Mechanism of superior cardiovascular protection: Clinical perspective on LIFE Tony ABDEL - MASSIH,...

Mechanism of superior cardiovascular protection:

Clinical perspective on LIFE

Tony ABDEL - MASSIH, MD.Tony ABDEL - MASSIH, MD.

Cardiologist Cardiologist

Hotel-Dieu de France Hotel-Dieu de France

ESH/ESC Guidelines: ESH/ESC Guidelines: Definitions and Classification of BP Levels (mmHg)Definitions and Classification of BP Levels (mmHg)

ESH/ESC Guidelines: ESH/ESC Guidelines: Definitions and Classification of BP Levels (mmHg)Definitions and Classification of BP Levels (mmHg)

6254 M6254 M

CategoryCategory

OptimalOptimalNormalNormalHigh normalHigh normalGrade 1 hypertension (mild)Grade 1 hypertension (mild)Grade 2 hypertension (moderate)Grade 2 hypertension (moderate)Grade 3 hypertension (severe)Grade 3 hypertension (severe)Isolated systolic hypertensionIsolated systolic hypertension

SystolicSystolic

< 120< 120120-129120-129130-139130-139140-159140-159160-179160-179

≥ ≥ 180180≥ ≥ 140140

DiastolicDiastolic

< 80< 8080-8480-8485-8985-8990-9990-99

100-109100-109≥ ≥ 110110 < 90< 90

When a patient’s SBP and DBP fall into different categories, the higher category should apply.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 Isolated systolic hypertension can also be graded (grades 1, 2, 3) according to SBP values in the ranges indicated, provided diastolic values are < 90ranges indicated, provided diastolic values are < 90

ESH/ESC Guidelines: Stratification of Risk to Quantify PrognosisESH/ESC Guidelines: Stratification of Risk to Quantify PrognosisESH/ESC Guidelines: Stratification of Risk to Quantify PrognosisESH/ESC Guidelines: Stratification of Risk to Quantify Prognosis

7772 M7772 M

Very high Very high added riskadded risk



High High added riskadded risk





Moderate Moderate added riskadded risk



Low Low added riskadded risk

Blood Pressure (mmHg)Blood Pressure (mmHg)

Other Risk FactorsOther Risk Factorsand Disease Historyand Disease History

No other risk factorsNo other risk factors

1-2 risk factors1-2 risk factors

Associated ClinicalAssociated ClinicalConditionsConditions

Grade 1Grade 1SBP 140-159 SBP 140-159

or DBP 90-99or DBP 90-99

Grade 2Grade 2SBP 160-179 SBP 160-179

or DBP 100-109or DBP 100-109

Grade 3Grade 3SBP ≥ 180SBP ≥ 180

or DBP ≥ 110or DBP ≥ 110

3 or more risk factors3 or more risk factorsor TOD or diabetesor TOD or diabetes





Average Average riskrisk

Low Low added riskadded risk

LowLowadded riskadded risk

Average Average riskrisk

NormalNormalSBP 120-129SBP 120-129


High NormalHigh NormalSBP 130-139SBP 130-139


Low risk: < 15%; Medium risk: 15-20%; High risk: 20-30%; Very high risk: > 30%Low risk: < 15%; Medium risk: 15-20%; High risk: 20-30%; Very high risk: > 30%

1910 11 11

81

3551

60

5538

29

0

20

40

60

80

100

Routine Af ter ECHO and US TSA Af ter ECHO Af ter US TSA

Low Medium High

Cuspidi et al, J Hypertens 2002

Echocardiography and US TSA in Low Risk Echocardiography and US TSA in Low Risk HypertensivesHypertensives

APROS STUDY RISK RE-CLASSIFICATIONAPROS STUDY RISK RE-CLASSIFICATION

23132313

Association of Hypertension with Other CAD Risk Factors:Association of Hypertension with Other CAD Risk Factors:Framingham StudyFramingham Study

