Clinical Review Cover Sheet

Supplemental NDA Submission

NDA 20-386

Cozaar Tablets

Merck & Co., Inc

Thomas A. Marciniak, MD

> Medical Officer
>
> Division of Cardiorenal Drug Products

# 

# Table of Contents

Table of Contents [2](#table-of-contents)

Executive Summary [5](#executive-summary)

I. Recommendations [5](#i.-recommendations)

A. Recommendation on Approvability
[5](#a.-recommendation-on-approvability)

B. Recommendation on Phase 4 Studies and/or Risk Management Steps
[5](#b.-recommendation-on-phase-4-studies-andor-risk-management-steps)

II\. Summary of Clinical Findings [6](#ii.-summary-of-clinical-findings)

A. Brief Overview of Clinical Program
[6](#a.-brief-overview-of-clinical-program)

B. Efficacy [6](#b.-efficacy)

C. Safety [7](#c.-safety)

D. Dosing [7](#d.-dosing)

E. Special Populations [7](#e.-special-populations)

Clinical Review [8](#clinical-review)

I. Introduction and Background [8](#i.-introduction-and-background)

A. Drug Established and Proposed Trade Name, Drug Class, Sponsor's
Proposed Indication(s), Dose, Regimens, Age Groups
[8](#a.-drug-established-and-proposed-trade-name-drug-class-sponsors-proposed-indications-dose-regimens-age-groups)

B. State of Armamentarium for Indication(s)
[8](#b.-state-of-armamentarium-for-indications)

C. Important Milestones in Product Development
[8](#c.-important-milestones-in-product-development)

D. Other Relevant Information [9](#d.-other-relevant-information)

E. Important Issues with Pharmacologically Related Agents
[9](#e.-important-issues-with-pharmacologically-related-agents)

F. Abbreviations Used in this Review
[12](#f.-abbreviations-used-in-this-review)

II\. Clinically Relevant Findings From Chemistry, Animal Pharmacology
and Toxicology, Microbiology, Biopharmaceutics, Statistics and/or Other
Consultant Reviews
[14](#ii.-clinically-relevant-findings-from-chemistry-animal-pharmacology-and-toxicology-microbiology-biopharmaceutics-statistics-andor-other-consultant-reviews)

III\. Human Pharmacokinetics and Pharmacodynamics
[15](#iii.-human-pharmacokinetics-and-pharmacodynamics)

A. Pharmacokinetics [15](#a.-pharmacokinetics)

B. Pharmacodynamics [16](#b.-pharmacodynamics)

IV\. Description of Clinical Data and Sources
[18](#iv.-description-of-clinical-data-and-sources)

A. Overall Data [18](#overall-data)

B. Tables Listing the Clinical Trials
[18](#tables-listing-the-clinical-trials)

C. Postmarketing Experience [18](#postmarketing-experience)

D. Literature Review [18](#d.-literature-review)

V. Clinical Review Methods [19](#v.-clinical-review-methods)

A. How the Review was Conducted [19](#a.-how-the-review-was-conducted)

B. Overview of Materials Consulted in Review
[19](#b.-overview-of-materials-consulted-in-review)

C. Overview of Methods Used to Evaluate Data Quality and Integrity
[19](#c.-overview-of-methods-used-to-evaluate-data-quality-and-integrity)

D. Were Trials Conducted in Accordance with Accepted Ethical Standards
[19](#d.-were-trials-conducted-in-accordance-with-accepted-ethical-standards)

E. Evaluation of Financial Disclosure
[20](#e.-evaluation-of-financial-disclosure)

VI\. Integrated Review of Efficacy
[21](#vi.-integrated-review-of-efficacy)

A. Brief Statement of Conclusions
[21](#a.-brief-statement-of-conclusions)

B. General Approach to Review of the Efficacy of the Drug
[21](#b.-general-approach-to-review-of-the-efficacy-of-the-drug)

C. Detailed Review of the LIFE Study
[21](#c.-detailed-review-of-the-life-study)

D. Efficacy Conclusions [90](#d.-efficacy-conclusions)

VII\. Integrated Review of Safety
[96](#vii.-integrated-review-of-safety)

A. Brief Statement of Conclusions
[96](#a.-brief-statement-of-conclusions-1)

B. Review of Safety Data in the LIFE Study
[96](#b.-review-of-safety-data-in-the-life-study)

C. Summary of Critical Safety Findings and Limitations of Data
[110](#c.-summary-of-critical-safety-findings-and-limitations-of-data)

VIII\. Dosing, Regimen, and Administration Issues
[112](#viii.-dosing-regimen-and-administration-issues)

IX\. Use in Special Populations [113](#ix.-use-in-special-populations)

A. Evaluation of Sponsor's Gender Effects Analyses and Adequacy of
Investigation
[113](#a.-evaluation-of-sponsors-gender-effects-analyses-and-adequacy-of-investigation)

B. Evaluation of Evidence for Age, Race, or Ethnicity Effects on Safety
or Efficacy
[113](#b.-evaluation-of-evidence-for-age-race-or-ethnicity-effects-on-safety-or-efficacy)

C. Evaluation of Pediatric Program
[113](#c.-evaluation-of-pediatric-program)

D. Comments on Data Available or Needed in Other Populations
[114](#d.-comments-on-data-available-or-needed-in-other-populations)

X. Conclusions and Recommendations
[114](#x.-conclusions-and-recommendations)

A. Conclusions [114](#a.-conclusions)

B. Recommendations [115](#b.-recommendations)

XI\. Appendix [117](#xi.-appendix)

A. References [117](#a.-references)

**Clinical Review for Supplemental NDA 20-386**

# Executive Summary

## I. Recommendations

### A. Recommendation on Approvability

> With this supplemental NDA the sponsor is seeking approval for a new
> indication for losartan, a drug approved for the treatment of
> hypertension. The sponsor proposes the new indication as "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." The sponsor submitted the data from a single study to
> support this indication. The study is the Losartan Intervention for
> Endpoint Reduction in Hypertension (LIFE) study, a large, long term
> international study.

The reviewer believes that the LIFE study demonstrates adequately that
antihypertensive regimens including losartan are superior to ones
including atenolol for reducing the composite endpoint of death,
myocardial infarction, and stroke in hypertensive patients with left
ventricular hypertrophy. The endpoint is a vital one and the magnitude
of the treatment effect is reasonable (about a 10% risk reduction) such
that a single trial is acceptable for supporting the new indication. The
reviewer recommends that the new indication be approved as "to reduce
the risk of death and cardiovascular morbidity as measured by the
combined incidence of death, stroke, and myocardial infarction in
hypertensive patients with left ventricular hypertrophy."

### B. Recommendation on Phase 4 Studies and/or Risk Management Steps

> The LIFE study raises a question regarding whether the beneficial
> effect of losartan is reversed in blacks. Other data sources should be
> sought to help address this issue.

## II. Summary of Clinical Findings 

### A. Brief Overview of Clinical Program

> Cozaar^^ (losartan potassium) is an oral angiotensin II receptor
> (type AT~1~) antagonist approved for the treatment of hypertension.
> The sponsor is seeking an indication to reduce the risk of
> cardiovascular morbidity and mortality in hypertensive patients with
> left ventricular hypertrophy based on one trial comparing regimens
> including losartan or atenolol in these patients. The trial is called
> the Losartan Intervention for Endpoint Reduction in Hypertension
> (LIFE) Trial. The LIFE study involved 9,193 patients (4,588 atenolol
> and 4,605 losartan). Mean length of follow-up was 4.8 years.

### B. Efficacy

> The LIFE study had a sponsor pre-specified primary endpoint of
> combined cardiovascular deaths, myocardial infarctions, and strokes.
> By the pre-specified analysis, a Cox regression with baseline measures
> of left ventricular hypertrophy and Framingham risk score as
> covariates, the losartan regimen produced a 13% reduction in risk
> relative to the atenolol regimen, p=0.023. For the FDA-recommended
> primary endpoint including total mortality the losartan regimen
> produced a 10% risk reduction, p=0.039. The effects upon the
> components of the primary endpoint were heterogeneous. The benefit
> from losartan was primary related to a reduction in strokes, a 25%
> risk reduction (p=0.009).
>
> The LIFE study is the only study supporting the proposed new
> indication. However, because the magnitude of the treatment effect (a
> 10% risk reduction) is reasonable and the endpoint is vital, the
> reviewer believes that a description of the beneficial effect of
> losartan in the LIFE study should be included in the losartan label.
>
> Some analyses of the LIFE study suggest a qualitative interaction,
> i.e., a reversal of the beneficial effect of losartan, in blacks.
> However, blacks were a subgroup with different baseline
> characteristics and different responses than the rest of the study
> population. The results of the LIFE study suggest that losartan is not
> superior to atenolol in blacks. The evidence from the LIFE study is
> not conclusive for establishing that losartan is inferior to atenolol
> in blacks.
>
> Other subgroups analyses also generated interesting differences.
> Because they are subgroup analyses they must be interpreted with
> caution.

-   Losartan appears to be more effective in the elderly. Losartan may
    be less effective in males younger than 65.

-   Losartan appears to be more effective in patients with isolated
    systolic hypertension at baseline. Isolated systolic hypertension is
    more frequent in the elderly.

-   Losartan appears to be more effective in patients with diabetes at
    baseline. Losartan was also associated with a lower rate of onset of
    new diabetes.

One finding that is surprising is that atenolol use appeared to be
associated with more atrial fibrillation and more strokes associated
with atrial fibrillation. These associations need verification from
other data.

### C. Safety

Both losartan and atenolol were tolerated well in this long-term study
in high risk patients. The majority of adverse effects, such as
bradycardia with atenolol, were expected ones. Losartan appeared to be
better tolerated than atenolol based on a higher rate of drug
discontinuations due to adverse effects with atenolol. Besides the
question of greater rates of atrial fibrillation with atenolol, atenolol
also was associated with slightly greater increases in blood uric acid
and glucose and higher rates of gout and diabetes. Losartan was
associated with greater decreases in blood hemoglobin and higher rates
of anemia. All of these latter adverse effects were still uncommon.

### D. Dosing

The LIFE study used standard approved dosages and once daily dosing
regimens for both atenolol and losartan.

### E. Special Populations

Possible differences in efficacy by race, age, and gender are mentioned
under Efficacy. Adverse effects were more frequent with increasing age
and slightly more frequent in females but differential patterns of
toxicity were not identified.

# Clinical Review 

## I. Introduction and Background

### A. Drug Established and Proposed Trade Name, Drug Class, Sponsor's Proposed Indication(s), Dose, Regimens, Age Groups

> Cozaar^^ (losartan potassium) is an angiotensin II receptor (type
> AT~1~) antagonist approved for the treatment of hypertension. The
> sponsor is seeking an indication to reduce the risk of cardiovascular
> morbidity and mortality in hypertensive patients with left ventricular
> hypertrophy based on one trial comparing regimens including losartan
> or atenolol in these patients. The trial is called the Losartan
> Intervention for Endpoint Reduction in Hypertension (LIFE) Trial. In
> this trial once daily losartan was titrated from 50 to 100 mg to
> control blood pressure. The protocol for the trial specified the
> addition of hydrochlorothiazide 12.5 mg daily before raising the dose
> of losartan and also specified increasing the dose of
> hydrochlorothiazide and adding other antihypertensives to control
> blood pressure. The protocol restricted the patient population to ages
> 55 to 80.

### B. State of Armamentarium for Indication(s) 

Many classes of drugs are approved for the treatment of hypertension.
Reducing blood pressure with drugs decreases cardiovascular morbidity
and mortality as demonstrated in a large number of clinical trials in
various countries regardless of sex, age, race, blood pressure level, or
socioeconomic status. (JNC 1997) A recent meta-analysis did not find
that different drugs have differential impacts upon overall
cardiovascular morbidity and mortality beyond blood pressure control.
(Staessen, Wang et al. 2001) A meta-analysis of antihypertensive trials
in the elderly did not identify differential treatment effects based on
patient risk factors, pre-existing cardiovascular disease, or competing
co-morbidities. (Mulrow, Lau et al. 2000) Guidelines do recommend
selecting agents based on co-morbidities, particularly type 1 diabetes
with proteinuria, heart failure, isolated systolic hypertension, and
myocardial infarction. (JNC 1997) Left ventricular hypertrophy (LVH) is
a recognized risk factor for cardiovascular events, but no controlled
studies demonstrate that reversal of LVH offers additional benefits
beyond that offered by reduction of blood pressure. (JNC 1997; Devereux,
Okin et al. 1999) Demonstration of a beneficial effect upon
cardiovascular morbidity and mortality of a losartan-based regimen
compared to acceptable alternative therapy would be valuable clinical
information.

### C. Important Milestones in Product Development

The sponsor submitted the LIFE Trial protocol to IND 33,383 on June 29,
1995 (Serial No. 496). The summary of the trial in the Efficacy section
below includes a brief history of the regulatory background of the
protocol and the trial.

### D. Other Relevant Information 

#### Approvals in the United States and Other Countries

The FDA approved Cozaar for the treatment of hypertension on April 14,
1995. This supplement proposes to expand the indication to reducing the
risk of cardiovascular morbidity and mortality in hypertensive patients
with left ventricular hypertrophy.

As of May 23, 2002, the sponsor reports that 94 countries have approved
the use of losartan 50 mg tablets and 25 countries have approved the use
of losartan 100 mg tablets. Applications are pending in 14 countries for
the 100 mg tablet. No marketing applications have been rejected or
withdrawn and marketing approval has not been suspended, revoked, or
withdrawn in any country.

#### Determination of Left Ventricular Hypertrophy

> The sponsor conducted the LIFE study in patient with left ventricular
> hypertrophy (LVH) because LVH is a major risk factor for
> cardiovascular disease and antihypertensive agents have differing
> impacts upon it. The Framingham study data show that left ventricular
> mass assessed by echocardiography provides prognostic information
> beyond other risk factors. (Levy, Garrison et al. 1990) A recent
> review of 20 studies examining cardiovascular risk relative to
> baseline LVH, determined either by echocardiography or
> electrocardiography (ECG), found that all but one of the studies
> showed higher risk with baseline LVH. (Vakili, Okin et al. 2001) More
> recent epidemiological data have associated ECG-determined LVH with
> increased risk of stroke. (Bots, Nikitin et al. 2002)
>
> The LIFE study used two standard ECG criteria for determining LVH:

-   Sokolow-Lyon voltage criterion (Sokolow and Lyon 1949)

-   Cornell voltage-duration product criterion (Casale, Devereux et al.
    1985; Casale, Devereux et al. 1987)

> ECG criteria are highly specific but not sensitive for detecting
> echocardiographically documented increases in left ventricular mass.
> The LIFE steering committee adjusted the ECG criteria used in LIFE to
> achieve reasonable sensitivity while maintaining high specificity for
> detection of increased left ventricular mass (see the review of the
> study in the Efficacy section below.)

### E. Important Issues with Pharmacologically Related Agents

The LIFE study was not a simple drug vs. placebo controlled trial. It
was a trial of regimens including hydrochlorothiazide plus other
investigator-selected antihypertensives and either losartan or atenolol.
The unique controlled comparator was atenolol. Hence the most relevant
issues regarding pharmacologically related agents are regarding the
characteristics and effects of atenolol and other beta blockers in
hypertension.

#### Appropriateness of Atenolol as a Comparator

The sponsor gives the following rationale for its selection of
comparator: "A β-blocker, atenolol, was chosen as the comparator agent
since it is among the class of drugs with proven morbidity and mortality
benefits in hypertensive patients and has also been established as an
effective agent in secondary prevention in high-risk patients, when
administered alone or in combination with diuretics." The sponsor
justified its dose selection as follows: "The doses selected for both
marketed agents were based on label-recommended prescribing information
for the treatment of hypertension."

In its "FDA Advisory Committee Background Information" document for the
January 6, 2003, meeting of the Cardiovascular and Renal Drugs Advisory
Committee the sponsor provides excellent reviews of trials of
beta-blockers in hypertensive patients with cardiovascular event
endpoints and trials of diuretic-based regimens including beta-blockers.
Please see that document for the details. The following is the
reviewer's interpretation of the background trials.

Beta-blockers, along with diuretics, are the most extensively studied
antihypertensives with the most trial results supporting their
effectiveness in reducing cardiovascular morbidity and mortality.
(Collins, Peto et al. 1990) The Joint National Committee (JNC) VI
guidelines suggest starting with a beta-blocker or a diuretic for
uncomplicated hypertension. However, the JNC guidelines recommend
diuretics as preferred for patients with isolated systolic hypertension
(older persons). They also suggest that a long-acting dihydropyridine
calcium antagonist may be useful for these patients based on the results
of the Systolic Hypertension-Europe Trial of a drug (nitrendipine) not
available in the United States. (Staessen, Fagard et al. 1997) The
relevance of the isolated systolic hypertension ISH) studies to the LIFE
Trial is that ISH is common in older patients with left ventricular
hypertrophy, the population of the LIFE Trial.

Beta blockers have clearly been effective in combination with diuretics
in treating hypertension in the elderly. The Systolic Hypertension in
the Elderly Program (SHEP) used a diuretic (chlorthalidone) as the first
step with atenolol 25-50 mg as additional steps. SHEP showed that this
regimen reduced the incidence of stroke by 36%. (SHEP 1991) The Swedish
Trial in Old Patients with Hypertension (STOP-Hypertension) randomized
elderly (age 70-84) hypertensives without isolated systolic hypertension
to one of three beta blockers (including atenolol 50 mg) daily plus
hydrochlorothiazide 25 mg/amiloride 2.5 mg vs. placebo. (Dahlof,
Lindholm et al. 1991). The active treatment groups had better results
for a composite primary endpoint similar to that used in the LIFE trial,
including improved stroke morbidity and mortality. One meta-analysis
suggests that beta blockers are less effective than diuretics as
monotherapy in the elderly, but even this meta-analysis concludes that
beta blockers reduce the risk of stroke but not myocardial infarctions
or cardiovascular deaths. (Messerli, Grossman et al. 1998) A more recent
meta-analysis of hypertensive trials in the elderly concludes that both
diuretics and beta blockers are effective. (Mulrow, Lau et al. 2000)

COMMENT: These studies and meta-analyses support atenolol, combined with
a diuretic, as a reasonable comparator for the LIFE study. The reviewer
believes that there is ample evidence that reducing blood pressure, as
is demonstrated in the LIFE study, reduces cardiovascular event rates
and that regimens including a beta blocker reduce event rates in a wide
range of hypertensive populations. Actually, for a favorable
interpretation of the LIFE study results, it is not necessary that the
atenolol regimen have efficacy; it is sufficient that the atenolol
regimen do no overall harm with regard to cardiovascular outcomes. The
difficult and critical question to answer is not whether an atenolol
regimen beats placebo. The difficult and critical questions are whether
the LIFE study provides sufficient evidence that the losartan regimen is
robustly superior to the atenolol regimen in reducing cardiovascular
events and whether the regimens were realistic enough and the conduct
appropriate enough to support translation of the results into routine
clinical practice.

#### Relevant Characteristics of Atenolol

Three characteristics of atenolol and other beta blockers are relevant
to the LIFE Trial:

-   Beta blockers are reported to be less effective in blacks.
    (JNC 1997) Combining a beta blocker with a diuretic is reported to
    increase antihypertensive efficacy in blacks. While this limitation
    is not described in the atenolol label, lower efficacy of losartan
    in blacks is described in the Cozaar label.

-   Beta blockers may not control the early morning rise in blood
    pressure as well as other drugs. (Raftery and Carrageta 1985) The
    elimination half-life of atenolol is 6-7 hours, but the
    antihypertensive effect does not appear to be related to plasma
    level. Raftery suggests that the early morning rise is due to alpha
    adrenergic receptors that are unaffected by pure beta blockade. Lack
    of control in the early morning hours may also be a problem with
    hydrochlorothiazide (Lacourciere, Poirier et al. 2000)

-   Beta blockers are used for rate control in patients with atrial
    fibrillation. One study has documented that asymptomatic paroxysmal
    atrial fibrillation occurs during treatment of atrial fibrillation
    with propranolol. (Wolk, Kulakowski et al. 1996)

COMMENT: The relevance of these observations is discussed in the
Efficacy section.

### F. Abbreviations Used in this Review

The following are abbreviations, other than standard measurement units,
used in this review:

ABPM ambulatory blood pressure monitoring

ACE angiotensin converting enzyme

ACEI angiotensin converting enzyme inhibitor

AE adverse event

Afib atrial fibrillation

AII angiotensin II

AIIA angiotensin II antagonist (= ARB)

ALT alanine transaminase (SGPT)

ARB angiotensin receptor blocker (= AIIA)

ASA aspirin

AUC area under the curve

BB beta blocker

BMI body mass index

BP blood pressure

C~max~ maximum concentration

CRF case report form

CV cardiovascular

DSMB Data Safety and Monitoring Board

DBP diastolic blood pressure

DSI Division of Scientific Investigations (FDA)

ECC Endpoint Classification Committee

ECG electrocardiogram

FDA Food and Drug Administration

GCP Good Clinical Practice

HCTZ hydrochlorothiazide

HDL high density lipoprotein

HR heart rate

ICH International Conference on Harmonization

IND Investigational New Drug

IRB Investigational Review Board

ISH isolated systolic hypertension

LIFE Losartan Intervention for Endpoint Reduction in Hypertension

LVH left ventricular hypertrophy

LVM left ventricular mass

LVMI left ventricular mass index (LVM/body surface area)

MI myocardial infarction

NDA New Drug Application

PEY patient exposure years

PP pulse pressure

S-L Sokolow-Lyon (LVH ECG voltage criterion)

SAE serious adverse event

SBP systolic blood pressure

SHEP Systolic Hypertension in the Elderly Program

Si Sitting

sNDA Supplemental New Drug Application

TIA transient ischemic attack

UK United Kingdom

US United States

## II. Clinically Relevant Findings From Chemistry, Animal Pharmacology and Toxicology, Microbiology, Biopharmaceutics, Statistics and/or Other Consultant Reviews

> The relevant statistical review is regarding the LIFE Trial. The
> Efficacy section incorporates relevant findings from the FDA
> statistician's review.
>
> This supplemental NDA does not provide any new data regarding
> chemistry (except an environmental assessment), animal pharmacology
> and toxicology, microbiology, or biopharmaceutics. It does provide a
> review of published nonclinical pharmacologic effects of losartan in
> animal models of left ventricular hypertrophy, injury or dysfunction
> from 1993 to the present. The reviewer did not critique this review or
> its references. The sponsor's conclusions regarding these studies is
> the following:
>
> "1. Nonclinical pharmacologic studies, in particular those utilizing
> chronic dosing regimens in a variety of rat models of myocardial
> infarction, genetic, surgical and pharmacologically-induced myocardial
> hypertrophy and injury, overwhelmingly demonstrate losartan to
> significantly reduce cardiac hypertrophy.
>
> "2. Nonclinical studies also report losartan to reduce left
> ventricular wall thickness and/or dilation, and to improve hemodynamic
> status when administered either chronically or acutely.
>
> "3. Studies in a variety of models and species report losartan to
> reduce ventricular collagen content and interstitial and perivascular
> fibrosis, in concert with reductions in the expression or activities
> of growth factors, neurohormones and enzymes implicated in the
> development of cardiac hypertrophy, collagen synthesis and/or
> degradation and fibrosis, including transforming growth factor (TGF) β
> 1 and Smad signaling proteins, matrix metalloproteinases, atrial
> natriuretic peptide (ANP) and aldosterone.
>
> "4. Of particular note, losartan administration to stroke-prone
> spontaneously hypertensive rats (SHR-SPs), an experimental model of
> malignant hypertension in which animals develop severe
> cerebrovascular, cardiac and renal lesions and exhibit high mortality
> primarily from stroke, is reported in numerous studies to prevent
> stroke, significantly reduce mortality, and to reduce the incidence
> and severity of histologically-defined cerebrovascular, cardiac and
> renal lesions. The benefits of losartan on survival and prevention of
> stroke in SHR-SPs have been demonstrated with early vs late treatment
> initiation (relative to appearance of cerebral edema) and persist
> after discontinuation of treatment. Several studies in SHR-SPs report
> a significant survival benefit and the prevention of stroke and
> cerebrovascular lesions by losartan in the absence of significant
> lowering of blood pressure. These findings suggest that in SHR-SPs,
> angiotensin II through AT1 receptor stimulation, plays a major role in
> cerebrovascular pathology and the occurrence of stroke, and that
> losartan, apparently independently of its effect on blood pressure,
> affords significant and prolonged protection against cerebrovascular
> histopathologic changes, stroke and mortality."

