PERCEVAL SUTURELESS HEART VALVE

P150011 · Corcym S.r.l. · LWR · Jan 8, 2016 · Cardiovascular

Device Facts

• Record ID: P150011
• Device Name: PERCEVAL SUTURELESS HEART VALVE
• Applicant: Corcym S.r.l.
• Product Code: LWR · Cardiovascular
• Decision Date: Jan 8, 2016
• Decision: APPR
• Device Class: Class 3
• Attributes: Therapeutic

Intended Use

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

Device Story

Perceval Sutureless Heart Valve is a bioprosthetic aortic valve consisting of bovine pericardial tissue and a self-expandable Nitinol stent. Designed for open-heart surgery, the device replaces diseased native or malfunctioning prosthetic valves. The stent features a proximal inflow ring with a pericardial sealing collar and a distal outflow ring, connected by straight and sinusoidal elements for anchoring in the aortic root. The valve is supplied un-mounted; physicians use a dedicated Dual Holder and Dual Collapser to reduce the valve size for delivery. Post-implantation, a post-dilation catheter is used to ensure proper seating. The device is coated with Carbofilm™ for biocompatibility. By eliminating the need for traditional sutures, the device aims to reduce cross-clamp and pump times. Clinical outcomes include improved hemodynamic performance and NYHA functional status. The device is MR Conditional.

Clinical Evidence

PMA approval based on the prospective, multi-center, non-randomized CAVALIER study (N=658). Primary endpoints included safety (adverse event rates vs. Objective Performance Criteria) and effectiveness (hemodynamic performance, NYHA functional class improvement). Results showed 75.1% of patients improved by ≥1 NYHA class at 1-3 years. Hemodynamic data (mean gradients, EOA) were comparable to literature controls. Safety analysis indicated a higher risk of permanent pacemaker implantation compared to traditional sutured valves. Bench testing included ISO 5840 hydrodynamic and structural performance (200M cycle wear, 600M cycle fatigue), and biocompatibility per ISO 10993.

Technological Characteristics

Materials: Bovine pericardium (glutaraldehyde-stabilized), Nitinol stent, Carbofilm™ coating. Components: Inflow/outflow rings, sinusoidal anchoring elements. Dimensions: Sizes S, M, L, XL (19-27mm annulus). Energy: Mechanical (self-expanding). Connectivity: None. Sterilization: Terminal liquid glutaraldehyde (valve); Ethylene Oxide (accessories). Software: None.

Indications for Use

Indicated for patients ≥ 65 years requiring replacement of diseased, damaged, or malfunctioning native or prosthetic aortic valves. Contraindicated in patients with aneurysmal dilation or dissection of the ascending aortic wall, hypersensitivity to nickel or cobalt alloys, or anatomical characteristics outside specified annulus/sinotubular junction dimensions.

Submission Summary (Full Text)

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SUMMARY OF SAFETY AND EFFECTIVENESS DATA (SSED)

I. GENERAL INFORMATION

Device Generic Name: Replacement Heart Valve
Device Trade Name: Perceval Sutureless Heart Valve
Device Procode: LWR
Applicant's Name and Address: Sorin Group Canada Inc.
5005 North Fraser Way
Burnaby, British Columbia V5J 5M1
Canada
Date(s) of Panel Recommendation: None
Premarket Approval Application (PMA) Number: P150011
Date of FDA Notice of Approval: January 8, 2016

II. INDICATIONS FOR USE

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

III. CONTRAINDICATIONS

1. Aneurysmal dilation or dissection of the ascending aortic wall;
2. Known hypersensitivity to nickel or cobalt alloys;
3. Anatomical characteristics outside the specification given in Table 1.

Table 1. Patient anatomical characteristics
| REF | SIZE | AORTIC ANNULUS DIAMETER [A] (mm) | SINOTUBULAR JUNCTION DIAMETER [≤1.3 A] (mm) |
| --- | --- | --- | --- |
| PVS21 | S | 19-21 | ≤24.7-27.3 |
| PVS23 | M | 21-23 | ≤27.3-29.9 |
| PVS25 | L | 23-25 | ≤29.9-32.5 |
| PVS27 | XL | 25-27 | ≤32.5-35.1 |

IV. WARNINGS AND PRECAUTIONS

The warnings and precautions can be found in the Perceval Sutureless Heart Valve labeling.

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V. DEVICE DESCRIPTION

The Perceval Sutureless Heart Valve (Perceval Valve) is a bioprosthetic valve (Figure 1) designed to replace a diseased native or a malfunctioning prosthetic aortic valve via open heart surgery. The Perceval prosthesis consists of a tissue component made from bovine pericardium and a self-expandable Nitinol stent. The self-expanding stent frame along with a dedicated delivery system which allows physicians to position and anchor the valve suturelessly.

The stent has two cylindrical ring segments on the proximal (inflow ring) and distal (outflow ring) sides, and a double set of elements to connect the two rings. The first set comprises 3 straight elements (columns) to support the valve. The second set comprises 6 sinusoidal elements radially protruding from the cylindrical section to provide prosthetic anchorage to the aortic root in the sinus of Valsalva.

The inflow ring of the prosthesis has an external pericardial sealing collar encouraging adaptation to the aortic annulus. In correspondence with each valve sinus, this ring has three eyelets through which guide threads are passed to aid prosthesis positioning.

The Pericardial tissue component is stabilized by glutaraldehyde and consists of a pericardial tissue valve and a pericardial sealing collar. The tissue valve is produced from two sheets of bovine pericardium. The first sheet takes the form of the three valve leaflets, assembled in order to allow only one-way blood flow. The second sheet is the anchorage element between leaflets and stent. The tissue valve is set into the metal stent by overstitching the pericardium to the inflow ring around the full circumference and to the three columns.

The stent frame and threads used to assemble the bioprosthesis are coated with Carbofilm™, to create a thin and homogeneous layer of biocompatible high density turbostratic carbon.

The Perceval heart valve is supplied un-mounted. Prior to implantation, the physician loads the valve onto the Dual Holder by reducing the valve size using the polycarbonate Dual Collapser (Figure 1).

The Dual Holder is available for sternal approaches and includes a rigid shaft with an end section that houses the valve prosthesis during delivery. The holder is composed of PTFE, Delrin, Ultem, and stainless steel. The Dual MICS Holder is also available for minimally invasive procedures and is identical to the Dual Holder but is approximately 3 cm longer. The Dual Holder and Dual Collapsers each come in two sizes (S/M and L/XL) to cover the range of implant sizes.

After implantation, the physician uses the Post-dilation catheter to dilate the valve in-situ (Figure 1).

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Figure 1. Top Left: Perceval Sutureless Heart Valve, Top Right: Perceval Dual Collapser, Bottom Left: Perceval Dual Holder, Bottom Right: Perceval Post-dilation Catheter.

# VI. ALTERNATIVE PRACTICES AND PROCEDURES

There are several other alternatives for the correction of diseased and malfunctioning heart valves: drug therapy, annuloplasty, valvuloplasty (with or without the use of implantable materials). If patients require replacement of his or her native or previously implanted prosthetic valve, the alternatives include other commercially available mechanical valves or bioprosthetic valves, or a homograft. The choice of replacement valve depends on an assessment of patient factors which include age, preoperative condition, anatomy, and the patient's ability to tolerate long-term anticoagulant therapy. 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 Perceval Sutureless Heart Valve is currently marketed in more than 40 countries worldwide including: Austria, Belgium, Czech Republic, Denmark, Finland, France, Germany, Greece, Hungary, Israel, Italy, Poland, Portugal, Russia, Saudi Arabia, Slovenia, Spain, Sweden, Switzerland, The Netherlands, Turkey, United Kingdom.

