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The Losartan Intervention For Endpoint reductionin hypertension study

An investigator-initiated, prospective, community-based, multinational, double-blind, double-dummy, randomised, active-controlled, parallel-group study from 945 centres

Dahlöf B et al Lancet 2002;359:995-1003.

Steering Committee Chair: Co-chair:B. Dahlöf R.B. Devereux

http://www.cozaar.ae/

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Clinical Experience with Losartan

• Losartan is a leader in comprehensive clinical trials, encompassing– 30,000 patients– 4 mega-trials (LIFE, OPTIMAAL, ELITE II, RENAAL)– > 4500 publications

• Losartan and losartan-based regimen have been prescribed to 12 million patients worldwide

• Losartan has proven excellent tolerability

Dahlöf B et al Am J Hypertens 1997; 10: 705713; Dickstein K et al Am J Cardiol 1999; 83: 477481; Pitt B et al Lancet 2000; 355: 15821587; Brenner BM et al N Eng J Med 2001; 345(12): 861869; Bloom BS Clin Ther 1998;20(4):671-681; Goldberg et al Am J Cardiol 1995;75:793-795.


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Hypertensive Patients Are at Increased Risk for Cardiovascular Events

Framingham Heart Study - Risk of Cardiovascular Events by Hypertensive Status in Patients Aged 35-64 Years; 36-Year Follow-Up

9.5

3.3 2.45

2 3.5 2.1

45.4

21.3

12.4

6.29.9

7.3

13.9

6.3

22.7

0

10

20

30

40

50

Men Women Men Women Men Women Men Women

Normotensive

Hypertensive

Risk Ratio 2.0 2.2 3.8 2.6 2.0 3.7 4.0 3.0

Excess Risk 22.7 11.8 9.1 3.8 4.9 5.3 10.4 4.2

Coronary Disease Stroke Peripheral ArteryDisease

Cardiac Failure

Bie

nni

al A

ge-A

djus

ted

Rat

e pe

r 10

00

Kannel WB JAMA 1996;275(24):1571-1576.


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Hypertension Treatment Significantly Reduced Mortality and MorbidityVA Cooperative Study Group – Estimated Cumulative Incidence of

All Morbid Events Over 5 Years

Veterans Administration Cooperative Study Group on antihypertensive agents JAMA 1970;213(7):1143-1152.

0

10

20

30

40

50

60

0 1 2 3 4 5Years

Est

imat

ed C

umul

ativ

e In

cide

nce

of A

ll M

orbi

d E

vent

s (%

)

Control - Placebo

Active Treatment Groups - Diuretic-based regimen and hydralazine


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Beta Blockers and Diuretics Lower Risk of Cardiovascular Events

• In hypertension, beta blockers and diuretics have proven risk reduction in cardiovascular morbidity and mortality vs. placebo

– STOP, HEP, MRC Trials

• Hypertension guidelines recommend beta blockers or diuretics as one of the initial treatments for hypertension

– JNC-VI, WHO/ISH Hypertension Treatment Guidelines

Dahlöf B et al. Lancet 1991;338:1281-85; Coope J et al Brit Med J 1986;293:1145-51; MRC Working Party Brit Med J 1985;291:97-104; JNC-VI Treatment of High Blood Pressure Guidelines,1999 WHO/ISH Hypertension Guidelines.


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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

Other Mega-trials Have Not Shown Superiority on Combined CV Morbidity and Mortality vs. an Active Comparator

These data are from 3 independent, non-comparative studies.

Hansson L et al Lancet 1999;353:611-616; Hannson L et al Lancet 2000;356:359-365; Hannson L et al Lancet 1999;354(9192):1751-1756.


