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Streptokinase in Acute MyocardialInfarction

FILTRATES of haemolytic streptococci stimulate theplasminogen-plasmin thrombolytic pathway; thatmuch has been known for forty years, and the activeconstituent has been called streptokinase (SK).’ Thepotential for dissolving the coronary thrombi thatcause sudden death and acute myocardial infarctionhas, however, received little attention until the past fewyears because treatment of acute myocardial infarctionhas been dominated, in turn, by anticoagulants,antiplatelet agents, antiarrhythmics, and beta-

blockers, each of which (with the notable exception ofantiarrhythmics) has been claimed to reduce the

fatality rate by 15-20%. Although various

thrombolytic agents undoubtedly increase the patencyrate of coronary arteries in patients who have had amyocardial infarction,2-4 there has been only limitedevidence to suggest that such agents decrease thenumber of deaths.5 A large Italian study from theGruppo Italiano per lo Studio della Streptochinasinell’Infarto Miocardico (GISSI), reported in this issue(p 397), now provides more convincing evidence that SKreduces fatality in patients with myocardial infarction.The organisation of this large study is an

unparalleled achievement. 176 of the 200 coronary careunits (CCUs) in Italy participated, indicating a degreeof national cooperation never previously seen in aclinical trial. The period from conception of the idea topublication was less than three years, patientrecruitment being completed in seventeen months.31 826 patients admitted to CCUs were considered

for entry to the study; although the trial was not blind,there was centralised randomisation. 11 806 patientswere randomised to treatment with 1 5 million units ofSK given intravenously over 1 h in addition to

conventional therapy, or to conventional therapyalone. Results are presented for 11 712 patients whowere followed for the duration of their hospital stay(14-21 days in 90%). On "intention to treat" analysisthere were 628 deaths (10-7%) among the 5860patients given SK, and 758 deaths (13 - 0%) among the5852 patients given conventional therapy. This 18%reduction in fatality rate was statistically highlysignificant. The data appear internally consistent: thegroups were well matched, and the benefit was

apparent in both sexes and in all age groups.Stratification into groups was carried out according to

1. Christensen LR, MacLeod CM. A proteolytic enzyme of serum: Characterization,activation, and reaction with inhibitors. J Gen Physiol 1945; 28: 559-83.

2. Anderson JL, Marshall HW, Bray BE, et al. A randomized trial of intracoronarystreptokinase in the treatment of acute myocardial infarction. N Engl J Med 1983;308: 1312-18.

3. Khaja F, Walton JA, Brymer JF, et al. Intracoronary fibrinolytic therapy in acutemyocardial infarction. N Engl J Med 1983; 308: 1305-11.

4 Van de Werf F, Ludbrook PA, Bergmann SR, et al. Coronary thrombolysis with tissue-type plasminogen activator in patients with evolving myocardial infarction. N EnglJ Med 1984; 310: 609-13.

5. YusufS, Collins R, Peto R, Furberg C, et al. Intravenous and intracoronary fibrinolytictherapy in acute myocardial infarction: Overview of results on mortality,reinfarction and side-effects from 33 randomized controlled trials. Europ Heart J1985; 6: 556-85.

the interval between onset of symptoms and admissionto hospital. The greatest benefit seen in the plannedanalysis was in the group treated within 3 h.

Retrospective analysis of a sub-group who had beenrandomised within 1 h showed that the fatality rate washalved by SK treatment. Administration of SK wasassociated with very few complications, although itmay be important that full anticoagulation with

heparin was not routine in this study.As in any clinical trial the report reveals some

