Losartan Intervention For Endpoint
Reduction in Hypertension Study
LIFE Study Overview
Double-blind, randomized trial to compare the effects of losartan and
atenolol on cardiovascular morbidity and mortality in high-risk
patients with hypertension and left ventricular hypertrophy (LVH)
Population
• 9,193 patients (55 to 80 years old) from 945 sites in 7 countries
– previously treated or untreated essential hypertension (systolic
BP 160–200 mmHg or diastolic BP 95–115 mmHg)
– ECG LVH
• 1,195 patients (13%) had diabetes at baseline
Dahlof B, et al. Lancet. 2002;359:995-1003. www.hypertensiononline.org
LIFE Study Design
Assessed for eligibility Ineligible (n=1,558)
n=10,780 • failed protocol
criteria (n=1,343)
• unwilling to
Randomized participate (n=215)
n=9,222
Excluded for irregularities (n=29)
Losartan Atenolol
n=4,605 n=4,588
4,605 available for 4,588 available for
intention-to-treat analyses intention-to-treat analyses
44 withdrew consent 34 withdrew consent
57 vital status only 50 vital status only
4 lost to follow-up 8 lost to follow-up
Dahlof B, et al. Lancet. 2002;359:995-1003.
Reprinted with permission from Elsevier Science.
www.hypertensiononline.org
LIFE Study Endpoints*
Primary Endpoint
• Composite of cardiovascular mortality, fatal and
non-fatal myocardial infarction, and fatal and
non-fatal stroke
Other predefined endpoints
– total mortality
– angina pectoris†
– heart failure†
– coronary or peripheral revascularization procedures
– resuscitated cardiac arrest
– new-onset diabetes mellitus
*Each endpoint includes only first event; patients could appear in more than one category.
† Requiring hospital admission
Dahlof B, et al. Lancet. 2002;359:995-1003. www.hypertensiononline.org
LIFE Study Distribution of 9,193
Participants Among 7 Countries
Iceland Finland
1% 16%
Denmark
15% Norway
15%
United
States
19%
Sweden
United Kingdom 24%
9%
Dahlof B, et al. Lancet. 2002;359:995-1003. www.hypertensiononline.org
LIFE Study Dosing
Losartan 100 mg
Titration to target + HCTZ 12.5-25 mg + others*
blood pressure
160/<90 mmHg)
Coronary heart disease 17 % 15 %
Cerebrovascular disease 8% 8%
Peripheral vascular disease 6% 5%
Atrial fibrillation 3% 4%
*P=NS for all comparisons
Dahlof B, et al. Lancet. 2002;359:995-1003.
Reprinted with permission from Elsevier Science.
www.hypertensiononline.org
LIFE Study Distribution of Therapy*
Losartan (mean dosage 82 mg)
23% 4%
50 mg only
50 mg + additional drugs*
50% 26% Off study drugs
18% 100 mg with or without
18%
additional drugs*
2%
9% Alone
Atenolol (mean dosage 79 mg) With HCTZ only
27% 4% With other drugs only
With HCTZ and
22% other drugs
43%
16%
20% *At endpoint or end of follow-up
2%
10%
Dahlof B, et al. Lancet. 2002;359:995-1003. www.hypertensiononline.org
LIFE Study Blood Pressure
and Heart Rate Results
Losartan Atenolol
(n=4,605) (n=4,588)
SBP last visit (mmHg) 144.1 145.4
Change in SBP* -30.2 -29.1
DBP last visit (mmHg) 81.3 80.9
Change in DBP -16.6 -16.8
MAP last visit (mmHg) 102.2 102.4
BP <140/<90 (%) 48 45
SBP <140 mmHg (%) 49 46
DBP < 90 mmHg (%) 87 89
Change in HR (bpm)† -1.8 -7.7
*P=0.017
†P<0.0001
Dahlof B, et al. Lancet. 2002;359:995-1003. www.hypertensiononline.org
LIFE Study Blood Pressure
During Follow-up
180
160 Systolic
140
120 Mean Arterial
mmHg
100
80
Diastolic
60 Losartan
Atenolol
40
20
0 6 12 18 24 30 36 42 48 54
Study Month
Dahlof B, et al. Lancet. 2002;359:995-1003.
Reprinted with permission from Elsevier Science. www.hypertensiononline.org
LIFE Study Primary Composite Endpoint
16
Intention-to-treat
14
Adjusted risk reduction 13·0%, P=0·021
Proportion of patients
with first event (%)
Unadjusted risk reduction 14·6%, P=0·009
12
10
Atenolol
8
Losartan
6
4
2
Study Month 0 6 12 18 24 30 36 42 48 54 60 66
Losartan (n) 4605 4524 4460 4392 4312 4247 4189 4112 4047 3897 1889 901
Atenolol (n) 4588 4494 4414 4349 4289 4205 4135 4066 3992 3821 1854 876
Dahlof B, et al. Lancet. 2002;359:995-1003.
Reprinted with permission from Elsevier Science. www.hypertensiononline.org
LIFE Study Cardiovascular Mortality
8
Intention-to-treat
7
Adjusted risk reduction 11·4%, P=0·21
Proportion of patients
Unadjusted risk reduction 13·3%, P=0·14
with first event (%)
6
5
Atenolol
4
3 Losartan
2
1
0 6 12 18 24 30 36 42 48 54 60 66
Study Month
Dahlof B, et al. Lancet. 2002;359:995-1003.
