← Product Code LWQ · P000037

# ON-X (R) PROSTHETIC HEART VALVE, MODEL ONXA (P000037)

_On-X Life Technologies, Inc. · LWQ · May 30, 2001 · Cardiovascular · APPR_

**Canonical URL:** https://fda.innolitics.com/device/P000037

## Device Facts

- **Applicant:** On-X Life Technologies, Inc.
- **Product Code:** LWQ
- **Decision Date:** May 30, 2001
- **Decision:** APPR
- **Device Class:** Class 3
- **Review Panel:** Cardiovascular
- **Attributes:** Therapeutic

## Intended Use

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

## Device Story

Bileaflet mechanical heart valve; consists of orifice housing two leaflets. Orifice features flared inlet to reduce turbulence; outflow rim includes leaflet guards. Leaflets rotate on tabs within orifice ring; 40° closed angle, 90° open angle. Orifice and leaflets composed of On-X® Carbon (pure pyrolytic carbon) on graphite substrate; leaflets impregnated with 10% tungsten for radiopacity. Sewing cuff made of PTFE fabric with titanium retaining rings; allows in situ rotation during implantation. Implanted in aortic position by cardiac surgeons. Functions as passive mechanical valve; regulates blood flow direction. Benefits patients by restoring valvular function in cases of stenosis or insufficiency. Requires lifelong anticoagulation therapy.

## Clinical Evidence

Prospective, non-randomized clinical study of 184 patients (mean age 60.2 years) undergoing isolated aortic valve replacement. Mean follow-up 2.2 years (411.8 patient-years). Primary endpoints: safety (adverse events, mortality) and effectiveness (NYHA classification, echocardiographic hemodynamic assessment). Results: 98.8% freedom from valve-related mortality at 3 years; 93.9% freedom from thromboembolism at 3 years. NYHA class improved postoperatively (e.g., 72.7% in Class I at 2 years). Hemodynamic data showed mean gradients ranging from 3.7 to 9.7 mmHg depending on valve size and follow-up interval.

## Technological Characteristics

Bileaflet mechanical valve. Materials: On-X® Carbon (pyrolytic carbon), graphite substrate, tungsten (radiopacity), PTFE fabric (sewing cuff), Ti6Al4V ELI titanium (retaining rings, ASTM F136). Sizes: 19, 21, 23, 25, 27/29 mm. Sterilization: Moist heat (steam). Standards: ISO 10993 (biocompatibility), ISO 5840 (cardiac implants), EN 554/556 (sterility), EN ISO 9001/46001 (quality systems).

## Submission Summary (Full Text)

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# Summary of Safety and Effectiveness Data
## On-X® Prosthetic Heart Valve, Model ONXA

## Table of Contents

1. GENERAL INFORMATION... 2
2. INDICATIONS FOR USE... 2
3. DEVICE DESCRIPTION... 2
4. CONTRAINDICATIONS... 3
5. WARNINGS AND PRECAUTIONS... 3
5.1 WARNINGS... 3
5.2 PRECAUTIONS... 4
6. ALTERNATIVE PRACTICES AND PROCEDURES... 4
7. MARKETING HISTORY... 4
8. ADVERSE EVENTS... 4
8.1 OBSERVED ADVERSE EVENTS... 4
8.2 POTENTIAL ADVERSE EVENTS... 5
9. SUMMARY OF NONCLINICAL STUDIES... 6
9.1 IN VITRO STUDIES... 6
9.1.1 Hydrodynamics and Flow Visualization... 6
9.1.2 Durability and Lifetime Analysis... 7
9.2 ANIMAL STUDIES... 9
9.3 BIOCOMPATIBILITY... 9
9.4 MAGNETIC RESONANCE IMAGING (MRI) COMPATIBILITY... 11
9.5 SHELF LIFE AND STERILITY... 11
10. SUMMARY OF CLINICAL STUDIES... 11
10.1 DESCRIPTION OF PATIENTS AND ANALYSIS FOR GENDER BIAS... 16
11. CONCLUSIONS DRAWN FROM THE STUDIES... 16
12. PANEL RECOMMENDATIONS... 16
13. FDA DECISION... 16
14. APPROVAL SPECIFICATIONS... 16

