beta blocantii in hf

7/28/2019 Beta Blocantii in Hf

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B et a B l o ck er s i n H ea r t F a i l u r eNorman SharpeDepartment of Medicine, University of AucklandSchool of Medicine, Auckland, New Zealand

Abstract. The rationale for beta blockade in heart failureis now well established. Heart failure mortality, which isp r e d i ct e d b y n e u r o h o r m o n a l a c t i v a t i o n , r e m a i n s h i g h d e s p i t emodern treatment, including angiotensin-converting nzyme(ACE) inhibition, a n d a d d i t i o n a l n e u r o h o r m o n a l blockadehas further t h e r a p e u t i c p o t e n t i a l . P r e v i o u s clinical trial ex-perience in heart failure, m o s t o f which has been in pa-tients with idiopathic cardiomyopathy, indicates c o n s i s t e n ti m p r o v e m e n t i n v e n t r i c u l a r f u n c t i o n , although variablec h a n g e s i n s y m p t o m s a n d e x e r c i s e performance. However,the major burden of heart failure occurs in patients withischemic heart disease , and in this respect it is n o t a b l e t h a tbeta blockade following myocardial infarct ion confers a sig-nificant mortalit y benefit in subgroups with heart fail ure. Ano v e r v i e w o f all currently available randomized clinical trialsof beta blockade in heart fai lure, which includes more than1600 p a t i e n t s , i n d i c a t e s a mo rtality risk re duction of approxi-matel y 20%, but with wide c o n f i d e n c e i n t e r v a l s . A l a r g e s c a l et r i a l w i t h s e v e r a l t h o u s a n d p a t i e n t s i s r e q u i r e d t o confirmreliably a plausible 20% mortality reducti on with beta block-ade i n h e a r t f a i l u r e . T h e d i s s o c i a t i o n of clinical and mortal-ity effects demonstrated with o t h e r h e a r t failure treatmentsi n d i c a t e s t h e n e c e s s i t y f o r a n a p p r o p r i at e l y powered mortal-ity study that could define a m a j o r i m p r o v e m e n t in heartf a i l u r e t h e r a p y f o r t h e f u t u r e . T h e r e s p o n s e t o b e t a blockadewill vary according t o h e a r t f a i l u r e s e v e r i ty . A cautious dose-t i t r a t i o n approach is required in all cases. In severe heartfailure, symptomatic improvement may result, but for thelarge group o f p a t i e n t s with moderate and stable heart fail-ure, the principal aim of treat ment is improved longevity.Key Words. beta blockers, heart failure

T h e r a t i o n a le fo r th e u s e o f b e t a b l o c k e r s in h e a r tfa i lu re re la tes to severa l fac to rs . F i rs t ly , a poor p rog-n o s i s fo r h e a r t f a i l u r e p a t i e n t s r e m a i n s d e s p i t e m o d -ern t rea tmen t , inc lud ing ang io tens in -conver t ing en -zyme (ACE) inh ib i t ion . Second ly , there have beeng o o d s t u d i e s o f n e u ro h o rm o n a l a l t e r a t io n s a n d t h e i rp rognos t ic impor tance in hear t fa i lu re . Th i rd ly , c l in i -c a l tr i a l s o f t h e e f f e c t s o f b e t a b l o c k e r s o n l e f t v e n t r ic -u la r func t ion and exerc i se capac i ty in pa t ien t s wi thhear t fa i lu re a re p romis ing . F ina l ly , l a rg er c l inica l tr i -a l s o f t h e e f f e c t s o f b e t a b l o c k e r s o n m o r t a l i ty i npa t ien t s wi th myocard ia l in farc t ion and ev idence o fhear t fa i lu re o f fe r hope .

In cons ider ing the poss ib le app l ica t ion o f be tab l o c k e r s i n h e a r t f a i lu r e a s p a r t o f a c o m b i n e d t r e a t -m e n t r e g i m e n , i t i s i m p o r t a n t t o e m p h a s i z e t h a t t h e

v a r i o u s a im s o f t r e a t m e n t fo r h e a r t f a i l u r e a r e m e tt h ro u g h a n u m b e r o f d i f f e r e n t m e c h a n i s m s t h a t a r en o t n e c e s s a r i l y a s s o c i a t e d . F o r e x a m p l e , c o n g e s t i v es y m p t o m s a n d s i g n s a r e r e l i e v e d t h ro u g h r e d u c t i o nof e lev a ted ve n t r icu la r f i ll ing p ressu res and d iu res i s .E x e rc i s e p e r fo rm a n c e m a y i m p ro v e t h ro u g h r e l i e f o fconges t ion , bu t more s ign i f ican t ly th rough per iphera lc i rcu la to ry changes and muscu lar cond i t ion ing . Ven-t r i cu la r func t ion is a l t e red th rou gh changes in myoc ar-d ia l con t rac t i l i ty o r load ing cond i t ions . F ina l ly , su r -v i v a l b e n e f i t m a y b e m e d i a t e d t h ro u g h fu n c t i o n a li m p ro v e m e n t , b u t a l so im p o r t a n t l y t h ro u g h n e u ro h o r -monal b lockade .

