Transcript Title slide
Downloaded from www.cozaar.ae The Losartan Intervention For Endpoint reduction in hypertension study An investigator-initiated, prospective, community-based, multinational, double-blind, double-dummy, randomised, active-controlled, parallel-group study from 945 centres Steering Committee Chair: Co-chair: B. Dahlöf R.B. Devereux 1 Dahlöf B et al Lancet 2002;359:995-1003. Downloaded from www.cozaar.ae 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 2 • 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. Downloaded from www.cozaar.ae Hypertensive Patients Are at Increased Risk for Cardiovascular Events Framingham Heart Study - Risk of Cardiovascular Events by Hypertensive Status in Patients Aged 35-64 Years; 36-Year Follow-Up Biennial Age-Adjusted Rate per 1000 50 Coronary Disease Peripheral Artery Disease Stroke 45.4 Cardiac Failure 40 Normotensive Hypertensive 30 22.7 21.3 20 13.9 12.4 9.9 9.5 10 6.2 3.3 2.4 7.3 5 3.5 2 6.3 2.1 0 Men Risk Ratio 2.0 Excess Risk 22.7 3 Women Men 2.2 11.8 3.8 9.1 Kannel WB JAMA 1996;275(24):1571-1576. Women Men 2.6 3.8 2.0 4.9 Women 3.7 5.3 Men 4.0 10.4 Women 3.0 4.2 Downloaded from www.cozaar.ae Hypertension Treatment Significantly Reduced Mortality and Morbidity VA Cooperative Study Group – Estimated Cumulative Incidence of All Morbid Events Over 5 Years Estimated Cumulative Incidence of All Morbid Events (%) 60 50 Control - Placebo 40 30 20 Active Treatment Groups Diuretic-based regimen and hydralazine 10 0 0 1 2 3 4 5 Years 4 Veterans Administration Cooperative Study Group on antihypertensive agents JAMA 1970;213(7):1143-1152. Downloaded from www.cozaar.ae 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 5 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. Downloaded from www.cozaar.ae Other Mega-trials Have Not Shown Superiority on Combined CV Morbidity and Mortality vs. an Active Comparator Mega-trials Comparator Treatments Number of Patients Number of Primary Endpoints CAPPP NORDIL STOP-2 ACE I CCB ACE Is/CCBs vs. vs. vs. ß blockers/Diur ß blockers/Diur ß blockers/Diur 10,985 10,881 6614 698 803 659 Composite Primary Endpoint MI, Stroke, CV Death Differences on Primary Endpoint NS p = 0.52 MI, Fatal MI, Fatal Stroke, CV Death Stroke, Fatal CV Disease NS p = 0.97 NS p = 0.89 These data are from 3 independent, non-comparative studies. 6 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. Downloaded from www.cozaar.ae Angiotensin II Plays a Central Role in Organ Damage Stroke Atherosclerosis* Vasoconstriction Vascular hypertrophy Endothelial dysfunction AII AT1 receptor Hypertension LV hypertrophy Fibrosis Remodeling Apoptosis Heart failure MI GFR Proteinuria Aldosterone release Glomerular sclerosis Renal failure DEATH *preclinical data LV = left ventricular; MI = myocardial infarction; GFR = glomerular filtration rate 7 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. Downloaded from www.cozaar.ae LIFE: Rationale 8 • 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; 75(suppl 3A): 411. Downloaded from www.cozaar.ae 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 9 Dahlöf B et al Am J Hypertens 1997; 10: 705713. Downloaded from www.cozaar.ae 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 10 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. Downloaded from www.cozaar.ae LIFE: A Landmark Study Investigator-initiated, prospective, double-blind, activecontrolled, intention-to-treat, community-based study • 9193 hypertensive patients with LVH, aged 55-80 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 11 Dahlöf B et al Lancet 2002;359:995-1003. Downloaded from www.cozaar.ae 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 12 Dahlöf B et al Am J Hypertens 1997;10:705713. Downloaded from www.cozaar.ae LIFE: Design/Dosing Titration * Titration to target blood pressure: <140/90 mmHg Losartan 100 mg + HCTZ 12.5- 25 mg + others** Losartan 100 mg + HCTZ 12.5 mg* Losartan 50 mg + HCTZ 12.5 mg* Placebo Losartan 50 mg 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** Day 