The Perceval Sutureless Heart Valve has never been withdrawn from marketing for any reason related to its safety or effectiveness.

# VIII. POTENTIAL ADVERSE EFFECTS OF THE DEVICE ON HEALTH

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

- arrhythmias
- cardiac tamponade
- conduction system disturbances (e.g., atrioventricular node block, left-bundle branch block, asystole)
- death
- dislodgement or migration
- endocarditis
- heart failure (acute cardiac failure)
- hemolysis
- hemolytic anemia
- hemorrhage (bleeding)
- infection other than endocarditis
- myocardial infarction
- nonstructural valve dysfunction (e.g., entrapment by pannus or suture, inappropriate sizing or positioning, etc.)
- pericardial effusion
- paravalvular and transvalvular leakage
- prosthesis thrombosis
- stroke or any related neurologic disorders
- structural valve deterioration (SVD) (e.g., regurgitation, stenosis, leaflet tear or perforation, etc.)
- thromboembolism
- tissue dehiscence
- stenosis
- stent distortion due to thoracic compression (i.e., cardiopulmonary resuscitation) or trauma.

It is possible that these adverse events could lead to:

- reoperation
- explantation
- permanent disability
- permanent pacemaker implantation
- death

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

IX. SUMMARY OF PRECLINICAL STUDIES

A. Laboratory Studies

In vitro testing was performed for the Perceval valve in accordance with the ISO 5840:2005 standard "Cardiovascular Implants - Cardiac Valve Prostheses."

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# 1. Hydrodynamic Performance

In vitro hydrodynamic performance studies were completed on Perceval valve in accordance with the ISO 5840 standard "Cardiovascular Implants - Cardiac Valve Prosthesis."

Valves were evaluated after deployment in circular and non-circular annuli. Testing included steady flow pressure drop, steady backflow leakage, pulsatile flow pressure drop, pulsatile flow regurgitation, flow visualization and the verification of the Bernoulli relationship. For test articles deployed in circular annulus, commercially available aortic valve replacements were used as controls, while for articles deployed in irregular shape nominal deployed Perceval valves. For test articles deployed in circular annulus, commercially available aortic valve replacements were used as controls, while for articles deployed in irregular shape nominal deployed Perceval valves were used as controls. The characterization was conducted using both low compliant and high compliant chambers. A matrix of the tests performed and corresponding results are provided in Table 2.

Table 2. Hydrodynamic Performance Testing Summary

| Test | Purpose/Objective | Test/Reference articles | Results |
| --- | --- | --- | --- |
| Steady Forward Flow Pressure Drop | To determine the pressure drop at various steady forward flow rates | Nominal: Test: Size S, M, L and XL Reference: Size 21, 23, 25 and 27 Irregular: Test: Size S and XL Reference: Nominal Perceval size S and XL | Perceval prostheses have small pressure drops and high EOAs and performance indexes when compared to the reference valves. |
| Steady Backflow Leakage | To determine the leakage rate at various steady back flow pressures | Nominal: Test: Size S, M, L and XL Reference: Size 23, 25, 27 and 29 Irregular: Test: Size L and XL Reference: Nominal Perceval size L and XL | Perceval prostheses offer satisfactory performance in terms of its competency to prevent significant transvalvular aortic backflow during the diastolic phase. |
| Pulsatile Flow Pressure Drop | To determine pressure drop and effective orifice area performance under pulsatile flow conditions. | Nominal: Test: Size S, M, L and XL Reference: Size 21, 23, 25, 27 and 29 Irregular: Test: Size S and XL | The Perceval valve offers satisfactory hydrodynamics with a larger effective orifice area than those required by the ISO 5840:2005 acceptance criteria for aortic valves, and similar pressure drop to the reference valves. |

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| Test | Purpose/Objective | Test/Reference articles | Results |
| --- | --- | --- | --- |
| | | Reference: Nominal Perceval size S and XL | |
| Pulsatile Flow Regurgitation | To determine regurgitation performance under pulsatile flow conditions. | Nominal:
Test: Size S, M, L and XL
Reference: Size 23, 25, 27 and 29

Irregular:
Test: Size L and XL
Reference: Nominal Perceval size L and XL | The Perceval valve offers satisfactory hydrodynamics with regurgitant fractions that were lower than those required by the ISO 5840:2005 acceptance criteria for aortic valves. |
| Flow Visualization | To qualitatively investigate flow characteristics in the vicinity of the valve | Test: Size S in low and high compliant chamber | The Perceval valve offers satisfactory aortic flow patterns throughout the entire cardiac cycle.
Single broad jet covering the complete flow cross-section was observed.
No flow stasis during valve opening and no regurgitation during the diastolic phase were observed. |
| Verification of the Bernoulli Relationship | | Test: Size S, M, L and XL | Pressure drop results for the Perceval valve demonstrated correlation with the Bernoulli relationship |

## 2. Structural Performance

In-vitro structural performance studies were conducted on Perceval valve in accordance with the ISO 5840 standard “Cardiovascular Implants – Cardiac Valve Prosthesis.” Commercially available aortic valve replacements and self-expandable stents were used as controls. A matrix of tests performed and corresponding results are provided in Table 3.

Table 3. Structural Performance of the Perceval Valve

| Test | Purpose/Objective | Test/Reference articles | Results |
| --- | --- | --- | --- |
| Accelerated Wear | To assess long-term performance of the valve though accelerated wear | Nominal:
Test: Size S, M, L and XL
Reference: Size 21, 23, 25 and 27

Irregular:
Test: Size S, L and XL
Reference: Nominal Perceval | All valves survived durability testing to 200 million cycles in accelerated wear testers without structural damage and/or functional impairment.
After testing to 200 million cycles, all valves met the minimum EOA and Total Regurgitation Fraction requirements of ISO 5840:2005. |

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| Test | Purpose/Objective | Test/Reference articles | Results |
| --- | --- | --- | --- |
| | | size S, L and XL | |
| Dynamic Failure Mode | To obtain information about the failure modes affecting the durability of the valve. | Test: Size S, M, L and XL | All of the failures for the test valves occurred at pressures well beyond what would be experienced in vivo. |
| Stent corrosion resistance | To characterize the corrosion resistance of the valve stent in accordance with ASTM F2129, ISO 16429 and ISO 10993-15 | Test: Perceval stents size S, M, L and XL Reference: commercially available self-expandable stents | All test results have shown the good corrosion resistance and electrochemical stability of the Perceval stent. |
| Stent fatigue testing | To determine stent fatigue resistance to 600 million cycles | Perceval stents size S, M, L and XL | No frame cracks or fractures observed at completion of 600 million cycles both in air and saline solution |
| Strain analysis (FEA) | To characterize the mechanical behavior of the stent during collapsing, deployment and operation | Modeling based on in vitro and clinical data of size S, M, L and XL Perceval stents | Results indicate that the worst-case size L and XL Perceval stents should not fracture for 600 million cycles, even under the unlikely simultaneous combination of all the worst case conditions. |

The following additional structural performance studies were completed with acceptable results: Nitinol raw tube characterization, Nitinol as-processed characterization, fatigue life assessment, stent residual stress evaluation.

