7th Annual International Diovan Symposium

1
7th Annual International Diovan Symposium

• Lisbon, 35 February 2006

2
From the Experts Files Case Presentation

• Victor Dzau
• Duke University, Durham, USA

3
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

4
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

5
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 lt5)
• Total cholesterol 5 mmol/L (193 mg/dL)
• Chest x-ray normal
• ECG sinus rhythm, LVH on voltage criteria
• Echo EF 55, LVH

6
7th Annual International Diovan Symposium

• Lisbon, 35 February 2006

VARIABLE 3 Hypertension andMicroalbuminuria
7
Pathophysiology of Microalbuminuria in
Hypertension

• Michel Burnier
• CHUV, Lausanne, Switzerland

8
Definition of Microalbuminuria
24-hour urines 24-hour urines Urine spot Urine spot
Category mg/24 hours µg/min mg/L mg/mmol creatinine
Normal lt30 lt20 lt20 lt2
Microalbuminuria 30300 20200 20200 220
Macroalbuminuria gt300 gt200 gt200 gt20
9
Natural History of Diabetic Nephropathy
Clinical type 2 diabetes
Functional changes
Structural changes
Rising blood pressure
Microalbuminuria
Proteinuria
Rising serum creatinine levels
End-stagerenal disease
Cardiovascular death
Onset of diabetes
2
5
10
20
30
Years
Renal haemodynamics altered, glomerular
hyperfiltration Glomerular basement membrane
thickening , mesangial expansion
,microvascular changes /-
10
Pathophysiological Processes Leading to
Albuminuria and Glomerular Lesions
Urinary protein
Glucose
Glycoxidation (glycation)
AGEs
angiotensin AT1 receptor
Increased glomerular pressure
Efferent arteriolar constriction
Ang II
Ang II
11
Albuminuria and Progression of Nephropathies
Glomerular permeability for macromolecules
Excessive reabsorption of proteins in the
proximal tubule
Intracellular accumulation of protein
degradation products
Gene activations chemokines and
cytokines
Proliferation of fibroblasts and extracellular
matrix
Development of fibrosis and renal atrophy
Remuzzi et al. Kidney Int 199751215
12
Prevalence of Microalbuminuria in Patients with
Hypertension
40 30 20 10 0
Prevalence ()
Bigazzi 1992
Calvino1999
Grandi 2000
Pontremoli1997
Palatini 1996
Jensen 1997
Mean
Defined as gt 140/90 mmHg except Calvino,
Palatini (135/85 mmHg)Jensen (gt 140/90 mmHg or
on AHY)
Diercks et al. Can J Cardiol 20021852535
13
Microalbuminuria is Associated with Left
Ventricular Hypertrophy and Carotid Hypertrophy
in Hypertensive Patients
Left ventricular mass index
Intima/media thickness

