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DEPARTMENT OF HEALTH AND HUMAN SERVICES

FOOD AND DRUG ADMINISTRATION

CENTER FOR DEVICES AND RADIOLOGICAL HEALTH

*Division of Cardiovascular Devices*

*Pacing, Defibrillator & Leads Branch*

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CLINICAL REVIEW

**PMA:** P030005

**Prepared By:** Scott Proestel, M.D.

**Date:** 06-14-2004

**Product:** CONTAK CD

**Sponsor:** Guidant Corporation

**Team Leader:** Owen Faris, Ph.D.

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### 

### TITLE

COMPANION (Comparison of Medical Therapy, Pacing, and Defibrillation in
Heart Failure)

**SYNOPSIS**

This was a prospective, multi-center, controlled trial intended to
enroll up to 2200 subjects with moderate to severe heart failure and
randomize them 1:2:2 to optimal pharmacologic therapy (OPT), OPT plus
cardiac resynchronization therapy without defibrillation (CRT-P), or OPT
plus CRT-P with defibrillation (CRT-D), respectively. There were four
efficacy endpoints: (1) all-cause mortality plus all-cause
hospitalization (primary endpoint), (2) total survival (secondary
endpoint), (3) cardiac morbidity (secondary endpoint), and (4) change in
maximal oxygen consumption from baseline to six months in an exercise
substudy (secondary endpoint).

The COMPANION protocol was approved by FDA on October 1, 1999, and the
first subject was enrolled on January 20, 2000. Following the enrollment
of 1638 subjects, the Data and Safety Monitoring Board (DSMB)
recommended termination of further enrollment, which the Steering
Committee implemented on December 1, 2002. The basis provided by the
DSMB for the recommendation was that the study had:

> *"...met the criteria specified in the protocol for success both for
> the primary endpoint of mortality and hospitalization combined and for
> mortality alone for biventricular pacing with defibrillator as
> compared to optimal medical therapy alone. In addition, the comparison
> of biventricular pacing alone to optimal medical therapy nearly
> crossed the boundary for statistical significance for the primary
> endpoint of mortality and hospitalization combined and was consistent
> but not significant for mortality alone."*

Based on the results of COMPANION, the sponsor is currently seeking the
following expanded indications for the approved CONTAK CD device
(P010012, approved May 2, 2002):

> *"Guidant Cardiac Resynchronization Therapy Defibrillators (CRT-Ds)
> are indicated for reduction of all-cause mortality and symptoms of
> moderate to severe heart failure (NYHA III/IV) in patients who remain
> symptomatic despite stable, optimal heart failure drug therapy, and
> have left ventricular dysfunction (EF 35%) and QRS duration 120 ms."*
>
> *"Guidant CRT-Ds provide ventricular antitachycardia pacing and
> ventricular defibrillation for the treatment of life-threatening
> ventricular arrhythmias."*

**INCLUSION CRITERIA**

1.  Moderate or severe heart failure, defined as symptomatic heart
    failure for at least six months with New York Heart Association
    (NYHA) class III or IV symptoms at the time of enrollment, and at
    least one of the following events in the previous 12 months:

    a.  Hospitalization for heart failure management

    b.  Outpatient visit in which intravenous (IV) inotropes or
        vasoactive infusion were administered continuously for at least
        4 hours

    c.  Emergency room visit of at least 12 hours duration in which IV
        heart failure medications were administered (including
        diuretics)

2.  QRS duration 120 ms and PR interval \> 150 ms from any two leads of
    a 12-lead ECG

3.  Left ventricular ejection fraction (EF) 35%

4.  Left ventricular end diastolic dimension 60 mm (required only if
    LVEF measured by echo) or \> 3.0 cm/m^2^

5.  Age 18 years

6.  Optimal pharmacological therapy for heart failure as defined below.
    All subjects were to be on optimal therapy for at least one month
    prior to randomization. Exceptions to this requirement were made for
    diuretics and beta blockers. Investigators were allowed to adjust
    diuretic doses at any time. Subjects on beta blockers must have
    completed up-titration to a stable dose for at least three months
    prior to randomization. All subjects were required to be receiving
    the following at the time of enrollment:

    a.  A loop diuretic unless contraindicated or not tolerated

    b.  An ACEI unless previously failed or contraindicated

    c.  Spironolactone if a candidate, unless contraindicated or not
        tolerated

    d.  A beta blocker if a candidate, unless contraindicated or not
        tolerated

*Note: The ECG, LVEF, and LVEDD (if applicable) must have been measured
within the three month period prior to randomization. Furthermore, if a
revascularization procedure occurred after the LVEF was measured, the
LVEF measurement must be repeated at least 30 days after the
revascularization procedure.*

**EXCLUSION CRITERIA**

1.  Meet the general indications for an implantable cardioverter
    defibrillator

2.  Meet the general indications for antibradycardia pacing

3.  Expected to receive a heart transplant in the next six months

4.  Chronic, medically refractory atrial tachyarrhythmias. "Chronic" is
    defined as not terminating spontaneously and cannot be terminated
    with medical intervention, or terminated with medical intervention
    but does not terminate spontaneously

5.  Unexplained syncope

6.  Myocardial infarction within 60 days of randomization

7.  History of non-compliance with oral heart failure therapy

8.  Progressive or unstable angina

9.  Uncontrolled blood pressure: systolic BP \> 160 mm Hg or \< 85 mm
    Hg, or diastolic BP \> 90 mm Hg

10. Hypersensitivity to a 0.7 mg dose of dexamethasone acetate

11. Surgically uncorrected primary valvular heart disease

12. Coronary artery disease with surgical or percutaneous correction
    within 60 days of randomization

13. Women who are pregnant or not using medically acceptable birth
    control

14. Hypertrophic obstructive cardiomyopathy

15. Amyloid disease

16. Hospitalization for heart failure or IV inotropic or vasoactive
    therapy in excess of four hours in the 30 days prior to enrollment

17. Tricuspid prosthesis

18. Life expectancy \< 6 months due to any other medical conditions

**SUBJECT MONITORING**

Subjects were evaluated during a clinic visit at one week, one month,
and at three-month intervals thereafter until study termination or
subject withdrawal. The data that was collected at each of these visits
included a physical assessment, 12-lead EKG, device evaluation, and a
global assessment (combines physician and subject assessments). In
addition, at the 3- and 6-month visits a six-minute walk and Minnesota
Living With Heart Failure Questionnaire (MLWHFQ) was administered.

**RESULTS**

***Baseline Characteristics***

A total of 1638 subjects were enrolled in COMPANION, with 1520 subjects
(92.8%) randomized to a treatment group. There were 118 subjects
enrolled but not randomized due to changes in clinical status between
enrollment and randomization such that the eligibility criteria were no
longer satisfied.

The baseline characteristics of enrolled subjects were analyzed by
treatment group (TABLE 1). The cohorts appear to be well matched
overall. Of note, there was a modestly higher percentage of NYHA
functional class IV subjects in the OPT cohort compared with CRT-D. As
class IV subjects had a 47.2% mortality rate during the trial, and class
III a 16.1% mortality rate, this baseline imbalance favored the device
arm. In addition, there was a higher percentage of ischemic subjects in
the OPT arm. As ischemic subjects had a 25.2% mortality rate during the
trial, and non-ischemic subjects a 15.0% mortality rate, this imbalance
also favored the device arm. However, other baseline characteristics
appeared to be well matched.

