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From First Class to Third Class: Recent Upheaval in Antiarrhythmic Therapy-Lessons from Clinical Trials
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, Inrecent years,theresults of largerandomized andcon- urewasprematurely terminated because of excess mortrolledtrialsof antiarrhythmic agentsfor primaryand talityattributed to proarrhythmia (torsades de pointes), theimportance of @docking pmperiiesof a secondarypreventionof ventriculartachycardiaand indicating ventricular fibrillationhavechangedperceptions of the classIllagent.A secondary ‘prevention trial(ESVEM)in actions of antiarrhythmic agentsregardingId efficacy patientssurvkingan isodeof VTar VF showedsigY sotalolcompared and risk.Theprematuretermination of theCASTtrials nificant superiority of d toanarrayof of primaryprevention in postinfarct patients highlighted agentsthatblocksodiumchannels withrespect to HI the proarrhythmicrisk and inefficacyof the sodium efficacy andtolemnce. Occurrence ratesof arrhythmias eitherby.suppreschannelblockers(classI action),encainide, flecainide, treatedwithdrugstestedfor efficacy and moricizine,in patientsat relativelylow risk for sionof inducible arrhythmias or by suppression of spandeathinthelongterm.Theexcess mo@litywiih thempy taneous ectopywerehigherandequivalent forbothtestwas attributedto proarrhyihmiadue to facilitdon of ing methods. A secondary prevention trial of reentry,especiallyduring acuteischemia.About the amiodaroneand multipleagentsthat block sodium sametime,European trialswithamiodarone, a complex channelsin sumivorsof cardiacarrest (CASCADE) increased efficacyof amiodarone agentwithantiadrenergic actionandpowerfulactionto showeda significant prolongrefractoriness, (classIII action),indicateden- butpoarbrlong-termtolerance compared withtheother hancedsurvivalaherinfarction withamiodarone butnot agents.Compamtive analysisof theresultsof thevariwithagentswithclass1action.Recent verbalreportsof oustrialssuggests thatclass111 actioncoupledwithanlargerand placebo-controlled trials(EMIATand CAM- tiadrenergic actionis moreefficacious in bothprimary IAT)confirma significant reduction in,arrhyihmiamor- andsecondary prevention of life-threatening ventricular andthatlethalpmarrhythmias maybe the tality,possiblywitha favorabletrendin totulmortali~. arrhythmias effectin attempts at primarypreventicm in Whilean oldertrialwithdkotalol(class IIIand@-block- predominant duetoclass1or so-called pureclass ing actions)showeda trendtowardimprovedsunrival low-riskpopulations afterinfarction,a recenttrialwithc+sotalol in patients Illaction. (AmJCardiol1996;78(suppl4A):28-33) withrecentinfarction or remoteinfarction andheartfail-
fu i tl o fc a ai m u o ri e ne n cri o l ce et ar o oc a e C a rar ucau l h r d ate uI sa h dho a fd v h f tap ro o l r rd no t eu e a o t i ac iv p p p o i e tro o h d t aahns diC t e 1r l i c h t v h e rv r nt e ern r o yt bte a a ab a V i @ r - r T rib ci n a Ci le I l / d dc y a v f ce ( i Sn t r ar t p i n t b o t c e t t o egV e o r c h n e ato ar h p ntl h t ag i eg or o eha ab ae e or sp nmc V h b b o a t h i c s ol r os iat ad a oe t e c p ixct rc cu a eo ht ia h i c is c ac p m yI i t V a rh l u l le C r r I paa o h l gdoa ( Wo cc ic t i i tgb o cc c oct h Sa a)e a ht ol u oi t s 1 a i s a h lf o a Id a r r o lebs ihl t ldgri f a w T V W c a e l ic ud l s f e w ot p re huo r s c d a o t cb ot c es r oh t es g a c Isi alhny cr s I et f dsi e l ee i nc t t wf r b o oi od p i f h c e eo d e t b c ob s u s oa o p n r w k o p t c r r na ug rnl c Tl ( h o t c hI a t c a a Iea M h a nh c o) r m (h eI A t dcy d na f w i usnl a o t 3ss of c o t V W i c a lh ei hlco i gc a u I M m a me u o er nc mea b w d r o zi r ie c c e ede c u h mA I I ac i I oa a o ki as n l n vhc g m u a w p t b f rt a h c h t i i nu a ~ l bs -S hts l r d i s c a ci i I a c 1 fa a oa h A c lo a a n a rh t b i r t cc rl a e o t e o tv c h b d io l v a l a me hv n r h p 1 p i p
