1 COZAAR (losartan) in Hypertensive Patients with Left Ventricular Hypertrophy Jeffrey R. Tucker, MD Director, Regulatory Affairs Merck Research Laboratories

1

COZAAR (losartan) in Hypertensive Patients

with Left Ventricular Hypertrophy

Jeffrey R. Tucker, MD

Director, Regulatory AffairsMerck Research Laboratories

2

The LIFE Study

Dr. J. Tucker, Regulatory Affairs– Introduction

Dr. J. Edelman, Clinical Development– Background and Rationale– Study Results

Dr. W. Keane, Clinical Development– Review of Evidence and Conclusions

Agenda

Losartan Intervention For Endpoint Reduction in Hypertension Study

3

Losartan Intervention For Endpoint Reduction in Hypertension Study

The LIFE Study

Active-control, double-blind

Multicenter – 945 sites

Multinational– 7 countries

Large study population– 9193 hypertensive patients with left

ventricular hypertrophy (LVH)

4

COZAAR (losartan): Proposed New Indication

COZAAR is indicated 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.

5

Evidence of Effectiveness from a Single Study

FDA Guidance - Providing Clinical Evidence of Effectiveness for Human Drug and Biological Products (1998)

– Generally limited to situations in which a trial shows a benefit on

• mortality or irreversible morbidity• the prevention of disease

and a second trial is not ethical or practical

– Additional information from within the single study, or from other sources, may provide confirmatory evidence to independently substantiate the results of the single study

The LIFE study compared losartan to an active control

6

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

7

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

8

Merck Clinical Consultants Dr. Björn Dahlöf - Chair, Steering Committee

Associate Professor of MedicineSahlgrenska University Hospital, Göteborg ,Sweden

Dr. Richard Devereux - Vice Chair, Steering CommitteeProfessor of Medicine and Director Echocardiography Laboratory Cornell Medical Center, New York, NY

Dr. John Kjekshus - Chair, DSMBProfessor of Medicine, Department of CardiologyUniversity of Oslo, Oslo, Norway

Dr. Stevo Julius- US Coordinator, Steering CommitteeProfessor of Medicine, Division of Hypertension and HyperlipidemiaUniversity of Michigan, Ann Arbor

Dr. Peter KoweyProfessor of Medicine, Jefferson Medical CollegeChief, Division of Cardiovascular DiseasesMain Line Hospitals, Philadelphia

9

Merck Statistical Consultants

Dr. James NeatonProfessor, Division of Biostatistics, School of Public Health, University of Minnesota

Dr. Scott ZegerProfessor and Chair, Department of Biostatistics, Bloomberg School of Public Health, Johns Hopkins University, Baltimore

10

COZAAR (losartan) in Hypertensive Patients

with Left Ventricular Hypertrophy

Jonathan M. Edelman, MD

Senior Director, Clinical DevelopmentMerck US Human Health

11

Losartan in Hypertensive Patients withLeft Ventricular Hypertrophy

Background and Rationale

LIFE Study Design

LIFE Patient Population

LIFE Efficacy Results

LIFE Safety Results

Agenda

12

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

13

Hypertension Increases Risk ofCardiovascular Morbidity and Mortality

Kannel WB Euro Heart J 1992;13(Suppl G):34-42.

29

14

65

35

0

10

20

30

40

50

60

70

Men Women

Ag

e-A

dju

ste

d R

ate

/10

00

NormotensiveHypertensive

The Framingham Heart Study

Risk Ratio 2.2 2.5

14

Adapted from MacMahon S, Rodgers A. Clin Exper Hypertension 1993;15(6):967-978.

0

100

200

300

400

500

600

Stroke CHD VascularDeaths

Treatment of Hypertension Reduces Cardiovascular Morbidity and Mortality

5 Randomized Trials in 12,483 Elderly Hypertensives

% Reduction in odds: 19%p<0.05

34%p<0.001

23%p<0.001

346383

288

438 Treatment

Control

Tot

al N

umbe

r of

In

divi

dual

s A

ffec

ted

438494

Overall BP DifferenceSystolic: 15 mm HgDiastolic: 6 mm Hg

15

LIFE: Primary Question

In hypertensive patients at high risk of cardiovascular outcomes:

– Does the mechanism of blood pressure reduction affect the magnitude of reduction of adverse cardiovascular outcomes?

• Does angiotensin II receptor blockade with losartan havea greater effect on cardiovascular morbidity and mortality than conventional antihypertensive therapy when peripheral blood pressure is similarly controlled?

16



LIFE Study Design



LIFE Safety Results

Agenda

17

LIFE: Choice of Primary Endpoint

A composite cardiovascular endpoint (including cardiovascular death, stroke, and myocardial infarction) was chosen to reflect:

– Systemic morbidity of hypertension on multiple organs (which may be mediated by different mechanisms)

– Systemic effects of angiotensin II

18

LIFE: Choice of Patient Population

Hypertensive patients at increased risk of cardiovascular outcomes (including cardiac and non-cardiac events):

– Left ventricular hypertrophy

• Consequence of long-standing hypertension

• Manifestation of systemic effects of angiotensin II

• Patients likely to benefit from angiotensin II antagonism

19

Prevalence of LVH in the US Hypertensive Population, by Age Group

NHANES III (1988-1994)

13

1618

22

0

5

10

15

20

25

40-54 55-64 65-74 75 +

Pe

rce

nt

Age Group

20

Risk of Cardiovascular Events Associated with ECG-LVH in the ElderlyThe Framingham Heart Study

Cupples LA, D’Agostino RB. NIH Publication No 87-2703, Feb 1987.

