~______._ .-..“_._l-__-.-_-_-- _~___-_-x____-_ ______._

Bscause thromhus flN3llihl is ala important source of

~li)~~id;ty during i~I~~i(~~l~lStV (3.1). t~~~~~~llb~)lyt~C tIlC~~p)r 1124 hccn Used in altempts to ikprovvc angioplasty outcome and

&crease complications. However, tllr~~~~~9[~ly~is could have il

IlCgiltiVC impact 1111 angioplasty 0utc0mc ali the rcSult of

promoting hcmorrhngc within the athcrosclcrotic plaque. Fur-

thermore. in some settings tl IllhOlytic ilgemS hVC btX1~ shown to hiWe a prothromhotic (5). This review discusses

the itvailitble data O~I thr{)~~~9~~lyt~c therapy HIS ~1 adjunct to

angioplasty.

There are inherent limitations in any review, the most

prominent of which is heterogeneity among the studies being

cvahmted. Thus, ditkrent thrombolytic agents were adminis-

tered in varying dosages and by vqing routes. Operational

definitions of angioplasty success and xutc occlusion may

differ from one investigation to the next. Some of the questions

addressed in this review were evaluated in randomized, con-

trolled trials, but many of these areas have been the subject of

only rc:rospectivc or uncontrolled studies. Thus, it is not

From the Cardiology Unit. M&i~i~l Center Hospital of Vermont. Univenily of Vcrmonl, Burlington. Vermont: and *Curdiovuscul;rr Division. Hu~pilid ofthc University of Pennsylvania. Philadelphia. Pcnnsylvaniu.

I&nuscript rcceivcd Augusl 31. 1993: rcvisud manuscript rcccivcd May 13.

1994. accepted June 3. 1994. Address for anwsnondence: Dr. Paul T. Vaitkus. Cardiology Unit.

I-McClure. Medical Center Hospital of Vermonl, The University of Vermont.

Burlington, Vermont 0.5401.

Q 1994 hy the Americ;m Collcgc of Cardiology

-~- “.. ^_ ” .-

pnSSil7lC I\) tlfiIW nmclusions 011 tlK rL_!lii(iVl’ men’it!3 08 tilt

drkre~lt t~lr~)~~~~lO~yt~c ajicnls or sfratcgics hccausc they lye

it ~CCU ~4uat~d in randomized. controlled trials. 111 an

attempt to synthesize the available data, we undcriook pooling

of puhlish~d studies where appropriate (6). Admittedly, pool-

ing may okurc important differences in trial design and

quality. klts~c~er. the results of the individtml studies arc

provided, znd the relevant clcmcnts of study design arc

highlighted t~ir~~ugl~{~Mt this review.

The rcportcd frcqucncy of acute occlusion complicating

~Ill~iO~~li~Sty hit!4 l2lllgCd fKNl1 7!,i, to I 1’; (7), with ;In incidence

of 4.4”i (3) and G-Y; (I) in llw I:lrgcst scriss lo date. ‘l‘hrcc

studies ll2W CO~llpillTd thC OUtclMll0 of ~lngiOpli~:;t~ ill il group

of ~atjcllts rccciving rou~inc administration of mxGasc lx-

fort or during elcctivc itingi@My with a control group not

receiving thromholytic agents hut undergoing treatment with

varying regimeas of antiplatelet agents and heparin (X-IO).

Two of rhcsc studies were randomized and prospective (KY),

and the third was ;I retrospective review (IO). Although all

three studies evaluated the impact of thromholysis in clectivc

angioplasty, two studies included patients with unstahlc angina

(IX% [ 101 and 20% [Xl of the total patient populatic~9). The

outcome in patients with unstable angma was no1 rcportcd

separately from the outcome in patients with stiII?Ic angina.

Figure I shows the odds ratios for angioplasty SUCCCSS id acute occlusion rates for the individual studier and the pooled

total (13). There was no significant ditfcrcnce Bbr as,gioplasty

success rates (odds ratio I XI, Wk confide~~ce imcrva~ [c’i]

