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 ß3- 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 Sø rg a a rd, K la us K o fo e d, Na na 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

Ba c kg ro und – c hro nic he a rt ) a nd intra c e llula r Na + fa ilure (HF • Ra ise d le ve ls o f intra c e llula r so dium (Na i ) in the c a rdio myo c yte s c o ntrib ute to c o ntra c tio n a b no rma litie s in he a rt fa ilure (HF ) • T 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) • ß3 a dre no c e pto r (AR) a g o nists stimula te the Na -K 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 -HF

Ba c kg ro und –Ac ute he mo dyna mic e ffe c ts o f ß3 AR stimula tio n in he a rt fa ilure LV function in stable severe HF after • I n the no rma l he a rt a ß3 AR coronary micro-embolization 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 • I n HF - c ha ra c te rize d b y ”Na i o ve rlo a de d myo c yte s” - a de c re a se in Na i with inje c tio n o f a ß3 AR a g o nist sho uld LV function in impro ve L V func tio n normal sheep heart • Do the se r e sults tr anslate into impr ove d L V func tion IV injection of ß3 AR agonist in increasing doses with c hr onic ß3 AR agonist tr e atme nt in human HF ? BE AT -HF Bundgaard H et al . Circulation. 2010. 122(25):2699-708

Ob je c tive a nd study de sig n T o inve stig a te the e ffe c t o f a ß3 AR a g o nist, Mira b e g ro n o n le ft ve ntric ula r e je c tio n fra c tio n in pa tie nts with c hro nic he a rt fa ilure • Sing le c e nte r, do ub le -b lind, pla c e b o - c o ntro lle d, ra ndo mize d tria l • Ra ndo miza tio n 1:1 to Mira b e g ro n 300 mg da ily, o r pla c e b o fo r 6 mo nths • Sa mple size : 70 pa tie nts - 90% po we r, - c ha ng e le ft ve ntric ula r e je c tio n fra c tio n o f 4% (the prima ry e nd -po int) - two -sid e d p<0.05, - d ro p-o ut ra te o f 30%. BE AT -HF

Study drug a nd do se • Mira b e g ro n; - F DA a nd E MA a ppro ve d fo r o ve ra c tive b la dde r (OAB) - Do se (25-)50 mg x 1 - T 1/ 2 =22-25 h, Cma x 3-4 h • Side e ffe c ts; – 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 • Ma ximum re po rte d do sa g e fo r OAB o ve r12 we e ks: 300 mg / da y • Do se s a dministe re d in this study: – 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 -HF

E ndpo ints Prima ry e ndpo int - Cha ng e in le ft ve ntric ula r e je c tio n fra c tio n (L VE F ) a s a sse sse d b y CT Se c o nda ry o utc o me s (c ha ng e s in) - NT -pro -BNP - Ca rdia c o utput/ stro ke vo lume - L e ft ve ntric ula r vo lume s - L e ft a tria l vo lume - Dia sto lic func tio n - QT inte rva l dura tio n - E xe rc ise to le ra nc e - Sympto ms BE AT -HF

E lig ib ility K e y inc lusio n c rite ria – 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 K e y e xc lusio n c rite ria o r re va sc ula riza tio n ( < 3 mo nths) o r CRT – 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) – R < 50 ml/ min/ 1.73 m 2 o r he pa tic (tra nsa mina se s >x3) dise a se s – Re na l (e GF – 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 -HF

Study de sig n Sc re e ne d (n=142) 33 Sc re e n fa ilure 1 2 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) 37 de c line d pa rtic ipa tio n Ra ndo mize d (n=70) Mira b e g ro n Pla c e b o (n=35) (n=35) 2 De a ths 1 Adve rse e ffe c ts F o llo w up 1 Adve rse e ffe c ts 1Admitte d - e ndo c a rditis 2 Re duc e d c o mplia nc e 6 mo nths 1 Admitte d - urina ry tra c t infe c tio n F o llo w-up da ta F o llo w-up da ta 1 Re duc e d c o mplia nc e a na lyze d (n=32) a na lyze d (n=29) BE AT -HF

