SUMMARY OF SAFETY AND EFFECTIVENESS

1.General Information

+----------------------------------+-----------------------------------+
| Device Generic Name:             | Implantable Pacemaker Pulse       |
|                                  | Generator                         |
+----------------------------------+-----------------------------------+
| Device Trade Name:               | Medtronic AT500™ DDDRP Pacing     |
|                                  | System (Model AT501)              |
|                                  |                                   |
|                                  | Medtronic AT500™ DDDRP Pacing     |
|                                  | System (Model 9968) Software      |
+----------------------------------+-----------------------------------+
| Applicant's Name and Address:    | Medtronic, Inc.\                  |
|                                  | 710 Medtronic Parkway NE\         |
|                                  | Minneapolis, MN 55432-5604        |
+----------------------------------+-----------------------------------+
| Premarket Approval (PMA)         | P980035/S13                       |
| Application Number:              |                                   |
+----------------------------------+-----------------------------------+
| Date of Panel Recommendation     | None                              |
+----------------------------------+-----------------------------------+
| Date of Notice of Approval to    | March 26, 2003                    |
| the Applicant:                   |                                   |
+----------------------------------+-----------------------------------+

II.Indications for Use

The Medtronic AT500 DDDRP pacing system is indicated for the following:

-   Rate adaptive pacing in patients who may benefit from increased
    pacing rates concurrent with increases in activity.

-   Accepted patient conditions warranting chronic cardiac pacing which
    include:

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-   Symptomatic paroxysmal or permanent second or third-degree AV block.

-   Symptomatic bilateral bundle branch block.

-   Symptomatic paroxysmal or transient sinus node dysfunctions with or
    without associated AV conduction disorders.

-   Bradycardia-tachycardia syndrome to prevent symptomatic bradycardia
    or some forms of symptomatic tachyarrhythmias.

The Medtronic AT500 system is also indicated for dual chamber and atrial
tracking modes in patients who may benefit from maintenance of AV
synchrony. Dual chamber modes are specifically indicated for treatment
of conduction disorders that require restoration of both rate and AV
synchrony, which include:

-   Various degrees of AV block to maintain the atrial contribution to
    cardiac output.

-   VVI intolerance (e.g., pacemaker syndrome) in the presence of
    persistent sinus rhythm.

Antitachycardia pacing (ATP) is indicated for termination of atrial
tachyarrhythmias in bradycardia patients with one or more of the above
pacing indications.

Atrial rhythm management features such as Atrial Rate Stabilization
(ARS), Atrial Preference Pacing (APP), and Post Mode Switch Overdrive
Pacing (PMOP) are indicated for the suppression of atrial
tachyarrhythmias in bradycardia patients with atrial septal lead
placement and one or more of the above pacing indications.

V.Device Description

The Medtronic AT500 DDDRP pacing system is a dual chamber, rate
responsive implantable pulse generator (IPG) and is labeled for patients
having standard bradycardia indications. The AT500 also contains Atrial
Anti-Tachycardia Pacing therapies. In addition, atrial pacing features
are provided to further control atrial rates either through increased
atrial pacing, rate stabilization, or overdrive pacing post mode switch.

By means of the InCheck™ Model 9465 Patient Assistant[^1], the patient
can verify whether the device has detected a suspected atrial arrhythmia
and initiate recording of cardiac event data in the device memory.

The Medtronic programmer (Model 9790/C or Model 2090[^2]), Model 9968
software, and a telemetry programming head constitute the external
portion of the DDDRP pacing system. Programmers from other manufacturers
are not compatible.

Overview Of Features

The AT500 contains bradycardia pacemaker features and in addition,
includes the following atrial pacing features and atrial arrhythmia
termination therapy:

Atrial Pacing Features

Atrial Preference Pacing (APP)

This feature attempts to achieve the maximum amount of atrial pacing
while the patient is not in an atrial arrhythmia. Changes to the pacing
interval are made after non-refractory atrial senses affecting a
stair-step increase in the pacing interval. Changes to the pacing
interval are also made after a consecutive number of atrial paces have
been delivered in which case the pacing rate is decreased. APP is
available in DDD, DDDR, AAI, and AAIR modes.

Atrial Rate Stabilization (ARS)

This feature is a programmable parameter designed to inhibit the onset
of atrial tachyarrhythmias by eliminating the long pause that typically
follows a premature atrial contraction (PAC). This feature is similar to
that approved in the Jewel AF.[^3]

Post Mode Switch Overdrive Pacing (PMOP)

This is a feature that can be used to effect high-rate overdrive DDIR
pacing after an atrial tachyarrhythmia episode has terminated. This is
accomplished by programming a high Overdrive Rate and an appropriately
long Overdrive Period. This feature is similar to that approved in the
Jewel AF.

AT Termination Therapy

Up to three automatic antitachycardia pacing AT therapies can be
delivered. Ventricular backup pacing during the ATP sequence is
available for patients with a high degree of AV Block. There is a
programmable delay between preliminary detection and therapy delivery:

-   Atrial Anti-Tachycardia Pacing (ATP)

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-   A-Ramp protocol

-   A-Burst + protocol

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-   Manual 50Hz High Frequency Burst

These features are identical to the Jewel AF Model 7250, with the
exception of the addition of the VVI backup option. The VVI backup
pacing does not affect the ATP therapy in any way.

The AT500 analyzes the timing and pattern of sensed events in the atrium
and ventricle to detect AF and AT. It also applies this analysis to
monitor for non-sustained ventricular arrhythmia episodes. Based on
patterns of atrial and ventricular events, and the timing relationships
between these events, the DDDRP pacing system classifies arrhythmias
into atrial and ventricular episodes.

When an atrial arrhythmia is detected as stable (such as flutter or
tachycardia - the device classifies these both as AT), the DDDRP pacing
system automatically delivers antitachycardia pacing (when enabled)
after the physician-programmed duration has expired. No pacing therapies
are available for episodes that the device classifies as AF. An episode
can change classifications as the rhythm of the episode changes -- for
example, an arrhythmia initially classified as AF and then change to AT,
or vice versa. In this case, antitachy pacing is delivered whenever the
rhythm currently is classified AT and the delivery criteria are met.

Arrhythmia and Symptom Monitoring

Patients may use a hand-held assistant device to create a log in the
device that documents when they felt symptomatic.

The AT500 uses its extensive memory to store information about
arrhythmias. Diagnostic information available includes electrograms of
specific episodes and long-term clinical trend information about daily
arrhythmia incidence for the past two years.

Other Features

Atrial 50Hz High Frequency Burst (HFB)

A-50 Hz burst is available as a therapy to terminate AF or AT. The
therapy works by depolarizing cardiac tissue, which has just
repolarized, preventing sustained reentry. The AT500 has the A-50Hz
Burst available as an In Clinic Only feature, to be available in a
physician-controlled environment only. This feature is identical to that
in the Jewel AF Model 7250.

Atrial Lead Position Check

Each night at midnight, the device checks for an atrial lead
dislodgement to prevent the delivery of atrial antitachycardia therapy
when the atrial lead position is not judged to be appropriate. The
atrial pacing amplitudes are increased from the brady settings to the
settings used for antitachy pacing. The device monitors for the next 256
ventricular events. If it sees 4 instances of atrial pace followed by
rapid ventricular sense (within 80ms), the device disables antitachy
pacing. No change in therapy occurs during the test so patients should
be unaware of its operation.

> System Description

The Medtronic AT500 DDDRP Pacing system consists of the Medtronic Model
AT501 (to be referred to as "AT500", where appropriate) and the
additional components listed below:

InCheck^™^ AT Model 9465 Patient Assistant[^4]

The InCheck AT Patient Assistant is a hand-held, battery-operated,
communicator and may be prescribed for a patient by their physician for
use in enabling prepro­grammed implantable devices capable of detecting
and/or treating atrial arrhyth­mias.

The Model 9465 is intended to be used with existing and future devices.
Dependent upon the implanted device, the functions of this device are
to:

-   Enable patient-activated, physician-programmed atrial therapy
    (cardioversion) for atrial arrhythmias if an atrial arrhythmia is
    present (The AT500 is not capable of this function),

-   Provide query capability of the implanted device regarding the
    presence of atrial arrhythmias for the patient,

-   Store dates and times within the implanted device, along with
    relevant data, when the patient is experiencing symptomatic events.

Model 9790/C and 2090 Programmer

These programmer families are used as a user interface for interrogating
the AT500 and for collection of data as needed.

Model 9968 Software

The Model 9968 software will be used to support the AT500.

III.Contraindications

The Medtronic AT500 DDDRP pacing system is contraindicated for:

-   Implantation with unipolar pacing leads.

-   Concomitant implantation with another bradycardia device.

-   Concomitant implantation with an implantable cardioverter
    defibrillator.

    There are no known contraindications for the use of pacing as a
    therapeutic modality to control heart rate. The patient's age and
    medical condition, however, may dictate the particular pacing
    system, mode of operation, and implantation procedure used by the
    physician.

-   Rate responsive modes may be contraindicated in those patients who
    cannot tolerate pacing rates above the programmed Lower Rate.

-   Dual chamber sequential pacing is contraindicated in patients with
    chronic or persistent supraventricular tachycardias, including
    atrial fibrillation or flutter.

-   Single chamber atrial pacing is contraindicated in patients with an
    A-V conduction disturbance.

-   ATP therapy is contraindicated in patients with an accessory
    antegrade pathway.

IV\. Warnings and Precautions

> Delete this section and just state:

Please refer to the device labeling for a list of warnings and
precautions

> Sterilization, Storage, and Handling

-   Contents of sterile package -- The sterile package contains one
    implantable Medtronic AT500 device, and one torque wrench.

-   Temperature limits -- Store and transport the package between -18°C
    (0°F) to 55°C (131°F).

-   "Use by" date -- Do not implant the Medtronic AT500 device after the
    "Use by" date, because the battery's longevity could be reduced.

-   Dropped device -- Do not implant the device if it has been dropped
    on a hard surface from a height of 30 cm (12 in) or more after
    removal from its packaging.

-   Checking and opening the package -- Before opening the sterile
    package tray visually check for any signs of damage that might
    invalidate the sterility of its contents. Return damaged packages to
    the manufacturer. For instructions on opening the sterile package,
    see the diagram inside the lid of the shelf box.

-   FOR SINGLE USE ONLY. -- Do not resterilize or re-implant an
    explanted Medtronic AT500 device.

-   Explant and disposal -- Return explanted devices to Medtronic for
    analysis and disposal. See the back cover for mailing addresses.

**Resterilization --** Medtronic has sterilized the device package
contents with ethylene oxide prior to shipment. Resterilization is
necessary only if the seal on the sterile package is broken.
(Resterilization does not affect the "Use By" date.) If necessary,
resterilize with ethylene oxide using a validated sterilization process,
observing the following precautions:

-   Do not resterilize using an autoclave, gamma radiation, organic
    cleaning agents (such as alcohol, acetone, etc.), or ultrasonic
    cleaners.

-   Do not resterilize more than twice.

-   Do not exceed 55 °C (131 °F) or 103 kPa (15 psi) when sterilizing.

-   Store the resterilized components for an appropriate period to
    permit aeration of ethylene oxide gas.

