Thrombolysis: The need for a critical review

EDITORIAL

REVIEWS

Thrombolysis: ERNEST

The Need for a Critical

SCOTT MONRAD.

MD

Bronr. New Y”,l

~oumal

The recently published lead amcle (11 I” d prommcnt repated

the results of a study on the comparative

two alternative adjunctive

lhempie$ Wwcnout

rdicacy of hepann and

low dose aspirin1 to thmmbolyuc therapy for .ICUIC’myocardi.d infarction. As the benefits of concomndn, rhcnpy m patienn with infarction are not well defmcd and the two drugs are commonly used. it wa, an amcle virh potrnnal rr~desprc.~d interest ,ha, merited publicatton m a prommrnr forum. However. the Heparin-Aspirin RepctiuGon ‘Tnal IH:\RTl (1) c: tied

far greater sign&mu

hecaue

oi ill

kcyuone

caliy the validity of the Gruppo I,akano per lo adio dell;! sopmvviveoze nell‘lnfano Miccardico IGISSI-1) wdy (?.I1 Befom wblicadon, acmss-lhe-counlrv use of the data from the HART kill

has been used to refule tie finding> ofGISSI-?

Therefore,

rhould be no IL\, rigorour dun thw of audiion. The .\uditing Standards Board 16) of the American Institute of Certified Public Accountants has defined thic rfandard 35 folloss: ” the audaor Imwrl be mdependea: hc must hc anhout

bias wth

rcs11ccI to Ihe client since other-

141.

it would have been preferable that the cditoridl pr&ciencv profewon

article.

mtgh! ulw be impaired by the exislence of CKCU~~~mces which rsa\onable people might believe likely ,o mRuence indspendsrce. Independem audltors should nor only bc mdrpendent m Lc,: they should avoid biluaom

would

accompanying

Ihe. art~clr

have been a r&w

by d hcmiwl~gw

In-

s&ad. a highly respected inverlwor. but one uilh rl bnpstanding research relation IO the parne~ involved. wrolc the edilorial

IS). Although

the edito-ial

wa

II uell-wrmcn

ic-

may be.

it is of ulmo~t imporlancc

151 had been ;m

independest, bdanced (even countervailmg) review of the subject. Parlicularly appropriate. gwcn Ihe focu\ of the

commentary

to the

,h,u the general public maintam confidence m the

indeprndencu

of mdependen,

auditora.

Pubhc confidence

,h.il may lead o&den lo doubt lhctr indrpendence.” A\ powrnmen, financial support for research has been reduced. lhc medical and nonmedical aisdemlc uorld ha\ forged EIUW Ibnks IO the business world. Becaurc a grotwmp yrrono11m” of c”rren, rexarch c,Ton I\ bem~ funded bv

Fur the pa\, 5 yew!, many *tudm have been performed lo try to confirm the hyputhesi\ Ihat recombinant liwe plasminopen activator(rl-PA1 i\thethrombolylic agentofchoice for ;in ewlving aate myocmdial infarclion (81. that is. to e\\e\\ whether >t cun reduce the morbiduy and morlalily ;woci;aed wih acute myocurdud infarction better than other uruilable diags A criucallg dwmced und mdcpcndcm cvabmtion m this field ha> been lacking in this country smcc Ihe results of the TIMI- lrial 19). This lack, and the rubaequent seleclion of n-PA a\ the 501~ study drug by Ihe TIM1 mve,t~&wxs ne)rl TIMI Irk&. conslituted a de facto endorsement by the Nalional Heart. Luns. and Blood Institute of rl-PA as the thrombolytic drug of choice. This development has been followed by a reversal of Ihe traditional scientific method. When mvesti&onal i&l) Liled lo confirm the hypolhesir lhat rl-PA is the agent ofchoice for infxtion, the biz!s rdther than the hypothesis underwenl reexamination. Trials cmxonilnr wth tha5 view have been widely promoled. while lnal$ cont:adicior:, In Lhis have heen discounted, some even before completion Iwitness the ISIS-3 triall. Yet. there is a significant. decade-long. literature !o merit B reconsideration of this.

