Transcript Document

Mechanism of superior cardiovascular protection:
Clinical perspective on LIFE
Tony ABDEL - MASSIH, MD.
Cardiologist
Hotel-Dieu de France
ESH/ESC Guidelines:
Definitions and Classification of BP Levels (mmHg)
Category
Systolic
Diastolic
Optimal
Normal
High normal
Grade 1 hypertension (mild)
Grade 2 hypertension (moderate)
Grade 3 hypertension (severe)
Isolated systolic hypertension
< 120
120-129
130-139
140-159
160-179
≥ 180
≥ 140
< 80
80-84
85-89
90-99
100-109
≥ 110
< 90
When a patient’s 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 < 90
6254 M
ESH/ESC Guidelines: Stratification of Risk to Quantify Prognosis
Blood Pressure (mmHg)
Normal
High Normal
Grade 1
Grade 2
Grade 3
Other Risk Factors
and Disease History
SBP 120-129
or DBP 80-84
SBP 130-139
or DBP 85-89
SBP 140-159
or DBP 90-99
SBP 160-179
or DBP 100-109
SBP ≥ 180
or DBP ≥ 110
No other risk factors
Average
risk
Average
risk
Low
added risk
Moderate
added risk
High
added risk
1-2 risk factors
Low
added risk
Low
added risk
Moderate
added risk
Moderate
added risk
Very high
added risk
3 or more risk factors
or TOD or diabetes
Moderate
added risk
High
added risk
High
added risk
High
added risk
Very high
added risk
Associated Clinical
Conditions
High
added risk
Very high
added risk
Very high
added risk
Very high
added risk
Very high
added risk
7772 M
Low risk: < 15%; Medium risk: 15-20%; High risk: 20-30%; Very high risk: > 30%
Echocardiography and US TSA in Low Risk Hypertensives
APROS STUDY RISK RE-CLASSIFICATION
Low
100
Medium
80
High
38
29
55
60
81
40
51
60
35
20
19
0
Routine
Cuspidi et al, J Hypertens 2002
10
11
11
After ECHO and US TSA
After ECHO
After US TSA
Association of Hypertension with Other CAD Risk Factors:
Framingham Study
One
26%
None
19%
Four or more
8%
Men
2313
One
27%
Two
25%
Three
22%
Two
24%
None
17%
Four or more
12%
Three
20%
Women
Kannel, Am J Hypertens 2000; 13: 3S-10S
Mean BP 
(mmHg)
Favours
active
Favours
control
Relative Risk
(95% CI)
Stroke
More vs less
-4 / -3
0.77 (0.63-0.95)
CHD
More vs less
-4 / -3
0.86 (0.72-1.03)
Heart failure
More vs less
-4 / -3
0.84 (0.59-1.18)
Major CV events
More vs less
-4 / -3
0.86 (0.77-0.96)
CV death
More vs less
-4 / -3
0.93 (0.77-1.11)
Total mortality
More vs less
-4 / -3
0.96 (0.84-1.09)
0.5
8175 = 6397 alt. M
1.0
Relative risk
2.0
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, β-blockers, calcium antagonists, ACE
inhibitors, angiotensin receptor antagonists are suitable for the initiation and maintenance
of therapy.
-10
-12
-14
Losartan
Valsartan
Irbesartan
Candesartan
-16
Conlin et al. Am J Hypertens 2000
181
298
Irb 150 ± Hctz 12.5 mg
Can 8 ± Hctz 12.5 mg
Val 80 ± Hctz 12.5 mg
-8
1605 190
Los 50 ± Hctz 12.5 mg
Can 8 - 16 mg
-6
Irb 150 - 300 mg
593
Los 50 - 100 mg
2217 855 610
Can 8 mg
Irb 150 mg
-4
Val 80 mg
-2
2359 1455 582 336
Los 50 mg
N=
Val 80 - 160 mg
Weighted Average Change in DBP at Trough
No Hypertension Trial Has Shown Superiority on Combined CV
Morbidity and Mortality vs. an Active Comparator
Mega-trials
Comparator
Treatments
Number of
Patients
Number of
Primary
Endpoints
CAPPP
NORDIL
STOP-2
ACE I
CCB
ACE Is/CCBs
vs.
vs.
vs.