200 150 100 50 0
1 0.8 0.6 0.4 0.2 0


LVMI (g/m2)
IMT (mm)
C Ht AI Ht AI
C Ht AI Ht AI
C control Ht hypertensive Al no
albuminuria Al with albuminuria plt0.001
intergroup comparison plt0.001 compared to
Cplt0.05 compared to Ht Al plt0.01
compared to Ht Al
Pontremoli et al. Am J Hypertens 1998114308
14
Microalbuminuria as a Predictor of Vascular
Disease in Non-diabetic Subjects
Odds ratio for coronary heart disease
Age (10 years)
Male sex
Systolic BP
Diastolic BP
Body mass index (10 kg/m2)
Current or ex-smoker
Treatment of hypertension
Diabetes or insulin resistance
Microalbuminuria
1 5 10 15 20
Odds ratio
Yudkin et al. Lancet 198825303
15
Microalbuminuria and Risk of CV Events, CHF and
Death in the HOPE Trial
MI/Stroke/CV death
All-cause mortality
CHF hospitalisation
4 3 2 1 0
Relative risk
lt0.22 0.220.57 0.581.62 gt1.62
Alb/Crea (mg/mmol)
Adjusted for age, sex, SBP/DBP, waist-hip ratio,
diabetes and HbA1c
Gerstein et al. JAMA 20012864216
16
Renal Insufficiency, Albuminuria and CV Survival
in the HOPE Trial
Systolic and diastolic BP NOT significant risk
factors
2.5 2.0 1.5 1.0 0.5 0
HR for primary outcome(CV death, MI, stroke)
S. creat gt124 µmol/L
Microalbuminuria
Both
Mann et al. Ann Intern Med 200113462936
17
Albuminuria and CV Diseases
LIFE study, 8,029 subjects with hypertensionand
LV hypertrophy, mean age 66 years
40 30 20 10 0
Normoalbuminuria Microalbuminuria (Alb/Crea gt3.5
mg/mmol) Macroalbuminuria (Alb/Crea gt35 mg/mmol)
Prevalence ()
Diabetes Cerebrovascular Peripheral Coronary di
sease vascular vascular disease disease
Wachtell et al. J Hypertens 20022040512
18
Composite Endpoints (CV Death, Non-fatal Stroke
and MI) Stratified by Time-varying Albuminuria in
the LIFE Trial
gt3 mg/mmoL (n2,435, 1,708, 1,760) 13 mg/mmoL
(n2,219, 1,827, 1,946) 0.51 mg/mmoL (n1,591,
1,587, 1,814) 0.5 mg/mmoL (n1,961, 3,385, 2,458)
24 22 20 18 16 14 12 10 8 6 4 2 0
Endpoint rate ()
0 6 12 18 24 30 36 42 48 54 60 66
Month
Ibsen et al. Hypertension 200545198202
19
Microalbuminuria and Mortality in the General
Population the PREVEND Study
n85,421 subjects, age 2875 years from the
Groningen area
CV death
Non-CV death
6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0
6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0
Hazard ratio
Hazard ratio
1 10 100 1,000
1 10 1,00 1000
Urinary albumin concentration (mg/L)
Urinary albumin concentration (mg/L)
Hillege et al. Circulation 2002106177782
20
Microalbuminuria and CV Complications in
Hypertension Is the Threshold Correct?The
Copenhagen City Heart Study
Cox-estimated age-adjusted curves of cumulative
incidence of coronary heart disease for a
60-year-old person based on 1,734
hypertensive subjects with microalbuminuria and
normoalbuminuria
4 3 2 1 0
UAE ³4.8 µg/min
UAE ³4.8 µg/min UAE lt4.8 µg/min
RR of CHD
30 20 10 0
Cumulative mortality ()
lt2.5 2.55 510 gt10
4 3 2 1 0
RR of death
0 2 4 6 8 10 12
Years from entry
lt2.5 2.55 510 gt10
UAE (µg/min)
Klausen et al. Hypertension 200546337
21
Microalbuminuria and Incidence of CV Events The
Framingham Study
Survival free of CVD According to sex-specific
median UACR
100 95 90
Percentage
lt Median ³ Median
0 1 2 3 4 5 6 7 8
Years
Arnlov et al. Circulation 200511296975
22
What Links Microalbuminuria to CV Risk ?
23
24-hour Blood Pressure Profile in Clinically
Healthy Subjects With or Without Microalbuminuria
Microalbuminuria (n26)
Normoalbuminuria (n45)
165 140 115 90 65 40
Blood pressure (mmHg)
0
0 4 8 12 16 20 24
Clock time
Clausen et al. Hypertension 199832717
24
Expression of Endothelial Dysfunction in Humans
Endothelial dysfunction
Impaired endothelium-dependent vasodilation
Reduces vasodilation Increased
endothelin Favours vasoconstriction Increased
transcapillary escape rate of albumin Increases
permeability (microalbuminaria) Increased von
Willebrand factor Increases prothrombotic
activity Increased tPA and PAI-1 Reduces
profibrinolytic activity Increased E-selectin
and VCAM-1 Leucocytes adhesion and
permeability Increased ICAM-1 Induces
inflammation Increased fibronectin and type IV
collagen fragments Alters matrix synthesis
25
Flow-associated Vasodilation of Brachial Artery
in Clinically Healthy Subjects According to
Microalbuminuria
plt0.05
105 104 103 102 101 100
Flow-associated dilatation ()
0
Normoalbuminuria
Elevated UAE
Clausen et al. Circulation 2001103186974
26
Pathobiological Processes Potentially Involved in
the Development and Progression of Vascular
Diseases
Dyslipidaemia Hypertension
Diabetes Smoking
Oxidative stress
Endothelial dysfunction
NO, local mediators, RAAS (Ang II)
Vasoconstriction Thrombosis Inflammation Plaque
rupture Vascular lesion and remodelling
Adapted from Dzau. Hypertension 200137104752
27
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

28
Vascular Effects of Angiotensin II
Vasoconstriction Stimulation of Ang II type 1
receptors Release of endothelin and
norepinephrine Reduction of NO bioactivity and
production of peroxynitrite Inflammation
Activation NADH/NADPH oxidase and production of
superoxide anion Induction of MCP-1, VCAM,
TNF-a, IL-6 expression Activation of monocytes
and macrophages Remodelling Stimulation
of SMC migration, hypertrophy and
replication Induction of PDGF, bFGF, IGF-1,
TGF-b expression Stimulation of matrix
glycoproteins and metalloproteinase
expression Thrombosis Stimulation of
PAI-1 synthesis and change in tPA/PAI-1
ratio Activation of platelet with increased
aggregation and adhesion
29
Angiotensin II Inhibition Retards the Progression
of Renal Diseases
Prevention
Protection
Benedict Study
IDNT RENAAL
IRMA 2 MARVAL
Microalbuminuria
Macroalbuminuria ESRD
Normoalbuminuria
Early stage Late stage
Terminal stage
Severity of renal disease
30
Reduction in Albuminuria Translates Into a
Decrease in CV Events in Hypertensive Patients
LIFE Study
0.20 0.15 0.10 0.05 0
High baseline/high year 1 High baseline/low year
1 Low baseline/high year 1 Low baseline/low year 1
Fraction suffering composite
endpoint
0 10 20 30 40 50 60 70
Follow-up (months)
Ibsen et al. Hypertension 200545198202
31
Effect of Fosinopril on CV Event Rates in
Patients with Microalbuminuria
1.00 0.98 0.96 0.94 0.92 0.90
Event-free survival
HR 0.60 0.331.10, p0.098 (Log-rank)
Placebo Fosinopril
0.10 0
0 10 20 30 40
Follow-up (months)
Asselbergs et al. Circulation 2004110280916
32
Event-free Survival According to the Level of
Microalbuminuria
1.00 0.95 0.90 0.85 0.80
Event-free survival
p0.008
UAE lt50 mg/24 hours, placebo UAE gt50 mg/24 hours,
placebo UAE lt50 mg/24 hours, fosinopril UAE gt50
mg/24 hours, fosinopril
0.10 0
0 10 20 30 40
Follow-up (months)
Asselbergs et al. Circulation 2004110280916
33
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

34
7th Annual International Diovan Symposium

• Lisbon, 35 February 2006

35
Point-CounterpointAre Benefits Beyond Blood
Pressure Lowering Clinically Relevant?
36
Albuminuria-associated DiseaseAre Benefits
Beyond BP Lowering Clinically Relevant?

