← Product Code [MOM](/productcode/MOM) · P100045S056

# CardioMEMs HF System (P100045S056)

_ABBOTT MEDICAL · MOM · Feb 18, 2022 · Cardiovascular · APPR_

**Canonical URL:** https://fda.innolitics.com/device/P100045S056

## Device Facts

- **Applicant:** ABBOTT MEDICAL
- **Product Code:** [MOM](/productcode/MOM.md)
- **Decision Date:** Feb 18, 2022
- **Decision:** APPR
- **Device Class:** Class 3
- **Review Panel:** Cardiovascular
- **Attributes:** Real-World Evidence

## Real-World Evidence

| Submission | Device | Sponsor | RWD Sources | RWE Use Summary | Key Tags |
| --- | --- | --- | --- | --- | --- |
| P100045S056 · Feb 18, 2022 | CardioMEMs HF System | ABBOTT MEDICAL | Post-approval study (PAS) data | The FDA has mandated a post-approval study to collect additional evidence of continued safety and effectiveness in the NYHA Class II patient population, explicitly allowing for the use of real-world evidence that meets regulatory criteria. | Post-approval study; NYHA Class II; Real-world evidence |

### Clinical Evidence

| Study Design | Population | Comparator | Key Endpoints |
| --- | --- | --- | --- |
| Post-Approval Study (PAS) for NYHA Class II patients; Post-approval study | NYHA Class II heart failure patients | Not applicable for this study | Safety and effectiveness in NYHA Class II population, including mortality analysis |

## Indications for Use

The CardioMEMS HF System is indicated for wirelessly measuring and monitoring pulmonary artery pressure and heart rate in NYHA Class II or III heart failure patients who either have been hospitalized for heart failure in the previous year and/or have elevated natriuretic peptides. The hemodynamic data are used by physicians for heart failure management with the goal of controlling pulmonary artery pressures and reducing heart failure hospitalizations.

## Device Story

System provides pulmonary artery (PA) hemodynamic data for heart failure management. Components include an implantable wireless PA sensor, hospital/patient electronics, and a web application (Merlin.net). Sensor is permanently implanted in the distal pulmonary artery via endovascular catheter. Patient takes daily readings at home; data (PA pressure waveform, systolic/diastolic/mean pressure, heart rate) are transmitted to a secure database. Physicians access data via web portal to proactively adjust heart failure medications. Goal is to control PA pressures and reduce hospitalizations. Used in clinic or home settings; operated by patients and physicians.

## Clinical Evidence

Pivotal GUIDE-HF trial (IDE#G170258) was a prospective, randomized, controlled, single-blind, multicenter study (N=1000 randomized). Primary endpoint: composite of HF hospitalization, urgent HF visits, and all-cause mortality. Primary endpoint not met (HR 0.88, p=0.1624). COVID-19 pandemic significantly impacted results; pre-pandemic analysis (N=1000) showed 19% reduction in primary endpoint (HR 0.81, 95% CI 0.66-1.00). Safety: 99.2% freedom from Device or System Related Complications at 12 months. No device-related deaths.

## Technological Characteristics

Wireless, implantable PA pressure sensor; permanent distal pulmonary artery placement. System includes external electronics for data transmission and cloud-based web application (Merlin.net). Sensing principle: wireless pressure measurement. Sterilization: not specified. Connectivity: networked/cloud-based.

## 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.
>
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# SUMMARY OF SAFETY AND EFFECTIVENESS DATA (SSED)

## I. GENERAL INFORMATION

Device Generic Name: System, Hemodynamic, Implantable

Device Trade Name: CardioMEMS™ HF System

Device Procode: MOM

Applicant's Name and Address: St. Jude Medical (Abbott)
387 Technology Circle NW
Suite 500
Atlanta, GA 30313

Date(s) of Panel Recommendation: None

Premarket Approval Application (PMA) Number: P100045/S056

Date of FDA Notice of Approval:

The original PMA (P100045) was approved on May 28, 2014 and is indicated for wirelessly measuring and monitoring pulmonary artery pressure and heart rate in New York Heart Association (NYHA) Class III heart failure patients who have been hospitalized for heart failure in the previous year. The hemodynamic data are used by physicians for heart failure management and with the goal of reducing heart failure hospitalizations. The SSED to support the indication is available on the CDRH website (http://www.accessdata.fda.gov/cdrh_docs/pdf10/P100045B.pdf) and is incorporated by reference here. The current supplement was submitted to expand the indication for the CardioMEMS HF System to include NYHA Class II or Class III patients who either have been hospitalized for heart failure in the previous year and/or have elevated natriuretic peptides in the previous 30 days.

## II. INDICATIONS FOR USE

The CardioMEMS HF System is indicated for wirelessly measuring and monitoring pulmonary artery pressure and heart rate in NYHA Class II or III heart failure patients who either have been hospitalized for heart failure in the previous year and/or have

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elevated natriuretic peptides. The hemodynamic data are used by physicians for heart failure management with the goal of controlling pulmonary artery pressures and reducing heart failure hospitalizations.

### III. CONTRAINDICATIONS

The CardioMEMS HF 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 CardioMEMS HF System labeling.

### V. DEVICE DESCRIPTION

The CardioMEMS™ HF System provides pulmonary artery (PA) hemodynamic data used for monitoring and management of heart failure (HF) patients. The system measures PA pressure and the data are used by the physician to proactively manage HF patients and initiate or modify heart failure treatment.

The CardioMEMS HF System consists of the following components:

- PA Sensor and Delivery System
- Hospital Electronics System
- Patient Electronics System
- Heart Failure Web Application (Merlin.net)

The wireless sensor (Figure 1) is designed for permanent implantation into the distal pulmonary artery. Once implanted, the CardioMEMS PA Sensor provides non-invasive hemodynamic data that are collected in the physician's office, clinic, hospital, or patient's home. The data provided by the system includes:

- PA pressure waveform
- Systolic, diastolic, and mean PA pressure
- Heart rate

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Figure 1: Pulmonary Artery Sensor

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

The sensor is provided mounted on the distal end of an endovascular delivery catheter, as shown in Figure 2.

Figure 2: PA Sensor and Delivery System

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

This hemodynamic data are transmitted by the Hospital Electronics System (Figure 3) and Patient Electronics System (Figure 4) to a secure website that serves as the patient database so that PA monitoring information is always available through the internet. Changes in PA pressure can be used in conjunction with heart failure signs and symptoms to guide adjustments to medications.

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**Figure 3: Hospital Electronics System**

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

**Figure 4: Patient Electronics System**

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

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## VI. ALTERNATIVE PRACTICES AND PROCEDURES

The only direct alternative method for obtaining pulmonary artery pressure is currently through a right heart catheterization (RHC) procedure. This 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. In the hospital setting, the RHC is used to measure pulmonary artery pressure and tailor chronic heart failure therapy, if necessary. However, use of this procedure to obtain pulmonary artery pressure may be impractical and associated with risks, including bruising and/or bleeding at the insertion site, trauma to the vein, trauma to the heart, and lung puncture. Other inherent risks include possible induction of cardiac arrhythmias, infection, and/or embolism.

Prior studies have concluded that changes in cardiac hemodynamics can be indicative of disease change or progression of the disease.

Each alternative has its own advantages and disadvantages. A patient should fully discuss these alternatives with his/her physician to select the method that best meets expectations and lifestyle.

## VII. MARKETING HISTORY

The CardioMEMS HF System is commercially available in the following countries: Argentina, Australia, Austria, Belgium, Canada, Colombia, Denmark, France, Germany, Ireland, Italy, Netherlands, Portugal, Spain, Switzerland, United Arab Emirates, United Kingdom, and United States of America.

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

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

- Air embolism
- Allergic reaction due to device component materials or procedure related
- Infection
  - Upper respiratory infection
  - Bronchitis
  - Pneumonia
  - Acute Bronchitis
  - Groin abscess
  - Methicillin-resistant staphylococcal aureus infection
  - Pulmonary Infiltration
  - Sepsis

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- Delayed wound healing
- Arrhythmias
  - Ventricular tachycardia
  - Atrial fibrillation
  - Ventricular arrhythmia
  - Ventricular fibrillation
  - Atrial fibrillation with rapid ventricular response
  - Atrial flutter
  - Cardiac dysrhythmias
  - Tachycardia
  - Wide complex tachycardia
  - Atrial dysrhythmia
- Bleeding
  - Epistaxis/Nose bleeds
  - GI bleed
  - Bleeding - Other
  - Blood in stool
  - Catheter site bleeding
  - Catheter site ecchymosis
  - Hematuria
- Hemoptysis
- Hematoma (Bruising)
  - Hematoma
  - Catheter site hematoma
  - Vessel puncture site hematoma
- Nausea
- Cerebrovascular accident
  - Stroke/Transient ischemic attack
- Thrombus
  - Arterial thrombosis (limbs)
  - Blood clot
- Cardiovascular Injury
  - Vascular rupture
  - Valve damage
  - Pseudoaneurysm formation
  - AV Fistula
  - Pulmonary artery injury
- Myocardial infarction (Heart attack)
- Death
- Embolism
  - Pulmonary infarct
  - Pulmonary embolism
  - Device embolization
- Thermal Burn
- Cardiac Perforation

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

### IX. SUMMARY OF NONCLINICAL STUDIES

Nonclinical studies that were summarized in the Summary of Safety and Effectiveness for the original PMA (P100045) are equally applicable to the expanded Indications for Use. A summary of the previously reported nonclinical studies can be found in the SSED for the original PMA (http://www.accessdata.fda.gov/cdrh_docs/pdf10/P100045B.pdf).

### X. SUMMARY OF PRIMARY CLINICAL STUDY

GUIDE-HF Trial - Randomized Arm

The applicant performed a clinical study in the US under IDE#G170258 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. Data from this clinical study were the basis for the current PMA supplement approval decision. A summary of the clinical study is presented below.

### A. Study Design

Patients were enrolled from 3/15/2018 to 12/20/2019. The database for the Panel Track Supplement reflected data collected through Jan 18, 2021 and included 1007 patients from 114 U.S. sites and 15 patients at 4 sites in Canada.

The study was a prospective, randomized, controlled, single-blind, multicenter, pivotal clinical trial. The study enrolled subjects with NYHA Class II, III, or IV heart failure and either elevated natriuretic peptides (N-terminal pro-B-type natriuretic peptide [NT-proBNP] or B-type natriuretic peptide [BNP]) and/or a prior HF hospitalization. All enrolled subjects underwent a right heart catheterization and implantation of a CardioMEMS device. Successfully implanted subjects were then randomized 1:1 to either hemodynamic-guided management using information provided by the CardioMEMS HF System (Treatment group) or heart failure management according to the standard of care (Control group). All patients took daily readings from home, but they were blinded to the treatment assignment or PA pressure measurements. Clinicians had access to pulmonary artery pressure information for patients in the Treatment group but not for patients in the Control group. Patient contacts were performed with scripted calls and equalized between two groups.

The study was evaluated for success based on the composite of HF hospitalization, PMA P100045/S056: FDA Summary of Safety and Effectiveness Data

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urgent HF visits (emergency department or hospital outpatient visits for intravenous diuretic therapy), and all-cause mortality at 12 months. The study would be considered successful by demonstrating that the hemodynamic-guided HF treatment is superior to the control therapy for heart failure outcomes.

An independent Clinical Events Committee (CEC) provided blinded adjudication for all primary endpoint events. An independent Data Safety Monitoring Board (DSMB) oversaw clinical data and safety.

# 1. Clinical Inclusion and Exclusion Criteria

Enrollment in the GUIDE-HF Trial (Randomized Arm) was limited to patients who met the following inclusion criteria:

1) Diagnosis and treatment for HF (regardless of LVEF) for > 90 days prior to the date of consent:
Subjects should be on stable, optimally titrated medical therapy for at least 30 days, as recommended according to current AHA/American College of Cardiology (ACC) guidelines as standard-of-care for HF therapy in the United States, with any intolerance documented.

2) NYHA Class II, III or IV HF symptoms documented within 30 days prior to consent.