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3. Design Specific Performance Studies
The following design-specific *in vitro* performance studies of Perceval were completed with acceptable results: stent radial strength, valve migration force, stent column deflection, and radiopacity.

4. MRI Compatibility
Testing of this device in magnetic fields of 1.5 and 3.0 Tesla showed that the device is MR Conditional. Perceval can be scanned safely under the following conditions:
- Static magnetic field of 1.5 Tesla or 3 Tesla
- Spatial gradient field of 2500 Gauss/cm or less.
- Maximum whole-body-averaged specific absorption rate (SAR) of 4 W/kg in the First Level Controlled Mode for the MR system for 15 minutes of scanning.

5. Accessory Performance Testing
The following tests were performed with the Perceval Dual Holder and MICS Dual Holder and showed acceptable results: dimensional verification, visual inspection, simulated use, and bond strength.

The following tests were performed for the Perceval Post-dilation Catheter and MICS Post-dilation Catheter and showed acceptable results: dimensional verification, simulated use, balloon characterization, bond strength, and balloon compliance.

The following tests were performed for the Perceval Dual Collapser and showed acceptable results: dimensional verification, visual inspection, and simulated use.

6. Biocompatibility
The biological safety assessment of the Perceval valve and its accessories was conducted in accordance with the requirements of the ISO 10993 standard series “Biological Evaluation of Medical Devices.” Based on the results of the biocompatibility testing performed, the Perceval valve was determined to be biocompatible, non-mutagenic, and non-toxic. A summary of the testing conducted on the prosthetic valve and its accessories (i.e., the Dual Collapser, valve sizer kit, Dual Holder, and Post-Dilation Catheter for standard surgery and MICS) is provided in Table 4 and Table 5, respectively. Chemical characterization was performed in lieu of carcinogenicity testing and the characterization evaluations demonstrated that residuals did not require long-term studies.

Table 4. Summary of Biocompatibility Testing for the Perceval Valve Prosthesis
| Test | Objectives | Results |
| --- | --- | --- |
| Cytotoxicity | Assessment of test device toxicity on specific in vitro cell culture | Non-cytotoxic |
| Irritation (ISO Rabbit Intracutaneous Reactivity) | Evaluation of local irritation or toxic effects of leachable chemicals extracted from the test article following intra-cutaneous injection in rabbits | Non-irritant |

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Table 5. Summary of Biocompatibility Testing for Perceval Accessories (Dual Holder, Post-Dilation Catheter, Dual Collapser, and sizer kit)

| Test | Objectives | Results |
| --- | --- | --- |
| Cytotoxicity | Assessment of test device toxicity on specific in vitro cell culture for the accessories. | Non-cytotoxic |
| Intracutaneous reactivity (ISO Rabbit Intracutaneous Reactivity) | Evaluation of local irritation or toxic effects of leachable chemicals extracted from the test article following intra-cutaneous injection in rabbits | Non-irritant |
| Sensitization (ISO Guinea Pig Maximization Test) | Determination of the potential for contact sensitization by extracts of test device | No evidence of sensitization |

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| Test | Objectives | Results |
| --- | --- | --- |
| Acute Systemic Toxicity (ISO Mouse Systemic Injection) | Evaluation of acute systemic toxicity of leachable chemicals extracted from the test article following a single intravenous injection in mice | Non-toxic |
| Pyrogen Test (USP Rabbit Pyrogenicity) | Assessment of the potential febrile response from material mediated reaction occurring after intravenous injection of the test article in rabbits | Non-pyrogenic |
| LAL test | Determination of the presence of bacterial endotoxin | Free of bacterial endotoxin |
| Hemocompatibility | Assessment of the in vitro effects of the test article or its extract on blood properties, including hemolytic potential and alterations of the coagulation response | No alterations in blood properties |

1. Testing of the Dual Collapser was limited to cytotoxicity, sensitization, intracutaneous reactivity based on the limited contact with the patient.
2. Testing of the sizer kit was limited to cytotoxicity, sensitization, irritation, systemic toxicity, and material mediated pyrogenicity based on the level of patient contact.

## B. Animal Studies

One GLP chronic *in vivo* study in sheep and two non-GLP *in vivo* studies (acute swine and chronic sheep) were conducted to assess procedural feasibility, sutureless anchoring, healing and inflammatory responses to the implant, hemodynamic performance and valve-related pathology. The studies were completed accordance with the requirements of ISO 5840:2005 - Cardiovascular Implants – Cardiac Valve Prostheses.

During the GLP chronic study a total of 12 Perceval valves were implanted in aortic position of juvenile sheep for a 20 weeks evaluation period and compared to four commercially available bioprosthetic heart valve used as control valves. The study included the evaluation of procedural handling and implant characteristics, animal survival, hemodynamic performance, hematology, valve pathology and mineralization.

The Perceval valve demonstrated acceptable handling and anchoring to the implant site, normal tissue healing response and no thrombogenicity, satisfactory hemodynamic performance and lower mineralization propensity compared to the control valve.

### 1. Handling and anchoring to implant site

The ease, repeatability and safety of the surgical procedure were confirmed. The deployment and anchoring of the sutureless Perceval bioprosthesis were demonstrated to be satisfactory since there was no evidence of dislodgement, migration or embolization of the valve either during the initial implantation or following 140 days of implantation. The low incidence of paravalvular leaks also confirms that adequate anatomic sizing and the design features of the Perceval allow the safe implantation of the valve within the aortic root as a replacement aortic valve.

### 2. Animal Survival

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Of the 12 sheep implanted with Perceval valve during the GLP chronic study, 7 animals were explanted as per the study protocol 20 weeks after surgery; 2 intraoperative deaths occurred as technical failures; 1 animal was euthanized 77 days after surgery for ethical reasons secondary to endocarditis; 2 early animal deaths occurred 68 and 104 days after surgery and determined to be non-valve related based on the necropsy findings.

## 3. Hemodynamic Performance

The hemodynamic performance of the Perceval valve – as assessed by transvalvular pressure gradient, EOA, regurgitation and leaflet motion – was comparable to the control valve and within the normal physiologic range.

## 4. Hematology and Clinical Chemistry

Hematology monitoring was performed at the following time-points throughout the scheduled follow-up: 0 (baseline), 7, 90 and 140 days. Although large variations were registered for almost all the parameters both in the test and control groups, the hematology results were within the normal range. No observable negative effect of the Perceval valve on blood chemistry was identified.

## 5. Valve-Related Pathology

Macroscopic findings demonstrated adequate biocompatibility and healing response of the Perceval prosthesis as aortic valve replacement in sheep. Histopathology results showed favorable tissue response to the implant with minimal pannus formation covering the inflow ring and the base of prosthetic cusps. Though there were focal sites of fibrin deposition as typically seen on the surface of porcine aortic valve and pericardial bioprostheses, no valve-related thrombosis was reported throughout the study.

