The document summarizes key findings from the LIFE study, a large clinical trial that compared losartan to atenolol for reducing cardiovascular risk in hypertensive patients with left ventricular hypertrophy. The main findings were: 1) Losartan reduced the primary composite endpoint of cardiovascular death, stroke or myocardial infarction by 13% compared to atenolol, with comparable blood pressure reduction in both groups. 2) Secondary analyses found losartan reduced risks for several individual components of the primary endpoint including stroke and heart failure hospitalizations. 3) Losartan provided greater regression of left ventricular hypertrophy compared to atenolol based on electrocardiogram and echocardiogram assessments

1. Effective COZAAR during treatment on
high blood pressure patients and further…

2. CV Risk factorsCV Risk factors
Role of
RAS
Cardiovascular disease as a sequence of related
pathological events
FromFrom CirculationCirculation 2006;114:2850-70.2006;114:2850-70.
Hypertension : LIFE
Stroke, MI: LIFE
Heart Failure:
ELITE II, LIFE,
HEAAL
Vascular : ELITE
II
Diabetes- Renal :
RENAAL

3. Clinical Experience with Losartan
 Losartan is a leader in comprehensive clinical trials, encompassing
– 30,000 patients
– 5 mega-trials (LIFE, OPTIMAAL, ELITE II, RENAAL,
HEAAL)
– > 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: 705−713; Dickstein K et al Am J Cardiol 1999; 83: 477−481; Pitt B et
al Lancet 2000; 355: 1582−1587; Brenner BM et al N Eng J Med 2001; 345(12): 861−869; Bloom BS Clin
Ther 1998;20(4):671-681; Goldberg et al Am J Cardiol 1995;75:793-795.

4. The Losartan Intervention For Endpoint reduction
in 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.

5. The LIFE Study
 Study hypothesis: Compared to atenolol, losartan would reduce
the incidence of cardiovascular morbidity and mortality in patients
with essential hypertension and LVH
 The primary endpoint was a composite of cardiovascular morbidity
and mortality as measured by the combined incidence of:
– Cardiovascular mortality
– Stroke
– Myocardial infarction
 The study evaluated whether a losartan-based regimen would
reduce the risk of cardiovascular morbidity and mortality more than
an atenolol-based regimen, in the face of comparable blood
pressure control in both treatment groups
Dahlöf B et al Lancet 2002;359:995-1003.

6. LIFE: Results
 Losartan reduced the risk of the primary composite endpoint
(cardiovascular mortality, stroke or MI)
 Both the atenolol- and losartan-based regimens reduced blood
pressure to a comparable level
 The safety profile of losartan was consistent with the currently
approved US product circular for COZAAR
Dahlöf B et al Lancet 2002;359:995-1003.

7. COZAAR (losartan)
in Hypertensive Patients
with Left Ventricular Hypertrophy
Dahlöf B et al Lancet 2002;359:995-1003.

8. Hypertension:
A Major Public Health Issue
 The most common cardiovascular condition in the world
 Risk factor for development of cardiovascular, cerebrovascular,
renovascular, and peripheral vascular disease
 Adverse sequelae may be due to morphologic and functional
changes in the cardiovascular system, including:
– Remodeling of left ventricle
– Remodeling of systemic vasculature
– Development of vascular endothelial dysfunction
Dahlöf B et al Lancet 2002;359:995-1003.

9. Adjudicated by Endpoint Classification Committee
LIFE: Other Endpoints
 Total mortality (cause of death)
 Hospitalization due to angina pectoris
 Hospitalization due to heart failure
 Coronary artery revascularizations
 Peripheral revascularizations
 Resuscitated cardiac arrest

10. * Other antihypertensives excluding ACEIs, AΙΙ antagonists, -blockers.
Day
14
Day
7
Day
1
Mth
1
Mth
2
Mth
4
Mth
6
Yr
1
Yr
1.5
Yr
2
Yr
2.5
Yr
3
Yr
3.5
Yr
4
Yr
5
Titration to target blood pressure: <140 / <90 mm Hg
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*
LIFE: Study Design (I)
Randomization
Dahlöf B et al Lancet 2002;359:995-1003.

