← Product Code OAE · P220032

# POLARx/POLARx FIT Cryoablation Catheters, SMARTFREEZE Cryoablation Console, Accessories (P220032)

_Boston Scientific Corporation · OAE · Aug 8, 2023 · Cardiovascular · APPR_

**Canonical URL:** https://fda.innolitics.com/device/P220032

## Device Facts

- **Applicant:** Boston Scientific Corporation
- **Product Code:** OAE
- **Decision Date:** Aug 8, 2023
- **Decision:** APPR
- **Device Class:** Class 3
- **Review Panel:** Cardiovascular
- **Attributes:** Therapeutic

## Intended Use

The Boston Scientific Cardiac Cryoablation System using the POLARx™ Cryoablation Balloon Catheters is indicated for the treatment of patients with drug refractory, recurrent symptomatic paroxysmal atrial fibrillation (PAF). The Boston Scientific Cardiac Cryoablation System is intended for cryoablation and electrical mapping of the pulmonary veins for pulmonary vein isolation (PVI) in the ablation treatment of patients with drug refractory, recurrent symptomatic paroxysmal atrial fibrillation. The SMARTFREEZE™ Cryo-Console is intended to be used with POLARx™ cryoablation balloon catheters only.

## Device Story

System uses N2O refrigerant to perform cryoablation of cardiac tissue for pulmonary vein isolation (PVI). Components include POLARx/POLARx FIT balloon catheters, SMARTFREEZE console, POLARMAP mapping catheter, and POLARSHEATH steerable sheath. Physician inserts catheters through sheath into left atrium; balloon occludes pulmonary vein ostium; console delivers liquid N2O to balloon, creating transmural tissue necrosis via thermal injury. System includes Diaphragm Movement Sensor (DMS) for phrenic nerve monitoring and esophageal temperature sensor integration. Console provides user interface for refrigerant control, monitoring, and alerts. Used in EP lab by physicians. Benefits include treatment of symptomatic PAF; potential reduction in esophageal injury via temperature monitoring; visual phrenic nerve monitoring via DMS.

## Clinical Evidence

Prospective, single-arm, multi-center study (FROzEN-AF) of 404 patients. Primary safety endpoint: 12-month event-free rate (96.0%, LCL 93.8% vs 89% goal). Primary effectiveness endpoint: 12-month failure-free rate (59.9%, LCL 55.2% vs 50% goal). Secondary effectiveness: 95.7% acute procedural success. POLARx FIT extension study (N=50) showed 100% acute success and 100% safety event-free rate at 3 months. No persistent phrenic nerve palsy or atrioesophageal fistula reported in clinical trials.

## Technological Characteristics

System uses N2O refrigerant for cryoablation. Catheters feature double-layer balloon (Pellethane/Pebax), internal thermocouple, and injection coil. Materials include PTFE, Pebax, stainless steel, and platinum/iridium electrodes. Connectivity via proprietary cables and Inter Connection Box (ICB). Sterilization via ethylene oxide (EO) per ISO 11135. Software-controlled console manages refrigerant delivery and sensor data (DMS, temperature).

## Regulatory Identification

For the treatment of atrial fibrillation.

## Predicate Devices

- POLARMAP™ Catheter ([K223824](/device/K223824.md))
- POLARSHEATH™ Steerable Sheath ([K223824](/device/K223824.md))

## Submission Summary (Full Text)

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# SUMMARY OF SAFETY AND EFFECTIVENESS DATA (SSED)

## I. GENERAL INFORMATION

Device Generic Name: Cardiac ablation percutaneous catheter, intended for treatment of symptomatic, drug refractory, recurrent, paroxysmal atrial fibrillation

Device Trade Name: The Boston Scientific Cardiac Cryoablation System ("Cryoablation System") consists of the following devices and components:

- POLARx™ and POLARx FIT™ Cryoablation Catheter ("Cryoablation Balloon Catheters")
- POLARMAP™ Catheter ("Cryo Mapping Catheter") (FDA Cleared via K223824)
- POLARSHEATH™ Steerable Sheath ("Cryo Steerable Sheath") (FDA Cleared via K223824)
- SMARTFREEZE™ Console ("Console")
- Diaphragm Movement Sensor (DMS)
- Related Accessories

Device Procode: OAE, Catheter, Percutaneous, Cardiac Ablation, For Treatment Of Atrial Fibrillation

Applicant's Name and Address: Boston Scientific Corporation
4100 Hamline Ave. N.
St. Paul, MN 55112,
USA

And

Boston Scientific International S.A.
Le Val Saint-Quentin,
2 rue René Caudron,
78960 Voisins le Bretonneux, France

Date(s) of Panel Recommendation: None

Premarket Approval Application (PMA) Number: P220032

Date of FDA Notice of Approval: 8/08/2023

Doc ID 04379.02.02
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## II. INDICATIONS FOR USE

### Cryoablation Balloon Catheters

The Boston Scientific Cardiac Cryoablation System using the POLARx™ Cryoablation Balloon Catheters is indicated for the treatment of patients with drug refractory, recurrent symptomatic paroxysmal atrial fibrillation (PAF).

### Console

The Boston Scientific Cardiac Cryoablation System is intended for cryoablation and electrical mapping of the pulmonary veins for pulmonary vein isolation (PVI) in the ablation treatment of patients with drug refractory, recurrent symptomatic paroxysmal atrial fibrillation. The SMARTFREEZE™ Cryo-Console is intended to be used with POLARx™ cryoablation balloon catheters only.

## III. CONTRAINDICATIONS

Use of the Boston Scientific Cardiac Cryoablation System is contraindicated as follows:

- In patients with an active systemic infection as this may increase the risk for endocarditis and sepsis.
- In patients with a myxoma or an intracardiac thrombus as the catheter could precipitate an embolic event.
- In patients with a prosthetic heart valve (mechanical or tissue).
- In the ventricle of the heart where the device may become entrapped in a valve or chordae structures.
- In patients with a recent ventriculotomy or atriotomy as this may increase the risk of cardiac perforation or embolic event.
- In patients with pulmonary vein stents as the POLARx™ cryoablation balloon catheters may dislodge or damage the stent.
- In patients with cryoglobulinemia as the cryoablation application may lead to vascular injury.
- In conditions where insertion into or manipulation in the atrium is unsafe as this may increase the risk of perforation or systemic embolic event.
- In patients with intra-atrial septal patch or any other surgical intervention in or adjacent to the intra-atrial septum.
- In patients with an interatrial baffle or path as the transseptal puncture could fail to close.
- In patients with hypercoagulopathy or an inability to tolerate anticoagulation therapy during an electrophysiology procedure.
- In patients with a contraindication to an invasive electrophysiology procedure where insertion or manipulation of a catheter in the cardiac chambers is deemed unsafe.
- In patients previously implanted with a percutaneous Left Atrial Appendage Occlusion device.

## IV. WARNINGS AND PRECAUTIONS

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The warnings and precautions can be found in the Cryoablation System instructions for use, and Boston Scientific Cryoablation System labeling.

V. DEVICE DESCRIPTION

The Boston Scientific Cardiac Cryoablation System (henceforth "Cryoablation System") is intended for treatment of symptomatic, drug refractory, recurrent, paroxysmal AF.

The individual devices within the Cryoablation system and their associated model numbers are listed in Table 1.

Table 1: Cryoablation System

|  Individual Devices within the System | Model Number  |
| --- | --- |
|  POLARx™ Cryoablation Catheter (Cryoablation Catheter) | 2315 (Short tip and long tip)  |
|  SMARTFREEZE™ Console (Console) | 2314  |
|  POLARMAP™ Catheter (Cryo Mapping Catheter) | 2317 (20 mm)  |
|  POLARSHEATH™ Steerable Sheath (Cryo Steerable Sheath) | 2316  |
|  Diaphragm Movement Sensor (DMS) | 2314  |
|  Inter Connection Box (ICB) | 2314  |
|  Esophageal Temperature Sensor Cable | 2314  |
|  Cryo-Console Foot Switch | 2314  |
|  Cryo-Cable | 2318  |
|  Cryo-Catheter Extension Cable | 2319  |
|  Cryo Mapping Catheter EP Electrical Cable | 2320  |

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# Cryoablation Balloon Catheter

The Cryoablation Catheter is a single use, flexible, over-the-wire balloon catheter used to ablate cardiac tissue. The Cryoablation catheter is used in conjunction with the Console to induce thermal injury and endocardial tissue necrosis when the balloon is in contact with cardiac tissue and reaches cryoablation temperatures created by a refrigerant injected from the Console into the balloon segment of the POLARx™ Cryoablation Balloon Catheter. The Cryoablation catheter connects to the Console with a Cryo-Cable (for N₂O delivery and removal) and an Extension Cable (for electrical connection via the Interconnection Box). The Cryoablation catheter is designed to be used with a Cryo Mapping Catheter, which is a circular mapping catheter deployed within the guidewire lumen during ablation procedures.

During an electrophysiology (EP) ablation procedure, the Cryoablation catheters (including the Cryo Mapping Catheter) are inserted through the Cryo Steerable Sheath into the venous system, and they are directed into the left atrium (LA) and towards the ostium of the target pulmonary vein (PV). Once positioning that occludes the PV has been verified, refrigerant is delivered through the Cryo-Cable to the injection coil, which directs the flow of refrigerant toward the interior distal surface of the balloon. This results in a cooled region at the balloon tissue interface, which adheres to the endocardial surface. The low temperature and pressure gradient allows the Balloon to thermally create transmural, circumferential tissue necrosis (lesions) and interrupt electrical conduction.