## 6. Mineralization

Mineralization was analyzed by X-ray radiography, histopathology of prosthetic cusps and quantitative calcium determination by inductively coupled plasma atomic emission spectroscopy. Some local sites of dystrophic calcification in the cusp tissue were observed as typically reported for porcine and pericardial prostheses after 20 weeks implantation in juvenile sheep. Quantitative inorganic calcium and phosphorous analysis demonstrated a lower mineralization rate in the Perceval valve compared to the control valve.

## C. Additional Studies

### 1. Sterilization

The Perceval valve bioprosthesis is sterilized by terminal liquid sterilization in glutaraldehyde sterilant solution. The sterilization process has been validated to assure a sterility assurance level (SAL) of $10^{-6}$.

The Perceval Dual Holder, Dual MICS Holder, Post-Dilation Catheter, Post-Dilation MICS Catheter, and Dual Collapser are provided sterile and sterilized using Ethylene Oxide. The sterilization process has been validated to assure a sterility assurance level

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(SAL) of $10^{-6}$. Validation was performed to ensure that reusable accessories could be appropriately sterilized.

## 2. Shelf Life

The shelf life of the Perceval Valve, Dual Holder, Dual MICS Holder, Post-Dilation Catheter, Post-Dilation MICS Catheter, and Dual Collapser has been established at 3 years based on real time aging. Packaging and product integrity studies were conducted to ensure that the shelf life for each package and product is maintained for a minimum of three (3) years based on accelerated aging-studies.

Integrity of the finished device was evaluated after 3 years of real-time ageing. This evaluation included testing on: pericardial tissue (shrinkage temperature, biomechanical properties, collagen content, tissue microstructure); storage solution (pH value, residuals); valve (hydrodynamic performance, accelerated wear testing, corrosion, valve migration force and stent radial strength); and jar (microbiological barrier and leaching analysis). Acceptable results were observed for all tests with samples aged to 3-years.

Functionality and product integrity of the Dual Holder, Dual MICS Holder, Post-Dilation Catheter, Post-Dilation MICS Catheter, and Dual Collapser was demonstrated after three years accelerated aging and simulated distribution testing.

## 3. Package Integrity

The Perceval prosthesis is provided sterile in a polycarbonate jar. The Dual Holder, Dual MICS Holder, Post-Dilation Catheter, Post-Dilation MICS Catheter, and Dual Collapser are packaged in a blister and closed in double sealed Tyvek pouches. The packaging systems were evaluated via physical testing (peel testing) and microbial challenge testing and shown to maintain the sterile barriers following three year accelerated aging.

Package integrity studies were conducted after simulated shipping process (manual handling, vehicle stacking, vibration, and low pressure hazard) to ensure integrity of packaging. Testing included package integrity, and microbial challenge after real-time aging. The results demonstrate that the package integrity is maintained.

## X. SUMMARY OF PRIMARY CLINICAL STUDIES

The applicant performed a clinical study to establish a reasonable assurance of safety and effectiveness of heart valve replacement with the Perceval valve in the European CAVALIER study. The study was conducted in the following countries: France, Germany, Poland, Belgium, England, Netherlands, and Austria. Data from the CAVALIER clinical study were the basis for the PMA approval decision. A summary of the clinical study is presented below.

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# A. Study Design

Patients were treated between February 23, 2010, and September 30, 2013. The database for this PMA reflected data collected through November 5, 2014, and included 658 patients. There were 26 investigational sites.

The study was a prospective, multi-center, non-randomized clinical study of the Perceval heart valve implanted in patients requiring native or prosthetic aortic valve replacement. Adverse Event (AE) rates as compared to a set of Objective Performance Criteria (OPC) and to literature-based control data were used for the design and analysis of this study. 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 used an independent Data Monitoring Committee (DMC). The purpose of the DMC was to review the progress of the trial. A Clinical Events Committee (CEC) was formed and the aim of the CEC was to independently review and adjudicate events. A core lab was used to independently evaluate echocardiogram data.

## 1. Clinical Inclusion and Exclusion Criteria

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

1. Patients of age ≥ 65 years;
2. Patients with aortic valve stenosis or steno-insufficiency;
3. Patients in which a preoperative evaluation indicated the need for native or prosthetic aortic valve replacement with a biological prosthesis;
4. Patients willing to sign the informed consent; and
5. Patients willing to undergo all the medical follow-ups and echocardiography examinations and laboratory tests in the study protocol.

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

1. Patients involved in any other clinical study for drugs or devices;
2. Patients with a previously implanted Perceval prosthesis, within the clinical study, that required replacement;
3. Patients with previous implantation of valve prostheses or annuloplasty ring not being replaced by the study valve;
4. Patients that required simultaneous cardiac procedures, apart from septal myectomy and/or coronary bypass;

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5. Patients who required double or multiple valve replacement or repair in whom the mitral, tricuspid, or pulmonic valve would be replaced with a non-Perceval valve or repaired;
6. Patients with aneurysmal dilation or dissection of the ascending aortic wall;
7. Patients needing non-elective intervention;
8. Patients with active endocarditis;
9. Patients with active myocarditis;
10. Patients with congenital bicuspid aortic valve;
11. Patients with aortic root enlargement, where the ratio between the diameter of the sino-tubular junction and the annulus diameter, assessed by TTE, is >1.3;
12. Patients with an aortic root height (measured from aortic annulus to sino-tubular junction) ≥ 21 mm for size S/21, ≥ 22.5 mm for size M/23, ≥ 24 mm for size L; and ≥ 25 mm for size XL/27;
13. Patient with myocardial infarction ≤ 90 days before the planned valve implant surgery;
14. Patients with known hypersensitivity to nickel alloys;
15. Patients with a documented history of substance (drug or alcohol) abuse;
16. Patients who were a prison inmate, institutionalized, or unable to give informed consent;
17. Patients with a major or progressive non-cardiac disease that, in the investigator's experience, results in a life expectancy of less than 12 months, or in whom the implant of the device would create an unacceptable risk to the patient;
18. Patients undergoing renal dialysis for chronic renal failure or suffering from hyperparathyroidism; or
19. Patients with an acute preoperative neurological deficit, myocardial infarction, or cardiac event that had not returned to baseline or stabilized ≥ 30 days prior to the planned valve implant surgery.

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2. Follow-up Schedule

All patients were scheduled for follow-up examinations at discharge or within 30 days post-procedure, between 3 and 6 months, 12 months, and annually thereafter to a minimum of five years post procedure.

Preoperatively, demographic and baseline data including NYHA functional classification were collected. Postoperatively, the objective parameters measured during the study included blood value, NYHA functional class and echocardiography data were collected at each follow-up. Adverse events and complications were recorded at the time of occurrence or site notification.

3. Clinical Endpoints

With regards to safety, the following criteria were evaluated:

1) the complication and survival rates for the Perceval valve are comparable to appropriate historical controls manifested as Objective Performance Criteria (OPCs), and to that reported in the literature for other stentless and stented bioprosthesis.

With regards to effectiveness, the following criteria were evaluated:

1) the hemodynamic performance of the Perceval valve is comparable to that reported in the literature for other bioprosthetic valves; and
2) clinically significant improvement in overall patient condition by comparison of preoperative and postoperative NYHA functional classification.

B. Accountability of PMA Cohort

At the time of database lock, of 815 patients enrolled in the PMA study, implant was attempted in a total of 658 patients and 599 patients were followed longer than 31 days post-procedure. A total of 157 patients were excluded before implant and 30 patients were classified as implant failures, received a non-study valve, and were not included in the main analysis. Study accountability is detailed in Table 6.