ß blockers/ Diur ß blockers/ Diur ß blockers/Diur
10,985
10,881
6614
698
803
659
Composite Primary
Endpoint
MI,
Stroke, CV
Death
Differences on
Primary Endpoint
NS
p = 0.52
MI,
Fatal MI, Fatal
Stroke, CV Death Stroke, Fatal
CV Disease
NS
p = 0.97
NS
p = 0.89
Hansson L et al Lancet 1999; Hannson L et al Lancet 2000;356:359-365; Hannson L et al Lancet 1999;354(9192):1751-1756.
Trials on “New” vs “Old” Treatments
Primary Endpoints (RR + 95% CI)
CAPPP*
STOP2*
ANBP2*
ALLHAT°
STOP2*
NORDIL*
INSIGHT*
ALLHAT°
INVEST*
ALLHAT°
SCOPE*
LIFE*
ACE-I
ACE-I
ACE-I
ACE-I
CCB
CCB
CCB
CCB
CCB
B
ARB
ARB
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
* CVD; ° CHD
5487 M
1.0
New better
n = 10985
n = 4418
n = 6083
n = 9054
n = 4209
n = 10881
n = 6321
n = 9048
n = 22599
n = 24335
n = 4506
n = 9193
2.0
Old better
Mancia G. et al., 2003
ANBP2: Primary End-Points among All, Male, and Female Subjects
All Subjects
ACE-I superior
0.2
End Point
Hazard Ratio (95% CI)
All CV events or death from any cause
0.89 (0.79-1.00)
First CV event or death from any cause
0.89 (0.79-1.01)
Death from any cause
0.90 (0.75-1.09)
ACE-I superior
0.2
5370 M
5.0
Diuretics superior
1.0
5.0
P Value
0.02
0.02
0.14
Female Subjects
End Point
Hazard Ratio (95% CI)
All CV events or death from any cause
1.00 (0.83-1.21)
First CV event or death from any cause
1.00 (0.83-1.20)
Death from any cause
1.01 (0.76-1.35)
1.0
P Value
0.05
0.06
0.27
Male Subjects
End Point
Hazard Ratio (95% CI)
All CV events or death from any cause
0.83 (0.71-0.97)
First CV event or death from any cause
0.83 (0.71-0.97)
Death from any cause
0.83 (0.66-1.06)
Diuretics superior
ACE-I superior
P Value
0.98
0.98
0.94
0.2
Diuretics superior
1.0
Wing et al., N Engl J Med 2003; 348: 583-92
5.0
LIFE Study: Blood Pressure
During Follow-up
180
160
Systolic
mmHg
140
120
Mean Arterial
100
80
60
Losartan
Atenolol
40
20
Diastolic
0
6
12
18
24
30
Study Month
36
42
48
54
LIFE Study Primary Composite Endpoint
Proportion of patients
with first event (%)
16
14
12
Intention-to-treat
Adjusted risk reduction 13·0%, P=0·021
Unadjusted risk reduction 14·6%, P=0·009
10
Atenolol
8
Losartan
6
4
2
Study Month
0
6
12
Losartan (n) 4605 4524 4460
Atenolol (n) 4588 4494 4414
18
24
30
36
42
48
54
60
4392 4312 4247 4189 4112 4047 3897 1889
4349 4289 4205 4135 4066 3992 3821 1854
66
901
876
LIFE Study Fatal and Non-Fatal
Myocardial Infarction
Proportion of patients
with first event (%)
7
Intention-to-treat
6
Adjusted Risk Reduction -7·3%, P=0·49
Unadjusted Risk Reduction -5·0%, P=0·63
5
Losartan
4
3
Atenolol
2
1
0
6
12
18
24
36
42
30
Study Month
48
54
60
66
LIFE Study Fatal and Non-Fatal Stroke
Proportion of patients
with first event (%)
8
7
6
Intention-to-treat
Adjusted risk reduction 24·9%, P=0·001
Unadjusted risk reduction 25·8%, P=0·0006
Atenolol
5
Losartan
4
3
2
1
0
6
12
18
24
36
42
30
Study Month
48
54
60
66
ANGIOTENSIN II ANTAGONISTS
IN ISOLATED SYSTOLIC HYPERTENSION
SBP
DBP
PP
0
mm
Hg
-5
-10
-15
-20
-25
Losartan 50mg
Valsartan 80-160mg
Telmisartan 80mg
Farsang C et al. J Hpertens 2000, NentelJ M et al. Clin Ther 2000, Manolis AJ et al. (Aramis study), J HYpertens 2003.
