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Thrombolysis with Tissue Plasminogen Activator in Suspected Acute Myocardial Infarction
Thrombolysis with Tissue Plasminogen Activator in Suspected Acute Myocardial Infarction* The ASSET Study Robert G. Wilcor, M.D., for the ASSET Study Group
Intravenous rtPA (total dose, 100 mg over 3 h) was compared with placebo in a prospective, randomized, double-blind trial in 5,011 patients with suspected AMI of less than 5 h duration. No ECG or enzymatic conflrmation of the diagnosis was required for study entry. At I month 9.8f!fl of patients given placebo had died compared with 7.2% of those who received rtPA (2.6flfl actual reduction, 26flfl relative reduction, with 95% con6dence intervals of 113K). The majority of deaths occurred in patients who had an in-hospital diagnosis of Ml (72% in both groups), with a 1-month infarct mortality of 13.1% in the placebo limb and 9.4% in the rtPA limb (relative reduction 28%, 95% CI, 1441%). Approximately 18% of patients in both groups had a
normal ECG on entry to the trial, and at 1 month the fatality was 1.6% in the rtPA group and 3.0'11 in the placebo group. 'Ireatment with rtPA did not reduce the number of patients with normal ECGs from developing Ml (28% rtPA vs 24% placebo). 'lreatment with rtPA was associated with signi&cantly more bleeding episodes, the vast majority of which were clinically minor. 1he risk of all strokes in the rtPA group was similar to that in the placebo group (1.1% vs 1.0%). 'lreatment with rtPA was unaccompanied by either allergic or hypotensive episodes, and, among rtPA treated patients, there was no increase in clinically important ventricular dysrhythmias. Neither age nor time from onset of symptoms reduced the beneflt from rtPA.
W
ically designed to compare rtPA and placebo, with death as the primary end point. 11
hen DeWood and colleagues' showed by very early coronary angiography what some pathologists had long speculated on, namely, the pivotal role of coronary artery thrombosis in the pathogenesis of AMI, interest in thrombolytic drugs was reawakened. This new therapeutic era coincided with the greater availability of diagnostic coronary angiography, coronary artery bypass grafting (CABG), and percutaneous transluminal coronary angioplasty (PTCA). Thus, after nearly two decades of observational coronary care dominated by the detection and prevention of lethal ventricular dysrhythmias and, more recently, of pharmacologic assistance to the jeopardized myocardium, clinicians have access to interventions for dealing directly with the causative factors-the fissured atherosclerotic plaque and the overlying occluding thrombus. Early clinical trials showed conclusively that streptokinase, the archetypal thrombolytic drug, was an effective thrombolytic agent when given by either the intracoronary or the IV route. 2 •3 The latter is clearly the more practical, but both modes of administration were accompanied by bleeding complications secondary to the drug-induced systemic hypoooagulable state. Although such complications are predominantly of little clinical importance, an agent with greater clot specificity and equal (or greater) thrombolytic efficacy may have fewer systemic effects. Recombinant tissue-type plasminogen activator (rtPA, Actilyse) was heralded as such a drug,• superior to streptokinase both in terms of coronary patency and in having a lesser effect on systemic coagulation. u However, several large trials have since demonstrated the effect of streptokinase on early mortality from AMI,H• so a trial with rtPA was essential to establish its efficacy and safety profile. This article presents the 1-month results of the only trial specif*From the Department of Medicine, University Hospital, Nottingham, England. 270S
MATERIAL AND METHODS Fifty-two centers in the UK, 17 Norway, 11 Sweden,'" and Denmark" took part. Each country had a national coordinator (Nottingham, Bergen, Lund, Copenhagen) who was responsible to the International Co-ordinating and Statistical Centres in Nottingham. All patients with suspected AMI admitted to the coronary care units of the participating centers were registered and considered for inclusion. Patients of either sex could be considered for the study if they were within 5 h of onset of major symptoms, aged 18-75 years, and had none of the exclusion reasons (see below). No ECG or enzymatic criterion of infarction was mandatory for consideration for the trial.
7Hal Medication and Concomitant Therapy Included patients were randomized to receive active rtPA or placebo. Active treatment comprised a 10-mg IV bolus dose of rtPA, followed by a 50-mg infusion in 1 h and then 20 mg in each of the next 2 h (total dose of rtPA, 100 mg). All included patients received an initial bolus dose of IV heparin, 5,000 units, and, following the administration of rtPA or placebo, a heparin infusion of 1,000 unitslh for the next 21 h. The infusion of trial medication or ofheparin could be terminated prematurely in the event of a clinically severe hemorrhage, if it became necessary to insert a central venous line, or if an adverse event was suspected. During the hospital phase, routine use of IV P-blockers, calciumchannel blockers, antiarrhythmics, and anticoagulants or antiplatelet drug was not permitted. After discharge from hospital, secondary prophylaxis with oral P-blockers was allowed. Stress testing and recourse to coronary angiography were permitted only for persisting symptoms. lbtient FoUow-up All excluded patients would be followed up to either hospital discharge or for 1 month. All included patients would be followed up to 6 months and, in some centers, to 12 months. Tl88ue Plasminogen Activator In Cardiopulmonary Oiuaae
Table 1-Beasontfor &elusion*
Table 2-Preadmiuion Characteriatics, Clinical StatuB
Reason
%
Duration of symptoms >5 h Age >75 yr Recent hemorrhage, known ulcer, bleeding diathesis Other serious disease Refused consent Receiving warfarin Emergency CPR Recent stroke, trauma, or surgery Lives away High systolic BP Proliferative retinopathy Pregnancy Gentamicin sensitivity
73.5 8.3 6.1 5.4 4.3 4.2 4.1 3.6 3.6 2.2 1.5 0.3 0.1
*NB: Some patients had more than one reason for exclusion.
7Hal Administration The trial was coordinated from the Department of Medicine, Nottingham University Hospital, and the data were handled independently of the supporting company (Boehringer lngelheim) by the Department of Mathematics, Nottingham University. This department provided at regular intervals the code-broken results to an independent Ethical Committee in London. This committee had the task of advising whether the study should be prematurely stopped according to precise predetermined differences between the treatments in terms of either efficacy or safety. In ASSET, the Ethical Committee did advise early termination based on the overwhelming evidence of efficacy of thrombolytic therapy coming from other trials. Fortuitously, this recommendation coincided with the inclusion of the intended total of 5,000 randomized patients into ASSET.
Statistical Consideration The trial was designed to detect a reduction in overall fatality at 6 months from an estimated 15% down to 12% (3% absolute, 20% relative reduction). A trial in 5,000 patients would have a greater than 90% power to detect such a difference and would be sufficient also to examine mortality at 1 month.
