A Trial to Evaluate the Safety and Efficacy of Pulmonary Artery Denervation for the Treatment of Pulmonary Hypertension Associated With Left Heart Disease

Study Overview
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Brief Summary
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It's a phase III, prospective, multicenter, randomized controlled trial to evaluate the safety and efficacy of the pulmonary artery denervation (PADN) for heart failure (HF) patients diagnosed with pulmonary hypertension associate with left heart disease (PH-LHD) by right heart catheterization.

Detailed Description
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Chronic heart failure (CHF) patients who have received guideline-directed medical therapy (GDMT) based on the 2022 American Heart Association (AHA)/American College of Cardiology (ACC) Guidelines for HF and have reached clinical stable, and diagnosed with PH-LHD by right heart catheterization, will be randomized to the PADN group or control group in a 1:1 ratio to receive PADN combined with HF GDMT or HF GDMT, respectively. After the primary endpoint follow-up is completed at the 6-months visit, participants in the control group who still meet the inclusion and exclusion criteria can also choose to receive PADN. Approximately 276 participants will be enrolled at up to 28 centers in China and followed for 3 years. The safety and efficacy of the PADN system, including RF ablation catheter and generator will be evaluated by comparing the therapeutic effect of the PADN group and the control group.

Official Title
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A Prospective, Multicenter, Randomized Controlled Trial to Evaluate the Safety and Efficacy of Single-use Ring-shaped Pulmonary Artery Radiofrequency (RF) Ablation Catheter and Pulmonary Artery RF Ablation Generator for the Treatment of Pulmonary Hypertension Associated With Left Heart Disease

Conditions
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Pulmonary Hypertension, Heart Failure With Reduced Ejection Fraction, Hypertension, Vascular Diseases, Cardiovascular Diseases, Heart Failure, Heart Failure With Preserved Ejection Fraction, Heart Failure With Mid Range Ejection Fraction

Intervention / Treatment
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* Procedure: Pulmonary arterial denervation
* Drug: Guideline-directed medical therapy (GDMT) for heart failure