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ANTIARRHYTHMIC ACTIONS ARRHYTHMIA MECHANISMS
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w a c co p on pho t nr Wi inn ao u e po TABLEI V H C t c f iR i r cr o e e c o e r u q e n r i m u n A c T io m p n o m i o d r i p u t o nh ui c R c d a t ic t a rc r u a i o M e o e( v c rk l c p lh tc o e t tx m b b t i o d i h h n l u rc u et e o ri b n i t o I g b n i et n nv h u o a he r e Q t u nb i p i b p d r hi l Pr r o ee c d om t i e a d x r iec s t tf is r D a t p c a n t ha o t k i p i o drm e o ri np c r c e u e o e n cul L f t w t ri p i i ta rm h M s oc p c s t i h eu o d e r i t T t n et r iT c e g r h e sc aa p t t o t c m e t r i p e ix I r kf u e rch c a m r h o a s i t c a w a t ri i e l ct ua e FP r f rh p o t m c ye t t c o o r i n c a n r h i r e c M T u e s c s i na o op l h uM n t d o a a ua i & r c o t c i r B h u T t s h f r r eP r a e e or tn i et t t eh ap P r c n o p i tr c a w oc b i p t a r h g i c ha S a bc s r c ui t e o e f Am d xf p u il c i cc c t c o p o r u e Eo f o B lr r o ax r cn t g rc o V r a c i r b c Iua it et c l di o r us t a t d o s c r d i f e e s o ux h D c p ut e r a o a a m v y m t e o a y n c o r t a c r r a i i d t H s i I m a s b r y b- d i p P e a hs r u a h a( l w edr s t t ka c I o I a i t t d o lc c i p e a s t a h l p s o p rv r e e e x e ni c f e s uax t a ct ( r r i ia i i o euto r iPn p vo a V f e r d et nh n T d o d ue i p o p V P r ro a h lr i waoad i a h b t r il dt t p b c Ir a V it e cp l m n a t t a c a r I r i o f P r a r r v e e ee hi r d t o h h d a gy r i f et e a g um ohn s i u y Tna l m en a ce o f d t r t c Ie a h c ep e I a w rl r algnt r ua ee f t tn nfae e n a e H f r cf b op i ce w c r a e r e o c ni ivm m o pa o I 1 C r lwi b c I a w c i s o gl i a p n t l h e d a u o r m h e f e b a ir an m p r c o l t e t ei t t n i e re r a rg n a i a np c t nd aa i r t hf i u t s t ou t r f p uae f a tg c h r a l he o r m T i fpe m lir i cl a l r ( 1 S a ee l F t p e f i reu o n g f ) o r t i h o f n o a ay drc t ir u h l h h c i my b a na t i g a r e r h n y P h f t ap or V r i m ae c T v o t e o h h e p i t p m e i h ( p o t ir f r e ii e v i . n e p i a b a ad h r o s e t ee n i i ct i e i oi ( p o r r i pi e we h c a v . u et r n ear i s a e o Vu pp r T i v / s i V P r r e i v em Zone of depressedconduction Depressexcitability r a i e do cp a er aq nca t u uti and conduction f ifurther i ri i and excitability i o p n t ris w e te h if v block) h e t + bidirectional e f u nr i (unidirectional block g e r I s r px et r e i c c e a vo e s e n t n t i p a r di o a s eeb t v n i ii i t ee l e h e x t ps p w to ea a r t bh i a l i n h h 1e o V i t ap o aT bi a / s v i s d a ep e p l rn fr te -e i v l cf e i i ni n i f a l t h a ar I s ei c c t a kun r ro e Zone of mildlydepressedconduction o p i i c r t nh a a e r v cd i e Depressexcitability ac t na u p o e r o t a ef n a td f and excitability i i g a and i conduction cr further r hc te (unidirectionalblock) s s c m n o e hi c a c n+ unidirectionalnbclock ao o