3) HFH within 12 months prior to consent and/or elevated NT-proBNP (or BNP) within 30 days prior to consent defined as:

a. Subjects with LVEF ≤ 40%: NT-proBNP ≥ 1000 pg/mL (or BNP ≥ 250 pg/mL).
b. Subjects with LVEF > 40%: NT-proBNP ≥ 700 pg/mL (or BNP ≥ 175 pg/mL).
c. Thresholds for NT-proBNP and BNP (for both LVEF ≤ 40% and LVEF > 40%) will be corrected for BMI using a 4% reduction per BMI unit over 25 kg/m²*

4) ≥ 18 years of age

5) Chest circumference of < 65 inches, if BMI is > 35 kg/m²

6) Written informed consent obtained from subject

7) Willing and able to upload PA pressure information and comply with the follow-up requirements

Patients were not permitted to enroll in the GUIDE-HF Trial (Randomized Arm) if they met any of the following exclusion criteria:

1) Intolerance to all neuro-hormonal antagonists (i.e., intolerance to angiotensin converting enzyme-inhibitors (ACE-I), angiotensin receptor

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blockers (ARB), angiotensin-neprilysin inhibitors (ARNi), and beta-blockers)

2) ACC/AHA Stage D refractory HF (including having received or currently receiving pharmacologic circulatory support with inotropes)

3) Received or are likely to receive an advanced therapy (e.g., mechanical circulatory support or cardiac transplant) in the next 12 months

4) NYHA Class IV HF patients with:

a. Continuous or chronic use of scheduled intermittent inotropic therapy for HF and an INTERMACS level of ≤ 4, OR
b. Persistence of fluid overload with maximum (or dose equivalent) diuretic intervention

5) Glomerular Filtration Rate (eGFR) < 25 mL/min and non-responsive to diuretic therapy, or receiving chronic dialysis

6) Inability to tolerate or receive dual antiplatelet therapy or anticoagulation therapy for one month post-implantation

7) Significant congenital heart disease that has not been repaired and would prevent implantation of the CardioMEMS PA Sensor

8) Implanted with mechanical right heart valve(s)

9) Unrepaired severe valvular disease

10) Pregnant or planning to become pregnant in the next 12 months

11) An active, ongoing infection, defined as being febrile, an elevated white blood cell count, on intravenous antibiotics, and/or positive cultures (blood, sputum or urine).

12) History of current or recurrent (≥ 2 episodes) pulmonary emboli and/or deep vein thromboses

13) Major cardiovascular event (e.g., unstable angina, myocardial infarction, percutaneous coronary intervention, open heart surgery, or stroke, etc.) within 90 days prior to consent

14) Implanted with Cardiac Resynchronization Therapy (CRT)-Pacemaker (CRT-P) or CRT-Defibrillator (CRT-D) for less than 90 days prior to consent

15) Enrollment into another trial with an active treatment arm

16) Anticipated life expectancy of < 12 months

17) Any condition that, in the opinion of the Investigator, would not allow for utilization of the CardioMEMS HF System to manage the subject using information gained from hemodynamic measurements to adjust medications, including the presence of unexpectedly severe pulmonary hypertension (e.g., trans-pulmonary gradient >15) at implant RHC, a history of non-compliance, or any condition that would preclude CardioMEMS PA Sensor implantation.

*Thresholds for NT-proBNP and BNP (for both LVEF ≤ 40% and LVEF > 40%) were corrected for BMI using a 4%

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reduction per BMI unit over 25 kg/m² per the Frankenstein equation.

## 2. Follow-up Schedule

All randomized patients were scheduled to return for follow-up examinations at 6 and 12 months. Adverse events and complications were recorded at all visits.

The key timepoints are shown in Table 1 summarizing schedule of treatments and evaluations.

Table 1. Schedule of Treatments and Evaluations

|  Visit Trial Activity | Baseline (up to -60 days) | Implant (time zero) | Prior to Discharge | Phone Contact^{1} (Randomized Arm Only) | 6 Months (+/-14 days) | 12 Months (+/-30 days)  |
| --- | --- | --- | --- | --- | --- | --- |
|  Informed Consent Process | X |  |  |  |  |   |
|  Assessment of Inclusion/Exclusion Criteria | X |  |  |  |  |   |
|  Demographic Information | X |  |  |  |  |   |
|  Cardiovascular History | X |  |  |  |  |   |
|  BMI (and Chest Circumference if BMI > 35kg/m²) | X |  |  |  |  |   |
|  Limited Echo for EF (if no EF documented) | (X) |  |  |  |  |   |
|  EQ-5D-5L and KCCQ-12 Administration | X |  |  |  | X | X  |
|  Creatinine and Calculation of eGFR | X |  |  |  | X | X  |
|  NT-proBNP (or BNP) | X |  |  |  | X | X  |
|  Medication Review and Documentation | X |  | X |  | X | X  |
|  HF Exam (Including NYHA Assessment) | X |  |  |  | X | X  |
|  6MHW Test | X |  |  |  | X | X  |
|  CardioMEMS™ HF System Information |  | X |  |  |  |   |
|  Catheterization Laboratory PA Pressure Measurements |  | X |  |  |  |   |
|  Randomization (Randomized Arm Only^{2}) |  |  | X |  |  |   |
|  Subject Teaching / Compliance Assessment |  |  | X | X | X | X  |
|  Subject Contact Worksheet |  |  |  | X |  |   |
|  Medication Update Documentation |  | (X) | (X) | (X) | (X) | (X)  |
|  Reportable AEs | (X) | (X) | (X) | (X) | (X) | (X)  |
|  Protocol Deviation | (X) | (X) | (X) | (X) | (X) | (X)  |
|  Non-AE Device Issues |  | (X) | (X) | (X) | (X) | (X)  |
|  Death | (X) | (X) | (X) | (X) | (X) | (X)  |

(X) If applicable/as it occurs

$^{1}$All sites will be required to be in contact with each subject in the Randomized Arm (including subjects in the Treatment and Control Groups) at least once every two weeks during the first three months from the date of implantation and then at least once per month from three months to the 12 month follow-up visit.

$^{2}$Randomization should be completed as soon as possible but within 24 hours of implant, and prior to discharge.

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### 3. Clinical Endpoints

With regards to effectiveness, the primary endpoint is a composite of the following:

- Hospitalization (≥ 24 hours) with the primary reason for admission being acute decompensated HF and intravenous administration of diuretic therapy
- An unscheduled or unplanned admission to the emergency department, hospital outpatient observation visit, or hospital inpatient visit and intravenous administration of diuretic therapy
- All-cause mortality.

With regards to safety, the secondary safety endpoint is freedom from Device or System Related Complications (DSRCs) at 12 months post-implantation.

DSRC was defined as an adverse event that was related to or possibly related to the system (wireless pressure sensor or external electronics) and had at least one of the following characteristics:

- Treated with invasive means (other than intramuscular medication or an RHC used for diagnostic purposes)
- resulted in the death of the subject
- resulted in the explant of the device

With regard to success/failure criteria, study success was defined as demonstrating superiority for the primary endpoint hypotheses below at a significance level of 2.5%:

H₀: Hazard ratio (HR) for the Composite Endpoint at 12 months (Treatment to Control) ≥ 1

H₁: HR for the Composite Endpoint at 12 months (Treatment to Control) < 1

or

H₀: e^(β₁) ≥ 1

H₁: e^(β₁) < 1

where e is the exponential function and β1 is the regression coefficient obtained from the covariate representing randomized group (Treatment or Control) in the Andersen-Gill model. Thus, the hazard ratio is the exponentiation of the regression coefficient for randomized group. This is equivalent to testing the regression coefficient against zero.

All randomized subjects were included in the analysis population.

### B. Accountability of PMA Cohort

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A total of 1022 patients were consented for trial enrollment and underwent a right heart catheterization and implantation of a CardioMEMS device. Of these, 22 did not receive an implant, primarily due to anatomical/physiological conditions identified during the right heart catheterization. The observed PA sensor implant success rate was 97.8%. The remaining 1000 subjects who received a successful implant were randomized 1:1 to either the Treatment group (N = 497) or the Control group (N = 503). At the time of database lock, 854 (85.4%) randomized subjects completed the 12-month follow-up visit. Figure 5 summarizes the subject disposition in the PMA study:

Figure 5. Subject Disposition

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

*Treatment Other:

Subject in Hospice: 2

Subject Moved Out of State: 1

Severe COVID-19: 1

PI Discretion:

Subject Refused Recalibration: 1

Difficulty Maintaining Blind: 1

Subject Mental Health Issues: 1

*Control Other:

Subject in Hospice: 3

Heart Transplant: 1

Subject in Nursing Home: 1

PI Discretion:

Need for device information for

subject management: 4

Subject Non-Compliance: 1

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The protocol specified the following analysis populations:

*Endpoint Analysis Population:* All randomized subjects (N = 1000)

*Safety Population:* All enrolled subjects (N = 1022)

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

The demographics of the study population are typical for a heart failure study that enrolls NYHA Class II-IV patients in the US. The mean age was 69.2 ± 11 years and 37.5% were female. NYHA II, III, and IV patients account for 29.6%, 65.0%, and 5.4% of the randomized subjects. Table 2 presents the demographics and patient characteristics by randomized group. The Treatment and Control groups were balanced in all relevant demographics and baseline characteristics.

**Table 2. Subject Demographics and Characteristics (Endpoint Analysis Population)**

|   | Treatment (N=497) | Control (N=503) | p-value^{1}  |
| --- | --- | --- | --- |
|  **Age - year** | 69.2 ± 11.1 (497) | 69.2 ± 11.0 (503) | 0.8996  |
|  **Female Sex** | 37.6% (187/497) | 37.4% (188/503) | 0.9480  |
|  **Race** |  |  |   |
|  White | 81.1% (403/497) | 80.5% (405/503) | 0.8725  |
|  Black | 17.5% (87/497) | 18.5% (93/503) | 0.7420  |
|  Asian | 0.0% (0/497) | 0.2% (1/503) | 1.0000  |
|  American Indian or Alaskan Native | 0.4% (2/497) | 0.4% (2/503) | 1.0000  |
|  Pacific Islanders | 0.0% (0/497) | 0.0% (0/503) |   |
|  Other | 1.2% (6/497) | 0.6% (3/503) | 0.3389  |
|  **Ethnicity** |  |  |   |
|  Hispanic | 3.2% (16/497) | 3.4% (17/503) | 1.0000  |
|  Non-Hispanic | 96.0% (477/497) | 96.0% (483/503) | 1.0000  |
|  Unknown | 0.8% (4/497) | 0.6% (3/503) | 0.7241  |
|  **Body mass index - kg/m^{2}** | 32.9 ± 8.3 (497) | 33.8 ± 8.4 (503) | 0.0571  |
|  **NYHA Class** |  |  |   |
|  II | 29.4% (146/497) | 29.8% (150/503) | 0.8900  |
|  III | 64.8% (322/497) | 65.2% (328/503) | 0.8947  |
|  IV | 5.8% (29/497) | 5.0% (25/503) | 0.5778  |
|  **Medical History** |  |  |   |
|  Ischemic etiology | 41.6% (207/497) | 37.8% (190/503) | 0.2198  |
|  Previous myocardial infarction | 29.0% (144/497) | 31.4% (158/503) | 0.4093  |
|  Previous percutaneous coronary intervention | 33.2% (165/497) | 31.4% (158/503) | 0.5885  |
|  Previous coronary artery bypass grafting | 27.2% (135/497) | 27.0% (136/503) | 1.0000  |
|  Diabetes | 48.9% (243/497) | 51.9% (261/503) | 0.3759  |
|  Cerebrovascular accident | 13.3% (66/497) | 12.9% (65/503) | 0.9254  |
|  Atrial flutter or fibrillation | 60.4% (300/497) | 57.9% (291/503) | 0.4404  |
|  **Vital Signs and Hemodynamic Analyses** |  |  |   |
|  Heart rate - bpm | 73.8 ± 12.5 (497) | 74.2 ± 12.3 (503) | 0.7438  |
|  Systolic blood pressure - mmHg | 121.6 ± 19.1 (497) | 120.8 ± 18.1 (503) | 0.6134  |
|  Diastolic blood pressure - mmHg | 69.2 ± 10.8 (497) | 69.0 ± 10.8 (503) | 0.7996  |
|  Left ventricular ejection fraction - % | 39.4 ± 17.3 (497) | 40.7 ± 16.9 (503) | 0.1870  |
|  Left ventricular ejection fraction > 40% | 45.1% (224/497) | 48.7% (245/503) | 0.2546  |