Table 6. Study Accountability

| Visit interval | Possible N (100%) | Clinical visit or phone call n (%) | Clinical visit n (%) | Phone call n (%) | Missed n (%) |
| --- | --- | --- | --- | --- | --- |
| Preoperative | 658 (100.0%) | 658 (100.0%) | 658 (100.0%) | - | - |
| Discharge (or 30 days) | 615 (100.0%) | 614 (99.8%) | 614 (99.8%) | - | 1 (0.2%) |
| 3-6 Months | 580 (100.0%) | 541 (93.3%) | 512 (88.3%) | 29 (5.0%) | 39 (6.7%) |

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| Visit interval | Possible N (100%) | Clinical visit or phone call n (%) | Clinical visit n (%) | Phone call n (%) | Missed n (%) |
| --- | --- | --- | --- | --- | --- |
| 12 Months | 554 (100.0%) | 537 (96.9%) | 498 (89.9%) | 39 (7.0%) | 17 (3.1%) |
| 2 Years | 453 (100.0%) | 435 (96.0%) | 396 (87.4%) | 39 (8.6%) | 18 (4.0%) |
| 3 Years | 318 (100.0%) | 308 (96.9%) | 279 (87.7%) | 29 (9.1%) | 10 (3.1%) |
| 4 Years | 83 (100.0%) | 83 (100.0%) | 77 (92.8%) | 6 (7.2%) | - |

# C. Study Population Demographics and Baseline Parameters

The demographics of the study population are typical for an aortic heart valve study (Table 7).

Table 7. CAVALIER Study Preoperative Patient Characteristics

| Patients | 658 | % |
| --- | --- | --- |
| Mean age ± SD (range) | 78.3 ± 5.6 (61.6; 92.6) | |
| Age | | |
| < 65 | 7 | 1.1% |
| 65-69 | 41 | 6.2% |
| 70-74 | 138 | 21.0% |
| 75-79 | 209 | 31.8% |
| 80-84 | 186 | 28.3% |
| 85-89 | 70 | 10.6% |
| ≥ 90 | 7 | 1.1% |
| Sex | | |
| Female | 424 | 64.4% |
| Male | 234 | 35.6% |
| Mean BSA ± SD (range) | 1.8 ± 0.2 (1.0 - 2.4) | |
| NYHA | | |
| I | 22 | 3.3% |
| II | 198 | 30.1% |
| III | 386 | 58.7% |
| IV | 32 | 4.9% |
| Not available | 20 | 3.0% |
| Mean EuroScore ± SD (range) | 10.2 ± 7.8 (1.2 - 75.3) | |
| Mean STS Score ± SD (range) | 7.2 ± 7.4 (0.8 - 50.0) | |
| Cardiac Rhythm1 | | |
| Sinus | 559 | 85.5% |
| Atrial Fibrillation | 52 | 8.0% |
| Paced | 21 | 3.2% |
| Other | 22 | 3.4% |
| Previous Cardiovascular Intervention2 | | |
| None | 531 (80.7%) | |
| Previous intervention | 127 (19.3%) | |

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| Valve replacement | 10 | 1.5% |
| --- | --- | --- |
| CABG surgery | 13 | 2.0% |
| PCI³ | 78 | 11.9% |
| Valve repair with annuloplasty ring | 1 | 0.2% |
| Pacemaker | 33 | 5.0% |
| Other | 10 | 1.5% |

1. Missing data for 4 patients.
2. Patients may have more than one previous intervention.
3. PCI=Percutaneous Coronary Intervention (with or without stents)

## D. Safety and Effectiveness Results

### 1. Safety Results

The analysis of safety was based on the implanted patient cohort of 628 patients over the course of 1,494.77 total patient-years and 1,444.44 late patient-years. The key safety outcomes and adverse event rates for aortic valve replacement for this study are presented in Table 8. The data are presented as percentages for early events, linearized late rates for late events, and "freedom from event" (actuarial analysis) at year 1, 2, 3, and 4 post-implant.

Table 8. Observed Adverse Event Rates

| Adverse event | Early events¹ | | Late events² | | Freedom From Event [95% CI]³ | | | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | N | % | N | %/pt-yr | 1 year | 2 years | 3 years | 4 years |
| All mortality | 23 | 3.7 | 74 | 5.1 | 91.7 [88.6 – 93.9] | 88.7 [86.1 – 91.3] | 83.2 [79.9 – 86.5] | 77.4 [72.5 – 82.4] |
| Valve-related and valve- and procedure-related death | 8 | 1.3 | 24 | 1.8 | 97.2 [95.9 – 98.5] | 96.2 [94.6 – 97.8] | 94.4 [92.4 – 96.5] | 89.5 [85.1 – 93.8] |
| Valve reintervention | 5 | 0.8 | 14 | 1.0 | 98.0 [96.9 – 99.1] | 97.4 [96.1 – 98.7] | 97.1 [95.7 – 98.5] | 95.2 [92.3 – 98.2] |
| Explant⁴ | 5 | 0.8 | 13 | 0.9 | 98.0 [96.9 – 99.1] | 97.4 [96.1 – 98.7] | 97.1 [95.7 – 98.5] | 95.2 [92.3 – 98.2] |
| All bleeding | 28 | 4.5 | 37 | 2.6 | 87.5 [84.8 – 90.1] | 86.6 [83.9 – 89.4] | 85.2 [82.2 – 88.2] | 84.1 [80.5 – 87.7] |
| Major bleeding | 22 | 3.5 | 28 | 1.9 | 89.1 [86.6 – 91.6] | 88.5 [85.9 – 91.0] | 87.6 [84.9 – 90.3] | 86.5 [83.1 – 89.9] |
| Major anticoagulation-related bleeding | 11 | 1.8 | 16 | 1.1 | 94.6 [92.8 – 96.5] | 94.3 [92.4 – 96.1] | 93.7 [91.6 – 95.7] | 92.6 [89.6 – 95.5] |
| Thromboembolism⁵ | 27 | 4.3 | 29 | 2.0 | 94.3 [92.4 – 96.1] | 92.8 [90.7 – 94.9] | 91.7 [89.3 – 94.0] | 89.4 [86.0 – 92.9] |
| Stroke | 14 | 2.2 | 12 | 0.8 | 96.7 [95.3 – 98.1] | 95.9 [94.3 – 97.5] | 95.1 [93.2 – 96.9] | 94.1 [91.4 – 96.7] |
| Endocarditis | 1 | 0.2 | 17 | 1.2 | 98.5 [97.5 – 99.5] | 97.7 [96.4 – 98.9] | 97.4 [96.0 – 98.8] | 93.7 [89.2 – 98.1] |
| Valve thrombosis | 0 | 0 | 0 | 0 | 100 [100 - 100] | 100 [100 - 100] | 100 [100 - 100] | 100 [100 - 100] |
| Structural valve deterioration⁶ | 0 | 0 | 9 | 0.6 | 100 [100 - 100] | 99.8 [99.4 – 100] | 99.8 [99.4 – 100] | 95.5 [91.0 – 100] |