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FIGURE4. Comparisonof satdol versus6 ather drugswith classI action with respectto the actuarial prababiiitYof arrhfimia recurrence,all. causedeath, cardiacdeath, and arrhylhmicdeath in ESVEM.The parisan includedonly patients dischargedan the agents,thosewho Iahsrcrledthe initial titrationand testedpositivefar efficacy.The mortali outcomestracked patientsacY Cw ‘Tb’’’etmdiwkwkw even therapy was changedbecause recurrence. (Reprinted of arrhythmia
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a t b e l c se ew pc t a 5 i 1 y ( 5 S m b o t F D T l w i t e p o t a t i ho a Drug N C ( C ( G ( % a m a s g p t a om g i r o % I s c f e t p r w r f h r i 129 25 6 M 226 8 p e g er l a i i nr l o Pirmenol 109 16 A 4 t a s hi l g e r on i h P 158 6 5 c h r T e ge to p s r P 3 220 24 b t d t m i i m e he f th A 1 Q 157 13 S 234 1A 3 2 1 p l r r r we e o o cl < < < < p Volue* — i t t m io c e a i e sl n f a w c Ia A g p2 d c pl Sotalol versus all other drugs, CV = cardiovascular; CNS = cenfral nervous system; ESVEM = Electrophys. t a 1 e l se r m c b d t t r iolqic Study versus Electrocardiographic Monitoring; GI = gastrointestinal. t f a c I a t w b t a e l o g i Adapted from N Eng/-l Med. ’ 1 f f ay i c e I b e l s e a Hc g t r o t tp a f ol op r w e c a s eea oa wc o s w m e io p tf e lp s s g i f s g t f t a r n w o i p t fh d e iy t s t fs ie f r ho e i ol c fI a i w f m e t t o f d i s o( t5 eI hr s a a s cFl dc u u h inc m ss e se ri p i V r ( n v 1 f te d o Tc su nb o p 3 / r e ci thr ta g cw d nc or o o d a a a e r a tt f o bfua a a Ia t rV c Srts 5 a i s P u ( gv 5 pf t pi t eE 5 e6 n O t h r v r w e b m e c t o d T a r r r rt w e r u c h h u g y ah i r ob to p e g a trlh u ai f a a noed e c fl s w a h t wo t c I a r h a s w m e i po fa r r t ft or e o ep ena vac r pgarf e ce m t e t c e x a o i t n m d c d a a dea ( l e r l Fa e ia - d i t n cp c a o t mo r 4 F e c m x o s awo r e m ) ti o t b thp d po a e a r es 0p t ti nu o mm t i ui al a 2 i 4y i ap o a b o r h yl e Ie ti n ce wp t i m org i ei dh 6o ee a e n d p p = y o aa w r r f ( r p p e i a rw ol i/ i V v n f P ( dT r 3 u e2 e / c V0 q Vc pi e d6 a se lt a ah i o n n ci n V o( a 8 as r i d l nuar w t r e e to a o2 ph y oo l t e Y a m e f o 3 j S rw a ca c h c t tm a Ca~iacArrest b t i t s ot (e I p l h T t einrSeattle:Conventional e r versus I Amioia th o a daroneDrug Evaluation i b t c Ia we a w s gl c s (CASCADE) l eTrial: a eoC h a i c a amo f iv v e rn m e s xe S t s fw i r e o cmc i eatca o i I l a i c so ag g ra u b e t h r b t i t l to e l teea ra r t r t ( o p m p e H r h ep E i a a d n a c S n ce a l Vf m l u o t h om f i o bbo T c fr e i w t f p o e r f o an i s o vhaa bi i t e ee t ml wi rra o h mmno n l p w d f a e ed o c o dt o r a m i d F l e a od r h t f f 4 nw s f u mui g e i gt r oc - f nl g c o d i pt l r r h eo Ve e rA nae e r r c c ( 1) i h t rb t i t s i ot wr u r f o C ae w ( t ( i hi dt b p t b t r oeit t t d1 A 2 ai i a o re r r l d enc t r hra u i t b e ( i h ft b t i ft ew c t3 l t a ( t a c nr r e o eh s c o I ar w s trt t c nlf y 4 i h ri nc T c e r fo a fw c I m p aa d h li p Si 3 e e ol i E (f> g d oc o TA81EII A
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FIGURE5. Actuarialyield of complete efficacyof treatmentwith ssstalolversusdru s witfrcfassI ati”on in tfse electrap !sysiolagy (EP)and Hoher monitoringgroupsin ESVEM.Compl~ efficacyas defined in tttetext is a .~bility tfsatan a ent ~~ Will be toleratedand e%caciousaver time. (Reprintedwith permissionfrom N Efsg/JMed.”)