## III. Human Pharmacokinetics and Pharmacodynamics

### A. Pharmacokinetics

This supplemental NDA does not provide any new data regarding
pharmaco­kinetics. The following pharmacokinetic summary is extracted
from the Cozaar label for ease of reference:

Losartan is an orally active agent that undergoes substantial first-pass
metabolism by cytochrome P450 enzymes. It is converted, in part, to an
active carboxylic acid metabolite that is responsible for most of the
angiotensin II receptor antagonism that follows losartan treatment. The
terminal half-life of losartan is about 2 hours and of the metabolite is
about 6-9 hours. The pharmacokinetics of losartan and its active
metabolite are linear with oral losartan doses up to 200 mg and do not
change over time. Neither losartan nor its metabolite accumulate in
plasma upon repeated once-daily dosing.

Following oral administration, losartan is well absorbed (based on
absorption of radiolabeled losartan) and undergoes substantial
first-pass metabolism; the systemic bioavailability of losartan is
approximately 33%. About 14% of an orally-administered dose of losartan
is converted to the active metabolite. Mean peak concentrations of
losartan and its active metabolite are reached in 1 hour and in 3-4
hours, respectively. While maximum plasma concentrations of losartan and
its active metabolite are approximately equal, the AUC of the metabolite
is about 4 times as great as that of losartan. A meal slows absorption
of losartan and decreases its C~max~ but has only minor effects on
losartan AUC or on the AUC of the metabolite (about 10% decreased).

Both losartan and its active metabolite are highly bound to plasma
proteins, primarily albumin, with plasma free fractions of 1.3% and
0.2%, respectively. Plasma protein binding is constant over the
concentration range achieved with recommended doses.

Losartan metabolites have been identified in human plasma and urine. In
addition to the active carboxylic acid metabolite, several inactive
metabolites are formed. Following oral and intravenous administration of
14 C-labeled losartan potassium, circulating plasma radioactivity is
primarily attributed to losartan and its active metabolite. In vitro
studies indicate that cytochrome P450 2C9 and 3A4 are involved in the
biotransformation of losartan to its metabolites. Minimal conversion of
losartan to the active metabolite (less than 1% of the dose compared to
14% of the dose in normal subjects) was seen in about one percent of
individuals studied.

The volume of distribution of losartan is about 34 liters and of the
active metabolite is about 12 liters. Total plasma clearance of losartan
and the active metabolite is about 600 mL/min and 50 mL/min,
respectively, with renal clearance of about 75 mL/min and 25 mL/min,
respectively. When losartan is administered orally, about 4% of the dose
is excreted unchanged in the urine and about 6% is excreted in urine as
active metabolite. Biliary excretion contributes to the elimination of
losartan and its metabolites. Following oral ^14^C-labeled losartan,
about 35% of radioactivity is recovered in the urine and about 60% in
the feces. Following an intravenous dose of ^14^C-labeled losartan,
about 45% of radioactivity is recovered in the urine and 50% in the
feces.

Plasma concentrations of losartan and its active metabolite are similar
in elderly and young hypertensives. Plasma concentrations of losartan
were about twice as high in female hypertensives as male hypertensives,
but concentrations of the active metabolite were similar in males and
females.

### B. Pharmacodynamics

#### Pharmacodynamics from Label

The following pharmacodynamic summary is extracted from the Cozaar label
for ease of reference:

Angiotensin II \[formed from angiotensin I in a reaction catalyzed by
angiotensin converting enzyme (ACE, kininase II)\], is a potent
vasoconstrictor, the primary vasoactive hormone of the renin-angiotensin
system and an important component in the pathophysiology of
hypertension. It also stimulates aldosterone secretion by the adrenal
cortex. Losartan and its principal active metabolite block the
vasoconstrictor and aldosterone-secreting effects of angiotensin II by
selectively blocking the binding of angiotensin II to the AT~1~ receptor
found in many tissues, (e.g., vascular smooth muscle, adrenal gland).
There is also an AT~2~ receptor found in many tissues but it is not
known to be associated with cardiovascular homeostasis. Both losartan
and its principal active metabolite do not exhibit any partial agonist
activity at the AT~1~ receptor and have much greater affinity (about
1000-fold) for the AT~1~ receptor than for the AT~2~ receptor. In vitro
binding studies indicate that losartan is a reversible, competitive
inhibitor of the AT~1~ receptor. The active metabolite is 10 to 40 times
more potent by weight than losartan and appears to be a reversible,
non-competitive inhibitor of the AT~1~ receptor.

Losartan inhibits the pressor effect of angiotensin II (as well as
angiotensin I) infusions. A dose of 100 mg inhibits the pressor effect
by about 85% at peak with 25-40% inhibition persisting for 24 hours.
Removal of the negative feedback of angiotensin II causes a 2-3 fold
rise in plasma renin activity and consequent rise in angiotensin II
plasma concentration in hypertensive patients.

The four studies of losartan monotherapy \[for hypertension\] included a
total of 1075 patients randomized to several doses of losartan and 334
to placebo. The 10 and 25 mg doses produced some effect at peak (6 hours
after dosing) but small and inconsistent trough (24 hour) responses.
Doses of 50, 100 and 150 mg once daily gave statistically significant
systolic/diastolic mean decreases in blood pressure, compared to placebo
in the range of 5.5-10.5/3.5-7.5 mmHg, with the 150 mg dose giving no
greater effect than 50-100 mg. Twice-daily dosing at 50-100 mg/day gave
consistently larger trough responses than once-daily dosing at the same
total dose. Peak (6 hour) effects were uniformly, but moderately, larger
than trough effects, with the trough-to-peak ratio for systolic and
diastolic responses 50-95% and 60-90%, respectively. Addition of a low
dose of hydrochlorothiazide (12.5 mg) to losartan 50 mg once daily
resulted in placebo-adjusted blood pressure reductions of 15.5/9.2 mmHg.
Analysis of age, gender, and race subgroups of patients showed that men
and women, and patients over and under 65, had generally similar
responses. Cozaar was effective in reducing blood pressure regardless of
race, although the effect was somewhat less in black patients (usually a
low-renin population).

#### Pharmacodynamic Effects Related to Left Ventricular Hypertrophy

> The sponsor chose the population of hypertensives with LVH for the
> LIFE study because of evidence that different antihypertensives have
> differing impacts upon LVH. The following is the reviewer's summary of
> the NDA discussion of possible pharmaco­dynamic effects related to LVH.
>
> A recent review summarized the non-hemodynamic actions of angiotensin
> II (AII). (Williams 2001) AII may induce cell growth leading to LVH
> and vascular remodeling. AII induces fibrosis in both the
> cardiovascular and renal systems. AII predisposes to endothelial
> dysfunction and atherosclerosis and contributes to the formation and
> instability of atherosclerotic plaques. These effects appear to be
> mediated via the AII AT~1~-receptor subtype. In contrast, there appear
> to be beneficial effects of stimulation of the AII AT~2~ receptor to
> offset these pathologic effects, such as vasodilation and inhibition
> of fibrosis.
>
> Although lowering of blood pressure produces a beneficial effect on
> LVH, meta-analyses
>
> of clinical trials have indicated that ACE inhibitors decrease LVH to
> a greater extent than other agents. (Dahlof, Pennert et al. 1992;
> Schmieder, Martus et al. 1996) A recent review suggests that
> angiotensin II antagonists, with the major one studied being losartan,
> have a similar effect upon LVH. (Dahlof 2001) A recent study compared
> losartan to atenolol for effects upon LVH. (Dahlof, Zanchetti et al.
> 2002) In this study 225 hypertensive patients with increased
> echocardiographically determined LVH at baseline found a significant
> reduction in LVH after 36 weeks in the losartan group, which was
> numerically greater than and significantly non-inferior to the
> atenolol group.
>
> COMMENT: While speculations about a possible mechanism of action are
> interesting, LIFE is not designed to differentiate whether event rates
> related to reduction in LVH are independent of other effects of the
> two drugs.

## IV. Description of Clinical Data and Sources 

### Overall Data

The reviewer relied predominantly upon the data sets and case report
forms from the LIFE study provided with this supplemental submission for
NDA 20-386, Serial 032, dated July 25, 2002. In response to questions
from this reviewer and other FDA reviewers the sponsor provided
additional information in submissions dated October 22 and 28 and
November 8, 13, 14, 18, 21, and 22, 2002. The reviewer incorporated the
data from all of these submissions into this review.

The sponsor originally submitted the protocol and the data analysis plan
for the LIFE study to IND 33,383. The sponsor provided copies of these
submissions in this NDA supplement. The reviewer did not consult the
original submissions for these documents or for other information in the
original IND or NDA. For background information the reviewer relied upon
the information provided in the approved labeling for losartan and for
atenolol and the literature reviews described below.

### Tables Listing the Clinical Trials

The LIFE study is the only trial submitted to support the new
indication.

### Postmarketing Experience

The sponsor provided a report from its Worldwide Adverse Experience
System database on spontaneous reports of adverse events of patients on
Cozaar ≥ 55 years of age with cardiac or left ventricular hypertrophy.
From September 2, 1994, through March 31, 2002, 56 reports were
identified. The reports cover a wide range of conditions without any
evident pattern.

### D. Literature Review

The sponsor provided a literature review of published nonclinical
pharmacologic effects of losartan in animal models of left ventricular
hypertrophy, injury or dysfunction from 1993 to the present and
background references for the rationale for the study, including the
selection of the comparator. The reviewer performed Medline searches
focusing on the efficacy of atenolol and other beta blockers in
hypertension, left ventricular hypertrophy as a cardiovascular risk
factor, and the electrocardiographic determination of LVH. The reviewer
incorporated the results of these Medline searches into the appropriate
sections of this review.

## V. Clinical Review Methods

### A. How the Review was Conducted

The reviewer relied predominantly upon the data sets and case report
forms from the LIFE study provided with this NDA submission. The
reviewer analyzed the raw data for this study provided in the NDA's
electronic case tabulations. The reviewer duplicated the sponsor's
primary analyses from the raw data as well as performed other pertinent
analyses not presented by the sponsor. The reviewer confirmed that the
sponsor's analyses corresponded to the data in the electronic case
tabulations.

### B. Overview of Materials Consulted in Review

> As stated above, the reviewer relied predominantly upon the electronic
> data sets and case report forms provided with this NDA submission.

### C. Overview of Methods Used to Evaluate Data Quality and Integrity

The Division of Scientific Investigations did not perform any field
audits for this supplemental NDA. One reason for not performing audits
is that this study involved a large number of sites with the
contribution of any one site being small.

To evaluate data quality the reviewer checked all case report forms for
endpoints for which the Endpoint Classification Committee disagreed with
the investigator (with an endpoint date difference of more than 30 days)
and random samples of other case report forms. The reviewer verified
that the data in the electronic data sets correspond to the data on the
case report forms. The reviewer also re-analyzed the results based on
his reclassification of endpoints. (The results for these reviewer
reclassifications are presented in the Efficacy section.) The reviewer
confirmed that the sponsor's analyses corresponded to the data in the
electronic case tabulations and case report forms.

### D. Were Trials Conducted in Accordance with Accepted Ethical Standards

The LIFE study appears to have been conducted in accordance with
accepted ethical standards. Institutional review boards (for US sites)
or independent ethics committees reviewed and approved the protocol.
Investigators obtained informed consent from the participants and were
bound by the Declaration of Helsinki. The overall design of the study,
comparing two active drugs without proved advantages and including a
diuretic and other investigator-selected antihypertensives to facilitate
blood pressure control, is an ethically acceptable design. Monitoring
for patient safety, with an unblinded Data Safety and Monitoring Board,
was good.

### E. Evaluation of Financial Disclosure

This study involved a large number of investigators and
subinvestigators. The sponsor's tabulation of their financial interest
disclosures is shown in the table below. Please see the secondary
medical review for an analysis of these disclosures. The large number of
investigators and the use of a blinded Endpoint Classification Committee
help protect the study results from prejudicial influence by any one
investigator.

![](media/image1.png){width="4.708333333333333in" height="4.59375in"}

##  

## VI. Integrated Review of Efficacy 

### A. Brief Statement of Conclusions

The reviewer concludes that the LIFE study shows that antihypertensive
regimens including losartan are superior to ones including atenolol for
reducing a composite endpoint of deaths, strokes, and myocardial
infarctions in hypertensive patients with left ventricular hypertrophy.
The reviewer does not conclude that this finding is robust. However,
because the magnitude of the treatment effect (a 10% risk reduction) is
reasonable and the endpoint is vital, the reviewer believes that a
description of the beneficial effect of losartan in the LIFE study
should be included in the losartan label.

Some analyses of the LIFE study suggest a qualitative interaction, i.e.,
a reversal of the beneficial effect of losartan, in blacks. The reviewer
concludes that blacks were a subgroup with different baseline
characteristics and different responses than the rest of the study
population. The results of the LIFE study suggest that losartan is not
superior to atenolol in blacks. The evidence from the LIFE study is not
conclusive for establishing that losartan is inferior to atenolol in
blacks.

The reviewer also notes the following findings not described by the
sponsor in its summaries of the LIFE study:

-   Atenolol uses appears to be associated with increased rates of
    atrial fibrillation and strokes.

-   Losartan appears to be more effective in the elderly. Losartan may
    be less effective in males younger than 65.

### B. General Approach to Review of the Efficacy of the Drug

Support for the proposed new indication is provided by the LIFE study
alone. Hence the review of the efficacy depends upon the review of the
LIFE study. There is one major question and several related minor
questions that are of prime interest. The major question is whether the
LIFE study alone is robust enough to support a new indication. The minor
questions are whether the indication should be qualified for various
subgroups. The sponsor has discussed qualifying the indication for
blacks. The reviewer also notes possible differential impacts in
patients with or at risk for atrial fibrillation and in patients with
isolated systolic hypertension.

### C. Detailed Review of the LIFE Study

The protocol for the LIFE study was entitled "A Triple-Blind, Parallel
Study to Investigate the Effect of Losartan Versus Atenolol on the
Reduction of Morbidity and Mortality in Hypertensive Patients With Left
Ventricular Hypertrophy" and numbered "133/COZ368/925." The protocol
number was 133 in the US and 925 in Europe and Iceland. The primary
objective was to evaluate the long-term effects (4 years) of losartan
compared to atenolol in hypertensive patients with documented left
ventricular hypertrophy (LVH) on the combined endpoint of cardiovascular
mortality, myocardial infarction, and stroke.

#### 1. Sites and Investigators

Nine hundred forty-five sites randomized 9,193 patients (4,605 losartan,
4,588 atenolol) in Denmark, Finland, Iceland, Norway, Sweden, the United
Kingdom (UK), and the United States (US). One site (925-964)
contributing 29 patients was disqualified by the sponsor in September
1997 because of issues concerning Good Clinical Practice (GCP)
noncompliance. Its data are excluded. Another site was closed in
December 2001 based on the suspension of the primary investigator's
licenses. For this latter site there was no issue regarding data
reliability, so the two patients from it are included in the analyses.
The distributions of patients by country are shown in the table below.

Table 2: Reviewer's Patients by Country

  -------------- -------------- --------------- --------- -------- -----------
  **Country**    **Atenolol**   **Losartan**    **N**     **%**    **Sites**

  Denmark        699            692             1391      15.1     89

  Finland        737            748             1485      16.2     106

  Iceland        68             65              133       1.5      8

  Norway         701            714             1415      15.4     142

  Sweden         1133           1112            2245      24.4     199

  US             838            869             1707      18.6     294

  UK             412            405             817       8.9      107

  All            4588           4605            9193      100      945
  -------------- -------------- --------------- --------- -------- -----------

The average site contributed only a small number of patients to the
study (median 7, interquartile range 3 to 11). Treatment groups were
very well balanced at sites. The Scandinavian sites contributed more
patients on the average than the US and UK sites. The ten largest sites
(n = 62 to 148) were all in Scandinavia except for one UK site with 85
patients.

#### 2. Background

#### 2.1. Initial Protocol

The initial protocol under which the study was conducted in the US was
Protocol Number 133-00/COZ 368, dated June 9, 1995. The earliest version
provided in the NDA of Protocol 925, the protocol used in Europe, is
Protocol 925-0A, dated March 19, 1995. In a letter dated November 13,
2002, the sponsor gives the following description of the differences in
the protocols: "The variations between the two sets of documents were
the result of the two authoring groups having different writing styles.
There were multiple amendments for each protocol, but summarily the
studies were similar. Although, the regulatory requirements regarding
clinical subjects and investigational supplies vary as they are based on
local regulations, the Study Designs both in table form and text are
identical in content. The Hypothesis, Objectives, Inclusion and
Exclusion Criteria were similar for each study, with one exception.
Protocol 133 included 'Pregnancy' as an exclusion criteria; it was not
noted on Protocol 925 as it may have been regarded as self-event with
the lower age of entry at 55 years of age. The Efficacy and Safety
sections of the studies were also similar." The reviewer did not
identify any significant differences between the two protocols.

#### 2.2. Protocol Amendments

> The following are the amendments to Protocol 133 included in the NDA:

-   Protocol Amendment 133-01, dated March 29, 1996, changed the LVH
    criteria to include a Sokolow-Lyon \>38 mm LVH criterion and
    modified the female adjustment for the Cornell Product LVH criterion
    from +8 to +6, specified that hydrochloro­thiazide could be titrated
    to 25 mg or more, allowed the addition of other open-label
    antihypertensive for down titrations due to AEs, removed endpoint
    classification procedures from the protocol, and made miscellaneous
    other administrative changes.

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-   Protocol Amendment 133-02, dated May 23, 1996, added an
    echocardiogram substudy of left ventricular mass for 30 selected
    centers.

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-   Protocol Amendment 133-05, dated July 2, 1996, added an
    African-American echocardiogram substudy of left ventricular mass,
    oversampling Blacks in the echo substudy and adding three additional
    centers.

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-   Protocol Amendment 133-0A, dated May 5, 1998, provided for a 25 mg
    dose of study drug to investigators who request it on a
    patient-by-patient basis.

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-   Protocol Amendment 133-0C, dated December 15, 2000, provided for
    echo acquisition yearly after year 4, if applicable, and for
    termination of the echo substudy prior to the termination of the
    overall LIFE study.

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-   Protocol Amendment 133-0D, dated December 15, 2000, provided for
    echo acquisition yearly after year 4 in the African-American
    substudy, if applicable, and for termination of the echo substudy
    prior to the termination of the overall LIFE study.

> The following are the amendments to Protocol 925 included in the NDA:

-   Protocol 925-0A, dated March 19, 1995 and the earliest version
    provided in the NDA, did not include Lyon criteria for LVH and
    described two primary endpoints (the combined stroke, myocardial
    infarction, and cardiovascular mortality composite and
    cardiovascular mortality alone.)

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-   Protocol 925-0B, dated May 22, 1995, specified the primary composite
    endpoint alone.

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-   Protocol 925-0B, dated June 19, 1995 (the protocol version in effect
    for the first randomized patients) made miscellaneous wording
    changes to the version dated May 22, 1995.

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-   Protocol 925-0C, dated June 9, 1995 (in error), made additional
    miscellaneous wording changes to the version dated June 19, 1995.

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-   Protocol 925-0C, dated March 29, 1996, amended the protocol like the
    Protocol Amendment 133-01 above.

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-   Protocol amendment 925-0D, dated May 5, 1998, provided for a 25 mg
    dose of study drug to investigators who request it on a
    patient-by-patient basis.

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-   Protocol Amendment 925-0F, dated December 15, 2000, provided for
    echo acquisition yearly after year 4, if applicable, and for
    termination of the echo substudy prior to the termination of the
    overall LIFE study.

> The final data analysis plan was not specified in the original
> protocol. A Data Analysis Plan (DAP) was finalized in November 2001
> and submitted on November 16, 2001 (Serial 971) prior to unblinding of
> study data but after completion of the interim analyses.
>
> 2.3. Study Dates
>
> Patients were started on treatment between June 25, 1995 (August 10,
> 1995 in the US), and May 2, 1997, with follow-up continuing to
> November 15, 2001. The endpoint cutoff date is September 16, 2001.

#### 3. Study Design

> LIFE was a randomized, double blind, double dummy, active controlled,
> parallel group study. The study drug was losartan and the active
> control was atenolol. The sponsor refers to the study as triple-blind
> because of blinding of patients, investigators, and evaluators
> (Endpoint Classification Committee).
>
> After a 2-week placebo-run-in period (10 to 28 days were allowed),
> there was a minimum 4-year period of active triple-blind treatment.
> Treatment for the first enrollees continued beyond year four until
> 1040 patients experienced a primary cardiovascular event. Clinic
> visits were made each week during the placebo baseline period.
> Patients who were eligible were randomized in a 1:1 ratio to either
> losartan or atenolol. During the triple-blind treatment period,
> patients were seen at the clinic at the end of months 1, 2, 4, and 6,
> and at year 1, and thereafter at 6-month intervals. At each visit,
> trough sitting blood pressure and heart rate were measured and the
> occurrences of adverse experiences and endpoints were assessed.
>
> The study design is diagrammed in the figure below. Following it is a
> table listing the schedule of observations. The screening and safety
> laboratory tests were hemoglobin, creatinine, ALT, glucose, uric acid,
> sodium, potassium, cholesterol, HDL cholesterol, urine
> microalbuminuria, and urine creatinine. The schedule of observations
> table below indicates when these tests or a subset of them were done.
> One central lab was used for US patients and a second one in Sweden
> for Scandinavian and UK patients. Östra University Hospital ECG Core
> Center, Göteborg, Sweden, analyzed all screening and protocol-required
> ECGs.

![](media/image2.png){width="5.998611111111111in" height="3.33125in"}

![](media/image3.png){width="6.05in" height="1.75625in"}

![](media/image4.png){width="6.0in" height="1.3819444444444444in"}

#### 3.1. Objectives

> The primary objective was to evaluate the long-term effects (≥ 4
> years) of losartan compared to atenolol in hypertensive patients with
> documented LVH on the combination of cardiovascular mortality and
> morbidity. Cardiovascular mortality was defined as death due to fatal
> MI, fatal stroke, sudden death, progressive heart failure, other
> cardiovascular deaths. Cardiovascular morbidity was defined as
> nonfatal MI, excluding silent MI, and nonfatal stroke.
>
> Secondary objectives were to compare the long-term effects of losartan
> with atenolol on

-   cardiovascular mortality

-   total mortality

-   fatal and nonfatal myocardial infarction

-   fatal and nonfatal stroke

-   angina pectoris requiring hospitalization

-   regression of LVH, as measured by ECG

-   the relationship between regression of LVH (ECG-LVH) and
    cardiovascular mortality and morbidity (defined as primary endpoint)

-   the incidence of coronary or peripheral revascularization procedures

-   the incidence of silent myocardial infarction as evaluated from
    serial readings of annual ECGs

-   safety and tolerability based upon adverse experience profile and
    incidence of discontinuations due to adverse events

Tertiary objectives were

-   to evaluate the relationship between blood pressure control and
    cardiovascular morbidity and mortality

-   to assess the influence of various risk factors on cardiovascular
    event rate, including microalbuminuria, smoking, age, gender, level
    of systolic and diastolic blood pressure at randomization, total
    serum cholesterol, HDL cholesterol, and diabetes mellitus

-   to evaluate the long-term effects of losartan versus atenolol on
    new-onset diabetes mellitus (WHO criteria)

COMMENT: The Division had suggested to the sponsor to use total
mortality rather than cardiovascular mortality in the composite endpoint
in a meeting on September 21, 1995, but the trial's Steering Committee
rejected the suggestion. The primary endpoint from the original protocol
is used for the primary efficacy analysis of the NDA. Note that the
effects of losartan vs. atenolol on new-onset diabetes by WHO criteria
was a tertiary endpoint in the original protocol.

