AVALUS(TM) BIOPROSTHESIS

P170006 · Medtronic, Inc. · LWR · Jul 31, 2017 · Cardiovascular

Device Facts

• Record ID: P170006
• Device Name: AVALUS(TM) BIOPROSTHESIS
• Applicant: Medtronic, Inc.
• Product Code: LWR · Cardiovascular
• Decision Date: Jul 31, 2017
• Decision: APPR
• Device Class: Class 3
• Attributes: Therapeutic

Intended Use

The Avalus™ bioprosthesis is indicated for the replacement of diseased, damaged, or malfunctioning native or prosthetic aortic valves.

Device Story

Avalus Bioprosthesis is a stented, trileaflet bovine pericardial tissue valve for surgical aortic valve replacement. Leaflets are laser-cut and treated with alpha oleic acid (AOA) to mitigate calcification; mounted on a PEEK base frame with a polyester sewing ring for supra-annular seating. Implanted by surgeons in an OR setting. Disposable valve holder and sizers facilitate implantation. Device functions as a passive mechanical replacement for native or prosthetic valves, restoring hemodynamic flow. Clinical benefit includes improved aortic valve hemodynamics and NYHA functional classification. Healthcare providers assess valve function post-operatively via echocardiography. Device is MR safe.

Clinical Evidence

Prospective, non-randomized, multi-center global PERIGON trial (IDE G140056) with 864 implanted patients. Primary endpoints: valve-related adverse events (thromboembolism, thrombosis, hemorrhage, paravalvular leak, endocarditis) compared to ISO 5840:2009 Objective Performance Criteria (OPC), and effectiveness via NYHA class and echocardiographic hemodynamics (mean gradient, EOA). Results: 75.1% of patients improved by ≥1 NYHA class at 1 year. Hemodynamic performance consistent with literature controls. Most safety endpoints met OPC; hemorrhage rates exceeded 2x OPC but were attributed to anticoagulant/antiplatelet therapy rather than device design.

Technological Characteristics

Stented bovine pericardial tissue valve; trileaflet configuration. Base frame and support frame constructed of PEEK. Polyester sewing ring. Treated with alpha oleic acid (AOA) for antimineralization. Sizes: 19, 21, 23, 25, 27 mm. Sterilized via glutaraldehyde solution. MR safe. No electronic components or software.

Indications for Use

Indicated for patients requiring replacement of diseased, damaged, or malfunctioning native or prosthetic aortic valves. No specific age or gender restrictions; contraindications include active endocarditis, myocarditis, systemic infection, or specific anatomical/comorbid conditions increasing surgical risk.

Reference Devices

• Edwards Perimount Magna Ease

Submission Summary (Full Text)

{0}

SUMMARY OF SAFETY AND EFFECTIVENESS DATA (SSED)

I. GENERAL INFORMATION

Device Generic Name: Replacement Heart Valve, Aortic

Device Trade Name: Avalus™ Bioprosthesis, Model 400

Device Procode: LWR

Applicant’s Name and Address: Medtronic, Inc.
1851 E. Deere Avenue
Santa Ana, CA 92705

Date(s) of Panel Recommendation: None

Premarket Approval Application (PMA) Number: P170006

Date of FDA Notice of Approval: July 31, 2017

II. INDICATIONS FOR USE

The Avalus™ bioprosthesis is indicated for the replacement of diseased, damaged, or malfunctioning native or prosthetic aortic valves.

III. CONTRAINDICATIONS

There are no known contraindications.

IV. WARNINGS AND PRECAUTIONS

The warnings and precautions can be found in the Avalus bioprosthesis labeling.

V. DEVICE DESCRIPTION

The Avalus bioprosthesis (Figure 1) is a stented bovine pericardial tissue valve intended to replace diseased, damaged or malfunctioning native or prosthetic aortic valves via surgical implantation. The valve is manufactured by suturing valve leaflets, made from laser cut bovine pericardial tissue, into a trileaflet configuration within a polyetheretherketone (PEEK) base frame and trileaflet support frame. A polyester sewing ring is integrated into the inflow aspect of the base frame cover to allow for suturing and seating of the valve in the supra-annular position.

PMA P170006: FDA Summary of Safety and Effectiveness Data

{1}

Figure 1: Avalus Bioprosthesis

The Avalus bioprosthesis is processed with alpha oleic acid (AOATM), which is an antimineralization treatment that has been shown to mitigate leaflet calcification in animal studies. A disposable valve holder (Figure 2) is attached to the outflow of the valve to facilitate implantation.

Figure 2: Avalus Valve Holder

The disposable holder is designed to fit the reusable Valve Handle, Model 7420 (Figure 3), and features a single cut point to remove the holder from the valve. Double ended sizers (Figure 4) are used to select the appropriate valve size. The barrel end represents the valve orifice while the replica end imitates the prosthesis geometry.

Figure 3: Avalus Valve Handle, Model 7420
Figure 4: Avalus Sizer, Model 7400S

PMA P170006: FDA Summary of Safety and Effectiveness Data

{2}

The Avalus bioprosthesis (Model 400) is available in sizes 19, 21, 23, 25, and 27 mm. For further details, refer to the Avalus Bioprosthesis Instructions for Use.