11. LIFE: Patient Follow-Up
Losartan (N=4605)
Follow-up through death or 16-Sep-01
Patients
All endpoints 4500 (98%)
Partial 105 (2%)
Vital status only 57 (1.0%)
Withdrawn consent 44 (0.9%)
Lost to follow-up 4 (0.1%)
Patient-days of follow-up
All endpoints 98.6%
Vital status 99.3%
Atenolol (N=4588)
Follow-up through death or 16-Sep-01
Patients
All endpoints 4496 (98%)
Partial 92 (2%)
Vital status only 50 (1.0%)
Withdrawn consent 34 (0.8%)
Lost to follow-up 8 (0.2%)
Patient-days of follow-up
All endpoints 99.0%
Vital status 99.4%

12. 0 6 12 18 24 30 36 42 48 54 60 66
Study Month
0
2
4
6
8
10
12
14
16
withFirstEvent Losartan
Atenolol
Los925 ACM Primary ITT 1 Dec. 24, 2002
Adjusted risk reduction 13.1%, p=0.021
Unadjusted risk reduction 14.6%, p=0.009
n at risk
Losartan (n) 4605 4460 4312 4189 4045 1888
Atenolol (n) 4588 4414 4289 4135 3992 1854
PercentofPatients
LIFE: Primary Endpoint

13. LIFE: Systolic Blood Pressure
Prestudy 12 24 36 48 60
Time (months)
120
140
160
180
mmHg
Los925 ACM BP SBP Mean1A Dec. 26, 2002
Losartan
Atenolol
Reduction at Last Visit Before
Endpoint or End of Follow-up
Losartan Atenolol p-Value
-30.2 -29.1 0.015
Time-Averaged Difference =
-1.15
mmHg(mean)

14. LIFE: Heart Rate
Prestudy 12 24 36 48 60
Time (months)
60
65
70
75
80
Beats/Min
Los925 ACM BP Heart Rate1A Dec. 26, 2002
Losartan
Atenolol
Reduction at Last Visit Before
Endpoint or End of Follow-up
Losartan Atenolol p-Value
-1.8 -7.7 <0.001
Time-Averaged Difference = 6.49
Beats/Min(mean)

15. LIFE: Primary Efficacy Result
 In hypertensive patients with ECG evidence of LVH, compared
to atenolol-based therapy:
– Losartan-based therapy reduced the risk of the primary
endpoint of cardiovascular morbidity and mortality
(cardiovascular death, stroke and myocardial infarction) by
13% with comparable reduction in blood pressure

16. LIFE: Secondary Component Endpoints
0.5 1 1.5 2
← Favors Losartan Favors Atenolol →
Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)
←
Endpoints
204
40
125
39
232
198
234
62
124
48
309
188
No. of Events
Los AtlAtlAtlAtlAtlAtlAtlAtlAtlAtlAtlAtlAtlAtlAtlAtlAtlAtl
Los925 ACM HEB Sec 7A Dec. 10, 2002
CV Death
Stroke
Coronary Disease
Other
Stroke (fatal/nonfatal)
MI (fatal/nonfatal)MI (fatal/nonfatal)MI (fatal/nonfatal)MI (fatal/nonfatal)MI (fatal/nonfatal)MI (fatal/nonfatal)MI (fatal/nonfatal)MI (fatal/nonfatal)MI (fatal/nonfatal)MI (fatal/nonfatal)MI (fatal/nonfatal)MI (fatal/nonfatal)MI (fatal/nonfatal)MI (fatal/nonfatal)MI (fatal/nonfatal)MI (fatal/nonfatal)MI (fatal/nonfatal)MI (fatal/nonfatal)MI (fatal/nonfatal)MI (fatal/nonfatal)MI (fatal/nonfatal)MI (fatal/nonfatal)MI (fatal/nonfatal)MI (fatal/nonfatal)MI (fatal/nonfatal)MI (fatal/nonfatal)MI (fatal/nonfatal)MI (fatal/nonfatal)MI (fatal/nonfatal)MI (fatal/nonfatal)MI (fatal/nonfatal)
Adjusted for FRS and ECG-LVH.
CHD

17. LIFE: Other Endpoints
Adjudicated by Endpoint Committee
Angina Hosp.
Heart Failure Hosp.
Coronary
Revascularization
Noncoronary
Revascularization
Resuscitated
Cardiac Arrest
EndpointsEndpointsEndpointsEndpointsEndpointsEndpointsEndpointsEndpointsEndpointsEndpointsEndpointsEndpointsEndpointsEndpointsEndpointsEndpointsEndpointsEndpointsEndpoints
No. of Events
Los Atl
160
153
169
102
9
141
161
168
129
55555555555555
Los925 ACM HEB Sec3A Dec. 11, 2002
0.5 1 2
← Favors Losartan Favors Atenolol →
Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)
N/A
Adjusted for FRS and ECG-LVH.