Kannel, Am J Hypertens 2000; 13: 3S-10SKannel, Am J Hypertens 2000; 13: 3S-10S

TwoTwo25%25%

OneOne26%26%

NoneNone19%19%

Four or moreFour or more8%8%

ThreeThree22%22%

TwoTwo24%24%

OneOne27%27%

NoneNone17%17%

Four or moreFour or more12%12%

ThreeThree20%20%

MenMenMenMen WomenWomenWomenWomen

8175 = 6397 alt. M 8175 = 6397 alt. M

StrokeStroke MoreMore vs lessvs less

CHDCHD MoreMore vs lessvs less

Heart failure Heart failure MoreMore vs lessvs less

Major CV events Major CV events MoreMore vs lessvs less

CV death CV death MoreMore vs lessvs less

Total mortality Total mortality MoreMore vs lessvs less

Mean BP Mean BP (mmHg)(mmHg)

-4 / -3-4 / -3

-4 / -3-4 / -3

-4 / -3-4 / -3

-4 / -3-4 / -3

-4 / -3-4 / -3

-4 / -3-4 / -3

Relative RiskRelative Risk(95% CI)(95% CI)

0.77 (0.63-0.95)0.77 (0.63-0.95)

0.86 (0.72-1.03)0.86 (0.72-1.03)

0.84 (0.59-1.18)0.84 (0.59-1.18)

0.86 (0.77-0.96)0.86 (0.77-0.96)

0.93 (0.77-1.11)0.93 (0.77-1.11)

0.96 (0.84-1.09)0.96 (0.84-1.09)

FavoursFavoursactiveactive

Favours Favours controlcontrol

0.50.5 1.01.0 2.02.0Relative riskRelative risk

ESH/ESC Position statement: ESH/ESC Position statement: Choice of antihypertensive drugsChoice 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.

Weighted Average Change in DBP at TroughWeighted Average Change in DBP at Trough

LosartanValsartanIrbesartanCandesartan

23592359 14551455 582582 336336 22172217 855855 610610 593593 16051605 190190 181181 298298N =N =

-2-2

-4-4

-6-6

-8-8

-10-10

-12-12

-14-14

-16-16

Los

50

mg

Val

80

mg

Irb

150

mg

Can

8 m

g

Los

50

- 10

0 m

g

Val

80

- 16

0 m

g

Irb

150

- 3

00 m

g

Can

8 -

16

mg

Los

50

± H

ctz

12.5

mg

Val

80

± H

ctz

12.5

mg

Irb

150

± H

ctz

12.5

mg

Can

8 ±

Hct

z 12

.5 m

g

Conlin et al. Am J Hypertens 2000

Mega-trials CAPPP NORDIL STOP-2

ComparatorTreatments

ACE Ivs.

ß blockers/Diur

CCBvs.

ß blockers/Diur

ACE Is/CCBsvs.

ßblockers/DiurNumber of

Patients 10,985 10,881 6614

Number ofPrimary

Endpoints698 803 659

Composite PrimaryEndpoint

MI,Stroke, CV

Death

MI,Stroke, CV Death

Fatal MI, FatalStroke, FatalCV Disease

Differences onPrimary Endpoint

NSp = 0.52

NSp = 0.97

NSp = 0.89

No Hypertension Trial Has Shown Superiority on Combined CV No Hypertension Trial Has Shown Superiority on Combined CV Morbidity and Mortality vs. an Active ComparatorMorbidity and Mortality vs. an Active Comparator

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.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.

5487 M5487 M

Trials on “New” vs “Old” TreatmentsTrials on “New” vs “Old” TreatmentsPrimary Endpoints (RR Primary Endpoints (RR ++ 95% CI) 95% CI)

Mancia G. et al., 2003Mancia G. et al., 2003

CAPPP*CAPPP*

STOP2*STOP2*

ANBP2*ANBP2*

ALLHAT°ALLHAT°

STOP2*STOP2*

NORDIL*NORDIL*

INSIGHT*INSIGHT*

ALLHAT°ALLHAT°

INVEST*INVEST*

ALLHAT°ALLHAT°

SCOPE*SCOPE*

LIFE*LIFE*

ACE-IACE-I

ACE-IACE-I

ACE-IACE-I

ACE-IACE-I

CCBCCB

CCBCCB

CCBCCB

CCBCCB

CCBCCB

BB

ARBARB

ARBARB

n = 10985n = 10985

n = 4418n = 4418

n = 6083n = 6083

n = 9054n = 9054

n = 4209n = 4209

n = 10881n = 10881

n = 6321n = 6321

n = 9048n = 9048

n = 22599n = 22599

n = 24335n = 24335

n = 4506n = 4506

n = 9193n = 91930.50.5 1.01.0 2.02.0

New betterNew better Old betterOld better

1.05 (0.90-1.22)1.05 (0.90-1.22)