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# Summary of Safety and Effectiveness Data
## On-X® Prosthetic Heart Valve, Model ONXA

![img-0.jpeg](img-0.jpeg)
Figure 1. On-X® Prosthetic Heart Valve

## 1. GENERAL INFORMATION

Device Generic Name: Replacement Heart Valve

Device Trade Name: On-X® Prosthetic Heart Valve
Model: ONXA, sizes 19, 21, 23, 25, and 27/29 mm

Applicant’s Name and Address: Medical Carbon Research Institute, LLC
(MCRI™)
8200 Cameron Road, A-196
Austin, Texas 78754

PMA Application Number: P000037

Date of Notice of Approval to the Applicant: MAY 30 2001

## 2. 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 aortic position.

## 3. 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 40° 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.

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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 aortic sizes 19, 21, 23, 25, and 27/29 mm. Valve sizes 19 mm through 25 mm are designed for supra-annular implantation, while the valve size 27/29 mm is designed for intra-annular implantation.

## 4. CONTRAINDICATIONS

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

## 5. WARNINGS AND PRECAUTIONS

### 5.1 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;
- 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;
- 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.

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## 5.2 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.

## 6. 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.

## 7. 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, 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.

## 8. ADVERSE EVENTS

A total of 184 aortic On-X® Prosthetic Heart Valves were implanted in 184 patients at 11 centers. The mean follow-up was 2.2 years (range of 0 to 4.0 years) with a total of 411.8 patient-years.

A total of 7 deaths occurred during the study and 2 of these were characterized as valve-related. The causes of the valve-related deaths were early thromboembolism (1 patient) and sudden, unexplained death (1 patient).

### 8.1 Observed Adverse Events

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

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Table 1: Observed Adverse Event Rates¹
All patients implanted, N = 184, Cumulative follow-up = 411.8 patient-years

|  Complication | Early Events |   | Late Events² |   | Freedom from Event³, % [SE]  |   |
| --- | --- | --- | --- | --- | --- | --- |
|   |  n | % (n/N)⁴ | n | %/pt-yr | 1 Year Postoperative (n=138) | 3 Year Postoperative (n=37)  |
|  Mortality (all) | 4 | 2.2% | 3 | 0.7% | 97.8% [1.1] | 96.0% [1.5]  |
|  Mortality (valve-related) | 1 | 0.5% | 1 | 0.2% | 99.4% [0.5] | 98.8% [0.9]  |
|  Endocarditis | 0 | 0.0% | 2 | 0.5% | 99.4% [0.6] | 98.9% [0.8]  |
|  Explant | 1 | 0.5% | 2 | 0.5% | 98.4% [0.9] | 97.8% [1.1]  |
|  Hemolysis⁵ | 0 | 0.0% | 0 | 0.0% | 100.0% [0] | 100.0% [0]  |
|  Hemorrhage⁶ (all) | 1 | 0.5% | 3 | 0.7% | 99.4% [0.5] | 97.3% [1.4]  |
|  Hemorrhage (major) | 1 | 0.5% | 1 | 0.2% | 100.0% [0] | 99.1% [0.9]  |
|  Perivalvular Leak (all) | 4 | 2.2% | 3 | 0.7% | 96.7% [1.3] | 96.7% [1.3]  |
|  Perivalvular Leak (major) | 1 | 0.5% | 0 | 0.0% | 100.0% [0] | 100.0% [0]  |
|  Nonstructural Valve Dysfunction | 0 | 0.0% | 0 | 0.0% | 100.0% [0] | 100.0% [0]  |
|  Reoperation (valve-related) | 2 | 1.1% | 3 | 0.7% | 97.8% [1.1] | 97.2% [1.2]  |
|  Structural Valve Dysfunction | 0 | 0.0% | 0 | 0.0% | 100.0% [0] | 100.0% [0]  |
|  Thromboembolism | 1 | 0.5% | 7 | 1.7% | 97.8% [1.1] | 93.9% [2.5]  |
|  Thrombosis | 0 | 0.0% | 0 | 0.0% | 100.0% [0] | 100.0% [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 69% AVR patients at 1-year, and all other analytes within normal range.
6. The anticoagulant agents used were reported. The target International Normalized Ratio was 2.5 to 3.5.