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GFRProteinuriaAldosterone releaseGlomerular sclerosis

Angiotensin II Plays a Central Role inOrgan Damage

Adapted from Willenheimer R et al Eur Heart J 1999; 20(14): 9971008; Dahlöf B J Hum Hypertens 1995; 9(suppl 5): S37S44; Daugherty A et al J Clin Invest 2000; 105(11): 16051612; Fyhrquist F et al J Hum Hypertens 1995; 9(suppl 5): S19S24; Booz GW, Baker KM Heart Fail Rev 1998; 3: 125130; Beers MH, Berkow R, eds. The Merck Manual of Diagnosis and Therapy. 17th ed. Whitehouse Station, NJ: Merck Research Laboratories 1999: 16821704; Anderson S Exp Nephrol 1996; 4(suppl 1): 3440; Fogo AB Am J Kidney Dis 2000; 35(2): 179188.

Atherosclerosis*VasoconstrictionVascular hypertrophyEndothelial dysfunction

LV hypertrophyFibrosisRemodelingApoptosis

Stroke

DEATH

*preclinical dataLV = left ventricular; MI = myocardial infarction; GFR = glomerular filtration rate

Hypertension

Heart failureMI

Renal failure

AII AT1 receptor


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LIFE: Rationale

• To date, no treatment of essential hypertension has proven additional protective benefits for prevention of combined CV morbidity and mortality beyond lowering blood pressure with beta blockers and diuretics

• LVH is a strong risk factor for cardiovascular events

• Selective AII antagonism with losartan may reduce the risk of cardiovascular morbidity and death beyond blood-pressure lowering in patients with HT and LVH

Adapted from Dahlöf B et al Lancet 2002;359:995-1003; Dahlöf B et al Am J Hypertens 1997; 10: 705713; Levy D Drugs 1988; 35(suppl 5): 15; Verdechhia et al Circulation 2001;104:2039-2044; Kannel WB Am J Med 1983;

75(suppl 3A): 411.


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Hypothesis

Losartan will reduce the incidence of the primary composite endpoint of cardiovascular morbidity and mortality (defined as stroke, MI or cardiovascular death) to a greater extent as compared to atenolol in patients with essential hypertension and LVH

Dahlöf B et al Am J Hypertens 1997; 10: 705713.


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LIFE: Choice of Atenolol as Comparator

• A rigorous test of the study hypothesis required a comparator that had already been shown to reduce the risk of cardiovascular morbidity and mortality

• Beta blockers have well established beneficial cardiovascular effects in higher-risk patients

• Atenolol is the most widely prescribed beta blocker

Dahlöf B et al Am J Hypertens 1997; 10: 705713; MacMahon S, Rodgers A J Vasc Med Biol 1993; 4: 265271; Collins R et al Lancet 1990; 335: 827838; Dahlöf B et al Am J Hypertens 1995; 8: 578583; IMS 2002, MAT Patient Days of Therapy - Beta Blocker Market Share.


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LIFE: A Landmark Study

• 9193 hypertensive patients with LVH, aged 55-80 years

• Mean 4.8-year follow-up

• 44,119 patient-years of follow-up

• 945 study sites in 7 countries

• 1096 patients with primary endpoints

Investigator-initiated, prospective, double-blind, active-controlled, intention-to-treat, community-based study



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Dahlöf B et al Am J Hypertens 1997;10:705713.

LIFE: Inclusion Criteria

• Age 55–80 years

• Previously treated or untreated hypertension

• Diastolic BP 95–115 mmHg or systolic BP 160–200 mmHg

• ECG-confirmed LVH

– Cornell Voltage Product > 2440 mm X msec

– Sokolow-Lyon > 38 mm


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* Titration encouraged if SiDBP >90 mmHg or SiSBP >140 mmHg but was mandatory if SiBP >160 / 95 mmHg**Other antihypertensives excluding ACEIs, AII antagonists, beta blockersHCTZ=hydrochlorothiazide, SiDBP= sitting diastolic blood pressure, SiSBP=sitting systolic blood pressure Dahlöf B et al Am J Hypertens 1997;10:705713.