> Lead Evaluation and Lead Connection

**Connector compatibility** -- Do no use any lead with this pacemaker
without first verifying connector compatibility. Using incompatible
leads can damage the connector or result in a leaking or intermittent
connection.

**Hex wrench** -- Do not use a hex wrench with a blue handle or a
right-angle hex wrench. These wrenches have torque capabilities greater
than is designed for the lead connector.

> Device Operation

**Fixed bipolar operation --** Use of unipolar leads will result in loss
of pacing output and sensing.

**Rate responsive modes --** Do not use rate responsive modes in those
patients who cannot tolerate pacing rates above the programmed Lower
Rate.

**Single chamber atrial modes --** Do not use single chamber atrial
modes in patients with impaired AV nodal conduction because ventricular
capture cannot be assured.

**Pacing and sensing safety margins --** Consider lead maturation when
choosing pacing amplitudes, pacing pulse widths, and sensing levels.

**Shipping values --** Do not use shipping values for pacing amplitude
and sensitivity without verifying that they provide adequate safety
margins for the patient.

**Electrical reset --** Electrical reset is indicated by a programmer
warning message displayed immediately upon interrogation. To restore the
pacemaker to its previous operation it must be reset and reprogrammed.

**Crosstalk --** Crosstalk occurs in dual chamber pacemakers when atrial
pacing output pulses are sensed by the ventricular lead. Crosstalk
results in self-inhibition and is more likely to occur at high
sensor-driven pacing rates, high atrial amplitudes, and wide atrial
pulse widths. To prevent self-inhibition caused by crosstalk, program
Ventricular Safety Pacing (VSP) on.

**Slow retrograde conduction --** Slow retrograde conduction, especially
with conduction time greater than 400 ms, may induce pacemaker-mediated
tachy­cardia (PMT).

**Use of a magnet --** Positioning a magnet or the programming head over
the implanted Medtronic AT500 device suspends detection and treatment of
atrial tachyarrhythmias. The magnet does not alter bradycardia therapy
or initiate a Threshold Margin Test.

**End of life (EOL) --** Replace the Medtronic AT500 ™ device when the
programmer displays an ERI or EOL message, and a battery voltage of 2.60
volts or less.

**Oversensing during telemetry --** Telemetry communication with the
device may cause inappropriate sensed events, resulting in a brief
inhibition of bradycardia therapy. Removing the programming head
restores the device to normal operation.

**Telemetry --** Exposure to EMI may briefly interrupt programming
and/or telemetry operations. Any successful interrogation or programming
verifies proper communication between device and programmer.

**Testing for cross-stimulation** -- At implant, and periodically when
ATP therapy is enabled, perform testing at the programmed ATP output
settings to ensure that ventricular capture does not occur. This is
particularly important when the lead is placed in the inferior atrium.

**Anti-coagulation** - Use of the pacemaker should not change the
application of established anti-coagulation protocols.

**Rate control** - Decisions regarding rate controls should not be based
on the ability of the pacemaker to prevent atrial arrhythmias.

Pacemaker-dependent Patients

**Diagnostic modes --** Never program diagnostic modes (ODO) for
pacemaker-dependent patients. For such patients, use the programmer's
Inhibit function for brief interruption of outputs.

**Inhibit function --** Exercise caution when using the programmer to
inhibit pacing (for example, to obtain an EGM of the patient's intrinsic
activity) because the patient is without pacing support when the Inhibit
function is in use.

**Ventricular Safety Pacing (VSP) --** Always program VSP on for
pacemaker-dependent patients.

> Medical Therapy Hazards

**Diathermy --** People with metal implants such as pacemakers,
implantable cardioverter defibrillators (ICDs), and accompanying leads
should not receive diathermy treatment. The interaction between the
implant and diathermy can cause tissue damage, fibrillation, or damage
to the device components, which could result in serious injury, loss of
therapy, and/or the need to reprogram or replace the device.

**Electrosurgical cautery --** Electrosurgical cautery could induce
ventricular arrhythmias and/or fibrillation, or may cause device
malfunction or damage. If electrocautery cannot be avoided, observe the
following precautions:

-   Use a bipolar electrocautery system, where possible.

-   Have temporary pacing and defibrillation equipment available.

-   Program the device to the DOO mode.

-   Use short, intermittent, and irregular bursts at the lowest feasible
    energy levels.

-   Avoid direct contact with the device or leads. If monopolar cautery
    is used, position the ground plate so that the current pathway does
    not pass through or near the device system.

**External defibrillation** -- External defibrillation may damage the
device or may result in temporary and/or permanent myocardial damage at
the electrode tissue interface as well as temporary or permanent
elevated pacing thresholds. Follow these precautions when using external
defibrillation on a patient with an implanted cardiac device:

-   Position defibrillation paddles as far from the implanted device as
    possible (minimum of 13 cm (5 in)), and perpendicular to the
    implanted device-lead system.

-   Use the lowest clinically appropriate energy output.

**High-energy radiation --** High radiation sources such as cobalt 60 or
gamma radiation should not be directed at the implanted device. If a
patient requires radiation therapy in the vicinity of the implanted
device, place lead shielding over the device to prevent radiation damage
and confirm its function after treatment.

**Lithotripsy --** Lithotripsy may permanently damage the implanted
device if it is at the focal point of the lithotripsy beam. If
lithotripsy must be used, keep the implanted device at least 2.5 to 5.0
cm (1 to 2 in) from the focal point of the lithotripsy beam.

**Magnetic resonance imaging (MRI) --** Magnetic Resonance Imaging (MRI)
should not be used on patients who have an implanted cardiac device
because of the potential damage to the implanted device.

**Radio frequency (RF) ablation --** Radio frequency ablation procedure
in a patient with an implanted cardiac device could cause device
malfunction or damage. RF ablation risks can be minimized by:

-   Have a Medtronic programmer available for temporary pacing.

-   Program tachyarrhythmia detection **Off**.

-   Program a non-rate responsive, asynchronous pacing mode prior to the
    procedure.

-   Avoid direct contact between the ablation catheter and the implanted
    lead or device.

-   Position the ground plate so that the current pathway does not pass
    through or near the device system.

-   Have defibrillation equipment available.

    **Therapeutic ultrasound --** Exposure of the device to therapeutic
    ultrasound is not recommended as it may permanently damage the
    device. Damage to the device may affect therapy.

> Home and Occupational Environments

Patients should be directed to avoid devices that generate strong
electric or magnetic interference (EMI). EMI could cause inappropriate
pacing inhibition, malfunction, or damage resulting in non-detection or
delivery of unneeded therapy. Moving away from the interference source,
or turning it off, usually allows the device to return to its normal
mode of operation.

**High voltage lines --** High voltage power transmission lines could
generate enough EMI to interfere with device operation if approached too
closely.

**Communication equipment --** Communication equipment such as microwave
transmitters, line power amplifiers, or high power amateur transmitters
could generate enough EMI to interfere with device operation if
approached too closely.

**Commercial electrical equipment --** Commercial electrical equipment
such as arc welders, induction furnaces, or resistance welders could
generate enough EMI to interfere with device operation if approached too
closely.

**Home appliances --** Home appliances which are in good working order
and properly grounded do not usually produce enough EMI to interfere
with device operation. There are reports of device disturbances caused
by electrical hand tools or electric razors used directly over the
device implant site.

**Static magnetic fields --** Patients should avoid equipment or
situations where they would be exposed to static magnetic fields
(greater than 10 gauss or 1 millitesla) since it could suspend
detection. Examples of magnetic sources that could interfere with normal
device operation include: stereo speakers, bingo wand, extractor wand,
magnetic badges, or magnetic therapy products.

**Electronic article surveillance (EAS) --** Electronic Article
Surveillance (EAS) equipment such as retail theft prevention systems may
interact with the implanted device. Patients should be advised to walk
directly through, and not to remain near an EAS system longer than is
necessary.

**Cellular phones --** Hand-held cellular phones do not need any special
precautions if you have a Medtronic AT500 device. For portable and
mobile cellular phones that transmit above 3 watts, keep the telephone
antenna 12 in (30 cm) away from the implanted device.

**Tips to keep these distances:**

Medtronic AT500 devices contain a filter that prevents most cellular
phone transmissions from interacting with device operation. To further
minimize the possibility of interaction, observe the following cautions:

-   Hold the phone to the ear opposite the side of the implanted device.

-   When carrying the phone, keep it in a location opposite the side of
    the implanted device. (When a cell phone is in the "listen" or
    "standby" mode, it can still send a signal).

> **Table 1**. Cellular Phone Transmission Technologies

+-----------------------------------------------+----------------------+
| Transmission Technology                       | Frequency Range      |
|                                               | (MHz)                |
+-----------------------------------------------+----------------------+
| **Analog**                                    | 824 -- 849           |
|                                               |                      |
| FM (Frequency Modulation)                     |                      |
+-----------------------------------------------+----------------------+
| **Digital TDMA^a^** North American Standards  | 806 - 821            |
|                                               |                      |
| TDMA -- 11 Hz                                 | 824 -- 849           |
|                                               |                      |
| NADC^b^ TDMA - 50 Hz                          | 1850 -- 1910         |
|                                               |                      |
| PCS^c^ 1900                                   |                      |
+-----------------------------------------------+----------------------+
| **Digital TDMA** International Standards      | 880 - 915            |
|                                               |                      |
| GSM^d^                                        | 1710 -- 1785         |
|                                               |                      |
| DCS^e^ 1800                                   |                      |
+-----------------------------------------------+----------------------+
| **Digital CDMA**                              | 824 - 849            |
|                                               |                      |
| CDMA -- DS^f^                                 |                      |
+-----------------------------------------------+----------------------+

> ^a^ Time Division Multiple Access ^d^ Global System for Mobile
> Communications\
> ^b^ North American Digital Cellular ^e^ Digital Cellular System\
> ^c^ Personal Communication System ^f^ Code Division Multiple Access -
> Direct Sequence

VI\. Adverse Events

> Potential Adverse Events

Adverse events (in alphabetical order), including those reported in
Table 2 and Table 4, associated with pacing systems may include, but are
not limited to:

-   Cardiac perforation

-   Cardiac tamponade

-   Death

-   Erosion through the skin

-   Hematoma/seroma

-   Infection

-   Improper operation caused by the electronic article surveillance
    systems

-   Myopotential sensing

-   Nerve and/or muscle stimulation

-   Pacemaker syndrome

-   Rejection phenomena\
    (local tissue reaction, fibrotic tissue formation, pacemaker
    migration)

-   Threshold elevation

AT500 DDDRP Pacing System Clinical Studies

Two clinical studies are used to demonstrate safety and efficacy of the
Medtronic AT500 DDDRP Pacing System and they are as follows:

-   ATTEST -- Atrial Therapy Efficacy and Safety Trial

-   ASPECT -- Atrial Septal Pacing Efficacy Clinical Trial

ATTEST Observed Adverse Events

For the ATTEST clinical study, reference Table 2 for a summary of all
adverse events.