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| Adverse event | Early events1 | | Late events2 | | Freedom From Event [95% CI]3 | | | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | N | % | N | %/pt-yr | 1 year | 2 years | 3 years | 4 years |
| Nonstructural valve dysfunction7 | 7 | 1.1 | 10 | 0.7 | 97.9 [96.7 – 99.0] | 97.5 [96.2 – 98.7] | 97.5 [96.2 – 98.7] | 93.4 [88.7 – 98.0] |
| All paravalvular leak | 4 | 0.6 | 5 | 0.3 | 98.9 [98.0 – 99.7] | 98.6 [97.7 – 99.6] | 98.6 [97.7 – 99.6] | 97.2 [95.0 – 99.5] |
| Major paravalvular leak | 2 | 0.3 | 3 | 0.2 | 99.3 [98.7 – 99.9] | 99.1 [98.4 – 99.9] | 99.1 [98.4 – 99.9] | 98.2 [96.1 – 100] |
| All hemolysis | 4 | 0.6 | 5 | 0.3 | 98.6 [97.7 – 99.6] | 98.4 [97.3 – 99.5] | 98.4 [97.3 – 99.5] | 98.4 [97.3 – 99.5] |
| Adverse events leading to pulse generator implant8 | 46 | 7.3 | 29 | 2.0 | 84.8 [81.9 – 87.6] | 83.9 [81.0 – 86.9] | 83.3 [80.3 – 86.4] | 81.6 [77.1 – 86.1] |

1. Early valve-related events include postoperative events occurring 1-30 days post implant. Early events rates are calculated as the percentage of events on total number of patients (628 evaluable patients).
2. Late postoperative events (&gt; 30 days). Linearized late rates calculated using 1444.44 late patient-years.
3. Freedom from first event (early or late) rates were calculated using the Kaplan-Meier method. In brackets the $95\%$ lower and upper limits are reported.
4. There was 1 additional explant which was perioperative on Day 0.
5. There was 1 additional thromboembolic event which was a perioperative transient ischemic attack on Day 0.
6. The Kaplan-Meier rates are calculated considering only the 7 cases out of 9, adjudicated by the CEC as SVD.
7. Includes paravalvular leak. Also includes 2 cases of late tricuspid regurgitation reported as nonstructural valve dysfunction (NSVD) but reclassified as non-NSVD by the CEC.
8. There were 27 additional adverse events leading to pulse generator implant which were perioperative on Day 0.

The results of the CAVALIER study were compared to the OPC per ISO 5840 requirements and detailed in Table 9. The study valve successfully met the OPC requirements.

Table 9. Linearized Hazard Rates (%/late patient-years) based on CEC adjudicated valve-related events and follow-up greater than 30 days after surgery). Total patients, N= 628.

| Adverse event | Linearized Hazard Rates for >30 days post-op (All patients = 599) (1,444.44 late patient-years; mean = 829.7 days; max = 1624 days) | | | |
| --- | --- | --- | --- | --- |
| | Number of patients | Number of events | one-sided 95% CI [Poisson distribution] | 2 x OPC1 |
| Bleeding | 20 | 22 | 2.1% | 2.8 |
| Major Bleeding | 15 | 16 | 1.6% | 1.8 |
| Thromboembolism | 19 | 21 | 2.1% | 5 |
| Non structural valve dysfunction PVL | 3 | 3 | 0.5% | 2.4 |
| Major PVL | 2 | 2 | 0.4% | 1.2 |
| Endocarditis | 15 | 16 | 1.6% | 2.4 |
| Valve thrombosis | 0 | 0 | - | 0.4 |

$^{1}$ FDA Objective Performance Criteria

Table 10 presents the results of the Clinical Event Committee (CEC) adjudication for the 102 new or worsened cardiac conduction disturbances and other adverse events, occurring in 100 patients, leading to pulse generator implantation in the CAVALIER

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study. One (1) patient had 2 different early arrhythmia events and a second patient had 2 late events.

Table 10. CEC-Adjudicated Cardiac Conduction Disturbances and Other Adverse Events Leading to Pulse Generator Implantation in CAVALIER Study ${}^{1,2}$

| Adverse Event Leading to Pulse Generator Implant | Perioperative [Day 0] | Early [1-30 Days] | Late [>30 Days] | Overall |
| --- | --- | --- | --- | --- |
| Device-Related | | | | |
| Cardiac Arrhythmia | 1 | 2 | 0 | 3 |
| \( 3^{rd} \) Degree AV Block | 1 | 0 | 0 | 1 |
| Bradycardia | 0 | 1 | 0 | 1 |
| Other Arrhythmias | 0 | 1 | 0 | 1 |
| Total | 1 | 2 | 0 | 3 |
| Device- and Procedure-Related | | | | |
| Cardiac Arrhythmia | 25 | 36 | 1 | 62 |
| \( 3^{rd} \) Degree AV Block | 24 | 25 | 0 | 49 |
| \( 2^{nd} \) Degree AV Block | 0 | 2 | 0 | 2 |
| \( 1^{st} \) Degree AV Block | 0 | 1 | 0 | 1 |
| Atrial Fibrillation | 1 | 2 | 0 | 3 |
| Left Bundle Branch Block | 0 | 2 | 1 | 3 |
| Right Bundle Branch Block | 0 | 1 | 0 | 1 |
| Bradycardia | 0 | 1 | 0 | 1 |
| Other Arrhythmias | 0 | 2 | 0 | 2 |
| Total | 25 | 36 | 1 | 62 |
| Procedure-Related | | | | |
| Cardiac Arrhythmia | 1 | 4 | 0 | 5 |
| \( 3^{rd} \) Degree AV Block | 0 | 1 | 0 | 1 |
| Atrial Fibrillation | 0 | 2 | 0 | 2 |
| Ventricular Fibrillation | 1 | 0 | 0 | 1 |
| Asystole | 0 | 1 | 0 | 1 |
| \( Heart Failure^3 \) | 0 | 1 | 0 | 1 |
| Total | 1 | 5 | 0 | 6 |
| Unrelated to Device or Procedure | | | | |
| Cardiac Arrhythmia | 0 | 3 | 24 | 27 |
| \( 3^{rd} \) Degree AV Block | 0 | 0 | 11 | 11 |
| \( 2^{nd} \) Degree AV Block | 0 | 1 | 3 | 4 |
| Atrial Fibrillation | 0 | 1 | 4 | 5 |
| Left Bundle Branch Block | 0 | 0 | 1 | 1 |
| Bradycardia | 0 | 0 | 2 | 2 |
| Asystole | 0 | 1 | 1 | 2 |
| Other Arrhythmias | 0 | 0 | 2 | 2 |
| Heart Failure | 0 | 0 | 2 | 2 |
| Myocardial Infarction | 0 | 0 | 1 | 1 |

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| Total | 0 | 3 | 27 | 30 |
| --- | --- | --- | --- | --- |
| TOTAL | 27 | 46 | 28 | 101 |

1. $\mathrm{N} = {628}$ implanted
2. Table presents 102 events in 100 patients, with 1 patient having 2 different early arrhythmia events and a second patient having 2 late events.
3. The event worsening of heart failure was not adjudicated by the CEC.

# 2. Effectiveness Results

Effectiveness of the Perceval heart valve was evaluated by NYHA functional class and echocardiographic assessment of the hemodynamic performance of the study valve.