#### 3.2. Number of Subjects, Randomization, and Blinding

> The study was sized to attain 1,040 primary endpoints. To achieve this
> number of endpoints the sponsor estimated that 8,300 patients were
> needed. The investigators ultimately assessed 10,779 patients and
> randomized 9,222. The sponsor excluded from all analyses 29 patients
> belonging to one site due to serious GCP compliance issues at that
> site in September 1997. The sponsor used the data from the remaining
> 9,193 patients for efficacy and safety analyses.
>
> The sponsor's statisticians created computerized allocation schedules
> separately for each participating country, with a statistical block
> size of four. The sponsor's agents packaged study drug and matching
> placebo in a blinded fashion and identified by allocation number. The
> agents shipped blocks of study drug (in multiples of four) to each
> site. Investigators assigned eligible patients the next available
> allocation number. There was no patient stratification at the sites.
>
> The sponsor provided study drug in a double-dummy format to maintain
> blinding of patients and investigators. The Endpoint Classification
> Committee was blinded but the Data Safety and Monitoring Board (DSMB)
> was not. The only individual of the sponsor's organization who was
> unblinded was the statistician designated to perform interim analyses
> for the DSMB. The statistician was instructed not to release unblinded
> information to the sponsor.

#### 3.3. Inclusion and Exclusion Criteria

> The inclusion criteria were the following:

1.  male or female aged 55 to 80 years

2.  previously untreated or treated hypertension

3.  a qualifying ECG (taken up to 30 days prior to Visit 1) with
    interpretation of LVH confirmed by the ECG Core Center before
    randomization

4.  trough sitting blood pressure measurement requirements per the table
    below

![](media/image5.png){width="4.625in" height="1.90625in"}

> LVH was confirmed by ECG interpreted at the core lab before
> randomization. The Cornell voltage-duration product was calculated as
> the QRS duration in msec times the sum of R~aVL~ and S~V3~ in mm plus
> 8 mm in women and was interpreted as LVH if \> 2,440 mm\*msec. An
> amendment date March 29, 1996, changed the adjustment in women to 6 mm
> and added a Sokolow-Lyon criterion of S~V1~ + R~V5\ or\ V6~ \> 38 mm
> (36 mm is usual, but 38 mm was used to achieve greater specificity.)
> The partition value has approximately 45% sensitivity in men and 25%
> sensitivity in women compared to echocardiographic LV mass using
> partition values of 125 g/m^2^ in men and 110 g/m^2^ in women.

Patients were excluded from entering the study if they had any of the
following conditions or histories:

1.  known secondary hypertension of any etiology (e.g., uncorrected
    renal artery stenosis), malignant hypertension, or hypertensive
    encephalopathy

2.  increased diastolic BP \>115 or systolic BP \>200 mm Hg during the
    placebo period

3.  a history of stroke or myocardial infarction within 6 months prior
    to study start

4.  angina pectoris requiring treatment with a beta-blocker or a calcium
    antagonist

5.  presence of heart failure or known left ventricular ejection
    fraction ≤40%

6.  a history of renal or hepatic disorders with severe impairment of
    function (serum creatinine \>160 µmol/L or 1.8 mg/dL) or patient
    with solitary kidney or renal transplant

7.  significant known aortic stenosis (known mean antegrade Doppler
    gradient ≥ 20 mm Hg)

8.  known hypersensitivity or contraindication to losartan, atenolol, or
    hydrochlorothiazide

9.  a condition that, in the treating physician\'s opinion, required
    treatment with atenolol or another beta-blocker, hydrochlorothiazide
    or another diuretic, losartan or another angiotensin II-receptor
    antagonist, or angiotensin-converting enzyme inhibitors (e.g.,
    patient requiring beta-blockers for angina)

10. other serious disease expected to cause a substantial deterioration
    of the patient's health during the next 4-6 years

11. patient currently abusing or having a recent history of alcohol or
    other drug substance abuse

12. mentally or legally incapacitated patient

13. patient participating, or has been participating during the last 30
    days, in another investigational drug or device trial using a
    non-approved drug or device (A patient may participate in a study
    using marketed drugs or devices provided they do not interfere with
    the study or are otherwise excluded by the study protocol.)

14. patients with a low compliance at the end of the placebo period, as
    judged by the investigator

15. patient unwilling to participate

16. pregnancy

#### 3.4. Dosage and Administration

> Starting dosages were 50 mg for both losartan and atenolol. Medication
> was given in a double dummy fashion, i.e., losartan with atenolol
> placebo or atenolol with losartan placebo. Study medication was to be
> taken once daily orally at the same time each day, preferably in the
> morning. It was not to be taken on the morning of any clinic visit.

#### 3.5. Duration and Adjustment of Therapy

> Study medication was taken for the duration of the study, up to six
> years for the first enrollees. The mean duration of follow-up from
> randomization through death or
>
> September 16, 2001, was 4.8 years.

Dosages and additional open-label antihypertensives were adjusted as
follows: Blood pressure was measured at trough, i.e., 22-26 hours after
the last dose (and time since last dose was recorded.) Target BP was
defined as sitting trough BP \<140/90 mm Hg. If the patient's BP was not
within target, additional anti-hypertensives were added or dosage was
increased to 100 mg according to the table below. The types of
additional anti-hypertensives were left to the discretion of the
investigators other than ACEIs, ARBs, and beta-blockers were not
permitted.

![](media/image6.png){width="5.625in" height="2.076388888888889in"}

> At month 6 and later throughout the study, HCTZ could be increased to
> 25 mg or more or other antihypertensive therapy could be added to
> study drug at the discretion of the investigator. If the blood
> pressure was ≥ 160/95 mm Hg, it was mandatory to try additional
> medication.
>
> When necessary, back-titration was performed in reverse order of the
> initial titration of the study test medication. However, if the
> back-titration was due to adverse experiences thought to be related to
> losartan 100 mg or atenolol 100 mg, the dosage of HCTZ could be
> increased or other additional antihypertensive medication added to
> losartan 50 mg or atenolol 50 mg in order to reach the target blood
> pressure. Open-label ACEIs, ARBs, or beta-blockers were not allowed as
> chronic therapy. In May 1998 a protocol amendment provided for the
> usage of a 25-mg dose of losartan or atenolol. This dosage was
> intended for use by patients who otherwise would have been
> discontinued from blinded study drug therapy by the investigator.
> Investigators were required to contact the Medical Monitor for
> approval to use this study drug dose, prior to prescribing.

The selection of an appropriate post study antihypertensive regimen was
at the discretion of the investigator. Since there was a 50% chance that
the blinded study medication was atenolol, a beta-blocker, and sudden
termination of long-term treatment with this medication could possibly
induce a rebound phenomenon in some patients, consisting of an
uncontrolled rise in blood pressure and/or heart rate, the Steering
Committee made an allowance for the tapering or down-titration of study
drug therapy over a 1- to 2-week period after the investigator performed
and recorded final protocol-required measurements.

#### 3.6. Safety and Efficacy Endpoints 

The primary endpoint was the composite of cardiovascular mortality,
myocardial infarction (MI), and stroke. The main section of the protocol
does not describe how the investigators were to monitor for these three
endpoint events. It defines briefly each event as follows:

-   myocardial infarction -- acute, recognized MI or recent MI by
    autopsy

-   stroke -- non-hemorrhagic, hemorrhagic, embolic, or stroke of
    uncertain etiology

-   death from coronary heart disease -- sudden death within 1 hour or
    24 hours, non-sudden death due to coronary heart disease, or death
    resulting from coronary revascularization

-   other cardiovascular death -- death due to stroke, aortic aneurysm,
    peripheral vascular disease or revascularization procedure, or heart
    failure

> Appendix III of the protocol expands the definitions as follows:

-   acute, recognized MI -- two out of three of serial ECG changes,
    consistent chest pain or discomfort, and elevated cardiac enzymes

-   stroke -- a neurologic deficit lasting 24 hours or more with one or
    more of depression of state of consciousness, disturbance of vision,
    paresis or paralysis of one or more extremities, sensory impairment,
    speech impairment, cranial nerve dysfunction, memory defect, ataxia,
    or movement disorder

> An amendment dated March 29, 1996, clarified the definition of MI for
> the primary endpoint to include MIs interrupted by cardiac
> revascularization and to exclude probable MIs and MIs associated with
> a non-cardiac procedure.
>
> A blinded Endpoint Classification Committee (ECC) adjudicated primary
> endpoints using an Endpoint Classification Committee Manual. This
> manual was submitted to the FDA on August 12, 1996 (Serial 578) and a
> revised version was submitted on May 6, 1999 (Serial 807). The
> Division had suggested to the sponsor to use total mortality rather
> than cardiovascular mortality in the composite endpoint in a meeting
> on September 21, 1995, but the trial's Steering Committee rejected the
> suggestion.
>
> The ECC consisted of two experienced clinicians. Each evaluated the
> endpoints initially working from endpoint worksheets, endpoint
> narratives, and reports of electrocardiograms (ECG) coded to the
> Minnesota code by the central ECG lab. They requested additional
> information if they believed it was needed to classify an endpoint.
> They resolved differences in their initial readings at face-to-face
> meetings.
>
> The ECC classified other secondary endpoints including total
> mortality, angina pectoris requiring hospitalization, heart failure
> requiring hospitalization, coronary or peripheral arterial
> revascularization procedures, and resuscitated cardiac arrest. They
> did not evaluate silent MI, regression of LVH as assessed by ECG,
> relationship between regression of LVH and cardiovascular morbidity
> and mortality, relationship between blood pressure control and
> cardiovascular morbidity and mortality, relationship between risk
> factors and cardiovascular event rate, and incidence of new-onset
> diabetes mellitus.
>
> Safety endpoints included adverse experiences, vital signs (other than
> blood pressure), and laboratory values. These were reported while the
> patient was on study drug or within 14 days of the last dose of study
> therapy. Exclusions for safety were applied after permanent study drug
> discontinuation as well as during gaps in study therapy \> 14 days.
>
> Two major articles regarding this study (the main results and a
> subgroup analysis of diabetics) were published in *The Lancet* in
> March 2002. The data, other than classified endpoints, included in the
> NDA are from the final CRF data set that was finalized after the
> submission of these publications. There are slight differences in the
> NDA reports of non-endpoint data from those in the published
> manuscripts (i.e., disease history counts, the number of patients with
> new-onset diabetes mellitus, and counts of prespecified adverse
> experiences of special interest).
>
> COMMENT: One weakness of this study is that there is no protocol
> requiring tests to be done to verify the occurrence of any of the
> components of the primary endpoint. This weakness is difficult and
> expensive to correct. The endpoints can occur at home or at hospitals
> other than the ones frequented by the investigators. The investigators
> do not have control over these environments. Hence all of the data
> needed for the primary endpoint determinations were not collected in a
> standardized fashion and even limited data may have been difficult to
> obtain or unobtainable in some cases.
>
> The sponsor attempted to provide standardization of the endpoints by
> using a blinded Endpoint Classification Committee. The process used
> for this committee was reasonable and should help to avoid bias and
> reduce variation. However, it cannot compensate for the unavailability
> of data. The components of the primary endpoint cannot be completely
> objectively determined. The reviewer's analyses in the Efficacy
> section explore the variability in the components from the
> investigator's, committee's, and reviewer's perspectives and the
> effects of different endpoint classifications upon the results.
>
> Another weakness of the study, now obvious in retrospect, is that the
> case report forms did not specify a rating of the severity of stroke.
> The one factor collected related to the severity of a stroke was
> whether the duration of the neurologic deficit was more than 24 hours
> or until death. Because differences in stroke rates are the major
> differences encountered between the two treatment arms, it would be
> illuminating to know whether there were differences in stroke severity
> between the two arms.

#### 3.7. Statistical Considerations

#### 3.7.1. Sample Size Calculations

> The sample size calculation for this trial was based on the combined
> incidence of cardiovascular morbidity and mortality. It assumed that
> the 5-year event rate in the atenolol group would be 15%, and that
> this rate would be reduced by 15%, to 12.75%, in the losartan group.
> The predicted event rate in the atenolol group was based on Framingham
> data, which show that the 5-year cardiovascular event rate in
> 65-year-old patients with systolic hypertension and left ventricular
> hypertrophy, but no other significant evidence of heart disease, is
> \~17% among men and 12% among women. The patient population in this
> trial was expected to be 2/3 male and have a mean age of 65 years,
> resulting in an estimated cardiovascular event rate of \~15%.
>
> Based on these assumptions, in order to have 80% power at the 5%
> (two-sided) significance level, the trial should proceed until a total
> of 1,040 patients experience one or more primary cardiovascular
> events. The study's sample size of 8,300 patients was chosen in an
> attempt to achieve the required 1,040 patients with an event at
> approximately the same time that the final patient reached four years
> of follow-up. The method used to calculate sample size was based on
> the log-rank test.

#### 3.7.2. Analysis Cohorts and Missing Data

> The efficacy analysis was based on the intention-to-treat principle.
> That is, all randomized patients were to be included in all analyses,
> regardless of any protocol violations or discontinuation of study
> medication. The one appropriate exception to this strict principle was
> the exclusion in September 1997 of 29 patients from a site with GCP
> noncompliance. All randomized patients (N = 9,193) were included in
> the efficacy and safety analyses.
>
> A goal for this study was to obtain complete endpoint follow-up on all
> randomized patients. However, as expected, some follow-up was
> unavailable. Two approaches were used for different types of missing
> endpoint data: (1) If the patient's survival status was known, but
> other endpoint data were unknown beginning at some date prior to death
> or final study termination, then the patient was counted as if full
> follow-up were available through death or study termination and no
> nonfatal endpoints had occurred. For endpoints other than mortality
> (all-cause or cause-specific) or the primary composite, the patient
> was censored at the date of the last known follow-up. (2) If the
> patients' survival status and other endpoint data were both unknown
> beginning at some date prior to final study termination, then the
> patient was counted as censored at the last known follow-up date for
> all endpoint analyses.
>
> Missing data for baseline covariates (Cornell voltage duration product
> and S-L voltage as measured at the Visit 3 ECG and baseline data used
> to calculate the patient's Framingham risk score) were interpolated by
> using the median value among all patients with non-missing data. These
> values were calculated from the pooled treatment groups. Missing data
> for other variables, such as blood pressure, pulse, weight, and
> laboratory measurements, were not interpolated, and patients with
> missing data were excluded from all relevant analyses.

#### 3.7.3. Pre-specified Analyses

> The primary efficacy analysis proposed was a Cox regression survival
> analysis comparing the two treatment groups with respect to the time
> to the first clinical endpoint. The analysis pre-specified covariates
> for degree of LVH (Cornell voltage duration product and Sokolow-Lyon
> voltage on the baseline ECG) and a Framingham risk score.
>
> The two interim analyses for the DSMB used O'Brien-Fleming boundaries
> with critical p-values of 0.0004 and 0.013. To maintain the overall
> significance level at 0.05, the significance level for the primary
> analysis was adjusted to a two-sided **α** of 0.046.
>
> The same Cox regression approach was proposed for all secondary and
> tertiary time-to-event endpoints. Safety analyses were to be
> tabulations of adverse experiences, reasons for discontinuing study
> follow-up and reasons for study drug discontinuation, mean changes in
> laboratory variables, changes outside predefined limits for selected
> laboratory variables, and tabulation of concomitant medications.

#### 4. Results

#### 4.1. Study Implementation

#### 4.1.1. Disposition of Subjects

> A total of 10,779 patients were assessed for eligibility for the LIFE
> study and 9,222
>
> were randomized. Twenty-nine patients belonging to one center were
> excluded
>
> from all analyses due to serious GCP compliance issues at the
> treatment center in
>
> September 1997. Therefore, data from the remaining 9,193 patients were
> used for efficacy and safety analyses. The dispositions of these
> patients are listed in the table below.

![](media/image7.png){width="5.9in" height="3.984722222222222in"}

Overall, significantly more patients discontinued study drug in the
atenolol group than in the losartan group. More patients in the atenolol
group discontinued study therapy due to an adverse experience.

COMMENT: The rate of completed follow-up (99%) is good. The number of
patients lost to follow-up (12, or about 0.1%) is excellent, but the
number of patients without vital status information due to withdrawal of
consent (78, or about 0.8%) is problematic.

One category in the figure above that needs further explanation is the
category "Other administrative reason". The reviewer examined the text
fields in the NDA data files provided by the investigators explaining
the reasons for discontinuation. The category "Other administrative
reasons" includes patient unwilling to continue therapy (common) or
unable to continue therapy because of residence moves or other reasons.
Note that this category is fairly evenly distributed between the two
groups.

Accounting for patients who discontinued study medication also requires
some explanation. Patients may have discontinued and restarted study
medication more than one time. The investigators may also have reported
more than one reason for discontinuing study medication, i.e., both an
adverse event and an endpoint. The timing of discontinuation may also be
close, i.e., within days, of death or other endpoint. For some
statistics the sponsor did not count discontinuations occurring within
14 days of death or other endpoint as discontinuations. Depending upon
how these various circumstances are counted the statistics for
discontinuations of study medications vary moderately.

4.1.2. Subject Demographics and Baseline Characteristics

#### 4.1.2.1. Overall Baseline Comparisons

The sponsor's summary of baseline demographics is shown in the following
table.

COMMENT: The reviewer confirmed that the summary demographic statistics
in the table above matched the data in the NDA data files. The baseline
demographic characteristics are very evenly distributed between the two
treatment groups. Basic demographics are virtually identical in the two
groups: the mean ages were 66.9 and the median age 67, 54% were female,
and 92.5% were white.

![](media/image8.png){width="5.246527777777778in"
height="7.2444444444444445in"}

> The baseline vital signs were also very similar in the two groups, as
> shown in the following table:

![](media/image9.png){width="6.0in" height="6.0784722222222225in"}

The baseline ECG indices for left ventricular hypertrophy, Framingham
risk scores, and lab test results were fairly evenly distributed between
the two treatment groups, as shown in the following two tables.

![](media/image10.png){width="5.990972222222222in"
height="3.422222222222222in"}

![](media/image11.png){width="6.0in" height="3.5965277777777778in"}

In addition to the baseline demographics, vital signs, ECG measurement,
Framingham risk scores, and lab test result compared in the figures
above, the sponsor also analyzed baseline disease histories, time since
most recent MI or stroke, and prior therapies. Pertinent results from
these analyses are shown in the following table.

> Table 8: Reviewer's Selected Other Baseline Comparisons

  ------------------------------------ ----------------- ----------------
                                       **Losartan**      **Atenolol**

  No tobacco                           50.8%             50.5%

  No alcohol                           45.8%             46.0%

  No exercise                          22.2%             21.7%

  Angina                               10.7%             9.3%

  Prior MI                             6.7%              5.7%

  Months since MI                      84                90

  Prior stroke                         4.1%              4.6%

  Months since stroke                  44                40

  Diabetes                             12.7%             13.3%

  Hypercholesterolemia                 16.1%             17.2%

  Prior ACEI                           20.2%             20.4%

  Prior BB                             26.4%             25.5%

  Prior aspirin                        34.2%             34.1%

  Prior statin                         6.2%              6.2%
  ------------------------------------ ----------------- ----------------

COMMENT: All baseline characteristics appear to be very well balanced
between the two treatment groups. The baseline characteristics reported
are comprehensive. There do not appear to be any observed baseline
imbalances that would explain the observed differences in outcomes. The
contributions of any of the slight differences in observed baseline
factors to the outcome differences should be small.

#### 4.1.2.2. Baseline Comparisons by Country

> LIFE was a multinational study. The FDA is most interested in the
> applicability of the results to the US population. In other studies of
> cardiovascular treatments differences in results by country have been
> observed. Hence differences in the patient populations and in the
> results by country are pertinent.
>
> Baseline demographic and behavioral characteristics are shown by
> country in the following table. Note the US patients include a
> slightly higher percentage of males and lower alcohol use and exercise
> rates.
>
> Table 9: Reviewer's Baseline Demographic Characteristics by Country

  ---------------------------------------------------------------------------------------------------
  **Country**   **Group**   **N**   **Median     **Male**   **Smoker**   **Alcohol**   **Exercise**
                                    Age**                                              
  ------------- ----------- ------- ------------ ---------- ------------ ------------- --------------
  Denmark       Atenolol    699     67           46.1%      29.8%        73.5%         72.4%

                Losartan    692     67           47.7%      26.4%        75.0%         74.4%

  Finland       Atenolol    737     64           47.8%      11.1%        57.8%         91.2%

                Losartan    748     64           44.9%      9.6%         56.7%         91.6%

  Iceland       Atenolol    68      70           55.9%      8.8%         58.8%         77.9%

                Losartan    65      69           63.1%      16.9%        56.9%         72.3%

  Norway        Atenolol    701     69           42.5%      16.7%        46.5%         75.0%

                Losartan    714     69           43.6%      20.3%        47.5%         72.0%

  Sweden        Atenolol    1133    69           45.3%      12.5%        53.0%         85.8%

                Losartan    1112    69           44.5%      10.3%        52.7%         86.3%

  US            Atenolol    838     66           48.4%      17.8%        34.0%         66.9%

                Losartan    869     67           50.7%      15.9%        37.2%         66.1%

  UK            Atenolol    412     67           44.4%      16.7%        69.7%         73.3%

                Losartan    405     67           40.5%      16.5%        66.7%         70.6%

  All                       9193    67           46.0%      16.4%        54.1%         78.0%
  ---------------------------------------------------------------------------------------------------

Selected baseline risk factors by country are shown in the following
table. Note that the US median BMI is slightly greater than the overall
median and the US median SBP is slightly less. Otherwise these risk
factors are very similar in all countries except for lower age and
Framingham risk score in Finland. In particular the Cornell voltage
duration products, the Sokolow-Lyon voltages, and Framingham risk
scores, the three risk factors pre-specified as covariates for the
primary efficacy analysis, are very similar in all countries (except for
Framingham risk score in Finland) despite the differences in outcome
rates.

> Table 10: Reviewer's Selected Baseline Risk Factor Medians by Country

  -------------------------------------------------------------------------------------------------------------
  **Country**   **Group**   **BMI**   **SBP**   **DBP**   **Cornell**   **S-L**   **Cholesterol**   **Risk
                                                                                                    Score**
  ------------- ----------- --------- --------- --------- ------------- --------- ----------------- -----------
  Denmark       Atenolol    27.0      178       100       26.5          29.0      6.1               20.9

                Losartan    27.5      177       100       26.0          29.0      6.1               20.9

  Finland       Atenolol    27.2      173       99        26.5          30.5      5.9               18.1

                Losartan    27.7      171       98        26.4          30.0      6.0               18.0

  Iceland       Atenolol    27.3      169.5     98.5      26.9          25.0      5.9               25.3

                Losartan    27.8      170       100       26.7          25.5      6.1               26.6

  Norway        Atenolol    26.5      174       98        26.7          29.0      6.4               22.0

                Losartan    26.5      173       98        26.7          29.0      6.4               21.6

  Sweden        Atenolol    27.6      175       98        27.1          28.5      6.0               22.2

                Losartan    27.4      174       98        27.6          28.3      6.0               21.4

  US            Atenolol    28.3      170       97        26.5          29.5      5.4               22.1

                Losartan    28.2      170       97        26.7          29.5      5.5               22.4

  UK            Atenolol    27.4      176       99        26.7          26.0      5.9               21.9

                Losartan    27.4      178       100       26.7          27.0      5.9               20.4

  All                       27.4      174       98        26.7          29.0      6.0               21.0
  -------------------------------------------------------------------------------------------------------------

> BMI = body mass index; SBP = systolic blood pressure; DBP = diastolic
> blood pressure
>
> Cornell = Cornell voltage duration product; S-L = Sokolow-Lyon
> voltage;
>
> Risk Score = Framingham risk score

Selected baseline disease histories by country are shown in the
following table. Note that the US patients have higher rates for all
diseases.

> Table 11: Reviewer's Baseline Disease Histories by Country

  ------------------------------------------------------------------------------------------
  **Country**   **Group**   **Angina**   **MI**   **Heart        **Stroke**   **Diabetes**
                                                  Failure**                   
  ------------- ----------- ------------ -------- -------------- ------------ --------------
  Denmark       Atenolol    7.2%         4.3%     1.7%           5.6%         8.2%

                Losartan    7.9%         6.6%     1.2%           5.5%         10.8%

  Finland       Atenolol    4.6%         1.5%     0.4%           3.7%         10.4%

                Losartan    4.3%         1.9%     1.1%           1.9%         9.6%

  Iceland       Atenolol    13.2%        2.9%     0.0%           5.9%         13.2%

                Losartan    12.3%        7.7%     1.5%           3.1%         7.7%

  Norway        Atenolol    6.8%         6.3%     1.0%           3.3%         10.8%

                Losartan    9.8%         7.0%     0.7%           3.9%         8.7%

  Sweden        Atenolol    11.9%        4.6%     1.1%           4.3%         14.2%

                Losartan    12.5%        6.1%     1.1%           3.2%         15.6%

  US            Atenolol    14.6%        12.3%    5.1%           7.2%         23.0%

                Losartan    18.3%        11.7%    5.3%           6.2%         19.8%

  UK            Atenolol    6.8%         4.9%     1.0%           1.9%         8.7%

                Losartan    7.2%         4.9%     1.0%           4.7%         6.7%

  All                       10.0%        6.2%     1.8%           4.4%         13.0%
  ------------------------------------------------------------------------------------------

> MI = myocardial infarction

Selected prior drug therapies are shown in the following table. Note the
greater use of ACEIs, aspirin, and statins in the US. Iceland also shows
a different pattern of drug use, although the numbers in Iceland are
relatively small. Finnish patients appear to have lower rates of prior
cardiac disease.