18. LIFE: ECG-LVH
Change in Cornell Voltage-Duration Product (mmmsec)
0 6 12 24 36 48 60
Study Month
-400
-300
-200
-100
0
Mean
Los925 ACM CP Mean 1B Dec. 26, 2002
Losartan
Atenolol
Reduction at Last Visit Before
Endpoint or End of Follow-up
Losartan Atenolol p-Value
-290 -124 <0.001

19. LIFE: ECG-LVH
Change in Sokolow-Lyon Criterion (mm)
Reduction at Last Visit Before
Endpoint or End of Follow-up
Losartan Atenolol p-Value
-4.6 -2.7 <0.001
0 6 12 24 36 48 60
Study Month
-5
-4
-3
-2
-1
0
Mean
Los925 ACM SL Mean 1B Dec. 26, 2002
Losartan
Atenolol

20. LIFE: ECHO Substudy (n=965)
Change in Left Ventricular Mass Index (g/m2
)
Reduction in LVMI
at last available echo (g/m2
):
Losartan Atenolol p-Value
-21.7 -17.7 0.011
0 12 24 36 48 60
Study Months
-30
-20
-10
0
Mean
Los925 ACM LVH Change Oct. 29, 2002
Losartan
Atenolol

21. LIFE: Disease Categories of Special Interest
Primary Endpoint
0.5 1 2
← Favors Losartan Favors Atenolol →
Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)
Diabetic (n=1195)
Non-Diabetic (n=7998)
ISH (n=1326)
Non-ISH (n=7867)Non-ISH (n=7867)Non-ISH (n=7867)Non-ISH (n=7867)Non-ISH (n=7867)Non-ISH (n=7867)Non-ISH (n=7867)Non-ISH (n=7867)Non-ISH (n=7867)Non-ISH (n=7867)Non-ISH (n=7867)Non-ISH (n=7867)Non-ISH (n=7867)Non-ISH (n=7867)Non-ISH (n=7867)Non-ISH (n=7867)Non-ISH (n=7867)Non-ISH (n=7867)Non-ISH (n=7867)Non-ISH (n=7867)
Los925 ACM heb all-diab-ish 3 Dec. 9, 2002
Population Los
103
405
75
433
Atl
139
449
104
484
Number
of Eventsof Eventsof Eventsof Eventsof Eventsof Eventsof Eventsof Events
p=0.170†
p=0.176†
†
Test for treatment-by-subgroup interaction.

22. LIFE: Patients with Diabetes
Primary Endpoint
0 6 12 18 24 30 36 42 48 54 60 66
Study Month
0
4
8
12
16
20
24
withFirstEvent Losartan
Atenolol
Los925 ACM Diabetes composite Dec. 24, 2002
Adjusted risk reduction 24.5%, p=0.031
n at risk
Losartan (n) 586 558 532 513 484 237
Atenolol (n) 609 562 540 507 472 204
PercentofpatientsPatients

23. LIFE: Patients with Diabetes
Secondary Component Endpoints
0.3 0.5 1 1.5 2
Favors Favors
Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)
← Losartan Atenolol →
CV Death
Stroke (Fatal/Non-Fatal)
MI (Fatal/Non-Fatal)MI (Fatal/Non-Fatal)MI (Fatal/Non-Fatal)MI (Fatal/Non-Fatal)MI (Fatal/Non-Fatal)MI (Fatal/Non-Fatal)MI (Fatal/Non-Fatal)MI (Fatal/Non-Fatal)MI (Fatal/Non-Fatal)MI (Fatal/Non-Fatal)MI (Fatal/Non-Fatal)MI (Fatal/Non-Fatal)MI (Fatal/Non-Fatal)MI (Fatal/Non-Fatal)MI (Fatal/Non-Fatal)MI (Fatal/Non-Fatal)MI (Fatal/Non-Fatal)MI (Fatal/Non-Fatal)MI (Fatal/Non-Fatal)
Endpoints Los
38
51
41
Atl
61
65
50
No. of EventsNo. of EventsNo. of EventsNo. of EventsNo. of EventsNo. of EventsNo. of EventsNo. of EventsNo. of EventsNo. of Events
Adjusted for FRS and ECG-LVH.