The differences between the NYHA class at 12 months and the baseline were calculated. The data are presented in Table 11. In total, $77.5\%$ of patients (362 over 467) showed a decrease of NYHA equal of at least one class, whereas $19.7\%$ of patients remained stable over the time. Only $2.8\%$ of patients showed a worsened clinical status.

Reduction in mean gradients and increase in EOA were observed at one year follow-up.

Table 11. Effectiveness Outcome, NYHA Functional Classification

| | NYHA class change at 12 months vs. baseline | | | | | | | | | | | | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | NYHA improved | | | | | | NYHA Stable | | NYHA worsened | | | | |
| NYHA class at baseline | -3 | | -2 | | -1 | | No change | | +1 | | +2 | | +3 |
| | N | % | N | % | N | % | N | % | N | % | N | % | N |
| NYHA I (N = 15) | - | - | - | - | - | - | 8 | 53.3 | 7 | 46.7 | - | - | - |
| NYHA II (N = 160) | - | - | - | - | 97 | 60.6 | 57 | 35.6 | 6 | 3.8 | - | - | - |
| NYHA III (N = 277) | - | - | 152 | 54.9 | 98 | 35.4 | 27 | 9.7 | - | - | - | - | - |
| NYHA IV (N = 15) | 8 | 53.3 | 7 | 46.7 | - | - | - | - | - | - | - | - | - |
| Total (N = 467) | 8 | 1.7 | 159 | 34.0 | 195 | 41.8 | 92 | 19.7 | 13 | 2.8 | - | - | - |

In Table 12 all of the main non-regurgitation hemodynamic data obtained at the 1 year follow-up echocardiographic exams are presented. Reduction in mean gradients and increase in EOA compared to pre-implant were observed at 1 year follow-up.

Table 12. Effectiveness Outcome at 1 Year Follow-up Visit: Hemodynamic Results

| Hemodynamic parameter | All sizes | S/21 mm | M/23 mm | L/25 mm | XL/27 mm |
| --- | --- | --- | --- | --- | --- |
| Mean Gradient [mmHg] | N1= 362 | n = 46 | n = 156 | n = 143 | n = 17 |
| Mean ± SD | 9.1 ± 5.0 | 10.1 ± 4.2 | 9.4 ± 5.5 | 8.5 ± 4.6 | 9.7 ± 4.7 |
| EOA [cm2] | N1= 300 | n=31 | n=131 | n=123 | n=15 |
| Mean ± SD | 1.5 ± 0.4 | 1.3 ± 0.3 | 1.5 ± 0.4 | 1.5 ± 0.4 | 1.6± 0.4 |

${}^{1}\mathrm{\;N} =$ number of subjects with available hemodynamic parameter.

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Valvular regurgitation data obtained at the echocardiographic exams at 1 year through 3 years follow-up are presented in Tables 13-15.

Table 13. Postoperative valvular regurgitation by valve size at 1 year in the CAVALIER Study¹

| Size | 21 mm | 23 mm | 25 mm | 27 mm |
| --- | --- | --- | --- | --- |
| Severity | | | | |
| None | 12 (24.5%) | 99 (51.3%) | 73 (43.2%) | 10 (45.5%) |
| Trace | 13 (26.5%) | 34 (17.6%) | 46 (27.2%) | 2 (9.1%) |
| Mild | 20 (40.8%) | 46 (23.8%) | 43 (25.4%) | 5 (22.7%) |
| Moderate | 2 (4.1%) | 5 (2.6%) | 4 (2.4%) | 0 (0%) |
| Severe | 1 (2.0%) | 1 (0.5%) | 1 (0.6%) | 0 (0%) |
| Not Evaluable | 1 (2.0%) | 8 (4.1%) | 2 (1.2%) | 5 (22.7%) |
| Total Number | 49 | 193 | 169 | 22 |
| Location | | | | |
| None | 12 (24.5%) | 99 (51.3%) | 73 (43.2%) | 10 (45.5%) |
| Central | 29 (59.2%) | 70 (36.3%) | 68 (40.2%) | 5 (22.7%) |
| Paravalvular | 3 (6.1%) | 6 (3.1%) | 9 (5.3%) | 1 (4.5%) |
| Both | 3 (6.1%) | 10 (5.2%) | 7 (4.1%) | 0 (0%) |
| Not Evaluable | 2 (4.1%) | 8 (4.1%) | 12 (7.1%) | 6 (27.3%) |
| Total Number | 49 | 193 | 169 | 22 |

1. N = 628 implanted. 433 patients with available regurgitation data at 1 year post-implant. Data updated to July 2, 2015.

Table 14. Postoperative valvular regurgitation by valve size at 2 years in the CAVALIER Study¹

| Size | 21 mm | 23 mm | 25 mm | 27 mm |
| --- | --- | --- | --- | --- |
| Severity | | | | |
| None | 5 (12.2%) | 54 (33.3%) | 48 (34.5%) | 5 (55.6%) |
| Trace | 10 (24.4%) | 36 (22.2%) | 30 (21.6%) | 1 (11.1%) |
| Mild | 16 (39.0%) | 48 (29.6%) | 45 (32.4%) | 3 (33.3%) |
| Moderate | 5 (12.2%) | 14 (8.6%) | 8 (5.8%) | 0 (0%) |
| Severe | 1 (2.4%) | 2 (1.2%) | 0 (0%) | 0 (0%) |
| Not Evaluable | 4 (9.8%) | 8 (4.9%) | 8 (5.8%) | 0 (0%) |
| Total Number | 41 | 162 | 139 | 9 |
| Location | | | | |
| None | 5 (12.2%) | 54 (33.3%) | 48 (34.5%) | 5 (55.6%) |
| Central | 32 (78.0%) | 79 (48.8%) | 65 (46.8%) | 4 (44.4%) |
| Paravalvular | 0 (0%) | 7 (4.3%) | 7 (5.0%) | 0 (0%) |
| Both | 2 (4.9%) | 12 (7.4%) | 8 (5.8%) | 0 (0%) |
| Not Evaluable | 2 (4.9%) | 10 (6.2%) | 11 (7.9%) | 0 (0%) |
| Total Number | 41 | 162 | 139 | 9 |

1. N = 628 implanted. 433 patients with available regurgitation data at 1 year post-implant. Data updated to July 2, 2015.

Table 15. Postoperative valvular regurgitation by valve size at 3 years in the CAVALIER Study¹

| Size | 21 mm | 23 mm | 25 mm | 27 mm |
| --- | --- | --- | --- | --- |
| Severity | | | | |
| None | 4 (12.9%) | 24 (21.1%) | 28 (23.5%) | - |
| Trace | 7 (22.6%) | 33 (28.9%) | 21 (17.6%) | - |

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| Mild | 13 (41.9%) | 37 (32.5%) | 45 (37.8%) | - |
| --- | --- | --- | --- | --- |
| Moderate | 5 (16.1%) | 13 (11.4%) | 9 (7.6%) | - |
| Severe | 1 (3.2%) | 0 (0%) | 1 (0.8%) | - |
| Not Evaluable | 1 (3.2%) | 7 (6.1%) | 15 (12.6%) | - |
| Total Number | 31 | 114 | 119 | 0 |
| Location | | | | |
| None | 4 (12.9%) | 24 (21.1%) | 28 (23.5%) | - |
| Central | 22 (71.0%) | 68 (59.6%) | 58 (48.7%) | - |
| Paravalvular | 0 (0%) | 4 (3.5%) | 9 (7.6%) | - |
| Both | 4 (12.9%) | 12 (10.5%) | 12 (10.1%) | - |
| Not Evaluable | 1 (3.2%) | 6 (5.3%) | 12 (10.1%) | - |
| Total Number | 31 | 114 | 119 | 0 |

1. $\mathrm{N} = {628}$ implanted. 433 patients with available regurgitation data at 1 year post-implant. Data updated to July 2, 2015.