forthe

Principles There are currently three approved activators ,I pl .a,nogen (“thrombolytw” drugs) for Ihe intravenous ,&e:dpy of acute myocardml infawion: streplokinase. aheplase Irecombinant tissue-tvpe plasminopen act~vafor In-PA11 and anisoylated plasminogen-clreptokinase activafor complex \APSAC). All three have undergone exlensive investiaatian for their efficacy in acute my&dial mfarclion, and ali have bea shown 10 effect coronary palency. prescrvc myocardium and reduce r.lortulity m the wake of acute myocar.iial infarction. These have become the standard end poinlb for assessing the efficacy of lhesc agenls. clearly in increasing order of imponance. Mortality must remain the overriding crilerion. not just because of its uniformity of measurement and clear primacy LO the patient being treated, but because il conslitutes a summation of the effects of immediate and sustamed cownary p~encv. of oreservation of venlricular function and of the-side e&s &cisted with the use of all these drugs. Simply. it alone i\ Ihe “hrrt predi-t-v” -(tonality! Parenthetically. in this review will refer only 10 survival data from stud!es with adequate randomized control arms. Reference to observed mortalily from single-arm studies (with respect Lo lhrombolylic therapy) as a reflection of thrombolytic efficacy wilhoul consideration of the baseline condition of Ihe study group has no scientific validity. Such morlalify dala reflect mulliple factors. including regional pauent characteristics. enrollmenl criteria and their application. physician approaches, concomitant drug and other Ihcrapies. and 1t.e specific effect of the pharmaceutical apnf in question; thus. they should no more be argued (or

I

accepted) as evidence of drug effect than would a study reporting pulmonary capillary wedge pressure only during drug treatment (without baseline or randomized control data) as evidence of. for example. the efficacy of a vasodilater in congeslive heart failure.

Clinical Studies S(reptokinase. Streplokinaae was the first of Ihe available agents approved for intravenous administration for the treatment of acule myocardial infarction. Angiogmphically demonstrated reperfusion or patency rates have typically been approximately 50% 10 60%. ranging from the low of 31% found in the TIMI-I trial (9110 81% in Ihe study by Karen et al. (101. In Ihe Intravenou; Strep!okinase in Acute Myocardial Infarction (ISAM) study (I I), left ventricular systolic function (ejeclion fraclion) was significantly better in patients treated with streptokinaae than m comrol patients 156.8% + 0.7 vs. 53.9% ? 0.7. p < OXIS). This difference was also seen in the study by While et al. 12) (59 ? IO.5 vs. 53 + 13.5. p < 0.005). In this Ialter study monalily (30 day) wus also significantly reduced (2.5% vs. 12.9%, p < 0.02). In the first GISSI (Cruppo It&no pa lo Studio della Strcptochinasi nell’ lniano Miocardico) sludy, intravenous streotokinase led to sifinificant reductions in mortalitv comparid to control early (21 days. 20% for those t&ted in <6 bl (13) and. imporlantly. lale (I year. 13% for those trea!ed in ~6 h) (141. In ISIS-2 IInternational Study of Infarct Survival) (IS), strepmkinase therapy within 6 h of pain onset led to a 21% reduction in mortality at 35 days. Recombinant tissue-type plasminogen BE(Iva1or. Recanbinant tissue-type plasminogen activator @t-PA) is an endogenous activator of plasminogen produced normally by endothelial cells. Enrymatically active single-chain (alteplase) and double-chain (duteplase) forms exist (16). the latter produced by cleavage of fhe former into a light and a heavy chain linked by B disulfide bond. Reported reperfusion and patency rates of 61% 10 8% (17) have been higher lhan those reponed for streptokinase. Preservation of ventricular function was demonstrated by O’Rmuke et a:. (18) and others. The ASSET trial (Anglo-Scandinavian Study of Early Thrombolysisl 119) is the major survival trial for R-PA: intravenous heprrin was used as adjunclive Iherapy. a 5.000 U bolus injection followed by infusion of I$00 U!h after compledon of Ihe 3-h r&PA infusion. Monality at I month in the &PA group was 26% below that for the conwol group and 13% below that of the control group at I year (201. This led Ihe investigators (19) to observe lhat I’. the superiorily of rl-PA over strepmkinase reported in coronary angiographic studier does not seem to be reflected in striking differences in latality rates” given the comparability of Ihe results 10 those seen with Ihe previously cited safety and survival Vials of inlravenous streptokinase. Anistreplae. Anistreplase IAPSAC) WBI bioengineered by the in vitro binding of weptokinase 10 plasminogen. and