**Table 2**. Adverse Event Summary -- ATTEST

+----------------+----------+----------+---------+----------+--------+
| Adverse Event  | Bra      |          | All     |          | Total  |
| Type           | dy+AT/AF |          | P       |          |        |
|                | Patients |          | atients |          |        |
+----------------+----------+----------+---------+----------+--------+
|                | Complica | Observa  | Compli  | Obse     |        |
|                | tions^1^ | tions^1^ | cations | rvations |        |
+----------------+----------+----------+---------+----------+--------+
| Sy             | 45 (40   | 218 (153 | 57 (49  | 263 (185 | 320    |
| stem/Procedure | Pts)     | Pts)     | Pts)    | Pts)     | (208   |
| Related        |          |          |         |          | Pts)   |
+----------------+----------+----------+---------+----------+--------+
| Non-System/\   | 188 (136 | 1461     | 251     | 174      | 1991   |
| Procedure      | Pts)     | (334     | ^**2**^ | 0^**2**^ | (399   |
| Related        |          | Pts)     | (168    |          | Pts)   |
|                |          |          | Pts)    | (385     |        |
|                |          |          |         | Pts)     |        |
+----------------+----------+----------+---------+----------+--------+
| **Total**      | **233    | **1679   | **308   | **2003** | **2311 |
|                | (162     | (341     | (198    |          | (413   |
|                | Pts)**   | Pts)**   | Pts)**  | **(395   | Pts)** |
|                |          |          |         | Pts)**   |        |
+----------------+----------+----------+---------+----------+--------+

^1^ A complication is defined as an adverse event requiring invasive
measures to correct; a therapy is considered invasive if it penetrates
the skin, excluding the administration of parenteral fluids or drugs. An
observation is defined as an adverse event that is resolved using only
non-invasive measures.

^2^ Includes adverse events categorized as "Unknown."

^Table\ 3^ is a listing of the system/procedure related adverse events
for the ATTEST study. Of the 2311 events reported, 320 were
system/procedure related.

**Table 3**. ATTEST System/Procedure Related Adverse Event Listing

  ----------------------------------------------------------------------------------------------------------------
                                   Complications                Observations                Total     
  ----------------------- -------- --------------- ------------ -------------- ------------ --------- ------------
  Primary Condition       Events                   Patients\*   Events         Patients\*   Events    Patients\*
                                                   (%)                         (%)                    (%)

  Atrial                           2               2 (0.5)      5              5 (1.2)      7         7 (1.6)
  Flutter/Fibrillation                                                                                
  Paroxysmal                                                                                          

  Atrial                           0               0 (0)        2              2 (0.5)      2         2 (0.5)
  Flutter/Fibrillation                                                                                
  Persistent                                                                                          

  Atrial Tachycardia               0               0 (0)        2              2 (0.5)      2         2 (0.5)

  Back Pain/ Discomfort            0               0 (0)        2              2 (0.5)      2         2 (0.5)

  Cardiac Perforation              1               1 (0.2)      0              0 (0)        1         1 (0.2)
  (Ventricular)                                                                                       

  Chest Pain- Angina               0               0 (0)        1              1 (0.2)      1         1 (0.2)

  Chest Pain -                     0               0 (0)        1              1 (0.2)      1         1 (0.2)
  non-cardiac                                                                                         

  Congestive Heart                 0               0 (0)        3              3 (0.7)      3         3 (0.7)
  Failure                                                                                             

  Cross-talk                       0               0 (0)        2              2 (0.5)      2         2 (0.5)
  (non-persistent)                                                                                    

  Daily Atrial Lead Check          0               0 (0)        24             22 (5.2)     24        22 (5.2)

  Dizziness                        0               0 (0)        3              3 (0.7)      3         3 (0.7)

  Drug Related                     0               0 (0)        1              1 (0.2)      1         1 (0.2)

  Dyspnea/ Shortness of            0               0 (0)        4              4 (0.9)      4         4 (0.9)
  Breath                                                                                              

  Elevated Pacing                  0               0 (0)        2              2 (0.5)      2         2 (0.5)
  Thresholds Atrial                                                                                   

  Elevated Pacing                  2               1 (0.2)      3              3 (0.7)      5         4 (0.9)
  Thresholds Ventricle                                                                                

  Emotional Distress               0               0 (0)        3              3 (0.7)      3         3 (0.7)

  Failure To Capture/Loss          0               0 (0)        3              3 (0.7)      3         3 (0.7)
  Of Capture Atrial                                                                                   

  Failure To Capture/Loss          1               1 (0.2)      1              1 (0.2)      2         2 (0.5)
  Of Capture Ventricle                                                                                

  Far-Field R-Wave                 3               3 (0.7)      9              8 (1.9)      12        11 (2.6)
  Sensing                                                                                             

  Fatigue/tiredness                1               1 (0.2)      1              1 (0.2)      2         2 (0.5)

  Headache                         0               0 (0)        1              1 (0.2)      1         1 (0.2)

  Hypotension                      0               0 (0)        2              2 (0.5)      2         2 (0.5)

  Inadequate Lead                  2               2 (0.5)      0              0 (0)        2         2 (0.5)
  Pacemaker connection                                                                                

  Inappropriate                    0               0 (0)        5              5 (1.2)      5         5 (1.2)
  programming                                                                                         

  Lead Dislodgment Atrial          18              17 (4.0)     0              0 (0)        18        17 (4.0)

  Lead Dislodgment                 5               5 (1.2)      0              0 (0)        5         5 (1.2)
  Ventricle                                                                                           

  Lead Insertion/Route             2               2 (0.5)      2              2 (0.5)      4         4 (0.9)
  Problem                                                                                             

  Lead Insulation Failure          0               0 (0)        1              1 (0.2)      1         1 (0.2)

  Loss Of Sensing                  1               1 (0.2)      8              8 (1.9)      9         9 (2.1)
  Intermittent                                                                                        

  Loss Of Sensing                  0               0 (0)        1              1 (0.2)      1         1 (0.2)
  Permanent                                                                                           

  Migration of pulse               0               0 (0)        1              1 (0.2)      1         1 (0.2)
  generator                                                                                           

  Musculoskeletal pain             0               0 (0)        2              2 (0.5)      2         2 (0.5)

  Nausea                           1               1 (0.2)      2              2 (0.5)      3         3 (0.7)

  Near Syncope                     0               0 (0)        1              1 (0.2)      1         1 (0.2)

  Other Conditions                 3               3 (0.7)      20             20 (4.7)     23        23 (5.4)

  Other Oversensing                0               0 (0)        6              6 (1.4)      6         6 (1.4)

  Pacemaker-Mediated               0               0 (0)        3              3 (0.7)      3         3 (0.7)
  Tachycardia                                                                                         

  Pain at pocket site              0               0 (0)        45             40 (9.4)     45        40 (9.4)

  Palpitations                     0               0 (0)        14             13 (3.0)     14        13 (3.0)

  Pericardial Effusion             4               4 (0.9)      5              5 (1.2)      9         9 (2.1)

  Peripheral Edema                 0               0 (0)        1              1 (0.2)      1         1 (0.2)

  Phrenic Nerve/Diaphragm          0               0 (0)        4              4 (0.9)      4         4 (0.9)
  Muscle Stimulation                                                                                  
  Atrial                                                                                              

  Phrenic Never/Diaphragm          4               4 (0.9)      1              1 (0.2)      5         5 (1.2)
  Muscle Stimulation                                                                                  
  Ventricle                                                                                           

  Pleural Effusion                 0               0 (0)        4              4 (0.9)      4         4 (0.9)

  Pneumonia                        0               0 (0)        1              1 (0.2)      1         1 (0.2)

  Pneumothorax as Result           2               2 (0.5)      6              6 (1.4)      8         8 (1.9)
  of Implant Procedure                                                                                

  Pocket Hematoma                  1               1 (0.2)      17             17 (4.0)     18        18 (4.2)

  Pocket Infection                 1               1 (0.2)      10             10 (2.3)     11        10 (2.3)

  Pocket Seroma                    0               0 (0)        4              4 (0.9)      4         4 (0.9)

  Pocket Stimulation               0               0 (0)        3              3 (0.7)      3         3 (0.7)

  Puncture of Subclavian           0               0 (0)        1              1 (0.2)      1         1 (0.2)
  artery                                                                                              

  Shoulder pain/                   0               0 (0)        2              2 (0.5)      2         2 (0.5)
  discomfort                                                                                          

  Sleep problems                   0               0 (0)        1              1 (0.2)      1         1 (0.2)

  Suspected pacemaker              1               1 (0.2)      5              4 (0.9)      6         5 (1.2)
  failure                                                                                             

  Suspected Programmer Or          0               0 (0)        1              1 (0.2)      1         1 (0.2)
  Software Failure                                                                                    

  Swelling of pocket site          2               2 (0.5)      7              7 (1.6)      9         9 (2.1)

  Thrombosis                       0               0 (0)        1              1 (0.2)      1         1 (0.2)

  Upper pacing rate too            0               0 (0)        1              1 (0.23)     1         1 (0.23)
  slow                                                                                                

  Upper respiratory                0               0 (0)        1              1 (0.2)      1         1 (0.2)
  symptom                                                                                             

  Ventricular Tachycardia          0               0 (0)        1              1 (0.2)      1         1 (0.2)
  Non-Sustained                                                                                       

  Ventricular tachycardia          0               0 (0)        1              1 (0.2)      1         1 (0.2)
  (Sustained)                                                                                         

  **Total**                        **57**          **49         **263**        **185        **320**   **208
                                                   (11.5)**                    (43.3)**               (48.7)**
  ----------------------------------------------------------------------------------------------------------------

\*Note for the patient totals that some patients had events in more than
one category.

ATTEST VT/VF Observations

Ten sustained VT/VF episodes were reported in four patients. The
investigator classification and adverse event committee review did not
indicate that any of the VT/VF episodes were caused by prevention pacing
or ATP therapies.

ATTEST Patient Discontinuations

Lost to Follow-up forms were received for 19 patients. Six patients
requested withdrawal from the study. Two forms were submitted at the
time of patient's death.

ATTEST Patients Requiring Device Explant

A total of eight patients required device explant during the study
period. Two pa­tients received replacement AT500; two patients were not
re-implanted with a pulse generator. Two patients required replacement
with an ICD as a result of inducible sustained ventricular tachycardia.
One patient was implanted with a Medtronic Kappa pulse generator as a
result of a random component failure in the AT500 and one patient was
implanted with an InSync 8040 pacemaker.

ATTEST Patient Deaths

Over the course of the study, 43 patients expired. For these deaths,
neither the in­vest­i­gator nor the Adverse Event Advisory Committee
attributed the cause of death to the AT500 system. The causes of death
were cardiac arrest (7), congestive heart failure (7), cardiopulmonary
arrest (5), renal failure (3), myocardial infarction (3), pulmonary
arrest (3), sepsis (2), cardiogenic shock (2), cardiomyopathy,
ventricular arrhythmia, perforation of superior vena cava, aspiration
pneumonitis, intracerebral hemorrhage, atherosclerotic heart disease,
emphysema, brain cancer, leukemia, pneumonia, and one death of unknown
cause.

ASPECT Observed Adverse Events

For the ASPECT clinical study, reference Table 4 for a summary of all
adverse events.