Neurohormonal Alterationsin Heart FailureAc t i v a t io n o f n e u ro h o rm o n a l s y s t e m s c a u s e s e x c e s -s ive vasocons t r ic t ion and vo lume expans ion , andwo rs e n i n g s y m p t o m s a n d s i g n s o f c o n g e s t i v e h e a r tfa i lu re . The benef i t o f b lockade o f the ren in -angio -t e n s i n -a ld o s t e ro n e s y s t e m wi t h A C E i n h ib i ti o n i s we lles tab l i shed . There may a l so be benef i t s f rom b lockadeo f t h e s y m p a t h e t i c n e r v o u s s y s t e m w i t h b e t a b l oc k a d et h a t a r e c o m p l e m e n t a r y t o t h o s e p r o v i d e d b y A C Einhibi tors .Neurohormonal activation and survivalDa t a f ro m t h e S t u d i e s o f L e f t Ve n t r i c u l a r Dy s fu n c t i o n(S OL VD) r e g i s t ry [1 ] h a v e s h o wn t h a t e l e v a t e dp lasma leve l s o f no rep ineph r ine , ren in , a rg in ine vaso -p re s s in , a n d a t r i a l n a t r iu r e t i c p e p t i d e (ANP ) a r e a s s o -c i a te d w i t h a p o o r p ro g n o si s . H o we v e r , o n l y AN P a n dre n i n we re i n d e p e n d e n t p r e d i c t o r s o f m o r t a l i t y b ym u l t i v a r i a t e a n a l y s i s . T h e Ve t e r a n s Ad m i n i s t r a t i o nC o o p e ra t i v e Va s o d i l a t o r He a r t F a i l u r e T r i a l [ 2 ] h a ss h o wn t h a t e l e v a t e d p l a s m a l e v e ls o f n o re p i n e p h ri n ea n d r e n i n a r e i n d e p e n d e n t l y r e l a t e d t o m o r t a l i t y a n dt h a t t h e m o s t b e n e f i c i a l r e s p o n s e t o AC E i n h i b i t i o no c c u r r e d i n t h o s e w i t h t h e m o s t n e u ro h o rm o n a l a c t i -

Address for correspondence: Norman Sharpe, Department of Medi-cine, University of Auckland School of Medicine, Auckland, NewZealand.Received 18 August 1995; accepted 18 September 1995.


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vat ion . These f ind ings emphas ize the impor tance o fthe re l a t ionsh ip be tween neurohormonal ac t iv i ty andmor ta l i ty , an d the re l evanc e o f neurohorm onal b lock-ade to im proved su rv iva l .Pl asma norep inephr in e leve lsThe p lasma concen t ra t ion o f norep inephr ine p rov idesan index o f sym pathe t i c ac t iv i ty . S evera l s tud ies haveshown tha t p l asma norep inephr ine l eve l s a re in -creased in hea r t fa i lu re [3 -5 ]. As wel l as be ing a p re-dictor of survival [2 ,5], th e level of ci rculat ing norepi-nephr ine i s d i rec t ly p ropor t iona l to the deg ree o f l e f tven t r i cu la r dys func t ion [3 ] . Me asurem ent s o f norep i -n e p h r i n e ma y p r o v i d e a b e t t e r p r o g n o st ic g u i d e t h a nd o h e mo d y n a m i c me a s u r e m e n t s , s u c h a s c a r d ia c i n-dex , s t roke w ork index , o r pu lmona ry cap i l la ry we dgepressu re [5 ] .Su b s t u d y d a t a f r o m t h e SO L V D t r i a l [ 6] h a v e d e m-ons t ra t ed tha t sym pathe t i c ac t iva t ion occurs p r io r tothe deve lop men t o f c lini ca l hear t fa i lu re and i s p res -en t in pa t i en t s wi th asymptomat i c l e f t ven t r i cu la rdys func t ion . Sympathe t i c ac t iva t ion i s t herefo re no tsolely a consequence of cl inical heart fai lure. Overac-t i v it y o f th e s y mp a t h e t i c n e r v o u s s y s t e m m a y r e s u l tf rom chron ic changes in s t roke vo lume, card iac ou t -pu t , and mean ar t e r i a l p res su re tha t resu l t i n deac t i -va t ion o f a r t e r i a l baro recep to rs , wh ich p lay an im-por t an t ro l e in nega t ive feedback con t ro l o f thesympathe t i c nervous sys t em [7 ,8 ] . Pro longed exces -s ive ac t iva t ion o f the sym pathe t i c nervous sys t em hasma ny po ten t i a l ad verse e f fec t s , inc lud ing d i rec t t ox icef fec t s on the myo card ium [9 ] , a r rhy th mo gene s i s [10],dec rease d coron ary blood f low, and t issue anox ia fromvasoco nstr ict ion [7].Card iac n orep inephr ine s toresDesp i t e increased p lasma concen t ra t ions o f norep i -nephr ine , t he my ocard ium i s dep le t ed o f norep ineph-r ine [11 ,12] due , a t l eas t par t ly , t o a p ro found de-crease in reup take [13 ,14] . The reup take mechan i smi s a ma j o r d e t e r mi n a n t o f b o th t h e c o n c e n t ra t i on o fnorep inephr ine wi th in the synap t i c c l e f t and thes to res o f norep inep hr ine in the neurone . In add i t ionto abnormal reup take o f norep inephr ine , i t has beensugges ted th a t abnormal i t i es occur in the syn thes i s o fnorep inephr ine wi th in the neurone [15 ,16] , a l thoughth i s has no t bee n a cons i s t en t f ind ing [17] . The exac tmechan i sm of the dep le t ed norep inephr ine s to res i ss t i l l uncer t a in and may depend on the under ly ingcause o f the hea r t fa i lu re .Effect of beta blockade on plasmanorep inephr i ne levelsA randomized t r ial of the effects of bucindolol in pa-t i en t s wi th id iopa th ic d i l a ted card iom yopathy [18] hasdem ons t ra t ed a 50% reduct ion in p l asma norep ineph-r ine l eve l s in buc indo lo l - t rea t ed pa t i en t s a f t e r 3months . These f ind ings and those f rom uncon t ro l l ed

