← Product Code [PNJ](/productcode/PNJ) · P150035S003

# Aveir DR Leadless System (P150035S003)

_ABBOTT MEDICAL · PNJ · Jun 29, 2023 · Cardiovascular · APPR_

**Canonical URL:** https://fda.innolitics.com/device/P150035S003

## Device Facts

- **Applicant:** ABBOTT MEDICAL
- **Product Code:** [PNJ](/productcode/PNJ.md)
- **Decision Date:** Jun 29, 2023
- **Decision:** APPR
- **Regulation:** 21 CFR 870.3610
- **Device Class:** Class 3
- **Review Panel:** Cardiovascular
- **Attributes:** Therapeutic, Real-World Evidence

## Real-World Evidence

| Submission | Device | Sponsor | RWD Sources | RWE Use Summary | Key Tags |
| --- | --- | --- | --- | --- | --- |
| P150035S003 · Jun 29, 2023 | Aveir DR Leadless System | ABBOTT MEDICAL | Medicare FFS claims | A post-approval study (PAS) is required to evaluate the long-term safety of the Aveir DR Leadless Pacemaker using real-world evidence methods, specifically linking patient data to Medicare FFS claims. | Post-approval study; Medicare FFS claims; Long-term safety; Real-world evidence |

### Clinical Evidence

| Study Design | Population | Comparator | Key Endpoints |
| --- | --- | --- | --- |
| Aveir DR Real-World Evidence Study; Post-approval study (PAS) using real-world evidence methods; Follow-up/Duration: 30-day and 5-years post implant | All de novo patients who had an implant of the Aveir DR LP device and met inclusion/exclusion criteria; Sample Size: 1,805 patients | Not applicable for this study | Complication-free rates |

## Indications for Use

The Aveir DR Leadless System is indicated for management of one or more of the following permanent conditions: Syncope Pre-syncope Fatigue Disorientation Rate-Modulated Pacing is indicated for patients with chronotropic incompetence, and for those who would benefit from increased stimulation rates concurrent with physical activity. Dual-Chamber Pacing is indicated for patients exhibiting: Sick sinus syndrome Chronic, symptomatic second- and third-degree AV block Recurrent Adams-Stokes syndrome Symptomatic bilateral bundle branch block when tachyarrhythmia and other causes have been ruled out Atrial Pacing is indicated for patients with: Sinus node dysfunction and normal AV and intraventricular conduction systems Ventricular Pacing is indicated for patients with: Significant bradycardia and normal sinus rhythm with only rare episodes of AV block or sinus arrest Chronic atrial fibrillation Severe physical disability MR Conditional: Aveir Leadless Pacemaker is conditionally safe for use in the MRI environment when used according to the instructions in the Abbott MRI-Ready Leadless System Manual. Aveir Delivery Catheter: The Aveir Delivery Catheter is intended to be used in the peripheral vasculature and the cardiovascular system to deliver and manipulate an LP. Delivery and manipulation includes implanting an LP within the target chamber of the heart. Aveir Link Module: The Aveir Link Module is intended to be used in conjunction with a Merlin™ PCS Programmer to interrogate and program an Aveir LP and to monitor LP function during an implant, retrieval, or follow-up procedure.

## Device Story

Aveir DR Leadless System comprises two leadless pacemakers (LP)—one atrial (LSP201A), one ventricular (LSP202V)—a delivery catheter, and a link module. LPs are implanted percutaneously via femoral vein into right atrium/ventricle. LPs communicate bi-directionally via implant-to-implant (i2i) conducted electrical signaling on a beat-to-beat basis. LPs sense intrinsic cardiac signals and blood pool temperature for rate-modulated pacing. Link module connects to Merlin PCS programmer to interrogate/program LPs via skin electrodes. Used in clinical settings by physicians. Output provides bradycardia pacing therapy. Benefits include dual-chamber pacing without transvenous leads, reducing lead-related complications. System supports upgradeability from existing single-chamber Aveir VR LPs.

## Clinical Evidence

Prospective, multi-center, single-arm pivotal study (Aveir DR i2i, NCT05252702) of 300 de novo subjects. Primary safety endpoint: 3-month complication-free rate (CFR) was 90.3% (97.5% LCB 87.0%, PG 78%, p<0.0001). Secondary safety endpoint: 3-month atrial LP-related CFR was 91.3% (97.5% LCB 88.1%, PG 84%, p=0.0003). Primary effectiveness #1: 3-month composite success rate (pacing/sensing) was 90.8% (97.5% LCB 87.5%, PG 82.5%, p<0.0001). Primary effectiveness #2: 3-month AV synchrony success rate was 98.2% (97.5% LCB 96.6%, PG 83%, p<0.0001). Secondary effectiveness: CAEP exercise protocol mean slope 0.94 ± 0.07 (95% CI 0.80, 1.08), meeting equivalence bounds.

## Technological Characteristics

Leadless pulse generators (atrial/ventricular) with fixation helix and dexamethasone sodium phosphate (DSP) elution. Communication: i2i conducted electrical signaling. Sensing: intrinsic cardiac signals and blood pool temperature. Dimensions: Atrial (32.2mm x 6.5mm), Ventricular (38.0mm x 6.5mm). Connectivity: Link module via USB to Merlin PCS programmer. Sterilization: Ethylene oxide. Biocompatibility: ISO 10993-1 compliant. MRI: Conditional (1.5T/3T).

## Regulatory Identification

An implantable pacemaker pulse generator is a device that has a power supply and electronic circuits that produce a periodic electrical pulse to stimulate the heart. This device is used as a substitute for the heart's intrinsic pacing system to correct both intermittent and continuous cardiac rhythm disorders. This device may include triggered, inhibited, and asynchronous modes and is implanted in the human body.

## Reference Devices

- Aveir VR Leadless Pacemaker ([P150035](/device/P150035.md))

## Submission Summary (Full Text)

> This content was OCRed from public FDA records by [Innolitics](https://innolitics.com). If you use, quote, summarize, crawl, or train on this content, cite Innolitics at https://innolitics.com.
>
> Innolitics is a medical-device software consultancy. We help companies design, build, and clear FDA-regulated software and AI/ML devices, including [a PMA](https://innolitics.com/services/regulatory/), [a 510(k)](https://innolitics.com/services/510ks/), [a SaMD](https://innolitics.com/services/end-to-end-samd/), [an AI/ML medical device](https://innolitics.com/services/medical-imaging-ai-development/), or [an FDA regulatory strategy](https://innolitics.com/services/regulatory/).

{0}

# SUMMARY OF SAFETY AND EFFECTIVENESS DATA (SSED)

# I. GENERAL INFORMATION

Device Generic Name: DR Leadless Pacing System; Implantable pacemaker pulse generator

Device Trade Name: Aveir™ DR Leadless System

- Aveir™ Leadless Pacemaker (Right Ventricular)
- Aveir™ Leadless Pacemaker (Right Atrial)
- Aveir™ Delivery Catheter
- Aveir™ Link Module

Device Procode: PNJ

Applicant's Name and Address: Abbott Medical
15900 Valley View Court
Sylmar, CA 91342

Date(s) of Panel Recommendation: None

Premarket Approval Application (PMA) Number: P150035/S003

Date of FDA Notice of Approval: 6/29/2023

Breakthrough Device: Granted breakthrough device status on March 27, 2020 because the proposed combination product and proposed indication for use meet the criteria.

The original PMA P150035 was approved on March 31, 2022 and the Aveir™ Leadless Pacemaker System is indicated for patients with bradycardia and:

- Normal sinus rhythm with only rare episodes of A-V block or sinus arrest
- Chronic atrial fibrillation
- Severe physical disability

Rate-Modulated Pacing is indicated for patients with chronotropic incompetence, and for those who would benefit from increased stimulation rates concurrent with physical activity.

MR Conditional Aveir™ Leadless Pacemaker is conditionally safe for use in the MRI environment and according to the instructions in the MRI-Ready Leadless System Manual.

Aveir™ Delivery Catheter: The Aveir Delivery Catheter is intended to be used in the peripheral vasculature and the cardiovascular system to deliver and manipulate an LP.

PMA P150035-S003: FDA Summary of Safety and Effectiveness Data

1 of 56

{1}

Delivery and manipulation include implanting an LP within the target chamber of the heart.

Aveir™ Link Module: The Aveir Link Module is intended to be used in conjunction with a Merlin™ PCS Programmer to interrogate and program an Aveir LP and to monitor LP function during an implant, retrieval, or follow-up procedure.

The SSED to support the indication is available on the CDRH website and is incorporated by reference here. The current supplement was submitted to expand the indication for the Aveir DR Leadless System.

## II. INDICATIONS FOR USE

The Aveir DR Leadless System is indicated for management of one or more of the following permanent conditions:

- Syncope
- Pre-syncope
- Fatigue
- Disorientation

Rate-Modulated Pacing is indicated for patients with chronotropic incompetence, and for those who would benefit from increased stimulation rates concurrent with physical activity.

Dual-Chamber Pacing is indicated for patients exhibiting:

- Sick sinus syndrome
- Chronic, symptomatic second- and third-degree AV block
- Recurrent Adams-Stokes syndrome
- Symptomatic bilateral bundle branch block when tachyarrhythmia and other causes have been ruled out

Atrial Pacing is indicated for patients with:

- Sinus node dysfunction and normal AV and intraventricular conduction systems

Ventricular Pacing is indicated for patients with:

- Significant bradycardia and normal sinus rhythm with only rare episodes of AV block or sinus arrest
- Chronic atrial fibrillation
- Severe physical disability

MR Conditional: Aveir Leadless Pacemaker is conditionally safe for use in the MRI environment when used according to the instructions in the Abbott MRI-Ready Leadless System Manual.

Aveir Delivery Catheter: The Aveir Delivery Catheter is intended to be used in the peripheral vasculature and the cardiovascular system to deliver and manipulate an LP.

PMA P150035-S003: FDA Summary of Safety and Effectiveness Data

2 of 56

{2}

Delivery and manipulation includes implanting an LP within the target chamber of the heart.

Aveir Link Module: The Aveir Link Module is intended to be used in conjunction with a Merlin™ PCS Programmer to interrogate and program an Aveir LP and to monitor LP function during an implant, retrieval, or follow-up procedure.

