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Cozaar

The document summarizes key findings from the LIFE study, a large clinical trial that compared losartan to atenolol for reducing cardiovascular risk in hypertensive patients with left ventricular hypertrophy. The main findings were: 1) Losartan reduced the primary composite endpoint of cardiovascular death, stroke or myocardial infarction by 13% compared to atenolol, with comparable blood pressure reduction in both groups. 2) Secondary analyses found losartan reduced risks for several individual components of the primary endpoint including stroke and heart failure hospitalizations. 3) Losartan provided greater regression of left ventricular hypertrophy compared to atenolol based on electrocardiogram and echocardiogram assessments

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Effective COZAAR during treatment on high blood pressure patients and further…
CV Risk factorsCV Risk factors Role of RAS Cardiovascular disease as a sequence of related pathological events FromFrom CirculationCirculation 2006;114:2850-70.2006;114:2850-70. Hypertension : LIFE Stroke, MI: LIFE Heart Failure: ELITE II, LIFE, HEAAL Vascular : ELITE II Diabetes- Renal : RENAAL
Clinical Experience with Losartan  Losartan is a leader in comprehensive clinical trials, encompassing – 30,000 patients – 5 mega-trials (LIFE, OPTIMAAL, ELITE II, RENAAL, HEAAL) – > 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):671-681; Goldberg et al Am J Cardiol 1995;75:793-795.
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 Dahlöf B et al Lancet 2002;359:995-1003.
The LIFE Study  Study hypothesis: Compared to atenolol, losartan would reduce the incidence of cardiovascular morbidity and mortality in patients with essential hypertension and LVH  The primary endpoint was a composite of cardiovascular morbidity and mortality as measured by the combined incidence of: – Cardiovascular mortality – Stroke – Myocardial infarction  The study evaluated whether a losartan-based regimen would reduce the risk of cardiovascular morbidity and mortality more than an atenolol-based regimen, in the face of comparable blood pressure control in both treatment groups Dahlöf B et al Lancet 2002;359:995-1003.
LIFE: Results  Losartan reduced the risk of the primary composite endpoint (cardiovascular mortality, stroke or MI)  Both the atenolol- and losartan-based regimens reduced blood pressure to a comparable level  The safety profile of losartan was consistent with the currently approved US product circular for COZAAR Dahlöf B et al Lancet 2002;359:995-1003.
COZAAR (losartan) in Hypertensive Patients with Left Ventricular Hypertrophy Dahlöf B et al Lancet 2002;359:995-1003.
Hypertension: A Major Public Health Issue  The most common cardiovascular condition in the world  Risk factor for development of cardiovascular, cerebrovascular, renovascular, and peripheral vascular disease  Adverse sequelae may be due to morphologic and functional changes in the cardiovascular system, including: – Remodeling of left ventricle – Remodeling of systemic vasculature – Development of vascular endothelial dysfunction Dahlöf B et al Lancet 2002;359:995-1003.
Adjudicated by Endpoint Classification Committee LIFE: Other Endpoints  Total mortality (cause of death)  Hospitalization due to angina pectoris  Hospitalization due to heart failure  Coronary artery revascularizations  Peripheral revascularizations  Resuscitated cardiac arrest
* Other antihypertensives excluding ACEIs, AΙΙ antagonists, -blockers. 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 mm Hg 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 12.5-25 mg + others* Atenolol 50 mg + HCTZ 12.5 mg Atenolol 100 mg + HCTZ 12.5 mg Atenolol 100 mg + HCTZ 12.5-25 mg + others* LIFE: Study Design (I) Randomization Dahlöf B et al Lancet 2002;359:995-1003.
LIFE: Patient Follow-Up Losartan (N=4605) Follow-up through death or 16-Sep-01 Patients All endpoints 4500 (98%) Partial 105 (2%) Vital status only 57 (1.0%) Withdrawn consent 44 (0.9%) Lost to follow-up 4 (0.1%) Patient-days of follow-up All endpoints 98.6% Vital status 99.3% Atenolol (N=4588) Follow-up through death or 16-Sep-01 Patients All endpoints 4496 (98%) Partial 92 (2%) Vital status only 50 (1.0%) Withdrawn consent 34 (0.8%) Lost to follow-up 8 (0.2%) Patient-days of follow-up All endpoints 99.0% Vital status 99.4%
0 6 12 18 24 30 36 42 48 54 60 66 Study Month 0 2 4 6 8 10 12 14 16 withFirstEvent Losartan Atenolol Los925 ACM Primary ITT 1 Dec. 24, 2002 Adjusted risk reduction 13.1%, p=0.021 Unadjusted risk reduction 14.6%, p=0.009 n at risk Losartan (n) 4605 4460 4312 4189 4045 1888 Atenolol (n) 4588 4414 4289 4135 3992 1854 PercentofPatients LIFE: Primary Endpoint
LIFE: Systolic Blood Pressure Prestudy 12 24 36 48 60 Time (months) 120 140 160 180 mmHg Los925 ACM BP SBP Mean1A Dec. 26, 2002 Losartan Atenolol Reduction at Last Visit Before Endpoint or End of Follow-up Losartan Atenolol p-Value -30.2 -29.1 0.015 Time-Averaged Difference = -1.15 mmHg(mean)
LIFE: Heart Rate Prestudy 12 24 36 48 60 Time (months) 60 65 70 75 80 Beats/Min Los925 ACM BP Heart Rate1A Dec. 26, 2002 Losartan Atenolol Reduction at Last Visit Before Endpoint or End of Follow-up Losartan Atenolol p-Value -1.8 -7.7 <0.001 Time-Averaged Difference = 6.49 Beats/Min(mean)
LIFE: Primary Efficacy Result  In hypertensive patients with ECG evidence of LVH, compared to atenolol-based therapy: – Losartan-based therapy reduced the risk of the primary endpoint of cardiovascular morbidity and mortality (cardiovascular death, stroke and myocardial infarction) by 13% with comparable reduction in blood pressure
LIFE: Secondary Component Endpoints 0.5 1 1.5 2 ← Favors Losartan Favors Atenolol → Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI) ← Endpoints 204 40 125 39 232 198 234 62 124 48 309 188 No. of Events Los AtlAtlAtlAtlAtlAtlAtlAtlAtlAtlAtlAtlAtlAtlAtlAtlAtlAtl Los925 ACM HEB Sec 7A Dec. 10, 2002 CV Death Stroke Coronary Disease Other Stroke (fatal/nonfatal) MI (fatal/nonfatal)MI (fatal/nonfatal)MI (fatal/nonfatal)MI (fatal/nonfatal)MI (fatal/nonfatal)MI (fatal/nonfatal)MI (fatal/nonfatal)MI (fatal/nonfatal)MI (fatal/nonfatal)MI (fatal/nonfatal)MI (fatal/nonfatal)MI (fatal/nonfatal)MI (fatal/nonfatal)MI (fatal/nonfatal)MI (fatal/nonfatal)MI (fatal/nonfatal)MI (fatal/nonfatal)MI (fatal/nonfatal)MI (fatal/nonfatal)MI (fatal/nonfatal)MI (fatal/nonfatal)MI (fatal/nonfatal)MI (fatal/nonfatal)MI (fatal/nonfatal)MI (fatal/nonfatal)MI (fatal/nonfatal)MI (fatal/nonfatal)MI (fatal/nonfatal)MI (fatal/nonfatal)MI (fatal/nonfatal)MI (fatal/nonfatal) Adjusted for FRS and ECG-LVH. CHD
LIFE: Other Endpoints Adjudicated by Endpoint Committee Angina Hosp. Heart Failure Hosp. Coronary Revascularization Noncoronary Revascularization Resuscitated Cardiac Arrest EndpointsEndpointsEndpointsEndpointsEndpointsEndpointsEndpointsEndpointsEndpointsEndpointsEndpointsEndpointsEndpointsEndpointsEndpointsEndpointsEndpointsEndpointsEndpoints No. of Events Los Atl 160 153 169 102 9 141 161 168 129 55555555555555 Los925 ACM HEB Sec3A Dec. 11, 2002 0.5 1 2 ← Favors Losartan Favors Atenolol → Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI) N/A Adjusted for FRS and ECG-LVH.
