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 heartfailure (HF) and intracellular Na+

BEAT-HF

Background –Acute hemodynamic effects of ß3 AR stimulation in heart failure

BEAT-HF Bundgaard H et al. Circulation. 2010. 122(25):2699-708

• In the normal heart a ß3 ARagonist has a negativeinotropic effect because itreduces Nai and, via Na-Caexchanger – reduces Cai

• In HF - characterized by ”Naioverloaded myocytes” - adecrease in Nai with injectionof a ß3 AR agonist shouldimprove LV function

LV function in normal sheep heart

LV function in stable severe HF after coronary micro-embolization

• Do these results translateinto improved LV functionwith chronic ß3 AR agonisttreatment 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

Secondary outcomes (changes in)- NT-pro-BNP- Cardiac output/ stroke volume- Left ventricular volumes- Left atrial volume- Diastolic function- QT interval duration- Exercise tolerance- Symptoms

BEAT-HF

Endpoints

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)

Randomized (n=70)

Placebo (n=35) Mirabegron (n=35)

2 Deaths1 Adverse effects1Admitted - endocarditis1 Admitted - urinary tract infection 1 Reduced complianceFollow-up data

analyzed (n=29)

1 Adverse effects2 Reduced compliance

Follow-up data analyzed (n=32)

Follow up 6 months

Baseline characteristics - 1Placebo (n=35)

Mirabegron (n=35) p

Demographic characteristicsAge – yr 56±12 62±12 0.05Female sex – no. (%) 4 (11) 4 (11) 1.0

Medical historyIschemic heart failure – no. (%) 16 (46) 15 (43) 0.91Revascularised – no. (% of patiens with ischemic HF) 12 (75) 11 (73)Non-ischemic heart heart failure 19 (54) 20 (57) 0.91Previous cardiac arrest, sustained VT and/or

a appropriate ICD shock – no. (%) 19 (54) 20 (57) 0.91

Diabetes – no. (%) 3(9) 5(14) 0.71Cardiac medications – no. (%)

Beta-blocker 35 (100) 35 (100) 1.0ACE/ARB 35 (100) 33(94) 0.49Spironolactone/Eplerenone – no. (%)Other diuretics – no. (%)

Symptoms and physical function

21 (60)17 (49)

27 (77)16 (46)

0.20.81

New York Heart Association class II/III – no. (%) 33 (94) / 2 (5) 34(97) / 1 (3) 0.51VO2 max (ml/kg/min) 21±6 20±7 0.40

BEAT-HF

Baseline characteristics - 2

BEAT-HF

Placebo (n=35)

Mirabegron (n=35)

P

Vital signsSystolic blood pressure – mmHg 124±19 122±20 0.75Diastolic blood pressure – mmHg 78±12 75±12 0.37Heart rate 66±10 62±9 0.11

Echocardiographic findingsLeft ventricular ejection fraction – % 34±7 32±10 0.36

Volumetric and mass parameters by CTLeft ventricular ejection fraction (%) 38±17 40±11 0.32Left ventricular end diastolic volume (ml/m2) 131±45 129±41 0.88Left ventricular end systolic volume (ml/m2) 84±42 80±38 0.71Left stroke volume (ml/m2) 47±11 49±13 0.47Left ventricular mass – g/m2 81±18 79±19 0.64Left atrial volume – ml/m2 62±20 70±18 0.12

• All 61 patients completing the study were compliant by pill count (> 98%) • 66 patients (94%) reached target dose of 300 mg daily, 3 patients 200 mg

(Mirabegron), 1 patient 100 mg daily (Placebo).

Compliance and safety

BEAT-HF

mm

Hg

Bea

ts p

r min

MirabegronPlacebo

Baseline 6 months Baseline 6 months Baseline 6 months

Mean difference 2.2 (95% CL, -5.2 to 9.5)P=0.55

Mean difference -0.3 (95% CL, -6.0 to 5.5)P=0.91

Systolic BP Diastolic BP

Mean difference 0.6 (95% CL, -3.2 to 6.3)P=0.52

Heart rate

200

406080

100120140

200

406080

100120140

mm

Hg

20

0

40

60

80

100

Primary endpoint

BEAT-HF

Left ventricular ejection fraction

P= 0.82

Mean difference 0.4% (95% CL, -3.5 to 3.8) LV

EF (%

)

Mirabegron

Placebo

Baseline 6 months

Secondary endpoints

BEAT-HF

Placebo (n=32) Mirabegron (n=29)

Baseline Follow-up Change Baseline Follow-up ChangeBetween group

difference (95%CI) p

Volumetric parameters by CTLeft ventricular end diastolic volume ml 276±114 269±116 -7±33 263±80 257±78 -6±27 1((-15)-16) 0.95

Left ventricular end systolic volume ml 178±103 175±107 -4±30 160±80 152±68 -8±27 -4((-19)-11) 0.56

Stroke volume ml 97±25 95±24 -3±13 102±26 101±28 -1±31 1((-11)-13) 0.85

Left atrial volume ML 131±48 125±47 -5±15 143±31 141±37 -2±17 3±((-5)-12 0.45

Physical capacity

NYHA class I/II/III (%) 0/8/91 16/72/13 - 0/97/3 24/72/2 - - 0.29

6 min walking distance m 487±101 494±98 7±52 493±83 492±98 -1±35 -8((-32)-15) 0.49

VO2 max (ml/kg/min) 21±6 21±6 -1±4 20±7 22±8 1±5 1((-4)-6) 0.74

Laboratory measurements

NT-pro-BNP - pmol/l 87±107 91±129 4±72 66±55 77±78 11±51 7((-25)-40) 0.65

ECG

QT interval ms 430±52 428±38 -2±36 446±35 440±43 -6±20 -4((-20)-11) 0.57

Exploratory analyses

BEAT-HF

Baseline 6 months 6 monthsBaseline

Baseline LVEF (CT) < 40% Baseline LVEF (CT) ≥ 40%

P= 0.40

Mean difference -2.0% (95% CL, -6.8 to 2.8)

P<0.03

Mean difference 5.5% (95% CL, 0.6-10.4)

Mirabegron

Placebo

Adverse events

BEAT-HF

Placebo (n=35) Mirabegron (n=35) p

Serious adverse events

Sudden death 0 2 NS

Appropriate ICD shock for VT/VF 3 1 NS

Chest pain 0 2 NS

Renal impairment 1 0 NS

Fever/infection 1 3 NS

Any adverse events

Serious adverse events (no. of patients) 5 8 NS

Other adverse event (no. of patients) 8 12 NS

Discontinuation for adverse events

Admitted with urinary tract infection 0 1 NS

Admitted with device endocarditis 0 1 NS

Hypersensitivity 0 1 NS

Unspecific symptoms 1 0 NS

• Mirabegron did not increase LVEF in patients with a mean EF of 40%

• There was no significant effects on the secondary endpoints

• The target dose was reached in 94% of the patients

• Safety profile – incl. blood pressure, heart rate, and │QT│ - seemed acceptable and adverse events were generally mild and transient

• The exploratory analysis indicated an increase in LVEF in patients with more severe HF at baseline, but not in patients with EF ≥ 40%

Conclusions

BEAT-HF

• The beneficial effect of the β3 AR agonist only in severe heart failure is in agreement with the mechanistic foundation of our study

• An additional study on effects of β3 AR agonists in patients with severe heart failure is needed for the design of a phase III trial

Implications

BEAT-HF

• The Research Fund of Rigshospitalet

• The Heart Center Research Foundation

• The Novo Nordic Foundation

• The A.P. Møller and Chastine Mc-Kinney Møller Foundation

Funding

INHERIT