> Table 12: Reviewer's Selected Prior Drug Therapies by Country

  ------------- ------------ ---------- --------- --------- --------- ------------
  **Country**   **Group**    **ACEI**   **ARB**   **BB**    **ASA**   **Statin**

  Denmark       Atenolol     20.7%      6.3%      17.6%     33.2%     2.1%

                Losartan     21.2%      6.6%      19.5%     27.7%     2.3%

  Finland       Atenolol     19.9%      0.4%      24.8%     27.8%     4.3%

                Losartan     17.0%      0.1%      26.6%     28.6%     3.5%

  Iceland       Atenolol     35.3%      1.5%      44.1%     7.4%      1.5%

                Losartan     35.4%      0.0%      35.4%     16.9%     1.5%

  Norway        Atenolol     21.7%      6.6%      21.4%     18.4%     6.8%

                Losartan     21.0%      6.7%      22.7%     16.9%     7.1%

  Sweden        Atenolol     14.7%      2.5%      33.5%     36.5%     4.9%

                Losartan     15.1%      1.9%      36.0%     35.8%     4.4%

  US            Atenolol     35.2%      7.3%      24.1%     49.5%     14.3%

                Losartan     34.5%      6.0%      26.5%     52.9%     15.1%

  UK            Atenolol     17.0%      1.5%      37.4%     39.3%     3.4%

                Losartan     20.2%      1.2%      32.3%     40.0%     2.7%

  All                        21.7%      3.9%      27.2%     33.9%     6.2%
  ------------- ------------ ---------- --------- --------- --------- ------------

> ACEI = ACE inhibitor; ARB = angiotensin receptor blocker;
>
> BB = beta blocker; ASA = aspirin

COMMENT: For the risk factors pre-specified by the sponsor for the
primary analysis the US patients are very similar to the Scandinavian
patients. However, for other risk factors (increased BMI and prior
ischemic heart disease, stroke, and diabetes) the US patients are worse
than the Scandinavian while baseline blood pressures were lower in the
US patients. However, note that all risk factors and baseline
characteristics are reasonably evenly distributed between the two
treatment groups, overall and by country.

#### 4.1.2.3. Baseline Comparisons by Race

> The FDA requires that differences in efficacy and safety be examined
> by age, gender, and race. The outcomes in LIFE appear to vary by race,
> so it is instructive to examine whether baseline characteristics
> differ by race. In LIFE the races with substantial representations
> were whites and blacks. Because only 2% of blacks were non-US and
> because the US study population appears to differ overall from the
> Scandinavian, the following baseline comparisons of blacks and
> non-blacks include US cases compared to the non-US cases. The
> following four tables by race show the same baseline factors as the
> preceding four tables by country.
>
> Table 13: Reviewer's Baseline Demographic and Behavioral
> Characteristics by Race

  ------------ ------------ ------------ ---------- ------------ ------------- --------------
               **N**        **Median     **Male**   **Smoker**   **Alcohol**   **Exercise**
                            Age**                                              

  US non-black 1184         68           48%        13%          37%           70%

  US black     523          64           54%        25%          33%           59%

  Non-US       7486         67           45%        16%          58%           81%
  ------------ ------------ ------------ ---------- ------------ ------------- --------------

> Table 14: Reviewer's Selected Baseline Risk Factor Medians by Race

  -------------- --------- --------- --------- ------------- --------- ----------------- ------------
                 **BMI**   **SBP**   **DBP**   **Cornell**   **S-L**   **Cholesterol**   **Risk
                                                                                         Score**

  US non-black   28.1      170       96        27            28        5.5               22.5

  US black       28.5      171       98        25.5          35        5.4               21.7

  Non-US         27.2      175       99        26.7          29        6.1               20.7
  -------------- --------- --------- --------- ------------- --------- ----------------- ------------

> BMI = body mass index; SBP = systolic blood pressure; DBP = diastolic
> blood pressure
>
> Cornell = Cornell voltage duration product; S-L = Sokolow-Lyon
> voltage;
>
> Risk Score = Framingham risk score
>
> Table 15: Reviewer's Baseline Disease Histories by Race

  ---------------- ------------ -------- ---------------- ------------ --------------
                   **Angina**   **MI**   **Heart          **Stroke**   **Diabetes**
                                         Failure**                     

  US non-black     18%          6%       14%              6%           20%

  US black         12%          4%       8%               9%           25%

  Non-US           9%           1%       5%               4%           11%
  ---------------- ------------ -------- ---------------- ------------ --------------

> Table 16: Reviewer's Selected Prior Drug Therapies by Race

  ------------------- ---------- --------- ---------- ---------- ------------
                      **ACEI**   **ARB**   **BB**     **ASA**    **Statin**

  US non-black        36%        7%        27%        54%        17%

  US black            31%        5%        21%        44%        9%

  Non-US              19%        3%        28%        30%        4%
  ------------------- ---------- --------- ---------- ---------- ------------

> ACEI = ACE inhibitor; ARB = angiotensin receptor blocker;
>
> BB = beta blocker; ASA = aspirin
>
> COMMENT: The preceding four tables confirm that there are significant
> differences among the three subgroups in baseline characteristics.
> Blacks are younger and heavier, more likely to be male and smokers,
> and less likely to use alcohol and to exercise. They have higher
> Sokolow-Lyon voltage but lower Cornell voltage duration products. They
> are intermediate between US non-blacks and non-US cases for heart
> disease and the selected CV drugs (except beta blockers, for which
> they have the lowest use) but have histories of more strokes and
> diabetes. US non-blacks are differentiated from non-US cases by lower
> blood pressures, lower smoking, alcohol use, and exercise rates, a
> slightly higher BMI, the highest rates of cardiac disease, higher use
> of ACEIs, ARBs, aspirin, and statins, and intermediate rates of stroke
> and diabetes.
>
> The baseline differences among the three subgroups raises the question
> of whether the three subgroups are best lumped together for the
> efficacy and safety analyses. Differences in safety and efficacy in
> these subgroups are explored in the reviewer's analyses in Section
> 4.2.

#### 4.1.3. Conduct

The sponsor's description of some features of the trial conduct is as
follows: "Numerous procedures were undertaken to ensure the study was
conducted according to Good Clinical Practices guidelines. All
investigators received an instruction manual, 'Guide to LIFE'. Study
start-up and subsequent yearly investigators' meetings were conducted to
ensure proper understanding of the protocol and all data collection
procedures. Periodic newsletters were utilized to disseminate and
reinforce important study administrative and procedural instructions."
The sponsor also employed a blinded Endpoints Classification Committee
to provide unbiased assessments of endpoints, two central labs (one in
the US and one in Europe) to insure consistency and accuracy of lab
results, and an unblinded Data Safety and Monitoring Board to insure
patient safety.

COMMENT: All of these measures help to ensure study integrity.

#### 4.1.3.1. Monitoring

The sponsor's description of the trial monitoring is as follows:
"Regular site monitoring was conducted by the SPONSOR to verify protocol
adherence and compare the accuracy of the study data against source
documentation. A data review plan was prepared and utilized by the
SPONSOR, and all data were reviewed through the use of computer and
manual queries. A random selection of both US and international
investigative sites was audited by the SPONSOR for compliance to ICH/GCP
guidelines and the SPONSOR's own internal standard operating procedures.
All authors reviewed this Clinical Study Report for accuracy and
scientific content."

Note that one site's data were dropped because of GCP noncompliance and
another site was closed, but its two cases retained, because of loss of
the investigator's medical license. The sponsor audited 48 sites at
random and did not identify any problems.

#### 4.1.3.2. Protocol Changes and Violations

Minor changes were made to the protocol during the course of the study:

-   Protocol Amendment 133-01, dated March 29, 1996, altered the LVH
    criteria for entry into the study. It lowered the correction factor
    for the calculation of Cornell product in women to 6 mm based on
    data published after the start of the study and introduced a second
    acceptance criterion based on the Sokolow-Lyon voltage combination
    (SV1 + RV5 or V6) \> 38 mm irrespective of gender, in order to
    increase the sensitivity of detecting ECG-LVH without loss of
    specificity. These changes took effect on May 1, 1996, at which time
    2,375 patients (1,453 women) had been enrolled.

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-   Resuscitated cardiac arrest was added as a secondary endpoint
    proposed by the Endpoint Classification Committee and approved by
    the Steering Committee on March 29, 1996.

-   Protocol Amendment 133-0A, dated May 5, 1998, provided for a 25 mg
    dose of study drug to investigators who request it on a
    patient-by-patient basis.

Protocol violations were infrequent: Thirty-two patients did not meet
LVH criteria by screening ECG, 20 patients did not have a qualifying
measurement, either SBP or DBP, at either of last 2 visits before study
start, 2 patients experienced a MI or stroke within 4 months prior to
study start, and 152 patients took prohibited medications during the
baseline period. See the Dosing section below for statistics on patients
taking prohibited medications during the study period.

Fifty-eight patients were unblinded prematurely. Ten patients (10065,
10591, 40463, 60717, 60841, 60028, 30169, 30355, 31470, and 30848)
continued on study drug therapy after unblinding.

#### 4.1.3.3. Dosing

#### 4.1.3.3.1. Study Drug

The mean dose for losartan was 74.4 mg and for atenolol was 71.4 mg.
Losartan-treated patients received study drug for 84% of study follow-up
compared to 79% for atenolol-treated patients. The study drug dosages at
the final visit are shown in the following table.

![](media/image12.png){width="5.875in" height="2.470138888888889in"}

At the final visit 2773 (60%) patients in the losartan treatment group
and 2569 (56%) patients in the atenolol group received
hydrochlorothiazide (HCTZ) as a study drug. The mean dose was \~20 mg in
each treatment group and the distribution of doses was similar between
the two treatment groups. These statistics on HCTZ use do not include
other open-label, non-study drug use of HCTZ.

#### 4.1.3.3.2. Concomitant Therapy

The sponsor tabulated concomitant therapy in the two groups by drug
class. Use of noncardiovascular drugs was very similar between the two
groups. Use of cardiovascular drugs is shown in the table below.

![](media/image13.png){width="5.990972222222222in"
height="4.486111111111111in"}

The reviewer also examined aspirin, other antiplatelet drug, and statin
use. Aspirin and other antiplatelet drug use were similar in the two
groups, e.g., for aspirin, 34.0% in the atenolol group and 33.8% in the
losartan group. Statin use was slightly higher in the atenolol group
(24.0% vs 21.9%).

COMMENT: Note that angiotensin II antagonists or ACE inhibitors were
taken by 178 (3.9%) patients on study drug in the losartan group and 195
(4.3%) in the atenolol group. Beta blockers were taken by 368 (8.0%) and
288 (6.3%) patients in the losartan and atenolol groups, respectively.
These differences are small, but they do suggest that blinding of the
study therapies was not perfect. Blinding of two agents with well known
and slightly different side effect profiles, e.g., reduction in heart
rate with a beta blocker, is difficult.

#### 4.1.3.4. Blinding

The study drug was dispensed in double dummy fashion to hide the
identity of the active drug for each patient. For emergency use each
site was given sealed envelopes with the drug identities by allocation
number. If a site broke the blind, the sponsor monitor was to be
notified as soon as possible or, if possible, prior to the unblinding.
The rates and results of premature unblinding are discussed above under
Protocol Changes and Violations.

The Endpoint Classification Committee was also blinded. The DSMB was
unblinded as was the one sponsor statistician who performed the two
interim analyses for the DSMB. The statistician was instructed not to
reveal any study findings prematurely to other sponsor staff.

COMMENT: The methodology for blinding is as sophisticated as is
practical for a trial of this size. There is slight evidence that the
blinding may have been partially broken in the field, i.e., the
differential use of open-label beta blockers noted in the previous
section. There is no consistent evidence that endpoint determination was
unblinded as discussed in the Efficacy section below.

#### 4.2. Efficacy

#### 4.2.1. Sponsor's Primary Endpoint

The sponsor's primary endpoint for the study is the composite of
cardiovascular mortality, myocardial infarction, and stroke. All three
components were adjudicated by the blinded Endpoint Classification
Committee. The pre-specified analysis for this primary endpoint was a
time-to-event analysis using a Cox proportional hazards regression with
degree of lefty ventricular hypertrophy (Cornell voltage duration
product and Sokolow-Lyon voltage on the baseline ECG) and Framingham
risk score as covariates.

The primary composite endpoint occurred in 508 patients in the losartan
group (23.8 per 1000 patient-years of follow-up) and in 588 patients in
the atenolol group (27.9 per 1000 patient-years of follow-up). The
hazard ratio (HR) was 0.869 (95% CI 0.772 to 0.979, p=0.021) for the
primary analysis including adjustment for baseline measures of LVH and
Framingham risk score as covariates. The unadjusted HR was 0.854 (95% CI
0.759 to 0.962, p=0.009). The Kaplan-Meier plot of the primary composite
endpoint is shown in the following figure.

![](media/image14.png){width="4.916666666666667in" height="3.21875in"}

The categorization of the event types of the primary composite endpoint
is shown in the following table.

> Table 19: Reviewer's Endpoint Types of Primary Composite Endpoint

+-------------------+------------------------+------------------------+
| **Type**          | **Atenolol**           | **Losartan**           |
|                   |                        |                        |
|                   | **N (%)**              | **N (%)**              |
+-------------------+------------------------+------------------------+
| CV death          | 154 (3.4)              | 137 (3.0)              |
+-------------------+------------------------+------------------------+
| MI                | 168 (3.7)              | 174 (3.8)              |
+-------------------+------------------------+------------------------+
| Stroke            | 266 (5.8)              | 197 (4.3)              |
+-------------------+------------------------+------------------------+

As can be seen in the table, myocardial infarction (MI) and
cardiovascular (CV) death primary endpoints were similar in the two
groups, with slightly more CV deaths in the atenolol group and scarcely
more MIs in the losartan group. The dominant factor in the composite
endpoint is the substantially greater stroke rate in the atenolol group
compared to the losartan group.

These differences are also seen in the Kaplan-Meier curves for the
separate components of the composite endpoint shown in the following
figure. Note that the figure differs from the previous table in that the
figure includes all first events of the designated types while in the
table includes only the first occurrence of any type of primary endpoint
event.

![](media/image15.png){width="5.197916666666667in" height="7.28125in"}

The reviewer's analyses of the data files in the NDA agree with the
sponsor's Kaplan-Meier curves and p values given in the preceding
figures. See the FDA statistician's review for additional comments on
the statistical methodology.

COMMENT: For the sponsor's primary composite endpoint losartan shows a
favorable effect with a relative risk reduction of about 13%. The
statistical significance of this effect is not extreme, i.e., p = 0.021.
Regarding the components of the primary composite endpoint the relative
risk reduction in strokes is impressive, about 25%. The differences in
the other two components are small and not statistically significant.
There is a slight, statistically insignificant difference favoring
atenolol in the rates of MIs while there is a trend towards lower
cardiovascular mortality with losartan.

All three components of the sponsor's primary composite endpoint have a
degree of softness or uncertainty in ascertainment. Because of this
softness and also because of its overall importance, the Division had
suggested to the sponsor that total mortality, rather than
cardiovascular mortality, be used in the primary composite endpoint. The
important issue of total mortality will be examined next. The other
issue that will be examined is the robustness of the results, i.e., how
much can a different interpretation of some of the endpoint events
affect the results?

#### 4.2.2. Total Mortality

Four hundred thirty one (9.4%) patients in the atenolol group died and
383 (8.3%) in the losartan group died. A Kaplan-Meier plot of the total
mortality curves is shown in the figure below.

![](media/image16.wmf){width="4.252777777777778in"
height="2.911111111111111in"}

There appears to be a trend towards improved survival in the losartan
group that does not quite achieve statistical significance by the
log-rank test (p = 0.076). Using the sponsor's Cox proportional hazards
model with baseline LVH and Framingham risk score as covariates the
statistical significance is reduced (p = 0.13).

COMMENT: Total mortality does not differ significantly between the two
groups. The effect of including total mortality rather than
cardiovascular mortality in the primary composite endpoint, the
Division's recommendation, is explored in a later section.

#### 4.2.3. Robustness of Primary Endpoint to Event Reclassification

All three components of the primary composite endpoint are subject to
interpretation. One example of differences in interpretation is the
difference in initial assessments by the Endpoint Classification
Committee (ECC). The ECC reviewed 4,365 cases. The two ECC members
agreed on the initial assessment for 3,567 cases (82%).

Another example of differences in interpretation of the primary endpoint
is the difference between the investigators' reporting of primary
endpoint events and the ECC's adjudication of them. Investigators
reported primary endpoints in 1,227 cases while the ECC classified 1,096
cases as meeting the pre-specified primary endpoint criteria, including
12 cases reported by investigators as angina that the ECC reclassified
as definite myocardial infarctions (MIs). The investigators' and the
ECC's classification of whether a primary endpoint occurred differ in
211 cases, the endpoint day differs in 244 cases, and either the day or
the endpoint occurrence differ in 314 cases, or about 29% of the
adjudicated endpoints. Of these 314 cases 55% were in the atenolol group
and 45% were in the losartan group. These differences probably
overestimate the variation in endpoint interpretation because
investigators should have reported endpoints that they considered
uncertain so that real endpoints were not missed.

To characterize better the variability of endpoint classification the
reviewer checked endpoints against the case report forms (CRFs). For
these checks the reviewer did not reference the cases' treatment groups.
The reviewer's primary focus for these checks was upon the cases for
which there are differences between the investigator's and the ECC's
endpoint classifications. The reviewer also examined random samples of
other cases.

For 20 randomly selected cases without an adjudicated primary endpoint
the NDA included CRFs for nine. The reviewer confirmed that the CRFs
lacked evidence of primary endpoints for all nine. Two cases had
secondary angina endpoints that the reviewer confirmed did not meet the
criteria for a MI.

For 40 randomly selected cases with an adjudicated primary endpoint but
without an investigator-committee difference the NDA included CRFs for
all 40. The reviewer confirmed that the CRFs contained acceptable
evidence of the primary endpoints for all 40 cases.

Of the 314 cases with investigator-committee endpoint differences, 73
cases represent endpoint day differences of 30 days or less. The
reviewer did not check these 73 cases systematically because of the low
impact of any changes. The reviewer checked CRFs for the other 241
cases.

Of the 211 cases for which the committee disagreed with the investigator
regarding the occurrence of any primary endpoint event, 58 cases
represent differences in classification of deaths as cardiovascular (CV)
deaths, or about 18% of adjudicated CV deaths. The reviewer agreed with
the committee for 28 cases, disagreed with the committee for 9 cases,
and judged the decision to be difficult based on available data in 21
cases. The reviewer's best estimate agreed with the committee's
assessment in 76% of cases.

> Of the 12 cases for which the committee adjudicated a primary endpoint
> and the investigator did not report one, all were adjudicated as
> definite myocardial infarctions (MIs). The reviewer disagreed with the
> committee for 6 cases, agreed for 3 cases, and judged the decision to
> be difficult for 3 cases. The reviewer's best estimate agreed with the
> committee's assessment in 33% of cases. Ten of the 12 cases were in
> the atenolol group. The reviewer classified 6 of these cases as not
> definite MIs and both losartan cases as not definite MIs.

The committee did not adjudicate any primary endpoint strokes not
reported by the investigators as strokes. The committee adjudicated five
secondary stroke endpoints (four in atenolol patients and 1 in a
losartan patient) not reported by the investigators as stroke endpoints.
In all but one of the cases the CRFs had supporting data regarding the
stroke (three on the death report and the other on a second CT scan
during a hospitalization for an earlier stroke.)

Of the 141 cases other than deaths for which the investigator reported a
primary endpoint but the committee did not confirm it, the reviewer
agree with the committee in 53 cases, disagreed in 72 cases, and judged
the decision to be difficult in 16. The reviewer's best estimate agreed
with the committee's assessment in 47% of cases.

For the 26 cases in which the investigator's endpoint day was earlier
than the adjudicated endpoint day, the reviewer's best estimate agreed
with the committee's assessment in 31% of the cases. For the four cases
in which the investigator's endpoint day was later than the adjudicated
endpoint day, the reviewer's best estimate agreed with the committee's
assessment in 75% of the cases.

The problematic events for classification had some similarities. For
MIs, investigators not uncommonly reported chest pain events with enzyme
rises less than twofold as MIs. For strokes, investigators not
uncommonly reported cerebral ischemic events of less than 24 hours
duration as strokes. For deaths, all classifiers had difficulty with
classifying deaths of unknown cause with no information about the time
course of events leading to death.

Overall for these 241 cases checked the reviewer agreed with the
committee's assessment in 48% of the cases. The direction of the
Endpoint Classification Committee's changes for these cases was
completely neutral, with 120 changes favoring atenolol and 121 changes
favoring losartan.

The different classifications of endpoint events have small effects upon
the primary endpoint results. The effects of the different endpoint
analyses upon the sponsor's primary composite endpoint analyses are
shown in the following table.

> Table 20: Reviewer's Comparison of Different Primary Endpoint Event
> Classifications

  ----------------------- ------------------ -------------- ----------------
                          **Endpoint Event                  
                          Classifier**                      

                          **Investigator**   **Reviewer**   **Committee**

  Atenolol events         651                619            588

  Losartan events         576                538            508

  Log rank p              0.02               0.01           0.009

  Cox regression\* p      0.039              0.023          0.021
  ----------------------- ------------------ -------------- ----------------

COMMENT: While each component of the sponsor's primary composite
endpoint is subject to interpretation in some cases, the Endpoint
Classification Committee's assessment of events appears to have been
conducted in a unbiased manner. Reclassification of problematic events,
whether by the reviewer or by the Endpoint Classification Committee,
produces similar results for the sponsor's primary composite endpoint.

#### 4.2.4. Primary Endpoint Including Total Mortality

The Division recommended that total mortality, rather than
cardiovascular mortality, be incorporated into the primary composite
endpoint. While the trial coordinating committee and the sponsor
rejected this recommendation, it is informative to examine the results
of including total mortality in the primary composite endpoint. There
were 814 deaths during the study of which 376 were classified as
non-cardiovascular deaths. The results of including total mortality in
the primary composite endpoint are shown in the following table.

> Table 21: Reviewer's Primary Composite Endpoint Results Incorporating
> Total Mortality

  --------------------------------------------------------------------------
                          **Endpoint Event                  
                          Classifier**                      
  ----------------------- ------------------ -------------- ----------------
                          **Investigator**   **Reviewer**   **Committee**

  Atenolol events         808                780            751

  Losartan events         730                701            670

  Log rank p              0.027              0.023          0.018

  Cox regression\* p      0.056              0.051          0.039
  --------------------------------------------------------------------------

COMMENT: Not surprisingly incorporating total mortality reduces the
statistical significance of the results. The results with endpoints
adjudicated by the Endpoint Classification Committee retain statistical
significance but the results with endpoints classified by the reviewer
fail to achieve statistical significance for the Cox regression.

#### 4.2.5. Composite Endpoints For Patients on Study Drug

The sponsor's pre-specified primary endpoint analysis and all of the
analyses presented previously follow a strict, as randomized,
intention-to-treat principle. For example, a stroke endpoint on day one
for a patient randomized to atenolol but occurring before the patient
received atenolol is included in the previous analyses. An alternative
analysis is to censor patients who discontinue treatment for other than
a primary endpoint occurrence. In all 3,484 patients (1,859 atenolol,
1,625 losartan) discontinued study drug at least once, and 440 patients
discontinued study drug more than once. The analyses below censor
patients at the times of their last study drug discontinuations if the
discontinuations were not for primary endpoints. Because of variations
in the reporting of dates and to capture events immediately following
drug discontinuation, study drug discontinuations dated within 30 days
prior to a primary endpoint event are not counted as discontinuations.
The results for all of the primary endpoint variations presented
previously are shown in the following two tables.