1.01 (0.84-1.22)1.01 (0.84-1.22)

0.89 (0.79-1.00)0.89 (0.79-1.00)

0.99 (0.91-1.08)0.99 (0.91-1.08)

0.97 (0.80-1.17)0.97 (0.80-1.17)

1.00 (0.87-1.15)1.00 (0.87-1.15)

1.10 (0.91-1.34)1.10 (0.91-1.34)

0.98 (0.90-1.07)0.98 (0.90-1.07)

0.98 (0.90-1.06)0.98 (0.90-1.06)

1.03 (0.90-1.17)1.03 (0.90-1.17)

0.89 (0.75-1.06)0.89 (0.75-1.06)

0.87 (0.77-0.98)0.87 (0.77-0.98)

* CVD; ° CHD* CVD; ° CHD

ANBP2: Primary End-Points among All, Male, and Female SubjectsANBP2: Primary End-Points among All, Male, and Female Subjects

5370 M5370 MWing et al., N Engl J Med 2003; 348: 583-92Wing et al., N Engl J Med 2003; 348: 583-92

All SubjectsAll Subjects

End PointEnd PointAll CV events or death from any causeAll CV events or death from any causeFirst CV event or death from any causeFirst CV event or death from any causeDeath from any causeDeath from any cause

Male SubjectsMale Subjects

End PointEnd PointAll CV events or death from any causeAll CV events or death from any causeFirst CV event or death from any causeFirst CV event or death from any causeDeath from any causeDeath from any cause

Female SubjectsFemale Subjects

End Point End Point All CV events or death from any causeAll CV events or death from any causeFirst CV event or death from any causeFirst CV event or death from any causeDeath from any causeDeath from any cause

Hazard Ratio (95% CI)Hazard Ratio (95% CI)0.89 (0.79-1.00)0.89 (0.79-1.00)0.89 (0.79-1.01)0.89 (0.79-1.01)0.90 (0.75-1.09)0.90 (0.75-1.09)



P ValueP Value0.050.050.060.060.270.27

P ValueP Value0.020.020.020.020.140.14

P ValueP Value0.980.980.980.980.940.94

ACE-I superiorACE-I superior Diuretics superiorDiuretics superior0.20.2 1.01.0 5.05.0



20

40

60

80

100

120

140

160

180

LIFE Study: Blood Pressure LIFE Study: Blood Pressure During Follow-upDuring Follow-up

Study Month

Systolic

Diastolic

Mean Arterial

mm

Hg

AtenololLosartan

6 5412 3018 24 36 42 480

LIFE Study Primary Composite EndpointLIFE Study Primary Composite Endpoint

0 6 12 18 24 30 36 42 48 54 60 66Losartan (n) 4605 4524 4460 4392 4312 4247 4189 4112 4047 3897 1889 901Atenolol (n) 4588 4494 4414 4349 4289 4205 4135 4066 3992 3821 1854 876

Study Month

Pro

port

ion

of

pati

en

ts

wit

h fi

rst

even

t (%

)Intention-to-treat

Losartan

Atenolol

2

4

6

8

10

12

14

16

Adjusted risk reduction 13·0%, P=0·021Unadjusted risk reduction 14·6%, P=0·009

LIFE Study Fatal and Non-Fatal LIFE Study Fatal and Non-Fatal Myocardial InfarctionMyocardial Infarction

Intention-to-treat

1

2

3

4

5

6

7

Pro

port

ion

of

pati

en

ts

wit

h fi

rst

even

t (%

)