  ----------------------------- ------------- -------------- -------------
  **TABLE 1: Baseline                                        
  Characteristics**                                          

                                **CRT-D**     **CRT-P**      **OPT**

  **Number Randomized**         595           617            308

  **Age (years)**               65.6 ± 11.2   65.3 ± 11.7    66.7 ± 10.7

  **Gender**                                                 

  Male                          401(67.4%)    415(67.3%)     211(68.5%)

  Female                        194(32.6%)    202(32.7%)     97(31.5%)

  **NYHA Functional Class**                                  

  Class III                     512(86.1%)    537(87.0%)     253(82.1%)

  Class IV                      83(14.0%)     80(13.0%)      55(17.9%)

  **Etiology of                                              
  Cardiomyopathy**                                           

  Ischemic                      325(54.6%)    331(53.7%)     181(58.8%)

  Non-Ischemic                  270(45.4%)    285(46.3%)     127(41.2%)

  **Ejection Fraction**         22.5 ± 6.9    22.0 ± 6.8     22.8 ± 7.2

  **Conduction Abnormality**                                 

  LBBB                          434(72.9%)    426(69.2%)     215(69.8%)

  RBBB                          61(10.3%)     76(12.3%)      27(8.8%)

  IVCD                          100(16.8%)    114(18.5%)     66(21.4%)

  **QRS Duration (ms)**         159 ± 24      159 ± 25       156 ± 24

  **PR Interval (ms)**          206 ± 40      203 ± 38       202 ± 35

  **Heart Rate (beats/min)**    73 ± 13       73 ± 13        72 ± 12

  **ACEI/ARB Use**              533(89.6%)    548(88.8%)     273(88.6%)

  **Beta-Blocker Use**          402(67.6%)    421(68.2%)     204(66.2%)

  **Spironolactone Use**        328(55.1%)    329(53.3%)     169(54.9%)

  **Digoxin Use**               422(70.9%)    471(76.3%)     207(67.2%)

  **Diuretic Use**              575(96.6%)    581(94.2%)     291(94.5%)
  ----------------------------- ------------- -------------- -------------

***Primary Efficacy Endpoint***

The protocol defined the primary efficacy endpoint as "...a combination
of all-cause mortality and all-cause hospitalization, where all-cause
mortality is defined as death from all causes and all-cause
hospitalization is defined as admission to a hospital for any reason."
The protocol excluded the hospitalization associated with the
investigational device implant, and included emergency department visits
or unscheduled office visits that resulted in treatment with intravenous
inotropes or vasoactive drugs for worsening heart failure. [However,
during the trial the definition of hospitalization was altered three
times. These changes were not documented within a protocol revision, and
the FDA was not notified. The definition was initially changed in March,
2001, to include only hospitalizations lasting greater than 24 hours.
Subsequently, the definition was changed in February, 2002, to include
only hospitalizations for which the discharge date differed from the
date of admission. The third change was a requirement that the inotrope
or vasoactive infusion last greater than 4 hours. The timing of the
third change is unknown to the FDA at the time of this
review.]{.underline}

It should also be noted that while the protocol only states that "...the
hospitalization associated with the investigational device implant..."
would not be considered, this was expanded to include all subsequent
additional hospitalizations for reimplant attempts. Finally, episodes
where subjects had their implant/reimplant hospitalizations prolonged
due to adverse events were not included as a hospitalization. It could
be argued that such subjects should have been included as having reached
the primary endpoint, as they were no longer in the hospital to receive
a device.

The changes in hospitalization definition may have been in response to
multiple early hospitalizations related to device implant issues. While
the Morbidity and Mortality Committee was blinded to treatment
assignment and did not have access to the data in aggregate form, the
Committee was aware of the nature of the adverse event. It is reasonable
to believe that the Committee would realize that admissions for lead
revision and other device-related adverse events would be specific to
subjects in the device arm of the trial. Based on the revised definition
of the primary endpoint, these hospitalizations were adjudicated as
"adverse events" if they were not associated with a calendar date
change, and therefore no longer counted towards the primary endpoint. In
addition, these events were no longer captured as hospitalizations, so
the data provided by the sponsor to FDA could not be used to calculate
the original primary endpoint.

The definition of hospitalization ultimately used for the trial was the
following:

1.  All hospitalizations associated with a calendar date change, without
    regard to whether the hospitalization was considered elective or
    related to heart failure, with the following exceptions:

    a.  index hospitalizations;

    b.  reimplant attempt hospitalizations;

    c.  hospitalizations that were considered elective and associated
        with the device (the sponsor further clarified on June 9, 2004,
        during a teleconference with this reviewer, that episodes such
        as lead revisions were not considered elective. The only
        hospitalizations excluded based on this criterion were ones in
        which an OPT subject was implanted with a CRT-P or CRT-D device
        without a documented medical need, or a CRT-P subject received a
        CRT-D device without a documented medical need)

2.  All outpatient (i.e., clinic and emergency department) infusions of
    inotropic or vasoactive therapy for greater than four hours for
    worsening heart failure

[The FDA statistician will provide formal statistical analyses of the
primary and secondary efficacy endpoints. This review will utilize only
descriptive statistics of the efficacy data to provide additional
insight into the results of the trial. It should be noted that the
protocol assigned 0.05 of alpha to four different endpoints. The sponsor
justified this excessive alpha allocation by stating that they would
"...be conservative in the interpretation of the multiple analyses,
looking for consistency across variables." No definition was provided
for what would constitute consistency, and therefore there was no
specific definition for what would constitute statistical success for
the trial.]{.underline}

***Withdrawals***

There was a higher than anticipated dropout rate during the trial,
particularly within the OPT arm. Prior to November 30, 2002, there were
80 withdrawals in the OPT arm and 39 within CRT-D. The sponsor has
attributed this imbalance to the desire of OPT subjects to receive
marketed CRT-P or CRT-D devices. Therefore, the sponsor attempted to
obtain information on subjects beyond the time at which they were
withdrawn from the trial. It should be noted that crossovers to a
different therapy were considered Class I deviations against the
investigator, defined as, "Investigator compromised patient's right
and/or welfare and/or study analysis groups." Apparently, in order to
avoid a Class I deviation, investigators sometimes withdrew subjects
from the trial for the purpose of crossing over to a different therapy.
However, withdrawal of subjects from a trial in order to obtain
alternative therapy is not consistent with the principles underlying an
intent to treat analysis. Subjects should only have been withdrawn if
further participation was felt to compromise their welfare, they refused
further participation, or participation was no longer possible.

The magnitude of the effect of including data obtained following subject
withdrawal was analyzed. Of the 595 CRT-D subjects, 390 had a reported
primary endpoint event (372 hospitalizations, 18 deaths). Of these, 4
had the primary endpoint event following withdrawal (2 hospitalizations,
2 deaths). The mean time to the primary endpoint following withdrawal in
these 4 subjects was 78.1 days. Of the 308 OPT subjects, 216 had a
reported primary endpoint event (196 hospitalizations, 20 deaths). Of
these, 14 had their primary endpoint event following withdrawal (10
hospitalizations, 4 deaths). The mean time to the primary endpoint
following withdrawal in these 14 subjects was 237.7 days.

Reasons for not using the data that was collected on subjects following
their withdrawal include:

1.  Withdrawal is intended to mark the end of a subject's trial
    participation.

2.  Allowing the inclusion of data collected after withdrawal increases
    the type I error rate due to the additional chances for an
    intervention to "win."

3.  Additional information was obtained on subjects following their
    withdrawal without necessarily obtaining consent, if the sponsor did
    not believe that consent had been rescinded. However, please see #1.

4.  The quality of subject follow-up after withdrawal is unclear. This
    follow-up included asking investigators to document retrospectively
    the primary endpoint events that they remembered.

