Mechanism of superior cardiovascular protection:

1
Mechanism of superior cardiovascular
protection Clinical perspective on LIFE
Tony ABDEL - MASSIH, MD. Cardiologist Hotel-Dieu
de France
2
ESH/ESC Guidelines Definitions and
Classification of BP Levels (mmHg)
Category Optimal Normal High normal Grade 1
hypertension (mild) Grade 2 hypertension
(moderate) Grade 3 hypertension (severe) Isolated
systolic hypertension
Systolic lt 120 120-129 130-139 140-159 160-179
180 140
Diastolic lt 80 80-84 85-89 90-99 100-109 110
lt 90
When a patients SBP and DBP fall into different
categories, the higher category should
apply. Isolated systolic hypertension can also be
graded (grades 1, 2, 3) according to SBP values
in the ranges indicated, provided diastolic
values are lt 90
6254 M
3
ESH/ESC Guidelines Stratification of Risk to
Quantify Prognosis
Blood Pressure (mmHg)
Grade 1 SBP 140-159 or DBP 90-99
Grade 2 SBP 160-179 or DBP 100-109
Grade 3 SBP 180 or DBP 110
Normal SBP 120-129 or DBP 80-84
High Normal SBP 130-139 or DBP 85-89
Other Risk Factors and Disease History No other
risk factors 1-2 risk factors Associated
Clinical Conditions
High added risk
Moderate added risk
Low added risk
Average risk
Average risk
Very high added risk
Moderate added risk
Moderate added risk
Low added risk
Low added risk
Very high added risk
High added risk
High added risk
High added risk
Moderate added risk
3 or more risk factors or TOD or diabetes
Very high added risk
Very high added risk
Very high added risk
Very high added risk
High added risk
Low risk lt 15 Medium risk 15-20 High risk
20-30 Very high risk gt 30
7772 M
4
Echocardiography and US TSA in Low Risk
HypertensivesAPROS STUDY RISK RE-CLASSIFICATION
Cuspidi et al, J Hypertens 2002
5
Association of Hypertension with Other CAD Risk
Factors Framingham Study
One 26
One 27
Two 25
Two 24
None 19
None 17
Three 22
Three 20
Four or more 8
Four or more 12
Men
Women
Kannel, Am J Hypertens 2000 13 3S-10S
2313
6
Stroke More vs less CHD More vs
less Heart failure More vs less Major CV
events More vs less CV death More vs
less Total mortality More vs less
Mean BP ? (mmHg) -4 / -3 -4 / -3 -4 / -3 -4
/ -3 -4 / -3 -4 / -3
Relative Risk (95 CI) 0.77 (0.63-0.95) 0.86
(0.72-1.03) 0.84 (0.59-1.18) 0.86
(0.77-0.96) 0.93 (0.77-1.11) 0.96 (0.84-1.09)
Favours active
Favours control
0.5
1.0
2.0
Relative risk
8175 6397 alt. M
7
ESH/ESC Position statement Choice of
antihypertensive drugs

• The main benefits of antihypertensive therapy are
  due to lowering of blood pressure per se.
• There is also evidence that specific drug classes
  may differ in some effect, or in special groups
  of patients.
• Drugs are not equal in terms of adverse
  disturbances, particularly in individual
  patients.
• The major classes of antihypertensive agents
  -diuretics, ß-blockers, calcium antagonists, ACE
  inhibitors, angiotensin receptor antagonists -
  are suitable for the initiation and maintenance
  of therapy.