Ethics The study was conducted in accordance with the Declaration of Helsinki, and the protocol was approved by the Ethical Committees of all participating centers. Dejinmons
The following definitions were used: Definite Ml: Convincing history plus pathologic Q waves in the ECG and peak enzyme levels exceeding twice the upper limit of normal. Probable Ml: Convincing history plus either pathologic Q waves or cardiac enzymes raised to twice the upper limit of normal. Possible Ml: Convincing history plus ECG abnormalities not diagnostic of MI and an increase of cardiac enzymes but to less than twice the upper limit of normal. Ischemic heart disease (IHD ): Previous MI or angina without new ECG or enzyme changes. Chest pain of unknown cause (CPPC ): No history of previous MI or angina and no ECG or enzyme evidence to suggest an event at this admission. No other cause of chest pain found. Bleeding complications were divided into major and minor categories, irrespective of the need for blood transfusion. Major bleeds comprised any hematemesis, melena, severe hemoptysis, or hematuria. Minor bleeds comprised slight hemoptysis or trace hematuria and skin or gum bleeding.
on Atlmiuion, and Time to Thratment in &ndomized lbtienta (%) rtPA (N=2,512)
Patient Data Men Age, yr >45
46-65 >65 Previous MI Angina Hypertension Diabetes Smokers Never Ex Current Drugs
Placebo (N=2,493)
77
77
9 58 33
9 57 34
27 27 49 26 7
46 24 6
33 33
~-blockers
Calcium blockers Diuretics (hypertension) Diuretics (heart failure) Glycosides ECG Normal Abnormal (any reason) Treatment for heart failure on admission Nil Nitrate Furosemide 40 mg Furosemide+ vasodilator Missing Tune to randomized treatment, h S1 1-2 2-3 3-4 4-5 >5
20
20
47
46
23 15 13 11 9 65
23 10 8
17
18 82
83
77 45 12 1.6 1.4 1.4 1.4
76 13
22 11 11 26 29 27 44
26 29
27
RESULTS
Recruitment began in England and Norway in November 1986, in Sweden in April1987, and in Denmark in autumn 1987. Recruitment stopped in all countries on Feb 29, 1988.
Table 3-Pmnatun~
1ennination of'IHallnfuaion or Heparin
Reason
rtPA
Placebo
All premature terminations Death Withdrawals Bleeding Transfusion needed Need for subclavian vein catheter Cardiac complications Fatal <24 h Administrative reasons* Other clinical events
265 (10.5%)
152 (6.1%) 41 111 10 2 30
36 229 101 4
36 41
40 16
37 24
18
27 5
*Altered diagnosis, administrative error, infusion pump failure, selfwithdrawal.
CHEST 195 I 5 I MAY, 1989 I Supplement
2718
13318
Total patient
popllat1on Entered
rt-PA
2516
/
5011
/"'
Placebo
Excluded
sm
2495
/"
contiL
w~rawn
continued withdrawn
22ff7
229
2384
111
135
47
204
41
Missing No. of deaths Total dead
'f.
dead
182/2515
245/2494
7.2
9.8
13.1
FIGURE !.Overall outcome at 1 month in the total registered population. Patients were electively withdrawn from allocated trial infusion (reasons stated in text), but all are included in a 6.nal intention-totreat analysis.
Over approximately 14 months, 13,318 patients were regis· tered, of whom 8,307 (62%) were excluded (Thble 1). Of the 8,148 documented patients at the time of writing, 4,944 (61%) had an in-hospital diagnosis ofMI (mortality 17.1%), 1,890 (23%) ischemic heart disease (mortality 2.4%), 798 (10%) chest pain query cause (mortality <1.0%), and 516 (6%) other diagnoses (mortality 6.5%). Patients who were excluded because their symptoms had begun >5 h before admission had an overall mortality of 10.6%.
to be withdrawn. Thus, at 1 month, 182/2,515 (7 .2%) patients in the rtPA group had died compared with 24512,494 (9.8%) in the placebo group. This 2.6% absolute reduction in death represents a 26% relative reduction, 95% confidence inter· val, 11-39%, and p=O.OOll. Most of the deaths occurred in patients with an in-hospital diagnosis of infarction, 9.4% in the rtPA group and 13.1% in the placebo group (relative reduction 28%, 95% CI, 14-41%) (Thble 5).
Included lbtients
7lme, sex, age, initial ECG: There was no prerandomiza· tion stratification according to either patient demography or presenting ECG, and analyses based on these must be interpreted accordingly.
Of the 5,011 included and randomized patients, full documentation is currently known for 5,005, and 1-month outcome for 5,009. The randomization procedure was successful in achieving two well-matched treatment groups in terms of patient demography and time to treatment (Thble 2). In particular, note that 17-18% of patients were considered to have normal ECGs at the time of randomization. Two hundred sixty-five (10.5%) patients in the rtPA group and 152 (6.1%) in the placebo group had their infusion prematurely terminated by either death (36 vs 41) or elective withdrawal (229 vs 111). The only major difference for elective withdrawal was in the incidence of bleeding com· plications, although very few patients needed any form of replacement transfusion (Table 3).
Clinical Cause and Outcome at 1 Month There was little difference in either the in-hospital diagnostic categorization or cardiovascular complications of in· farction apart from cardiogenic shock (p <0.05, Thble 4). In particular there was no difference with regard to reinfarction, serious ventricular arrhythmias requiring treatment, and either pulmonary or other embolism. The overall outcome at 1 month by treatment but irre· spective of diagnosis is shown in Figure 1. Patients allocated to receive rtPA did better than those allocated to placebo, whether or not they continued with the trial infusion or had 272S
Subset Analysis
'Dlble 4-ln-hoapital Diagnoeia and Complieationt Other than Strolrs (%) rtPA
Patient Data Diagnoses Ml definite probable possible IHD
Chest pain of unknown cause Other diagnosis Missing data Complications Recurrent Ml Ventricular arrhythmias (day 1) Ventricular fibrillation Asystole Pulmonary embolism Cardiogenic shock Heart failure Other embolism
(N=2,512) 72.1 56.5 58.7 9.2 6.3 17.0 7.8 2.9 1.0
Placebo (N=2,493) 71.5 7.6 5.1 17.0 8.1 3.2 1.0
3.9 5.8
4.5 4.3
3.7 3.9 0.4 3.8 17.7 0.4
4.6 4.8 0.7 5.1 18.4 0.5
Table 5-Subset Analysis-Outcome at 1 Month According to Diagno8i8
rtPA
Placebo
No
Patients
No.
%Dead
No.