24. LIFE: Patients with Diabetes
Other Endpoints
0.3 0.5 1 1.5 2
← Favors Losartan Favors Atenolol →
Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)
Total Mortality
Heart Failure Hosp.
Angina Hosp.Angina Hosp.Angina Hosp.Angina Hosp.Angina Hosp.Angina Hosp.Angina Hosp.Angina Hosp.Angina Hosp.Angina Hosp.Angina Hosp.Angina Hosp.Angina Hosp.Angina Hosp.Angina Hosp.Angina Hosp.Angina Hosp.Angina Hosp.
Los925 ACM heb Diab 2B2 Dec. 11, 2002
Endpoints Los
63
32
30
Atl
104
55
30
Number
of Eventsof Eventsof Eventsof Eventsof Eventsof Eventsof Eventsof Events
Adjusted for FRS and ECG-LVH.

25. LIFE: Patients with Isolated Systolic Hypertension
Primary Endpoint
0 6 12 18 24 30 36 42 48 54 60 66
Study Month
0
2
4
6
8
10
12
14
16
18
PercentofPatients
Losartan (n) 666 639 612 585 562 260
n at risk
Atenolol (n) 660 628 603 573 555 239
withEvent
Los925 ACM ISH Subset 1 Dec. 24, 2002
Adjusted risk reduction 25.0%, p=0.059
Losartan
Atenolol

26. LIFE: Patients with Isolated Systolic Hypertension
Secondary Component Endpoints
0.3 0.5 1 1.5 2
Favors Favors
Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)
← Losartan Atenolol →
Endpoints Los
27
32
31
Atl
52
56
36
No. of EventsNo. of EventsNo. of EventsNo. of EventsNo. of EventsNo. of EventsNo. of Events
Los925 ACM HEB ISH 3B1A Dec. 24, 2002
CV Death
Stroke (Fatal/Non-Fatal)
MI (Fatal/Non-Fatal)MI (Fatal/Non-Fatal)MI (Fatal/Non-Fatal)MI (Fatal/Non-Fatal)MI (Fatal/Non-Fatal)MI (Fatal/Non-Fatal)MI (Fatal/Non-Fatal)MI (Fatal/Non-Fatal)MI (Fatal/Non-Fatal)MI (Fatal/Non-Fatal)MI (Fatal/Non-Fatal)MI (Fatal/Non-Fatal)MI (Fatal/Non-Fatal)MI (Fatal/Non-Fatal)MI (Fatal/Non-Fatal)MI (Fatal/Non-Fatal)
Adjusted for FRS and ECG-LVH.

27. LIFE: Patients with Isolated Systolic Hypertension
Other Endpoints
0.3 0.5 1 1.5 2
← Favors Losartan Favors Atenolol →
Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)
→
Total Mortality
Heart Failure Hosp.
Angina Hosp.
Endpoints Los
66
26
34
Atl
93
40
23
Number
of Eventsof Eventsof Events
Los925 ACM heb ISH 3B2 Dec. 23, 2002
Adjusted for FRS and ECG-LVH.

28. LIFE: Overall Efficacy Summary
 Primary endpoint:
– Losartan reduced the combined risk of CV death, stroke
and MI by 13%
 Secondary endpoints:
– Losartan reduced the risk of stroke by 25%
– Losartan produced a nonsignificant 11% reduction in the
risk of CV death:
• Reduction of fatal stroke by 35%
– No significant difference in the risk of fatal and nonfatal MI
– Losartan produced a greater reduction of LVH by ECG
 Losartan provided consistent reduction in the incidence of
cardiovascular events in high risk patients with diabetes or
isolated systolic hypertension, compared to atenolol

29. Intention-to-Treat
LIFE: New-Onset Diabetes
Losartan
Atenolol
Atenolol (N=3979)
Losartan (N=4019)
Study Month 0 6 12 18 24 30 36 42 48 54 60 66
0.00
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<0.001
Unadjusted Risk Reduction 25 %, p<0.001
B. Dahlöf at the American College of Cardiology, Atlanta, GA, March 17-20, 2002.
EndpointRate

30. LIFE: Safety Summary
 Losartan was well-tolerated and was associated with fewer
drug-related adverse experiences and discontinuations due
to adverse experiences than atenolol
– New diabetes was more likely with atenolol treatment
 The observed adverse experience profile of losartan in the
LIFE study population was consistent with that presented in
the currently approved US product circular for COZAAR

