Sponsored by Novartis Pharma AG 7th Annual International Diovan Symposium Lisbon, 3–5 February...

141
Sponsored by Novartis Pharma AG 7th Annual International Diovan Symposium Lisbon, 3–5 February 2006

Transcript of Sponsored by Novartis Pharma AG 7th Annual International Diovan Symposium Lisbon, 3–5 February...

Page 1: Sponsored by Novartis Pharma AG 7th Annual International Diovan Symposium Lisbon, 3–5 February 2006.

Sponsored by Novartis Pharma AG

7th Annual International Diovan Symposium

Lisbon, 3–5 February 2006

Page 2: 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

Page 3: Sponsored by Novartis Pharma AG 7th Annual International Diovan Symposium Lisbon, 3–5 February 2006.

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

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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

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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

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Sponsored by Novartis Pharma AG

7th Annual International Diovan Symposium

Lisbon, 3–5 February 2006

VARIABLE 3: Hypertension andMicroalbuminuria

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Sponsored by Novartis Pharma AG

Pathophysiology of Microalbuminuria in Hypertension

Michel Burnier

CHUV, Lausanne, Switzerland

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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

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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

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Ang II

Increasedglomerularpressure

Ang II

Urinary proteinGlucose

AGEs

Glycoxidation (glycation)

Efferent arteriolar

constriction

= angiotensin AT1 receptor

Pathophysiological Processes Leading to Albuminuria and Glomerular Lesions

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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

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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)

Page 13: Sponsored by Novartis Pharma AG 7th Annual International Diovan Symposium Lisbon, 3–5 February 2006.

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–

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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

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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)

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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

Page 17: Sponsored by Novartis Pharma AG 7th Annual International Diovan Symposium Lisbon, 3–5 February 2006.

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)

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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)

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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

Page 20: Sponsored by Novartis Pharma AG 7th Annual International Diovan Symposium Lisbon, 3–5 February 2006.

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

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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

Page 22: Sponsored by Novartis Pharma AG 7th Annual International Diovan Symposium Lisbon, 3–5 February 2006.

Microalbuminuria

What Links Microalbuminuria to CV Risk ?

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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

)

Page 24: Sponsored by Novartis Pharma AG 7th Annual International Diovan Symposium Lisbon, 3–5 February 2006.

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

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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

Page 26: Sponsored by Novartis Pharma AG 7th Annual International Diovan Symposium Lisbon, 3–5 February 2006.

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

Page 27: Sponsored by Novartis Pharma AG 7th Annual International Diovan Symposium Lisbon, 3–5 February 2006.

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…

Page 28: Sponsored by Novartis Pharma AG 7th Annual International Diovan Symposium Lisbon, 3–5 February 2006.

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

Page 29: Sponsored by Novartis Pharma AG 7th Annual International Diovan Symposium Lisbon, 3–5 February 2006.

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

Page 30: Sponsored by Novartis Pharma AG 7th Annual International Diovan Symposium Lisbon, 3–5 February 2006.

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

Page 31: Sponsored by Novartis Pharma AG 7th Annual International Diovan Symposium Lisbon, 3–5 February 2006.

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)

Page 32: Sponsored by Novartis Pharma AG 7th Annual International Diovan Symposium Lisbon, 3–5 February 2006.

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

Page 33: Sponsored by Novartis Pharma AG 7th Annual International Diovan Symposium Lisbon, 3–5 February 2006.

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

Page 34: Sponsored by Novartis Pharma AG 7th Annual International Diovan Symposium Lisbon, 3–5 February 2006.

Sponsored by Novartis Pharma AG

7th Annual International Diovan Symposium

Lisbon, 3–5 February 2006

Page 35: 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?

Page 36: Sponsored by Novartis Pharma AG 7th Annual International Diovan Symposium Lisbon, 3–5 February 2006.

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

Page 37: Sponsored by Novartis Pharma AG 7th Annual International Diovan Symposium Lisbon, 3–5 February 2006.

Prospective Studies Collaboration. Lancet 2002;360:1903–13

Age-specific Relation of Usual BP to Vascular Mortality In Individuals With No Previous Vascular Disease

Page 38: Sponsored by Novartis Pharma AG 7th Annual International Diovan Symposium Lisbon, 3–5 February 2006.
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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%)

Page 40: Sponsored by Novartis Pharma AG 7th Annual International Diovan Symposium Lisbon, 3–5 February 2006.

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

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Risk factors for microalbuminuria in type 1

diabetic patients with baseline normoalbuminuria

(7 yr follow-up)

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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

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Epidemiology

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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

Page 45: Sponsored by Novartis Pharma AG 7th Annual International Diovan Symposium Lisbon, 3–5 February 2006.