%Dead
Patients
Overall MI Non-MI
2,512 1,811 701
7.2 9.4 1.7
2,493 1,783 710
9.8 13.1 1.4
Previous MI Angina HighBP Diabetes Treatment p-blocker Calcium blocker Heart failure Smoker Exsmoker
There was evidence that the beneficial effect of treatment was irrespective of time, sex, and age ('Thble 6). Of the 1718% of patients in either group with a normal ECG on admission, eventual diagnostic categorization was similar {rtPA vs placebo, MI 28% vs 24%, IHD 33% vs 33%, CP?C 30% vs 32%, other diagnoses 9% vs 11%), although overall fatality at 1 month was 1.6% in the normal ECG rtPA group and 3% in the normal ECG placebo group (Table 6). 1Tevious clinical events and treatment: The presence at randomization of cardiovascular morbidity (infarction, angina, hypertension, diabetes) or treatment with ~-blockers, calcium-channel blocker, or diuretics increased the risk of death, but there was a consistent trend toward benefit from rtPA ('Thble 7). An exhaustive analysis of all possible combinations has not been carried out, but to date no patient subgroup has been identified which might conceivably do worse if given rtPA.
Adverse Events Clinicians were asked to notify the coordinating center of any event that they considered "adverse." This strategy was probably too ftexible; many notifications could have been expected in a population of patients with AMI. Further, a recorded adverse event did not necessarily lead to premature termination of treatment. Nevertheless, they have all been accounted for without bias and broadly categorized ('Thble 8). The greatest difference between the groups was the significant excess of bleeds in the rtPA group. As mentioned above, these were usually clinically trivial and rarely led to specific corrective action. Strokes were categorized clinically by CT scan, or at Table 6-Subset Analysis-Outcome at 1 Month by Time to li'eatment, Se:t, Age, and Initial ECG rtPA Patient Data
Placebo
0-3
>3 Missing Men Women Age, yr <55 65
75 ECG result Normal Abnormal Missing
%Dead
992 1,504 16 1,935 576
8.1 6.5
979 1,488
10.9 8.6
6.8 8.6
1,928 565
9.4 10.9
3.8 6.5 10.8
745 896 852
4.4 7.9 16.4
Event
1.6 8.5
431 2,062
3.0 11.2
Cardiac Major bleeds Minor bleeds Other adverse events
963
827 443
2,067 2
Placebo
rtPA
Placebo
7.3 6.5 7.6 7.3
9.0 7.7 8.8 9.3
8.4 8.8 7.7 12.1
10.7 11.6 11.9 13.5
7.0 6.8 6.0 8.8
9.0 9.0 7.6 11.3
8.0 12.1 13.0 6.8 6.9
12.3 13.3 15.6 7.6 10.1
This trial, which may be the last placebo-controlled study of thrombolysis in AMI, has clearly shown that treatment with rtPA within 5 h saves lives. The relative reduction in fatality is similar to that seen in all of the other large mortality trials using streptokinase (ISAM 12%; GISSI 18%; ISIS-2 21%; or 16%, 20%, and an estimated 27%, respectively, for patients treated within 6 h of onset of symptoms). The 95% Cis for all of the trials overlap, which suggests that there may be no true difference between them (Fig 2). Only very large prospective studies comparing one against another can answer this question, and several are planned (GISSI-2, ISIS-3). Such trials will need large numbers of patients to give confident answers {estimated 20,000 for GISSI-2 comparing rtPA with streptokinase), but several issues can be addressed. For instance, in the AIMS trial streptokinase was given in a form already complexed with plasminogen and as a bolus rather than an infusion. This mode of administration has practical advantages, not least of which is the very early {possibly prehospital) initiation of thrombolytic treatment. In addition, the AIMS trial, though terminated prematurely for precise predetermined statistical reasons, yielded a 47% relative reduction in 30-day mortality {95% CI, 21-65%). This remarkable result clearly needs to be confirmed, particularly as subgroup analysis of the AIMS patients shows
No.
748
rtPA
DISCUSSION
%Dead
26
Yes
postmortem study. There were 7 hemorrhagic, 11 embolic, and 10 unclassified strokes in the rtPA group (total 28, incidence 1.1%, 11 deaths), and 2 hemorrhagic, 17 embolic, and 6 unclassified in the placebo group (total 25, incidence 1%, 6 deaths). There were 8 dissecting aortic aneurysms in the rtPA group (5 deaths) and 5 in the placebo group {2 deaths).
No.
Tune, h ·.,
Table 7 -Mortality at 1 Month by Previoua Morbidity and 1i'eatment ('lfl)
Table 8-Advene Eventa, No. (%) rtPA (N=2,512) 192 35 158 27
Placebo (N=2,493)
(7.6) (1.4) (6.2) (1.0)
CHEST I 95 I 5 I MAY, 1989 I Supplement
185 (7.4) 12 (0.5) 8 (0.3) 30 (1.2) 2738
ISAM GISSI ISIS -2 SK ASSET ASSET - MI ISIS -2 ASA/SK APSAC
+40
+20
-20
-40
-60
-80
FIGURE 2. Results of the major large thrombolytic trials. Percent relative change in mortality (vertical bar in each rectangle) and 95% confidence interval about that point estimate is represented by the extremes of the rectangles: the observed result thus would be consistent with a result anywhere iB-that rectangle. For acronyms see reference list.