0.85 to 2.17) or acute occlusion rates (odds ratio 0.X9, 05’G C’I

(I.47 to 1.60) in any of the illdiVidl.liil studicb or the ptj(jled

totals. There were 742 patients in tllu p~lcd analysis, will1 iIll

87.2~ success rate and a 5.9% acute ocrlnsilm rate in c~~tr~~i

patients. Therefore, this pooled analysis had ~1 XW ]w’cr 10

detect an improvomcnt in the angioplasty success rate to 93.6% (a 50% decrease in the ritk? of failure of a~~~~)pl~~sly)

and a 50% improvement in angioplasty complication rates (to

3.0%). To detect an improvement in the angioplasly success rate to 90.4% (a 25% decrease in angioplasty failure), the

anatysis would require a sample of 1,531 patients. To detect a 25% reduction in the complication rate, the sample size would

need to be 5,503. Table I lists the beta errors of the individual trials (assuming a desired alpha error of 0.05) to detect a 50%

improvement in angioplasty succe.ss and complication rates. The small size of the individual studies limits their ability to

detect a clinically important difference. Although the av;rilablc data do not S\JPPOZ F he hypothesis that routine thrombolytic therapy in electtve angiophrsty will result in ii 50% i~~~r~~v~~ ment in a@oplasty success and complications. a more modest

F&yre 1. Ampact of antcccdcnt tl~r~n~~~~ lytic thwpy on success rates (le complication rates (right) for elective an- giopktsty. Odds ratios and 95% confidence intcrwls for the individucrl studies and the p~olled results :lre shown.

eating a~~io~~asty are increased in the setting of unstable

angina.

The c@cacy of tbr~~~~b~~~~ti~ thera for acute myo~ardia~

infarction has been firmly established, but a similar benefit in

unstable angina cannot be automaiieally assumed. The com-

position of coronary thrombi in unstable angina and myocar-

dial infarction may differ substantially (16). Studies examining the use of thro~,lbolytic therapy in patients with unstable

angina have failed to es,tablisb a clinical benefit for tbrombol-

ysis (17-26). Whether thrombolytic therapy in this setting can improve the outcome cd angioplasty has been the subject of

numerous investigations.

~n~iQ~~~~~~c appearance. Table 2 summarizes the studies

that kave evaluated the impact of thrombolysis on the angio-

graphic appearance of coronary lesions in patients with unsta-

ble angina (18.19,22,23,~!7-33). Most of these studici analyzed angiograms before and after a course of thrombolytic therapy

and measured the change in coronary stenosis severity. Uni-

formly, the stenosis severity showed a trend toward lessening,

although this reached statistical s~g~~~ca~~e in only four stud-

ies (l&19,23,28). Furthermore, when control patients treated with heparin and aspirin were evaluated, as was done in the

majority of studies, stenosis severity in the control group

lessened to a similar degree as that in the thrombolysis group

(23.27,29,32,33), with one notable exception (1X). However, most of these studies were fairly small and had limited power to detect a significant difference.

Four studies (17.21,29,32) have evaluated the frequency of intracoronary thrombus identified on angiography in patients with unstable angina after treatment with thrombolytic rher- apy. These studies did not obtain baseline angiograms before treatment was initiated. The rate of intracoronary thrumbi in patients receiving thrombolysis (21 of 78 [27%]) was -50% that in control patients (37 of 74 [50%]), suggesting that thrombolysis effected clot dissolution.

Ten studies (20,27-20,34-40) with baseline angitsgraphy before the initiaiion of therapy have examined the fate of intracoronary thrombi. Three of these studies (27,29,35) pro- vided a control group with intracoronary thrombus who did not receive thrombolytic therapy but received antithrombotic ther- apy for 24 to 48 h. Bf 139 patients with intracoronary thrombus who received thrombolytic therapy, reduction or resolution of the thrombus was evident in 113 (81%) compared with 44 (80%) of 55 control patients. In the only randomized, con- trolled, prospective trial (27), the frequency of clot reduction did not differ, but the degree of thrombus dissolution was greater in patients receiving thrombolysis. There was a notable variability in the response to thrombolytic therapy in individual patients (27) in that some patients demonstrated improvc- ment, whereas in others the severity of stenosis increased (27), including progression to complete occlusion (l&28-30). In several of the studies, follow-up angiography assessing the changes in intracoronary thrombus was delayed from 18 to 72 h (27,28,36). This is an important confounding variable because extended antithrombotic therapy with aspirin and heparin has been shown to be associated with improvement or resolution of intracoronary thrombus (40). Several studies using immediate angiographic follow-up reported angiographic improvement in 45 (73%) of 62 thrombi, suggesting that the changes in the

angiographic appearance of thrombus may be, in part. attrib- uted to the thrombotytic therapy (.&34-M).