2315

10 8

69

55

32

42

0

10

20

30

40

50

60

70

80

Men Women Men Women

Ag

e-A

dju

ste

d R

ate

/10

00

No LVHLVH

Risk Ratio 3.2 5.33.73.0CHD Stroke

21

LIFE: Choice of Active Comparator

In order to answer the study question, it was necessary to utilize a comparator with:

– Effective blood pressure lowering– Different primary pharmacologic mechanism– Established reduction in cardiovascular morbidity and

mortality in hypertensive patients

Only -blocker- and diuretic-based regimens had proven effects on cardiovascular morbidity and mortality at the time of the initiation of LIFE study (1995)

22

JNC V (1993)

Arch Intern Med 1993; 153:2413-2446.

LIFE: Choice of Active Comparator

“Because diuretics and -blockers are the only classes of drugs that have been used in long-term controlled clinical trials and shown to reduce morbidity and mortality, they are recommended as first-choice agents unless they are contraindicated or unacceptable, or unless there are special indications for other agents.”

23

Meta-Analysis of -Blocker Regimens in HypertensionAll Cardiovascular Events

0.3 1 1.5Favors Favors

Odds Ratio (95% CI)Odds Ratio (95% CI)Odds Ratio (95% CI)Odds Ratio (95% CI)Odds Ratio (95% CI)Odds Ratio (95% CI)Odds Ratio (95% CI)Odds Ratio (95% CI)Odds Ratio (95% CI)Odds Ratio (95% CI)Odds Ratio (95% CI)Odds Ratio (95% CI)Odds Ratio (95% CI)Odds Ratio (95% CI)Odds Ratio (95% CI)Odds Ratio (95% CI)Odds Ratio (95% CI)Odds Ratio (95% CI)Odds Ratio (95% CI)Odds Ratio (95% CI)Odds Ratio (95% CI)Odds Ratio (95% CI)Odds Ratio (95% CI)Odds Ratio (95% CI)Odds Ratio (95% CI)Odds Ratio (95% CI)Odds Ratio (95% CI)Odds Ratio (95% CI)Odds Ratio (95% CI)Odds Ratio (95% CI)Odds Ratio (95% CI)Odds Ratio (95% CI)Odds Ratio (95% CI)Odds Ratio (95% CI)Odds Ratio (95% CI)Odds Ratio (95% CI)

Treatment Control

MRC

HEP†

MRCII†

STOP†

UKPDS†

OverallOverallOverallOverallOverallOverallOverallOverallOverallOverallOverallOverallOverallOverallOverallOverallOverallOverallOverallOverallOverallOverallOverallOverallOverallOverallOverallOverallOverallOverallOverall

Los925 ACM Main BB-All CVE 4 Dec. 27, 2002

++

StudyTotal

Patients OR

13057

884

3315

1627

748

19631

0.82

0.81

0.96

0.60

0.65

0.79

TotalEvents

498

145

460

152

167

1422142214221422142214221422142214221422

† Atenolol arm.‡ -blocker and/or diuretic arm.

24

LIFE: Choice of Atenolol-Based Regimen as Comparator

-blockers were known to be effective in prevention of myocardial infarction

Atenolol was effective in combination with diuretics

Atenolol had shown antihypertensive efficacy similar to losartan

Addition of diuretic to both treatment groups ensured balance in concomitant antihypertensive therapy

25

The Losartan Intervention For EndpointReduction in Hypertension Study

LIFE

A multicenter, multinational, double-blind, randomized, parallel study to investigate the effect of losartan, compared to atenolol, on the reduction of cardiovascular morbidity and mortality in hypertensive patients with left ventricular hypertrophy.

26

Data and SafetyMonitoring Board

(Unblinded)

Chair:Dr. John KjekshusUniversity of Oslo,

Oslo, Norway

SteeringCommittee

(Blinded)

Chair:Dr. Björn Dahlöf

Sahlgrenska University HospitalGöteborg, Sweden

Vice Chair:Dr. Richard Devereux

Cornell Medical CenterNew York, NY

Endpoint ClassificationCommittee

(Blinded)

Dr. Daniel LevyFramingham Heart Study

Framingham, MA

Dr. Kristian ThygesenÅrhus University Hospital

Århus, Denmark

Merck & Co., Inc. - coordinating and data management center

945 clinical centers in 7 countries

LIFE: Study Organization

27

LIFE: Hypothesis, Primary Endpoint and Secondary Component Endpoints

Hypothesis– Losartan will reduce the incidence of cardiovascular morbidity and

mortality in patients with essential hypertension and left ventricular hypertrophy, as compared to atenolol

Primary endpoint– Composite of cardiovascular morbidity and mortality as adjudicated by

the Endpoint Classification Committee

Secondary component endpoints– Cardiovascular mortality– Fatal and non-fatal stroke– Fatal and non-fatal myocardial infarction

28

LIFE: Primary Endpoint Analysis

1996 1997 1998 1999 2000 2001

1996 1997 1998 1999 2000 2001

Patient A

Patient B

May 1997Non-fatal MI

Dec 1995Randomized

Feb 1999Non-fatal

stroke

Sept 2000Fatal MI

Feb 1997Randomized

June 1998Fatal stroke

29

LIFE: Primary Endpoint Analysis

1996 1997 1998 1999 2000 2001

1996 1997 1998 1999 2000 2001

Patient A

Patient B

Feb 1999Non-fatal

stroke

Sept 2000Fatal MI


June 1998Fatal stroke

Dec 1995Randomized

Feb 1997Randomized

30

Adjudicated by Endpoint Classification CommitteeLIFE: 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

31

LIFE: Other Endpoints

Reported by central reading laboratory– ECG: All patients (N=9193)

• Left ventricular hypertrophy• Silent myocardial infarction

– Echocardiography: Substudy (n=965)• Left ventricular mass index

Reported by investigator– Blood pressure– Adverse experiences

• New-onset diabetes mellitus

32

LIFE: Disease Categories of Special Interest

Pre-specified to be of special interest:– Patients with diabetes mellitus– Patients with isolated systolic hypertension

Endpoints analyzed:– Primary endpoint– Secondary component endpoints– Total mortality– Hospitalization for angina– Hospitalization for heart failure

33

LIFE: Key Inclusion Criteria

Age 55-80 years

Elevated blood pressure– Systolic BP 160-200 mm Hg

or Diastolic BP 95-115 mm Hg

ECG LVH– Cornell Voltage Duration Product

or Sokolow-Lyon Criterion

34

LIFE: Key Exclusion Criteria

Secondary hypertension

MI or stroke within 6 months

Angina pectoris requiring treatment with -blocker or calcium channel antagonist

Heart failure or known left ventricular ejection fraction 40%

Conditions that required treatment with an angiotensin II receptor antagonist, -blocker, diuretic, or ACE inhibitor

35

* Other antihypertensives excluding ACEIs, AII antagonists, -blockers.