s tud ies [19,20] sugges t t ha t be ta b lockade m ay reduc ec i rcu la t ing norep inephr ine l eve l s bo th by reduc ingsp i l lover to the p l asma f rom the synap t i c c l e f t andby increas ing the c l earance o f norep inephr ine . Betab lockers a re a l so ab le to b lock d i rec t ly the tox ic e f fec t so f ca t echo lamines , as demons t ra t ed in v i t ro by thep r e v e n t i o n o f n o r e p i n e p h r in e - i n d u ce d m y o c y t e n e c r o -s is by 1-propranolol [21] and in vivo by r eve rsal of thec a r d i o my o p a t h y a s so c i a te d w i t h p h e o c h r o mo c y t o ma[22]. In add i t ion to th e inc rease in p l asma norep ineph-r ine , o ther a l t e ra t ions occur in the ad renerg ic pa th -way , inc lud ing changes in be ta - recep to r dens i ty andfunct ion , guan ine nuc leo t ide regu la to ry p ro te ins (o rG-proteins) , and cycl ic AM P levels .

Beta-adrenergic receptorsI n t h e n o r ma l my o c a r d i u m t h e r e i s a p r e d o mi n a n c e o fthe be ta l - subgroup o f recep to rs . In hea r t fa i lu re therei s a decrea se in the to t a l be ta - recep to r dens i ty , wh ichi s re l a t ed to th e deg ree o f hear t fa i lu re [23] ; t h i s i sdue to a se l ec t ive reduc t ion , o r downregulation, in thebe ta l - rec ep to r den s i ty o f abou t 60-70% [24] . In as tudy o f pap i l l a ry musc le ex t rac t s ob ta ined f rom pa-t i en t s wi th severe hear t fa i lu re undergo ing t rans -p lan ta t ion [25] , i t was shown tha t downregu la t ion o fbe ta l - recep to rs i s accompan ied by a reduc t ion in thec o r r e s po n d i n g me s s e n g e r RN A ( mRN A ) f o r t h ebe ta l - recep to r . No such changes were seen in be tae-r e c e p t o r d e n s i t y o r i n b e t a e - re c e p t o r mR N A . T h e s ef ind ings sugges t t ha t be ta l - recep to r downregu la t ioni s, a t l eas t par t ly , t he consequence o f a reduc t ion inthe syn thes i s o f the be ta l - recep to rs . How ever , i t isa l so poss ib le tha t t he be ta l - recep to r downregu la t ionref l ec t s an increase in recep to r degrada t ion [26] , a l -though th i s remains to be p roven in fa i l i ng humanhear t s .The abso lu te den s i ty o f the b e tae- recep to r is un -changed in he ar t fa i lu re , a l though the ra t io o f beta2 -to be ta l - rec ep to rs i s i ncreased and the i r func t iona l ac-t iv i ty i s reduced [27] . Severa l d i f fe ren t mechan i smsare invo lved in th i s recep to r uncoupling [28]. Oneimpor tan t pa thway invo lves in i t i a l phosphory la t ionof the agon i s t -occup ied ac t ive recep to rs by be ta -adrenerg ic recep to r k inase [29]. Subsequen t ly , an in -hibi tory protein , beta-arres t in [30], b inds to the phos-phory la t ed rec ep to r , resu l t ing in uncoup l ing o f thebe ta- recep to r and the G-pro te ins , and a reduc t ion intheir funct ion.A l t e r a t i o n s i n t h e b e t a - r e c e p t o r s ma y b e a r e -sponse to increa sed sym pathe t i c ac t iv i ty and /o r a re -su l t o f p rogress ive hear t musc le damage [31] . Thus ,i t i s uncer t a in whether these a l t e ra t ions in be ta -recep to rs a re speci fi c to h ear t fa i lu re o r wheth er theyme r e l y r e f l e c t th e ma r k e d s y mp a t h e t i c a c ti v a ti o n t h a toccurs in this condi t ion [28]. Downregulat ion of thebe ta- rec ep to rs does no t occur un i fo rmly th roug hou tt h e my o c a r d i u m a n d i s mo r e m a r k e d i n t h e s u b e n d o -


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Beta Blockers in Heart Failure 7

