Renal Denervation to Treat Heart Failure With Preserved Ejection Fraction (UNLOAD-HFpEF)

Renal Denervation to Treat Heart Failure With Preserved Ejection Fraction - A Pilot Trial

Heart failure with preserved ejection fraction has a high mortality, which is contrasted by a total absence of therapy options besides symptomatic diuretic treatment. This study aims to explore the potential of renal denervation as a treatment option for heart failure with preserved ejection fraction.

Study Overview

• Status: Recruiting
• Conditions: Heart Failure With Preserved Ejection Fraction; Hypertension, Renal
• Intervention / Treatment: Procedure: Renal Denervation; Procedure: Sham

Detailed Description

Heart failure is one of the most important diseases worldwide, with a 5-year mortality of up to 75% in symptomatic patients. While substantial progress has been made in the treatment of patients with reduced left ventricular ejection fraction (HFrEF), mortality for patients with heart failure and preserved ejection fraction (HFpEF) remains unchanged, despite a comparable prevalence and mortality of the disease as for heart failure with reduced ejection fraction.

HFpEF is a heterogeneous condition and has been a diagnostic and therapeutic challenge for clinicians and researchers over the past decades. While some rare cases of HFpEF can be attributed to specific diseases like amyloidosis, in most other patients common characteristics are increased ventricular filling pressures and ventricular and arterial stiffening as frequently caused by ageing, diabetes and arterial hypertension. Furthermore, increased sympathetic activity has been described as one pathogenic contributor to chronic heart failure and is associated with poor clinical prognosis. It also leads to a more pulsatile BP profile which can cause a mismatch in arterio-ventricular coupling.

The modulating effects on the sympathetic nervous system induced by renal denervation (RDN) should be beneficial in HFpEF, as they improve resting and exercise hemodynamics due to an improved ventriculoarterial coupling by reduced aortic stiffness and lower systemic blood pressure. In addition, RDN leads to optimized stroke volume and stroke work and might affect cardiac preload by improving blood distribution into the splanchnic compartment.

This study aims to explore the potential of RDN as a therapy for HFpEF in a single center pilot trial using a randomized, sham-controlled double-blind design.

• Study Type: Interventional
• Enrollment (Estimated): 68
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Karl Fengler, PhD; Phone Number: 8651426 49 341; Email: Karl.Fengler@medizin.uni-leipzig.de
• Study Contact Backup: Name: Philipp Lurz, Prof. Dr.; Phone Number: 177251 49 6131; Email: lurzphil@uni-mainz.de

Study Locations

• Germany
  • Berlin, Germany, 13683
    • Recruiting
    • BG Klinikum Unfallkrankenhaus Berlin gGmbH
    • Contact: Sebastian Winkler, MD, PhD; Phone Number: 5681 3684 +49 30; Email: sebastian.winkler@ukb.de
    • Contact: Leonhard Bruch, MD, PhD; Phone Number: 5681 3601 +49 30; Email: leonhard.bruch@ukb.de
  • Leipzig, Germany, 04289
    • Recruiting
    • Herzzentrum Leipzig, Universitätsklinik für Kardiologie
    • Contact: Karl Fengler, MD, PhD; Email: karl.fengler@medizin.uni-leipzig.de
    • Contact: MD, PhD
  • Leipzig, Germany, 04103
    • Not yet recruiting
    • Universitätsklinikum Leipzig, Klinik und Poliklinik für Kardiologie
    • Contact: Rolf Wachter, MD, Prof; Phone Number: 9720958 +49 341; Email: rolf.wachter@medizin.uni-leipzig.de
  • Mainz, Germany, 55131
    • Recruiting
    • Universitätsmedizin der Johannes Gutenberg Universität Mainz, Zentrum für Kardiologie / Kardiologie 1
    • Contact: Philipp Lurz, MD, Prof; Phone Number: 177251 +49 6131; Email: lurzphil@uni-mainz.de
    • Contact: Karl-Philipp Rommel, MD, PhD; Email: rommelka@uni-mainz.de
  • Sachsen Anhalt
    • Halle, Sachsen Anhalt, Germany, 06120
      • Recruiting
      • Universitätsklinikum Halle (Saale), Klinik und Poliklinik für Innere Medizin III
      • Contact: Alexander Vogt, MD, PhD; Phone Number: 557 3134 +49 345; Email: alexander.vogt@uk-halle.de

