma AG
7th Annual International Diovan Symposium
Lisbon, 3–5 February 2006
VARIABLE 3: Hypertension andMicroalbuminuria
Sponsored by Novartis Pharma AG
Pathophysiology of Microalbuminuria in Hypertension
Michel Burnier
CHUV, Lausanne, Switzerland
Definition of Microalbuminuria
24-hour urines Urine spot
Categorymg/24 hours µg/min mg/L
mg/mmol
creatinine
Normal <30 <20 <20 <2
Microalbuminuria 30–300 20–200 20–200 2–20
Macroalbuminuria >300 >200 >200 >20
Functional changes*
Proteinuria
Clinical type 2 diabetes
Structural changes†
Rising blood pressure
Rising serum creatinine levels
Cardiovascular death
Microalbuminuria
Onset of diabetes 2 5 10 20 30
Years
*Renal haemodynamics altered, glomerular hyperfiltration†Glomerular basement membrane thickening , mesangial expansion ,microvascular changes +/-
Natural History of Diabetic Nephropathy
End-stagerenal disease
Ang II
Increasedglomerularpressure
Ang II
Urinary proteinGlucose
AGEs
Glycoxidation (glycation)
Efferent arteriolar
constriction
= angiotensin AT1 receptor
Pathophysiological Processes Leading to Albuminuria and Glomerular Lesions
Glomerular permeability for macromolecules
Excessive reabsorption of proteins in the proximal tubule
Intracellular accumulation of protein degradation products
Gene activations chemokines and cytokinesGene activations chemokines and cytokines
Proliferation of fibroblasts and extracellular matrix
Development of fibrosis and renal atrophyRemuzzi et al. Kidney Int 1997;51:2–15
Albuminuria and Progression of Nephropathies
Diercks et al. Can J Cardiol 2002;18:525–35
Bigazzi1992
Calvino1999
Grandi2000
Pontremoli1997
Palatini1996
Jensen 1997
Mean
Prevalence of Microalbuminuria in Patients with Hypertension*
33.7
6.7 6.14.1
19.8
30.0
38.040
30
20
10
0
Pre
vale
nce
(%
)
*Defined as > 140/90 mmHg except Calvino, Palatini (135/85 mmHg)Jensen (> 140/90 mmHg or on AHY)
Pontremoli et al. Am J Hypertens 1998;11:430–8
Left ventricular mass index Intima/media thickness
Microalbuminuria is Associated with Left Ventricular Hypertrophy and Carotid Hypertrophy in Hypertensive Patients
200
150
100
50
0
LV
MI
(g/m
2)
C Ht AI– Ht AI+
1
0.8
0.6
0.4
0.2
0
IMT
(m
m)
C Ht AI– Ht AI+
******
***
**
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–
Odds ratio
Odds ratio for coronary heart disease
Microalbuminuria
Diabetes or insulin resistance
Treatment of hypertension
Current or ex-smoker
Body mass index (10 kg/m2)
Systolic BP
Male sex
Age (10 years)
Diastolic BP
Yudkin et al. Lancet 1988;2:530–3
Microalbuminuria as a Predictor of Vascular Disease in Non-diabetic Subjects
1 5 10 15 20
4
3
2
1
0
Rela
tive r
isk
MI/Stroke/CV death All-cause mortality CHF hospitalisation
Gerstein et al. JAMA 2001;286:421–6
Adjusted for age, sex, SBP/DBP, waist-hip ratio, diabetes and HbA1c
<0.22 0.22–0.57 0.58–1.62 >1.62
Microalbuminuria and Risk of CV Events, CHF and Death in the HOPE Trial
Alb/Crea (mg/mmol)
S. creat >124 µmol/L
Microalbuminuria Both
Systolic and diastolic BP NOT significant risk factors
Mann et al. Ann Intern Med 2001;134:629–36
Renal Insufficiency, Albuminuria and CV Survival in the HOPE Trial
HR
fo
r p
rim
ary
ou
tco
me
(CV
dea
th,
MI,
str
oke
)
2.5
2.0
1.5
1.0
0.5
0
Wachtell et al. J Hypertens 2002;20:405–12
LIFE study, 8,029 subjects with hypertensionand LV hypertrophy, mean age 66 years
Albuminuria and CV Diseases
Pre
vale
nce
(%
)
40
30
20
10
0 Diabetes Cerebrovascular Peripheral Coronarydisease vascular vascular
disease disease
NormoalbuminuriaMicroalbuminuria (Alb/Crea >3.5 mg/mmol)Macroalbuminuria (Alb/Crea >35 mg/mmol)
Composite Endpoints (CV Death, Non-fatal Stroke and MI) Stratified by Time-varying Albuminuria in the LIFE Trial
Ibsen et al. Hypertension 2005;45:198–202
En
dp
oin
t ra
te (
%)
2422201816141210
86420
Month
0 6 12 18 24 30 36 42 48 54 60 66
>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)
n=85,421 subjects, age: 28–75 years from the Groningen area
Hillege et al. Circulation 2002;106:1777–82
Microalbuminuria and Mortality in the General Population: the PREVEND Study
Haz
ard
ra
tio
CV death Non-CV death
6.05.55.04.54.03.53.02.52.01.51.00.5
0
Urinary albumin concentration (mg/L)
1 10 100 1,000
Urinary albumin concentration (mg/L)
1 10 1,00 1000
Haz
ard
ra
tio
6.05.55.04.54.03.53.02.52.01.51.00.5
0
Microalbuminuria and CV Complications in Hypertension: Is the Threshold Correct?The Copenhagen City Heart Study
Klausen et al. Hypertension 2005;46:33–7
4
3
2
1
0
4
3
2
1
0
30
20
10
0
Cu
mu
lati
ve m
ort
alit
y (%
)
RR
of
dea
thR
R o
f C
HD
<2.5 2.5–5 5–10 >10UAE (µg/min)
<2.5 2.5–5 5–10 >10
0 2 4 6 8 10 12Years from entry
UAE 4.8 µg/minUAE 4.8 µg/minUAE <4.8 µg/min
Cox-estimated age-adjusted curves of cumulative incidence of coronaryheart disease for a 60-year-old person based on 1,734 hypertensive
subjects with microalbuminuria and normoalbuminuria
Microalbuminuria and Incidence of CV Events: The Framingham Study
Arnlov et al. Circulation 2005;112:969–75
100
95
90
Per
cen
tag
e
0 1 2 3 4 5 6 7 8Years
< Median
Median
Survival free of CVDAccording to sex-specific median UACR
Microalbuminuria
What Links Microalbuminuria to CV Risk ?