card ia l my ocy tes , sugges t ing tha t i t is no t s imply re -l a t ed to the increase in sym pathe t i c ac t iv i ty [32] .Effect of be t a b lockade on be t a . r ecep t o rd en s i t yUncont ro l l ed s tud ies o f metopro lo l i n pa t i en t s wi thid iopa th ic d i l a t ed card iom yopa thy have sug ges tedt h a t c h r on i c t r e a t m e n t w i t h t h i s a g e n t i n c r e a s e s b e ta -rece p to r den s i ty [33 ,34]. The pa t i en t s in these se r i esa l so showed s ign if i can t hem odyna mic improv em ent . Arec en t random ized t r ia l wi th m etopro lo l has a l so dem -ons t ra t ed a s ign i f i can t increase in be ta - recep to r den-s i t y a f t e r 6 mo n t h s o f t r e a t m e n t c o mp a r e d w i t h p la -cebo [35]. How ever , t her e w ere no s igni f ican t changesin e j ec t ion f rac t ion be tween the two g roups [36] .W h i le t h e i n c r e a s e in b e t a l - r e c e p t o r d e n s i t y s e e n a f t e rt r e a t m e n t w i t h b e t a b l o c k e r s a p p e a r s t o o c c u r w i t h indays [37], the cl inical benefi ts of beta blockade occuraf t e r se vera l mon ths ' t he rap y [18 ,38-56], and thus i ti s un like ly tha t t h i s im prov em ent is exp la ined s implyb y b e t a - r e c e p t o r u p r e g u l a t i o n a l o n e.T h e u n d e r l y i n g c a u s e o f t h e h e a r t f a i lu r e ma y i n -f l u e n c e t h e c h a n g e s s e e n i n t h e b e t a - r e c e p t o r c o m-p lex . Br i s tow and co l l eagues [57] have shown tha t ,compared wi th id iopa th ic d i l a t ed card iomyopathy ,i schemic card iom yopath y has l es s to t a l be ta - recep to rdownre gu la t ion and g rea te r uncoup l ing o f l e f t ven t r i c -u la r be tae- recep to rs and r igh t ven t r i cu la r be ta l -r e c e p t o r s . T h e s e d i f f e r e n c e s ma y e x p l a i n w h y b e t ab lockade appears to p roduce g rea te r e f fec t s on l e f tven t r i cu la r func t ion in id iopa th ic d i la t ed card iomyopa-t h y t h a n i n i sc h e mi c c a r d i o my o p a t h y [ 45 ] . H o w e v e r ,th i s app aren t d i f fe rence in response m igh t a l so be a t -t r ib u t a b l e t o a g r e a t e r d e g r e e o f s p on t a n e o us i m-provement in pa t i en t s wi th id iopa th ic d i l a t ed card io -m y o p a t h y .G . p r o t e i n sThe guan ine nuc leo t ide regu la to ry p ro te ins , o r G-pro te ins , ex i s t on the inner su r face o f the ce ll mem-b r a n e a n d p r o v i d e t h e l in k b e t w e e n t h e b e t a - r e c e p t o rand ad eny la t e cyc lase . Some G-pro te ins s t imula te ad -eny la t e cyc lase (Gs-p ro te ins ) and o thers a re inh ib i to ry(Gi-pro te ins ). The y share a com mon s t ruc tu re , eachbeing composed o f a lpha , be ta , and gam ma subun i t s ,wi th the a lpha subun i t t hough t to be respons ib le fo rr e g u l a t i n g t h e e f f e c t o r s y s t e ms [ 5 8] . T h e r e a r e a l t er -a t ions in these p ro te ins in the fa i l i ng human myo-card ium, inc lud ing an increase o f as much as a th i rdin the Gi -p ro te in [59 ,60] and a reduc t ion in the Gs-p ro te in [61] . These a l t e ra t ions in the G-pro te ins , aswel l as the recep to r modi f i ca t ions men t ioned ear l i e r ,p robab ly accoun t fo r the "uncoup l ing" o f the be ta2 -recep to rs seen in hear t fa i lu re [31] . The Gs-p ro te insin te rac t d i rec t ly wi th the ca t a ly t i c un i t o f aden y la t ecyc lase , and i t appea rs th a t t h i s subun i t i s no t a l t e redin hea r t fa i lu re [31].

C l i n ic a l T r i a l s o f B e t a B l o c k e r si n H e a r t F a i l u r eTrad i t iona l ly be ta b lockers have b een c ons idered con-t ra ind ica ted in he ar t fa i lu re because o f the i r ac u tenega t ive ino t rop ic e f fec t . The f i r s t repor t o f the i r ap -p l ica t ion in he ar t fa i lu re descr ibed seven pa t i en t s w i thseve re id iopa th ic d i l a ted c ard iom yopathy who ap-peared to have a favorab le c l in i ca l response to be tab l o c ka d e w i t h me t o p r o lo l [ 6 2 ] . T h e s a me w o r k e r sl a t e r repor t ed a fu r ther 24 pa t i en t s (wi th 13 con t ro lsub jec t s ) who showed c l in i ca l improvement dur ingbeta b lockade [63] . I t w as sugg es ted tha t , i n compar i -son wi th h i s to r i ca l con t ro l s , su rv iva l was p ro longedw i t h t h e b e t a b l o c k e r t r e a t m e n t . A f u r t h e r r e p o r t o fpa t i en t s wi th id iopa th ic d i la t ed card iom yopathy ind i-c a t e d i mp r o v e me n t i n h e mo d y n a mi c s a n d s y mp t o mswi th b e ta b lockade [64] , and s ign if i can t hemodynam icde ter io ra t ion on w i thdraw al [65] .