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

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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

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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

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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)

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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

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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

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Hillege et al. Circulation 2002;106:1777–82

Albuminuria and CVD/Non-CVD Mortality in The General Population

PREVEND Study

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The Clinical Trial Evidence

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Change in AER Predicts Loss of GFR

Rossing et al. Diabetologia 1994;37:511–16

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*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

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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

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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

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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

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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

Page 59: Sponsored by Novartis Pharma AG 7th Annual International Diovan Symposium Lisbon, 3–5 February 2006.

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

Page 60: Sponsored by Novartis Pharma AG 7th Annual International Diovan Symposium Lisbon, 3–5 February 2006.

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

Page 61: Sponsored by Novartis Pharma AG 7th Annual International Diovan Symposium Lisbon, 3–5 February 2006.

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

Page 62: Sponsored by Novartis Pharma AG 7th Annual International Diovan Symposium Lisbon, 3–5 February 2006.

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

Page 63: Sponsored by Novartis Pharma AG 7th Annual International Diovan Symposium Lisbon, 3–5 February 2006.

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

Page 64: Sponsored by Novartis Pharma AG 7th Annual International Diovan Symposium Lisbon, 3–5 February 2006.

How do we obtain better evidence?

Page 65: Sponsored by Novartis Pharma AG 7th Annual International Diovan Symposium Lisbon, 3–5 February 2006.

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

Page 66: Sponsored by Novartis Pharma AG 7th Annual International Diovan Symposium Lisbon, 3–5 February 2006.

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

Page 67: Sponsored by Novartis Pharma AG 7th Annual International Diovan Symposium Lisbon, 3–5 February 2006.

Sponsored by Novartis Pharma AG

Are Benefits Beyond BP Lowering Clinically Relevant? No

Giuseppe Mancia

University of Milan-Bicocca, Italy

Page 68: Sponsored by Novartis Pharma AG 7th Annual International Diovan Symposium Lisbon, 3–5 February 2006.

The Question

Does BP reduction per se substantially contribute to CV protection (i.e. reduction in CV morbidity and mortality) in hypertension?

Page 69: Sponsored by Novartis Pharma AG 7th Annual International Diovan Symposium Lisbon, 3–5 February 2006.

* 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*

Page 70: Sponsored by Novartis Pharma AG 7th Annual International Diovan Symposium Lisbon, 3–5 February 2006.

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

Page 71: Sponsored by Novartis Pharma AG 7th Annual International Diovan Symposium Lisbon, 3–5 February 2006.

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

Page 72: Sponsored by Novartis Pharma AG 7th Annual International Diovan Symposium Lisbon, 3–5 February 2006.

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

Page 73: Sponsored by Novartis Pharma AG 7th Annual International Diovan Symposium Lisbon, 3–5 February 2006.

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

Page 74: Sponsored by Novartis Pharma AG 7th Annual International Diovan Symposium Lisbon, 3–5 February 2006.

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)

Page 75: Sponsored by Novartis Pharma AG 7th Annual International Diovan Symposium Lisbon, 3–5 February 2006.

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?

Page 76: Sponsored by Novartis Pharma AG 7th Annual International Diovan Symposium Lisbon, 3–5 February 2006.

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

Page 77: Sponsored by Novartis Pharma AG 7th Annual International Diovan Symposium Lisbon, 3–5 February 2006.

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

Page 78: Sponsored by Novartis Pharma AG 7th Annual International Diovan Symposium Lisbon, 3–5 February 2006.

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

Page 79: Sponsored by Novartis Pharma AG 7th Annual International Diovan Symposium Lisbon, 3–5 February 2006.

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

Page 80: Sponsored by Novartis Pharma AG 7th Annual International Diovan Symposium Lisbon, 3–5 February 2006.

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)

Page 81: Sponsored by Novartis Pharma AG 7th Annual International Diovan Symposium Lisbon, 3–5 February 2006.

BPreduction

Drug

Mancia, 2004

Short-term Protection

Page 82: Sponsored by Novartis Pharma AG 7th Annual International Diovan Symposium Lisbon, 3–5 February 2006.

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?

Page 83: Sponsored by Novartis Pharma AG 7th Annual International Diovan Symposium Lisbon, 3–5 February 2006.

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

Page 84: Sponsored by Novartis Pharma AG 7th Annual International Diovan Symposium Lisbon, 3–5 February 2006.

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

?

