***Summary of Safety and Effectiveness Data***

***On-X^®^ Prosthetic Heart Valve, Models ONXM and ONXMC***

**Table of Contents**

1\. GENERAL INFORMATION [2](#general-information)

2\. INDICATIONS For Use [2](#indications-for-use)

3\. Device DESCRIPTION [2](#device-description)

4\. CONTRAINDICATIONS [3](#contraindications)

5\. Warnings and Precautions [3](#warnings-and-precautions)

5.1 Warnings [3](#warnings)

5.2 Precautions [4](#precautions)

6\. ALTERNATive PRACTICES AND PROCEDURES
[4](#alternative-practices-and-procedures)

7\. MARKETING HISTORY [4](#marketing-history)

8\. Adverse Events [4](#adverse-events)

8.1 Observed Adverse Events [4](#observed-adverse-events)

8.2 Potential Adverse Events [5](#potential-adverse-events)

9\. SUMMARY OF nonclinical STUDIES [6](#summary-of-nonclinical-studies)

9.1 IN VITRO STUDIES [6](#in-vitro-studies)

9.1.1 Hydrodynamics and Flow Visualization
[6](#hydrodynamics-and-flow-visualization)

9.1.2 Durability and Lifetime Analysis
[7](#durability-and-lifetime-analysis)

9.2 ANIMAL STUDIES [9](#animal-studies)

9.3 BIOCOMPATIBILITY [9](#biocompatibility)

9.4 MAGNETIC RESONANCE IMAGING (MRI) COMPATIBILITY
[11](#magnetic-resonance-imaging-mri-compatibility)

9.5 SHELF LIFE AND STERILITY [11](#shelf-life-and-sterility)

10\. summary of clinical studies [11](#summary-of-clinical-studies)

10.1 Description of Patients and Analysis for Gender Bias
[16](#description-of-patients-and-analysis-for-gender-bias)

11\. CONCLUSIONS drawn from the studies
[16](#conclusions-drawn-from-the-studies)

12\. Panel Recommendations [16](#panel-recommendations)

13\. FDA DECISION [16](#fda-decision)

14\. Approval Specifications [16](#approval-specifications)

***Summary of Safety and Effectiveness Data***

***On-X^®^ Prosthetic Heart Valve, Models ONXM and ONXMC***

Figure 1 -- On-X^^ Prosthetic Heart
Valve![](media/image1.jpeg){width="2.2819444444444446in"
height="1.6298611111111112in"}

# GENERAL INFORMATION

Device Generic Name: Replacement Heart Valve

Device Trade Name: On-X^^ Prosthetic Heart Valve

Model: ONXM, sizes 25, 27/29 and 31/33 mm

ONXMC size 25/33

Applicant's Name and Address: Medical Carbon Research Institute, LLC

(MCRI^^)

8200 Cameron Road, A-196

Austin, Texas 78754

PMA Application Number: P000037/S1

Date of Notice of Approval to the Applicant: March 6, 2002

# INDICATIONS For Use 

The On-X^®^ Prosthetic Heart Valve is indicated for the replacement of
diseased, damaged, or malfunctioning native or prosthetic heart valves
in the mitral position.

# Device DESCRIPTION 

The On-X^®^ Prosthetic Heart Valve (Figure 1) is a bileaflet mechanical
heart valve, which consists of an orifice housing two leaflets. The
orifice inflow area has a flared inlet designed to reduce flow
turbulence, and the outflow rim consists of leaflet guards designed to
protect the leaflets while in the closed position. The leaflets rotate
around tabs located within the inner circumference of the orifice ring.
In the closed position, the each leaflet forms a nominal angle of 40º
relative to the plane of the orifice. In the open position, the plane of
each leaflet forms a nominal angle of 90° relative to the plane of the
orifice. The leaflets have a travel arc of 50° to the closed position.

The orifice is composed of graphite substrate coated with On-X^®^
Carbon, a pure unalloyed form of pyrolytic carbon. The leaflets consist
of On-X^®^ Carbon deposited on a graphite substrate, which is
impregnated with 10 weight% tungsten to provide radiopacity.

The sewing cuff is constructed of polytetrafluoroethylene (PTFE) fabric
mounted on the orifice using titanium retaining rings and 5-0 suture
material. This form of sewing cuff attachment to the orifice allows for
rotation of the sewing cuff *in situ* during implantation. Orientation
reference marks are provided on the sewing ring for valve orientation.

The On-X^®^ Prosthetic Heart Valve is available in mitral sizes 25,
27/29, 31/31 and 25/33 mm. The valve is designed for intra-annular
implantation.

# CONTRAINDICATIONS

The On-X^®^ Prosthetic Heart Valve is contraindicated for patients
unable to tolerate anticoagulation therapy.

# Warnings and Precautions

## Warnings

FOR SINGLE USE ONLY.

DO NOT use the On-X^®^ Prosthetic Heart Valve if:

-   the prosthesis has been dropped, damaged, or mishandled in any way;

-   the tamper evident seal is broken;

-   the serial number tag does not match the container label;

-   the expiration date has elapsed.

DO NOT resterilize any On-X^®^ Prosthetic Heart Valve:

-   once it is removed from its plastic container;

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```
-   more than 3 times - resterilization of a valve which has passed the
    sterility expiration date is permitted, up to this limit, only if
    the valve has remained in the original unopened container and
    undamaged;

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```
-   with any method other than steam sterilization, with the identified
    resterilization parameters. Note: Gamma radiation is known to damage
    the sewing ring.

DO NOT pass a catheter, surgical instrument, or transvenous pacing lead
through the prosthesis as this may cause valvular insufficiency, leaflet
damage, leaflet dislodgment, and/or catheter/instrument/lead entrapment.

## Precautions

Handle the prosthesis with only MCRI^™^ On-X^®^ Prosthetic Heart Valve
Instruments, particularly during selection of the valve size; other
sizers may result in improper valve selection.

Avoid damaging the prosthesis through the application of excessive force
to the valve orifice or leaflets.

Avoid contacting the carbon surfaces of the valve with gloved fingers or
any metallic or abrasive instruments as they may cause damage to the
valve surface not seen with the unaided eye that may lead to accelerated
valve structural deterioration, leaflet escape, or serve as a nidus for
thrombus formation.

# ALTERNATive PRACTICES AND PROCEDURES

Alternative forms of treatment other than the On-X Prosthetic Heart
Valve include medical therapy with drugs or surgical treatments such as
annuloplasty or valvuloplasty with or without the use of implantable
materials (i.e., sutures and/or annuloplasty rings). When the patient
requires replacement of his/her native or previously placed prosthetic
valve, the option of choosing a mechanical or biological valve exists.
The choice of replacement valve depends upon factors that include the
patient's age, preoperative conditions, cardiac anatomy, and ability to
tolerate anticoagulation therapy.

# MARKETING HISTORY

The On-X^®^ Prosthetic Heart Valve is distributed in Argentina, Austria,
Brazil, Canada, Chile, China, Czech Republic, Denmark, Finland, France,
Germany, Greece, Hungary, India, Indonesia, Iran, Italy, Jordan, South
Korea, Norway, Pakistan, Philippines, Portugal, Romania, Slovakia, South
Africa, Spain, Sweden, Syria, Taiwan R.O.C., Tunisia, Turkey, Vietnam,
and the United Kingdom.