[For the above reasons, only the events from randomization to subject
withdrawal, death, or November 30, 2002, (whichever came first) were
included in the analyses for this review. The only exception is for the
mortality analysis, which was performed prior to this reviewer's
awareness that the data included events subsequent to a subject's
withdrawal. Upon further review, it was found that this additional
follow-up increased the overall mortality rate in the CRT-D arm from
15.8% (94/595) to 17.6% (105/595), and in the OPT arm from 21.1%
(65/308) to 25.0% (77/308). While this change modestly favored the
device arm, the difference was not expected to change the overall
conclusions of this review with respect to mortality. In addition, vital
status is more readily verifiable than whether a hospitalization
occurred, so issue #4 may not be a concern. However, issues regarding
informed consent and type I error remain, and it may be reasonable to
only include data up to subject withdrawal, death, or November 30, 2002,
in the device label.]{.underline}

***Mortality***

All-cause mortality was decreased in the CRT-D cohort as compared to OPT
(TABLE 2). While this TABLE does not take into account the modest
difference in mean observed time between the two cohorts, it does allow
observation of the effects of the intervention in absolute terms (please
see TABLE 4 for an adjustment for duration of observation). There was a
7.4 % absolute reduction in all-cause mortality associated with CRT-D
therapy. CRT-D therapy was also associated with a decrease in cardiac
deaths, due to important decreases in pump failure death and sudden
cardiac death (SCD). The pump failure mortality rates in the CRT-D and
CRT-P cohorts were quite similar (8.7% and 8.6%, respectively), and were
both less than the 11.0% pump failure death rate associated with OPT.
Given the known physiologic effects of CRT-P, it appears reasonable to
believe that these results represent an improvement in pump failure
mortality due to CRT-P.

There was a modest increase in SCD associated with CRT-P in comparison
with OPT. This difference is not likely due to chance, as the median
time to SCD in the CRT-P cohort was substantially shorter than in either
the OPT or CRT-D cohorts (TABLE 3 \[Please note that this TABLE only
includes subjects who died during the trial, and is not intended to
characterize the median mortality for the cohorts as a whole\]).
However, the decrease in pump failure deaths associated with CRT-P in
both of the device arms overwhelms the increase in SCD associated with
CRT-P. It is possible that the increase in SCD associated with CRT-P is
due to an improvement in pump function from CRT-P leading to fewer pump
failure deaths, therefore rendering subjects more available to die from
another cause such as SCD. However, if this were the case, one would not
expect the median time to SCD to be substantially shorter with CRT-P
compared to OPT. As might be expected, the SCD rate was lowest in the
CRT-D arm, and the impact of the CRT-P component of the CRT-D device is
that it may lead to a decrease in pump failure death but an increase in
defibrillation therapy delivery. It should also be noted that there were
10 deaths secondary to sepsis in the CRT-D cohort, 5 in the CRT-P
cohort, and only one death attributed to sepsis in the OPT cohort. As
the device therapy arms involve implantation and maintenance of an
intravascular device, it is reasonable to believe that this increase in
septic deaths was not due to chance.

There was a modest difference in mean observation time per subject
between the three cohorts (CRT-D 1.31 years/subject, CRT-P 1.32
years/subject, and OPT 1.22 years/subject. As stated previously, the
time of observation that was calculated for mortality included time
beyond subject withdrawal if additional follow-up was possible.)
Therefore, mortality was adjusted for duration of observation (TABLE 4).
This adjustment improved the mortality results for the CRT-D and CRT-P
cohorts relative to OPT, due to the slightly longer periods of
observation in these groups. However, the effect was modest and did not
change any of the overall conclusions regarding the effect of CRT-D and
CRT-P on mortality.

  ------------------------------------ ------------ ------------ -----------
  **TABLE 2: Mortality Rates**                                   

                                       **CRT-D**    **CRT-P**    **OPT**

  **Total Subjects**                   595          617          308

  **Total Deaths**                     105(17.6%)   131(21.2%)   77(25.0%)

  **Cardiac Deaths**                   76(12.8%)    109(17.7%)   58(18.8%)

  **Pump Failure Deaths**              52(8.7%)     53(8.6%)     34(11.0%)

  **Sudden Cardiac Deaths**            17(2.9%)     48(7.8%)     18(5.8%)

  **Ischemic Deaths**                  4(0.7%)      2(0.3%)      4(1.3%)

  **Implant Procedure Deaths**         2(0.3%)      6(1.0%)      0(0.0%)

  **Other Cardiac Procedure Deaths**   0(0.0%)      0(0.0%)      2(0.6%)

  **Hyperkalemic Deaths**              1(0.2%)      0(0.0%)      0(0.0%)

  **Deaths Within 30 Days of           7(1.2%)      11(1.8%)     3(1.0%)
  Randomization**                                                
  ------------------------------------ ------------ ------------ -----------

  ------------------------------------ ----------- ----------- ----------
  **TABLE 3: Median Days to                                    
  Mortality\***                                                

                                       **CRT-D**   **CRT-P**   **OPT**

  **All Deaths**                       258.0       236.0       253.0

  **Cardiac Deaths**                   265.5       205.0       215.5

  **Pump Failure Deaths**              282.0       289.0       182.5

  **Sudden Cardiac Deaths**            341.0       186.5       253.0
  ------------------------------------ ----------- ----------- ----------

*\*Includes only subjects who died*

  ------------------------------------ ----------- ----------- ----------
  **TABLE 4: Mortality Rate Adjusted                           
  for Time Observed**                                          

                                       **CRT-D**   **CRT-P**   **OPT**

  **Total Subjects**                   595         617         308

  **Cumulative Follow-Up (Years)**     777.2       812.9       374.8

  **Deaths/100 Subject-Years**         13.5        16.1        20.5

  **Cardiac Deaths/100 Subject-Years** 9.8         13.4        15.5

  **Pump Failure Deaths/100            6.7         6.5         9.1
  Subject-Years**                                              

  **Sudden Cardiac Deaths/100          2.2         5.9         4.8
  Subject-Years**                                              
  ------------------------------------ ----------- ----------- ----------

An evaluation of all-cause mortality with respect to subject baseline
characteristics was performed (TABLE 5). For continuous variables, data
was separated into quartiles for analysis by treatment assignment.
Overall, CRT-D was associated with substantial improvement in all-cause
mortality across the majority of baseline characteristic subgroups.
However, it should be noted that improvement in survival associated with
CRT-D therapy diminished markedly with improving EF at baseline. This is
biologically plausible as subjects with a higher EF would on average be
healthier, and thus less able to benefit from the intervention. With
respect to baseline conduction abnormality, the majority of benefit was
associated with subjects who had LBBB, and there was a slight increase
in mortality associated with both CRT-D and CRT-P as compared to OPT in
subjects with IVCD. Based on the relatively small size of the IVCD
subgroup, small differences in mortality, and the issue of multiple
comparisons, it is not reasonable to conclude that CRT-D caused an
increase in mortality in this subgroup. The only other subgroup with an
increased mortality associated with CRT-D was in the first quartile of
PR interval duration. A consistent increase in mortality can be seen in
the OPT cohort with increasing PR interval, which is biologically
plausible as PR interval prolongation may be an indicator of worsening
cardiac disease. Therefore, it may be reasonable to believe that this
subgroup is less likely to benefit from CRT-D than the trial population
as a whole, due to being more healthy and thus less able to benefit from
the therapy.