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 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

36

LIFE: Study Design (II)

Study duration:– Follow-up for minimum of 4 years

and– Until at least 1040 patients experienced a primary

cardiovascular event

Study follow-up:– Patients were to remain on study drug

• Even after a study endpoint– Patients were to continue clinic visits

• Even if study therapy was discontinued• Telephone contact if clinic visits not feasible

– Re-start of study therapy was allowed at any time

37

LIFE: Endpoint Reporting and Classification

Investigators reported all potential endpoints for review by ECC

Regular monitoring visits ensured all potential endpoints reported

ECC members reviewed potential endpoints and classified independently

Differences between the initial classifications were resolved at periodic meetings

– Referral to Steering Committee for resolution, if needed(no cases referred)

All potential endpoints were adjudicated (N=4363)– 21% were determined not to be endpoints – 7 with unknown cause of death

38

LIFE: Study Timeline

June 1995First patientrandomized

May 1997Last patientrandomized

March 2001Steering Committee

set endpoint cut-off date(September 16, 2001)

based on pooled event rate

September 16, 2001Endpoint cut-off

1096 patients withat least one

primary endpoint

1996 1997 1998 1999 2000 2001 2002

November 2001Final patient visit

39



LIFE Study Design



LIFE Safety Results

Agenda

40

Entered baseline(N=10,779)

Entered baseline(N=10,779)

Randomized(N=9222)

Randomized(N=9222)

Allocated to losartan(N=4605)

Allocated to losartan(N=4605)

Allocated to atenolol(N=4588)

Allocated to atenolol(N=4588)

Excluded for irregularities (n=29)Excluded for irregularities (n=29)

All included in ITT analyses:

Complete follow-up4500 (98%)

Partial follow-up

105 (2%)


Complete follow-up4500 (98%)

Partial follow-up

105 (2%)


Complete follow-up:4496 (98%)

Partial follow-up92 (2%)


Complete follow-up:4496 (98%)

Partial follow-up92 (2%)

LIFE: Patient Disposition

Followed for study duration(N=9193)

Followed for study duration(N=9193)

41

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%

42

LIFE: Patient Recruitment

Denmark

Iceland

Finland

Norway

Sweden

UK

USA

Country

1391

133

1485

1415

2245

817

1707

n

N=9193

15.1

1.4

16.2

15.4

24.4

8.9

18.6

%

43

Age (mean), years

Gender, % female

Ethnic group, %WhiteBlackHispanicAsianOther

66.9

54.0

92.55.91.00.50.1

Losartan(N=4605)

66.9

54.0

92.55.71.20.40.2

Atenolol(N=4588)

LIFE: Baseline Characteristics (I)

44

Systolic BP, mm Hg

Diastolic BP, mm Hg

Pulse rate, bpm

BMI, kg/cm2

Smokers, %

174.3

97.9

73.9

28.0

15.8

174.5

97.7

73.7

28.0

16.8

LIFE: Baseline Characteristics (II)

Losartan(N=4605)

Atenolol(N=4588)

45

Diabetes mellitus

ISH (160 / <90 mm Hg)

Coronary heart diseaseMyocardial infarction

Cerebrovascular diseaseStroke

12.7

14.3

16.76.7

8.24.1

Losartan %(N=4605)

13.3

14.5

15.25.7

8.04.6

Atenolol %(N=4588)

Medical HistoryLIFE: Baseline Characteristics (III)

46

Cornell Product, mmmsec

Sokolow-Lyon, mm

Framingham Risk Score, %

2828.0

30.0

22.3

Losartan(N=4605)

2818.9

30.0

22.5

Atenolol(N=4588)

Variables Utilized in Covariate AnalysisECG-LVH and Framingham Risk Score

LIFE: Baseline Characteristics (IV)

Framingham Risk Score predicts the 5-year probabilityof developing coronary heart disease based ongender, age, systolic blood pressure, smoking,

total / HDL cholesterol, diabetes, ECG-LVH

47

At Endpoint or End of Follow-UpLIFE: Study Therapy

50 mg alone

50 mg with additional drugs

100 mg with or without additional drugs

Off study drug

Losartan %(N=4605)

9

18

50

23

Atenolol %(N=4588)

10

20

43

27

48

LIFE: Study Therapy

50 mg alone

50 mg with additional drugsWith HCTZ onlyWith other drugs onlyWith HCTZ and other drugs

100 mg with or without additional drugsAloneWith HCTZ onlyWith other drugs onlyWith HCTZ and other drugs

Off study drug

Losartan %(N=4605)

9

18 14 2 2

50 2 18 4 26

23

Atenolol %(N=4588)

10

20 14 2 4

43 2 16 4 22

27

At Endpoint or End of Follow-Up

49

Time on study drug, %

Mean dose of study drug, mg

Time on diuretic, %

Mean dose of HCTZ, mg

Mean number of antihypertensive agents (including study therapy for those on drug)

Losartan(N=4605)

86

82

72

20

2.3

Atenolol(N=4588)