> Table 22: Reviewer's Composite Endpoint Results on Study Drug

  ----------------------- ------------------ -------------- ----------------
                          **Endpoint Event                  
                          Classifier**                      

                          **Investigator**   **Reviewer**   **Committee**

  Atenolol events         482                450            418

  Losartan events         440                413            378

  Log rank p              0.033              0.047          0.033

  Cox regression\* p      0.052              0.073          0.055
  ----------------------- ------------------ -------------- ----------------

> Table 23: Reviewer's Composite Endpoint with Total Mortality Results
> on Study Drug

  ----------------------- ------------------ -------------- ----------------
                          **Endpoint Event                  
                          Classifier**                      

                          **Investigator**   **Reviewer**   **Committee**

  Atenolol events         546                519            492

  Losartan events         512                489            453

  Log rank p              0.063              0.080          0.039

  Cox regression\* p      0.097              0.12           0.064
  ----------------------- ------------------ -------------- ----------------

The sponsor performed a per protocol analysis that excluded patients
with important protocol violations and censored patients 14 days after
permanently discontinuing study medications or 14 days after starting
prohibited therapy. The results are similar to the above and are
presented in the table below.

![](media/image17.png){width="5.9847222222222225in" height="1.425in"}

COMMENT: Note that 170 (29%) atenolol and 130 losartan primary
committee-adjudicated events occurred more than 30 days after
discontinuation of study drug. The statistical significance of all
results is reduced by this alternative analysis.

The intention-to-treat analysis is the preferred analysis. The
interpretation of the on drug or per protocol analysis is difficult
because of the potential for informative censoring. The ideal is to have
no or minimal drug discontinuations or protocol violations such that all
analyses are identical. For LIFE that ideal was not achieved.

#### 4.2.6. Blood Pressure Reduction in Relationship to the Primary Endpoint

One potential confounder is difference in blood pressure control between
the two treatment groups. The NDA summarizes well the differences in
mean blood pressures (BP) between the two groups. The figure below
graphs the BP over time and is followed by a table containing the
values.

![](media/image18.png){width="4.6in" height="3.6256944444444446in"}

![](media/image19.png){width="5.995833333333334in" height="6.99375in"}

The sponsor's summary of these mean changes is reasonable: "In general,
systolic blood pressure tended to be slightly lower in the losartan
group while diastolic pressure tended to be slightly lower in the
atenolol group, resulting in consistently lower mean pulse pressure
values in the losartan group. At Year 4, mean systolic blood pressure
was 144.9 in the losartan group and 146.4 in the atenolol group
(p=0.003), while mean diastolic pressure was similar in the 2 groups
(81.8 versus 81.5, NS). Year 4 mean pulse pressure was lower in the
losartan group (63.2 versus 64.9, p\<0.001)."

The mean changes in BP and heart rate (HR) at the primary endpoint or at
the end of follow-up are shown in the following table.

> Table 26: Sponsor's Last Vital Signs Using Primary Endpoint Censoring
> Rule

  --------------------- --------------- --------------- ------------------
                        **Atenolol**    **Losartan**    **Difference**

  **SBP**               145.4           144.1           1.3

  **DBP**               80.9            81.3            -0.4

  **PP**                64.5            62.8            1.7

  **SBP change**        -29.1           -30.2           1.1

  **DBP change**        -16.8           -16.6           -0.2

  **PP change**         -12.4           -13.6           1.2

  **SBP SD**            17.2            16.4            0.8

  **DBP SD**            9.5             9.6             -0.1

  **HR**                66              72.1            -6.1

  **HR change**         -7.7            -1.8            -5.9
  --------------------- --------------- --------------- ------------------

The difference in SBP is statistically significant (p = 0.015). To
explore the effects of the differences in BP upon the endpoints the
sponsor incorporated SBP, DBP, and PP as time-varying covariates into
separate Cox regression models. The results of these analyses are shown
in the following tables.

![](media/image20.png){width="6.0in" height="2.6638888888888888in"}

![](media/image21.png){width="5.85in" height="2.6083333333333334in"}

![](media/image22.png){width="5.85in" height="2.4569444444444444in"}

The sponsor's summary of these analyses is the following: "Higher
systolic blood pressure was associated with a significant increase in
the risk of the primary composite endpoint, as well as an increase in
the risk of MI and stroke. The results were reversed for diastolic blood
pressure with a tendency for higher diastolic blood pressures to be
associated with a decrease in the risk of the primary composite endpoint
(NS, p=0.087) and higher diastolic pressure associated with a
significant decrease in the risk of cardiovascular mortality and MI.
There was no apparent relationship between diastolic pressure and the
risk of stroke. The results for pulse pressure were similar to those
observed for systolic pressure but with the additional tendency for
higher pulse pressure to be associated with an increase in
cardiovascular mortality (NS, p=0.078)."

Note that the sponsor's Cox regressions with time-varying covariates do
not include the baseline covariates of degree of LVH and Framingham risk
score. When the reviewer added these baseline covariates to the
sponsor's time-varying models, the statistical significance of the
treatment covariate is reduced slightly in the time-varying models
compared to the Cox models without the time-varying covariates. The
reviewer's results when SBP was included as a time-varying covariate are
shown in the table below.

> Table 30: Reviewer's Cox Regression Results for the Primary Composite
> Endpoint with SBP as a Time-Varying Covariate

  -------------------- ----------- --------------- ------------ -----------
  **Covariate**        **Hazard    **95%                        **p**
                       ratio**     Confidence**                 

                                   **Lower**       **Upper**    

  Treatment            0.87        0.78            0.98         0.027

  SBP                  1.004       1.001           1.008        0.012

  Cornell              1.012       1.01            1.02         \<0.001

  Sokolow-Lyon         1.016       1.01            1.022        \<0.001

  Framingham           1.049       1.043           1.055        \<0.001
  -------------------- ----------- --------------- ------------ -----------

The time-varying covariate with the strongest relationship to the
primary composite endpoint was not blood pressure but pulse. The results
for a Cox regression model including blood pressure and pulse as
time-varying covariates is shown in the table below.

> Table 31: Reviewer's Cox Regression Results for the Primary Composite
> Endpoint with S/DBP and Pulse as Time-Varying Covariates

  -------------------- ----------- --------------- ------------ -----------
  **Covariate**        **Hazard    **95%                        **p**
                       ratio**     Confidence**                 

                                   **Lower**       **Upper**    

  Treatment            0.78        0.69            0.88         \<0.001

  SBP                  1.004       1               1.008        0.04

  DBP                  1.001       0.99            1.007        0.86

  Pulse                1.018       1.013           1.023        \<0.001

  Cornell              1.012       1.007           1.017        \<0.001

  Sokolow-Lyon         1.017       1.011           1.023        \<0.001

  Framingham           1.05        1.04            1.06         \<0.001
  -------------------- ----------- --------------- ------------ -----------

COMMENT: A major limitation of these analyses is that the blood
pressures were recorded only at trough. It is interesting that pulse is
the most significant time-varying covariate, but one can only speculate
on possible explanations.

While the NDA summarizes well mean BP and attempts to relate the BP
levels to outcomes through these Cox regression analyses, it does not
otherwise attempt to relate levels of BP or degree of BP control to the
outcomes. The reviewer explored the relationship between BP and outcomes
further as follows.

Patients who suffered primary endpoints tended to have higher baseline
SBP than patients who did not. The mean baseline SBPs by primary
endpoint are shown in the following table.

> Table 32: Reviewer's Mean Baseline SBP by Primary Endpoint Category

  ------------------------ ---------------------- -----------------------
  **Endpoint**             **Atenolol**           **Losartan**

  None                     174.2                  174.0

  MI                       175.5                  176.5

  CV death                 175.3                  176.7

  Stroke                   178.4                  176.5
  ------------------------ ---------------------- -----------------------

Note that the mean baseline SBP is highest in patients treated with
atenolol who eventually had a primary stroke endpoint. The mean baseline
DBPs do not vary significantly by endpoint category. Mean baseline pulse
rates tend to be slightly higher in patients who suffered a CV death.

Baseline isolated systolic hypertension, defined as SBP ≥ 160 with DBP
\< 90, occurred more frequently in patients with primary endpoints
treated with atenolol than with losartan. The rates of baseline isolated
systolic hypertension are shown in the following table.

> Table 33: Reviewer's Rates of Baseline Isolated Systolic Hypertension
> by Endpoint Category

  ------------------------ ---------------------- -----------------------
  **Endpoint**             **Atenolol**           **Losartan**

  None                     14.1%                  14.3%

  MI                       19.0%                  15.5%

  CV death                 17.5%                  15.3%

  Stroke                   16.9%                  13.7%
  ------------------------ ---------------------- -----------------------

For the following analyses the reviewer examined mean SBPs recorded
prior to a primary endpoint event or the last recorded SBP for patients
without primary endpoint events. If the SBP prior to a primary endpoint
event was recorded within 30 days of the event, then the reviewer used
the previous SBP in order to avoid BP values that may have been
influenced by the event. The reviewer selected values that were recorded
between 22 and 26 hours after the last dose of study medication. For
brevity the reviewer refers to these SBPs as "at end".

Mean SBPs recorded at end were higher in patients with primary endpoints
than in those without them. The mean SBPs were consistently higher in
atenolol patients as shown in the following table.

> Table 34: Reviewer's Mean SBP at End

  -----------------------------------------------------------------------
  **Endpoint**               **Atenolol**          **Losartan**
  -------------------------- --------------------- ----------------------
  None                       146.3                 145.1

  MI                         155.4                 150.1

  CV death                   153.9                 151.6

  Stroke                     156.4                 152.1

  All patients               147.5                 145.8
  -----------------------------------------------------------------------

Investigators were to titrate patients to a target BP of \< 140/90. The
rates of patients achieving this goal at end are shown in the following
table.

> Table 35: Reviewer's Rates of Achieving Target BP \< 140/90 at End

  -------------------------- --------------------- ----------------------
  **Endpoint**               **Atenolol**          **Losartan**

  None                       34%                   38%

  MI                         21%                   25%

  CV death                   22%                   29%

  Stroke                     20%                   25%

  All patients               32%                   36%
  -------------------------- --------------------- ----------------------

Overall the rates of patients achieving the target BP were low. Blood
pressure control was poorer with atenolol than with losartan.

The rates of poor BP control varied. Rates of poor BP control, defined
as a SBP ≥ 160 or DBP ≥ 100, are shown in the following table.

> Table 36: Reviewer's Rates of Poor BP Control (SBP ≥ 160 or DBP ≥ 100)
> at End

  -------------------------- --------------------- ----------------------
  **Endpoint**               **Atenolol**          **Losartan**

  None                       21%                   19%

  MI                         35%                   32%

  CV death                   42%                   39%

  Stroke                     44%                   36%

  All patients               24%                   20%
  -------------------------- --------------------- ----------------------

For the vast majority (96 percent) of these patients SBP was poorly
controlled, i.e., SBP ≥ 160. Note that poor control was more common for
all endpoints. Poor control was more frequent with atenolol than with
losartan.

The changes in BP from baseline varied in a pattern similar to the
differences in absolute BP. Changes from baseline in SBP are shown in
the following table.

> Table 37: Reviewer's Mean Changes in SBP from Baseline to End

  -------------------------- --------------------- ----------------------
  **Endpoint**               **Atenolol**          **Losartan**

  None                       -27.9                 -28.9

  MI                         -20.0                 -25.5

  CV death                   -21.3                 -25.1

  Stroke                     -22.1                 -24.3

  All patients               -27.1                 -28.5
  -------------------------- --------------------- ----------------------

The reductions in SBP from baseline to prior to a primary endpoint were
less with atenolol than with losartan. A pertinent question is whether
the variations in BP reduction are related to differential study drug
usage. Study drug usage at the time of primary endpoint occurrence (in
patients with primary endpoints) or at last follow-up (in patients
without primary endpoints) is summarized in the following table.

> Table 38: Reviewer's Study Drug Usage

  ----------------- -------------- -------------- -------------- --------------
                    **Primary                     **No Primary   
                    Endpoint**                    Endpoint**     

                    **Atenolol**   **Losartan**   **Atenolol**   **Losartan**

  N                 588            508            4000           4097

  On primary drug   70%            74%            74%            78%

  Mean primary dose 52             55             59             65

  On HCTZ           48%            50%            57%            62%

  Mean HCTZ dose    9              9              11             12
  ----------------- -------------- -------------- -------------- --------------

Note that atenolol usage was slightly lower than losartan usage.
Hydrochlorothiazide use was higher in patients not suffering a primary
endpoint. Atenolol and hydrochloro­thiazide use was slightly higher for
patients with stroke primary endpoints compared to other endpoints.

Study drug usage varied by BP control and is shown in the following
table.

> Table 39: Reviewer's Study Drug Usage by BP Control at End

+-------------+--------+-------+--------+------+---------+---------+
|             | **Good |       | **Fair |      | **Poor  |         |
|             | Con    |       | Con    |      | Co      |         |
|             | trol** |       | trol** |      | ntrol** |         |
|             |        |       |        |      |         |         |
|             | **SB   |       |        |      | **      |         |
|             | P\<140 |       |        |      | SBP≥160 |         |
|             | &      |       |        |      | or      |         |
|             | DBP    |       |        |      | DB      |         |
|             | \<90** |       |        |      | P≥100** |         |
+-------------+--------+-------+--------+------+---------+---------+
|             | **Aten | **    | **Aten | **Lo | **Ate   | **Los   |
|             | olol** | Losar | olol** | sart | nolol** | artan** |
|             |        | tan** |        | an** |         |         |
+-------------+--------+-------+--------+------+---------+---------+
| N           | 1467   | 1671  | 2042   | 1995 | 1079    | 939     |
+-------------+--------+-------+--------+------+---------+---------+
| On primary  | 82%    | 85%   | 77%    | 81%  | 55%     | 59%     |
| drug        |        |       |        |      |         |         |
+-------------+--------+-------+--------+------+---------+---------+
| Mean        | 62     | 66    | 62     | 67   | 46      | 51      |
| primary     |        |       |        |      |         |         |
| dose        |        |       |        |      |         |         |
+-------------+--------+-------+--------+------+---------+---------+
| On HCTZ     | 60%    | 63%   | 60%    | 65%  | 42%     | 45%     |
+-------------+--------+-------+--------+------+---------+---------+
| Mean HCTZ   | 12     | 12    | 12     | 13   | 9       | 9       |
| dose        |        |       |        |      |         |         |
+-------------+--------+-------+--------+------+---------+---------+

Study drug usage was lowest in patients with poor control. It was
slightly higher with losartan than with atenolol for all levels of
control.

There are some interesting variations in dosing and BP control by
country. Levels of control by country are shown in the following table.

> Table 40: Reviewer's Levels of BP Control at End by Country

  ---------------------------- --------------- ------------ --------------
                               **Good**        **Fair**     **Poor**

  US white                     48%             33%          19%

  US black                     41%             37%          22%

  UK                           33%             41%          25%

  Scandinavia                  31%             47%          22%
  ---------------------------- --------------- ------------ --------------

BP control was better in the US compared to non-US. Note that mean
baseline BP levels were lower for US patients than non-US patients so
that mean reductions in BP from baseline are similar for all countries.
Primary study drug use was lower in the US than in other countries while
hydrochlorothiazide use was lower in US whites and intermediate in US
blacks and in the UK as shown in the following two tables.

> Table 41: Reviewer's Primary Study Drug Use at End by Country

  --------------------------- --------------------- ----------------------
                              **Atenolol**          **Losartan**

  US white                    63%                   68%

  US black                    65%                   70%

  UK                          67%                   74%

  Scandinavia                 77%                   81%
  --------------------------- --------------------- ----------------------

> Table 42: Reviewer's Study Hydrochlorothiazide Use at End by Country

  ------------------------------------------------------------------------
                              **Atenolol**          **Losartan**
  --------------------------- --------------------- ----------------------
  US white                    46%                   51%

  US black                    51%                   59%

  UK                          48%                   58%

  Scandinavia                 59%                   62%
  ------------------------------------------------------------------------

For patients on the primary study drug hydrochlorothiazide use was
highest in blacks. Hydrochlorothiazide use was higher in patients
treated with losartan than in patients treated with atenolol in the US
and the UK and comparable in the two groups in Scandinavia.

Endpoint rates were particularly high for patients with poor control as
shown in the following table.

> Table 43: Reviewer's Primary Endpoint Rates by Level of BP Control

  ----------------------------------------- -------------- ---------------
  **Control**                               **Atenolol**   **Losartan**

  Good (SBP\<140 & DBP\<90)                 8%             8%

  Fair                                      11%            10%

  Poor (SBP≥160 or DBP≥100)                 22%            19%
  ----------------------------------------- -------------- ---------------

If the blood pressure control distribution for losartan is used with the
atenolol endpoint rates by level of blood pressure control, then one
would estimate that 22 fewer primary endpoint events would have occurred
for atenolol. This reduction in events is sufficient to eliminate the
statistical significance of the difference in the endpoint rates between
the two groups (p = 0.008 by Fishers exact test for the observed rates,
p = 0.055 by Fishers exact test for the rates with 22 fewer atenolol
events).

COMMENT:

Blood pressure control was slightly poorer in the atenolol group than in
the losartan group. Study drug usage was also lower in the atenolol
group. The difference in study drug use appears to be comparable to the
difference in control. One can only speculate regarding the reasons for
lower study drug usage in the atenolol group. It could be related to
more side effects with atenolol, but the data are not available to prove
or disprove that speculation.

Worse control, particularly poor control, is associated with worse
outcomes. The difference in blood pressure control may account a
significant portion of the difference in endpoint rates. If the BP
control rates for atenolol were identical to those for losartan, then
the expected differences in endpoint rates would not be statistically
significant.

One major limitation of these observations regarding blood pressure
control is that they are based on blood pressure measurements at only
one point in time during the dosing interval, i.e., trough. It would be
very interesting to have BP measurements at other times during the
dosing interval.

#### 4.2.7. Stroke Endpoint Differences

Most of the difference in the primary composite endpoint is due to
strokes. Hence it is informative to examine differences in factors
associated with strokes. For these comparisons it is more appropriate to
consider all stroke events rather than strokes that happened to occur
first as a primary endpoint. The numbers of stroke primary endpoints,
adjudicated strokes, and patients with strokes are shown in the
following table.

> Table 44: Reviewer's Numbers of Stroke Endpoints, Strokes, and
> Patients with Strokes

  --------------------------------------- --------------- ----------------
                                          **Atenolol**    **Losartan**

  Primary stroke endpoint                 266             197

  Adjudicated strokes                     359             255

  Patients with strokes                   308             228

  \% of patients with strokes             6.7%            5.0%
  --------------------------------------- --------------- ----------------

As can be seen from the table, strokes were not infrequent in this
high-risk hypertensive population, occurring in about six percent of
subjects over the four-year follow-up. Multiple strokes also were not
rare.

Stroke rates increased with age, particularly with atenolol, as shown in
the following table. Strokes were slightly more frequent in females than
males in both groups, probably due to the older age of females in the
study.

> Table 45: Reviewer's Stroke Rates by Age

  ----------------------------------------- -------------- ---------------
  **Age**                                   **Atenolol**   **Losartan**

  \<65                                      3%             3%

  65-74                                     8%             5%

  ≥75                                       13%            9%
  ----------------------------------------- -------------- ---------------

The type of stroke is also worth examining. Embolic strokes,
particularly ones secondary to atrial fibrillation, may not be as
directly related to hypertension as ischemic strokes. The Endpoint
Classification Committee's (ECC's) classification of stroke types is
shown in the following table:

> Table 46: Reviewer's Endpoint Classification Committee's Type of
> Stroke by Treatment Group

  ---------- ---- -------------- ----------------- ----------------- ----------- -----------
                  **Ischemic**                     **Hemorrhagic**   **Other**   **Total**

                  **Embolic**    **Non-embolic**                                 

  Atenolol   N    52             269               34                4           359

             \%   14%            75%               9%                1%          100%

  Losartan   N    38             186               30                1           255

             \%   15%            73%               12%               0%          100%
  ---------- ---- -------------- ----------------- ----------------- ----------- -----------

Note that the distributions of the types of strokes are similar between
the two treatment groups even though the stroke rate is significantly
higher in the atenolol group. After reviewing case report forms of the
stroke endpoints, the reviewer believes that the ECC was conservative in
classifying strokes as embolic, e.g., the ECC classified strokes as
ischemic even though atrial fibrillation was documented. The reviewer
believes that this conservative classification tends to obscure
differences in the stroke types.

Classifying strokes as embolic or ischemic based on clinical history and
findings is frequently difficult. It is doubly difficult in this study
because of the limited information in the case report forms. As a
surrogate for embolic stroke the reviewer examined stroke rates in
patients with atrial fibrillation or flutter, reported either by
baseline history or as an adverse event. Rates of atrial fibrillation or
flutter are shown in the following table.

> Table 47: Reviewer's Rates of Atrial Fibrillation or Flutter

  ----------------------------- -------------------- --------------------
                                **Atenolol**         **Losartan**

  History                       4.0%                 3.5%

  Adverse event                 7.9%                 6.8%

  Either                        10.7%                9.4%
  ----------------------------- -------------------- --------------------

Atrial fibrillation was not uncommon in the study population. It was
slightly more frequent in atenolol patients. It was also more frequent
among US white patients (15.9%) and Danish and Swedish patients (11.1
and 12.1% respectively) and less frequent among the rest (e.g., US
blacks 6.7%).

Patients with evidence of atrial fibrillation were older (mean age 69.6
vs 66.6), more frequently male (53 vs. 45%), higher risk (mean
Framingham risk score 24.8 vs. 22.1), with more isolated systolic
hypertension (18.8 vs 13.9%), and had more frequent histories of stroke
(7.4 vs. 4.0%), myocardial infarction (9.3 vs. 5.8%), heart failure (6.1
vs. 1.3%), and diabetes (17.8 vs. 12.5%) than patients without evidence
of atrial fibrillation. These baseline factors were not different by
evidence of atrial fibrillation between the atenolol and losartan
groups.

Strokes occurred in about 15% of patients with a history or adverse
event of atrial fibrillation, about three times as frequent as in
patients without evidence of atrial fibrillation. Strokes associated
with atrial fibrillation were more frequent with atenolol than with
losartan as shown in the following table.

> Table 48: Reviewer's Rates of Patients with Stroke by Evidence of
> Atrial Fibrillation

  --------------------------------- ------------------ ------------------
                                    **Atenolol**       **Losartan**

  No atrial fibrillation            5.3%               4.3%

  Atrial fibrillation               18.3%              11.6%

  Total                             6.7%               5.0%
  --------------------------------- ------------------ ------------------

29% of the atenolol and 22% of the losartan patients with strokes had
evidence of atrial fibrillation.

The majority (67%) of strokes classified as embolic were associated with
evidence of atrial fibrillation. The 30 strokes classified as embolic
but not associated with atrial fibrillation included strokes associated
with myocardial infarction and strokes associated with revascularization
procedures.

Stroke patients on atenolol were slightly older than stroke patients on
losartan, particularly for strokes associated with atrial fibrillation.
Stroke patients, particularly in the atenolol group, had higher baseline
SBP but similar baseline DBP. Poor control was more frequent in patients
both with strokes associated with atrial fibrillation and with those
that were not. Aspirin use was less frequent in stroke patients on
atenolol than those on losartan while warfarin use was more frequent.
These differences are quantified in the following tables.