The Cryoablation Catheter is comprised of the following major components, distal to proximal:

- Atraumatic tip
- Double layer balloon system
- Guide wire lumen
- Internal balloon thermocouple
- Injection coil and manifold for delivery of the refrigerant; liquid nitrous oxide (N₂O)
- Catheter shaft; to retrieve the expanded N₂O gas
- Catheter handle
- Distal handle connections

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![img-0.jpeg](img-0.jpeg)
Figure 1: Cryoablation Catheter Distal Tip

![img-1.jpeg](img-1.jpeg)
Figure 2: Cryoablation Catheter Handle

Table 2: Cryoablation Catheter Specifications

|   | POLARx™/ POLARx FIT™  |
| --- | --- |
|  Balloon diameter | 28 mm/ 31 mm  |
|  Nominal Distal Tip Length | 5 mm  |
|   |  12 mm  |
|  Shaft diameter | 4.0 mm / 11.8F  |
|  Working length | 99 cm  |

# Cyro Mapping Catheter (FDA Cleared via K223824)

The Cryo Mapping Catheter is a single-use, sterile, multi-electrode, diagnostic catheter designed to map cardiac signals during ablation procedures. The catheter is  $20\mathrm{mm}$  in diameter with 8 evenly spaced radiopaque electrodes. The proximal end of the handle contains an electrical connection that integrates with EP lab recording systems. Once deployed through the central guidewire lumen of the Cryoablation Catheter and into the pulmonary vein (PV), a circular shape is established such that the electrodes contact the endovascular/endocardial surface. This allows for recording and interrogation of electrical conduction between the LA and the pulmonary veins. The Cryo Mapping

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Catheter also allows for delivery of pacing stimuli used in the interpretation of PV isolation (PVI).

![img-2.jpeg](img-2.jpeg)
Figure 3: Mapping Catheter Assembly

![img-3.jpeg](img-3.jpeg)
Figure 4: Cryo Mapping Catheter with Electrode Arrangements

Table 3: Cryoablation Catheter Specifications

|  Catheter Model Number | Catheter Diameter | Evenly Spaced Electrodes  |
| --- | --- | --- |
|  2317 | 20mm | 8  |

# Cryo Steerable Sheath (FDA Cleared via K223824)

The Cryo Steerable Sheath is a single use, disposable, steerable percutaneous introducer sheath designed for additional maneuverability of standard catheters that are advanced through the sheath and into cardiac chambers. It is comprised of a composite structured single lumen shaft, an ergonomic handle to provide torque and active deflection, and a hemostasis valve to allow safe introduction, withdrawal, and swapping of catheters and wires while preventing air ingress and minimizing blood loss. A side-port is integrated to allow continuous drip infusion, injection through the center lumen, flushing, aspiration, blood sampling and pressure monitoring.

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As a component of the Cryoablation System, the Cryo Steerable Sheath is intended to facilitate the placement of diagnostic and/or therapeutic intracardiac devices during percutaneous catheter ablation procedures. The device is indicated for left-sided cardiac procedures via a transseptal approach.

Table 4: Cryo Steerable Sheath Specifications

|  Inner diameter | 0.165in / 12.7F  |
| --- | --- |
|  Outer diameter | 0.208in / 15.9F  |
|  Working length | 68 cm  |
|  Total length | 82 cm  |
|  Dilator working length | 85cm  |
|  Reach at 90° | 4.6 cm  |
|  Guidewire compatibility | 0.035 inches  |

# Console

The Console is a device that uses N2O provided from a refillable cylinder to safely pressurize (inflate) and cool the Cryoablation Catheter to cryogenic ablative temperatures. The console houses the electrical and components and software/firmware needed to perform cryoablation procedures. It controls the delivery, recovery, and disposal of N2O (cryoablation refrigerant) safely and efficiently. The Console user interface provides a means for initiating and ceasing refrigerant delivery. Once the command is received from the console, N2O is delivered as a chilled liquid to the Cryoablation Catheter for a programmable time duration. The user interface also displays key information allowing the operator to focus attention on critical tasks and speed up the overall procedure.

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![img-4.jpeg](img-4.jpeg)
Figure 5: Cryo Console

Integration between the Cryoablation Catheter and the Console includes monitoring the catheter as well as console functionality, aided by a number of accessory devices that make up the overall system such as: power cords, extension cables, connection box, foot switch, diaphragmatic movement sensor, esophageal temperature sensor cable. In addition, the system incorporates a number of non-medical device items such as a scavenging hose, wrench, and nitrous oxide tank.

## Diaphragm Movement Sensor

The Diaphragm Movement Sensor (DMS) is a patch device placed on the patient just below the costal cartilage on the right side and used to monitor a phrenic nerve pacing response. It is connected to the Inter Connection Box (ICB) sending data to be displayed on the user interface of the Console. By integrating the information into the Cryoablation Console, the user can be notified when the measured pacing response decreases below a pre-set value.

Phrenic nerve monitoring is essential for ensuring safety during a cryoablation procedure. It has been reported with cryoablation balloon technology that the incidence of phrenic nerve injury ranges from 1.7-11.2% in the acute setting and persists in 0.3%-1.8% of patients at one year. The 2017 HRS Expert Consensus states monitoring of diaphragmatic excursion with abdominal palpation, fluoroscopy or intracardiac ultrasound while pacing the phrenic nerve from the SVC or subclavian vein during

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ablation is now considered standard of care when ablating the right sided PVs. The physician should stop ablating if a significant reduction in diaphragmatic excursion is detected. Currently, manually palpating the abdomen is the most common monitoring method. However, this technique is subjective and experience dependent.

The accelerometer based DMS provides an additional means to visually monitor diaphragmatic excursions during ablation. The DMS is designed to detect motion and can be used as an adjunct to palpation during phrenic nerve pacing while delivering cryo energy. The DMS is connected to the ICB of the Cryoablation Console and sends data to be displayed on the Cryoablation Console's user interface (see Figure 6 below).

![img-5.jpeg](img-5.jpeg)
Figure 6: Diaphragm Movement Sensor (DMS) Data Cryoablation Console Display Phrenic Nerve Pacing Signal & Alert

By integrating the information into the Console, the physician can visually monitor the pacing response throughout the ablation. Additionally, the console can alert the physician with audible and visual notifications if the pacing response decreases below a pre-set value. The measured pacing response is displayed graphically and as a percentage of a baseline measurement; with the first physical excursion establishing the baseline at 100%. The default threshold for notification is 80% and can be adjusted as desired by the physician. The measurement display changes from "Blue" to "Red" if the value falls below the physician's programmed set notification value (see Figure 6 above).

The DMS is an adjunct tool designed to complement physicians' established clinical practice for phrenic nerve assessment. The DMS is not a substitute for physicians' standard of care for phrenic nerve assessment during a cryoablation.

## Esophageal Temperature Sensor Cable

Esophageal ulceration may occur due to thermal damage from cryoablation in areas with close proximity to the esophagus, with a reported incidence of up to 17% of patients.

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Although generally reversible, it may lead to the fatal complication of atrioesophageal fistula. Although not proven to reduce the incidence of esophageal injury, esophageal temperature monitoring is frequently used during cryoablation. As noted above, the ICB is designed to receive information from other proprietary devices such as an esophageal temperature probe. When connected, the esophageal temperature probe provides monitoring and alert data to the console for display. Esophageal temperature probes are widely available in stand-alone measurement systems and used as such within the EP lab. The Esophageal Temperature Sensor Cable enables the connection of a commercially available 400 series temperature probe (for example, Truer Medical 400 Series General Purpose Probes and DeRoyal Temperature Monitoring, Product No. 81-020409) to be connected to the Console.

This feature integrates the detection of the esophageal temperature and provides a reminder alert to the physician if the esophageal temperature goes below a physician preset notification value. The default threshold for notification is 20°C and can be adjusted as desired by the physician. The measured esophageal temperature turns the measurement display from "Blue" to "Red" if the temperature probe falls below a physician pre-set value (see Figure 7 below). This feature potentially reduces adverse events such as esophageal ulcerations and fistulas.

![img-6.jpeg](img-6.jpeg)
Figure 6: Esophagus Temperature Monitoring Data Display

## Inter Connection Box

The ICB interfaces the Cryoablation Catheter with the Console. It receives the Catheter monitoring signals, DMS data, as well as information from other proprietary devices such as an esophageal temperature probe, a tip pressure sensor and various other safety systems. The ICB then transmits this information to the Console for display and user analysis.

## Console Foot Switch

The Console Foot Switch interfaces with the Console and allows the user to inflate the Cryoablation Catheter, start and stop flow of N2O (cryoablation) as well as deflate the Cryoablation Catheter at the conclusion of the ablation.

## Cryo Cable

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The Cryo Cable is a sterile, single-use cable that provides the connectivity between the Cryoablation Catheter to the Console to support the delivery of liquid refrigerant and the evacuation of remaining N2O gas.

## Cryoablation Catheter Extension Cable

The Cryoablation Catheter Extension Cable is a sterile, single-use cable that provides the connectivity between the Cryoablation Catheter and the Console ICB to support the delivery of liquid refrigerant and the evacuation of remaining N2O gas.

## Cryo Mapping Catheter EP Electrical Cable

The EP Electrical Cable is a sterile, single-use accessory for the Cryo Mapping Catheter and is designed to interface (connect) the Cryo Mapping Catheter with standard EP recording systems.

This medical device product has functions subject to FDA premarket review as well as functions that are not subject to FDA premarket review. For this application, if the product has functions that are not subject to FDA premarket review, FDA assessed those functions only to the extent that they either could adversely impact the safety and effectiveness of the functions subject to FDA premarket review or they are included as a labeled positive impact that was considered in the assessment of the functions subject to FDA premarket review.