### III. CONTRAINDICATIONS

The use of Aveir Leadless Pacemaker (LP) is contraindicated in these cases:

- Use of any pacemaker is contraindicated in patients with a co-implanted ICD because high-voltage shocks damage the pacemaker, and the pacemaker could reduce shock effectiveness.
- Single-chamber ventricular demand pacing is relatively contraindicated in patients who have demonstrated pacemaker syndrome, have retrograde VA conduction, or suffer a drop in arterial blood pressure with the onset of ventricular pacing.
- Programming of rate-responsive pacing is contraindicated in patients with intolerance of high sensor-driven rates.
- Use is contraindicated in patients with an implanted vena cava filter or mechanical tricuspid valve because of interference between these devices and the delivery system during implantation.
- Persons with known history of allergies to any of the components of this device may suffer an allergic reaction to this device. Prior to use on the patient, the patient should be counseled on the materials (listed in IFU Product Materials) contained in the device and a thorough history of allergies must be discussed.

For the MRI contraindications for patients implanted with Aveir Leadless Pacemaker, refer to the MRI Procedure Manual.

There are no contraindications for use of the Aveir Link Module.

### IV. WARNINGS AND PRECAUTIONS

The warnings and precautions can be found in the Aveir Leadless System Product Instructions for Use.

### V. DEVICE DESCRIPTION

Aveir™ Leadless System:

The Aveir™ Leadless System contains the following components:

- Aveir™ Leadless Pacemakers (Models LSP201A and LSP202V)
- Aveir™ Delivery Catheter (Model LSCD201)
- Aveir™ Link Module (Model LSL02)

Aveir DR Leadless Pacemakers (Models LSP201A and LSP202V)

PMA P150035-S003: FDA Summary of Safety and Effectiveness Data

3 of 56

{3}

The Aveir DR Leadless Pacemaker (LP) System provides bradycardia pacing as a pulse generator with built-in battery and electrodes for implantation into the target heart chamber (right atrium – model number LSP201A, right ventricle – model number LSP202V). Figure 1 includes both the Atrial Aveir LP (LSP201A) and the Ventricular Aveir LP (LSP202V). The Aveir Leadless Pacemaker is intended to provide sensing of intrinsic cardiac signals and delivery of cardiac pacing therapy to the target population.

Aveir DR LPs achieve their dual-chamber functionality by communicating bi-directionally and on a beat-to-beat basis via conducted electrical signaling — a paradigm termed implant-to-implant (i2i) communication. The tip electrode includes a single dose of dexamethasone sodium phosphate (DSP), intended to reduce local inflammation. The proximal end has the docking button for docking to the Aveir Delivery Catheter and Aveir Retrieval Catheter for positioning and retrieval.

The LP communicates bi-directionally with the programmer system via electrical signals conducted between the implanted LP's electrodes and skin electrodes applied to the patient's chest and connected to the programmer system. Consequently, the LP transmits signals using circuits and electrodes already provided for pacing, with data encoded in pulses delivered during the refractory period of the heart.

The LP senses local blood pool temperature to provide rate modulated pacing with changes in metabolic demand.

![img-0.jpeg](img-0.jpeg)

Figure 1: Aveir DR Leadless Pacemakers (Bottom: Atrial LP, Top: Ventricular LP)

### Aveir Delivery Catheter (Model LSCD201)

The Aveir Delivery Catheter (Figure 2) includes a steerable catheter, an integrated guiding catheter with a protective sleeve designed to protect an attached LP's fixation helix and electrode, and a valve bypass tool to dilate the 25Fr inner diameter Introducer sheath hemostasis valve and advance the system into the femoral vein.

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

Figure 2: Aveir DR Delivery Catheter

PMA P150035-S003: FDA Summary of Safety and Effectiveness Data

4 of 56

{4}

### **Aveir Link Module (Model LSL02)**

The Aveir Link Module (**Figure 3**) communicates with an implanted Aveir Leadless Pacemaker via conducted communication through the patient cable and skin electrodes. Safe, high frequency electrical pulses are sent between the LP and programmer system to program and interrogate the Aveir Leadless Pacemaker. The Link Module also uses the patient cable and skin electrodes to acquire a patient's ECG waveform. The Link Module is powered via USB port of the Merlin Patient Care System Model 3650.

![img-2.jpeg](img-2.jpeg)

**Figure 3: Aveir Link Module**

## **VI. ALTERNATIVE PRACTICES AND PROCEDURES**

There are several other alternatives for the rate adaptive pacing. Each alternative has its own advantages and disadvantages. Alternative therapies include the use of commercially available conventional pacemaker systems or other marketed leadless pacing systems. 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 Aveir Leadless Pacemakers (LSP201A and LSP202V) and Aveir Delivery Catheter (LSCD201) have not been marketed in the United States or any foreign country.

The Aveir Link Module (LSL02) was approved by the FDA on March 31, 2022 as part of the P150035/A009 PMA Amendment and remains unchanged as part of this PMA Supplement.

## **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 Aveir Leadless Pacemaker System.

The potential complications associated with the use of the Aveir Leadless Pacemaker System are the same as the use of single or dual chamber pacemakers with active fixation pacing leads including but not limited to:

---PMA P150035-S003: FDA Summary of Safety and Effectiveness Data

5 of 56

{5}

- Cardiac perforation
- Cardiac tamponade
- Pericardial effusion
- Pericarditis
- Endocarditis
- Valve damage or regurgitation
- Heart failure
- Pneumothorax/hemothorax
- Cardiac arrhythmias
- Diaphragmatic/ phrenic nerve stimulation/ extra-cardiac stimulation
- Palpitations
- Hypotension
- Syncope
- Cerebrovascular accident
- Infection
- Hypersensitivity reaction to device materials, medications, or direct toxic effect of contrast media on kidney function
- Pacemaker syndrome
- Inability to interrogate or program the LP due to programmer or LP malfunction
- Intermittent or complete loss of capture, pacing or sensing (non-battery related)
- Oversensing
- Increased capture threshold
- Inappropriate sensor response
- Corrupted, intermittent, or loss of i2i communications
- Interruption of desired LP function due to electrical interference, either electromyogenic or electromagnetic
- Battery malfunction/ premature battery depletion
- Device-related complications:
  - Premature deployment
  - Device dislodgment/ embolization of foreign material
  - Inability to release/re-dock of the LP from catheter
  - Helix distortion
- Additional surgery or intervention
- Death

As with any percutaneous catheterization procedure, potential complications include, but are not limited to:

- Vascular access complications, such as perforation, dissection, puncture, groin pain
- Bleeding or hematoma
- Thrombus formation
- Thromboembolism
- Air embolism
- Local and systemic infection

PMA P150035-S003: FDA Summary of Safety and Effectiveness Data

6 of 56

{6}

- Peripheral nerve damage
- General surgery risks and complications from comorbidities, such as hypotension, dyspnea, respiratory failure, syncope, pneumonia, hypertension, cardiac failure, reaction to sedation, renal failure, anemia, and death

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

# IX. SUMMARY OF NONCLINICAL STUDIES

# A. Laboratory Studies

# i. Design Verification Tests

Design verification testing and material characterization was performed on the Aveir DR system devices (LP, delivery catheter and Link Module) to ensure the design meets all required inputs per the product specification. The test results demonstrate that the Aveir DR system devices meet all design requirements. The testing is summarized in Table 1 - Table 3 below.

Each device in the Aveir DR system (LP, delivery catheter and Link Module) underwent verification testing utilizing standard test suites, including tests such as automated functional test, functional interrogation test, visual/X-ray inspection, applicable EMI, electrical, and mechanical testing. The samples used in the testing passed applicable verification tests, confirming compliance with respective product requirements, and providing assurance that each device in the Aveir DR system will perform safely and effectively in their intended use.

The system functional verification and validation testing was conducted successfully for the Aveir DR system devices (LP, delivery catheter and Link Module) with passing results and demonstrated that the system design input functionality requirements have been met. Clinical test flows followed in the validation testing were intended to mimic use of the system in clinically relevant scenarios where multiple system functionalities were tested. System functions were tested during scenarios that include: (1) during implant use, (2) out-of-clinic use, and (3) in-clinic follow-up use.

Table 1: Aveir DR LP Non-Clinical Bench Testing Results

|  Test | Test Description / Acceptance Criteria | Results  |
| --- | --- | --- |
|  **System Compatibility** | Functional tests assessed the ability of the connections between various component of the Aveir DR Leadless System to properly communicate and interconnect, as appropriate. | Pass  |

PMA P150035-S003: FDA Summary of Safety and Effectiveness Data

7 of 56

{7}

|  **Biocompatibility** | The biological evaluation of the LP devices was performed to demonstrate the biocompatibility of the products, or extracts of the products, resulting from contact of the device/component materials with the body as appropriate to the intended use of the device. Biological evaluation and the selection of testing requirements were performed in accordance with ISO 10993-1:2018 and in accordance with the FDA Biocompatibility Guidance issued September 04, 2020 (*Use of international standard ISO 10993, “Biological evaluation of medical devices – Part 1: Evaluation and testing within a risk management process”*). Results demonstrated that the LP devices are biologically safe for their intended use. See Section iii below for details. | Pass  |
| --- | --- | --- |
|  **Packaging** | The LP devices are packaged separately. The packaging is designed to protect the device from damage and prevent contamination during storage, shipping, handling and introduction to the sterile field. Qualification testing was successfully completed to verify that the packaging protects the system during transportation and storage. | Pass  |
|  **Shelf Life** | The LP device shelf life is based on a combination of battery capacity, package sterility, and steroid stability. Testing was performed to support a shelf-life labeling of 12 months. | Pass  |
|  **Device Level Verification Testing** intended to verify the specified physical attributes of the Aveir Leadless Pacemaker (LP). The design verification testing was performed according to the product specifications as well as to ISO 14708-1, ISO 14708-2 and ISO 14117.  |   |   |
|  **Physical Dimensions** | The test verified the following dimensions: Atrial Aveir DR LP: - Length: 32.2 mm (1.27 in) - Diameter: 6.5 mm (0.26 inches) - Volume: 1.0 cm³ - Mass: 2.1 grams - Fixation depth: approximately 1.63 mm (0.064 in) - Tip electrode geometric surface area: approximately 5 mm² - Ring electrode geometric surface area: approximately 124 mm² Ventricular Aveir DR LP: - Length: 38.0 mm (1.50 in) - Diameter: 6.5 mm (0.26 inches) - Volume: 1.1 cm³ - Mass: 2.4 grams - Fixation depth: approximately 1.63 mm (0.064 in) - Tip electrode geometric surface area: approximately 2 mm² - Ring electrode geometric surface area: approximately 244 mm² | Pass  |

