Cordella Pulmonary Artery Sensor System (CorPASS)

P230040 · Endotronix, Inc. · MOM · Jun 20, 2024 · Cardiovascular

Device Facts

• Record ID: P230040
• Device Name: Cordella Pulmonary Artery Sensor System (CorPASS)
• Applicant: Endotronix, Inc.
• Product Code: MOM · Cardiovascular
• Decision Date: Jun 20, 2024
• Decision: APPR
• Device Class: Class 3

Indications for Use

The Cordella Pulmonary Artery Sensor System is intended to measure, record and transmit pulmonary artery pressure (PAP) data from NYHA Class III heart failure patients who are at home on diuretics and guideline-directed medical therapy (GDMT) as well as have been stable for 30 days on GDMT. The device output is meant to aid clinicians in the assessment and management of heart failure, with the goal of reducing heart failure hospitalizations.

Device Story

Implantable, battery-less capacitive pressure sensor (20x4x2mm) resides in interlobar right pulmonary artery; anchors via nitinol struts. Patient uses handheld myCordella Reader against chest to wirelessly power sensor and acquire PAP frequency data. Reader transmits data to off-the-shelf tablet; tablet uploads to Cordella Data Analysis Platform (CDAP). CDAP processes data into systolic, diastolic, mean pressures and waveforms; makes data available to clinicians via secure portal. Clinicians use PAP trends, vital signs, and symptoms to guide diuretic/medication titration. System facilitates home-based monitoring to proactively manage heart failure, potentially reducing hospitalizations. Implant procedure is minimally invasive RHC; sensor calibrated to fluid-filled reference pressure at implant using Calibration Equipment (CalEQ).

Clinical Evidence

Prospective, multi-center, open-label, single-arm pivotal trial (PROACTIVE-HF, N=456 evaluable). Primary endpoint: 6-month incidence of HF hospitalization or all-cause mortality. Result: 0.1589 events/patient-6mo (95% CI: 0.1200-0.2106), meeting performance goal of 0.43 (p<0.0001). Safety: 99.2% freedom from device/system-related complications at 6 months. Hemoptysis rate 3.0%.

Technological Characteristics

Battery-less capacitive pressure sensor; glass body with medical-grade silicone coating; nitinol anchors. Dimensions ~20x4x2mm. Resonant frequency sensing principle. Wireless power/data transfer via handheld reader. MRI conditional (1.5T/3T). Sterilized via Ethylene Oxide (ISO 11135). Connectivity: Bluetooth peripherals to tablet, Wi-Fi/cellular to cloud platform.

Indications for Use

Indicated for NYHA Class III heart failure patients, age 18+, on stable diuretics and GDMT for at least 30 days. Contraindicated for patients unable to take dual antiplatelet or anticoagulants for one month post-implant.

Predicate Devices

• CardioMEMS HF System

Reference Devices

• CHAMPION-HF
• CardioMEMS Post approval study
• MEMS-HF
• GUIDE-HF
• LAPTOP-HF
• MONITOR-HF

Submission Summary (Full Text)

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# SUMMARY OF SAFETY AND EFFECTIVENESS DATA (SSED)

## I. GENERAL INFORMATION

Device Generic Name: Heart Failure Monitoring System

Device Trade Name: Cordella Pulmonary Artery Sensor System

Device Procode: MOM

Applicant’s Name and Address: Endotronix, Inc.
1415 W. Diehl Road Suite 500W
Naperville, IL 60563

Date(s) of Panel Recommendation: None

Premarket Approval Application (PMA) Number: P230040

Date of FDA Notice of Approval: 6/20/2024

Breakthrough Device: N/A

## II. INDICATIONS FOR USE

The Cordella Pulmonary Artery Sensor System is intended to measure, record and transmit pulmonary artery pressure (PAP) data from NYHA Class III heart failure patients who are at home on diuretics and guideline-directed medical therapy (GDMT) as well as have been stable for 30 days on GDMT. The device output is meant to aid clinicians in the assessment and management of heart failure, with the goal of reducing heart failure hospitalizations.

## III. CONTRAINDICATIONS

The Cordella Pulmonary Artery Sensor System is contraindicated for patients with an inability to take dual antiplatelet or anticoagulants for one month post implant.

## IV. WARNINGS AND PRECAUTIONS

The warnings and precautions can be found in the Cordella Pulmonary Artery Sensor System labeling.

## V. DEVICE DESCRIPTION

The Cordella PA Sensor System is designed to be used with the Cordella Heart Failure System to better connect healthcare professionals and patients with tools for heart failure management.

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The Cordella PA Sensor is an implantable blood pressure monitor that permanently resides in the patient's pulmonary artery. With this Sensor, PA pressure can be wirelessly measured from the patient's home on demand. Active management of a patient using PA pressure data from the Cordella Sensor and vital signs and patient-reported symptoms data from Cordella HF System may improve long-term outcomes in patients with NYHA Class III heart failure.

The Cordella PA Sensor System is comprised of the following subsystems:

Cordella PA Sensor
Cordella Delivery System
myCordella Handheld Patient Reader (including Dock)
Cordella Calibration Equipment (CalEQ)
Cordella Data Analysis Platform (CDAP)

The Cordella PA Sensor System, schematized in Figure 1 and described in the paragraphs that follow, interfaces with the commercial Cordella HF System to facilitate PA Pressure (PAP) readings at a patient's home and transmission of the results to a care provider for evaluation. The Cordella HF System is a commercially available convenience kit with Bluetooth connected off-the-shelf peripherals for vital signs monitoring (weight, heart rate, systolic blood pressure, and SpO2), myCordella Tablet (running the myCordella Patient App), and the myCordella Patient Management Portal (PMP), that interfaces with the Cordella PA Sensor System as shown in Figure 1.

Figure 1: Functional Block Diagram of the Cordella PA Sensor System (CorPASS) and its interface with the Cordella Heart Failure System (CHFS)

The heart of the Cordella PA Sensor System is the Cordella PA Sensor, a permanent implant that resides in the patient's interlobar right pulmonary artery, provided that the RPA downturn

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diameter is $12 - 26\mathrm{mm}$ for secure stabilization of the sensor. The wireless Sensor, illustrated in Figure 2 and 4, is a battery-less capacitive pressure sensor packaged in a glass body approximately $20\times 4\times 2\mathrm{mm}$ in size with a coating of medical grade silicone. Nitinol anchors extend from either end to hold the Sensor body in place against the wall of the pulmonary artery (PA), such that the pressure sensitive surface of the Sensor body faces away from the vessel wall and towards the bloodstream. The Sensor resonates electrically, changing its resonant frequency in proportion to the PAP. The Sensor is shipped sterile to a hospital pre-attached to the distal end of the Cordella Delivery System, a custom catheter depicted in Figure 3. Attachment wires in the Catheter hold the Sensor's nitinol anchors flat (Figure 4) during vascular ingress. A physician uses the Delivery System to place the Sensor via percutaneous venous access in the patient's interlobar right pulmonary artery, provided that the RPA downturn diameter is $12 - 26\mathrm{mm}$ for secure stabilization of the sensor. Once placed, the physician uses the Delivery System handle to retract the attachment wires and release the Sensor. At this point, the Sensor's nitinol anchors unfold and hold the device in place for the lifetime of the patient. The Delivery System is removed and discarded following calibration of the Sensor to a fluid-filled reference pressure measurement (described below). The minimally invasive implant procedure is designed to resemble existing Right Heart Catheterization (RHC) procedures, and to be safe..

Figure 2: Cordella PA Sensor

Figure 3: Cordella Delivery System with Sensor

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Figure 4: Cordella PA Sensor tied down to Delivery System

The myCordella Reader (including Dock) (Figure 5) is a handheld wireless device used for obtaining Sensor readings. At home the patient acquires a PAP reading by holding their myCordella Reader against their chest. The Patient App running on an off-the-shelf myCordella Tablet (part of Cordella HF System) provides audio and visual prompts for the patient to guide them through signal acquisition. During the reading, the Reader powers the Sensor wirelessly and obtains the pressure reading by measuring the Sensor frequency that changes in proportion to the pressure on the Sensor. Once the signal is acquired, the patient is notified of the successful reading and the Reader transmits data to the Tablet, where the Patient App connected to the internet using Wi-Fi or cellular transmits the data to the Cordella Data Analysis Platform (CDAP), a web-based application that stores configuration and calibration data, processes raw data from the daily readings, and makes the final PA pressure data (systolic, diastolic, mean pressures and a waveform) available to clinicians through the secure myCordella PMP (also part of Cordella HF System). Changes in PAP can be used in conjunction with vital signs and patient-reported symptoms to guide adjustments to diuretic and other medications. The myCordella Dock connects to a wall plug and recharges the Reader's battery. The entire PA pressure home reading sequence is designed for patient convenience and is generally completed in less than one minute with the entire reading session comprising PA Pressure, vital signs and patient-reported symptoms taking less than 5 minutes. The Reader remains docked at all other times when the patient is not actively taking a reading.

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Figure 5A: myCordella Reader and Dock Figure 5B: Depiction of patient taking seated PAP with the myCordella Reader


The Calibration Equipment (CalEQ) (Figure 6) installed in the cath lab supports the calibration of the Sensor to a reference pressure at the time of implantation.

Figure 6: Cordella Calibration Equipment (CalEQ)

Implant Procedure

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The Sensor implantation takes place during a minimally invasive RHC that typically takes less than an hour.

Once the target location for the Sensor has been identified in the interlobar right pulmonary artery (provided that the RPA downturn diameter is $12 - 26\mathrm{mm}$ for secure stabilization of the sensor), the PA Sensor is deployed. Using the calibration feature in CalEQ, the physician is able to collect simultaneous pressure readings using a reference fluid-filled catheter and the Sensor. The CalEQ software zeroes out any difference in the mean PAP between the reference fluid-filled measurement and the Sensor. Figure 7 below is a simulated waveform and data presentation available only for the physician during implant.


