# SUMMARY OF SAFETY AND PROBABLE BENEFIT

## For The AbioCor Replacement Heart

1.  **General Information**

Device Generic Name: Implantable Replacement Heart

Device Trade Name: AbioCor Replacement Heart

Applicant's Name and Address ABIOMED, Inc.

22 Cherry Hill Drive

Danvers, MA 01923

Humanitarian Device Exemption Number: H040006

Date of Panel Recommendation: June 23, 2005

Date of Good Manufacturing Practices Inspection:

Date of Notice to Applicant:

2.  **Indications for Use**

The AbioCor is indicated for use in severe end stage heart disease
patients who

-   are less than 75 years old,

-   are not transplant candidates at the time of assessment,

-   require multiple inotropic support,

-   are in biventricular failure not treatable by LVAD destination
    therapy,

-   are not weanable from biventricular support if on such support and
    not awaiting transplantation.

**3. Contraindications**

Contraindications include patients

• with other irreversible end organ functions that would compromise
survival,

• with inadequate psychosocial support,

> • in whom preoperative noninvasive anatomical assessment reveals
> inadequate fit.

4.  **Warnings and Precautions**

There are a few basic warnings and cautions:

• Stay clear of MRI or high magnetic field environment

• Do not place TET near metal elements

• Internal low battery alarm requires immediate eTET attachment

• Low flow alarm requires clinical attention

• eTET decoupling alarm requires need to check eTET coupling

Other detailed warnings and cautions are given in the Instructions for
Use.

5.  **Device Description**

The AbioCor is a pulsatile electrohydraulic implantable replacement
heart

capable of delivering up to 8 L/min over a broad range of physiologic
pressures.

System control is achieved on a beat-by-beat basis targeting a constant
stroke volume to insure repeated full filling and full ejection.

Except for the inflow cuffs and the outflow graft connectors, which are
constructed from standard medical grade velour patches and grafts, the
blood contacting components of the AbioCor are made from Angioflex, a
polyether-urethane. Titanium is used as the casing material to avoid
corrosion. Medical grade epoxy is used to provide rigidity to nonmoving
portions of the blood pumps. The flow paths through the pumps are
designed to avoid regions of stasis. The inflow and outflow valves are
designed to maintain proper washout of the leaflets. With the use of
polyurethane valves, the AbioCor ventricles are quiet in operation.

The hydraulic system that powers the device consists of a miniature
centrifugal pump and a reciprocating switching valve which reverses the
direction of the fluid flow on every beat. The hydraulic fluid actuating
the flexing membranes, separating the fluid from the blood,
simultaneously effects the filling of blood on one side while ejecting
blood on the other side. Systole on the left side is diastole on the
right side and vice versa.

The AbioCor accommodates the difference in outputs required between the
left and the right ventricles. Physiologic shunts exist which normally
require higher left side outputs compared to the right side. In the
AbioCor, a hydraulic balance chamber is used to shunt the right chamber
volume, thus reducing the right side output relative to the left side.
This feature allows the maintenance of physiologic left atrial pressure.

Implantation of the AbioCor is achieved while on cardiopulmonary bypass
(CPB). The diseased ventricles are excised and cuffs are sewn to the two
atrial remnants. Aortic and pulmonary grafts are sewn in place. The
cuffs and grafts have mating connectors to the inflow and outflow ports
of the device facilitating a snap on coupling. De-airing completes the
transition from CPB to the AbioCor.

The system can be divided into 3 subsystems: the Implantable, the
External Console, and the Patient Carried Electronics (PCE) Subsystems.
The general description of their respective functions follows.

# The Implantable Subsystem

The Implantable Subsystem consists of all of the components that are
required to be implanted for normal operation of the AbioCor^®^. The
main components of this subsystem are described below.

## Thoracic Unit (TU)

The thoracic unit (TU) converts the electrical power into blood motion
to support the circulatory system of the patient. The TU is implanted in
the space vacated after excising the native ventricles. The TU
alternately ejects blood into the systemic and pulmonary circulation.

## Implantable Controller

The Implantable Controller is the brain of the entire system. It is
microprocessor based and provides control and monitoring of the TU. It
also has the capability to receive and transmit information to the
external systems via a radio frequency (RF) communication link.

## Implantable Battery

The Implantable Battery is a rechargeable, lithium ion based power
source that can maintain normal operation of the implantable system in
the absence of an external power source for more than 30 minutes.