curiosities. Patients who were admitted to the CCUscould enter the trial provided they had had symptomsfor less than 12 h (half the exclusions occurred becausethis limit was exceeded) and provided there was at least1 mm of ST segment elevation or depression in a limblead of the electrocardiogram (ECG), or 2 mm in a chestlead. Very few patients were excluded for lack of theseECG changes, but despite early admission to the studyand despite not making use of enzyme data, 94% of thepatients who were included were eventually believed tohave had a definite myocardial infarction. This is a verymuch higher proportion than is usually seen in "early-entry" studies. With such a high infarct rate, and withinclusion of patients of all ages, a higher fatality ratemight have been expected in the placebo group. Inmost trials a lowish fatality rate in the placebo group isexplained by a high rate among patients who have beenexcluded, but this did not happen in the GISSI study, inwhich 2507 (12’ 5%) of the 20 020 excluded patientsdied. Another unexpected finding was that SK did notreduce fatality in the 1816 patients who had previouslyhad an infarction.

Although differences in drug therapy clearly do notaccount for the difference in fatality between thegroups given SK or conventional therapy, the studyprovides an interesting insight into Italian

cardiological practice, which is quite different from thatin the United Kingdom and many other countries.14-21 days is evidently the usual period of hospitaladmission for infarct patients. Some form of

anticoagulant was given to 60% of patients in bothgroups; it was not specified as an adjunct to SK.Approximately 70% in both groups received nitratesand nearly 50% received calcium antagonists. 18% ofpatients were given antiplatelet agents and a similarproportion received antiarrhythmic drugs. Only 8%,however, received beta-blockersPerhaps the most heartening feature of the GISSI

results is that there is clearly a potential for intravenousrather than intracoronary administration of

thrombolytic agents. Even if intracoronary SK doeslead to a better rate of patency of the coronary arteriesthan does intravenous SK,6 intracoronary treatmentcan never become routine except in specialised units,and the extra time needed to arrange a patient’s

6. Rogers WJ, Mantle JA, Hood WP, et al. Prospective randomised trial of intravenousand mtracoronary streptokinase in acute myocardial infarction. Circulation 1983;68: 1056-61.

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admission to such a unit might well negate its possiblebenefits. Nevertheless, although the results of theGISSI trial are encouraging, it would be inappropriatefor SK immediately to become routine treatment forpatients with suspected myocardial infarction. Theresults so far apply only to the initial 21 days aftermyocardial infarction. A similar benefit shown in theWestern Washington Study of intracoronary SK haddisappeared when treated and control groups werecompared after a year,’ and, since in the GISSI studythere was a higher rate of reinfarction in the SK group,the outlook for treated patients may be less good in thelong term. To accept the results of GISSI prematurelywould make it both illogical and impracticable to

- continue with other studies of SK in acute infarction,or with studies of other thrombolytic agents, such ,asacylated SK-plasminogen complex and tissueplasminogen activator (rt-PA), which have at leasttheoretical advantages over SK.8-10 Although SK ischeaper than the new thrombolytic agents are likely tobe, it is still expensive and should not be used wholesaleuntil its effects have been clarified beyond doubt.Finally, it is a good principle never to base clinicalpractice on a single clinical trial; there have been manyclaims for a reduction of 20% in-the fatality rate fromacute myocardial infarction for a variety of other agentsthat have not ultimately been accepted into routinepractice.

AN EXPERIMENT INTERRUPTED

THE Pioneer Health Centre at Peckham opened 50 yearsago. Its active life was only 9 years and even this was split intotwo phases by the 1939-45 war. But, as a unique cluster ofprovocative ideas, it has survived. The attendance at a RoyalSociety of Medicine meeting devoted to it (December 1985)made this obvious. "Peckham" produced five books. Themost important and readable of them-The Peckham

Experiment-has lately been republished. What was theexperiment? ,

George Scott Williamson was a pathologist at the RoyalFree Hospital, London. Innes Pearse, who had been a

medical registrar at the same hospital, was his second wife. In1926, with a group of like-minded friends, mostly youngparents, they set up on a very small scale a combined healthcentre and club. Their common concern was the building of

7 Kennedy JW, Ritchie JL, Davis KB, Stadius ML, Maynard C, Fritz JK. The WesternWashington randomised trial of intracoronary streptokinase in acute myocardialinfarction. A 12 month follow-up. N Engl J Med 1985; 312: 1073-78.

