1 Downloaded from The L osartan I ntervention F or E ndpoint reduction in hypertension study An investigator-initiated, prospective, community-based, multinational, double-blind, double-dummy, randomised, active-controlled, parallel-group study from 945 centres Dahlöf B et al Lancet 2002;359: Steering Committee Chair: Co-chair: B. Dahlöf R.B. Devereux

2 Downloaded from Clinical Experience with Losartan 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: 705  713; Dickstein K et al Am J Cardiol 1999; 83: 477  481; Pitt B et al Lancet 2000; 355: 1582  1587; Brenner BM et al N Eng J Med 2001; 345(12): 861  869; Bloom BS Clin Ther 1998;20(4): ; Goldberg et al Am J Cardiol 1995;75:

3 Downloaded from Hypertensive Patients Are at Increased Risk for Cardiovascular Events Framingham Heart Study - Risk of Cardiovascular Events by Hypertensive Status in Patients Aged Years; 36-Year Follow-Up Risk Ratio Excess Risk Coronary DiseaseStroke Peripheral Artery Disease Cardiac Failure Biennial Age-Adjusted Rate per 1000 Kannel WB JAMA 1996;275(24):

4 Downloaded from Hypertension Treatment Significantly Reduced Mortality and Morbidity VA Cooperative Study Group – Estimated Cumulative Incidence of All Morbid Events Over 5 Years Veterans Administration Cooperative Study Group on antihypertensive agents JAMA 1970;213(7): Control - Placebo Active Treatment Groups - Diuretic-based regimen and hydralazine

5 Downloaded from Beta Blockers and Diuretics Lower Risk of Cardiovascular Events In hypertension, beta blockers and diuretics have proven risk reduction in cardiovascular morbidity and mortality vs. placebo –STOP, HEP, MRC Trials Hypertension guidelines recommend beta blockers or diuretics as one of the initial treatments for hypertension –JNC-VI, WHO/ISH Hypertension Treatment Guidelines Dahlöf B et al. Lancet 1991;338: ; Coope J et al Brit Med J 1986;293: ; MRC Working Party Brit Med J 1985;291:97-104; JNC-VI Treatment of High Blood Pressure Guidelines,1999 WHO/ISH Hypertension Guidelines.

6 Downloaded from Mega-trialsCAPPPNORDILSTOP-2 Comparator Treatments ACE I vs. ß blockers/Diur CCB vs. ß blockers/Diur ACEIs/CCBs vs. ß blockers/Diur Number of Patients 10,98510, Number of Primary Endpoints Composite Primary Endpoint MI, Stroke, CV Death MI, Stroke, CV Death Fatal MI, Fatal Stroke, Fatal CV Disease Differences on Primary Endpoint NS p = 0.52 NS p = 0.97 NS p = 0.89 Other Mega-trials Have Not Shown Superiority on Combined CV Morbidity and Mortality vs. an Active Comparator These data are from 3 independent, non-comparative studies. Hansson L et al Lancet 1999;353: ; Hannson L et al Lancet 2000;356: ; Hannson L et al Lancet 1999;354(9192):

7 Downloaded from GFR Proteinuria Aldosterone release Glomerular sclerosis Angiotensin II Plays a Central Role in Organ Damage Adapted from Willenheimer R et al Eur Heart J 1999; 20(14): 997  1008; Dahlöf B J Hum Hypertens 1995; 9(suppl 5): S37  S44; Daugherty A et al J Clin Invest 2000; 105(11): 1605  1612; Fyhrquist F et al J Hum Hypertens 1995; 9(suppl 5): S19  S24; Booz GW, Baker KM Heart Fail Rev 1998; 3: 125  130; Beers MH, Berkow R, eds. The Merck Manual of Diagnosis and Therapy. 17th ed. Whitehouse Station, NJ: Merck Research Laboratories 1999: 1682  1704; Anderson S Exp Nephrol 1996; 4(suppl 1): 34  40; Fogo AB Am J Kidney Dis 2000; 35(2): 179  188. Atherosclerosis* Vasoconstriction Vascular hypertrophy Endothelial dysfunction LV hypertrophy Fibrosis Remodeling Apoptosis Stroke DEATH *preclinical data LV = left ventricular; MI = myocardial infarction; GFR = glomerular filtration rate Hypertension Heart failure MI Renal failure AII AT 1 receptor

8 Downloaded from LIFE: Rationale 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: ; Dahlöf B et al Am J Hypertens 1997; 10: 705  713; Levy D Drugs 1988; 35(suppl 5): 1  5; Verdechhia et al Circulation 2001;104: ; Kannel WB Am J Med 1983; 75(suppl 3A): 4  11.

9 Downloaded from Hypothesis 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 Dahlöf B et al Am J Hypertens 1997; 10: 705  713.