-100
% relative change in mortality a very high mortality in the elderly in the placebo group. The other crucial issue is whether adjunctive medical therapy will increase the benefit from thrombolysis. In the group of patients in ISIS-2 who received IV streptokinase and oral aspirin, their !-month reduction in fatality was 39% compared with placebo (95% CI, 29-49%). In ISIS-2, treatment with aspirin given as soon as possible after admission and continued for 1 month resulted in an almost identical relative reduction in !-month fatality as did sole treatment with streptokinase. Would aspirin confer any additional benefit to thrombolytic treatment with either streptokinaseplasminogen activator complex (APSAC, or anistreplase) or rtPA? It is not yet clear, though it seems unlikely that IV heparin is an important adjunct to thrombolytic or antiplatelet treatment. Also to be clarified is whether acute treatment with IV P-blockers increases the benefit from thrombolytic or antiplatelet treatment. There may still be virtue in investigating a regimen of ~-blockers plus aspirin to avoid the particular complications of thrombolytic therapy. On the whole, however, IV thrombolytic therapy appears to have a gratifyingly low risk of serious complications. Despite the theoretical advantages of rtPA or APSAC, nearly all the trials report a very similar proportion of bleeding complications. There is approximately a 5% risk of a bleeding problem, but most of this is of no major clinical concern. However, the effect on the coagulation system must be taken into account if deep venous access becomes necessary; selecting a compressible vessel (antecubital, femoral) avoids most trouble. There appears not to be an increased risk of stroke, although the types of stroke may differ-more early hemorrhagic and less embolic with thrombolytic therapy. Allergic reactions, too, appear very low: none with rtPA in ASSET, and about 4% overall with streptokinase in ISIS-2. The ASSET and GISSI studies included a register of all the patients entering the participating CCUs, but as yet only ASSET has reported on their outcome. In both studies, however, approximately 60% of patients were excluded, mainly due to time from onset of symptoms (74% ASSET 2748
exclusions and 56% GISSI exclusions). The excluded patients included some high-risk categories, for in ASSET overall fatality was 13.1%, and in those diagnosed as having an AMI it was 17.1%. The problem of the "time-window" for effective thrombolysis is not yet clarified. In the GISSI trial, patients entered late did slightly worse if given streptokinase, whereas in the larger ISIS-2 late entry subgroup there was evidence of continuing benefit for up to 24 h from onset of major symptoms. Peto (personal communication) has estimated that the value of late treatment based on current evidence (mainly GISSI and ISIS-2) is a relative reduction in death of about 14%. This issue clearly needs answering and late-entry, placebo-controlled randomized trials of thrombolytic therapy should not be considered unethical. Neither ASSET nor ISIS-2 required ECG changes before randomization, although in the latter trial, only 2% of entered patients had a normal ECG compared with 17% in ASSET. The potential risks of giving a thrombolytic drug, especially when the diagnosis of infarction is not confirmed, may argue against its early use. In the ASSET trial, however, there was no evidence that an "infarct in evolution" was prevented, but there was some evidence that patients with normal admission ECGs may even have benefited in terms of overall fatality. The relative place of the different thrombolytic drugs must await direct comparison trials. Until more is known about antibodies to streptokinase, it seems reasonable to recommend rtPA as the drug of choice if a second thrombolytic treatment is necessary within an arbitrary 6-month exposure to streptokinase. ASSET Study Group
The ASSET Study Group was: International coordinator, Dr. R. G. Wilcox (Nottingham); chairman, Prof. J. R. Hampton (Nottingham); national coordinators, Dr. R. G. Wilcox (UK), Dr. G. von der Lippe (Norway), Dr. C. G. Olsson (Sweden~ and Dr. G. Jensen (Deniiw-k). The principal investigators were: United Kingdom-E. Barnes (Darlington); J. Birkhead (Northampton); R. M. Boyle (York); M. Bramble (Middlesborough General Hospital, Middlesborough); L. Bryson (South Shields); A. Davies Ti811U8 Plasminogen Activator In C&rdlopulmonary ~
(South Cleveland Hospital, .Middlesborousth); S. P; Hanley (Manchester); M. J. Hayes (Swmdon); E. Jacmn (Lincoln); M. Joy (Chertsey}; G. K. Morris (Nottingham City Hospital); D. S. Reid and Lesley Barker (North-East Regional Co-oidination Centre, Newcastle upon Tyne); G. Terry (Durham); R. D. Thomas (Bath); P. Walker (Southmead Hospital, Bristol); R. G. Wilcox (Nottingham University); P. Wilkinson (Ashford, Middlesex); W. Wright (Ham Green Hospital, Bristol). NOI'Wdfi-B. Aslalcsen and F. Gallefoss (Arendal); E. Gerdts (Bergen); A. Kallhovd (Halden); R. Ml!llstad and P. Christensen B. Linnestad (Hamar); IC. Waage and L. Holst-Larsen (Haugesu~ and K. Refsal (ASkim); K. Overskeid and 0. Bru (Sarpsborg)· T. Pedersen and M. Heldal (Aker Sykehus, Oslo); A. Fossli ana S. Njalla (Narvik); 0. Slg~estad and K. Gjesdal (Ullevaal Sykehus, Oslo); H. Wang and P. FriiS (Tromso). Sweden- J. Eideback (Skovde); T. Fraser (Lindesbell[); 0. Hesselgren (Nolrtalje); S. Jensen (Karlshamn), L. Karel(l (Boras); B. Moller (SundSvall); C. Nemeczek (Varberg); G. Nilsson, F. Band (Vasteras); H. Pemer, (Hamosand); B. Ritter (Ostersund); B. RyttLerg (Orebro); H. Saetre (Falun); A. Stjerna (Eskilstuna); D. Ursing (Angelholm); A. Waldenstrom and B. Lagerqvist (Uppsala). Denmark-P. Aurup (Hvidovre)· B. Enemark (Sundby Hospital, Copenhagen); J. Haarboe and H. Ihsen (Holbaek); S. MUnkvad and N. Tolstrup (Esbjerg); B. S~ (Nykoebing}; A. Hoestholm and I. Eidemak (Naestved); K. Thygesen (County HospitaT, Aarhus); T. Toftengaard (Skejby Hospital, Aarhus); J. VidebaCk (Bispebjerg Hospital, Copenhagen). The data centre was in the Deprtment of Mathematics, UniversityofNottingham: A.M. Skene (Director, British Heart Foundation Cardiovascu1iir Statistics Group), P. Skene, A. Willcinson, and M. Anderson. The Ethical Review Committee was: G. A. Rose, M. J. Healy, and P. Sever (all London). Boehringer Ingelheim was represented by: P. Laraway (U.K.), J. Nerby (Norway), S. Gerle (Sweiien), and F. Molgaard (Denmark).
REFERENCES 1 DeWood MA, Spores J, Notske R, et al. Prevalence of total coronary occlusion during the early hours of transmural myo-
cardial infarction. N Engl J Med 1980; 303:897-902 2 Kennedy .Jw. Ritchie JL, Davies KB, Fritz JIC. W!stem Washington randomized trial of intracoronary streptokinase in acute myocardial infarction. N Engl J Med 1983; 309:1477-82 3 Schroder R, Biamino G, Leitner E-Rv, et al. Intravenous shortterm infusion of streptokinase in acute myocardial infarction. Circulation 1983; 67:536-48 4 van de Werf F, Collen D. Coronary thrombolysis with tissuetype plasminogen activator: an overview. Eur Heart J 1985; 6: 902-()4 5 Verstraete M, Bernard R, Rory M, et al. Randomised trial of intravenous recombinant tissue-type plasminogen activator versus intravenous streptokinase in acute myocardial infarction. Lancet 1985; 1:842-47 6 The TIMI Study Group. The thrombolysis in myocardial infarction (TIMI) Trial: phase I &ndings. N Engl J Med 1985; 312:93236 7 The ISAM Study Group. A prospective trial of intravenous· streptokinase in acute myocardial infarction (ISAM): mortality, morbidity, and infarct size at 21 days. N Engl J Med 1986; 314: 1465-71 8 GISSI. EfFectiveness of intravenous thrombolytic treatment in acute myocardial infarction. Lancet 1986; 1:397-402 9 AIMS Trial Study Group. EfFect of intravenous APSAC on mortality after acute myocardial infarction: preliminary report of a placebo-controlled clinical trial. Lancet 1988; 1:545-49 10 ISIS-2 (Second International Study of Infarct Survival) Collaborative Group. Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2. Lancet 1988; 2:349-60 11 WJicox RG, von der Lippe G, Olsson CG, Jensen G, Skene AM, Hampton JR. Trial of tissue plasminogen activator for mortality reduction in acute myocardial infarction: AngloScandinavian Study of Early Thrombolysis (ASSET). Lancet 1988; 2:525-30
CHEST I 95 I 5 I MAY, 11189 I Supplement
2758
Intravenous rtPA (total dose, 100 mg over 3 h) was compared with placebo in a prospective, randomized, double-blind trial in 5,011 patients with suspected AMI of less than 5 h duration. No ECG or enzymatic conflrmation of the diagnosis was required for study entry. At I month 9.8f!fl of patients given placebo had died compared with 7.2% of those who received rtPA (2.6flfl actual reduction, 26flfl relative reduction, with 95% con6dence intervals of 113K). The majority of deaths occurred in patients who had an in-hospital diagnosis of Ml (72% in both groups), with a 1-month infarct mortality of 13.1% in the placebo limb and 9.4% in the rtPA limb (relative reduction 28%, 95% CI, 1441%). Approximately 18% of patients in both groups had a
normal ECG on entry to the trial, and at 1 month the fatality was 1.6% in the rtPA group and 3.0'11 in the placebo group. 'Ireatment with rtPA did not reduce the number of patients with normal ECGs from developing Ml (28% rtPA vs 24% placebo). 'lreatment with rtPA was associated with signi&cantly more bleeding episodes, the vast majority of which were clinically minor. 1he risk of all strokes in the rtPA group was similar to that in the placebo group (1.1% vs 1.0%). 'lreatment with rtPA was unaccompanied by either allergic or hypotensive episodes, and, among rtPA treated patients, there was no increase in clinically important ventricular dysrhythmias. Neither age nor time from onset of symptoms reduced the beneflt from rtPA.
