# Presentation: 493765

## COZAAR (losartan) in Hypertensive Patientswith Left Ventricular Hypertrophy

- Jeffrey R. Tucker, MD
*Director, Regulatory Affairs**Merck Research Laboratories*

## The LIFE Study

*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

- Agenda

_**L**_osartan _**I**_ntervention _**F**_or _**E**_ndpoint
- Reduction in Hypertension Study

## The LIFE Study

- 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*

## 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

- Background and Rationale
- LIFE Study Design
- LIFE Patient Population
- LIFE Efficacy Results
- LIFE Safety Results

- Agenda

## 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

- Kannel WB *Euro Heart J *1992;13(Suppl G):34-42.

- The Framingham Heart Study

- Risk Ratio

- 2.2

- 2.5

## Treatment of Hypertension Reduces Cardiovascular Morbidity and Mortality

- 5 Randomized Trials in 12,483 Elderly Hypertensives

- % Reduction in odds:

- 19%
- p<0.05

- 34%
- p<0.001

- 23%
- p<0.001

- 346

- 383

- 288

- 438

- Total Number of Individuals Affected

- 438

- 494

**Overall BP Difference**
- Systolic:  15 mm Hg
- Diastolic:   6 mm Hg

## 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 havea greater effect on cardiovascular morbidity and mortality than conventional antihypertensive therapy when peripheral blood pressure is similarly controlled?

## Losartan in Hypertensive Patients withLeft Ventricular Hypertrophy

- Background and Rationale
- LIFE Study Design
- LIFE Patient Population
- LIFE Efficacy Results
- LIFE Safety Results

- Agenda

## 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 (1988-1994)

- Age Group

## Risk of Cardiovascular Events Associated with ECG-LVH in the Elderly

- The Framingham Heart Study

- Cupples LA, D’Agostino RB. *NIH Publication No 87-2703*, Feb 1987.

- Risk Ratio

- 3.2

- 5.3

- 3.7

- 3.0

**CHD**

**Stroke**

## 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

*Arch Intern Med* 1993; 153:2413-2446.

- “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.”

## 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

- 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

- Hypothesis
- 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

## LIFE: Primary Endpoint Analysis

## 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

## 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 55-80 years
- Elevated blood pressure
- Systolic BP 160-200 mm Hg ***or*** Diastolic BP 95-115 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

## LIFE: Study Design (I)

**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***

**Randomization**

## LIFE: Study Design (II)

- Study duration:
- Follow-up for minimum of 4 yearsand
- 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

**June 1995**
- First patientrandomized

**May 1997**
- Last patientrandomized

**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

- 1996

- 1997

- 1998

- 1999

- 2000

- 2001

- 2002

**November 2001**
- Final patient visit

## Losartan in Hypertensive Patients withLeft Ventricular Hypertrophy

- Background and Rationale
- LIFE Study Design
- LIFE Patient Population
- LIFE Efficacy Results
- LIFE Safety Results

- Agenda

## LIFE: Patient Disposition

**Entered baseline**
**(N=10,779)**

**Randomized**
**(N=9222)**

**Excluded for irregularities (n=29)**

**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%)**

**Followed for study duration**
**(N=9193)**

## 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%

## LIFE: Patient Recruitment

- Denmark
- Iceland
- Finland
- Norway
- Sweden
- UK
- USA

- Country

- 1391
- 133
- 1485
- 1415
- 2245
- 817
- 1707

- n

- N=9193

## LIFE: Baseline Characteristics (I)

- Gender, % female
- Ethnic group, %
- 	White
- 	Black
- 	Hispanic
- 	Asian
- 	Other

- 66.9
- 54.0
- 92.5
- 5.9
- 1.0
- 0.5
- 0.1

- Losartan
- (N=4605)

- 66.9
- 54.0
- 92.5
- 5.7
- 1.2
- 0.4
- 0.2

- Atenolol
- (N=4588)

## LIFE: Baseline Characteristics (II)

- 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

- Losartan
- (N=4605)

- Atenolol
- (N=4588)

## LIFE: Baseline Characteristics (III)

- Medical History

## LIFE: Baseline Characteristics (IV)

- Sokolow-Lyon, mm
- Framingham Risk Score, %

- 2828.0
- 30.0
- 22.3

- Losartan(N=4605)

- 2818.9
- 30.0
- 22.5

- Atenolol(N=4588)

- Variables Utilized in Covariate Analysis
- ECG-LVH and Framingham Risk Score

- Framingham Risk Score predicts the 5-year probabilityof developing coronary heart disease based on
- gender, age, systolic blood pressure, smoking,total / HDL cholesterol, diabetes, ECG-LVH

## LIFE: Study Therapy

**50 mg alone**
**50 mg with additional drugs**
**100 mg with or without additional drugs**
**Off study drug**

- Losartan %(N=4605)