## VI. ALTERNATIVE PRACTICES AND PROCEDURES

There are several other alternatives for the correction of symptomatic, drug refractory, recurrent, paroxysmal atrial fibrillation, including:

- Commercially available PMA-approved ablation devices
- Pharmacological therapy for rate and/or rhythm control
- Electrical or pharmacological cardioversion
- Surgical intervention to create atrial lesions
- Implantable devices to control heart rate

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 Cryoablation System is commercially available in the following countries: Andorra, Unit. Arab Emir., Dutch Antilles, Austria, Australia, Azerbaijan, Belgium, Bulgaria, Belarus, Switzerland, Chile, Costa Rica, Cyprus, Czech Republic, Germany, Denmark, Algeria, Estonia, Spain, Finland, France, Great Britain, Georgia, Greece, Hong Kong, Croatia, Hungary, Ireland, Israel, Iraq, Iran, Iceland, Italy, Japan, South Korea, Kuwait, Kazakhstan, Liechtenstein, Lithuania, Luxembourg, Latvia, Macau, Malta, Malaysia, Netherlands, Norway, New Zealand, Oman, Poland, W. Bank Gaza Strip, Portugal,

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Qatar, Romania, Serbia, Russian Fed., Saudi Arabia, Sweden, Singapore, Slovenia, Slovakia, Thailand, Turkey, Ukraine, Kosovo and South Africa.

There are no countries from which the Cryoablation System has been withdrawn from marketing for any reason related to safety and effectiveness. The Cryoablation System has not been marketed in the United States.

## 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.

Table 5: Potential Adverse Events and Adverse Device Effects for PAF Ablation and Study Device

|  Access site complications | Headache  |
| --- | --- |
|  Allergic reaction | Heart failure  |
|  Anemia | Hematoma  |
|  Arrhythmias | Hemothorax  |
|  Bleeding/Hemorrhage | Hemodynamic instability  |
|  Blurred vision | Hypertension/Hypotension  |
|  Cardiac perforation | Inadvertent injury to adjacent structures  |
|  Cardiac/pulmonary arrest | Infection  |
|  Catheter entrapment | Myocardial infarction  |
|  Cerebrovascular accident (CVA) | Nerve weakness/palsy/injury (i.e. phrenic/ vagus)  |
|  Chest discomfort/pain or pressure | Pericarditis  |
|  Complete heart block (transient/permanent) | Pneumothorax  |
|  Complications of sedative agents/anesthesia/medications | Pseudoaneurysm  |
|  Coronary artery spasm | Pulmonary complications (i.e. edema, pulmonary hypertension, pleuritis, pneumonia)  |
|  Cough | Pulmonary vein stenosis  |
|  Death | Radiation injury/exposure  |
|  Diaphragmatic paralysis | Renal insufficiency/failure  |
|  Dizziness or lightheadedness | Respiratory Depression  |
|  Edema | Residual atrial septal defect (ASD)  |
|  Pericardial effusion/pleural effusion | Skin burns (i.e. radiation/defibrillator/ cardioverter)  |
|  Elevated cardiac enzymes | ST segment Elevation  |
|  Embolism (venous/arterial) (i.e. air, gas, thrombo, pulmonary) | Sore Throat  |
|  Endocarditis | Tamponade  |
|  Esophageal injury | Thrombus/thrombosis  |
|  Fever | Transient ischemic attack (TIA)  |
|  Exacerbation of existing conditions | Valvular damage  |
|  Fatigue | Vasospasm  |

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

## IX. SUMMARY OF NONCLINICAL STUDIES

### A. Laboratory Studies

Testing of the Boston Scientific Cardiac Cryoablation System included verification and validation testing (device, system and software), device electrical safety testing, biocompatibility of patient-contacting materials, sterilization, packaging testing, and animal studies. Performance testing was conducted to demonstrate design integrity. Tests that were identified in standards or guidance documents were performed based on product specification requirements. Test results confirm that the POLARx™, POLARx FIT™, POLARMAP™, POLARSHEATH™ and SMARTFREEZE™ devices met product specifications. In all cases, specifications must be met with a capability appropriate to the patient risk relevant to the specification being tested, as determined by a risk assessment. Test results for POLARx™ and POLARx FIT™, POLARSHEATH™, POLARMAP™ and SMARTFREEZE™ are summarized in Table 6, Table 7, Table 8, and Table 9 respectively. There have been no major changes to the design or materials for these devices.

Table 6: Summary of POLARx™ and POLARx FIT™ Bench Testing

|  Test | Purpose | Acceptance Criteria | Results  |
| --- | --- | --- | --- |
|  Catheter and balloon dimensions | Ensure the catheter shaft and balloon dimensions are consistent and enable compatibility with other devices | All 7 dimensions measured must meet specified tolerances. | Passed  |
|  Balloon surface temperature | Ensure the balloon surface temperature during ablation is consistent | Balloon surface temperature during the last 2 minutes of a 4 minute ablation, as measured in an in vitro model, must meet specified tolerances. | Passed  |
|  Balloon pressure control | Ensure the internal balloon pressure is consistent whenever it is | Average internal balloon pressure during all inflated states must meet specified tolerances. | Passed  |

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|   | inflated, including during ablation |  |   |
| --- | --- | --- | --- |
|  Simulated use cycling (including balloon inflation/deflation cycling, temperature cycling, catheter articulation cycling, insertion/withdrawal cycling into/out of POLARSHEATH TM) | Ensure the catheter appropriately communicates with the console, responds to the console's commands and user articulation, and is compatible with other single-use devices over 16 cycles of cryoablation, and is free of mechanical defects or leaks after cycling | All specifications for communication with the console, response to console commands and user articulation, compatibility with other single-use devices, and freedom from mechanical defects must be met via visual inspection, and leak integrity via pressure decay testing and visual inspection, during and/or after 16 cycles of cryoablation in a vascular simulation apparatus. | Passed  |
|  Catheter steering function | Ensure the catheter tip can be deflected and held in a deflected shape using the handle knobs | The deflection angle of the tip must achieve and hold its minimum specified value when the tip is deflected and locked via the handle knobs. | Passed  |
|  Catheter steering reliability | Ensure the catheter steering will be reliable in use | The catheter must be visually intact after 50 steering cycles in both directions. | Passed  |
|  Contrast injection | Ensure the catheter can operate reliably with an automated contrast injection system operating at ≤ 500 psi injection pressure | When the guidewire lumen is modified to allow pressurization and pressurized to failure, the burst pressure must meet its specified minimum value. | Passed  |
|  Leak integrity | Ensure the catheter will not leak refrigerant during use | When tested in pressure or vacuum decay testing, the catheter inner balloon channel pressure and vacuum decay rates and outer balloon channel vacuum decay rate must meet their specified maximum values. | Passed  |
|  Guidewire lumen reliability | Ensure the guidewire lumen can operate reliably when pressurized and aspirated in use | The guidewire lumen must be free of leaks or aspirated air in accordance with ISO 10555-1 (Intravascular Catheters – Sterile and Single-Use Catheters – Part 1: General Requirements), Annexes C and D. | Passed  |

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|  Tensile strength | Ensure the catheter components and assembly joint tensile strengths are consistent and adequate to be reliable in use | All 40 tensile strengths measured must meet specified minimum values. | Passed  |
| --- | --- | --- | --- |
|  Buckling force | Ensure that appropriate use of the catheter will not damage the surrounding tissue | The force required to buckle the distal 3.5 inches of the catheter must meet specified maximum values. | Passed  |
|  Kink resistance | Ensure that appropriate use of the catheter will not kink the catheter shaft | The catheter must be free of visual evidence of kinks or bond separation when subjected to a bend radius of 0.6 inches. | Passed  |
|  Torque response | Ensure that balloon will turn in response to turning the catheter handle | The torque induced at the balloon when the catheter handle is rotated 180° must meet the specified minimum value. | Passed  |
|  Torque strength | Ensure that catheter mechanical integrity is adequate to be reliable when the handle is turned in use | The specifications for leak integrity via pressure decay testing and visual inspection must be met when the catheter handle is turned 360° relative to the balloon. | Passed  |
|  Relief pressure | Ensure the catheter internal pressure will not exceed the burst pressure in use | When the catheter is modified to observe the relief valve in the handle, the valve must be closed at the maximum internal operating pressure and open at the minimum burst pressure. | Passed  |
|  Burst pressure | Ensure the catheter can reliably withstand the internal pressure it will experience in use | When the catheter is modified to disable the relief valve in the handle and pressurized to failure, the balloon must be observed to burst and the burst pressure must meet its specified minimum value. | Passed  |
|  Blood detection system | Ensure the system can detect presence of conductive liquid (e.g. blood) inside the catheter | The system must trigger a console error for blood detection when the blood detection sensor is exposed to physiologic saline. | Passed  |

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Table 7: Summary of POLARSHEATH™ Bench Testing (FDA Cleared via K223824)

|  Test | Purpose | Acceptance Criteria | Results  |
| --- | --- | --- | --- |
|  Sheath dimensional requirements | Ensure the sheath and dilator dimensions are consistent and compatible with other devices | All 7 dimensions must meet specified tolerances. | Passed  |
|  Tensile strength | Ensure the sheath assembly joint tensile strengths are consistent and adequate to be reliable in use. | All 5 tensile strengths must meet specified minimum values. | Passed  |
|  Torque response | Ensure the shaft will turn in response to turning the sheath handle | The torque induced at the shaft tip when the sheath handle is rotated 180° must meet the specified minimum value. | Passed  |
|  Torque strength | Ensure the sheath mechanical integrity is adequate to be reliable when the handle is turned in use | The specifications for leak integrity via aspiration testing and visual inspection must be met when the sheath handle is turned 360° relative to the shaft tip. | Passed  |
|  Curve deflection | Ensure the sheath tip articulates, achieves specified deflection profiles, maintains deflection and articulates without failure for at least 16 cycles. | All specifications related to curve deflection must be met via dimensional inspection with specified tolerances or visual confirmation when the sheath tip is articulated. | Passed  |
|  Leak integrity | Ensure the sheath components related to the fluid pathway are free from fluid leakage or air ingress during use. | All specifications related to leak integrity must be met via visual confirmation during aspiration or fluid pressure testing. | Passed  |