8
Weighted Average Change in DBP at Trough
2359
1455
582
336
2217
855
610
593
1605
190
181
298
N
-2
Can 8 mg
Los 50 mg
Val 80 mg
Irb 150 mg
Can 8 - 16 mg
Val 80 - 160 mg
Los 50 - 100 mg
Irb 150 - 300 mg
-4
Can 8 Hctz 12.5 mg
Val 80 Hctz 12.5 mg
Los 50 Hctz 12.5 mg
Irb 150 Hctz 12.5 mg
-6
-8
-10
Losartan Valsartan Irbesartan Candesartan
-12
-14
-16
Conlin et al. Am J Hypertens 2000
9
No Hypertension Trial Has Shown Superiority on
Combined CV Morbidity and Mortality vs. an Active
Comparator
Hansson L et al Lancet 1999 Hannson L et al
Lancet 2000356359-365 Hannson L et al Lancet
1999354(9192)1751-1756.
10
Trials on New vs Old TreatmentsPrimary
Endpoints (RR 95 CI)
CAPPP STOP2 ANBP2 ALLHAT STOP2 NORDIL INSIGH
T ALLHAT INVEST ALLHAT SCOPE LIFE
ACE-I ACE-I ACE-I ACE-I CCB CCB CCB CCB CCB ?B ARB
ARB
n 10985 n 4418 n 6083 n 9054 n
4209 n 10881 n 6321 n 9048 n 22599 n
24335 n 4506 n 9193
1.05 (0.90-1.22) 1.01 (0.84-1.22) 0.89
(0.79-1.00) 0.99 (0.91-1.08) 0.97
(0.80-1.17) 1.00 (0.87-1.15) 1.10
(0.91-1.34) 0.98 (0.90-1.07) 0.98
(0.90-1.06) 1.03 (0.90-1.17) 0.89
(0.75-1.06) 0.87 (0.77-0.98)
0.5
1.0
2.0
CVD CHD
New better
Old better
Mancia G. et al., 2003
5487 M
11
ANBP2 Primary End-Points among All, Male, and
Female Subjects
All Subjects End Point All CV events or death
from any cause First CV event or death from any
cause Death from any cause Male Subjects End
Point All CV events or death from any cause First
CV event or death from any cause Death from any
cause Female Subjects End Point All CV events
or death from any cause First CV event or death
from any cause Death from any cause
Hazard Ratio (95 CI) 0.89 (0.79-1.00) 0.89
(0.79-1.01) 0.90 (0.75-1.09) Hazard Ratio (95
CI) 0.83 (0.71-0.97) 0.83 (0.71-0.97) 0.83
(0.66-1.06) Hazard Ratio (95 CI) 1.00
(0.83-1.21) 1.00 (0.83-1.20) 1.01 (0.76-1.35)
P Value 0.05 0.06 0.27 P Value 0.02 0.02 0.14
P Value 0.98 0.98 0.94
ACE-I superior
Diuretics superior
0.2
1.0
5.0
ACE-I superior
Diuretics superior
0.2
1.0
5.0
ACE-I superior
Diuretics superior
0.2
1.0
5.0
Wing et al., N Engl J Med 2003 348 583-92
5370 M
12
LIFE Study Blood Pressure During Follow-up
Systolic
Mean Arterial
mmHg
Diastolic
Losartan
Atenolol
54
48
6
12
30
18
24
36
42
0
Study Month
13
LIFE Study Primary Composite Endpoint
16
Intention-to-treat
14
Adjusted risk reduction 130, P0021 Unadjusted
risk reduction 146, P0009
12
10
Atenolol
Proportion of patients with first event ()
8
Losartan
6
4
2
0
6
12
18
24
30
36
42
48
54
60
66
Study Month
14
LIFE Study Fatal and Non-Fatal Myocardial
Infarction
7
Intention-to-treat
6
Adjusted Risk Reduction -73, P049 Unadjusted
Risk Reduction -50, P063
5
Losartan
4
Proportion of patients with first event ()
Atenolol
3
2
1
0
6
12
18
24
36
42
48
54
60
66
30
Study Month
15
LIFE Study Fatal and Non-Fatal Stroke
Proportion of patients with first event ()
16
ANGIOTENSIN II ANTAGONISTS IN ISOLATED SYSTOLIC
HYPERTENSION
SBP
DBP
PP
mm Hg
Farsang C et al. J Hpertens 2000, NentelJ M et
al. Clin Ther 2000, Manolis AJ et al. (Aramis
study), J HYpertens 2003.
17
LIFE Study ISH Subgroup Composite of CV Death,
Stroke, and MI
Unadjusted relative risk29 P0.02 Adjusted
relative risk reduction25 P0.06
18
16
14
12
10
Endpoint rate ()
8
6
Atenolol
4
Losartan
2
0
0
6
12
18
24
30
36
42
48
54
60
66
Study month
CVcardiovascular MImyocardial infarction
18
LIFE Study Diabetes Subgroup Primary Composite
CV Endpoint
24
Adjusted risk reduction 245, P0031 Unadjusted
risk reduction 26.7, P0017
20
16
Atenolol
Losartan
Proportion of patients with first event ()
12
8
4
Study Month
19
Effect of Losartan on Sudden Cardiac Death in
People with Diabetes Data From the LIFE Study
Adjusted HR (95 CI)
10
0
-10
-20
-30
-40

plt0.052
-50

-60
Non Coronary CV Death
CV Death
CHD Death
Sudden Death
Non SD
Lindholm LH, et al Lancet 2003
plt 0.03
20
LIFE Primary Composite Endpointin Subgroup
Patients without LVH (n662)
15
12,1
10
7,2