31. 0.5 1 1.5 2
← Favors Losartan Favors Atenolol →
Hazard Ratio (95% CI)
Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)
Endpoints
508
204
232
198
588
234
309
188
No. of Events
Los Atl
Endpoints Los AtlAtlAtlAtlAtlAtlAtlAtlAtlAtlAtlAtlAtlAtlAtlAtlAtlAtlAtl
Los925 ACM heb1A4-div Dec. 28, 2002
Primary
CV Death
Stroke (Fatal/Non-Fatal)
MI (Fatal/Non-Fatal)
Secondary ComponentsSecondary ComponentsSecondary ComponentsSecondary ComponentsSecondary ComponentsSecondary ComponentsSecondary ComponentsSecondary ComponentsSecondary ComponentsSecondary ComponentsSecondary ComponentsSecondary ComponentsSecondary ComponentsSecondary ComponentsSecondary ComponentsSecondary ComponentsSecondary ComponentsSecondary ComponentsSecondary ComponentsSecondary ComponentsSecondary ComponentsSecondary ComponentsSecondary ComponentsSecondary ComponentsSecondary ComponentsSecondary ComponentsSecondary ComponentsSecondary ComponentsSecondary ComponentsSecondary ComponentsSecondary Components
LIFE: Summary of Findings - Primary and
Secondary Component Endpoints
Adjusted for FRS and ECG-LVH at Baseline

32. ICARUS Sub-Study
Change from Baseline at Year 3
LIFE: Regression of Carotid Artery Hypertrophy
-9
-8
-7
-6
-5
-4
-3
-2
-1
0
Losartan (n=19) Atenolol (n=20)
%ChangeinIntima-Media
Cross-SectionalArea
-7.9 %
-1.7 %
p<0.05

33. Relationship Between Atrial Fibrillation
and Stroke
 Presence of atrial fibrillation is associated with 2- to 5-fold
increase in the risk of stroke†
 In the LIFE study:
– Diagnosis of atrial fibrillation
• Reported by investigator
• Detected on annual ECG by core reading center
– Baseline atrial fibrillation is associated with a 3.5-fold
increase in the risk of stroke
– Occurrence of new atrial fibrillation during treatment is
associated with a 5-fold increase in the risk of stroke
†
Ryder KM et al. Am J Cardiol 1999;84:131R-138R.

34. LIFE: Post-Hoc Analyses of Incidence of
Atrial Fibrillation
 Analyses of new occurrence of atrial fibrillation following
randomization:
– Excluded patients with baseline history or atrial fibrillation
on baseline ECG (Minnesota code)
– Three scenarios evaluated:
• Reported by investigator
• Detected by ECG
• Either of the above

35. LIFE: New Onset Atrial Fibrillation
Post-Hoc Analysis
Atrial Fibrillation
Atrial Fibrillation by ECG
Atrial Fibrillation by Inv./ECG
Endpoints
No. of Events
by Investigatorby Investigatorby Investigatorby Investigatorby Investigatorby Investigatorby Investigatorby Investigatorby Investigatorby Investigatorby Investigatorby Investigatorby Investigator
Los925 ACM Atrial Febr B Jan. 2, 2003
Los
304
165
346
Atl
360
240
416416416416416416416416416416416416416
0.5 1 1.5 2
Favors Favors
Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)
← Losartan Atenolol →

36. LIFE: Conclusion
 The LIFE study results support the proposed new indication
for COZAAR:
To reduce the risk of cardiovascular morbidity and
mortality as measured by the combined incidence of
cardiovascular death, stroke, and myocardial infarction in
hypertensive patients with left ventricular hypertrophy.

48. Losartan Heart Failure Survival Study
ELITE II
A Multicenter, Double-Blind, Randomized, Parallel,A Multicenter, Double-Blind, Randomized, Parallel,
Captopril-Controlled Study to Evaluate the Effects of LosartanCaptopril-Controlled Study to Evaluate the Effects of Losartan
on Mortality in Patients with Symptomatic Heart Failureon Mortality in Patients with Symptomatic Heart Failure
46 Countries; 289 Sites; 3152 Patients46 Countries; 289 Sites; 3152 Patients
• Steering CommitteeSteering Committee Co-ChairsCo-Chairs B. Pitt, P. Poole-WilsonB. Pitt, P. Poole-Wilson
• Data and Safety Monitoring CommitteeData and Safety Monitoring Committee ChairChair C. FurbergC. Furberg
• Clinical Endpoint Classification CommitteeClinical Endpoint Classification Committee ChairChair L. FrameL. Frame
• Coordinating Center: Merck Research LabsCoordinating Center: Merck Research Labs Study DirectorStudy Director R. SegalR. Segal