  ----------------------------- --------------- ---------------- ---------------
  **TABLE 5: All-Cause                                           
  Mortality and Baseline                                         
  Characteristics**                                              

                                **CRT-D**       **CRT-P**        **OPT**

  **Age (years)**                                                

  Q~1~\*(20-58)                 20/150(13.3%)   29/163(17.8%)    11/61(18.0%)

  Q~2~ (59-66)                  28/156(17.9%)   29/141(20.6%)    17/74(23.0%)

  Q~3~ (67-74)                  24/150(16.0%)   30/160(18.8%)    23/97(23.7%)

  Q~4~ (75-92)                  33/139(23.7%)   43/153(28.1%)    26/76(34.2%)

  **Gender**                                                     

  Male                          83/401(20.1%)   108/415(26.0%)   59/211(28.0%)

  Female                        22/194(11.3%)   23/202(11.4%)    18/97(18.6%)

  **NYHA Functional Class**                                      

  Class III                     68/512(13.3%)   95/537(17.7%)    47/253(18.6%)

  Class IV                      37/83(44.6%)    36/80(45.0%)     30/55(54.5%)

  **Etiology of                                                  
  Cardiomyopathy**                                               

  Ischemic                      77/325(23.7%)   80/331(24.2%)    54/181(29.8%)

  Non-Ischemic                  28/270(10.4%)   51/285(17.9%)    23/127(18.1%)

  **Ejection Fraction**                                          

  Q~1~ (5-17)                   27/153(17.6%)   54/169(32.0%)    25/75(33.3%)

  Q~2~ (18-21)                  30/138(21.7%)   29/160(18.1%)    20/74(27.0%)

  Q~3~ (22-28)                  29/160(18.1%)   30/155(19.4%)    19/76(25.0%)

  Q~4~ (29-35)                  19/144(13.2%)   18/133(13.5%)    13/83(15.7%)

  **Conduction Abnormality**                                     

  LBBB                          67/434(15.4%)   81/426(19.0%)    55/215(25.6%)

  RBBB                          15/61(24.6%)    22/76(28.9%)     8/27(29.6%)

  IVCD                          23/100(23.0%)   28/114(24.6%)    14/66(21.2%)

  **QRS Duration (ms)**                                          

  Q~1~ (120-140)                30/144(20.8%)   47/177(26.6%)    20/93(21.5%)

  Q~2~ (141-160)                37/203(18.2%)   35/184(19.0%)    25/92(27.2%)

  Q~3~ (161-175)                17/102(16.7%)   13/94(13.8%)     13/58(22.4%)

  Q~4~ (176-276)                21/146(14.4%)   36/162(22.2%)    19/65(29.2%)

  **PR Interval (ms)**                                           

  Q~1~ (150-178)                27/143(18.9%)   23/161(14.3%)    12/84(14.3%)

  Q~2~ (179-200)                30/205(14.6%)   43/201(21.4%)    22/97(22.7%)

  Q~3~ (201-221)                15/87(17.2%)    23/111(20.7%)    14/52(26.9%)

  Q~4~ (222-560)                33/160(20.6%)   42/144(29.2%)    29/75(38.7%)

  **Heart Rate (beats/min)**                                     

  Q~1~ (44-64)                  24/172(14.0%)   32/189(16.9%)    20/92(21.7%)

  Q~2~ (65-72)                  27/143(18.9%)   29/129(22.5%)    20/69(29.0%)

  Q~3~ (73-80)                  23/131(17.6%)   29/154(18.8%)    17/83(20.5%)

  Q~4~ (81-122)                 31/149(20.8%)   41/145(28.3%)    20/64(31.3%)
  ----------------------------- --------------- ---------------- ---------------

Q~1~ = first quartile, Q~2~ = second quartile, Q~3~ = third quartile,
Q~4~ = fourth quartile

***All-Cause Hospitalization***

The total number of hospitalizations and the total amount of time spent
in the hospital were not endpoints for this trial. However, they are
clinically meaningful, and relevant to the concerns of patients and
physicians. It has been claimed that the index hospitalization for the
device implant procedure, as well as the additional hospitalizations
following failed implant attempts, are not recurring events and should
therefore be excluded for the purposes of calculating the rate of "all
cause hospitalization." While they are not recurring events with the
same frequency as heart failure hospitalizations, they none the less
need to be considered if one is to understand what happened to subjects
during the trial with respect to all causes of hospitalization. One of
the presumed strengths of a claim of reduction in all cause
hospitalization (or time to hospitalization) is that one would spend
less time in the hospital. If in fact there is simply an exchange from
heart failure hospitalizations to device hospitalizations for implants,
reimplants, and adverse events related to the implant procedure or
device, the clinical benefit is far from clear. In addition, while it is
true that heart failure hospitalizations recur at a much higher rate
than implant procedures, the strength of the data is not compelling with
respect to understanding an annualized hospitalization rate anyway.
Subjects in the CRT-D group were followed on average approximately 1.29
years, and in the OPT group approximately 1.01 years (only considering
the follow-up that occurred up to the time of withdrawal). In addition,
only 122 of the original 903 CRT-D and OPT subjects had 2 years of
follow-up, and no subjects had 3 years of follow-up. This should give
some pause to the interpretation of annualized hospitalization rates
based on this trial, regardless of whether the implant procedures are
included.

Finally, it has also been claimed that one should not calculate the
overall number of hospitalizations for the CRT-D and OPT cohorts due to
the issue of competing risks of death and hospitalization. Therefore, it
may be that the CRT-D device keeps people alive who would otherwise have
died, therefore enriching the CRT-D cohort over time with sicker
subjects who may be more likely to require hospitalization. While this
is a reasonable concern and may very well have occurred during
COMPANION, it does not undermine the value of such an analysis. This is
because whatever hospitalization rate occurred during the trial, it
represents what the subjects experienced, regardless of the underlying
cause. It is only if one were to attempt to assign a specific cause for
an increase in hospitalizations associated with the device, such as a
direct effect of the CRT-P component, that the issue of competing risks
would apply.

An analysis was performed which included all hospitalizations documented
by the sponsor (i.e., hospitalizations for which there was a date
change, including elective device hospitalizations, all index
hospitalizations, all re-implant attempt hospitalizations, and all
outpatient inotropic infusions for worsening heart failure). All events
from randomization to subject withdrawal, death, or November 30, 2002,
(whichever came first) were included. Hospitalizations that were not
associated with a date change or were not associated with an implant
attempt were not included as these events were not captured as
hospitalizations during the trial.

Within the CRT-D cohort, there were 1548 hospitalizations (mean duration
5.42 +/- 8.82 days, median 3.0 days, minimum 1 day, maximum 166 days). A
total of 314 of these hospitalizations were attributed to heart failure.
Within the OPT cohort, there were 507 hospitalizations (mean duration
6.57 +/- 7.32 days, median 4.0 days, minimum 1 day, maximum 88 days). A
total of 216 of these hospitalizations were attributed to heart failure.

However, the preceding description does not take into consideration the
difference in overall duration of follow-up between the two cohorts. For
CRT-D, the mean duration of follow-up was 469.3 +/- 233.3 days, median
471 days, minimum 2 days, and maximum 1020 days. For OPT, the mean
duration of follow-up was 370.5 +/- 241.0 days, median 356 days, minimum
1 day, maximum 1042 days.

[Therefore, the mean all-cause hospitalization rate in the CRT-D cohort
was 2.02 hospitalizations/year, and in the OPT cohort 1.62
hospitalizations/year. The mean days spent hospitalized for any cause in
the CRT-D cohort was 11.0 days/year, and in the OPT cohort 10.7
days/year.]{.underline}

Listed in TABLE 6 is the frequency of hospitalizations subjects
experienced in the two cohorts.

+------------------------------+-------------------+-------------------+
| **TABLE 6: Frequency of      |                   |                   |
| Hospitalizations by Cohort** |                   |                   |
+------------------------------+-------------------+-------------------+
| **\# OF HOSPITALIZATIONS**   | **CRT-D**         | **OPT**           |
|                              |                   |                   |
|                              | **(n = 595)**     | **(n = 308)**     |
+------------------------------+-------------------+-------------------+
| 1                            | 199 (33.4%)       | 71 (23.1%)        |
+------------------------------+-------------------+-------------------+
| 2                            | 160 (26.9%)       | 43 (14.0%)        |
+------------------------------+-------------------+-------------------+
| 3                            | 96 (16.1%)        | 26 (8.4%)         |
+------------------------------+-------------------+-------------------+
| 4                            | 56 (9.4%)         | 20 (6.5%)         |
+------------------------------+-------------------+-------------------+
| 5                            | 37 (6.2%)         | 15 (4.9%)         |
+------------------------------+-------------------+-------------------+
| 6                            | 19 (3.2%)         | 4 (1.3%)          |
+------------------------------+-------------------+-------------------+
| \> 6                         | 23 (3.9%)         | 10 (3.2%)         |
+------------------------------+-------------------+-------------------+

***Cardiac Morbidity***

Cardiac morbidity was a secondary endpoint for the trial. The definition
that was provided in the protocol was the occurrence of the following
events:

