Director, Regulatory Affairs Merck Research Laboratories

Director, Regulatory Affairs Merck Research Laboratories
COZAAR (losartan) in Hypertensive Patients with Left Ventricular Hypertrophy Jeffrey R. Tucker, MD Director, Regulatory Affairs Merck Research Laboratories

The LIFE Study Losartan Intervention For Endpoint
Reduction in Hypertension Study Agenda Dr. J. Tucker, Regulatory Affairs Introduction Dr. J. Edelman, Clinical Development Background and Rationale Study Results Dr. W. Keane, Clinical Development Review of Evidence and Conclusions

The LIFE Study Losartan Intervention For Endpoint
Reduction in Hypertension Study Active-control, double-blind Multicenter 945 sites Multinational 7 countries Large study population 9193 hypertensive patients with left ventricular hypertrophy (LVH)

COZAAR (losartan): Proposed New Indication
COZAAR is indicated 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.

Evidence of Effectiveness from a Single Study
FDA Guidance - Providing Clinical Evidence of Effectiveness for Human Drug and Biological Products (1998) Generally limited to situations in which a trial shows a benefit on mortality or irreversible morbidity the prevention of disease and a second trial is not ethical or practical Additional information from within the single study, or from other sources, may provide confirmatory evidence to independently substantiate the results of the single study The LIFE study compared losartan to an active control

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

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

Merck Clinical Consultants
Dr. Björn Dahlöf - Chair, Steering Committee Associate Professor of Medicine Sahlgrenska University Hospital, Göteborg ,Sweden Dr. Richard Devereux - Vice Chair, Steering Committee Professor of Medicine and Director Echocardiography Laboratory Cornell Medical Center, New York, NY Dr. John Kjekshus - Chair, DSMB Professor of Medicine, Department of Cardiology University of Oslo, Oslo, Norway Dr. Stevo Julius- US Coordinator, Steering Committee Professor of Medicine, Division of Hypertension and Hyperlipidemia University of Michigan, Ann Arbor Dr. Peter Kowey Professor of Medicine, Jefferson Medical College Chief, Division of Cardiovascular Diseases Main Line Hospitals, Philadelphia

Merck Statistical Consultants
Dr. James Neaton Professor, Division of Biostatistics, School of Public Health, University of Minnesota Dr. Scott Zeger Professor and Chair, Department of Biostatistics, Bloomberg School of Public Health, Johns Hopkins University, Baltimore

Senior Director, Clinical Development Merck US Human Health
COZAAR (losartan) in Hypertensive Patients with Left Ventricular Hypertrophy Jonathan M. Edelman, MD Senior Director, Clinical Development Merck US Human Health

Losartan in Hypertensive Patients with Left Ventricular Hypertrophy
Agenda Background and Rationale LIFE Study Design LIFE Patient Population LIFE Efficacy Results LIFE Safety Results

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

Hypertension Increases Risk of Cardiovascular Morbidity and Mortality
The Framingham Heart Study Risk Ratio 2.2 2.5 Kannel WB Euro Heart J 1992;13(Suppl G):34-42.

Treatment of Hypertension Reduces Cardiovascular Morbidity and Mortality
5 Randomized Trials in 12,483 Elderly Hypertensives 494 438 438 Treatment Control 383 346 Total Number of Individuals Affected 288 Overall BP Difference Systolic: 15 mm Hg Diastolic: 6 mm Hg % Reduction in odds: 34% p<0.001 19% p<0.05 23% p<0.001 Adapted from MacMahon S, Rodgers A. Clin Exper Hypertension 1993;15(6):

LIFE: Primary Question
In hypertensive patients at high risk of cardiovascular outcomes: Does the mechanism of blood pressure reduction affect the magnitude of reduction of adverse cardiovascular outcomes? Does angiotensin II receptor blockade with losartan have a greater effect on cardiovascular morbidity and mortality than conventional antihypertensive therapy when peripheral blood pressure is similarly controlled?