49. Study DesignStudy Design
Losartan Heart Failure Survival Study
ELITE II
≥60 yrs; NYHA II-IV; EF60 yrs; NYHA II-IV; EF ≤ 40%40%
ACE-I/AIIA naive or <7 days in 3 months prior to entryACE-I/AIIA naive or <7 days in 3 months prior to entry
Standard Rx (± Dig/Diuretics), ß-blocker stratificationStandard Rx (± Dig/Diuretics), ß-blocker stratification
CaptoprilCaptopril
50 mg 3 times daily50 mg 3 times daily
(N=1574)(N=1574)
Primary Endpoint: All-Cause MortalityPrimary Endpoint: All-Cause Mortality
Secondary Endpoint: Sudden Cardiac Death and/or Resuscitated ArrestSecondary Endpoint: Sudden Cardiac Death and/or Resuscitated Arrest
Other Endpoin: All-cause Mortality/HospitalizationsOther Endpoin: All-cause Mortality/Hospitalizations
Safety and TolerabilitySafety and Tolerability
Event DrivenEvent Driven
(Target 510 Deaths)(Target 510 Deaths)
~ 2 years~ 2 years
LosartanLosartan
50 mg Daily50 mg Daily
(N=1578)(N=1578)

50. Losartan Heart Failure Survival Study -
ELITE II Mortality by Cause
(Adjudicated)
0
5
10
15
Sudden
Death
Heart Failure MI Stroke Other CV Non-CV
%ofPatients
Losartan (N=1578) Captopril (N=1574)

51. Losartan Heart Failure Survival Study - ELITE
II Mortality by Subgroup
Hazard Ratio
Age
Gender
NYHA Class.
% EF
Beta Blockers
Overall
> 71
≤ 71
Male
Female
III/IV
II
≤ 32
> 32
With
Without
731
846
1102
476
801
777
793
785
354
1224
1578
730
844
1083
491
798
776
783
790
325
1249
1574
0.93
0.84
0.89
0.87
0.93
0.80
1.02
0.71
0.56
0.95
0.88
N N
Hazard
Ratio
LosartanCaptopril
1.00.80.60.4 2.0
Hazard Ratio of Death
with 95% C.I.Subgroups at Baseline
Favors Captopril Favors Losartan

52. Losartan Heart Failure Survival Study - ELITE II
Secondary Endpoint: Sudden Death / Resuscitated
Arrest
0 100 200 300 400 500 600 700
Days of Follow-up
0.0
0.2
0.4
0.6
0.8
1.0
Event-FreeProbability
LosartanLosartan (N=1578)(N=1578) 142 Events142 Events
CaptoprilCaptopril (N=1574)(N=1574) 115 Events115 Events
Captopril/Losartan Hazard Ratio (95% C.I.):Captopril/Losartan Hazard Ratio (95% C.I.):
0.80 (0.63, 1.03) P=0.080.80 (0.63, 1.03) P=0.08

53. Losartan Heart Failure Survival Study - ELITE
II Hospitalization By Cause (Adjudicated)
0
10
20
30
Heart
Failure
MI CAD Stroke/TIA Resusc
Arrest
Non-CV
%ofPatients
Losartan (N=1578) Captopril (N=1574)
p=NS between groupsp=NS between groups
##
## CAD includes angina, unstable angina, revascularization, etcCAD includes angina, unstable angina, revascularization, etc

54. Losartan Heart Failure Survival Study - ELITE II
Tertiary Endpoint: All-Cause Mortality / Hospitalization
0 100 200 300 400 500 600 700
Days of Follow-up
0.0
0.2
0.4
0.6
0.8
1.0
Event-FreeProbability
LosartanLosartan (N=1578)(N=1578) 752 Events752 Events
CaptoprilCaptopril (N=1574)(N=1574) 707 Events707 Events
Captopril/Losartan Hazard Ratio (95% C.I.):Captopril/Losartan Hazard Ratio (95% C.I.):
0.94 (0.85, 1.04) P=0.210.94 (0.85, 1.04) P=0.21

55. Losartan Heart Failure Survival Study - ELITE II
Withdrawal for Adverse Experience (Excluding
Death)
0
5
10
15
20
Any AE Drug-Related
AE
Cough HF
%ofPatients
Losartan (N=1578) Captopril (N=1574)**
****
pp0.001 between groups0.001 between groups
**
**

