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The Losartan Intervention For Endpoint reductionin hypertension study
An investigator-initiated, prospective, community-based, multinational, double-blind, double-dummy, randomised, active-controlled, parallel-group study from 945 centres
• Losartan is a leader in comprehensive clinical trials, encompassing– 30,000 patients– 4 mega-trials (LIFE, OPTIMAAL, ELITE II, RENAAL)– > 4500 publications
• Losartan and losartan-based regimen have been prescribed to 12 million patients worldwide
• Losartan has proven excellent tolerability
Dahlöf B et al Am J Hypertens 1997; 10: 705713; Dickstein K et al Am J Cardiol 1999; 83: 477481; Pitt B et al Lancet 2000; 355: 15821587; Brenner BM et al N Eng J Med 2001; 345(12): 861869; Bloom BS Clin Ther 1998;20(4):671-681; Goldberg et al Am J Cardiol 1995;75:793-795.
Dahlöf B et al. Lancet 1991;338:1281-85; Coope J et al Brit Med J 1986;293:1145-51; MRC Working Party Brit Med J 1985;291:97-104; JNC-VI Treatment of High Blood Pressure Guidelines,1999 WHO/ISH Hypertension Guidelines.
Angiotensin II Plays a Central Role inOrgan Damage
Adapted from Willenheimer R et al Eur Heart J 1999; 20(14): 9971008; Dahlöf B J Hum Hypertens 1995; 9(suppl 5): S37S44; Daugherty A et al J Clin Invest 2000; 105(11): 16051612; Fyhrquist F et al J Hum Hypertens 1995; 9(suppl 5): S19S24; Booz GW, Baker KM Heart Fail Rev 1998; 3: 125130; Beers MH, Berkow R, eds. The Merck Manual of Diagnosis and Therapy. 17th ed. Whitehouse Station, NJ: Merck Research Laboratories 1999: 16821704; Anderson S Exp Nephrol 1996; 4(suppl 1): 3440; Fogo AB Am J Kidney Dis 2000; 35(2): 179188.
• To date, no treatment of essential hypertension has proven additional protective benefits for prevention of combined CV morbidity and mortality beyond lowering blood pressure with beta blockers and diuretics
• LVH is a strong risk factor for cardiovascular events
• Selective AII antagonism with losartan may reduce the risk of cardiovascular morbidity and death beyond blood-pressure lowering in patients with HT and LVH
Adapted from Dahlöf B et al Lancet 2002;359:995-1003; Dahlöf B et al Am J Hypertens 1997; 10: 705713; Levy D Drugs 1988; 35(suppl 5): 15; Verdechhia et al Circulation 2001;104:2039-2044; Kannel WB Am J Med 1983;
Losartan will reduce the incidence of the primary composite endpoint of cardiovascular morbidity and mortality (defined as stroke, MI or cardiovascular death) to a greater extent as compared to atenolol in patients with essential hypertension and LVH
• A rigorous test of the study hypothesis required a comparator that had already been shown to reduce the risk of cardiovascular morbidity and mortality
• Beta blockers have well established beneficial cardiovascular effects in higher-risk patients
• Atenolol is the most widely prescribed beta blocker
Dahlöf B et al Am J Hypertens 1997; 10: 705713; MacMahon S, Rodgers A J Vasc Med Biol 1993; 4: 265271; Collins R et al Lancet 1990; 335: 827838; Dahlöf B et al Am J Hypertens 1995; 8: 578583; IMS 2002, MAT Patient Days of Therapy - Beta Blocker Market Share.
* Titration encouraged if SiDBP >90 mmHg or SiSBP >140 mmHg but was mandatory if SiBP >160 / 95 mmHg**Other antihypertensives excluding ACEIs, AII antagonists, beta blockersHCTZ=hydrochlorothiazide, SiDBP= sitting diastolic blood pressure, SiSBP=sitting systolic blood pressure Dahlöf B et al Am J Hypertens 1997;10:705713.
LIFE: Design/Dosing Titration
Day 14
Day7
Day1
Mth1
Mth2
Mth 4
Mth6
Yr1
Yr1.5
Yr2
Yr2.5
Yr3
Yr3.5
Yr4
Yr5
* Titration to target blood pressure: <140/90 mmHg
Losartan Atenolol RR p RR p (n=4605) (n=4588) (%) (%)
Primary composite** 508 588 -13 0.021 -15 0.009
CV mortality 204 234 -11 0.206 -13 0.136
Stroke 232 309 -25 0.001 -26 0.0006
MI 198 188 +7 0.491 +5 0.628
Total mortality 383 431 -10 0.128 -12 0.077
New-onset DM*** 241 319 -25 0.001 -25 0.001
LIFE: Primary and Secondary Outcomes
* For degree of LVH and Framingham risk score at randomization ** CV mortality, stroke and MI; patients with a first primary event*** Among patients without diabetes at randomization (losartan n=4019; atenolol, n=3979)
Losartan Is the First Antihypertensive to Provide Superior Benefits
on Combined CV Morbidity and Death vs. an Active Comparator
These data are from four independent, noncomparative studies.
Hansson L et al Lancet 1999;353:611-616; Hannson L et al Lancet 2000;356:359-365; Hannson L et al Lancet 1999;354(9192):1751-1756; Dahlöf et al Lancet 2002;359:995-1003.
• Losartan with LIFE is the only antihypertensive that has demonstrated a superior benefit over another active treatment, atenolol, in reducing the risk of combined CV morbidity and death in patients with hypertension and LVH*
• The superior benefit of losartan therapy on combined CV morbidity and death* compared to atenolol was:
– beyond blood-pressure control
* Defined as composite of CV death, MI, and stroke
• 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
• “Our results are directly applicable in clinical practice and should affect future guidelines.”1
• Steering Committee– Björn Dahlöf (Chair), Richard B. Devereux (Co-chair),
Stevo Julius (US Coordinator), Sverre E. Kjeldsen (Secretaryand Scandinavian Coordinator), Gareth Beevers, Ulf de Faire,Frej Fyhrquist, Hans Ibsen, Lars H. Lindholm, Markku Nieminen, Per Omvik, Suzanne Oparil, Ole Lederballe-Pedersen, Hans Wedel, Krister Kristianson (non-voting)
• Endpoint Classification Committee– Daniel Levy (US), Kristian Thygesen (Denmark)
• Data Safety Monitoring Board– John Kjekshus (Chairman, Norway), Lewis Kuller (US),
Pierre Larochelle (Canada), Giuseppe Mancia (Italy), Joël Ménard (France), Stuart Pocock (UK), John Reid (UK), Michael Weber (US)