Date: February 3, 2003

From: Ellis F. Unger, M.D.

Team Leader

General Medicine Branch

Division of Clinical Trial Design and Analysis (DCTDA)

Office of Therapeutics Research and Review (OTRR)

Center for Biologics Evaluation and Research

U.S. Food and Drug Administration

Subject: Briefing Document for Arthritis Advisory Committee

Etanercept (Enbrel®) and Congestive Heart Failure

Through: Marc Walton, M.D., Ph.D., Chief, General Medicine Branch, DCTDA

Karen Weiss, M.D., Director, DCTDA

####### Table of Contents

Background [3](#background)

Objectives [4](#objectives)

Study Design [4](#study-design)

Data Safety Monitoring Board (DSMB)
[4](#data-safety-monitoring-board-dsmb)

Patient Population [4](#patient-population)

Major Inclusion Criteria [4](#major-inclusion-criteria)

Major Exclusion Criteria [5](#major-exclusion-criteria)

Randomization [5](#randomization)

Primary Endpoint [5](#primary-endpoint)

Secondary Endpoints [6](#secondary-endpoints)

Statistical Analysis Plan [6](#statistical-analysis-plan)

Interim Analyses [6](#interim-analyses)

Study Results [6](#study-results)

Patient Disposition [6](#patient-disposition)

Protocol Deviations [7](#protocol-deviations)

Study Population: Baseline Characteristics
[7](#study-population-baseline-characteristics)

Concomitant Medications [11](#concomitant-medications)

Study Agent Dosing [14](#study-agent-dosing)

Efficacy Results [14](#efficacy-results)

Clinical Composite Score [14](#clinical-composite-score)

All-Cause Mortality and CHF Hospitalizations (Combined Studies)
[15](#all-cause-mortality-and-chf-hospitalizations-combined-studies)

NYHA Functional Classification [17](#nyha-functional-classification)

Global Assessment of Heart Failure
[17](#global-assessment-of-heart-failure)

MLWHF Quality of Life Questionnaire
[17](#mlwhf-quality-of-life-questionnaire)

Safety [17](#safety)

Mortality and CHF Hospitalizations
[17](#mortality-and-chf-hospitalizations)

Exploratory Analyses on Mortality and CHF Hospitalizations
[21](#exploratory-analyses-on-mortality-and-chf-hospitalizations)

Functional Class and Mortality [22](#functional-class-and-mortality)

Cardiovascular Adverse Events [25](#cardiovascular-adverse-events)

Vital Signs [27](#vital-signs)

Summary and Recommendations [28](#summary-and-recommendations)

#  {#section .unnumbered}

# Background

Etanercept, recombinant human TNF receptor (rhu TNFR:Fc), is a fusion
protein dimer consisting of 2 identical molecules of the extracellular
portion of the (p75) TNF receptor fused to the Fc portion of IgG1. The
product binds to and inactivates the pro-inflammatory cytokine TNF-;
neutralization of TNF- is the anticipated mode of action of the agent.

Several lines of experimental evidence support a potential role of TNF-
in the pathogenesis of congestive heart failure (CHF). Elevated
circulating levels of TNF- have been associated with advanced CHF, and
TNF- has been immunolocalized in cardiac myocytes of explanted hearts
from patients with dilated cardiomyopathy and ischemic heart disease.
TNF- is also negatively inotropic *in vivo*, and can produce
cardiomyopathy and pulmonary edema in animal models. It has been
hypothesized that expression of cytokines such as TNF- constitutes an
adaptive response to myocardial injury, and that TNF- overexpression may
lead to deleterious cardiac remodeling with progressive left ventricular
(LV) dysfunction.

Two phase 2/3 studies were conducted concurrently: A North American
study: Randomized Etanercept North American Strategy to Study Antagonism
of Cytokines ("RENAISSANCE"), protocol 1600.21, conducted by Immunex
Corporation, and a similar study conducted by Wyeth in Europe,
Australia, and New Zealand: Randomized, Double-Blind,
Placebo-Controlled, Multicenter Trial of the Efficacy and Safety of
Soluble Recombinant Human Tumor Necrosis Factor Receptor Fc Fusion
Protein in Patients with Congestive Heart Failure (class 2-4),
"RECOVER," study 0881A2-200-EU. Combined analyses of all-cause mortality
and CHF hospitalizations were provided in "RENEWAL."

The two studies share similarities in their objectives, designs and
patient populations, and are described together in this briefing
document. Where appropriate, similarities and differences between the
studies are discussed.

**Protocol 1600.21 -- "RENAISSANCE"**

Title: Multicenter, Double-Blind, Randomized, Placebo-controlled, Phase
2/3 Study of the Efficacy and Safety of Recombinant Human Tumor Necrosis
Factor Receptor (p75) Fc Fusion Protein (TNFR:Fc) (etanercept) in
Patients with Chronic Heart Failure (Class II-IV).
[R]{.underline}andomized [E]{.underline}tanercept [N]{.underline}orth
[A]{.underline}mer[i]{.underline}can [S]{.underline}trategy to
[S]{.underline}tudy [An]{.underline}tagonism of
[C]{.underline}ytokin[e]{.underline}s "RENAISSANCE"

Study Period: March 18, 1999 -- June 21, 2001

Funding: Immunex Corporation

Centers: 105 sites in the US and Canada

**Protocol 0881A2-200-EU/AU/NZ -- "RECOVER"**

Title: A Phase 2/3, Randomized, Double-Blind, Placebo-Controlled,
Multicenter Trial of the Efficacy and Safety of Soluble Recombinant
Human Tumor Necrosis Factor Receptor Fc Fusion Protein
(etanercept/TNR-001) in Patients with Congestive Heart Failure (class
II-IV). [R]{.underline}esearch into [E]{.underline}tanercept:
[C]{.underline}yt[o]{.underline}kine Antagonism in
[Ve]{.underline}ntricula[r]{.underline} Dysfunction Trial "RECOVER"

Study Period: July, 1999 -- June, 2001

Funding: Wyeth-Ayerst Research

Centers: 194 sites in the European Union (EU), Australia, and New
Zealand

## Objectives

Each study had two primary objectives. The first primary objective of
each study was to compare the effect of Etanercept and placebo as
measured by a clinical composite score at 24 weeks. The clinical
composite score was to classify subjects as improved, unchanged, or
worsened, based on vital status, hospitalizations for worsening CHF, New
York Heart Association (NYHA) Functional Class (FC), and patient global
assessment of heart failure. For each study, the second primary
objective was a combined analysis of all-cause mortality and
hospitalizations for CHF across both studies.

## Study Design

RENAISSANCE was a double-blind, randomized, placebo-controlled,
multicenter trial. Subjects were randomized to three (3) treatment
groups:

> a\) etanercept 25 mg SC BIW and placebo QW
>
> b\) etanercept 25 mg SC TIW
>
> c\) placebo SC TIW

An overall sample size of 900 was planned, with 300 subjects for each
treatment group (1:1:1 randomization). There was a 24 week study period,
during which treatment was maintained, followed by a blinded maintenance
period with safety evaluations every 12 weeks. Subjects were to continue
study agent until all subjects across both studies had completed 24
weeks of follow-up. Accrual of 900 subjects over 12 months at 100 sites
(average 9 subjects/ site) was planned.

Treatment assignment followed a 2 to 4-week screening period.
Randomization was blocked within study sites, and stratified based on
baseline beta-blocker use and NYHA functional classification. A
centralized interactive randomization system was used to randomize
subjects once consent was signed, and randomization was irreversible.

RECOVER followed the same basic study design, with the exception of the
dosing regimens:

> a\) etanercept 25 mg SC QW and placebo QW
>
> b\) etanercept 25 mg SC BIW
>
> c\) placebo SC BIW

An n of 300 subjects was planned for each treatment group.

### Data Safety Monitoring Board (DSMB)

A DSMB monitored major clinical events (deaths and hospitalizations) and
safety during the studies. The DSMB could recommend early study
termination for persuasive evidence of harm, evidence of futility, or
evidence of very considerable benefit.

## Patient Population

### Major Inclusion Criteria

-   Adult subjects with CHF on ischemic or non-ischemic basis, NYHA FC
    II-IV, LV ejection fraction (EF) 30%

-   Medications required: diuretic and angiotensin converting enzyme
    (ACE) inhibitor, unless intolerance or contraindication to ACE
    inhibitor

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-   Medications allowed: digoxin, angiotensin II antagonists (if
    intolerant to ACE inhibitors), beta-blockers, nitrates, hydralazine,
    amiodarone, and warfarin

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```
-   Ambulatory, able to traverse \< 375 meters in a 6-minute walk test,
    or \< 425 meters if hospitalized for CHF within 6 previous months

### Major Exclusion Criteria

-   inability to exercise; congenital heart disease; uncorrected
    valvular disease; hypertrophic or peripartum cardiomyopathy;
    constrictive pericarditis; primary pulmonary HTN or severe primary
    lung disease; sick sinus syndrome, advanced heart block (in the
    absence of a functioning pacemaker); systolic blood pressure (BPs)
    \> 160 or \< 80 mm Hg; diastolic blood pressure (BPd) 100 mm Hg;
    serum creatinine 3.0 mg/dL

-   recent acute MI, coronary angioplasty; revascularization or valve
    surgery; hospitalization for unstable angina; ventricular
    tachycardia (VT), fibrillation (VF), or sudden cardiac death without
    implantable cardiac defibrillator; implantable cardiac defibrillator
    discharge; cerebrovascular accident; transient ischemic attack;
    active/severe infection

### Randomization

For both studies, randomization was blocked by study site, NYHA FC, and
use of beta-blockers at screening. Randomization was considered an
irreversible event.