Figure 7: Implanting Physician Interface via the Calibration Equipment

Once the implant procedure is completed, a Reader is given to the patient to take home so that they may begin transmitting pressure readings.

The Cordella PA Sensor System and each of its subsystems only support diagnostic functions. Their purpose is to provide clinicians with accurate PAP data from the patients' home. The system does not recommend therapy or any other clinical action, nor does it draw conclusions from the data.

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## Notification Algorithm

The CDAP is able to calculate and send to PMP the mean PA pressure (mPAP) trend (7 day average) of a patient and notifications when the patient is outside the target trend range of 5 - 20 mmHg in accordance with the treatment guidelines of the study (Appendix 14.5 in protocol/ CIP Guidelines for managing HF using Pulmonary Artery Pressures). 3 types of notifications are generated consistent with treatment recommendations A, B, and C in the guidelines: “mPAP trend is below target range” when seated mPAP is &lt; 5 mmHg. “mPAP trend is above target range” when seated mPAP is above 20 mmHg, and “mPAP trend is &gt; 10 mmHg above target range” when seated mPAP is over 30 mmHg.

## VI. ALTERNATIVE PRACTICES AND PROCEDURES

There are a couple other alternative methods for obtaining pulmonary artery pressure (PAP) in patients with chronic heart failure.

These methods include a right heart catheterization (RHC) procedure or PAP monitoring with an implantable hemodynamic monitoring system which also gets implanted via a RHC.

A RHC is a procedure during which a catheter is inserted through a large vein in the neck or groin and subsequently advanced into the pulmonary artery. However, use of a RHC procedure to obtain pulmonary artery pressure frequently is impractical and associated with significant risks.

The risks of a RHC either for direct measurements or used for the implantation of a PAP monitoring medical device include entry site complications such as bruising or blood vessel injury, bleeding (during or after the procedure), blood clots and thromboembolisms. Other inherent risks include chest pain or cardiac arrest, induction of cardiac arrhythmias, possible abnormal heart rate (pulse) or heart rhythm, hemoptysis, infection or fever, injury of the valves in the right heart (tricuspid and/or pulmonary), respiratory distress or failure. Of note, this RHC procedure will be performed prior to introduction of the Cordella sensor. However, it will only be done one time.

Of note, insertion of the Cordella PA Sensor is performed via the same RHC procedure described above, as such it exposes the patient to the same peri-procedural risks of a RHC procedure, as described above - albeit for one single procedure, rather than repeated RHC over time.

The primary other implantable pulmonary artery sensor system for the management of heart failure is the CardioMEMS HF System. Each treatment 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 Cordella PA Sensor System has not been marketed in the United States or any foreign country.

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## 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 Cordella Pulmonary Artery Sensor System.

- Allergic reaction
- Arrhythmias
- Bleeding complications (which may require transfusion)
- Cardiac arrest
- Chest pain
- Death
- Device embolization/migration
- Device explant
- Emergent or urgent cardiac, vascular, and/or other surgery necessitated by the device or implant procedure (e.g., coronary sinus lead revision)
- Endocarditis or device infection
- Entry site complications (e.g., hematoma, dissection)
- Fracture of a component of the device/system that may or may not lead to serious injury or surgical intervention
- Gastrointestinal bleed (secondary to antiplatelet therapy)
- Hemoptysis
- Hypo or hypertension
- Infection or fever
- Lead dislodgement
- Peripheral embolism/thrombus
- Pulmonary embolism/pulmonary occlusion
- Pseudoaneurysm of the vein
- Radiation exposure
- Reaction to contrast media/ medication
- Renal insufficiency or failure
- Respiratory distress or failure (breathing problems)
- Sepsis
- Valvular injury (tricuspid and/or pulmonary)
- Vascular complications (e.g., venous dissection, perforation, rupture, arteriovenous fistula)
- Vessel trauma which may require surgical repair
- Worsening heart failure

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

## IX. SUMMARY OF NON-CLINICAL STUDIES

A. Laboratory Studies

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Table 1. Summary of Testing – System, Sensor, Delivery System, Reader, and Calibration Equipment

| System Functional Testing | | | |
| --- | --- | --- | --- |
| Test | Acceptance Criteria | Results | Analysis Type |
| System Accuracy (short-term under typical environmental conditions) | System must measure within ± 2 mmHg at baseline (740 mmHg) and ± 3% across the pressure range compared to a reference pressure measurement for a pressure range of 600-860 mmHg (absolute). | PASS | Variable |
| Worst Case System Error | System Root Sum Square (RSS) error after combining all sources of variation must remain within +/- 7.8 mmHg over 10 years. | PASS | Variable |
| Sensor Detection Distance | Sensor must be detectable by the Reader up to 16 cm of link distance with ≥ 80% signal strength in air. | PASS | Variable |
| Sensor Functional Testing | | | |
| --- | --- | --- | --- |
| Test | Acceptance Criteria | Results | Analysis Type |
| Simulated Use Pressure Cycle Conditions | The Sensor shall meet all safety and functional requirements after 10 years of simulated use (>400 million cycles). | PASS | Variable for functional requirements
Attribute for safety requirements |
| Temperature Sensitivity | Change in output pressure signal from the Sensor shall be within < -3 mmHg per °C across the range of 36-40°C. | PASS | Variable |
| Pressure (Over/Under) Exposure | The Sensor shall meet all safety, functional, and accuracy requirements after exposure to high pressure (150 kP/1.5atm) and low pressure (70 kP/0.7 atm) conditions, per ISO 14708-1 | PASS | Variable for functional and accuracy requirements
Attribute for safety requirements |

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| Sensor Compatibility Testing | | | |
| --- | --- | --- | --- |
| Test | Acceptance Criteria | Results | Analysis Type |
| MRI | Device must meet “MR Conditional” requirements for safe scanning immediately after placement under the following conditions: • Static magnetic field of 1.5 or 3 Tesla • Maximum spatial gradient magnetic field of 4000 Gauss/cm (40 T/m) Maximum MR system reported, whole body averaged specific absorption rate (SAR) of 2 W/kg for 15 minutes of scanning in the Normal Operating Mode | PASS | Attribute - Third Party Testing and Review |
| | In non-clinical testing with 1.5 and 3 Tesla systems, device must meet standard requirements for: • Displacement Force, per ASTM F2052-15 • RF Heating, per ASTM F2182-11a • Torque, per ASTM F2213-17 • Image Artifact, per ASTM F2119-07 | | |
| | The Sensor shall meet all safety and functional requirements after exposure to 1.5T and 3T MRI and comply with applicable clauses of ISO/TS 10974. | PASS | Variable for functional requirements |

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| Defibrillation | The Sensor shall meet safety and accuracy requirements after exposure to a defibrillation pulse per ISO 14708-1 part 20.2. | PASS | Attribute |
| --- | --- | --- | --- |
| Ultrasound | The Sensor shall meet all safety and functional requirements after exposure to conventional ultrasonic imaging per ISO 14708 section 22.1. | PASS | Attribute |
| Pacemaker and ICD Compatibility | The Sensor shall meet all safety and accuracy requirements when placed next to commercially available pacemakers, cardiac rhythm management devices, and implantable cardiac defibrillators.

The normal operation of the system, pacemakers, and ICD’s must not be affected during simultaneous operation for potential modes of use.
The in vitro test plan includes:
• Representative relative placement in a human torso anatomical model
• Multiple ICD and pacemaker models
• Variables addressed in the test plan:
• Number of pacing chambers
• Potential operating modes
• Unipolar and bipolar lead configurations
• Relative orientations between the external system and implanted devices. | PASS | Attribute - Third Party Testing and Review |
| Delivery System with Sensor | | | |
| --- | --- | --- | --- |
| Test | Acceptance Criteria | Results | Analysis Type |
| Simulated Implant Procedure Testing | The Cordella PA Pressure Sensor System must meet the following requirements in simulated use testing:
1) The Delivery System shall navigate tortuosity of target vasculature during simulated use.
2) The Delivery System shall be capable of rotating the Sensor at a target location to the desired deployment orientation in a clinically relevant simulated vasculature. | PASS | Attribute |

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| | 3) The Delivery System shall be capable of fully deploying the Sensor within +/-1.5 cm and +/- 20° of the target location within a clinically relevant simulated vasculature in the range of vessel diameters and downturn angles.
4) The Sensor shall remain within +/-1.5 cm and +/-20° of the target location after the Delivery System is retracted post Sensor deployment in a clinically relevant simulated vasculature in the range of vessel sizes and downturn angles. | | |
| --- | --- | --- | --- |
| Catheter Shaft Tensile | Catheter shaft and hub tensile forces must be ≥ 15N. Test performed per ISO 10555-1, Annex B. | PASS | Variable |
| Catheter Shaft Torsional | When the distal tip of the Delivery System is fixed, the Delivery System shall be able to withstand torsional forces and remain intact during 360 degrees of rotation. | PASS | Attribute |
| Catheter Shaft Air and Liquid Leakage | Air shall not leak into the hub assembly during aspiration when tested in accordance with ISO 10555-1, Annex D
The catheter shall not leak liquid when tested in accordance with ISO 10555-1, Annex C | PASS | Attribute |
| Catheter Shaft Radiopacity | Parts of the catheter shall be radio-detectable per ISO 10555-1, Clause 4.2. | PASS | Attribute |
| Pouch Bubble Emission Test | Delivery System pouch shall meet sterile barrier pouch integrity per ISO 11607, testing per ASTM F2096-11. | PASS | Attribute |
| Pouch Seal Tensile Test | Delivery System pouch seal shall maintain minimum tensile strength per ISO 11607 (≥ 1 lbf), testing per ASTM F88/F88M-15. | PASS | Variable |
| **Delivery System with Sensor** | | | |
| Test | Acceptance Criteria | Results | Analysis Type |
| Shipping and Environmental Conditions | The Sensor shall meet all safety and functional requirements after being subjected to simulated transportation and storage conditions per ASTM D4432 and ASTM D4169.

