Effects of losartan compared with Effects of losartan compared with captopril on mortality in patients with captopril on mortality in patients with

symptomatic heart failure: randomized symptomatic heart failure: randomized trial -- the Losartan Heart Failure Survival trial -- the Losartan Heart Failure Survival

Study ELITE IIStudy ELITE II

Bertram Pitt, Philip A Poole-Wilson, Robert Segal, Felipe A Martinez, Kenneth Bertram Pitt, Philip A Poole-Wilson, Robert Segal, Felipe A Martinez, Kenneth Dickstein, A John Camm, Marvin A Konstam, Gunter Riegger, George H Klinger, Dickstein, A John Camm, Marvin A Konstam, Gunter Riegger, George H Klinger,

James Neaton, Divakar Sharma, Balasamy Thiyagarajan on behalf of the ELITE II James Neaton, Divakar Sharma, Balasamy Thiyagarajan on behalf of the ELITE II investigatorsinvestigators

Lancet Lancet 2000;355:1582-872000;355:1582-87

Background48-week ELITE Study:48-week ELITE Study:In 722 ACEI naïve elderly patients with heart failure due In 722 ACEI naïve elderly patients with heart failure due to systolic left ventricular dysfunction comparing losartan to systolic left ventricular dysfunction comparing losartan to captopril:to captopril:

•No difference in persistent rise in serum creatinine concentrations No difference in persistent rise in serum creatinine concentrations (primary endpoint)(primary endpoint)•46% reduction in all-cause mortality (17 vs 32 for losartan and 46% reduction in all-cause mortality (17 vs 32 for losartan and captopril, respectively)captopril, respectively)•64% reduction in sudden death (5 vs 14 for losartan and captopril, 64% reduction in sudden death (5 vs 14 for losartan and captopril, respectively)respectively)•Similar improvement in functional status (NYHA, quality of life)Similar improvement in functional status (NYHA, quality of life)•Superior tolerability with losartanSuperior tolerability with losartan

Lancet Lancet 2000;355:1582-872000;355:1582-87

ELITE IIELITE IIStudy DesignStudy Design

>> 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 entryACE I/AIIA naive or < 7 days in 3 months prior to entryStandard Rx (Standard Rx (++ Dig/Diuretics ), B-Blocker stratification Dig/Diuretics ), B-Blocker stratification

CaptoprilCaptopril50 mg 3 times daily50 mg 3 times daily (N = 1574)(N = 1574)

LosartanLosartan50 mg daily50 mg daily(N = 1578)(N = 1578)

Primary endpoint: Primary endpoint: All Cause-MortalityAll Cause-MortalitySecondary endpoint: Secondary endpoint: Sudden Cardiac Death or Sudden Cardiac Death or

Resuscitated ArrestResuscitated ArrestOther endpoints: Other endpoints: All-cause Mortality/HospitalizationsAll-cause Mortality/Hospitalizations Safety and TolerabilitySafety and Tolerability

Event DrivenEvent Driven(Target 510 (Target 510

Deaths)Deaths)1.5 years follow-up1.5 years follow-up

Lancet Lancet 2000;355:1582-872000;355:1582-87

ELITE IIELITE IIBaseline CharacteristicsBaseline Characteristics

Losartan (n=1578)Losartan (n=1578) Captopril (n=1575)Captopril (n=1575)

Age (mean, yrs)* 71.4 Age (mean, yrs)* 71.4 71.571.5

Gender (male/female %) 70/30 Gender (male/female %) 70/30 69/31 69/31

Ejection Fraction (mean %) 31 Ejection Fraction (mean %) 31 31 31

NYHA Funct. Class II/III/IV (%) 52/43/5 NYHA Funct. Class II/III/IV (%) 52/43/5 52/43/5 52/43/5

Ischemic History (%) 79 Ischemic History (%) 79 79 79

Prior ACE Inhibitor 23 Prior ACE Inhibitor 23 24 24

Beta Blocker (%) 23 Beta Blocker (%) 23 21 21

Diuretic (%) 77 Diuretic (%) 77 79 79

Cardiac Glycoside (%) 50 Cardiac Glycoside (%) 50 50 50

Analgesic/Salicylates (%) 59 Analgesic/Salicylates (%) 59 59 59

Lancet Lancet 2000;355:1582-872000;355:1582-87*85% *85% >> 65 years of age 65 years of age