## Implantable Transcutaneous Energy Transmission Coil (iTET)

The Implantable Transcutaneous Energy Transmission Coil (iTET) receives
power inductively from an external power source and converts it into DC
to power the implantable subsystem.

## 5.1.5 Implantable Cable

The Implantable Cable connects the various components of the Implantable
Subsystem together. The cable also has an integral antenna that is used
for the RF communications.

#  External Subsystem

The External Subsystem consists of all of the components that are
required to support normal operation of the AbioCor^®^ for implantation,
ICU recovery, patient ambulation and out-of hospital use. The main
components of this subsystem are described below.

## Console

The Console allows monitoring primarily of the Implantable Subsystem
parameters and alarms as well as the ability to make changes in system
run conditions. There are several modes of access for system operation
intended to insure patient safety. For instance, the console can stop
operation of the TU only during implantation. This function, essential
during de-airing of the TU in the operating room, is not accessible in
any other functional mode. In the home screen mode, the display is
significantly simplified to avoid information overload, or potentially
harmful actions by the user.

The Console also has drive circuitry to power the External
Transcutaneous Energy Transmission Coil (eTET).

1.  **External Transcutaneous Energy Transmission Coil (eTET)**

The eTET allows delivery of energy to the iTET. There are two different
eTET cable lengths to accommodate various use environments. A Duoderm
based Velcro patch is used to anchor the eTET at the skin region
overlying the iTET.

## Radio Frequency Communications Assembly (RF Comm)

The Radio Frequency Communications Assembly (RF Comm) gives the console
the wireless communication bi-directionally between the external and the
Implantable Subsystems.

# Patient Carried Electronics (PCE) Subsystem

The Patient Carried Electronics (PCE) Subsystem consists of all of the
components that are required to support normal operation of the
AbioCor^®^ for periods of full patient ambulation. It supplies power to
the internal system via the eTET. The main components of this subsystem
are described below.

## PCE TET Driver

The lightweight PCE TET Driver has the circuitries to drive the eTET and
to enunciate simple alarms such as low battery, eTET decoupling, excess
PCE temperature, and a general Implantable Subsystem alarm.

## External Transcutaneous Energy Transmission (eTET) Coil

The PCE uses the same eTET coils as that used for the external console.

## PCE Power and Bag

The PCE Batteries are the primary power source for the PCE TET Driver.
The PCE Batteries are discharged in pairs. Two sets of batteries are
provided to allow for appropriate backup. The battery sets and the eTET
are housed in a PCE bag specifically designed for portability.

## Handheld Alarm Monitor

The Handheld Alarm Monitor allows the user to find out specific details
regarding Implantable Subsystem alarms that are enunciated on the PCE
TET Driver. This device allows clearing of the alarm when the condition
has resolved. This unit relieves the patient from needing to be near the
console to have full diagnostic capability. This unit does not provide
control of the internal system, that function requires the console.

## 5.2.4 PCE AC Converter

The PCE AC Converter is an alternate power source for the PCE TET
Driver. It permits a patient while stationary to be able to use the PCE
TET Driver for an unrestricted amount of time without the need to
actively manage PCE Batteries.

## PCE Battery Charger

The PCE Battery Charger is a 10-bay charger that allows the patient to
charge up to 5 sets of PCE Batteries. It also provides diagnostic
information on the state of charge of the PCE Batteries.

2.  **Implantation Accessories**

Accessories to facilitate implantation include specially designed
wrenches to tighten or loosen electrical connectors between implantable
components, tools to connect the device to the atrial cuffs and arterial
grafts, instruments to check the integrity of anastomoses, dummy models
of electronic packs for pocket sizing, and dummy thoracic unit for
sizing graft lengths needed for the anastomoses.

3.  **Safety Elements**

Many safety elements are incorporated into the AbioCor system including:

• 24x7 clinical and technical support

• complete backup system in each hospital

• backup external Patient Carried Electronics for home use

• Multiple alarm paths for low internal battery, low flow conditions

• TET self shut down under overload condition

• No skin penetration for external power transfer

• Internal battery capacity of greater than 30 minutes

6.  **Alternative Practices and Procedures**

There are no other devices on the market that address the same patient
population as the AbioCor. None of the devices in clinical use today,
BVS5000, AB5000, Heartmate, Thoratec PVAD, Novacor, or CardioWest can
adequately support those patients that are AbioCor candidates. Neither
can devices on the horizon, such as the Lion Heart, and a class of
rotary pumps in clinical trials address the patient population addressed
by the AbioCor.