LIFE: ECG-LVH Change in Cornell Voltage-Duration Product (mmmsec) 0 6 12 24 36 48 60 Study Month -400 -300 -200 -100 0 Mean Los925 ACM CP Mean 1B Dec. 26, 2002 Losartan Atenolol Reduction at Last Visit Before Endpoint or End of Follow-up Losartan Atenolol p-Value -290 -124 <0.001
LIFE: ECG-LVH Change in Sokolow-Lyon Criterion (mm) Reduction at Last Visit Before Endpoint or End of Follow-up Losartan Atenolol p-Value -4.6 -2.7 <0.001 0 6 12 24 36 48 60 Study Month -5 -4 -3 -2 -1 0 Mean Los925 ACM SL Mean 1B Dec. 26, 2002 Losartan Atenolol
LIFE: ECHO Substudy (n=965) Change in Left Ventricular Mass Index (g/m2 ) Reduction in LVMI at last available echo (g/m2 ): Losartan Atenolol p-Value -21.7 -17.7 0.011 0 12 24 36 48 60 Study Months -30 -20 -10 0 Mean Los925 ACM LVH Change Oct. 29, 2002 Losartan Atenolol
LIFE: Disease Categories of Special Interest Primary Endpoint 0.5 1 2 ← Favors Losartan Favors Atenolol → Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI) Diabetic (n=1195) Non-Diabetic (n=7998) ISH (n=1326) Non-ISH (n=7867)Non-ISH (n=7867)Non-ISH (n=7867)Non-ISH (n=7867)Non-ISH (n=7867)Non-ISH (n=7867)Non-ISH (n=7867)Non-ISH (n=7867)Non-ISH (n=7867)Non-ISH (n=7867)Non-ISH (n=7867)Non-ISH (n=7867)Non-ISH (n=7867)Non-ISH (n=7867)Non-ISH (n=7867)Non-ISH (n=7867)Non-ISH (n=7867)Non-ISH (n=7867)Non-ISH (n=7867)Non-ISH (n=7867) Los925 ACM heb all-diab-ish 3 Dec. 9, 2002 Population Los 103 405 75 433 Atl 139 449 104 484 Number of Eventsof Eventsof Eventsof Eventsof Eventsof Eventsof Eventsof Events p=0.170† p=0.176† † Test for treatment-by-subgroup interaction.
LIFE: Patients with Diabetes Primary Endpoint 0 6 12 18 24 30 36 42 48 54 60 66 Study Month 0 4 8 12 16 20 24 withFirstEvent Losartan Atenolol Los925 ACM Diabetes composite Dec. 24, 2002 Adjusted risk reduction 24.5%, p=0.031 n at risk Losartan (n) 586 558 532 513 484 237 Atenolol (n) 609 562 540 507 472 204 PercentofpatientsPatients
LIFE: Patients with Diabetes Secondary Component Endpoints 0.3 0.5 1 1.5 2 Favors Favors Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI) ← Losartan Atenolol → CV Death Stroke (Fatal/Non-Fatal) MI (Fatal/Non-Fatal)MI (Fatal/Non-Fatal)MI (Fatal/Non-Fatal)MI (Fatal/Non-Fatal)MI (Fatal/Non-Fatal)MI (Fatal/Non-Fatal)MI (Fatal/Non-Fatal)MI (Fatal/Non-Fatal)MI (Fatal/Non-Fatal)MI (Fatal/Non-Fatal)MI (Fatal/Non-Fatal)MI (Fatal/Non-Fatal)MI (Fatal/Non-Fatal)MI (Fatal/Non-Fatal)MI (Fatal/Non-Fatal)MI (Fatal/Non-Fatal)MI (Fatal/Non-Fatal)MI (Fatal/Non-Fatal)MI (Fatal/Non-Fatal) Endpoints Los 38 51 41 Atl 61 65 50 No. of EventsNo. of EventsNo. of EventsNo. of EventsNo. of EventsNo. of EventsNo. of EventsNo. of EventsNo. of EventsNo. of Events Adjusted for FRS and ECG-LVH.
LIFE: Patients with Diabetes Other Endpoints 0.3 0.5 1 1.5 2 ← Favors Losartan Favors Atenolol → Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI) Total Mortality Heart Failure Hosp. Angina Hosp.Angina Hosp.Angina Hosp.Angina Hosp.Angina Hosp.Angina Hosp.Angina Hosp.Angina Hosp.Angina Hosp.Angina Hosp.Angina Hosp.Angina Hosp.Angina Hosp.Angina Hosp.Angina Hosp.Angina Hosp.Angina Hosp.Angina Hosp. Los925 ACM heb Diab 2B2 Dec. 11, 2002 Endpoints Los 63 32 30 Atl 104 55 30 Number of Eventsof Eventsof Eventsof Eventsof Eventsof Eventsof Eventsof Events Adjusted for FRS and ECG-LVH.
LIFE: Patients with Isolated Systolic Hypertension Primary Endpoint 0 6 12 18 24 30 36 42 48 54 60 66 Study Month 0 2 4 6 8 10 12 14 16 18 PercentofPatients Losartan (n) 666 639 612 585 562 260 n at risk Atenolol (n) 660 628 603 573 555 239 withEvent Los925 ACM ISH Subset 1 Dec. 24, 2002 Adjusted risk reduction 25.0%, p=0.059 Losartan Atenolol
LIFE: Patients with Isolated Systolic Hypertension Secondary Component Endpoints 0.3 0.5 1 1.5 2 Favors Favors Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI) ← Losartan Atenolol → Endpoints Los 27 32 31 Atl 52 56 36 No. of EventsNo. of EventsNo. of EventsNo. of EventsNo. of EventsNo. of EventsNo. of Events Los925 ACM HEB ISH 3B1A Dec. 24, 2002 CV Death Stroke (Fatal/Non-Fatal) MI (Fatal/Non-Fatal)MI (Fatal/Non-Fatal)MI (Fatal/Non-Fatal)MI (Fatal/Non-Fatal)MI (Fatal/Non-Fatal)MI (Fatal/Non-Fatal)MI (Fatal/Non-Fatal)MI (Fatal/Non-Fatal)MI (Fatal/Non-Fatal)MI (Fatal/Non-Fatal)MI (Fatal/Non-Fatal)MI (Fatal/Non-Fatal)MI (Fatal/Non-Fatal)MI (Fatal/Non-Fatal)MI (Fatal/Non-Fatal)MI (Fatal/Non-Fatal) Adjusted for FRS and ECG-LVH.
LIFE: Patients with Isolated Systolic Hypertension Other Endpoints 0.3 0.5 1 1.5 2 ← Favors Losartan Favors Atenolol → Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI) → Total Mortality Heart Failure Hosp. Angina Hosp. Endpoints Los 66 26 34 Atl 93 40 23 Number of Eventsof Eventsof Events Los925 ACM heb ISH 3B2 Dec. 23, 2002 Adjusted for FRS and ECG-LVH.
LIFE: Overall Efficacy Summary  Primary endpoint: – Losartan reduced the combined risk of CV death, stroke and MI by 13%  Secondary endpoints: – Losartan reduced the risk of stroke by 25% – Losartan produced a nonsignificant 11% reduction in the risk of CV death: • Reduction of fatal stroke by 35% – No significant difference in the risk of fatal and nonfatal MI – Losartan produced a greater reduction of LVH by ECG  Losartan provided consistent reduction in the incidence of cardiovascular events in high risk patients with diabetes or isolated systolic hypertension, compared to atenolol
Intention-to-Treat LIFE: New-Onset Diabetes Losartan Atenolol Atenolol (N=3979) Losartan (N=4019) Study Month 0 6 12 18 24 30 36 42 48 54 60 66 0.00 0.01 0.02 0.03 0.04 0.05 0.06 0.07 0.08 0.09 0.10 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, 2002. EndpointRate
LIFE: Safety Summary  Losartan was well-tolerated and was associated with fewer drug-related adverse experiences and discontinuations due to adverse experiences than atenolol – New diabetes was more likely with atenolol treatment  The observed adverse experience profile of losartan in the LIFE study population was consistent with that presented in the currently approved US product circular for COZAAR
0.5 1 1.5 2 ← Favors Losartan Favors Atenolol → Hazard Ratio (95% CI) Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI) Endpoints 508 204 232 198 588 234 309 188 No. of Events Los Atl Endpoints Los AtlAtlAtlAtlAtlAtlAtlAtlAtlAtlAtlAtlAtlAtlAtlAtlAtlAtlAtl Los925 ACM heb1A4-div Dec. 28, 2002 Primary CV Death Stroke (Fatal/Non-Fatal) MI (Fatal/Non-Fatal) Secondary ComponentsSecondary ComponentsSecondary ComponentsSecondary ComponentsSecondary ComponentsSecondary ComponentsSecondary ComponentsSecondary ComponentsSecondary ComponentsSecondary ComponentsSecondary ComponentsSecondary ComponentsSecondary ComponentsSecondary ComponentsSecondary ComponentsSecondary ComponentsSecondary ComponentsSecondary ComponentsSecondary ComponentsSecondary ComponentsSecondary ComponentsSecondary ComponentsSecondary ComponentsSecondary ComponentsSecondary ComponentsSecondary ComponentsSecondary ComponentsSecondary ComponentsSecondary ComponentsSecondary ComponentsSecondary Components LIFE: Summary of Findings - Primary and Secondary Component Endpoints Adjusted for FRS and ECG-LVH at Baseline
ICARUS Sub-Study Change from Baseline at Year 3 LIFE: Regression of Carotid Artery Hypertrophy -9 -8 -7 -6 -5 -4 -3 -2 -1 0 Losartan (n=19) Atenolol (n=20) %ChangeinIntima-Media Cross-SectionalArea -7.9 % -1.7 % p<0.05
Relationship Between Atrial Fibrillation and Stroke  Presence of atrial fibrillation is associated with 2- to 5-fold increase in the risk of stroke†  In the LIFE study: – Diagnosis of atrial fibrillation • Reported by investigator • Detected on annual ECG by core reading center – Baseline atrial fibrillation is associated with a 3.5-fold increase in the risk of stroke – Occurrence of new atrial fibrillation during treatment is associated with a 5-fold increase in the risk of stroke † Ryder KM et al. Am J Cardiol 1999;84:131R-138R.