W
ically designed to compare rtPA and placebo, with death as the primary end point. 11
hen DeWood and colleagues' showed by very early coronary angiography what some pathologists had long speculated on, namely, the pivotal role of coronary artery thrombosis in the pathogenesis of AMI, interest in thrombolytic drugs was reawakened. This new therapeutic era coincided with the greater availability of diagnostic coronary angiography, coronary artery bypass grafting (CABG), and percutaneous transluminal coronary angioplasty (PTCA). Thus, after nearly two decades of observational coronary care dominated by the detection and prevention of lethal ventricular dysrhythmias and, more recently, of pharmacologic assistance to the jeopardized myocardium, clinicians have access to interventions for dealing directly with the causative factors-the fissured atherosclerotic plaque and the overlying occluding thrombus. Early clinical trials showed conclusively that streptokinase, the archetypal thrombolytic drug, was an effective thrombolytic agent when given by either the intracoronary or the IV route. 2 •3 The latter is clearly the more practical, but both modes of administration were accompanied by bleeding complications secondary to the drug-induced systemic hypoooagulable state. Although such complications are predominantly of little clinical importance, an agent with greater clot specificity and equal (or greater) thrombolytic efficacy may have fewer systemic effects. Recombinant tissue-type plasminogen activator (rtPA, Actilyse) was heralded as such a drug,• superior to streptokinase both in terms of coronary patency and in having a lesser effect on systemic coagulation. u However, several large trials have since demonstrated the effect of streptokinase on early mortality from AMI,H• so a trial with rtPA was essential to establish its efficacy and safety profile. This article presents the 1-month results of the only trial specif*From the Department of Medicine, University Hospital, Nottingham, England. 270S
MATERIAL AND METHODS Fifty-two centers in the UK, 17 Norway, 11 Sweden,'" and Denmark" took part. Each country had a national coordinator (Nottingham, Bergen, Lund, Copenhagen) who was responsible to the International Co-ordinating and Statistical Centres in Nottingham. All patients with suspected AMI admitted to the coronary care units of the participating centers were registered and considered for inclusion. Patients of either sex could be considered for the study if they were within 5 h of onset of major symptoms, aged 18-75 years, and had none of the exclusion reasons (see below). No ECG or enzymatic criterion of infarction was mandatory for consideration for the trial.
7Hal Medication and Concomitant Therapy Included patients were randomized to receive active rtPA or placebo. Active treatment comprised a 10-mg IV bolus dose of rtPA, followed by a 50-mg infusion in 1 h and then 20 mg in each of the next 2 h (total dose of rtPA, 100 mg). All included patients received an initial bolus dose of IV heparin, 5,000 units, and, following the administration of rtPA or placebo, a heparin infusion of 1,000 unitslh for the next 21 h. The infusion of trial medication or ofheparin could be terminated prematurely in the event of a clinically severe hemorrhage, if it became necessary to insert a central venous line, or if an adverse event was suspected. During the hospital phase, routine use of IV P-blockers, calciumchannel blockers, antiarrhythmics, and anticoagulants or antiplatelet drug was not permitted. After discharge from hospital, secondary prophylaxis with oral P-blockers was allowed. Stress testing and recourse to coronary angiography were permitted only for persisting symptoms. lbtient FoUow-up All excluded patients would be followed up to either hospital discharge or for 1 month. All included patients would be followed up to 6 months and, in some centers, to 12 months. Tl88ue Plasminogen Activator In Cardiopulmonary Oiuaae
Table 1-Beasontfor &elusion*
Table 2-Preadmiuion Characteriatics, Clinical StatuB
Reason
%
Duration of symptoms >5 h Age >75 yr Recent hemorrhage, known ulcer, bleeding diathesis Other serious disease Refused consent Receiving warfarin Emergency CPR Recent stroke, trauma, or surgery Lives away High systolic BP Proliferative retinopathy Pregnancy Gentamicin sensitivity
73.5 8.3 6.1 5.4 4.3 4.2 4.1 3.6 3.6 2.2 1.5 0.3 0.1
*NB: Some patients had more than one reason for exclusion.
7Hal Administration The trial was coordinated from the Department of Medicine, Nottingham University Hospital, and the data were handled independently of the supporting company (Boehringer lngelheim) by the Department of Mathematics, Nottingham University. This department provided at regular intervals the code-broken results to an independent Ethical Committee in London. This committee had the task of advising whether the study should be prematurely stopped according to precise predetermined differences between the treatments in terms of either efficacy or safety. In ASSET, the Ethical Committee did advise early termination based on the overwhelming evidence of efficacy of thrombolytic therapy coming from other trials. Fortuitously, this recommendation coincided with the inclusion of the intended total of 5,000 randomized patients into ASSET.
Statistical Consideration The trial was designed to detect a reduction in overall fatality at 6 months from an estimated 15% down to 12% (3% absolute, 20% relative reduction). A trial in 5,000 patients would have a greater than 90% power to detect such a difference and would be sufficient also to examine mortality at 1 month.