• Giancarlo Viberti, MDProfessor of Diabetes and
  Metabolic Medicine
• Cardiovascular DivisionKCL School of
  MedicineGuys HospitalKings College
  LondonLondon, UK

37
Age-specific Relation of Usual BP to Vascular
Mortality In Individuals With No Previous
Vascular Disease
Prospective Studies Collaboration. Lancet
2002360190313
38
(No Transcript)
39
Annual Transition Rates Through Stages of
Diabetic Nephropathy
No nephropathy
1.4(1.3 to 1.5)
Microalbuminuria
3.0(2.6 to 3.4)
DEATH
Macroalbuminuria
4.6(3.6 to 5.7)
Elevated plasma creatinine or renal replacement
therapy
19.2(14.0 to 24.4)
Adler et al. Kidney Int 20036322532
40
Relationship Between SBP and ACR in T2DM Patients
with Different Degrees of AER
100
10
ACR mg/mmol
1
0.1
240
220
200
180
160
140
120
100
80
SBP mmHg
Smith et al. JASN 200516106975
41
Risk factors for microalbuminuria in type 1
diabetic patients with baseline
normoalbuminuria (7 yr follow-up)
42
Excess Mortality With Hypertensionand
Proteinuria In Type 2 Diabetes
Status of hypertension (H) and proteinuria (P) in
type 2 diabetes
1000
Standardisedmortality ratio
500
0
P-H- P-H PH- PH
P-H- P-H PH- PH
Men
Women
Wang et al. Diabetes Care 19961930512
43
Epidemiology
44
Relative Risk of Cardiovascular Disease and
Mortality in Diabetes Mellitus By Quartile of
Albuminuria (ACR)
ACR (mg/mmol) quartiles RR (95 CI)

1st 2nd 3rd 4th
Variable lt0.22 0.220.57 0.581.62 gt1.62 p for trend
MI, strokeand CV death 1 0.85 (0.631.14) 1.11 (0.861.43) 1.89 (1.522.63) lt0.001
All-cause mortality 1 0.86 (0.581.28) 1.41 (1.011.95) 2.38 (1.803.20) lt0.001
CHF 1 0.72 (0.321.63) 1.83 (0.983.43) 3.65 (2.066.46) lt0.001
n3,498
Gerstein et al. JAMA 20012864216
45
Rate of eGFR Decline in Type 2 DM With
Normoalbuminuria
AER categories I 10 mg/24h II 10.1 to 20
mg/24h III 20.1 to 30 mg/24h
Rachmani et al. Diabetes Res Clin Pract
20004918794
46
Survival Curves in Type 2 DM According To
Baseline AER Category
AER categories I 10 mg/24h II 10.1 to 20
mg/24h III 20.1 to 30 mg/24h
Rachmani et al. Diabetes Res Clin Pract
20004918794
47
Albuminuria and CVD risk in hypertensive
patients with LVH The LIFE Study
ACR (mg/mmol) ACR (mg/mmol) ACR (mg/mmol) ACR (mg/mmol) ACR (mg/mmol) ACR (mg/mmol) ACR (mg/mmol)
Composite endpoint lt0.25 0.25 to lt0.82 0.82 tolt1.62 1.67 tolt4.32 4.32 to lt9.45 P value for trend
HR 1 1.3 1.8 2.3 2.7 lt0.001
Adjusted HR 1 1.3 1.5 1.9 2 lt0.001
Composite endpoint CVD death, fatal or
non-fatal stroke, fatal or non-fatal MI
48
Relative Risk of CVD and Mortality in5,545
High-risk Patients Without Diabetes by Quartile
of Albuminuria (ACR)
ACR (mg/mmol) quartiles RR (95 CI)