The On-X^®^ Prosthetic Heart Valve has not been withdrawn from the
market in any country for any reason.

# Adverse Events

A total of 229 mitral On-X^®^ Prosthetic Heart Valves were implanted in
229 patients at 16 centers. The mean follow-up was 1.8 years (range of 0
to 4.5 years) with a total of 417.9 patient-years.

A total of 18 deaths occurred during the study and 3 of these were
characterized as valve-related. The causes of the valve-related deaths
were early uncontrolled bleeding (1 patient) and late, sudden,
unexplained death (2 patients).

## Observed Adverse Events

Adverse events were reported in the clinical study as shown in the
following table.

**Table 1: Mitral Observed Adverse Event Rates^1^**

All patients implanted, N = 229, Cumulative follow-up = 417.9
patient-years

+------------------+---+-----+---+-----+---------------+---------------+
| Complication     | E |     | L |     | Freedom from  |               |
|                  | a |     | a |     | Event^3^, %   |               |
|                  | r |     | t |     | \[SE\]        |               |
|                  | l |     | e |     |               |               |
|                  | y |     | E |     |               |               |
|                  | E |     | v |     |               |               |
|                  | v |     | e |     |               |               |
|                  | e |     | n |     |               |               |
|                  | n |     | t |     |               |               |
|                  | t |     | s |     |               |               |
|                  | s |     | ^ |     |               |               |
|                  |   |     | 2 |     |               |               |
|                  |   |     | ^ |     |               |               |
+------------------+---+-----+---+-----+---------------+---------------+
|                  | n | \%  | n | %   | 1Year         | 3 Year        |
|                  |   | (n  |   | /pt | Postoperative | Postoperative |
|                  |   | /N) |   | -yr | (n=134)       | (n=44)        |
|                  |   | ^4^ |   |     |               |               |
+------------------+---+-----+---+-----+---------------+---------------+
| Mortality (all)  | 9 | 3   | 9 | 2   | >             | >             |
|                  |   | .9% |   | .2% |  95.4%\[1.4\] |  89.2%\[2.7\] |
+------------------+---+-----+---+-----+---------------+---------------+
| Mortality        | 1 | 0   | 2 | 0   | >             | >             |
| (valve-related)  |   | .4% |   | .5% |  99.5%\[0.5\] |  97.2%\[1.7\] |
+------------------+---+-----+---+-----+---------------+---------------+
| Endocarditis     | 0 | 0   | 3 | 0   | >             | >             |
|                  |   | .0% |   | .7% |  99.0%\[0.7\] |  99.0%\[0.7\] |
+------------------+---+-----+---+-----+---------------+---------------+
| Explant          | 1 | 0   | 3 | 0   | >             | >             |
|                  |   | .4% |   | .7% |  98.0%\[1.0\] |  98.0%\[1.0\] |
+------------------+---+-----+---+-----+---------------+---------------+
| Hemolysis^5^     | 0 | 0   | 0 | 0   | > 100.0%\[0\] | > 100.0%\[0\] |
|                  |   | .0% |   | .0% |               |               |
+------------------+---+-----+---+-----+---------------+---------------+
| Hemorrhage^6^    | 4 | 1   | 6 | 1   | >             | >             |
| (all)            |   | .8% |   | .4% |  96.4%\[1.3\] |  94.4%\[2.0\] |
+------------------+---+-----+---+-----+---------------+---------------+
| Hemorrhage       | 4 | 1   | 2 | 0   | >             | >             |
| (major)          |   | .8% |   | .5% |  97.0%\[1.2\] |  97.0%\[1.2\] |
+------------------+---+-----+---+-----+---------------+---------------+
| Perivalvular     | 2 | 0   | 3 | 0   | >             | >             |
| Leak (all)       |   | .9% |   | .7% |  98.0%\[1.0\] |  97.1%\[1.2\] |
+------------------+---+-----+---+-----+---------------+---------------+
| Perivalvular     | 1 | 0   | 1 | 0   | >             | >             |
| Leak (major)     |   | .4% |   | .2% |  99.4%\[0.6\] |  99.4%\[0.6\] |
+------------------+---+-----+---+-----+---------------+---------------+
| Nonstructural    | 0 | 0   | 1 | 0   | > 100.0%\[0\] | >             |
| Valve            |   | .0% |   | .2% |               |  99.1%\[0.9\] |
| Dysfunction      |   |     |   |     |               |               |
+------------------+---+-----+---+-----+---------------+---------------+
| Reoperation      | 3 | 1   | 5 | 1   | >             | >             |
| (valve-related)  |   | .3% |   | .2% |  97.0%\[1.2\] |  97.0%\[1.2\] |
+------------------+---+-----+---+-----+---------------+---------------+
| Structural Valve | 0 | 0   | 0 | 0   | > 100.0%\[0\] | > 100.0%\[0\] |
| Dysfunction      |   | .0% |   | .0% |               |               |
+------------------+---+-----+---+-----+---------------+---------------+
| Thromboembolism  | 2 | 0   | 7 | 1   | >             | >             |
|                  |   | .9% |   | .7% |  97.0%\[1.2\] |  96.3%\[1.4\] |
+------------------+---+-----+---+-----+---------------+---------------+
| Thrombosis       | 0 | 0   | 0 | 0   | > 100.0%\[0\] | > 100.0%\[0\] |
|                  |   | .0% |   | .0% |               |               |
+------------------+---+-----+---+-----+---------------+---------------+

Notes:

1.  Data does not include results from double valve replacement.

2.  Late events calculated as linearized rates based on total
    patient-years.

3.  Freedom from event was calculated based on the method of
    Kaplan-Meier. SE = Standard Error.

4.  n = number of patients in each category; N = total number of study
    patients.

5.  Blood studies conducted at a core laboratory established that the
    valve creates a low level of fully compensated hemolysis typified by
    an increase in SLDH with a mean within normal range, a decrease in
    haptoglobin to below normal in 65% MVR patients at 1-year, and all
    other analytes within normal range.

6.  The anticoagulant agents used were reported. The target
    International Normalized Ratio was 3.0 to 4.5.

## Potential Adverse Events

Adverse events potentially associated with the use of prosthetic heart
valves (in alphabetical order) include, but are not limited to:

-   angina

-   cardiac arrhythmia

-   endocarditis

-   heart failure

-   hemolysis

-   hemolytic anemia

-   hemorrhage

-   myocardial infarction

-   prosthesis leaflet entrapment (impingement)

-   prosthesis nonstructural dysfunction

-   prosthesis pannus

-   prosthesis perivalvular leak

-   prosthesis regurgitation

-   prosthesis structural dysfunction

-   prosthesis thrombosis

-   stroke

-   thromboembolism

It is possible that these complications could lead to:

-   reoperation

-   explantation

-   permanent disability

-   death

# SUMMARY OF nonclinical STUDIES

All testing of the On-X^®^ Prosthetic Heart Valve was conducted in
accordance with the applicable sections of the GLP regulation (21
CFR58).