## VI. ALTERNATIVE PRACTICES AND PROCEDURES

There are several other alternatives for the correction of diseased, damaged, or malfunctioning aortic heart valves. Alternative treatments include palliative medical therapy, aortic balloon valvuloplasty (opening the narrowed aortic valve with a balloon catheter), aortic valve repair, transcatheter aortic valve replacement, treatment with homografts, and surgical replacement with another commercially available mechanical or bioprosthetic valve. Each alternative has its own advantages and disadvantages. A patient should fully discuss these alternatives with his/her physician to select the method that best meets expectations and lifestyle.

## VII. MARKETING HISTORY

The Avalus bioprosthesis has not been marketed in the United States or any foreign country.

## VIII. POTENTIAL ADVERSE EFFECTS OF THE DEVICE ON HEALTH

Below is a list of the potential adverse effects (e.g., complications) associated with the use of the device.

- Angina
- Cardiac dysrhythmias
- Endocarditis
- Heart failure
- Hemolysis
- Hemolytic anemia
- Hemorrhage
- Infection other than endocarditis
- Leak, transvalvular or paravalvular
- Myocardial infarction
- Nonstructural valve dysfunction (leaflet entrapment/impingement, obstructive pannus ingrowth, suture dehiscence, inappropriate sizing or positioning, or other)
- Pericardial effusion or tamponade
- Prosthesis regurgitation
- Prosthesis stenosis
- Prosthesis thrombosis
- Stroke
- Structural valve deterioration (calcification, leaflet tear or perforation, or other)
- Thromboembolism
- Tissue dehiscence
- Transient ischemic attack

PMA P170006: FDA Summary of Safety and Effectiveness Data
Page 3

{3}

These complications could lead to:

Reoperation
- Explant of the bioprosthesis
Permanent disability
Death

For the specific adverse events that occurred in the clinical study, please see Section X below.

## IX. SUMMARY OF NONCLINICAL STUDIES

## A. Laboratory Studies

### 1. Biocompatibility

Biocompatibility evaluations were completed on the Avalus bioprosthesis in accordance with ISO 10993-1:2009/AC:2010, Biological Evaluation of Medical Devices Part 1: Evaluation and testing within a risk management process, and FDA's General Program Memorandum No. G95-1, Use of International Standard ISO-10993, "Biological Evaluation of Medical Devices Part 1: Evaluation and Testing." The required testing for each component was determined based on the nature and duration of body contact in accordance with ISO 10993-1:2009/AC:2010. Test articles consisted of the patient-contacting device components after exposure to all manufacturing processes, including sterilization. The biocompatibility test results for the Avalus bioprosthesis are summarized in Table 1.

Table 1. Summary of Avalos Bioprosthesis Biocompatibility Testing

| Biological Effect per ISO 10993-1 | Test Method | Results |
| --- | --- | --- |
| Cytotoxicity | Colony Assay | Pass |
| Sensitization | ISO Guinea Pig Maximization Sensitization | Pass |
| Irritation or Intracutaneous Reactivity | Intracutaneous Irritation in Rabbits | Pass |
| Systemic Toxicity | Acute Systemic Toxicity in Mice | Pass |
| | USP Material Mediated Pyrogen | Pass |
| Genotoxicity | Ames Bacterial Reverse Mutation | Pass |
| | Chromosomal Aberration in Chinese Hamster Ovary (CHO) Cells | Pass |
| | Mouse Peripheral Blood Micronucleus Study | Pass |
| Implantation | 4 weeks - ISO Muscle Implantation Study in Rabbit | Pass |
| | 13 Weeks - Systemic Toxicity in Rats Following Subcutaneous Implantation | Pass |
| Hemocompatibility | In vitro Hemolysis (Indirect) | Pass |
| | In vitro Hemolysis (Direct Method) | Pass |
| | Partial Thromboplastin Time | Pass |
| | Complement Activation (C3a/SC5b-9) | Pass |

PMA P170006: FDA Summary of Safety and Effectiveness Data

{4}

# 2. Hydrodynamic Performance

A comprehensive in vitro testing program was completed in accordance with EN ISO 5840:2009, Cardiovascular implants – Cardiac valve prostheses. Hydrodynamic performance testing results are provided in Table 2.

Table 2: Summary of Avalos Hydrodynamic Performance Testing

| Test | Test Description | Test/Reference Articles | Results |
| --- | --- | --- | --- |
| Pulsatile Forward Flow | This test evaluated the pressure gradients and effective orifice area of the Avalus bioprosthesis under pulsatile flow conditions. | Test: Avalos, all sizes Reference: Edwards Perimount Magna Ease sizes 19, 23, 29 mm | The Avalos bioprosthesis demonstrated hydrodynamic results comparable to the reference valve and met the minimum effective orifice area required by ISO 5840:2009. |
| Pulsatile Back Pressure | This test provided information about the regurgitant volumes of the Avalus bioprosthesis under pulsatile flow conditions. | Test: Avalos, all sizes Reference: Edwards Perimount Magna Ease sizes 19, 23, 29 mm | The Avalos bioprosthesis showed acceptable hydrodynamic results, comparable to those of the reference valve, and did not exceed the regurgitant fractions specified in ISO 5840:2009. |
| Dynamic Regurgitation | This test characterized the regurgitant volume of the Avalus bioprosthesis under pulsatile flow conditions at various beats per minute. | Test: Avalos, all sizes Reference: Edwards Perimount Magna Ease sizes 19, 23, 29 mm | The total regurgitant volumes for all sizes showed a decrease with increase in beat rate. Varying back pressure had minimal to no impact on the regurtitant volumes for all sizes. |
| Leaflet Kinematic Characterization | This test was performed to provide qualitative information about the Avalos bioprosthesis leaflet function during valve opening and closing under pulsatile flow conditions. | Test: Avalos, all sizes Reference: Edwards Perimount Magna Ease sizes 19, 23, 29 mm | All valves exhibited synchronicity in leaflet closure, with full opening and closing. |
| Flow Visualization Characterization | This test provided information about the flow characteristics of the Avalos bioprosthesis under pulsatile conditions. | Test: Avalos, smallest size Reference: N/A | The Avalos bioprosthesis demonstrated acceptable flow characteristics. The flow profile was symmetric and centered and flow exited the valve in |
| | | | the flow of the valve. |