Nine studies (18,19,27,29,33-36) have reported the out- cume cf thrombolytic therapy in patients with unstable angina and total occlusion of the culprit coronary artery. Of 69 patients studied, thrombolysis achieved patency in 39 (57%). Of 27 control patients treated with aspirin and heparin, patency was established in 4 (15%). Data on the outcome of angioplasty in this patient subgroup are limited to a report (36) of two patients who underwent succrssful angioplasty after receiving thrombolylic agents.

Thus, the overall frequency of clot dissolu?ion appears

similar in patients receiving thrombolysis and those wceiving

24 to 48 h of hcparin and aspirin. Thrombolysis appears to permit these changes to occur sooner and, in some cases, to a greater degree than antithrombotic therapy.

Aslgioplasty outcome. Whether the modest angiographic improvement with thrombolysis in patients with unstable an- gina translates into improved angioplasty results has been addressed in six studies (29,37,42-45) (Fig. 2). One study (37) demonstrated a significant improvement in angioplastj success rates, whereas another demonstrated a lower rate of angio- plasty success with antecedent thrombolysis (45). The pooled result did not reveal an improvement in angioplasty success rates with thrombolysis (odds ratio 1.18,95% CI 0.54 to 2.57). The largest study to date (45) reported a significant increase in

abrupt closure rates among patients treated with urokinax. The trend for a detrimental effect did not reach signilicawes: 111 the pouled analysis (odds ratio 1.40, 95% CI 0.79 to 2.47).

The published data on the impact of thrombolysis on aqiopl:lsty success in unstable angina includes 204 patients with an 85.8% angioplasty success rate in the control group. This pooled analysis is underpowered. To achieve 80% cer- tainty of detecting an improvement in the angioplasty SUCCCSS

rate to 92.9% (a 50% reduction in angioplasty failure) or

VAITKUS AND LASKEY ADJUNCI‘IVE THROMUOLYSIS IN ANOIOPLASI’Y

Unstable Angina success tes

unstable Angina

K &&

2.49 Ambu!x (TAVSA) 1

X$4% (a 25% reduction in illlgiOplil!Q failurr) would rcquirc

ZW and 1,363 patients, rcspcctivcly. The beta errors of the

individual trials iWC summarbcd in Table 1. The published data on abrupt closure complicating angio-

plasty include 3% patients. The abrupt closure rate among

control patients was 8.2%: among patients trcntcd with throm- bolytics it was 9.4%. To detect a 2SCi or SQ% &Oti~SC in t

ilbrllpt closure rilk would require 2.W and ShO 9Wticn

respectively. The Thromholysis in Myoc*irdial Ischcmia (T9M9)-~~ trial

(46). which randomized 902 patients with ~t~~tahlu it@I;l. bund no impact of untcccdent thrombolysis on il~~~il~~hls~y success and complication rates. 1 Iowcvcr. ;1 dcriailcd tcport of ~ll~g9t~~l~~s~y outcome in this trial has not yet been ptll~l~she~9. Also, the Thrombolysis and Angioplasty in lJnstt\blc Angina

(TAUSA) trial (4s) investigak~rs have reported ~rclim9~~1~ data on abrupt closure during angioplasty. but information concxAng angioplnsty success rates has not ycr been puh- lishcd.

tients with unstably angina an id icnts with unstable angina and ~n~~~~raphicilll~ demonstrable intncoronary thrombus are at parkularly increased risk of complications during angioplasty (3,4&U). FOUP retrospective studies (35,3X,30,42) have exam- in~d the i~~p.~t of thrombolytic therapy on ~~ngiopt~~s[y out- come in these patients. Overall angiopli~sty succc~s was achieved in 20 (cI: 3) of 22 patients with intracoronq throm-

bus who re:LP‘iv~~d thromholytic agents. ,~ngiopl~~s~y success rates for control patients receiving aspirin and heparin hut not thrombolytic therapy were not reported in any of these trials. However. complications of angioplasry occurred in 3 (6%) of 52 treated patients and 5 (19%) of .?7 control patients. The

strategy of de9ay9ng angiopiasty for several days of aspirin and intravenous heparin therapy has been shown to reduce com- plication rates and increase angioplasty success rates (41). No

direct comparison of thrombolytic therapy before angiop9asty

this group of patients is not y& avaiiablc.

role

The outcome of angioplnsly is associated with diminished

success rates in chronically occluded vessels compared with

patent vessels. The possibility that thrombus formation con- tributes to the dcvclopment of chronic total occlusions has prompted some investigators to attempt prolonged intracoro- naq urokinasc infusions to achieve vessel patency and pro-

mote il~@phSty Success. Seven studies (49-S) hilVC cxam-

incd the utility of prolonged urokitlase infusion in rec~~~~9izing

chronically occluded saphenous vein grafts. Urokinase dosage ranged from 36.W to 31H),o(M) U/h. Patency was achieved in