1.  Worsening heart failure resulting in use of intravenous vasoactive
    or inotropic therapy exceeding four hours

2.  Mechanical respiratory or cardiac support

3.  Any cardiac surgery, including heart transplant

4.  Resuscitated cardiac arrest or sustained ventricular tachycardia
    requiring intervention (e.g., chest thump, external cardioversion,
    or external defibrillation)

5.  Hospitalization for acute decompensation of heart failure

6.  Hospitalization that results in death from cardiac causes

7.  Significant device-related events resulting in

    a.  Permanent disability

    b.  Hospitalization for pending death or permanent disability

[However, the cardiac morbidity endpoint was analyzed by
hospitalizations, not by cardiac morbid events as described in the
protocol. Therefore, each hospitalization was determined to be "cardiac
morbid" if any of the above events occurred, and counted as a single
event regardless of the number of events that took place during the
hospitalization. This change was not documented within a protocol
revision, and the FDA was not notified. The datasets provided to FDA did
not allow the possibility of calculating the endpoint as described in
the protocol.]{.underline}

In addition, the inclusion of external cardioversion/defibrillation in
the definition of cardiac morbidity is problematic. This is because
subjects with an ICD would not be anticipated to receive external
cardioversion/defibrillation, as the device already provides internal
cardiac defibrillation. If one is to assume that the delivery of such an
intervention signals a worsened clinical status, then the episodes of
cardioversion/defibrillation by the device should also be included.
However, this would also be problematic as the device is continuously
monitoring cardiac rhythm, and would therefore be likely to
cardiovert/defibrillate on many occasions that would otherwise not have
been captured in the absence of a device. Due to the multiple
difficulties in interpretation, criterion #4 should not have included
external cardioversion/defibrillation.

Based on the definition of cardiac morbidity used by the sponsor, there
were 368 cardiac morbid events in the CRT-D cohort, and 312 in the OPT
cohort. The number of times cardiac event descriptions were reported is
provided (TABLE 7). However, single events could have multiple
descriptions within TABLE 7. Therefore, no percentages were calculated,
and this data must be interpreted with caution.

+-------------------------------------------------+---------+---------+
| **TABLE 7: Reported Descriptions of Cardiac     |         |         |
| Morbid Events**                                 |         |         |
+-------------------------------------------------+---------+---------+
| **Description**                                 | **      | **OPT** |
|                                                 | CRT-D** |         |
|                                                 |         | **(n    |
|                                                 | **(n    | =308)** |
|                                                 | =595)** |         |
+-------------------------------------------------+---------+---------+
| Any cardiac surgery                             | 33      | 88      |
+-------------------------------------------------+---------+---------+
| Hospitalization for acute decompensation of HF  | 312     | 215     |
+-------------------------------------------------+---------+---------+
| Hospitalization resulting in death from cardiac | 27      | 24      |
| causes                                          |         |         |
+-------------------------------------------------+---------+---------+
| Mechanical respiratory/cardiac support          | 33      | 17      |
+-------------------------------------------------+---------+---------+
| Resuscitation for cardiac arrest/sustained VT   | 13      | 5       |
+-------------------------------------------------+---------+---------+
| Worsening HF resulting in vaso/inotropic tx \>4 | 203     | 166     |
| hrs (Inpat)                                     |         |         |
+-------------------------------------------------+---------+---------+
| Worsening HF resulting in vaso/inotropic tx \>4 | 9       | 14      |
| hrs (Outpt)                                     |         |         |
+-------------------------------------------------+---------+---------+

***Implant Hospitalizations***

Characterization of the implant hospitalization was not an endpoint for
this trial. However, as subjects must undergo this hospitalization to
receive the device, it was felt to be reasonable to provide descriptive
statistics related to these events. Of the 595 CRT-D subjects, 541
underwent a successful implant procedure, 47 had unsuccessful attempts,
and 7 were intents (randomized to CRT-D, but no implant procedure ever
occurred). Additionally, within the CRT-D cohort there were a total of
588 subjects who underwent 641 implant hospitalizations. The mean
duration of these hospitalizations was 2.91 +/- 4.93 days, median 2.0
days, minimum 1.0 day, maximum 116 days). Of the 588 CRT-D subjects who
underwent an implant attempt, 537 underwent 1 attempt, 49 underwent 2
attempts, and 2 underwent 3 attempts.

***Additional Efficacy Data***

Additional efficacy data collected for all subjects during the trial
included a six-minute walk, global assessment (composed of physician and
subject assessments combined), NYHA functional class, and Minnesota
Living With Heart Failure Questionnaire (MLWHFQ). However, as of June
14, 2004, only the NYHA functional class and MLWHFQ data have been
submitted for FDA review (TABLE 8). These results appear to suggest an
improvement in both NYHA functional class and MLWHFQ scores associated
with the device. However, it should be noted that (1) these are
subjective assessments performed in the context of an unblinded trial,
(2) there is a large amount of missing data, particularly at 6 months,
and (3) the missing data is heavily weighted towards the OPT arm (TABLE
9).

  ---------------------------------- ------------------ ------------------
  **TABLE 8: Mean NYHA and MLWHFQ                       
  Scores**                                              

                                     **CRT-D**          **OPT**

  **NYHA Baseline**                  3.14 +/- 0.35      3.18 +/- 0.38

  **3 Months**                       2.49 +/- 0.70      2.95 +/- 0.66

  **6 Months**                       2.44 +/- 0.71      2.78 +/- 0.69

                                                        

  **MLWHFQ Baseline**                62.7 +/- 22.9      60.6 +/- 22.7

  **3 Months**                       38.8 +/- 26.2      51.5 +/- 26.4

  **6 Months**                       37.5 +/- 26.5      47.6 +/- 26.9
  ---------------------------------- ------------------ ------------------

+---------------------------------+-----------------+-----------------+
| **TABLE 9: NYHA and MLWHFQ      |                 |                 |
| Missing Data**                  |                 |                 |
+---------------------------------+-----------------+-----------------+
|                                 | **CRT-D**       | **OPT**         |
|                                 |                 |                 |
|                                 | **(n=595)**     | **(n=308)**     |
+---------------------------------+-----------------+-----------------+
| **NYHA Baseline**               | 0 (0%)          | 0 (0%)          |
+---------------------------------+-----------------+-----------------+
| **3 Months**                    | 52 (8.7%)       | 66 (21.4%)      |
+---------------------------------+-----------------+-----------------+
| **6 Months**                    | 97 (16.3%)      | 109 (35.4%)     |
+---------------------------------+-----------------+-----------------+
|                                 |                 |                 |
+---------------------------------+-----------------+-----------------+
| **MLWHFQ Baseline**             | 16 (2.7%)       | 9 (2.9%)        |
+---------------------------------+-----------------+-----------------+
| **3 Months**                    | 77 (12.9%)      | 65 (21.1%)      |
+---------------------------------+-----------------+-----------------+
| **6 Months**                    | 115 (19.3%)     | 101 (32.8%)     |
+---------------------------------+-----------------+-----------------+

***Medication Use***

The percentage of subjects on various cardiac medications at the time of
their final study visit was analyzed by treatment group (TABLE 10). The
proportion of subjects on these medications appears to be well matched.