PMA P170006: FDA Summary of Safety and Effectiveness Data

{5}

PMA P170006: FDA Summary of Safety and Effectiveness Data
Page 6

## 3. Structural Performance, Material Property, and Device Specific Testing

Structural performance, material property, and device specific testing was performed on the Avalus bioprosthesis in accordance with EN ISO 5840:2009 and is summarized in Table 3.

Table 3. Summary of Avalos Bioprosthesis Structural Performance

| Test | Test Description | Test/Reference Articles | Results |
| --- | --- | --- | --- |
| Structural Performance Testing | | | |
| Accelerated Wear Testing | This test assessed the structural longevity of the Avalos bioprosthesis over simulated conditions out to 200M cycles (equates to five-year lifetime). | Test: Avalos, smallest, medium, and largest sizes
Reference: Edwards Perimount Magna Ease sizes 19, 23, 29 mm | All valves survived durability testing to 200 million cycles in accelerated wear testers without functional impairment. At the completion of 200 million cycles, all valves met the effective orifice area and regurgitation fraction requirements of ISO 5840:2009. |
| Dynamic Failure Mode | This test applied increasing pressure loading to determine the ultimate failure | Test: Avalos, largest size | All test valve failures occurred |

{6}

| Test | Test Description | Test/Reference Articles | Results |
| --- | --- | --- | --- |
| | mode(s) of the Avalus bioprosthesis. | Reference: N/A | at pressures well above those expected in vivo. |
| Sewing Ring Integrity | This test evaluated the structural integrity and attachment strength of the sewing ring to the covered stent under static loading conditions. | Test: Avalus, smallest, medium, and largest sizes Reference: N/A | All test samples met the device specification for ultimate attachment strength. |
| Finite Element Analysis | This test characterized the maximum principal stress of the trileaflet support frame and base models using a finite element analysis model. | Test: All Avalus sizes were included in the analysis Reference: N/A | The findings of the stress analysis provide confidence that the structural components of the Avalus bioprosthesis are durable for their intended use. |
| Stent Post Deflection | This test provided information about the in vitro deflections for each commissure post of the Avalus bioprosthesis as a function of applied backpressure. | Test: Avalus, all sizes Reference: N/A | The test results showed that commissure post deflection increases directly with the valve size and differential pressure. |
| Stent Fatigue Testing | This test evaluated commissure post fatigue of the PEEK stent. | Test: Avalus, largest size Reference: N/A | No loss of structural integrity was observed in any of the frames at the completion of 600 million cycles. |
| Material Property Testing | | | |
| Stent Mechanical and Creep Characterization | This test characterized the mechanical properties of the PEEK material used in the trileaflet support frame and base component. | Test: PEEK specimens Reference: N/A | The PEEK material properties were within expectations. |
| Tissue Mechanical Properties | This test characterized the uniaxial tensile properties of bovine pericardium with respect to tissue orientation. | Test: Fixed bovine pericardium samples Reference: N/A | Testing indicated that bovine pericardial tissue is anisotropic in nature. |
| Absorption Study | This test characterized PEEK water absorption rate in an aqueous solution. | Test: PEEK specimens | The PEEK material |

PMA P170006: FDA Summary of Safety and Effectiveness Data

{7}

| Test | Test Description | Test/Reference Articles | Results |
| --- | --- | --- | --- |
| | | Reference: N/A | properties were within expectations. |
| Device Specific Testing | | | |
| Magnetic Resonance Imaging (MRI) | The purpose of this test is to evaluate the safety and compatibility of the device in conjunction with the use of MRI. | Test: N/A
Reference: N/A | Because the Avalus bioprosthesis does not contain metal and poses no known hazards in an MR environment, it was determined to be MR safe on the basis of scientific rationale. |
| Dimensional Verification | This test verified the final dimensional specifications of the Avalus bioprosthesis. | Test: Avalus, all sizes
Reference: N/A | All valve sizes met the dimensional specifications. |
| Human Factors Validation | This test validated that the usability of the Avalus bioprosthesis and its accessories was acceptable to qualified, trained, and experienced physicians. | Test: Avalus, all sizes
Reference:N/A | The Avalus bioprosthesis showed generally very good performance and there were no surgical errors observed that would result in issues with patient safety. |

## B. Animal Studies

Two preclinical in vivo studies (90-day and 150-day) were performed to support the safety of the Avalus bioprosthesis. The studies evaluated the Avalus bioprosthesis compared to a Carpentier-Edwards PERIMOUNT Magna Ease control valve. A total of 10 test articles and four (4) control articles were implanted for 90 days, and a total of 11 test articles and four (4) control articles were implanted for 150 days. In both studies, the valves were implanted in the aortic position in an adult sheep model to most accurately simulate the human anatomy and physiology. The hemodynamic performance and valve related pathology characteristics observed in the test group (Avalus valve) were assessed in a chronic setting and compared with the same characteristics in the control group (Carpentier-Edwards PERIMOUNT Magna Ease

PMA P170006: FDA Summary of Safety and Effectiveness Data

{8}

valve). As demonstrated through the results, the test articles met all the following acceptance criteria:

- Survival at 90 days and at 150 days with mortality rates consistent with literature and historic experience with the sheep model.
- Blood chemistry within normal ranges.
- Pathological findings were comparable to the control device within the normal variation seen in the sheep model.
- Hemodynamic changes over time were comparable to the control device, consistent with the variation in pathologic findings.