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p ta w rV v t w et h a io s e ib aigo mo n T da vha mi a d h t a W tf as p fS e r e l n aV at e a ci n e E aah t oot t e & pg h l hh ia a T y Ie s o ct s a t i i d rm e m e y a o r so t t nS l i na oa dh n b c A l o dt ee t C e s b ar I nt J e t t l o dl-sot i s u b s tm t ( ~ a i- p ap wboc t w as g o a 2 u w ht r SHORTCOMINGS OF THE SO-CAlliD ( a s sc t iI c ha g n PURECIASS Ill ACTION A r t i l t a e n n t rS tW c iWah (v i o r& h e d hi are w ani e i d a s l dt t c u p a o onI ii ol a w c I a m g b a o b lc o ep of w p i a si e ti err g m t t r e e n a a p t a ec rw p tr g pr b o e gox h /u c Ia f t p o V r c lt c e o e T m t v ei at t ic nr on t i o r 2 ass a r a d u iv t em t h a C r lmi d utta i pha h po r e s o p ha s i pt rae u fi ~ bmu c u p n e T r a d2 m r r a gl a d T l sc d a i s u h t n fp a dIe t d io c I sa t aa n vo t t t ep ai nne s r r e u sc a te e do v - i on glv d t b d e ene r t a i nb P ab ac t dh e l r p o i h t e i pe f o Vi rr fe Reverseuse-dependence: The i o i n n b N h t ve i b l p en e a p h r c w t r h i t a ev a c itoe an i c t ena - r d I g e c Ia i upe s s e nc lpe e n a ddct eo t ae r e vi a n ( i i m i a h hi r bn ib o. et e a e g d ec e t a t t e a b t gc d nh e l e ha tu n n n o i t d eo t a p p oO o l c t a n r eh t i n hz W ag Co a hil h t o h m a a w vc t I a 1 V ni e l a g e r e cu x s n S eF t e 1-h S v d C r A e i i e pa Se ( po d r ei m io p a lo l oE r t gS i a W no A an C g a ah s r T m c t Seo f l ta r e u he c v h w sa o a a u d i n e c A p n i a mC e l1 t i n o i de m o d e r e i t i lx a p ec d oC n Aec hS t Ig p u P t re t t a t t as e a ar io r T x e is c e m mf aai m ta r r1 i t o r u s i te c e o t c - I v dL elpO a e hnr M e A a d e ia h r g a pf m i fr eF a n i oi R in cm I M m p r p r o a rc r h y t f p A S N Torsades depointes: T t o p ri o ; a y r r h C A S i, d b a w c I a a ug t b lc.p. e cI p t a nI m r t p ee h a t pr m c f ea la t 3 e a n s r am l di o e B Po oo i K B t w t P a V in r t h V F irt g n n sT t m st h h m i eh a nh d p T i om f ti e p no tcc s a v a A n a u i nbo t o v v n e m s c t h r i d e i g I S ( C 1 C l t e u xc u w c do n ne Ka uK d p sh N il d o i S D M Z L z i d a t a pae b l r l t h o a i on my r K M P S d p ( i d b e aa fr i a u sa r di t. a d r i yp oo c m m l p i t c r o ah c w y uC rr 1 t b ih d s h i Ha a o t p ra e op x oa r r oc r F l I Me h p o yr s n i S h t n tr s de ( n J ri t Q i a c nc o i T a h s h ( pa Ch S Uw f p i to r I t ac l a l I uv y o p a hw C a v a o s i t Q i oi < m an t t s t r 5 e s h d d W H C C A oo Tr i d i 3 m t i o t nd p c E o 2C g hi ds s P R F P a t b < p 2 p e o a E~ E a t h i C u
