Exercise Right Ventricular Coupling in HFpEF (ENDURE)

Exercise Measurement of Right Ventricular-arterial Coupling to Predict Hemodynamic Worsening in Heart Failure and Preserved Ejection Fraction

The investigators aim to evaluate the feasibility and prognostic value of right ventricular-arterial coupling (RVAC) during exercise in patients with HFpEF-PH using a hybrid technique of real-time CMRderived volume measures and CardioMEMS-derived pulmonary artery pressure measurements.

The investigators will determine:

1. Whether exercise RV-arterial coupling at baseline (assessed using hybrid CMRCardioMEMS) predicts development or worsening of exercise RV-arterial uncoupling during follow-up in HFpEF-PH patients.
2. If HFpEF-PH patients developing RV dysfunction have a particular PAP pattern as assessed remotely using the CardioMEMS system. The investigators will determine differential characteristics in CardioMEMS pressure patterns in those developing RV dysfunction versus those who do not develop RV dysfunction, both at rest and during exercise. Hence, HFpEF-PH patients developing RV dysfunction may harbor a plateau of pulmonary artery pressures (as a reflection of RV-arterial uncoupling) despite clinical worsening.
3. Whether extraction of raw pressure data obtained by the CardioMEMS system is feasible and enables post-processing using machine learning methods (artificial intelligence) for deep phenotyping of patients (in addition to clinical evaluation of pressure waveforms).

The investigators aim to evaluate the effect of SGLT-2 inhibitors on RV-arterial coupling in patients with HFpEF-PH. In case a patient is not using an SGLT-2 inhibitor, the investigators will prescribe this after baseline testing, since SGLT-2 inhibitors are clinically indicated in these patients.

Study Overview

• Status: Recruiting
• Conditions: Pulmonary Hypertension; Heart Failure With Preserved Ejection Fraction
• Intervention / Treatment: Device: CardioMems HF System

Detailed Description

In this prospective, two-center study, the investigators will recruit 30 HFpEF-PH patients in whom a CardioMEMS device will be implanted because of clinical indication. Potential study candidates will be enrolled in the outpatient clinic or during hospitalization.

Subjects who sign the informed consent form and meet the eligibility criteria at the baseline visit will be eligible for the trial. Subjects will undergo the study-related procedures, including clinical laboratory measurements and body mass index (BMI) calculation.

Eligible subjects will be scheduled for the Implant procedure (PA sensor implant in conjunction with a RHC procedure).

Subjects must also have an appropriately sized (≥7mm diameter) pulmonary artery branch identified by a selective pulmonary angiogram prior to Sensor implant. Subjects who do not meet this inclusion criteria will be documented as consented not implanted.

After implantation of the CardioMEMS device, the patient will be asked to perform cardiopulmonary exercise testing (CPET) with continuous expiratory gas monitoring on an upright cycle ergometer (ER900 and Alpha, Jaeger, Germany), using a continuous ramp protocol until exhaustion.

During the next visit, exercise RVAC will be assessed using a hybrid approach of exercise CMR and PAP measurement using the CardioMEMS system (Figure 1). Firstly, subjects will perform supine bicycle exercise within the CMR bore using a cycle-ergometer with adjustable electronic resistance (Lode, Groningen, The Netherlands). Exercise workloads for the exercise CMR protocol will be determined as 25%, 50% and 66% of peak power (Pmax) achieved during previous CPET, as the investigators previously demonstrated that supine exercise at 66% of peak power closely corresponds to maximal sustainable exercise intensity in an upright position. After the exercise test in the CMR bore, a second exercise test will be repeated on a supine bicycle ergometer. The CardioMEMS transmit-receive coil will be put under the back of the supine patient. After waiting one minute for the patient to stabilize, the CardioMEMS measurement will be initiated at rest and subsequently at the same workloads as during the exercise CMR protocol. This second exercise test will be combined with a exercise echocardiography.

CMR imaging will be performed on a Philips 1.5T CMR (Philips Medical Systems, Best, The Netherlands). RV-arterial coupling will be evaluated using a combined approach of CardioMEMS-derived pulmonary artery pressure data and CMR-derived volume data, thereby enabling the calculation of RV end-systolic pressure volume relationships. In addition, RVEF will be assessed as surrogate measure of RV-arterial coupling.

Prior to hospital discharge, subjects will be trained on the home monitoring system and instructed to take pulmonary artery pressure measurements daily at approximately the same time each day in the morning or as directed by their physician. Subjects will be supplied with a patient implant identification card, a Patient System Manual, and a Helpline phone number.

After discharge, the subject will take PA pressure measurements at home, as directed by the investigator, utilizing the CardioMEMS HF System. These measurements will be transmitted via modem to a secure data base. Patient compliance will be monitored by the Investigator.

Follow-up study visits will be scheduled at Month 1, Month 6, and every 6 months thereafter for 2 years (± 14 days visit window). Follow-up visits will include a physical exam, evaluation of NYHA Class, heart failure medications review, quality of life assessment, and assessment of any hospitalizations (including HF hospitalizations), that may have occurred between visits. In addition, all contacts between site staff and study subjects post implant will be recorded on a log to capture frequency, purpose and outcome of each contact.

The hybrid exercise CMR-CardioMEMS-derived assessment of exercise RVAC will be repeated at Month 6 and after 1 year following the same exercise protocol as detailed above.

All subjects included in this trial meet the criteria to start a SGLT-2 inhibitor on clinical indication following the latest evidence. Those who currently lack a SGLT-2 inhibitor, this medication will be initiated after the run-in period and the baseline testing (6 weeks after implantation of de CardioMems device).

