Early Pharmacologic Therapy for Ste Acss

Pharmacotherapy for early treatment of ACS is outlined in Figure 8-2. According to the ACC/AHA STE ACS practice guidelines, in addition to reperfusion therapy, early pharmacotherapy of STE should include intranasal oxygen (if oxygen saturation is less than 90%), sublingual (SL) nitroglycerin (NTG) followed bylVNTG in selected patients, ASA, clopidogrel, an anticoagulant, a ft-blocker in selected patients, andfib-rinolysis in eligible candidates (not undergoing primary PCI). Recent results from two clinical trials in patients with STE ACS indicate that clopidogrel should be administered along with ASA to patients receiving fibrinolytics to reduce mortality and re-infarction as well as to improve the patency of the infarcted artery.17-18 Morphine is administered to patients with refractory angina as an analgesic and a venodilator that lowers preload. These agents should be administered early, while the patient is still in the emergency department. Dosing and contraindications for SL and IV NTG, ASA,

clopidogrel, P-blockers, anticoagulants, and fibrinolytics are listed in Table 8-2. Table 8-2 Evidence-Based Pharmacotherapy for STE and NSTE ACSs

AifUn SU MulavjIiKonmrndaionlwa»

NSn^dMlNttvnmmlrattaal wviwl*vdoQ.nl pMMt

OopriojM SU W.<taMli*«OTmrT.WB«inm(flTi» HypoxmilMty.

«Inge K>*i{Mt\<bHl<r<cmT*ndncn jiwilnk.)

to *dd 'o rt*v, mmbk*öngn* Nsn ACV I wconmoUKA to Ii hovaulBtd hKln ST( jf.3 NSU /CS (Ins I

U^xllcnalrd heparin VU Mllia» I wormulilOT»1 piOeVi mtogomg Kl and kt tNr* (umm heftann -«du «d »nIkI weh lt>*i>»t«:y etat ta ihtcrrtocyvcerti

«KorrnvndalKntapallrnitnMimtrd «w Mredng m*. A«h M»ix*,T< Ihnacv «rce* Uro»»

NSn ACS. (litt I wcmwniMwi In ccmbnjtlcn n«h ¿repu*« »*<ap,fo« <OV<C<VJ»* Ol »W«JVf «ÇfMOKh Kl <tou I i«cnvnmdKon INSU ACS *d SUMI

fruupann f<nli|>iina

F<xnoMK thei-apy

SU Mi <ltu I narimiiUui in pttMi «<« .t«) J Jnd claw »a toi reí tr*¡n¡fmj irpeifwK«

HSU ACS. cl«» I »«cmmerKWon ri (ontmjiK« »»h ait«« toi anMraM a raw.» «iii»h F« Kl dm ta iKcnvnrndawn « ^««vMSVf » WM » pj«ifr<» »th HS! /CS

fopmavKInStt M.<U"lt>

NsTt «!i<lr» I icccrrmmdanon toi

CUM I »«rTmmdalCii toi SU MI «(Mr.) ihKrvttayiK 1 JI>J ta ta palier** nc« un*«»:«) wpcrtiMwi

CU» I tor NSU ACStoHmM* « convoafivp jpçKkKh

SU Ml cU» I leconvwdancn ta pafrnl \

|aevent«g wuhri li hour* tatafting he «w« rf iyffl(*crm. <lr.\ ta m [orwi .h pttMfWig bot wren I.» and M hO«v

Mt»») the omri cí iynftom mtfi «un»») \kfrr. ol « torna HSn ACS. ttei N ie«ivmmdatlcn

«ctjcnoupcniiOO

ItMIhan ISnOVntv MOMfCAK urgw,

Actfvebkxdng WWre UMVV.) ink

160USmjoat»omen tomatald* I

2S-K-2 mg <«red»F< otrfy Uaiong hcoj.tal d*y ; jndcorenxd «vfctaAHy n pac«i*inol

.<* Mi nttKcrcnaiy M2-WS mg ont <l»t» oía»» ta amwnin(/ JO dm" pMktt mde«')ar»a Kl leceMraj t b*e frétai umt. í morttnwlh a wolrruiMatng líní. and 6my<tn «wo. a pacMa*< rtun*ï totoved t* ^ • 1« mg once da»» c»a«y nTw Coronar tndcfrifeFr