PMA P150035-S003: FDA Summary of Safety and Effectiveness Data

8 of 56

{8}

|  Mechanical Shock and Vibration | Assess the mechanical performance and safety of the LP to withstand mechanical shock loads and vibration imposed during handling, implantation, and intended use per standards EN 45502-2-1 and ISO 14708-2-1. | Pass  |
| --- | --- | --- |
|  Pressure | Evaluate LP device safety and functionality after exposure to multiple cycles of low-pressure and high-pressure as specified by applicable clauses of ISO 14708-2. | Pass  |
|  Corrosion | Assess corrosion resistance of the blood and tissue contacting materials chosen for the LP. | Pass  |
|  Hermeticity Leak Test | Verify the hermeticity helium leak rate of the LP device is equal to or less than 1.8 x 10^{-9} atm-cc/sec air equivalent as specified per applicable clauses of MIL-STD-883. | Pass  |
|  Electromagnetic Compatibility (EMC) | Evaluate LP device safety and functionality with regard to exposure to external EM fields, as per the applicable requirements of ISO 14708-2 and ISO 14117. | Pass  |
|  EMI-EAS, RFID, Tag deactivators, Metal Detectors | Evaluate LP device safety and functionality with regard to exposure to EAS and RFID, with no irreversible damage or effect on device programmed parameters caused by the exposure to EAS systems, EAS tag deactivators, RFID systems, or metal detector systems. | Pass  |
|  Safety-Exposure to Electrosurgery | Evaluate the LP device safety and functionality with regard to exposure to electrosurgery conditions as specified by the applicable clauses of ISO 14117. | Pass  |
|  Safety- Exposure to External Defibrillation | Evaluate the LP device safety and functionality with regard to exposure to external defibrillation conditions as specified by the applicable clauses of ISO 14117. | Pass  |
|  Safety- Ultrasound | Evaluate the LP device safety and functionality with regard to exposure to ultrasound conditions as specified by the applicable clauses of ISO 14708-1. | Pass  |
|  Safety- Protection against device heat generation | Verify the outer surface of the LP device does not exceed 2°C above the normal surrounding body temperature of 37° C when implanted in normal operating mode as specified per ISO 14708-1 and EN 45502-2-1. | Pass  |
|  Safety – Irradiation | Verify the LP device remains electrically functional after exposure to irradiation levels of at least 7000 rads (70 Gy) per the applicable clauses of MIL-STD-883E. | Pass  |
|  MRI Compatibility Testing | Assess the compatibility of the LP device with MRI scanning. Additional MRI Information is provided in section ii below. | Pass  |
|  Firmware | Firmware verification testing was conducted to ensure that the LP device firmware was tested to its specified requirements. Testing included unit testing, integration testing and system testing. Firmware verification testing was successfully completed and demonstrated that the LP device firmware meets its requirements. | Pass  |
|  Merlin PCS Programmer Software | Programmer software verification testing of all software requirements was conducted to ensure that the Programmer software was tested to its specified requirements. Testing included unit testing, integration testing and system testing. | Pass  |

PMA P150035-S003: FDA Summary of Safety and Effectiveness Data

9 of 56

{9}

|   | Software verification testing demonstrated that the Programmer Software meets its requirements. |   |
| --- | --- | --- |
|  **Cybersecurity** | The Aveir DR System was developed and tested using methodologies intended to ensure product quality and patient safety. | Pass  |
|  **Component Level Testing** intended to verify the specified component specifications are met. Safety testing, capacity testing and long-term performance testing and stability testing were performed. All the tests were successfully performed, and all pre-determined acceptance criteria were met.  |   |   |
|  **Button Tensile** | Verify that the LP docking button can withstand a minimum axial tensile force of at least 18 lb-f without separation from the LP body. | Pass  |
|  **Button Fatigue** | Verify the LP device docking button fatigue limit. | Pass  |
|  **Fixation Helix Fatigue** | Verify the LP device fixation helix survives 400 million cycles without helix fracture or detachment from helix mount. | Pass  |
|  **Fixation Helix Deformation** | Verify the LP device fixation helix length maintains an axial plastic deformation of less than or equal to 20% of its original length after an extension force is applied to the tip of the helix. | Pass  |
|  **Feedthrough** | - Verify that the LP feedthrough insulation resistance is 10 giga-ohm minimum. - Verify that the LP feedthrough does not exhibit a leak rate greater than 1.5x10^{-9} atm-cc/sec air. - Verify that the LP feedthrough does not exhibit any signs of breakage, fracture or cracks under load. | Pass  |
|  **Hybrid** | Confirm that the LP hybrid can pass all substrate level electrical tests after withstanding stress conditions (thermal cycling and burn-in). | Pass  |
|  **Battery** | - The LP battery meets the UN Recommendations on the Transport of Dangerous Goods, Manual of Tests and Criteria. - Accelerated discharge testing of LP battery capacity from Beginning of Service to End of Service at 37°C. | Pass  |

**Table 2: Aveir Delivery Catheter Non-Clinical Bench Testing Results**

|  Test | Test Description / Acceptance Criteria | Results  |
| --- | --- | --- |
|  **Biocompatibility** | The biological evaluation of the delivery catheter was performed to demonstrate the biocompatibility of the products, or extracts of the products, resulting from contact of the device/component materials with the body as appropriate to the intended use of the device. Biological evaluation and the selection of testing requirements were performed in accordance with ISO 10993-1:2018 and in accordance with the FDA Biocompatibility Guidance issued September 04, 2020 (*Use of international standard ISO 10993, 'Biological evaluation of medical devices – Part 1: Evaluation and testing within a risk management* | Pass  |

PMA P150035-S003: FDA Summary of Safety and Effectiveness Data

10 of 56

{10}

|   | *process*”). Results demonstrated that the delivery catheter is biologically safe for its intended use. See Section iii below for details. |   |
| --- | --- | --- |
|  **Torque** | The catheter withstands at least one full rotation prior to kinking. | Pass  |
|  **Tensile** | The tensile strength of the delivery catheter assembly was assessed based on ISO 10555-1. | Pass  |
|  **Flexibility/Deflection** | The device was verified to have sufficient flexibility to enable navigation through clinically relevant anatomical configurations. | Pass  |
|  **Corrosion** | The corrosion resistance of the blood- and tissue-contacting materials chosen for the delivery catheter was verified. | Pass  |
|  **Particulate Testing** | The particulate levels generated from the delivery catheter, when used with the introducer and DR LPs during simulated clinical use, meets USP <788>. | Pass  |
|  **Shelf Life** | The shelf-life testing was performed to support shelf-life labeling of 15 months. | Pass  |
|  **Packaging** | The delivery catheter is packaged separately from the LP and Link Module. The packaging is designed to protect the delivery catheter from damage and maintain sterility during storage, shipping, handling and introduction to the sterile field (see Section iv for additional sterilization information). Qualification testing verified that the packaging protects the delivery catheter during transportation and storage. | Pass  |

**Table 3: Aveir Link Module Non-Clinical Bench Testing Results**

|  Test | Test Description / Acceptance Criteria | Results  |
| --- | --- | --- |
|  **Physical Dimensions** | - The Link Module shall have weight less than or equal to 0.7 kg (1.5 lbf). - The Link Module’s length, width and height shall be less than or equal to 230mm, 155 mm and 40 mm, respectively. - The measured cable length shall be between 0.9 m to 1.1 m. | Pass  |
|  **Mechanical** | - The tensile strength of the USB cable shall be at least 65 N - The USB cable shall survive at least 1000 flex cycles without demonstrating any of the electrical failure conditions | Pass  |
|  **Security** | - The Link Module shall use tamper resistant screws. - The Link Module shall include snap retainer features. - The Link Module shall include tamper evident labels. - The Link Module AES key shall be un-readable and unmodifiable from an external device. | Pass  |
|  **Electrical** | - The Link Module shall interrogate, program, and read information from the device when connected to | Pass  |

PMA P150035-S003: FDA Summary of Safety and Effectiveness Data

11 of 56

{11}

|   | a power supply of approximately 5V. • The Link Module transmission pulses shall be biphasic with period 4 μs ±15% |   |
| --- | --- | --- |
|  Safety | • The Link Module shall pass applicable safety compliance tests per IEC 60601-1 Ed. 3.1. • The Link Module shall not exceed the radiated and conducted emissions limit requirements per IEC 60601-1-2. • The Link Module shall pass radiated electromagnetic fields per IEC 61000-4-3 and 61000-4-6. • The Link Module shall pass test requirements related to basic safety and essential performance for medical electrical equipment per IEC 60601-1-2 | Pass  |
|  Cleaning | The test verifies the integrity of the label, marking, and mechanical enclosure after cleaning the Link Module, as per the cleaning and disinfection instructions. | Pass  |
|  Packaging | The Link Module is packaged separately from the LP devices and delivery catheter. The packaging is designed to protect the device from damage during storage, shipping and handling. Qualification testing was successfully completed to verify that the packaging protects the Link Module unit during transportation and storage. | Pass  |

## ii. Magnetic Resonance Imaging (MRI) Compatibility

MRI safety of the MR Conditional Aveir Leadless Pacemaker has been tested per the requirements in ISO/TS 10974. The test results demonstrate that the Aveir Leadless Pacemaker is conditionally safe for use in the MRI environments when used according to the instructions in the MRI Manual using the 1.5T and 3T MR scanner.

A patient with the Aveir Leadless Pacemaker can be safely scanned in a MR system under following conditions (see Table 4).

Table 4: Magnetic Resonance Imaging (MRI) Compatibility Testing Conditions

|  Parameter | 1.5 MRI Scan Parameter Setting | 3T MRI Scan Parameter Setting  |
| --- | --- | --- |
|  Static Magnetic Field Strength and Type of Nuclei | 1.5T/64 MHz excitation frequency (hydrogen atom only) | 3 T/128 MHz excitation frequency (hydrogen atom only)  |
|  Magnet Type and Static Magnetic Field Orientation | Cylindrical-bore magnet, horizontal field orientation | Cylindrical-bore magnet, horizontal field orientation  |
|  Maximum Spatial Field Gradient | 30 T/m (3000 Gauss/cm) | 30 T/m (3000 Gauss/cm)  |
|  Maximum Gradient Slew Rate per axis | 200 T/m/s | 200 T/m/s  |

PMA P150035-S003: FDA Summary of Safety and Effectiveness Data

12 of 56

{12}

|  Scan Region / Patient Landmarking Criteria | Full body scans allowed. Any landmark is acceptable | Full body scans allowed. Any landmark is acceptable  |
| --- | --- | --- |

### iii. Biocompatibility

All biocompatibility testing was conducted in accordance with ISO 10993-1, Biological Evaluation of Medical Devices and Good Laboratory Practices Regulation (21 CFR 58). According to ISO 10993, the Aveir DR LPs are classified as a long-term (>30 days) implantable device with circulating blood contact. The accessory Aveir Delivery Catheter packaged separately is classified as externally communicating with limited (<24 hours) circulating blood contact device. The required testing for the implant and delivery catheter was determined based on these classifications, in accordance with ISO 10993-1. A summary of the tests performed, and test results are presented in Table 5 below.