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, Inrecent years,theresults of largerandomized andcon- urewasprematurely terminated because of excess mortrolledtrialsof antiarrhythmic agentsfor primaryand talityattributed to proarrhythmia (torsades de pointes), theimportance of @docking pmperiiesof a secondarypreventionof ventriculartachycardiaand indicating ventricular fibrillationhavechangedperceptions of the classIllagent.A secondary ‘prevention trial(ESVEM)in actions of antiarrhythmic agentsregardingId efficacy patientssurvkingan isodeof VTar VF showedsigY sotalolcompared and risk.Theprematuretermination of theCASTtrials nificant superiority of d toanarrayof of primaryprevention in postinfarct patients highlighted agentsthatblocksodiumchannels withrespect to HI the proarrhythmicrisk and inefficacyof the sodium efficacy andtolemnce. Occurrence ratesof arrhythmias eitherby.suppreschannelblockers(classI action),encainide, flecainide, treatedwithdrugstestedfor efficacy and moricizine,in patientsat relativelylow risk for sionof inducible arrhythmias or by suppression of spandeathinthelongterm.Theexcess mo@litywiih thempy taneous ectopywerehigherandequivalent forbothtestwas attributedto proarrhyihmiadue to facilitdon of ing methods. A secondary prevention trial of reentry,especiallyduring acuteischemia.About the amiodaroneand multipleagentsthat block sodium sametime,European trialswithamiodarone, a complex channelsin sumivorsof cardiacarrest (CASCADE) increased efficacyof amiodarone agentwithantiadrenergic actionandpowerfulactionto showeda significant prolongrefractoriness, (classIII action),indicateden- butpoarbrlong-termtolerance compared withtheother hancedsurvivalaherinfarction withamiodarone butnot agents.Compamtive analysisof theresultsof thevariwithagentswithclass1action.Recent verbalreportsof oustrialssuggests thatclass111 actioncoupledwithanlargerand placebo-controlled trials(EMIATand CAM- tiadrenergic actionis moreefficacious in bothprimary IAT)confirma significant reduction in,arrhyihmiamor- andsecondary prevention of life-threatening ventricular andthatlethalpmarrhythmias maybe the tality,possiblywitha favorabletrendin totulmortali~. arrhythmias effectin attempts at primarypreventicm in Whilean oldertrialwithdkotalol(class IIIand@-block- predominant duetoclass1or so-called pureclass ing actions)showeda trendtowardimprovedsunrival low-riskpopulations afterinfarction,a recenttrialwithc+sotalol in patients Illaction. (AmJCardiol1996;78(suppl4A):28-33) withrecentinfarction or remoteinfarction andheartfail-
fu i tl o fc a ai m u o ri e ne n cri o l ce et ar o oc a e C a rar ucau l h r d ate uI sa h dho a fd v h f tap ro o l r rd no t eu e a o t i ac iv p p p o i e tro o h d t aahns diC t e 1r l i c h t v h e rv r nt e ern r o yt bte a a ab a V i @ r - r T rib ci n a Ci le I l / d dc y a v f ce ( i Sn t r ar t p i n t b o t c e t t o egV e o r c h n e ato ar h p ntl h t ag i eg or o eha ab ae e or sp nmc V h b b o a t h i c s ol r os iat ad a oe t e c p ixct rc cu a eo ht ia h i c is c ac p m yI i t V a rh l u l le C r r I paa o h l gdoa ( Wo cc ic t i i tgb o cc c oct h Sa a)e a ht ol u oi t s 1 a i s a h lf o a Id a r r o lebs ihl t ldgri f a w T V W c a e l ic ud l s f e w ot p re huo r s c d a o t cb ot c es r oh t es g a c Isi alhny cr s I et f dsi e l ee i nc t t wf r b o oi od p i f h c e eo d e t b c ob s u s oa o p n r w k o p t c r r na ug rnl c Tl ( h o t c hI a t c a a Iea M h a nh c o) r m (h eI A t dcy d na f w i usnl a o t 3ss of c o t V W i c a lh ei hlco i gc a u I M m a me u o er nc mea b w d r o zi r ie c c e ede c u h mA I I ac i I oa a o ki as n l n vhc g m u a w p t b f rt a h c h t i i nu a ~ l bs -S hts l r d i s c a ci i I a c 1 fa a oa h A c lo a a n a rh t b i r t cc rl a e o t e o tv c h b d io l v a l a me hv n r h p 1 p i p