WO mg K I»» I ruorrtnmimcrl «o «00 itkj fclau I« iKOTvnmdafXr) kuOnj 4m <n hcnpuJ day I fotOM-d b» » nutMntK* dov» ol » m) po ox* da»» tutos on hot(rtjl da»im(xan«m»«hNSI( ACS « SUM uxtogen; Kl MO mg den» tAno*d by TS rr.) po da*r r. ic«Mr>) J rcnndytic o< rm do no« >«»»* «p«fu!a«> thwap, m pall««» »wh j SU M 4m*J loadng dw» n (uomvt ai)fO KtMto m») Adri>.vu»i rxWrvW, n paivMv nnh «can Kta» I aKonvmndMunl AdmtMn a(*M9inümfon[vX!<r«tw«hNSU ACS Mtw ar« mvuged nrntcaCy Ktotl if««nm<ndaiion>

foípOílKHif/wlpaiiMttwthWSiilnwvvtwjiWa« UircmlnCMASOWKeAAeciyl

I» harr nvj tff iv idww« fin i Wví I mcrtfMdMty ta límerth» In pMi*f(t M«Mr>j t Httnd,oe cu Ilia« do noi Mf»ív«y> Ihfiapy m paoarti ar» * SU MUdfT»«« ta al Kau U davtKUu O and 14» lo I yr« Ktau lil i cu sil M with teiinovio. »dfTW.«« <0IWI Vtg rv txí>A ^nimmun 4000 wwijtoftwwd by amnUM « «Amen lí vSj>t> twmn 1000 uwvtí FoiSUMpnma»yKT*Jmnru«6i>?OintVfc}k*>»<dWJ<orBUM Wuücntí lí-ISuralvV^t»

fo« MSTI ACS &0 WWvlq W botín (nv»rtv<jm *00 l>wi}to*w»d by a<cmWI N

riiMii jt i; Umv1u>t< i-fuiiirun I.OOOUiXvN tmattd to iTüíftjo jn aPí I oí 15-20 x ccooc<üw»oönjw^ SO » wcortfi) ta SU Wl and ta NSU ACS

It* fw aPn rfoaM t» mMVuird ol 4-« hou» ta HSU ACS and SU ACS r> |Ul«nh no«

IKSMrd wlh ril»íKÍ,r<\ TI* Im aPn íhoutl b» moa-Awd a« I houn n pa«l«ii> »«1 SU /CS iM» « »*a««>

(nou(uf n I rr.>1g SC #vny 1} hotn ta paomlt mili NSU ACS gr<Mirf iKan o rqu* H>»«n/n»í

I .W .«IL» n I fT»>lg Xw. ílhMi 1C1CIIS-W TlArm) ta MSU ot SU VI Foi uxl«i)<»g Kl nlUllsn oí SC «««apjiin ta NSU ACS, «

'•ccptommul 0 Î nfítfVdM d «ixoJta-n thoJd bo a.l»Mr.r,i«o3 al Ih» in* Ol PO I II* laM <ta-» o< SC «wapam »» gwn 8-12 toun píK* 10 PO Foi(UI«*i«KlhSU M*<n«rijM»r»jíy1icv Agr tn^ iMn 7% nt rr^upann » ing M by I my kj SC M»r 12 ho«i ft* ¡4xn »Jminuti mamum o» WO mg ta pal*«* "v/«ij mc«r tfvKi 100 kg)

AQ»^.aMlhjna«qualto7S>fv*dromM«fK!U<uin0ftmi)ta)SC#«*iy l2l>om 4Wm 2 d«« admnnw« mmrrumol nmgta pairrtt n*4/tng mo* llun Akgl Coronar iNowjhoul hoH*a»/j««3n o< w lo 8 ta SU M¡ Cotí*** ta M -tó hoin ta FíSU ACS a II* «>d oí Pa

<«Msri AC5,a*Tw»^Olm.vSgrvbcíknWo«vrt«)y02Sm>'W»'»iWuiW» FaKln FftU ACV Jdwnw*t»«c«)lx*n</OSmg4ijW*da*i»«»«íuucn«al»lo

Atwraivrt, ta POOn NSU ACS 0« SU Vft támnun »02S mj'Sg W bAn tofcwwdbyj IÄ mj^jt. IVMtfon On<omnur o <nd oí PO o (omn* ta IV lo 4 howv

A<u* Mxrdng fd SU Mi 2 S mg KMn lo»cw««í by ÍS n*} SC o«» <i*, tfjttng on h<y«<ial day 2

«wcWrcdojiB». 1« NSU ACS 2 S my SC <•*» da^r

SCigr^al»tlhanoir.iuaHoJO »01 Kl gw jw^lo fi bc»n oí UM j»>mm nol ngowA ifuftcdl n.>\* (M tmcll) or GO Ccrdrur utá t«S4*M d«fur^» iX Hl lu 8 IruiMn WmtAWn

Niwrtiajf. liamiirvclaJ <nctn>«cviai inauK. wach n an arxnjl wtnouv Tjlwrunon I it»" nil »: i jr«al nufcyort nehtme «ta* «Mlhn ) monlhv MDV» MMdtn.) tnciidng ftttri Ugrtfcani <»y*d r*ad 01 (acut liftnuwiHn Jrmjrt^