## 8.2 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

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It is possible that these complications could lead to:

- reoperation
- explantation
- permanent disability
- death

## 9. 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

## 9.1 IN VITRO STUDIES

### 9.1.1 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.

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Table 3 – Hydrodynamic Performance Testing and Results

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

## 9.1.2 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.

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Table 4 – Structural Performance Testing and Results

|  Test | Sample Size: Control | Sample Size: On-X® Prosthetic Heart Valve | Results  |
| --- | --- | --- | --- |
|  Fracture mechanics of materials | N/A | On-X® Carbon on graphite
On-X® Carbon solid | K_{IC} = 2.46 MPa-m^{1/2}, ΔK_{th} = 1.24 MPa-m^{1/2}, m = 40.2, log C = -14.6
K_{IC} = 1.67 MPa-m^{1/2}, ΔK_{th} = 1.11 MPa-m^{1/2}, m = 70.3, log C = -14.4
Worst-case properties used for fatigue life calculations.  |
|  Accelerated durability testing | 2 of 23 mm, 1 each of 27 and 29 mm | 5 each 19, 21, 23, 25, 27/29 mm | All valves survived cycling 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 impact factor | N/A | 25 mm dynamic model and test valve | Impact factor of 2.0, predicted from FEA model, was confirmed by strain gage measurements during pulse duplicator testing at 200 mmHg peak systolic pressure.  |
|  Physiological stresses | N/A | Finite element model of 19, 21, 23, 25 mm | FEA results and impact factor combined to result in worst-case stress of 3040 psi used in fatigue lifetime calculations.  |
|  Fatigue life | N/A | 19, 21, 23, 25 mm | Paris law 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 failure mode | N/A | 3 each 19, 21, 23, 25 mm | Minimum static load to failure was 94 psi. Failure mode was spalled sockets and shattered leaflets.  |
|  Dynamic failure mode | 1 of 27 mm | 3 each 25 mm after wear test | Cycle to 30 psi without failure. Failure of valve by leaflet shatter at 72 psi for On-X®. Control failed by housing fracture at 67 psi.  |

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|  Test | Sample Size: Control | Sample Size: On-X® Prosthetic Heart Valve | Results  |
| --- | --- | --- | --- |
|  Cavitation potential | 2 of 27 mm
3 of 29 mm | 3 each 25 mm | The dp/dt at threshold was higher for the On-X® than the control.  |
|  Sewing ring integrity
Tear out | 1 of size 29 mm | 3 each 19, 21, 23, 25 mm aortic | Suture broke most of the time, minimum tear out 11.7 lbs, control tear out at 10.5 lbs.  |
|  Sewing ring integrity
Push off | N/A | 3 each 19, 21, 23, 25 | Minimum push off force 111 N, over 7 times physiologic force.  |
|  Load deflection tests
Bind
Escape | N/A | 3 each 25 mm | Minimum to bind – 20N without sewing ring, 28N with sewing ring
Minimum to escape – 110N.  |
|  Valve sounds
Clinical study | 13 (2 of 21 mm, 5 of 23 mm, 4 of 25 mm, 2 of 27 mm) | 11 (1 of 19 mm, 2 of 21 mm, 3 of 23 mm, 3 of 25 mm, 2 of 27/29 mm) | No differences in perceived sounds were found between valves.  |

## 9.2 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.

## 9.3 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.

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Table 5 – Biocompatibility Studies Results Summary