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|   | Treatment (N=497) | Control (N=503) | p-value^{1}  |
| --- | --- | --- | --- |
|  Pulmonary artery systolic pressure - mmHg | 44.9 ± 13.9 (497) | 45.2 ± 14.6 (503) | 0.9194  |
|  Pulmonary artery diastolic pressure - mmHg | 18.9 ± 8.0 (497) | 18.8 ± 7.7 (503) | 0.8203  |
|  Pulmonary artery mean pressure - mmHg | 29.2 ± 9.5 (497) | 29.4 ± 10.0 (503) | 0.9631  |
|  Pulmonary capillary wedge pressure - mmHg | 17.3 ± 8.0 (495) | 17.6 ± 7.9 (503) | 0.6171  |
|  Cardiac output - L/min | 4.83 ± 2.62 (497) | 4.70 ± 1.46 (503) | 0.8459  |
|  Cardiac index - L/min/m^{2} | 2.27 ± 1.11 (497) | 2.19 ± 0.63 (503) | 0.4609  |
|  **Ambulatory Hemodynamics during First Week**  |   |   |   |
|  Pulmonary artery systolic pressure - mmHg | 46.3 ± 14.4 (497) | 46.2 ± 13.3 (499) | 0.7640  |
|  Pulmonary artery diastolic pressure - mmHg | 22.4 ± 7.8 (497) | 22.7 ± 7.4 (499) | 0.4141  |
|  Pulmonary artery mean pressure - mmHg | 31.8 ± 10.2 (497) | 31.9 ± 9.6 (499) | 0.6693  |
|  Heart rate - bpm | 78.8 ± 11.7 (497) | 79.4 ± 11.9 (499) | 0.7893  |
|  **Laboratory Analyses**  |   |   |   |
|  Serum creatinine level - μmol/L | 128.5 ± 44.5 (495) | 133.5 ± 48.5 (495) | 0.1548  |
|  Estimated glomerular filtration rate - ml/min/1.73m^{2} | 54.3 ± 21.3 (495) | 52.8 ± 20.8 (494) | 0.2469  |
|  B-type natriuretic peptide level - pg/mL | 520.7 ± 689.2 (261) | 552.4 ± 954.0 (256) | 0.8499  |
|  N-terminal pro-B-type natriuretic peptide level - pg/mL | 2460 ± 3707 (219) | 2183 ± 2803 (225) | 0.5287  |
|  **Treatment History**  |   |   |   |
|  Previous cardiac resynchronization therapy | 28.6% (142/497) | 32.4% (163/503) | 0.1926  |
|  Previous implantation of defibrillator | 42.9% (213/497) | 40.8% (205/503) | 0.5217  |
|  Guideline-Directed Medical Therapy  |   |   |   |
|  ACE-Inhibitor or ARB or ARNi | 64.2% (319/497) | 63.6% (320/503) | 0.8953  |
|  ARNi | 29.2% (145/497) | 27.6% (139/503) | 0.6236  |
|  Beta Blocker | 89.3% (444/497) | 87.9% (442/503) | 0.4873  |
|  Mineralocorticoid Receptor Antagonist | 47.7% (237/497) | 42.9% (216/503) | 0.1440  |
|  Diuretic | 95.4% (474/497) | 95.0% (478/503) | 0.8827  |
|  Hydralazine | 16.3% (81/497) | 15.9% (80/503) | 0.9315  |
|  Nitrate | 19.9% (99/497) | 20.5% (103/503) | 0.8749  |
|  SGLT2 Inhibitor | 1.3% (2/152) | 1.4% (2/140) | 1.0000  |
|  **Enrollment Type**  |   |   |   |
|  Heart failure hospitalization in year prior only | 34.2% (170/497) | 38.0% (191/502) | 0.2114  |
|  Elevated natriuretic peptide level in 30 day prior only | 46.3% (230/497) | 42.2% (212/502) | 0.2032  |
|  Heart failure hospitalization in year prior and elevated natriuretic peptide level in 30 day prior | 19.5% (97/497) | 19.7% (99/502) | 0.9367  |
|  **KCCQ-12 at Baseline – Overall Summary Score** | 54.9 ± 24.3 (494) | 54.9 ± 23.8 (497) | 0.8876  |
|  **6MHW at Baseline – m** | 235.2 ± 120.2 (474) | 229.6 ± 123.0 (482) | 0.4459  |

Continuous Variables: Mean ± SD (n); Categorical Variables: Percent (n/N)

$^{1}$Continuous variables compared using Wilcoxon Rank Sum test, and categorical variables compared using Fisher's exact test.

### D. Safety and Effectiveness Results

#### 1. Effectiveness Results

# *Primary Endpoint*

The primary endpoint analysis was based on all randomized subjects. At 12 months, there were 253 primary endpoint events in the Treatment group compared with 289 events in the Control group. The difference between the groups represented a non-significant 12% relative risk reduction in the primary endpoint events (0.563 vs. 0.640 events per patient-year; HR 0.88, 95% CI 0.74-1.05, p=0.1624). Since the 97.5% upper confidence bound of the hazard ratio was not

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less than 1, the primary endpoint was not met.

Table 3 presents the primary endpoint analysis and the components. There were 185 heart failure hospitalizations in the treatment group and 225 in the control group (0.410 vs. 0.497 events per patient; HR 0.83, 95% CI 0.68-1.01). The rates of urgent heart failure ED/outpatient visits or mortality were similar between the two groups.

The timing of the pivotal study overlapped with the COVID-19 pandemic. The effects of the pandemic on the study outcomes are further assessed in the sensitivity analysis section below.

**Table 3. Primary Endpoint Analysis and Components**

|  Endpoint^{1} | Treatment (N=497) Events (Rate^{2}) | Control (N=503) Events (Rate^{2}) | Hazard Ratio (95% CI) p-value^{3}  |
| --- | --- | --- | --- |
|  **HF Hospitalization + ED/OP + Death (Primary Endpoint)** | 253 (0.563) | 289 (0.640) | 0.88 (0.74, 1.05), p=0.1624  |
|  HF Hospitalization + ED/OP (Secondary Endpoint) | 213 (0.474) | 252 (0.557) | 0.85 (0.70, 1.03)  |
|  HF Hospitalization | 185 (0.410) | 225 (0.497) | 0.83 (0.68, 1.01)  |
|  HF Emergency Department/Hospital Outpatient Visit (ED/OP) | 28 (0.065) | 27 (0.063) | 1.04 (0.61, 1.77)  |
|  Death | 40 (0.094) | 37 (0.086) | 1.09 (0.70, 1.70)  |

$^{1}$Endpoints include CEC adjudicated Heart Failure (HF) Hospitalizations or HF Emergency Department/Hospital Outpatient Visits (ED/OP) with an admission date after the date of implant hospitalization discharge through 395 days after the date of implant. All Cause Deaths are included from implant date to 395 days after implant date.

$^{2}$Event Rate is an annualized rate estimated from the Andersen-Gill model.

$^{3}$Hazard Ratio, 95% Confidence Interval, and p-value estimated from the Andersen-Gill model with robust sandwich variance estimates.

## COVID-19 Impact Sensitivity Analysis

### *COVID-19 Sensitivity Analysis for Interaction*

The COVID-19 pandemic occurred while the pivotal study was still ongoing. Across North America, hospitals saw notable reduction in heart failure hospital admissions during COVID-19 lockdowns. Using the national emergency declaration date (March 13, 2020) in the United States as the onset date, a total of 71.7% of follow-up had been completed prior to COVID-19. The median follow-up prior to COVID-19 was 8.4 months.

The applicant added a COVID-19 impact sensitivity analysis (dated July 7, 2020) to the statistical analysis plan prior to data unblinding. The sensitivity analysis would descriptively compare the primary endpoint event rates observed during subject follow-up occurring prior to the start of the COVID-19 pandemic to rates

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observed during subject follow-up occurring after the start of the pandemic to evaluate impact of COVID-19, as shown in Figure 6.

Figure 6. Follow-up Based Sensitivity Analysis

![img-5.jpeg](img-5.jpeg)

The sensitivity analysis demonstrated a qualitative interaction with a significant p-value of p=0.1129 (<p=0.15, pre-specified interaction p-value threshold), suggesting an impact of COVID-19 on the treatment effect observed in the Randomization Arm of the GUIDE-HF trial (Table 4). The hazard ratio for the primary endpoint events reversed from 0.81 prior to COVID-19 to 1.11 during COVID-19.

Table 4. Primary Endpoint – Follow-Up Based COVID-19 Sensitivity Analysis

|  Endpoint1 | Treatment (N=497) Events | Control (N=503) Events | Forest Plot | Hazard Ratio (95% CI)2  |
| --- | --- | --- | --- | --- |
|  Heart Failure Hospitalization + ED/OP + Death (Primary Endpoint) |   |   |   | Interaction p-value3p=0.1129  |
|  Prior to COVID-194 | 177 | 224 | ![img-6.jpeg](img-6.jpeg) | 0.81 (0.66, 1.00)  |
|  During COVID-194 | 76 | 65 |   | 1.11 (0.80, 1.55)  |

\( ^{1} \) Endpoints include CEC adjudicated Heart Failure (HF) Hospitalizations or HF Emergency Department/Hospital Outpatient Visits (ED/OP) with an admission date after the date of implant hospitalization discharge through 395 days after the date of implant. All Cause Deaths are included from implant date to 395 days after implant date.

\( ^{2} \) Contrast Comparison Hazard Ratio and 95% Confidence Interval estimated from the Anderson-Gill model with robust sandwich estimates.

\( ^{3} \) Interaction p-value is a joint test on the interaction term of treatment group by COVID analysis time period.

\( ^{4} \) Primary Endpoint events are analyzed through March 13, 2020 for Prior to COVID-19 and analyzed after March 13, 2020 for During COVID-19.

Since the COVID-19 sensitivity analysis suggested an effect of COVID-19 on the primary endpoint, the pre-pandemic data were further explored.

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### *Pre-COVID-19 Analysis*

#### Pre-pandemic Primary Endpoint Events

Prior to COVID-19, there were a total of 177 primary endpoint events in the Treatment group compared with 224 events in the Control group (0.595 events vs. 0.730 events per patient, respectively). An HR of 0.81 (95% CI 0.66-1.00) for the primary endpoint, largely driven by a 27% reduction in risk for HFH, was observed.

The results of the analysis including data prior to COVID-19 only are shown in Table 5 below:

**Table 5. Primary Endpoint and Components – Including Data Prior to COVID-19 Only**

|  Endpoint^{1} | Treatment (N=497) Events (Rate^{2}) | Control (N=503) Events (Rate^{2}) | Hazard Ratio (95% CI)^{3}  |
| --- | --- | --- | --- |
|  **HF Hospitalization + ED/OP + Death (Primary Endpoint)** | 177 (0.595) | 224 (0.730) | 0.81 (0.66, 1.00)  |
|  HF Hospitalization + ED/OP (Secondary Endpoint) | 147 (0.502) | 199 (0.660) | 0.76 (0.61, 0.95)  |
|  HF Hospitalization | 124 (0.426) | 176 (0.587) | 0.73 (0.57, 0.92)  |
|  HF Emergency Department/Hospital Outpatient Visit (ED/OP) | 23 (0.077) | 23 (0.076) | 1.02 (0.57, 1.82)  |
|  Death | 30 (0.103) | 25 (0.083) | 1.24 (0.73, 2.10)  |

$^{1}$Endpoints include CEC adjudicated Heart Failure (HF) Hospitalizations or HF Emergency Department/Hospital Outpatient Visits (ED/OP) with an admission date after the date of implant hospitalization discharge through 395 days after the date of implant. All Cause Deaths are included from implant date to 395 days after implant date. Primary Endpoint events are analyzed through March 13, 2020.

$^{2}$Event Rate is an annualized rate estimated from the Andersen-Gill model.

$^{3}$Hazard Ratio and 95% Confidence Interval estimated from the Andersen-Gill model with robust sandwich variance estimates.

### *Quality of Life Assessment and Functional Assessment (6MHW)*

Health status changes over time were assessed by EuroQol 5-Dimension, 5-Level (EQ-5D-5L) Questionnaire and Kansas City Cardiomyopathy Questionnaire (KCCQ-12) at baseline, 6, and 12 months. While both Treatment and Control groups gained improvement at 6 months, there were no significant differences between the groups (Table 6).

The functional assessment of 6MHW distance did not show a significant improvement either within or between groups over the follow-up period.

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Table 6. KCCQ-12, EQ-5D-5L, and 6MHW

|  Component/Analysis | 6 Month Paired Change from Baseline |   |   | 12 Month Paired Change from Baseline  |   |   |
| --- | --- | --- | --- | --- | --- | --- |
|   |  Treatment Mean ± SD (n) | Control Mean ± SD (n) | Between Group p-value | Treatment Mean ± SD (n) | Control Mean ± SD (n) | Between Group p-value  |
|  KCCQ-12 Overall Summary Score | 7.44 ± 20.68 (449) | 6.14 ± 24.72 (440) | 0.3545^{1} | 5.20 ± 21.35 (421) | 4.12 ± 22.50 (408) | 0.4783^{1}  |
|  EQ-5D-5L Visual Analogue Scale | 3.09 ± 19.40 (449) | 3.20 ± 21.69 (441) | 0.9363^{1} | 0.94 ± 20.17 (421) | 2.90 ± 20.71 (409) | 0.1658^{1}  |
|  6MHW Test Distance | 0.01 ± 87.78 (332) | 2.29 ± 93.69 (342) | 0.7439^{1} | -12.83 ± 100.08 (288) | -6.46 ± 106.57 (291) | 0.4586^{1}  |

$^{1}$Student t-test comparing Treatment vs. Control change from baseline at 6 months and 12 months

### PA Pressures

A greater reduction in PA mean pressure over time was observed in the Treatment group compared to Control (-2.4 ± 5.2 mmHg vs. -1.7 ± 5.0; Figure 7). A greater reduction in Treatment group PA mean pressure was also observed when limited to data prior to COVID-19 (-2.1 ± 4.8 mmHg vs. -1.4 ± 4.8; Figure 8).