^Uv ISmgWbc*nWt>w>byO»mg'SiJNwt» «mn*ru.50iT»jlfo»c»wdby

0Sir.).1u}«T\M IS in^ .Mltomn tMoiun - 100 mg) AMtptac »m»«ilV*2. »mnamipait

In-, »un tú b, - » mg f/ttauk «0-«Mm-3SmglVbota

Ofioçt&tin RVKj NSTE ACS. cil» Hi icccrrwolal on Ac im- t i«cc6*blxlm tcx rah« i^/Hun « «*<*v*iV kr Hrcmfcocitocwlx ptffeoli «Ihn «rringr.) «t»r« irxx rtcvjvd Kccnn. aatmi^irei taiMn. cla» I iwoTíTwndílKn k* iMiix.n xt.yvfun) «a (UM «> i«cn*t**>dir*in 1« cuemii wihoj h.jh irJ fciMuwi »tK> arc no«

SU M. tUtt la to« abciumab k» ra <lm U> l:< «ihn :«ottun a rf«/í>y» to. p*TiMy «I

urug

ßtotumtb fftHbM

Oiim^fV bcfcjiMl>««i1 by012S

mplp'tTm tnKmjn 10 momrik* 12

houn IWu/fcjVbcJui * 2. »mnm jpM vsrh an

MM FDA jppwd

Oowl«*STl ACS WIllVWKllOUl Pvl intUffXMIKT

HO|Vlg)IVbotA lotûvwd by an irA/aonof 2mcg' quinto I2-72 hoi«

04rr.yVjf«,Ui.ji

OTT K rrteiAn foítMWdbyan trAocn c/01 mc.yVj'ttWifc» l«-72hom

W'ji' marwrwnc» riinOn ii> I 4M {uricrt* i ««h oa Itw Itvn SO rri,W>\ no» WaKO * in w«h inurn ««jum» 0»alrfitar.40n>>»*OS4 irrrf.1t P*<i*i 121

kg o nw «<«♦.*• .i nuuruii rftr>:o i»0l.V6 n»j pM boka er») •> mrtTMll rtuvxiMeol lim^h (Mu* mwemtKr «talon lo OOS iTKi'Vj'mo fo« >W!t>GakMtton»rrC*T«n

Sit Ml M-Í r«SI£ ACS. <Utt I «r.JtCJßOri «i (i*<-oii witt coo:».} «hm* <^<M1*C<I. «1*1014 lift* UlYttCn« nv>ri»)«r«í ot pt*iK<M«y ccnjruto

■«wmrvlifxri far <"> fefad«««» n ■»• fouvn viT.jO! (C<«UIIIKJK« nih» 1 «M 24 rojrv 4M» II fo< rv í Mort« «n t*fmim*i» furwnii

MrfrtfnKfl. iJdMUR cx VJXIMVAI n ^ iomi a l*UM Alltui <5 llOl

4T{ M cía» Ij itcommcojjeqr. »id fvaMra wtth CT«xx>3 Kcfww »t>o

*r j»*«)/ tjlog »»jMir Oer»« CÍ rilitfn *>d jVtAxim <» n «% «Mb «rtijoXKtm lo a rt(*ty»f 10 0-btoclm (iJÄUwn o« w<jpjml irWwwd Ounj rJtJ (tmrixorii W>rt ACS. <l»H «> n«crintnixt>n (en dttutm to« pxMi wuh AVJ

NSn ACSc*SItMLCUwl»cc«i»«»d»cn t» pjOcfKi «vit» hturt tetar. Wt

«ornoiJt <VJvixt«:r. jr«j I« Invm« a »Ulli lo 2 dJÍM<n n**1vn *

anncXiárty iiw*

înl c«*iv xnomertiiM hwrWoc». hc»l air If« iMn <0

90irmHg. liotlr.

Wt wWciA»

0M wírth ki .<• md dKvnm. ¡ma îicljIIK-vWiKvb'hNiltitortto' vit.«or»il a «MlUuwri liM«t <.*r If» Ihtn tiO

«M «Miiunnc» WJ(«II S»v.o»i btood (tn-Aji* kit tluri

KOrrmKj \r.vx, d waokirte ioji ACS

rttbtot bi»!«j( r«ru< *!«r vnim pcttMijm ginum itun

Si rri<vl iytiln kmc i«ul f p>«ga>rci>

4-10 mcc»Tr m W Ir/uslOO itr J*á if lo 7S -100 mc^rw ur a MM c/ »tr<rxmi a W».) ■>if-«««6 weh « irvuk tiMó |w,wr leu :fon 90 rrrr+lg « mar llvn »

l«!«l Ukw ajilng rrwfi »int* («nw« Wv>+> * jqfitjn n pwvrr

Il<kjI pMCvi Ct aiI mum jtlnrJAvH fc< (iü«rti »KliOil cnçoan) «

íutme U HMon loi.M 48 hou«v t«unm«v>MtMtrU »ooi^vjivti».