The Delivery System shall meet all package integrity, safety and functional requirements after being subjected to simulated transportation and storage conditions per ASTM D4332 and ASTM D4169. | PASS | Variable for Sensor functional requirements
Attribute for Sensor safety requirements
Variable for pouch seal strength, |

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| Shelf-Life | The Sensor should meet all safety and functional requirements after real-time aging of 2 years.
The Delivery System should meet package integrity, safety, and functional requirements after real-time aging of 2 years. | PASS | Attribute for bubble emission, safety and functional Delivery System requirements |
| --- | --- | --- | --- |
| | | | Variable for Sensor functional requirements
Attribute for Sensor safety requirements
Variable for pouch seal strength, Attribute for bubble emission, safety and functional Delivery System requirements |
| Sterilization | | | |
| --- | --- | --- | --- |
| Test | Acceptance Criteria | Results | Analysis Type |
| Sterilization | The Delivery System with attached Sensor shall be EO sterilized and achieve a sterility assurance level (SAL) of 10^{-6} in a sterilization process validation performed per ISO 11135.

The hardest-to-sterilize location in the Delivery System does not create a more difficult-to-sterilize area than the non-product EPCDs or IPCDs, which are used as the biological challenge device.

A validated EtO sterilization process is used. It is considered an overkill sterilization cycle. | PASS | Attribute - Third Party Testing and Review |

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| Sterilization | | | |
| --- | --- | --- | --- |
| Test | Acceptance Criteria | Results | Analysis Type |
| | The sterilization process must demonstrate a sterility assurance level of < 10^{-6} using a “worst-case” challenge configuration of the product in a sterilization process validation performed per ISO-11135 requirements | | |
| Sterilization Byproducts | EO residuals must be within acceptable limits per ISO 10993-7. | PASS | Attribute - Third Party Testing and Review |
| Handheld Reader | | | |
| --- | --- | --- | --- |
| Test | Acceptance Criteria | Results | Analysis Type |
| Electrical Safety Testing | The system shall be compliant with safety requirements of medical electronics per IEC 60601-1. | PASS | Attribute - Third Party Testing and Review |
| Emissions Testing (FCC and International) | The Reader shall comply with emissions requirements of FCC Part 15.209. | PASS | Attribute - Third Party Testing and Review |
| Electromagnetic Compatibility Testing | The Reader shall meet electromagnetic compatibility requirements of AIM RFID Reader Immunity, RED 2014/53/EU, and EMC 2014/30/EU. | PASS | Attribute - Third Party Testing and Review |
| Design Testing | Reader predicted frequency output should not vary greater than +/- 1.0kHz due to axial rotation of the Reader relative to the Sensor. | PASS | Variable |
| | Reader predicted frequency output should not vary greater than +/-3.0kHz when Sensor or simulated Sensor position translates up to +/- 2 cm in X and/or Y planes | PASS | Variable |
| | Reader predicted frequency output should not vary greater than +/- 11.6kHz when subjected to environmental temperatures of +5°C to 40°C AND rH of 15% to 90%, non condensing | PASS | Variable |

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| Handheld Reader | | | |
| --- | --- | --- | --- |
| Test | Acceptance Criteria | Results | Analysis Type |
| | Reader predicted frequency output should not vary greater than +/- 13.4kHz when the distance between the Sensor and Reader is within the reading window. | PASS | Variable |
| | Reader predicted frequency output should not vary greater than +/- 11.0kHz across the operating frequency bandwidth of 12.880MHz to 14.120MHz. | PASS | Variable |
| | Reader predicted frequency output should not vary greater than 0.6kHz throughout the battery operating voltage range. | PASS | Variable |
| Thermal Assessment Test | The Reader and Dock shall comply with IEC 60601-1 Clause II Protection against excessive temperatures.
Reader and Dock must function accurately (within +/- 11.6 kHz of a reference standard) over the range of normal operating temperatures (5°C to 35°C) as defined in IEC 60601-1-11 and not exceed surface and internal temperatures as defined by IEC 60601-1. | PASS | Attribute - Third Party Testing and Review |
| Reader and Dock Functional Lifetime Testing | The Reader and Dock shall continue to meet functional and accuracy requirements through 4 years of simulated use. | PASS | Variable for accuracy requirements, Attribute for functional requirements |
| Mechanical Testing | The Reader and Dock shall function after rough handling, shock, and vibration for handheld devices as required per IEC 60601-1 and 60601-1-11. | PASS | Attribute - Third Party Testing and Review |
| Label Durability Testing | The labeling on the Reader shall meet label legibility and durability requirements per IEC 60601-1 Clause 7.1.2 and Clause 7.1.3. | PASS | Attribute - Third Party Testing and Review |
| Shipping and Environmental Conditions | The Reader and Dock shall meet transport and storage conditions defined by IEC 60601-1-11.
Reader shall meet all accuracy and functional requirements after simulated transportation | PASS | Variable for accuracy requirements, Attribute for |

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| Handheld Reader | | | |
| --- | --- | --- | --- |
| Test | Acceptance Criteria | Results | Analysis Type |
| | conditions within packaging per guidance of ISTA-2A or ASTM D4332 and ASTM D4169.
The Dock shall charge the Reader and display charging status after simulated transportation conditions within packaging per guidance of ISTA-2A or ASTM D4332 and ASTM D4169. | | functional requirements |
| Calibration Equipment | | | |
| --- | --- | --- | --- |
| Test | Acceptance Criteria | Results | Analysis Type |
| Electrical Safety Testing | Calibration Equipment shall meet safety requirements for medical electronic equipment defined by IEC 60601-1. | PASS | Attribute - Third Party Testing and Review |
| Emissions Testing (FCC and International) | Calibration Equipment shall meet emissions requirements as defined by IEC 60601-1-2 and FCC Part 15. | PASS | Attribute - Third Party Testing and Review |
| Electromagnetic Compatibility Testing | Calibration Equipment shall meet requirements for electromagnetic compatibility as defined by IEC 60601-1-2. | PASS | Attribute - Third Party Testing and Review |
| Design Testing | Calibration Equipment should operate on battery power for at least 2 hours. | PASS | Attribute |
| | Calibration Equipment shall make calibration reading data available within 10 seconds of the completed reading | PASS | Attribute |
| Calibration Equipment Functional Lifetime Testing | Calibration Equipment shall have a functional lifetime of 5 years. | PASS | Attribute |
| Mechanical Testing | Calibration Equipment shall maintain basic safety after rough handling and meet stability and transportability requirements per IEC 60601-1. | PASS | Attribute - Third Party Testing and Review |

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| Calibration Equipment | | | |
| --- | --- | --- | --- |
| Test | Acceptance Criteria | Results | Analysis Type |
| Label Durability Testing | The labeling on the Calibration Equipment shall meet label legibility and durability requirements per IEC 60601-1 Clause 7.1.2 and Clause 7.1.3. | PASS | Attribute - Third Party Testing and Review |
| Shipping and Environmental Conditioning | N/A - not performed since Calibration Equipment is assembled by Endotronix personnel and 100% inspected upon delivery. | N/A | N/A |

The engineering study results for the implantable Sensor demonstrated the following conclusions:

- Remains functional, hermetic and accurate after 10 years of simulated use;
- Temperature, over-pressurization and mechanical shock have a negligible effect on Sensor function;
- Meets its specifications for accuracy during the hermeticity and calibration testing;
- Meets RF signal detection requirements for distance between the Reader and the implanted sensor in a simulation;
- Remains securely attached to the Delivery System during delivery and rotation until release;
- Is resistant to corrosion; and
- Is compatible with MRI, defibrillators, ultrasound, pacemakers, ICDs, and glucose monitors.

The engineering study results for the Delivery System demonstrated the following conclusions:

- May be removed from the packaging, flushed with saline, advanced over an 0.018" or 0.025" guidewire and loaded into a venous sheath;
- Positions the Sensor in the target vessel via femoral or jugular access, rotates and retracts the Sensor as needed before deployment, facilitates reference pressure measurements and releases the Sensor at the appropriate location in the downturn of the pulmonary artery;
- Does not damage the catheter or Sensor during delivery and has sufficient tensile strength to maintain its integrity during use;
- Is corrosion resistant and is sufficiently radiopaque.