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w a c co p on pho t nr Wi inn ao u e po TABLEI V H C t c f iR i r cr o e e c o e r u q e n r i m u n A c T io m p n o m i o d r i p u t o nh ui c R c d a t ic t a rc r u a i o M e o e( v c rk l c p lh tc o e t tx m b b t i o d i h h n l u rc u et e o ri b n i t o I g b n i et n nv h u o a he r e Q t u nb i p i b p d r hi l Pr r o ee c d om t i e a d x r iec s t tf is r D a t p c a n t ha o t k i p i o drm e o ri np c r c e u e o e n cul L f t w t ri p i i ta rm h M s oc p c s t i h eu o d e r i t T t n et r iT c e g r h e sc aa p t t o t c m e t r i p e ix I r kf u e rch c a m r h o a s i t c a w a t ri i e l ct ua e FP r f rh p o t m c ye t t c o o r i n c a n r h i r e c M T u e s c s i na o op l h uM n t d o a a ua i & r c o t c i r B h u T t s h f r r eP r a e e or tn i et t t eh ap P r c n o p i tr c a w oc b i p t a r h g i c ha S a bc s r c ui t e o e f Am d xf p u il c i cc c t c o p o r u e Eo f o B lr r o ax r cn t g rc o V r a c i r b c Iua it et c l di o r us t a t d o s c r d i f e e s o ux h D c p ut e r a o a a m v y m t e o a y n c o r t a c r r a i i d t H s i I m a s b r y b- d i p P e a hs r u a h a( l w edr s t t ka c I o I a i t t d o lc c i p e a s t a h l p s o p rv r e e e x e ni c f e s uax t a ct ( r r i ia i i o euto r iPn p vo a V f e r d et nh n T d o d ue i p o p V P r ro a h lr i waoad i a h b t r il dt t p b c Ir a V it e cp l m n a t t a c a r I r i o f P r a r r v e e ee hi r d t o h h d a gy r i f et e a g um ohn s i u y Tna l m en a ce o f d t r t c Ie a h c ep e I a w rl r algnt r ua ee f t tn nfae e n a e H f r cf b op i ce w c r a e r e o c ni ivm m o pa o I 1 C r lwi b c I a w c i s o gl i a p n t l h e d a u o r m h e f e b a ir an m p r c o l t e t ei t t n i e re r a rg n a i a np c t nd aa i r t hf i u t s t ou t r f p uae f a tg c h r a l he o r m T i fpe m lir i cl a l r ( 1 S a ee l F t p e f i reu o n g f ) o r t i h o f n o a ay drc t ir u h l h h c i my b a na t i g a r e r h n y P h f t ap or V r i m ae c T v o t e o h h e p i t p m e i h ( p o t ir f r e ii e v i . n e p i a b a ad h r o s e t ee n i i ct i e i oi ( p o r r i pi e we h c a v . u et r n ear i s a e o Vu pp r T i v / s i V P r r e i v em Zone of depressedconduction Depressexcitability r a i e do cp a er aq nca t u uti and conduction f ifurther i ri i and excitability i o p n t ris w e te h if v block) h e t + bidirectional e f u nr i (unidirectional block g e r I s r px et r e i c c e a vo e s e n t n t i p a r di o a s eeb t v n i ii i t ee l e h e x t ps p w to ea a r t bh i a l i n h h 1e o V i t ap o aT bi a / s v i s d a ep e p l rn fr te -e i v l cf e i i ni n i f a l t h a ar I s ei c c t a kun r ro e Zone of mildlydepressedconduction o p i i c r t nh a a e r v cd i e Depressexcitability ac t na u p o e r o t a ef n a td f and excitability i i g a and i conduction cr further r hc te (unidirectionalblock) s s c m n o e hi c a c n+ unidirectionalnbclock ao o