Ethics The study was conducted in accordance with the Declaration of Helsinki, and the protocol was approved by the Ethical Committees of all participating centers. Dejinmons
The following definitions were used: Definite Ml: Convincing history plus pathologic Q waves in the ECG and peak enzyme levels exceeding twice the upper limit of normal. Probable Ml: Convincing history plus either pathologic Q waves or cardiac enzymes raised to twice the upper limit of normal. Possible Ml: Convincing history plus ECG abnormalities not diagnostic of MI and an increase of cardiac enzymes but to less than twice the upper limit of normal. Ischemic heart disease (IHD ): Previous MI or angina without new ECG or enzyme changes. Chest pain of unknown cause (CPPC ): No history of previous MI or angina and no ECG or enzyme evidence to suggest an event at this admission. No other cause of chest pain found. Bleeding complications were divided into major and minor categories, irrespective of the need for blood transfusion. Major bleeds comprised any hematemesis, melena, severe hemoptysis, or hematuria. Minor bleeds comprised slight hemoptysis or trace hematuria and skin or gum bleeding.
on Atlmiuion, and Time to Thratment in &ndomized lbtienta (%) rtPA (N=2,512)
Patient Data Men Age, yr >45
46-65 >65 Previous MI Angina Hypertension Diabetes Smokers Never Ex Current Drugs
Placebo (N=2,493)
77
77
9 58 33
9 57 34
27 27 49 26 7
46 24 6
33 33
~-blockers
Calcium blockers Diuretics (hypertension) Diuretics (heart failure) Glycosides ECG Normal Abnormal (any reason) Treatment for heart failure on admission Nil Nitrate Furosemide 40 mg Furosemide+ vasodilator Missing Tune to randomized treatment, h S1 1-2 2-3 3-4 4-5 >5
20
20
47
46
23 15 13 11 9 65
23 10 8
17
18 82
83
77 45 12 1.6 1.4 1.4 1.4
76 13
22 11 11 26 29 27 44
26 29
27
RESULTS
Recruitment began in England and Norway in November 1986, in Sweden in April1987, and in Denmark in autumn 1987. Recruitment stopped in all countries on Feb 29, 1988.
Table 3-Pmnatun~
1ennination of'IHallnfuaion or Heparin
Reason
rtPA
Placebo
All premature terminations Death Withdrawals Bleeding Transfusion needed Need for subclavian vein catheter Cardiac complications Fatal <24 h Administrative reasons* Other clinical events
265 (10.5%)
152 (6.1%) 41 111 10 2 30
36 229 101 4
36 41
40 16
37 24
18
27 5
*Altered diagnosis, administrative error, infusion pump failure, selfwithdrawal.
CHEST 195 I 5 I MAY, 1989 I Supplement
2718
13318
Total patient
popllat1on Entered
rt-PA
2516
/
5011
/"'
Placebo
Excluded
sm
2495
/"
contiL
w~rawn
continued withdrawn
22ff7
229
2384
111
135
47
204
41
Missing No. of deaths Total dead
'f.
dead
182/2515
245/2494
7.2
9.8
13.1
FIGURE !.Overall outcome at 1 month in the total registered population. Patients were electively withdrawn from allocated trial infusion (reasons stated in text), but all are included in a 6.nal intention-totreat analysis.
Over approximately 14 months, 13,318 patients were regis· tered, of whom 8,307 (62%) were excluded (Thble 1). Of the 8,148 documented patients at the time of writing, 4,944 (61%) had an in-hospital diagnosis ofMI (mortality 17.1%), 1,890 (23%) ischemic heart disease (mortality 2.4%), 798 (10%) chest pain query cause (mortality <1.0%), and 516 (6%) other diagnoses (mortality 6.5%). Patients who were excluded because their symptoms had begun >5 h before admission had an overall mortality of 10.6%.
to be withdrawn. Thus, at 1 month, 182/2,515 (7 .2%) patients in the rtPA group had died compared with 24512,494 (9.8%) in the placebo group. This 2.6% absolute reduction in death represents a 26% relative reduction, 95% confidence inter· val, 11-39%, and p=O.OOll. Most of the deaths occurred in patients with an in-hospital diagnosis of infarction, 9.4% in the rtPA group and 13.1% in the placebo group (relative reduction 28%, 95% CI, 14-41%) (Thble 5).
Included lbtients
7lme, sex, age, initial ECG: There was no prerandomiza· tion stratification according to either patient demography or presenting ECG, and analyses based on these must be interpreted accordingly.
Of the 5,011 included and randomized patients, full documentation is currently known for 5,005, and 1-month outcome for 5,009. The randomization procedure was successful in achieving two well-matched treatment groups in terms of patient demography and time to treatment (Thble 2). In particular, note that 17-18% of patients were considered to have normal ECGs at the time of randomization. Two hundred sixty-five (10.5%) patients in the rtPA group and 152 (6.1%) in the placebo group had their infusion prematurely terminated by either death (36 vs 41) or elective withdrawal (229 vs 111). The only major difference for elective withdrawal was in the incidence of bleeding com· plications, although very few patients needed any form of replacement transfusion (Table 3).
Clinical Cause and Outcome at 1 Month There was little difference in either the in-hospital diagnostic categorization or cardiovascular complications of in· farction apart from cardiogenic shock (p <0.05, Thble 4). In particular there was no difference with regard to reinfarction, serious ventricular arrhythmias requiring treatment, and either pulmonary or other embolism. The overall outcome at 1 month by treatment but irre· spective of diagnosis is shown in Figure 1. Patients allocated to receive rtPA did better than those allocated to placebo, whether or not they continued with the trial infusion or had 272S
Subset Analysis
'Dlble 4-ln-hoapital Diagnoeia and Complieationt Other than Strolrs (%) rtPA
Patient Data Diagnoses Ml definite probable possible IHD
Chest pain of unknown cause Other diagnosis Missing data Complications Recurrent Ml Ventricular arrhythmias (day 1) Ventricular fibrillation Asystole Pulmonary embolism Cardiogenic shock Heart failure Other embolism
(N=2,512) 72.1 56.5 58.7 9.2 6.3 17.0 7.8 2.9 1.0
Placebo (N=2,493) 71.5 7.6 5.1 17.0 8.1 3.2 1.0
3.9 5.8
4.5 4.3
3.7 3.9 0.4 3.8 17.7 0.4
4.6 4.8 0.7 5.1 18.4 0.5
Table 5-Subset Analysis-Outcome at 1 Month According to Diagno8i8
rtPA
Placebo
No
Patients
No.
%Dead
No.