Atenolol

Losartan

Adjusted Risk Reduction -7·3%, P=0·49Unadjusted Risk Reduction -5·0%, P=0·63

Study Month

0 6 12 18 24 36 42 48 54 60 6630

LIFE Study Fatal and Non-Fatal StrokeLIFE Study Fatal and Non-Fatal StrokeP

rop

ort

ion

of

pati

en

ts

wit

h fi

rst

even

t (%

)

Intention-to-treat

Losartan

Atenolol

Adjusted risk reduction 24·9%, P=0·001Unadjusted risk reduction 25·8%, P=0·0006

Study Month

1

2

3

4

5

6

7

8

0 6 12 18 24 36 42 48 54 60 6630

-25

-20

-15

-10

-5

0

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.Farsang C et al. J Hpertens 2000, NentelJ M et al. Clin Ther 2000, Manolis AJ et al. (Aramis study), J HYpertens 2003.

SBPSBP DBPDBP PPPP

mm

mm

Hg

Hg

ANGIOTENSIN II ANTAGONISTS ANGIOTENSIN II ANTAGONISTS IN ISOLATED SYSTOLIC HYPERTENSIONIN ISOLATED SYSTOLIC HYPERTENSION

LIFE StudyLIFE Study ISH ISH SubgroupSubgroup Composite of CV Death, Stroke, and MIComposite of CV Death, Stroke, and MI

0 6 12 18 24 30 36 42 48 54 60 66Study month

0

2

4

6

8

10

12

14

16

18

En

dp

oin

t ra

te (

%)

AtenololLosartan

Unadjusted relative risk=29%; P=0.02Adjusted relative risk reduction=25%; P=0.06

CV=cardiovascular MI=myocardial infarction

LIFE StudyLIFE Study DiabetesDiabetes SubgroupSubgroup Primary Composite CV EndpointPrimary Composite CV Endpoint

Adjusted risk reduction 24·5%, P=0·031Unadjusted risk reduction 26.7%, P=0·017

24

20

16

12

8

4

Pro

port

ion

of

pati

en

ts

wit

h fi

rst

even

t (%

)

LosartanAtenolol

0 6 12 18 24 36 42 48 54 60 6630Losartan (n) 586 569 558 548 532 520 513 501 484 459 237 127Atenolol (n) 609 588 562 552 540 527 507 486 472 434 204 99

Study Month

Effect of Losartan on Sudden Cardiac Death Effect of Losartan on Sudden Cardiac Death

in People with Diabetes: Data From the LIFE Studyin People with Diabetes: Data From the LIFE Study

CV DeathCV Death CHD DeathCHD Death Sudden DeathSudden Death Non SDNon SD Non Coronary CV Death

Non Coronary CV Death

-60-60

-50-50

-40-40

-30-30

-20-20

-10-10

00

1010

## p<0.052p<0.052

Lindholm LH, et al: Lancet 2003Lindholm LH, et al: Lancet 2003

Adjusted HR (95% CI)Adjusted HR (95% CI)

#: p< 0.03#: p< 0.03

##

12,112,1

7,27,2

0

5

10

15

Atenolol n=330

Losartan n=332

%

* Cornell Voltage < 2400 and Sokolow-Lyon < 24

RR: 45%RR: 45%

p=0.019p=0.019

LIFE Primary Composite EndpointLIFE Primary Composite Endpointin Subgroup: Patients without LVH* (n=662)in Subgroup: Patients without LVH* (n=662)



ACEIvs.

ß blockers/Diur

CCBvs.

ß blockers/Diur

ACEIs/ CCBsvs.

ß bockers/Diur

Losartanvs.

Atenolol

Number of Patients 10,985 10,881 6614 9193

Number ofPrimary

Endpoints698 803 659 1096


MI,Stroke, CV

Death

MI,Stroke, CV Death


MI,Stroke, CV

Death


NSp = 0.52

NSp = 0.97

NSp = 0.89

13% RRp = 0.021

Losartan Is the First Antihypertensive to Provide Superior Benefits Losartan Is the First Antihypertensive to Provide Superior Benefits on Combined CV Morbidity and Death vs. an Active Comparatoron Combined CV Morbidity and Death vs. an Active Comparator

LIFE

LIFE: ConclusionsLIFE: 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* Defined as composite of CV death, MI, and stroke