82

79

70

20

2.3

LIFE: Study TherapyAt Endpoint or End of Follow-Up

50



LIFE Study Design



LIFE Safety Results

Agenda

51

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

Study Month

0

2

4

6

8

10

12

14

16w

ith F

irst

Eve

ntLosartanAtenolol

Los925 ACM Primary ITT 1 Dec. 24, 2002

Adjusted risk reduction 13.1%, p=0.021Unadjusted risk reduction 14.6%, p=0.009

n at riskLosartan (n) 4605 4460 4312 4189 4045 1888Atenolol (n) 4588 4414 4289 4135 3992 1854

Per

cent

of

Pat

ient

s

LIFE: Primary Endpoint

52

0.5 1 1.5 2Favors 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)

p-value

0.021

0.0090.0090.0090.0090.0090.0090.0090.0090.0090.0090.0090.0090.0090.0090.0090.0090.009

Endpoint

508 588

No. of Events

Los AtlAtlAtlAtlAtlAtlAtlAtlAtlAtlAtlAtlAtl

Los925 ACM heb PrimeComp 1 Dec. 28, 2002

Adjusted for FRSand ECG-LVHUnadjusted

Primary


53

LIFE: Systolic Blood Pressure

Prestudy 12 24 36 48 60

Time (months)

120

140

160

180

mm

Hg

Los925 ACM BP SBP Mean1A Dec. 26, 2002

LosartanAtenolol

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

mm

Hg

(mea

n)

54

LIFE: Diastolic Blood Pressure

Prestudy 12 24 36 48 60

Time (months)

60

80

100

120

mm

Hg

Los925 ACM BP DBP Mean1A Dec. 26, 2002

LosartanAtenolol



-16.6 -16.8 0.345

Time-Averaged Difference = 0.76

mm

Hg

(mea

n)

55

At Last Visit Before Endpoint or End of Follow-Up

Diastolic 90 mm Hg

Systolic 140 mm Hg

Systolic 140 and Diastolic 90 mm Hg

Blood Pressure Response

Atenolol(N=4588)

(%)

89

46

45

Losartan(N=4605)

(%)

88

49

48

LIFE: Categories of Hypertensive Response

56

LIFE: Heart Rate

Prestudy 12 24 36 48 60

Time (months)

60

65

70

75

80

Bea

ts /

Min

Los925 ACM BP Heart Rate1A Dec. 26, 2002

LosartanAtenolol



-1.8 -7.7 <0.001

Time-Averaged Difference = 6.49

Bea

ts /

Min

(m

ean)

57

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

58



LIFE Study Design


LIFE Efficacy Results– Other Endpoints

LIFE Safety Results

Agenda

59

LIFE: Secondary Component Endpoint Analyses

Patient A

1996 1997 1998 1999 2000 2001


Dec 1995Randomized

Feb 1999Non-fatal

stroke

Sept 2000Fatal MI

60


1996 1997 1998 1999 2000 2001

Patient A

Included inanalysis of

MI

Included inanalysis ofCV death

Included inanalysis of

stroke


Feb 1999Non-fatal

stroke

Sept 2000Fatal MI

Dec 1995Randomized

61


Intent-to-treat analyses

Each patient counted in all relevant endpoint analyses

Each patient included only once in each endpoint analysis

62


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

232

198

234

309

188

No. of Events

Los AtlAtlAtlAtlAtlAtlAtlAtlAtlAtlAtlAtl

Los925 ACM HEB Prim-Sec 1A 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)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)

LIFE: Secondary Component Endpoints

Adjusted for FRS and ECG-LVH.

63



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)

p=0.023Heterogeneity

Endpoints

204

232

198

234

309

188

No. of EventsLos AtlAtlAtlAtlAtlAtlAtlAtlAtlAtlAtlAtl

Los925 ACM HEB Prim-Sec 1B Dec. 24, 2002

CV Death


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)MI (Fatal/Non-Fatal)MI (Fatal/Non-Fatal)MI (Fatal/Non-Fatal)MI (Fatal/Non-Fatal)


64

LIFE: Secondary Component EndpointFatal and Non-Fatal Stroke

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

0

2

4

6

8P

erce

nt o

f P

atie

nts

Losartan (n) 4605 4469 4332 4224 4117 1928n at risk

Atenolol (n) 4588 4424 4317 4180 4055 1901

with

Firs

t E

vent

Los925 ACM Stroke Dec. 24, 2002

Adjusted risk reduction 24.8%, p=0.001

LosartanAtenolol

65

Fatal and Non-Fatal MILIFE: Secondary Component Endpoint

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

0

2

4

6

8P

erce

nt o

f P

atie

nts


Atenolol (n) 4588 4466 4367 4243 4134 1953

with

Firs

t E

vent

Los925 ACM MI Dec. 24, 2002

Adjusted risk reduction -7.3%, p=0.491

LosartanAtenolol

66

LIFE: Secondary Component EndpointCardiovascular Mortality

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

Study Month

0

2

4

6

8P

erce

nt o

f P

atie

nts


Atenolol (n) 4588 4513 4442 4341 4252 2006

with

Eve

nt

Los925 ACM CardioMort Dec. 24, 2002


LosartanAtenolol

67




Hazard Ratio (95% CI)Endpoints

204 234

No. of EventsLos Atl

CV Death

68



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

234

62

124

48

No. of Events

Los AtlAtlAtlAtlAtlAtlAtlAtlAtlAtlAtlAtlAtlAtlAtlAtlAtlAtlAtlAtlAtlAtlAtlAtl

Los925 ACM HEB Sec 7 Dec. 10, 2002

CV Death

Stroke

Coronary Disease

OtherOtherOtherOtherOtherOtherOtherOtherOtherOtherOtherOtherOtherOtherOtherOtherOtherOtherOtherOtherOtherOtherOtherOtherOtherOtherOtherOtherOtherOtherOtherOtherOther


CHD

69



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)


CHD

70

LIFE: Mortality and Causes of DeathAdjudicated by Endpoint Committee

Total Mortality

Cardiovascular MortalityStrokeCHDHeart FailureNoncoronary Vasc.Other CV Mortality

Noncardiovascular

EndpointsEndpointsEndpointsEndpointsEndpointsEndpointsEndpointsEndpointsEndpointsEndpointsEndpointsEndpointsEndpointsEndpointsEndpointsEndpointsEndpointsEndpointsEndpointsEndpointsEndpointsEndpoints

No. of Events

Los Atl383

20440

1251615

8179

431

23462

1241722

9197197197197197197197197197197197197197197

Los925 ACM HEB Sec6B Dec. 24, 2002

0.5 1 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)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 Adjusted for FRS and ECG-LVH.