Microalbuminuria (n=26)
Normoalbuminuria (n=45)
24-hour Blood Pressure Profile in Clinically Healthy Subjects With or Without Microalbuminuria
Clausen et al. Hypertension 1998;32:71–7
165
140
115
90
65
400
0 4 8 12 16 20 24Clock time
Blo
od
pre
ssu
re (
mm
Hg
)
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
Expression of Endothelial Dysfunction in Humans
Normoalbuminuria Elevated UAE
Flo
w-a
sso
ciat
ed d
ilat
atio
n (
%)
p<0.05
Flow-associated Vasodilation of Brachial Artery in Clinically Healthy Subjects According to Microalbuminuria
105
104
103
102
101
1000
Clausen et al. Circulation 2001;103:1869–74
Adapted from Dzau. Hypertension 2001;37:1047–52
Dyslipidaemia Hypertension Diabetes Smoking
Oxidative stress
Endothelial dysfunction
NO, local mediators, RAAS (Ang II)
Vasoconstriction Thrombosis Inflammation Plaque rupture Vascular lesionand remodelling
Pathobiological Processes Potentially Involved in the Development and Progression of Vascular Diseases
Chronic Kidney Disease and CV Risk
Traditional risk factors Non-traditional risk factors
Age
Sex
Hypertension
HDL and LDL cholesterol
Diabetes
Smoking
Physical activity
Family history of CVD
LVH
Albuminuria
Homocysteine
LP(a) and apolipoproteins
Anaemia
Ca/phosphate metabolism
Salt and water overload
Oxidative stress
Inflammation
Malnutrition
Thrombogenic factors
Sleep disturbance
NO/endothelin balance…
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-, IL-6 expression
Activation of monocytes and macrophages
Remodelling Stimulation of SMC migration, hypertrophy and replication
Induction of PDGF, FGF, IGF-1, TGF- 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
Vascular Effects of Angiotensin II
Early stage Late stage Terminal stage
Severity of renal disease
IRMA 2
MARVAL
IDNT
RENAAL
Microalbuminuria Macroalbuminuria ESRD
CV morbidity and mortality
Prevention ProtectionBenedict
Study
Normoalbuminuria
Angiotensin II Inhibition Retards the Progression of Renal Diseases
Reduction in Albuminuria Translates Into a Decrease in CV Events in Hypertensive Patients: LIFE Study
Ibsen et al. Hypertension 2005;45:198–202
High baseline/high year 1High baseline/low year 1Low baseline/high year 1Low baseline/low year 1
Follow-up (months)0 10 20 30 40 50 60 70
Fra
ctio
n s
uff
erin
g
co
mp
osi
te e
nd
po
int
0.20
0.15
0.10
0.05
0
Asselbergs et al. Circulation 2004;110:2809–16
Effect of Fosinopril on CV Event Rates in Patients with Microalbuminuria
1.00
0.98
0.96
0.94
0.92
0.90
0.10
0
Eve
nt-
free
su
rviv
al
0 10 20 30 40
Follow-up (months)
Placebo
Fosinopril
HR 0.60 [0.33–1.10], p=0.098 (Log-rank)
Event-free Survival According to the Level of Microalbuminuria
Eve
nt-
free
su
rviv
al
Follow-up (months)
1.00
0.95
0.90
0.85
0.80
0.10
0
UAE <50 mg/24 hours, placeboUAE >50 mg/24 hours, placeboUAE <50 mg/24 hours, fosinoprilUAE >50 mg/24 hours, fosinopril
0 10 20 30 40
p=0.008
Asselbergs et al. Circulation 2004;110:2809–16
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
Sponsored by Novartis Pharma AG
7th Annual International Diovan Symposium
Lisbon, 3–5 February 2006
Sponsored by Novartis Pharma AG
Point-CounterpointAre Benefits Beyond Blood Pressure Lowering Clinically Relevant?
Albuminuria-associated Disease:Are Benefits Beyond BP Lowering
Clinically Relevant?