5
RR 45 p0.019
0
Atenolol n330
Losartan n332
Cornell Voltage lt 2400 and Sokolow-Lyon lt 24
21
Losartan Is the First Antihypertensive to Provide
Superior Benefits on Combined CV Morbidity and
Death vs. an Active Comparator
LIFE
22
LIFE Conclusions

• Losartan with LIFE is the only antihypertensive
  that has demonstrated a superior benefit over
  another active treatment, atenolol, in reducing
  the risk of combined CV morbidity and death in
  patients with hypertension and LVH
• The superior benefit of losartan therapy on
  combined CV morbidity and death compared to
  atenolol was
• beyond blood-pressure control
• only partially explained by superior LVH
  regression
• potentially linked to molecule-specific effects

Defined as composite of CV death, MI, and stroke
23
How Could Losartan Reduce the Risk of Stroke
Beyond Blood Pressure? Potential Sites of Action
Cardiac remodeling/enlargement
Ref 3, p 831, C1, 1, L1 Ref 4, p 469, C2, L4 Ref
9, p 493, C1, 3, L1 p 496, C1, 3, L10 Ref 5, p
1439, Fig 74-1 Ref 27, p 1653, 2
Vascular remodeling
Endothelial dysfunction
Prothrombotic state
Please refer to notes page for reference
citations.
24
LIFE Study Diabetes Subgroup Primary Composite
CV Endpoint
24
Adjusted risk reduction 245, P0031 Unadjusted
risk reduction 26.7, P0017
20
16
Atenolol
Losartan
Proportion of patients with first event ()
12
8
4
Study Month
25
Effect of Losartan on Sudden Cardiac Death in
People with Diabetes Data From the LIFE Study
Adjusted HR (95 CI)
10
0
-10
-20
-30
-40

plt0.052
-50

-60
Non Coronary CV Death
CV Death
CHD Death
Sudden Death
Non SD
Lindholm LH, et al Lancet 2003
plt 0.03
26
LIFE Primary Composite Endpointin Subgroup
Patients without LVH (n662)
15
12,1
10
7,2

5
RR 45 p0.019
0
Atenolol n330
Losartan n332
Cornell Voltage lt 2400 and Sokolow-Lyon lt 24
27
Losartan Is the First Antihypertensive to Provide
Superior Benefits on Combined CV Morbidity and
Death vs. an Active Comparator
LIFE
28
LIFE Conclusions

• Losartan with LIFE is the only antihypertensive
  that has demonstrated a superior benefit over
  another active treatment, atenolol, in reducing
  the risk of combined CV morbidity and death in
  patients with hypertension and LVH
• The superior benefit of losartan therapy on
  combined CV morbidity and death compared to
  atenolol was
• beyond blood-pressure control
• only partially explained by superior LVH
  regression
• potentially linked to molecule-specific effects