»mjslwHprflin« 1-2mrl.nf»*«)«v«y Smr.ii«^to«aio«jl0« IS mj n 1-2 b» 2S-Î0 mj by nwuth rwy t> hc**\ « * w«y wmtrtM*

it^trtn a <1««d. «»lui dy^i ein b« rxJxrJ ul-2 rr«j rte«*MicW0 S-l m^ í/ifaí fokwxd ift 1-2 teuii by 40-93n.)by rncutti 6-8 houiv

Al «toW S iwj IV m 5 mnutn by t VKOri S n>> it Oovr fo« » total d 10 mj

(e&MfO ir, J-2 fcuii by SO-IOO rrr) by "Orth ore«- daf, AJVmilM-fy Ir«ul oliwan Ilm jpycjn I* arniwd CiS-Wxk/f

Wtunm I20-KO mj vWjnp) frW* c«jlV orce VnapjmJ ISO 4»n>3v^,l*-cdirlr*x-c»^c<*rd>i( Î0-90 nvj ununed wtoM« o«a»y axe 4a#y S-» m? o« a»y cíxí Cor«nu> ir>Mnt(4y I <criitn3<MKo <n<*it$ t*xin («iv.li

Drug

Captotrfl lrvjL«ril IHn^xl

I>ao(tota(ri

Initial Do»

625-12 S mg

lOmg

Í0 mj d»V lo 50 HKtrurmilary lOm)tM<crdJ*ycrJty lO-Mmjcrvr-daifCaOy Jir^l«« W,« lOmgono da^wjty

(.orwip ■"■•J' pjt^fiîwthiyu Idlm I «rcannicfidMKm. ¿tas Kl In knrriA

fVfltCfllii]

ivfcLiUftj rdrinëHy far M pHfrftKYrth FF

toiihai 44%-fcLa.s I r«ûn-iTiff>dj< tord ÎCSri Mi m S1F Wf. i.Lt'i1.1 iK iMii-ir^vljIk'n ■I (uiinii'i Htihdncid «]ind Pi'.nr Î Jutr:*: Irfl vniliE iiLr FF Iffri Tlbi 40% jtfd II«diw.Jiïl ti m\ itT ÈlMsim lIjt.ï Li MNrcmfrawfiUHfi in prawn wf!h clif« à UgfHd luut IIAJU- I» iF k -.i dun jftd i>:- ctot >jr,w*Kjitofi ii ACE rfttMor «miA-iaxe CIau I m oiftM nuc-can (HiWTtii vuth tfffmlcfiuon STI ATS, i Lui j l^WrVdMiïi toi ifulinih w«h M h kl FF ït\ tikrt cm 1 iû lTpJ «ihff tiuiJCWj n-if*iij. or Iwai tiakr? vrfTÇfciTY! w*» arc- .ïie-riv un KL IfiHbfeor

S-jisfc. (jA>xL l'nruuji r ir" Efi llïj u ni ri-.| béjlxujj rwJ aim Tirorah, •rfiun fp-*j"itiLi'r'i lUin

HrJVJtrVr^y'i

SCr gtcvMCf ihai M n>jtt îçjmmi ihjfi 221 prnci-11

ipHug

Duuf

(ptartYXir >4uiKïi>: lune (crfHHV MfAfifriy

Inibul Ûow

Maiirrurn Durs»

Ît'rng i.HK.r iljyfy i.Hjlly j'S-W iiïj r.r- p dify Ërfjly v&ptènt vfîmv STt ACS.d*T.II»«rmwTifTKljiifsn fc* pa**.-, v^itrti irfTpii*Tr; M* M itfwiKJ |hn« j*I|J! M raiiQ^KÇfin m «W V^MWM r. in ^^ n aJeijuafraMrbitx-f»: itwia>

W.rr h.;- iPH'jl^w f VS rrcujlf, JXrtirtY Kùtïiùtl

Livi ! r#i imiii«k-lT*>Dfn .ti» rraicllt fix whfch Ihnp h pvikra,'? astS-i gwifr.ï iKif i-pwn [iikrilir# rr Im-iirrort n.u.rti.4 ,r«l Hlrr^

□«4 l«iOTfiiefîdjjom*i-î^»f conto-m-Boi w^ifcti ih«e- h-corflcH^] rrtXfK* irdAM 4H**Qtrtoe of oç&ion jt«>r & t ir*rxnrrwT-i Liimlhr> «fc./d cï lhp n-d-ivc^« mr, r, In livru ri ipjH JiH-ï.vVllr l'Lp.-, fc m-:i-r*n«Kl+.i.ifn .r- fftw 1er h h i.cjjHiinpi.v'H'fk.k.y r> k-.'. Cl«s ■ i<KcnvTM«KLadc<H at ihwe- prfw* tfve p<««dL««- M wjirwf« b-riM irtrfj a^d nu» b* KamiJ

:r pu h iirtrjHEtr.jfM-ifcj JÀ i Jhmfj)