14 13 Day Day 7 1 Mth 1 Mth Mth 2 4 Mth 6 Yr 1 Yr 1.5 Yr 2 Yr 2.5 Yr 3 Yr 3.5 * 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;10:705713. Yr 4 Yr 5 Downloaded from www.cozaar.ae LIFE: Baseline Characteristics Age, years Female, % BMI, kg/m2 Race, % Caucasian Others BP, mmHg Heart Rate, bpm LVH-Cornell Product, mm X msec LVH-Sokolow-Lyon, mm Framingham Risk Score Smokers, % Data are presented as mean. 14 Dahlöf B et al Lancet 2002;359:995-1003. Losartan Atenolol (n=4605) (n=4588) 66.9 54% 28.0 66.9 54% 28.0 92.5% 7.5% 174.3/97.9 73.9 2834.4 30.0 0.223 16% 92.5% 7.5% 174.5/97.7 73.7 2824.1 30.1 0.225 17% Downloaded from www.cozaar.ae LIFE: Baseline Characteristics (cont’d) Losartan Atenolol (n=4605) (n=4588) • Medical History, % – DM – ISH (>160/<90 mmHg) – CHD – CVD 13% 14% 17% 8% 13% 15% 15% 8% • Total Cholesterol, mmol/L 6.0 6.1 • Glucose, mmol/L 6.0 6.0 Data are presented as mean. 15 Dahlöf B et al Lancet 2002;359:995-1003. Proportion of patients with first event (%) LIFE: Primary Composite Endpoint 16 Composite of CV death, stroke and MI 14 Atenolol 12 10 Losartan 8 6 4 2 Adjusted Risk Reduction Unadjusted Risk Reduction 13.0%, p=0.021 14.6%, p=0.009 0 Number at Risk Losartan Atenolol 16 0 4605 4588 6 4524 4494 12 4460 4414 Dahlöf B et al Lancet 2002;359:995-1003. 18 4392 4349 24 4312 4289 30 4247 4205 36 4189 4135 42 4112 4066 48 4047 3992 54 3897 3821 60 1889 1854 66 Study Month 901 876 Downloaded from www.cozaar.ae Proportion of patients with first event (%) Stroke Number at Risk Losartan Atenolol 17 Fatal and nonfatal stroke 8 7 Atenolol 6 5 Losartan 4 3 2 1 Adjusted Risk Reduction 24.9%, p=0.001 Unadjusted Risk Reduction 25.8%, p=0.0006 0 0 4605 4588 6 4528 4490 12 18 24 4469 4408 4332 4424 4372 4317 Dahlöf B et al Lancet 2002;359:995-1003. 30 4273 4245 36 42 4224 4166 4180 4119 48 54 4117 3974 4055 3894 60 1928 1901 66 925 897 Study Month Downloaded from www.cozaar.ae LIFE: Primary and Secondary Outcomes Adjusted* 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 * 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) 18 Unadjusted Dahlöf B et al Lancet 2002;359:995-1003. Downloaded from www.cozaar.ae LIFE: Comparable Blood-Pressure Reductions 180 170 160 Atenolol 145.4 mmHg* 150 Systolic 140 Losartan 144.1 mmHg* mmHg 130 120 110 Atenolol 102.4 mmHg* 100 Mean Arterial Losartan 102.2 mmHg* 90 80 Losartan 81.3 mmHg* Atenolol 80.9 mmHg* Diastolic 70 60 50 40 0 19 6 12 * Mean BP at last visit Dahlöf B et al Lancet 2002;359:995-1003. 18 24 30 Study Month 36 42 48 54 Downloaded from www.cozaar.ae LIFE: Number of Patients on Study Drug at Endpoint or Termination of Follow-Up • 50 mg only • 50 mg plus additional therapy* including HCTZ • 100 mg with or without additional therapy* including HCTZ • Off-study therapy Mean Dosage: *Excluding ACEIs, AIIAs, beta blockers. 20 Dahlöf B et al Lancet 2002;359:995-1003. Losartan Atenolol 9% 10% 18% 20% 50% 23% 43% 27% 82 mg 79 mg Downloaded from www.cozaar.ae LIFE: Change from Baseline in LVH Regression Mean change from baseline (%) Cornell Product 0 -2 -4 4.4 % -6 -8 -10 -12 -14 9.0 % 10.2 % p<0.0001 -16 15.3 % -18 p<0.0001 Losartan 21 Sokolow-Lyon Dahlöf B et al Lancet 2002;359:995-1003. Atenolol Downloaded from www.cozaar.ae LIFE: Adjustments for Difference • 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 * Unadjusted for Framingham risk score and LVH 22 B. Dahlöf at the American College of Cardiology, Atlanta, GA, March 17-20, 2002. Downloaded from www.cozaar.ae LIFE: New-Onset Diabetes Intention-to-Treat 0.10 0.09 Atenolol Atenolol (N=3979) Losartan (N=4019) 0.08 Endpoint Rate 0.07 0.06 Losartan 0.05 0.04 0.03 0.02 Adjusted Risk Reduction 25 %, p<0.001 Unadjusted Risk Reduction 25 %, p<0.001 0.01 0.00 Study Month 23 0 6 12 18 24 30 36 42 B. Dahlöf at the American College of Cardiology, Atlanta, GA, March 17-20, 2002. 