+------------------------------------+----------------+---------------+
| **TABLE 10: Medication Use at      |                |               |
| Final Study Visit**                |                |               |
+------------------------------------+----------------+---------------+
|                                    | **CRT-D**      | **OPT**       |
|                                    |                |               |
|                                    | **(n=556)**    | **(n=272)**   |
+------------------------------------+----------------+---------------+
| **ACEI/ARB Use**                   | 460 (82.7%)    | 237 (87.1%)   |
+------------------------------------+----------------+---------------+
| **Beta-Blocker Use**               | 416 (74.8%)    | 191 (70.2%)   |
+------------------------------------+----------------+---------------+
| **Aldosterone Antagonist Use**     | 257 (46.2%)    | 133 (48.9%)   |
+------------------------------------+----------------+---------------+
| **Digoxin Use**                    | 380 (68.3%)    | 183 (67.3%)   |
+------------------------------------+----------------+---------------+
| **Diuretic Use**                   | 502 (90.3%)    | 251 (92.3%)   |
+------------------------------------+----------------+---------------+

***Safety***

There were no safety endpoints for the CONTAK CD system, only for the
EASYTRAK left ventricular lead (P010012, approved May 2, 2002). The
sponsor therefore proposed a post hoc safety endpoint of system-related
complication-free rate. However, as there was no pre-specified safety
endpoint, it is more reasonable to compare all adverse events (AEs)
between the CRT-D and OPT cohorts. In addition, the system-related
complication-free rate did not include subjects with failed implant
attempts. As the events surrounding a failed implant would not have
occurred if the subject had received optimal pharmacologic therapy only,
it is not reasonable to exclude them from a safety analysis.

[All AEs through November 30, 2002, were included. It should be noted
that the adverse event data in this review was not adjusted for the
difference in observation time between the two cohorts (mean observation
time for CRT-D subjects, 1.29 years, and for OPT subjects, 1.01 years).
There were a total of 3732 AEs in the CRT-D arm and 1230 in the OPT
arm.]{.underline}

An observation was defined as a clinical adverse event that was
correctable by noninvasive measures. This included reprogramming of the
pulse generator as well as antibiotic treatment of a pocket infection. A
complication was defined as a clinical adverse event which required
invasive measures to correct, such as evacuation of a hematoma or lead
dislodgment. Of the CRT-D AEs, 540 (14.5%) were complications and 3192
(85.5%) observations. Of the 1230 AEs in the OPT cohort, 241 (19.6%)
were complications and 989 (80.4%) observations.

The number of AEs experienced by subjects was evaluated (TABLE 11). For
example, 202 subjects experienced between 1 and 3 AEs during the trial.
A total of 562 of the 595 subjects in CRT-D arm experienced at least one
AE, while 247 of 308 subjects in the OPT arm experienced at least one
AE.

+----------------------------+--------------------+--------------------+
| **TABLE 11: Number of AEs  |                    |                    |
| Experienced by Cohort**    |                    |                    |
+----------------------------+--------------------+--------------------+
| **Number of AEs**          | **CRT-D**          | **OPT**            |
|                            |                    |                    |
|                            | **(n=595)**        | **(n=308)**        |
+----------------------------+--------------------+--------------------+
| 1-3                        | 202 (33.9%)        | 118 (38.3%)        |
+----------------------------+--------------------+--------------------+
| 4-6                        | 150 (25.2%)        | 63 (20.5%)         |
+----------------------------+--------------------+--------------------+
| 7-9                        | 100 (16.8%)        | 32 (10.4%)         |
+----------------------------+--------------------+--------------------+
| \>9                        | 110 (18.5%)        | 34 (11.0%)         |
+----------------------------+--------------------+--------------------+
| **TOTAL**                  | 562 (94.5%)        | 247 (80.2%)        |
+----------------------------+--------------------+--------------------+

The sponsor provided an adjudicated classification of the AEs (TABLE
12). However, this adjudication allowed for events such as heart failure
episodes and ventricular arrhythmias to be classified in multiple
different ways. For instance, congestive heart failure could be
classified as shortness of breath, volume overload, physiological
reaction, pulmonary edema, loss of left ventricular lead capture, or
congestive heart failure. Therefore, this data should be interpreted
with caution.

With respect to arrhythmias, there was a marked increase associated with
CRT-D. However, this was likely due to ascertainment bias due to the
device's ability to capture such events. In addition, there has been
concern that ICD therapy may be associated with an increased risk of
depression or anxiety. While there were episodes of depression and
anxiety specifically attributed to ICD therapy during COMPANION, the
overall reported rate of episodes in the CRT-D cohort (36 episodes/595
subjects, 6.1%), was fairly similar to OPT (14 episodes/308 subjects,
4.5%).