ELITE IIELITE IIEndpoint ResultsEndpoint Results

EndpointEndpoint Losartan Losartan Captopril Captopril Hazards Hazards PP (n=1578)(n=1578) (n=1574) (n=1574) ratio ratio

All-cause mortality (primary endpoint)All-cause mortality (primary endpoint)Total mortalityTotal mortality 280 (17.7%)280 (17.7%) 250 (15.9%)250 (15.9%) 1.13 (0.95-1.35)1.13 (0.95-1.35) 0.160.16 Sudden deathSudden death 130 (8.2%)130 (8.2%) 101 (6.4%)101 (6.4%) 1.30 (1.00-1.69)1.30 (1.00-1.69) Progressive heart failureProgressive heart failure 46 (2.9%)46 (2.9%) 53 (3.4%)53 (3.4%) 0.88 (0.59-1.30)0.88 (0.59-1.30) Myocardial infarctionMyocardial infarction 31 (2.0%)31 (2.0%) 28 (1.8%)28 (1.8%) 1.11 (0.66-1.85)1.11 (0.66-1.85) StrokeStroke 18 (1.1%)18 (1.1%) 11 (0.7%)11 (0.7%) 1.65 (0.78-3.49)1.65 (0.78-3.49) Other cardiovascularOther cardiovascular 5 (0.3%)5 (0.3%) 6 (0.4%)6 (0.4%) 0.84 (0.26-2.76)0.84 (0.26-2.76) Non-cardiovascularNon-cardiovascular 50 (9.0%)50 (9.0%) 51 (3.2%)51 (3.2%) 0.99 (0.67-1.47)0.99 (0.67-1.47)Sudden death or resuscitated Sudden death or resuscitated cardiac arrestcardiac arrest 142 (9.0%)142 (9.0%) 115 (7.3%)115 (7.3%) 1.25 (0.98-1.50)1.25 (0.98-1.50) 0.080.08Combined total mortality orCombined total mortality orhospital admission for any reasonhospital admission for any reason 752 (47.7%)752 (47.7%) 707 (44.9%)707 (44.9%) 1.07 (0.97-1.19)1.07 (0.97-1.19) 0.180.18Hospital admissionsHospital admissionsAny reasonAny reason 659 (41.8%)659 (41.8%) 638 (40.5%)638 (40.5%) 1.04 (0.94-1.16)1.04 (0.94-1.16) 0.450.45Heart failureHeart failure 270 (17.1%)270 (17.1%) 293 (18.6%)293 (18.6%) 0.92 (0.78-1.08)0.92 (0.78-1.08) 0.320.32

Lancet Lancet 2000;355:1582-872000;355:1582-87

ELITE IIELITE II Primary Endpoint: All-Cause MortalityPrimary Endpoint: All-Cause Mortality

00 100100 200200 300300 400400 500500 600600 700700

Days of Follow-upDays of Follow-up

0.00.0

0.20.2

0.40.4

0.60.6

0.80.8

1.01.0

Pro

babi

lity

of S

urvi

val

Pro

babi

lity

of S

urvi

val

LosartanLosartanCaptopril Captopril

Hazard Ratio (95-7% C.I.) = 1.13 (0.95-1.35) P = 0.16Hazard Ratio (95-7% C.I.) = 1.13 (0.95-1.35) P = 0.16

Lancet Lancet 2000;355:1582-872000;355:1582-87

ELITE II Secondary Endpoint: Sudden Death / Resuscitated Arrest

00 100100 200200 300300 400400 500500 600600 700700

Days of Follow-upDays of Follow-up

0.00.0

0.20.2

0.40.4

0.60.6

0.80.8

1.01.0

Eve

nt-F

ree

Pro

babi

lity

Eve

nt-F

ree

Pro

babi

lity

Hazard Ratio (95% C.I.) = 1.25 (0.98-1.50) P = 0.08Hazard Ratio (95% C.I.) = 1.25 (0.98-1.50) P = 0.08