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. confirmed arterial hypertension (1-5 antihypertensive drugs without any dosage change in the preceding 4 weeks) and average systolic BP between >125 and ≤170 mmHg and diastolic BP ≤110 mmHg in 24h ambulatory blood pressure measurement (ABPM)
2. HFpEF (defined by clinical signs and/or symptoms of heart failure, objective structural cardiac abnormalities according to the ESC (European Society of Cardiology) criteria [1], elevated NT-proBNP ≥125 pg/mL and left-ventricular ejection fraction ≥55%)
3. NYHA-Class II or III
4. Confirmation of an elevated cardiac filling pressures (either LVEDP >= 16 mmHg or PCWP >= 15 mmHg at rest or >=25 mmHg during exercise) by catheterization
5. Age 18-80 years
6. Written informed consent

Exclusion Criteria:

1. ≥1 main renal artery diameter <3.0 mm
2. main renal artery length < 20 mm
3. a single functioning kidney
4. presence of abnormal kidney tumors
5. renal artery aneurysm
6. pre-existing renal stent or history of renal artery angioplasty
7. fibromuscular disease of the renal arteries
8. presence of renal artery stenosis of any origin ≥50%
9. iliac/femoral artery stenosis precluding femoral access for RDN
10. fertile women (within two years of their last menstruation) without appropriate contraceptive measures (implanon, injections, oral contraceptives, intrauterine devices, partner with vasectomy) while participating in the trial (participants using a hormone-based method have to be informed of possible effects of the trial device on contraception).
11. participation in other interventional trials
12. patients under legal supervision or guardianship
13. suspected lack of compliance
14. pregnant women
15. Presence of intracardiac pacemakers or implantable cardioverter/defibrillators

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: RDN; Renal Denervation	Procedure: Renal Denervation; Renal denervation in patients with HFpEF and uncontrolled hypertension
Sham Comparator: Sham; Sham Procedure	Procedure: Sham; Sham Treatment. After six months, cross-over is planned in all sham-treated patients and this patients will also receive a renal denervation.; Other Names: Sham Procedure

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
exercise pulmonary capillary wedge pressure (PCWP) at 20 W workload	To assess the hemodynamic effects of RDN in patients with HFpEF in comparison to sham-treatment	6 months after randomization