### Primary Endpoint 

Each study had two co-primary efficacy endpoints: 1) Clinical Composite
Score at Week 24; and 2) all-cause mortality and CHF hospitalizations
across both studies together. The Clinical Composite Score could take
values of "improved," "unchanged," or "worse," based on vital status,
hospitalizations for CHF, change in NYHA FC, and subject-self
assessment.

The Clinical Composite Score was to take a value of worse if NYHA FC and
Global Assessment were discordant.

A subject was considered to have had a CHF hospitalization if he/she was
hospitalized for, or with, worsening CHF (involving an overnight stay
defined as a change in dates) and received IV diuretics, vasodilators,
or positive inotropic drugs for the treatment of CHF. A blinded Endpoint
Committee was to make this determination.

For the co-primary endpoint across the two studies, a treatment failure
was defined as death or at least one hospitalization for CHF.

### Secondary Endpoints

Numerous secondary endpoints included: number of hospitalizations for
CHF and emergency department visits for worsening CHF; changes in NYHA
FC, patient global assessment, and Minnesota Living with Heart Failure
(MLWHF) Scale (baseline to 24 weeks).

## Statistical Analysis Plan

The Clinical Composite Score was analyzed using a proportional odds
logistic regression model controlling for baseline NYHA FC and
beta-blocker use. To control type I error across the two components of
the 1° endpoint, an alpha of 0.04 was to be allocated to the Clinical
Composite Score in both studies. The combined all-cause mortality and
morbidity endpoint was allocated an alpha of 0.01, such that the overall
2-sided alpha for each study was 0.05. A true intention-to-treat
approach was used, including all randomized subjects.

"RENEWAL" was the combined analysis across both studies. All-cause
mortality and morbidity (CHF hospitalizations) were summarized using
Kaplan-Meier curves in a time to first event analysis. Treatment
comparisons were planned by log-rank test, stratified by study, baseline
beta-blocker use, and NYHA FC. Subjects lost to follow-up were censored
at the time of loss. The single primary outcome was the comparison
between the combined placebo group and the combined BIW and TIW
Etanercept groups. A Cox proportional hazards model was used to assess
the importance of major covariates on the results.

### Interim Analyses

An independent DSMB monitored unblinded safety and major clinical events
in both trials. After a planned interim review of unblinded data from
both RENAISSANCE and RECOVER, the DSMB recommended that both studies be
halted because of futility.

## Study Results

### Patient Disposition

RENAISSANCE: A total of 925 subjects were randomized in the study: 309
subjects were randomized to placebo, and 308 subjects were randomized to
each of the Etanercept groups. When the study was closed at the
recommendation of the DSMB, 76% of subjects were still participating in
the blinded study, and 82% had completed the Week 24 evaluations. The
rates of discontinuation were similar in the 3 treatment groups (\~23 to
26%). More than half of the discontinuations were for death (\~14%), 5%
were for patient refusal, and 2% were for other reasons.

RECOVER: A total of 1123 subjects were randomized: 373 were assigned to
placebo, 375 were assigned to each of the Etanercept groups (25 mg QW;
25 mg BIW). Across all three treatment groups, approximately 85% of
subjects were withdrawn from the study because of the sponsor's decision
to discontinue the investigation. Death accounted for 7% of
discontinuations, followed in decreasing frequency by subject request
(2%), adverse event (2%), and miscellaneous reasons. There were no
imbalances in discontinuations between groups.

### Protocol Deviations

Protocol violations were relatively sporadic in both studies, and
unlikely to importantly affect the study results or interpretation.

## Study Population: Baseline Characteristics

Table 2 and Table 1 provide summaries of baseline demographic
characteristics and cardiovascular disease status by treatment group for
RENAISSANCE and RECOVER, respectively. Table 3 and Table 4 summarize CHF
etiologies and related illnesses for the two studies.