Table 5: Biocompatibility Test and Results

|  Biological Endpoint and ISO Standard | Test Name/ Description | Leadless Pacemaker | Delivery Catheter | Results*  |
| --- | --- | --- | --- | --- |
|  Cytotoxicity ISO 10993-5:2009 | ISO Minimum Essential Medium Elution Assay | ✓ | ✓ | Pass Non-cytotoxic  |
|  Sensitization ISO 10993-10:2021 | ISO Guinea Pig Maximization Sensitization | ✓ | ✓ | Pass Non-sensitizer  |
|  Irritation or Intracutaneous Reactivity ISO 10993-23:2021 | Intracutaneous Reactivity Test Irritation | ✓ | ✓ | Pass Non-irritant  |
|  Systemic Toxicity ISO 10993-11:217 | ISO Acute Systemic Toxicity | ✓ | ✓ | Pass No evidence of systemic toxicity  |
|   |  USP Material Mediated Rabbit Pyrogen | ✓ | ✓ | Pass Non-pyrogenic  |
|   |  Subacute/Sub- Chronic/Chronic Systemic Toxicity (17 and 26 weeks) | ✓ | N/A | Pass No evidence of systemic toxicity  |
|  Genotoxicity ISO 10993-3:2014 | ISO Bacterial Reverse Mutation | ✓ | N/A | Pass Non-mutagenic  |

PMA P150035-S003: FDA Summary of Safety and Effectiveness Data

13 of 56

{13}

|   | ISO Mouse Lymphoma Assay | ✓ | N/A | Pass Non-genotoxic  |
| --- | --- | --- | --- | --- |
|  Implantation ISO 10993-6:2016 | 90-day Chronic implantation in ovine | A | N/A | Pass Non-irritant  |
|  Hemocompatibility ISO 10993-4:2017 | Hemolysis – Direct Contact and Extract | B | ✓ | Pass Acceptable hemocompatibility profile  |
|   |  Complement Activation Assay – SC5b-9 | B | ✓ | Pass Not a complement activator  |
|   |  *In vivo* Thrombogenicity | B | ✓ | Pass Clinically acceptable response  |
|  Chemical Characterization ISO 10993-18:2020 | GC-MS, LC-MS, and ICP-MS | ✓ | B | No leachables of toxicological concern  |
|  Toxicological Risk Assessment ISO 10993-17:2002 | Toxicological Risk Assessment | ✓ | N/A  |   |
|  **Key:** A: Biological endpoint was covered in the GLP animal studies B: indicates justification provided for not testing N/A: indicates testing was not required per ISO 10993-1 ✓: indicates testing was conducted * “Pass” denotes that the test results met the product specifications or acceptance criteria.  |   |   |   |   |

For the Aveir DR LPs, endpoints of sub-chronic systemic toxicity and 90-day chronic implantation were performed as part of the in vivo study (GLP animal studies) conducted to evaluate the safety and effectiveness of the device. The overall results of the GLP animal study indicate there was no signs of systemic toxicity or inflammation post implantation of the Aveir DR LPs and therefore, the device is considered clinically acceptable.

Additionally, the omission of the carcinogenicity testing was supported by chemical characterization data. Toxicological risk assessment concluded that extractables and leachable chemicals from the Aveir DR LPs were not present in quantities to present a systemic toxicity or carcinogenicity risk. Toxicological evaluation of the extractables detected concluded there was no toxicological concerns from the compounds detected.

PMA P150035-S003: FDA Summary of Safety and Effectiveness Data

14 of 56

{14}

Based on the acceptable results provided, the Aveir DR LPs and delivery catheter are biocompatible and considered safe for the device's intended use.

#### **iv. Sterilization**

The Aveir DR LPs are an implant device and provided sterile for single use only. The Aveir Delivery Catheter is also provided sterile and for single use only. These tests assessed the ability of the device packaging system to maintain sterility of the package. The Aveir LP devices and the delivery catheter are sterilized using 100% Ethylene oxide (EO). Sterilization validation established a minimum Sterility Assurance Level (SAL) of 10-6 as defined in EN 556-1, for routine sterilization of the pacemaker and catheter, per EN ISO 11135. The devices are intended for single use only and labeled sterile. The Aveir Link Module is an external non-sterile medical device.

#### **v. Shelf-Life and Packaging**

The shelf life of a combination product is defined not only based on the capability of a drug component in a specific container/closure system to remain within its physical, chemical, microbiological, toxicological, protective and informational specifications, but also based on the device design characteristics and sterile barrier system materials in relation to the device being packaged, sterilized, shipped, and stored. The Aveir DR LPs shelf life is labeled for 12 months and Aveir Delivery Catheter shelf life is labeled for 15 months. Both devices were validated to ensure that the device performance and package integrity is maintained for this shelf life.

Package performance and package stability are evaluated independently, built to the worst-case manufacturing sealing process settings (i.e., low and high settings), and exposed to the worst case environmental, distribution, and accelerated aging conditioning, to cover both evaluations.

### **B. Animal Studies**

The following five (5) GLP animal evaluations were conducted:

- **91-Day Chronic Safety Evaluation of the Atrial Aveir DR LP (LSP201A)**
  - Purpose: To demonstrate the safety and performance of the Atrial Aveir DR LP model LSP201A as well as the acute safety and handling of the Aveir DR Delivery Catheter model LSCD201. A total of nine (9) sheep were used in this study.
  - Safety Objective Results: There were no dislodgements or embolization of the LP during the follow-up period in any study animals. There was no cardiac or vascular perforation that resulted in significant blood loss or death in any of the animals. There were no tricuspid valve leaflet

PMA P150035-S003: FDA Summary of Safety and Effectiveness Data

15 of 56

{15}

tears, endocardial/myocardial tears, or ruptured chordae in any of the animals which meets the acceptance criteria of none to mild tears. All test articles had acceptable handling and performance.

- ○ **Performance Objective Results:** The LP was able to pace the heart at implant and each follow-up in all animals. The LP was able to sense intrinsic heart beats throughout the study in all animals. Throughout the study, impedance measurements could be collected in all animals. Throughout the study, the programmer was able to communicate with implanted LPs to retrieve diagnostics, program parameters, and perform electrical performance tests. There were no visual or mechanical anomalies from typical implant handling that affected the functionality of the leadless pacer.
- ● **91-Day Chronic Retrieval Study for the Atrial Aveir DR LP (LSP201A)**
  - ○ **Purpose:** To demonstrate the safety of retrievability of the Atrial Aveir DR LP device at least 91 days post implant. Retrieval procedures were performed by clinicians familiar with pacemaker implantation/retrieval and catheter handling. A total of seven (7) sheep were used in this study.
  - ○ **Safety Objective Results:** All animals received a rating of “0”, denoting acceptable clear to light yellow/serous pericardial fluid. There were no ratings of “2”, frank blood in the pericardial sac at necropsy. All animals had a rating of “0” – no change present in the IVC as assessed at necropsy. All animals had a rating of “0” – no change present in the femoral vein as assessed at necropsy. There were no tricuspid leaflet tears, endocardial/ myocardial tears, or ruptured chordae in any animal. All lung findings in all animals were acceptable as assessed at necropsy.
  - ○ **Performance Objective Results:** Physicians evaluated the safety and performance of the Aveir Retrieval Catheter. All ratings were the highest rating of 4 (very good and acceptable). There was no clear pattern of errors to suggest an issue with the design or training that may lead to unacceptable patient harm.
- ● **Chronic Evaluation of Safety and Performance for the Aveir DR System (LSP201A, LSP202V)**
  - ○ **Purpose:** To demonstrate the chronic safety and performance of the Aveir DR System and the acute safety and handling of the Aveir DR Delivery Catheter. The animals were implanted with one Atrial Aveir DR LP LSP201A in the right atrium (RA) and one Ventricular Aveir DR LP LSP202V in the right ventricle (RV). The LPs were implanted for 91 days. A total of nine (9) sheep were used in this study.
  - ○ **Safety Objective Results:** There were no dislodgements or embolization of the LPs during the follow-up study period in any of the animals. There was no cardiac or vascular perforation that resulted in significant blood loss or death in any of the animals. There were no tricuspid valve leaflet tears, endocardial/myocardial tears, or ruptured chordae in any of the animals. All lung findings in all animals were acceptable at necropsy. There was no thrombus found in any of the animals. All test articles had acceptable handling and performance.

PMA P150035-S003: FDA Summary of Safety and Effectiveness Data

16 of 56

{16}

- ○ **Performance Objective Results:** Throughout the study, the programmer was able to communicate with implanted LPs to retrieve diagnostics, program parameters, and perform electrical performance tests. The RA to RV and RV to RA i2i throughput (overall: good marker) was  $\geq 70\%$  between day 42 and day 91 follow-up for all animals. There were no visual or mechanical anomalies from typical implant handling that affected the functionality of the leadless pacer.
- ● **77-Day Chronic Evaluation of Side-by-Side LPs Study**
  - ○ **Purpose:** To demonstrate the chronic safety of retrievability of the side-by-side functionality of an active Aveir DR LP implanted next to an inactive Aveir DR LP in the ovine. A total of five (5) sheep were used in this study.
  - ○ **Safety Objective Results:** There were no tricuspid leaflet tears, endocardial/myocardial tears, or ruptured chordae in any of the animals meeting the acceptance criteria of none to mild tears. All lung findings in all animals were acceptable at necropsy. There was no thrombus found in any of the animals. There were no dislodgements or embolization of the LPs (20 of 20) during the follow-up study period in any (5 of 5) of the animals.
  - ○ **Performance Objective Results:** All Aveir DR LPs (5 atrial and 5 ventricular) could be permanently deactivated using the Merlin programmer at time of secondary implant. All Aveir DR LPs (5 atrial and 5 ventricular) could communicate with the programmer, be programmed, and electrical performance data can be collected when co-implanted in the same chamber with an inactive LP. The Merlin programmer software supported the ability to program: a) one active LP within the RV; b) one active LP within the RA; and c) one new LP to replace an existing LP.
- ● **182-Day Chronic Retrieval Study for the Atrial Aveir DR LP (LSP201A)**
  - ○ **Purpose:** To demonstrate the safety of retrievability of the Aveir Atrial Leadless Pacemaker (LP) device model LSP201A at least 182 days post-implant. A total of nine (9) sheep were used in this study.
  - ○ **Safety Objective Results:** All animals (implanted with an Atrial Aveir LP) received a rating of '0', denoting acceptable clear to light yellow/serous pericardial fluid. There were no ratings of '2', frank blood in the pericardial sac at necropsy. No ratings of '2' moderate to severe injury from the retrieval of an atrial LP were observed. There were no tears present the IVC for all animals at necropsy. One animal had a rating of '1'- present, but minimal feature due to acute focal hemorrhage in the wall of the IVC. Four (4) animals had a rating of none/'0' – no change present and five (5) animals had a rating of '1'- present, but minimal feature in the femoral vein at necropsy. There were no tricuspid leaflet tears, endocardial/myocardial tears, or ruptured chordae as a result of the atrial LP retrieval procedure in any animal at necropsy. All lung findings in all animals chronically implanted with an atrial LP were acceptable at necropsy.