8. Collen D, Stassen JM, Marafino BJ, et al. Biologic properties of human tissue-typeplasminogenactivator obtained by expression of recombinant DNA in mammaliancells. J Pharm Exp Therap 1984; 231: 146-52.

9. Collen D, Topol EJ, Tiefenbrunn AJ, et al. Coronary thrombolysis with recombinanthuman tissue-type plasminogen activator: A prospective, randomised placebo-controlled trial. Circulation 1984, 70: 1012-17.

10. Verstraete M, Bernard R, Bory M, et al. Randomised trial of intravenous recombinanttissue-type plasmmogen activator versus intravenous streptokinase in acute

myocardial infarction. Lancet 1985; i 842-47.

1. Pearse IH, Crocker LH. The Peckham experiment A study in the living structure ofsociety First published in 1943 by George Allen and Unwin Ltd for the MalleyStewart Trust; republished in 1985 by Scottish Academic Press, Edinburgh. £5(paperback).

healthy families. They were convinced that this had to startbefore birth, that parents should be as healthy as possiblein preparation for conception, and that they should want thechild and be able and eager to rear it. But, if they were tocultivate health, they had to study its nature. Why are somepeople resistant to prevailing infections while otherssuccumb? Why do some people carry on oblivious to thepresence of disease or disability while others complain,consult, or collapse? What are the reserves, so quicklyexhausted in some, so abundant in others?Such questions may form part of the study of pathology, as

a mirror-image. But the authors of this experiment did not seea mirror-image; they imagined a coin of which the other sidewas different. If health were to be examined closely, a

different laboratory and new methods would be necessary-alaboratory in which the presumed healthy could be broughttogether and observed; methods which would limit neithertheir freedom of action nor the observer’s field of vision. The

study of health should be distinct from the study of. diseases-even of their prevention. So they conceived and

created their laboratory as a club. This at first occupied onesmall house.The main experiment came 6 years later. with a building

designed for the purpose. Much larger and better equipped, itwas a club which families could join (not individuals), wherethey could find new friends and choose among a great varietyof activities; at the same time their physical state, familyinteractions, and social performance were observed,recorded, and discussed with them. A swimming bath andgym formed central and obvious foci of activity, but therewere many alternative activities to choose from. Through thisunusual combination of influences it was hoped that familiesand individuals would develop more fully their potential forhealth and personal growth. Case-histories suggest that thisdid happen.This experience was interrupted first by the war and finally

by lack of money and of support from the new NationalHealth Service. What matters today is the rich flow of ideaswhich the experiment embodied and was intended to test. Inthe event there was neither time nor adequate methods to testthem fully. Some have been confirmed by work sinceundertaken in other places or by the trend of opinion; othersremain as untested hypotheses; some still look untestable.Confirmed are some of the findings of the annual family healthoverhauls. Only 9% of 4000 individuals were found to bewithout blemish ("physiological defect, deficiency or

aberration"). Yet the population had been drawn from adistrict where it was expected that the general level of healthat that time might be above average for Londoners. Althoughthe exact figure must depend on the criteria and methods ofexamination, other subsequent studies have provided figuresnot essentially different.2,3Only 25% complained of pain, discomfort, disability or

limitation of action-so saw themselves as ill or disabled.What then of the largest proportion of this population-660/0?They were seemingly well, oblivious of disorder, said theywere in their usual health, were not seeking care from anymedical service. Yet disorders were found in them; some ofthem were serious and some, even at that time, could havebeen relieved. The "iceberg of disease" has been confirmed

2. Epsom JE. The mobile health clinic A report on the first year’s work. London Boroughof Southwark Health Department, 1969.

3. South-east London Screening Group. A controlled trial of multi-phasic screening inmiddle-age. Int J Epidemiol 1977; 6: 357-62.