RENAISSANCE: Seventy-eight percent (78%) of subjects were male, and 84%
were Caucasian. Mean age was 62 years. The subjects were predominantly
NYHA FC III (73%), with two-thirds of these subjects categorized as FC
IIIA; one-third classed as FC IIIB. Twenty-four percent (24%) and 5% of
subjects categorized as FC II and FC IV, respectively. Median BPs and
BPd were 108 and 66 mm Hg, respectively. Median heart rate was 72 beats
per minute. Median EF was 23%. The mean duration of CHF was 5.6 years,
with 36% of subjects having a history of a hospitalization within the
previous 6 months. Beta-blocker use was reported in 61% of subjects.
Balance between treatment groups was adequate, with the exceptions of
systolic/diastolic BP (lower in the Etanercept groups) and 6-minute walk
distance (less in the Etanercept groups).

*[Reviewer\'s Comment:]{.underline}* Blood pressure and 6-minute walk
distance have prognostic implications in CHF, and these imbalances
impart a less favorable prognosis in the Etanercept groups.

Sixty-two percent (62%) of subjects were reported to have CHF on an
ischemic basis, with a previous myocardial infarction reported in 40% of
subjects (Table 3). An idiopathic basis for CHF was reported in 26% of
subjects. The next leading etiology was HTN (4%). Of note, 22% of
placebo subjects had an implanted cardioverter/ defibrillator, compared
to 16% of Etanercept-treated subjects. The frequencies of related
illnesses were fairly well-balanced between treatment groups, with the
exceptions of HTN, chronic lung disease, and atrial
fibrillation/flutter - - all of which were reported more frequently in
the Etanercept groups (Table 3).

*[Reviewer\'s Comment:]{.underline}* The greater percentage of placebo
subjects with implanted defibrillators suggests more of a propensity
towards arrhythmias in this group. Paradoxically, however, it could be
argued that the placebo subjects are better protected against sudden
death, because of the presence of the defibrillators.

RECOVER: The vast majority of subjects were white (99%) and male 78%
(Table 1). Mean age was 64.6 years. The breakdown with respect to
functional classification was very similar to that of the North American
study, with excellent balance between treatment arms. Median EF was 24%.
Mean systolic and diastolic blood pressures were 120 mm Hg and 75 mm Hg,
respectively. Mean heart rate was 72 beats per min. Median duration of
CHF was 4.6 years.

There was good balance of these parameters across the treatment groups.

The etiologies of CHF in RECOVER were very similar to those of the North
American study: 62% of subjects were reported to have CHF on an ischemic
basis, 26% were idiopathic, and 5% were related to HTN. Related
illnesses were reasonably well-balanced between treatment groups.

Compared with subjects in the North American study, subjects in RECOVER
were, on average, slightly older (64.6 versus 62.3 years) and lighter
(79 versus 85 kg), with a higher BP (120/75 versus 108/66 mm Hg), and a
shorter duration of CHF (4.6 versus 5.6 years). Eighty-four percent
(84%) of North American subjects were Caucasian, compared to 99% in
RECOVER. The breakdown of NYHA FC and mean EF were similar in the two
studies, and the underlying etiologies of CHF were similar, as above.

Concomitant illnesses were generally similar in frequency, with the
exception of HTN (overall reported frequencies of 45% in RECOVER versus
55% in RENAISSANCE), VT/VF (23% in RENAISSANCE versus 11% in RECOVER),
and hyperlipidema (61% in RENAISSANCE versus 44% in RECOVER).
Differences in the frequencies of VT/VF and hyperlipidema may relate, in
part, to differing diagnostic criteria.

![](media/image1.wmf){width="5.446527777777778in"
height="5.7131944444444445in"}![](media/image2.wmf){width="5.446527777777778in"
height="4.636805555555555in"}

![](media/image3.wmf){width="5.9944444444444445in"
height="5.770138888888889in"}

![](media/image4.wmf){width="5.9944444444444445in"
height="4.126388888888889in"}

### Concomitant Medications

RENAISSANCE: Concomitant medication use was similar across treatment
groups (Table 5), with the exception of antiarrhythmics (21% in the
Etanercept groups versus 15% in the placebo group). Virtually all
subjects were taking an ACE inhibitor or angiotensin II antagonist,
although use of angiotensin II antagonists was slightly greater in the
Etanercept groups, and use of ACE inhibitors was correspondingly less.
Beta-blocker use was recorded in 61% of subjects overall. Digoxin use
was recorded in 82% of subjects, with nitrate use in 44%. Spironolactone
use was reported in approximately one-third of subjects overall, with
calcium channel blocker use and vasodilator use reported in 7% and 6% of
subjects, respectively.

RECOVER: There was good balance across treatment groups with respect to
recorded concomitant medication use (Table 6). Virtually all subjects
were taking a diuretic and an ACE inhibitor or angiotensin II
antagonist; 91% of subjects were taking a potassium-sparing diuretic;
63% of subjects were taking beta-blockers; and 54% of subjects were
taking digitalis compounds.

