Renal Denervation in Heart Failure Patients With Preserved Ejection Fraction (RESPECT-HF)

National University Health System (NUHS)

Status and phase: Unknown; Phase 2

Conditions: Heart Failure

Treatments: Device: Renal Denervation

Study type: Interventional

Funder types: Other

Identifiers

NCT02041130

DSRB: 2013/00457

Details and patient eligibility

About

Investigators will test a new approach to a form of heart failure (HF) with no current treatment proven to reduce death rates or hospitalisations. Over a third of HF cases have preserved ejection fraction (HFPEF) often on a background of high blood pressure (BP). These "stiff" hearts pump strongly but fill inefficiently resulting in poor exercise capacity and high death rates. Treatments that help when heart pumping action is poor are of no benefit in HFPEF. Recently a simple catheter procedure removing excess nerve signals to and from the kidneys ("renal denervation"; RDN) has been able to reduce BP in patients with high BP resistant to multi-drug treatment. Through removing excess nervous drive to the kidneys, heart and circulation this treatment has promise in HF. The investigators will compare effects of RDN and standard medical treatment on heart function, exercise capacity and quality of life in 144 patients with HFPEF

Full description

Rationale for Research:- Heart failure (HF) is common and lethal. It is the most common diagnosis for medical admissions over 60 years of age, carries a >50% 5 year mortality and accounts for 1-2% of the total national health care budget. HF with preserved ejection fraction (HFPEF) includes over a third of HF cases presenting to New Zealand and Singapore Hospitals and has no treatment proven to reduce mortality or recurrent admissions. Renal denervation (RDN) has proven efficacy in refractory hypertension and its array of effects upon haemodynamic status, neurohumoral activity and renal function make it a rational candidate therapy in HFPEF.

Aims:- The investigators aim to conduct a phase 2 randomized controlled trial of RDN in HFPEF to determine effects upon cardiac structure and function, exercise capacity, and quality of life.

Primary Hypothesis: RDN will reduce left atrial volume index (LAVi) and/or left ventricular mass index (LVMi) on cardiac magnetic resonance imaging (cMRI).

Secondary Hypotheses: RDN will:

1. improve exercise capacity and functional status.
2. reduce E/e' and echocardiographic grade of diastolic dysfunction.
3. reduce circulating biomarkers of cardiac load, interstitial fibrosis and inflammation.
4. improve ventricular-vascular function.
5. improve Minnesota Living with Heart Failure (MLWHF) scores.
6. reduce the composite end-point of death or re-admission with HF.

Design and Methods:- Renal denervation will be tested as a therapy for HFPEF in a multi-centre open, randomized controlled trial of bilateral renal artery denervation compared with ongoing medical management. Sample size (n=144) will be sufficient to provide 90% power to detect clinically relevant effects on the primary endpoints of change in left atrial volume and left ventricular mass over 6 months post-RDN. Secondary end-points will include assessment of exercise capacity, ventricular-vascular coupling, biomarkers (of cardiac haemodynamic load, fibrosis, inflammation and cardiomyocyte loss), quality of life and cardiovascular events.

Research Impact:- Heart Failure with Preserved Ejection Fraction (HFPEF) is common, triggers recurrent hospital admissions has a high mortality and carries a high burden of health care costs. There is currently no treatment which reduces admissions or improves survival in this condition. If efficacy is proven, renal nerve denervation represents a simple, cost-effective, one time only, approach that will find rapid uptake potentially for thousands of cases.If the current proposal generates positive results (followed by positive phase 3 trials) the investigators conservatively estimate RDN may reduce both mortality and HF admissions in HFPEF by at least 30%.

Enrollment: 144 estimated patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion criteria

1. Patients with HFPEF (based upon ESC diagnostic criteria9)

   1. Symptoms and signs of heart failure; NYHA Class II or higher
   2. Left ventricular ejection fraction 50% or greater on echocardiography
   3. Echocardiographic evidence of left ventricular diastolic dysfunction (echo-Doppler E/e' > 15 )AND/OR plasma NTproBNP > 220pg/ml.

2. Episode of acute decompensation (ADHF)

3. Patients with and without background hypertension may be recruited. In the case of patients with background hypertension (ie history of fulfilling the diagnostic WHO criteria for hypertension: SBP > 140 mmHg and/or DBP > 90 mmHg) those with both controlled (<140/90mmHg by 24 hour ambulatory BP) and inadequately controlled BP (on 3 anti-hypertensive drugs including a diuretic) can be recruited.

Exclusion criteria

1. Known secondary cause of hypertension
2. Renal artery stenosis >30% or anatomy otherwise unsuitable for RDN.
3. Heart failure with reduced LV ejection fraction (LVEF < 50%).
4. Estimated glomerular filtration rate (eGFR) of < 30mL/min/1.73m2 (MDRD calculation).
5. Systolic blood pressure < 105mmHg.
6. Implanted pacemaker, prosthetic heart valve or other precluding cMR scanning.
7. Medical condition adversely affecting safety and/or effectiveness of the participant (including peripheral vascular disease, abdominal aortic aneurysm, thrombocytopenia or atrial fibrillation).
8. Pregnant, nursing or planning to be pregnant.
9. Uncontrolled atrial fibrillation, ie with heart rate over 120 bpm

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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144 participants in 2 patient groups

Renal Denervation and standard medical management

Experimental group

Description:

Renal Denervation (RDN) is a simple catheter procedure removing excess nerve signals to and from the kidneys. The renal denervation system consists of a small steerable treatment catheter and an automatically-controlled treatment delivery generator. A guiding catheter is inserted through a tiny incision in the groin into the femoral artery to direct the treatment catheter to the renal arteries. The treatment catheter delivers high -frequency radio waves, called radiofrequency wavees, to 4-6 locations within each of the two renal arteries. the energy delivered is about 8 watts and aims to disrupt the nerves and lower blood pressure over a period of months. The procedure takes 40-60 minutes.

Treatment:

Device: Renal Denervation

Contorl and Standard Medical Management

No Intervention group

Description:

Continued medical management will comprise management of all cardiovascular risk factors (hypertension, diabetes, dyslipidaemia) in accord with international guidelines. Lifestyle and dietary counselling will also be part of the patient management. As there is no established evidence-based pharmacotherapy for HFPEF per se, therapy aimed at HF specifically will adopt treatments recommended for HFREF with prescription of diuretic, ACE inhibitor/ARB, beta blocker and mineralocorticoid antagonist accordingly.