LIFE: Design/Dosing Titration

Day 14

Day7

Day1

Mth1

Mth2

Mth 4

Mth6

Yr1

Yr1.5

Yr2

Yr2.5

Yr3

Yr3.5

Yr4

Yr5

* Titration to target blood pressure: <140/90 mmHg

Placebo Losartan 50 mg

Atenolol 50 mg

Losartan 50 mg + HCTZ 12.5 mg*

Losartan 100 mg + HCTZ 12.5 mg*

Losartan 100 mg + HCTZ 12.5- 25 mg + others**

Atenolol 50 mg + HCTZ 12.5 mg*

Atenolol 100 mg + HCTZ 12.5 mg*

Atenolol 100 mg + HCTZ 12.5- 25 mg + others**


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LIFE: Baseline CharacteristicsLosartan Atenolol(n=4605) (n=4588)

Age, years 66.9 66.9Female, % 54% 54%BMI, kg/m2 28.0 28.0Race, % Caucasian 92.5% 92.5% Others 7.5% 7.5%BP, mmHg 174.3/97.9 174.5/97.7Heart Rate, bpm 73.9 73.7LVH-Cornell Product, mm X msec 2834.4 2824.1LVH-Sokolow-Lyon, mm 30.0 30.1Framingham Risk Score 0.223 0.225Smokers, % 16% 17%

Data are presented as mean.



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LIFE: Baseline Characteristics (cont’d)

Losartan Atenolol (n=4605) (n=4588)

• Medical History, %– DM 13% 13%– ISH (>160/<90 mmHg) 14% 15%– CHD 17% 15%– CVD 8% 8%

• Total Cholesterol, mmol/L 6.0 6.1

• Glucose, mmol/L 6.0 6.0

Data are presented as mean.



0

2

4

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8

10

12

14

16

Pro

po

rtio

n o

f p

ati

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ts w

ith

fir

st

ev

en

t (%

)Composite of CV death, stroke and MI

Losartan

Atenolol

LIFE: Primary Composite Endpoint

Study Month0 6 12 18 24 30 36 42 48 54 60 66

Losartan 4605 4524 4460 4392 4312 4247 4189 4112 4047 3897 1889 901Atenolol 4588 4494 4414 4349 4289 4205 4135 4066 3992 3821 1854 876

Adjusted Risk Reduction 13.0%, p=0.021Unadjusted Risk Reduction 14.6%, p=0.009


Number at Risk

16

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Stroke

Losartan

Atenolol

Adjusted Risk Reduction 24.9%, p=0.001Unadjusted Risk Reduction 25.8%, p=0.0006

Study Month0 6 12 18 24 30 36 42 48 54 60 660

1

2

3

4

5

6

7

8



Fatal and nonfatal strokeP

rop

ort

ion

of

pa

tie

nts

wit

h f

irs

t e

ve

nt

(%)

Number at Risk


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Losartan Atenolol RR p RR p (n=4605) (n=4588) (%) (%)

Primary composite** 508 588 -13 0.021 -15 0.009

CV mortality 204 234 -11 0.206 -13 0.136

Stroke 232 309 -25 0.001 -26 0.0006

MI 198 188 +7 0.491 +5 0.628

Total mortality 383 431 -10 0.128 -12 0.077

New-onset DM*** 241 319 -25 0.001 -25 0.001

LIFE: Primary and Secondary Outcomes

* For degree of LVH and Framingham risk score at randomization ** CV mortality, stroke and MI; patients with a first primary event*** Among patients without diabetes at randomization (losartan n=4019; atenolol, n=3979)


UnadjustedAdjusted*


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LIFE: Comparable Blood-Pressure Reductions

0 6 12 18 24 30 36 42 48 54

Study Month

40

50

60

70

80

90

100

110

120

130

140

150

160

170

180

Systolic

Diastolic

Mean Arterialmm

Hg

Atenolol 145.4 mmHg*

Losartan 144.1 mmHg*

Atenolol 80.9 mmHg*

Losartan 81.3 mmHg*

* Mean BP at last visitDahlöf B et al Lancet 2002;359:995-1003.

