The first‐in‐man randomized trial of a beta3 adrenoceptor agonist in chronic heart failure: the <scp>BEAT‐HF</scp> trial

Bundgaard, Henning; Axelsson, Anna; Thomsen, Jakob Hartvig; Sørgaard, Mathias; Kofoed, Klaus F.; Hasselbalch, Rasmus Bo; Fry, N.; Valeur, Nana; Boesgaard, Søren; Gustafsson, Finn; Køber, Lars; Iversen, Kasper; Rasmussen, Helge H.

doi:10.1002/ejhf.714

Cited by 65 publications

(79 citation statements)

References 33 publications

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“…That administration of BRL37344, a β 3 AR agonist, in large animal models of HF does not translate to decreased cardiac performance in vivo , mitigates these concerns. In addition, administration of mirabegron in a small group of patients with severe HFrEF (ejection fraction <40%) resulted in improvement of LV function in the BEta 3 Agonists Treatment in HF (BEAT‐HF) trial (see the succeeding texts) …”

Section: Discussionmentioning

confidence: 99%

“…23 The-first-in-man randomized trial of a β 3 AR agonist in chronic HF (BEAT-HF) was recently conducted in 70 patients with NYHA Classes II and III HF and LVEF <40% at screening echocardiography. 49 Patients received mirabegron or placebo for 6 months as add-on to optimized standard therapy. The primary endpoint of an increase in LVEF after 6 months as measured by computed tomography was not reached.…”

Section: Safety and Tolerability Of Mirabegron In The Target Populationmentioning

confidence: 99%

“…In addition, administration of mirabegron in a small group of patients with severe HFrEF (ejection fraction <40%) resulted in improvement of LV function in the BEta 3 Agonists Treatment in HF (BEAT-HF) trial (see the succeeding texts). 49 Importantly, β 3 AR also mediate antioxidant effects 22 that, unlike previous therapeutic approaches with guanylyl cyclase stimulators (vericiguat) or PDE5 inhibitors (sildenafil), would protect the NO/cGMP signalling from oxidative degradation and preserve its efficacy in remodelling myocardium with prevailing oxidant stress. This antioxidant effect also contributes to decrease paracrine pro-fibrotic signalling.…”

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Rationale and design of a multicentre, randomized, placebo‐controlled trial of mirabegron, a Beta3‐adrenergic receptor agonist on left ventricular mass and diastolic function in patients with structural heart disease Beta3‐left ventricular hypertrophy (Beta3‐LVH)

et al. 2018

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AimsProgressive left ventricular (LV) remodelling with cardiac myocyte hypertrophy, myocardial fibrosis, and endothelial dysfunction plays a key role in the onset and progression of heart failure with preserved ejection fraction. The Beta3‐LVH trial will test the hypothesis that the β3 adrenergic receptor agonist mirabegron will improve LV hypertrophy and diastolic function in patients with hypertensive structural heart disease at high risk for developing heart failure with preserved ejection fraction.Methods and resultsBeta3‐LVH is a randomized, placebo‐controlled, double‐blind, two‐armed, multicentre, European, parallel group study. A total of 296 patients will be randomly assigned to receive either mirabegron 50 mg daily or placebo over 12 months. The main inclusion criterion is the presence of LV hypertrophy, that is, increased LV mass index (LVMi) or increased wall thickening by echocardiography. The co‐primary endpoints are a change in LVMi by cardiac magnetic resonance imaging and a change in LV diastolic function (assessed by the E/e′ ratio). Secondary endpoints include mirabegron's effects on cardiac fibrosis, left atrial volume index, maximal exercise capacity, and laboratory markers. Two substudies will evaluate mirabegron's effect on endothelial function by pulse amplitude tonometry and brown fat activity by positron emission tomography using 17F‐fluorodeoxyglucose. Morbidity and mortality as well as safety aspects will also be assessed.ConclusionsBeta3‐LVH is the first large‐scale clinical trial to evaluate the effects of mirabegron on LVMi and diastolic function in patients with LVH. Beta3‐LVH will provide important information about the clinical course of this condition and may have significant impact on treatment strategies and future trials in these patients.

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Section: Discussionmentioning

confidence: 99%

Section: Safety and Tolerability Of Mirabegron In The Target Populationmentioning

confidence: 99%

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confidence: 99%

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Rationale and design of a multicentre, randomized, placebo‐controlled trial of mirabegron, a Beta3‐adrenergic receptor agonist on left ventricular mass and diastolic function in patients with structural heart disease Beta3‐left ventricular hypertrophy (Beta3‐LVH)

et al. 2018

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“…Currently, there are three clinical studies investigating potential beneficial effects of mirabegron. One of them, the BEAT-HF trial, has already been completed (Bundgaard et al, 2017). This double-blind clinical trial has examined the effectiveness of mirabegron treatment versus placebo in 70 patients with NYHA class II-III heart failure.…”

Section: β 3 -Adrenoceptors As a Therapeutic Target In Cardiac Pathmentioning

confidence: 99%

Cardiac β₃‐adrenoceptors—A role in human pathophysiology?