PMA P150035-S003: FDA Summary of Safety and Effectiveness Data

17 of 56

{17}

- ○ Performance Objective Results: Physicians evaluated the safety and performance of the Aveir Retrieval Catheter while retrieving an atrial LP. All ratings were the highest rating of 4 (very good and acceptable). There were no observed use errors. 100% of the retrievals in animal were successful.

## X. SUMMARY OF PRIMARY CLINICAL STUDY

The applicant performed a clinical study to establish a reasonable assurance of safety and effectiveness of the Abbott Medical Aveir Dual-Chamber (DR) Leadless Pacemaker (LP) system in patients indicated for DDD(R) pacing in the US, Canada, Europe, and Asia Pacific under IDE #G210339. Data from this clinical study were the basis for the PMA approval decision. A summary of the clinical study is presented below.

The Aveir DR i2i Study was a first-in-human clinical evaluation of the Aveir DR Leadless Pacemaker System (ClinicalTrials.gov identifier: NCT05252702). The Aveir DR LP system is considered an expanded technology from the Abbott Medical single-chamber Aveir VR Leadless System.

The Aveir DR LP system is a programmable system comprising of two implantable LPs that provide dual-chamber rate-responsive bradycardia pacing therapy. The first LP is the Aveir DR Ventricular LP (model LSP202V) that is physically identical to the single-chamber Aveir VR LP (model LSP112V) for the implantation into the right ventricle (RV). The Aveir VR LP (LSP112V) was previously evaluated in the Leadless II IDE Study- Phase 2 (ClinicalTrials.gov identifier: NCT04559945) and has received FDA approval (P150035) on March 31, 2022. The second LP is the Aveir DR Atrial LP (model LSP201A) for the implantation into the right atrium. Each leadless pacemaker is delivered to the target heart chamber percutaneously via the femoral vein.

### A. Study Design

The Aveir DR i2i study was a prospective, multi-center, international, single-arm, pivotal investigational study designed to evaluate the safety and effectiveness of the Aveir DR system in a subject population indicated for a DDD(R) pacemaker. The primary objectives of this study were to evaluate the safety and effectiveness of the Aveir DR system through 3 months post-implant in a subject population indicated for a DDD(R) pacemaker system.

Patients were treated between February 2, 2022 and August 5, 2022. The database for this Panel Track Supplement reflected data collected through October 26, 2022.

The clinical investigation was designed to enroll up to 550 subjects from up to 85 participating centers from the United States, Canada, Europe, and Asia Pacific. The 550 subjects included at least 300 *de novo* subjects (i.e., no prior pacemaker implantation) in a “full analysis population” to evaluate the primary endpoints and up

---PMA P150035-S003: FDA Summary of Safety and Effectiveness Data

18 of 56

{18}

to 200 additional de novo subjects that were enrolled continuously after the first 300 de novo subject enrollments. The additional 200 de novo subjects were included in the study design in the event more subjects were needed to evaluate the primary endpoints based on the results of a planned interim analysis.

In addition to the 300 enrolled de novo subjects, up to 50 subjects who were previously implanted with the Aveir VR LP single chamber system were also permitted to concurrently enroll with the de novo subjects from the full analysis population to evaluate the upgradeability to an Aveir DR LP system. This part of the study evaluated upgradeability, a key feature of the Aveir DR System, in which an Atrial LP is implanted and functionally paired with a pre-existing Aveir VR LP, resulting in dual-chamber therapy in a DDD(R) (or other) pacing mode. Since the Aveir VR upgrade population is a separate population from the full analysis cohort, the clinical outcomes from this population did not contribute toward the primary or secondary endpoints and are thus reported separately.

The study used an independent Data Safety Monitoring Board (DSMB) that was responsible for informing Abbott Medical of any safety or compliance issues and a Clinical Events Committee (CEC) that was responsible for adjudicating adverse events reported during the IDE study. The study also used an independent ECG Core Laboratory that evaluated Holter data collected from sites to determine AV synchrony success.

1. Clinical Inclusion and Exclusion Criteria

Enrollment in the Aveir DR i2i study was limited to patients who met the following inclusion criteria:

i. Subject must have at least one of the clinical indications before device implant in adherence with ACC/AHA/HRS/ESC dual chamber pacing guidelines
ii. Subject is ≥ 18 years of age or age of legal consent, whichever age is greater
iii. Subject has a life expectancy of at least one year
iv. Subject is willing to comply with clinical investigation procedures and agrees to return to clinic for all required follow-up visits, tests, and exams
v. Subject has been informed of the nature of the clinical investigation, agrees to its provisions and has provided a signed written informed consent, approved by the IRB/EC

Patients were not permitted to enroll in the Aveir DR i2i study if they met any of the following exclusion criteria:

i. Subject is currently participating in another clinical investigation that may confound the results of this study as determined by the Sponsor
ii. Subject is pregnant or nursing and those who plan pregnancy during the clinical investigation follow-up period

PMA P150035-S003: FDA Summary of Safety and Effectiveness Data

19 of 56

{19}

iii. Subject has presence of anatomic or comorbid conditions, or other medical, social, or psychological conditions that, in the investigator's opinion, could confound the assessment of the investigational device and/or implant procedure, limit the subject's ability to participate in the clinical investigation or to comply with follow-up requirements of the clinical investigation results
iv. Subject has a known allergy or hypersensitivity to < 1 mg of dexamethasone sodium phosphate or any blood or tissue contacting material listed in the IFU
v. Subject has an implanted vena cava filter or mechanical tricuspid valve prosthesis
vi. Subject has pre-existing, permanent endocardial pacing or defibrillation leads (does not include lead fragments)
vii. Subject has current implantation of either conventional or subcutaneous implantable cardioverter defibrillator (ICD) or cardiac resynchronization therapy (CRT) device
viii. Subject has an implanted leadless cardiac pacemaker (except for an Aveir ventricular LP)
ix. Subject is implanted with an electrically-active implantable medical device with stimulation capabilities (such as neurological or cardiac stimulators)*
x. Subject is unable to read or write

*NOTE: Does not apply to a medical device with no known impact to the Aveir Leadless Pacemaker System, including the Aveir Link Module. Patient evaluation and the decision to implant the LP should take into account the presence of other active implantable devices and should include consultation with the Sponsor and/or manufacturer of the co-existing device.

# 2. Follow-up Schedule

The following study evaluations were to occur after implant:

- Pre-discharge assessment (in-hospital)
- 1-month follow-up visit (in-office or clinic)
- 3-month follow-up visit (in-office or clinic)
- 6-month follow-up visit (in-office or clinic)
- 12-month follow-up visit (in-office or clinic)
- Every 6 months thereafter until study completion

Follow-up schedules were to be calculated from the date of implant procedure. The subject follow-up period was necessary to demonstrate safety and effectiveness. Additionally, during this follow-up period, the Sponsor would identify any residual risks and complications. Subjects were to undergo the following assessments as described in the study flow diagram in Figure 3 below.

PMA P150035-S003: FDA Summary of Safety and Effectiveness Data

20 of 56

{20}

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

Figure 3: Study Flow Diagram

![img-3.jpeg](img-3.jpeg)

PMA P150035-S003: FDA Summary of Safety and Effectiveness Data

21 of 56

{21}

# 3. Clinical Endpoints

# Primary Objectives

The primary objectives of this study were to evaluate the safety and effectiveness of the Aveir DR LP system through 3 months post-implant in a subject population indicated for a DDD(R) pacemaker system.

# Secondary Objectives

The secondary objectives of this study were to evaluate the safety and effectiveness of the Aveir Atrial LP through 3 months post-implant in a subject population indicated for a DDD(R) pacemaker system to support an indication for AAI(R) pacing.

# Primary Safety Endpoint

The primary safety endpoint evaluated the 3-month Aveir DR LP system complication-free rate (CFR) based on CEC adjudication of adverse events. A complication is defined as a device-or-procedure-related serious adverse device effects (SADE), including those that prevented initial implantation (includes both Atrial LP and Ventricular LP complications and implant procedure-related complications).

The primary safety endpoint hypothesis at 3 months was formally expressed as:

$$\begin{array}{l} \mathrm{H}_{0}: \mathrm{CFR} \leq 78\% \quad \text{vs.} \quad \mathrm{H}_{1}: \mathrm{CFR} > 78\% \\ \text{where } 78\% \text{ was the performance goal.} \end{array}$$

The CFR was estimated as a binomial proportion and a one-sided 97.5% (or the two-sided 95%) lower confidence bound (LCB) of the CFR was calculated using the normal approximation. The null hypothesis was to be rejected at the 2.5% significance level if the LCB exceeded the Performance Goal (PG) of 78%. The p-value from a one-sided Z-test for the binomial proportion was to be calculated and compared to the 0.025 significance level.

The primary analysis population for the primary safety endpoint analysis was based on subjects in the full analysis population, and the analysis was conducted on all subjects with data available for the evaluation.