48 54 60 66 Downloaded from www.cozaar.ae Proportion of patients who dropped out because of AE (%) LIFE: Discontinuations Due to Adverse Experiences 20 p<0.0001 Atenolol 15 Losartan p<0.0001 10 5 p=0.006 0 Discontinuation due to all AEs 24 Dahlöf B et al Lancet 2002;359:995-1003. Discontinuation due to drug-related AE Discontinuation due to serious drug-related AE Downloaded from www.cozaar.ae Losartan Is the First Antihypertensive to Provide Superior Benefits on Combined CV Morbidity and Death vs. an Active Comparator Mega-trials CAPPP Comparator Treatments NORDIL STOP-2 ACEI CCB ACEIs/ CCBs vs. vs. vs. ß blockers/Diur ß blockers/Diur ß bockers/Diur Number of Patients Losartan vs. Atenolol 10,985 10,881 6614 9193 698 803 659 1096 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 = 0.89 13% RR p = 0.021 Number of Primary Endpoints These data are from four independent, noncomparative studies. 25 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. Downloaded from www.cozaar.ae 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 26 * No significant differences in cardiovascular death and MI vs. atenolol Downloaded from www.cozaar.ae 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 27 * Defined as composite of CV death, MI, and stroke Downloaded from www.cozaar.ae 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 28 Downloaded from www.cozaar.ae 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) 29 Dahlöf B et al Lancet 2002;359:995-1003. Downloaded from www.cozaar.ae Back-Up Slides 30 LIFE: Myocardial Infarction and CV Mortality 8 7 Atenolol Losartan 6 5 4 Cardiovascular mortality 3 8 2 Adjusted RR -7.3%, p=0.491 Unadjusted RR -5.0%, p=0.628 1 0 Study Month 0 Losartan Atenolol 6 12 18 24 30 36 42 48 54 60 66 4605 4525 4478 4430 4367 4307 4258 4196 4139 3999 1953 936 4588 4517 4466 4415 4364 4302 4243 4192 4134 3975 1953 937 7 Proportion of patients (%) Proportion of patients with first event (%) Fatal and nonfatal MI Atenolol Losartan 6 5 4 3 2 Adjusted RR 11.4%, p=0.206 Unadjusted RR 13.3%, p=0.136 1 Study Month Losartan Atenolol 31 Dahlöf B et al Lancet 2002;359:995-1003. 0 0 6 12 18 24 30 36 42 48 54 60 66 4605 4563 4532 4496 4448 4410 4373 4327 4284 4152 2005 976 4588 4453 4513 4474 4442 4388 4341 4299 4252 4107 2006 965 Downloaded from www.cozaar.ae Proportion of patients with first event (%) LIFE: Cardiovascular Benefits of Losartan Confirmed in Diabetic Subgroup 24 Atenolol 20 16 Losartan 12 8 4 0 Study Month 0 Losartan (n) 586 Atenolol (n) 609 32 Primary composite endpoint (composite of CV death, MI and stroke)* Adjusted RR = 24.5%; p=0.031 Unadjusted RR = 26.7%; p=0.017 6 569 588 12 558 562 18 548 552 24 532 540 30 520 527 36 513 507 42 501 486 48 484 472 54 459 434 60 237 204 * No significant differences in cardiovascular death and MI vs. atenolol. Lindholm LH et al Lancet 2002;359:1004-1010. 66 127 99 Downloaded from www.cozaar.ae LIFE: Key Lab Values Lab Value Losartan (n=4605) Baseline Year 4 Hemoglobin, gm/L 142.5 Sodium, mmol/L 140.3 Potassium, mmol/L 4.2 ALT, IU/L 28.2 Glucose, mmol/L 6.0 Total cholesterol, mmol/L 6.0 HDL, mmol/L 1.50 Uric acid, mmol/L 328.2 Creatinine, mmol/L 85.9 Data are presented as mean. ALT = alanine aminotransferase Dahlöf B et al Lancet 2002;359:995-1003. 33 138.8 139.9 4.1 27.0 6.2 5.7 1.47 347.7 97.0 Change -3.7 -0.5 0.0 1.2 0.3 -0.3 -0.03 19.5 11.2 Atenolol (n=4588) Baseline Year 4 Change 142.8 140.3 4.2 28.4 6.0 6.1 1.50 328.9 85.2 141.5 140.0 4.1 27.6 6.3 5.8 1.41 375.9 96.2 -1.3 -0.3 -0.1 0.8 0.4 -0.3 -0.09 47.2 11.0 Downloaded from www.cozaar.ae LIFE: References Before prescribing, please consult full product information. 34 Downloaded from www.cozaar.ae LIFE: References Before prescribing, please consult full product information. 35 Downloaded from www.cozaar.ae LIFE: References Before prescribing, please consult full product information. 36 Downloaded from www.cozaar.ae LIFE: References Before prescribing, please consult full product information. 37 Downloaded from www.cozaar.ae LIFE: References Before prescribing, please consult full product information. 38 Downloaded from www.cozaar.ae Before prescribing, please consult full product information. 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