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Table 8: Summary of POLARMAP™ Bench Testing (FDA Cleared via K223824)

|  Test | Purpose | Acceptance Criteria | Results  |
| --- | --- | --- | --- |
|  Catheter dimensional requirements | Ensure the catheter dimensions are consistent and compatible with other devices | All 8 dimensions must meet specified tolerances. | Passed  |
|  Electrical continuity | Ensure sufficient number of functioning electrodes | A minimum of 7 electrodes must be free of open or short circuits with a resistance less than the specified maximum value. | Passed  |
|  Buckling force | Ensure that appropriate use of the catheter will not damage the surrounding tissue | The force required to buckle the distal 2.0 inches of the catheter must meet specified maximum values. | Passed  |

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|  Stiffness | Ensure the distal section of the catheter has sufficient column strength to position the distal section of the catheter in the vein in use | The stiffness of the distal segment of the catheter must exceed the specified minimum value. | Passed  |
| --- | --- | --- | --- |
|  Kink resistance | Ensure that appropriate use of the catheter will not kink the catheter shaft. | The catheter must be free of visual evidence of kinks or defects when subjected to the specified bend radii. | Passed  |
|  Cryo fatigue cycling | Ensure sufficient number of functioning electrodes after simulating cryoablations. | A minimum of 7 electrodes must be free of bond joint failures and free of open or short circuits with a resistance less than the specified maximum value after simulating exposure to 16 cryoablation cycles. | Passed  |
|  Simulated use cycling | Ensure the mechanical and electrical integrity of the catheter can withstand repeated expected use with compatible devices. | The catheter must be free of kinks, material or bond joint failures, and free of opens or shorts on a minimum of 7 electrodes, and the distal loop shall conform to a percentage of the nominal loop diameter after cycling without damage that causes extraneous material to be expelled from the balloon catheter. The connector must be free of opens or shorts on a minimum of 7 electrodes after connection/disconnection cycles with the EP electrical cable. | Passed  |
|  Tensile strength | Ensure the catheter assembly joint tensile strengths are consistent and adequate to be reliable in use. | All 3 tensile strengths must meet specified minimum values. | Passed  |
|  Torque resistance | Ensure the catheter mechanical integrity is adequate to be reliable when turned in use | The catheter must be free of bond joint or material failures via visual inspection after rotating the connector 720° relative to a fixed tip. | Passed  |
|  Corrosion resistance | Ensure catheter meets applicable requirements | The metallic components of the catheter intended for fluid path | Passed  |

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Table 9: Summary of SMARTFEEZETM System Bench Testing

|  Test | Purpose | Acceptance Criteria | Results  |
| --- | --- | --- | --- |
|  Electrical Safety | Ensure the SMARTFREEZETM System is compliant to basic safety and essential performance requirements. | IEC 60601-1:2005/AMD2:2020 (edition 3.2) | Passed  |
|  Electromagnetic Compatibility | Ensure the SMARTFREEZETM System is compliant to basic safety and essential performance requirements with respect to electromagnetic disturbances and emissions. | IEC 60601-1-2:2014+A1:2020 (edition 4.1) | Passed  |
|  System Verification | Ensure the SMARTFREEZETM System meets the design requirements. | SMARTFREEZTME System must meet the design inputs defined in the product requirements. | Passed  |
|  System Validation | Ensure the SMARTFREEZETM System meets the user needs. | SMARTFREEZETM System must meet the design inputs defined in the user requirements. | Passed  |

# Biocompatibility Testing

Biocompatibility testing of the Cryoablation Balloon Catheters, POLARMAP™ Circular Mapping Catheter, and POLARSHEATH™ Steerable Sheath was conducted in accordance with ISO 10993-1 Biological Evaluation of Medical Devices – Part 1: Evaluation and Testing within a Risk Management Process, FDA Guidance – Use of International Standard ISO 10993-1 – Guidelines for Industry and Food and Drug Administration Staff, and Boston Scientific’s internal procedures for Biocompatibility.

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The summary data in Table 10 supports that the Cryoablation Balloon Catheters, POLARMAP™, and POLARSHEATH™ devices have acceptable biological risk and remain biocompatible for their intended uses as an externally communicating, limited (<24 hours) contact devices with circulating blood.

Table 10: Biocompatibility Testing Summary

|  Test | Result  |
| --- | --- |
|  MEM Elution Cytotoxicity | Pass  |
|  Guinea Pig Maximization/Sensitization | Pass  |
|  Intracutaneous Reactivity | Pass  |
|  Acute Systemic Toxicity | Pass  |
|  Material-Mediated Rabbit Pyrogenicity | Pass  |
|  SC5b-9 Complement Activation Assay | Pass  |
|  Hemolysis (Direct Contact and Extract) | Pass  |
|  In-Vivo Thrombogenicity (Heparinized) | Pass  |
|  In-Vivo Thrombogenicity (Non-Heparinized) | Met Expected Outcome*  |
|  Genotoxicity: Ames Bacterial Reverse Mutation Study | Pass  |

* Test and predicate control responses are equivalent in the absence of heparin. Test Article Scores: 4/4/4 and Control Article Scores: 4/4/4

Patient contacting materials of the POLARx™ Cryoablation Balloon Catheters, POLARMAP™, and POLARSHEATH™ tested for biocompatibility are listed in Table 11.

Table 11: Patient Contacting Material Tested for Biocompatibility

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|  POLARx™ Cryoablation Balloon Catheters  |   |   |
| --- | --- | --- |
|  Component | Material | Color  |
|  Balloon Protector | Polyetrafluoroethylene (PTFE) | Natural  |
|  Adhesive | Loctite 3321 | Natural  |
|  Luer Lock Connector | Makrolon 2658-550115 | Natural  |
|  Steerable Shaft | Pebax 3533
Pebax 4533
Pebax 5533
Pebax 7233 | Pantone 292C
Pantone 295C  |
|  Outer Balloon | Pellethane 2363-90AE
Pebax 6333 SA01 MED | Natural  |
|  Guidewire Lumen | Evonik Vestamid Care ML32
Pebax 6333 SA01 MED
Pebax 7233 | Pantone 295C  |
|  Metallic Indicator | Sharpie Silver Marker | Natural  |
|  POLARMAP™ (FDA Cleared via K223824)  |   |   |
|  Component | Material | Color  |
|  Introducer | FEP |   |

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|  Distal Shaft | Pebax 6333 SA01 Med
(20% Barium Sulfate + PROPELL)

Pebax 5533 SA01 Med | Pantone 295C  |
| --- | --- | --- |
|  Hypotube | 304 Stainless Steel | Natural  |
|  Adhesive | Adhesive, Dymax, 203A-CTH-F-VT | Natural  |
|  Electrode Band | Platinum, Irridium | Natural  |
|  POLARSHEATH™ (FDA Cleared via K223824  |   |   |
|  Component | Material | Color  |
|  Adhesive | Adhesive, Loctite 3321 | Natural  |
|  Steerable Shaft | PTFE
Pebax 3533
Pebax 5333
Pebax 6333
Pebax 7233 | Pantone 292C
Pantone 6C
Pantone 11C
Pantone 11C  |
|  Dilator L | HDPE DMDA-8904
LDPE 2020T |   |
|  Extension Line, Female Luer Lock to Male Luer Slip | PolyOne PVC Geon
M4910TN29494

Natvar Non-DEHP PVC |   |
|  Silicon Sheet | Silastic Q7-4850 | Natural  |
|  Valve, Housing | Lexan Polycarbonate HP1-1H112 | Natural  |

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|  Valve, Cap | Lexan HP1-1H112 | Natural  |
| --- | --- | --- |
|  Silicone Oil | Silicone Oil | Natural  |

# B. Animal Studies

The sponsor submitted one (1) non-GLP and one (1) GLP animal study to support their IDE application (G190060) using the Boston Scientific Cardiac Cryoablation System. Testing demonstrated that the system rapidly and successfully delivered cryo energy to targeted left superior and right superior pulmonary veins in the left atria. Lesions were created using nominal (240 sec) and "worst case" (480 sec) refrigerant applications and myocardial lesions were visually verified grossly and microscopically. The overall device performance from a pathological perspective was characteristic of cardiac ablation and the electrophysiologists who conducted the studies found the catheter easy to navigate to each PV. There were no procedural complications, such as myocardial infarction, myocardial perforation, or esophageal/lung/pericardial/phrenic nerve injury, with any test subject. However, several significant adverse events occurred:

1. Clinically significant PV stenosis, i.e.,  $>70\%$ , was observed in one (1) non-GLP study animal and two (2) GLP study animals, all with 240 sec refrigerant application. Also, mild  $(<50\%)$  to moderate  $(>50\%, <70\%)$  PV stenosis was frequently observed, primarily in the LSPV per the 2017 HRS/EHRA/ECAS/APHRS/SOLAECE Expert Consensus Statement. Canine PVs are small in diameter relative to human anatomy. Close review of procedural imaging provided convincing evidence that the protocol instruction to achieve a full occlusion of the targeted PV with the balloon before delivering cryo energy exerted greater axial force in the smaller diameter PVs which resulted in compression of anatomical structures. Data from a small OUS CE Mark clinical study with forty-eight (48) patients treated at the time of the IDE submission showed that, to date, no patient reported symptoms of PV stenosis, which supported the conclusion that challenging anatomy of the animal model contributed to the stenotic observations.

2. A clinically significant thrombus in one (1) high dose (480 sec) GLP study animal was found; however, downstream microemboli were not observed. Minimal thrombosis was observed at a markedly stenotic LSPV in another animal, also high dose, that the pathologist suggested was secondary to ostial healing and adjacent focal endocardial trauma from the transseptal puncture. Neurological deficits were observed in this animal that may have been associated with the thrombus observed at the LSPV. The neurological symptoms were not life-threatening and resolved prior to the 30-day pre-termination examination. Observations of thrombus were restricted to PVs that were cryoablated with a double dose (2 x 240 sec) and the dogs did not receive anti-coagulation therapy post-procedure per standard clinical practice. If the dogs had received anti-coagulation therapy this may have minimized this risk. In the OUS CE Mark study with forty-eight (48) patients treated at the time of the IDE submission four

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(4/48) patients had AF recurrence and were admitted for follow-up RF ablation. Prior to the procedure patients were screened for LA thrombus and PV stenosis with ICE and 3D EAMs; there was no evidence of thrombus or PV stenosis at the time of the second RF procedure.