Atenolol 102.4 mmHg*

Losartan 102.2 mmHg*


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LIFE: Number of Patients on Study Drug atEndpoint or Termination of Follow-Up

Losartan Atenolol

• 50 mg only 9% 10%• 50 mg plus additional therapy*

including HCTZ 18% 20%• 100 mg with or without additional

therapy* including HCTZ 50% 43%• Off-study therapy 23% 27%

Mean Dosage: 82 mg 79 mg

*Excluding ACEIs, AIIAs, beta blockers.



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LIFE: Change from Baseline in LVH Regression

-18

-16

-14

-12

-10

-8

-6

-4

-2

0Cornell Product Sokolow-Lyon

Mea

n c

han

ge

fro

m b

asel

ine

(%)

Losartan Atenolol

p<0.0001


10.2 %9.0 %

15.3 %

4.4 %

p<0.0001


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LIFE: Adjustments for Difference

* Unadjusted for Framingham risk score and LVH

B. Dahlöf at the American College of Cardiology, Atlanta, GA, March 17-20, 2002.

• Adjustment none*– Treatment effect -15%

Achieved BP– Adjustment for SBP

• Treatment effect -14%

Regression of ECG-confirmed LVH – Adjustment for Cornell Voltage Duration Product (CVDP) and

Sokolow-Lyon (SL)• Treatment effect -10%

Conclusion: Adjusting for differences in achieved BP and degree of LVH regression only explains part of the study outcome


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Intention-to-Treat

LIFE: New-Onset Diabetes

Losartan

AtenololAtenolol (N=3979)Losartan (N=4019)

Study Month 0 6 12 18 24 30 36 42 48 54 60 660.00

0.01

0.02

0.03

0.04

0.05

0.06

0.07

0.08

0.09

0.10

Adjusted Risk Reduction 25 %, p<0.001Unadjusted Risk Reduction 25 %, p<0.001

B. Dahlöf at the American College of Cardiology, Atlanta, GA, March 17-20, 2002.

En

dp

oin

t R

ate


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0

5

10

15

20

Discontinuation due to all AEs

Discontinuation due todrug-related AE

Discontinuation due toserious drug-related AE

p<0.0001

p<0.0001

p=0.006

LIFE: Discontinuations Due to Adverse Experiences

Atenolol

Losartan


Pro

po

rtio

n o

f p

ati

en

ts w

ho

dro

pp

ed

ou

t b

ec

au

se

of

AE

(%

)


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Mega-trials CAPPP NORDIL STOP-2

ComparatorTreatments

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

Composite PrimaryEndpoint

MI,Stroke, CV

Death

MI,Stroke, CV Death

Fatal MI, FatalStroke, FatalCV Disease

MI,Stroke, CV

Death

Differences onPrimary Endpoint

NSp = 0.52

NSp = 0.97

NSp = 0.89

13% RRp = 0.021

Losartan Is the First Antihypertensive to Provide Superior Benefits

on Combined CV Morbidity and Death vs. an Active Comparator

These data are from four independent, noncomparative studies.

Hansson L et al Lancet 1999;353:611-616; Hannson L et al Lancet 2000;356:359-365; Hannson L et al Lancet 1999;354(9192):1751-1756; Dahlöf et al Lancet 2002;359:995-1003.