LIFE: Choice of Primary Endpoint
A composite cardiovascular endpoint (including cardiovascular death, stroke, and myocardial infarction) was chosen to reflect: Systemic morbidity of hypertension on multiple organs (which may be mediated by different mechanisms) Systemic effects of angiotensin II

LIFE: Choice of Patient Population
Hypertensive patients at increased risk of cardiovascular outcomes (including cardiac and non-cardiac events): Left ventricular hypertrophy Consequence of long-standing hypertension Manifestation of systemic effects of angiotensin II Patients likely to benefit from angiotensin II antagonism

Prevalence of LVH in the US Hypertensive Population, by Age Group
NHANES III ( ) Age Group

Risk of Cardiovascular Events Associated with ECG-LVH in the Elderly
The Framingham Heart Study CHD Stroke Risk Ratio 3.0 3.7 3.2 5.3 Cupples LA, D’Agostino RB. NIH Publication No , Feb 1987.

LIFE: Choice of Active Comparator
In order to answer the study question, it was necessary to utilize a comparator with: Effective blood pressure lowering Different primary pharmacologic mechanism Established reduction in cardiovascular morbidity and mortality in hypertensive patients Only -blocker- and diuretic-based regimens had proven effects on cardiovascular morbidity and mortality at the time of the initiation of LIFE study (1995)

LIFE: Choice of Active Comparator
JNC V (1993) “Because diuretics and -blockers are the only classes of drugs that have been used in long-term controlled clinical trials and shown to reduce morbidity and mortality, they are recommended as first- choice agents unless they are contraindicated or unacceptable, or unless there are special indications for other agents.” Arch Intern Med 1993; 153:

Meta-Analysis of -Blocker Regimens in Hypertension
All Cardiovascular Events † Atenolol arm. ‡ -blocker and/or diuretic arm.

LIFE: Choice of Atenolol-Based Regimen as Comparator
-blockers were known to be effective in prevention of myocardial infarction Atenolol was effective in combination with diuretics Atenolol had shown antihypertensive efficacy similar to losartan Addition of diuretic to both treatment groups ensured balance in concomitant antihypertensive therapy

LIFE The Losartan Intervention For Endpoint
Reduction in Hypertension Study A multicenter, multinational, double-blind, randomized, parallel study to investigate the effect of losartan, compared to atenolol, on the reduction of cardiovascular morbidity and mortality in hypertensive patients with left ventricular hypertrophy.

LIFE: Study Organization
Data and Safety Monitoring Board (Unblinded) Chair: Dr. John Kjekshus University of Oslo, Oslo, Norway Steering Committee (Blinded) Chair: Dr. Björn Dahlöf Sahlgrenska University Hospital Göteborg, Sweden Vice Chair: Dr. Richard Devereux Cornell Medical Center New York, NY Endpoint Classification Committee (Blinded) Dr. Daniel Levy Framingham Heart Study Framingham, MA Dr. Kristian Thygesen Århus University Hospital Århus, Denmark Merck & Co., Inc. - coordinating and data management center 945 clinical centers in 7 countries

LIFE: Hypothesis, Primary Endpoint and Secondary Component Endpoints
Losartan will reduce the incidence of cardiovascular morbidity and mortality in patients with essential hypertension and left ventricular hypertrophy, as compared to atenolol Primary endpoint Composite of cardiovascular morbidity and mortality as adjudicated by the Endpoint Classification Committee Secondary component endpoints Cardiovascular mortality Fatal and non-fatal stroke Fatal and non-fatal myocardial infarction

LIFE: Primary Endpoint Analysis
1996 1997 1998 1999 2000 2001 Patient A Patient B May 1997 Non-fatal MI Dec 1995 Randomized Feb 1999 Non-fatal stroke Sept 2000 Fatal MI Feb 1997 June 1998 Fatal stroke