C

the complex was then anisoylated to retard IIF enr~mauc degradation. restthing in the iongerl half-IiR of a\miable agems. Bonnier et al. 121) demonstrated a coronary parcncy rate similar to that achicvcd with intracoronery ?treptokinase (64% vs. 68%. p = NS). a short time (45 mitt) to patency. with only a 5% reocclusion rate. E&sand et al. 112). in addition

to ti 77% patency

raw,

found

a 31% reduction

in

myocsrdial infarct siLe Iby single-phaion emwon computed tomography ISPECT]l with salvage of left ventricular sy’itatic function (ejection fraction S3F vs. 47%. In the German multicenter rrial 123,. there was a 565 reduction in mortality (5.6% vs. I?.h%, P < O.O~i after admmistration of anistreplase. Similar findings cilane from the AIMS (APSAC Intervention Mortality Sudr, trial (241. which demonstrated a 47% reduction m 3lLday mortality (6.4% vs. 12.270, p < 0.002). Reduction in mortality at I year was 39% (25).

p< 0.003.

Charhonnier et al. 1331 reported higher patency mtec at ‘10 min \blth amurcplare than atth rtreptokinase. Not unlike the rcuIt\ of me P\IMS trial. late patency was slrnllx for ~t~cptnk~nax and amstreplase. The Thrombolytic Tnal of Eminazc in acute 4lyQcardial infarction (TEAM-21 lnal(14I reported bu,ui.~, late=, ofl-h vec~ei patency ITIM Erddc ? to ; flow) uith an~\trcplnsc and slreptokinase but si+ficantlv hlaher MWA ulTlWl grade 3 flow wilh anis;replasc. ii;r5r;slinc more complete rhromholysis. Baraasd et al (351 compared rt-PA and anistreplasc in a double-blind tr~tl and found equal effects on pwnc), wntricular function and bleedine lderoite wnificantlv diflerent re~lldnlfibrinogsn levels). An’~inn et al. 13s: alsofound \Imilar 24-h Qiltencv mtes r+ith rt-PA and anistreolase

.._.

Comparative Studies Several studies have directly compared the relAve et% cacies OF the available thrombolytic drugs. The TIMItual (9) probably ittflutccd care in the United Stzates mwc than any ether single study. In this study, iniravenoo~ rt-P.4 t90V duteplase 1261) and intravenous streptokinax wre compared in a randomized double-bhnd study. The relativr fibrin selectivity of &PA. despite significantly htgher fibrinogen levels, and the shorter half-lift of rt-PA afforded no advantage in bleeding complications (27). which were equal in each group. The rcpxfusion rate al ‘90 min ws significantly higher in the group treated with rt-PA than in the group treated with slreorokinase (62% vs. 31%. D < 0.0011. Ho\
late

GISSI-2. The molt controversml comparative wdy ha\ been the GISSI-~:lnterndtiunaI Suldy Group study 12.3;. :&+,~aiilcomparingII-PA and srreptokinase. This two-tiered Ttudy I”2 x 2 Guorlal deslgn”i. performed in the aspirin ela that followd ths Impressiwz rewtts of ISIS-2. invsstisatrd tuo queuion? the relative eficacg of the !wQ thrombolyhc apeor\ m reducing mortality. and Z) the possible incrsmenui conrrlbulion of heparin (above rhat achievable with Ihe umformly administered cotherapy. aspuml. The hcparin re~m~en. 12.SlO IJ subcutaneously every I2 h star!me I! h after imtiation of thrombolvtic therwv has been the hiusof the controversy. In rhl, $tudy no rignificant di@zncc was found between rl-PA nod btreptokmase in morlalitv (8.9% vs. 8.3~). and mortality w, eecn numerically lower in rhe weptokinase group. Thu\. ihi\ study confirmed the simrlar rcdirciions in aorta@ xen in the GISSI-I. ISIS-? and ASSET triolc. Howewr. there rwre rienilicant differences in comorbidnv. Ovcrsli. mcks &red more commonly in patie& trcn:cd wth rt-PA I I.370 VS. 0.955, p = 0.05). principally m those patient> \\hQse condition wab calegorized as hemorrhap~ or undcfmcd (“whemic” strokes occurred equally in the iuo groupsl. This difference was comparable to Ihe tre:wored difference m suruval. Overail. ail other bleeding. both “major” and “minor.” occurred more commonly in patients rreated with n-PA than in those receiwng slreptokinasc. whereas ‘?IujQr” blcedtng trcquiring more than a 2 U trannlusionl WBF more cQtttmQn IQ the aircpiokmase emup. All&c reactions were slatirlic:allY more common in the streptukinase group 10.2% vs. 1.7%). High dose subcurancoun heparin was found to effect no advanlage in either the rt-PA or the streptokinase arms but wa\ as
I)

trial (I ). as dkcussed. has been the central study lo supporl this. Its finding of significantly different patency rbies between the heparin and low dose aspirin groups has been intcrprcrcd 10 show that r&PA efficacy is depcndenr on concurrent intravenous hcpsrin administration and that the GISSI-2 study is thus fatally Rawcd and should be cilher dircardcd or repcared. Howcvcr. the use’ of low dose aspirin 180 mgl limils the comparahllity of the trial to the GISSI-2 study. in which fult dose aspirin (303 to 325 mg) was used in YW of patients. There have been no major clinical end point trials of the efficacy of this low dose regimen 137); the lowest dose of aspirin proved clinically etlicaciou$ was the 160 mg dose used in ISIS.?. Although one group (38) studying normal volunlerrs with IO0 mg aspirin found near complete platelet thrombuxane Bz synthesis inhibition at 24 h after dosing. another (393 found that high degree inhibition required cumulative daring for several days. How these findings would apply to mfarct size and mortality reduction in palients with unstable coronary disease and the hemodynamic and circulatory derangements associated with acute myocardial infarction can only be hypothesized. In unstable angina. where the unstable coronary plaque typically also has associated intracoronary thrombus (40). no statistical difference was found between full dose aspirin and heparin (411. By contrast. it would appear fojrn the HART that the 8U mg dose is relatively clinically inefficacious. European Cooperalive Study Croup 6 Irial. The editorial (5) accompanying the study of I-Isis et al. (I) observed that snnilar results had been found in the European Cooperative Study Group 6 vial with a higher dose of aspirin. But this was a comparison of full dose loading aspirin followed again by low dose (on alternalc days only) aspirin and randomization between intravenous heparin and no heparin. The incremental patency etfect of intravenous heparin with this WPS less impreswe (83% vs. 75% p < 0.01). and no data are prvvided fur ultimate effects on survival. the end point of GISSl-2. Neither of these trials used asairin doses equivalent to those in GISSI-2, which have been proved clinically &acious in multiple prior studies (371: none address ultimate effects of this therapy leg.. survival), and, most importantly. none provide any weptokinase arm that the obwved benefits are unique to n-PA.

trlai

tosuggest

Cotnments Role of adjurclive therapy with baparin. The rcstilts of the HART and European Cooperative Study Group 6 trials would be cautionary to GISSl-2 only if one treatment arm (i.e., rt-PA) was uniqsdy disadvantaged compared with the other, and there is no study offering evidence to this effect. Several studies (31.32) have shown comparable late patency of rt-PA and streptokinase despite the early advan:age demonstmied with n-PA in TIM&l. This result would nuggest that sireptokinasc may be equally dependent (and