71

LIFE: Other EndpointsAdjudicated by Endpoint Committee

Angina Hosp.

Heart Failure Hosp.

Coronary Revascularization

Noncoronary Revascularization

Resuscitated Cardiac Arrest

EndpointsEndpointsEndpointsEndpointsEndpointsEndpointsEndpointsEndpointsEndpointsEndpointsEndpointsEndpointsEndpointsEndpointsEndpointsEndpointsEndpointsEndpointsEndpointsNo. 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


72

LIFE: Other EndpointsMeasured by ECG Reading Center

Left ventricular hypertrophy:– Cornell voltage duration product– Sokolow-Lyon

Silent myocardial infarction (ECG)

73

LIFE: ECG-LVHChange in Cornell Voltage-Duration Product (mmmsec)

0 6 12 24 36 48 60

Study Month

-400

-300

-200

-100

0

Mea

n

Los925 ACM CP Mean 1B Dec. 26, 2002

LosartanAtenolol



-290 -124 <0.001

74

LIFE: ECG-LVHChange in Sokolow-Lyon Criterion (mm)



-4.6 -2.7 <0.001

0 6 12 24 36 48 60

Study Month

-5

-4

-3

-2

-1

0

Mea

n

Los925 ACM SL Mean 1B Dec. 26, 2002

LosartanAtenolol

75

LIFE: ECHO Substudy (n=965)Change in Left Ventricular Mass Index (g/m2)

Reduction in LVMI at last available echo (g/m2):


-21.7 -17.7 0.011

0 12 24 36 48 60

Study Months

-30

-20

-10

0

Mea

n

Los925 ACM LVH Change Oct. 29, 2002

LosartanAtenolol

76

LIFE: Results in Predefined Subsets of the Population

Disease categories of special interest - primary endpoint, secondary component endpoints, total mortality, hospitalization for heart failure and angina

– Patients with diabetes mellitus– Patients with isolated systolic hypertension

Subgroups - primary endpoint– 23 subgroups defined in Data Analysis Plan

• Demographic• Disease history• Clinical characteristics

77

LIFE: Disease Categories of Special InterestIncreased Risk of Primary Endpoint

23

46

0

10

20

30

40

50

60

Primary EndpointRat

e pe

r 10

00 P

atie

nt-Y

ears

Non-DiabeticDiabetic

2530

0

10

20

30

40

50

60

Primary EndpointRat

e pe

r 10

00 P

atie

nt-Y

ears

Non-ISHISH(n=1195)

(n=7998)

(n=1326)

(n=7867)

Relative Risk: 2.0 1.2

78

LIFE: Disease Categories of Special InterestPrimary Endpoint

0.5 1 2Favors 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

Numberof Eventsof Eventsof Eventsof Eventsof Eventsof Eventsof Eventsof Events

p=0.170†

p=0.176†

† Test for treatment-by-subgroup interaction.

79

LIFE: Patients with DiabetesPrimary Endpoint

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

Study Month

0

4

8

12

16

20

24w

ith F

irst

Eve

ntLosartanAtenolol

Los925 ACM Diabetes composite Dec. 24, 2002


n at riskLosartan (n) 586 558 532 513 484 237Atenolol (n) 609 562 540 507 472 204

Per

cent

of

patie

nts

Pa

tient

s

80

LIFE: Patients with DiabetesSecondary Component Endpoints

0.3 0.5 1 1.5 2Favors 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


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)

Los925 ACM heb Diab 2B1A Dec. 24, 2002

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


81

LIFE: Patients with DiabetesOther Endpoints

0.3 0.5 1 1.5 2Favors Losartan Favors Atenolol


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

Numberof Eventsof Eventsof Eventsof Eventsof Eventsof Eventsof Eventsof Events


82

LIFE: Patients with Isolated Systolic HypertensionPrimary Endpoint

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

02468

1012141618P

erce

nt o

f Pat

ient

s


Atenolol (n) 660 628 603 573 555 239

with

Eve

nt

Los925 ACM ISH Subset 1 Dec. 24, 2002


LosartanAtenolol

83

LIFE: Patients with Isolated Systolic HypertensionSecondary Component Endpoints

0.3 0.5 1 1.5 2Favors 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


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)


84

LIFE: Patients with Isolated Systolic HypertensionOther Endpoints

0.3 0.5 1 1.5 2Favors Losartan Favors Atenolol


Total Mortality

Heart Failure Hosp.

Angina Hosp.

Endpoints Los

66

26

34

Atl

93

40

23

Numberof Eventsof Eventsof Events

Los925 ACM heb ISH 3B2 Dec. 23, 2002Adjusted for FRS and ECG-LVH.