**Table 4**. Adverse Event Summary -- ASPECT

  -------------------------- ----------------- ---------------- --------------- -------------- ---------
  Adverse Event Type         Septal (n=148)                     Non-Septal                     Total
                                                                (n=150)                        

                             Complications\*   Observations\*   Complications   Observations   

  System/Procedure-Related   21 (19 Pts)       68 (55 Pts)      23 (21 Pts)     66 (50 Pts)    178 (127
                                                                                               Pts)

  Non-System/\               72 (56 Pts)       252 (106 Pts)    75 (54 Pts)     244 (112 Pts)  643 (235
  Procedure Related                                                                            Pts)

  **Total**                  **93 (66 Pts)**   **320 (121       **98 (68 Pts)** **310 (121     **821
                                               Pts)**                           Pts)**         (261
                                                                                               Pts)**
  -------------------------- ----------------- ---------------- --------------- -------------- ---------

\* A complication is defined as an adverse event requiring invasive
measures to correct; a therapy is considered invasive if it penetrates
the skin, excluding the administration of parenteral fluids or drugs. An
observation is defined as an adverse event that is resolved using only
non-invasive measures.

Table 5 lists the system/procedure related adverse events for the ASPECT
study. Of the 821 events reported, 178 were system or procedure related.

**Table 5**. ASPECT System/Procedure Related Adverse Event Listing

  -----------------------------------------------------------------------------------------------------------
  Primary Condition           Complications                Observations                Total     
  --------------------------- --------------- ------------ -------------- ------------ --------- ------------
                              Events          Patients\*   Events         Patients\*   Events    Patients\*
                                              (%)                         (%)                    (%)

  Allergic Reaction           0               0 (0)        1              1 (0.34)     1         1 (0.34)

  Anxiety                     0               0 (0)        2              2 (0.67)     2         2 (0.67)

  Atrial Flutter/Fibrillation 1               1 (0.34)     16             15 (5.03)    17        16 (5.37)
  Paroxysmal                                                                                     

  Atrial Flutter/Fibrillation 0               0 (0)        2              2 (0.67)     2         2 (0.67)
  Persistent                                                                                     

  Aware of Pacing System      0               0 (0)        3              3 (1.01)     3         3 (1.01)

  Belching                    0               0 (0)        2              1 (0.34)     2         1 (0.34)

  Chest Muscle Stimulation    1               1 (0.34)     0              0 (0)        1         1 (0.34)

  Chest Pain - non-cardiac    0               0 (0)        3              3 (1.01)     3         3 (1.01)

  Chronic Obstructive         1               1 (0.34)     0              0 (0)        1         1 (0.34)
  Pulmonary Disease                                                                              

  Congestive Heart Failure    1               1 (0.34)     0              0 (0)        1         1 (0.34)

  Cough                       0               0 (0)        1              1 0.34)      1         1 (0.34)

  Daily Atrial Lead Check     0               0 (0)        10             7 (2.35)     10        7 (2.35)
  Failure                                                                                        

  Delayed Ventricular Pace    0               0 (0)        1              1 (0.34)     1         1 (0.34)

  Deep Vein Thrombosis        0               0 (0)        1              1 (0.34)     1         1 (0.34)

  Dyspnea/Shortness of Breath 0               0 (0)        2              2 (0.67)     2         2 (0.67)

  Edema                       0               0 (0)        1              1 (0.34)     1         1 (0.34)

  Electromagnetic             0               0 (0)        1              1 (0.34)     1         1 (0.34)
  Interference Sensing                                                                           

  Elevated Pacing Thresholds  0               0 (0)        3              3 (1.01)     3         3 (1.01)
  Atrial                                                                                         

  Elevated Pacing Thresholds  3               3 (1.01)     4              4 (1.34)     7         7 (2.35)
  Ventricle                                                                                      

  Endocarditis                1               1 (0.34)     0              0 (0)        1         1 (0.34)

  Failure To Capture/Loss Of  1               1 (0.34)     1              1 (0.34)     2         2 (0.67)
  Capture Atrial                                                                                 

  Failure To Capture/Loss Of  1               1 (0.34)     0              0 (0)        1         1 (0.34)
  Capture Ventricle                                                                              

  Failure To Position The     0               0 (0)        1              1 (0.34)     1         1 (0.34)
  Lead At The Atrial Septum                                                                      

  False Rejection of Episodes 0               0 (0)        1              1 (0.34)     1         1 (0.34)
  Due To FFRW Criterion                                                                          

  Far-Field R-Wave Sensing    0               0 (0)        4              4 (1.34)     4         4 (1.34)

  Fatigue/tiredness           0               0 (0)        2              2 (0.67)     2         2 (0.67)

  Inappropriate Programming   0               0 (0)        3              3 (1.01)     3         3 (1.01)

  Incision Problem            0               0 (0)        5              5 (1.68)     5         5 (1.68)

  Insufficient Slack in       1               1 (0.34)     0              0 (0)        1         1 (0.34)
  Atrial and Ventricular                                                                         
  Leads                                                                                          

  Lead Dislodgment Atrial     7               7 (2.35)     2              2 (0.67)     9         9 (3.02)

  Lead Dislodgment Ventricle  6               6 (2.01)     0              0 (0)        6         6 (2.01)

  Lead Insertion/Route        0               0 (0)        3              3 (1.01)     3         3 (1.01)
  Problem                                                                                        

  Loss Of Sensing             0               0 (0)        4              4 (1.34)     4         4 (1.34)
  Intermittent                                                                                   

  Migration of lead           1               1 (0.34)     0              0 (0)        1         1 (0.34)

  Muscular Stimulation        0               0 (0)        1              1 (0.34)     1         1 (0.34)

  Nausea                      0               0 (0)        1              1 (0.34)     1         1 (0.34)

  Other Oversensing           0               0 (0)        1              1 (0.34)     1         1 (0.34)

  Pacemaker Syndrome          0               0 (0)        1              1 (0.34)     1         1 (0.34)

  Pacemaker-Conducted Atrial  0               0 (0)        1              1 (0.34)     1         1 (0.34)
  Tachyarrhythmia                                                                                

  Pacemaker-Mediated          0               0 (0)        9              8 (2.68)     9         8 (2.68)
  Tachycardia                                                                                    

  Pain                        0               0 (0)        14             14 (4.70)    14        14 (4.70)

  Palpitations                0               0 (0)        3              3 (1.01)     3         3 (1.01)

  Patient Activator           0               0 (0)        1              1 (0.34)     1         1 (0.34)
  Malfunction                                                                                    

  Pericardial Effusion        2               2 (0.67)     0              0 (0)        2         2 (0.67)

  Phrenic Nerve/Diaphragm     1               1 (0.34)     0              0 (0)        1         1 (0.34)
  Muscle Stimulation Atrial                                                                      

  Phrenic Never/Diaphragm     0               0 (0)        1              1 (0.34)     1         1 (0.34)
  Muscle Stimulation                                                                             
  Ventricle                                                                                      

  Pneumothorax As Result Of   5               5 (1.68)     0              0 (0)        5         5 (1.68)
  The Implant Procedure                                                                          

  Pocket Hematoma             3               3 (1.01)     12             12 (4.03)    15        15 (5.03)

  Pocket Infection            1               1 (0.34)     2              2 (0.67)     3         3 (1.01)

  Pocket Site Opened          1               1 (0.34)     0              0 (0)        1         1 (0.34)

  Presyncope                  0               0 (0)        1              1 (0.34)     1         1 (0.34)

  Skin Rash                   0               0 (0)        1              1 (0.34)     1         1 (0.34)

  Stroke/CVA/TIA              0               0 (0)        1              1 (0.34)     1         1 (0.34)

  Subclavian Vein Perforation 1               1 (0.34)     0              0 (0)        1         1 (0.34)

  Suspected Lead Conductor    1               1 (0.34)     0              0 (0)        1         1 (0.34)
  Fracture Ventricle                                                                             

  Suspected Programmer Or     0               0 (0)        1              1 (0.34)     1         1 (0.34)
  Software Failure                                                                               

  Swelling Of Pocket Site     0               0 (0)        1              1 (0.34)     1         1 (0.34)

  Syncope                     1               1 (0.34)     1              1 (0.34)     2         2 (0.67)

  Thrombosis                  0               0 (0)        1              1 (0.34)     1         1 (0.34)

  Thrombosis Formation At     1               1 (0.34)     0              0 (0)        1         1 (0.34)
  Lead Ventricle                                                                                 

  Ventricular Fibrillation    1               1 (0.34)     0              0 (0)        1         1 (0.34)

  Ventricular Tachycardia     1               1 (0.34)     0              0 (0)        1         1 (0.34)
  Non-Sustained                                                                                  

  **Total**                   **44**          **40         **134**        **105        **178**   **127
                                              (13.40)**                   (35.20)**              (42.60)**
  -----------------------------------------------------------------------------------------------------------

\*Note for the patient totals that some patients had events in more than
one category.

ASPECT VT/VF Observations

Three sustained VT/VF episodes were reported in three patients. The
investigator classification and adverse event committee review did not
indicate that any of the VT/VF episodes were caused by prevention pacing
or ATP therapies.

ASPECT Patient Discontinuations

Six patients requested withdrawal from the study. Four of them were
never implanted with an AT500 and requested withdrawal. Two patients in
Europe requested withdrawal after refusing to come to the investigator
for follow-up visits.

ASPECT Patients Requiring Device Explant

Over the course of the study, eleven devices were explanted for reasons
including worsening of congestive heart failure (five patients),
ventricular fibrillation, MAZE procedure, endocarditis, pericardial
effusion, and infection (two patients). Two devices were replaced with
AT500 devices. Two devices were not replaced. Five devices were replaced
with biventricular pacing devices, one device was replaced with an ICD,
and one device was replaced with a Medtronic Kappa pulse generator.

ASPECT Patient Deaths

There were 17 patient deaths recorded in the study; all but one were
determined to be non-system related by the investigator and the Adverse
Event Advisory Committee. For one death it was unknown if it was related
to the system since the patient, whose cause of death was congestive
heart failure, was cremated before an explant or autopsy could be
performed. Causes of death included congestive heart failure (4
patients), cancer (2 patients), cerebral vascular accident, myocardial
infarction, coronary artery disease, cardiomegaly, respiratory failure,
anoxic encephalopathy, acute heart failure, cardiac cachexy,
cardiopulmonary arrest, cardiac arrhythmia and one death of unknown
cause.

VII\. Alternative Practices and Procedures

While surgery or drug therapy may be alternatives to cardiac pacing in
certain instances, cardiac pacing is often the standard treatment for
the indications described above. Other commercially available single
chamber or dual chamber pacemakers provide alternatives to the AT500.

VIII.Marketing History

The Medtronic AT500 DDDRP pacing system is currently distributed
commercially outside the United States. Specifically, this product is
approved for sale in Canada, Australia and the European Community. This
device has not been withdrawn from the market in any country for any
reason related to the safety and effectiveness of the device.

IX\. Summary of Preclinical Studies

Nonclinical Laboratory Testing

Nonclinical testing of the Medtronic AT500 DDDRP pacing system was
conducted to ensure that the components and the finished device perform
in accordance with their design specifications.