Figure 7. Average PA Mean Pressure Over Time

![img-7.jpeg](img-7.jpeg)

|  No. At Risk  |   |   |   |   |   |   |   |   |   |   |   |   |   |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
|  Treatment | 497 | 496 | 491 | 486 | 480 | 473 | 468 | 465 | 456 | 447 | 441 | 422 | 193  |
|  Control | 503 | 500 | 494 | 488 | 482 | 476 | 468 | 463 | 459 | 456 | 442 | 434 | 180  |

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Figure 8. Average PA Mean Pressure Over Time – Data Prior to COVID-19 Only

![img-8.jpeg](img-8.jpeg)

No. At Risk

|  Treatment | 497 | 496 | 491 | 459 | 404 | 360 | 328 | 290 | 251 | 216 | 182 | 155 | 58  |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
|  Control | 503 | 500 | 494 | 459 | 405 | 365 | 335 | 303 | 272 | 237 | 200 | 172 | 59  |

## 2. Safety Results

Freedom from Device or System Related Complications (DSRC)

A total of 8 DSRC events occurred in 8 subjects in the safety population. The observed rate of freedom from Device or System Related Complications was 99.2% (1014/1022). None of the 8 DSRCs resulted in death or explant of the device, and most were vascular injury events due to vascular access or device implant. Table 7 presents a summary of DSRCs.

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**Table 7. Summary of DSRCs as Adjudicated by the CEC (Safety Population)**

|  Cohort System Organ Class Preferred Term | Number of DSRCs | Proportion of Subjects with DSRCs | DSRC Criteria Met  |   |   |
| --- | --- | --- | --- | --- | --- |
|   |   |   |  Treated with Invasive Means | Resulted in Death | Resulted in Device Explant  |
|  **Safety Population (N=1022)**  |   |   |   |   |   |
|  **General Disorders and Administration Site Conditions** | **5** | **0.49% (5/1022)** | **5** | **0** | **0**  |
|  Catheter Site Hematoma | 1 | 0.10% (1/1022) | 1 | 0 | 0  |
|  Catheter Site Hemorrhage | 2 | 0.20% (2/1022) | 2 | 0 | 0  |
|  Device Dislocation | 1 | 0.10% (1/1022) | 1 | 0 | 0  |
|  Device Malfunction | 1 | 0.10% (1/1022) | 1 | 0 | 0  |
|  **Injury, Poisoning and Procedural Complications** | **3** | **0.29% (3/1022)** | **3** | **0** | **0**  |
|  Arterial Injury | 2 | 0.20% (2/1022) | 2 | 0 | 0  |
|  Vascular Pseudoaneurysm | 1 | 0.10% (1/1022) | 1 | 0 | 0  |
|  **Total** | **8** | **0.78% (8/1022)** | **8** | **0** | **0**  |

### *Hospitalizations*

Table 8 summarizes the all-cause hospitalizations reported during the 12-month follow-up for all randomized subjects. Treatment group experienced a lower all-cause hospitalizations rate comparing to the Control group (468 vs. 493) though similar proportion of subjects in each group had at least one hospitalization during the study.

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**Table 8. Summary of Hospitalizations as Adjudicated by the CEC (Endpoint Analysis Population)**

|  Adjudicated Cause | Treatment (N=497) |   | Control (N=503)  |   |
| --- | --- | --- | --- | --- |
|   |  Count [Rate^{1}] | Percent of Subjects with Event | Count [Rate^{1}] | Percent of Subjects with Event  |
|  **Worsening heart failure** | **233 [50.3]** | **27.4% (136/497)** | **269 [57.7]** | **30.4% (153/503)**  |
|  HF Hospitalization | 185 [39.9] | 24.1% (120/497) | 225 [48.2] | 27.6% (139/503)  |
|  Urgent HF Visit | 28 [6.04] | 4.4% (22/497) | 27 [5.79] | 5.0% (25/503)  |
|  Not a Protocol Defined HF Admission | 20 [4.32] | 3.4% (17/497) | 17 [3.65] | 3.0% (15/503)  |
|  **Other cardiovascular** | **200 [43.2]** | **27.4% (136/497)** | **186 [39.9]** | **25.0% (126/503)**  |
|  CABG | 0 [0.00] | 0.0% (0/497) | 1 [0.21] | 0.2% (1/503)  |
|  Myocardial Infarction or Other Forms of Ischemic Heart Disease | 26 [5.61] | 4.0% (20/497) | 46 [9.86] | 7.6% (38/503)  |
|  Product Issue^{2} | 1 [0.22] | 0.2% (1/497) | 0 [0.00] | 0.0% (0/503)  |
|  Thrombosis or Thromboembolism | 12 [2.59] | 2.0% (10/497) | 6 [1.29] | 1.2% (6/503)  |
|  Valve Surgery | 5 [1.08] | 0.8% (4/497) | 6 [1.29] | 1.2% (6/503)  |
|  Ventricular or Atrial Arrhythmia | 57 [12.3] | 9.1% (45/497) | 55 [11.8] | 8.5% (43/503)  |
|  Other | 99 [21.4] | 14.7% (73/497) | 72 [15.4] | 11.9% (60/503)  |
|  **Non-cardiovascular** | **35 [7.55]** | **6.8% (34/497)** | **37 [7.93]** | **6.4% (32/503)**  |
|  **Total** | **468 [101.0]** | **47.1% (234/497)** | **492 [105.5]** | **46.5% (234/503)**  |

$^{1}$Rate is number of events per 100 subject years.

$^{2}$Hospitalization due to events related to the device.

### *Mortality*

A total of 77 subjects died in the study. There were 40 (0.094) all-cause deaths in the Treatment group and 37 (0.086) all-cause deaths in the Control group. Table 9 presents the causes of deaths between the two groups per CEC adjudication.

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**Table 9. Summary of Deaths as Adjudicated by the CEC (Endpoint Analysis Population)**

|  Adjudicated Cause | Treatment (N=497) | Control (N=503)  |
| --- | --- | --- |
|  **Cardiovascular** | **6.0% (30/497)** | **4.8% (24/503)**  |
|  Cardiovascular procedure | 0.2% (1/497) | 0.0% (0/503)  |
|  Heart failure | 3.4% (17/497) | 3.0% (15/503)  |
|  Sudden cardiac death | 2.2% (11/497) | 1.8% (9/503)  |
|  Other | 0.2% (1/497) | 0.0% (0/503)  |
|  **Non-cardiovascular** | **1.6% (8/497)** | **2.6% (13/503)**  |
|  Gastrointestinal | 0.0% (0/497) | 0.2% (1/503)  |
|  Hemorrhage | 0.0% (0/497) | 0.2% (1/503)  |
|  Infection | 0.6% (3/497) | 0.6% (3/503)  |
|  Inflammatory, Immune (including autoimmune) | 0.0% (0/497) | 0.2% (1/503)  |
|  Neurological | 0.2% (1/497) | 0.2% (1/503)  |
|  Pulmonary | 0.2% (1/497) | 0.4% (2/503)  |
|  Renal | 0.4% (2/497) | 0.4% (2/503)  |
|  Other non-cardiovascular | 0.2% (1/497) | 0.4% (2/503)  |
|  **Undetermined cause of death** | **0.4% (2/497)** | **0.0% (0/503)**  |
|  **Total** | **8.0% (40/497)** | **7.4% (37/503)**  |

There were no device-related deaths.

Two subjects died within 30 days after the procedure. A patient with ischemic cardiomyopathy, atrial fibrillation and a history of valvular heart disease status post TAVR developed abdominal pain post-operatively. The patient was found to have ischemic bowel and died on post-operative day 2. The death was adjudicated as procedure-related but not device-related. Another patient died of sudden cardiac arrest on day 29 after the procedure. CEC adjudicated the death as not device- or procedure-related.

#### *Adverse Events*

Table 10 presents a summary of adverse events as reported by investigators. There were no unanticipated adverse device effects. Tables 11 and 12 present the serious and non-serious adverse device effects reported in the pivotal study.

**Table 10. Summary of Adverse Events (As Reported by Investigator)**

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|  Adverse Event Class | Treatment (N=497) |   | Control (N=503)  |   |
| --- | --- | --- | --- | --- |
|   |  Events [Rate^{1}] | Percent of Subjects with Event | Events [Rate^{1}] | Percent of Subjects with Event  |
|  SAE | 729 [157.3] | 56.7% (282/497) | 799 [171.3] | 53.3% (268/503)  |
|  ADE | 16 [3.45] | 3.0% (15/497) | 20 [4.29] | 4.0% (20/503)  |
|  SADE | 9 [1.94] | 1.8% (9/497) | 15 [3.22] | 2.4% (12/503)  |
|  UADE | 0 [0.00] | 0.0% (0/497) | 0 [0.00] | 0.0% (0/503)  |

$^{1}$Rate is number of events per 100 subject years.

**Table 11. Summary of Serious Adverse Device Effects (As Reported by Investigator)**

|  System Organ Class Preferred Term | Treatment (N=497) |   | Control (N=503)  |   |
| --- | --- | --- | --- | --- |
|   |  Events [Rate^{1}] | Percent of Subjects with Event | Events [Rate^{1}] | Percent of Subjects with Event  |
|  **Overall Follow-Up**  |   |   |   |   |
|  **Cardiac Disorders** | **2 [0.43]** | **0.4% (2/497)** | **0 [0.00]** | **0.0% (0/503)**  |
|  Arrhythmia | 1 [0.22] | 0.2% (1/497) | 0 [0.00] | 0.0% (0/503)  |
|  Cardiac Failure Congestive | 1 [0.22] | 0.2% (1/497) | 0 [0.00] | 0.0% (0/503)  |
|  **General Disorders and Administration Site Conditions^{2}** | **4 [0.86]** | **0.8% (4/497)** | **4 [0.86]** | **0.8% (4/503)**  |
|  Catheter Site Hematoma | 0 [0.00] | 0.0% (0/497) | 1 [0.21] | 0.2% (1/503)  |
|  Catheter Site Hemorrhage | 4 [0.86] | 0.8% (4/497) | 1 [0.21] | 0.2% (1/503)  |
|  Device Deployment Issue^{3} | 0 [0.00] | 0.0% (0/497) | 1 [0.21] | 0.2% (1/503)  |
|  Device Dislocation^{4} | 0 [0.00] | 0.0% (0/497) | 1 [0.21] | 0.2% (1/503)  |
|  **Injury, Poisoning and Procedural Complications** | **1 [0.22]** | **0.2% (1/497)** | **2 [0.43]** | **0.4% (2/503)**  |
|  Arterial Injury | 1 [0.22] | 0.2% (1/497) | 1 [0.21] | 0.2% (1/503)  |
|  Vascular Pseudoaneurysm | 0 [0.00] | 0.0% (0/497) | 1 [0.21] | 0.2% (1/503)  |
|  **Respiratory, Thoracic and Mediastinal Disorders** | **0 [0.00]** | **0.0% (0/497)** | **6 [1.29]** | **1.0% (5/503)**  |
|  Hemoptysis | 0 [0.00] | 0.0% (0/497) | 4 [0.86] | 0.6% (3/503)  |
|  Pulmonary Embolism | 0 [0.00] | 0.0% (0/497) | 2 [0.43] | 0.4% (2/503)  |
|  **Vascular Disorders** | **2 [0.43]** | **0.4% (2/497)** | **3 [0.64]** | **0.6% (3/503)**  |
|  Embolism | 0 [0.00] | 0.0% (0/497) | 1 [0.21] | 0.2% (1/503)  |
|  Hematoma | 1 [0.22] | 0.2% (1/497) | 2 [0.43] | 0.4% (2/503)  |
|  Thrombosis | 1 [0.22] | 0.2% (1/497) | 0 [0.00] | 0.0% (0/503)  |
|  **Total** | **9 [1.94]** | **1.8% (9/497)** | **15 [3.22]** | **2.4% (12/503)**  |

$^{1}$Rate is number of events per 100 subject years.

$^{2}$Administration Site Conditions refers to events associated with site at which the device is administered.

$^{3}$Device did not completely detach from delivery catheter upon initial deployment, but was ultimately deployed and confirmed to be working successfully.

$^{4}$Partial dislodgment of a left ventricular pacemaker lead during the CardioMEMS device implantation procedure, requiring subsequent lead revision. All SADEs occurred in NYHA Class II/III subjects prior to COVID-19.