## C. Additional Studies

### 1. Sterilization

The Avalus bioprosthesis is sterilized by liquid chemical sterilization in a glutaraldehyde solution. The sterilization process involves incubation of the valve in sterilant solution at an elevated temperature for a defined period of time. This process has been validated to a Sterility Assurance Level (SAL) of $10^{-6}$.

### 2. Packaging and Shelf Life

The Avalus bioprosthesis is packaged in a glass jar filled with glutaraldehyde solution. The glass jar is placed in a shelf carton with a temperature indicator to identify products exposed to transient temperature extremes. The accessory components are packaged and marketed separately from the Avalus bioprosthesis.

The shelf life of the Avalus bioprosthesis is 1.5 years as demonstrated by functional product integrity testing on real-time aged samples and package integrity testing on accelerated-aged samples.

## X. SUMMARY OF PRIMARY CLINICAL STUDY

The applicant performed a clinical study to establish a reasonable assurance of safety and effectiveness of aortic heart valve replacement with the Avalus bioprosthesis in the US, Canada, and Europe under IDE # G140056. Data from this clinical study were the basis for the PMA approval decision. A summary of the clinical study is presented below.

### A. Study Design

Patients were treated between May 12, 2014 and September 7, 2016. The database for this PMA reflected data collected through October 31, 2016 and included 962 patients. There were 36 investigational sites.

The Pericardial Surgical Aortic Valve Replacement (PERIGON) Trial was a prospective, non-randomized, multi-center, global trial for the Avalus bioprosthesis

PMA P170006: FDA Summary of Safety and Effectiveness Data
Page 9

{9}

implanted in patients requiring native or prosthetic aortic valve replacement. The design and analysis of this study was based on adverse event rates as compared to a set of established Objective Performance Criteria (OPC) and to literature-based control data. New York Heart Association (NYHA) functional classification status and hemodynamic performance of the valve by echocardiography were evaluated using a comparison to literature-based control data. The study utilized an independent Data Safety Monitoring Board (DSMB), a Clinical Events Committee (CEC) that was responsible for adjudicating adverse events, and an echocardiography core laboratory.

## 1. Clinical Inclusion and Exclusion Criteria

Enrollment in the PERIGON study was limited to patients who met the following inclusion criteria:

- Patient has moderate or greater aortic stenosis or regurgitation, and there is clinical indication for replacement of their native or prosthetic aortic valve with a bioprosthesis, with or without concomitant procedures, which are limited to any of the following:
- LAA ligation
- CABG
- PFO closure
- Ascending aortic aneurysm or dissection repair not requiring circulatory arrest
- Resection of a sub-aortic membrane not requiring myectomy
- Patient is geographically stable and willing to return to the implanting site for all follow-up visits
- Patient is of legal age to provide informed consent in the country where they enroll in the trial
- Patient has been adequately informed of risks and requirements of the trial and is willing and able to provide informed consent for participation in the clinical trial

Patients were not permitted to enroll in the PERIGON study if they met any of the following exclusion criteria:

- Patient has a pre-existing prosthetic valve or annuloplasty device in another position or requires replacement or repair of the mitral, pulmonary, or tricuspid valve
- Patient has had previous implant and then explant of the Avalus Model 400 aortic valve bioprosthesis
- Patient presents with active endocarditis, active myocarditis, or other systemic infection
- Patient has an anatomical abnormality which would increase surgical risk of mobility or mortality, including:
- Ascending aortic aneurysm or dissection repair requiring circulatory arrest

PMA P170006: FDA Summary of Safety and Effectiveness Data
Page 10

{10}

- Acute Type A aortic dissection
- Ventricular aneurysm
- Porcelain aorta
- Hostile mediastinum
- Hypertrophic obstructive cardiomyopathy (HOCM)
- Documented pulmonary hypertension (systolic > 60 mmHg)

- Patient has a non-cardiac major or progressive disease, with a life expectancy of less than 2 years. These conditions include, but are not limited to:
- Child-Pugh Class C liver disease
- Terminal cancer
- End-stage lung disease

- Patient has renal failure, defined as dialysis therapy or GFR < 30 mL/min/1.73 m²
- Patient has hyperparathyroidism
- Patient is participating in another investigational device or drug trial or observational competitive study
- Patient is pregnant, lactating, or planning to become pregnant during the trial period
- Patient has a documented history of substance (drug or alcohol) abuse
- Patient has greater than mild mitral valve regurgitation or greater than mild tricuspid valve regurgitation as assessed by echocardiography
- Patient has systolic EF < 20% as assessed by echocardiography
- Patient has Grade IV Diastolic Dysfunction
- Patient has documented bleeding diatheses
- Patient has had an acute preoperative neurological deficit or myocardial infarction and has not returned to baseline or stabilized ≥ 30 days prior to enrollment
- Patient requires emergency surgery

2. Follow-up Schedule

All patients were scheduled to return for follow-up examinations at baseline, index procedure, discharge, 3-6 months, 1 year, and annually thereafter up to 5 years.

