Jouke P Bokma1,2, Michiel M Winter1, Arie P van Dijk3, Hubert W Vliegen4, Joost P van Melle5, Folkert J Meijboom6, Martijn C Post7, Jacqueline K Berbee8, S Matthijs Boekholdt1, Maarten Groenink1, Aeilko H Zwinderman9, Barbara J M Mulder1,2, Berto J Bouma10,2. 1. Department of Cardiology, Academic Medical Center Amsterdam, The Netherlands (J.P.B., M.M.W., S.M.B., M.G., B.J.M.M., B.J.B.). 2. Netherlands Heart Institute, Utrecht (J.P.B., B.J.M.M., B.J.B.). 3. Department of Cardiology, Radboud University Medical Center, Nijmegen, The Netherlands (A.P.v.D.). 4. Department of Cardiology, Leiden University Medical Center, The Netherlands (H.W.V.). 5. Department of Cardiology, Groningen University Medical Center, The Netherlands (J.P.v.M.). 6. Department of Cardiology, Utrecht University Medical Center, The Netherlands (F.J.M.). 7. Department of Cardiology, St. Antonius Hospital, Nieuwegein, The Netherlands (M.C.P.). 8. Department of Hospital Pharmacy, Academic Medical Center Amsterdam, The Netherlands (J.K.B.). 9. Department of Clinical Epidemiology and Biostatistics, Academic Medical Center Amsterdam, The Netherlands (A.H.Z.). 10. Department of Cardiology, Academic Medical Center Amsterdam, The Netherlands (J.P.B., M.M.W., S.M.B., M.G., B.J.M.M., B.J.B.) b.j.bouma@amc.uva.nl.
Abstract
BACKGROUND: The effect of angiotensin II receptor blockers on right ventricular (RV) function is still unknown. Angiotensin II receptor blockers are beneficial in patients with acquired left ventricular dysfunction, and recent findings have suggested a favorable effect in symptomatic patients with systemic RV dysfunction. The current study aimed to determine the effect of losartan, an angiotensin II receptor blocker, on subpulmonary RV dysfunction in adults after repaired tetralogy of Fallot. METHODS: The REDEFINE trial (Right Ventricular Dysfunction in Tetralogy of Fallot: Inhibition of the Renin-Angiotensin-Aldosterone System) is an investigator-initiated, multicenter, prospective, 1:1 randomized, double-blind, placebo-controlled study. Adults with repaired tetralogy of Fallot and RV dysfunction (RV ejection fraction [EF] <50%) but without severe valvular dysfunction were eligible. Patients were randomly assigned between losartan (150 mg daily) and placebo with target treatment duration between 18 and 24 months. The primary outcome was RV EF change, determined by cardiovascular MRI in intention-to-treat analysis. RESULTS:Of 95 included patients, 47 patients received 150 mg losartan daily (age, 38.0±12.4 years; 74% male), and 48 patients receivedplacebo (age, 40.6±11.4 years; 63% male). Overall, RV EF did not change in patients allocated to losartan (n=42) (44.4±5.1% to 45.2±5.0%) and placebo (n=46) (43.2±6.3% to 43.6±6.9%). Losartan did not significantly improve RV EF in comparison with placebo (+0.51%; 95% confidence interval, -1.0 to +2.0; P=0.50). No significant treatment effects were found on secondary outcomes: left ventricular EF, peak aerobic exercise capacity, and N-terminal pro-brain natriuretic peptide (P>0.30 for all). In predefined subgroup analyses, losartan did not have a statistically significant impact on RV EF in subgroups with symptoms, restrictive RV, RV EF<40%, pulmonary valve replacement, or QRS fragmentation. However, in a post hoc analysis, losartan was associated with improved RV EF in a subgroup (n=30) with nonrestrictive RV and incomplete remodeling (QRS fragmentation and previous pulmonary valve replacement) (+2.7%; 95% confidence interval, +0.1 to +5.4; P=0.045). CONCLUSIONS:Losartan had no significant effect on RV dysfunction or secondary outcome parameters in repaired tetralogy of Fallot. Future larger studies may determine whether there might be a role for losartan in specific vulnerable subgroups. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02010905.
RCT Entities:
BACKGROUND: The effect of angiotensin II receptor blockers on right ventricular (RV) function is still unknown. Angiotensin II receptor blockers are beneficial in patients with acquired left ventricular dysfunction, and recent findings have suggested a favorable effect in symptomatic patients with systemic RV dysfunction. The current study aimed to determine the effect of losartan, an angiotensin II receptor blocker, on subpulmonary RV dysfunction in adults after repaired tetralogy of Fallot. METHODS: The REDEFINE trial (Right Ventricular Dysfunction in Tetralogy of Fallot: Inhibition of the Renin-Angiotensin-Aldosterone System) is an investigator-initiated, multicenter, prospective, 1:1 randomized, double-blind, placebo-controlled study. Adults with repaired tetralogy of Fallot and RV dysfunction (RV ejection fraction [EF] <50%) but without severe valvular dysfunction were eligible. Patients were randomly assigned between losartan (150 mg daily) and placebo with target treatment duration between 18 and 24 months. The primary outcome was RV EF change, determined by cardiovascular MRI in intention-to-treat analysis. RESULTS: Of 95 included patients, 47 patients received 150 mg losartan daily (age, 38.0±12.4 years; 74% male), and 48 patients received placebo (age, 40.6±11.4 years; 63% male). Overall, RV EF did not change in patients allocated to losartan (n=42) (44.4±5.1% to 45.2±5.0%) and placebo (n=46) (43.2±6.3% to 43.6±6.9%). Losartan did not significantly improve RV EF in comparison with placebo (+0.51%; 95% confidence interval, -1.0 to +2.0; P=0.50). No significant treatment effects were found on secondary outcomes: left ventricular EF, peak aerobic exercise capacity, and N-terminal pro-brain natriuretic peptide (P>0.30 for all). In predefined subgroup analyses, losartan did not have a statistically significant impact on RV EF in subgroups with symptoms, restrictive RV, RV EF<40%, pulmonary valve replacement, or QRS fragmentation. However, in a post hoc analysis, losartan was associated with improved RV EF in a subgroup (n=30) with nonrestrictive RV and incomplete remodeling (QRS fragmentation and previous pulmonary valve replacement) (+2.7%; 95% confidence interval, +0.1 to +5.4; P=0.045). CONCLUSIONS:Losartan had no significant effect on RV dysfunction or secondary outcome parameters in repaired tetralogy of Fallot. Future larger studies may determine whether there might be a role for losartan in specific vulnerable subgroups. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02010905.
Authors: Odilia I Woudstra; Joey M Kuijpers; Folkert J Meijboom; Marco C Post; Monique R M Jongbloed; Anthonie L Duijnhouwer; Arie P J van Dijk; Joost P van Melle; Thelma C Konings; Aeilko H Zwinderman; Barbara J M Mulder; Berto J Bouma Journal: Eur Heart J Cardiovasc Pharmacother Date: 2019-10-01
Authors: Alexander C Egbe; Patricia A Pellikka; Arslan Afzal; Vaibhav Jain; Sahith Thotamgari; William R Miranda; Heidi M Connolly Journal: CJC Open Date: 2019-11-18