+----------------------------------------+--------------+-------------+
| **TABLE 12: Adverse Events by Cohort** |              |             |
+========================================+==============+=============+
| **Sponsor Adjudicated**                | **CRT-D**    | **OPT**     |
|                                        |              |             |
| **AE Classifications**                 | **(n=595)**  | **(n=308)** |
+----------------------------------------+--------------+-------------+
| AV Block - heart block, complete       | 10 (1.7%)    | 1 (0.3%)    |
+----------------------------------------+--------------+-------------+
| Aneurysm                               | 0 (0%)       | 2 (0.6%)    |
+----------------------------------------+--------------+-------------+
| Angina                                 | 0 (0%)       | 6 (1.9%)    |
+----------------------------------------+--------------+-------------+
| Allergic reaction                      | 12 (2.0%)    | 0 (0%)      |
+----------------------------------------+--------------+-------------+
| Altered hemodynamic status             | 1 (0.2%)     | 0 (0%)      |
+----------------------------------------+--------------+-------------+
| Arrhythmia                             | 20 (3.4%)    | 9 (2.9%)    |
+----------------------------------------+--------------+-------------+
| Arrhythmia - atrial fibrillation       | 74 (12.4%)   | 21 (6.8%)   |
+----------------------------------------+--------------+-------------+
| Arrhythmia - atrial flutter            | 12 (2.0%)    | 3 (1.0%)    |
+----------------------------------------+--------------+-------------+
| Arrhythmia - sinus tachycardia         | 8 (1.3%)     | 2 (0.6%)    |
+----------------------------------------+--------------+-------------+
| Bleeding/fluid accumulation            | 6 (1.0%)     | 0 (0%)      |
+----------------------------------------+--------------+-------------+
| Brady capture - LV                     | 55 (9.2%)    | 2 (0.6%)    |
+----------------------------------------+--------------+-------------+
| Brady capture - RV                     | 10 (1.7%)    | 0 (0%)      |
+----------------------------------------+--------------+-------------+
| Brady capture - atrium                 | 16 (2.7%)    | 1 (0.3%)    |
+----------------------------------------+--------------+-------------+
| Bruise                                 | 1 (0.2%)     | 0 (0%)      |
+----------------------------------------+--------------+-------------+
| Cancer, other                          | 14 (2.4%)    | 12 (3.9%)   |
+----------------------------------------+--------------+-------------+
| Cardiac arrest                         | 7 (1.2%)     | 4 (1.3%)    |
+----------------------------------------+--------------+-------------+
| Cardiac tamponade                      | 2 (0.3%)     | 0 (0%)      |
+----------------------------------------+--------------+-------------+
| Change in arrhythmia                   | 1 (0.2%)     | 0 (0%)      |
+----------------------------------------+--------------+-------------+
| Change in arrhythmia - brady           | 46 (7.7%)    | 12 (3.9%)   |
+----------------------------------------+--------------+-------------+
| Change in arrhythmia - junctional      | 7 (1.2%)     | 1 (0.3%)    |
+----------------------------------------+--------------+-------------+
| Change in arrhythmia - SVT             | 49 (8.2%)    | 8 (2.6%)    |
+----------------------------------------+--------------+-------------+
| Change in arrhythmia - VT              | 0 (0%)       | 1 (0.3%)    |
+----------------------------------------+--------------+-------------+
| Change in drug therapy                 | 1 (0.2%)     | 0 (0%)      |
+----------------------------------------+--------------+-------------+
| Change in physical status              | 59 (9.9%)    | 17 (5.5%)   |
+----------------------------------------+--------------+-------------+
| Chest pain                             | 202 (33.9%)  | 90 (29.2%)  |
+----------------------------------------+--------------+-------------+
| Chronotropic incompetence              | 1 (0.2%)     | 0 (0%)      |
+----------------------------------------+--------------+-------------+
| Claudication                           | 1 (0.2%)     | 2 (0.6%)    |
+----------------------------------------+--------------+-------------+
| Coagulopathy                           | 6 (1.0%)     | 2 (0.6%)    |
+----------------------------------------+--------------+-------------+
| Congestive heart failure               | 391 (65.7%)  | 251 (81.5%) |
+----------------------------------------+--------------+-------------+
| Diabetes complications                 | 2 (0.3%)     | 1 (0.3%)    |
+----------------------------------------+--------------+-------------+
| Digoxin level                          | 1 (0.2%)     | 0 (0%)      |
+----------------------------------------+--------------+-------------+
| Dissection, coronary sinus             | 15 (2.5%)    | 3 (1.0%)    |
+----------------------------------------+--------------+-------------+
| Distal thromboemboli                   | 1 (0.2%)     | 0 (0%)      |
+----------------------------------------+--------------+-------------+
| Dizziness, cause undetermined          | 92 (15.5%)   | 40 (13.0%)  |
+----------------------------------------+--------------+-------------+
| Dysfunctional dialysis catheter        | 2 (0.3%)     | 0 (0%)      |
+----------------------------------------+--------------+-------------+
| Dyspnea                                | 165 (27.7%)  | 67 (21.8%)  |
+----------------------------------------+--------------+-------------+
| ERI, premature (early)                 | 1 (0.2%)     | 0 (0%)      |
+----------------------------------------+--------------+-------------+
| Edema                                  | 23 (3.9%)    | 10 (3.2%)   |
+----------------------------------------+--------------+-------------+
| Electrolyte/lab                        | 85 (14.3%)   | 30 (9.7%)   |
+----------------------------------------+--------------+-------------+
| Endocrine                              | 91 (15.3%)   | 23 (7.5%)   |
+----------------------------------------+--------------+-------------+
| Epistaxis                              | 8 (1.3%)     | 5 (1.6%)    |
+----------------------------------------+--------------+-------------+
| Fatigue                                | 62 (10.4%)   | 24 (7.8%)   |
+----------------------------------------+--------------+-------------+
| Febrile                                | 10 (1.7%)    | 3 (1.0%)    |
+----------------------------------------+--------------+-------------+
| Finishing wire stripped                | 1 (0.2%)     | 0 (0%)      |
+----------------------------------------+--------------+-------------+
| Fistula                                | 1 (0.2%)     | 0 (0%)      |
+----------------------------------------+--------------+-------------+
| GI                                     | 243 (40.8%)  | 54 (17.5%)  |
+----------------------------------------+--------------+-------------+
| GI bleed                               | 23 (3.9%)    | 7 (2.3%)    |
+----------------------------------------+--------------+-------------+
| Genitourinary                          | 16 (2.7%)    | 13 (4.2%)   |
+----------------------------------------+--------------+-------------+
| Helix related (screw tip), broken or   | 1 (0.2%)     | 0 (0%)      |
| stretched                              |              |             |
+----------------------------------------+--------------+-------------+
| Hematoma                               | 44 (7.4%)    | 3 (1.0%)    |
+----------------------------------------+--------------+-------------+
| Hematuria                              | 6 (1.0%)     | 2 (0.6%)    |
+----------------------------------------+--------------+-------------+
| Hemoglobin drop                        | 29 (4.9%)    | 10 (3.2%)   |
+----------------------------------------+--------------+-------------+
| Hemorrhage                             | 4 (0.7%)     | 0 (0%)      |
+----------------------------------------+--------------+-------------+
| High DFTs - tachy                      | 4 (0.7%)     | 0 (0%)      |
+----------------------------------------+--------------+-------------+
| Hypertension                           | 19 (3.2%)    | 7 (2.3%)    |
+----------------------------------------+--------------+-------------+
| Hypotension                            | 90 (15.1%)   | 26 (8.4%)   |
+----------------------------------------+--------------+-------------+
| Inappropriate shock above rate cutoff  | 59 (9.9%)    | 2 (0.6%)    |
+----------------------------------------+--------------+-------------+
| Inappropriate shock due to oversensing | 19 (3.2%)    | 0 (0%)      |
+----------------------------------------+--------------+-------------+
| Infection                              | 125 (21.0%)  | 31 (10.1%)  |
+----------------------------------------+--------------+-------------+
| Insulation breach suspected            | 1 (0.2%)     | 0 (0%)      |
+----------------------------------------+--------------+-------------+
| Insulation breech observed             | 1 (0.2%)     | 0 (0%)      |
+----------------------------------------+--------------+-------------+
| Insulation problem, cut or damage      | 1 (0.2%)     | 0 (0%)      |
+----------------------------------------+--------------+-------------+
| Intermittent sensing - atrium pace -   | 1 (0.2%)     | 0 (0%)      |
| brady                                  |              |             |
+----------------------------------------+--------------+-------------+
| Ischemia                               | 6 (1.0%)     | 1 (0.3%)    |
+----------------------------------------+--------------+-------------+
| Malfunction, memory problem            | 1 (0.2%)     | 0 (0%)      |
+----------------------------------------+--------------+-------------+
| Malfunction, tone/alarms, appropriate  | 1 (0.2%)     | 0 (0%)      |
+----------------------------------------+--------------+-------------+
| Malfunction, tone/alarms,              | 1 (0.2%)     | 0 (0%)      |
| inappropriate                          |              |             |
+----------------------------------------+--------------+-------------+
| Materials unretrieved in body          | 1 (0.2%)     | 0 (0%)      |
+----------------------------------------+--------------+-------------+
| Migration of device                    | 2 (0.3%)     | 0 (0%)      |
+----------------------------------------+--------------+-------------+
| Multiple counting - tachy              | 30 (5.0%)    | 0 (0%)      |
+----------------------------------------+--------------+-------------+
| Muscle stimulation                     | 2 (0.3%)     | 0 (0%)      |
+----------------------------------------+--------------+-------------+
| Myocardial infarction                  | 13 (2.2%)    | 7 (2.3%)    |
+----------------------------------------+--------------+-------------+
| Neurologic                             | 34 (5.7%)    | 14 (4.5%)   |
+----------------------------------------+--------------+-------------+
| Occlusion                              | 1 (0.2%)     | 0 (0%)      |
+----------------------------------------+--------------+-------------+
| Oversensing - atrium pace - tachy      | 1 (0.2%)     | 0 (0%)      |
+----------------------------------------+--------------+-------------+
| Oversensing - atrium pace sense        | 2 (0.3%)     | 0 (0%)      |
+----------------------------------------+--------------+-------------+
| Oversensing - vent. pace - tachy       | 2 (0.3%)     | 0 (0%)      |
+----------------------------------------+--------------+-------------+
| Oversensing - ventricle pace sense     | 3 (0.5%)     | 0 (0%)      |
+----------------------------------------+--------------+-------------+
| Pacemaker syndrome                     | 1 (0.2%)     | 0 (0%)      |
+----------------------------------------+--------------+-------------+
| Pacemaker-mediated tachycardia (PMT)   | 13 (2.2%)    | 1 (0.3%)    |
+----------------------------------------+--------------+-------------+
| Pain                                   | 185 (31.1%)  | 72 (23.4%)  |
+----------------------------------------+--------------+-------------+
| Palpitations                           | 21 (3.5%)    | 4 (1.3%)    |
+----------------------------------------+--------------+-------------+
| Pectoral muscle stimulation            | 1 (0.2%)     | 0 (0%)      |
+----------------------------------------+--------------+-------------+
| Perforation, coronary venous           | 5 (0.8%)     | 2 (0.6%)    |
+----------------------------------------+--------------+-------------+
| Perforation, venous                    | 2 (0.3%)     | 0 (0%)      |
+----------------------------------------+--------------+-------------+
| Pericardial effusion                   | 2 (0.3%)     | 0 (0%)      |
+----------------------------------------+--------------+-------------+
| Pericarditis                           | 3 (0.5%)     | 0 (0%)      |
+----------------------------------------+--------------+-------------+
| Phantom shock                          | 3 (0.5%)     | 0 (0%)      |
+----------------------------------------+--------------+-------------+
| Phrenic nerve/diaphragm stimulation    | 98 (16.5%)   | 1 (0.3%)    |
+----------------------------------------+--------------+-------------+
| Physical trauma                        | 70 (11.8%)   | 15 (4.9%)   |
+----------------------------------------+--------------+-------------+
| Physiological reaction                 | 145 (24.4%)  | 51 (16.6%)  |
+----------------------------------------+--------------+-------------+
| Placement difficulty, stylet related   | 1 (0.2%)     | 0 (0%)      |
+----------------------------------------+--------------+-------------+
| Pleural effusion                       | 15 (2.5%)    | 2 (0.6%)    |
+----------------------------------------+--------------+-------------+
| Pleurisy                               | 2 (0.3%)     | 0 (0%)      |
+----------------------------------------+--------------+-------------+
| Pneumonia (respiratory infection)      | 0 (0%)       | 4 (1.3%)    |
+----------------------------------------+--------------+-------------+
| Pneumothorax                           | 11 (1.8%)    | 5 (1.6%)    |
+----------------------------------------+--------------+-------------+
| Pocket erosion/extrusion               | 3 (0.5%)     | 0 (0%)      |
+----------------------------------------+--------------+-------------+
| Pocket infection                       | 22 (3.7%)    | 1 (0.3%)    |
+----------------------------------------+--------------+-------------+
| Post-surgical wound discomfort         | 60 (10.1%)   | 1 (0.3%)    |
+----------------------------------------+--------------+-------------+
| Pseudoaneurysm                         | 1 (0.2%)     | 0 (0%)      |
+----------------------------------------+--------------+-------------+
| Psychological effects                  | 51 (8.6%)    | 23 (7.5%)   |
+----------------------------------------+--------------+-------------+
| Pulmonary edema                        | 10 (1.7%)    | 3 (1.0%)    |
+----------------------------------------+--------------+-------------+
| Pulmonary embolism                     | 3 (0.5%)     | 2 (0.6%)    |
+----------------------------------------+--------------+-------------+
| Rate response insufficient - brady     | 2 (0.3%)     | 0 (0%)      |
+----------------------------------------+--------------+-------------+
| Renal failure                          | 104 (17.5%)  | 31 (10.1%)  |
+----------------------------------------+--------------+-------------+
| Respiratory arrest                     | 6 (1.0%)     | 0 (0%)      |
+----------------------------------------+--------------+-------------+
| Respiratory distress                   | 2 (0.3%)     | 0 (0%)      |
+----------------------------------------+--------------+-------------+
| Respiratory failure                    | 11 (1.8%)    | 2 (0.6%)    |
+----------------------------------------+--------------+-------------+
| Respiratory related                    | 256 (43.0%)  | 101 (32.8%) |
+----------------------------------------+--------------+-------------+
| Sensing T-wave - tachy                 | 1 (0.2%)     | 0 (0%)      |
+----------------------------------------+--------------+-------------+
| Sensing myopotential - tachy           | 1 (0.2%)     | 0 (0%)      |
+----------------------------------------+--------------+-------------+
| Set screw, not tight                   | 1 (0.2%)     | 0 (0%)      |
+----------------------------------------+--------------+-------------+
| Shock                                  | 3 (0.5%)     | 2 (0.6%)    |
+----------------------------------------+--------------+-------------+
| Statement from witness - HCP           | 1 (0.2%)     | 0 (0%)      |
+----------------------------------------+--------------+-------------+
| Stroke syndrome or CVA                 | 12 (2.0%)    | 3 (1.0%)    |
+----------------------------------------+--------------+-------------+
| Syncope                                | 27 (4.5%)    | 12 (3.9%)   |
+----------------------------------------+--------------+-------------+
| Thrombosis                             | 14 (2.4%)    | 4 (1.3%)    |
+----------------------------------------+--------------+-------------+
| Transient heart block                  | 3 (0.5%)     | 1 (0.3%)    |
+----------------------------------------+--------------+-------------+
| Transient ischemic attack (TIA)        | 5 (0.8%)     | 3 (1.0%)    |
+----------------------------------------+--------------+-------------+
| Tumors, growths                        | 4 (0.7%)     | 2 (0.6%)    |
+----------------------------------------+--------------+-------------+
| Ulceration                             | 3 (0.5%)     | 2 (0.6%)    |
+----------------------------------------+--------------+-------------+
| Undersensing - atrium pace sense -     | 4 (0.7%)     | 0 (0%)      |
| brady                                  |              |             |
+----------------------------------------+--------------+-------------+
| Undersensing - vent. pace sense -      | 1 (0.2%)     | 0 (0%)      |
| tachy                                  |              |             |
+----------------------------------------+--------------+-------------+
| Vascular related                       | 21 (3.5%)    | 8 (2.6%)    |
+----------------------------------------+--------------+-------------+
| Ventricular fibrillation               | 17 (2.9%)    | 2 (0.6%)    |
+----------------------------------------+--------------+-------------+
| Ventricular tachycardia                | 115 (19.3%)  | 32 (10.4%)  |
+----------------------------------------+--------------+-------------+
| Volume overload                        | 30 (5.0%)    | 6 (1.9%)    |
+----------------------------------------+--------------+-------------+