LIFE: Post-Hoc Analyses of Incidence of Atrial Fibrillation  Analyses of new occurrence of atrial fibrillation following randomization: – Excluded patients with baseline history or atrial fibrillation on baseline ECG (Minnesota code) – Three scenarios evaluated: • Reported by investigator • Detected by ECG • Either of the above
LIFE: New Onset Atrial Fibrillation Post-Hoc Analysis Atrial Fibrillation Atrial Fibrillation by ECG Atrial Fibrillation by Inv./ECG Endpoints No. of Events by Investigatorby Investigatorby Investigatorby Investigatorby Investigatorby Investigatorby Investigatorby Investigatorby Investigatorby Investigatorby Investigatorby Investigatorby Investigator Los925 ACM Atrial Febr B Jan. 2, 2003 Los 304 165 346 Atl 360 240 416416416416416416416416416416416416416 0.5 1 1.5 2 Favors Favors Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI) ← Losartan Atenolol →
LIFE: Conclusion  The LIFE study results support the proposed new indication for COZAAR: To reduce the risk of cardiovascular morbidity and mortality as measured by the combined incidence of cardiovascular death, stroke, and myocardial infarction in hypertensive patients with left ventricular hypertrophy.
Losartan Heart Failure Survival Study ELITE II A Multicenter, Double-Blind, Randomized, Parallel,A Multicenter, Double-Blind, Randomized, Parallel, Captopril-Controlled Study to Evaluate the Effects of LosartanCaptopril-Controlled Study to Evaluate the Effects of Losartan on Mortality in Patients with Symptomatic Heart Failureon Mortality in Patients with Symptomatic Heart Failure 46 Countries; 289 Sites; 3152 Patients46 Countries; 289 Sites; 3152 Patients • Steering CommitteeSteering Committee Co-ChairsCo-Chairs B. Pitt, P. Poole-WilsonB. Pitt, P. Poole-Wilson • Data and Safety Monitoring CommitteeData and Safety Monitoring Committee ChairChair C. FurbergC. Furberg • Clinical Endpoint Classification CommitteeClinical Endpoint Classification Committee ChairChair L. FrameL. Frame • Coordinating Center: Merck Research LabsCoordinating Center: Merck Research Labs Study DirectorStudy Director R. SegalR. Segal
Study DesignStudy Design Losartan Heart Failure Survival Study ELITE II ≥60 yrs; NYHA II-IV; EF60 yrs; NYHA II-IV; EF ≤ 40%40% ACE-I/AIIA naive or <7 days in 3 months prior to entryACE-I/AIIA naive or <7 days in 3 months prior to entry Standard Rx (± Dig/Diuretics), ß-blocker stratificationStandard Rx (± Dig/Diuretics), ß-blocker stratification CaptoprilCaptopril 50 mg 3 times daily50 mg 3 times daily (N=1574)(N=1574) Primary Endpoint: All-Cause MortalityPrimary Endpoint: All-Cause Mortality Secondary Endpoint: Sudden Cardiac Death and/or Resuscitated ArrestSecondary Endpoint: Sudden Cardiac Death and/or Resuscitated Arrest Other Endpoin: All-cause Mortality/HospitalizationsOther Endpoin: All-cause Mortality/Hospitalizations Safety and TolerabilitySafety and Tolerability Event DrivenEvent Driven (Target 510 Deaths)(Target 510 Deaths) ~ 2 years~ 2 years LosartanLosartan 50 mg Daily50 mg Daily (N=1578)(N=1578)
Losartan Heart Failure Survival Study - ELITE II Mortality by Cause (Adjudicated) 0 5 10 15 Sudden Death Heart Failure MI Stroke Other CV Non-CV %ofPatients Losartan (N=1578) Captopril (N=1574)
Losartan Heart Failure Survival Study - ELITE II Mortality by Subgroup Hazard Ratio Age Gender NYHA Class. % EF Beta Blockers Overall > 71 ≤ 71 Male Female III/IV II ≤ 32 > 32 With Without 731 846 1102 476 801 777 793 785 354 1224 1578 730 844 1083 491 798 776 783 790 325 1249 1574 0.93 0.84 0.89 0.87 0.93 0.80 1.02 0.71 0.56 0.95 0.88 N N Hazard Ratio LosartanCaptopril 1.00.80.60.4 2.0 Hazard Ratio of Death with 95% C.I.Subgroups at Baseline Favors Captopril Favors Losartan
Losartan Heart Failure Survival Study - ELITE II Secondary Endpoint: Sudden Death / Resuscitated Arrest 0 100 200 300 400 500 600 700 Days of Follow-up 0.0 0.2 0.4 0.6 0.8 1.0 Event-FreeProbability LosartanLosartan (N=1578)(N=1578) 142 Events142 Events CaptoprilCaptopril (N=1574)(N=1574) 115 Events115 Events Captopril/Losartan Hazard Ratio (95% C.I.):Captopril/Losartan Hazard Ratio (95% C.I.): 0.80 (0.63, 1.03) P=0.080.80 (0.63, 1.03) P=0.08
Losartan Heart Failure Survival Study - ELITE II Hospitalization By Cause (Adjudicated) 0 10 20 30 Heart Failure MI CAD Stroke/TIA Resusc Arrest Non-CV %ofPatients Losartan (N=1578) Captopril (N=1574) p=NS between groupsp=NS between groups ## ## CAD includes angina, unstable angina, revascularization, etcCAD includes angina, unstable angina, revascularization, etc
Losartan Heart Failure Survival Study - ELITE II Tertiary Endpoint: All-Cause Mortality / Hospitalization 0 100 200 300 400 500 600 700 Days of Follow-up 0.0 0.2 0.4 0.6 0.8 1.0 Event-FreeProbability LosartanLosartan (N=1578)(N=1578) 752 Events752 Events CaptoprilCaptopril (N=1574)(N=1574) 707 Events707 Events Captopril/Losartan Hazard Ratio (95% C.I.):Captopril/Losartan Hazard Ratio (95% C.I.): 0.94 (0.85, 1.04) P=0.210.94 (0.85, 1.04) P=0.21
Losartan Heart Failure Survival Study - ELITE II Withdrawal for Adverse Experience (Excluding Death) 0 5 10 15 20 Any AE Drug-Related AE Cough HF %ofPatients Losartan (N=1578) Captopril (N=1574)** **** pp0.001 between groups0.001 between groups ** **
Losartan Heart Failure Survival Study - ELITE II Study Endpoint Summary Crude Rate Losartan (N=1578) Captopril (N=1574) Adjusted Hazards Ratio (95%CI) All-cause Mortality 280 (17.7%)250 (15.9%) 0.88 (0.75, 1.05) All-cause Mortality/ Hospitalization 752 (47.7%)707 (44.9%) 0.94 (0.85, 1.04) Sudden Death/ Resusc. Arrest 142 (9.0%)115 (7.3%) 0.80 (0.63, 1.03) Primary Endpoint: Secondary Endpoint: Tertiary Endpoints: P-Value 0.16 0.21 0.08 Withdrawal for Adverse Experience 149 (9.4%)228 (14.5%) <0.001
Comparison of Low-Dose Versus High-Dose Losartan Treatment on Morbidity and Mortality in Angiotensin-Converting-Enzyme-Inhibitor- Intolerant Patients with Heart Failure and Reduced Left Ventricular Ejection Fraction: Results of the HEAAL* Study Marvin A. Konstam, James D. Neaton, Kenneth Dickstein, Helmut Drexler, Michel Komajda, Felipe A. Martinez, Gunter A.J. Riegger, Ronald D. Smith, William Malbecq, Soneil Guptha, Philip A. Poole-Wilson for the HEAAL investigators * Heart failure Endpoint evaluation with the Angiotensin II Antagonist Losartan Lancet 2009; 374: 1840–48
ARBs in Heart Failure Val-HeFT CHARM-Alternative VALIANT ELITE-2 Valsartan 320 mg Placebo Candesartan 32 mg Placebo Captopril 150 mg Losartan 50 mg Captopril 150 mg Survival Event-freeSurvival CVDeathorHFHosp Mortality Pfeffer et al. NEJM 2003 Pitt B et al: Lancet 2000 Granger et al: Lancet 2003Cohn et al: NEJM 2001 Valsartan 320mg 0 .3 1.0 0 1.0 .6 .5 0 23 mos 42 mos27 mos 36 mos HYPOTHESIS: Increased ARB dose is associated with improved clinical outcomes in heart failure POPULATION: Patients with clinical heart failure, low LVEF and ACE-inhibitor intolerance
Study Design and Sample Size Screen Open Titration Follow-up 50 mg qd + P 2 weeks Randomization 50 mg qd 100 mg qd 50 mg qd +P 1 week 1 week (1 week) 150 mg qd Losartan 12.5 mg- 25 mg qd • Primary endpoint: death or hospitalization for HF • 1710 patients with primary endpoint events provided 95% power for HR = 0.837 for superiority with 2-sided  = 0.043 150 mg group 50 mg group Konstam MA et al, Lancet 2009; 374: 1840–48
