TY - JOUR

T1 - The first-in-man randomized trial of a beta3 adrenoceptor agonist in chronic heart failure

T2 - the BEAT-HF trial

AU - Bundgaard, Henning

AU - Axelsson, Anna

AU - Hartvig Thomsen, Jakob

AU - Sørgaard, Mathias

AU - Kofoed, Klaus F

AU - Hasselbalch, Rasmus

AU - Fry, Natasha A S

AU - Valeur, Nana

AU - Boesgaard, Søren

AU - Gustafsson, Finn

AU - Køber, Lars

AU - Iversen, Kasper

AU - Rasmussen, Helge H

N1 - © 2016 The Authors. European Journal of Heart Failure © 2016 European Society of Cardiology.

PY - 2017/4

Y1 - 2017/4

N2 - AIMS: The third isotype of beta adrenergic receptors (β3 ARs) has distinctly different effects on cardiomyocytes compared with β1 and β2 ARs. Stimulation of β3 ARs may reduce cardiomyocyte Na+overload and reduce oxidative stress in heart failure (HF). We examined if treatment with the β3 AR agonist mirabegron increases LVEF in patients with HF.METHODS AND RESULTS: In a double-blind trial we randomly assigned 70 patients with NYHA class II-III HF and LVEF <40% at screening-echocardiography to receive mirabegron or placebo for 6 months as add-on to optimized standard therapy. The primary endpoint was an increase in LVEF after 6 months as measured by computed tomography (CT). Changes in LVEF after 6 months between treatment groups were not significantly different (0.4%, -3.5 to 3.8%, P = 0.82). In an exploratory analysis, based on an expectation that the pathophysiological substrate targeted with treatment is dependent on the baseline LVEF, patients with LVEF <40% by CT given mirabegron had a significant increase in LVEF while no increase was seen in patients given placebo. The changes were significantly different between groups (5.5%, 0.6-10.4%, P < 0.03). Additionally, there was interaction between baseline LVEF and change in LVEF in the entire group of patients treated with mirabegron (R2 = 0.40, β  = -0.63, P < 0.001), but not in the placebo group (R2 = 0.00, β  = -0.01, P = 0.95). Treatment was generally well tolerated. Three patients in each group had fatal or life-threatening events.CONCLUSIONS: The primary endpoint was not reached. Exploratory analysis indicated that β3 AR stimulation by mirabegron increased LVEF in patients with severe HF. Treatment appeared safe. Additional studies in severe HF are needed.TRIAL REGISTRATION: NCT01876433.

AB - AIMS: The third isotype of beta adrenergic receptors (β3 ARs) has distinctly different effects on cardiomyocytes compared with β1 and β2 ARs. Stimulation of β3 ARs may reduce cardiomyocyte Na+overload and reduce oxidative stress in heart failure (HF). We examined if treatment with the β3 AR agonist mirabegron increases LVEF in patients with HF.METHODS AND RESULTS: In a double-blind trial we randomly assigned 70 patients with NYHA class II-III HF and LVEF <40% at screening-echocardiography to receive mirabegron or placebo for 6 months as add-on to optimized standard therapy. The primary endpoint was an increase in LVEF after 6 months as measured by computed tomography (CT). Changes in LVEF after 6 months between treatment groups were not significantly different (0.4%, -3.5 to 3.8%, P = 0.82). In an exploratory analysis, based on an expectation that the pathophysiological substrate targeted with treatment is dependent on the baseline LVEF, patients with LVEF <40% by CT given mirabegron had a significant increase in LVEF while no increase was seen in patients given placebo. The changes were significantly different between groups (5.5%, 0.6-10.4%, P < 0.03). Additionally, there was interaction between baseline LVEF and change in LVEF in the entire group of patients treated with mirabegron (R2 = 0.40, β  = -0.63, P < 0.001), but not in the placebo group (R2 = 0.00, β  = -0.01, P = 0.95). Treatment was generally well tolerated. Three patients in each group had fatal or life-threatening events.CONCLUSIONS: The primary endpoint was not reached. Exploratory analysis indicated that β3 AR stimulation by mirabegron increased LVEF in patients with severe HF. Treatment appeared safe. Additional studies in severe HF are needed.TRIAL REGISTRATION: NCT01876433.

KW - Acetanilides/therapeutic use

KW - Adrenergic beta-3 Receptor Agonists/therapeutic use

KW - Adult

KW - Aged

KW - Double-Blind Method

KW - Female

KW - Heart Failure/diagnostic imaging

KW - Humans

KW - Male

KW - Middle Aged

KW - Stroke Volume

KW - Thiazoles/therapeutic use

KW - Tomography, X-Ray Computed

U2 - 10.1002/ejhf.714

DO - 10.1002/ejhf.714

M3 - Journal article

C2 - 27990717

VL - 19

SP - 566

EP - 575

JO - European Journal of Heart Failure

JF - European Journal of Heart Failure

SN - 1567-4215

IS - 4

ER -