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a t b e l c se ew pc t a 5 i 1 y ( 5 S m b o t F D T l w i t e p o t a t i ho a Drug N C ( C ( G ( % a m a s g p t a om g i r o % I s c f e t p r w r f h r i 129 25 6 M 226 8 p e g er l a i i nr l o Pirmenol 109 16 A 4 t a s hi l g e r on i h P 158 6 5 c h r T e ge to p s r P 3 220 24 b t d t m i i m e he f th A 1 Q 157 13 S 234 1A 3 2 1 p l r r r we e o o cl < < < < p Volue* — i t t m io c e a i e sl n f a w c Ia A g p2 d c pl Sotalol versus all other drugs, CV = cardiovascular; CNS = cenfral nervous system; ESVEM = Electrophys. t a 1 e l se r m c b d t t r iolqic Study versus Electrocardiographic Monitoring; GI = gastrointestinal. t f a c I a t w b t a e l o g i Adapted from N Eng/-l Med. ’ 1 f f ay i c e I b e l s e a Hc g t r o t tp a f ol op r w e c a s eea oa wc o s w m e io p tf e lp s s g i f s g t f t a r n w o i p t fh d e iy t s t fs ie f r ho e i ol c fI a i w f m e t t o f d i s o( t5 eI hr s a a s cFl dc u u h inc m ss e se ri p i V r ( n v 1 f te d o Tc su nb o p 3 / r e ci thr ta g cw d nc or o o d a a a e r a tt f o bfua a a Ia t rV c Srts 5 a i s P u ( gv 5 pf t pi t eE 5 e6 n O t h r v r w e b m e c t o d T a r r r rt w e r u c h h u g y ah i r ob to p e g a trlh u ai f a a noed e c fl s w a h t wo t c I a r h a s w m e i po fa r r t ft or e o ep ena vac r pgarf e ce m t e t c e x a o i t n m d c d a a dea ( l e r l Fa e ia - d i t n cp c a o t mo r 4 F e c m x o s awo r e m ) ti o t b thp d po a e a r es 0p t ti nu o mm t i ui al a 2 i 4y i ap o a b o r h yl e Ie ti n ce wp t i m org i ei dh 6o ee a e n d p p = y o aa w r r f ( r p p e i a rw ol i/ i V v n f P ( dT r 3 u e2 e / c V0 q Vc pi e d6 a se lt a ah i o n n ci n V o( a 8 as r i d l nuar w t r e e to a o2 ph y oo l t e Y a m e f o 3 j S rw a ca c h c t tm a Ca~iacArrest b t i t s ot (e I p l h T t einrSeattle:Conventional e r versus I Amioia th o a daroneDrug Evaluation i b t c Ia we a w s gl c s (CASCADE) l eTrial: a eoC h a i c a amo f iv v e rn m e s xe S t s fw i r e o cmc i eatca o i I l a i c so ag g ra u b e t h r b t i t l to e l teea ra r t r t ( o p m p e H r h ep E i a a d n a c S n ce a l Vf m l u o t h om f i o bbo T c fr e i w t f p o e r f o an i s o vhaa bi i t e ee t ml wi rra o h mmno n l p w d f a e ed o c o dt o r a m i d F l e a od r h t f f 4 nw s f u mui g e i gt r oc - f nl g c o d i pt l r r h eo Ve e rA nae e r r c c ( 1) i h t rb t i t s i ot wr u r f o C ae w ( t ( i hi dt b p t b t r oeit t t d1 A 2 ai i a o re r r l d enc t r hra u i t b e ( i h ft b t i ft ew c t3 l t a ( t a c nr r e o eh s c o I ar w s trt t c nlf y 4 i h ri nc T c e r fo a fw c I m p aa d h li p Si 3 e e ol i E (f> g d oc o TA81EII A
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FIGURE5. Actuarialyield of complete efficacyof treatmentwith ssstalolversusdru s witfrcfassI ati”on in tfse electrap !sysiolagy (EP)and Hoher monitoringgroupsin ESVEM.Compl~ efficacyas defined in tttetext is a .~bility tfsatan a ent ~~ Will be toleratedand e%caciousaver time. (Reprintedwith permissionfrom N Efsg/JMed.”)