56. Losartan Heart Failure Survival Study -
ELITE II Study Endpoint Summary
Crude Rate
Losartan
(N=1578)
Captopril
(N=1574)
Adjusted
Hazards
Ratio (95%CI)
All-cause
Mortality
280 (17.7%)250 (15.9%) 0.88 (0.75, 1.05)
All-cause Mortality/
Hospitalization
752 (47.7%)707 (44.9%) 0.94 (0.85, 1.04)
Sudden Death/
Resusc. Arrest
142 (9.0%)115 (7.3%) 0.80 (0.63, 1.03)
Primary Endpoint:
Secondary Endpoint:
Tertiary Endpoints:
P-Value
0.16
0.21
0.08
Withdrawal for
Adverse Experience
149 (9.4%)228 (14.5%) <0.001

58. Comparison of Low-Dose Versus High-Dose
Losartan Treatment on Morbidity and Mortality in
Angiotensin-Converting-Enzyme-Inhibitor-
Intolerant Patients with Heart Failure and
Reduced Left Ventricular Ejection Fraction:
Results of the HEAAL* Study
Marvin A. Konstam, James D. Neaton, Kenneth Dickstein, Helmut Drexler, Michel Komajda,
Felipe A. Martinez, Gunter A.J. Riegger, Ronald D. Smith, William Malbecq, Soneil Guptha,
Philip A. Poole-Wilson for the HEAAL investigators
* Heart failure Endpoint evaluation with the Angiotensin II Antagonist Losartan
Lancet 2009; 374: 1840–48

59. ARBs in Heart Failure
Val-HeFT CHARM-Alternative
VALIANT ELITE-2
Valsartan
320 mg
Placebo
Candesartan
32 mg
Placebo
Captopril
150 mg
Losartan
50 mg
Captopril
150 mg
Survival
Event-freeSurvival
CVDeathorHFHosp
Mortality
Pfeffer et al. NEJM 2003 Pitt B et al: Lancet 2000
Granger et al: Lancet 2003Cohn et al: NEJM 2001
Valsartan
320mg
0
.3
1.0
0
1.0
.6
.5
0
23 mos
42 mos27 mos
36 mos
HYPOTHESIS:
Increased ARB dose is associated with improved
clinical outcomes in heart failure
POPULATION:
Patients with clinical heart failure, low LVEF and
ACE-inhibitor intolerance

60. Study Design and Sample Size
Screen Open Titration
Follow-up
50 mg qd + P
2 weeks
Randomization
50 mg qd
100 mg qd
50 mg qd +P
1 week 1 week (1 week)
150 mg qd
Losartan 12.5 mg- 25 mg qd
• Primary endpoint: death or hospitalization for HF
• 1710 patients with primary endpoint events provided 95% power for
HR = 0.837 for superiority with 2-sided  = 0.043
150 mg group
50 mg group
Konstam MA et al, Lancet 2009; 374: 1840–48

61. Disposition of Patients
N=1913 Analyzed
889 experienced primary endpoint
54 primary endpoint status
unknown; 62 vital status unknown
at closing date
6 excluded for
data quality
1919 Randomized
to losartan 50 mg
3846 Randomized
1927 Randomized
to losartan 150 mg
6 excluded for
data quality
N=1921 Analyzed
828 experienced primary endpoint
41 primary endpoint status
unknown; 48 vital status unknown
at closing date
Konstam MA et al, Lancet 2009; 374: 1840–48

62. Patient Follow-up and Dosing
Losartan
150 mg
Losartan
50 mg
Median follow-up time (yrs)* 4.7 4.7
Discontinuations (%) 28.3 27.3
Discontinuations for AE (%) 7.7 7.0
Mean dose (mg/day)** 128.9 45.6
*Follow up = time from randomization to study end or primary endpoint
**Including time off drug
Konstam MA et al, Lancet 2009; 374: 1840–48

63. Primary Endpoint
Death or Hospitalization for HF
0 1 2 3 4 5
0
10
20
30
40
50
Percentageofpatientswithfirstevent
Losartan 50 mg
Losartan 150 mg
Losartan 150 mg
Losartan 50 mg
Number of patients at risk
Hazard ratio: 0.90, p=0.027
1646
1683
1421
1492
1275
1343
1126
1205
644
711
%ofPatientswithFirstEvent
HR 0.90 (0.82, 0.99)
P=0.027
Years
1646 1422 1277 1126 644
1684 1493 1344 1205 711
Konstam MA et al, Lancet 2009; 374: 1840–48

