BE AT -HF He nning Bundg a a rd, Anna Axe lsso n, Ja ko b H T - - PowerPoint PPT Presentation
T he -F irst-I n-Ma n Ra ndo mize d T ria l o f a 3- a dre no c e pto r Ag o nist in Chro nic He a rt F a ilure BE AT -HF He nning Bundg a a rd, Anna Axe lsso n, Ja ko b H T ho mse n, Ma thia s S rg a a rd, K la us K o fo e d,
He nning Bundg a a rd, Anna Axe lsso n, Ja ko b H T ho mse n, Ma thia s Sø rg a a rd, K la us K
ø b e r, Ra smus B Ha sse lb a lc h, He nry K rum, Sø re n Bo e sg a a rd, F inn Gusta fsso n, L a rs K ø b e r, K a spe r I ve rse n, He lg e Ra smusse n
c o ntrib ute to c o ntra c tio n a b no rma litie s in he a rt fa ilure (HF )
he Na -K pump in the c a rdio myo c yte s me dia te s Na i e xpo rt – a nd e vide nc e -b a se d HF tre a tme nts stimula te the Na -K pump (ß b lo c ke rs, ACE inhib ito rs, a ldo ste ro ne a nta g o nists)
pump thro ug h the NO/ c GMP/ PK G pa thwa y – me dia ting Na i e xpo rt
(Bund g a a rd e t a l, Circ ulatio n 2010)
BE AT
BE AT
Bundgaard H et al. Circulation. 2010. 122(25):2699-708
n the no rma l he a rt a ß3 AR a g o nist ha s a ne g a tive ino tro pic e ffe c t b e c a use it re duc e s Na i a nd , via Na -Ca e xc ha ng e r – re duc e s Ca i
n HF - c ha ra c te rize d b y ”Na i
myo c yte s”
de c re a se in Na iwith inje c tio n
ß3 AR a g o nist sho uld impro ve L V func tio n
LV function in normal sheep heart LV function in stable severe HF after coronary micro-embolization
the se r e sults tr anslate into impr
L V func tion with c hr
ß3 AR agonist tr e atme nt in human HF ?
IV injection of ß3 AR agonist in increasing doses
BE AT
DA a nd E MA a ppro ve d fo r o ve ra c tive b la dde r (OAB)
1/ 2 =22-25 h, Cma x 3-4 h
– I
nc re a se d BP a nd HR (o ff-ta rg e t ß1/ 2 AR stimula tio n),
– “Co ld” sympto ms, – Ga stro inte stina l disc o mfo rt
– Sta rt; 25 mg x 2 – the n – if to le ra te d - we e kly inc re a se s; – 50 mg x 2, 100 mg x 2, 150 mg x 2 (a fte r a we e k 300 mg x1)
BE AT
VE F ) a s a sse sse d b y CT
e ft ve ntric ula r vo lume s
e ft a tria l vo lume
inte rva l dura tio n
xe rc ise to le ra nc e
BE AT
–
Sta b le he a rt fa ilure o n isc he mic o r no n-isc he mic b a sis
–
L e ft ve ntric ula r e je c tio n fra c tio n < 40% o n sc re e ning e c ho c a rdio g ra phy
–
On o ptimize d e vide nc e -b a se d pha rma c o the ra py - sta b le > 4 we e ks
–
T he the ra py must inc lude a b e ta -b lo c ke r - to c o unte rb a la nc e ß1/ 2 e ffe c ts
–
Re c e nt AMI
(< 6 mo nths)
–
Sig nific a nt o b struc tive va lvula rdise a se