Disposition of Patients N=1913 Analyzed 889 experienced primary endpoint 54 primary endpoint status unknown; 62 vital status unknown at closing date 6 excluded for data quality 1919 Randomized to losartan 50 mg 3846 Randomized 1927 Randomized to losartan 150 mg 6 excluded for data quality N=1921 Analyzed 828 experienced primary endpoint 41 primary endpoint status unknown; 48 vital status unknown at closing date Konstam MA et al, Lancet 2009; 374: 1840–48
Patient Follow-up and Dosing Losartan 150 mg Losartan 50 mg Median follow-up time (yrs)* 4.7 4.7 Discontinuations (%) 28.3 27.3 Discontinuations for AE (%) 7.7 7.0 Mean dose (mg/day)** 128.9 45.6 *Follow up = time from randomization to study end or primary endpoint **Including time off drug Konstam MA et al, Lancet 2009; 374: 1840–48
Primary Endpoint Death or Hospitalization for HF 0 1 2 3 4 5 0 10 20 30 40 50 Percentageofpatientswithfirstevent Losartan 50 mg Losartan 150 mg Losartan 150 mg Losartan 50 mg Number of patients at risk Hazard ratio: 0.90, p=0.027 1646 1683 1421 1492 1275 1343 1126 1205 644 711 %ofPatientswithFirstEvent HR 0.90 (0.82, 0.99) P=0.027 Years 1646 1422 1277 1126 644 1684 1493 1344 1205 711 Konstam MA et al, Lancet 2009; 374: 1840–48
Summary  HEAAL represents the first study to investigate the dose-response of an ARB on clinical outcomes in patients with HF.  Compared with losartan 50 mg daily, losartan 150 mg daily reduced the rate of the combined endpoint of all-cause mortality or HF hospitalization  The 150 mg dose was associated with higher rates of hypotension, hyperkalemia, and renal impairment, although the overall rates of clinically relevant adverse events were small. Conclusions  In patients with HF, reduced LVEF, and ACE inhibitor intolerance, incremental value is derived from up-titrating ARB doses to levels demonstrated to confer benefit on clinical outcomes.  Our findings confirm the view that incremental inhibition of the renin-angiotensin system, within the range explored in HF trials to date, achieves a progressively favorable impact on clinical outcomes.
Thumbs up/Thumbs down – Oct 2002 OPTIMAAL ACE inhibitor vs ARB Patients with complicated acute MI with heart failure or significant systolic dysfunction are at high risk OPTIMAAL pitted an angiotensin receptor blocker (losartan) vs standard ACE inhibitor (captopril) in these patients
Mean uric acid level during follow-up among patients in the losartan and placebo groups. Yan Miao et al. Hypertension. 2011;58:2-7
MI occurrence in ARB trials
Kunz R et al. Ann Intern Med 2008; 148:30-48 Ratio of means (95% CI)* for change in proteinuria, by randomized therapy, over two follow-up intervals Randomized therapy Over 1-4 mo Over 5-12 mo ARBs vs placebo 0.57 (0.47–0.68) 0.66 (0.63–0.69) ARBs vs ACE-I 0.99 (0.92–1.05) 1.08 (0.96–1.22) ARBs vs CCBs 0.69 (0.62–0.77) 0.62 (0.55–0.70) ARB+ACE-I vs ARBs 0.76 (0.68–0.85) 0.75 (0.61–0.92) ARB+ACE-I vs ACE-I 0.78 (0.72–0.84) 0.82 (0.67–1.01) ACE-I=angiotensin-converting-enzyme inhibitor ARB=angiotensin-receptor blocker CCB=calcium-channel blocker *Ratio of means=ratio of the average treatment effect in the intervention group (either ARBs alone or in combination with ACE-I) relative to the control group (placebo or single-drug comparator), with 95% CI
ARBs in Secondary Prevention Superior to placebo? YES / NO More effective than ACEi? NO Less effective than ACEi? NO Equal than ACEi? YES Should be used with ACE? NO Superior to placebo? YES / NO More effective than ACEi? NO Less effective than ACEi? NO Equal than ACEi? YES Should be used with ACE? NO
ARBs in Heart Failure Superior to placebo? YES More effective than ACEi? NO Less effective than ACEi? NO Equal than ACEi? YES Should be used with ACE? NO / YES but only to reduce hospitalisation Superior to placebo? YES More effective than ACEi? NO Less effective than ACEi? NO Equal than ACEi? YES Should be used with ACE? NO / YES but only to reduce hospitalisation
Prevention of Progression of Renal Disease Primary prevention Primary prevention Secondary prevention Secondary prevention Tertiary prevention Tertiary prevention Glycemic control BP control ACE inhibitor Glycemic control BP control ACE inhibitor ACE inhibitor BP control ARB ACE inhibitor BP control ARB ARB ACE inhibitor BP Control ARB ACE inhibitor BP Control ESRDMADM Diabetic nephropathy Ref. Tobe SW et al. CMAJ 2002; 167(5): 499-503 In People with Diabetes
Losartan Metabolite EXP3179 Activates Akt and Endothelial Nitric Oxide Synthase via Vascular Endothelial Growth Factor Receptor-2 in Endothelial Cells Circulation Volume 112(12):1798-1805 September 20, 2005 Copyright © American Heart Association, Inc. All rights reserved. and further…
Schematic representation of losartan metabolism via cytochrome P450. Gian Paolo Rossi Hypertension. 2009;54:710-712 Copyright © American Heart Association, Inc. All rights reserved.

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Cozaar

  • 1.
    Effective COZAAR duringtreatment on high blood pressure patients and further…
  • 2.
    CV Risk factorsCVRisk factors Role of RAS Cardiovascular disease as a sequence of related pathological events FromFrom CirculationCirculation 2006;114:2850-70.2006;114:2850-70. Hypertension : LIFE Stroke, MI: LIFE Heart Failure: ELITE II, LIFE, HEAAL Vascular : ELITE II Diabetes- Renal : RENAAL
  • 3.
    Clinical Experience withLosartan  Losartan is a leader in comprehensive clinical trials, encompassing – 30,000 patients – 5 mega-trials (LIFE, OPTIMAAL, ELITE II, RENAAL, HEAAL) – > 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):671-681; Goldberg et al Am J Cardiol 1995;75:793-795.
  • 4.
    The Losartan InterventionFor 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 Dahlöf B et al Lancet 2002;359:995-1003.
  • 5.
    The LIFE Study Study hypothesis: Compared to atenolol, losartan would reduce the incidence of cardiovascular morbidity and mortality in patients with essential hypertension and LVH  The primary endpoint was a composite of cardiovascular morbidity and mortality as measured by the combined incidence of: – Cardiovascular mortality – Stroke – Myocardial infarction  The study evaluated whether a losartan-based regimen would reduce the risk of cardiovascular morbidity and mortality more than an atenolol-based regimen, in the face of comparable blood pressure control in both treatment groups Dahlöf B et al Lancet 2002;359:995-1003.
  • 6.
    LIFE: Results  Losartanreduced the risk of the primary composite endpoint (cardiovascular mortality, stroke or MI)  Both the atenolol- and losartan-based regimens reduced blood pressure to a comparable level  The safety profile of losartan was consistent with the currently approved US product circular for COZAAR Dahlöf B et al Lancet 2002;359:995-1003.
  • 7.
    COZAAR (losartan) in HypertensivePatients with Left Ventricular Hypertrophy Dahlöf B et al Lancet 2002;359:995-1003.
  • 8.
