Losartan Intervention For Endpoint Reduction in Hypertension Study

1
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 160200 mmHg or
  diastolic BP 95115 mmHg)
• ECG LVH
• 1,195 patients (13) had diabetes at baseline

www.hypertensiononline.org
Dahlof B, et al. Lancet. 2002359995-1003.
2
LIFE Study Design
Assessed for eligibility n10,780

• Ineligible (n1,558)
• failed protocol
• criteria (n1,343)
• unwilling to
• participate (n215)

Randomized n9,222
Excluded for irregularities (n29)
Losartan n4,605
Atenolol n4,588
4,605 available for intention-to-treat
analyses 44 withdrew consent 57 vital status
only 4 lost to follow-up
4,588 available for intention-to-treat
analyses 34 withdrew consent 50 vital status
only 8 lost to follow-up
Dahlof B, et al. Lancet. 2002359995-1003.
Reprinted with permission from Elsevier Science.
www.hypertensiononline.org
3
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
www.hypertensiononline.org
Dahlof B, et al. Lancet. 2002359995-1003.
4
LIFE Study Distribution of 9,193 Participants
Among 7 Countries
Finland16
Iceland1
Denmark15
Norway15
United States19
Sweden24
United Kingdom9
www.hypertensiononline.org
Dahlof B, et al. Lancet. 2002359995-1003.
5
LIFE Study Dosing
Losartan 100 mg HCTZ 12.5-25 mg others
Titration to target blood pressure lt140/90 mmHg
Losartan 100 mg HCTZ 12.5 mg
Losartan 50 mg HCTZ 12.5 mg
Losartan 50 mg
Placebo
Atenolol 50 mg
Atenolol 50 mg HCTZ 12.5 mg
Atenolol 100 mg HCTZ 12.5 mg
Atenolol 100 mg HCTZ 12.5-25 mg others
?14
?7
1
2
4
6
1
1.5
2
2.5
3
3.5
4
5
1
DAY
MONTH
YEAR
Other antihypertensives excluding ACEIs, AII
antagonists, beta-blockers
Dahlof B, et al. Lancet. 2002359995-1003.
Reprinted with permission from Elsevier Science.
www.hypertensiononline.org
6
LIFE Study Baseline Characteristics (1)
PNS for all comparisons
Dahlof B, et al. Lancet. 2002359995-1003.
Reprinted with permission from Elsevier Science.
www.hypertensiononline.org
7
LIFE Study Baseline Characteristics (2)
PNS for all comparisons
Dahlof B, et al. Lancet. 2002359995-1003.
Reprinted with permission from Elsevier Science.
www.hypertensiononline.org
8
LIFE Study Distribution of Therapy
Losartan (mean dosage 82 mg)
50 mg only
50 mg additional drugs
Off study drugs
100 mg with or without additional drugs
Alone
Atenolol (mean dosage 79 mg)
With HCTZ only
With other drugs only
With HCTZ and other drugs
At endpoint or end of follow-up
www.hypertensiononline.org
Dahlof B, et al. Lancet. 2002359995-1003.
9
LIFE Study Blood Pressure and Heart Rate Results
P0.017 Plt0.0001
www.hypertensiononline.org
Dahlof B, et al. Lancet. 2002359995-1003.
10
LIFE Study Blood Pressure During Follow-up
Systolic
Mean Arterial
mmHg
Diastolic
Losartan
Atenolol
54
48
6
12
30
18
24
36
42
0
Study Month
Dahlof B, et al. Lancet. 2002359995-1003. Reprin
ted with permission from Elsevier Science.
www.hypertensiononline.org
11
LIFE Study Primary Composite Endpoint
16
Intention-to-treat
14
Adjusted risk reduction 130, P0021 Unadjusted
risk reduction 146, P0009
12
10
Atenolol
Proportion of patients with first event ()
8
Losartan
6
4
2
0
6
12
18
24
30
36
42
48
54
60
66
Study Month
Dahlof B, et al. Lancet. 2002359995-1003. Reprin
ted with permission from Elsevier Science.
www.hypertensiononline.org
12
LIFE Study Cardiovascular Mortality
8
Intention-to-treat
7
Adjusted risk reduction 114, P021 Unadjusted
risk reduction 133, P014
6
5
Atenolol
Proportion of patients with first event ()
4