MCRI^™^ certified that the On-X^®^ Prosthetic Heart Valve complies with
the following international regulatory and/or voluntary standards:

1\. ISO 10993 Parts 1-12 as applicable (Also prEN30993) for
biocompatibility

2\. ISO 5840 (Also prEN12006-1) Cardiac Implants - Cardiac Valve
Prostheses

3\. EN554 and EN556 Sterility

4\. EN ISO 9001 Quality Systems, EN 46001 Medical Device Quality Systems

## IN VITRO STUDIES

### Hydrodynamics and Flow Visualization

Hydrodynamic studies of the On-X^®^ Prosthetic Heart Valve were
conducted according to section VI.A.2.a of the Draft Replacement Heart
Valve Guidance Document, October 14, 1994. Commercially available valves
were used as controls. Table 3 provides a summary of hydrodynamic tests.

**Table 3 -- Hydrodynamic Performance Testing and Results**

+--------------+----------------+---------------+---------------------+
| **Test**     | **Sample       | **Sample      | **Results**         |
|              | Size:**        | Size: On-X^^ |                     |
|              |                | Prosthetic    |                     |
|              | **Control**    | Heart Valve** |                     |
+--------------+----------------+---------------+---------------------+
| Steady       | 1 each 19, 21, | 3 each 19,    | At 30 LPM, On-X^®^  |
| forward flow | 23, 25, 27, 29 | 21, 23, 25 mm | gradients were      |
| pressure     | mm             |               | substantially lower |
| gradient     |                |               | size for size than  |
|              |                |               | the controls.       |
+--------------+----------------+---------------+---------------------+
| Steady       | 1 each 19, 21, | 3 each 19,    | At 180 mmHg,        |
| backflow     | 23, 25, 27, 29 | 21, 23, 25 mm | On-X^®^ leakage was |
| leakage      | mm and a       |               | higher by design    |
|              | reference      |               | compared to         |
|              | nozzle         |               | equivalent          |
|              |                |               | geometric size      |
|              |                |               | controls and lower  |
|              |                |               | than the reference  |
|              |                |               | nozzle.             |
+--------------+----------------+---------------+---------------------+
| Pulsatile    | 1 each 19, 21, | 3 each 19,    | Under all           |
| flow         | 23, 25, 27, 29 | 21, 23, 25 mm | conditions, On-X^®^ |
| pressure     | mm             |               | gradients were      |
| gradients    |                |               | lower than the      |
|              |                |               | equivalent control  |
|              |                |               | valve.              |
+--------------+----------------+---------------+---------------------+
| Pulsatile    | 1 each 19, 21, | 3 each 19,    | Equivalent          |
| flow         | 23, 25, 27, 29 | 21, 23, 25 mm | geometric size      |
| r            | mm             |               | valves had          |
| egurgitation |                |               | equivalent total    |
|              |                |               | regurgitation.      |
|              |                |               | On-X^®^ closure     |
|              |                |               | volume was lower,   |
|              |                |               | but leakage volume  |
|              |                |               | was higher.         |
+--------------+----------------+---------------+---------------------+
| Verification | Not applicable | 1 each 19,    | The Bernoulli       |
| of Bernoulli | (N/A)          | 23, 25 mm     | equation accurately |
| equation     |                |               | projects true       |
|              |                |               | pressure gradient   |
|              |                |               | for the valve.      |
+--------------+----------------+---------------+---------------------+
| Flow         | 1 of 25 mm     | 1 of 25 mm    | Similar flow        |
| vi           |                |               | patterns exist, but |
| sualization: |                |               | On-X^®^ has lower   |
| Laser        |                |               | peak velocities and |
| Doppler      |                |               | shear stresses. No  |
| anemometry   |                |               | adverse flow        |
|              |                |               | patterns.           |
+--------------+----------------+---------------+---------------------+
| Flow         | N/A            | 1 of 25 mm    | Four major leakage  |
| vi           |                |               | jets emanate from   |
| sualization: |                |               | the four pivots     |
| Backflow     |                |               | similar to all      |
| leakage jets |                |               | bileaflet valves.   |
+--------------+----------------+---------------+---------------------+
| Flow         | 5X model 25 mm | 5X model 25   | No areas of stasis  |
| vi           | control and    | mm            | at any time in the  |
| sualization: | second control |               | cycle for On-X^®^,  |
| Hinge flow   |                |               | no vortex formation |
|              |                |               | for On-X^®^ or      |
|              |                |               | control, prominent  |
|              |                |               | vortexes for second |
|              |                |               | control.            |
+--------------+----------------+---------------+---------------------+

### Durability and Lifetime Analysis

Structural performance of the On-X^®^ Prosthetic Heart Valve was studied
in accordance with the Draft Replacement Heart Valve Guidance Document.
Commercially available valves were used as controls where applicable.
Table 4 summarizes these tests.