1st 2nd 3rd 4th
Variable lt0.22 0.220.57 0.581.62 gt1.62 p for trend
MI, stroke and CV death 1 1.24 (1.031.49) 1.54 (1.291.85) 1.83 (1.522.20) lt0.001
All-cause mortality 1 1.17 (0.931.47) 1.49 (1.191.87) 2.27 (1.822.82) lt0.001
CHF 1 1.45 (0.872.44) 1.86 (1.123.10) 2.93 (1.794.81) lt0.001
Gerstein et al. JAMA 200128642126
49
Albuminuria and Incidence of CVD Events in
Non-hypertensive and Non-diabetic Subjects The
Framingham Heart Study
Survival free of CVD According to sex-specific
median UACR
Median UAER M 3.9 µg/mg F 7.5 µg/mg
Arnlov et al. Circulation 200511296975
50
Albuminuria and Risk of CHD and Death In The
General Population Third Copenhagen City Heart
Study
25-ile 2.1 µg/min 50-ile 3.0 µg/min 75-ile
4.8 µg/min
Klausen et al. Circulation 20041103235
51
Albuminuria and CVD/Non-CVD Mortality in The
General Population PREVEND Study
Hillege et al. Circulation 2002106177782
52
The Clinical Trial Evidence
53
Change in AER Predicts Loss of GFR
Rossing et al. Diabetologia 19943751116
54
RENAAL Change From Baselinein Proteinuria
40
Placebo
20
0
Medianpercent change
p0.0001 35 overall reduction
-20
-40
Losartan
-60
0
12
24
36
48
Months
P (CT)
762
632
529
390
130
751
661
558
438
167
L (CT)
Proteinuria measured as the urine
albumincreatinine ratio from a first morning
void
Brenner et al. N Engl J Med 20013458619
55
RENAAL Baseline Proteinuria As A Determinant of
Renal Events In T2DM
De Zeeuw et al. Kidney Int 200465230920
56
RENAAL Baseline Proteinuria As A Determinant For
Cardiac Events In T2DM
CV Endpoint
Heart Failure
De Zeeuw et al. Circulation 20041109217
57
RENAAL Initial Antiproteinuric Response vs Renal
Risk
De Zeeuw et al. Kidney Int 200465230920
58
RENAAL Proteinuria Reduction (lt0 versus gt30)
Determines the Cardiovascular Outcome
De Zeeuw et al. Circulation 20041109217
59
Changes In BP and AER By Valsartan and Amlodipine
in T2DM Patients With Microalbuminuria
UAER (µg/min)
The MARVAL Study
Mean BP change (mmHg)
70
SBP
p lt0.001
DBP
0
60
2
50
4
40
6
30
8
20
-6.6
-6.5
10
10
12
-11.2
-11.6
0
Valsartan
Amlodipine
Baseline
Valsartan 24 Wks
Amlodipine 24 Wks
Viberti et al. Circulation 20021066728
60
Blood Pressure According To Treatment Group
Systolic
160
150
140
130
Trandolapril
120
Arterial blood pressure (mmHg)
Verapamil
110
Trandolapril plus Verapamil
Placebo
100
Diastolic
90
80
70
0
3
6
9
12
15
18
21
24
27
30
33
36
39
42
45
48
Follow-up (months)
Ruggenenti et al. N Engl J Med 2004
61
20
No ACE inhibitor (66 events)
15
10
Cumulative incidence of microalbuminuria ()
5
ACE inhibitor (35 events)
A.F. (95 C.I.) 0.44 (0.27 0.70) p0.001
0
0
6
12
18
24
30
36
42
48
Follow-up (months)
No. at risk ACE inhibitor No ACE inhibitor
601 603
503 463
469 424
441 405
417 376
399 357
380 338
311 270
220 188
Ruggenenti et al. N Engl J Med 2004
62
Rate of CVD Events By Time-varying Albuminuria
In Subjects With Essential Hypertension and LVH
The LIFE Study
Composite endpoint CV death, fatal or non-fatal
stroke, fatal or non-fatal MI
Ibsen et al. Hypertension 200545198202
63
Risk of ESRD vs Initial Change( 60 months) in
Proteinuria in African Americans with
Hypertension and Non-diabetic Kidney DiseaseAASK
Lea et al. Arch Intern Med 2005165947953
64
How do we obtain better evidence?
65
Antihypertensive and Antiproteinuric Responses To
Increasing ACE-I Dose
Lisinopril dose (mg)
5 mg
10 mg
15 mg
20 mg
0
-10
-20
-30
reduction vs control
-40
-50
-60
-70
BP
Urinary protein
-80
Adapted from Palla et al. Int J Clin Pharmacol
Res 1994143543
66
Conclusions
Albuminuria is a powerful and independent risk
factor for renal and cardiovascular disease. The
relationship is linear across a range which
includes normalcy Correction of albuminuria per
se appears to be related to reduction of risk of
renal and cardiovascular events To acquire direct
clinical evidence a trial is required that
compares different doses of the same compound
with similar BP-lowering effects but different
albuminuria reduction potency
67
Are Benefits Beyond BP Lowering Clinically
Relevant? No

• Giuseppe Mancia
• University of Milan-Bicocca, Italy

68
The Question

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

69
Effects of Antihypertensive Drugs on CVD in
Controlled Trials
?CVD () Comparator
Diuretics 16 Placebo
Beta-blockers 21 Placebo
Calcium antagonists 28 Placebo
ACE inhibitors 24 Placebo
Ang II antagonists 10 Active therapy
?BP 2/1 mmHg
70
Metanalysis of Trials Comparing Different
Treatments or Treatment Versus Placebo in
Hypertension
1.50 1.25 1.00 0.75 0.50 0.25
1.50 1.25 1.00 0.75 0.50 0.25
1.50 1.25 1.00 0.75 0.50 0.25
Stroke
Major CVD
CHD
Relative risk of outcome event
10 8 6 4 2 0 2 4
10 8 6 4 2 0 2 4
10 8 6 4 2 0 2 4
1.50 1.25 1.00 0.75 0.50 0.25
1.50 1.25 1.00 0.75 0.50 0.25
CVD death
Total mortality
Relative risk of outcome event
10 8 6 4 2 0 2 4
10 8 6 4 2 0 2 4
SBP difference between randomised groups
(mmHg)Turnbull et al. Lancet 2003362152735
71
VALUE Analysis of Results Based on BP Control
at 6 Months
Patients treated with valsartan
Patients treated with amlodipine
Odds ratio
Odds ratio
Fatal/non-fatal cardiac events

0.76 (0.660.88)
0.73 (0.630.85)

Fatal/non-fatal stroke
0.60 (0.480.74)
0.50 (0.390.64)



0.79 (0.690.92)

0.79 (0.690.91)
All-cause death
0.83 (0.661.03)
0.91 (0.711.17)
Myocardial infarction
Heart failure hospitalisations
0.62 (0.500.77)