LIFE: Primary Endpoint Analysis
1996 1997 1998 1999 2000 2001 Patient A Patient B Feb 1999 Non-fatal stroke Sept 2000 Fatal MI May 1997 Non-fatal MI June 1998 Fatal stroke Dec 1995 Randomized Feb 1997

Adjudicated by Endpoint Classification Committee
LIFE: Other Endpoints Adjudicated by Endpoint Classification Committee Total mortality (cause of death) Hospitalization due to angina pectoris Hospitalization due to heart failure Coronary artery revascularizations Peripheral revascularizations Resuscitated cardiac arrest

LIFE: Other Endpoints Reported by central reading laboratory
ECG: All patients (N=9193) Left ventricular hypertrophy Silent myocardial infarction Echocardiography: Substudy (n=965) Left ventricular mass index Reported by investigator Blood pressure Adverse experiences New-onset diabetes mellitus

LIFE: Disease Categories of Special Interest
Pre-specified to be of special interest: Patients with diabetes mellitus Patients with isolated systolic hypertension Endpoints analyzed: Primary endpoint Secondary component endpoints Total mortality Hospitalization for angina Hospitalization for heart failure

LIFE: Key Inclusion Criteria
Age years Elevated blood pressure Systolic BP mm Hg or Diastolic BP mm Hg ECG LVH Cornell Voltage Duration Product or Sokolow-Lyon Criterion

LIFE: Key Exclusion Criteria
Secondary hypertension MI or stroke within 6 months Angina pectoris requiring treatment with -blocker or calcium channel antagonist Heart failure or known left ventricular ejection fraction 40% Conditions that required treatment with an angiotensin II receptor antagonist, -blocker, diuretic, or ACE inhibitor

Titration to target blood pressure: <140 / <90 mm Hg
LIFE: Study Design (I) Titration to target blood pressure: <140 / <90 mm Hg Losartan 100 mg + HCTZ mg + others* Randomization 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 mg + others* 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 * Other antihypertensives excluding ACEIs, AII antagonists, -blockers.

LIFE: Study Design (II)
Study duration: Follow-up for minimum of 4 years and Until at least 1040 patients experienced a primary cardiovascular event Study follow-up: Patients were to remain on study drug Even after a study endpoint Patients were to continue clinic visits Even if study therapy was discontinued Telephone contact if clinic visits not feasible Re-start of study therapy was allowed at any time

LIFE: Endpoint Reporting and Classification
Investigators reported all potential endpoints for review by ECC Regular monitoring visits ensured all potential endpoints reported ECC members reviewed potential endpoints and classified independently Differences between the initial classifications were resolved at periodic meetings Referral to Steering Committee for resolution, if needed (no cases referred) All potential endpoints were adjudicated (N=4363) 21% were determined not to be endpoints 7 with unknown cause of death

LIFE: Study Timeline 1996 1997 1998 1999 2000 2001 2002 June 1995
First patient randomized May 1997 Last patient randomized March 2001 Steering Committee set endpoint cut-off date (September 16, 2001) based on pooled event rate September 16, 2001 Endpoint cut-off 1096 patients with at least one primary endpoint November 2001 Final patient visit

LIFE: Patient Disposition
Entered baseline (N=10,779) Randomized (N=9222) Excluded for irregularities (n=29) Followed for study duration (N=9193) Allocated to losartan (N=4605) Allocated to atenolol (N=4588) All included in ITT analyses: Complete follow-up 4500 (98%) Partial follow-up 105 (2%) All included in ITT analyses: Complete follow-up: 4496 (98%) Partial follow-up 92 (2%)

LIFE: Patient Follow-Up
Losartan (N=4605) Follow-up through death or 16-Sep-01 Patients All endpoints 4500 (98%) Partial (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 % Vital status % 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 % Vital status %

LIFE: Patient Recruitment
Country n 15.1 1.4 16.2 15.4 24.4 8.9 18.6 % Denmark Iceland Finland Norway Sweden UK USA 1391 133 1485 1415 2245 817 1707

