Spironolactone Therapy in Chronic Stable Right HF Trial (STAR-HF)

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.

Study Overview

• Status: Completed
• Conditions: Pulmonary Arterial Hypertension; Pulmonary Hypertension, Primary, 4; Chronic Right-Sided Heart Failure; Pulmonary Hypertension, Primary, 2; Pulmonary Hypertension, Primary, 3; Cardiomyopathy Right Ventricular
• Intervention / Treatment: Drug: Spironolactone; Radiation: PET/CT Scan: Two PET scans using 1. C-11 HED and 2. N-13 Ammonia or rubidium-82; Diagnostic test: Cardiac MRI (Gadolinium enhanced); Drug: Placebo

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.

• Study Type: Interventional
• Enrollment (Actual): 15
• Phase: Phase 4

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Ottawa, Ontario, Canada, K1Y4W7
      • University of Ottawa Heart Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Provide a personally signed and dated inform consent form.
• Male or female ≥ 18 years.
• Able to comply with all study procedures.

• 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.

• Current NYHA II-IV

• 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

• NT-proBNP>400 pg/ml
• Chronic use of diuretics
• Clinical stability: defined as no need for increased diuretics, hospitalization or emergency room visit 3 months prior to enrollment

Exclusion Criteria:

• 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 Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 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.	Drug: Spironolactone; Spironolactone 12.5mg daily up to a maximum dose of 50 mg daily if tolerated for a total duration of 12 weeks.; Radiation: PET/CT Scan: Two PET scans using 1. C-11 HED and 2. N-13 Ammonia or rubidium-82; At baseline and 12 weeks, all participants will undergo rest perfusion PET imaging according to standard protocols with either 82-Rb or N-13 NH3, followed by C-11 HED PET.; Diagnostic test: Cardiac MRI (Gadolinium enhanced); At baseline and 12 weeks all participants will undergo cMR to assess RV function and structure. We will acquire precontrast T2 and native T1 maps, and post gadolinium T1 maps.
Placebo Comparator: Placebo; Participants with chronic right-sided heart failure will receive placebo daily for a total duration of 12 weeks.	Radiation: PET/CT Scan: Two PET scans using 1. C-11 HED and 2. N-13 Ammonia or rubidium-82; At baseline and 12 weeks, all participants will undergo rest perfusion PET imaging according to standard protocols with either 82-Rb or N-13 NH3, followed by C-11 HED PET.; Diagnostic test: Cardiac MRI (Gadolinium enhanced); At baseline and 12 weeks all participants will undergo cMR to assess RV function and structure. We will acquire precontrast T2 and native T1 maps, and post gadolinium T1 maps.; Drug: Placebo; Placebo daily for a total of duration of 12 weeks

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Ventricular Wall Stress	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.	Baseline and 12 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Cardiac Sympathetic Nervous System Activity	Changes in cardiac sympathetic activity, as assessed by an increase in 11[C]-hydroxy-ephedrine (HED) retention by cardiac PET imaging.	Baseline to 12 weeks
Change in Cardiac Autonomic Nervous System Function	Heart rate variability	Baseline to 12 weeks
Change in Systemic Sympathetic Activation	Changes in plasma levels of epinephrine and norepinephrine	Baseline to 12 weeks
Change in Right Ventricle Structure	Changes in RV end-diastolic and end-systolic size.	Baseline to 12 weeks
Change in Right Ventricle Function	Changes in RV ejection fraction	Baseline to 12 weeks
Change in Right Ventricle areas of fibrosis	Changes in RV areas of fibrosis assessed with T1 weighted MR imaging.	Baseline to 12 weeks
Number of participants with treatment-related adverse events.	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)	number of adverse events from baseline to 12 weeks.
Change in Biomarkers of Fibrosis	Changes in biomarkers of fibrosis (ST2, PIINP, CITB, TIMP1, MMP-9)	Baseline to 12 weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Serum Aldosterone	changes in plasma levels of aldosterone	Baseline to 12 weeks
Change in Six Minute walk test	Distance a participant can walk in a period of 6 walks.	Baseline, 6 weeks, 12 weeks
Change in NYHA function class	changes in NYHA functional class.	baseline to 12 weeks
Change in Right heart failure Severity	Worsening right HF- defined as need for increase in diuretic dose or open-label initiation of a potassium sparing diuretic, or hospitalization or need for IV diuretics	Baseline to 12 weeks
Clinical Outcomes	Hospitalization and/or all cause mortality	12 weeks

Collaborators and Investigators

• Sponsor: Ottawa Heart Institute Research Corporation

Study record dates

Study Major Dates

• Study Start (Actual): April 1, 2018
• Primary Completion (Actual): August 30, 2022
• Study Completion (Actual): November 30, 2022

Study Registration Dates

• First Submitted: September 28, 2017
• First Submitted That Met QC Criteria: November 14, 2017
• First Posted (Actual): November 17, 2017

Study Record Updates

• Last Update Posted (Estimate): January 9, 2023
• Last Update Submitted That Met QC Criteria: January 5, 2023
• Last Verified: January 1, 2023

More Information

Terms related to this study

• Keywords: Sympathetic Nervous System; Mineralocorticoid receptor antagonist; Brain natriuretic peptide (BNP); Positron Emissions Tomography
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Respiratory Tract Diseases; Lung Diseases; Congenital Abnormalities; Heart Defects, Congenital; Cardiovascular Abnormalities; Situs Inversus; Heart Failure; Hypertension; Pulmonary Arterial Hypertension; Familial Primary Pulmonary Hypertension; Hypertension, Pulmonary; Cardiomyopathies; Dextrocardia; Physiological Effects of Drugs; Hormones, Hormone Substitutes, and Hormone Antagonists; Natriuretic Agents; Diuretics; Hormone Antagonists; Mineralocorticoid Receptor Antagonists; Diuretics, Potassium Sparing; Spironolactone
• Other Study ID Numbers: 20170694

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No
• IPD Plan Description: There is no plan to share individual participant data with researchers outside of Dr. Mielniczuk's research team.

Drug and device information, study documents

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