Table12: Summary of the in vivo Animal Studies

|  Animal Model | 21 CFR § 58 Compliant | Type of Study | Time Point | Number of Animals | Study Groups  |   |
| --- | --- | --- | --- | --- | --- | --- |
|   |   |   |   |   |  Acute | Chronic  |
|  Canine | No | Safety Assessment | Acute/Chronic (34-35 days) | 5 | n=2 | n=3  |
|  Canine | Yes | Safety and Effectiveness | Acute/Chronic (34-35 days) | 12 | n=8* | n=8*  |

*In the GLP study, groups were designated by the number of treatments a PV received. Two (2) PVs were targeted in each animal (n=8, total) with one PV receiving 240 sec refrigerant application and one (1) PV receiving two (2) 240 sec refrigerant applications separated by five (5) minutes between applications.

A non-GLP Animal Study was conducted to assess adverse events (AEs) associated with the pulmonary vein (PV) isolation (PVI) procedure evaluating the subject device at acute and chronic time points. Two (2) electrophysiologists conducted the study. The study enrolled five (5) mongrel dogs as follows:

- Acute: n=2 (a second dog was added from the chronic cohort after the dog experienced non-device related complications that necessitated early euthanasia).
- Chronic: n=3 animals.
- Ten (10) PVs were targeted for ablation:

- Nine (5/10, RSPV plus 4/10 LSPV) PVs were ablated with a single 240sec application of refrigerant.
- One (1/10) LSPV was too small for targeted ablation.
- The phrenic nerve was monitored during RSPV ablation with no detrimental effects noted.

- Animals were maintained for  $\sim 35$  days. Prior to euthanasia animals were anesthetized to assess PVI durability via pacing EGMs and PV stenosis (PVS) by ICE or fluoroscopy (compared to baseline).

# Results:

- PV ablations in the acute animals were uneventful; necropsies were not performed.

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- In chronic animals (n=3), six (6) PVs were ablated, targeted pathology of PVs performed:

- Ablations averaged 24-30sec to reach target temperature with time-to-isolation (TTI) of 17-42sec.
- 100% acute PVI was achieved following a single cryoablation.
- 100% chronic PVI assessment demonstrated lesion durability.
- 5/6 ablated PVs had 100% circumferential lesions.

- Clinically significant PV stenosis was observed in one (1) ablated PV.

- A single LSPV was completely occluded.
- Additional data was provided for FDA review that supported the observation that the balloon catheter was placed too deep into the PV and that the LSPV was very small (~6mm). The data and procedural images demonstrated that the balloon catheter significantly compressed the LSPV wall/myocardial sleeve.

Further evaluation of the procedural images allowed calculation of PV vascular compression. Greater levels of vascular compression resulted in more severe stenosis, which was further corroborated by larger lesion widths, as would be expected with compressed PVs. Overall, the cryoballoon appeared too large for the small diameter PVs of the canine heart.

A GLP Animal Study conducted to demonstrate the overall safety of the Boston Scientific Cardiac Cryoablation System when used for pulmonary vein (PV) isolation (PVI) in a chronic canine model. Four (4) electrophysiologists performed the cryoablations with the Polar X Cryoablation Catheter System. The study enrolled eight (8) mongrel dogs, distributed between two (2) groups (n=4, each), as follows:

- In all animals two PVs (RSPV, LSPV) were targeted for ablation.
- In Group 2 animals, the two 240 sec ablations were delivered five (5) minutes apart for a total of 480 sec ablation.
- Animals were maintained for ~35 days. Prior to euthanasia animals were anesthetized to assess PVI durability and PV stenosis (PVS) by ICE (compared to baseline).
- Safety of the test device was further characterized through gross necropsy and histopathology.

Results:

- Cryoablation was completed per the protocol except ablation was terminated early due to transient phrenic nerve palsy (nerve function returned) in a Group 1 animal and a Group 2 animal, each.
- Average time-to-isolation (TTI) was 22sec (range: 13sec - 28sec).

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- All treated PVs were evaluated microscopically, and lesions appeared to be circumferential and transmural.
- 87.5% (14/16 PVs) achieved Acute PVI
- Chronic PVI was confirmed in 9/14 (64.3%) treated PVs as verified by pacing EGMs prior to euthanasia.

- Two (2/16) PVs had severe PVS > 70% when compared to baseline.
- Both animals were in Group 1 treatment, i.e., 240 sec refrigerant application.
- Neither animal had clinical signs of stenosis such as coughing, dyspnea, or hemoptysis.

The OUS CE Mark study reviewed at IDE submission (48 patients successfully treated) showed that no patient reported symptoms suggestive of PVS. The OUS data and the additional evidence provided FDA demonstrating small canine pulmonary veins, especially the LSPV, led to the determination of "reasonable safety prior to first use in man" for approval of the IDE application.

- Observation of thrombus in two (2) Group 2 (double dose) animals:
- A significant thrombus (8-9mm in diameter and 20mm long) was observed in the LA via ICE, confirmed by gross necropsy, in a Group 2 animal.
- Histopathology confirmed the thrombus overlay the cryoablation site and was independent of the transseptal puncture.
- No downstream thrombotic emboli were observed in this animal.
- In another Group 2 animal minimal thrombus on the LSPV cryolesion was observed microscopically by the pathologist.
- The pathologist suggested the thrombus may have been secondary to a marked healing response of a stenotic LSPV ostium and a healing response from adjacent transseptal puncture site.
- Non-life-threatening neurological deficits that spontaneously resolved were observed during the in-life phase of the study. The pathologist suggested these deficits may have been secondary to upstream thromboemboli from the thrombus.

- The electrophysiologists found performance of the catheter clinically acceptable, and they found the catheter easy to navigate. The EPs gave PV occlusion scores by the catheter balloon, prior to each ablation, as "4" (i.e., complete).

The results suggest that the double-dose refrigerant application is very risky, and the single-dose refrigerant application raises concerns, as well. Possibly the recommended dose should be lowered to minimize safety concerns. The pathologist suggested that the large mural thrombus resulted from increased levels of mural necrosis from the double-dose of cryoablation making the associated endocardium more thrombogenic. The animals did not receive anti-coagulation therapy post-procedure and if they had, this may have minimized thrombus formation. BSC argued that standard clinical practice, i.e., anti-coagulation therapy, will mitigate this risk in

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patients. The minimal thrombus observed on the LSPV cryolesion may have contributed to the neurological deficits observed in this animal, i.e., transient cerebral ischemia that resolved.

## C. Additional Studies

### Packaging

All devices that comprise the Boston Scientific Cardiac Cryoablation System are packaged separately. Packaging verification testing was performed to demonstrate that the POLARx™ Cryoablation Balloon Catheters, POLARMAP™, and POLARSHEATH™ packaging can withstand the hazards of the distribution environment, and that the sterility of the device is maintained throughout the labeled shelf life. Package integrity testing included a visual assessment, bubble leak testing, and seal strength testing.

Testing was conducted on both packaging at the baseline condition and packaging aged to the product shelf life.

### Bioburden

Bioburden data is generated to ensure that sterility assurance level (SAL) is not impacted by the product bioburden levels. Bioburden testing is routinely conducted for POLARx™ Cryoablation Balloon Catheters, POLARMAP™, and POLARSHEATH™ to meet the acceptance criteria of less than 10,000 CFU/device per Boston Scientific’s internal procedures based upon EN ISO 11737-1.

The devices are manufactured and packaged in an ISO 8 controlled area.

### Sterilization

POLARx™ Cryoablation Balloon Catheters, POLARMAP™, and POLARSHEATH™ are sterilized using ethylene oxide (EO) gas and has been validated per AAMI / ISO 11135:2014, Sterilization of health care products – Ethylene oxide; Requirements for the development, validation, and routine control of sterilization process for medical devices. Results from the sterilization studies demonstrate the product satisfies a minimum Sterility Assurance Level (SAL) of 10^{-6} and residual EO levels were within acceptable ranges in accordance with EN ISO 10993-7, Biological Evaluation of Medical Devices - Part 7: Ethylene Oxide Sterilization Residuals.

## SUMMARY OF PRIMARY CLINICAL STUDIES

The applicant performed a clinical study to establish a reasonable assurance of safety and effectiveness of catheter ablation with the Cryoablation System for the treatment of symptomatic, drug refractory, recurrent, Paroxysmal Atrial Fibrillation (PAF) in the US, Europe, Canada, Asia-Pacific under IDE # G190060. Data from this clinical study were the basis for the PMA approval decision. A summary of the clinical study is presented below.

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## FRoZEN AF Clinical Study:

A maximum of 405 subjects treated with the Cryoablation System and POLARx™ Cryoablation Balloon Catheter were required to be enrolled in the study, inclusive of 325 non roll-in treatment subjects and a maximum of 80 roll-in treatment subjects undergoing the index ablation procedure. Up to 50 sites in North America, Europe and Asia-Pacific could participate in this study. At least 50% of the sites and 50% of the subjects were required to be enrolled in the United States, and potentially up to 10% of subjects were allowed to be enrolled in 3 to 5 combined sites from Hong Kong and Taiwan. Up to 10 sites in Europe could contribute to enrollments. No study site was allowed to contribute more than 15% of the required enrollment.

## PV Stenosis Substudy:

A minimum of fifty (50) non roll-in treatment subjects were required to be enrolled in a PV Stenosis Substudy at up to 8 study sites. The PV Stenosis Substudy included a baseline and a 3 to 6 months CT/MRI imaging data post index procedure to evaluate the potential extent of PV stenosis. Each site participating to the PV Stenosis substudy was allowed to enroll a maximum of 18 substudy subjects.

