Spironolactone Therapy in Chronic Stable Right HF Trial
- Conditions
- Pulmonary Hypertension, Primary, 2Chronic Right-Sided Heart FailurePulmonary Arterial HypertensionPulmonary Hypertension, Primary, 3Pulmonary Hypertension, Primary, 4Cardiomyopathy Right Ventricular
- Interventions
- Registration Number
- NCT03344159
- Lead Sponsor
- Ottawa Heart Institute Research Corporation
- Brief Summary
The purpose of this study is to evaluate the safety, tolerability and mechanistic effects of spironolactone, an aldosterone receptor antagonist, on sympathetic nervous system activity and right heart function and remodeling in patients with chronic right heart failure.
- Detailed Description
This study is a phase 4, single center, randomized, double blind, placebo-controlled trial evaluating the safety, tolerability and mechanistic effects of spironolactone, an aldosterone antagonist, on neurohormonal activity and remodeling in patients with chronic right heart failure (RHF).
RHF is one of the most important predictors of prognosis in many cardiac disease states including pulmonary hypertension (PH), and left heart failure. Sympathetic nervous system activation plays an important role in the development and progression of heart failure. It remains to be determined whether there is a role for neurohormonal therapy in chronic right HF, but evidence points to the role of sympathetic nervous system stimulation and activation of the renin-angiotensin and aldosterone system as a contributor to progressive right heart failure.
The study will determine if treatment with spironolactone is associated with reduction in right ventricular wall stress. In addition, the study aims to evaluate the effects of spironolactone on cardiac sympathetic activity assessed by HED(11 C-hydroxy-ephedrine) retention on PET(positron emission tomography) imaging, and global autonomic function assessed by heart rate variability.
Approximately 30 patients with RHF will be randomized to receive either spironolactone daily or placebo.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 15
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Provide a personally signed and dated inform consent form.
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Male or female ≥ 18 years.
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Able to comply with all study procedures.
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History of right heart failure (RHF) secondary to either:
i) WHO, group 1 pulmonary arterial hypertension PAH OR ii) WHO group II PH with normal LV systolic function OR iii) WHO group III or IV PH OR iv) primary RV cardiomyopathy.
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Current NYHA II-IV
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RV dysfunction as measured by 2D echocardiogram:
i)defined as a tricuspid annular plane systolic excursion (TAPSE) <16 mm ii) and /or a two dimensional fractional area change <35% on screening echo plus
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NT-proBNP>400 pg/ml
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Chronic use of diuretics
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Clinical stability: defined as no need for increased diuretics, hospitalization or emergency room visit 3 months prior to enrollment
- Patients on chronic MRA therapy or other potassium sparing diuretics.
- Baseline serum potassium>5 ummol/l.
- Estimated glomerular filtration rate <30 ml/min.
- LV ejection fraction <45%,
- Moderate or severe LV diastolic function,
- Moderate or severe aortic or valvular disease.
- Patients requiring augmentation of diuretics or otherwise not meeting definition for clinical stability.
- Severe Liver Failure (Child-Pugh Class C)
- Claustrophobia or inability lie still in a supine position
- Patients with contraindications to either PET or CMR imaging
- Pregnancy or lactation.
- Unable to provide consent and comply with follow up visits.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Placebo Placebo Participants with chronic right-sided heart failure will receive placebo daily for a total duration of 12 weeks. Spironolactone Spironolactone Participants with chronic right-sided heart failure will receive spironolactone 12.5mg daily up to a maximum dose of 50 mg daily for a total duration of 12 weeks. Spironolactone Cardiac MRI (Gadolinium enhanced) Participants with chronic right-sided heart failure will receive spironolactone 12.5mg daily up to a maximum dose of 50 mg daily for a total duration of 12 weeks. Placebo Cardiac MRI (Gadolinium enhanced) Participants with chronic right-sided heart failure will receive placebo daily for a total duration of 12 weeks.
- Primary Outcome Measures
Name Time Method Change in Ventricular Wall Stress Baseline and 12 weeks To determine if treatment with spironolactone is associated with a significant reduction in RV ventricular wall stress, as reflected by a reduction in serum NT-proBNP, in patients with chronic stable right HF when compared to placebo.
- Secondary Outcome Measures
Name Time Method Change in Cardiac Sympathetic Nervous System Activity Baseline to 12 weeks Changes in cardiac sympathetic activity, as assessed by an increase in 11\[C\]-hydroxy-ephedrine (HED) retention by cardiac PET imaging.
Change in Biomarkers of Fibrosis Baseline to 12 weeks Changes in biomarkers of fibrosis (ST2, PIINP, CITB, TIMP1, MMP-9)
Change in Systemic Sympathetic Activation Baseline to 12 weeks Changes in plasma levels of epinephrine and norepinephrine
Change in Cardiac Autonomic Nervous System Function Baseline to 12 weeks Heart rate variability
Change in Right Ventricle Function Baseline to 12 weeks Changes in RV ejection fraction
Change in Right Ventricle areas of fibrosis Baseline to 12 weeks Changes in RV areas of fibrosis assessed with T1 weighted MR imaging.
Change in Right Ventricle Structure Baseline to 12 weeks Changes in RV end-diastolic and end-systolic size.
Number of participants with treatment-related adverse events. number of adverse events from baseline to 12 weeks. 1. incidence of worsening renal function (defined as a change in estimated glomerular filtration rate\>30%). 2. Incidence of hyperkalemia (\>4.5, 5 or 5.5 mmol/L)
Trial Locations
- Locations (1)
University of Ottawa Heart Institute
🇨🇦Ottawa, Ontario, Canada