Defined as composite of CV death, MI, and stroke
29
How Did Losartan Reduce the Risk of Stroke
Beyond Blood Pressure? Losartan Data
Reduced ECGLVH
Cardiac remodeling/enlargement
Vascular remodeling
Inhibited atherosclerosis formation Reduced
carotid artery hypertrophy Reduced gluteal
artery hypertrophy
Endothelial dysfunction
Improved endothelial function
Inhibition of platelet aggregation Reduced
proaggregatory factors
Prothrombotic state
Please refer to notes page for reference
citations.
30
Hypothesis Losartan May Reduce the Risk of
Ischemic Strokes by an Effect on Cardiac
Remodeling
Cardiac remodeling/enlargement
Hemodynamic factors (central and peripheral
blood pressure)
Emboli formation
Vascular remodeling
Embolic occlusion
Plaque fragments
Atherosclerotic plaque formation
Ischemic stroke
Plaque rupture
Endothelial dysfunction
Thrombotic occlusion
Circulating factors (glucose, insulin, RBCs,
PAI, TXA2, uric acid)
Thrombus/ platelet aggregation
Prothrombotic state
Hemorrhagic stroke
Vascular hemorrhage
Please refer to notes page for reference
citations.
31
LIFE Losartan vs. Atenolol Reduced ECGLVH
Cornell product
Sokolow-Lyon
0
2
Ref 25, p 1001, Fig 7
4
6
8
Change from baseline ()
10
plt0.0001
12
14
16
plt0.0001
18
Adapted from Dalhöf B et al Lancet
20023599951003.
32
How Did Losartan Reduce the Risk of Stroke
Beyond Blood Pressure? Losartan Data
Reduced ECGLVH
Cardiac remodeling/enlargement
Vascular remodeling
Inhibited atherosclerosis formation Reduced
carotid artery hypertrophy Reduced gluteal
artery hypertrophy
Endothelial dysfunction
Improved endothelial function
Inhibition of platelet aggregation Reduced
proaggregatory factors
Prothrombotic state
Please refer to notes page for reference
citations.
33
Hypothesis Losartan May Reduce the Risk of
Stroke by Altering Vascular Remodeling and
Atherosclerosis
Cardiac remodeling/enlargement
Hemodynamic factors (central and peripheral
blood pressure)
Emboli formation
Vascular remodeling
Embolic occlusion
Atherosclerotic plaque formation
Plaque fragments
Ischemic stroke
Plaque rupture
Endothelial dysfunction
Thrombotic occlusion
Circulating factors (glucose, insulin, RBCs,
PAI, TXA2, uric acid)
Thrombus/ platelet aggregation
Prothrombotic state
Hemorrhagic stroke
Vascular hemorrhage
Please refer to notes page for reference
citations.
34
Losartan Reduced Atherosclerosis (Fatty Streaks)
in Nonhuman Primates
Simian thoracic aorta dissected after 6-month
exposure to a high-cholesterol diet (n4)
Ref 28, p 1586, C2, 1, L1, 2, L1,7 p 1590,
Fig 4
Control
Losartan
Adapted from Strawn WB et al Circulation
200010115861593.
35
LIFE Losartan vs. Atenolol Reduced Carotid
Artery Hypertrophy
Intima-medial thicknesschange from baseline at
year 3
Losartan (n23)
Atenolol (n22)
0
1
Ref 26, Source C, p 34, Table 5
2
1.7
3
Change in intima-medialcross-sectional area
4
5
6
7
8
7.9
9
plt0.05
36
ANGIOTENSIN II ANTAGONISTS IN ISOLATED SYSTOLIC
HYPERTENSION
SBP
DBP
PP
mm Hg
Farsang C et al. J Hpertens 2000, NentelJ M et
al. Clin Ther 2000, Manolis AJ et al. (Aramis
study), J HYpertens 2003.
37
LIFE Study ISH Subgroup Composite of CV Death,
Stroke, and MI
Unadjusted relative risk29 P0.02 Adjusted
relative risk reduction25 P0.06
18
16
14
12
10
Endpoint rate ()
8
6
Atenolol
4
Losartan
2
0
0
6
12
18
24
30
36
42
48
54
60
66
Study month
CVcardiovascular MImyocardial infarction
38
LIFE Study Diabetes Subgroup Primary Composite
CV Endpoint
24
Adjusted risk reduction 245, P0031 Unadjusted
risk reduction 26.7, P0017
20
16
Atenolol
Losartan
Proportion of patients with first event ()
12
8
4
Study Month
39
Effect of Losartan on Sudden Cardiac Death in
People with Diabetes Data From the LIFE Study
Adjusted HR (95 CI)
10
0
-10
-20
-30
-40

plt0.052
-50

-60
Non Coronary CV Death
CV Death
CHD Death
Sudden Death
Non SD
Lindholm LH, et al Lancet 2003
plt 0.03
40
LIFE Primary Composite Endpointin Subgroup
Patients without LVH (n662)
15
12,1
10
7,2