**Table 4 -- Structural Performance Testing and Results**

+-------------+----------------+------------------+--------------------+
| **Test**    | **Sample Size: | **Sample Size:   | **Results**        |
|             | Control**      | On-X^^          |                    |
|             |                | Prosthetic Heart |                    |
|             |                | Valve**          |                    |
+-------------+----------------+------------------+--------------------+
| Fracture    | N/A            | On-X^^ Carbon   | K~IC~ = 2.46       |
| mechanics   |                | on graphite      | MPa-m^1/2^, ∆K~th~ |
| of          |                |                  | = 1.24 MPa-m^1/2^, |
| materials   |                | On-X^^ Carbon   | m = 40.2, log C =  |
|             |                | solid            | -14.6              |
|             |                |                  |                    |
|             |                |                  | K~IC~ = 1.67       |
|             |                |                  | MPa-m^1/2^, ∆K~th~ |
|             |                |                  | = 1.11 MPa-m^1/2^, |
|             |                |                  | m = 70.3, log C =  |
|             |                |                  | -14.4              |
|             |                |                  |                    |
|             |                |                  | Worst-case         |
|             |                |                  | properties used    |
|             |                |                  | for fatigue life   |
|             |                |                  | calculations.      |
+-------------+----------------+------------------+--------------------+
| Accelerated | 2 of 23 mm, 1  | 5 each 19, 21,   | All valves         |
| durability  | each of 27 and | 23, 25, 27/29 mm | survived cycling   |
| testing     | 29 mm          |                  | for 600 million    |
|             |                |                  | cycles without     |
|             |                |                  | failure or damage. |
|             |                |                  | The maximum wear   |
|             |                |                  | depth was 26.7     |
|             |                |                  | microns (25 mm) as |
|             |                |                  | compared to the    |
|             |                |                  | control wear depth |
|             |                |                  | of 3.1 microns.    |
|             |                |                  | The worst-case     |
|             |                |                  | total *in-vitro*   |
|             |                |                  | wear at 15 years   |
|             |                |                  | was less than half |
|             |                |                  | the minimum        |
|             |                |                  | coating thickness  |
|             |                |                  | (102 microns).     |
+-------------+----------------+------------------+--------------------+
| Dynamic     | N/A            | 25 mm dynamic    | Impact factor of   |
| impact      |                | model and test   | 2.0, predicted     |
| factor      |                | valve            | from FEA model,    |
|             |                |                  | was confirmed by   |
|             |                |                  | strain gage        |
|             |                |                  | measurements       |
|             |                |                  | during pulse       |
|             |                |                  | duplicator testing |
|             |                |                  | at 200 mmHg peak   |
|             |                |                  | systolic pressure. |
+-------------+----------------+------------------+--------------------+
| Ph          | N/A            | Finite element   | FEA results and    |
| ysiological |                | model of 19, 21, | impact factor      |
| stresses    |                | 23, 25 mm        | combined to result |
|             |                |                  | in worst-case      |
|             |                |                  | stress of 3040 psi |
|             |                |                  | used in fatigue    |
|             |                |                  | lifetime           |
|             |                |                  | calculations.      |
+-------------+----------------+------------------+--------------------+
| Fatigue     | N/A            | 19, 21, 23, 25   | Paris law          |
| life        |                | mm               | calculations were  |
|             |                |                  | made, for an       |
|             |                |                  | assumed lifetime   |
|             |                |                  | of 600 million     |
|             |                |                  | cycles, to         |
|             |                |                  | determine critical |
|             |                |                  | flaw size under    |
|             |                |                  | worst-case         |
|             |                |                  | conditions. Proof  |
|             |                |                  | testing and other  |
|             |                |                  | non-destructive    |
|             |                |                  | tests were used to |
|             |                |                  | assure that        |
|             |                |                  | critical flaws     |
|             |                |                  | were not in final  |
|             |                |                  | product. Based on  |
|             |                |                  | the critical flaw  |
|             |                |                  | size, the          |
|             |                |                  | worst-case life    |
|             |                |                  | calculation was    |
|             |                |                  | well in excess of  |
|             |                |                  | the human          |
|             |                |                  | lifespan.          |
+-------------+----------------+------------------+--------------------+
| Static      | N/A            | 3 each 19, 21,   | Minimum static     |
| failure     |                | 23, 25 mm        | load to failure    |
| mode        |                |                  | was 94 psi.        |
|             |                |                  | Failure mode was   |
|             |                |                  | spalled sockets    |
|             |                |                  | and shattered      |
|             |                |                  | leaflets.          |
+-------------+----------------+------------------+--------------------+
| Dynamic     | 1 of 27 mm     | 3 each 25 mm     | Cycle to 30 psi    |
| failure     |                | after wear test  | without failure.   |
| mode        |                |                  | Failure of valve   |
|             |                |                  | by leaflet shatter |
|             |                |                  | at 72 psi for      |
|             |                |                  | On-X^®^. Control   |
|             |                |                  | failed by housing  |
|             |                |                  | fracture at 67     |
|             |                |                  | psi.               |
+-------------+----------------+------------------+--------------------+
| **Test**    | **Sample Size: | **Sample Size:   | **Results**        |
|             | Control**      | On-X^^          |                    |
|             |                | Prosthetic Heart |                    |
|             |                | Valve**          |                    |
+-------------+----------------+------------------+--------------------+
| Cavitation  | 2 of 27 mm     | 3 each 25 mm     | The dp/dt at       |
| potential   |                |                  | threshold was      |
|             | 3 of 29 mm     |                  | higher for the     |
|             |                |                  | On-X^®^ than the   |
|             |                |                  | control.           |
+-------------+----------------+------------------+--------------------+
| Sewing ring | 1 of size 29   | 3 - 25 mm mitral | Suture breaks      |
| integrity   | mm             |                  | before tear out,   |
|             |                |                  | tear out at 10.5   |
| Tear out    |                |                  | lbs for control    |
+-------------+----------------+------------------+--------------------+
| Sewing ring | N/A            | 25, 27/29, 31/31 | Minimum push off   |
| integrity   |                | mitral           | force 111 N, over  |
|             |                |                  | 7 time physiologic |
| Push off    |                |                  | force              |
+-------------+----------------+------------------+--------------------+
| Load        | N/A            | 3 each 25 mm     | Minimum to bind -- |
| deflection  |                |                  | 20N without sewing |
| tests       |                |                  | ring, 28N with     |
|             |                |                  | sewing ring        |
| Bind        |                |                  |                    |
|             |                |                  | Minimum to escape  |
| Escape      |                |                  | -- 110N.           |
+-------------+----------------+------------------+--------------------+
| Valve       | 3 29mm mitral  | 7 mitral -- 2 25 | No differences in  |
| sounds      |                | mm, 5 27/29 mm   | perceived sounds   |
|             |                |                  | were found between |
| Clinical    |                |                  | valves.            |
| study       |                |                  |                    |
+-------------+----------------+------------------+--------------------+

## ANIMAL STUDIES

Preclinical animal studies were conducted using the standard adult sheep
model at the University of Minnesota with implants occurring between
October and December 1995. Eight sheep were implanted with 25 mm On-X^®^
Prosthetic Heart Valves. Two sheep were implanted with the control
valves. One animal was found to have a large atrial septal defect and
was sacrificed on the operating table. All other animals survived the 20
week minimum implant duration. Serial postoperative blood samples showed
no difference between valves and no negative experimental device effect.
Hemodynamic parameters measured for each device were normal and there
were no surgical handling difficulties for the test valve. Pathology
studies demonstrated that the interior surfaces of the housing, the
hinge region, and the leaflets were free of thrombus and pannus.
However, a single thrombus was observed in one explanted valve at the
interface of the sewing cuff and the outflow region of the valve
housing. Postmortem examination of the major organs was normal in all
animals, except for foreign material in the renal artery of one control
valve sheep. The control valve from this animal displayed chipping and
pitting in the pivot regions upon microscopic examination believed to
have occurred *in situ*, and possibly explaining the renal artery
observation. All other valves had normal surfaces under microscopy after
implant.

## BIOCOMPATIBILITY

Biocompatibility tests were conducted according to ISO 10993 guidelines
for the On-X^®^ Carbon and polytetrafluoroethylene (PTFE) yarn
materials. Yarn with an ink mark was tested, also. Biocompatibility
testing was not conducted for the titanium (Ti6Al4V ELI) alloy because
the material meets ASTM F136 Standard Specification for Wrought Titanium
6Al-4V ELI Alloy for Surgical Implant Applications and because of the
long history of successful biomedical implant applications for this
alloy. No significant reactions were observed in the tests performed.
Results are presented in Table 5.