## FROzEN-AF Extension Study:

In February 2022, the overall FROzEN-AF Clinical Study was expanded, to include the "POLARx FIT™: FROzEN-AF Extension Study", in addition to the FROzEN-AF Study. Details of the POLARx FIT™: FROzEN-AF Extension Study are included below.

## FRoZEN AF Clinical Study

### A. Study Design

The study was a prospective, single-arm, multi-center clinical study. Patients were treated between June 24, 2020 and August 24, 2021. The database for this PMA reflected data collected through September 14, 2022 and included 404 patients. There were 44 investigational sites.

An independent Clinical Events Committee (CEC) adjudicated all deaths, all composite primary safety endpoint events, all potentially procedure or POLARx™ Cardiac Cryoablation System related adverse events, and all unanticipated device effects. An independent Data Monitoring Committee (DMC) reviewed accumulating safety data to ensure patient safety. Additionally, several core laboratories were employed to provide external review of study data.

### 1. Clinical Inclusion and Exclusion Criteria

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

- History of recurrent symptomatic paroxysmal atrial fibrillation (PAF), defined as atrial fibrillation that terminates spontaneously or with

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intervention (either procedure or drug therapy) within seven days of onset. Minimum documentation includes the following:

- a physician's note indicating recurrent self-terminating atrial fibrillation (AF) which includes at least two symptomatic AF episodes within six months prior to enrollment, and
- one electrocardiographically documented AF episode within 12 months prior to enrollment.

- No amiodarone use within 90 days prior to enrollment;
- Subjects who are indicated for an ablation procedure for paroxysmal atrial fibrillation (PAF) according to 2017 HRS expert consensus statement on catheter and surgical ablation of atrial fibrillation;
- Subjects refractory or intolerant to at least one class I or III antiarrhythmic medication or contraindicated to any class I or III medications
- Subjects who are willing and capable of providing informed consent;
- Subjects who are willing and capable of participating in all testing associated with this clinical investigation at an approved clinical investigational center;
- Subjects whose age is 18 years or above, or who are of legal age to give informed consent specific to state and national law.

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

- Any known contraindication to an AF ablation or anticoagulation;
- Continuous AF lasting longer than seven (7) days from onset;
- History of previous left atrial ablation or surgical treatment for AF/ AFL/AT;
- Atrial fibrillation secondary to electrolyte imbalance, thyroid disease, or any other reversible or non-cardiac cause;
- Structural heart disease or implanted devices as described below:

1. Left ventricular ejection fraction (LVEF) < 40% based on the most recent transthoracic echocardiogram (TTE) ≤180 days prior to enrollment);
2. Left atrial diameter > 55 mm OR left atrial volume > 50 ml/m2 ml indexed based on the most recent TTE (≤ 180 days prior to enrollment);
3. An implanted pacemaker, ICD, CRT device or an arrhythmia loop recorder;
4. Previous cardiac surgery: i.e. ventriculotomy or atriotomy (excluding atriotomy for CABG);

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5. Previous cardiac valvular surgical or percutaneous procedure, or prosthetic valve, including mitral valve clips;
6. Interatrial baffle, closure device, patch, or patent foramen ovale (PFO) occlude;
7. Presence of a left atrial appendage occlusion device;
8. Presence of any pulmonary vein stents;
9. Coronary artery bypass graft (CABG), PTCA/ PCI/ coronary stent procedures within 90 days prior to enrollment;
10. Unstable angina or ongoing myocardial ischemia;
11. myocardial infarction within 90 days prior to enrollment;
12. Moderate or severe mitral insufficiency assessed on the most recent TTE (≤180 days prior to enrollment, e.g. pulmonary artery pressure >30 mmHg);
13. Evidence of left atrial thrombus;

- Any previous history of cryoglobulinemia;
- Stage 3B or higher renal disease (estimated glomerular filtration rate, eGFR <45 mL/min);
- History of blood clotting or bleeding disease;
- Any prior history of documented cerebral infarct, TIA or systemic embolism [excluding a post-operative deep vein thrombosis (DVT)] ≤180 days prior to enrollment;
- Active systemic infection;
- Pregnant, lactating (current or anticipated during study follow up), or women of childbearing potential who are, or plan to become, pregnant during the time of the study (method of assessment upon physician's discretion);
- Subjects who are currently enrolled in another investigational study or registry that would directly interfere with the current study, except when the subject is participating in a mandatory governmental registry, or a purely observational registry with no associated treatments; each instance must be brought to the attention of the sponsor to determine eligibility;
- Subjects who in the judgment of the investigator have a life expectancy of less than two years.

2. Follow-up Schedule

All patients were scheduled to return for follow-up examinations at pre-discharge, day 7 follow-up, and at 3-, 6- and 12-months post index ablation procedure. Adverse events and device deficiencies were recorded at all visits. Table 13 lists the protocol-required baseline, procedural, and follow-up assessments.

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Table 13: Data Collection Schedule

|  Procedure/Assessment | Enrollment (up to 30 days before Index procedure) | Baseline (up to 30 days before Index procedure) | Index Procedure (Day 0) | Blanking Period |   | Repeat Procedure | Effectiveness Evaluation Period  |   |   |   |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
|   |   |   |   |  Pre-Discharge (1-7 days post procedure) | Day 7 Follow-up Contact (+/-1 day) | Repeat Procedure for PAF | Month 3 Follow Up (91±14 days) | Month 6 Follow Up (180±30 days) | Month 12 Follow Up (365±30 days) | Unscheduled Visit  |
|  Informed Consent Process, including informed consent signature date | X |  |  |  |  |  |  |  |  |   |
|  Eligibility Criteria | X | X | X |  |  |  |  |  |  |   |
|  Demographics |  | X |  |  |  |  |  |  |  |   |
|  Medical History |  | X |  |  |  |  |  |  |  |   |
|  Blood Tests |  | X1 |  |  |  |  |  |  |  |   |
|  TTE (medical history) |  | X2 |  |  |  |  |  |  |  |   |
|  NIH Stroke Scale (NIHSS) |  | X3 |  | X3 |  |  |  |  |  |   |
|  Neurology Consultation4 |  |  |  | (X)4 |  |  |  |  |  |   |
|  Brain MRI Scan5 |  |  |  | (X)5 |  |  |  |  |  |   |
|  Physical Assessment |  | X |  |  |  |  | X | X | X | X  |
|  Physical Assessment with Cardiovascular/Pulmonary Examination |  |  |  | X6 |  |  |  |  |  |   |
|  Quality of Life (AFEQT and EQ-5D-5L) |  | X |  |  |  |  | X | X | X |   |
|  PV Anatomical Assessment (CT/MRI) |  | X7 |  |  |  |  |  |  |  |   |
|  Screening for LA thrombus (TEE or ICE) |  | X8 |   |  |  | X6 |  |  |  |   |
|  PV Stenosis Assessment (CT/MRI) |  |  |  | (X)9 |  |  | (X)9 | (X)9 | (X)9 | (X)9  |
|  PV Stenosis Screening Substudy (CTMRI) |  | X |  |  |  |  | X |   |  |   |
|  Procedural Data |  |  | X |  |  | X |  |  |  |   |
|  12-Lead ECG |  | X | X | X |  | X | X | X | X | X  |

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|  Procedure/Assessment | Enrollment (up to 30 days before Index procedure) | Baseline (up to 30 days before Index procedure) | Index Procedure (Day 0) | Blanking Period |   | Repeat Procedure | Effectiveness Evaluation Period  |   |   |   |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
|   |   |   |   |  Pre-Discharge (1-7 days post procedure) | Day 7 Follow-up Contact (+/-1 day) | Repeat Procedure for PAF | Month 3 Follow Up (91±14 days) | Month 6 Follow Up (180±30 days) | Month 12 Follow Up (365±30 days) | Unscheduled Visit  |
|  Phrenic Nerve Palsy Assessment |  |  | X10 | (X)10 |  | (X)10 | (X)10 | (X)10 | (X)10 | (X)10  |
|  Holter Monitor (24 hours) |  |  |  |  |  |  |  |  | X |   |
|  Arrhythmia/Event Monitor |  |  |  | X |  |  | X | X | X | X  |
|  Documentation of intervention for AF/AT/AFL (if any) |  |  |  |  |  | X | X | X | X | X  |
|  Medications | Prior and current AAD medications and Anticoagulant therapy regimen from Enrollment through End of Study Visit  |   |   |   |   |   |   |   |   |   |
|  Protocol deviations | From Enrollment through End of Study Visit  |   |   |   |   |   |   |   |   |   |
|  Adverse Event Assessment | Continuous from Enrollment through End of Study Visit  |   |   |   |   |   |   |   |   |   |

1 Blood tests up to 90 days prior to enrollment,
2 TTE either new or from medical file,  $\leq 180$  days prior to enrollment;
3 NIH Stroke Scale (NIHSS) performed at baseline and at the pre-discharge visit
4 Neurology consult is only required if NIH scale worsens from the previous assessment
5 Brain DW-MRI scan required if neurology consultation determines possibility of new stroke
6 Physical Assessment at discharge to include a Cardiovascular/Pulmonary Examination including: weight, resting heart rate, systolic and diastolic blood pressure, O2 saturation, lung auscultation (includes respiratory rate and respiratory rhythm), and temperature,
7 Performed before the case (CT/MRI);
8 TEE within 48 hours prior to the procedure or ICE during procedure
9 Assessed in case of suspected PV stenosis;
10 Screening for phrenic nerve palsy will be performed during ablation, and prior to leaving the EP lab at the completion of the ablation procedure in all subjects. Assessment at discharge and at follow-up visits is only applicable for subjects who had phrenic nerve palsy detected at the index procedure.
Abbreviations: IP = index procedure, NIH = National Institutes of Health, ECG = electrocardiogram, ICE = Intracardiac Echography; PV= pulmonary vein, TTM = trans-telephonic monitor,
TTE = trans-thoracic echocardiogram, TEE = trans-esophageal echocardiogram, CT = Computed Tomography, MRI = Magnetic Resonance Imaging, FU = follow-up. TTE = trans-thoracic echocardiogram, TEE = trans-esophageal echocardiogram, CT = Computed Tomography, MRI = Magnetic Resonance Imaging, FU = follow-up.