85

Baseline SubgroupsLIFE: Primary Endpoint

23 subgroups defined in Data Analysis Plan– Primary endpoint only

• Demographic• Disease history• Clinical characteristics

Test for interaction planned (positive: p<0.05)

No planned subgroup had a positive interaction

86

LIFE: Primary EndpointBaseline Subgroups - Test for Interaction with Treatment

DemographicAgeGenderCountryEthnic group

Disease historyMIStrokeIHDAnginaHeart failureDiabetesMicroalbuminuriaISH

Clinical characteristicsSmoking statusAlcohol intakeExercise statusBMISystolic BPDiastolic BPTotal cholesterolHDL cholesterolECG-LVH (Cornell)ECG-LVH (SL)Framingham Risk

0.1850.4200.6070.057

0.3160.2110.2090.2500.7330.1700.3830.176

0.2820.4200.8920.2900.7250.4020.9750.1140.4850.4220.922

Subgroup p-Value Subgroup p-Value

87

LIFE: Primary EndpointBaseline Subgroups - Test for Interaction with Treatment

DemographicAgeGenderCountryEthnic group

Disease historyMIStrokeIHDAnginaHeart failureDiabetesMicroalbuminuriaISH

Clinical characteristicsSmoking statusAlcohol intakeExercise statusBMISystolic BPDiastolic BPTotal cholesterolHDL cholesterolECG-LVH (Cornell)ECG-LVH (SL)Framingham Risk

0.1850.4200.6070.057

0.3160.2110.2090.2500.7330.1700.3830.176

0.2820.4200.8920.2900.7250.4020.9750.1140.4850.4220.922

Subgroup p-Value Subgroup p-Value

88

LIFE: Ethnic SubgroupsPrimary Endpoint

White

Black

Hispanic

Asian

Other

Ethnic Group No.No.No.No.No.

8503

533

100

43

1414

Los925 ACM HEB Ethnic2 Dec. 9, 2002

Favors Losartan Favors Atenolol 0.5 1 2

N/A

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)

p=0.057†


89

LIFE: Post-Hoc Analysis Black vs. Non-Black Patients

Primary Endpoint

Test for qualitativeinteraction, p=0.016


Ethnic Group

No. of EventsNo. of EventsNo. of EventsNo. of EventsNo. of EventsNo. of EventsNo. of EventsNo. of EventsNo. of EventsNo. of EventsNo. of EventsNo. of EventsNo. of EventsNo. of EventsNo. of EventsNo. of EventsNo. of EventsNo. of Events

Los925 ACM HEB demog 2B V4 Dec. 9, 2002

Non-Black

BlackBlackBlackBlackBlackBlackBlackBlackBlackBlackBlackBlackBlackBlackBlackBlackBlackBlack

(N=8660)

(N=533)(N=533)(N=533)(N=533)(N=533)(N=533)(N=533)(N=533)(N=533)(N=533)(N=533)(N=533)(N=533)(N=533)(N=533)(N=533)(N=533)(N=533)

Los

462

46

Alt

559

29292929292929292929292929

Favors Losartan Favors Atenolol 0.5 1 2

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)

p=0.005†

Favors Losartan Favors Atenolol

90

Exploratory Analyses

LIFE: Post-Hoc Analysis Black vs. Non-Black Patients

Baseline covariates– Demographics– Disease history– Biochemistry– Prior therapy

Regional differences– US vs. Europe– Within US

Impact of study drug discontinuation

– Per-protocol analysis

Secondary component endpoints

– Categorization of stroke etiology

Vital signs– Blood pressure– Heart rate

Left ventricular hypertrophy– ECG– Echocardiography

91

LIFE: Post-Hoc AnalysisBlack vs. Non-Black Patients

US Patients (n=1707)Change at End of Follow-Up or Last Visit Prior to Primary Endpoint

-30

-20

-10

0

mm

Hg

Los925 ACM BP race bars v2 Dec. 29, 2002

Non-Black BlackSystolic BP

Losartan

-20

-15

-10

-5

0

mm

Hg

Atenolol

Diastolic BPNon-Black Black

92

-8

-6

-4

-2

0

Bea

ts /

Min

ute

Losartan AtenololLos925 ACM BP race bars 2-1 Dec. 27, 2002

Non-Black Black


Change in Heart Rate at End of Follow-Up or Last Visit Prior to Primary EndpointUS Patients (n=1707)

93

-250

-200

-150

-100

-50

0

Cor

nell

Pro

duct

(m

m*m

sec)

Los925 ACM CP-SL race bars v2 Dec. 27, 2002

Losartan

Cornell Product

-6

-5

-4

-3

-2

-1

0

Sok

olow

-Lyo

n (m

m)

Non-Black Black

Atenolol

Non-Black BlackSokolow-Lyon


US Patients (n=1707)Change in ECG-LVH at End of Follow-Up or Last Visit Prior to Primary Endpoint

94

Summary


Analysis of primary endpoint– Significant test for interaction with treatment– Greater reduction in risk with atenolol compared to

losartan in Black patients– Unexplained by differences in baseline characteristics

Additional analyses– Blood pressure: Decreased to similar level in each group– Heart rate: Greater reduction with atenolol compared

to losartan– ECG-LVH: Greater reduction with losartan compared

to atenolol

95

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

96



LIFE Study Design



LIFE Safety Results

Agenda

97

With any AE

With drug-related AE†

With serious AE

Discontinued due to AE

Discontinued due to drug-related AE†

Discontinued due to serious AE

† Possibly, probably, or definitely drug related as assessed by the investigator.