**Table 12. Summary of Adverse Device Effects (As Reported by Investigator)**

|  Treatment (N=497) | Control (N=503)  |
| --- | --- |
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|  System Organ Class Preferred Term | Events [Rate^{1}] | Percent of Subjects with Event | Events [Rate^{1}] | Percent of Subjects with Event  |
| --- | --- | --- | --- | --- |
|  **Cardiac Disorders** | **0 [0.00]** | **0.0% (0/497)** | **2 [0.43]** | **0.4% (2/503)**  |
|  Arrhythmia | 0 [0.00] | 0.0% (0/497) | 2 [0.43] | 0.4% (2/503)  |
|  **General Disorders and Administration Site Conditions** | **9 [1.94]** | **1.8% (9/497)** | **18 [3.86]** | **3.6% (18/503)**  |
|  Catheter Site Hematoma | 2 [0.43] | 0.4% (2/497) | 3 [0.64] | 0.6% (3/503)  |
|  Catheter Site Hemorrhage | 4 [0.86] | 0.8% (4/497) | 6 [1.29] | 1.2% (6/503)  |
|  Device Deployment Issue | 0 [0.00] | 0.0% (0/497) | 1 [0.21] | 0.2% (1/503)  |
|  Device Dislocation | 0 [0.00] | 0.0% (0/497) | 3 [0.64] | 0.6% (3/503)  |
|  Device Information Output Issue | 2 [0.43] | 0.4% (2/497) | 2 [0.43] | 0.4% (2/503)  |
|  Device Malfunction | 0 [0.00] | 0.0% (0/497) | 1 [0.21] | 0.2% (1/503)  |
|  Pyrexia | 0 [0.00] | 0.0% (0/497) | 1 [0.21] | 0.2% (1/503)  |
|  Vessel Puncture Site Pain | 1 [0.22] | 0.2% (1/497) | 1 [0.21] | 0.2% (1/503)  |
|  **Injury, Poisoning and Procedural Complications** | **2 [0.43]** | **0.4% (2/497)** | **0 [0.00]** | **0.0% (0/503)**  |
|  Arterial Injury | 1 [0.22] | 0.2% (1/497) | 0 [0.00] | 0.0% (0/503)  |
|  Laceration | 1 [0.22] | 0.2% (1/497) | 0 [0.00] | 0.0% (0/503)  |
|  **Nervous System Disorders** | **1 [0.22]** | **0.2% (1/497)** | **0 [0.00]** | **0.0% (0/503)**  |
|  Presyncope | 1 [0.22] | 0.2% (1/497) | 0 [0.00] | 0.0% (0/503)  |
|  **Respiratory, Thoracic and Mediastinal Disorders** | **3 [0.65]** | **0.6% (3/497)** | **0 [0.00]** | **0.0% (0/503)**  |
|  Hemoptysis | 3 [0.65] | 0.6% (3/497) | 0 [0.00] | 0.0% (0/503)  |
|  **Vascular Disorders** | **1 [0.22]** | **0.2% (1/497)** | **0 [0.00]** | **0.0% (0/503)**  |
|  Hypotension | 1 [0.22] | 0.2% (1/497) | 0 [0.00] | 0.0% (0/503)  |
|  **Total** | **16 [3.45]** | **3.0% (15/497)** | **20 [4.29]** | **4.0% (20/503)**  |

$^{1}$Rate is number of events per 100 subject years.

All ADEs occurred in NYHA Class II/III subjects prior to COVID-19.

### *Serious Adverse Events*

A serious adverse event (SAE) was defined as an adverse event not related to the use of the device but meeting seriousness criteria (requiring hospitalization or invasive intervention or resulting in a life-threatening illness or injury). A summary of non-device-related investigator-reported SAEs is provided in Table 13 below.

**Table 13. Summary of Serious Adverse Events (As Reported by Investigator)**

|  System Organ Class Preferred Term | Treatment (N=497) |   | Control (N=503)  |   |
| --- | --- | --- | --- | --- |
|   |  Events [Rate^{1}] | Percent of Subjects with Event | Events [Rate^{1}] | Percent of Subjects with Event  |
|  **Blood and Lymphatic System Disorders** | **11 [2.37]** | **1.6% (8/497)** | **8 [1.72]** | **1.4% (7/503)**  |
|  Anemia | 9 [1.94] | 1.2% (6/497) | 8 [1.72] | 1.4% (7/503)  |
|  Thrombocytopenia | 2 [0.43] | 0.4% (2/497) | 0 [0.00] | 0.0% (0/503)  |
|  **Cardiac Disorders** | **302 [65.2]** | **32.6% (162/497)** | **389 [83.4]** | **38.8% (195/503)**  |
|  Acute Myocardial Infarction | 0 [0.00] | 0.0% (0/497) | 1 [0.21] | 0.2% (1/503)  |
|  Angina Pectoris | 1 [0.22] | 0.2% (1/497) | 1 [0.21] | 0.2% (1/503)  |

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|  System Organ Class | Treatment (N=497) |   | Control (N=503)  |   |
| --- | --- | --- | --- | --- |
|   |  Events [Rate^{1}] | Percent of | Events [Rate^{1}] | Percent of  |
|  Angina Unstable | 0 [0.00] | 0.0% (0/497) | 1 [0.21] | 0.2% (1/503)  |
|  Aortic Valve Disease | 0 [0.00] | 0.0% (0/497) | 1 [0.21] | 0.2% (1/503)  |
|  Arrhythmia | 53 [11.4] | 9.5% (47/497) | 54 [11.6] | 9.1% (46/503)  |
|  Atrioventricular Block Complete | 0 [0.00] | 0.0% (0/497) | 1 [0.21] | 0.2% (1/503)  |
|  Cardiac Aneurysm | 0 [0.00] | 0.0% (0/497) | 1 [0.21] | 0.2% (1/503)  |
|  Cardiac Arrest | 3 [0.65] | 0.6% (3/497) | 4 [0.86] | 0.8% (4/503)  |
|  Cardiac Failure Congestive | 216 [46.6] | 26.2% (130/497) | 276 [59.2] | 30.8% (155/503)  |
|  Cardiac Perforation | 0 [0.00] | 0.0% (0/497) | 1 [0.21] | 0.2% (1/503)  |
|  Cardiac Valve Disease | 1 [0.22] | 0.2% (1/497) | 4 [0.86] | 0.6% (3/503)  |
|  Cardiogenic Shock | 8 [1.73] | 1.6% (8/497) | 6 [1.29] | 1.0% (5/503)  |
|  Cardiomyopathy | 1 [0.22] | 0.2% (1/497) | 0 [0.00] | 0.0% (0/503)  |
|  Coronary Artery Disease | 1 [0.22] | 0.2% (1/497) | 9 [1.93] | 1.6% (8/503)  |
|  Intracardiac Thrombus | 1 [0.22] | 0.2% (1/497) | 1 [0.21] | 0.2% (1/503)  |
|  Ischemic Cardiomyopathy | 1 [0.22] | 0.2% (1/497) | 1 [0.21] | 0.2% (1/503)  |
|  Mitral Valve Disease | 1 [0.22] | 0.2% (1/497) | 3 [0.64] | 0.4% (2/503)  |
|  Mitral Valve Incompetence | 1 [0.22] | 0.2% (1/497) | 0 [0.00] | 0.0% (0/503)  |
|  Myocardial Infarction | 11 [2.37] | 2.0% (10/497) | 16 [3.43] | 3.2% (16/503)  |
|  Pericardial Effusion | 1 [0.22] | 0.2% (1/497) | 3 [0.64] | 0.6% (3/503)  |
|  Pericarditis | 0 [0.00] | 0.0% (0/497) | 1 [0.21] | 0.2% (1/503)  |
|  Prinzmetal Angina | 0 [0.00] | 0.0% (0/497) | 2 [0.43] | 0.4% (2/503)  |
|  Restrictive Cardiomyopathy | 1 [0.22] | 0.2% (1/497) | 0 [0.00] | 0.0% (0/503)  |
|  Tachycardia | 1 [0.22] | 0.2% (1/497) | 2 [0.43] | 0.4% (2/503)  |
|  **Ear and Labyrinth Disorders** | **2 [0.43]** | **0.4% (2/497)** | **0 [0.00]** | **0.0% (0/503)**  |
|  Vertigo | 1 [0.22] | 0.2% (1/497) | 0 [0.00] | 0.0% (0/503)  |
|  Vertigo Positional | 1 [0.22] | 0.2% (1/497) | 0 [0.00] | 0.0% (0/503)  |
|  **Endocrine Disorders** | **2 [0.43]** | **0.4% (2/497)** | **0 [0.00]** | **0.0% (0/503)**  |
|  Hypothyroidism | 1 [0.22] | 0.2% (1/497) | 0 [0.00] | 0.0% (0/503)  |
|  Inappropriate Antidiuretic Hormone Secretion | 1 [0.22] | 0.2% (1/497) | 0 [0.00] | 0.0% (0/503)  |
|  **Gastrointestinal Disorders** | **29 [6.26]** | **4.8% (24/497)** | **33 [7.08]** | **5.0% (25/503)**  |
|  Abdominal Pain | 0 [0.00] | 0.0% (0/497) | 2 [0.43] | 0.4% (2/503)  |
|  Colitis | 1 [0.22] | 0.2% (1/497) | 0 [0.00] | 0.0% (0/503)  |
|  Colitis Ischemic | 1 [0.22] | 0.2% (1/497) | 0 [0.00] | 0.0% (0/503)  |
|  Colonic Stenosis | 1 [0.22] | 0.2% (1/497) | 0 [0.00] | 0.0% (0/503)  |
|  Constipation | 2 [0.43] | 0.4% (2/497) | 1 [0.21] | 0.2% (1/503)  |
|  Diarrhea | 2 [0.43] | 0.4% (2/497) | 1 [0.21] | 0.2% (1/503)  |
|  Duodenal Ulcer | 1 [0.22] | 0.2% (1/497) | 0 [0.00] | 0.0% (0/503)  |
|  Dysphagia | 0 [0.00] | 0.0% (0/497) | 1 [0.21] | 0.2% (1/503)  |
|  Gastritis | 1 [0.22] | 0.2% (1/497) | 1 [0.21] | 0.2% (1/503)  |
|  Gastrointestinal Hemorrhage | 10 [2.16] | 1.8% (9/497) | 20 [4.29] | 3.2% (16/503)  |
|  Gastrointestinal Necrosis | 1 [0.22] | 0.2% (1/497) | 0 [0.00] | 0.0% (0/503)  |
|  Gastroesophageal Reflux Disease | 1 [0.22] | 0.2% (1/497) | 0 [0.00] | 0.0% (0/503)  |
|  Hemorrhoidal Hemorrhage | 1 [0.22] | 0.2% (1/497) | 0 [0.00] | 0.0% (0/503)  |
|  Ileus | 0 [0.00] | 0.0% (0/497) | 1 [0.21] | 0.2% (1/503)  |
|  Impaired Gastric Emptying | 1 [0.22] | 0.2% (1/497) | 0 [0.00] | 0.0% (0/503)  |
|  Intestinal Ischemia | 0 [0.00] | 0.0% (0/497) | 1 [0.21] | 0.2% (1/503)  |

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|  System Organ Class | Treatment (N=497) |   | Control (N=503)  |   |
| --- | --- | --- | --- | --- |
|   |  Events [Rate^{1}] | Percent of | Events [Rate^{1}] | Percent of  |
|  Nausea | 1 [0.22] | 0.2% (1/497) | 0 [0.00] | 0.0% (0/503)  |
|  Pancreatic Mass | 0 [0.00] | 0.0% (0/497) | 1 [0.21] | 0.2% (1/503)  |
|  Pancreatitis | 2 [0.43] | 0.4% (2/497) | 0 [0.00] | 0.0% (0/503)  |
|  Pancreatitis Acute | 1 [0.22] | 0.2% (1/497) | 0 [0.00] | 0.0% (0/503)  |
|  Proctitis | 0 [0.00] | 0.0% (0/497) | 1 [0.21] | 0.2% (1/503)  |
|  Small Intestinal Obstruction | 1 [0.22] | 0.2% (1/497) | 2 [0.43] | 0.4% (2/503)  |
|  Spigelian Hernia | 1 [0.22] | 0.2% (1/497) | 0 [0.00] | 0.0% (0/503)  |
|  Vomiting | 0 [0.00] | 0.0% (0/497) | 1 [0.21] | 0.2% (1/503)  |
|  **General Disorders and Administration Site Conditions^{1}** | **49 [10.6]** | **8.2% (41/497)** | **34 [7.29]** | **6.2% (31/503)**  |
|  Accidental Death^{2} | 0 [0.00] | 0.0% (0/497) | 1 [0.21] | 0.2% (1/503)  |
|  Asthenia | 4 [0.86] | 0.8% (4/497) | 3 [0.64] | 0.6% (3/503)  |
|  Catheter Site Hematoma | 0 [0.00] | 0.0% (0/497) | 1 [0.21] | 0.2% (1/503)  |
|  Chest Pain | 32 [6.90] | 5.4% (27/497) | 25 [5.36] | 4.6% (23/503)  |
|  Death^{3} | 3 [0.65] | 0.6% (3/497) | 0 [0.00] | 0.0% (0/503)  |
|  Device Dislocation^{4} | 2 [0.43] | 0.4% (2/497) | 0 [0.00] | 0.0% (0/503)  |
|  Device Electrical Impedance Issue^{5} | 1 [0.22] | 0.2% (1/497) | 0 [0.00] | 0.0% (0/503)  |
|  Device Malfunction^{6} | 0 [0.00] | 0.0% (0/497) | 3 [0.64] | 0.6% (3/503)  |
|  Fatigue | 1 [0.22] | 0.2% (1/497) | 0 [0.00] | 0.0% (0/503)  |
|  Generalized Edema | 2 [0.43] | 0.2% (1/497) | 0 [0.00] | 0.0% (0/503)  |
|  Hypothermia | 1 [0.22] | 0.2% (1/497) | 0 [0.00] | 0.0% (0/503)  |
|  Implant Site Hemorrhage | 1 [0.22] | 0.2% (1/497) | 0 [0.00] | 0.0% (0/503)  |
|  Multi-Organ Failure | 1 [0.22] | 0.2% (1/497) | 0 [0.00] | 0.0% (0/503)  |
|  Polyp | 0 [0.00] | 0.0% (0/497) | 1 [0.21] | 0.2% (1/503)  |
|  Sudden Cardiac Death^{7} | 1 [0.22] | 0.2% (1/497) | 0 [0.00] | 0.0% (0/503)  |
|  **Hepatobiliary Disorders** | **4 [0.86]** | **0.8% (4/497)** | **4 [0.86]** | **0.8% (4/503)**  |
|  Cholangitis | 0 [0.00] | 0.0% (0/497) | 1 [0.21] | 0.2% (1/503)  |
|  Cholelithiasis | 1 [0.22] | 0.2% (1/497) | 0 [0.00] | 0.0% (0/503)  |
|  Hepatic Cirrhosis | 2 [0.43] | 0.4% (2/497) | 2 [0.43] | 0.4% (2/503)  |
|  Hepatic Function Abnormal | 0 [0.00] | 0.0% (0/497) | 1 [0.21] | 0.2% (1/503)  |
|  Ischemic Hepatitis | 1 [0.22] | 0.2% (1/497) | 0 [0.00] | 0.0% (0/503)  |
|  **Immune System Disorders** | **0 [0.00]** | **0.0% (0/497)** | **2 [0.43]** | **0.4% (2/503)**  |
|  Drug Hypersensitivity | 0 [0.00] | 0.0% (0/497) | 1 [0.21] | 0.2% (1/503)  |
|  Heart Transplant Rejection | 0 [0.00] | 0.0% (0/497) | 1 [0.21] | 0.2% (1/503)  |
|  **Infections and Infestations** | **99 [21.4]** | **15.3% (76/497)** | **113 [24.2]** | **16.9% (85/503)**  |
|  Abscess | 1 [0.22] | 0.2% (1/497) | 0 [0.00] | 0.0% (0/503)  |
|  Anal Abscess | 1 [0.22] | 0.2% (1/497) | 0 [0.00] | 0.0% (0/503)  |
|  Bronchitis | 2 [0.43] | 0.4% (2/497) | 7 [1.50] | 1.4% (7/503)  |
|  Cellulitis | 6 [1.29] | 1.0% (5/497) | 8 [1.72] | 1.4% (7/503)  |