-   **9**
**18**
**50**
**23**

- Atenolol %(N=4588)

**10**
**20**
**43**
**27**

## LIFE: Study Therapy

**50 mg alone**
**50 mg with additional drugs**With HCTZ onlyWith other drugs onlyWith HCTZ and other drugs
**100 mg with or without additional drugs**AloneWith HCTZ onlyWith other drugs onlyWith HCTZ and other drugs
**Off study drug**

- Losartan %(N=4605)

-   **9**
**18****  **14    2    2
**50****    **2  18    4  26
**23**

- Atenolol %(N=4588)

**10**
**20**  14    2    4
**43****    **2  16    4  22
**27**

- At Endpoint or End of Follow-Up

## LIFE: Study Therapy

- 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)

- Losartan(N=4605)

- 	86
- 	    82
- 	72
- 	  20
- 	2.3

- Atenolol(N=4588)

- 	  82
- 	  79
- 	  70
- 	  20
- 	  2.3

- At Endpoint or End of Follow-Up

## Losartan in Hypertensive Patients withLeft Ventricular Hypertrophy

- Background and Rationale
- LIFE Study Design
- LIFE Patient Population
- LIFE Efficacy Results
- LIFE Safety Results

- Agenda

## LIFE: Primary Endpoint

## LIFE: Primary Endpoint

## LIFE: Systolic Blood Pressure

- 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

- mm Hg (mean)

## LIFE: Diastolic Blood Pressure

- Reduction at Last Visit Before Endpoint or End of Follow-up
- 	Losartan	Atenolol	p-Value
- 	-16.6	-16.8	0.345
- Time-Averaged Difference = 0.76

- mm Hg (mean)

## LIFE: Categories of Hypertensive Response

## LIFE: Heart Rate

- 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

## Losartan in Hypertensive Patients withLeft Ventricular Hypertrophy

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

- Agenda

## LIFE: Secondary Component Endpoint Analyses

- Patient A

## LIFE: Secondary Component Endpoint Analyses

**Dec 1995**
- Randomized

## LIFE: Secondary Component Endpoint Analyses

- 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 Endpoints

- Adjusted for FRS and ECG-LVH.

## LIFE: Secondary Component Endpoint

- Fatal and Non-Fatal Stroke

## LIFE: Secondary Component Endpoint

## LIFE: Secondary Component Endpoint

- Cardiovascular Mortality

## LIFE: Secondary Component Endpoints

- Adjusted for FRS and ECG-LVH.

## LIFE: Secondary Component Endpoints

- Adjusted for FRS and ECG-LVH.

- CHD

## LIFE: Secondary Component Endpoints

- Adjusted for FRS and ECG-LVH.

- CHD

## LIFE: Mortality and Causes of DeathAdjudicated by Endpoint Committee

- Adjusted for FRS and ECG-LVH.

## LIFE: Other EndpointsAdjudicated by Endpoint Committee

- Adjusted for FRS and ECG-LVH.

## 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
- 	-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

## LIFE: ECHO Substudy (n=965)

- Change in Left Ventricular Mass Index (g/m**2**)

**Reduction in LVMI **
**at last available echo (g/m****2****):**
**Losartan     Atenolol****	****p-Value**
**   ****-21.7           -17.7                0.011         **

## 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

## LIFE: Disease Categories of Special Interest

- Increased Risk of Primary Endpoint

- (n=1195)

- (n=7998)

- (n=1326)

- (n=7867)

- Relative Risk:           2.0                                                              1.2

## LIFE: Disease Categories of Special Interest

- Primary Endpoint

- p=0.170**†**

- p=0.176**†**

**† **Test for treatment-by-subgroup interaction.

## LIFE: Patients with Diabetes

- Primary Endpoint

- Patients

## LIFE: Patients with Diabetes

- Secondary Component Endpoints

- Adjusted for FRS and ECG-LVH.

## LIFE: Patients with Diabetes

- Other Endpoints

- Adjusted for FRS and ECG-LVH.

## LIFE: Patients with Isolated Systolic Hypertension

- Primary Endpoint

## LIFE: Patients with Isolated Systolic Hypertension

- Secondary Component Endpoints

- Adjusted for FRS and ECG-LVH.

## LIFE: Patients with Isolated Systolic Hypertension

- Other Endpoints

- Adjusted for FRS and ECG-LVH.