LIFE: Baseline Characteristics (I)
Losartan (N=4605) Atenolol (N=4588) Age (mean), years Gender, % female Ethnic group, % White Black Hispanic Asian Other 66.9 54.0 92.5 5.9 1.0 0.5 0.1 66.9 54.0 92.5 5.7 1.2 0.4 0.2

LIFE: Baseline Characteristics (II)
Losartan (N=4605) Atenolol (N=4588) Systolic BP, mm Hg Diastolic BP, mm Hg Pulse rate, bpm BMI, kg/cm2 Smokers, % 174.3 97.9 73.9 28.0 15.8 174.5 97.7 73.7 28.0 16.8

LIFE: Baseline Characteristics (III)
Medical History Diabetes mellitus ISH (160 / <90 mm Hg) Coronary heart disease Myocardial infarction Cerebrovascular disease Stroke 12.7 14.3 Losartan % (N=4605) 13.3 14.5 Atenolol % (N=4588)

LIFE: Baseline Characteristics (IV)
Variables Utilized in Covariate Analysis ECG-LVH and Framingham Risk Score Losartan (N=4605) Atenolol (N=4588) Cornell Product, mmmsec Sokolow-Lyon, mm Framingham Risk Score, % 2828.0 30.0 22.3 2818.9 30.0 22.5 Framingham Risk Score predicts the 5-year probability of developing coronary heart disease based on gender, age, systolic blood pressure, smoking, total / HDL cholesterol, diabetes, ECG-LVH

At Endpoint or End of Follow-Up
LIFE: Study Therapy At Endpoint or End of Follow-Up Losartan % (N=4605) Atenolol % (N=4588) 50 mg alone 50 mg with additional drugs 100 mg with or without additional drugs Off study drug 9 18 50 23 10 20 43 27

LIFE: Study Therapy At Endpoint or End of Follow-Up Losartan % (N=4605) Atenolol % (N=4588) 50 mg alone 50 mg with additional drugs With HCTZ only With other drugs only With HCTZ and other drugs 100 mg with or without additional drugs Alone With HCTZ only With other drugs only With HCTZ and other drugs Off study drug 9 23 10 27

LIFE: Study Therapy At Endpoint or End of Follow-Up Losartan (N=4605) Atenolol (N=4588) Time on study drug, % Mean dose of study drug, mg Time on diuretic, % Mean dose of HCTZ, mg Mean number of antihypertensive agents (including study therapy for those on drug) 86 82 72 20 2.3 82 79 70 20 2.3

LIFE: Primary Endpoint

LIFE: Systolic Blood Pressure
Reduction at Last Visit Before Endpoint or End of Follow-up Losartan Atenolol p-Value Time-Averaged Difference = -1.15 mm Hg (mean)

LIFE: Diastolic Blood Pressure
Reduction at Last Visit Before Endpoint or End of Follow-up Losartan Atenolol p-Value Time-Averaged Difference = 0.76 mm Hg (mean)

LIFE: Categories of Hypertensive Response
At Last Visit Before Endpoint or End of Follow-Up Diastolic 90 mm Hg Systolic 140 mm Hg Systolic 140 and Diastolic 90 mm Hg Blood Pressure Response Atenolol (N=4588) (%) 89 46 45 Losartan (N=4605) (%) 88 49 48

Reduction at Last Visit Before Endpoint or End of Follow-up
LIFE: Heart Rate Reduction at Last Visit Before Endpoint or End of Follow-up Losartan Atenolol p-Value <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

Agenda Background and Rationale LIFE Study Design LIFE Patient Population LIFE Efficacy Results Other Endpoints LIFE Safety Results

LIFE: Secondary Component Endpoint Analyses
Patient A 1996 1997 1998 1999 2000 2001 May 1997 Non-fatal MI Dec 1995 Randomized Feb 1999 Non-fatal stroke Sept 2000 Fatal MI

1996 1997 1998 1999 2000 2001 Patient A Included in analysis of MI CV death stroke May 1997 Non-fatal MI Feb 1999 Non-fatal Sept 2000 Fatal MI Dec 1995 Randomized

Intent-to-treat analyses Each patient counted in all relevant endpoint analyses Each patient included only once in each endpoint analysis

LIFE: Secondary Component Endpoints
Adjusted for FRS and ECG-LVH.