Biochemistry will involve traditional parameters, such as hemoglobin, hematocrit, ionogram, renal function, NTproBNP, hs-troponin hs-CRP, ferritin, transferrin and iron level. In addition, at each time point, samples (serum and whole blood) will be stored for future analyses at Biobank UZ Leuven.

• Study Type: Interventional
• Enrollment (Anticipated): 30
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Guido Claessen, MD, PhD; Phone Number: +32 16 34 20 09; Email: guido.claessen@uzleuven.be
• Study Contact Backup: Name: Youri Bekhuis, MD; Phone Number: +32 16 34 66 56; Email: youri.bekhuis@uzleuven.be

Study Locations

• Belgium
  • Leuven, Belgium, 3000
    • Recruiting
    • UZ Leuven
    • Contact: Guido Claessen, MD PhD; Phone Number: +3216340136; Email: guido.claessen@uzleuven.be
    • Contact: Youri Bekhuis, MD; Phone Number: +3216346656; Email: youri.bekhuis@uzleuven.be
    • Sub-Investigator: Walter Droogne, MD
    • Sub-Investigator: Stefan Janssens, MD PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Written informed consent obtained from subject
2. > 18 years of age
3. Diagnosis of NYHA Class III Heart Failure with preserved ejection fraction defined as LVEF≥45%
4. At least 1 heart failure related hospitalization or urgent outpatient visit within 12 months of baseline visit
5. Presence of pulmonary hypertension defined as mPAP>25 mmHg at rest or mPAP/CO slope >3 mmHg/L/min during exercise during right heart catheterization or tricuspid regurgitation velocity of > 2.8 m/s assessed by transthoracic echocardiography (data must be taken within the last 6 months prior to implantation)
6. Subjects with a BMI ≤ 35. Subjects with BMI >35 will require their chest circumference to be measured at the axillary level, if > 65 inches the patient will not be eligible for the study.
7. Subjects with pulmonary artery branch diameter ≥ 7mm - (implant target artery - assessed during the RHC)
8. Subjects willing and able to comply with the follow-up requirements of the study
9. All participants need to be able to perform at least 40 watts on an upright bicycle stress test.

Exclusion Criteria:

1. Subjects with an active infection
2. Subjects with history of recurrent (> 1) pulmonary embolism or deep vein thrombosis
3. Subjects who, in the Investigator's opinion, are unable to tolerate a right heart catheterization
4. Subjects who have had a major cardiovascular event (e.g., myocardial infarction, open heart surgery, stroke, etc.) within 2 months of Baseline Visit
5. Subjects with Cardiac Resynchronization Device (CRT) , pacemaker or Implantable Cardioverter Defibrillator (ICD)
6. Subjects with a Glomerular Filtration Rate (GFR) < 25 ml/min (obtained within 2 weeks of the baseline visit) who are non-responsive to diuretic therapy or who are on chronic renal dialysis
7. Subjects with congenital heart disease or mechanical heart valve(s)
8. Subjects likely to undergo heart transplantation or VAD within 6 months of baseline visit
9. Subjects with known coagulation disorders
10. Subjects with a hypersensitivity or allergy to aspirin, and/or clopidogrel (not applicable for subjects taking anti-coagulation therapy or other approved anti-platelets therapy).
11. Subjects with history of coronary artery bypass surgery (CABG)
12. Subjects with severe valvular disease (4/4)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Diagnostic
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: CardioMems (Clinical Indication); Single Arm, CardioMems implantation on clinical indication. No control group. Every participant is his/her own control (longitudinal follow-up)	Device: CardioMems HF System; Implantation CardioMems device.; Evaluation of right ventricular-arterial coupling during exercise using a hybrid technique of real-time CMR-derived volume measures and CardioMems-derived pulmonary artery pressure measurements.; Other Names: CMR

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Right ventricular-arterial coupling (RVAC)	Whether baseline exercise RV-arterial coupling, determined by exercise CMR-CardioMems, can predict the development of progressive RV dysfunction after one year	12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
VO2max (mL/kg/min)	Evaluation whether exercise RV-arterial uncoupling is associated with clinical worsening by a relative VO2max ≥6% change (i.e. change of VO2max (ml/kg/min) from baseline to follow-up)	12 months
Right heart failure hospitalisation	Number of participants with the combined secondary endpoint of (1) hospitalization for right heart failure requiring intravenous diuretics or (2) death from any cause	12 months
SGLT-2	Whether initiation of a SGLT-2 inhibitor, after baseline evaluation, has a positive effect on exercise RV-arterial coupling at one year of follow up. (Only in patients who lack a SGLT-2 at inclusion)	12 months

Collaborators and Investigators

• Sponsor: Universitaire Ziekenhuizen KU Leuven
• Collaborators: Abbott

Study record dates

Study Major Dates

• Study Start (Actual): October 13, 2021
• Primary Completion (Anticipated): October 13, 2024
• Study Completion (Anticipated): December 31, 2025

Study Registration Dates

• First Submitted: December 21, 2022
• First Submitted That Met QC Criteria: February 7, 2023
• First Posted (Estimate): February 16, 2023

Study Record Updates

• Last Update Posted (Estimate): February 16, 2023
• Last Update Submitted That Met QC Criteria: February 7, 2023
• Last Verified: February 1, 2023

More Information

Terms related to this study

• Keywords: Pulmonary Hypertension; Heart Failure with Preserved Ejection Fraction; CardioMems; Exercise cardiovascular magnetic resonance
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Respiratory Tract Diseases; Lung Diseases; Heart Failure; Hypertension; Hypertension, Pulmonary
• Other Study ID Numbers: ENDURE

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: Yes
• product manufactured in and exported from the U.S.: Yes