7.  **Marketing History**

The AbioCor has never been marketed in or outside the United States.

8.  **Potential Adverse Events**

Based on the experience of the AbioCor initial clinical, the following
adverse events can potentially occur in patients implanted with the
AbioCor:

• Bleeding

• Reoperation

• Hemolysis

• Infection (all causes)

• Renal dysfunction

• Hepatic dysfunction

• Respiratory dysfunction

• Neurologic dysfunction

• Thromboembolism

• Mechanical failure

• Electrical failure

• Psychiatric event

-   Stroke

-   Death

9.  **Summary of Preclinical Studies**

Preclinical testing consisted of bench testing and animal testing.

1.  **Benching Testing**

Benching testing consisted of performance, safety, and reliability
testing.

1.  **In Vitro Testing**

Performance testing was conducted over a physiologic range between 60
and 120 mmHg for AOP, 10-40 mmHg for PAP, 3-25 mmHg for LAP, 3-25 mmHg
for RAP, and a shunt flow (left minus right flow) of 0 to 10 % of
cardiac output. Within these ranges, the system is capable of providing
4 to 8 L/min of cardiac output. The TET system is capable of supporting
system operation with radial and/or axial misalignments of ± 0.5". The
internal battery is capable of supporting a 60 minute untethered
operational at a cardiac output of 6 L/min and 100 mmHg systemic
afterload. The external Patient Carried Electronics can provide 60
minutes of operation from one set of batteries. The internal-external RF
communication module functions to provide alarms and inputs to the
internal system. All input requirements were tested and verified.

2.  **Safety Testing**

The AbioCor system passed all Electromagnetic Interference and
Electromagnetic Compatibility requirements based on FCC CFR 47 Parts 15
and 18, CISPR11, and IEC 60601-1-2 for intentional and unintentional
radiators. All implanted components of the AbioCor were tested for
Biocompatibility to EN ISO 10993-1:1997. The Implanted Components are
ETO sterilized. The process was verified according to ANSI/AAMI/ISO
11135-1994. Sterility shelf life has been verified for 15 months.
Immunity to shock was tested according to NTIS/ECRI PB296-892 and
vibration according to RTCA/DO-160C. Packaging integrity for various
parts was tested to ISTA 3C. Components were subjected to fluid ingress
testing (EN 60529). The AbioCor system satisfied additional electrical
and mechanical safety requirements of UL 2601.

3.  **Reliability**

Twenty-five implantable subsystems have been placed on reliability
testing. Failure times have ranged between 8.2 to 40.5 months. The
average runtime time is 18.8 months (± 11.5). System reliability is
determined to be greater than 80% at a confidence level of 80% for a
one-year operation. Three major failure modes were observed: bearing,
membrane wear, and fluid ingress. Two of the three failure modes have
been observed clinically, a bearing failure at 5 months and a membrane
wear at 17 months. Fluid ingress due to a breach of system hermiticity
has not been encountered. A needle puncture of a cable sheath was
encountered and the cable was surgically exchanged without patient
compromise.

Backup consoles are required in the hospital environment and backup PCEs
and Handheld Monitors are required for discharged patients.

2.  **Animal Testing**

Fourteen studies completed the 30-day duration. The AbioCor was
implanted in calves weighing 90 to 120 kg. The results of the studies
indicated that after the one-month implants, blood pumps and end organs
were generally clean without evidence of thromboembolic problems. Based
on the animal studies, no thermal injury problem was anticipated in the
operation of the Transcutaneous Energy Transmission system (TET) in
humans, and none has been encountered.

10. **Summary of Clinical Study**

The goal of this initial trial is to assess the safety and potential
efficacy of the fully implantable AbioCor replacement heart as a
potential therapy for those cardiac patients whose therapeutic options
have been exhausted.

**10.1 Objectives**

For those patients implanted with the AbioCor, the initial evaluation of
safety and potential efficacy is to be assessed at 60 days
post-implantation. For those who recover sufficiently on the AbioCor,
heart transplantation could be reassessed after the initial 60-day
period. For those not eligible for transplantation, patients would be
supported for life on the AbioCor.

The primary endpoint of this study is the absence of significant
neurologic deficit at 60 days post implant.

**10.2 Methods**

Candidate selection proceeded in two stages, a screening stage and an
implant consent stage. During the screening stage, a basic medical
assessment is performed. This assessment involves the determination of
the severity of a candidate's heart failure and the potential fit of the
device in the patient's thoracic cavity.