Table 2. Biocompatibility

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| Biocompatibility | | | | |
| --- | --- | --- | --- | --- |
| Test | | Acceptance Criteria | Results | Analysis Type |
| Cytotoxicity | Sensor | Meet requirements in an ISO Elution Method study (1xMEM Extract), per ISO 10993-5. | PASS (non-cytotoxic) | Attribute -- Third Party Testing |
| | Delivery System | Meet requirements in an ISO Elution Method study (1xMEM Extract), per ISO 10993-5. | PASS (non-cytotoxic) | |
| Sensitization | Sensor | Meet requirements in an ISO Maximization Sensitization Study (Extract), per ISO 10993-10. | PASS (Non-sensitizer) | Attribute -- Third Party Testing |
| | Delivery System | Meet requirements in an ISO Maximization Sensitization Study (Extract), per ISO 10993-10. | PASS (Non-sensitizer) | |
| Intracutaneous Reactivity (Irritation) | Sensor | Meet requirements in an ISO Intracutaneous Study (Extract), per ISO 10993-10. | PASS (Non-irritant) | Attribute -- Third Party Testing |
| | Delivery System | Meet requirements in an ISO Intracutaneous Study (Extract), per ISO 10993-10. | PASS (Non-irritant) | |
| Acute Systemic Toxicity | Sensor | Meet requirements in an ISO Acute Systemic Toxicity Study (Extract), per ISO 10993-11. | PASS (Non-toxic) | Attribute -- Third Party Testing |
| | Delivery System | Meet requirements in an ISO Acute Systemic Toxicity Study (Extract), per ISO 10993-11. | PASS (Non-toxic) | |
| Hemolysis | Sensor | Meet requirements in an In Vitro Hemolysis Study (ASTM-Extraction Method), per ISO 10993-4. | PASS (Non-hemolytic) | Attribute -- Third Party Testing |
| | Delivery System | Meet requirements in an In Vitro Hemolysis Study (ASTM-Extraction Method), per ISO 10993-4. | PASS (Non-hemolytic) | |
| SC5b-9 Complement Activation | Sensor | Meet requirements in a complement activation study (SC5b-9), per ISO 10993-4. | PASS (Non-activator) | Attribute -- Third Party Testing |
| | Delivery System | Meet requirements in a complement activation study (SC5b-9), per ISO 10993-4. | PASS (Non-activator) | |
| USP Pyrogen Study | Sensor | Meet requirements in a USP Pyrogen Study (Material Mediated), per ISO 10993-11. | PASS (Non-pyrogenic) | Attribute -- Third Party Testing |
| | Delivery System | Meet requirements in a USP Pyrogen Study (Material Mediated), per ISO 10993-11. | PASS (Non-pyrogenic) | |
| ASTM Partial Thromboplastin Time (PTT) | Sensor | Meet requirements in a Partial Thromboplastin Time Study (ASTM-Extraction Method), per ISO 10993-4. | PASS (non-activator) | Attribute -- Third Party Testing |
| | Delivery System | Meet requirements in a Partial Thromboplastin Time Study (ASTM-Extraction Method), per ISO 10993-4. | PASS (non-activator) | |

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| Biocompatibility | | | | |
| --- | --- | --- | --- | --- |
| Test | | Acceptance Criteria | Results | Analysis Type |
| Genotoxicity (Bacterial Reverse Mutation) | Sensor | Meet requirements in a bacterial reverse mutation study per ISO 10993-3. | PASS (Non-mutagenic) | Attribute -- Third Party Testing |
| Genotoxicity (Mouse Lymphoma) | Sensor | Meet requirements in a Mouse Lymphoma Assay study per ISO 10993-3. | PASS (Non-mutagenic) | Attribute -- Third Party Testing |
| Carcinogenicity | Sensor | Scientific rationale provided for no risk of carcinogenesis associated with clinical use. | PASS | Third Party Review |
| Subacute/Subchronic and Chronic Toxicity | Sensor | Scientific rationale provided for waiving subacute, subchronic, and chronic toxicity testing of the Sensor for the following reasons:
• Materials are known materials with an established history of biocompatibility in devices with similar applications. The materials are not known to cause systemic toxicity.
• No acute systemic toxicity was observed during the acute systemic toxicity study in mice. Additionally, no evidence of systemic toxicity was observed in the clinically relevant (ovine) implantation study at any of the following timepoints: 30, 90, 180, and 365-days.
• Chemical characterization and associated toxicological evaluation demonstrated no potential for significant patient exposure to the specific compounds that could pose a potential risk of systemic toxicity.
• The results of the cytotoxicity assay indicated that the amounts and types of leachable chemicals from the Sensor are not likely to result in adverse biological effects in in vivo long term systemic toxicity studies or clinical use of the device. | PASS | Third Party Review |
| Thromboresistance, and Histopathology | Sensor | Must demonstrate acceptable long term tissue response and thromboresistance after 12-months implantation in an ovine animal model. | PASS | Attribute -- Third Party Testing |

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Table 3. US and International Standards

| Standard Number | Description |
| --- | --- |
| ISO 11607-1 | Packaging for terminally sterilized medical devices – Part 1: Requirements for materials, sterile barrier systems and packaging systems |
| ISO 10993 | Biological Evaluation of Medical Devices |
| ASTM F1980-21 | Standard Guide for Accelerated Aging of Sterile Barrier Systems for Medical Devices |
| ASTM D4332-14 | Standard Practice for Conditioning Containers, Packages, or Packaging Components for Testing |
| ASTM D4169-22 | Standard Practice for Performance Testing of Shipping Containers and Systems |
| ISO 11135 | Sterilization of health-care products - Ethylene oxide - Requirements for the development, validation and routine control of a sterilization process for medical device |

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| Standard Number | Description |
| --- | --- |
| ISO 11737-1 | Sterilization of health care products — Microbiological methods — Part 1: Determination of a population of microorganisms on products- Amendment 1 |
| ISO 14708-1 | Implants for surgery – Active implantable medical devices, Part 1: General requirements for safety, marking and for information to be provided by the manufacturer |
| IEC 60601-1 | Medical electrical equipment - Part 1: General requirements for basic safety and essential performance. |
| IEC 60601-1-6 | Medical electrical equipment - Part 1-6: General requirements for basic safety and essential performance - Collateral standard: Usability |
| IEC 60601-1-2 | Medical electrical equipment – Part 1-2: General requirements for basic safety and essential performance – Collateral standard: Electromagnetic disturbances – Requirements and tests. |
| IEC 60601-1-11 | Medical electrical equipment - Part 1-11: General requirements for basic safety and essential performance - Collateral Standard: Requirements for medical electrical equipment and medical electrical systems used in the home healthcare environment. |
| IEC 60601-2-34 | Medical electrical equipment – Part 2-34: Particular requirements for the basic safety and essential performance of invasive blood pressure monitoring equipment |
| ISO 14117 | Active implantable medical devices -- Electromagnetic compatibility -- EMC test protocols for implantable cardiac pacemakers, implantable cardioverter defibrillators and cardiac resynchronization devices |
| AIM 7351731 | Medical Electrical Equipment & System Electromagnetic Immunity Test for RFID readers. |

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| Standard Number | Description |
| --- | --- |
| IEC 61000-4-2 | Testing and measurement techniques – Electrostatic discharge immunity test |
| AAMI TIR69 | Technical Information Report Risk Management of Radio-Frequency Wireless Co-existence for Medical Devices and Systems |
| ISO 10555-1 | Intravascular catheters – Sterile and single-use catheters – Part 1: General requirements |
| ISO 80369-7 | Small-bore connectors for liquids and gases in healthcare applications -- Part 7: Connectors for intravascular or hypodermic applications |
| ASTM F2477-07 | Standard Test Methods for in vitro Pulsatile Durability Testing of Vascular Stents |
| ASTM F2129-17b | Standard Test Method for Conducting Cyclic Potentiodynamic Polarization Measurements to Determine the Corrosion Susceptibility of Small Implant Devices |
| ASTM D1002 | Apparent Shear Strength of Single-Lap-Joint Adhesively Bonded Metal Specimens by Tension Loading |
| ASTM D4896-01 | Standard Guide for Use of Adhesive-Bonded Single-Lap-Joint Specimen Test Results |
| IEC 62304 | Medical device software - Software life cycle processes |
| TIR57 | Principles for medical device security – Risk Management |
| ISO 13485 | Medical devices - Quality management systems - Requirements for regulatory purposes |
| ISO 14644-1 | Cleanrooms and associated controlled environments, Part 1: Classification of air cleanliness by particle concentration |
| ISO 14644-2 | Cleanrooms and associated controlled environments, Part 2: Monitoring to provide evidence of cleanroom performance related to air cleanliness by particle concentration. |

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| Standard Number | Description |
| --- | --- |
| ISO 14644-3 | Cleanrooms and associated controlled environments - Part 3: Test methods |
| IEC 62366-1 | Medical devices - Part 1: Application of usability engineering to medical devices |
| ISO/IEC 15459-4 | Information technology — Automatic identification and data capture techniques — Unique identification — Part 4: Individual products and product packages |

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## B. Animal Studies

A chronic, GLP animal study was performed in twenty-eight (28) sheep with follow-up periods of 30 days, 90 days, 180 days and 365 days. The results of the animal study indicated that:

- No device related adverse safety outcomes occurred during the survival period and clinical pathology findings were acceptable.
- There were no Sensor displacements or Sensor migrations during the study period (this was confirmed via imaging at every follow up time point).
- Pulmonary artery pressure comparisons between Swan Ganz and the Sensor readings demonstrated Cordella PA Sensor System accuracy at 30 days, 90 days, 180 days and 365 days.
- There was no device related injury along the Delivery System pathway.
- Subchronic systemic toxicity assessment did not show device related changes.
- Implant site histopathology assessment showed low to no inflammation, variable neointimal coverage as expected in a sheep model, and overall acceptable biocompatibility of the Sensor body and anchors.
- Readings were obtained from all Sensors throughout the study.

## C. Additional Studies

N/A

## X. SUMMARY OF PRIMARY CLINICAL STUDY(IES)

The applicant performed a clinical study to establish a reasonable assurance of safety and effectiveness of the Cordella Pulmonary Artery Sensor System to guide the treatment of patients with New York Heart Association (NYHA) Class III heart failure in the US under IDE #G190020. Data from this clinical study were the basis for the PMA approval decision. A summary of the clinical study is presented below.