Compared to subjects in the North American study, subjects in RECOVER
were more likely to be using a potassium-sparing diuretic, and slightly
more likely to be taking an ACE inhibitor in favor of an angiotensin II
antagonist. In addition, subjects in RECOVER were more likely to be
taking nitrates (52% versus 44% in RENAISSANCE), and less likely to be
taking digitalis compounds (54% versus 82%) and lipid lowering agents
(37% versus 55%). Use of antiarrhythmics, beta-blockers, and
antithrombotic agents was similar in the two studies overall.

![](media/image5.wmf){width="5.995833333333334in"
height="3.0083333333333333in"}

Overall, the subject populations in the two studies were generally
similar. There were no substantial differences between studies in the
etiology of CHF, baseline NYHA functional classification, or LVEF. Key
differences between the subject populations are summarized in Table 7.
Of note, despite a higher mean weight and a greater frequency of HTN in
the North American subjects, the mean BP was actually substantially
*lower* in RENAISSANCE. This suggests more aggressive use of ACE
inhibitors, beta-blockers, and/or diuretics in the North American
subjects. In addition, the North American study is notable for a much
lower rate of potassium-sparing diuretic use, and higher rates of use of
digitalis and lipid-lowering agents (statins).
![](media/image6.wmf){width="5.995833333333334in"
height="3.1805555555555554in"}

### Study Agent Dosing![](media/image7.wmf){width="4.770138888888889in" height="2.3069444444444445in"}

RENAISSANCE: Compliance was similar between treatment groups. The 70% of
subjects who prematurely discontinued study agent did so because of the
sponsor's decision to close the study. There were no important
differences in the numbers of subjects who discontinued study agent
prematurely because of adverse events, death, or worsening CHF.

RECOVER: All subjects prematurely discontinued the study agent, largely
because of the sponsor's decision to close the investigation. Study
closure accounted for discontinuation in 85% of subjects. Aside from
study closure and death, other reasons for discontinuation were uncommon
and similar in the three treatment groups. Adverse events led to
discontinuation in 5 subjects (1%) in the placebo group, and 18 subjects
(2%) in the combined Etanercept groups.

## Efficacy Results

### Clinical Composite Score

RENAISSANCE: The clinical composite score data are summarized in Table
8. There were no statistically significant differences between groups.
In general, relative to control subjects, a larger fraction of
Etanercept-treated subjects experienced worsening of clinical status.

![](media/image8.wmf){width="5.003472222222222in"
height="1.1868055555555554in"}

RECOVER: Fifty-six percent (56%) underwent the protocol-specified
evaluation of clinical status at Week 24, or reached a protocol-defined
endpoint (death or CHF hospitalization) while on study. Ninety-five
percent (95%) of subjects achieved at least 16 weeks of study, and 78%
of subjects achieved at least 20 weeks. Clinical composite data for all
subjects are summarized in Table 9.

![](media/image9.wmf){width="5.003472222222222in"
height="1.1868055555555554in"}

There were no significant differences in outcome among treatment groups.
Results were similar across NYHA functional classes. Though there was a
statistically significant difference in favor of Etanercept in NYHA FC
IV patients, the number of subjects with FC IV CHF was very limited (3%
of the total), and the relevance of this observation is questionable
(data not shown). There was a trend in favor of Etanercept in patients
who did not report beta blocker use at baseline; however, the trend was
observed only in the BIW dosing group (data not shown).

### All-Cause Mortality and CHF Hospitalizations (Combined Studies)

Results of all-cause mortality and CHF hospitalizations for "RENEWAL,"
the combined analysis over "RENAISSANCE" and "RECOVER" and the
co-primary endpoint for both studies, are shown in Table 10. The data
must be interpreted cautiously, however, because of the disparity
between the two investigations with respect to time-on-study. There were
no significant differences between groups, although there was a trend
towards higher mortality in the Etanercept BIW + TIW group.

![](media/image10.wmf){width="5.99375in" height="1.8145833333333334in"}

Of note, the trend towards higher all-cause mortality/CHF in the
Etanercept BIW + TIW group is driven almost entirely by the difference
in all-cause morality. For CHF hospitalizations alone, shown at the
bottom of Table 10, the rates are fairly similar.

The interpretation of this trend is also confounded by imbalances in a
few prognostically important variables, specifically BP, 6-minute walk,
and baseline use of antiarrhythmics, all of which favor placebo.

Figure 1 shows the Kaplan-Meier survival curves for "RENEWAL." The
pre-specified endpoint compares the placebo group to the combined BIW
and TIW Etanercept groups. The log-rank p-value for this analysis is
0.35. The survival curves are superimposable thorough week 48, with a
clear divergence developing thereafter, favoring survival in the placebo
group. At week 48, however, roughly only 37% of the original subjects in
each group remain at risk.