$^{1}$ Administration Site Conditions refers to events associated with site at which the device is administered.

$^{2}$ Traumatic death in an accident.

$^{3}$ Unknown event leading to death.

$^{4}$ Hip prosthesis dislocation, unrelated to study device.

$^{5}$ Broken pacemaker lead, unrelated to study device.

$^{6}$ Cardiac pacemaker or ICD malfunction, unrelated to study device.

$^{7}$ Sudden cardiac death due to ischemic heart disease.

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|  System Organ Class | Treatment (N=497) |   | Control (N=503)  |   |
| --- | --- | --- | --- | --- |
|   |  Events [Rate^{1}] | Percent of | Events [Rate^{1}] | Percent of  |
|  Central Nervous System Abscess | 0 [0.00] | 0.0% (0/497) | 1 [0.21] | 0.2% (1/503)  |
|  Clostridial Infection | 1 [0.22] | 0.2% (1/497) | 0 [0.00] | 0.0% (0/503)  |
|  Corona Virus Infection | 1 [0.22] | 0.2% (1/497) | 2 [0.43] | 0.4% (2/503)  |
|  Cystitis | 0 [0.00] | 0.0% (0/497) | 1 [0.21] | 0.2% (1/503)  |
|  Endocarditis | 0 [0.00] | 0.0% (0/497) | 1 [0.21] | 0.2% (1/503)  |
|  Gastroenteritis | 1 [0.22] | 0.2% (1/497) | 0 [0.00] | 0.0% (0/503)  |
|  Gastroenteritis Viral | 1 [0.22] | 0.2% (1/497) | 0 [0.00] | 0.0% (0/503)  |
|  Gastrointestinal Infection | 1 [0.22] | 0.2% (1/497) | 0 [0.00] | 0.0% (0/503)  |
|  Herpes Zoster | 0 [0.00] | 0.0% (0/497) | 1 [0.21] | 0.2% (1/503)  |
|  Infection | 29 [6.26] | 5.4% (27/497) | 39 [8.36] | 6.8% (34/503)  |
|  Influenza | 3 [0.65] | 0.6% (3/497) | 1 [0.21] | 0.2% (1/503)  |
|  Intervertebral Discitis | 1 [0.22] | 0.2% (1/497) | 0 [0.00] | 0.0% (0/503)  |
|  Mycotic Aneurysm | 1 [0.22] | 0.2% (1/497) | 0 [0.00] | 0.0% (0/503)  |
|  Pneumonia | 27 [5.83] | 4.8% (24/497) | 32 [6.86] | 5.8% (29/503)  |
|  Sepsis | 18 [3.88] | 3.4% (17/497) | 10 [2.14] | 2.0% (10/503)  |
|  Septic Shock | 0 [0.00] | 0.0% (0/497) | 4 [0.86] | 0.8% (4/503)  |
|  Upper Respiratory Tract Infection | 1 [0.22] | 0.2% (1/497) | 2 [0.43] | 0.4% (2/503)  |
|  Urinary Tract Infection | 3 [0.65] | 0.6% (3/497) | 4 [0.86] | 0.8% (4/503)  |
|  Wound Infection | 1 [0.22] | 0.2% (1/497) | 0 [0.00] | 0.0% (0/503)  |
|  **Injury, Poisoning and Procedural Complications** | **15 [3.24]** | **2.8% (14/497)** | **16 [3.43]** | **3.0% (15/503)**  |
|  Cervical Vertebral Fracture | 2 [0.43] | 0.4% (2/497) | 0 [0.00] | 0.0% (0/503)  |
|  Fall | 4 [0.86] | 0.8% (4/497) | 6 [1.29] | 1.0% (5/503)  |
|  Femur Fracture | 1 [0.22] | 0.2% (1/497) | 0 [0.00] | 0.0% (0/503)  |
|  Hip Fracture | 2 [0.43] | 0.4% (2/497) | 3 [0.64] | 0.6% (3/503)  |
|  Iliotibial Band Syndrome | 1 [0.22] | 0.2% (1/497) | 0 [0.00] | 0.0% (0/503)  |
|  Joint Injury | 1 [0.22] | 0.2% (1/497) | 1 [0.21] | 0.2% (1/503)  |
|  Laceration | 1 [0.22] | 0.2% (1/497) | 0 [0.00] | 0.0% (0/503)  |
|  Multiple Fractures | 0 [0.00] | 0.0% (0/497) | 1 [0.21] | 0.2% (1/503)  |
|  Pelvic Fracture | 0 [0.00] | 0.0% (0/497) | 1 [0.21] | 0.2% (1/503)  |
|  Road Traffic Accident^{8} | 0 [0.00] | 0.0% (0/497) | 1 [0.21] | 0.2% (1/503)  |
|  Spinal Compression Fracture | 1 [0.22] | 0.2% (1/497) | 1 [0.21] | 0.2% (1/503)  |
|  Spinal Fracture | 0 [0.00] | 0.0% (0/497) | 1 [0.21] | 0.2% (1/503)  |
|  Subdural Hematoma | 2 [0.43] | 0.4% (2/497) | 0 [0.00] | 0.0% (0/503)  |
|  Vascular Pseudoaneurysm | 0 [0.00] | 0.0% (0/497) | 1 [0.21] | 0.2% (1/503)  |
|  **Investigations** | **21 [4.53]** | **3.8% (19/497)** | **21 [4.50]** | **3.0% (15/503)**  |
|  Anticoagulation Drug Level Below Therapeutic | 1 [0.22] | 0.2% (1/497) | 1 [0.21] | 0.2% (1/503)  |
|  Blood Creatinine Increased | 18 [3.88] | 3.4% (17/497) | 17 [3.65] | 2.6% (13/503)  |
|  International Normalized Ratio Decreased | 1 [0.22] | 0.2% (1/497) | 0 [0.00] | 0.0% (0/503)  |
|  International Normalized Ratio Increased | 0 [0.00] | 0.0% (0/497) | 1 [0.21] | 0.2% (1/503)  |
|  Left Ventricular End-Diastolic Pressure Increased | 0 [0.00] | 0.0% (0/497) | 1 [0.21] | 0.2% (1/503)  |

$^{8}$ Multiple injuries and surgical procedures resulting from a motor vehicle accident.

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|  System Organ Class | Treatment (N=497) |   | Control (N=503)  |   |
| --- | --- | --- | --- | --- |
|   |  Events [Rate^{1}] | Percent of | Events [Rate^{1}] | Percent of  |
|  Transaminases Increased | 0 [0.00] | 0.0% (0/497) | 1 [0.21] | 0.2% (1/503)  |
|  Troponin Increased | 1 [0.22] | 0.2% (1/497) | 0 [0.00] | 0.0% (0/503)  |
|  **Metabolism and Nutrition Disorders** | **25 [5.39]** | **4.8% (24/497)** | **24 [5.15]** | **4.0% (20/503)**  |
|  Dehydration | 8 [1.73] | 1.6% (8/497) | 2 [0.43] | 0.4% (2/503)  |
|  Diabetes Mellitus | 1 [0.22] | 0.2% (1/497) | 0 [0.00] | 0.0% (0/503)  |
|  Diabetic Ketoacidosis | 0 [0.00] | 0.0% (0/497) | 2 [0.43] | 0.4% (2/503)  |
|  Fluid Overload | 2 [0.43] | 0.4% (2/497) | 2 [0.43] | 0.2% (1/503)  |
|  Gout | 2 [0.43] | 0.4% (2/497) | 2 [0.43] | 0.4% (2/503)  |
|  Hyperglycemia | 5 [1.08] | 1.0% (5/497) | 5 [1.07] | 0.8% (4/503)  |
|  Hyperkalemia | 1 [0.22] | 0.2% (1/497) | 1 [0.21] | 0.2% (1/503)  |
|  Hypoglycemia | 2 [0.43] | 0.4% (2/497) | 4 [0.86] | 0.8% (4/503)  |
|  Hypokalemia | 1 [0.22] | 0.2% (1/497) | 3 [0.64] | 0.6% (3/503)  |
|  Hypovolemia | 1 [0.22] | 0.2% (1/497) | 3 [0.64] | 0.6% (3/503)  |
|  Lactic Acidosis | 1 [0.22] | 0.2% (1/497) | 0 [0.00] | 0.0% (0/503)  |
|  Type 2 Diabetes Mellitus | 1 [0.22] | 0.2% (1/497) | 0 [0.00] | 0.0% (0/503)  |
|  **Musculoskeletal and Connective Tissue Disorders** | **14 [3.02]** | **2.4% (12/497)** | **4 [0.86]** | **0.8% (4/503)**  |
|  Arthralgia | 2 [0.43] | 0.4% (2/497) | 0 [0.00] | 0.0% (0/503)  |
|  Back Pain | 5 [1.08] | 0.6% (3/497) | 0 [0.00] | 0.0% (0/503)  |
|  Compartment Syndrome | 1 [0.22] | 0.2% (1/497) | 0 [0.00] | 0.0% (0/503)  |
|  Fibromyalgia | 0 [0.00] | 0.0% (0/497) | 1 [0.21] | 0.2% (1/503)  |
|  Muscular Weakness | 0 [0.00] | 0.0% (0/497) | 1 [0.21] | 0.2% (1/503)  |
|  Myopathy | 1 [0.22] | 0.2% (1/497) | 0 [0.00] | 0.0% (0/503)  |
|  Osteoarthritis | 2 [0.43] | 0.4% (2/497) | 1 [0.21] | 0.2% (1/503)  |
|  Rhabdomyolysis | 1 [0.22] | 0.2% (1/497) | 1 [0.21] | 0.2% (1/503)  |
|  Rheumatoid Arthritis | 1 [0.22] | 0.2% (1/497) | 0 [0.00] | 0.0% (0/503)  |
|  Spinal Osteoarthritis | 1 [0.22] | 0.2% (1/497) | 0 [0.00] | 0.0% (0/503)  |
|  **Neoplasms Benign, Malignant and Unspecified (Incl Cysts and Polyps)** | **2 [0.43]** | **0.4% (2/497)** | **2 [0.43]** | **0.4% (2/503)**  |
|  Colon Cancer | 1 [0.22] | 0.2% (1/497) | 0 [0.00] | 0.0% (0/503)  |
|  Lung Neoplasm | 0 [0.00] | 0.0% (0/497) | 1 [0.21] | 0.2% (1/503)  |
|  Esophageal Adenocarcinoma | 1 [0.22] | 0.2% (1/497) | 0 [0.00] | 0.0% (0/503)  |
|  Squamous Cell Carcinoma | 0 [0.00] | 0.0% (0/497) | 1 [0.21] | 0.2% (1/503)  |
|  **Nervous System Disorders** | **42 [9.06]** | **7.4% (37/497)** | **28 [6.00]** | **4.8% (24/503)**  |
|  Carotid Artery Stenosis | 1 [0.22] | 0.2% (1/497) | 1 [0.21] | 0.2% (1/503)  |
|  Cerebrovascular Accident | 12 [2.59] | 2.2% (11/497) | 6 [1.29] | 1.2% (6/503)  |
|  Cerebrovascular Disorder | 0 [0.00] | 0.0% (0/497) | 1 [0.21] | 0.2% (1/503)  |
|  Cervicogenic Headache | 0 [0.00] | 0.0% (0/497) | 1 [0.21] | 0.2% (1/503)  |
|  CNS Ventriculitis | 0 [0.00] | 0.0% (0/497) | 1 [0.21] | 0.2% (1/503)  |
|  Complicated Migraine | 0 [0.00] | 0.0% (0/497) | 1 [0.21] | 0.2% (1/503)  |
|  Convulsion | 0 [0.00] | 0.0% (0/497) | 1 [0.21] | 0.2% (1/503)  |
|  Dizziness | 4 [0.86] | 0.8% (4/497) | 4 [0.86] | 0.8% (4/503)  |
|  Encephalopathy | 0 [0.00] | 0.0% (0/497) | 1 [0.21] | 0.2% (1/503)  |
|  Hemorrhage Intracranial | 1 [0.22] | 0.2% (1/497) | 0 [0.00] | 0.0% (0/503)  |
|  Headache | 1 [0.22] | 0.2% (1/497) | 0 [0.00] | 0.0% (0/503)  |