5
RR 45 p0.019
0
Atenolol n330
Losartan n332
Cornell Voltage lt 2400 and Sokolow-Lyon lt 24
41
Losartan Is the First Antihypertensive to Provide
Superior Benefits on Combined CV Morbidity and
Death vs. an Active Comparator
LIFE
42
LIFE Conclusions

• Losartan with LIFE is the only antihypertensive
  that has demonstrated a superior benefit over
  another active treatment, atenolol, in reducing
  the risk of combined CV morbidity and death in
  patients with hypertension and LVH
• The superior benefit of losartan therapy on
  combined CV morbidity and death compared to
  atenolol was
• beyond blood-pressure control
• only partially explained by superior LVH
  regression
• potentially linked to molecule-specific effects

Defined as composite of CV death, MI, and stroke
43
How Could Losartan Reduce the Risk of Stroke
Beyond Blood Pressure? Potential Sites of Action
Cardiac remodeling/enlargement
Ref 3, p 831, C1, 1, L1 Ref 4, p 469, C2, L4 Ref
9, p 493, C1, 3, L1 p 496, C1, 3, L10 Ref 5, p
1439, Fig 74-1 Ref 27, p 1653, 2
Vascular remodeling
Endothelial dysfunction
Prothrombotic state
Please refer to notes page for reference
citations.
44
How Did Losartan Reduce the Risk of Stroke
Beyond Blood Pressure? Losartan Data
Reduced ECGLVH
Cardiac remodeling/enlargement
Vascular remodeling
Inhibited atherosclerosis formation Reduced
carotid artery hypertrophy Reduced gluteal
artery hypertrophy
Endothelial dysfunction
Improved endothelial function
Inhibition of platelet aggregation Reduced
proaggregatory factors
Prothrombotic state
Please refer to notes page for reference
citations.
45
Hypothesis Losartan May Reduce the Risk of
Ischemic Strokes by an Effect on Cardiac
Remodeling
Cardiac remodeling/enlargement
Hemodynamic factors (central and peripheral
blood pressure)
Emboli formation
Vascular remodeling
Embolic occlusion
Plaque fragments
Atherosclerotic plaque formation
Ischemic stroke
Plaque rupture
Endothelial dysfunction
Thrombotic occlusion
Circulating factors (glucose, insulin, RBCs,
PAI, TXA2, uric acid)
Thrombus/ platelet aggregation
Prothrombotic state
Hemorrhagic stroke
Vascular hemorrhage
Please refer to notes page for reference
citations.
46
LIFE Losartan vs. Atenolol Reduced ECGLVH
Cornell product
Sokolow-Lyon
0
2
Ref 25, p 1001, Fig 7
4
6
8
Change from baseline ()
10
plt0.0001
12
14
16
plt0.0001
18
Adapted from Dalhöf B et al Lancet
20023599951003.
47
How Did Losartan Reduce the Risk of Stroke
Beyond Blood Pressure? Losartan Data
Reduced ECGLVH
Cardiac remodeling/enlargement
Vascular remodeling
Inhibited atherosclerosis formation Reduced
carotid artery hypertrophy Reduced gluteal
artery hypertrophy
Endothelial dysfunction
Improved endothelial function
Inhibition of platelet aggregation Reduced
proaggregatory factors
Prothrombotic state
Please refer to notes page for reference
citations.
48
Losartan vs. Atenolol Improved Structure of
Small Gluteal Arteries
10
Ref 27, p 1654, C2, 4, L1 p 1656, Table 2, Row
4
8
6
Media/lumen ratio ()
4
2
0
Losartan
Atenolol
Structure
Adapted from Schiffrin EL et al Circulation
2000101(14)16531659.
49
How Did Losartan Reduce the Risk of Stroke
Beyond Blood Pressure? Losartan Data
Reduced ECGLVH
Cardiac remodeling/enlargement
Vascular remodeling
Inhibited atherosclerosis formation Reduced
carotid artery hypertrophy Reduced gluteal
artery hypertrophy
Endothelial dysfunction
Improved endothelial function
Inhibition of platelet aggregation Reduced
proaggregatory factors
Prothrombotic state
Please refer to notes page for reference
citations.
50
Losartan vs. Atenolol Improved Endothelial
Function of Small Gluteal Arteries