Integrated Circuit

Electrical testing of each IC was performed on a sample of 77 units.
Electrical stability of the IC was assessed through accelerated life
testing. Each unit was stressed at 150°C for 184 hours minimum.
Electrical testing of each IC was conducted prior to life testing, and
following life testing using a mixed signal automated test system
verifying significant performance parameters of the pacing system
environment. There were no failures observed during the 184 hour life
test, and no significant shifts in the electrical performance of any of
the critical parameters were observed over the 184 hour life test.

Hybrid

Electrical qualification testing was performed on a sample of 149
hybrids. Electrical stability of the hybrid module was assessed through
accelerated life testing. Each unit was stressed at 2.55V and 125°C for
a minimum of 77000 device hours. Electrical testing of each hybrid was
conducted prior to life testing, and after life testing using a
computerized electronic test system verifying significant performance
parameters of the pacing system environment. There were no design
related failures observed during the77000 device hours life test, and
there were no significant shifts in the electrical performance of any of
the critical parameters due to design or manufacturing over the 77000
device hours.

Testing indicated that there were no design-related failures during the
qualification testing. Electrical test data showed no trend that would
affect the stability of the final product performance. All qualification
activities indicate that the Hybrid Circuitry is of acceptable quality
and reliability for use in the AT500.

Battery Testing

The AT500 utilizes one power source, the Delta 30H lithium hybrid
cathode medium-rate cell. The battery was subjected to Accelerated
Discharge (64 samples), Application Discharge (8 samples) and
Environmental Tests (16 samples).

All the Accelerated Discharge test samples exceeded the specified
requirements.

The 1.0 mA test results easily exceed the capacity to ERI and ERI to EOL
requirements. At the 30μA rate, the results also easily exceed the
capacity to ERI requirements.

The Environmental Test results show normal and expected behavior for the
Delta 30H lithium hybrid cathode medium-rate cell batteries.

Current Drain Characterization

Current Drain Characterization for the AT500 was performed at the hybrid
level (1 hybrid), and measured current drain over various environmental
and device conditions. All test results were within specification.

Connector Testing

The AT500 uses one connector assembly: IS-1 bipolar. The IS-1 bipolar
connector is the same connector used on the Medtronic Thera-*i*[^5] and
Medtronic Kappa 700/600[^6] series family of pulse generators and did
not require requalification.

Environmental and Mechanical Testing

Environmental and mechanical qualification testing was performed with 22
samples. Additionally, characterization tests were performed using
various quantities of test samples. Test devices were subjected to the
following tests:

**Table 6**. Mechanical Qualification and Characterization Tests

+---+-----------+-----------------+-----------------+---------+-------+
|   | Test      | Objective       | Method          | Number  | Test  |
|   |           |                 |                 | of Test | Re    |
|   |           |                 |                 | Samples | sults |
+===+===========+=================+=================+=========+=======+
| 1 | Te        | Verify the      | Devices are     | 22      | P     |
| . | mperature | device will     | exposed to a    |         | assed |
|   | Storage   | withstand       | minimum of 6    |         |       |
|   |           | extreme         | hours at -18º   |         |       |
|   |           | temperatures    | C. This is      |         |       |
|   |           | experienced in  | followed by a   |         |       |
|   |           | a normal        | minimum 6 hour  |         |       |
|   |           | handling and    | exposure at     |         |       |
|   |           | distribution    | +55º C with a 1 |         |       |
|   |           | environment.    | hour            |         |       |
|   |           | This is a       | stabilization   |         |       |
|   |           | qualification   | at room         |         |       |
|   |           | test.           | temperature     |         |       |
|   |           |                 | between         |         |       |
|   |           |                 | exposures.      |         |       |
+---+-----------+-----------------+-----------------+---------+-------+
| 2 | M         | Verify the      | Devices are     | 22      | P     |
| . | echanical | device will     | subjected to    |         | assed |
|   | Vibration | withstand       | vibration in    |         |       |
|   |           | vibration       | three 15 minute |         |       |
|   |           | frequencies     | cycles in each  |         |       |
|   |           | experienced in  | of 3 orthogonal |         |       |
|   |           | a normal        | axes. The       |         |       |
|   |           | handling and    | frequency of    |         |       |
|   |           | distribution    | vibration       |         |       |
|   |           | environment.    | sweeps from 5   |         |       |
|   |           | This is a       | to 500 to 5 Hz  |         |       |
|   |           | qualification   | with a 2.5G     |         |       |
|   |           | test.           | acceleration.   |         |       |
+---+-----------+-----------------+-----------------+---------+-------+
| 3 | M         | Verify that the | Devices are     | 22      | P     |
| . | echanical | device will     | subjected to a  |         | assed |
|   | Shock     | function safely | minimum change  |         |       |
|   |           | after           | in velocity of  |         |       |
|   |           | mechanical      | 118             |         |       |
|   |           | shock impacts   | inches/second   |         |       |
|   |           | experienced in  | with a 1        |         |       |
|   |           | normal handling | millisecond     |         |       |
|   |           | and             | Haversine wave  |         |       |
|   |           | distribution    | form in each of |         |       |
|   |           | environment.    | three           |         |       |
|   |           | This is a       | orthogonal axes |         |       |
|   |           | qualification   | (six            |         |       |
|   |           | test.           | positions).     |         |       |
|   |           |                 | This shock      |         |       |
|   |           |                 | equates to an   |         |       |
|   |           |                 | effective free  |         |       |
|   |           |                 | fall height of  |         |       |
|   |           |                 | 18 inches.      |         |       |
+---+-----------+-----------------+-----------------+---------+-------+
| 4 | Te        | Determine if    | Devices are     | 4       | P     |
| . | mperature | devices will    | exposed to ten  |         | assed |
|   | Shock     | withstand       | cycles of       |         |       |
|   |           | extreme and     | air-to-air      |         |       |
|   |           | rapid           | thermal shock   |         |       |
|   |           | temperature     | at -40º C and   |         |       |
|   |           | changes. This   | +65º C.         |         |       |
|   |           | is a            | Transition time |         |       |
|   |           | c               | between         |         |       |
|   |           | haracterization | temperatures is |         |       |
|   |           | test.           | less than one   |         |       |
|   |           |                 | minute. Dwell   |         |       |
|   |           |                 | at each         |         |       |
|   |           |                 | temperature     |         |       |
|   |           |                 | extreme is 1    |         |       |
|   |           |                 | hour.           |         |       |
+---+-----------+-----------------+-----------------+---------+-------+
| 5 | I         | Determine if    | Devices are     | 4       | P     |
| . | ncreasing | devices can     | exposed to      |         | assed |
|   | Heights   | withstand       | mechanical      |         |       |
|   | M         | extreme         | shocks at       |         |       |
|   | echanical | mechanical      | effective       |         |       |
|   | Shock     | shocks. This is | heights         |         |       |
|   |           | a               | starting at 24  |         |       |
|   |           | c               | inches and      |         |       |
|   |           | haracterization | increasing to   |         |       |
|   |           | test.           | 60 inches in 6  |         |       |
|   |           |                 | inch increments |         |       |
|   |           |                 | (7 heights).    |         |       |
|   |           |                 | Three           |         |       |
|   |           |                 | orthogonal axes |         |       |
|   |           |                 | in two          |         |       |
|   |           |                 | orientations    |         |       |
|   |           |                 | are tested for  |         |       |
|   |           |                 | a total of six  |         |       |
|   |           |                 | applications at |         |       |
|   |           |                 | each height     |         |       |
|   |           |                 | (Total of 42    |         |       |
|   |           |                 | shocks).        |         |       |
+---+-----------+-----------------+-----------------+---------+-------+
| 6 | M         | Determine if    | Devices are     | 4       | P     |
| . | echanical | devices will    | subjected to    |         | assed |
|   | 20G       | withstand       | the 20G Italian |         |       |
|   | Vibration | extreme         | Standard        |         |       |
|   |           | mechanical      | Vibration test  |         |       |
|   |           | vibration. This | consisting of a |         |       |
|   |           | is a            | 30 minute cycle |         |       |
|   |           | c               | from            |         |       |
|   |           | haracterization | 10-to-500-to-10 |         |       |
|   |           | test.           | Hz at 20G       |         |       |
|   |           |                 | acceleration    |         |       |
|   |           |                 | with a          |         |       |
|   |           |                 | displacement of |         |       |
|   |           |                 | 8 mm along each |         |       |
|   |           |                 | of three        |         |       |
|   |           |                 | orthogonal axes |         |       |
|   |           |                 | with a          |         |       |
|   |           |                 | crosso          |         |       |
|   |           |                 | ver-to-constant |         |       |
|   |           |                 | acceleration at |         |       |
|   |           |                 | 35 Hz.          |         |       |
+---+-----------+-----------------+-----------------+---------+-------+
| 7 | M         | Verify the      | Physical        | 10      | P     |
| . | echanical | devices meet    | measurements    |         | assed |
|   | (Dim      | requirements    | are recorded.   |         |       |
|   | ensional) | for mechanical  | Mass is         |         |       |
|   | Speci     | dimensions,     | determined by   |         |       |
|   | fications | mass, and       | triple beam     |         |       |
|   |           | volume. This is | balance and     |         |       |
|   |           | a qualification | volume by       |         |       |
|   |           | test.           | liquid          |         |       |
|   |           |                 | displacement.   |         |       |
+---+-----------+-----------------+-----------------+---------+-------+
| 8 | Telemetry | Evaluate the    | A RF head is    | 2       | P     |
| . | Mapping   | performance of  | incrementally   |         | assed |
|   |           | telemetry       | positioned in   |         |       |
|   |           | uplink and      | the space       |         |       |
|   |           | downlink. This  | around a device |         |       |
|   |           | is a            | to map the      |         |       |
|   |           | c               | space where     |         |       |
|   |           | haracterization | successful      |         |       |
|   |           | test.           | interrogations  |         |       |
|   |           |                 | with the device |         |       |
|   |           |                 | occur.          |         |       |
+---+-----------+-----------------+-----------------+---------+-------+
| 9 | De        | Verify device   | Visually        | 5       | P     |
| . | structive | did not         | inspect pulse   |         | assed |
|   | Analysis  | experience any  | generator       |         |       |
|   |           | damage to       | shield, shield  |         |       |
|   |           | components,     | weld, and lead  |         |       |
|   |           | solder joints,  | connector for   |         |       |
|   |           | wire bonds,     | damage, dents,  |         |       |
|   |           | hybrid, or      | cracks.         |         |       |
|   |           | battery during  |                 |         |       |
|   |           | mechanical      |                 |         |       |
|   |           | qualification   |                 |         |       |
|   |           | or              |                 |         |       |
|   |           | c               |                 |         |       |
|   |           | haracterization |                 |         |       |
|   |           | tests. Inspect  |                 |         |       |
|   |           | workmanship of  |                 |         |       |
|   |           | hybrid and      |                 |         |       |
|   |           | pulse generator |                 |         |       |
|   |           | assembly.       |                 |         |       |
+---+-----------+-----------------+-----------------+---------+-------+

Full functionality of each device was verified at the completion of all
environmental and mechanical tests. All testing passed.

Parameter Stability

Testing was performed on the AT500 to determine the stability of the
device pacing parameters when exposed to varying environmental
conditions. Sensitivity, amplitude, accelerometer interface, pace
current detector and capture detector were evaluated under varying load
impedance, and supply (battery) voltage conditions. The test results
demonstrate that the device parameters met specifications and remained
stable under varying pacing load and supply voltage conditions.