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{28}

|  System Organ Class | Treatment (N=497) |   | Control (N=503)  |   |
| --- | --- | --- | --- | --- |
|   |  Events [Rate^{1}] | Percent of | Events [Rate^{1}] | Percent of  |
|  Hepatic Encephalopathy | 0 [0.00] | 0.0% (0/497) | 1 [0.21] | 0.2% (1/503)  |
|  Hypoesthesia | 1 [0.22] | 0.2% (1/497) | 0 [0.00] | 0.0% (0/503)  |
|  Metabolic Encephalopathy | 1 [0.22] | 0.2% (1/497) | 1 [0.21] | 0.2% (1/503)  |
|  Myoclonus | 1 [0.22] | 0.2% (1/497) | 0 [0.00] | 0.0% (0/503)  |
|  Partial Seizures | 1 [0.22] | 0.2% (1/497) | 0 [0.00] | 0.0% (0/503)  |
|  Presyncope | 3 [0.65] | 0.6% (3/497) | 0 [0.00] | 0.0% (0/503)  |
|  Sciatica | 1 [0.22] | 0.2% (1/497) | 0 [0.00] | 0.0% (0/503)  |
|  Subarachnoid Hemorrhage | 1 [0.22] | 0.2% (1/497) | 0 [0.00] | 0.0% (0/503)  |
|  Syncope | 12 [2.59] | 2.4% (12/497) | 8 [1.72] | 1.6% (8/503)  |
|  Transient Ischemic Attack | 2 [0.43] | 0.4% (2/497) | 0 [0.00] | 0.0% (0/503)  |
|  Vertebral Artery Stenosis | 0 [0.00] | 0.0% (0/497) | 1 [0.21] | 0.2% (1/503)  |
|  **Psychiatric Disorders** | **3 [0.65]** | **0.6% (3/497)** | **6 [1.29]** | **1.0% (5/503)**  |
|  Depression | 0 [0.00] | 0.0% (0/497) | 3 [0.64] | 0.4% (2/503)  |
|  Mental Disorder | 1 [0.22] | 0.2% (1/497) | 0 [0.00] | 0.0% (0/503)  |
|  Mental Status Changes | 2 [0.43] | 0.4% (2/497) | 3 [0.64] | 0.6% (3/503)  |
|  **Renal and Urinary Disorders** | **29 [6.26]** | **4.8% (24/497)** | **41 [8.79]** | **7.6% (38/503)**  |
|  Hematuria | 0 [0.00] | 0.0% (0/497) | 1 [0.21] | 0.2% (1/503)  |
|  Nephrolithiasis | 0 [0.00] | 0.0% (0/497) | 1 [0.21] | 0.2% (1/503)  |
|  Obstructive Uropathy | 0 [0.00] | 0.0% (0/497) | 1 [0.21] | 0.2% (1/503)  |
|  Renal Failure | 3 [0.65] | 0.6% (3/497) | 1 [0.21] | 0.2% (1/503)  |
|  Renal Failure Acute | 21 [4.53] | 3.6% (18/497) | 29 [6.22] | 5.6% (28/503)  |
|  Renal Failure Chronic | 2 [0.43] | 0.4% (2/497) | 6 [1.29] | 1.0% (5/503)  |
|  Urinary Retention | 3 [0.65] | 0.6% (3/497) | 2 [0.43] | 0.4% (2/503)  |
|  **Reproductive System and Breast Disorders** | **1 [0.22]** | **0.2% (1/497)** | **1 [0.21]** | **0.2% (1/503)**  |
|  Benign Prostatic Hyperplasia | 1 [0.22] | 0.2% (1/497) | 0 [0.00] | 0.0% (0/503)  |
|  Vaginal Hemorrhage | 0 [0.00] | 0.0% (0/497) | 1 [0.21] | 0.2% (1/503)  |
|  **Respiratory, Thoracic and Mediastinal Disorders** | **42 [9.06]** | **6.8% (34/497)** | **52 [11.2]** | **7.6% (38/503)**  |
|  Acute Respiratory Failure | 3 [0.65] | 0.6% (3/497) | 8 [1.72] | 1.6% (8/503)  |
|  Asthma | 1 [0.22] | 0.2% (1/497) | 1 [0.21] | 0.2% (1/503)  |
|  Chronic Obstructive Pulmonary Disease | 13 [2.80] | 1.8% (9/497) | 24 [5.15] | 2.8% (14/503)  |
|  Chronic Respiratory Disease | 0 [0.00] | 0.0% (0/497) | 1 [0.21] | 0.2% (1/503)  |
|  Cough | 1 [0.22] | 0.2% (1/497) | 0 [0.00] | 0.0% (0/503)  |
|  Dyspnea | 7 [1.51] | 1.4% (7/497) | 8 [1.72] | 1.6% (8/503)  |
|  Epistaxis | 2 [0.43] | 0.4% (2/497) | 0 [0.00] | 0.0% (0/503)  |
|  Hemoptysis | 0 [0.00] | 0.0% (0/497) | 1 [0.21] | 0.2% (1/503)  |
|  Hypoxia | 1 [0.22] | 0.2% (1/497) | 0 [0.00] | 0.0% (0/503)  |
|  Pleural Effusion | 5 [1.08] | 0.8% (4/497) | 4 [0.86] | 0.8% (4/503)  |
|  Pneumothorax | 0 [0.00] | 0.0% (0/497) | 1 [0.21] | 0.2% (1/503)  |
|  Pulmonary Alveolar Hemorrhage | 1 [0.22] | 0.2% (1/497) | 0 [0.00] | 0.0% (0/503)  |
|  Pulmonary Embolism | 1 [0.22] | 0.2% (1/497) | 1 [0.21] | 0.2% (1/503)  |
|  Pulmonary Hypertension | 2 [0.43] | 0.4% (2/497) | 0 [0.00] | 0.0% (0/503)  |
|  Respiratory Failure | 4 [0.86] | 0.8% (4/497) | 3 [0.64] | 0.6% (3/503)  |
|  Sleep Apnea Syndrome | 1 [0.22] | 0.2% (1/497) | 0 [0.00] | 0.0% (0/503)  |

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|  System Organ Class | Treatment (N=497) |   | Control (N=503)  |   |
| --- | --- | --- | --- | --- |
|   |  Events [Rate^{1}] | Percent of | Events [Rate^{1}] | Percent of  |
|  Skin and Subcutaneous Tissue Disorders | 2 [0.43] | 0.4% (2/497) | 0 [0.00] | 0.0% (0/503)  |
|  Angioedema | 1 [0.22] | 0.2% (1/497) | 0 [0.00] | 0.0% (0/503)  |
|  Hyperhidrosis | 1 [0.22] | 0.2% (1/497) | 0 [0.00] | 0.0% (0/503)  |
|  Surgical and Medical Procedures | 0 [0.00] | 0.0% (0/497) | 1 [0.21] | 0.2% (1/503)  |
|  Cardiac Pacemaker Replacement | 0 [0.00] | 0.0% (0/497) | 1 [0.21] | 0.2% (1/503)  |
|  Vascular Disorders | 35 [7.55] | 5.0% (25/497) | 20 [4.29] | 3.6% (18/503)  |
|  Aortic Aneurysm | 1 [0.22] | 0.2% (1/497) | 0 [0.00] | 0.0% (0/503)  |
|  Bleeding Varicose Vein | 2 [0.43] | 0.2% (1/497) | 0 [0.00] | 0.0% (0/503)  |
|  Embolism | 2 [0.43] | 0.4% (2/497) | 0 [0.00] | 0.0% (0/503)  |
|  Extremity Necrosis | 1 [0.22] | 0.2% (1/497) | 0 [0.00] | 0.0% (0/503)  |
|  Hematoma | 2 [0.43] | 0.4% (2/497) | 0 [0.00] | 0.0% (0/503)  |
|  Hypertension | 1 [0.22] | 0.2% (1/497) | 0 [0.00] | 0.0% (0/503)  |
|  Hypertensive Crisis | 1 [0.22] | 0.2% (1/497) | 2 [0.43] | 0.4% (2/503)  |
|  Hypotension | 14 [3.02] | 2.6% (13/497) | 11 [2.36] | 2.2% (11/503)  |
|  Lymphoedema | 2 [0.43] | 0.2% (1/497) | 0 [0.00] | 0.0% (0/503)  |
|  Orthostatic Hypotension | 1 [0.22] | 0.2% (1/497) | 2 [0.43] | 0.4% (2/503)  |
|  Peripheral Arterial Occlusive Disease | 1 [0.22] | 0.2% (1/497) | 0 [0.00] | 0.0% (0/503)  |
|  Peripheral Vascular Disorder | 1 [0.22] | 0.2% (1/497) | 2 [0.43] | 0.4% (2/503)  |
|  Shock | 1 [0.22] | 0.2% (1/497) | 0 [0.00] | 0.0% (0/503)  |
|  Thrombosis | 5 [1.08] | 0.8% (4/497) | 3 [0.64] | 0.4% (2/503)  |
|  Total | 729 [157.3] | 56.7% (282/497) | 799 [171.3] | 53.3% (268/503)  |

$^{1}$Rate is number of events per 100 subject years.

### 3. Subgroup Analyses

The primary endpoint was evaluated in subgroups of NYHA Class, qualifying category, ejection fraction, age, sex, race, ethnicity, ischemic cardiomyopathy, and prior cardiac device implant. Figures 9 and 10 show the forest plots for all follow-up and pre-COVID 19, respectively. Women notably derived more benefit than men with 36% reduction in primary endpoint events. African American subjects also gained a larger treatment effect, though minorities (African American and Hispanic subjects) in both the Treatment group and the Control group experienced high rates of primary endpoint events.

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Figure 9. Subgroup Analyses – All Follow-up

|  Subgroup | N | Treatment Events (Rate) | Control Events (Rate) |  | HR (95% CI) | Subgroup p-value | Interaction p-value  |
| --- | --- | --- | --- | --- | --- | --- | --- |
|  Overall | 1000 | 253 (0.563) | 289 (0.640) |  | 0.88 (0.74, 1.05) | 0.16 |   |
|  NYHA Class  |   |   |   |   |   |   |   |
|  NYHA Class II | 296 | 53 (0.401) | 75 (0.554) |  | 0.72 (0.50, 1.05) | 0.086 | 0.095  |
|  NYHA Class III* | 650 | 171 (0.589) | 198 (0.677) |  | 0.87 (0.70, 1.08) | 0.21 |   |
|  NYHA Class IV | 54 | 29 (1.527) | 16 (0.910) |  | 1.68 (0.88, 3.20) | 0.12 |   |
|  NYHA Class II and III | 946 | 224 (0.525) | 273 (0.633) |  | 0.83 (0.69, 1.00) | 0.050 | \( 0.046^† \)  |
|  Qualification  |   |   |   |   |   |   |   |
|  HFH in year prior | 557 | 181 (0.757) | 212 (0.820) |  | 0.92 (0.74, 1.14) | 0.47 | 0.71  |
|  Elevated BNP/NT pro-BNP only | 442 | 72 (0.350) | 77 (0.409) |  | 0.86 (0.62, 1.19) | 0.36 |   |
|  Ejection Fraction  |   |   |   |   |   |   |   |
|  HFpEF (EF>40%)* | 469 | 90 (0.442) | 114 (0.518) |  | 0.85 (0.64, 1.14) | 0.28 | 0.90  |
|  HFrEF (EF≤40%)* | 531 | 163 (0.677) | 175 (0.773) |  | 0.88 (0.70, 1.10) | 0.26 |   |
|  Age  |   |   |   |   |   |   |   |
|  Below Median (<71 Years)* | 492 | 156 (0.730) | 173 (0.758) |  | 0.96 (0.76, 1.22) | 0.75 | 0.30  |
|  Median and Above (≥71 Years)* | 508 | 97 (0.420) | 116 (0.529) |  | 0.79 (0.60, 1.05) | 0.11 |   |
|  Sex  |   |   |   |   |   |   |   |
|  Men* | 625 | 178 (0.656) | 171 (0.625) |  | 1.05 (0.84, 1.31) | 0.67 | 0.010  |
|  Women* | 375 | 75 (0.434) | 118 (0.681) |  | 0.64 (0.47, 0.87) | 0.004 |   |
|  Race  |   |   |   |   |   |   |   |
|  Caucasian* | 807 | 189 (0.516) | 194 (0.531) | ![img-9.jpeg](img-9.jpeg) | 0.97 (0.79, 1.20) | 0.78 | 0.095  |
|  African American* | 179 | 60 (0.811) | 94 (1.184) |  | 0.68 (0.48, 0.97) | 0.035 |   |
|  Ethnicity  |   |   |   |   |   |   |   |
|  Hispanic* | 33 | 18 (1.257) | 21 (1.383) |  | 0.91 (0.45, 1.83) | 0.79 | 0.95  |
|  Non-Hispanic* | 960 | 232 (0.544) | 264 (0.615) |  | 0.88 (0.73, 1.07) | 0.20 |   |
|  Ischemic Cardiomyopathy  |   |   |   |   |   |   |   |
|  Ischemic* | 397 | 99 (0.545) | 112 (0.670) |  | 0.81 (0.61, 1.08) | 0.16 | 0.40  |
|  Non-Ischemic* | 560 | 142 (0.578) | 160 (0.607) |  | 0.95 (0.75, 1.21) | 0.69 |   |
|  Device Implant  |   |   |   |   |   |   |   |
|  With CRT-D/CRT-P/ICD* | 562 | 162 (0.633) | 188 (0.759) |  | 0.83 (0.67, 1.04) | 0.11 | 0.48  |
|  Without CRT-D/CRT-P/ICD* | 438 | 91 (0.482) | 101 (0.508) |  | 0.95 (0.71, 1.28) | 0.73 |   |