■Clwfci-cf îtW ■{*-<'K ftM m ir&jii.j|. t-n'j>.v| rt-.y kqtfa tNlIt^ifiy | ifwHr ap :00C«m ri».' pji^nr «iJ(rf-itm.ï iJuc'iS «Wing pJiT.iiijiy rU'^iJj? r!£•:■■ ^Jj aTillnu. liui îlkXàJ Ijwr A ttorl j. Iih| a^TJ. u h in.l'rcfaacid'u1 -jt liir lilià JKrlvK lrii .vjrtf.. infiutJ fAèi w/iwfiftVfùi ji*iJL«H -a! ilroiéc: cirlsix 1 prf" |Maihjiji4''Ji-.--j-^

fiWTip i I'd ù tfttïKUï} xjtTt « ¿■■■-iJjx-'j dow k 0- î.ï mg imiMïntxfi mwapAitoi. 12 5 nrj ¡ysi mncfKM.« ÎS meg/fe^nn «mett -r, mwjiiii^J catm confirte «voUmc ni ^-(i^fcfi Ififffpy

ACC JMmicai CiJ^p-cf CuMogy «E.Aftjtai ii'wir-i.vv JrtHy Îtycifis IJIJII. CAO.E.nnvv«-rfi^nA F.1 rryocMM iYai:ocï\ HJIE, nifiî ijrir* jkxijçffj tyfuito

min conwnhfl kw rhtiii«1 W-1A. A^^ai Mear a:S Mit iiMErtav ivrpSoiw tfTr. rf-^J panU tfmriSaptHln

.iflMV iF'-f ("rij.■■"r-"nrr Ifp. 0tS. iVuj-r4-¡Jrnl. FlY-i rfc1-: EF. r^rrii.n ïia.lKn.Fl."!A.fcBaj jnj fjiiig AiJnirMr.^tiin. W

r ^jfrtni dr-.-jfoùfï I. ptiyjjta*wi. >mmindo^SC ni'iuiapfo^i SCî, vrtuTiiirartw ii -kjCiHp^juI STC ST ruignwn «teiMijfi UH

Fibrinolytic Therapy

Administration of a fibrinolytic agent is indicated in patients with STE ACS who present to the hospital within 24 hours of the onset of chest discomfort, have at least a 1 mm STE in two or more contiguous ECG leads, and are not able to undergo primary PCI within 90 minutes of hospital presentation. The mortality benefit of fibrinolysis is highest with early administration and diminishes after 12 hours. The use of fib-rinolytics between 12 and 24 hours after symptom onset should be limited to patients with ongoing ischemia. Fibrinolytic therapy is preferred over primary PCI where there is no cardiac catheterization laboratory or there would be a delay in "door-to-primary PCI" of more than 90 minutes. Indications and contraindications for fibrinolysis are listed in

Table 8-3.9 It is not necessary to obtain the results of biochemical markers before initiating fibrinolytic therapy. Because administration of fibrinolytics result in clot lysis, patients who are at high risk of major bleeding (including intracranial hemorrhage) presenting with an absolute contraindication will likely not receive fib-rinolytic therapy, as primary PCI is preferred. In patients who have a contraindication to fibrinolytics and PCI, or who don't have access to a facility that can perform PCIs, treatment with an anticoagulant (other than unfractionated heparin [UFH]) for up to 8 days can be administered.

In patients with symptoms lasting less than 6 hours, a more fibrin-specific agent such as alteplase, reteplase, or tenecteplase is preferred over a non-fibrin-specific agent such as streptokinase. ,19 Fibrin-specific fibrinolytics open a greater percentage of infarcted arteries. In a large clinical trial, administration of alteplase reduced mortality by 1% (absolute reduction) and cost about $30,000 per year of life saved compared to streptokinase.20 Two other trials compared alteplase to reteplase and alteplase to tenecteplase and found similar mortality between agents.2 ,22 Therefore, either alteplase, reteplase, or tenecteplase are acceptable as first-line agents. Intracra-nial hemorrhage and major bleeding are the most serious side effects of fibrinolytic agents. The risk of intracranial hemorrhage is higher with fibrin-specific agents than with streptokinase. However, the risk of systemic bleeding other than intracrani-al hemorrhage is higher with streptokinase than with other more fibrin-specific agents and was higher with alteplase versus tenecteplase in one study.19,20,22

As mentioned previously, less than 20% of patients with STE ACS receive fibrinolysis compared with more than 60% receiving primary PCI. However, 17% of eligible patients receive neither primary PCI nor fibrinolysis despite being eligible. The primary reason for lack of reperfusion therapy is that most patients present more than 12 hours after the time of symptom onset. The percentage of eligible patients who receive reperfusion therapy is a quality performance measure of care in patients with MI.3,14 The "door-to-needle time," the time from hospital presentation to start of fibrinolytic therapy, is another quality performance measure. ,14 The ACC/AHA guidelines recommend a "door-to-needle time" of less than 30 minutes from the time of hospital presentation until start of fibrinolytic therapy. The median national average is decreasing and is currently 30 minutes. All hospitals should have protocols addressing fibrinolysis eligibility, dosing and monitoring.