Arioglu‐Inan

Kaykı-Mutlu

Michel

2019

British J Pharmacology

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As β3‐adrenoceptors were first demonstrated to be expressed in adipose tissue they have received much attention for their metabolic effects in obesity and diabetes. After the existence of this subtype had been suggested to be present in the heart, studies focused on its role in cardiac function. While the presence and functional role of β3‐adrenoceptors in the heart has not uniformly been detected, there is a broad consensus that they become up‐regulated in pathological conditions associated with increased sympathetic activity such as heart failure and diabetes. When detected, the β3‐adrenceptor has been demonstrated to mediate negative inotropic effects in an inhibitory G protein‐dependent manner through the NO–cGMP–PKG signalling pathway. Whether these negative inotropic effects provide protection from the adverse effects induced by overstimulation of β1/β2‐adrenoceptors or in themselves are potentially harmful is controversial, but ongoing clinical studies in patients with congestive heart failure are testing the hypothesis that β3‐adrenceptor agonism has a beneficial effect. Linked Articles This article is part of a themed section on Adrenoceptors—New Roles for Old Players. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.14/issuetoc

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“…The rationale for prescribing mirabegron was in part based on our previous study on patients with stable, mostly Class II NYHA HFrEF. Mirabegron seemed safe during treatment for 6 months, and an exploratory secondary analysis suggested the treatment increased left ventricular ejection fraction (LVEF) in patients with a particularly low baseline EF, but not in similar placebo treated patients 9 . We felt this, combined with a mechanistically plausible rationale and beneficial effects of β3 AR agonists on organ congestion we identified in the rabbits, justified prescribing mirabegron to our patients.…”

Section: Introductionmentioning

confidence: 99%

Targeting cardiac myocyte Na⁺-K⁺ pump function with β3 adrenergic agonist in rabbits and patients with severe congestive heart failure

Fry

Liu

García

et al. 2019

Preprint

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RationaleA high cytosolic Na + concentration ([Na + i]) impairs contractility of myocardium from patients with advanced heart failure (HF) and since the Na + -K + pump maintains a low [Na + i], targeting pump function might be beneficial. Objective Determine if cardiac myocyte Na + -K + pump function is impaired in rabbits with severe congestive HF and whether in vivo treatment with β3 adrenoceptor (β3 AR) agonists, that are known to stimulate the pump in vitro, reverses the HF syndrome. Assess the clinical response when patients with advanced treatment-resistant HF are prescribed a β3 AR agonist. Methods and ResultsCoronary ligation caused marked organ congestion and ascites in rabbits. Na + -K + pump current of myocytes from non-infarcted myocardium was decreased. This was reversed by β3 AR agonist treatment that also significantly reduced organ congestion and prevalence of ascites. Animal models cannot examine if efficacy is additive to guideline-directed drugs up-titrated to maximal tolerated doses. We studied outcomes of 9 patients hospitalized with advanced HF (stage D) refractory to maximally tolerated treatment as assessed by ≥ 2 cardiologists. One-year mortality of such patients is 75% with medical treatment and almost all die within 2 years, 90% from HF. The off-label oral treatment with the β3 AR agonist mirabegron rapidly improved signs and symptoms on a time scale similar to that of the rabbits. Improvement of ≥1 NYHA Class was maintained early post-discharge with continued treatment. One patient died from HF at 16 months, 4 died from other causes at 2 -30 months and 4 remain alive at 32 ± 5 months with NYHA Class II symptoms. ConclusionsParallel treatment-induced reversal of Na + -K + pump inhibition and features of HF in rabbits provides mechanistic rationale for efficacy of β3 AR agonists. Improved in-hospital clinical trajectory and more favourable post-discharge course than expected suggest efficacy of mirabegron in advanced human HF.

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The first‐in‐man randomized trial of a beta3 adrenoceptor agonist in chronic heart failure: the BEAT‐HF trial

Abstract: NCT01876433.

Cited by 65 publications

References 33 publications

Rationale and design of a multicentre, randomized, placebo‐controlled trial of mirabegron, a Beta3‐adrenergic receptor agonist on left ventricular mass and diastolic function in patients with structural heart disease Beta3‐left ventricular hypertrophy (Beta3‐LVH)

Rationale and design of a multicentre, randomized, placebo‐controlled trial of mirabegron, a Beta3‐adrenergic receptor agonist on left ventricular mass and diastolic function in patients with structural heart disease Beta3‐left ventricular hypertrophy (Beta3‐LVH)

Cardiac β₃‐adrenoceptors—A role in human pathophysiology?

Targeting cardiac myocyte Na⁺-K⁺ pump function with β3 adrenergic agonist in rabbits and patients with severe congestive heart failure

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The first‐in‐man randomized trial of a beta3 adrenoceptor agonist in chronic heart failure: the BEAT‐HF trial

Abstract: NCT01876433.

Cited by 65 publications

References 33 publications

Rationale and design of a multicentre, randomized, placebo‐controlled trial of mirabegron, a Beta3‐adrenergic receptor agonist on left ventricular mass and diastolic function in patients with structural heart disease Beta3‐left ventricular hypertrophy (Beta3‐LVH)

Rationale and design of a multicentre, randomized, placebo‐controlled trial of mirabegron, a Beta3‐adrenergic receptor agonist on left ventricular mass and diastolic function in patients with structural heart disease Beta3‐left ventricular hypertrophy (Beta3‐LVH)

Cardiac β3‐adrenoceptors—A role in human pathophysiology?

Targeting cardiac myocyte Na+-K+ pump function with β3 adrenergic agonist in rabbits and patients with severe congestive heart failure

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Product

Resources

About

Cardiac β₃‐adrenoceptors—A role in human pathophysiology?

Targeting cardiac myocyte Na⁺-K⁺ pump function with β3 adrenergic agonist in rabbits and patients with severe congestive heart failure