    Hypertension: A Major PublicHealth Issue  The most common cardiovascular condition in the world  Risk factor for development of cardiovascular, cerebrovascular, renovascular, and peripheral vascular disease  Adverse sequelae may be due to morphologic and functional changes in the cardiovascular system, including: – Remodeling of left ventricle – Remodeling of systemic vasculature – Development of vascular endothelial dysfunction Dahlöf B et al Lancet 2002;359:995-1003.
  • 9.
    Adjudicated by EndpointClassification Committee LIFE: Other Endpoints  Total mortality (cause of death)  Hospitalization due to angina pectoris  Hospitalization due to heart failure  Coronary artery revascularizations  Peripheral revascularizations  Resuscitated cardiac arrest
  • 10.
    * Other antihypertensivesexcluding ACEIs, AΙΙ antagonists, -blockers. 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 mm Hg 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 12.5-25 mg + others* Atenolol 50 mg + HCTZ 12.5 mg Atenolol 100 mg + HCTZ 12.5 mg Atenolol 100 mg + HCTZ 12.5-25 mg + others* LIFE: Study Design (I) Randomization Dahlöf B et al Lancet 2002;359:995-1003.
  • 11.
    LIFE: Patient Follow-Up Losartan(N=4605) Follow-up through death or 16-Sep-01 Patients All endpoints 4500 (98%) Partial 105 (2%) Vital status only 57 (1.0%) Withdrawn consent 44 (0.9%) Lost to follow-up 4 (0.1%) Patient-days of follow-up All endpoints 98.6% Vital status 99.3% Atenolol (N=4588) Follow-up through death or 16-Sep-01 Patients All endpoints 4496 (98%) Partial 92 (2%) Vital status only 50 (1.0%) Withdrawn consent 34 (0.8%) Lost to follow-up 8 (0.2%) Patient-days of follow-up All endpoints 99.0% Vital status 99.4%
  • 12.
    0 6 1218 24 30 36 42 48 54 60 66 Study Month 0 2 4 6 8 10 12 14 16 withFirstEvent Losartan Atenolol Los925 ACM Primary ITT 1 Dec. 24, 2002 Adjusted risk reduction 13.1%, p=0.021 Unadjusted risk reduction 14.6%, p=0.009 n at risk Losartan (n) 4605 4460 4312 4189 4045 1888 Atenolol (n) 4588 4414 4289 4135 3992 1854 PercentofPatients LIFE: Primary Endpoint
  • 13.
    LIFE: Systolic BloodPressure Prestudy 12 24 36 48 60 Time (months) 120 140 160 180 mmHg Los925 ACM BP SBP Mean1A Dec. 26, 2002 Losartan Atenolol Reduction at Last Visit Before Endpoint or End of Follow-up Losartan Atenolol p-Value -30.2 -29.1 0.015 Time-Averaged Difference = -1.15 mmHg(mean)
  • 14.
    LIFE: Heart Rate Prestudy12 24 36 48 60 Time (months) 60 65 70 75 80 Beats/Min Los925 ACM BP Heart Rate1A Dec. 26, 2002 Losartan Atenolol Reduction at Last Visit Before Endpoint or End of Follow-up Losartan Atenolol p-Value -1.8 -7.7 <0.001 Time-Averaged Difference = 6.49 Beats/Min(mean)
  • 15.
    LIFE: Primary EfficacyResult  In hypertensive patients with ECG evidence of LVH, compared to atenolol-based therapy: – Losartan-based therapy reduced the risk of the primary endpoint of cardiovascular morbidity and mortality (cardiovascular death, stroke and myocardial infarction) by 13% with comparable reduction in blood pressure
  • 16.
    LIFE: Secondary ComponentEndpoints 0.5 1 1.5 2 ← Favors Losartan Favors Atenolol → Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI) ← Endpoints 204 40 125 39 232 198 234 62 124 48 309 188 No. of Events Los AtlAtlAtlAtlAtlAtlAtlAtlAtlAtlAtlAtlAtlAtlAtlAtlAtlAtl Los925 ACM HEB Sec 7A Dec. 10, 2002 CV Death Stroke Coronary Disease Other Stroke (fatal/nonfatal) MI (fatal/nonfatal)MI (fatal/nonfatal)MI (fatal/nonfatal)MI (fatal/nonfatal)MI (fatal/nonfatal)MI (fatal/nonfatal)MI (fatal/nonfatal)MI (fatal/nonfatal)MI (fatal/nonfatal)MI (fatal/nonfatal)MI (fatal/nonfatal)MI (fatal/nonfatal)MI (fatal/nonfatal)MI (fatal/nonfatal)MI (fatal/nonfatal)MI (fatal/nonfatal)MI (fatal/nonfatal)MI (fatal/nonfatal)MI (fatal/nonfatal)MI (fatal/nonfatal)MI (fatal/nonfatal)MI (fatal/nonfatal)MI (fatal/nonfatal)MI (fatal/nonfatal)MI (fatal/nonfatal)MI (fatal/nonfatal)MI (fatal/nonfatal)MI (fatal/nonfatal)MI (fatal/nonfatal)MI (fatal/nonfatal)MI (fatal/nonfatal) Adjusted for FRS and ECG-LVH. CHD
  • 17.
    LIFE: Other Endpoints Adjudicatedby Endpoint Committee Angina Hosp. Heart Failure Hosp. Coronary Revascularization Noncoronary Revascularization Resuscitated Cardiac Arrest EndpointsEndpointsEndpointsEndpointsEndpointsEndpointsEndpointsEndpointsEndpointsEndpointsEndpointsEndpointsEndpointsEndpointsEndpointsEndpointsEndpointsEndpointsEndpoints No. of Events Los Atl 160 153 169 102 9 141 161 168 129 55555555555555 Los925 ACM HEB Sec3A Dec. 11, 2002 0.5 1 2 ← Favors Losartan Favors Atenolol → Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI) N/A Adjusted for FRS and ECG-LVH.
  • 18.
    LIFE: ECG-LVH Change inCornell Voltage-Duration Product (mmmsec) 0 6 12 24 36 48 60 Study Month -400 -300 -200 -100 0 Mean Los925 ACM CP Mean 1B Dec. 26, 2002 Losartan Atenolol Reduction at Last Visit Before Endpoint or End of Follow-up Losartan Atenolol p-Value -290 -124 <0.001
  • 19.
    LIFE: ECG-LVH Change inSokolow-Lyon Criterion (mm) Reduction at Last Visit Before Endpoint or End of Follow-up Losartan Atenolol p-Value -4.6 -2.7 <0.001 0 6 12 24 36 48 60 Study Month -5 -4 -3 -2 -1 0 Mean Los925 ACM SL Mean 1B Dec. 26, 2002 Losartan Atenolol
  • 20.
    LIFE: ECHO Substudy(n=965) Change in Left Ventricular Mass Index (g/m2 ) Reduction in LVMI at last available echo (g/m2 ): Losartan Atenolol p-Value -21.7 -17.7 0.011 0 12 24 36 48 60 Study Months -30 -20 -10 0 Mean Los925 ACM LVH Change Oct. 29, 2002 Losartan Atenolol
  • 21.
    LIFE: Disease Categoriesof Special Interest Primary Endpoint 0.5 1 2 ← Favors Losartan Favors Atenolol → Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI) Diabetic (n=1195) Non-Diabetic (n=7998) ISH (n=1326) Non-ISH (n=7867)Non-ISH (n=7867)Non-ISH (n=7867)Non-ISH (n=7867)Non-ISH (n=7867)Non-ISH (n=7867)Non-ISH (n=7867)Non-ISH (n=7867)Non-ISH (n=7867)Non-ISH (n=7867)Non-ISH (n=7867)Non-ISH (n=7867)Non-ISH (n=7867)Non-ISH (n=7867)Non-ISH (n=7867)Non-ISH (n=7867)Non-ISH (n=7867)Non-ISH (n=7867)Non-ISH (n=7867)Non-ISH (n=7867) Los925 ACM heb all-diab-ish 3 Dec. 9, 2002 Population Los 103 405 75 433 Atl 139 449 104 484 Number of Eventsof Eventsof Eventsof Eventsof Eventsof Eventsof Eventsof Events p=0.170† p=0.176† † Test for treatment-by-subgroup interaction.
  • 22.
    LIFE: Patients withDiabetes Primary Endpoint 0 6 12 18 24 30 36 42 48 54 60 66 Study Month 0 4 8 12 16 20 24 withFirstEvent Losartan Atenolol Los925 ACM Diabetes composite Dec. 24, 2002 Adjusted risk reduction 24.5%, p=0.031 n at risk Losartan (n) 586 558 532 513 484 237 Atenolol (n) 609 562 540 507 472 204 PercentofpatientsPatients
  • 23.