Losartan %(N=4605)

94.7

37.2

37.2

13.1

6.1

3.8

Atenolol %(N=4588)

95.0

45.2

36.2

18.1

10.7

4.6

p-Value

0.481

<0.001

0.299

<0.001

LIFE: Overall Adverse Experiences (AE)

98

LIFE: Prespecified Adverse Experiences of Special Interest

More Frequent with LosartanDizzinessCancerCoughHypotension

More Frequent with AtenololCold extremitiesSexual dysfunctionBradycardiaSleep disturbanceAngioedema

16.77.82.92.6

3.93.61.40.70.1

Losartan %(N=4605)

15.87.02.51.6

5.94.78.50.80.2

Atenolol %(N=4588)

0.2470.1510.22

<0.001

<0.0010.009

<0.0010.3330.237

p-Value

99

Asthenia / fatigueBack painLower extremity edemaChest painDyspneaPalpitationHyperglycemiaPneumoniaAlbuminuriaPeripheral vascular disorder

Losartan %(N=4605)

15.012.311.711.3

9.95.55.24.74.63.7

Atenolol %(N=4588)

17.510.413.910.114.1

3.26.55.96.45.6

LIFE: Common Adverse ExperiencesIncidence >5% and Difference Between Groups >1%

100

LIFE: Key Laboratory Values

Parameters assessed included:– Serum / plasma: sodium, potassium, hemoglobin,

creatinine, ALAT, glucose, cholesterol (total and HDL), uric acid

– Urine: albumin, creatinine

No clinically significant differences between treatment groups were noted

– Assessed changes from baseline values and changes outside of predefined limits

101

LIFE: New Onset Diabetes

New Onset Diabetes

EventEventEventEventEventEventEventEvent

No. of Events

Los Atl

242 320320320320320320320

0.5 1 1.5 Favors Losartan Favors Atenolol

Los925 ACM HEB No Diab 2 Oct. 30, 2002

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)

102

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

103


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

204232198

588

234309188

No. of Events

Los Atl

Endpoints Los AtlAtlAtlAtlAtlAtlAtlAtlAtlAtlAtlAtlAtlAtlAtlAtlAtlAtlAtl

Los925 ACM heb1A4-div Dec. 28, 2002

Primary

CV DeathStroke (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 EndpointsAdjusted for FRS and ECG-LVH at Baseline

104

LIFE:Review of Evidence and Conclusions

William F. Keane, MD

Vice President, Clinical DevelopmentMerck US Human Health

105

Evidence of Effectiveness from a Single StudyLIFE: Strength of the Evidence

Use of a single study:– Mortality, irreversible morbidity, or prevention of disease– Impractical or unethical to repeat

Characteristics to consider:– Study design– Consistency across study subsets– Multiple endpoints involving different events– Study findings consistent with external scientific literature

106

LIFE: Study Design

Large multicenter, multinational study– 9193 patients followed for a mean of 4.8 years– 945 clinical sites, 7 countries– 1096 patients with primary endpoints– Complete endpoint reporting for 99% of patient-days– Endpoints adjudicated by independent committee

Hypertensive patients with left ventricular hypertrophy

Active control with proven benefit in reduction of cardiovascular morbidity and mortality

107

Benefit of Blood Pressure Reduction in Patients with LVH

LIFE is the first trial to exclusively study hypertensive patients with LVH

Blood pressure is a surrogate for cardiovascular outcomes– Including patients with LVH

Prevalence of LVH in hypertensive patients over 55 years of age is 20%

108

Meta-Analysis of -Blocker Regimens in HypertensionAll Cardiovascular Events

0.3 1 1.5Favors Favors

Odds Ratio (95% CI)Odds Ratio (95% CI)Odds Ratio (95% CI)Odds Ratio (95% CI)Odds Ratio (95% CI)Odds Ratio (95% CI)Odds Ratio (95% CI)Odds Ratio (95% CI)Odds Ratio (95% CI)Odds Ratio (95% CI)Odds Ratio (95% CI)Odds Ratio (95% CI)Odds Ratio (95% CI)Odds Ratio (95% CI)Odds Ratio (95% CI)Odds Ratio (95% CI)Odds Ratio (95% CI)Odds Ratio (95% CI)Odds Ratio (95% CI)Odds Ratio (95% CI)Odds Ratio (95% CI)Odds Ratio (95% CI)Odds Ratio (95% CI)Odds Ratio (95% CI)Odds Ratio (95% CI)Odds Ratio (95% CI)Odds Ratio (95% CI)Odds Ratio (95% CI)Odds Ratio (95% CI)Odds Ratio (95% CI)Odds Ratio (95% CI)Odds Ratio (95% CI)Odds Ratio (95% CI)Odds Ratio (95% CI)Odds Ratio (95% CI)Odds Ratio (95% CI)

Treatment Control

MRC

HEP†

MRCII†

STOP†

UKPDS†

OverallOverallOverallOverallOverallOverallOverallOverallOverallOverallOverallOverallOverallOverallOverallOverallOverallOverallOverallOverallOverallOverallOverallOverallOverallOverallOverallOverallOverallOverallOverall

Los925 ACM Main BB-All CVE 4 Dec. 27, 2002

++

StudyTotal

Patients OR

13057

884

3315

1627

748

19631

0.82

0.81

0.96

0.60

0.65

0.79

TotalEvents

498

145

460

152

167

1422142214221422142214221422142214221422

† Atenolol arm.‡ -blocker and/or diuretic arm.

109

Meta-Analysis of CCB or ACEI vs.-Blocker / Diuretic Regimens

Adapted from Staessen, Wang & Thijs. Lancet 2001; 358:1305-15.

All Cardiovascular Events

0.99

1.01

CCB

ACEI

26,527

18,357

3,048

2,247

TotalEvents

Total Patients OROROROROROROR

0.5 1 1.5

Odds Ratio (95% CI)Odds Ratio (95% CI)Odds Ratio (95% CI)Odds Ratio (95% CI)Odds Ratio (95% CI)Odds Ratio (95% CI)Odds Ratio (95% CI)Odds Ratio (95% CI)Odds Ratio (95% CI)Odds Ratio (95% CI)Odds Ratio (95% CI)Odds Ratio (95% CI)Odds Ratio (95% CI)Odds Ratio (95% CI)Odds Ratio (95% CI)Odds Ratio (95% CI)

Favors Favors Diuretics/B CCB or ACEI

110


0.5 1 1.5Favors 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)

508 588588588588588588588588588588588

Los925 ACM heb1A4-div B Dec. 28, 2002

Primary

Endpoints

No. of Events

Los AtlAtlAtlAtlAtlAtlAtlAtl

2.0

111

LIFE: Summary of Blood Pressure EffectsAt Last Visit Before Endpoint or End of Follow-Up