Giancarlo Viberti, MDProfessor of Diabetes and Metabolic Medicine
Cardiovascular DivisionKCL School of Medicine
Guy’s HospitalKing’s College London
London, UK
Prospective Studies Collaboration. Lancet 2002;360:1903–13
Age-specific Relation of Usual BP to Vascular Mortality In Individuals With No Previous Vascular Disease
Adler et al. Kidney Int 2003;63:225–32
Annual Transition Rates Through Stages of Diabetic Nephropathy
No nephropathy
Microalbuminuria
Macroalbuminuria
Elevated plasma creatinine or renal replacement therapy
2.0%(1.9% to 2.2%)
2.8%(2.5% to 3.2%)
2.3%(1.5% to 3.0%)
1.4%(1.3% to 1.5%)
3.0%(2.6% to 3.4%)
4.6%(3.6% to 5.7%)
19.2%(14.0% to 24.4%)
SBP mmHg
24022020018016014012010080
AC
R m
g/m
mol
0.1
1
10
100
Relationship Between SBP and ACR in T2DM Patients with Different Degrees of AER
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 Hypertensionand Proteinuria In Type 2 Diabetes
Standardisedmortality ratio
Status of hypertension (H) and proteinuria (P) in type 2 diabetes
Wang et al. Diabetes Care 1996;19:305–12
0
500
1000
P-H- P-H+ P+H- P+H+ P-H- P-H+ P+H- P+H+Men Women
Epidemiology
Relative Risk of Cardiovascular Disease and Mortality in Diabetes Mellitus By Quartile of Albuminuria (ACR)
Gerstein et al. JAMA 2001;286:421–6
1st 2nd 3rd 4th
Variable <0.22 0.22–0.57 0.58–1.62 >1.62 p for trend
MI, strokeand CV death
1 0.85
(0.63–1.14)
1.11
(0.86–1.43)
1.89
(1.52–2.63)
<0.001
All-cause mortality
1 0.86
(0.58–1.28)
1.41
(1.01–1.95)
2.38
(1.80–3.20)
<0.001
CHF 1 0.72
(0.32–1.63)
1.83
(0.98–3.43)
3.65
(2.06–6.46)
<0.001
ACR (mg/mmol) quartiles RR (95% CI)
n=3,498
Rachmani et al. Diabetes Res Clin Pract 2000;49:187–94
Rate of eGFR Decline in Type 2 DM With Normoalbuminuria
AER categories:I = ≤10 mg/24hII = 10.1 to 20 mg/24hIII = 20.1 to 30 mg/24h
Survival Curves in Type 2 DM According To Baseline AER Category
AER categories:I = ≤10 mg/24hII = 10.1 to 20 mg/24hIII = 20.1 to 30 mg/24h
Rachmani et al. Diabetes Res Clin Pract 2000;49:187–94
ACR (mg/mmol)
Composite endpoint
<0.25≥0.25 to
<0.82≥0.82
to<1.62≥1.67
to<4.32≥4.32 to
<9.45P 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 = CVD death, fatal or non-fatal stroke, fatal or non-fatal MI
Albuminuria and CVD risk in hypertensive patients with LVHThe LIFE Study
Relative Risk of CVD and Mortality in5,545 High-risk Patients Without Diabetes by
Quartile of Albuminuria (ACR)
Gerstein et al. JAMA 2001;286:421–26
1st 2nd 3rd 4th
Variable <0.22 0.22–0.57 0.58–1.62 >1.62 p for trend
MI, stroke and CV death
1 1.24
(1.03–1.49)
1.54
(1.29–1.85)
1.83
(1.52–2.20)
<0.001
All-cause mortality
1 1.17
(0.93–1.47)
1.49
(1.19–1.87)
2.27
(1.82–2.82)
<0.001
CHF 1 1.45
(0.87–2.44)
1.86
(1.12–3.10)
2.93
(1.79–4.81)
<0.001
ACR (mg/mmol) quartiles RR (95% CI)
Arnlov et al. Circulation 2005;112:969–75
Albuminuria and Incidence of CVD Events in Non-hypertensive and Non-diabetic Subjects
The Framingham Heart Study
Median UAER:M: 3.9 μg/mg F: 7.5 μg/mg
Survival free of CVDAccording to sex-specific median UACR
Klausen et al. Circulation 2004;110:32–35
Albuminuria and Risk of CHD and Death In The General Population
Third Copenhagen City Heart Study
25%-ile: 2.1 μg/min50%-ile: 3.0 μg/min75%-ile: 4.8 μg/min
Hillege et al. Circulation 2002;106:1777–82
Albuminuria and CVD/Non-CVD Mortality in The General Population
PREVEND Study
The Clinical Trial Evidence
Change in AER Predicts Loss of GFR
Rossing et al. Diabetologia 1994;37:511–16
*Proteinuria measured as the urine albumin:creatinine ratio from a first morning void
0 12 24 36 48Months
Medianpercent change
-60
-40
-20
0
20
40
751 661 558 438 167L (+CT)P (+CT) 762 632 529 390 130
p=0.0001 35% overall reduction
RENAAL: Change From Baselinein Proteinuria*
Placebo
Losartan
Brenner et al. N Engl J Med 2001;345:861–9
RENAAL: Baseline Proteinuria As A Determinant of Renal Events In T2DM
De Zeeuw et al. Kidney Int 2004;65:2309–20
Composite Endpoint ESRD
0 12 24 36 48
Month
0
20
40
60
80
100
% w
ith r
enal
end
poin
t
3.0 g/24h
<1.5 g/24h
0 12 24 36 48
Month
0
20
40
60
80
100
% w
ith E
SR
D e
ndpo
int
3.0 g/24h
<1.5 g/24h
RENAAL: Baseline Proteinuria As A Determinant For Cardiac Events In T2DM
De Zeeuw et al. Circulation 2004;110:921–7
CV Endpoint Heart Failure
0 12 24 36 48
Month
0
20
40
60
% w
ith C
V e
ndpo
int
≥3.0g/24h
<1.5 g/24h
0 12 24 36 48
Month
0
20
40
60
% w
ith h
eart
failu
re e
ndpo
int
3.0 g/24h
<1.5 g/24h
RENAAL: Initial Antiproteinuric Response vs Renal Risk
Albuminuria reduction (%)
-90 -25 0 25 50 72
Albuminuria reduction (%)
0.0
0.5
1.0
1.5
2.0
2.5
Haz
ard
ratio
-90 -25 0 25 50 72
Renal Endpoint ESRD
0.0
0.5
1.0
1.5
2.0
2.5
De Zeeuw et al. Kidney Int 2004;65:2309–20
RENAAL: Proteinuria Reduction (<0% versus >30%) Determines the Cardiovascular Outcome
CV Endpoint Heart Failure
0 12 24 36 48
Month
0
10
20
30
40
% w
ith C
V e
ndpo
int >30%
<0%
0 12 24 36 48
Month
0
10
20
30
40
% w
ith h
eart
failu
re
<0%
>30%
De Zeeuw et al. Circulation 2004;110:921–7
Viberti et al. Circulation 2002;106:672–8
Mean BP change (mmHg)
-11.2 -11.6
-6.6 -6.5
SBP DBP
UAER (µg/min)
0
10
20
30
40
50
60
70
Valsartan Amlodipine
p <0.001
Baseline
Valsartan 24 Wks
Amlodipine 24 Wks
The MARVAL Study
0
2
4
6
8
10
12
Changes In BP and AER By Valsartan and Amlodipine in T2DM Patients With Microalbuminuria
70
80
90
100
110
120
130
140
150
160
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48
Systolic
Diastolic
Art
eri
al b
loo
d p
ress
ure
(m
mH
g)
Follow-up (months)
VerapamilTrandolapril
Trandolapril plus VerapamilPlacebo
Ruggenenti et al. N Engl J Med 2004
Blood Pressure According To Treatment Group
0
5
10
15
0 6 12 18 24 30 36 42 48
Cu
mu
lati
ve
inci
den
ce o
f m
icro
alb
um
inu
ria
(%)
Follow-up (months)
601
603
503
463
469
424
441
405
417
376
399
357
380
338
311
270
220
188
No. at risk
ACE inhibitor
No ACE inhibitor
No ACE inhibitor(66 events)
ACE inhibitor (35 events)
20
A.F. (95 % C.I.) = 0.44 (0.27 – 0.70) p=0.001
Ruggenenti et al. N Engl J Med 2004
Ibsen et al. Hypertension 2005;45:198–202
Rate of CVD Events By Time-varying Albuminuria In Subjects With Essential Hypertension and LVH
The LIFE Study
Composite endpointCV death, fatal or non-fatal stroke,fatal or non-fatal MI
Lea et al. Arch Intern Med 2005;165:947–953
Risk of ESRD vs Initial Change( 6–0 months) in Proteinuria in African Americans with Hypertension
and Non-diabetic Kidney DiseaseAASK
How do we obtain better evidence?