Candidates eligible for the trial are those who are not eligible for
heart transplantation based on the center's criteria at the time of
screening, are in biventricular failure not treatable with implantable
LVAD, and are under optimal medical management yet unable to sustain
continued life. Alternatively, a patient who could not be weaned from
biventricular cardiac support and is not a transplant candidate is
eligible for the AbioCor. Patients with irreversible end-organ failure,
and inadequate psychosocial support are excluded from the trial.

Candidates are excluded if the prognosis for survival is greater than
30% within the next 30 days. The prognosis of survival is based on a
combination of hemodynamic status, cardiac conditions and end organ
status.

A screening tool is used to assess the potential for anatomic fit. MRI
or CT scans from candidates are used to reconstruct the internal chest
dimensions and the anatomy of the patient. A virtual surgery is
performed to remove the ventricles and place the AbioCor in the vacated
space. Three critical observations are made to insure fit. The AbioCor
must stay within the rib cage, while not interfering with the left
bronchus and the left pulmonary veins.

If a candidate passes all the established criteria, a patient advocate
would participate in the informed consent process. Although direct
patient consent is preferred, in cases where this is not practical, such
as AMI shock patients, a legal surrogate can sign on the patient's
behalf.

3.  **Description of Patients**

Fourteen patients have been enrolled in the trial. All candidates were
males due primarily to fit constraints. Table 1 is a summary of patient
demographics. The mean age of this initial cohort is 67 ± 7.9 ranging
between 51 and 79 years old. The percentage of patients excluded from
transplant due to age was 43% (6/14), to irreversible pulmonary
hypertension was 29% (4/14), to malignancy was 14% (2/14), and to
multiple factors, such as diabetes, neuropathy, renal dysfunction,
hepatic dysfunction, etc was 14% (2/14). The BSA, body weights, and
heights are also given in the table.

> Table 1 Patient Demographics (n=14)

+---------------+---------------+-------------+----------+------------+
|               | Average       | Stdev       | Min      | #### Max   |
+---------------+---------------+-------------+----------+------------+
| Age yo        | 67            | 7.9         | 51       | 79         |
+---------------+---------------+-------------+----------+------------+
| BSA M^2^      | 1.97          | 0.15        | 1.72     | 2.24       |
+---------------+---------------+-------------+----------+------------+
| Height cm     | 180\.         | 6.2         | 170.2    | 189        |
+---------------+---------------+-------------+----------+------------+
| Weight kg     | 78.1          | 10.9        | 60.8     | 96.3       |
+---------------+---------------+-------------+----------+------------+

The preoperative cardiac conditions and comorbidities of patients are
summarized in Table 2. All patients were in NY Class IV heart failure
primarily of ischemic origin (12/14) with two being idiopathic. All
patients were bedbound. A majority of the patients had prior cardiac
operations, pacer or AICD implanted, and/or required IABP support.
Pulmonary hypertension and renal dysfunction were the two primary
comorbidities.

> Table 2 Pre-Operative Conditions

  ------------------------------------ ----------------------------------
  Pre-implant Cardiac Condition or     \# of Patients with Condition
  Comorbidity                          (n=14)

  Re-op                                10

  Pacer/AICD                           10

  IABP                                 10

  Ventilator Support                   4

  Pulmonary Hypertension               8

  Renal Dysfunction                    9

  Liver Dysfunction                    4

  Diabetes                             6
  ------------------------------------ ----------------------------------

Pre-operative hemodynamics is summarized in Table 3. All data were
collected within two weeks of implantation. Ten of the fourteen
candidates required IABP support. In addition, high levels of inotropic
support averaging 2.5 ± 1.0 drug types were needed to maintain marginal
cardiac output and systemic pressure. Mean systemic pressure was 75 ± 9
mmHg. The mean cardiac index was 2.1 ± 0.5 L/min•M^2^ under such maximal
inotropic support concurrent with counterpulsation support. Table 4
shows the mean dosages for the inotropes used. The dosages were in the
medium to high range. Wedge pressure was elevated (LAP = 20 ± 6 mmHg)
characteristic of these end stage heart failure patients. The central
venous pressure (CVP = 13 ± 7 mmHg) spanned a broad range (2-24 mmHg)
reflecting patients being actively volume managed by infusion, diuresis,
and vasoactive drugs. The systemic vascular resistance (SVR) was 1231 ±
349 dyne•sec/cm^5^ spanning a broader range than normal indicative of
hypotensive to hypertensive conditions of multiple etiologies. The
pulmonary vascular resistance (PVR) was 305 ± 106 and nearly three to
four times higher than normal reflecting the pulmonary hypertensive
condition of the patients.