How Could Losartan Reduce the Risk of Stroke How Could Losartan Reduce the Risk of Stroke “Beyond Blood Pressure”? Potential Sites of Action“Beyond Blood Pressure”? Potential Sites of Action

Cardiac remodeling/enlargement

Endothelial dysfunction

Prothrombotic state

Vascular remodeling

Ref 3, p 831, C1,¶1, L1Ref 4, p 469,C2, L4Ref 9, p 493,C1, ¶3, L1;p 496, C1, ¶3, L10Ref 5, p 1439,Fig 74-1 Ref 27,p 1653, ¶2

Please refer to notes page for reference citations.



24

20

16

12

8

4

Pro

port

ion

of

pati

en

ts

wit

h fi

rst

even

t (%

)

LosartanAtenolol


Study Month





-60-60

-50-50

-40-40

-30-30

-20-20

-10-10

00

1010

## p<0.052p<0.052



#: p< 0.03#: p< 0.03

##

12,112,1

7,27,2

0

5

10

15

Atenolol n=330

Losartan n=332

%


RR: 45%RR: 45%

p=0.019p=0.019




ACEIvs.

ß blockers/Diur

CCBvs.

ß blockers/Diur

ACEIs/ CCBsvs.

ß bockers/Diur

Losartanvs.

Atenolol


Number ofPrimary

Endpoints698 803 659 1096


MI,Stroke, CV

Death

MI,Stroke, CV Death


MI,Stroke, CV

Death


NSp = 0.52

NSp = 0.97

NSp = 0.89

13% RRp = 0.021


LIFE











How Did Losartan Reduce the Risk of Stroke How Did Losartan Reduce the Risk of Stroke “Beyond Blood Pressure”? Losartan Data“Beyond Blood Pressure”? Losartan Data



Prothrombotic state

Vascular remodeling

Reduced ECG–LVH

Improved endothelial function

Inhibition of platelet aggregationReduced proaggregatory factors

Inhibited atherosclerosis formationReduced carotid artery hypertrophy Reduced gluteal artery hypertrophy


Hemodynamic factors(central and

peripheral blood pressure)

Circulating factors(glucose, insulin, RBCs, PAI, TXA2,

uric acid)


Vascular remodeling


Prothrombotic state

Atheroscleroticplaque formation

Emboli formation

Thrombus/platelet aggregation

Embolic occlusion

Thrombotic occlusion

Ischemic stroke

Hemorrhagicstroke

Vascular hemorrhage

Hypothesis: Losartan May Reduce the Risk of Ischemic Strokes by an Effect on Cardiac Remodeling


Plaque fragments

Plaque rupture

LIFE: Losartan vs. Atenolol Reduced LIFE: Losartan vs. Atenolol Reduced ECG–LVHECG–LVH

–18

–16

–14

–12

–10

–8

–6

–4

–2

0Cornell product Sokolow-Lyon

Ch

ang

e fr

om

bas

elin

e (%

)

p<0.0001

p<0.0001LosartanAtenolol

Adapted from Dalhöf B et al Lancet 2002;359:995–1003.

Ref 25, p 1001, Fig 7




Prothrombotic state

Vascular remodeling

Reduced ECG–LVH





Hemodynamic factors (central and peripheral

blood pressure)


uric acid)


Vascular remodeling


Prothrombotic state


Emboli formation


Embolic occlusion


Ischemic stroke

Hemorrhagicstroke

Vascular hemorrhage

Hypothesis: Losartan May Reduce the Risk of Stroke by Altering Vascular Remodeling and Atherosclerosis


Plaque fragments

Plaque rupture

Losartan Reduced Atherosclerosis (Fatty Streaks) in Nonhuman Primates

Control

Losartan

Simian thoracic aorta dissected after 6-month exposure to a high-cholesterol diet (n=4)

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 LIFE: Losartan vs. Atenolol Reduced Carotid Artery HypertrophyArtery Hypertrophy

% C

han

ge

in in

tim

a-m

edia

lcr

oss

-sec

tio

nal

are

a

Intima-medial thickness—change from baseline at year 3

–7.9 %

–1.7 %

p<0.05

–9

–8

–7

–6

–5

–4

–3

–2

–1

0Atenolol (n=22)Losartan (n=23)

Ref 26,Source C,p 34, Table 5

-25

-20

-15

-10

-5

0

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.Farsang C et al. J Hpertens 2000, NentelJ M et al. Clin Ther 2000, Manolis AJ et al. (Aramis study), J HYpertens 2003.

