Beta3_LVH: towards a treatment against heart failure

EXCLUSION CRITERIA:

 

• Unstable arterial hypertension with systolic BP≥160 mm Hg and/or diastolic BP≥100 mm Hg (confirmed at three consecutive office measurements in sitting position); if so, the patient may be re-screened after optimization of anti-hypertensive treatment

• Hypertensive patients not under stable therapy according to current guideline algorithm (Mancia et al. 2013) (including stable medication for at least 4 weeks before inclusion)

• Documented ischemic cardiac disease:

  • current angina pectoris or

  • ischemia on stress test or

  • untreated coronary stenosis >50% or

  • history of acute myocardial infarction (AMI) or

  • coronary artery bypass graft (CABG, < than 3 months prior to screening) or

  • percutaneous transluminal coronary angioplasty (PTCA) less than 3 months prior to screening.

• Patients with uncontrolled recurrent persistent and permanent atrial fibrillation (AF) according to AHA/ACC/ESC guidelines (Dixon et al. 2005) (with a heart rate > 100/min, RACE II - (Groenveld et al. 2013, 2013)). If AF with HR>100/min, the patient may be rescreened after treatment for rate control.

• History of hospitalization for overt heart failure within last 12 months

• History of high degree impulse conduction blocks (> 2nd degree AV block type 2)

• Patients after heart transplantation

• Genetic hypertrophic or dilated cardiomyopathy

• Dysthyroidism

• Severe valvulopathy (less than 1 cm2 aortic valve area, mitral insufficiency of severe grade at Doppler echo)

• Congenital valvulopathies

• Patients with a known history of QT prolongation (QT>450ms) or patients with documented QT prolongation (QT>450 ms) while taking medicinal products known to prolong the QT interval.

• NYHA-class > II

• BMI > 40 kg/m2

• EF < 50%, regardless of symptoms

• Known other cause (i.e. COPD) of respiratory dysfunction; patients under positive pressure (CPAP) treatment for sleep apnea syndrome may be included, provided they have been efficiently controlled by CPAP for at least one year before inclusion in the study

• Moderate renal impairment defined as eGFR < 30 ml/min

• Abnormal liver function tests (AST or ALT >2 X upper normal limit or patients with known hepatic impairment defined as Child-Pugh class B or higher)

• Type I diabetes, complicated type II diabetes (i.e. with documented coronary macroangiopathy , cfr exclusion criterion 1 or documented other vascular complication) (National Diabetes Education Initiative - NDEI).

• Patients with anemia (male: Hb <130 g/l, female: Hb <120 g/l)

• Patients with bladder outlet obstruction

• Patients using antimuscarinic cholinergic drugs for treatment of OAB

• Current use of digitalis, bupranolol, propranolol, nebivolol (known to interfere with β3AR signalling)

• Note: patients are allowed to take a β(1-2)-blocker, other than the drugs listed above (for explanation, see chapter 5.4.5).

• Patients continuously treated with Sildenafil or other PDE5 inhibitors.

• Current use of antifungal azole derivatives (fluconazole, itraconazole, miconazole, posaconazole, voriconazole) (known inhibitors of CYP3A4, the main metabolizer of mirabegron)

• Current treatment with mirabegron or indication for future treatment with mirabegron due to other indications

• Contraindication for MRI (e.g.defibrillator, ferromagnetic devices or severe claustrophobia, pacemaker - the latter only, if MRI is contraindicated)

• Pregnant or nursing women

• Women of child bearing potential without highly effective contraceptive measures (Clinical Trial Facilitation Group (CTFG) 9/15/2014): 

  • combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, transdermal)

  • progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, implantable)

  • intrauterine device (IUD)

  • intrauterine hormone-releasing system ( IUS)

  • bilateral tubal occlusion

  • vasectomised partner

  • sexual abstinence (only if in agreement with the preferred and usual lifestyle of the subject)

while participating in the trial. There are no known interactions of the trial medication and hormone-based methods of contraception. In particular, no clinically relevant interactions have been observed when mirabegron was co-administered with therapeutic doses of a combined oral contraceptive medicinal product containing ethinylestradiol and levonorgestrel.

• Participation in any other interventional trial

• Patients unable to give informed consent (people under legal guardianship)

• Patients placed in an institution by official or court order

• Contraindication to mirabegron (e.g. hypersensitivity) or any other components of the trial medication