> Table 3 Pre-operative Hemodynamics

+---------------------------------+-----------+------------+---------+
|                                 | Average   | Stdev      | N       |
+---------------------------------+-----------+------------+---------+
| PAP mmHg                        | 34        | 6.6        | 14      |
+---------------------------------+-----------+------------+---------+
| AoP mmHg                        | 74        | 6          | 14      |
+---------------------------------+-----------+------------+---------+
| CVP mmHg                        | 11        | 6.4        | 14      |
+---------------------------------+-----------+------------+---------+
| PCWP mmHg                       | 19.9      | 5.5        | 14      |
+---------------------------------+-----------+------------+---------+
| Cardiac Index L/min-M^2^        | 2.1       | 0.5        | 14      |
+---------------------------------+-----------+------------+---------+
| Cardiac Output L/min            | 4.3       | 1.2        | 14      |
+---------------------------------+-----------+------------+---------+
| Ejection Fraction %             | 18.6      | 3.5        | 14      |
+---------------------------------+-----------+------------+---------+
| PVR                             | 305       | 107        | 12      |
|                                 |           |            |         |
| dynes-sec/cm^5^                 |           |            |         |
+---------------------------------+-----------+------------+---------+
| SVR                             | 1231      | 349        | 14      |
|                                 |           |            |         |
| dynes-sec/cm^5^                 |           |            |         |
+---------------------------------+-----------+------------+---------+

> Table 4 Pre-operative Inotrope Dosages (n=14)

  --------------------------- ------------- --------------- --------------
  Inotrope                    Mean Dosage   Standard        Number of
                                            Deviation       Patients

  Dobutamine - μg/kg/min      7.89          4.08            8

  Dopamine - μg/kg/min        9.16          10.53           6

  Primacor - μg/kg/min        0.43          0.24            12

  Epinephrine - μg/min        3.3           \--             1

  Levophed - μg/min           9.11          \--             1

  Digoxin -- mg/day           0.14          0.05            7
  --------------------------- ------------- --------------- --------------

Pre-operative blood chemistry is summarized in Table 5. The low albumin
level (2.8 ± 0.7 g/dl) is indicative of cachexia common to severe end
stage heart failure patients. The low sodium level (132 ± 6 meq/L) is
another end of life indicator. The elevated creatinine (1.7 ± 0.7 mg/dl)
and BUN (45 ± 30 mg/dl) levels reflect renal dysfunction. Similarly,
total bilirubin (1.7 ± 1.8 mg/dl), AST (73 ± 126 mg/dl), and ALT (64 ±
100 mg/dl) reflect liver dysfunction common to these patients.

Table 5 Pre-operative Blood Chemistry

  ------------------ ------------ ---------- ---------- ---------- ----------
                     Average      Stdev      Min        Max        N

  Na mEq/L           131.7        6.4        120        141        14

  Albumin g/dl       2.8          0.7        2          3.9        11

  Creat mg/dl        1.7          0.7        1          3          14

  BUN mg/dl          45.1         30.2       16         110        14

  Tbil mg/dl         1.7          1.8        0.5        7.4        14

  ALT mg/dl          63.5         100.2      3          333        14

  AST mg/dl          73.1         125.8      10         491        14

  Glucose mg/dl      116.7        39.5       59         186        14
  ------------------ ------------ ---------- ---------- ---------- ----------

All patients entered into the trial met the inclusion criterion of
biventricular failure as the basis for exclusion from potential
implantable LVAD support. In addition, all patients met the exclusion
criterion of less than 70% probability of dying within 30 days based on
the AbioScore or AMI Shock Index. The inotrope requirements of AbioCor
patients averaged 2.5 inotropes, suggesting that based solely on
inotropic needs, mortality would have been high, averaging around 60%
within 30 days. Accounting for additional comorbid conditions, the
mortality would be further increased as is anticipated of the AbioCor
candidates.