LIFE Study ISH Subgroup
Composite of CV Death, Stroke, and MI
Endpoint rate (%)
18
16
Unadjusted relative risk=29%; P=0.02
Adjusted relative risk reduction=25%; P=0.06
14
12
10
8
6
Atenolol
Losartan
4
2
0
0
6
12
18
24
30 36 42
Study month
48
54
60
66
CV=cardiovascular
MI=myocardial infarction
LIFE Study Diabetes Subgroup
Primary Composite CV Endpoint
Proportion of patients
with first event (%)
24
20
Adjusted risk reduction 24·5%, P=0·031
Unadjusted risk reduction 26.7%, P=0·017
16
Atenolol
Losartan
12
8
4
Study Month 0
Losartan (n) 586
Atenolol (n) 609
6
569
588
12
558
562
18
548
552
24
532
540
30
520
527
36
513
507
42
501
486
48
484
472
54
459
434
60
237
204
66
127
99
Effect of Losartan on Sudden Cardiac Death
in People with Diabetes: Data From the LIFE Study
10
Adjusted HR (95% CI)
0
-10
-20
-30
-40
#
-50
p<0.052
#
-60
CV Death
#: p< 0.03
CHD Death
Sudden Death
Non SD
Non Coronary
CV Death
Lindholm LH, et al: Lancet 2003
LIFE Primary Composite Endpoint
in Subgroup: Patients without LVH* (n=662)
15
12,1
10
7,2
%
5
RR: 45%
p=0.019
0
Atenolol
n=330
* Cornell Voltage < 2400 and Sokolow-Lyon < 24
Losartan
n=332
Losartan Is the First Antihypertensive to Provide Superior Benefits
on Combined CV Morbidity and Death vs. an Active Comparator
Mega-trials
Comparator
Treatments
Number of
Patients
CAPPP
NORDIL
STOP-2
ACEI
CCB
ACEIs/ CCBs
vs.
vs.
vs.
ß blockers/Diur ß blockers/Diur ß bockers/Diur
LIFE
Losartan
vs.
Atenolol
10,985
10,881
6614
9193
698
803
659
1096
Composite Primary
Endpoint
MI,
Stroke, CV
Death
MI,
Stroke, CV Death
Fatal MI, Fatal
Stroke, Fatal
CV Disease
MI,
Stroke, CV
Death
Differences on
Primary Endpoint
NS
p = 0.52
NS
p = 0.97
NS
p = 0.89
13% RR
p = 0.021
Number of
Primary
Endpoints
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
How Could Losartan Reduce the Risk of Stroke
“Beyond Blood Pressure”? Potential Sites of Action
Cardiac remodeling/
enlargement
Vascular remodeling
Endothelial dysfunction
Prothrombotic state
Please refer to notes page for reference citations.
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
LIFE Study Diabetes Subgroup
Primary Composite CV Endpoint
Proportion of patients
with first event (%)
24
20
Adjusted risk reduction 24·5%, P=0·031
Unadjusted risk reduction 26.7%, P=0·017
16
Atenolol
Losartan
12
8
4
Study Month 0
Losartan (n) 586
Atenolol (n) 609
6
569
588
12
558
562
18
548
552
24
532
540
30
520
527
36
513
507
42
501
486
48
484
472
54
459
434
60
237
204
66
127
99
Effect of Losartan on Sudden Cardiac Death
in People with Diabetes: Data From the LIFE Study
10
Adjusted HR (95% CI)
0
-10
-20
-30
-40
#
-50
p<0.052
#
-60
CV Death
#: p< 0.03
CHD Death
Sudden Death
Non SD
Non Coronary
CV Death
Lindholm LH, et al: Lancet 2003
LIFE Primary Composite Endpoint
in Subgroup: Patients without LVH* (n=662)
15
12,1
10
7,2
%
5
RR: 45%
p=0.019
0
Atenolol
n=330
* Cornell Voltage < 2400 and Sokolow-Lyon < 24
Losartan
n=332
Losartan Is the First Antihypertensive to Provide Superior Benefits
on Combined CV Morbidity and Death vs. an Active Comparator
Mega-trials
Comparator
Treatments
Number of
Patients
CAPPP
NORDIL
STOP-2
ACEI
CCB
ACEIs/ CCBs
vs.
vs.
vs.
ß blockers/Diur ß blockers/Diur ß bockers/Diur
LIFE
Losartan
vs.