Ba se line c ha ra c te ristic s - 1 Plac e bo Mirabe gron p (n=35) (n=35) 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 19 (54) 20 (57) 0.91 a a ppro pria te ICD sho c k – no . (%) 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 . (%) 21 (60) 27 (77) 0.2 Othe r diure tic s – no . (%) 17 (49) 16 (46) 0.81 Symptoms and physic al func tion 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 -HF

Ba se line c ha ra c te ristic s - 2 Plac e bo Mirabe gron P (n=35) (n=35) 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 e ft ve ntric ula r e nd d ia sto lic vo lume (ml/ m 2 ) L 131±45 129±41 0.88 e ft ve ntric ula r e nd systo lic vo lume (ml/ m 2 ) L 84±42 80±38 0.71 e ft stro ke vo lume (ml/ m 2 ) L 47±11 49±13 0.47 e ft ve ntric ula r ma ss – g / m 2 L 81±18 79±19 0.64 e ft a tria l vo lume – ml/ m 2 L 62±20 70±18 0.12 BE AT -HF

Co mplia nc e a nd sa fe ty • All 61 pa tie nts c o mple ting the study we re c o mplia nt b y pill c o unt (> 98%) • 66 pa tie nts (94%) re a c he d ta rg e t do se o f 300 mg da ily, 3 pa tie nts 200 mg (Mira b e g ro n), 1 pa tie nt 100 mg da ily (Pla c e b o ). Mira b e g ro n Pla c e b o Systo lic BP Dia sto lic BP He a rt ra te 100 140 140 120 Be a ts pr min 120 80 100 Me a n d iffe re nc e mmHg mmHg 100 60 2.2 (95% CL , -5.2 to 9.5) 80 80 P=0.55 60 40 60 Me a n d iffe re nc e Me a n d iffe re nc e -0.3 (95% CL , -6.0 to 5.5) 0.6 (95% CL , -3.2 to 6.3) 40 40 P=0.91 P=0.52 20 20 20 0 0 0 Ba se line 6 mo nths Ba se line 6 mo nths Ba se line 6 mo nths BE AT -HF

Prima ry e ndpo int L e ft ve ntr ic ular e je c tion fr ac tion Mira b e g ro n Pla c e b o (%) P= 0.82 F VE Me a n diffe re nc e L 0.4% (95% CL , -3.5 to 3.8) Ba se line 6 mo nths BE AT -HF

Se c o nda ry e ndpo ints Plac e bo (n=32) Mir abe gr on (n=29) Between group difference (95%CI) Base line F ollow- up Change Base line F ollow- up Change p Volume tr ic par ame te r s by CT L e ft ve ntric ula r e nd d ia sto lic 276±114 269±116 -7±33 263±80 257±78 -6±27 1((-15)-16) 0.95 vo lume ml L e ft ve ntric ula r e nd systo lic 178±103 175±107 -4±30 160±80 152±68 -8±27 -4((-19)-11) 0.56 vo lume ml Stro ke vo lume ml 97±25 95±24 -3±13 102±26 101±28 -1±31 1((-11)-13) 0.85 L e ft a tria l vo lume ML 131±48 125±47 -5±15 143±31 141±37 -2±17 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 - 0/ 97/ 3 24/ 72/ 2 - - 0.29 6 min wa lking d ista nc e m 487±101 494±98 7±52 493±83 492±98 -1±35 -8((-32)-15) 0.49 VO 2 ma x (ml/ kg / min) 21±6 21±6 -1±4 20±7 22±8 1±5 1((-4)-6) 0.74 L abor ator y me asur e me nts NT -pro -BNP - pmo l/ l 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 -2±36 446±35 440±43 -6±20 -4((-20)-11) 0.57 BE AT -HF

E xplo ra to ry a na lyse s Mira b e g ro n Baseline LVEF (CT) ≥ 40% Base line L VE F (CT ) < 40% Pla c e b o P= 0.40 P<0.03 Me a n diffe re nc e -2.0% (95% CL , -6.8 to 2.8) Me a n diffe re nc e 5.5% (95% CL , 0.6-10.4) Ba se line 6 mo nths Ba se line 6 mo nths BE AT -HF