Figure 1 illustrates the survival probability of our study population
compared with those recruited in the REMATCH trial^(3.2)^. The Kaplan
Meier plot for the REMATCH group is based on the control group from that
trial. The plot for the AbioCor group was based on patients that met all
medical inclusion and exclusion criteria but did not enter the trial due
either to identifiable anatomic fit problem or failure to consent. These
patients were followed to 60 days. The median survival of the REMATCH
patients was around five months while that for

the AbioCor candidates were two weeks. This comparison illustrates the
very much sicker patient population recruited for the AbioCor compared
to any other patient cohort. Due to the small sample size, no
statistical significance is implied.

![](media/image1.wmf)

Figure 1 Survival Plots of REMATCH and AbioCor Reference Candidates

4.  **Results**

Twelve patients survived surgery. For these twelve patients, ten
survived beyond the 60-day endpoint for evaluation in this initial
trial. Support for two patients was withdrawn prior to 60 days at the
request of the respective family. For the ten patients that survived
beyond 60 days, seven reached 60 days with no neurologic incidents, the
principal end point of the trial. One did not recover from the incident,
while the other two patients recovered from their respective incident.
The mean support duration for the ten patients that reached 60 days of
support is 6.0 months (± 4.3).

Of the fourteen patients, 86% (12/14) survived surgery. This rate is not
unlike that of transplant acute survival rate. For those that survived
surgery, 83% (10/12) survived beyond 60 days, twice the expected
survival duration for these patients.

1.  **Adverse Events**

Recovery has been a lengthy process for these patients. Table 6 lists
the major adverse event types experienced by the patients during the
course of recovery. Event rates are given in reported incidents per
patient per month. The CVA category includes embolic strokes confirmed
by CT scans. The TIA category includes events that were transient or
showed no clinical evidence of embolic strokes. There were many surgical
bleeding events, such as tamponade, occurring during the first few weeks
post operatively. The leading event rates were bleeding, infection
unrelated to the device, and respiratory complications. These were
followed by neurologic, renal, and hepatic complications.

> Table 6. Adverse Event Rate (n=12)

  ---------------------- ----------------- -------------- ---------------
  Event Type             Event Rate (per   Total Number   Event Rate --
                         patient•month)    of Events      Approved
                                                          Devices

  CVA -- CT confirmed    0.22              14             0.01-0.28

  TIA or non-clinical    0.09              6              0.01-0.2

  Non-surgical bleeding  0.41              26             0.04-0.27

  Surgical bleeding      \-                42             \-

  Sepsis                 0.03              2              0.03-0.17

  Infection              0.52              33             0.02-0.24

  Hepatic                0.11              7              0.02-0.26

  Renal                  0.13              8              0.02-0.16
  ---------------------- ----------------- -------------- ---------------

The ranges of reported adverse event rates for approved cardiac support
devices are also listed in Table 6. Patients supported by these devices
were mostly for bridge to transplant indication requiring the patients
to be in better condition to be qualified for transplantation. In
addition, the results of these devices represent recent experiences
following decades of learning and improvements in clinical use. For the
AbioCor, this represents the first clinical experience.

Only two adverse event types appear to be outside the reported range for
other devices. These are bleeding and infection. The propensity for
bleeding has been high for AbioCor patients due to comorbidities. This
has been the reason why 10 of 12 patients could not tolerate the
recommended level of anticoagulation (INR\>2.5 or PTT\>50 sec) more than
60% of the time, and of these 10 patients, seven of them could not
tolerate more than 80% of the time. The higher infection rate is due to
the long hospital stay due to the debilitated condition of the patients
coming into the trial. Long hospital stay exposes patients to higher
risk of infection.

Despite the sicker condition of AbioCor patients, renal and hepatic
complications did not appear to be more pronounced than the mature
devices. Septic event rate experienced with the AbioCor was at the low
end of those of established devices. The fully implantable AbioCor has a
beneficial feature in not leading to septic conditions despite the
higher observed infection rate. There were two septic events associated
with the AbioCor patients, one as a sequella to an abdominal massive
bleeding episode. This episode was caused by a femoral vein puncture
during a dialysis catheter exchange. The second event occurred in a
patient whose suture line did not heal following surgery. Although the
infection rate was high, none of the incidents were related to device
infection.

Following the reintroduction of the modified caged cuff as an option,
three patients were implanted with the AbioCor using caged cuffs sewn to
atrial tissue avoiding tissue contact of the cages. Two patients have
not suffered CVA events. One patient has had an event attributable to
the inability to anticoagulate.