### Feasibility Studies

#### A. Study Design

SIRONA (ETX-HFS-PA-01; clinicaltrial.gov identifier: NCT03375710) was a multi-center, open-label, first-in-human, feasibility study to evaluate the Cordella HF System and the safety and accuracy of the Cordella PA Sensor System in 15 NYHA Class III patients in Europe. The study met its primary endpoints of safety and accuracy and supported a larger prospective trial powered to test the primary accuracy endpoint at 90 days.¹

SIRONA 2 (ETX-HFS-PA-02: clinicaltrial.gov identifier: NCT04012944) was a prospective, multi-center, open-label, single-arm trial evaluating the safety and efficacy of the Cordella PA

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Sensor System and Cordella HF System in NYHA Class III HF patients in Europe with either HF hospitalization (HFH) and/or an increase in natriuretic peptides in the previous 12 months. The PA sensor was successfully implanted in 70 patients. The primary safety endpoint was freedom from adverse events associated with use of the Cordella PA Sensor System through 30 days post-implant in the intent-to-treat population $(N = 75)$ . There was a total of 6 $(8.0\%)$ adverse events. There were 2 $(2.7\%)$ serious adverse events related to the implant procedure with one being classified as device/system-related complication (LV Lead dislodgement), both occurred in the same patient. There were no pressure sensor failures. By 12 months post-implant, there were 10 predefined adverse events in 9 $(12.0\%)$ subjects as adjudicated by the clinical events committee and there were no further device/system-related complications nor pressure sensor failures. The primary efficacy endpoint was the accuracy of the PA sensor mPAP measurement compared to fluid-filled catheter (RHC) at 90 days. Equivalence between the PA sensor and RHC for mPAP was excellent with mean difference between the measurements confined within the equivalence bounds of -4.0 to $4.0\mathrm{mmHg}$ (mPAP: avg diff $= 1.4$ , $90\%$ CI 0.0 to $2.9\mathrm{mmHg}$ , $\mathrm{P} = 0.003$ ) (Figure 8). Differences between Cordella PA sensor and RHC readings were statistically identical at 90-day and 12-month measurements for supine mPAP $(1.4 \pm 6.7$ vs. $3.0 \pm 6.8\mathrm{mmHg}$ , $\mathrm{p} = 0.12)$ . Levene's test for equality of variance showed that the variance in measurement accuracy (i.e., measurement error) of the Cordella PA Sensor mPAP, compared to RHC mPAP, did not change from 90-days to 12-months (all p-values $&gt;0.05$ ). Table 4.

Figure 8: Two one-sided t-tests (TOST) Plot for Mean Pulmonary Artery Pressure (SIRONA 2)

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Table 4: Comparison of 90-day and 12-month Supine PAP measures by both PA sensor and RHC

| Timepoint | PAP Parameter (mmHg) | PAP Measurement Method | Average ± SD (mmHg) | Levene's Test p-value | Δ (RHC-PA Sensor) | Δ p-value |
| --- | --- | --- | --- | --- | --- | --- |
| 90-day | Supine Mean PAP | RHC | 26.1 ± 10.4 | 0.13 | 1.4 ± 6.7 | 0.12 |
| | | Cordella | 27.6 ± 12.1 | | | |
| 12-month | Supine Mean PAP | RHC | 25.6 ± 10.0 | 0.77 | 3.0 ± 6.8 | |
| | | Cordella | 28.5 ± 10.0 | | | |

The results observed during these feasibility studies provided a basis for prospective evaluation of safety and clinical efficacy in larger cohort studies.

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## Pivotal Study/ ETX-HFS-PA-03 (PROACTIVE -HF)

## Summary / Background

In its final design, the PROACTIVE-HF study was a prospective, single-arm, open-label, multi-center clinical trial to evaluate the safety and effectiveness of the Cordella PA Sensor System in NYHA functional class III HF patients. Adults with a diagnosis of HFrEF or HFpEF and NYHA functional class III symptoms were eligible for enrollment if they were treated with GDMT for a minimum of 3 months (stable doses at least 30 days prior to enrollment) and, within the past year, the patient had either 1) one HF hospitalization, or 2) HF treatment in a hospital day care setting, or 3) urgent outpatient clinic HF visit for IV diuretics, or 4) a persistently elevated NT-proBNP level at the time of screening. The Institutional Review Board of each participating center approved the study protocol, each patient provided written informed consent, and events were adjudicated by a Clinical Events Committee.

All patients enrolled into PROACTIVE-HF received the Cordella HF System (recording weight, BP, HR, and $\mathrm{SpO}_2$ ). After demonstrating compliance with utilization, all patients underwent right heart catheterization and deployment of the Cordella PA pressure sensor into the interlobar right pulmonary artery, provided that the RPA downturn diameter is 12-26 mm for secure stabilization of the sensor. Patients were instructed to take their daily PAP measurements along with their weight, BP, HR, $\mathrm{SpO}_2$ , and HF symptoms by using Bluetooth-connected peripherals. Vital signs were visible to both clinicians and patients, while pulmonary artery pressures were visible to the clinicians only. All patients were then managed according to the trial specific seated mPAP treatment guidelines, with a target seated mean pulmonary artery pressure goal of 5-20 mmHg, achieved through titration of diuretics and GDMT via a trial specific treatment guideline as shown in Figure 9.

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Figure 9: PROACTIVE-HF Treatment Guidelines for Seated Mean Pulmonary Artery Pressure

Of note, the aforementioned final study design resulted from a deviation of the original study design for the PROACTIVE-HF, which was initially designed by the manufacturer of this device to be a prospective, randomized, controlled, multi-center clinical trial. In the initial phases of this trial, patients were initially randomized 1:1 to either Control or Treatment groups. All readings

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pulmonary artery pressure and vital signs) were visible to clinicians of patients within the treatment arm, while only the vital signs were visible to treatment arm patients themselves. However, once PROACTIVE-HF began enrolling subjects, prospective clinical evidence from CardioMEMS was published in 2019-2021, including the GUIDE-HF Trial in 2021. The GUIDE-HF Trial was a prospective, randomized, controlled, single-blind, multicenter, pivotal clinical trial whose purpose was to establish a reasonable assurance of safety and effectiveness of the CardioMEMS HF System to guide the treatment of patients with New York Heart Association (NYHA) Class II - IV heart failure. The GUIDE-HF Trial demonstrated a positive clinical benefit of PAP-guided heart failure management in NYHA functional class III patients using the CardioMEMS device.^{3} With this new evidence, in December 2021 the manufacturer of this device petitioned to the Food and Drug Administration (FDA), to change the study design from a randomized controlled clinical trial to a single-arm trial (described above), with pre-specified safety and efficacy endpoints to provide objective evidence of a similar risk-benefit profile to the CardioMEMS HF System in NYHA functional class III subjects.^{6} At the time of crossover to a single-arm, patients in the randomized Control arm (Cohort #1) were unblinded and both clinicians and patients, who opted, in received immediate access to mPAP data and all patients were then managed according to the trial specific seated mPAP treatment guidelines. Cohort #1 subjects did not contribute to the primary safety and efficacy endpoints of PROACTIVE-HF but contributed to a patient engagement substudy. Patients in the randomized Treatment arm (Cohort #2) continued follow-up per protocol and, along with the newly enrolled single arm Treatment group (Cohort #3), contributed to the primary safety and efficacy endpoints of PROACTIVE-HF.

Study Objectives

The objectives of this study are to demonstrate the safety and efficacy of the Cordella PA Sensor System

A. Study Design

Patients were treated between January 10, 2020 and September 30, 2023. The database for this PMA reflected data collected through September 30, 2023 and included 456 patients. There were 77 investigational sites.

This study was a prospective, multi-center, open-label, single-arm clinical trial to assess device safety and efficacy of the Cordella PA Sensor System in NYHA Class III Heart Failure patients compared to a Performance Goal (PG) of the rate of HF hospitalizations or all-cause mortality at 6 months based on a meta-analysis on the combined cohorts of CHAMPION-HF^{7}, CardioMEMS Post approval study^{8}, MEMS-HF^{9}, GUIDE-HF (NYHA Class III cohort)^{3}, and LAPTOP-HF^{10} (control group only). This trial was conducted under the IDE# G190020. The patient population was composed of patients with a HF diagnosis of > 3 months with either preserved or reduced LVEF.

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Subjects in this trial were categorized into three (3) different cohorts:

a. Cohort #1- Previously enrolled Control Arm subjects
- Upon change to single arm, subjects in this cohort were unblinded to their PAP measurements and informed about their previous group assignment and continued their Follow-up visit schedule.
- Additionally, subjects were asked, throughout the remaining Follow-up period, to complete a regular subject survey on their experience with PAP Measurements and PAP values.
- Upon change to single arm, clinicians were unblinded to PAP measurements and started managing the patients to target PA pressures per protocol/ CIP and according to Guideline Directed Medical Therapy (GDMT).
- Additionally, the clinical site was asked to contact the subject on a regular basis to discuss their PAP values.
- Separate subgroup analysis (safety and effectiveness) were performed.

b. Cohort #2- Previously enrolled Treatment Arm subjects
- As of month 12, subjects in this cohort were able to see their own PAP measurements for the remaining duration of the study.
- Clinicians continued to manage the patients to target PA pressures per protocol/CIP and according to GDMT.
- All primary and secondary safety and effectiveness analyses were performed.

c. Cohort #3- Newly enrolled subjects
- Subjects participated in the Screening/ Enrollment Visit, Cordella PA Sensor Implant Visit, and Follow-Up Visits.
- Clinicians managed the patients to target PA pressures per protocol/ CIP and according to GDMT.
- As of month 12, subjects in this cohort will be able to see their own PAP measurements for the remaining duration of the study.
- All primary and secondary safety and effectiveness analyses were performed.

The Cordella PA Sensor was implanted in conjunction with a right heart catheterization (RHC) procedure. During this visit, the Cordella PA Sensor, which is pre-mounted on a catheter Delivery System, was introduced via percutaneous venous access to the pulmonary artery. Once deployed, the Sensor PAP was calibrated using the Delivery System's fluid-filled catheter for independent reference measurements. The calibration coefficients for that Sensor/Reader/

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Subject were stored in a database, allowing for consistent PAP calculations throughout the study duration. Also, at the Screening Visit, eligible subjects were provided with the commercially available Cordella HF System to measure BP, HR, $\mathrm{SpO}_2$ and weight.

Subjects were observed until stable and discharged home with instructions to take their PAP measurements daily in addition to their weight, BP, HR and $\mathrm{SpO}_2$, which were all wirelessly transmitted to a secure website for review using the myCordella Patient Management Portal.

Visibility to patients' daily data trends enabled the clinician to proactively manage the patients to target PA pressures per protocol and according to GDMT. The clinician contacted all subjects on a regular basis to discuss their health status and all patients were treated according to GDMT. All Subjects will return for follow up visits at 1, 6, 12, 18, 24 months, as well as at Year 3, 4 and 5, after the Cordella PA Sensor implant, or until study termination. The 3 month follow-up visit was performed as a remote/ virtual telemonitoring visit.