0.64 (0.520.79)
0.4
0.6
0.8
1.0
1.2
0.4
0.6
0.8
1.0
1.2
Controlled patients (n5,253)
Non-controlled patients (n2,396)
Controlled patients (n5,502)
Non-controlled patients (n2,094)
Hazard ratio 95 CI
Hazard ratio 95 CI
plt0.01 SBP lt140 mmHg at 6 months
Weber et al. Lancet 2004363204749
72
FEVER Endpoint Analysis (First Time Occurrence
in Each Category)
Per 1,000 patient-years
Stroke Fatal Non-fatal All CV events All
cardiac events All-cause death CV death Coronary
events Heart failure New-onset diabetes Cancer
Felodipine (138.1/82.3 mmHg) 11.2 2.1
9.1 15.2 4.6 7.1 4.6 4.5 1.1 3.1 2.6
Placebo (141.6/83.9 mmHg) 15.9 3.1 12.7 21.2
6.6 9.6 6.4 6.2 1.7 2.7 3.9
Hazard ratio (95 CI)
0.72 0.70 0.72 0.72 0.66 0.70
0.68 0.68 0.76 1.03 0.60
0.4
0.6
0.8
1.0
1.5
2.0
Felodipine better
Placebo better
Liu Lisheng et al. J Hypertens 2005
73
More Versus Less Intensive Treatmentin DM
DM (n3,599) ? BP 6.0/4.6 mmHg
Total Stroke CHD CHF CVD CV death mortality
0 10 20 30 40
16
Risk ratio
25
27
31
33
36
Statistically significant
Turnbull et al. Arch Intern Med 2005165141019
74
Clinical Outcomes Unadjusted
Reduced risk
Increased risk
BP control by visit
Percent of visits with BPcontrol (lt140/90
mmHg) HR (95 CI) Primary outcome lt25
1.00 ?25lt50 0.67
(0.590.76) ?50lt75 0.60
(0.530.67) ?75 0.54
(0.480.61)
MI (fatal non-fatal) lt25
1.00 ?25lt50 0.70 (0.570.86) ?50
lt75 0.63 (0.530.76) ?75
0.55 (0.460.65)
Stroke (fatal non-fatal) lt25
1.00 ?25lt50 0.88
(0.661.18) ?50lt75 0.62
(0.470.82) ?75 0.43 (0.320.58)
0.40 0.60 0.80 1.00 1.20 HR (95 CI)
Group with lt25 of visits with BP control used as
reference Primary Outcome first occurrence of
death (all cause), non-fatal MI, or non-fatal
stroke
75

• 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?

76
CV Events in Patient Subgroups
? 2.9/1.7 mmHg
Amlodipine/perindopril (BP 164.1/94.8 ?
135.5/79.1 mmHg)
Atenolol/thiazide (BP 163.9/94.5 ? 136.3/78.4
mmHg)
Diabetes No diabetes Current smoker Non-current
smoker Obese Non-obese LVH No LVH Older (gt60
years) Younger (60 years) Female Male Previous
vascular disease No previous vascular
disease Renal dysfunction No renal
dysfunction With metabolic syndrome Without
metabolic syndrome
1.00
0.80
1.50
0.70
0.90
77
Major CVD with ACE-I Versus D/BB Versus CA
Favours first
Favours second
ACE-I versus D/BB Diabetes No
diabetes Overall CA versus D/BB Diabetes No
diabetes Overall ACE-I versus CA Diabetes No
diabetes Overall
? 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 (0.741.11) 1.04 (0.981.10) p
homog 0.19 0.95 (0.821.10) 1.04
(0.981.10) p homog 0.82 0.92
(0.791.07) 0.99 (0.921.07) p homog 0.37
I2 () 55 0 0 0 0 0
0.25
0.5
1
2
Risk ratio
Turnbull et al. Arch Intern Med 2005165141019
78
Meta-analysis of Trials Comparing ACE-I-based
with ARB-based Regimens for the Outcomes of
Stroke, CHD and Heart Failure
Outcome Stroke Major CHD Heart failure
Trial ELITE II OPTIMAAL VALIANT Overall ELITE
II OPTIMAAL VALIANT Overall ELITE
II OPTIMAAL VALIANT Overall
Relative risk (95 CI) 1.63 (0.773.44) 1.06
(0.841.33) 0.95 (0.761.17) 1.02
(0.871.19) 1.24 (1.001.55) 1.01
(0.881.15) 0.97 (0.891.05) 1.03
(0.921.16) 0.87 (0.591.28) 1.14
(0.991.31) 1.01 (0.931.11) 1.05 (0.951.15)
Favours ARB
Favours ACE-I
0.5
1.0
1.5
Relative risk
Blood Pressure Lowering Treatment Trialists
Collaboration
79
Relative Risk of MI for ARBs and ACE-Is Versus
Active Drugs and Placebo
ARBs versus ACE-I ARBs versus placebo and active
drug ARBs versus active drug ARBs versus placebo
0.4 0.5 0.6 0.7 0.8 0.9 1.0 1.1 1.2 1.3 1.4
Favours other drug
Favours ARB
Volpe et al. J Hypertens 200523211318
80
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)

81
Short-term Protection
BP reduction
Drug
Mancia, 2004
82
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?
83
Differences Between Drugs on Factors Responsible
for Progression of Disease
Probably not Yes, minor Yes Yes Yes Yes Yes Yes Ye
s

• BP lowering
• Lipid profile
• Insulin resistance
• New-onset diabetes
• Metabolic syndrome
• LVH progression/regression
• Small vessel remodelling
• Large artery structure/function/atherosclerosis
• Renal protection

84
Role of Drug-specific Properties Versus BP
Reduction per se in CV Protection of Hypertensive
Patients
Short-term protection
Long-term protection
BP reduction
BP reduction
Drug
?
Drug
Mancia, 2004
85
Effect of Antihypertensive Treatment (n10)
125 115 105 95
Start of treatment
MAP (mmHg)
105 95 85 75 65
GFR (ml/min/1.73 m2)
1,250 750 250
Albuminuria (?g/min)
30 24 18 12 6 0 6 12 18 24 30 36
Months
Parving et al. Lancet 1983211759
86
7th Annual International Diovan Symposium

• Lisbon, 35 February 2006

87
From the Experts Files Case Presentation

• Marc Pfeffer
• Harvard Medical School, USA

88
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

89
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

90
Investigations

• Dipstick protein ve
• Creatinine 141 mmol/L (1.5 mg/dL)
• eGFR 52
• ECG Evidence of old anterior MI

I
aVR
V1
V4
II
aVL
V5
V2
III
aVF
V6
V3
IV
II
V5

• Echo Ejection fraction 35 dilated left
  ventricle

91
The Multiplicative Effect of Global Risk Factors
in Post-MI HF Patients The Root Cause

• Peter Liu
• University of Toronto, Canada

92
Incidence of Post-MI HF
Based on the 44-year follow-up of the NHLBIs
Framingham Heart Study

• The incidence of HF approaches 10 per 1,000
  population after age 65
• Approximately 22 of male and 46 of female MI
  patients will experience HF within 6 years