SBPSBP DBPDBP PPPP

mm

mm

Hg

Hg

ANGIOTENSIN II ANTAGONISTS ANGIOTENSIN II ANTAGONISTS IN ISOLATED SYSTOLIC HYPERTENSIONIN ISOLATED SYSTOLIC HYPERTENSION

LIFE StudyLIFE Study ISH ISH SubgroupSubgroup Composite of CV Death, Stroke, and MIComposite of CV Death, Stroke, and MI

0 6 12 18 24 30 36 42 48 54 60 66Study month

0

2

4

6

8

10

12

14

16

18

En

dp

oin

t ra

te (

%)

AtenololLosartan

Unadjusted relative risk=29%; P=0.02Adjusted relative risk reduction=25%; P=0.06

CV=cardiovascular MI=myocardial infarction



24

20

16

12

8

4

Pro

port

ion

of

pati

en

ts

wit

h fi

rst

even

t (%

)

LosartanAtenolol


Study Month





-60-60

-50-50

-40-40

-30-30

-20-20

-10-10

00

1010

## p<0.052p<0.052



#: p< 0.03#: p< 0.03

##

12,112,1

7,27,2

0

5

10

15

Atenolol n=330

Losartan n=332

%


RR: 45%RR: 45%

p=0.019p=0.019




ACEIvs.

ß blockers/Diur

CCBvs.

ß blockers/Diur

ACEIs/ CCBsvs.

ß bockers/Diur

Losartanvs.

Atenolol


Number ofPrimary

Endpoints698 803 659 1096


MI,Stroke, CV

Death

MI,Stroke, CV Death


MI,Stroke, CV

Death


NSp = 0.52

NSp = 0.97

NSp = 0.89

13% RRp = 0.021


LIFE











How Could Losartan Reduce the Risk of Stroke How Could Losartan Reduce the Risk of Stroke “Beyond Blood Pressure”? Potential Sites of Action“Beyond Blood Pressure”? Potential Sites of Action



Prothrombotic state

Vascular remodeling

Ref 3, p 831, C1,¶1, L1Ref 4, p 469,C2, L4Ref 9, p 493,C1, ¶3, L1;p 496, C1, ¶3, L10Ref 5, p 1439,Fig 74-1 Ref 27,p 1653, ¶2





Prothrombotic state

Vascular remodeling

Reduced ECG–LVH





Hemodynamic factors(central and

peripheral blood pressure)


uric acid)


Vascular remodeling


Prothrombotic state


Emboli formation


Embolic occlusion


Ischemic stroke

Hemorrhagicstroke

Vascular hemorrhage

Hypothesis: Losartan May Reduce the Risk of Ischemic Strokes by an Effect on Cardiac Remodeling


Plaque fragments

Plaque rupture

LIFE: Losartan vs. Atenolol Reduced LIFE: Losartan vs. Atenolol Reduced ECG–LVHECG–LVH

–18

–16

–14

–12

–10

–8

–6

–4

–2

0Cornell product Sokolow-Lyon

Ch

ang

e fr

om

bas

elin

e (%

)

p<0.0001

p<0.0001LosartanAtenolol

Adapted from Dalhöf B et al Lancet 2002;359:995–1003.

Ref 25, p 1001, Fig 7




Prothrombotic state

Vascular remodeling

Reduced ECG–LVH





Losartan vs. Atenolol Improved Structure Losartan vs. Atenolol Improved Structure of Small Gluteal Arteriesof Small Gluteal Arteries

Adapted from Schiffrin EL et al Circulation 2000;101(14):1653–1659.