Antihypertensive and Antiproteinuric Responses To Increasing ACE-I Dose
% reduction vs control
-80
-70
-60
-50
-40
-30
-20
-10
05 mg 10 mg 15 mg 20 mg
Lisinopril dose (mg)
BP Urinary protein
Adapted from Palla et al. Int J Clin Pharmacol Res 1994;14:35–43
ConclusionsAlbuminuria 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
Sponsored by Novartis Pharma AG
Are Benefits Beyond BP Lowering Clinically Relevant? No
Giuseppe Mancia
University of Milan-Bicocca, Italy
The Question
Does BP reduction per se substantially contribute to CV protection (i.e. reduction in CV morbidity and mortality) in hypertension?
* BP –2/–1 mmHg
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*
SBP difference between randomised groups (mmHg)Turnbull et al. Lancet 2003;362:1527–35
Rel
ati
ve
risk
of
ou
tco
me
eve
nt
Metanalysis of Trials Comparing Different Treatments or Treatment Versus Placebo in Hypertension
1.50
1.25
1.00
0.75
0.50
0.25–10 –8 –6 –4 –2 0 2 4
Stroke1.50
1.25
1.00
0.75
0.50
0.25–10 –8 –6 –4 –2 0 2 4
Major CVD1.50
1.25
1.00
0.75
0.50
0.25–10 –8 –6 –4 –2 0 2 4
CHD
1.50
1.25
1.00
0.75
0.50
0.25–10 –8 –6 –4 –2 0 2 4
CVD death1.50
1.25
1.00
0.75
0.50
0.25–10 –8 –6 –4 –2 0 2 4
Total mortality
Rel
ati
ve
risk
of
ou
tco
me
eve
nt
VALUE: Analysis of Results Based on BP Control at 6 Months
Fatal/non-fatal cardiac events
Fatal/non-fatal stroke
All-cause death
Myocardial infarction
Heart failure hospitalisations
*p<0.01; †SBP <140 mmHg at 6 months
Patients treated with valsartan Patients treated with amlodipine
Hazard ratio 95% CI
0.4 0.6 0.8 1.0 1.2
Controlled patients†
(n=5,253)
Non-controlled patients(n=2,396)
*
*
*
*
0.4 0.6 0.8 1.0 1.2
Controlled patients†
(n=5,502)
Non-controlled patients(n=2,094)
Hazard ratio 95% CI
*
*
*
*
0.76 (0.66–0.88)
0.60 (0.48–0.74)
0.79 (0.69–0.91)
0.83 (0.66–1.03)
0.62 (0.50–0.77)
Odds ratio
0.73 (0.63–0.85)
0.50 (0.39–0.64)
0.79 (0.69–0.92)
0.91 (0.71–1.17)
0.64 (0.52–0.79)
Odds ratio
Weber et al. Lancet 2004;363:2047–49
StrokeFatalNon-fatal
All CV eventsAll cardiac eventsAll-cause deathCV deathCoronary eventsHeart failureNew-onset diabetesCancer
Felodipine(138.1/82.3 mmHg)
11.2 2.1 9.115.2 4.6 7.1 4.6 4.5 1.1 3.1 2.6
Placebo(141.6/83.9 mmHg)
15.9 3.112.721.2 6.6 9.6 6.4 6.2 1.7 2.7 3.9
Hazard ratio (95% CI)
Per 1,000 patient-years
0.4 0.6 0.81.0 1.5 2.0
Felodipine better Placebo better
0.72 0.70 0.72 0.72 0.66 0.70 0.68 0.68 0.76 1.03 0.60
FEVER: Endpoint Analysis (First Time Occurrence in Each Category)
Liu Lisheng et al. J Hypertens 2005
Turnbull et al. Arch Intern Med 2005;165:1410–19
*Statistically significant
More Versus Less Intensive Treatmentin DM +
DM + (n=3,599) BP –6.0/–4.6 mmHg
TotalStroke CHD CHF CVD CV death mortality
0
–10
–20
–30
–40–36*
–16
–31
–25*
–33
–27*
Ris
k ra
tio
MI (fatal + non-fatal)<25% 1.0025%–<50% 0.70 (0.57–0.86)50%–<75% 0.63 (0.53–0.76)75% 0.55 (0.46–0.65)
Clinical Outcomes – Unadjusted
0.40 0.60 0.80 1.00 1.20HR (95% CI)
Reduced riskPercent of visits with BPcontrol (<140/90 mmHg) HR (95% CI)Primary outcome<25% 1.0025%–<50% 0.67 (0.59–0.76)50%–<75% 0.60 (0.53–0.67)75% 0.54 (0.48–0.61)
Increased risk
Group with <25% of visits with BP control used as referencePrimary Outcome = first occurrence of death (all cause), non-fatal MI, or non-fatal stroke
BP control by visit
Stroke (fatal + non-fatal)<25% 1.0025%–<50% 0.88 (0.66–1.18)50%–<75% 0.62 (0.47–0.82)75% 0.43 (0.32–0.58)
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
DiabetesNo diabetesCurrent smokerNon-current smokerObeseNon-obeseLVHNo LVHOlder (>60 years)Younger (≤60 years)FemaleMalePrevious vascular diseaseNo previous vascular diseaseRenal dysfunctionNo renal dysfunctionWith metabolic syndromeWithout metabolic syndrome
1.000.80 1.50
Amlodipine/perindopril(BP 164.1/94.8 135.5/79.1 mmHg)
Atenolol/thiazide(BP 163.9/94.5 136.3/78.4 mmHg)
0.70 0.90
2.9/1.7 mmHg
ACE-I versus D/BBDiabetesNo diabetesOverall
CA versus D/BBDiabetesNo diabetesOverall
ACE-I versus CADiabetesNo diabetesOverall
BP (mmHg)
–0.5/0.1 0.6/0.1
0.7/–0.6 1.4/–0.2
0.4/1.2 0.4/0.8
RR (95% CI)
0.90 (0.74–1.11)1.04 (0.98–1.10)p homog = 0.19
0.95 (0.82–1.10)1.04 (0.98–1.10)p homog = 0.82