74% of cases. Although the specific definitions for recanaliza-

tie!: were not specified in the majority of the reports, it is dear

that in many cases the degree of flow that was established by

thrombolysis alone was insufficient to adequately alleviate

ischemia. Subsequent angioplasty was performed in 43 patients

and was successful in all. In three studies (56-58) of prolonged

cardial i~~farctii~U has been reported (49-5 P .54,(96) as a

WI ation of Q~olo~l~ed thrombolytic infusions in c tally occluded sapbenous vein grafts. Furthermore, the nalizition of Chronically Occluded Bypass Gr

longod Urokinasc Infusion Site Trial (R

investigators have reported a greater incidence of infarction. ventricular arrhythmias, stroke, hemorrhage and death in patients who had successful recanalization than in patients whose grafts remained occluded. In some Casey. myocardial

infarction is pain&i, sugcsting Illilt this mily bc m0rC CWlb

man Ihan previously suspcctcd (SO). Tbc mechanism of some

of these complications has not been de Iled, but they IlMy

result from distal embolization of a partially Iysed lbrombus

compromising the collateral blood supply. Finally, the long-term patency of these recanalized vein

grafts is limited. In the ROBUST study (XT), 50% of grafts had

reoccluded within h months despite therapy with aspirin and

warfarin. Only a prospective, randomized trial can answer whether a

prolonged urokinasc infusion in this setting improves angio-

plasty outcome. However, in view of the reported complica-

tions of this modality and the limited long-term patency rates, prolonged infusion should not presently be adopted as a

routine method for rccanalizing chronic total occlusions.

Acute vessel occlusion, the most common serious compli-

cation of angioplasty, has been reported to occur in 2% to 11% of angioplasties (1,2,4,7). Thrombolysis as a rescue strategy for

angioplasty complicated by acute vessel occlusion or thrombus

formation h KWW bCC~ compared in clinical trials with oihCr

I’C’SCUC Str~tcgies. SUCI? ;IS prolonged bijllO6,n infjations wit,11

perfusion catbctcrs. Seven studies (7.37...!l.h7-70) enrolling

I-i5 patWIts have examined the sole of IhY)rnhl9l,Si!, in rc-

csaahkhing Qatellcy e9f an acutely c9ccluded vcsseli. Thrombol-

ysi~ ws most often administrred in conjunction wirb or immediately after repeated balloon inflations and rarely as the sole therapy. Successful angioplasty was subsequently achieved in ‘50~6 of CZXS. Complications (myocardial infarction, emer- gcncv bypass surgery, deat

r$Kree groups of investi occurred in 51% of cases,

ors (37.71.72) administered intra- coronary urokinase for intracoronary thr:9mbus L9rmation dur-

ing angioplasty before progression to complete occlusion. Illowcvcr. most of the tbrombi that were so trcnted cxbibitcd

occlusive h&ilViOr and wcrc rncroaclIi?lg on the coronary

lumCn bcforc urokinasc ;Idministlation. Such a strategy Was

~lsSl9ciillcd with ;I SlKcCSSfUl angioplasty ~91~tc0mc in 30 (74% ) trl’ 01 (m6ic.m. \h,*rcYrs 2.4 (Z-i!‘; ) 01’ %t plkclP3 sustained

serious ccamplicasions.

iI SUCCChSfUl OUlCOmc Of thrOmh9lylic Ihcrilpy i~dmilliStcrCd

for ilCUlC vcsssl occlusion 01’ intracoranary tlirombus form;!tion is less likely to bc achieved in the presence of concomitant intimal dissection (37,h7,72). This may b due to intraplaque

hemorrhage promoted by tbrombolysis. owcvcr, it is often not possible to precisely dclinc lbc ctiolog,y. rhat is, ahrombus versus dissection. in many GISCS of threatened vessel occlusion

during anpioplasty. Fiflidly. preliminary investigations (73-75) of prolonged

intracoronary urokinase infusions in patients whose angioplas- tics are complicated by thrombus k9rmation have reported conflicting results on the benefits and Cl9mQ~iCiltil9llS Of this

strategy. Additiclnal ev;lIuation of this thcrapcutic i\Itcrnittive is

IlCCdCJ.

