Clinical trial NCT02010905: Right Ventricular Dysfunction in Tetralogy of Fallot: Inhibition of the Renin-angiotensin-aldosterone System
Official title: Right Ventricular Dysfunction in Tetralogy of Fallot: Inhibition of the Renin-angiotensin-aldosterone System
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE2
Conditions: Tetralogy of Fallot
Heart Defects, Congenital
Ventricular Dysfunction, Right
Keywords: Losartan
Lead sponsor: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
Sponsor class: OTHER
Collaborators: name: The Interuniversity Cardiology Institute of the Netherlands
First posted: 2013-12-13
Enrollment: 120
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Rationale: The prevalence of adult patients with congenital heart disease (CHD) has steadily increased over the last decades, due to the advances in cardiac surgery. A large number of these patients cope with right ventricular (RV) volume or pressure overload, largely caused by residual lesions after cardiac surgery in childhood. Previous RV overload due to pulmonary regurgitation in Tetralogy of Fallot (TOF) can lead to RV dysfunction. These findings warrant close surveillance of RV function, and adequate and evidence-based pharmacological therapy to reduce both morbidity and mortality in this young patient group. The renin-angiotensin-aldosterone system (RAAS) is activated in patients with ventricular failure, irrespective of the effected (left or right) ventricle. Angiotensin converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARB's) are drugs which act as inhibitors of RAAS. Previously, large trials have demonstrated the beneficial effect of angiotensin converting enzyme (ACE) inhibitors on morbidity and mortality in patients with acquired left ventricular (LV) dysfunction. ARB's have a similar effect as ACE inhibitors in patients with acquired LV dysfunction but discontinuation because of side effects such as cough is less frequent. In TOF patients with RV overload due to pulmonary regurgitation, pulmonary valve replacement leads to a decrease in RV size and pulmonary regurgitation. Current guidelines advise empiric use of RAAS inhibitors for right ventricular dysfunction in adult patients with congenital heart disease. However, the actual effect of RAAS inhibition on right ventricular dysfunction in adult TOF patients without severe valvular lesions has not been sufficiently investigated. Therefore, we set-up the proposed study, and hypothesize that ARB's have a beneficial effect on RV ejection fraction in adult TOF patients with RV dysfunction without severe valvular lesions.

Objective: to improve RV ejection fraction in adult TOF patients with RV dysfunction without severe valvular lesions.

Study design: a prospective, multicenter, double-blind, randomized, placebo-controlled trial. Follow up two years Study population: adult patients with Tetralogy of Fallot with right ventricular dysfunction, defined as right ventricular ejection fraction \< 50% and without severe valvular lesions Intervention: patients are randomized to receive either losartan 150 mg once daily, or placebo in the same regimen. Main study parameters/endpoints: the primary endpoint is difference in change in RV ejection fraction, determined by cardiovascular magnetic resonance imaging (CMR), between the treatment and the control group at two years follow-up.

Nature and extent of the burden and risks associated with participation, benefit and group relatedness: All investigations, except blood analysis, are non-invasive and free of risk. The burden for the patients mainly consists of the time that is consumed by the visits to the clinic. At these visits time will be consumed by: history taking and physical investigation (15 minutes); quality of life score (15 minutes); laboratory tests (6 times venopuncture, total amount of blood withdrawn approximately 90ml). Cardiopulmonary exercise testing (1hour), echocardiography (15 minutes) and CMR (45 minutes) are part of regular medical care. Adverse effects from losartan are usually limited and consist of dizziness due to hypotension, renal impairment, hyperkalemia and liver impairment. We expect no change or an increase in RV function in the intervention group compared to the control group over the two-year follow up period, which would be a great benefit for this young study population.


Eligibility criteria: Inclusion Criteria:

In order to be eligible to participate in this study, a subject must meet all of the following criteria: adult age and mentally competent; and Tetralogy of Fallot; and right ventricular dysfunction, defined as right ventricular ejection fraction 50% or lower as measured by Cardiovascular Magnetic Resonance Imaging (CMR). Not more than moderate tricuspid or pulmonary regurgitation or more than moderate pulmonary stenosis as measured by CMR or echocardiography.

Exclusion Criteria:

* Incapable of giving informed consent
* Hypersensitivity to losartan or any of its help substances
* Contraindications for CMR
* Previous or current angioedema whether or not in relation to the use of an ACE inhibitor or ARB
* Known bilateral renal artery stenosis
* Current symptomatic hypotension
* Estimated glomerular filtration rate of 30 ml/min or lower
* Plasma potassium level of 5,5 mmol/L or higher
* Moderate to severe liver disease: Child Pugh class B or C
* Raised plasma transaminases level more than three times upper normal limit
* Current treatment of hypertension with an ACE-inhibitor or ARB, which cannot be discontinued
* Current treatment with potassium chloride, trimethoprim, tacrolimus or cyclosporine which cannot be discontinued
* Pregnant or nursing women
* Desire to have children within the study period

Primary outcomes:
measure: Right ventricular ejection fraction
timeFrame: two years
Secondary outcomes:
measure: RV volumes (CMR)
timeFrame: two years
measure: pulmonary regurgitation (CMR and echocardiography)
timeFrame: two years
measure: aortic root diameter (CMR and echocardiography)
timeFrame: two years
measure: echocardiographic parameters for RV and LV function
timeFrame: one year and two years
measure: maximal exercise capacity (VO2 max)
timeFrame: two years
measure: hospitalization for heart failure
timeFrame: two years
measure: the prevalence of (supra) ventricular arrhythmias
timeFrame: within two years
measure: the serum ntproBNP levels
timeFrame: one year and two years
measure: NYHA class
timeFrame: two years
measure: Quality of life (SF 36 and SQUASH)
timeFrame: two years
measure: death
timeFrame: two years
measure: RV mass (CMR)
timeFrame: two years
measure: LV EF (CMR)
timeFrame: two years
measure: LV volumes (CMR)
timeFrame: two years
measure: LV mass (CMR)
timeFrame: two years
measure: serum Galectin-3 levels
timeFrame: two years
measure: circulating microRNA's
timeFrame: two years
Other outcomes:
Locations:
city: Amsterdam
country: Netherlands
facility: Academic Medical Center
city: Groningen
country: Netherlands
facility: Universitair Medisch Centrum Groningen
city: Leiden
country: Netherlands
facility: Leids Universitair Medisch Centrum
city: Nieuwegein
country: Netherlands
facility: St Antonius ziekenhuis
city: Nijmegen
country: Netherlands
facility: St Radboud Universitair Medisch Centrum
city: Utrecht
country: Netherlands
facility: Universitair Medisch Centrum Utrecht
Study officials:
References:
citation: Bokma JP, Winter MM, van Dijk AP, Vliegen HW, van Melle JP, Meijboom FJ, Post MC, Berbee JK, Boekholdt SM, Groenink M, Zwinderman AH, Mulder BJM, Bouma BJ. Effect of Losartan on Right Ventricular Dysfunction: Results From the Double-Blind, Randomized REDEFINE Trial (Right Ventricular Dysfunction in Tetralogy of Fallot: Inhibition of the Renin-Angiotensin-Aldosterone System) in Adults With Repaired Tetralogy of Fallot. Circulation. 2018 Apr 3;137(14):1463-1471. doi: 10.1161/CIRCULATIONAHA.117.031438. Epub 2017 Dec 8.