64. Summary
 HEAAL represents the first study to investigate the dose-response of an ARB on
clinical outcomes in patients with HF.
 Compared with losartan 50 mg daily, losartan 150 mg daily reduced the rate of the
combined endpoint of all-cause mortality or HF hospitalization
 The 150 mg dose was associated with higher rates of hypotension, hyperkalemia,
and renal impairment, although the overall rates of clinically relevant adverse
events were small.
Conclusions
 In patients with HF, reduced LVEF, and ACE inhibitor intolerance, incremental
value is derived from up-titrating ARB doses to levels demonstrated to confer
benefit on clinical outcomes.
 Our findings confirm the view that incremental inhibition of the renin-angiotensin
system, within the range explored in HF trials to date, achieves a progressively
favorable impact on clinical outcomes.

65. Thumbs up/Thumbs down – Oct 2002
OPTIMAAL
ACE inhibitor vs ARB
Patients with complicated acute MI with heart
failure or significant systolic dysfunction are at
high risk
OPTIMAAL pitted an angiotensin receptor blocker
(losartan) vs standard ACE inhibitor (captopril) in
these patients

67. Mean uric acid level during follow-up among patients in the losartan and placebo groups.
Yan Miao et al. Hypertension. 2011;58:2-7

68. MI occurrence in ARB trials

69. Kunz R et al. Ann Intern Med 2008; 148:30-48
Ratio of means (95% CI)* for change in
proteinuria, by randomized therapy, over two
follow-up intervals
Randomized therapy Over 1-4 mo Over 5-12 mo
ARBs vs placebo 0.57 (0.47–0.68) 0.66 (0.63–0.69)
ARBs vs ACE-I 0.99 (0.92–1.05) 1.08 (0.96–1.22)
ARBs vs CCBs 0.69 (0.62–0.77) 0.62 (0.55–0.70)
ARB+ACE-I vs ARBs 0.76 (0.68–0.85) 0.75 (0.61–0.92)
ARB+ACE-I vs ACE-I 0.78 (0.72–0.84) 0.82 (0.67–1.01)
ACE-I=angiotensin-converting-enzyme inhibitor
ARB=angiotensin-receptor blocker
CCB=calcium-channel blocker
*Ratio of means=ratio of the average treatment effect in the intervention group (either ARBs alone or in combination
with ACE-I) relative to the control group (placebo or single-drug comparator), with 95% CI

70. ARBs in Secondary
Prevention
Superior to placebo? YES / NO
More effective than ACEi? NO
Less effective than ACEi? NO
Equal than ACEi? YES
Should be used with ACE? NO
Superior to placebo? YES / NO
More effective than ACEi? NO
Less effective than ACEi? NO
Equal than ACEi? YES
Should be used with ACE? NO

71. ARBs in Heart
Failure
Superior to placebo? YES
More effective than ACEi? NO
Less effective than ACEi? NO
Equal than ACEi? YES
Should be used with ACE? NO / YES
but only to reduce hospitalisation
Superior to placebo? YES
More effective than ACEi? NO
Less effective than ACEi? NO
Equal than ACEi? YES
Should be used with ACE? NO / YES
but only to reduce hospitalisation

72. Prevention of Progression of Renal Disease
Primary
prevention
Primary
prevention
Secondary
prevention
Secondary
prevention
Tertiary
prevention
Tertiary
prevention
Glycemic control
BP control
ACE inhibitor
Glycemic control
BP control
ACE inhibitor
ACE inhibitor
BP control
ARB
ACE inhibitor
BP control
ARB
ARB
ACE inhibitor
BP Control
ARB
ACE inhibitor
BP Control
ESRDMADM
Diabetic
nephropathy
Ref. Tobe SW et al. CMAJ 2002; 167(5): 499-503
In People with Diabetes

76. Losartan Metabolite EXP3179 Activates Akt and Endothelial
Nitric Oxide Synthase via Vascular Endothelial Growth
Factor Receptor-2 in Endothelial Cells
Circulation
Volume 112(12):1798-1805
September 20, 2005
Copyright © American Heart Association, Inc. All rights reserved.
and further…

77. Schematic representation of losartan metabolism via cytochrome P450.
Gian Paolo Rossi Hypertension. 2009;54:710-712
Copyright © American Heart Association, Inc. All rights reserved.