The in i t ia l observa t ions sugges t ive o f benef i t we rea ll der ived f rom nonrandom ized stud ies , bu t t h i s hass ince been fo l lowed by a num ber o f randomized , p l a-cebo-con t ro l led t r i a l s o f be ta b lockers in pa t i en t s wi thhe ar t fa i lu re o f d i f fe ren t types . Tab le 1 ou t l ines therandomized con t ro l l ed t r i a l s o f be ta b lockade in pa-t i e n t s w i t h h e a r t f a i l u r e t h a t h a v e b e e n r e p o r t e d t oda te [18 ,38-56]. Ear l i e r t r i a l s p redom inan t ly inc ludedpat i en t s wi th id iopa th ic d i l a t ed card iomyopathy , a l -t h o u g h m o r e r e c e n t l y mo r e p a t i e n t s w i t h i s c he mi ccard iom yopath y have bee n s tud ied . M ost , bu t n o t a ll ,h a v e r e p o r t e d a n i mp r o v e me n t i n s y mp t o ms a n d areduct ion in N YH A funct iona l c l ass wi th longer t e rmt r e a t me n t . S t u d i e s t h a t d i d n o t r e p o r t i mp r o v e me n tg e n e r a l l y h a d a s h o r t t r e a t me n t p e r i o d a n d r e la t i v e lysmal l num bers o f pa t i en t s .

H emodyn am i c e f f e c t s o f bet a b l o c k adei n h e ar t f a i l u r eIn pa t i en t s wi th h ear t fa i lu re p r inc ipa l ly due to id io -pa th ic d i l a t ed card iom yopathy , l ong- t e rm be ta b lock-ade has been shown to resu l t i n s ign i f i can t hemody-n a mi c i mp r o v e me n t w i t h i n c r e a s e d l e f t v e n t r i c u l a rs t roke work index , l e f t ven t r i cu la r e j ec t ion f rac t ion ,a n d d e c r e a s e d p u l m o n a r y c a p il la r y w e d g e p r e s s u r e .In those s tud ies tha t measured e j ec t ion f rac t ion , t hemean increase in the be ta b locker g roup re l a t ive tothe control was 5 .7% (Table 1) . (This increase is de-r i v e d f r o m t h e me a n e j e c ti o n fr a c ti o n d a t a f r o m t h epub l i shed s tud ies in which th i s was as sessed).T h e m e c h a n i s ms o f h e mo d y n a m i c i mp r o v e me n twi th long- t e rm be ta b lockade in hear t fa i lu re a re un-c l e ar . A c u t e i n t r a v e n o u s b e t a b l o c ka d e h as b e e n d e m-ons t ra t ed to adve rse ly a f fec t le f t ven t r i cu la r sys to li cfunc t ion [66] . Ho wev er , l ong- t e rm ora l t herap y i s wel lto l e ra t ed and can resu l t i n s ign i f i can t improvement .Mos t s tud ies inves t iga t ing the poss ib le mechan i sms o fi mp r o v e me n t h a v e b e e n u n c o n t r o l l e d a n d h a v e i n -


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Tab le 1. Randomized, controlled trials of beta blockers in congestive heart failureTrial Yea r N Beta blocker FU (mo.) DE F (%) ExerciseIkram 1981 17 Acebutolol 1 NA DecreaseCurrie 1984 10 Metoprolol 1 + 3.0% No changeAnd erson 1985 50 Metoprolol 19 NA No chang eEngelm eier 1985 25 Metoprolol 12 + 2.0% Inc reas eSano 1989 22 Metoprolol 12 NA NALeung 1990 12 Labetolol 2 NA Increas ePollock 1990 20 Bucindolol 3 0.0% Inc reas eGilbert 1990 23 Bucindolol 3 + 8.0% No chang eWo odley 1991 50 Bucindolol 3 + 0.5% No chang ePaolisso 1992 10 Metoprolol 3 NA Increa seMDC trial 1992 383 Metoprolol 12-18 + 6.0% No changeKrum 1993 49 Carved ilol 3.5 + 5.5% NAOlsen 1993 60 Carved ilol 4 + 10.0% NAWisenbaugh 1993 29 Nebivolol 3 + 8.0% No changeFish er 1994 50 Metoprolol 6 + 5.0% NABristow 1994 139 Bucindolol 3 + 4.1% DecreaseEichhorn 1994 25 Metoprolol 3 + 8% NACI BIS 1994 641 Bisoprolol 23 NA NAMetra 1994 40 Carved ilol 6 + 11% No chang eAN Z Trial 1995 415 Carved ilol 18-24 5.2% No chang eTotals 2047 + 5.7%Def = mea n difference in ejection fraction % (calculated as me an change during active treatment - mean change during control, and adjustedfor number of patients); NA = data not available.

v o l v e d s m a ll n u m b e r s o f p a t i e n ts , a n d t h e d a t a a r econf l i c t i ng .E i c h h o r n a n d c o l l e a g u e s [ 6 7 ] , i n a n u n c o n t r o l l e ds t u d y o f t h e e f f e c ts o f 3 m o n t h s o f t r e a t m e n t w i t hb u c i n d o l o l i n p a t i e n t s w i t h h e a r t f a i l u r e , d e m o n -s t r a t e d a n i n c r e a s e i n l e f t v e n t r i c u l a r e j e c t i o n f ra c t i o nt h a t w a s r e l a t e d t o re d u c t i o n s i n b o t h e n d - s y s t o l i c a n de n d - d i a s t o l i c v o l u m e s . T h e d e c r e a s e i n e n d - s y s t o l i cv o l u m e a n d t h e i n c r e a s e i n e je c t i o n f r a c ti o n o c c u r r e dd e s p i t e a d e c r e a s e i n p r e l o a d a n d a n i n c r e a s e i na f te r l o ad , s u g g e s t i n g i m p r o v e m e n t i n m y o c a r d ia l c on -t r a ct il i ty . T h i s w a s c o n f ir m e d b y i m p r o v e m e n t s i n t h ee n d - s y s t o l i c p r e s s u r e - v o l u m e r e la t i o n s h i p a n d t h ep e a k d P / d t e n d - d i a s t o l ic v o l u m e r e l a t io n , b o t h r e l a -t i v e l y l o a d - i n d e p e n d e n t m e a s u r e s o f c o n t r a c t il i ty . D e -s p i te t h e s e i m p r o v e m e n t s i n c o n tr a c ti l it y a n d m e c h a n -i ca l w o r k , t h e r e w a s n o i n c r e a s e i n m y o c a r d i a l o x y g e nc o n s u m p t i o n .