Table 8-3 Indications and Contraindications to Fibrinolytic Therapy per ACC/AHA Guidelines for Management of Patients With STE Ml

Indications

1. Ischemic chest discomfort at least 20 minutes in duration but 12 hours or less since symptom onset and

STE of at least 1 mm in height in two or more contiguous leads, or new or presumed new left bundle-branch block

2. Ongoing ischemic chest discomfort at least 20 minutes in duration 12-24 hours since symptom onset and

STE of at least 1 mm in height in two or more contiguous leads Absolute Contraindications

• Active internal bleeding (not including menses)

• Previous intracranial hemorrhage at any time; ischemic stroke within 3 months

• Known intracranial neoplasm

• Known structural vascular lesion (e.g., arteriovenous malformation)

• Suspected aortic dissection

• Significant closed head or facial trauma within 3 months

ACC, American College of Cardiology; AHA, American Heart Association. From Ref. 3.

Aspirin

ASA has become the preferred antiplatelet agent in the 1 treatment of all ACS ' ASA

administration to all patients who do not have contraindications to ASA therapy within 24 hours before or after hospital arrival is a quality performance measure for MI.3'14 The antiplatelet effects of ASA are mediated by inhibiting the synthesis of TXA2 through an irreversible inhibition of platelet cyclooxygenase-1. In patients undergoing PCI, ASA prevents acute thrombotic occlusion during the procedure. In patients receiving fibrinolytics, ASA reduces mortality, and its effects are additive to fibrinolysis alone.23

Although an initial dose of 160 to 325 mg is required to achieve rapid platelet inhibition, long-term therapy with doses of 75 to 150 mg daily are as effective as higher doses. In addition, doses of less than 325 mg daily are associated with a lower rate of 24 25

bleeding. ' The major bleeding rate associated with chronic ASA administration in doses less than 100 mg per day is 1.6%, whereas the rate with doses more than 100 mg per day is 2.3%25 Therefore, a daily maintenance dose of 75 to 162 mg is recommended. Although evidence-based data are sparse, a dose of 162 to 325 mg daily is recommended for at least 1 month following intracoronary placement of a bare metal stent, 3 months after a sirolimus stent and 6 months after a paclitaxel stent.3,4

Nonsteroidal anti-inflammatory drugs other than ASA should not be used because they increase the risk of mortality, reinfarction, hypertension (HTN), heart failure and myocar-dial rupture. In response to shear stress, endothelial cells produce cyclooxy-genase-2 (COX-2). COX-2 inhibition maybe associated with a reduction in prostacyclin synthesis, sodium and water retention and increased blood pressure (BP). During MI, the balance between thrombosis and inhibition of thrombosis may be shifted to a prothrombotic state, increasing infarct size. Other GI disturbances, including dyspepsia and nausea, are infrequent when low-dose ASA is used. ASA therapy should be continued indefinitely.

Thienopyridines

Administration of clopidogrel, in addition to ASA, is recommended for all patients with STE ACS (Table 8-2). Clopidogrel blocks adenosine diphosphate receptors on platelets, preventing the expression of glycoprotein IIb/IIIa receptors and thus platelet activation and aggregation.

Clopidogrel reduces death, MI, or stroke in patients with NSTE ACS when combined with ASA.26 Early therapy with clopidogrel 75 mg once daily administered during hospi-talization and up to 28 days (mean 14 days) in patients with STE ACS reduced mortality and reinfarction in patients treated with fibrinolytics without increasing the risk of major bleeding.17,1 Therefore, the combination of clopidogrel and ASA is indicated for all patients with ACS. For PCI, clopidogrel is administered as a 300 to 600 mg loading dose followed by a 75 mg per day maintenance dose, in combination with ASA, to prevent subacute stent thrombosis and long-term events, such as the composite endpoint of death, MI, or need to undergo repeat PCI.3,4 Clopidogrel should be continued for at least 14 days (and up to one year) for patients with STE ACS who do not undergo PCI and a minimum of 4 weeks up to 12 months for patients undergoing primary PCI with a bare metal stent.3,4 In patients receiving a DES, clopidogrel should be administered for at least 12 months.4 For patients not undergoing PCI or early revascularization with CABG surgery, clopidogrel should be admin-2,3

istered for 14 days^J If CABG

is planned, clopidogrel should be withheld preferably for 5 days, to reduce the risk of postoperative bleeding, unless the need for revascu-larization outweighs the bleeding risk. The most frequent side effect of clopidogrel is rash or GI events (nausea, vomiting, or diarrhea). Rarely, thrombotic thrombocytopenic purpura has been reported with clopidogrel.