Packaging Qualification

With the exception of the inner tray, the AT500 package design is
identical to those designed for other Tachy products (e.g, Gem[^7]).
Qualification testing for the packaging configuration consisted of a)
environmental stress tests including extreme vibration, stacking, and
drop testing, and b) visual inspection of sterile package seals and
package materials and contents. All 22 of the AT500 inner tray packages
tested met the package design test requirements.

FMEA/System Hazard Analysis

Utilizing both a fault tree analysis and a Failure Mode and Effects
Analysis (FMEA) approach, a complete analysis of the device and hybrid
microcircuit has been performed on all critical components included in
the AT500. A systems hazard analysis was performed to assess the design
and development processes of the pacing system to ensure that critical
failures modes or potentially hazard situations have been identified and
adequately eliminated or mitigated.

Animal Testing

A canine study was conducted to verify the function and performance of
the Medtronic AT500 DDDRP pacing system. The primary objectives of this
study were to demonstrate the expected operation of the AT500, including
proper performance in dual chamber pacing modes, Modeswitching, Atrial
Rate Stabilization and Atrial Preference Pacing features, Arrhythmia
detection, therapy delivery, and rate response performance. In summary,
the sensing/pacing operation of the device, Modeswitching and device
performance during treadmill operation performed as expected. The
arrhythmia detection algorithms and atrial anti-tachy pacing feature
also performed appropriately and as expected.

This animal study was conducted in compliance with the Good Laboratory
Practices (GLP) Regulation 21 CFR Part 58.

Firmware Testing

The firmware for AT500 was developed in accordance with applicable
Medtronic development processes. Three levels of testing were performed
on the firmware, including unit, integration and verification testing.
All tests passed.

Software Validation

The AT500 application software (Model 9968) was developed and tested in
accordance with Medtronic's formal procedures for software development
and testing. These procedures include development of a Software
Requirements Specification, a detailed design specification, a Hazard
Analysis, a retest strategy, and a Verification Test Specification. The
software was tested per the Verification Test Specification. Errors,
anomalies, and inconsistencies were noted in Software Change Reports and
all issues resolved.

Following final retest of the software, a final configuration audit was
performed by Software Quality Engineering to ensure that all documents
and code were properly controlled and released.

System Testing

System Testing of Medtronic AT500 DDDRP pacing system evaluated use of
pulse generators with programmer, Medtronic Vision software, AT500
application software (Model 9968) and Medtronic patient
activator/assistant to assure their operation is within the limits of
their respective specifications. Issues associated with the technical
literature and/or software were identified and resolved during testing.

Electromagnetic Compatibility (EMC) and Cell Phone Testing

Electromagnetic Compatibility (EMC) testing was performed using a
minimum of twenty-two (22) pulse generators (where appropriate). The
test devices were subjected to radiated electric fields (pulsed radiated
and continuous wave), sinusoidal currents, electrosurgical cautery
currents, X-ray compatibility, and transthoracic (high level)
defibrillation pulses. In addition, characterizational testing was
performed subjecting the devices to cellular phone transmission
frequencies.

The AT500 was found to meet performance specifications for exposure to
radiated electric fields. When subjected to sinusoidal currents, no
devices were observed to exhibit rates above or below the specified test
tolerances, and the pulse amplitude and duration of all devices were
observed to remain within acceptable tolerances. Electrosurgical cautery
testing demonstrated that the AT500 meets all EMC compatibility
requirements. ICD compatibility testing consisted of exposing the pulse
generators to ICD discharges to ensure the pulse generator does not
experience electrical resets. All devices tested remained fully
functional and met the testing requirements. The second type of ICD
testing consisted of exposing the pulse generator to highenergy
discharges used for defibrillation therapies. No anomalies were observed
in the devices tested. However, it should be noted that the AT500 is
contraindicated for implantation with an ICD. The AT500 was found to
meet the performance specifications for devices exposed to in-vitro
transthoracic defibrillation currents and no anomalies were observed
during testing. Cell phones were tested per CDRH "In-Vitro Pacemaker EMI
Test Protocol for Cellular Phones." No anomalies were observed while
testing eight different analog and digital cellular phones in different
modulation modes and frequencies.

Biocompatibility Testing

The materials used in the AT500 that are directly exposed to body tissue
and/or fluids are titanium, silicone rubber, silicone rubber adhesive,
and polyurethane. These materials have all been used in Medtronic pulse
generators for several years and have an established history of
biocompatibility through long-term human use. In addition to long-term
human use, the materials listed have been previously tested for
biocompatibility per the Medtronic submissions referenced herein.

Medtronic certifies that all of the direct and indirect tissue
contacting materials used to fabricate the AT500 are identical to the
Medtronic Kappa 700/600 devices, as they were approved on January 29,
1999, (PMA Document Control No. P980035), in formulation, processing and
sterilization, and no other chemicals have been added (e.g.
plasticizers, fillers, coloring agents, mold release agents, cleaning
agents, etc.), with the exception of Parylene C coating which is not
used for the AT500.

Conclusion Drawn from Nonclinical Laboratory Tests

Medtronic conducted a system hazard analysis on all new features and
critical components and then conducted testing to evaluate these and
other device features. All test results were found to be acceptable.

X. Summary of Clinical Studies

Two clinical studies are used to demonstrate safety and efficacy of the
Medtronic AT500 DDDRP Pacing System and they are as follows:

-   ATTEST -- Atrial Therapy Efficacy and Safety Trial

-   ASPECT -- Atrial Septal Pacing Efficacy Clinical Trial

Reference Table 7 for additional information.

**Table 7. Overview of Clinical Studies**

  ------------ ------------ --------- ------------ -------- -------------- ------- ----------- -------- ------------ ------- --------- ---------- --------- ----------
  **Study**    **Cohort**             **No. of              **Cumulative           **Average            **No. of             **First              **Data    
                                      Patients              No. of Device          No. of               Implant­ing           Implant              Cut-off   
                                      Enrolled**            Months**               Device               Centers**            Date**               Date**    
                                                                                   Months/                                                                  
                                                                                   Patient**                                                                

  **ATTEST**                Brady                  370                     6447                17.4                  28                18 Oct               26 April
                            +AT/AF                                                                                                     1999                 2002

                            Other                  57                      1113                19.5                                                         
                            Brady                                                                                                                           

  **ASPECT**   Brady +AT/AF           298                   5330                   18.1                 37                   01 Sept              26 April  
                                                                                                                             1999                 2002      
  ------------ ------------ --------- ------------ -------- -------------- ------- ----------- -------- ------------ ------- --------- ---------- --------- ----------

ATTEST Clinical Study

Design of Study

The ATTEST clinical study was a multi-center (28 implanting centers
worldwide), prospective, randomized, parallel group, two-sample,
single-blinded design performed to characterize the safety and
effectiveness of the Medtronic AT500 DDDRP pacing system. Patients with
or without a history of atrial tachyarrhythmias (AT/AF) were enrolled in
the study. The location for placement of the atrial lead was left to the
discretion of the investigator for patients indicated for a dual-chamber
pacemaker. Reference Figure 1 for a description of the clinical study
design.

To evaluate effectiveness of the atrial prevention (Atrial Preference
Pacing (APP), Atrial Rate Stabilization (ARS) and Post Mode Switch
Overdrive Pacing (PMOP)) and termination therapies (Atrial
Antitachycardia Pacing (ATP)), all patients were stratified based on the
presence or absence of documented history of AT/AF at enrollment.
Patients with a documented history of AT/AF were categorized as Brady
+AT/AF, and the patients without a documented history of AT/AF were
categorized as Other Brady.

![](media/image1.wmf){width="5.997916666666667in"
height="3.154861111111111in"}Patients were randomized to having
prevention and termination therapies either all ON or all OFF at the
one-month follow-up. A three-month evaluation period followed the
randomization. Upon completion of the four-month follow-up visit, the
protocol allowed the AT500 to be programmed according to the physician's
preference.

**Figure 1. ATTEST Clinical Study Design**

ATTEST -- Patient Assessment

Patients enrolled into the study represented a general dual chamber
pacing population, as specified by the ACC/AHA guidelines for pacing
indications. A total of 427 patients were enrolled and 424 were
implanted. Of these patients, 370 were enrolled in the Brady +AT/AF
group and the remaining 57 were enrolled in the Other Brady group. Three
patients were not implanted with an AT500. Ventricular lead placement
was not possible for two patients; one expired as a result of
complications during the AT500 implant procedure prior to implantation
of the device.

Primary Objectives

-   To establish the safety of the AT500 system as demonstrated by
    freedom from system/procedure related complications at three months
    post-implant.

-   Two measures of effectiveness of AT/AF prevention and termination
    therapies were evaluated:

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-   Demonstration of the effectiveness of the prevention and termination
    therapies in reducing the frequency of spontaneous AT/AF episodes by
    30%.

-   Demonstration of the effectiveness of the AT500 prevention and
    termination therapies in reducing the burden of spontaneous AT/AF
    episodes by 30%.

Secondary Objectives

-   To estimate the accuracy (positive predictive value) of the atrial
    tachyarrhythmia detection algorithm in classification of atrial
    tachyarrhythmias (AT/AF).

-   To characterize the effectiveness of ATP in terminating spontaneous
    AT/AF episodes.

-   To characterize the potential reduction of frequency and burden in
    patients who had no documented history of atrial tachyarrhythmias at
    enrollment.

-   To demonstrate the impact of the AT500 system on patients' quality
    of life as measured by the SF-36 Health Survey and Symptom
    Checklist.

-   To characterize the pacing and sensing performance of the AT500
    system using the Medtronic DR180 digital Holter recorder.

-   To characterize the effect of prevention and termination therapies
    on the frequency of symptomatic episodes of atrial tachyarrhythmias
    (AT/AF).

ATTEST -- Demographic Data

The mean age of the total population was 70.0 years; the mean age of the
Brady+AT/AF population was 69.9 years. Male patients comprised 54.6% of
the Brady+AT/AF group and 54.3% of all patients were male.