T h e f i n d in g o f i m p r o v e d c o n t r a c t i l i ty f o ll o w in gl o n g - t e r m b e t a b l o c k a d e h a s a l s o b e e n d e m o n s t r a t e di n a p l a c e b o - c o n t r o l l e d s t u d y o f n e b i v o l o l , a b e t a 1-s e l e c t i v e a n t a g o n i s t w i t h v a s o d i l a t i n g p r o p e r t i e s , i np a t i e n t s w i t h d i l a te d c a r d i o m y o p a t h y [ 52 ]. T h i s s t u d yd e m o n s t r a t e d n o s i g n i f i c a n t c h a n g e i n w a l l s t r e s s ,s u g g e s t i n g t h a t t h e s i g n i f i c a n t i n c r e a s e i n e j e c t i o nf r a c t i o n o b s e r v e d w a s d u e t o i m p r o v e d c o n t r a c t i l i t yr a t h e r t h a n v e n t r i c u l a r u n l o a d i n g . I n a d d i ti o n t o i m -p r o v e m e n t s i n r e s t i n g h e m o d y n a m i c s f o l l o w i n g b e t ab l o c k ad e , i m p r o v e m e n t s h a v e a ls o b e e n d e m o n s t r a t e di n c a r d i a c i n d e x , s t r o k e v o l u m e i n d e x , s t r o k e w o r ki n de x , a n d p u l m o n a r y c a p i l l a ry w e d g e p r e s s u r e w i t h

e x e r c i s e [ 1 7 ,1 9 ]. I n a s s o c i a t io n w i t h t h e s e i m p r o v e -m e n t s , t h e r e w a s n o i n c r ea s e i n m y o c a r d ia l o x y g e nc o n s u m p t io n , s u g g e s t i n g i n c r e a s e d m y o c a r d i a l w o r kl o a d w i t h o u t h i g h e r m e t a b o l i c c o s t s .

L i t t l e d a t a a r e a v a i l a b l e r e g a r d i n g t h e e f f e c t s o fb e t a b l o c k a d e o n d i a s t o l i c f u n c t i o n i n h e a r t f a i l u r e .I m p r o v e m e n t s h a v e b e e n d e m o n s t r a te d in i so v o lu m icr e l a x a t i o n , w i t h n o c h a n g e i n c h a m b e r s t i f f n e s s , f o l -l o w i n g t r e a t m e n t w i t h b u c in d o l o l [6 7]. I m p r o v e d d ia -s t o li c f u n c t i o n m a y b e a n i m p o r t a n t c o m p o n e n t o f t h er e s p o n s e t o b e t a b l o c k a d e a n d r e q u i r e s f u r t h e r i n v e s -t i g a t i o n .E f f e c t s o f b e t a b l o c k a d e o n ex e r c i s e t o l e r a n c ei n h e a r t failureT h e f i n d i n g s r e l a t e d t o e x e r c i s e c a p a c i t y in t h e s e s t u d -i e s h a v e b e e n c o n f l i c t i n g . W h i l e s o m e s t u d i e s h a v er e p o r t e d s t a t i s t i c a l l y s i g n i f i c a n t i m p r o v e m e n t s i n t o -t a l e x e r c i s e d u r a t i o n w i t h b e t a b l o c k a d e , o t h e r s h a v en o t ( T a b l e 1 ). L o n g - t e r m b e t a b l o c k a d e c a n a tt e n u -a t e m a x i m u m o x y g e n c o n s u m p t i o n [ 68 ], a n d , c o n s e -q u e n t ly , m a x i m a l e x e r c is e t o le r a n c e t e s t i n g m a y n o tb e t h e a p p r o p r i a t e m e t h o d f o r a ss e s s i n g a n i m p r o v e -m e n t i n f u n c t i o n a l c a p a c i t y . I n a r a n d o m i z e d t r i a l o ft h e e f f e c t s o f t h e v a s o d i l a t i n g b e t a b l o c k e r c a r v e d i lo l[6 9], s u b m a x i m a l e x e r c i s e t i m e ( d e t e r m i n e d b y s t r e s s -i n g p a t i e n t s a t a w o r k l o a d f i x e d a t 8 5 % o f t h e i r b a s e -l i n e m a x i m a l o x y g e n c o n s u m p t i o n ) w a s s i g n i f i c a n t l yi n c r e a se d i n th e b e t a b l o c k e r g r o u p c o m p a r e d w i t hp l a c e b o , w h i l e m a x i m a l e x e r c i s e t i m e w a s n o tc h a n g e d . A s i m i l a r s t u d y [5 2] h a s r e c e n t l y s h o w n a


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B e t a B l o c k e rs i n H e a r t F a i l u r e 9