Preoperatively, demographic and baseline data were collected. Postoperatively, the objective parameters measured during the study included echocardiographic data and NYHA functional classification. Adverse events and complications were recorded at all visits.

The key timepoints are shown below in the tables summarizing safety and effectiveness.

PMA P170006: FDA Summary of Safety and Effectiveness Data
Page 11

{11}

PMA P170006: FDA Summary of Safety and Effectiveness Data
Page 12

3. Clinical Endpoints

With regards to safety, the study evaluated the time-related incidence of valve-related adverse events and death, including:

- Thromboembolism
- Thrombosis
- Hemorrhage (all and major)
- Paravalvular leak (all and major)
- Endocarditis
- Hemolysis
- Structural valve deterioration
- Non-structural dysfunction
- Reintervention
- Explant
- Death

With regards to effectiveness, the following criteria were evaluated:

- NYHA functional classification status
- Hemodynamic performance evaluated by echocardiography, including peak gradient, mean gradient, effective orifice area (EOA), effective orifice area index (EOAI), performance index, cardiac output, cardiac index, and valvular regurgitation (transvalvular, paravalvular, and total)

With regard to success/failure criteria, success was defined by comparing event rates with 2x the OPC values listed in ISO 5840:2009 as well as a comparison of literature controls from commercially available devices.

B. Accountability of PMA Cohort

At the time of database lock, of 962 patients enrolled in the PMA study, 89.8% (864) patients were implanted with the Avalus bioprosthesis and are available for analysis, and 904.1 total patient-years were collected (834.2 late patient-years). Twenty five (25) subjects were classified as attempted but not implanted and were not included in the main analysis. Subject follow-up compliance is detailed in Table 4.

Table 4. Subject Follow-up Compliance

| Visit interval | Number expected | Number evaluated % (n) | Censored^a |
| --- | --- | --- | --- |
| Baseline | 962 | 99.3% (955) | 0 |
| Procedure | 864 | 100.0% (864) | 98 |
| Discharge | 859 | 100.0% (859) | 5 |
| 3–6 Months | 821 | 99.0% (813) | 38 |
| 1 Year | 581 | 99.3% (577) | 240 |
| 2 Year | 101 | 99.0% (100) | 480 |

{12}

${}^{a}$ Censored includes visits due but not yet occurred,visits not yet due,death, explant, lost to follow-up (LTF), or withdrawn (by self or physician).

# C. Study Population Demographics and Baseline Parameters

The demographics of the study population are typical for a surgical aortic valve replacement study performed in the US. Baseline demographics and characteristics are shown in Table 5.

Table 5. Baseline demographics and characteristics

| Age at implant | N: Mean ± SD (min – max) |
| --- | --- |
| Age (years) | 864: 70.4 ± 8.9 (21.1 – 90.9) |
| Gender | % (n / N) |
| Female | 25.5% (220/864) |
| Male | 74.5% (644/864) |
| Body surface area | N: Mean ± SD (min – max) |
| BSA (m2) | 864: 2.0 ± 0.2 (1.4 – 2.9) |
| NYHA classification | % (n / N) |
| Class I | 11.3% (98/864) |
| Class II | 47.5% (410/864) |
| Class III | 39.6% (342/864) |
| Class IV | 1.6% (14/864) |
| STS risk scores | N: Mean ± SD (min – max) |
| STS risk of mortality | 864: 2.0 ± 1.4 (0.4 – 10.1) |
| STS risk of morbidity or mortality | 864: 14.8 ± 6.0 (5.6 – 48.7) |

# D. Safety and Effectiveness Results

# 1. Safety Results

The analysis of safety was based on the 864 patients that received the Avalus bioprosthesis over the course of 904.1 total patient-years. The key safety outcomes and adverse events for this study are presented below in Tables 6 and 7. Simple proportions are used to describe early event rates, linearized rates (%/patient-year) are presented for late events, and "freedom from event" at 1-year based on Kaplan-Meier analysis are provided based on all reported events both "early" and "late".

Table 6. Summary of observed adverse event rates

| Adverse events | Early eventsa | | | Late eventsb | | | Freedom from eventc at 1 Year (95% CI)d n = 577 |
| --- | --- | --- | --- | --- | --- | --- | --- |
| | Number of events | Number of subjects | Early event rate | Number of events | Number of subjects | Linearized late event ratee | |
| All-cause mortality | 10 | 10 | 1.2% | 28 | 28 | 3.4% | 96.4 (94.8,97.5) |
| Valve-related mortality | 0 | 0 | 0.0% | 4 | 4 | 0.5% | 99.7 (98.6,99.9) |
| Thromboembolism | 12 | 11 | 1.4% | 14 | 14 | 1.7% | 97.2 (95.7,98.1) |

PMA P170006: FDA Summary of Safety and Effectiveness Data

{13}

The results of the PERIGON study were compared to the OPC as described in Table R.1 in EN ISO 5840:2009, Annex R.1. Thromboembolism, valve thrombosis, all and major paravalvular leak, and endocarditis met the OPC. The OPC for all and major hemorrhage were not met; however, all of the hemorrhage events were anticoagulant- and/or antiplatelet-related and did not indicate a direct relation to the Avalus bioprosthesis.