> Table 49: Reviewer's Mean Ages by Stroke and Atrial Fibrillation

  ------------------------------ ------------------- --------------------
                                 **Atenolol**        **Losartan**

  Neither                        66.4                66.6

  Atrial fibrillation            69.6                69.5

  Stroke                         70.1                69.0

  Both                           72.3                70.9

  Total                          66.9                66.9
  ------------------------------ ------------------- --------------------

> Table 50: Reviewer's Rates of Poor Control by Stroke and Atrial
> Fibrillation

  ------------------------------ ------------------- --------------------
                                 **Atenolol**        **Losartan**

  Neither                        22%                 19%

  Atrial fibrillation            27%                 22%

  Stroke                         42%                 38%

  Both                           50%                 40%

  Total                          24%                 21%
  ------------------------------ ------------------- --------------------

> Table 51: Reviewer's Rates of Aspirin Use by Stroke and Atrial
> Fibrillation

  -----------------------------------------------------------------------
                                 **Atenolol**        **Losartan**
  ------------------------------ ------------------- --------------------
  Neither                        30%                 30%

  Atrial fibrillation            49%                 51%

  Stroke                         61%                 70%

  Both                           64%                 72%

  Total                          34%                 34%
  -----------------------------------------------------------------------

> Table 52: Reviewer's Rates of Warfarin Use by Stroke and Atrial
> Fibrillation

  -------------------------- ---------------- ----------------- -----------
                             **Atenolol**     **Losartan**      **Total**

  Neither                    4%               3%                3%

  Atrial fibrillation        45%              39%               42%

  Stroke                     15%              8%                12%

  Both                       56%              50%               54%

  Total                      9%               6%                8%
  -------------------------- ---------------- ----------------- -----------

The case report forms collected general information on the type of
neurologic deficit, i.e., visual disturbance, motor disorder, etc., but
they did not try to capture the severity of the stroke. One metric of
stroke severity is whether the stroke is associated with death. In 34
patients, 23 in the atenolol group and 11 in the losartan group, death
occurred within 30 days of the stroke. Hence death was more frequent
following stroke with atenolol (7.5% of patients with strokes) than with
losartan (4.8% of patients with strokes).

The timing of the occurrence of strokes is interesting. The reviewer
calculated stroke rates by group and by quarter (90-day intervals) to
provide reasonable stability of stroke rates. These quarterly stroke
rates are shown in the following two figures. Note that stroke rates in
the atenolol group appear to be greater in the first quarter and
possibly also at the end of the study. Stroke rates do not seem to vary
similarly for losartan. Quarterly rates of myocardial infarction (MI) or
angina for both atenolol and losartan also do not show similar peaks.
Quarterly rates of MI by treatment group are shown in the two figures
following the quarterly stroke rates.

Strokes that occurred early, i.e., in the first quarter, were more
frequently associated with atrial fibrillation than later occurring
strokes (37% for atenolol and 50% for losartan). Otherwise there are no
consistent variations in the types of stroke by time.

The timing of the occurrence of atrial fibrillation adverse events (afib
AEs) is also interesting. The quarterly rates of afib AEs are shown in
the two figures following the ones with MI rates. The rates of afib AEs
appear to be slowly increasing with time with a cyclical variation. What
appear to be dramatic are the increased rates of afib AEs in the
atenolol group at the end of the study.

![](media/image23.wmf){width="5.5in" height="3.6666666666666665in"}

![](media/image24.wmf){width="5.4in" height="3.6in"}

![](media/image25.wmf){width="5.5in" height="3.6666666666666665in"}

![](media/image26.wmf){width="5.375in" height="3.5833333333333335in"}

![](media/image27.wmf){width="5.5in" height="3.6666666666666665in"}

![](media/image28.wmf){width="5.600694444444445in"
height="3.734027777777778in"}

The increased stroke rate with atenolol at the beginning and at the end
of study raises the question of whether atenolol dose changes increase
the risk of stroke. Interpreting association between strokes and dose
changes is difficult because it is difficult to determine whether a dose
change preceding an event by a few days was initiated because of
developing signs or symptoms of the event or whether the dose change was
initiated for unrelated reasons. Strokes were preceded by a dose change
on the day before the event in 29 cases, 22 with atenolol and 7 with
losartan. All but one of these dose changes were discontinuations of the
study drug. Strokes were preceded by a dose change within 30 days prior
to the event in 100 cases, 67 on atenolol and 33 on losartan. Of these
latter dose changes 16 were initial dosing, 12 were increases in dosage,
and 6 were restarts of dosing. Twenty-three of these 34 changes were in
atenolol patients. These statistics suggest that atenolol dose changes
are associated with strokes more frequently than losartan dose changes.

The relationship between changes in dose and atrial fibrillation adverse
events (afib AE) does not appear to differ for atenolol and losartan.
For 27 atenolol and 34 losartan patients an afib AE was reported on the
day following a dosage change. For 106 atenolol and 90 losartan patients
an afib AE was reported 1-30 days following a dosage change. The
distribution of types of dose changes preceding afib AEs are similar for
the two treatment groups.

An interesting analysis that the reviewer was unable to accomplish
because of lack of data is the relationship between patient compliance,
stroke, and atrial fibrillation. One wonders whether patient-initiated
discontinuations are associated with either event.

The NDA did not include any discussion of a possible association of
atrial fibrillation and stroke with atenolol use. That the sponsor may
be aware of this association is shown by the topic of one of the
proposed initial publications from the LIFE study listed at the December
10, 2001, meeting of the Steering Committee: "A fib, Rx and outcome".

COMMENT: Atenolol patients had more strokes associated with atrial
fibrillation. This appears to represent a second mechanism that explains
the differences in outcomes.

#### 4.2.3. Subgroup Analyses

#### 4.2.3.1. Country

Subgroup analyses by country are potentially useful to understand how
the study results are relevant to the US population. Note that as
documented in Section 4.1.2.2 there are some baseline differences among
the subjects in the various countries. The rates of the primary
composite endpoint by country are shown in the following table.

> Table 53: Reviewer' Primary Composite Endpoint Rates by Country

  ------------------------------------------------------------------------
  **Country**             **Atenolol**            **Losartan**
  ----------------------- ----------------------- ------------------------
  Denmark                 14.2%                   10.7%

  Finland                 8.8%                    7.8%

  Iceland                 8.8%                    12.3%

  Norway                  16.7%                   12.2%

  Sweden                  13.0%                   11.5%

  US                      13.7%                   13.1%

  UK                      9.5%                    9.6%

  Total                   12.8%                   11.0%
  ------------------------------------------------------------------------

Please note that Iceland is included in the table above and subsequent
ones for completeness, but so few subjects were enrolled in Iceland that
the Iceland results have extremely wide confidence limits. For the
primary composite endpoint only the UK results favor atenolol very
slightly, while the advantage of losartan is lower in the US. The
results are more consistent for stroke as shown in the following table.

> Table 54: Reviewer's Primary Endpoint Stroke Rates by Country

  ----------------------- ----------------------- ------------------------
  **Country**             **Atenolol**            **Losartan**

  Denmark                 7.9%                    5.3%

  Finland                 4.5%                    3.2%

  Iceland                 2.9%                    1.5%

  Norway                  7.6%                    3.9%

  Sweden                  6.0%                    5.1%

  US                      4.9%                    4.5%

  UK                      3.4%                    2.7%

  Total                   5.8%                    4.3%
  ----------------------- ----------------------- ------------------------

From Section 4.1.2.2 one can appreciate that the US study population is
not homogeneous. Baseline characteristics of US blacks differ
significantly from US whites and from the subjects in other countries.
If one treats US blacks and US whites as different subgroups, then the
primary composite endpoint and stroke endpoint rates are as shown in the
following two tables.

> Table 55: Reviewer' Primary Composite Endpoint Rates by Country/Race

  ------------------------------------------------------------------------
                          **Atenolol**            **Losartan**
  ----------------------- ----------------------- ------------------------
  Denmark                 14.2%                   10.7%

  Finland                 8.8%                    7.8%

  Iceland                 8.8%                    12.3%

  Norway                  16.7%                   12.2%

  Sweden                  13.0%                   11.5%

  US white                14.9%                   11.2%

  US black                11.2%                   17.4%

  UK                      9.5%                    9.6%

  Total                   12.8%                   11.0%
  ------------------------------------------------------------------------

> Table 56: Reviewer's Primary Endpoint Stroke Rates by Country/Race

  ----------------------- ----------------------- ------------------------
                          **Atenolol**            **Losartan**

  Denmark                 7.9%                    5.3%

  Finland                 4.5%                    3.2%

  Iceland                 2.9%                    1.5%

  Norway                  7.6%                    3.9%

  Sweden                  6.0%                    5.1%

  US white                5.5%                    3.6%

  US black                3.5%                    6.4%

  UK                      3.4%                    2.7%

  Total                   5.8%                    4.3%
  ----------------------- ----------------------- ------------------------

The results for whites in all countries are consistent with the possible
exception of the neutral results for the composite endpoint in the UK.
If total mortality is substituted for cardiovascular mortality in the
composite endpoint, then the results are more consistent for whites as
shown in the following table.

> Table 57: Reviewer' Primary Composite Endpoint with Total Mortality
> Rates by Country/Race

  ----------------------- ----------------------- ------------------------
                          **Atenolol**            **Losartan**

  Denmark                 18.5%                   15.3%

  Finland                 10.7%                   10.2%

  Iceland                 11.8%                   13.8%

  Norway                  19.5%                   16.1%

  Sweden                  16.6%                   13.8%

  US white                18.8%                   15.9%

  US black                15.4%                   23.5%

  UK                      14.8%                   12.8%

  Total                   16.4%                   14.5%
  ----------------------- ----------------------- ------------------------

Note that the UK now shows an advantage to losartan, although the
advantage of losartan in Finland is reduced.

COMMENT: If one accepts that US blacks are a substantially different
population, then the results are reasonably consistent for whites by
country particularly for the primary composite endpoint using total
mortality in place of cardiovascular mortality. The results in US whites
are consistent with the overall study. The differences in US blacks are
explored further in the next section.

#### 4.2.3.2. Race

The sponsor did not specify assessing the influence of race or ethnicity
as one of its secondary or tertiary endpoints but did include subgroup
analyses by ethnicity in its Data Analysis Plan. The sponsor's summary
of its initial approach to examining ethnicity is the following:

"Although there was not a significant effect of ethnic background on the
risk of an event in the prespecified groups, there was a suggestion of
interaction between ethnic background and treatment (p=0.057). The
prespecified test for the interaction between ethnic background and
treatment was based on a comparison of the effect of losartan among the
5 different ethnic background categories: White (n=8503), Black (n=533),
Hispanic (n=100), Asian (n=43), and Other (n=14). White patients
appeared to have lower risk with losartan (hazard ratio: 0.819 \[95% CI
0.724 to 0.928\]), while Black patients appeared to have lower risk with
atenolol (hazard ratio: 1.598 \[95% CI 1.004 to 2.543\]) (Table 19). The
amount of data for all but the White and Black groups was very limited,
which made the prespecified test for interaction unreliable. A further
exploratory analysis dichotomizing patients into Black (N=533) and
non-Black (N=8660) yielded a statistically significant interaction
(p=0.005). Further, a test for qualitative interaction (i.e., effect of
losartan differs in direction between Blacks and non-Blacks, not just in
magnitude) was also statistically significant (p=0.016)."

Because of the suggestion of a qualitative interaction the sponsor
performed additional analyses, the major ones of which are summarized in
the following table.

![](media/image29.png){width="6.120138888888889in"
height="2.651388888888889in"}

Please see the FDA statistician's review for a complete discussion of
these analyses. However, the validity of these analyses is dependent
upon assuming that the black and white subgroups are relatively
homogeneous for factors not included in the analyses and that the
statistical model employed, in this case Cox regression, adequately
adjusts for the factors included in the model. Because quantitative
tests of these assumptions are not available, it is helpful to examine
differences in factors between the black and white subgroups and the two
treatment groups in the black subgroup.

Baseline characteristics of US blacks are summarized in Section 4.1.2.3.
Black were younger and heavier, more likely to be male and smokers, and
less likely to use alcohol and to exercise. They had higher Sokolow-Lyon
voltage but lower Cornell voltage duration products. They were
intermediate between US non-blacks and non-US cases for heart disease
and prior cardiovascular drug use (except beta blockers, for which they
have the lowest prior use.) They had histories of more strokes and
diabetes. While these differences do not prove that blacks and whites
are nonhomogeneous populations that should not be analyzed in
combination, they do provide support for looking at the black subgroup
separately.

Baseline characteristics are reasonably well balanced between the two
treatment groups in blacks. There are minor imbalances shown in the
following table that are not statistically significant. Note, however,
the age and gender differences.

> Table 59: Reviewer's Selected Baseline Characteristic in Blacks

  -------------------------------------- -------------- -------------- ---------
                                         **Atenolol**   **Losartan**   **p\***

  Mean age                               64.4           65.5           

  Median age                             63             66             0.07

  Age \<65                               56%            46%            

  Female                                 50%            43%            0.09

  SBP                                    172            172            0.9

  Isolated systolic hypertension         15%            17%            0.5

  Framingham risk score                  22.2           22.2           0.7

  Smoker                                 17%            16%            0.2

  Prior angina                           11%            14%            0.3

  Prior myocardial infarction            7%             9%             0.3

  Prior heart failure                    3.5%           3.8%           0.8

  Prior stroke                           9%             9%             0.9

  Prior diabetes                         27%            23%            0.3

  Aspirin use                            41%            48%            0.2
  -------------------------------------- -------------- -------------- ---------

A Kaplan-Meier plot for the primary composite endpoint in blacks is
shown in the figure below.

> ![](media/image30.wmf){width="3.3229166666666665in"
> height="2.2708333333333335in"}
>
> Figure 13: Reviewer's Kaplan-Meier Plot of Primary Composite Endpoint
> in Blacks

Note that the curves diverge after about 1.5 years. There appears to be
a substantial benefit to atenolol (log rank p = 0.02). The results are
similar if total mortality is incorporated into the composite endpoint.

Kaplan-Meier plots for the components of the composite endpoint and for
total mortality in blacks are shown in the following four figures.

> ![](media/image31.wmf){width="3.3229166666666665in"
> height="2.2708333333333335in"}
>
> Figure 14: Reviewer's Kaplan-Meier Plot of Strokes in Blacks

![](media/image32.wmf){width="3.3229166666666665in"
height="2.2708333333333335in"}

> Figure 15: Reviewer's Kaplan-Meier Plot of Myocardial Infarctions in
> Blacks
>
> ![](media/image33.wmf){width="3.3229166666666665in"
> height="2.2708333333333335in"}
>
> Figure 16: Reviewer's Kaplan-Meier Plot of CV Mortality in Blacks
>
> ![](media/image34.wmf){width="3.3229166666666665in"
> height="2.2708333333333335in"}
>
> Figure 17: Reviewer's Kaplan-Meier Plot of Total Mortality in Blacks

Note that the curves for both cardiovascular and total mortality cross
at about two years, with atenolol having a small survival advantage
prior to two years and losartan having a survival advantage thereafter.
However, the differences in survival are not statistically significant.
The difference in stroke rates for blacks is statistically significant
(log rank p = 0.02).

The number of events is relatively small and all components of the
composite contribute to the benefit of atenolol in blacks as shown in
the following table.

> Table 60: Reviewer's Primary Composite Endpoint Events in Blacks

  ------------------------------------------------------------------------
                  **MI**    **CV death**       **Stroke**    **Total**
  --------------- --------- ------------------ ------------- -------------
  Atenolol        6         14                 9             29

  Losartan        11        18                 17            46

  Total           17        32                 26            75
  ------------------------------------------------------------------------

The difference in primary composite endpoints between the two groups is
statistically significant (p = 0.03) by the sponsor's usual Cox
regression including LVH and Framingham risk score as covariates,
although the LVH measures are not significant covariates for the
regression. If age is substituted as a covariate, age is a highly
significant covariate and group loses significance (p = 0.07). Gender is
not a significant covariate.

There are slight differences in treatment and response to treatment.
Fewer black patients than white were on their primary study drugs at the
time of an endpoint or end of study (68 vs. 76%). Fewer black atenolol
patients were on primary study drug at the end than black losartan
patients (65 vs 70%). Blood pressure control in blacks was mixed. Good
control was more frequent with losartan (42 vs. 39%) but so was poor
control (24 vs 19%). The mean SBP at end was slightly lower with
atenolol (144.2 vs. 145.0) corresponding to a slightly greater SBP
reduction with atenolol (-27.6 vs --27.0). Heart rate change in blacks
differed from those in whites, with blacks showing less of a reduction
in heart rate on atenolol (-5.8 vs --8.5) and an increase rather than a
decrease with losartan (1.0 vs. --1.5).

The Kaplan-Meier plots suggest that there is a difference, favoring
atenolol, in the rates of stroke by treatment. In addition to the 26
primary composite endpoint strokes there were 17 other strokes, for a
total of 17 strokes in blacks in the atenolol group and 26 strokes in
the losartan group.

There appear to be only subtle differences in the characteristics of
strokes in blacks vs. whites. The distribution of types of strokes is
similar, with the majority of strokes in both races being classified as
ischemic (blacks 77%, whites 74%). Strokes followed by death within 30
days were more frequent with losartan in blacks, but the numbers are too
small to have significance (3 vs. 0). Any evidence of atrial
fibrillation was reported less frequently in blacks (7%) then whites
(10%). It was slightly but not significantly more frequent with losartan
in blacks while it was slightly and significantly more frequent with
atenolol in whites. More strokes associated with atrial fibrillation
occurred in blacks on losartan than on atenolol, but the numbers are too
small (4 vs. 2) to have any significance.

The LIFE study included an echocardiographic substudy at selected
centers that enrolled 916 patients (459 atenolol and 457 losartan). This
substudy oversampled blacks, but the numbers of blacks enrolled were
still low (65 atenolol, 64 losartan). Patients in this substudy
underwent baseline and annual echocardiograms to estimate left
ventricular mass and left ventricular mass index (LVMI---left
ventricular mass divided by body surface area). LVMI is greater in men
than women. (Shub, Klein et al. 1994) Various thresholds for defining
LVH by increased LVMI have been published, ranging from 111 to 134
g/m^2^ in men and from 100 to 125 g/m^2^ in women.

> Table 61: Sponsor's Baseline LVMI and Changes at Final Visit

  ------------ -------------- -------------- ------------ -------------- -------------- ------------
               **Atenolol**                               **Losartan**                  

               **N**          **Baseline**   **Change**   **N**          **Baseline**   **Change**

  **All**      459            123            -18          457            125            -22

  **Black**    65             130            -19          64             126            -16

  **US white** 55             123            -16          50             121            -19

  **All        394            121            -18          393            125            -23
  white**                                                                               

  **Female**   184            115            -15          193            119            -20

  **Male**     275            127            -19          264            129            -23
  ------------ -------------- -------------- ------------ -------------- -------------- ------------

Blacks in the atenolol group experienced a greater LVMI reduction
compared with blacks in the losartan group. Note that atenolol blacks
had the highest baseline LVMIs so that final visit LVMIs in blacks are
very similar in both groups. Whites, including US whites analyzed
separately, had greater reduction in LVMI on losartan than atenolol.

In contrast to the echocardiographic measures, a similar pattern of
change in the ECG measures of LVH (Cornell product and Sokolow-Lyon
voltage) was seen in black and white echocardiographic substudy patients
and was consistent with the results in blacks and whites in the main
LIFE population. Reduction in Cornell product was less in blacks than in
whites for both treatments. The reduction in Sokolow-Lyon voltage was
greater in blacks than whites in both treatment groups. The reduction of
both ECG measures of LVH in both racial groups was greater with losartan
than with atenolol.

COMMENT: The black population in this study does appear to be a
different population than the white population with regard to baseline
characteristics, response to therapy, and outcomes. Some of the
difference in outcomes may be explained by the differences in age and
gender between the two groups. The critical question in this reviewer's
opinion is whether the difference in outcomes represents a reversal of
the apparent beneficial effect of losartan in hypertensive whites with
LVH or a lack of difference between the two drugs in hypertensive blacks
with LVH confounded by random baseline differences. This reviewer does
not believe that the evidence is sufficient to conclude that there is an
actual reversal of the effect seen in whites.

#### 4.2.3.3. Age and Gender

The overall study population was well represented with the elderly (61%
age 65 or older, 17% age 75 or older) and with both genders (54%
female). Females tended to be older than males as is shown in the
following table.

> Table 62: Reviewer's Age Categories by Gender

  --------------- -------------- ---------------------- ------------------
                                 **Female**             **Male**

  \<65            N              1677                   1812

                  \%             34%                    43%

  65-74           N              2268                   1854

                  \%             46%                    44%

  ≥75             N              1018                   564

                  \%             21%                    13%
  --------------- -------------- ---------------------- ------------------

Baseline SBP was higher for older ages (mean 171 for ages \<65 vs. 174
for ages ≥ 75) while DBP was lower for older ages (mean 100 for ages
\<65 vs. 94 for ages ≥ 75). Hence isolated systolic hypertension was
more frequent at older ages (7.5% for ages \<65 vs. 26% for ages ≥ 75).
Blood pressure control worsened with age in both treatment groups. Rates
of poor control by age category are shown in the following table.

> Table 63: Reviewer's Rates of Poor Blood Pressure Control (SBP≥160 or
> DBP≥100) by Age

  ------------------ ------------------------- ---------------------------
                     **Atenolol**              **Losartan**

  \<65               18%                       15%

  65-74              25%                       22%

  ≥75                31%                       27%
  ------------------ ------------------------- ---------------------------

The treatment groups were well balanced for age and gender. However,
rates of the primary composite endpoint varied by age and treatment
group as shown in the following table.

> Table 64: Reviewer's Primary Composite Endpoint Rates by Age Category

  ------------------ ------------------------- ---------------------------
                     **Atenolol**              **Losartan**

  \<65               6.9%                      7.4%

  65-74              14.2%                     11.3%

  ≥75                22.5%                     18.2%
  ------------------ ------------------------- ---------------------------

Note that losartan was slightly less beneficial than atenolol for ages
\< 65 as measured by the sponsor's primary composite endpoint. However,
if total mortality rather than cardiovascular mortality is incorporated
into the composite endpoint, then there is no difference in the endpoint
rate for ages \< 65 between atenolol and losartan as shown in the
following table.

> Table 65: Reviewer's Primary Composite Endpoint with Total Mortality
> Rates by Age Category

  ------------------ ------------------------- ---------------------------
                     **Atenolol**              **Losartan**

  \<65               9.1%                      9.1%

  65-74              17.8%                     15.1%

  ≥75                28.8%                     24.9%
  ------------------ ------------------------- ---------------------------

Losartan appears to show the greatest net benefit over atenolol in the
older age groups. This pattern is also present with regard to the stroke
and mortality components of the primary composite endpoint. Stroke rates
are slightly lower (2.7 vs 3.2%) with atenolol for ages \< 65.
Myocardial infarction rates vary slightly and inconsistently between the
two groups by age.

Gender differences appear to reflect the age differences by gender noted
above, although females have slightly higher SBP and slightly lower DBP
than males in the same age category. Both genders show a beneficial
effect of losartan compared to atenolol by the primary composite
endpoint as shown in the following table.

> Table 66: Reviewer's Primary Composite Endpoint Rates by Gender

  --------------------- ------------------------ -------------------------
                        **Atenolol**             **Losartan**

  Female                10.5%                    8.6%

  Male                  15.5%                    13.8%
  --------------------- ------------------------ -------------------------

The beneficial effect of losartan appears reduced in males when total
mortality is incorporated into the composite endpoint as shown in the
following table.

> Table 67: Reviewer's Primary Composite Endpoint with Total Mortality
> Rates by Gender

  --------------------- ------------------------ -------------------------
                        **Atenolol**             **Losartan**

  Female                14.1%                    11.1%

  Male                  19.1%                    18.6%

  Total                 16.4%                    14.5%
  --------------------- ------------------------ -------------------------

Total mortality in males was the same for both treatment groups for
males, while females on atenolol had a higher total mortality rate
(8.4%) than females on losartan (6.4%). Note that mean ages were nearly
identical in the two groups but were higher for females (67.7) vs. males
(66.1) in both groups.

Calculating primary composite endpoint with total mortality rates by
gender and age produces the results shown in the following table.

> Table 68: Reviewer's Primary Composite Endpoint with Total Mortality
> Rates by Gender and Age

  ------------- ---------- ----------- ----------------- -----------------
  **Gender**    **Age**    **N**       **Atenolol**      **Losartan**

  Female        \<65       1539        7.4%              5.6%

                65-74      2190        13.6%             10.1%

                ≥75        991         26.3%             21.0%

  Male          \<65       1685        10.6%             12.3%

                65-74      1732        23.1%             20.6%

                ≥75        533         33.3%             31.9%
  ------------- ---------- ----------- ----------------- -----------------

Note that losartan is less beneficial than atenolol in younger males
(age \<65). There also appears to be a reduced benefit in elderly males
(age ≥75) but the number of cases is small.

COMMENT: One must be cautious about overinterpreting these subgroup
analyses. Losartan appears to be more effective in higher risk
individuals such as the elderly. Losartan may be less beneficial in
males, particularly younger males (age \<65).

#### 4.2.3.4. Diabetics

The sponsor analyzed various endpoint results in patients with diabetes
at baseline. The sponsor's analyses are summarized in the following
table.