## LIFE: Primary Endpoint

- 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

## LIFE: Primary Endpoint

- Baseline Subgroups - Test for Interaction with Treatment

- DemographicAgeGenderCountryEthnic group
- Disease historyMIStrokeIHDAnginaHeart failureDiabetesMicroalbuminuriaISH

- Clinical characteristicsSmoking statusAlcohol intakeExercise statusBMISystolic BPDiastolic BPTotal cholesterolHDL cholesterolECG-LVH (Cornell)ECG-LVH (SL)Framingham Risk

- 0.1850.4200.6070.057
- 0.3160.2110.2090.2500.7330.1700.3830.176

- 0.2820.4200.8920.2900.7250.4020.9750.1140.4850.4220.922

- Subgroup

- p-Value

- Subgroup

- p-Value

## LIFE: Primary Endpoint

- Baseline Subgroups - Test for Interaction with Treatment

- DemographicAgeGenderCountryEthnic group
- Disease historyMIStrokeIHDAnginaHeart failureDiabetesMicroalbuminuriaISH

- Clinical characteristicsSmoking statusAlcohol intakeExercise statusBMISystolic BPDiastolic BPTotal cholesterolHDL cholesterolECG-LVH (Cornell)ECG-LVH (SL)Framingham Risk

- 0.1850.4200.6070.057
- 0.3160.2110.2090.2500.7330.1700.3830.176

- 0.2820.4200.8920.2900.7250.4020.9750.1140.4850.4220.922

- Subgroup

- p-Value

- Subgroup

- p-Value

## 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

- Test for qualitativeinteraction, p=0.016

**† **Test for treatment-by-subgroup interaction.

## LIFE: Post-Hoc Analysis Black vs. Non-Black Patients

- LIFE: Post-Hoc Analysis Black vs. Non-Black Patients

- 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

## LIFE: Post-Hoc AnalysisBlack vs. Non-Black Patients

- US Patients (n=1707)

- Change at End of Follow-Up or Last Visit Prior to Primary Endpoint

## LIFE: Post-Hoc AnalysisBlack vs. Non-Black Patients

- LIFE: Post-Hoc AnalysisBlack vs. Non-Black Patients

## LIFE: Post-Hoc AnalysisBlack vs. Non-Black Patients

- LIFE: Post-Hoc AnalysisBlack vs. Non-Black Patients

## LIFE: Post-Hoc AnalysisBlack vs. Non-Black Patients

- LIFE: Post-Hoc AnalysisBlack vs. Non-Black Patients

- 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

## Losartan in Hypertensive Patients withLeft Ventricular Hypertrophy

- Background and Rationale
- LIFE Study Design
- LIFE Patient Population
- LIFE Efficacy Results
- LIFE Safety Results

- Agenda

## LIFE: Overall Adverse Experiences (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

**More Frequent with Losartan**DizzinessCancer	CoughHypotension
**More Frequent with Atenolol**Cold extremitiesSexual dysfunctionBradycardiaSleep disturbanceAngioedema

## LIFE: Common Adverse Experiences

- Back pain
- Lower extremity edema
- Chest pain
- Dyspnea
- Palpitation
- Hyperglycemia
- Pneumonia
- Albuminuria
- Peripheral vascular disorder

- Incidence **>**5% and Difference Between Groups **>**1%

## 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

- 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

- Adapted from Staessen, Wang & Thijs. *Lancet *2001; 358:1305-15.

- All Cardiovascular Events

## LIFE: Primary Endpoint

## LIFE: Summary of Blood Pressure Effects

- At Last Visit Before Endpoint or End of Follow-Up

## LIFE Substudy: 24-Hour Ambulatory Blood Pressure - Systolic Pressure

- mm Hg (mean)

##      Systolic BP

- LIFE: Primary Endpoint Adjusted for Blood Pressure as Time-Varying Covariate

-      Diastolic BP

-      BP control category

- Unadjusted result

- Adjusted results

## Impact of Observed Systolic Blood Pressure Differences on Risk of Stroke

- Data from: Staessen, et al 2000; He et al 1999; MacMahon and Rodgers, 1993.

- LIFE Compared to Meta-Analyses of Hypertension Trials

## Impact of Observed Systolic Blood Pressure Differences on Risk of Stroke

- Data from: Staessen, et al 2000; He et al 1999; MacMahon and Rodgers, 1993.

- LIFE Compared to Meta-Analyses of Hypertension Trials

## Impact of Observed Systolic Blood Pressure Differences on Risk of Stroke

- Data from: Staessen, et al 2000; He et al 1999; MacMahon and Rodgers, 1993.

- LIFE Compared to Meta-Analyses of Hypertension Trials

## Impact of Observed Systolic Blood Pressure Differences on Risk of Stroke

- Data from: Staessen, et al 2000; He et al 1999; MacMahon and Rodgers, 1993.

- LIFE Compared to Meta-Analyses of Hypertension Trials

## Impact of Observed Systolic Blood Pressure Differences on Risk of Stroke

- Data from: Staessen, et al 2000; He et al 1999; MacMahon and Rodgers, 1993.

- LIFE Compared to Meta-Analyses of Hypertension Trials

## 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

## LIFE: Post-Hoc AnalysisBlack vs. Non-Black Patients

- 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

## 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

- 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

- Secondary Component Endpoints

## 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

- 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.