|  Test | Objective | Sample: Control | Sample: Test Article | Results  |
| --- | --- | --- | --- | --- |
|  Cytotoxicity L-929 Membrane Elution | To determine the biological reactivity of a cell culture to an extract of the test article | Negative control: silicone rubber
Positive control: natural rubber | On-X® Carbon | Non-cytotoxic  |
|  Hemolysis | To assess the hemolytic activity of the test article | Negative control: water for injection
Positive control: 0.9% saline | On-X® Carbon | Non-hemolytic at 0% hemolysis  |
|  Physicochemical tests to USP | To determine physical and chemical properties of extracts | Negative control: water for injection
Positive control: N/A | On-X® Carbon | Passed USP physicochemical tests for plastics  |
|  Ames mutagenicity test | To assess the mutagenic potential of the test article | Negative control: 0.9% NaCl
Positive controls: 2-aminoanthracene, sodium azide, 2-nitrofluorene, 9-aminoacridene | On-X® Carbon | Non-mutagenic  |
|  Intracutaneous injection | To assess toxic effects of extracts of the test article | Negative control: 0.9% NaCl, cottonseed oil
Positive control: N/A | On-X® Carbon | Negligible irritant  |
|  Systemic injection | To assess the systemic toxic effect of extracts of the test article | Negative control: 0.9% NaCl, cottonseed oil
Positive control: N/A | On-X® Carbon | Negative, non-toxic  |
|  Rabbit pyrogen | To determine the presence of chemical pyrogens on finished components | Negative control: 0.9% NaCl
Positive control: N/A | On-X® Carbon | Non-pyrogenic  |
|  Klingman sensitization | To evaluate the allergenic potential of test articles | Negative control: 0.9% NaCl, cottonseed oil
Positive control: dinitrochlorobenzene | On-X® Carbon | 0% sensitization: Grade I reaction  |
|  Cytotoxicity L-929 Membrane Elution | To determine the biological reactivity of a cell culture to an extract of the test article | Negative control: MEM extractant
Positive control: Known toxic material | PTFE yarn
PTFE yarn with surgical marker | Non-cytotoxic  |

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|  Test | Objective | Sample: Control | Sample: Test Article | Results  |
| --- | --- | --- | --- | --- |
|  Hemolysis | To assess the hemolytic activity of the test article | Negative control: water for injection
Positive control: 0.9% saline | PTFE yarn | Non-hemolytic  |
|  Intracutaneous injection | To assess toxic effects of extracts of the test article | Negative control: 0.9% NaCl, cottonseed oil
Positive control: N/A | PTFE yarn | Negligible irritant  |
|  Systemic injection | To assess the systemic toxic effect of extracts of the test article | Negative control: 0.9% NaCl, cottonseed oil
Positive control: N/A | PTFE yarn | Negative, non-toxic  |
|  Rabbit implantation (1 and 4 weeks) | To assess the effects of implantation of the test article | Negative control: USP strips
Positive control: N/A | PTFE yarn | Macroscopic: non-significant
Microscopic: slight irritant  |

## 9.4 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.

## 9.5 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.

## 10. SUMMARY OF CLINICAL STUDIES

The On-X® Prosthetic Heart Valve clinical trials were designed to study the safety and effectiveness of the valve in aortic valve replacement. Patients requiring isolated aortic heart valve replacement were enrolled from September 12, 1996 to December 1999 at 11 European centers in a prospective, non-randomized study with retrospective controls.

The cohort included 184 patients (121 men, 63 women), aged from 20 to 80 years (mean of 60.2 years). The cumulative follow-up was 411.8 patient-years with a mean follow-up of 2.2 years (SD = 0.8 years, range = 0 to 4.0 years). Tables 2 and 3 present preoperative and operative patient demographics. Figure 2 shows the number of patients implanted versus

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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 preoperatively, 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 = 184, Cumulative follow-up = 411.8 patient-years

|  Patient Characteristic |   |   | n | % (n/N)^{1}  |
| --- | --- | --- | --- | --- |
|  Age at implant in years |   |   | 60.2 ± 8.4  |   |
|  Gender: | • | Male | 121 | 65.8%  |
|   |  • | Female | 63 | 34.2%  |
|  NYHA Classification: | • | I | 9 | 4.9%  |
|   |  • | II | 91 | 49.5%  |
|   |  • | III | 79 | 42.9%  |
|   |  • | IV | 5 | 2.7%  |
|   |  • | Unknown | 0 | 0.0%  |
|  Valve Lesion: | • | Stenosis | 86 | 46.7%  |
|   |  • | Insufficiency | 39 | 21.2%  |
|   |  • | Mixed | 59 | 32.1%  |
|   |  • | Other | 0 | 0%  |

