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