![](media/image35.png){width="6.095138888888889in"
height="2.0243055555555554in"}

Losartan appears to be even more beneficial in this subgroup, with a
risk reduction for the composite endpoint of about 25%. The pattern of
benefit is different from the study as a whole, with a dramatic
difference in total mortality in diabetics between the two groups. The
atenolol group had more deaths due to heart failure (10 vs. 5),
myocardial infarction (17 vs. 13), sudden death or arrest (20 vs. 8),
stroke (12 vs. 6), and pneumonia or other infection (12 vs. 1), while
the losartan group had a clear excess of deaths only for respiratory
failure (7 vs. 0).

#### 4.2.3.5. Isolated Systolic Hypertension

The sponsor also analyzed various endpoint results in patients with
isolated systolic hypertension (ISH) at baseline. The sponsor's analyses
are summarized in the following table.

![](media/image36.png){width="6.0in" height="2.5083333333333333in"}

ISH appears to be one surrogate for the effects of age. Rates of ISH
increase substantially with increasing age as shown in the following
table.

> Table 71: Reviewer's Rates of Isolated Systolic Hypertension by Age

  -------------------- ------------------------ --------------------------
  **Age**              **Atenolol**             **Losartan**

  \<65                 7%                       8%

  65-74                16%                      16%

  ≥75                  27%                      25%
  -------------------- ------------------------ --------------------------

COMMENT: Both subgroup analyses in diabetics and patients with isolated
systolic hypertension are interesting ones that must be interpreted with
caution. If real they would be clinically useful because the
distinguishing characteristics are easy to determine. The difficult
question is how much to trust these subgroup results. ISH may be a
surrogate for age.

#### 4.2.3. Secondary Endpoints

The most important secondary endpoints, the components of the primary
composite endpoint and total mortality, have been discussed in
conjunction with the primary endpoint. The sponsor also defined a number
of secondary endpoints that are summarized briefly below.

#### 4.2.3.1. Other Endpoint Classification Committee Endpoints

> The Endpoint Classification Committee also adjudicated several other
> events that the sponsor judged to be relevant to the interpretation of
> the study results. The sponsor's summary of the these other secondary
> endpoints are shown in the following table.
>
> ![](media/image37.png){width="6.095138888888889in" height="1.98125in"}
>
> The reviewer has discussed total mortality results in conjunction with
> the primary endpoint. There are no statistically significant
> differences in these secondary endpoints.
>
> 4.2.3.2. Left Ventricular Hypertrophy
>
> The sponsor postulated based on other evidence that losartan might
> improve LVH more than atenolol. The results appear to support this
> hypothesis. The sponsor's summary of changes in LVH by ECG criteria
> are shown in the following table.
>
> ![](media/image38.png){width="6.035416666666666in"
> height="3.7291666666666665in"}**Table 73: Sponsor's Changes in ECG
> Measures of LVH**
>
> The sponsor also incorporated the ECG criteria for LVH as time-varying
> covariates into its Cox regression analyses of the primary endpoint
> and components. The results are shown in the following table.
>
> ![](media/image39.png){width="5.677083333333333in" height="2.0625in"}

After adjustment for ECG criteria for LVH as time-varying covariates
treatment effect for the composite endpoint and for stroke are slightly
smaller, while the treatment effect for MI becomes slightly larger.

#### 4.2.3.3. Hospitalizations

The sponsor defined the rate of hospitalization for any reason as a
tertiary endpoint. The reviewer includes hospitalizations here as one
available measure of whether overall patient morbidity was different
between the two groups. Hospitalization numbers were similar in the two
groups and are shown in the following table.

> Table 75: Sponsor's Numbers of Hospital Admissions
>
> ![](media/image40.png){width="5.954166666666667in"
> height="2.4770833333333333in"}

First hospitalization rates by reason for hospitalization are shown in
the following table.

> ![](media/image41.png){width="5.990972222222222in"
> height="1.875in"}Table 76: Sponsor's Rates of First Hospitalizations
> by Reason

Times to first hospitalization for any reasons were similar in the two
groups. Times to first hospitalization were shorter in the losartan
group for angina and in the atenolol group for stroke.

COMMENT: The secondary endpoint analyses do not reveal any other major
differences between atenolol and losartan, although there is a
suggestion of slight differences in hospitalizations for angina. The LVH
analyses suggest that losartan is superior to atenolol in reducing LVH.
The unknown factor is whether there were differences in blood pressure
control, including differences in 24-hour control, that might explain
the observed differences in LVH reduction.

### D. Efficacy Conclusions

#### 1. Primary Endpoint

The reviewer believes that there are two critical questions to ask
regarding the primary results of the LIFE study:

(a) Does the LIFE study show that a losartan regimen is robustly
    superior to an atenolol regimen in reducing cardiovascular morbidity
    and mortality?

(b) Were the LIFE regimens realistic enough and the conduct of the trial
    adequate to support transfer of the results into routine clinical
    practice?

The reviewer judges that the answer to both questions is a qualified
yes.

The sponsor's pre-specified analysis for its primary composite endpoint
of cardiovascular mortality, myocardial infarction, and stroke was a Cox
regression in including treatment group, baseline Cornell and
Sokolow-Lyon ECG LVH scores, and Framingham risk score as covariates.
For this Cox regression the hazard ratio for losartan treatment is 0.869
with p=0.21. Without the baseline covariates the hazard ratio is 0.854
with p=0.009.

Because all three components of the primary composite endpoint have a
degree of subjectivity in their ascertainment, the reviewer examined
case report forms and reclassified all endpoints for which the Endpoint
Classification Committee (ECC) changed the investigator's assignment.
The results based on the reviewer' reclassifications are nearly
identical for the sponsor's primary composite endpoint and the reviewer
did not identify any biases in the ECC's assignments.

The reviewer believes that the Division's original recommendation to use
total mortality rather than cardiovascular mortality in the primary
composite endpoint is appropriate because of subjectivity in assessing
cardiovascular mortality and the unquestionable importance of mortality
regardless of cause. Using a modified composite endpoint incorporating
total mortality p=0.029 for the Cox regression with baseline LVH and
risk score covariates and p=0.018 for an unadjusted log rank analysis.
For the reviewer's reclassifications p=0.051 for the Cox regression and
p=0.023 for an unadjusted log rank analysis. The primary composite
endpoint results are not statistically extreme.

The sponsor appropriately performed the pre-specified primary endpoint
analysis and the reviewer performed all endpoint analyses discussed so
far using a strict, as-randomized intention-to-treat approach. The
sponsor also performed a per-protocol analysis and the reviewer
performed an on-study drug analysis. These analyses are relevant because
discontinuation of study drug was not uncommon: 170 (29%) atenolol and
130 (26%) losartan primary endpoint events occurred more than 30 days
after study drug discontinuation. All Cox regression analyses by
per-protocol or on-study drug approaches are non-significant (p=0.053 to
0.12).

The sponsor refers to the reduction in the secondary endpoint of stroke,
an adjusted risk reduction of about 25%, p=0.001, as robust. However,
the reviewer does not consider a selected secondary endpoint to be
robust in view of non-robustness of the primary endpoint. Furthermore,
if components of the primary endpoint are to be highlighted, then one
must also consider the relevance of the point estimate of the hazard
ratio for myocardial infarction with losartan, 1.07. While this hazard
ratio is not statistically significant, it is arguably consistent with
the positive impact beta blockers have shown upon cardiovascular
morbidity and mortality in post-myocardial infarction studies.

The reviewer's conclusion regarding the first question is that the LIFE
study does show that an antihypertensive regimen including losartan is
superior to one including atenolol for reducing cardiovascular morbidity
and mortality in hypertensive patients with LVH. The qualification is
that the evidence is not very robust. It is also a single study.
However, the magnitude of the point estimate of the benefit is
reasonable. An adjusted risk reduction of about 10% for a composite
endpoint of total mortality, myocardial infarction, and stroke is
clinically significant. Repetition of the trial would be difficult.

The second question, whether the LIFE regimens were realistic enough and
the conduct of the trial adequate, has several subordinate questions.
The first is how much impact the small difference in blood pressure (BP)
control had on the results. Mean systolic BP (SBP) at year 4 was 1.5 mm
Hg higher in the atenolol group while diastolic BP (DBP) was 0.3 mm Hg
lower. These mean differences translate into small differences in
control, e.g., 24% of atenolol and 20% of losartan patients had poor
control defined as SBP≥160 or DBP≥100. Endpoint rates were substantially
higher with poor control, e.g., 2-3 fold higher than in patients with
good control defined as SBP\<140 and DBP\<90. If the atenolol group had
achieved the same level of BP control as the losartan group, then 22
fewer endpoints would be expected in the atenolol group. The difference
in the primary composite endpoint rates would not be statistically
significant.

By the reviewer's calculations BP control in the LIFE study was only
fair. Prior to the endpoint in patients with primary endpoints or at
last recording for patients without primary endpoints only about a third
of patients had good control. This level of control is probably typical
of routine practice, so one can argue that the LIFE results will
transfer into routine practice.

Study drug usage was slightly lower in the atenolol group. The magnitude
of the difference is about the same as the magnitude of the difference
in control. While the study was blinded, the effect of atenolol on heart
rate is observable. Whether the differences in drug dosage and BP
control are consequences of adverse effects, differing efficacy, or
investigator perception is impossible to unravel.

The reviewer's conclusion regarding the second question is that the LIFE
regimens were realistic enough and the conduct of the trial adequate to
support transfer of the results into practice. The qualification
regarding the second question is similar to that for the first---the
reviewer's confidence in the affirmative answer is not great. The
potential for neutralizing the benefit with a small increase in BP
control for the atenolol group is not reassuring. On the other hand, the
LIFE study is probably similar to routine practice so its results may
transfer well.

#### 2. Atrial Fibrillation and Strokes

One of the possible surprise findings of the LIFE study may be that
atenolol is associated with more atrial fibrillation and consequently
more strokes. The evidence is not conclusive but includes the following:

-   Atrial fibrillation and flutter adverse events reported at any time
    during the study were slightly more common in the atenolol group
    (7.9%) than in the losartan group (6.8%). Atrial fibrillation led to
    discontinuation in about 1% of atenolol patients vs. 0.5% of
    losartan patients.

-   Strokes occurred in about 18% of atenolol patients with some
    evidence of atrial fibrillation, 12% of losartan patients with some
    evidence of atrial fibrillation, and 5% of patients without evidence
    of atrial fibrillation.

-   Stroke rates in the atenolol group peaked in the first quarter and
    at year five as patients were being discontinued. Atrial
    fibrillation adverse event rates also peaked at year five. The
    losartan group did not show these peaks.

-   Strokes were preceded by a dose change on the day before the event
    in 22 atenolol and 7 losartan patients. Strokes were preceded by a
    dose change within 30 days prior to the event in 67 patients and 33
    losartan patients.

This association between atenolol use and atrial fibrillation and stroke
appears to explain some of the difference in outcomes not explained by
the difference in blood pressure control. Confirmation, or refutation,
of this association is needed from other studies.

#### 3. Differential Effect in Blacks

Although the sponsor did not pre-specify the comparison, there is a
significant interaction between race, characterized as black and white,
and treatment (p=0.005). Blacks fared worse with losartan (hazard ratio
1.666, p=0.033, by the sponsor's usual Cox regression analysis with
baseline covariates) than with atenolol. A test for a qualitative
interaction (i.e., that the effect of losartan differs in direction, not
just in magnitude, between blacks and whites) was statistically
significant (p=0.016).

However, the interpretation of these analyses is confounded because the
blacks in the LIFE study have different baseline characteristics than
the whites and the blacks in the losartan groups have different baseline
characteristics than the blacks in the atenolol group. There are some
inconsistencies in the results between the two racial groups. The
pertinent findings are the following:

-   The vast majority of blacks were enrolled only in the US. To take
    into account this difference the sponsor also compared US blacks to
    US whites and still noted the difference in effect. However, US
    blacks are also dissimilar from US whites.

-   Baseline characteristics of US blacks differ from the other ethnic
    subgroups. Blacks were younger and heavier, more likely to be male
    and smokers, and less likely to use alcohol and to exercise. They
    had higher Sokolow-Lyon voltage but lower Cornell voltage duration
    products. They had histories of more strokes and diabetes.

-   Blacks in the losartan group were older and more likely to be male.
    While these differences are not statistically significant, the
    maldistributions of baseline risk factors probably influence the
    results. If primary endpoints in blacks are analyzed by the
    sponsor's usual Cox regression with covariates of baseline ECG LVH
    measures and Framingham risk score, then treatment group is a
    significant factor (hazard ratio 1.66, p=0.033). As with the overall
    study and white subgroup analyses, Framingham risk score is a highly
    significant covariate. Different from the overall study and white
    subgroup analyses, baseline ECG LVH measures are not significant
    covariates. If age is added as a covariate, then treatment group
    becomes insignificant (p=0.07).

-   Blacks were treated differently and responded differently to
    treatment. Fewer blacks than whites were on their primary study
    drugs at the time of an endpoint or end of study (68 vs. 76%). Fewer
    black atenolol patients were on primary study drug at the end than
    black losartan patients (65 vs 70%). Blood pressure control in
    blacks was mixed. Good control was more frequent with losartan (42
    vs. 39%) but so was poor control (24 vs 19%). The mean SBP at end
    was slightly lower with atenolol (144.2 vs. 145.0). Heart rate
    change in blacks differed from those in whites, with blacks showing
    less of a reduction in heart rate on atenolol (-5.8 vs --8.5) and an
    increase rather than a decrease with losartan (1.0 vs. --1.5).

-   Blacks in the atenolol group in the echocardiographic substudy had a
    greater reduction in left ventricular mass index (LVMI) compared to
    blacks in the losartan group, although the absolute values at final
    visit were similar. Whites had greater reductions in LVMI with
    losartan. Reductions in electrocardiographic left ventricular
    hypertrophy measures were greater with losartan for both ethnic
    groups, although blacks had greater reductions in Sokolow-Lyon
    voltage and lesser reductions in Cornell products than whites.

-   Blacks on atenolol had fewer adverse events, serious adverse events,
    and discontinuations for adverse events than blacks on losartan.
    Rates of adverse events for blacks on losartan were very similar to
    rates for whites. While it is conceivable that the same mechanism
    that led to better efficacy with atenolol in blacks also produced
    fewer adverse events, it is simpler to conclude that blacks on
    atenolol were lower risk.

The reviewer concludes that blacks in the LIFE study were a different
population than whites. They had different baseline characteristics and
responded differently to treatment. There were baseline imbalances in
important risk factors, i.e., age and gender, between the two treatment
groups in blacks. While the LIFE study results suggest that losartan is
not superior to atenolol in reducing cardiovascular morbidity and
mortality in black hypertensives with LVH, it does not provide
sufficient consistent evidence that losartan is inferior to atenolol in
this subgroup.

#### 4. Differential Effects by Age and Gender

The LIFE study was well represented with the elderly (61% age 65 or
older, 17% age 75 or older) and with both genders (54% female). Females
were older than males on the average (mean age for females 67.7, for
males 66.1). Older patients had higher baseline SBP (mean 171 for ages
\<65 vs. 174 for ages ≥ 75) , lower baseline DBP (mean 100 for ages \<65
vs. 94 for ages ≥ 75), and hence more isolated systolic hypertension
(7.5% for ages \<65 vs. 26% for ages ≥ 75). Blood pressure control
declined with age.

The rates of the primary composite endpoint, with or without total
mortality, varied by age and gender. The rates of the primary composite
endpoint with total mortality are shown in the following table.

> Table 77: Reviewer's Primary Composite Endpoint with Total Mortality
> Rates by Gender and Age

  ------------------------------------------------------------------------
  **Gender**    **Age**    **N**       **Atenolol**      **Losartan**
  ------------- ---------- ----------- ----------------- -----------------
  Female        \<65       1539        7.4%              5.6%

                65-74      2190        13.6%             10.1%

                ≥75        991         26.3%             21.0%

  Male          \<65       1685        10.6%             12.3%

                65-74      1732        23.1%             20.6%

                ≥75        533         33.3%             31.9%
  ------------------------------------------------------------------------

While one must be cautious about overinterpreting these subgroup
analyses, losartan appears to be more beneficial in the elderly.
Losartan may be less beneficial in males, particularly younger males
(age \<65).

#### 5. Other Subgroups

Losartan appears to be even more beneficial in diabetics at baseline,
with a risk reduction for the composite endpoint of about 25%. The
pattern of benefit is different from the study as a whole, with a
dramatic difference in total mortality in diabetics between the two
groups. Atenolol use was also associated with more new onset diabetes as
is discussed in the Safety section.

Losartan also appears to be more beneficial in patients with isolated
systolic hypertension (ISH) at baseline, with a risk reduction for the
composite endpoint also of about 25%. ISH appears to be one surrogate
for age, increasing from about 7% for ages \<65 to 27% for ages ≥ 75.

#### 6. Other Endpoints

The sponsor postulated based on other evidence that losartan might
improve left ventricular hypertrophy (LVH) more than atenolol. At the
last visit before a primary endpoint or at the last recording the
Cornell product was reduced by 4.4% in the atenolol group and 10% in the
losartan group. The Sokolow-Lyon voltage was reduced by 9% in the
atenolol group and 15% in the losartan group. While these results also
may be confounded by differences in blood pressure control, they appear
to support the sponsor's hypothesis.

The sponsor defined the rate of hospitalization for any reason as a
tertiary endpoint. Rates of hospitalizations are informative as one
available measure of whether overall patient morbidity was different
between the two groups. Rates of hospitalizations were similar in the
two groups, with 50.8% of atenolol patients and 49.1% of losartan
patients having at least one hospital admission. Times to first
hospitalization for any reasons were similar in the two groups. Times to
first hospitalization were shorter in the losartan group for angina and
in the atenolol group for stroke.

## 

## VII. Integrated Review of Safety

### A. Brief Statement of Conclusions

The tolerability of atenolol and losartan appears comparable when judged
by total adverse event (AE) rates, AEs leading to hospitalization, and
serious AE rates. Only for AEs leading to discontinuation and
investigator-classified drug-related AEs, rates that are more
susceptible to investigator subjectivity, are losartan rates lower than
atenolol rates. Overall both drugs were tolerated well.

The most common AEs were ones that would be expected with these drugs.
Dizziness was the most frequently reported AE with both drugs.
Bradycardia was common with atenolol. Bradycardia was the most frequent
reason, and fatigue and dyspnea were other common reasons, for
discontinuation with atenolol.

This large, long-term study helps to define better rarer complications
of both drugs. Atenolol was associated with an increase in atrial
fibrillation. Atenolol also raised uric acid and glucose levels slightly
and was associated with slightly increased rates of gout and greater
risk of diabetes. Losartan lowered hemoglobin levels slightly and was
associated with slightly increased rates of anemia.

### B. Review of Safety Data in the LIFE Study

#### 1. Exposure

The sponsor's summary statistics on drug exposure, including dosages at
the final visit, are provided in the Efficacy section. The dosages by
study visit are listed in the following table.

![](media/image42.png){width="4.825694444444444in"
height="6.763888888888889in"}

The reviewer calculated that the atenolol patients remained on study
drug for a mean of 3.94 years (18,076 person exposure years) and
losartan patients remained on study drug for a mean of 4.12 years
(19,006 person exposure years).

Investigators reported adverse events during the screening period prior
to the initiation of treatment, during treatment with study drug, and
after treatment with study drug until termination of follow-up. The
sponsor restricted safety analyses to the period while the patients were
receiving study drug and the 14-day periods immediately following study
drug discontinuation. The sponsor's description of this restriction is
as follows: "Safety analyses included laboratory measurements and
adverse experiences that were reported while the patient was on study
drug or within 14 days of the last dose of study therapy. Exclusions for
safety were applied after permanent study drug discontinuation as well
as during gaps in study therapy \>14 days." This sponsor did not include
this restriction in the original protocol but it does appear in the Data
Analysis Plan dated November 1, 2001.

The sponsor's justification for not analyzing adverse events (AEs)
occurring more than 14 days after discontinuation of study medication is
the following: "Since patients who discontinued blinded study medication
often took another antihypertensive medication that had its own set of
potential adverse experiences, the adverse experiences that occurred
during the period following discontinuation would tend to obscure the
true differences between losartan and atenolol. For this reason, the
adverse experience results summarized below do not include adverse
experiences that occurred more than 14 days after the patient
discontinued study medication or more than 14 days after the start of a
gap in study therapy." It is not obvious how long AEs may be delayed
after study drug discontinuation. The reviewer examined AE rates in the
days following discontinuation to determine how soon the rates would
stabilize. A graph of daily AE rates post discontinuation is shown in
the following figure. The curve was drawn using a lowess smoothing
algorithm.

![](media/image43.wmf){width="4.70625in" height="3.1375in"}

AE rates do not stabilize until 90 days post discontinuation. Although
not shown, the reviewer also graphed AE rates post-discontinuation for
atenolol and losartan separately; the graphs for both drugs are very
similar to the above and to each other. The AE rates around 14 days
post-continuation are still substantially higher than the stabilized
rates. Because the excess AEs from days 15 through 90 may help
differentiate atenolol from losartan toxicities and because the sponsor
has analyzed the AEs excluding them and provided good summaries of its
analyses, the reviewer analyzed AEs including all ones occurring up to
90 days post-discontinuation.

#### 2. Serious Adverse Events

The sponsor counted serious adverse events (SAEs) in 36.2% of atenolol
and 37.2% of losartan patients using its 14-day criteria; the reviewer
counted SAEs in 37.7% of atenolol patients and 38.4% of losartan
patients using his 90-day criteria. The sponsor's tabulation of SAEs
occurring in ≥ 0.5% of patients is shown in the following table.

Specific SAEs were uncommon, i.e., \< 2%. The one SAE that occurred with
a frequency ≥ 2% in both groups was atrial fibrillation, with nearly
identical rates in both groups.

The patterns of SAEs in the reviewer's analyses including SAEs through
90 days post treatment are very similar to those in the table above. One
slight difference is worthy of comment: Atrial fibrillation SAEs through
90 days show a slight excess in the atenolol group (0.89/100 PEY with
atenolol vs 0.74/100 PEY with losartan). A second comparison is
noteworthy because of a lack of difference: depression SAEs were rare in
both groups and comparable in frequency.

COMMENT: Rates of SAEs were similar in both treatment groups. There may
be some minor distinguishing SAEs, such as more bradycardia and atrial
arrhythmic events in the atenolol group. The greater differences in
atrial fibrillation with atenolol when a longer period post-treatment
discontinuation is included raises the question again of whether
discontinuing atenolol increases event rates.

![](media/image44.png){width="6.134027777777778in"
height="7.808333333333334in"}

#### 2.1. Deaths

Total mortality rates are presented in the Efficacy section. The death
rate was slightly higher in the atenolol group (431 deaths, 9.4%) than
in the losartan group (383 deaths, 8.3%).

Causes of death were similar in the two groups with the exception of
more stroke deaths in the atenolol group. The major causes of death are
listed in the following table.

> Table 80: Reviewer's Death Causes

  ------------------------- -------------- ---------- -------------- ----------
                            **Atenolol**              **Losartan**   

                            **N**          **%**      **N**          **%**

  Aortic aneurysm           13             3.0%       10             2.6%

  Heart failure             29             6.7%       24             6.3%

  Myocardial infarction     74             17.2%      68             17.8%

  Cancer                    111            25.8%      115            30.0%

  Other                     91             21.1%      83             21.7%

  Stroke                    59             13.7%      35             9.1%

  Sudden                    54             12.5%      48             12.5%

  Total                     431            100.0%     383            100.0%
  ------------------------- -------------- ---------- -------------- ----------

In the above table cardiac arrests and a few deaths reported as
arrhythmias have been lumped into the "Sudden" death category. A few
other deaths reported as cardiac hypertrophy have been placed into the
"Heart failure" category. These consolidations were done to eliminate
small, imprecise categories. Aortic aneurysm, uncommon but not rare as a
cause of death, did not fit clearly into any other category. It is a not
rare cause of death in both treatment groups in these high risk
hypertensives with LVH.

The "Other" category includes a diverse range of non-cardiovascular
diagnoses with only the following diagnoses comprising more than 1% of
deaths: pneumonia (4.1%), other infections (2.7%), other respiratory
failure (2.7%), gastrointestinal bleeds (1.4%), pulmonary embolism
(1.2%), and renal failure (1.1%). There are no significant differences
or unusual patterns of noncardiovascular deaths in either group.