Dehydration appeared to be more common in the CRT-D cohort. In
particular, there were 24 episodes of renal failure attributed to
dehydration in the CRT-D cohort compared to 1 episode in the OPT cohort.
Given the presumed mechanism of action of CRT-P in improving cardiac
function, it is plausible that dehydration might be more common with
this intervention if the diuretic dose were not decreased. TABLE 13
lists the sponsor's adjudication with the number of episodes attributed
to dehydration for CRT-D and OPT.

+------------------------------------+----------------+---------------+
| **TABLE 13: Episodes of            |                |               |
| Dehydration**                      |                |               |
+------------------------------------+----------------+---------------+
| **Sponsor Adjudication**           | **CRT-D**      | **OPT**       |
|                                    |                |               |
|                                    | **(n=595)**    | **(n=308)**   |
+------------------------------------+----------------+---------------+
| Renal failure                      | 24 (4.0%)      | 1 (0.3%)      |
+------------------------------------+----------------+---------------+
| Electrolyte/lab                    | 10 (1.7%)      | 4 (1.3%)      |
+------------------------------------+----------------+---------------+
| Physiological reaction             | 10 (1.7%)      | 2 (0.6%)      |
+------------------------------------+----------------+---------------+
| Hypotension                        | 20 (3.4%)      | 9 (2.9%)      |
+------------------------------------+----------------+---------------+
| Dizziness, cause unspecified       | 10 (1.7%)      | 3 (1.0%)      |
+------------------------------------+----------------+---------------+
| Physiological effect               | 1 (0.2%)       | 0 (0%)        |
+------------------------------------+----------------+---------------+
| Syncope                            | 7 (1.2%)       | 1 (0.3%)      |
+------------------------------------+----------------+---------------+
| Fatigue                            | 6 (1.0%)       | 2 (0.6%)      |
+------------------------------------+----------------+---------------+
| **TOTAL**                          | 88 (14.8%)     | 22 (7.1%)     |
+------------------------------------+----------------+---------------+

**AGREEMENT MEETINGS**

[The preceding analyses are consistent with the agreements reached
between the sponsor and FDA during the Agreement Meetings as described
in the FDA letters dated September 8, 1999, and November 14, 2002. The
latter agreement letter included the *COMPANION Trial Revised Analysis
Plan* dated November 1, 2002. Neither agreement makes any reference to
whether the CRT-D and CRT-P data could be compared, or of using any
available CRT-P data in the analysis of the CRT-D device. In fact, the
COMPANION protocol on page 17 states, "Descriptive statistics will be
used to describe any similarity or difference between CONTAK TR and
CONTAK CD." It should be noted that descriptive statistics were used
exclusively in this review.]{.underline}