Page 85: Sponsored by Novartis Pharma AG 7th Annual International Diovan Symposium Lisbon, 3–5 February 2006.

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

Page 86: Sponsored by Novartis Pharma AG 7th Annual International Diovan Symposium Lisbon, 3–5 February 2006.

Sponsored by Novartis Pharma AG

7th Annual International Diovan Symposium

Lisbon, 3–5 February 2006

Page 87: 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

Page 88: Sponsored by Novartis Pharma AG 7th Annual International Diovan Symposium Lisbon, 3–5 February 2006.

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

Page 89: Sponsored by Novartis Pharma AG 7th Annual International Diovan Symposium Lisbon, 3–5 February 2006.

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

Page 90: Sponsored by Novartis Pharma AG 7th Annual International Diovan Symposium Lisbon, 3–5 February 2006.

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

Page 91: Sponsored by Novartis Pharma AG 7th Annual International Diovan Symposium Lisbon, 3–5 February 2006.

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

Page 92: Sponsored by Novartis Pharma AG 7th Annual International Diovan Symposium Lisbon, 3–5 February 2006.

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…

Page 93: Sponsored by Novartis Pharma AG 7th Annual International Diovan Symposium Lisbon, 3–5 February 2006.

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

Page 94: Sponsored by Novartis Pharma AG 7th Annual International Diovan Symposium Lisbon, 3–5 February 2006.

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%

Page 95: Sponsored by Novartis Pharma AG 7th Annual International Diovan Symposium Lisbon, 3–5 February 2006.

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

Page 96: Sponsored by Novartis Pharma AG 7th Annual International Diovan Symposium Lisbon, 3–5 February 2006.

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

Page 97: Sponsored by Novartis Pharma AG 7th Annual International Diovan Symposium Lisbon, 3–5 February 2006.

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)

Page 98: Sponsored by Novartis Pharma AG 7th Annual International Diovan Symposium Lisbon, 3–5 February 2006.

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

Page 99: Sponsored by Novartis Pharma AG 7th Annual International Diovan Symposium Lisbon, 3–5 February 2006.

Myocyte Stretch and AII Production

Angiotensin II Myocyte Transillum’n

Leri. J Clin Invest 1998;101:1326–42

Page 100: Sponsored by Novartis Pharma AG 7th Annual International Diovan Symposium Lisbon, 3–5 February 2006.

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

Page 101: Sponsored by Novartis Pharma AG 7th Annual International Diovan Symposium Lisbon, 3–5 February 2006.

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

Page 102: Sponsored by Novartis Pharma AG 7th Annual International Diovan Symposium Lisbon, 3–5 February 2006.

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

Page 103: Sponsored by Novartis Pharma AG 7th Annual International Diovan Symposium Lisbon, 3–5 February 2006.

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

Page 104: Sponsored by Novartis Pharma AG 7th Annual International Diovan Symposium Lisbon, 3–5 February 2006.

Localised ACE/Chymase Presence Post MI

Control 3 days

7 days 28 days

Page 105: Sponsored by Novartis Pharma AG 7th Annual International Diovan Symposium Lisbon, 3–5 February 2006.

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

Page 106: Sponsored by Novartis Pharma AG 7th Annual International Diovan Symposium Lisbon, 3–5 February 2006.

Post-MI Remodelling: Ang II Modulationby RAAS Blockade

Control Ang II modulation

Page 107: Sponsored by Novartis Pharma AG 7th Annual International Diovan Symposium Lisbon, 3–5 February 2006.

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

Page 108: Sponsored by Novartis Pharma AG 7th Annual International Diovan Symposium Lisbon, 3–5 February 2006.

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

Page 109: Sponsored by Novartis Pharma AG 7th Annual International Diovan Symposium Lisbon, 3–5 February 2006.

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

Page 110: Sponsored by Novartis Pharma AG 7th Annual International Diovan Symposium Lisbon, 3–5 February 2006.

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

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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

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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

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MI and CAD: Secondary Prevention

Treatment objectives

Improve survival

Prevent reinfarction

Prevent LV remodelling

Prevent progression to

HF

Reduce risk of arrhythmias

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How can we help thesehigh-risk patients?

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Severity of LV damage

Antiplatelet

Statin

Treatment of Post-MIPatients with LVSD/Acute HF

LVSD or Acute HF

LVSD and Acute HF

+

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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

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+

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

+

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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

(–) (–) (+) (–) (–)

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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

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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

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+

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

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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

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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)

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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

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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

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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

*

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+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

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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

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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

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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

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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

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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

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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

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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

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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)

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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

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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

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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

(%

)

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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

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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

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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