The Kaplan-Meier curves for all-cause mortality and CHF hospitalizations
are shown in Figure 2. again comparing placebo to combined BIW and TIW
Etanercept. The log-rank p-value is 0.15.

###  ![](media/image11.wmf){width="4.629861111111111in" height="3.7243055555555555in"}![](media/image12.wmf){width="4.259722222222222in" height="3.55in"}

### NYHA Functional Classification

RENAISSANCE: For the categorical change from baseline to Week 24, there
was no significant difference across treatment groups with respect to
improvement. There was, however, a significant difference in the
proportions of subjects with worsened NYHA FC at Week 24. Six percent
(6%) of placebo-treated subjects experienced worsening of their NYHA FC,
compared to 11% of subjects in each of the Etanercept-treated groups.

RECOVER: There were no significant differences among treatment groups
with respect to either the final distributions of NYHA FC, or the
changes in NYHA FC.

### Global Assessment of Heart Failure

There were no significant differences across treatment groups with
respect to patient or physician global assessments of heart failure at
Week 24.

### MLWHF Quality of Life Questionnaire

There were no significant differences across treatment groups in change
from baseline for the MLWHF questionnaire scores.

## Safety

### Mortality and CHF Hospitalizations

RENAISSANCE: The mean duration of exposure to study agent was 10.8
months. Table 11 (top) summarizes results for all-cause mortality,
all-cause mortality or CHF hospitalization, and CHF hospitalization.
Though morality rates for the three groups are statistically
indistinguishable, there is a trend towards greater mortality in the
Etanercept groups, as well as a trend suggesting a dose-response. The
rates of CHF hospitalizations are virtually the same in each group, such
that the trend in all-cause mortality/CHF hospitalizations is driven
entirely by differences in mortality.

RECOVER: RECOVER was initiated after RENAISSANCE and discontinued at the
same time. As a result, the mean duration of exposure in RECOVER was
approximately 60% of that of RENAISSANCE - - 6.4 months. Table 11
(bottom) shows all-cause mortality and CHF hospitalizations for RECOVER.
Mortality and CHF hospitalizations tended to be less frequent in RECOVER
than in RENAISSANCE. Much but not all of this difference can be
accounted for by the difference in time on-study.

![](media/image13.wmf){width="5.379861111111111in"
height="1.7965277777777777in"}![](media/image14.wmf){width="5.379861111111111in"
height="1.7965277777777777in"}

Figure 3 shows the Kaplan-Meier curves for all-cause mortality for
RENAISSANCE (top) and RECOVER (bottom). In RENAISSANCE, there is a trend
toward lower risk with placebo (log-rank p =0.236). In RECOVER, the
trend is towards minimally lower risk with Etanercept: at Week 27, a
point in time at which 40% of the subjects are still at risk, survival
rates are 93.0%, 95.0%, and 94.5% for the placebo, Etanercept QW, and
Etanercept BIW groups,
respectively.![](media/image15.wmf){width="3.875in"
height="3.0in"}![](media/image16.wmf){width="3.875in" height="3.0in"}

Figure 4 shows the Kaplan-Meier curves for all-cause mortality and CHF
hospitalizations for RENAISSANCE (top) and RECOVER (bottom). For
RENAISSANCE, there is some separation between the placebo group and the
two Etanercept groups, favoring the placebo group. After Week 30, the
Etanercept groups diverge, with less favorable outcomes in the TIW
versus the BIW group. In RECOVER, there is no appreciable sustained
separation of the curves.

![](media/image17.wmf){width="4.125in"
height="3.527083333333333in"}![](media/image18.wmf){width="4.125in"
height="3.527083333333333in"}

### Exploratory Analyses on Mortality and CHF Hospitalizations

Given the trend in favor of excess mortality for Etanercept-treated
subjects in RENAISSANCE and the absence of a similar trend in RECOVER,
CBER focused on disparities between the patient populations of the two
studies that might contribute to the difference in outcome. Such
analyses had the potential to define particular subgroups at heightened
risk of Etanercept-related morbidity. The primary differences,
summarized in Table 7, include race, BP (lower in NA), use of
potassium-sparing diuretics (less frequent in NA), use of digitalis
compounds (more frequent in NA), and use of lipid lowering agents (more
frequent in NA).

[Race]{.underline}

Overall, 11.5% of subjects in RENAISSANCE were of African ancestry,
compared to \<1% of subjects in RECOVER. For the RENAISSANCE study, CBER
performed time-to-event mortality analyses by race. There were no
apparent differences in mortality trends between Caucasians and African
Americans.