0.92 (0.79–1.07)0.99 (0.92–1.07)p homog = 0.37
I2 (%)
55 0
00
00
Turnbull et al. Arch Intern Med 2005;165:1410–19
Favoursfirst
Favourssecond
0.25 0.5 1 2Risk ratio
Major CVD with ACE-I Versus D/BB Versus CA
Blood Pressure Lowering Treatment Trialists’ Collaboration
Outcome
Stroke
Major CHD
Heart failure
Trial
ELITE IIOPTIMAALVALIANTOverall
ELITE IIOPTIMAALVALIANTOverall
ELITE IIOPTIMAALVALIANTOverall
Relative risk (95% CI)
1.63 (0.77–3.44)1.06 (0.84–1.33)0.95 (0.76–1.17)1.02 (0.87–1.19)
1.24 (1.00–1.55)1.01 (0.88–1.15)0.97 (0.89–1.05)1.03 (0.92–1.16)
0.87 (0.59–1.28)1.14 (0.99–1.31)1.01 (0.93–1.11)1.05 (0.95–1.15)
Favours ARB Favours ACE-I
0.5 1.0 1.5Relative risk
Meta-analysis of Trials Comparing ACE-I-based with ARB-based Regimens for the Outcomes of Stroke, CHD and Heart Failure
Volpe et al. J Hypertens 2005;23:2113–18
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 1.1 1.2 1.3 1.4
Favours other drugFavours ARB
Relative Risk of MI for ARBs and ACE-Is Versus Active Drugs and Placebo
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)
BPreduction
Drug
Mancia, 2004
Short-term Protection
May Event-based Trials Underestimate Potential Differences Between Drugs?
Trial limitations
– High-risk patients
– Patients’ drop-out/cross-over (dilution factor)
– Short-term duration
Prevention of events not superimposable to prevention of disease
Pseudoequivalence?
Probably not
Yes, minor
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Differences Between Drugs on Factors Responsible for Progression of Disease
BP lowering
Lipid profile
Insulin resistance
New-onset diabetes
Metabolic syndrome
LVH progression/regression
Small vessel remodelling
Large artery structure/function/atherosclerosis
Renal protection
Short-termprotection
Long-termprotection
BPreduction
Drug
BPreduction
Drug
Role of Drug-specific Properties Versus BP Reduction per se in CV Protection of Hypertensive Patients
Mancia, 2004
?
Parving et al. Lancet 1983;2:1175–9
MA
P(m
mH
g)
GF
R(m
l/m
in/1
.73
m2)
Alb
um
inu
ria
(g
/min
)
Start of treatment
Effect of Antihypertensive Treatment (n=10)
–30 –24 –18 –12 –6 0 6 12 18 24 30 36
125
115
105
95105
95
85
75
65
1,250
750
250
Months
Sponsored by Novartis Pharma AG
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
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
II
III
IV
II
V5
aVR V1 V4
aVL
aVF
V2
V3
V5
V6
Echo = Ejection fraction 35%; dilated left ventricle
Sponsored by Novartis Pharma AG
The Multiplicative Effect of Global Risk Factors in Post-MI HF Patients: The Root Cause
Peter Liu
University of Toronto, Canada
Incidence of Post-MI HF
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
Based on the 44-year follow-up of the NHLBI’s Framingham Heart Study…
2.5
16
2.2
13
86
0.91.42.3
7.1
0
5
10
15
20
25
Death Reinfarction AF Stroke LOS (days)
Pat
ien
ts (
%)
HF/LVSD (n=2,347) No HF/LVSD (n=3,219)
VALIANT Registry: In-hospital Clinical Events Among Post-MI Patients With and Without HF/LVSD
LVSD = left ventricular systolic dysfunction; AF = atrial fibrillationLOS = length of stay
Velazquez et al. Eur Heart J 2004;25:1911–9
Beta-blocker: Carvedilol Post-MI Reduces Cardiovascular Mortality
Adapted from The CAPRICORN Investigators. Lancet 2001;357:1385–90
Pro
po
rtio
n E
ven
t-fr
ee
0 0.5 1.0 1.5 2.0
Time (years)
1.00
0.90
0.80
0.70
0.60
0
Carvedilol n=975
Placebo n=984
Risk reduction: 25% (4%, 42%)
p=0.024
Cardiovascular mortality rates:placebo 14%; carvedilol 11%
0
2
4
6
8
10
12
Day 28 Day 29 to 1 year Composite
Antiplatelet Therapy: Clopidogrel and AspirinReduce Risk of Death, MI or Stroke at One Year
Adapted from Steinhubl et al. for the CREDO Investigators. JAMA 2002;288:2411–20
Dea
th,
MI,
or
stro
ke (
%)
RRR = Relative risk reduction; NS = non significant
5.5
6.9
2.9
4.6
8.5
11.5
RRR19.7%p=NS RRR
37.4%p=0.04
RRR 26.9%p=0.02
Aspirin/clopidogrel
Placebo
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)
Serruys et al. JAMA 2002;287:3215–19
100
90
80
70Pat
ien
ts f
ree
fro
m M
AC
E (
%)
0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0Time post-randomisation (years)
Placebo(n=833)
Fluvastatin (80 mg/d, n=844)
Risk reduction
= 22%
0