Glycoprotein IIb/IIIa Receptor Inhibitors

Abciximab is a first-line glycoprotein IIb/IIIa receptor inhibitor for patients undergoing primary PCI3,16 who have not received fibrinolytics. It should not be administered for medical management of the STE ACS patient who will not be undergoing PCI. Abciximab, in combination with ASA, a thienopyridine, and UFH (administered as an infusion for the duration of the procedure), is given a higher recommendation in the ACC/AHA guidelines over eptifibatide and tirofiban in this setting because abcixim-ab is the most common glycoprotein IIb/IIIa receptor inhibitor studied in primary PCI

trials, and a meta-analysis of trials demonstrated a reduction in short-and long-term

Dosing and contraindications for abciximab are described in Table 8-2. Glycopro-tein IIb/IIIa receptor inhibitors block the final common pathway of platelet aggregation; namely, cross-linking of platelets by fibrinogen bridges between the glycoprotein lla and Illa receptors on the platelet surface. Administration of a glycoprotein IIb/ IIIa receptor inhibitor increases the risk of bleeding, especially if it is given in the

setting of recent (less than 4 hours) administration of fibrinolytic therapy. It is important to note that failure to decrease the dose of eptifibatide and tirofiban in patients with renal dysfunction increases bleeding risk. Glycoprotein IIb/IIIa inhibitors are given in addition to ASA, clopidogrel and an anticoagulant, usually UFH or en-

oxaparin and not bivalirudin. An immune-mediated thrombocytopenia occurs in ap-

proximately 5% of patients receiving abciximab. Anticoagulants

UFH, administered as a continuous infusion, is a first-line anticoagulant for treatment of patients with STE ACS for patients undergoing PCI.2-4,19,29 In those patients, UFH is initiated in the emergency department and continued until the end of the PCI procedure. For patients undergoing reperfusion with fibrinolytics, newer guidelines have favored the use of enoxaparin.3,1 Anticoagulant therapy should be initiated in the emergency department and continued for at least 48 hours, and up to eight days when fibrinolytics are administered. UFH and enoxaparin dosing for STE ACS are described in Table 8-2. The dose of the UFH infusion is adjusted frequently to a target activated partial thromboplastin time (aPTT) (Table 8-2). When coadministered with a fibrinolytic, aPTTs above the target range are associated with an increased rate of bleeding, while aPTTs below the target range are associated with increased mortality

and reinfarction.

A meta-analysis of small randomized studies from the 1970s and 1980s suggests that UFH reduces mortality by approximately 17% compared to no anticoagulant therapy.9 In studies of patients receiving fibrinolytics, both fondaparinux and revi-parin have shown mortality reductions compared to placebo (no anticoagulant ther-

31 32

apy). ' Other beneficial effects of anticoagulation are prevention of cardioembol-ic stroke, as well as venous thromboembolism in MI patients. Besides bleeding, the most frequent adverse effect of UFH is an immune-mediated clotting disorder, heparin-induced thrombocytopenia, which occurs in up to 5% of patients treated with UFH. Heparin-induced thrombocytopenia is less common in patients receiving low-molecular weight heparins (LMWHs), such as enoxaparin or dalteparin.

Low-molecular-weight heparins have not been studied in the setting of primary

PCI. Low-molecular-weight heparins, like UFH, bind to antithrombin and inhibit both factor Xa and IIa. However, because their composition contains mostly short sacchar-

ide chain lengths, they preferentially inhibit factor Xa over factor IIa, which requires larger chain lengths for binding and inhibition. A large trial comparing enoxaparin administered for up to 8 days or until hospital discharge versus UFH administered for

48 hours in patients who received fibrinolytics found that enoxaparin reduced the rate of death or MI by 17% but also increased the risk of major bleeding (2.1% versus 33

1.4%). Fondaparinux, an indirect-acting specific inhibitor of factor Xa, has also been compared to UFH in conjunction with fibrinolytics in the setting of STE MI. The rate of death or MI was similar between fondaparinux (administered as a low-dose for 8 days) and UFH. There was no significant difference in bleeding rates between fondaparinux and UFH.34 Current guidelines by both the AHA/ACC and the American College of Chest Physicians (ACCP) recommend that patients undergoing reperfusion with fibrinolytics receive an anticoagulation treatment with enoxaparin for up to eight days, over a 48-hour regimen of UFH.3,19 Nonetheless, these organizations have provided conflicting recommendations regarding the use of fondaparinux in suchpa-tients, illustrating well the more modest results of this agent compared to UFH.3,1