1.  **Device Related Adverse Events**

There were two device related patient deaths. A patient passed away due
to a membrane wear out at 17 months, an anticipated wear out mode at
operating times of around one and one-half years. The patient declined
the option for a device replacement. A second patient died due to a
motor bearing stoppage at 4.8 months. The cause was traced to a
combination of factors leading to system operation outside of the system
design. Corrective actions have been implemented to avoid such
combination of circumstances. The system has been tested to an 80%
reliability at an 80% confidence level for a 12 month operation.
Excluding the anticipated wearout at 17 months, the cumulative clinical
runtime was ∼ 47 device-months. The 4.8 months to failure of the one
device represented an overall probability of survival to 12 months of ∼
85% (1- (12-4.8)/47) consistent with our demonstrated reliability of
80%.

2.  **Outcome**

For AbioCor patients, the majority of them lived or will live out the
remaining portions of their lives on the device. In this initial trial,
transplantation was considered an option following AbioCor support
provided patient condition has improved to a level that transplantation
may be considered. None of the candidates enrolled in the trial had
potentially reversible contraindications to transplantation to be
considered for this treatment in the future. There were two operative
deaths. Support to five patients was withdrawn secondary to CVA events.
There were two device failures. Four patients died of MOF or sepsis,
unrelated to the device. Support was withdrawn in one patient based on
family wishes.

2.  **Patient Activity**

Due to the preexisting debilitated state of the patients coming into the
trial, time to recovery has been long. There have been a total of ∼50
in-hospital excursions, ∼50 PCE uses, and ∼30 out-of hospital
excursions. Out-of-hospital excursions included normal activities such
as attending sports events, religious services, shows, eating in
restaurants, visiting parks, etc.

Two patients were discharged from the hospital. One was discharged to
home for nine months. Six patients lived to see their next birthday. Two
lived to enjoy anniversaries. One patient lived to welcome the first
member of the fourth family generation. The trial to date has
demonstrated that the AbioCor can restore quality life to the
recipients.

3.  **Post-operative Clinical Performance**

Clinical performance of the AbioCor is given in Figures 3 to 6,
including parameters representative of hemodynamics, renal function,
hepatic function, coagulation, hematology, and nutritional status. The
figures contain data for the twelve supported patients. Every figure
includes the preoperative average of each parameter (▪) as the first
datum plotted. Daily averages are plotted along with the respective
standard deviations. The number of contributing patients decreased as
time progressed. Aggregate data are presented here to illustrate the
general course of recovery.

Figure 2 shows the cardiac output provided by the AbioCor. Cardiac
output increased by 50% on the AbioCor.

![](media/image2.wmf){width="4.329861111111111in"
height="2.2916666666666665in"}

Figure 2 Cardiac Output

Physiologic pressures are monitored only for a short duration post
operatively mainly to avoid complications associated with extended use
of indwelling lines. Table 7 shows the mean pre vs post AOP, LAP, and
CVP for the patients. The increased AOP and the reduction in the LAP
were expected on the AbioCor. CVP did not show significant change due
primarily to the need for fluid management in these patients. However,
the standard deviation is tighter post AbioCor implant than pre-implant,
suggesting that while patients were supported on the AbioCor, fluid
management was more routine than under heart failure condition.

Table 7. Physiologic Pressures (mmHg) Across Patients

  ---------- ------------------------ -------------------------- ---------
             Pre-op Mean and Stdv     Post-op Mean and Stdv      p-value

  AOP        74 ± 6                   86.9 ± 6.4                 0.0001

  LAP        19.9 ± 5.4               13.6 ± 5.4                 0.001

  CVP        11 ± 6.4                 13.7 ± 2.8                 N.S.
  ---------- ------------------------ -------------------------- ---------

Return of renal function is shown in Figure 3 for creatinine (Cr in
mg/dl). Pre-operative mean was 1.7 mg/dl ± 0.7. There was a
postoperative overshoot with a gradual return to pre-operative over a
2-week period followed by a gradual return to high normal over a
one-month period followed by further normalization over the second post
operative month. A similar behavior was seen in the BUN trend (not
shown).