PCI = percutaneous coronary intervention; MACE = Major Adverse Cardiac Events
Modified from Jessup and Brozena. New Engl J Med 2003;348:2007–18
Remodelling Post MI: Renin–Angiotensin Activation
Initial infarct Infarct expansion(hours to days)
Global remodelling(days to months)
Acute Ischemia
IschemicMyocytes
ECMOsteopontinTIMPs, MMPs
Chronic Repair
ApoptoticMyocytes
HypertrophiedMyocytes
CytokineAII, OFR
AngiogenesisVEGF, AngiopoietinsIntergin 3
= Neutrophils = Macrophages
Mechanical stressOxydative stressHypoxia
Initial cytokine release
= Monocyte
NecroticMyocytes
Cytokine Angiotensin
= 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
Valgimigli et al. Circulation 2005;111:863–70
Group 1: made up of patients free from death and HF; Group 2: patients with HF and/or death
Infl
amm
ato
ry c
yto
kin
e le
vels
80
70
60
50
40
30
20
10
0
p<0.0001
p<0.01TNF- IL- 6
Group 1 Group 2 Group 1 Group 2(n=140) (n=44) (n=141) (n=30)
Intrahospital Follow-up
p<0.0001
p<0.01
0
10
3,000
4,000
5,000
202,000
Control
Deoxyuridine triphosphate labelling
Nu
mb
er o
f la
bel
led
myo
cyte
N
ucl
ei/1
06 N
ucl
ei
CM = cardiomyopathy; DCM = dilated cardiomyopathy
Olivetti et al. N Engl J Med 1997;336:1131–41
Propidium Iodide
Deoxyuridine Triphosphate
IschaemicCM
IdiopathicDCM
Apoptosis in the Failing Human Heart
Matrix Metalloproteinase (MMP) post MI
uPA/PlasminuPA/PlasminMTMMP/ADAMsMTMMP/ADAMsIL-1, CD40IL-1, CD40
TNF, EMPRINNTNF, EMPRINN
OFR, ChymaseOFR, ChymaseACE / AIIACE / AII
ZnZn
Sun et al. Circulation 2004;110:3221–8;Kassiri et al. Circulation Research 2005;97:380–90
TIMP3
MMP InhibitorsACEi/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)
Angiotensinogen
Non-ACE pathways(e.g. chymase)
Vasoconstriction Cell growth Na/H2O retention Sympathetic activation
ReninAngiotensin I
Angiotensin II
ACE
Cough,angio-oedema
benefits? Bradykinin
Inactivefragments
Vasodilation Antiproliferation
(kinins)
Aldosterone
AT1 receptor
AT2 receptor
ACE = angiotensin-converting enzyme;AT1 = angiotensin II type 1; AT2 = angiotensin II type 2
Post-MI Remodelling: Ang II Modulationby RAAS Blockade
Control Ang II modulation
Effects of ACE Inhibitor Treatment onAll-Cause Mortality Post-MI
EF = ejection fraction; OR = odds ratioFlather et al. Lancet 2000;355:1575–81
ACE inhibitor
Placebo
OR: 0.74 (0.66–0.83)OR: 0.74 (0.66–0.83)
ACE inhibitor: 702/2995 (23.4%)ACE inhibitor: 702/2995 (23.4%)
Placebo: 866/2971 (29.1%)Placebo: 866/2971 (29.1%)
TRACEEchocardiographicEF ≤ 35%
AIREClinical and/or radiographic signs of HF
SAVERadionuclideEF ≤ 40%
Pro
bab
ility
of
even
t
0.40
0.35
0.30
0.25
0.20
0.15
0.10
0.05
0.0Years 0 1 2 3 4
2,995 2,250 1,617 892 223ACE inhibitor
2,971 2,184 1,521 853 138Placebo
VALIANT: Valsartan Shows Non-inferiority to ACE Inhibitors
Hazard ratio for death from any cause
Favoursactive drug
Favoursplacebo
Pfeffer et al. N Engl J Med 2003;349:1893–906
0.5 1 2
SAVE, TRACE andAIRE combined
TRACE
SAVE
AIRE
VALIANT
(Imputed placebo)
Valsartan
preserves
99.6% of the
mortality
benefit of
captopril
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
Sponsored by Novartis Pharma AG
RAAS Blockade in Post-MI HF and Chronic HF: What’s the Evidence for This Treatment Strategy?
Eric J Velazquez
Duke University, Durham, USA
Target organdamage
Risk factors:diabetes,
hypertension
Vascular dysfunction
Atherosclerosis and LVH
Tissue injury(MI, stroke)
Pathologicremodelling
Target organdysfunction (HF, renal)
Endstageorgan failure
Death
Oxidative stress/endothelialdysfunction
LVH = left ventricular hypertrophyMI = myocardial infarction; HF = heart failure
Adapted from Dzau and Braunwald. Am Heart J 1991;121:1244–63
The Cardiovascular Continuum
AT1 receptor
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
1http//www.who.int/cardiovascular_diseases2American Heart Association. 2005 Heart and Stroke Statistical Update. 2004
*Coronary attack=definite or probable MI, or fatal CHDCHD=coronary heart disease
MI and CAD: Secondary Prevention
Treatment objectives
Improve survival
Prevent reinfarction
Prevent LV remodelling
Prevent progression to
HF
Reduce risk of arrhythmias
How can we help thesehigh-risk patients?