For 220 atenolol and 202 losartan patients the investigators reported
AEs as resulting in death. For none of these AEs did the investigators
consider the study medication to be the cause. About half of these
deaths were cancer related in each group. The other deaths were due to
the causes noted in the previous paragraph. There is no obvious pattern
to the causes in either group.

#### 2.2. Hospitalizations

Hospitalization rates are presented in the Efficacy section as secondary
endpoints.

Overall 3,128 adverse events led to one or more hospitalizations in
1,587 (33.9%) atenolol patients and 3,266 adverse events led to one or
more hospitalizations in 1,609 (34.9%) losartan patients. The top 20
adverse events leading to hospitalization for each group are shown in
the following table.

> Table 81: Reviewer's Top 20 Adverse Events Leading to Hospitalization

  ----------------------------------------------------------------------------------
  **Rank**   **Atenolol**                        **Losartan**                
  ---------- --------------------------- ------- --------------------------- -------
             **AE**                      **N**   **AE**                      **N**

  1          atrial fibrillation         101     atrial fibrillation         95

  2          pneumonia                   98      pneumonia                   81

  3          syncope                     47      syncope                     59

  4          transient ischemic attack   46      cholelithiasis              52

  5          cholelithiasis              46      vertigo                     40

  6          bradycardia                 43      hip osteoarthritis          35

  7          vertigo                     40      anemia                      34

  8          hip osteoarthritis          33      transient ischemic attack   34

  9          breast malignant neoplasm   32      knee osteoarthritis         33

  10         abdominal pain              32      breast malignant neoplasm   33

  11         inguinal hernia             27      cholecystitis               30

  12         musculoskeletal chest pain  27      abdominal pain              30

  13         pulmonary embolism          26      inguinal hernia             29

  14         chest pain                  26      prostatic malignant         29
                                                 neoplasm                    

  15         cholecystitis               25      deep venous thrombosis      28

  16         prostatic malignant         24      colonic malignant neoplasm  28
             neoplasm                                                        

  17         cataract                    24      prostatic disorder          28

  18         prostatic disorder          23      musculoskeletal chest pain  28

  19         colonic malignant neoplasm  22      cataract                    27

  20         spinal stenosis             21      lung malignant neoplasm     24
  ----------------------------------------------------------------------------------

Note that same three adverse event are the leading reasons for
hospitalization for both treatment groups. Some adverse events are more
frequently associated with hospitalizations in one treatment group vs.
the other: TIAs and bradycardia in the atenolol group and anemia in the
losartan group.

COMMENT: Overall rates of AEs leading to hospitalization are similar in
the two groups. There appear to be minor differences in the types of AEs
leading to hospitalization. Anemia appears to be an uncommon but
clinically important adverse effect of losartan.

#### 2.3. Other Serious Adverse Events

> The reviewer did not identify any other serious adverse events of
> interest other than those already presented.

#### 3. Events Leading to Discontinuation

Adverse events reported by the investigator as resulting in study drug
discontinuation occurred in 831 (18.1%) of atenolol patients and 604
(13.1%) of losartan patients. (These numbers include temporary
discontinuations for AEs after which the study drug was restarted.) The
AEs leading to discontinuation with a frequency ≥ 0.5% in either group
are shown in the following table. Note that asthenia, atrial
fibrillation, bradycardia, and dyspnea were substantially more frequent
causes for discontinuation in the atenolol group than the losartan
group.

> Table 82: Sponsor' Adverse Events Leading to Discontinuation at Rates
> ≥ 0.5%

![](media/image45.png){width="5.784722222222222in"
height="5.408333333333333in"}

#### 4. Events of Special Interest

The sponsor specified the following AEs to be of special interest:

-   angioedema (angioedema, tongue edema)

-   bradycardia (bradycardia, sinus bradycardia)

-   sleep disturbance (dream abnormality)

-   hypotension (blood pressure decreased, hypotension, orthostatic
    hypotension)

-   dizziness (dizziness, orthostatic dizziness, presyncope, orthostatic
    presyncope)

-   sexual dysfunction (sexual dysfunction, impotence, erectile
    dysfunction, libido decreased)

-   cold extremities (peripheral vascular disorder, skin cool to touch,
    Raynaud's phenomenon)

-   cough (ACE inhibitor induced cough, dry cough)

-   cancer

The sponsor's analysis of these events of special interest is shown in
the following table.

> Table 83: Sponsor's Rates of Events of Special Interest

![](media/image46.png){width="6.0in" height="2.408333333333333in"}

More atenolol patients experienced bradycardia, cold extremities, and
sexual dysfunction; more losartan patients experienced hypotension.

The reviewer re-analyzed the sponsor's events of special interest by the
alternative approach considering all events through 90 days after study
drug discontinuation and expressing the rates per 100 person exposure
years (PEYs). The reviewer added additional events regarding anemia (a
label note for losartan), atrial and ventricular arrhythmias, hepatic
and renal insufficiency, fatigue, depression, hyperkalemia, and
hyponatremia. The reviewer's rates for these events are shown in the
following table.

> Table 84: Reviewer's Rates of Patients with Events of Special Interest
> per 100 Person-Exposure Years

  ------------------------------------ ---------------- -----------------
                                       **Atenolol**     **Losartan**

  anemia                               1.21             1.72

  angioedema                           0.07             0.03

  atrial arrhythmia                    2.07             1.78

  bradycardia                          2.20             0.39

  cancer                               1.85             1.99

  cold extremities                     1.81             1.16

  cough                                1.82             1.84

  depression                           1.67             1.62

  dizziness                            4.13             4.11

  fatigue                              4.53             3.72

  hepatic disorder                     0.77             0.67

  hyperkalemia                         0.18             0.22

  hyponatremia                         0.26             0.27

  hypotension                          0.45             0.66

  renal dysfunction                    0.32             0.43

  sexual dysfunction                   1.21             0.87

  sleep disturbance                    0.57             0.48

  ventricular arrhythmia               0.23             0.42
  ------------------------------------ ---------------- -----------------

COMMENT: The reviewer confirmed the sponsor's observations of more
bradycardia, cold extremities, and sexual dysfunction in the atenolol
patients and slightly more hypotension in the losartan patients. The
reviewer also found more fatigue and atrial arrhythmias in the atenolol
patients and more anemia, ventricular arrhythmias, and renal dysfunction
in the losartan patients. However, the differences are small (\< 1 event
per 100 PEYs) except for bradycardia.

The sponsor defined new onset diabetes mellitus as a tertiary endpoint.
Because diabetes mellitus is also considered to be an adverse event, the
sponsor's analysis of diabetes mellitus is shown in the table below.

![](media/image47.png){width="5.94375in" height="1.082638888888889in"}

The sponsor analyzed new onset diabetes similarly to other endpoints.
Losartan patients had about a 25% lower risk of developing diabetes than
atenolol patients. Note the effects of atenolol upon blood glucose
presented in the Clinical Laboratory Tests section.

#### 5. Overall Adverse Events

Adverse event (AE) reports were common in this elderly, high-risk study
population followed for more than four years. Investigators reported
39,161 AEs in 4,376 atenolol patients and 39,623 AEs in 4,375 losartan
patients. AEs occurring at rates of greater than 1 per 100 PEYs in
either group are shown in the following table.

> Table 86: Reviewer's AE Rates Greater than 1 per 100 Person Exposure
> Years

  -----------------------------------------------------------------------
                                           **Atenolol**   **Losartan**
  ---------------------------------------- -------------- ---------------
  abdominal pain                           1.7            1.8

  albuminuria                              1.7            1.1

  asthenia/fatigue                         4.5            3.7

  atrial fibrillation                      1.5            1.3

  back pain                                2.7            3.1

  bradycardia                              2.0            0.3

  bronchitis                               2.3            2.1

  cataract                                 1.1            1.1

  chest pain                               2.7            2.8

  cough                                    1.8            1.8

  cystitis                                 1.2            1.3

  depression                               1.7            1.6

  diabetes mellitus                        1.2            1.0

  diarrhea                                 1.8            1.8

  dizziness                                3.9            3.9

  dyspnea                                  3.7            2.5

  eczematous dermatitis                    1.6            1.3

  gout                                     1.1            0.6

  headache                                 3.4            3.4

  hypercholesterolemia                     1.6            1.5

  hyperglycemia                            1.7            1.3

  hypokalemia                              1.3            1.0

  influenza-like disease                   1.6            1.6

  insomnia                                 1.3            1.2

  knee pain                                1.3            1.3

  leg pain                                 1.0            1.2

  lower extremity edema                    3.7            3.0

  muscular weakness                        1.1            0.8

  myalgia                                  1.2            1.3

  nausea                                   1.6            1.6

  peripheral vascular disorder             1.4            0.9

  pneumonia                                1.6            1.2

  rash                                     1.1            1.2

  shoulder pain                            1.3            1.3

  sinusitis                                1.2            1.2

  upper respiratory infection              4.6            4.5

  uric acid increased                      1.2            0.7

  urinary tract infection                  1.8            1.7

  vertigo                                  2.7            2.7
  -----------------------------------------------------------------------

The sponsor also tabulated AEs that the investigator judged to be
drug-related. Investigators reported drug-related AEs more frequently in
the atenolol group (45%) than in the losartan group (37%).

COMMENT: Most of the AEs with rates greater than 1 per 100 PEYs are
minor illnesses also common in the general population and probably not
related to study treatment. Of the AEs with differential rates in the
two groups only the greater rates of dyspnea, pneumonia, hyperglycemia,
lower extremity edema, gout, and uric acid increased in the atenolol
group have not been mentioned previously. The differences in rates are
small.

The difference in the two treatment groups in drug-related AEs is
similar to the difference in AEs leading to discontinuation. Given that
rates of all AEs, SAEs, and AEs leading to hospitalization were similar,
one wonders whether the differences in drug-related and AEs leading to
discontinuation are real differences in tolerability or subjective
judgments influenced by other factors. Reduction in heart rate was
common with atenolol as would be expected. One wonders whether
investigators might be more likely to call another AE in the same
patient drug-related or to discontinue treatment because of concomitant
reduced heart rate or borderline or frank bradycardia in the patient.

#### 6. Vital Signs

Changes in blood pressure and pulse are discussed in the Efficacy
section. Mean pulse rates in beats/minutes decreased by 10.1 in the
atenolol group and 1.2 in the losartan group at study end. Mean weight
in kg increased by 0.4 in the atenolol group and decreased by 0.4 in the
losartan group at study end.

#### 7. Clinical Laboratory Tests

During the study standard hematology and chemistry tests and urinary
microalbumin were monitored. The tests with mean changes that appear to
differ between the two treatment groups are shown in the following
table.

> Table 87: Sponsor's Mean Changes in Hemoglobin, Glucose, Uric Acid,
> and Urine Microalbumin by Study Year

![](media/image48.png){width="5.999305555555556in"
height="1.7479166666666666in"}

![](media/image49.png){width="5.995138888888889in"
height="2.307638888888889in"}

![](media/image50.png){width="5.930555555555555in"
height="1.211111111111111in"}

The sponsor pre-specified limits against which changes in lab values
were checked. The rates of patients exceeding these pre-specified limits
are shown in the following table.

> Table 88: Sponsor's Patient's Exceeding Predefined Limits of Change in
> Lab Test Values

![](media/image51.png){width="5.995833333333334in"
height="5.057638888888889in"}

COMMENT: The atenolol group shows small increases in serum glucose and
uric acid while the losartan group shows small decreases in serum
hemoglobin and urine microalbumin. All of these changes appear to be
related to differences in clinical event rates except the changes in
urine microalbumin. The atenolol group had more incident cases of
diabetes and gout adverse events. The losartan group had more anemia
adverse events. The reduced urine microalbumin does not appear to be
associated with a reduction in renal adverse events.

#### 8. Electrocardiograms

The NDA does not provide data or discuss changes in electrocardiograms
other than the changes in left ventricular hypertrophy criteria in the
Efficacy section.

#### 9. Overdose

Overall 72 overdoses were reported in 69 atenolol patients and 93
overdoses were reported in 88 losartan patients. The overdoses are
difficult to evaluate because other drugs may have been taken in
addition to the study drug. Other AEs were reported with the overdose in
about fourth of the losartan cases and included hypotension, dizziness,
and vertigo. Details of the overdoses, e.g., dosages, are not provided.

#### 10. Special Populations

Elderly patients (≥65) experienced more serious AEs than younger (\<65)
patients. For SAEs the rates in the elderly were 39% for atenolol and
41% for losartan; for younger patients the SAE rates were about 32% for
both atenolol and losartan. Discontinuations due to AEs also were more
frequent in the elderly and, as in the study as a whole, were more
common with atenolol. In the elderly 21% of atenolol and 15% of losartan
patients discontinued due to AEs; 14% of younger atenolol and 10% of
younger losartan patients discontinued due to AEs. Overall about 95% of
patients of either age or treatment group experienced at least one AE.

Males and females experienced AEs at similar rates in both treatment
groups. Overall about 94% of males in both groups and 96% of females
experienced one or more AEs. SAEs were slightly more frequent in males
on losartan (38%) than on atenolol (37%) and than females of either
treatment group (36%). Both males and females had fewer discontinuations
due to AEs with losartan.

Blacks on atenolol had fewer AEs overall (90%) and SAEs (28%) than
blacks on losartan. Rates of AEs and SAEs for blacks on losartan were
very similar to rates for whites. More blacks on losartan (16%) than on
atenolol (13%) discontinued treatment due to an AE. Rates of
drug-related AEs were similar in blacks on losartan (39%) and on
atenolol (40%).

COMMENT: The most pertinent finding regarding AEs in special populations
is that blacks on atenolol had fewer AEs and SAEs. While it is
conceivable that the same mechanism that led to better efficacy with
atenolol in blacks also produced fewer AEs, it is simpler to conclude
that blacks on atenolol were lower risk.

### C. Summary of Critical Safety Findings and Limitations of Data 

> The tolerability of atenolol and losartan appears comparable when
> judged by total adverse event (AE) rates (about 95% of patients in
> each group or 39,161 vs. 39,623 AEs), AEs leading to hospitalization
> (34% vs. 35%), and serious adverse (SAE) event rates (38% vs. 38%).
> Only for AEs leading to discontinuation (losartan 13% vs. atenolol
> 18%) and investigator-classified drug-related AEs (losartan 37% vs.
> atenolol 45%) does losartan appear to be superior to atenolol. While
> these rates may appear high, they must be considered in view of the
> fact that this was a prolonged research study (4+ years) in high risk
> patients with mandated reporting of any suspected AE. Overall both
> drugs appeared to be tolerated well.

The common, expected AEs included bradycardia with atenolol (9%) and
dizziness with both drugs (about 16%). Bradycardia was the most frequent
reason, and fatigue and dyspnea were other common reasons, for
discontinuation with atenolol.

One unexpected AE is that atrial fibrillation led to discontinuation in
about 1% of atenolol patients vs 0.5% of losartan patients. Atrial
fibrillation overall was only a slightly more common AE with atenolol
(1.5/100 PEY) than with losartan (1.3/100 PEY). (PEY = person exposure
year.) While the rates of and difference in reported atrial fibrillation
are not great, see the discussion of atrial fibrillation in the Efficacy
section for the possible implications regarding stroke.

An AE not totally unexpected but probably unappreciated is anemia with
losartan. Losartan has a label caution regarding small decreases in
hemoglobin. Such a decrease (about --0.5 gm/dL vs.-0.2 gm/dL with
atenolol) was seen in this study. Losartan also was associated with more
anemia AEs (1.7 vs. 1.2/100 PEY) and hospitalizations for anemia.

Atenolol also led to slightly greater increases uric acid (about 1
mg/dL) and glucose (about 4 mg/dL). These lab value changes appear to be
associated with slightly increased AE rates for gout (1.1 vs. 0.6/100
PEY) and diabetes mellitus (1.7 vs 1.3/100 PEY) respectively.

The most pertinent finding regarding AEs in special populations is that
blacks on atenolol had fewer AEs and SAEs. While it is conceivable that
the same unknown mechanism that led to better efficacy with atenolol in
blacks also produced fewer AEs, it is simpler to conclude that blacks in
the atenolol group were lower risk.

The limitation of this study is that it is not a simple comparison of
losartan to atenolol. The comparison is between regimens including
losartan or atenolol and other antihypertensives, particularly
hydrochlorothiazide. While one can presume that differences in AEs in
one treatment group are probably related to the unique comparator in
that treatment group, one is less confident that real differences in AE
rates aren't obscured by the multiple co-treatments.

AE relationships to drug and discontinuations for AEs are subjective
investigator judgments. Given that rates of all AEs, SAEs, and AEs
leading to hospitalization were similar, the review wonders whether the
differences in drug-related and AEs leading to discontinuation are real
differences in tolerability or subjective judgments influenced by other
factors. Reduction in heart rate was common with atenolol as would be
expected. The reviewer suspects that investigators might have been more
likely to call another AE drug-related or to discontinue treatment in
patients with reduced heart rate or borderline or frank bradycardia.
Overall the reviewer concludes that the losartan regimen was slightly
better tolerated than the atenolol regimen in the LIFE study, but the
evidence is not overwhelming.

## 

## VIII. Dosing, Regimen, and Administration Issues

The LIFE study used standard dosages and once daily dosing regimens for
all three specified study drugs (atenolol, losartan, and
hydrochlorothiazide.) The dosing adjustment scheme in the protocol with
a target blood pressure of \<140/90 was reasonable. The once daily
dosing is the most convenient for patients and approved for all three
drugs.

While the dosing and regimen are reasonable, there are several issues
regarding them:

-   All three drugs are approved for once daily dosing but may be more
    effective with twice daily dosing. Could differences in 24-hour
    blood pressure control contribute to the outcome differences?

-   The blood pressure goal was reasonable but not typically achieved.
    Would the outcome differences persist if blood pressure control had
    been more aggressive?

-   Atenolol was discontinued more frequently than losartan. Was this
    due to real efficacy or safety problems or a perception of problems
    heightened by bradycardia? Would the outcomes be the same if
    atenolol and losartan exposures were equal?

-   Additional antihypertensive use was not controlled. How much of the
    outcome difference is due to additional antihypertensive use?

COMMENT: Such what-if issues are easy to generate but hard to answer.
All the questions above are unanswerable by the LIFE study. The
reviewer's interpretation of the LIFE study as conducted is that it is a
reasonable comparison of antihypertensive regimens including losartan to
antihypertensive regimens including atenolol. The level of control and
use of atenolol are similar to what is achieved in current practice. The
results should be applicable to current practice.

## 

##  

## IX. Use in Special Populations

### A. Evaluation of Sponsor's Gender Effects Analyses and Adequacy of Investigation

The LIFE study included a majority (54%) of females. The sponsor
examined gender effects for both efficacy and safety. Neither the
sponsor nor the reviewer identified differential effects by gender. The
results of the LIFE study appear to be equally applicable to both
genders.

### B. Evaluation of Evidence for Age, Race, or Ethnicity Effects on Safety or Efficacy

The Efficacy section contains extensive evaluations of differential
effects by age and ethnicity. The apparent beneficial effect of losartan
overall appears to be eliminated or even reversed in blacks. Losartan
appears to be more effective in the elderly (age ≥ 65). Please see the
Efficacy section for detailed discussion of these assertions.

The Safety section contains a brief evaluation of differential safety
findings by age and ethnicity. Adverse events are more common in the
elderly but the patterns of adverse events for the two treatment groups
are not different. Blacks in the atenolol group had fewer AEs and SAEs
than blacks in the losartan group, while the rates of AEs and SAEs were
similar for whites in both treatment groups and blacks in the losartan
group. Please see the Safety section for the specifics.

### C. Evaluation of Pediatric Program

The sponsor is requesting a waiver of pediatric studies for this
indication with the following justification:

"Pursuant to 21 CFR 314.55(c), Merck is requesting a full waiver to the
pediatric data requirement for the use of losartan to reduce the risk of
cardiovascular morbidity and mortality in pediatric patients with
hypertension and LVH. The rationale for this full waiver is that
necessary studies are impossible or highly impractical because 1) the
number of such patients is very small and 2) the occurrence of stroke
and myocardial infarction in such patients is very rare.

"LIFE was an outcome study with a composite endpoint of cardiovascular
death, myocardial infarction, and stroke. Since stroke and myocardial
infarction are rare in pediatric patients with hypertension and LVH
(Sorof, Cardwell et al. 2002), it would be impractical or impossible to
conduct a study with sufficient power to measure a treatment effect in
this population.

"Please note that the FDA previously issued a Written Request for
pediatric studies for the use of losartan in children with hypertension
and that Merck submitted a sNDA fully responding to the WR. The FDA
Pediatric Exclusivity Board determined on March 20, 2000, that Merck's
sNDA for losartan pediatric studies met the terms of the agency's
Written Request. Proposed labeling changes based on the sNDA are still
under review at the FDA."

COMMENT: The reviewer believes that the request for a waiver of
pediatric studies for this new indication is justified.

### D. Comments on Data Available or Needed in Other Populations

> Two issues raised by the LIFE study are important ones that need
> additional data to confirm or refute:

-   Is the beneficial effect of losartan reversed vs. reduced or neutral
    in blacks? The reviewer believes that this question can not be
    answered definitively with the LIFE data. There is probably no other
    existing data that can answered definitively, so another trial is
    needed.

-   Is atenolol associated with more atrial fibrillation and strokes?
    There may be data from existing studies using atenolol for
    hypertension or angina that could provide additional evidence to
    answer this question.

## X. Conclusions and Recommendations

### A. Conclusions

The LIFE study is not a simple study to interpret. If one focuses on the
primary composite endpoint alone, then the LIFE study was successful in
showing that regimens including losartan are superior to regimens
including atenolol in the LIFE study population. However, the
statistical significance is not extreme and the results are not terribly
robust. There are several factors (differences in blood pressure
control, differences in endpoint determinations, differences in study
drug usage) that could make the results even more uncertain than the
simple p value indicates. Overall, however, the reviewer believes that
it is most reasonable to stick with the simple analysis of the primary
composite, substituting only the Division's recommendation of
incorporating total mortality rather than cardiovascular mortality. By
this standard the LIFE study was successful.

The LIFE study is the only study supporting the new indication. However,
because the magnitude of the treatment effect (a 10% risk reduction) is
reasonable and the endpoint is vital, the reviewer believes that a
description of the beneficial effect of losartan in the LIFE study
should be included in the losartan label.

> Some analyses of the LIFE study suggest a qualitative interaction,
> i.e., a reversal of the beneficial effect of losartan, in blacks.
> However, blacks were a subgroup with different baseline
> characteristics and different responses than the rest of the study
> population. The results of the LIFE study suggest that losartan is not
> superior to atenolol in blacks. The evidence from the LIFE study is
> not conclusive for establishing that losartan is inferior to atenolol
> in blacks.
>
> Other subgroups analyses also generated interesting differences.
> Because they are subgroup analyses they must be interpreted with
> caution.

-   Losartan appears to be more effective in the elderly. Losartan may
    be less effective in males younger than 65.

-   Losartan appears to be more effective in patients with isolated
    systolic hypertension at baseline. Isolated systolic hypertension is
    more frequent in the elderly.

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-   Losartan appears to be more effective in patients with diabetes at
    baseline. Losartan was also associated with a lower rate of onset of
    new diabetes.

One finding that is surprising is that atenolol use appeared to be
associated with more atrial fibrillation and more strokes associated
with atrial fibrillation. These associations need verification from
other data.

This large, long-term study helps to define better the safety profiles
of both losartan and atenolol. Overall the LIFE study confirms the
tolerability of both drugs. The one additional detail regarding losartan
safety that should be considered for the label is the rate of anemia.
For atenolol, the increases rates of gout and diabetes should be
considered for the label. The possible association of atenolol with
increased rates of atrial fibrillation needs verification before being
incorporated into labeling.

### B. Recommendations

The reviewer recommends that the new indication be approved as "to
reduce the risk of death and cardiovascular morbidity as measured by the
combined incidence of death, stroke, and myocardial infarction in
hypertensive patients with left ventricular hypertrophy." The reviewer
will add more detailed recommendations on labeling in an addendum to
this review.

Two issues need follow-up:

-   The LIFE study raises a question regarding whether the beneficial
    effect of losartan is reversed in blacks. Other data sources should
    be sought to help address this issue.

-   The possible association of atenolol use with increased rates of
    atrial fibrillation and strokes needs verification. Other data
    sources should be consulted to address this issue as well.

## XI. Appendix

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