NHLBI National Heart, Lung, and Blood
InstituteHurst. 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
93
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 20042519119
94
Beta-blocker Carvedilol Post-MI Reduces
Cardiovascular Mortality
1.00 0.90 0.80 0.70 0.60 0
Carvedilol n975
Placebo n984
Proportion Event-free
Risk reduction 25 (4, 42) p0.024
Cardiovascular mortality rates placebo 14
carvedilol 11
0 0.5 1.0 1.5 2.0
Time (years)
Adapted from The CAPRICORN Investigators. Lancet
2001357138590
95
Antiplatelet Therapy Clopidogrel and
AspirinReduce Risk of Death, MI or Stroke at One
Year
Aspirin/clopidogrel Placebo
RRR 26.9 p0.02
11.5
RRR 19.7 pNS
8.5
RRR 37.4 p0.04
6.9
Death, MI, or stroke ()
5.5
4.6
2.9
RRR Relative risk reduction NS non
significant
Adapted from Steinhubl et al. for the CREDO
Investigators. JAMA 2002288241120
96
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 (p0.0127)

100 90 80 70
Fluvastatin (80 mg/d, n844)
Patients free from MACE ()
Risk reduction 22
Placebo (n833)
0
0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0
Time post-randomisation (years)
PCI percutaneous coronary intervention MACE
Major Adverse Cardiac Events
Serruys et al. JAMA 2002287321519
97
Remodelling Post MI ReninAngiotensin Activation
Initial infarct
Infarct expansion (hours to days)
Global remodelling (days to months)
Modified from Jessup and Brozena. New Engl J Med
2003348200718
98
Acute Ischemia
Mechanical stress Oxydative stress Hypoxia
ECM Osteopontin TIMPs, MMPs
Initial cytokine release
IschemicMyocytes
Neutrophils
Macrophages
Monocyte
Mast Cells
Angiogenesis
Collagen
Nian et al. Circ Res 200494154353
99
Myocyte Stretch and AII Production
Angiotensin II
Myocyte Transillumn
Leri. J Clin Invest 1998101132642
100
Inflammatory Cytokine Levels in Post-MI Patients
With and Without HF/Death
TNF- a
IL- 6
plt0.01
plt0.01
80 70 60 50 40 30 20 10 0
plt0.0001
plt0.0001
Inflammatory cytokine levels
Group 1 Group 2 Group 1 Group 2 (n140) (n44) (
n141) (n30)
Intrahospital
Follow-up
Group 1 made up of patients free from death and
HF Group 2 patients with HF and/or death
Valgimigli et al. Circulation 200511186370
101
Apoptosis in the Failing Human Heart
Propidium Iodide
Deoxyuridine triphosphate labelling
5,000
4,000
3,000
Number of labelled myocyte Nuclei/106 Nuclei
Deoxyuridine Triphosphate
2,000
20
10
0
Control
Ischaemic CM
Idiopathic DCM
CM cardiomyopathy DCM dilated
cardiomyopathy Olivetti et al. N Engl J Med
1997336113141
102
Matrix Metalloproteinase (MMP) post MI
Zn
Sun et al. Circulation 200411032218 Kassiri
et al. Circulation Research 20059738090
103
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

104
Localised ACE/Chymase Presence Post MI
Control
3 days
7 days
28 days
105
ReninAngiotensin Aldosterone System (RAAS)
Non-ACE pathways(e.g. chymase)

• Vasoconstriction
• Cell growth
• Na/H2O retention
• Sympathetic activation

Angiotensinogen
AT1 receptor
Angiotensin I
Renin
Angiotensin II
ACE
AT2 receptor
Aldosterone

• Vasodilation
• Antiproliferation(kinins)

Cough,angio-oedema benefits?
Inactivefragments
? Bradykinin
ACE angiotensin-converting enzymeAT1
angiotensin II type 1 AT2 angiotensin II type 2
106
Post-MI Remodelling Ang II Modulationby RAAS
Blockade
Control
Ang II modulation
107
Effects of ACE Inhibitor Treatment onAll-Cause
Mortality Post-MI
AIREClinical and/or radiographic signs of HF
TRACEEchocardiographicEF 35
SAVERadionuclideEF 40
0.40 0.35 0.30 0.25 0.20 0.15 0.10 0.05 0.0
Placebo
ACE inhibitor
Probability of event
Placebo 866/2971 (29.1)
ACE inhibitor 702/2995 (23.4)
OR 0.74 (0.660.83)
EF ejection fraction OR odds ratio Flather
et al. Lancet 2000355157581
108
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 20033491893906
109
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

110
RAAS Blockade in Post-MI HF and Chronic HF
Whats the Evidence for This Treatment Strategy?

• Eric J Velazquez
• Duke University, Durham, USA

111
The Cardiovascular Continuum
Target organ damage
Oxidative stress/ endothelial dysfunction
Tissue injury (MI, stroke)
Pathologic remodelling
Atherosclerosis and LVH
Target organ dysfunction (HF, renal)
Vascular dysfunction
Endstage organ failure
AT1 receptor
Risk factors diabetes, hypertension
Death
LVH left ventricular hypertrophyMI
myocardial infarction HF heart failure Adapted
from Dzau and Braunwald. Am Heart J
1991121124463
112
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
  attack2
• In 2002, nearly 180,000 people died of an MI2

Coronary attackdefinite or probable MI, or
fatal CHD CHDcoronary heart disease
1http//www.who.int/cardiovascular_diseases 2Americ
an Heart Association. 2005 Heart and Stroke
Statistical Update. 2004
113
MI and CAD Secondary Prevention