[Blood]{.underline} [Pressure]{.underline}

On average, BP was \~10 mmHg lower in RENAISSANCE subjects than in
RECOVER subjects. Therefore, it is reasonable to hypothesize that lower
BP might make patients more susceptible to deleterious effects of
Etanercept, which could explain the differences in study outcomes. CBER
analyzed all-cause mortality and CHF hospitalizations by treatment and
BP tertile, across both studies. Mean arterial pressure (MAP) was
defined as: 1/3 X systolic pressure + 2/3 X diastolic pressure. Tertile
1 was defined as a MAP \< 80 mmHg; tertile 2 was defined as: 80 mmHg MAP
\<91.67 mmHg; and tertile 3 was defined as a MAP 91.67 mmHg. Because MAP
tertiles were constructed over the combined studies, and because MAP
tended to be lower in the NA study, roughly half of the patients in
RENAISSANCE fell into the lowest MAP tertile. If a lower BP imparted a
heightened sensitivity to deleterious effects of Etanercept, this would
be most apparent in subjects in RENAISSANCE within the lowest BP
tertile. In fact, subjects in this tertile had similar results,
irrespective of whether or not they received Etanercept. Thus, the data
for the lowest BP tertile do not support a particular susceptibility to
harmful effects of Etanercept. The disparity in outcomes (i.e., greater
frequency of mortality and CHF hospitalizations with Etanercept) was
primarily evident in the two upper MAP tertiles, i.e., patients with MAP
80 mmHg. In RECOVER, the lines crossed fairly frequently within each MAP
tertile, and there was no apparent interaction between treatment and
MAP.

Overall, differences in BP between the two studies do not appear to
account for the disparate outcome trends.

[Use of Potassium-Sparing Diuretics]{.underline}

Given that roughly a third of subjects in RENAISSANCE reported
potassium-sparing diuretic use at baseline, compared with \~90% of
subjects in RECOVER, the two-thirds of subjects in RENAISSANCE who were
not using potassium-sparing diuretics at baseline represent a subgroup
of interest. CBER analyzed mortality and CHF hospitalizations by
treatment group, separately for subjects with and without reported use
of potassium-sparing diuretics at baseline. The analysis showed
consistent outcomes with respect to Etanercept, for subjects with and
without baseline use of potassium-sparing diuretics.

[Use of Digitalis Agents]{.underline}

In both studies, there was a negative association between digoxin use
and outcome. This was particularly evident in RECOVER.

Digitalis glycoside use was reported in 82% of subjects in RENAISSANCE.
Thus, the results in these subjects were entirely consistent with those
of the study as a whole. For the 18% of subjects wherein digoxin use was
not reported, the trend was also similar to that of the study as a
whole.

Digoxin use was reported in 54% of subjects in RECOVER. For these
subjects, outcomes tended to be better in the Etanercept groups. For
subjects wherein digoxin use was not reported, outcomes tended to be
worse with Etanercept. Considered together, these data do not suggest a
unifying hypothesis regarding digoxin and Etanercept use in patients
with CHF

[Use of Lipid Lowering Agents]{.underline}

There was no apparent association between the use of lipid-lowering
agents and outcome in either study, and no apparent interaction between
the use of these agents and Etanercept.

In summary, these analyses fail to identify factors predictive of a
negative outcome in patients with CHF who received Etanercept - -
factors that might be of value in labeling.

### Functional Class and Mortality 

In light of the prognostic importance of NYHA FC, CBER examined
mortality data for possible interactions between treatment group and
NYHA FC.

Figure 5 shows all-cause mortality within NYHA FC by treatment group.
Because so few NYHA FC IV subjects were enrolled (5% in Renaissance; 3%
in Recover), only the Kaplan-Meier plots for NYHA FC II, IIIa, and IIIb
are shown. The curves for Renaissance are shown in the left panels;
curves for Recover are shown in the right panels.

For Renaissance, the trend towards greater mortality in the Etanercept
groups is most evident in the FC II subjects. The major importance of
this observation is that it suggests that the risk of Etanercept in the
CHF patient population is not restricted to patients who are most
severely affected with CHF. The results suggest that it would not be
appropriate to provide reassurance in labeling regarding the risk of
Etanercept in patients with only mild CHF (i.e., NYHA FC II). For
Recover, there are no clear trends, and it is important to note that
only half of the total number of subjects remain at risk after 23 weeks.

Figure 6 shows the complementary analysis - - the relation between NYHA
FC and mortality by treatment group. Again, the Kaplan-Meier curves for
Renaissance and Recover are depicted on the left and right,
respectively. Note that the NYHA FC IV subjects are included in these
plots. Associations between more advanced FC and mortality are generally
apparent for each treatment group in both studies.

