ASCOT Study - Anglo Scandinavian Cardiac Outcomes Trial LIFE Study - Losartan Intervention For Endpoint Reduction in HPN

A Randomized controlled trial of the prevention of CHD and the other Cardiovascular morbidity and mortality in the Losartan Intervention For
Study Title vascular events by BP and cholesterol lowering in factorial study Endpoint reduction in hypertension study (LIFE): a randomised trial against
design atenolol.

Björn Dahlöf (Chair),

Björn Dahlöf,
Richard B. Devereux (Co-chair),
Peter S. Sever,
Stevo Julius (US Coordinator),
Neil R Poulter,
Sverre E. Kjeldsen (Scandinavian Coordinator),
Hans Wedel,
Gareth Beevers,
Gareth Beevers,
Ulf de Faire,
Mark Caulfield,
Frej Fyhrquist,
Rory Collins,
Author Hans Ibsen,
Sverre E Kjeldsen,
Lars H. Lindholm,
Arni Kristinsson,
Markku Nieminen,
Gordon T McInnes,
Per Omvik,
Jesper Mehlsen,
Suzanne Oparil,
Markku Nieminen,
Ole Lederballe - Pedersen,
Eoien O’Brien,
Hans Wedel,
Jan Ostergren,
Krister Kristianson

Reference Dahlöf B et al Lancet 2005;366: 895-906. Dahlöf B et al Lancet 2002;359: 995-1003.

• To compare the effect on non-fatal myocardial infarction and fatal • To investigate the effect of losartan, compared to atenolol, on the
Objective of the Study CHD of combinations of atenolol with a thiazide versus amlodipine reduction of cardiovascular morbidity and mortality in hypertensive
with perindopril. patients with left ventricular hypertrophy.

• Investigator-initiated,
• Prospective,
Prospective,
Randomized,
Multi-center / Multinational - 945 study centres in 7 countries
Placebo -controlled,
Study Design Double-blind,
Open,
Active-controlled,
Double Blinded-Endpoint (PROBE),
Randomised,
Multi-center / International,
Community-based study.

• 19,257 patients with hypertension plus more than 3 other CVD risks
No of Patients • 9,193 hypertensive patients with LVH
factors

Duration • 5.5 years mean follow-up • Mean 4.8 year follow-up

• Age 40-79 years

• Age 55–80 years
• Patients with hypertension plus three or more cardiovascular • Previously treated or untreated hypertension
risk factors like (LVH, DM, PAD, previous stroke or TIA, male • Diastolic BP 95–115 mmHg or systolic BP 160–200 mmHg
Inclusion Criteria sex, age 55 years or older, micro albuminuria or proteinuria,
smoking, cholesterol or family history of CHD. • ECG-confirmed LVH /
Cornell Voltage Product > 2440 mm X m sec

• Diastolic BP 100 mmHg or more & systolic BP 160 mmHg or
more Sokolow -Lyon > 38 mm

• Secondary hypertension
• Previous MI • Angina pectoris requiring treatment with β- blocker or calcium
• Currently treated angina channel antagonist
Exclusion Criteria • Heart Failure; uncontrolled arrhythmias • Heart failure or known left ventricular ejection fraction ≤40%
• Cerebrovascular events within the previous 3 months • Conditions that required treatment with an angiotensin II receptor
• Fasting triglycerides higher than 4.5 mmol;/L antagonist, β-blocker, diuretic, or ACE inhibitor
• MI or stroke within 6 months

• Composite of cardiovascular mortality, fatal and non-fatal MI & fatal and

Primary Endpoints • Non-fatal (including silent MI) and fatal CHD)
non-fatal stroke.

• All Cause mortality, stroke, non-fatal MI (excluding non-fatal MI), all

• Total mortality, angina pectoris, heart failure, coronary or peripheral
Secondary Endpoints coronary events, CV events procedures, CV mortality, fatal & non-
revascularization procedures, resuscitated cardiac arrest, new onset DM.
fatal HF.

• Amlodipine 5-10 mg + Perindopril 4-8 mg • Losartan 50-100 mg + HCTZ 12.5 - 25 mg

Treatment Regimen vs. vs.
Atenolol 50-100 mg + Bendroflumethiazide 1.25-2.5 mg/potassium Atenolol 50-100 mg + HCTZ 12.5 - 25 mg

• Amlodipine-based regimen was beneficial in lowering BP and • Losartan reduced the risk of the primary composite endpoint
prevention of CV events compared to beta-blocker ± diuretic-based (cardiovascular mortality, MI or Stroke).
regimen
• Losartan provided superior benefit on combined cardiovascular morbidity

Results of the Study • Amlodipine ± perindopril showed reductions in: and mortality and death vs atenolol.
– Major CV events 16%
 – Risk reduction in composite endpoints(death, stroke & MI) 13%

– New-onset diabetes 30%
 – New-onset diabetes 25%

– Stroke 30% 
 – Stroke 25% 

– Mortality 11% – In the diabetes sub-group, losartan reduced the rate of mortality by 39%

• ASCOT BPLA results reaffirm that most hypertensive patients need
at least two agents to reach recommended blood - pressure targets.
It has shown that blood pressure can be lowered effectively in most
patients.
Implications • Reduction in cardiovascular events associated with a CCB
(amlodipine) with addition of perindopril if necessary, particularly
• The greater clinical benefit and enhanced tolerability demonstrated by
losartan in The LIFE Study Group suggest that broader use of losartan may
improve outcomes for hypertensive patients with LVH
• Losartan reduced the rate of new-onset diabetes
• Losartan was significantly better tolerated than atenolol

when used in combination with effective lipid lowering, results in the • Among diabetics, losartan reduced cardiovascular morbidity and mortality
prevention of most major cardiovascular events associated with
hypertension. • LIFE is the first trial to exclusively study hypertensive patients with LVH