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p ta w rV v t w et h a io s e ib aigo mo n T da vha mi a d h t a W tf as p fS e r e l n aV at e a ci n e E aah t oot t e & pg h l hh ia a T y Ie s o ct s a t i i d rm e m e y a o r so t t nS l i na oa dh n b c A l o dt ee t C e s b ar I nt J e t t l o dl-sot i s u b s tm t ( ~ a i- p ap wboc t w as g o a 2 u w ht r SHORTCOMINGS OF THE SO-CAlliD ( a s sc t iI c ha g n PURECIASS Ill ACTION A r t i l t a e n n t rS tW c iWah (v i o r& h e d hi are w ani e i d a s l dt t c u p a o onI ii ol a w c I a m g b a o b lc o ep of w p i a si e ti err g m t t r e e n a a p t a ec rw p tr g pr b o e gox h /u c Ia f t p o V r c lt c e o e T m t v ei at t ic nr on t i o r 2 ass a r a d u iv t em t h a C r lmi d utta i pha h po r e s o p ha s i pt rae u fi ~ bmu c u p n e T r a d2 m r r a gl a d T l sc d a i s u h t n fp a dIe t d io c I sa t aa n vo t t t ep ai nne s r r e u sc a te e do v - i on glv d t b d e ene r t a i nb P ab ac t dh e l r p o i h t e i pe f o Vi rr fe Reverseuse-dependence: The i o i n n b N h t ve i b l p en e a p h r c w t r h i t a ev a c itoe an i c t ena - r d I g e c Ia i upe s s e nc lpe e n a ddct eo t ae r e vi a n ( i i m i a h hi r bn ib o. et e a e g d ec e t a t t e a b t gc d nh e l e ha tu n n n o i t d eo t a p p oO o l c t a n r eh t i n hz W ag Co a hil h t o h m a a w vc t I a 1 V ni e l a g e r e cu x s n S eF t e 1-h S v d C r A e i i e pa Se ( po d r ei m io p a lo l oE r t gS i a W no A an C g a ah s r T m c t Seo f l ta r e u he c v h w sa o a a u d i n e c A p n i a mC e l1 t i n o i de m o d e r e i t i lx a p ec d oC n Aec hS t Ig p u P t re t t a t t as e a ar io r T x e is c e m mf aai m ta r r1 i t o r u s i te c e o t c - I v dL elpO a e hnr M e A a d e ia h r g a pf m i fr eF a n i oi R in cm I M m p r p r o a rc r h y t f p A S N Torsades depointes: T t o p ri o ; a y r r h C A S i, d b a w c I a a ug t b lc.p. e cI p t a nI m r t p ee h a t pr m c f ea la t 3 e a n s r am l di o e B Po oo i K B t w t P a V in r t h V F irt g n n sT t m st h h m i eh a nh d p T i om f ti e p no tcc s a v a A n a u i nbo t o v v n e m s c t h r i d e i g I S ( C 1 C l t e u xc u w c do n ne Ka uK d p sh N il d o i S D M Z L z i d a t a pae b l r l t h o a i on my r K M P S d p ( i d b e aa fr i a u sa r di t. a d r i yp oo c m m l p i t c r o ah c w y uC rr 1 t b ih d s h i Ha a o t p ra e op x oa r r oc r F l I Me h p o yr s n i S h t n tr s de ( n J ri t Q i a c nc o i T a h s h ( pa Ch S Uw f p i to r I t ac l a l I uv y o p a hw C a v a o s i t Q i oi < m an t t s t r 5 e s h d d W H C C A oo Tr i d i 3 m t i o t nd p c E o 2C g hi ds s P R F P a t b < p 2 p e o a E~ E a t h i C u
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