100
Ref 27, p 1654, C2, 4, L1 p 1656, Table 2, Row
4 p 1657, Fig 3
80
60
Maximal acetylcholine response ()
40
20
0
Losartan
Atenolol
Endothelium-dependent relaxation
Adapted from Schiffrin EL et al Circulation
2000101(14)16531659.
51
How Did Losartan Reduce the Risk of Stroke
Beyond Blood Pressure? Losartan Data
Reduced ECGLVH
Cardiac remodeling/enlargement
Vascular remodeling
Inhibited atherosclerosis formation Reduced
carotid artery hypertrophy Reduced gluteal
artery hypertrophy
Endothelial dysfunction
Improved endothelial function
Inhibition of platelet aggregation Reduced
proaggregatory factors
Prothrombotic state
Please refer to notes page for reference
citations.
52
Losartan Had Effects on Platelet Aggregation and
Thrombus Formation

• Losartan
• Reduced TXA2dependent platelet activation
  (platelets from 15 healthy men)
• Reduced plasma levels of PAI-1 antigen, PAI-1
  activity, and sTM level in 12 hypertensive
  patients
• Increased the concentration of thrombin
  receptor-activating peptide (SRLRRN-NH2) required
  to induce platelet aggregation in 10 hypertensive
  patients
• Reduced plasma PAI-1 levels in hypertensive
  postmenopausal women
• Reduced the aggregatory response to thromboxane
  but not thrombin in hypertensive patients

Please refer to notes page for reference
citations.
53
Losartan Inhibited Platelet Aggregation in Man
(via EXP3179)
100
Ref 36, p 774, Fig 4A
80
60
Platelet aggregation ()
40


20
plt0.0001 vs. placebo
0
4
2
0
6
8
Time (months)
Adapted from Krämer C et al Circ Res
200290770776.
54
Losartan May Reduce the Risk of CV events by
Molecular-Specific Effects
Cardiac remodeling/enlargement
Hemodynamic factors (central and
peripheral, blood pressure)
Emboli formation
Vascular remodeling
Embolic occlusion
Plaque fragments
Losartan reduces uric acid
Atherosclerotic plaque
Ischemic stroke
Plaque rupture
Endothelial dysfunction
Thrombotic occlusion
Circulating factors (Glucose, Insulin, RBCs,
PAI, TXA2, uric acid)
Thrombus formation
Prothrombotic state
Hemorrhagic stroke
Vascular hemorrhage
Please refer to notes page for reference
citations.
55
LIFE Losartan vs. Atenolol Reduced the Rise in
Serum Uric Acid without Affecting Renal Function
45
40
Ref 40, p 4, C2, 2, L1,3 p 5, C1, 1, L1, 2,
L1 calc Calc 96.987.49.5 96.186.59.6
35
30
25
µmol/L
plt0.0001
20
15
NS
10
5
0
Adapted from Høieggen A et al Kidney Int
20046519.
56
CRP -at Concentrations Known to Predict CV
Events- Upregulates AT-1 Receptors in Vascular
Smooth Muscle
Wang CH et al, Circulation. 20031071783
57
CRP stimulates VSM cell migration. This effect
was inhibited by losartan. Losartan per se did
not affect VSM migration in the basal state. Ang
II increased VSM migration this effect was
potentiated in the presence of CRP and attenuated
by N-acetylcysteine (an anti-oxidant)
Wang CH et al, Circulation. 20031071783
58
Conclusions
? Reduced ECGLVH
Cardiac remodeling/enlargement
Vascular remodeling
? Inhibited atherosclerosis formation ? Reduced
carotid artery hypertrophy ? Reduced gluteal
artery hypertrophy
Endothelial dysfunction
? Improved endothelial function
? Inhibition of platelet aggregation ? Reduced
proaggregatory factors
Prothrombotic state
Please refer to notes page for reference
citations.
59
Conditions Associated with CV Disease Obesity/MS/D
iabetes, PCOS, HTN, Dyslipidemias, COPD, Systemic
Inflammatory Disorders, CRF, Chronic Infections,
Homocystenemia, Pschyosocial Stress
Insulin Resistance
Atherogenesis
Inflammation
Thrombogenesis
CV DISEASES CHD, PVD, CVD, Cardiomyopathy,
Arrhythmias, Restenosis, Valvular HD, Vein Graft
failure, Cardiac Allograft Vasculopathy,
Pulmonary Arterial Hypertension