# Secondary Safety Endpoint

The secondary safety endpoint evaluated the 3-month Aveir Atrial LP related CFR based on CEC adjudication of adverse events. The secondary safety endpoint was evaluated if the primary endpoints were met. An Atrial LP complication was defined as an atrial device- or procedure-related SADE, including those that prevented initial LP implantation. Complications exclusively related to the ventricular LP, or its delivery/retrieval were not considered atrial LP complications and were excluded from this evaluation. Complications where the relationship could not exclusively be determined to be related to the ventricular or atrial LP were considered Atrial LP

PMA P150035-S003: FDA Summary of Safety and Effectiveness Data

22 of 56

{22}

complications (e.g., femoral access complications, embolism, etc.). The secondary safety endpoint hypothesis is:

$$\mathrm{H}_{0}: \mathrm{CFR}_{\mathrm{A}} \leq 84\% \text{ vs. } \mathrm{H}_{1}: \mathrm{CFR}_{\mathrm{A}} > 84\%$$
where 84% is the PG

The CFR$_{A}$ was estimated as a binomial proportion and a one-sided 97.5% LCB (or the two-sided 95%) LCP of the CFR$_{A}$ was calculated using the normal approximation. The null hypothesis was rejected at the 2.5% significance level if the LCB exceeds the PG of 84%. The p-value for the one-sided Z-test was calculated and compared to the 2.5% significance level.

The secondary safety endpoint analysis was based on *de novo* subjects in the full analysis population.

### Primary Effectiveness Endpoint #1

The primary effectiveness endpoint #1 evaluated the 3-month composite success rate (Rate) evaluating acceptable atrial pacing thresholds and P-wave amplitudes in *de novo* subjects. These *de novo* subjects are the evaluable population within the full analysis population.

The primary effectiveness endpoint #1 hypothesis at 3 months was formally expressed as:

$$\mathrm{H}_{0}: \text{Rate}_{\mathrm{EP}} \leq 82.5\% \text{ vs. } \mathrm{H}_{1}: \text{Rate}_{\mathrm{EP}} > 82.5\%$$
where 82.5% was the performance goal (PG).

The Rate$_{EP}$ is the proportion of subjects who have met success criteria in the primary effectiveness endpoint #1. The acceptable ranges for atrial sensing and pacing which define success criteria are shown below:

Table 6: Acceptable Ranges for Sensing and Pacing

|  Parameter | Acceptable test values  |
| --- | --- |
|  Pacing voltage | Pacing threshold < 3.0 V at 0.4 ms  |
|  P Sensitivity | P-wave amplitude > 1.0 mV  |

Success Criteria: A subject was considered to have met the primary effectiveness endpoint #1 if the pacing threshold voltage was ≤ 3.0 V at 0.4 ms at the 3-month visit and the sensed P-wave amplitude was ≥ 1.0 mV at the 3-month visit.

The Rate$_{EP}$ at 3 months was estimated as a binomial proportion and the one-sided 97.5% LCB of the Rate was calculated using the normal approximation. The null hypothesis was to be rejected at the 2.5% significance level if the LCB exceeded the PG of 82.5%. The p-value for the one-sided Z-test was to be calculated and compared to the 2.5% significance level.

PMA P150035-S003: FDA Summary of Safety and Effectiveness Data

23 of 56

{23}

## Primary Effectiveness Endpoint #2

The primary effectiveness endpoint #2 evaluated the 3-month AV synchrony success rate (RateAV) at rest/seated using a Holter monitor in-clinic. AV synchrony success was defined as subjects with a paced or sensed ventricular beat within 300 ms following a paced or sensed atrial beat for at least 70% of evaluable cardiac cycles. The primary effectiveness endpoint #2 hypothesis is:

$$\begin{array}{l} \mathrm{H}_{0}: \text { Rate}_{\mathrm{AV}} \leq 83 \% \text { vs. } \mathrm{H}_{1}: \text { Rate}_{\mathrm{AV}} > 83 \% \\ \text { where } 83 \% \text { is the PG } \end{array}$$

The RateAV is the proportion of subjects who met success criteria in the primary effectiveness endpoint #2.

The RateAV was estimated as a binomial proportion and the 97.5% LCB of the RateAV was calculated using the normal approximation. The null hypothesis was rejected at the 2.5% significance level if the LCB exceeded the performance goal of 83%. The p-value for the one-sided Z-test was calculated and compared to the 2.5% significance level.

## Secondary Effectiveness Endpoint

The secondary effectiveness endpoint included the evaluation of a Chronotropic Assessment Exercise Protocol (CAEP). If the primary endpoints and the secondary safety endpoint were met, then the following hypothesis was to be evaluated in de novo subjects:

### Secondary Effectiveness CAEP Endpoint

H0: Mean Slope < 0.65 or Mean Slope > 1.35

H1: 0.65 ≤ Mean Slope ≤ 1.35.

### 6 Minute Walk Test (6MWT)

All capable subjects were to be asked to perform a minimal effort six-minute walk test (6MWT) simulating daily walking activity to identify the appropriate sensor parameters for each subject prior to conducting the CAEP exercise protocol. After completion of the 6MWT, the appropriate sensor parameters were to be programmed into the Aveir device and used for the subsequent CAEP protocol.

### CAEP exercise protocol

All capable subjects who have completed the 6MWT protocol were to be asked to perform a maximal effort CAEP exercise protocol to demonstrate an appropriate and proportional response of sensor-indicated rate in graded exercise tests.

Data from subjects who had completed the 6MWT protocol and had completed at least stage 3 of the CAEP exercise protocol, or 3.6 metabolic equivalent of task (METs) were to be included in the analysis. The results of subjects who did not meet the analysis criteria would still be reported. Approximately thirty subjects among the

PMA P150035-S003: FDA Summary of Safety and Effectiveness Data

24 of 56

{24}

full analysis population with a successful implant would provide data contributing to the analysis.

A mixed effects model for repeated measures were to be used to estimate the mean slope (through origin) and standard error of mean slope across N subjects. A no intercept model with unstructured covariance matrix for the random effect (subject) was used for this analysis. A 95% confidence interval for the mean slope were to be provided and if this interval falls within the equivalence bounds of (0.65,1.35), the null hypothesis was rejected.

Based on recently reported studies of marketed rate-responsive pacemakers the expected slope for similar devices, including the Aveir device, was estimated to be approximately 77%, with an associated standard deviation of 14%. It was estimated based on these data that a sample size of 8 subjects would be sufficient to demonstrate that the lower and upper 95% confidence bounds meet the success criterion, based on a normally distributed random variable. To ensure that a robust cross-section of subjects was evaluated, however, up to 30 subjects would undergo this assessment.

The 6MWT was to be performed any time after the beginning of the 1-month visit window and 3-month visit window. The CAEP protocol was to be performed after completion of the 6MWT protocol and any time after the beginning of the 3-month visit window and the 6-month visit window. The CAEP protocol was to be administered on a treadmill that could be programmed to the speed and grade/incline settings for each stage of the protocol.

### **B. Accountability of PMA Cohort**

The Aveir DR i2i Study enrolled a total of 300 subjects within the full analysis population from 55 investigational sites. The full analysis population included the first 300 consecutive *de novo* subjects who provided written informed consent and had an attempted implant. A *de novo* subject was a subject who did not have an implanted pacemaker on the date of consent through the date of the attempted Aveir LP implant.

The study enrolled the first subject on February 2, 2022 and enrolled the final subject in the full analysis population on August 5, 2022. A total of 184 subjects (61.3%) were enrolled in the United States, 89 subjects (29.7%) were enrolled in Europe, and 27 subjects (9%) were enrolled in Canada. In total, 116 subjects (38.7%) were enrolled outside the United States (OUS).

The final 6-month follow-up visit for all subjects within the full analysis cohort occurred on February 1, 2023. The maximum enrollment per site was less than 15% of the total subjects required to evaluate the primary endpoints (i.e., 45 subjects). By the cut-off date of February 3, 2023, the full analysis population had a mean follow-up duration of $6.4 \pm 1.6$ subject-months (median duration 6.0 subject-months) with a cumulative total of 1,907 subject-months.

---PMA P150035-S003: FDA Summary of Safety and Effectiveness Data

25 of 56

{25}

Figure 4 shows the disposition of all 300 subjects within the full analysis population. All subjects within this population had an attempted implant procedure where there was an attempt to implant both the Atrial and Ventricular LPs. All subjects either completed their 6-month visit or passed the window for their 6-month visit by the data cut-off date.

Figure 4: Disposition of Subjects

![img-4.jpeg](img-4.jpeg)

Note: Subjects who missed a follow-up visit could return for a subsequent follow-up visit

Table 7 below summarizes the reasons for all subject discontinuations and withdrawals.

Table 7: Subject Withdrawals and Discontinuations through 6 Months (Full Analysis Population)

|  Withdrawal Reason | Percent (Number) of Subjects (N=300)  |
| --- | --- |
|  System Explant and Not Re-Implanted | 0.3% (1/300)  |
|  Subject Death | 1.3% (4/300)  |
|  Total | 1.7% (5/300)  |

PMA P150035-S003: FDA Summary of Safety and Effectiveness Data

26 of 56

{26}

Five (5) subjects (1.7%) withdrew or discontinued from the study by the end of each subject's 6-month visit window (210 days post-implant). Four (4) subjects discontinued due to subject death. Among these 4 deaths, 3 subjects died prior to their 3-month visit, while 1 subject died between the 3-month and 6-month visits.

One subject discontinued due to system explant between the 3-month and 6-month visits. This subject had both Atrial and Ventricular LPs explanted due to a medical condition change and commercial CRT-P device upgrade and was not re-implanted with Aveir LPs.

### **C. Study Population Demographics and Baseline Parameters**

**Table 8** shows the baseline demographics for all 300 subjects within the full analysis population. Overall, the demographics represent a typical dual-chamber pacemaker population, with a mean subject age of $69.2 \pm 13.5$ years (median age 72 years); 62.3% were male.

Race and ethnicity data were not collected at European centers due to local data privacy regulations. For this reason, the race and ethnicity data below represent the demographics from US and Canadian centers only.

Among the 211 subjects where demographic data was provided (excluding declined data), 94.8% identified as white or Caucasian, 2.8% identified as Black or African American, and 2.4% identified as Asian. Additionally, 4.7% identified with the ethnicity of Hispanic or Latino. One subject who identified as white also identified as American Indian or Alaskan Native. This is similar to the typical US population who have recently received dual-chamber transvenous pacemakers. Among US Medicare Fee-For-Service patients implanted with dual-chamber pacemakers between January 2019 and December 2019, 88.8% identified as white or Caucasian, 5.7% identified as Black, and 1.4% identified as Asian.