10 Downloaded from LIFE: Choice of Atenolol as Comparator 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: 705  713; MacMahon S, Rodgers A J Vasc Med Biol 1993; 4: 265  271; Collins R et al Lancet 1990; 335: 827  838; Dahlöf B et al Am J Hypertens 1995; 8: 578  583; IMS 2002, MAT Patient Days of Therapy - Beta Blocker Market Share.

11 Downloaded from LIFE: A Landmark Study 9193 hypertensive patients with LVH, aged years Mean 4.8-year follow-up 44,119 patient-years of follow-up 945 study sites in 7 countries 1096 patients with primary endpoints Investigator-initiated, prospective, double-blind, active- controlled, intention-to-treat, community-based study Dahlöf B et al Lancet 2002;359:

12 Downloaded from Dahlöf B et al Am J Hypertens 1997;10:705  713. LIFE: Inclusion Criteria Age 55–80 years Previously treated or untreated hypertension Diastolic BP 95–115 mmHg or systolic BP 160–200 mmHg ECG-confirmed LVH –Cornell Voltage Product > 2440 mm X msec –Sokolow-Lyon > 38 mm

13 Downloaded from * 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 blockers HCTZ=hydrochlorothiazide, SiDBP= sitting diastolic blood pressure, SiSBP=sitting systolic blood pressure Dahlöf B et al Am J Hypertens 1997;10:705  713. LIFE: Design/Dosing Titration Day  14 Day  7 Day 1 Mth 1 Mth 2 Mth 4 Mth 6 Yr 1 Yr 1.5 Yr 2 Yr 2.5 Yr 3 Yr 3.5 Yr 4 Yr 5 * Titration to target blood pressure: <140/90 mmHg Placebo Losartan 50 mg Atenolol 50 mg Losartan 50 mg + HCTZ 12.5 mg* Losartan 100 mg + HCTZ 12.5 mg* Losartan 100 mg + HCTZ mg + others** Atenolol 50 mg + HCTZ 12.5 mg* Atenolol 100 mg + HCTZ 12.5 mg* Atenolol 100 mg + HCTZ mg + others**

14 Downloaded from LIFE: Baseline Characteristics Losartan Atenolol (n=4605)(n=4588) Age, years Female, %54%54% BMI, kg/m Race, % Caucasian92.5% 92.5% Others 7.5%7.5% BP, mmHg174.3/ /97.7 Heart Rate, bpm LVH-Cornell Product, mm X msec LVH-Sokolow-Lyon, mm Framingham Risk Score Smokers, % 16%17% Data are presented as mean. Dahlöf B et al Lancet 2002;359:

15 Downloaded from LIFE: Baseline Characteristics (cont’d) Losartan Atenolol (n=4605) (n=4588) Medical History, % –DM13% 13% –ISH (>160/<90 mmHg) 14% 15% –CHD17% 15% –CVD8% 8% Total Cholesterol, mmol/L Glucose, mmol/L Data are presented as mean. Dahlöf B et al Lancet 2002;359:

Proportion of patients with first event (%) Composite of CV death, stroke and MI Losartan Atenolol LIFE: Primary Composite Endpoint Study Month Losartan Atenolol Adjusted Risk Reduction 13.0%, p=0.021 Unadjusted Risk Reduction 14.6%, p=0.009 Dahlöf B et al Lancet 2002;359: Number at Risk 16

17 Downloaded from Stroke Losartan Atenolol Adjusted Risk Reduction 24.9%, p=0.001 Unadjusted Risk Reduction 25.8%, p= Study Month Dahlöf B et al Lancet 2002;359: Losartan Atenolol Fatal and nonfatal stroke Proportion of patients with first event (%) Number at Risk

18 Downloaded from LosartanAtenololRRp RRp (n=4605)(n=4588)(%) (%) Primary composite ** CV mortality Stroke MI Total mortality New-onset DM *** 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) Dahlöf B et al Lancet 2002;359: UnadjustedAdjusted *

19 Downloaded from LIFE: Comparable Blood-Pressure Reductions Study Month Systolic Diastolic Mean Arterial mmHg Atenolol mmHg* Losartan mmHg* Atenolol 80.9 mmHg* Losartan 81.3 mmHg* * Mean BP at last visit Dahlöf B et al Lancet 2002;359: Atenolol mmHg* Losartan mmHg*

20 Downloaded from LIFE: Number of Patients on Study Drug at Endpoint or Termination of Follow-Up Losartan Atenolol 50 mg only9%10% 50 mg plus additional therapy* including HCTZ18%20% 100 mg with or without additional therapy* including HCTZ50%43% Off-study therapy23%27% Mean Dosage: 82 mg 79 mg *Excluding ACEIs, AIIAs, beta blockers. Dahlöf B et al Lancet 2002;359:

21 Downloaded from LIFE: Change from Baseline in LVH Regression Cornell ProductSokolow-Lyon Mean change from baseline (%) LosartanAtenolol p< Dahlöf B et al Lancet 2002;359: % 9.0 % 15.3 % 4.4 % p<0.0001