## 3. Clinical Endpoints

With regards to safety, the primary safety endpoint was defined as the event free rate at 12 months post procedure. Primary safety events consist of a composite of the following procedure-related and device-related adverse events.

- Acute primary safety endpoint events, events occurring up to 7 days post index or hospital discharge, whichever is later, include:
- Death
- Myocardial infarction

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Transient ischemic attack (TIA)
Stroke/Cerebrovascular accident (CVA)
Vascular access complications
Mitral or tricuspid valvular damage
Thromboembolism/Air embolism leading to a life-threatening event such as a ventricular arrhythmia, stroke, pulmonary embolism, or myocardial infarction and, thromboembolic events that result in permanent injury, require intervention for treatment or prolongs or require hospitalization for more than 48 hours
Gastroparesis/injury to vagus nerve
Pneumothorax
Pulmonary edema/heart failure
AV block

- Cardiac tamponade/perforation, occurring up to 30 days post index procedure.
- Chronic primary safety endpoint events, events occurring through 12 months post procedure, include:
- Atrial esophageal fistula
- Severe pulmonary vein stenosis (≥ 70% reduction in the diameter of the PV or PV branch from baseline)
- Persistent phrenic nerve palsy*

*A non-recovered phrenic nerve palsy at 12 months post index procedure was counted as a chronic primary endpoint. The study collected information on phrenic nerve palsy observed before the end of the index procedure and, when it occurred, potential recovery of the phrenic nerve was assessed during the subsequent study visits.

The secondary safety endpoint was defined as reportable Adverse Events rates at 12 months. Adverse events were collected at all subject follow-up visits.

Reportable events include:
- All Serious Adverse Events
- All Study Procedure-Related Adverse Events
- All Study Device-Related Adverse Events
- All Study Device Deficiencies
- Unanticipated Adverse Device Effects/Unanticipated Serious Adverse Device Effects previously not defined in DFU/Investigator’s Brochure

With regards to effectiveness, the primary effectiveness endpoint was assessed at the Failure-free rate at 12 months post procedure.

Failure is defined as:
- Failure to achieve acute procedural success in the index procedure or repeat procedure during the blanking period
- Use of amiodarone post index procedure
- Surgical treatment for AF/AFL/AT post index procedure

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- Use of a non-study ablation catheter for AF targets in the index procedure or repeat procedure during the blanking period
- More than one repeat procedure with the POLARx catheter during the blanking period (90 days post index procedure)
- Documented atrial fibrillation, or new onset of atrial flutter or atrial tachycardia event (≥ 30 seconds in duration from the study-specific event monitor, Holter Monitor, or from a 10 second 12-lead ECG) between 91 and 365 days post index procedure*
- Any of the following interventions for atrial fibrillation, or new onset of atrial flutter or atrial tachycardia between 91 and 365 days post procedure:
- Repeat procedure
- Electrical and/or pharmacological cardioversion for AF/AFL/AT
- Prescribed any anti-arrhythmic drug (AAD)**

*12-lead ECGs performed during scheduled or unscheduled visits and assessed by the ECG core lab counted for primary effectiveness endpoint assessment. Additional documentation of arrhythmias coming from sources different from those listed above were collected and analyzed separately.

**AADs for endpoint consist of all Class I/III and any Class II/IV medications taken for control of AF/AT/AFL recurrence

The secondary effectiveness endpoint as assessed at the rate of acute procedural success defined as the achievement of electrical isolation of all PVs by using the Cardiac Cryoablation system only. Electrical isolation of a PV is demonstrated by entrance and exit block.

With regard to success/failure criteria, there is one primary safety endpoint and one primary effectiveness endpoint. Both the primary endpoints must pass in order for study success to be achieved.

## Primary Safety Endpoint Hypothesis

Ho: The primary safety endpoint event-free rate at 12 months post procedure ≤ 89%

Ha: The primary safety endpoint event-free rate at 12 months post procedure > 89%

The 12-month primary safety event-free rate will be calculated using Kaplan-Meier methodology. Subjects who withdraw from the study prior to 12 months without experiencing an event will be censored on the date of the withdrawal. The 95% one-sided lower confidence limit (LCL) of the observed safety event-free rate will be compared to the PG of 89%. The null hypothesis will be rejected if the LCL is greater than the performance goal.

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PMA P220032: FDA Summary of Safety and Effectiveness Data

# Primary Effectiveness Endpoint Hypothesis

Ho: The 12-month failure-free rate ≤ 50%

Ha: The 12-month failure-free rate > 50%

The Kaplan-Meier 12-month primary effectiveness event-free rate will be calculated. Subjects who withdraw from the study prior to 12 months without experiencing an event will be censored on the date of the withdrawal. The 95% one-sided lower confidence limit (LCL) of the observed primary effectiveness event-free rate will be compared to the PG of 50%. The null hypothesis will be rejected if the LCL is greater than the performance goal.

# B. Accountability of PMA Cohort

At the time of database lock, of 404 patients enrolled in the PMA study, 76% (308) patients are available for analysis at the 12-month post-operative visit.

All subjects who signed and dated the Informed Consent Form were considered enrolled in the study.

All treatment subjects (per definition below) were counted against the enrollment ceiling of 325 subjects. Subjects were classified as either part of the Roll-In cohort or the Non Roll-In cohort:

Roll-In Subject – To help facilitate investigators' familiarity with the new investigational system and avoid learning curve bias, Roll-in subjects were enrolled at each study site. Each ablating physician needed to treat 1 (one) Roll-in subject with the Cryoablation System.

Non Roll-In Subject – After the Roll-In subject criteria or case review was satisfied (documentation of waiver) for the treating physician, non Roll-in subjects could be enrolled.

Roll-in and non roll-in subjects were further classified as Intent, Attempt, and Treatment as described below.

- Intent - Refers to a subject who was enrolled but did not have any study investigational devices inserted into the body.
- Attempt - Refers to a subject who was enrolled and had any study device inserted into the body but did not receive any Cryoablation application.
- Treatment - Refers to all enrolled subjects who had the study device inserted into the body and received at least one Cryoablation application.

Figure 8 shows the subject disposition for all Roll-In and Non Roll-In subjects in the FROzEN-AF study. Data from Roll-In subjects are not included in endpoint analyses.

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Figure 8 : Subject Disposition and Accountability for Endpoint Analysis
![img-7.jpeg](img-7.jpeg)
*Includes subjects with 'Completed Study' status who missed 12M visit and holter

There were 15 Non Roll-In Treatment subjects that withdrew from the study.

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# C. Study Population Demographics and Baseline Parameters

The demographics of the study population are shown in table 14 below. However, as noted in Table 14, a limited number of Black subjects were enrolled in the study. Additional information on the use of the device on Black subjects will need to be collected by the sponsor in the Post Approval Study to understand if race has any impact in this subgroup on the safety and efficacy of the device.

The average age of the subjects was 62 years. The majority of subjects were male (61.8%). The male gender predominance is consistent with previous clinical studies on PAF ablation. The eligibility criteria involving age limit and BMI limit were removed as of protocol revision H. Thirty-five (35) subjects  $>75$  years were enrolled under protocol version H. Eight (8) patients with BMI  $>40$  were enrolled under protocol version H.

Table 14 presents the demographics and physical assessment data for all Non Roll-In Treatment subjects.

Table 14: Subject Demographics and Physical Assessment Data

|  Characteristic | Measurement | Result  |
| --- | --- | --- |
|  Age at Enrollment (years) | Mean +/- SD | 62 +/- 11  |
|   | Min - Max | 23 - 83  |
|  Gender [N (%)] | Female | 124 (38.2)  |
|   | Male | 201 (61.8)  |
|  Race* [N (%)] | Hispanic or Latino | 5 (1.6)  |
|   | Native American | 1 (0.3)  |
|   | Asian | 35 (11.2)  |
|   | Black | 4 (1.3)  |
|   | Pacific Islander | 0 (0.0)  |
|   | White | 274 (87.5)  |
|   | Other | 1 (0.3)  |
|   | Race Undisclosed | 12 (3.7)  |
|  Height (cm) | Mean +/- SD | 174 +/- 10  |
|   | Min - Max | 147 - 196  |
|  Weight (kg) | Mean +/- SD | 86 +/- 19  |
|   | Min - Max | 45 - 154  |

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Pre-existing conditions and arrhythmia history of Non Roll-In Treatment subjects are summarized in Table 15 and Table 16.