• Treatment objectives

Prevent reinfarction
Prevent LV remodelling
Prevent progression to HF
Reduce risk of arrhythmias
Improve survival
114
How can we help thesehigh-risk patients?
115
Treatment of Post-MIPatients with LVSD/Acute HF
LVSD or Acute HF
LVSD and Acute HF
Severity of LV damage
Antiplatelet Statin

116
Death and Major CV Events
TRACEEchocardiographicEF 35
AIREClinical and/or radiographic signs of HF
SAVERadionuclideEF 40
40
Placebo (n2,971)
ACE-I (n2,995)
30
Events ()
20
10
n 460
n 355
n324
n391
n 1,049
n 1244
0
Readmission for HF
Reinfarction
Death/MI or Readmission for HF
Odds ratio (95 CI)
Flather et al. Lancet 2000355157581
117
Early Treatment of Post-MIPatients with
LVSD/Acute HF
LVSD or Acute HF
LVSD and Acute HF
Severity of LV damage
Proven ACE-I
Antiplatelet Statin


SAVE/AIRE/TRACE
118
Potential Pharmacological Benefits of
AT1-receptor Blockade Versus ACE Inhibition
AT1-R antagonists
ACE inhibitors
Chymase
Ang II
Plasma Ang II
Bradykinin
()
()
()
()
()
Prostagladins
AT2
AT1
AT1
AT2
NO
NO
CardioprotectionVasodilation
CardioprotectionVasodilationNegative
chronotropismAnti-fibrosisAnti-growth

• 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
1998831182911Unger. JRAAS 20012(suppl
2)S4S7
2Petrie et
al. J Am Coll Cardiol 200137105661
119
HF Patients Not Receiving an ACE-I
Data from the SPICE registry N9,580
9
Intolerant
High risk
2
3
New diagnosis
80
On ACE-I
5
Unable to determine
1
Data missing
Despite the proven benefits of ACE inhibitors,
the reported prevalence of ACE inhibitor use
among heart failure patients varies from 17 to
86.
Bart BA et al. Eur Heart J 1999
120
OPTIMAALAll-cause Mortality
25
Captopril (n447 events)
20
15
Event rate ()
10
5
Relative risk 1.13 (0.991.28) p0.069
0
0
Month
6
12
18
24
30
36
Losartan 2,744 2,504 2,432 2,390 2,344 2,301 1,28
5
Captopril 2,733 2,534 2,463 2,423 2,374 2,329 1,3
09
Dickstein et al. Lancet 2002
121
Early Treatment of Post-MIPatients with
LVSD/Acute HF
LVSD or Acute HF
LVSD and Acute HF
Severity of LV damage
Proven ACE-I or Losartan 50 mg qd
Antiplatelet Statin


SAVE/AIRE/TRACE OPTIMAAL
122
VALIANT
Acute MI (0.510 days)SAVE, AIRE, or TRACE
eligible(either clinical/radiological signs of
HF or LV systolic dysfunction)

• Major exclusion criteria
• Serum creatinine gt2.5 mg/dL
• BP lt100 mmHg
• Prior intolerance of an ARB or ACE-I
• Non-consent

Double-blind, active-controlled
Captopril 50 mg tid (n4,909)
Valsartan 160 mg bid (n4,909)
Captopril 50 mg tid Valsartan 80 mg
bid (n4,885)
Median duration 24.7 monthsEvent-driven
Primary endpoint All-cause mortality Secondary
endpoints CV Death, MI, or HF Other
endpoints Safety and tolerability
Pfeffer et al. Am Heart J 200014072750
123
VALIANT All-cause Mortality
0.30 0.25 0.20 0.15 0.10 0.05 0
Captopril
Valsartan
Valsartan captopril
Probability of event
Valsartan vs captopril HR1.00 p0.982
Valsartan captopril vs captopril HR0.98
p0.726
0 6 12 18 24 30 36
Time (months)
No. at risk
Captopril 4,909 4,428 4,241 4,018 2,635 1,432 364

Valsartan 4,909 4,464 4,272 4,007 2,648 1,43
7 357
ValsartanCaptopril 4,885 4,414 4,265 3,994 2,648
1,435 382
HR hazard ratio Pfeffer et al. N Engl J Med
20033491893906
124
VALIANT Valsartan is Effective at Reducing
Cardiovascular Morbidity and Mortality
Hazard ratio(97.5 CI)
p value
CV death(1,657 events)
0.62
CV death or MI(2,234 events)
0.25
CV death or HF(2,661 events)
0.51
CV death, MI, or HF(3,096 events)
0.20
0.8
1
1.2
Favours valsartan
Favours captopril
Pfeffer et al. N Engl J Med 20033491893906
125
The Effect of Valsartan, Captopril or Both on
Atherosclerotic Events After Acute MI
An Analysis of VALIANT
25 20 15 10 5 0
Captopril (n4,909)
Valsartan (n4,909)
Valsartan captopril (n4,885)
Patients with at least one event ()
Myocardial Angina Revascularisation Stroke
infraction
Adapted from McMurray et al. Presented at ESC 2005
126
Study Drug Discontinuation
0.4
0.3
All
0.2
Probability of event
Due to Adverse Events

0.1

0
0
6
12
18
24
30
36
Months
plt0.05 vs captopril
127
Early Treatment of AMIPatients with LVSD/Acute HF
LVSD or Acute HF
LVSD and Acute HF
Severity of LV damage
Proven ACE-I (Captopril) or Valsartan 160 mg
bid or Captopril Valsartan
Antiplatelet Statin