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥18, ≤75 years old; Diagnosed with chronic heart failure for at least 3 months, and have received the GDMT pharmacological treatment based on the 2022 AHA/ACC Guidelines for Heart Failure for at least 1 month; Clinically stable defined by No intravenous diuretics, inotropes or vasodilators for at least 1 month, and Systolic blood pressure (SBP) ≥ 100 and < 160 mmHg and resting heart rate (HR) ≥50 and <100 bpm (<110 bpm for atrial fibrillation) on the day of the procedure ACC/AHA stage of heart failure B-C; New York Heart Association (NYHA) class II-IVa; World Health Organization (WHO) functional class II-IV; 6MWD ≥ 100 m and < 450 m; NT-proBNP > 600 pg/mL (BNP > 150 pg/mL), or NT-proBNP > 400 pg/mL (BNP >100pg/mL) and has been hospitalized for heart failure in the past 1 year; Hemodynamic indicators (RHC) : Mean pulmonary arterial pressure (mPAP) > 25mmHg Pulmonary capillary wedge pressure (PCWP) >15mmHg Understand and be willing to sign informed consent, and be willing to follow the follow-up plan required by the protocol. Exclusion Criteria: Any of the following: Hypertrophic cardiomyopathy with left ventricular (LV) outflow tract obstruction or systolic anterior motion (SAM); pericardial disease; infiltrative or inflammatory myocardial disease; valvular heart disease with moderate or severe stenosis of any of the 4 valves, or severe regurgitation of any of the 4 valves, or active endocarditis; or Symptomatic carotid stenosis, or transient ischemic attack (TIA) or stroke within 30 days prior to randomization; or Complex congenital heart disease; or Have received any revascularization, including coronary artery bypass grafting (CABG) or percutaneous coronary intervention (PCI) within 6 months prior to randomization; or anticipated to undergo coronary revascularization (CABG or PCI) within 6 months; or Artificial pacemakers, including single-chamber, dual-chamber and three-chamber pacemakers, have been implanted or are anticipated to be implanted within 6 months; or Anticipated to undergo ablation of atrial fibrillation within 6 months; or Anticipated to undergo heart valve surgery (valve replacement, valvuloplasty) within 6 months; or Listing for heart/heart-lung transplantation or anticipated to implant a ventricular assist device (VAD) Other types of pulmonary hypertension, including WHO Group1, Group3, Group4, Group5; Received pulmonary arterial hypertension (PAH) targeted drugs within 1 month prior to randomization; Anticipated to undergo any surgery within 6 months; The cardiac index (CI) of RHC < 1.5L/min/m²; Severe renal insufficiency (eGFR <30mL/min/1.73m² by MDRD formula); Severe liver insufficiency (Child-Pugh classification B-C); Platelet count < 50 × 10^9/L; Life expectancy <1 year; Systemic inflammation or other disease requiring long-term use of glucocorticoids or immunosuppressants; Active infection requiring oral or intravenous antibiotics; Cannot tolerate any GDMT medicine; Body mass index (BMI) >40 kg/m²; Pregnant or lactating women, or plan to pregnant in one year; Participated in other clinical trials within 3 months prior to signing the informed consent; Any other circumstances that investigators deem inappropriate to participate in this trial.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: At the 6-months visit, participants in the control group who still meet the inclusion and exclusion criteria can choose to receive PADN procedure.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pulmonary Artery Denervation (PADN)<br>Patients in the PADN group will receive pulmonary artery denervation procedure. | Procedure: Pulmonary arterial denervation<br>* Contrast pulmonary artery (PA) angiography will be performed to localize the pulmonary artery bifurcation level and calculate the PA diameter. Once the anatomy deemed acceptable, the radiofrequency ablation catheter will be introduced into ostium of the left PA and the distal bifurcation area of the main PA. The catheter will be manoeuvred within the PA to allow energy delivery in a circumferential manner to ensure that the electrodes are tightly in contact with the endovascular surface. About three ablations at 45-55 ℃ for 120 seconds each will be performed in ostium of the left PA and the distal bifurcation area of the main PA.<br>* Other names: PADN;Drug: Guideline-directed medical therapy (GDMT) for heart failure<br>* GDMT medication recommendation including: Angiotensin-converting enzyme inhibitor (ACEI) or angiotensin-receptor blocker (ARB) or angiotensin receptor-neprilysin inhibitor (ARNI) Beta-receptor blocker (BB) Mineralocorticoid receptor antagonist (MRA) Sodium-glucose co-transporter 2 (SGLT2) inhibitor Diuretics The medication regimen (type and dosage) will be the investigator's discretion in accordance with the 2022 AHA/ACC Guidelines for Heart Failure. The type and dosage of all GDMT medications (except for diuretics) should remain unchanged through follow-up duration (at 6-month visit), unless the participant's conditions need adjust of GDMT regimens. Dosage and single or combination of diuretics are all left at physician's discretion.<br>* Other names: GDMT medication for heart failure;|