**Table 5 -- Biocompatibility Studies Results Summary**

+-------------+-------------+--------------+------------+------------+
| **Test**    | **          | **Sample:    | **Sample:  | *          |
|             | Objective** | Control**    | Test       | *Results** |
|             |             |              | Article**  |            |
+-------------+-------------+--------------+------------+------------+
| C           | To          | Negative     | On-X^^    | Non        |
| ytotoxicity | determine   | control:     | Carbon     | -cytotoxic |
| L-929       | the         | silicone     |            |            |
| Membrane    | biological  | rubber       |            |            |
| Elution     | reactivity  | Positive     |            |            |
|             | of a cell   | control:     |            |            |
|             | culture to  | natural      |            |            |
|             | an extract  | rubber       |            |            |
|             | of the test |              |            |            |
|             | article     |              |            |            |
+-------------+-------------+--------------+------------+------------+
| Hemolysis   | To assess   | Negative     | On-X^^    | Non        |
|             | the         | control:     | Carbon     | -hemolytic |
|             | hemolytic   | water for    |            | at 0%      |
|             | activity of | injection    |            | hemolysis  |
|             | the test    | Positive     |            |            |
|             | article     | control:     |            |            |
|             |             | 0.9% saline  |            |            |
+-------------+-------------+--------------+------------+------------+
| Phys        | To          | Negative     | On-X^^    | Passed USP |
| icochemical | determine   | control:     | Carbon     | physi      |
| tests to    | physical    | water for    |            | cochemical |
| USP         | and         | injection    |            | tests for  |
|             | chemical    |              |            | plastics   |
|             | properties  | Positive     |            |            |
|             | of extracts | control: N/A |            |            |
+-------------+-------------+--------------+------------+------------+
| Ames        | To assess   | Negative     | On-X^^    | Non        |
| m           | the         | control:     | Carbon     | -mutagenic |
| utagenicity | mutagenic   | 0.9% NaCl    |            |            |
| test        | potential   |              |            |            |
|             | of the test | Positive     |            |            |
|             | article     | controls:    |            |            |
|             |             | 2-amin       |            |            |
|             |             | oanthracene, |            |            |
|             |             | sodium       |            |            |
|             |             | azide,       |            |            |
|             |             | 2-ni         |            |            |
|             |             | trofluorene, |            |            |
|             |             | 9-a          |            |            |
|             |             | minoacridene |            |            |
+-------------+-------------+--------------+------------+------------+
| Int         | To assess   | Negative     | On-X^^    | Negligible |
| racutaneous | toxic       | control:     | Carbon     | irritant   |
| injection   | effects of  | 0.9% NaCl,   |            |            |
|             | extracts of | cottonseed   |            |            |
|             | the test    | oil Positive |            |            |
|             | article     | control: N/A |            |            |
+-------------+-------------+--------------+------------+------------+
| Systemic    | To assess   | Negative     | On-X^^    | Negative,  |
| injection   | the         | control:     | Carbon     | non-toxic  |
|             | systemic    | 0.9% NaCl,   |            |            |
|             | toxic       | cottonseed   |            |            |
|             | effect of   | oil Positive |            |            |
|             | extracts of | control: N/A |            |            |
|             | the test    |              |            |            |
|             | article     |              |            |            |
+-------------+-------------+--------------+------------+------------+
| Rabbit      | To          | Negative     | On-X^^    | Non        |
| pyrogen     | determine   | control:     | Carbon     | -pyrogenic |
|             | the         | 0.9% NaCl    |            |            |
|             | presence of | Positive     |            |            |
|             | chemical    | control: N/A |            |            |
|             | pyrogens on |              |            |            |
|             | finished    |              |            |            |
|             | components  |              |            |            |
+-------------+-------------+--------------+------------+------------+
| Klingman    | To evaluate | Negative     | On-X^^    | 0%         |
| se          | the         | control:     | Carbon     | sens       |
| nsitization | allergenic  | 0.9% NaCl,   |            | itization: |
|             | potential   | cottonseed   |            | Grade I    |
|             | of test     | oil          |            | reaction   |
|             | articles    | Possitive    |            |            |
|             |             | control:     |            |            |
|             |             | dinitroc     |            |            |
|             |             | hlorobenzene |            |            |
+-------------+-------------+--------------+------------+------------+
| C           | To          | Negative     | PTFE yarn  | Non        |
| ytotoxicity | determine   | control: MEM |            | -cytotoxic |
| L-929       | the         | extractant   | PTFE yarn  |            |
| Membrane    | biological  | Positive     | with       |            |
| Elution     | reactivity  | control:     | surgical   |            |
|             | of a cell   | Known toxic  | marker     |            |
|             | culture to  | material     |            |            |
|             | an extract  |              |            |            |
|             | of the test |              |            |            |
|             | article     |              |            |            |
+-------------+-------------+--------------+------------+------------+
| **Test**    | **          | **Sample:    | **Sample:  | *          |
|             | Objective** | Control**    | Test       | *Results** |
|             |             |              | Article**  |            |
+-------------+-------------+--------------+------------+------------+
| Hemolysis   | To assess   | Negative     | PTFE yarn  | Non        |
|             | the         | control:     |            | -hemolytic |
|             | hemolytic   | water for    |            |            |
|             | activity of | injection    |            |            |
|             | the test    | Positive     |            |            |
|             | article     | control:     |            |            |
|             |             | 0.9% saline  |            |            |
+-------------+-------------+--------------+------------+------------+
| Int         | To assess   | Negative     | PTFE yarn  | Negligible |
| racutaneous | toxic       | control:     |            | irritant   |
| injection   | effects of  | 0.9% NaCl,   |            |            |
|             | extracts of | cottonseed   |            |            |
|             | the test    | oil Positive |            |            |
|             | article     | control: N/A |            |            |
+-------------+-------------+--------------+------------+------------+
| Systemic    | To assess   | Negative     | PTFE yarn  | Negative,  |
| injection   | the         | control:     |            | non-toxic  |
|             | systemic    | 0.9% NaCl,   |            |            |
|             | toxic       | cottonseed   |            |            |
|             | effect of   | oil Positive |            |            |
|             | extracts of | control: N/A |            |            |
|             | the test    |              |            |            |
|             | article     |              |            |            |
+-------------+-------------+--------------+------------+------------+
| Rabbit      | To assess   | Negative     | PTFE yarn  | Ma         |
| i           | the effects | control: USP |            | croscopic: |
| mplantation | of          | strips       |            | non-s      |
| (1 and 4    | i           |              |            | ignificant |
| weeks)      | mplantation | Positive     |            | Mi         |
|             | of the test | control: N/A |            | croscopic: |
|             | article     |              |            | slight     |
|             |             |              |            | irritant   |
+-------------+-------------+--------------+------------+------------+

## MAGNETIC RESONANCE IMAGING (MRI) COMPATIBILITY

The On-X^®^ Prosthetic Heart Valve has been shown to be MRI safe when
tested using systems operating with shielded static magnetic field
strengths of 1.5 Tesla or less. Note, however, that the effects of a
time-varying magnetic field were not examined. The testing should not
cause significant MRI image artifacts or distortion -- should this
occur, this phenomenon produces no harmful effects to the patient.

## SHELF LIFE AND STERILITY

The On-X^®^ Prosthetic Heart Valve is sterilized by standard moist heat
(steam) methods. It carries a shelf life of 5 years from its date of
sterilization. Packaging and sterility tests were provided that
establish the integrity of the package materials and sterile barrier
throughout their 5 year life, including challenges of simulated
shipping, storage temperature, pressure and humidity variations, and
sterility by vacuum dust drum.

#  summary of clinical studies

The On-X^^ Prosthetic Heart Valve clinical trials were designed to
study the safety and effectiveness of the valve in mitral valve
replacement. Patients requiring isolated mitral heart valve replacement
were enrolled from September 12, 1996 to June 2001 at 8 European centers
and 8 North American centers in a prospective, non-randomized study with
retrospective controls.

The cohort included 229 patients (86 men, 143 women), aged from 21 to 78
years (mean of 59.4 years). The cumulative follow-up was 417.9
patient-years with a mean follow-up of 1.8 years (SD = 1.3 years, range
= 0 to 4.5 years). Tables 2 and 3 present preoperative and operative
patient demographics. Figure 2 shows the number of patients implanted
versus duration of follow-up. Table 4 presents implant information by
valve size, including the number of patients implanted and the number of
patient-years.

The safety endpoints captured in the studies were complications; blood
analyses were used to confirm the absence or presence of certain
complications. The safety results are provided above in Table 1.
Effectiveness endpoints were New York Heart Association (NYHA)
classification and echocardiographic assessments. NYHA and blood data
were obtained pre-operatively, intra-operatively, and post-operatively
at 3 to 6 months, at one year, and annually thereafter. Hemodynamic data
were obtained at discharge and at one year. Tables 5 and 6 present these
effectiveness results.