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

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Table 3: Operative Patient Demographics
All patients implanted, N = 184, Cumulative follow-up = 411.8 patient-years

|  Variable | Category^{1} | n | % (n/N)^{2}  |
| --- | --- | --- | --- |
|  Etiology^{3} | Calcific | 92 | 50.0%  |
|   |  Degenerative | 51 | 27.7%  |
|   |  Rheumatic | 24 | 13.0%  |
|   |  Congenital | 18 | 9.8%  |
|   |  Endocarditis | 8 | 4.4%  |
|   |  Prosthetic Valve Dysfunction | 0 | 0.0%  |
|   |  Other | 6 | 3.3%  |
|  Concomitant Procedures^{3} | None | 141 | 76.7%  |
|   |  Coronary Artery Bypass Graft | 21 | 11.4%  |
|   |  Myotomy | 10 | 5.4%  |
|   |  Mitral Repair | 5 | 2.7%  |
|   |  Aorta Repair or Replacement | 4 | 2.2%  |
|   |  Tricuspid Repair | 1 | 0.5%  |
|   |  Muscle Bridge | 1 | 0.5%  |
|   |  Tricuspid Replacement | 0 | 0.0%  |
|   |  Explant of Annuloplasty Ring | 0 | 0.0%  |
|   |  Maze Procedure | 0 | 0.0%  |
|   |  Closure of Atrial Appendage | 0 | 0.0%  |
|   |  Ventricular Aneurysm Repair | 0 | 0.0%  |
|   |  Other | 0 | 0.0%  |
|  Pre-existing Conditions^{3} | Systemic Hypertension | 90 | 48.9%  |
|   |  Hyperlipidemia | 83 | 45.1%  |
|   |  Angina | 42 | 22.8%  |
|   |  Coronary Artery Disease | 42 | 22.8%  |
|   |  Diabetes Mellitus | 33 | 17.9%  |
|   |  Atrial Arrhythmias | 25 | 13.6%  |
|   |  Left Ventricular Dysfunction | 23 | 12.5%  |
|   |  Congestive Heart Failure | 22 | 12.0%  |
|   |  Myocardial Infarction | 12 | 6.5%  |
|   |  Cerebrovascular Accident | 10 | 5.4%  |
|   |  Carotid Artery Disease | 7 | 3.8%  |
|   |  Endocarditis | 4 | 2.2%  |
|   |  Cardiomyopathy | 3 | 1.6%  |
|   |  Pacemaker Implant | 2 | 1.1%  |
|   |  Coronary Artery Bypass Graft | 1 | 0.5%  |
|   |  Previous Aortic Valve Replacement | 1 | 0.5%  |
|   |  Previous Mitral Valve Replacement | 0 | 0.0%  |
|  Other | 27 | 14.8%  |   |
|  Valve Size | 19 mm | 17 | 9.2%  |
|   |  21 mm | 35 | 19.0%  |
|   |  23 mm | 70 | 38.0%  |
|   |  25 mm | 38 | 20.6%  |
|   |  27/29 mm | 24 | 13.0%  |

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.

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All patients implanted, $N = 184$, Cumulative follow-up = 411.8 patient-years

![img-1.jpeg](img-1.jpeg)

Figure 2: Patient Follow-up Over Time

Table 4: Number of Patients Implanted and Number of Patient-years by Valve Size
All patients implanted, $N = 184$, Cumulative follow-up = 411.8 patient-years

|   | Numbers by Valve size  |   |   |   |   |   |
| --- | --- | --- | --- | --- | --- | --- |
|   |  19 mm | 21 mm | 23 mm | 25 mm | 27/29 mm | Total  |
|  Number of Patients Implanted | 17 | 35 | 70 | 38 | 24 | 184  |
|  Number of Patient-years | 36.9 | 82.2 | 151.5 | 85.9 | 55.3 | 411.8  |