LIFE: Secondary Component Endpoint
Fatal and Non-Fatal Stroke

Fatal and Non-Fatal MI

Cardiovascular Mortality

0.5 1 1.5 2 Favors Losartan Favors Atenolol Hazard Ratio (95% CI) Endpoints 204 234 No. of Events Los Atl CV Death Adjusted for FRS and ECG-LVH.

CHD Adjusted for FRS and ECG-LVH.

LIFE: Mortality and Causes of Death Adjudicated by Endpoint Committee

LIFE: Other Endpoints Adjudicated by Endpoint Committee

LIFE: Other Endpoints Measured by ECG Reading Center
Left ventricular hypertrophy: Cornell voltage duration product Sokolow-Lyon Silent myocardial infarction (ECG)

LIFE: ECG-LVH Change in Cornell Voltage-Duration Product (mmmsec)
Reduction at Last Visit Before Endpoint or End of Follow-up Losartan Atenolol p-Value <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 <0.001

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

LIFE: Results in Predefined Subsets of the Population
Disease categories of special interest - primary endpoint, secondary component endpoints, total mortality, hospitalization for heart failure and angina Patients with diabetes mellitus Patients with isolated systolic hypertension Subgroups - primary endpoint 23 subgroups defined in Data Analysis Plan Demographic Disease history Clinical characteristics

Increased Risk of Primary Endpoint (n=7998) (n=7867) (n=1195) (n=1326) Relative Risk:

Primary Endpoint p=0.170† p=0.176† † Test for treatment-by-subgroup interaction.

LIFE: Patients with Diabetes
Primary Endpoint Patients

Secondary Component Endpoints Adjusted for FRS and ECG-LVH.

Other Endpoints Adjusted for FRS and ECG-LVH.

LIFE: Patients with Isolated Systolic Hypertension
Primary Endpoint

Secondary Component Endpoints Adjusted for FRS and ECG-LVH.

Other Endpoints Adjusted for FRS and ECG-LVH.

Baseline Subgroups 23 subgroups defined in Data Analysis Plan Primary endpoint only Demographic Disease history Clinical characteristics Test for interaction planned (positive: p<0.05) No planned subgroup had a positive interaction

Baseline Subgroups - Test for Interaction with Treatment Subgroup p-Value Subgroup p-Value Demographic Age Gender Country Ethnic group Disease history MI Stroke IHD Angina Heart failure Diabetes Microalbuminuria ISH Clinical characteristics Smoking status Alcohol intake Exercise status BMI Systolic BP Diastolic BP Total cholesterol HDL cholesterol ECG-LVH (Cornell) ECG-LVH (SL) Framingham Risk

LIFE: Ethnic Subgroups
Primary Endpoint p=0.057† † Test for treatment-by-subgroup interaction.

LIFE: Post-Hoc Analysis Black vs. Non-Black Patients
Primary Endpoint p=0.005† Favors Losartan Favors Atenolol Test for qualitative interaction, p=0.016 † Test for treatment-by-subgroup interaction.