Table 15: Pre-Existing Conditions Recorded at Baseline

|  Characteristic | Measurement | Result  |
| --- | --- | --- |
|  Cardiac Disease History [N (%)] | Ischemic Cardiomyopathy | 8 (2.5)  |
|   | Non-ischemic Cardiomyopathy | 11 (3.4)  |
|   | Myocardial Infarction | 8 (2.5)  |
|   | Angina Pectoris | 17 (5.2)  |
|   | Congenital Heart Disease | 11 (3.4)  |
|   | Congestive Heart Failure | 15 (4.6)  |
|   | Cerebrovascular Disease | 8 (2.5)  |
|   | Peripheral Vascular Disease | 11 (3.4)  |
|   | Hypertension | 183 (56.5)  |
|   | Pulmonary Hypertension | 10 (3.1)  |
|   | Dyslipidaemia | 100 (31.0)  |

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|  Characteristic | Measurement | Result  |
| --- | --- | --- |
|   | Pulmonary Embolism | 1 (0.3)  |
|   | DVT | 2 (0.6)  |
|   | Other Cardiovascular Disease | 13 (4.0)  |
|  Comorbidities [N (%)] | COPD | 10 (3.1)  |
|   | Diabetes | 36 (11.1)  |
|   | Type 2 | 36 (100.0)  |
|   | Hepatic Disease | 7 (2.2)  |
|   | Renal Disease | 4 (1.2)  |
|   | Gastrointestinal Disorder | 57 (17.6)  |
|   | Sleep Disordered Breathing | 67 (20.9)  |
|   | Blood Disorder | 0 (0.0)  |
|   | Carotid Artery Disease | 9 (2.8)  |
|   | TIA | 2 (0.6)  |
|   | CVA | 8 (2.5)  |
|  COVID-19 History [N (%)] | History of COVID-19 | 15 (4.6)  |
|   | Tested Positive for Virus | 14 (93.3)  |
|   | Tested Positive for Antibodies | 5 (33.3)  |
|  Cardiac Procedure History [N (%)] | PTCA | 9 (2.8)  |
|   | Stent | 14 (4.3)  |
|   | CABG | 5 (1.5)  |
|   | Pacemaker/ICD/CRT | 0 (0.0)  |
|   | Cardiac Valve | 0 (0.0)  |
|   | LAAC | 0 (0.0)  |
|   | PFO Intervention | 0 (0.0)  |
|   | ASD Intervention | 0 (0.0)  |
|   | Heart Transplant | 0 (0.0)  |
|   | Other Cardiovascular Procedure | 16 (4.9)  |
|  Other cardiovascular disease include:Other cardiovascular procedures include: Cardioversion, PAD/RCA stents, coronary angiogram, diagnostic heart cath, AAA repair  |   |   |

Table 16: Arrhythmia History

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|  Characteristic | Measurement | Result  |
| --- | --- | --- |
|  Ventricular Arrhythmia History [N (%)] | Ventricular Tachycardia | 11 (3.4)  |
|   | Ventricular Fibrillation | 4 (1.2)  |
|   | Other Ventricular Arrhythmia | 17 (5.2)  |
|  Atrial Arrhythmia History [N (%)] | Atrial Fibrillation | 325 (100.0)  |
|   | Atrial Tachycardia | 36 (11.1)  |
|   | Atrial Flutter | 85 (26.4)  |
|   | Other Atrial Arrhythmia | 7 (2.2)  |
|  Brady Arrhythmia History [N (%)] | Sinus Bradycardia | 149 (45.8)  |
|   | Sinus Node Dysfunction | 12 (3.7)  |
|   | Sick Sinus Syndrome Chronotropic Incompetence | 6 (1.9)  |
|   | Sinus Arrest | 1 (0.3)  |
|   | AV Block 1 | 27 (8.3)  |
|   | AV Block 2 | 1 (0.3)  |
|   | AV Block 3 | 0 (0.0)  |
|   | Other Brady Arrhythmia | 4 (1.2)  |
|  Cardiac Ablation History [N (%)] | Any Cardiac Ablation | 19 (5.8)  |
|  Previous Ablation Arrhythmia [N (%)] | Atrio-Ventricular Nodal Reentrant Tachycardia (AVNRT) | 4 (1)  |
|   | Atypical AFI | 1 (0)  |
|   | Concealed Accessory Pathway (AP) | 1 (0)  |
|   | Other | 3 (1)  |
|   | Premature Ventricular Contraction (PVC) | 1 (0)  |
|   | Typical AFI (CW or CCW) | 9 (3)  |
|   | WPW syndrome | 2 (1)  |
|  Other ventricular arrhythmias include: premature ventricular contractions, rapid ventricular response, supraventricular tachycardia, LAD, LAFB Other atrial arrhythmias include: premature atrial contractions, supraventricular ectopy, AVRT, sinus tachycardia Other brady arrhythmias include: sinus pauses, AV node disease, brady-tachy syndrome, junctional rhythm Other previous ablation arrhythmias include: SVT  |   |   |

The average time between first diagnosis and subject enrollment for the Non Roll-In Treatment subjects was 1.0 years (IQR:0.3 - 3.8 years).

Historical anti-arrhythmic medication status is summarized in Table 17.

Table 17: Historical Anti-Arrhythmic Medication Status

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|  Category | N (%)  |
| --- | --- |
|  History of Amiodarone use | 26/325 (8)  |
|  Subject refractory or intolerant to any Class I or Class III anti-arrhythmic drug taken prior to enrollment* | 268/325 (82.5)  |
|  Subject with contraindication to Class I or III anti-arrhythmic medications* | 88/325 (27.1)  |
|  *Subjects may contribute to both categories. All subjects contributed to at least one category  |   |

## D. Safety and Effectiveness Results

### 1. Safety Results

The analysis of safety was based on the Non Roll-In Treatment and Attempt subjects (N= 326). The results of the main analysis for the primary safety endpoint of the safety event free rate at 12 months post procedure are presented in Figure 9. Adverse effects are reported in Tables 18 to 19.

![img-8.jpeg](img-8.jpeg)
Figure 9: Primary Safety Endpoint Main Analysis

The observed event-free rate at 12 months follow-up was 96.0% with a one-sided 95% lower confidence limit of 93.8%. The lower confidence limit is greater than the performance goal of 89%, resulting in a rejection of the null hypothesis and the primary safety endpoint is passed.

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Thirteen (13) subjects out of the 326 subjects in the primary safety endpoint analysis experienced a safety endpoint event prior to 12 months follow-up Table 18).

Table 18: Summary of Primary Safety Events in Non Roll-In Subjects

|  Endpoint Event | N (% Subjects)  |
| --- | --- |
|  MI | 1 (0.3)  |
|  Pulmonary edema / heart failure | 1 (0.3)  |
|  Thromboembolism/Air embolism | 1 (0.3)  |
|  Cardiac Tamponade/Perforation | 2 (0.6)  |
|  Gastroparesis / Injury to vagus nerve | 3 (0.9)  |
|  Vascular Access Complication | 5 (1.5)  |
|  Total | 13 (4)  |

## Adverse effects that occurred in the PMA clinical study:

A total of 100 serious adverse events (SAEs) in 73 study subjects were reported by Investigators during the first 12 months of study follow-up: 79 SAEs occurred in 60 Non Roll-In subjects and 21 SAEs occurred in 13 Roll-In subjects. The overall proportion of Non Roll-In subjects with SAEs was 17.9% and for the Roll-In subjects 20.6%. There were no confirmed PV stenosis events. No persistent phrenic nerve palsies were reported. No Atrioesophageal Fistulas were reported.

The SAEs occurring in Non Roll-In and Roll-In subjects are listed in the following tables. SAEs were further classified between serious adverse events and serious adverse device effects (SADE) per ISO classification.

Table 19: Serious Adverse Events in Non Roll-In Subjects

|   | ISO Classification |   |   |   |   |   |
| --- | --- | --- | --- | --- | --- | --- |
|   | Serious Adverse Event |   | Serious Adverse Device Effect |   | Total  |   |
|  Adverse Event | N events | N subjects (%) | N events | N subjects (%) | N events | N subjects (%)  |
|  |   |   |   |   |   |   |
|  Total Adverse Events | 41 | 33 (9.8) | 38 | 32 (9.5) | 79 | 60 (17.9)  |
|  |   |   |   |   |   |   |

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|   | ISO Classification |   |   |   |   |   |
| --- | --- | --- | --- | --- | --- | --- |
|   | Serious Adverse Event |   | Serious Adverse Device Effect |   | Total  |   |
|  Adverse Event | N events | N subjects (%) | N events | N subjects (%) | N events | N subjects (%)  |
|  Ablation Related (N=326) | 0 | 0 (0) | 38 | 32 (9.8) | 38 | 32 (9.8)  |
|  Ablation induced arrhythmia | 0 | 0 (0) | 2 | 2 (0.6) | 2 | 2 (0.6)  |
|  Angina/Chest pain | 0 | 0 (0) | 3 | 3 (0.9) | 3 | 3 (0.9)  |
|  Atrial Fibrillation (AF) | 0 | 0 (0) | 3 | 3 (0.9) | 3 | 3 (0.9)  |
|  Atrial flutter, not specified | 0 | 0 (0) | 2 | 2 (0.6) | 2 | 2 (0.6)  |
|  Edema | 0 | 0 (0) | 1 | 1 (0.3) | 1 | 1 (0.3)  |
|  Embolism – Air | 0 | 0 (0) | 1 | 1 (0.3) | 1 | 1 (0.3)  |
|  Esophagitis | 0 | 0 (0) | 1 | 1 (0.3) | 1 | 1 (0.3)  |
|  Gastroparesis | 0 | 0 (0) | 1 | 1 (0.3) | 1 | 1 (0.3)  |
|  Hematoma | 0 | 0 (0) | 4 | 4 (1.2) | 4 | 4 (1.2)  |
|  Myocardial infarction | 0 | 0 (0) | 1 | 1 (0.3) | 1 | 1 (0.3)  |
|  Myocardial perforation with tamponade | 0 | 0 (0) | 2 | 2 (0.6) | 2 | 2 (0.6)  |
|  Oozing/Bleeding | 0 | 0 (0) | 4 | 4 (1.2) | 4 | 4 (1.2)  |
|  Pericarditis | 0 | 0 (0) | 4 | 4 (1.2) | 4 | 4 (1.2)  |
|  Phrenic nerve injury temporary | 0 | 0 (0) | 4 | 4 (1.2) | 4 | 4 (1.2)  |
|  Post procedure infection/Sepsis | 0 | 0 (0) | 1 | 1 (0.3) | 1 | 1 (0.3)  |
|  Procedure related Hypertension | 0 | 0 (0) | 1 | 1 (0.3) |…

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**Source:** [https://fda.innolitics.com/device/P220032](https://fda.innolitics.com/device/P220032)

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