SAVE/AIRE/TRACE
VALIANT
128
CAPRICORNSurvival
Carvedilol
Placebo
p0.031OR 0.77 (0.600.98)
The CAPRICORN Investigators. Lancet. 2001
129
EPHESUSAll-cause Mortality
10 9 8 7 6 5 4 3 2 1 0
Cumulative incidence ()
Placebo Eplerenone
RR 0.79 (95 CI, 0.640.97) p0.03
0 3 6 9 12 15 18 21 24 27 30 33 36
Months since randomisation
Eplerenone 3,319 3,044 2,463 1,260 336 0 0
Placebo 3,313 2,983 2,418 1,213 323 2 0
Pitt et al. for EPHESUS Investigators. N Engl J
Med 2003348130921
130
Early Treatment of AMIPatients with LVSD/Acute HF
LVSD or Acute HF
LVSD and Acute HF
Severity of LV damage
Proven ACE-I or valsartan 160 mg bid
Antiplatelet Statin
Eplerenone 2550 mg qd



Carvedilol
SAVE/AIRE/TRACE VALIANT CAPRICORN
EPHESUS
131
Cardiac Events Following High-risk MI The
VALIANT Experience
0.50
Any CV event
0.40
0.30
Death
Heart failure
Cumulative incidence
0.20
Recurrent MI
0.10
Sudden death or cardiac arrest
0.00
YEAR 1
0
YEAR 2
YEAR 3
YEAR 4
132
The Framingham Heart Study 1987
Risk of heart failure after MI (Age 35 to 94 at
diagnosis)
0.5
0.4
0.3
0.2
0.1
0
MI male MI female Matched male Matched female
Cumulative probability of event

0 2 4 6 8 10 12 14 16 18 20
Years following MI
Cupples et al. The Framingham Study, NIH
Publication No. 872703. 1987
133
Baseline BNP and NE and All-cause Mortality
BNP
NE
1.0
1.0
BNP (pg/mL)
Mortality
0.9
NE (pg/mL)
Mortality
0.9
lt41
9.7
0.8
4197
14.3
0.8
lt274
13.8
Survival probability
274394
16.5
98238
20.7
0.7
0.7
395572
23.0
gt572
24.2
0.6
0.6
gt238
32.4
0.5
0.5
20
10
30
0
40
Time Since Randomization, months
Time Since Randomization, months
Anand IS. Circulation 20031071278-83
134
Kaplan-Meier Analysis of Cumulative Rates of
Survival in Patients with Heart Failure
Chronically Treated With ACE Inhibitor Stratified
By Plasma Angiotensin II Levels
1.0 0.8 0.6 0.4 0.2 0
Normal Ang II
Ang II gt16 pg.mL1
p0.0002
0 2 4 6 8 10 12
Months
Roig et al. Eur Heart J 200021537
135
Val-HeFT Study Design
5,010 heart failure patients 18 years old NYHA
IIIV EF lt40 LVIDd gt2.9 cm/m2 of BSA
Receiving standard therapy
ACE inhibitors (93), diuretics (86),digoxin
(67), beta-blockers (35)
Randomized to
Valsartan 40 mg bid titrated to 160 mg bid
Placebo
906 deaths (events recorded)
Primary endpoint was all-cause mortality and the
combined endpoint of all-cause mortality and
heart failure morbidity
LVIDd left ventricular internal diastolic
diameter BSA body surface areaCohn J et al.
Eur J Heart Fail 2000243946
136
Val-HeFT Valsartan Significantly Reduces
Combined Endpoint of Mortality and Morbidity in
Overall Population
100 95 90 85 80 75 70 65 0
Probability of event-free survival
Valsartan (n2,511)
Placebo (n2,499)
0 3 6 9 12 15 18 21 24 27
Time (months)
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 p0.009
Cohn et al. N Engl J Med 2001345166775
137
Val-HeFT Valsartan Significantly Reduces Heart
Failure-related Hospitalisations
100 95 90 85 80 75 70 65 0
Valsartan (n2,511)
Probability of event-free survival
Placebo (n2,499)
0 3 6 9 12 15 18 21 24 27
Time (months)
First hospitalisation plt0.001 Cohn et al. N
Engl J Med 2001345166775
138
Val-HeFT Reduction in Combined
Morbidity/Mortalityand Mortality With Valsartan
(No ACE-I Subgroup)
Mortality
Combined morbidity/mortality
Valsartan (n185)
Placebo (n181)
100 90 80 70 60 50 40
100 90 80 70 60 50
Proportion survived ()
Probability of event-free survival
44.0 risk reduction
33.1 risk reduction
p0.0171
p0.0002
0 3 6 9 12 15 18 21 24 27 30
0 3 6 9 12 15 18 21 24 27 30
Time since randomisation (month)
Time since randomisation (month)
First morbid event, including death or
hospitalisation
Adapted from Maggioni et al. J Am Coll Cardiol
200240141421
139
CHARM-Added CV Death or CHF Hospitalization
50
40
30
20
10
0
538 (42)
Placebo
483 (38)
Candesartan

HR 0.85 (95 CI 0.750.96), p0.011Adjusted HR
0.85, p0.010

0 1 2 3 3.5
Years
Number at risk Candesartan 1,276 1,176 1,063 948
457 Placebo 1,272 1,136 1,013 906 422
NNT 14
McMurray et al. Lancet 200336276771
140
Val-HeFT Change in Plasma BNP and NE Over Time
Valsartan
Placebo
n844
20 0 20 40
40 30 20 10 0 10
n1,696
n1,710
n1,886
n829
n1,890
p0.005
p0.001
plt0.001
plt0.001
plt0.001
plt0.001
? Plasma BNP (pg/mL)
? NE (pg/mL)
n823
n1,633
n1,835
n1,605
n800
n1,850
0 4 12 24
0 4 12 24
Time (months)
Time (months)
Mean SEMLatini et al. J Card Fail
20017(Suppl 2)Abstract 198l Anand et al.
Circulation 2001104(suppl II)Abstract 2813
141
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