Blood Pressure ReductionSystolic BP change, mm HgDiastolic BP change, mm Hg

Blood Pressure Control CategorySBP140 and DBP90, %SBP160 or DBP100, %

Losartan(N=4605)

-30.2-16.6

48 17

Atenolol(N=4588)

-29.1-16.8

45 19

112

LIFE Substudy: 24-Hour Ambulatory Blood Pressure - Systolic Pressure

Mean 24-Hour Systolic Blood Pressure at

Year 1

Losartan Atenolol(n=57) (n=53)

136.1 134.7

Baseline

Year 1

10 12 2 4 6 8 10 12 2 4 6 8 10

Time of Day

100

120

140

160

180

mm

Hg

ABPM: Systolic Blood Pressure

Baseline

Year 1

LosartanAtenolol

A.M. P.M. A.M.

Los925 ACM ABPM-sbp 1 Dec. 27, 2002

10

mm

Hg

(mea

n)

113

Systolic BP

LIFE: Primary Endpoint Adjusted for Blood Pressure as Time-Varying Covariate

Diastolic BP

BP control category

Change

-0.7

-0.4

-0.6

HazardRatio

0.861

0.858

0.860

0.854

RiskReduction (%)

13.9

14.2

14.0

14.6Unadjusted result

Adjusted results

114

Impact of Observed Systolic Blood Pressure Differences on Risk of Stroke

0 5 10 15 20

Difference in Systolic Blood Pressure (mm Hg)

0

10

20

30

40

50P

erce

nt R

isk

Red

uctio

n

Los925 ACM Epi BP1 Dec. 27, 2002Data from: Staessen, et al 2000; He et al 1999; MacMahon and Rodgers, 1993.

LIFE Compared to Meta-Analyses of Hypertension Trials

115


0 5 10 15 20


0

10

20

30

40

50P

erce

nt R

isk

Red

uctio

n

Los925 ACM Epi BP1 Dec. 27, 2002Data from: Staessen, et al 2000; He et al 1999; MacMahon and Rodgers, 1993.


116

0 5 10 15 20


0

10

20

30

40

50P

erce

nt R

isk

Red

uctio

n

Los925 ACM Epi BP1 Dec. 27, 2002


Data from: Staessen, et al 2000; He et al 1999; MacMahon and Rodgers, 1993.


117

0 5 10 15 20


0

10

20

30

40

50P

erce

nt R

isk

Red

uctio

n





118

0 5 10 15 20


0

10

20

30

40

50P

erce

nt R

isk

Red

uctio

n





119

LIFE: Consistency Across Study Subsets

No significant treatment by subgroup interactions

– Disease categories of special interest

• Diabetes

• Isolated systolic hypertension

– Pre-specified subgroups

• Demographic

• Disease history

• Clinical characteristics

120


Primary endpoint: Significant test for interaction– Greater risk reduction with atenolol in Black patients

No biological basis found for the observed interaction– Blood pressure: Decreased to similar level in each group– LVH: Greater reduction with losartan compared to atenolol– Heart rate: Greater reduction with atenolol compared to

losartan

Recommend description of findings in product circular

121

LIFE: Multiple Endpoints InvolvingDifferent Events

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 MI– Losartan produced a greater reduction of ECG-LVH

Other measurements:– Losartan reduced carotid artery wall thickness (ICARUS

substudy)– Losartan reduced incidence of atrial fibrillation

122

ICARUS Sub-StudyChange from Baseline at Year 3

LIFE: Regression of Carotid Artery Hypertrophy

-9-8-7-6-5-4-3-2-10

Losartan (n=19) Atenolol (n=20)

% C

hang

e in

Int

ima-

Med

iaC

ross

-Sec

tiona

l Are

a

-7.9 %

-1.7 %

p<0.05

123

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.

124

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

125

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 2Favors Favors


Losartan Atenolol

126

LIFE: Multiple Endpoints InvolvingDifferent Events

Heterogeneity among secondary component endpoints

– Similar incidence of myocardial infarction

• Cardioprotective effects of atenolol

• Greater reduction in LVH with losartan

– Greater reduction in stroke with losartan

• Reduction in carotid artery wall thickness with losartan

• Reduction in incidence of atrial fibrillation with losartan

Secondary Component Endpoints

127

LIFE: Results Consistent with External Scientific Data

Preclinical data with AT1 blockade, independent of blood pressure:– Reduction in stroke mortality and cerebral lesions– Improvement in myocardial hypertrophy– Reduction in myocardial fibrosis

Clinical data with interference in RAS in hypertensive patients:– Greater regression of LVH– Structural and functional benefit on peripheral vasculature

128

Evidence of Effectiveness from a Single StudyLIFE: Strength of the Evidence

Use of a single study:– Significant result with losartan on primary endpoint of

cardiovascular morbidity and mortality– Impractical to repeat

Characteristics to consider:– Large, multicenter, active-control design– Generally consistent effect of losartan in subgroups– Benefit of losartan on incidence of stroke, degree of LVH,

carotid artery IMT, incidence of atrial fibrillation– Preclinical and clinical pharmacodynamic literature are

corroborative

129

LIFE: Favorable Benefit to Risk Ratio

Efficacy– Significant beneficial effects of losartan on clinically important

endpoints compared to atenolol with comparable reduction in blood pressure

Safety– Losartan was better tolerated than atenolol– Adverse experience profile of losartan was consistent with

that presented in the currently approved US product circular for COZAAR

– Lower incidence of new-onset diabetes mellitus with losartan compared to atenolol

130

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.

Documents

1 COZAAR (losartan) in Hypertensive Patients with Left Ventricular Hypertrophy Jeffrey R. Tucker, MD Director, Regulatory Affairs Merck Research Laboratories