Severity of LV damage
Antiplatelet
Statin
Treatment of Post-MIPatients with LVSD/Acute HF
LVSD or Acute HF
LVSD and Acute HF
+
Flather et al. Lancet 2000;355:1575–81*Odds ratio (95% CI)
Readmission for HF
n = 460
n =355
(0.63 – 0.85)
0.73*
Reinfarction
n=324
n=391
(0.69 – 0.95)
0.80*
Placebo (n=2,971)ACE-I (n=2,995)
Death/MI or Readmission for HF
Eve
nts
(%
)
0
10
20
30
40
n =1,049
n =1244
(0.67–0.83)
0.75*
TRACEEchocardiographicEF 35%
AIREClinical and/or radiographic signs of HF
SAVERadionuclideEF 40%
Death and Major CV Events
+
Proven ACE-I
SAVE/AIRE/TRACE
Early Treatment of Post-MIPatients with LVSD/Acute HF
Severity of LV damage
Antiplatelet
Statin
LVSD or Acute HF
LVSD and Acute HF
+
Potential Pharmacological Benefits of AT1-receptor Blockade Versus ACE Inhibition
AT1-R antagonists ACE inhibitorsChymase
Ang II
AT2 AT1 AT1 AT2 NO
NO
Prostagladins
CardioprotectionVasodilationNegative chronotropismAnti-fibrosisAnti-growth
CardioprotectionVasodilation
Plasma Ang II Plasma Ang II Bradykinin
Cardioprotective effects via angiotensin II binding to AT2 receptor
Angiotensin II generated by non-ACE dependent pathways1,2 also blocked from binding to the AT1 receptor
Reduced side-effect profile (ACE inhibition: increased bradykinin = cough)
Adapted from Matsubara. Circ Res 1998;83:1182–911Unger. JRAAS 2001;2(suppl 2):S4–S7 2Petrie et al. J Am Coll Cardiol 2001;37:1056–61
(–) (–) (+) (–) (–)
Bart BA et al. Eur Heart J 1999
Data from the SPICE registry; N=9,580
“Despite the proven benefits of ACE inhibitors, the reported prevalence of ACE inhibitor use among heart failure patients varies from 17% to 86%.”
80%
9%
5%
1%
3%
2%
On ACE-I
Intolerant
High risk
New diagnosis
Unable to determine
Data missing
HF Patients Not Receiving an ACE-I
OPTIMAAL:All-cause Mortality
Month 6 12 18 24 30 36
0
5
10
15
20
25
Eve
nt
rate
(%
)
Captopril (n=447 events)
Relative risk = 1.13 (0.99–1.28); p=0.069
0
Losartan (n=499 events)
Losartan 2,744 2,504 2,432 2,390 2,344 2,3011,285Captopril 2,733 2,534 2,463 2,423 2,374 2,3291,309 Dickstein et al. Lancet 2002
+
Antiplatelet
Statin
Proven ACE-I
or
Losartan
50 mg qd
SAVE/AIRE/TRACEOPTIMAAL
Early Treatment of Post-MIPatients with LVSD/Acute HF
+
Severity of LV damage
LVSD or Acute HF
LVSD and Acute HF
VALIANT
Primary endpoint: All-cause mortalitySecondary endpoints: CV Death, MI, or HFOther endpoints: Safety and tolerability
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)
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
Median duration: 24.7 monthsEvent-driven
Pfeffer et al. Am Heart J 2000;140:727–50
VALIANT: All-cause Mortality
HR = hazard ratio Pfeffer et al. N Engl J Med 2003;349:1893–906
Valsartan 4,909 4,464 4,272 4,007 2,648 1,437 357
Captopril 4,909 4,428 4,241 4,018 2,635 1,432 364
Valsartan+Captopril 4,885 4,414 4,265 3,994 2,648 1,435 382
Captopril0.30
0.25
0.20
0.15
0.10
0.05
00 6 12 18 24 30 36
Pro
bab
ility
of
even
t
No. at risk
Valsartan vs captopril: HR=1.00; p=0.982Valsartan + captopril vs captopril: HR=0.98; p=0.726
Valsartan
Valsartan + captopril
Time (months)
VALIANT: Valsartan is Effective at Reducing Cardiovascular Morbidity and Mortality
Hazard ratio(97.5% CI) p value
0.8 1 1.2
CV death(1,657 events)
0.62
CV death or HF(2,661 events)
0.51
CV death or MI(2,234 events)
0.25
CV death, MI, or HF
(3,096 events)0.20
Favours valsartan Favours captopril
Pfeffer et al. N Engl J Med 2003;349:1893–906
Captopril (n=4,909)
The Effect of Valsartan, Captopril or Both on Atherosclerotic Events After Acute MI: An Analysis of VALIANT
Valsartan (n=4,909)
Valsartan + captopril (n=4,885)
25
20
15
10
5
0
Pat
ien
ts w
ith
at
leas
t o
ne
even
t (%
)
Myocardial Angina Revascularisation Stroke infraction
Adapted from McMurray et al. Presented at ESC 2005
0
0.1
0.2
0.3
0.4
0 6 12 18 24 30 36
Months
Pro
bab
ilit
y o
f ev
ent
Study Drug Discontinuation
All
Due to Adverse Events
*p<0.05 vs captopril
*
Captopril
Valsartan + Captopril
Valsartan
*
+Antiplatelet
+
Statin
Proven ACE-I (Captopril)orValsartan 160 mg bidorCaptopril + Valsartan
SAVE/AIRE/TRACE
Early Treatment of AMIPatients with LVSD/Acute HF
VALIANT
Severity of LV damage
LVSD or Acute HF
LVSD and Acute HF
0.70
0.75
0.80
0.85
0.90
0.95
1.00
0 0.5 1 1.5 2 2.5
Years
Pro
po
rtio
n E
ven
t-F
ree
p=0.031OR 0.77 (0.60–0.98)
CAPRICORNSurvival
Carvedilol
Placebo
The CAPRICORN Investigators. Lancet. 2001
EPHESUSAll-cause Mortality