**Table 2: Preoperative Patient Demographics**

All patients implanted, N = 229, Cumulative follow-up = 417.9
patient-years

+------------------+-----------------------+----------+---------------+
| Patient          |                       | n        | \% (n/N)^1^   |
| Characteristic   |                       |          |               |
+------------------+-----------------------+----------+---------------+
| Age at implant   |                       | 59.2 ±   |               |
| in years         |                       | 10.6     |               |
+------------------+-----------------------+----------+---------------+
| Gender:          | -   Male              | 86       | 37.6%         |
+------------------+-----------------------+----------+---------------+
|                  | -   Female            | 143      | 62.4%         |
+------------------+-----------------------+----------+---------------+
| NYHA             | -   I                 | 5        | 2.2%          |
| Classification:  |                       |          |               |
+------------------+-----------------------+----------+---------------+
|                  | -   II                | 68       | 29.7%         |
+------------------+-----------------------+----------+---------------+
|                  | -   III               | 134      | 58.5%         |
+------------------+-----------------------+----------+---------------+
|                  | -   IV                | 18       | 7.9%          |
+------------------+-----------------------+----------+---------------+
|                  | -   Unknown           | 4        | 1.7%          |
+------------------+-----------------------+----------+---------------+
| Valve Lesion:    | -   Stenosis          | 29       | 12.7%         |
+------------------+-----------------------+----------+---------------+
|                  | -   Insufficiency     | 111      | 48.5%         |
+------------------+-----------------------+----------+---------------+
|                  | -   Mixed             | 87       | 38.0%         |
+------------------+-----------------------+----------+---------------+
|                  | -   Other             | 2        | 0.9%          |
+------------------+-----------------------+----------+---------------+

> Notes:

1.  n = number of patients in each category; N = total number of study
    patients.

**Table 3: Operative Patient Demographics**

All patients implanted, N = 229, Cumulative follow-up = 417.9
patient-years

  ------------------- -------------------------------- --------- ----------
  Variable            Category^1^                      N         \%
                                                                 (n/N)^2^

  Etiology^3^         Calcific                         36        15.7%

                      Degenerative                     62        27.1%

                      Rheumatic                        86        37.6%

                      Congenital                       4         1.8%

                      Endocarditis                     16        7.0%

                      Prosthetic Valve Dysfunction     6         2.6%

                      Other                            38        16.6%

  Concomitant         None                             130       56.8%
  Procedures^3^                                                  

                      Coronary Artery Bypass Graft     44        19.2%

                      Tricuspid Repair                 22        9.6%

                      Closure of Atrial Appendage      12        5.2%

                      Mitral Repair                    12        5.2%

                      Maze Procedure                   12        5.2%

                      Septal Defect Closure            8         3.5%

                      Ventricular Aneurysm Repair      3         1.3%

                      Muscularization                  2         0.9%

                      Tricuspid Replacement            1         0.4%

                      Explant of Annuloplasty Ring     1         0.4%

  Pre-existing        Atrial Arrhythmias               137       59.3%
  Conditions^3^                                                  

                      Pulmonary Hypertension           108       46.8%

                      Systemic Hypertension            88        38.1%

                      Hyperlipidemia                   88        38.1%

                      Congestive Heart Failure         80        34.6%

                      Other                            77        33.3%

                      Coronary Artery Disease          67        29.0%

                      Cigarette Smoker                 64        27.7%

                      Left Ventricular Dysfunction     47        20.4%

                      Cerebrovascular Accident         43        18.6%

                      Diabetes Mellitus                40        17.3%

                      Angina                           38        16.4%

                      Myocardial Infarction            30        13.0%

                      Hyperthyriodism                  27        11.7%

                      Chronic Obstructive Pulmonary    25        10.8%
                      Disease                                    

                      Endocarditis                     18        7.8%

                      Gastroinestinal Ulcer            18        7.8%

                      Chronic Kidney Failure           13        5.6%

                      Carotid Artery Disease           12        5.2%

                      Coronary Artery Bypass Graft     10        4.4%

                      Cancer                           10        4.4%

                      Previous Mitral Valve            9         3.9%
                      Replacement                                

                      Cardiomyopathy                   8         3.5%

                      Pacemaker Implant                6         2.6%

  Valve Size          25 mm                            33        14.4%

                      27/29 mm                         131       57.2%

                      31/33 mm                         65        28.4%
  ------------------- -------------------------------- --------- ----------

> Notes:

1.  Ordered by frequency of occurrence, except for valve size.

2.  n = number of patients in each category; N = total number of study
    patients.

3.  May be more than one per patient.

**Figure 2: Patient Follow-up Over Time**

All patients implanted, N = 229, Cumulative follow-up = 417.9
patient-years

![](media/image2.wmf)

  ----------- ----------- ---------------- ---------------- ----------------
  Patients    Discharge   1Year            2 Year           3 Year
  Followed,               Postoperative    Postoperative    Postoperative
  N~f~                                                      

              216         134              74               44
  ----------- ----------- ---------------- ---------------- ----------------

**Table 4: Number of Patients Implanted and Number of Patient-years by
Valve Size**

All patients implanted, N = 229, Cumulative follow-up = 417.9
patient-years

  --------------------- --------- ------- -------- --------- -------- -------
                        Numbers                                       
                        by Valve                                      
                        size                                          

                                  25 mm   27/29 mm 31/33 mm           Total

  Number of Patients              33      131      65                 229
  Implanted                                                           

  Number of                       60.2    239.1    118.6              417.9
  Patient-years                                                       
  --------------------- --------- ------- -------- --------- -------- -------