All subjects who received a Cordella PA Sensor Implant were followed for 6 months for the Primary Efficacy and Primary Safety Endpoints and will be followed for up to 5 years post implant. Additional monitoring of safety and efficacy assessments will be performed throughout the study duration, including evaluation of subject functional and health status, adverse events, Heart Failure (HF) related hospitalizations or equivalent (e.g., intravenous (IV) diuretics).

A total of 75 sites (71 US/4 EU) enrolled a subject in this trial. A subject is considered enrolled if the subject signed the consent form, completes the screening visit, and is reviewed by the Eligibility Committee. A subject is considered to be a screen failure if the subject signed the consent form but was subsequently determined ineligible based on the trial inclusion and/or exclusion criteria prior to implant.

The trial began in the USA with the first site for the trial initiated on November 8, 2019, and Enrollment into the trial started on January 10, 2020. After approval of protocol amendment V7.0 (November 21, 2021), the amendment not only increased the number of participating centers to one-hundred twenty (120) in the United States (US) and Europe (EU), as well as a change in trial design from a randomized to a single arm trial. After the approval of protocol amendment V7.0 (November 21, 2021) in December 2021 all sites were consequently converted to this single arm trial.

Enrollment was completed on March 8, 2023, and the last subject was implanted on March 31, 2023.

Out of the 738 enrolled subjects, 528 subjects received an implant (Figure 9). Five-hundred twenty-eight (528) are a combination of 72 subjects in Cohort #1,

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the previously enrolled Control Arm subjects; 88 subjects in Cohort #2, the previously enrolled Treatment Arm subjects; and 368 subjects in Cohort #3, the newly enrolled subjects. One-hundred twenty-five (125) subjects failed screening and 85 subjects were withdrawn prior to implant. Thirty-seven (37) subjects had an aborted implant.

## 1. Clinical Inclusion and Exclusion Criteria

Enrollment in the PROACTIVE-HF study was limited to patients who met the following inclusion criteria:

- Subject has given written informed consent
- Male or female, at least 18 years of age
- Diagnosis and treatment of HF (regardless of left ventricular ejection fraction (LVEF)) for ≥ 3 months and NYHA Class III HF at time of Screening
- Subjects should be on stable, optimally titrated medical therapy for at least 30 days, as recommended according to current American Heart Association (AHA)/American College of Cardiology (ACC) guidelines as standard-of-care for HF therapy in the United States, or current European Society of Cardiology (ESC) guidelines for HF treatment in Europe, with any intolerance documented
- Subjects who qualified for the following:
1. HF related hospitalization in the past year i.e. one calendar day change
2. HF treatment in a hospital day-care setting
3. Or urgent outpatient clinic HF visit for IV diuretics within 12 month (last hospitalization should be 30 days before Screening /Enrollment)
- Or N-terminal pro-Brain Natriuretic Peptide (NT-proBNP)) at time of Screening/ Enrollment defined as:
- Subjects with LVEF ≤ 50%: NT-proBNP ≥ 1500 pg/mL.
- Subjects with LVEF &gt; 50%: NT-proBNP ≥ 800 pg/mL.

Thresholds for NT-proBNP for both LVEF ≤ 50% and LVEF &gt; 50%) will be corrected for body mass index (BMI) using a 4% reduction per BMI unit over 25 kg/m²

- Subjects should be on diuretic therapy
- Subjects who are physically able to hold the Patient Reader unit (approximate weight 1.3lb) against the ventral thoracic surface for up to 2 minutes per day while in a seated position, as well as dock and undock the Patient Reader
- Subjects with sufficient eyesight, hearing, and mental capacity to respond to the Patient Reader’s audio/visual cues and operate the Patient Reader
- Subject has sufficient Cellular and/or Wi-Fi Internet coverage at home
- Subject agrees to return to the treating Investigator for all scheduled follow up

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visits and can return to the hospital for follow up

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

- Intolerance to all neuro-hormonal antagonists (i.e., intolerance to ACE-I, ARB, ARNI, and beta-blockers) due to hypotension or renal dysfunction
- ACC/AHA Stage D refractory HF (including having received or currently receiving pharmacologic circulatory support with inotropes)
- Subjects with history of recurrent pulmonary embolism (≥ 2 episodes within 5 years prior to Screening Visit) and/or deep vein thrombosis within 3 months of the Screening Visit
- Subjects who have had a major CV event (e.g., myocardial infarction, stroke) within 3 months of the Screening Visit
- Unrepaired severe valvular disease
- Subjects with significant congenital heart disease that has not been repaired and would prevent implantation of the Cordella PA Sensor or mechanical/tissue right heart valve(s)
- Subjects with known coagulation disorders
- Subjects with a hypersensitivity or allergy to platelet aggregation inhibitors including aspirin, clopidogrel, prasugrel, and ticagrelor; or patients unable to take dual antiplatelet or anticoagulants for one- month post implant
- Known history of life threatening allergy to contrast dye.
- Subjects whereby RHC is contraindicated
- Subjects with an active infection at the Sensor Implant Visit
- Subjects with a GFR &lt; 25 ml/min or who are on chronic renal dialysis
- Implanted with CRT-P or CRT-D for less than 90 days prior to screening visit
- Received or are likely to receive an advanced therapy (e.g., mechanical circulatory support or lung or heart transplant) in the next 12 months
- Subjects who are pregnant or breastfeeding
- Subjects who are unwilling or deemed by the Investigator to be unwilling to comply with the study protocol, or subjects with a history of non-compliance
- Severe illness, other than heart disease, which would limit survival to &lt; 1 year
- Subjects whose clinical condition, in the opinion of the Investigator, makes them an unsuitable candidate for the study
- Subjects enrolled in another investigational trial with an active Treatment Arm
- Subject who is in custody by order of an authority or a court of law

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## 2. Follow-up Schedule

All patients were scheduled to return for follow-up examinations at 1, 6, 12, 18, 24 months, as well as at Year 3, 4 and 5, after the Cordella PA Sensor implant, or until study termination. Adverse events and complications were recorded at all visits. The key timepoints and assessments are shown in Table 5:

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Table 5. PROACTIVE-HF / ETX-HFS-PA-03: Study Visit Schedule

| Assessment | V1: Screening/ Enrollment (30 days)^{15} | V2: Cordella PA Sensor Implant Visit | V3: Month 1 (±7 days) | V4^{15}: Month 3 (±7 days) | V5: Month 6 (±14 days) | V6: Month 12 (±30 days) | V7 to V8: Months 18, 24 (±30 days) | V9 to V11 Year 3, 4, 5 (±30 days) |
| --- | --- | --- | --- | --- | --- | --- | --- | --- |
| Informed Consent | X | | | | | | | |
| Subject Demographics | X | | | | | | | |
| Study Eligibility Review and Committee Approval | X | | | | | | | |
| Cardiac/Medical & Surgical History | X | | | | | | | |
| Physical Exam, height, weight, and vital signs^{1, 5} | X | X | X^{12} | | X | X | X | X |
| 12-Lead ECG with Interpretation | X | | | | X | X | X^{4} | X |
| Urinalysis^{2} | X | | | | | | | |
| Safety Labs (Chemistry/Hematology/ aPTT/ INR) | X | | | | X | X | X^{4} | X |
| Serum NT-pro BNP | X | | X | X^{12} | X | X | X | X |
| aPTT/ INR (if indicated) | | | | | | | | |
| Echocardiogram^{3} | X | | | | | X | | X |
| Subject Training: Cordella™ HF System^{14} | X | | | | | | | |
| Subject Training: CorPASS | | X | | | | | | |
| Cordella™ PA Sensor Implant | | X | | | | | | |
| Cordella System Use (daily) | X | X | X | X | X | X | X | X |
| Cordella™ PAP – dia/sys/mean/pulse | | X^{9} | X^{5,6} | X^{5,6} | X^{5,6} | X^{5,6} | X^{5,6} | X^{6} |
| RHC PAP / RAP/ PCWP/ CO/ CI/ RVP^{8} | | X | | | | | | X^{17} |
| Subject Status | X | | X | X | X^{10} | X^{10} | X | X |
| 6- Minute Walk Test | X | | | | X | X^{7} | X^{4,7} | X^{7} |
| NYHA Functional Classification | X^{16} | | X | X | X | X | X | X |
| KCCQ Quality of Life Questionnaires^{5} | X | | X | X | X | X | X | X |
| Concurrent/Cardiac Medications | X | X | X | X | X | X | X | X |
| Adverse Events | X | X | X | X | X | X | X | X |
| Health Economic Questionnaire | | | | | | | X^{4} | |
| Subject Survey (optional)/ Cohort #1 only^{13} | 1. Month 1 after Unblinding
2. Quarterly until V11 / Year 5 | | | | | | | |
| Site Survey (optional)/ Cohort #1 only^{13} | 1. Month 1 after Unblinding
2. Quarterly until V11 / Year 5 | | | | | | | |

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| 1. Full Physical Examination and Height performed at Screening Visit only | 9. Via CalEQ |
| --- | --- |
| 2. Urine (V1) pregnancy test for females | 10. Incl. question on assigned treatment at Visit 5 and 6 |
| 3. Echo may be obtained within 3 or 6 months of Screening details are in section 8.1.10 | 11. Visit should be completed remote/ virtually |
| 4. At Month 24 only | 12. If available |
| 5. via myCordella™ Patient App at home prior to visit. Baseline KCCQ will be completed on myCordella tablet following Cordella System distribution at Screening Visit | 13. After subject gets unblinded to PAP Pressures at V6 or cross-over whatever comes first |
| 6. via myCordella™ Patient App seated and supine | 14. Subject training on and distribution of the commercial Cordella™ System (should occur at Screening Visit (Visit 1). |
| 7. Additional PAP Measurements will be obtained before and after 6-minute walk test | 15. Some study procedures need to be repeated in case a subject is implanted >30 days after Visit 1, details are in section 8.3.1. |
| 8. Additional RHC as needed for Re-calibration purposes at the clinician's discretion | 16. may be obtained within the 30 day Study Visit 1 window |
| | 17. At V9/ Year 3 only |

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## 3. Clinical Endpoints

With regards to safety, the study had primary and secondary safety endpoints which are discussed below:

### Primary Safety Endpoints:

- Freedom from device or system-related complications (DSRC) at 6 months will be tested against the null rate of 90%. Based on a one sample test of a proportion, a sample size of 450 patients provides greater than 95% power assuming a population rate of 95% based on a two-sided Type I error rate of 5%.
- Freedom from pressure sensor failure at 6 months will be tested against a null rate of 95%

### Secondary Safety Endpoints:

- Frequency of serious adverse events (SAEs) throughout the study
- Frequency of implant procedure and procedure related adverse events
- Pressure sensor failure rate throughout the study

With regards to effectiveness, the study had primary and secondary efficacy endpoints which are discussed below.