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LIFE: Summary

• Losartan-based antihypertensive therapy provided superior benefit on combined cardiovascular morbidity and death vs. atenolol:

– Superior risk reduction in the primary composite endpoint (CV death, stroke, and MI) of 13% (p=0.021)*

– Superior risk reduction in stroke of 25% (p=0.001)

• Losartan and atenolol provided substantial and comparable effective blood-pressure reduction

• Losartan was better tolerated with significantly fewer discontinuations due to adverse events

* No significant differences in cardiovascular death and MI vs. atenolol


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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

* Defined as composite of CV death, MI, and stroke


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LIFE: Implications

• The greater clinical benefit and enhanced tolerability demonstrated by losartan in The LIFE Study Group suggest that broader use of losartan may improve outcomes for hypertensive patients with LVH

• “Our results are directly applicable in clinical practice and should affect future guidelines.”1

The LIFE Study Group


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LIFE: Committees

• Steering Committee– Björn Dahlöf (Chair), Richard B. Devereux (Co-chair),

Stevo Julius (US Coordinator), Sverre E. Kjeldsen (Secretaryand Scandinavian Coordinator), Gareth Beevers, Ulf de Faire,Frej Fyhrquist, Hans Ibsen, Lars H. Lindholm, Markku Nieminen, Per Omvik, Suzanne Oparil, Ole Lederballe-Pedersen, Hans Wedel, Krister Kristianson (non-voting)

• Endpoint Classification Committee– Daniel Levy (US), Kristian Thygesen (Denmark)

• Data Safety Monitoring Board– John Kjekshus (Chairman, Norway), Lewis Kuller (US),

Pierre Larochelle (Canada), Giuseppe Mancia (Italy), Joël Ménard (France), Stuart Pocock (UK), John Reid (UK), Michael Weber (US)



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Back-Up Slides


LIFE: Myocardial Infarction and CV Mortality


Cardiovascular mortality

AtenololLosartan

Pro

po

rtio

n o

f p

atie

nts

(%

)Adjusted RR 11.4%, p=0.206Unadjusted RR 13.3%, p=0.136

Fatal and nonfatal MI

0 6 12 18 24 30 36 42 48 54 60 660

1

2

3

4

5

6

7

8

Pro

po

rtio

n o

f p

atie

nts

wit

h f

irst

eve

nt

(%)

Adjusted RR -7.3%, p=0.491Unadjusted RR -5.0%, p=0.628

AtenololLosartan


0 6 12 18 24 30 36 42 48 54 60 660

1

2

3

4

5

6

7

8


Study Month

Study Month

31

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LIFE: Cardiovascular Benefits of Losartan Confirmed in Diabetic Subgroup

Study Month 0 6 12 18 24 30 36 42 48 54 60 66Losartan (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

24

20

16

12

8

4

0Pro

po

rtio

n o

f p

atie

nts

wit

h f

irs

t e

ven

t (%

)

Adjusted RR = 24.5%; p=0.031Unadjusted RR = 26.7%; p=0.017

Losartan

Atenolol

* No significant differences in cardiovascular death and MI vs. atenolol.Lindholm LH et al Lancet 2002;359:1004-1010.

Primary composite endpoint (composite of CV death, MI and stroke)*

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LIFE: Key Lab Values

Lab Value Losartan (n=4605) Atenolol (n=4588)

Baseline Year 4 Change Baseline Year 4 Change

Hemoglobin, gm/L 142.5 138.8 -3.7 142.8 141.5 -1.3Sodium, mmol/L 140.3 139.9 -0.5 140.3 140.0 -0.3Potassium, mmol/L 4.2 4.1 0.0 4.2 4.1 -0.1ALT, IU/L 28.2 27.0 1.2 28.4 27.6 0.8Glucose, mmol/L 6.0 6.2 0.3 6.0 6.3 0.4Total cholesterol, mmol/L 6.0 5.7 -0.3 6.1 5.8 -0.3HDL, mmol/L 1.50 1.47 -0.03 1.50 1.41 -0.09Uric acid, mol/L 328.2 347.7 19.5 328.9 375.9 47.2Creatinine, mmol/L 85.9 97.0 11.2 85.2 96.2 11.0

Data are presented as mean.ALT = alanine aminotransferase


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LIFE: References

Before prescribing, please consultfull product information.

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LIFE: References


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LIFE: References


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LIFE: References


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LIFE: References


1 downloaded from the l osartan i ntervention f or e ndpoint reduction in hypertension study an...

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