Atenolol
10,985
10,881
6614
9193
698
803
659
1096
Composite Primary
Endpoint
MI,
Stroke, CV
Death
MI,
Stroke, CV Death
Fatal MI, Fatal
Stroke, Fatal
CV Disease
MI,
Stroke, CV
Death
Differences on
Primary Endpoint
NS
p = 0.52
NS
p = 0.97
NS
p = 0.89
13% RR
p = 0.021
Number of
Primary
Endpoints
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
How Did Losartan Reduce the Risk of Stroke
“Beyond Blood Pressure”? Losartan Data
Cardiac remodeling/
enlargement
Reduced ECG–LVH
Vascular remodeling
Inhibited atherosclerosis formation
Reduced carotid artery hypertrophy
Reduced gluteal artery hypertrophy
Endothelial dysfunction
Prothrombotic state
Please refer to notes page for reference citations.
Improved endothelial function
Inhibition of platelet aggregation
Reduced proaggregatory factors
Hypothesis: Losartan May Reduce the Risk of
Ischemic Strokes by an Effect on Cardiac Remodeling
Cardiac remodeling/
enlargement
Emboli formation
Hemodynamic factors
(central and
peripheral blood
pressure)
Embolic
occlusion
Vascular remodeling
Atherosclerotic
plaque formation
Plaque rupture
Ischemic
stroke
Thrombotic
occlusion
Endothelial dysfunction
Circulating factors
(glucose, insulin,
RBCs, PAI, TXA2,
uric acid)
Plaque fragments
Thrombus/
platelet aggregation
Prothrombotic state
Vascular
hemorrhage
Please refer to notes page for reference citations.
Hemorrhagic
stroke
LIFE: Losartan vs. Atenolol Reduced
ECG–LVH
Cornell product
Sokolow-Lyon
Change from baseline (%)
0
–2
Ref 25, p 1001,
Fig 7
–4
–6
–8
–10
–12
p<0.0001
–14
–16
–18
Losartan
Atenolol
Adapted from Dalhöf B et al Lancet 2002;359:995–1003.
p<0.0001
How Did Losartan Reduce the Risk of Stroke
“Beyond Blood Pressure”? Losartan Data
Cardiac remodeling/
enlargement
Reduced ECG–LVH
Vascular remodeling
Inhibited atherosclerosis formation
Reduced carotid artery hypertrophy
Reduced gluteal artery hypertrophy
Endothelial dysfunction
Prothrombotic state
Please refer to notes page for reference citations.
Improved endothelial function
Inhibition of platelet aggregation
Reduced proaggregatory factors
Hypothesis: Losartan May Reduce the Risk of Stroke
by Altering Vascular Remodeling and Atherosclerosis
Cardiac remodeling/
enlargement
Emboli formation
Hemodynamic factors
(central and
peripheral
blood pressure)
Embolic
occlusion
Vascular remodeling
Atherosclerotic
plaque formation
Plaque rupture
Ischemic
stroke
Thrombotic
occlusion
Endothelial dysfunction
Circulating factors
(glucose, insulin,
RBCs, PAI, TXA2,
uric acid)
Plaque
fragments
Thrombus/
platelet aggregation
Prothrombotic state
Vascular
hemorrhage
Please refer to notes page for reference citations.
Hemorrhagic
stroke
Losartan Reduced Atherosclerosis
(Fatty Streaks) in Nonhuman Primates
Simian thoracic aorta dissected after 6-month
exposure to a high-cholesterol diet (n=4)
Control
Losartan
Adapted from Strawn WB et al Circulation 2000;101:1586–1593.
Ref 28, p 1586,
C2, ¶1, L1, ¶2,
L1,7; p 1590,
Fig 4
LIFE: Losartan vs. Atenolol Reduced Carotid
Artery Hypertrophy
Intima-medial thickness—change from baseline at year 3
% Change in intima-medial
cross-sectional area
Losartan (n=23)
Atenolol (n=22)
0
–1
–2
–1.7 %
–3
–4
–5
–6
–7
–8
–9
–7.9 %
p<0.05
Ref 26,
Source C,
p 34,
Table 5
ANGIOTENSIN II ANTAGONISTS
IN ISOLATED SYSTOLIC HYPERTENSION
SBP
DBP
PP
0
mm
Hg
-5
-10
-15
-20
-25
Losartan 50mg
Valsartan 80-160mg
Telmisartan 80mg
Farsang C et al. J Hpertens 2000, NentelJ M et al. Clin Ther 2000, Manolis AJ et al. (Aramis study), J HYpertens 2003.