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
number of combination of death, increase in diuretic therapy, hospitalization for heart failure, worsening NYHA-class, change in pulmonary pressure parameters	number of combined endpoint in RDN and SHAM patients	6, 12 and 24 months after RDN
Change in mean PA pressure, ePAD and PA pressure variability from pulmonary pressure sensor measurements	Change in mean PA pressure, ePAD and PA pressure variability from pulmonary pressure sensor measurements, compared to baseline values	6, 12 and 24 months after RDN
Change in Systolic/Diastolic 24h blood pressure by ABPM and blood pressure variability	difference between RDN and sham	6 months after randomization
Change in Systolic/Diastolic 24h blood pressure by ABPM and blood pressure variability	Change in Systolic/Diastolic 24h blood pressure by ABPM and blood pressure variability, compared to baseline values	6, 12 and 24 months after RDN
Difference in ventriculo-arterial coupling	Difference in ventriculo-arterial coupling (by end-systolic elastance and arterial elastance) as acquired by invasive measurement	6 months after randomization
Change in ventriculo-arterial coupling	Change in ventriculo-arterial coupling (cMRI and echocardiogram) (difference between RDN and sham) as compared to baseline values	6 months after randomization
Difference in resting and exercise PCWP (at 20, 40, 60, 80 W, and maximum workload)	Difference in resting and exercise PCWP (at 20, 40, 60, 80 W, and maximum workload) (difference between RDN and sham) as compared to baseline values	6 months after randomization
Difference in peak PCWP	Difference in peak PCWP (difference between RDN and sham) as compared to baseline values	6 months after randomization
Difference in NT-proBNP	Difference in NT-proBNP (difference between RDN and sham) as compared to baseline	6 months after randomization
Difference in NT-proBNP	Difference in NT-proBNP as compared to baseline	6, 12 and 24 months after RDN
number of patients with Hospitalizations for heart failure	number of patients with Hospitalizations for heart failure (difference between RDN and sham)	6 months after randomization
difference in All-cause Mortality	All-cause Mortality (difference between RDN and sham)	6 months after randomization
difference in cardiac mortality	cardiac mortality (difference between RDN and sham)	6 months after randomization
difference in major adverse cardiovascular events	major adverse cardiovascular events (composite of cardiac death, myocardial infarction, stroke and hospitalization for heart failure) (difference between RDN and sham)	6 months after randomization
difference in number of Adverse Events	Adverse events (difference between RDN and sham)	6 months after randomization
difference in Frequency of patients with controlled hypertension	Frequency of patients with controlled hypertension (blood pressure within treatment goals in ABPM as recommended by the European Society of Cardiology) (difference between RDN and sham)	6 months after randomization
difference in Frequency of patients with controlled hypertension	Frequency of patients with controlled hypertension (blood pressure within treatment goals in ABPM as recommended by the European Society of Cardiology) as compared to baseline	6, 12 and 24 months after RDN
Difference in 6-minute walk distance	Difference in 6-minute walk distance (difference between RDN and sham)	6 months after randomization
Difference in 6-minute walk distance	Difference in 6-minute walk distance as compared to baseline	6, 12 and 24 months after RDN
Change in exercise BP and maximum maximum exercise capacity	Change in exercise BP between baseline and 6 months and maximum exercise capacity between baseline and 6 months (difference between RDN and sham)	6 months after randomization
Change in Minnesota living with heart failure questionnaire (difference between RDN and sham)	Change in Minnesota living with heart failure questionnaire (difference between RDN and sham)	6 months after randomization
Change in Minnesota living with heart failure questionnaire	Change in Minnesota living with heart failure questionnaire, compared to baseline	6, 12 and 24 months after RDN
Change in mean Pulmonary artery (PA) pressure, estimated pulmonary artery diastolic pressure (ePAD) and PA pressure variability from pulmonary pressure sensor measurements	difference between RDN and sham	6 months after randomization
Change in Cardiac magnetic resonance (CMR) based hemodynamics	Change in CMR-based hemodynamics (difference between RDN and sham) as compared to baseline values	6 months after randomization

Collaborators and Investigators

• Sponsor: University of Leipzig
• Collaborators: ReCor Medical, Inc.
• Investigators: Study Chair: Karl Fengler, PhD, Herzzentrum Leipzig, Universitätsklinik für Kardiologie

Study record dates

Study Major Dates

• Study Start (Actual): November 30, 2021
• Primary Completion (Estimated): December 31, 2024
• Study Completion (Estimated): March 31, 2026

Study Registration Dates

• First Submitted: August 30, 2021
• First Submitted That Met QC Criteria: August 30, 2021
• First Posted (Actual): September 1, 2021

Study Record Updates

• Last Update Posted (Actual): July 17, 2024
• Last Update Submitted That Met QC Criteria: July 15, 2024
• Last Verified: July 1, 2024

More Information

Terms related to this study

• Keywords: Hypertension; Heart Failure with Preserved Ejection Fraction; Renal Denervation
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Heart Failure; Hypertension; Hypertension, Renal
• Other Study ID Numbers: UNLOAD-HFpEF; CIV-20-10-034846 (Other Identifier: Eudamed-Nr.)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

After publication of the major results and upon reasonable request from researchers performing an individual patient data meta-analysis, individual patient data that underlie published results will be shared after de-identification. This requires approval by the local Institutional Review Board (IRB) of the researcher requesting the data along with public registration of the meta-analysis.

Summary statistics that go beyond the scope of published material will be made available to researchers for meta-analysis upon reasonable request and if the necessary data analysis is not unduly time-consuming. Together with publication of the main results, the trial protocol in full will be made publically available as well as the statistical analysis plan.

• IPD Sharing Time Frame: after publication of the major results
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No