Clinical trial NCT02041130: Renal Denervation in Heart Failure Patients With Preserved Ejection Fraction (RESPECT-HF)
Official title: Renal Sympathectomy in Heart Failure (the RESPECT-HF Study) - a Study of Renal Denervation for Heart Failure With Preserved Ejection Fraction
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE2
Conditions: Heart Failure
Keywords: Heart Failure
Heart Failure with Preserved Ejection Fraction
Lead sponsor: National University Hospital, Singapore
Sponsor class: OTHER
Collaborators: name: University of Otago
name: Wellington Hospital
name: University of Auckland, New Zealand
name: Monash University
name: Tan Tock Seng Hospital
name: Changi General Hospital
name: Singapore Clinical Research Institute
First posted: 2014-01-20
Enrollment: 144
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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

Detailed 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%.

Eligibility criteria: 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

Primary outcomes:
measure: Compare the changes in left atrial volume index (LAVi) and/or left ventricular mass index (LVMi) on cardiac magnetic resonance imaging (cMRI) between baseline and 6 months
timeFrame: baseline, 6 months
Secondary outcomes:
measure: Compare the changes in exercise capacity and functional status as assessed by maximal oxygen consumption (VO2max) on cardiopulmonary exercise testing and by 6-minute walk test between baseline and 6 months
timeFrame: baseline, 6 months
measure: Compare the changes in chocardiographic grade of diastolic dysfunction as assessed by Tissue Doppler E/e', (a non-invasive estimate of left atrial filling pressure).
timeFrame: baseline, 6 months
measure: Compare the changes in biomarkers of cardiac load and interstitial fibrosis as assessed by plasma assays of relevant biomarkers
timeFrame: baseline, 6 months
measure: Compare the changes in ventricular-vascular function as evaluated by echocardiographic measures of arterial elastance, Left Ventricular (LV) end-systolic elastance, LV filling pressure, and LV diastolic stiffness between baseline and 6 months
timeFrame: baseline, 6 months
measure: Compare the changes of Quality of life as assessed by the Minnesota Living with Heart Failure between baseline and 6 months.
timeFrame: baseline, 6 months
measure: Compare the difference in composite end-point of death or hospitalization with Heart Failure between control arm and treatment arm
timeFrame: baseline, 6 months
Other outcomes:
Locations:
city: Melbourne
country: Australia
facility: Monash University
city: Auckland
country: New Zealand
facility: The University of Auckland
city: Christchurch
country: New Zealand
facility: University of Otago
city: Wellington
country: New Zealand
facility: Wellington Hospital
city: Singapore
country: Singapore
facility: Changi General Hospital
city: Singapore
country: Singapore
facility: National University Heart Centre
city: Singapore
country: Singapore
facility: Tan Tock Seng Hospital
Study officials:
affiliation: University of Otago, Christchurch
name: Arthur Mark Richards, MBChB, MD (Distinction), PhD
role: STUDY_CHAIR
affiliation: Monash University
name: Henry Krum, MBBS, PhD, FRACP, FCSANZ
role: PRINCIPAL_INVESTIGATOR
affiliation: National University Heart Centre, Singapore
name: Carolyn Lam Su Ping, MBBS, MRCP, MS
role: PRINCIPAL_INVESTIGATOR
References: