Transcript Bundgaard_BEATx - Clinical Trial Results

The-First-In-Man Randomized Trial of a ß3adrenoceptor 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
Background – chronic heart
failure (HF) and intracellular Na+
• 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)
BEAT-HF
Background –Acute hemodynamic effects
of ß3 AR stimulation in heart failure
• 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
• Do these results translate
into improved LV function
with chronic ß3 AR agonist
treatment in human HF?
BEAT-HF
LV function in stable severe HF after
coronary micro-embolization
LV function in
normal sheep heart
IV injection of ß3 AR
agonist in increasing doses
Bundgaard H et al. Circulation. 2010. 122(25):2699-708
Objective and study design
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, placebocontrolled, 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%.
BEAT-HF
Study drug and dose
•
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
Endpoints
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
Eligibility
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
–
–
–
–
–
–
BEAT-HF
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
Study design
33 Screen failure
12 ejection fraction ≥ 40%
5 Renal failure
5 Atrial fibrillation
4 BMI > 35
3 Drug contra-indications
6 Other
Screened (n=142)
Eligible (n=107)
37 declined
participation
Randomized
(n=70)
Mirabegron
(n=35)
Placebo (n=35)
Follow up
6 months
1 Adverse effects
2 Reduced compliance
BEAT-HF
Follow-up data
analyzed (n=32)
Follow-up data
analyzed (n=29)
2 Deaths
1 Adverse effects
1Admitted - endocarditis
1 Admitted - urinary tract
infection
1 Reduced compliance
Baseline characteristics - 1
Placebo
(n=35)
Mirabegron
(n=35)
p
Age – yr
56±12
62±12
0.05
Female sex – no. (%)
4 (11)
4 (11)
1.0
Ischemic heart failure – no. (%)
16 (46)
15 (43)
0.91
Revascularised – no. (% of patiens with ischemic HF)
12 (75)
11 (73)
Non-ischemic heart heart failure
Previous cardiac arrest, sustained VT and/or
appropriate ICD shock – no. (%)
Diabetes – no. (%)
19 (54)
20 (57)
0.91
19 (54)
20 (57)
0.91
3(9)
5(14)
0.71
35 (100)
35 (100)
1.0
35 (100)
21 (60)
17 (49)
33(94)
27 (77)
16 (46)
0.49
0.2
0.81
33 (94) / 2 (5)
34(97) / 1 (3)
0.51
21±6
20±7
0.40
Demographic characteristics
Medical history
a
Cardiac medications – no. (%)
Beta-blocker
ACE/ARB
Spironolactone/Eplerenone – no. (%)
Other diuretics – no. (%)
Symptoms and physical function
New York Heart Association class II/III – no. (%)
VO2 max (ml/kg/min)
BEAT-HF
Baseline characteristics - 2
Placebo
(n=35)
Mirabegron
(n=35)
P
Systolic blood pressure – mmHg
124±19
122±20
0.75
Diastolic blood pressure – mmHg
78±12
66±10
75±12
62±9
0.37
34±7
32±10
0.36
38±17
40±11
0.32
131±45
129±41
0.88
84±42
47±11
80±38
49±13
0.71
Left ventricular mass – g/m
81±18
79±19
0.64
Left atrial volume – ml/m2
62±20
70±18
0.12
Vital signs
Heart rate
0.11
Echocardiographic findings
Left ventricular ejection fraction – %
Volumetric and mass parameters by CT
Left ventricular ejection fraction (%)
2
Left ventricular end diastolic volume (ml/m )
2
Left ventricular end systolic volume (ml/m )
2
Left stroke volume (ml/m )
2
BEAT-HF
0.47
•
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).
Mirabegron
Placebo
Systolic BP
Mean difference
2.2 (95% CL, -5.2 to 9.5)
P=0.55
Heart rate
140
100
120
80
100
80
60
40
20
Mean difference
-0.3 (95% CL, -6.0 to 5.5)
P=0.91
Beats pr min
140
120
100
80
60
40
20
0
Diastolic BP
mmHg
mmHg
Compliance and safety
BEAT-HF
6 months
40
20
Mean difference
0.6 (95% CL, -3.2 to 6.3)
P=0.52
0
0
Baseline
60
Baseline
6 months
Baseline
6 months
Primary endpoint
Left ventricular ejection fraction
Mirabegron
LVEF (%)
Placebo
BEAT-HF
P= 0.82
Mean difference
0.4% (95% CL, -3.5 to 3.8)
Baseline
6 months
Secondary endpoints
Placebo (n=32)
Mirabegron (n=29)
Baseline Follow-up Change
Baseline
Follow-up Change
Between group
difference (95%CI)
p
Volumetric parameters by CT
Left ventricular end diastolic
volume ml
Left ventricular end systolic
volume ml
Stroke volume ml
Left atrial volume ML
276±114
269±116
-7±33
263±80
257±78
-6±27
1((-15)-16)
0.95
178±103
175±107
-4±30
160±80
152±68
-8±27
-4((-19)-11)
0.56
97±25
95±24
-3±13
102±26
101±28
-1±31
1((-11)-13)
0.85
131±48
125±47
-5±15
143±31
141±37
-2±17
3±((-5)-12
0.45
0/8/91
16/72/13
-
0/97/3
24/72/2
-
-
0.29
487±101
494±98
7±52
493±83
492±98
-1±35
-8((-32)-15)
0.49
21±6
21±6
-1±4
20±7
22±8
1±5
1((-4)-6)
0.74
87±107
91±129
4±72
66±55
77±78
11±51
7((-25)-40)
0.65
430±52
428±38
-2±36
446±35
440±43
-6±20
-4((-20)-11)
0.57
Physical capacity
NYHA class I/II/III (%)
6 min walking distance m
VO2 max (ml/kg/min)
Laboratory measurements
NT-pro-BNP - pmol/l
ECG
QT interval ms
BEAT-HF
Exploratory analyses
Baseline LVEF (CT) < 40%
Mirabegron
Placebo
Baseline LVEF (CT) ≥ 40%
P= 0.40
P<0.03
Mean difference
5.5% (95% CL, 0.6-10.4)
Baseline
BEAT-HF
6 months
Mean difference
-2.0% (95% CL, -6.8 to 2.8)
Baseline
6 months
Adverse events
Placebo (n=35)
Mirabegron (n=35)
p
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
Serious adverse events (no. of patients)
5
8
NS
Other adverse event (no. of patients)
8
12
NS
Admitted with urinary tract infection
0
1
NS
Admitted with device endocarditis
0
1
NS
Hypersensitivity
0
1
NS
Unspecific symptoms
1
0
NS
Serious adverse events
Any adverse events
Discontinuation for adverse events
BEAT-HF
Conclusions
• 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%
BEAT-HF
Implications
• 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
BEAT-HF
Funding
• The Research Fund of Rigshospitalet
• The Heart Center Research Foundation
• The Novo Nordic Foundation
• The A.P. Møller and Chastine Mc-Kinney Møller Foundation
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