The-First-In-Man Randomized Trial of a ß3-adrenoceptor Agonist in Chronic Heart Failure BEAT-HF Henning Bundgaard, Anna Axelsson, Jakob H Thomsen, Mathias Sørgaard, Klaus Kofoed, Nana Køber, Rasmus B Hasselbalch, Henry Krum, Søren Boesgaard, Finn Gustafsson, Lars Køber, Kasper Iversen, Helge Rasmussen
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The-First-In-Man Randomized Trial of a ß3- adrenoceptor Agonist in Chronic Heart Failure BEAT-HF Henning Bundgaard, Anna Axelsson, Jakob H Thomsen, Mathias.
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The-First-In-Man Randomized Trial of a ß3-adrenoceptor Agonist in Chronic Heart
Failure
BEAT-HF
Henning Bundgaard, Anna Axelsson, Jakob H Thomsen, Mathias Sørgaard, Klaus Kofoed, Nana Køber, Rasmus B Hasselbalch, Henry
Krum, Søren Boesgaard, Finn Gustafsson, Lars Køber, Kasper Iversen, Helge Rasmussen
• Raised levels of intracellular sodium (Nai) in the cardiomyocytes contribute to contraction abnormalities in heart failure (HF)
• The Na-K pump in the cardiomyocytes mediates Nai export – and evidence-based HF treatments stimulate the Na-K pump (ß blockers, ACE inhibitors, aldosterone antagonists)
• ß3 adrenoceptor (AR) agonists stimulate the Na-K pump through the NO/cGMP/PKG pathway – mediating Nai export
(Bundgaard et al, Circulation 2010)
Background – chronic heart failure (HF) and intracellular Na+
BEAT-HF
Background –Acute hemodynamic effects of ß3 AR stimulation in heart failure
BEAT-HFBundgaard H et al. Circulation. 2010. 122(25):2699-708
• In the normal heart a ß3 AR agonist has a negative inotropic effect because it reduces Nai and, via Na-Ca exchanger – reduces Cai
• In HF - characterized by ”Nai overloaded myocytes” - a decrease in Nai with injection of a ß3 AR agonist should improve LV function
LV function in normal sheep heart
LV function in stable severe HF after coronary micro-embolization
• Do these results translate into improved LV function with chronic ß3 AR agonist treatment in human HF?
IV injection of ß3 AR agonist in increasing doses
To investigate the effect of a ß3 AR agonist, Mirabegron on left ventricular ejection fraction in patients with chronic heart failure
• Single center, double-blind, placebo-controlled, randomized trial
• Randomization 1:1 to Mirabegron 300 mg daily, or placebo for 6 months
• Sample size: 70 patients- 90% power,- change left ventricular ejection fraction of 4% (the primary end-point)- two-sided p<0.05,- drop-out rate of 30%.
Objective and study design
BEAT-HF
• Mirabegron; - FDA and EMA approved for overactive bladder (OAB)- Dose (25-)50 mg x 1- T1/2 =22-25 h, Cmax 3-4 h
• Side effects; – Increased BP and HR (off-target ß1/2 AR stimulation), – “Cold” symptoms, – Gastrointestinal discomfort
• Maximum reported dosage for OAB over12 weeks: 300 mg/day
• Doses administered in this study:– Start; 25 mg x 2 – then – if tolerated - weekly increases;– 50 mg x 2, 100 mg x 2, 150 mg x 2 (after a week 300 mg x1)
BEAT-HF
Study drug and dose
Primary endpoint- Change in left ventricular ejection fraction (LVEF) as assessed by CT
Key inclusion criteria– Stable heart failure on ischemic or non-ischemic basis– Left ventricular ejection fraction < 40% on screening echocardiography– On optimized evidence-based pharmacotherapy - stable > 4 weeks– The therapy must include a beta-blocker - to counterbalance ß1/2 effects
Key exclusion criteria– Recent AMI or revascularization (< 3 months) or CRT (< 6 months)– Significant obstructive valvular disease– Atrial fibrillation– Uncontrolled hypertension (sBT ≥180 mmHg, dBT ≥ 110 mmHg)– Renal (eGFR < 50 ml/min/1.73 m2 or hepatic (transaminases >x3) diseases – Treatment with digoxin, tricyclic antidepressants or other CYP2D6
inhibitors than betablockers
Eligibility
BEAT-HF
Study design
BEAT-HF
Screened (n=142)
37 declined participation
33 Screen failure12 ejection fraction ≥ 40%5 Renal failure5 Atrial fibrillation4 BMI > 353 Drug contra-indications6 Other Eligible (n=107)