**Table 8: Baseline Demographics (Full Analysis Population)**

|  Characteristics | All Subject (N=300)  |
| --- | --- |
|  **Gender** |   |
|  Male | 62.3% (187/300)  |
|  Female | 37.7% (113/300)  |
|  **Age (years)** |   |
|  Mean ± SD (n) | 69.2 ± 13.5 (300)  |
|  Median (Q1,Q3) | 72.0 (63.0, 79.0)  |
|  (Min, Max) | (20.0, 90.0)  |
|  **Height (cm)** |   |
|  Mean ± SD (n) | 171.6 ± 10.1 (300)  |
|  Median (Q1,Q3) | 172.7 (164.5, 180.0)  |
|  (Min, Max) | (140.0, 195.6)  |
|  **Weight (kg)** |   |
|  Mean ± SD (n) | 82.9 ± 19.1 (300)  |
|  Median (Q1,Q3) | 81.7 (70.0, 92.5)  |

PMA P150035-5003: FDA Summary of Safety and Effectiveness Data

27 of 56

{27}

|  (Min, Max) | (43.5, 163.3)  |
| --- | --- |
|  **BMI (kg/m^{2})**  |   |
|  Mean ± SD (n) | 28.1 ± 5.6 (300)  |
|  Median (Q1,Q3) | 27.5 (24.4, 31.2)  |
|  (Min, Max) | (15.1, 49.7)  |
|  **Ethnicity**  |   |
|  Hispanic or Latino | 3.3% (10/300)  |
|  Not Hispanic or Latino | 67.0% (201/300)  |
|  Declined/Unable to Disclose | 29.7% (89/300)  |
|  **Race**  |   |
|  American Indian or Alaska Native | 0.3% (1/300)  |
|  Asian | 1.7% (5/300)  |
|  Chinese | 60.0% (3/5)  |
|  Korean | 20.0% (1/5)  |
|  Other Asian | 40.0% (2/5)  |
|  Black or African American | 2.0% (6/300)  |
|  White | 66.7% (200/300)  |
|  Declined/Unable to Disclose | 29.7% (89/300)  |

**Table 9** summarizes the medical history for all subjects in the full analysis population. Only subjects who had at least one of the indications in the ACC/AHA/HRS/ESC dual chamber pacing guidelines were eligible to enroll.

The most common primary indication in the Aveir DR full analysis population was sinus node dysfunction (63.3%). This indication included patients with the following conditions: sinus bradycardia, sinus arrest, brady-tachy syndrome, sick sinus syndrome, supra-ventricular tachycardias alternating with periods of bradycardia or asystole, and symptomatic chronotropic incompetence. New sinus node dysfunction (SND) associated with symptoms or hemodynamic instability unresolved after surgery were also included within this population.

The second most common indication was AV block (33.3%). Among this population, the most predominant heart block severities were 3$^{rd}$ degree AV Block (41.0%) and 2$^{nd}$ degree – Type 2 (34.0%), irrespective of symptoms. The AV block population also included symptomatic 1$^{st}$ degree AV block (11.0%) and symptomatic 2$^{nd}$ degree – Type 1 AV block (14.0%).

Finally, 2.0% and 1.3% of the population included those with vasovagal syncope and conduction disorders with 1:1 AV ventricular conduction, respectively. Subjects with these conduction disorders included those with alternating bundle branch block, Kearns-Sayre syndrome, and Anderson Fabry disease with QRS prolongation.

**Table 9: Medical History (Full Analysis Population)**

|  Characteristics | All Subjects (N=300)  |
| --- | --- |
|  **Primary Pacemaker Indication**  |   |
|  Sinus Node Dysfunction | 63.3% (190/300)  |

PMA P150035-S003: FDA Summary of Safety and Effectiveness Data

28 of 56

{28}

|  Atrio Ventricular (AV) Block | 33.3% (100/300)  |
| --- | --- |
|  1st Degree | 11.0% (11/100)  |
|  2nd Degree – Type 1 | 14.0% (14/100)  |
|  2nd Degree – Type 2 | 34.0% (34/100)  |
|  3rd Degree | 41.0% (41/100)  |
|  Conduction Disorder with 1:1 Atrio Ventricular Conduction | 1.3% (4/300)  |
|  Vasovagal (Reflex) Syncope | 2.0% (6/300)  |
|  **Congestive Heart Failure**  |   |
|  Congestive Heart Failure | 12.3% (37/300)  |
|  Class I | 18.9% (7/37)  |
|  Class II | 56.8% (21/37)  |
|  Class III | 8.1% (3/37)  |
|  NYHA Assessment Not Done | 16.2% (6/37)  |
|  No Congestive Heart Failure | 87.7% (263/300)  |
|  **LV Ejection Fraction**  |   |
|  Mean ± SD (n) | 59.6 ± 6.9 (226)  |
|  Median (Q1, Q3) | 60.0 (55.0, 65.0)  |
|  (Min, Max) | (40.0, 77.0)  |
|  **History of Tobacco Use** | 35.7% (107/300)  |
|  **Hypertension** | 67.0% (201/300)  |
|  Controlled with Medication(s) | 95.0% (191/201)  |
|  Uncontrolled | 4.5% (9/201)  |
|  **Diabetes** | 25.0% (75/300)  |
|  Type I | 6.7% (5/75)  |
|  Type II | 93.3% (70/75)  |
|  **Diabetes Current Status**  |   |
|  Controlled with Diet | 12.0% (9/75)  |
|  Controlled with Medication(s) | 88.0% (66/75)  |
|  **Hyperlipidemia** | 61.3% (184/300)  |
|  Controlled with Diet | 13.6% (25/184)  |
|  Controlled with Medication(s) | 82.1% (151/184)  |
|  Uncontrolled | 4.3% (8/184)  |
|  **Peripheral Vascular Disease** | 13.0% (39/300)  |
|  **Cardio-Pulmonary History**  |   |
|  Coronary Artery Disease | 34.0% (102/300)  |
|  Myocardial Infarction | 11.7% (35/300)  |
|  Unstable Angina | 5.7% (17/300)  |
|  **Prior Ablation** | 20.0% (60/300)  |
|  AV Junction | 1.7% (1/60)  |
|  AFib / Aflutter | 78.3% (47/60)  |
|  SVT | 11.7% (7/60)  |
|  Other | 13.3% (8/60)  |
|  **Tricuspid Valve Disease** | 24.3% (73/300)  |
|  Insufficiency / Prolapse / Regurgitation | 98.6% (72/73)  |
|  Repair / Replacement | 4.1% (3/73)  |
|  **Arrhythmia History**  |   |
|  Ventricular | 4.3% (13/300)  |
|  Non-Ventricular / Supraventricular | 45.0% (135/300)  |
|  **Medications**  |   |
|  Antiarrhythmics (Class I) | 4.7% (14/300)  |
|  Antiarrhythmics (Class III) | 9.7% (29/300)  |
|  Anticoagulants | 31.0% (93/300)  |
|  Anti-platelets | 39.0% (117/300)  |

PMA P150035-S003: FDA Summary of Safety and Effectiveness Data

29 of 56

{29}

|  ACE Inhibitors | 22.0% (66/300)  |
| --- | --- |
|  Angiotensin II Receptor Blockers | 23.0% (69/300)  |
|  Beta Blockers | 23.7% (71/300)  |
|  **Prior Extractions**  |   |
|  Transvenous Lead Extraction | 8.0% (24/300)  |
|  Leadless Pacemaker Extraction | 0.7% (2/300)  |
|  **Prior Percutaneous Procedures**  |   |
|  TAVR | 2.3% (7/300)  |
|  Mitral Valve Replacement/Repair | 2.7% (8/300)  |
|  Tricuspid Valve Intervention | 1.0% (3/300)  |
|  Percutaneous Coronary Intervention | 16.3% (49/300)  |
|  Left Atrial Appendage Closure (LAAC) | 3.7% (11/300)  |
|  Peripheral Vascular Intervention of Femoral Veins | 2.3% (7/300)  |
|  **Prior Open Heart Surgical Procedures**  |   |
|  CABG | 10.3% (31/300)  |
|  Heart Transplant | 0.3% (1/300)  |
|  Ventricular Assist Device | 0.3% (1/300)  |
|  Aortic Valve replacement | 4.7% (14/300)  |
|  ASD/PFO Closure | 0.3% (1/300)  |
|  Other | 1.7% (5/300)  |
|  **Right Atrial Tissue Modification** | 6.7% (20/300)  |
|  Right Atrial Appendix Removed | 10.0% (2/20)  |
|  **Uncorrected Atrial Septal Defect** | 0.3% (1/300)  |

A majority of the full analysis population was comprised of patients with hypertension, hyperlipidemia, and a history of cardio-pulmonary disease with rates of 67.0%, 61.3%, and 51.3% respectively. Additionally, at least 25% of subjects had any of the following comorbidities: diabetes, a history of non-ventricular/supraventricular arrhythmias, and a history of tobacco use. Thirty-nine percent (39.0%) and 31.0% of subjects were on antiplatelet or anticoagulation drug therapy at the time of consent, respectively.

Overall, 20.0% of the full analysis population had a prior history of ablation, of which 78.3% had prior atrial fibrillation or atrial flutter ablation.

Most of the subject population also had prior cardiovascular interventions or surgeries, including 26 subjects (8.7%) with a history of transvenous lead or leadless pacemaker extraction. There were 53 subjects (17.7%) with prior open heart surgical procedures. The study did not require a waiting period between prior percutaneous or surgical procedures and the Aveir DR implant procedure. Subjects were only excluded if, in the investigator’s opinion, the presence of anatomic or comorbid conditions could confound the assessment of the investigational device and/or implant procedure, limit the subject’s ability to participate in the clinical investigation or to comply with follow-up requirements of the clinical investigation results.

Finally, there were 20 subjects (6.7%) with a history of a surgery or intervention where the right atrial tissue may have permanently been modified during the procedure, two of which had their right atrial appendix removed. These modification

PMA P150035-S003: FDA Summary of Safety and Effectiveness Data

30 of 56

{30}

procedures also included right atrial ablation, Cox-Maze, aortic valve replacement, and bypass surgery cannulation.

### D. Safety and Effectiveness Results

#### 1. Primary Safety Results

The primary analysis population for the primary safety endpoint was based on subjects in the full analysis population. The full analysis population included the first 300 consecutive *de novo* subjects who provided written informed consent and had an attempted implant. The primary safety endpoint evaluated a 3-month complication-free rate (CFR) based on CEC adjudication of adverse events. In addition, a 6-month primary safety analysis evaluated a 6-month CFR based on CEC adjudication of adverse events. Complications included Atrial LP, Ventricular LP, and implant procedure-related complications. The key safety outcomes for this study are presented below in **Table 10**. Adverse effects are reported in **Table 11**.