possibly more soi on anticoagulant coverage with hepatin for this “catch-up” in observed patency. ln fact. Mahan et al. (42) have demonstrated that vessel patency with streptokinare iq dependent on concomitant heparin therapy. both for maintaining initial patency and for late developing patency (i.e.. catch-up patency). Polentially improved vcwzl patency with adjunctivc heparin therapy is not unique to rt-PA. The measured mortality in GISSI-2 in the patients treated with rt.PA and heparin was higher than for those treated with n-PA without heparin. This observation is opposite to that for the rtreptokinase-treated group. and contradicts the hypothesis of a unique dependence of n-PA on hepsrin for efficacy. Although this difference of effect might be secondary to artifacts in randomization. one would have anticipated a trend to benefit. Furthermore. reinfarctian (a postulated clinically resulting sequela of “inadequate” heparimzation) occurred numerically more commonly 12.6% VS. 3.0%, p = NSl in the rtreptokinasc-treated group, a finding also artwing against a unique dependence of n-PA on concomitant hep arin administration. While none of these achieved sralistical sigmficance. none were directionally consonant (i.e.. a “trend”) with the hypothe$i$ that the hepdrin regimen employed was uniquely prejudicial against rt-PA. Indeed. as observed earlier. the results of the GISSI-2 trial were consistent with the body of existenl data (: ‘.+ the preceding safety and efficacy rurvival rrials). Aspirin versus heparin; ISIS-3. Finally, while only preliminarily presented at the recent American College of Cardiology scientific sessions, the WS-3 trial further confirms the preceding studies. A direct, randomized comparison of streptokinase. recombinant tissue plasminqen activator fduteplascl, and anistreplare. this lrial found no significant difference among these agents in mortality after their use for acute myocardial infarction (10.5%. 10.3% and 10.4%. respectively). Administering the subcutaneous heparin at completion of the r&PA infusion in ISIS-3 did not lead to different results from those of the delayed regimen of GISSI-I. The addition of heparin to “thrombolysis plus aspirin” (the standard of care since ISIS-2) reduced absolute mortality by 0.5% (7% ~5. 7.5% p = 0.03 at 7 days; 10% vs. IDS%, p = NS at 35 daysl. But major (transfusion-requiring) bleeding increased by 0.3% with the addition of heparin. and intmcerebral hemorrhage by 0.2% (0.1% increase in total strokes). In contrast, in ISiS- aspirin improved thrombolysis-reduced mortality by almost five times the improvement achieved in ISIS.3 with heparin (2.4% 19.4% vs. I with no increase in major bleeding and a 0.4% reduction in strokes. Clearly, the benefit/risk ratio of adding heparin to thrombolysis plus aspirin is far lower than that of adding aspirin to thrombolysis. and far more complex than vessel patency indexes alone would reflect. ISIS-3 directly compares the three approved drugs for intravenously administered thrombolysis and provides further informalion as to their relative efficacy. Rather than

I.8%])

being preemptively discounitd to rupport esrabli\hcd convictions. its findings should be approached Gth er.ormoui interest. Although smal!~ trials may illustrate the pharmacologic actions of various drugs, appropnately rized survival trials will always be required to assess the ultunnte elects. as survival more completely retlcc~s the to~dl actmn (prow mal and distant therapeutic effects versus vde effectQ of the treatment.

Summary Thepast decade has seen an unprecedented investigational aTort to understand and apply a revolutvxxy new approach to the treatment of the leading cause of death. Thig effort has required approaches.

a reevaluation

However.

of traditional

concepts

and

it would he unreasonable to expect

that canelusions from the 1st 5 yexs of such study wwid remain unshaken by the inevitably more focused studier that have and will follow. As new agems (scu-PA. for enamplel and new concomitant therapies such as hirudin are developed it can only be anticipated that the approach to the patient with acute myocardinl infarction *ill change. Currently :hree available thrombolytic activators are approved for the therapy ofacute myocardial Infarction. Each of these has been shown IO reduce significantly the monality associated with acute myocardial infarction. After the TIM14 trial. it was hywthesized that the early patency advantage of fl-PA over streptokinase would he a consistent finding (over streptokinase and over other drugs). and tdat it would translate equally into advantages in survival. Despite multiple trials evaluating this issue. both those comparing drug against placebo and one drug against an. other. the striking superiority of rt-PA in patency demonstrated in TIM14 has not been conf~nmed. and has not resulted in a mtasur-able advantage in wrwval outcome. However. in a reversal of traditional scientific meihod, these findings, rather than leading to a reexamination of the initial hvnothesir. have been followed by cntical reexamination (iid reject& of the completed tri&. This field has been dominated by research commitled IO this hypothesis. Review has often lacked true independence and has promoted articles consonant with rhe hypothesis and rejected those antithetical to il. The recent handling of the HRRT and GISSI-2 trials (and the just presented ISIS-3 trial, even before release of its results) typify the. What have been hypotheses will undergo focused acientific study of their validity. Testing serves IO validate hypotheses, not Ihe inverse. New data must continually he reviewed openly. cti!ically and independently. The went&. medical communily, and particularly the medical journals. must assure

that the data are crilically

investigators

revuewed

by indcpen-

dent end presented in n balanced fashion. Rigorous criteria to aswe scientific independence in editorial review similarly tnus~ be followed. Only thus can we assure the qualiry of scientific inquiry. _

. _

4 ...

comment

mandating

be followd.

true critical

distance

and indcpcndence

By wch. greater independence inquiry. re\*ieP and debate may rewlt.

of wentlfic