22 Downloaded from LIFE: Adjustments for Difference * Unadjusted for Framingham risk score and LVH B. Dahlöf at the American College of Cardiology, Atlanta, GA, March 17-20, Adjustment none* –Treatment effect -15% Achieved BP –Adjustment for SBP Treatment effect -14% Regression of ECG-confirmed LVH –Adjustment for Cornell Voltage Duration Product (CVDP) and Sokolow-Lyon (SL) Treatment effect -10% Conclusion:Adjusting for differences in achieved BP and degree of LVH regression only explains part of the study outcome

23 Downloaded from Intention-to-Treat LIFE: New-Onset Diabetes Losartan Atenolol Atenolol (N=3979) Losartan (N=4019) Study Month Adjusted Risk Reduction 25 %, p<0.001 Unadjusted Risk Reduction 25 %, p<0.001 B. Dahlöf at the American College of Cardiology, Atlanta, GA, March 17-20, Endpoint Rate

24 Downloaded from p< p=0.006 LIFE: Discontinuations Due to Adverse Experiences Atenolol Losartan Dahlöf B et al Lancet 2002;359: Proportion of patients who dropped out because of AE (%)

25 Downloaded from Mega-trialsCAPPPNORDILSTOP-2 Comparator Treatments ACEI vs. ß blockers/Diur CCB vs. ß blockers/Diur ACEIs/CCBs vs. ßbockers/Diur Losartan vs. Atenolol Number of Patients10,98510, Number of Primary Endpoints Composite Primary Endpoint MI, Stroke, CV Death MI, Stroke, CV Death Fatal MI, Fatal Stroke, Fatal CV Disease MI, Stroke, CV Death Differences on Primary Endpoint NS p = 0.52 NS p = 0.97 NS p = % RR p = 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: ; Hannson L et al Lancet 2000;356: ; Hannson L et al Lancet 1999;354(9192): ; Dahlöf et al Lancet 2002;359:

26 Downloaded from LIFE: Summary Losartan-based antihypertensive therapy provided superior benefit on combined cardiovascular morbidity and death vs. atenolol: –Superior risk reduction in the primary composite endpoint (CV death, stroke, and MI) of 13% (p=0.021)* –Superior risk reduction in stroke of 25% (p=0.001) Losartan and atenolol provided substantial and comparable effective blood-pressure reduction Losartan was better tolerated with significantly fewer discontinuations due to adverse events * No significant differences in cardiovascular death and MI vs. atenolol

27 Downloaded from LIFE: Conclusions 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

28 Downloaded from LIFE: Implications 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 The LIFE Study Group

29 Downloaded from LIFE: Committees Steering Committee –Björn Dahlöf (Chair), Richard B. Devereux (Co-chair), Stevo Julius (US Coordinator), Sverre E. Kjeldsen (Secretary and 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) Dahlöf B et al Lancet 2002;359:

30 Downloaded from Back-Up Slides

LIFE: Myocardial Infarction and CV Mortality Dahlöf B et al Lancet 2002;359: Cardiovascular mortality Atenolol Losartan Proportion of patients (%) Adjusted RR 11.4%, p=0.206 Unadjusted RR 13.3%, p=0.136 Fatal and nonfatal MI Proportion of patients with first event (%) Adjusted RR -7.3%, p=0.491 Unadjusted RR -5.0%, p=0.628 Atenolol Losartan Losartan Atenolol Losartan Atenolol Study Month 31

32 Downloaded from LIFE: Cardiovascular Benefits of Losartan Confirmed in Diabetic Subgroup Study Month Losartan (n) Atenolol (n) Proportion of patients with first event (%) Adjusted RR = 24.5%; p=0.031 Unadjusted RR = 26.7%; p=0.017 Losartan Atenolol * No significant differences in cardiovascular death and MI vs. atenolol. Lindholm LH et al Lancet 2002;359: Primary composite endpoint (composite of CV death, MI and stroke)*

33 Downloaded from LIFE: Key Lab Values Lab Value Losartan (n=4605) Atenolol (n=4588) Baseline Year 4 Change Baseline Year 4 Change Hemoglobin, gm/L Sodium, mmol/L Potassium, mmol/L ALT, IU/L Glucose, mmol/L Total cholesterol, mmol/L HDL, mmol/L Uric acid,  mol/L Creatinine, mmol/L Data are presented as mean. ALT = alanine aminotransferase Dahlöf B et al Lancet 2002;359:

34 Downloaded from LIFE: References Before prescribing, please consult full product information.

35 Downloaded from LIFE: References Before prescribing, please consult full product information.

36 Downloaded from LIFE: References Before prescribing, please consult full product information.

37 Downloaded from LIFE: References Before prescribing, please consult full product information.

38 Downloaded from LIFE: References Before prescribing, please consult full product information.

39 Downloaded from Before prescribing, please consult full product information. Copyright © Merck & Co., Inc., Whitehouse Station, NJ, USA. All rights reserved CZR 2002-W-6783-SS Printed in USA VISIT US ON THE WORLD WIDE WEB AT