Table 7. Late linearized event rates compared to objective performance criteria (OPC)

| Adverse event | Late linearized event ratea(%) LPYb= 834.2 | Number of events | Number of subjects | 95% Upper confidence boundc of late linearized rate | 2x OPCd (%/patient-year) |
| --- | --- | --- | --- | --- | --- |
| Thromboembolism | 1.7% | 14 | 14 | 2.55% | 5.0% |
| Valve thrombosis | 0.0% | 0 | 0 | 0.00% | 0.4% |
| All hemorrhage | 3.6% | 30 | 28 | 4.81% | 2.8% |
| Major hemorrhage | 2.5% | 21 | 19 | 3.55% | 1.8% |
| All paravalvular leak | 0.6% | 5 | 5 | 1.18% | 2.4% |

PMA P170006: FDA Summary of Safety and Effectiveness Data

{14}

PMA P170006: FDA Summary of Safety and Effectiveness Data
Page 15

| Major paravalvular leak | 0.0% | 0 | 0 | 0.00% | 1.2% |
| --- | --- | --- | --- | --- | --- |
| Endocarditis | 1.3% | 11 | 11 | 2.11% | 2.4% |
| a Late linearized event rate calculated by number of events/LPY, expressed as a percentage.
b LPY = Late patient-years. LPY are calculated from post-implant day 31 through last point of contact.
c Upper confidence bound calculated by Greenwood formula.
d OPC = Objective performance criteria for tissue valves, as described in Table R.1 of EN ISO 5840:2009, Annex R.1. | | | | | |

# 2. Effectiveness Results

The analysis of effectiveness was based on the 864 patients that received the Avalus bioprosthesis over the course of 904.1 total patient-years. Key effectiveness outcomes are presented in Tables 8 to 12.

Table 8. New York Heart Association (NYHA) classification

| NYHA classification | Baseline (N = 864) | 1 Year (N = 577) | 2 Year (N = 100) |
| --- | --- | --- | --- |
| I | 11.3% (98/864) | 73.4% (423/576) | 67.0% (67/100) |
| II | 47.5% (410/864) | 22.4% (129/576) | 29.0% (29/100) |
| III | 39.6% (342/864) | 3.5% (20/576) | 4.0% (4/100) |
| IV | 1.6% (14/864) | 0.2% (1/576) | 0.0% (0/100) |
| Not done | 0.0% (0/864) | 0.5% (3/576) | 0.0% (0/100) |

Table 9. Change in NYHA classification from baseline

| NYHA classification | 1 Year (N = 577) | 2 Year (N = 100) |
| --- | --- | --- |
| Improved 3 class | 1.4% (8/573) | 0.0% (0/100) |
| Improved 2 class | 24.8% (142/573) | 26.0% (26/100) |
| Improved 1 class | 48.9% (280/573) | 48.0% (48/100) |
| No change | 23.2% (133/573) | 24.0% (24/100) |
| Worsened 1 class | 1.7% (10/573) | 2.0% (2/100) |
| Worsened 2 class | 0.0% (0/573) | 0.0% (0/100) |
| Worsened 3 class | 0.0% (0/573) | 0.0% (0/100) |

Mean gradient and effective orifice area (EOA) at 1-year follow-up are presented in Table 10, and transvalvular and paravalvular regurgitation at 1-year are presented in Tables 11 and 12, respectively.

Table 10. Hemodynamic Results at 1-Year

| Parameter | 19 mm Mean ± SD (n#) | 21 mm Mean ± SD (n#) | 23 mm Mean ± SD (n#) | 25 mm Mean ± SD (n#) | 27 mm Mean ± SD (n#) |
| --- | --- | --- | --- | --- | --- |
| Mean gradient (mmHg) | 17.1 ± 5.0 (27) | 14.5 ± 4.3 (106) | 12.1 ± 3.8 (205) | 11.7 ± 4.0 (170) | 10.3 ± 4.2 (43) |
| EOA (cm2) | 1.11 ± 0.25 (25) | 1.25 ± 0.25 (99) | 1.47 ± 0.32 (201) | 1.57 ± 0.31 (167) | 1.77 ± 0.41 (41) |
| a n represents the number of subjects with evaluable data. | | | | | |

{15}

Table 11. Transvalvular Aortic Regurgitation

| Visits | 19mm % (n/N^{a}) | 21mm % (n/N^{a}) | 23mm % (n/N^{a}) | 25mm % (n/N^{a}) | 27mm % (n/N^{a}) | All Sizes % (n/N^{a}) |
| --- | --- | --- | --- | --- | --- | --- |
| 1 Year | | | | | | |
| None | 70.4% (19/27) | 74.1% (80/108) | 87.9% (181/206) | 91.9% (158/172) | 93.0% (40/43) | 86.0% (478/556) |
| Trace | 22.2% (6/27) | 17.6% (19/108) | 8.7% (18/206) | 4.7% (8/172) | 7.0% (3/43) | 9.7% (54/556) |
| Mild | 7.4% (2/27) | 5.6% (6/108) | 2.4% (5/206) | 2.9% (5/172) | 0.0% (0/43) | 3.2% (18/556) |
| Moderate | 0.0% (0/27) | 0.0% (0/108) | 0.0% (0/206) | 0.0% (0/172) | 0.0% (0/43) | 0.0% (0/556) |
| Severe | 0.0% (0/27) | 0.0% (0/108) | 0.0% (0/206) | 0.6% (1/172) | 0.0% (0/43) | 0.2% (1/556) |
| Not evaluable | 0.0% (0/27) | 2.8% (3/108) | 1.0% (2/206) | 0.0% (0/172) | 0.0% (0/43) | 0.9% (5/556) |
| a n represents the number of subjects with evaluable data. N represents the number of subjects with data whose echo was performed. | | | | | | |