T r i a l N17 Smaller Trials 608Larger Trials

MDC 383CIBIS 641Subtotal 1024

TOTAL 1632

% E v e n t sS t u d y C o n t r o l4.7% 6.9%

11.9% 10.1%16.6% 20.9%1 4 . 8 % 1 6 . 9 %10.7% 13.2%

T r e a t m e n t e f fe c t 2 p = 0 . 2 2for heterog eneity: subgroups = 0.02, ldf , p=0.9

X for heter ogenei ty: overall = 5.63, 10dr, p=0.85

O d d s R a t i o& 9 5 % C L

m

, lOR = 0 . 8 39 5 % C I 0 . 6 1 - 1 . 1 2

I I

0 0.5 1.0 1.5 2.0Beta-BlockerFavourable

B e t a - B l o c k e rWorse

Fig . 1 . Be ta b lockers in hear t fa i lure : mor ta l i t y da ta .

significant increase in the distance traversed during a6-minute walk test in the beta blocker treated groupcompared with the placebo group. This method of as-sessing submaximal performance is often preferred bypatients and may reflect an improvement in their reg-ular daily physical activity that is bette r than maximalexercise testing might show.E f f e c t s o f b e t a b l o c k a d e on s u r v i v a li n h e a r t f a i l u r eIn the Metoprolol in Dilated Cardiomyopathy (MDC)study [47], 383 patients with heart failure on standardtreatment were randomized to receive either meto-prolol or placebo, and were followed for 12-18 months.There were significant improvements in hemodynam-ics and symptoms, as well as fewer hospital readmis-sions, in the beta blocker treated group. There wasno statistically significant effect on total mortality , butfewer metoprolol treated patients were placed on thetransplant list. In the Cardiac Insufficiency BisoprololStudy (CIBIS) [54], 641 patients with heart failure ofvarious etiologies on standard treatment were ran-domized to bisoprolol or placebo for a mean periodof 1.9 years. Significantly fewer patients in the betablocker group required hospitalization, and signifi-cantly more showed improvement in functional class.There was no significant difference between thegroups in mortality. Definitive larger scale mortalitystudies currently in progress should reliably assessthe plausible survival benefit of beta blocker treat-ment.

An overview of the likely survival benefit from betablockade in heart failure can be obtained from a recta-analysis of all randomized controlled trials. Data from19 trials with a total of 1632 patients have been in-cluded in the analysis [18,38-55]. In these trials, 74%of the patients had idiopathic dilated cardiomyopathy,the median ejection fraction was 23%, the medianNYHA class was 2.7, and theaverage duration of fol-low-up was 15 months. There were 17 smaller trials,and the majority of the patients were from the MDCor CIBIS studies. None of the trials individually waslarge enough to detect reliably an effect of betablocker treatment on mortality. Mortality in patientsassigned beta blocker treatment was 10.7%, versus13.2% in controls (odds ratio 0.83, 95% CI 0.6-1.1;Figure 1). When the meta-analysis was repeated us-ing the MDC study combined endpoint of mortalityand transplant listing, the mortality in treated pa-tients was 10.8% versus 15.3% in controls (odds ratio0.69, 95% CI 0.51-0.92). A large scale trial withlonger follow-up is required for reliable determinat ionof a plausible effect of beta blocker trea tment on mor-tality in heart failure.Currently available data indicating improvementsin hemodynamics, clinical symptoms, and exerciseperformance are not yet sufficient to justi fy the wide-spread use of beta blockers in all patients with heartfailure. The experience with other agents in hear t fail-ure, such as milrinone [70], which produce favorableacute hemodynamic and clinical effects but actuallyincrease mortali ty long term, indicates the importance


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of mortality data in the consideration of general treat-ment recommendations.

N e w G en e r a t i o n B e ta B l o c k er sIn the context of heart failure treatment, most clinicalinterest is now focused on agents such as bucindololand carvedilol that provide an atypical beta blocking(modulation) effect and some vasodilator effect with-out intrinsic sympathomimetic action. Bucindolol is anonselective beta blocker with weak vasodilator ac-tion, whereas carvedilol has weak betarselectivityand significant vasodilator action due to alphal-blockade [71]. These complementary actions of car-vedilol provide a most favorable profile, which maybe further enhanced by antioxidant and antiprolifera-tive effects demonstrated in vitro [72,73]. Carvedilolis well tolerated and improves ventricular function instable heart failure of ischemic etiology, with no sig-nificant change in symptoms or exercise performance[56]. The mortality benefit with such treatment maybe greater than that estimated from the overview ofexperience with other beta blockers. Further clinicalstudies with carvedilol are coming to completion inthe United States, and definitive mortality studieswith both bucindolol are carvedilol are being initiated.

Beta Blockers Fo l lowing Myocard ia lI n f a r c t i o nObservations from the placebo group of the Multi-centre Diltiazem Post-infarction Research Group [74]suggested that beta blocker use was less frequent inpatients with ejection fraction