| Active Comparator: Guideline-directed medical therapy (GDMT) for heart failure<br>Patients in the control group will take their baseline anti-heart failure medications at the original doses according to 2022 AHA/ACC Guidelines for heart failure, without any changes except when medically required. The anti-heart failure drugs treatment is consistent in both arms. | Drug: Guideline-directed medical therapy (GDMT) for heart failure<br>* GDMT medication recommendation including: Angiotensin-converting enzyme inhibitor (ACEI) or angiotensin-receptor blocker (ARB) or angiotensin receptor-neprilysin inhibitor (ARNI) Beta-receptor blocker (BB) Mineralocorticoid receptor antagonist (MRA) Sodium-glucose co-transporter 2 (SGLT2) inhibitor Diuretics The medication regimen (type and dosage) will be the investigator's discretion in accordance with the 2022 AHA/ACC Guidelines for Heart Failure. The type and dosage of all GDMT medications (except for diuretics) should remain unchanged through follow-up duration (at 6-month visit), unless the participant's conditions need adjust of GDMT regimens. Dosage and single or combination of diuretics are all left at physician's discretion.<br>* Other names: GDMT medication for heart failure;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical Deterioration, defined as the occurrence of any of the followings: | The type and/or dosage of oral diuretics need to be increased due to worsening of heart failure Requiring intravenous medication (inotropes, diuretics or vasodilators) due to worsening of heart failure Rehospitalization due to heart failure 6MWD decreased by > 15% or > 30m compared with baseline Referral for heart/heart-lung transplantation All-cause death | immediately after the procedure to 6 months follow-up | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Hemodynamics measured by right heart catheterization(RHC) | Change in mean pulmonary artery pressure (mPAP) from baseline. | 6 months | 
| Hemodynamics measured by right heart catheterization(RHC) | Change in pulmonary vascular resistance(PVR) from baseline. | 6 months | 
| Hemodynamics measured by right heart catheterization(RHC) | Change in pulmonary artery wedge pressure(PAWP) from baseline. | 6 months | 
| Parameters measured by transthoracic echocardiography(TTE) | Changes in left ventricular Tei index from baseline. | 6 months, 1 year, 3 years | 
| Parameters measured by transthoracic echocardiography(TTE) | Changes in left ventricular ejection fraction (LVEF) from baseline. | 6 months, 1 year, 3 years | 
| Parameters measured by transthoracic echocardiography(TTE) | Changes in left ventricular end-diastolic diameter (LVDd) from baseline. | 6 months, 1 year, 3 years | 
| Parameters measured by transthoracic echocardiography(TTE) | Changes in left ventricular end-systolic diameter (LVSd) from baseline. | 6 months, 1 year, 3 years | 
| Parameters measured by transthoracic echocardiography(TTE) | Changes in E/E' ratio from baseline. | 6 months, 1 year, 3 years | 
| Parameters measured by transthoracic echocardiography(TTE) | Changes in septum E' from baseline. | 6 months, 1 year, 3 years | 
| Parameters measured by transthoracic echocardiography(TTE) | Changes in lateral wall E' from baseline. | 6 months, 1 year, 3 years | 
| Parameters measured by transthoracic echocardiography(TTE) | Changes in left ventricular global longitudinal strain (LVGLS) from baseline. | 6 months, 1 year, 3 years | 
| N-terminal pro-B-type natriuretic peptide (NT-proBNP) | Changes in N-terminal pro-B-type natriuretic peptide (NT-proBNP) from baseline | 6 months | 
| 6 minute walk distance(6MWD) difference from baseline | The 6MWD test was conducted according to the American Thoracic Society guidelines. | 6 months, 1 year, 3 years | 
| Changes in the Kansas City Cardiomyopathy Questionnaire(KCCQ) overall summary score from baseline | The KCCQ is a self-administered, 23-item questionnaire to provide a better description of quality of life in patients with heart failure. The overall summary score range from 0 to 100, higher score means higher quality of life. | 1 month, 6 months, 1 year, 2 years, 3 years | 
| Diuretics need to be increased due to worsening of heart failure | The type and/or dosage of oral diuretics need to be increased due to worsening of heart failure | 1 month, 6 months, 1 year, 2 years, 3 years | 
| Intravenous medication due to worsening of heart failure | Number of patients requiring intravenous medication (inotropes, diuretics or vasodilators) due to worsening of heart failure | 1 month, 6 months, 1 year, 2 years, 3 years | 
| Rehospitalization due to heart failure | Number of patients with rehospitalization due to heart failure | 1 month, 6 months, 1 year, 2 years, 3 years | 
| Heart/heart-lung transplantation | Number of patients referred for heart/heart-lung transplantation | 1 month, 6 months, 1 year, 2 years, 3 years | 
| All-cause death | Number of death due to any cause | 1 month, 6 months, 1 year, 2 years, 3 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pulmonary Artery Denervation, Pulmonary Hypertension Due to Left Heart Disease, Heart Failure, pulmonary hypertension, left heart failure