%Dead
Patients
Overall MI Non-MI
2,512 1,811 701
7.2 9.4 1.7
2,493 1,783 710
9.8 13.1 1.4
Previous MI Angina HighBP Diabetes Treatment p-blocker Calcium blocker Heart failure Smoker Exsmoker
There was evidence that the beneficial effect of treatment was irrespective of time, sex, and age ('Thble 6). Of the 1718% of patients in either group with a normal ECG on admission, eventual diagnostic categorization was similar {rtPA vs placebo, MI 28% vs 24%, IHD 33% vs 33%, CP?C 30% vs 32%, other diagnoses 9% vs 11%), although overall fatality at 1 month was 1.6% in the normal ECG rtPA group and 3% in the normal ECG placebo group (Table 6). 1Tevious clinical events and treatment: The presence at randomization of cardiovascular morbidity (infarction, angina, hypertension, diabetes) or treatment with ~-blockers, calcium-channel blocker, or diuretics increased the risk of death, but there was a consistent trend toward benefit from rtPA ('Thble 7). An exhaustive analysis of all possible combinations has not been carried out, but to date no patient subgroup has been identified which might conceivably do worse if given rtPA.
Adverse Events Clinicians were asked to notify the coordinating center of any event that they considered "adverse." This strategy was probably too ftexible; many notifications could have been expected in a population of patients with AMI. Further, a recorded adverse event did not necessarily lead to premature termination of treatment. Nevertheless, they have all been accounted for without bias and broadly categorized ('Thble 8). The greatest difference between the groups was the significant excess of bleeds in the rtPA group. As mentioned above, these were usually clinically trivial and rarely led to specific corrective action. Strokes were categorized clinically by CT scan, or at Table 6-Subset Analysis-Outcome at 1 Month by Time to li'eatment, Se:t, Age, and Initial ECG rtPA Patient Data
Placebo
0-3
>3 Missing Men Women Age, yr <55 65
75 ECG result Normal Abnormal Missing
%Dead
992 1,504 16 1,935 576
8.1 6.5
979 1,488
10.9 8.6
6.8 8.6
1,928 565
9.4 10.9
3.8 6.5 10.8
745 896 852
4.4 7.9 16.4
Event
1.6 8.5
431 2,062
3.0 11.2
Cardiac Major bleeds Minor bleeds Other adverse events
963
827 443
2,067 2
Placebo
rtPA
Placebo
7.3 6.5 7.6 7.3
9.0 7.7 8.8 9.3
8.4 8.8 7.7 12.1
10.7 11.6 11.9 13.5
7.0 6.8 6.0 8.8
9.0 9.0 7.6 11.3
8.0 12.1 13.0 6.8 6.9
12.3 13.3 15.6 7.6 10.1
This trial, which may be the last placebo-controlled study of thrombolysis in AMI, has clearly shown that treatment with rtPA within 5 h saves lives. The relative reduction in fatality is similar to that seen in all of the other large mortality trials using streptokinase (ISAM 12%; GISSI 18%; ISIS-2 21%; or 16%, 20%, and an estimated 27%, respectively, for patients treated within 6 h of onset of symptoms). The 95% Cis for all of the trials overlap, which suggests that there may be no true difference between them (Fig 2). Only very large prospective studies comparing one against another can answer this question, and several are planned (GISSI-2, ISIS-3). Such trials will need large numbers of patients to give confident answers {estimated 20,000 for GISSI-2 comparing rtPA with streptokinase), but several issues can be addressed. For instance, in the AIMS trial streptokinase was given in a form already complexed with plasminogen and as a bolus rather than an infusion. This mode of administration has practical advantages, not least of which is the very early {possibly prehospital) initiation of thrombolytic treatment. In addition, the AIMS trial, though terminated prematurely for precise predetermined statistical reasons, yielded a 47% relative reduction in 30-day mortality {95% CI, 21-65%). This remarkable result clearly needs to be confirmed, particularly as subgroup analysis of the AIMS patients shows
No.
748
rtPA
DISCUSSION
%Dead
26
Yes
postmortem study. There were 7 hemorrhagic, 11 embolic, and 10 unclassified strokes in the rtPA group (total 28, incidence 1.1%, 11 deaths), and 2 hemorrhagic, 17 embolic, and 6 unclassified in the placebo group (total 25, incidence 1%, 6 deaths). There were 8 dissecting aortic aneurysms in the rtPA group (5 deaths) and 5 in the placebo group {2 deaths).
No.
Tune, h ·.,
Table 7 -Mortality at 1 Month by Previoua Morbidity and 1i'eatment ('lfl)
Table 8-Advene Eventa, No. (%) rtPA (N=2,512) 192 35 158 27
Placebo (N=2,493)
(7.6) (1.4) (6.2) (1.0)
CHEST I 95 I 5 I MAY, 1989 I Supplement
185 (7.4) 12 (0.5) 8 (0.3) 30 (1.2) 2738
ISAM GISSI ISIS -2 SK ASSET ASSET - MI ISIS -2 ASA/SK APSAC
+40
+20
-20
-40
-60
-80
FIGURE 2. Results of the major large thrombolytic trials. Percent relative change in mortality (vertical bar in each rectangle) and 95% confidence interval about that point estimate is represented by the extremes of the rectangles: the observed result thus would be consistent with a result anywhere iB-that rectangle. For acronyms see reference list.
