Losartan Heart Failure Survival StudyELITE IILosartan Heart Failure Survival StudyELITE II

A Multicenter, Double-Blind, Randomized, Parallel, A Multicenter, Double-Blind, Randomized, Parallel, Captopril-Controlled Study to Evaluate the Effects of Losartan Captopril-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 Committee Steering Committee Co-ChairsCo-Chairs B. Pitt, P. Poole-WilsonB. Pitt, P. Poole-Wilson• Data and Safety Monitoring Committee Data 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

Losartan Heart Failure Survival StudyELITE II

Primary Hypothesis:Primary Hypothesis:

Treatment with losartan will reduce all-cause mortality Treatment with losartan will reduce all-cause mortality compared to captoprilcompared to captopril

Power: 90% to detect a 25% difference [p=0.043] intention-to-treatPower: 90% to detect a 25% difference [p=0.043] intention-to-treat

Secondary Hypothesis:Secondary Hypothesis:

Treatment with losartan will reduce the incidence of sudden Treatment with losartan will reduce the incidence of sudden death and/or resuscitated arrest compared to captopril death and/or resuscitated arrest compared to captopril

Other Endpoints:Other Endpoints:

All-cause mortality/hospitalizationsAll-cause mortality/hospitalizations

Safety and tolerabilitySafety and tolerability

Study DesignStudy Design

Losartan Heart Failure Survival StudyELITE II

60 yrs; NYHA II-IV; EF 60 yrs; NYHA II-IV; EF 40% 40% ACE-I/AIIA naive or <7 days in 3 months prior to ACE-I/AIIA naive or <7 days in 3 months prior to

entryentryStandard Rx (± Dig/Diuretics), ß-blocker Standard Rx (± Dig/Diuretics), ß-blocker

stratificationstratification

CaptoprilCaptopril50 mg 3 times 50 mg 3 times daily (N=1574)daily (N=1574)

Primary Endpoint: All-Cause MortalityPrimary Endpoint: All-Cause MortalitySecondary Endpoint: Sudden Cardiac Death and/or Resuscitated Secondary Endpoint: Sudden Cardiac Death and/or Resuscitated

ArrestArrestOther 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

LosartanLosartan50 mg Daily50 mg Daily

(N=1578)(N=1578)

Age (mean, yrs)Age (mean, yrs) 71.4 71.4 71.5 71.5

Gender (male/female %)Gender (male/female %) 70/30 70/30 69/31 69/31Ejection Fraction (mean %)Ejection Fraction (mean %) 31 31 31 31NYHA Funct. Class II/III/IV (%)NYHA Funct. Class II/III/IV (%) 49/45/6 49/45/6 49/45/6 49/45/6Ischemic History (%)Ischemic History (%) 80 80 79 79Prior ACE InhibitorPrior ACE Inhibitor 23 23 24 24 Beta Blocker (%)Beta Blocker (%) 24 24 23 23 Diuretic (%)Diuretic (%) 77 77 78 78Cardiac Glycoside (%) Cardiac Glycoside (%) 49 49 50 50Aspirin/Salicylates (%) Aspirin/Salicylates (%) 59 59 59 59

LosartanLosartan(N=1578)

CaptoprilCaptopril(N=1574)(N=1574)

p= NS losartan p= NS losartan vsvs captopril captopril

Losartan Heart Failure Survival Study - ELITE II Baseline Characteristics

Losartan Heart Failure Survival Study - ELITE II Primary Endpoint: All-Cause Mortality

0 100 200 300 400 500 600 700

Days of Follow-up

0.0

0.2

0.4

0.6

0.8

1.0

Pro

babi

lity

of S

urvi

val

Losartan Losartan (N=1578)(N=1578) 280 Events280 EventsCaptoprilCaptopril (N=1574) (N=1574) 250 Events250 Events

Captopril/Losartan Hazard Ratio (95% C.I.):Captopril/Losartan Hazard Ratio (95% C.I.):0.88 (0.75, 1.05) P=0.160.88 (0.75, 1.05) P=0.16

Losartan Heart Failure Survival Study - ELITE II Mortality by Cause (Adjudicated)

0

5

10

15

SuddenDeath

HeartFailure

MI Stroke Other CV Non-CV

% o

f P

ati

en

ts

Losartan (N=1578) Captopril (N=1574)

Losartan Heart Failure Survival Study - ELITE II Mortality by Subgroup

Hazard Ratio

Age

Gender

NYHA Class.

% EF

Beta Blockers

Overall

71 71

MaleFemale

III/IVII

32 32

WithWithout

731846

1102476

801777

793785

3541224

1578

730844

1083491

798776

783790

3251249

1574

0.930.84

0.890.87

0.930.80

1.020.71

0.560.95

0.88

N NHazardRatio

LosartanCaptopril

1.00.80.60.4 2.0

Hazard Ratio of Deathwith 95% C.I.Subgroups at Baseline

Favors Captopril Favors Losartan

Losartan Heart Failure Survival Study - ELITE IISecondary 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

Eve

nt-

Fre

e P

rob

abili

ty

Losartan Losartan (N=1578)(N=1578) 142 Events142 EventsCaptoprilCaptopril (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

Losartan Heart Failure Survival Study - ELITE II Hospitalization By Cause (Adjudicated)

0

10

20

30

HeartFailure

MI CAD Stroke/TIA ResuscArrest

Non-CV

% o

f P

ati

en

ts

Losartan (N=1578) Captopril (N=1574)

p=NS between groupsp=NS between groups

##

## CAD includes angina, unstable angina, revascularization, etc CAD includes angina, unstable angina, revascularization, etc

Losartan Heart Failure Survival Study - ELITE IITertiary 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

Eve

nt-

Fre

e P

rob

abili

ty

Losartan Losartan (N=1578)(N=1578) 752 Events752 EventsCaptoprilCaptopril (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

Losartan Heart Failure Survival Study - ELITE IIWithdrawal for Adverse Experience (Excluding Death)

0

5

10

15

20

Any AE Drug-RelatedAE

Cough HF

% o

f Pat

ient

s Losartan (N=1578) Captopril (N=1574)**

**** p p0.001 between groups0.001 between groups

**

**

Losartan Heart Failure Survival Study - ELITE II Study Endpoint Summary

Crude Rate

Losartan(N=1578)

Captopril(N=1574)

AdjustedHazards

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