# 3. Subgroup Analyses

Gender was evaluated for potential association with outcomes. Among the attempted implant $(N = 658)$ , there were 424 females $(64.4\%)$ and 234 males $(35.6\%)$ patients in the CAVALIER study cohort. Analyses were performed on the 628 patients who were successfully implanted (females $= 404$ ; males $= 224$ ). The results do not include the 30 patients who were classified as failure to implant. The CAVALIER study was not designed nor powered to study safety and effectiveness differences between sexes, so this analysis is considered exploratory without definitive conclusions.

Safety endpoints stratified by gender are listed in Table 16.

Effectiveness endpoints were compared for both males and females. The two groups exhibited a significant improvement in NYHA classification at 12-months. However, there was a potential observed difference in the 12 month NYHA distribution between males and females (Table 17).

Table 16. Early Mortality and Survival Comparisons by Gender

| Parameter | Total (N=628) | Female (N=404) | Male (N=224) |
| --- | --- | --- | --- |
| Early (≤30 day) mortality | 3.5% | 3.2% | 4.0% |
| All mortality | 77.43 (72.47 - 82.39) | 76.39 (69.65 – 83.13) | 78.93 (71.81 – 86.04) |
| Cardiac-related death | 88.32 (84.19 - 92.45) | 88.86 (83.6 – 94.11) | 87.45 (80.91 - 94.0) |
| Valve-related death | 89.45 (85.07 - 93.83) | 89.32 (83.48 - 95.17) | 89.60 (83.18 - 96.03) |

Table 17. Comparison of 12 Month NYHA Functional Classification by Gender

| Postoperative NYHA (12 months) | All (N=476) | | Female (N=303) | | Male (N=173) | |
| --- | --- | --- | --- | --- | --- | --- |
| | N | % | N | % | N | % |
| No NYHA classification | 12 | 100 | 10 | 100 | 1 | 100 |
| No NYHA classification + 12 months | 12 | 100 | 10 | 100 | 1 | 100 |

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| Postoperative NYHA (12 months) | All (N=476) | | Female (N=303) | | Male (N=173) | |
| --- | --- | --- | --- | --- | --- | --- |
| CLASS I | 271 | 56.9% | 155 | 51.2% | 116 | 67.1% |
| CLASS II | 171 | 35.9% | 131 | 43.2% | 40 | 23.1% |
| CLASS III | 34 | 7.1% | 17 | 5.6% | 17 | 9.8% |
| CLASS IV | - | - | - | - | - | - |

Although the study population included a greater proportion of female patients, the comparisons of safety and effectiveness data by gender support the conclusion that the results of the overall study can be applied equally well to males and females. Patients of both genders demonstrated acceptable hemodynamic outcomes and significant improvement in functional status.

## 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 26 investigators. None of the clinical investigators had disclosable financial interests/arrangements as defined in sections 54.2(a), (b), (c), and (f). 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. Safety Conclusions

The results from pre-clinical studies performed on the Perceval Sutureless Heart Valve for hydrodynamic performance, and structural performance demonstrate that this device is suitable for long term implant.

In-vivo animal studies in sheep demonstrate that the Perceval Sutureless Heart Valve is safe for aortic valve replacement.

The results of the CAVALIER trial demonstrate that the linearized late adverse event rates for valvular thrombosis, valve-related thromboembolism, all and major perivalvular leak, and endocarditis are significantly lower than the established

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standard of twice the FDA Objective Performance Criterion (OPC). Comparisons of the early, linearized late, and actuarial rates for the 11 standard safety endpoints in the CAVALIER study to the corresponding data in the literature-based control articles for the study do not raise clinical concerns about the safety of the Perceval valve.

The rate for all-cause pulse generator implant following aortic valve replacement (AVR) with the Perceval valve in the CAVALIER study is higher than the 3.1-11.8% rate range for all-cause permanent cardiac pacemaker implant after surgical AVR noted in the published literature. Thus implant of the Perceval valve likely has a higher risk of permanent cardiac pacemaker implant than does surgical AVR with a sutured prosthetic valve.

## B. Effectiveness Conclusions

The assessment of effectiveness was based on the evaluation of NYHA functional classification data and echocardiographic hemodynamic data.

The CAVALIER study results demonstrate improvement in NYHA class for the majority of patients throughout the study period. At the 1-year, 2-year, and 3-year follow-up time-points 75.1% or greater of the implanted patients with available data had improved by 1 to 3 classes and at the 4-year follow-up time-point 72.6% of the patients had improved by 1 to 3 classes. The data further show that at the 1-year, 2-year, and 3-year follow-up time-points 92.9% or greater of the patients were in Class I and Class II, and at the 4-year follow-up time-point 86.3% of the patients were in Class I and Class II.

The CAVALIER study peak gradient, mean gradient, and effective orifice area (EOA) hemodynamic data are overall similar to the corresponding data in the literature-based control articles for the study and indicate acceptable hemodynamic performance of the Perceval valve.

In the CAVALIER study there were higher percentages of patients with mild regurgitation than the percentages of patients with no or trace regurgitation. Most of the mild regurgitation was central and did not progress over the duration of the study. The predominance of central regurgitation likely reflects the conformability of the Perceval valve stent which is designed to help prevent perivalvular leak.

## C. Benefit-Risk Conclusions

The probable benefits of the Perceval Sutureless Heart Valve include improved aortic valve hemodynamic performance, improved NYHA functional classification as compared to baseline, and reduction in pump time and cross-clamp time. Approximately 75% of patients implanted with the Perceval valve experienced improvement in their functional clinical status. The device design allows implantation through smaller incisions in comparison to typical surgical prosthetic aortic valves that are sutured in place.

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The risks of the Perceval Sutureless Heart Valve include complications such as valvular thrombosis, thromboembolism, paravalvular leak, endocarditis, structural valve deterioration, nonstructural dysfunction, reoperation, explant, and death. However, these risks are similar to those observed with other surgical prosthetic aortic valves.

The data presented from the CAVALIER trial indicate relatively high percentages of patients with mild regurgitation and the likelihood that implant of the Perceval valve has a higher risk of permanent pacemaker implant than does surgical AVR with a sutured prosthetic valve. However, most of the mild regurgitation did not progress in severity. Additionally, the probable benefits of receiving the Perceval valve to restore aortic valve function outweigh the risks of requiring a permanent pacemaker.

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 of implanting the Perceval Sutureless Heart Valve outweigh the 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 Perceval Sutureless Heart Valve is safe and effective for replacement of diseased, damaged, or malfunctioning native or prosthetic aortic valves.

## XIII. CDRH DECISION

CDRH issued an approval order on January 8, 2016.

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 P150011: FDA Summary of Safety and Effectiveness Data
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