–
Atria l fib rilla tio n
–
Unc o ntro lle d hype rte nsio n (sBT≥180 mmHg, dBT≥ 110 mmHg)
–
Re na l (e GF R < 50 ml/ min/ 1.73 m2 o r he pa tic (tra nsa mina se s >x3) dise a se s
–
T re a tme nt with dig o xin, tric yc lic a ntide pre ssa nts o r o the r CYP2D6 inhib ito rs tha n b e ta b lo c ke rs
BE AT
BE AT
Sc re e ne d (n=142)
37 de c line d pa rtic ipa tio n
33 Sc re e n fa ilure
12 ejection fraction ≥ 40% 5 Re na l fa ilure 5 Atria l fib rilla tio n 4 BMI > 35 3 Drug c o ntra -indic a tio ns 6 Othe r
E lig ib le (n=107) Ra ndo mize d (n=70) Pla c e b o (n=35) Mira b e g ro n (n=35)
2 De a ths 1 Adve rse e ffe c ts 1Admitte d - e ndo c a rditis 1 Admitte d - urina ry tra c t infe c tio n 1 Re duc e d c o mplia nc e
F
a na lyze d (n=29)
1 Adve rse e ffe c ts 2 Re duc e d c o mplia nc e
F
a na lyze d (n=32)
F
6 mo nths
Plac e bo (n=35) Mirabe gron (n=35) p De mographic c harac te ristic s
Ag e – yr 56±12 62±12 0.05 F e ma le se x – no . (%) 4 (11) 4 (11) 1.0
Me dic al history
Isc he mic he a rt fa ilure – no . (%) 16 (46) 15 (43) 0.91 Re va sc ula rise d – no . (% o f pa tie ns with isc he mic HF ) 12 (75) 11 (73) No n-isc he mic he a rt he a rt fa ilure 19 (54) 20 (57) 0.91 Pre vio us c a rdia c a rre st, susta ine d VT a nd/ o r a a ppro pria te ICD sho c k – no . (%) 19 (54) 20 (57) 0.91 Dia b e te s – no . (%) 3(9) 5(14) 0.71
Cardiac me dic ations – no. (% )
Be ta -b lo c ke r 35 (100) 35 (100) 1.0 ACE / ARB 35 (100) 33(94) 0.49 Spiro no la c to ne / E ple re no ne – no . (%) Othe r diure tic s – no . (%)
Symptoms and physic al func tion
21 (60) 17 (49) 27 (77) 16 (46) 0.2 0.81 Ne w Yo rk He a rt Asso c ia tio n c la ss II / I I I – no . (%) 33 (94) / 2 (5) 34(97) / 1 (3) 0.51 VO 2 ma x (ml/ kg / min) 21±6 20±7 0.40
BE AT
BE AT
Plac e bo (n=35) Mirabe gron (n=35) P Vital signs
Systo lic b lo o d pre ssure – mmHg 124±19 122±20
0.75
Dia sto lic b lo o d pre ssure – mmHg 78±12 75±12
0.37
He a rt ra te 66±10 62±9
0.11 E c hoc ardiogra phic findings
L e ft ve ntric ula r e je c tio n fra c tio n – % 34±7 32±10
0.36 Volume tric and mass parame te rs by CT
L e ft ve ntric ula r e je c tio n fra c tio n (%) 38±17 40±11
0.32 L e ft ve ntric ula r e nd d ia sto lic vo lume (ml/ m 2)
131±45 129±41
0.88
L e ft ve ntric ula r e nd systo lic vo lume (ml/ m2) 84±42 80±38
0.71
L e ft stro ke vo lume (ml/ m2) 47±11 49±13
0.47
L e ft ve ntric ula r ma ss – g / m2 81±18 79±19
0.64
L e ft a tria l vo lume – ml/ m2 62±20 70±18
0.12
(Mira b e g ro n), 1 pa tie nt 100 mg da ily (Pla c e b o ).