**Table 8**. Patient Demographics -- ATTEST

+-----------------------------+------------+------------+-------------+
|                             | Br         | Other      | All\        |
|                             | ady+AT/AF\ | Brady\     | (N=427)     |
|                             | (N=370)    | (N=57)     |             |
+=============================+============+============+=============+
| **Gender (N,%)**            | 202        | 30 (52.6%) | 232 (54.3%) |
|                             | (54.6%)    |            |             |
| Male                        |            | 27 (47.4%) | 195 (45.7%) |
|                             | 168        |            |             |
| Female                      | (45.4%)    |            |             |
+-----------------------------+------------+------------+-------------+
| **Age (years)**             | 69.9       | 70.5       | 70.0        |
|                             |            |            |             |
| Mean                        | 10.0 -     | 13.0 -     | 10.0 - 98.0 |
|                             | 98.0       | 90.0       |             |
| Range                       |            |            | 13.4        |
|                             | 12.9       | 16.1       |             |
| Standard deviation          |            |            |             |
+-----------------------------+------------+------------+-------------+
| **Primary Indication\       | 42 (11.4%) | 27 (47.4%) | 69 (16.2%)  |
| **(mutually exclusive, N,   |            |            |             |
| %)                          | 2 (0.5%)   | 2 (3.5%)   | 4 (0.9%)    |
|                             |            |            |             |
| Acquired AV Block           | 2 (0.5%)   | \--        | 2 (0.5%)    |
|                             |            |            |             |
| Chronic Bi/tri-fascicular   | 267        | 24 (42.1%) | 291 (68.1%) |
| Block                       | (72.2%)    |            |             |
|                             |            | 1 (1.8%)   | 46 (10.8%)  |
| AV Block with Acute MI      | 45 (12.2%) |            |             |
|                             |            | 3 (5.3%)   | 15 (3.5%)   |
| Sinus Node Dysfunction      | 12 (3.2%)  |            |             |
|                             |            |            |             |
| Prevention and Termination  |            |            |             |
| of Tachy                    |            |            |             |
|                             |            |            |             |
| Other                       |            |            |             |
+-----------------------------+------------+------------+-------------+

ATTEST -- Data Analysis and Results

Accumulating 7561 device months of experience, the performance of the
Medtronic AT500 DDDRP pacing system was found to meet or exceed all
safety objectives as shown in Table 9. The rate of complications was
found to be similar to that observed in Medtronic studies of pacemakers
that are commercially available.

**Table 9. Results of Primary Objectives -- ATTEST**

+-----------------------+----------------------------------------------+
| **Primary             | **Results:**                                 |
| Objectives:**         |                                              |
+-----------------------+----------------------------------------------+
| **Safety** (n=427)    | 40 patients experienced their first          |
|                       | system/procedure-related complication        |
| **Hypothesis:** 3     | through 3 months of follow-up                |
| Month System /        |                                              |
| Procedure-Related     | Complication Free Survival Probability:      |
| Complication-Free     | 90.3%                                        |
| Survival Greater than |                                              |
| 80% --\               | **95% Lower Confidence Bound: 87.7% (\>      |
| All Patients          | 80%)**                                       |
+-----------------------+----------------------------------------------+
| **Effectiveness:**    | For patients in the efficacy cohort of the   |
| AT/AF Frequency       | Brady+AT/AF group, the median frequency in   |
| Reduction, AT/AF      | the ON arm was 0.043 episodes/day and in the |
| Burden Reduction      | OFF arm it was 0.039 episodes/day. The       |
|                       | median burden in the ON arm was 0.136        |
| **Hypothesis:** The   | hrs/day and in the OFF arm it was 0.037      |
| frequency of AT/AF    | hrs/day. **The difference between arms was   |
| episodes with         | not statistically significant for either     |
| prevention and        | frequency or burden.**                       |
| termination ON will   |                                              |
| be at least 30% less  |                                              |
| than the frequency    |                                              |
| with prevention and   |                                              |
| termination OFF.      |                                              |
+-----------------------+----------------------------------------------+

**Table 10**. Results of Secondary Objectives -- ATTEST

  -----------------------------------------------------------------------
  Secondary Objectives:   Results:
  ----------------------- -----------------------------------------------
  Accuracy (positive      According to investigator classifications, the
  predictive value) of    positive predictive value for detection of
  appropriately detecting atrial arrhythmias was 98%.
  atrial tachyarrhythmias 

  Effectiveness of        ATP therapies effectively terminated 53.3% of
  terminating spontaneous all treated episodes based on crude estimates
  AT/AF episodes          and 40.8% when adjusted using the Generalized
                          Estimating Equations methodology.

  Reduction of frequency  No statistically significant difference was
  and burden in patients  found in frequency and burden comparisons
  who had no history of   between treatment groups in the Other Brady
  atrial tachyarrhythmias patient group.
  at enrollment           

  Patients' quality of    As measured by the SF-36 and the Symptom
  life as measured by the Checklist, there was no statistically
  SF-36 Health Survey and significant difference in quality of life
  Symptom Checklist       between the ON and OFF groups at Baseline and
                          4-months. However, quality of life of all
                          patients improved from Baseline to 4-months,
                          and at 4 months patients in both groups scored
                          in the normal range for the age-matched
                          population at large.[^8]

  Pacing and sensing      One hundred five (105) Holter recordings were
  performance using the   reviewed from 66 patients to characterize
  DR180 digital Holter    pacing and sensing performance of the AT500.
  recorder.               The Holter recordings confirm that the AT500
                          operated as expected.

  Frequency of            The ON group had a frequency of 0.057
  symptomatic AT/AF       symptomatic episodes per day, while the OFF
  episodes                group had a frequency of 0.064 symptomatic
                          episodes per day. There was no statistically
                          significant difference in frequency of
                          symptomatic episodes between ON and OFF
                          treatment groups.
  -----------------------------------------------------------------------

ATTEST -- Device Failures and Replacement

There was one device failure reported as part of the ATTEST Clinical
study. This device was explanted as a result of a ventricle sense
failure. The device was re­turned to Medtronic for further analysis.
Analyses indicated that this was a random component failure caused by a
resistive leakage in the pre-amp of the L292 IC.

ASPECT Clinical Study

Design of Study

The ASPECT clinical study was a multi-center (37 implanting centers
worldwide), prospective, randomized, single-blinded, cross-over design
performed to investigate the safety and efficacy of the Medtronic AT500
DDDRP pacing system and its atrial arrhythmia prevention pacing features
with specific atrial lead placement. Patients were candidates for a
standard pacemaker and had a history of symptomatic atrial
tachyarrhythmia. Lead placement sites included septal and non-septal
atrial pacing sites.

This study was a prospective evaluation of the following features of the
Medtronic AT500 DDDRP Pacing System: Atrial Preference Pacing (APP),
Atrial Rate Stabilization (ARS) and Post Mode Switch Overdrive Pacing
(PMOP). Patient data was collected at implant, pre-discharge, one month,
four month, and seven months post implant.

At implant, patients were randomized to either a septal or non-septal
atrial lead site placement. A second randomization was performed for
prevention pacing features (APP, ARS, PMOP) ON-OFF vs. OFF-ON crossover
periods at the one-month follow-up. The crossover period was 3 months,
with the first 2 weeks of each crossover period considered a
stabilization period to account for atrial remodeling effects. Data from
the 2-week stabilization period was not utilized for the efficacy
objectives. Data was collected at the end of each crossover period of 3
months (See Figure 2).

![](media/image2.wmf){width="5.955555555555556in"
height="2.390972222222222in"}

**Figure 2. ASPECT Clinical Study Design**

ASPECT -- Patient Assessment

Patients enrolled into the study represented a general dual chamber
pacing population, as specified by the ACC/AHA guidelines for pacing
indications. A total of 298 patients were enrolled and 294 were
implanted. Of the four not implanted, one patient was discovered to be
in permanent AF at implant, one patient was found to have 1:1 conducted
sinus tachycardia at implant, one patient had high atrial thresholds at
implant, and one patient could not be transferred to the study center
after enrollment.

Primary Objectives

-   To establish the safety of the AT500 system as demonstrated by
    freedom from system/procedure related complications at three months
    post-implant.

-   To establish the safety of atrial leads when used in the septal
    pacing site as demonstrated by freedom from atrial lead related
    adverse events at three months post-implant.

-   To demonstrate that the prevention pacing features reduce atrial
    tachyarrhythmia frequency by at least 30% in at least 50% of
    patients when used in conjunction with an atrial septal pacing site.

-   To demonstrate that the proportion of patients with at least a 30%
    reduction in frequency in the septal site (prevention pacing
    features ON vs. OFF) will be greater than the proportion in the
    non-septal site (prevention pacing features ON vs. OFF).

Secondary Objectives

-   To observe the performance of the prevention pacing features during
    Holter monitoring.

-   To characterize the electrical performance (pulse width thresholds
    at 2.0V, sensing thresholds, and lead impedance) of atrial leads
    over time.

-   To characterize the effect that the prevention pacing features have
    on atrial tachyarrhythmia burden in the septal and non-septal atrial
    pacing sites.

-   To characterize the effect the prevention pacing features have on
    patient quality of life in the septal and non-septal atrial pacing
    sites.

-   To characterize the effect that the prevention pacing features have
    on the frequency of symptomatic episodes of atrial tachyarrhythmias
    in the septal and non-septal atrial pacing sites.

-   To characterize the effect that the prevention pacing features have
    on the frequency of premature atrial contractions in the septal and
    non-septal atrial pacing sites.

-   To characterize the placement of an atrial lead in the septal pacing
    site.

ASPECT -- Demographic Data

Information regarding patient demographics and cardiovascular history is
presented in Table 11. The mean age of the 298 enrolled patients was
69.6 years. There were 182 males (61.1%) and 116 females (38.9%) in the
ASPECT study. The patients' indications for pacemaker implants are also
shown in Table 11.

> **Table 11**. Patient Characteristics at Enrollment -- ASPECT

+-----------------------------+-------------+------------+------------+
| Patient Characteristics     | Septal      | Non-Septal | Total      |
|                             |             |            |            |
|                             | (N=148)     | (N=150)    | (N=298)    |
+=============================+=============+============+============+
| **Gender (N,%)**            | 91 (61.5%)  | 91 (60.7%) | 182        |
|                             |             |            | (61.1%)    |
| Male                        | 57 (38.5%)  | 59 (39.3%) |            |
|                             |             |            | 116        |
| Female                      |             |            | (38.9%)    |
+-----------------------------+-------------+------------+------------+
| **Age (years)**             | 68.6        | 70.7       | 69.6       |
|                             |             |            |            |
| Mean                        | 42.6 - 87.5 | 45.4 --    | 42.6 -     |
|                             |             | 88.5       | 88.5       |
| Range                       | 10.1        |            |            |
|                             |             | 9.5        | 9.9        |
| Standard deviation          |             |            |            |
+-----------------------------+-------------+------------+------------+
| **Primary Indication (N,%)\ | 18 (12.2%)  | 18 (12.0%) | 36 (12.1%) |
| **(mutually exclusive)      |             |            |            |
|                             | 3 (2.0%)    | 2 (1.3%)   | 5 (1.7%)   |
| Acquired AV Block           |             |            |            |
|                             | 104 (70.3%) | 103        | 207        |
| Chronic Bi/Tri-fascicular   |             | (68.7%)    | (69.5%)    |
| Block                       | 23 (15.5%)  |            |            |
|                             |             | 27 (18.0%) | 50 (16.8%) |
| Sinus Node Dysfunction      |             |            |            |
|                             |             |            |            |
| Other                       |             |            |            |
+-----------------------------+-------------+------------+------------+

ASPECT -- Data Analysis and Results

Accumulating 5330.3 device months of experience, the performance of the
AT500 was found to meet or exceed all safety objectives as shown in
Table 12. The rate of complications was found to be similar to that
observed in Medtronic studies of pacemakers that are commercially
available.