Table 12. Paravalvular Aortic Regurgitation

| Visits | 19mm % (n/N^{a}) | 21mm % (n/N^{a}) | 23mm % (n/N^{a}) | 25mm % (n/N^{a}) | 27mm % (n/N^{a}) | All Sizes % (n/N^{a}) |
| --- | --- | --- | --- | --- | --- | --- |
| 1 Year | | | | | | |
| None | 96.3% (26/27) | 89.8% (97/108) | 92.7% (191/206) | 93.0% (160/172) | 93.0% (40/43) | 92.4% (514/556) |
| Trace | 3.7% (1/27) | 6.5% (7/108) | 4.4% (9/206) | 1.2% (2/172) | 2.3% (1/43) | 3.6% (20/556) |
| Mild | 0.0% (0/27) | 0.9% (1/108) | 1.9% (4/206) | 4.7% (8/172) | 2.3% (1/43) | 2.5% (14/556) |
| Moderate | 0.0% (0/27) | 0.0% (0/108) | 0.0% (0/206) | 1.2% (2/172) | 2.3% (1/43) | 0.5% (3/556) |
| Severe | 0.0% (0/27) | 0.0% (0/108) | 0.0% (0/206) | 0.0% (0/172) | 0.0% (0/43) | 0.0% (0/556) |
| Not Evaluable | 0.0% (0/27) | 2.8% (3/108) | 1.0% (2/206) | 0.0% (0/172) | 0.0% (0/43) | 0.9% (5/556) |
| a n represents the number of subjects with evaluable data. N represents the number of subjects with data whose echo was performed. | | | | | | |

3. Subgroup Analyses

Gender was evaluated for potential association with outcomes. Analysis was performed on the 864 subjects who were successfully implanted in order to assess potential differences between genders that may be relevant to the clinical evaluation of the Avalos bioprosthesis. Among the 864 subjects implanted, 74.5% were male and 25.5% were female. The PERIGON trial was not designed nor powered to study safety and effectiveness differences between genders, so this analysis is considered exploratory without definitive conclusions.

Safety endpoints stratified by gender are listed in Table 13.

PMA P170006: FDA Summary of Safety and Effectiveness Data

{16}

Table 13. Death and Valve-Related Endpoints by Gender

| | Male (N = 644) | | Female (N = 220) | |
| --- | --- | --- | --- | --- |
| Events | # of events (# of subjects) | 1 Year KM Event Rate (95% CI) | # of events (# of subjects) | 1 Year KM Event Rate (95% CI) |
| All Death | 27 (27) | 3.2% (1.9,4.9) | 11 (11) | 4.8% (2.3,8.5) |
| Valve-related Death | 4 (4) | 0.5% (0.1,1.6) | 0 (0) | 0.0% (NA) |
| Thromboembolism | 22 (20) | 3.1% (1.9,4.8) | 4 (4) | 2.0% (0.7,4.8) |
| Valve Thrombosis | 0 (0) | 0.0% (NA) | 0 (0) | 0.0% (NA) |
| All Hemorrhage | 36 (32) | 5.3% (3.6,7.5) | 8 (8) | 3.7% (1.6,7.2) |
| Major Hemorrhage | 25 (22) | 3.5% (2.2,5.3) | 4 (4) | 2.0% (0.7,4.8) |
| All Paravalvular Leak | 6 (6) | 0.8% (0.3,1.9) | 1 (1) | 0.5% (0.0,2.4) |
| Major Paravalvular Leak | 1 (1) | 0.2% (0.0,0.8) | 0 (0) | 0.0% (NA) |
| Endocarditis | 11 (11) | 1.4% (0.6,2.8) | 2 (2) | 1.1% (0.2,3.5) |
| Clinically Significant Hemolysis | 0 (0) | 0.0% (NA) | 0 (0) | 0.0% (NA) |
| Non-structural Valve Dysfunction | 6 (6) | 0.8% (0.3,1.9) | 1 (1) | 0.5% (0.0,2.4) |
| Structural Valve Deterioration | 0 (0) | 0.0% (NA) | 0 (0) | 0.0% (NA) |
| Reintervention | 7 (7) | 0.9% (0.4,2.1) | 2 (2) | 1.1% (0.2,3.6) |
| Explant | 7 (7) | 0.9% (0.4,2.1) | 2 (2) | 1.1% (0.2,3.6) |

Effectiveness endpoints were compared for both males and females. The two (2) groups exhibited a clinically significant improvement in NYHA classification at all time points.

Table 14. NYHA Classification By Gender

| NYHA Classification | I / II | | III / IV | |
| --- | --- | --- | --- | --- |
| Interval / Gender | Male %(n/Na) | Female %(n/Na) | Male %(n/Na) | Female %(n/Na) |
| Discharge up to 30 days | 90.0% (439/488) | 89.6% (155/173) | 10.0% (49/488) | 10.4% (18/173) |
| 3-6 Months | 97.5% (584/599) | 96.0% (194/202) | 2.5% (15/599) | 4.0% (8/202) |
| 1 Year | 97.1% (408/420) | 94.1% (144/153) | 2.9% (12/420) | 5.9% (9/153) |
| 2 Year | 97.3% (72/74) | 92.3% (24/26) | 2.7% (2/74) | 7.7% (2/26) |
| aN is the number of subjects with available data at each visit. | | | | |

The comparisons of safety and effectiveness data support the conclusion that the results of the overall study can be applied equally well to males and females.