**Table 5: Effectiveness Outcomes, Functional New York Heart (NYHA)
Classification^1^**

**All patients implanted, N = 229, Cumulative follow-up = 417.9
patient-years**

+------------+----+-----+------+-------+------+-------+------+------+
| NYHA Class | Pr |     | P    |       |      |       |      |      |
|            | eo |     | osto |       |      |       |      |      |
|            | pe |     | pera |       |      |       |      |      |
|            | ra |     | tive |       |      |       |      |      |
|            | ti |     | Ass  |       |      |       |      |      |
|            | ve |     | essm |       |      |       |      |      |
|            | As |     | ents |       |      |       |      |      |
|            | se |     |      |       |      |       |      |      |
|            | ss |     |      |       |      |       |      |      |
|            | me |     |      |       |      |       |      |      |
|            | nt |     |      |       |      |       |      |      |
|            |    |     |      |       |      |       |      |      |
|            | (  |     |      |       |      |       |      |      |
|            | N~ |     |      |       |      |       |      |      |
|            | d~ |     |      |       |      |       |      |      |
|            | =  |     |      |       |      |       |      |      |
|            | 22 |     |      |       |      |       |      |      |
|            | 9) |     |      |       |      |       |      |      |
+------------+----+-----+------+-------+------+-------+------+------+
|            |    |     | 1    |       | 2    |       | 3    |      |
|            |    |     | Year |       | Year |       | Year |      |
|            |    |     | (1   |       | (2   |       | (3   |      |
|            |    |     | 0-14 |       | 2-26 |       | 4-38 |      |
|            |    |     | Mon  |       | Mon  |       | Mon  |      |
|            |    |     | ths) |       | ths) |       | ths) |      |
|            |    |     |      |       |      |       |      |      |
|            |    |     | (    |       | (    |       | (    |      |
|            |    |     | N~f~ |       | N~f~ |       | N~f~ |      |
|            |    |     | =    |       | =    |       | =    |      |
|            |    |     | 134, |       | 74,  |       | 44,  |      |
|            |    |     | N~d~ |       | N~d~ |       | N~d~ |      |
|            |    |     | =    |       | =    |       | =    |      |
|            |    |     | 127  |       | 69)  |       | 42)  |      |
|            |    |     | )^2^ |       |      |       |      |      |
+------------+----+-----+------+-------+------+-------+------+------+
|            | n^ | \%  | N    | \%    | n    | \%    | N    | \%   |
|            | 3^ | (n  |      | (n/   |      | (n/   |      | (n/N |
|            |    | /N~ |      | N~d~) |      | N~d~) |      | ~d~) |
|            |    | d~) |      |       |      |       |      |      |
+------------+----+-----+------+-------+------+-------+------+------+
| I          | 5  | 2.2 | 85   | 66.9  | 35   | 50.7  | 14   | 33.3 |
+------------+----+-----+------+-------+------+-------+------+------+
| II         | 68 | 2   | 29   | 22.8  | 24   | 34.8  | 22   | 52.4 |
|            |    | 9.7 |      |       |      |       |      |      |
+------------+----+-----+------+-------+------+-------+------+------+
| III        | 1  | 5   | 5    | 3.9   | 5    | 7.2   | 6    | 14.3 |
|            | 34 | 8.5 |      |       |      |       |      |      |
+------------+----+-----+------+-------+------+-------+------+------+
| IV         | 18 | 7.9 | 0    | 0     | 1    | 1.4   | 0    | 0    |
+------------+----+-----+------+-------+------+-------+------+------+
| Undet      | 4  | 1.7 | 8    | 6.3   | 4    | 5.8   | 0    | 0    |
| ermined^4^ |    |     |      |       |      |       |      |      |
+------------+----+-----+------+-------+------+-------+------+------+
| Missing^5^ | 0  | N/A | 7    | N/A   | 5    | N/A   | 2    | N/A  |
+------------+----+-----+------+-------+------+-------+------+------+

> Notes:

1.  Data does not include results from double valve replacement.

2.  N~f~ = number of patients followed (reproduced from Figure 2); N~d~
    = number of patients for which NYHA data were collected.

3.  n = number of patients in each category.

4.  Undetermined means data were collected but Class could not be
    determined during exam

5.  Missing refers to the difference between the number of patients
    followed, N~f~, and the number of patients for which NYHA data were
    collected, N~d~.