-100
% relative change in mortality a very high mortality in the elderly in the placebo group. The other crucial issue is whether adjunctive medical therapy will increase the benefit from thrombolysis. In the group of patients in ISIS-2 who received IV streptokinase and oral aspirin, their !-month reduction in fatality was 39% compared with placebo (95% CI, 29-49%). In ISIS-2, treatment with aspirin given as soon as possible after admission and continued for 1 month resulted in an almost identical relative reduction in !-month fatality as did sole treatment with streptokinase. Would aspirin confer any additional benefit to thrombolytic treatment with either streptokinaseplasminogen activator complex (APSAC, or anistreplase) or rtPA? It is not yet clear, though it seems unlikely that IV heparin is an important adjunct to thrombolytic or antiplatelet treatment. Also to be clarified is whether acute treatment with IV P-blockers increases the benefit from thrombolytic or antiplatelet treatment. There may still be virtue in investigating a regimen of ~-blockers plus aspirin to avoid the particular complications of thrombolytic therapy. On the whole, however, IV thrombolytic therapy appears to have a gratifyingly low risk of serious complications. Despite the theoretical advantages of rtPA or APSAC, nearly all the trials report a very similar proportion of bleeding complications. There is approximately a 5% risk of a bleeding problem, but most of this is of no major clinical concern. However, the effect on the coagulation system must be taken into account if deep venous access becomes necessary; selecting a compressible vessel (antecubital, femoral) avoids most trouble. There appears not to be an increased risk of stroke, although the types of stroke may differ-more early hemorrhagic and less embolic with thrombolytic therapy. Allergic reactions, too, appear very low: none with rtPA in ASSET, and about 4% overall with streptokinase in ISIS-2. The ASSET and GISSI studies included a register of all the patients entering the participating CCUs, but as yet only ASSET has reported on their outcome. In both studies, however, approximately 60% of patients were excluded, mainly due to time from onset of symptoms (74% ASSET 2748
exclusions and 56% GISSI exclusions). The excluded patients included some high-risk categories, for in ASSET overall fatality was 13.1%, and in those diagnosed as having an AMI it was 17.1%. The problem of the "time-window" for effective thrombolysis is not yet clarified. In the GISSI trial, patients entered late did slightly worse if given streptokinase, whereas in the larger ISIS-2 late entry subgroup there was evidence of continuing benefit for up to 24 h from onset of major symptoms. Peto (personal communication) has estimated that the value of late treatment based on current evidence (mainly GISSI and ISIS-2) is a relative reduction in death of about 14%. This issue clearly needs answering and late-entry, placebo-controlled randomized trials of thrombolytic therapy should not be considered unethical. Neither ASSET nor ISIS-2 required ECG changes before randomization, although in the latter trial, only 2% of entered patients had a normal ECG compared with 17% in ASSET. The potential risks of giving a thrombolytic drug, especially when the diagnosis of infarction is not confirmed, may argue against its early use. In the ASSET trial, however, there was no evidence that an "infarct in evolution" was prevented, but there was some evidence that patients with normal admission ECGs may even have benefited in terms of overall fatality. The relative place of the different thrombolytic drugs must await direct comparison trials. Until more is known about antibodies to streptokinase, it seems reasonable to recommend rtPA as the drug of choice if a second thrombolytic treatment is necessary within an arbitrary 6-month exposure to streptokinase. ASSET Study Group
The ASSET Study Group was: International coordinator, Dr. R. G. Wilcox (Nottingham); chairman, Prof. J. R. Hampton (Nottingham); national coordinators, Dr. R. G. Wilcox (UK), Dr. G. von der Lippe (Norway), Dr. C. G. Olsson (Sweden~ and Dr. G. Jensen (Deniiw-k). The principal investigators were: United Kingdom-E. Barnes (Darlington); J. Birkhead (Northampton); R. M. Boyle (York); M. Bramble (Middlesborough General Hospital, Middlesborough); L. Bryson (South Shields); A. Davies Ti811U8 Plasminogen Activator In C&rdlopulmonary ~
(South Cleveland Hospital, .Middlesborousth); S. P; Hanley (Manchester); M. J. Hayes (Swmdon); E. Jacmn (Lincoln); M. Joy (Chertsey}; G. K. Morris (Nottingham City Hospital); D. S. Reid and Lesley Barker (North-East Regional Co-oidination Centre, Newcastle upon Tyne); G. Terry (Durham); R. D. Thomas (Bath); P. Walker (Southmead Hospital, Bristol); R. G. Wilcox (Nottingham University); P. Wilkinson (Ashford, Middlesex); W. Wright (Ham Green Hospital, Bristol). NOI'Wdfi-B. Aslalcsen and F. Gallefoss (Arendal); E. Gerdts (Bergen); A. Kallhovd (Halden); R. Ml!llstad and P. Christensen B. Linnestad (Hamar); IC. Waage and L. Holst-Larsen (Haugesu~ and K. Refsal (ASkim); K. Overskeid and 0. Bru (Sarpsborg)· T. Pedersen and M. Heldal (Aker Sykehus, Oslo); A. Fossli ana S. Njalla (Narvik); 0. Slg~estad and K. Gjesdal (Ullevaal Sykehus, Oslo); H. Wang and P. FriiS (Tromso). Sweden- J. Eideback (Skovde); T. Fraser (Lindesbell[); 0. Hesselgren (Nolrtalje); S. Jensen (Karlshamn), L. Karel(l (Boras); B. Moller (SundSvall); C. Nemeczek (Varberg); G. Nilsson, F. Band (Vasteras); H. Pemer, (Hamosand); B. Ritter (Ostersund); B. RyttLerg (Orebro); H. Saetre (Falun); A. Stjerna (Eskilstuna); D. Ursing (Angelholm); A. Waldenstrom and B. Lagerqvist (Uppsala). Denmark-P. Aurup (Hvidovre)· B. Enemark (Sundby Hospital, Copenhagen); J. Haarboe and H. Ihsen (Holbaek); S. MUnkvad and N. Tolstrup (Esbjerg); B. S~ (Nykoebing}; A. Hoestholm and I. Eidemak (Naestved); K. Thygesen (County HospitaT, Aarhus); T. Toftengaard (Skejby Hospital, Aarhus); J. VidebaCk (Bispebjerg Hospital, Copenhagen). The data centre was in the Deprtment of Mathematics, UniversityofNottingham: A.M. Skene (Director, British Heart Foundation Cardiovascu1iir Statistics Group), P. Skene, A. Willcinson, and M. Anderson. The Ethical Review Committee was: G. A. Rose, M. J. Healy, and P. Sever (all London). Boehringer Ingelheim was represented by: P. Laraway (U.K.), J. Nerby (Norway), S. Gerle (Sweiien), and F. Molgaard (Denmark).
REFERENCES 1 DeWood MA, Spores J, Notske R, et al. Prevalence of total coronary occlusion during the early hours of transmural myo-
cardial infarction. N Engl J Med 1980; 303:897-902 2 Kennedy .Jw. Ritchie JL, Davies KB, Fritz JIC. W!stem Washington randomized trial of intracoronary streptokinase in acute myocardial infarction. N Engl J Med 1983; 309:1477-82 3 Schroder R, Biamino G, Leitner E-Rv, et al. Intravenous shortterm infusion of streptokinase in acute myocardial infarction. Circulation 1983; 67:536-48 4 van de Werf F, Collen D. Coronary thrombolysis with tissuetype plasminogen activator: an overview. Eur Heart J 1985; 6: 902-()4 5 Verstraete M, Bernard R, Rory M, et al. Randomised trial of intravenous recombinant tissue-type plasminogen activator versus intravenous streptokinase in acute myocardial infarction. Lancet 1985; 1:842-47 6 The TIMI Study Group. The thrombolysis in myocardial infarction (TIMI) Trial: phase I &ndings. N Engl J Med 1985; 312:93236 7 The ISAM Study Group. A prospective trial of intravenous· streptokinase in acute myocardial infarction (ISAM): mortality, morbidity, and infarct size at 21 days. N Engl J Med 1986; 314: 1465-71 8 GISSI. EfFectiveness of intravenous thrombolytic treatment in acute myocardial infarction. Lancet 1986; 1:397-402 9 AIMS Trial Study Group. EfFect of intravenous APSAC on mortality after acute myocardial infarction: preliminary report of a placebo-controlled clinical trial. Lancet 1988; 1:545-49 10 ISIS-2 (Second International Study of Infarct Survival) Collaborative Group. Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2. Lancet 1988; 2:349-60 11 WJicox RG, von der Lippe G, Olsson CG, Jensen G, Skene AM, Hampton JR. Trial of tissue plasminogen activator for mortality reduction in acute myocardial infarction: AngloScandinavian Study of Early Thrombolysis (ASSET). Lancet 1988; 2:525-30
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