Most research on the topic of thrombolysis and angioplasty for acute myocardial infarction has focused on defining the

role of ungioplasly after successful thrombolytic therapy. Re- cently, several trials (X,77) have compared direct, primary angioplasty with thrombolytic therapy for the trcatmcnt of

acute myocardial infarction and have demonstrated that an- gioplasty has a high success rilte and prevents recurrent

ischcmia more effectively than thrombolytic tl

cnt thrombolytic therapy could conceivably i

come of angioplast acute myocardial infarction by reduc-

ing clot burden. ever, palbologic CXa~llillilli~9llS haVc

revtxhd intramural hemorh~gc: at the angioplasty dilation site in smw p;dC~~ts wit11 ;I myocardial infarction who rcccivcd

antecedent thrombolysis (7X-W)). Occasionally. this hcmor-

rhage has been associated with cncroachmcnt (91t the vcsscl

lumen (78). Three studies (81-83) have addressed the qucslion of the

1420 VAIIXUS AND LASKEY ADJUNCl’IVE THRC9MBOLYSIS IN ANCIOPLASTY

impact of i~9~~~~~~~~9~ ~~~~9~~~~91~~~~ lit9 angi~~~~s~ outcome

and mortality in patients underg~~~?~ direct angiop~~sty for

acute myoCardial infarction (Fig. 3). Only one of the three studies was a randamized, prospective cliniczf trial (81). In or16

study, strcptokinase was used (131); in another, either strep tokinase or tissue-type plasminogen activator (t-PA) was ad-

ministered (83); and in the third, details of thrombolysis were not specified (82). In the pooled analysis, neither the angio-

plasty sutzzess rate (odds ratio 2.05,95% CT 0.83 to 5.07) nor the mortality rate (odds ratio 1.34, 95% CI 0.M to 2.73) was improved by antecedent thrombolysis. The analysis of angio-

plasty success rates included 39‘7 patients with a 94.7% angio- plasty success rate in the control group. To detect a 50% or

2S% improvement in angioplasty success rates, there would

have to be Xl8 and 4,141 patients, respectively, in the analysis.

Furthermore, several recent trials of primary angioplasty (without thrombolysis) for acute myacardial ~nf~rcti~R

plasty success rates of ~.~~~~ (~~~~4,$5)” a Id be difficult to improve in any eirCumstance.

efore, it is unlikely that thrombolytic therapy will be

demonstrated to improve angioplasty outcome in this setting. In the mortality rate analysis, there were 659 patients with a

6.4% death rate in the control group. To achieve an 80% chance of detecting a 50% reduction or a 25% reduction in

mortality, there would need to be 706 and 3,279 patients,

res~Ctively. The beta erron of the individual trials are sum-

marized in Table 1. Thus, we conclude that antecedent throm- bolysis is not likely to improve angioplasty success rates in the

setting of acute myocardial infarction, whereas insufficient data are ~~~~il~~lc to assess the impact on mortality rates.

sis With the recognition of the role of activated platelets and

platelet-derived growth factor in the pathogenesis of restenosis

after angioplasty, there has been considerable interest in examining whether antithrombotic therapy can prevent resten-

ra~hy. Alth~~u~~ there was no di~e~en~e in the

rcstenusis, th:re WBS a tr~~ld for ~r~)ki~as treated patients lo

have restenosis lesions of lesser severity. ecause the criteria

for ~~orrni~~ follo~~~~ a~~~i~~grapbi~ e~~l~~t~~~ were not

that incomplete ar :xaphic ‘t;lllow-up

ant selection bias. Gishita et al. (89) retrospectively au~~~y2ed their results; in patients M~d~~goi~g

primary a~gio~~as~ for acute myocardial infarction. 0f 70

patients who bad angiogra~b~~ evidence of thrombrrs after

essful angioplasty, 27 received iotr~~corona~ ~rokin~~se.

l-month restenosis rate was 4% in the urokinase-treated

in the patients not receiving urokinase (p <

rishita et al. (89) to Conclude that thrombol-

nosis. Because the study was retrospective,

treatment assignment was not randomized, and angiographic

follow-up was incomplete and was Mndertaken very early after

angioplasty, this study cannot conclusively establish whether

thrombolytic therapy reduces restenosis.

The currently available data have not yet established a

benefit of adjunctive thrombolysis in improving ang~o~~as~

success rates or decreasing angioplasty complication rates in

routine, elective angioplasty or in acute myocardial infarction. In unstable angina, the data suggest that antecedent thrombol- ysis may be detrimental.

The outcome of prolonged administration of thrombolytics for chronic total occlusions may not be superior to conven- tional angioplasty, and this procedure has been associated with

complications and limited long-term patency rates. Random-

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