With regard to success/failure criteria, results of individual CardioMEMS studies and an internally derived meta-analysis were considered in determining the Primary Endpoint Performance Goal (PG) for the re-designed study. The meta-analysis was performed on the combined cohorts of CHAMPION-HF⁷, CardioMEMS Post approval study⁸, MEMS-HF⁹, GUIDE-HF (NYHA Class III cohort)³, and LAPTOP-HF¹⁰ (control group only) as shown in Figure 10.

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Figure 10: Results of Individual CardioMEMS Studies and Meta Analysis for Determining the Primary Endpoint Performance Goal

To meet the new objectives of the study, observed event rates in the single-arm PROACTIVE-HF should be similar to observed event rates in the treatment arm of CardioMEMS studies and lower than observed event rates in the control arm of CardioMEMS studies. Therefore, we set the PG below the meta-analysis upper bound 95% confidence interval of CardioMEMS treated patients, and below the meta-analysis estimates of CardioMEMS control patients and adjusted the goal downwards to account for a potential impact of treatment with SGLT2i. Furthermore, we also require that the single-arm PROACTIVE-HF observed event rate be lower than both the meta-analysis estimate of CardioMEMS treatment patients, and the lowest observed event rates of CardioMEMS control patients, further adjusted down by potential impact of SGLT2i.

## Primary Efficacy Endpoint:

The primary endpoint was the 6-month incidence of HF related hospitalizations (HFH) or all-cause mortality.

For the primary endpoint of HFH and all-cause mortality at 6 months, the PG is 0.43 events per patient 6-month and, for study success, the upper confidence bound of the observed event rate for the planned study must be less than the PG. Additionally, the observed event rate must be lower than 0.37 events per patient 6-month.

Evaluating the upper bound of the confidence interval for the rate, ensures:

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- the observed rate will be comparable to prior studies of active treatment (highest observed value = 0.44),
- the observed rate will be less than the mean rate from meta-analysis of prior studies of treatment and control, and
- the observed rate will be less than the lowest rate observed in the control studies (GUIDE-HF). The added requirement for the observed rate to be less than 0.37 provides further assurance that results are comparable to studies of prior treatment.

Based on this, the study will implant 450 subjects (single arm cohorts) leading to an expected evaluable cohort of 406 subjects. With a PG of 0.43 and a one-sided 0.025 alpha level, the study will have greater than 80% power assuming a population treatment rate of 0.34.

## Secondary Efficacy Endpoints:

- The first secondary efficacy endpoint is incidence of HF Hospitalizations or all-cause mortality at 12 months compared to a PG. The PG of 0.70 for the first secondary efficacy endpoint of 12-month incidence of HFH or all-cause mortality was derived from clinically relevant, contemporary studies of NYHA class III HF subjects. Additionally, we require the observed event rate to be less than 0.59.
- Number of HFH at 6 and 12 months post-implant compared to the number of HFH in the 6 and 12 months prior to implant
- Comparison of the number of HFH or emergency department / hospital outpatient IV diuretic visits of Cohort #1 and Cohort #2 at 6 and 12 months post-implant
- Change of NT-pro BNP from baseline through 6 and 12 months
- Combined outcome of:
- First and recurrent HFH
- Emergency department / hospital outpatient IV diuretic visits
- All-cause mortality

At 6 months, added together with equal weighting into a total number of events

- HFH or emergency department / hospital outpatient IV diuretic visits at 6 and 12 months
- Cardiac and all-cause mortality
- Days alive and out of the hospital (DAOH)
- IV diuretic visits
- Heart failure related medication changes
- Change in PAP:
- a. From baseline through 6 and 12 months in subjects with a baseline mean PAP
- i. Above target range
- ii. Within or below target range
- iii. Overall
- b. Before and after 6-minute walk test (6MWT)

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- Percentage of device success as documented by ability of the system to successfully transmit PAP data
- Patient outcome measures, measured by KCCQ
- Functional status improvement, as measured by NYHA and 6MWT
- Health economic analysis

## B. Accountability of PMA Cohort

At the time of database lock, 738 patients had enrolled in the PROACTIVE-HF study (85.5% of screened patients) and a total of 528 patients (71.5% of enrolled patients) implanted with the device are available for analysis at the completion of the study on 29 September 2023. Implanted subjects were included in either the randomized Control Arm prior to the trial redesign (Cohort #1, N = 72 subjects), in the randomized Treatment Arm prior to the trial redesign (Cohort #2, N=88 subjects), or in the Treatment Arm after the trial redesign (Cohort #3, N=368 subjects). Subjects in Cohorts #2 and #3 (N = 456) contribute to the primary safety and efficacy endpoints in PROACTIVE-HF. Subjects in Cohort #1 contribute to a substudy examining patient engagement with pulmonary artery pressures.

1. Intent-to-Treat Population (ITT), includes all enrolled subjects intended to receive the Cordella PA Sensor who entered the Cath Lab, including those in whom Implant Procedure was not completed for whatever reason (e.g., Cordella PA Sensor Implant could not be performed due to anatomical reasons) from Cohort #2 and #3. The ITT was used for all analyses of safety endpoints.
2. Modified Intent-to-Treat Population (mITT), includes all implanted subjects from Cohort #2 and Cohort #3. All primary and secondary effectiveness analyses were performed on the mITT.
3. Per Protocol Population (PP), includes all mITT subjects without any major protocol deviations. All primary and secondary safety and effectiveness analyses were performed in addition on PP population. If PP and mITT populations were identical, analysis was performed based on mITT only.
4. Cohort #1- Previously enrolled Control Arm subjects- Population, this subgroup includes all Cohort #1 (previously enrolled Control Arm) subjects and was reported separately for all endpoints.

The trial enrollment and subject population are presented below in Figure 11.

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Figure 11: PROACTIVE-HF / ETX-HFS-PA-03: Patient Disposition

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## C. Study Population Demographics and Baseline Parameters

The demographics of the study population are typical for a single arm study performed in the US.

**Study Population and Baseline Parameters**

**mITT &amp; mITT Stratified by Cohort Number**

There were some differences between the cohorts as illustrated in the Table below, for example the proportion of patients in Cohort #3 on SGLT2i at baseline was greater than that of Cohort #1 (64.1% vs. 29.2%) and Cohort #2 (64.1% vs. 33.0%). Table 6 presents the demographics and patient characteristics by the mITT population and stratified by Cohort assignment.

Table 6. Demographics for mITT, Cohort #1, Cohort #2, and Cohort #3:

| Characteristic | mITT (N=456) | Cohort #1 (N=72) | Cohort #2 (N=88) | Cohort #3 (N=368) |
| --- | --- | --- | --- | --- |
| Demographics | | | | |
| Age (years), Mean (SD) | 63.5 (12.5) | 65.9 (11.3) | 64.5 (11.5) | 63.3 (12.8) |
| Male, n (%) | 276 (60.5%) | 42 (58.3%) | 56 (63.6%) | 220 (59.8%) |
| Female, n (%) | 180 (39.5%) | 30 (41.7%) | 32 (36.4%) | 148 (40.2%) |
| Weight (kg), Mean (SD) | 105.8 (25.8) | 102.9 (22.8) | 102.0 (23.3) | 106.7 (26.4) |
| Height (cm), Mean (SD) | 172.0 (10.6) | 171.3 (11.3) | 172.5 (9.9) | 171.9 (10.8) |
| Body mass index (kg/m2), Mean (SD) | 35.9 (8.8) | 35.3 (8.4) | 34.4 (7.8) | 36.2 (9.0) |
| Race | | | | |
| White, n (%) | 347 (76.1%) | 56 (77.8%) | 68 (77.3%) | 279 (75.8%) |
| Black, n (%) | 84 (18.4%) | 11 (15.3%) | 14 (15.9%) | 70 (19.0%) |
| Asian, n (%) | 7 (1.5%) | 0 (0%) | 3 (3.4%) | 4 (1.1%) |
| Hawaiian or Pacific Islander, n (%) | 3 (0.7%) | 1 (1.4%) | 1 (1.1%) | 2 (0.5%) |
| American Indian/Alaskan native, n (%) | 2 (0.4%) | 1 (1.4%) | 1 (1.1%) | 1 (0.3%) |
| Other, n (%) | 4 (0.9%) | 0 (0%) | 0 (0%) | 4 (1.1%) |
| Race not reported, n (%) | 9 (2.0%) | 3 (4.2%) | 1 (1.1%) | 8 (2.2%) |
| Ethnicity | | | | |
| Hispanic or Latino, n (%) | 20 (4.4%) | 5 (6.9%) | 3 (3.4%) | 17 (4.6%) |
| Not Hispanic or Latino, n (%) | 401 (87.9%) | 61 (84.7%) | 81 (92.0%) | 320 (87.0%) |
| Ethnicity not reported, n (%) | 13 (2.9%) | 2 (2.8%) | 0 (0%) | 13 (3.5%) |
| Unknown, n (%) | 22 (4.8%) | 4 (5.6%) | 4 (4.5%) | 18 (4.9%) |
| Smoking History | | | | |
| Never, n (%) | 210 (46.1%) | 34 (47.2%) | 33 (37.5%) | 177 (48.1%) |
| Previous, n (%) | 209 (45.8%) | 31 (43.1%) | 43 (48.9%) | 166 (45.1%) |
| Smoker, n (%) | 37 (8.1%) | 7 (9.7%) | 12 (13.6%) | 25 (6.8%) |
| Heart Failure Ejection Fraction | | | | |

