Right Ventricular Dysfunction in Tetralogy of Fallot: Inhibition of the Renin-angiotensin-aldosterone System
Status:
Unknown status
Trial end date:
2018-01-01
Target enrollment:
Participant gender:
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.
Phase:
Phase 2
Details
Lead Sponsor:
Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
Collaborator:
The Interuniversity Cardiology Institute of the Netherlands