Exploratory Analyses Baseline covariates Demographics Disease history Biochemistry Prior therapy Regional differences US vs. Europe Within US Impact of study drug discontinuation Per-protocol analysis Secondary component endpoints Categorization of stroke etiology Vital signs Blood pressure Heart rate Left ventricular hypertrophy ECG Echocardiography

US Patients (n=1707) Change at End of Follow-Up or Last Visit Prior to Primary Endpoint

Change in Heart Rate at End of Follow-Up or Last Visit Prior to Primary Endpoint US Patients (n=1707)

US Patients (n=1707) Change in ECG-LVH at End of Follow-Up or Last Visit Prior to Primary Endpoint

Summary Analysis of primary endpoint Significant test for interaction with treatment Greater reduction in risk with atenolol compared to losartan in Black patients Unexplained by differences in baseline characteristics Additional analyses Blood pressure: Decreased to similar level in each group Heart rate: Greater reduction with atenolol compared to losartan ECG-LVH: Greater reduction with losartan compared to atenolol

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

LIFE: Overall Adverse Experiences (AE)
Losartan % (N=4605) 94.7 37.2 13.1 6.1 3.8 Atenolol % (N=4588) 95.0 45.2 36.2 18.1 10.7 4.6 p-Value 0.481 <0.001 0.299 With any AE With drug-related AE† With serious AE Discontinued due to AE Discontinued due to drug-related AE† Discontinued due to serious AE † Possibly, probably, or definitely drug related as assessed by the investigator.

LIFE: Prespecified Adverse Experiences of Special Interest
Losartan % (N=4605) Atenolol % (N=4588) <0.001 < < p-Value More Frequent with Losartan Dizziness Cancer Cough Hypotension More Frequent with Atenolol Cold extremities Sexual dysfunction Bradycardia Sleep disturbance Angioedema

LIFE: Common Adverse Experiences
Incidence >5% and Difference Between Groups >1% Losartan % (N=4605) 15.0 12.3 11.7 11.3 9.9 5.5 5.2 4.7 4.6 3.7 Atenolol % (N=4588) 17.5 10.4 13.9 10.1 14.1 3.2 6.5 5.9 6.4 5.6 Asthenia / fatigue Back pain Lower extremity edema Chest pain Dyspnea Palpitation Hyperglycemia Pneumonia Albuminuria Peripheral vascular disorder

LIFE: Key Laboratory Values
Parameters assessed included: Serum / plasma: sodium, potassium, hemoglobin, creatinine, ALAT, glucose, cholesterol (total and HDL), uric acid Urine: albumin, creatinine No clinically significant differences between treatment groups were noted Assessed changes from baseline values and changes outside of predefined limits

LIFE: New Onset Diabetes

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

LIFE: Summary of Findings - Primary and Secondary Component Endpoints
Adjusted for FRS and ECG-LVH at Baseline

LIFE: Review of Evidence and Conclusions
William F. Keane, MD Vice President, Clinical Development Merck US Human Health

LIFE: Strength of the Evidence
Evidence of Effectiveness from a Single Study Use of a single study: Mortality, irreversible morbidity, or prevention of disease Impractical or unethical to repeat Characteristics to consider: Study design Consistency across study subsets Multiple endpoints involving different events Study findings consistent with external scientific literature

LIFE: Study Design Large multicenter, multinational study
9193 patients followed for a mean of 4.8 years 945 clinical sites, 7 countries 1096 patients with primary endpoints Complete endpoint reporting for 99% of patient-days Endpoints adjudicated by independent committee Hypertensive patients with left ventricular hypertrophy Active control with proven benefit in reduction of cardiovascular morbidity and mortality

Benefit of Blood Pressure Reduction in Patients with LVH
LIFE is the first trial to exclusively study hypertensive patients with LVH Blood pressure is a surrogate for cardiovascular outcomes Including patients with LVH Prevalence of LVH in hypertensive patients over 55 years of age is 20%

Meta-Analysis of -Blocker Regimens in Hypertension
All Cardiovascular Events † Atenolol arm. ‡ -blocker and/or diuretic arm.