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| Characteristic | mITT (N=456) | Cohort #1 (N=72) | Cohort #2 (N=88) | Cohort #3 (N=368) |
| --- | --- | --- | --- | --- |
| LVEF ≤ 40% (HFrEF), n % | 208 (45.6%) | 33 (45.8%) | 40 (45.5%) | 168 (45.7%) |
| LVEF ≥ 50% (HFpEF), n % | 201 (44.1%) | 31 (43.1%) | 37 (42.0%) | 164 (44.6%) |
| 40% < LVEF < 50% (HFmrEF), n (%) | 45 (9.9%) | 8 (11.1%) | 10 (11.4%) | 35 (9.5%) |
| Medical History/Surgical History | | | | |
| Diabetes mellitus, n (%) | 161 (35.3%) | 26 (36.1%) | 30 (34.1%) | 131 (35.6%) |
| Chronic kidney disease, n (%) | 198 (43.4%) | 37 (51.4%) | 32 (36.4%) | 166 (45.1%) |
| Chronic obstructive pulmonary disease, n (%) | 92 (20.2%) | 15 (20.8%) | 21 (23.9%) | 71 (19.3%) |
| Coronary artery bypass graft, n (%) | 81 (17.8%) | 12 (16.7%) | 15 (17.0%) | 66 (17.9%) |
| Percutaneous coronary intervention, n (%) | 134 (29.4%) | 23 (31.9%) | 28 (31.8%) | 106 (28.8%) |
| Valve repair / replacement, n (%) | 21 (4.6%) | 5 (6.9%) | 6 (6.8%) | 15 (4.1%) |
| Heart Failure History | | | | |
| Time since first diagnosis of HF [months], Mean (SD) | 58.1 (68.4) | 66.3 (62.5) | 54.0 (59.0) | 59.1 (70.5) |
| Time since first diagnosis of HF [months], Median | 33.08 | 46.98 | 31.67 | 33.53 |
| Time since first diagnosis of HF [months], Min | 2.97 | 0.03 | 2.97 | 3.03 |
| Time since first diagnosis of HF [months], Max | 454.37 | 257.73 | 309.43 | 454.37 |
| Etiology of Heart Failure | | | | |
| Ischemic, n (%) | 143 (31.4%) | 26 (36.1%) | 33 (37.5%) | 110 (29.9%) |
| Non-Ischemic, n (%) | 313 (68.6%) | 46 (63.9%) | 55 (62.5%) | 258 (70.1%) |
| Number of HFH in prior year, Count (%) | | | | |
| 0 | 90 (19.7%) | 7 (9.7%) | 17 (19.3%) | 73 (19.8%) |
| 1 | 208 (45.6%) | 48 (66.7%) | 45 (51.1%) | 163 (44.3%) |
| 2 | 88 (19.3%) | 9 (12.5%) | 19 (21.6%) | 69 (18.8%) |
| 3 | 46 (10.1%) | 5 (6.9%) | 3 (3.4%) | 43 (11.7%) |
| 4 | 9 (2.0%) | 1 (1.4%) | 1 (1.1%) | 8 (2.2%) |
| 5 | 8 (1.8%) | 2 (2.8%) | 1 (1.1%) | 7 (1.9%) |
| 5+ | 7 (1.5%) | 0 (0%) | 2 (2.3%) | 5 (1.4%) |
| Number of HFH in prior year, Mean (SD) | 1.4 (1.3) | 1.3 (1.0) | 1.3 (1.2) | 1.4 (1.3) |
| Number of HFH in prior year, Min | 0 | 0 | 0 | 0 |
| Number of HFH in prior year, Max | 8 | 5 | 6 | 8 |
| Other Cardiovascular History | | | | |
| Hypertension, n (%) | 403 (88.4%) | 65 (90.3%) | 74 (84.1%) | 329 (89.4%) |
| Coronary artery disease, n (%) | 269 (59.0%) | 45 (62.5%) | 57 (64.8%) | 212 (57.6%) |
| Myocardial infarction, n (%) | 118 (25.9%) | 16 (22.2%) | 21 (23.9%) | 97 (26.4%) |
| Atrial fibrillation, n (%) | 236 (51.8%) | 39 (54.2%) | 43 (48.9%) | 193 (52.4%) |
| Transient ischemic attack, n (%) | 23 (5.0%) | 4 (5.6%) | 3 (3.4%) | 20 (5.4%) |
| Stroke, n (%) | 48 (10.5%) | 7 (9.7%) | 7 (8.0%) | 41 (11.1%) |

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| Characteristic | mITT (N=456) | Cohort #1 (N=72) | Cohort #2 (N=88) | Cohort #3 (N=368) |
| --- | --- | --- | --- | --- |
| Peripheral vascular disease, n (%) | 61 (13.4%) | 14 (19.4%) | 10 (11.4%) | 51 (13.9%) |
| Carotid artery disease, n (%) | 33 (7.2%) | 8 (11.1%) | 4 (4.5%) | 29 (7.9%) |
| Ventricular tachycardia, n (%) | 88 (19.3%) | 16 (22.2%) | 19 (21.6%) | 69 (18.8%) |
| Ventricular fibrillation, n (%) | 18 (3.9%) | 2 (2.8%) | 4 (4.5%) | 14 (3.8%) |
| Atrial flutter, n (%) | 58 (12.7%) | 9 (12.5%) | 9 (10.2%) | 49 (13.3%) |
| Implantable cardioverter defibrillator, n (%) | 160 (35.1%) | 21 (29.2%) | 36 (40.9%) | 124 (33.7%) |
| Cardiac resynchronization therapy, n (%) | 82 (18.0%) | 15 (20.8%) | 15 (17.0%) | 67 (18.2%) |
| **Laboratory** | | | | |
| Estimated glomerular filtration rate [mL/min/1.73m2], Mean (SD) | 54.7 (18.7) | 50.1 (19.7) | 54.3 (18.2) | 54.8 (18.8) |
| NT-proBNP [pg/mL], Mean (SD) | 1731.4 (3012.8) | 1768.8 (3809.4) | 2061.0 (4401.6) | 1655.1 (2590.4) |
| **Hemodynamics (Right Heart Catheterization)** | | | | |
| Systolic pulmonary artery pressure (mmHg), Mean (SD) | 43.3 (14.9) | 40.9 (13.0) | 43.9 (16.4) | 43.2 (14.6) |
| Diastolic pulmonary artery pressure (mmHg), Mean (SD) | 18.8 (7.9) | 18.4 (6.4) | 19.6 (8.9) | 18.6 (7.7) |
| Mean pulmonary artery pressure (mmHg), Mean (SD) | 28.2 (10.1) | 26.7 (8.9) | 29.1 (11.6) | 28.0 (9.7) |
| Right atrial pressure (mmHg), Mean (SD) | 9.7 (6.7) | 9.0 (4.6) | 10.1 (5.7) | 9.6 (7.0) |
| Pulmonary capillary wedge pressure (mmHg), Mean (SD) | 16.5 (8.7) | 15.3 (6.8) | 16.9 (9.9) | 16.4 (8.3) |
| Cardiac output (L/min), Mean (SD) | 5.3 (3.2) | 5.6 (3.3) | 5.0 (1.3) | 5.4 (3.5) |
| Cardiac index (L/min/m2), Mean (SD) | 2.4 (0.6) | 2.7 (1.4) | 2.3 (0.5) | 2.4 (0.6) |
| **Vital Signs** | | | | |
| Systolic blood pressure, Mean (SD) | 121.8 (19.1) | 116.6 (18.7) | 120.6 (17.6) | 122.0 (19.5) |
| Diastolic blood pressure, Mean (SD) | 72.9 (12.6) | 67.9 (11.3) | 72.7 (11.8) | 73.0 (12.8) |
| Heart rate, Mean (SD) | 77.2 (14.1) | 77.7 (14.1) | 77.6 (14.4) | 77.1 (14.1) |
| Blood oxygen saturation, Mean (SD) | 95.8 (2.8) | 96.1 (2.5) | 95.9 (2.9) | 95.8 (2.8) |
| **Heart Failure Medications** | | | | |
| Agents acting on the renin-angiotensin system, n (%) | 310 (68.0%) | 47 (65.3%) | 61 (69.3%) | 249 (67.7%) |
| Angiotensin receptor-neprilysin inhibitor, n (%) | 199 (43.6%) | 23 (31.9%) | 36 (40.9%) | 163 (44.3%) |
| Angiotensin II receptor blocker, n (%) | 84 (18.4%) | 21 (29.2%) | 16 (18.2%) | 68 (18.5%) |
| Angiotensin-converting enzyme inhibitor, n (%) | 32 (7.0%) | 4 (5.6%) | 12 (13.6%) | 20 (5.4%) |
| Beta blocker, n (%) | 395 (86.6%) | 61 (84.7%) | 75 (85.2%) | 320 (87.0%) |
| Diuretic, n (%) | 454 (99.6%) | 72 (100.0%) | 88 (100.0%) | 366 (99.5%) |
| Loop diuretic, n (%) | 444 (97.4%) | 72 (100.0%) | 85 (96.6%) | 359 (97.6%) |
| Thiazide diuretic…