Pitt et al. for EPHESUS Investigators. N Engl J Med 2003;348:1309–21
Months since randomisation0 3 6 9 12 15 18 21 24 27 30 33 36
Cu
mu
lati
ve in
cid
ence
(%
)
10
9
8
7
6
5
4
3
2
1
0
RR = 0.79 (95% CI, 0.64–0.97)p=0.03
Placebo
Eplerenone
Eplerenone 3,319 3,044 2,463 1,260 336 0 0
Placebo 3,313 2,983 2,418 1,213 323 2 0
Severity of LV damage
+ +
Antiplatelet
Statin
Proven ACE-I
orvalsartan 160 mg bid
Eplerenone
25–50 mg qd
SAVE/AIRE/TRACEVALIANT
CAPRICORN
EPHESUS
Early Treatment of AMIPatients with LVSD/Acute HF
LVSD or Acute HF
LVSD and Acute HF
+
Carvedilol
0.00
0.10
0.20
0.30
0
Death
0.40
0.50Any CV event
YEAR 1 YEAR 2 YEAR 3 YEAR 4
Cardiac Events Following High-risk MI: The VALIANT Experience
Cu
mu
lati
ve in
cid
enc
e
Heart failure
Recurrent MISudden death or cardiac arrest
The Framingham Heart Study: 1987
Cupples et al. The Framingham Study, NIH Publication No. 87–2703. 1987
Cu
mu
lati
ve p
rob
abili
ty o
f ev
ent
Years following MI
Risk of heart failure after MI(Age 35 to 94 at diagnosis)
0 2 4 6 8 10 12 14 16 18 20
0.5
0.4
0.3
0.2
0.1
0
MI maleMI femaleMatched maleMatched female
Time Since Randomization, months
Su
rviv
al p
rob
abil
ity
2010 300 40
BNP(pg/mL)
<41
41–97
98–238
>238
BNP
0.5
0.6
0.7
0.8
1.0
0.9
9.7
14.3
20.7
32.4
% Mortality
NE
Time Since Randomization,months
>572
<274
274–394
395–572
NE(pg/mL)
0.5
0.6
0.7
0.8
1.0
0.9
24.2
% Mortality
13.8
16.5
23.0
2010 300 40
Anand IS. Circulation 2003;107:1278−83
Baseline BNP and NE and All-cause Mortality
Kaplan-Meier Analysis of Cumulative Rates of Survival in Patients with Heart Failure Chronically Treated With ACE Inhibitor Stratified By Plasma Angiotensin II Levels
Roig et al. Eur Heart J 2000;21:53–7
p=0.0002
Ang II >16 pg.mL–1
Normal Ang II1.0
0.8
0.6
0.4
0.2
00 2 4 6 8 10 12
Months
LVIDd = left ventricular internal diastolic diameter; BSA = body surface areaCohn J et al. Eur J Heart Fail 2000;2:439–46
Val-HeFT: Study Design
Primary endpoint was all-cause mortality and the combined endpoint of all-cause mortality and heart failure morbidity
5,010 heart failure patients≥ 18 years old; NYHA II–IV; EF <40 %; LVIDd >2.9 cm/m2 of BSA
Randomized to
ACE inhibitors (93%), diuretics (86%),digoxin (67%), beta-blockers (35%)
Valsartan 40 mg bid titrated to 160 mg bid Placebo
Receiving standard therapy
906 deaths (events recorded)
Val-HeFT: Valsartan Significantly Reduces Combined Endpoint of Mortality and Morbidity in Overall Population
Cohn et al. N Engl J Med 2001;345:1667–75
Time (months)
100
95
90
85
80
75
70
65
0Pro
bab
ility
of
even
t-fr
ee s
urv
ival
Valsartan (n=2,511)
Placebo (n=2,499)
13.2%Risk
reduction**
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
0 3 6 9 12 15 18 21 24 27
First hospitalisation**p<0.001
Cohn et al. N Engl J Med 2001;345:1667–75
Placebo (n=2,499)
Val-HeFT: Valsartan Significantly Reduces Heart Failure-related Hospitalisations
27.5%Risk
reduction**
Valsartan (n=2,511)
Time (months)
100
95
90
85
80
75
70
65
00 3 6 9 12 15 18 21 24 27
Pro
bab
ility
of
even
t-fr
ee s
urv
ival
Val-HeFT: Reduction in Combined Morbidity/Mortality*and Mortality With Valsartan (No ACE-I Subgroup)
*First morbid event, including death or hospitalisation
Valsartan (n=185) Placebo (n=181)
Time since randomisation (month)
p=0.0002
44.0% risk reduction
Pro
bab
ilit
y o
f ev
ent-
fre
e s
urv
ival
p=0.0171
33.1% risk reduction
Combined morbidity/mortality Mortality
Adapted from Maggioni et al. J Am Coll Cardiol 2002;40:1414–21
100
90
80
70
60
50
400 3 6 9 12 15 18 21 24 27 30
Time since randomisation (month)
100
90
80
70
60
500 3 6 9 12 15 18 21 24 27 30
Pro
po
rtio
n s
urv
ived
(%
)
CHARM-Added: CV Death or CHF Hospitalization
McMurray et al. Lancet 2003;362:767–71
0 1 2 3 3.5
50
40
30
20
10
0
Years
Placebo
Candesartan
%
HR 0.85 (95% CI 0.75–0.96), p=0.011Adjusted HR 0.85, p=0.010
Number at risk
Candesartan 1,276 1,176 1,063 948 457
Placebo 1,272 1,136 1,013 906 422
538 (42%)
483 (38%)
NNT = 14
Val-HeFT: Change in Plasma BNP and NE Over Time
*Mean ± SEMLatini et al. J Card Fail 2001;7(Suppl 2):Abstract 198l Anand et al. Circulation 2001;104(suppl II):Abstract 2813
20
0
–20
–40
P
lasm
a B
NP
* (
pg
/mL
)
N
E*
(pg
/mL
)
40
30
20
10
0
–100 4 12 24
Time (months)0 4 12 24
Time (months)
n=1,890
n=1,710
n=1,850
n=1,633
n=823
p<0.001 p<0.001 p<0.001
n=844
n=1,886 n=1,696
n=1,835 n=1,605 n=800
p=0.005 p=0.001 p<0.001
n=829
Valsartan Placebo
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