LIFE Study ISH Subgroup
Composite of CV Death, Stroke, and MI
Endpoint rate (%)
18
16
Unadjusted relative risk=29%; P=0.02
Adjusted relative risk reduction=25%; P=0.06
14
12
10
8
6
Atenolol
Losartan
4
2
0
0
6
12
18
24
30 36 42
Study month
48
54
60
66
CV=cardiovascular
MI=myocardial infarction
LIFE Study Diabetes Subgroup
Primary Composite CV Endpoint
Proportion of patients
with first event (%)
24
20
Adjusted risk reduction 24·5%, P=0·031
Unadjusted risk reduction 26.7%, P=0·017
16
Atenolol
Losartan
12
8
4
Study Month 0
Losartan (n) 586
Atenolol (n) 609
6
569
588
12
558
562
18
548
552
24
532
540
30
520
527
36
513
507
42
501
486
48
484
472
54
459
434
60
237
204
66
127
99
Effect of Losartan on Sudden Cardiac Death
in People with Diabetes: Data From the LIFE Study
10
Adjusted HR (95% CI)
0
-10
-20
-30
-40
#
-50
p<0.052
#
-60
CV Death
#: p< 0.03
CHD Death
Sudden Death
Non SD
Non Coronary
CV Death
Lindholm LH, et al: Lancet 2003
LIFE Primary Composite Endpoint
in Subgroup: Patients without LVH* (n=662)
15
12,1
10
7,2
%
5
RR: 45%
p=0.019
0
Atenolol
n=330
* Cornell Voltage < 2400 and Sokolow-Lyon < 24
Losartan
n=332
Losartan Is the First Antihypertensive to Provide Superior Benefits
on Combined CV Morbidity and Death vs. an Active Comparator
Mega-trials
Comparator
Treatments
Number of
Patients
CAPPP
NORDIL
STOP-2
ACEI
CCB
ACEIs/ CCBs
vs.
vs.
vs.
ß blockers/Diur ß blockers/Diur ß bockers/Diur
LIFE
Losartan
vs.
Atenolol
10,985
10,881
6614
9193
698
803
659
1096
Composite Primary
Endpoint
MI,
Stroke, CV
Death
MI,
Stroke, CV Death
Fatal MI, Fatal
Stroke, Fatal
CV Disease
MI,
Stroke, CV
Death
Differences on
Primary Endpoint
NS
p = 0.52
NS
p = 0.97
NS
p = 0.89
13% RR
p = 0.021
Number of
Primary
Endpoints
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
How Could Losartan Reduce the Risk of Stroke
“Beyond Blood Pressure”? Potential Sites of Action
Cardiac remodeling/
enlargement
Vascular remodeling
Endothelial dysfunction
Prothrombotic state
Please refer to notes page for reference citations.
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
How Did Losartan Reduce the Risk of Stroke
“Beyond Blood Pressure”? Losartan Data
Cardiac remodeling/
enlargement
Reduced ECG–LVH
Vascular remodeling
Inhibited atherosclerosis formation
Reduced carotid artery hypertrophy
Reduced gluteal artery hypertrophy
Endothelial dysfunction
Prothrombotic state
Please refer to notes page for reference citations.
Improved endothelial function
Inhibition of platelet aggregation
Reduced proaggregatory factors
Hypothesis: Losartan May Reduce the Risk of
Ischemic Strokes by an Effect on Cardiac Remodeling
Cardiac remodeling/
enlargement
Emboli formation
Hemodynamic factors
(central and
peripheral blood
pressure)
Embolic
occlusion
Vascular remodeling
Atherosclerotic
plaque formation
Plaque rupture
Ischemic
stroke
Thrombotic
occlusion
Endothelial dysfunction
Circulating factors
(glucose, insulin,
RBCs, PAI, TXA2,
uric acid)
Plaque fragments
Thrombus/
platelet aggregation
Prothrombotic state
Vascular
hemorrhage
Please refer to notes page for reference citations.
Hemorrhagic
stroke
LIFE: Losartan vs. Atenolol Reduced
ECG–LVH
Cornell product
Sokolow-Lyon
Change from baseline (%)
0
–2
Ref 25, p 1001,
Fig 7
–4
–6
–8
–10
–12
p<0.0001
–14
–16
–18
Losartan
Atenolol
Adapted from Dalhöf B et al Lancet 2002;359:995–1003.
p<0.0001
How Did Losartan Reduce the Risk of Stroke
“Beyond Blood Pressure”? Losartan Data
Cardiac remodeling/
enlargement
Reduced ECG–LVH
Vascular remodeling
Inhibited atherosclerosis formation
Reduced carotid artery hypertrophy
Reduced gluteal artery hypertrophy
Endothelial dysfunction
Prothrombotic state
Please refer to notes page for reference citations.