![](media/image3.wmf){width="4.350694444444445in"
height="2.4402777777777778in"}

> Figure 3. Creatinine

Figures 4 and 5 show respectively the total bilirubin, and a
representative liver enzyme, AST (in mg/dl). Immediately
post-operatively, total bilirubin jumped higher due to the surgical
insult. Relatively high mean levels (∼6 mg/dl) followed with large
standard deviations. Subsequent large drops near POD 56, POD 86, and POD
115 each represents the withdrawal of patient support. The first case
was a patient in acute liver failure due to fluid overload and was
deemed reversible by the medical team. However, the family requested the
withdrawal of support. The patient in the second case had chronic liver
failure with cirrhosis. His total bilirubin reached a peak of around 35
mg/dl. The patient in the third case went into septic shock and acute
liver failure prior to the withdrawal of support. The AST data
paralleled the bilirubin data both reflecting liver condition.

![](media/image4.wmf){width="4.138194444444444in"
height="2.3222222222222224in"}

> Figure 4. Total Bilirubin
>
> ![](media/image5.wmf){width="4.100694444444445in"
> height="2.301388888888889in"}
>
> Figure 5. AST

**10.4.5 Special Clinical features of the AbioCor**

During the course of the clinical trial, the AbioCor has demonstrated
performance in some areas that surpassed those of the native heart.
Figure 6 shows plot of a patient undergoing extreme acidosis with pH\<7
for a period of ∼ 3 hrs. The AbioCor continued to pump while the patient
was treated with veno-veno ECMO which reversed the hypoxic condition. A
native heart would have failed under such extreme acidosis.

> ![](media/image6.wmf)
>
> Figure 6 Reversal of Extreme Acidosis

![](media/image7.wmf)Figure 7 shows a patient with an extreme case of
malignant hyperthermia lasting for ∼ 40 hrs. The AbioCor continued to
perform during this extreme temperature of 106-107 ^o^F. The patient's
temperature was controlled by the used of Dantrolene. Again a native
heart in failure would not likely have survived under such extreme
condition.

> Figure 7. Hemodynamics Maintained During Hyperthermia

![](media/image8.wmf){width="3.6in" height="2.1180555555555554in"}Figure
8 shows signs of recovery of a patient with identified pre-operative
ascites. Although total bilirubin rose post-operatively, over a
one-month duration, with reliable cardiac output, the liver recovered.

> Figure 8 Recovery from Liver Dysfunction

A final condition in which the AbioCor could function without compromise
while the native heart might have problem maintaining adequate output is
illustrated in Figure 9. In the figure, the Abiocor was able to maintain
6-8 L/min of cardiac output despite having to pump against a pulmonary
pressure of ∼ 60 mmHg. A native heart in cardiac failure would not have
been able to provide the adequate flow to the patient.

![](media/image9.wmf){width="4.184722222222222in"
height="2.4881944444444444in"}Figure 9. AbioCor Can Pump Against
Pulmonary Hypertension

The AbioCor has demonstrated that under abnormal physiologic states such
as extreme acidosis, hyperthermia, elevated PAP, and severe liver
dysfunction, the system can continue to perform while medical treatment
can be implemented without concerns for cardiac function to reverse the
abnormality.

**11. Safety and Probable Benefit**

The results of the initial fourteen patients implanted with the AbioCor
provided sufficient data to demonstrate that the AbioCor is a safe
device in patients with severe end-stage heart failure facing imminent
risk of death. Only one device failure occurred unexpectedly,
representing ∼ 92% (11/12) failure-free device operation clinically for
the demonstrated one year bench operation. The observed stroke rate is
within the bounds observed in VADs approved for use in a much less sick
patient population. No device related infection problems, common to
exteriorized implantable VADs have caused complications in AbioCor
patients. This safety feature is a substantial advantage for fully
implantable devices such as the AbioCor. Safety features for power
management have been built into the system to avoid unintentional
misuses that may result in hazards. The system has been shown to be safe
in a broad range of settings, inside the hospital, outside the hospital
in various ordinary locales, such as restaurants, theaters, sports
arenas, stores and shops, the home environment and in vehicles.

The probable benefits of the AbioCor are many. The device restores
normal hemodynamics and affords dysfunctional end organs, such as
kidneys and livers, a fair chance of recovery as have been seen in a
number of cases in the trial. The AbioCor has demonstrated that it can
support patients with chronic pulmonary hypertension, a condition that
would cause heart transplant failures and could not be overcome with
LVAD support. Most importantly, clinical experience has shown that
patients and caregivers can manage the system outside of the hospital
environment, in their home and community settings. The probable benefits
are that patients with no chance of survival from end stage heart
failure could be offered the opportunity to return home to their loved
ones.

12. **Panel Recommendation**

13. **CDRH Decision**

**14. Approval Specifications**