**Table 12**. Results of Primary Objectives -- ASPECT

+-----------------------------+----------------------------------------+
| Primary Objectives:         | Results:                               |
+-----------------------------+----------------------------------------+
| Safety (n=298)              | 37 patients experienced their first    |
|                             | system/procedure-related complication  |
| **Hypothesis:** 3 Month     | through 3 months of follow-up          |
| System / Procedure-Related  |                                        |
| Complication-Free Survival  | Complication-Free Survival             |
| Greater than 80%            | Probability: 87.4%                     |
|                             |                                        |
|                             | **95% Lower Confidence Bound: 84.3%    |
|                             | (\> 80 %)**                            |
+-----------------------------+----------------------------------------+
| Safety of atrial leads when | 11 septal patients and 7 non-septal    |
| used in septal sites (n=148 | patients experienced their first       |
| septal, 150 non-septal)     | atrial lead related adverse event      |
|                             | through three months of follow-up      |
| **Hypothesis:** Difference  |                                        |
| in 3 Month Atrial           | Event Free Survival Probability        |
| Lead-Related Event-Free     | (Septal): 92.5%                        |
| Survival of Septal and      |                                        |
| Non-Septal Leads is \<10%   | 95% Confidence Interval (Septal):      |
|                             | (88.3%, 96.8%)                         |
|                             |                                        |
|                             | Event Free Survival Probability        |
|                             | (Non-septal): 95.3%                    |
|                             |                                        |
|                             | 95% Confidence Interval (Non-septal):  |
|                             | (92.0%, 98.8%)                         |
|                             |                                        |
|                             | **95% Upper Confidence Bound           |
|                             | (difference in survival rate): 7.5%    |
|                             | (\< 10 %)**                            |
+-----------------------------+----------------------------------------+
| Effectiveness: AT/AF        | In the atrial septal patients in the   |
| Frequency Reduction with an | efficacy cohort, 30.7% of patients had |
| Atrial Septal Pacing Site   | 30% or greater reduction of frequency  |
|                             | in the ON period as compared to the    |
| **Hypothesis:** The         | OFF period of the study with a         |
| proportion of patients with | one-sided 95% lower confidence bound   |
| a significant (at least     | of 21.9%. **The proportion of septal   |
| 30%) reduction in frequency | patients with a 30% or greater         |
| of AT/AF episodes with      | reduction in frequency was not at      |
| prevention pacing ON vs.    | least 50% (the a priori objective      |
| OFF must be at least 50%.   | performance criterion).**              |
+-----------------------------+----------------------------------------+
| Effectiveness: AT/AF        | The proportion of patients with        |
| Frequency Reduction for     | non-septal atrial leads who had 30% or |
| Septal Compared to          | greater reduction in frequency in the  |
| Non-Septal Patients         | ON period as compared to the OFF       |
|                             | period was 32.2%, and the proportion   |
| **Hypothesis:** The         | of patients with septal atrial leads   |
| proportion of patients with | who had a 30% or greater frequency     |
| a significant (at least     | reduction was 30.7%. **The proportion  |
| 30%) reduction in frequency | of septal patients with a frequency    |
| of AT/AF episodes in the    | reduction of at least 30% was not      |
| septal site (prevention     | significantly greater than the percent |
| pacing features ON vs. OFF) | of non-septal patients with at least   |
| will be greater than the    | 30% frequency reduction.**             |
| proportion in the           |                                        |
| non-septal site (prevention |                                        |
| pacing features ON vs.      |                                        |
| OFF).                       |                                        |
+-----------------------------+----------------------------------------+

**Table 13**. Results of Secondary Objectives -- ASPECT

  ------------------------------------------------------------------------
  Secondary          Results:
  Objectives:        
  ------------------ -----------------------------------------------------
  Observation of the At the one-month follow-up, 20 patients with septal
  performance of     atrial lead implants and 22 patients with non-septal
  prevention pacing  atrial lead implants were Holter monitored for 24
  features during    hours with the prevention features ON. Analysis of
  Holter monitoring. the Holter recordings showed that all evaluated
                     features operated as expected and there were no
                     differences noted between septal and non-septal
                     patients.

  Electrical         Pulse width thresholds, sensing thresholds, and lead
  performance of the impedance were measured for both septal and
  atrial leads.      non-septal patients from implant through seven
                     months. The electrical performance of the leads was
                     not significantly different in the septal and
                     non-septal groups.

  Atrial             For patients in the efficacy cohort, in the septal
  tachyarrhythmia    site, the median difference in burden between the ON
  burden in septal   and OFF periods was not significantly different from
  and non-septal     zero. In the non-septal site, the median difference
  pacing sites.      in burden was also not significantly different from
                     zero. The change in burden for the septal group was
                     not significantly different from the corresponding
                     change in the non-septal group.

  Quality of Life in For patients in the efficacy cohort, as measured by
  septal and         the SF-36 Health Survey, patients in both the septal
  non-septal pacing  and non-septal arms had no significant difference in
  sites.             quality of life scores for prevention pacing features
                     ON vs. OFF. All patients scored in the normal range
                     for the age-matched population at large during both
                     the ON and OFF crossover periods.^7^ Similarly, the
                     Symptom Checklist measurements had no significant
                     difference in the number of symptoms, symptom
                     frequency, or symptom severity for patients in both
                     the septal and non-septal arms with prevention pacing
                     features ON vs. OFF.

  Frequency of       For patients in the efficacy cohort, in the septal
  symptomatic        site, the mean difference in symptomatic episodes
  episodes of atrial between the ON and OFF periods was -1.1
  tachyarrhythmias   episodes/month (1.4 episodes/month ON versus 2.5
  in septal and      episodes/month OFF), which is significantly different
  non-septal pacing  from zero (p=0.013); in the non-septal site, the mean
  sites              difference in symptomatic episodes was not
                     significantly different from zero.

  Frequency of       For patients that were in the efficacy cohort, in the
  premature atrial   septal site, the median difference in PACs for ON -
  contractions in    OFF was --202.5.0 PACs/day, which was not
  septal and         significantly different from zero (p=0.073). In the
  non-septal atrial  non-septal site, the median difference in PACs for
  pacing sites.      ON - OFF was --273.3 PACs/day, which was
                     significantly different from zero (p\<0.001). The
                     change in PACs for the septal group was not
                     significantly different from the corresponding change
                     in the non-septal group.

  Atrial lead        There were 148 patients randomized to the septal
  placement.         atrial lead site. Of these, 136 (91.9%) were placed
                     in the septal site. Of the 12 patients who were not
                     placed in the septal site as randomized, four were
                     never implanted with an AT500, four were mechanically
                     unable to reach and fixate on the septum (failure to
                     implant AT500 was not related to septal lead
                     randomization), two were unable to find acceptable
                     thresholds on the septum, one discovered after
                     implant that the lead was not on the septum, and one
                     abandoned septal positioning for a medical reason. In
                     addition, after implant, two patients with septal
                     lead placement had lead dislodgements resulting in a
                     repositioning of the lead to a non-septal position
                     because the physician mechanically unable to reach
                     and fixate on the septum. Of the 150 leads randomized
                     to the non-septal site, 150 (100%) were placed as
                     randomized.
  ------------------------------------------------------------------------

ASPECT -- Prevention Pacing and Percentage Atrial Pacing

The prevention pacing features (APP, ARS and PMOP) were observed to
increase the percentage of atrial pacing while minimizing increase in
atrial rate. The atrial pacing percentage increased from 69.0% with
prevention pacing features OFF to 95.5% with prevention pacing features
ON. The average atrial rate increased only slightly, from 72 ppm with
prevention pacing features OFF to 77 ppm with prevention pacing features
ON.

ASPECT -- Reduction in symptomatic episode burden

The prevention pacing features were observed to reduce the burden of
symptomatic episodes in patients with an atrial septal lead placement.
Burden was defined, *post hoc*, as the number of symptomatic days
divided by the number of total days of follow up. A symptomatic day was
a day in which a symptomatic episode was reported by the patient. For
all patients with atrial septal lead placement (N=125), the burden of
symptomatic episodes was 4.48% when the prevention features were OFF
compared to 2.76% when the prevention features were ON, for a 38.4%
reduction (p = 0.0043).

ASPECT -- Device Failures and Replacement

There were no device failures reported as part of the ASPECT Clinical
study.

Compassionate Use Device Clinical Experience

To date, there have also been 41 compassionate uses implants of the
Medtronic AT500 system. The compassionate use experience has a similar
safety profile to the ATTEST and ASPECT clinical studies.

Gender Bias

A standard epidemiological approach was used to assess the poolability
of data with respect to gender. The results of the analyses show no
statistically significant associations between the primary objectives
and gender so the results presented are representative of both genders.

XI\. Conclusions Drawn from Studies

The Medtronic AT500 introduces incremental features for the treatment of
atrial arrhythmias. These include atrial arrhythmia termination
features, atrial pacing features, and enhanced diagnostic features.
Bench, animal and clinical data support the safety and effectiveness of
these features when used in combination in this device, as indicated in
the labeling.

*In vitro* testing, consisting of component-level testing, device
testing, system testing, and *in vivo* animal studies, demonstrate the
proper operation of the AT500 system. This testing provides reasonable
assurance that the device is safe and performs as intended.

Clinical studies have demonstrated that the AT500 has an adequate
overall safety profile. The device appropriately detects atrial
arrhythmias. Atrial arrhythmia termination therapies are appropriately
delivered, successfully terminate atrial arrhythmia episodes, and do not
induce ventricular arrhythmias. The combination of atrial termination
and atrial pacing features do not have a significant effect on the
amount of time patients spent in atrial arrhythmias or the number of
episodes experienced. The results of the clinical study suggest that the
atrial pacing features, by themselves, significantly increase the
percentage of atrial pacing. When the atrial pacing features alone are
looked at in terms of the percentage of symptomatic days, a reduction
was observed in patients with the atrial septal lead placement.

XII\. Panel Recommendation

Pursuant to section 515(c)(2) of the Food, Drug and Cosmetic Act (the
Act) as amended by the Safe Medical Devices Act of 1990, this PMA
supplement was not referred to Circulatory System Devices Panel, and FDA
Advisory Panel, for review and recommendation because the information in
the PMA substantially duplicates information previously reviewed by this
panel.

XIII\. CDRH Decision

The results of the preclinical and clinical studies demonstrated that
the new design features, when used as indicated in the labeling, are
safe and effective.

FDA found Medtronic's manufacturing facility to be in compliance with
the Device Quality System Regulation, (21 CFR part 820). CDRH issued an
approval order on March 26, 2003.

XIV\. Approval Specifications

Directions for use: See product labeling.

Hazards to Health from Use of the Device: See Indications,
Contraindications, Warnings, Precautions and Adverse Events in the
Labeling.

Post-approval Requirements and Restrictions: See approval order.

[^1]: P980050/S02, Approved 13 February 2001

[^2]: P890003/S36, Approved 31 July 1995, P890003/S44, Approved 21 May
    1998 and 2090-P890003, S65, Approved 13 March 2002

[^3]: Jewel AF, Model 7250 (P980050, Approved 14 June 2000)

[^4]: P980050/S02, Approved 13 February 2001

[^5]: Thera-i (P890003/S37, Approved 31 Oct 1995)

[^6]: Kappa 700/600 (P980035, Approved 29 Jan 1999)

[^7]: Gem (P980016, Approved 09 October 1998)

[^8]: Ware JE, Snow KK, Kosinski M et al. SF-36 Health Survey Manual and
    Interpretation Guide. QualityMetric Incorporated, Lincoln, RI,
    2000,pg 7:15.