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g e n d e m a n d [6 5 ] , a n a n t i t h ro m b o t i c e f f e c t [ 8 3 ], a n dp re v e n t i o n o f p la q u e ru p t u re [8 4 ] . B e t a b l o c k e r s a r ea b l e t o d e c re a s e m y o c a rd i a l o x y g e n d e m a n d b y d e -c r e a s i n g h e a r t r a t e , b l o o d p re s s u re , a n d m y o c a rd i a lc o n t r a c t il i t y a n d t h u s m a y p re v e n t i s c h e m ia . I n k e e p -ing wi th th i s , a fou rfo ld reduct ion in the inc idence o fn o n fa ta l r e i n f a rc t i o n wa s o b s e rv e d i n a n o v e rv i e w o ft h e l o n g - t e rm t r e a t m e n t t r i a ls [ 8 5 ] . A r e d u c t i o n i n t h era t e o f r e c u r r e n t m y o c a rd i a l in f a r c ti o n h a s a l s o b e e ndemons t ra ted wi th ACE inh ib i t ion [86 ,87] , a l thought h e m e c h a n i s m s o f b e n e f i t a r e p ro b a b l y d i f f e re n t .AC E i n h i b i t o r s m a y h a v e u s e fu l v a s c u l a r p ro t e c t i v eand poss ib le an t ia therosc le ro t ic e f fec t s [88 ] , thus ex -t e n d i n g t h e r a t i o n a le fo r c o m p l e m e n t a ry b e n e f i t s fro mbeta b lockade fo l lowing myocard ia l in farc t ion and inh e a r t f a i l u r e w i t h c o m b i n a t i o n t r e a t m e n t .Overa l l , i t appears tha t the mos t s ign i f ican t benef i to f b e t a b l o c k e r t r e a t m e n t i n h e a r t f a i l ur e i s i m p ro v e dl o n g e v i t y . W h i l e s y m p t o m s m a y b e i m p ro v e d i n p a -t i e n t s w i t h s e v e re h e a r t f a i l u r e , s y m p t o m s m a y n o tchange in those wi th more s tab le hear t fa i lu re . A cau-t ious , c lose ly mon i to red dos e- t i t ra t ion appro ach i s re -qu i red to ach ieve op t imal ou tcomes and to min imizep o s s ib l e a d v e r s e e f f e c t s.

Con c l u s i o n sC o n g e s t i v e h e a r t f a i l u r e i s a c o m m o n p ro b l e m a n d ,d e s p i t e r e c e n t i m p ro v e m e n t s i n t r e a t m e n t , m o r t a l i t yrem ains h igh . Com plex neurohorm onal a l t e ra t ions oc-c u r i n h e a r t f a i lu r e t h a t a r e d e l e t e r i o u s l o n g - t e rm a n dadverse ly a f fec t su rv iva l . Ang io tens in -conver t ing en -zyme inh ib i t ion has been shown to have benef ic ia l e f -f e c t s o n h e m o d y n a m i c s , s y m p t o m s , a n d s u rv i v a l .B e t a - a d re n e rg i c a n t a g o n i s t s a r e a l s o a b l e t o m o d u l a t ethe neurohorm onal ac t iva t ion o f hea r t fa i lu re . C l in ica lt r i a l s o f be ta b lockers in i schemic and id iopa th ic d i -l a t e d c a rd i o m y o p a t h y h a v e s h o wn g o o d t o l e r a b i l i t ya n d i m p ro v e d h e m o d y n a m i c s a n d s y m p t o m s . F o l l o w-ing myocard ia l in farc t ion , be ta b lockers reduce mor-ta l i ty , par t i cu la r ly in pa t ien t s wi th hea r t fa i lu re . Fu r-t h e r s t u d i e s a r e r e q u i r e d t o d e t e r m i n e w h e t h e r b e t ab l o c k a d e ca n fu r t h e r r e d u c e m o r t a l i t y i n h e a r t f a il u r eand p rov id e a usefu l add i t ion to ex i s t ing thera py . Th ist r e a t m e n t w i ll n e e d t o b e c a r e fu l ly a p p l ie d fo r o p t im a lo u t c o m e s .R e fe re nc e s

1 . Nick las JM, Bened ic t C , Johns tone ED, e t a l . Re la t ionsh ipbe tween neurohormona l p ro f i l e and one yea r mor ta l i ty inpa t ien t s wi th conges t ive hea r t f a i lu re and /o r l e f t ven t r i c -u la r dys func t ion (abs t r ) . Circulation 1991;84(Suppl II):II468.2 . Cohn JN, S imon A, Johnson G.an d VHeF T S tudy Group.Re la t ionsh ip o f p lasma norep inep hr ine and p lasm a ren in ac -t i v i t y t o m o r t a l i t y i n h e a r t f a il u r e: V - H e F T I I ( a b s tr ) . Cir-culation 1991;84(Suppl II) : II310 .3 . Thomas JA, Marks BH. P lasma norep inephr ine in conges -

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be tab lock er vasod i la to r the rapy improves ca rd iac func tionin id iopa th ic d i l a ted ca rd iomyo pa thy : A doub le -b l ind , r an -domised s tudy o f buc indo lo l ve r sus p lacebo . Am J Med1990;88:223-229.19. N emanich JW , Ve i th RC, Abrass IB , S t ra t to n JR . Ef fec t so f metopro lo l on res t and exerc i se ca rd iac func t ion andp lasma ca techo lamines in chronic conges t ive hea r t f a i lu resecondary to i schaemic o r id iopa th ic ca rd iomyopa thy . AmJ Cardiot 1990;66:843-848.20 . Andersson B , B lomst rom-L undqvis t C , Hedn er T , Waag -s te in F . Exerc i se haemodynamics and myocard ia l me tabo-l i sm dur ing long- te rm, be ta -adrenerg ic b lockade in severehear t f a i lu re . J Am Coll Cardiol 1991;18:1059-1066.21 . M ann DL, C ooper G . Proprano lo l p reve n ts the myopa th ice f fec t s o f ca techo lamines in v i t ro : Imp l ica t ions fo r pa t i en t s


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