LosartanLosartanCaptopril Captopril

Lancet Lancet 2000;355:1582-872000;355:1582-87

ELITE IIELITE IITertiary Endpoint: All-Cause Mortality / HospitalizationTertiary Endpoint: All-Cause Mortality / Hospitalization

00 100100 200200 300300 400400 500500 600600 700700

Days of Follow-upDays of Follow-up

0.00.0

0.20.2

0.40.4

0.60.6

0.80.8

1.01.0

Eve

nt-F

ree

Pro

babi

lity

Eve

nt-F

ree

Pro

babi

lity

Hazard Ratio (95% C.I.) = 1.07 (0.97-1.19) P = 0.18 Hazard Ratio (95% C.I.) = 1.07 (0.97-1.19) P = 0.18

LosartanLosartanCaptopril Captopril

Lancet Lancet 2000;355:1582-872000;355:1582-87

Hazard RatioHazard Ratio

AgeAge

GenderGender

NYHA Class.NYHA Class.

% EF% EF

Beta BlockersBeta Blockers

OverallOverall

7070 7070

MaleMaleFemaleFemale

III/IVIII/IVIIII

< 25< 25>> 25 25

WithWithWithoutWithout

1.051.051.331.33

1.121.121.141.14

1.191.191.371.37

1.001.001.191.19

1.771.771.051.05

1.131.13

HazardHazardRatioRatio

3.03.01.01.00.80.80.60.6 2.02.0

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

Favors LosartanFavors Losartan Favors CaptoprilFavors Captopril

ELITE IIELITE II Mortality by SubgroupMortality by Subgroup

Lancet Lancet 2000;355:1582-872000;355:1582-87

913913661661

10831083491491

798798776776

29029012841284

32532512491249

15741574

NNCaptoprilCaptopril

901901677677

11021102476476

801801777777

26726713111311

35435412241224

15781578

NNLosartanLosartan

ELITE IIELITE IIWithdrawal for Adverse Experience (Excluding Death)Withdrawal for Adverse Experience (Excluding Death)

0

5

10

15

20

Any AE Drug-RelatedAE

Cough HF

% o

f P

atie

nts

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

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

****

****

Lancet Lancet 2000;355:1582-872000;355:1582-87

ELITE IIELITE IIDiscussionDiscussion

• In controlled clinical trials involving about 5000 patients, of In controlled clinical trials involving about 5000 patients, of whom 2800 received losartan, acute and sustained whom 2800 received losartan, acute and sustained hemodynamic benefits with chronic dosing have been seen, hemodynamic benefits with chronic dosing have been seen, as well as effects similar to enalapril on exercise duration.as well as effects similar to enalapril on exercise duration.

• The ELITE II findings, together with previous experience in The ELITE II findings, together with previous experience in heart failure and the known pharmacology of losartan, make heart failure and the known pharmacology of losartan, make it probable that losartan resembles an ACE inhibitor in heart it probable that losartan resembles an ACE inhibitor in heart failure.failure.

• It still remains to be established, however, whether It still remains to be established, however, whether angiotensin II antagonists are a fully effective substitute for angiotensin II antagonists are a fully effective substitute for ACE inhibitors in heart failure.ACE inhibitors in heart failure.

Lancet Lancet 2000;355:1582-872000;355:1582-87

ELITE IIELITE IIDiscussionDiscussion

• Losartan was not superior to captopril in improving Losartan was not superior to captopril in improving survival in elderly heart-failure patients, but was survival in elderly heart-failure patients, but was significantly better tolerated.significantly better tolerated.

• Based on extensive randomized, placebo-controlled Based on extensive randomized, placebo-controlled observations, ACE inhibitors should be the initial observations, ACE inhibitors should be the initial treatment for heart failure, although angiotensin II treatment for heart failure, although angiotensin II receptor antagonists may be useful to block the receptor antagonists may be useful to block the renin angiotensin aldosterone system when ACE renin angiotensin aldosterone system when ACE inhibitors are not tolerated.inhibitors are not tolerated.

Lancet Lancet 2000;355:1582-872000;355:1582-87