PMA P170006: FDA Summary of Safety and Effectiveness Data

{17}

PMA P170006: FDA Summary of Safety and Effectiveness Data
Page 18

4. Pediatric Extrapolation

In this premarket application, existing clinical data was not leveraged to support approval of a pediatric patient population.

E. Financial Disclosure

The Financial Disclosure by Clinical Investigators regulation (21 CFR 54) requires applicants who submit a marketing application to include certain information concerning the compensation to, and financial interests and arrangement of, any clinical investigator conducting clinical studies covered by the regulation. The pivotal clinical study included 318 investigators of which none were full-time or part-time employees of the sponsor and 5 had disclosable financial interests/arrangements as defined in 21 CFR 54.2(a), (b), (c) and (f) and described below:

- Compensation to the investigator for conducting the study where the value could be influenced by the outcome of the study: none
- Significant payment of other sorts: 5
- Proprietary interest in the product tested held by the investigator: none
- Significant equity interest held by investigator in sponsor of covered study: none

The applicant has adequately disclosed the financial interest/arrangements with clinical investigators. Statistical analyses were conducted by FDA to determine whether the financial interests/arrangements had any impact on the clinical study outcome. The information provided does not raise any questions about the reliability of the data.

XI. PANEL MEETING RECOMMENDATION AND FDA'S POST-PANEL ACTION

In accordance with the provisions of section 515(c)(3) of the act as amended by the Safe Medical Devices Act of 1990, this PMA 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.

XII. CONCLUSIONS DRAWN FROM PRECLINICAL AND CLINICAL STUDIES

A. Effectiveness Conclusions

In the clinical study, the analysis of effectiveness is based on NYHA functional classification and echocardiographic hemodynamic data at 1-year. The PERIGON study results demonstrate an improvement in NYHA classification by at least one class for 75.1% of patients at 1-year from baseline.

{18}

Echocardiographic results from the Core Lab indicate that mean effective orifice areas and mean gradients are consistent with the corresponding data in the literature-based control articles for the study. Furthermore, 95.7% of patients had either no or trace transvalvular regurgitation at 1-year, and 96.1% of patients had either no or trace paravalvular regurgitation at 1-year. These results indicate acceptable hemodynamic performance of the Avalus valve. In all, the study results provide a reasonable assurance that the Avalus valve is effective for its intended use.

## B. Safety Conclusions

The risks of the device are based on nonclinical laboratory and animal studies, as well as data collected in a clinical study conducted to support PMA approval as described above. The results from the preclinical studies performed on the Avalus bioprosthesis for biocompatibility, hydrodynamic performance and structural integrity demonstrate that the device meets all specifications and is suitable for long-term implant. The animal studies performed in sheep further support the in vivo safety of the Avalus bioprosthesis.

The results of the PERIGON clinical study demonstrate that the adverse event rates for the major safety endpoints are lower than the established standard of twice the Objective Performance Criteria for a bioprosthetic valve, with the exception of all hemorrhage and major hemorrhage rates. In the PERIGON study, the upper 95% confidence limit for the late linearized rate for all hemorrhage was 4.81% and major hemorrhage was 3.55%, which exceed the criterion of twice the OPC (all hemorrhage: 2.8% and major hemorrhage: 1.8%). However, detailed analyses of the hemorrhage rates do not indicate a direct relation to the Avalus bioprosthesis. In all, the study results provide a reasonable assurance that the Avalus valve is safe in its intended use.

## C. Benefit-Risk Determination

The probable benefits of the device are based on data collected in a clinical study conducted to support PMA approval as described above. The probable benefits of the Avalus bioprosthesis include improved aortic valve hemodynamic performance and NYHA functional classification compared to baseline values. The risks associated with the Avalus bioprosthesis include complications such as valvular thrombosis, thromboembolism, paravalvular leak, endocarditis, structural valve deterioration, non-structural valve dysfunction, reoperation, explant, and death. However, these risks are similar to those observed with other surgical prosthetic aortic valves.

1. Patient Perspectives

This submission did not include specific information on patient perspectives for this device.

PMA P170006: FDA Summary of Safety and Effectiveness Data
Page 19

{19}

In conclusion, given the available information above, the data support that for replacement of diseased, damaged, or malfunctioning native or prosthetic aortic valves the probable benefits outweigh the probable risks.

## D. Overall Conclusions

The data in this application support the reasonable assurance of safety and effectiveness of this device when used in accordance with the indications for use. Preclinical and clinical studies provided in the PMA application demonstrate reasonable assurance that the Avalus bioprosthesis is safe and effective for replacement of diseased, damaged, or malfunctioning native or prosthetic aortic heart valves.

## XIII. CDRH DECISION

CDRH issued an approval order on July 31, 2017.

The applicant’s manufacturing facilities have been inspected and found to be in compliance with the device Quality System (QS) regulation (21 CFR 820).

## XIV. APPROVAL SPECIFICATIONS

Directions for use: See device labeling.

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

Post-approval Requirements and Restrictions: See approval order.

PMA P170006: FDA Summary of Safety and Effectiveness Data
Page 20