Meta-Analysis of CCB or ACEI vs. -Blocker / Diuretic Regimens
All Cardiovascular Events 0.99 1.01 CCB ACEI 26,527 18,357 3,048 2,247 Total Events Total Patients OR 0.5 1 1.5 Odds Ratio (95% CI) Favors Favors Diuretics/B CCB or ACEI Adapted from Staessen, Wang & Thijs. Lancet 2001; 358:

2.0

LIFE: Summary of Blood Pressure Effects
At Last Visit Before Endpoint or End of Follow-Up Blood Pressure Reduction Systolic BP change, mm Hg Diastolic BP change, mm Hg Blood Pressure Control Category SBP140 and DBP90, % SBP160 or DBP100, % Losartan (N=4605) Atenolol (N=4588)

LIFE Substudy: 24-Hour Ambulatory Blood Pressure - Systolic Pressure
Mean 24-Hour Systolic Blood Pressure at Year 1 Losartan Atenolol (n=57) (n=53) Baseline Year 1 10 mm Hg (mean)

LIFE: Primary Endpoint Adjusted for Blood Pressure as Time-Varying Covariate
Hazard Ratio 0.861 0.858 0.860 0.854 Risk Reduction (%) 13.9 14.2 14.0 14.6 Change -0.7 -0.4 -0.6 Unadjusted result Adjusted results Systolic BP Diastolic BP BP control category

LIFE Compared to Meta-Analyses of Hypertension Trials
Impact of Observed Systolic Blood Pressure Differences on Risk of Stroke LIFE Compared to Meta-Analyses of Hypertension Trials Data from: Staessen, et al 2000; He et al 1999; MacMahon and Rodgers, 1993.

LIFE: Consistency Across Study Subsets
No significant treatment by subgroup interactions Disease categories of special interest Diabetes Isolated systolic hypertension Pre-specified subgroups Demographic Disease history Clinical characteristics

Primary endpoint: Significant test for interaction Greater risk reduction with atenolol in Black patients No biological basis found for the observed interaction Blood pressure: Decreased to similar level in each group LVH: Greater reduction with losartan compared to atenolol Heart rate: Greater reduction with atenolol compared to losartan Recommend description of findings in product circular

LIFE: Multiple Endpoints Involving Different Events
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 MI Losartan produced a greater reduction of ECG-LVH Other measurements: Losartan reduced carotid artery wall thickness (ICARUS substudy) Losartan reduced incidence of atrial fibrillation

LIFE: Regression of Carotid Artery Hypertrophy
ICARUS Sub-Study Change from Baseline at Year 3 Losartan (n=19) Atenolol (n=20) % Change in Intima-Media Cross-Sectional Area -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

LIFE: Multiple Endpoints Involving Different Events
Secondary Component Endpoints Heterogeneity among secondary component endpoints Similar incidence of myocardial infarction Cardioprotective effects of atenolol Greater reduction in LVH with losartan Greater reduction in stroke with losartan Reduction in carotid artery wall thickness with losartan Reduction in incidence of atrial fibrillation with losartan

LIFE: Results Consistent with External Scientific Data
Preclinical data with AT1 blockade, independent of blood pressure: Reduction in stroke mortality and cerebral lesions Improvement in myocardial hypertrophy Reduction in myocardial fibrosis Clinical data with interference in RAS in hypertensive patients: Greater regression of LVH Structural and functional benefit on peripheral vasculature

LIFE: Strength of the Evidence
Evidence of Effectiveness from a Single Study Use of a single study: Significant result with losartan on primary endpoint of cardiovascular morbidity and mortality Impractical to repeat Characteristics to consider: Large, multicenter, active-control design Generally consistent effect of losartan in subgroups Benefit of losartan on incidence of stroke, degree of LVH, carotid artery IMT, incidence of atrial fibrillation Preclinical and clinical pharmacodynamic literature are corroborative

LIFE: Favorable Benefit to Risk Ratio
Efficacy Significant beneficial effects of losartan on clinically important endpoints compared to atenolol with comparable reduction in blood pressure Safety Losartan was better tolerated than atenolol Adverse experience profile of losartan was consistent with that presented in the currently approved US product circular for COZAAR Lower incidence of new-onset diabetes mellitus with losartan compared to 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.

Director, Regulatory Affairs Merck Research Laboratories

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