Improved endothelial function
Inhibition of platelet aggregation
Reduced proaggregatory factors
Losartan vs. Atenolol Improved Structure
of Small Gluteal Arteries
Media/lumen ratio (%)
10
Ref 27, p 1654,
C2, ¶4, L1;
p 1656, Table 2,
Row 4
8
6
4
2
0
Losartan
Atenolol
Structure
Adapted from Schiffrin EL et al Circulation 2000;101(14):1653–1659.
How Did Losartan Reduce the Risk of Stroke
“Beyond Blood Pressure”? Losartan Data
Cardiac remodeling/
enlargement
Reduced ECG–LVH
Vascular remodeling
Inhibited atherosclerosis formation
Reduced carotid artery hypertrophy
Reduced gluteal artery hypertrophy
Endothelial dysfunction
Improved endothelial function
Prothrombotic state
Please refer to notes page for reference citations.
Inhibition of platelet aggregation
Reduced proaggregatory factors
Losartan vs. Atenolol Improved Endothelial
Function of Small Gluteal Arteries
Maximal acetylcholine
response (%)
100
*
Ref 27, p 1654,
C2, ¶4, L1; p
1656, Table 2,
Row 4; p 1657,
Fig 3
80
60
40
20
0
Losartan
Atenolol
Endothelium-dependent
relaxation
Adapted from Schiffrin EL et al Circulation 2000;101(14):1653–1659.
How Did Losartan Reduce the Risk of Stroke
“Beyond Blood Pressure”? Losartan Data
Cardiac remodeling/
enlargement
Reduced ECG–LVH
Vascular remodeling
Inhibited atherosclerosis formation
Reduced carotid artery hypertrophy
Reduced gluteal artery hypertrophy
Endothelial dysfunction
Prothrombotic state
Please refer to notes page for reference citations.
Improved endothelial function
Inhibition of platelet aggregation
Reduced proaggregatory factors
Losartan Had Effects on Platelet
Aggregation and Thrombus Formation
• Losartan
– Reduced TXA2–dependent 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 receptoractivating 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.
Losartan Inhibited Platelet Aggregation
in Man (via EXP3179)
Platelet aggregation (%)
100
Ref 36, p 774,
Fig 4A
80
60
40
*
20
Placebo
Losartan
*
*p<0.0001 vs. placebo
0
0
2
4
Time (months)
Adapted from Krämer C et al Circ Res 2002;90:770–776.
6
8
Losartan May Reduce the Risk of CV events
by Molecular-Specific Effects
Cardiac remodeling/
enlargement
Emboli formation
Hemodynamic factors
(central and
peripheral,
blood pressure)
Embolic
occlusion
Vascular remodeling
Plaque fragments
Atherosclerotic
plaque
Losartan
reduces uric acid
Ischemic
stroke
Thrombotic
occlusion
Endothelial dysfunction
Circulating factors
(Glucose, Insulin,
RBCs, PAI, TXA2,
uric acid)
Plaque rupture
Thrombus formation
Prothrombotic state
Vascular
hemorrhage
Please refer to notes page for reference citations.
Hemorrhagic
stroke
LIFE: Losartan vs. Atenolol Reduced the Rise in
Serum Uric Acid without Affecting Renal Function
45
40
Atenolol
Losartan
Ref 40, p 4, C2,
¶2, L1,3; p 5,
C1, ¶1, L1, ¶2,
L1 + calc
35
µmol/L
30
Calc:
96.9–87.4=9.5
96.1–86.5=9.6
25
20
15
p<0.0001
NS
10
5
0
Serum creatinine
Adapted from Høieggen A et al Kidney Int 2004;65:1–9.
SUA
CRP
-at Concentrations Known to Predict CV EventsUpregulates AT-1 Receptors in Vascular Smooth Muscle
Wang CH et al, Circulation. 2003;107:1783
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 antioxidant)
Wang CH et al, Circulation. 2003;107:1783
Conclusions
Cardiac remodeling/
enlargement
 Reduced ECG–LVH
Vascular remodeling
 Inhibited atherosclerosis formation
 Reduced carotid artery hypertrophy
 Reduced gluteal artery hypertrophy
Endothelial dysfunction
Prothrombotic state
Please refer to notes page for reference citations.
 Improved endothelial function
 Inhibition of platelet aggregation
 Reduced proaggregatory factors
Conditions Associated with CV Disease
Obesity/MS/Diabetes, 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