**Table 6: Effectiveness Outcomes, Hemodynamic Results^1^**

**All patients implanted, N = 229, Cumulative follow-up = 417.9
patient-years**

<table style="width:100%;">
<colgroup>
<col style="width: 21%" />
<col style="width: 5%" />
<col style="width: 9%" />
<col style="width: 5%" />
<col style="width: 9%" />
<col style="width: 5%" />
<col style="width: 9%" />
<col style="width: 5%" />
<col style="width: 10%" />
<col style="width: 5%" />
<col style="width: 10%" />
</colgroup>
<tbody>
<tr class="odd">
<td rowspan="2">Hemodynamic Parameter</td>
<td colspan="10">Results by Valve Size</td>
</tr>
<tr class="even">
<td colspan="2"></td>
<td colspan="2">25 mm</td>
<td colspan="2">27/29 mm</td>
<td colspan="2">31/33 mm</td>
<td colspan="2"></td>
</tr>
<tr class="odd">
<td colspan="11">Early Postoperation (&lt; 30 days),
N<sub>f</sub><sup>2</sup> = 216</td>
</tr>
<tr class="even">
<td>Mean Gradient<sup>3</sup></td>
<td colspan="2"></td>
<td colspan="2">N<sub>d</sub> = 31</td>
<td colspan="2">N<sub>d</sub> = 117</td>
<td colspan="2">N<sub>d</sub> = 59</td>
<td colspan="2"></td>
</tr>
<tr class="odd">
<td><ul>
<li><p>Mean ± SD</p></li>
</ul></td>
<td colspan="2"></td>
<td colspan="2">4.3 ± 1.3</td>
<td colspan="2">4.3 ± 1.6</td>
<td colspan="2">4.5 ± 2.2</td>
<td colspan="2"></td>
</tr>
<tr class="even">
<td><ul>
<li><p>Min, max</p></li>
</ul></td>
<td colspan="2"></td>
<td colspan="2">1.7, 7.5</td>
<td colspan="2">1.2, 10.0</td>
<td colspan="2">1.0, 11.7</td>
<td colspan="2"></td>
</tr>
<tr class="odd">
<td colspan="11"></td>
</tr>
<tr class="even">
<td>EOA<sup>5</sup></td>
<td colspan="2"></td>
<td colspan="2">N<sub>d</sub> = 25</td>
<td colspan="2">N<sub>d</sub> = 97</td>
<td colspan="2">N<sub>d</sub> = 53</td>
<td colspan="2"></td>
</tr>
<tr class="odd">
<td><ul>
<li><p>Mean ± SD</p></li>
</ul></td>
<td colspan="2"></td>
<td colspan="2">2.4 ± 0.8</td>
<td colspan="2">2.2 ± 0.6</td>
<td colspan="2">2.2 ± 0.8</td>
<td colspan="2"></td>
</tr>
<tr class="even">
<td><ul>
<li><p>Min, max</p></li>
</ul></td>
<td colspan="2"></td>
<td colspan="2">0.9, 4.2</td>
<td colspan="2">1.0, 4.3</td>
<td colspan="2">0.8, 4.4</td>
<td colspan="2"></td>
</tr>
<tr class="odd">
<td colspan="11"></td>
</tr>
<tr class="even">
<td rowspan="2">Regurgitation<sup>6</sup></td>
<td colspan="2"></td>
<td colspan="2">N<sub>d</sub> = 28</td>
<td colspan="2">N<sub>d</sub> = 104</td>
<td colspan="2">N<sub>d</sub> = 56</td>
<td colspan="2"></td>
</tr>
<tr class="odd">
<td></td>
<td></td>
<td>n</td>
<td>% (n/N<sub>d</sub>)</td>
<td>N</td>
<td>% (n/N<sub>d</sub>)</td>
<td>N</td>
<td>% (n/N<sub>d</sub>)</td>
<td></td>
<td></td>
</tr>
<tr class="even">
<td><ul>
<li><p>0</p></li>
</ul></td>
<td></td>
<td></td>
<td>20</td>
<td>71.4%</td>
<td>73</td>
<td>70.2%</td>
<td>40</td>
<td>71.4%</td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td><ul>
<li><p>1-2+</p></li>
</ul></td>
<td></td>
<td></td>
<td>4</td>
<td>14.3%</td>
<td>25</td>
<td>24.0%</td>
<td>16</td>
<td>28.6%</td>
<td></td>
<td></td>
</tr>
<tr class="even">
<td><ul>
<li><p>3+</p></li>
</ul></td>
<td></td>
<td></td>
<td>0</td>
<td>0.0%</td>
<td>0</td>
<td>0.0%</td>
<td>0</td>
<td>0.0%</td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td><ul>
<li><p>4+</p></li>
</ul></td>
<td></td>
<td></td>
<td>0</td>
<td>0.0%</td>
<td>0</td>
<td>0.0%</td>
<td>0</td>
<td>0.0%</td>
<td></td>
<td></td>
</tr>
<tr class="even">
<td><ul>
<li><p>Not available</p></li>
</ul></td>
<td></td>
<td></td>
<td>4</td>
<td>14.3%</td>
<td>6</td>
<td>5.8%</td>
<td>0</td>
<td>0.0%</td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td colspan="11">1 Year Postoperation, N<sub>f</sub> = 134</td>
</tr>
<tr class="even">
<td>Mean Gradient</td>
<td colspan="2"></td>
<td colspan="2">N<sub>d</sub> = 18</td>
<td colspan="2">N<sub>d</sub> = 79</td>
<td colspan="2">N<sub>d</sub> = 30</td>
<td colspan="2"></td>
</tr>
<tr class="odd">
<td><ul>
<li><p>Mean ± SD</p></li>
</ul></td>
<td colspan="2"></td>
<td colspan="2">3.7 ± 2.0</td>
<td colspan="2">4.4 ± 1.8</td>
<td colspan="2">4.0 ± 1.5</td>
<td colspan="2"></td>
</tr>
<tr class="even">
<td><ul>
<li><p>Min, max</p></li>
</ul></td>
<td colspan="2"></td>
<td colspan="2">1.7, 7.5</td>
<td colspan="2">1.7, 10.0</td>
<td colspan="2">2.0, 7.1</td>
<td colspan="2"></td>
</tr>
<tr class="odd">
<td colspan="11"></td>
</tr>
<tr class="even">
<td>EOA</td>
<td colspan="2"></td>
<td colspan="2">N<sub>d</sub> = 15</td>
<td colspan="2">N<sub>d</sub> = 70</td>
<td colspan="2">N<sub>d</sub> = 28</td>
<td colspan="2"></td>
</tr>
<tr class="odd">
<td><ul>
<li><p>Mean ± SD</p></li>
</ul></td>
<td colspan="2"></td>
<td colspan="2">2.1 ± 0.6</td>
<td colspan="2">2.1 ± 0.6</td>
<td colspan="2">2.1 ± 0.6</td>
<td colspan="2"></td>
</tr>
<tr class="even">
<td><ul>
<li><p>Min, max</p></li>
</ul></td>
<td colspan="2"></td>
<td colspan="2">1.2, 3.1</td>
<td colspan="2">0.9, 4.0</td>
<td colspan="2">1.4, 4.3</td>
<td colspan="2"></td>
</tr>
<tr class="odd">
<td colspan="11"></td>
</tr>
<tr class="even">
<td rowspan="2">Regurgitation</td>
<td colspan="2"></td>
<td colspan="2">N<sub>d</sub> = 15</td>
<td colspan="2">N<sub>d</sub> = 66</td>
<td colspan="2">N<sub>d</sub> = 29</td>
<td colspan="2"></td>
</tr>
<tr class="odd">
<td></td>
<td></td>
<td>n</td>
<td>% (n/N<sub>d</sub>)</td>
<td>n</td>
<td>% (n/N<sub>d</sub>)</td>
<td>N</td>
<td>% (n/N<sub>d</sub>)</td>
<td></td>
<td></td>
</tr>
<tr class="even">
<td><ul>
<li><p>0</p></li>
</ul></td>
<td></td>
<td></td>
<td>11</td>
<td>73.3%</td>
<td>53</td>
<td>80.3%</td>
<td>23</td>
<td>79.3%</td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td><ul>
<li><p>1-2+</p></li>
</ul></td>
<td></td>
<td></td>
<td>3</td>
<td>20.0%</td>
<td>11</td>
<td>16.7%</td>
<td>6</td>
<td>20.7%</td>
<td></td>
<td></td>
</tr>
<tr class="even">
<td><ul>
<li><p>3+</p></li>
</ul></td>
<td></td>
<td></td>
<td>1</td>
<td>6.7%</td>
<td>1</td>
<td>1.5%</td>
<td>0</td>
<td>0.0%</td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td><ul>
<li><p>4+</p></li>
</ul></td>
<td></td>
<td></td>
<td>0</td>
<td>0.0%</td>
<td>0</td>
<td>0.0%</td>
<td>0</td>
<td>0.0%</td>
<td></td>
<td></td>
</tr>
<tr class="even">
<td><ul>
<li><p>Not available</p></li>
</ul></td>
<td></td>
<td></td>
<td>0</td>
<td>0.0%</td>
<td>1</td>
<td>1.5%</td>
<td>0</td>
<td>0.0%</td>
<td></td>
<td></td>
</tr>
</tbody>
</table>

> Notes:

1.  Hemodynamic evaluations were performed using transthoracic
    echocardiography (TEE) and in some cases, transesophageal
    echocardiography (TEE). Data does not include results from double
    valve replacement.

2.  N~f~ = number of patients followed (reproduced from Figure 2).

3.  Mean gradient represents the pressure drop measured across the valve
    in mmHg.

4.  N~d~ = number of patients for which hemodynamic data were collected.

5.  EOA = effective orifice area measured in cm^2^~.~

6.  Regurgitation represents the valvular backflow of blood due to
    normal leakage and perivalvular leakage; 0 = none, 1+ = mild, 2+ =
    moderate, 3+ = moderate/severe, 4+ = severe.

7.  n = number of patients in each category.

## Description of Patients and Analysis for Gender Bias

In the mitral On-X^^ Prosthetic Heart Valve clinical trial the patients
were 37.6 % male (86/229). The gender distribution is consistent with
its incidence within the heart valve replacement population. No patient
selection bias based on gender could be identified. An analysis of
outcomes, including adverse event rates and NYHA changes, for gender
differences showed no significant differences due to gender; thus, no
gender bias was found.

# CONCLUSIONS drawn from the studies

The results from pre-clinical laboratory studies performed on the
On-X^®^ Prosthetic Heart Valve for biocompatibility, hydrodynamic
performance, and structural integrity demonstrate that this device is
suitable for long-term implant.

The animal studies show that the On-X^®^ Prosthetic Heart Valve is safe
for valve replacement.

The clinical studies submitted in the PMA application provide scientific
evidence that the On-X^®^ Prosthetic Heart Valve is safe and effective
for the replacement of native or prosthetic mitral valves.

# Panel Recommendations

In accordance with the provisions of section 515(c)(2) of the act as
amended by the Safe Medical Devices Act of 1990, this PMA application
was not referred to the Circulatory Systems Device Panel, an FDA
advisory committee, for review and recommendation because the
information in the PMA substantially duplicates information previously
reviewed by this panel.

# FDA DECISION

FDA issued an approval order on [March 6, 2002]{.underline}.

The applicant's manufacturing and control facilities were inspected on
10/12/00 (TX) and 11/21/00 (Germany), and the facilities were found to
be in compliance with the Quality Systems Regulation (Part 820).

# Approval Specifications

Directions for use: See final labeling (Instructions for Use).

Hazards to Health from Use of the Device: See Indications,
Contraindications, Warnings, Precautions, and Adverse Events in the
final labeling (Instructions for Use).

Post-approval Requirements and Restrictions: See Approval Order.