Bivalirudin, an IV direct thrombin inhibitor, may also be a choice of an anticoagulant for patients undergoing primary PCI. Potential advantages of direct thrombin inhibitors over UFH are that they bind to and inhibit clot-bound thrombin in addition to circulating thrombin and have no significant binding to plasma proteins. Thereby, they have a more predictable anticoagulant response. In addition, because thrombin is a potent stimulus for platelet aggregation, direct thrombin inhibitors have antiplatelet as well as anticoagulant activity. Like lepirudin, bivalirudin exhibits bivalent binding to thrombin, that is, it binds to both the active site and exosite-1, while argatroban binds only to the active site. Unlike lepirudin, both argatroban and bivalirudin exhibit reversible binding to thrombin, whereas lepirudin binds irreversibly. After bivalirudin binds to thrombin, thrombin cleaves a bivalirudin Arg3-Pro4 bond, re-exposing the thrombin catalytic site. Thus, bivalirudin provides consistent anticoagulation when administered as an IV bolus and infusion, but its activity is short-lived when discontinued. These potential advantages suggest that bivalirudin may have similar or superior efficacy and fewer bleeding complications compared to traditional anticoagulants. Recently, the results of a clinical trial demonstrated lower mortality at 30 days (34% reduction) and 1 year (31% reduction), with a 40% reduction in bleeding and similar rates of reinfarction with bivalirudin (administered during primary PCI) compared to UFH plus a glycoprotein IIb/IIIa inhibitor (administered during and for 12-18 hours

following primary PCI). Nitrates

One SL NTG tablet should be administered every 5 minutes for up to three doses in order to relieve myocardial ischemia. If patients have been previously prescribed SL NTG and ischemic chest discomfort persists for more than 5 minutes after the first dose, the patient should be instructed to contact emergency medical services before self-administering subsequent doses in order to activate emergency care sooner. IV NTG should then be initiated in all patients with an ACS who have persistent ischemia, heart failure, or uncontrolled high BP, in the absence of contraindications.9 IV NTG should be continued for approximately 24 hours after ischemia is relieved (Table 8-2). Nitrates promote the release of nitric oxide from the endothelium, which results in venous and arterial vasodilation. Venodilation lowers preload and myocar-dial oxygen demand. Arterial vasodilation may lower BP, thus reducing myocardial oxygen demand. Arterial vasodilation also relieves coronary artery vasospasm, dilating coronary arteries to improve myocardial blood flow and oxygenation. Although used to treat ACS, nitrates have been suggested to play a limited role in the treatment of ACS patients, as two large, randomized clinical trials failed to show a mortality benefit for IV nitrate therapy followed by oral nitrate therapy in acute MI36,37 The most significant adverse effects of nitrates are tachycardia, flushing, headache, and hypotension. Nitrate administration is contraindicated in patients who have received oral phosphodiesterase 5 inhibitors, such as sildenafil and vardenafil, within the past 24 hours, and tadalafil within the past 48 hours.9

P-Blockers

A P-blocker should be administered early in the care of a patient with STE ACS and continued indefinitely. Early administration of a P-blocker to patients lacking a contraindication within the first 24 hours of hospital arrival as well as prescription at hospital discharge for patients with MI is a quality performance measure.14 In ACS, the benefit of P-blockers mainly results from the competitive blockade of Pi-adrenergic receptors located on the myocardium. ^-Blockade produces a reduction in heart rate (HR), myocardial contractility, and BP, decreasing myocardial oxygen demand. As a result of these effects, P-blockers reduce the risk for recurrent ischemia, infarct size and risk of reinfarction, and occurrence of ventricular arrhythmias in the hours and days following MI.38

Landmark clinical trials have established the role of early P-blocker therapy in reducing MI mortality, reinfarction, and arrhythmias. Most of these trials were performed in the 1970s and 1980s before routine use of early reperfusion therapy. 9,40 However, data regarding the acute benefit of P-blockers in MI in the reperfusion era is derived mainly from a recently reported large clinical trial, which suggests that there may be an early risk of cardiogenic shock when initiating IV P-blockers followed by oral P-blockers early in the course of STE MI, especially in patients presenting with pulmonary congestion.41 Therefore, a low-dose of an oral P-blocker should be initiated, followed by careful assessment for signs of hypotension and heart failure prior to any dose titration in patients with STE MI. IV P-blockers are reserved for patients presenting with HTN.

The most serious side effects of P-blocker administration early in ACS are hypotension, bradycardia, and heart block. While initial acute administration of P-blockers is not appropriate for patients who present with decompensated heart failure, initiation of P-blockers may be attempted before hospital discharge in the majority of patients following treatment of acute heart failure.

Calcium Channel Blockers

Calcium channel blockers in the setting of STE ACS are used for relief of ischemic symptoms in patients who have certain contraindications to P-blockers. Current data suggest little benefit on clinical outcomes beyond symptom relief for calcium channel

blockers in the setting of ACS. Therefore, calcium channel blockers should be avoided in the acute management of MI unless there is a clear symptomatic need or a contraindication to P-blockers. Agent selection is based on HR and left ventricular dysfunction (diltiazem and verapamil are contraindicated in patients with bradycardia, heart block, or systolic heart failure). Dosing and contraindications are described in Table 8-2.

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