All patients implanted, $N = 184$, Cumulative follow-up = 411.8 patient-years

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

|  NYHA Class | Preoperative Assessment (N_{d} = 184) | Postoperative Assessments  |   |   |   |   |   |   |
| --- | --- | --- | --- | --- | --- | --- | --- | --- |
|   |   |   |  1 Year (10-14 Months) (N_{f} = 138, N_{d} = 129)^{2} |   | 2 Year (22-26 Months) (N_{f} = 66, N_{d} = 66) |   | 3 Year (34-38 Months) (N_{f} = 37, N_{d} = 36)  |   |
|   |  n^{3} | % (n/N_{d}) | n | % (n/N_{d}) | n | % (n/N_{d}) | N | % (n/N_{d})  |
|  I | 9 | 4.9 | 83 | 60.1 | 48 | 72.7 | 20 | 54.0  |
|  II | 91 | 49.5 | 35 | 25.4 | 12 | 18.2 | 10 | 27.0  |
|  III | 79 | 42.9 | 4 | 2.9 | 6 | 9.1 | 4 | 10.8  |
|  IV | 5 | 2.7 | 0 | 0 | 0 | 0 | 0 | 0  |
|  Undetermined^{4} | 0 | 0 | 7 | 5.1 | 0 | 0 | 2 | 5.4  |
|  Missing^{5} | 0 | 0 | 9 | 6.5 | 0 | 0 | 1 | 2.7  |

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, $N_{d}$.

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Table 6: Effectiveness Outcomes, Hemodynamic Results¹
All patients implanted, N = 184, Cumulative follow-up = 411.8 patient-years

|  Hemodynamic Parameter | Results by Valve Size  |   |   |   |   |   |
| --- | --- | --- | --- | --- | --- | --- |
|   |  19 mm | 21 mm | 23 mm | 25 mm | 27/29 mm |   |
|  Mean Gradient² | Nd² = 20 | Nd = 31 | Nd = 58 | Nd = 33 | Nd = 20 |   |
|  Mean ± SD | 11.6 ± 4.5 | 9.4 ± 3.6 | 8.4 ± 4.3 | 7.5 ± 3.8 | 6.1 ± 2.9 |   |
|  Min, max | 5.6, 21.5 | 4.0, 18.4 | 2.0, 26.4 | 2.1, 18.6 | 1.0, 11.5 |   |
|  |   |   |   |   |   |   |
|  EOA³ | Nd = 19 | Nd = 31 | Nd = 57 | Nd = 33 | Nd = 20 |   |
|  Mean ± SD | 1.4 ± 0.2 | 1.8 ± 0.3 | 2.1 ± 0.5 | 2.5 ± 0.8 | 2.8 ± 0.4 |   |
|  Min, max | 1.1, 1.9 | 1.3, 2.4 | 1.0, 3.6 | 0.9, 4.3 | 1.9, 3.5 |   |
|  |   |   |   |   |   |   |
|  Regurgitation⁴ | Nd = 22 | Nd = 40 | Nd = 72 | Nd = 38 | Nd = 24 |   |
|   |  n¹ % (n/Nd) | n % (n/Nd) | n % (n/Nd) | n % (n/Nd) | n % (n/Nd) |   |
|  0 | 9 40.9% | 14 35.0% | 31 43.1% | 19 50.0% | 9 37.5% |   |
|  1-2+ | 12 54.6% | 25 62.5% | 37 51.4% | 19 50.0% | 13 54.2% |   |
|  3+ | 0 10.0% | 0 0.0% | 2 2.8% | 0 0.0% | 0 0.0% |   |
|  4+ | 0 0.0% | 0 0.0% | 0 0.0% | 0 0.0% | 0 0.0% |   |
|  Not available | 1 4.6% | 1 2.5% | 2 2.8% | 0 0.0% | 2 8.3% |   |
|  ¹ Year Postoperation, Nf = 138  |   |   |   |   |   |   |
|  Mean Gradient | Nd = 13 | Nd = 22 | Nd = 55 | Nd = 24 | Nd = 16 |   |
|  Mean ± SD | 9.7 ± 2.6 | 7.7 ± 2.8 | 6.6 ± 3.0 | 3.7 ± 2.2 | 5.6 ± 2.9 |   |
|  Min, max | 5.7, 14.3 | 3.1, 15.2 | 2.0, 16.0 | 0.5, 11.3 | 1.0, 10.8 |   |
|  |   |   |   |   |   |   |
|  EOA | Nd = 13 | Nd = 22 | Nd = 54 | Nd = 25 | Nd = 16 |   |
|  Mean ± SD | 1.4 ± 0.3 | 1.9 ± 0.4 | 2.3 ± 0.6 | 2.8 ± 0.8 | 2.8 ± 0.6 |   |
|  Min, max | 0.9, 1.8 | 1.2, 2.9 | 1.0, 4.1 | 0.8, 4.2 | 2.0, 4.1 |   |
|  |   |   |   |   |   |   |
|  Regurgitation | Nd = 16 | Nd = 28 | Nd = 60 | Nd = 30 | Nd = 21 |   |
|   |  n % (n/Nd) | n % (n/Nd) | n % (n/Nd) | n % (n/Nd) | n % (n/Nd) |   |
|  0 | 4 25.0% | 6 21.4% | 24 40.0% | 12 40.0% | 5 23.8% |   |