BE AT
mmHg Be a ts pr min
Mira b e g ro n Pla c e b o Ba se line 6 mo nths Ba se line 6 mo nths Ba se line 6 mo nths
Me a n d iffe re nc e 2.2 (95% CL , -5.2 to 9.5) P=0.55 Me a n d iffe re nc e
, -6.0 to 5.5) P=0.91
Systo lic BP Dia sto lic BP
Me a n d iffe re nc e 0.6 (95% CL , -3.2 to 6.3) P=0.52
He a rt ra te
20 40 60 80 100 120 140 20 40 60 80 100 120 140
mmHg
20 40 60 80 100
BE AT
L e ft ve ntr ic ular e je c tion fr ac tion
P= 0.82 Me a n diffe re nc e 0.4% (95% CL , -3.5 to 3.8)
L VE F (%)
Mira b e g ro n Pla c e b o
Ba se line 6 mo nths
BE AT
Plac e bo (n=32) Mir abe gr
Base line F
Change Base line F
Change
Between group difference (95%CI)
p Volume tr ic par ame te r s by CT
L e ft ve ntric ula r e nd d ia sto lic vo lume ml 276±114 269±116
263±80 257±78
1((-15)-16) 0.95 L e ft ve ntric ula r e nd systo lic vo lume ml 178±103 175±107
160±80 152±68
0.56 Stro ke vo lume ml 97±25 95±24
102±26 101±28
1((-11)-13) 0.85 L e ft a tria l vo lume ML 131±48 125±47
143±31 141±37
3±((-5)-12 0.45
Physic al c apac ity
NYHA c la ss I/ I I / I I I (%) 0/ 8/ 91 16/ 72/ 13
24/ 72/ 2
6 min wa lking d ista nc e m 487±101 494±98 7±52 493±83 492±98
0.49 VO 2 ma x (ml/ kg / min) 21±6 21±6
20±7 22±8 1±5 1((-4)-6) 0.74
L abor ator y me asur e me nts
NT
87±107 91±129 4±72 66±55 77±78 11±51 7((-25)-40) 0.65
E CG
QT inte rva l ms 430±52 428±38
446±35 440±43
0.57
BE AT
Ba se line 6 mo nths 6 mo nths Ba se line
Base line L VE F (CT ) < 40%
Baseline LVEF (CT) ≥ 40%
P= 0.40 Me a n diffe re nc e
, -6.8 to 2.8) P<0.03 Me a n diffe re nc e 5.5% (95% CL , 0.6-10.4) Mira b e g ro n Pla c e b o
BE AT
Plac e bo (n=35) Mirabe gron (n=35) p Se rious adve rse e ve nts
Sudde n de a th 2 NS Appro pria te ICD sho c k fo r VT / VF 3 1 NS Che st pa in 2 NS Re na l impa irme nt 1 NS F e ve r/ infe c tio n 1 3 NS
Any adve rse e ve nts
Se rio us a dve rse e ve nts (no . o f pa tie nts) 5 8 NS Othe r a dve rse e ve nt (no . o f pa tie nts) 8 12 NS
Disc ontinuation for adve rse e ve nts
Admitte d with urina ry tra c t infe c tio n 1 NS Admitte d with de vic e e ndo c a rditis 1 NS Hype rse nsitivity 1 NS Unspe c ific sympto ms 1 NS
VE F in pa tie nts with a me a n E F
he re wa s no sig nific a nt e ffe c ts o n the se c o nda ry e ndpo ints
he ta rg e t do se wa s re a c he d in 94% o f the pa tie nts
a c c e pta b le a nd a dve rse e ve nts we re g e ne ra lly mild a nd tra nsie nt
he e xplo r
ato r y analysis indic a te d a n inc re a se in L
VE F in pa tie nts with mo re se ve re HF a t b a se line , b ut no t in pa tie nts with EF ≥ 40%
BE AT
he b e ne fic ia l e ffe c t o f the β3 AR a g o nist o nly in se ve re he a rt fa ilure is in a g re e me nt with the me c ha nistic fo unda tio n o f o ur study
se ve re he a rt fa ilure is ne e de d fo r the de sig n o f a pha se I I I tria l
BE AT
he Re se a rc h F und o f Rig sho spita le t
he He a rt Ce nte r Re se a rc h F
he No vo No rdic F
he A.P. Mø lle ra nd Cha stine Mc -K inne y Mø lle rF
I NHE RI T