The primary safety endpoint analysis was only conducted on subjects within the full analysis population with data available for evaluation. For the 3-month endpoint analysis, subjects who withdrew from the study or died prior to the 3-month follow-up visit (lower window) without an event (SADE) were excluded from this analysis. Only SADE events that occurred on or before the 3 months (up to 90 days from the attempted implant date) were included. For the 6-month analysis, subjects who withdrew from the study or died prior to the 6-month follow-up visit (lower window) without an event (SADE) were excluded from this analysis. Only SADE events that occurred on or before the 6 months (up to 180 days from the attempted implant date) were included. To eliminate the possible impact of COVID-19, safety events (SADEs) that were adjudicated as related or possibly related to COVID-19 by the CEC were excluded from the analyses.

For the 3-month endpoint analysis, among the 300 evaluable subjects, 29 subjects experienced 35 complications (i.e., SADEs as adjudicated by the CEC). Therefore, 90.3% of subjects were free from complications within 3-months post-implant. The one-sided 97.5% lower confidence bound (or the lower bound of the two-sided 95% confidence interval) for the CFR was 87.0% and exceeded the performance goal of 78% ($p<0.0001$). Hence, the null hypothesis is rejected at the 2.5% significance level, and it is concluded that the primary safety endpoint was met.

For the 6-month analysis, among the 294 evaluable subjects, 32 subjects experienced 38 complications (i.e., SADEs as adjudicated by the CEC). Therefore, 89.1% of subjects were free from complications within 6-months post-implant. The one-sided 97.5% lower confidence bound (or the lower bound of the two-sided 95% confidence interval) for the CFR was 85.6%.

---PMA P150035-S003: FDA Summary of Safety and Effectiveness Data

31 of 56

{31}

**Table 10: Primary Safety Analysis (Full Analysis Population)**
**(Excludes COVID-19 Complications)**

|  Analysis | Number of Subjects Analyzed (N) | Number of Complications | Number of Subjects with Complications (n) | Freedom from Complications (1-(n/N)) *100% | 95% Confidence Interval^{1} | P-value^{2} (PG = 78%) | Endpoint Met?  |
| --- | --- | --- | --- | --- | --- | --- | --- |
|  Primary Safety Endpoint at 3 months | 300 | 35 | 29 | 90.3% | (87.0%, 93.7%) | <0.0001 | Yes  |
|  Primary Safety Analysis at 6 months | 294 | 38 | 32 | 89.1% | (85.6%, 92.7%) | N/A | N/A  |
|  Source: S:\SHRDATA\AMD\AVG\CRD_1023 LEADLESS DR\Regulatory Reports\PMA\6M\Sasprog\CRD1023_PSEP.sas (March 30, 2023 (17:37). Data Cutoff Date: 03FEB2023 Data Snapshot Date: 17FEB2023)  |   |   |   |   |   |   |   |
|  ^{1} Normal approximation interval  |   |   |   |   |   |   |   |
|  ^{2} Z-test  |   |   |   |   |   |   |   |

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

A complication was defined as a device-or-procedure-related serious adverse event. This definition of complication was equivalent to the term “SADE” (Serious Adverse Device Effect).

A serious adverse device effect (SADE) is any untoward medical occurrence that would happen in a subject or other person and related to the investigational device, comparator, or procedure, and meets the definition of serious, but is not unanticipated. Serious is defined as meeting at least one of the following criteria:

a) Led to death
b) Led to serious deterioration in the health of the subject that either resulted in:
- Life-threatening illness or injury; or
- Permanent impairment of a body structure or a body function; or
- Inpatient or prolongation of existing hospitalization; or
- Medical or surgical intervention to prevent life-threatening illness or injury or permanent impairment to a body structure or a body function; or
- Chronic disease
c) Led to fetal distress, fetal death or a congenital abnormality or birth defect

**Table 11** summarizes all 40 SADEs that took place within the 6-month visit window among the full analysis population.

Thirty-five (35) of the SADEs within Table 11 contributed toward the 3-month primary safety endpoint analysis; two events were not included. One pulmonary

PMA P150035-S003: FDA Summary of Safety and Effectiveness Data

32 of 56

{32}

embolism complication was related to COVID-19 and therefore did not contribute toward the primary safety endpoint analysis. One pre-syncope complication took place after 90 days post-implant but was still within the 3-month visit window, and therefore it also did not contribute toward the primary safety endpoint analysis.

Thirty-eight (38) of the SADEs within Table 11 contributed toward the 6-month primary safety analysis; two events were not included. One pulmonary embolism complication was related to COVID-19 and therefore did not contribute toward the primary safety endpoint analysis. One oversensing complication took place after 180 days post-implant but was still within the 6-month visit window, and therefore it also did not contribute toward the primary safety analysis.

**Table 11: Serious Adverse Device Effects through 6 Months

|  Event Description | Number of Events | Percent of Subjects with Events %(n/N) | Related to Avoir Implant Procedure | Related to Avoir Ventricular LP | Related to Avoir Atrial LP | Related to Avoir Delivery Catheter RV | Related to Avoir Delivery Catheter RA | Related to COVID-19  |
| --- | --- | --- | --- | --- | --- | --- | --- | --- |
|  Cardiac Arrhythmia - Atrial Fibrillation | 9 | 3.0% (9/300) | 8 | 0 | 7 | 0 | 1 | 0  |
|  Device Dislodgement | 5 | 1.7% (5/300) | 0 | 0 | 5 | 0 | 0 | 0  |
|  Inadequate Fixation During Implant Without LP Migration | 3 | 0.7% (2/300) | 3 | 0 | 1 | 0 | 2 | 0  |
|  Urinary Retention | 3 | 1.0% (3/300) | 3 | 0 | 0 | 0 | 0 | 0  |
|  Threshold Elevation | 2 | 0.7% (2/300) | 0 | 1 | 1 | 0 | 0 | 0  |
|  Pericardial Effusion or Rub | 2 | 0.7% (2/300) | 2 | 0 | 2 | 0 | 0 | 0  |
|  Inadequate Fixation During Implant With LP Migration | 2 | 0.7% (2/300) | 2 | 1 | 1 | 0 | 0 | 0  |
|  False Magnet Mode | 1 | 0.3% (1/300) | 0 | 0 | 1 | 0 | 0 | 0  |
|  Syncope | 1 | 0.3% (1/300) | 0 | 0 | 1 | 0 | 0 | 0  |
|  Intermittent Capture | 1 | 0.3% (1/300) | 0 | 1 | 0 | 0 | 0 | 0  |
|  Intermittent or Loss of i2i Communication | 1 | 0.3% (1/300) | 0 | 1 | 0 | 0 | 0 | 0  |
|  Oversensing | 1 | 0.3% (1/300) | 0 | 1 | 0 | 0 | 0 | 0  |
|  Pre-Syncope | 1 | 0.3% (1/300) | 0 | 1 | 0 | 0 | 0 | 0  |

PMA P150035-S003: FDA Summary of Safety and Effectiveness Data

33 of 56

{33}

|  Access Site Bleeding Event | 1 | 0.3% (1/300) | 1 | 0 | 0 | 0 | 0 | 0  |
| --- | --- | --- | --- | --- | --- | --- | --- | --- |
|  Heart Failure | 1 | 0.3% (1/300) | 1 | 0 | 0 | 0 | 0 | 0  |
|  Hematoma Formation, Including Retroperitoneal Hematoma/Hemorrhage | 1 | 0.3% (1/300) | 1 | 0 | 0 | 0 | 0 | 0  |
|  Pain | 1 | 0.3% (1/300) | 1 | 0 | 0 | 0 | 0 | 0  |
|  Pleural Effusion | 1 | 0.3% (1/300) | 1 | 0 | 0 | 0 | 0 | 0  |
|  Pulmonary Embolism | 1 | 0.3% (1/300) | 1 | 0 | 0 | 0 | 0 | 1  |
|  Other | 2 |  |  |  |  |  |  |   |
|  Mechanical Device Dislodgement | 1 | 0.3% (1/300) | 1 | 0 | 0 | 0 | 0 | 0  |
|  Complete Av Block | 1 | 0.3% (1/300) | 1 | 0 | 0 | 1 | 0 | 0  |
|  **Total** | 40 | 11.0% (33/300) | 26 | 6 | 19 | 1 | 3 | 1  |

Note: Subjects may experience more than one event.

Note: Related includes Probable, Possible, or Causally related.

Note: Covid-Related includes Related or Possibly Related. Note: Cardiac Arrhythmias –Supraventricular arrhythmia exclude atrial fibrillation events that are presented as a separate category in this table.

There were 40 SADEs reported in 33 subjects constituting 11.0% of the full analysis population. Twenty-six (26) events were considered to be related to the Aveir DR implant procedure, 19 events were related to the Aveir Atrial LP, and 6 events were related to the Aveir Ventricular LP. Additionally, 3 events were related to the Aveir Delivery Catheter used to implant the Atrial LP, while 1 event was related to the Aveir Delivery Catheter used to implant the Ventricular LP. There was one pulmonary embolism event related to COVID-19.

The most frequent complications were 9 atrial fibrillation events in 9 subjects (3.0%), 5 device dislodgement events in 5 subjects (1.7%), and 5 inadequate fixation events in 4 subjects (1.3%), 2 of which resulted in LP migration.

Among all SADEs, 75% (30/40) were peri-procedural events that occurred within 30 days of the implant date (28 events occurred within 2 days of the implant date). The remaining 25% (10/40) all occurred between 32 and 200 days post-implant. Three (3) events of threshold elevation, false magnet mode, and oversensing took place between 3 and 6 months post-implant (after 120 days).

All events, apart from the pulmonary embolism and pre-syncope event, were resolved by the data cut-off date of this report. The pulmonary embolism remains in stable condition after medical therapy. The pre-syncopal symptoms remained ongoing at the time of subject study withdrawal due to system explant.

## 2. Secondary Safety Results

The primary analysis population for the secondary safety endpoint was base…

---

**Source:** [https://fda.innolitics.com/device/P150035S003](https://fda.innolitics.com/device/P150035S003)

**Published by [Innolitics](https://innolitics.com)** — a medical-device software consultancy. We help companies design, build, and clear FDA-regulated software and AI/ML devices. If you're preparing [a PMA](https://innolitics.com/services/regulatory/), [a 510(k)](https://innolitics.com/services/510ks/), [a SaMD](https://innolitics.com/services/end-to-end-samd/), [an AI/ML medical device](https://innolitics.com/services/medical-imaging-ai-development/), or [an FDA regulatory strategy](https://innolitics.com/services/regulatory/), [get in touch](https://innolitics.com/contact).

**Cite:** Innolitics at https://innolitics.com