|  1-2+ | 11 68.8% | 21 75.0% | 33 55.0% | 16 53.3% | 15 71.4% |   |
|  3+ | 0 0.0% | 0 0.0% | 2 3.3% | 2 6.7% | 1 4.8% |   |
|  4+ | 0 0.0% | 0 0.0% | 0 0.0% | 0 0.0% | 0 0.0% |   |
|  Not available | 1 6.2% | 1 3.6% | 1 1.7% | 0 0.0% | 0 0.0% |   |
|  ² Year Postoperation, Nf = 101 (total of 2 yr (65) and 3 yr (37) follow-up)  |   |   |   |   |   |   |
|  Mean Gradient | Nd = 17 | Nd = 29 | Nd = 61 | Nd = 30 | Nd = 18 |   |
|  Mean ± SD | 9.0 ± 3.2 | 8.1 ± 3.2 | 6.6 ± 3.1 | 4.2 ± 2.5 | 5.5 ± 3.0 |   |
|  Min, max | 2.2, 14.3 | 3.5, 16.6 | 2.0, 14.1 | 0.8, 12.8 | 1.0, 10.8 |   |
|  |   |   |   |   |   |   |
|  EOA | Nd = 17 | Nd = 29 | Nd = 60 | Nd = 31 | Nd = 18 |   |
|  Mean ± SD | 1.5 ± 0.2 | 1.8 ± 0.5 | 2.3 ± 0.7 | 2.7 ± 0.8 | 2.9 ± 0.8 |   |
|  Min, max | 0.9, 1.9 | 0.7, 2.9 | 1.4, 4.7 | 0.8, 4.2 | 2.0, 4.3 |   |
|  |   |   |   |   |   |   |
|  Regurgitation | Nd = 20 | Nd = 37 | Nd = 68 | Nd = 36 | Nd = 25 |   |
|   |  n % (n/Nd) | n % (n/Nd) | n % (n/Nd) | n % (n/Nd) | n % (n/Nd) |   |
|  0 | 5 25.0% | 9 24.3% | 27 39.7% | 17 47.2% | 7 28.0% |   |
|  1-2+ | 12 60.0% | 25 67.6% | 37 54.4% | 16 44.4% | 17 68.0% |   |
|  3+ | 2 10.0% | 0 0.0% | 3 4.4% | 2 5.6% | 1 4.0% |   |
|  4+ | 0 0.0% | 0 0.0% | 0 0.0% | 1 2.8% | 0 0.0% |   |
|  Not available | 1 5.0% | 3 8.1% | 1 1.5% | 0 0.0% | 0 0.0% |   |

Notes:
1. Hemodynamic evaluations were performed using transthoracic echocardiography (TEE) and in some cases, transesophageal echocardiography (TEE). Data does include results from double valve replacement.
2. Nf = number of patients followed (reproduced from Figure 2).
3. Mean gradient represents the pressure drop measured across the valve in mmHg.
4. Nd = number of patients for which hemodynamic data were collected.
5. EOA = effective orifice area measured in cm².
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.

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# 10.1 Description of Patients and Analysis for Gender Bias

In the aortic On-X® Prosthetic Heart Valve clinical trial the patients were 65.8% male (121/184). Also all seventeen 19mm valves were placed in females, while only 1 of 24 size 27/29mm valves were placed in females. The gender distribution is consistent with its incidence within the heart valve replacement population, and the implanted size shift is consistent with the difference in physical size of the male and female populations. 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.

# 11. 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 aortic valves.

# 12. 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.

# 13. FDA DECISION

FDA issued an approval order on MAY 30 2001

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).

# 14. APPROVAL SPECIFICATIONS

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

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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.

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**Source:** [https://fda.innolitics.com/device/P000037](https://fda.innolitics.com/device/P000037)

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