*Pre-specified subgroup

\( ^{\dagger} \) Interaction p-value testing Randomization Group by NYHA Class II and III vs. Class IV

←Treatment Better Control Better→

PMA P100045/S056: FDA Summary of Safety and Effectiveness Data

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Figure 10. Subgroup Analyses – Prior to COVID-19

|  Subgroup | N | Treatment Events (Rate) | Control Events (Rate) |  | HR (95% CI) | Interaction p-value  |
| --- | --- | --- | --- | --- | --- | --- |
|  Overall | 1000 | 177 (0.595) | 224 (0.730) |  | 0.81 (0.66, 1.00) |   |
|  NYHA Class  |   |   |   |   |   |   |
|  NYHA Class II | 296 | 43 (0.393) | 70 (0.591) |  | 0.67 (0.45, 0.99) | 0.074  |
|  NYHA Class III | 650 | 114 (0.552) | 141 (0.686) |  | 0.80 (0.62, 1.04) |   |
|  NYHA Class IV | 54 | 20 (3.123) | 13 (1.632) |  | 1.91 (0.88, 4.18) |   |
|  NYHA Class II and III | 946 | 157 (0.497) | 211 (0.653) |  | 0.76 (0.61, 0.95) | 0.035*  |
|  Qualification  |   |   |   |   |   |   |
|  HFH in year prior | 557 | 133 (0.771) | 166 (0.905) |  | 0.85 (0.67, 1.09) | 0.58  |
|  Elevated BNP/NT pro-BNP only | 442 | 44 (0.358) | 58 (0.474) |  | 0.76 (0.51, 1.13) |   |
|  Ejection Fraction  |   |   |   |   |   |   |
|  HFpEF (EF>40%) | 469 | 57 (0.401) | 85 (0.551) |  | 0.73 (0.51, 1.03) | 0.50  |
|  HFrEF (EF≤40%) | 531 | 120 (0.738) | 139 (0.870) |  | 0.85 (0.65, 1.10) |   |
|  Age  |   |   |   |   |   |   |
|  Below Median (<71 Years) | 492 | 112 (0.746) | 130 (0.820) |  | 0.91 (0.69, 1.19) | 0.22  |
|  Median and Above (≥71 Years) | 508 | 65 (0.442) | 94 (0.635) |  | 0.70 (0.50, 0.97) |   |
|  Sex  |   |   |   |   |   |   |
|  Men | 625 | 121 (0.687) | 139 (0.763) |  | 0.90 (0.70, 1.17) | 0.21  |
|  Women | 375 | 56 (0.462) | 85 (0.683) |  | 0.68 (0.48, 0.96) |   |
|  Race  |   |   |   |   |   |   |
|  White | 807 | 135 (0.607) | 154 (0.673) | ![img-10.jpeg](img-10.jpeg) | 0.90 (0.71, 1.15) | 0.091  |
|  Black | 179 | 38 (0.721) | 70 (1.221) |  | 0.59 (0.39, 0.89) |   |
|  Ethnicity  |   |   |   |   |   |   |
|  Hispanic | 33 | 17 (1.575) | 19 (1.860) |  | 0.85 (0.41, 1.76) | 0.84  |
|  Non-Hispanic | 960 | 157 (0.586) | 202 (0.726) |  | 0.81 (0.65, 1.01) |   |
|  Ischemic Cardiomyopathy  |   |   |   |   |   |   |
|  Ischemic | 397 | 83 (0.682) | 87 (0.760) |  | 0.90 (0.65, 1.24) | 0.61  |
|  Non-Ischemic | 560 | 91 (0.526) | 125 (0.658) |  | 0.80 (0.60, 1.06) |   |
|  Device Implant  |   |   |   |   |   |   |
|  With CRT-D/CRT-P/ICD | 562 | 117 (0.776) | 144 (0.945) |  | 0.82 (0.63, 1.06) | 0.92  |
|  Without CRT-D/CRT-P/ICD | 438 | 60 (0.424) | 80 (0.535) |  | 0.79 (0.56, 1.12) |   |
|   |  |  |  | 0.5 1 2 4 |  |   |

*Interaction p-value testing Randomization Group by NYHA Class II and III vs. Class IV

Within the subgroup analyses, an interaction was observed for NYHA class, with the subgroup of NYHA Class IV patients (N = 54) demonstrating a different treatment effect than NYHA Class II and/or III patients. NYHA Class II/III patients overall demonstrated a 24% reduction in primary endpoint events prior to COVID-19 (HR 0.76, 95% CI 0.61-0.95) while NYHA Class IV patients did worse with hemodynamic-guided HF therapy during the same period (HR 1.91, CI 0.88-4.18). The NYHA Class sensitivity analysis demonstrated an interaction p-value of p=0.035, and separate analysis for each NYHA Class is provided below.

### NYHA Class II

The baseline demographics and key characteristics for the NYHA Class II patients in the Treatment group and the Control group were balanced and listed in

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Table 14 below.

**Table 14. Demographics and Baseline Assessments – NYHA Class II Subjects**

|   | Treatment (N=146) | Control (N=150)  |
| --- | --- | --- |
|  **Age - yr** | 69.8 ± 10.9 (146) | 69.8 ± 10.5 (150)  |
|  **Female Sex** | 33.6% (49/146) | 34.0% (51/150)  |
|  **Race** |  |   |
|  White | 84.2% (123/146) | 82.0% (123/150)  |
|  Black | 15.1% (22/146) | 17.3% (26/150)  |
|  Other | 0.7% (1/146) | 0.7% (1/150)  |
|  **Ethnicity** |  |   |
|  Hispanic | 2.7% (4/146) | 4.0% (6/150)  |
|  Non-Hispanic | 95.2% (139/146) | 96.0% (144/150)  |
|  Unknown | 2.1% (3/146) | 0.0% (0/150)  |
|  **Body mass index - kg/m^{2}** | 30.7 ± 7.3 (146) | 32.5 ± 7.4 (150)  |
|  **Medical History** |  |   |
|  Ischemic etiology | 43.2% (63/146) | 45.3% (68/150)  |
|  Diabetes | 49.3% (72/146) | 44.7% (67/150)  |
|  Atrial flutter or fibrillation | 56.8% (83/146) | 58.0% (87/150)  |
|  **Vital Signs and Hemodynamic Analyses** |  |   |
|  Left ventricular ejection fraction - % | 39.2 ± 17.2 (146) | 39.8 ± 16.1 (150)  |
|  Left ventricular ejection fraction > 40% | 42.5% (62/146) | 44.0% (66/150)  |
|  Pulmonary capillary wedge pressure - mmHg | 16.9 ± 8.2 (145) | 17.7 ± 8.4 (150)  |
|  Cardiac output - L/min | 4.61 ± 1.30 (146) | 4.51 ± 1.10 (150)  |
|  Cardiac index - L/min/m^{2} | 2.27 ± 0.61 (146) | 2.14 ± 0.48 (150)  |
|  **Laboratory Analyses** |  |   |
|  Serum creatinine level - μmol/L | 123.1 ± 40.7 (146) | 128.3 ± 44.7 (144)  |
|  Estimated glomerular filtration rate - ml/min/1.73m^{2} | 56.7 ± 21.5 (146) | 54.6 ± 19.2 (143)  |
|  B-type natriuretic peptide level - pg/mL | 472.8 ± 480.3 (61) | 525.4 ± 727.7 (69)  |
|  N-terminal pro-B-type natriuretic peptide level - pg/mL | 2526 ± 3842 (76) | 1537 ± 985 (72)  |
|  **Treatment History** |  |   |
|  Previous cardiac resynchronization therapy | 26.7% (39/146) | 35.3% (53/150)  |
|  Previous implantation of defibrillator | 49.3% (72/146) | 40.0% (60/150)  |
|  **Guideline-Directed Medical Therapy** |  |   |
|  ACE-Inhibitor or ARB or ARNi | 69.2% (101/146) | 70.0% (105/150)  |
|  ARNi | 32.9% (48/146) | 30.0% (45/150)  |
|  Beta Blocker | 89.7% (131/146) | 91.3% (137/150)  |
|  Mineralocorticoid Receptor Antagonist | 43.2% (63/146) | 33.3% (50/150)  |
|  Diuretic | 90.4% (132/146) | 93.3% (140/150)  |
|  Hydralazine | 11.6% (17/146) | 20.0% (30/150)  |
|  Nitrate | 17.8% (26/146) | 16.7% (25/150)  |
|  SGLT2 Inhibitor | 2.2% (1/46) | 0.0% (0/41)  |
|  **Enrollment Type** |  |   |
|  Heart failure hospitalization in year prior only | 32.2% (47/146) | 32.7% (49/150)  |
|  Elevated natriuretic peptide level in 30 day prior only | 50.7% (74/146) | 49.3% (74/150)  |
|  Heart failure hospitalization in year prior and elevated natriuretic peptide level in 30 day prior | 17.1% (25/146) | 18.0% (27/150)  |

PMA P100045/S056: FDA Summary of Safety and Effectiveness Data

{33}

Patient Reported Outcomes

KCCQ-12 at Baseline - Overall Summary Score

69.7 ± 20.7 (145)

66.4 ± 20.5 (147)

6MHW as Baseline - n

285.5 ± 111.3 (142)

264.8 ± 120.3 (146)

Continuous Variables: Mean ± SD (n); Categorical Variables: Percent (n/N)

The primary endpoint event rates and components for NYHA Class II subjects for the full follow-up and prior to COVID-19 are presented in Table 15 below.

Before the pandemic, there were 43 primary endpoint events in the Treatment group compared with 70 events in the Control group, representing a 33% reduction in the 12-month rate of primary endpoint events (0.393 events per patient in the Treatment group vs. 0.591 events per patient in the Control group, HR 0.67).

Table 15. Primary Endpoint and Components – NYHA Class II Subjects

|  Endpoint^{1} | Treatment (N=146) Events (Rate^{2}) | Control (N=150) Events (Rate^{2}) | Hazard Ratio (95% CI)^{3}  |
| --- | --- | --- | --- |
|  **Full Follow-Up**  |   |   |   |
|  Heart Failure Hospitalization + ED/OP + Death (Primary Endpoint) | 53 (0.401) | 75 (0.554) | 0.72 (0.50, 1.05)  |
|  Heart Failure Hospitalization + ED/OP | 42 (0.317) | 67 (0.493) | 0.64 (0.43, 0.96)  |
|  Heart Failure Hospitalization | 39 (0.298) | 56 (0.417) | 0.71 (0.47, 1.09)  |
|  HF Emergency Department/Hospital Outpatient Visit (ED/OP) | 3 (0.025) | 11 (0.089) | 0.28 (0.08, 0.99)  |
|  Death | 11 (0.086) | 8 (0.061) | 1.39 (0.56, 3.46)  |
|  **Prior to COVID-19** |   |   | COVID-19 Interaction p-value^{4}, p=0.1579  |
|  Heart Failure Hospitalization + ED/OP + Death (Primary Endpoint) | 43 (0.393) | 70 (0.591) | 0.67 (0…

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**Source:** [https://fda.innolitics.com/device/P100045S056](https://fda.innolitics.com/device/P100045S056)

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