Losartan
3
2
1
0
6
12
18
24
36
42
48
54
60
66
30
Study Month
Dahlof B, et al. Lancet. 2002359995-1003. Reprin
ted with permission from Elsevier Science.
www.hypertensiononline.org
13
LIFE Study Fatal and Non-Fatal Myocardial
Infarction
7
Intention-to-treat
6
Adjusted Risk Reduction -73, P049 Unadjusted
Risk Reduction -50, P063
5
Losartan
4
Proportion of patients with first event ()
Atenolol
3
2
1
0
6
12
18
24
36
42
48
54
60
66
30
Study Month
Dahlof B, et al. Lancet. 2002359995-1003. Reprin
ted with permission from Elsevier Science.
www.hypertensiononline.org
14
LIFE Study Fatal and Non-Fatal Stroke
8
Intention-to-treat
Adjusted risk reduction 249, P0001 Unadjusted
risk reduction 258, P00006
7
6
Atenolol
5
Proportion of patients with first event ()
Losartan
4
3
2
1
0
6
12
18
24
36
42
48
54
60
66
30
Study Month
Dahlof B, et al. Lancet. 2002359995-1003. Reprin
ted with permission from Elsevier Science.
www.hypertensiononline.org
15
LIFE Study New-Onset Diabetes
10
Intention-to-treat
Adjusted risk reduction 25, P0001 Unadjusted
risk reduction 25, P0001
Atenolol
Proportion of patients with first event ()
Losartan
Study Month
Dahlof B, et al. Lancet. 2002359995-1003. Presen
ted by B Dahlof at the American College of
Cardiology Scientific Sessions Late-Breaking
Clinical Trials III, 2002.
www.hypertensiononline.org
16
LIFE Study Discontinuation Rates Due to Adverse
Events (AE)
20
Plt0.0001
16
Atenolol
Losartan
Plt0.0001
12
Proportion of patients who dropped-out because of
AE ()
8
4
P0.006
0
Serious, drug-related
All
Drug-related
Dahlof B, et al. Lancet. 2002359995-1003. Reprin
ted with permission from Elsevier Science.
www.hypertensiononline.org
17
LIFE Study Change in Cornell Voltage Duration
Product and Sokolow-Lyon
Cornell Product
Sokolow-Lyon
0
-2
-4
-6
-8
Change from baseline ()
-10
Plt0.0001
-12
-14
Losartan
-16
Atenolol
Plt0.0001
-18
Dahlof B, et al. Lancet. 2002359995-1003. Reprin
ted with permission from Elsevier Science.
www.hypertensiononline.org
18
LIFE Study Diabetes Subgroup Primary Composite
Endpoint
24
Adjusted risk reduction 245, P0031 Unadjusted
risk reduction 26.7, P0017
20
16
Atenolol
Losartan
Proportion of patients with first event ()
12
8
4
Study Month
Lindholm LH, et al. Lancet. 20023591004-1010. Re
printed with permission from Elsevier Science.
www.hypertensiononline.org
19
LIFE Study Diabetes Subgroup Primary Composite
Endpoint and Components
Adjusted hazard ratio (95 CI)
No. of events
P value
Endpoints
Composite
242
0.031
CV Death
99
0.028
116
NS
Stroke
Myocardial infarction
91
NS
Total Mortality
167
0.002
0.5
1
1.5
Favors losartan


Favors atenolol
Lindholm LH, et al. Lancet. 20023591004-1010. Pr
esented by B Dahlof at the American College of
Cardiology Scientific Sessions Late-Breaking
Clinical Trials III, 2002.
www.hypertensiononline.org
20
LIFE Study Diabetes Subgroup Total Mortality
24
Adjusted risk reduction 387, P0002 Unadjusted
risk reduction 401, P0001
20
16
Atenolol
Proportion of patients with first event()
12
8
Losartan
4
Study Month
Lindholm LH, et al. Lancet. 20023591004-1010. Re
printed with permission from Elsevier Science.
www.hypertensiononline.org
21
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. 2002359995-1003.
Lindholm LH, et al. Lancet. 20023591004-1010.
www.hypertensiononline.org
22
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. 2002359995-1003.
Lindholm LH, et al. Lancet. 20023591004-1010.
www.hypertensiononline.org