### ![](media/image19.wmf){width="4.0in" height="2.6805555555555554in"}![](media/image20.wmf){width="4.0in" height="2.6805555555555554in"}![](media/image21.wmf){width="4.0in" height="2.6805555555555554in"}![](media/image22.wmf){width="4.0in" height="2.6805555555555554in"}![](media/image23.wmf){width="4.0in" height="2.6805555555555554in"}![](media/image24.wmf){width="4.000694444444444in" height="2.6805555555555554in"}

###  ![](media/image25.wmf){width="3.3743055555555554in" height="2.261111111111111in"}![](media/image26.wmf){width="3.375in" height="2.2618055555555556in"}![](media/image27.wmf){width="3.3743055555555554in" height="2.261111111111111in"}![](media/image28.wmf){width="3.3743055555555554in" height="2.261111111111111in"}![](media/image29.wmf){width="3.3743055555555554in" height="2.261111111111111in"}![](media/image30.wmf){width="3.375in" height="2.261111111111111in"}

### Cardiovascular Adverse Events

Analysis of cardiovascular adverse event rates has the potential to
provide supportive evidence regarding deleterious effects of Etanercept
in the CHF patient population, as well as to provide clues to help
elucidate mechanism of action. Major factors to consider in the CHF
patient population include: 1) genesis of arrhythmias; 2) hemodynamic
effects; 3) exacerbation of ischemia; and 4) negative inotropism.

RENAISSANCE: Adverse events most relevant to CHF are summarized in Table
12. There is a trend towards excess chest pain in the Etanercept groups,
as well as a dose response trend. Although this trend might suggest
Etanercept-induced ischemia in the setting of CHF, the reverse trend is
apparent for angina pectoris. Thus, if chest pain and angina are
construed as essentially the same phenomenon, the percentage of subjects
reporting either event is essentially the same in all 3 treatment
groups. The rates of adverse events suggestive of dysrhythmias (syncope,
atrial fibrillation, ventricular tachycardia, and palpitations) were
very similar in all three treatment groups. Hypotension tended to be
reported less commonly in the Etanercept groups.

![](media/image31.wmf){width="4.559722222222222in"
height="2.033333333333333in"}

Cardiovascular severe adverse events are summarized in Table 13. Of
note, the frequencies of these events were similar across all three
treatment groups.

![](media/image32.wmf){width="4.909722222222222in"
height="2.2430555555555554in"}

RECOVER: Adverse events relevant to CHF are summarized in Table 14.
There is a trend towards excess aggravated CHF in the Etanercept groups,
as well as trends towards excess hypotension and postural hypotension.
Incidences of ischemic symptoms and rhythm disturbances are similar in
the three treatment groups.

Overall, these data do not suggest a specific mechanism of action
leading to Etanercept-related adverse consequences in the CHF patient
population.

![](media/image33.wmf){width="5.072916666666667in"
height="5.616666666666666in"}

### Vital Signs

RENAISSANCE and RECOVER: For the comparisons between Etanercept and
placebo treatment groups, there were no clinically significant
differences in heart rate or blood pressure. There were no notable
changes in vital signs with respect to time in the Etanercept groups.
There was no suggestion of a hemodynamic effect of Etanercept that might
account for the study results.

# Summary and Recommendations

Both Renaissance and Recover were fairly large, multicenter, randomized,
double-blind, placebo-controlled "add-on" studies of Etanercept in CHF.
The investigations enrolled patients who were NYHA FC II-IV with an EF
of 30%. Both studies failed on their primary efficacy endpoint.

For the Renaissance study, the key finding was a trend towards higher
mortality in Etanercept-treated subjects, a concern heightened by the
apparent dose-response relation. Specifically, mortality rates were
14.2%, 17.9%, and 19.8% in the placebo, Etanercept BIW, and Etanercept
TIW treatment groups. There were imbalances in baseline characteristics
(BP, 6-minute walk distance, and antiarrhythmic use) that favored the
placebo group. To some extent, these imbalances call into question the
magnitude of the concern; however, they do not eliminate it.

The results of Recover do not substantiate the findings of Renaissance
with respect to Etanercept-induced mortality in CHF. The mortality rate
for the placebo, Etanercept QW, and BIW groups were 8.8%, 5.9%, and
7.2%, respectively. In terms of labeling, when all of the results are
considered together, the level of concern probably rises to that of a
warning. Because the risk can not be considered definitive, either a
boxed warning or contraindication seems unwarranted at present.

Of note, exploratory analyses did not identify specific factors
associated with increased risk of adverse outcomes in CHF patients. In
particular, patients in Renaissance with milder CHF (NYHA FC II) or
higher BP did not appear to be at a lower risk of adverse outcomes.
Thus, there is no basis to provide a measure of reassurance for patients
with mild forms of CHF.