Reprinted with permission from Elsevier Science. www.hypertensiononline.org
LIFE Study Fatal and Non-Fatal
Myocardial Infarction
7
Intention-to-treat
6 Adjusted Risk Reduction -7·3%, P=0·49
Proportion of patients
with first event (%)
Unadjusted Risk Reduction -5·0%, P=0·63
5
Losartan
4
3 Atenolol
2
1
0 6 12 18 24 30 36 42 48 54 60 66
Study Month
Dahlof B, et al. Lancet. 2002;359:995-1003.
Reprinted with permission from Elsevier Science. www.hypertensiononline.org
LIFE Study Fatal and Non-Fatal Stroke
8
Intention-to-treat
7 Adjusted risk reduction 24·9%, P=0·001
Proportion of patients
Unadjusted risk reduction 25·8%, P=0·0006
with first event (%)
6
5 Atenolol
4 Losartan
3
2
1
0 6 12 18 24 30 36 42 48 54 60 66
Study Month
Dahlof B, et al. Lancet. 2002;359:995-1003.
Reprinted with permission from Elsevier Science. www.hypertensiononline.org
LIFE Study New-Onset Diabetes
10
9
Intention-to-treat
Adjusted risk reduction 25%, P=0·001
8 Unadjusted risk reduction 25%, P=0·001
Proportion of patients
with first event (%)
7
Atenolol
6
5
Losartan
4
3
2
1
0 6 12 18 24 30 36 42 48 54 60 66
Dahlof B, et al. Lancet. 2002;359:995-1003. Study Month
Presented by B Dahlof at the American College of Cardiology
Scientific Sessions Late-Breaking Clinical Trials III, 2002. www.hypertensiononline.org
LIFE Study Discontinuation Rates
dropped-out because of AE (%)
Due to Adverse Events (AE)
20
P<0.0001
Proportion of patients who
16
Atenolol
12 P<0.0001 Losartan
8
4
P=0.006
0
Serious,
All Drug-related
drug-related
Dahlof B, et al. Lancet. 2002;359:995-1003.
Reprinted with permission from Elsevier Science. www.hypertensiononline.org
LIFE Study Change in Cornell Voltage
Duration Product and Sokolow-Lyon
Cornell Product Sokolow-Lyon
0
Change from baseline (%)
-2
-4
-6
-8
-10
-12
P<0.0001
-14
Losartan
-16 Atenolol P<0.0001
-18
Dahlof B, et al. Lancet. 2002;359:995-1003.
Reprinted with permission from Elsevier Science. www.hypertensiononline.org
LIFE Study Diabetes Subgroup
Primary Composite Endpoint
24
Adjusted risk reduction 24·5%, P=0·031
20 Unadjusted risk reduction 26.7%, P=0·017
Proportion of patients
with first event (%)
16
Atenolol
Losartan
12
8
4
Study Month 0 6 12 18 24 30 36 42 48 54 60 66
Losartan (n) 586 569 558 548 532 520 513 501 484 459 237 127
Atenolol (n) 609 588 562 552 540 527 507 486 472 434 204 99
Lindholm LH, et al. Lancet. 2002;359:1004-1010.
Reprinted with permission from Elsevier Science. www.hypertensiononline.org
LIFE Study Diabetes Subgroup Primary
Composite Endpoint and Components
No. of P Adjusted
Endpoints events value hazard ratio (95% CI)
Composite 242 0.031
CV Death 99 0.028
Stroke 116 NS
Myocardial
infarction 91 NS
Total Mortality 167 0.002
0.5 1 1.5
Favors Favors
Lindholm LH, et al. Lancet. 2002;359:1004-1010. losartan atenolol
Presented by B Dahlof at the American College of Cardiology
Scientific Sessions Late-Breaking Clinical Trials III, 2002. www.hypertensiononline.org
LIFE Study Diabetes Subgroup
Total Mortality
24
Adjusted risk reduction 38·7%, P=0·002
20 Unadjusted risk reduction 40·1%, P=0·001
Proportion of patients
with first event(%)
16
Atenolol
12
8
Losartan
4
0 6 12 18 24 30 36 42 48 54 60 66
Study Month
Lindholm LH, et al. Lancet. 2002;359:1004-1010.
Reprinted with permission from Elsevier Science. www.hypertensiononline.org
LIFE Study Summary
• Losartan-based compared with atenolol-based
antihypertensive therapy was associated with:
– A reduction in the combined primary endpoint of
cardiovascular death, stroke or MI (-13%)
– fewer strokes (-25%)
– similar blood pressure reduction
• Losartan reduced the rate of new-onset diabetes
(-25%)
• In the diabetic subgroup, losartan reduced the
rate of:
– combined endpoint of cardiovascular death, stroke and
MI (-25%)
– all-cause mortality (-39%)
Dahlof B, et al. Lancet. 2002;359:995-1003.
Lindholm LH, et al. Lancet. 2002;359:1004-1010. www.hypertensiononline.org
LIFE Study Conclusions
• Losartan reduced the combined risk of
cardiovascular morbidity and mortality
compared to atenolol with benefits not
explained by blood pressure reduction
• Losartan reduced the rate of new-onset
diabetes
• Losartan was significantly better tolerated
than atenolol
• Among diabetics, losartan reduced
cardiovascular morbidity and mortality
Dahlof B, et al. Lancet. 2002;359:995-1003.
Lindholm LH, et al. Lancet. 2002;359:1004-1010. www.hypertensiononline.org