    LIFE: Patients withDiabetes Secondary Component Endpoints 0.3 0.5 1 1.5 2 Favors Favors Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI) ← Losartan Atenolol → CV Death Stroke (Fatal/Non-Fatal) MI (Fatal/Non-Fatal)MI (Fatal/Non-Fatal)MI (Fatal/Non-Fatal)MI (Fatal/Non-Fatal)MI (Fatal/Non-Fatal)MI (Fatal/Non-Fatal)MI (Fatal/Non-Fatal)MI (Fatal/Non-Fatal)MI (Fatal/Non-Fatal)MI (Fatal/Non-Fatal)MI (Fatal/Non-Fatal)MI (Fatal/Non-Fatal)MI (Fatal/Non-Fatal)MI (Fatal/Non-Fatal)MI (Fatal/Non-Fatal)MI (Fatal/Non-Fatal)MI (Fatal/Non-Fatal)MI (Fatal/Non-Fatal)MI (Fatal/Non-Fatal) Endpoints Los 38 51 41 Atl 61 65 50 No. of EventsNo. of EventsNo. of EventsNo. of EventsNo. of EventsNo. of EventsNo. of EventsNo. of EventsNo. of EventsNo. of Events Adjusted for FRS and ECG-LVH.
  • 24.
    LIFE: Patients withDiabetes Other Endpoints 0.3 0.5 1 1.5 2 ← Favors Losartan Favors Atenolol → Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI) Total Mortality Heart Failure Hosp. Angina Hosp.Angina Hosp.Angina Hosp.Angina Hosp.Angina Hosp.Angina Hosp.Angina Hosp.Angina Hosp.Angina Hosp.Angina Hosp.Angina Hosp.Angina Hosp.Angina Hosp.Angina Hosp.Angina Hosp.Angina Hosp.Angina Hosp.Angina Hosp. Los925 ACM heb Diab 2B2 Dec. 11, 2002 Endpoints Los 63 32 30 Atl 104 55 30 Number of Eventsof Eventsof Eventsof Eventsof Eventsof Eventsof Eventsof Events Adjusted for FRS and ECG-LVH.
  • 25.
    LIFE: Patients withIsolated Systolic Hypertension Primary Endpoint 0 6 12 18 24 30 36 42 48 54 60 66 Study Month 0 2 4 6 8 10 12 14 16 18 PercentofPatients Losartan (n) 666 639 612 585 562 260 n at risk Atenolol (n) 660 628 603 573 555 239 withEvent Los925 ACM ISH Subset 1 Dec. 24, 2002 Adjusted risk reduction 25.0%, p=0.059 Losartan Atenolol
  • 26.
    LIFE: Patients withIsolated Systolic Hypertension Secondary Component Endpoints 0.3 0.5 1 1.5 2 Favors Favors Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI) ← Losartan Atenolol → Endpoints Los 27 32 31 Atl 52 56 36 No. of EventsNo. of EventsNo. of EventsNo. of EventsNo. of EventsNo. of EventsNo. of Events Los925 ACM HEB ISH 3B1A Dec. 24, 2002 CV Death Stroke (Fatal/Non-Fatal) MI (Fatal/Non-Fatal)MI (Fatal/Non-Fatal)MI (Fatal/Non-Fatal)MI (Fatal/Non-Fatal)MI (Fatal/Non-Fatal)MI (Fatal/Non-Fatal)MI (Fatal/Non-Fatal)MI (Fatal/Non-Fatal)MI (Fatal/Non-Fatal)MI (Fatal/Non-Fatal)MI (Fatal/Non-Fatal)MI (Fatal/Non-Fatal)MI (Fatal/Non-Fatal)MI (Fatal/Non-Fatal)MI (Fatal/Non-Fatal)MI (Fatal/Non-Fatal) Adjusted for FRS and ECG-LVH.
  • 27.
    LIFE: Patients withIsolated Systolic Hypertension Other Endpoints 0.3 0.5 1 1.5 2 ← Favors Losartan Favors Atenolol → Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI) → Total Mortality Heart Failure Hosp. Angina Hosp. Endpoints Los 66 26 34 Atl 93 40 23 Number of Eventsof Eventsof Events Los925 ACM heb ISH 3B2 Dec. 23, 2002 Adjusted for FRS and ECG-LVH.
  • 28.
    LIFE: Overall EfficacySummary  Primary endpoint: – Losartan reduced the combined risk of CV death, stroke and MI by 13%  Secondary endpoints: – Losartan reduced the risk of stroke by 25% – Losartan produced a nonsignificant 11% reduction in the risk of CV death: • Reduction of fatal stroke by 35% – No significant difference in the risk of fatal and nonfatal MI – Losartan produced a greater reduction of LVH by ECG  Losartan provided consistent reduction in the incidence of cardiovascular events in high risk patients with diabetes or isolated systolic hypertension, compared to atenolol
  • 29.
    Intention-to-Treat LIFE: New-Onset Diabetes Losartan Atenolol Atenolol(N=3979) Losartan (N=4019) Study Month 0 6 12 18 24 30 36 42 48 54 60 66 0.00 0.01 0.02 0.03 0.04 0.05 0.06 0.07 0.08 0.09 0.10 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, 2002. EndpointRate
  • 30.
    LIFE: Safety Summary Losartan was well-tolerated and was associated with fewer drug-related adverse experiences and discontinuations due to adverse experiences than atenolol – New diabetes was more likely with atenolol treatment  The observed adverse experience profile of losartan in the LIFE study population was consistent with that presented in the currently approved US product circular for COZAAR
  • 31.
    0.5 1 1.52 ← Favors Losartan Favors Atenolol → Hazard Ratio (95% CI) Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI) Endpoints 508 204 232 198 588 234 309 188 No. of Events Los Atl Endpoints Los AtlAtlAtlAtlAtlAtlAtlAtlAtlAtlAtlAtlAtlAtlAtlAtlAtlAtlAtl Los925 ACM heb1A4-div Dec. 28, 2002 Primary CV Death Stroke (Fatal/Non-Fatal) MI (Fatal/Non-Fatal) Secondary ComponentsSecondary ComponentsSecondary ComponentsSecondary ComponentsSecondary ComponentsSecondary ComponentsSecondary ComponentsSecondary ComponentsSecondary ComponentsSecondary ComponentsSecondary ComponentsSecondary ComponentsSecondary ComponentsSecondary ComponentsSecondary ComponentsSecondary ComponentsSecondary ComponentsSecondary ComponentsSecondary ComponentsSecondary ComponentsSecondary ComponentsSecondary ComponentsSecondary ComponentsSecondary ComponentsSecondary ComponentsSecondary ComponentsSecondary ComponentsSecondary ComponentsSecondary ComponentsSecondary ComponentsSecondary Components LIFE: Summary of Findings - Primary and Secondary Component Endpoints Adjusted for FRS and ECG-LVH at Baseline
  • 32.
    ICARUS Sub-Study Change fromBaseline at Year 3 LIFE: Regression of Carotid Artery Hypertrophy -9 -8 -7 -6 -5 -4 -3 -2 -1 0 Losartan (n=19) Atenolol (n=20) %ChangeinIntima-Media Cross-SectionalArea -7.9 % -1.7 % p<0.05
  • 33.
    Relationship Between AtrialFibrillation and Stroke  Presence of atrial fibrillation is associated with 2- to 5-fold increase in the risk of stroke†  In the LIFE study: – Diagnosis of atrial fibrillation • Reported by investigator • Detected on annual ECG by core reading center – Baseline atrial fibrillation is associated with a 3.5-fold increase in the risk of stroke – Occurrence of new atrial fibrillation during treatment is associated with a 5-fold increase in the risk of stroke † Ryder KM et al. Am J Cardiol 1999;84:131R-138R.
  • 34.
    LIFE: Post-Hoc Analysesof Incidence of Atrial Fibrillation  Analyses of new occurrence of atrial fibrillation following randomization: – Excluded patients with baseline history or atrial fibrillation on baseline ECG (Minnesota code) – Three scenarios evaluated: • Reported by investigator • Detected by ECG • Either of the above
  • 35.
    LIFE: New OnsetAtrial Fibrillation Post-Hoc Analysis Atrial Fibrillation Atrial Fibrillation by ECG Atrial Fibrillation by Inv./ECG Endpoints No. of Events by Investigatorby Investigatorby Investigatorby Investigatorby Investigatorby Investigatorby Investigatorby Investigatorby Investigatorby Investigatorby Investigatorby Investigatorby Investigator Los925 ACM Atrial Febr B Jan. 2, 2003 Los 304 165 346 Atl 360 240 416416416416416416416416416416416416416 0.5 1 1.5 2 Favors Favors Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI) ← Losartan Atenolol →
  • 36.