Structure

Med

ia/lu

men

rat

io (

%)

0

2

4

6

8

10B

efo

re

1 y

ear

Be

fore

1 y

ear

Losartan Atenolol

Ref 27, p 1654, C2, ¶4, L1; p 1656, Table 2, Row 4




Prothrombotic state

Vascular remodeling

Reduced ECG–LVH





Losartan vs. Atenolol Improved Endothelial Losartan vs. Atenolol Improved Endothelial Function of Small Gluteal ArteriesFunction of Small Gluteal Arteries

Adapted from Schiffrin EL et al Circulation 2000;101(14):1653–1659.

Endothelium-dependent relaxation

0

20

40

60

80

100 *

Max

imal

ace

tylc

ho

line

resp

on

se (

%)

Be

fore

1 y

ear

Be

fore

1 y

ear

Losartan Atenolol

Ref 27, p 1654, C2, ¶4, L1; p 1656, Table 2, Row 4; p 1657, Fig 3




Prothrombotic state

Vascular remodeling

Reduced ECG–LVH





Losartan Had Effects on Platelet Losartan Had Effects on Platelet Aggregation and Thrombus FormationAggregation 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 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


Losartan Inhibited Platelet Aggregation Losartan Inhibited Platelet Aggregation in Man (via EXP3179) in Man (via EXP3179)

Adapted from Krämer C et al Circ Res 2002;90:770–776.

Ref 36, p 774, Fig 4A

0

20

40

60

80

100

Pla

tele

t ag

gre

gat

ion

(%

)

Time (months)

420 6 8

* *

*p<0.0001 vs. placebo

PlaceboLosartan

Hemodynamic factors (central and peripheral,

blood pressure)

Circulating factors(Glucose, Insulin, RBCs, PAI, TXA2,

uric acid)


Vascular remodeling


Prothrombotic state

Atheroscleroticplaque

Emboli formation

Thrombus formation

Embolic occlusion


Ischemic stroke

Plaque fragments

Plaque rupture

Hemorrhagicstroke

Vascular hemorrhage

Losartan May Reduce the Risk of CV events by Molecular-Specific Effects


Losartanreduces uric acid

LIFE: Losartan vs. Atenolol Reduced the Rise in LIFE: Losartan vs. Atenolol Reduced the Rise in Serum Uric Acid without Affecting Renal FunctionSerum Uric Acid without Affecting Renal Function

Adapted from Høieggen A et al Kidney Int 2004;65:1–9.

Serum creatinine SUA

NS

µm

ol/L

0

5

10

15

20

25

30

35

40

45 Atenolol Losartan

p<0.0001

Ref 40, p 4, C2, ¶2, L1,3; p 5, C1, ¶1, L1, ¶2, L1 + calc

Calc:96.9–87.4=9.596.1–86.5=9.6

CRP CRP --at Concentrations Known to Predict CV Eventsat Concentrations Known to Predict CV Events- -

Upregulates AT-1 Receptors in Vascular Smooth MuscleUpregulates 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 CRP stimulates VSM cell migration. This effect was inhibited by losartan. losartan. Losartan per se did not affect VSM migration in the basal state. Losartan per se did not affect VSM migration in the basal state. Ang II increased VSM migration; this effect was potentiated in the Ang II increased VSM migration; this effect was potentiated in the presence of CRP and attenuated by presence of CRP and attenuated by NN-acetylcysteine (an anti--acetylcysteine (an anti-oxidant)oxidant)

Wang CH et al, Circulation. 2003;107:1783

ConclusionsConclusions



Prothrombotic state

Vascular remodeling

Reduced ECG–LVH


Inhibition of platelet aggregation Reduced proaggregatory factors

Inhibited atherosclerosis formation Reduced carotid artery hypertrophy Reduced gluteal artery hypertrophy


AtherogenesisAtherogenesis Inflammation

Insulin Resistance

Thrombogenesis

Conditions Associated with CV DiseaseObesity/MS/Diabetes, PCOS, HTN, Dyslipidemias, COPD, Systemic Inflammatory

Disorders, CRF, Chronic Infections, Homocystenemia, Pschyosocial Stress

CV DISEASESCHD, PVD, CVD, Cardiomyopathy, Arrhythmias, Restenosis,

Valvular HD, Vein Graft failure, Cardiac Allograft Vasculopathy, Pulmonary Arterial Hypertension

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