    LIFE: Conclusion  TheLIFE study results support the proposed new indication for COZAAR: To reduce the risk of cardiovascular morbidity and mortality as measured by the combined incidence of cardiovascular death, stroke, and myocardial infarction in hypertensive patients with left ventricular hypertrophy.
  • 48.
    Losartan Heart FailureSurvival Study ELITE II A Multicenter, Double-Blind, Randomized, Parallel,A Multicenter, Double-Blind, Randomized, Parallel, Captopril-Controlled Study to Evaluate the Effects of LosartanCaptopril-Controlled Study to Evaluate the Effects of Losartan on Mortality in Patients with Symptomatic Heart Failureon Mortality in Patients with Symptomatic Heart Failure 46 Countries; 289 Sites; 3152 Patients46 Countries; 289 Sites; 3152 Patients • Steering CommitteeSteering Committee Co-ChairsCo-Chairs B. Pitt, P. Poole-WilsonB. Pitt, P. Poole-Wilson • Data and Safety Monitoring CommitteeData and Safety Monitoring Committee ChairChair C. FurbergC. Furberg • Clinical Endpoint Classification CommitteeClinical Endpoint Classification Committee ChairChair L. FrameL. Frame • Coordinating Center: Merck Research LabsCoordinating Center: Merck Research Labs Study DirectorStudy Director R. SegalR. Segal
  • 49.
    Study DesignStudy Design LosartanHeart Failure Survival Study ELITE II ≥60 yrs; NYHA II-IV; EF60 yrs; NYHA II-IV; EF ≤ 40%40% ACE-I/AIIA naive or <7 days in 3 months prior to entryACE-I/AIIA naive or <7 days in 3 months prior to entry Standard Rx (± Dig/Diuretics), ß-blocker stratificationStandard Rx (± Dig/Diuretics), ß-blocker stratification CaptoprilCaptopril 50 mg 3 times daily50 mg 3 times daily (N=1574)(N=1574) Primary Endpoint: All-Cause MortalityPrimary Endpoint: All-Cause Mortality Secondary Endpoint: Sudden Cardiac Death and/or Resuscitated ArrestSecondary Endpoint: Sudden Cardiac Death and/or Resuscitated Arrest Other Endpoin: All-cause Mortality/HospitalizationsOther Endpoin: All-cause Mortality/Hospitalizations Safety and TolerabilitySafety and Tolerability Event DrivenEvent Driven (Target 510 Deaths)(Target 510 Deaths) ~ 2 years~ 2 years LosartanLosartan 50 mg Daily50 mg Daily (N=1578)(N=1578)
  • 50.
    Losartan Heart FailureSurvival Study - ELITE II Mortality by Cause (Adjudicated) 0 5 10 15 Sudden Death Heart Failure MI Stroke Other CV Non-CV %ofPatients Losartan (N=1578) Captopril (N=1574)
  • 51.
    Losartan Heart FailureSurvival Study - ELITE II Mortality by Subgroup Hazard Ratio Age Gender NYHA Class. % EF Beta Blockers Overall > 71 ≤ 71 Male Female III/IV II ≤ 32 > 32 With Without 731 846 1102 476 801 777 793 785 354 1224 1578 730 844 1083 491 798 776 783 790 325 1249 1574 0.93 0.84 0.89 0.87 0.93 0.80 1.02 0.71 0.56 0.95 0.88 N N Hazard Ratio LosartanCaptopril 1.00.80.60.4 2.0 Hazard Ratio of Death with 95% C.I.Subgroups at Baseline Favors Captopril Favors Losartan
  • 52.
    Losartan Heart FailureSurvival Study - ELITE II Secondary Endpoint: Sudden Death / Resuscitated Arrest 0 100 200 300 400 500 600 700 Days of Follow-up 0.0 0.2 0.4 0.6 0.8 1.0 Event-FreeProbability LosartanLosartan (N=1578)(N=1578) 142 Events142 Events CaptoprilCaptopril (N=1574)(N=1574) 115 Events115 Events Captopril/Losartan Hazard Ratio (95% C.I.):Captopril/Losartan Hazard Ratio (95% C.I.): 0.80 (0.63, 1.03) P=0.080.80 (0.63, 1.03) P=0.08
  • 53.
    Losartan Heart FailureSurvival Study - ELITE II Hospitalization By Cause (Adjudicated) 0 10 20 30 Heart Failure MI CAD Stroke/TIA Resusc Arrest Non-CV %ofPatients Losartan (N=1578) Captopril (N=1574) p=NS between groupsp=NS between groups ## ## CAD includes angina, unstable angina, revascularization, etcCAD includes angina, unstable angina, revascularization, etc
  • 54.
    Losartan Heart FailureSurvival Study - ELITE II Tertiary Endpoint: All-Cause Mortality / Hospitalization 0 100 200 300 400 500 600 700 Days of Follow-up 0.0 0.2 0.4 0.6 0.8 1.0 Event-FreeProbability LosartanLosartan (N=1578)(N=1578) 752 Events752 Events CaptoprilCaptopril (N=1574)(N=1574) 707 Events707 Events Captopril/Losartan Hazard Ratio (95% C.I.):Captopril/Losartan Hazard Ratio (95% C.I.): 0.94 (0.85, 1.04) P=0.210.94 (0.85, 1.04) P=0.21
  • 55.
    Losartan Heart FailureSurvival Study - ELITE II Withdrawal for Adverse Experience (Excluding Death) 0 5 10 15 20 Any AE Drug-Related AE Cough HF %ofPatients Losartan (N=1578) Captopril (N=1574)** **** pp0.001 between groups0.001 between groups ** **
  • 56.
    Losartan Heart FailureSurvival Study - ELITE II Study Endpoint Summary Crude Rate Losartan (N=1578) Captopril (N=1574) Adjusted Hazards Ratio (95%CI) All-cause Mortality 280 (17.7%)250 (15.9%) 0.88 (0.75, 1.05) All-cause Mortality/ Hospitalization 752 (47.7%)707 (44.9%) 0.94 (0.85, 1.04) Sudden Death/ Resusc. Arrest 142 (9.0%)115 (7.3%) 0.80 (0.63, 1.03) Primary Endpoint: Secondary Endpoint: Tertiary Endpoints: P-Value 0.16 0.21 0.08 Withdrawal for Adverse Experience 149 (9.4%)228 (14.5%) <0.001
  • 58.
    Comparison of Low-DoseVersus High-Dose Losartan Treatment on Morbidity and Mortality in Angiotensin-Converting-Enzyme-Inhibitor- Intolerant Patients with Heart Failure and Reduced Left Ventricular Ejection Fraction: Results of the HEAAL* Study Marvin A. Konstam, James D. Neaton, Kenneth Dickstein, Helmut Drexler, Michel Komajda, Felipe A. Martinez, Gunter A.J. Riegger, Ronald D. Smith, William Malbecq, Soneil Guptha, Philip A. Poole-Wilson for the HEAAL investigators * Heart failure Endpoint evaluation with the Angiotensin II Antagonist Losartan Lancet 2009; 374: 1840–48
  • 59.
    ARBs in HeartFailure Val-HeFT CHARM-Alternative VALIANT ELITE-2 Valsartan 320 mg Placebo Candesartan 32 mg Placebo Captopril 150 mg Losartan 50 mg Captopril 150 mg Survival Event-freeSurvival CVDeathorHFHosp Mortality Pfeffer et al. NEJM 2003 Pitt B et al: Lancet 2000 Granger et al: Lancet 2003Cohn et al: NEJM 2001 Valsartan 320mg 0 .3 1.0 0 1.0 .6 .5 0 23 mos 42 mos27 mos 36 mos HYPOTHESIS: Increased ARB dose is associated with improved clinical outcomes in heart failure POPULATION: Patients with clinical heart failure, low LVEF and ACE-inhibitor intolerance
  • 60.
    Study Design andSample Size Screen Open Titration Follow-up 50 mg qd + P 2 weeks Randomization 50 mg qd 100 mg qd 50 mg qd +P 1 week 1 week (1 week) 150 mg qd Losartan 12.5 mg- 25 mg qd • Primary endpoint: death or hospitalization for HF • 1710 patients with primary endpoint events provided 95% power for HR = 0.837 for superiority with 2-sided  = 0.043 150 mg group 50 mg group Konstam MA et al, Lancet 2009; 374: 1840–48
  • 61.
    Disposition of Patients N=1913Analyzed 889 experienced primary endpoint 54 primary endpoint status unknown; 62 vital status unknown at closing date 6 excluded for data quality 1919 Randomized to losartan 50 mg 3846 Randomized 1927 Randomized to losartan 150 mg 6 excluded for data quality N=1921 Analyzed 828 experienced primary endpoint 41 primary endpoint status unknown; 48 vital status unknown at closing date Konstam MA et al, Lancet 2009; 374: 1840–48
  • 62.
    Patient Follow-up andDosing Losartan 150 mg Losartan 50 mg Median follow-up time (yrs)* 4.7 4.7 Discontinuations (%) 28.3 27.3 Discontinuations for AE (%) 7.7 7.0 Mean dose (mg/day)** 128.9 45.6 *Follow up = time from randomization to study end or primary endpoint **Including time off drug Konstam MA et al, Lancet 2009; 374: 1840–48
  • 63.
    Primary Endpoint Death orHospitalization for HF 0 1 2 3 4 5 0 10 20 30 40 50 Percentageofpatientswithfirstevent Losartan 50 mg Losartan 150 mg Losartan 150 mg Losartan 50 mg Number of patients at risk Hazard ratio: 0.90, p=0.027 1646 1683 1421 1492 1275 1343 1126 1205 644 711 %ofPatientswithFirstEvent HR 0.90 (0.82, 0.99) P=0.027 Years 1646 1422 1277 1126 644 1684 1493 1344 1205 711 Konstam MA et al, Lancet 2009; 374: 1840–48
  • 64.
    Summary  HEAAL representsthe first study to investigate the dose-response of an ARB on clinical outcomes in patients with HF.  Compared with losartan 50 mg daily, losartan 150 mg daily reduced the rate of the combined endpoint of all-cause mortality or HF hospitalization  The 150 mg dose was associated with higher rates of hypotension, hyperkalemia, and renal impairment, although the overall rates of clinically relevant adverse events were small. Conclusions  In patients with HF, reduced LVEF, and ACE inhibitor intolerance, incremental value is derived from up-titrating ARB doses to levels demonstrated to confer benefit on clinical outcomes.  Our findings confirm the view that incremental inhibition of the renin-angiotensin system, within the range explored in HF trials to date, achieves a progressively favorable impact on clinical outcomes.
  • 65.
    Thumbs up/Thumbs down– Oct 2002 OPTIMAAL ACE inhibitor vs ARB Patients with complicated acute MI with heart failure or significant systolic dysfunction are at high risk OPTIMAAL pitted an angiotensin receptor blocker (losartan) vs standard ACE inhibitor (captopril) in these patients
  • 67.
    Mean uric acidlevel during follow-up among patients in the losartan and placebo groups. Yan Miao et al. Hypertension. 2011;58:2-7
  • 68.
    MI occurrence inARB trials
  • 69.
    Kunz R etal. Ann Intern Med 2008; 148:30-48 Ratio of means (95% CI)* for change in proteinuria, by randomized therapy, over two follow-up intervals Randomized therapy Over 1-4 mo Over 5-12 mo ARBs vs placebo 0.57 (0.47–0.68) 0.66 (0.63–0.69) ARBs vs ACE-I 0.99 (0.92–1.05) 1.08 (0.96–1.22) ARBs vs CCBs 0.69 (0.62–0.77) 0.62 (0.55–0.70) ARB+ACE-I vs ARBs 0.76 (0.68–0.85) 0.75 (0.61–0.92) ARB+ACE-I vs ACE-I 0.78 (0.72–0.84) 0.82 (0.67–1.01) ACE-I=angiotensin-converting-enzyme inhibitor ARB=angiotensin-receptor blocker CCB=calcium-channel blocker *Ratio of means=ratio of the average treatment effect in the intervention group (either ARBs alone or in combination with ACE-I) relative to the control group (placebo or single-drug comparator), with 95% CI
  • 70.
    ARBs in Secondary Prevention Superiorto placebo? YES / NO More effective than ACEi? NO Less effective than ACEi? NO Equal than ACEi? YES Should be used with ACE? NO Superior to placebo? YES / NO More effective than ACEi? NO Less effective than ACEi? NO Equal than ACEi? YES Should be used with ACE? NO
  • 71.
    ARBs in Heart Failure Superiorto placebo? YES More effective than ACEi? NO Less effective than ACEi? NO Equal than ACEi? YES Should be used with ACE? NO / YES but only to reduce hospitalisation Superior to placebo? YES More effective than ACEi? NO Less effective than ACEi? NO Equal than ACEi? YES Should be used with ACE? NO / YES but only to reduce hospitalisation
  • 72.
    Prevention of Progressionof Renal Disease Primary prevention Primary prevention Secondary prevention Secondary prevention Tertiary prevention Tertiary prevention Glycemic control BP control ACE inhibitor Glycemic control BP control ACE inhibitor ACE inhibitor BP control ARB ACE inhibitor BP control ARB ARB ACE inhibitor BP Control ARB ACE inhibitor BP Control ESRDMADM Diabetic nephropathy Ref. Tobe SW et al. CMAJ 2002; 167(5): 499-503 In People with Diabetes
  • 76.
    Losartan Metabolite EXP3179Activates Akt and Endothelial Nitric Oxide Synthase via Vascular Endothelial Growth Factor Receptor-2 in Endothelial Cells Circulation Volume 112(12):1798-1805 September 20, 2005 Copyright © American Heart Association, Inc. All rights reserved. and further…
  • 77.
    Schematic representation oflosartan metabolism via cytochrome P450. Gian Paolo Rossi Hypertension. 2009;54:710-712 Copyright © American Heart Association, Inc. All rights reserved.

Editor's Notes

  • #4 Slide 2: Clinical Experience with Losartan Losartan was the first angiotensin II antagonist available with a highly specific mechanism of action. Losartan clinical trials have involved more than 30,000 patients, and losartan has been documented in excess of 4500 publications.2 Losartan and losartan-based regimen have been prescribed to 12 million patients worldwide. 2 Losartan is also a leader in comprehensive clinical trials, which notably include four mega-trials: LIFE  comparison of losartan- and atenolol-based regimens in 9193 patients with hypertension and left ventricular hypertrophy (LVH) 3 OPTIMAAL  The Losartan Post-MI Survival Study, comparing losartan and captopril in 5000 patients after acute MI4 ELITE II  The Losartan Heart Failure Study, comparing losartan and captopril in 3152 elderly patients with heart failure 5 RENAAL  The Losartan Renal Protection Study, comparing losartanand placebo (in addition to conventional therapy in both treatment groups) in 1513 patients with hypertension and Type 2 diabetes and nephropathy.6 Losartan has demonstrated excellent tolerability comparable to placebo and highly effective blood-pressure lowering comparable to other antihypertensives.7,8
  • #5 Slide 1: LIFE: The Losartan Intervention For Endpoint reduction in hypertension study LIFE was an investigator-initiated, prospective, community-based, multinational, double-blind, randomised, active-controlled, parallel-group study conducted in 945 sites.1 Chair of the LIFE Steering Committee was Björn Dahlöf, University of Göteberg, Sweden. Co-chair was Richard B. Devereux, Cornell University, USA.
  • #30 Slide 23: LIFE: New-Onset Diabetes A 25% lower incidence of new-onset diabetes mellitus occurred in patients treated with losartan compared to those treated with atenolol in a highly significant between-group difference (p&amp;lt;0.001).1 Because blood-pressure reduction was similar in both treatment arms, this reduction in risk of new-onset diabetes suggests an additional benefit of losartan beyond blood-pressure control.1 The LIFE findings regarding new-onset diabetes are of interest in light of the results of the recent Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) trial in patients with Type 2 diabetes and nephropathy, in which treatment with losartan added to conventional therapy significantly reduced the risk of the primary endpoint of the composite of doubling of serum creatinine by 16%, end-stage renal disease, or death versus placebo and conventional therapy (p=0.02).6 RENAAL also demonstrated, for the first time, a statistically significant 28% risk reduction of end-stage renal disease (p=0.002) and a cardio-protective benefit with losartan – 32% risk reduction in first hospitalizations for heart failure (p=0.005) in hypertensive patients with Type 2 diabetes and nephropathy.6
  • #59 The full title of the study is ” A Multi-center, Double-Blind, Randomized, Paralleled Group Study to Evaluate the Effects of Two Different Doses of Losartan on Morbidity and Mortality in patients with Symptomatic Heart Failure Intolerant to ACE Inhibitor Treatment”. [PN 948-05 Protocol p10A]
  • #62 Chuck please add data from Appendix 2 page 23
  • #63 do not have the data yet - hopefully will know when soon
  • #64 Chuck please add fig 3 of ERM
  • #65 have to await text
  • #68 Mean uric acid level during follow-up among patients in the losartan and placebo groups. Bars represent standard errors.
  • #73 When applied to renal disease, primary prevention means to prevent microalbuminuria, secondary prevention to prevent overt nephropathy and tertiary prevention to prevent the development of end stage renal disease in overt proteinurics. There are a lot of trials confirming the action of glycemic control, BP reduction and ACE inhibitor usage in preventing the progression of kidney disease at various stages.
  • #78 Figure. Schematic representation of losartan metabolism via cytochrome P450. See text for explanation.